Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:25]([CH3:38])=[C:26]([CH3:37])[C:27]4[O:31][C:30]([CH3:33])([CH3:32])[CH:29]([OH:34])[C:28]=4[C:35]=3[CH3:36])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.C(OC(C)C)(C)C.CO>>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[C:25]([CH3:38])=[C:26]([CH3:37])[C:27]4[O:31][C:30]([CH3:33])([CH3:32])[CH:29]([O:34][CH2:2][C:3]5[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=5)[C:28]=4[C:35]=3[CH3:36])[CH2:22][CH2:23]2)=[CH:16][CH:17]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)C(C)(C)O4)CC2)cc1
Solvent: CC(C)OC(C)C
Solvent: CO
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(OCc3ccc(C)cc3)C(C)(C)O4)CC2)cc1
Yield: 68 %

Procedure:
Using α-bromo-p-xylene and 5-(4-(4-methoxyphenyl)piperazin-1-yl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol obtained in Reference Example 18, the title compound was synthesized in the same manner as in Example 74. Yield 68%. mp. 84–85° C. (diisopropyl ether-methanol). 1H-NMR (CDCl3) δ: 1.36 (3H, s), 1.59 (3H, s), 2.07 (3H, s), 2.24 (3H, s), 2.25 (3H, s), 2.33 (3H, s), 3.05–3.35 (8H, m), 3.78 (3H, s), 4.49 (2H, s), 4.66 (1H, s), 6.86 (2H, d, J=9.2 Hz), 6.97 (2H, d, J=9.2 Hz), 7.13 (2H, d, J=8.2 Hz), 7.23 (2H, d, J=8.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[N:17]=[C:16]([CH3:18])[C:15]([C:19]([OH:21])=O)=[C:11]2[O:12][C:13]=1[CH3:14].O=S(Cl)[Cl:24]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[N:17]=[C:16]([CH3:18])[C:15]([C:19]([Cl:24])=[O:21])=[C:11]2[O:12][C:13]=1[CH3:14]
Reactant: O=S(Cl)Cl
Reactant: Cc1nn2c(-c3ccc(Cl)cc3Cl)c(C)oc2c1C(=O)O
Product: Cc1nn2c(-c3ccc(Cl)cc3Cl)c(C)oc2c1C(=O)Cl

Procedure:
A mixture comprising 3-(2,4-dichloro-phenyl)-2,6-dimethyl-pyrazolo[5,1-b]oxazole-7-carboxylic acid (Intermediate IBB) (1 g, 3.08 mmol) and SOCl2 (10 ml, 137 mmol) is heated at reflux for 2 hours. After cooling to room temperature excess SOCl2 is removed under vacuum. The resulting solid is azeotroped with toluene until any remaining SOCl2 is removed to afford the title compound as a solid; 1H NMR (400 MHz, CDCl3) δ 2.48 (s, 3H), 2.53 (s, 3H), 7.48 (q, 1H), 7.52 (q, 1H), 7.62 (d, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:18]3[C:13](=[CH:14][C:15]4[O:21][CH2:20][CH2:19][C:16]=4[CH:17]=3)[O:12][CH2:11][CH2:10]2)[C:2]1=[O:22].CC(C)=O.Br[CH2:28][C:29]1[O:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=1.BrCC1CCCCO1>CC(=O)CC>[F:35][C:34]([F:37])([F:36])[C:31]1[O:30][C:29]([CH2:28][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:18]4[C:13](=[CH:14][C:15]5[O:21][CH2:20][CH2:19][C:16]=5[CH:17]=4)[O:12][CH2:11][CH2:10]3)[C:2]2=[O:22])=[CH:33][CH:32]=1
Reactant: O=C1Nc2ccccc2C12CCOc1cc3c(cc12)CCO3
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: BrCC1CCCCO1
Solvent: CCC(C)=O
Solvent: CC(C)=O
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2C12CCOc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2,3,6,7-tetrahydrospiro[furo[3,2-g]chromene-5,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, acetone to replace butanone, and 2-(bromomethyl)-5-(trifluoromethyl)furan to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3,6,7-tetrahydrospiro[furo[3,2-g]chromene-5,3′-indol]-2′(1′H)-one was obtained (43%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.36-6.93 (m, 4H), 6.76-6.70 (m, 1H), 6.38 (d, J=3.5 Hz, 1H), 6.36 (s, 1H), 6.21 (s, 1H), 4.98 (ABq, 2H), 4.80-4.69 (m, 1H), 4.45 (t, J=8.6 Hz, 2H), 4.36-4.28 (m, 1H), 2.92 (t, J=8.5 Hz, 2H), 2.23-2.16 (m, 2H); 13C NMR (75 MHz, CDCl3) δ179.3, 160.6, 155.5, 152.2, 152.1, 141.8, 141.6, 141.3, 135.2, 128.3, 124.1, 123.5, 123.5, 120.6, 120.4, 117.0, 112.6 (2C), 112.5 (2C), 112.1, 109.1, 108.6, 98.6, 71.8, 62.0, 47.8, 36.7, 32.4, 28.8; MS (ES+) m/z 441.7 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH2:11])=S)=[N:6][CH:7]=1.CI.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:17]=1[CH2:18][NH2:19]>CO>[CH3:25][O:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:16]([O:15][CH3:14])[C:17]=1[CH2:18][NH:19][C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:7][N:6]=1)=[NH:11]
Reactant: COc1cccc(OC)c1CN
Reactant: NC(=S)Nc1ccc(I)cn1
Solvent: CO
Solvent: CI
Product: COc1cccc(OC)c1CNC(=N)Nc1ccc(I)cn1
Temperature: 75 °C
Yield: 835.9 %

Procedure:
2.019 g (7.233 mmol) N-(5-iodopyridin-2-yl)thiourea was dissolved in 50 mL methanol, 0.60 mL (9.553 mmol) methyl iodide in 2 mL methanol was added dropwise, and the mixture was heated for 2.7 hr at 75° C. (oil bath temperature). The solvent was removed under vacuum, and the intermediate product was redissolved in 50 mL ethanol. 1.870 g (0.736 mmol) 2,6-dimethoxybenzylamine was added to the reaction mixture and heated for 2.25 hr at 90° C. (oil bath temperature). The solvent was then evaporated under vacuum. The crude product was dissolved in acetonitrile, and the product crystallized out with addition of water. The solid was suctioned off and washed with water. 2.698 g (6.152 mmol, 85%) N-(2,6-dimethoxybenzyl)-N′-(5-iodopyridin-2-yl)guanidine was isolated and used for further reaction.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1.[C:10]1([C:16]2[CH:25]=[C:24]3[C:19]([CH:20]=[CH:21][C:22](B(O)O)=[CH:23]3)=[CH:18][CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(#N)C>[CH3:8][C:7]1[C:2]([C:22]2[CH:21]=[CH:20][C:19]3[C:24](=[CH:25][C:16]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:17][CH:18]=3)[CH:23]=2)=[N:3][CH:4]=[C:5]([CH3:9])[N:6]=1
Reactant: Cc1cnc(Cl)c(C)n1
Reactant: OB(O)c1ccc2ccc(-c3ccccc3)cc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1cnc(-c2ccc3ccc(-c4ccccc4)cc3c2)c(C)n1
Yield: 65 %

Procedure:
First, into a recovery flask equipped with a reflux pipe were placed 0.62 g of 2-chloro-3,5-dimethylpyrazine, 1.07 g of 7-phenylnaphthalene-2-boronic acid, 0.46 g of sodium carbonate, 0.020 g of bis(triphenylphosphine)palladium(II) dichloride (abbreviation: Pd(PPh3)2Cl2), 10 mL of water, and 10 mL of acetonitrile, and the air in the flask was replaced with argon. This reaction container was irradiated with microwaves (2.45 GHz, 100 W) for 15 minutes, so that heating was performed. Then, the reaction container was cooled to 50° C. or less. Water was added to the reaction solution, and the organic layer was extracted with dichloromethane. The obtained organic layer was washed with water and dried with magnesium sulfate. The solution which had been dried was filtered. The solvent of this solution was distilled, and the obtained residue was purified by silica gel column chromatography with a developing solvent of dichloromethane, whereby Hdm7p2npr, which is the pyrazine derivative to be produced, was found to be obtained (as a white powder in 65% yield). Note that the microwave irradiation was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). The synthesis scheme of Step 4 is illustrated in the following (d-5).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:6]([O:8][CH3:9])=[O:7])=[O:2].[N+:18]([O-])([OH:20])=[O:19]>O>[CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:18]([O-:20])=[O:19])[C:12]=1[NH:13][S:14]([CH3:17])(=[O:15])=[O:16])[C:6]([O:8][CH3:9])=[O:7])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(NS(C)(=O)=O)c(C=O)c1
Solvent: O
Product: COC(=O)c1cc(C=O)c(NS(C)(=O)=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
Methyl 3-formyl-4-[(methylsulfonyl)amino]benzoate (3.85 g, 0.015 mol) was added portionwise to fuming nitric acid (45 mL) at 5°-10° C. over 0.25 h. The mixture was further stirred for 1.0 h at room temperature and then poured into cold water (200 mL). The yellow precipitate was collected by filtration and washed several times with cold water. The cake was recrystallized from ethyl acetate-hexane to give 2.5 g (55.3%) of methyl 3-formyl-4-[(methylsulfonyl)amino]-5-nitrobenzoate as light yellow needles, mp 158°-160° C.
Reaction SMILES: [Cl-:1].[C:2]([C:5]1[CH:10]=[CH:9][N+:8]([C:11]2[CH:16]=[CH:15][C:14]([N+]([O-])=O)=[CH:13][C:12]=2[N+]([O-])=O)=[CH:7][CH:6]=1)(=[O:4])[NH2:3].NC1C=CC=CC=1>CO>[Cl-:1].[C:2]([C:5]1[CH:6]=[CH:7][N+:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:9][CH:10]=1)(=[O:4])[NH2:3]
Reactant: NC(=O)c1cc[n+](-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Agent: [Cl-]
Solvent: Nc1ccccc1
Solvent: CO
Product: NC(=O)c1cc[n+](-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-carbamoyl-1-(2,4-dinitrophenyl)pyridinium chloride (50 g, prepared in a similar manner to that described in Example 2), aniline (35 ml) and methanol (11) was stirred at ambient temperature for 48 hours. The resulting suspension was heated at 50° C. for 1 hour, then cooled and the solvent removed in vacuo. The solid residue was triturated with acetone (2×11) then collected by filtration to give 4-carbamoyl-1-phenylpyridinium chloride (33.24 g), mp 290°-292° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C:4]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1>CCOC(C)=O.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH:32][C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@H:11]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:18][CH:19]=3)[CH2:12][O:13][C:8]=2[CH:7]=1
Reactant: COC(=O)C(=Cc1ccc2c(c1)OC[C@@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-tert-Butoxycarbonylamino-3-{(R)-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-acrylic acid methyl ester (4.9 g) was suspended in 300 mL EtOAc. 400 mg (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(cyclooctadiene)rhodium(I)trifluoromethanesulfonate in 30 mL DCM was added. The mixture was then degassed and a hydrogen balloon was added. The mixture was stirred at room temperature for 2 hours and the solvent was evaporated. The residue was purified by silica gel flash chromatography (hexanes to 8:2 hexanes/EtOAc) to give 4.8 g after drying. 1H NMR (400 MHz, CDCl3): 7.54 (d, 1H), 7.46 (d, 1H), 7.34 (m, 2H), 7.24-7.28 (m, 1H), 6.98 (m, 2H), 6.87 (d, 1H), 6.69 (d, 1H), 6.62 (m, 1H), 5.07-4.96 (m, 4H), 4.54 (m, 1H), 4.30 (m, 1H), 4.0 (m, 1H), 3.74 (s, 3H), 3.0 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: [CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]2[CH:9]=[C:8]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:7]=[CH:6][C:5]=2[N:4]1[S:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33]C)=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH3:2].C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]2[CH:9]=[C:8]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:7]=[CH:6][C:5]=2[N:4]1[S:24]([C:27]1[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=1)(=[O:26])=[O:25])[CH3:2]
Reactant: CCC1c2cc(F)ccc2-c2cc(-c3cccnc3)ccc2N1S(=O)(=O)c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: CCC1c2cc(F)ccc2-c2cc(-c3cccnc3)ccc2N1S(=O)(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A stirred suspension of 6-ethyl-8-fluoro-5-[(4-methoxyphenyl)sulfonyl]-2-pyridin-3-yl-5,6-dihydrophenanthridine (0.24 g, 0.51 mmol) and cyclohexene (11.4 mL), 9.22 mmol) was treated at room temperature under nitrogen with a solution of 1.0 boron tribromide in dichloromethane (3.1 mL, 3.1 mmol). After stirring for 20 hours at room temperature, the reaction was quenched with a saturated, aqueous sodium bicarbonate solution (100 mL), and extracted with dichloromethane (6×20 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent concentrated in vacuo. The crude residue was triturated with hexane, filtered, and recrystallized from dichloromethane-methanol to afford the title compound as a homogeneous, white, crystalline solid (0.17 g, 73%), m.p. 195-200° C.;
Reaction SMILES: Cl([O-])(=O)(=O)=O.[CH3:6][C:7]1[N+:12]2[C:13]3[C:18]([C:19]([CH3:21])([CH3:20])[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3.N([CH:29]=[C:30]1[C:35](=[O:36])[N:34]([CH2:37][CH3:38])[C:33](=[S:39])[N:32]([CH2:40][CH3:41])[C:31]1=[O:42])C1C=CC=CC=1.CN(C)C(=N)N(C)C>C(#N)C>[CH2:37]([N:34]1[C:35](=[O:36])[C:30](=[CH:29][CH:6]=[C:7]2[N:12]3[C:13]4[C:18]([C:19]([CH3:21])([CH3:20])[C:11]3=[CH:10][CH:9]=[CH:8]2)=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:31](=[O:42])[N:32]([CH2:40][CH3:41])[C:33]1=[S:39])[CH3:38]
Reactant: CCN1C(=O)C(=CNc2ccccc2)C(=O)N(CC)C1=S
Reactant: Cc1cccc2[n+]1-c1ccccc1C2(C)C
Agent: CN(C)C(=N)N(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: CCN1C(=O)C(=CC=C2C=CC=C3N2c2ccccc2C3(C)C)C(=O)N(CC)C1=S
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6,10,10-Trimethylpyrido[1,2-a]indolium perchlorate (0.62 g.) and 5-anilinomethylene-1,3-diethyl-2-thiobarbituric acid (0.6 g.) are dissolved in acetonitrile. Tetramethylguanidine (0.23 g.) is added and the reaction mixture is stirred at room temperature overnight. The precipitated dye is filtered off and recrystallized from acetonitrile. The λmax of the product in a mixture of pyridine and methyl alcohol is 513 nm.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]#[C:11][C:12]1[N:13]=[CH:14][C:15]([NH:18][C:19]2[N:24]=[CH:23][N:22]=[C:21]([NH:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]3)[CH:20]=2)=[N:16][CH:17]=1)(C(C)(C)C)(C)C>[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[NH:30]1[CH2:31][CH2:32][CH:27]([CH2:26][NH:25][C:21]2[N:22]=[CH:23][N:24]=[C:19]([NH:18][C:15]3[N:16]=[CH:17][C:12]([C:11]#[C:10][CH2:9][OH:8])=[N:13][CH:14]=3)[CH:20]=2)[CH2:28][CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(Nc3cnc(C#CCO[Si](C)(C)C(C)(C)C)cn3)ncn2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: OCC#Cc1cnc(Nc2cc(NCC3CCNCC3)ncn2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.3 %

Procedure:
Crude tert-butyl 4-((6-(5-(3-(tert-butyldimethylsilyloxy)prop-1-ynyl)pyrazin-2-ylamino)pyrimidin-4-ylamino)-methyl)piperidine-1-carboxylate (0.15 mmol) was dissolved in tetra n-butylammonium fluoride (1M in THF, 225 μL). After 30 minutes the solution was evaporated and the residue was purified by preparative HPLC. The resulting solid was dissolved in 30% trifluoroacetic acid in dichloromethane and stirred at room temperature for 30 minutes. The mixture was adsorbed onto then MP-TsOH SPE cartridge and eluted with 2M ammonia in methanol. The basic fractions were concentrated to give 3-(5-(6-(piperidin-4-ylmethylamino)pyrimidin-4-ylamino)pyrazin-2-yl)prop-2-yn-1-ol (7.8 mg, 7.5% over two steps) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2)([O-:3])=[O:2].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:18]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[C:8]1[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2n1C(=O)c1ccccc1
Reaction time: 16 h
Yield: 85.3 %

Procedure:
Ethyl 5-nitroindole-2-carboxylate (3.1) (1.5 g, 6.41 mmol) in CH2Cl2 (30 ml) was treated with benzoyl chloride (1.19 ml, 10.26 mmol), Et3N (891 μl, 6.41 mmol) and DMAP (783 mg, 6.41 mmol). The mixture was stirred for 16 h. 10% NaHCO3 (10 ml) and CH2Cl2 (10 ml) were added and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (3×5 mL). The combined organic layers were washed with H2O (10 ml), 5% HCl (10 ml) and H2O (10 ml). The solution was dried (MgSO4) and concentrated. The 10 residue was crystalised from EtOAc/Hex 1:9 to afford 1.85 g (87%) of 3.2 as a yellow powder: 1H NMR (250 MHz, CDCl3) δ ppm 8.66 (d, 1H), 8.25 (d, 1H), 7.80 (d,1H), 7.6-7.72 (m, 3H), 7.48 (m, 3H), 4.00 (q, 2H), 1.10 (t, 3H). FABMS (NBA/NaI) m/z 339 (M+H+ expected 339)
Reaction SMILES: [Cl:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][C:6]([CH3:14])=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.C(=O)=O.[NH3:18]>C1COCC1>[Cl:1][C:2]1[C:11]([NH2:18])=[N:10][C:9]2[C:4]([N:3]=1)=[CH:5][C:6]([CH3:14])=[C:7]([CH3:13])[CH:8]=2
Reactant: Cc1cc2nc(Cl)c(Cl)nc2cc1C
Reactant: N
Agent: O=C=O
Solvent: C1CCOC1
Product: Cc1cc2nc(N)c(Cl)nc2cc1C
Temperature: 100 °C

Procedure:
A mixture of 2,3-dichloro-6,7-dimethyl-quinoxaline (30 g) in 300 mL of THF was cooled with dry-ice in a sealed vessel. Ammonia gas was added for 10 min, then the mixture was heated to 100° C. for 20 h. After removal of the solvent in vaccuo the residue was purified by flash chromatography to yield 14 g of the title compound. 1H-NMR (300 MHz, d6-DMSO): δ=7.43 (1H, s), 7.37 (1H, s), 7.00 (2H, s), 2.28 (6H, s) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18](OC)=[O:19])[CH2:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[OH:19][CH2:18][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)[C@H](CSc1ccccc1)NC(=O)OC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(CO)CSc1ccccc1
Temperature: 25 °C

Procedure:
A solution of Example 175A (1.22 g, 3.91 mmol) in toluene (10 mL) at −78° C. was treated with 1M DIBAL-H in toluene (8.6 mL), warmed to room temperature over 4 hours, diluted with ethyl acetate (100 mL), washed sequentially with 0.1N HCl (30 mL), water (15 mL), and brine (50 mL), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 30% ethyl acetate/hexanes to provide the desired product. MS (DCI) m/e 284 (M+H)+.
Reaction SMILES: Cl.Cl.C[O:4][C:5](=[O:56])[C@@H:6]([NH:23][C:24]([C@@H:26]1[CH2:35][C:34]2[CH:33]=[C:32]3[O:36][CH2:37][C@H:38]([C:40]4[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]5[CH:53]=[CH:52][C:51]([Cl:54])=[C:50]([Cl:55])[CH:49]=5)=[CH:42][CH:41]=4)[O:39][C:31]3=[CH:30][C:29]=2[CH2:28][NH:27]1)=[O:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[C:16]=2[CH3:22])=[CH:10][CH:9]=1.[CH3:57][CH:58]([S:60](Cl)(=[O:62])=[O:61])[CH3:59]>>[Cl:55][C:50]1[CH:49]=[C:48]([CH:53]=[CH:52][C:51]=1[Cl:54])[CH2:47][O:46][C:43]1[CH:42]=[CH:41][C:40]([C@H:38]2[CH2:37][O:36][C:32]3=[CH:33][C:34]4[CH2:35][C@@H:26]([C:24]([NH:23][C@@H:6]([CH2:7][C:8]5[CH:13]=[CH:12][C:11]([O:14][C:15]6[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[C:16]=6[CH3:22])=[CH:10][CH:9]=5)[C:5]([OH:4])=[O:56])=[O:25])[N:27]([S:60]([CH:58]([CH3:59])[CH3:57])(=[O:62])=[O:61])[CH2:28][C:29]=4[CH:30]=[C:31]3[O:39]2)=[CH:45][CH:44]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: Cl
Product: Cc1nccc(Oc2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3S(=O)(=O)C(C)C)O[C@@H](c3ccc(OCc4ccc(Cl)c(Cl)c4)cc3)CO5)C(=O)O)cc2)c1C

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester bis hydrochloride was coupled with propane-2-sulfonyl chloride according to General Procedure E. The resulting compound was hydrolyzed according to General Procedure B to give the title compound (3 mg). LCMS (m/z) 861.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][Si](C)(C)C)[CH:3]=1.[OH-].[K+]>CO.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=[CH2:9])[CH:3]=1
Reactant: C[Si](C)(C)C#Cc1cccc(Br)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=Cc1cccc(Br)c1
Temperature: 25 °C
Yield: 87.7 %

Procedure:
To a solution of 1-bromo-3trimethylsilylethynylbenzene (20.5 g, 81.0 mmol) in degassed methanol (500 ml) was added potassium hydroxide (31 mg, 0.55 mmol) in water (1 ml). The solution was stirred at room temperature until G.C. analysis indicated the reaction was complete (5.0 h). The reaction mixture was diluted with an equal volume of water, and extracted with n-pentane (5×500 ml). The combined organic layers were dried (MgSO4) and the solvent removed under reduced pressure to yield a yellow liquid. The liquid was distilled via bulb-to-bulb vacuum distillation to yield the product (1c) (13.0 g, 90%) as a clear liquid: bp 40° C.C/1 torr; 1H NMR (200 MHz, CDCl3) c3.35(s), 7.23(t), 7.40(m), 7.65(t).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:6]=2[CH:25]=1.[I-].[K+].[CH2:28]([NH2:31])[CH:29]=[CH2:30]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:31][CH2:28][CH:29]=[CH2:30])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=3[F:23])[C:6]=2[CH:25]=1
Reactant: Fc1cccc(F)c1C1=NCc2nnc(CCl)n2-c2ccc(Cl)cc21
Reactant: C=CCN
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCNCc1nnc2n1-c1ccc(Cl)cc1C(c1c(F)cccc1F)=NC2

Procedure:
In the manner given in Example 31, 8-chloro-1-(chloromethyl)-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, potassium iodide and allylamine in tetrahydrofuran are reacted to give 8-chloro-1-[(allylamino)-methyl]-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3=[CH:8][CH:9]=[C:10]([OH:21])[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@@H:18]2[C@:5]5([C:6]=43)[CH2:4][CH2:3]1)=[O:15].Cl.CS(O)(=O)=O.[CH2:28](O)[CH2:29][OH:30]>>[CH3:1][N:2]1[CH2:3][CH2:4][C@@:5]23[C:6]4[C:7]5[CH2:20][C@@H:19]1[C@@H:18]2[CH2:17][CH2:16][C:14]1([C@@H:13]3[O:12][C:11]=4[C:10]([OH:21])=[CH:9][CH:8]=5)[O:30][CH2:29][CH2:28][O:15]1
Reactant: OCCO
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@H]3[C@H]1C5
Agent: CS(=O)(=O)O
Agent: Cl
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C2(CC[C@H]3[C@H]1C5)OCCO2
Temperature: 80 °C
Yield: 99.9 %

Procedure:
To Hydromorphone HCl (15.0 g, 46.7 mmol) was added ethylene glycol (80 mL) and methane sulfonic acid (10 mL) and the reaction heated at 80° C. overnight. The reaction was cooled to room temperature and poured into ice/NH3(aq) (˜350 mL). The product was extracted with dichloromethane and dried over MgSO4 before concentration under reduced pressure to give (4R,4aR,7aR,12bS)-3-methyl-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolan]-9-ol (19 g, 99.9% LCMS); [M+H]+ 330.5. This was taken onto the next step without purification.
Reaction SMILES: CS([CH2:5][CH2:6][O:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1)(=O)=O.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+]>>[N:19]1([CH2:5][CH2:6][O:7][C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CCOC(=O)c1ccc(OCCS(C)(=O)=O)cc1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1ccc(OCCN2CCCCC2)cc1
Temperature: 80 °C

Procedure:
To a 25 mL round bottom flask with magnetic stirring and condenser and under nitrogen were added the following: the solution from step 2 containing about 10.0 mmol of ethyl 4-(2-methanesulfonylethoxy)benzoate, 2 mL (20 mmol) of piperidine, and 1.5 g K2CO3. The mixture was heated to 80° C. for 24 hours and then to 125° C. for an additional 24 hours to yield product. The yield was estimated to exceed 90%. The product was identical by chromatography and 1H-NMR to that found by published methods.