Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:5](=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=1)[OH:6].C1(C)C=CC(S(O[CH2:23][CH2:24][Cl:25])(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]([O:6][CH2:23][CH2:24][Cl:25])=[C:4]([CH:10]=1)[C:3]([O:2][CH3:1])=[O:12]
Reactant: COC(=O)c1cc(Cl)ccc1O
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)ccc1OCCCl
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A mixture of methyl-5-chlorosalicylate (19.5 g, 105 mmol), 2-chloroethyl p-toluenesulfonate (19.3 mL, 107 mmol) and K2CO3 (28.9 g, 210 mmol) in 105 mL of N,N-dimethylformamide was warmed to 50° C. and allowed to stir for 18 hours. The mixture was cooled to ambient temperature, diluted with 25 mL of ethyl acetate and 25 mL of H2O. The layers were separated and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification via column chromatography (SiO2, 75% hexanes in ethyl acetate) afforded the title compound. MS (DCI/NH3) m/z 249 (M+H)+, 266 (M+NH4)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH2:17])[C:14]([N+:18]([O-])=O)=[C:13]([NH2:21])[N:12]=3)=[N:9][N:8]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:5]2=[N:6][CH:7]=1>N1C=CC=CC=1.[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[C:13]([NH2:21])[N:12]=3)=[N:9][N:8]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:5]2=[N:6][CH:7]=1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncc(F)cc23)nc(N)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: c1ccncc1
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncc(F)cc23)nc(N)c1N
Reaction time: 8 h

Procedure:
In pyridine (30 ml), 378 mg (0.949 mmol) of the compound from Example 7A were introduced and then 143 mg (0.135 mmol) of palladium (10% on carbon) were added. The mixture was hydrogenated overnight at RT under standard hydrogen pressure. The suspension was then filtered through kieselguhr and the filtercake was washed with ethanol. The filtrate was concentrated and yielded 233 mg (81% purity, 51% of theory) of the desired compound, which was reacted without further purification.
Reaction SMILES: OC[C@@H](NC(C1C=NC(N2CCCC2)=C(OCCC)N=1)=O)CC(C)C.[CH2:26]([N:28]([CH2:42][CH3:43])[C:29]1[N:30]=[CH:31][C:32]([C:39]([OH:41])=O)=[N:33][C:34]=1[O:35][CH:36]([CH3:38])[CH3:37])[CH3:27].[CH3:44][O:45][C:46](=[O:53])[C:47]([NH2:52])([CH2:50][CH3:51])[CH2:48][CH3:49]>>[CH3:44][O:45][C:46](=[O:53])[C:47]([NH:52][C:39]([C:32]1[CH:31]=[N:30][C:29]([N:28]([CH2:26][CH3:27])[CH2:42][CH3:43])=[C:34]([O:35][CH:36]([CH3:37])[CH3:38])[N:33]=1)=[O:41])([CH2:50][CH3:51])[CH2:48][CH3:49]
Reactant: CCC(N)(CC)C(=O)OC
Reactant: CCN(CC)c1ncc(C(=O)O)nc1OC(C)C
Agent: CCCOc1nc(C(=O)N[C@H](CO)CC(C)C)cnc1N1CCCC1
Product: CCN(CC)c1ncc(C(=O)NC(CC)(CC)C(=O)OC)nc1OC(C)C

Procedure:
In analogy to the procedure described for the synthesis of 6-propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide (example 10, step d) the title compounds was prepared from 5-diethylamino-6-isopropoxy-pyrazine-2-carboxylic acid and 2-amino-2-ethyl-butyric acid methyl ester (European Journal of Medicinal Chemistry 1984, 19, 261). m/z (ES+): 381.2 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[O:5][C:4](=[O:13])[CH:3]=1>C(O)C>[CH2:4]([O:5][CH:6]1[O:1][C:2]2[C:11]3[CH:10]=[C:9]([CH3:12])[CH:8]=[CH:7][C:6]=3[O:5][C:4](=[O:13])[C:3]=2[CH:7]1[C:3]1[C:4](=[O:13])[O:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=2)[CH3:3]
Reactant: Cc1ccc2oc(=O)cc(O)c2c1
Solvent: CCO
Product: CCOC1Oc2c(c(=O)oc3ccc(C)cc23)C1c1c(O)c2cc(C)ccc2oc1=O
Temperature: 25 °C
Yield: 70 %

Procedure:
4-Hydroxy-6-methylcoumarin (88 mg, 0.5 mmole) was dissolved in ethanol (3 mL). A 40% aqueous gyloxal solution (287 μL, 2.5 mmole) was added and the reaction mixture was refluxed for 3 hours. By cooling to room temperature a white precipitate was precipitated, which was filtered off and washed with ethanol. Obtained was the title compound in a 70% yield and of sufficient purity to be used the next synthesis step:
Reaction SMILES: Br[CH2:2][C:3]1([CH3:16])[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[C:17]1([CH2:23][CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:16][C:3]1([CH2:2][N:29]2[CH2:30][CH2:31][CH:26]([CH2:25][CH2:24][CH2:23][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:27][CH2:28]2)[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CBr)O2
Reactant: c1ccc(CCCC2CCNCC2)cc1
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(CCCc3ccccc3)CC1)O2
Yield: 42 %

Procedure:
Using 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine and 4-(3-phenylpropyl)piperidine, the procedure of Example 1 was otherwise repeated to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]([C:6]([NH:8][C:9]2[C:10]([NH:24][C:25]([O:27][CH:28]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)=[O:26])=[CH:11][C:12]([NH:15]NC(OC(C)(C)C)=O)=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[C:10]([NH:24][C:25]([O:27][CH:28]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[C:29]3[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=3)=[O:26])=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)=[O:7])=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)NNc1ccc(NC(=O)c2ccc(Cl)cc2)c(NC(=O)OC(c2ccncc2)C2CCNCC2)c1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(NC(=O)c2ccc(Cl)cc2)c(NC(=O)OC(c2ccncc2)C2CCNCC2)c1
Reaction time: 2 h
Yield: 88.1 %

Procedure:
N1-(4-Chlorobenzoyl)-N2-[1-(4-pyridyl)piperidin-4-ylmethoxycarbonyl]-N4-tert-butoxycarbonylamino-1,2,4-benzenetriamine (150 mg, 0.26 mmol) was dissolved in trifluoroacetic acid (2 mL). After 2 h, the mixture was concentrated and the residue partitioned between EtOAc and 1N NaOH and sat'd NaHCO3 (aq). The aqueous layer was washed with EtOAc (2×) and the combined extracts were dried (MgSO4) and concentrated. The residue was purified by chromatography (9:1 CH2Cl2:MeOH) affording 110 mg (89%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH2:32][C:33]1[N:37]=[CH:36][NH:35][N:34]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:32][C:33]3[N:37]=[CH:36][NH:35][N:34]=3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Nc1nc[nH]n1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Product: Cc1cc(F)ccc1-c1nc(Nc2nc[nH]n2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 18.9 %

Procedure:
Following the general procedure outlined in Example 217, the product of Example 48 (150 mg, 0.33 mmol) and 3-amino-1,2,4-triazole (141 mg, 1.68 mmol) were reacted to give the crude material. Preparative hplc afforded the title compound 28 mg (15%). LC-MS: 450.2 (MR+, m/z), 1.79 (Rt, min).
Reaction SMILES: [ClH:1].[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[S:7]([O-:9])=[O:8].[Li+].ClCl>O>[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[S:7]([Cl:1])(=[O:9])=[O:8]
Reactant: Cl
Reactant: O=S([O-])c1ccco1
Agent: ClCl
Agent: [Li+]
Solvent: O
Product: O=S(=O)(Cl)c1ccco1
Reaction time: 0.5 h

Procedure:
Ninety ml of water, 410 ml of conc. HCl, and 68.0 g of lithium 2-furansulfinate were stirred and cooled to 10°-15°. Liquid chlorine (12.3 ml, 39.4 g) was added dropwise over a 30-minute period. The mixture was stirred an additional 30 minutes at 5°, poured onto ice and extracted with methylene chloride. Evaporation of the methylene chloride yielded 44 g of 2-furansulfonyl chloride, b.p. 95° at 7 mm Hg; IR (neat) 3400 (m), 3120, 1800, 1550 (m), 1450 (S), 1380 (VS), 1210, 1160, 1120 (VS), 1035 (m), 1010 (VS), 913, 882 (S).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[N:8]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:7]=1.[NH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+].CCCCCCC>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH:16]1([N:8]2[C:6]3[N:7]=[C:2]([NH:21][C:22]4[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][N:23]=4)[N:3]=[CH:4][C:5]=3[CH:10]=[C:9]2[C:11](=[O:12])[N:13]([CH3:15])[CH3:14])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCCCCCC
Product: COC(=O)c1ccc(Nc2ncc3cc(C(=O)N(C)C)n(C4CCCC4)c3n2)nc1
Temperature: 100 °C
Yield: 95.1 %

Procedure:
To a suspension of 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (5.0 g, 17 mmol) in 1,4-dioxane (80 mL) in a sealed tube were added methyl 6-aminonicotinate (2.86 g, 1.10 eq), Pd(OAc)2 (0.096 g, 0.025 eq) and BINAP (0.532 g, 0.050 eq). N2 was bubbled through the resulting mixture for 20 min to degas and treated with Cs2CO3 (8.35 g, 1.5 eq). The reaction mixture was heated at 100° C. for 2.2 h. The reaction mixture was cooled to room temperature, treated with 100 mL of heptane and sonicated. Red precipitate was collected by filtration and suspended in 200 mL of water. After sonication, the solid was collected by filtration, rinsed with water (3×50 mL) and dried. The solid was triturated in THF to obtain tan solid methyl 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinate (6.6 g, 94% yield). The filtrated was concentrated in vacuo and purified by column chromatography (Ethyl acetate/Heptane) to give additional product (0.4 g, 6% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.33 (s, 1H), 8.89 (s, 1H), 8.83 (d, J=2.1 Hz, 1H), 8.44 (d, J=8.9 Hz, 1H), 8.22 (dd, J=8.9, 2.2 Hz, 1H), 6.67 (s, 1H), 4.77 (m, 1H), 3.86 (s, 3H), 3.06 (s, 6H), 2.42 (m, 2H), 2.00 (m, 4H), 1.68 (m, 2H); MS m/z 409.4 (M+H)+.
Reaction SMILES: [OH-].[Na+].[C:3]([C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:20]=1[C:21]1[CH:22]=[C:23]([CH:42]=[CH:43][CH:44]=1)[O:24][CH2:25][C:26]1[CH:41]=[CH:40][C:29]([CH2:30][N:31]3[CH:35]=[CH:34][CH:33]=[C:32]3[C:36]([O:38]C)=[O:37])=[CH:28][CH:27]=1)=[CH:18][CH:17]=[CH:16][C:15]=2[C:45]([F:48])([F:47])[F:46])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>>[C:3]([C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:20]=1[C:21]1[CH:22]=[C:23]([CH:42]=[CH:43][CH:44]=1)[O:24][CH2:25][C:26]1[CH:41]=[CH:40][C:29]([CH2:30][N:31]3[CH:35]=[CH:34][CH:33]=[C:32]3[C:36]([OH:38])=[O:37])=[CH:28][CH:27]=1)=[CH:18][CH:17]=[CH:16][C:15]=2[C:45]([F:47])([F:46])[F:48])(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1cccn1Cc1ccc(COc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCc2ccc(Cn3cccc3C(=O)O)cc2)c1

Procedure:
Prepared by NaOH hydrolysis of methyl 1-[4-({3-[3-Benzoyl-8-(trifluoromethyl)quinolin-4-yl]phenoxy}methyl) benzyl]-1H-pyrrole-2-carboxylate; MS (ESI) m/z 607; MS (ESI) m/z 605.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:14])=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].S(=O)(=O)(O)O.C(=O)([O-])O.[Na+].[CH2:25](O)[CH3:26]>>[F:1][C:2]1[C:3]([OH:14])=[C:4]([CH2:10][C:11]([O:13][CH2:25][CH3:26])=[O:12])[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: CCO
Reactant: O=C(O)Cc1cc(F)c(F)c(F)c1O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)Cc1cc(F)c(F)c(F)c1O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of (3,4,5-trifluoro-2-hydroxyphenyl)acetic acid (6.0 g), sulfuric acid (0.016 mL) and ethanol (50 mL) was stirred at 80° C. overnight, neutralized with saturated aqueous sodium hydrogen carbonate solution, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (5.6 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:14][CH2:13][C:5]2([C@@H:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6]2)[CH2:4][CH2:3]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CC(C)=O.O.CCOC(C)=O>[O:1]=[C:2]1[CH2:14][CH2:13][C:5]2([CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6]2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)[C@H]1CC12CCC(=O)CC2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C1CC12CCC(=O)CC2
Temperature: 60 °C
Reaction time: 45 h
Yield: 85 %

Procedure:
To a solution of ethyl (1S)-6-oxospiro[2.5]octane-1-carboxylate (1.9 g, 7.91 mmol) in acetone (20 mL) and water (5 mL) was added PPTS (0.1 g, 0.398 mmol). The reaction mixture was heated at 60° C. for 5 h, and then stirred at rt for 45 h. The reaction mixture was diluted with EtOAc, washed with water, brine, dried (MgSO4) and concentrated to afford ethyl 6-oxospiro[2.5]octane-1-carboxylate as an oil (1.32 g). 1H NMR (400 MHz, CDCl3) δ ppm 4.13-4.21 (2H, m), 2.35-2.51 (3H, m), 2.19-2.30 (1H, m), 2.00-2.09 (3H, m), 1.86 (1H, ddd, J=13.68, 8.16, 5.27 Hz), 1.64-1.77 (2H, m), 1.23-1.35 (3H, m), 1.08 (1H, dd, J=8.16, 4.64 Hz).
Reaction SMILES: ClC[C:3]1[N:4]=[C:5]2[CH2:14][C:13]3[N:12]=[CH:11][C:10]([C:15]#[N:16])=[C:9]([NH:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)[C:8]=3[CH:7]=[C:6]2[N:30]=1.N1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:25][O:24][C:22]1[CH:23]=[C:18]([CH:19]=[C:20]([O:28][CH3:29])[C:21]=1[O:26][CH3:27])[NH:17][C:9]1[C:8]2[CH:7]=[C:6]3[N:30]=[CH:3][NH:4][C:5]3=[CH:14][C:13]=2[N:12]=[CH:11][C:10]=1[C:15]#[N:16]
Reactant: COc1cc(Nc2c(C#N)cnc3c2C=C2N=C(CCl)N=C2C3)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1COCCN1
Product: COc1cc(Nc2c(C#N)cnc3cc4[nH]cnc4cc23)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.09 g (0.2 mmol) of 2-(chloromethyl)-8-(3,4,5-trimethoxyanilino)imidazo[4,5-g]quinoline-7-carbonitrile, 0.2 mL (2.3 mmol) of morpholine and 0.3 g (2.2 mmol) of anhydrous potassium carbonate in 5 mL of ethanol is stirred at room temperature overnight. The product mixture is filtered to remove the inorganic salts and the filtrate is evaporated to dryness to yield an oil. The oil is purified by silica gel chromatography utilizing a gradient of methylene chloride/methanol(97:3 to 90:10) to yield 0.087 g of 2-(4-morpholinylmethyl)-8-(3,4,5-trimethoxyanilino)-3H-imidazo[4,5-g]quinoline-ylmethyl)-8-(3,4,5-trimethoxyanilino)-3H-imidazo[4,5-g]quinoline-7-carbonitrile as a yellow solid, mp 258-260° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH:10]2[C:27]([O:29]CC)=[O:28])=[CH:5][CH:4]=1.[OH-].[Na+]>CCO.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH:10]2[C:27]([OH:29])=[O:28])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1C(c2ccc(OC)cc2)c2ccccc2C1c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
To a solution of ethyl (1RS,2RS,3SR)-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate (0.10 g, 0.2 mmol) in EtOH (5 ml) was added a solution of sodium hydroxide (0.10 g, 2.5 mmol) in H2O (2 ml). The resulting mixture was stirred at room temperature overnight. The mixture was acidified, and the solid which formed was collected by filtration and dried under reduced pressure to afford the title compound as a tan solid (0.04 g, 86%).
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:15]#[C:16][CH:17]2[CH2:19][CH2:18]2)=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].[CH3:20][S:21]([CH2:24][CH2:25][N:26]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]2[CH:38]=[CH:37]C(N)=[CH:35][CH:34]=2)[CH2:28][CH2:27]1)(=[O:23])=[O:22]>>[CH:17]1([C:16]#[C:15][C:7]2[S:6][C:5]3[C:3](=[O:4])[N:12]([C:14]4[CH:37]=[CH:38][C:33]([N:29]5[CH2:30][CH2:31][CH2:32][N:26]([CH2:25][CH2:24][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:27][CH2:28]5)=[CH:34][CH:35]=4)[CH:11]=[N:10][C:9]=3[CH:8]=2)[CH2:18][CH2:19]1
Reactant: CS(=O)(=O)CCN1CCCN(c2ccc(N)cc2)CC1
Reactant: COC(=O)c1sc(C#CC2CC2)cc1N=CN(C)C
Product: CS(=O)(=O)CCN1CCCN(c2ccc(-n3cnc4cc(C#CC5CC5)sc4c3=O)cc2)CC1

Procedure:
5-Cyclopropylethynyl-3-(dimethylamino-methyleneamino)-thiophene-2-carboxylic acid methyl ester was reacted with 4-[4-(2-Methanesulfonyl-ethyl)-[1,4]diazepan-1-yl]-phenylamine by method A1. The product with the molecular weight of 496.64 (C25H28N4O3S2) was obtained in this way; MS (ESI): 497 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]#[CH:12])[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[O:17][CH3:18])([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][C:21](=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1.C(N(CC)CC)C.O1CCCC1>CCCCCC.[Cu]I.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.C(OCC)(=O)C>[CH3:19][O:20][C:21](=[O:30])[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:12]#[C:11][C:9]2[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]([O:17][CH3:18])=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=2)=[CH:27][CH:28]=1
Reactant: C#Cc1cc(C(C)(C)C)c(OC)c(C(C)(C)C)c1
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(C#Cc2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)cc1
Yield: 90.8 %

Procedure:
Following General Procedure F and using 1,3-di-tert-butyl-5-ethynyl-2-methoxy-benzene (Intermediate 169, 0.094 g, 0.36 mmol), methyl-4-iodo phenyl acetate (Reagent B, 0.09 g, 0.32 mmol), triethyl amine (5 mL), anhydrous tetrahydrofuran (5 mL), copper(I)iodide (0.02 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.06 g, 0.085 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent, the title compound (0.114 g, 81%) was obtained as an oil.
Reaction SMILES: [Cl:1]Cl.[N+]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=1)([O-])=O>>[Cl:1][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=1
Reactant: ClCl
Reactant: O=[N+]([O-])c1ccc(OC(F)(F)F)cc1
Product: FC(F)(F)Oc1ccc(Cl)cc1
Yield: 83 %

Procedure:
Chlorine and p-nitrotrifluoromethoxybenzene (10.7 parts) were fed simultaneously at a molar ratio of 3:1, Cl2 :organic reactant, into a vapor phase reactor maintained at 300° to 320° C. over a 30 minute period to yield 8.2 parts of p-chlorotrifluoromethoxybenzene (83% yield). The structure of the product was confirmed by gas chromatographic-mass spectrum and F19 nuclear magnetic resonance analysis.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[N:4]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C)C=O>[F:22][C:20]1[CH:19]=[CH:18][C:17]2[N:11]3[CH:10]=[N:9][C:8]([C:5]4[N:4]=[C:3]([CH2:2][N:25]5[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]5)[O:7][N:6]=4)=[C:12]3[CH2:13][N:14]([CH3:24])[C:15](=[O:23])[C:16]=2[CH:21]=1
Reactant: C1CCNCC1
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccc(F)cc2C1=O
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3noc(CN4CCCCC4)n3)ncn2-c2ccc(F)cc2C1=O
Yield: 74.8 %

Procedure:
1.04 g (3.0 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5,6-dihydro-5-methyl-4H-imidazo[1,5-a][1,4]-benzodiazepin-6-one, 0.64 g (7.5 mmol) of piperidine and 10 ml of N,N-dimethylformamide were stirred at room temperature for 4 hours. The reaction mixture was concentrated, the residue was dissolved in methylene chloride and the solution was made alkaline with 4N sodium hydroxide solution. The solution was washed once with saturated sodium chloride solution, dried with magnesium sulfate and evaporated. By chromatography of the residue on silica gel while eluting with methylene chloride/methanol 9/1 there was obtained 0.89 g (75%) of 8-fluoro-5-methyl-3-[5-(piperidin-1-ylmethyl)-1,2,4-oxadiazol-3-yl]-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of m.p. 182°-4°, which was converted into the hydrochloride of m.p. 254°-6°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][S:11][CH2:12][CH:13]([OH:16])[CH2:14]Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH:13]([OH:16])[CH2:12][S:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCSCC(O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCSCC(O)C1
Temperature: 25 °C
Yield: 47.9 %

Procedure:
(2-(t-Butyloxycarbonyl-amino)-ethyl)-(3-chloro-2-hydroxypropyl)-thioether (30 g, 111.52 mmole) from Example 3, was dissolved in dimethylformamide (500 mL) at 0° C. and treated with sodium hydride (9.81 g, 245 mmole) in 3 portions over 15 minutes. The reaction was allowed to warm to room temperature over 1 hour and 15 minutes, poured into 2.5 L ice water and extracted with 3×1 L chloroform. The combined organic extracts were dried with brine and Na2SO4, evaporated, and the resulting residue chromatographed (3:1 hexane:ethyl acetate, silica gel) to obtain the product as a white solid (12.47 g, 48% yield) D.C.I.M.S. 234(M+H) M.P. 80°-82° C.
Reaction SMILES: C([CH:3]1[CH2:9][CH:8]2[N:10]([CH3:11])[CH:5]([CH2:6][CH2:7]2)[CH2:4]1)#N.CN1C2CC(CC1CC2)=O.S(C[N+]#[C-])(C1C=CC(C)=CC=1)(=O)=O.[O-]CC.[K+].CN1C2CC(O)CC1CC2.S(Cl)([Cl:51])=O>>[Cl:51][CH:3]1[CH2:9][CH:8]2[N:10]([CH3:11])[CH:5]([CH2:6][CH2:7]2)[CH2:4]1
Reactant: CN1C2CCC1CC(C#N)C2
Reactant: O=S(Cl)Cl
Agent: CC[O-]
Agent: CN1C2CCC1CC(=O)C2
Agent: CN1C2CCC1CC(O)C2
Product: CN1C2CCC1CC(Cl)C2

Procedure:
3-Cyano-8-methyl-8-azabicyclo[3.2.1]octane (IV) can be prepared by treating tropinone (V) with tosylmethyl isocyanide in the presence of a suitable base, such as potassium ethoxide. Alternatively, 3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (IV) can be prepared by treating tropine (X) with thionyl chloride to give 3-chloro-8-methyl-8-azabicyclo[3.2.1]octane (XII) and reacting (XII) with cyanide as described in J. Am. Chem. Soc., (1958) 80, 4677.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:22][CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCC(CC)CBr
Reactant: CCOC(=O)CSc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CSc1ccc(OCC(CC)CC)cc1
Temperature: 25 °C

Procedure:
To stirred solution of (4-Hydroxy-phenylsulfanyl)-acetic acid ethyl ester (2.12 g, 10 mmol), K2CO3 (anhydrous, 10 g) and 1-bromo-2-ethyl butane (3 g, excess) was added in boiling acetone. The reaction mixture was refluxed for 24 hrs and cooled to room temperature. The reaction mixture was filtered and concentrated. The residue obtained was extracted with chloroform; washed well with water and concentrated. The crude product obtained was taken to next step without purification. Yield 2.8 g (94%); (M+H)+ 297.