Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:9]=[CH:8]2.O.[OH-].[Na+]>Br>[F:16][C:13]([F:14])([F:15])[C:10]1[CH:9]=[CH:8][C:7]2[C:12](=[C:3]([OH:2])[CH:4]=[CH:5][CH:6]=2)[N:11]=1
Reactant: COc1cccc2ccc(C(F)(F)F)nc12
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1cccc2ccc(C(F)(F)F)nc12

Procedure:
A solution of 8-methoxy-2-trifluoromethylquinoline (10.0.g) in 48% hydrobromic acid (40 ml) was stirred at reflux overnight. The reaction mixture was poured into water (200 ml) and the pH adjusted to 12.5 using 46-48% sodium hydroxide solution. After extraction with dichloromethane (2×25 ml) the aqueous layer was acidified to pH5.3 by the addition of 37% hydrochloric acid solution. The mixture was then extracted using dichloromethane (2×100 ml) and the combined organic extracts washed with water, dried over sodium sulfate, filtered and the solvent removed in vacuo to give the product (9.3 g) as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH:22]([CH3:24])[CH3:23])[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)=[CH:13][N:14]=1)=[O:4].C([N:42]=[C:43]=[S:44])(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2.N1CCCCC1>C(Cl)Cl>[Br:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[NH:11][C:10]([C@@H:6]3[CH2:7][CH2:8][CH2:9][N:5]3[C:3](=[O:4])[C@@H:2]([NH:1][C:43]([NH2:42])=[S:44])[CH:22]([CH3:24])[CH3:23])=[N:14][CH:13]=2)=[CH:20][CH:19]=1
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)[C@H](N)C(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(C)[C@H](NC(N)=S)C(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (S)-2-amino-1-((S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methylbutan-1-one (1.530 g, 3.91 mmol) in CH2Cl2 (10 mL) was added O-(9H-fluoren-9-yl)methyl carbonisothiocyanatidate (1.100 g, 3.91 mmol) as a solid in one portion. The mixture was allowed to stir at room temperature for 12 h. Piperidine (2 mL) was added to the mixture and it was allowed to stir at room temperature for 1 h. A further portion of piperidine (2 mL) was added and the solution allowed to stir 1 h. The solution was concentrated to dryness and the residue was purified by column chromatography (biotage, eluting with 5:4.5:0.5 hex:EtOAc:MeOH, and then 5% MeOH in EtOAc). The title compound as obtained as a light yellow glass (1.30 g, 74%). 1HNMR (300 MHz, DMSO-d6) δ 11.81 (s, H), 7.65 (d, J=8.8 Hz), 7.63-7.71 (m, overlap with previous peak, 2H total), 7.42-7.56 (m, 2H), 7.10-7.14 (m, 1H), 5.06 (dd, J=7.0, 3.0 Hz, 1H), 4.94 (app t, J=8.0 Hz, 1H), 4.72-4.76 and 4.56-4.62 (m, 1H, rotamers, 1:1 ratio), 3.77-3.90 (m, 1H), 2.07-2.14 (m, 2H), 1.90-1.98 (m, 3H), 0.93 (d, J=7.0 Hz, 3H), 0.84 (d, J=7.0 Hz, 3H). LCMS: Anal. Calcd. for C19H24BrN5OS: 449, 451; found: 450, 452 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.[NH:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[NH2:20]>CC1CCCO1.C(O)(=O)CC>[CH:16]1[CH:17]=[CH:18][C:10]([OH:9])=[C:11]([C:12]2[N:13]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:19]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)[N:20]=2)[CH:15]=1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Solvent: CCC(=O)O
Solvent: CC1CCCO1
Product: O=C(O)c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1
Temperature: 98 °C
Yield: 50.4 %

Procedure:
A suspension of 0.7 g (2.92 mmol) of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one and 0.52 g (3.44 mmol) of 4-hydrazinobenzoic acid in 8 ml of 2-methyltetrahydrofuran and 5 ml of propionic acid is heated to its boiling point and maintained at this temperature (98° C.) for 2 hours. After completion of the reaction, the mixture is cooled and filtered. The product is washed with 2-methyltetrahydrofuran. After drying, 0.55 g of raw deferasirox is obtained, i.e. 50% of the theory, with an HPLC purity of 95.3% and a melting temperature of 255 to 262° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH2:10])=[CH:5][CH:4]=1)=[CH2:2].C1CCCCC1.[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18]>C([Li])CCC.CO>[CH2:17]([N:19]([CH2:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH2:10])=[CH:5][CH:4]=1)[CH2:20][CH3:21])[CH3:18]
Reactant: C=Cc1ccc(C=C)cc1
Reactant: CCNCC
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: CO
Product: C=Cc1ccc(CCN(CC)CC)cc1
Temperature: 50 °C
Yield: 71.4 %

Procedure:
In a 200 ml three necked flask were placed 26 g of p-divinylbenzene and 40 ml of cyclohexane, and to the mixture were further added 40 ml of a cyclohexane solution of an amide-amine complex prepared from 14.8 g of diethylamine and 0.512 g of n-butyllithium. The mixture thus obtained was heated at 50° C. for 3 hours with stirring. Then the reaction solution was added with 10 ml of methanol and subjected to distillation to give 29.0 g of p-diethylaminoethylstyrene having a boiling point of about 84° C./1 mmHg.
Reaction SMILES: [CH3:1][C:2]([S:5](/[N:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][N:10]=1)=O)([CH3:4])[CH3:3].[CH:21]([Mg]Br)=[CH2:22]>O1CCCC1>[C:2]([S:5][NH:7][C@@H:8]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][N:10]=1)[CH:21]=[CH2:22])([CH3:4])([CH3:3])[CH3:1]
Reactant: C=C[Mg]Br
Reactant: CC(C)(C)S(=O)/N=C/c1ccc(OCC(F)(F)F)cn1
Solvent: C1CCOC1
Product: C=C[C@@H](NSC(C)(C)C)c1ccc(OCC(F)(F)F)cn1
Temperature: -78 °C
Yield: 73.5 %

Procedure:
To a mixture of 2-methyl-N-{(1E)-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylidene}propane-2-sulfinamide (10.0 g, 32.4 mmol) and tetrahydrofuran (150 ml) at −78° C. was added dropwise 1.0M vinylmagnesium bromide in tetrahydrofuran (58.4 ml, 58.4 mmol), maintaining temperature during addition below −70° C. Reaction was stirred at −78° C. for an hour. To complete reaction, an additional amount of 1.0M vinylmagnesium bromide (19.4 ml, 19.4 mmol) was required. The reaction was then quenched by pouring mixture into a cold solution of saturated NH4Cl (800 ml) and ethyl acetate (600 ml) with vigorous stirring at 0° C. Layers were separated and organic extracts were combined, dried over Na2SO4, filtered and concentrated in vacuum. The resulting brown oil was purified by flash chromatography (Si2O, 25-100% ethyl acetate in hexanes, gradient) to give 2-{(1R)-1-[(tert-butylthio)amino]prop-2-enyl}-5-(2,2,2-trifluoroethoxy)pyridine as a white solid (8.10 g, 73.5%). 1H NMR (400 MHz, CDCl3) 8.30 (d, J=2.8 Hz, 1H), 7.28 (m, 2H), 5.92-5.83 (m, 1H), 5.34 (dd, J=16 Hz and 33 Hz, 2H), 5.01 (m, 1H), 4.99 (bs, 1H), 4.39 (q, J=8.0 Hz, 2H), 1.28 (s, 9H); MS (Electrospray): m/z 337.1 (+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][C:23]([CH3:25])=[CH2:24])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17](N)=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].[OH-:26].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][C:23]([CH3:25])=[CH2:24])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([OH:26])=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: [OH-]
Reactant: C=C(C)COc1ccc(Br)cc1CN(CC)c1ccc(C(N)=O)nn1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C=C(C)COc1ccc(Br)cc1CN(CC)c1ccc(C(=O)O)nn1
Reaction time: 16 h
Yield: 87 %

Procedure:
6-[N-(5-Bromo-2-(2-methylprop-2-en-1-yloxy)benzyl)-N-ethylamino]pyridazine-3-carboxamide (430 mg, 1.09 mmol) was dissolved in THF/methanol (30 ml, 1:1) and sodium hydroxide solution added (2.9 ml, 2M, 5.8 mmol). The mixture was heated at reflux for 72 hours, allowed to cool and evaporated. The residue was dissolved in water (25 ml) and acetic acid added to pH-4. The solution was stirred for 16 hours and then the resulting colourless precipitate collected by filtration, washed with water and dried under vacuum to give the title compound as a colourless powder (387 mg, 87%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Br[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Reactant: BrCCc1ccccc1
Product: Cc1cc(C#Cc2cn(CCc3ccccc3)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=302.2 (M+H30), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and (2-bromoethyl)benzene.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([Cl:19])=[C:9]([CH:18]=1)[C:10]([NH:12][C:13]1[NH:14][CH:15]=[CH:16][N:17]=1)=[O:11].C(N(CC)CC)C.[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29]>C1COCC1>[Cl:19][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][NH:3][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])=[CH:18][C:9]=1[C:10]([NH:12][C:13]1[NH:14][CH:15]=[CH:16][N:17]=1)=[O:11]
Reactant: NCc1ccc(Cl)c(C(=O)Nc2ncc[nH]2)c1
Reactant: CC(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2ncc[nH]2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
To a suspension of 5-(aminomethyl)-2-chloro-N-(1H-imidazol-2-yl)benzamide dihydrochloride (50 mg, 0.154 mmol, 1.0 equiv) in THF (0.77 mL), add triethylamine (80 μL, 0.57 mmol, 3.7 equiv) and isobutyryl chloride (16.3 μL, 0.154 mmol, 1.0 equiv), and stir the reaction mixture for 1 h at room temperature. Concentrate the reaction mixture under reduced pressure, triturate the crude solids with a mixture of water (10 mL), hexanes (10 mL), and diethyl ether (10 mL), isolate the white solid by filtration and dry in a 40° C. vacuum oven to give the title compound (19 mg, 38% yield): 1H NMR (DMSO-d6, 400 MHz): δ 11.74 (br s, 2H), 8.30 (t, 1H, J=6.0 Hz), 7.42 (d, 1H, J=8.0 Hz), 7.36 (d, 1H, J=2.0 Hz), 7.26 (dd, 1H, J=8.0, 2.0 Hz), 6.73 (br s, 2H), 4.22 (d, 2H, J=5.9 Hz), 2.37 (septet, 1H, J=6.6 Hz), 0.97 (d, 6H, J=6.8 Hz). MS (m/z) (35Cl/37Cl) 321/323 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]([O:6][CH2:7][CH2:8]P(OCC)(OCC)=O)(=[O:5])[CH3:4].[Br:17][C:18]1[N:23]=[C:22]([CH:24]=O)[CH:21]=[CH:20][CH:19]=1.C(OCC)C>C1COCC1>[Br:17][C:18]1[N:23]=[C:22]([CH:24]=[CH:4][C:3]([O:6][CH2:7][CH3:8])=[O:5])[CH:21]=[CH:20][CH:19]=1
Reactant: CCOP(=O)(CCOC(C)=O)OCC
Reactant: O=Cc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1cccc(Br)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
In THF (10 ml) was suspended sodium hydride (60%, 440 mg, 11.0 mmol), and to the mixture was added at −30° C. a solution of diethylphosphonoethyl acetate (2.47 g, 11.0 mmol) in THF (10 ml). The mixture was stirred at the same temperature for 30 minutes, and to the mixture was added at −30° C. a solution of 6-bromo-2-pyridinecarbaldehyde (1.86 g, 10.0 mmol) in THF (10 ml). While warming the temperature of the mixture from −30° C. to −10° C., the mixture was stirred for 1.5 hours. To the mixture was added diethylether (40 ml), and the mixture was washed with water (20 ml, 5 ml×2) and saturated brine (5 ml). The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue was added hexane (10 ml), and the mixture was cooled to 0° C. The precipitated insoluble materials were filtered, which were washed with hexane cooled to 0° C., and dried under reduced pressure to give ethyl 6-bromo-2-pyridineacrylate (2.00 g, 7.81 mmol, 78%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:31]([C:33]1[CH:34]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1)#[N:32]>ClCCl>[C:31]([C:33]1[CH:34]=[C:35]([S:39]([NH:23][CH2:22][C:16]2([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][CH:12]=3)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1)#[N:32]
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cccc(S(=O)(=O)NCC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (100 mg, 0.314 mmol) and triethylamine (0.1 mL, 0.63 mmol) in anhydrous dichloromethane (3 mL) under nitrogen atmosphere at 0° C. was added 3-cyanobenzenesulfonylchloride (100 mg, 0.47 mmol). The reaction mixture was stirred for 2 h allowing it to warm up to room temperature. It was then diluted with dichloromethane and quenched with water. The organic layer was separated and washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with DCM:MeOH (95:5 to 90:10) to give the title compound. 1H NMR (400 MHz, CDCl3) δ7.97 (s, 1H), 7.93-7.91 (d, 1H), 7.83-7.81 (d, 1H), 7.62-7.58 (m, 1H), 7.11-7.09 (d, 2H), 6.89-6.86 (d, 2H), 4.06-4.03 (m, 3H), 3.77-3.72 (m, 2H), 3.56-3.51 (m, 2H), 3.08 (br s, 2H), 2.70-2.67 (m, 2H), 3.08 (br s, 4H), 2.08-2.01 (m, 4H), 1.85-1.82 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][CH2:6][C@H:7]1[O:11][CH:10]([O:12][CH3:13])[C:9](=[O:14])[C@@H:8]1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24].[CH2:30]1COC[CH2:31]1>>[Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][CH2:6][C@H:7]1[O:11][CH:10]([O:12][CH3:13])[C@:9]([C:30]#[CH:31])([OH:14])[C@@H:8]1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24]
Reactant: COC1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)C1=O
Reactant: C1CCOC1
Product: C#C[C@]1(O)C(OC)O[C@H](COCc2ccc(Cl)cc2Cl)[C@H]1OCc1ccc(Cl)cc1Cl
Reaction time: 1 h

Procedure:
To a cold (−20° C.) solution of (4R,5R)-5-(2,4-Dichlorobenzyloxymethyl)-4-(2,4-dichlorobenzyloxy)-2-methoxy-dihydrofuran-3-one (9.16 g, 19.07 mmol,) in dry THF (20 mL) is added dropwise a solution of 0.5M alkynylmagnesium bromide (e.g. where R3=H, alkynylmagnesium bromide is ethynylmagnesium bromide) in THF (57.2 mL, 28.6 mmol). The yellow reaction mixture is stirred at the same temperature for 1 h and quenched with saturated NH4Cl (50 ml) and extracted with IPAC (2×70 mL). The organic layer is washed with water (50 mL), concentrated to give (3R,4R,5R)-5-(2,4-Dichlorobenzyloxymethyl)-4-(2,4-dichlorobenzyloxy)-3-ethynyl-2-methoxy-tetrahydrofuran-3-ol (I-4) (R3=H) as dark red oil which is directly used for the next step.
Reaction SMILES: [CH:1]([C:4]1[C:13]([NH2:14])=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C1C=CN=CC=1)C>[CH:1]([C:4]1[C:13]([NH:14][S:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:23])=[O:22])=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc2cccnc2c1N
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Product: CC(C)c1ccc2cccnc2c1NS(=O)(=O)c1ccccc1
Yield: 39.7 %

Procedure:
In a similar fashion using route 14 general procedure 27, 7-isopropylquinolin-8-amine (Intermediate 62) (150 mg, 0.81 mmol), bezenesulfonyl chloride (170 mg, 1.0 mmol) and DMAP (cat.) gave the title compound (105 mg, 40%) after purification by column chromatography with n-hexane/EtOAc (17:3-4:1) gradient elution.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:6]2[S:14][CH:13]=[C:12]([CH3:15])[C:7]=2[N:8]=[C:9](Cl)[N:10]=1)[CH:2]=[CH2:3].[CH2:16]([NH2:19])[CH2:17][CH3:18].C(=O)([O-])O.[Na+]>>[CH2:1]([NH:4][C:5]1[C:6]2[S:14][CH:13]=[C:12]([CH3:15])[C:7]=2[N:8]=[C:9]([NH:19][CH2:16][CH2:17][CH3:18])[N:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1nc(Cl)nc2c(C)csc12
Reactant: CCCN
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NCCC)nc2c(C)csc12
Yield: 40 %

Procedure:
288 mg (1.2 mmol) of 4-allylamino-2-chloro-7-methylthieno[3,2-d]pyrimidine and 1.13 mg (19.2 mmol) of propylamine were heated in a sealed tube at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, followed by adding a saturated aqueous sodium hydrogen carbonate solution thereto and extraction with ethyl acetate (50 ml×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by a silica gel chromatography (eluent: ethyl acetate-hexane=1/2) to give 126 mg (yield: 60.0%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[CH:16][CH:15]=2)=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH3:1][O:2][C:3]([C:5]1([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:16][CH:15]=2)=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(NC(=O)c2ccc(CCl)cc2)CCCCC1
Reactant: C1COCCN1
Product: COC(=O)C1(NC(=O)c2ccc(CN3CCOCC3)cc2)CCCCC1
Reaction time: 8 h
Yield: 83 %

Procedure:
30 ml of morpholine was added to 4 g (13 mmol) of 1-[[[4-(chloromethyl)phenyl]carbonyl]amino]cyclohexanecarboxylic acid methyl ester, and the mixture was heated under reflux for 1 hour. The reaction solution was distilled off under reduced pressure, a saturated aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and it was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, diethyl ether was added to the residue, and the mixture was stirred overnight. The precipitated solid was collected by filtration to obtain 3.8 g (83%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][CH:27]=2)[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:29])[C:19](=[O:28])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-:30].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[Br:30])[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:29])[C:19](=[O:28])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [Br-]
Reactant: CC1C(=O)NN=C2COc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CO
Product: CC1C(=O)NN=C2COc3cc(Br)c(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
To a solution of 4-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (Example #71, Step B, 0.50 g, 1.249 mmol) in DCM (5 mL) and MeOH (5 mL) was added tetrabutylammonium tribromide (0.662 g, 1.373 mmol) in portions and the mixture was stirred for 30 min at ambient temperature. The reaction was quenched by addition of saturated aqueous Na2S2O3 solution (5 mL) and the pH was adjusted to 7 with saturated aqueous NaHCO3 solution. The mixture was extracted with DCM (3×20 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 20% EtOAc in petroleum ether) to give 4-(7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.34 g, 57%). LC/MS (Table 1, Method 2) Rt=1.289 min.; MS m/z: 479/481 [M+H]+.
Reaction SMILES: C[CH:2]([C@H:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5](=[O:7])[CH3:6])C.[BH4-].[Na+].[CH3:18]O>>[OH:7][CH:5]([CH3:6])[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])([CH3:2])[CH3:18]
Reactant: CO
Reactant: CC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Agent: [BH4-]
Agent: [Na+]
Product: CC(O)C(C)(C)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of (S)-tert-butyl 2-methyl-4-oxopentan-3-ylcarbamate (2.65 g, 12.31 mmol) in MeOH (30 mL) at 0° C. was added portion wise NaBH4 (0.931 g, 24.62 mmol). Cold bath was removed and the reaction was stirred for 1 hour. HCl solution (1 M, 0.3 mL) was then added cautiously to quench the reaction. The reaction mixture was then concentrated and diluted with EtOAc (50 mL) and water (10 mL). The phases were separated and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organics were then dried (Na2SO4) and concentrated. The residue was purified via silica gel flash chromatography (10-50% EtOAc-Hexanes) to afford the desired product as a white solid (2.05 g). LCMS m/z 240.2 (M+Na)+, Rt 0.69 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].Cl[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:18]=1[N+:26]([O-:28])=[O:27].C(N(CC)CC)C>O1CCCC1>[CH3:15][N:13]([CH3:14])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:17]3[C:18]([N+:26]([O-:28])=[O:27])=[CH:19][CH:20]=[CH:21][C:22]=3[N+:23]([O-:25])=[O:24])[CH:3]=2)[NH:7][CH:6]=1
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Reactant: CN(C)CCc1c[nH]c2ccc(N)cc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)CCc1c[nH]c2ccc(Nc3c([N+](=O)[O-])cccc3[N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
5-Amino-3-(2-dimethylaminoethyl)indole and 1-chloro-2,6-dinitrobenzene were used. Triethylamine was used as base, tetrahydrofuran was used as solvent, and the reaction was stirred at room temperature for 1 hour. Chromatography afforded the title compound (57%) as a dark red solid: mp, 187.0°-188.0° C.; 13C NMR (DMSO-d6) δ139.9, 135.2, 134.0, 132.0, 131.8, 127.2, 123.8, 117.0, 115.4, 112.9, 112.0, 109.3, 59.9, 45.1, 23.0; HRMS calculated for C18H19N5O 369.1439, found 369.1428. Anal. calcd. for C18H19N5O: C, 58.53; H, 5.18; N, 18.96. Found: C, 58.45; H, 4.96; N, 18.63.
Reaction SMILES: [N+:1]([C:3](S(C1C=CC(C)=CC=1)(=O)=O)=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)#[C-:2].[N:23]1[CH:28]=[CH:27][C:26]([CH2:29]C(OCC)=O)=[CH:25][CH:24]=1.CC(C)([O-])C.[K+]>COCCOC>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:4]2[C:29]([C:26]3[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=3)=[CH:2][NH:1][CH:3]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: [C-]#[N+]C(=Cc1cccc(OC)c1)S(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)Cc1ccncc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: COc1cccc(-c2c[nH]cc2-c2ccncc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.1 %

Procedure:
1-[(1-isocyano-2-(3-methoxyphenyl)ethenyl)sulfonyl]-4-methylbenzene (9.0 g, 0.0285 mol) was dissolved in dry DME (200 mL) and added dropwise to a cooled (0° C.) mixture of ethyl 4-pyridylacetate (9.0 g, 0.545 mol) and potassium t-butoxide (7.1 g, 0.0633 mol) in dry DME (100 mL). After the addition was complete the reaction was warmed to 25° C. and stirred for 3 h. The reaction was then poured into ice water (1200 mL) and extracted into CH2Cl2 (3×500 mL). The combined organics were dried over Na2SO4, filtered and evaporated in vacuo to give a solid. This solid was then triturated with ether and filtered to give 3.0 g of pure 3-(3-methoxyphenyl)-4-(4-pyridyl)pyrrole. The filtrate was again evaporated in vacuo and then triturated with a 50/50 mixture of CH2Cl2 and ether to give an additional 1.5 g of pure product. Finally the filtrate was evaporated in vacuo and purified on SiO2 eluting with ethyl acetate to give another 0.5 g of pure product resulting in a 70% combined yield. 1HNMR (DMSO-d6) δ 11.38 (1H, br s, NH), 8.37 (2H, d, J=6.1), 7.24-7.17 (4H, m), 7.02-7.00 (1H, m), 6.80-6.77 (3H, m), 3.68 (3H, s).