Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[CH:7]([NH2:13])[CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1.[C:14]([O:18][C:19]([N:21]([CH2:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:14]([O:18][C:19](=[O:20])[N:21]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:34][NH:13][CH:7]2[C:6]3[N:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:12][C:11]=3[CH2:10][CH2:9][CH2:8]2)=[CH:36][CH:37]=1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: COc1cnc2c(c1)CCCC2N
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C=O)cc1)Cc1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cnc2c(c1)CCCC2NCc1ccc(CN(Cc2ccccn2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
To a solution of (3-methoxy-5,6,7,8-tetrahydroquinolin-8-yl)-amine (0.27 g, 1.5 mmol) and 4-[[N-(t-butoxycarbonyl)-N-(2-pyridinylmethyl)amino]methyl]benzaldehyde (prepared as described by Bridger et al, U.S. patent application Ser. No 09/535,314) (0.57 g, 1.7 mmol) in CH2Cl2 (15 mL) was added NaBH(OAc)3 (0.48 g, 2.3 mmol) and the mixture stirred at room temperature for 16 h. Purification of the crude material by column chromatography on silica gel (5% MeOH/CH2Cl2) gave {4-[(3-methoxy-5,6,7,8-tetrahydroquinolin-8-ylamino)-methyl]-benzyl}-pyridin-2-ylmethyl-carbamic acid tert-butyl ester (0.43 g, 58%). 1H NMR (CDCl3) δ1.45 (m, 9H), 1.77 (m, 2H), 2.00 (m, 1H), 2.12 (m, 1H), 2.77 (m, 2H), 3.80 (m, 1H), 3.81 (s, 3H), 3.85 (d, 1H, J=12.0 Hz), 3.95 (d, 1H, J=12.0 Hz), 4.44 (br s, 2H), 4.55 (br s, 2H), 6.88 (d, 1H, J=1.5 Hz), 7.15 (m, 2H), 7.23 (br s, 2H), 7.34 (d, 2H, J=6.0 Hz), 7.62 (t, 1H, J=7.5 Hz), 8.11 (d, 1H, J=1.5 Hz), 8.52 (d, 1H, J=6.0 Hz).
Reaction SMILES: [NH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1.C1(=O)CCCC1.[C-]#N.[K+].CN(C)[C:17]1([C:22]#[N:23])[CH2:21][CH2:20][CH2:19][CH2:18]1>O>[N:1]1([C:17]2([C:22]#[N:23])[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: C1=CCNC1
Reactant: CN(C)C1(C#N)CCCC1
Agent: [C-]#N
Agent: [K+]
Solvent: O=C1CCCC1
Solvent: O
Product: N#CC1(N2CC=CC2)CCCC1
Yield: 64 %

Procedure:
The title compound (2.8 g; 64%) was prepared from 3-pyrroline (1.86 g; 27 mmol), cyclopentanone (2.26 g; 27 mmol) and potassium cyanide (1.75 g; 27 mmol) in water (15 ml) in a similar manner to that described in D1. 1H NMR (CDCl3) δ: 1.85 (6H, m), 2.08 (2H, m), 3.61 (4H, s), 5.78 (2H, s).
Reaction SMILES: Cl.C([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:26]=[C:25]([O:27][C:28]([O:30][CH3:31])=[O:29])[C:24]([CH3:32])=[CH:23][C:22]=3[F:33])=[N:15][CH:16]=[N:17]2)=[CH:12][CH:11]=1)C1C=CC=CC=1.CN(C=O)C.[Cl:39]C(Cl)Cl>[Pd].CO>[ClH:39].[F:33][C:22]1[CH:23]=[C:24]([CH3:32])[C:25]([O:27][C:28]([O:30][CH3:31])=[O:29])=[CH:26][C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[CH:19][C:10]([OH:9])=[CH:11][CH:12]=2)[N:17]=[CH:16][N:15]=1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(OCc4ccccc4)ccc23)c(F)cc1C
Reactant: ClC(Cl)Cl
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)Oc1cc(Nc2ncnc3cc(O)ccc23)c(F)cc1C
Reaction time: 0.75 h
Yield: 84 %

Procedure:
7-Benzyloxy-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)quinazoline hydrochloride (1.53 g, 3.25 mmol) and 10% palladium-on-charcoal catalyst (180 mg) in a mixture of methanol (75 ml), DMF (6 ml) and trichloromethane (30 ml) was stirred under hydrogen at 1.5 atmospheres pressure for 45 minutes. The catalyst was removed by filtration through diatomaceous earth and the solvent removed from the filtrate by evaporation. The residue was triturated with ether, the resulting solid was collected by filtration and dried under vacuum to give 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxyquinazoline hydrochloride (1.23 g, 84%) as an orange solid. m.p. 205-210° C.
Reaction SMILES: N1C2C(=CC(C(OCC3C=CC=CC=3)=O)=CC=2)C=C1.Br[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[O:32][CH3:33].[I-:34].[K+]>CN(C)C=O>[I:34][CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[O:32][CH3:33]
Reactant: [I-]
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: O=C(OCc1ccccc1)c1ccc2[nH]ccc2c1
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CI)c(OC)c1
Yield: 26.3 %

Procedure:
A solution of benzyl indole-5-carboxylate (86.8 g), methyl 4-bromomethyl-3-methoxybenzoate (89.5 g) and potassium iodide (57.4 g) in N,N-dimethylformamide (900 mL) was heated to 80° C. for 10 hours. The reaction mixture was evaporated and partitioned between diethyl ether and water. The organic layer was separated and washed with water. The aqueous washes were combined and extracted with diethyl ether. The combined organic extract was dried (MgSO4) and evaporated. The residue was purified by flash chromatography, eluting sequentially with 0:1:1, 2:48:50, 4:46:50, 5:45:50, and 10:40:50 ethyl acetate:hexane:methylene chloride, to afford methyl 4-iodomethyl-3-methoxybenzoate (27.8 g), recovered benzyl indole-5-carboxylate (29.6 g), and the crude product as a tan solid (50.6 g). Treatment of the recovered benzyl indole-5-carboxylate (29.6 g) in N,N-dimethylformamide (250 mL) with methyl 4-iodomethyl-3-methoxybenzoate (29.8 g) at 80° C. for 12 hours, followed by evaporation, gave a dark residue, which was dissolved in diethyl ether and washed with water (3 times). The aqueous washes were combined and extracted with diethyl ether. The combined organic extract was dried (MgSO4) and evaporated. The residue was purified by flash chromatography, eluting sequentially with 0:1:1, 2:48:50, 5:45:50, and 10:40:50 ethyl acetate:hexane:methylene chloride, to give further crude product as a tan solid (31.9 g). The combined crude product (82.5 g) was suspended in diethyl ether (400 mL), heated to reflux for 30 min, cooled and filtered to obtain methyl 4-(5-benzyloxycarbonylindol-3-ylmethyl)-3-methoxybenzoate as an ivory solid (46.1 g, 31%); partial NMR (250 MHz, CDCl3): 3.84 (s, 3H, CO2CH), 3.88 (s, 3H, OCH3), 4.14 (s, 2H, CH2), 5.35 (s, 2H, OCH2), 6.97 (d, 1H, indole-H(2)), 8.15 (br, 1 H, NH), 8.37 (s, 1H, indole-H(4)).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]([Cl:14])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][CH:8]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)CCC>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].C1(C)C=CC=CC=1>[Cl:14][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][CH:8]=2)[N:3]=[C:2]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:11]=1[C:12]#[N:13]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: N#Cc1c(Cl)nc2cc(F)ccc2c1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: N#Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Temperature: 100 °C
Reaction time: 18 h

Procedure:
Prepared according to procedure E using 2,4-dichloro-7-fluoroquinoline-3-carbonitrile (230 mg, 0.95 mmol) (described herein), 2-(tributylstannyl)pyridine (0.42 mL, 1.15 mmol), tetrakis(triphenylphosphine)palladium(o) (110 mg, 0.095 mmol), and toluene (4.1 mL). The reaction mixture was stirred at 100° C. for 18 h, and subsequent purification afforded 4-chloro-7-fluoro-2-(pyridin-2-yl)quinoline-3-carbonitrile as an off-white solid. Mass Spectrum (ESI) m/e=284 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]2[CH:6]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH2:20][C:21]([OH:23])=[O:22])[C:12]=3[CH3:24])[NH:7][S:8](=[O:10])(=[O:9])[C:4]=2[CH:3]=1.Cl[CH2:28][C:29]1[C:30]([CH3:35])=[N:31][O:32][C:33]=1[CH3:34]>>[CH3:35][C:30]1[C:29]([CH2:28][N:7]2[CH:6]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH2:20][C:21]([OH:23])=[O:22])[C:12]=3[CH3:24])[C:5]3[CH:25]=[CH:26][C:2]([F:1])=[CH:3][C:4]=3[S:8]2(=[O:10])=[O:9])=[C:33]([CH3:34])[O:32][N:31]=1
Reactant: Cc1noc(C)c1CCl
Reactant: Cc1c(C2NS(=O)(=O)c3cc(F)ccc32)c2ccccc2n1CC(=O)O
Product: Cc1noc(C)c1CN1C(c2c(C)n(CC(=O)O)c3ccccc23)c2ccc(F)cc2S1(=O)=O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 13, step e) and chloromethyl-3,5-dimethyl-isoxazole. 1H NMR (DMSO-d6) δ 13.1 (bs, 1H), 7-99 (dd, J=2.4, 7.5 Hz, 1H), 7.47 (dt, J=2.1, 8.8 Hz, 1H), 7.14-6.74 (m, 4H), 5.93 (s, 1H), 5.01 (s, 2H), 4.02 (d, J=15 Hz, 1H), 3.98 (d, 1H, J=15 Hz, 1H), 2.40 (s, 3H), 2.04 (s, 3H), 1.71 (s, 3H); MS: ESI (negative): 482 (M−H).
Reaction SMILES: [CH:1]([NH:4][S:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[NH2:14])(=[O:7])=[O:6])([CH3:3])[CH3:2].[CH2:15]=O.Cl>C(O)(C)C.C(OCC)(=O)C>[CH:1]([N:4]1[CH2:15][NH:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[S:5]1(=[O:7])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NS(=O)(=O)c1cnccc1N
Reactant: C=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC(C)N1CNc2ccncc2S1(=O)=O
Reaction time: 2 h

Procedure:
A mixture of 0.5 g of N-isopropyl-4-aminopyridine-3-sulfonamide (Preparation 7) and 0.5 g of paraformaldehyde in 15 cm3 of isopropanol to which 50 drops of ethyl acetate saturated with gaseous HCl have been added is brought to reflux for 24 hours. After this lapse of time, the solvent is removed under partial vacuum. The residue is redissolved in 20 cm3 of methanol. The possible insoluble material is removed by filtration. The filtrate, treated with 40 cm3 of water and stored for 2 hours at +4° C., produces a precipitate of the isopropoxymethylenated derivative of Preparation 7. It is collected on a filter, washed with water, dried and recrystallized from a CHCl3 /petroleum ether (40°-60° C.) (1/2) mixture. The dry product is introduced into an open round-bottomed flask and brought to a temperature of 180°-190° C. After 15 to 30 minutes, the molten mass solidifies. It is then cooled and then dissolved in a small volume of chloroform. The addition of 1 volume of petroleum ether (40°-60° C.) causes precipitation of crystals of the title compound. They are collected on a filter, washed with petroleum ether (40°-60° C.) and dried.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([N:12]1[CH2:17][CH2:16][O:15][C@H:14]([CH3:18])[CH2:13]1)=[CH:8][C:7]2=[O:19].C([Sn](CCCC)(CCCC)[C:29]([O:31]CC)=[CH2:30])CCC>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:29]([C:2]1[CH:3]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([N:12]1[CH2:17][CH2:16][O:15][C@H:14]([CH3:18])[CH2:13]1)=[CH:8][C:7]2=[O:19])(=[O:31])[CH3:30]
Reactant: COC(=O)c1cc(Br)c2oc(N3CCO[C@H](C)C3)cc(=O)c2c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(C(C)=O)c2oc(N3CCO[C@H](C)C3)cc(=O)c2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
Methyl 8-bromo-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylate (1.45 g, 3.79 mmol), bis(triphenylphosphine) palladium(II) chloride (0.107 g, 0.15 mmol) and tributyl(1-ethoxyvinyl)stannane (1.346 mL, 3.98 mmol) in 1,4-dioxane (20 mL) were degased, purged with argon and heated to 90° C. for 4 hrs. After cooling to RT, HCl2N (1.9 mL, 3.79 mmol) was added and the mixture was left to stir for 1 h. The reaction mixture was concentrated, suspended in water, neutralised with NaHCO3 and extracted with DCM. The combined organic phases were washed with water, brine, dried over magnesium sulfate and concentrated. The crude product was triturated with n-heptane, filtered and retriturated with ether, filtered and dried to give methyl 8-acetyl-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylate (1.15 g, 88%) as a grey solid. Mass Spectrum: M+H+ 346.
Reaction SMILES: Cl.[C:2]1([NH:8][NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:17]([NH:19][C:20](=O)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O>C(O)(=O)C>[CH2:21]([C:20]1[N:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=[CH:17][N:19]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NNc1ccccc1
Reactant: O=CNC(=O)Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: c1ccc(Cc2ncnn2-c2ccccc2)cc1
Temperature: 70 °C

Procedure:
Phenylhydrazine hydrochloride (0.09 g, 0.6 mmol) in 5 mL glacial acetic acid was treated with triethylamine (0.06 g, 0.6 mmol), warmed to 70° C., treated with N-formylphenylacetamide (0.1 g, 0.6 mmol), and heated at 90° C. for 1 hour. The mixture was then allowed to cool to room temperature and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the organics were washed with saturated NaHCO3, 1M NaOH, water, and brine. The organics were then dried (MgSO4), and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (40% hexanes/ethyl acetate) to provide the title compound. MS (ESI) m/e: 236 (M+H)+; 1H NMR (DMSO-d6) δ 4.2 (s, 2H), 7.05-7.1 (d, 2H), 7.17-7.3 (m, 3H), 7.45-7.6 (m, 5H), 8.1 (s, 1H); Anal. calcd. for C, 76.57; H, 5.57; N, 17.86. Found C, 76.32; H: 5.81; N, 17.63.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:26]=[C:25]([C:27]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37]C(C3C=CSC=3)=O)[CH:32]=2)=[O:28])[CH:24]=[C:23]([Cl:45])[C:5]=1[C:6]([NH:8][C@H:9]([C:19]([O:21]C)=[O:20])[CH2:10][NH:11][C:12]([C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)=[O:13])=[O:7].ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=C(Cl)C=1C(N[C@H](C(OC)=O)CNC(C1C=CSC=1)=O)=O>CO>[Cl:3][C:4]1[CH:26]=[C:25]([C:27]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=2)=[O:28])[CH:24]=[C:23]([Cl:45])[C:5]=1[C:6]([NH:8][C@H:9]([C:19]([OH:21])=[O:20])[CH2:10][NH:11][C:12]([C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)=[O:13])=[O:7]
Reactant: COC(=O)[C@H](CNC(=O)c1ccsc1)NC(=O)c1c(Cl)cc(C(=O)NCc2cccc(OC(=O)c3ccsc3)c2)cc1Cl
Agent: COC(=O)[C@H](CNC(=O)c1ccsc1)NC(=O)c1c(Cl)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NCc1cccc(O)c1)c1cc(Cl)c(C(=O)N[C@@H](CNC(=O)c2ccsc2)C(=O)O)c(Cl)c1
Reaction time: 8 h
Yield: 130.4 %

Procedure:
An aqueous solution of sodium hydroxide (1 M; 0.305 mL, 0.305 mmol) was added to a solution of N-[2,6-dichloro-4-[[[[3-[(thiophene-3-carbonyl)oxy]phenyl]methyl]amino]carbonyl]benzoyl]-3-[(thiophene-3-carbonyl)amino]-L-alanine, methyl ester (101 mg, 0.153 mmol) in methanol (2 mL). The solution was allowed to stir overnight and then concentrated. An aqueous solution of sodium hydroxide (1 M; 0.210 mL, 0.210 mmol) was added to a solution of N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]-benzoyl]-3-[(thiophene-3-carbonyl)amino]-L-alanine, methyl ester (58 mg, 0.105 mmol) in methanol (2 mL). The solution was allowed to stir overnight and then concentrated. The residues from the two reactions were purified by HPLC and lyophilized to give N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]-benzoyl]-3-[(thiophene-3-carbonyl)amino]-L-alanine (107 mg, 78%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C.Br[CH2:32][CH2:33][CH2:34][N:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[N:36]1>O>[N:35]1([CH2:34][CH2:33][CH2:32][N:13]2[CH2:12][CH2:11][CH:10]([N:6]3[C:5]4[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][C:4]=4[NH:8][C:7]3=[O:9])[CH2:15][CH2:14]2)[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[N:36]1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Reactant: BrCCCn1nnc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=c1[nH]c2cc(Cl)ccc2n1C1CCN(CCCn2nnc3ccccc32)CC1
Reaction time: 8 h
Yield: 25 %

Procedure:
A mixture of 5 parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 3.7 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed with water-separator. Then there are added 4.8 parts of 1-(3-bromopropyl)-1H-benzotriazole and stirring is continued overnight at reflux temperature. The reaction mixture is cooled, water is added and the undissolved product is filtered off and set aside. The organic phase is separated from the filtrate, dried, filtered and evaporated. The residue is combined with the undissolved product (see above) and purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone, yielding 2 parts (25%) of 1-{1-[3-(1H-benzotriazol-1-yl)propyl]-4-piperidinyl}-5-chloro-1,3-dihydro-2H-benzimidazol-2-one; mp. 203.4° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][S:11]([OH:14])(=O)=[O:12])=[N:2]1.C(#[N:17])C.P(Cl)(Cl)(Cl)=O>C(OCC)(=O)C>[CH:8]1[CH:7]=[CH:6][C:5]2[O:1][N:2]=[C:3]([CH2:10][S:11]([OH:14])(=[O:12])=[NH:17])[C:4]=2[CH:9]=1
Reactant: O=S(=O)(O)Cc1noc2ccccc12
Reactant: CC#N
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: N=S(=O)(O)Cc1noc2ccccc12
Temperature: 65 °C

Procedure:
1,2-Benzisoxazole-3-methanesulfonic acid (1) (20.0 g, 93.8 mmol) was mixed with acetonitrile (60 mL) and heated to reflux. The clear solution was cooled to 65° C. and phosphorous oxychloride (5.7 mL; 62.3 mmol) was added. The mixture was heated to reflux for 10 hours and then cooled to room temperature. Ethyl acetate (100 mL) was added and the mixture was filtered through CELITE™, which was subsequently washed with ethyl acetate (40 mL). The filtrate was cooled in an ice bath and ammonia gas was bubbled through the solution for 1 hour. The mixture was concentrated and water (100 mL) was added. The mixture was heated to reflux and cooled. It was concentrated, cooled in an ice-bath and filtered to yield crude zonisamide. Purification was achieved by recrystallization from iso-propanol/water. The yield of purified product was 78.8%.
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:30](OCC)=[O:31])[N:18]([CH2:28][CH3:29])[C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])=[CH:11][CH:10]=1>>[CH2:1]([NH:7][C:30]([C:17]1[N:18]([CH2:28][CH3:29])[C:19]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=2)[N:16]=1)=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1CC
Product: CCCCCCNC(=O)c1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1CC

Procedure:
Using essentially the same procedure as Example 42, Step C, but using neat hexylamine (2 mL), ethyl 4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-1-ethylimidazole-2-carboxylate (25 mg, 0.060 mmol) from Example 42, Step B was converted to the title compound after purification by Prep TLC (25% ethyl acetate in hexanes).
Reaction SMILES: [C:1]([C:3]([CH:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].[OH-:21].[Na+]>S(=O)(=O)(O)O.O>[C:1]([C:3]([CH:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:21])[NH2:2]
Reactant: [OH-]
Reactant: N#CC(c1ccccc1)(c1ccccc1)C1CCNC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Temperature: 85 °C
Reaction time: 9 h

Procedure:
3-(R,S)-(1-Cyano-1,1-diphenylmethyl)pyrrolidine (30 g-see Preparation 7) was dissolved in 95% sulphuric acid (210 ml) and the mixture was heated, with stirring, at 85° C. for 9 hours and then at 100° C. for 30 minutes. The mixture was allowed to cool to room temperature and poured onto ice (2 kg). The mixture was basified (pH 12) by addition, in portions with cooling in an ice bath, of a cold solution of sodium hydroxide (340 g) in water (500 ml). The resulting mixture was extracted with dichloromethane (3×300 ml) and the combined extracts were dried (MgSO4) and concentrated in vacuo to give the title compound as a foam, yield 16.4 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH:23]=[CH2:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[CH3:25][O-:26].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][O:26][CH3:25])(=[O:22])=[O:21])[CH2:16][CH2:15]1
Reactant: C[O-]
Reactant: C=CS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: [Na+]
Solvent: CO
Product: COCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
The mixture of 5-bromo-3-[1-(ethenylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (150 mg, 0.36 mmol), sodium methoxide in methanol (25%, 1.0 mL) and methanol (2.0 mL) was stirred at 80° C. for 1 hr. After which time the reaction mixture was concentrated under reduced pressure. The residue was purified by combiflash to give the title compound (100.0 mg, 63%).
Reaction SMILES: [CH:1]1([C:6]2([C:12]3[C:24]4[CH2:23][C:22]5[C:17](=[CH:18][C:19]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:20][CH:21]=5)[C:16]=4[CH:15]=[C:14]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:13]=3)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li]CCCC.Cl[Si:39]([CH3:42])([CH3:41])[CH3:40]>C1COCC1>[CH3:40][Si:39]([CH3:42])([CH3:41])[C:3]1[CH:4]=[CH:5][CH:1]([C:6]2([C:12]3[C:24]4[CH2:23][C:22]5[C:17](=[CH:18][C:19]([C:25]([CH3:26])([CH3:28])[CH3:27])=[CH:20][CH:21]=5)[C:16]=4[CH:15]=[C:14]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:13]=3)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH:2]=1
Reactant: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)cc(C3(C4C=CC=C4)CCCCC3)c1C2
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)cc(C3(C4C=CC([Si](C)(C)C)=C4)CCCCC3)c1C2
Yield: 45.8 %

Procedure:
In a 30 ml Schlenk flask purged with nitrogen, 0.86 g (2.02 mmol, 1 eq) of 1-(cyclopentadienyl)-1-(3,6-di-tert-butylfluorenyl)cyclohexane was placed at room temperature. Then, 12 ml of dehydrated THF was added, and the mixture was stirred by a magnetic stirrer to give a solution. The solution was cooled with an ice bath (colorless transparent solution). To the solution, 1.4 ml (2.28 mmol, 1.13 eq) of n-BuLi (hexane solution) was dropwise added. Then, the ice bath was removed, and the solution was stirred at room temperature for 19 hours. The solution was cooled with an ice bath, and to the solution, 1.6 ml (12.6 mmol, 6.24 eq) of chlorotrimethylsilane was dropwise added by a syringe. The ice bath was removed, and the solution was stirred at room temperature for 4 hours. The resulting yellow solution was poured into 50 ml of a diluted hydrochloric acid solution to perform quenching. After the soluble component was extracted with 70 ml of diethyl ether, the organic phase was washed with 50 ml of a saturated saline solution. The organic phase was dried over MgSO4 then the MgSO4 was filtered off, and from the filtrate the solvent was vacuum distilled off by a rotary evaporator to obtain a yellow amorphous product. The amorphous product was purified by silica gel column chromatography (developing solution: hexane) to obtain 0.46 g a white amorphous product (yield: 46%).