Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:8][N:9]=[C:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]([F:19])([F:18])[F:17].[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:8]1[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[C:15]2[C:10]([C:11]([C:16]([F:19])([F:17])[F:18])=[CH:12][CH:13]=[CH:14]2)=[N:9]1
Reactant: FC(F)(F)c1cccc2c(-c3ccccn3)[nH]nc12
Reactant: Cc1ccccc1B(O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccccc1-n1nc2c(C(F)(F)F)cccc2c1-c1ccccn1

Procedure:
A solution of 3-pyridin-2-yl-7-(trifluoromethyl)-2H-indazole (0.2633 g, 1 mmol), 2-methylphenylboronic acid (0.271 g, 2 mmol, copper(II)acetate (0.181 g, 1 mmol) and pyridine (0.161 mL, 2 mmol) in 20 mL of methylene chloride was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated in vacuo and purified by flash chromatography (silica gel 60, methylene chloride-ethyl acetate, 3:1) to give the title compound (0.08 g).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[CH2:4][CH2:3]1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=O)[O:34]CC)[N:27]=1.NC1N=NC=CC=1.C(N(CC)CC)C>C(#N)C>[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33]([N:2]2[CH2:7][CH2:6][C:5](=[CH:8][C:9]3[CH:25]=[CH:24][CH:23]=[C:11]([O:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=4)[CH:10]=3)[CH2:4][CH2:3]2)=[O:34])[N:27]=1
Reactant: CCOC(=O)Nc1cccnn1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Agent: Cl
Agent: Nc1cccnn1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Nc1cccnn1)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 180 °C

Procedure:
2-(3-Piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (500 mg, 1.35 mmol, from Example 1, Step 5), ethyl pyridazin-3-ylcarbamate (248 mg, 1.48 mmol, prepared according to the procedure described in Synthesis, 1997, 1189-1194 from 3-aminopyridazine) and triethylamine (0.376 mL, 2.7 mmol) were combined in acetonitrile (4.5 mL) and heated in a microwave at 180° C. for 40 minutes. The reaction mixture was cooled to rt and concentrated to form a residue. The residue was purified by silica gel chromatography (50-100% EtOAc in CH2Cl2) to provide the title compound (340 mg). MS (APCI 10 V) AP+ 456.2, 376.2, 335.2; 1H NMR (400 MHz, CD3OD) δ ppm 2.54 (dt, J=50.71, 5.84 Hz, 4H) 3.64 (dt, J=36.50, 5.84 Hz, 4H) 6.47 (s, 1H) 6.96-7.07 (m, 2H) 7.08-7.20 (m, 2H) 7.40 (td, J=7.72, 0.52 Hz, 1H) 7.59 (dd, J=9.13, 4.62 Hz, 1H) 8.08 (dd, J=8.67, 2.68 Hz, 1H) 8.13 (d, J=8.92 Hz, 1H) 8.43 (dt, J=1.79, 0.81 Hz, 1H) 8.79 (d, J=4.19 Hz, 1H).
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[C:9][CH2:10]Br.[OH:12][C:13]1[CH:14]=[C:15]([C:19]2([O:25][CH3:26])[CH2:23][CH2:22][O:21][CH:20]2[CH3:24])[CH:16]=[CH:17][CH:18]=1>>[CH3:26][O:25][C:19]1([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH2:10][C:9]#[C:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=3)[CH:14]=2)[CH2:23][CH2:22][O:21][CH:20]1[CH3:24]
Reactant: COC1(c2cccc(O)c2)CCOC1C
Reactant: BrCC#Cc1ccccn1
Agent: Br
Product: COC1(c2cccc(OCC#Cc3ccccn3)c2)CCOC1C
Yield: 90 %

Procedure:
Using the procedure described in Example 1, 3-(2-pyridyl)prop-2-yn-1-yl bromide hydrobromide was reacted with (2RS,3SR)-3-(3-hydroxyphenyl)-3-methoxy-2-methyltetrahydrofuran to give (2RS,3SR)-3-methoxy-2-methyl-3-[3-(3-(2-pyridyl)prop-2-yn-1-yloxy)phenyl]tetrahydrofuran, as an oil in 90% yield.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=CC=C[CH:8]=2)[CH:3]=[CH:2]1.C([N:17]1[C:29]2[C:28]([OH:30])=[C:27]3[N:31](C(OC(C)(C)C)=O)[C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Cl:46])[CH:22]=2)(OC(C)(C)C)=O.C(OC(N1CCC[C@H]1CO)=O)(C)(C)C>>[Cl:38][C:35]1[CH:36]=[C:37]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:27]1[C:28]([O:30][CH2:8][C@@H:9]3[CH2:4][CH2:3][CH2:2][NH:1]3)=[C:29]3[NH:17][C:18]4[CH:19]=[CH:20][C:21]([Cl:46])=[CH:22][C:23]=4[C:24]3=[CH:25][C:26]2=1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Cl)cc2c2cc3c4cc(Cl)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Reactant: c1ccc2[nH]ccc2c1
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Product: Clc1ccc2[nH]c3c(OC[C@@H]4CCCN4)c4[nH]c5ccc(Cl)cc5c4cc3c2c1

Procedure:
The title compound was prepared in a manner analogous to Example 28 except the starting indole is 5,7-diBOC-2,10-dichloro-6-hydroxyindolo[2,3-b]carbazole and the reagent is (S)-(+)-1-(tert-butoxycarbonyl)-2-pyrrolidinemethanol. 1H-NMR (400 MHz, CD3OD) δ ppm 8.46 (s, 1 H), 8.11 (d, J=2.4 Hz, 2 H), 7.41 (d, J=8.4 Hz, 2 H), 7.30 (dd, J=8.4, 2.4 Hz, 2 H), 4.33 (dd, J=10.0, 3.2 Hz, 1 H), 4.11 (dd, J=10.0, 8.4 Hz, 1 H), 3.91-3.82 (m, 1 H), 3.16 (t, J=7.2 Hz, 2 H), 2.16-2.05 (m, 1 H), 2.03-1.84 (m, 2 H), 1.72-1.62 (m, 1 H); MS (ESI) m/z 422.2 (M−H)−; MS (ESI) m/z 424.0 (M+H)+
Reaction SMILES: ClC(N(C)C)=C(C)C.[Cl:9][C:10]1[C:15]([CH2:16][NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][CH:13]=[C:12]([Cl:24])[C:11]=1[NH:25][C:26]1[N:30]([CH3:31])[C:29]2[CH:32]=[C:33]([O:39][CH2:40][CH:41]([F:43])[F:42])[C:34]([C:36]([OH:38])=O)=[CH:35][C:28]=2[N:27]=1.[NH2:44][C:45]1[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=1)[C:48]#[N:49].N1C=CC=CC=1>C(#N)C>[C:48]([C:47]1[CH:46]=[C:45]([NH:44][C:36]([C:34]2[C:33]([O:39][CH2:40][CH:41]([F:42])[F:43])=[CH:32][C:29]3[N:30]([CH3:31])[C:26]([NH:25][C:11]4[C:12]([Cl:24])=[CH:13][CH:14]=[C:15]([CH2:16][NH:17][C:18](=[O:23])[C:19]([CH3:21])([CH3:22])[CH3:20])[C:10]=4[Cl:9])=[N:27][C:28]=3[CH:35]=2)=[O:38])[CH:52]=[CH:51][CH:50]=1)#[N:49]
Reactant: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)O)c(OCC(F)F)cc21
Reactant: N#Cc1cccc(N)c1
Agent: CC(C)=C(Cl)N(C)C
Solvent: CC#N
Solvent: c1ccncc1
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)Nc3cccc(C#N)c3)c(OCC(F)F)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(1-Chloro-2-methyl-propenyl)-dimethylamine (20 μl) is added to a mixture of 2-{2,6-dichloro-3-[(2,2-dimethyl-propionylamino)-methyl]-phenylamino}-6-(2,2-difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-carboxylic acid (53 mg, 0.10 mmol) in 2.0 mL acetonitrile and it is stirred 10 min at rt. Additional (1-chloro-2-methyl-propenyl)-dimethylamine (20 μl) is added and the mixture is stirred for additional 20 min at rt. The crude acid chloride solution is added to a mixture of 3-aminobenzonitrile (12 mg, 0.10 mmol), pyridine (24 μL, 0.30 mmol) and acetonitrile (1.0 mL) and it is stirred for 15 min at rt and additional 5 h at 55° C. The solvent is removed in vacuo and the residue is dissolved in 2 mL of a 19:1 DMF/water-solution and is purified via preparative HPLC to furnish the title compound.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:7]1[CH:27]=[CH:26][C:10]2[N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH:15]=3)[CH:12]=[N:13][C:9]=2[CH:8]=1)[CH3:6])[CH3:2].[H-].[Na+].Br[CH:31](C)C>CN(C=O)C.O>[CH:1]([O:3][N:4]=[C:5]([C:7]1[CH:27]=[CH:26][C:10]2[N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH:15]=3)[CH:12]=[N:13][C:9]=2[CH:8]=1)[CH3:6])([CH3:31])[CH3:2]
Reactant: CC(C)Br
Reactant: CCON=C(C)c1ccc2c(c1)ncn2-c1cccc(-c2cccnc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=NOC(C)C)c1ccc2c(c1)ncn2-c1cccc(-c2cccnc2)c1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 33.2 %

Procedure:
To a suspension of 33i (Example 14) (0.4 g, 1.22 mmol) in dry DMF (5 ml) is added sodium hydride (50 mg of a 60% dispersion in mineral oil). The mixture is stirred at 30-40° C. for 30 min. 2-Bromopropane (0.14 ml, 1.49 mmol) is added and the mixture is stirred at 40° C. over night. After cooling the mixture is diluted with 4 volumes of water and extracted with dichloromethane. The organic extract is concentrated and eluted through silica gel with ethyl acetate to yield 0.15 g 33j (33%). Mp 77-80° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(N(CC)CC)C.[CH3:17][O:18][C:19](=[O:30])[N:20]([CH2:28]Cl)[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1>C1C=CC=CC=1>[CH3:17][O:18][C:19](=[O:30])[N:20]([CH2:28][O:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1
Reactant: COC(=O)N(CCl)c1ccc(Cl)cc1
Reactant: Oc1ccc(Cl)cc1Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)N(COc1ccc(Cl)cc1Cl)c1ccc(Cl)cc1

Procedure:
A solution of 16.3 g (0.1 mole) of 2,4-dichlorophenol and 14 ml (0.1 mole) of triethylamine in 100 ml of benzene was added dropwise, over the course of 15 minutes, to a solution of 23.4 g (0.1 mole) of Methyl-N-chloromethyl-N-(4-chlorophenyl)-carbamate in 200 ml of dry benzene. Thereafter the triethylamine hydrochloride was filtered off, the filtrate was washed with 5% strength sodium hydroxide solution and water, and after drying over calcined sodium sulphate the benzene was distilled off under reduced pressure. 52.4 g (92% of theory) of Methyl-N-(2,4-dichlorophenoxymethyl)-N-(4-chlorophenyl)-carbamate, melting at 70° - 80° C after recrystallization from ethanol, were obtained.
Reaction SMILES: [O:1]=[S:2]1(=[O:27])[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([CH2:12][N:13](C3C=CC=CC=3C#N)[N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)[CH:10]=[CH:11][C:4]=2[O:3]1.[BH4-].[Na+].[NH4+:30].[Cl-].O>CO>[O:1]=[S:2]1(=[O:27])[NH:7][CH2:6][C:5]2[CH:8]=[C:9]([CH2:12][N:13]([C:10]3[CH:9]=[CH:8][C:5]([C:6]#[N:30])=[CH:4][CH:11]=3)[N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)[CH:10]=[CH:11][C:4]=2[O:3]1
Reactant: N#Cc1ccccc1N(Cc1ccc2c(c1)C=NS(=O)(=O)O2)n1ccnc1
Reactant: [NH4+]
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#Cc1ccc(N(Cc2ccc3c(c2)CNS(=O)(=O)O3)n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
To a suspension of +[N-[(2,2-dioxido-1,2,3-benzoxathiazin-6-yl)methyl]-N-(1H-imidazol-1-yl)amino]benzonitrile (0.40 g, 1.05 mmol) in methanol (8 ml) was added portionwise NaBH4 (0.08 g, 2.11 mmol) and the reaction mixture was stirred at room temperature for 3 h. After addition of a saturated solution of NH4Cl (3 ml) and water (40 ml), the precipitate obtained was filtered, washed with water and dried to give a white solid. Crystallization from ethyl acetate with ethanol yielded the expected product (0.40 g, 82%, mp: 190° C.).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[C:3]=1[C:14]([N:40]1[CH2:39][CH2:38][N:37]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[O:30][CH3:29])[CH2:42][CH2:41]1)=[O:16]
Reactant: Nc1onc(-c2ccccc2F)c1C(=O)O
Reactant: COc1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C(=O)c2c(-c3ccccc3F)noc2N)CC1
Yield: 9273.9 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(2-fluorophenyl)isoxazol-4-carboxylic acid (409 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(2-methoxyphenyl)piperazine (354 mg, 1.84 mmol), a white solid required compound (464 mg, 1,170.64 mmol, 77%) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]([OH:23])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]([O:23][CH3:24])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)cc2C(=O)O)CC1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Cl)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2-Carboxy-4-chloro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.64 g, 1.88 mmol) in toluene:methanol (9:1) was added a trimethylsilyldiazomethane (2.0 M in hexanes) (1.05 mL, 2.07 mmol) and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and purified using gradient elution from hexane/ethyl acetate (10%) to hexane/ethyl acetate (50%). 1H-NMR (CDCL3) δ: 1.45 (9H, s), 2.90-3.00 (4H, m), 3.50-3.60 (4H, m), 3.90 (3H, s), 6.90-7.00 (1H, d), 7.35-7.45 (1H, dd), 7.80 (1H, d).
Reaction SMILES: C(OCC)(=O)C.[N+:7]([C:10]1[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=1[O:12][CH2:13][CH2:14][C:15]#[N:16])([O-])=O.[H][H]>[Pd]>[NH2:7][C:10]1[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=1[O:12][CH2:13][CH2:14][C:15]#[N:16]
Reactant: [H][H]
Reactant: N#CCCOc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#CCCOc1ccccc1N
Reaction time: 4 h
Yield: 98 %

Procedure:
To palladium (0.00748 g, 0.0702 mmol) in a 50 mL flask with stirbar was added ethyl acetate (11.7 g, 133 mmol) under nitrogen, and then nitrile 83 (0.675 g, 3.51 mmol) was added (FIG. 18). The flask was fitted with a balloon containing hydrogen, and the nitrogen inlet was removed. The reaction was stirred vigorously for 4 hours, and then was filtered through celite, washing with ethyl acetate. The product 84 required no further purification, 98% yield. 1H NMR (500 MHz, CDCl3) δ 6.85-6.77 (m, 1H), 6.74-6.62 (m, 3H), 4.08 (t, J=6.1 Hz, 2H), 3.94-3.74 (m, 2H), 2.72 (t, J=6.1 Hz, 2H). LRMS m/z Calcd. for C9H10N2O: 162.07931. found: 163.1 [M+1].
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[C:28]([CH2:32][OH:33])[CH:29]=[CH:30][CH:31]=2)O1>>[OH:33][CH2:32][C:28]1[CH:27]=[C:26]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]4[CH2:17][CH2:16]4)=[O:14])[N:8]=[CH:9]3)=[CH:4][N:3]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Nc1cc2cnc(Cl)cc2cn1)C1CC1
Reactant: CC1(C)OB(c2cccc(CO)c2)OC1(C)C
Product: O=C(Nc1cc2cnc(-c3cccc(CO)c3)cc2cn1)C1CC1

Procedure:
The title compound was prepared following a procedure similar to example 162 using N-(7-chloro-2,6-naphthyridin-3-yl)cyclopropanecarboxamide and (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]1([CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=2)[NH2:17])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1(C)C=CC=CC=1>[C:5]1([CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([N:17]=[C:1]=[O:2])[CH:18]=[CH:19][CH:20]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Nc1cccc(CCCc2ccccc2)c1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1cccc(CCCc2ccccc2)c1
Reaction time: 6 h
Yield: 95.8 %

Procedure:
170 g of phosgene are dissolved in 200 ml of toluene at -10° C. At the same temperature, 145 g of 3-(3-phenylpropyl)-aniline in 300 ml of toluene are then slowly added dropwise. The mixture is warmed slowly, the introduction of phosgene is started when 60° C. is reached, and the mixture is brought to the boil. After 6 hours, excess phosgene is flushed out with nitrogen and the mixture is distilled. 156 g of 3-(3-phenylpropyl)-phenyl isocyanate, of boiling point 107°-110° C./0.1 mbar, are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13](CC3CCN(CC4C=CC=CC=4)CC3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].COC1C=C2C(=CC=1OC)C(=O)CC2.[N:43]1[CH:48]=[CH:47][C:46]([CH:49]=O)=[CH:45][CH:44]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][C:8]=1[O:9][CH3:10])[C:11](=[O:12])[CH:49]([C:46]1[CH:45]=[CH:44][N:43]=[CH:48][CH:47]=1)[C:14]2=[CH2:13]
Reactant: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Reactant: O=Cc1ccncc1
Agent: COc1cc2c(cc1OC)C(=O)CC2
Product: C=C1c2cc(OC)c(OC)cc2C(=O)C1c1ccncc1

Procedure:
U.S. Pat. No. 4,895,481, incorporated herein by reference in its entirety, describes donepezil, its related compounds along with their pharmaceutical acceptable salts including composition and method of treatment using them. The process for the preparation of donepezil is disclosed by the aforesaid product patent involves the conversion of 1-benzyl-4-piperidinone to 1-benzyl-4-piperidine carboxaldehyde in the presence of n-butyl lithium, which on further reaction with 5,6-dimethoxy-1-indanone in the presence of strong base such as lithium diisopropylamide under inert atmosphere followed by reduction of the obtained compound to give the title compound of Formula (I) with an overall yield of 27.4%. U.S. Pat. No. 5,606,064, incorporated herein by reference in its entirety, also discloses the process for the preparation of donepezil, which involves reacting 5,6-dimethoxy indanone and pyridine-4-carboxaldehyde to yield 5,6 dimethoxy-2-pyridin-4-yl methylene-indan-1-one, which upon condensation with benzyl bromide followed by reduction of the obtained compound with platinum oxide to afford the title compound with an overall yield of 58.5%. U.S. Pat. No. 6,252,081 B1, incorporated herein by reference in its entirety, also discloses a process for preparation of donepezil (e.g., examples 1, 2, and 3) that provides a satisfactory yield, but utilizes platinum oxide as a reagent. International Application No. WO 97/22584 discloses a process for preparation of donepezil in the (preparations 1–3 and examples 1–6), with an asserted overall yield of 19.3%.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([C:13]#[N:14])=[CH:8][C:7]=1[Cl:15])=[O:4].CC(O)C.Cl.[H][H]>[Pd].CO>[NH2:14][CH2:13][C:9]1[CH:8]=[C:7]([Cl:15])[C:6]([NH:5][C:3](=[O:4])[CH2:2][Cl:1])=[C:11]([Cl:12])[CH:10]=1
Reactant: N#Cc1cc(Cl)c(NC(=O)CCl)c(Cl)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: NCc1cc(Cl)c(NC(=O)CCl)c(Cl)c1
Yield: 100 %

Procedure:
A mixture of 10.5 parts of 2-chloro-N-(2,6dichloro-4-cyanophenyl) acetamide, 22 parts of 2-propanol, saturated with hydrogen chloride and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in water and treated with a sodium hydroxide solution 50%. The product was extracted twice with dichloromethane. The combined extracts were dried, filtered and evaporated, yielding 10.7 parts (100%) of N-[4-(aminomethyl)-2,6-dichlorophenyl]-2-chloroacetamide as a residue (int. 100).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH2:13][C:14]2([C:19]([F:22])([F:21])[F:20])[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.C(N=C=NCCCN(C)C)C.[N:35]1([S:39]([NH2:42])(=[O:41])=[O:40])[CH2:38][CH2:37][CH2:36]1.Cl>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[N:35]1([S:39]([NH:42][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[C:3]([O:12][CH2:13][C:14]3([C:19]([F:21])([F:22])[F:20])[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:4][C:5]=2[F:11])(=[O:41])=[O:40])[CH2:38][CH2:37][CH2:36]1
Reactant: NS(=O)(=O)N1CCC1
Reactant: O=C(O)c1cc(Cl)c(OCC2(C(F)(F)F)CCCC2)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(OCC2(C(F)(F)F)CCCC2)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.9 %

Procedure:
To a stirred solution of 5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclopentyl)-methoxy)benzoic acid (0.34 g, 1.00 mmol) in dichloromethane (20 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.29 g, 1.50 mmol) and 4-dimethylaminopyridine (0.28 g, 2.30 mmol). The reaction mixture was stirred at ambient temperature for 10 minutes, azetidine-1-sulfonamide (0.20 g, 1.50 mmol) was added and the stirring was continued at ambient temperature for 17 hours. 5% aqueous hydrochloric acid solution (10 mL) were added and diluted with ethyl acetate (100 mL), washed with water and brine; dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (30% ethyl acetate in hexanes) afforded the title compound (0.22 g, 46%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.61 (br s, 1H), 8.11 (d, J=7.2 Hz, 1H), 6.69 (d, J=12.9 Hz, 1H), 4.22 (br s, 4H), 4.03 (s, 2H), 2.31-2.17 (m, 2H), 2.08-1.92 (m, 2H), 1.89-1.70 (m, 6H); MS (ES+) m/z 459.0, 461.0 (M+1); MS (ES−) m/z 457.1, 459.1 (M−1).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:20])[CH2:5][NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[ClH:1].[CH3:2][O:3][C:4](=[O:20])[CH2:5][N:6]([C:21](=[O:23])[CH3:22])[CH:7]1[CH2:8][CH2:9][N:10]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:11][CH2:12]1
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)CNC1CCN(Cc2ccccc2)CC1
Agent: Cl
Product: COC(=O)CN(C(C)=O)C1CCN(Cc2ccccc2)CC1

Procedure:
Prepared from N-[1-benzyl-4-piperidinyl]glycine methyl ester hydrochloride and acetic anhydride.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C@:12]2([CH3:15])[CH2:14][O:13]2)=[O:11])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2].[Na].[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([O-:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)(Cl)Cl.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:15][C:12]([OH:13])([C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:5]=1)=[O:11])[CH2:14][S:28]([C:25]1[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=1)(=[O:30])=[O:29]
Reactant: C[C@@]1(C(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)CO1
Reactant: O=S([O-])c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(O)(CS(=O)(=O)c1ccc(F)cc1)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
180 mg of the chiral epoxide of example 17 was dissolved in a mixture of 12 ml chloroform and 12 ml of water. 133 mg of sodium-p-fluorobenzenesulfinate and 107 mg of tetrabutylammonium bromide were added. The reaction mixture was heated till reflux and kept at reflux, while stirring vigorously. The reaction was monitored with HPLC. After 4 days at reflux, the starting epoxide was completely converted. The mixture was cooled to room temperature. 10 ml of chloroform was added. The organic layer was washed with 3×20 ml of water, dried (Na2SO4), filtrated and evaporated to dryness. Residue: 226 mg (brown oil). Purification of the residue by column chromatography (Merck silica gel 60; eluens: heptane/ethyl acetate=1/1) afforded R-enantiomer of bicalutamide as a white/yellow solid material. Purified yield: 122 mg (43%). HPLC: 96.3% purity. HPLC (chiral column): 94.7% e.e. 1H and 13C NMR in agreement with R-bicalutamide