Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([CH:11]2[CH2:13][CH2:12]2)[CH:9]=O)[C:3]=1[O:14][CH:15]([F:17])[F:16].N1CCCCC1.C(O)(=O)C.[C:28](OCC)(=[O:35])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:4]([C:3]=1[O:14][CH:15]([F:17])[F:16])=[C:8]([CH:11]1[CH2:13][CH2:12]1)[CH:9]=[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:28]2=[O:35]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=CC(c1nccc(Cl)c1OC(F)F)C1CC1
Solvent: CCO
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C2CC2)c2c(OC(F)F)c(Cl)ccn2c1=O
Temperature: 100 °C

Procedure:
71.6 mg of 2-(4-chloro-3-difluoromethyl-2-pyridyl)-2-cyclopropylethanal (XII) was dissolved in 3 ml of anhydrous ethanol, to which were added 80 μl of piperidine, 80 μl of acetic acid and 220 μl of diethyl malonate and the resulting mixture was heated at 100° C. for 5 hours. The solvent was distilled off by under reduced pressure, and thereafter, the resulting mixture was diluted with ether, and the resulting organic layer was washed with water and saturated salt water, and dried over anhydrous sodium sulfate, and the solvent was distilled off by under reduced pressure. 2 ml of Dowtherm A was added to the resulting residue, and the resulting mixture was heated at 240° C. for 30 minutes. The reaction solution was purified directly by silica gel column chromatography (eluent; hexane→hexane:ethyl acetate=1:1) to obtain 51.3 mg of ethyl 8-chloro-1-cyclopropyl-9-difluoromethyl-4-oxo-4H-quinolidine-3-carboxylate (XIII).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:19])=[C:4]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][C:21]1[N:22]=[CH:23][NH:24][C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27].ClC1C(F)=C(B(O)O)C=CC=1>CO.C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:19])=[C:4]([N:24]2[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([CH3:20])[N:22]=[CH:23]2)[CH:5]=[CH:6][CH:7]=1.[Cl:1][C:2]1[C:3]([F:19])=[C:4]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1[nH]cnc1C
Agent: CCOC(=O)c1ncn(-c2cccc(Cl)c2F)c1C
Agent: OB(O)c1cccc(Cl)c1F
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1c(C)ncn1-c1cccc(Cl)c1F
Reaction time: 20 h
Yield: 2 %

Procedure:
Ethyl 1-(3-chloro-2-fluorophenyl)-5-methyl-1H-imidazole-4-carboxylate: Using a modified procedure of Sreedhar. (Reference: Sreedhar, B., Synthesis, 795 (2008)). To a suspension of ethyl 4-methyl-1H-imidazole-5-carboxylate (0.530 g, 3.44 mmol) and (3-chloro-2-fluorophenyl)boronic acid (0.500 g, 2.87 mmol) in MeOH (5.74 mL) was added cuprous oxide (0.041 g, 0.287 mmol). The resulting purple suspension was stirred vigorously under an atmosphere of air (drying tube used). After 20 h, the reaction mixture was filtered to remove the solids and the clear blue filtrate was concentrated to give a blue solid. The blue solid was suspended in DCM and filtered to remove the solids and the blue filtrate was concentrated to give a pale blue solid weighing 0.187 g. Purification by normal phase chromatography gave ethyl 1-(3-chloro-2-fluorophenyl)-4-methyl-1H-imidazole-5-carboxylate (0.0187 g, 2%) as a clear, colorless residue and ethyl 1-(3-chloro-2-fluorophenyl)-5-methyl-1H-imidazole-4-carboxylate (Intermediate 24A) (0.0079 g, 1%) as a clear, colorless residue. MS(ESI) m/z: 283.1 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[NH2:31][CH2:32][CH2:33][C:34]1[CH:35]=[C:36]([OH:41])[C:37]([OH:40])=[CH:38][CH:39]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:31][CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([OH:41])[CH:35]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Reactant: NCCc1ccc(O)c(O)c1
Product: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc(O)c(O)c3)n2)c1

Procedure:
Intermediate 4 from above was coupled with 4-(2-Amino-ethyl)-benzene-1,2-diol following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 472. 1H NMR (Varian 300 MHz, CDCl3—CD3OD, shifts relative to the solvent peak at 7.24 ppm) δ 8.1 (m, 2H) 8.0 (d, 1H) 7.7 (d, 1H) 7.5 (m, 1H) 7.2 (m, 1H) 6.7 (d, 1H) 6.6 (m, 2H) 4.7 (s, 2H) 3.8 (m, 2H) 3.6 (m, 2H) 2.9 (s, 3H) 2.8 (m, 4H) 1.8 (m, 2H).
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]([NH:8][C:9]([NH:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[N:15]=[CH:14][N:13]=1)=[O:10])([CH3:7])[CH3:6])C.[Li+].[OH-]>C1COCC1.O>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[N:15]=[CH:14][N:13]=[C:12]([NH:11][C:9](=[O:10])[NH:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:26])=[O:3])[CH:17]=1
Reactant: CCOC(=O)C(C)(C)NC(=O)Nc1cc(-c2ccccc2OC)ncn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1-c1cc(NC(=O)NC(C)(C)C(=O)O)ncn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-{3-[6-(2-methoxy-phenyl)-pyrimidin-4-yl]-ureido}-2-methyl-propionic acid ethyl ester (LVI) (370 mg, 1.03 mmol) in a mixture of THF and water (1:1) was added a solution of LiOH (87.0 mg, 2.06 mmol) in water at ice bath temperature over 10 min and then allowed to stir for two hours at room temperature. THF was evaporated and the aqueous solution was acidified with 2N HCl. This aqueous phase was then extracted with ethyl acetate (2×100 ml), the combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in a vacuum rotavapor to afford 2-{3-[6-(2-methoxy-phenyl)-pyrimidin-4-yl]-ureido}-2-methyl-propionic acid as a white solid. Yield: 235 mg, 69.1%.
Reaction SMILES: Cl.[CH2:2]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)[CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[S:27]1[CH2:31][CH:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[NH:29][CH2:28]1.C(Cl)(Cl)Cl.C(N(CC)CC)C>C(Cl)Cl>[CH2:2]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([N:29]2[CH:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:31][S:27][CH2:28]2)=[O:23])=[CH:20][CH:19]=1)[CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCOC(=O)C1CSCN1
Reactant: CCCCCCCCCCC=CCCCNc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCC=CCCCNc1ccc(C(=O)N2CSCC2C(=O)OCC)cc1

Procedure:
One-tenth mole of 4-(4-pentadecenylamino)benzoyl chloride hydrochloride in methylene chloride is added to a solution of 0.1 mole of ethyl thiazolidine-4-carboxylate in chloroform containing two equivalents of triethylamine. After 5 hours at 20° C. the solution is filtered and evaporated to a white solid which is recrystallized from acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10](SC)[N:11]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10]([NH:25][CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[O:21][CH3:20])[N:11]=1
Reactant: COc1ccccc1CN
Reactant: CSc1nc(Cc2cccc(Cl)c2)[nH]c(=O)c1C#N
Product: COc1ccccc1CNc1nc(Cc2cccc(Cl)c2)[nH]c(=O)c1C#N

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.34 mmol) of 2-(3-chlorobenzyl)-4-(methylsulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are reacted with 470 mg (3.43 mmol) of 2-methoxybenzylamine to give 37 mg (28% of theory) of the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[OH:38][CH2:39]C1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1>>[NH2:37][C:9]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH2:39][OH:38])=[CH:7][CH:6]=2)=[C:13]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:33])[F:34])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)[N:12]=[CH:11][N:10]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Reactant: CC1(C)OB(c2ccc(CO)cc2)OC1(C)C
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(CO)cc2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 4-(hydroxymethyl)benzeneboronic acid pinacol ester instead of 4-fluorophenylboronic acid. LC-MS: (M+1=527, obsd.=527).
Reaction SMILES: BrC1N=C([C@@H]([NH:17][C:18](=[O:24])[O:19]C(C)(C)C)[C@H](O)C2C=CC=CC=2)C=CC=1.[Br:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][N:33]=1)[CH:29]=O.C([C:36](CC)(P(=O)([O-])[O-])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=1)C>>[Br:25][C:26]1[CH:27]=[C:28]([C@@H:29]2[C@@H:36]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=3)[O:24][C:18](=[O:19])[NH:17]2)[CH:31]=[CH:32][N:33]=1
Reactant: CC(C)(C)OC(=O)N[C@H](c1cccc(Br)n1)[C@H](O)c1ccccc1
Reactant: CCC(CC)(c1cccc(OC)c1)P(=O)([O-])[O-]
Reactant: O=Cc1ccnc(Br)c1
Product: COc1cccc([C@H]2OC(=O)N[C@@H]2c2ccnc(Br)c2)c1

Procedure:
Prepared according to the same procedure as (±)-tert-Butyl (1R,2R)-1-(6-bromopyridin-2-yl)-2-hydroxy-2-phenylethylcarbamate, starting with 2-bromoisonicotinaldehyde and diethyl-3-methoxybenzylphosphonate. 1H-NMR (CDCl3, 500 MHz) δ 8.42 (d, J=5.2 Hz, 1H), 7.48 (s, 1H), 7.37 (t, J=8.2 Hz, 1H), 7.20 (d, J=5.2 Hz, 1H), 6.98 (m, 1H), 6.86 (s, 1H), 6.71 (s, 1H), 5.18 (d, J=7.3 Hz, 1H), 4.79 (d, J=7.3 Hz, 1H), 3.84 (s, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 160.4, 158.6, 151.1, 150.6, 143.3, 138.0, 130.5, 125.6, 120.3, 118.2, 115.3, 111.6, 85.1, 63.3, 55.5. Mass spec.: 349.0 (MH)+.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[CH2:6][NH:5][C:4]1=[O:14].[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25](O)=[O:26])=[CH:19]2.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25]([NH:2][C@@H:3]1[CH2:9][C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[CH2:6][NH:5][C:4]1=[O:14])=[O:26])=[CH:19]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: N[C@@H]1Cc2ccccc2CNC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H]1Cc2ccccc2CNC1=O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 16 h
Yield: 44 %

Procedure:
(R)-4-amino-2, 3,4,5-tetrahydro-2-benzazepin-3 (1H)-one hydrochloride salt (387 mg) (amine free base prepared in U.S. Pat. No. 5,545,735) was added to a mixture of tetrahydrofuran (40 mL), 5-chloroindole-2-carboxylic acid (356 mg), 1-hydroxy-7-azabenzotriazole (272 mg), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (382 mg) at room temperature. Diisopropylethylamine (202 mg) was added, and the resulting yellow suspension was stirred under argon for 16 h, during which a solution formed. The solution was evaporated under vacuum and the residue was redissolved in ethyl acetate (100 mL). This was washed sequentially with 1.0 M aqueous hydrochloric acid (50 mL), 1.0 M aqueous sodium hydroxide (50 mL), water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and evaporated under vacuum. The resulting solid crude product was triturated with 20% methanol in diethyl ether (20 mL four times). Drying under vacuum provided pure title compound (283 mg). HPLC/MS [M+H]+, 354.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]3[C:13](=[O:19])[CH:14]=[C:15]([OH:18])[C:16]([OH:17])=[C:9]3[C:8]2=[O:20])=[CH:4][CH:3]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[CH2:29]=O>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]3[C:13](=[O:19])[C:14]([CH2:29][N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[C:15]([OH:18])[C:16]([OH:17])=[C:9]3[C:8]2=[O:20])=[CH:21][CH:22]=1
Reactant: O=C1c2c(O)c(O)cc(=O)n2CCN1Cc1ccc(F)cc1
Reactant: C=O
Reactant: C1CCNCC1
Solvent: CCO
Product: O=C1c2c(O)c(O)c(CN3CCCCC3)c(=O)n2CCN1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (0.2 g, 0.66 mmol), piperidine (0.13 mL, 1.3 mmol), and formaldehyde (0.08 mL, 37% solution in water) in absolute ethanol (5 mL) was stirred at room temperature for 6 h. The product mixture was concentrated under vacuum, and the residue was subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound.
Reaction SMILES: [O:1]=[C:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].C(N(CC)C(C)C)(C)C.FC(F)(F)C(O[C:24]1[C:29]([F:30])=[C:28]([F:31])[C:27]([F:32])=[C:26]([F:33])[C:25]=1[F:34])=O>C(Cl)Cl>[O:1]=[C:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6]([O:8][C:24]1[C:25]([F:34])=[C:26]([F:33])[C:27]([F:32])=[C:28]([F:31])[C:29]=1[F:30])=[O:7]
Reactant: CC(=O)CCCC(=O)O
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)CCCC(=O)Oc1c(F)c(F)c(F)c(F)c1F
Reaction time: 1 h
Yield: 79.3 %

Procedure:
5-Oxohexanoic acid (2.6 g; 20 mmol) was dissolved in CH2Cl2 (50 mL). N,N-Diisopropylethylamine (10.4 mL, 60 mmol) was added followed by pentafluorophenyl trifluoroacetate (3.61 mL; 21 mmol). The reaction mixture was kept at room temperature for 1 hour and evaporated. The residue was resuspended in EtOAc:Hexanes (1:1) and loaded on a silica gel column (5×20 cm) equilibrated and developed with the same mixture. Fractions containing the product (14) (Rf˜0.7) were pooled and concentrated to give 4.7 g (79%) of yellowish oil after drying in vacuum. 1H NMR (CDCl3) δ 2.05 (m, 2H), 2.18 (s, 3H), 2.61 (t, 2H), 2.74 (t, 2H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]([CH3:46])([CH3:45])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[CH:21][C:20]=1[C:38]1[N:39]([CH3:44])[N:40]=[CH:41][C:42]=1[Cl:43].[CH:47](=O)[CH2:48][CH2:49][CH3:50].C(Cl)(=O)C>C1COCC1.CO>[CH2:47]([NH:15][C:16]([CH3:46])([CH3:45])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=2)=[CH:21][C:20]=1[C:38]1[N:39]([CH3:44])[N:40]=[CH:41][C:42]=1[Cl:43])[CH2:48][CH2:49][CH3:50]
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCC(C)(C)N
Reactant: CCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCCCNC(C)(C)COc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.9 %

Procedure:
Sodium triacetoxyborohydride (34 mg, 161 μmol) was added to a solution of N-(4-(2-amino-2-methylpropoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)phenyl)-3-(trifluoromethyl)benzamide (53.8 mg, 115 μmol) and butyraldehyde (8 mg, 115 μmol) in THF (0.5 mL), and the mixture was stirred at room temperature. After 4 hours, the reaction was quenched with saturated sodium bicarbonate and extracted with dichloromethane. The extract was evaporated to dryness, the residue was redissolved in methanol, and the products were isolated by preparative HPLC. Product containing fractions were combined and concentrated in a vacuum centrifuge to one fourth of the original volume. The solution was made alkaline with saturated sodium bicarbonate, the product was extracted with dichloromethane, and the extract was evaporated to dryness. The residue was dissolved in a solution of acetyl chloride (16 μl, 230 μmol) in methanol (1 mL) and evaporated to dryness. The residue was dissolved in water and lyophilized to give the title compound (24 mg, 37%) as the hydrochloride salt. LCMS m/z (%)=553.6 (M+H, 37Cl 34.5), 551.6 (M+H, 35Cl 100.0%). 1H NMR (400 MHz, DMSO-d6) δ 0.88 (t, J=7.33 Hz, 3H) 1.21-1.34 (m, 2H) 1.26 (s, 6H) 1.40-1.54 (m, 2H) 2.55-2.71 (m, 2H) 3.65 (s, 3H) 4.05 (d, J=10.36 Hz, 1H) 4.15 (d, J=10.36 Hz, 1H) 7.32 (d, J=9.09 Hz, 1H) 7.68 (s, 1H) 7.72 (d, J=2.78 Hz, 1H) 7.80 (t, J=7.71 Hz, 1H) 7.93-8.01 (m, 2H) 8.27 (d, J=7.83 Hz, 1H) 8.30 (s, 1H) 8.58 (s, 2H) 10.58 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@:11]2(C(N)=O)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23]C(OC)N(C)C.Cl.[CH3:31][OH:32]>C(O)C>[CH2:1]([N:8]1[CH2:12][C@:11]2([C:31]([O:23][CH3:22])=[O:32])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C@@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: NC(=O)[C@]12CN(Cc3ccccc3)C[C@H]1c1ccccc12
Reactant: COC(OC)N(C)C
Agent: Cl
Solvent: CCO
Product: COC(=O)[C@]12CN(Cc3ccccc3)C[C@H]1c1ccccc12
Reaction time: 8 h

Procedure:
8.10 g of the product obtained in Step B are dissolved in 90 ml of methanol. 11.6 ml of N,N-dimethylformamide dimethyl acetal are added and the mixture is left overnight, with stirring. A solution of hydrogen chloride in ethanol is then added, and evaporation to dryness is carried out. The residue is taken up in water and washed with ethyl acetate. The aqueous phase is rendered basic with sodium carbonate and then extracted with methylene chloride. After drying and evaporating, 8.1 g of expected product are obtained.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[CH:10][NH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[OH2:37]>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:37])[NH:11]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O
Reactant: c1ccc(-c2cccc3[nH]ccc23)cc1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: CCO
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2ccccc2)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To the suspension of 4-phenyl-1H-indole (1.1 g, 5.7 mmol) in 2-methyl-2-propanol (33 mL), ethanol (22 mL) and acetic acid (11 mL) was added pyridinium tribromide (90% purity from Aldrich, 6.1 g, 17.1 mmol) portionwise over 10 minutes. The mixture was stirred at room temperature for 2 hours, and then to the mixture was added acetic acid (50 mL). After stirring at room temperature for one hour, water (0.5 mL) and zinc (3.7 g, 57 mmol) were added to the reaction mixture and stirring was continued for another hour. The unreacted zinc dust was filtered off and washed with methanol. The filtrate was concentrated and the syrupy residue was suspended in water (100 mL) for overnight. The solid product was filtered, washed repeatedly with water to remove the zinc salt and pyridine salt. After high vacuum dry, 800 mg (67%) of 4-phenyl-1,3-dihydro-indol-2-one as a light yellow solid was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[NH:11][C:12]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[NH:11][C:12]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[S:29]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(OC)c(NC(=O)C2CCCCC2)c1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(OC)c(NC(=S)C2CCCCC2)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 81.4 %

Procedure:
1.46 g (5.54 mmol) of N-(2,5-dimethoxyphenyl)cyclohexanecarboxamide is put into solution in 40 ml of anhydrous toluene. The solution is taken to 100° C., and 3.34 g (8.26 mmol; 1.5 eq.) of Lawesson's reagent are added to the reaction medium which is then maintained under stirring at 100° C. for 4 hours. After returning to ambient temperature, the solution is poured into 50 ml of iced water and extracted using toluene. The organic phases are dried over magnesium sulphate and the solvent is evaporated off. The N-(2,5-dimethoxyphenyl)cyclohexanecarbothioamide is then purified by chromatography on a silica column (eluent: dichloromethane/heptane: 1/1 then 3/2). 1.26 g (yield=81%) of product is obtained in the form of yellow oil.
Reaction SMILES: [C:1]1([O:7][CH2:8][CH:9]=[CH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][SiH:12]([CH3:14])[Cl:13]>[Pt].[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[O:7]([CH2:8][CH2:9][CH2:10][Si:12]([CH3:14])([CH3:11])[Cl:13])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[SiH](C)Cl
Reactant: C=CCOc1ccccc1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [Pt]
Agent: [H+]
Product: C[Si](C)(Cl)CCCOc1ccccc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 74.2 %

Procedure:
4 mg of platinum in the form of hexachloroplatinic acid are added to 88.5 g (0.66 mol) of allyl phenyl ether under a nitrogen atmosphere and the mixture is heated to 80° C. 125 g of dimethylchlorosilane are metered into the mixture over a period of 2 hours, the liquid-phase temperature falling to below 50° C. The mixture is stirred for a further 6 hours under gentle reflux. Fractional distillation gives a total of 112 g of 3-phenoxypropyldimethylchlorosilane. The product has an acid number of 248 (theoretically 244).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[C:27]5[CH:28]=[CH:29][CH:30]=[C:21]([C:22]=45)[S:20]3(=[O:32])=[O:31])[CH2:14][CH:15]=2)=[CH:2]1.[H-].[Na+].[CH3:35]I>O1CCOCC1.O>[CH3:35][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[C:27]5[CH:28]=[CH:29][CH:30]=[C:21]([C:22]=45)[S:20]3(=[O:32])=[O:31])[CH2:12][CH:11]=2)=[CH:2]1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CC=C(c2c[nH]c3ccccc23)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(C2=CCN(CCCN3c4cccc5cccc(c45)S3(=O)=O)CC2)c2ccccc21
Temperature: 20 °C
Reaction time: 2 h
Yield: 29.1 %

Procedure:
A mixture of 2-{3-[4-(3-indolyl)-1,2,3,6-tetrahydro-1-pyridyl]propyl}naphtho [1,8-cd]isothiazole 1,1-dioxide (11 g) in dmethylformamide (150 cc) is added over 30 minutes to sodium hydride (1.3 g) in a 50% dispersion in vaseline oil, under a current of argon, maintaining the temperature at about 20° C. The reaction medium is stirred for 2 hours at a temperature of about 20° C. then a solution of methyl iodide (3.9 g) in dioxane (50 cc) is added over 15 minutes. Stirring is maintained for 15 hours at a temperature of about 20° C. The reaction mixture is redissolved in distilled water (250 cc) and the organic phase is extracted with dichloromethane (4×100 cc) and then washed with distilled water (400 cc), dried over anhydrous magnesium sulphate, filtered and concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue obtained is purified by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with dichloromethane as eluant, and recrystallized from boiling methyl ethyl ketone (70 cc). 2-{3-[4-(1-Methyl-3-indolyl)1,2,3,6-tetrahydro-1-pyridyl]propyl }naphtho[1,8-cd]isothiazole 1,1-dioxide (3.3 g) is obtained, m.p. 161° C.