Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH3:14])[N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:7]2=[O:23].[CH:24]1([C:27](Cl)=[O:28])[CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:8]2[C:7](=[O:23])[C:6]3[C:11](=[CH:12][CH:13]=[C:4]([CH2:3][NH:2][C:27]([CH:24]4[CH2:26][CH2:25]4)=[O:28])[CH:5]=3)[N:10]=[C:9]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: Cc1nc2ccc(CN)cc2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc2ccc(CNC(=O)C3CC3)cc2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.2 %

Procedure:
To a stirred suspension of 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.51 g, 1.5 mmol) in acetonitrile (10 mL), was added cyclopropanecarbonyl chloride (0.21 mL, 2.3 mmol) and N,N-diisopropyl ethylamine (0.62 mL, 3.8 mmol). The mixture was stirred at room temperature for one hour. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give cyclopropanecarboxylic acid [3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-amide as an off-white solid (233 mg, 42% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 5.01 min (98.4%); mp, 281-283° C.; 1HNMR (DMSO-d6) δ 0.64-0.74 (m, 4H, CH2CH2 of cyclopropane ring), 1.57-1.66 (m, 1H, CH of cyclopropane ring), 2.15-2.21 (m, 1H, CH), 2.57-2.89 (m, 6H, CHCH2, CH3), 4.39 (d, J=5 Hz, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.57-7.89 (m, 3H, Ar), 8.68 (t, J=6 Hz, 1H, CH2NH), 11.03 (s, 1H, NH); 13C NMR (DMSO-d6) δ 6.31, 13.55, 20.93, 23.40, 30.61, 41.77, 56.53, 120.01, 123.78, 126.58, 134.02, 138.34, 145.78, 154.55, 160.44, 169.47, 172.62, 172.70. LCMS MH=413; Anal Calcd For C19H20N4O4: C, 61.95; H, 5.47; N, 15.21. Found: C, 61.86; H, 5.49; N, 15.04.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH:9]=[CH:10][CH:11]=1)#[N:2].CO>CN1CCCC1=O.[C].[Pd]>[NH2:23][C:21]1[CH:20]=[CH:19][C:4]([O:5][C:6]2[CH:7]=[C:8]([NH:12][C:13](=[O:18])[C:14]([F:15])([F:16])[F:17])[CH:9]=[CH:10][CH:11]=2)=[C:3]([C:1]#[N:2])[CH:22]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Oc1cccc(NC(=O)C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Solvent: CN1CCCC1=O
Product: N#Cc1cc(N)ccc1Oc1cccc(NC(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.4 %

Procedure:
To a solution of N-[3-(2-cyano-4-nitrophenoxy)phenyl]-2,2,2-trifluoroacetamide (2.81 g, 8.01 mmol) in 1-methylpyrrolidin-2-one (20 mL)/methanol (80 ml) was added 10% palladium-carbon (300 mg), and the mixture was stirred at room temperature for 6 hr under a hydrogen atmosphere (1 atm). Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (200 ml), washed successively with water (100 mL×2) and saturated brine (100 mL×2), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=50/50→80/20), and the fraction containing the object product was concentrated under reduced pressure to give the title compound (2.48 g, 97%) as a pale-yellow oil.
Reaction SMILES: [CH2:1]([N:4]([CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C@@H:18]2[C@@H:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:21][N:20]([C@@H:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]3[CH2:35][C:36]([O:38]CC3C=CC=CC=3)=[O:37])[CH2:19]2)[CH2:13][CH2:12]1)[C:5]1[N:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[CH2:2][CH3:3].[H][H]>CO.[Pd]>[CH2:1]([N:4]([CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C@@H:18]2[C@@H:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:21][N:20]([C@@H:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]3[CH2:35][C:36]([OH:38])=[O:37])[CH2:19]2)[CH2:13][CH2:12]1)[C:5]1[N:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[CH2:2][CH3:3]
Reactant: CCCN(c1ncccn1)C1CCN(C[C@H]2CN([C@@H]3CCCCC3CC(=O)OCc3ccccc3)C[C@@H]2c2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCN(c1ncccn1)C1CCN(C[C@H]2CN([C@@H]3CCCCC3CC(=O)O)C[C@@H]2c2ccccc2)CC1
Yield: 40.1 %

Procedure:
A solution of 2-(R)-(3-(S)-((4-(N-(prop-1-yl)-N-(pyrimid-2-yl)amino)-piperidin-1-yl)methyl)-4-(S)-phenylpyrrolidin-1-yl)-cyclohexylacetic acid, benzyl ester (0.026 ml, 0.24 mmol) from Step A), in 3.0 mL of MeOH was hydrogenated using 10% palladium on carbon (28 mg, 0.026 mmol) under one atmosphere of hydrogen gas. After TLC indicated the absence of the starting benzylester, the reaction was filtered through a 0.45 micron nylon membrane polypropylene filter and concentrated under reduced pressure to give 50 mg (74%) of the title compound as a white solid. HPLC (Zorbax SB-C8 column, 4.6 mm×7.5 cm, Gradient: 90 H2O:10 CH3CN to 0 H2O:100 CH3CN over 7.5 minutes then hold at 100 CH3CN:0 H2O for 45 seconds, 2.25 mL/min, 220 nm): Retention Time: 3.28 minutes. ESI-MS: 520 (M+1).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].I[C:16]1[N:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]([CH3:21])=[CH:19][N:20]=1>>[CH3:8][C:7]1[O:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[C:1]#[C:2][C:16]1[N:17]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:18]([CH3:21])=[CH:19][N:20]=1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Reactant: Cc1cnc(I)n1-c1ccccc1
Product: Cc1onc(-c2ccccc2)c1C#Cc1ncc(C)n1-c1ccccc1
Yield: 21 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted [using 2-iodo-5-methyl-1-phenyl-1H-imidazole (prepared from 5-methyl-1-phenyl-1H-imidazole by reaction of 4(5)-methyl-1-phenyl-1H-imidazole with N-iodosuccinimide in N,N-dimethylformamide at ambient temperature) instead of 2-chloro-4-iodopyridine] to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 35 mg, 21%) which was obtained as a brown solid. MS: m/e=340.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([S:19](Cl)(=[O:21])=[O:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[NH2:24][C:25]1[CH:29]=[C:28]([Cl:30])[S:27][C:26]=1[Cl:31]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([S:19]([NH:24][C:25]3[CH:29]=[C:28]([Cl:30])[S:27][C:26]=3[Cl:31])(=[O:21])=[O:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: Nc1cc(Cl)sc1Cl
Reactant: O=S(=O)(Cl)c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)sc1Cl)c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Yield: 15 %

Procedure:
3.0 g of 3-chloro-2-(4-chloro-3-chlorosulfonylphenyl)-5-trifluoromethylpyridine and 1.7 g of 3-amino-2,5-dichlorothiophene hydrochloride in a mixture of 100 ml of toluene and 100 ml of pyridine were refluxed for 6 hours. The residue after concentration was dissolved in 100 ml of ethyl acetate. The solution was extracted with 50 ml of dilute hydrochloric acid and 50 ml of water, dried over sodium sulfate and concentrated. Chromatography on silica gel with methylene chloride resulted in 0.6 g of colorless crystals. Yield: 15%, melting point: 106°-108° C.
Reaction SMILES: [SH:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4][OH:5].N1C=CC=CC=1[CH2:19][CH2:20][CH:21]1[CH2:26][C:25](=O)[CH2:24][CH2:23][NH:22]1>C(Cl)(Cl)Cl>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]2[S:1][C:25]3([CH2:24][CH2:23][N:22]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[CH2:21][CH2:26]3)[O:5][CH2:4][C:3]=2[CH:6]=1)([O-:12])=[O:11]
Reactant: O=C1CCNC(CCc2ccccn2)C1
Reactant: O=[N+]([O-])c1ccc(S)c(CO)c1
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc2c(c1)COC1(CCN(CCc3ccccn3)CC1)S2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-Mercapto-5-nitrobenzyl alcohol (150 mg, 0.81 mmol) and 208 mg (0.80 mm) of N-[2-(2'-pyridylethyl]-4-piperidone was dissolved in 5 mL of CHCl3. HCl Gas was bubbled in to saturate the solution, the mixture stirred at 25° C. for 2 days, then diluted with water and the pH adjusted to 10.0 with 40% aqueous NaOH. Extraction with CHCl3 and drying the organic phase (Na2SO4) gave after concentration and recrystallization from ethyl acetate 75 mg of an orange solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].C(N(C(C)C)C(C)C)C.[CH3:21][O:22][CH2:23]Cl>ClCCl>[CH3:21][O:22][CH2:23][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11]
Reactant: O=C1CCc2c(O)cccc21
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1cccc2c1CCC2=O
Reaction time: 8 h

Procedure:
To a solution of 4.12 g of 4-hydroxy-1-indanone and 7.3 ml of N-ethyldiisopropylamine in 30 m of dichloromethane, 2.3 ml of chloromethyl methyl ether was added dropwise while stirring under ice cooling. An ice bath was removed and the mixture was continuously stirred overnight. The reaction solution was diluted with diethyl ether, washed with water, an aqueous 10% citric acid solution and an aqueous 5% sodium hydroxide solution, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 4.23 g of the desired compound as a pale orange crystal having a melting point of 51 to 54° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([NH:9][CH2:10][CH2:11][N:12]1[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[C:21]([O:23]C)=[O:22])[CH:14]=[CH:13]1)[CH2:2]2.O.O.[OH-].[Li+:28]>C1COCC1>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([NH:9][CH2:10][CH2:11][N:12]1[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[C:21]([O-:23])=[O:22])[CH:14]=[CH:13]1)[CH2:2]2.[Li+:28]
Reactant: COC(=O)c1cccc2ccn(CCN[C@@H]3CN4CCC3CC4)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])c1cccc2ccn(CCN[C@@H]3CN4CCC3CC4)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (S)-methyl 1-(2-(quinuclidin-3-ylamino)ethyl)-1H-indole-7-carboxylate (1.4 g, 4.3 mmol) from Step C above in THF (20 ml) and water (20 ml) was added lithium hydroxide monohydrate (535 mg, 12.8 mmol). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was dried overnight under vacuum to afford crude lithium (S)-1-(2-(quinuclidin-3-ylamino)ethyl)-1H-indole-7-carboxylate which was used in the next step without further purification: MS (ESI+) m/z 314 (M+H).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[C:4]1[CH:12]=[O:13].Br[CH2:15][CH:16]1[CH2:18][CH2:17]1>CN(C)C=O.C(Cl)Cl>[CH:16]1([CH2:15][N:3]2[C:7]3=[N:8][CH:9]=[CH:10][CH:11]=[C:6]3[CH:5]=[C:4]2[CH:12]=[O:13])[CH2:18][CH2:17]1
Reactant: BrCC1CC1
Reactant: O=Cc1cc2cccnc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=Cc1cc2cccnc2n1CC1CC1
Temperature: 0 °C
Reaction time: 21 h
Yield: 73.3 %

Procedure:
A solution of sodium hydride (60.2 mg, 1.51 mmol) in N,N-dimethylformamide (20 mL) was stirred at 0° C. for 10 min. 1H-Pyrrolo[2,3-b]pyridine-2-carbaldehyde (200 mg, 1.37 mmol) was added and the mixture was stirred at 0° C. for 30 min and at it for 30 min. (Bromomethyl)cyclopropane (0.16 mL, 1.64 mmol available, for example, from Alfa Aesar) was added and the resulting mixture was stirred at 0° C. for 30 min and at it for 21 h. Reaction mixture was quenched by the addition of water (50 mL). After addition of Et2O (50 mL), the layers were separated. The aqueous layer was further extracted with Et2O (2×50 mL) and the combined organic layers were washed with H2O (2×35 mL). The organic phase was dried through a hydrophobic frit and concentrated under reduced pressure to give a brown oil which was loaded in DCM on a 50 g SNAP silica cartridge and purified by SP4, eluting with a gradient of 0-20% ethyl acetate/cyclohexane (15CV). The appropriate fractions were combined and evaporated under reduced pressure to give the required product 1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (201 mg, 73.4%) as a colourless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)[N:4]=1.C([O:16][C:17](=[O:28])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([Cl:27])[CH:21]=1)C>>[Cl:27][C:22]1[CH:21]=[C:20]([CH2:19][CH2:18][C:17]([OH:28])=[O:16])[CH:25]=[CH:24][C:23]=1[O:26][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)[N:4]=1
Reactant: CCOC(=O)CCc1ccc(O)c(Cl)c1
Reactant: ClCc1cccc(SC2CCC2)n1
Product: O=C(O)CCc1ccc(OCc2cccc(SC3CCC3)n2)c(Cl)c1
Yield: 54.5 %

Procedure:
2-Chloromethyl-6-cyclobutylsulfanyl-pyridine (34 mg, 0.17 mmol) obtained in Step C of Preparation Example 37 and 3-(3-chloro-4-hydroxy-phenyl)-propionic acid ethyl ester (43 mg, 0.19 mmol) obtained in Step C of Preparation Example 42 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (35 mg, 63%).
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[C:11](=[O:12])[CH2:10][CH2:9][NH:8][C:7]2[N:13]=[CH:14][CH:15]=[CH:16][C:6]=2[CH2:5]1.C(OCC)C>C(O)(=O)C>[Br:1][C:15]1[CH:14]=[N:13][C:7]2[NH:8][CH2:9][CH2:10][C:11](=[O:12])[N:4]([CH3:3])[CH2:5][C:6]=2[CH:16]=1
Reactant: CN1Cc2cccnc2NCCC1=O
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CCOCC
Product: CN1Cc2cc(Br)cnc2NCCC1=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Bromine (189 μL, 3.7 mmol) was added to a solution of 5-methyl-2,3,5,6-tetrahydropyrido[2,3-b][1,5]diazocin-4(1H)-one (460 mg, 2.4 mmol) in 10 mL of acetic acid and stirred at room temperature for 17 h. Add 30 mL of diethyl ether and collect orange solid product via suction filtration. Redissolve the solid in DCM and wash with NaHCO3, dry the organic layer over MgSO4, and concentrate in vacuo to obtain orange solid product. Yield 670 mg (quant); 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=2.0 Hz, 1H), 7.50 (d, J=2.4 Hz, 1H), 5.17 (bs, 1H), 4.49 (s, 2H), 3.59 (bm, 2H), 3.04 (t, J=6.8 Hz, 2H), 2.85 (s, 3H); ESI MS m/z 270, 272 [C10H12N3OBr+H]+
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:10]([SH:13])[CH:11]=[CH2:12].[OH-].[K+]>C(O)C>[CH2:6]([O:5][C:3](=[O:4])[C:2]([S:13][CH2:10][CH:11]=[CH2:12])([CH3:9])[CH3:8])[CH3:7]
Reactant: C=CCS
Reactant: CCOC(=O)C(C)(C)Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=CCSC(C)(C)C(=O)OCC
Yield: 35 %

Procedure:
Ethyl 2-bromoisobutyrate (40.0 g, 0.205 mole), allyl mercaptan (16.8 g, 0.0226 mole), potassium hydroxide (14.4 g, 0.226 mole), ethyl alcohol (100 g) were combined and reaction mixture was refluxed for six hours prior to quenching. Crude yield: 79.3%; Distilled yield: 35.0%.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7]([NH2:9])=[O:8])=[CH:3][CH:2]=1.[Cl:11][C:12]([Cl:17])([Cl:16])[CH:13](O)[OH:14]>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:10][C:1]1[CH:6]=[CH:5][C:4]([C:7]([NH:9][CH:13]([OH:14])[C:12]([Cl:17])([Cl:16])[Cl:11])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(C(N)=O)cc1
Reactant: OC(O)C(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: Cc1ccc(C(=O)NC(O)C(Cl)(Cl)Cl)cc1
Reaction time: 12 h
Yield: 87.9 %

Procedure:
A mixture of p-toluamide (11.0 g, 81.3 mmol) and 2,2,2-trichloro-1,1-ethanediol (16.6 g, 100 mmol) in benzene (175 mL) was stirred at reflux in a Soxhlet extraction device charged with molecular sieves (20 g). After 12 hours, the extraction thimble of molecular sieves was replaced with a fresh portion of molecular sieves (20 g), and the reaction was allowed to heat at reflux for an additional 12 hours. Concentration in vacuo provided a heavy syrup which was dissolved in ethyl acetate (15 mL) and diluted with hexanes (175 mL). Refrigeration at 8° C. facilitated precipitation of a white solid that was collected by filtration and washed with hexanes to provide 20.2 g of the desired product.
Reaction SMILES: [NH3:1].CC(O)C.Cl[C:7]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)([C:28]1[N:32]([CH3:33])[CH:31]=[N:30][CH:29]=1)[C:8]1[CH:9]=[CH:10][C:11]2[N:17]([CH3:18])[C:16](=[O:19])[CH2:15][S:14][CH:13]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:12]=2[CH:27]=1>C1COCC1>[NH2:1][C:7]([C:34]1[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=1)([C:28]1[N:32]([CH3:33])[CH:31]=[N:30][CH:29]=1)[C:8]1[CH:9]=[CH:10][C:11]2[N:17]([CH3:18])[C:16](=[O:19])[CH2:15][S:14][CH:13]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:12]=2[CH:27]=1
Reactant: N
Reactant: CN1C(=O)CSC(c2cccc(Cl)c2)c2cc(C(Cl)(c3ccc(Cl)cc3)c3cncn3C)ccc21
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CN1C(=O)CSC(c2cccc(Cl)c2)c2cc(C(N)(c3ccc(Cl)cc3)c3cncn3C)ccc21
Temperature: 5 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
NH3/2-propanol (10 ml) was added dropwise at 5° C. under N2 flow to a mixture of 7-[chloro(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-5-(3-chlorophenyl)-1,5-dihydro-1-methyl-4,1-benzothiazepin-2(3H)-one (described in Example B11a) (0.00247 mol) in THF (15 ml). The mixture was stirred at 5° C. for 1 hour and at room temperature for 2 hours, then poured out into ice water and extracted with CH2Cl2. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue (1.2 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.5; 15–40 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.35 g, 27%). was crystallized from acetonitrile and diethyl ether. The precipitate was filtered off and dried in vacuo, yielding 0.28 g (22%) of 7-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-5-(3-chlorophenyl)-1,5-dihydro-1-methyl-4,1-benzothiazepin-2(3H)-one, mp. 218° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12](COCC[Si](C)(C)C)[C:13]([C:18]([OH:21])([CH3:20])[CH3:19])=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=2)[CH:3]=1.[F-].CCOC(C)=O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][C:13]([C:18]([OH:21])([CH3:20])[CH3:19])=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=2)[CH:3]=1
Reactant: CC(C)(O)c1c(C#N)nc(C(=O)Nc2ccc(Br)cc2C2=CCCCC2)n1COCC[Si](C)(C)C
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(O)c1[nH]c(C(=O)Nc2ccc(Br)cc2C2=CCCCC2)nc1C#N
Temperature: 50 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
A solution of 4-cyano-5-(1-hydroxy-1-methyl-ethyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (4-bromo-2-cyclohex-1-enyl-phenyl)-amide (as prepared in the previous step, 40.0 mg, 0.0715 mmol) and tetrabutylammomium fluoride (357 μL, 0.357 mmol, 1.0 M in THF) in 2.0 mL of THF was stirred under Ar at 50° C. for 16 h and at reflux for 3 h. After cooling to RT, the mixture was treated with EtOAc (40 mL) and washed with saturated NH4Cl aqueous solution (5 mL), brine (10 mL) and dried (Na2SO4). The organic layer was concentrated in vacuo and residue was purified by flash chromatography on silica gel (5-10% EtOAc/DCM) to give 26 mg (84%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 11.79 (s, 1H), 9.55 (s, 1H), 8.23 (d, 1H, J=8.6 Hz), 7.42 (dd, 1H, J=8.6, 2.3 Hz), 7.33 (d, 1H, J=2.3 Hz), 5.87 (m, 1H), 5.08 (s, 1H), 2.16-2.34 (m, 4H), 1.83 (s, 6H), 1.71-1.88 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C20H21BrN4O2, 429.1 (M+H), found 428.9.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[CH:7][C:6]=1[C:21]1[N:22]([CH3:26])[N:23]=[CH:24][CH:25]=1.Cl.[F:28][C:29]1([F:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:28][C:29]1([F:35])[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[CH:7][C:6]=2[C:21]2[N:22]([CH3:26])[N:23]=[CH:24][CH:25]=2)[CH2:31][CH2:30]1
Reactant: Cn1nccc1-c1cc(NC(=O)c2cccc(F)c2)ccc1OCCBr
Reactant: FC1(F)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1nccc1-c1cc(NC(=O)c2cccc(F)c2)ccc1OCCN1CCC(F)(F)CC1
Temperature: 120 °C
Yield: 17.4 %

Procedure:
A mixture of N-[4-(2-bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-benzamide (104 mg, 0.25 mmol), 4,4-difluoropiperidine hydrochloride (43 mg, 0.275 mmol) and potassium carbonate (103 mg, 0.75 mmol) in DMF (2 mL) was heated in microwave at 120° C. for 20 min. The crude was purified by HPLC to give the title compound (20 mg, 18%) as a white solid as TFA salt. 1H NMR (DMSO-d6, 400 MHz) δ 2.10-2.23 (m, 4H), 3.10-3.40 (m, 4H), 3.57 (t, 2H), 3.68 (s, 3H), 4.37 (t, 2H), 6.30 (d, 1H), 7.25 (d, 1H), 7.45 (dt, 1H), 7.50 (d, 1H), 7.57-7.62 (m, 1H), 7.72 (d, 1H), 7.74-7.82 (m, 2H), 7.89 (dd, 1H), 10.3 (s, 1H). Exact mass calculated for C24H25F3N4O2 458.2. found 459.4 (MH+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH2:6][NH2:7].[N-:12]([C:15]#[N:16])[C:13]#[N:14].[Na+]>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH2:6][NH:7][C:15]([NH:12][C:13]#[N:14])=[NH:16]
Reactant: N#C[N-]C#N
Reactant: NCc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: N#CNC(=N)NCc1ccc(Cl)c(Cl)c1
Yield: 79.2 %

Procedure:
Putting 63.7 g (300 mM) of 3,4-dichlorobenzylamine hydrochloride and 30.9 g (1.1 eq.) of sodium dicyanamide in 950 ml (15 V) of acetonitrile, the mixture was heated and refluxed for 3.5 hours. Distilling away the solvent, 600 ml of water was added to the residue (white solid) to disperse and wash. Obtained crystals were filtered off, and dispersed and washed in 600 ml of dichloromethane. Since residue of amine was recognized, the crystals were dispersed and washed again in 600 ml of water and 500 ml of dichloromethane. Crystals were filtered off, and dried overnight at 60° C., and 57.7 g (78.9%) of the captioned compound was obtained.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][N:13]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:14](=[O:25])[CH2:15][CH2:16][N:17]=[CH:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>CO.[Pd]>[C:1]12([CH2:11][CH2:12][N:13]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:14](=[O:25])[CH2:15][CH2:16][NH:17][CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)CCN=Cc1ccncc1
Agent: [Pd]
Solvent: CO
Product: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)CCNCc1ccncc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 36 %

Procedure:
3-(4-Pyridylmethylideneamino)propionic acid N-[2-(1-adamantyl)ethyl]-N-pentylamide (Compound No. 21-1, 1.6 g, 3.9 mmol) was dissolved in methanol, 10% palladium on carbon (catalytic amount) was added to the solution, and the mixture was stirred at room temperature under hydrogen at 1 atm for seven hours. The 10% palladium on carbon was filtered out, the filtrate was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography to give the target compound (0.58 g, 36%) as an oily matter.