Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[NH:24][N:23]=4)[N:20]=3)[N:15]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].[H-].[Na+].Br[CH2:44][CH2:45][O:46][CH3:47]>CN(C=O)C>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH2:44][CH2:45][O:46][CH3:47])[N:23]=4)[N:20]=3)[N:15]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCn1nc(-c2cnc3c(n2)c(C(=O)N[C@H](C)C(=O)N2CC(C#N)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
In a round-bottomed flask, 2-(6-chloro-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (90 mg, 0.155 mmol) was dissolved in DMF (1 ml). The reaction mixture was cooled to 0° C. and sodium hydride (60% dispersion in mineral oil, 8 mg, 0.20 mmol) was added. The reaction mixture was stirred at 0° C. for 30 min then 1-bromo-2-methoxyethane (22 μl, 0.23 mmol) was added. The reaction mixture was stirred at 0° C. for 3 h and then at room temperature overnight. The reaction mixture was quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-3% MeOH) to afford 51 mg (52%) of 2-[6-chloro-1-(2-methoxy-ethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a yellow foam.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:26]3[CH2:31][CH2:30][C@@H:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[CH2:28][CH2:27]3)[N:9]=[C:10]([C:11]3[CH:25]=[CH:24][C:14]([O:15][C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=4)=[CH:13][CH:12]=3)[C:3]=12>CO.[OH-].[NH4+].O.[Ni]>[NH2:21][CH2:20][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:14]2[CH:24]=[CH:25][C:11]([C:10]3[C:3]4[C:4](=[N:5][CH:6]=[N:7][C:2]=4[NH2:1])[N:8]([C@H:26]4[CH2:31][CH2:30][C@@H:29]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)[CH2:28][CH2:27]4)[N:9]=3)=[CH:12][CH:13]=2)=[CH:23][CH:22]=1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccc(C#N)cc5)cc4)c4c(N)ncnc43)CC2)CC1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccc(CN)cc5)cc4)c4c(N)ncnc43)CC2)CC1
Reaction time: 18 h
Yield: 745.8 %

Procedure:
Cis-4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzonitrile (0.600 g, 0.00118 mol) was dissolved in a mixture of methanol (50 mL) and concentrated solution of ammonium hydroxide in water (3 mL), 50% slurry of Raney nickel in water (2 mL) was added and the resulting mixture was hydrogenated at atmospheric pressure for 18 hours. The reaction mixture was filtered through a Celite pad, concentrated under reduced pressure and the residue digested with dichloromethane (50 mL). The organic phase was dried with magnesium sulfate, concentrated under reduced pressure and the residue suspended in diethyl ether (25 mL). The precipitate was collected by filtration and dried to yield cis-3-{4-[4-(aminomethyl)phenoxy]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.45 g, 0.0088 mol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:16]#[N:17])=[CH:11][CH:10]=3)[CH:2]=1.[H-].[Na+].[CH3:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([CH3:30])[CH:29]=1)[C:24](Cl)=[O:25]>C1COCC1>[CH3:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([CH3:30])[CH:29]=1)[C:24]([N:8]1[C:9]2[C:14](=[CH:13][C:12]([C:16]#[N:17])=[CH:11][CH:10]=2)[CH:15]=[C:7]1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:25]
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Reactant: N#Cc1ccc2[nH]c(-c3cccnc3)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(C(=O)n2c(-c3cccnc3)cc3cc(C#N)ccc32)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-pyridin-3-yl-1H-indole-5-carbonitrile (Example 8, 200 mg, 0.913 mmol) at 0° C. in THF (6 mL) is added 60% sodium hydride (72 mg, 1.826 mmol) and the mixture is stirred for 10 min at 0° C. The reaction mixture is then warmed to room temperature and stirred for 30 min. 3,5-Dimethyl-benzoyl chloride (460 mg, 2.740 mmol) in THF (2 mL) is added dropwise at 0° C. and the reaction is stirred at room temperature for 1 h. The reaction is quenched by adding saturated sodium bicarbonate. The THF is removed under vacuum, and the resulting residue is purified by silica gel flash chromatography (ethyl acetate-heptane, 0:1 to 1:1). The resulting product is further purified by HPLC using an X-bridge RP18 and an acetonitrile-0.1% ammonia hydroxide gradient to yield 1-(3,5-dimethyl-benzoyl)-2-pyridine-3-yl-1H-indole-5-carbonitrile. 1H NMR (400 MHz, CDCl3) δ ppm 2.25 (s, 6H), 6.88 (s, 1H), 7.10 (s, 1H), 7.14 (dd, J=7.6, 5.3 Hz, 1H), 7.22 (s, 2H), 7.50-7.56 (m, 2H), 7.70 (d, J=8.8 Hz, 1H), 8.01 (s, 1H), 8.43 (dd, J=4.8, 1.5 Hz, 1H), 8.62 (s, 1H). HRMS (ESI) m/z 352.1452 [(M+H)+: Calcd for C23H18N3O: 352.1450].
Reaction SMILES: [CH3:1][O:2][C:3](Cl)=[O:4].C(N(CC)CC)C.[C:13]([NH:17][C:18](=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=1)([CH3:16])([CH3:15])[CH3:14]>CC(C)=O>[C:13]([NH:17][C:18](=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:3]([O:2][CH3:1])=[O:4])[CH:21]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)NC(=O)Cc1cccc(N)c1
Reactant: COC(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)Nc1cccc(CC(=O)NC(C)(C)C)c1
Temperature: 17.5 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
10.45 g (0.1 mol) of chloroformic acid methyl ester, followed by 10.1 g (0.1 mol) of triethylamine, were added dropwise to a solution of 20.6 g (0.1 mol) of 3-amino-phenylacetic acid tert.-butylamide in 200 ml of acetone whilst cooling at 15 to 20° C. The mixture was stirred for a further 2 hours at room temperature, the triethylamine hydrochloride which had precipitated was filtered off and the filtrate was concentrated by evaporation under reduced pressure. The residue which hereupon remained was stirred with very dilute hydrochloric acid, filtered off, dried and recrystallized from a little carbon tetrachloride. 22 g (83.5% of theory) of 3-methoxycarbonylamino-phenylacetic acid tert.-butylamide of melting point 123°-124° C were obtained.
Reaction SMILES: [C:1]([C:3]1([CH3:6])[CH2:5][CH2:4]1)#[CH:2].Cl/[C:8](=[N:14]\[OH:15])/[C:9]([O:11][CH2:12][CH3:13])=[O:10].C(N(CC)CC)C>C(OCC)C>[CH2:12]([O:11][C:9]([C:8]1[CH:2]=[C:1]([C:3]2([CH3:6])[CH2:5][CH2:4]2)[O:15][N:14]=1)=[O:10])[CH3:13]
Reactant: CCOC(=O)/C(Cl)=N/O
Reactant: C#CC1(C)CC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)c1cc(C2(C)CC2)on1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.1 %

Procedure:
To a mixture of 1-ethynyl-1-methylcyclopropane (Preparation 4B, 5.0 g, 62.4 mmol) and (Z)-ethyl 2-chloro-2-(hydroxyimino)acetate (4.73 g, 31.2 mmol) in diethyl ether (80 mL) was added a solution of triethylamine (8.67 mL, 62.4 mmol) in diethyl ether (20 mL) dropwise over 75 min. After complete addition, the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography using a 10% mixture of ethyl acetate in hexane to give ethyl-5-(1-methylcyclopropyl)isoxazole-3-carboxylate (3.54 g, 65% yield) as a yellow liquid. The product had an HPLC ret. time=2.23 min.-(condition B); LC/MS M+1=196.07. 1H NMR (400 MHz, CDCl3) δ ppm 0.79 (m, 2H), 1.13 (m, 2H), 1.26 (t, J=7.15 Hz, 3H), 1.35 (s, 3H), 4.31 (q, J=7.12 Hz, 2H), and 6.23 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[N:11]=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.N.[CH3:22][N:23](C=O)[CH3:24]>>[CH3:22][N:23]([CH3:24])[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[N:11]=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CN(C)C=O
Reactant: Cc1cccc(-n2nc(C)cc2-c2ccnc(Cl)c2)c1
Agent: N
Product: Cc1cccc(-n2nc(C)cc2-c2ccnc(N(C)C)c2)c1
Temperature: 180 °C
Reaction time: 72 h
Yield: 78 %

Procedure:
A mixture of 2-chloro-4-[1-(3-methylphenyl)-3-methyl-1H-pyrazol-5-yl]pyridine (Example 45; 0.91 g, 0.0032 mol) and 50 mL of liquid ammonia in 20 mL of DMF was stirred in a sealed tube under 1800 psi, at 180° C. for 72 hours. After the solution was cooled, the solvent was removed under vacuum and the residue was purified by chromatography on silica gel (ethyl acetate/hexane, 2:8) to give 0.73 g (78% yield) of product as a yellow crystal: mp: 84-85° C.; Anal. Calc'd. for C18H20N4: C, 73.94; H, 6.89; N. 19.16. Found: C, 73.68; H, 6.74; N, 19.13.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([Br:12])=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:13][C:14](N)=[O:15]>>[Br:12][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][C:9]=1[Cl:11])[NH:1][C:14](=[O:15])[NH:13][C:4]2=[O:5]
Reactant: NC(N)=O
Reactant: Nc1cc(Cl)c(Br)cc1C(=O)O
Product: O=c1[nH]c(=O)c2cc(Br)c(Cl)cc2[nH]1

Procedure:
Prepared according to general method C from 2-amino-5-bromo-4-chlorobenzoic acid (987 mg) and urea (2.36 g). Yield: 1.00 g (92%) of a solid. 1H-NMR (DMSO-δ6) δ (ppm) 8.01 (s, 1H), 7.36 (s, 1H).
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[NH:35]1[CH:39]=[C:38]([CH2:40][C:41](O)=[O:42])[N:37]=[CH:36]1>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:41](=[O:42])[CH2:40][C:38]2[N:37]=[CH:36][NH:35][CH:39]=2)[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Fc1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Reactant: O=C(O)Cc1c[nH]cn1
Agent: Cl
Product: O=C(Cc1c[nH]cn1)N1CC[C@H](OCc2cc(F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (28.8 mg) obtained in Example 26 and 4-imidazoleacetic acid hydrochloride (19.5 mg) were reacted and treated in the same manner as in the method described in Example 32 to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[NH:4][CH3:5].Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)=[CH:17][CH:16]=1)=[O:13]>>[F:29][C:28]([F:31])([F:30])[C:25]1[CH:26]=[CH:27][C:22]([O:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][C:12](=[O:13])[N:4]([C:3]3[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=3[F:1])[CH3:5])=[CH:16][CH:17]=2)=[N:23][CH:24]=1
Reactant: CNc1ccc(F)cc1F
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Product: CN(C(=O)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)c1ccc(F)cc1F

Procedure:
The title product was prepared from 2,4-difluoro-N-methylaniline and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, preparative HPLC (method C) (37%, white crystals). HPLC-MS m/z=425.1 (M+1), Rt: 4.90 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[F:17][C:18]([F:28])([F:27])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>C(#N)C>[F:17][C:18]([F:27])([F:28])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:1][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=2)[C:5]([NH2:7])=[O:6])=[CH:21][CH:20]=1
Reactant: NC(=O)c1cccc(O)c1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1cccc(OCc2ccc(C(F)(F)F)cc2)c1

Procedure:
3-hydroxybenzamide (0.137 g; 1 mmol) was dissolved in anhydrous acetonitrile (20 ml) under a nitrogen atmosphere. To this was added potassium carbonate (0.138 g; 1 mmol) and 4-(trifluoromethyl)benzyl bromide (0.155 ml; 1 mmol). This mixture was left to reflux for 17 hours.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[F:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=1[NH:21][C:22](=[O:34])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1[O:20][C:17]1[CH:18]=[CH:19][C:14]([F:13])=[C:15]([NH:21][C:22](=[O:34])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=2)[CH:16]=1)#[N:2]
Reactant: O=C(Cc1cccc(C(F)(F)F)c1)Nc1cc(O)ccc1F
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cc([N+](=O)[O-])ccc1Oc1ccc(F)c(NC(=O)Cc2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.2 %

Procedure:
To a solution of 3-cyano-4-fluoronitrobenzene (0.530 g, 3.19 mmol) and N-(2-fluoro-5-hydroxyphenyl)-2-[3-(trifluoromethyl)phenyl]acetamide (1.00 g, 3.19 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (0.530 g, 3.83 mmol), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed successively with water (100 mL) and saturated brine (100 mL), and dried over anhydrous magnesium sulfate. Insoluble material was filtered off. The obtained organic layer was purified by basic silica gel column chromatography (eluate: 50% ethyl acetate/n-hexane), and the obtained solution was concentrated under reduced pressure to give the title compound (1.38 g, 94%) as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([F:9])[C:6]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:5]([F:15])[CH:4]=1)#[N:2].[ClH:16]>CO.O1CCCC1.[C].[Pd]>[ClH:16].[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([F:15])[C:6]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:7]([F:9])[CH:8]=1
Reactant: CS(=O)(=O)Nc1c(F)cc(C#N)cc1F
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1c(F)cc(CN)cc1F
Yield: 80 %

Procedure:
A mixture of N-(4-cyano-2,6-difluorophenyl)methanesulfonamide (1.01 g, 4.35 mmol) in methanol (15 ml), tetrahydrofuran (15 ml) and 12 M aqueous solution of hydrogen chloride (5 ml) was hydrogenated over 10% palladium-carbon (250 mg) under ballon pressure for 3 h at ambient temperature. The catalyst was filtered through a pad of celite and the filter cake was washed with methanol. After the filtrate and washings were evaporated in vacuo, the residue was recrystallized from methanol and diisopropyl ether to give to furnish 953 mg (80% yield) of the title compound as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([O:20][CH2:21][C:22]([OH:24])=O)[S:18][CH:19]=2)=[CH:11][CH:10]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:22](=[O:24])[CH2:21][O:20][C:17]2[S:18][CH:19]=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([F:8])=[CH:14][CH:13]=3)[N:16]=2)[CH2:27][CH2:26]1
Reactant: NC1CC1
Reactant: O=C(O)COc1nc(-c2ccc(F)cc2)cs1
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1nc(-c2ccc(F)cc2)cs1)NC1CC1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.27 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-yloxy]-acetic acid trifluoroacetic acid salt and 31.1 mg (0.54 mmol) of cyclopropylamine. Yield: 21.5 mg.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.C([Mg]Br)C.O1CCCC1.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C>C(OCC)C>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([B:18]([OH:23])[OH:19])[CH:7]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1ccnc(Br)c1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccnc(B(O)O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2-bromo-4-methylpyridine (0.5 g, 2.9 mmol) in diethyl ether (5 mL) was added a 1M solution of ethylmagnesium bromide in tetrahydrofuran (3.48 mL, 3.48 mmol) slowly at 0° C. over 10 minutes under a nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature and stirred for 3 hours. To the above mixture was added tri-isopropyl borate (0.65 g, ˜0.8 mL, 3.48 mmol) dropwise at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for another 1 hour. The reaction was quenched with saturated aqueous ammonium chloride solution (6 mL) at 0° C. and then extracted with diethyl ether (50 mL×4). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-methylpyridine-2-boronic acid, which was used without further purification.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][C:7]=2[CH:8]=O)[CH2:3][CH2:2]1.[C:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)(=[O:23])[CH3:22]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][C:7]=2/[CH:8]=[CH:22]/[C:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)=[O:23])[CH2:3][CH2:2]1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1cc(OCC2CC2)c(C=O)cc1-c1cccs1
Product: COc1cc(OCC2CC2)c(/C=C/C(=O)c2ccc(C(=O)O)cc2)cc1-c1cccs1

Procedure:
The title compound was prepared by condensing 2-cyclopropylmethoxy-4-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-32B) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 187–191° C. 1H-NMR (DMSO-d6) δ 8.22 (d, 2H), 8.19 (s, 1H), 7.01 (m, 4H), 7.62 (d, 1H), 7.47 (d, 1H), 7.09 (t, 1H), 6.76 (s, 1H), 4.06 (d, 2H), 3.94 (s, 3H), 1.34 (m, 1H), 0.62 (q, 2H), 0.38 (q, 2H). MS m/z=434 ([M]+, 82%), 363 (100%). 10%. Anal. for C25H22O5S. HRMS m/z: calc. 435.1266, found 435.1266.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)#[N:2]>[Ni].CO>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: [Ni]
Solvent: CO
Product: NCc1ccc(C(=O)O)cc1
Reaction time: 16 h
Yield: 83.7 %

Procedure:
A mixture of 4-cyano benzoic acid (500 g, 3.4 mol) and Raney Nickel (100 g) in methanol (5 L) was hydrogenated at a pressure of 10 kg for 16 h. The catalyst was removed by filtration, followed by the removal of the solvent under reduced pressure to afford 4-(aminomethyl)benzoic acid (430 g, 84%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([O:14][CH2:15][CH2:16][O:17][C:18]3[CH:33]=[CH:32][C:21]([CH:22]=[C:23]([C:28]([O:30][CH3:31])=[O:29])[C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=3)[CH:5]=[CH:4][C:3]1=2.[H][H]>CO.O1CCOCC1.[Pd]>[CH3:1][C:2]1([CH3:34])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([O:14][CH2:15][CH2:16][O:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:22][CH:23]([C:24]([O:26][CH3:27])=[O:25])[C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: [H][H]
Reactant: COC(=O)C(=Cc1ccc(OCCOc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1)C(=O)OC
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)C(Cc1ccc(OCCOc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1)C(=O)OC
Yield: 95.6 %

Procedure:
To a solution of dimethyl 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthoxy)ethoxy]benzylidenemalonate (2.55 g, 5.47 mmol) in a mixture of methanol (20 ml) and 1,4-dioxane (150 ml) is added 5% palladium on charcoal (1.20 g). Then the mixture is stirred under an atmosphere of hydrogen at room temperature until hydrogen uptake ceased. The solution is filtered through Celite, and the filtrate is evaporated under a vacuum. The residue is crystallized from ethyl acetate to give the title compound (2.45 g, 96%). HRMS calcd for C28H36O6: 468.5902. Found: 468.5905. MA calcd for C28H36O6: C, 71.77%; H, 7.74%. Found: C, 71.52%; H, 7.76%.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([S:14]([N:17]1[CH2:22][C:21](=[O:23])[N:20]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31]4[CH:36]=[CH:35][N:34]=[C:33]([CH3:37])[CH:32]=4)[CH2:27][CH2:26]3)[CH:19]([C:38]([OH:40])=[O:39])[CH2:18]1)(=[O:16])=[O:15])[CH:8]=[CH:7]2.[CH2:41](Cl)Cl>>[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([S:14]([N:17]1[CH2:22][C:21](=[O:23])[N:20]([NH:24][CH:25]3[CH2:26][CH2:27][N:28]([C:31]4[CH:36]=[CH:35][N:34]=[C:33]([CH3:37])[CH:32]=4)[CH2:29][CH2:30]3)[CH:19]([C:38]([O:40][CH3:41])=[O:39])[CH2:18]1)(=[O:16])=[O:15])[CH:8]=[CH:7]2
Reactant: ClCCl
Reactant: Cc1cc(N2CCC(NN3C(=O)CN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3C(=O)O)CC2)ccn1
Agent: Cl
Product: COC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC(=O)N1NC1CCN(c2ccnc(C)c2)CC1

Procedure:
Methyl 1-[[4-[(6-chloro-2-naphthyl)sulfonyl]-1-[[1-(2-methyl-4-pyridinyl)-4-piperidinyl]amino]-6-oxo-2-piperazinecarboxylate dihydrochloride (1.94 g) obtained in Example 127 was dissolved in methylene chloride (20 ml) and saturated aqueous sodium bicarbonate (20 ml) and partitioned. The organic phase was dried over magnesium sulfate, concentrated under reduced pressure to obtain methyl 4-[(6-chloro-2-naphthyl)sulfonyl]-1-[[1-(2-methyl-4-pyridinyl)-4-piperidinyl]amino]-6-oxo-2-piperazinecarboxylate. This material was dissolved in a 37% aqueous solution of formaldehyde (25.2 ml) and formic acid (12.8 ml), and reflux for 2 hours. The reaction mixture was cooled, made alkaline by adding saturated aqueous sodium bicarbonate, extracted with dichloromethane, dried and then concentrated. The residue was purified on a CHP-20 column (water→1% 1N hydrochloric acid-containing 30% aqueous solution of acetonitrile) and converted into a hydrochloride using a 4 N solution of hydrochloric acid in ethyl acetate (0.15 ml) to obtain the title compound (1.67 g) as a colorless non-crystalline powder.
Reaction SMILES: [NH:1]1[CH:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:4][CH:3]=[N:2]1.C([BH3-])#N.[Na+].[CH:17]1[CH:22]=[CH:21][C:20]([CH2:23][O:24][C:25](Cl)=[O:26])=[CH:19][CH:18]=1>C(O)(=O)C>[N:2]1([C:25]([O:24][CH2:23][C:20]2[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=2)=[O:26])[CH2:3][CH2:4][CH:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[NH:1]1
Reactant: CC(C)(C)OC(=O)C1CC=NN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C1CCN(C(=O)OCc2ccccc2)N1
Reaction time: 2 h
Yield: 62.2 %

Procedure:
To a solution of 1,1-dimethylethyl 4,5-dihydro-1H-pyrazole-5-carboxylate (5 g, 29.4 mmol) dissolved in acetic acid (75 mL) was added sodium cyanoborohydride (3.69 g, 58.8 mmol) over 10 minutes. After 30 min. the reaction mixture was concentrated. The intermediate was diluted with ethyl acetate and basified with sat. Na2CO3. The ethyl acetate was dried over sodium sulfate, filtered, and concentrated. The intermediate was diluted with tetrahydrofuran (THF) (75 mL), and triethylamine was added (8.19 mL, 58.8 mmol), followed by Cbz-Cl (2.1 mL, 14.69 mmol). After 2 h, the organic salts were filtered and the crude product was purified by silica gel column using 20-80% EtOAc/hexanes to afford 2.8 g (9.14 mmol) of 3-(1,1-dimethylethyl) 1-(phenylmethyl) 1,3-pyrazolidinedicarboxylate. LC-MS (ES) m/e 307.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[S:19])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([N+:13]([O-])=O)[C:5]=1[CH:16]([CH3:18])[CH3:17]>O1CCCC1.[Ni]>[CH3:1][O:2][C:3](=[S:19])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[C:6]([NH2:13])[C:5]=1[CH:16]([CH3:17])[CH3:18]
Reactant: COC(=S)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1C(C)C
Agent: [Ni]
Solvent: C1CCOC1
Product: COC(=S)c1cc(N)cc(N)c1C(C)C

Procedure:
26.6 g (0.0886 mol) of 3,5-dinitro-2-isopropylthiobenzoic acid methyl ester are dissolved in 270 ml of tetrahydrofuran and hydrogenated with the addition of 10 g of Raney nickel at from 30° to 35° C. The catalyst is then isolated by filtration, the filtrate is concentrated and the residue is crystallised from ethyl acetate/hexane.