Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6](Cl)[C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)=[CH:2]1.[OH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20]/[CH:21]=[CH:22]/[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])[CH2:16][CH2:15]1>>[S:1]1[CH:5]=[CH:4][C:3]([CH:6]([C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)[O:13][CH:14]2[CH2:15][CH2:16][N:17]([CH2:20]/[CH:21]=[CH:22]/[CH2:23][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N+:31]([O-:33])=[O:32])[CH2:18][CH2:19]2)=[CH:2]1
Reactant: ClC(c1ccsc1)c1ccsc1
Reactant: O=[N+]([O-])c1ccccc1OC/C=C/CN1CCC(O)CC1
Product: O=[N+]([O-])c1ccccc1OC/C=C/CN1CCC(OC(c2ccsc2)c2ccsc2)CC1

Procedure:
The procedure of Example 39 (a) was repeated except for using di(3-thienyl)methyl chloride and 4-hydroxy-1-[4-(2-nitrophenoxy)-2(E)-butenyl]piperidine instead of phenyl-2-thienylmethyl chloride and 4-hydroxy-1-[4-(2-nitrophenoxy)-2(E)-butenyl]piperidine to give oily 4-di(3-thienyl)methoxy-1-[4-(2-nitrophenoxy)-2(E)-butenyl]piperidine.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:14])[CH2:12][NH2:13].[Cl:15][C:16]1[CH:34]=[CH:33][C:19]([C:20]([C:22]2[N:26]([CH3:27])[C:25]([CH2:28][C:29](Cl)=[O:30])=[CH:24][C:23]=2[CH3:32])=[O:21])=[CH:18][CH:17]=1>C(Cl)(Cl)Cl>[Cl:15][C:16]1[CH:34]=[CH:33][C:19]([C:20]([C:22]2[N:26]([CH3:27])[C:25]([CH2:28][C:29]([NH:13][CH2:12][C:11]([O:10][CH3:9])=[O:14])=[O:30])=[CH:24][C:23]=2[CH3:32])=[O:21])=[CH:18][CH:17]=1
Reactant: Cc1cc(CC(=O)Cl)n(C)c1C(=O)c1ccc(Cl)cc1
Reactant: COC(=O)CN
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Temperature: 0 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
A 22.6 ml (0.16 mole) sample of triethylamine was added to a suspension of 6.78 g (0.054 mole) of glycine methyl ester hydrochloride in 200 ml of spectral grade chloroform. The mixture was cooled to 0° C. and a solution of 16.8 g (0.54 mole) of [5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-yl]-acetyl chloride in 80 ml of chloroform was added slowly. The mixture was stirred at room temperature overnight. The solution was washed successively with dilute hydrochloric acid and water and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo. The residue was recrystallized successively from methanol and acetonitrile to give 9.2 g (47% yield) of crystalline methyl N-{[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-yl]-acetyl}-glycinate, m.p. 198°-201° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][CH2:9][CH2:10][CH2:11][CH:12]([O:18][CH2:19]Cl)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].O>CCOCC>[Cl:8][CH2:9][CH2:10][CH2:11][CH:12]([O:18][CH2:19][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCC(CCCCl)OCCl
Reactant: Brc1ccccc1
Solvent: O
Solvent: CCOCC
Product: CCCCCC(CCCCl)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.7 %

Procedure:
A solution of bromobenzene (13.18 g., 0.084 mole) in ether (50 ml.) is added to a suspension of Mg (2.04 g., 0.084 mole) in ether (50 ml.) dropwise so as to maintain a gentle reflux. After complete addition of the bromobenzene, the mixture is heated on a steam bath for an additional hour. The reaction mixture is then cooled to 5°-10° C. by means of an ice-water bath, and 1-chloro-4-chloromethoxynonane (19.05 g., 0.084 mole) is added dropwise over 15 minutes. The resulting suspension is stirred for 18 hours at room temperature. The reaction mixture is diluted with ether (100 ml.), cooled to 0°-5° C., and cold water (75 ml.) is added with vigorous stirring while the temperature is kept below 5° C. Let stir at 0°-5° C. for about 15 minutes. The aqueous phase is separated from the ether phase (A), and the aqueous layer is extracted with ether (150 ml., B). Organic solution A is combined with B, washed with H2O (100 ml.), 5% K2CO3 (100 ml.), again with H2O (100 ml.), finally with saturated NaCl solution, and is dried over anhydrous Na2SO4. Removal of the solvent in vacuo yields 1-chloro-4-benzyloxynonane (19.28 g., 0.072 mole, 85.7% yield).
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[NH:9])[NH2:8].[Cl:10][C:11]([SH:14])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:10][C:11]1[S:14][N:8]=[C:7]([C:3]2[S:2][CH:6]=[CH:5][CH:4]=2)[N:9]=1
Reactant: N=C(N)c1cccs1
Reactant: SC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Clc1nc(-c2cccs2)ns1
Temperature: 25 °C
Yield: 69.1 %

Procedure:
To a solution of thiophene-2-carboximidamide hydrochloride (1.62 g, 10.0 mmol) and perchloromethyl mercaptan (1.07 ml, 10.0 mmol) in dichloromethane (10 ml) was added dropwise a solution of sodium hydroxide (1.60 g, 40.0 mmol) in water (4 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 1.40 g (69.3%) of the desired product as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH:6]=[CH:5]2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
A solution of 6-bromonaphthalen-2-ol (5.0 g, 22.4 mmol) and imidazole (2.3 g, 33.6 mmole) in N,N-dimethylformamide (DMF) (5.0 mL) was added t-butyldimethylsilyl chloride (TBDMSCI) (3.7 g, 24.6 mmole) in one portion at 0° C. The mixture was allowed to warm to room temperature and stirred for 3 h. The reaction mixture was partitioned between EtOAc (500 mL) and water (300 mL). The aqueous layer was separated and extracted with EtOAc (2×100 mL) and the combined organic extracts were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, hexanes) to afford (6-bromonaphthalen-2-yloxy)(tert-butyl)dimethylsilane (28, 7.4 g, 98%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.91 (d, J=1.8 Hz, 1H), 7.64 (d, J=8.7 Hz, 1H), 7.56 (d, J=8.7 Hz, 1H), 7.48 (dd, J=8.7, 1.8 Hz, 1H), 7.15 (d, J=2.4 Hz, 1H), 7.09 (dd, J=9.0, 2.4 Hz, 1H), 1.01 (s, 9H), 0.24 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]([N:13]2[C:21]3[C:16](=[CH:17][C:18]([O:26][CH3:27])=[C:19]([C:22]([F:25])([F:24])[F:23])[CH:20]=3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[C:6](Br)[C:7]=1[CH3:8].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]([N:13]2[C:21]3[C:16](=[CH:17][C:18]([O:26][CH3:27])=[C:19]([C:22]([F:24])([F:25])[F:23])[CH:20]=3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[C:6]([C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)[C:7]=1[CH3:8]
Reactant: OB(O)c1cccnc1
Reactant: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cc(Br)c(C)c(Br)c1)CC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cc(Br)c(C)c(-c3cccnc3)c1)CC2
Yield: 27.7 %

Procedure:
A mixture of 1-(3,5-dibromo-4-methylphenylcarbamoyl)-5-methoxy-6-trifluoromethylindoline (D25, 0.51 g, 1 mmol), 3-pyridylboronic acid (0.12 g, 1 mmol), tetrakis (triphenylphosphine)palladium (0) (35 mg, 0.03 mmol) and sodium carbonate (0.41 g, 4 mmol) in dimethoxyethane (30 mL) and water (3 mL) was heated under reflux, under argon, for 18 h. The mixture was cooled and poured into water. The precipitate was filtered off, washed with water and dried. The crude product was chromatographed on silica gel, eluted with ethyl acetate, and the eluted material was triturated with ether to give the title compound (0.14 g, 28%), m.p. 216-8° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[C:13]([CH2:19][NH:20][CH3:21])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1C2C(=CC=CC=2)C=C1CNC.[OH:35][CH2:36][C@@H:37]1[C:43](=[O:44])[N:42]([CH3:45])[CH2:41][C:40]2[CH:46]=[C:47]([C:50](O)=[O:51])[CH:48]=[CH:49][C:39]=2[NH:38]1.C(C[C@@H]1C(=O)N(C)CC2C=C(C(O)=O)C=CC=2N1)(OC)=O>>[CH3:21][N:20]([CH2:19][C:13]1[N:14]([CH3:18])[C:15]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[CH:17][CH:16]=2)[C:50]([C:47]1[CH:48]=[CH:49][C:39]2[NH:38][C@H:37]([CH2:36][OH:35])[C:43](=[O:44])[N:42]([CH3:45])[CH2:41][C:40]=2[CH:46]=1)=[O:51]
Reactant: CNCc1cc2cc(OCc3ccccc3)ccc2n1C
Reactant: CN1Cc2cc(C(=O)O)ccc2N[C@H](CO)C1=O
Agent: CNCc1cc2ccccc2n1C
Agent: COC(=O)C[C@H]1Nc2ccc(C(=O)O)cc2CN(C)C1=O
Product: CN(Cc1cc2cc(OCc3ccccc3)ccc2n1C)C(=O)c1ccc2c(c1)CN(C)C(=O)[C@@H](CO)N2
Yield: 94 %

Procedure:
According to the procedure of Example 1(a), except substituting 5-benzyloxy-1-methyl-2-(methylaminomethyl)indole (0.42 g, 1.50 mmole) for the 1-methyl-2-(methylaminomethyl)indole, and substituting (2R)-2-(hydroxymethyl)-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxylic acid (0.34 g, 1.37 mmole) for the (2R)-2-[(carbomethoxy)methyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxylic acid, the title compound (0.66 g, 94%) was prepared as an off-white solid: MS (ES) m/e 513 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:48]=[CH:47][C:6]([CH2:7][N:8]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH2:23][N:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][C@@H:25]4[CH3:37])[CH:19]=[N:20][C:21]=3[F:22])[N:10]=2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O.[CH3:56][S:57](Cl)(=[O:59])=[O:58]>C(Cl)Cl>[F:22][C:21]1[C:16]([C:11]2[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([N:8]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[CH2:7][C:6]3[CH:47]=[CH:48][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=2)=[CH:17][C:18]([CH2:23][N:24]2[CH2:29][CH2:28][N:27]([S:57]([CH3:56])(=[O:59])=[O:58])[CH2:26][C@@H:25]2[CH3:37])=[CH:19][N:20]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C(=O)OC(C)(C)C)C[C@@H]4C)cnc3F)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)C[C@@H]4C)cnc3F)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 135.5 %

Procedure:
A stirred solution of (S)-tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)methyl)-3-methylpiperazine-1-carboxylate (10.386 g, 15.79 mmol) in DCM (25.0 mL, 389 mmol) was cooled in an ice bath and slowly treated with TFA (25.0 mL, 324 mmol). The resulting mixture was stirred at room temperature for 1 h and then concentrated. The sticky residue was taken up in DCM (100 mL) and cooled to −45° C. TEA (22.0 mL, 158 mmol) was then added via additional funnel, followed by slow addition of methanesulfonyl chloride (6.15 mL, 79 mmol) in DCM (20 mL). The heterogeneous mixture was stirred at −30° C. for 30 min and then quenched with water and NH4Cl(aq) (50 mL each). The organic layer was separated, and the aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were then washed with brine, dried over Na2SO4, and concentrated to give (S)-4-(2-fluoro-5-((2-methyl-4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (13.6 g crude) as a pale-yellow foam, which was taken directly to the next step without further purification. m/z (ESI, +ve ion) 636 (M+H)+.
Reaction SMILES: C([NH:8][CH:9]1[CH2:12][CH:11]([CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]1[F:22])C1C=CC=CC=1.CCN(CC)CC.[N+](C1C=CC([N:39]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:40](=[O:42])[O-])=CC=1)([O-])=O>C(Cl)Cl>[CH2:43]([NH:39][C:40]([NH:8][CH:9]1[CH2:12][CH:11]([CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]1[F:22])=[O:42])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: FC1C(COCc2ccccc2)CC1NCc1ccccc1
Reactant: O=C([O-])N(Cc1ccccc1)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1ccccc1)NC1CC(COCc2ccccc2)C1F
Reaction time: 0.08 h
Yield: 92.5 %

Procedure:
In a 25 mL flask with benzyl-(3-benzyloxymethyl-2-fluoro-cyclobutyl)-amine (25.8 mg, 0.12 mmol) inside, dry CH2Cl2 2 mL was added under argon at room temperature to give a colorless solution, followed by the addition of Et3N (0.02 mL, 0.14 mmol). After stirring for 5 min, 4-nitrophenyl-N-benzylcarbamate (32.1 mg, 0.12 mmol) was added to give a yellow solution. This was left stirring at room temperature for 10 hr and the reaction was quenched by adding 10 mL CH2Cl2. The organic phase was washed with 1 M NaOH 10 mL, H2O 10 mL and brine 10 mL and was dried over MgSO4. Solvent evaporation gave the crude product 42 mg that is pure enough and crystallization gave the pure product 38 mg (90%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 1.96-2.01 (m, 2H), 2.65-2.80 (m, 1H), 3.48-3.58 (m, 2H), 4.31-4.36 (m, 3H), 4.52 (s, 2H), 4.82-4.99 (td, 1H, J=54.8, 5.2), 7.19-7.39 (m, 10H). 13C NMR (CDCl3, 100 MHz): δ 27.11-27.19 (d, J=7.6), 41.75-41.96 (d, J=21), 47.92, 48.44-48.51 (d, J=7.0), 71.12-71.16 (d, J=4.0), 74.26, 90.34-92.48 (d, J=214), 128.14, 128.30, 128.84, 128.96, 129.56, 129.62, 139.81, 141.35, 160.85. MS (FAB): expected for C20H23FN2O2 (M+H)+ 343.41. Found 343.18178. IR (neat) νmax 2923, 2851, 1558, 1458, 1378, 1265, 895, 740, 704. The absolute stereochemistry was established by X-ray crystallographic analyses.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[C:25]([F:26])=[C:24]([F:27])[CH:23]=[CH:22][C:21]=1B(O)O>>[O:16]=[C:15]1[C:8]2=[CH:7][C:6]3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=[C:2]([C:23]4[CH:22]=[CH:21][C:20]([F:19])=[C:25]([F:26])[C:24]=4[F:27])[C:10]=3[N:9]2[CH2:11][CH2:12][CH2:13][NH:14]1
Reactant: OB(O)c1ccc(F)c(F)c1F
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Product: N#Cc1cc(-c2ccc(F)c(F)c2F)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, white solid (18 mg, 20%), MS (ISP) m/z=356.5 [(M+H)+], mp 187° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 2,3,4-trifluoro-phenylboronic acid (57.2 mg, 0.325 mmol).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[N:19]=[C:18]([C:28]([N:30]3[CH2:34][C:33](=[O:35])[NH:32][CH2:31]3)=[O:29])[CH:17]=2)[CH:11]=1)(=O)=O.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.[CH:43]([OH:45])=[O:44].ClC1C=C(N2C(C3C=CC=C(OCCCN(C)C)C=3)=CC(C(N3CC(=O)NC3)=O)=N2)C=CC=1>O1CCCC1>[CH:43]([OH:45])=[O:44].[Cl:27][C:23]1[CH:22]=[C:21]([N:20]2[C:16]([C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:40]4[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]4)[CH:11]=3)=[CH:17][C:18]([C:28]([N:30]3[CH2:34][C:33](=[O:35])[NH:32][CH2:31]3)=[O:29])=[N:19]2)[CH:26]=[CH:25][CH:24]=1
Reactant: CN1CCNCC1
Reactant: CS(=O)(=O)OCCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Agent: CN(C)CCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Solvent: O=CO
Solvent: C1CCOC1
Product: CN1CCN(CCCOc2cccc(-c3cc(C(=O)N4CNC(=O)C4)nn3-c3cccc(Cl)c3)c2)CC1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 120A and 1-methylpiperazine without the addition of tetrahydrofuran in analogy to the synthesis of the compound of Example 29. 45 mg (38% of theory) of the title compound are obtained.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]#[N:21])=[CH:10][CH:9]=2)[C:5]2[C:22]([C:26]([O:28][CH3:29])=[O:27])=[CH:23][CH:24]=[CH:25][C:4]=2[N:3]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[C:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]([CH2:7][N:6]2[C:5]3[C:22]([C:26]([O:28][CH3:29])=[O:27])=[CH:23][CH:24]=[CH:25][C:4]=3[N:3]=[C:2]2[N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:9][CH:10]=1)#[N:21]
Reactant: C1COCCN1
Reactant: COC(=O)c1cccc2nc(Cl)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Product: COC(=O)c1cccc2nc(N3CCOCC3)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Temperature: 100 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A mixture of methyl 2-chloro-1-[(2′-cyanobiphenyl-4-yl)methyl]benzimidazole-7-carboxylate (0.8 g) in morpholine (15 ml) was stirred at 100° C. for 2 hours and the reaction mixture was concentrated to dryness. The residue was extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The resulting crystals were recrystallized from ethyl acetate-hexane to afford colorless prisms (0.69 g, 77%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.Cl>C1C=CC=CC=1.CO>[NH2:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Nc1nc(Cl)c2c(n1)CCCS2
Reactant: C1CNCCN1
Agent: Cl
Solvent: CO
Solvent: c1ccccc1
Product: Nc1nc2c(c(N3CCNCC3)n1)SCCC2
Yield: 80.2 %

Procedure:
11 g of 2-amino-4-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine was dissolved in 150 ml of benzene and 30 g of anhydrous piperazine was added thereto while hot. After heating for 3 hours, the mixture was concentrated under reduced pressure and water was added thereto. The mixture was rendered alkaline with potassium carbonate and extracted with chloroform. The organic layer was dried over magnesium sulfate and the solvent was distilled off to obtain crystals. The resulting crystals were converted into the corresponding hydrochloride in methanol and, after treatment with activated carbon, the hydrochloride was again converted into a free base form. The free base was recrystallized from a mixture of chloroform and diethyl ether to obtain 11 g of 2-amino-4-piperazino-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine as colorless needles having a melting point of 176°-178° C.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[N:11][CH:12]=1.[CH:17]([CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)=[O:18]>C1COCC1>[OH:18][CH:17]([C:7]1[CH:12]=[N:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: FC(F)(F)c1ccc(Br)cn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(C(F)(F)F)nc2)CC1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
A solution of isopropylmagnesium chloride (2.0 M in THF, 40.3 mL, 80.6 mmol) was added dropwise by syringe to a solution of 5-bromo-2-(trifluoromethyl)pyridine (19.5 g, 86.3 mmol) in dry THF (12 mL) at 2° C. After 30 minutes, tert-butyl 4-formylpiperidine-1-carboxylate (12.3 g, 57.3 mmol) was added to the Grignard solution at 2° C. as a solid. The reaction mixture was warmed to 10° C. over 1.5 hours after which it was quenched with saturated aqueous ammonium chloride solution. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate and washed with saturated aqueous NaCl solution. The organic phase was dried (MgSO4), filtered, and concentrated to afford the title compound which was used without further purification in the next step.
Reaction SMILES: [Na].[CH2:2]([OH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15](Br)[CH:16]=1>O.[Cu]>[Br:10][C:11]1[CH:16]=[C:15]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:14]=[N:13][CH:12]=1
Reactant: OCc1ccccc1
Reactant: Brc1cncc(Br)c1
Agent: [Cu]
Agent: [Na]
Solvent: O
Product: Brc1cncc(OCc2ccccc2)c1
Temperature: 70 °C

Procedure:
Under a nitrogen atmosphere, small pieces of sodium (1.48 g, 64.4 mmol) were added to benzyl alcohol (17.11 g, 158 mmol), and the mixture was stirred and heated at 70° C. for 18 h. To the stirring, viscous mixture was added 3,5-dibromopyridine (5.00 g, 21.1 mmol), copper powder (0.255 g, 4.0 mmol) and benzyl alcohol (15 mL). The mixture was further heated at 100° C. for 48 h. The reaction mixture was allowed to cool to ambient temperature, diluted with water (50 mL), and extracted with ethyl ether (5×50 mL). The combined ether layers were dried (Na2SO4), filtered, and concentrated. Distillation at 68-72° C. and 2.6 mm Hg removed excess benzyl alcohol. The remaining yellowish, brown residue was purified by vacuum distillation at 0.05 mm Hg to yield 3.17 g (38.0%) of a white, crystalline solid, mp 64-66° C.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([NH2:12])[N:3]=1.C(N(CC)CC)C.[CH:20]1([CH2:26][NH2:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(O)CCC>[NH2:12][C:4]1[N:3]=[C:2]([NH:27][CH2:26][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=1
Reactant: Nc1nc(Cl)c2c(n1)CCCC2
Reactant: NCC1CCCCC1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Nc1nc2c(c(NCC3CCCCC3)n1)CCCC2

Procedure:
A mixture of 4-chloro-5,6,7,8-tetrahydroquinazoline-2-ylamine (107 mg, 0.58 mmol), triethylamine (221 mg, 2.18 mmol), cyclohexylmethylamine (132 mg, 1.17 mmol) and n-butanol (3 ml) was reacted for 4 hours at 80-90° C. According to the post-treatment of Example 1, the object compound was obtained (102 mg, 67.9%).
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.Br[C:32]1[N:33]=[C:34]2[CH:40]=[C:39]([C:41]3[C:49]4[C:44](=[CH:45][CH:46]=[C:47]([O:50][CH3:51])[CH:48]=4)[N:43]([CH3:52])[CH:42]=3)[N:38]([CH2:53][O:54][CH2:55][CH2:56][Si:57]([CH3:60])([CH3:59])[CH3:58])[C:35]2=[N:36][CH:37]=1.[NH:61]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[NH2:62].CC(C)([O-])C.[Na+]>O1CCOCC1>[CH3:51][O:50][C:47]1[CH:48]=[C:49]2[C:44](=[CH:45][CH:46]=1)[N:43]([CH3:52])[CH:42]=[C:41]2[C:39]1[N:38]([CH2:53][O:54][CH2:55][CH2:56][Si:57]([CH3:60])([CH3:59])[CH3:58])[C:35]2=[N:36][CH:37]=[C:32]([NH:62][NH:61][C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[N:33]=[C:34]2[CH:40]=1
Reactant: COc1ccc2c(c1)c(-c1cc3nc(Br)cnc3n1COCC[Si](C)(C)C)cn2C
Reactant: CC(C)(C)OC(=O)NN
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc2c(c1)c(-c1cc3nc(NNC(=O)OC(C)(C)C)cnc3n1COCC[Si](C)(C)C)cn2C
Temperature: 80 °C
Yield: 70.1 %

Procedure:
A round bottom flask was charged with tris(dibenzylidineacetone)dipalladium(0) (0.066 g, 0.072 mmol) and di-tert-butyl-(2′,4′,6′-triisopropyl-biphenyl-2-yl)-phosphane (0.061 g, 0.14 mmol) in 1,4-dioxane (10 mL) to give a black solution which was degassed via vacuum/nitrogen purge (3 times). The mixture was heated to about 80° C. for about 10 min. To the reaction mixture were added 2-bromo-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (0.35 g, 0.72 mmol, Example #20, Step D) and tert-butyl hydrazinecarboxylate (0.142 g, 1.08 mmol), followed by sodium tert-butoxide (0.104 g, 1.08 mmol). The mixture was heated at about 80° C. for about 20 min. The reaction mixture was cooled and filtered through Celite®. The filter pad was further rinsed with EtOAc (40 mL). The filtrate was concentrated under reduced pressure and purified by silica gel chromatography eluting with a gradient of 0-100% EtOAc in heptane to give tert-butyl 2-(6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazine-carboxylate (0.272 g, 70%): LC/MS (Table 1, Method d) Rt=1.78 min; MS m/z: 539 (M+H)+.