Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1.[CH3:40][NH:41][CH2:42][C:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:46]([CH3:53])=[CH:45][CH:44]=1.CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([N:41]([CH3:40])[CH2:42][C:43]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:46]([CH3:53])=[CH:45][CH:44]=2)=[O:13])=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: CNCc1ccc(C)c2ccccc12
Reactant: Nc1ncc(/C=C/C(=O)O)cc1CN1CCOCC1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: Cc1ccc(CN(C)C(=O)/C=C/c2cnc(N)c(CN3CCOCC3)c2)c2ccccc12
Yield: 62 %

Procedure:
According to the procedure of Example 1, except substituting (E)-3-(6-amino-5-morpholin-4-ylmethyl-pyridin-3-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting methyl-N-(4-methyl-naphthalen-1-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (66 mg, 62%) was prepared as a pale, yellow powder and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 8.61-8.35 (m, 2H), 8.14-8.05 (m, 2H), 7.61-7.52 (m, 3H), 7.36-7.03 (m, 3H), 5.30-5.07 (m, 2H), 4.45-4.23 (m, 2H), 3.94-3.65 (m, 6H), 3.45-3.17 (m, 4H), 3.04-2.94 (m, 4H), 2.65 (s, 3H); MS (ESI) m/e 431 (M+H)+.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]3[N:14]=[C:15]([NH2:17])[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:18]1([CH2:23][CH2:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][N:26]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:1]1([NH:7][C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:29](=[O:30])[C:28]4[CH:32]=[CH:33][C:25]([CH2:24][CH2:23][N:18]5[CH2:22][CH2:21][CH2:20][CH2:19]5)=[N:26][CH:27]=4)[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Cl)c1ccc(CCN2CCCC2)nc1
Reactant: Nc1nc2cccc(NC3CCCCC3)n2n1
Product: O=C(Nc1nc2cccc(NC3CCCCC3)n2n1)c1ccc(CCN2CCCC2)nc1

Procedure:
The title compound was prepared following procedure described for intermediate B1 but starting from N5-cyclohexyl[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine ((A9), 116 mg; 0.5 mmol; 1.0 eq.) and 6-(2-pyrrolidin-1-ylethyl)nicotinoyl chloride (239 mg, 1.0 mmol; 2.0 eq.) as a white powder (130 mg, 60%). HPLC, Rt: 2.67 min. (purity 99.9%). LC/MS, M+(ESI): 434.1, M−(ESI): 432.1.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1.N1C2C(=CC=CC=2)C=C1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33]([O:35]C)=O)=[CH:25]1>>[S:11]1[CH:12]=[CH:13][N:14]=[C:10]1[NH:9][C:33]([C:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:24]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:25]=1)=[O:35]
Reactant: BrCc1ccccc1
Reactant: Nc1nccs1
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: c1ccc2[nH]ccc2c1
Product: O=C(Nc1nccs1)c1cn(Cc2ccccc2)c2ccccc12

Procedure:
R5Br=Bromomethylbenzene; NH2A=2-aminothiazole; Indole starting material=methyl indole 3-carboxylate
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[CH2:16]([O:23][C:24](=[O:36])[CH2:25][N:26]([C:28]1[CH:33]=[C:32]([CH3:34])[N:31]=[C:30](Cl)[N:29]=1)[CH3:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:16]([O:23][C:24](=[O:36])[CH2:25][N:26]([C:28]1[CH:33]=[C:32]([CH3:34])[N:31]=[C:30]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:29]=1)[CH3:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: Cc1cc(N(C)CC(=O)OCc2ccccc2)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(Nc2nc(C)cc(N(C)CC(=O)OCc3ccccc3)n2)ccc1-n1cnc(C)c1
Yield: 56 %

Procedure:
Prepared in analogy to example 81b) from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and [(2-chloro-6-methyl-pyrimidin-4-yl)-methyl-amino]acetic acid benzyl ester, using potassium carbonate as a base. The title compound was isolated as a colorless solid in a yield of 56%. MS ISP (m/e): 473.3 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.58 (s, 1H), 7.54 (s broad, 1H), 7.35-7.20 (m, 4H), 7.10-6.95 (m, 2H), 6.89 (s broad, 1H), 6.82 (s, 1H), 5.95 (s, 1H), 5.16 (s, 2H), 4.39 (s broad, 2H), 3.80 (s, 3H), 3.14 (s, 3H), 2.31 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: C(OC(C1N=NC=CC=1)=O)C.[F:12][C:13]1[CH:18]=[C:17]([O:19][C:20]2[S:21][CH:22]=[CH:23][N:24]=2)[CH:16]=[CH:15][C:14]=1[NH2:25].[CH2:26]([O:28][C:29]([C:31]1[C:32]([CH3:57])=[C:33]2[C:38](NC3C=CC(SC4N(C)C=CN=4)=C(Cl)C=3)=[C:37]([C:54]#[N:55])[CH:36]=[N:35][N:34]2[CH:56]=1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1[C:32]([CH3:57])=[C:33]2[C:38]([NH:25][C:14]3[CH:15]=[CH:16][C:17]([O:19][C:20]4[S:21][CH:22]=[CH:23][N:24]=4)=[CH:18][C:13]=3[F:12])=[C:37]([C:54]#[N:55])[CH:36]=[N:35][N:34]2[CH:56]=1)=[O:30])[CH3:27]
Reactant: Nc1ccc(Oc2nccs2)cc1F
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c2c1C
Agent: CCOC(=O)c1cccnn1
Product: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4nccs4)cc3F)c2c1C
Yield: 83 %

Procedure:
Compound 427 (361 mg, 83%) was prepared from 4-chloro-3-cyano-5-methyl-pyrrolo]1,2-b]pyridazine-6-carboxylic acid ethyl ester (Example 1D) (264 mg, 1.0 mmol) and 427B (210 mg, 1.0 mmol) by a route analogous to that used for the preparation of compound 426. It is a dim yellow solid and has a retention time of 6.76 min (standard LC1 method, 8 min run). MS Found: (M+H)+=438.1
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[N:8][NH:9]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[CH:32][C:31]=1[O:39][CH3:40].CN(C)C=O>O>[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([N:12]3[CH2:13][CH2:14][N:15]([CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]4[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[CH:32][C:31]=4[O:39][CH3:40])[CH2:16][CH2:17]3)=[N:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: Fc1ccc2c(N3CCNCC3)n[nH]c2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)=O)ccc1OCCCCN1CCN(c2n[nH]c3cc(F)ccc23)CC1
Temperature: 75 °C
Yield: 35.8 %

Procedure:
A stirred mixture of 6-fluoro-3-(1-piperazinyl)-1H-indazole hydrochloride (5.0 g, 19 mmol), K2CO3 (5.8 g) and 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (6.3 g, 21 mmol) and dimethylformamide (80 ml) was heated at 75° C for 6 hours. The reaction was poured into water, and an off-white solid formed from solution. The solid was collected and dried to yield 4.5 g of crude product. The compound was recrystallized from ethanol (3 times) to afford 3.0 g of an off-white solid. The solid was chromatographed on a Waters Prep 500 utilizing silica gel columns and eluting with methylene chloride/methanol (7%). Concentration of the appropriate fractions afford 2.3 g of an off-white solid, which when recrystallized from ethanol yielded 1.9 g (26%) of analytically pure 1-[4-[4-[4-(6-fluoro-1H-indazol-3-yl)-]-piperazinyl]butoxy]-3-methoxyphenyl]ethanone, m.p.: 156°-158° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1Br.[Li][CH2:22][CH2:23][CH2:24]C.[CH2:26]1[CH2:30][O:29][CH2:28][CH2:27]1>CCCCCC>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[CH:28]([OH:29])[C:27]1[CH:26]=[CH:30][CH:24]=[CH:23][CH:22]=1
Reactant: [Li]CCCC
Reactant: C1CCOC1
Reactant: COC(OC)c1cc(OCc2ccccc2)ccc1Br
Solvent: CCCCCC
Product: COC(OC)c1cc(OCc2ccccc2)ccc1C(O)c1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-bromo-5-benzyloxy benzaldehyde dimethylacetal (Tet. Lett., 22, 5027 (1981)) (130 g) in THF (2.0 L), cooled to -78° C., was added dropwise a solution of n-BuLi (210 ml, 1.91 M) in hexane. After 15 min., a solution of benzalde48 mL) in THF (50 ml) was added dropwise. The cooling bath was removed, then the reaction mixture was warmed slowly (40 min.) to -10° C. and quenched with a saturated NH4Cl solution. The reaction mixture was diluted with Et2O (2.0 L). The organic phase decanted, washed with H2O (3×), brine, dried over MgSO4 and the solvents evaporated. The residue was chromatographed on silica gel (hexane/EtOAc 95:5 to 85:15) to give the title product as a foam.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][C:6](=[N:8][OH:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1.[C:13]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43]Br)=[CH:39][CH:38]=1)(=[O:34])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32]Br)=[CH:28][CH:27]=1)=[O:23]>>[CH3:1][C:2]1([CH3:12])[CH2:7][CH:6]([N:8]([CH2:43][C:40]2[CH:41]=[CH:42][C:37]([CH2:36][O:35][C:13](=[O:34])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][N:8]([CH:6]4[CH2:7][C:2]([CH3:12])([CH3:1])[NH:3][C:4]([CH3:11])([CH3:10])[CH2:5]4)[OH:9])=[CH:28][CH:27]=3)=[O:23])=[CH:38][CH:39]=2)[OH:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1
Reactant: CC1(C)CC(=NO)CC(C)(C)N1
Reactant: O=C(CCCCCCCCC(=O)OCc1ccc(CBr)cc1)OCc1ccc(CBr)cc1
Product: CC1(C)CC(N(O)Cc2ccc(COC(=O)CCCCCCCCC(=O)OCc3ccc(CN(O)C4CC(C)(C)NC(C)(C)C4)cc3)cc2)CC(C)(C)N1

Procedure:
from 2,2,6,6-tetramethylpiperidin-4-one oxime and di-(4-bromomethylbenzyl) sebacate
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11](=[O:27])[CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][N:17]([CH2:20]C4C=CC=CC=4)[CH2:16][CH2:15]3)[CH:8]=[CH:7][C:5]=2[N:6]=1.ClC(O[CH:32]([Cl:34])[CH3:33])=O.[OH2:35]>ClCCCl>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11](=[O:27])[CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][N:17]([C:20]([CH:32]([Cl:34])[CH3:33])=[O:35])[CH2:16][CH2:15]3)[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O
Reactant: CC(Cl)OC(=O)Cl
Reactant: Cc1nc2ccc(C(=O)CCC3CCN(Cc4ccccc4)CC3)cc2s1
Solvent: ClCCCl
Product: Cc1nc2ccc(C(=O)CCC3CCN(C(=O)C(C)Cl)CC3)cc2s1
Temperature: 25 °C
Yield: 100 %

Procedure:
A mixture of 0.90 g (2.38 mM) of 1-(2-methyl-6-benzthiazolyl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone (Example 27) and 0.33 mL (3.1 mM) of 1-chloroethyl chloroformate was refluxed in 10 mL of 1,2-dichloroethane for 2 hours. The resulting brown solution was cooled to room temperature and diluted with 15 mL of water. This mixture was extracted twice with 20 mL of ethyl acetate. The ethyl acetate extracts were combined, dried (Na2SO4), and evaporated to yield 1.0 g (100%) 1-(2-methyl-6-benzothiazolyl)-3-[(1-chloroethylformyl)-4-piperidinyl]-1-propanone as an oil.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)=[CH:7][C:6]=1[CH3:27].[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1.C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[N:28]1([CH2:2][CH2:3][O:4][C:5]2[C:10]([CH3:11])=[CH:9][C:8]([C:12]3[NH:21][C:20](=[O:22])[C:19]4[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=4[O:23][CH3:24])[N:13]=3)=[CH:7][C:6]=2[CH3:27])[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: c1c[nH]cn1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCBr)c(C)c3)nc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCn4ccnc4)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[4-(2-bromoethoxy)-3,5-dimethylphenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.12 g, 0.27 mmol) in acetone (5 mL) was added imidazole (0.18 g, 2.70 mmol) and Cs2CO3 (0.26 g, 0.80 mmol). The reaction mixture was stirred at room temperature for 16 hours. Solvent was removed under reduced pressure, and the residue was purified by column chromatography (silica gel 230-400 mesh; 3% methanol in dichloromethane as eluent) to give the title compound as a white solid. Yield: 0.04 g (35%). MP 218-219° C. 1H NMR (400 MHz, DMSO-d6): δ 11.80 (br s, 1H), 7.83 (s, 2H), 7.72 (s, 1H), 7.29 (s, 1H), 6.92 (s, 1H), 6.70 (d, J=2.4 Hz, 1H), 6.49 (d, J=2.4 Hz, 1H), 4.36 (t, J=4.8 Hz, 2H), 4.02 (t, J=4.8 Hz, 2H), 3.86 (s, 3H), 3.81 (s, 3H), 2.06 (s, 6H). MS (ES) m/z: 419.57 (M−1).
Reaction SMILES: CN[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([Li])(C)(C)C.[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][C:29]2([C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:10])[O:32]2)[CH2:28][CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CNC(=O)c1ccccc1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: O=C1OC2(CCN(C(=O)OCc3ccccc3)CC2)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 553.5 %

Procedure:
A solution of N-methylbenzamide (0.38 g) in 200 mL of anhydrous tetrahydrofuran was cooled to -78° C. and treated with tert-butyl lithium (30 mL, 1.7M). At the end of the addition, the reaction mixture was allowed to warm to 0° C. and stirred at this temperature for 1 hour and then cooled back to -78° C. After treatment with a solution of 1-benzyloxycarbonyl-4-piperidone (5.83 g) in 2 mL of tetrahydrofuran, the reaction mixture was stirred at -78° C. for 40 minutes and then quenched with 300 mL of saturated ammonium chloride solution. Extraction with ethyl acetate, washing the organic layer with brine, drying over magnesium sulfate and evaporation afforded the crude product. This material was partially purified by column chromatography; elution with ethyl acetate:hexane (6:4) afforded the named material (5.25 g); MS: 238 (M-99); NMR: 1.6-1.7 (m, 2), 2.0-2.1 (m, 2), 3.4 (br., 2), 4.0-4.1 (br, 2), 5.2(s, 1), 7.2-7.4 (m, 5), 7.5 (m, 1), 7.7 (m, 1), 7.9 (m, 1).
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:3]=1[CH2:4][N:5]1[C:13](=[O:14])[N:12](C(OC(C)(C)C)=O)[C:11]2[C:6]1=[N:7][C:8]([N:22]1[C:26]3[CH:27]=[C:28]([C:31]#[N:32])[CH:29]=[CH:30][C:25]=3[N:24]=[CH:23]1)=[N:9][CH:10]=2>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:37][C:33]1[CH:34]=[CH:35][CH:36]=[C:2]([F:1])[C:3]=1[CH2:4][N:5]1[C:13](=[O:14])[NH:12][C:11]2[C:6]1=[N:7][C:8]([N:22]1[C:26]3[CH:27]=[C:28]([C:31]#[N:32])[CH:29]=[CH:30][C:25]=3[N:24]=[CH:23]1)=[N:9][CH:10]=2
Reactant: CC(C)(C)OC(=O)n1c(=O)n(Cc2c(F)cccc2F)c2nc(-n3cnc4ccc(C#N)cc43)ncc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc2ncn(-c3ncc4[nH]c(=O)n(Cc5c(F)cccc5F)c4n3)c2c1
Reaction time: 1 h

Procedure:
A 1:1 solution of TFA/DCM (10 mL) was added to tert-Butyl 9-(2,6-difluorobenzyl)-2-(6-cyano-1H-benzo[d]imidazol-1-yl)-8-oxo-8,9-dihydropurine-7-carboxylate (60) and stirred for 1 hr. The solvents were removed en vacuo and the resulting solid was triturated with Et2O, and suspended in 6N HCl. Removal of solvents and trituration with Et2O of the resulting solid gave the titled compound (61) (68 mg) as a HCl salt, MH+=404, 1H NMR (d6-DMSO) δ 11.8 (s, 1H), 9.2 (s, 1H), 8.8 (s, 1H), 8.0 (s, 1H), 7.9 (d, 1H), 7.8 (broad s, 1H), 7.4 (d, 1H), 7.4 (quintet, 1H), 7.1 (m, 2H), 5.2 (s, 2H) ppm, 19F NMR δ −114.3 (m).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[C:7]1[C:13]2[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=2[N:11]([C:19](=[O:37])[C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[CH:22][C:21]=2[CH3:36])[CH2:10][CH2:9][CH2:8]1)=[O:5])[CH3:2].[BH4-].[Na+]>O1CCCC1.CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH2:1]([O:3][C:4]([CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=2[N:11]([C:19](=[O:37])[C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[CH:22][C:21]=2[CH3:36])[CH2:10][CH2:9][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C=C1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2C)c2ccc(Cl)cc21
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2C)c2ccc(Cl)cc21
Yield: 43.2 %

Procedure:
5-Ethoxycarbonylmethylidene-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.30 g) and nickel chloride hexahydrate (0.55 g) are dissolved in a mixture of tetrahydrofuran/methanol (1:1) (30 ml), and to the mixture is added slowly sodium borohydride (0.26 g) with stirring under ice-cooling, and then the mixture is further stirred for 10 minutes under ice-cooling. The insoluble materials are filtered with Celite, and the filtrate is concentrated. The resulting residue is purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:1) to give 5-ethoxycarbonylmethyl-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.13 g) as colorless amorphous.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:37])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:35])(=[O:34])[NH:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:36])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[Cl:36][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:37])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25](=[O:34])(=[O:35])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)Nc3ccc(F)cc3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(S(=O)(=O)Nc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.6 %

Procedure:
Lithium hydroxide monohydrate (0.012 g, 0.28 mmol) was added to a stirred solution of {6-chloro-4-[4-(4-fluoro-phenylsulfamoyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.035 g, 0.07 mmol) in a 3:1 mixture of THF—H2O mixture (5 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane afforded {6-chloro-4-[4-(4-fluoro-phenylsulfamoyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid (0.03 g, 88%) as a solid. 1H NMR (DMSO-d6) δ: 12.50 (br. s, 1H), 10.25 (br. s, 1H), 7.75-8.06 (m, 5H), 7.32-7.56 (m, 3H), 7.13 (d, J=6.4 Hz, 4H), 6.81 (s, 1H), 3.84 (s, 3H), 2.01 (s, 3H). MS calcd. for C25H18ClFNO4S [(M−H)−] 482, obsd. 481.8.
Reaction SMILES: C([O-])(=O)C.[C:5]([C:7](=[N:11][O:12][CH3:13])[C:8]([NH2:10])=[NH2+:9])#[N:6].C(N(CC)CC)C.BrBr.[C:23]([S-:25])#[N:24].[K+]>CO>[NH2:24][C:23]1[S:25][N:10]=[C:8]([C:7](=[N:11][O:12][CH3:13])[C:5]#[N:6])[N:9]=1
Reactant: CON=C(C#N)C(N)=[NH2+]
Reactant: N#C[S-]
Agent: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CON=C(C#N)c1nsc(N)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 97.5 %

Procedure:
To a suspension of 2-cyano-2-methoxyiminoacetamidinium acetate (125 g, 0.672 mole) in CH3OH (1.25 L) were added dropwise triethylamine (234 ml, 1.68 mole) at -10° C., and subsequently Br2 (41.6 ml, 0.806 mole) over 20 minutes at -15° to -10° C., and the mixture was stirred for 20 minutes. To the mixture was added dropwise a solution of KSCN (78.3 g, 0.806 mole) in CH3OH (550 ml) over 1 hour at -15° to -10° C. After stirring at 0°-5° C. for 1 hour, the mixture was poured into ice-water (12 L) to form a crystalline precipitate, which was collected by filtration, washed with water and air-dried to give 120 g (98%) of the title compound. M.p. 263°-5° C. (dec.). The m.p. of the compound prepared by us is higher by about 60° C. than that given in the literature* [m.p. 210°-15° C. (dec.)], but our spectral and microanalytical data are consistent for the structure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1.[CH3:10][O:11][CH2:12][CH2:13][CH2:14][Mg]Cl.CO.[BH4-].[Na+]>O1CCCC1.C(OCC)(=O)C.[OH-].[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([NH2:9])[CH2:14][CH2:13][CH2:12][O:11][CH3:10])[CH:3]=1
Reactant: N#Cc1cc(Br)ccn1
Reactant: COCCC[Mg]Cl
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: COCCCC(N)c1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 4.3 g of 4-bromopyridine-2-carbonitrile [62150-45-2] in 10 ml of tetrahydrofuran is added to a solution of 8.79 g of 3-methoxypropylmagnesium chloride [14202-12-1] in 10 ml of tetrahydrofuran. The reaction solution is stirred at room temperature for 10 minutes and then 50 ml of methanol are added. 2.7 g of sodium borohydride are added to the solution over the course of 30 minutes, and the mixture is stirred at room temperature for 2.5 hours. It is diluted with ethyl acetate and basified with 1M sodium hydroxide solution. The phases are separated. The aqueous phase is extracted with ethyl acetate (2×). The combined organic phases are evaporated. The crude title compound is obtained as an orange oil from the residue. Rt=2.47 (Gradient I).
Reaction SMILES: [NH2:1][C:2](=[N:42][OH:43])[C:3]1[CH:4]=[CH:5][C:6]([CH3:41])=[C:7]([N:9]([CH2:26][C:27]([N:29]([N:31]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([F:40])[CH:37]=3)[CH2:32]2)[CH3:30])=[O:28])[CH2:10][C:11]([NH:13][CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH3:18])=[O:12])[CH:8]=1.[O-2].[Mg+2].[Cl:46][CH2:47][C:48](Cl)=O>O1CCOCC1.C(OCC)(=O)C>[Cl:46][CH2:47][C:48]1[O:43][N:42]=[C:2]([C:3]2[CH:4]=[CH:5][C:6]([CH3:41])=[C:7]([N:9]([CH2:26][C:27]([N:29]([N:31]3[CH2:39][C:38]4[C:33](=[CH:34][CH:35]=[C:36]([F:40])[CH:37]=4)[CH2:32]3)[CH3:30])=[O:28])[CH2:10][C:11]([NH:13][CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:17][CH3:18])=[O:12])[CH:8]=2)[N:1]=1
Reactant: O=C(Cl)CCl
Reactant: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccc(F)cc2C1)c1cc(C(N)=NO)ccc1C)C(=O)OC(C)(C)C
Agent: [Mg+2]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccc(F)cc2C1)c1cc(-c2noc(CCl)n2)ccc1C)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
The compound (4.82 g, 8.04 mmol) of Example 290, step B was dissolved in 1,4-dioxane (70 ml), magnesium oxide (355 mg, 8.81 mmol) and chloroacetyl chloride (0.67 ml, 8.42 mmol) were added at room temperature, and the mixture was stirred at 100° C. for 1 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (3.40 g, yield 64%) as a pale-yellow amorphous solid
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([CH2:13]N2C=NC=N2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:19]1([CH:25]=NC2C=CC=CC=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[C:7]1([C:13]#[C:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C(=Nc1ccccc1)c1ccccc1
Reactant: c1ccc(Cn2cncn2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C(#Cc1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 11 %

Procedure:
To potassium t-butoxide (5.6 g, 50 mmol) in DMF (40 mL) at 75° C. was added N-(phenylmethyl)-1H-1,2,4-triazole (1.59 g, 10 mmol) and N-(phenylmethylene)benzenamine (1.81 g, 10 mmol) dissolved in DMF (10 mL). After 30 minutes the solution is poured into ice-cold water (150 mL), extracted with CHCl3 (3×50 mL) and chromatographed (PE). Diphenylacetylene was obtained in 11% yield.