Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:23]([F:26])([F:25])[F:24])[N:3]=1.NC1N=C(N2CCC3(CN(C(OCC4C=CC=CC=4)=O)[C@@H](C(OCC)=O)C3)CC2)C=C(O[C@H](C2C=CC(Cl)=CC=2Br)C(F)(F)F)N=1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][NH:14][C@@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:19][CH2:20]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:23]([F:26])([F:25])[F:24])[N:3]=1
Reactant: Nc1nc(O[C@H](c2ccc(Cl)cc2-c2ccccc2)C(F)(F)F)cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)n1
Agent: CCOC(=O)[C@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Cl)cc4Br)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Product: Nc1nc(O[C@H](c2ccc(Cl)cc2-c2ccccc2)C(F)(F)F)cc(N2CCC3(CC2)CN[C@@H](C(=O)O)C3)n1

Procedure:
The title compound was prepared as described above for (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 34c) by using (R)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.[CH2:13]([O:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH2:20])[CH:14]([CH3:16])[CH3:15]>>[CH2:13]([O:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH:20][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CC(C)COC(=O)[C@H](C)N
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1ccc(Cl)cc1

Procedure:
Following General Procedure BB and using 4-chlorophenylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 111°-13° C. The reaction was monitored by tlc on silica gel and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:12][CH2:13][CH2:14][CH3:15])=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][NH:7][CH3:8].CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:32].[N:33]1([CH2:39][CH2:40][N:41]2[CH2:46][C:45]3[CH:47]=[C:48](/[CH:51]=[CH:52]/[C:53]([OH:55])=O)[CH:49]=[N:50][C:44]=3[NH:43][C:42]2=[O:56])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[ClH:32].[CH3:1][O:2][C:3]1[C:4]([O:12][CH2:13][CH2:14][CH3:15])=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][N:7]([CH3:8])[C:53](=[O:55])/[CH:52]=[CH:51]/[C:48]1[CH:49]=[N:50][C:44]2[NH:43][C:42](=[O:56])[N:41]([CH2:40][CH2:39][N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)[CH2:46][C:45]=2[CH:47]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN(CCN1CCOCC1)C(=O)N2
Reactant: CCCOc1c(CNC)cccc1OC
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: Cl
Product: CCCOc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(CCN2CCOCC2)C(=O)N3)cccc1OC
Yield: 35 %

Procedure:
According to the procedure of Example 1, except substituting 3-methoxy-2-propoxy-benzyl-methylamine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-[3-(2-morpholin-4-yl-ethyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-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, the title compound (0.10 g, 35%) was prepared as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.68 (br s, 1H), 10.13 (m, 1H), 8.40-8.30 (m, 1H), 8.01-7.90 (m, 1H), 7.60-7.42 (m, 1H), 7.29-7.15 (m, 1H), 7.01-6.90 (m, 2H), 6.70-6.60 (m, 1H), 4.80-4.51 (m, 4H), 4.02-3.70 (m, 10H), 3.60-3.50 (m, 2H), 3.42-3.30 (m, 2H), 3.20-2.87 (m, 6H), 1.74-1.67 (m, 2H), 1.00-0.91 (m, 3H); MS (ESI) m/e 524 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:17]3[O:21][C:20]([P:22]([OH:25])([OH:24])=[O:23])=[C:19]([CH2:26][CH3:27])[C:18]=3[CH2:28][CH3:29])[CH:14]=[C:13]([C:30]([OH:32])=[O:31])[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:33][CH2:34]N=C=NCCCN(C)C.C(O)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:17]3[O:21][C:20]([P:22]([OH:25])([OH:24])=[O:23])=[C:19]([CH2:26][CH3:27])[C:18]=3[CH2:28][CH3:29])[CH:14]=[C:13]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CCc1c(-c2cc(C(=O)O)cc(C(=O)Nc3cccc(Br)c3)c2)oc(P(=O)(O)O)c1CC
Agent: CN(C)c1ccncc1
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(=O)Nc2cccc(Br)c2)cc(-c2oc(P(=O)(O)O)c(CC)c2CC)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 1-(3-bromophenylcarbamoyl)-3-carboxy-5-(diethyl 2-phosphonofuran-5-yl)benzene (1 mmol), EDCI (2 mmol), DMAP (0.1 mmol) and ethanol (1.5 mmol) in 70 mL of CH2Cl2 were stirred at rt for 14 h. After evaporation the mixture was redissolved in MeOH and slurried with 5 g of DOWEX 50WX8-400 free acid and 5 g of DOWEX 1X8-400 bicarbonate resin for 4 h and then filtered. The filtrate was evaporated to provide 1-(3-bromophenylcarbamoyl)-3-carboethoxy-5-(diethyl 2-phosphonofuran-5-yl)benzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:15]([N:17](CC)CC)[CH3:16].ClCC#N>C(#N)C>[C:15]([CH2:16][N:12]1[CH2:13][CH2:14][N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1)#[N:17]
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: CCN(CC)CC
Agent: N#CCCl
Solvent: CC#N
Product: COc1ccc(N2CCN(CC#N)CC2)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of 19.2 g (100 mmol) of commercially available 4-methoxyphenyl piperazine in acetonitrile (300 ml), 12.1 g (120 mmol) of triethylamine and 7.6 g (100 mmol) of chloroacetonitrile were subsequently added. The reaction mixture was refluxed for 2 hrs, cooled to room temperature and concentrated in vacuo. To the residue dichloromethane (300 ml) and water (150 ml) were added, the water layer was further extracted with dichloromethane (50 ml), the combined organic layers were dried over sodiumsulphate and concentrated in vacuo. In this manner 18.5 g of 1-(cyanomethyl)-4-(4-methoxyphenyl) piperazine (80%) was obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Mg:11]>O1CCCC1>[CH2:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Br:1][Mg:11]
Reactant: BrC1=Cc2ccccc2C1
Reactant: [Mg]
Solvent: C1CCOC1
Product: C1=Cc2ccccc2C1
Product: [Mg]Br

Procedure:
Bromomagnesium indene was prepared by reacting 3.1 g (15.9 mmol) of 2-bromoindene and 1.6 g of magnesium in 50 ml of tetrahydrofuran in a nitrogen stream.
Reaction SMILES: CN1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:17][CH:18]=2)=[N:5][CH2:4][C:3]1=[O:23].[CH2:24]([O:26]C(=O)OCC)[CH3:25].[H-].[Na+]>>[CH2:24]([O:26][C:3]([C:4]1[NH:5][C:6]([C:13]2[CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:17][CH:18]=2)=[C:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)=[O:23])[CH3:25]
Reactant: CCOC(=O)OCC
Reactant: CN1C(=O)CN=C(c2cccc(C(F)(F)F)c2)c2ccccc21
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1[nH]c(-c2cccc(C(F)(F)F)c2)c2ccccc12

Procedure:
According to the procedure described in Example 1, 1,3-dihydro-1-methyl-5-(α,α,α-trifluoro-m-tolyl)-2H-1,4-benzodiazepin-2-one is reacted with diethylcarbonate in the presence of sodium hydride, and there is obtained 3-(α,α,α-trifluoro-m-tolyl)-isoindole-1-carboxylic acid ethyl ester, having a melting point of 155°-157° C. Recrystallization from ethanol does not increase the melting point.
Reaction SMILES: [F:1][C:2]([F:10])([C:5]([F:9])([F:8])[CH2:6][OH:7])[CH2:3][OH:4].[H-].[Na+].[CH2:13](Br)[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[F:1][C:2]([F:10])([C:5]([F:9])([F:8])[CH2:6][O:7][CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][OH:4]
Reactant: OCC(F)(F)C(F)(F)CO
Reactant: BrCC=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCC(F)(F)C(F)(F)COC/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 1.3 h
Yield: 52.6 %

Procedure:
To a solution 2,2,3,3-tetrafluoro-1,4-butanediol (2.0 g, 12.3 mmol) in dimethylformamide (30 mL) was added 60% sodium hydride (0.140 g, 18.4 mmol). The mixture was stirred at room temperature for 1.30 hours. Then, a solution of cinnamyl bromide (3.2 g, 12.3 mmol) in dimethylformamide (40 mL) was added. The mixture was stirred at room temperature overnight and concentrated. The residue was dissolved with ethyl acetate (50 mL), washed with water (2×25 mL) and brine (25 mL), dried (Na2SO4), and the solvent removed under reduced pressure. Purification by column chromatography with silica gel and n-hexane/ethyl acetate (from pure n-hexane to 5:1) gave the title compound (1.8 g, 54%) as oil.
Reaction SMILES: O1CC[O:3][CH:2]1[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:7]=1[CH:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].N1C=CN=C1.[C:28]([Si:32](Cl)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([CH3:31])([CH3:30])[CH3:29].CN(C=[O:50])C>CCOCC>[Si:32]([O:50][CH:17]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:16][C:7]1[CH:8]=[C:9]([O:14][CH3:15])[C:10]([O:12][CH3:13])=[CH:11][C:6]=1[CH:2]=[O:3])([C:28]([CH3:31])([CH3:30])[CH3:29])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCCCCC(O)c1cc(OC)c(OC)cc1C1OCCO1
Agent: c1c[nH]cn1
Solvent: CCOCC
Product: CCCCC(Cc1cc(OC)c(OC)cc1C=O)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Yield: 99 %

Procedure:
A solution of (±)-1-(1,3-dioxolanyl)-2-(1-hydroxy)hexyl-4,5-dimethoxybenzene (Compound 32, 2.2 g, 7.09 mmol), imidazole (0.97 g, 14.19 mmol) and t-butylchlorodiphenylsilane (2.8 mL, 10.64 mmol) in DMF (14 mL) was stirred at 23° C. for 72 hours. The reaction was diluted with Et2O and washed with 1N HCl, H2O and brine. The organic portion was dried (MgSO4), filtered and concentrated in vacuo. Flash column chromatography (silica gel, 5:1 hex/EtOAc) gave 3.52 g (99%) of the title compound wherein absence of the acetal blocking group to give the free aldehyde function was unexpected.
Reaction SMILES: N.CC1C=CC(S([N:12]2[CH2:20][CH2:19][O:18][C:17]3[CH:21]=[CH:22][C:23]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][C:16]=3[O:15][CH2:14][CH2:13]2)(=O)=O)=CC=1.[Na].[Cl-:31].[NH4+]>C(OCC)(=O)C.CO>[ClH:31].[O:18]1[C:17]2[CH:21]=[CH:22][C:23]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][C:16]=2[O:15][CH2:14][CH2:13][NH:12][CH2:20][CH2:19]1
Reactant: [Cl-]
Reactant: Cc1ccc(S(=O)(=O)N2CCOc3ccc(NS(C)(=O)=O)cc3OCC2)cc1
Agent: N
Agent: [NH4+]
Agent: [Na]
Solvent: CO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccc2c(c1)OCCNCCO2
Product: Cl
Temperature: 25 °C

Procedure:
To ammonia (50 mL) and CH3OH (9 mL) at -78° C. add 4-[(4-methylphenyl)sulfonyl]-9-[(methylsulfonyl)amino]-3,4,5,6-tetrahydro-2H-1,7,4-benzodioxazonine (8.5 g, 20 mmol) and sodium spheres (4.5 g, 0.20 mol). Monitor the progress of the reaction by thin-layer chromatography. Upon completion add ammonium chloride (11 g) and allow the reaction to warm to room temperature. Slurry the residue in ethyl acetate and remove the solid material by suction filtration through celite. Remove the solvent in vacuo. Dissolve the residue in CH3OH and add methanolic hydrochloric acid. Remove the solvent in vacuo and recrystallize from acetonitrile to obtain the title compound.
Reaction SMILES: Br.Br.Br.[NH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)=[O:12])[N:9]=1.[F:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[C:30](O)=[O:31]>>[F:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[C:30]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][C:11]([N:13]2[CH2:14][CH2:15][N:16]([CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[CH2:17][CH2:18]2)=[O:12])[N:9]=1)=[O:31]
Reactant: CN1CCC(N2CCN(C(=O)Cc3csc(N)n3)CC2)CC1
Reactant: COc1ccc(C(=O)O)cc1F
Agent: Br
Product: COc1ccc(C(=O)Nc2nc(CC(=O)N3CCN(C4CCN(C)CC4)CC3)cs2)cc1F

Procedure:
In analogy to example 47.3, 2-(2-amino-thiazol-4-yl)-1-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-ethanone trihydrobromide (example 47.2) was coupled with 3-fluoro-4-methoxybenzoic acid, using general method D, to give 3-fluoro-4-methoxy-N-(4-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-benzamide. Off-white amorphous solid. MS 476.3 ([M+H]+)
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[F:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][NH2:38].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[F:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][NH:38][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:31])([F:1])[F:32])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:30]
Reactant: NCc1cccc(F)c1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(NCc1cccc(F)c1)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (50 mg, 0.11 mmol) was combined with 3-fluorobenzylamine (14 mg, 0.11 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg, 0.14 mmol), 1-hydroxybenzotriazole (17 mg, 0.13 mmol), and triethylamine (0.064 ml, 0.46 mmol) in 1 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 30 ml of ethyl acetate, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to afford 49 mg of the title compound as a colorless solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[C@@H:21]4[C@@H:16]([C:17]5[CH:25]=[CH:24][C:23]([C:26]([OH:28])=O)=[CH:22][C:18]=5[CH2:19][CH2:20]4)[CH2:15][CH2:14][CH2:13]3)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH3:29]>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[C@@H:21]4[C@@H:16]([C:17]5[CH:25]=[CH:24][C:23]([C:26]([NH2:29])=[O:28])=[CH:22][C:18]=5[CH2:19][CH2:20]4)[CH2:15][CH2:14][CH2:13]3)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2c(c1)CC[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Reactant: N
Product: NC(=O)c1ccc2c(c1)CC[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Yield: 58 %

Procedure:
The title compound is prepared from cis-4-(1H-benzoimidazole-5-carbonyl)-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline-8-carboxylic acid and ammonia (28% in water) following a procedure analogous to that described in Example 1. Yield: 58% of theory; LC (method 1): tR=1.78 min; Mass spectrum (ESI+): m/z=375 [M+H]+.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:8]([CH:12]=O)=[N:9][NH:10][CH:11]=1)=[O:6])([CH3:3])[CH3:2].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH2:24])[C:19]([NH2:23])=[CH:20][C:21]=1[CH3:22]>ClCCl.CO>[CH:1]([NH:4][C:5]([C:7]1[C:8]([C:12]2[NH:23][C:19]3[CH:20]=[C:21]([CH3:22])[C:16]([O:15][CH3:14])=[CH:17][C:18]=3[N:24]=2)=[N:9][NH:10][CH:11]=1)=[O:6])([CH3:2])[CH3:3]
Reactant: CC(C)NC(=O)c1c[nH]nc1C=O
Reactant: COc1cc(N)c(N)cc1C
Solvent: CO
Solvent: ClCCl
Product: COc1cc2nc(-c3n[nH]cc3C(=O)NC(C)C)[nH]c2cc1C

Procedure:
By proceeding in a manner similar to Example 235(a) above but using 3-formyl-pyrazole-4-carboxylic acid-isopropylamide [198 mg, Reference Example 60)] and 4-methoxy-5-methyl-benzene-1,2-diamine [166 mg, Reference Example 29(b)] and subjecting the reaction product to flash chromatography on silica eluting with dichloromethane/methanol (95:5) followed by recrystallisation from a mixture of ethyl acetate and n-pentane there was prepared 3-(5-methoxy-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid isopropylamide (145 mg) as a white solid. LC-MS (Method H): RT=2.09 minutes, 314.27 (M+H)+, 312.29 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][NH2:38]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:38][CH2:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=1)=[O:29]
Reactant: COc1cc2c(c(OC)c1)C(Cc1ccc(OC)c(OC)c1)NCC2
Reactant: O=C(Br)CBr
Reactant: NCc1ccccn1
Product: COc1cc2c(c(OC)c1)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NCc1ccccn1)CC2

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-picolylamine
Reaction SMILES: Cl([O-])(=O)(=O)=[O:2].[Cl:6][C:7]([C:13]([C:18]#N)=[CH:14][N:15](C)C)=[N:8][CH:9]=[N+:10]([CH3:12])[CH3:11]>C(#N)C.O>[Cl:6][C:7]([N:8]=[CH:9][N:10]([CH3:12])[CH3:11])=[C:13]([CH:18]=[O:2])[C:14]#[N:15]
Reactant: [O-][Cl+3]([O-])([O-])[O-]
Reactant: CN(C)C=C(C#N)C(Cl)=NC=[N+](C)C
Solvent: CC#N
Solvent: O
Product: CN(C)C=NC(Cl)=C(C#N)C=O
Reaction time: 6 h
Yield: 60.7 %

Procedure:
100 g of N-(3-chloro-4-cyano-5-dimethylamino-2-aza-2,4-pentadienylidene)N,N-dimethylammonium perchlorate are dissolved in a mixture of 400 ml of acetonitrile and 400 ml of water. Stirring is carried out for 6 hours at 20° to 22°C and is followed by double extraction with two 400 ml portions of trichloromethane. Following this the combined trichloromethane phases are extracted twice with two 1000 ml portions of water. The organic phase is dried with Na2SO4 or MgSO4 and reduced in volume by distilling off of the solvent at 30° to 35°C to a quarter of the original volume. After allowing the resultant to stand for one hour in an ice-box at about 0°C, the precipitate is vacuum filtered to yield yellowish crystals. 36 g (61%) of 3-chloro-5-dimethylamino-2-formyl-4-aza-2,4-pentadienenitrile, with a melting point of 144°C (with decomposition), are thus obtained.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:11]1[N:16]=[CH:15][C:14]2[C:17](=[C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([F:31])[CH:29]=4)[NH:24][C:23]3=[O:32])[O:18][CH:19]([CH2:20][CH3:21])[C:13]=2[C:12]=1[Cl:33].O>O1CCOCC1>[Cl:33][C:12]1[C:13]2[CH:19]([CH2:20][CH3:21])[O:18][C:17](=[C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([F:31])[CH:29]=4)[NH:24][C:23]3=[O:32])[C:14]=2[CH:15]=[N:16][C:11]=1[NH:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCC1OC(=C2C(=O)Nc3ccc(F)cc32)c2cnc(Cl)c(Cl)c21
Reactant: NCCN1CCOCC1
Solvent: C1COCCO1
Solvent: O
Product: CCC1OC(=C2C(=O)Nc3ccc(F)cc32)c2cnc(NCCN3CCOCC3)c(Cl)c21
Temperature: 100 °C
Yield: 17.8 %

Procedure:
A solution of 2-morpholin-4-yl-ethylamine (178 mg, 1.37 mmol) in 3 mL of dioxane is treated with 3-(6,7-dichloro-1-ethyl-1H-furo[3,4-c]pyridin-3-ylidene)-5-fluoro-1,3-dihydro-indol-2-one (100 mg, 0.27 mmol) in one portion and the reaction mixture is heated to 100° C. for 12 hr. The reaction mixture is treated with 12 mL of water and then heated at reflux for 1 hr. The reaction mixture is cooled to room temperature and the precipitate which formed is collected by filtration and dried under vacuum to give the title compound as a yellow solid (22 mg, 18%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]1[CH2:15][O:14]C(C)(C)[O:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([OH:12])[CH2:15][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OC[C@H](CCOCc2ccccc2)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: OC[C@@H](O)CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.2 %

Procedure:
In methanol (50 ml) were dissolved (S)-4-(2-benzyloxyethyl)-2,2-dimethyl-1,3-dioxolane (2.06 g, 8.73 mmol) and p-toluenesulfonic acid hydrate (1.68 g, 8.8 mmol), and the solution was stirred at room temperature for 24 hours. After removal of methanol in vacuo, aqueous saturated sodium hydrogen carbonate was added to neutralize the solution. The solution was extracted with ethyl acetete and the extract was washed with saturated brine, dried on sodium sulfate, filtered, and condensed in vacuo. The residue was subjected to silica gel chromatography to give (S)-4-benzyloxy-1,2-butanediol (1.70 g, yield 99%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:17][CH2:16][CH2:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:7]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](=[O:28])[CH3:27])=[CH:21][CH:20]=1>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:7]=[C:2]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][C:26](=[O:28])[CH3:27])=[CH:23][CH:24]=3)[C:3]3[CH2:17][CH2:16][CH2:15][C:4]=3[N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cccc(-c2nc(Cl)c3c(n2)CCC3)c1
Reactant: CC(=O)Cc1ccc(N)cc1
Product: CC(=O)Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Yield: 59.4 %

Procedure:
Following general procedure B1, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.140 g, 0.53 mmol) was reacted with 1-(4-aminophenyl)propan-2-one (0.094 g, 0.63 mmol) to afford the title compound (0.119 g, 60%) as a light yellow solid. MW=377.87. 1H NMR (DMSO-d6, 500 MHz) δ 8.84 (s, 1H), 8.29-8.22 (m, 2H), 7.75 (d, J=8.5 Hz, 2H), 7.55-7.48 (m, 2H), 7.20 (d, J=8.5 Hz, 2H), 3.74 (s, 2H), 2.94-2.84 (m, 4H), 2.15 (s, 3H), 2.14-2.06 (m, 2H); APCI MS m/z 378 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29]O)=[N:27][CH:28]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.CCOC(C)=O>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][O:18][C:15]2[CH:16]=[CH:17][N:12]([C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:20]([CH3:21])=[C:4]([CH:1]5[CH2:3][CH2:2]5)[N:5]=4)[CH:8]=3)[C:13](=[O:19])[CH:14]=2)=[N:27][CH:28]=1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Reactant: OCc1ccc(Cl)cn1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(Cl)cn4)cc3=O)cn12
Reaction time: 3 h
Yield: 53.1 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), (5-chloropyridin-2-yl)methanol (102 mg) and tributylphosphine (266 μl) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (269 mg) at 60° C., and the mixture was stirred at the same temperature for 3 h. The mixture was diluted with EtOAc, and washed with water and brine. The organic layer was concentrated, and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (76.8 mg) as a white solid.