Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([NH:7][C:8]2[CH:27]=[CH:26][C:11]([O:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[CH:10][CH:9]=2)=[O:6])[CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[N:37]1[CH:38]=[CH:39][CH:40]=[C:35]([N:1]2[CH2:4][CH:3]([C:5]([NH:7][C:8]3[CH:9]=[CH:10][C:11]([O:12][CH:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:17][CH2:18]4)=[CH:26][CH:27]=3)=[O:6])[CH2:2]2)[CH:36]=1
Reactant: Brc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)C3CNC3)cc2)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)C3CN(c4cccnc4)C3)cc2)CC1
Temperature: 100 °C

Procedure:
tert-Butyl 4-(4-(azetidine-3-carboxamido)phenoxy)piperidine-1-carboxylate (4.97 g, 13.24 mmol), cesium carbonate (10.78 g, 33.1 mmol), 3-bromopyridine (1.307 ml, 13.24 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.764 g, 1.32 mmol) and bis(dibenzylideneacetone)palladium(0) (0.606 g, 0.662 mmol) were suspended in dioxane (50 ml), bubbled with nitrogen for 30 minutes and heated at 100° C. overnight. The mixture was filtered through a celite pad with dichloromethane washes and the filtrate was concentrated. Normal phase chromatography provided the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)=[O:14])[C:6]([CH3:12])=[N:7]2.[CH3:27][O-:28].[Na+]>CO>[CH3:27][O:28][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)=[O:14])[C:6]([CH3:12])=[N:7]2
Reactant: Cc1nc2nccc(Cl)c2cc1C(=O)NCc1cccc(C(F)(F)F)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccnc2nc(C)c(C(=O)NCc3cccc(C(F)(F)F)c3)cc12
Yield: 78.9 %

Procedure:
5-Chloro-2-methyl-N-(3-(trifluoromethyl)benzyl)-1,8-naphthyridine-3-carboxamide (100 mg, 0.26 mmol) was dissolved in MeOH (10 ml) together with sodium methoxide (30 mg, 0.55 mmol) and refluxed for 18 hours. The reaction was cooled and evaporated, the residue was purified by flash chromatography using CH2Cl2/CH3OH (20:1→10:1) as eluent to give 77 mg (79%) of 5-methoxy-2-methyl-N-(3-(trifluoromethyl)benzyl)-1,8-naphthyridine-3-carboxamide as a pale mass.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]3=[N:18][S:19](=[O:23])(=[O:22])[CH2:20][CH2:21][N:16]3[CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1>C1COCC1.CO.[Pt](=O)=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[C:17]3=[N:18][S:19](=[O:22])(=[O:23])[CH2:20][CH2:21][N:16]3[CH2:15][CH2:14][CH2:13]2)=[CH:10][CH:11]=1
Reactant: Cc1cccc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)c1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cccc(Oc2ccc(C3CCCN4CCS(=O)(=O)N=C34)cc2)c1
Temperature: 50 °C
Reaction time: 6 h
Yield: 67.5 %

Procedure:
Platinum(IV) oxide (30 mg) was added to a solution of 9-[4-(3-methylphenoxy)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (357 mg) in THF (dry) (80 mL) and MeOH (80 mL) and the mixture was stirred at 50° C. under hydrogen for 6 hr. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from MeCN-THF/IPE to give the title compound (243.5 mg) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]([N:11]1[CH:15]=[C:14]([NH:16][C:17](=[O:23])[CH:18]([NH2:22])[CH2:19][CH2:20][CH3:21])[N:13]=[CH:12]1)([CH3:10])[CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[F:24][C:25]1[CH:26]=[C:27]([CH2:32][C:33](O)=[O:34])[CH:28]=[C:29]([F:31])[CH:30]=1>>[CH3:1][C:2]([N:11]1[CH:15]=[C:14]([NH:16][C:17](=[O:23])[CH:18]([NH:22][C:33](=[O:34])[CH2:32][C:27]2[CH:26]=[C:25]([F:24])[CH:30]=[C:29]([F:31])[CH:28]=2)[CH2:19][CH2:20][CH3:21])[N:13]=[CH:12]1)([CH3:10])[CH2:3][N:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9]1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCOCC2)cn1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)CN2CCOCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide was coupled with (3,5-Difluoro-phenyl)-acetic acid to provide the title compound: C13 NMR (100 MHz, CDCl3) 14.0, 19.0, 25.8, 35.7, 43.1, 53.3, 55.5, 59.7, 67.4, 68.6, 102.9, 105.4, 112.4, 112.6, 130.9, 136.7, 169.4, 169.5; MS m/z 478.2 (M+1).
Reaction SMILES: CC1C=CC(S(OCC2CC3C(C4C=CC=CC=4)=CC=CC=3O2)(=O)=O)=CC=1.[N-]=[N+]=[N-].[Na+].[C:32]1([C:38]2[C:43]3[CH2:44][CH:45]([CH2:47][N:48]=[N+]=[N-])[O:46][C:42]=3[CH:41]=[CH:40][CH:39]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[N-]=[N+]=[N-].Cl>C(O)C.[Pd].C(O)(C)C>[C:32]1([C:38]2[C:43]3[CH2:44][CH:45]([CH2:47][NH2:48])[O:46][C:42]=3[CH:41]=[CH:40][CH:39]=2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: [N-]=[N+]=NCC1Cc2c(cccc2-c2ccccc2)O1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)OCC2Cc3c(cccc3-c3ccccc3)O2)cc1
Agent: Cl
Solvent: CCO
Solvent: CC(C)O
Product: NCC1Cc2c(cccc2-c2ccccc2)O1
Reaction time: 6 h
Yield: 94 %

Procedure:
Treatment of (±)-(4-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.36 g, 3.57 mmol) with sodium azide (0.929 g, 14.29 mmol) generally according to the procedure described for intermediate 98 afforded (±)-(4-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl azide. The azide was dissolved in ethanol (50 mL) and palladium on carbon (0.083 g, 10 wt. %) was added and the reaction mixture was shaken under an H2 atmosphere (50 psi) for 6 h. The reaction mixture was filtered (celite) and the solvent removed in vacuo to provide a colorless oil. The oil was re-dissolved in isopropanol (3 mL) and hydrogen chloride (1.0 N in diethyl ether, 10.0 mL) was added. The resulting precipitate was filtered, washed (diethyl ether), and dried to afford 0.700 g (94%) of (±)-1-(4-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. mp 229-230° C.; Anal. calcd. for C15H15NOHCl: C, 68.83; H, 6.16; N, 5.35. Found: C, 66.11; H, 6.25; N, 5.02.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9].[Na+].[O:25]1[CH2:30][CH2:29][N:28]([C:31]2([C:34]([O-])=[O:35])[CH2:33][CH2:32]2)[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:34]([C:31]2([N:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)[CH2:33][CH2:32]2)=[O:35])[C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: O=C([O-])C1(N2CCOCC2)CC1
Agent: [Na+]
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)C2(N3CCOCC3)CC2)CC1
Yield: 65 %

Procedure:
The reaction of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7H with 1-morpholinocyclopropanecarboxylic acid sodium salt 16J carried out according to the general procedure L yielded (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-morpholinocyclopropanecarbonyl)pyrrolidine-2-carboxamide as a yellow oil (65%). MS ISP (m/e): 507.2 (100) [(M+H)]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][C:13](=[N:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)SC)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.[NH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1>C1COCC1>[CH2:19]([O:18][C:17]([N:16]=[C:13]([NH:12][C:10]([C:3]1[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=1)=[O:11])[NH:27][CH:28]1[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:33]1)=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CSC(=NC(=O)OCc1ccccc1)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(NC(=NC(=O)OCc2ccccc2)NC(=O)c2nc(Cl)c(N)nc2N)CC1

Procedure:
A suspension of benzyl (3,5-diamino-6-chloropyrazine-2-carboxamido)(methylthio)methylenecarbamate (Intermediate B) (6.7 g, 17 mmol) and 4-amino-1-Boc-piperidine (4.1 g, 20.4 mmol) in dry THF (150 mL) is heated at reflux overnight. The solvent is removed in vacuo and a solid forms on concentration. The solid is separated and retained and the remaining mother liquor is concentrated to form a solid. The solid is partitioned between EtOAc and water and the organic portion is dried (MgSO4) and part concentrated in vacuo and then left to crystallise. The crystals are filtered and combined with the retained solid to afford the title product. [M+H]+ 547
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[C@H:6]([CH3:8])[NH2:7])[CH3:3].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1.[O:32]=[C:33]1[NH:37][CH:36]([CH2:38][CH2:39][C:40](O)=[O:41])[CH2:35][CH2:34]1>ClCCl.CN(C)C1C=CN=CC=1>[O:41]=[C:40]([NH:7][C@H:6]([C:5]([O:4][CH2:2][CH3:3])=[O:9])[CH3:8])[CH2:39][CH2:38][CH:36]1[CH2:35][CH2:34][C:33](=[O:32])[NH:37]1
Reactant: O=C(O)CCC1CCC(=O)N1
Reactant: CCOC(=O)[C@H](C)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](C)NC(=O)CCC1CCC(=O)N1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 5.0 g (0.033 mol) L-alanine ethyl ester hydrochloride is dissolved in 30 ml of dichloromethane. The solution is cooled to 0° C. and 5.42 ml (0.039 mol) of triethylamine is added dropwise over a ten minute period. The mixture is stirred 15 minutes, filtered, concentrated, and diluted with 60 ml of dichloromethane. A mixture of the following is added in a single addition: 4.84 g (0.025 mol) of dicyclohexylcarbodiimide; 200 mg (0.0016 mol) of 4-dimethylaminopyridine; 3.08 g (0.02 mol) of 5-oxo-2-pyrrolidinepropanoic acid. The reaction is allowed to warm to room temperature and stirred for 24 hours. The solids are removed by filtration and are washed with 15 ml of 0° C. dichloromethane. The filtrate is concentrated at reduced pressure to an oil. The oil is chromatographed over silica gel using 19:1 dichloromethane-methanol for elution. Concentration at reduced pressure followed by heating at 0.1 mm pressure and 60° C. yields crystalline analytically pure N-[1-oxo-3-(5-oxo-2-pyrrolidinyl)propyl]-L-alanine, ethyl ester with a melting point of 88°-90° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]2[NH:11][C:12](=[O:28])[C:13]3[C:14](=[C:16]([CH2:26][CH3:27])[N:17]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:18]=3)[N:15]=2)=[CH:8][C:7]([S:29]([N:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH3:39])[CH2:34][CH2:33]2)(=[O:31])=[O:30])=[CH:6][N:5]=1)[CH3:2].ClC1C=C(C=CC=1)C(O)=[O:45].ClC1C=C(C=CC=1)C(OO)=O>ClCCl>[CH2:1]([O:3][C:4]1[C:9]([C:10]2[NH:11][C:12](=[O:28])[C:13]3[C:14](=[C:16]([CH2:26][CH3:27])[N:17]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:18]=3)[N:15]=2)=[CH:8][C:7]([S:29]([N:32]2[CH2:37][CH2:36][N+:35]([CH2:38][CH3:39])([O-:45])[CH2:34][CH2:33]2)(=[O:30])=[O:31])=[CH:6][N:5]=1)[CH3:2]
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(Cc3ccccn3)nc2c(=O)[nH]1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOc1ncc(S(=O)(=O)N2CC[N+]([O-])(CC)CC2)cc1-c1nc2c(CC)n(Cc3ccccn3)nc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 180.3 %

Procedure:
A mixture of the title compound of Example 1 (180 mg, 0.32 mmol), 3-chlorobenzoic acid (13 mg, 0.08 mmol) and dichloromethane (10 ml) was stirred at room temperature for 20 minutes, 3-chloroperoxybenzoic acid (112 mg, 0.32 mmol) added and the reaction mixture stirred for a further 18 hours, then partitioned between dichloromethane (20 ml) and aqueous sodium bicarbonate solution (10 ml). The phases were separated, the aqueous phase extracted with dichloromethane (2×20 ml) and the combined organic solutions dried (MgSO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using dichloromethane: methanol (80:20) as eluant, to furnish the title compound (82 mg, 45%) as a white powder. Found: C, 52.73; H, 5.67; N, 17.69. C26H32N8O5S; 0.50 CH2Cl2 requires C, 52.08; H, 5.44; N, 18.34%. δ (CDCl3): 1.30 (3H,t), 1.40 (3H,t), 1.58 (3H,t), 3.02 (2H,q), 3.20 (2H,m), 3.32 (4H,m), 3.48 (2H,m), 3.72 (2H,m), 4.76 (2H,q), 5.68 (2H,s), 7.08 (1H,d), 7.22 (1H,m), 7.63 (1H,m), 8.58 (1H,d), 8.65 (1H,s), 9.03 (1H,s), 10.70 (1H,s).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl[CH:26]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(OC(N1CCC2NN(C3CCCCCC3)C(C3C=CC(Cl)=CC=3)C=2CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH:26]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: ClC1CCCCCC1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: CC(C)(C)OC(=O)N1CCC2=C(CC1)C(c1ccc(Cl)cc1)N(C1CCCCCC1)N2
Product: Clc1ccc(-c2nn(C3CCCCCC3)c3c2CCNCC3)cc1
Yield: 21.3 %

Procedure:
The title compound (22 mg) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.30 mmol) using chloro-cycloheptane (1.0 mmol) in place of chloro-cyclobutane according to Example 238. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-cycloheptyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C20H26ClN3, 343.18; found, m/z 344.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.40-7.34 (m, 4H), 4.31-4.27 (m, 1H), 3.39-3.37 (m, 2H), 3.28-3.26 (m, 2H), 3.17-3.16 (m, 2H), 2.95-2.92 (m, 2H), 2.04-2.01 (m, 2H), 1.92-1.90 (m, 2H), 1.77-1.75 (m, 2H), 1.63-1.53 (m, 6H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:20]1[N:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]3)=[C:31]([O:41][CH3:42])[CH:30]=2)[N:21]=1>CO>[CH3:27][O:26][C:24]1[N:23]=[C:22]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]3)=[C:31]([O:41][CH3:42])[CH:30]=2)[N:21]=[C:20]([N:2]2[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][CH2:3]2)[N:25]=1
Reactant: O=C(O)CC1CCNCC1
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc(N2CCC(CC(=O)O)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
4-Piperidineacetic acid hydrochloride (381 mg, 2.12 mmol) was suspended in 10 ml of methanol. Triethylamine (0.9 ml, 6.45 mmol) was added, followed by (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine (700 mg, 2.02 mmol). The resulting mixture was stirred overnight at room temperature, concentrated and subjected to column chromatography on Si—NH2 (Isolute) using dichloromethane/methanol 95:5 v/v as an eluent. The material isolated was further purified by several triturations in water to give the final compound (792 mg, 87%) as a slightly brownish solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](C2C=CC(C(OC)=O)=CC=2)=[CH:4][C:3]=1[C:18]1[N:19]=[CH:20][C:21]2[C:26]([CH:27]=1)=[C:25]([Cl:28])[CH:24]=[CH:23][C:22]=2[F:29].BrC1C=C(C2N=CC3C(C=2)=C(Cl)C=CC=3F)C(N)=NC=1.[C:50]([C:54]1[CH:55]=[C:56](B(O)O)[CH:57]=[CH:58][CH:59]=1)([O:52][CH3:53])=[O:51].C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:58]2[CH:59]=[C:54]([CH:55]=[CH:56][CH:57]=2)[C:50]([O:52][CH3:53])=[O:51])=[CH:4][C:3]=1[C:18]1[N:19]=[CH:20][C:21]2[C:26]([CH:27]=1)=[C:25]([Cl:28])[CH:24]=[CH:23][C:22]=2[F:29]
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: COC(=O)c1ccc(-c2cnc(N)c(-c3cc4c(Cl)ccc(F)c4cn3)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Nc1ncc(Br)cc1-c1cc2c(Cl)ccc(F)c2cn1
Agent: O=C([O-])[O-]
Product: COC(=O)c1cccc(-c2cnc(N)c(-c3cc4c(Cl)ccc(F)c4cn3)c2)c1

Procedure:
Following the procedure for methyl 4-[6-amino-5-(5-chloro-8-fluoroisoquinolin-3-yl)-pyridin-3-yl]-benzoate, the title compound was prepared from 5-bromo-3-(5-chloro-8-fluoroisoquinolin-3-yl)-pyridin-2-ylamine (BB4) (0.4 g, 1.13 mmol), 3-(carbomethoxy)phenylboronic acid (0.214 g, 1.2 mmol), Pd(PPh3)4 (5 mol %) and Cs2CO3 (0.89 g, 2.3 mmol). 1H NMR (CDCl3, 300 MHz): δ=6.59 (bs, 2H), 7.20 (dd, J=8.4, 7.8 Hz, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.43 (dd, J=5.2, 4.8 Hz, 1H), 7.80 (dd, J=6.8, 2.4 Hz, 1H), 8.01 (dd, J=6.8, 2.4 Hz, 1H), 8.17 (d, J=2.1 Hz, 1H), 8.28 (t, J=1.8 Hz, 1H), 8.44 (d, J=2.4 Hz, 1H), 9.59 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])=[CH:23][CH:22]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)=[O:33])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: COc1ccc(-c2ocnc2C(=O)O)cc1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: COc1ccc(-c2ocnc2C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)c2)cc1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(4-methoxy-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[C:14]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[N:13]=[C:12]1[CH3:30])C.[OH-].[Na+]>CCO.CCOC(C)=O>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:14]2[N:13]=[C:12]([CH3:30])[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:31])=[O:3])[C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:28][CH:27]=1
Reactant: CCOC(=O)CCCCCCn1c(C)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1CCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
(Scheme 1, (C)) To a solution of 7-[4,5-Bis-(4-fluoro-phenyl)-2-methyl-imidazol-1-yl]-heptanoic acid ethyl ester (1.9 g, 4.4 mmol) in EtOH (10 mL) was added NaOH (10 N, 2 mL, 20 mmol). The resulting mixture was stirred at rt for 1 hour, diluted with EtOAc (100 mL), washed by HCl (0.5 N), and then was dried over MgSO4. After filtration and concentration in vacuo, the residue was purified by flash chromatography (SiO2: MeOH/CH2Cl2). This compound was obtained as a white solid in HCl salt form (1.9 g, 4.3 mmol, 98% yield): 1H NMR (DMSO): δ1.15 (m, 4H), 1.37 (t, 2H), 1.47 (t, 2H), 2.13 (t, 2H), 2.73 (s, 3H), 4.03 (t, 2H), 7.35 (t,2H), 7.45 (m, 4H), 7.57 (m, 2H), 12.1 (b, 1H).
Reaction SMILES: [CH:1]1[C:11]2[CH:10](O)[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:19])=O>C(Cl)Cl>[Cl:19][CH:10]1[C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[CH2:7][O:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]1=2
Reactant: O=S(Cl)Cl
Reactant: OC1c2ccccc2COc2ccccc21
Solvent: ClCCl
Product: ClC1c2ccccc2COc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cooled suspension of 6,11-dihydrodibenzo[b,e] oxepine-11-ol (4.0 g) in methylene chloride (80 ml) was added thionyl chloride (2.74 ml). The mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure to give 11-chloro-6,11-dihydrodibenzo[b,e] oxepine as an oily substance. The whole substance was used for next reaction without isolation and purification.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([OH:17])[C:9]2[C:8](=[O:18])[CH2:7][C:6]([CH3:20])([CH3:19])[CH2:5][C:4]=2[N:3]=1.[CH2:21]([Zn]CC)[CH3:22]>>[CH2:21]([C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([OH:17])[C:9]2[C:8](=[O:18])[CH2:7][C:6]([CH3:20])([CH3:19])[CH2:5][C:4]=2[N:3]=1)[CH3:22]
Reactant: CC[Zn]CC
Reactant: CCOC(=O)c1c(Cl)nc2c(c1O)C(=O)CC(C)(C)C2
Product: CCOC(=O)c1c(CC)nc2c(c1O)C(=O)CC(C)(C)C2

Procedure:
Obtained by starting from ethyl 2-chloro-4-hydroxy-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline-3-carboxylate. Diethylzinc (1 M in hexane) is used instead of isopropyl-zinc-bromide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([CH3:14])[CH2:8][C:9](OCC)=[O:10])=[CH:3][CH:2]=1.[NH3:15]>>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([CH3:14])[CH2:8][C:9]([NH2:15])=[O:10])=[CH:3][CH:2]=1
Reactant: N
Reactant: CCOC(=O)CC(C)c1ccncc1
Product: CC(CC(N)=O)c1ccncc1
Yield: 47 %

Procedure:
A solution of ethyl 3-(pyridin-4-yl)butanoate (0.50 g, 2.59 mmol) in methanolic ammonia (10 ml) was heated to 100° C. in a pressure bomb for 48 h. The solvent was evaporated under reduced pressure to afford the crude compound, which was washed with n-pentane and dried under reduced pressure to afford 0.2 g (47%) of 3-(pyridin-4-yl)butanamide as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.[OH-].[Na+].[Cl:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[CH:16][N:15]=1>O.CC(C)=O>[Cl:13][C:14]1[N:19]=[C:18]([O:9][C:5]2[C:4]([CH3:10])=[CH:3][C:2]([NH2:1])=[C:7]([CH3:8])[CH:6]=2)[CH:17]=[CH:16][N:15]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Cc1cc(O)c(C)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(Oc2ccnc(Cl)n2)c(C)cc1N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 7.55 g (55 mmol) 4-amino-2,5-dimethylphenol and 2.4 g NaOH (2M) in 30 ml water were added dropwise to a solution of 7.45 g (50.0 mmol) of 2,4-dichloropyrimidine in 50 ml of acetone. The reaction mixture was stirred for 20 h at ambient temperature. After concentration in vacuo and addition of 150 ml water the formed precipitate was filtered by suction. Yield 10.6 g (75%) with a purity of 88% log P (pH=2.3)=1.37.
Reaction SMILES: C([O:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]([O:18][CH2:19][CH3:20])[CH3:17])=[CH:11][CH:10]=1)[CH3:8])(=O)CCC>C(O)C.[OH-].[K+]>[CH2:19]([O:18][CH:16]([O:15][C:12]1[CH:11]=[CH:10][C:9]([CH:7]([OH:6])[CH3:8])=[CH:14][CH:13]=1)[CH3:17])[CH3:20]
Reactant: CCCC(=O)OC(C)c1ccc(OC(C)OCC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(C)Oc1ccc(C(C)O)cc1
Yield: 90 %

Procedure:
In 210 ml of 1N ethanol solution of potassium hydroxide was dissolved 28 g (0.1 mole) of the R-form of 1-(4-(1-ethoxyethoxy)phenyl)ethyl butyrate obtained in Example 2 (i), (ii) or (iii), the mixture was reacted at room temperature over night, and the reaction mixture was concentrated under reduced pressure To the residue was added 200 ml of ether, and it was washed with 2N aqueous solution of sodium hydroxide 2 times and then with water 3 times. The resulting ether layer was dried with anhydrous magnesium sulfate and ether was distilled under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane=1/4) to give 18.9 g of R-form of 1-(4-(1-ethoxyethyoxy)phenyl)ethanol (yield: 90%).