Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:10]1[N:15]=[C:14]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH:13]=[CH:12][CH:11]=1)([C:5]1[S:6][CH:7]=[CH:8][N:9]=1)[CH2:3][CH3:4].[CH3:25]I>C1COCC1>[CH3:25][O:1][C:2]([C:10]1[N:15]=[C:14]([CH2:16][O:17][Si:18]([C:21]([CH3:23])([CH3:22])[CH3:24])([CH3:19])[CH3:20])[CH:13]=[CH:12][CH:11]=1)([C:5]1[S:6][CH:7]=[CH:8][N:9]=1)[CH2:3][CH3:4]
Reactant: CI
Reactant: CCC(O)(c1cccc(CO[Si](C)(C)C(C)(C)C)n1)c1nccs1
Solvent: C1CCOC1
Product: CCC(OC)(c1cccc(CO[Si](C)(C)C(C)(C)C)n1)c1nccs1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 156.1 %

Procedure:
To a solution of alcohol from Step 1 (740 mg, 2.03 mmol) in 20 mL THF at 0° C. was added KH (466 mg, 4.06 mmol, 35% in oil). After 10 min. MeI (1.44 g, 10.1 mmol) was added dropwise. The solution was stirred for 30 min. at 0° C., then poured into an aqueous saturated NH4C1. The aqueous layer was extracted with EtOAc (3×25 mL) and the combined organic layers were washed with brine and dried over anhydrous MgSO4. Evaporation of the solvent and flash chromatography on silica gel (hexane:EtOAc=9:1) gave the title compound (1.2 g) which was used directly in the next step.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][C:19](=[CH:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[H][H]>[Pd].C(OCC)(=O)C>[NH2:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][CH:19]2[CH2:18][CH2:17][N:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:3]([OH:8])([C:4]([F:7])([F:5])[F:6])[C:2]([F:1])([F:32])[F:33])=[CH:10][CH:11]=3)[CH2:21][CH2:20]2)=[CH:28][CH:27]=1
Reactant: O=[N+]([O-])c1ccc(C=C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(CC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Yield: 62.6 %

Procedure:
A stirred mixture of 1,1,1,3,3,3-hexafluoro-2-(4-((4-(4-nitrobenzylidene)piperidin-1-yl)methyl)phenyl)propan-2-ol (15.39 mmol, 7.3 g) and palladium on carbon (5%) (0.308 mmol, 0.328 g) in ethyl acetate was hydrogenated at 3 bar until the desired amount of hydrogen was consumed. The mixture was filtered through celite washing with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was chromatographed on silica (eluting with a gradient of dichloromethane to ethyl acetate) to give the title compound (4.3 g). MS (ESI) m/z 447.2 [M+H]+
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([N:12]([CH2:27][CH2:28][CH3:29])[CH:13]3[CH2:18][CH2:17][N:16]([C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:20])[CH2:15][CH2:14]3)[CH2:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[S:46](Cl)(=[O:48])=[O:47]>C1COCC1>[N:21]1([C:19]([N:16]2[CH2:15][CH2:14][CH:13]([N:12]([CH2:27][CH2:28][CH3:29])[CH:8]3[CH2:9][C:10]4[CH:11]=[C:2]([O:1][S:46]([C:41]5[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=5[Cl:39])(=[O:48])=[O:47])[CH:3]=[CH:4][C:5]=4[CH2:6][CH2:7]3)[CH2:18][CH2:17]2)=[O:20])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CCCN(C1CCN(C(=O)N2CCOCC2)CC1)C1CCc2ccc(O)cc2C1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(C1CCN(C(=O)N2CCOCC2)CC1)C1CCc2ccc(OS(=O)(=O)c3ccccc3Cl)cc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of {4-[(7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanone (50 μmole in 420 μL DCM) was added 30 μL of DIEA followed by 220 μL of a 0.25M solution of 2-chlorobenzenesulfonyl chloride in THF. The solution was allowed to stir for 24 h at 25° C. under N2. Concentrated in vacuo. The final product was isolated by preparative RPHPLC (YMC Combiprep ODS-A column, 10-90% acetonitrile: water (0.1% TFA)) to afford 2-Chloro-benzenesulfonic acid 7-{[1-(morpholine4-carbonyl)-piperidin-4-yl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-yl ester 40 (5.1 mg), [M+H]+=690.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:18]2[O:17][CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.C(OCC)(=O)C.[ClH:32]>C(OCC)(=O)C>[ClH:32].[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:18]2[O:17][CH2:16][CH2:15][NH:14][CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1ccccc1-c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1cccc2c1OCCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
A mixture of tert-butyl 9-(2-methylphenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (180 mg, 0.530 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) were stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (120 mg, 82.2%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.[C:23]1([CH3:32])[C:24]([N:29]=[C:30]=[O:31])=[CH:25][CH:26]=[CH:27][CH:28]=1.CO>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:30]([NH:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH3:32])=[O:31])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: Cc1ccccc1N=C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4ccccc4C)cc3)c2cc1OC
Yield: 41 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in chloroform (3 ml), and o-toluyl isocyanate (0.25 μl) was then added to the solution. The mixture was heated under reflux overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 30 mg (yield 41%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[I-].C[N+]1C=CN([C:20](=[O:29])[N:21]([CH3:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)C=1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[C:3]([O:12][C:20](=[O:29])[N:21]([CH3:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: Oc1ncc(C(F)(F)F)cc1Cl
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(C(=O)Oc1ncc(C(F)(F)F)cc1Cl)c1ccccc1
Yield: 14.7 %

Procedure:
A solution of 3-chloro-5-(trifluoromethyl)-2-pyridinol (0.59 g, 3.00 mmol), 1-methyl-3-(methyl -phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (15:85)) yielding the title compound (146 mg, 15% yield) as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][O:7][CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.CCN(CC)CC.[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](Cl)=[O:29]>>[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([NH:1][CH:2]1[CH2:8][O:7][CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1)=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCOCC(N)C1
Reactant: O=C(Cl)CCCCBr
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCOCC(NC(=O)CCCCBr)C1
Reaction time: 1 h

Procedure:
To an ice bath stirring solution of tert-butyl 6-amino-1,4-oxazepane-4-carboxylate 38.4 (1.01 g, 4.67 mmol) and Et3N (1.95 mL, 14.0 mmol) was added 5-bromo-pentanoyl chloride (0.62 mL, 4.7 mmol). The ice bath was removed and the solution was stirring for 1 h and then diluted with water and extracted with DCM. The organic phase was washed with diluted citric acid, water, sat. NaHCO3, dried (MgSO4), filtered and concentrated in vacuo to afford an oil which was purification by flash column chromatography (gradient EtOAc/hexanes). LCMS m/z 324.1 & 325.1 [M-tBu]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][CH:13]([NH:16][CH:17]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:18]([O:20][CH3:21])=[O:19])[CH2:12][CH2:11]2)=[CH:2]1.[F:28][C:29]1[CH:30]=[C:31]([CH:37]=[C:38]([F:40])[CH:39]=1)/[CH:32]=[CH:33]/[C:34](O)=[O:35]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C@H:10]2[CH2:15][CH2:14][C@H:13]([NH:16][CH:17]([CH:22]3[CH2:23][CH2:24][N:25]([C:34](=[O:35])/[CH:33]=[CH:32]/[C:31]4[CH:30]=[C:29]([F:28])[CH:39]=[C:38]([F:40])[CH:37]=4)[CH2:26][CH2:27]3)[C:18]([O:20][CH3:21])=[O:19])[CH2:12][CH2:11]2)=[CH:2]1
Reactant: COC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCNCC1
Reactant: O=C(O)/C=C/c1cc(F)cc(F)c1
Product: COC(=O)C(N[C@H]1CC[C@H](c2c[nH]c3ccccc32)CC1)C1CCN(C(=O)/C=C/c2cc(F)cc(F)c2)CC1

Procedure:
The title compound was prepared from methyl 2-(4-(1H-indol-3-yl)cyclohexyl)amino)-2-(piperidin-4-yl)acetate (from Example 24, step A) and trans-3,5-difluorocinnamic acid, by the method of Example 1, step K, giving a solid that was mostly the more polar cyclohexyl diastereomer by LCMS. Mass spectrum (LCMS, APCI pos.) calcd. for C31H35F2N3O3: 536 (M+H). Found: 536.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=1)[CH2:6][NH:7][C:8]1[CH:13]=[C:12](F)[CH:11]=[CH:10][C:9]=1[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17].[C:26]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=1)[CH2:6][NH:7][C:8]1[CH:13]=[C:12]([N:36]2[CH2:35][CH2:34][N:33]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:38][CH2:37]2)[CH:11]=[CH:10][C:9]=1[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc(CNc2cc(F)ccc2C(=O)C(F)(F)F)cc(OC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(CNc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2C(=O)C(F)(F)F)cc(OC)c1
Yield: 135.1 %

Procedure:
A solution of 1-(2-(3,5-dimethoxybenzylamino)-4-fluorophenyl)-2,2,2-trifluoroethanone (527 mg, 1.47 mmol), N-Boc-piperazine (296 mg, 1.62 mmol) and N,N-diisopropylethylamine (0.51 mL, 2.94 mmol) in acetonitrile was stirred at reflux for 48 h. The reaction mixture was cooled down and concentrated under reduced pressure. The residue was taken up in dichloromethane, washed with water, dried and concentrated in vacuo to yield 1.04 g of the crude aniline. The crude product was purified by PTLC (20% ethyl acetate in hexanes) to yield 230 mg (30%) of tert-butyl 4-(3-(3,5-dimethoxybenzylamino)-4-(2,2,2-trifluoroacetyl)phenyl)piperazine-1-carboxylate: 1H NMR (400 MHz, CD3OD): δ 9.32 (br t, 1H), 7.63 (dd, 1H), 6.50 (d, 2H), 6.37 (t, 1H), 6.19 (dd, 1H), 5.81 (d, 1H), 4.39 (d, 2H), 3.77 (s, 6H), 3.52-3.49 (m, 4H), 3.35-3.32 (m, 4H), 1.48 (s, 9H). MS (ESI) m/z: Calculated: 523.23; Observed: 546.3 (M++23).
Reaction SMILES: [C:1]([N:8]([CH2:15][C:16]1[CH:35]=[CH:34][C:19]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30])=[O:21])=[CH:18][CH:17]=1)[CH2:9][C:10]1[NH:11][CH:12]=[CH:13][N:14]=1)(OC(C)(C)C)=O.C([C:38]1[S:39][CH:40]=[CH:41][N:42]=1)=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:28]([N:27]([CH2:31][CH2:32][CH3:33])[CH2:26][CH2:25][CH2:24][CH2:23][NH:22][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:8]([CH2:9][C:10]2[NH:11][CH:12]=[CH:13][N:14]=2)[CH2:1][C:38]2[S:39][CH:40]=[CH:41][N:42]=2)=[CH:35][CH:34]=1)[CH2:29][CH3:30]
Reactant: O=Cc1nccs1
Reactant: CCCN(CCC)CCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)C(=O)OC(C)(C)C)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2nccs2)cc1
Temperature: 25 °C
Reaction time: 39.5 h

Procedure:
The compound (39.8 mg) obtained in Example 1-3 and 2-formylthiazole (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (16.9 mg) were dissolved in anhydrous methanol (2.0 ml) and then added with sodium cyanoborohydride (18.9 mg). The solution was adjusted to pH 5 with acetic acid and then stirred at room temperature for 39.5 hours. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and then washed with 1 mol/l sodium hydroxide and saturated saline solution, followed by drying with anhydrous magnesium sulfate. The solvent was distilled off and the residue was then treated with hydrochloric acid. The residue was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (9.20 mg) of the subject compound as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])[CH:16]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: C1CCNC1
Product: CCc1cc(-c2cncc(C(=O)N3CCCC3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and pyrrolidine to afford the title compound. MS: m/e=312 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]2=3)(=[O:10])=[O:9])=[CH:4][C:3]=1[NH:22][C:23](=[O:28])[CH2:24][C:25](=O)[CH3:26].C([O-])(=O)C.[NH4+:33]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]2=3)(=[O:10])=[O:9])=[CH:4][C:3]=1[NH:22][C:23](=[O:28])[CH2:24][C:25](=[NH:33])[CH3:26]
Reactant: CC(=O)CC(=O)Nc1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: CC(=N)CC(=O)Nc1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Temperature: 65 °C
Reaction time: 16 h
Yield: 57.2 %

Procedure:
To N-[2-chloro-5-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenyl]-3-oxo-butyramide (0.42 g, 1 mmol) in dry ethanol (4 mL) was added ammonium acetate (0.37 g, 3 mmol). The mixture was heated at 65° C. under stirring for 16 hrs. The filtration of the reaction mixture afforded N-[2-chloro-5-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenyl]-3-imino-butyramide as white solid (0.24 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[C:15]4=[N:16][CH:17]=[CH:18][CH:19]=[C:14]4[C:13]([C:20]([OH:22])=O)=[CH:12]3)[C:5]=2[CH:4]=[CH:3]1.S(Cl)([Cl:25])=O>C(Cl)(Cl)Cl>[Cl:25][C:20]([C:13]1[C:14]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:11]([C:10]2[C:5]3[CH:4]=[CH:3][N:2]([CH3:1])[C:6]=3[N:7]=[CH:8][N:9]=2)[CH:12]=1)=[O:22]
Reactant: O=S(Cl)Cl
Reactant: Cn1ccc2c(-n3cc(C(=O)O)c4cccnc43)ncnc21
Solvent: ClC(Cl)Cl
Product: Cn1ccc2c(-n3cc(C(=O)Cl)c4cccnc43)ncnc21
Temperature: 20 °C
Yield: 125.3 %

Procedure:
To 0.93 g (3.2 mmol) of 1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid in 20 cm3 of chloroform at about 20° C. and under argon atmosphere, was added dropwise 10 cm3 (0.14 mol) of thionyl chloride. The reaction mixture was then heated and stirred at reflux temperature for 1 hour, and then it was cooled to about 20° C. and concentrated to dryness in vacuo (2.7 kPa). The residue was taken up in 20 cm3 of chloform and concentrated to dryness in vacuo (2.7 kPa) to yield 1.25 g of 3-chlorocarbonyl-1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine as a yellow powder which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=2)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(Cl)cn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Cl)cn1)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.4 %

Procedure:
A solution of 4-chloro-3-nitrobenzoyl chloride (1.00 g, 4.99 mmol) in dry methylene chloride (20 mL) under a nitrogen atmosphere was treated with 2-amino-5-chloropyridine (643 mg, 4.99 mmol) and N,N-diisopropylethylamine (1.05 mL, 6.00 mmol), and the resulting mixture stirred at room temperature for 18 hours. The solvent was removed by rotary evaporation in vacuo, the residue taken up in ethyl acetate (100 mL), and washed with saturated aqueous sodium bicarbonate (50 mL), water (2×50 mL), and brine (50 mL). The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Trituration with 5% ethyl acetate/methylene chloride afforded the title compound as a dark yellow solid (660 mg, 42%).
Reaction SMILES: [Cl:1][C:2]1[N:12]=[C:11]([Cl:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5]>FC(F)(F)C(O)=O.Cl>[Cl:1][C:2]1[N:12]=[C:11]([Cl:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1cc(F)c(Cl)nc1Cl
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(F)c(Cl)nc1Cl
Reaction time: 26 h
Yield: 62.3 %

Procedure:
Ethyl 2,6-dichloro-5-fluoronicotinate (1) (30.0 g) was dissolved in a mixture of 60 mL of trifluoro acetic acid and 60 mL of 7.5 N HCl. The mixture was refluxed with stirring for 26 h. It was cooled and the trifluoroacetic acid was removed under reduced pressure. The solution was mixed with 150 mL water, the resulting precipitate was filtered, washed with hexane and dried to yield 16.5 g of 2,6-dichloro-5-fluoro nicotinic acid (2). m.p.=152-156° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([Cl:25])[CH:24]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=3[CH:17]=2)[CH:22]=[C:23]([Cl:25])[CH:24]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3cc(Cl)cc(Cl)c3)cc21

Procedure:
Prepared from 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 3,5-dichlorophenylboronic acid according to the coupling protocol of example 1. 1H NMR (DMSO-d6): δ 8.55 (s, 1H), 7.16 (dd, J=8.7, 2.3 Hz, 1H), 7.09 (d, J=8.7 Hz, 1H), 6.97 (d, J=2.4 Hz, 1H), 6.84 (m, 1H), 6.82 (m, 2H), 3.28 (s, 3H), 2.00 (m, 2H), 1.92 (m, 2H), 0.82 (t, J=7.4 Hz, 6H); MS (ESI) m/z 379/381/383 ([M+H]+); MS (ESI) m/z 377/379/381 ([M−H]−); Anal. calcd for C19H20C12N2O2: C, 60.17; H, 5.32; N, 7.39. Found: C, 60.10; H, 5.26; N, 7.26.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1.O.[NH2:17]N>CO.[Ni]>[NH2:17][C:6]1[C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][C:8]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1cccc2c1oc1ccccc12
Reactant: NN
Agent: [Ni]
Solvent: CO
Solvent: O
Product: COc1ccc(N)c2c1oc1ccccc12
Reaction time: 2 h

Procedure:
Intermediate 38 (550 mg, 2.26 mmol) was taken in methanol (10 ml) and raney nickel catalyst (100 mg, 18% w/w) was added. The reaction mixture was refluxed and to this was added hydrazine hydrate (99%) solution (2 ml) slowly over a period of 10 min. The refluxing continued for 2 h. The catalyst was filtered and the filterate was concentrated and diluted with water (100 ml) and further extracted with ethyl acetate (3×25 ml). The organic layer was washed with water and concentrated to give the product as brown solid (500 mg);mp: 167-169° C.
Reaction SMILES: C(OC([N:11]1[CH2:15][C@@H:14]([OH:16])[C@H:13]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.O1CCCC1.[OH-].[Pd+2].[OH-]>[OH:16][C@@H:14]1[CH2:15][NH:11][CH2:12][C@H:13]1[NH:17][C:18](=[O:19])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H]1O
Yield: 85.3 %

Procedure:
To a solution of trans-3-tert-butoxycarbonylamino-4-hydroxy-pyrrolidine-1-carboxylic acid benzyl ester (3.9 g) in methanol (31 mL) and tetrahydrofuran (7 mL) was added palladium hydroxide (20 wt % Pd on carbon, 500 mg) and the mixture was stirred at room temperature under 40-45 psi of hydrogen atmosphere overnight. The resulting mixture was filtered and the filtrate was concentrated in vacuo. The residue was triturated in the mixture of ethyl acetate and diisopropylether and filtered to remove the insoluable materials. The filtrate was concentrated in vacuo to afford 2.0 g of trans-tert-butyl [4-hydroxypyrrolidin-3-yl]carbamate (yield was 94%) as a powder. MS obsd. (ESI+) [(M+H)+] 203.
Reaction SMILES: [F:1][C:2]1([CH2:15][OH:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[F:1][C:2]1([CH2:15][O:16][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(CO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(F)(COS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
tert-Butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (0.150 g, 0.643 mmol) was dissolved in dichloromethane (1.8 mL) and cooled to 0° C. The solution was treated with triethylamine (0.134 ml, 0.964 mmol) followed by methanesulfonyl chloride (0.0547 ml, 0.707 mmol). The reaction was stirred at 0° C. for 2 hours then diluted with methylene chloride and quenched with saturated NH4Cl and separated. The organic layer was washed with saturated NH4Cl, 6% NaHCO3, dried over Na2SO4, filtered and concentrated in vacuo to provide the desired product (200 mg).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](=[CH2:15])[CH2:12][CH2:13][OH:14])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>[Pt].CO>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([CH3:15])[CH2:12][CH2:13][OH:14])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C=C(CCO)c1ccc2ncccc2c1
Agent: [Pt]
Solvent: CO
Product: CC(CCO)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.4 %

Procedure:
A mixture of 3-quinolin-6-ylbut-3-en-1-ol (1.0 g, 0.0050 mol), platinum on carbon (5 wt. % supported on activated carbon, wet, Degussa type F100 ra/w, 0.20 g) in methanol (15.0 mL) was stirred under hydrogen (with a balloon) at RT for 5 h. The mixture was filtered and the filtrate was concentrated to give the desired product (1.0 g, 99%). LCMS: (M+H)=202.1.
Reaction SMILES: [CH2:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:18][OH:19]>CN(C1C=CN=CC=1)C.C(N(CC)CC)C>[CH2:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:19][CH3:18])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CO
Reactant: CCCCCCCCc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CCCCCCCCc1ccc(C(=O)OC)cc1

Procedure:
4-Octylbenzoyl chloride (obtained by reacting 4-octylbenzoic acid with thionyl chloride) is esterified with methanol in the presence of an equimolar amount of triethylamine and 0.1 mol % of DMAP. Customary work-up followed by purification by distillation affords methyl 4-octylbenzoate as a colorless liquid, b.p. 112° C./0.25 mbar.