Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:5](=O)[CH2:6][C:7]#[N:8])[CH2:4][CH2:3]1.Cl.[C:11]1([CH3:19])[CH:16]=[CH:15][C:14]([NH:17][NH2:18])=[CH:13][CH:12]=1>C(O)C>[CH3:1][C:2]1([C:5]2[CH:6]=[C:7]([NH2:8])[N:17]([C:14]3[CH:15]=[CH:16][C:11]([CH3:19])=[CH:12][CH:13]=3)[N:18]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc(NN)cc1
Reactant: CC1(C(=O)CC#N)CC1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(-n2nc(C3(C)CC3)cc2N)cc1

Procedure:
Heat to reflux a solution of 3-(1-methyl-cyclopropyl)-3-oxo-propionitrile (60 g, 487.2 mmol) and p-tolyl-hydrazine hydrochloride (78 g, 478.2 mmol) in ethanol (975 mL) for 4 hours. Evaporate the solvent and dissolve the remaining solid in water. Increase pH of the solution to pH 8 using a 1.0 N solution of sodium hydroxide. Filter the precipitate to obtain 5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-ylamine as a white solid. 1H NMR (DMSO): 7.39 (d, J=8 Hz, 2H), 7.22 (d, J=8 Hz, 2H), 5.12 (s, 2H), 2.31 (s, 3H), 1.30 (s, 3H), 0.80 (q, J=4 Hz, 2H), 0.61 (q, J=4 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][C:28](O)=[O:29])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][C:28]([NH:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CN
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)O)c[nH]c34)no2)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 40 °C
Reaction time: 3 h
Yield: 55.6 %

Procedure:
To a solution of 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E1) (150 mg), ethyl glycinate (73 mg) and HATU (402 mg) in DCM (20 mL) was added DIPEA (0.2 mL). The reaction was stirred at 40° C. for 3 h. The reaction mixture was cooled to room temperature and partitioned between DCM (25 mL) and water (25 mL). The organic phase was washed with water, dried over sodium sulphate and evaporated in vacuo to afford the crude product ethyl N-{3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoyl}glycinate as an off-white solid (D125) (100 mg), which was used directly in the next step. MS (ES): C26H27ClN4O5 requires 510; found 511.2 (M+H+).
Reaction SMILES: S(O)(O)(=O)=O.[N:6]1[C:10]2[CH2:11][CH2:12][CH:13](C(O)=O)[CH2:14][C:9]=2[NH:8][CH:7]=1.S(Cl)(Cl)=O>ClCCCl>[N:6]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=2[NH:8][CH:7]=1
Reactant: O=C(O)C1CCc2nc[nH]c2C1
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: c1nc2c([nH]1)CCCC2
Temperature: 30 °C

Procedure:
4,5,6,7-Tetrahydrobenzimidazole-5-carboxylic acid sulfate (1.32 g) was refluxed in 10 ml of 1,2-dichloroethane together with 1.78 g of thionyl chloride for 30 minutes, and the excess of thionyl chloride and the solvent were removed by distillation under reduced pressure. To the residue was added 10 ml of 1,2-dichloroethane, and 1.6 ml of indoline was added dropwise thereto at 30° C. or lower while stirring followed by stirring at room temperature for 2 hours. The reaction mixture was successively extracted once with 30 ml of water and twice with 20 ml of water. The combined aqueous layer was adjusted to a pH of 9 to 10 with a 10% sodium hydroxide aqueous solution and then extracted with methylene chloride. The combined methylene chloride layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from ethyl acetate to obtain 1.1 g (82.7%) of 5-(2,3-dihydroindol-1-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole.
Reaction SMILES: Cl.[F:2][C:3]([F:23])([F:22])[C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH:6]([O:13][CH:14]1[CH2:17][NH:16][CH2:15]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N-:24]=[C:25]=[O:26]>>[F:23][C:3]([F:2])([F:22])[C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH:6]([O:13][CH:14]1[CH2:17][N:16]([C:25]([NH:24][CH2:3][C:4]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:5]=2)=[O:26])[CH2:15]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: FC(F)(F)c1ccccc1C(OC1CNC1)c1ccccc1
Reactant: [N-]=C=O
Agent: Cl
Product: O=C(NCc1ccccc1)N1CC(OC(c2ccccc2)c2ccccc2C(F)(F)F)C1

Procedure:
This material was prepared 3-[2-(trifluoromethyl)benzhydryloxy]azetidine hydrochloride (133) and the corresponding isocyanate using the procedure described for compound (10).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:16])[CH3:15])[C:5]2[O:9][CH:8]([CH2:10][NH2:11])[CH2:7][C:6]=2[C:12]=1[CH3:13].C(N(C(C)C)CC)(C)C.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>>[CH2:30]([O:29][C:27](=[O:28])[NH:11][CH2:10][CH:8]1[CH2:7][C:6]2[C:12]([CH3:13])=[C:2]([Cl:1])[CH:3]=[C:4]([CH:14]([CH3:16])[CH3:15])[C:5]=2[O:9]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1c(Cl)cc(C(C)C)c2c1CC(CN)O2
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)cc(C(C)C)c2c1CC(CNC(=O)OCc1ccccc1)O2
Yield: 81.3 %

Procedure:
Treatment of (±)-1-(5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methanamine (3.41 g, 12.3 mmol) with diisopropylethylamine (1.99 g, 14.2 mmol) and benzyl chloroformate (2.42 g, 14.2 mmol) generally according to the procedure described for Intermediate 12 gave 3.74 g (81%) of (±)-benzyl(5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate as a colorless oil. Anal. calcd. for C21H24ClNO3 C, 67.46; H, 6.47; N, 3.75. Found C, 67.01; H, 6.52; N, 3.56. Chiral HPLC separation of (±)-benzyl(5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralpak AD, ethanol) provided two fractions.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]1[CH:10]=[C:9]([C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([C:19]3[S:23][C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)=[N:21][C:20]=3[CH3:34])=[O:18])[CH2:12]2)[CH:8]=[CH:7][C:6]=1[CH3:35])C.C(=O)([O-])[O-].[K+].[K+].CO>O>[CH3:35][C:6]1[CH:7]=[CH:8][C:9]([C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([C:19]3[S:23][C:22]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=4)=[N:21][C:20]=3[CH3:34])=[O:18])[CH2:12]2)=[CH:10][C:5]=1[C:4]([OH:36])=[O:3]
Reactant: CCOC(=O)c1cc([C@H]2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ccc([C@H]2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)cc1C(=O)O
Temperature: 25 °C
Yield: 94.2 %

Procedure:
A mixture of (R)-2-methyl-5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-piperidin-3-yl}-benzoic acid ethyl ester (3.31 g, 6.41 mmol), potassium carbonate (1.77 g, 12.82 mmol), methanol (25 mL) and water (6 mL) was heated at reflux for 3 h, cooled to room temperature and concentrated under reduced pressure. The resulting residue was taken up in water (150 mL), acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to yield 2.95 g (94%) (R)-2-methyl-5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-piperidin-3-yl}-benzoic acid as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([I:19])=[C:14]([OH:18])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(O)c12
Reactant: O=C1CCC(=O)N1I
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1c(C(=O)OC(C)(C)C)oc2ccc(I)c(O)c12
Temperature: 0 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
To 4.4 g (17.7 mmol) of 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester was added 40 mL of carbon tetrachloride, and the mixture was cooled with a water/ice bath while 1 equivalent of N-iodosuccinimide was added in small portions. After stirring at 0° C. for 3 h, the reaction mixture was loaded onto a column and purified by column chromatography to give 2.55 g mg (38% yield) of 5-iodo-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:55][N:56]1[CH:60]=[C:59]([NH2:61])[CH:58]=[N:57]1>CN(C=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:61][C:59]2[CH:58]=[N:57][N:56]([CH3:55])[CH:60]=2)=[O:21])=[CH:17][N:16]=1
Reactant: Cn1cc(N)cn1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)Nc2cnn(C)c2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.9 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) in DMF (2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (114 mg, 0.35 mmol), N,N-diisopropyl ethyl amine (275 μL, 1.6 mmol) and 1-methyl-1H-pyrazol-4-ylamine (1 M solution in MeOH, 0.35 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (51 mg, 41%) which was obtained as a white solid. MS: m/e=388.1 [M−H]−.
Reaction SMILES: ClC1C=C(Cl)C(Cl)=CC=1O[C:11](=[O:18])[C@@H:12]1[CH2:16][CH2:15][C:14](=[O:17])[NH:13]1.[NH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH2:25])=[O:24].ON1C2C=CC=CC=2N=N1.C(N1CCOCC1)C>CN(C)C=O>[NH:13]1[C:14](=[O:17])[CH2:15][CH2:16][C@H:12]1[C:11]([CH:22]([CH2:21][CH2:20][NH2:19])[C:23]([NH2:25])=[O:24])=[O:18]
Reactant: O=C1CC[C@@H](C(=O)Oc2cc(Cl)c(Cl)cc2Cl)N1
Reactant: NCCCC(N)=O
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: NCCC(C(N)=O)C(=O)[C@@H]1CCC(=O)N1
Reaction time: 1 h

Procedure:
3.9 g (12.65 mmols) of L-pyroglutamic acid 2,4,5-trichlorophenyl ester were added to a solution of 1.76 g (12.9 mmols) 4-amino butyric acid amide and 1.72 g (12.75 mmols) of 1-hydroxybenzotriazole and 1.65 ml of N-ethylmorpholine in 40 ml of dimethyl formamide. The solution was allowed to stand for 1 hour at room temperature. It was concentrated and triturated with ether. The substance was suction-filtered and chromatographed in methanol/water (1:1) through Serdolit Blau. The eluate was concentrated and the residue was triturated with ether and suction-filtered.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH:9]=[CH:10][NH:11][C:6]2=[CH:5][C:4]=1[B:12]([OH:14])[OH:13].[H-].[Na+].Cl[Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20]>O1CCCC1>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH:9]=[CH:10][N:11]([Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[C:6]2=[CH:5][C:4]=1[B:12]([OH:14])[OH:13]
Reactant: COc1nc2cc[nH]c2cc1B(O)O
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nc2ccn([Si](C(C)C)(C(C)C)C(C)C)c2cc1B(O)O
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
To a white suspension of 5-methoxy-1H-pyrrolo[3,2-b]pyridin-6-ylboronic acid (500 mg, 2.60 mmol) in tetrahydrofuran (25 mL) was added sodium hydride (281 mg, 11.72 mmol) in several portions at 0° C., the resulting light grey suspension was stirred for 30 min, followed by dropwise addition of chlorotriisopropylsilane (2260 mg, 11.72 mmol) through a syringe over 30 sec. under N2. The mixture, as a suspension, was continued stirring at 0° C. for 2 hr, and the conversion was completed as determined by LC/MS. The reaction was carefully quenched with sat. NH4Cl (10 mL), extracted with Et2O (2×50 mL), the combined organic solution was washed with brine (20 mL), dried (Na2SO4), concentrated on rotary vacuo to afford the expected product, 5-methoxy-1-(triisopropylsilyl)-1H-pyrrolo[3,2-b]pyridin-6-ylboronic acid (900 mg, 99%), as a grey gum. 1H-NMR (500 MHz, CHLOROFORM-D) s ppm 1.11 (d, J=7.63 Hz, 21 H) 1.62-1.72 (m, 3 H) 4.03-4.10 (m, 2 H) 6.67 (d, J=3.36 Hz, 1 H) 7.31 (s, 1 H) 7.43 (d, J=3.05 Hz, 1 H); Mass spec 349.21 (MH+) Calc for C17H29BN2O3Si 348.2.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@@H:7]1[C@@H:11]([C:12](=[O:21])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:10][NH:9][CH2:8]1)=[O:6])[CH3:3].C(N(CC)C(C)C)(C)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(#N)C>[CH2:2]([O:4][C:5]([C@@H:7]1[C@@H:11]([C:12](=[O:21])[NH:13][C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[CH2:10][N:9]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:8]1)=[O:6])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)[C@H]1CNC[C@@H]1C(=O)Nc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)[C@H]1CN(S(C)(=O)=O)C[C@@H]1C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Compound 39c (1.44 g; 4.32 mmol) is dissolved in acetonitrile (10 ml) under addition of N,N-diisopropyl ethyl amine (2200 μl; 12.96 mmol). Methanesulfonylchloride (990 mg; 8.64 mmol) is added and the mixture is stirred for 18 h at 25° C. The reaction mixture is evaporated to dryness and purified with silica gel chromatography. Yield: 0.895 g (55.3%), ESI-MS: m/z=375 [M+H]+, Cl-pattern
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[NH:16][C:15]([CH:17]3[CH2:21][CH2:20][CH2:19][NH:18]3)=[N:14][CH:13]=1)[CH:6]=[CH:5]2.[CH3:22][O:23][C:24]([NH:26][CH:27]([CH:31]([CH3:33])[CH3:32])[C:28](O)=[O:29])=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH3:22][O:23][C:24](=[O:25])[NH:26][CH:27]([C:28]([N:18]1[CH2:19][CH2:20][CH2:21][CH:17]1[C:15]1[NH:16][C:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[CH:8]=2)=[CH:13][N:14]=1)=[O:29])[CH:31]([CH3:33])[CH3:32]
Reactant: COC(=O)NC(C(=O)O)C(C)C
Reactant: Brc1ccc2cc(-c3cnc(C4CCCN4)[nH]3)ccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.7 %

Procedure:
5-(6-Bromo-naphthalen-2-yl)-2-pyrrolidin-2-yl-1H-imidazole (3.80 g), 2-methoxycarbonylamino-3-methyl-butyric acid (2.21 g), and HATU (5.06 g) were dissolved in anhydrous DMF (75 mL), and N-methylmorpholine (2.68 mL) was added. The reaction mixture was stirred at ambient temperature for 16 hours and evaporated under vacuum. The oil was dissolved in dichloromethane, purified by chromatography (0-100% ethyl acetate:hexanes), and evaporated under vacuum, giving (1-{2-[5-(6-bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.814 g, 72%) as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:25](Cl)(=[O:27])[CH3:26]>C(Cl)Cl>[C:25]([NH:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:11]1)(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCN)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCN1CCC(CNC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)ethylamine (1 g) was dissolved in methylene chloride (10 ml) and triethylamine (0.86 ml) was added. Then, a solution of acetyl chloride (0.29 ml) in methylene chlride was dropwise added under ice-cooling. The mixture was stirred at room temperature for 1 hr, and the reaction mixture was concentrated under reduced pressure to give 1-(2-acetylaminoethyl)-3-tert-butoxycarbonylaminomethylpyrrolidine.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:18][O:19][C:20]([O:23][Si](C)(C)C)=[CH:21][CH3:22].C(Cl)Cl>CC#N.Cl[Ti](Cl)(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:21]([CH3:22])[C:20]([O:19][CH3:18])=[O:23])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: OC(c1ccccc1)c1ccc2[nH]ncc2c1
Reactant: CC=C(OC)O[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CC#N
Solvent: ClCCl
Product: COC(=O)C(C)C(c1ccccc1)c1ccc2[nH]ncc2c1
Reaction time: 1 h

Procedure:
To a solution of (1H-indazol-5-yl)(phenyl)methanol (180 mg, 0.71 mmol) and (1-methoxyprop-1-enyloxy)trimethylsilane (0.32 mL, 1.78 mmol) in 10 mL of dry MeCN was added TiCl4 (2.5 mL of 1.0 M DCM solution, 2.5 mmol) and then stirred 1 h. The reaction was incomplete so added 10 mL of DCM and additional (1-methoxyprop-1-enyloxy)trimethylsilane (0.3 mL, 1.7 mmol) After 1 h, the reaction was quenched with MeOH, poured into aqueous sodium bicarbonate and extracted 2×EtOAc. The organic layers were dried over MgSO4, filtered, and concentrated. HPLC purification resulted in the resolution of the two diastereomers of methyl 3-(1H-indazol-5-yl)-2-methyl-3-phenylpropanoate which were taken independently to the next step. MS found: (M+H)+=295.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:5][CH:4]([CH2:17][N:18]2[CH:22]=[C:21]([C:23](O)=[O:24])[CH:20]=[N:19]2)[CH2:3]1.[NH2:26][C:27]1[C:28](=[O:38])[N:29]([CH2:35][CH2:36][CH3:37])[C:30](=[O:34])[NH:31][C:32]=1[NH2:33].CCN=C=NCCCN(C)C>CO>[NH2:33][C:32]1[NH:31][C:30](=[O:34])[N:29]([CH2:35][CH2:36][CH3:37])[C:28](=[O:38])[C:27]=1[NH:26][C:23]([C:21]1[CH:20]=[N:19][N:18]([CH2:17][CH:4]2[CH2:3][C:2](=[O:1])[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=3)[CH2:5]2)[CH:22]=1)=[O:24]
Reactant: O=C(O)c1cnn(CC2CC(=O)N(c3cccc(C(F)(F)F)c3)C2)c1
Reactant: CCCn1c(=O)[nH]c(N)c(N)c1=O
Agent: CCN=C=NCCCN(C)C
Solvent: CO
Product: CCCn1c(=O)[nH]c(N)c(NC(=O)c2cnn(CC3CC(=O)N(c4cccc(C(F)(F)F)c4)C3)c2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To a stirred solution of 1-[5-Oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidin-3-ylmethyl]-1H-pyrazole-4-carboxylic acid (1 g, 2.83 mmol) and 5,6-Diamino-3-propyl-1H-pyrimidine-2,4-dione (521 mg, 2.83 mmol) in MeOH (40 mL) was added EDCI (813 mg, 4.24 mmol) under argon atmosphere. After stirring at overnight at room temperature the reaction mixture was quenched with water (10 mL) and white solid was precipitated out. The solid was filtered and washed with water to give the crude product which on purification by column chromatography (eluting with 5% MeOH:DCM) furnished the title compound as a white solid (1.3 g, 88%).
Reaction SMILES: Br[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH:5]3[NH:12][C:13]3[C:18]([C:19]([NH2:21])=[O:20])=[CH:17][N:16]=[C:15]4[NH:22][CH:23]=[CH:24][C:14]=34)[CH2:3]1)[CH2:9]2.[CH2:25]([C:28]#[N:29])[CH2:26][OH:27]>C(N(CC)CC)C>[C:28]([CH2:25][CH2:26][O:27][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH:5]3[NH:12][C:13]3[C:18]([C:19]([NH2:21])=[O:20])=[CH:17][N:16]=[C:15]4[NH:22][CH:23]=[CH:24][C:14]=34)[CH2:3]1)[CH2:9]2)#[N:29]
Reactant: NC(=O)c1cnc2[nH]ccc2c1NC1C2CC3CC1CC(Br)(C3)C2
Reactant: N#CCCO
Solvent: CCN(CC)CC
Product: N#CCCOC12CC3CC(C1)C(Nc1c(C(N)=O)cnc4[nH]ccc14)C(C3)C2
Reaction time: 0.33 h

Procedure:
To 4-[(5-bromoadamantan-2-yl)amino]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (52 mg) were added ethylene cyanhydrin (250 μl) and triethylamine (56 μl), and the mixture was stirred for 20 minutes using a microwave reaction system at 150° C. The reaction solution was cooled and purified by silica gel column chromatography (chloroform:methanol). The obtained fraction was concentrated under reduced pressure, and water was added. The obtained solid was collected by filtration to obtain 4-{[5-(2-cyanoethoxy)adamantan-2-yl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (16 mg).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:5]=[CH:6][C:7]2[C:16](=[O:17])[N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=3)[CH2:14][CH:13]3[N:9]([CH2:10][CH2:11][CH2:12]3)[C:8]=2[N:28]=1)[CH3:2].[H][H]>C(O)C.C1COCC1.[Pd]>[NH2:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:15]2[CH2:14][CH:13]3[N:9]([CH2:10][CH2:11][CH2:12]3)[C:8]3[N:28]=[C:4]([NH:3][CH2:1][CH3:2])[N:5]=[CH:6][C:7]=3[C:16]2=[O:17])=[CH:24][CH:23]=1
Reactant: [H][H]
Reactant: CCNc1ncc2c(n1)N1CCCC1CN(Cc1ccc([N+](=O)[O-])cc1)C2=O
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCNc1ncc2c(n1)N1CCCC1CN(Cc1ccc(N)cc1)C2=O
Yield: 89.5 %

Procedure:
Compound 5 (0.496 g, 1.30 mmol) obtained in Example 5 was dissolved in ethanol/THF=5/1 (12 mL), and the mixture was stirred under a stream of hydrogen gas for 2 hours after adding 10% palladium-on-carbon (Pd—C) (50% water, 276 mg, 0.130 mmol). Insolubles were separated by filtration through sellite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (Compound 6) (0.410 g, 90%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=2[F:13])[CH2:3][CH2:2]1.CCCCCC.C([Li])CCC.[C:25](=[O:27])=[O:26].C(=O)([O-])O.[Na+]>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:25]([OH:27])=[O:26])=[C:8]([F:12])[C:7]=2[F:13])[CH2:2][CH2:3]1
Reactant: Fc1cccc(OCC2CC2)c1F
Reactant: O=C=O
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCC2CC2)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(cyclopropylmethoxy)-2,3-difluorobenzene (19.0 g) in THF (200 mL) was added 1.6 M n-butyllithium hexane solution (64.5 mL) at −78° C., and the mixture was stirred at the same temperature for 1 hr. To the reaction mixture was added dry ice, and the mixture was allowed to warm to room temperature, and stirred for 15 min. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the aqueous layer was washed with diethyl ether, and acidified with 6N hydrochloric acid. This mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained solid was washed with diethyl ether to give the title compound was obtained.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]2[N:15]=[CH:16][S:17][CH:18]=2)[CH:3]=1.C(C1N=C(C2C=C(O[CH:38]3[CH2:56][CH:55]4[N:40]([C:41](=[O:61])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH:48]=[CH:49][CH:50]5[C:52]([C:58]([OH:60])=[O:59])([NH:53][C:54]4=[O:57])[CH2:51]5)[CH2:39]3)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([O:1][CH:38]3[CH2:56][CH:55]4[N:40]([C:41](=[O:61])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH:48]=[CH:49][CH:50]5[C:52]([C:58]([OH:60])=[O:59])([NH:53][C:54]4=[O:57])[CH2:51]5)[CH2:39]3)=[CH:3][C:4]([C:14]3[N:15]=[CH:16][S:17][CH:18]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Reactant: COc1ccc2c(O)cc(-c3cscn3)nc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3cscn3)nc2c1

Procedure:
The title compound was prepared from 4-hydroxy-7-methoxy-2-(thiazol-4-yl)quinoline and intermediate 7 following the procedure (Step F-H) reported for 18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid 10: m/z=591 (M+H)+.