Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC[C@@H:3]1[CH2:5][C@@H:4]1[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36]Br)=[N:34][CH:35]=1.[OH2:38]>C1COCC1>[Br:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36][O:38][C@@H:3]2[CH2:5][C@@H:4]2[CH:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]2)=[N:34][CH:35]=1
Reactant: O
Reactant: BrCc1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2CO)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2OCc2ccc(Br)cn2)CC1

Procedure:
To a solution of tert-butyl 4-[(1R,2R)-2-(hydroxymethyl)cyclopropyl]piperidine-1-carboxylate (Intermediate 4: 3.5 g, 13.71 mmol) in THF (40 mL) was added NaHMDS (16.45 mL of a 1.0M soln in THF, 16.45 mmol) followed by the product of step A (4.13 g, 16.45 mmol) and the resulting mixture heated at reflux overnight. The mixture was cooled and poured into water (100 mL) and extracted with EtOAc (2×75 mL); combined EtOAc layers washed with sat. NaCl, dried over MgSO4, filtered and evaporated in vacuo. Residue purified by silica gel column chromatography (eluent: gradient 0-25% EtOAc in Hexanes) to give the title compound. 1H NMR (500 MHz, CDCl3) δ 8.82 (d, J 2.0 Hz, 1H), 7.84 (dd, J 8.0 & 2.0 Hz, 1H), 7.38 (d, J 8.0 Hz, 1H), 4.65 (d, J 13.5 Hz, 1H), 4.57 (d, J 13.5 Hz, 1H), 4.18-3.97 (br m, 2H), 3.64-3.58 (m, 1H), 3.58-3.52 (m, 1H), 2.74-2.58 (m, 2H), 1.86-1.79 (m, 1H), 1.77-1.69 (m, 1H), 1.47 (s, 9H), 1.36-1.20 (m, 3H), 0.98-0.89 (m, 1H), 0.79-0.68 (m, 2H), 0.07-0.03 (m, 1H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][C:22]#[CH:23])[CH:18]=3)[N:13]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-])=O)[CH:26]=3)[C:12](=[O:34])[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(OCC)(=O)C.O>C(O)(=O)C.[Fe]>[NH2:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH2:24][N:13]1[C:14]2[C:19](=[CH:18][C:17]([O:20][CH2:21][C:22]#[CH:23])=[CH:16][CH:15]=2)[C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:5][CH:6]=2)=[N:11][C:12]1=[O:34]
Reactant: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccc([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccc(N)c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 110.5 %

Procedure:
A mixture of 5.7 g (12.57 mmol) of the aromatic nitro-compound prepared in step B and 5.7 g (0.10 mol; 8 eq.) iron powder in 85 ml acetic acid is heated to 40° C. and stirred overnight. After 16 h another 3.5 g iron powder is added and stirring continued for 4 h. The brown suspension is distributed between ethyl acetate and water. The organic layer is washed with sodium bicarbonate solution and brine. Concentration in vacuo leaves 5.88 g of yellow foam. Flash chromatography (petroleum ether/ethyl acetate) yields 2.80 g (53%) of a yellow solid. m.p. 186° C.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:25])[C:13]([CH:23]=[O:24])=[CH:14][N:15]3[CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:10][C:9]=2[F:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[P:27]([O-:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30].C1CCN2C(=NCCC2)CC1.[Cl-].[NH4+]>ClCCl>[CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:25])[C:13]([CH:23]([P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])[OH:24])=[CH:14][N:15]3[CH:18]([CH2:19][CH3:20])[CH2:21][CH3:22])=[CH:10][C:9]=2[F:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC(CC)n1cc(C=O)c(=O)c2cc(F)c(NC3CCCCC3)cc21
Reactant: CCOP([O-])OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCOP(=O)(OCC)C(O)c1cn(C(CC)CC)c2cc(NC3CCCCC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 5.0 ml dichloromethane solution of 500 mg of 7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde were added 0.23 ml of diethyl phosphite and 0.22 ml of 1,8-diazabicyclo[5.4.0]-7-undecene at −40° C., followed by overnight stirring at room temperature. Aqueous saturated ammonium chloride was added to the reaction mixture, followed by extraction with chloroform and then washing with aqueous saturated sodium chloride. After drying over anhydrous sodium sulfate and subsequent evaporation under a reduced pressure, the resulting residue was purified by silica gel column chromatography to obtain 400 mg of diethyl [[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl](hydroxy)methyl]phosphonate.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:11]2[CH2:12][CH2:13][C:14]3([CH3:18])[O:16][O:17][C@:10]42[C@H:5]([C@@H:6]([CH3:20])[C@@H:7]([OH:19])[O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1.CO.B(F)(F)F.[CH3:27]COCC>C(Cl)(Cl)Cl>[CH3:1][C@H:2]1[C@@H:11]2[CH2:12][CH2:13][C@@:14]3([CH3:18])[O:16][O:17][C@:10]42[C@H:5]([C@@H:6]([CH3:20])[C@@H:7]([O:19][CH3:27])[O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1
Reactant: CCOCC
Reactant: C[C@H]1[C@@H](O)O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Agent: FB(F)F
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CO[C@H]1O[C@@H]2O[C@@]3(C)CC[C@H]4[C@H](C)CC[C@@H]([C@H]1C)[C@@]24OO3
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of the crude dihydroartemisinin in chloroform (40 mL) and methanol (1 mL, 24.8 mmol) was added boron trifluoride etherate (0.16 mL, 1.24 mmol) at 0° C. The reaction was stirred at 0° C. for 15 minutes, slowly warmed up to room temperature and stirred at room temperature for 3 hours. The reaction was monitored by TLC until all starting material was consumed. The reaction mixture was quenched with water (50 mL) and diluted with chloroform (25 mL). The two phases were separated, and the aqueous layer was extracted with chloroform (30×2 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford crude product which was further purified by column chromatography on Florisil (1%-10% EtOAc/hexanes) to give two artemether isomers as white solids: β-isomer (0.29 g, 0.98 mmol, 79%) mp 73°-74.5° C.; α-isomer (0.05 g, 0.17 mmol, 14%), with each having a 1H NMR spectrum identical to that reported in the literature.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:21][C:22]([NH2:24])=[O:23]>CN(C=O)C.C(OCC)(=O)C.CO>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:21][C:22]([NH2:24])=[O:23])=[CH:15][CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: NC(=O)CCl
Reactant: Oc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)COc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1
Temperature: 60 °C

Procedure:
To a mixture of 4-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)phenol (58 mg, 0.2 mmol) and sodium hydride (55-65%, 18 mg, 0.4 mmol) in DMF (6 ml), 2-chloroacetamide (19 mg, 0.2 mmol) was added and the mixture was heated to 60° C. for 1 h. Column chromatography on silica using ethyl acetate/methanol as eluent afforded the title compound.
Reaction SMILES: [NH2:1][C@H:2]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.FC(F)(F)S(O[C@H:32]([CH2:43][CH:44]([CH3:46])[CH3:45])[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])(=O)=O>ClCCl>[CH2:36]([O:35][C:33](=[O:34])[C@H:32]([CH2:43][CH:44]([CH3:45])[CH3:46])[NH:1][C@H:2]([P:11]([O:12][CH2:13][CH3:14])([O:15][CH2:16][CH3:17])=[O:18])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)C[C@@H](OS(=O)(=O)C(F)(F)F)C(=O)OCc1ccccc1
Reactant: CCOP(=O)(OCC)[C@@H](N)CCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)[C@H](CCc1ccccc1)N[C@@H](CC(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.9 %

Procedure:
To a solution of 400 mg of diethyl 1-(R)-amino-3-phenylpropylphosphonate in 5 ml of anhydrous dichloromethane was added a solution of 0.25 ml of triethylamine and 627 mg of benzyl 2-(R)-trifluoromethanesulfonyloxy-4-methylpentanoate in 2.5 ml of anhydrous dichloromethane, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with 30 ml of dichloromethane, and the diluted solution was washed with 20 ml of water and dried over anhydrous magnesium sulfate. Then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate=1:1) to yield the title compound as a colorless oil (238 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17](=[O:18])[NH:16][C:15]2[C:10]1=[N:11][C:12]([NH:24][C@@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1)=[N:13][C:14]=2[C:19]([O:21]CC)=O.C(OC([N:37]1CC[C@@H](NC2N=C3C(NC(=O)N3C3C=CC=CC=3OC)=C(C(OCC)=O)N=2)C1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17](=[O:18])[NH:16][C:15]2[C:10]1=[N:11][C:12]([NH:24][C@@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1)=[N:13][C:14]=2[C:19]([NH2:37])=[O:21]
Reactant: CCOC(=O)c1nc(N[C@@H]2CCNC2)nc2c1[nH]c(=O)n2-c1ccccc1OC
Reactant: CCOC(=O)c1nc(N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)nc2c1[nH]c(=O)n2-c1ccccc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(N[C@@H]3CCNC3)nc21
Reaction time: 2 h
Yield: 100 %

Procedure:
(R)-Ethyl 9-(2-methoxyphenyl)-8-oxo-2-(pyrrolidin-3-ylamino)-8,9-dihydro-7H-purine-6-carboxylate. (R)-Ethyl 2-(1-(tert-butoxycarbonyl)pyrrolidin-3-ylamino)-9-(2-methoxy-phenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate (0.333 g, 0.668 mmol) were dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL). The solution was stirred for two hours and condensed under reduced pressure to afford the crude title compound (0.300 g, 100%). MS (ESI) m/z 399.3 [M+1]+.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][C:15]3=[O:30])[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].I[CH2:34][CH2:35][CH2:36][CH3:37].O>CN(C=O)C>[CH2:34]([N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:9][CH2:10]2)[C:15]1=[O:30])[CH2:35][CH2:36][CH3:37]
Reactant: O=C1Nc2ccccc2C(c2ccccc2)N1C1CCN(CC2CCCCC2)CC1
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCN1C(=O)N(C2CCN(CC3CCCCC3)CC2)C(c2ccccc2)c2ccccc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of 100 mg (0.25 mmol) of 3-[1-(cyclohexylmethyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone in 2 ml of DMF, 22 mg (0.55 mmol) of sodium hydride (60%) were added at room temperature and stirred at about 60° C. for one hour. After allowing the reaction mixture to stand cool, a solution of 69 mg (0.38 mmol) of 1-iodobutane in 1 ml of DMF was added thereto at room temperature and stirred at about 60° C. for 2 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform—10% methanol/chloroform) to give 88 mg (0.19 mmol) of the title compound as colorless oil.
Reaction SMILES: C([O:5][C:6]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][C@H:66]([CH:71](OC)[O:72]C)[CH2:67]/[CH:68]=[CH:69]\[CH3:70])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[C:51]([CH3:54])([CH3:53])[CH3:52])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])=[O:36])[CH2:26][CH2:27][C:28](=[O:34])[O:29]C(C)(C)C)=[O:23])[CH2:14][C:15](=[O:21])[O:16]C(C)(C)C)=[O:11])=[O:7])(C)(C)C>ClCCl.FC(F)(F)C(O)=O.O>[C:6]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][C@@H:66]([CH2:67]/[CH:68]=[CH:69]\[CH3:70])[CH:71]=[O:72])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[C:51]([CH3:52])([CH3:53])[CH3:54])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])=[O:36])[CH2:26][CH2:27][C:28](=[O:29])[OH:34])=[O:23])[CH2:14][C:15](=[O:16])[OH:21])=[O:11])([OH:7])=[O:5]
Reactant: C/C=C\C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CCC(=O)OC(C)(C)C)C(C)(C)C)C(OC)OC
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C/C=C\C[C@@H](C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1C)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)CCC(=O)O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
0.05 g (0.04 mmol) of (Z)-N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-N1-[1(S)-(dimethoxymethyl)-3-pentenyl]-L-leucinamide was dissolved in 4 ml of a 1:1 solution of dichloromethane and trifluoroacetic acid containing 3 drops of water. The resulting solution was stirred for 1 hour at room temperature. After removal of the solvent by evaporation the crude product was triturated in diethyl ether to give 0.03 g of (Z)-2(S)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-α-aspartyl]-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4-hexenal as a white solid, MS: m/e 845.7 [M+H]+.
Reaction SMILES: NC1C=CC(S(CC)(=O)=O)=C(C=1)C#N.[CH:15]([S:18]([C:21]1[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][C:22]=1[C:23]#[N:24])(=[O:20])=[O:19])([CH3:17])[CH3:16]>>[NH2:29][C:26]1[CH:27]=[CH:28][C:21]([S:18]([CH:15]([CH3:17])[CH3:16])(=[O:20])=[O:19])=[C:22]([CH:25]=1)[C:23]#[N:24]
Reactant: CC(C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1C#N
Agent: CCS(=O)(=O)c1ccc(N)cc1C#N
Product: CC(C)S(=O)(=O)c1ccc(N)cc1C#N
Yield: 95.3 %

Procedure:
Using a procedure analogous to that used to prepare 6B, 9A (632 mg, 2.48 mmol) was hydrogenated to give 9B (530 mg, 95%) as a white solid. MS (ESI) m/z 225.3 (M+H)+.
Reaction SMILES: C(O)CCCCCCCCCCC.[CH3:14][CH2:15][CH2:16][CH2:17][CH:18]([C:21]([O-:23])=[O:22])[CH2:19]C.CCC[CH2:27][CH:28]([C:31]([O-:33])=[O:32])CC.[Sn+2]>>[C:21]1(=[O:23])[O:22][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1.[CH3:27][C@@H:28]1[O:23][C:21](=[O:22])[C@H:18]([CH3:19])[O:33][C:31]1=[O:32]
Reactant: CCCCC(CC)C(=O)[O-]
Agent: [Sn+2]
Solvent: CCCCCCCCCCCCO
Product: C[C@@H]1OC(=O)[C@H](C)OC1=O
Product: O=C1CCCCCO1

Procedure:
The procedure in Example 1 was substantially repeated, except that 13.6 mL of 1-dodecanol instead of 4.00 mL of glycerol and 0.12 mL (40 pmol) instead of 0.10 mL of stannous octoate solution were used. The copolymer was dried under vacuum (0.1 mm Hg) at 110° C. for about 16 hours to remove any unreacted monomer. The copolymer had an inherent viscosity of 0.15 dL/g in HFIP at 25° C. The copolymer was viscous liquid at room temperature. The molar ratio of PCL/PLA was found to be 51.5/48.5 by proton NMR.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1([NH2:12])[CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.CN([CH:25]=[O:26])C>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2]([C:25](=[O:26])[NH:12][C:9]32[CH2:11][CH2:10]3)=[CH:7][CH:6]=1
Reactant: CN(C)C=O
Reactant: NC1(c2cc(Cl)ccc2Br)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NC2(CC2)c2cc(Cl)ccc21
Temperature: 130 °C
Reaction time: 16 h
Yield: 44.6 %

Procedure:
A mixture of 1-(2-bromo-5-chlorophenyl)cyclopropanamine (2 g, 8.1 mmol), Pd(dppf)Cl2 (0.2 g), DIPEA (3.1 g, 24.3 mmol) in DMF (20 mL) was stirred in an autoclave under 2 MPa of CO (g) at 130° C. for 16 hours. The reaction mixture was diluted with EtOAc (300 mL), and washed with brine. The organic layer was dried over anhy. Na2SO4, filtered, and concentrated under reduced pressure to give a crude product which was purified by chromatography to afford title compound (700 mg, yield 44.6%) as a yellow solid. MS: 193.8 (M+H+, 1C1).
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[C-:17]#[N:18].[Na+]>C(OCC)C.O.Cl>[C:17]([CH:2]([OH:1])[CH2:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1)#[N:18]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(CC(O)C#N)CC1
Reaction time: 4 h
Yield: 99.8 %

Procedure:
To a solution of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (60 g) in diethylether (150 mL) were added a solution of sodium cyanide (32.4 g) in water (100 mL) and concentrated hydrochloric acid (55 mL) by small portions at 0° C. The reaction system was stirred for 4 hr, and the organic layer was washed with brine, dried, and concentrated to give the title compound (67.0 g).
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[N:8]=[C:7]2I.[CH:16]([Mg]Cl)(C)C.[CH2:21]([Sn:25]([CH2:30][CH2:31][CH2:32][CH3:33])(Cl)[CH2:26][CH2:27][CH3:28])[CH2:22][CH2:23][CH3:24]>C1COCC1>[F:1][CH:2]([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[N:8]=[C:7]2[Sn:25]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:26][CH2:27][CH2:28][CH3:16])[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCC[Sn](Cl)(CCC)CCCC
Reactant: Cn1nc(I)c2cc(OC(F)F)ccc21
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(OC(F)F)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-(difluoromethoxy)-3-iodo-1-methyl-1H-indazole (400 mg, 1.23 mmol) in dry THF (15 mL) was added isopropylmagnesium chloride (0.75 mL, 1.3 mmol, 2M in THF) drop-wise at −16° C. under nitrogen atmosphere, stirred for 30 minutes, then dibutylchloro(propyl)stannane (0.5 mL, 1.45 mmol) was added drop-wise, the reaction mixture was warmed to room temperature slowly and stirred for 2 hours. The reaction mixture was quenched with a saturated solution of NH4Cl (40 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure and the residue was used into the next step without purification (500 mg, crude) as oil.
Reaction SMILES: N1C2C(=N[C:7](=[O:16])[C:8]3[CH:15]=[CH:14]C=NC=3N=2)C=CC=1.I[C:18]1[CH:19]=NN[CH:22]=1.C(N(CC)CC)C.CN(C)C=[O:33]>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:19]([O:16][CH2:7][CH3:8])(=[O:33])[CH3:18].[CH:18]([O:33][CH:15]([CH3:14])[CH3:8])([CH3:19])[CH3:22]
Reactant: O=c1nc2cccnc2nc2ncccc12
Reactant: Ic1cn[nH]c1
Reactant: CN(C)C=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)OC(C)C
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture of 5,11-dihydro-11-ethyl-8-ethynyl-4-methyl-(-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (obtained by procedures analogous to those described in Example 51) (147 mg), 4-iodopyrazole (199 mg), bis(triphenylphosphine)palladium(II) chloride (22 mg), copper(I) iodide (21 mg), and triethylamine (2 mL) in 4 mL of N,N-dimethylformamide was heated at 100° C. in a sealed tube for 40 min. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and concentrated. The crude residue was dissolved in 60 mL of methanol and hydrogenated at 50 p.s.i. over 10% palladium on carbon (70 mg). After 24 hours, the reaction mixture was filtered and concentrated. The residue was purified by flash chromatography, eluting with methanol/ethyl acetate, to afford the compound of Example 52, m.p. 184°-187° C. (ethyl acetate/isopropyl ether), and the compound of Example 53, m.p. 199°-201° C. (ethyl acetate/hexanes).
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C@H:4]1[CH2:7][C@H:6]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:14]=[C:15]([I:18])[CH:16]=3)[C:11](=[O:23])[C:10]2=[O:24])[CH2:5]1)[CH3:2].[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[Mg]I.C(=O)(O)[O-].[Na+]>O1CCCC1.CCOCC>[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[C:11]1([OH:23])[C:12]2[C:17](=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[C:19]([F:21])([F:20])[F:22])[N:9]([CH2:8][C@H:6]2[CH2:5][C@H:4]([N:3]([CH2:1][CH3:2])[CH2:25][CH3:26])[CH2:7]2)[C:10]1=[O:24]
Reactant: Clc1ccc([Mg]I)c(Cl)c1
Reactant: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(=O)c3c2cc(I)cc3C(F)(F)F)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O)(c3ccc(Cl)cc3Cl)c3c2cc(I)cc3C(F)(F)F)C1
Reaction time: 1 h

Procedure:
To a solution of the compound of Example 1-1 (3.13 g, 6.52 mmol) in tetrahydrofuran (65 mL) was added dropwise a solution of 2,4-dichlorophenylmagnesium iodide (9.78 mmol) in ether (19.6 mL) at −78° C. The mixture was stirred for 1 hour, and to the reaction solution was added saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, and then evaporated. The residue was purified by silica gel column chromatography (chloroform/methanol=1/0 to 20/1 to 10/1 to 5/1) to give the titled compound (2.95 g, 86%).
Reaction SMILES: CC(=O)CC.Br[CH2:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.[F:23][C:24]1[CH:31]=[C:30]([OH:32])[CH:29]=[CH:28][C:25]=1[C:26]#[N:27].C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[C:26]([C:25]1[CH:28]=[CH:29][C:30]([O:32][CH2:7][CH2:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:31][C:24]=1[F:23])#[N:27]
Reactant: N#Cc1ccc(O)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(CCCBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCCOc2ccc(C#N)c(F)c2)CC1
Temperature: 25 °C
Yield: 54.5 %

Procedure:
A 2-butanone (7.6 mL) solution of 1.12 g of tert-butyl 4-(3-bromopropyl)-1-piperidinecarboxylate was added to a 2-butanone (7.0 mL) mixture of 0.50 g of 2-fluoro-4-hydroxybenzonitrile and 0.56 g of potassium carbonate, which was then heated to reflux for 6 hours and 30 minutes. After cooling down to room temperature, the reaction mixture was added to a mixture of ethyl acetate and water. The organic layer was separated, washed with water, and dried with anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The resultant residue was purified using silica gel column chromatography (eluent; hexane:ethyl acetate=4:1) to provide 0.72 g of tert-butyl 4-[3-(4-cyano-3-fluorophenoxy)propyl]-1-piperidinecarboxylate as colorless oily form.