Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:6]1[CH2:10][CH2:9][O:8][C:7]1=[O:11])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH:3]([CH3:4])[CH2:2][C:1]([N:6]2[CH2:10][CH2:9][O:8][C:7]2=[O:11])=[O:5])=[CH:16][CH:15]=1
Reactant: COc1ccc(N)cc1
Reactant: C/C=C/C(=O)N1CCOC1=O
Solvent: Cc1ccccc1
Product: COc1ccc(NC(C)CC(=O)N2CCOC2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.9 %

Procedure:
To a solution of Pd((R)-binap)(OH2)2(OTf)2 (26.6 mg, 0.025 mmol) in toluene (3 ml) were added 3-crotonoyl-1,3-oxazolidin-2-one (155 mg, 1.0 mmol) and anisidine (148 mg, 1.2 mmol). After the resulting mixture was stirred at room temperature for 3 hours, the reaction solution was concentrated and purified by a silica gel column chromatography (hexane:ethyl acetate=4:1) to give the objective 3-[3-(4-methoxyphenylamino)butyryl]-1,3-oxazolidin-2-one (228 mg, 82% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[CH2:12]([O:14][C:15](=[O:23])[N:16]([CH2:20][CH2:21]Br)[CH2:17][CH2:18]Br)[CH3:13].[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[C:6]1([CH2:21][CH2:20][N:16]([C:15]([O:14][CH2:12][CH3:13])=[O:23])[CH2:17][CH2:18]1)[CH2:5]2
Reactant: CCOC(=O)N(CCBr)CCBr
Reactant: O=C1CCc2cc(F)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCC2(CC1)Cc1cc(F)ccc1C2=O
Temperature: 50 °C
Reaction time: 16 h
Yield: 32.1 %

Procedure:
To a stirred solution of 5-fluoro-1-indanone (302 mg, 2.013 mmol) and bis-(2-bromo-ethyl)-carbamic acid ethyl ester (610 mg, 2.01 mmol) in DMF (5 mL) at 50° C. was added NaH (121 mg, 5.03 mmol) by small portions. After being stirred at 50° C. for 16 hr, the reaction was cooled to 25° C. The reaction was diluted with 15 mL of ethyl acetate and washed twice with 10 mL of water, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column (gradient of 85:15 to 60:40 heptane/ethyl acetate in 20 min to give the title compound (188 mg, 0.645 mmol, 32.1% yield). MS (ESI) [m/e, (M+H)+]=292.4. HPLC retention time=1.46 minutes (Agilent 1100 HPLC system; 3.0 cm×3.0 mm×3.0 um C8 column; flow rate of 2.0 mL/min; gradient of 5-95% acetonitrile/water with 0.1% formic acid over 2 minutes).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:14]1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.N>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10](=[O:12])[NH2:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
To a solution of N-(t-butoxycarbonyl)glycine (3.01 g, 17.2 mmol) in anhydrous methylene chloride (150 ml) were added 1-hydroxybenzotriazole (4.63 g, 34.3 mmol), WSC (6.60 g, 34.4 mmol) and 4-dimethylaminopyridine (210 mg, 1.72 mmol) in an ice bath. The mixture was stirred at room temperature under an atmosphere of nitrogen overnight. After checking the completion of the reaction, 28% aqueous ammonia solution was added thereto and resulting mixture was stirred for 15 minutes. After checking the completion of the reaction, the reaction mixture was partitioned between methylene chloride and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (10:1) as the eluant to afford (carbamoylmethyl)carbamic acid t-butyl ester (717.7 mg, yield 24%) as a colorless and transparent syrup.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH2:25][CH2:26][CH2:27]I)=[CH:21][NH:22]2)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH2:25][CH2:26][CH2:27][N:12]3[CH2:13][CH2:14][N:9]([C:3]4[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=4[Cl:1])[CH2:10][CH2:11]3)=[CH:21][NH:22]2)=[CH:18][CH:17]=1
Reactant: Clc1ccc2c(CCCI)c[nH]c2c1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Product: Clc1ccc2c(CCCN3CCN(c4cccc(Cl)c4Cl)CC3)c[nH]c2c1

Procedure:
from 1-(2,3-dichlorophenyl)piperazine and 6-chloro 3-(3-iodopropyl)-1H-indole. 1H NMR (CDCl3): 1.95 (t, 2H); 2.55 (t, 2H); 2.65 (b s, 4H); 2.80 (t, 2H); 3.10 (b s, 4H); 6.95–7.05 (m, 2H); 7.10 (d, 1H); 7.10–7.20 (m, 2H); 7.35 (s, 1H); 7.55 (d, 1H); 7.95 (b s, 1H). Ms m/z: 422 (MH+), 424.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][C:11]([F:16])=[C:12]([CH3:15])[CH:13]=3)[C:8]([C:17]([O:19][CH3:20])=[O:18])=[C:7]2B(O)O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:25]1[N:30]=[CH:29][C:28]([S:31]([NH:34][C@@H:35]([CH3:40])[C:36]([F:39])([F:38])[F:37])(=[O:33])=[O:32])=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C(#N)C>[CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][C:11]([F:16])=[C:12]([CH3:15])[CH:13]=3)[C:8]([C:17]([O:19][CH3:20])=[O:18])=[C:7]2[C:25]2[CH:26]=[CH:27][C:28]([S:31](=[O:33])(=[O:32])[NH:34][C@@H:35]([CH3:40])[C:36]([F:38])([F:37])[F:39])=[CH:29][N:30]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1c(B(O)O)n(C2CCCC2)c2cc(C)c(F)cc12
Reactant: C[C@H](NS(=O)(=O)c1ccc(Cl)nc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1c(-c2ccc(S(=O)(=O)N[C@@H](C)C(F)(F)F)cn2)n(C2CCCC2)c2cc(C)c(F)cc12
Temperature: 25 °C
Yield: 53.9 %

Procedure:
A mixture of 1-cyclopentyl-5-fluoro-3-(methoxycarbonyl)-6-methyl-1H-indol-2-ylboronic acid (2.2 mmol), (S)-6-chloro-N-(1,1,1-trifluoropropan-2-yl)pyridine-3-sulfonamide (0.53 g, 1.83 mmol), PdCl2dppf (0.15 g, 0.183 mmol), aq. K2CO3 (2.0 M, 3.6 mL, 7.2 mmol) in acetonitrile (10 mL) was stirred at room temperature over the weekend. The mixture was treated with ethyl acetate and washed with water and brine and then concentrated. The residue was purified by flash chromatography with 0-15% ethyl acetate in CH2Cl2 to provide (S)-methyl 1-cyclopentyl-5-fluoro-6-methyl-2-(5-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)pyridin-2-yl)-1H-indole-3-carboxylate (0.52 g, 54%). MS m/z 528.2 M+H+; 1H NMR (500 MHz, CDCl3): δ 9.21 (1H, d, J=1.8 Hz), 8.25 (1H, dd, J=8.2 Hz, J=2.2 Hz), 7.87 (1H, d, J=10.6 Hz), 7.73 (1H, d, J=8.2 Hz), 7.27 (1H, d, J=5.2 Hz), 5.09 (1H, d, J=9.6 Hz), 4.39-4.31 (1H, m), 4.17-4.10 (1H, m), 3.70 (3H, s), 2.44 (3H, d, J=1.8 Hz), 2.41-2.36 (2H, m), 2.20-1.96 (4H, m), 1.67-1.63 (2H, m), 1.45 (3H, d, J=7.0 Hz).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][NH2:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(Cl)(Cl)Cl>[O:27]=[C:21]([NH:12][NH:11][C:9](=[O:10])[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C(=O)Cl
Reactant: NNC(=O)CCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=O)NNC(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The 3-phenylpropionic acid hydrazide mixture (499 mg) obtained in Production Example 22-1 was dissolved in chloroform (30 mL), and triethylamine (0.86 mL) and ethyl chloroglyoxalate (0.4 mL) were added thereto, and stirred at room temperature for 5 hours. After the reaction, the reaction liquid was entirely concentrated, and the resulting residue was purified through silica gel column chromatography (chloroform/methanol=94/6) to obtain the entitled compound (760 mg).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](O)=O.S(=O)(=O)(O)O.[NH2:15][NH:16][C:17]([NH2:19])=[S:18].N>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[S:18][C:17]([NH2:19])=[N:16][N:15]=1
Reactant: O=C(O)CCCCCBr
Reactant: NNC(N)=S
Agent: N
Agent: O=S(=O)(O)O
Product: Nc1nnc(CCCCCBr)s1
Yield: 59 %

Procedure:
6-Bromohexanoic acid (5.35 g, 27.4 mmol), concentrated sulphuric acid (15 mL), and thiosemicarbazide (3.0 g, 32.9 mmol) were slowly heated to 80-90° C. for 12 h. After cooling, the content was poured onto crushed ice. The mixture was neutralized with 10% aqueous ammonia and extracted with ethyl acetate (3×100 mL). The organic extracts were washed with 10% Na2CO3 (2×50 mL), water (100 mL), and brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography over silica gel 60 (70-230 mesh) eluted with CH2Cl2:MeOH 19:1 to give the product as a solid, mp 128-130° C., in 59% yield (4.03 g, 16.2 mmol). 1H NMR (300 MHz, CDCl3) δ 1.51-1.60 (m, 2), 1.71-1.79 (m, 2), 1.81-1.92 (m, 2), 2.92 (t, 2, J=7.5 Hz), 3.40 (t, 2, J=6.9 Hz), 5.33 (s, 2); 13C NMR (75 MHz, CDCl3) δ 26.9, 28.1, 29.3, 31.8, 35.0, 158.1, 168.2; HRMS (ESI+, m/z) calculated for C7H13BrN3S 250.0014, observed 250.0005 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]([CH2:17][CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13].CCCCC>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[C:17](\[CH3:18])/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Solvent: CCCCC
Product: CCOC(=O)/C(C)=C/c1ccc([N+](=O)[O-])cc1
Reaction time: 8 h

Procedure:
4-Nitrobenzaldehyde (4.20 g) and (carbetoxyethylidene)triphenylphosphorane (10 g) were dissolved in toluene (36 ml), and the obtained mixture was stirred overnight under reflux conditions. After the obtained reaction mixture was allowed to cool, N-pentane (50 ml) was added thereto, and the produced white precipitate was filtered off. The filtrate was concentrated, and N-pentane (70 ml) was added to the residue. Then, ultrasonic waves were applied to the mixture. The produced precipitate was filtered off and dried under reduced pressure to obtain crude (E)-ethyl 3-(4-nitrophenyl)-2-methylacrylate as a yellow powder.
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3]Cl.[C:9]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([NH:25]C(OC(C)(C)C)=O)[CH2:17][C@:18]([CH2:23][OH:24])([CH3:22])[C:19]([OH:21])=[O:20])=[CH:11][CH:10]=1.CCN(CC)CC>CC(C)=O>[CH2:6]([O:5][C:1]([O:2][CH2:3][O:21][C:19](=[O:20])[C@@:18]([CH2:23][OH:24])([CH3:22])[CH2:17][C@H:16]([NH2:25])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:10][CH:11]=1)=[O:8])[CH3:7]
Reactant: CCOC(=O)OCCl
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@](C)(CO)C(=O)O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCOC(=O)OCOC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1

Procedure:
Chloromethyl ethyl carbonate (54 mg, 387 μmol) was added to a mixture of (2S,4R)-5-biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-2-methyl-pentanoic acid (100 mg, 242 μmol) and Et3N (35 μL, 254 μmol) in acetone (10 mL). The mixture was refluxed for 24 hours and the reaction monitored for completion. When the reaction was complete, the product was purified ((Interchim reverse phase chromatography column) the solvent was removed under vacuum to yield (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid ethoxycarbonyloxymethyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[I:11]N1C(=O)CCC1=O>CN(C=O)C>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1ncnc2[nH]ccc12
Solvent: CN(C)C=O
Product: Clc1ncnc2[nH]cc(I)c12
Yield: 74.6 %

Procedure:
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine 10.75 g (70 mmol) (Toronto Research Chemicals, Inc) and N-iodosuccinimide (16.8 g, 75 mmol) were dissolved in 400 mL of dry DMF and left at ambient temperature in the darkness over night. The solvent was evaporated. The yellow residue was suspended in hot 10% solution of Na2SO3, filtered, washed twice with hot water and crystallized from ethanol to yield 14.6 g (74.6%) of the title compound as off-white crystals. The mother liquid was evaporated up to ⅓ volume and crystallized again from ethanol to give 2.47 g (12.3%) of the title product.
Reaction SMILES: Br[C:2]1[C:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=12.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[F:19][C:20]([F:31])([F:32])[O:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:4][N:5]3[CH:10]=[CH:9][CH:8]=[N:7][C:6]=23)=[CH:24][CH:23]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)Nc1nn2cccnc2c1Br
Product: CC(C)(C)OC(=O)Nc1nn2cccnc2c1-c1ccc(OC(F)(F)F)cc1

Procedure:
The product from Example 148A and 4-trifluoromethoxyphenylboronic acid were processed using the method analogous to that described in example 110C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.52-9.54 (bs, 1H), 9.08 (dd, J=6.9, 1.7 Hz, 1H), 8.61 (dd, J=4.1, 1.7 Hz, 1H), 7.87-7.90 (m, 2H), 7.44-7.46 (m, 2H), 7.12 (dd, J=6.9, 4.1 Hz, 1H), 1.25 (s, 9H); MS (ESI) m/z 393 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]#[N:16].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28]>C(O)C.CO>[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28].[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([N:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]1)=[NH:16]
Reactant: N#CNc1ccccc1-c1ccccc1F
Reactant: CN1CCNCC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CO
Product: CN1CCN(C(=N)Nc2ccccc2-c2ccccc2F)CC1

Procedure:
A mixture of 2'-fluoro-2-biphenylylcyanamide (2.1 g) and N-methylpiperazine (1.5 g) in ethanol (25 ml) was heated at 90°-95° C. for 3 hours to yield the free base which was reacted with fumaric acid (1.78 g) in methanol (70 ml) to give N-(2'-fluoro-2-biphenylyl)-4-methylpiperazine-1-carboxamidine difumarate (m.p. 201°-202° C.) which was recrystallised from a 2:3 mixture of methanol and ether.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1F)[C:14]#[N:15].C(=O)([O-])[O-].[Cs+].[Cs+].CC(N(C)C)=O>O>[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:14]#[N:15]
Reactant: O=Cc1ccc(O)cc1
Reactant: N#Cc1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Oc2ccc(C=O)cc2)c(Cl)c1
Temperature: 100 °C
Yield: 94.8 %

Procedure:
Mix 4-hydroxy-benzaldehyde (0.86 g, 7.07 mmol), 3-chloro-4-fluoro-benzonitrile (1.00 g, 6.43 mmol), cesium carbonate (3.14 g, 9.64 mmol) and dimethylacetamide (30 mL) in a flask. Heat to 100° C. for 4 hrs. Let cool to room temperature (rt) and pour into water (200 mL). After trituration, filter the solid formed and dry on a vacuum pump to obtain the product (1.57 g, 95%). 1H NMR (DMSO-d6) 9.96 (s, 1H), 8.29 (d, J=1.8 Hz, 1H), 7.97 (d, J=8.6 Hz, 2H), 7.89 (dd, J=1.8 Hz, 8.6 Hz, 1H), 7.35 (d, J=8.6 Hz, 1H), 7.23 (d, J=8.6 Hz, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].N1C=CC=CC=1.[C:19](Cl)(=[O:23])[O:20][CH2:21][CH3:22]>C(OCC)(=O)C>[C:19](=[O:23])([O:20][CH2:21][CH3:22])[O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([O:7][C:8]([CH3:9])([CH3:11])[CH3:10])=[O:12]
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: CCOC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)OCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.5 %

Procedure:
To a mixture of tert-butyl 3-hydroxypropylcarbamate (8.00 g) obtained in Reference Example 40 and ethyl acetate (50 mL) were added pyridine (4.06 mL) and ethyl chlorocarbonate (5.95 g) under ice-cooling, and the mixture was stirred at room temperature for 24 hrs. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed with water (50 mL), an aqueous copper sulfate solution (30 mL), water (30 mL) and saturated brine (30 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave the title compound (9.31 g) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[CH:38]=[C:37]([C:42](Cl)=[O:43])[CH:36]=[CH:35]2.C(=O)(O)[O-].[Na+]>ClCCl>[F:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[CH:38]=[C:37]([C:42]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:8]3)=[CH:22][CH:23]=1)=[O:43])[CH:36]=[CH:35]2
Reactant: CCOC(=O)Cc1nn(Cc2ccc(N)cc2)c2ccccc12
Reactant: O=C(Cl)c1ccc2cc(F)ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc4cc(F)ccc4c3)cc2)c2ccccc12
Yield: 54.4 %

Procedure:
The crude ethyl 2-[1-(4-aminobenzyl)-1H-indazol-3-yl]acetate (about 1.0 mmol) obtained in the last step and triethylamine (1.4 mL) were dissolved in dichloromethane (15 mL). In an ice bath, dichloromethane solution (10 mL) of the prepared 6-fluoro-2-naphthoyl chloride (about 1.2 mmol) was added dropwise slowly. Upon completion of the dropwise addition, it was reacted at room temperature for 16 hours. An aqueous solution of sodium bicarbonate was added to quench, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and filtered. The filtrate was removed under reduced pressure, and the resulting residue was chromatographed on a silica gel column (petroleum ether:ethyl acetate=2:1) to obtain a white solid 262 mg, at a total yield over two steps of reactions of 54.4%.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][O:25][C:26]1[C:31]([N+:32]([O-:34])=[O:33])=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:29]5[CH:28]=[N:27][C:26]([O:25][CH3:24])=[C:31]([N+:32]([O-:34])=[O:33])[CH:30]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1[N+](=O)[O-]
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: COc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1[N+](=O)[O-]

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-methoxy-3-nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 66.1.1) to give the title compound as a white solid. (HPLC: tR 2.62 min (Method A); M+H=446 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.00 (s, 1H), 8.72-8.66 (m, 1H), 8.46-8.39 (m, 1H), 8.18-8.10 (m, 2H), 8.05-7.96 (m, 1H), 7.58-7.53 (m, 1H), 4.07 (s, 3H), 3.91 (s, 3H), 3.59 (s, 3H), 1.94 (s, 3H))
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[N:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:39]2[CH2:40][CH2:41][N:36]([C:33]4[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=4)[CH2:37][CH2:38]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: c1cc(N2CCNCC2)ccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CN3CCN(c4ccncc4)CC3)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 1-(pyridin-4-yl)piperazine (32 mg, 0.20 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-(1-(tert-butoxycarbonyl)-5-[4-(pyridin-4-yl)piperazin-1-ylmethyl]indol-2-yl)isoindolinone.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1.CN(C)C=O>O>[O:1]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)[Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 1.24 g (0.01 mole) of 4-hydroxymethylphenol, 1.8 g (0.012 mole) of tert-butyldimethylsilyl chloride, 1.7 g (0.025 mole) of imidazole and 3 ml of dimethylformamide was stirred under nitrogen at room temperature for 12 h. The reaction mixture was poured into water and extracted with three portions of ether. Ether extracts were combined and washed successively with water and saturated NaCl solution and then dried (Na2SO4). The ether solution was concentrated in-vacuo and the resultant crude product was purified by flash chromatography (silica; 10% ethyl acetate in hexanes) to give the title compound as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]([NH:11][CH:12]([CH:26]([CH3:28])[CH3:27])[CH:13]([O:18][Si](C(C)(C)C)(C)C)[C:14]([F:17])([F:16])[F:15])=[O:10])[C:6]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:5][CH:4]=[C:3]1[NH:35][C:36]([NH:38][CH2:39][C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1)=[O:37]>CO.ClCCl>[O:1]=[C:2]1[N:7]([CH2:8][C:9]([NH:11][CH:12]([CH:26]([CH3:28])[CH3:27])[CH:13]([OH:18])[C:14]([F:15])([F:17])[F:16])=[O:10])[C:6]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:5][CH:4]=[C:3]1[NH:35][C:36]([NH:38][CH2:39][C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1)=[O:37]
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(=O)NCc2cccnc2)c1=O)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(=O)NCc2cccnc2)c1=O)C(O)C(F)(F)F

Procedure:
2-[6-Oxo-2-phenyl-5-[3-(3-pyridylmethyl)ureido]-1,6-dihydro-1-pyrimidinyl]-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide was subjected to a method similar to that described in Example 2.d. Chromatography, with methanol:dichloromethane (5:95) as the eluent, gave 2-[6-oxo-2-phenyl-5-[3-(3-pyridyl)methylureido]-1,6-dihydro-1-pyrimidinyl]-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide as a white solid; MS: m/z=533(M+1).
Reaction SMILES: [CH3:1][C:2]([C:10]([Cl:12])=[CH2:11])([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:13]([Br:16])(Br)[Br:14].[OH-].[K+]>C(Cl)Cl>[CH3:9][C:2]([C:10]1([Cl:12])[CH2:11][C:13]1([Br:16])[Br:14])([CH3:1])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C=C(Cl)C(C)(C)c1ccccc1
Reactant: BrC(Br)Br
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(c1ccccc1)C1(Cl)CC1(Br)Br

Procedure:
Into a 100 ml round bottomed flask equipped with magnetic stirring was added 4.5 g (25 mmol) of 1-(α,α-dimethylbenzyl)-1-chloroethylene, 25 g (100 mmol) of bromoform, 27 g of methylene chloride, 0.37 g of N,N′-dibenzyl-N,N,N′N′-tetramethylethylenediammonium dibromide, and 12.4 g (100 mmol) of 45% aqueous KOH. Rapid stirring overnight gave a 20% conversion to the desired cyclopropane. Washing the aqueous layer with water and resubmitting with fresh bromoform, catalyst, and KOH overnight gave further conversion. A third submission was deemed adequate. The aqueous washed organic layer was evaporated in vacuo and chromatographed on silica gel using 2% diethyl ether in hexane yielding 4.2 g of 1-(α,α-dimethylbenzyl)-1-chloro-2,2-dibromocyclopropane.