Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[Cl:12].[CH3:13][C:14]1[N:19]=[C:18]([SH:20])[N:17]=[C:16]([OH:21])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[CH2:2][S:20][C:18]1[N:17]=[C:16]([OH:21])[CH:15]=[C:14]([CH3:13])[N:19]=1
Reactant: O=[N+]([O-])c1ccc(CBr)c(Cl)c1
Reactant: Cc1cc(O)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2ccc([N+](=O)[O-])cc2Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
1-(bromomethyl)-2-chloro-4-nitrobenzene, 6-methyl-2-sulfanylpyrimidin-4-ol (425 mg, 3 mmol), and potassium carbonate (420 mg, 3 mmol) were mixed in DMF (10 mL). The mixture was stirred at room temperature for 2 hours. To the mixture, water (100 mL) was added. The suspension was filtered and washed with water and ethyl acetate to provide pure titled product (500 mg, 54% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.20 (s, 3H), 4.55 (s, 2H), 6.03 (s, 1H), 7.92 (d, 1H), 8.19 (d, 1H), 8.31 (s, 1H); M+ 312.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7](I)[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:36]=[CH:37][CH:38]=1)[CH2:15][C:16]1[CH:35]=[CH:34][C:19]([C:20]([NH:22][CH2:23][CH2:24][C:25]#[C:26][Si:27]([CH2:32][CH3:33])([CH2:30][CH3:31])[CH2:28][CH3:29])=[O:21])=[CH:18][CH:17]=1.[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd](Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]2[C:5](=[C:4]([F:10])[CH:3]=1)[NH:6][C:26]([Si:27]([CH2:32][CH3:33])([CH2:30][CH3:31])[CH2:28][CH3:29])=[C:25]2[CH2:24][CH2:23][NH:22][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:16]([CH2:15][C:14]2[CH:36]=[CH:37][CH:38]=[C:12]([F:11])[CH:13]=2)=[CH:35][CH:34]=1
Reactant: CC[Si](C#CCCNC(=O)c1ccc(Cc2cccc(F)c2)cc1)(CC)CC
Reactant: Nc1c(F)cc(Cl)cc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)c1[nH]c2c(F)cc(Cl)cc2c1CCNC(=O)c1ccc(Cc2cccc(F)c2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 51.4 %

Procedure:
4-Chloro-2-fluoro-6-iodoaniline (0.100 g; 0.368 mmol), 4-(3-fluorobenzyl)-N-(4-(triethylsilyl)but-3-ynyl)benzamide (0.145 g; 0.368 mmol), bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.015 g; 0.018 mmol), lithium chloride (0.016 mg; 0.368 mmol) and sodium carbonate (0.078 g; 0.737 mmol) were suspended in DMF (5 mL) and the mixture was stirred at 100° C. for 18 hours. The solution was concentrated under reduced pressure and diluted in ethyl acetate. The organic layer was successively washed with brine, sodium thiosulfate, dried and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 2 to 60% ethyl acetate in heptane) to afford 0.102 g (51%) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1OS(C(F)(F)F)(=O)=O.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:4]1[C:5]([C:34]2[CH:35]=[CH:36][C:31]([C:30]([F:41])([F:40])[F:29])=[CH:32][CH:33]=2)=[CH:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)=[O:20]
Reactant: COC(=O)c1ccc(OC)cc1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1ccc(OC)cc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 91.9 %

Procedure:
To a stirred solution of 4-methoxy-2-(trifluoro-methanesulfonyloxy)-benzoic acid methyl ester (6.28 g) in toluene (100 mL) was added LiCl (2.54 g) and Pd(PPh3)4 (1.15 g). After few minutes at room temperature, a 2M solution of Na2CO3 (26 mL) was added followed by a solution of 4-trifluoromethylphenyl boronic acid (4.17 g) in EtOH (30 mL). The resulting mixture was stirred under reflux for 6 hours. The mixture was cooled to room temperature and the phases were separated. The organic layer was then dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with hexane/AcOEt (90/10) to give the title compound (5.7 g) as white crystals.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[C:8]([CH2:15][CH2:16]Cl)[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:18]([O:22][C:23](=[O:39])[NH:24][CH2:25][C@H:26]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][C:32]=2[F:38])[CH2:27]1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23](=[O:39])[NH:24][CH2:25][C@H:26]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:16][CH2:15][C:8]4[C:9](=[CH:13][CH:14]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:7]=4)[C:10]3=[O:11])=[CH:33][C:32]=2[F:38])[CH2:27]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CCCCOc1ccc(C(=O)Cl)c(CCCl)c1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CCN(c2ccc(N)cc2F)C1
Product: CCCCOc1ccc2c(c1)CCN(c1ccc(N3CC[C@H](CNC(=O)OC(C)(C)C)C3)c(F)c1)C2=O

Procedure:
4-Butoxy-2-(2-chloroethyl)benzoyl chloride was reacted by method A with [(R)-1-(4-amino-2-fluorophenyl)pyrrolidin-3-yl]methylcarbamic acid tert-butyl ester. The product with the molecular weight of 511.64 (C29H38FN3O4) was obtained in this way; MS (ESI): 512 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH:18][C:19](=[O:21])[CH3:20])=[CH:4][CH:3]=1.Cl[C:23]1C=CC=CC=1.[OH-].[K+].CCl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[I-].[K+].C(O)(=O)C.O>[Br:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([N:18]([CH3:23])[C:19](=[O:21])[CH3:20])=[CH:4][CH:3]=1
Reactant: Clc1ccccc1
Reactant: CC(=O)Nc1ccc(Br)c2c1C(=O)c1ccccc1C2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCl
Agent: [Br-]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)N(C)c1ccc(Br)c2c1C(=O)c1ccccc1C2=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A mixture of 4-bromo-1-acetylaminoanthraquinone (purity 98%, 35.1 g), monochlorobenzene (420 g), tetra-n-butyl ammonium bromide (0.3 g), 96% potassium hydroxide (12.0 g) and potassium iodide (0.5 g) was stirred for 1 hour in an autoclave, while being maintained at 30° C. Then, methyl chloride (10.2 g) was added. The mixture was stirred at 50° C. for 2 hours and 70° C. for 10 hours, successively. After the temperature was lowered to 30° C. and pressure was released, the solution was transferred to a flask by adding water (200 g), and then acetic acid (1.2 g) was added thereto. The aqueous phase had pH of 7. After monochlorobenzene was recovered by heating, the solution was cooled down to 50° C. and filtered. The solid material was washed and dried to obtain 4-bromo-N-acetyl-1-methylaminoanthraquinone (34.7 g, purity 92.9%, yield 90.0%).
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH:13]2[CH2:18][CH2:17][CH:16]3[O:19][CH:15]3[CH2:14]2)[CH2:8][C:7]1=[O:20])(=O)[CH2:2][CH2:3][CH3:4].[CH2:21]([O:23][NH2:24])[CH3:22]>CO>[CH2:21]([O:23][N:24]=[C:1]([C:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH:13]2[CH2:18][CH2:17][CH:16]3[O:19][CH:15]3[CH2:14]2)[CH2:8][C:7]=1[OH:20])[CH2:2][CH2:3][CH3:4])[CH3:22]
Reactant: CCCC(=O)C1C(=O)CC(C2CCC3OC3C2)CC1=O
Reactant: CCON
Solvent: CO
Product: CCCC(=NOCC)C1=C(O)CC(C2CCC3OC3C2)CC1=O

Procedure:
3.5 parts by weight of 2-butyryl-5-(3,4-epoxycyclohexyl)-cyclohexane-1,3-dione and 0.8 part by weight of ethoxyamine in 100 parts by volume of methanol were stirred for 16 hours at room temperature. The solvent was distilled off under reduced pressure, the residue was dissolved in dichloromethane, the solution was washed with 5% strength by weight hydrochloric acid and water and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. 2-(1-Ethoxyiminobutyl)-5-(3,4-epoxycyclohexyl)-3-hydroxycyclohex-2-en-1-one (active ingredient No. 2) was obtained.
Reaction SMILES: [C:1]([CH:3]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:4][C:5]([NH:7][C:8]1[C:13]([O:14][CH3:15])=[CH:12][C:11]([O:16][CH3:17])=[CH:10][C:9]=1[O:18][CH3:19])=[O:6])#[N:2].C([Sn]([N:39]=[N+:40]=[N-:41])(CCCC)CCCC)CCC>O1CCOCC1>[NH:39]1[C:1]([CH:3]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:4][C:5]([NH:7][C:8]2[C:9]([O:18][CH3:19])=[CH:10][C:11]([O:16][CH3:17])=[CH:12][C:13]=2[O:14][CH3:15])=[O:6])=[N:2][N:41]=[N:40]1
Reactant: COc1cc(OC)c(NC(=O)CC(C#N)c2ccccc2)c(OC)c1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: C1COCCO1
Product: COc1cc(OC)c(NC(=O)CC(c2ccccc2)c2nnn[nH]2)c(OC)c1
Reaction time: 0.5 h
Yield: 34.2 %

Procedure:
To a suspension of the material from step (a) (5.1 g, 0.016 mol) in dioxane (150 mL) at room temperature was added tri-n-butyltin azide (9.36 g, 0.016 mol) under N2 with stirring. The resulting solution was heated to reflux for 24 hours. The solution was then cooled and concentrated in vacuo. The residue was redissolved in ether and HCl gas was then passed through the solution for 30 minutes. This was then concentrated in vacuo to give β-(1H-tetrazol-5-yl)-N-(2,4,6-trimethoxyphenyl)benzene propanamide as a white solid (2.1 g) which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.[F-].[K+]>C1(C)C=CC=CC=1>[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)OCO2
Reactant: Cc1ccccc1B(O)O
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1ccc2c(c1)OCO2
Yield: 100.7 %

Procedure:
4-Bromo-1,2-(methylenedioxy)benzene (201 mg, 1.02 mmol) reacted with 2-methylphenylboronic acid (150 mg, 1.10 mmol) using 1 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (116 mg, 2.00 mmol) in toluene at room temperature for 3 h to give the title compound (218 mg, 99%): 1H-NMR (300 MHz, CDCl3): δ 7.31-7.27 (m, 4H), 6.94-6.82 (m, 3H), 6.04 (s, 2H), 2.35 (s, 3H). 13C{1H}-NMR (125 MHz, CDCl3): δ 147.24, 146.39, 141.52, 135.84, 135.42, 130.26, 129.79, 127.10, 125.69, 122.44, 109.76, 107.98, 100.95, 20.45. GC/MS(EI): m/z 212 (M+), 181, 153. Anal. Calcd for C14H12O2: C, 79.23; H, 5.70. Found: C, 79.36; H, 5.73.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Sn](CCCC)(CCCC)CCCC)[CH:15]=2)[N:10]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:9]1=[O:38])([CH3:4])([CH3:3])[CH3:2].Br[C:41]1[CH:45]=[CH:44][S:43][CH:42]=1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:39])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:41]3[CH:45]=[CH:44][S:43][CH:42]=3)[CH:15]=2)[N:10]([CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:9]1=[O:38])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2c(c1)CC(NC(=O)OC(C)(C)C)C(=O)N2Cc1ccccc1
Reactant: Brc1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1Cc2cc(-c3ccsc3)ccc2N(Cc2ccccc2)C1=O
Temperature: 25 °C

Procedure:
To a solution of 4A (25 mg, 0.043 mmol) in degas sed THF (2 mL) was added tetrakis(triphenylphosphine)palladium (10 mg, 0.009 mmol), K2C3 (18 mg, 0.13 mmol), and 3-bromothiophene (21 mg, 0.13 mmol). The resulting mixture was heated at 70° for 16 h under argon. After cooling to RT, the mixture was filtered through Celite®, rinsing with CH2Cl2. The filtrate was evaporated under vacuum and the resulting residue was chromatographed on silica gel eluted with EtOAc in hex ane to obtain the title compound (14.5 mg, somewhat impure).
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[CH:8]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CON(C)[C:31](=[O:47])[C:32]1[CH:37]=[CH:36][C:35]([B:38]2[O:42][C:41]([CH3:44])([CH3:43])[C:40]([CH3:46])([CH3:45])[O:39]2)=[CH:34][CH:33]=1.O>C1COCC1>[CH3:43][C:41]1([CH3:44])[C:40]([CH3:45])([CH3:46])[O:39][B:38]([C:35]2[CH:34]=[CH:33][C:32]([C:31]([C:8]3[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:17])([CH3:16])[CH3:1])[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)=[O:47])=[CH:37][CH:36]=2)[O:42]1
Reactant: C[Si](C)(C)CCOCn1cnc2ccccc21
Reactant: CON(C)C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(C(=O)c3nc4ccccc4n3COCC[Si](C)(C)C)cc2)OC1(C)C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
To a solution of 1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzo[d]imidazole (6.06 g) in THF (50 mL) was added LiHMDS (1 M solution in THF, 30 ml) dropwise at 0° C. After stirring for 1 h, a solution of N-methoxy-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (7.10 g) in THF (50 mL) was added dropwise, and the mixture was stirred for 1 h at 0° C. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/AcOEt) and crystallized from hexane to give the title compound (6.20 g). 1H NMR (300 MHz, CDCl3) δ −0.11 (9H, s), 0.84-0.91 (2H, m), 1.37 (12H, s), 3.55-3.62 (2H, m), 6.03 (2H, s), 7.37-7.43 (1H, m), 7.45-7.50 (1H, m), 7.65-7.70 (1H, m), 7.91-7.98 (3H, m), 8.22-8.26 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][CH:10]([CH2:14][O:15][C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)[CH2:9]2)=[CH:4][CH:3]=1.Cl.[NH2:26][C:27]1[C:28](=[O:41])[N:29]([CH2:38][CH2:39][CH3:40])[C:30](=[O:37])[N:31]([CH2:34][CH2:35][CH3:36])[C:32]=1[NH2:33].CCN=C=NCCCN(C)C>CO>[NH2:33][C:32]1[N:31]([CH2:34][CH2:35][CH3:36])[C:30](=[O:37])[N:29]([CH2:38][CH2:39][CH3:40])[C:28](=[O:41])[C:27]=1[NH:26][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([O:15][CH2:14][CH:10]2[CH2:11][C:12](=[O:13])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:9]2)=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccc(OCC2CC(=O)N(c3ccc(F)cc3)C2)cc1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Product: CCCn1c(N)c(NC(=O)c2ccc(OCC3CC(=O)N(c4ccc(F)cc4)C3)cc2)c(=O)n(CCC)c1=O
Temperature: 22.5 °C
Reaction time: 16 h
Yield: 89.5 %

Procedure:
To a stirred solution of 4-[1-(4-fluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethoxy]-benzoic acid obtained in step 2 (0.140 g, 0.426 mmol) and HCl salt of 5,6-diamino-1,3-dipropyl-1H-pyrimidine-2,4-dione (0.112 g, 0.426 mmol) in MeOH (5 mL) was added EDCI (0.0136 g, 0.593 mmol). After stirring at 20-25° C. for 16 hours, the reaction mixture was quenched with water (5 mL). The solid obtained was filtered and washed with water to provide the crude product which was purified by column chromatography to afford N-(6-amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-4-[1-(4-fluorophenyl)-5-oxo-pyrrolidin-3-ylmethoxy]-benzamide (0.205 g, 90%) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH2:10][CH2:11][CH3:12])=[N:5][CH:6]=[CH:7][CH:8]=1.C[O:14][C:15]([CH:17]1[CH2:19][CH:18]1[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([F:27])[CH:21]=1)=[O:16]>>[F:27][C:22]1[CH:21]=[C:20]([CH:18]2[CH2:19][CH:17]2[C:15]([OH:16])=[O:14])[CH:25]=[CH:24][C:23]=1[O:26][CH2:2][C:3]1[C:4]([S:9][CH2:10][CH2:11][CH3:12])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCCSc1ncccc1CCl
Reactant: COC(=O)C1CC1c1ccc(O)c(F)c1
Product: CCCSc1ncccc1COc1ccc(C2CC2C(=O)O)cc1F
Yield: 48 %

Procedure:
3-Chloromethyl-2-propylsulfanyl-pyridine (0.016 g, 0.08 mmol) obtained in Step C of Preparation Example 14 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (less polar) (0.017 g, 0.08 mmol) obtained in Step C of Preparation Example 64 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.014 g, 48%).
Reaction SMILES: Cl.[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH:5]3[C:12]([OH:14])=[O:13])[CH2:3]1)[CH2:9]2.S(=O)(=O)(O)O.[CH3:20][CH2:21]O>>[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH:5]3[C:12]([O:14][CH2:20][CH3:21])=[O:13])[CH2:3]1)[CH2:9]2
Reactant: CCO
Reactant: O=C(O)C1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1C2CC3CC1CN(C3)C2

Procedure:
To a solution of 1-azatricyclo[3.3.1.13,7]decane-4-carboxylic acid hydrochloride in EtOH was added concentrated sulfuric acid, followed by heating under reflux for 18 hours. The reaction liquid was concentrated under reduced pressure and then diluted with EtOAc. The EtOAc layer was washed with an aqueous NaHCO3 solution and brine in this order, dried over MgSO4, and then concentrated under reduced pressure to obtain a yellow oily substance. This was purified by silica gel column chromatography (CHCl3:MeOH) to obtain ethyl 1-azatricyclo[3.3.1.13,7]decane-4-carboxylate as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH2:20][C:21](O)=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19].[N:24]1([C:30]2[N:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])[CH2:20][C:21](=[O:22])[N:27]1[CH2:28][CH2:29][N:24]([C:30]2[N:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:25][CH2:26]1
Reactant: c1cnnc(N2CCNCC2)c1
Reactant: COc1ccccc1C1(CC(=O)O)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccccc1C1(CC(=O)N2CCN(c3cccnn3)CC2)C(=O)Nc2ccc(Cl)cc21
Yield: 34.3 %

Procedure:
With 800 mg of [5-chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]acetic acid, which is the compound described in Preparation 1.1 of the brochure Publication No. WO03/008407, and 677 mg of 3-piperazin-1-yl pyridazin as starting materials, 395 mg of the title compound (colorless solid) was obtained by a similar method to Step 45-1.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH:19]=[CH:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([F:45])[C:27]([F:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=C(F)C=CC=2C2C=C3C=CC=2)CC1)C(OC)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([F:45])[C:27]([F:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:47][CH2:48]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)c(F)cc1-c1cccc-3c1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)c(F)cc1-c1cccc-3c1
Yield: 75 %

Procedure:
Prepared in 75% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-17,18-difluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetate following the same procedure as methyl(2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate. 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J=8.0 Hz, 1H), 8.08 (s, 1H), 8.02 (s, 1H), 7.53 (t, J=7.7 Hz, 1H), 7.32 (s, 1H), 7.27-7.16 (m, 2H), 6.82 (dd, J=12.7, 6.9 Hz, 1H), 6.04 (br. s., 1H), 4.44 (d, J=5.0 Hz, 1H), 3.96 (t, J=11.0 Hz, 1H), 3.81-3.72 (m, 1H), 3.70 (s, 3H), 3.57-3.42 (m, 2H), 3.10 (d, J=10.5 Hz, 1H), 2.70 (d, J=10.8 Hz, 1H), 2.46 (s, 3H), 2.00-1.70 (m, 10H), 1.29 (s, 3H), 1.25 (s, 9H), 1.16 (d, J=6.0 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −137.12-−137.51 (m, 1F), −148.56-−149.02 (m, 1F); LCMS (ESI, M+1): 676.25.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:21][C:22]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[CH2:18][NH:17][CH2:16][C:15](=[O:19])[NH:14][C:13]=3[CH:20]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:40][CH2:41][C:42]([F:45])([F:44])[F:43]>C(O)CCC>[Cl:1][C:2]1[C:3]([NH:21][C:22]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[CH2:18][N:17]([CH2:40][CH2:41][C:42]([F:45])([F:44])[F:43])[CH2:16][C:15](=[O:19])[NH:14][C:13]=3[CH:20]=2)=[N:6][CH:7]=1
Reactant: FC(F)(F)CCI
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CNC3)ncc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CN(CCC(F)(F)F)C3)ncc1Cl
Yield: 25.7 %

Procedure:
A solution of 2-[5-chloro-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide (50 mg, 0.11 mmol), potassium carbonate (31 mg, 0.22 mmol) and 1-iodo-3,3,3-trifluoropropane (58 mg, 0.25 mmol) was heated at 115° C. in butanol (3 mL) for 24 hours. After evaporated solvent, chromatography of the crude solid on a TLC plate with methylene chloride and methanol (25:1) to give 15.6 mg of 2-{5-chloro-2-[2-oxo-4-(3,3,3-trifluoro-propyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino]-pyrimidin-4-ylamino}-3-fluoro-N-methyl-benzamide in 14% yield: 1H NMR (300 MHz, CDCl3) δ 8.82 (s, 1H), 8.2 (s, 1H), 7.6 (m, 2H), 7.43 (m, 2H), 7.24 (s, 1H), 7.15 (d, 1H), 6.9 (d, 1H), 6.43 (d, 1H), 3.85 (s, 2H), 3.53 (s, 2H), 3.07 (d, 3H), 2.97 (m, 2H), 2.46 (m, 2H); MS (m/e): 552.2 (M+1).
Reaction SMILES: O.[OH-].[Na+].[CH3:4][CH:5]1[O:10][C:9]([CH2:18][NH2:19])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH2:8][CH2:7][O:6]1.[Cl:20][CH2:21][C:22](Cl)=[O:23]>ClCCl>[CH3:4][CH:5]1[O:10][C:9]([CH2:18][NH:19][C:22](=[O:23])[CH2:21][Cl:20])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH2:8][CH2:7][O:6]1
Reactant: CC1OCCC(CN)(c2ccccc2Cl)O1
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC1OCCC(CNC(=O)CCl)(c2ccccc2Cl)O1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Fifteen milliliters (ml) of water, 25 ml of dichloromethane, 4 ml (0.075 mole) of 50% sodium hydroxide and 7.2 grams (g) (0.03 mole) of 2-methyl-4-(aminomethyl)-4-(2-chlorophenyl)-1,3-dioxane were added to a reaction flask and cooled to 5° C. with an ice bath. Four and a half g of chloroacetyl chloride in 10 ml of dichloromethane were added at a rate slow enough to keep the temperature under 10° C. The reaction mixture was stirred for 1/2 hour and allowed to come to room temperature.