Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([CH2:18][N:19]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH:33]([C:36]#[N:37])[CH2:34][CH3:35])=[CH:26][CH:25]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-:39].[K+].[K+].OO>CS(C)=O>[OH:1][C@@H:2]([CH2:18][N:19]([C:24]1[CH:25]=[CH:26][C:27]([O:30][CH2:31][CH2:32][CH:33]([C:36](=[O:39])[NH2:37])[CH2:34][CH3:35])=[CH:28][CH:29]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: CCC(C#N)CCOc1ccc(N(CC(C)C)C[C@H](O)COc2cccc3[nH]c4ccccc4c23)cc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CCC(CCOc1ccc(N(CC(C)C)C[C@H](O)COc2cccc3[nH]c4ccccc4c23)cc1)C(N)=O
Temperature: 0 °C
Reaction time: 48 h
Yield: 67.6 %

Procedure:
The nitrile prepared in example 108 (0.40 g, 0.80 mmol) and potassium carbonate (0.24 g, 1.70 mmol) were slurried in DMSO (5 mL) and cooled to 0° C. in an ice bath. Aqueous hydrogen peroxide (30%, 1.0 mL) was added slowly, and the reaction stirred at room temperature for 48 hours. The reaction was quenched by pouring into water, and extracting the aqueous layer with ethyl acetate. The combined organic layers were dried (MgSO4), and concentrated in vacuo to a light tan oil. The material was purified by flash chromatography over silica gel eluting with EtOAc/hexanes/10% NH4OH in MeOH (5:4:1) to provide 0.28 g (67%) of a colorless oil. MS (FD+) 518.07 (MH+). NMR.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:6]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18].[NH:27]1[CH:31]=[CH:30][CH:29]=[N:28]1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH:7]2[N:6]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:5]([CH2:4][CH2:3][CH2:2][N:27]3[CH:31]=[CH:30][CH:29]=[N:28]3)[CH2:9][CH2:8]2)=[CH:11][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCCl)CCC2c2ccc(F)cc2)cc1
Reactant: c1cn[nH]c1
Product: Cc1ccc(S(=O)(=O)N2C(CCCn3cccn3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=428.5 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(3-chloro-propyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 1H-pyrazole.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([NH:23][CH2:24][CH2:25][CH2:26][NH2:27])[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([C:41](O)=[O:42])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C(N(CC)C(C)C)(C)C.Cl.C(N(CC)CCCN=C=NCC)C.ON1C2C=CC=CC=2N=N1>ClCCl>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([C:41](=[O:42])[NH:27][CH2:26][CH2:25][CH2:24][NH:23][C:18]2[N:17]=[C:16]([C:13]3[S:12][C:11]4[CH:10]=[CH:9][CH:8]=[C:7]([C:5](=[O:6])[NH:4][CH:1]5[CH2:2][CH2:3]5)[C:15]=4[CH:14]=3)[C:21]([Cl:22])=[CH:20][N:19]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: NCCCNc1ncc(Cl)c(-c2cc3c(C(=O)NC4CC4)cccc3s2)n1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(CC)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Yield: 92.1 %

Procedure:
A suspension of 2-[2-(3-aminopropylamino)-5-chloropyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (500 mg, 1.24 mmol) in dichloromethane (30 mL) is treated at room temperature with piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (340 mg, 1.48 mmol) in the presence of N,N-diisopropylethylamine (0.220 mL, 163 mg, 1.26 mmol), 1-(3-diethylaminopropyl)-3-ethylcarbodiimide hydrochloride (240 mg, 1.25 mmol), and 1-hydroxybenzotriazole (171 mg, 1.21 mmol) for 24 hours. The mixture is then diluted with dichloromethane (30 mL), filtered, washed with H2O (30 mL), and diethyl ether (30 mL), and dried to provide 4-{3-[5-chloro-4-(4-cyclopropylcarbamoyl-benzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-propylcarbamoyl}-piperidine-1-carboxylic acid tert-butyl ester (700 mg, 92%). A stirred mixture of this intermediate (695 mg, 1.13 mmol) in dichloromethane (25 mL) is treated at room temperature with TFA (2.5 mL) for 72 hours. The mixture is then concentrated under reduced pressure, and subjected to chromatographic purification on silica gel, eluting with 2 M NH3/MeOH in dichloromethane: 16-40%, to provide the title compound (492 mg, 85% yield).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([CH3:10])[CH:3]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].OS([O-])(=O)=O.[Na+]>C(Cl)Cl.O>[CH3:10][C:4]1[CH:3]=[C:2]([OH:1])[CH:9]=[CH:8][C:5]=1[CH2:6][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C1CCNC1
Reactant: Cc1cc(O)ccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(O)ccc1CN1CCCC1
Yield: 94.8 %

Procedure:
4-Hydroxy-2-methylbenzaldehyde (1.1 g, 8 mmol) was added in portions for 30 min to a mixture of pyrrolidine (0.84 mL, 10 mmol) and NaB(OAc)3H (2.14 g, 10 mmol) in CH2Cl2 (10 mL) under vigorous stirring and cooling with an ice bath in an atmosphere of argon. The mixture was stirred for 12 h and cooled with an ice bath. Water (20 mL) and 5N NaHSO4 (to pH 1) were added. The organic layer was separated and discarded. The aqueous one was alkalized with saturated K2CO3 to pH 6 and extracted with chloroform (2×25 mL). The combined extracts were dried with Na2SO4, and evaporated to give the title compound (1.45 g, 94%) was obtained as dark-yellow crystals. LCMS-data: (M+H)+ 193.1 and 192.1 (calculated for C12H17NO 191.3). 1H NMR data (DMSO-d6): 9.08 (br. s, 1H ArOH), 6.97 (d, 1H, J=8.1 Hz, Ar—H), 6.54 (d, 1H, J=2.4 Hz, Ar—H); 6.49 (dd, 1H, J1=2.4 Hz, J2=8.1 Hz, Ar—H), 3.40 (s, 2H, ArCH2), 2.33-2.45 (m, 4H, pyrrolidine (CH2)2N),), 2.21 (s, 3H, OCH3), 1.60-1.68 (m, 4H, CH2CH2CH2CH2).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[C:28]([C:30]1[CH:31]=[C:32]([CH:40]([CH2:44][CH:45]2[CH2:49][CH2:48][CH2:47][CH2:46]2)[C:41]([OH:43])=O)[CH:33]=[CH:34][C:35]=1[S:36]([CH3:39])(=[O:38])=[O:37])#[N:29].[NH2:50][C:51]1[S:52][CH:53]=[CH:54][N:55]=1>C(Cl)Cl>[C:28]([C:30]1[CH:31]=[C:32]([CH:40]([CH2:44][CH:45]2[CH2:46][CH2:47][CH2:48][CH2:49]2)[C:41]([NH:50][C:51]2[S:52][CH:53]=[CH:54][N:55]=2)=[O:43])[CH:33]=[CH:34][C:35]=1[S:36]([CH3:39])(=[O:38])=[O:37])#[N:29]
Reactant: Nc1nccs1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C#N
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1C#N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.5 %

Procedure:
A solution of triphenylphosphine (98 mg, 0.37 mmol) in methylene chloride (1 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (67 mg, 0.37 mmol). The reaction mixture was stirred at 0° C. for 15 min and then treated with 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (100 mg, 0.31 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminothiazole (68 mg, 0.68 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) to afford 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (117 mg, 93%) as a white solid: mp 145-148° C.; EI-HRMS m/e calcd for C19H21N3O3S2 (M+) 403.1024, found 403.1023.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][CH2:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.CC(N(C)C)=O>C(OCC)(=O)C.Cl[Cu]>[CH:7]1[CH:8]=[C:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[CH:17][CH:18]=2)[N:1]2[C:2]=1[CH:3]=[CH:4][CH:5]=[CH:6]2
Reactant: N#Cc1ccc(CCC#Cc2ccccn2)cc1
Agent: Cl[Cu]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Cc2ccc3ccccn23)cc1
Temperature: 130 °C
Yield: 92.8 %

Procedure:
A dried 1 L of three-neck round-bottom flask was flushed with N2, connected to a N2 inlet, equipped with a thermometer and a magnetic stirrer. 4-(4-Pyridin-2-yl-but-3-ynyl)-benzonitrile (58.73 g, 0.25 mol), DMA (490 mL) and TEA (70 mL) were successively added to the flask, resulting in a light brown solution. CuCl (25.05 g, 0.25 mol) was then added, after which the reaction turned dark brown. The reaction mixture was kept stirring at 130° C. After stirring for 3 h at 130° C., the reaction was complete, and cooled to room temperature. The reaction was then quenched with water (300 mL), and ethyl acetate (400 mL) was added. The resulting dark brown mixture was then filtered through a celite cake to give a clear two-layer mixture. After separation, drying, and concentration, a dark oil was obtained. The dark oil was dissolved in 250 mL of ethyl acetate, applied to 15 g of decoloring carbon, and stirred for 20 minutes. After filtration through a celite cake, the filtrate was washed with water (100 mL) twice, dried over sodium sulfate. Concentration gave 53.89 g (89%) of 4-indolizin-3-ylmethyl-benzonitrile. 1H NMR (CDCl3): δ (ppm) 7.55 (d, J=8.1 Hz, 2H); 7.50 (d, J=9.0 Hz, 1H); 7.39 (d, J=9.0 Hz, 1H); 7.23 (d, J=7.8 Hz, 2H); 6.64 (m, 2H), 6.44 (m, 2H); 4.27 (s, 2H). ESMS calcd. (C16H12N2): 232.1. found: 233.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[NH2:25][CH2:26][CH2:27][S:28][CH2:29][CH2:30][OH:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:31][CH2:30][CH2:29][S:28][CH2:27][CH2:26][NH:25][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:21]
Reactant: NCCSCCO
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCCSCCO)ccc21
Yield: 77.7 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [2-(2-hydroxy-ethylsulfanyl)-ethyl]-amide (70 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (70 mg), 2-(2-amino-ethylsulfanyl)-ethanol (50 mg), HBTU (150 mg), and DIEA (100 uL) in DMF (1 mL).
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]#[C:17][C:18]3[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=3)=[C:14]([CH2:25][CH3:26])[N:13]=[C:12]([NH2:27])[N:11]=2)=[CH:6][C:5]=1[F:28]>C1COCC1>[NH2:27][C:12]1[N:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:29])=[O:2])=[C:5]([F:28])[CH:6]=2)[C:15]([C:16]#[C:17][C:18]2[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=2)=[C:14]([CH2:25][CH3:26])[N:13]=1
Reactant: CCc1nc(N)nc(-c2ccc(C(=O)OC)c(F)c2)c1C#Cc1ccc(C)nc1
Solvent: C1CCOC1
Product: CCc1nc(N)nc(-c2ccc(C(=O)O)c(F)c2)c1C#Cc1ccc(C)nc1

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 130 mg (0.47 mmol) 4-[2-amino-6-ethyl-5-(6-methyl-pyridin-3-ylethynyl)-pyrimidin-4-yl]-2-fluoro-benzoic acid methyl ester using 470 μL (0.47 mmol) 1 N NaOH in 3 mL THF. The product precipitates from the reaction mixture and is isolated by filtration.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:17]=3[F:25])[N:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[Cl-].[NH4+]>[Zn].CO.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=3[F:25])[N:12]=[CH:11][N:10]=2)=[CH:26][CH:27]=1
Reactant: COc1ccc(CNc2cc(Oc3ccc([N+](=O)[O-])cc3F)ncn2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CNc2cc(Oc3ccc(N)cc3F)ncn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.9 %

Procedure:
A solution of N-(4-methoxybenzyl)-6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-amine (150 mg, 0.41 mmol) in 1:1 MeOH/THF (20 mL) was treated with ammonium chloride (0.22 g, 4.1 mmol), and zinc dust (<20 microns, 0.27 g, 4.2 mmol). The reaction mixture was stirred at RT for 1 h. An additional portion of zinc dust (150 mg) was added to the mixture and the reaction mixture was stirred at RT for 1 h and heated at 70° C. for 20 min. The mixture was filtered to remove the inorganic solids, concentrated in vacuo, and the residue partitioned between EtOAc and brine. The EtOAc phase was separated, washed with brine, dried (MgSO4) and concentrated in vacuo to give the title compound (145 mg, 99%). 1H NMR (DMSO-d6) δ 8.10 (br s, 1H), 7.76 (br s, 1H), 7.21 (d, 2H, J=8.6 Hz), 6.88 (d, 3H, J=8.6 Hz), 6.44 (dd, 1H, J=12.7, 2.0 Hz), 6.36 (dd, 1H, J=8.3, 2.3 Hz), 5.79 (s, 1H), 4.41 (br s, 2H), 3.73 (s, 3H); MS(ESI+) m/z 341.18 (M+H)+.
Reaction SMILES: B(F)(F)F.[F:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20].O>C(OCC)C>[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][C:8]=1[OH:12])=[O:20]
Reactant: O=C(Cl)CCCCCCl
Reactant: Oc1cccc(F)c1
Agent: FB(F)F
Solvent: O
Solvent: CCOCC
Product: O=C(CCCCCCl)c1ccc(F)cc1O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 85.3 %

Procedure:
Reaction under N2 atmosphere. BF3 in diethylether (215 ml) was cooled to 0° C. 3-Fluoro-phenol (0.25 mol) was added. 6-Chloro-hexanoyl chloride (0.51 mol) added and the resulting reaction mixture was stirred for 15 min at 0° C., then allowed to warm to room temperature. The reaction mixture was then stirred overnight at 130° C. The mixture was cooled room temperature. Water was added while cooling. This mixture was extracted twice with diisopropyl ether. The separated organic layer was dried, filtered and the solvent evaporated. The residue was by column chromatography over silica gel (eluent: CH2Cl2/hexane 50/50), then by HPLC (eluent: CH2Cl2/hexane 50/50). The fractions were collected and the solvent was evaporated, yielding 52.2 g of 6-chloro-1-(4-fluoro-2-hydroxyphenyl)-1-hexanone (interm 17).
Reaction SMILES: O[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1
Reactant: Oc1ncc(Br)cc1C(F)(F)F
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1cc(Br)cnc1Cl
Temperature: 0 °C

Procedure:
A mixture of 1.83 g (7.6 mmol) of 2-hydroxy-3-trifluoromethyl-5-bromopyridine (from Step A) in 15 mL of POCl3 was heated at reflux for 3 h. The mixture was cooled and poured onto 200 g of ice. The resulting mixture was extracted with 200 mL of CH2Cl2. The extract was dried and concentrated. Chromatography on a Biotage 40 M cartridge using hexanes as the eluant afforded 1.11 g of the title compound: 1H NMR (500 MHz, CDCl3) δ 8.14 (d, J=2.0, 1H), 8.64 (d, J=2.0, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:7]C(=O)OC(C)(C)C)[S:5][CH:6]=1.[C:15]([OH:21])([C:17]([F:20])([F:19])[F:18])=[O:16]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([NH2:7])[S:5][CH:6]=1.[F:18][C:17]([F:20])([F:19])[C:15]([OH:21])=[O:16]
Reactant: Cc1csc(NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1csc(N)c1

Procedure:
A solution of tert-butyl 4-methylthiophen-2-ylcarbamate (0.880 g, 4.13 mmol) in CH2Cl2 (8 mL) and TFA (6 mL) wad stirred at room temperature for 3 h. Solvents was removed in vacuo to give 4-methylthiophen-2-amine as trifluoroacetic acid salt (0.920 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+].[CH2:21]([N:23]1[C:29](=[O:30])[C:28]([CH3:32])([CH3:31])[C:27](=[O:33])[N:26]([CH3:34])[C:25]2[CH:35]=[C:36]([O:39][CH2:40][CH2:41][CH2:42]I)[CH:37]=[CH:38][C:24]1=2)[CH3:22]>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:42][CH2:41][CH2:40][O:39][C:36]2[CH:37]=[CH:38][C:24]3[N:23]([CH2:21][CH3:22])[C:29](=[O:30])[C:28]([CH3:32])([CH3:31])[C:27](=[O:33])[N:26]([CH3:34])[C:25]=3[CH:35]=2)[C:4](=[O:12])[C:3]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=c1[nH]c2ccccc2c(Cl)c1-c1ccccc1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCI)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCn3c(=O)c(-c4ccccc4)c(Cl)c4ccccc43)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.8 %

Procedure:
4-Chloro-3-phenyl-1H-quinoline-2-one(0.3 g) was suspended in DMF(6 ml). Sodium hydride (60% in oil) (51 mg) was added, and the mixture was stirred for 15 minutes at room temperature. 1-Ethyl-7-(3-iodopropoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(0.55 g) was added thereto and the mixture was stirred at room temperature for 7 days. The reaction mixture was poured to ice water(50 ml), and the generated insoluble matter was separated. The insoluble matter was dissolved in ethyl acetate. The liquid was dried over sodium sulfate and condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=1:1→1:3). The purified product was condensed under reduced pressure, and the residue was recrystallized from ether, thereby obtaining the title compound(0.28 g) as a white powder.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:18]([C:25]1[CH:26]=[C:27]([CH2:31][C:32](O)=[O:33])[CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([C:25]1[CH:26]=[C:27]([CH2:31][C:32]([NH:17][C:14]2[CH:15]=[C:16]3[C:11]([CH:10]=[N:9][N:8]3[CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:12][CH:13]=2)=[O:33])[CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccc2cnn(CCN3CCCC3)c2c1
Reactant: O=C(O)Cc1cccc(Oc2ccccc2)c1
Product: O=C(Cc1cccc(Oc2ccccc2)c1)Nc1ccc2cnn(CCN3CCCC3)c2c1

Procedure:
According to the procedure for Example 49, 1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-ylamine and (3-phenoxy-phenyl)-acetic acid were processed to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.82 (m, 2 H), 1.99 (m, 2 H), 3.03 (m, 2 H), 3.51 (m, 2 H), 3.68 (m, 4 H), 4.66 (t, J=6.24 Hz, 2 H), 6.89 (m, 1 H), 7.03 (m, 3 H), 7.12 (m, 3 H), 7.37 (m, 3 H), 7.72 (m, 1 H), 8.08 (s, 1 H), 8.26 (s, 1 H), 9.55 (br s, N H); MS (DCI/NH3) m/z 441 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2[O:8][C:9](/[CH:12]=[CH:13]/[N+:14]([O-:16])=[O:15])=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.CS(C)=O.[BH4-].[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[O:8][C:9]([CH2:12][CH2:13][N+:14]([O-:16])=[O:15])=[CH:10][CH:11]=2)=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(Cc2ccc(F)cc2)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=[N+]([O-])CCc1ccc(Cc2ccc(F)cc2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
To a solution of 2-(4-fluoro-benzyl)-5-((E)-2-nitro-vinyl)-furan (1.21 g, 4.89 mmol) described in Manufacturing Example 208-1-3 in acetic acid (0.6 mL) and dimethyl sulfoxide (10 mL) was added sodium borohydride (296 mg, 7.82 mmol), which was stirred for 30 minutes at room temperature. The mixture was cooled with ice water and partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (1.14 g). The title compound was used in the following reaction without any further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16](OC(C)(C)C)=O)[CH:5]=[N:6][C:7]=1[Cl:8].C=O>C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[CH3:16])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(Br)c1
Agent: C=O
Solvent: O=CO
Product: CN1CCC[C@@H]1COc1cnc(Cl)c(Br)c1
Temperature: 70 °C
Yield: 66.7 %

Procedure:
To 5-bromo-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine from step 69a (210 mg, 0.54 mmol) was added formalin (37%, 7 mL) and formic acid (3.5 mL), and the mixture was heated at 70° C. for 2.5 hours. The solvent was concentrated, and solid NaHCO3 was added to the residue. At pH 8 the mixture was extracted with CH2Cl2, which was dried over MgSO4 and concentrated. The residue was chromatographed on a silica gel column, eluting with CH2Cl2:MeOH 100:5-100:10 to afford to give the free base of the title compound (110 mg, 67% yield). MS (CI/NH3) m/z 305/307 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 1.68 (m, 3H), 2.02 (m, 1H), 2.32 (m, 1H), 2.48 (s, 3H), 2.67 (m, 1H), 3.12 (m, 1H), 3.96 (m, 2H), 7.52 (m, 1H), 8.06 (m, 1H). The base was converted to the salt by treatment with hydrogen chloride in THF to give the title compound. MS (CI/NH3) m/z 305/307 (M+H)+. 1HH NMR (D2O, 300 MHz) δ: 2.20-2.17 (m, 2H), 2.18-2.31 (m, 1H), 2.32-2.47 (m, 1H), 3.03 (s, 3H), 3.27 (m, 1H), 3.73 (m, 1H), 3.96 (m, 1H), 4.36 (dd, J=6.1, 11.2 Hz, 1H), 4.53 (dd, J=3.1, 11.2 Hz, 1H), 7.91 (d, J=2.7 Hz, 1H), 8.13 (d, J=2.7 Hz, 1H). Anal. Calcd for C11H14N2OBrCl.1.1 HCl: C, 38.22; H, 4.40; N, 8.10. Found: C, 37.95; H, 4.81; N, 7.76. [α]25D=+11.06° (c 0.24, MeOH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[CH:9]=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1>CO.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:16])([CH3:17])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=CC(C)(C)c1ccc(Cl)cc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCC(C)(C)c1ccc(Cl)cc1

Procedure:
Ethyl 4-(4-chlorophenyl)-4-methylpent-2-enoate (Intermediate I-9B, 0.24 g, 0.950 mmol) was dissolved in methanol (20 mL) and treated with 10% Pd/C (0.06 g, 0.282 mmol) under a hydrogen atmosphere for 1 hr using a balloon. The reaction mixture was filtered through CELITE®. The filtrate was concentrated under reduced pressure to yield ethyl 4-(4-chlorophenyl)-4-methylpentanoate in quantitative yield. LC/MS M+1=255.11.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([N:9]2[C:18]3[CH:17]=[CH:16][C:15]4[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=4[C:13]=3[NH:12][C:11](=[O:23])[C:10]2=[O:24])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.ClCCl.C(=O)([O-])O.[Na+]>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([N:9]2[C:18]3[CH:17]=[CH:16][C:15]4[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=4[C:13]=3[NH:12][C:11](=[O:23])[C:10]2=[O:24])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-n2c(=O)c(=O)[nH]c3c4ccccc4ccc32)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1[nH]c2c3ccccc3ccc2n(-c2cccc(O)c2)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 52 %

Procedure:
To an anhydrous dichloromethane (5 mL) suspension of 4-(3-methoxyphenyl)-1,4-dihydrobenzo[f]quinoxaline-2,3-dione (562 mg, 1.77 mmol) was added 1M boron tribromide/dichloromethane solution (2.12 mL, 2.12 mmol) under cooling in an ice-bath, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution. The precipitated solid was washed with water and ethanol. The solid was further washed with hexane, and dried to obtain the titled compound as an off-white crystal (280 mg, yield 52%).