Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[CH2:3][CH2:4][CH2:5][C:6](=O)[C:7]([OH:9])=[O:8].[NH2:12][C@H:13]([C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=[O:20])=[O:16])[CH3:14].C([BH3-])#N.[Na+]>>[C:7]([CH:6]([NH:12][C@H:13]([C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=[O:20])=[O:16])[CH3:14])[CH2:5][CH2:4][CH2:3][CH:2]([CH3:11])[CH3:1])([OH:9])=[O:8]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(C)CCCC(=O)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)CCCC(N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O)C(=O)O
Yield: 64.8 %

Procedure:
6-Methyl-2-oxoheptanoic acid (0.90 g) and L-alanyl-L-proline (0.21 g) were treated with sodium cyanoborohydride (0.21 g) as described above. A white fluffy solid, N-(1-carboxy-5-methylhexyl)-L-alanyl-L-proline (0.24 g) was obtained. After purification by chromatography the mass spectrum showed a peak at 472 (disilyl derivative). The nmr spectrum showed absorption centered at 4.5, 3.65, 2.0, 1.6, 1.3, and 0.85 ppm.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][OH:8])=[CH:4][CH:3]=1.[CH2:9]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)[CH2:10][CH2:11][CH3:12].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.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>[CH2:9]([C:13]1[CH:18]=[CH:17][C:16]([C:2]2[S:6][C:5]([CH2:7][OH:8])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1)[CH2:10][CH2:11][CH3:12]
Reactant: OCc1ccc(Br)s1
Reactant: CCCCc1ccc(B(O)O)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: [K+]
Solvent: Cc1ccccc1
Product: CCCCc1ccc(-c2ccc(CO)s2)cc1
Temperature: 95 °C
Reaction time: 8 h
Yield: 18.9 %

Procedure:
A mixture of 60.2 (0.300 g, 1.55 mmol), 4-n-butylbenzeneboronic acid 60.3 (0.553 g, 3.11 mmol), K2CO3 (0.644 g, 4.66 mmol), and Pd(PPh3)4 (0.180 g, 0.16 mmol) in toluene (5 mL) was stirred overnight at 95° C. The mixture was cooled to room temperature, filtered through a pad of silica gel (EtOAc), and concentrated. The crude product was chromatographed on silica gel (0-40% EtOAc/hexane) to afford 60.4 (0.072 g, 19%). 1H NMR (400 MHz, CDCl3) δ 7.49 (d, 2H), 7.18 (d, 2H), 7.13 (d, 1H), 6.97 (d, H), 4.82 (s, 2H), 2.62 (t, 2H), 1.60 (m, 2H), 1.37 (m, 2H),
Reaction SMILES: C[S:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].O.S(Cl)(Cl)(=O)=[O:13]>ClC1C=CC=CC=1>[S:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[C:5](=[O:13])[NH:6]1
Reactant: CSc1ccccc1C#N
Reactant: O=S(=O)(Cl)Cl
Solvent: Clc1ccccc1
Solvent: O
Product: O=c1[nH]sc2ccccc12
Temperature: 25 °C
Yield: 95.9 %

Procedure:
To a 500 ml four-necked flask equipped with a stirrer, a thermometer, and a condenser, 29.8 g (0.2 mol) of 2-(methylthio)benzonitrile, 100 g of monochlorobenzene, and 4.32 g (0.24 mol) of water were added. To the flask, 29.7 g (0.22 mol) of sulfuryl chloride was added with stirring at a temperature of from 5° to 15° C., heated to a temperature of from 70° to 80° C., and allowed to react for 1 hour. After the completion of the reaction, the reaction mixture was cooled to room temperature to precipitate white crystals. The white crystals were washed with monochlorobenzene, and dried to give 29.0 g of 1,2-benzisothiazol-3-one (melting point: 157° to 158° C.). The yield of the product was 96% against the starting 2-(methylthio)benzonitrile.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[Cl:31])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[Cl:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O.[F-].[Cs+]>COCCOC.CO.O.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>[Cl:31][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:16]=1[O:15][C:14]1[CH:32]=[CH:33][C:11]([C:9](=[O:10])[NH:8][CH2:7][CH2:6][C:5]3[CH:34]=[CH:35][C:2]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[Cl:36])=[CH:3][CH:4]=3)=[CH:12][CH:13]=1)[O:23][CH2:22][CH2:21][CH:20]2[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: OB(O)c1ccccc1Cl
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Br)cc4)cc3)c(Cl)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(-c5ccccc5Cl)cc4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
To a stirred suspension of ethyl 7-(4-(4-bromophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (0.56 g, 1.0 mmol) and 2-chlorophenylboronic acid (0.17 g, 1.1 mmol) in a mixture of 1,2-dimethoxyethane (4 mL) and methanol (2 mL) was added cesium fluoride (0.30 g, 2.0 mmol), followed by tetrakis(triphenylphosphine)palladium(0) (0.035 g, 0.03 mmol). The resulting mixture was stirred in an oil bath set to 80° C. for 1 hour. The mixture was cooled to ambient temperature and diluted with water (20 mL) and extracted with dichloromethane (2×20 mL). The organic layers were combined and dried over sodium sulfate, then concentrated. The residue was purified by chromatography on silica gel, eluting with 80/20 hexanes/ethyl acetate, to afford ethyl 6-chloro-7-(4-(2-(2′-chlorobiphenyl-4-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylate as a light brown oil (0.35 g, 59% yield).
Reaction SMILES: Cl[CH:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][N:17]3[CH:25]=[CH:26][CH:27]=[C:16]3[CH2:15]2)=[O:13])=[CH:8][CH:7]=1)=[O:4].Cl.[CH3:35][N:36]([CH3:40])[CH2:37][CH2:38][SH:39].C(N(CC)CC)C.CN1CCCN(C)C1=O>CO>[CH3:35][N:36]([CH3:40])[CH2:37][CH2:38][S:39][CH:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][N:17]3[CH:25]=[CH:26][CH:27]=[C:16]3[CH2:15]2)=[O:13])=[CH:8][CH:7]=1)=[O:4]
Reactant: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)C(Cl)c1ccccc1
Reactant: CN(C)CCS
Agent: Cl
Solvent: CO
Solvent: CN1CCCN(C)C1=O
Solvent: CCN(CC)CC
Product: CN(C)CCSC(C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccccc1
Temperature: 60 °C
Yield: 93.1 %

Procedure:
A mixture of 0.14 g of α-chloro-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]benzeneacetamide, 0.47 g of 2-dimethylaminoethanethiol hydrochloride in 2 ml of methyl alcohol, 0.30 g of triethylamine and 3 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone is heated at 60° C. for 48 hours. The methyl alcohol is evaporated and the residue diluted with water. The resulting suspension is filtered and the precipitate washed with water. The solid is dissolved in ethyl acetate and washed with saturated NaHCO3, brine and dried with Na2SO4. The mixture is filtered and the filtrate evaporated in vacuo to a residue which is stirred with ether-hexane to give 0.15 g of beige solid. MS(CI): 525(M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:32]=[CH:31][C:15]3[N:16]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:18][C:14]=3[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:35][O:36][C:37](=[O:42])[CH2:38][CH2:39][CH2:40]Br.O>CN(C)C=O>[CH3:35][O:36][C:37](=[O:42])[CH2:38][CH2:39][CH2:40][N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[C:12]1[CH:32]=[CH:31][C:15]2[N:16]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:18][C:14]=2[CH:13]=1
Reactant: COC(=O)CCCBr
Reactant: O=S(=O)(Nc1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCN(c1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
100 mg of 4-chloro-N-(1,2-diphenyl-1H-benzimidazol-5-yl)benzenesulfonamide was suspended in 0.5 ml of N,N-dimethylformamide, mixed with 6 mg of sodium hydride and stirred for 30 minutes at 20° C. 56 mg of 4-bromobutyric acid methyl ester was added, it was allowed to stir for 15 hours, mixed with water, extracted three times with ethyl acetate, the extracts were dried on sodium sulfate, concentrated by evaporation in a vacuum, and the residue was digested with diisopropyl ether.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[C:15]1[N:23]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[C:22]2[C:21](=[O:32])[N:20]([CH2:33][CH2:34][CH2:35][O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[C:19](=[O:44])[N:18]([CH3:45])[C:17]=2[N:16]=1>CN(C=O)C.O>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([C:15]1[N:23]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[C:22]2[C:21](=[O:32])[N:20]([CH2:33][CH2:34][CH2:35][O:36][Si:37]([C:40]([CH3:41])([CH3:43])[CH3:42])([CH3:38])[CH3:39])[C:19](=[O:44])[N:18]([CH3:45])[C:17]=2[N:16]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)c1nc2c(c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C)n1Cc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 40.2 %

Procedure:
Step 1 Diethyl malonate (0.35 mL, 2.31 mmol) was dissolved in DMF (5 mL) and sodium hydride (60% in oil, 0.74 g, 1.85 mmol) was added portion wise. The mixture was stirred for 15 min and 8-bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.50 g, 0.92 mmol, intermediate 77) was added. The reaction was heated at 100° C. for 15 h. The reaction was cooled, diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined extracts were washed with 1N lithium chloride (2×100 mL), dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure to a golden oil. The oil was purified using a 25 g silica gel flash column eluted with 20% ethyl acetate/hexanes to give diethyl-2-(1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)malonate (0.23 g, 40% yield) as a clear oil. LCMS retention time=5.015 min and 95% purity, LCMS MH+ 621. 1H NMR (DMSO-d6) δ 7.27 (dd, 4H, J=8 Hz and 72 Hz), 5.62 (d, 2H, J=12 Hz), 5.54 (s, 2H), 5.61 (s, 1H), 3.90-4.03 (m, 6H), 3.62 (t, 2H, J=8 Hz), 3.37 (s, 3H), 1.70-1.78 (m, 2H), 1.08 (t, 6H, J=8 Hz), 0.80 (s, 9H).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](CCN)=[CH:21][CH:20]=1.C(OCC)(=O)C>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]2[NH:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[S:12])=[CH:21][CH:20]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: S=C(Nc1nc2ccccc2[nH]1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: S=C(NCCc1ccc(Cl)cc1)Nc1nc2ccccc2[nH]1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
A solution of 1-[(2-benzimidazolyl)thiocarbamoyl]imidazole (1.22 g, 5.0 mmol) and 2-(4-chlorophenyl)ethylamine (0.79 g, 5.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 1.31 g (79%) of the titled product as a white solid:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4](Cl)[N:3]=1.Cl.[CH3:13][O:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH2:23])=[CH:18][CH:17]=1.C([O-])(O)=O.[Na+]>O>[CH3:13][O:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:4]2[N:3]=[C:2]([Cl:1])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][NH:8]3)=[CH:18][CH:17]=1
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Reactant: COC(=O)c1ccc(CN)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(CNc2nc(Cl)nc3[nH]cnc23)cc1
Temperature: 100 °C
Yield: 59.4 %

Procedure:
A suspension of 2,6-dichloro-9H-purine (1 g, 5.29 mmol), 4-aminomethyl-benzoic acid methyl ester hydrochloride (1.2 equiv., 1.28 g) and NaHCO3 (2.1 equiv., 935 mg) in water was heated at 100° C. The homogeneous solution thus formed was refluxed 30 min. The resulting white precipitate was filtered, washed with cold water and dried under vacuum giving the title compound 241 (1 g, 3.14 mmol, 60%). LRMS calc:317.7. found: 318.3 (MH)+.
Reaction SMILES: [CH3:1][N:2]([CH2:6][CH2:7]Cl)[CH2:3][CH2:4]Cl.[CH2:9]([C:16]#[N:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH2-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:6][CH2:7][C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:16]#[N:17])[CH2:4][CH2:3]1
Reactant: CN(CCCl)CCCl
Reactant: N#CCc1ccccc1
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN1CCC(C#N)(c2ccccc2)CC1
Temperature: 25 °C
Yield: 58.5 %

Procedure:
To a solution of mechlorethamine (4 g, 25.6 mmol) and benzyl cyanide (4 g, 34.2 mmol) in toluene (25 ml) was added sodium amide (2 g, 51.2 mmol) at 40-50° C. in portions for 1 hour. The reaction mixture was heated to reflux about 2 hours after the addition. The reaction mixture was cooled to room temperature and washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated. The residue was applied to flash column chromatography using methylene chloride and methanol (100:5) as eluents to give 3 g of desired product.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[NH:9][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:21]([OH:24])(=[O:23])=[O:22])[C:11](=[O:13])[CH:12]=1)=[O:7])C.Cl>O>[C:6]([C:8]1[NH:9][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:21]([OH:24])(=[O:22])=[O:23])[C:11](=[O:13])[CH:12]=1)([OH:7])=[O:5]
Reactant: CCOC(=O)c1cc(=O)n(Cc2ccccc2S(=O)(=O)O)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(=O)n(Cc2ccccc2S(=O)(=O)O)[nH]1
Temperature: 70 °C
Reaction time: 5 h
Yield: 86.8 %

Procedure:
To a solution prepared by dissolving 7.8 g of sodium hydroxide in 20 ml of water was added 17.9 g of Intermediate A, and the resulting mixture was heated with stirring for 5 hours at a reaction mixture temperature of 70° C. After cooling the reaction mixture to room temperature, 16 ml of concentrated hydrochloric acid was added thereto, and the concentration treatment was continued under reduced pressure until a white crystalline precipitate started to separate from the reaction mixture, and then the concentrated solution was cooled with ice-cold water to precipitate the white crystals. These crystals were filtered off, washed with acetone, and dried. Thus, 14.2 g (yield: 87%) of Intermediate B was obtained. Melting Point: 223°-226° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1CC#N.Cl.[C:18]([OH:21])(=[O:20])[CH3:19]>>[F:16][C:2]([F:1])([F:15])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[CH2:19][C:18]([OH:21])=[O:20]
Reactant: N#CCc1ccc(F)cc1OCC(F)(F)F
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)Cc1ccc(F)cc1OCC(F)(F)F

Procedure:
To a stirred solution of 2-(2,2,2-trifluoroethoxy)-4-fluorophenylacetonitrile (0.60 g, 2.7 mmol) from Step 4 above in acetic acid (10 mL) was added 12 N aqueous HCl (5 mL). The mixture was refluxed for 4 h. The solvents were removed under reduced pressure and the residue was partitioned between EtOAc (100 mL) and water (2-50 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give 2-(2,2,2-trifluoroethoxy)-4-fluorophenylacetic acid as an amorphous solid (HPLC retention time=7.5 min (method A)).
Reaction SMILES: OC(C(F)(F)F)=O.[Cl:8][C:9]1[CH:14]=[C:13]([N:15]([CH3:17])[CH3:16])[C:12]([F:18])=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][N:22]=[C:21](OS(C(F)(F)F)(=O)=O)[C:20]=1[N+:33]([O-:35])=[O:34].Cl.[CH:37]1([C@H:40]([NH2:42])[CH3:41])[CH2:39][CH2:38]1>>[Cl:8][C:9]1[CH:14]=[C:13]([N:15]([CH3:17])[CH3:16])[C:12]([F:18])=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:42][C@@H:40]([CH:37]2[CH2:39][CH2:38]2)[CH3:41])[C:20]=1[N+:33]([O-:35])=[O:34]
Reactant: CN(C)c1cc(Cl)c(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])cc1F
Reactant: C[C@@H](N)C1CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](Nc1nccc(-c2cc(F)c(N(C)C)cc2Cl)c1[N+](=O)[O-])C1CC1
Yield: 48.8 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl ester TFA (1.06 g, 2.49 mmol) and (R)-1-cyclopropyl-ethylamine HCl (202 mg, 1.7 mmol) were treated substantially as described in Part C of Example 19a to produce 314 mg of crude (R)-[4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-ethyl)-amine.
Reaction SMILES: [C:1]([CH:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:12][CH:11]=1)[C:5]([O:7]C)=[O:6])(=[O:3])[NH2:2].[OH-].[Na+]>CO.O1CCCC1>[C:1]([CH:4]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:14][CH:15]=1)[C:5]([OH:7])=[O:6])(=[O:3])[NH2:2]
Reactant: COC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC(C(N)=O)C(=O)O)cc1
Reaction time: 15 h
Yield: 97.7 %

Procedure:
Methyl 2-carbamoyl-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionate (1.80 g, 4.41 mmol) obtained in Example 2 was dissolved in methanol (20 ml) and tetrahydrofuran (20 ml), and 2.5N aqueous sodium hydroxide solution (2.5 ml, 6.16 mmol) was added at room temperature. The mixture was stirred for 15 hr and the solvent was evaporated. To the residue was added 10% aqueous sodium hydroxide solution (50 ml) and the mixture was washed three times with ethyl acetate (30 ml). To the aqueous layer was added sodium chloride to saturate the same, and the mixture was acidified with 3N hydrochloric acid. The precipitated white solid was collected by filtration, washed with water, and dried to give the title compound (1.70 g, yield 98%).
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:26]([NH2:28])=[O:27])[CH:13]=[C:14](B4OC(C)(C)C(C)(C)O4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.Br[C:31]1[S:32][CH:33]=[CH:34][N:35]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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].C(Cl)Cl>[O:1]=[S:2]1(=[O:29])[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:26]([NH2:28])=[O:27])[CH:13]=[C:14]([C:31]4[S:32][CH:33]=[CH:34][N:35]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: Brc1nccs1
Reactant: CC1(C)OB(c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)CC4)c3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: NC(=O)c1cc(-c2nccs2)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Temperature: 10 °C
Yield: 22.8 %

Procedure:
3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (60 mg, 0.14 mmol), 2-bromo-1,3-thiazole (29 mg, 1.2 eq), PdCl2(dppf)-CH2Cl2 adduct (19 mg, 0.02 mmol, 0.16 eq), potassium carbonate (90 mg, 4.6 eq) were diluted in a mixture of dioxane (3 mL) and water (1.5 mL) in a 2-5 mL biotage microwave reaction tube. After the mixture was degassed by bubbling argon through for 5 minutes, it was heated in a biotage microwave at normal absorption for 5 minutes at 10° C. The reaction mixture was filtered through a thiol SPE cartridge (polymer labs), then was concentrated and purified by ammonium hydroxide gilson hplc. The desired fractions were combined and concentrated in an EZ2 Genevac evaporator, giving the title compound (12 mg, 25%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[N:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:5]=[CH:6][C:7]=1[N+:8]([O-])=O>[C].[Pd].CO>[NH2:1][C:2]1[C:3](=[O:15])[N:4]([C:11]([CH3:13])([CH3:12])[CH3:14])[N:5]=[CH:6][C:7]=1[NH2:8]
Reactant: CC(C)(C)n1ncc([N+](=O)[O-])c(N)c1=O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)n1ncc(N)c(N)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
Into 150 ml of an absolute methanol solution of 10.8 g of 4-amino-2-tert-butyl-5-nitropyridazin-3-(2H)-one, 1.1 g of palladium-carbon (containing 5% of Pd) was added in a few times with stirring at room temperature. Then, catalytic reduction was carried out overnight under hydrogen gas pressure. After completion of the reaction, palladium-carbon was separated with celite and washed a few times with absolute methanol. Then, methanol was combined with the filtrate, and the mixture was distilled under reduced pressure to obtain 9.3 g of powdery 4,5-diamino-2-tert-butylpyridazin-3-(2H)-one.
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][C:11]=2[C:19]([O:21][CH3:22])=[O:20])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.B.C1COCC1>C1COCC1>[F:1][C:2]1[C:3]([C:10]2[CH:18]=[CH:17][C:13]([CH2:14][OH:15])=[CH:12][C:11]=2[C:19]([O:21][CH3:22])=[O:20])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1cc(C(=O)O)ccc1-c1cc(OC)ncc1F
Agent: B
Solvent: C1CCOC1
Product: COC(=O)c1cc(CO)ccc1-c1cc(OC)ncc1F
Temperature: 23 °C
Reaction time: 46 h
Yield: 105.4 %

Procedure:
To a stirred solution of 4-(5-fluoro-2-methoxypyridin-4-yl)-3-(methoxycarbonyl)benzoic acid 83.21B (0.416 g, 1 mmol) in THF (14 mL) at 0° C. was added borane-THF (3 mL, 3 mmol, 1.0M). The reaction was warmed to 23° C. and stirred for 46 hours. The reaction was then concentrated in vacuo. The reaction was diluted with 1N HCl and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-40% EtOAc in hexanes) to yield 83.21C as a colorless solid (0.307 g, 77% yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:26](=[O:27])[C:24]2=[C:25]3[C:20](=[CH:21][CH:22]=[CH:23]2)[C:19](Cl)=[CH:18][CH:17]=[C:16]3[C:14]1=[O:15].[CH3:29][NH:30][CH2:31][CH2:32][NH2:33].C(N(CC)CC)C.C(Cl)(Cl)Cl.CO>COCCO>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:26](=[O:27])[C:24]2=[C:25]3[C:20](=[CH:21][CH:22]=[CH:23]2)[C:19]([NH:33][CH2:32][CH2:31][NH:30][CH3:29])=[CH:18][CH:17]=[C:16]3[C:14]1=[O:15]
Reactant: O=C1c2cccc3c(Cl)ccc(c23)C(=O)N1CCCCCOC1CCCCO1
Reactant: CNCCN
Solvent: COCCO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CNCCNc1ccc2c3c(cccc13)C(=O)N(CCCCCOC1CCCCO1)C2=O
Yield: 56.5 %

Procedure:
This was prepared analogously to 2ay. The reaction of 1cx (0.613 g, 1.53 mmol), N-methyl-1,2-diaminoethane (0.672 mL, 7.62 mmol), and triethylamine (213 μL, 1.53 mmol) in 2-methoxyethanol, followed by chromatography on silica with a chloroform/methanol gradient, yielded 2cz as a pure yellow powder (0.380 g, 570%). 1H NMR (CDCl3): δ=8.56 (d, 1H, J=7.7 Hz), 8.44 (d, 1H, J=8.4 Hz), 8.16 (d, 1H, J=8.1 Hz), 7.60 (t, 1H, J=7.8 Hz), 6.67 (d, 1H, J=8.4 Hz), 6.25 (br t, 1H, J=4.2 Hz), 4.58 (t, 1H, J=3.6 Hz), 4.16 (t, 2H, J=7.6 Hz), 3.85 (m, 1H), 3.74 (m, 1H), 3.49 (m, 1H), 3.43 (m, 1H), 3.06 (t, 2H, J=5.7 Hz), 2.52 (s, 3H), 1.78-1.66 (m, 6H), 1.53-1.49 (m, 6H). 13C{1H} NMR: δ=164.9, 164.3, 149.8, 134.7, 131.3, 130.0, 126.5, 124.8, 123.3, 120.6, 110.4, 104.6, 98.9, 67.6, 62.4, 49.7, 42.0, 40.3, 36.1, 30.9, 29.7, 28.3, 25.7, 24.1, 19.8. ESI/MS m/z 440 (M+H)+.