Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][N:13]([CH2:16]/[CH:17]=[CH:18]/[C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)[CH2:12][CH2:11]3)[CH2:9][NH:8][C:5]2=[CH:6][CH:7]=1.[CH2:26]1[CH2:30][O:29][CH2:28][CH2:27]1>>[C:5]([C:4]1[CH:28]=[CH:27][C:26]([C:30]([N:8]2[C:5]3[C:4](=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)[C:10]3([CH2:15][CH2:14][N:13]([CH2:16]/[CH:17]=[CH:18]/[C:19]4[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=4)[CH2:12][CH2:11]3)[CH2:9]2)=[O:29])=[CH:2][CH:3]=1)#[N:8]
Reactant: C1CCOC1
Reactant: Cc1ccc2c(c1)C1(CCN(C/C=C/c3ccc(Cl)cc3)CC1)CN2
Product: Cc1ccc2c(c1)C1(CCN(C/C=C/c3ccc(Cl)cc3)CC1)CN2C(=O)c1ccc(C#N)cc1
Reaction time: 0.5 h

Procedure:
This step was achieved using a Zymark XP2 synthetic chemistry robot. A solution of 5-methyl-1′-[trans-3-(4-chlorophenyl)allyl]spiro[indoline-3,4′-piperidine] (2 ml of a solution derived from dissolving 1.43 g in 100 ml of THF) was added to a robot tube and the solvent was removed in vacuo. 4-Cyanobenzoic acid (28 mg) was weighed into a different robot tube. A solution of 2-chloro-1,3-dimethyl-2-imidazolinium hexafluorophosphate (2 ml of a solution derived from dissolving 4.80 g in 180 ml of chloroform) and a solution of triethylamine (2 ml of a solution derived from dissolving 8.68 ml in 250 ml of chloroform) were added to the acid and the tube was agitated and allowed to stand for 30 minutes. A 2 ml aliquot of the acid solution was added to the tube containing the dry amine. This tube was agitated and allowed to stand overnight. The reaction mixture was washed with 1M aqueous sodium carbonate solution and the solvents were evaporated. The crude mixture was purified by MS directed liquid chromatography to give the desired amide, 2.9 mg. MS (ES+) 482/484 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[Cl-].[OH:16][NH3+:17]>N1C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6]/[C:7](/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[N:17]/[OH:16]
Reactant: COCCCCC(=O)c1ccccc1
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: c1ccncc1
Product: COCCCC/C(=N/O)c1ccccc1
Temperature: 25 °C
Yield: 76 %

Procedure:
A mixture of the above ketone (8.8 g, 46 mmol), hydroxylammonium chloride (5.5 g, 78 mmol) and anhydrous pyridine (50 ml) was heated at reflux for 16 h. The reaction mixture was allowed to cool to room temperature and the solvent then evaporated in vacuo. To the residue was added 10% aqueous citric acid (100 ml) and the mixture was extracted with ethyl acetate (100 ml+50 ml). The combined organic phases were washed with 10% aqueous citric acid (25 ml), brine (25 ml) and dried (Na2SO4). The solvent was evaporated in vacuo and the residue purified by column chromatography on silica gel (250 g, n-heptane/ethyl acetate gradient 1/4 to 1/2 to give 7.25 g of Z-5-methoxy-1-phenyl-1-pentanone oxime as a colourless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][C:25]#[N:26]>CN(C=O)C>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:24][C:25]#[N:26])=[CH:11][CH:10]=2)[O:5]1
Reactant: N#CCBr
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OB(c2ccc(OCC#N)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A slurry of 357 mg (1.6 mmol) of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol and 650 mg (4.7 mmol) of K2CO3 in 5 ml DMF was cooled to 0° C. and treated with 220 μl (3.2 mmol) of bromoacetonitrile dropwise. The brown slurry was warmed to room temperature, stirred for 1.5 h, then was quenched with water (20 ml) and was extracted with benzene (3×). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was purified by chromatography on silica gel (hexanes:EtOAc, 17:3) to give the title compound. 1H-NMR (CDCl3) δ 1.34 (s, 12 H), 4.79 (s, 2 H), 6.96 (d, J=8.5 Hz, 2 H), 7.80 (d, J=8.5 Hz, 2 H). Mass Spectrum (ESI) m/e=260.2 (M+1, triplet).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[CH:16][C:17]3[NH:18][C:19](=[O:25])[CH2:20][CH2:21][CH2:22][C:23]=3[N:24]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[N:11]1([C:14]2[N:15]=[CH:16][C:17]3[NH:18][C:19](=[O:25])[CH2:20][CH2:21][CH2:22][C:23]=3[N:24]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: [H][H]
Reactant: O=C1CCCc2nc(N3CCN(Cc4ccccc4)CC3)ncc2N1
Agent: [Pd]
Solvent: CCO
Product: O=C1CCCc2nc(N3CCNCC3)ncc2N1
Yield: 99.7 %

Procedure:
Added to 20 ml of ethanol were 0.1 g (0.3 mmol, Referential Example 51) of 2-(4-benzylpiperazino)-6-oxo-6,7,8,9-tetrahydro(5H)pyrimido[5,4-b]azepine and 0.01 g of 10% Pd-C. In a hydrogen atmosphere, they were reacted at 50° C. for 4 hours. After filtering off the Pd-C, the filtrate was dried to solid to obtain 0.074 g of colorless crystals in a quantitative yield.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([O:11]N2C(=O)CCC2=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([CH2:25][CH2:26][CH2:27][OH:28])[CH2:20]1.C(N(CC)CC)C>ClCCl>[OH:28][CH2:27][CH2:26][CH2:25][CH:21]1[CH2:22][CH2:23][CH2:24][N:19]([C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:11])[CH2:20]1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: OCCCC1CCCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCCC(CCCO)C1
Reaction time: 18 h
Yield: 87.3 %

Procedure:
1-({[(Phenylmethyl)oxy]carbonyl}oxy)-2,5-pyrrolidinedione (8.70 g), 34.9 mmol) was added portionwise to a stirred mixture of 3-(3-piperidinyl)-1-propanol (5.02 g, 35 mmol) and triethylamine (5 ml, 3.63 g, 35.9 mmol) in dichloromethane (100 ml) at room temperature. The resultant mixture was allowed to stand at room temperature for 18 hours. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate (100 ml). The organic phase was dried (MgSO4), filtered and evaporated. The sample was purified by chromatography on silica (100 g cartridge loaded in dichloromethane) using a gradient of 0-100% ethyl acetate-cyclohexane over 40 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a colourless liquid (8.45 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:9]2[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH2:16][N:7]3[C:8]=2[C:4]=1[CH:5]=[C:6]3[C:18]([O:20][CH2:21][CH3:22])=[O:19].[C:23]([O-:26])(=[O:25])[CH3:24].[K+].[Cl-].[Na+]>CN(C)C=O>[C:23]([O:26][CH2:2][C:3]1[CH:11]=[CH:10][C:9]2[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH2:16][N:7]3[C:8]=2[C:4]=1[CH:5]=[C:6]3[C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:25])[CH3:24]
Reactant: CCOC(=O)c1cc2c(CBr)ccc3c2n1CCCCC3=O
Reactant: CC(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(COC(C)=O)ccc3c2n1CCCCC3=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.6 %

Procedure:
A mixture of ethyl 5,6,7,8-tetrahydro-11-bromomethyl-8-oxo-4H-azocino [3.2.1-hi]indole-2-carboxylate (2.92 g, 8.02 mmol), potassium acetate (1.18 g, 12.0 mmol) and N,N-dimethylformamide (30 ml) was stirred at room temperature for 2.5 hours. The reaction mixture was poured into 10% aqueous sodium chloride solution and extracted with ethyl acetate. The extract was washed with 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified with silica gel column chromatography (eluated with ethyl acetate/n-hexane= 1/5) to give 2.33 g of ethyl 5,6,7,8-tetrahydro-11-acetoxymethyl-8-oxo-4H-azocino [3.2.1-hi]indole-2-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11](=[O:14])[NH:12][CH:13]=2)=[CH:4][CH:3]=1.CN(C)[CH:17]=[O:18]>C(N(CC)CC)C>[N:1]([C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][C:11](=[O:14])[NH:12][CH:13]=2)=[CH:6][CH:7]=1)=[C:17]=[O:18]
Reactant: CN(C)C=O
Reactant: Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Solvent: CCN(CC)CC
Product: O=C=Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Reaction time: 0.5 h

Procedure:
5-(4-Aminophenyl)pyrazin-2(1H)-one (1 g) was dissolved in dimethylformamide (20 ml) and triethylamine (1.0 ml). The dark solution was filtered through diatomaceous earth, and then added dropwise to an ice-cooled solution of N,N'-carbonyldiimidazole (3.0 g) in dimethylformamide (20 ml) over 11/2 hours. The mixture was stirred for a further 30 minutes, to form 5-[4-(isocyanato)phenyl]-2(1H)-pyrazinone.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:19]=[CH:18][C:12]2[N:13]=[CH:14][N:15]=[C:16](O)[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>CN(C=O)C>[CH2:1]([O:8][C:9]1[N:19]=[CH:18][C:12]2[N:13]=[CH:14][N:15]=[C:16]([Cl:22])[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ncnc2cnc(OCc3ccccc3)cc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1ncnc2cnc(OCc3ccccc3)cc12
Reaction time: 5.5 h

Procedure:
6-Benzyloxy-4-hydroxy-pyrido[3,4-d]pyrimidine (1.033 g, 4.1 mmol) was suspended in thionyl chloride (10 ml) under a nitogen atmosphere. DMF (3 drops) was added and the mixture was heated to reflux with stirring for 5.5 hours to give a dark solution, and then left to stand under nitrogen overnight. The mixture was concentrated in vacuo, azeotroping twice with toluene to remove all traces of thionyl cloride and acidic by-products. The material was further dried for two hours in vacuo to give the title compound as a brown solid, used without further purification; δH [2H6]DMSO 8.77(1H,s), 8.13(1H,s), 7.30-7.52 (6H,m), 5.45 (2H,s).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C:24]([OH:40])([C:27]([S:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)([CH3:29])[CH3:28])[CH2:25][OH:26].[C:41]1([C@H:47]([CH3:51])[C:48](O)=[O:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(OCC)(=O)C>ClCCl>[C:41]1([C@H:47]([CH3:51])[C:48]([O:26][CH2:25][C:24]([C:18]2[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=2[F:16])([OH:40])[C:27]([S:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)([CH3:29])[CH3:28])=[O:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: C[C@H](C(=O)O)c1ccccc1
Reactant: COc1ccc(CSC(C)(C)C(O)(CO)c2ccc(F)cc2F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(CSC(C)(C)C(O)(COC(=O)[C@@H](C)c2ccccc2)c2ccc(F)cc2F)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 11.7 g (56.7 mmol) of 1,3-dicyclohexylcarbodiimide in 38 ml of dichloromethane was added dropwise to a mixture of 14.0 g (38.0 mmol) of (±)-2-(2,4-difluorophenyl)-3-((4-methoxyphenyl)methylthio)-3-methylbutane-1,2-diol, 6.3 g (41.8 mmol of (S)-(+)-2-phenylpropionic acid, 0.47 g (3.8 mmol) of 4-dimethyl-aminopyridine, and 190 ml of dichloromethane with stirring under ice-cooling, followed by stirring for 3 hours. The mixture was warmed to room temperature, and the stirring was continued for 12 hours. Ethyl acetate was added to the reaction mixture, and the precipitated insoluble matter was removed by filtration. The filtrate was washed successively with a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography using a mixed solvent of hexane and ethyl acetate (10:1) as an eluent. The solvent was removed from each fraction by distillation under reduced pressure to obtain diastereomers (A-1) and (A-2) of 2-(2,4-difluoro-phenyl)-2-hydroxy-3-((4-methoxyphenyl)methylthio)-3-methylbutyl (S)-(+)-2-phenylpropionate in a yield of 9.3 g (49%) and 8.7 g (46%), respectively, as a colorless oily substance.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:9][C@H:8]1[CH2:20][CH2:21][CH2:22][OH:23])=[O:6])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:15])[CH3:14])[CH2:9][C@H:8]1[CH2:20][CH2:21][CH2:22][O:23][S:32]([CH3:31])(=[O:34])=[O:33])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of (2R,4R)-1-allyloxycarbonyl-4-t-butyldimethylsilyloxy-2-(3-hydroxypropyl)pyrrolidine (17.1 g) in dichloromethane (170 ml) were added successively triethylamine (10.4 ml) and methanesulfonyl chloride (4.63 ml) under an ice-bath. The mixture was stirred at 0° C. for 1.5 hours and quenched by the addition of water (85 ml). The aqueous layer was separated and extracted with dichloromethane (50 ml×2). The organic layers were combined and washed with 1N hydrochloric acid (85 ml), brine (85 ml) and dried over magnesium sulfate. Evaporation of the solvent gave (2R,4R)-1-allyloxycarbonyl-4-t-butyldimethylsilyloxy-2-(3-methanesulfonyloxypropyl)pyrrolidine (21.2 g) as a yellow paste.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:27])[C:10]([NH:12][C:13]1[C:14]([NH:23][CH:24]2[CH2:26][CH2:25]2)=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17])=O)=O)(C)(C)C.Cl>CC(O)=O.O1CCOCC1>[NH2:8][C@H:9]([C:10]1[N:23]([CH:24]2[CH2:26][CH2:25]2)[C:14]2[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=[CH:22][C:13]=2[N:12]=1)[CH3:27]
Reactant: COC(=O)c1cccc(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1NC1CC1
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COC(=O)c1cccc2nc([C@H](C)N)n(C3CC3)c12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A stirred solution of (S)-methyl 3-(2-(tert-butoxycarbonylamino)propanamido)-2-(cyclopropylamino)benzoate (600 mg, 1.6 mmol) in HOAc (20 mL) was heated at 60° C. for 1.5 h, and cooled to rt. After concentration of the mixture in vacuo, the residue was subjected to 4M HCl in dioxane (10 mL), and stirred at rt for 40 min. The mixture was concentrated in vacuo, dissolved in water (5 mL) and basified with 1N NaOH to pH 9.5. The mixture was concentrated and MeOH-DCM (1:1) was added to the residue to get the desired product into solution. The solution was concentrated in vacuo and the residue was purified by column chromatography on a silica gel column using DCM-MeOH—NH4OH (9:1:0.05) as eluent to give (S)-methyl 2-(1-aminoethyl)-1-cyclopropyl-1H-benzo[d]imidazole-7-carboxylate: 1H NMR (400 MHz, CDCl3) δ 7.86 (1H, d, J=8.0 Hz), 7.63 (1H, d, J=8.0 Hz), 7.27 (1H, t, J=8.0 Hz), 4.62 (1H, q, J=8.0 Hz), 4.01 (3H, s), 3.58-3.50 (3H, m), 1.65 (3H, d, J=8.0 Hz), 1.22-1.06 (2H, m), 0.95-0.65 (2H, m); LC-MS (ESI) m/z 260.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:22][O:23][CH2:24][C@@H:25]1[CH2:29][CH2:28][CH2:27][NH:26]1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:26]4[CH2:27][CH2:28][CH2:29][C@@H:25]4[CH2:24][O:23][CH3:22])=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COC[C@@H]1CCCN1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CN(C)C=O
Solvent: CCO
Product: COC[C@H]1CCCN1C[C@@H](O)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and (S)-(+)-2-(methoxymethyl)pyrrolidine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=401.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](=[O:22])[N:19]([CH2:23][CH2:24][NH:25][CH3:26])[C:18]4=[O:27])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.[N:34]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:27])[N:19]([CH2:23][CH2:24][N:25]([CH3:26])[S:39]([N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)(=[O:41])=[O:40])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:30]([F:31])([F:33])[F:32])[CH:3]=1
Reactant: CNCCN1C(=O)SC(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Reactant: O=S(=O)(Cl)N1CCCC1
Product: CN(CCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O)S(=O)(=O)N1CCCC1

Procedure:
N-{2-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]ethyl}-N-methylpyrrolidine-1-sulfonamide was prepared from 5-[1-(4-chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-3-(2-methylaminoethyl)thiazolidine-2,4-dione (from Example 394) and pyrrolidine-1-sulfonyl chloride following General Procedure U.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[NH:13][C:12]3[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:11]=3[N:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[N:19]1([C:26](=[O:28])[CH3:27])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CN1C(=O)CCC1>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([N:22]2[CH2:23][CH2:24][CH2:25][N:19]([C:26](=[O:28])[CH3:27])[CH2:20][CH2:21]2)=[N:3][C:4]=1[C:9]1[NH:13][C:12]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:11]=2[N:10]=1
Reactant: Cc1ccc2nc(-c3nc(Br)cnc3N)[nH]c2c1
Reactant: CC(=O)N1CCCNCC1
Solvent: CN1CCCC1=O
Product: CC(=O)N1CCCN(c2cnc(N)c(-c3nc4ccc(C)cc4[nH]3)n2)CC1
Temperature: 190 °C
Yield: 56.3 %

Procedure:
A mixture of 5-bromo-3-(6-methyl-1H-benzimidazol-2-yl)pyrazin-2-amine (100 mg, 0.3288 mmol) and 1-(1,4-diazepan-1-yl)ethanone (701 mg, 4.932 mmol) in NMP (200.0 μL) was heated at 190° C. in the microwave for 2 hours. The reaction mixture was partitioned between DCM and water and the organics separated and concentrated to dryness. The resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound (67.7 mg, 54% Yield). 1H NMR (400.0 MHz, DMSO) d 1.80-1.94 (2H, m), 1.78 (3H, s), 2.43-2.46 (3H, s), 3.40 (2H, m), 3.63-3.83 (5H, m), 3.92 (1H, m), 7.04-7.11 (3H, m), 7.38-7.59 (2H, m), 7.90 (1H, m), 12.37 (1H, m) ppm; MS (ES+) 366
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]2[N:23]=[CH:22][O:21][N:20]=2)[C:3]=1[S:24]C#N.[BH4-].[Na+].[OH2:29]>CO>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:16])([F:17])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]2[N:23]=[CH:22][O:29][N:20]=2)[C:3]=1[S:24][S:24][C:3]1[C:4]([C:19]2[N:23]=[CH:22][O:21][N:20]=2)=[N:5][N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:16])([F:15])[F:17])=[CH:9][C:8]=2[Cl:18])[C:2]=1[NH2:1]
Reactant: N#CSc1c(-c2ncon2)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Nc1c(SSc2c(-c3ncon3)nn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c2N)c(-c2ncon2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 55 %

Procedure:
5-Amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-(1,2,4-oxadiazol-3-yl)-4-thiocyanatopyrazole 1.00 g (2.37 mmol) was dissolved in 20 ml of dry methanol, and then 210 mg (5.00 mmol) of 90% sodium borohydride was added at 0° C. After the mixture was was stirred at 0° C. for 3.5 hrs, the reaction mixture was poured into 80 ml iced water, and then the precipitate was collected by filtration. After drying in vacuo, the resulting yellow crystal was recrystalized from ethyl acetate-n-hexane mixed solvent to obtain 512 mg (0.65 mmol) of the title compound as a yellow crystal. Yield 55%.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[F:13][C:14]1[C:15]([C:20]([OH:22])=O)=[N:16][CH:17]=[CH:18][CH:19]=1.[NH2:23][C:24]1[N:29]=[C:28]([N:30]([CH3:38])[C:31]2[CH:36]=[CH:35][CH:34]=[C:33](C)[CH:32]=2)[N:27]=[C:26]([C:39]([NH:41]O)=[NH:40])[N:25]=1>N1C=CC=CC=1.CCOC(C)=O>[F:13][C:14]1[C:15]([C:20]2[O:22][N:41]=[C:39]([C:26]3[N:27]=[C:28]([N:30]([CH3:38])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:29]=[C:24]([NH2:23])[N:25]=3)[N:40]=2)=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1cccc(N(C)c2nc(N)nc(C(=N)NO)n2)c1
Reactant: O=C(O)c1ncccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ncccc3F)n2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-[3-(Dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (633 mg, 3.3 mmol) was added to a solution of 3-fluoropyridine-2-carboxylic acid (400 mg, 2.83 mmol) in anhydrous pyridine (6 mL) in a sealed tube at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 1 h. 4-Amino-N-hydroxy-6-(methyl-3-methylphenyl-amino)-[1,3,5]triazine-2-carboxamidine (prepared in an analogous manner to Intermediate 1, 611 mg, 2.36 mmol) was added and the mixture was stirred at room temperature for approximately 18 h. A solution of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (315 mg, 1.15 mmol) in anhydrous pyridine (1 mL) was added and the mixture was stirred for 2 h. Further N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (100 mg, 0.52 mmol) and 3-fluoropyridine-2-carboxylic acid (70 mg, 0.5 mmol) were then added and the mixture was stirred at room temperature for 1 h and then at 60 C for approximately 18 h. The mixture was then diluted with EtOAc (75 mL) and washed with saturated aq. ammonium chloride (4×15 mL), then saturated aq. sodium bicarbonate (3×15 mL) and brine (15 mL). The organic layer was dried over sodium sulfate and evaporated under vacuum. The crude residue was purified by flash chromatography (0-2% MeOH in DCM) to afford the title compound (220 mg). 20 mg of this material was dissolved in hot DMSO (0.3 mL) and MeOH (0.5 mL) and then 1:1 MeCN:water (1 mL) was added. The resultant precipitate was filtered, the solids were washed with water (2×1 mL) and then dried under vacuum to afford the title compound as a white solid (14 mg, 2%).
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:9]([NH2:14])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([O:19][C:20]([NH:22][CH:23]([CH3:27])[C:24](O)=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[C:15]([O:19][C:20](=[O:21])[NH:22][CH:23]([C:24](=[O:25])[NH:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[NH:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:27])([CH3:16])([CH3:17])[CH3:18]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccccc1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.4 %

Procedure:
N-Phenylbenzene-1,2-diamine (1.84 g, 0.01 mol), racemic (R/S)-2-tertbutoxycarbonylaminopropionic acid (1.89 g, 0.01 mol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.92 g), 4-methylmorpholine (1.0 g, 0.01 mol), HOBt (1.53 g, 0.01 mol) were suspended in THF (10 mL) under a nitrogen atmosphere. The resulting mixture was stirred for 12 h at RT. After this period of time, additional amounts of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (500 mg×3) and of (R/S)-2-tertbutoxycarbonylaminopropionic acid (500 mg) were added and the mixture was stirred for further 4 h. The reaction mixture was then partitioned between water and EtOAc. The organic layer was separated, dried (MgSO4) and concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC ISCO 24 g column, gradient 0-20% EtOAc in cyclohexane). The product containing fractions were combined and concentrated in vacuo affording [1-(2-Phenylaminophenylcarbamoyl)ethyl]carbamic acid tertbutyl ester as a white crystalline solid (3.07 g, 86%). LCMS: RT 3.61 min [M+H-tBu]+ 300.1.