Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:22]([O-:24])=[O:23])=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])=O.Cl.B>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:22]([O-:24])=[O:23])=[C:6]([CH2:7][NH:9][CH2:10][C:11]2[C:12]([O:19][CH3:20])=[CH:13][CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[CH:21]=1
Reactant: COc1cccc(OC)c1CNC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: COc1cccc(OC)c1CNCc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
5-Chloro-N-(2,6-dimethoxybenzyl)-2-nitrobenzamide (31.3 g, 89.2 mmol) was placed in suspension in 500 mL tetrahydrofuran and the solution was heated at reflux. A mixture of borane-dimethyl sulfide complex (33.9 g, 446.2 mmol) and 50 mL tetrahydrofuran was added slowly by drops within 45 minutes to the heated reaction mixture. During the addition of the borane complex, a colorless precipitate was formed by flocculation and then went into solution again slowly after the addition was complete. The batch was heated at reflux for a total of 6 hours and stirred for 12 hours at room temperature until achieving complete conversion (TLC monitoring). The mixture was cooled to 0° C. for workup and 42 mL 2N hydrochloric acid was added slowly by drops over a period of 30 minutes, with a great evolution of gas and an increase in temperature to 10° C. due to the exothermic reaction. The reaction mixture was thawed to room temperature. According to the mass spectrometric analysis, the borane-product complex (ESI-MS [M+H+]=349.15/351.15) could not be cleaved completely to the desired product. Therefore the solids obtained after workup had to be treated again in 300 mL tetrahydrofuran with 180 mL 2N hydrochloric acid, by dropwise addition of the acid for 1 hour to the product mixture heated to 50° C. The mixture was stirred for a total of 6 hours at reflux and 12 hours at room temperature. The organic fraction, consisting mainly of tetrahydrofuran, was distilled off in vacuo, the solution was adjusted to a pH of 10 to 11 with 50% sodium hydroxide solution and extracted with dichloromethane (3×). The organic phase was dried over sodium sulfate and filtered out and the solvent was evaporated in vacuo. The isolated yellow oil was stirred into diethyl ether and a yellow precipitant of 1-(5-chloro-2-nitrophenyl)-N-(2,6-dimethoxybenzyl)-methanamine was filtered out. Yield: 19.2 g (57.0 mmol, 64%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][C:11]([OH:13])=O)[C:4]=2[N:3]=[CH:2]1.[NH2:14][CH:15]([CH2:23][CH3:24])[C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17]>>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([NH:14][C:11](=[O:13])[CH2:10][C:9]1[C:4]2[N:3]=[CH:2][S:1][C:5]=2[CH:6]=[CH:7][CH:8]=1)[CH2:23][CH3:24])[CH:20]([CH3:21])[CH3:22]
Reactant: O=C(O)Cc1cccc2scnc12
Reactant: CCC(N)C(=O)OCC(C)C
Product: CCC(NC(=O)Cc1cccc2scnc12)C(=O)OCC(C)C

Procedure:
Following General Procedure I above and using 4-benzothiazol-yl acetic acid (Chemservice) and iso-butyl 2-aminobutyrate (prepared following General Procedure J above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:19]([NH:21][NH2:22])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:27]1[C:39]2[CH:38]([CH2:40][O:41][C:42]([NH:44][CH2:45][C:46](O)=[O:47])=[O:43])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]=2[CH:30]=[CH:29][CH:28]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:19]([NH:21][NH:22][C:46](=[O:47])[CH2:45][NH:44][C:42]([O:41][CH2:40][CH:38]1[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:39]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:43])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@@H](C(=O)NN)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)NNC(=O)CNC(=O)OCC1c2ccccc2-c2ccccc21)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
A solution of 1.0 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvalerohydrazide in 10 ml of dimethylformamide was treated with 1.24 g of N-(9-fluorenylmethyloxycarbonyl)-glycine and 0.80 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. The mixture was stirred overnight at room temperature and evaporated. The residue was dissolved in ethyl acetate and washed with 2M aqueous hydrogen chloride, 5% aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. Drying over anhydrous magnesium sulphate followed by evaporation and trituration with diethyl ether gave 1.54 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-2′-[N-(9-fluorenylmethyloxycarbonyl)-glycinyl]-4-methylvalerohydrazide in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]([OH:13])=O)[NH:10][C:4]=2[CH:3]=1.Cl.[NH2:15][C@@H:16]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]([N:19]([CH3:21])[CH3:20])=[O:18].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:21][N:19]([CH3:20])[C:17]([CH:16]([NH:15][C:11]([C:9]1[NH:10][C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=[CH:6][C:5]=2[CH:8]=1)=[O:13])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:18]
Reactant: CN(C)C(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)c1cc2cnc(Cl)cc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)C(Cc1ccccc1)NC(=O)c1cc2cnc(Cl)cc2[nH]1
Reaction time: 0.08 h

Procedure:
To a solution of 6-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (Preparation 116, 47 mg, 0.24 mmol) in DMF (5 mL, anhydrous) was added 2-(S)-amino-N,N-dimethyl-3-phenylpropionamide hydrochloride (Preparation 8, 56 mg, 0.25 mmol), DIPEA (131 μL, 0.75 mmol) and HOBt (40 mg, 0.26 mmol) sequentially. The solution was stirred for 5 min prior to the addition of EDCI (55 mg, 0.29 mmol) in one portion. The resulting solution was stirred for 12 h at rt. The reaction mixture was partitioned between ethyl acetate (50 mL) and water/brine (150 mL, 1:1). The layers were separated and the aqueous phase extracted with ethyl acetate (3×50 mL), then the combined organics were washed with dilute HCl solution (1M, 50 mL), dilute NaOH solution (1M, 50 mL) and brine (50 mL). The organic phase was dried (MgSO4), filtered and concentrated in vacuo. Purification via flash column chromatography eluting with toluene/acetone (3:1) gave the title compound. δH (CDCl3): 2.88, 3.05 (6H, 2s), 3.18, 3.28 (2H, 2 dd), 5.41 (2H, m), 7.02 (1H, s), 7.28-7.34 (6H, m), 8.17 (1H, d), 8.68 (1H, s), 10.58 (1H, br s); m/z (ES+)=371.13 [M+H]+; RT=3.28 min.
Reaction SMILES: CS[C:3]1[N:4]=[CH:5][C:6]2[C:12](=[O:13])[C:11]([C:14]([OH:16])=[O:15])=[CH:10][N:9]([CH2:17][CH2:18][CH3:19])[C:7]=2[N:8]=1.O.O.O.O.O.O.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>CS(C)=O>[N:26]1([C:3]2[N:4]=[CH:5][C:6]3[C:12](=[O:13])[C:11]([C:14]([OH:16])=[O:15])=[CH:10][N:9]([CH2:17][CH2:18][CH3:19])[C:7]=3[N:8]=2)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1
Reactant: C1CNCCN1
Reactant: CCCn1cc(C(=O)O)c(=O)c2cnc(SC)nc21
Solvent: O
Solvent: CS(C)=O
Product: CCCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Yield: 88 %

Procedure:
A mixture containing 1.40 g of 5,8-dihydro-2-methylthio-8-n-propyl-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid, 2.94 g of piperazine hexahydrate, and 20 ml of dimethylsulfoxide was heated at 100 - 110°C for 1.5 hours. The precipitate was collected, washed with ethanol, and then recrystallized from water to yield 1.40 g of the product, as colorless needles, m.p. 259°- 261°C.
Reaction SMILES: [CH3:1][C:2]1[C:23]([CH3:24])=[CH:22][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:15]=[C:14]([OH:16])[C:13]([CH2:17][C:18]([OH:20])=[O:19])=[C:12]([CH3:21])[N:11]=3)[NH:8][C:4]=2[CH:3]=1.[CH2:25](O)[CH3:26]>OS(O)(=O)=O>[CH3:1][C:2]1[C:23]([CH3:24])=[CH:22][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:15]=[C:14]([OH:16])[C:13]([CH2:17][C:18]([O:20][CH2:25][CH3:26])=[O:19])=[C:12]([CH3:21])[N:11]=3)[NH:8][C:4]=2[CH:3]=1
Reactant: CCO
Reactant: Cc1cc2nc(Nc3nc(C)c(CC(=O)O)c(O)n3)[nH]c2cc1C
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1c(C)nc(Nc2nc3cc(C)c(C)cc3[nH]2)nc1O
Yield: 19 %

Procedure:
A solution of (2) (0.935 g, 2.86 mmol) in ethanol (20 mL) and concentrated H2SO4 (3.5 mL) was heated at reflux for 24 h. The ethanol was evaporated in vacuo, cold water (30 mL) was added and the solution was then neutralised with NaOH 10M. The mixture was extracted with CHCl3 (4×20 ml,) and the combined organic phases were dried (MgSO4) and evaporated in vacuo. The resulting residue was triturated with ethanol and filtered to give 0.190 g (19%) of 2-[(5,6-Dimetlhyl-2-benzoimidazolyl)amino]-4-hydroxy-6-methyl-5-pyrimidine acetic acid, ethyl ester (1). mp: >300° C. (CF3CO2H/C2H5OH). IR (KBr): υ=3254, 2968, 2922, 1737, 1623, 1560, 1344, 1294, 774 cm−1. Accurate mass: calculated: 355.1644. Found 327.1644. Analysis calculated for C18H21N5O3: C, 60.83; H, 5.96; N, 19.71. Found: C, 60.1; H, 5.7; N, 18.7.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][OH:7].[C:11]([Si:15](Cl)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:14])([CH3:13])[CH3:12].N1C=CN=C1>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][O:7][Si:15]([C:11]([CH3:14])([CH3:13])[CH3:12])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCCc1cccc(Br)c1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCc1cccc(Br)c1)(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
3-Bromophenethyl alcohol was dissolved in 110 ml of N,N-dimethylformamide, and 16 ml of t-butyl chlorodiphenyl silane and 8.3 g of imidazole were added. After stirring was continued at room temperature overnight, the solution was diluted with ethyl acetate, and washed successively with 1N hydrochloric acid and saturated brine. After drying the organic layer over anhydrous magnesium sulfate, the solvent was evaporated. The residue was purified by silica gel column chromatography, to give 22.1 g of [(3-bromophenethyl)oxy] (t-butyl)diphenyl silane in the 4:1 hexane-ethyl acetate fraction. Then, the obtained 22.1 g of [(3-bromophenethyl)oxy] (t-butyl) diphenyl silane was dissolved in 200 ml of tetrahydrofuran, and the mixture was cooled to −78° C. under nitrogen atmosphere. 37 ml of Butyl lithium (1.52 M solution in hexane) was added thereto, and the mixture was stirred for 30 minutes, and then 10 ml of 4-formylmorpholine was added. After stirring was continued at −78° C. for 1 hour, 1N-hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography, to give 17 g of the title compound in the 4:1 hexane-ethyl acetate fraction.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([F:15])[CH:14]=1)[CH2:5][N:6]1[CH:10]=[N:9][N:8]=[C:7]1[SH:11].[CH3:16]I.C[O-].[Na+]>CO>[F:15][C:13]1[CH:12]=[C:4]([CH:3]=[C:2]([F:1])[CH:14]=1)[CH2:5][N:6]1[CH:10]=[N:9][N:8]=[C:7]1[S:11][CH3:16]
Reactant: CI
Reactant: Fc1cc(F)cc(Cn2cnnc2S)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CSc1nncn1Cc1cc(F)cc(F)c1

Procedure:
The reaction of 4-(3',5'-difluorobenzyl)-1,2,4-triazole-3-thiol (prepared as in Example 3) with methyl iodide and sodium methoxide in methanol by known techniques yields 4-(3',5'-difluorobenzyl)-3-methylthio-1,2,4-triazole.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][C:16]=1[CH3:17]>N1C=CC=CC=1>[C:1]([NH:10][C:11]1[CH:12]=[C:13]([C:18]([F:19])([F:20])[F:21])[CH:14]=[CH:15][C:16]=1[CH3:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc(C(F)(F)F)cc1N
Solvent: c1ccncc1
Product: Cc1ccc(C(F)(F)F)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Under ice-cooling, 4.0 ml (34.5 mmol) of benzoyl chloride was added dropwise to a mixture of 4.97 g (28.8 mmol) of 3-amino-4-methyl-benzotrifluoride and 10 ml of pyridine. After stirring the mixture at room temperature for 1 hour, the solvent was removed under reduced pressure, and water was added to the residue. The precipitated solid was collected by filtration and then washed with water and a 50% aqueous methanol solution to give 8.04 g of 3-benzoylamino-4-methyl-benzotrifluoride.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N:14]1([C:2]2[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=2)[C:7]([NH2:9])=[O:8])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: NC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 24 h
Yield: 19.9 %

Procedure:
A mixture of 5-chloro-2-nitrobenzamide (2.0 g, 10.0 mmol), morpholine (2.6 mL, 30 mmol), and K2CO3 (4.1 g, 30 mmol) in DMF (20 ml) was stirred at 110° C. for 24 h. The reaction mixture was poured into water (100 mL) and the resulting precipitate was collected by filtration and recrystallized from ethanol to yield the product as a yellow solid (0.5 g, 20%).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:22]=[CH:21][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[O:12])=[CH:9][C:8]=2[N+:23]([O-:25])=[O:24])=[CH:4][CH:3]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:11](=[O:12])[C:10]2[CH:21]=[CH:22][C:7]([O:6][C:5]3[CH:26]=[CH:27][C:2]([NH:1][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:3][CH:4]=3)=[C:8]([N+:23]([O-:25])=[O:24])[CH:9]=2)=[CH:15][CH:16]=1
Reactant: Nc1ccc(Oc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(Oc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 97.6 %

Procedure:
The product of Example 91A (195 mg, 0.4554 mmol) was dissolved in anhydrous pyridine (5 mL) under a nitrogen atmosphere, treated with methanesulfonyl chloride (0.106 mL, 1.366 mmol), and stirred at room temperature for 19 hours. The solvent was removed by rotary evaporation under vacuum, and the residue dissolved in ethyl acetate (100 mL) and washed with 1N aqueous hydrochloric acid (2×50 mL), water (50 mL), and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford the title compound as a light orange solid (225 mg, 98%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[N:18]=[C:17]2[CH2:19][CH2:20][CH2:21][C:16]2=[CH:15][CH:14]=1>C(Cl)Cl>[Cl:12][C:13]1[N+:18]([O-:9])=[C:17]2[CH2:19][CH2:20][CH2:21][C:16]2=[CH:15][CH:14]=1
Reactant: Clc1ccc2c(n1)CCC2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1c(Cl)ccc2c1CCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of m-chloroperbenzoic acid 70% (520.9 mg, 2.113 mmol) in 5 mL of CH2Cl2 was added drop wise to a stirring solution of 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine (295 mg, 1.921 mmol) in 3 mL of CH2Cl2 and the resulting solution was allowed to stir at room temperature overnight. The reaction mixture was quenched with a saturated aqueous solution of NaHCO3 and the CH2Cl2 layer was separated. The aqueous phase was then extracted with CH2Cl2 (3×), and the combined organic extracts were washed with brine and then dried over anhydrous Na2SO4. After removing solvent at reduced pressure, the residue was purified by preparative TLC (eluting with 70% EtOAc/Hexane) to afford the title compound (I-1a).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4].[S:22]1(=[O:28])(=[O:27])[CH:26]=[CH:25][CH2:24][CH2:23]1.CO>C1COCC1>[CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:17][CH2:18][N:19]([CH:24]4[CH2:25][CH2:26][S:22](=[O:28])(=[O:27])[CH2:23]4)[CH2:20][CH2:21]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4]
Reactant: O=S1(=O)C=CCC1
Reactant: CCCCc1cc(OC2CCNCC2)c2ncccc2c1
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1cc(OC2CCN(C3CCS(=O)(=O)C3)CC2)c2ncccc2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 8 %

Procedure:
To a solution of 6-butyl-8-(4-piperidinyloxy)quinoline (for example, as prepared for Intermediate 4) (0.15 g, 0.53 mmol) in THF (5 ml) was added 2,3-dihydrothiophene 1,1-dioxide (commercially available, for example, from AKOS) (0.150 g, 1.27 mmol). The solution was heated to 80° C. for 2.5 h. To the solution at ambient temperature was added a further amount of 2,3-dihydrothiophene 1,1-dioxide (0.150 g, 1.27 mmol) and the solution stirred overnight at ambient temperature. The solution was heated to reflux for 2 h and then at ambient temperature for 7 days. The reaction was applied to an SCX-2 cartridge (20 g), preconditioned with methanol, and the cartridge washed with methanol (2 column volumes). The cartridge was eluted with 10% 0.880 s.g. ammonia in methanol (2 column volumes) and the basic fractions concentrated in vacuo. The residue was purified by MDAP and the appropriate fractions combined and evaporated. The combined fractions were applied to an SCX-2 cartridge (20 g), preconditioned with methanol, and the cartridge washed with methanol. The cartridge was eluted with 10% 0.88 s.g. ammonia in methanol (2 column volumes) and the basic fractions concentrated in vacuo to give the title compound (17 mg, 8%). LCMS RT=2.59 min, ES+ve m/z 403 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.CC(C)=O>[CH2:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1Br
Yield: 95 %

Procedure:
A solution of 4-Bromo-3-nitrophenol (1.0 g, 4.6 mmol) and benzyl bromide (0.82 mL, 7 mmol) in acetonitrile (30 mL) and acetone (15 mL) was treated with K2CO3 (970 mg, 7 mmol). The resulting mixture was heated at reflux under nitrogen for 17 h. The reaction mixture was evaporated in vacuo and the residue was dissolved in 40 mL ethyl acetate. The solution was filtered under vacuum then the filtrate was washed successively with distilled water (30 mL ), 1M HCl solution (30 mL×3), brine (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was chromatographed over 100 g of silica gel using 3:1 mixture respectively of hexanes and ethyl acetate to give the benzyl alcohol in 95% yield; 1H NMR(CDCl3) δ5.11(2H, s), 7.02(1 H, dd, J1=2.9, J2=8.9), 7.41(5H, m), 7.46(1 H, d, J=2.9), 7.60(1H, d, J=8.9); 13C NMR(CDCl3) δ71.4, 105.4, 112.4, 121.1, 128.1, 128.9, 129.1, 129.3, 129.5, 135.8, 136.0, 138.2, 158.7; HRMS calcd for C13H10NO3Br: 306.9844; found: 306.9846.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][O:7][CH2:8][C:9]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH3:31][C:32]([CH3:34])=O.C([BH3-])#N.[Na+]>CO.FC(F)(F)C(O)=O>[F:30][C:2]([F:29])([F:1])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][O:7][CH2:8][C:9]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:15][CH2:14][CH2:13][N:12]([CH:32]([CH3:34])[CH3:31])[CH2:11][CH2:10]1
Reactant: CC(C)=O
Reactant: FC(F)(F)c1cc(COCC2(c3ccccc3)CCCNCC2)cc(C(F)(F)F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)N1CCCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
Mixture of isomer A of 4-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-4-phenylazepane (3 mg) and acetone (1.2 mg) in methanol (0.15 mL) was stirred at room temperature for 0.5 hr, then sodium cyanoborohydride (1.0 M solution in THF, 0.02 mL) was added followed by 1 drop of trifluoroacetic acid. The mixture was stirred at 65° C. for overnight and concentrated under vacuum. Then saturated sodium bicarbonate solution and dichloromethane was added to the mixture and the organic layer was separated. The aqueous layer was extracted with dichloromethane 2 times and the combined organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum to give the product as a clear sticky oil (2.5 mg, 76% yield).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[N:11]2[N:12]=[C:13]([CH3:26])[C:14]([C:15]3[S:19][C:18]([C:20]4[N:21]([CH3:25])[N:22]=[CH:23][N:24]=4)=[N:17][CH:16]=3)=[C:10]2[N:9]=[C:8]([CH3:27])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[Cl:28]N1C(=O)CCC1=O>ClCCl.C(#N)C>[Cl:28][C:16]1[N:17]=[C:18]([C:20]2[N:21]([CH3:25])[N:22]=[CH:23][N:24]=2)[S:19][C:15]=1[C:14]1[C:13]([CH3:26])=[N:12][N:11]2[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][C:8]([CH3:27])=[N:9][C:10]=12
Reactant: CCC(CC)c1cc(C)nc2c(-c3cnc(-c4ncnn4C)s3)c(C)nn12
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Solvent: ClCCl
Product: CCC(CC)c1cc(C)nc2c(-c3sc(-c4ncnn4C)nc3Cl)c(C)nn12
Yield: 74 %

Procedure:
Stir a mixture of 7-(1-ethyl-propyl)-2,5-dimethyl-3-[2-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiazol-5-yl)-pyrazolo[1,5-a]pyrimidine (20 mg, 0.052 mmol) and N-chlorosuccinimide (7.6 mg, 0.0569 mmol) in dichloromethane (0.5 mL) and acetonitrile (0.5 mL) at room temperature overnight in a vial. Concentrate to a residue. Purify by flash chromatography, eluting with hexanes and then with hexanes/ethyl acetate (10/1.5) to give the title compound (16 mg). ES/MS m/z (35Cl) 416.0 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[C:14]2[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]2)[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[C:14]2[CH2:15][NH:16][CH2:17]2)[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(=C(c2cc(F)cc(F)c2)C(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=C1CNC1)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 210 mg (0.623 mmol) of tert-butyl 3-[1(3,5-difluorophenyl)-2,2-dimethylpropylidene]azetidine-1-carboxylate in 1 mL of CH2Cl2, was added 1.5 mL of TFA followed by stirring for 1 h at rt. The reaction mixture was concentrated and washed with ether to afford the title compound as white solid; Mass Spectrum: m/e=238 (M+1).