Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15]([OH:17])=O)[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]([OH:52])([CH3:51])[CH3:50])=[CH:45][CH:44]=1>CN(C=O)C.CS(C)=O>[CH3:2][N:1]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15]([NH:42][C:43]3[CH:44]=[CH:45][C:46]([C:49]([OH:52])([CH3:50])[CH3:51])=[CH:47][CH:48]=3)=[O:17])[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4]
Reactant: Cn1c(=O)c2c(ncn2CC(=O)O)n(C)c1=O
Reactant: CC(C)(O)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ncn2CC(=O)Nc2ccc(C(C)(C)O)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a 0° C. solution of acid 101 (0.32 g, 1.34 mmol) in DMF/DMSO (1:1, 20 mL) was added HATU (0.0.76 g, 2.01 mmol). The reaction was then stirred an additional 15 min at room temperature. The solution was cooled to 0° C. and amine 135 (0.30 g, 2.01 mmol) was added. The reaction was then stirred at rt overnight. The DMF was concentrated in vacuo and water was added to the reaction. The aqueous layer was extracted with EtOAc The ethyl acetate layer was then washed again with water and the organic layer was concentrated in vacuo. The product was purified by flash chromatography on silica gel eluting with EtOAc/hexanes and EtOAc/MeOH to yield 402 as a pure light brown semi solid (0.086 g, 17.5%). MS (APCI): m/z 372.2 [M−H]+ Anal. Calcd. For C18H21N5O4.0.35 EtOAc: C, 57.93; H, 5.96; N, 17.41; Found C, 58.36; H, 6.14; N, 16.96.
Reaction SMILES: [CH2:1]([S:7][CH:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:9](Cl)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:20][C:21]1[C:22]([S:30][CH3:31])=[N:23][C:24]([CH3:29])=[CH:25][C:26]=1[S:27][CH3:28]>C(Cl)Cl.N1C=CC=CC=1>[CH3:31][S:30][C:22]1[C:21]([NH:20][C:9](=[O:10])[CH:8]([S:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:26]([S:27][CH3:28])[CH:25]=[C:24]([CH3:29])[N:23]=1
Reactant: CSc1cc(C)nc(SC)c1N
Reactant: CCCCCCCCC(SCCCCCC)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCC(SCCCCCC)C(=O)Nc1c(SC)cc(C)nc1SC
Temperature: 5 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
A solution of 4.19 g (13.7 mmol) 2-hexylthiodecanoyl chloride, prepared according to Example 4A, in 15 ml methylene chloride was added dropwise with stirring under nitrogen to a solution of 2.75 g (13.7 mmol) 3-amino-2,4-bis(methylthio)-6-methylpyridine in 30 ml pyridine cooled to 5° C. The reaction mixture was stirred at room temperature under nitrogen overnight. Methylene chloride (250 ml) was then added to the reaction mixture and the resulting solution was washed with 3×50 ml 3N aqueous hydrochloric acid solution, 2×50 ml water, 1×50 ml saturated aqueous sodium bicarbonate solution and 1×50 ml brine. The methylene chloride solution was dried over anhydrous sodium sulfate, filtered and concentrated to dryness in vacuo. The solid residue (6.5 g) was recrystallized from petroleum ether to yield 4.7 g of the title compound, m.p. 75°-76.5° C. (72.8% yield).
Reaction SMILES: [C:1](O)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[OH:31])([CH2:23][CH3:24])[CH3:22].S(=O)(=O)(O)O>C(O)(=O)C>[CH:21]([C:25]1[CH:30]=[C:29]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:28]=[CH:27][C:26]=1[OH:31])([CH2:23][CH3:24])[CH3:22]
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCC(C)c1ccccc1O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCC(C)c1cc(C(c2ccccc2)(c2ccccc2)c2ccccc2)ccc1O
Temperature: 25 °C
Yield: 75 %

Procedure:
A 250 mL 1-neck flask was equipped with a magnetic stirrer and a reflux condenser with nitrogen blanket. The flask was charged with 6.52 grams (0.025 moles) of trityl alcohol, 3.77 grams (0.025 moles) of o-sec-butylphenol, and 50 mL of glacial acetic acid. The mixture was stirred under nitrogen at room temperature to give a clear, yellow solution. Concentrated sulfuric acid (5 mL) was then added in one portion. The solution immediately became dark red-brown. The solution was stirred at room temperature for 2 days, during which time solids separated out. The reaction mixture was filtered, and the solids were washed on the filter with several portions of water. After drying in a vacuum oven at 65° C. for 3 hours, the yield of product was 7.34 grams (75% yield). MP=135-136° C. GPC analysis showed a purity of >99%. The structure was confirmed by IR, 1H- and 13C-NMR analyses.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[NH2:18][CH2:19][C:20]1[CH:31]=[CH:30][C:23]([CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:18][CH2:19][C:20]2[CH:31]=[CH:30][C:23]([CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:22][CH:21]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CCN(CC)Cc1ccc(CN)cc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CCN(CC)Cc1ccc(CNc2nc(N)nc(-c3ccco3)c2C#N)cc1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, (4-aminomethyl-benzyl)-diethyl-amine and DBU in DME. ES-MS m/e (%): 377 (M+H+, 100), 304 ([M+H-Et2NH]+, 40).
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].[F:6][C:7]([F:20])([C:16]([F:19])([F:18])[F:17])[C:8]([CH2:10][C:11](OCC)=[O:12])=O>CCO>[CH3:3][C:2]1[NH:5][C:11](=[O:12])[CH:10]=[C:8]([C:7]([F:6])([F:20])[C:16]([F:17])([F:18])[F:19])[N:4]=1
Reactant: CC(=N)N
Reactant: CCOC(=O)CC(=O)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: CCO
Product: Cc1nc(C(F)(F)C(F)(F)F)cc(=O)[nH]1
Reaction time: 0.25 h
Yield: 52.6 %

Procedure:
A solution of Na (2.3 g, 0.1 mol) in EtOH (125 mL) was mixed with acetamidine hydrochloride (4.72 g, 50 mmol) and the reaction mixture was stirred for 15 min. Ethyl pentafluoropropionylacetate (11.7 g, 50 mmol) was added and the reaction mixture was refluxed for 6 h. The solvent was removed in vacuo, and the residue was taken up in H2O and acidified with dilute HCl to pH 2. The aqueous solution was extracted with EtOAc and the organic layer was dried over Na2SO4, then evaporated to afford 6 g of a yellowish solid. The crude product was purified by flash chromatography (CHCl3 containing MeOH 0% to 4%) to provide 2 g (17.5% yield) of a solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15](Br)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1.[NH2:18][C:19]1[S:20][CH:21]=[C:22]([CH3:24])[N:23]=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:18][C:19]3[S:20][CH:21]=[C:22]([CH3:24])[N:23]=3)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1
Reactant: Cc1ccc(Br)c(C(=O)Nc2ccn(C)n2)n1
Reactant: Cc1csc(N)n1
Product: Cc1csc(Nc2ccc(C)nc2C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Bromo-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide in accordance with the general method of Example 78, step 3 using 2-Amino-4-methylthiazole instead of 3-Amino-1-methyl-pyrazole to yield the final compound as a yellow solid, MS (ISP): m/e=329.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=[S:11].Cl.C([O:15][C:16](=O)[CH2:17][NH:18][CH3:19])C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:16](=[O:15])[CH2:17][N:18]([CH3:19])[C:10]1=[S:11]
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: CCOC(=O)CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN1CC(=O)N(c2c(Cl)cccc2Cl)C1=S
Yield: 87.8 %

Procedure:
The title compound was prepared by the procedure described in Example 1 using 14.28 g of 2,6-dichlorophenyl-isothiocyanate, 10.75 g of sarcosine ethyl ester hydrochloride, 14.5 g of triethyl amine, and 200 mL of chloroform. Crystallization from diethyl ether afforded the title compound (16.9 g) as a light peach solid, m.p. 207°-209° C. Anal. Calcd. for C10H8C12N2O S: C, 43.65; H, 2.93; N, 10.18. Found: C, 43.57; H, 2.61; N, 10.14. Mass spectrum (El, M.+) m/z 274.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([CH2:8]Cl)[N:4]1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>COCCOCCOC.C(OCC)C>[CH2:23]([N:30]1[CH2:8][CH:5]2[N:4]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[CH:3]([CH2:7][CH2:6]2)[CH2:2]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: ClCC1CCC(CCl)N1c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: COCCOCCOC
Product: Clc1ccc(N2C3CCC2CN(Cc2ccccc2)C3)cc1
Temperature: 25 °C
Yield: 23.6 %

Procedure:
2,5-Bis-chloromethyl-1-(4-chlorophenyl)-pyrrolidine (3.73 g, 13.57 mmol), potassium carbonate (3.75 g, 27.14 mmol), and benzyl amine (4.45 mL, 40.71 mmol) in diglyme (25 mL) was heated at reflux for 15 h. The reaction mixture was cooled to room temperature, diluted with diethyl ether (600 mL) and washed with water (6×300 mL). The combined organic layers were dried with magnesium sulfate and concentrated to a brown oil. Silica gel flash chromatography using 50% chloroform/hexanes as eluent yielded 3-Benzyl-8-(4-chloro-phenyl)-3,8-diaza-bicyclo[3.2.1]octane (1.0 g, 23.5%) as a golden solid which had the following properties: Mp. 115-117° C.; 1H NMR CDCl3 δ: 7.29 (s, 5H), 7.14 (d, J=8.1 Hz, 2H), 6.67 (d, J=8.3 Hz, 2H), 4.08 (brd s, 2H), 3.38 (s, 2H), 2.54-2.42 (m, 4H), 2.08-2.00 (m, 2H), 1.95-1.86 (m,2H).
Reaction SMILES: ClCC([O:5][C:6]1[CH:14]=[CH:13][C:12]2[N:11]([CH3:15])[C:10]3[C:16](=O)[CH2:17][CH2:18][C:9]=3[C:8]=2[CH:7]=1)=O.CC([O-])=O.[Na+].Cl.[NH2:26][OH:27]>CCO.O>[OH:27][N:26]=[C:16]1[C:10]2[N:11]([CH3:15])[C:12]3[CH:13]=[CH:14][C:6]([OH:5])=[CH:7][C:8]=3[C:9]=2[CH2:18][CH2:17]1
Reactant: Cn1c2c(c3cc(OC(=O)CCl)ccc31)CCC2=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cn1c2c(c3cc(O)ccc31)CCC2=NO

Procedure:
7-Chloroacetyloxy-1,4-dihydro-4-methylcyclopent[b]indol-3(2H)-one (8.0 g) was suspended in EtOH (200 ml) and a solution of NaOAc (15.6 g) in water (25 ml) and a solution of hydroxylamine hydrochloride (8.0 g) in water (25 ml) were added and the mixture was refluxed for 3 hours. The mixture was concentrated in vacuo and the residue was recrystallized from 95% EtOH to provide 3-hydroxyimino-4-methyl-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol as an off-white solid. The oxime was dissolved in tetrahydrofuran (100 ml), and thereafter acetic anhydride (8.1 g) and 4-dimethylaminopyridine (400 mg) were added and the mixture was stirred under nitrogen at ambient temperature overnight. The mixture was concentrated in vacuo, CH2Cl2 (100 ml) was added and the solution was washed successively with water (50 ml), 5% NaHCO3 (50 ml) and water (50 ml). After drying (Na2SO4), the solvent was removed in vacuo and the product recrystallized from EtOH to provide 3-acetyloximino-4-methyl-1,2,3,4-tetrahydrocyclopent[b]indol-7-yl acetate (1.7 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc([N+](=O)[O-])cc23)cc1Cl
Reactant: c1cn[nH]c1
Product: COc1ccc(CNc2nc(-n3cccn3)nc3sc([N+](=O)[O-])cc23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-nitro-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-nitro-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:6]=[C:7]([CH:28]=[CH:29][CH:30]=1)[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]3=[N:21][S:22](=[O:26])(=[O:25])[CH2:23][CH2:24][N:19]3[CH:18]=[C:17]([CH3:27])[CH:16]=2)=[CH:11][CH:10]=1)([F:4])[CH3:3]>C1COCC1.CO.[Pt](=O)=O>[F:4][C:2]([C:5]1[CH:6]=[C:7]([CH:28]=[CH:29][CH:30]=1)[O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[C:20]3=[N:21][S:22](=[O:26])(=[O:25])[CH2:23][CH2:24][N:19]3[CH2:18][CH:17]([CH3:27])[CH2:16]2)=[CH:13][CH:14]=1)([F:1])[CH3:3]
Reactant: CC1=CN2CCS(=O)(=O)N=C2C(c2ccc(Oc3cccc(C(C)(F)F)c3)cc2)=C1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CO
Product: CC1CC(c2ccc(Oc3cccc(C(C)(F)F)c3)cc2)C2=NS(=O)(=O)CCN2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of NaH (60%, 96 mg) in THF (dry) (10 mL) was added 2-chloroethanesulfonyl chloride (0.101 mL) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 3-(4-(3-(1,1-difluoroethyl)phenoxy)phenyl)-5-methylpyridin-2-amine (164 mg) in THF (dry) (10 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen overnight. The mixture was quenched with water at 0° C. Water, EtOAc and THF were added and the mixture was extracted. Silica-gel was added to the organic phase and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) and concentrated in vacuo to give 9-{4-[3-(1,1-difluoroethyl)phenoxy]phenyl}-7-methyl-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide as a white solid. Platinum(IV) oxide (30 mg) was added to a solution of the prepared 9-{4-[3-(1,1-difluoroethyl)phenoxy]phenyl}-7-methyl-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide in THF (dry) (15 mL) and MeOH (15 mL). The mixture was stirred at room temperature under hydrogen for 3 hr. Activated carbon was added and the insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc, to remove catalytic poison). Platinum(IV) oxide (30 mg) was added and the mixture was stirred at room temperature under hydrogen overnight. Activated carbon was added and the insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (47.6 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:8][C:7]=1[CH2:15]Br)=[O:5])[CH3:2].[CH2:17]([O:19][C:20](=[O:34])[CH2:21][NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1[O:32][CH3:33])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:8][C:7]=1[CH2:15][N:22]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1[O:32][CH3:33])[CH2:21][C:20]([O:19][CH2:17][CH3:18])=[O:34])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(C(C)(C)C)nc1CBr
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(C(C)(C)C)sc1C(=O)OCC
Yield: 66.2 %

Procedure:
A portion of the crude 4-bromomethyl-2-tert-butyl-thiazole-5-carboxylic acid ethyl ester (12.6 g, 41.0 mmol), N-(2,4-dimethoxy-benzyl)glycine ethyl ester (11.6 g, 41.0 mmol), and potassium carbonate (6.2 g, 45 mmol) in 100 ml of anhydrous DMF was stirred for 18 h. The mixture was partitioned into a biphasic water-ethyl acetate mixture and the isolated organic layer was then washed with brine, dried over anhydrous magnesium sulfate, concentrated to a residue, and purified by flash chromatography: eluting the desired product from silica gel with a gradient of 10-35% ethyl acetate in hexanes. 13 g of a yellow oil was isolated. MS (ESI+): 479.4 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:28])[C:5]([N:8]2[C:14]3=[N:15][C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[C:18]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:17]=4[N:13]3[CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:29][S:30]([O-:32])=[O:31].[Na+]>CN1CCCC1=O.C(OCC)(=O)C.[Cu]I>[Cl:22][C:21]1[C:16]2[N:15]=[C:14]3[N:8]([C:5]4[C:4]([CH3:28])=[CH:3][C:2]([S:30]([CH3:29])(=[O:32])=[O:31])=[CH:7][N:6]=4)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]3[C:17]=2[C:18]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:19][CH:20]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ncc(Br)cc1C
Reactant: CS(=O)[O-]
Agent: [Cu]I
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ncc(S(C)(=O)=O)cc1C
Temperature: 180 °C
Yield: 36.2 %

Procedure:
A mixture of 1-(5-bromo-3-methylpyridin-2-yl)-10-chloro-7-(1-ethylpropyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazole (463 mg, 0.216 mmol), sodium methanesulfinate (66 mg, 0.648 mmol) and copper(I) iodide (123 mg, 0.648 mmol) in 1-methyl-2-pyrrolidinone (1.0 mL) was heated under microwave irradiation at 180° C. for 1 hr. After cooling, the mixture was diluted with ethyl acetate, filtered through a pad of celite, washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture followed by recrystallization from ethyl acetate/n-hexane to afford the title compound (36 mg, 36%) as a colorless solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH2:11][CH2:10][CH:9]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH2:8][C:7]2=1.[N+:23]([C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Br)([O-:25])=[O:24].O>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:28][C:27]1[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=1[N+:23]([O-:25])=[O:24])[C:12]1[CH2:11][CH2:10][CH:9]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH2:8][C:7]2=1
Reactant: CC(C)C(=O)NC1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: O=[N+]([O-])c1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C(=O)NC1CCc2c(c3cc(Cl)ccc3n2Cc2ccccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
Suspend sodium hydride (60%, 120 mg, 3 mmol) in anhydrous DMF (2.5 mL) under nitrogen and cool in an ice bath. Slowly add N-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide (prepare essentially as described in Preparation 4)(727 mg, 2.5 mmol) dissolved in DMF (8 mL). After 10 min remove ice bath and allow the reaction to warm to ambient temperature over 1 h. Add DMF (25 mL) and cool in a dry ice/acetone bath. Add dropwise a solution of 2-nitrobenzylbromide (648 mg, 3 mmol) in DMF (2.5 mL). Stir for 18 h, allowing to warm to ambient temperature. Pour into water and extract with ethyl acetate/diethyl ether (100 mL/50 mL). Separate and wash the aqueous portion with ethyl acetate (50 mL). Combine organics and wash with 1N hydrochloric acid (2×100 mL), brine (2×100 mL), dry (MgSO4), and concentrate in vacuo to obtain a yellow solid. Purify by flash chromatography eluting with dichloromethane and then a gradient up to 10% ethyl acetate/dichlorometbane to obtain 833 mg (79%) of a yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][Cl:11].CN(C)C=O.[OH:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1>>[Cl:11][CH2:10][CH2:9][CH2:8][O:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:26][CH:27]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCCCl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.7 %

Procedure:
A suspension of potassium carbonate (48.4 g) in a mixture of methyl 4-hydroxybenzoate (10.65 g), 1-bromo-3-chloropropane (55.1 g) and N,N-dimethylformamide (100 mL) is stirred at room temperature for 15 h. Solids are separated by filtration and washed three times with ethanol (30 mL). The combined filtrates are concentrated under reduced pressure, and then dissolved in ethyl acetate (200 mL). The organic layer is washed twice with water (50 mL), dried over magnesium sulphate and concentrated under reduced pressure to give 15 g of methyl 4-(3-chloropropoxy)benzoate used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH:11]2[O:15][N:14]=[C:13]([CH3:16])[CH2:12]2)=[C:9]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[OH:21][C:22]1[N:26]([CH:27]2[CH2:29][CH2:28]2)[N:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC>[Cl:1][C:2]1[C:10]([CH:11]2[O:15][N:14]=[C:13]([CH3:16])[CH2:12]2)=[C:9]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:8]=[CH:7][C:3]=1[C:4]([C:23]1[CH:24]=[N:25][N:26]([CH:27]2[CH2:29][CH2:28]2)[C:22]=1[OH:21])=[O:5]
Reactant: CC1=NOC(c2c(S(C)(=O)=O)ccc(C(=O)Cl)c2Cl)C1
Reactant: Oc1ccnn1C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC1=NOC(c2c(S(C)(=O)=O)ccc(C(=O)c3cnn(C4CC4)c3O)c2Cl)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
At 0–5° C., a solution of 1.0 g (3 mmol) of 2-chloro-3-(3-methyl-4,5-dihydroisoxazol-5-yl)-4-methylsulfonylbenzoyl chloride in 50 ml of dimethoxyethane was added dropwise to a solution of 0.47 g (3 mmol) of 5-hydroxy-1-cyclopropylpyrazole and 0.5 g (3.6 mmol) of potassium carbonate in 36 ml of anhydrous dimethoxyethane. After 12 hours of stirring at room temperature, a further 1.0 g (7.2 mmol) of potassium carbonate were added and the batch was refluxed for 6 hours. After cooling, the reaction mixture was stirred into 600 ml of water and extracted with methylene chloride. The aqueous phase was then adjusted to pH 4 using 10% strength hydrochloric acid and extracted with methylene chloride. Drying of the organic phase and removal of the solvent gave 0.8 g (1.8 mmol, 63%) of the desired compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([S:13][CH3:14])=[N:6][CH:7]=[N:8]2.C(O)(C(F)(F)F)=O.[CH2:22]([O:25][C:26]([C@@H:28]1[CH2:33][CH2:32][NH:31][CH2:30][C@@H:29]1[C:34]([O:36][CH3:37])=[O:35])=[O:27])[CH:23]=[CH2:24]>ClC(Cl)C>[CH2:22]([O:25][C:26]([C@@H:28]1[CH2:33][CH2:32][N:31]([CH2:2][C:3]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:4]=2[C:5]([S:13][CH3:14])=[N:6][CH:7]=[N:8]3)[CH2:30][C@@H:29]1[C:34]([O:36][CH3:37])=[O:35])=[O:27])[CH:23]=[CH2:24]
Reactant: C=CCOC(=O)[C@@H]1CCNC[C@@H]1C(=O)OC
Reactant: CSc1ncnc2cccc(CBr)c12
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)[C@@H]1CCN(Cc2cccc3ncnc(SC)c23)C[C@@H]1C(=O)OC
Temperature: 25 °C
Yield: 93.4 %

Procedure:
A mixture of 15A (2.02 g, 7.5 mmol), TFA salt of (3R,4R)-methyl 4-(allyloxycarbonyl)piperidine-3-carboxylate (2.8 g, 7.87 mmol), (prepared as described in U.S. patent application Ser. No. 11/019,901) and TEA (3.14 ml, 22.5 mmol) in dichloroethane (50 ml) was heated at 70° C. for 1 h. After cooling to room temperature, the reaction mixture was washed with water, dried and concentrated in vacuo. Purification using silica gel flash column (DCM/MeOH=98/2) gave 15B (2.91 g, 90%) as a solid. The compound has an analytical HPLC retention time=1.547 min (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254 nm) and a LC/MS M++H=431+.