Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28].[H-].[Na+].I[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].[Cl-].[NH4+]>CN(C)C=O>[F:28][C:3]1[CH:4]=[C:5]([F:27])[C:6]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)=[CH:9][C:8](=[O:26])[C:7]=2[C:2]=1[NH:1][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reactant: CCCCCI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCCCNc1c(F)cc(F)c2oc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)cc(=O)c12
Reaction time: 0.5 h
Yield: 56 %

Procedure:
505 mg (1.29 mmol) of the resulting 5-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one was dissolved in 15 ml of dimethylformamide under argon atmosphere, 155 mg of sodium hydride (60% oil dispersion) and 0.35 ml of 1-iodopentane were added and the mixture was stirred at the same temperature for 30 minutes. 0.17 ml of 1-iodopentane was added and the mixture was stirred for additional 2 hours. An aqueous saturated solution of ammonium chloride was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to give 333 mg (56%) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-pentylamino-4H-1-benzopyran-4-one.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39].[CH3:47][C:48]1[O:52][N:51]=[C:50]([C:53](Cl)=[O:54])[CH:49]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][N:43]([C:53]([C:50]2[CH:49]=[C:48]([CH3:47])[O:52][N:51]=2)=[O:54])[CH2:42][CH2:41]1)=[O:39]
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2CCC(C(=O)Nc3ccc4cc3CCc3cccc(c3)Nc3ncc(Cl)c(n3)N4)CC2)no1
Yield: 12 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as starting materials in 12% yield. LCMS for C29H29ClN7O3 (M+H)+: m/z=558.2.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:10]=[O:11])=[C:7]([OH:9])[CH:8]=1)[CH3:2].CS(O[CH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][O:19]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:10]=[O:11])=[C:7]([O:9][CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][O:19]2)[CH:8]=1)[CH3:2]
Reactant: CS(=O)(=O)OCC1CCOCO1
Reactant: CCc1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(C=O)c(OCC2CCOCO2)c1
Temperature: 80 °C
Yield: 55.3 %

Procedure:
A stirred solution of 3.8 grams (0.026 mole) of 5-ethyl-2-formylphenol, 5.0 grams (0.026 mole) of 4-methylsulfonyloxymethyl-1,3-dioxane, and 7.0 grams (0.051 mole) of potassium carbonate in 150 mL of N,N-dimethylformamide was heated at 80° C. for about 18 hours. Analysis by thin layer chromatography (TLC) indicated the reaction was not complete. An additional 2.5 grams (0.013 mole) of 4-methylsulfonyloxymethyl-1,3-dioxane was added, and the reaction mixture was heated at 80° C. for an additional five hours. After this time the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with aqueous 10% lithium chloride, dried with magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel, yielding 3.6 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C@@H:8]([NH:10][S:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])[CH3:9])[CH:5]=[CH:4][N:3]=1.[CH3:17][S:18]([O-:20])=[O:19].[Na+]>CS(C)=O.[NH4+].[Cl-].C([O-])(O)=O.[Na+].CCOC(C)=O.[Cu]I>[CH3:17][S:18]([C:2]1[CH:7]=[C:6]([C@@H:8]([NH:10][S:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])[CH3:9])[CH:5]=[CH:4][N:3]=1)(=[O:20])=[O:19]
Reactant: C[C@H](NS(=O)C(C)(C)C)c1ccnc(Br)c1
Reactant: CS(=O)[O-]
Agent: [Cu]I
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C[C@H](NS(=O)C(C)(C)C)c1ccnc(S(C)(=O)=O)c1
Temperature: 130 °C

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid [(S)-1-(2-bromopyridin-4-yl)-ethyl]-amide (3.10 g, 10.2 mmol) (containing 5 wt % of the other diastereomer) in DMSO (120 mL) is added sodium methanesulfinate (3.7 g, 31 mmol) and copper (I) iodide (5.8 g, 31 mmol). The mixture is warmed at 130° C. for 45 minutes. The reaction is diluted with saturated aqueous NH4Cl (90 mL), saturated aqueous NaHCO3 (10 mL), and EtOAc (150 mL), and sonicated for 10 minutes to dissolve all the solids. The aqueous phase is separated and the organic layer is washed with a mixture of saturated aqueous NH4Cl (90 mL) in saturated aqueous NaHCO3 (10 mL). The combined aqueous layers are extracted with EtOAc (150 mL). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated. The crude material is purified by silica gel chromatography eluting with a gradient of 75-100% EtOAc in hexanes to afford 2-methyl-propane-2-sulfinic acid [(S)-1-(2-methanesulfonyl-pyridin-4-yl)-ethyl]-amide as an oil as a single diastereomer.
Reaction SMILES: O1C2C=CC=CC=2OCC1CN1CCCC(CO)(C)C1.C([O:23][C:24]([C:26]1([CH2:43][CH3:44])[CH2:31][CH2:30][CH2:29][N:28]([CH2:32][CH:33]2[O:38][C:37]3[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=3[O:35][CH2:34]2)[CH2:27]1)=O)C>>[O:38]1[C:37]2[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=2[O:35][CH2:34][CH:33]1[CH2:32][N:28]1[CH2:29][CH2:30][CH2:31][C:26]([CH2:24][OH:23])([CH2:43][CH3:44])[CH2:27]1
Reactant: CCOC(=O)C1(CC)CCCN(CC2COc3ccccc3O2)C1
Agent: CC1(CO)CCCN(CC2COc3ccccc3O2)C1
Product: CCC1(CO)CCCN(CC2COc3ccccc3O2)C1

Procedure:
Prepared according to the procedure described for [1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]methanol except that 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethyl-piperidine-3-carboxylic acid ethyl ester was used instead of 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidine-3-carboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[C:30]4[C@H:37]([CH3:38])[CH2:36][CH2:35][C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:25][CH2:24]2)=[O:22])[CH2:9][N:10]([CH:18]([CH3:20])[CH3:19])C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.[ClH:39]>C(Cl)Cl>[ClH:1].[ClH:39].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:9][NH:10][CH:18]([CH3:20])[CH3:19])[C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[C:30]4[C@H:37]([CH3:38])[CH2:36][CH2:35][C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:25][CH2:24]2)=[O:22])=[CH:4][CH:3]=1
Reactant: CC(C)N(CC(C(=O)N1CCN(c2ncnc3c2[C@H](C)CC3)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)NCC(C(=O)N1CCN(c2ncnc3c2[C@H](C)CC3)CC1)c1ccc(Cl)cc1
Yield: 99 %

Procedure:
tert-Butyl 2-(4-chlorophenyl)-3-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate was treated with HCl (4M in dioxane, 2 mL) in DCM (10 mL) for 6 hours to provide 2-(4-chlorophenyl)-3-(isopropylamino)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one dihydrochloride (24 mg, 99%). MS (APCI+) [M+H]+442.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH:17]4[CH2:19][CH:14]3[CH2:15][CH:16]4[O:20][CH2:21][CH2:22][OH:23])=[N:10][CH:9]=[N:8][C:7]=2[S:6][CH:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([O:23][CH2:22][CH2:21][O:20][CH:16]1[CH2:15][CH:14]2[CH2:19][CH:17]1[CH2:18][N:13]2[C:11]1[C:12]2[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][S:6][C:7]=2[N:8]=[CH:9][N:10]=1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)c1csc2ncnc(N3CC4CC3CC4OCCO)c12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1csc2ncnc(N3CC4CC3CC4OCCOS(C)(=O)=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.8 %

Procedure:
2-[[2-(5-Isopropylthieno[2,3-d]pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptan-5-yl]oxy]ethanol (0.56 g, 1.7 mmol) was stirred in DCM (13.25 g, 10 mL, 156.0 mmol) at 0° C. Triethylamine (0.52 g, 0.71 mL, 5.0 mmol) was added. Methanesulfonyl chloride (0.29 g, 0.20 mL, 2.5 mmol) was added dropwise and the reaction allowed to warm slowly to room temperature and stirred for 1 hour. The reaction mixture was diluted with DCM, washed with water, dried over Na2SO4 and concentrated in vacuo to afford 2-[[2-(5-isopropylthieno[2,3-d]pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptan-5-yl]oxy]ethyl methanesulfonate (0.747 g). LCMS RT=3.94 min. M+1=412.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[C:5]([NH:7][NH:8][C:9](=[O:12])[CH2:10][Cl:11])=O.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:11][CH2:10][C:9]1[O:12][C:5]([C:4]2[CH:13]=[CH:14][C:15]([Cl:16])=[C:2]([Cl:1])[CH:3]=2)=[N:7][N:8]=1
Reactant: O=C(CCl)NNC(=O)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCc1nnc(-c2ccc(Cl)c(Cl)c2)o1
Temperature: 25 °C
Yield: 40 %

Procedure:
A mixture of compound 9 (120 mg, 0.263 mmol), compound A (76 mg, 0.263 mmol) and K2CO3 (72.58 mg, 0.526 mmol) was heated under reflux in 25 ml of acetone for 3 hours. The reaction mixture was cooled to ambient temperature, filtered and the filtrate was evaporated to obtain crude residue which was purified by column chromatography using MeOH/DCM (15:85) as an eluent to obtain compound 10 as a yellow colored gummy material (75 mg). Yield: 40%.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[NH:13][CH2:12][C:11]2[NH:10][C:9]3[N:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:8]=3[C:7]=2[CH2:6]1)=[O:4].[Se](=O)=O>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[N:13]=[CH:12][C:11]2[NH:10][C:9]3[N:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:8]=3[C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)C1Cc2c([nH]c3nccc(Cl)c23)CN1
Agent: O=[Se]=O
Solvent: C1COCCO1
Product: COC(=O)c1cc2c(cn1)[nH]c1nccc(Cl)c12
Temperature: 100 °C

Procedure:
A mixture of 4-chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid methyl ester (2.1 g, 7.9 mmol) and selenium dioxide (1.20 g, 11.1 mol) in 1,4-dioxane (50 mL) was heated at 100° C. for 3.5 hours. The resulting grey slurry was filtered whilst hot through a pad of celite and the pad washed with hot THF and 25% methanol in dichloromethane. The combined filtrate was concentrated in-vacuo and the resultant residue triturated with methanol (10 mL). The resultant solid was collected by filtration and left to air dry to afford the title compound as an off white solid (1.03 g, 48%). 1H NMR (400 MHz, DMSO-d6): 13.02 (s, 1H), 9.06 (d, J=1.1 Hz, 1H), 8.94 (d, J=1.0 Hz, 1H), 8.63 (d, J=5.3 Hz, 1H), 7.54 (d, J=5.3 Hz, 1H), 3.93 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1(O)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[Cl:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][CH:21]=[CH:20]2>>[Cl:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][CH:21]=[C:20]2[C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1
Reactant: CCC1(O)CCc2cc(F)ccc21
Reactant: Clc1cccc2cc[nH]c12
Product: CCC1(c2c[nH]c3c(Cl)cccc23)CCc2cc(F)ccc21

Procedure:
Utilizing 1-ethyl-5-fluoro-indan-1-ol and 7-chloroindole, the title compound is prepared as in example 1. 90 mg (60%). NMR (400 MHz, CDCl3): δ 0.85 (t, 3H), 2.15 (m, 1H), 2.22 (m, 1H), 2.34 (m, 1H), 2.59 (m, 1H), 2.98 (m, 2H), 6.82 (t, 1H), 6.87 (m, 2H), 7.00 (m, 2H), 7.11 (d, 1H), 7.16 (d, 1H), 8.12 (s, 1H, NH).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[NH:3][CH:2]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([NH:13][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Reactant: Nc1ccccc1
Product: O=C(Nc1ccccc1)c1ccc2[nH]cnc2c1
Yield: 28.4 %

Procedure:
In a procedure analogous to example 20, reaction of benzimidazole-5-carboxylic acid (400 mg, 5.50 mmol) and aniline (510 mg, 5.50 mmol) furnished the product (370 mg, 63%).
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:5]=[CH:6][C:7]2[N+:12]([O-:13])=[N:11][C:10]([NH:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[N:9][C:8]=2[CH:20]=1.[CH3:21][O:22][CH2:23][CH2:24][OH:25]>C1COCC1>[CH3:21][O:22][CH2:23][CH2:24][O:25][C:4]1[CH:5]=[CH:6][C:7]2[N+:12]([O-:13])=[N:11][C:10]([NH:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[N:9][C:8]=2[CH:20]=1
Reactant: COCCO
Reactant: CN(C)CCNc1nc2cc(F)ccc2[n+]([O-])n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1ccc2c(c1)nc(NCCN(C)C)n[n+]2[O-]
Temperature: 20 °C
Yield: 96.3 %

Procedure:
NaH (66 mg, 60% dispersion in oil, 1.7 mmol) was added to a stirred solution of fluoride 12 (261 mg, 1.0 mmol) and 2-methoxyethanol (0.12 mL, 1.6 mmol) in THF (10 mL) at 20° C. and the mixture stirred at reflux temperature for 2 h. More NaH (66 mg, 1.6 mmol) and 2-methoxyethanol (0.12 mL, 1.6 mmol) were added and the mixture stirred at reflux temperature for 16 h. The mixture was cooled to 20° C. and carefully quenched with water (5 mL). The solvent was evaporated and the residue partitioned between DCM (50 mL) and water (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 13 (296 mg, 93%) as a yellow solid, mp (MeOH/EtOAc) 139-141° C.; 1H NMR δ 8.14 (d, J=9.4 Hz, 1 H, H-8), 6.91 (dd, J=9.4, 2.6 Hz, 1 H, H-7), 6.84 (d, J=2.6 Hz, 1 H, H-5), 5.91 (br s, 1 H, NH), 4.20-4.23 (m, 2 H, CH2O), 3.71-3.74 (m, 2 H, CH2O), 3.51-3.56 (m, 2 H, CH2N), 3.46 (s, 3 H, OCH3), 2.55 (br dd, J=6.0, 5.9 Hz, 2 H, CH2N), 2.28 [s, 6 H, (CH3)2]; 13C NMR δ 164.6, 159.6, 151.4, 126.1, 122.1, 118.0, 104.6, 70.5, 68.0, 59.3, 57.5, 45.1 (2), 38.7. Anal. Calcd for C14H21N5O3: C, 54.7; H, 6.9; N, 22.8. Found: C, 54.5; H, 6.7; N, 22.7%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[S:11][C:12]1[S:13][C:14]2[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][C:15]=2[N:16]=1.O.O.[Sn](Cl)(Cl)(Cl)Cl>>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([S:11][C:12]2[S:13][C:14]3[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][C:15]=3[N:16]=2)=[C:2]([Cl:1])[CH:7]=1
Reactant: N#Cc1ccc2nc(Sc3ccc([N+](=O)[O-])cc3Cl)sc2c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Product: N#Cc1ccc2nc(Sc3ccc(N)cc3Cl)sc2c1
Yield: 93 %

Procedure:
The title compound was prepared using the method of example 270, starting with 2-(2-chloro-4-nitro-phenylsulfanyl)-benzothiazole-6-carbonitrile (261) (1.6 g, 4.6 mmol), tin chloride dihydrate (Aldrich, 5.21 g, 23.1 mmol). Compound 273 (1.36 g, 93%) was obtained as a yellowish solid. MS (M+H) 318.
Reaction SMILES: [CH2:1]([C:11]1[CH:30]=[CH:29][C:14]([C:15]([NH:17][C:18]2([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH2:21][NH:20][CH2:19]2)=[O:16])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:31]=O>>[CH2:1]([C:11]1[CH:30]=[CH:29][C:14]([C:15]([NH:17][C:18]2([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH2:21][N:20]([CH3:31])[CH2:19]2)=[O:16])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C=O
Reactant: CCCCCCCCCCc1ccc(C(=O)NC2(CC(=O)OCC)CCNC2)cc1
Product: CCCCCCCCCCc1ccc(C(=O)NC2(CC(=O)OCC)CCN(C)C2)cc1
Yield: 75 %

Procedure:
According to the method described in example 17c, ethyl 2-(3-(4-decylbenzamido)-pyrrolidin-3-yl)acetate was reacted with formalin to give the title compound as a yellow oil (58 mg, 75%). 1H NMR (400 MHz, CDCl3) δ 7.67 (d, 2H, J=7.9 Hz), 7.21 (d, 2H, J=8.1 Hz), 6.70 (s, 1H), 4.10 (q, 2H, J=7.1 Hz), 3.17-2.82 (m, 4H), 2.77-2.67 (m, 2H), 2.63 (t, 2H, J=7.8 Hz), 2.37 (s, 3H), 2.35-2.30 (m, 1H), 1.64-1.55 (m, 2H), 1.36-1.24 (m, 14H), 1.20 (t, 3H, J=7.3 Hz), 0.89 (t, 311, J=6.6 Hz); MS ESI 431.4[M+H]+, calcd for [C26H42N2O3+H] 431.32.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][O:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])=[O:5])C.C(O)(=O)C.Cl>O>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:10]1[O:9][N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnoc1-c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cnoc1-c1ccc(Cl)cc1Cl
Yield: 91.2 %

Procedure:
Ethyl-5-(2',4'-dichlorophenyl)-4-isoxazolecarboxylate (50.0 g.; 0.17 mol.) was dissolved in 250 ml. of glacial acetic acid. To the mixture was added 250 ml. of hydrochloric acid and the resultant solution was rapidly stirred at 100° C. for 4 hours. The mixture was then allowed to cool and poured into 2 liters of water. The resultant precipitate was collected, dried, and recrystallized from pentane to yield 5-(2',4'-dichlorophenyl)-4-isoxazolecarboxylic acid (40.0 g.; 93.6% yield) having a melting point of 122°-123° C. and the following analysis:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH2:9])=O)([O-:3])=[O:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:7][NH2:9])[CH:10]=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: NC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCc1cccc([N+](=O)[O-])c1

Procedure:
Commercially available 3-nitrobenzamide is reduced with LAH under standard conditions to afford (3-nitrophenyl)methanamine, which is reacted with succinic anhydride under standard conditions to afford 1-(3-nitrobenzyl)pyrrolidine-2,5-dione. This material is reduced at the nitro group and oxidized to afford 1-(3-hydrazinobenzyl)pyrrolidine-2,5-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([F:19])=[CH:12][C:13]=2[O:15][CH2:16][CH2:17]Cl)[C:8]([S:20]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[N:7]1.[N-:36]=[N+:37]=[N-:38].[Na+]>CS(C)=O.O>[N:36]([CH2:17][CH2:16][O:15][C:13]1[CH:12]=[C:11]([F:19])[CH:10]=[C:9]2[C:14]=1[N:6]([CH2:5][C:4]1[CH:33]=[CH:34][CH:35]=[C:2]([Cl:1])[CH:3]=1)[N:7]=[C:8]2[S:20]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)(=[O:21])=[O:22])=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=[N-]
Reactant: O=S(=O)(c1cccc2ccccc12)c1nn(Cc2cccc(Cl)c2)c2c(OCCCl)cc(F)cc12
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NCCOc1cc(F)cc2c(S(=O)(=O)c3cccc4ccccc34)nn(Cc3cccc(Cl)c3)c12
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(3-chloro-benzyl)-7-(2-chloro-ethoxy)-5-fluoro-3-(naphthalene -1-sulfonyl)-1H-indazole (0.1 g, 0.19 mmoles) and sodium azide (0.014 g, 0.22 mmoles) in DMSO (3 mL) was stirred together in a round bottom flask under nitrogen at 90° C. for 3 hours. Reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAC, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (0.09 g, 0.17 mmoles).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:18]([O-])=O.C(OCC)(=O)C>[Pd].C(O)C>[NH2:18][C:3]1[CH:4]=[C:5]([S:8]([NH:11][O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)(=[O:9])=[O:10])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1ccc(S(=O)(=O)NOC2CCCC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)NOC2CCCC2)cc1N
Reaction time: 72 h
Yield: 100.7 %

Procedure:
A solution of 4-amino-N-(cyclopentyloxy)-3-nitrobenzenesulfonamide (4.50 g, 14.95 mmol) in 1:1 ethyl acetate : ethanol (150 mL) was combined with 5% Pd on barium sulfate and reduced under a hydrogen atmosphere over 72 hours. The reaction mixture was filtered through a pad of diatomaceous earth and evaporated in vacuo to a residue which crystallized on standing. The solid was slurried in hexane, filtered and dried under high vacuum to provide 3,4-diamino-N-(cyclopentyloxy)benzenesulfonamide (4.086 g, 100%) as a light brown solid H1-NMR (dimethylsulfoxide-D6): 1.61 (m, 8H), 4.37 (m, 1H), 4.90 (b, 2H), 5.38 (b, 2H), 6.57 (d, 1H), 6.88 (m, 1H), 6.96 (d, 1H), 9.64 (s, !H). . MS(ESI): 272(M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][C:19]([O:21]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:25][NH2:26]>C(O)C>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][C:19]([NH:25][NH2:26])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)CSc1nc2ccccc2n1Cc1ccccc1
Solvent: CCO
Solvent: O
Product: NNC(=O)CSc1nc2ccccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of ethyl 2-(1-benzyl-1H-benzo[d]imidazol-2-ylthio)acetate 4b (200 mg, 0.61 mmol, 1.0 eq.) in ethanol (5 mL), was added hydrazine monohydrate (61 mg, 1.23 mmol, 2.0 eq.), and the reaction mixture was heated to reflux and stirred at that temperature for 16 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The mixture was dissolved in ethyl acetate (20 mL) and washed with water (20 mL) and brine (20 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo giving 4c as a pale yellow solid which was used without further purification (200 mg, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[C:8]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[CH:9]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=1.O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)[CH:7]=[C:8]([C:10](=[O:14])[CH:11]([CH3:12])[CH3:13])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(C(=O)C(C)C)c[nH]1
Reactant: Fc1ccc(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C(=O)C(C)C)cn1Cc1ccc(F)c(F)c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A mixture of 4-isobutyryl-1H-pyrrole-2-carboxylic acid methyl ester (B1-I) and cesium carbonate were stirred in dry DMF for 10 minutes at 40-50° C. To it 1-bromomethyl-3,4-difluorobenzene was added and the reaction was stirred for 18 hrs at 50° C. Water was added to the reaction and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 1-(3,4-difluoro-benzyl)-4-isobutyryl-1H-pyrrole-2-carboxylic acid methyl ester (B1-II).