Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:22])=[C:5]([C:13]([C:15]2[CH:16]=[N:17][N:18]([CH3:21])[C:19]=2[OH:20])=[O:14])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10].C(N(CC)CC)C.[CH3:30][CH2:31][S:32][C:33](Cl)=[O:34].C(OCC)(=O)C>O1CCCC1>[CH3:1][O:2][C:3]1[C:4]([CH3:22])=[C:5]([C:13]([C:15]2[CH:16]=[N:17][N:18]([CH3:21])[C:19]=2[O:20][C:33]([S:32][CH2:31][CH3:30])=[O:34])=[O:14])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:10])=[O:11]
Reactant: COc1c(S(C)(=O)=O)ccc(C(=O)c2cnn(C)c2O)c1C
Reactant: CCSC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCSC(=O)Oc1c(C(=O)c2ccc(S(C)(=O)=O)c(OC)c2C)cnn1C
Reaction time: 1 h

Procedure:
To a solution of 5-hydroxy-1-methylpyrazol-4-yl 3-methoxy-2-methyl-4-(methylsulfonyl)phenyl ketone (100 mg, 0.3 mmol) in dry tetrahydrofuran (5 mL) were added triethylamine (61 mg) and 96% S-ethyl chlorothiolformate (50 mg) at room temperature. After the reaction solution was stirred for 1 hour, 150 mL of ethyl acetate was added. The mixture was washed twice with a saturated brine, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to obtain the desired product as an oil.
Reaction SMILES: [CH2:1]([NH:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[O:18]1[CH2:20][CH2:19]1>>[CH2:1]([NH:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][O:16][CH2:20][CH2:19][OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C1CO1
Reactant: CCCCCCCCCCNC(=O)CCCO
Product: CCCCCCCCCCNC(=O)CCCOCCO
Reaction time: 2 h
Yield: 97.8 %

Procedure:
In a steel autoclave, 243 grams (1 mole) of N-decyl-4-hydroxybutyramide at a temperature of 130° C. was admixed with 44 grams (1 mole) of oxirane which was added to the autoclave as a compressed gas. The reaction mixture was stirred and autogenous pressure caused a drop in pressure during the reaction. After the reaction was complete in a period of about 2 hours, 281 grams of product were obtained. The product was then cooled to room temperature whereupon a light solid having a melting point of 48° C. was obtained. IR=6.11 mu.
Reaction SMILES: [Br:1][Si](C)(C)C.[CH2:6]([O:8][C:9](=[O:18])[CH2:10][C:11]1[CH:12]=[N:13][C:14](Cl)=[N:15][CH:16]=1)[CH3:7].C(OCC)C.[OH-].[Na+]>C(#N)CC>[CH2:6]([O:8][C:9](=[O:18])[CH2:10][C:11]1[CH:12]=[N:13][C:14]([Br:1])=[N:15][CH:16]=1)[CH3:7]
Reactant: C[Si](C)(C)Br
Reactant: CCOC(=O)Cc1cnc(Cl)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCC#N
Product: CCOC(=O)Cc1cnc(Br)nc1
Temperature: 101.5 °C
Yield: 90.6 %

Procedure:
Bromotrimethylsilane (1.7 mL, 12 mmol) was added to a solution of (2-chloro-pyrimidin-5-yl)acetic acid ethyl ester (Example 43-(2); 810 mg, 4.04 mmol) in propionitrile (4 mL), and the mixture was heated under reflux at an external temperature of 98 to 105° C. for nine hours. After cooling the reaction mixture to room temperature, diethyl ether was added to the reaction mixture, which was neutralized with a 2 N sodium hydroxide aqueous solution (6.3 mL). The reaction mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=2/1) to give the title compound (897 mg, 91%).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[N:22][C:21]([CH3:24])=[CH:20][N:19]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl.CO.[OH-].[NH4+]>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[N:22][C:21]([CH3:24])=[CH:20][N:19]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cnc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)cn1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.6 %

Procedure:
To a solution of N-tert-butyl-2-(5-methylpyrazin-2-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (72 mg, 158 mol) in dichloromethane (2.5 mL) was added trifluoroacetic acid (360 mg, 243 μL, 3.16 mmol) and stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue obtained diluted with dichloromethane (2.5 mL), methanol (1.2 mL) and ammonium hydroxide (0.35 mL) and the mixture stirred at room temperature for 1 h. The mixture was concentrated and triturated with water. The solid was collected by filtration and washed with water and ether to give N-tert-butyl-2-(5-methylpyrazin-2-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (26 mg, 79.9 mol, 51%) as a light green solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.45 (s, 1H), 10.12 (s, 1H), 9.17 (d, J=1.5, 1 H), 8.40 (s, 1H), 8.21 (s, 1H), 8.10 (d, J=3.2, 1 H), 7.73 (s, 1H), 2.42 (s, 3H), 1.46 (s, 9H); MS (EI/CI) m/z: 326.1 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].O.[CH2:13]([NH2:16])[CH2:14][NH2:15].C(N)CN.Cl>>[ClH:1].[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:15][CH2:14][CH2:13][NH2:16])=[C:3]([CH3:11])[CH:4]=1)([O-:10])=[O:9]
Reactant: Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: NCCN
Agent: Cl
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1NCCN
Yield: 87 %

Procedure:
51.45 g (0.3 mole) of 2-chloro-5-nitro-toluene is added to 200 cm3 (2.5 moles) ethylenediamine hydrate. The mixture is heated at reflux for 5 hours, and the excess of ethylene diamine is then eliminated under vacuum. The residue is treated with 300 cm3 of a 5N solution of hydrochloric acid, Drying yields 60.5 g of 4-nitro-2-methyl-N-(β-aminoethyl)aniline monohydrochloride, which is washed with acetone.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[K+].[Br-].Br[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1>C(#N)C>[Br-:10].[CH2:11]([C:29]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]([CH3:20])[C:30]=1[N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[NH:5][CH:4]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: BrCc1ccc2ccccc2c1
Reactant: Clc1nc[nH]c1Cl
Reactant: CCCCCCBr
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCCCCCc1c(-[n+]2c[nH]c(Cl)c2Cl)c(C)cc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
4,5-Dichloroimidazole (1.23 g, 9 mmol) was dissolved into 27 mL of acetonitrile. Potassium hydroxide (0.61 g, 9.9 mmol) was added and the mixture was allowed to stir for 0.5 h. 1-bromohexane (1.26 mL, 9 mmol) was added and the solution was allowed to reflux overnight. The solution was filtered hot to remove a white precipitate (presumed to be KBr) and 2-bromomethylnaphthalene (1.98 g, 9 mmol) was added and the mixture was returned to reflux overnight. The mixture was then allowed to cool to room temperature, resulting in a yellow precipitate (2.57, 65% yield). 1H NMR (500 MHz, DMSO-d6) 9.64 (1H, s, NCHN), 8.02 (4H, m, Ar), 7.57 (3H, m, Ar), 5.66 (2H, s, NCH2), 4.22 (2H, t, NCH2), 1.80 (2H, tt, CH2), 1.30 (6H, m, CH2), 0.93 (3H, t, CH3). 13C{1H} NMR (125 MHz, DMSO-d6) 136.4 (NCN), 132.8 (Ar), 132.6 (Ar), 130.0 (Ar), 128.8 (Ar), 127.8 (Ar), 127.7 (Ar), 127.6 (Ar), 126.8 (Ar), 126.7 (Ar), 125.5 (Ar), 119.1 (Ar), 51.6 (CH2), 48.3 (CH2), 30.5 (CH2), 28.0 (CH2), 24.9 (CH2), 21.8 (CH2), 13.2 (CH3). MS: m/z=332.9 (theor for C20H23Cl2N2Br1=414.17).
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[CH3:16][C:17]1[NH:18][C:19]2[C:24]([C:25]=1[CH:26]=O)=[CH:23][CH:22]=[CH:21][CH:20]=2.[CH:28]([C:30]1[N:34]([CH3:35])[CH:33]=[C:32]([C:36]#[N:37])[CH:31]=1)=O>>[CH2:9]([N:8]1[C:3]2=[N:1][N:2]([CH2:26][C:25]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][C:17]=3[CH3:16])[C:28]([C:30]3[N:34]([CH3:35])[CH:33]=[C:32]([C:36]#[N:37])[CH:31]=3)=[C:4]2[C:5](=[O:15])[N:6]([CH3:14])[C:7]1=[O:13])[CH:10]([CH3:11])[CH3:12]
Reactant: Cc1[nH]c2ccccc2c1C=O
Reactant: Cn1cc(C#N)cc1C=O
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Product: Cc1[nH]c2ccccc2c1Cn1nc2c(c1-c1cc(C#N)cn1C)c(=O)n(C)c(=O)n2CC(C)C

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 2-methyl-1H-indole-3-carbaldehyde, followed by 5-formyl-1-methyl-1H-pyrrole-3-carbonitrile. Mass: 470.20 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[IH:13].[OH-].[Na+]>>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([I:13])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: I
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccc2c(I)ccnc2c1
Temperature: 130 °C

Procedure:
4,7-Dichloroquinoline (50 g) (Aldrich) was added in small portions to HI (425 mL) at r.t. and then heated at 130° C. for 5 h. The mixture was cooled, poured into ice/H2O (600 mL), made basic (pH 10) with 10N NaOH, and extracted with CHCl3. The combined organics were washed with NH4OAc buffer, 10% Na2S2O3, brine, dried (Na2SO4) and concentrated providing the title compound which was used as such.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=O)=[N:2]1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([NH2:20])[CH:14]=1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CN(C)C=O>[Br:12][C:13]1[CH:18]=[CH:17][C:16]2[N:19]=[C:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)[NH:20][C:15]=2[CH:14]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: O=Cc1n[nH]c2ccccc12
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc2nc(-c3n[nH]c4ccccc34)[nH]c2c1

Procedure:
Starting with 643 mg of 1H-indazole-3-carboxaldehyde, 816 mg of 4-bromo-1,2-phenylenediamine, and 836.5 mg of sodium metabisulphite in 15 ml of dimethylformamide, and after purification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol) followed by a chromatography under pressure on silica, 939 mg of 5-bromo-2-(1H-indazol-3-yl)-3H-benzimidazole are obtained in the form of a brick-red powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].C([N:29]=[C:30]=[S:31])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:30](=[S:31])[NH2:29])[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Reactant: CCOC(=O)C1CCCNC1
Product: CCOC(=O)C1CCCN(C(N)=S)C1
Yield: 92.5 %

Procedure:
1-Thiocarbamoyl-piperdine-3-carboxylic acid ethyl ester (400 mg) was prepared following general procedure D using piperdine-3-carboxylic acid ethyl ester (315 mg, 2.0 mmol), and Fmoc-isothiocyanate (562 mg, 2.0 mmol). Purification: (Silica gel, ethyl acetate/hexane 1:1). LCMS m/z 217.0 (M+1)+
Reaction SMILES: [C:1]([O-])(=O)C.[Na+].C(OCOCC)C.P(Cl)(Cl)(Cl)=O.[CH3:18][C:19]1[C:36](=[O:37])[CH2:35][CH2:34][C@@:33]2([CH3:38])[C:20]=1[CH2:21][CH2:22][C@@H:23]1[C@@H:32]2[CH2:31][CH2:30][C@@:28]2([CH3:29])[C@H:24]1[CH2:25][CH2:26][C:27]2=[O:39].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:18][C:19]1[C:36](=[O:37])[CH2:35][CH2:34][C@@:33]2([CH3:38])[C:20]=1[C:21](=[CH2:1])[CH2:22][C@@H:23]1[C@@H:32]2[CH2:31][CH2:30][C@@:28]2([CH3:29])[C@H:24]1[CH2:25][CH2:26][C:27]2=[O:39]
Reactant: CC(=O)[O-]
Reactant: CC1=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCOCC
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)C(C)=C12
Yield: 60 %

Procedure:
Alternatively, a mixture of androst-4-ene-3,17-dione, thiophenol, 40% aqueous formaldehyde, triethylamine and ethanol was heated under reflux for a period of about 48 hours. The cooled solution was poured onto an aqueous sodium hydroxide solution and the product isolated by ether extraction. The ether extracts were washed with water and dried over magnesium sulfate. The resulting residue was triturated with hexane to remove any condensation by-product derived from the thiophenol and formaldehyde. The 4-phenylthiomethylandrost-4-ene-3,17-dione so obtained was desulfurized by dissolving in acetone and adding to a suspension of Raney Nickel in refluxing acetone. The mixture was refluxed for about 5 hours under stirring. The hot solution was filtered and the catalyst washed with boiling ethanol and water. The combined filtrates were concentrated under vacuum whereupon the product separated as a solid mass. Recrystallization from acetone/hexane yielded 4-methylandrost-4-ene-3,17-dione. A mixture of sodium acetate (1 g), absolute chloroform (30 ml), formaldehyde diethyl acetal (30 ml, 0.24 mol), phosphoryl chloride (3.8 ml, 0.04 mol), and 4-methylandrost-4-ene-3,17-dione (0.81 g, 2.7 mmol) was refluxed for about 7 hours, i.e. until the starting material has disappeared. The suspension was allowed to cool and under vigorous stirring a saturated sodium carbonate solution was added dropwise until the pH of the aqueous layer became alcaline (~1 hour). The organic layer was separated, neutralized with water, and dried over sodium sulfate. After concentration under reduced pressure the oily residue was purified by chromatography on silica gel using hexane/ethylacetate as eluent. Thus the pure 4-methyl-6-methylenandrost-4-ene-3,17-dione was obtained in 60% yield; I.R. (KBr): 3080 (6=CH2), 1735 (17-oxo), 1665 (3-oxo), 1635, 1595 cm-1 (Δ4 and 6=CH2).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O.[NH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCCN1CCOCC1
Reactant: O=[N+]([O-])c1c(F)ccc(Br)c1Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1c(NCCN2CCOCC2)ccc(Br)c1Oc1ccccc1
Temperature: 20 °C
Reaction time: 24 h
Yield: 78.9 %

Procedure:
A solution of 1-bromo-4-fluoro-3-nitro-2-phenoxybenzene (0.057 g, 0.18 mmol) and cesium carbonate (0.0715 g, 0.220 mmol) in dimethyl sulfoxide (0.20 mL, 2.8 mmol) was treated with N-(2-aminoethyl)morpholine (0.0289 mL, 0.220 mmol) and stirred at 20° C. for 24 h, after which time the reaction mixture was diluted with water and ethyl acetate. Layers were separated and the organic layer was washed with brine, dried with magnesium sulfate, filtered, and concentrated in vacuo to give the crude product. Purification by flash column chromatography (100% hexanes to 100% EtOAc) gave the desired product (60 mg, 78%) a brown oil. LCMS calculated for C18H21BrN3O4 (M+H)+: m/z=422.1, 424.1. found: 422.1, 424.1.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N=C(N(C)C)N(C)C)(C)(C)C.[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]2[CH2:31][CH2:30][N:29]([C@H:32]3[CH2:36][CH2:35][N:34]([C:37]4[CH:42]=[C:41]([F:43])[C:40]([S:44](Cl)(=[O:46])=[O:45])=[C:39]([F:48])[CH:38]=4)[C:33]3=[O:49])[CH2:28]2)[CH:23]=[C:24]([Cl:26])[CH:25]=1>C(#N)C.CS(C)=O>[Cl:26][C:24]1[CH:23]=[C:22]([CH:27]2[CH2:31][CH2:30][N:29]([C@H:32]3[CH2:36][CH2:35][N:34]([C:37]4[CH:42]=[C:41]([F:43])[C:40]([S:44]([NH:1][C:2]5[S:3][CH:4]=[CH:5][N:6]=5)(=[O:45])=[O:46])=[C:39]([F:48])[CH:38]=4)[C:33]3=[O:49])[CH2:28]2)[CH:21]=[C:20]([Cl:19])[CH:25]=1
Reactant: O=C1[C@@H](N2CCC(c3cc(Cl)cc(Cl)c3)C2)CCN1c1cc(F)c(S(=O)(=O)Cl)c(F)c1
Reactant: Nc1nccs1
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CS(C)=O
Solvent: CC#N
Product: O=C1[C@@H](N2CCC(c3cc(Cl)cc(Cl)c3)C2)CCN1c1cc(F)c(S(=O)(=O)Nc2nccs2)c(F)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Synthesized according to General Procedure 12, Method B. To a solution of 2-aminothiazole (35 mg, 0.35 mmol) in acetonitrile (0.4 mL) at 0° C. was added 2-tert-butyl-1,1,3,3-tetramethylguanidine (61 mg, 0.35 mmol) dropwise and the reaction mixture stirred at 0° C. for 10 min. 4-[(3′S)-3-(3,5-dichlorophenyl)-2′-oxo-1,3′-bipyrrolidin-1′-yl]-2,6-difluorobenzene-1-sulfonyl chloride (60 mg, 0.12 mmol) was added and the reaction mixture was stirred at RT for 16 hours. The reaction mixture was diluted with DMSO, filtered and purified by reverse phase HPLC using 5%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to afford 4-[(3′S)-3-(3,5-dichlorophenyl)-2′-oxo-1,3′-bipyrrolidin-1′-yl]-2,6-difluoro-N-(thiazol-2-yl)benzenesulfonamide. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=573.3; tR=1.32 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:12][CH2:13][CH2:14][Cl:15]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:12][CH2:13][CH2:14][Cl:15])[CH:3]=1
Reactant: ClCCCBr
Reactant: Oc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: ClCCCOc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.6 %

Procedure:
To 3-bromophenol (2.23 g, 12.9 mmol) in DMF (100 mL) was added, in small portions, sodium hydride (60% dispersion, 0.54 g, 13 mmol) over 30 min. 1-Bromo-3-chloropropane (2.1 g, 13 mmol) was then added dropwise and the mixture was stirred at r.t. for 24 h. It was then partitioned between ether and water, the organic phase was washed with water and brine, dried (anhydrous MgSO4) and concentrated to afford 1-bromo-3-(3-chloropropoxy)benzene (362, 2.95 g, 91% yield) (used as is with no additional purification).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]=O)[C:21]3[C:20](=[O:31])[N:19]([CH3:32])[C:18](=[O:33])[N:17]([CH3:34])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:36][OH:37].C([O-])(=O)C.[K+]>C(O)C.O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]=[N:36][OH:37])[C:21]3[C:20](=[O:31])[N:19]([CH3:32])[C:18](=[O:33])[N:17]([CH3:34])[C:16]=3[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: NO
Reactant: Cn1c(=O)c2c(nc(N3CCN(C(=O)OC(C)(C)C)CC3)n2-c2ccccc2C=O)n(C)c1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Cn1c(=O)c2c(nc(N3CCN(C(=O)OC(C)(C)C)CC3)n2-c2ccccc2C=NO)n(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-[7-(2-Formylphenyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (13 mg) and hydroxylamine hydrochloride (10 mg) were dissolved in ethanol (1 ml) and water (0.2 ml), and potassium acetate (ca. 10 mg) was added thereto. The reaction solution was stirred for 0.5 hour at room temperature, diluted with ethyl acetate, and washed with sodium bicarbonate aqueous solution. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 4-[7-[2-(hydroxyiminomethyl)phenyl]-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester. This was dissolved in dichloromethane (0.5 ml) and triethylamine (ca. 0.05 ml) and methanesulfonyl chloride (0.05 ml) were added thereto. The reaction mixture was stirred at room temperature for 0.5 hour, and the solvent was removed. The residue was dissolved in trifluoroacetic acid, and the solution was concentrated. The residue was purified by reversed phase high performance liquid chromatography to give 4.14 mg of the title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)(=[O:4])=[O:3].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C@@H:24]([O:27][C:28]2[CH:29]=[N:30][C:31](Cl)=[CH:32][CH:33]=2)[C@H:23]([F:35])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C@@H:24]([O:27][C:28]2[CH:29]=[N:30][C:31]([N:10]3[C:11]4[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=4)[CH:8]=[CH:9]3)=[CH:32][CH:33]=2)[C@H:23]([F:35])[CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CS(=O)(=O)c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc(Cl)nc2)[C@H](F)C1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc(-n3ccc4cc(S(C)(=O)=O)ccc43)nc2)[C@H](F)C1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using 5-(methylsulfonyl)-1H-indole (intermediate-21) and trans(±)-tert-butyl-4-((6-chloropyridin-3-yl)oxy)-3-fluoropiperidine-1-carboxylate (intermediate-63) (0.220 g, 37%).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[C:12]([N+:15]([O-])=O)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].O.NN>CO.[Fe](Cl)(Cl)Cl>[CH3:20][N:2]([CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[C:12]([NH2:15])[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:1]
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CN(C)C)CC2
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: CO
Solvent: O
Product: COc1cc2c(cc1N)N(C(=O)CN(C)C)CC2
Temperature: 65 °C
Yield: 69.5 %

Procedure:
A suspension of N,N-dimethyl-2-[5-(methyloxy)-6-nitro-2,3-dihydro-1 H-indol-1-yl]-2-oxoethanamine (26.6 g, 95 mmol), iron(III)chloride (3.09 g, 19.05 mmol), activated carbon (25 g, 95 mmol), and hydrazine hydrate (37.4 mL, 762 mmol) in methanol (500 mL) was warmed to 65° C. and maintained overnight. The reaction was filtered through celite while still warm and all methanol was removed under reduced pressure. The solids were partitioned between ethyl acetate (ca 1 L) and saturated sodium chloride (ca 1 L) and the aqueous layer was washed twice with ethyl acetate (ca 500 mL). The combined organic layers were dried over sodium sulfate, taken to a residue under reduced pressure, and the derived solids triturated with hexanes/diether ether and filtered to afford 1-[(dimethylamino)acetyl]-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine (16.46 g, 69.3% yield) as an off-white solid: NMR: 1H NMR (400 MHz, DMSO-d6) δ ppm 2.23 (s, 6 H), 2.95 (t, J=8.25 Hz, 2 H), 3.11 (s, 2H), 3.69 (s, 3 H), 4.07 (s, 2 H), 4.61 (s, 2 H), 6.68 (s, 1 H), 7.53 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[K+].[CH3:13]I>CC(C)=O.C(OCC)(=O)C>[CH3:13][N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH2:1]
Reactant: Nc1nc2ccccc2[nH]1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Cn1c(N)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-aminobenzimidazole (3.0 g, 0.0225 mol) in acetone (30 ml) was added KOH (6.32 g, 0.112 mol) followed by methyl iodide (3.51 g, 0.025 mol) and stirred at room temperature for 10 min. The reaction mixture was diluted with ethyl acetate and the organic layer washed with water, brine and dried over anhydrous Na2SO4 to afford crude residue which was column purified to yield the desired product: 1H NMR (300 MHz, DMSO-d6) δ 3.47 (s, 3H), 6.34 (br s, 2H), 6.82-6.92 (m, 2H), 7.06-7.09 (m, 2H); ESI-MS (m/z) 148.49 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:4](OC)=[O:5].[CH3:14][NH:15][CH3:16]>C(O)C>[CH3:1][O:2][CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:4]([N:15]([CH3:16])[CH3:14])=[O:5]
Reactant: COC(=O)C(OC)c1ccccn1
Reactant: CNC
Solvent: CCO
Product: COC(C(=O)N(C)C)c1ccccn1

Procedure:
A mixture of 18.1 g. of methyl 2-methoxy-2-(2-pyridyl)acetate and 10 g. of dimethylamine in ethanol is stirred at room temperature for 26 hours. The mixture is concentrated, dissolved in chloroform and extracted with brine. The organic phase is dried over magnesium sulfate and filtered and the solvent is removed under reduced pressure to give 2-methoxy-N,N-dimethyl-2-(2-pyridyl)acetamide.