Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:8][CH2:9][CH3:10])(=[O:7])/[CH:4]=[CH:5]/[CH3:6].CC1C=CC(S([CH2:21][N:22]=C)(=O)=O)=CC=1.[CH2:24](OCC)C>CS(C)=O>[CH2:9]([O:8][C:3]([C:4]1[C:5]([CH3:24])=[CH:6][NH:22][CH:21]=1)=[O:7])[CH3:10]
Reactant: CCOCC
Reactant: C=NCS(=O)(=O)c1ccc(C)cc1
Reactant: C/C=C/C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)c1c[nH]cc1C
Yield: 78 %

Procedure:
To a suspension of sodium hydride (4 g of 60% dispersion, 2 eq, washed with diethyl ether) in diethyl ether (200 mL), cooled in an ice bath with stirring was added slowly a solution of ethyl crotonate (6.2 mL, 50 mmol) and p-tosylmethyl isocyanide (9.7 g, 50 mmol) in 80 mL of DMSO and 160 mL diethyl ether. Upon complete addition of the solution, the reaction mixture was stirred at room temperature for 1 hr. The reaction was quenched with 400 mL water and extracted into diethyl ether (2×100 mL), dried (MgSO4) and concentrated to afford 6 g (78%) of 4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester as a brown oil which solidified upon standing.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([CH2:33][NH-:34])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([CH2:33][NH:34][S:16]([C:14]2[S:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: CC(C)(C)OC(=O)N1CCC(C[NH-])CC1
Product: CCc1cc(-c2ccc(S(=O)(=O)NCC3CCN(C(=O)OC(C)(C)C)CC3)s2)c(C)[nH]c1=O
Yield: 54 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with (1-tert-butyloxycarbonylpiperidin-4-yl)methylamide as described in Step 5, Example 24 to give the title compound as a solid (54% yield). LC/MS: RT 3.09 min; m/e 496 (M+H); 1H NMR (CDCl3, δ, ppm): 12.19 (1H, br s), 7.56 (1H, d), 7.29 (1H, s), 6.94 (1H, d); 5.15 (1H, t); 4.16 (2H, br t), 3.00 (2H, t), 2.71 (2H, br m), 2.58 (2H, q), 2.45 (3H, s), 1.66 (2H, br m), 1.45 (9H, s), 1.24 (3H, t).
Reaction SMILES: [CH2:1]([N:3]1CN(C)C[N:5]([C:10]2[S:11][C:12]3[C:18]([C:19]4[CH:24]=[C:23]([CH2:25][N:26]5[CH2:29][C:28]([OH:31])([CH3:30])[CH2:27]5)[CH:22]=[CH:21][N:20]=4)=[CH:17][C:16]([C:32]4[CH:33]=[N:34][C:35]([C:38]([OH:41])([CH3:40])[CH3:39])=[N:36][CH:37]=4)=[CH:15][C:13]=3[N:14]=2)[C:4]1=[O:42])[CH3:2].Cl>CO.C(Cl)Cl>[CH2:1]([NH:3][C:4]([NH:5][C:10]1[S:11][C:12]2[C:18]([C:19]3[CH:24]=[C:23]([CH2:25][N:26]4[CH2:27][C:28]([OH:31])([CH3:30])[CH2:29]4)[CH:22]=[CH:21][N:20]=3)=[CH:17][C:16]([C:32]3[CH:33]=[N:34][C:35]([C:38]([OH:41])([CH3:40])[CH3:39])=[N:36][CH:37]=3)=[CH:15][C:13]=2[N:14]=1)=[O:42])[CH3:2]
Reactant: CCN1CN(C)CN(c2nc3cc(-c4cnc(C(C)(C)O)nc4)cc(-c4cc(CN5CC(C)(O)C5)ccn4)c3s2)C1=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCNC(=O)Nc1nc2cc(-c3cnc(C(C)(C)O)nc3)cc(-c3cc(CN4CC(C)(O)C4)ccn3)c2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.4 %

Procedure:
An ice-cold solution of ii (0.25 g, 0.42 mmol) in MeOH-DCM (0.50 and 10 mL respectively) was purged with HCl (g) for 10 min and the mixture stirred at RT for 16 h. The solvent was evaporated and the residue triturated with a mixture of MeOH and Et2O to obtain Compound 2 (0.225 g, 90%).
Reaction SMILES: [CH2:1]([N:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:9][CH2:10][N:11]1[C:16]2[CH:17]=C(C#N)[C:19]([F:21])=[CH:20][C:15]=2[O:14][C:13]([CH3:25])([CH3:24])[C:12]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O.[C:36]([OH:39])(=[O:38])[CH3:37]>>[CH2:1]([N:8]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:37]([C:36]([OH:39])=[O:38])[C:19]([F:21])=[CH:20][C:15]=2[O:14][C:13]([CH3:25])([CH3:24])[C:12]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)Oc2cc(F)c(C#N)cc2N(CCN(Cc2ccccc2)Cc2ccccc2)C1=O
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: CC1(C)Oc2cc(F)c(C(=O)O)cc2N(CCN(Cc2ccccc2)Cc2ccccc2)C1=O

Procedure:
4-[2-(Dibenzylamino)ethyl]-7-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile (588 mg) was dissolved in acetic acid (5 ml), and thereto was added conc. hydrochloric acid (5 ml), and the mixture was refluxed for 75 hours. The reaction solution was cooled, and thereto was added water, and filtered. The solid collected by filtration was washed with water and dried at 70° C. for 18 hours to give the title compound (406 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][NH:3]1.[OH-].[Na+].Cl[C:8]([CH2:10][CH2:11][O:12][C:13](=[O:16])[CH:14]=[CH2:15])=[O:9]>O.C(Cl)Cl>[CH3:1][CH:2]1[CH2:4][N:3]1[C:8](=[O:9])[CH2:10][CH2:11][O:12][C:13](=[O:16])[CH:14]=[CH2:15]
Reactant: CC1CN1
Reactant: C=CC(=O)OCCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)OCCC(=O)N1CC1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To a stirred 0° C. solution of 2-methylaziridine (5.1 g, about 80 mmol, 90% pure, available from Aldrich) and NaOH (3.6 g, 90 mmol) in a mixture of 50 mL of water and 25 mL of methylene chloride was added dropwise a solution of acrylic acid-2-chlorocarbonylethyl ester (11.6 g, 59 mmol) in 25 mL of methylene chloride. When the addition was complete, the reaction flask was removed from the ice bath and the reaction mixture was allowed to warm to room temperature and was stirred overnight. The phases were then separated and the methylene chloride phase was washed once with 25 mL of water, dried over K2CO3, filtered, and solvent removed at reduced pressure to leave 8.1 g of acrylic acid-3-(2-methylaziridin-1yl)-3-oxopropyl ester as a colorless oil. NMR and IR spectral analyses confirmed the structure of the product.
Reaction SMILES: [NH2:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][O:4]1.C(N(CC)CC)C.[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24]>C(Cl)Cl.CCOC(C)=O>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][O:4]1)=[O:24]
Reactant: O=C(Cl)CCCCCCBr
Reactant: NOC1CCCCO1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(CCCCCCBr)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.9 %

Procedure:
to a solution of H2N-OTHP (1.0 g, 8.54 mmol) and triethylamine (2.46 g, 24.39 mmol) in CH2Cl2 (20 mL) was added a solution of 7-bromoheptanoyl chloride (1.84 g, 8.13 mmol) obtained above in CH2Cl2 (10 mL) dropwise cooling in an ice-water bath. The mixture was stirred at room temperature for 1 h. It was diluted with EtOAc and washed with aqueous saturated NaHCO3, water, and brine, before being dried over MgSO4. Filtration and concentration in vacuo and purification by silica gel flash chromatography (n-hexane/EtOAc=3/1) gave 1.3 g (52%) of 7-bromo-N-(tetrahydro-2H-pyran-2-yloxy)-heptanamide as yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][N:3]=1.Cl.[CH3:18][NH:19][O:20][CH3:21].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:21][O:20][N:19]([CH3:18])[C:14]([C:8]1([C:5]2[CH:6]=[N:7][C:2]([CH3:1])=[N:3][CH:4]=2)[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)=[O:16]
Reactant: CNOC
Reactant: Cc1ncc(C2(C(=O)O)CCOCC2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1(c2cnc(C)nc2)CCOCC1
Yield: 62.8 %

Procedure:
A solution of 4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-carboxylic acid (4.0 g, 18.02 mmol), N,O-dimethylhydroxylamine hydrochloride (2.1 g, 21.6 mmol), HOBt (2.92 g, 21.6 mmol), EDCI.HCl (4.15 g, 21.62 mmol) and DIPEA (15.6 mL, 90.1 mmol) in DMF (50 mL) was stirred at room temperature overnight. To the reaction mixture was added water and extracted with EtOAc (3×200 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated to give crude product, which was purified by flash column chromatography (EtOAc:petroleum ether=1:1) to give N-methoxy-N-methyl-4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-carboxamide (3.0 g, yield: 63%). 1H NMR (CDCl3 400 MHz): δ8.55 (s, 2H), 3.90-3.75 (m, 4H), 3.14 (s, 3H), 2.95 (s, 3H), 2.72 (s, 3H), 2.55-2.45 (m, 2H), 2.06-1.95 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10](=[O:19])[N:11]=[C:12]3[CH:17]=[C:16](C)[CH:15]=[CH:14][C:13]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1.[Br:32]Br.S(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:32][CH:9]1[CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10]1=[O:19]
Reactant: BrBr
Reactant: Cc1ccc2c(-c3ccccc3)ccc(=O)nc2c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1Nc2ccccc2C(c2ccccc2)CC1Br
Temperature: -70 °C
Reaction time: 2 h
Yield: 49.2 %

Procedure:
To a 200 mL three neck round-bottomed flask equipped with a nitrogen inlet and septum were added 5.48 grams (21.8 mmol) 5-phenyl-8-methyl-2-oxobenzazepine, 100 mL dichloromethane, and 4.55 grams (21.8 mmol) phosphorus pentachloride. After dissolution, 1.85 mL (22.9 mmol) pyridine was added, and the solution cooled to -70° C. To the stirring solution (some precipitate appeared at this temperature, but did not affect the reaction) was added a solution of 1.12 mL (21.8 mmol) bromine in 10 mL methylene chloride dropwise over 20 minutes. The reaction was then allowed to warm quickly (10 minutes) to 0° C., and 50 mL of saturated aqueous sodium bisulfite solution was added. The reaction was then diluted with methylene chloride and allowed to stand under sodium bisulfite solution with periodic shaking for 2 hours, until the organic phase no longer exhibited a reddish color. The organic phase was then dried over sodium sulfate and evaporated. The residue was suspended in methylene chloride and filtered, and the solid dissolved to afford 3.39 grams (47%) of product as a white solid. The filtrate was adsorbed onto silica gel and chromatographed using 7:3 hexane/ethyl acetate as eluant to afford additional product as a white solid, 1.38 g, total 5.14 (71%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[S:15])=[CH:9][CH:8]=2)[CH:6]=1.Br[CH:18]([CH3:29])[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([Cl:28])[CH:22]=1)=O>>[Cl:28][C:23]1[CH:22]=[C:21]([C:19]2[N:16]=[C:14]([NH:13][C:10]3[CH:9]=[CH:8][C:7]([N:5]4[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]4)=[CH:12][CH:11]=3)[S:15][C:18]=2[CH3:29])[CH:26]=[CH:25][C:24]=1[CH3:27]
Reactant: Cc1ccc(C(=O)C(C)Br)cc1Cl
Reactant: Cc1cn(-c2ccc(NC(N)=S)cc2)cn1
Product: Cc1cn(-c2ccc(Nc3nc(-c4ccc(C)c(Cl)c4)c(C)s3)cc2)cn1
Yield: 67.7 %

Procedure:
Prepared in analogy to example 64d) from 100 mg (0.43 mmol) [4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (example 72c)) and 124 mg (0.47 mmol) 2-bromo-3′-chloro-4′-methylpropiophenone. 115 mg (68%) of the product was isolated as a colorless solid. MS ISP (m/e): 395.1 (100) (M+H)+. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.50 (s, 1H), 9.47 (s, 1H), 7.95 (s, 1H), 7.87 (d, 2H), 7.70-7.60 (m, 3H), 7.52 (d, 2H), 2.45 (s, 3H), 2.41 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: [NH4+].[N:2]#[C:3][S-:4].[Cl:5][C:6]1[CH:11]=[C:10]([C:12](Cl)=[O:13])[CH:9]=[C:8]([CH3:15])[N:7]=1.[F:16][C:17]1[CH:18]=[C:19]([NH2:24])[CH:20]=[CH:21][C:22]=1[F:23]>CC(C)=O>[Cl:5][C:6]1[CH:11]=[C:10]([C:12]([NH:2][C:3]([NH:24][C:19]2[CH:20]=[CH:21][C:22]([F:23])=[C:17]([F:16])[CH:18]=2)=[S:4])=[O:13])[CH:9]=[C:8]([CH3:15])[N:7]=1
Reactant: Nc1ccc(F)c(F)c1
Reactant: Cc1cc(C(=O)Cl)cc(Cl)n1
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CC(C)=O
Product: Cc1cc(C(=O)NC(=S)Nc2ccc(F)c(F)c2)cc(Cl)n1
Reaction time: 0.5 h

Procedure:
Thiocyanic acid ammonium salt (10.6 g) was added to a mixture of 2-chloro-6-methyl-4-pyridinecarbonyl chloride (22.04 g; 116 mmol) and acetone (400 ml). The reaction mixture was stirred for 30 minutes and then 3,4-difluorobenzenamine (14.98 g; 116 mmol) was added slowly via an additional funnel. The resulting solution was stirred for 2 hours, quenched by water (100 ml) and then extracted by CH2Cl2 (3×100 ml). The combined organic phase was dried over MgSO4, filtered and the solvent was evaporated in vacuo. Yield: 38.1 g of intermediate D1.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2].[H-].[Na+].Cl[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21].O>CN(C)C=O>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])([O-:3])=[O:2].[N+:1]([C:4]1[C:5]2[C:9]([CH:10]=[CH:11][CH:12]=1)=[N:8][N:7]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:6]=2)([O-:3])=[O:2]
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc2c([N+](=O)[O-])cccc2n1
Product: C[Si](C)(C)CCOCn1ncc2c([N+](=O)[O-])cccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38 %
Yield: 42 %

Procedure:
To a solution of 4nitroindazole (2.55 g, 15.6 mmol) in anhydrous dimethylformamide (20 ml) at room temperature was added sodium hydride (902 mg, 37.6 mmol, 2.4 eq, 60% dispersion in oil) portionwise. This was allowed to stir at room temperature for 10 minutes. 2-(Chloromethoxy)ethyl-trimethylsilane (3.3 ml, 18.8 mmol, 1.2 eq) was added and the reaction stirred at room temperature for a further 90 minutes. Water (30 ml) was added and the reaction extracted into diethyl ether (2×50 ml). The combined organic layers were washed with brine (2×50 ml), the layers separated and the organic layer dried over MgSO4, filtered and evaporated. The resulting oil was purified by column chromatography on silica eluting with 20% ethyl acetate in isohexane, to give 4-nitro-1-{[2-trimethylsilylethoxy]methyl}-1H-indazole (1.74 g, 38%) as the less polar product and 4-nitro-2-{[2-trimethylsilylethoxy]methyl}-2H-indazole (1.93 g, 42%) as the more polar product. 1H NMR—1-Substituted isomer—(360 MHz, CDCl3) δ 0.00 (9H, s), 0.94 (2H, t, J 8.4), 3.63 (2H, t, J 8.2), 5.89 (2H, s), 7.62 (1H, t, J 8.0), 8.03 (1H, d, J 8.3), 8.26 (1H, d, J 7.7), 8.71 (1H, s).
Reaction SMILES: [C:1]([C@@](C(O)=O)(O)[C@@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][C@@:28]1([C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([F:62])[C:57]=2[F:63])[CH2:32][O:31][C@H:30]([CH2:33][O:34][C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@H:29]1[CH2:54][OH:55].[OH-].[Na+].C([N:73]=[C:74]=[S:75])C1C=CC=CC=1>CCOC(C)=O>[F:63][C:57]1[C:58]([F:62])=[CH:59][CH:60]=[CH:61][C:56]=1[C@@:28]1([NH:27][C:74]([NH:73][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[S:75])[C@H:29]([CH2:54][OH:55])[C@@H:30]([CH2:33][O:34][C:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[O:31][CH2:32]1
Reactant: O=C(O)[C@@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)O)C(=O)c1ccccc1
Reactant: S=C=NCc1ccccc1
Reactant: N[C@@]1(c2cccc(F)c2F)CO[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]1CO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C(NC(=S)N[C@@]1(c2cccc(F)c2F)CO[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]1CO)c1ccccc1
Temperature: 1.7000000476837158 °C
Reaction time: 0.08 h
Yield: 100.9 %

Procedure:
A suspension of ((2S,3R,4S)-4-amino-4-(2,3-difluorophenyl)-2-((trityloxy)methyl)tetrahydrofuran-3-yl)methanol (−)dibenzoyl-L-tartaric acid (44.21 g, 0.051 mol, 1.0 equiv.) in EtOAc (133 mL) was cooled down to 1.7° C. Aq. NaOH (1.0 M, 121 mL, 0.12 mol, 2.4 equiv.) was added while maintaining temperature below 5° C. The reaction was stirred for 5 min then benzyl isothiocyanate (9.43 g, 0.058 mol, 1.12 equiv.) was added over 5 min. After 1.5 h, EtOAc (133 mL) was added. The organic phase was isolated and successively washed with saturated aq. NaHCO3 (130 mL) and 18% aq.NaCl (44 mL). The combined aqueous phases were extracted with EtOAc (66 mL) and CH2Cl2 (30 mL). All the organic phase were combined, filtered and concentrated under reduced pressure. The title compound (34.2 g) was isolated as a foam after chasing the residual solvent with CH2Cl2 (88 mL). 1H NMR (500 MHz, DMSO) δ ppm 11.97 (br s, 1H), 11.20 (br s, 1H), 7.94 (d, J=7.4 Hz, 2H), 7.63 (t, J=7.4 Hz, 1H), 7.51 (t, J=7.8 Hz, 2H), 7.38-7.21 (m, 17H), 7.13 (dd, J=13.4, 7.9 Hz, 1H), 5.13 (t, J=4.4 Hz, 1H), 5.07 (d, J=9.7 Hz, 1H), 4.47 (d, J=9.8 Hz, 1H), 4.24-4.16 (m, 1H), 3.68 (t, J=4.6 Hz, 2H), 3.19 (dd, J=10.1, 2.9 Hz, 1H), 3.01 (dd, J=10.1, 4.8 Hz, 1H), 2.63-2.52 (m, 1H); 13C NMR (125 MHz, DMSO) δ ppm 180.06, 168.14, 150.75 (dd, JCF=244.6, 13.2 Hz), 147.93 (dd, JCF=247.5, 13.5 Hz), 144.15, 133.46, 132.55, 131.90 (d, JCF=6.4 Hz), 129.04, 128.86, 128.67, 128.28, 127.43, 124.41, 124.25, 116.12 (d, JCF=17.0 Hz), 86.27, 79.75, 75.03, 68.04, 64.63, 58.16, 53.35.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH2:35][CH3:36])[CH2:23]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:17][CH:16]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F-:37].[K+].C1N2CCOCCOCCN(CCOCCOCC2)CCOCCOC1>C(#N)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH2:35][CH3:36])[CH2:23][F:37])=[CH:17][CH:16]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [F-]
Reactant: CCC(COS(=O)(=O)c1ccc(C)cc1)Oc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Agent: C1COCCN2CCOCCOCCN(CCO1)CCOCCOCC2
Agent: [K+]
Solvent: CC#N
Product: CCC(CF)Oc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Reaction time: 1.5 h
Yield: 64.8 %

Procedure:
The product of Example 3F (28 mg, 52.4 μmol) was dissolved in 0.5 mL acetonitrile in a 5 mL flask and to this was added a solution of potassium fluoride (4.5 mg, 78.6 μmol) and Kryptofix 222 (29.6 mg, 78.6 μmol) in 0.5 mL acetonitrile. The above solution was then immersed in a oil bath preheated to 90° C. The reaction was allowed to stir for 90 minutes after which all the volatiles were removed under reduced pressure and the crude mixture purified by preparative thin layer chromatography to obtain 13 mg (65%) of pure desired compound. 1H (CDCl3) δ (ppm): 7.72 (s, 1H), 7.3 (d, 2H), 6.9 (d, 2H), 5.23 (s, 2H), 4.57-4.59 (m, 2H), 4.4 (m, 4H), 1.74 (m, 2H), 1.6 (s, 9H), 1.0 (t, 3H). 13C (CDCl3) δ (ppm): 159, 158.7, 153.7, 129, 127.5, 125.2, 118.3, 116.4, 83.85 (d, 1JCF=172.2), 78, 71.1, 66.3, 27.8, 23.2, 9.48. 19F (CDCl3, CFCl3 as internal standard) δ (ppm): −228 (d of t, J=−19, −60 Hz)
Reaction SMILES: CSC[C@@H](C(O)=O)NC(=O)C.C(N)C.[CH2:15]([S:17][CH2:18][C@@H:19]([C:24]([OH:26])=O)[NH:20][C:21](=[O:23])[CH3:22])[CH3:16].[CH2:27]([NH2:31])[CH2:28][CH2:29][CH3:30]>>[CH2:27]([NH:31][C:24](=[O:26])[C@H:19]([CH2:18][S:17][CH2:15][CH3:16])[NH:20][C:21](=[O:23])[CH3:22])[CH2:28][CH2:29][CH3:30]
Reactant: CCSC[C@H](NC(C)=O)C(=O)O
Reactant: CCCCN
Agent: CCN
Agent: CSC[C@H](NC(C)=O)C(=O)O
Product: CCCCNC(=O)[C@H](CSCC)NC(C)=O

Procedure:
S-Ethyl-N-acetyl-L-cysteine butylamide was synthesized in exactly the same manner as described in Example 14 except that the S-methyl-N-acetyl-L-cysteine and aqueous 70% ethylamine solution used in that example was replaced by S-ethyl-N-acetyl-L-cysteine and n-butylamine, respectively.
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[N:11]1([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:4][N:3]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: C1CNCCN1
Reactant: Clc1n[nH]c2ccccc12
Product: c1ccc2c(N3CCNCC3)n[nH]c2c1
Temperature: 250 °C

Procedure:
A neat mixture of 3-chloroindazole (15.72 g, 0.103 mol) and piperazine (46.00 g, 0.534 mol) was heated at 250° C. for 14 h in a stainless steel sealed vessel Upon cooling to room temperature, the viscous residue was partitioned between 1.0 N aqueous NaOH and methylene chloride. The organic layer was dried over magnesium sulfate, filtered, and the filtrate treated with 4.1 N HCl in dioxane which resulted in the precipitation of both products as a greenish-yellow gummy residue. The gum was collected and taken up in water where it was observed that the disubstituted piperazine precipitated out of solution. The precipitate was filtered off and the filtrate was concentrated in vacuo to give exclusively the monosubstituted piperazine, 3-piperazin-1-yl-1H-indazole, as a green foam. Yield, 19.03 g (77%). MS (APCI): 203 [M+H]+, 201 [M-H]−.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][CH2:3][C@@H:2]1/[CH:11]=[N:12]\[S@:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14].C1(C)C=CC=CC=1.[Cl:26][C:27]1[CH:28]=[C:29]([Mg]Br)[CH:30]=[CH:31][C:32]=1[Cl:33]>O>[Cl:26][C:27]1[CH:28]=[C:29]([C@@H:11]([C@H:2]2[CH2:3][O:4][C:5]3([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)[O:1]2)[NH:12][S@:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])[CH:30]=[CH:31][C:32]=1[Cl:33]
Reactant: Clc1ccc([Mg]Br)cc1Cl
Reactant: CC(C)(C)[S@](=O)/N=C\[C@H]1COC2(CCCCC2)O1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)[S@](=O)N[C@@H](c1ccc(Cl)c(Cl)c1)[C@H]1COC2(CCCCC2)O1
Temperature: 0 °C
Yield: 58.7 %

Procedure:
To a solution of 248 (2.0 g, 7.3 mmol) and toluene (30 mL) cooled to −78° C. was added (3,4-dichlorophenyl)magnesium bromide (29 mL, 15 mmol) and warmed to 0° C. for 30 min. The reaction was poured into water and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with a hexane/EtOAc gradient (4:1 to 1:1) to afford 1.8 g (59%) of (S)—N—((S)-(3,4-dichlorophenyl)((S)-1,4-dioxaspiro[4.5]decan-2-yl)methyl)-2-methylpropane-2-sulfinamide (250) which appears to be a ca. 10:1 mixture of diastereomers by 1H NMR.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[CH:8]=2)[NH:3]1.C1COCC1.[CH3:21][O:22][CH2:23][C@@H:24]1[CH2:28][CH2:27][CH2:26][NH:25]1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[CH3:21][O:22][CH2:23][C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[S:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:1])[C:10]2=[O:11])(=[O:14])=[O:13]
Reactant: COC[C@@H]1CCCN1
Reactant: O=C1Nc2ccc(S(=O)(=O)Cl)cc2C1=O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2
Reaction time: 0.33 h
Yield: 92.9 %

Procedure:
To a cold suspension of 2,3-dioxo-2,3-dihydro-1H-indole-5-sulfonylchloride (5.28 g, 21.5 mmol) in a 1:1 mixture of THF:CHCl3 (254 mL) was added drop-wise via syringe pump a solution of (S)-(+)-2-(methoxymethyl)-pyrrolidine (3.45 mL, 28.0 mmol, 1.3 eq) (Aldrich) and N,N-diisopropylethylamine (7.49 mL, 43 mmol, 2 eq) in CHCl3 (42 mL) over a period of 70 minutes under a dry N2 atmosphere with cooling in an ice bath. After stirring an additional 20 minutes the mixture was concentrated. The residue was flash chromatographed (Biotage KP silica gel, 98/2 CH2Cl2/CH3OH) to give the title compound as a dark greenish-yellow foam (6.48 g. 93% yield). NMR (400 MHz, DMSO-d6): consistent MS: (API-ES−) m/z 323 [M−H].