Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]#[C:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:26])=[CH:10][CH:11]=3)[N:6]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.C1C=CC(N[S:45]([C:48]([F:51])([F:50])[F:49])(=[O:47])=[O:46])=CC=1>O>[F:49][C:48]([F:51])([F:50])[S:45]([O:26][C:9]1[CH:8]=[C:7]2[C@@:5]3([CH2:4][O:3][C:2]([NH2:1])=[N:6]3)[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]#[C:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH:18]=3)[O:13][C:12]2=[CH:11][CH:10]=1)(=[O:47])=[O:46]
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Reactant: CC(C)(C)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(O)ccc1O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(OS(=O)(=O)C(F)(F)F)ccc1O2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 66.4 %

Procedure:
A vial charged with (S)-2′-amino-3-(3,3-dimethylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol (0.200 g, 0.572 mmol) and potassium carbonate (0.087 g, 0.630 mmol) was treated with 2 mL DMF and was allowed to stir for 15 minutes. The reaction mixture was cooled to 0° C. and n-phenyltriflamide (0.245 g, 0.630 mmol) was added. After stirring for one hour the reaction mixture was poured into water and extracted with EtOAc. The organics were dried over MgSO4 and concentrated. Purification of the crude residue by column chromatography gave (S)-2′-amino-3-(3,3-dimethylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl trifluoromethanesulfonate (0.183 g, 0.380 mmol, 66.4% yield)
Reaction SMILES: Cl.Cl.Cl.[NH2:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]2[N:13]=[C:14]([N:17]=[C:18]([NH2:20])[NH2:19])[S:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=1.[CH2:21]([N:23](CC)CC)C.[CH2:28]([S:30](C(=N)OCC)(=[O:32])=[O:31])[CH3:29]>CO>[NH2:19][C:18](=[N:17][C:14]1[S:15][CH:16]=[C:12]([C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([CH2:5][NH:4][CH:21]=[N:23][S:30]([CH2:28][CH3:29])(=[O:31])=[O:32])[N:11]=2)[N:13]=1)[NH2:20]
Reactant: NCc1cccc(-c2csc(N=C(N)N)n2)n1
Reactant: CCOC(=N)S(=O)(=O)CC
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CO
Product: CCS(=O)(=O)N=CNCc1cccc(-c2csc(N=C(N)N)n2)n1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
A mixture of 4-(6-aminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole trihydrochloride (3.0 g), triethylamine (3.5 ml) and ethyl ethanesulfonylformimidate (1.5 g) in methanol (60 ml) was stirred at ambient temperature for 6.5 hours and after solvent was removed by concentration in vacuo. To the residue was added a mixture of tetrahydrofuran, ethyl acetate and water and the mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate. The separated organic layer was washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (9:1, V/V). The eluted fractions containing the desired product were collected and evaporated in vacuo. The residue was recrystallized from a mixture of methanol, dioxane and diisopropyl ether to give 2-(diaminomethyleneamino)-4-(6-ethanesulfonyliminomethylaminomethylpyridin-2-yl)thiazole (0.88 g).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][C:15]([F:18])([F:17])[F:16])[CH:11]=2)[N:6]1[C:19](=[O:31])[C@@H:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][CH3:22])=[O:4].[OH-].[Na+].ClCCl>CO.O>[C:27]([O:26][C:24]([NH:23][C@@H:20]([CH2:21][CH3:22])[C:19]([N:6]1[C:7]2[C:12](=[CH:11][C:10]([O:14][C:15]([F:18])([F:16])[F:17])=[CH:9][CH:8]=2)[CH2:13][CH:5]1[C:3]([OH:4])=[O:2])=[O:31])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(OC(F)(F)F)cc2CC1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(OC(F)(F)F)cc2CC1C(=O)O
Temperature: 7.5 °C
Reaction time: 4 h

Procedure:
To the solution of 1-(N-t-butoxycarbonyl-2(S)-aminobutyryl)-5-trifluoromethoxyindoline-2(R/S)-carboxylic acid methyl ester (1.0 g, 2.24 mmol) in methanol (15 ml), was added sodium hydroxide (0.134 g, 3.36 mmol) in water (10 ml). The solution was stirred at 5 to 10° C. for 4 hours. The mixture was poured into dichloromethane (40 ml), and washed with cold potassium hydrogen sulphate (3×20 ml), and water (20 ml). The organic layer was dried over sodium sulphate, and evaporated to provide a white foam which was pure enough for the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[C:33](=[O:35])=[O:34].Cl>C(OCC)(=O)C.O.C1COCC1>[Si:11]([O:10][CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:33]([OH:35])=[O:34])([C:24]([CH3:25])([CH3:26])[CH3:27])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)[Si](OCCc1cccc(Br)c1)(c1ccccc1)c1ccccc1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OCCc1cccc(C(=O)O)c1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 3.27 g of [2-(3-bromophenyl)ethoxy](tert-butyl)diphenylsilane and 50 mL of THF was slowly added 5.5 mL of butyllithium (1.62 M hexane solution) at −78° C., followed by stirring for 30 minutes at −78° C. In addition, carbon dioxide was blown into the reaction mixture at −78° C., and the temperature thereof was slowly increased to room temperature, followed by stirring for 1 hour at room temperature. Water was added to the reaction mixture, and the mixture was neutralized with 9.0 ml of 1.0 M hydrochloric acid. Ethyl acetate was added thereto to separate the organic layer, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:6), thereby obtaining 1.45 g of 3-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)benzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[F:11][C:12]([F:16])([F:15])[CH2:13][NH2:14]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:14][CH2:13][C:12]([F:16])([F:15])[F:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1cccc(Br)c1
Reactant: NCC(F)(F)F
Solvent: C1CCOC1
Product: O=C(NCC(F)(F)F)Nc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.9 %

Procedure:
3-Bromophenyl isocyanate (1.0 ml, 8.1 mmol) was added slowly to a stirred solution of 2,2,2-trifluoroethyl amine (3.2 ml, 40 mmol) in THF (10 ml) at 0° C. under N2. After 1 hour the reaction was allowed to warm to RT and kept at this temperature for 16 hours. The volatiles were removed in vacuo to give the title compound (2.5 g, solid). 1H NMR (400 MHz, DMSO-d6): 9.00 (1H, s), 7.86 (1H, t), 7.33 (1H, ddd), 7.26 (1H, t), 7.18 (1H, ddd), 6.89 (1H, t), 4.03-3.92 (2H, m).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([S:14][CH3:15])[C:11]2[C:6](=[CH:7][C:8]([Cl:16])=[CH:9][CH:10]=2)[N:5]=1)([OH:3])=O.[CH2:17]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]([CH:30]([NH2:40])[CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:29])[CH2:24][CH2:23]1)=[O:21])[CH3:18].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C1COCC1.CN(C=O)C.C(OCC)(=O)C>[CH2:17]([O:19][C:20]([N:22]1[CH2:23][CH2:24][N:25]([C:28]([CH:30]([NH:40][C:1]([C:4]2[CH:13]=[C:12]([S:14][CH3:15])[C:11]3[C:6](=[CH:7][C:8]([Cl:16])=[CH:9][CH:10]=3)[N:5]=2)=[O:3])[CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:29])[CH2:26][CH2:27]1)=[O:21])[CH3:18]
Reactant: CSc1cc(C(=O)O)nc2cc(Cl)ccc12
Reactant: CCOC(=O)N1CCN(C(=O)C(N)CCC(=O)OC(C)(C)C)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c2cc(SC)c3ccc(Cl)cc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
To a solution of 2-carboxy-7-chloro-4-mercaptoquinoline HCl salt (75 mg, 0.31 mmol) in DMF (3 mL) was added MeI (0.0425 mL, 2.5 eq.) and cesium carbonate (340 mg, 3.5 eq.). The resulting reaction mixture was stirred at 70° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with water, brine, and dried over sodium sulfate. The solvent was evaporated. Flash column chromatograpgy with 1%–2% MeOH in methylene chloride afforded 2-(methoxycarbonyl)-7-chloro-4-methylthioquinoline (40 mg). To 2-(methoxycarbonyl)-7-chloro-4-methylthioquinoline (40 mg) was added THF:H2O (2:1, 2 mL) and LiOH (10 mg, 1.5 eq.). The reaction mixture was stirred for 2 hours. The pH was adjusted to pH 4.5 with 1N HCl. Extraction with ethyl acetate, washing with brine, drying over sodium sulfate and evaporation gave 2-carboxy-7-chloro-4-methylthioquinoline (29 mg). To a solution of 2-carboxy-7-chloro-4-methylthioquinoline (29 mg) in THF (6 mL) and DMF (1 mL) was added 4-ethoxycarbonyl-1-(1-amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine (46 mg, 1.1 eq.), EDCl (28 mg, 1.2 eq.), and HOBt (18 mg, 1.1 eq.). The resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was evaporated in vacuo to afford a crude product, which was dissolved in ethyl acetate, washed with saturated NaHCO3, 1M NaHSO4 and brine. The organic layer was evaporated. Flash column chromatography with 1%–3% MeOH in CH2Cl2 afforded the product, 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-7-chloro-4-(methylthio)quinoline (36 mg). The product (32 mg) was treated with TFA:CH2Cl2 (1:1, 1 mL) at ambient temperature for 2 hours. The solvents were then evaporated to afford the desired product, 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-chloro-4-(methylthio)quinoline; NMR (CDCl3) 1.35 (t, 3), 2.10 (m, 1), 2.25 (m, 1), 2.55 (m, 2), 2.7 (s, 3), 3.4–3.9 (m, 8), 4.2 (q, 2), 5.3 (m, 1), 7.55 (d, 1), 7.9 (s, 1), 8.02 (d, 1), 8.15 (s, 1) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].Cl.[N:13]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[CH3:22][C:23]([SH:26])([CH3:25])[CH3:24]>O>[C:23]([S:26]/[N:13]=[N:1]/[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6])([CH3:25])([CH3:24])[CH3:22]
Reactant: O=N[O-]
Reactant: CC(C)(C)S
Reactant: Cc1ccc(C(=O)O)cc1N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C(=O)O)cc1/N=N/SC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-amino-4-methyl benzoic acid (5.0 g) in water (50 mL) was added concentrated hydrochloric acid (15 mL). The mixture was chilled to 0° C. in an ice/acetone bath. Sodium nitrite (2.28 g) was dissolved in water (10 mL) and slowly added to the mixture at 0° C. The pH was adjusted to 6 with saturated sodium acetate and 2-methyl-2-propanethiol (1.8 mL) was added. The mixture was stirred for 1 h and the resulting solids were collected by filtration, washed with water and dried under reduced pressure to give 5.7 g of the title compound: 1H NMR (CDCl3) δ 1.61, 2.20, 7.38, 7.55, 9.67.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].Cl>CN(C)C(=O)C>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([C:26]1[CH:27]=[CH:28][C:29]([NH:32][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:30][CH:31]=1)(=[O:24])=[O:25]
Reactant: COc1ccccc1S(=O)(=O)c1ccc(N)cc1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: COc1ccccc1S(=O)(=O)c1ccc(NC(=O)C(C)(O)C(F)(F)F)cc1
Reaction time: 1 h

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.42 g, 9.0 mmol) in N,N-dimethylacetamide (13 mL) was added thionyl chloride (1.13 g, 9.5 mmol) and the mixture stirred at -15° to -5° C. for 1 hour. 4-(2-Methoxyphenyl)sulfonyl-benzeneamine (1.58 g, 6.0 mmol) was added in one portion and the reaction mixture stirred at room temperature overnight. The mixture was poured into 250 mL of 0.5N HCl. The clear supernatient was decanted from the resulting gum. The gum was crystallized from methylene chloride/hexane to yield the title propanamide which contained about 10 mole % of methylene chloride by NMR analysis. The methylene chloride was not removed by heating at 140° C./0.1 mm for 40 hours. The yield of white solid was 1.70 g (69%), mp 209°-211° C. 1H-NMR (300 MHz, d6-DMSO): 1.55 (s, 3H, CH3) 3.72 (s, 3H, OCH3) 5.73 (s, CH2Cl) 7.11-7.17 (m, 2H, aromatic) 7.53 (s, 1H, OH) 7.60-7.63 (m, 1H, aromatic) 7.80-7.83 (m, 2H, aromatic) 0.92-7.97 (m, 3H, aromatic) 10.36 (s, 1H, NH). MS (CI, CH4): 294 (M+1). Analysis for C17H16F3NO5S.0.1 CH2Cl2 : Calculated: C, 49.87; H, 3.96; N, 3.40. Found: C, 49.71; H, 3.96; N, 3.35.
Reaction SMILES: [OH:1][C@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[C:13]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:1][C@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:13])=[O:4]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)[C@H](O)Cc1ccccc1
Solvent: CO
Product: COC(=O)[C@H](O)Cc1ccccc1
Yield: 407 %

Procedure:
Following the procedure of Cohen (J. Am. Chem. Soc., 1964, 86, 5326), the resultant compound from Example 89 (8.6 g, 52 mmol) was dissolved in dry methanol (250 ml). p-Toluenesulfonic acid (2 g, 10.5 mmol) was added and the solution was refluxed for 2 h. The cooled solution was concentrated in vacuo and the residue was dissolved in ether (400 ml). The ether solution was washed with saturated aqueous NaHCO3 (3×50 ml), water (2×50 ml), 0.1N H2SO4 (1×50 ml), water (1×50 ml), dried over Na2SO4, and concentrated in vacuo to afford a colorless solid. The solid was recrystallized from hexane to provide the title compound as colorless needles (7.7 g, 83%); mp=46°-47° C.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16]([OH:18])=O)(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.Cl.[NH2:25][C@H:26]([CH3:36])[C@H:27]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[OH:28]>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16]([NH:25][C@H:26]([CH3:36])[C@H:27]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[OH:28])=[O:18])(=[O:11])=[O:12])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: C[C@@H](N)[C@@H](O)c1ccc(Cl)cc1
Agent: Cl
Product: C[C@@H](NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12)[C@@H](O)c1ccc(Cl)cc1

Procedure:
2-(Benzo[1,2,5]-thiadiazole-4-sulfonylamino)-4-chlorobenzoic acid was coupled with (1S,2R)-2-amino-1-(4-chloro-phenyl)-propan-1-ol hydrochloride as in EXAMPLE 1, Part C. HPLC: RT=10.17 min. MS (ESI−): mass calcd. for C22H18Cl2N4O4S2, 536.01; m/z found, 535/537 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.64 (s, 1H), 8.39 (dd, J=7.0, 1.0, 1H), 8.23 (dd, J=8.8, 1.0, 1H), 7.73 (dd, J=8.8, 7.0, 1H), 7.72 (d, J=2.0, 1H), 7.38-7.33 (m, 2H), 7.33-7.28 (m, 2H), 7.24 (d, J=8.5, 1H), 6.95 (dd, J=8.4, 2.0, 1H), 6.22 (br d, J=8.1, 1H), 4.97 (d, J=2.9, 1H), 4.42 (ddq, J=8.3, 7.0, 2.9, 1H), 1.04 (d, J=6.9, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:8])[NH2:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CI.[CH3:13]N(C=O)C>O1CCCC1>[C:1]([O:5][C:6](=[O:8])[NH:7][CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
(1S,2S)-3-(tert-butyl-diphenyl-silanyloxy)-1-furan-2-yl-2-methyl-propyl)-carbamic acid tert-butyl ester 2.5.1a (3.9 g, 7.9 mmol, 1.0 equiv) was added to a suspension of 60% sodium hydride (0.94 g, 23.5 mmol, 3.0 equiv) in dry tetrahydrofuran (30 mL) at 0° C. under nitrogen. After stirring at 0° C. for 15 min, to this solution was added methyl iodide (3.7 g, 16.0 mL, 26.0 mmol, 3.3 eqiuv) and DMF (3 mL). The reaction mixture was then stirred at room temperature for 3 hours. The reaction was quenched with sat. ammonium chloride aq. solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give obtain (1S,2S)-3-(tert-Butyl-diphenyl-silanyloxy)-1-furan-2-yl-2-methyl-propyl)-methyl-carbamic acid tert-butyl ester (4.0 g, 100%). 1H NMR (400 MHz, CDCl3) 0.84 (m, 3H); 1.00 (s, 9H); 1.50 (s, 9H); 2.33 (m, 1H); 2.71 (m, 3H); 3.47 (m, 3H); 5.26 (m, 1H); 6.09 (m, 1H); 5.93 (s, 1H); 6.16 (m, 1H); 6.26 (m, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:31])[F:30])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(O[C:38](=O)[N:39]([CH2:41][CH2:42][NH2:43])C)(C)(C)C.Cl>>[ClH:1].[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:31])[F:30])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([NH:43][CH2:42][CH2:41][NH:39][CH3:38])=[O:14])=[CH:4][CH:3]=1
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: O=C(O)Cn1cc(C(=O)N2CCC(c3ccccc3C(F)(F)F)CC2)c2ccc(Cl)cc21
Agent: Cl
Product: CNCCNC(=O)Cn1cc(C(=O)N2CCC(c3ccccc3C(F)(F)F)CC2)c2ccc(Cl)cc21

Procedure:
Analogous to general procedure I, the coupling of {6-chloro-3-[4-(2-trifluoromethyl-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetic acid (prepared herein) with (commercially available) (2-amino-ethyl)-methyl-carbamic acid tert-butyl ester gave, after treatment with HCl the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([O:11][CH2:12][CH3:13])[CH:3]=1.CCO.O>[Fe].CC(O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([O:11][CH2:12][CH3:13])[CH:3]=1
Reactant: CCOc1cc(Br)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOc1cc(Br)ccc1N
Temperature: 25 °C
Yield: 94.8 %

Procedure:
To a refluxing solution of 62A (3.0 g, 12.2 mmol), EtOH (60 mL), water (15 mL) and AcOH (10 mL) was added portion-wise Fe powder (5 g, 89.3 mmol) over 30 min. The mixture was heated for 1 h before cooling to ambient temperature and filtering through celite. The filtrate was concentrated in vacuo to afford 62B (2.5 g, 96%) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.42 (t, J=7.03 Hz, 3 H) 4.02 (q, J=6.88 Hz, 2 H) 6.57 (d, J=7.91 Hz, 1 H) 6.85-6.90 (m, 2 H).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]3[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=3)=[N:11][N:10]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[F:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[C:35]([C:42]([F:45])([F:44])[F:43])[CH:34]=1>C(Cl)Cl>[F:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([N:2]([CH3:1])[CH:3]2[CH2:4][CH2:5][N:6]([C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=4)=[N:11][N:10]=3)[CH2:7][CH2:8]2)=[O:38])=[C:35]([C:42]([F:45])([F:44])[F:43])[CH:34]=1
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Reactant: CNC1CCN(c2nnc(-c3ccnn3C)c3ccccc23)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)c1ccc(F)cc1C(F)(F)F)C1CCN(c2nnc(-c3ccnn3C)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
Treat a solution of N-methyl-1-(4-(1-methyl-1H-pyrazol-5-yl)phthalazin-1-yl)piperidin-4-amine (2.8 g, 8.68 mmol) and triethylamine (3.36 mL, 26 1 mmol) in CH2Cl2 (30 mL) with 4-fluoro-2-(trifluoromethyl)benzoyl chloride (2.14 mL, 10.42 mmol). Stir for 3 h at ambient temperature. Concentrate the reaction mixture under reduced pressure. Purify the resulting residue by flash silica gel chromatography (hexane:ethyl acetate:2 M NH3 in MeOH=20:5:1) to provide the free base as a yellow foam (3.83 g, 86%). ES/MS m/z 513.0 (M+1).
Reaction SMILES: C(NC(C)C)(C)C.[Li][CH2:9]CCC.[NH2:13]/[C:14](/[C:25]([F:28])([F:27])[F:26])=[C:15](/[C:21](=[O:24])[CH2:22][CH3:23])\[C:16]([O:18][CH2:19][CH3:20])=[O:17].[Cl:29][C:30]([F:37])([F:36])C(OCC)=O>CCOCC>[Cl:29][C:30]([F:37])([F:36])[C:23]1[N:13]=[C:14]([C:25]([F:26])([F:27])[F:28])[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:21]([OH:24])[C:22]=1[CH3:9]
Reactant: CCOC(=O)C(F)(F)Cl
Reactant: CCOC(=O)/C(C(=O)CC)=C(\N)C(F)(F)F
Reactant: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C)c1O
Temperature: -78 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To 85 ml of dry ether and 21.4 ml (0.152 mol) of diisopropylamine at -78° C. was added 97 ml (0.150 mol) of 1.55M n-BuLi. After stirring at -78° C. for 20 minutes a solution of 16.3 g (0.068 mol) of product of Example 34 in 10 ml of dry ether was added. After stirring at -78° C. for 1 hour, 35 g (0.221 mol) of ethyl chlorodifluoroacetate was added. Stirring at -78° C. was continued for 1 hour and then warmed to room temperature in 11/2 hour. The reaction mixture was poured into 200 ml of ice water and extracted with ether. The ether was extracted with 15% K2CO3 and water. The water extracts were combined, acidified with concentrated HCl and extracted with ether. The original aqueous layer was acidified with concentrated HCl, extracted with ether and combined with the above ether extract, dried (MgSO4) and concentrated in vacuo affording 17.7 g of solid. This solid was heated on the kugelrohr apparatus at 125° C. for 1/2 hour at atm. pressure and then distilled at 19 Pa, pot temperature 69° C. to give 13.57 g (59.8%) of product as a white solid; mp 37°-39° C.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=3[C:6]3[C:13]([OH:23])=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:15]([CH3:17])=[N:16][C:5]2=3)[CH2:3][CH2:2]1.CCN(CC)CC.[O:31](S(C(F)(F)F)(=O)=O)[S:32]([C:35]([F:38])([F:37])[F:36])(=O)=[O:33]>ClCCl>[CH:1]1([N:4]2[C:12]3[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=3[C:6]3[C:13]([O:23][S:32]([C:35]([F:38])([F:37])[F:36])(=[O:33])=[O:31])=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:15]([CH3:17])=[N:16][C:5]2=3)[CH2:3][CH2:2]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1c(C)nc2c(c1O)c1c(n2C2CC2)CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C)nc2c(c3c(n2C2CC2)CCCC3)c1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 94.9 %

Procedure:
An ice cold mixture of ethyl 9-cyclopropyl-4-hydroxy-2-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-3-carboxylate (1.362 g, 4.33 mmol) in dichloromethane (DCM) (20 ml) was treated with Et3N (0.906 ml, 6.50 mmol) and Tf2O (0.805 ml, 4.77 mmol), and then stirred at 0° C. for 90 min. The mixture was concentrated and purified with column chromatography (0-50% EtOAc/Hexane, 120 g silica gel) to give ethyl 9-cyclopropyl-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-3-carboxylate (1.8341 g, 4.11 mmol, 95% yield) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.39 (q, J=7.2 Hz, 2 H), 3.17-2.98 (m, 1 H), 2.90-2.78 (m, 4 H), 2.75 (s, 3 H), 1.99-1.88 (m, 2 H), 1.88-1.76 (m, 2 H), 1.40 (t, J=7.2 Hz, 3 H), 1.22-1.07 (m, 4 H); LCMS (m/z) ES+=447 (M+1).
Reaction SMILES: C([O:3][C:4]([CH2:6][S:7][C:8](=[N:16][OH:17])[C:9]([CH3:15])(S(C)(=O)=O)[CH3:10])=O)C.[OH-].[NH4+:19].N>O>[N:16](=[C:8]1[C:9]([CH3:15])([CH3:10])[NH:19][C:4](=[O:3])[CH2:6][S:7]1)[OH:17]
Reactant: CCOC(=O)CSC(=NO)C(C)(C)S(C)(=O)=O
Reactant: [NH4+]
Agent: N
Agent: [OH-]
Solvent: O
Product: CC1(C)NC(=O)CSC1=NO
Temperature: 25 °C

Procedure:
A mixture of 5.0 g 1-(ethoxycarbonylmethylthio)-2-methyl-2-(methylsulfonyl)propionaldoxime and 150 ml. of ammonium hydroxide was charged into a pyrex pressure bottle and stirred at room temperature for forty hours. The mixture was stripped of excess ammonia and water under reduced pressure. The solid crystalline residue was washed with water, then dried at room temperature to yield 3 g of 2-oximino-3,3-dimethyltetrahydro-1,4-thiazin-5-one, m.p. 234° C. The nmr spectrum was identical with those of the compounds from Examples II and III.