Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].C(=O)([O-])O.[Na+]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][O:14][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cnn(Cc2ccccc2)c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cnn(Cc2ccccc2)c1
Reaction time: 2 h
Yield: 97.2 %

Procedure:
To a solution of (1-benzyl-1H-pyrazol-4-yl)methanol (3.84 g) in methylene chloride (100 mL) were added triethylamine (2.80 mL), 4-dimethylaminopyridine (100 mg) and tert-butyldimethylsilyl chloride (3.80 g) at room temperature, and the mixture was stirred for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and insoluble material was removed by filtration. Ethyl acetate (100 mL) was added to extract the filtrate, and the organic layer was washed with brine. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (6.00 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19](Br)=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:74](=[O:81])([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])[NH2:75].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([NH:75][C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:81])=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1cncc2cccc(S(=O)(=O)N3CC[C@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 100 °C
Reaction time: 15 h
Yield: 32.5 %

Procedure:
A suspension of Intermediate 1a (137 mg) obtained in Example 1-1, Step A, tris(dibenzylideneacetone)dipalladium(0) (55 mg, Aldrich), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (37 mg, Aldrich), tert-butyl carbamate (70 mg, Aldrich), and cesium carbonate (196 mg, Aldrich) in toluene (5 ml) was stirred at 100° C. for 15 hours. The reaction mixture was cooled to room temperature, and then added with ethyl acetate (5 ml), and the insoluble solids were removed by filtration through Celite. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:1) to obtain the title compound (48 mg).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:5]([NH:8][C:9]([C:11]2[N:12]([CH3:21])[N:13]=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:15]=2[Cl:16])=[O:10])=[N:6][CH:7]=1.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C1(C)C=CC=CC=1>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][NH:22][C:4]2[C:5]([NH:8][C:9]([C:11]3[N:12]([CH3:21])[N:13]=[C:14]([C:17]([CH3:19])([CH3:18])[CH3:20])[C:15]=3[Cl:16])=[O:10])=[N:6][CH:7]=[C:2]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[C:33]([F:44])([F:43])[F:32])[N:3]=2)=[CH:25][CH:26]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: COc1ccc(CNc2nc(Br)cnc2NC(=O)c2c(Cl)c(C(C)(C)C)nn2C)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc(CNc2nc(-c3ccccc3C(F)(F)F)cnc2NC(=O)c2c(Cl)c(C(C)(C)C)nn2C)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [5-bromo-3-(4-methoxy-benzylamino)-pyrazin-2-yl]-amide (87 mg, 0.17 mmol), 2-trifluoromethyl-phenylboronic acid (36 mg, 0.19 mmol), in DMF (0.5 mL), toluene (2 mL) and water (2 mL), K2CO3 (33 mg, 0.23 mmol) was added. The resulting solution was placed under Ar and (dppf)PdCl2.DCM (14 mg, 0.02 mmol) was added. The resulting mixture was stirred at 100° C. overnight. The organic layer was separated, dried (Na2SO4) and concentrated. The residue obtained was purified on silica (20:80-100:0 EtOAc: hexane) to yield 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [3-(4-methoxy-benzylamino)-5-(2-trifluoromethyl-phenyl)-pyrazin-2-yl]-amide. Mass Spectrum (LCMS, ESI pos.): Calculated for C28H28ClF3N6O: 573.1 (M+H); Measured: 573.3.
Reaction SMILES: [Br:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+].C(OCC)(=O)C.CCCCCC>CO>[Br:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]([OH:12])[CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCNc2nc(Br)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: OC1CCNc2nc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
7-Bromo-2,3-dihydro-1H-[1,8]naphthyridin-4-one (1.459 g) was placed in methanol (25 mL) and sodium borohydride (437 mg, 1.84 eq) was added portionwise over five (5) minutes. The reaction was stirred at room temperature for 15 minutes and then quenched with acetic acid (3 mL). The reaction mixture was concentrated under reduced pressure and the residue was taken up in toluene (100 mL). Silica gel was added and the mixture was concentrated under reduced pressure. Purification by silica gel chromatography using dry loading and a gradient of 0-80% ethyl acetate/hexane as the eluting solvent gave the title compound as a pale yellow solid (78% yield). M.p. 130-131° C., LCMS: m/z=230.71 (M+H+), 1H-NMR (MeOH-d4, 400 MHz) δ 1.80-1.94 (m, 2H), 3.33-3.48 (m, 2H), 4.66 (t, J=4.4 Hz, 1H), 6.66 (d, J=7.6 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H).
Reaction SMILES: N1C=CC=C(CN)C=1.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][NH2:16].FC1C=CC(CN2[C@@H](C)CN(C3SC(C(O)=O)=C(C)N=3)C2=O)=CC=1.[F:41][C:42]1[CH:64]=[CH:63][C:45]([CH2:46][N:47]2[CH2:51][C@@H:50]([CH3:52])[N:49]([C:53]3[S:54][C:55]([C:59](O)=[O:60])=[C:56]([CH3:58])[N:57]=3)[C:48]2=[O:62])=[CH:44][CH:43]=1>>[F:41][C:42]1[CH:64]=[CH:63][C:45]([CH2:46][N:47]2[CH2:51][C@@H:50]([CH3:52])[N:49]([C:53]3[S:54][C:55]([C:59]([NH:16][CH2:15][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=4)=[O:60])=[C:56]([CH3:58])[N:57]=3)[C:48]2=[O:62])=[CH:44][CH:43]=1
Reactant: NCc1ccccn1
Reactant: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)C[C@H]2C)sc1C(=O)O
Agent: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)C[C@H]2C)sc1C(=O)NCc1ccccn1

Procedure:
Following the procedure as described in EXAMPLE 2, making variations as required to replace pyridin-3-ylmethanamine with pyridin-2-ylmethanamine and replace (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with (R)-2-(3-(4-fluorobenzyl)-5-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white solid (68%): mp 55-57° C. (diethyl ether/hexane); 1H NMR (300 MHz, DMSO-D6) δ 8.54-8.50 (m, 2H), 7.79-7.73 (m, 1H), 7.37-7.17 (m, 6H), 4.59-4.43 (m, 5H), 3.64-3.58 (m, 1H), 3.04 (dd, J=9.1, 3.2 Hz, 1H), 2.50 (s, 3H), 1.39 (d, J=6.2 Hz, 3H); MS (ES+) m/z 440.0 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]([O:8][CH2:9][C:10]1[C:11]([CH3:34])=[N:12][C:13]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[CH:15]=1)([CH3:7])[CH3:6])C.[Li+].[OH-].Cl>C1COCC1.O>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[C:14]1[CH:15]=[C:10]([CH2:9][O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:35])=[O:3])[C:11]([CH3:34])=[N:12][C:13]=1[C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=1
Reactant: CCOC(=O)C(C)(C)OCc1cc(-c2ccc(Cl)cc2Cl)c(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)c(-c2ccc(Cl)cc2Cl)cc1COC(C)(C)C(=O)O
Reaction time: 16 h

Procedure:
To a solution of 200 mg of 2-[5-(2,4-Dichloro-phenyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-2-methyl-propionic acid ethyl ester in 2 ml THF was added a solution of 18 mg of LiOH in 2 ml water at room temperature. After 16 h, the mixture was brought to pH 2 by addition of 1 M hydrochloric acid. The reaction mixture was concentrated under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. Yield: 22 mg.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.COC1C=C(OC)C=CC=1C[NH:18][C:19]([C:21]1[C:25]([N:26]([CH3:37])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-:36])=[O:35])[CH:29]=2)=[CH:24][NH:23][N:22]=1)=[O:20].CO.[OH-].[Na+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[CH3:37][N:26]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-:36])=[O:35])[CH:29]=1)[C:25]1[C:21]([C:19]([NH2:18])=[O:20])=[N:22][NH:23][CH:24]=1
Reactant: COc1ccc(CNC(=O)c2n[nH]cc2N(C)Cc2cccc([N+](=O)[O-])c2)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CN(Cc1cccc([N+](=O)[O-])c1)c1c[nH]nc1C(N)=O
Temperature: 25 °C
Yield: 87.5 %

Procedure:
4.45 g of para-toluenesulfonic acid monohydrate are added to a solution of 2.49 g of 4-[methyl(3-nitrobenzyl)amino]-1H-pyrazole-3-carboxylic acid 2,4-dimethoxybenzylamide in 30 ml of toluene, and the reaction medium is then heated at the reflux temperature of the toluene for 17 hours. After cooling the reaction medium to room temperature, 15 ml of methanol are added, followed by 700 ml of ethyl acetate and finally 300 ml of distilled water. The pH of this medium is adjusted to a value of 11 by adding 100 ml of aqueous 1N sodium hydroxide solution. This solution is filtered, the solid is extracted twice with 30 ml of ethyl acetate, and the liquid phases are combined and then separated by settling of the phases. The aqueous phase is extracted with twice 200 ml of methylene chloride, the organic phases are combined, washed with 300 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. 1.41 g of 4-[methyl(3-nitrobenzyl)amino]-1H-pyrazole-3-carboxamide are obtained in the form of a beige-colored solid melting at 166° C. ([M+H]+): 276). RT: 2.61 min (Method A).
Reaction SMILES: NN=C([C:10]1[C:20]2[CH2:19][CH2:18][C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[N:15](N)[C:14]=2[CH:13]=[CH:12][C:11]=1CC1C=CC=CC=1)C1C=CC=CC=1.[ClH:33].[NH:34]1[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1.S(=O)(=O)(O)O.N>O.C(O)C>[ClH:33].[CH2:24]1[C:16]2[N:15]3[C:37]4[CH:38]=[CH:39][N:34]=[CH:35][C:36]=4[C:13]4[CH2:12][CH2:11][CH:10]=[C:20]([C:14]=43)[CH:19]=[CH:18][C:17]=2[CH2:21][CH2:22][CH2:23]1
Reactant: O=C1CCNCC1
Reactant: NN=C(c1ccccc1)c1c(Cc2ccccc2)ccc2c1CCc1ccccc1N2N
Agent: Cl
Agent: N
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: C1=CC2=C(CCCC2)n2c3c(c4cnccc42)CCC=C13
Reaction time: 0.67 h

Procedure:
A mixture of 24.6 g of N-aminoiminodibenzyl (5-amino-10,11-dihydro-5H-dibenz[b,f]azepine) and 14.8 g. of 4-piperidone hydrochloride in 250 ml. ethanol was heated on a steam bath for 15 minutes and cooled; a solution of 20 g. of concentrated sulfuric acid in 250 ml. ethanol was added. The resulting mixture was reheated on the steam bath for additional 40 minutes; the solution which formed was cooled, basified with ammonia, and diluted with 1.1 of water. The crude, semisolid material which separated was taken up in ether, and the aqueous mother liquors were extracted with additional portions of ether. The combined etheral extracts were concentrated to 500 ml. and treated, under an atmosphere of nitrogen and with vigorous stirring, with 50 ml. of 5N hydrochloric acid. The resulting precipitate was filtered off, washed with ether and 1N hydrochloric acid, and dried in vacuo at 100° to yield 1,2,3,4,8,9-hexahydropyrido[4',3':2,3]indolo[1,7-ab][1]benzazepine hydrochloride, m.p. 309°, a salt only very slightly soluble in water. Dissolving the above salt in aqueous acetic acid, basifying with ammonia, filtering off the crude product and recrystallizing it from benzene regenerated the free 1,2,3,4,8,9-hexahydropyrido[4',3' :2,3]indolo[1,7-ab][1]benzazepine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25](F)=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:35][CH2:36][C:37]([CH3:40])([OH:39])[CH3:38].O>CS(C)=O>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([NH:35][CH2:36][C:37]([OH:39])([CH3:40])[CH3:38])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(O)CN
Reactant: CC(C)(C)OC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(O)CNc1ccc(S(=O)(=O)Oc2ccc3nc(NC(=O)OC(C)(C)C)sc3c2)cc1
Yield: 83.1 %

Procedure:
A solution of 4-fluorobenzenesulfonic acid 2-tert-butoxycarbonylaminobenzo-thiazol-6-yl ester (intermediate 15) (300 mg, 0.707 mmol), cesium carbonate (230 mg, 0.707 mmol) and 1-amino-2-methylpropan-2-ol (126 mg, 1.414 mmol) in 5 ml of dimethyl sulfoxide is stirred at 80° C. for 72 hours. Water is added to the reaction medium, and the mixture is extracted 3 times with ethyl acetate. The organic phase is washed with saturated sodium chloride solution and then dried over magnesium sulfate and finally evaporated to dryness to give 290 mg of 4-(2-hydroxy-2-methylpropylamino)benzenesulfonic acid 2-tert-butoxycarbonylaminobenzo-thiazol-6-yl ester in a yield of 83%.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1([C:12]([OH:14])=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:15]O>>[NH2:5][C:6]1([C:12]([O:14][CH3:15])=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CO
Reactant: NC1(C(=O)O)CCCCC1
Solvent: O=S(Cl)Cl
Product: COC(=O)C1(N)CCCCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
51 ml of thionyl chloride were added in portions at −5° C. to 50 g (350 mmol) of 1-aminocyclohexane-1-carboxylic acid in 1.25 l of methanol. The reaction mixture was subsequently stirred at room temperature for 5 hours and allowed to stand overnight at room temperature. The methanol was removed in vacuo, the residue was mixed with water, and the aqueous solution was adjusted to pH 9 using saturated sodium carbonate solution and extracted twice with dichloromethane. The organic phase was dried over sodium sulfate and, after filtration, the solvent was removed in vacuo. Yield: 36.35 g (66%).
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[CH3:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[NH2:29]>>[CH3:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[NH:29][C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19]
Reactant: CC1CCCCC1N
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c2[nH]c(C(F)(F)F)nc12
Product: CC1CCCCC1Nc1c(C(F)(F)F)cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c12

Procedure:
4-Chloro-7-nitro-2,5-bis(trifluoromethyl)benzimidazole is reacted with 2-methylcyclohexylamine to obtain 4-(2-methylcyclohexylamino)-7-nitro-2,5-bis(trifluoromethyl)-benzimidazole, which is reacted with potassium ethoxide to yield the corresponding potassium salt, m.w., 448.4.
Reaction SMILES: [SH:1][CH2:2][CH2:3]O.[O-]CC.[Na+].Br[CH:10]([CH:17]=[O:18])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)C>[O:18]1[CH2:3][CH2:2][S:1][C:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:17]1
Reactant: OCCS
Reactant: CCOC(=O)CC(Br)C=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC1=COCCS1
Temperature: 25 °C
Reaction time: 15 h
Yield: 18.3 %

Procedure:
A solution of 2-mercaptoethanol (38.2 g.) in anhydrous ethanol (146 cc.) is added, at about 10° C. and over the course of one hour, to a solution of sodium ethoxide in ethanol [prepared by reacting sodium (11.2 g.) with anhydrous ethanol (350 cc.)]. After heating the reaction mixture to a temperature of 45°-f 50° C., ethyl 3-bromo-3-formylpropionate (102.8 g.) is added over the course of 20 minutes. The reaction mixture is stirred for 15 hours at a temperature of about 25° C. After filtration, the solvent is evaporated at about 50° C. under reduced pressure (20 mm.Hg). The residue is dissolved in anhydrous toluene (500 cc.); the solution is filtered and toluene-p-sulphonic acid monohydrate (1.5 g.) is then added. The reaction mixture is heated under reflux until complete dehydration has taken place (the water formed being removed in a Dean-Stark apparatus) and then the solvent is evaporated at about 50° C. under reduced pressure (20 mm.Hg). The residue is taken up in diethyl ether (700 cc.); some insoluble matter appears and is removed by filtration through "Supercel". The ether solution is washed three times with water (total 600 cc.), then dried over sodium sulphate, treated with decolourizing charcoal and filtered. The solution is concentrated to dryness under reduced pressure (20 mm.Hg); a residue (65 g.) is obtained and is chromatographed on alumina (600 g.). Elution is effected using a mixture (2.6 liters) of ethyl acetate and cyclohexane (1-19 by volume). After concentration to dryness under reduced pressure (20 mm.Hg), ethyl (5,6-dihydro-1,4-oxathiin-3-yl )acetate (16.8 g.) is obtained in the form of an oil.
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18]([O:20]C)=O.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]
Reactant: COC(=O)C1=C(O)c2sc3ccccc3c2S(=O)(=O)N1C
Reactant: Nc1ccccc1
Product: CN1C(C(=O)Nc2ccccc2)=C(O)c2sc3ccccc3c2S1(=O)=O
Yield: 60 %

Procedure:
Prepared analogous to Example 1 from methyl 4-hydroxy-2-methyl-2H-[1]benzothieno[2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and aniline with a yield of 60% of theory.
Reaction SMILES: [CH3:1][NH2:2].COS([CH2:8][CH2:9][CH:10]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)(=O)=O>O1CCCC1.C(OCC)(=O)C>[CH3:1][NH:2][CH2:8][CH2:9][CH:10]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1
Reactant: COS(=O)(=O)CCC(Cc1ccc(C(F)(F)F)cc1)c1ccccc1
Reactant: CN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNCCC(Cc1ccc(C(F)(F)F)cc1)c1ccccc1
Temperature: 22 °C
Reaction time: 8 h

Procedure:
Methylamine (37.2 ml of a 40% by weight aqueous solution, 481 mmole) was added to a 250 ml flask containing 4.47 g (12.0 mmole) of 3-phenyl-4-(4-trifluoromethylphenyl)butane sulfonic acid methyl ester dissolved in 50 ml of tetrahydrofuran. The resulting solution was stirred overnight at room temperature (22° C.) and concentrated under reduced pressure to provide a residue. The residue was dissolved in ethyl acetate and the resulting solution was washed with water and a saturated brine solution. The organic solution was dried over anhydrous sodium sulfate and the volatiles were removed under reduced pressure to provide 3.5 g of N-methyl-3-phenyl-4-(4-trifluoromethylphenyl)butanamine as an oil. A sample of the oil was crystallized from an acetone/diethyl ether solution containing 1.5 equivalents of concentrated hydrochloric acid to yield N-methyl-3-phenyl-4-(4-trifluoromethylphenyl)butanamine hydrochloride as white crystals. mp=156°-157.5° C.
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:12]1[C:13]([F:30])=[C:14]([C:26]([Cl:29])=[CH:27][CH:28]=1)[C:15]([C:17]1[CH:18]=[CH:19][C:20]([C:23]([OH:25])=[O:24])=[N:21][CH:22]=1)=[O:16])[CH2:10][CH3:11])=O)(C)(C)C.Cl.CCOC(C)=O>>[NH2:8][C@@H:9]([C:12]1[C:13]([F:30])=[C:14]([C:26]([Cl:29])=[CH:27][CH:28]=1)[C:15]([C:17]1[CH:18]=[CH:19][C:20]([C:23]([OH:25])=[O:24])=[N:21][CH:22]=1)=[O:16])[CH2:10][CH3:11]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2ccc(C(=O)O)nc2)c1F
Agent: Cl
Solvent: CCOC(C)=O
Product: CC[C@@H](N)c1ccc(Cl)c(C(=O)c2ccc(C(=O)O)nc2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a stirred solution of Intermediate 2 (0.4 g, 1.39 mmol) in THF (10 mL) at −78° C. was added butyllithium solution (2.5 M in hexanes, 1.28 mL, 3.19 mmol) dropwise. The solution was stirred at −78° C. for 1 hour and then a solution of 5-(methoxycarbonyl)pyridine-2-carboxylic acid (0.252 g, 1.39 mmol) in THF (10 mL) pretreated with 60% NaH (0.061 g, 1.59 mmol) for 15 mins was added dropwise. The reaction was stirred at −78° C. for 45 mins, and then quenched by the addition of saturated NH4Cl solution. Water and EtOAc were added and the phases were separated. The organic extract was dried (Na2SO4), filtered and concentrated. Biotage column eluting with a gradient of 0%-50% EtOAc/petrol gave 5-[3-((R)-1-tert-butoxycarbonylamino-propyl)-6-chloro-2-fluoro-benzoyl]-pyridine-2-carboxylic acid (0.06 g), MS: [M+H] 437. 5-[3-((R)-1-tert-Butoxycarbonylamino-propyl)-6-chloro-2-fluoro-benzoyl]-pyridine-2-carboxylic acid (0.06 g, 0.137 mmol) was treated with saturated HCl/EtOAc and stirred at ambient temperature for 1 hour. The resulting solid was filtered off and washed with ether to give 5-[3-((R)-1-amino-propyl)-6-chloro-2-fluoro-benzoyl]-pyridine-2-carboxylic acid (0.03 g).
Reaction SMILES: [NH:1]([C:3]1[C:4](=[O:18])[N:5]([CH3:17])[C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=2)[NH2:2].C(N(CC)CC)C.[CH3:26][CH:27]([CH3:32])[CH2:28][C:29](Cl)=[O:30]>O1CCOCC1>[CH3:17][N:5]1[C:6]2[C:11](=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=2)[N:12]=[C:3]([NH:1][NH:2][C:29](=[O:30])[CH2:28][CH:27]([CH3:32])[CH3:26])[C:4]1=[O:18]
Reactant: CC(C)CC(=O)Cl
Reactant: Cn1c(=O)c(NN)nc2cc(C(F)(F)F)ccc21
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)CC(=O)NNc1nc2cc(C(F)(F)F)ccc2n(C)c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 3-hydrazino-1-methyl-6-trifluoromethyl-1H-quinoxalin-2-one (10.0 g., 52.6 mmol) and triethylamine (6.38 g., 63.2 mmol) in 500 ml. of dioxane is added dropwise 3-methylbutanoyl chloride (7.62 g., 65.2 mmol) and the mixture stirred at room temperature for 20 hours. The dioxane is then removed under vacuum and the residue washed with water and ether, filtered and dried under vacuum to give the product.