Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([CH:7]=[O:8])[CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:27][C:28]([Si](C)(C)C)([F:30])[F:29]>O1CCCC1>[F:27][C:28]([F:30])([F:29])[CH:7]([CH:4]1[CH2:5][CH2:6][S:1][CH2:2][CH2:3]1)[OH:8]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=CC1CCSCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(C1CCSCC1)C(F)(F)F
Yield: 89.7 %

Procedure:
According to Reference Example 8-12, by use of tetrahydro-2H-thiopyran-4-carbaldehyde (300 mg, 2.30 mmol) dissolved in tetrahydrofuran (6 mL), a 1 mol/L solution of tetrabutylammonium fluoride in tetrahydrofuran (0.460 mL, 0.460 mmol) and (trifluoromethyl)trimethylsilane (0.408 mL, 2.76 mmol), the mixture was stirred and reacted at room temperature for 2 hours. Then, purification by extraction gave 2,2,2-trifluoro-1-(tetrahydro-2H-thiopyran-4-yl)ethanol (Compound EH) (413 mg, yield: 90%).
Reaction SMILES: [CH2:1]([C:14]1[CH:15]=[C:16](C(OC)=O)[NH:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(O)CO.[OH-].[K+]>O>[CH2:1]([C:14]1[CH:15]=[CH:16][NH:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCCc1c[nH]c(C(=O)OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: CCCCCCCCCCCCCc1cc[nH]c1
Temperature: 190 °C
Reaction time: 5 h
Yield: 97.3 %

Procedure:
Into a mixture of 9.50 g (30.9 mmol) of methyl 4-tridecylpyrrole-2-carboxylate obtained in Synthesis Example 3,200 ml of ethylene glycol and 10 ml of water, was added 20 g of potassium hydroxide and the mixture was heated at 190° C. under stirring for 5 hours. After cooling, the mixture was added with water and extracted with ethyl acetate. The organic layer was collected, washed with water, dried over anhydrous magnesium sulfate and then evaporated. The residue was purified by a silica-gel column chromatography (eluent: ethyl acetate/hexane=1/5) to obtain 7.50 g of 3-tridecylpyrrole. The yield was 97% and the melting point was 32.5° to 33.5° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.Cl[CH2:10][C:11]1[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:18][O:17][C:12]1[C:11]([CH2:10][N:2]2[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]2)=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: O=C1CCNCC1
Reactant: COc1ncccc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncccc1CN1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 96 %

Procedure:
4.0 g of 4-piperidone hydrochloride, 4.1 g of 3-(chloromethyl)-2-methoxypyridine and 12.6 g of potassium carbonate were suspended in 26 ml of N,N-dimethylformamide, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (ethyl acetate), to give 5.5 g of the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=4)[CH:17]=3)=[C:11]([CH3:27])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[CH:26]=[CH:25][C:21]([C:22]([NH:28][N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)=[O:24])=[CH:20][N:19]=4)[CH:17]=3)=[C:11]([CH3:27])[N:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Reactant: NN1CCOCC1
Product: Cc1nnn(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)NN3CCOCC3)cn2)cn1
Yield: 61 %

Procedure:
As described for example 36b, 6-(4-(1-(4-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (65 mg, 0.178 mmol) was converted, using 4-aminomorpholine instead of isopropylamine, to the title compound (49 mg, 61%) which was obtained as a white solid after recrystallisation from ethyl acetate in hexane. MS: m/e=449.2 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][CH:11]([O:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14]CC)=[O:13])[CH:7]=[CH:8][CH:9]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]=[C:30]=[O:31])[CH:24]=1>>[CH:18]([O:17][CH:11]([CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][CH2:2][O:1][C:30]([NH:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([C:22]([F:21])([F:32])[F:33])[CH:24]=2)=[O:31])[CH:5]=1)[C:12]([OH:14])=[O:13])([CH3:19])[CH3:20]
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C(Cc1cccc(CCO)c1)OC(C)C
Product: CC(C)OC(Cc1cccc(CCOC(=O)Nc2cccc(C(F)(F)F)c2)c1)C(=O)O

Procedure:
Using ethyl 3-[3-(2-hydroxyethyl)phenyl]-2-isopropoxypropanoate and α,α,α-trifluoro-m-tolylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=[O:4].[H-].[Na+].[Cl:10]/[CH:11]=[CH:12]/[CH2:13]Cl.[Cl-].[NH4+]>C1COCC1.O>[Cl:10][CH:11]=[CH:12][CH2:13][NH:5][C:3](=[O:4])[C:2]([F:7])([F:6])[F:1]
Reactant: Cl/C=C/CCl
Reactant: NC(=O)C(F)(F)F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCC=CCl)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Trifluoroacetamide (10.44 g, 92.4 mmol) is dissolved in THF (30 mL). Sodium hydride (60% weight dispersion in mineral oil, 3.1 g, 77 mmol) is then added in small portions at room temperature while regulating the temperature of the reaction with a water bath. The mixture is stirred at room temperature for 5 min., after which E-1,3-dichloropropene (4.5 mL, 49.4 mmol) is added. After 2 min., the mixture thickened, and the reaction was heated to reflux for 45 min. The mixture is then cooled to room temperature, and saturated aqueous ammonium chloride (20 mL) and water (40 mL) are added. The mixture is transferred to a separatory funnel and extracted with ether (2×400 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to obtained a colorless oil that was used for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][S:11][CH3:12].C1C=C(Cl)C=C(C(OO)=[O:21])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][S:11]([CH3:12])=[O:21]
Reactant: CSCOc1ccc(Cl)cc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)COc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 16 h
Yield: 55.4 %

Procedure:
To an ice cooled solution of the above crude 2,4-dichloro-1-methylsulfanylmethoxy-benzene (17 g) in DCM (200 mL) was added portion wise m-CPBA (13.8 g, 79.75 mmol) during 30 min. The resulting mixture was allowed to reach room temperature and stirring was continued for 16 hrs. The organic phase was washed with water (2×100 mL), 1N NaOH until pH 6-7, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified on silicagel (10 cm) using first heptane (1 L) followed by EtOAc:heptane (1:1) (1 L) and finally EtOAc as eluents. Pure fractions were collected from the pure EtOAc phase and evaporated in vacuo affording 10.1 g (69%) of 2,4-dichloro-1-methanesulfinylmethoxy-benzene as a solid.
Reaction SMILES: C([NH:14][CH:15]([P:20]([OH:22])[OH:21])[CH:16]([CH3:19])[CH2:17][CH3:18])(C1C=CC=CC=1)C1C=CC=CC=1.C(NC(P(O)O)C(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[NH2:14][CH:15]([P:20]([OH:22])[OH:21])[CH:16]([CH3:19])[CH2:17][CH3:18]
Reactant: CCC(C)C(NC(c1ccccc1)c1ccccc1)P(O)O
Agent: CC(C)C(NC(c1ccccc1)c1ccccc1)P(O)O
Product: CCC(C)C(N)P(O)O

Procedure:
The procedure described in Example 1C was repeated using DL-1-benzhydrylamino-2-methylbutanephosphonous acid as starting material instead of DL-1-benzhydrylamino-2-methylpropanephosphonous acid to give DL-1-amino-2-methylbutanephosphonous acid of melting point 203° (dec.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:65][C:66]1[CH:74]=[CH:73][CH:72]=[CH:71][C:67]=1[C:68]([NH2:70])=[O:69]>C(Cl)Cl>[C:68]([C:67]1[CH:71]=[CH:72][CH:73]=[CH:74][C:66]=1[NH:65][C:28]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:31])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10]1)=[O:29])(=[O:69])[NH2:70]
Reactant: NC(=O)c1ccccc1N
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccccc2C(N)=O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.26 mmol) was added followed by the addition of DIPEA (90 uL, 0.52 mmol) and 2-amino benzamide (Aldrich, 35 mg, 0.26 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, eluent, 20% EtOAc/hexanes) to give a white solid. 30 mg.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH:24]=[C:23]([C:25]#[C:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=3)[N:22]=[C:21]2[CH3:34])=[CH:16][CH:15]=1.CI>O1CCCC1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]([CH3:1])=[C:23]([C:25]#[C:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=3)[N:22]=[C:21]2[CH3:34])=[CH:16][CH:15]=1
Reactant: Cc1cc(C#Cc2cn(-c3ccc(F)cc3)c(C)n2)ccn1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc(C#Cc2nc(C)n(-c3ccc(F)cc3)c2C)ccn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Diisopropylamine (0.260 mg, 2.6 mmol) was dissolved in 5 mL dry tetrahydrofurane, n-butyllithium (1.6 mL, 1.6 M in hexane, 2.6 mmol) were added at −78° C. and the mixture was kept at −78° C. for 10 min. 4-[1-(4-Fluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-2-methyl-pyridine (1) (500 mg, 1.72 mmol) in 5 mL dry tetrahydrofurane was added at −78° C. and stirring was continued for 45 min at this temperature. Methyl iodide (410 mg, 2.9 mmol) was added at −78° C. and the reaction mixture was slowly warmed to RT. The reaction mixture was quenched by addition of 50 mL water and extracted three times with diethylether (100 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography on silica gel (methylenchloride/methanol 9:1) and the desired compound was obtained as a white solid (325 mg, 62%), MS: m/e=306.4 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:21])[CH2:9][N:10]([CH3:20])[S:11]([C:14]2[S:15][C:16]([Br:19])=[CH:17][CH:18]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[BH4-].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:21])[CH2:9][N:10]([CH3:20])[S:11]([C:14]2[S:15][C:16]([Br:19])=[CH:17][CH:18]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: CN(CC(=O)c1ccc(F)cc1)S(=O)(=O)c1ccc(Br)s1
Agent: [BH4-]
Agent: [Na+]
Product: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1ccc(Br)s1
Yield: 94 %

Procedure:
5-bromothiophene-2-sulfonic acid [2-(4-fluorophenyl)-2-oxoethyl]-methyl-amide (270 mg) was reduced with sodium borohydride (26 mg) on an ice-bath and the title compound (255 mg) was obtained as a yellow oily substance.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14](S(C2C=CC(C(C)(C)C)=CC=2)(=O)=O)[C:15]2[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:16]=2[C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][CH2:23][O:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:16]=2[C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2c(OCCOc3ccccc3)nn(C)c2N(S(=O)(=O)c2ccc(C(C)(C)C)cc2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2c(OCCOc3ccccc3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reaction time: 16 h

Procedure:
To 4-(tert-butyl)-N-{[4-(tert-butyl)phenyl]sulfonyl}-N-[1-methyl-4-(4-methylphenyl)-3-(2-phenoxyethoxy)-1H-pyrazol-5-yl]benzenesulfonamide (Preparation 1) (80 mg) in ethanol (20 ml) at room temperature was added sodium hydroxide (2N, 2 ml) and the mixture was stirred for 16 hrs. The mixture was reduced in volume to 10 ml under reduced pressure, diluted with water (50 ml) and extracted with ethyl acetate (30 ml). The organic fraction was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (10 g) eluted with dichloromethane:ether (7:1) to yield the title compound as a colourless glass-like solid (7 mg).
Reaction SMILES: [CH3:1][N-:2][CH3:3].[CH3:4][N-:5][CH3:6].[CH3:7][N-:8][CH3:9].[CH3:10][N-]C.[Ti+4:13].C[C:15]1[CH2:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[CH3:1][N-:2][CH3:3].[CH3:4][N-:5][CH3:6].[CH3:7][N-:8][CH3:9].[CH3:10][Ti+3:13][CH:18]1[CH:17]=[CH:16][CH:15]=[CH:19]1
Reactant: [Ti+4]
Reactant: CC1=CC=CC1
Agent: C[N-]C
Solvent: Cc1ccccc1
Product: C[Ti+3]C1C=CC=C1

Procedure:
A 250 mL Schlenk flask is charged with titanium tetrakis(dimethylamide), 3.73 g (16.64 mmole), and toluene, 100 mL. Methylcyclopentadiene, 5.33 g (66.54 mmole), is added to the magnetically stirred solution. The mixture is refluxed 1.5 hours. Solvent and volatiles are removed under vacuum leaving a brown residue. The residue is transferred to a microdistillation apparatus and a forerun of titanium tetrakis(dimethylamide) is distilled from the mixture (at 35°-40° C. and 0.025 mm Hg) followed by a red low melting solid (at 104°-108° C. and 0.025 mm Hg) which is determined to be methylcyclopentadienyltitanium tris(dimethylamide) by proton NMR.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[C:19]=1[N+:35]([O-:37])=[O:36]>CN(C)C(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][O:14][C:18]2[C:19]([N+:35]([O-:37])=[O:36])=[C:20]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:29][CH:30]=3)[N:21]=[CH:22][N:23]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(Cl)c2[N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(COc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.3 %

Procedure:
(S)-3-Hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.65 mmol, 131 mg) and sodium hydride (1.3 mmol, 31 mg) were dissolved in N,N-dimethyl acetamide (1.5 mL) and stirred for 30 minutes at room temperature. Then, (6-chloro-5-nitro-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine (0.26 mmol, 84 mg) was added. The reaction was stirred at 70° C. for 30 minutes. Its progress was monitored by thin layer chromatography and LCMS. Sodium hydride was quenched with water and the desired compound was extracted in ethyl acetate. Organic solvents were evaporated in vacuo. Flash chromatography (Silica gel 60; 50/50 EtoAc/Hexanes) provided Compound A17 as a yellow solid (26 mg, 15%). 1H NMR (400 MHz, CDCl3) δ (ppm): 10.22 (s, 1H), 8.41 (s, 1H), 7.97 (d, 2H), 7.87 (d, 2H), 4.52 (m, 2H), 3.49 (m, 2H), 3.09 (s, 3H), 2.75 (m, 1H), 1.97 (m, 2H), 1.67 (m, 2H), 1.49 (s, 9H). LCMS (ESI), m/z 394.1 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:18])=[CH:5][C:6]=1[CH:7]1[CH2:15][C:14]2[NH:13][N:12]=[C:11]([CH3:16])[C:10]=2[C:9](=O)[CH2:8]1.Cl.[NH2:20][NH:21][C:22]([NH:24][OH:25])=[NH:23].Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[S:3][C:4]([Cl:18])=[CH:5][C:6]=1[CH:7]1[CH2:15][C:14]2[NH:13][N:12]=[C:11]([CH3:16])[C:10]=2[C:9](=[N:20][NH:21][C:22](=[NH:23])[NH:24][OH:25])[CH2:8]1
Reactant: Cc1n[nH]c2c1C(=O)CC(c1cc(Cl)sc1Cl)C2
Reactant: N=C(NN)NO
Agent: Cl
Solvent: CCO
Product: Cc1n[nH]c2c1C(=NNC(=N)NO)CC(c1cc(Cl)sc1Cl)C2
Temperature: 90 °C
Reaction time: 4 h
Yield: 156.8 %

Procedure:
To a mixture of 6-(2,5-dichlorothiophen-3-yl)-3-methyl-4,5,6,7-tetrahydroindazol-4-one (0.211 g) and 1-amino-3-hydroxyguanidine hydrochloride (102 mg) were added ethanol (4 ml) and concentrated hydrochloric acid (0.1 ml), and the mixture was stirred at 90° C. for 4 hours. Under reduced pressure, the solvent was evaporated, and to the residue was ethanol (2 ml). Precipitated crystals were filtered, washed with ethanol and dried to give 6-(2,5-dichlorothiophen-3-yl)-4-(1-hydroxyguanidin-3-yl)imino-3-methyl-4,5,6,7-tetrahydroindazole hydrochloride (Compound 128) (0.225 g) as pale yellow crystals.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:28])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:18][S:19]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)(=[O:21])=[O:20])[CH:12]=1)([CH3:6])([CH3:5])[CH3:4].[CH2:29]([O:31][C:32](=[O:44])[C:33]([C:36]1[CH:41]=[CH:40][C:39]([CH2:42]Br)=[CH:38][CH:37]=1)([CH3:35])[CH3:34])[CH3:30].O>CN(C=O)C>[CH2:29]([O:31][C:32](=[O:44])[C:33]([C:36]1[CH:41]=[CH:40][C:39]([CH2:42][N:18]([CH2:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH2:9][C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:28])[CH:12]=2)[S:19]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)(=[O:21])=[O:20])=[CH:38][CH:37]=1)([CH3:34])[CH3:35])[CH3:30]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNS(=O)(=O)c2cccnc2)c1
Reactant: CCOC(=O)C(C)(C)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)c1ccc(CN(Cc2cccc(OCC(=O)OC(C)(C)C)c2)S(=O)(=O)c2cccnc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
NaH (60% by weight in oil, 23 mg, 0.55 mmol) was washed with DMF (5 mL) and fresh DMF (5 mL) was added. The reaction was cooled to 0° C. and a solution of {3-[(pyridine-3-sulfonylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester (184 mg, 0.486 mmol) in DMF (1 mL) was added. The reaction was stirred for 1 h and 2-(4-bromomethyl-phenyl)-2-methyl-propionic acid ethyl ester (145 mg, 0.51 mmol) in DMF (1 mL) was added. The reaction was warmed to room temperature and was heated at 100° C. for 2 h. Water was added and the aqueous solution was washed with EtOAc (3×). The combined organic solutions were washed with water (5×), dried (MgSO4), filtered and concentrated. Flash chromatography (2:1 hexanes:EtOAc) provided 2-(4-{[(3-tert-butoxycarbonylmethoxy-benzyl)-(pyridine-3-sulfonyl)-amino]-methyl}-phenyl)-2-methyl-propionic acid ethyl ester (138 mg). 1H NMR (400 MHz, CDCl3) δ 9.01 (s, 1H), 8.76 (m, 1H), 7.97 (m, 1H), 7.40 (m, 1H), 7.19 (d, 2H), 7.13 (m, 1H), 7.02 (d, 2H), 6.76 (m, 1H), 6.67 (m, 2H), 4.41 (s, 2H), 4.33 (s, 4H), 4.10 (q, 2H), 1.52 (s, 6H), 1.49 (s, 9H), 1.17 (t, 3H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH3:30])[CH:20]=[C:21]([C:22]4[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[Cl:29][C:23]1[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=[C:19]([CH3:30])[CH:20]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C)cc(-c4cc(Cl)ccc4Cl)c3O2)cc1
Product: CNCC1Cc2cc(C)cc(-c3cc(Cl)ccc3Cl)c2O1

Procedure:
The title compound was prepared (0.034 g, 27%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,5-dichlorophenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.16 g, 0.34 mmol) and methylamine (0.107 g, 3.4 mmol). mp 158-160° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH3:12])[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:13]#[N:14].[F:15][C:16]([F:35])([F:34])[C:17]1[CH:18]=[C:19]([C:27]2[O:31][N:30]=[C:29]([CH2:32]Cl)[N:28]=2)[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1>>[F:35][C:16]([F:15])([F:34])[C:17]1[CH:18]=[C:19]([C:27]2[O:31][N:30]=[C:29]([CH2:32][N:7]3[C:6]4[CH:5]=[CH:4][C:3]([C:13]#[N:14])=[C:2]([Cl:1])[C:10]=4[N:9]=[C:8]3[CH2:11][CH3:12])[N:28]=2)[CH:20]=[C:21]([C:23]([F:25])([F:24])[F:26])[CH:22]=1
Reactant: CCc1nc2c(Cl)c(C#N)ccc2[nH]1
Reactant: FC(F)(F)c1cc(-c2nc(CCl)no2)cc(C(F)(F)F)c1
Product: CCc1nc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 197B from 4-chloro-2-ethyl-1H-benzimidazole-5-carbonitrile and 5-[3,5-bis(trifluoromethyl)phenyl]-3-(chloromethyl)-1,2,4-oxadiazole: MS (ESI) m/z 500 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][C:23]([C:25]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)=[N:22][C:21]=3[C:38](O)=[O:39])=[CH:16][CH:15]=2)[CH2:10][C:9]1([CH3:42])[CH3:41])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:45]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.N.O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[O:24][C:23]([C:25]4[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:35])[F:37])=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)=[N:22][C:21]=3[C:38](=[O:39])[NH2:45])=[CH:18][CH:19]=2)[CH2:10][C:9]1([CH3:41])[CH3:42])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3oc(-c4ccc(C(F)(F)F)c5[nH]ccc45)nc3C(=O)O)cc2)CC1(C)C
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3oc(-c4ccc(C(F)(F)F)c5[nH]ccc45)nc3C(N)=O)cc2)CC1(C)C
Reaction time: 2 h

Procedure:
A mixture of 4-{4-[4-carboxy-2-(7-trifluoromethyl-1H-indol-4-yl)-oxazol-5-yl]-phenyl}-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester, EDCI HCl (0.36 g, 0.002 mol) and HOBt (0.3 g, 0.002 mol) in 15 mL of DMF and 15 mL of NH3 in dioxane was stirred for 2 hrs. The solvents were removed in vacuo. The residue was partitioned between water and EtOAc, the organic phase dried over Na2SO4 and the solvent removed in vacuo to give the crude title compound product (0.18 g crude).
Reaction SMILES: [CH3:1][C@:2]1([C:18]([O-])=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1.[Li+].Cl.[NH2:23][C:24]1([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)C[CH2:25]1>>[CH3:1][C@:2]1([C:18]([NH:23][C@H:24]([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)[CH3:25])=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:15])[F:17])[CH:9]=1
Reactant: C[C@]1(C(=O)[O-])CCCN1Cc1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Agent: [Li+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@@]2(C)CCCN2Cc2cccc(C(F)(F)F)c2)cc1
Yield: 53 %

Procedure:
The title compound (D37) (30.9 mg) was prepared according to the general procedure for amides preparation starting from lithium (R)-2-methyl-1-(3-(trifluoromethyl)benzyl)pyrrolidine-2-carboxylate (D17) (37 mg, 0.13 mmol) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (27.2 mg, 0.13 mmol).