Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:13])[C@@H:6]([NH2:12])[CH2:7][CH:8]([CH3:11])[CH2:9][CH3:10])[CH3:3].C(N(CC)C(C)C)(C)C.[Cl:23][C:24]1[CH:57]=[CH:56][CH:55]=[CH:54][C:25]=1[O:26][C:27]1[CH2:31]N([C@@H](CC2CCCCC2)C(NC2C=CN(CC(O)(C)C)N=2)=O)[C:29](=[O:53])[CH:28]=1>C(#N)C>[CH2:2]([O:4][C:5](=[O:13])[C@@H:6]([N:12]1[CH2:31][C:27]([O:26][C:25]2[CH:54]=[CH:55][CH:56]=[CH:57][C:24]=2[Cl:23])=[CH:28][C:29]1=[O:53])[CH2:7][CH:8]([CH3:11])[CH2:9][CH3:10])[CH3:3]
Reactant: CCOC(=O)[C@@H](N)CC(C)CC
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3ccccc3Cl)=CC2=O)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)[C@H](CC(C)CC)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 51.9 %

Procedure:
A suspension of (S)-2-amino-4-methyl-hexanoic acid ethyl ester hydrochloride salt (1.05 g, 5.01 mmol) in acetonitrile (6 mL) was treated with N,N-diisopropylethylamine (1.0 mL) and stirred at 60° C. for 15 min. To this mixture was added N,N-diisopropylethylamine (1.2 mL) and a solution of (E)-4-bromo-3-(2-chloro-phenoxy)-but-2-enoic acid ethyl ester (prepared in Example 61, 1.6 g, 5.0 mmol) in acetonitrile (4 mL) via a dropping funnel and the resulting mixture refluxed for 20 h. The resulting mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The layers were separated and the organic layer was dried over sodium sulfate. The mixture was filtered and concentrated in vacuo and the residue dissolved in tetrahydrofuran (8 mL). The resulting solution was transferred to an Emrys Optimizer microwave tube and microwaved at 160° C. for 4 h. The mixture was concentrated in vacuo and the residue purified by ISCO flash chromatography (RediSep silica column 80 g, 20% to 80% ethyl acetate/hexanes) which afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-hexanoic acid ethyl ester (950 mg, 52%).
Reaction SMILES: [N+:1]([O:4][CH2:5][CH2:6][CH2:7][OH:8])([O-:3])=[O:2].C(N(CC)CC)C.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:16]([O:8][CH2:7][CH2:6][CH2:5][O:4][N+:1]([O-:3])=[O:2])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])OCCCO
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OCCCO[N+](=O)[O-])c1ccccc1
Temperature: 3 °C
Reaction time: 24 h

Procedure:
16.5 mmol 3-Nitrooxypropanol dissolved in 10 ml TMBE and 18.2 mmol Triethylamine were cooled to 3° C. 18.2 mmol benzoylchloride in 5 ml TMBE were dropped over a period of 7 minutes at 3 to 6° C. After 24 hours and 30 minutes stirring without cooling, the reaction mixture was extracted with sated. NaHCO3, water, 1N HCl, twice with water, washed with brine, dried over Na2SO4 and the solvent was removed in vacuo leaving 3.3 g.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.C(N(CC)CC)C.[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>ClCCl>[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2)=[O:22]
Reactant: Oc1ccc2c(c1)CCC2
Reactant: Cc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Oc1ccc2c(c1)CCC2
Temperature: 0 °C

Procedure:
To an ice-cooled mixture of 5-hydroxyindan (13.4 g), triethylamine (14.0 ml) and dichloromethane (150 ml) was added 2-methylbenzoyl chloride (15.4 ml) dropwise with constant stirring. The mixture was further stirred under ice-cooling for one hour, after which it was washed with water and dried (MgSO4). The solvent was then distilled off to give 5-(2-methylbenzoyloxy)indan as oil in quantitative yield.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([N:21]1[C:25](=[O:26])[CH:24]=[CH:23][C:22]1=[O:27])[CH2:18][CH2:19][CH3:20]>C(N(CC)CC)C>[CH2:17]([N:21]1[C:25](=[O:26])[CH2:24][CH:23]([S:11][C:9]2[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]([OH:16])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=2)[C:22]1=[O:27])[CH2:18][CH2:19][CH3:20]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CCCCN1C(=O)C=CC1=O
Solvent: CCN(CC)CC
Product: CCCCN1C(=O)CC(Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O

Procedure:
The procedure of Example 1 is repeated using 11.92 grams 2,6-di-tert-butyl-4-mercaptophenol, 7.66 grams N-n-butylmaleimide, and 0.5 grams triethylamine. The residue is purified by dry column chromatography to give a white solid, m.p. 80°-85° C.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7](O)[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1)#[N:2].O=S(Cl)[Cl:16]>C(Cl)Cl>[Cl:16][CH:7]1[C:6]2[C:11](=[CH:12][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[O:10][CH2:9][CH2:8]1
Reactant: O=S(Cl)Cl
Reactant: N#Cc1ccc2c(c1)OCCC2O
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)OCCC2Cl
Temperature: 10 °C
Reaction time: 8 h

Procedure:
7-Cyano-4-chromanol (Step B) (8.0 g, 46 mmol) was dissolved in CH2Cl2 (120 mL) and cooled to 10° C. SOCl2 (5.0 mL, 70 mmol) was added, the reaction was warmed to RT and stirred overnight. The reaction was concentrated in vacuo and azeotroped with CH2Cl2 (2×50 mL). The residue was dissolved in EtOAc (500 mL), washed with saturated NaHCO3 (250 mL), and with brine (150 mL), dried over MgSO4, filtered and concentrated in vacuo to provide the title compound which was used without further purification.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]1([F:46])[C:44]2[C:39](=[CH:40][CH:41]=[C:42](O)[CH:43]=2)[C:20]2=[N:21][O:22][C:23]([C:24]3[C:28]([C:29]([F:32])([F:31])[F:30])=[C:27]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:26][N:25]=3)=[C:19]2[CH2:18]1>N1C=CC=CC=1>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][C:42]1[CH:43]=[C:44]2[C:39](=[CH:40][CH:41]=1)[C:20]1=[N:21][O:22][C:23]([C:24]3[C:28]([C:29]([F:31])([F:30])[F:32])=[C:27]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:26][N:25]=3)=[C:19]1[CH2:18][C:17]2([F:46])[F:16])(=[O:8])=[O:9]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1ccc2c(c1)C(F)(F)Cc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Solvent: c1ccncc1
Product: O=S(=O)(Oc1ccc2c(c1)C(F)(F)Cc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F)C(F)(F)F
Temperature: 0 °C
Yield: 91.3 %

Procedure:
Trifluoromethanesulfonic anhydride (0.012 mL, 0.069 mmol) was added to a solution of 5,5-difluoro-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-ol (Preparation 66D, 0.020 g, 0.046 mmol) in pyridine (5.0 mL) at 0° C. over a period of 5 min. The reaction mixture was stirred at 0° C. for ten minutes, warmed to room temperature, and stirred overnight. The reaction mixture was concentrated, and the yellowish-brown residue was partitioned between ethyl acetate (10 mL) and water (10 mL). The ethyl acetate layer was collected, washed with 1N aqueous Hydrochloric acid (10 mL), saturated aqueous solution of sodium bicarbonate (10 mL), brine (10 mL), and dried over sodium sulfate. Concentration followed by purification by silica gel chromatography eluting with a mixture of ethyl acetate and hexane (10%-20%) afforded 5,5-difluoro-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl trifluoromethanesulfonate (0.024 g, 0.042 mmol, 92% yield) as a viscous liquid. The product had an HPLC ret. time=3.34 min. (condition B). LC/MS M+1=566.3, 568.4.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[C:9]([S:10](=[O:17])(=[O:16])[NH:11][C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=[C:6]([F:18])[CH:5]=1.[OH-].[Na+]>O1CCOCC1>[F:18][C:6]1[CH:5]=[C:4]([C:9]([S:10](=[O:16])(=[O:17])[NH:11][C:12]([F:14])([F:15])[F:13])=[CH:8][CH:7]=1)[C:3]([OH:19])=[O:2]
Reactant: COC(=O)c1cc(F)ccc1S(=O)(=O)NC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1cc(F)ccc1S(=O)(=O)NC(F)(F)F

Procedure:
Analogously to Example 21(b), 2.41 g (8 mmol) of 3-fluoro-6-(trifluoromethylsulfamoyl)-benzoic acid methyl ester in aqueous dioxane is saponified with NaOH and isolated. 1.55 g=67.3% of the theoretical yield is obtained as a partially crystalline product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])=[C:21]2[C:16]([NH:17][C:18]([CH3:36])([CH3:35])[C:19](=[O:34])[N:20]2[CH3:33])=[CH:15][CH:14]=1.C(=O)([O-])O.[Na+].[CH:42]1[C:54]2[CH:53]([CH2:55][O:56][C:57](Cl)=[O:58])[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:46]=2[CH:45]=[CH:44][CH:43]=1>O1CCOCC1.O.C(OCC)(=O)C>[CH:42]1[C:54]2[CH:53]([CH2:55][O:56][C:57]([N:24]([CH2:23][C:22]3[C:13]([C:4]4[CH:5]=[CH:6][C:7]([O:9][CH2:10][O:11][CH3:12])=[CH:8][C:3]=4[O:2][CH3:1])=[CH:14][CH:15]=[C:16]4[C:21]=3[N:20]([CH3:33])[C:19](=[O:34])[C:18]([CH3:36])([CH3:35])[NH:17]4)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])=[O:58])[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:46]=2[CH:45]=[CH:44][CH:43]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: COCOc1ccc(-c2ccc3c(c2CNc2ccccc2OC)N(C)C(=O)C(C)(C)N3)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COCOc1ccc(-c2ccc3c(c2CN(C(=O)OCC2c4ccccc4-c4ccccc42)c2ccccc2OC)N(C)C(=O)C(C)(C)N3)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
7-(2-Methoxy-4-methoxymethoxyphenyl)-8-(2-methoxyphenylaminomethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 8-4, 104 mg, 0.212 mmol) and sodium hydrogen carbonate (22.0 mg, 0.262 mmol) were dissolved in a mixed solvent of 1,4-dioxane (1.5 mL) and water (1 mL), and 9-fluorenylmethoxycarbonyl chloride (60.3 mg, 0.233 mmol) was added thereto. After the reaction mixture was stirred at room temperature for 30 minutes, the mixture was diluted with ethyl acetate (50 mL). The mixture was washed with water (50 mL) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (149 mg) as a colorless amorphous product. (Yield 99%)
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[C:19]2[C:18](=[O:20])[N:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:16](=[O:27])[N:15]([CH2:28][C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])[C:14]=2[S:13][C:12]=1[C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44]([NH:46][O:47][CH3:48])=[O:45])=[CH:39][CH:38]=1)C)C1C=CC=CC=1.Cl>C(O)C.[C].[Pd]>[F:36][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([F:35])[C:29]=1[CH2:28][N:15]1[C:14]2[S:13][C:12]([C:37]3[CH:42]=[CH:41][C:40]([NH:43][C:44]([NH:46][O:47][CH3:48])=[O:45])=[CH:39][CH:38]=3)=[C:11]([CH2:10][NH:8][CH3:1])[C:19]=2[C:18](=[O:20])[N:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:16]1=[O:27]
Reactant: CONC(=O)Nc1ccc(-c2sc3c(c2CN(C)Cc2ccccc2)c(=O)n(-c2ccccn2)c(=O)n3Cc2c(F)cccc2F)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CNCc1c(-c2ccc(NC(=O)NOC)cc2)sc2c1c(=O)n(-c1ccccn1)c(=O)n2Cc1c(F)cccc1F
Reaction time: 20 h
Yield: 71.2 %

Procedure:
To a solution of the compound obtained in Example 1 (1.59 g, 2.38 mmol) in ethanol (40 ml) were added 1N hydrochloric acid (7 ml) and 10% palladium-carbon (60% wet, 0.63 g), and the mixture was stirred vigorously under hydrogen atmosphere for 20 hours. The catalyst was removed, and the filtrate was neutralized with 1N sodium hydroxide solution. The solvent was distilled off. The residue was distributed between ethyl acetate and water, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the obtained powders were washed with diethyl ether to give the title compound (980 mg, 71%) as pale yellow powders.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:34]1[C:38]([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[N:37][N:36]=[N:35]1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:42]4[CH2:43][CH2:44][CH:39]([C:38]5[NH:37][N:36]=[N:35][N:34]=5)[CH2:40][CH2:41]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: C1CC(c2nnn[nH]2)CCN1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCC(c3nnn[nH]3)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(1H-tetrazol-5-yl)-piperidin-1-yl]-thiazol-4-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 4-(1H-tetrazol-5-yl)-piperidine following General Procedure B.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH2:12][O:11][C:10]([NH2:13])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(CCC)=CC(CCC)=CC=1CCC)(C)(C)C.[CH3:58][O:59][C:60]1[CH:61]=[C:62]([CH:64]=[CH:65][CH:66]=1)[NH2:63]>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.O.C1(C)C=CC=CC=1>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:8]2([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([NH:63][C:62]4[CH:64]=[CH:65][CH:66]=[C:60]([O:59][CH3:58])[CH:61]=4)[CH:3]=3)[CH2:12][O:11][C:10]([NH2:13])=[N:9]2)=[CH:15][CH:16]=1
Reactant: COc1ccc(C2(c3cccc(Br)c3)COC(N)=N2)cc1
Reactant: COc1cccc(N)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CCCc1cc(CCC)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(CCC)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(C2(c3cccc(Nc4cccc(OC)c4)c3)COC(N)=N2)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A microwave tube was charged with (RS)-4-(3-bromo-phenyl)-4-(4-methoxy-phenyl)-4,5-dihydro-oxazol-2-ylamine (Building Block C, 100 mg, 0.288 mmol), sodium tert-butoxide (55 mg, 0.58 mmol), 2-di-t-butylphosphino-2′,4′,6′-tri-1-propyl-1,1′biphenyl (11 mg, 0.028 mmol), tris(dibenzylideneacetone)dipalladium (7 mg, 0.008 mmol) and 3-methoxyaniline (71 mg, 0.576 mmol). After three vacuum-nitrogen cycles, toluene was introduced (0.7 mL), the tube was scaled and stirred at 100° C. for 16 hours. After cooling to room temperature, water (1 mL) and ethyl acetate (1 mL) were added. The organic fraction of the reaction mixture was placed on an SCX column. This was then washed with dichloromethane/methanol. The desired product was obtained by eluting with 2 M ammonia in methanol. Fractions containing the compound were combined and the product purified further using preparative HPLC to yield 35 mg (31% yield) of the title compound as a white solid.
Reaction SMILES: N1C=CC=C(CNC(C2C=CC3NC(C4C(C(=O)NC(C)C)=CNN=4)=NC=3C=2)=O)C=1.[NH2:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=1[NH:40][C:41]([C:43]1[C:47]([N+:48]([O-:50])=[O:49])=[CH:46][NH:45][N:44]=1)=O.[OH-].[Na+]>O>[CH3:39][O:38][C:36]1[CH:35]=[CH:34][C:33]2[NH:40][C:41]([C:43]3[C:47]([N+:48]([O-:50])=[O:49])=[CH:46][NH:45][N:44]=3)=[N:31][C:32]=2[CH:37]=1
Reactant: COc1ccc(NC(=O)c2n[nH]cc2[N+](=O)[O-])c(N)c1
Agent: CC(C)NC(=O)c1c[nH]nc1-c1nc2cc(C(=O)NCc3cccnc3)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2[nH]c(-c3n[nH]cc3[N+](=O)[O-])nc2c1
Temperature: 120 °C

Procedure:
By proceeding in a manner similar to Example 252(a) above but (i) using 4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4-methoxy-phenyl)-amide [410 mg, Reference Example 36(d)] and heating at 120° C. for 5 minutes, (ii) pouring the reaction mixture into water, adjusting to pH14 with 2N sodium hydroxide and filtering, and (iii) adjusting the pH of the filtrate to 6 with 2N hydrochloric acid and collecting the precipitate by filtration, there was prepared 5-methoxy-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole (327 mg) as a yellow powder. LC-MS (Method H): RT=1.61 minutes, 260.25 (M+H)+, 258.26 (M−H)−.
Reaction SMILES: [CH:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[I:15])=[CH2:2].Cl[CH2:17]I.C([Zn]CC)C>ClCCCl>[CH:1]1([O:3][C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]([F:12])([F:13])[F:14])=[CH:6][C:5]=2[I:15])[CH2:17][CH2:2]1
Reactant: C=COc1ccc(OC(F)(F)F)cc1I
Reactant: ClCI
Agent: CC[Zn]CC
Solvent: ClCCCl
Product: FC(F)(F)Oc1ccc(OC2CC2)c(I)c1
Temperature: 0 °C
Yield: 73.9 %

Procedure:
1-(Vinyloxy)-2-iodo-4-(trifluoromethoxy)benzene (Description 11; 7.6 g, 23 mmol) and chloroiodomethane (5.4 mL, 74 mmol) were dissolved in 1,2-dichloroethane (40 mL) and cooled to 0° C. Diethyl zinc (3.8 mL, 36.8 mmol) was then added dropwise. The solution was allowed to warm to room temperature for 10 minutes, then cooled back to 0° C. when it was quenched with saturated aqueous ammonium chloride solution (50 mL). The suspension formed was extracted with 50% diethyl ether/hexane (2×100 mL) and the extracts dried (MgSO4). Concentration yielded a yellow oil which was purified by silica chromatography to give the title compound as a clear oil (5.84 g, 17 mmol).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([N+:9]#[C-:10])[CH2:7][CH3:8].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH2:21][CH2:22][CH2:23]Cl)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>>[CH2:7]([C:6]([N+:9]#[C-:10])([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:23][CH2:22][CH2:21][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:13]([O:12][CH3:11])[CH:14]=1)[CH3:8]
Reactant: COc1ccc(CCCCl)cc1OC
Reactant: [C-]#[N+]C(CC)c1cccs1
Product: [C-]#[N+]C(CC)(CCCc1ccc(OC)c(OC)c1)c1cccs1
Yield: 68.3 %

Procedure:
4.84 g of 1-(2-thienyl)propyl isocyanide and 6.87 g of 3-(3,4-dimethoxyphenyl)propyl chloride are treated in the same manner as described in Example 1-(1) to give 7.2 g of 1-ethyl-4-(3,4-dimethoxyphenyl)-1-(2-thienyl)butyl isocyanide as a colorless oil. Yield; 68.3%
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:23](Cl)=[O:24])=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[NH:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43][CH2:42][CH2:41]1>C1(C)C=CC=CC=1>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:23]([N:40]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:43][CH2:42][CH2:41]2)=[O:24])=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc2c(c1)CCCN2
Reactant: CCCCCN(Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCN(Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)C(=O)N1CCCc2ccccc21
Temperature: 25 °C
Yield: 67.2 %

Procedure:
A solution of 100 mg (0.22 mmole) of N-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]-N-pentylcarbamoyl chloride (from Example 2, Step B), 0.2 mL (1.15 mmole) of N,N-diisopropylethylamine, and 44 mg (0.33 mmole) of 1,2,3,4-tetrahydroquinoline in 2.5 mL of toluene was stirred at 110° C. for two days. After cooling to room temperature, volatiles were removed by rotary evaporation, and the residue was flash chromatographed over silica gel (gradient elution using 10% to 12.5% EtOAc in hexane) to give 81 mg (66%) of the desired product as an oil, homogeneous by TLC (4:1 hexane-EtOAc), FAB-MS m/e 548 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14](C1CCCCO1)[N:13]=[C:12]2[C:24]1[N:29]=[C:28]([N:30]2[CH2:35][CH2:34][CH2:33][CH:32]([NH:36]C(=O)OC(C)(C)C)[CH2:31]2)[CH:27]=[N:26][CH:25]=1.Cl>CCOCC.O.C([O-])([O-])=O.[K+].[K+]>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[C:24]1[N:29]=[C:28]([N:30]2[CH2:35][CH2:34][CH2:33][CH:32]([NH2:36])[CH2:31]2)[CH:27]=[N:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2cncc(-c3nn(C4CCCCO4)c4ccc(-c5c(F)cccc5F)cc34)n2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: NC1CCCN(c2cncc(-c3n[nH]c4ccc(-c5c(F)cccc5F)cc34)n2)C1
Temperature: 80 °C

Procedure:
To a solution of tert-butyl 1-(6-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-3-ylcarbamate (350 mg, 0.592 mmol) in Et2O (6 mL) was added HCl in Et2O (6 mL). The reaction mixture was heated at 80° C. overnight and cooled to RT. The resulting mixture was diluted with water and neutralized with K2CO3. The resulting precipitate was collected by filtration, washed with water and a mixture of EtOH/EtOA (1:10), and dried overnight to give 1-(6-(5-(2,6-difluorophenyl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-3-amine MS (ESI, pos. ion) m/z: 407 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[Cl:16][C:17]1[CH:18]=[C:19]([CH:29]([NH2:31])[CH3:30])[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][C:25]([F:28])([F:27])[CH3:26]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:31]([CH:29]([C:19]3[CH:20]=[CH:21][C:22]([O:23][CH2:24][C:25]([F:27])([F:28])[CH3:26])=[C:17]([Cl:16])[CH:18]=3)[CH3:30])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CC(N)c1ccc(OCC(C)(F)F)c(Cl)c1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: CC(c1ccc(OCC(C)(F)F)c(Cl)c1)N1Cc2c(ccnc2Cl)C1=O
Yield: 59 %

Procedure:
The title compound is prepared in 59% yield (331 mg, colorless oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (389 mg, 1.40 mmol, Step-1 of Intermediate-1) and 1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethanamine hydrochloride (400 mg, 1.40 mmol, Amine-85, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][S:9][C:10]2[N:15]=[N:14][C:13]([C:16]3[CH:57]=[CH:56][C:19]([CH2:20][C:21]4[N:22]([C:34]5[CH:35]=[C:36]([N:40]6[S:44](=[O:46])(=[O:45])[N:43](COCC[Si](C)(C)C)[C:42](=[O:55])[CH2:41]6)[CH:37]=[CH:38][CH:39]=5)[CH:23]=[C:24]([C:26]5[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=5[Cl:33])[N:25]=4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH:1]1([CH2:7][CH2:8][S:9][C:10]2[N:15]=[N:14][C:13]([C:16]3[CH:57]=[CH:56][C:19]([CH2:20][C:21]4[N:22]([C:34]5[CH:35]=[C:36]([N:40]6[S:44](=[O:46])(=[O:45])[NH:43][C:42](=[O:55])[CH2:41]6)[CH:37]=[CH:38][CH:39]=5)[CH:23]=[C:24]([C:26]5[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=5[Cl:33])[N:25]=4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(SCCC5CCCCC5)nn4)cc3)c2)S1(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(SCCC5CCCCC5)nn4)cc3)c2)S(=O)(=O)N1

Procedure:
5-{3-[2-{4-[6-(2-Cyclohexyl-ethylsulfanyl)-pyridazin-3-yl]-benzyl}-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one (17 mg, 0.02 mmol) was treated as described in general procedure W using tetrabutylammonium fluoride (26 mg, 0.1 mmol) to give 5-{3-[2-{4-[6-(2-cyclohexyl-ethylsulfanyl)-pyridazin-3-yl]-benzyl}-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)[CH:10]=[N:9]2)[CH2:7][NH:6][CH2:5]1)#[N:2].[O:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[CH2:42][C:43](O)=[O:44]>>[C:1]([CH2:3][C:4]1([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:35])([F:36])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)[CH:10]=[N:9]2)[CH2:5][N:6]([C:43](=[O:44])[CH2:42][CH:38]2[CH2:39][CH2:40][CH2:41][O:37]2)[CH2:7]1)#[N:2]
Reactant: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CNC1
Reactant: O=C(O)CC1CCCO1
Product: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CN(C(=O)CC2CCCO2)C1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 77 starting from N-[3-(7-{1-[3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea and tetrahydrofuran-2-ylacetic acid (Matrix Scitific, cat. No. 020454). LCMS (M+H)+: m/z=608.2.