Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH3:12])=[C:7]([O:13][CH2:14][O:15][CH3:16])[C:6]([O:17][CH3:18])=[C:5]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[C:29]([O:30][CH2:31][O:32][CH3:33])=[C:28]([O:34][CH3:35])[C:27]([OH:36])=[C:26]([O:37][CH2:38][O:39][CH3:40])[C:25]=2[O:41][CH3:42])[C:4]=1[O:43][CH2:44][O:45][CH3:46].[CH3:47]O>>[CH3:1][O:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH3:12])=[C:7]([O:13][CH2:14][O:15][CH3:16])[C:6]([O:17][CH3:18])=[C:5]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[C:29]([O:30][CH2:31][O:32][CH3:33])=[C:28]([O:34][CH3:35])[C:27]([O:36][CH3:47])=[C:26]([O:37][CH2:38][O:39][CH3:40])[C:25]=2[O:41][CH3:42])[C:4]=1[O:43][CH2:44][O:45][CH3:46]
Reactant: CCCCc1c(OC)c(OCOC)c(CCCCCc2c(OC)c(OCOC)c(O)c(OC)c2OCOC)c(OC)c1OCOC
Reactant: CO
Product: CCCCc1c(OC)c(OCOC)c(CCCCCc2c(OCOC)c(OC)c(OC)c(OCOC)c2OC)c(OC)c1OCOC
Reaction time: 3 h

Procedure:
1.3 Grams of 1,4-dimethoxy-2,5-bis(methoxymethoxy)-6-butyl-3-{5-[2,5-dimethoxy-3,6-bis(methoxymethoxy)-4-hydroxyphenyl]pentyl}benzene was dissolved in 50 ml of methanol, to this solution was added an excess amount of diazomethane-ether solution was added and the reaction mixture was stirred for 3 hours. The reaction mixture was concentrated to obtain 1.3 g of 1,4-dimethoxy-2,5-bis(methoxymethoxy)-6-butyl-3-{5-[2,4,5-trimethoxy-3,6-bis(methoxymethoxy)phenyl]pentyl}benzene. Colorless oily substance.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=S.O.O.O.C([O-])(=O)C.[Pb+2].C([O-])(=O)C.[NH3:31].[OH-].[K+]>C(O)C>[CH3:1][N:2]([CH3:18])[C:3]([NH2:31])=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: N
Reactant: CN(C)C(=S)Nc1ccccc1N1CCOCC1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(C)C(N)=Nc1ccccc1N1CCOCC1

Procedure:
A mixture of 1,1-dimethyl-3-(2-morpholinophenyl)thiourea (2.65 g prepared as described in Example 232), lead acetate trihydrate (3.8 g), saturated ethanolic ammonia solution (25 ml), potassium hydroxide (1.12 g) and ethanol (20 ml) where heated at 90°-95° C. is a sealed stainless steel pressure vessel for 5 hours. The reaction mixture was filtered and the solid collected washed with ethanol. The washings were added to the filtrate and the volume reduced by evaporation. Ice was added and the resulting solid was collected by filtration, washed with water and dried to give 1,1-dimethyl-2-(2-morpholinophenyl)guanidine (m.p. 141°-142° C.) which was recrystallised from hexane.
Reaction SMILES: [O:1]=[S:2]1(=[O:27])[C:8]2[CH:9]=[C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=3)[C:17]([NH:19]/[C:20](=[N:22]\[OH:23])/[CH3:21])=O)[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH2:4][NH:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:21][C:20]1[N:19]=[C:17]([C:16]2[CH:15]=[C:14]([CH:26]=[CH:25][CH:24]=2)[O:13][C:10]2[CH:11]=[CH:12][C:7]3[O:6][CH2:5][CH2:4][NH:3][S:2](=[O:27])(=[O:1])[C:8]=3[CH:9]=2)[O:23][N:22]=1
Reactant: C/C(=N/O)NC(=O)c1cccc(Oc2ccc3c(c2)S(=O)(=O)NCCO3)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1noc(-c2cccc(Oc3ccc4c(c3)S(=O)(=O)NCCO4)c2)n1

Procedure:
To a solution of 390 mg (0.99 mmol) of the product obtained in Step B above in 50 ml of toluene there are added 35 mg of para-toluenesulphonic acid and the reaction mixture is heated at reflux using a Dean-Stark system for 12 hours. After evaporation, the crude reaction product is purified over silica gel eluting with a mixture of CH2Cl2/AcOEt 9/1 to yield the expected product.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:22](O)[CH3:23]>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([O:10][CH2:22][CH3:23])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
2,2-Diphenylacetic acid (50 g) was dissolved in ethanol (350 mL). Concentrated sulfuric acid (3 mL) was added, and the mixture was refluxed overnight. After cooling to room temperature, the reaction mixture was concentrated and diluted with diethyl ether. The organic solvent solution was then extracted with water, saturated aqueous sodium bicarbonate solution, and brine. The organic layer was then dried with magnesium sulfate, filtered, and concentrated to obtain the title compound. MS (DCI+) m/z 241 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][C:9]2=O)=[CH:4][C:3]=1[CH3:15].Cl.[O:17]([NH2:19])[CH3:18].N1C=CC=CC=1>C(O)C>[CH3:18][O:17][N:19]=[C:9]1[C:10]2[C:5](=[CH:4][C:3]([CH3:15])=[C:2]([Br:1])[CH:11]=2)[C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8]1
Reactant: Cc1cc2c(cc1Br)C(=O)CCC2(C)C
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C1CCC(C)(C)c2cc(C)c(Br)cc21
Yield: 99.9 %

Procedure:
A solution of 7-bromo-1-oxo-4,4,6-trimethyl-1,2,3,4-tetrahydronaphthalene (1.02 g, 3.82 mmol), methoxylamine hydrochloride (0.638 mg, 7.63 mmol) and pyridine (0.93 mL, 11.46 mmol) in ethanol (30 mL) was refluxed for 3 hours. The mixture was concentrated in vacuo then diluted with water and extracted twice with ethyl acetate. The combined organic layer was dried (Mg2SO4), filtered and evaporated to give 1.13 g of 7-bromo-1-oxo-4,4,6-trimethyl-1,2,3,4-tetrahydronaphthalene-O-methyloxime as a yellow oil (quantitative) and used without further purification in the Suzuki coupling (step a). 1H NMR (300 MHz; CDCl3): 1.25 (s, 6 H), 1.75 (t, J=6.9 Hz, 2 H), 2.38 (s, 3 H), 2.73 (t, J=6.9 Hz, 2 H), 3.98 (s, 3 H), 7.17 (s, 1 H), 8.11 (s, 1 H).
Reaction SMILES: Br[CH2:2][CH:3]([N:10]1[C:14]2[CH:15]=[C:16]([F:20])[C:17]([F:19])=[CH:18][C:13]=2[N:12]=[C:11]1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[OH:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:11]2[N:10]([CH:3]([CH:4]3[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]3)[CH2:2][O:28][C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)[C:14]3[CH:15]=[C:16]([F:20])[C:17]([F:19])=[CH:18][C:13]=3[N:12]=2)=[CH:22][CH:23]=1
Reactant: Oc1ccncc1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(CBr)C3CCCCC3)c2cc1F
Product: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(COc3ccncc3)C3CCCCC3)c2cc1F

Procedure:
The title compound was prepared in analogy to Example 35 from 1-(2-bromo-1-cyclohexyl-ethyl)-2-(4-chloro-phenyl)-5,6-difluoro-1H-benzoimidazole (Ex. 34, int.) and 4-hydroxypyridine after a reaction time of 3 days at room temperature. White solid (32%). MS (Turbo Spray): m/z=468.2 [M+H].
Reaction SMILES: [CH3:1][S:2]([NH:5][C@@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C@@H:7]1OS(C)(=O)=O)(=[O:4])=[O:3].[N-:20]=[N+]=[N-].[Na+]>CC(N(C)C)=O.CCOC(C)=O>[NH2:20][C@@H:7]1[CH2:8][C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@H:6]1[NH:5][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)N[C@@H]1c2ccccc2C[C@@H]1OS(C)(=O)=O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N[C@@H]1c2ccccc2C[C@H]1N
Temperature: 90 °C
Reaction time: 3 h
Yield: 84.2 %

Procedure:
(1R,2S)-1-Methanesulphonamido-2-methylsulphonyloxyindan (2.0 g, 6.56 mmol) was dissolved in dry dimethyl acetamide (20 ml). Sodium azide (1.7 g, 26.2 mmol) was added and the mixture heated to 90° C. for 1 hour. The reaction was cooled, diluted with EtOAc (100 ml), washed with water (6×50 ml), dried over magnesium sulphate and filtered. 10% Palladium on activated carbon was added and the mixture stirred under a hydrogen atmosphere for 3 hours. Filtration through celite followed by evaporation gave the title compound (1.25 g, 83%) as a pale green solid.
Reaction SMILES: [Cl:1][C:2]1[C:9](I)=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].[CH2:12]([Sn](CCCC)(CCCC)CCCC)[CH:13]=[CH2:14].[Li+].[Cl-]>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:9]([CH2:14][CH:13]=[CH2:12])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(F)ccc(I)c1Cl
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCc1ccc(F)c(C#N)c1Cl
Temperature: 100 °C

Procedure:
A mixture of 2-chloro-6-fluoro-3-iodobenzonitrile (800 mg, 2.85 mmol), allyltributylstannane (1.245 mg, 3.761 mmol), LiCl (431 mg, 10.3 mmol) and Pd(PPh3)4 (100 mg) in 50 mL toluene was heated at 100° C. overnight. Cooled to rt. and diluted with 50 mL EtOAc and filtered. The filtrate was washed with water and brine, dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified via prep-TLC (ethyl acetate/Pet ether=1:5) to give 2-chloro-6-fluoro-3-(prop-2-en-1-yl)benzonitrile. 1H-NMR (400 MHz, CDCl3) δ ppm 7.37˜7.41 (m, 1H), 7.01˜7.06 (m, 1H), 5.78˜5.87 (m, 1H), 4.99˜5.12 (m, 2H), 3.44 (d, J=6.3 Hz, 2H).
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1>C(O)C.[Pd]>[Cl:1][CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1
Reactant: O=[N+]([O-])c1ccc2c(c1)OC(CCl)CO2
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)OC(CCl)CO2

Procedure:
150 g of 2-chloromethyl 7-nitro 2,3-dihydro [4H] 1,4-benzodioxin are dissolved in 2600 ml ethanol. 15 g of palladium on coal are added and the whole mixture is hydrogenated at room temperature and atmospheric pressure.
Reaction SMILES: CO.C[O-].[Na+].[O:6]1CCC[CH2:7]1.[Cl:11][C:12]1[N:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=1>O>[CH3:7][O:6][C:15]1[N:14]=[N:13][C:12]([Cl:11])=[CH:17][CH:16]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: C1CCOC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A 0.5 M sodium methoxide methanol solution (NaOMe in MeOH, 7.4 mL, 3.69 mmol) was slowly added to an anhydrous tetrahydrofuran (12 mL) solution having 3,6-dichloropyridazine (107, 500 mg, 3.36 mmol) dissolved therein, stirred at room temperature for one hour, followed by adding water. Organic compounds were extracted with ethyl acetate. Then, the recovered organic solution was washed with an aqueous solution of saturated sodium chloride and evaporated after a treatment with sodium sulfate. Purification was performed by column chromatograph to give the target compound 3-methoxy-6-chloropyridazine (108a, 436 mg, 90%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]1[NH:23][N:22]=[CH:21][CH:20]=1.[C:27]([CH:29]=[C:30]1[CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]1)#[N:28].N12CCCN=C1CCCCC2.Cl.O1CCOCC1.N>C(#N)C.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]1[CH:20]=[CH:21][N:22]([C:30]2([CH2:29][C:27]#[N:28])[CH2:33][NH:32][CH2:31]2)[N:23]=1
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Reactant: Cc1nnc2ccc3c(cc(-c4ccn[nH]4)n3Cc3cccc(Cl)c3)n12
Agent: Cl
Agent: N
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cc1nnc2ccc3c(cc(-c4ccn(C5(CC#N)CNC5)n4)n3Cc3cccc(Cl)c3)n12
Reaction time: 1.17 h
Yield: 73 %

Procedure:
6-(3-Chlorobenzyl)-1-methyl-7-(1H-pyrazol-5-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (25 mg, 0.069 mmol, from Example 103, Step 5) in acetonitrile (0.90 mL), was treated with tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (27 mg, 0.14 mmol, prepared as described in WO 2009114512) and 1,8-diazabicyclo[5.4.0]undec-7-ene (10. μL, 0.069 mmol, Aldrich). After 70 minutes, 4.0 M hydrogen chloride in dioxane (0.23 mL, 0.90 mmol) was added into the reaction. After 30 minutes, the reaction was diluted with methanol, and adjusted to pH˜10 by the addition of a small amount of aqueous ammonia. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) afforded product (23 mg, 73%).
Reaction SMILES: [CH3:1][N:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:6](=[O:7])[N:5]([C:14]2[CH:26]=[CH:25][C:17]3[N:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[NH:20][C:16]=3[CH:15]=2)[C:3]1=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH:35]=[CH2:36].O>CN(C)C=O>[CH3:1][N:2]1[C:9]([C:10]([F:11])([F:12])[F:13])=[CH:8][C:6](=[O:7])[N:5]([C:14]2[CH:26]=[CH:25][C:17]3[N:18]=[C:19]([C:21]([F:23])([F:24])[F:22])[N:20]([CH2:36][CH:35]=[CH2:34])[C:16]=3[CH:15]=2)[C:3]1=[O:4]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3nc(C(F)(F)F)[nH]c3c2)c1=O
Reactant: C=CCBr
Agent: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3[nH]c(C(F)(F)F)nc3c2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(C(F)(F)F)nc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, 1.3 grams (0.003 mole) of a tautomeric mixture of 1-methyl-3-(2-trifluoromethylbenzimidazol-5-yl)-6-trifluoromethyluracil and 1-methyl-3-(2-trifluoromethylbenzimidazol-6-yl)-6-trifluoromethyluracil (prepared in Example 4) in 15 mL of N,N-dimethylformamide was stirred, and 0.9 gram (0.007 mole) of potassium carbonate was added. The reaction mixture was then stirred at ambient temperature for one hour, and 0.5 gram (0.004 mole) of 3-bromopropene was added in one portion. Upon completion of the addition, the reaction mixture was stirred at ambient temperature for an additional two hours. The reaction mixture was then poured into water, and the resultant solid precipitate was collected by filtration. The solid was washed with water and then with diethyl ether. Thin layer chromatographic analysis of the solid indicated it to be a 1:1 mixture of the proposed products. The solid was subjected to high pressure liquid chromatography, with 5% 1-methylethanol in hexane as the eluant. The appropriate product-containing fractions were combined and concentrated under reduced pressure, yielding 0.3 gram of 1-methyl-3-[1-(2-propen-1-yl)-2-trifluoromethylbenzimidazol-6-yl]-6-trifluoromethyluracil, mp 171°-173° C. (compound 9). Other appropriate product-containing fractions were combined and concentrated under reduced pressure, yielding 0.4 gram of 1-methyl-3-[1-(2-propen-1-yl)-2-trifluoromethylbenzimidazol-5-yl]-6-trifluoromethyluracil, mp 185°-187° C. The NMR spectra were consistent with the proposed structures.
Reaction SMILES: NC1C=C(Br)SC=1C(N)=O.C(OC(N1CCC[C@H]1C(O)=O)=O)(C)(C)C.C(N(C(C)C)C(C)C)C.C(=O)([O-])O.[Na+].[Br:40][C:41]1[S:45][C:44]([C:46](=[O:48])[NH2:47])=[C:43]([NH:49][C:50]([C@@H:52]2[CH2:56][CH2:55][CH2:54][N:53]2[C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])=O)[CH:42]=1.[OH-].[Na+].Cl>CN(C)C=O.C(O)C.C(OCC)(=O)C>[Br:40][C:41]1[S:45][C:44]2[C:46](=[O:48])[NH:47][C:50]([C@@H:52]3[CH2:56][CH2:55][CH2:54][N:53]3[C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])=[N:49][C:43]=2[CH:42]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1cc(Br)sc1C(N)=O
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Agent: NC(=O)c1sc(Br)cc1N
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(Br)sc2c(=O)[nH]1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A solution of 3-amino-5-bromothiophene-2-carboxamide (300 mg) produced in Example 1, step D, 1-(tert-butoxycarbonyl)-L-proline (700 mg), O-(7-azabenzotriazol-1-yl)-N,N,N′-tetramethyluronium hexafluorophosphate (1.55 g) and N-ethyl-N-(1-methylethyl)propan-2-amine (0.713 mL) in N,N-dimethylformamide (8 mL) was stirred at 90° C. for 16 hr. Ethyl acetate (40 mL) and aqueous sodium hydrogen carbonate (20 mL) were added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layers were washed with brine (10 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give an inseparable mixture of tert-butyl (2S)-2-[(5-bromo-2-carbamoylthiophen-3-yl)carbamoyl]pyrrolidine-1-carboxylate and 3-amino-5-bromothiophene-2-carboxamide (starting material) as a yellow oil. To a solution of the mixture of tert-butyl (2S)-2-[(5-bromo-2-carbamoylthiophen-3-yl)carbamoyl]pyrrolidine-1-carboxylate and 3-amino-5-bromothiophene-2-carboxamide produced above in ethanol (6 mL) was added 2M aqueous sodium hydroxide solution (2.04 mL), and the mixture was stirred at 70° C. for 4 hr. 6M Hydrochloric acid (1 mL), ethyl acetate (20 mL) and aqueous sodium hydrogen carbonate (10 mL) were added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate (5 mL×2). The combined organic layers were washed with brine (5 mL) and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (175 mg) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].Cl.[NH2:12][C:13]1[CH:19]=[CH:18][C:16]([OH:17])=[CH:15][C:14]=1O.[OH-].[Na+].C1COCC1>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][C:14]3[CH:15]=[C:16]([OH:17])[CH:18]=[CH:19][C:13]=3[N:12]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Nc1ccc(O)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Oc1ccc2nc(-c3cccc(Cl)c3)oc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.5 %

Procedure:
4.5 ml (35.2 mmol) of 3-chlorobenzoyl chloride and 1.0 g (6.19 mmol) of 4-aminoresorcinol hydrochloride were introduced into a three-necked flask provided with a thermometer and a cooling condenser, and the mixture was heated at 170° to 235° C. for 1 hour, then the excessive acid chloride was removed by distillation. To the residue, 1.5 g (38.5 mmol) of NaOH, 20 ml of THF, 20 ml of water and 10 ml of ethanol were added, and the mixture was stirred at room temperature for about 2 hours. The reaction solution was extracted with ethyl acetate, the extract was washed with saturated sodium chloride water solution, and ethyl acetate was distilled off. Recrystallizing the residue with water/methanol/THF and drying the crystal, there was obtained 250 mg (1.02 mmol) of 2-(3-chlorophenyl)-6-hydroxybenzoxazole. The yield was 16.5%.
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([C:10]2[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:11]=2[C:12]([O:14]C)=[O:13])[CH2:7]1)(=O)=O.[F:24][C:25]([F:35])([F:34])[O:26][C:27]1[CH:28]=[C:29](O)[CH:30]=[CH:31][CH:32]=1>>[F:24][C:25]([F:34])([F:35])[O:26][C:27]1[CH:32]=[C:31]([CH:30]=[CH:29][CH:28]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10]2[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:11]=2[C:12]([OH:14])=[O:13])[CH2:7]1
Reactant: Oc1cccc(OC(F)(F)F)c1
Reactant: COC(=O)c1cc(C(F)(F)F)cnc1N1CC(OS(C)(=O)=O)C1
Product: O=C(O)c1cc(C(F)(F)F)cnc1N1CC(Oc2cccc(OC(F)(F)F)c2)C1
Yield: 101 %

Procedure:
The title compound (D126) (110 mg) was prepared according to the experimental procedure described in Description 103A starting from methyl 2-(3-((methylsulfonyl)oxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinate (D68) (100 mg, 0.258 mmol) and 3-(trifluoromethoxy)phenol (0.043 ml, 0.338 mmol).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:9]=[CH:8][C:7]=1[CH3:16])=[O:4].[C:17]([C:19]1[CH:20]=[C:21]([S:25]([N:28]2[C@H:33]([CH3:34])[CH2:32][NH:31][CH2:30][C@@H:29]2[CH3:35])(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1)#[N:18]>>[C:17]([C:19]1[CH:20]=[C:21]([S:25]([N:28]2[C@@H:33]([CH3:34])[CH2:32][N:31]([CH2:2][C:3]([NH:5][C:6]3[CH:11]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:9]=[CH:8][C:7]=3[CH3:16])=[O:4])[CH2:30][C@H:29]2[CH3:35])(=[O:26])=[O:27])[CH:22]=[CH:23][CH:24]=1)#[N:18]
Reactant: Cc1ccc(S(C)(=O)=O)cc1NC(=O)CCl
Reactant: C[C@@H]1CNC[C@H](C)N1S(=O)(=O)c1cccc(C#N)c1
Product: Cc1ccc(S(C)(=O)=O)cc1NC(=O)CN1C[C@@H](C)N(S(=O)(=O)c2cccc(C#N)c2)[C@@H](C)C1

Procedure:
The title compound was prepared from the product of step (i) (0.14 g) and the product of Example 80 step (ii) by the method of Example 80 step (iii) as a white solid. Yield: 0.03 g
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1([CH2:19][N+:20]([O-])=O)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)C>C(O)C.[Ni]>[C:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][C:6]2([CH2:19][NH:20][C:4](=[O:3])[CH2:5]2)[CH2:7][CH2:8]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)CC1(C[N+](=O)[O-])CCN(C(=O)OC(C)(C)C)CC1
Agent: [Ni]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(=O)C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of tert-butyl 4-(2-ethoxy-2-oxoethyl)-4-(nitromethyl)piperidine-1-carboxylate (330 g, 990 mmol, 1.00 equiv, 99%) and Ni (40 g, 0.15 equiv) in ethanol (1200 mL) was stirred for 24 h under a hydrogen atmosphere at room temperature. The solid was filtered out. The filtrate was concentrated under vacuum. The crude product was purified by re-crystallization from ether to afford the title compound. LC-MS (ES, m/z): 199 [M+H]+; 1H-NMR (400 MHz, CDCl3, ppm): 1.447-1.476(9H, s), 1.597-1.673(4H, m, J=30.4 Hz), 2.235(2H, s), 3.226(2H, s), 3.284-3.348(2H, m, J=25.6 Hz), 3.507-3.567(2H, m, J=24 Hz), 6.048(1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:5]=[C:6]([N+:9]([O-])=O)[C:7]=1[Cl:8]>[Pt]=O>[NH2:9][C:6]1[C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=[C:4]([C:12]([F:13])([F:14])[F:15])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc(Cl)c1Cl
Agent: O=[Pt]
Product: Nc1cc(C(F)(F)F)cc(Cl)c1Cl
Yield: 78.4 %

Procedure:
500 ml. of an ethanolic solution containing 3,4-dichloro-5-nitro-α,α,α-trifluorotoluene (188 g. 0.72 mol), and platinum oxide (Adam's catalyst) (0.2 g.) is reduced at room temperature in a low pressure hydrogenation apparatus to give 5-Amino-3,4-dichloro-α,α,α-trifluorotoluene (129.9 g. 78%) b.p. 65°-70° C./1-2 mm.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13])(=O)C.[OH-].[K+].Cl>O>[N+:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][OH:4])([O-:14])=[O:13]
Reactant: CC(=O)OCc1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccccc1CO
Reaction time: 2 h
Yield: 98 %

Procedure:
To a suspension of compound 62 (70 mg, 0.18 mmol) in H2O (10 mL) was added 10% aq. KOH solution (0.5 mL). The reaction mixture was heated under reflux for 24 h. The reaction solution was cooled to r. t., and adjusted to pH 7 with 1 M HCl, then concentrated to half volume. The solution was kept at 0° C. for 2 h, and filtered. The crude precipitate was purified by silica gel column (elute hexane/EtOAc:1/1) to afford 63 (27 mg, 50%) as white solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][CH2:38][C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[N:41]1[CH:42]=[CH:43][CH:44]=[C:39]([CH2:38][NH:37][S:34]([C:30]2[CH:29]=[C:28]([NH:27][C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]5[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=5)=[N:6][C:7]=34)=[O:13])[CH:33]=[CH:32][CH:31]=2)(=[O:36])=[O:35])[CH:40]=1
Reactant: Nc1cccc(S(=O)(=O)NCc2cccnc2)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=C(Nc1cccc(S(=O)(=O)NCc2cccnc2)c1)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-pyridin-3-ylmethyl-benzenesulfonamide (example B.5) according to general procedure II. Yellow solid. MS (ISP) 619.2 [(M−H−]; mp 257° C.