Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[CH2:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.BrC(C)C.O>C(OCC)C>[CH:2]([CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)([CH3:3])[CH3:1]
Reactant: C1=Cc2ccccc2C1
Reactant: [Li]CCCC
Solvent: CC(C)Br
Solvent: CCOCC
Solvent: O
Product: CC(C)C1C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
n-Butyl lithium (37 ml in hexane) was added to a solution of 1H-indene (6.30 ml) in anhydrous diethyl ether (40 ml) under nitrogen atmosphere at 15° C. The solution was stirred at room temperature for 10 min, 2-bromopropane (18.8 g) in anhydrous ether (100 ml) was added, and stirring was continued for 72 hours. Water (30 ml) was added, the phases were separated, and the aqueous phase was extracted with ether. The combined ether solutions was washed with water, dried (MgSO4) and condensed. The residue was distilled (50°-55° C., 0.03 mmHg) to give 1-isopropyl-1H-indene (5.95 g).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=[O:4].[CH:28]1([Mg]Br)[CH2:30][CH2:29]1>C1COCC1>[CH:28]1([C:3]([C:5]2[CH:6]=[CH:7][C:8]([N:11]3[CH2:16][CH2:15][N:14]([S:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH2:13][CH2:12]3)=[CH:9][CH:10]=2)([OH:4])[C:2]([F:1])([F:26])[F:27])[CH2:30][CH2:29]1
Reactant: Br[Mg]C1CC1
Reactant: O=C(c1ccc(N2CCN(S(=O)(=O)c3ccccc3)CC2)cc1)C(F)(F)F
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)N1CCN(c2ccc(C(O)(C3CC3)C(F)(F)F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 67.6 %

Procedure:
A 100 mL round-bottom flask was charged with 2,2,2-trifluoro-1-(4-(4-(phenylsulfonyl)-1-piperazinyl)phenyl)ethanone (0.50 g, 1.26 mmol) and 10 mL of THF. After cooling to 0° C., cyclopropylmagnesium bromide (5.02 mL, 0.5 M in THF, 2.51 mmol, Sigma-Aldrich, St. Louis, Mo.) was added. After 10 min, the mixture was quenched with saturated aqueous NH4Cl (15 mL), extracted with EtOAc (2×50 mL), dried (MgSO4), and concentrated to give an oil. This oil was purified via column chromatography (40 g of silica, 0 to 40% EtOAc in hexanes) to give 1-cyclopropyl-2,2,2-trifluoro-1-(4-(4-(phenylsulfonyl)-1-piperazinyl)phenyl)ethanol (0.375 g) as a mixture of two enantiomers.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[Cl:9][C:10]1[C:11]([C:29]2[CH:30]=[N:31][N:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=23)=[N:12][C:13]([NH:16][C:17]2[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[C:20](F)=[CH:19][C:18]=2[O:27][CH3:28])=[N:14][CH:15]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O.CO>[Cl:9][C:10]1[C:11]([C:29]2[CH:30]=[N:31][N:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=23)=[N:12][C:13]([NH:16][C:17]2[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[C:20]([N:5]3[CH2:6][CH2:7][C@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]3)=[CH:19][C:18]=2[O:27][CH3:28])=[N:14][CH:15]=1
Reactant: CN(C)[C@H]1CCNC1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Solvent: CC(=O)N(C)C
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CC[C@H](N(C)C)C2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Temperature: 140 °C
Yield: 98.2 %

Procedure:
(3S)—N,N-Dimethylpyrrolidin-3-amine (0.092 mL, 0.72 mmol) was added to a suspension of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 20, 250 mg, 0.60 mmol) and DIPEA (0.125 mL, 0.72 mmol) in DMA (3 mL) and the mixture was heated at 140° C. in a microwave for 0.5 h. The mixture was then diluted with CH3OH and absorbed onto an SCX column. The column was washed with CH3OH and then eluted with 1:1 7M methanolic ammonia in CH2Cl2. Appropriate fractions were concentrated and further purification by FCC, eluting with 2% 7N methanolic ammonia in CH2Cl2 gave the title compound (300 mg, 98%) as an orange foam; 1H NMR: 1.75-1.95 (1H, m), 2.09-2.30 (7H, m), 2.72-2.87 (1H, m), 3.11-3.27 (3H, m), 3.42-3.56 (1H, m), 3.90 (3H, s), 6.57 (1H, s), 7.13 (1H, t), 7.26-7.41 (1H, m), 8.09 (1H, s), 8.28-8.50 (2H, m), 8.67 (1H, s), 8.84 (1H, d), 8.95 (1H, s); m/z: ES+ MH+ 509.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.C[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[C:39]=1O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][C:26]2[C:42]([CH3:41])=[CH:43][CH:38]=[CH:39][C:40]=2[CH3:44])=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: Cc1cccc(C)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)Oc4c(C)cccc4C)cc3C)c2cc1OC
Yield: 104.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2,6-dimethylphenol (28 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (76 mg, yield 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([CH3:8])[CH:7]=1.C([Li])(C)(C)C.[CH2:15]([C@@H:17]1[O:19][CH2:18]1)[Cl:16]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:16][CH2:15][C@H:17]([OH:19])[CH2:18][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([CH3:8])[CH:7]=1
Reactant: ClC[C@H]1CO1
Reactant: Cc1cc(Br)ccc1Cl
Agent: [Li]C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(C[C@@H](O)CCl)ccc1Cl
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
The solution of 1.0 g (4.9 mmol) 5-bromo-2-chlorotoluene in 10 mL toluene was cooled down to −70° C. and treated dropwise with 3.6 mL (5.4 mmol; 1.5M solution in toluene) tert-butyllithium. After 30 min. 0.42 mL (5.3 mmol) (R)-(−)-epichlorohydrin was added and the temperature was allowed to rise to 0° C. After 1 h the reaction mixture was diluted with ethyl acetate and extracted with 10% aqueous sodium bicarbonate solution followed by brine. The organic layer was dried over magnesium sulfate, filtered and evaporated and the residue was purified by column chromatography on silica gel with n-hexane:ethyl acetate (1:1) as eluant to give the title compound as a colorless oil (44.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([Cl:25])[CH:20]=3)[N:17]=[C:16]([C:26](O)=[O:27])[CH:15]=2)[CH:6]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:8]=1.ClC1C=C(C2N(C3C=NC=CC=3)N=C(C([N:50]3[CH2:55][CH2:54][NH:53][C:52](=[O:56])[CH2:51]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[Cl:25][C:21]1[CH:20]=[C:19]([N:18]2[C:14]([C:5]3[CH:6]=[C:7]([O:9][C:10]([F:12])([F:11])[F:13])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:15][C:16]([C:26]([N:50]3[CH2:55][CH2:54][NH:53][C:52](=[O:56])[CH2:51]3)=[O:27])=[N:17]2)[CH:24]=[CH:23][N:22]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3cccnc3)n2)CCN1
Reactant: COc1cc(OC(F)(F)F)cc(-c2cc(C(=O)O)nn2-c2ccnc(Cl)c2)c1
Agent: O=C1CNCCN1
Product: COc1cc(OC(F)(F)F)cc(-c2cc(C(=O)N3CCNC(=O)C3)nn2-c2ccnc(Cl)c2)c1

Procedure:
31 mg (0.08 mmol) of the compound of Example 57A is reacted analogously to the synthesis of the compound of Example 4 with 8 mg (0.08 mmol) of 2-oxopiperazine. 37 mg (99% of theory) of the title compound is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:3]=1[OH:17].[S:18]1[C:22]([C:23](Cl)=O)=[CH:21][C:20]2[CH:26]=[CH:27][CH:28]=[CH:29][C:19]1=2.CS(O)(=O)=O.O>O1CCOCC1.C1(C)C=CC=CC=1>[S:18]1[C:22]([C:23]2[O:17][C:3]3[C:4]([CH2:9][CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=4)=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[N:1]=2)=[CH:21][C:20]2[CH:26]=[CH:27][CH:28]=[CH:29][C:19]1=2
Reactant: O=C(Cl)c1cc2ccccc2s1
Reactant: Nc1cc(Cl)cc(CCc2ccccn2)c1O
Agent: CS(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Clc1cc(CCc2ccccn2)c2oc(-c3cc4ccccc4s3)nc2c1
Yield: 41 %

Procedure:
This compound is prepared from 2-amino-4-chloro-6-[2-(pyridin-2-yl)ethyl]-phenol and benzo[b]thiophene-2-carbonyl chloride using method A with 1,4-dioxan as solvent to give the crude amide (73%). This is treated with methanesulphonic acid in toluene at reflux with azeotropic removal of water to give the title compound, (41%) as a white crystalline solid m.p.=183-184° C. TLC (SiO2, EtOAc:hexanes 1:1, Rf=0.56). CI Mass Spectrum (methane) m/z=391 [M+H]+.
Reaction SMILES: C([C:4]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=1)(=O)C.Cl[O-:17].[Na+].[O:19]1[CH2:24]COCC1>S(Cl)(Cl)=O>[CH:5]1[C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:14]=[CH:15][C:4]=1[C:24]([OH:19])=[O:17]
Reactant: C1COCCO1
Reactant: [O-]Cl
Reactant: CC(=O)c1ccc2c(c1)-c1ccccc1-2
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: O=C(O)c1ccc2c(c1)-c1ccccc1-2

Procedure:
2-Biphenylene carboxylic acid is prepared from the oxidation of 2-acetylbiphenylene in dioxane with sodium hypochlorite solution by the process described by W. Baker et al., J. Chem. Soc. 1476 (1954). The acid is refluxed in excess thionyl chloride to produce the acid chloride.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10]O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15](N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].Cl>ClCCl>[CH3:15][O:14][C:12](=[O:13])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][S:23]([CH3:22])(=[O:25])=[O:24]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C(CS(C)(=O)=O)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
A solution of N-tert-butoxycarbonylserine (1.1 g, 5.0 mmol) and triethylamine (0.84 mL, 6.0 mmol) in dichloromethane (50 mL) was cooled to 0° C. and treated with methylsulfonyl chloride (0.44 mL, 5.8 mmol)). After stirring an additional 2 h, the reaction mixture was acidified with 2% HCl (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were washed successively with sat. aq NaHCO3, and sat. aq NaCl, dried over MgSO4 and concentrated. Purification by flash column chromatography (5% ethyl acetate in heptane) gave the desired product (1.25 g, 84%) as an oil. 1H NMR (CDCl3), 5.71 (d, J=7 Hz, 1H), 4.56 (m, 3H), 3.82 (s, 3H), 3.02 (s, 3H), 1.44 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:16](Cl)(=[O:18])=[O:17])[CH:5]=[CH:6][C:7]=1[NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10].[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21]>O1CCCC1>[C:20]([NH:24][S:16]([C:4]1[CH:5]=[CH:6][C:7]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:2]([CH3:1])[CH:3]=1)(=[O:18])=[O:17])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)N
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1NS(=O)(=O)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1cc(S(=O)(=O)NC(C)(C)C)ccc1NS(=O)(=O)C(F)(F)F
Reaction time: 8 h
Yield: 34.3 %

Procedure:
3-Methyl-4-(trifluoromethanesulfonamido)benzenesulfonyl chloride (1.5 g) was added to tetrahydrofuran (40 ml) containing t-butylamine (0.65 g), and the resultant mixture was allowed to stand at room temperature overnight. The reaction mixture was concentrated and extracted with chloroform. The extract was washed with 5% hydrochloric acid and water in order, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from benzene and then from toluene to give 0.57 g of N-t-butyl-3-methyl-4-(trifluoromethanesulfonamido)benzenesulfonamide (Compound No. 16). M.P., 139.5°-140.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]([C:14]2([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16][CH2:15]2)=[CH:4][C:3]=1Br.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.[F-].[Cs+].CCOC(C)=O>COCCOC.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.O>[NH2:1][C:2]1[C:3]([C:29]2[CH:30]=[CH:31][C:26]([C:25]([F:36])([F:35])[F:24])=[CH:27][CH:28]=2)=[CH:4][C:5]([C:14]2([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16][CH2:15]2)=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: CCOC(=O)C1(c2cc(Br)c(N)c(OCC(F)(F)F)c2)CCC1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C1(c2cc(OCC(F)(F)F)c(N)c(-c3ccc(C(F)(F)F)cc3)c2)CCC1
Yield: 73.1 %

Procedure:
A mixture of ethyl 1-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (0.32 g, 0.86 mmol), 4-trifluoromethylphenylboronic acid (0.246 g, 1.3 mmol), CsF (0.262 g, 1.7 mmol) and Pd (PPh3)4 (0.1 g, 0.08 mmol) in 10 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled, and 25 mL of EtOAc and 75 mL of water were added. The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 1-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate (0.290 g) as a yellow oil.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1)=[C:2]=[O:3].[CH:28]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=1[NH:38][C:39]([NH2:41])=[S:40])([CH3:30])[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+].[C:48](Cl)(=[O:51])[CH:49]=[CH2:50]>C(#N)C.C(OCC)(=O)C>[CH:28]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=1[N:38]1[C:48](=[O:51])[CH2:49][CH2:50][S:40]/[C:39]/1=[N:41]\[C:2]([NH:1][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:26])([F:25])[F:27])=[CH:19][CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1)=[O:3])([CH3:30])[CH3:29]
Reactant: O=C=NCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: C=CC(=O)Cl
Reactant: Cc1ccc(C(C)C)c(NC(N)=S)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1ccc(C(C)C)c(N2C(=O)CCS/C2=N\C(=O)NCCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1
Temperature: 40 °C
Yield: 43.4 %

Procedure:
3-(4-(2-Isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C34a) (0.18 g, 0.47 mmol), 1-(2-isopropyl-5-methylphenyl)thiourea (0.10 g, 0.50 mmol), and cesium carbonate (0.21 g, 0.63 mmol) in acetonitrile (2.3 mL) were stirred at room temperature overnight. The reaction was diluted with ethyl acetate and washed with water. The organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was dissolved in butanone (2.3 mL) followed by addition of acryloyl chloride (0.045 mL, 0.55 mmol). The reaction was heated at 40° C. for 4 hours. The reaction was cooled and concentrated. Purification by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent followed by drying in a vacuum oven provided the title compound as a yellow oil (0.13 g, 44%).
Reaction SMILES: [CH3:1][C:2]([CH:6](C)[CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:3][CH:4]=[O:5].Br[CH:14]=[CH:15][CH:16](C)C>>[CH3:1][C:2]1[CH:3]([C:4](=[O:5])/[CH:14]=[CH:15]\[CH3:16])[C:9]([CH3:10])([CH3:11])[CH2:8][CH2:7][CH:6]=1
Reactant: CC(C)C=CBr
Reactant: CC(C)=CCC(C)C(C)=CC=O
Product: C/C=C\C(=O)C1C(C)=CCCC1(C)C

Procedure:
2,6,6-Trimethyl-1-tetrolyl-2-cyclohexene obtained according to the description of paragraph (c) herebelow was hydrogenated according to the method described in Example 18, paragraph (a). Thus, cis-2,6,6-trimethyl-1-crotonoyl-2-cyclohexene was obtained in 85-00% yield. The spectral characteristics were as follows: NMR spectrum (CCl4): 0.85 (3 H, s); 0.96 (3 H, s), 1.62 (3 H, s broad), 2.12 (3 H, d, J=5.5 cps), 1.0-2.3 (4 H, complex band), 2.95 (1 H, s broad), 5.49 (1 H, s broad), 6.25 (2 H, complex band) ppm (δ).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=2)[NH2:10])[CH:2]=1.Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16].C(N(CC)CC)C>O1CCCC1>[C:18]1([O:17][C:15](=[O:16])[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:8]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cccc(-c2cccnc2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cccc(-c2cccnc2)c1)Oc1ccccc1
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
A solution of 3-pyridin-3-ylaniline (500 mg, 2.94 mmol) in tetrahydrofuran (6 mL) was added at room temperature to a solution of phenyl chloroformate (450 mg, 2.94 mmol), then triethylamine (288 mg, 2.84 mmol) was added. After 15 min the reaction mixture was concentrated under vacuum, then the residue was partitioned between ethyl acetate and 1 M aq. sodium hydrogencarbonate solution. The organic layer was dried (MgSO4) and evaporated. The residue was taken up in tetrahydrofuran (1 mL), then heptane (10 mL) was added. The slurry was stirred for 30 min, then the precipitate was collected by filtration to afford the title compound (566 mg, 68%). Off-white solid, MS (ISP)=291.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Cl:11].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:24](OCCC(C)C)=O.Cl>C(Cl)(Cl)Cl.CO>[Cl:11][C:3]1[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[C:9]2[C:2]=1[NH:1][N:24]=[CH:10]2
Reactant: CC(C)CCON=O
Reactant: Cc1cc(C#N)cc(Cl)c1N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: N#Cc1cc(Cl)c2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 18.3 %

Procedure:
To a mixture of 4-amino-3-chloro-5-methyl-benzonitrile (3.0 g, 18.0 mmol) in chloroform (50 mL) was added acetic anhydride (3.92 mL, 41.4 mmol). The mixture was heated at reflux for 5 hours and then cooled to room temperature. To the mixture was added potassium acetate (530 mg, 5.4 mmol) and isoamyl nitrite (5.28 mL, 39.6 mmol). The reaction was heated at reflux for 16 hours. The reaction mixture was cooled to room temperature, extracted with saturated aqueous sodium bicarbonate, the organics were dried over sodium sulfate, and concentrated in vacuo to afford a brown oil. The oil was dissolved in methanol (25 mL) and concentrated hydrochloric acid (25 mL) was added. The reaction was stirred at room temperature for 22 hours and the methanol was concentrated in vacuo. The remaining aqueous layer was adjusted to a pH of 7 and the resultant precipitate was filtered to afford a brown solid which was purified by flash chromatography using 50% dichloromethane in heptane as eluent to afford 7-chloro-1H-indazole-5-carbonitrile as a solid (585 mg, 18%): −ESI MS (M−1) 176.0; 1H NMR (400 MHz, CDCl3) δ ppm 8.29 (br. s., 2 H), 8.08 (s, 1 H), 7.61 (s, 1 H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:15]([OH:17])=O)[C:7]3[CH:12]=[N:11][N:10]([CH2:13][CH3:14])[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.[NH2:18][CH2:19][C:20]1[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=1[CH3:26].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CS(C)=O>[CH:1]1([C:4]2[CH:5]=[C:6]([C:15]([NH:18][CH2:19][C:20]3[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=3[CH3:26])=[O:17])[C:7]3[CH:12]=[N:11][N:10]([CH2:13][CH3:14])[C:8]=3[N:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CCn1ncc2c(C(=O)O)cc(C3CC3)nc21
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CS(C)=O
Solvent: CN1CCOCC1
Product: CCn1ncc2c(C(=O)NCc3c(C)cc(C)[nH]c3=O)cc(C3CC3)nc21

Procedure:
The title compound was prepared in the same manner as described for intermediate 56 using 6-cyclopropyl-1-ethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (91 mg, 0.394 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (75 mg, 0.493 mmol), 1-hydroxy-7-azabenzotriazole (107 mg, 0.788 mmol), DMSO (10 mL), EDC (151 mg, 0.788 mmol), and N-methylmorpholine (0.173 mL, 1.577 mmol). The final product was collected as 0.090 g (63%). LCMS E-S (M+H)=366.3 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07 (d, J=6.32 Hz, 4H), 1.39 (t, J=7.20 Hz, 3H), 2.13 (s, 3H), 2.19-2.32 (m, 4H), 4.36 (d, J=4.80 Hz, 2H), 4.42 (q, J=7.07 Hz, 2H), 5.90 (s, 1H), 7.43 (s, 1H), 8.21 (s, 1H), 8.75 (t, J=4.67 Hz, 1H), 11.57 (br. s., 1H).
Reaction SMILES: C[Si](C)(C)[NH:3][C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:11].[F:14][CH2:15][C:16]1[CH:21]=[C:20](Cl)[N:19]2[N:23]=[C:24]([S:26](Cl)(=[O:28])=[O:27])[N:25]=[C:18]2[N:17]=1.CS(C)=O.[C:34](O)(=[O:36])C>C(#N)C.C(Cl)Cl>[F:14][CH2:15][C:16]1[CH:21]=[C:20]([O:36][CH3:34])[N:19]2[N:23]=[C:24]([S:26]([NH:3][C:4]3[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=3[Cl:11])(=[O:28])=[O:27])[N:25]=[C:18]2[N:17]=1
Reactant: O=S(=O)(Cl)c1nc2nc(CF)cc(Cl)n2n1
Reactant: C[Si](C)(C)Nc1c(Cl)cccc1Cl
Reactant: CC(=O)O
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CC#N
Product: COc1cc(CF)nc2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nn12
Temperature: 25 °C

Procedure:
A solution containing 3.08 g (13.1 mmol) of N-trimethylsilyl-2,6-dichloroaniline and 1.50 g (5.26 mmol) of 5-fluoromethyl-7-chloro-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonyl chloride in 15 ml of dry acetonitrile was prepared and 0.075 ml (1.05 mmol) of dimethyl sulfoxide was added with stirring at ambient temperature. The mixture was allowed to react over 4 days and the resulting brown solution was then diluted with 150 ml of methylene chloride, washed with water, and dried over magnesium sulfate. The solvent was removed by evaporation under reduced pressure and replaced with hexane to obtain, after collection of the solids and drying, 1.80 g (84 percent of theory) of the 7-chloro analog of the title compound in about 80 percent purity. This was dissolved in 25 ml of dry methanol, the solution cooled to 0°-5° C. and a mixture of 1.70 g (7.89 mmol) of 25 weight percent sodium methoxide in methanol and 5 ml of methanol was added dropwise with stirring over a 10 min. period. The mixture was allowed to react for 10 min. and then about 1 ml of acetic acid was added. The solid that formed was collected, washed with methanol and with water, and dried to obtain 1.15 g (54 percent of theory) of the title compound as a light brown solid. This was extracted by stirring in boiling methanol, cooling, collecting the solids, and drying to obtain 1.09 g of product melting at 189°-191° C. The proton and fluorine nmr spectra were compatible with the assigned structure.