Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].Br[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][C:3](=[O:24])[C@@H:4]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:21][CH:22]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)[C@@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)[C@@H](Cc1ccc(OCC(=O)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1

Procedure:
(R)-N-benzyloxycarbonyl-tyrosine methyl ester was reacted in a manner analogous to that described in Example 3 with t-butyl bromoacetate in the presence of potassium carbonate to give N-benzyloxycarbonyl-3-[p-(tert-butoxycarbonylmethoxy)phenyl]-D-alanine methyl ester. The colorless oil was hydrogenated in methanol, after addition of 5% palladium/carbon, in a shaking apparatus at room temperature under atmospheric pressure, obtaining, after filtration and removal of the solvent, 3-[p-(tertbutoxycarbonylmethoxy)phenyl]-D-alanine methyl ester in the form of a colorless oil.
Reaction SMILES: C([O:4][C@@H:5]1[CH2:9][C:8](=O)[N:7]([C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[O:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:22]([O:34][CH3:35])[CH:21]=2)[C:6]1=O)(=O)C.B.C1COCC1.CO>C1COCC1>[CH2:27]([O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][O:17][C@@H:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]2[N:7]2[CH2:8][CH2:9][C@@H:5]([OH:4])[CH2:6]2)=[CH:21][C:22]=1[O:34][CH3:35])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1cc(CCO[C@@H]2CCCC[C@H]2N2C(=O)C[C@@H](OC(C)=O)C2=O)ccc1OCc1ccccc1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(CCO[C@@H]2CCCC[C@H]2N2CC[C@@H](O)C2)ccc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 119.4 %

Procedure:
To a solution of (1R,2R)-1-{2-[2-(4-benzyloxy-3-methoxyphenyl)ethoxy]-cyclohexyl}-(3R)-2,5-dioxopyrrolidin-3-yl acetate (49.0 g, 100 mmol) in anhydrous THF (100 mL) under nitrogen was added slowly BH3.THF (1.0 M solution in THF, 400 mmol, 400 mL). The solution was heated to 80° C. and stirred for 3 hours. The solution was cooled to ambient temperature and methanol (100 mL) was added slowly until no more bubbling was observed. The solution was concentrated and methanolic HCl (1.25 M solution in CH3OH, 500 mL) was added. The solution was heated to 80° C. and stirred for 1 hour. The cooled solution was then concentrated to afford (1R,2R)-1-{2-[2-(4-benzyloxy-3-methoxyphenyl)ethoxy]cyclohexyl}-(3R)-pyrrolidin-3-ol (50.8 g, quantitative yield) as a yellow syrup. The crude product was used in the next step without further purification; 1H NMR (400 MHz, CDCl3) δ 11.45 (br, s, 1H), 7.50-7.10 (m, 5H), 6.90-6.60 (m, 3H), 4.22 (br, s, 1H), 4.00-3.85 (m, 5H), 3.75-3.55 (m, 2H), 3.35-2.50 (m, 7H), 2.45-2.20 (m, 2H), 2.08 (br, s, 1H), 1.90-1.50 (m, 3H), 1.35-1.05 (m, 6H); MS (ESI): 426.2 [M+H]+
Reaction SMILES: C(O[CH:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[S:8]1)CC(C)C.[B:16]([F:19])([F:18])[F:17].[FH:20].C(OCC)C>C(OC(=O)C)(=O)C>[F:17][B-:16]([F:20])([F:19])[F:18].[S+:8]1[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[S:11][CH:7]=1
Reactant: CC(C)CCOC1Sc2ccccc2S1
Reactant: FB(F)F
Reactant: F
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: F[B-](F)(F)F
Product: c1ccc2[s+]csc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
16.0 g (0.067 mole) of 2-isopentyloxy-1,3-benzodithiol (V) obtained in Synthesis Example 1 was dissolved in 200 ml of acetic anhydride. A 42% aqueous solution of hydrofluoroboric acid was added dropwise to the reaction solution in 30 minutes under cooling with ice. After the reaction solution was stirred at room temperature for 30 minutes, 200 ml of diethyl ether was added thereto. The formed salt was filtered off and washed with 100 ml of diethyl ether. The resulting salt was dried to obtain 12.0 g (yield: 50%) of the desired compound (VI) as a white crystal (decomposition temperature: 150°-151° C.). The physical properties of the compound were as follows:
Reaction SMILES: [C:1]12([CH3:13])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10](Cl)=[O:11].[C:14]([C:16]1[CH:38]=[CH:37][C:19]([NH:20][C:21](=[O:36])[C:22]([OH:35])([C:31]([F:34])([F:33])[F:32])[CH2:23][S:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:18][C:17]=1[C:39]([F:42])([F:41])[F:40])#[N:15]>N1C=CC=CC=1>[C:14]([C:16]1[CH:38]=[CH:37][C:19]([NH:20][C:21](=[O:36])[C:22]([O:35][C:10]([CH:2]2[CH2:3][CH:4]3[C:7]([CH3:9])([CH3:8])[C:1]2([CH3:13])[CH2:6][CH2:5]3)=[O:11])([C:31]([F:32])([F:33])[F:34])[CH2:23][S:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:18][C:17]=1[C:39]([F:41])([F:42])[F:40])#[N:15]
Reactant: N#Cc1ccc(NC(=O)C(O)(CSc2ccccc2)C(F)(F)F)cc1C(F)(F)F
Reactant: CC1(C)C2CCC1(C)C(C(=O)Cl)C2
Solvent: c1ccncc1
Product: CC1(C)C2CCC1(C)C(C(=O)OC(CSc1ccccc1)(C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1)C(F)(F)F)C2
Temperature: 95 °C

Procedure:
(-)-Camphanoyl chloride (4.33 g.) was added portionwise during 5 minutes to a solution of 4-cyano-3-trifluoromethyl-N-(2-hydroxy-3-phenylthio-2-trifluoromethylpropionyl)aniline (5.8 g.) in pyridine (35 ml.) and the mixture was heated at 95° C. for 150 minutes and then evaporated to dryness. Toluene (50 ml.) was added and the mixture was again evaporated to dryness. The residue was dissolved in ethyl acetate (200 ml.) and the solution was washed with water (30 ml.) and then twice with saturated aqueous sodium chloride solution (20 ml. each time), dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue was dissolved in methylene chloride (10 ml.) and the solution was flash chromatographed on silica gel (Merck 9385) using methylene chloride as eluant. There were thus obtained the two disastereoisomers of 4-cyano-3-trifluoromethyl-N-[2-(-)-camphanoyloxy-3-phenylthio-2-trifluoromethylpropionyl)aniline, the less polar isomer having m.p. 121°-123° C. and the more polar isomer having m.p. 140°-143° C.
Reaction SMILES: [C:1]1([CH2:7][NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[O:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][CH2:22][CH2:23][C:24]#[N:25].CN(C)C=O>C(N(CC)CC)C>[O:11]1[C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[CH2:14][CH2:15][CH:10]1[CH2:9][N:8]([CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:21][CH2:22][CH2:23][C:24]#[N:25]
Reactant: c1ccc(CNCC2CCc3ccccc3O2)cc1
Reactant: N#CCCCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCCCN(Cc1ccccc1)CC1CCc2ccccc2O1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.6 %

Procedure:
A mixture of 12.5 g of 3,4-dihydro-N-(phenylmethyl)-2H-1-benzopyran-2-methanamine, 9 g of 4-bromobutanenitrile, 200 ml of N,N-dimethylformamide and 10 ml of N,N-diethylethanamine was stirred for 72 hour at room temperature. The reaction mixture was evaporated and the residue was partitioned between 1,1'-oxybisethane and water. The organic layer was separated, dried, filtered and evaporated, yielding 11 g (68.7% ) of (±)-4-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl](phenylmethyl)amino]butanenitrile (interm. 53).
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:26])[CH2:15][N:16]3[C:20]([CH3:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[N:17]3)[CH2:10][CH2:9]2)[S:6][CH:7]=1)=O.[NH2:27][OH:28]>C(O)C>[OH:28][N:27]=[CH:1][C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:26])[CH2:15][N:16]3[C:20]([CH3:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[N:17]3)[CH2:10][CH2:9]2)[S:6][CH:7]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C=O)cs2)CC1
Reactant: NO
Solvent: CCO
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C=NO)cs2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-(4-formyl-2-thiazolyl)-1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]piperidine (i.e. the product of Example 8, Step B) (0.8 g, 2.07 mmol) in ethyl alcohol (15 mL) was added hydroxylamine (50% aqueous solution, 0.136 g, 4.1 mmol) and the reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure to give a yellow oil, which was purified by flash column chromatography on silica gel using 50% ethyl acetate in hexanes as eluant to give 0.7 g of the title compound as a white solid. This compound can be used as an intermediate to make compounds of the invention (via alkylation of the hydroxyimino group).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][CH2:11][N:12]=2)=[CH:4][C:3]=1OC.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[O:27][N:26]=[C:25]([CH3:28])[CH:24]=1.C[C:30]1[O:34]N=C(CCC(OC)=O)C=1>>[OH:34][CH2:30][CH:10]1[O:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[O:27][N:26]=[C:25]([CH3:28])[CH:24]=3)=[CH:7][CH:6]=2)=[N:12][CH2:11]1
Reactant: COc1cc(C2=NCCO2)ccc1O
Reactant: Cc1cc(CCCCCCCBr)on1
Reactant: COC(=O)CCc1cc(C)on1
Product: Cc1cc(CCCCCCCOc2ccc(C3=NCC(CO)O3)cc2)on1

Procedure:
5-{7-[4-(4,5-Dihydro-2-oxazolyl)-2-methoxyphenoxy]heptyl}-3-methylisoxazole [IX; R=CH3, R2, R3, R4, R5 and R6 =H, R1 =2-OCH3, Y=(CH2)7, oxazole at 4-position] was prepared from 4,5-dihydro-2-(4-hydroxy-3-methoxyphenyl)oxazole and 5-(7-bromoheptyl)-3-methylisoxazole according to the procedure of Example 9, part (d), and was obtained in the form of colorless crystals, m.p. 71°-73° C. when recrystallized from a hexane-isopropyl acetate mixture.
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[C:12]1([CH:22]([OH:38])[CH2:23][O:24][CH2:25][CH2:26][O:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.[O:39]1[CH:44]=[CH:43][CH2:42][CH2:41][CH2:40]1>C(Cl)Cl>[C:12]1([CH:22]([O:38][CH:40]2[CH2:41][CH2:42][CH2:43][CH2:44][O:39]2)[CH2:23][O:24][CH2:25][CH2:26][O:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)(=[O:29])=[O:30])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: C1=COCCC1
Reactant: Cc1ccc(S(=O)(=O)OCCOCC(O)c2cccc3ccccc23)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOCC(OC2CCCCO2)c2cccc3ccccc23)cc1
Reaction time: 0.17 h

Procedure:
0.82 g of pyridimium p-toluenesulfonate was added to a solution of 6.3 g of 1-(1-naphthyl)-2-[2-(p-toluenesulfonyloxy)ethoxy]ethanol and 2.97 ml of 3,4-dihydro-2H-pyran dissolved in 63 ml of methylene chloride at room temperature. The resulting mixture was stirred at the same temperature for 20 minutes and further at 35°-40° C. for 10 minutes. The reaction mixture was cooled, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: toluene/ethyl acetate=10/1) to obtain 7.53 g of colorless, oily 1(1-naphthyl)-1-(tetrahydropyran-2-yloxy)-2-[2-(p-toluenesulfonyloxy)ethoxy]ethane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19](O)=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@H:23]2[CH2:28][CH2:27][CH2:26][N:25]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:24]2)[CH:3]=1.CC[N:35](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([NH2:35])=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@H:23]2[CH2:28][CH2:27][CH2:26][N:25]([S:29]([CH3:32])(=[O:30])=[O:31])[CH2:24]2)[CH:3]=1
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCN(S(C)(=O)=O)C3)c12
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CO
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCN(S(C)(=O)=O)C3)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-[4-Fluoro-2-((S)-1-methanesulfonyl-piperidin-3-yloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (120 mg) at 0° C. was added DIPEA (49 μl) followed by HATU (104 mg) and the solution was stirred for 30 min. A solution of ammonia in methanol (7M; 0.3 ml) was added and the solution allowed to warm to room temperature and stirred for 1 h. The solvent was evaporated and traces of DMF removed by co-evaporation with toluene. The residue was triturated with MeOH and the solid collected by filtration to give the desired product.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1.C(O)(=O)C>O1CCCC1>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][C:7]2[S:6][CH:10]=[CH:9][CH:8]=2)=[CH:15][CH:14]=1
Reactant: c1ccsc1
Reactant: COc1ccc(CBr)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(Cc2cccs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Butyllithium (12.5 ml of 1.6N in hexanes) was added to a stirred solution of thiophene (1.68 g) in dry tetrahydrofuran (80 ml). The mixture was stirred at room temperature for 0.5 h and then a solution of 4-methoxybenzylbromide (2.62 g) in tetrahydrofuran (10 ml) was added dropwise. The mixture was stirred for 1 h and then acetic acid (1.2 ml) was added and the solvent evaporated. The residue was partitioned between ethyl acetate and water, the organic phase was washed with water and brine dried over magnesium sulphate and evaporated. The product was isolated by column chromatography (Kieselgel:hexane). δ(CDCl3) 3.80 (3H, s), 4.10 (2H, s), 6.78-6.94 (4H, m), 7.13-7.20 (3H, m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20](F)=[C:21]([F:24])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C1COCC1.CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[C:21]([F:24])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)c(F)cc23)CC1
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(N4CCOCC4)c(F)cc23)CC1
Yield: 89.4 %

Procedure:
A solution of 4-(6,7-Difluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (37.8 mg, 108 μmol) (preparation in Example 90c) and morpholine (19.8 μL, 227 μmol) in THF (100 μL) and DMSO (50 μL) was heated at 100° C. for 1 hr. The crude reaction was loaded onto a flash silica cartridge (1 :1 hexanes/EtOAc eluent) to provide the title compound (40.2 mg, 89%). NOe experiments support the assigned regioisomer. Select 1H-NMR resonances and nOes (300 MHz, CDCl3) δ 7.68 (d, J=13.7 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 3.45 (tt, 1H), 3.31 (m, 4H). Irradiation of the diagnostic methine proton at δ 3.45 generates an nOe to the quinazoline C5 proton at δ 7.68, but not to the quinazoline C8 proton at δ 7.37. The C5 proton has a larger coupling constant than the C8 proton, indicating fluorine substitution at C6 of the quinazoline. Furthermore, irradiation of the C8 proton at δ 7.37 generates an nOe only to the morpholine C3 protons at δ 3.31, while irradiation of the C5 proton generates an nOe only to the methine proton at δ 3.45. These data indicate morpholine substitution at the quinazoline C7 carbon. LC/MS (ESI): calcd mass 416.2, found 417.3 (MH)+.
Reaction SMILES: [Na].[CH2:2]([NH:9][C:10]([NH2:12])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:13]([O:19]C(CC)CC)(=O)[CH2:14][C:15]([O-:17])=O.[CH2:25](O)C>>[CH2:2]([N:9]1[C:13](=[O:19])[CH:14]([CH3:25])[C:15](=[O:17])[NH:12][C:10]1=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCO
Reactant: CCC(CC)OC(=O)CC(=O)[O-]
Reactant: NC(=O)NCc1ccccc1
Agent: [Na]
Product: CC1C(=O)NC(=O)N(Cc2ccccc2)C1=O

Procedure:
Sodium metal (7.68 g, 334 mmol) was dissolved in 100% ethanol (500 mL), benzyl urea (25.12 g, 168 mmol) and diethylmethyl malonate (29 mL, 169 mmol) were added, and the mixture was heated at just below ethanol reflux overnight. The reaction mixture was concentrated to remove ethanol, water (200 mL), and 1 N hydrochloric acid (350 mL) was added, and an oil separated. The oil would not crystallize and could not be purified by chromatography. The oil was treated with ethanol/sodium ethoxide, (400 mL/7.4 g, 322 mmol) overnight at just below ethanol reflux and was worked up as before to give an oil that would not crystallize. This material was used directly in the next step.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].Cl.[NH2:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])=[CH:19][CH:18]=1)=O.[OH2:31]>>[NH2:13][C:14]1[C:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])=[CH:19][CH:18]=2)=[N:1][C:11]2[C:6]([C:4]=1[C:2]([OH:31])=[O:3])=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: O=C1Nc2ccccc2C1=O
Reactant: O
Reactant: NCC(=O)c1ccc(-c2ccc(F)cc2F)cc1
Agent: Cl
Product: Nc1c(-c2ccc(-c3ccc(F)cc3F)cc2)nc2ccccc2c1C(=O)O

Procedure:
A basic aqueous solution of 3.5 g of isatin in water was reacted with 9.3 g of 2-amino-1-(2',4'-difluoro[1,1'-biphenyl]-4-yl)ethanone hydrochloride by the procedure described in example 20, giving 2.8 g of the desired compound as a yellow solid, mp 244°-247° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:11]=[C:10]([O:12][CH:13]([F:15])[F:14])[N:9]([CH3:16])[N:8]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18].[Br:19]Br>C(O)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[C:11]([Br:19])=[C:10]([O:12][CH:13]([F:14])[F:15])[N:9]([CH3:16])[N:8]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18]
Reactant: Cn1nc(-n2ncc(C#N)c2N)cc1OC(F)F
Reactant: BrBr
Solvent: CC(=O)O
Product: Cn1nc(-n2ncc(C#N)c2N)c(Br)c1OC(F)F
Reaction time: 0.25 h

Procedure:
5.0 g (20 mmol) 5-Amino-1-(5-difluoromethoxy-1-methyl-3-pyrazolyl)-4-pyrazolecarbonitrile was dissolved in 80 ml acetic acid. At room temperature, 1.2 ml (23 mmol) bromine was added, dropwise. After stirring for 15 minutes, the mixture was concentrated and stirred with diisopropyl ether/propanol. The solid material was suction filtered and dried.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>CC(C)=O>[F:19][C:20]([F:29])([F:30])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25][O:12][C:10]2[CH:9]=[CH:8][C:6]3[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]=3[CH:11]=2)=[CH:23][CH:22]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: N#Cc1nc2ccc(O)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1nc2ccc(OCc3ccc(C(F)(F)F)cc3)cc2s1
Temperature: 25 °C
Yield: 89.5 %

Procedure:
A suspension of 2-cyano-6-hydroxybenzothiazole (1.0 g, 5.68 mmol) in acetone (5 mL) was prepared in a 100-mL 2-necked round-bottomed flask fitted with a reflux condenser. Anhydrous potassium carbonate (0.94 g, 6.82 mmol) was added to the reaction mixture and the suspension turned to a yellow solution. Then 4-(trifluoromethyl)benzyl bromide (1.49 g, 6.25 mmol) was added and the reaction mixture was heated at reflux for 15 h using a heated stir plate and oil bath. The reaction mixture was allowed to cool to ambient temperature and then filtered to remove inorganic salts. The filtrate was concentrated by rotoevaporation to provide 1.7 g (89% yield) of an off-white solid that was used without purification. The structure was confirmed by 1H NMR analysis in DMSO-d6.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH2:3][CH2:4][CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]1=[O:12].[CH2:14](O)[CH:15]([CH3:17])[CH3:16].O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][CH:2]([CH3:13])[CH2:3][CH2:4][C:5]1[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]=1[O:12][CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)CCC1C(=O)CCCC1=O
Reactant: CC(C)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)CCC1=C(OCC(C)C)CCCC1=O
Temperature: 25 °C
Yield: 98.7 %

Procedure:
A solution of ketoenol 7 (68.0 g, 374 mmol), isobutanol (83.0 g, 1120 mmol), and p-toluenesulfonic acid (1.0 g, 1.2 mmol) in anhydrous benzene (730 mL) was refluxed overnight with azeotropic removal of water (Dean-Stark trap). The reaction mixture was cooled to room temperature, washed with saturated sodium bicarbonate solution (3×250 mL), brine (2×250 mL) and concentrated to give 88.0 g (98.9%) of 8 as a thick oil, which solidified upon cooling. MS m/z 239 (M+1); 1H NMR (300 MHz, CDCl3) δ 3.75 (d, 2H), 2.5 (t, 2H), 2.3-2.2 (m, 4H), 2.0-1.9 (m, 3H), 1.6-1.5 (m, 1H), 1.2-1.1 (m, 2H), 1.0 (d, 6H), 0.9 (d, 6H); 13C NMR (CDCl3) δ 198.4, 171.5, 120.1, 73.9, 38.0, 36.5, 28.8, 28.4, 25.5, 22.6, 21.1, 20.1, 19.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]2[N:12]=[C:13]([NH2:15])[N:14]=[C:10]2[CH:9]=[C:8]([Br:16])[CH:7]=1)=[O:5])[CH3:2].[CH2:17]([N:19]=[C:20]=[O:21])[CH3:18]>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:11]2[N:12]=[C:13]([NH:15][C:20]([NH:19][CH2:17][CH3:18])=[O:21])[N:14]=[C:10]2[CH:9]=[C:8]([Br:16])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(Br)cc2nc(N)nn12
Reactant: CCN=C=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2cc(Br)cc(C(=O)OCC)n2n1
Temperature: 100 °C

Procedure:
2-Amino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid ethyl ester (7) (760 mg, 2.66 mmol) was dissolved in THF/toluene (1:1, 40 mL), then ethyl isocyanate (1.89 g, 26.6 mmol) and a catalytic quantity of dibutyltindiacetate (10 drops) were added to the mixture. The reaction was then heated in a sealed tube at 100° C. for 15 h. This mixture was allowed to cool, then the solvents removed under reduced pressure to afford a solid which was purified by flash chromatography on silica 2% MeOH/CH2Cl2 as eluant) to give 7-bromo-2-(3-ethyl-ureido)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid ethyl ester (8) LCMS (APCI+) 356, 358.
Reaction SMILES: [Br-].[Li+].C(=O)([O-])[O-].[Li+].[Li+].CN(C)C=O.Br[C@@H:15]1[CH2:41][C@@:40]2([CH3:42])[C@@H:18]([CH2:19][CH2:20][C@@H:21]3[C@@H:39]2[CH2:38][CH2:37][C@@:36]2([CH3:43])[C@H:22]3[CH2:23][C@@H:24]3[O:29][C@@:28]4([O:35][CH2:34][C@H:32]([CH3:33])[CH2:31][CH2:30]4)[C@@H:26]([CH3:27])[C@@H:25]32)[CH2:17][C:16]1=[O:44]>C(OCC)(=O)C>[CH3:27][C@@H:26]1[C@:28]2([O:35][CH2:34][C@H:32]([CH3:33])[CH2:31][CH2:30]2)[O:29][C@H:24]2[CH2:23][C@@H:22]3[C@@:36]([CH3:43])([C@@H:25]12)[CH2:37][CH2:38][C@H:39]1[C@H:21]3[CH2:20][CH2:19][C@@H:18]2[C@:40]1([CH3:42])[CH:41]=[CH:15][C:16](=[O:44])[CH2:17]2
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5CC(=O)[C@H](Br)C[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5CC(=O)C=C[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Temperature: 95 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
A mixture of lithium bromide (0.700 g, 8.06 mmol), lithium carbonate (1.20 g, 16.24 mmol) and anhydrous N,N-dimethylformamide (30 mL) were heated under nitrogen atmosphere to 95° C. To this mixture, (2α,5α,25R)-2-bromospirostan-3-one (4.00 g, 8.11 mmol) was added. The reaction mixture was stirred at 130° C. for 3 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water (3×), brine (1×), dried (sodium sulfate), filtered and concentrated in vacuo to afford 3.31 g, (98%) of the title compound.