Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([C:16]#[C:17][CH2:18][N:19]2[CH2:24][CH2:23][C:22]3([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:21][CH2:20]2)[CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[OH-].[Na+]>CO>[ClH:3].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:16][CH2:17][CH2:18][N:19]2[CH2:20][CH2:21][C:22]3([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:23][CH2:24]2)[CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Clc1cc(C#CCN2CCC3(CCCCC3)CC2)ccc1C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Clc1cc(CCCN2CCC3(CCCCC3)CC2)ccc1C1CCCCC1

Procedure:
3 g of the hydrochloride of the acetylene compound obtained in Example 1 are liberated with aqueous 10% sodium hydroxide solution. The oil obtained after extraction with diethyl ether is washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated under vacuum. The residual oil is then taken up in 100 ml of ethyl acetate, after which 5 ml of methanol are added, followed by 0.2 g of Pd/BaSO4, and the reaction mixture is hydrogenated at room temperature and at atmospheric pressure. The catalyst is separated out by filtration through Celite and the filtrate is concentrated under vacuum. The residue obtained is taken up in the minimum amount of methanol in the presence of 50 ml of 2 N hydrochloric acid and is then successively extracted with dichloromethane, washed with 2N hydrochloric acid solution, with saturated sodium chloride solution, dried over magnesium sulphate and concentrated under vacuum in order to obtain 2 g of the expected hydrochloride; m.p.=266° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][Cl:9])[N:7]=1.CN(C)C=O.[C:15](Cl)(=[O:18])[CH2:16][CH3:17]>N1C=CC=CC=1>[C:15]([NH:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][Cl:9])[N:7]=1)(=[O:18])[CH2:16][CH3:17]
Reactant: CCC(=O)Cl
Reactant: Nc1nc(CCl)cs1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCC(=O)Nc1nc(CCl)cs1
Temperature: 0 °C
Yield: 50.9 %

Procedure:
To a mixture of 2-amino-4-chloromethylthiazole hydrochloride (50 g), anhydrous N,N-dimethylformamide (250 ml) and anhydrous pyridine (50 ml) was added dropwise propionyl chloride (30 g) keeping the temperature below 3° C. with stirring and the mixture was stirred for 20 minutes at the same temperature. The reaction mixture was poured into ice water (1500 ml) and stirred. The crystal was collected by filtration and washed with water to give 2-propionylamino-4-chloromethylthiazole (28.15 g).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[S:22][N:21]=[C:20]([CH3:23])[CH:19]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl.CO.[OH-].[NH4+]>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[S:22][N:21]=[C:20]([CH3:23])[CH:19]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)sn1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)sn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.4 %

Procedure:
To a solution of N-tert-butyl-2-(3-methylisothiazol-5-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (32 mg, 69.5 mol) in dichloromethane (1.2 mL) was added trifluoroacetic acid (158 mg, 107 μL, 1.39 mmol) and the mixture stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue obtained diluted with dichloromethane (1.2 mL), methanol (0.6 mL) and ammonium hydroxide (0.15 mL) and stirred at room temperature for 2 h. The mixture was concentrated and triturated with water. The solid was collected by filtration and washed with water and ether to give N-tert-butyl-2-(3-methylisothiazol-5-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (18 mg, 54.5 mol, 78.4%) as a brown solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.55 (s, 1H), 11.39 (s, 1H), 8.15 (d, J=3.2, 1 H), 8.11 (s, 1H), 7.37 (s, 1H), 6.70 (s, 1H), 2.33 (s, 3H), 1.55 (s, 9H); MS (EI/CI) m/z: 331.1 [M+H].
Reaction SMILES: [CH2:1]([C:5]1([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:13][C:12]2[C:7](=[C:8]([Cl:20])[C:9]([Cl:19])=[C:10]([O:14]CC(O)=O)[CH:11]=2)[C:6]1=[O:21])[CH2:2][CH2:3][CH3:4]>C(O)(=O)C>[CH2:1]([C:5]1([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:13][C:12]2[C:7](=[C:8]([Cl:20])[C:9]([Cl:19])=[C:10]([OH:14])[CH:11]=2)[C:6]1=[O:21])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(C2CCCC2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Solvent: CC(=O)O
Product: CCCCC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O

Procedure:
By following substantially the procedure in Example 8, Step A, but substituting for (+) 6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]acetic acid an equimolar quantity of (-) [(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)oxy]acetic acid, there is obtained (-) 2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-1H-inden-1-one which is used in Step C without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13].Cl.O1CCOC[CH2:18]1>CO>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:18])=[O:7])=[CH:4][C:3]=1[O:11][C:12]([F:13])([F:14])[F:15]
Reactant: C1COCCO1
Reactant: Nc1ccc(C(=O)O)cc1OC(F)(F)F
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc(N)c(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 98.5 %

Procedure:
A mixture of 4-amino-3-(trifluoromethoxy)benzoic acid (8.88 g 40.2 mmol), MeOH (142 mL) and hydrochloric acid in 1,4-dioxane (4.0 M, 142 mL, 568 mmol) was stirred at room temperature for 72 h. After removal of the organic solvent the pH of the residue was adjusted to pH 8 and the aqueous layer was extracted with ethyl acetate (50 mL×3). The combined organic layers were dried and concentrated under vacuum to afford the title compound (9.3 g, 39.6 mmol, 95% yield). MS (ESI) m/z 236.1 [M+1]+.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:5][N:4]=1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:32][CH:31]2[NH2:33])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([CH:30]2[CH2:32][CH:31]2[NH:33][CH2:2][C:3]2[O:7][C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:5][N:4]=2)=[CH:28][CH:29]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NC1CC1c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)Nc1nnc(CCl)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1nnc(CNC2CC2c2ccc(OCc3ccccc3)cc2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.7 %

Procedure:
Tert-butyl (5-(chloromethyl)-1,3,4-oxadiazol-2-yl)carbamate (141 mg, 0.606 mmol) was added to a solution of 2-(4-(benzyloxy)phenyl)cyclopropanamine (enantiomer (−)) (145 mg, 0.606 mmol) and K2CO3 (166 mg, 1.213 mmol) in dry DMF (1.5 mL) and stirred at RT for 2 h. After completion, the reaction mixture was poured into ice water (10 mL) and extracted with EtOAc (4×10 mL). The combined organic extracts were washed with water (3×10 mL), brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue obtained was purified by column chromatography (SiO2) using MeOH:CHCl3 (1:99) as eluent to afford tert-butyl (5-(((2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-yl)carbamate (enantiomer-(−)) (100 mg, 37.7%) as a pale green liquid.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[C:13](OC)=[O:14])=[O:6])[CH:2]=[CH2:3]>C1COCC1>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:13][OH:14])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1CO
Temperature: 25 °C
Yield: 99.2 %

Procedure:
A solution of the ester 13 (19.5 g, 85 mmol) in THF (326 mL) was cooled to 0° C. (ice/acetone) and treated with LiBH, (2.78 g, 128 mmol) in portions. The reaction mixture was allowed to warm to room temperature and stirred under a nitrogen atmosphere for 2.5 hours at which time TLC (50% EtOAc/Petroleum Ether) revealed complete consumption of ester 13. The mixture was cooled to 0° C. and water (108 mL) was carefully added followed by 2 N HCl (54 mL). After evaporation of the THF in vacuo, the mixture was neutralised to pH 7 with 10 N NaOH and saturated with solid NaCl. The saturated aqueous solution was then extracted with EtOAc (5×100 mL), the combined organic layers washed with brine (200 mL), dried (MgSO4), filtered and evaporated in vacuo to furnish the pure diol 14 as a clear colourless oil (16.97 g, 99%): [α]24D=−57.0° (c=0.61, CHCl3); 1H NMR (270 MHz, CDCl3) δ 6.01-5.87 (m, 1H, NCO2CH2CH═CH2), 5.36-5.20 (m, 2H, NCO2CH2CH═CH2), 4.84 (br s, 1H, NCHCH2OH), 4.60 (d, 2H, J=5.31 Hz, NCO2CHCH═CH2), 4.39 (br s, 1H, NCHCH2OH), 4.18-4.08 (m, 1H, 3.35, NCH2CHOH), 3.90-3.35 (m, 4H+, NCH2CHOH, NCHCH2OH, and OH), 3.04 (br s, 1H, OH), 2.11-2.03 (m, 1H, NCH2CHOHCH2), 1.78-1.69 (m, 1H, NCH2CHOHCH2); 13 C NMR (67.8 MHz, CDCl3) δ 157.1 (NC═O), 132.6 (NCO2CH2CH═CH), 117.7 (NCO2CH2CH═CH2), 69.2 (NCH2CHOH), 66.4 and 66.2 (NCO2CH2CH═CH2 and NCHCH2OH), 59.2 (NCHCH2OH), 55.5 (NCH2CHOH); 37.3 (NCH2CHOHCH2); MS (EI), m/z (relative intensity) 201 (M+., 2), 170 (M-CH2OH, 100), 144 (M-OC3H3, 6), 126 (26), 108 (20), 68 (9); IR (Neat) 3394 (br, OH), 2946, 2870, 1679 (C═O), 1413, 1339, 1194, 1126, 1054, 980, 772 cm−1; exact mass calcd for C9H15NO4 m/e 201.1001, obsd m/e 201.1028.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[C:11](=[O:22])[C:10]([C:23]#[N:24])=[C:9]([C:25]([F:28])([F:27])[F:26])[CH:8]=2)=[CH:4][CH:3]=1.[CH2:29]([S:31][C:32]1[CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH3:30].C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH2:13][N:12]1[C:7]([C:5]2[O:6][C:2]([C:34]3[CH:35]=[C:36]([C:38]([F:40])([F:39])[F:41])[CH:37]=[C:32]([S:31][CH2:29][CH3:30])[CH:33]=3)=[CH:3][CH:4]=2)=[CH:8][C:9]([C:25]([F:28])([F:27])[F:26])=[C:10]([C:23]#[N:24])[C:11]1=[O:22]
Reactant: N#Cc1c(C(F)(F)F)cc(-c2ccc(Br)o2)n(Cc2ccc(F)cc2F)c1=O
Reactant: CCSc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCSc1cc(-c2ccc(-c3cc(C(F)(F)F)c(C#N)c(=O)n3Cc3ccc(F)cc3F)o2)cc(C(F)(F)F)c1
Temperature: 85 °C
Reaction time: 16 h
Yield: 56.2 %

Procedure:
6-(5-Bromo-furan-2-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile (310 mg, 0.7 mmoles), 2-(3-Ethylsulfanyl-5-trifluoromethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (287 mg, 0.86 mmoles), tetrakis(triphenylphosphine)palladium (0) (81 mg, 0.07 mmoles), K2CO3 (450 mg, 3.3 mmoles) were combined in 12 ml of DME/H2O (9:1, degassed), and were stirred at 85° C. for 16 hours. After this period the reaction mix was evaporated and purified using flash silica chromatography (0-20% EtOAc/Hexane) to yield 1-(2,4-difluoro-benzyl)-6-[5-(3-ethylsulfanyl-5-trifluoromethyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile (0.23 g, 55%) as a yellow residue.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19]Cl)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[OH:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19][O:23][C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: Oc1cccnc1
Reactant: CCN1c2ncc(CCl)cc2C(=O)N(C)c2ccc(Cl)nc21
Product: CCN1c2ncc(COc3cccnc3)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 72 %

Procedure:
Using a procedure analogous to that described in Example 98, the title compound, m.p. 183°-184° C., was prepared from 2-chloro-8-chloromethyl-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and 3-hydroxypyridine. The yield was 72% of theory.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:41][CH2:40][C:32]2([O:36][C@H:35]3[CH2:37][O:38][CH2:39][C@H:34]3[O:33]2)[CH2:31][CH2:30]1.C([BH3-])#N.[Na+].O1CCCC1>C(OCC)(=O)C>[OH:36][C@H:35]1[CH2:37][O:38][CH2:39][C@H:34]1[O:33][C@H:32]1[CH2:31][CH2:30][C@H:29]([N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:11][CH:10]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)[CH2:41][CH2:40]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)O[C@H]2COC[C@H]2O3)c2ncnn12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O[C@@H]3COC[C@@H]3O)CC2)c2ncnn12
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A mixture of 4′-({5-oxo-7-propyl-4-[(3a′R,6a′S)-tetrahydrospiro[cyclohexane-1,2′-furo[3,4-d][1,3]dioxol]-4-yl]-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.77 g), sodium cyanoborohydride (0.45 g), boron trifluoride-diethyl ether complex (0.88 mL) and tetrahydrofuran (20 mL) was stirred at 70° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.14 g, 18%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.CCN(CC)CC.[O:16](S(C(F)(F)F)(=O)=O)[S:17]([C:20]([F:23])([F:22])[F:21])(=O)=[O:18]>C(Cl)Cl>[F:21][C:20]([F:23])([F:22])[S:17]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[N:4][CH:3]=1)(=[O:18])=[O:16]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1ccc(O)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(OS(=O)(=O)C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5 g of 3-hydroxy-6-methylpyridine in 100 mL of CH2Cl2 at 0° C. was added successively 7.7 mL of Et3N and 8.1 mL of Tf2O. The reaction was stirred at room temperature for 30 minutes, then diluted with more CH2Cl2 (220 mL). The organic phase was washed successively with 1N HCl, brine, dried over MgSO4, filtered, and concentrated to give after purification using flash chromatography on silica gel (hexane:EtOAc 65:35) the title compound.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[N:13]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:12]=[C:11]([CH2:23][N:24](C)[C:25](=O)OC(C)(C)C)[C:10]=2[F:33])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].C(OCC)(=O)C.[ClH:40]>C(O)C>[ClH:40].[F:33][C:10]1[C:11]([CH2:23][NH:24][CH3:25])=[CH:12][N:13]([S:14]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[C:9]=1[C:8]1[C:3]([C:1]#[N:2])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2ccccc2)c(-c2cccnc2C#N)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCc1cn(S(=O)(=O)c2ccccc2)c(-c2cccnc2C#N)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
To a solution of tert-butyl {[5-(2-cyanopyridin-3-yl)-4-fluoro-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (433 mg) in ethanol (5 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 175 mg, 47%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH:9]([CH3:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.Br[C:16]1[CH:17]=[CH:18][C:19]([F:24])=[C:20]([CH:23]=1)[C:21]#[N:22]>>[F:24][C:19]1[CH:18]=[CH:17][C:16]([C:2]2[CH:3]=[CH:4][C:5]3[NH:10][CH:9]([CH3:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=3[CH:14]=2)=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: CC1Nc2ccc(Br)cc2C(C)(C)O1
Product: CC1Nc2ccc(-c3ccc(F)c(C#N)c3)cc2C(C)(C)O1

Procedure:
Prepared according to the coupling procedure for Example 13 from 6-bromo-2,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazine and 5-bromo-2-fluorobenzonitrile. A white solid: mp 184-186° C.; 1H-NMR (DMSO-d6) δ 8.17 (dd, 1H, J=5.86, 3.42 Hz), 8.00-7.98 (m, 1H), 7.52 (t, 1H, J=9.28 Hz), 7.45 (d, 1H, J=1.95 Hz), 7.34 (dd, 1H, J=8.30, 1.95 Hz), 6.63 (d, 1H, J=8.3 Hz), 6.45 (d, 1H), 4.8 (q, 1H, J=5.37 Hz), 1.53 (s, 3H), 1.49 (s, 3H), 1.29 (d, 3H, J=5.37 Hz); MS (ES) m/z 297 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH:4]([Cl:8])[C:5]([CH3:7])=[O:6].[H-].[Na+].[Li]CCCC.[CH:17]1([C:22](=[O:36])[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[C:27]([F:35])[CH:26]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1.BrC1C=CC(OC(C)C)=C(F)C=1.BrC1C=CC=CN=1>C1COCC1>[Cl:8][CH:4]([C:5](=[O:6])[CH2:7][C:22]([CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)([OH:36])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[C:27]([F:35])[CH:26]=1)[C:3]([O:2][CH3:1])=[O:9]
Reactant: COC(=O)C(Cl)C(C)=O
Reactant: CC(C)Oc1ccc(CCC(=O)C2CCCC2)cc1F
Agent: Brc1ccccn1
Agent: CC(C)Oc1ccc(Br)cc1F
Agent: [H-]
Solvent: C1CCOC1
Product: COC(=O)C(Cl)C(=O)CC(O)(CCc1ccc(OC(C)C)c(F)c1)C1CCCC1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Methyl-2-chloroacetoacetate (2.0 mL, 16.2 mmol) was added to a cooled 0° C. suspension of NaH (0.65 g, 16.2 mmol, 60% dispersion in mineral oil) in THF (54 mL). After 15 min the solution was cooled to −40° C. and n-BuLi (10.0 mL, 16.2 mmol, 1.6M in hexanes) was added. The resulting dianion was stirred for an additional 30 min and then treated with a solution of 1-cyclopentyl-3-(3-fluoro-4-isopropoxyphenyl)propan-1-one (1.5 g, 5.4 mmol, compound was prepared analogously to Step 1 of Example A(82), where 4-(bromo)-2-fluoro-1-isopropoxybenzene was substituted in place of 2-Bromopyridine) in THF (10 ml). After stirring for 1 h at −40° C., the reaction mixture was quenched with saturated NH4Cl and extracted with EtOAc. The organic layers were washed with brine, dried with Na2SO4 and concentrated to an orange oil that was used without further purification.
Reaction SMILES: N[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]([CH3:20])([CH3:19])[CH:8]2[C:11]2[C:12]([S:17][CH3:18])=[N:13][CH:14]=[N:15][CH:16]=2)=[CH:4][CH:3]=1.F[B-](F)(F)F.N#[O+].[C-:28]#[N:29].[K+].O>C(#N)C.CS(C)=O>[C:28]([C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]([CH3:19])([CH3:20])[CH:8]2[C:11]2[C:12]([S:17][CH3:18])=[N:13][CH:14]=[N:15][CH:16]=2)=[CH:4][CH:3]=1)#[N:29]
Reactant: [C-]#N
Reactant: CSc1ncncc1C1c2cc(N)ccc2CC1(C)C
Agent: F[B-](F)(F)F
Agent: N#[O+]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CS(C)=O
Product: CSc1ncncc1C1c2cc(C#N)ccc2CC1(C)C
Temperature: 40 °C

Procedure:
To a mixture of 1.0 g (3.5 mmol) of 5-(6-amino-2,2-dimethylindan-1-yl)-4-methylthiopyrimidine in 25 mL of dry acetonitrile was added with stirring 1.0 g (7.0 mmol) of nitrosonium tetrafluoroborate. The brown solution was allowed to react for 10 min and was then poured, with stirring, into a solution of 2.5 g (28 mmol) of cuprous cyanide and 3.0 g (47 mmol) of potassium cyanide in 150 mL of dry dimethyl sulfoxide. The resulting mixture was heated to 40° C. to form a solution and this solution was poured into 750 mL of water. The mixture obtained was extracted with ether (2×300 mL) and the ethereal extract was washed with water, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography on silica gel to obtain 500 mg (48 percent of theory) of the title compound as a light yellow solid melting at 157°-158° C.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[O:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].[CH2:16](I)C>>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[O:14][CH2:15][CH3:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(C(=O)O)ccc1C(C)(C)C
Reactant: CCI
Product: CCOc1cc(C(=O)O)ccc1C(C)(C)C

Procedure:
Prepared in a similar manner to that described for 4-tert-butyl-3-methoxybenzoic acid (J. Org. Chem. (1961) 26,1732), replacing methyl iodide with ethyl iodide.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[NH2:14][C:15](=O)[CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30]([C:32]3[O:33][C:34]([NH:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[F:44])=[N:35][N:36]=3)=[O:31])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1.N1C=CC=CC=1>C(Cl)Cl>[C:15]([CH2:16][C@H:17]1[CH2:18][CH2:19][C@H:20]([C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:30]([C:32]3[O:33][C:34]([NH:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[F:44])=[N:35][N:36]=3)=[O:31])=[CH:27][CH:28]=2)[CH2:21][CH2:22]1)#[N:14]
Reactant: NC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4ccccc4F)o3)cc2)CC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#CC[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4ccccc4F)o3)cc2)CC1

Procedure:
Trifluoroacetic anhydride 0.042 mL, 0.05 mmol) was added to a stirred solution of N-{4-[trans-4-(2-amino-2-oxoethyl)cyclohexyl]phenyl}-5-[(2-fluorophenyl)amino]-1,3,4-oxadiazole-2-carboxamide (Example 516) (20 mg, 0.05 mmol) and pyridine (90 uL, 0.11 mmol) in DCM (2 mL). After 15 minutes DCM (10 mL) was added and the reaction mixture was washed sequentially with 1M HCl (5 mL), water (10 mL) and 10% ammonium hydroxide solution (5 mL) then dried and concentrated under reduced pressure to give the title compound (18 mg, 95%) as a solid; 1H NMR δ 1.13-1.30 (m, 3H), 1.40-1.54 (m, 2H), 1.60-1.75 (m, 1H), 1.76-1.92 (m, 5H), 2.40-2.50 (m, 1H), 7.10-7.19 (m, 1H), 7.20-7.35 (m, 4H), 7.68 (d, 2H), 8.03 (t, 1H), 10.75 (s, 1H), 10.93 (s, 1H); MS m/e MH+ 420.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][C:14]([O:17]C(C)(C)C)=[CH:13][C:12]=2[F:22])=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].B(Br)(Br)Br>C(Cl)Cl>[F:22][C:12]1[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=1[C:3]1[C:2]([Cl:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=1
Reactant: CC(C)(C)Oc1ccc(-c2noc(C(F)(F)F)c2Cl)c(F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-c2noc(C(F)(F)F)c2Cl)c(F)c1

Procedure:
This compound is prepared in a manner analogous to that of Step H of Example 1, using 3.2 grams (0.010 mole) of 4-chloro-3-[2-fluoro-4-(1,1-dimethylethoxy)phenyl]-5-trifluoromethylisoxazole and 20 mL (0.020 mole) of 1M boron tribromide (in methylene chloride) in 50 mL of methylene chloride, yielding 3-fluoro-4-(4-chloro-5-trifluoromethyl-isoxazol-3-yl)phenol.
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][NH2:24])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:10][C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:3]2=[O:12])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: COc1ccc(CCCN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(CCCN2Cc3ccccc3C2=O)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (0.115 g, 0.5 mmol), 3-(4-methoxy-phenyl)-propylamine (0.110 g, 0.6 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (3 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-[3-(4-methoxy-phenyl)-propyl]-2,3-dihydro-isoindol-1-one (0.114 g, 81%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.98 (m, 2H), 2.63 (t, 2H), 3.64 (t, 2H), 3.76 (s, 3H), 4.36 (s, 2H), 6.78 (d, 2H), 7.18 (d, 2H), 7.52 (m, 3H), 7.82 (d, 1H). GC-MS: m/z 281 (M)+.