Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([C:10]2[N:14]=[C:13]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:16]=3[C:26]([F:29])([F:28])[F:27])[O:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH:30]1[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]1.C([BH3-])#N.[Na+]>CO.ClC(Cl)C.C(O)(=O)C.ClCCl>[CH3:1][C:2]1[CH:9]=[C:8]([C:10]2[N:14]=[C:13]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:16]=3[C:26]([F:28])([F:27])[F:29])[O:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[CH2:4][N:30]1[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]1
Reactant: Cc1cc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)ccc1C=O
Reactant: O=C(O)C1CNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CC(Cl)Cl
Product: Cc1cc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)ccc1CN1CC(C(=O)O)C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a mixture of 2-methyl-4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde (0.050 g, 0.125 mmol) and azetidine-3-carboxylic acid (0.015 g, 0.150 mmol) in methanol (0.5 mL) and dichloroethane (0.5 mL) at room temperature was added 3 drops of acetic acid via a pasteur pipette. The reaction mixture was heated at 60° C. for 1 h. The reaction was cooled to room temperature, sodium cyanoborohydride (9.59 mg, 0.150 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed with water, washed with brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded a white solid which was triturated with methanol with sonication and filtered. The resulting white solid was purified by flash silica gel chromatography using a mixture of methanol, dichloromethane, and ammonium hydroxide (10:90:0-20:80:1) to give 1-(2-methyl-4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid (0.032 g, 0.065 mmol, 52% yield) as a white solid. The compound had an HPLC ret. time=2.82 min.−Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. MS M+1=485.2. 1H NMR (500 MHz, DMSO-d6) δ ppm 2.38 (s, 3H), 3.17 (s, 2H), 3.22-3.24 (m, 1H), 3.46 (br. s., 2H), 3.63 (s, 2H), 7.51 (d, J=7.77 Hz, 1H), 7.57-7.73 (m, 5H), 7.86-7.94 (m, 2H), and 12.33 (br. s., 1H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48]([OH:50])=O)[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(CC)C(C)C)(C)C.[NH2:60][CH:61]([C:68]1[CH:73]=[CH:72][C:71]([Cl:74])=[CH:70][CH:69]=1)[CH2:62][CH2:63][NH:64][C:65](=[O:67])[CH3:66]>CN1C(=O)CCC1.C(OC(NC1(C(O)=O)CCN(C2C3C=CNC=3N=CN=2)CC1)=O)(C)(C)C.NC(C1C=CC(Cl)=CC=1)CCNC(=O)C>[C:65]([NH:64][CH2:63][CH2:62][CH:61]([NH:60][C:48]([C:33]1([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:26])([CH3:28])[CH3:27])[CH2:34][CH2:35][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:37][CH2:38]1)=[O:50])[C:68]1[CH:69]=[CH:70][C:71]([Cl:74])=[CH:72][CH:73]=1)(=[O:67])[CH3:66]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: CC(=O)NCCC(N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(=O)NCCC(NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 86 %

Procedure:
O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (98 mg, 0.26 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (62.2 mg, 0.17 mmol) and N,N-diisopropylethylamine (0.085 mL, 0.52 mmol) in NMP (2 mL) at 20° C. under nitrogen. The resulting solution was stirred at 20° C. for 5 minutes. N-(3-amino-3-(4-chlorophenyl)propyl)acetamide (Intermediate 27) (39 mg, 0.17 mmol) in NMP (2 mL) was then added to the reaction and stirred for 1 hour. The reaction mixture was concentrated and diluted with EtOAc (20 mL) and washed with water (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford tert-butyl 4-(3-acetamido-1-(4-chlorophenyl)propylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (1.04 g, 86%) as a white solid. m/z (ESI+) (M+H)+=570; HPLC tR=1.95 min.
Reaction SMILES: O[CH:2]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH2:3][CH3:4].P(Br)(Br)[Br:21]>C(Cl)(Cl)Cl.O>[Br:21][CH:2]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH2:3][CH3:4]
Reactant: CCC(O)c1ccc(-c2ccc(C(N)=O)cc2)cn1
Reactant: BrP(Br)Br
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCC(Br)c1ccc(-c2ccc(C(N)=O)cc2)cn1
Temperature: 25 °C
Yield: 96.4 %

Procedure:
To a solution of 4-(6-(1-hydroxypropyl)pyridin-3-yl)benzamide (0.1 g, 0.39 mmol) in chloroform (15 mL) was added PBr3 (0.316 g, 1.17 mmol) at 0-5° C. The solution was maintained at the same temperature for 1 h, was slowly warmed to rt and maintained at rt for another 2 h. The contents were diluted with water (75 mL) and chloroform (100 mL), the layers separated, the organic layer was washed with bicarbonate solution (2×30 mL), and the organic layer was dried over sodium sulphate and distilled off to get the crude product. The non-polar impurity was removed by pentane washings (2×7 mL) to provide 4-(6-(1-bromopropyl)pyridin-3-yl)benzamide (0.12 g, crude). LC-MS m/z calcd for [M+H]+ 321.03. found 321.0.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([CH3:15])=[CH:6][C:7]([CH3:14])=[C:8]([CH2:10][C:11](O)=[O:12])[CH:9]=2)[CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:19])=O.CN(C)C=O>ClCCl>[CH:1]1([C:4]2[C:5]([CH3:15])=[CH:6][C:7]([CH3:14])=[C:8]([CH2:10][C:11]([Cl:19])=[O:12])[CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(C)c(C2CC2)cc1CC(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C)c(C2CC2)cc1CC(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.3 g of (5-cyclopropyl-2,4-dimethyl-phenyl)-acetic acid in 20 ml of dichloromethane were treated with 2.1 g of oxalyl chloride and a catalytic amount of dimethylformamide. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the crude residue of (5-cyclopropyl-2,4-dimethyl-phenyl)-acetyl chloride (2.5 g) was used for the next step.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:31](I)[CH3:32]>>[CH2:31]([NH:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1)[CH3:32]
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(Nc2ncccc2N)c1)C(=O)OC(C)(C)C
Reactant: CCI
Product: CCNc1cccnc1Nc1cccc(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Yield: 54 %

Procedure:
Using the compound obtained in Example 3 as a starting material and also using ethyl iodide as a reagent, the procedure of Example 5 was repeated to give the titled compound (yield, 54%).
Reaction SMILES: [ClH:1].C1(OC)C=CC=CC=1.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][C@H:20]([NH:26]C(=O)OC(C)(C)C)[C:21]2[NH:25][N:24]=[N:23][N:22]=2)=[CH:11]1>C(OCC)(=O)C>[ClH:1].[NH:25]1[C:21]([C@@H:20]([NH2:26])[CH2:19][C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][CH:11]=2)=[N:22][N:23]=[N:24]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)c1nnn[nH]1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: COc1ccccc1
Product: N[C@@H](Cc1c[nH]c2ccccc12)c1nnn[nH]1
Reaction time: 1 h

Procedure:
Ethyl acetate (30 mL) was saturated with HCl gas at 0° C. at which point anisole (7.4 mL) was added followed by (S)-[2-(1H-indol-3-yl)-1-(1H-tetrazol-5-yl)ethyl]carbamic acid, 1,1-dimethylethyl ester (1.24 g., 3.77 mmol.) dissolved in ethyl acetate (7 mL). The resulting solution was stirred at 0° for one hour at which time TLC showed that no starting material remained. The reaction mixture was evaporated and chased with methylene chloride and ether and finally pumped to 0.95 g. of (S)-α-(1H-tetrazol-5-yl)-1H-indol-3-ethanamine, hydrochloride as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].[C:17]([NH:21][S:22]([CH2:25]Cl)(=[O:24])=[O:23])([CH3:20])([CH3:19])[CH3:18].Cl>CN(C=O)C>[C:17]([NH:21][S:22]([CH2:25][O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8])(=[O:24])=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: CC(C)(C)NS(=O)(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)NS(=O)(=O)COc1ccc(Cl)cc1C=O
Temperature: 60 °C
Yield: 49.5 %

Procedure:
A mixture of 5-chloro-2-hydroxy-benzaldehyde (13.9 g, 89.2 mmol), K2CO3 (24.6 g, 178.3 mmol) and N-tert-butyl-C-chloro-methanesulfonamide (16.5 g, 89.2 mmol) in DMF (20 mL) was heated at 60° C. overnight. After cooled to room temperature, the mixture was neutralized by addition of aqueous HCl solution and extracted with ethyl acetate. The organic phase was washed with water, brine, dried over anhydrous Na2SO4 and concentrated to give the crude product. The crude product was washed with diethyl ether to give the title compound (13.5 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.CCOCC.[Mg].Cl[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=[O:22]>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=[O:22])=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1Cl
Reactant: Fc1ccc(Br)cc1
Agent: [Mg]
Solvent: c1ccccc1
Solvent: CCOCC
Product: O=C1CCCCC1c1ccc(F)cc1
Reaction time: 18 h

Procedure:
The Grignard reagent prepared by adding 210 g of p-fluorobromobenzene in 800 ml. of anhydrous ether to 29.1 g of magnesium turnings in 50 ml. of ether was added, with cooling to keep the temperature of the reaction less than 15° C., to a solution of 158.4 g of 2-chlorocyclohexanone in 800 ml. of anhydrous benzene. The reaction was stirred at 25° for 18 hrs. then the ether was distilled off and the resulting benzene solution refluxed for 24 hrs. It was then poured into a mixture of 1 liter water and 200 ml. hydrochloric acid and extracted with ether. After evaporation of the ether the residue was distilled to yield 117 g (51%), b.p. 115 (0.2 mm). The material solidified on standing and was recrystallized from hexane, m.p. 56°-59° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:17]=1[O:18][C:19]1[CH:30]=[CH:29][C:22]([C:23]([N:25]([O:27][CH3:28])[CH3:26])=[O:24])=[CH:21][CH:20]=1>>[Cl:35][C:33]1[CH:32]=[CH:31][C:17]([O:18][C:19]2[CH:30]=[CH:29][C:22]([C:23]([N:25]([O:27][CH3:28])[CH3:26])=[O:24])=[CH:21][CH:20]=2)=[C:16]([NH:15][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:34]=1
Reactant: CON(C)C(=O)c1ccc(Oc2ccc(Cl)cc2N)cc1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Product: CCCc1ccc2c(Nc3cc(Cl)ccc3Oc3ccc(C(=O)N(C)OC)cc3)ccnc2n1

Procedure:
The product from Example 2g (75 mg, 0.36 mmol) was reacted with the product from Example 128b (111 mg, 0.36 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (76.3 mg, 36%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.88-1.03 (m, 3 H) 1.70-1.91 (m, 2 H) 2.88-3.00 (m, 2 H) 3.18 (s, 3 H) 3.42 (s, 3 H) 6.71 (d, J=7.35 Hz, 1 H) 6.94 (d, J=8.82 Hz, 2 H) 7.36 (d, J=8.82 Hz, 1 H) 7.50 (d, J=8.82 Hz, 2 H) 7.59-7.66 (m, 1 H) 7.71-7.79 (m, 2 H) 8.53 (d, J=6.99 Hz, 1 H) 8.84 (d, J=8.82 Hz, 1 H) 10.89 (s, 1 H) 14.54 (s, 1 H); MS (ESI+) m/z 477 (M+H−TFA)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[C:9]([NH2:13])=[N:10][NH:11][CH:12]=1)=[O:7])[CH3:4].C[N:15](C)[CH:16]=[C:17]([CH:20]=O)[C:18]#N>O1CCCC1>[CH2:3]([O:5][C:6]([C:8]1[CH:12]=[N:11][N:10]2[CH:20]=[C:17]([C:16]#[N:15])[CH:18]=[N:13][C:9]=12)=[O:7])[CH3:4]
Reactant: CN(C)C=C(C#N)C=O
Reactant: CCOC(=O)c1c[nH]nc1N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn2cc(C#N)cnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.9 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.52 g, 13.0 mmol) was added, at 0° C., to a mixture of 3-amino-1H-pyrazole-4-carboxylic acid ethyl ester (0.9 g, 5.8 mmol) and 3-dimethylamino-2-formyl-acrylonitrile (0.72 g, 5.8 mmol) in anhydrous tetrahydrofuran (30 mL) and the reaction mixture was stirred overnight while warming up to room temperature. Ice-water was added and the resulting mixture was partitioned between water and ethyl acetate; the organic layer was separated and the aqueous layer was extracted 3 times with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated. The yellow crude residue was purified twice on a silica gel plug (EtOAc/hexane) to afford 0.4 g (32% yield) of 6-cyano-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:23][CH:22]=1.CCOC(C)=O>CN(C=O)C>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[CH:25][CH:26]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(NC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Temperature: 120 °C
Yield: 46.7 %

Procedure:
A mixture of 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.200 g, 0.667 mmol) and tert-butyl (4-aminophenyl)carbamate (0.278 g, 1.344 mmol) in DMF (2 ml) was heated in a microwave reactor at 120° C. for 30 mins. EtOAc was added, and the mixture was washed with brine and evaporated. The residue was triturated in MeOH, the solvent was decanted and the residue was purified by silica gel column chromatography using 15-65% EtOAc in petroleum ether 40-60° C. as eluent, to give the title compound (0.147 g, 47%) as a solid. 1H NMR (500 MHz, d6-DMSO): δ 9.18 (s, 1H), 9.16 (s, 1H), 7.22 (dt, 1H), 7.18 (dt, 2H), 7.08-7.00 (m, 4H), 6.64 (d, 2H), 1.65 (s, 9H), 1.44 (s, 9H); 13C NMR (d6-DMSO): δ 160.3, 153.0, 136.8, 132.3, 131.9, 129.6, 129.3, 128.6, 125.9, 123.2, 117.9, 109.2, 79.8, 61.4, 28.8, 27.9; Mass Spectrum: M−H+ 470.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28].Cl>CN(C)C=O>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:16][CH2:17][N:18]2[C:22](=[O:23])[C:21]3=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]3[C:19]2=[O:28])=[CH:3][CH:4]=1
Reactant: Oc1ccc(S)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCSc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.5 %

Procedure:
To a mixture of 4-mercaptophenol (3.78 g), potassium carbonate (8.2 g) and N,N-dimethylformamide (40 ml) was added dropwise under ice cooling a solution of N-(2-bromoethyl)phthalimide (7.62 g) in N,N-dimethylformamide (50 ml). The reaction mixture was stirred at room temperature for 16 hours and poured into 3% hydrochloric acid (220 ml), and the resulting crystals were collected by filtration and dried to give N-[2-(4-hydroxyphenylthio)ethyl]phthalimide (9.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](C#N)[CH:5]=[CH:4][N:3]=1.CC[O:12][CH2:13][CH3:14]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:13](=[O:12])[CH3:14])[CH:5]=[CH:4][N:3]=1
Reactant: CCOCC
Reactant: N#Cc1ccnc(Cl)c1
Product: CC(=O)c1ccnc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Chloropyridine-4-carbonitrile (250 g, 1.80 mol, 1.00 equiv) and ether (3750 mL) were combined in a 10000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen. A solution of MeMgI in ether (1200 mL) was added dropwise with stirring at 0° C. in 30 min. The resulting solution was stirred for 6 h at room temperature and then poured into water/ice/6N hydrogen chloride (3000 mL) and stirred for 10 min. The organic phase was separated and the aqueous phase was extracted with ether (3×2000 mL). The combined organic layer was washed with brine (2×2000 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel (1:20 ethyl acetate/petroleum ether) to afford 1-(2-chloropyridin-4-yl)ethan-1-one as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:18])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:19][Si]([N-][Si](C)(C)C)(C)C.[K+].N[C@H](C(O)=O)CCSC.CCOC(C)=O>COCCOC>[Cl:1][C:2]1[N:3]=[C:4]([Cl:18])[C:5]2[CH2:10][CH2:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)([CH3:19])[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: CSCC[C@H](N)C(=O)O
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC1(c2ccc(F)cc2)CCc2c(Cl)nc(Cl)nc21
Reaction time: 0.17 h
Yield: 81 %

Procedure:
To a solution of 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, (Preparation S, 3.56 g, 12.57 mmol) in DME (Volume: 84 mL) at −78° C. was added KHMDS (0.91 M in THF, 15.20 ml, 13.83 mmol) dropwise. After 10 min, Met (2.36 mL, 37.7 mmol) was added. The reaction was kept at −78° C. for 10 min, then allowed to come to rt. An aliquot taken while the reaction was still cool was quenched with water and extracted with EtOAc. TLC (10% EtOAc/Hex) and LC/MS showed the clean conversion to a new product. The bulk of the material was then quenched and extracted as above. The combined organic extracts were dried over MgSO4, filtered, and the solvent removed in vacuo. SG chromatography (0 to 40% EtOAc/Hex) gave 2,4-dichloro-7-(4-fluorophenyl)-7-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (3.01 g, 10.13 mmol, 81% yield). LC-MS (*M*+H)+=293.1 (*product reacts with methanol during analysis*). 1H NMR (500 MHz, CDCl3) δ ppm 7.21-7.29 (2H, m), 6.96-7.04 (2H, m), 2.88-3.02 (2H, m), 2.62 (1H, ddd, J=13.28, 7.93, 5.04 Hz), 2.26-2.35 (1H, m), 1.68 (3H, s).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C@@:11]([OH:29])([CH2:23][N:24]1[CH:28]=[N:27][CH:26]=[N:25]1)[C@H:12]([S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])=[O:15])[CH3:13].Cl.Cl[CH2:32][C:33]1[N:37]([CH3:38])[CH:36]=[N:35][N:34]=1.C[O-].[Na+]>CO>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C@@:11]([OH:29])([CH2:23][N:24]1[CH:28]=[N:27][CH:26]=[N:25]1)[C@H:12]([S:14]([N:17]1[CH2:22][CH2:21][N:20]([CH2:32][C:33]2[N:37]([CH3:38])[CH:36]=[N:35][N:34]=2)[CH2:19][CH2:18]1)(=[O:16])=[O:15])[CH3:13]
Reactant: Cn1cnnc1CCl
Reactant: C[C@H]([C@](O)(Cn1cncn1)c1ccc(F)cc1F)S(=O)(=O)N1CCNCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C[C@H]([C@](O)(Cn1cncn1)c1ccc(F)cc1F)S(=O)(=O)N1CCN(Cc2nncn2C)CC1
Temperature: 70 °C
Yield: 25.8 %

Procedure:
In methanol (6 ml) were dissolved 1-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butylsulfonyl]piperazine-dihydrochloride (Compound 20, 0.40 g) and 3-chloromethyl-4-methyl-4H1,2,4-triazole.hydrochloride (255 mg). To the solution was added 1N-methanol solution of sodium methylate (3.69 ml), and the mixture was heated at 70° C. for 14 hours, then the reaction mixture was concentrated. The concentrate was dissolved in dichloromethane (30 ml), washed with water, dried and concentrated. The concentrate was recrystallized from ethyl acetate to give 1-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1, 2,4-triazol-1-yl)-2-butylsulfonyl]-4-(4-methyl-4H-1,2,4-triazol-3-ylmethyl) piperazine (Compound 26, 108 mg) as pale yellow crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:13](=[O:14])[N:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:7]=1[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=1)=[O:5])C.[OH-].[Na+]>C1COCC1.C([O-])(O)=O.[Na+]>[CH3:22][S:21][C:17]1[N:16]=[C:15]([C:7]2[N:8]3[CH2:12][CH2:11][CH2:10][N:9]3[C:13](=[O:14])[C:6]=2[C:4]([OH:5])=[O:3])[CH:20]=[CH:19][N:18]=1
Reactant: CCOC(=O)c1c(-c2ccnc(SC)n2)n2n(c1=O)CCC2
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CSc1nccc(-c2c(C(=O)O)c(=O)n3n2CCC3)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-(2-methylsulfanyl-pyrimidin-4-yl)-1-oxo-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-carboxylic acid ethyl ester, 13, (2.7 g, 8.4 mmol) in THF (85 mL) is added aqueous NaOH (42 mL of 1N solution, 42.0 mmol). The solution is stirred for 18 hours at room temperature then diluted with aqueous saturated NaHCO3 and the aqueous phase is extracted twice with CHCl3. The aqueous phase is then acidified to pH 1 with aqueous 1N HCl and extracted twice with CHCl3. The combined organic layers are dried (MgSO4), filtered and concentrated in vacuo to afford 2.3 g of the desired product which is used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[N:25]=1)[C:20]([O:22][CH3:23])=[O:21]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[N:25]=2)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)C(N)c1cccc(N)n1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: COC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1cccc(N)n1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(6-aminopyrid-2-yl)acetate (prepared from 2-(methoxyimino)-2-(6-aminopyrid-2-yl)acetic acid [CAS 71470-33-2] using General Procedures G and AC above), the title compound was prepared. The product was purified by LC 2000 preparative column chromatography using 1:1 EtOAc/hexanes as the eluent.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl[C:12]([CH3:16])([CH3:15])[C:13]#[CH:14].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[OH-].[Na+]>C(Cl)Cl.O>[CH3:15][C:12]([CH3:16])([O:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1)[C:13]#[CH:14]
Reactant: C#CC(C)(C)Cl
Reactant: N#Cc1ccc(O)cc1F
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: C#CC(C)(C)Oc1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
10 g (0.072 M) of 2-fluoro-4-hydroxybenzonitrile, 0.072 M of 3-chloro-3,3-dimethylpropyn and 15 g (equivalent to 16.3 ml or 0.036 M) of benzyl-trimethylammonium hydroxide (40% strength in methanol) are suspended in 80 ml of methylene chloride, a solution of 4.32 g (0.108 M) of NaOH in 80 ml of water is added, and the mixture is stirred at room temperature for 3 days. The phases are separated, and the aqueous phase is extracted several times with methylene chloride. The organic solution is washed with 10% strength NaOH and then with water and the organic solvent is distilled off under reduced pressure. 4-(1,1-Dimethyl-2-propynyloxy)-2-fluorobenzonitrile is obtained as a red-colored oily product.