Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[CH2:11][C:10]([C:20]([C:26]([F:29])([F:28])[F:27])([C:22]([F:25])([F:24])[F:23])[OH:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:30]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:12]1[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([N:40]3[CH2:39][CH2:38][N:37]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:42][CH2:41]3)[CH:3]=2)[N:9]=[C:10]([C:20]([C:22]([F:23])([F:25])[F:24])([C:26]([F:28])([F:27])[F:29])[OH:21])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: OC(C1=NN(c2cccc(Br)c2)C(c2ccccc2Cl)C1)(C(F)(F)F)C(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(N3N=C(C(O)(C(F)(F)F)C(F)(F)F)CC3c3ccccc3Cl)c2)CC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 15.7 %

Procedure:
1-(3-Bromo-phenyl)-5-(2-chloro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (500.0 mg, 1.00 mmol) prepared in Step 2 of Preparation 25, 1-BOC-piperazine (275.0 mg, 1.49 mmol), Pd2(dba)3 (47.0 mg, 0.05 mmol), BINAP (63.0 mg, 0.10 mmol) and sodium t-butoxide (143.0 mg, 1.79 mmol) were added to toluene (12.0 mL). The reaction mixture was stirred at 100° C. for 12 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to give 95.0 mg the titled compound as a yellow liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:23][CH:24]=[CH2:25])[C:13]([NH:15][C@H:16]([C:20]([OH:22])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26](OC(NC(CC=C)C(O)=O)=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[CH2:26]([O:21][C:20](=[O:22])[C@H:16]([CH:17]([CH3:18])[CH3:19])[NH:15][C:13](=[O:14])[CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:23][CH:24]=[CH2:25])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C=CCC(NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)O)C(C)C
Reactant: C=CCC(NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C=CCC(NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)OCc1ccccc1)C(C)C
Reaction time: 19 h

Procedure:
N-(N-Benzyloxycarbonyl-2-Amino-4-Pentenoyl)-L-Valine Benzxyl Ester (4) To a cooled (0-5° C.) solution of 24 mg (0.096 mmol) N-(N-benzyloxycarbonyl-2-amino-4-pentenoic acid (3), 36 mg (0.096 mmol) valine benzyl ester p-toluenesulfonyl salt, and 11 μL (0.096 mmol) N-methylmorpholine in 2 mL CH2Cl2 was added 14 mg (0.101 mmol) HOBt and 21 mg (0.101 mmol) DCC and the mixture was stirred for 19 h. The solution was filtered and the filtrate diluted with 10 mL CH2Cl2 and washed with two 10-mL portions of 0.5 N HCl, with two 10-mL portions of saturated aqueous NaHCO3, and with 10 mL brine. The organic phase was dried (MgSO4) and concentrated. The crude product was applied to a silica gel column (1×15 cm) and elution with 5% MeOH in CH2Cl2 gave pure N-(N-benzyloxycarbonyl-2-amino-4-Pentenoyl)-L-valine benzyl ester (4) as a colorless oil: yield 35 mg (83%); 1H NMR (CDCl3) δ0.80-0.90 (m, 6H); 2.14-2.20 (m, 1H); 2.49-2.56 (m, 2H); 4.20-4.32 (M, 1H); 4.55-4.60 (m, 1H0; 5.07-5.30 (M, 6H); 5.65-5.83 (m, 1H); 6.42-6.49 (m, 1H); 7.30-7.34 (m, 10H); mass spectrum (CI, methane) m/z 439 (M+H)+, 225.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH:6]([NH:9][C:10](=[O:18])[C:11](=[N:16][OH:17])[CH2:12][CH:13]([CH3:15])[CH3:14])[C:7]#[N:8])[CH:2]=[CH2:3]>C(O)(=O)C>[CH2:1]([O:4][CH2:5][C:6]1[NH:9][C:10](=[O:18])[C:11]([CH2:12][CH:13]([CH3:14])[CH3:15])=[N+:16]([O-:17])[C:7]=1[NH2:8])[CH:2]=[CH2:3]
Reactant: C=CCOCC(C#N)NC(=O)C(CC(C)C)=NO
Solvent: CC(=O)O
Product: C=CCOCc1[nH]c(=O)c(CC(C)C)[n+]([O-])c1N
Yield: 22.7 %

Procedure:
To 220 ml of acetic acid was added 22 g of 3-allyloxy-2-(α-hydroxyiminoisocaproylamino)propionitrile. The mixture was subjected to a reaction for 1 hour at 85° C. After completion of the reaction, acetic acid was removed by evaporation under reduced pressure. The residue was purified by using Frorisil (60-100 mesh) (eluting solvent: 30 volume % ethyl acetate-n-hexane→ 60% volume of ethyl acetate-n-hexane), then washed with diethyl ether, followed by recrystallization from benzene, to obtain 5 g of 6-allyloxymethyl-5-amino-3-isobutyl-1,2-dihydropyrazin-2-one 4-oxide (Compound B-3) as pale yellow plate-like crystals having a melting point of 149°-151° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[CH:25]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:42][NH2:43]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:25]=[C:26]3[C:27]([C:30]([NH2:31])=[N:42][NH:43]3)=[CH:28][CH:29]=2)[N:3]=1
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)NCc4ccccc4)C3)nc(N)n2)cc1F
Reactant: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCC[C@H](C(=O)NCc3ccccc3)C2)n1
Temperature: 150 °C
Yield: 14.9 %

Procedure:
Into a microwave tube, (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-(phenylmethyl)-3-piperidinecarboxamide (190 mg, 0.441 mmol), 3 mL of EtOH, Hunig's base (0.308 ml, 1.761 mmol), and hydrazine anhydrous (0.083 ml, 2.64 mmol) were added, and the yellow mixture was heated at 150° C. for 180 minutes under microwave conditions. The solution turned black. LCMS showed mainly product. The black solids were filtered and the yellow filtrate was evaporated. The resulting yellow residue was dissolved in CH3OH, and EtOAc was used to triturate, affording the title compound (29 mg) as a light yellow solid. LC-MS (ES) m/z=443 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.31-1.52 (m, 1H), 1.61-1.81 (m, 2H), 1.86-2.04 (m, 1H), 2.29-2.45 (m, 1H), 2.77-3.05 (m, 2H), 4.17-4.25 (m, 1H), 4.31-4.69 (m, 3H), 5.38 (s, 2H), 6.09 (s, 2H), 6.58-6.70 (m, 1H), 7.17-7.39 (m, 5H), 7.58 (dd, J=8.6, 1.3 Hz, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.96 (s, 1H), 8.46 (t, J=5.9 Hz, 1H), 11.50 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]2[NH:14][CH:15]=[CH:16][C:17](=[O:19])[N:18]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[N:20]1[CH:25]=[CH:24][C:23]([CH:26]=[O:27])=[CH:22][CH:21]=1>Cl>[Cl:1][C:2]1[C:3]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]2[NH:14][CH:15]=[C:16]([CH:26]([C:23]3[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=3)[OH:27])[C:17](=[O:19])[N:18]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc[nH]c(NCCCCc2ncccc2Cl)n1
Reactant: O=Cc1ccncc1
Agent: Cl
Product: O=c1nc(NCCCCc2ncccc2Cl)[nH]cc1C(O)c1ccncc1
Yield: 80.1 %

Procedure:
2-[[4-(3-Chloro-2-pyridyl)butyl]amino]-4-(1H)-pyrimidinone (1.37 g) and pyridine 4-aldehyde (0.52 g) were refluxed in concentrated hydrochloric acid (5 ml) for 24 hours. The reaction mixture was evaporated under reduced pressure to afford an oil which was partitioned between chloroform (25 ml) and water (25 ml) with the addition of sodium hydroxide to take the aqueous layer to pH 6.5. The aqueous layer was washed with more chloroform (25 ml) and the combined chloroform extracts were dried (MgSO4) and evaporated under reduced pressure to give a red oil (1.5 g). This oil was stirred under hot diethyl ether which was subsequently decanted (removing some pyridine-4-aldehyde), and the oil was subjected to chromatography on silica gel with gradient elution (100% chloroform→5% methanol in chloroform). The fractions containing the desired product were collected, combined and evaporated under reduced pressure to an oil which solidified on trituration with diethyl ether. Crystallisation from aqueous ethanol afforded a white crystalline solid (0.78 g). This was further purified by dissolution in chloroform, washing with sodium hydroxide solution (pH 13), extraction into dilute hydrochloric acid (pH 4), washing with chloroform, taking to pH 7.5 and extracting back into chloroform. This was evaporated under reduced pressure to afford an oil which was crystallised from aqueous ethanol to afford the title compound (0.53 g), m.p. 90° C.; δ(CDCl3) 1.75 (4H, m), 2.95 (2H, m), 3.40 (2H, m), 5.71 (1H, s), 7.07 (1H, dd), 7.32 (2H, d), 7.40 (3H, br), 7.46 (1H, s), 7.62 (1H, dd), 8.23 (1H, dd), 8.49 (2H, d) ppm.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:15]=[CH:14][C:13]([N:16]=CC2C=CC=CC=2)=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:3])[CH3:2]>O.C(O)C>[C:1]([O:4][C:5]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cc(N=Cc2ccccc2)ccc1OC(C)=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(N)ccc1OC(C)=O
Yield: 41.7 %

Procedure:
Ethyl 2-acetoxy-5-benzylideneaminobenzoate (10.0 g, 32.2 mmole) was refluxed in water-ethanol (3:1, 750 ml) for about 1 hour, after which time the mixture was cooled and the precipitate isolated by filtration. After a further recrystallization this gave the title compound (3.0 g, 42%), m.p. 82.5°-83° C. Found (Calc. for C11H13NO4) C 58.96 (59.19). H 5.98 (5.83), N 6.22 (6.28).
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:25]=[C:26]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.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>[OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:24]2[CH:29]=[C:28]([C:30]([F:32])([F:33])[F:31])[CH:27]=[C:26]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:25]=2)=[CH:7][CH:6]=1
Reactant: NS(=O)(=O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
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: [Na+]
Solvent: CCO
Product: C[C@H](Oc1ccc(-c2cc(C(F)(F)F)cc(S(N)(=O)=O)c2)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C
Yield: 75.2 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.20 g, Example 33), 3-bromo-5-trifluoromethylbenzosulphonamide (0.40 g, Example 74), 2M aqueous sodium carbonate (0.76 ml) and tetrakis(triphenylphosphine)palladium (0) (0.019 g) in ethanol (5 ml) with heating at 90° C. for 4 hours. After work up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as a solid (0.24 g). m.p. 57-59° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]([F:16])([F:15])[F:14])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[F:15][C:13]([F:16])([F:14])[C:6]1[C:5]2[C:10](=[CH:11][C:2]([NH:1][S:24]([C:21]3[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=3)(=[O:26])=[O:25])=[CH:3][CH:4]=2)[O:9][C:8](=[O:12])[CH:7]=1
Reactant: Nc1ccc2c(C(F)(F)F)cc(=O)oc2c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: O=c1cc(C(F)(F)F)c2ccc(NS(=O)(=O)c3ccc(Cl)cc3)cc2o1
Reaction time: 0.83 h
Yield: 72 %

Procedure:
To a solution of 7-amino-4-trifluoromethylcoumarin (200 mg, 0.87 mmol) and 4-dimethylaminopyridine (1 mg) in pyridine (3 ml) was added 4-chlorobenzenesulfonyl chloride (203 mg, 0.96 mmol), followed by stirring at 70 degrees for 50 minutes. To the reaction mixture was added 2 N hydrochloric acid, followed by extracting with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated. The resulting residue was crystallized from ethyl acetate-diisopropyl ether, to give 253 mg of the title compound as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].I[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CI
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCN(C(=O)OCc2ccccc2)CC1=O
Temperature: -10 °C
Yield: 81 %

Procedure:
To a solution of 4-benyloxycarbonylpiperazin-2-one (M.W.=234.26, 2.34 g, 10 mmol) in anhydrous THF (150 mL) at −78° C. under argon was added lithium bis(trimethylsilyl) amide (1 M in THF, 12 mL, 12 mmol) dropwise. The mixture was stirred at −78° C. for 30 min Ethyl iodoacetate (M.W.−214, 2.14 g, 10 mmol) was added to the mixture at −78° C., stirred, warmed up to −10° C., and then kept in the freezer over night. The reaction was quenched by adding 1N HCl (60 mL) and extracted with EtOAc (200 mL+100 mL). The combined organic layers were washed with sat. NaCl three times, dried with MgSO4, and evaporated to give the crude title compound as a yellowish oil. Reversed-phase HPLC purification afforded the pure compound in 81% yield.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[CH2:15][O:14][NH:13][C:12]2=[O:16])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:25]1([C:31]([O:33][CH3:34])=[O:32])[CH:29]=[CH:28][C:27](=[O:30])[O:26]1>ClCCl>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[CH2:15][O:14][N:13]([C:25]3([C:31]([O:33][CH3:34])=[O:32])[CH:29]=[CH:28][C:27](=[O:30])[O:26]3)[C:12]2=[O:16])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1CONC1=O
Reactant: COC(=O)C1(Cl)C=CC(=O)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1(N2OC[C@@H](NC(=O)Cc3ccccc3)C2=O)C=CC(=O)O1
Yield: 43.3 %

Procedure:
In 8 ml of dichloromethane was suspended 110 mg of (4R)-4-phenylacetamido-3-isoxazolidinone. To the suspension were added, under ice-cooling and stirring, 0.14 ml of triethylamine and 2 ml of dichloromethane solution dissolving 106 mg of the Compound (27) obtained in Example (27). The reaction solution was stirred at room temperature for 40 minutes, washed with water and dried (Na2SO4). The solvent was then evaporated off. The residue was subjected to a silica gel column chromatography, followed by elution with hexane-ethyl acetate (2:3) to give 78 mg of the subject Compound (30) as colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCc1cc2c(NCc3ccc(F)cc3)nc(Cl)nc2s1
Reactant: c1cn[nH]c1
Product: CCc1cc2c(NCc3ccc(F)cc3)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-ethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-ethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:16]([O:18]CC)=[CH2:17])CCC>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:16]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1)(=[O:18])[CH3:17]
Reactant: N#Cc1ccc(Br)cc1F
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(C#N)c(F)c1
Reaction time: 0.5 h
Yield: 11.6 %

Procedure:
A mixture of 4-bromo-2-fluorobenzonitrile (10.6 g, 52.8 mmol), tributyl(1-ethoxyvinyl)tin (21 g, 58.1 mmol), and trans-dichlorobis(triphenylphosphine)palladium (II) (371 mg, 0.53 mmol) in 190 mL of dry toluene were refluxed for 2 h and then quenched with 5% HCl and stirred for 30 min. Ethyl acetate was added and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 6.5 g of crude product. Purification of the product on silica gel using 5% ethyl acetate:hexane gave 4-acetyl-2-fluorobenzonitrile (1.0 g, 11%), MS (ES) m/z 164 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:14]([OH:16])=[O:15].[CH3:17]O>>[CH3:17][O:15][C:14]([C:3]1[N:2]([CH3:1])[C:10]2[C:5]([CH:4]=1)=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)=[O:16]
Reactant: Cn1c(C(=O)O)cc2cc([N+](=O)[O-])ccc21
Reactant: CO
Product: COC(=O)c1cc2cc([N+](=O)[O-])ccc2n1C

Procedure:
1-Methyl-5-nitro-1H-indole-2-carboxylic acid (99 mg, 0.45 mmol) was esterified with MeOH using Method A to give the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:15]Br)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]([CH2:15][N:20]2[CH2:19][CH2:18][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21]2)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2)CC1
Reaction time: 8 h
Yield: 56.1 %

Procedure:
3,5-Bis(t-butyl)-1-(bromomethyl)benzene (170 mg, 0.60 mmol), t-butyl piperazine carboxylate (102 mg, 0.55 mmol) and potassium carbonate (151 mg, 1.10 mmol) were dissolved in a solvent mixture of acetone (2 ml) and DMF (0.2 ml), and the mixture was stirred overnight while heated under reflux. The reaction mixture was extracted with ethyl acetate, dried over sodium sulfate, and then the filtrate was evaporated under reduced pressure. The concentrate was subjected to silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give 120 mg (yield: 56%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.[Cl:11][C:12]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15]>C1(C)C(C)=CC=CC=1>[Cl:11][C:12]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:13]=1[C:14]([NH:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1)=[O:15]
Reactant: Nc1nc(C(Cl)(Cl)Cl)ns1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1C
Product: O=C(Nc1nc(C(Cl)(Cl)Cl)ns1)c1ccc(Cl)cc1Cl
Yield: 69.5 %

Procedure:
A solution of 10.9 g (0.05 mole) 5-amino-3-trichloromethyl-1,2,4-thiadiazole and 20.9 g (0.10 mole) 2,4-dichlorobenzoyl chloride was refluxed in 200 ml xylene for 20 hours. The reaction mixture was concentrated in vacuo and the resulting residue extracted with benzene. Addition of hexane resulted in precipitation of 13.6 g (69% yield) pure product; m.p. 136° C.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([OH:13])=[O:12].[CH2:14](O)[CH3:15].OS(O)(=O)=O>C(Cl)Cl.O>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCO
Reactant: O=C(O)C1CCc2ccccc2O1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1CCc2ccccc2O1

Procedure:
Chroman-2-carboxylic acid (35.6 g, 0.2 mol) prepared according to the method of Augstein et al., J. Med. Chem., v. 11, pp. 844-848, 1968) and absolute ethanol (24.3 g, 0.6 mol) were combined in 300 ml of CH2Cl2. H2SO4 (0.6 ml, 96%) was added and the mixture gently refluxed for 21 hours, then cooled and diluted with 500 ml H2O. The organic layer was separated, washed with saturated NaHCO3 and then H2O, dried (MgSO4) and stripped to yield present title product as an oil; 38.6 g (93%); 1H-NMR (CDCl3), 300 MHz) delta 7.12 (t, 1H), 7.02 (d, 1H), 6.92 (d, 1H), 6.85 (t, 1H), 4.71 (q, 1H), 4.25 (q. 2H), 2.80 (m, 2H), 2.22 (m, 2H), 1.29 (t, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH2:30]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH2:30][O:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
To p-benzyloxyphenol (7.05 g, 35.2 mmol) was added to a solution of NaH (60% dispersion in oil, 1.70 g, 42.2 mmol) in anhy. DMF (70 mL) at 0° C. The mixture was stirred at ambient temperature for 30 min, then cooled to −10° C. and (R)-2-(Toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (12.5 g, 35.2 mmol) in anhy.DMF (20 mL) was added dropwise over 5 min. The mixture was stirred at 92° C. for 5 h and then ambient temperature overnight. The reaction mixture was poured into ice water and stirred for one h. The subsequent mixture was filtered and the organic portion was extracted into ether. The portion was dried over anhy. MgSO4, and concentrated to afford the product (11.7 g, 86%).
Reaction SMILES: [CH3:1][C:2]([CH3:40])([O:4][C:5]([N:7]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:8]1[C:13]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])[N:17]=[N:16][N:15]=2)=[CH:12][C:11]([C:27]#[C:28][Si](C)(C)C)=[CH:10][N:9]=1)=[O:6])[CH3:3].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[CH3:38][C:36]([CH3:39])([O:35][C:33]([N:7]([C:5]([O:4][C:2]([CH3:40])([CH3:3])[CH3:1])=[O:6])[C:8]1[C:13]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])[N:17]=[N:16][N:15]=2)=[CH:12][C:11]([C:27]#[CH:28])=[CH:10][N:9]=1)=[O:34])[CH3:37]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(C#C[Si](C)(C)C)cc1-c1nnnn1-c1cccc(F)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: ClCCl
Product: C#Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c2nnnn2-c2cccc(F)c2F)c1
Temperature: 0 °C
Yield: 83.3 %

Procedure:
N,N-Di(1,1-dimethylethoxycarbonyl)-3-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-(2-(trimethylsilyl)ethynyl)pyridin-2-amine (713 mg, 1.2 mmol) was dissolved in methylene chloride (10 mL) and cooled to 0° C. To this was added tetrabutylammonium fluoride hydrate (163 mg, 625 μmol) in methylene chloride (1 mL). The reaction was loaded directly onto silica and chromatographed (10% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give N,N-di(1,1-dimethylethoxycarbonyl)-3-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-ethynylpyridin-2-amine (496 mg, 1.0 mmol, 83%) as a yellow solid; 1H NMR (CDCl3): 1.37 (s, 18H), 3.35 (s, 1H), 7.30 (m, 1H), 7.40 (m, 2H), 7.89 (s, 1H), 8.75 (s, 1H).