Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]I)#[N:2].[Br:16][C:17]1[N:22]=[C:21]([O:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:20]=[CH:19][CH:18]=1>>[C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][N:29]1[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][O:23][C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([Br:16])[N:22]=2)[CH2:27][CH2:28]1)#[N:2]
Reactant: CC(C)C(C#N)(CCCI)c1cccs1
Reactant: Brc1cccc(OCCN2CCNCC2)n1
Product: CC(C)C(C#N)(CCCN1CCN(CCOc2cccc(Br)n2)CC1)c1cccs1

Procedure:
The title compound was synthesized in accordance with Example 75 from 4-cyano-4-(2-thienyl)-5-methylhexyl iodide and 1-[2-(6-bromo-2-pyridyloxy)ethyl]piperazine. The physico-chemical data of the compound was as below.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[O-]CC.[Na+].[C:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(O)C>[CH2:9]([O:8][C:1](=[O:7])[C:2](=[O:4])[CH:16]([C:15](=[O:21])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:17][CH2:18][CH2:19][CH3:20])[CH3:10]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCCCCC(=O)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCC(C(=O)C(=O)OCC)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethyl oxalate (7.31 g, 0.05 mol) is added to freshly made sodium ethoxide (1.05 eq.) in ethanol. Hexanophenone (8.81 g, 0.05 mol) is added dropwise, and the resulting mixture is stirred at room temperature overnight. After concentration the residue is partitioned between 3N HCl and ethyl acetate, extracted with ethyl acetate. Combined organic layers are washed with brine and dried with anhydrous Na2SO4. Purification by column chromatography with hexane/ethyl acetate gives the product (172).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23](Br)[CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH2:36][CH2:37][CH:38]1[CH2:40][CH2:39]1>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([NH:36][CH2:37][CH:38]4[CH2:40][CH2:39]4)[CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: NCC1CC1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2cccc(Br)c2)[C@H](c2ccccc2)C1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2cccc(NCC3CC3)c2)[C@H](c2ccccc2)C1

Procedure:
The title compound, MS: m/e=547.2 (M+), was prepared in accordance with the general method of example 10 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[4-(3-bromo-phenyl)-3-phenyl-piperidin-1-yl]-methanone and aminomethylcyclopropane.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Br:15][C:12]1[CH:11]=[CH:10][C:9]([C:6]2([CH2:4][OH:3])[CH2:7][CH2:8]2)=[CH:14][CH:13]=1
Reactant: CCOC(=O)C1(c2ccc(Br)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1(c2ccc(Br)cc2)CC1
Temperature: -4 °C

Procedure:
1-(4-Bromo-phenyl)-cyclopropanecarboxylic acid ethyl ester (25 g, 92.89 mmol) was dissolved in THF (175 mL) and was stirred under N2 atmosphere at −4° C. Lithium aluminum hydride (4.58 g, 120.75 mmol) was added in portions and the reaction stirred between 2 to 8° C. for 1 hour. The reaction was worked up using the Fieser method, filtered and concentrated to afford the title compound.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][CH:20]=2)[N:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[NH:7][C:6]1[N:15]=[CH:16][CH:17]=[CH:18][C:5]2=1.C(N(C(C)C)CC)(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:36][S:37]([O:26][CH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:3]2[N:4]3[C:5]4[CH:18]=[CH:17][CH:16]=[N:15][C:6]=4[NH:7][C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[C:10]3=[N:1][N:2]=2)=[CH:20][CH:21]=1)(=[O:39])=[O:38]
Reactant: OCc1ccc(-c2nnc3n2-c2cccnc2Nc2ccccc2-3)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCc1ccc(-c2nnc3n2-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of (4-(9H-benzo[f]pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepin-3-yl)phenyl)methanol (1.35 g, 3.95 mmol) in dichloromethane (70 mL) was added diisopropylethylamine (1.72 mL, 9.89 mmol) and methanesulfonyl chloride (0.767 mL, 9.89 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The mixture was washed with water (50 mL), saturated aqueous sodium bicarbonate solution (50 mL) and water (3×50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo, yielding the 4-(9H-benzo[f]pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepin-3-yl)benzyl methanesulfonate as a light yellow solid (1.7 g, quantitative). M.p.=252-253° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.82 (br.s, 1H), 8.22 (dd, J=4.8, 1.6 Hz, 1H), 7.97 (dd, J=7.6, 1.6 Hz, 1H), 7.6-7.4 (m, 5H), 7.36 (dd, J=8.0, 1.2 Hz, 1H), 7.2-7.1 (m, 2H), 6.92 (dd, J=7.6, 4.4 Hz, 1H), 5.33 (s, 2H), 3.28 (s, 3H); LCMS [M+H]: 420.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:10]2[CH:9]=[C:8]3[N:11]=[C:12]([NH:14][C:15](=[O:22])[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[NH:13][C:7]3=[CH:6][C:5]=2[N:4]([CH2:23][CH2:24][CH:25]=O)[C:3]1=[O:27].Cl.[C:30]([O:34][NH2:35])([CH3:33])([CH3:32])[CH3:31]>CO.O>[C:30]([O:34][N:35]=[CH:25][CH2:24][CH2:23][N:4]1[C:5]2[CH:6]=[C:7]3[NH:13][C:12]([NH:14][C:15](=[O:22])[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[N:11][C:8]3=[CH:9][C:10]=2[C:2]([CH3:28])([CH3:1])[C:3]1=[O:27])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC1(C)C(=O)N(CCC=O)c2cc3[nH]c(NC(=O)c4ccccc4)nc3cc21
Reactant: CC(C)(C)ON
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(C)(C)ON=CCCN1C(=O)C(C)(C)c2cc3nc(NC(=O)c4ccccc4)[nH]c3cc21
Yield: 11.8 %

Procedure:
A solution of N-[7,7-dimethyl-6-oxo-5-(3-oxo-propyl)-3,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl]-benzamide (50 mg) and O-tert-butyl-hydroxylamine hydrochloride (117 mg; 0.93 mmol) in MeOH (10 ml) and water (1 ml) is stirred at RT for 18 h. After evaporating to dryness the crude material is purified by preparative RP-HPLC eluting with MeCN/water to give the desired compound (7 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])[N+:5]([O-:13])=[C:4]([NH:14][C:15]([O:17][CH3:18])=[O:16])[CH:3]=1.[NH:19]1[CH2:24][CH2:23][CH:22]=[CH:21][CH2:20]1>C(Cl)Cl>[N:19]1([C:2]2[N:7]=[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])[N+:5]([O-:13])=[C:4]([NH:14][C:15]([O:17][CH3:18])=[O:16])[CH:3]=2)[CH2:20][CH:21]=[CH:22][CH2:23][CH2:24]1
Reactant: COC(=O)Nc1cc(Cl)nc(NC(=O)OC)[n+]1[O-]
Reactant: C1=CCNCC1
Solvent: ClCCl
Product: COC(=O)Nc1cc(N2CC=CCC2)nc(NC(=O)OC)[n+]1[O-]

Procedure:
A suspension of 10 g. of dimethyl 6-chloro-2,4-pyrimidine-dicarbamate-3-oxide in 40 ml. of methylene chloride is treated with 20 ml. of 1,2,5,6-tetrahydropyridine and stirred at room temperature under an argon atmosphere for 16 hours. The resulting precipitate is filtered off and recrystallized from a mixture of methylene chloride and methanol, there being obtained pure dimethyl 6-[3,6-dihydro-1(2H)-pyridyl]-2,4-pyrimidine-dicarbamate-3-oxide, having a melting point of 203° C.
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][CH3:6])[CH2:3]O.[CH3:7][S:8](Cl)(=[O:10])=[O:9]>>[CH2:5]([C@@H:2]1[CH2:3][CH2:7][S:8](=[O:10])(=[O:9])[NH:1]1)[CH3:6]
Reactant: CS(=O)(=O)Cl
Reactant: CC[C@@H](N)CO
Product: CC[C@@H]1CCS(=O)(=O)N1

Procedure:
Using (R)-2-amino-1-butanol (1.78 g) and methanesulfonyl chloride (3.2 mL) and by the reaction and treatment in the same manner as in Preparation Example 1, the title compound (1.54 g) was obtained.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[N:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[S:5]1(=[O:22])=[O:21].[CH3:23][NH2:24]>C(O)C>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:6]1[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH2:9][N:4]([CH2:3][CH2:2][NH:24][CH3:23])[S:5]1(=[O:22])=[O:21]
Reactant: CN
Reactant: O=S1(=O)N(CCBr)Cc2ccccc2N1c1ccccc1F
Solvent: CCO
Product: CNCCN1Cc2ccccc2N(c2ccccc2F)S1(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
3-(2-bromoethyl)-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.96 g, 0.25 mmol) was dissolved in an 8 M solution of methylamine in ethanol (4 ml) and was stirred in a capped vial at room temperature for two hours. The reaction mixture was evaporated and the residue purified by flash chromatography (SiO2, 0-5% 7 M NH3-methanol/dichloromethane). The purified free-base was dissolved in dichloromethane (3 mL) and treated with hydrogen chloride (1.0 mL of a 2 M solution in ethyl ether), resulting in a white precipitate that was evaporated and dried under vacuum to afford 2-[1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylethanamine (0.071 g, 85%) as a white solid:
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]2OCC[O:19]2)[CH:13]=1)[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2]>C(O)(=O)C>[C:1]([O:4][CH2:5][CH:6]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[O:19])[CH:13]=1)[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(COC(C)=O)c1cccc(C2OCCO2)c1
Solvent: CC(=O)O
Product: CC(=O)OCC(COC(C)=O)c1cccc(C=O)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 101.4 %

Procedure:
A mixture of 1.83 g of 2-[3-(1,3-dioxolan-2-yl)phenyl]propane-1,3-diyl diacetate and 60 ml of a 83% aqueous acetic acid solution was stirred at 50° C. for 2 hours. The reaction solution was concentrated under reduced pressure to obtain 1.59 g of 2-(3-formylphenyl)propane-1,3-diyl diacetate as a colorless oily substance.
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21](OC2C=CC([N+]([O-])=O)=CC=2)=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2].[NH2:45][C:46]([CH3:50])([CH3:49])[CH2:47][OH:48]>C(#N)C>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:18])=[O:19])[N:7]([C:21]([NH:45][C:46]([CH3:50])([CH3:49])[CH2:47][OH:48])=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:41])[F:42])[CH:35]=2)[C:4]=1[CH3:44])#[N:2]
Reactant: CC(C)(N)CO
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Solvent: CC#N
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)NC(C)(C)CO)C(=O)N1c1cccc(C(F)(F)F)c1

Procedure:
According to the General Procedure 1, 4-nitrophenyl (6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate (75.0 mg, 0.120 mmol; Example 6A) was reacted with 2-amino-2-methylpropanol (32.1 mg, 0.360 mmol) in acetonitrile (0.96 ml) to give the target compound (51 mg, 74% of theory).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:33]=[CH:34][CH:35]=1)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:23]=[C:24]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:25]=[CH:26][CH:27]=4)[CH:20]=3)[NH:15][CH:14]=2)[CH:10]=[N:9]1)([O-])=O.[H][H]>[Pd].C1COCC1.CO>[NH2:1][C:4]1[CH:5]=[C:6]([CH:33]=[CH:34][CH:35]=1)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:23]=[C:24]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:25]=[CH:26][CH:27]=4)[CH:20]=3)[NH:15][CH:14]=2)[CH:10]=[N:9]1
Reactant: CS(=O)(=O)Nc1cccc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc([N+](=O)[O-])c5)c4)c3c2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)Nc1cccc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc(N)c5)c4)c3c2)c1
Yield: 16.1 %

Procedure:
N-(3-(3-(1-(3-nitrobenzyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)methane sulfonamide (Example-7) (80 mg, 0.163 mmol), was reduced by palladium on carbon (8 mg, 10% W/W) in THF/MeOH (2/2 mL) under positive pressure of hydrogen using a bladder. The catalyst filtered off and concentrated to get crude compound. This was then purified by preparative TLC using 10% ethyl acetate in hexanes as eluent yielded 12 mg (16% yield) of pure titled compound. 1H NMR (DMSO-d6, 400 MHz): δ11.85 (s, 1H), 9.83 (s, 1H), 8.47-8.46 (d, 1H), 8.33-8.32 (m, 2H), 7.92 (s, 1H), 7.775-7.770 (d, 1H), 7.53-7.44 (m, 3H), 7.24-7.22 (d, 1H), 6.96-6.94 (t, 1H), 6.46-6.42 (m, 2H), 5.20 (s, 2H), 5.10 (b, 2H), 3.05 (s, 3H). MS: m/z=459.3 (M+1), HPLC: 92.06% (method B).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH:6]([O:9][B:10](OC(C)C)[O:11][CH:12]([CH3:14])[CH3:13])([CH3:8])[CH3:7]>>[CH2:1]([B:10]([O:11][CH:12]([CH3:14])[CH3:13])[O:9][CH:6]([CH3:8])[CH3:7])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: [Li]CCCC
Product: CCCCB(OC(C)C)OC(C)C

Procedure:
Following the method of Example 1, reaction of n-butyllithium (115 mL, 218 mmol) and triisopropoxyborane (41 g, 218 mmol) yielded n-butyldiisopropoxyborane, 37.3 g, (291 mmol, 93%). Proton NMR (neat) δ4.20 (septet, J=18 Hz, 2H), 1.23-0.63 (m, 9H) overlap with isopropyl doublet at 0.98 (d, J=18 HZ, 12H); boron NMR (neat) δ+30.2 ppm (s).
Reaction SMILES: Br[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[S:9][C:4]=2[C:3]=1[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O)=[CH2:21].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH:14]1([C:3]2[C:4]3[S:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][C:5]=3[NH:6][C:2]=2[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:20]=[CH2:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1cc2[nH]c(Br)c(C3CCCCC3)c2s1
Reactant: C=Cc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=Cc1ccccc1-c1[nH]c2cc(C(=O)OC)sc2c1C1CCCCC1
Reaction time: 1 h
Yield: 71 %

Procedure:
Methyl 5-bromo-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (prepared as described in Example 7, Step 1) and (2-vinylphenyl)boronic acid (1.5 eq.) were dissolved in dioxane (0.06 M) and 2M aq. Na2CO3 (6 eq.) was added. The solution was degassed by bubbling argon, Pd(PPh3)2Cl2 (0.2 eq.) was added, and the reaction mixture was placed in an oil bath preheated to 110° C. and stirred for 1 h; after removing all volatiles the title compound was isolated by chromatography (PE/EtOAc 10:1). Yield: 71%. 1H-NMR (400 MHz, CDCl3, 300 K, δ) 8.16 (bs, 1H), 7.69 (d, 1H, J 7.9), 7.68 (s, 1H), 7.45-7.35 (m, 3H), 6.67 (dd, 1H, J 17.5, 11.0), 5.74 (d, 1H, J 17.5), 5.25 (d, 1H, J 11.0), 3.91 (s, 3H), 2.54-2.47 (m, 1H), 1.81-1.23 (m, 10H); MS (ES+) m/z 366 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]([Br:24])(Br)Br.[F:25][C:26]1[CH:27]=[CH:28][C:29]([O:34][CH2:35][C:36]#[C:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=2)=[C:30](CO)[CH:31]=1>C1COCC1>[F:25][C:26]1[CH:27]=[CH:28][C:29]([O:34][CH2:35][C:36]#[C:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:45])([F:46])[F:47])=[CH:40][CH:39]=2)=[C:30]([CH:31]=1)[CH2:21][Br:24]
Reactant: OCc1cc(F)ccc1OCC#Cc1ccc(C(F)(F)F)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(OCC#Cc2ccc(C(F)(F)F)cc2)c(CBr)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23.6 %

Procedure:
834 mg (3.18 mmol) of triphenylphosphine and 1.05 g (3.18 mmol) of tetrabromomethane are dissolved in 2 ml of THF and stirred at room temperature for 10 min. Then 860 mg (2.63 mmol) of {5-fluoro-2-[3-(4-trifluoromethylphenyl)prop-2-ynyloxy]phenyl}methanol, dissolved in 2 ml of THF, are added dropwise, and the mixture is stirred at room temperature overnight. The solvent is distilled out in vacuo, and the residue is chromatographed on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1). 240 mg (0.62 mmol, 24% of theory) of 5-fluoro-2-[3-(4-trifluoromethylphenyl)prop-2-ynyloxy]benzyl bromide are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[O:10][CH:9]=[C:8]([C@H:11]3[C@:15]([CH3:17])([OH:16])[C@H:14]([OH:18])[C@@H:13]([CH2:19][OH:20])[O:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>C1COCC1.[Cl-].[Cl-].[Zn+2]>[NH2:1][C:2]1[C:3]2[O:10][CH:9]=[C:8]([C@H:11]3[C@:15]4([CH3:17])[O:16][CH:26]([C:25]5[CH:28]=[CH:29][C:22]([Cl:21])=[CH:23][CH:24]=5)[O:18][C@@H:14]4[C@@H:13]([CH2:19][OH:20])[O:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1c1coc2c(N)ncnc12
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: C[C@@]12OC(c3ccc(Cl)cc3)O[C@@H]1[C@@H](CO)O[C@H]2c1coc2c(N)ncnc12
Temperature: 60 °C
Reaction time: 14 h
Yield: 55.5 %

Procedure:
A suspension of (2S,3R,4R,5R)-2-(4-aminofuro[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)-3-methyl-tetrahydrofuran-3,4-diol (281 mg, 1.0 mmol) in THF (4 mL) was treated with ZnCl2 (695 mg, 98%, 5 0 mmol) and 4-chlorobenzaldehyde (1.43 g, 10.0 mmol) followed by stirring at 60° C. for 14 h. The reaction mixture was quenched with aqueous 2N NaOH (6.5 mL) followed by dilution with water (80 mL), and extraction with CHCl3 (2×100 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated. The residue was purified on a silica gel column using chloroform/MeOH (1:0 to 20:1, Rf=0.31, CHCl3/MeOH=20:1) as eluent to give 224 mg (55%) of the desired product as a white solid. 1H NMR (MeOH-d4, a mixture of diastereoisomers): δ 8.23 (s, 1H), 8.22 (s, 1H), 7.72-7.50 (m, 4H), 7.44 (s, 2H), 6.16 (s, 1H), 5.47-5.41(m, 1H), 5.31 (s, 1H), 4.53 (d, J=3.1 Hz, 1H), 4.17-4.11 (m, 1H), 3.73-3.57 (m, 2H), 1.25 (s, 3H); MS (ES+): 404.3 (M+H)+.
Reaction SMILES: C1COCC1.C([O:8][C:9]([C:11]1[N:12]=[C:13]([C:16]2[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)[N:19]=[C:18]3[N:39]4[CH2:45][CH2:44][CH2:43][N:40]4[C:41](=[O:42])[C:17]=23)[O:14][CH:15]=1)=[O:10])C.[OH-].[Na+]>CCO>[CH2:25]([O:24][C:22]([C:21]1[C:16]([C:13]2[O:14][CH:15]=[C:11]([C:9]([OH:10])=[O:8])[N:12]=2)=[C:17]2[C:41](=[O:42])[N:40]3[CH2:43][CH2:44][CH2:45][N:39]3[C:18]2=[N:19][C:20]=1[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=1)=[O:23])[CH3:26]
Reactant: CCOC(=O)c1coc(-c2c(C(=O)OCC)c(CCc3ccc(C(F)(F)F)cc3)nc3c2c(=O)n2n3CCC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1c(CCc2ccc(C(F)(F)F)cc2)nc2c(c1-c1nc(C(=O)O)co1)c(=O)n1n2CCC1

Procedure:
A THF (4 mL) of ethyl 4-[4-(ethoxycarbonyl)-1,3-oxazol-2-yl]-5-oxo-2-{2-[4-(trifluoromethyl)phenyl]ethyl}-8,9-dihydro-5H,7H-pyrazolo[1′2′:1,2]pyrazolo[3,4-b]pyridine-3-carboxylate (0.400 g, 0.717 mmol), 0.717 mL of 1 N NaOH and EtOH (0.717 mL) was stirred for 6 h at ambient temperature and then concentrated. The residue was treated with 1 N HCl until acidic and the organics extracted with EtOAc (2×) and then dried (Na2SO4), filtered and concentrated to a yellowish-orange solid and used in the proceeded step with no further purification: 1H NMR (CDCl3, 400 MHz) δ 8.39 (s, 1H), 7.51 (d, J=8.1 Hz, 2H), 7.29 (d, J=7.9 Hz, 2H), 4.12–4.00 (m, 6H)), 3.18–3.08 (m, 4H), 2.81–2.74 (m, 2H), 1.00 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([NH:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])(=[S:3])[CH3:2].[C:15]([O-])([O-])=O.[K+].[K+].IC>C(#N)C>[CH3:15][S:3][C:1](=[N:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])[CH3:2]
Reactant: CC(=S)NC(=O)c1ccc(Cl)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CSC(C)=NC(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 96.8 %

Procedure:
A mixture of N-(thioacetyl)-2,4-dichlorobenzamide (400 mg, 1.6 mmol) and K2CO3 (445 mg, 3.22 mmol) in anhydrous acetonitrile (20 mL) was stirred at ambient temperature. Iodomethane (458 mg, 0.2 mL, 3.22 mmol) was added and the reaction mixture was then stirred for 2.5 h. Solvent was removed in vacuo and the residue was partitioned between ether and water. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give an oil (406 mg): NMR (CDCl3,300 MHz): δ 7.86 (d, 1H, J=8), 7.47 (d, 1H, J=2), 7.32 (dd, 1H, J=8, 2), 2.40 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1>CN(C)C=O>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:6]2[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]2)=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: Clc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccn(Cc2ccc(Cl)cc2)n1
Yield: 81.8 %

Procedure:
To a solution of 3-nitro-1H-pyrazole (prepared in example 3, 200 mg, 1.77 mmol) in anhydrous N,N-dimethylformamide (2 mL), a 60% dispersion of sodium hydride in mineral oil (92 mg, 2.30 mmol) was added while stirring under nitrogen. After the effervescence ceased and the mixture was stirred for additional 30 min, 4-chlorobenzylbromide (473 mg, 2.30 mmol) was added. The mixture was continued to stir under nitrogen for an additional 2 h. The solvent was removed in vacuo and purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 2% methanol/methylene chloride to 5% methanol/methylene chloride) afforded 1-(4-chloro-benzyl)-3-nitro-1H-pyrazole (344 mg, 82%) as a white solid: H1-NMR (400 MHz, CDCl3) δ: 5.33 (2H, s), 6.90 (1H, d, J=2.3 Hz), 7.22 (2H, d, J=8.4 Hz), 7.34 (2H, d J=8.6 Hz), 7.40 (1H, d, J=2.6 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12])([O-])=O.[C:15](OC(=O)C)(=[O:17])[CH3:16]>C1(C)C=CC=CC=1.[Pd]>[C:15]([NH:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12])(=[O:17])[CH3:16]
Reactant: COC(=O)Cc1ccccc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccccc1NC(C)=O
Yield: 83.8 %

Procedure:
Methyl (2-nitrophenyl)acetate (26.6 g, 0.14 mol) and acetic anhydride (51.5 ml, 0.55 mol) were subjected to catalytic hydrogenation for 15 hours in toluene (150 ml) in the presence of 10% Pd/C (53.2% wet, 4.5 g). The reaction mixture was filtered to remove therefrom the catalyst, followed by washing with toluene. The filtrate was distilled under reduced pressure to remove the solvent. The residue was crystallized by the addition thereto of n-hexane and diisopropyl ether. The crystals thus precipitated were collected by filtration, washed with n-hexane, and dried under reduced pressure to give methyl (2-acetamidophenyl)acetate (24.3 g, 84%) as a pale yellow solid.
Reaction SMILES: [OH-:1].[Na+].O.[C:4]([S:8][CH2:9][C:10]1([CH3:17])[NH:14][C:13](=[O:15])[NH:12][C:11]1=[O:16])([CH3:7])([CH3:6])[CH3:5]>C(#N)C>[C:13]([NH:14][C@:10]([CH3:17])([C:11]([OH:1])=[O:16])[CH2:9][S:8][C:4]([CH3:7])([CH3:6])[CH3:5])(=[O:15])[NH2:12]
Reactant: CC(C)(C)SCC1(C)NC(=O)NC1=O
Reactant: [OH-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)SC[C@](C)(NC(N)=O)C(=O)O

Procedure:
First, sodium hydroxide and water were added to 5-tert-butylthiomethyl-5-methylhydantoin, and the resultant mixture was heated to a predetermined temperature and stirred. The reaction solution was analyzed by HPLC (column: COSMOSIL 5C18-AR (produced by Nacalai Tesque Inc.), mobile phase: acetonitrile/10 mM aqueous potassium dihydrogen phosphate solution=30/70, flow rate: 1.0 ml/min, detection wavelength: 210 nm, column temperature: 40° C.) to determine the yield of the title compound. The results are shown in Table 1.