Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11](OC)=[O:12])=[CH:9][C:8]=2[O:17][CH3:18])[CH:6]=1.O.[NH2:20][NH2:21]>CO>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([NH:20][NH2:21])=[O:12])=[CH:9][C:8]=2[O:17][CH3:18])[CH:6]=1
Reactant: COC(=O)c1ccc(-n2cnc(Cl)c2)c(OC)c1
Reactant: NN
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)NN)ccc1-n1cnc(Cl)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a mixture of methyl 4-(4-chloro-1H-imidazol-1-yl)-3-methoxybenzoate (25.5 mg) in methanol (1 mL) was added hydrazine monohydrate (0.019 mL) at room temperature, the mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate to give the title compound (12.7 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)[N:3]=1.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1>C(Cl)Cl.CO>[Cl:16][C:11]1[CH:10]=[C:9]([C:4]2[N:3]=[C:2]([NH:29][C:28]3[CH:27]=[CH:26][C:25]([CH2:24][N:21]4[CH2:20][CH2:19][N:18]([CH3:17])[CH2:23][CH2:22]4)=[CH:31][CH:30]=3)[N:7]=[C:6]([NH2:8])[CH:5]=2)[CH:14]=[CH:13][C:12]=1[F:15]
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: Nc1cc(-c2ccc(F)c(Cl)c2)nc(Cl)n1
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(Nc3nc(N)cc(-c4ccc(F)c(Cl)c4)n3)cc2)CC1
Yield: 84 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-chloro-6-(3-chloro-4-fluorophenyl)pyrimidin-4-amine and 4-((4-methylpiperazin-1-yl)methyl)aniline in 84% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). MS (ESI): 214.2 [M+2H]2+.
Reaction SMILES: ClC1C=CC=C(C(OO)=O)C=1.[Cl:12][C:13]1[C:14]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([NH:30][NH:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:24]=2)=[N:15][N:16]([CH3:22])[C:17]=1[O:18][CH:19]([F:21])[F:20].O>ClCCl>[Cl:12][C:13]1[C:14]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([N:30]=[N:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:24]=2)=[N:15][N:16]([CH3:22])[C:17]=1[O:18][CH:19]([F:21])[F:20]
Reactant: CCOC(=O)NNc1cc(-c2nn(C)c(OC(F)F)c2Cl)ccc1Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)N=Nc1cc(-c2nn(C)c(OC(F)F)c2Cl)ccc1Cl
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
A solution of 2.1 g (6.6 mmol) of m-chloroperbenzoic acid in 10 ml of dichloromethane was added dropwise to a solution of 2.1 g (5.3 mmol) of 4chloro-3-[4-chloro-3-(2-ethoxycarbonylhydrazino)-phenyl]-5-difluoromethoxy-1-methyl-1H-pyrazole in 15 ml of dichloromethane. The mixture was stirred at 35° C. for 30 minutes and poured into 50 ml of water. The organic phase was separated off and washed with 10% strength by weight sodium hydrogen carbonate solution, then dried over magnesium sulfate and finally concentrated. The crude product was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=4:1). Yield: 0.5 g.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[N:10]([C@H:12]([C:14](=[O:24])[NH:15][C:16]1[C:17](=[O:23])[NH:18][C:19]([Br:22])=[CH:20][CH:21]=1)[CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Li+].[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([C:37]2[CH:38]=[N:39][CH:40]=[C:41]([CH2:43]Cl)[CH:42]=2)=[O:36])=[CH:31][CH:30]=1.C(N(C(C)C)CC)(C)C>O(C(OC)C)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9](=[O:25])[N:10]([C@H:12]([C:14](=[O:24])[NH:15][C:16]1[C:17](=[O:23])[N:18]([CH2:43][C:41]2[CH:40]=[N:39][CH:38]=[C:37]([C:35](=[O:36])[C:32]3[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=3)[CH:42]=2)[C:19]([Br:22])=[CH:20][CH:21]=1)[CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)c1cncc(CCl)c1
Reactant: C[C@@H](C(=O)Nc1ccc(Br)[nH]c1=O)N(C)C(=O)OCc1ccccc1
Agent: COC(C)OC
Agent: [I-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@@H](C(=O)Nc1ccc(Br)n(Cc2cncc(C(=O)c3ccc(F)cc3)c2)c1=O)N(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 61.6 %

Procedure:
To a solution of [(S)-1-(6-bromo-2-oxo-1,2-dihydro-pyridin-3-ylcarbamoyl)-ethyl]-methyl-carbamic acid benzyl ester (1C) (100 mg, 0.25 mmol) in dimethoxylethane (DME) (3 mL) at room temperature, is added lithium iodide (36 mg, 0.27 mmol) in one portion. After being stirred at room temperature for 5 minutes, to the reaction mixture, is added 4-fluoro-phenyl-(5-chloromethyl-pyridin-3-yl)-methanone (IF) (80 mg, 0.32 mmol) in one portion. After being stirred at room temperature for 5 minutes, to the reaction mixture, is added drop wise diisopropylethylamine (DIPEA) (0.09 mL, 0.50 mmol). The reaction mixture is stirred at 60□C for 6 hours. The reaction solution is diluted with ethyl acetate (EtOAc) (30 mL) and washed with 2×8 mL of water. After concentration, the crude product is purified by chromatography (heptanes 60%, EtOAc 40%) to give ((S)-1-{6-bromo-1-[5-(4-fluoro-benzoyl)-pyridin-3-ylmethyl]-2-oxo-1,2-dihydro-pyridin-3-ylcarbamoyl}-ethyl)-methyl-carbamic acid benzyl ester (1D) (95.7 mg, yield 63%) as light yellow solid, MS (ESI) m/e 621.2, 623.3 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=1[CH2:18][CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[BrH:32].BrBr>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH2:16][Br:32])=[CH:11][C:10]=1[CH2:18][CH2:19][O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(CCOCc2ccccc2)c1
Reactant: Br
Agent: BrBr
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=C(CBr)c1ccc(OCc2ccccc2)c(CCOCc2ccccc2)c1
Temperature: 25 °C

Procedure:
4'-Benzyloxy-3'-(2-benzyloxyethyl)acetophenone (8.0 g) and 0.4 ml of 30% hydrogen bromide acetic acid solution were dissolved in 80 ml of chloroform, and a solution of 1.1 ml of bromine in 30 ml of chloroform was added to the solution dropwise during 2 hours with stirring at room temperature. The reaction solution was concentrated under reduced pressure and the resulting residue was purified by silica gel medium pressure liquid column chromatography (eluent: hexane/diethyl ether=2/1) to give 3.9 g of 4'-benzyloxy-3'-(2-benzyloxyethyl)-2-bromoacetophenone having a melting point of 53 to 56° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:22])[C:13](=[O:21])[N:14]([C@H:15]4[CH2:18][C@@H:17]([O:19][CH3:20])[CH2:16]4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:23][N:24]([CH3:44])[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[CH3:44][N:24]([CH3:23])[CH2:25][CH2:26][CH2:27][O:28][C:29]1[N:30]=[CH:31][C:32]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:22])[C:13](=[O:21])[N:14]([C@H:15]5[CH2:18][C@@H:17]([O:19][CH3:20])[CH2:16]5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:33][CH:34]=1
Reactant: CN(C)CCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CO[C@H]1C[C@@H](n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CO[C@H]1C[C@@H](n2c(=O)n(C)c3cnc4ccc(-c5ccc(OCCCN(C)C)nc5)cc4c32)C1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
Pd(Ph3P)4 (2.074 g, 1.79 mmol) was added to a mixture of 8-bromo-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one (13 g, 35.89 mmol), N,N-dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxypropan-1-amine (13.15 g, 43.07 mmol) and cesium carbonate (23.39 g, 71.78 mmol) in 1,4-dioxane (200 mL) and water (40 mL) under nitrogen. The resulting mixture was stirred at 90° C. for 3 h before being allowed to cool. The reaction mixture was concentrated and diluted with EtOAc (750 mL), and washed sequentially with water (2×150 mL), and sat. brine (150 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by FCC, elation gradient 0 to 10% MeOH in DCM, to afford the desired material (12.50 g, 75%) as a white solid. NMR Spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.90 (2H, q), 2.16 (6H, s), 2.37 (2H, t), 2.72-2.92 (2H, m), 3.01 (2H, d), 3.21 (3H, s), 3.50 (3H, s), 3.79-3.95 (1H, m), 4.37 (2H, t), 5.12 (1H, t), 6.97 (1H, d), 7.82-7.98 (1H, m), 8.11 (1H, d), 8.19 (2H, dd), 8.42 (1H, s), 8.67 (1H, d), 8.87 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=462.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][C:2]1=[O:11].[N:12]([O-])=[O:13].[Na+]>Cl.O>[N:12]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:1][C:2](=[O:11])[CH2:3]1)=[O:13]
Reactant: O=N[O-]
Reactant: O=C1CNc2ccccc2N1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=NN1CC(=O)Nc2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 66.8 %

Procedure:
3,4-Dihydro-1H-quinoxalin-2-one (500 mg, 3.378 mmol) was dissolved in 3N HCl (10 mL) and stirred for 5 min. at 0° C. A solution of sodium nitrite (256 mg, 3.716 mmol) in water (2 mL) was added at 0° C., and the reaction mixture was stirred for 2 h at RT. After completion of reaction, water was added and the mixture extracted twice with DCM (100 mL). The combined organic layers were washed with water, dried over sodium sulfate and concentrated under reduced pressure to obtain 400 mg of 3,4-dihydro-4-nitrosoquinoxalin-2(1H)-one.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: N#CCCCCCCCCCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCCCCCCCCC#N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 15 g. of 12-hydroxydodecanonitrile and 14 ml. of triethylamine in 320 ml. of methylene chloride is stirred at 0° C. while 5.7 ml. of methanesulfonylchloride is added dropwise. The mixture is stirred at 0° C. for 1 hour, diluted with methylene chloride and extracted with water; cold, dilute hydrochloric acid; saturated aqueous sodium bicarbonate; and brine. The solution is dried over anhydrous magnesium sulfate and eaporated to yield 12-(methanesulfonyloxy)dodecanonitrile as a yellow oil
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:9])[CH3:8].[C:10]([O:14][C:15]([N:17]1[C@@H:21]([C@H:22]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20][CH2:19][C@H:18]1[CH2:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](O)=[O:43])=[CH:40][CH:39]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Si:30]([O:29][C@H:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C@H:21]1[CH2:20][CH2:19][C@@H:18]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([C:42](=[O:43])[NH:9][CH:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH3:8])=[CH:45][CH:46]=2)[N:17]1[C:15]([O:14][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:16])([C:33]([CH3:34])([CH3:35])[CH3:36])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)O)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Reactant: CC(N)c1ccccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3ccccc3)N2C(=O)OC(C)(C)C)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.3 %

Procedure:
1-Pyridin-2-yl-ethylamine (77 mg, 0.628 mmol) was added to a stirred, room temperature mixture of 4-({(2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]pyrrolidin-2-yl}methyl)benzoic acid (300 mg, 0.571 mmol), HATU (260 mg, 0.685 mmol, 1.2 equivalents) and DIPEA (470 μL, 2.69 mmol, 4.7 equivalents) in DMF (1.2 mL). The reaction was stirred at room temperature for 16 hours before being loaded directly onto a silica column and purified by normal phase flash chromatography using silica gel (20-100% hexanes/ethyl acetate). The product fractions were collected and concentrated in vacuo to afford the title compound as a colorless gum (350 mg, 97%). LC-MS=630.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH:42]1[CH2:47][CH3:48])=[O:40])([CH3:37])([CH3:36])[CH3:35]>>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][N:44]([C:19]2[S:20][C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:29])[F:30])=[CH:27][C:3]=3[C:2]([F:32])([F:33])[F:1])[N:7]=[CH:8]4)[C:17](=[O:23])[N:18]=2)[CH2:43][CH:42]1[CH2:47][CH3:48])=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CCC1CNCCN1C(=O)OC(C)(C)C
Product: CCC1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CCN1C(=O)OC(C)(C)C

Procedure:
4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-ethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 2-ethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure B.
Reaction SMILES: Br[C:2]1(Br)[C:7]([F:8])=[C:6]([F:9])[C:5]([S:10][C:11]2[C:16]([F:17])=[C:15]([F:18])[C:14](Br)(Br)[CH:13]([F:21])[C:12]=2[F:22])=[C:4]([F:23])[CH:3]1[F:24].[CH3:26][C:27]([OH:31])([C:29]#[CH:30])[CH3:28]>[Pd].C([O-])(=O)C.[Cu+]>[OH:31][C:27]([CH3:28])([CH3:26])[C:29]#[C:30][C:2]1([C:30]#[C:29][C:27]([CH3:28])([OH:31])[CH3:26])[C:7]([F:8])=[C:6]([F:9])[C:5]([S:10][C:11]2[C:16]([F:17])=[C:15]([F:18])[C:14]([C:30]#[C:29][C:27]([CH3:28])([OH:31])[CH3:26])([C:30]#[C:29][C:27]([CH3:28])([OH:31])[CH3:26])[CH:13]([F:21])[C:12]=2[F:22])=[C:4]([F:23])[CH:3]1[F:24]
Reactant: FC1=C(F)C(Br)(Br)C(F)C(F)=C1SC1=C(F)C(F)C(Br)(Br)C(F)=C1F
Reactant: C#CC(C)(C)O
Agent: [Cu+]
Agent: [Pd]
Agent: CC(=O)[O-]
Product: CC(C)(O)C#CC1(C#CC(C)(C)O)C(F)=C(F)C(SC2=C(F)C(F)C(C#CC(C)(C)O)(C#CC(C)(C)O)C(F)=C2F)=C(F)C1F
Temperature: 25 °C

Procedure:
To a solution of bis(4,4'-dibromo tetrafluorophenyl) sulfide (4.86 g, 10 mmol) in dry deoxygenated diisopropylamine was added dichlorobis(triphenylphasphine) palladium (700 mg, 1 mmol) and copper (1) acetate (200 mg, 1 mmol). The solution was cooled by means of an ice bath and to the cooled solution was added 2-methyl 3-butyn 2-ol (2.13 g, 25 mmol). The solution was allowed to warm to room temperature over a period of 1 hour and was then heated at reflux for a period of 24 hours. The solution was cooled and filtered to remove the precipitate of diisopropylammonium bromide. The residue was dissolved in methylene chloride, extracted with water, the organic layer was dried (magnesium sulfate), and the solvent removed. The residue was chromatographed on silica gel using diethyl ether/hexane (3:7 v/v) as the eluent. A white crystalline compound was removed from the column which was identified by mass spectrometry as 1,4-bis-(3-hydroxy 3-methyl-1-butynyl)tetrafluorobenzene. Further elution with diethyl ether/hexane (1:1 v/v) then yielded the desired product as pale yellow crystals. The yield was 2.2 g (44.5%), mp 148-150 C. IR (KBr) 3300, 2980, 2220, 1360, 1190, 1150, 975, 940 cm-1. 1H NMR (80 MHz, d6 -acetone) δ2.8(s, 2H), 1.55(s, 12H); Mass Spectrum (E1)(rel. intensity) 494 (1.0), 479 (0.3), 262 (100). Anal. Calcd. or C22H14F8O2S: C, 53.44; H, 2.83. Found: C, 53.87, H, 2.62.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:29])=[C:7]([C:10]2[O:14][C:13]([C:15]3[CH:26]=[C:25]([CH3:27])[C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22]O)=[C:17]([CH3:28])[CH:16]=3)=[N:12][N:11]=2)[S:8][CH:9]=1)[CH:2]([CH3:4])[CH3:3].CC[N:32](CC)CC.CS(Cl)(=O)=O.N>C1COCC1.CO>[NH2:32][CH2:22][CH:21]([OH:24])[CH2:20][O:19][C:18]1[C:25]([CH3:27])=[CH:26][C:15]([C:13]2[O:14][C:10]([C:7]3[S:8][CH:9]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:6]=3[CH3:29])=[N:11][N:12]=2)=[CH:16][C:17]=1[CH3:28]
Reactant: CCN(CC)CC
Reactant: Cc1cc(-c2nnc(-c3scc(CC(C)C)c3C)o2)cc(C)c1OCC(O)CO
Agent: CS(=O)(=O)Cl
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-c2nnc(-c3scc(CC(C)C)c3C)o2)cc(C)c1OCC(O)CN
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-{4-[5-(4-isobutyl-3-methyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol (90 mg, 0.22 mmol) in THF (4 mL) are added NEt3 (0.14 mL) and, subsequently, methanesulfonlychloride (0.02 mL, 0.26 mmol). The mixture is stirred at rt for 3 h. A solution of NH3 in MeOH (7M, 4 mL) is added and the mixture is heated at 60° C. for 15 h. The mixture is evaporated, 1M aq. NaOH (3 mL) is added and the mixture is extracted with EA (2×20 mL). The organic extracts are dried (Na2SO4), filtered and evaporated to give crude 1-amino-3-{4-[5-(4-isobutyl-3-methyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethylphenoxy}-propan-2-ol; LC-MS: tR=0.86 min, [M+1]+=416.32.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:11][N:12]2[CH:17]([C:18](O)=[O:19])[CH2:16][N:15]([CH3:21])[C:14](=[O:22])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:31])=O>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:11][N:12]2[CH:17]([C:18]([Cl:31])=[O:19])[CH2:16][N:15]([CH3:21])[C:14](=[O:22])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2C(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3-benzyloxy-2-ethoxycarbonyl-5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-7-carboxylic acid (250 mg, 0.670 mmol) in anhydrous CH2Cl2 at 0° C. were added 2M oxalyl chloride in CH2Cl2 (1.339 mL, 2.678 mmol) and DMF (1 drop). The reaction was stirred at 0° C. for 30 minutes and allowed to warm to room temperature for 1 hour. The mixture was concentrated in vacuo and azeotroped twice with anhydrous CH2Cl2 to afford the title product. ES MS (M+H)=392.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:15]([CH3:16])=[C:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=2)[C:13]([O:28][C@@H:29]2[O:37][C@H:36]([CH2:38][OH:39])[C@@H:34]([OH:35])[C@H:32]([OH:33])[C@H:30]2[OH:31])=[N:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:41]([O:43][CH2:44][CH3:45])=[O:42].O.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CC1C=C(C)C=C(C)N=1>[CH2:1]([O:8][C:9]([N:11]1[C:15]([CH3:16])=[C:14]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:23]=2)[C:13]([O:28][C@@H:29]2[O:37][C@H:36]([CH2:38][O:39][C:41]([O:43][CH2:44][CH3:45])=[O:42])[C@@H:34]([OH:35])[C@H:32]([OH:33])[C@H:30]2[OH:31])=[N:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cc2ccc(OC(C)C)cc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)nn1C(=O)OCc1ccccc1
Reactant: CCOC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1cc(C)nc(C)c1
Solvent: O
Product: CCOC(=O)OC[C@H]1O[C@@H](Oc2nn(C(=O)OCc3ccccc3)c(C)c2Cc2ccc(OC(C)C)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1-(benzyloxycarbonyl)-3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methylpyrazole (0.20 g) in 2,4,6-trimethylpyridine (4 mL) was added ethyl chloroformate (0.092 mL), and the mixture was stirred at room temperature for 1 day. To the reaction mixture were added water and citric acid monohydrate, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give 1-(benzyloxycarbonyl)-3-(6-O-ethoxycarbonyl-β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methylpyrazole (0.17 g).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([O:30]CC)=O)[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:43]>>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:36][C@@H:37]([CH3:42])[O:38][C@H:39]([CH3:41])[CH2:40]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([NH2:43])=[O:30])[C:24]=2[CH:33]=1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Reactant: N
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc3c(C(N)=O)noc3c2F)C[C@@H](C)O1

Procedure:
Starting materials: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6R)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 210) and ammonia (0.5 M in dioxane).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]3[CH:15]=[C:14]([C:16]4[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=4)[CH:13]=[N:12][C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:25]1([CH2:24][NH:31][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([C:14]3[CH:13]=[N:12][C:11]4[N:10]([N:9]=[CH:8][C:7]=4[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:15]=3)=[CH:17][CH:18]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: O=Cc1ccc(-c2cnc3c(-c4ccccc4)cnn3c2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: c1ccc(CNCc2ccc(-c3cnc4c(-c5ccccc5)cnn4c3)cc2)cc1

Procedure:
A solution of 4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)benzaldehyde (1-5, 75 mg, 0.25 mmol), benzylamine (0.056 mL, 0.50 mmol), acetic acid (14 TL, 0.25 mmol), and sodium triacetoxyborohydride(106 mg, 0.50 mmol) in 1,2-dichloro-ethane (6 mL) was stirred under ambient conditions overnight. The residue was partitioned between sat. NaHCO3 solution (4 mL) and ethyl acetate (3×4 mL). The organic layer was washed with brine and dried over MgSO4 and concentrated. The residue was purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present) to provide 1-phenyl-N-[4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)benzyl]methanamine (1-6) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ9.21 (d, 1H, J=2.4 Hz), 8.96 (d, 1H, J=2.4 Hz), 8.61 (s, 1H), 8.12 (br d, 2H, J=7.8 Hz), 7.91 (d, 2H, J=8.2 Hz), 7.67 (d, 2H, J=7.8 Hz), 7.49 (m, 5H), 7.44 (br t, 2H, J=7.8 Hz), 7.27 (t, 1H, J=7.5 Hz), 4.34 (s, 2H), 4.29 (s, 2H).