Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:10][C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([O:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:16][CH:15]=2)=[O:12])[NH:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([C:5]1[CH:6]=[C:7]([NH:10][C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([O:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:16][CH:15]=2)=[O:12])[N:8]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)[nH]n1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 77.9 %

Procedure:
A mixture of the above urea (0.022 g, 0.050 mmol), phenylboronic acid (0.012 g, 0.1 mmol), copper (II) acetate (0.014 g, 0.075 mmol), pyridine (0.01 mL, 0.1 mmol) and molecular sieves (4 Å activated, 0.030 g) in methylene chloride (2 mL) was stirred at room temperature for 14 h under air. After filtration through diatomaceous earth, the filtrate was concentrated in vacuo and purified by flash chromatography (EtOAc 100% to EtOH 100%) to give the title compound as a yellow-white solid (0.02 g, 73%), mp 142-143° C.; 1H NMR (DMSO) δ 1.26(s, 9H), 2.53(t, 4H) 2.83(t, 2H), 3.57(t, 4H), 4.24(t, 2H), 6.34(s, 1H), 6.94(d, 1H), 7.40(d, 1H), 7.55(m, 7H), 7.90(d, 1H), 8.15(d, 1H), 8.82(s, 1H), 8.92(s, 1H); MS (CI) 514(M++H).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:11]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1.C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:11]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(S(=O)(=O)N2c3ccc(Br)cc3-c3ccccc3C2c2ccccc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: O=S(=O)(c1ccc(O)cc1)N1c2ccc(Br)cc2-c2ccccc2C1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
A stirred suspension of 2-bromo-5-[(4-methoxyphenyl)sulfonyl]-6-phenyl-5,6-dihydrophenanthridine (1.01 g, 2.0 mmol) and cyclohexene (3.70 g, 45 mmol) was treated at room temperature under nitrogen with a solution of 1.0 M boron tribromide in dichloromethane (12 mL, 12 mmol). After stirring for approximately two hours at room temperature, the reaction was quenched with methanol (20 mL) and diluted with dichloromethane. The mixture was washed sequentially with an aqueous potassium carbonate solution, a saturated, aqueous, sodium chloride solution, and water. The organic phase was dried over anhydrous sodium sulfate, filtered through a short column of silica gel, and eluted with ethyl acetate. The ethyl acetate phase was evaporated in vacuo to a crude orange residue (1.0 g,). The crude residue was purified by preparative chromatography on a Biotage® 40 Mi column of pre-packed silica gel (90 g) with gradient elution of between 10% to 30% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min; and afforded, after evaporation of the solvent, a colorless oil. Crystallization of the colorless oil from a mixture of ethyl acetate-diethyl ether-hexane yielded the title compound (0.845 g, 1.72 mmol, 86%) as a homogeneous, colorless, crystalline solid, m.p. 262-265° C.;
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[C:4]([O:14][CH3:15])=[N:5][C:6](F)=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>C(O)C>[NH2:1][C:6]1[C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:3]([Cl:2])=[C:4]([O:14][CH3:15])[N:5]=1
Reactant: COc1nc(F)c(C(F)(F)F)cc1Cl
Reactant: N
Solvent: CCO
Product: COc1nc(N)c(C(F)(F)F)cc1Cl
Temperature: 110 °C
Reaction time: 15 h

Procedure:
16.2 g (0.954 mol) of gaseous ammonia were injected into an autoclave containing 36.5 g (0.159 mol) of 3-chloro-6-fluoro-2-methoxy-5-trifluoromethylpyridine and 150 ml of ethanol and the mixture was then stirred for 15 hours at 110° C. After cooling and releasing the pressure, the reaction mixture was concentrated and the residue was partitioned in methylene chloride/water. After 0.4 g of insoluble matter had been separated off, the organic phase was separated off, and the aqueous phase was reextracted twice using methylene chloride. The organic extracts were dried and concentrated, giving 30.6 g (85% of theory) of the title compound as an oil. NMR (400 MHz, CDCl3) δ 7.6 pyr (1/s); 3.95 CH3O (3/s); 4.9 NH2 (2/s). After silica gel chromatography with methylene chloride, a further 33.2 g (72% of theory) of the title compound were obtained as a colorless oil of ηD24 =1.5140 (Table II, No. 2.001).
Reaction SMILES: [C:1](/[C:9](=[CH:15]/[C:16]1[CH:17]=[N:18][C:19]([Cl:22])=[CH:20][CH:21]=1)/[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][C:24]1[N:28]([CH2:29][CH3:30])[N:27]=[CH:26][CH:25]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C([O-])(O)=O.[Na+]>CN1CCCC1=O>[Cl:22][C:19]1[N:18]=[CH:17][C:16]([C:15]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:23]=[C:24]3[N:28]([CH2:29][CH3:30])[N:27]=[CH:26][C:25]=23)=[CH:21][CH:20]=1
Reactant: CCn1nccc1N
Reactant: CCOC(=O)/C(=C\c1ccc(Cl)nc1)C(=O)c1ccccc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1c(-c2ccccc2)nc2c(cnn2CC)c1-c1ccc(Cl)nc1
Temperature: 140 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
A mixture of ethyl (2Z)-2-benzoyl-3-(6-chloro-3-pyridyl)acrylate (2.018 g) and 5-amino-1-ethylpyrazole (710 mg) in N-methylpyrrolidone (15 ml) was heated at 140° C. for 3.5 hours. Another 5-amino-1-ethylpyrazole (200 mg) was added and the mixture was heated at 140° C. for 2 hours. After cooling, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.45 g) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3 (×4), brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a mixture of EtOAc and n-hexane (1:7) to give ethyl 4-(6-chloro-3-pyridyl)-1-ethyl-6-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (2.024 g) as a brown oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]([O:18][C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]2=[O:38])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([C:2]2[CH:3]=[CH:4][C:5]([S:8]([CH:11]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]([O:18][C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:12]3=[O:38])(=[O:9])=[O:10])=[CH:6][CH:7]=2)=[CH:43][CH:42]=1
Reactant: O=C1C(S(=O)(=O)c2ccc(Br)cc2)CCCCN1OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(B(O)O)cc1
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: Cc1ccccc1
Product: COc1ccc(-c2ccc(S(=O)(=O)C3CCCCN(OC(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)cc1

Procedure:
The mixture of 3-(4-Bromo-benzenesulfonyl)-1-trityloxy-azepan-2-one prepared from step F (10.1 mg, 0.0171 mmol), 4-Methoxybenzeneboronic acid (10.2 mg, 0.0671 mmol) and Pd(PPh3)4 (3.1 mg, 0.00268 mmol) in 2.0 ml of toluene was added 0.4 ml of saturated Na2CO3 aqueous solution and the resulting mixture was stirred and heated to reflux for 4 hours. The reaction mixture was filtered through celite and diluted with EtOAc and water. The organic phase was washed sequentially with water and saturated NaCl solution, and then dried over anhydrous Na2SO4. The EtOAc solution was concentrated under reduced pressure to give a crude material, which was then purified by a column chromatography (0˜30% EtOAc in hexane). MS: 618.2 (M+H)+, 640.2 (M+Na)+.
Reaction SMILES: C([N:8]1[CH2:18][CH:17]2[CH2:19][CH:10]([C:11]3[CH:12]=[CH:13][N:14]=[CH:15][C:16]=32)[CH2:9]1)C1C=CC=CC=1.[ClH:20].CCOC(C)=O>CO.[OH-].[OH-].[Pd+2]>[ClH:20].[ClH:20].[CH:17]12[CH2:19][CH:10]([CH2:9][NH:8][CH2:18]1)[C:11]1[CH:12]=[CH:13][N:14]=[CH:15][C:16]2=1
Reactant: c1ccc(CN2CC3CC(C2)c2cnccc23)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: c1cc2c(cn1)C1CNCC2C1

Procedure:
10-Benzyl-4,10-diaza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene (900 mg, 3.6 mmol) and HCO2NH4 (4 g) were dissolved in methanol (35 mL) and treated with Pd(OH)2/C (10 wt %, 200 mg). The mixture was stirred and warmed to reflux for 2 h, cooled, filtered through Celite™ and rinsed with methanol. The filtrate was stripped, slurried in dichloromethane and filtered through a fritted-glass filter. The filtrate was concentrated and azeotroped from methanol (2×50 mL). A sample of this material was isolate and found to melt at 104–105° C. The material was dissolved in methanol and treated with 3N HCl/EtOAc. This was concentrated and azeotroped from methanol (2×50 mL). This residue was dissolved in a minimum of methanol then Et2O until cloudy and allowed to stir for 60 h. Product was collected by filtration (370 mg, 52%). (TLC 1% NH4OH/7% MeOH/dichloromethane Rf 0.18); 1H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 8.83 (d, J=5.9 Hz, 1H), 8.16 (d, J=5.9 Hz, 1H), 3.75 (m, 2H), 3.60 (m, 2H), 3.40 (d, J=12.4 Hz, 2H), 2.57 (m, 1H), 2.34 (d, J=12.0 Hz, 1H); 13C NMR (100 MHz, CDCl3, free base) δ 151.4, 149.5, 144.5, 137.7, 119.7, 45.8, 45.2, 41.0, 38.4, 36.4; GCMS m/z 160 (M)+; Anal. Calcd. for C10H12N22. HCl: C, 51.52; H, 6.05; N, 12.02. Found C, 51.35; H, 6.05; N, 12.05.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH:15]=[CH2:16])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:25][C:26]1([CH3:38])[O:30][CH:29]([C:31]2[S:35][C:34]([CH:36]=[O:37])=[N:33][CH:32]=2)[CH2:28][O:27]1.C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH2:15][CH2:16][C:36]([C:34]3[S:35][C:31]([CH:29]4[CH2:28][O:27][C:26]([CH3:38])([CH3:25])[O:30]4)=[CH:32][N:33]=3)=[O:37])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CC1(C)OCC(c2cnc(C=O)s2)O1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC1(C)OCC(c2cnc(C(=O)CCC(=O)C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)s2)O1
Temperature: 25 °C
Yield: 29.5 %

Procedure:
To a solution of 4-[4-(cyclopropylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (2.00 g) in ethanol (20 mL) were added 5-(2,2-dimethyl-1,3-dioxolan-4-yl)-1,3-thiazole-2-carbaldehyde (1.50 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (170 mg) and triethylamine (345 μL), and the mixture was stirred with heating under reflux for 2 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (950 mg, yield 30%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio). MS: 562 (MH+).
Reaction SMILES: [C:1]1([N:7]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:8]([C:10]2[S:21][C:13]3[N:14]=[C:15]([CH2:18]OC)[N:16]([CH3:17])[C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br.C(N(C(C)C)C(C)C)C.[NH2:41][C:42]1[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=1>C(Cl)Cl.N.C(Cl)Cl.C(O)C>[C:1]1([N:7]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:8]([C:10]2[S:21][C:13]3[N:14]=[C:15]([CH2:18][NH:41][C:42]4[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=4)[N:16]([CH3:17])[C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: COCc1nc2sc(C(=O)N(CCC(=O)OC)c3ccccc3)cc2n1C
Agent: BrB(Br)Br
Agent: N
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCN(C(=O)c1cc2c(nc(CNc3ccc(C#N)cc3)n2C)s1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.73 g (1.88 mmol) of 1-methyl-2-methoxymethyl-thieno[2.3-d]imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide in 30 ml of methylene chloride were added dropwise at 5° C. 2.9 ml (2.9 mmol) of a 1-molar solution of boron tribromide in methylene chloride. After 16 hours' stirring at ambient temperature the mixture was washed with 20 ml of saturated sodium hydrogen carbonate solution, the organic phase was separated off, dried with sodium sulphate and filtered. The filtrate was mixed with 14 ml of N-ethyl-diisopropylamine and 0.43 g (3.64 mmol) of 4-aminobenzonitrile. Then the methylene chloride was distilled off in vacuo, the residue obtained was heated to 5° C. for 1 hour and then the residual solvent was distilled off in vacuo. After chromatography (silica gel; methylene chloride/ethanol=99:1 to 97:3) a yellow oil was obtained which slowly solidified. Yield: 0.37 g (42% of theory), Rf value: 0.29 (silica gel; methylene chloride/ethanol=50:1+a few drops of ammonia)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([O:20]C)=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[Li+].[OH-].Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)c1ccc2c(ccn2-c2ccc(F)c(F)c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2c(ccn2-c2ccc(F)c(F)c2)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 100.3 %

Procedure:
A mixture of methyl 1-(3,4-difluorophenyl)-indole-5-carboxylate 1p (3.0 g, 10.4 mmol) and LiOH (1.0 g, 41.8 mmol) in THF (120 mL) and H2O (60 mL) was stirred at room temperature for 5 days. Aqueous 10% HCl solution was added to the reaction mixture to adjust pH=3˜4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aq. NaCl, dried over Na2SO4 and concentrated to give 1q (2.85 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=1)[C:8](O)=[O:9])([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:20])=O>>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=1)[C:8]([Cl:20])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1
Reactant: O=S(Cl)Cl
Product: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1

Procedure:
This compound was prepared by chlorination of 3,5-di-t-butylbenzoic acid with thionyl chloride using standard procedures to give 3,5-di-t-butylbenzoyl chloride. 3.26 g (12.9 mmol) of the chloride was then reacted with 1.95 g (16.8 mmol) of N,N-diethylethylenediamine in dry chloroform. The reaction mixture was concentrated by evaporation of chloroform and treated with sodium bicarbonate in a mixture of ethanol and water. Following extraction with chloroform, the combined chloroform extracts were dried and concentrated, upon which the amide began to crystallize. Without further purification, the amide was reduced with lithium aluminum hydride in THF using standard procedures. After quenching and filtration of the reaction mixture, the filtrate was dried and concentrated then distilled under reduced pressure to yield 2.00 g (49%) of the diamine.(bp 105-108°, 10 v). Purity by GC>99%.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18].[CH3:19][S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][S:20]([CH3:19])(=[O:22])=[O:21])=[C:3]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(N)c(Nc2ccc(F)cc2F)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(C#N)cc1Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-amino-3-(2,4-difluorophenylamino)benzonitrile (1.2 g) and methanesulfonyl chloride (0.45 ml) in pyridine (12 ml) was stirred for 4 hours at room temperature. Pyridine was evaporated and the residue was stirred with an aqueous solution of sodium hydroxide (5%; 40 ml) for 10 minutes. The solution was washed with toluene, acidified to pH 3 with hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried and evaporated to dryness. The residue (1.4 g) was recrystallized from ethanol to give colorless prisms of 4'-cyano-2'-(2,4-difluorophenylamino)methanesulfonanilide (1.2 g).
Reaction SMILES: B(C1CCCCC1)C1CCCCC1.[CH3:14][C:15]([CH3:19])([CH3:18])[C:16]#[CH:17].[Zn](CC)CC.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:33]=[CH:32][C:29]([C@@H:30]([OH:31])[CH:17]=[CH:16][C:15]([CH3:19])([CH3:18])[CH3:14])=[CH:28][CH:27]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: C#CC(C)(C)C
Agent: B(C1CCCCC1)C1CCCCC1
Agent: CC[Zn]CC
Product: CC(C)(C)C=C[C@H](O)c1ccc(F)cc1
Yield: 82 %

Procedure:
The product was prepared by General procedure S using 98 mg (0.55 mmol) Cy2BH, 68 μL (0.55 mmol) 3,3-dimethyl-1-butyne, 0.55 mL (1.1 mmol, 2.0 M in hexanes) Et2Zn, 4.8 mg (0.02 mmol) (−)-MIB, and 54 μL (0.50 mmol) p-fluorobenzaldehyde. The crude product was purified by column chromatography (5% ethyl acetate in hexanes) to afford the title compound as a white solid in 82% yield (85 mg, 0.41 mmol). m.p.: 38-40° C.; [α]D20=+21.3 (c=1.2, CHCl3, 93% ee); 1H NMR (CDCl3, 500 MHz): δ 1.01 (s, 9H), 1.84 (br s, 1H), 5.13 (d, 1H, J=6.9 Hz), 5.52 (dd, 1H, J=15.6, 6.9 Hz), 5.77 (d, 1H, J=15.6 Hz), 7.01 (t, 2H, J=8.7 Hz), and 7.31 (dd, 2H, J=8.3, 5.6 Hz) ppm; 13C{1H} NMR (CDCl3, 125 MHz): δ 29.4, 32.9, 74.7, 115.1, 115.3, 127.1, 127.77, 127.83, 139.18, 139.20, 143.7, 161.1, and 163.1 ppm; IR (film): 3344, 3025, 2959, 2866, 1725, 1661, 1604, 1509, 1463, 1363, 1294, 1225, and 1156 cm−1; HRMS-CI m/z 208.1267 [M+; calcd for C13H17FO: 208.1263].
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[Cl:10][C:11]1[CH:12]=[C:13]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([CH2:32]O)=[CH:28][CH:27]=3)[N:22]=2)[CH:14]=[CH:15][C:16]=1[CH2:17][CH:18]([CH3:20])[CH3:19].O>ClCCl>[Cl:10][C:11]1[CH:12]=[C:13]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([CH2:32][Cl:3])=[CH:28][CH:27]=3)[N:22]=2)[CH:14]=[CH:15][C:16]=1[CH2:17][CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)Cc1ccc(-c2nc(-c3ccc(CO)cc3)no2)cc1Cl
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cc1ccc(-c2nc(-c3ccc(CCl)cc3)no2)cc1Cl
Temperature: 42.5 °C
Reaction time: 0.5 h

Procedure:
Thionyl chloride (3.1 mL, 0.043 mol) and N,N-dimethylformamide (0.2 mL) are added to a stirred solution of {4-[5-(3-chloro-4-isobutylphenyl)-[1,2,4]-oxadiazol-3-yl]-phenyl}methanol (4.9 g, 0.0143 mol) in dichloromethane (30 mL) at 0° C. The reaction mixture is heated at 40-45° C. and is stirred at this temperature for 30 minutes. It is then cooled to 0-5° C. temperature, treated with demineralized water (3 mL) and neutralized with caustic lye to adjust the pH to 8-9. Finally it is extracted with dichloromethane (2×20 mL) and the combined extract is dried over sodium sulfate. Removal of solvent under reduced pressure gives 5-(3-chloro-4-isobutylphenyl)-3-(4-chloromethylphenyl)-[1,2,4]-oxadiazole.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[C:15]([NH2:17])[N:14]4[N:18]=[CH:19][CH:20]=[C:13]4[N:12]=3)[CH2:7][CH2:6]2)[O:4]CC1.CCO.O.Cl>C(Cl)Cl.O1CCOCC1>[NH2:17][C:15]1[N:14]2[N:18]=[CH:19][CH:20]=[C:13]2[N:12]=[C:11]([CH:8]2[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]2)[CH:16]=1
Reactant: Nc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Solvent: C1COCCO1
Product: Nc1cc(C2CCC(=O)CC2)nc2ccnn12
Temperature: 80 °C
Reaction time: 18 h
Yield: 92.5 %

Procedure:
In a 40 mL scintillation vial was combined 5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidin-7-amine (Int-5g, 5.54 mmol, 1.52 g), EtOH (10 mL), H2O (4 mL) and 4N HCl:dioxane (4 mL). The vial was capped, sealed and the reaction was heated to 80° C. overnight. After 18 hours, the reaction was cooled to room temperature and diluted with DCM (100 mL). The solution was washed with saturated NaHCO3(aq) and extracted with DCM twice more. The combined organics were dried over Na2SO4 and the solvent was removed in vacuo to yield 4-(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone (Int-5h) (1.18 g, 93% yield) as a pale orange solid.
Reaction SMILES: Cl[Si:2]([CH:9]([CH3:11])[CH3:10])([CH:6]([CH3:8])[CH3:7])[CH:3]([CH3:5])[CH3:4].[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([CH:21]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([CH2:35][OH:36])=[CH:32][CH:33]=4)[N:28]([CH3:37])[CH:27]=3)[C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:15]=2[O:14][CH2:13]1.N1C=CN=C1>CN(C)C=O>[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([CH:21]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([CH2:35][O:36][Si:2]([CH:9]([CH3:11])[CH3:10])([CH:6]([CH3:8])[CH3:7])[CH:3]([CH3:5])[CH3:4])=[CH:32][CH:33]=4)[N:28]([CH3:37])[CH:27]=3)[C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:15]=2[O:14][CH2:13]1
Reactant: COC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2cc(CO)ccc12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2cc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc12
Yield: 80.9 %

Procedure:
Chlorotriisopropylsilane (0.19 ml, 0.88 mmol) was added to a solution of methyl 2-(1,3-benzodioxol-5-yl)-2-[6-(hydroxymethyl)-1-methyl-1H-3-indolyl]acetate (from step (d), 260 mg, 0.74 mmol) and imidazole (100 mg, 1.47 mmol) in anhydrous dimethylformamide (3 ml). After 3 hours the mixture was partitioned between diethyl ether and water, the organic layer was separated and washed with water. The organic layer was dried (magnesium sulphate), and the solvent removed in vacuo. The residue was flash chromatographed (using 50% dichloromethane, 50% hexane as eluent) to give the subtitle compound (305 mg) as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]([C:16]([C:18]2[S:19][C:20]([CH3:24])=[C:21]([Cl:23])[CH:22]=2)=[O:17])([CH2:13][CH2:14][CH3:15])[CH2:9]1)=O)(C)(C)C.CO.ClCCl.Cl>CCOCC>[ClH:23].[Cl:23][C:21]1[CH:22]=[C:18]([C:16]([C:10]2([CH2:13][CH2:14][CH3:15])[CH2:11][CH2:12][NH:8][CH2:9]2)=[O:17])[S:19][C:20]=1[CH3:24]
Reactant: CCCC1(C(=O)c2cc(Cl)c(C)s2)CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: CCCC1(C(=O)c2cc(Cl)c(C)s2)CCNC1
Temperature: 25 °C
Yield: 194.6 %

Procedure:
A solution of 3-(4-chloro-5-methyl-thiophene-2-carbonyl)-3-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.16 g, 0.43 mmoles) in a mixed solvent of methanol and dichloromethane (3 ml/3 ml) was added a solution of hydrochloride acid in anhydrous ether (1M, 10 ml). The solution was stirred at room temperature over night, and concentrated under reduced pressure. The residue was triturated with hexanes and diethyl ether to yield (4-chloro-5-methyl-thiophen-2-yl)-(3-propyl-pyrrolidin-3-yl)-methanone hydrochloride as solid (0.129 g, 97%). [M+H]+: 272