Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:23]1[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[CH:24]=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>[CH2:1]([N:8]1[CH:12]=[C:11]([C:23]2[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[CH:24]=2)[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OB(c2cnn(Cc3ccccc3)c2)OC1(C)C
Reactant: O=C1C=C(Br)CCC1
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: O=C1C=C(c2cnn(Cc3ccccc3)c2)CCC1
Temperature: 110 °C
Yield: 55.6 %

Procedure:
To 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (406 mg, 1.43 mmol), 3-bromocyclohex-2-enone (200 mg, 1.14 mmol), and Pd(PPh3)4 (132 mg, 0.114 mmol) in toluene (2 mL) was added 2M Na2CO3 (1 mL). The reaction mixture was purged with nitrogen and heated at 110° C. for 16 h. The reaction was diluted with water (10 mL) and extracted DCM (3×15 mL), dried over Na2SO4 and purified by flash chromatography (24 g silica gel) using hexanes/EtOAc (0-50% over 15 min, flow rate 35 mL/min) to isolate Intermediate 45A (160 mg, 0.634 mmol, 55.5% yield) as a tan solid. LC-MS (ESI) 253.0 (M+H), RT=1.70 min (Method B).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:17][C:9]2=[C:10]3[C:14](=[CH:15][CH:16]=[C:8]2[O:7][CH2:6][CH2:5]1)[NH:13][CH:12]=[CH:11]3.[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27])#[N:19].O>CN(C=O)C>[CH3:3][N:4]1[CH2:17][C:9]2=[C:10]3[C:14](=[CH:15][CH:16]=[C:8]2[O:7][CH2:6][CH2:5]1)[N:13]([S:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]#[N:19])(=[O:28])=[O:27])[CH:12]=[CH:11]3
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Reactant: CN1CCOc2ccc3[nH]ccc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCOc2ccc3c(ccn3S(=O)(=O)c3ccccc3C#N)c2C1
Reaction time: 1 h
Yield: 35.4 %

Procedure:
NaH (60% in mineral oil, 0.040 g, 1.0 mmol) was charged into a pyrex tube under nitrogen gas and 2-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole (Intermediate 6, 100 mg, 0.492 mmol) in dry DMF (1 mL) was added. The reaction mixture was stirred at room temperature for 20 minutes before 2-cyanobenzenesulfonyl chloride (0.11 g, 0.50 mmol) was added and the reaction mixture was stirred for 1 hour. Water (2 mL) was added and the solution was extracted with DCM. The combined organics were evaporated and the solid residue was washed with diethyl ether to give 64 mg of the title compound. MS m/z 368 [M+H]+.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][N:16]([C:19]2[S:23][C:22]([C:24]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)=[O:25])=[C:21]([CH3:35])[CH:20]=2)[C:15](=[O:36])[CH:14]=1)(C(C)(C)C)(C)C>C(O)(=O)C>[F:34][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=1)[CH2:27][NH:26][C:24]([C:22]1[S:23][C:19]([N:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11][CH2:10][CH2:9][OH:8])=[CH:14][C:15]2=[O:36])=[CH:20][C:21]=1[CH3:35])=[O:25]
Reactant: Cc1cc(-n2ccc(OCCCO[Si](C)(C)C(C)(C)C)cc2=O)sc1C(=O)NCc1cccc(F)c1
Solvent: CC(=O)O
Product: Cc1cc(-n2ccc(OCCCO)cc2=O)sc1C(=O)NCc1cccc(F)c1
Temperature: 25 °C
Yield: 61 %

Procedure:
A solution of 5-(4-(3-(tert-butyldimethylsilyloxy)propoxy)-2-oxopyridin-1(2H)-yl)-N-(3-fluorobenzyl)-3-methylthiophene-2-carboxamide (0.368 mmol) in acetic acid (5 mL) was stirred at 60° C. for 16 hours. The reaction mixture was allowed to cool to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography eluted with 0-10% methanol in dichloromethane to afford the title compound as a pinkish solid in 61% yield (0.093 g): mp 135-137° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.58 (t, J=6.0 Hz, 1H), 8.14 (d, J=7.9 Hz, 1H), 7.42-7.33 (m, 1H), 7.26 (s, 1H), 7.18-7.03 (m, 3H), 6.21 (dd, J=7.9, 2.7 Hz, 1H), 6.01 (d, J=2.7 Hz, 1H), 4.60 (br s, 1H), 4.42 (d, J=6.0 Hz, 2H), 4.09 (t, J=6.2 Hz, 2H), 3.54 (t, J=6.2 Hz, 2H), 2.42 (s, 3H), 1.86 (p, J=6.2 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ 166.6, 162.5, 162.1 (d, JC-F=243.2 Hz), 161.0, 142.7 (d, JC-F=7.0 Hz), 138.9, 137.4, 134.8, 130.1 (d, JC-F=8.3 Hz), 127.0, 123.1 (d, JC-F=2.7 Hz), 120.4, 113.8 (d, JC-F=21.5 Hz), 113.4 (d, JC-F=20.9 Hz), 102.6, 96.6, 65.6, 56.9, 42.1, 31.4, 15.5; MS (ES+) m/z 417.3 (M+1).
Reaction SMILES: [CH:1]1([N:7]([CH2:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([CH2:27][N:28]([CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)[C:29]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([N+:38]([O-])=O)=[CH:34][CH:33]=3)=[O:30])[CH2:23][CH2:22]2)[C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[C].[Pd].[Pd].CN(C=O)C>[CH:1]1([N:7]([CH2:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([CH2:27][N:28]([CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)[C:29]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=3)=[O:30])[CH2:23][CH2:22]2)[C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)N(C[C@H]1CC[C@H](CN(C(=O)Nc2ccc([N+](=O)[O-])cc2)C2CCCCC2)CC1)C1CCCCC1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1ccc(NC(=O)N(C[C@H]2CC[C@H](CN(C(=O)Nc3ccc(N)cc3)C3CCCCC3)CC2)C2CCCCC2)cc1

Procedure:
A 0.6 g quantity of 10% palladium carbon was added to 100 ml of a DMF solution containing 5.7 g of trans-1,4-bis[[1-cyclohexyl-3-(4-nitrophenyl)ureido]-metyl]cyclohexane synthesized in accordance with Example 2. Hydrogen was added at ordinal pressure and normal temperature for 15 hours. After completion of the reaction, palladium was separated by filtration and the reaction mixture was concentrated under reduced pressure. The reaction mixture was dissolved in chloroform and a 4N hydrochloric acid-dioxyane solution was added to provide 5.5 g (95%) of white crystals precipitated.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:13]([NH:16][CH:17]([CH2:20][O:21][CH3:22])[CH:18]=[O:19])[CH:14]=[CH2:15]>C1C=CC=CC=1>[CH2:13]([N:16]([CH:17]([CH2:20][O:21][CH3:22])[CH:18]=[O:19])[C:11]([NH:10][C:8]1[S:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6][N:7]=1)=[O:12])[CH:14]=[CH2:15]
Reactant: C=CCNC(C=O)COC
Reactant: CC(C)(C)c1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: C=CCN(C(=O)Nc1nnc(C(C)(C)C)s1)C(C=O)COC

Procedure:
5-t-Butyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-allylamino-3-methoxypropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 30 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. This residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-allyl-3-(5-t-butyl-1,3,4-thiadiazol-2-yl)ureido]-3-methoxypropionaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[N:26]([CH2:27][C:28]4[O:32][C:31]([C:33]([O:35]CC)=[O:34])=[CH:30][CH:29]=4)[CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[N:26]([CH2:27][C:28]4[O:32][C:31]([C:33]([OH:35])=[O:34])=[CH:30][CH:29]=4)[CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: CCOC(=O)c1ccc(Cn2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c32)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cn2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c32)o1
Temperature: 25 °C
Reaction time: 14 h
Yield: 67.2 %

Procedure:
To a solution of ethyl 5-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}-2-furoate (280 mg) in a mixed solvent of tetrahydrofuran (1.34 mL) and ethanol (1.34 mL) was added 1N aqueous sodium hydroxide solution (1.34 mL) and the mixture was stirred at room temperature for 14 hrs. 1N Hydrochloric acid (1.34 mL) and water (10 mL) were added to the reaction mixture and the mixture was stirred at room temperature for 30 min. The resultant precipitate was collected by filtration, washed with water (10 mL×3) and diisopropyl ether (10 mL×3) and dried under reduced pressure (80° C.) to give the title compound (178 mg) as a white powder.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([NH:12][C:13]2[N:17]=[C:16]([NH2:18])[NH:15][N:14]=2)=[CH:4][C:3]=1[Cl:19].[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[C:7]([C:8]([F:11])([F:9])[F:10])=[CH:6][C:5]([NH:12][C:13]2[N:17]=[C:16]([NH:18][CH2:26][C:25]3[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:30])[F:31])=[CH:29][CH:28]=3)[NH:15][N:14]=2)=[CH:4][C:3]=1[Cl:19]
Reactant: Nc1nc(Nc2cc(Cl)c(Br)c(C(F)(F)F)c2)n[nH]1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: FC(F)(F)c1ccc(CNc2nc(Nc3cc(Cl)c(Br)c(C(F)(F)F)c3)n[nH]2)cc1
Reaction time: 1 h
Yield: 73 %

Procedure:
A solution of N3-(4-bromo-3-chloro-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 1 (50 mg, 140 μmol) and 4-(trifluoromethyl)benzaldehyde (48.8 mg, 280 μmol) in MeOH (3 ml) was stirred at room temperature for 2 days, NaBH4 (31.8 mg, 841 μmol) was added and the reaction was stirred for 1 hour. The solvent was removed, and the reaction mixture was re-dissolved in DCM and was washed with water (2×4 ml), dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 24 g, 3% to 5% MeOH in DCM) and recrystallized from DCM to give a light yellow powder as desired product (53 mg, 73% yield). MS +m/z: 514 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:17]=2[CH3:26])=[CH:11][C:10]=1[S:27]([OH:30])(=O)=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cs].CN(C=O)C.C(Cl)(=O)C([Cl:40])=O>C(Cl)Cl.CCOCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:17]=2[CH3:26])=[CH:11][C:10]=1[S:27]([Cl:40])(=[O:30])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(OCc2ccccc2)c(S(=O)(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Cs]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(OCc2ccccc2)c(S(=O)(=O)Cl)c1
Reaction time: 1 h

Procedure:
A suspension of the title D compound, 2-benzyloxy-5-(2,6-dimethyl-4-nitrophenoxy)-benzenesulfonic acid, cesium salt (9.9 g, 20 mmol) in 200 mL of CH2Cl2 is treated with DMF (3.1 mL, 40 mmol), then oxalyl chloride (3.5 mL, 40 mmol) is added over 30 min at RT. The reaction mixture is stirred for 1 h further, then diluted with Et2O (200 mL) and washed with water and brine, dried over anhydrous sodium sulfate (Na2SO4) and concentrated. The product is washed with Et2O (5 mL) and dried in vacuo to afford 2-benzyloxy-5-(2,6-dimethyl-4-nitro-phenoxy)benzenesulfonyl chloride: NMR (CDCl3) 2.24 (s, 6H), 5.31 (s, 2H), 7.02 (dd, 1H, J=8.7, 3.8), 7.10 (d, 1H, J=8.7), 7.32-7.47 (m, 4H), 7.52 (d, 2H, J=7.5), 8.05 (s, 2H).
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)=[CH:7][CH:6]=1.[CH3:21][NH:22][CH3:23]>C(N(CC)CC)C>[CH3:21][N:22]([CH3:23])[CH2:20][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)=[CH:7][CH:6]=1
Reactant: CNC
Reactant: FC(F)(F)c1c[nH]c(-c2ccc(OCC3CO3)cc2)n1
Solvent: CCN(CC)CC
Product: CN(C)CC(O)COc1ccc(-c2nc(C(F)(F)F)c[nH]2)cc1

Procedure:
A solution of 2-[4-(2,3-epoxypropoxy)phenyl-4-trifluoromethylimidazole in triethylamine (15 ml) is added 1.1 equivalents of a dimethylamine. This solution is refluxed until reaction is complete as indicated by TLC. The solvent is removed under reduced pressure and the residue recrystallized to yield 2-[4-(3-dimethylamino-2-hydroxypropoxy)phenyl]-4-trifluoromethylimidazole.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([N:12]([CH2:14][CH2:15]O)[CH3:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1C=CC=CC=1.C(OCC)(=O)C>[CH2:5]([N:12]([CH2:14][CH2:15][Cl:3])[CH3:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(CCO)Cc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CN(CCCl)Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (2 ml) was added dropwise to a stirred, ice cooled solution of 2-[N-benzyl-N-methylamino]ethanol (4 g) obtained in preparation 8, in dry benzene (10 ml). The resulting mixture was stirred at 0° C. for 2 h and then diluted with ethyl acetate (40 ml), washed with saturated aqueous sodium bicarbonate solution (2×25 ml), water (50 ml), brine (50 ml) and dried. The ethyl acetate layer was evaporated and the residue was chromatographed on silica gel with 20% ethyl acetate in petroleum ether as eluent to give 2.6 g of the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH2:11])=[O:10].[C:12]([C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17])#[CH:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.[Cu]I.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>[NH2:17][C:16]1[CH:15]=[C:14]([C:12]#[C:13][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][C:9]([NH2:11])=[O:10])[CH:20]=[CH:19][CH:18]=1
Reactant: NC(=O)Nc1ccccc1I
Reactant: C#Cc1cccc(N)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)Nc1ccccc1C#Cc1cccc(N)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To the nitrogen degassed solution of 1-(2-iodophenyl)urea (1.31 g, 5 mmol, 1 eq), 3-ethynylaniline (0.8 mL, 1.5 eq), triphenylphosphine (32.8 mg, 0.025 eq), and triethylamine (2.1 mL, 3 eq) in anhydrous DMF (12.5 mL) was added copper(I) iodide (190.4 mg, 0.2 eq) and bis(triphenylphosphine)palladium(II) dichloride (351 mg, 0.1 eq). After the reaction mixture was stirred at room temperature for 10 minutes, it was diluted with ethyl acetate, washed sequentially with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, brine, and lastly dried with anhydrous sodium sulfate. The upper solution was decanted, concentrated, and the solid mixture was subject to a gradient column chromatography (EtOAc-Hex 1:2 to MeOH-EtOAc 1:9) to give 1-{2-[(3-aminophenyl)ethynyl]phenyl}urea as a brown solid in amount of 1.26 g.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:2]1.C1C=CN=CC=1.[FH:15].O>CCOCC>[F:15][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:2][OH:1]
Reactant: CCCCCC1CO1
Reactant: F
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: O
Product: CCCCCC(F)CO
Reaction time: 0.5 h

Procedure:
A solution of 1.14 g (10.0 mM) of (+)-1,2-epoxyheptane ([α]D +15.1° (neat)) in 5 ml of dry ether was quickly added dropwise into ice-cooled 2 ml of hydrogen fluoride/pyridine. After the addition, the mixture was stirred for 30 minutes in an ice bath, followed by addition of 10 ml of cold water and 3 times of extraction with 10 ml of ether. The extract liquid was washed 3 times with 10 ml of 1N-sodium carbonate, followed by drying with anhydrous magnesium sulfate, removal of ether by vacuum distillation and distillation with Kugelrohr distiallation apparatus, to obtain 0.492 g of crude (-)-2-fluoroheptanol. Further, by repeating the above operations, 1.35 g of the crude product was obtained and rectified by means of a Claisen flask to obtain 0.80 g (600 mM) of objective (-)-2-fluoroheptanol. Yield: 20.0%. The product showed the following properties:
Reaction SMILES: C([BH-](CC)CC)C.[Li+].[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)#[CH:10].[I:24]I>C1COCC1>[I:24]/[CH:10]=[CH:9]/[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1
Reactant: C#COc1ccc(-c2ccccc2)cc1
Reactant: II
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: I/C=C/Oc1ccc(-c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
To an oven dried, two-necked flask (250 mL) under nitrogen and protected from light was added Cp2ZrCl2 (5.2 g, 20.3 mmol, 2 eq), dry THF (30 mL), and 1M lithium triethylborohydride (Super Hydride) in THF (20 mL, 20 mmol, 1.9 eq). The mixture was stirred for 1 h where the alkyne 3 (1.97 g, 10.2 mmol, 1 eq) was added. After 30 min, iodine (2.57 g, 20.3 mmol, 2 eq) was added and the reaction mixture was stirred for 30-40 min while protected from light. The reaction was quenched by diluting with ethyl acetate/hexane (1:1, 50 mL). The diluted mixture was then washed twice with saturated solution of sodium bicarbonate (150 mL) and the combined aqueous layers were extracted with ethyl acetate/hexane mixture (1:1). 10% aqueous sodium thiosulphate (100 mL) was used to wash the combined organic phases followed by brine (100 mL), dried over sodium sulfate, filtered, concentrated to yellowish slurry which was purified by silica gel column chromatography using 100% hexane as eluent (silica gel was pretreated with 2.5% v/v triethylamine) to afford 4 as white amorphous crystals (1.80 g, 55%): mp 64-660° C. 1H NMR (300 MHz, CDCl3): 7.64-7.52 (m, 4H, HAr), 7.49-7.41 (m, 2H), 7.38-7.32 (m, 1H, HAr), 7.13-7.01 (m, 3H, HAr), 5.74 (s, 1H, CH═CH, J=12.2 Hz) ppm; 13C NMR (75 MHz, CDCl3): 155.5, 150.3, 140.3, 137.0, 128.9, 128.4, 127.2, 126.9, 117.5, 57.9 ppm; IR (cm−1): 3316, 3077, 3034, 2960, 2924, 2874, 2174, 1643, 1623, 1601, 1515, 1485, 1330, 1307, 1226, 1186, 1173, 1093, 1008, 919, 854, 837, 697, 579, 549.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][OH:7].[CH3:8][S:9](Cl)(=[O:11])=[O:10]>C(Cl)Cl>[CH3:8][S:9]([O:7][CH2:6][C@H:2]1[CH2:3][CH2:4][CH2:5][O:1]1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@H]1CCCO1
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1CCCO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.6 %

Procedure:
A mixture of (R)-(tetrahydrofuran-2-yl)methanol (600 mg, 5.87 mmol), DCM (35 ml), TEA (0.983 ml, 7.05 mmol) was diluted with methanesulfonyl chloride (0.467 ml, 5.99 mmol), via a dropwise addition. The reaction mixture was stirred at ambient temperature for 5 hours and the reaction progress was followed by LCMS. The crude reaction mixture was washed with saturated sodium bicarbonate (1×), water (2×), filtered and concentrated to a constant mass, giving 980 mg of the title compound, which was used without further purification. LCMS (m/z): 181.0 (MH+), retention time=0.40 min
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[CH:8].Cl.CN(C)[CH:13]=[O:14]>[Cu](I)I>[CH3:7][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:7][C:2]2[CH:1]=[CH:6][C:5]([CH:13]=[O:14])=[CH:4][CH:3]=2)=[CH:6][CH:1]=1
Reactant: CN(C)C=O
Reactant: C#Cc1ccccc1C
Agent: I[Cu]I
Agent: Cl
Product: Cc1ccc(C#Cc2ccc(C=O)cc2)cc1
Reaction time: 5 h

Procedure:
According to the method of J. Cole et al., J. Chem. Soc., 244 (1962), a mixture of toluylacetylene (200 mmol), 2-(4-bromophenyl)-1,3-dioxalane (200 mmol), dimethylformamide (500 ml), and copper iodide (I) (300 mmol) was heated while stirring for 5 hours. After allowed to cool, 500 ml of 6M hydrochloric acid was added and stirred for 1 hour. It was extracted with 500 ml of toluene, and the organic layer was washed with water thrice and dried with anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by a silica gel column chromatography (eluent:toluene) to obtain 120 mmol of 4-(2-(4-methylphenyl)ethynyl)benzaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Br.Br.Br.[CH2:13]([C:15]1[C:16]([C:23]2[CH:31]=[C:30]3[C:26]([C:27]([C:32]4[NH:33][C:34]5[CH2:39][CH2:38][NH:37][CH2:36][C:35]=5[N:40]=4)=[N:28][NH:29]3)=[CH:25][CH:24]=2)=[CH:17][C:18]([F:22])=[C:19]([OH:21])[CH:20]=1)[CH3:14]>>[CH2:13]([C:15]1[C:16]([C:23]2[CH:31]=[C:30]3[C:26]([C:27]([C:32]4[NH:33][C:34]5[CH2:39][CH2:38][N:37]([CH2:6][C:5]6[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=6)[CH2:36][C:35]=5[N:40]=4)=[N:28][NH:29]3)=[CH:25][CH:24]=2)=[CH:17][C:18]([F:22])=[C:19]([OH:21])[CH:20]=1)[CH3:14]
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Reactant: O=Cc1ccc(F)cc1
Agent: Br
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(Cc3ccc(F)cc3)C4)n[nH]c2c1
Yield: 5.3 %

Procedure:
The title compound was prepared from 4-fluoro-benzaldehyde (25 mg, 198 μmol) and 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50 mg, 132 μmol) using the method of Example 22. The crude material was purified by HPLC Method A to afford 3.4 mg of the title compound.
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].[CH:5]([C:7]1[C:16]2[O:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:13]([CH3:23])[C:12](=[O:24])[C:11]=2[CH:10]=[CH:9][CH:8]=1)=O.Cl.CN.C(N(CC)CC)C>CO.[Cl-].[Zn+2].[Cl-]>[CH3:1][NH:2][CH2:5][C:7]1[C:16]2[O:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:13]([CH3:23])[C:12](=[O:24])[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: [BH3-]C#N
Reactant: Cc1c(-c2ccccc2)oc2c(C=O)cccc2c1=O
Agent: CN
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CO
Product: CNCc1cccc2c(=O)c(C)c(-c3ccccc3)oc12
Reaction time: 5 h
Yield: 78.8 %

Procedure:
A solution of 15.1 g of anhydrous zinc chloride and 14.5 g of sodium cyanoborohydride in 400 ml of anhydrous methanol was added dropwise at 0° C. into a stirred mixture of 58.8 g of 8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 60.7 g of methylamine hydrochloride and 125 ml of triethylamine in 600 ml of anhydrous methanol. After stirring for 5 hours at 20°-25° C., the solvent was evaporated off in vacuo and the residue was taken up in 200 ml of water and collected by suction filtration. The crude product was dissolved in aqueous acetic acid, washed with ethyl acetate and re-precipitated by addition of cold 6N aqueous sodium hydroxide solution. 49 g of the title compound was obtained. m.p. 97°-99° C., after crystallization from 75% ethanol.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][CH2:13][CH3:14])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15]Br>ClCCl>[Br:15][C:11]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][NH:9][C:10]=1[CH2:12][CH2:13][CH3:14]
Reactant: BrBr
Reactant: CCCc1cc(-c2ccccc2)n[nH]1
Solvent: ClCCl
Product: CCCc1[nH]nc(-c2ccccc2)c1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.1 %

Procedure:
To a solution of 3-phenyl-5-propyl-1H-pyrazole (3.83 g, 20.56 mmol) in dichloromethane (118.0 mL) was added bromine (1.05 mL, 20.56 mmol) at 25° C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then quenched with 2 M Na2CO3 (aq.) to pH 12 and the organics were separated. The aqueous layer was extracted with DCM (thrice). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to give a red oil. This oil was purified by silica gel flash chromatography to give the title compound as a yellow oil (3.44 g). LCMS m/z=265.1, 267.1 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.97 (t, J=7.33 Hz, 3H), 1.63-1.74 (m, 2H), 2.57 (t, J=7.58 Hz, 2H), 7.37-7.48 (m, 3H), 7.77-7.82 (m, 2H).