Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:14])=O>>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([Cl:14])=[N:8][CH3:9])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1ccc(F)cc1
Reactant: O=S(Cl)Cl
Product: CN=C(Cl)c1ccc(F)cc1

Procedure:
A suspension of 4-fluoro-N-methyl-benzamide (CAS: 701-49-5, 0.106 g, 0.69 mmol) in thionyl chloride (202 mL, 2.78 mmol) was refluxed for 1 h 30 min. The solvent was removed under reduced pressure, then toluene was added and the solvent was evaporated under reduced pressure to afford a yellow oil used immediately for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][C:6]#[N:7].[NH2:12][C:13]1[N:18]=[C:17]([NH2:19])[C:16]([CH:20]=O)=[CH:15][N:14]=1>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]1[C:6]([NH2:7])=[N:19][C:17]2[N:18]=[C:13]([NH2:12])[N:14]=[CH:15][C:16]=2[CH:20]=1
Reactant: COc1ccccc1CC#N
Reactant: Nc1ncc(C=O)c(N)n1
Product: COc1ccccc1-c1cc2cnc(N)nc2nc1N

Procedure:
The title compound was prepared according to Example 1, starting from 2-methoxybenzyl cyanide and 2,4 -diamino-5-pyrimidine-carboxaldehyde; mp 304-306° C. (dec).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25]([OH:27])=O)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][C:32]1[N:37]=[C:36]([N:38]([CH3:40])[CH3:39])[CH:35]=[CH:34][CH:33]=1)[CH3:29]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:22])[CH3:23])[CH:16]=2)[CH2:24][C:25]([N:30]([CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[C:36]([N:38]([CH3:39])[CH3:40])[N:37]=2)[CH2:28][CH3:29])=[O:27])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNCc1cccc(N(C)C)n1
Reactant: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Product: CCN(Cc1cccc(N(C)C)n1)C(=O)CN(c1cccc(N(C)C)c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid with (6-ethylaminomethyl-pyridin-2-yl)-dimethyl-amine
Reaction SMILES: [CH2:1]([C:4]([CH2:9][CH2:10][CH3:11])([CH2:7][OH:8])[CH2:5][OH:6])[CH2:2][CH3:3].[CH3:12]I>>[CH2:9]([C:4]([CH2:1][CH2:2][CH3:3])([CH2:5][O:6][CH3:12])[CH2:7][OH:8])[CH2:10][CH3:11]
Reactant: CI
Reactant: CCCC(CO)(CO)CCC
Product: CCCC(CO)(CCC)COC

Procedure:
2,2-Di-n-propyl-3-methoxy-1-propanol was prepared from 2,2-di-n-propyl-1,3-propandiol and methyl iodide through the same procedure as described above.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[CH3:21][N:22]([CH3:33])[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[C:25]([O:31][CH3:32])[CH:24]=1>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:27]([C:26]3[CH:29]=[CH:30][C:23]([N:22]([CH3:33])[CH3:21])=[CH:24][C:25]=3[O:31][CH3:32])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: COc1cc(N(C)C)ccc1C=O
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: COc1cc(N(C)C)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Br)cnc2[nH]1
Yield: 42.6 %

Procedure:
In a similar fashion to Compound LXXVI, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (40.0 mg, 0.118 mmol) and 4-dimethylamino-2-methoxy-benzaldehyde (23.3 mg, 0.130 mmol) were reacted to produce 25 mg (43%) of the title compound. mp: 218-220° C., 1H NMR (300 MHz, DMSO-d6): 13.00 (s, 1H), 8.24 (s, 1H), 8.00 (s, 1H), 7.96 (s, 1H), 7.73 (s, 1H), 6.99 (d, J=8 Hz, 2H), 6.43 (br s, 1H), 6.33 (br s, 1H), 5.16 (t, J=8 Hz, 1H), 3.94 (s, 3H), 2.87 (s, 1H), 2.73 (s, 1H), 2.59 (d, J=7 Hz, 1H), 2.23 (d, J=8 Hz, 1H), 1.90 (s, 1H), 1.37 (d, J=8 Hz, 1H). MS: 497, 499 (M+H), HPLC: 2.65 min (G method).
Reaction SMILES: [CH:1]1([C:4]2([CH2:23]O)[CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]4[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=4)[N:10]=3)[C:5]2=[O:22])[CH2:3][CH2:2]1.CS(Cl)(=O)=O.[CH2:30]([N:32](CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH:1]1([C:4]2([CH2:23][C:30]#[N:32])[CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]4[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=4)[N:10]=3)[C:5]2=[O:22])[CH2:3][CH2:2]1
Reactant: Cn1cc(Nc2nccc(N3CCC(CO)(C4CC4)C3=O)n2)cn1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc(Nc2nccc(N3CCC(CC#N)(C4CC4)C3=O)n2)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-cyclopropyl-3-(hydroxymethyl)-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyrrolidin-2-one (45 mg) obtained in Example 393 in tetrahydrofuran (1.0 mL) were added methanesulfonyl chloride (15 μL) and triethylamine (29 μL) at 0° C., and the mixture was stirred at 0° C. for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the residue in N,N-dimethylformamide (1.0 mL) were added potassium cyanide (36 mg) and sodium iodide (82 mg) at room temperature, and the mixture was stirred overnight at 120° C. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (17 mg).
Reaction SMILES: [K].Br[C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[OH-].[K+].[CH3:16][NH:17][CH2:18][C:19]([OH:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].Cl>CC(O)C.O.[Cu]>[C:19]([CH2:18][N:17]([CH3:16])[C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])([OH:21])=[O:20]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: CNCC(=O)O
Agent: [Cu]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Solvent: O
Product: COc1ccc(N(C)CC(=O)O)c(C(=O)O)c1
Temperature: 0 °C
Yield: 86 %

Procedure:
A mixture of 244 g (0.91 mole) of the potassium salt of 2-bromo-5-methoxybenzoic acid (prepared by treating a solution of the parent carboxylic acid in 2-propanol with excess methanolic potassium hydroxide), 196 g (1.54 mole) of the potassium salt of N-methylglycine (prepared as above), 13 g (0.82 mole) of anhydrous potassium carbonate and 0.66 g (0.01 mole) of copper powder in 220 ml of water was stirred at reflux for five hours. The mixture was cooled, added to 4.0 kg of ice/water, and acidified with concentrated hydrochloric acid to precipitate the crude product. THe solid was filtered and washed with water to yield 186 g (86% yield) of the carboxylic acid product. A sample recrystallized from aqueous 2-methoxyethanol was analytically pure, mp 196° C.-dec.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[C:24]1([OH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:3][CH:4]=1
Reactant: Oc1ccccc1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2ccccc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and phenol: 1H-NMR (CDCl3) δ 8.54 (1H, d, J=2.8 Hz), 8.21 (1H, d, J=7.3 Hz), 8.13 (1H, d, J=2.6 Hz), 8.00 (2H, dd, J=6.6, 1.8 Hz), 7.50–7.41 (4H, m), 7.34–7.29 (1H, m), 7.20–7.15 (2H, m), 5.42–5.33 (1H, m), 3.89 (3H, s), 1.61 (3H, d, J=7.0 Hz); MS (ESI) m/z 411 (M+H)+, 409 (M−H)−.
Reaction SMILES: C([N:4](CC)C(C)C)(C)C.[I-].ClC1C=CC=C[N+]=1C.[CH3:19][C:20]1[CH:21]=[C:22]([CH2:49][C:50]([OH:52])=O)[CH:23]=[CH:24][C:25]=1/[CH:26]=[CH:27]/[S:28]([N:31]1[CH2:48][CH2:47][C:34]2([N:38]=[C:37]([CH:39]3[CH2:44][CH2:43][CH:42]([CH3:45])[CH2:41][CH2:40]3)[NH:36][C:35]2=[O:46])[CH2:33][CH2:32]1)(=[O:30])=[O:29].N.CO>ClCCl.CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:19][C:20]1[CH:21]=[C:22]([CH2:49][C:50]([NH2:4])=[O:52])[CH:23]=[CH:24][C:25]=1/[CH:26]=[CH:27]/[S:28]([N:31]1[CH2:48][CH2:47][C:34]2([N:38]=[C:37]([CH:39]3[CH2:40][CH2:41][CH:42]([CH3:45])[CH2:43][CH2:44]3)[NH:36][C:35]2=[O:46])[CH2:33][CH2:32]1)(=[O:30])=[O:29]
Reactant: Cc1cc(CC(=O)O)ccc1/C=C/S(=O)(=O)N1CCC2(CC1)N=C(C1CCC(C)CC1)NC2=O
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Agent: C[n+]1ccccc1Cl
Agent: N
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc(CC(N)=O)ccc1/C=C/S(=O)(=O)N1CCC2(CC1)N=C(C1CCC(C)CC1)NC2=O
Reaction time: 0.17 h
Yield: 60.7 %

Procedure:
N,N-Diisopropylethylamine (31.4 μL, 0.185 mmol) and 2-chloro-1-methylpyridinium iodide (18.9 mg, 0.074 mmol) were added to a solution of (3-methyl-4-{(E)-2-[2-(4-methyl-cyclohexyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-vinyl}-phenyl)-acetic acid (30.0 mg, 0.062 mmol) in dichloromethane (0.5 mL) and DMF (0.1 mL), and the mixture was stirred for 10 minutes. A 2.0 M ammonia-methanol solution (0.15 mL, 0.308 mmol) and DMAP (0.8 mg, 0.006 mmol) were then added, and the mixture was stirred overnight. The reaction mixture was then quenched by adding a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, and then dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 2-(3-methyl-4-{(E)-2-[2-(4-methyl-cyclohexyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-vinyl}-phenyl)-acetamide as a white powder (18.3 mg, 61%).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][CH2:9][C:10]([NH:12][CH3:13])=[O:11])=[O:7])=[CH:4][CH:3]=1.[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl.N1CCCCC1.[OH-].[Na+]>ClCCl>[O:20]1[CH2:19][CH:18]1[CH2:16][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:8][CH2:9][C:10]([NH:12][CH3:13])=[O:11])=[O:7])=[CH:14][CH:15]=1
Reactant: ClCC1CO1
Reactant: CNC(=O)CCC(=O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CNC(=O)CCC(=O)c1ccc(OCC2CO2)cc1
Yield: 81.1 %

Procedure:
A mixture of finely ground 3-(4-hydroxybenzoyl)-N-methylpropionamide (20.7 g, 0.1 mole), epichlorohydrin (77 g, 0.83 mole), and piperidine (0.5 ml) was heated on a steam bath for 90 minutes. Evaporation under reduced pressure gave a viscous oil which was dissolved in dichloromethane (500 ml) and shaken with dilute sodium hydroxide (100 ml). The organic phase was washed with water, dried and evaporated to a slurry. Addition of ether gave the required 3-[4-(2,3-epoxypropoxy)benzoyl]-N-methyl-propionamide (21.36 g., 81%) which was recrystallised from chloroform/ether, m.p. 133°-140°C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[NH:12][CH:13]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH2:15][CH2:14]1)([O-])=O.C([O-])=O.[NH4+]>[Pd].CO>[NH2:1][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[NH:12][CH:13]1[CH2:14][CH2:15][N:16]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH2:17][CH2:18]1
Reactant: N#Cc1ccc([N+](=O)[O-])c(NC2CCN(C3CCOCC3)CC2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: N#Cc1ccc(N)c(NC2CCN(C3CCOCC3)CC2)c1
Reaction time: 1 h

Procedure:
4-Nitro-3-{[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]amino}benzonitrile (D58, 592 mg, 0.0018 mol, 1 eq), 10% palladium on carbon (200 mg, 0.00018 mol, 0.1 eq), ammonium formate (375 mg, 0.0057 mol, 3.2 eq), and methanol (15 ml) (degassed with nitrogen) were combined and stirred for 1 hour. The catalyst was then filtered off, and the reaction evaporated, water and dichloromethane added and shaken. Separation and drying of the dichloromethane layer with sodium sulfate followed by evaporation yielded a crude product which was purified exactly as in Example 1 where A=H2O and B=acetonitrile to afford the title compound. MS (ESI): 301 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][C:3]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:9])=[CH:4][C:3]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1ccc(F)c(OCC(F)(F)F)c1
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(F)c(OCC(F)(F)F)c1
Yield: 83 %

Procedure:
The title compound is prepared in 83% yield (0.21 g, colorless oil) from 1-(4-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)ethanone (0.18 g, 0.76 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: C(O)(=O)C.Br[C:6]1[CH:7]=[C:8]([C:12]2([C:22]3[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=3)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([NH2:21])=[N:13]2)[CH:9]=[CH:10][CH:11]=1.[N:32]1[CH:37]=[C:36](B(O)O)[CH:35]=[N:34][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.C(O)C.O>[N:32]1[CH:37]=[C:36]([C:6]2[CH:7]=[C:8]([C:12]3([C:22]4[CH:23]=[N:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=4)[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]([NH2:21])=[N:13]3)[CH:9]=[CH:10][CH:11]=2)[CH:35]=[N:34][CH:33]=1
Reactant: NC1=NC(c2ccc(C(F)(F)F)nc2)(c2cccc(Br)c2)c2ccccc21
Reactant: OB(O)c1cncnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: NC1=NC(c2ccc(C(F)(F)F)nc2)(c2cccc(-c3cncnc3)c2)c2ccccc21
Temperature: 130 °C
Yield: 28.3 %

Procedure:
1-(3-Bromophenyl)-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-isoindol-3-amine acetate (Example 52, 0.046 g, 0.09 mmol), pyrimidine-5-boronic acid (0.023 g, 0.186 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane adduct (0.004 g, 0.0046 mmol) and cesium carbonate (0.092 g, 0.284 mmol) were dissolved in 1,2-dimethoxy ethane:ethanol:water (6:3:1, 2 mL) and heated to 130° C. for 20 minutes in a microwave oven. Additional [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane adduct (0.004 g, 0.0046 mmol) was added and the resulting mixture was heated to 130° C. for additional 20 minutes. After cooled to ambient temperature the mixture was filtered and purified by preparative HPLC to give 0.011 g (26% yield) of the title compound. 1H NMR (MeOD) δ 9.12 (s, 1 H), 9.02-8.95 (m, 2 H), 8.64 (d, J=2.02 Hz, 1 H), 8.06-7.92 (m, 2 H), 7.80 (dd, J=7.96, 2.40 Hz, 2 H), 7.76-7.69 (m, 2 H), 7.68-7.61 (m, 2 H), 7.57 (t, J=7.83 Hz, 1 H), 7.49-7.41 (m, 1 H), 1.94 (s, 2 H); MS (ES) m/z 430 [M−H]−, m/z 432 [M+H]+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([O:18][B:19](OC(C)C)[O:20]C(C)C)(C)C.C([Li])CCC.CCCCCC.[Cl-].[NH4+]>C1COCC1>[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([B:19]([OH:20])[OH:18])=[CH:3][CH:4]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Ic1ccc(N2CCCCCC2)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(N2CCCCCC2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 35.7 %

Procedure:
Under an argon atmosphere, 1-(4-iodophenyl)azepane (200 mg) and triisopropylborate (162 mg) were dissolved in THF (2 ml), followed by cooling to −78° C. A 1.59 M butyl lithium/hexane solution (0.5 ml) was added thereto, followed by elevating the temperature to 0° C. over 1 hour, and further stirring at the same temperature for 1 hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain (4-azepan-1-ylphenyl)boronic acid (52 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:12]2[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].[CH:20]1([C:23](Cl)=[O:24])[CH2:22][CH2:21]1.O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:6]=[CH:7][C:8]([O:11][CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:23]([CH:20]3[CH2:22][CH2:21]3)=[O:24])[CH2:14][CH2:13]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(OC2CCC(N)CC2)cc1
Reactant: O=C(Cl)C1CC1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(OC2CCC(NC(=O)C3CC3)CC2)cc1
Reaction time: 2 h
Yield: 90.9 %

Procedure:
To a solution of 4-(4-aminocyclohexyloxy)benzoic acid ethyl ester (4.15 g, 15.76 mmol) in DCM (40 mL) at 0° C. was added TEA (1.6 g, 15.7 mmol) followed by cyclopropane carbonyl chloride (1.98 g, 18.9 mmol) over a period of 1 hr. Stirring was continued at 0-5° C. for 2 h. Water (40 mL) was then added and extracted with EtOAc. The organic layer was washed with 2N HCl, satd.NaHCO3 and brine solution. It was dried and concentrated under vacuum affording 4.75 g (91%) of 4-[4-(cyclopropanecarbonyl-amino)-cyclohexyloxy]-benzoic acid ethyl ester as an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:15][C:14]2[C:13]3[CH:16]=[C:17]([Br:20])[CH:18]=[CH:19][C:12]=3[O:11][CH2:10][CH2:9][C:8]=2[CH:7]=1)=[O:5])C.[OH-].[Na+].CCO>C1COCC1.O>[Br:20][C:17]1[CH:18]=[CH:19][C:12]2[O:11][CH2:10][CH2:9][C:8]3[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[S:15][C:14]=3[C:13]=2[CH:16]=1
Reactant: CCOC(=O)c1cc2c(s1)-c1cc(Br)ccc1OCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc2c(s1)-c1cc(Br)ccc1OCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred suspension of 9-bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-2-carboxylic acid ethyl ester (4.24 g; 12 mmol) in THF (40 ml) at room temperature was added a solution of NaOH (0.96 g; 24 mmol) in water (20 ml) followed by EtOH (20 ml). The reaction mixture was stirred at room temperature for 4 h (now a clear solution) upon which time it was quenched with 2M HCl (20 ml) and diluted with water (50 ml). The resulting solid was collected by filtration, washed with water and dried to give 9-bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-2-carboxylic acid as a white solid (3.64 g; 93%). δH (400 MHz, d6-DMSO) 3.22 (t, J=5.2, 2H), 4.31 (t, J=5.2, 2H), 7.02 (d, J=8.4, 1H), 7.43 (dd, J=8.4 and 2.4, 1H), 7.62 (s, 1H), 7.78 (d, J=2.4, 1H).
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:9][OH:10])[O:8][CH2:7][CH2:6]C[O:4]1.OC(O)C(=O)C>C(O)CO>[F:1][CH2:2][C:3]1([CH2:9][OH:10])[O:4][CH2:6][CH2:7][O:8]1
Reactant: OCC1(CF)OCCCO1
Agent: CC(=O)C(O)O
Solvent: OCCO
Product: OCC1(CF)OCCO1
Yield: 13.8 %

Procedure:
The same procedure as in the steps (44a) to (44c) using dihydroxyacetone except that ethylene glycol was used instead of 1,3-propanediol used in Example 44 to obtain the title compound (543 mg, total yield: 13.8%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:14][C:15]([F:33])([F:32])[C:16]1[CH:17]=[C:18]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1>C(N(CC)CC)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:29]2[CH2:28][CH2:27][N:26]([C:18]3[CH:17]=[C:16]([C:15]([F:33])([F:32])[F:14])[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=3)[CH2:31][CH2:30]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: FC(F)(F)c1cc(N2CCNCC2)cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCN(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)cc1

Procedure:
In the manner given in Example 1A, p-nitrobenzenesulfonyl chloride, 1-[3,5-di(trifluoromethyl)phenyl]piperazine and triethylamine are stirred at reflux to give 1-[(p-nitrophenyl)sulfonyl]-4-[3,5-di(trifluoromethyl)phenyl]piperazine.
Reaction SMILES: [CH:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[C:16]([F:19])([F:18])[F:17])[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=3)=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.C1CCCCC=1>>[CH:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[C:16]([F:17])([F:18])[F:19])[C:9]([C:20]3[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=3)=[N:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(-c2nn(C3CCCCC3)c3c(C(F)(F)F)cccc23)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: Oc1ccc(-c2nn(C3CCCCC3)c3c(C(F)(F)F)cccc23)cc1
Yield: 15.5 %

Procedure:
Prepared according to Method C step B from 1-cyclohexyl-3-(4-methoxyphenyl)-7-trifluoromethyl-1H-indazole (0.5 mmol), boron tribromide (0.188 mL, 2.0 mmol) and 0.2 mL of cyclohexene to give the product (0.028 g) as a tan solid.
Reaction SMILES: [C:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=2)[CH:10]=[N:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=2)[CH:10]=[N:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)n1ncc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1ncc2ccc(N)cc21
Reaction time: 12 h

Procedure:
To a stirring solution of 1-Boc-6-nitroindazole (2.5 g, 9.5 mmol) in ethyl acetate (75 mL) under nitrogen was added 10% Pd/C (500 mg). The mixture was placed under vacuum and the atmosphere was replaced with hydrogen (1 atm). After stirring for 12 h, the hydrogen balloon was removed and diatomaceous earth was added. The mixture was then filtered over a pad of diatomaceous earth and the solvent was removed by rotary evaporation to give 2.17 g (98%) of light pink solid.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH2:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:6]([CH3:8])[CH3:7].Br[C:16]([CH3:21])([CH3:20])[C:17](Br)=[O:18].Cl>C(Cl)Cl>[CH3:20][CH:16]1[CH2:21][C:13]2[C:12](=[CH:11][CH:10]=[C:9]([CH2:5][CH:6]([CH3:8])[CH3:7])[CH:14]=2)[C:17]1=[O:18]
Reactant: CC(C)Cc1ccccc1
Reactant: CC(C)(Br)C(=O)Br
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)Cc1ccc2c(c1)CC(C)C2=O
Temperature: 0 °C
Yield: 83 %

Procedure:
17.3 g (125 mmol) of aluminum trichloride were added with ice cooling to a solution of 6.7 g (50 mmol) of isobutyl benzene in 30 ml of methylene chloride. 11.9 g (52 mmol) of 2-bromoisobutyryl bromide were subsequently added rapidly, and the mixture was refluxed for 15 hours. The reaction mixture was poured into 100 ml of ice water, 25 ml of conc. aqueous HCl were added, and the mixture was extracted 3 times with 50 ml of diethyl ether in each case. The combined organic phases were washed with 50 ml each of saturated aqueous NaHCO3 solution and NaCl solution and dried (MgSO4). After removal of the solvent on a rotary evaporator, the crude product was chromatographed on 100 g of silica gel (hexane/methylene chloride 1:1), giving 8.4 g (83%) of 1 as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH:24]1([N:30]=[C:31]=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:31]([NH:30][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:32])=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-n2nc3ccccc3c2Nc2ccccc2)cc1
Reactant: O=C=NC1CCCCC1
Solvent: Cc1ccccc1
Product: O=C(NC1CCCCC1)N(c1ccccc1)c1c2ccccc2nn1-c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-phenyl-amine was reacted with cyclohexylisocyanate ([3173-53-3]) in toluene for 5 days under reflux conditions to give the title compound as yellow oil. MS: m/e=445.1 [M+H+].