Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:25]([CH2:26][C:27](O)=[O:28])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[ClH:30].Cl.[NH:32]1[CH2:36][CH2:35][N:34]=[C:33]1[C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][NH2:45])=[CH:39][CH:38]=1>>[ClH:30].[NH:34]1[CH2:35][CH2:36][N:32]=[C:33]1[C:37]1[CH:38]=[CH:39][C:40]([CH2:43][CH2:44][NH:45][C:27](=[O:28])[CH2:26][CH:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]2[S:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:11])=[O:10])=[CH:41][CH:42]=1
Reactant: NCCc1ccc(C2=NCCN2)cc1
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3C2CC(=O)O)cc1
Agent: Cl
Product: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3C2CC(=O)NCCc2ccc(C3=NCCN3)cc2)cc1

Procedure:
The title compound was prepared from [5-(4-methoxy-benzenesulfonyl)-5,6-dihydro-phenanthridin-6-yl]-acetic acid and 2-[4-(4,5-dihydro-1H-imidazol-2-yl)-phenyl]-ethylamine dihydrochloride (Reference Example 2) according to the method described in Example 1e. MS (EI) 581.6 (MH+).
Reaction SMILES: O.O[N:3]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:24]([O:28][C:29]([NH:31][C@H:32]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:33][C:34](O)=[O:35])=[O:30])([CH3:27])([CH3:26])[CH3:25].N>ClCCl>[NH2:3][C:34](=[O:35])[CH2:33][C@H:32]([NH:31][C:29](=[O:30])[O:28][C:24]([CH3:27])([CH3:26])[CH3:25])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)c1ccccc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-hydroxybenzotriazole hydrate (3.46 g, 25.6 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.91 g, 25.6 mmol), and (S)-N-tert-butoxycarbonyl-3-amino-3-phenylpropanoic acid (6.80 g, 25.6 mmol) in dichloromethane (250 ml) was stirred at room temperature for 1 hour. 0.88 Ammonia (20 ml) was added and the mixture stirred at room temperature for a further 18 hours. The resulting solid was filtered off and washed with sodium bicarbonate solution, then water and dried under vacuum at 50° C. to afford the title compound, 6.78 g.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:14][NH:15][CH3:16]>>[CH3:14][N:15]([CH3:16])[C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: CNC
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Product: CN(C)c1ccc([N+](=O)[O-])c(C(=O)O)c1

Procedure:
Concretely, 5-chloro-2-nitrobenzoic acid is dissolved in a dimethylamine aqueous solution and heated to produce 5-dimethylamino-2-nitrobenzoic acid. Hydrochloric acid is added to the reaction solution to precipitate out the product as a solid material. The solid material is separated to obtain 5-dimethylamno-2-nitrobenzoic acid almost quantitatively.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[C:20]([C:21]#[N:22])=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][OH:32])=[CH:25][CH:24]=4)[C:18]([C:33]#[N:34])=[CH:17][N:16]=3)[N:12]=2)=[CH:4][CH:3]=1.[CH:35]([NH2:38])([CH3:37])[CH3:36].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[C:20]([C:21]#[N:22])=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][OH:32])=[CH:25][CH:24]=4)[C:18]([C:33]#[N:34])=[C:17]([NH:38][CH:35]([CH3:37])[CH3:36])[N:16]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1cnc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: CC(C)N
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Nc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At RT, 60 mg (0.11 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-ylmethyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 0.011 ml (0.13 mmol) of isopropylamine were stirred in 1.5 ml of THF for 60 min. Another 11 μl (0.13 mmol) of isopropylamine were then added, and the mixture was stirred at RT for another 60 min. About 10 ml of water were added to the reaction mixture, and the precipitate formed was filtered off, washed with water and dried under high vacuum. This gave 35 mg (56% of theory) of the desired target compound.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=O)[CH:2]([CH3:4])[CH3:3].S(Cl)(Cl)(=O)=O.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22]([C:25](=[S:27])[NH2:26])=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[CH3:3][CH:2]([C:1]1[N:26]=[C:25]([C:22]2[CH:21]=[CH:20][C:19]([C:18]([F:28])([F:17])[F:29])=[CH:24][CH:23]=2)[S:27][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:4]
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)CC(=O)C(C)C
Solvent: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.1 %

Procedure:
Ethyl isobutyrylacetate (XI-3a) (3.006 g, 19.0 mmol) was dissolved in chloroform (20 mL). Sulfuryl chloride (1.70 mL, 21.2 mmol) was added and the solution was stirred at RT for 18 hours, then was concentrated. The residue was dissolved in ethanol (50 mL). 4-(Trifluoromethyl)benzenethioamide (4.234 g, 20.6 mmol) was added and the solution was heated to reflux for 24 hours. The mixture was cooled to RT and filtered. The solid was washed with cold ethanol and dried to provide the title product (2.68 g, 32%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J=8.1 Hz, 2H), 7.69 (d, J=8.1 Hz, 2H), 4.35 (q, J=7.1 Hz, 2H), 3.99 (qu, J=6.8 Hz, 1H), 1.39 (t, J=7.1 Hz, 3H), 1.35 (d, J=6.8 Hz, 6H).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=3Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:31].[C:33]1(C)[C:38]([OH:39])=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:31][C:7]1[CH:8]=[C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][C:21]=3[O:39][C:38]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:14]=2)[CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][C:3]([OH:2])=[O:32]
Reactant: Cc1ccccc1O
Reactant: COC(=O)CCc1ccc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Product: Cc1cc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3Oc3ccccc3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepare by reacting the compound of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester with o-cresol as in Example 45 to afford 0.229 g (21%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C30H25O5F3 522, found 523 (M+1, 100%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:45][CH:46]2[CH2:48][CH2:47]2)[C:6]2[N:11]=[C:10]3[N:12]([C:16]([CH3:19])([CH3:18])[CH3:17])[N:13]=[C:14]([CH3:15])[C:9]3=[CH:8][C:7]=2[CH2:20][N:21]([CH2:30][C:31]2[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[C:33]([C:41]([F:44])([F:43])[F:42])[CH:32]=2)[C:22]2[N:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][N:23]=2)[CH2:3][CH2:2]1.[OH-:49].[K+].OO>C(O)C>[CH:1]1([CH2:4][N:5]([CH2:45][CH:46]2[CH2:48][CH2:47]2)[C:6]2[N:11]=[C:10]3[N:12]([C:16]([CH3:17])([CH3:18])[CH3:19])[N:13]=[C:14]([CH3:15])[C:9]3=[CH:8][C:7]=2[CH2:20][N:21]([CH2:30][C:31]2[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[C:33]([C:41]([F:43])([F:44])[F:42])[CH:32]=2)[C:22]2[N:27]=[CH:26][C:25]([C:28]([NH2:29])=[O:49])=[CH:24][N:23]=2)[CH2:2][CH2:3]1
Reactant: Cc1nn(C(C)(C)C)c2nc(N(CC3CC3)CC3CC3)c(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3ncc(C#N)cn3)cc12
Reactant: [OH-]
Agent: OO
Agent: [K+]
Solvent: CCO
Product: Cc1nn(C(C)(C)C)c2nc(N(CC3CC3)CC3CC3)c(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3ncc(C(N)=O)cn3)cc12
Temperature: 40 °C

Procedure:
2-(((6-(Bis(cyclopropylmethyl)amino)-1-(tert-butyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)(3,5-bis(trifluoromethyl)benzyl)amino)pyrimidine-5-carbonitrile obtained in Example 10, (0.000074 mmol, 0.050 g) in ethanol was treated with 1% solution of KOH (5 ml) and catalytic amount of hydrogen peroxide. The reaction mixture was heated at 40° C. for 30 min. The reaction mixture was then concentrated under reduced pressure, treated with water and extracted with EtOAc. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by column chromatography using silica gel and 40% EtOAc in petroleum ether as eluent to obtain the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1>>[C:10]1([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:11]=[CH:12][C:7]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:8][CH:9]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: c1cn[nH]c1
Product: c1ccc(-c2ccc(-n3cccn3)cc2)cc1

Procedure:
Following general procedure A (90° C., 30 hours), 1H-pyrazole (205 mg, 3.0 mmol) is coupled with 4-bromo-1,1′-biphenyl (446 mg, 2.0 mmol). The crude brown oil is purified by flash chromatography on silica gel (eluent: dichloromethane/hexanes=50/50) to provide 410 mg (93% isolated yield) of the desired product as a white crystal.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19](C)[CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[C:24](O)(=[O:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31]>>[Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([CH:10]2[CH2:11][CH2:12][N:13]([C:24](=[O:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH2:14][CH2:15]2)[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[N:4][CH:3]=1
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(Cl)s2)C2CCNCC2)CC1
Reactant: O=C(O)CCCCCC(=O)O
Product: O=C(O)CCCCCC(=O)N1CCC(N(C(=O)Nc2ncc(Cl)s2)C2CCCCC2)CC1

Procedure:
Prepared as described in general procedure (G) using 3-(5-chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-piperidin-4-yl-urea and pimelic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[CH2:7][OH:8])([O-:3])=[O:2].[F:15][C:16]([F:42])([F:41])[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:40]=[CH:39][C:24]([C:25]([O:27][C:28]2[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36](O)=[O:37])=[CH:30][CH:29]=2)=[O:26])=[CH:23][CH:22]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[F:15][C:16]([F:41])([F:42])[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:40]=[CH:39][C:24]([C:25]([O:27][C:28]2[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]([O:8][CH2:7][C:6]3[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=3)=[O:37])=[CH:30][CH:29]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(O)/C=C/c1ccc(OC(=O)c2ccc(OCCCC(F)(F)F)cc2)cc1
Reactant: O=[N+]([O-])c1cc(CO)cc([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(OC(=O)c2ccc(OCCCC(F)(F)F)cc2)cc1)OCc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 7.2 %

Procedure:
1.00 g (51.0 mmol) of 3,5-dinitrobenzylalcohol, 2.00 g (51.0 mmol) of (2E)-3-(4-{[4-(4,4,4-trifluorobutoxy)benzoyl]oxy}phenyl)acrylic acid, 62 mg (0.51 mmol) of 4-Dimethylaminopyridine are dissolved in 10 ml of dichloromethane. 1.07 g (56.0 mmol) of N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC hydrochloride) are added at 0° C. The solution is stirred for 1 h at 0° C. and allowed to stir at room temperature overnight. After 22 hours at room temperature the reaction mixture is partitioned between dichloromethane and water. The organic phase is washed repeatedly with water, dried over sodium sulphate, filtered and concentrated by rotary evaporation to yield 3,5-dinitrobenzyl (2E)3-{4-[(4-(4,4,4-trifluorobutoxy)benzoyl)oxy]phenyl}acrylate 2.1 g as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:23])[CH:9]([NH:21][CH3:22])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[C:24]1([C:34](Cl)=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:23])[CH:9]([N:21]([CH3:22])[C:34]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)=[O:35])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CNC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C(=O)c1cccc2ccccc12)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.9 %

Procedure:
To a solution of (1RS,2SR)-1-(4-fluorophenyl)-2-(methylamino)-3-(4-(trifluoromethyl)phenyl)-1-propanol (150 mg, 0.46 mmol) in ethyl acetate (5 ml) were added 1-naphthoyl chloride (76 ml, 0.50 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred at room temperature for 6 hrs. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-1:1) and recrystallized from ethyl acetate-hexane to give the title compound (166 mg, 75%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=O)C.Cl.[NH2:15][C:16]([NH2:18])=[NH:17].CC(C)([O-])C.[K+]>CO>[NH2:17][C:16]1[NH:18][C:4](=[O:3])[CH:5]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:15]=1
Reactant: CCOC(=O)CC(=O)C1CCCC1
Reactant: N=C(N)N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: Nc1nc(C2CCCC2)cc(=O)[nH]1
Temperature: 60 °C
Yield: 87.6 %

Procedure:
To a solution of 3-cyclopentyl-3-oxo-propionic acid ethyl ester (5.0 g, 27.4 mmol) and guanidine hydrochloride (3.1 g, 33.0 mmol) in MeOH (50 mL) at 23° C. was added potassium tert-butoxide, portionwise (16.7 g. 149 mmol) over 15 min with vigorous stirring and the reaction warmed to 60° C. The reaction was cooled to room temperature (rt) and stirred overnight and the precipitated salt was removed by filtration. The solution was concentrated to approximately 10 mL then diluted with 10 mL of water and adjusted to pH=5 by the addition of 6.0 N HCl (6.1 mL). The resulting precipitate was filtered and dried via suction then vacuum to yield a white solid (4.3 g, 87%) that was used without further purification. 1H NMR (MeOD): 10.71-10.54 (m, 1H), 6.58-6.32 (m, 2H), 5.44-5.37 (m, 1H), 2.66 (p, J=8.1, 1H), 1.91-1.73 (m, 2H), 1.72-1.48 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[C:12]([OH:14])=O.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[C:20]([CH:23]=1)[C:21]#[N:22]>>[C:21]([C:20]1[CH:23]=[C:16]([NH:15][C:12]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]=2[CH3:11])=[O:14])[CH:17]=[CH:18][C:19]=1[O:24][CH2:25][C:26]([CH3:28])([CH3:27])[CH3:29])#[N:22]
Reactant: Cc1[nH]c2ccc(F)cc2c1C(=O)O
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Product: Cc1[nH]c2ccc(F)cc2c1C(=O)Nc1ccc(OCC(C)(C)C)c(C#N)c1
Yield: 30.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using 5-fluoro-2-methyl-1H-indole-3-carboxylic acid (1 g) and 5-amino-2-neopentyloxybenzonitrile (1.1 g), the title compound (0.6 g) was obtained. melting point: 169-171° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[CH2:19]([O:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1)[CH2:20][CH2:21][CH3:22]>>[CH2:19]([O:23][C:24]1[CH:25]=[CH:26][C:27]([NH:30][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=3)[N:3]=2)=[CH:28][CH:29]=1)[CH2:20][CH2:21][CH3:22]
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: CCCCOc1ccc(N)cc1
Product: CCCCOc1ccc(Nc2nc(Nc3cc(C)[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-butoxy-phenylamine to give N1-(4-butoxy-phenyl)-N3-(5-methyl-1H-pyrazol-3-yl)-isoquinoline-1,3-diamine. LC-MS m/e 388(MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([Br:18])[C:3]=1[N:19]([CH3:33])[C:20](=[O:32])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[C:22]=1[O:30][CH3:31].Cl>C(O)(C)C>[NH2:27][C:23]1[C:22]([O:30][CH3:31])=[C:21]([CH:26]=[CH:25][CH:24]=1)[C:20]([N:19]([C:3]1[C:2]([Br:1])=[CH:7][C:6]([C:8]([F:17])([C:9]([F:10])([F:11])[F:12])[C:13]([F:15])([F:16])[F:14])=[CH:5][C:4]=1[Br:18])[CH3:33])=[O:32]
Reactant: COc1c(C(=O)N(C)c2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Br)cccc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(C)O
Product: COc1c(N)cccc1C(=O)N(C)c1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1Br
Reaction time: 2.25 h

Procedure:
To a solution of N-[2,6-dibromo-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]-2-methoxy-N-methyl-3-nitro-benzamide (described above) (0.500 g, 0.612 mmole) in 5 ml isopropanol, under argon atmosphere was added stannous chloride (SnCl2, 0.558 g, 2.94 mmole) followed by concentrated hydrochloric acid (0.250 ml). The suspension was stirred under reflux conditions for 2.25 hours. The mixture was then concentrated under vacuum. The residue was treated with water and the product was extracted twice with ethyl acetate. The combined organic extracts were washed with water and dried over sodium sulfate. Afer removal of the solvent, the residue was purified by flash chromatography over silica gel with a mixture of 15% ethyl acetate and 85% cyclohexane. The title compound was obtained as a yellow oil with a retention time of 1.15 min and a M+H+ mass peak of 581 (LC-MS method 6 described after the tables).
Reaction SMILES: [CH2:1]([S:3]([NH:6][CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9][CH2:8]1)(=[O:5])=[O:4])[CH3:2].[H-].[Na+].[CH3:20]I>C1COCC1>[CH2:1]([S:3]([N:6]([CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9][CH2:8]1)[CH3:20])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)NC1CCCOc2ccccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)N(C)C1CCCOc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
A solution of 1.0 g (3.9 mmol) of 5-ethylsulfonylamino-2,3,4,5-tetrahydro-1-benzoxepine in 15 ml of THF were added dropwise under nitrogen to a suspension of 0.16 g (5.4 mmol) of 80 percent sodium hydride in 10 ml of THF. After stirring at RT for 3 h, 1.6 g (11 mmol) of methyl iodide were added dropwise and the mixture was additionally stirred overnight at RT. After distilling off the solvent, the residue was treated with water and extracted with EA. The organic phase was concentrated in vacuo after drying over sodium sulfate. 1.0 g of 5-(N-ethylsulfonyl-N-methylamino)-2,3,4,5-tetrahydro-1-benzoxepine was obtained, m.p. 122-124° C.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]#[CH:22].[Br:23]N1C(=O)CCC1=O>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[Br:23][C:22]#[C:21][C:3]1[C:4]([C:19]#[N:20])=[N:5][N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:15])([F:17])[F:16])=[CH:11][C:12]=2[Cl:13])[C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: C#Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1Cl
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(Cl)c1C#CBr
Reaction time: 1 h

Procedure:
To a stirred solution of 5-chloro-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)4-ethynylpyrazole (0.499 g) in acetone (5 ml) was added N-bromosuccinimide (0.244 g) followed by silver nitrate (0.023 g). Stirring was continued for one hour then the reaction mixture was evaporated to dryness. The residue was partitioned between ether and water. The aqueous layer was separated and extracted with ether. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel eluted with dichloromethane: hexane (1:1). Combination and evaporation of suitable fractions followed by recrystallisation from hexane provided the title compound as a white solid m.p. 152.9-153.4° C.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:8][CH2:7]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[CH2:31][C:32]1[CH:41]=[CH:40][CH:39]=[CH:38][C:33]=1[C:34]([O:36]C)=[O:35].O.[OH-].[Li+]>CO.O>[O:1]=[C:2]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:10][CH2:11]2)[N:5]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:4][N:3]1[CH2:31][C:32]1[CH:41]=[CH:40][CH:39]=[CH:38][C:33]=1[C:34]([OH:36])=[O:35]
Reactant: COC(=O)c1ccccc1CN1CN(c2ccccc2)C2(CCN(CCCn3c(=O)[nH]c4ccccc43)CC2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccccc1CN1CN(c2ccccc2)C2(CCN(CCCn3c(=O)[nH]c4ccccc43)CC2)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 2-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.27 g, 0.49 mmol) in methanol (3 mL) was added lithium hydroxide monohydrate (0.041 g, 0.98 mmol) in water (1 mL). After stirring at room temperature for 18 h, the reaction mixture was concentrated in vacuo and isolated by reverse phase HPLC to obtain the title compound as an acetate salt (0.124 g, 47%); 1H NMR (DMSO-d6): δ 1.68 (d, 2H, J=13.2 Hz), 1.85 (t, 2H, J=6.8 Hz), 2.42 (t, 2H, J=6.8 Hz), 2.59-2.65 (m, 2H), 2.71-2.75 (m, 4H), 3.85 (t, 2H, J=6.8 Hz), 4.61 (s, 2H), 4.90 (s, 2H), 6.74 (t, 1H, J=7.2 Hz), 6.83 (d, 2H, J=8.8 Hz), 6.96 (d, 3H, J=3.6 Hz), 7.18-7.26 (m, 4H), 7.39 (t, 1H, J=8 Hz), 7.55 (t, 1H, J=6.8 Hz), 7.89 (dd, 1H, J=8 and 1.2 Hz), 10.83 (s, 1H), 12.60 (br, 1H); MS for C31H33N5O4 m/z 540.01 (M+H)+.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>N1C=CC=CC=1.ClCCl>[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15]([NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=2)(=[O:17])=[O:16])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccccc2NS(=O)(=O)c2ccc(C)cc2)cc1
Yield: 95 %

Procedure:
To a solution in which 1,2-phenylenediamine (0.5 mmol) was dissolved in pyridine (1 mL) was added p-toluenesulfonyl chloride (1.1 mmol) at room temperature, and the mixture was reacted for 6 hours with stirring. After completion of the reaction, the reaction mixture was diluted with dichloromethane, and back extracted using 1N hydrochloric acid to remove pyridine. After the organic layer was dried with anhydrous sodium sulfate, and concentrated. The obtained solid was washed using diethyl ether on a Buchner funnel, and dried under reduced pressure to obtain an objective substance as a white solid in a yield of more than 95% yield.