Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([OH:24])[CH3:23])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:25](O)(=[O:29])[CH2:26][CH2:27][CH3:28]>>[C:25]([O:24][CH:22]([CH3:23])[CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:10][CH:11]=2)=[CH:16][CH:17]=1)(=[O:29])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCOc1ccc(-c2ccc(CC(C)O)cc2)cc1
Reactant: CCCC(=O)O
Product: CCCCCCCOc1ccc(-c2ccc(CC(C)OC(=O)CCC)cc2)cc1

Procedure:
Esterification of optically active 1-(4'-heptyloxybiphenyl-4-yl)-propane-2-ol (prepared from R-propylenoxide and 4'-heptyloxybiphenyl-4-yl-magnesiumbomide) with butyric acid in a similar way as described in example 2 yields optically active 1-(4'-heptyloxybiphenyl-4-yl)-2-propyl butyrate. In a similar way the following 2-propanol derivatives yield the corresponding esters by sterification with aliphatic carboxylic acids: ##STR60##
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Br[CH:21]([CH3:31])[C:22]([O:29][CH3:30])=[CH:23][C:24]([O:26]CC)=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH:21]([CH3:31])[C:22]([O:29][CH3:30])=[CH:23][C:24]([OH:26])=[O:25])=[CH:9][CH:10]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Reactant: CCOC(=O)C=C(OC)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=CC(=O)O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1

Procedure:
A mixture of 4-(2-chloro-4-trifluoromethylphenoxy) phenol (1.16 g), ethyl 4-bromo-3-methoxy-2-pentenoate (1.74 g) and potassium carbonate (0.73 g) in DMF (5 ml.) is heated at about 130° for 2 hours. Thereafter, DMF is removed. The residue is filtered and washed with methylene dichloride. The filtrate is washed, dried and evaporated to dryness. The oily residue is subjected to prep. thin layer chromatography using 20% ethylacetate/hexane to yield the ethyl ester of 4-[4-(2-chloro-4-trifluoromethylphenoxy) phenoxy]-3-methoxy-2-pentenoic acid, MS m/e 444 (M+).
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[CH:16][C:17](Cl)=[N:18][CH:19]=1.[CH3:23][O:24][N:25]=[C:26]([C:35]1[N:39]=[C:38]([CH3:40])[O:37][N:36]=1)[C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[OH:34]>CCOCC>[CH3:23][O:24][N:25]=[C:26]([C:35]1[N:39]=[C:38]([CH3:40])[O:37][N:36]=1)[C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[O:34][C:17]1[CH:16]=[CH:15][C:14]([C:13]([F:22])([F:21])[F:12])=[CH:19][N:18]=1
Reactant: CON=C(c1noc(C)n1)c1cc(Cl)ccc1O
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CON=C(c1noc(C)n1)c1cc(Cl)ccc1Oc1ccc(C(F)(F)F)cn1
Temperature: 110 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
N,N-Dimethylformamide (1 ml), potassium carbonate (0.10 g, 0.74 mmol) and 5-trifluoromethyl-2-chloropyridine (0.10 g, 0.56 mmol) were added to 5-chloro-2-hydroxyphenyl 5-methyl-1,2,4-oxadiazol-3-yl ketone O-methyloxime (0.10 g, 0.37 mmol), and the mixture was stirred at 110° C. for 2 hours. After completion of the reaction, ether (100 ml) was added, and the mixture was washed with saturated brine (80 ml) twice. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 5-chloro-2-(5-trifluoromethyl-2-pyridyloxy)phenyl 5-methyl-1,2,4-oxadiazol-3-yl ketone O-methyloxime (0.14 g, 91.7%) as a colorless oil.
Reaction SMILES: C([BH3-])#[N:2].[Na+].[C:5]([C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1)(=O)[CH2:6][CH2:7][CH3:8].C([O-])(=O)C.[NH4+]>CO>[NH2:2][CH:5]([C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1)[CH2:6][CH2:7][CH3:8]
Reactant: [BH3-]C#N
Reactant: CCCC(=O)c1ccc(C(=O)OCC)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCCC(N)c1ccc(C(=O)OCC)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Sodium cyanoborohydride (29.8 g, 0.450 mol) was added to a solution of Intermediate 1 (66.1 g, 0.300 mol) and ammonium acetate (236 g, 3.00 mol) in methanol (1000 mL). The solution was fitted with a reflux condenser and heated to 60° C. for 16 h. The solution was allowed to cool to room temperature. The reaction was quenched by dropwise addition of 1N HCl (300 mL) and allowed to stir at room temperature for 1 h. The reaction mixture was concentrated to remove methanol. This mixture was diluted by careful addition of 1N NaOH (500 mL) followed by extraction with dichloromethane (3×500 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by silica gel flash chromatography (methanol/dichloromethane) gave ethyl(+/−)-4-(1-aminobutyl)benzoate (Intermediate 2). 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J=8.2 Hz, 2H), 7.40 (d, J=8.2 Hz, 2H), 4.38 (q, J=7.2 Hz, 2H), 3.98 (t, J=6.9 Hz, 1H), 1.95 (br. s., 2H), 1.74-1.56 (m, 2H), 1.40 (t, J=7.1 Hz, 3H), 1.16-1.37 (m, 2H), 0.91 (t, J=7.4 Hz, 3H).
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:10]=[CH:9][C:8]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][N:20]=3)[CH2:17][NH:16][CH2:15][CH2:14]4)=[CH:7][N:6]=2)[CH2:4][CH2:3]1.[CH3:21][C@@:22]1([CH2:29][S:30](Cl)(=[O:32])=[O:31])[C:26](=[O:27])[NH:25][C:24](=[O:28])[NH:23]1>C(Cl)Cl.C1COCC1>[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][N:20]=3)[CH2:17][N:16]([S:30]([CH2:29][C@@:22]3([CH3:21])[NH:23][C:24](=[O:28])[NH:25][C:26]3=[O:27])(=[O:31])=[O:32])[CH2:15][CH2:14]4)=[CH:9][N:10]=2)[CH2:4][CH2:3]1
Reactant: C[C@]1(CS(=O)(=O)Cl)NC(=O)NC1=O
Reactant: c1nc(C2CC2)ncc1-c1cc2c(cn1)CNCC2
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@]1(CS(=O)(=O)N2CCc3cc(-c4cnc(C5CC5)nc4)ncc3C2)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
To a stirred solution of 6-(2-cyclopropylpyrimidin-5-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine hydrochloride (0.12 g, 0.42 mmol) in DCM (10 mL) was added TEA (0.12 mL, 0.84 mmol) followed by the dropwise addition of [(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl chloride (0.090 g, 0.40 mmol) in THF (10 mL) at −10° C. The mixture was stirred at RT overnight, concentrated, taken up in water (10 mL) and extracted four times with EtOAc. The combined organic phases were dried, filtered and concentrated. Purification by prep-HPLC gave 0.12 g (64%) of the title compound as a white solid.
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[CH:4]=O.[NH2:11][NH2:12]>C1COCC1>[I:10][C:6]1[CH:7]=[CH:8][N:9]=[C:2]2[NH:11][N:12]=[CH:4][C:3]=12
Reactant: O=Cc1c(I)ccnc1F
Reactant: NN
Solvent: C1CCOC1
Product: Ic1ccnc2[nH]ncc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 2-fluoro-4-iodonicotinaldehyde (11.33 g, 45.1 mmol) in THF (200 mL) was added hydrazine (5.67 ml, 181 mmol) dropwise. The resulting mixture was stirred at RT under a nitrogen atmosphere for 5 h. The reaction was concentrated, diluted with 10:1 acetone/MeOH and filtered through a pad of silica gel. Removed most of the solvent in vacuo, then diluted with some hexanes and filtered resulting solid. Dried to yield 4-iodo-1H-pyrazolo[3,4-b]pyridine as an off-white solid. MS m/z=246 [M+1]+. Calc'd for C6H4IN3: 245.02.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14](Cl)(=O)C(Cl)=O.CO>O1CCCC1>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
To a solution of 2-chloro-3-nitrobenzoic acid (100 g, 0.496 mol) in tetrahydrofuran (1000 mL) was added dropwise oxalyl chloride (46.8 mL, 0.546 mol) at 0° C., and the mixture was stirred at room temperature for 3 hr. To the mixture was added dropwise methanol (300 mL) at 0° C., and the mixture was stirred at room temperature for 14 hr. The mixture was concentrated and the residue was neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the solid, which was washed with n-hexane to give the title compound (103 g, 0.478 mol, 96%).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:24]([OH:26])=O)[CH2:9]2)=[O:7])[CH2:3]1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[N:36]O)[NH2:35])=[CH:30][CH:29]=1>>[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[N:36]=[C:24]([CH:10]3[CH2:11][CH:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][CH:15]=4)[CH2:13][N:8]([C:6]([N:4]4[CH2:5][CH:2]([OH:1])[CH2:3]4)=[O:7])[CH2:9]3)[O:26][N:35]=2)=[CH:30][CH:29]=1
Reactant: NC(=NO)c1ccc(F)cc1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CC(O)C2)C1
Product: O=C(N1CC(O)C1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3ccc(F)cc3)no2)C1

Procedure:
90.0 mg (0.242 mmol) of 1-[(3-hydroxyazetidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 101A) and 41.0 mg (0.266 mmol) of 4-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 52.1 mg (42% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10][C:11]([NH:13][C:14]1[C:18]([Cl:19])=[CH:17][S:16][CH:15]=1)=S.[OH-].[Na+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1COCC1.O>[Cl:19][C:18]1[C:14]([NH:13][C:11]2[NH:10][C:3]3[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=3[N:1]=2)=[CH:15][S:16][CH:17]=1
Reactant: Nc1cc(F)c(F)cc1NC(=S)Nc1cscc1Cl
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Fc1cc2nc(Nc3cscc3Cl)[nH]c2cc1F
Yield: 39.8 %

Procedure:
To 1-(2-amino-4,5-difluoro-phenyl)-3-(4-chloro-thiophen-3-yl)-thiourea (773 mg) in THF (20 ml) a solution of NaOH (240 mg) in water (9 ml) was added followed by a solution of p-toluenesulfonyl chloride (528 mg) in THF (10 ml). Following the analogous description in example 54b) the desired product (275 mg) was obtained.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[NH:25]([C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][C:35]=1[O:43][CH3:44])=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[C:26]1([NH:25][C:32](=[O:33])[C:34]2[CH:39]=[CH:38][C:37]([C:2]3[C:10]4[C:5](=[N:6][CH:7]=[N:8][C:9]=4[NH2:11])[N:4]([C@H:12]4[CH2:17][CH2:16][C@@H:15]([N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)[CH2:14][CH2:13]4)[N:3]=3)=[CH:36][C:35]=2[O:43][CH3:44])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1cc(B(O)O)ccc1C(=O)Nc1ccccc1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1C(=O)Nc1ccccc1

Procedure:
cis-3-Iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (148 mg, 0.335 mmol), 4-(anilinocarbonyl)-3-methoxyphenylboronic acid (100 mg, 0.369 mmol), palladium tetrakistriphenyphosphine (23 mg, 0.020 mmol) and sodium carbonate (85 mg, 0.845 mmol) were mixed with ethylene glycol dimethyl ether (4 mL) and water (2 mL). The reaction mixture was heated at reflux overnight. Organic solvent was removed under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (95:5) as mobile phase to give cis-N1-Phenyl-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxybenzamide (125 mg, 69%). 1H NMR (CDCl3) δ 1.69 (m, 2H), 1.86 (m, 2H), 2.17 (m, 2H), 2.31 (s, 3H), 2.44 (m, 11H), 4.15 (s, 3H), 4.96 (m, 1H), 5.69 (bs, 2H), 7.14 (m, 1H), 7.37 (m, 2H), 7.45 (m, 2H), 7.68 (m, 2H), 8.41 (m, 2H), 9.77 (s, 1H). LC/MS (Micromass-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min.(B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.5 mL/min.): MH+ =541.2, Rt=2.58 min.
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].[CH3:15][NH:16][CH3:17]>CCCCCC>[C:11]([N:3]1[CH:4]=[CH:5][N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[SiH:2]1[N:16]([CH3:17])[CH3:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CNC
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Solvent: CCCCCC
Product: CN(C)[SiH]1N(C(C)(C)C)C=CN1C(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 91 %

Procedure:
In an argon atmosphere, 3.98 g (17.1 mmol) of Si(tBuNCHCHNtBu)(H)Cl was dissolved in 20 mL of hexane. The resulting solution was deaerated by Freeze-Pump-Thaw cycling and after creating a dimethylamine atmosphere in the reaction vessel by connecting thereto a balloon having an internal volume of 5 L and being filled with dimethylamine, the solution was stirred at room temperature for 20 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 84° C./4.7×102 Pa) to obtain 1,3-di-tert-butyl-2-dimethylamino-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)NMe2) as a colorless liquid (yielded amount: 3.76 g, yield: 91%).
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:22]=[CH:21][C:11]([O:12][CH2:13][CH2:14][CH2:15]OS(C)(=O)=O)=[CH:10][CH:9]=2)[C:6](=[O:23])[CH:5]=[CH:4][C:3]=1[C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1.[CH:33]1([O:38][C:39](=[O:46])[C@H:40]([CH2:42][CH:43]([CH3:45])[CH3:44])[NH2:41])[CH2:37][CH2:36][CH2:35][CH2:34]1>>[NH2:1][C:2]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][CH2:15][NH:41][C@@H:40]([CH2:42][CH:43]([CH3:44])[CH3:45])[C:39]([O:38][CH:33]3[CH2:34][CH2:35][CH2:36][CH2:37]3)=[O:46])=[CH:21][CH:22]=2)[C:6](=[O:23])[CH:5]=[CH:4][C:3]=1[C:24](=[O:32])[C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1
Reactant: CS(=O)(=O)OCCCOc1ccc(-n2c(N)c(C(=O)c3ccc(F)cc3)ccc2=O)cc1
Reactant: CC(C)C[C@H](N)C(=O)OC1CCCC1
Product: CC(C)C[C@H](NCCCOc1ccc(-n2c(N)c(C(=O)c3ccc(F)cc3)ccc2=O)cc1)C(=O)OC1CCCC1

Procedure:
From Intermediate 4B and L-leucine cyclopentyl ester (Intermediate 8), LCMS purity 97%, m/z 564 [M+H]+, 1H NMR (400 MHz, d6-DMSO), δ: 0.90 (6H, m), 1.60-1.75 (10H, m), 1.90 (2H, m), 2.15 (2H, m), 3.10-3.30 (2H, m), 4.10 (1H, m), 4.15 (2H, m), 5.30 (1H, m), 5.70 (1H, d). 7.15 (2H, d), 7.30 (2H, d), 7.35 (2H, t), 7.50 (1H, d), 7.55 (1H, m) 9.05-30 (2H, m).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.Cl.[F:15][C:16]([F:21])([F:20])[CH2:17][CH2:18][NH2:19].CCN(C(C)C)C(C)C>CS(C)=O>[F:11][C:10]([F:13])([F:12])[C:4]1[CH:3]=[C:2]([NH:19][CH2:18][CH2:17][C:16]([F:21])([F:20])[F:15])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: NCCC(F)(F)F
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(NCCC(F)(F)F)cc1C(F)(F)F
Temperature: 200 °C
Yield: 60.8 %

Procedure:
A mixture of 4-fluoro-2-(trifluoromethyl)benzonitrile (0.158 g, 0.84 mmol), (3,3,3-trifluoropropyl)amine hydrochloride (0.125 g, 0.84 mmol) and DIEA (0.326 g, 2.52 mmol) in 1.5 mL of DMSO was heated in a microwave at 200° C. for 20 min. Upon cooling, the mixture was partitioned between Et2O and 0.1N HCl. The organic phase was washed with 0.1N HCl (×2) and brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (10-80% EtOAc-hexanes gradient) and the product crystallized from Et2O-hexanes to give 0.144 g (61% yield) of the title compound: 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J=8.6 Hz, 1H), 6.87 (d, J=2.4 Hz, 1H), 6.71 (dd, J=8.6, 2.4 Hz, 1H), 4.56 (bs, NH), 3.53 (q, J=6.5 Hz, 2H), 2.51-2.40 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(N(CC)CC)C.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>CC(C)=O>[OH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=1)(=[O:24])=[O:23]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccccc1O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Nc2ccccc2O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.4 %

Procedure:
A flask with a stirrer was charged with 10.9 g of 2-aminophenol, 10.1 g of triethylamine and 100 ml of acetone, and a solution of 19.1 g of p-toluenesulfonyl chloride in 50 ml of acetone was dropwise added with cooling with ice over 30 minutes. After completion of the addition, the reaction mixture was stirred at room temperature for 2 hours and then poured into 500 ml of ice water. A precipitated crystal was recovered by filtration and washed with water. The obtained crystal was recrystallized from ethyl acetate/n-hexane mixed solvents, to give 13.0 g of an end product. Melting point 140.0° C.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:12]2[O:11][CH:10]([C:13]([O:15]CC)=[O:14])[O:9][C:8]=2[CH:7]=[C:6]([C:18]([C:20]2[N:24]([CH3:25])[N:23]=[CH:22][CH:21]=2)=[O:19])[C:5]=1[Cl:26]>O.C(O)C>[Cl:3][C:4]1[C:12]2[O:11][CH:10]([C:13]([OH:15])=[O:14])[O:9][C:8]=2[CH:7]=[C:6]([C:18]([C:20]2[N:24]([CH3:25])[N:23]=[CH:22][CH:21]=2)=[O:19])[C:5]=1[Cl:26]
Reactant: CCOC(=O)C1Oc2cc(C(=O)c3ccnn3C)c(Cl)c(Cl)c2O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1nccc1C(=O)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
A solution of 0.36 g of sodium hydroxide in 15 ml of water is added to a suspension of 1.86 g of ethyl 4,5-dichloro-6-(1-methyl-5-pyrazolylcarbonyl)-1,3-benzodioxole-2-carboxylate in 35 ml of ethanol and the mixture is stirred at room temperature for 0.5 hour. The reaction mixture is concentrated to remove ethanol and adjusted to pH 1 with aqueous 10% hydrochloric acid. The resultant crystals are collected by filtration, washed successively with water and isopropyl ether and dried to give 1.66 g of 4,5-dichloro-6-(1-methyl-5-pyrazolylcarbonyl)-1,3-benzodioxole-2-carboxylic acid. Yield: 97%
Reaction SMILES: [CH2:1]([O:8][C:9]1([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:31][C:32]1[N:33]=[C:34]([CH3:37])[S:35][CH:36]=1>>[CH2:1]([O:8][C:9]1([C:19]([N:21]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:31][C:32]2[N:33]=[C:34]([CH3:37])[S:35][CH:36]=2)=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(CCl)cs1
Reactant: COc1ccc(NC(=O)C2(OCc3ccccc3)CCCc3ccccc32)cc1
Product: COc1ccc(N(Cc2csc(C)n2)C(=O)C2(OCc3ccccc3)CCCc3ccccc32)cc1
Yield: 78.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 132 using 5 benzyloxy -N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.63 g) and 4-(chloromethyl)-2-methylthiazole (0.30 g) as starting materials, 5 benzyloxy-N-(4-methoxyphenyl)-N-[(2-methylthiazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.64 g) was obtained. By the reaction and treatment in the same manner as in Example 133 using this compound (0.50 g), 5-hydroxy-N-(4-methoxyphenyl)-N-1(2-methylthiazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.31 g) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][S:7]([O-])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Na+].S(Cl)([Cl:16])=O>CN(C)C=O>[CH3:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][S:7]([Cl:16])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(CS(=O)(=O)[O-])cc1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(CS(=O)(=O)Cl)cc1
Temperature: -10 °C

Procedure:
In dimethylformamide (90 ml) is dispersed sodium p-methylbenzylsulfonate (30 g, 0.145 mol) which is sufficientry dry. The dispersion is cooled to -10° C. and under stirring, thionyl chloride (19.2 ml, 0.29 mol) is added dropwise. The mixture is stirred at room temperature for 3 hours and poured in ice-water (500 g) and extracted with ether (3 times, 150 ml each). The ethereal layers are combined, washed twice with cold water and dried over sodium sulfate. The ether is distilled off and petroleum ether is added to the crystalline residue, followed by cooling. The crystals are collected by filtration.
Reaction SMILES: Cl.CCO.[Cl:5][C:6]1[CH:13]=[C:12]([C:14]2[N:18](C3CCCCO3)[N:17]=[CH:16][CH:15]=2)[CH:11]=[CH:10][C:7]=1[C:8]#[N:9]>>[ClH:5].[Cl:5][C:6]1[CH:13]=[C:12]([C:14]2[CH:15]=[CH:16][NH:17][N:18]=2)[CH:11]=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(-c2ccnn2C2CCCCO2)cc1Cl
Agent: Cl
Solvent: CCO
Product: N#Cc1ccc(-c2cc[nH]n2)cc1Cl
Temperature: 10 °C
Reaction time: 2 h
Yield: 166.6 %

Procedure:
HCl/EtOH ˜10% (35.1 ml, 115 mmol) was set into the reaction flask under nitrogen atmosphere. 2-Chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-benzonitrile (12 g, 46.2 mmol) was added. The mixture was cooled to 10° C. and agitated for 2 h. Temperature was set to 0° C. and the mixture was stirred additional 2 hours. The precipitation was filtered, washed with ethanol and dried under vacuum overnight to obtain 9.24 g of the title compound. 1H-NMR (400 MHz, DMSO-d6): δ 6.99 (d, 3H), 7.86 (d, 1H), 7.96-8.02 (m, 2H), 8.14-8.17 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([S:27]([NH:30][CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[C:22]([S:27]([NH:30][CH2:31][C:32]([CH3:34])([CH3:33])[CH3:35])(=[O:28])=[O:29])[CH:23]=[CH:24][C:25]=1[CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)NCC(C)(C)C)cc1Br
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: Cc1ccc(S(=O)(=O)NCC(C)(C)C)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 3-bromo-N-(2,2-dimethyl-propyl)-4-methyl-benzenesulfonamide (Intermediate 145), the title compound was obtained after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.