Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:14])[CH:8]=[C:9]([N+:11]([O-])=O)[N:10]=1)=[O:5])[CH3:2].N1C=CN=C1.[CH3:20][N:21]1[CH:25]=[C:24]([NH:26][C:27]([O:29][CH2:30][CH2:31][S:32]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)(=[O:34])=[O:33])=[O:28])[CH:23]=[C:22]1[C:45](O)=[O:46].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC(=O)OCC.CN(C=O)C.C(Cl)Cl.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:14])[CH:8]=[C:9]([NH:11][C:45]([C:22]2[N:21]([CH3:20])[CH:25]=[C:24]([NH:26][C:27]([O:29][CH2:30][CH2:31][S:32]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:42])[F:43])=[CH:37][CH:36]=3)(=[O:34])=[O:33])=[O:28])[CH:23]=2)=[O:46])[N:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc([N+](=O)[O-])cn1C
Reactant: Cn1cc(NC(=O)OCCS(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1C(=O)O
Agent: [Pd]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1nc(NC(=O)c2cc(NC(=O)OCCS(=O)(=O)c3ccc(C(F)(F)F)cc3)cn2C)cn1C
Temperature: 25 °C
Reaction time: 10 h
Yield: 75.1 %

Procedure:
1-Methyl-4-nitroimidazole-2-carboxylic acid ethyl ester (71.05 mg, 0.3567 mmol) was dissolved in EA (10 ml) and 10% Pd/C (10 mg, catalytic weight) was added thereto. The reaction solution was stirred for 10 hours at room temperature under hydrogen atmosphere to reduce a nitro group (NO2) into an amino group (NH2), whereby an imidazole-type amino acid was obtained. 10% Pd/C was filtered out by celite 545 and the filtrate was washed with EA and methanol. 1-Methyl-4-[2-(4-trifluoromethyl-benzenesulfonyl)-ethoxycarbonylamino]-1H-pyrrole-2-carboxylic acid (49.98 mg, 0.1189 mmol) dissolved in a solvent mixture of anhydrous DMF (6 ml) and DCM (2 ml) was added thereto, PyBroP (166.29 mg, 0.3567 mmol) and DIEA (62.13 ml, 0.3567 mmol) were also added thereto, and the reaction solution was reacted according to the same procedure as Step (4-1) of Example 2 to give 1-methyl-4-({1-methyl-4-[2-(4-trifluoromethyl-benzenesulfonyl)ethoxycarbonylamino]-1H-pyrrole-2-carbonyl}-amino)--1H-imidazole-2-carboxylic acid ethyl ester (51.05 mg, 75.12%) of a pale yellow solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=2)O1.Br[C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[C:34]1[CH:43]=[CH:42][CH:41]=[C:40]2[C:35]=1[CH2:36][CH2:37][N:38]([S:44]([NH:47][C:48]1[S:52][N:51]=[CH:50][N:49]=1)(=[O:46])=[O:45])[CH2:39]2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O>[S:52]1[C:48]([NH:47][S:44]([N:38]2[CH2:37][CH2:36][C:35]3[C:40](=[CH:41][CH:42]=[CH:43][C:34]=3[C:25]3[CH:26]=[CH:27][C:28]([C:30]([F:33])([F:32])[F:31])=[CH:29][C:24]=3[C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH:10]=3)[CH2:39]2)(=[O:46])=[O:45])=[N:49][CH:50]=[N:51]1
Reactant: O=S(=O)(Nc1ncns1)N1CCc2c(cccc2-c2ccc(C(F)(F)F)cc2Br)C1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2-c2cccc3c2CCN(S(=O)(=O)Nc2ncns2)C3)CC1
Yield: 53 %

Procedure:
A solution of Cl2Pd(AmPhos) (Sigma-Aldrich, St. Louis, Mo., 0.136 g, 0.193 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Frontier Scientific, Logan, Utah, 1.191 g, 3.85 mmol), 5-(2-bromo-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (Example 4, 1.000 g, 1.925 mmol), and potassium phosphate (1.635 g, 7.70 mmol) in 20 mL dioxane, 10 mL water was heated to 120° C. for 2 hours. The reaction mixture was diluted with EtOAc and washed with 1 N citric acid solution. The organics were dried over MgSO4 and concentrated. Purification of the resulting residue by silica gel column chromatography (0 to 100% EtOAc/heptane) gave tert-butyl 4-(2-(2-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (0.635 g, 1.021 mmol). [M+H]+=522.0 1H NMR (400 MHz, Acetone-d6) δ ppm: 8.28 (s, 1H), 7.63-7.70 (m, 2H), 7.43 (d, J=7.8 Hz, 1H), 7.15-7.30 (m, 2H), 7.07 (d, J=7.4 Hz, 1H), 5.72 (s, 1H), 4.31-4.44 (m, 2H), 3.87 (br. s., 2H), 3.41-3.48 (m, 1H), 3.16-3.36 (m, 1H), 2.78 (br. s., 4H), 2.69 (m, 1H), 2.48-2.55 (m, 1H), 1.37-1.47 (m, 9H)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=O.[S:11]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)(=[O:14])(=[O:13])[NH2:12]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=[N:19][C:18]1[CH:20]=[CH:21][C:15]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:16][CH:17]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1ccc(C=O)cc1C
Product: Cc1ccc(C=Nc2ccc(S(N)(=O)=O)cc2)cc1C

Procedure:
Following a procedure similar to that described in Example 1(i), but using 3,4-dimethylbenzaldehyde and 4-sulfamoylaniline as starting materials, the title compound was obtained as a pale yellow powder (yield 45%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.B(F)(F)F.CCOCC>>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][C:16]=2[OH:20])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(O)c1
Reactant: O=C(O)Cc1cccc(F)c1
Agent: FB(F)F
Solvent: CCOCC
Product: COc1ccc(C(=O)Cc2cccc(F)c2)c(O)c1
Temperature: 65 °C
Reaction time: 9 h

Procedure:
(3-Fluorophenyl)acetic acid (3.7 g) and 3-methoxyphenol (3.0 g) were dissolved into BF3.Et2O (60 ml, 20 eq) under argon. The mixture was stirred at 60-70° C. until disappearance of the starting materials (9 h) and poured into large volume of ice water. After extraction with ethyl acetate the combined organic layers were washed with water, dried and evaporated. The crude product was purified by column chromatography using CH2Cl2 as an eluant. 1H NMR (400 MHz, d6-DMSO) δ: 12.41 (br s, 1H), 8.02 (d, 1H, J 9.0 Hz), 7.34-7.38 (m, 1H), 7.09-7.13 (m, 3H), 6.56 (dd, 1H, J 9.0, 2.5 Hz), 6.49 (d, 1H, J 2.5 Hz), 4.41 (s, 2H), 3.83 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH3:20])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH2:44][CH2:45][C:46]([C:48]1[C:49](=[O:59])[N:50]([CH3:58])[C:51]2[C:56]([CH:57]=1)=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:47].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH3:20])[C:10]([NH:44][CH2:45][C:46]([C:48]1[C:49](=[O:59])[N:50]([CH3:58])[C:51]2[C:56]([CH:57]=1)=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:47])=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1c(=O)c(C(=O)CN)cc2ccccc21
Reactant: CCC(=O)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCC(=O)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)c1cc2ccccc2n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (S)-2-((tert-butoxycarbonyl)amino)-8-oxodecanoic acid (0.76 mmol, 1 eq; prepared as described in J. Med. Chem. 2008, 51(8), pp 2350-2353), EDC.HCl (1 eq), HOBT (1 eq) in DMF (0.2 M) was stirred at room temperature for 10 min. 3-(2-aminoacetyl)-1-methylquinolin-2(1 H)-one (1.1 eq) in DMF (3 eq) was subsequently added, followed by DIPEA (2.2 eq) and the mixture was stirred at room temperature for 2 h. The mixture was diluted with DCM and washed with brine. The organic phase was dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (SiO2, Petroleum ether/EtOAc, from 10% EtOAc to 80% EtOAc), to give the title compound as an oil. MS (ES) C27H37N3O6 requires: 499.60, found: 500.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](I)[CH2:9][S:10]([C:13]2[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[C:4]([F:21])[CH:3]=1.CCN(CC)CC.OS([O-])(=O)=O.[Na+].O>CCOCC.C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[S:10]([C:13]2[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[C:4]([F:21])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)CC(I)c2ccc(Cl)cc2F)cc1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)/C=C/c2ccc(Cl)cc2F)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Crude 4-chloro-2-fluoro-1-(1-iodo-2-tosylethyl)benzene (51.8 g, max. 154 mmol) was dissolved in a mixture of Et2O (250 mL), THF (50 mL) and EtOAc (80 mL) after some warming. Carefully, Et3N (23.6 mL, 170 mmol) was added in 2 mL portions at room temperature. The mixture was stirred for 90 min at room temperature. Aqueous 1 M NaHSO4 (200 mL) and H2O (100 mL) were added and the organic layer was separated. The aqueous layer was extracted with EtOAc (50 mL). The combination of organic layers was washed with saturated aqueous NaHCO3 and with brine, dried (Na2SO4) and filtered. The solvent was evaporated in vacuo to give a yellow solid. The residue was triturated in MeOH (50 mL), filtration and air-drying provided 23.04 g (48% over two steps) of the desired product as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[CH:18][C:11]=12)[NH2:5].Cl[C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:23]=[C:22]([NH2:32])[N:21]=1.Cl.C(=O)(O)[O-].[Na+]>O>[NH2:32][C:22]1[N:21]=[C:20]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]4[NH:16][CH:17]=[CH:18][C:11]=34)=[C:2]([F:1])[CH:3]=2)[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:23]=1
Reactant: Nc1nc(Cl)cc(-c2ccncc2)n1
Reactant: Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1nc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)cc(-c2ccncc2)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
55.6 mg (230 μmol) of 3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)aniline (from example XIX) are suspended in 5 ml of water. 47.2 mg (230 μmol) of 4-chloro-6-(4-pyridinyl)-2-pyrimidineamine (from example XXIX) and 0.01 ml of concentrated hydrochloric acid are added, and the mixture is stirred at 100° C. overnight. For work-up, the reaction solution is made alkaline using saturated sodium bicarbonate solution and extracted 3× with ethyl acetate, and the extracts are dried over sodium sulfate and concentrated using a rotary evaporator. The residue is purified by preparative HPLC.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[S:3]([C:6]1[C:7]2[C:8]3[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=S)[C:9]=3[CH:16]=[CH:17][CH:18]=2)(=[O:5])=[O:4].[N:20]1([CH:25]([CH3:29])[CH2:26][CH2:27][NH2:28])[CH:24]=[CH:23][N:22]=[CH:21]1>C(O)C>[N:20]1([CH:25]([CH3:29])[CH2:26][CH2:27][NH:28][C:10]2[C:9]3[CH:16]=[CH:17][CH:18]=[C:7]4[C:8]=3[C:12](=[CH:13][CH:14]=[C:6]4[S:3]([N:2]([CH3:19])[CH3:1])(=[O:5])=[O:4])[N:11]=2)[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: CN(C)S(=O)(=O)c1ccc2c3c(cccc13)C(=S)N2
Reactant: CC(CCN)n1ccnc1
Solvent: CCO
Product: CC(CCNC1=Nc2ccc(S(=O)(=O)N(C)C)c3cccc1c23)n1ccnc1
Yield: 55.4 %

Procedure:
A mixture of 7.3 g of 1,2-dihydro-N,N-dimethyl-2-thioxobenz(cd)indole-6-sulfonamide, 4.2 g of 3-(1H-imidazol-l-yl)butanamine, 150 ml of ethanol and 9.6 g of mercuric acetate was reacted as described in Example 1, giving 5.5 g of the desired product, mp 221° C.-222° C.
Reaction SMILES: [F:1][C:2]1([F:15])[CH2:6][CH2:5][CH:4]([NH:7]C(=O)OC(C)(C)C)[CH2:3]1.C(Cl)Cl.[C:19]([OH:25])([C:21]([F:24])([F:23])[F:22])=[O:20]>>[F:1][C:2]1([F:15])[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3]1.[C:19]([OH:25])([C:21]([F:24])([F:23])[F:22])=[O:20]
Reactant: CC(C)(C)OC(=O)NC1CCC(F)(F)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCC(F)(F)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of tert-butyl 3,3-difluorocyclopentylcarbamate and DCM/TFA (50%, 7 mL) was stirred at 25° C. for 30 min. The reaction mixture was concentrated down and dried in vacuo to afford the title compound as an orange semi-solid, TFA salt (0.51 g, 99%). 1H NMR (400 MHz, DMSO-d6) δ 1.69-1.88 (m, 1 H) 2.00-2.22 (m, 3 H) 2.22-2.38 (m, 1 H) 2.56 (d, J=6.32 Hz, 1 H) 3.71 (d, J=5.31 Hz, 1 H) 8.20 (br. s., 3 H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:14]1([C:17](Cl)=[O:18])[CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C.CCOC(C)=O>ClCCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:17]([CH:14]2[CH2:16][CH2:15]2)=[O:18])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C1CC1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: O=C(C1CC1)N1CCN(Cc2ccccc2)CC1
Temperature: 50 °C
Reaction time: 15 h
Yield: 99.2 %

Procedure:
To a mixture of 1-benzyl-piperazine (1.20 g, 6.81 mmol) in anhydrous DCE (23 mL) was added cyclopropane carboxylic acid chloride (854 mg, 8.17 mmol, 1.2 eq) followed by diisopropylethylamine (1.3 mL, 7.49 mmol, 1.1 eq), and the reaction mixture was stirred at 50° C. under N2 for 15 h. The mixture was cooled to rt and poured into EtOAc. The organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by MPLC (Biotage®, gradient elution 75% EtOAc/hexane) to give the product (1.65 g, 99%) as a brown oil. 1H-NMR (300 MHz, DMSO-d6) 7.34 to 7.23 (m, 5H), 3.64 (broad s, 2H), 3.48 (s, 2H), 3.44 (broad s, 2H), 2.37 (broad s, 2H), 2.28 (broad s, 2H), 1.95 to 1.91 (m, 1H), 0.70 to 0.65 (m, 4H); ES-MS m/z 245.2 [M+H]+, RT (min) 1.12.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[N:10]=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4([NH:30]C(=O)OC(C)(C)C)[CH2:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:13][C:5]1=2)(=[O:3])[CH3:2]>Cl.CCOCC>[NH2:30][C:26]1([C:23]2[CH:22]=[CH:21][C:20]([C:11]3[C:12]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)=[CH:13][C:5]4[N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8][O:7][C:6]=4[N:10]=3)=[CH:25][CH:24]=2)[CH2:27][CH2:28][CH2:29]1
Reactant: CC(=O)N1CCOc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Agent: Cl
Solvent: CCOCC
Product: CC(=O)N1CCOc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 131.4 %

Procedure:
Tert-butyl (1-(4-(1-acetyl-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (20 mg, 0.04 mmol) was dissolved in 2M HCl in Et2O (1 ml). The resulting mixture was stirred overnight at room temperature and evaporated under reduced pressure. The deprotected compound was taken back twice into diethyl ether. The remaining solvent was removed under reduced pressure and dried to afford the title compound (21 mg, quantitative). LCMS (Method A): RT=3.87 min, M-16=383. 1H NMR (500 MHz, MeOD): 8.70 (1H, br s), 7.44-7.43 (4H,m), 7.30-7.28 (3H, m), 7.21-7.19 (2H, m), 4.63 (2H, t), 4.11 (2H, t), 2.75-2.70 (2H, m), 2.56-2.50 (2H, m), 2.42 (3H, s), 2.24-2.15 (1H, m), 1.97-1.88 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[C:9]([N:14]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:10][N:11](C)[CH3:12])[CH:5]=[CH:6][CH:7]=1.C[NH:27]N>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([NH2:14])=[CH:10][N:11]([CH3:12])[N:27]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CNN
Reactant: CN(C)C=C(C(=O)c1cccc(Cl)c1)N1C(=O)c2ccccc2C1=O
Solvent: CCO
Product: Cn1cc(N)c(-c2cccc(Cl)c2)n1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(3-(3-chlorophenyl)-1-(dimethylamino)-3-oxoprop-1-en-2-yl)isoindoline-1,3-dione (2.30 g, 6.48 mmol, 1 eq) in 50 mL ethanol was added N-methylhydrazine (1.4 mL, 26 mmol, 4.0 eq). The reaction mixture was stirred at 80° C. for 2 hours and then concentrated onto silica gel. The crude mixture of regioisomers was separated and purified by flash chromatography on silica gel (0 to 80% ethyl acetate in dichloromethane) to yield: 715 mg (53%) of 3-(3-chlorophenyl)-1-methyl-1H-pyrazol-4-amine LCMS (ESI) m+H=208.2; 1H NMR (400 MHz, CDCl3) δ: 7.78 (s, 1H), 7.63 (d, 1H), 7.33 (t, 1H), 7.25 (overlapping with CDCl3, 1H), 7.04 (s, 1H), 3.84 (s, 3H), and 274.6 mg (20%) of 5-(3-chlorophenyl)-1-methyl-1H-pyrazol-4-amine. LCMS (ESI) m+H=208.2; 1H NMR (400 MHz, CDCl3) δ: 7.43 (t, 1H), 7.38 (overlapping d and s, 2H), 7.27 (d, 1H), 7.23 (s, 1H), 3.76 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][OH:25])=[C:17]([O:26][CH3:27])[CH:16]=1.[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][OH:25])=[C:17]([O:26][CH3:27])[CH:16]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCCO)c(OC)c3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)ccc1OCCCO
Temperature: 70 °C
Reaction time: 24 h
Yield: 38.8 %

Procedure:
To a mixture of methyl 6-chloro-5-[4-(3-hydroxypropoxy)-3-methoxyphenyl]-1H-indole-3-carboxylate (92 mg, 0.24 mmol) in MeOH (5 mL) and water (2 mL) was added NaOH (94 mg, 2.4 mmol). The reaction mixture was heated at 70° C. and stirred for 24 hours. TLC (petroleum ether/ethyl acetate=1:1) showed the reaction was complete. The mixture was acidified by 1N HCl to pH 4 and extracted with ethyl acetate (10 mL×3). The combined organic layers was dried over sodium sulfate, filtered, and concentrated in vacuo to give a brown residue. It was purified by preparative HPLC to give the title compound (35 mg, 35% yield) as a white solid. MS (AP−) 398.1 (M+Na)−. 1H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 8.07 (s, 1H), 7.93 (s, 1H), 7.60 (s, 1H), 7.02 (d, 1H), 6.97 (s, 1H) 6.89 (dd, 1H), 4.04 (t, 2H), 3.77 (s, 3H), 3.51 (t, 2H), 1.88 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]([C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:7])[CH3:2].[CH3:16][N:17]([CH3:20])[CH:18]=O>OC1CCOC1>[CH2:1]([O:3][C:4](=[O:15])[C:5]([C:6]([C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:7])=[CH:16][N:17]([CH3:20])[CH3:18])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)CC(=O)c1ncccc1F
Agent: OC1CCOC1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1ncccc1F
Temperature: 50 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 3-(3-fluoro-pyridin-2-yl)-3-oxo-propionic acid ethyl ester (3) (15 mg, 0.07 mmol) in 3-hydroxytetrahydrofuran (2 mL) was added slowly dimethylformamide diethylacetale (0.085 mL, 0.5 mmol) at room temperature. The mixture was stirred at 50° C. for 6 h. After completion of the reaction, solvent was evaporated under vacuum to get the crude 3-dimethylamino-2-(3-fluoro-pyridine-2-carbonyl)-acrylic acid ethyl ester (4) (18 mg, crude) as a brown sticky liquid LC-MS: 267.4 (M+H). The crude compound was used in the next step without purification.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:31][C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O.O1CCCC1>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[C:13]([C:21]([F:22])([F:23])[F:24])[CH:12]=2)[C:8]([NH:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C(F)(F)F
Reactant: Nc1ccc2ccccc2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccc3ccccc3n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.2 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic acid (182 mg, 0.5 mmol) in methylene chloride (5.0 mL) was cooled to 0° C. and then treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.28 mL, 0.56 mmol) and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 15 min and at 25° C. for 30 min. The reaction mixture was then treated with a solution of 2-aminoquinoline (153 mg, 1.06 mmol) in tetrahydrofuran (2 mL) and triethylamine (0.17 mL, 1.20 mmol). This solution was stirred at 25° C. for 50 h. At this time, the reaction was concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica 70/30 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-quinolin-2-yl-propionamide (140.3 mg, 57.2%) as a pale yellow solid: mp 90-95° C.; EI-HRMS m/e calcd for C25H25F3N2O3S (M+) 490.1538, found 490.1532.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([C:9]([CH3:11])=[CH2:10])[CH2:4][CH2:3]1>O>[CH3:1][C@@H:2]1[CH2:7][C@H:6]([OH:8])[C@@H:5]([C:9]([CH3:11])=[CH2:10])[CH2:4][CH2:3]1
Reactant: C=C(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Solvent: O
Product: C=C(C)[C@H]1CC[C@H](C)C[C@@H]1O
Temperature: 2.5 °C
Reaction time: 8 h

Procedure:
The catalyst solution obtained in Example 7-1 was cooled to 0 to 5° C., and 1.54 g (10.0 mmol) of l-citronellal was added dropwise to the solution, followed by stirring at 0 to 5° C. overnight. After completion of the reaction, 2 ml of water was added to the reaction mixture, and an organic layer was analyzed with gas chromatography. As a result, substrate conversion was 89.2%, isopulegol conversion was 88.1%, and the ratio of l-n-isopulegol to the other isomers was 96.9:3.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][C@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:30][N:31]1[CH:35]=[CH:34][C:33]([NH2:36])=[N:32]1.C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][C@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=1)[C:12]([NH:36][C:33]1[CH:34]=[CH:35][N:31]([CH3:30])[N:32]=1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ccc(N)n1
Reactant: COC[C@@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC[C@@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C)n2)c1
Reaction time: 3 h

Procedure:
DMF (2 drops) was added to a solution of 3-(benzyloxy)-5-[(1R)-2-methoxy-1-methylethoxy]benzoic acid (3.79 g, 0.012 mol) and oxalyl chloride (1.25 mL, 0.015 mol) in DCM (60 mL) and stirred for 3 hours, following which the organics were removed in vacuo. The crude material was dissolved in DCM (30 mL) and slowly added, at 0° C., to a stirred suspension of 1-methyl-1H-pyrazol-3-amine (1.22 g, 0.013 mol) and triethylamine (3.5 mL, 0.025 mol) in DCM (30 mL). The mixture was stirred at ambient temperature for 24 hours and the organics evaporated in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with 1M aqueous hydrochloric acid (50 mL) and brine (50 mL), dried (MgSO4), filtered and evaporated in vacuo to give the crude product which was chromatographed on silica, eluting with a 50% ethyl acetate in isohexane, to give the desired compound. (4.23 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])[CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][S:8]2)=[CH:6][CH:7]=1
Reactant: CC(C)=CCSc1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)CCSc2cc(Br)ccc21
Yield: 86.6 %

Procedure:
A solution of 1-bromo-3-(3-methyl-but-2-enylsulfanyl)-benzene (5.651 g, 22 mmole) in 100 mL of toluene was treated with 5.433 g of p-toluenesulfonic acid monohydrate and heated at reflux for 15 hours. The mixture was diluted with 100 mL of water, neutralized with solid sodium bicarbonate and extracted with two 100 mL portions of ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The product was purified by short path distillation (T=190° C. at 1.08 Torr) to give 4.902 g of 7-bromo-4,4-dimethyl-thiochroman as a pale yellow oil, which contained approximately 20% 5-bromo-4,4-dimethyl-thiochroman.