Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][C:5]1([CH3:23])[O:9][N:8]=[C:7]([S:10][CH2:11][C:12]2[C:13]([C:19]([F:22])([F:21])[F:20])=[N:14][N:15]([CH3:18])[C:16]=2F)[CH2:6]1.O>CO>[CH3:4][C:5]1([CH3:23])[O:9][N:8]=[C:7]([S:10][CH2:11][C:12]2[C:13]([C:19]([F:22])([F:21])[F:20])=[N:14][N:15]([CH3:18])[C:16]=2[O:2][CH3:1])[CH2:6]1
Reactant: Cn1nc(C(F)(F)F)c(CSC2=NOC(C)(C)C2)c1F
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1c(CSC2=NOC(C)(C)C2)c(C(F)(F)F)nn1C
Reaction time: 4 h
Yield: 96.6 %

Procedure:
0.77 g (4.0 mmoles) of sodium methoxide (a 28% methanol solution) was added to a solution of 0.5 g (1.6 mmoles) of 5,5-dimethyl-3-(5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline dissolved in 20 ml of methanol. The mixture was stirred for 4 hours under refluxing, to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 0.5 g (yield: 96.7%) of 5,5-dimethyl-3-(5-methoxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline as a yellow oily substance.
Reaction SMILES: [C:1]1(=[O:12])[O:7][C:5](=O)[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1.[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17].CO>C1(C)C=CC=CC=1.C(Cl)Cl>[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][N:17]1[C:1](=[O:12])[CH2:2][C:3]2[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5]1=[O:7]
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: NCc1ccccc1F
Solvent: CO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C1Cc2ccccc2C(=O)N1Cc1ccccc1F
Yield: 68.2 %

Procedure:
A mixture of 800 mg (4.9 mmol) homophthalic anhydride, 680 mg (5.4 mmol) 2-fluorobenzylamine and 500 mg 4 Å molecular sieves in 1.5 mL toluene was stirred and heated at reflux overnight. A solution of 30% MeOH in CH2Cl2 was added, the resulting hot mixture filtered and the tiltrate concentrated to give 900 mg 2-(2-fluorobenzyl)-4H-isoquinoline-1,3-dione, mp 140°-144° C. A 500 mg (1.86 mmol) portion of this product was combined with 570 mg (3.71 mmol) DBU in 5 mL CH2Cl2 under argon, and cooled to -10° C. Isopropylsulfonyl chloride (290 mg, 2.04 mmol) was added, and after stirring 15 min the reaction was allowed to warm to room temperature. After 4 hr the reaction was diluted with EtOAc and worked up as in Example 1 giving 329 mg of the title compound, mp 174°-181° C.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:27][N:28](C=O)[CH3:29].CNC>O.C1COCC1>[CH3:27][N:28]([CH3:29])[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: CN(C)C=O
Agent: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)c1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 60 °C

Procedure:
To a mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.14 g of potassium carbonate and 3 ml of DMF, 3 ml of a THF solution of dimethylamine was added and stirred while heating at 60° C. for 3.3 hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the resultant crystals were washed with diethyl ether to give 0.27 g of dimethyl-{4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridin-3-yl}amine (hereinafter, referred to as “active compound 131”).
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([CH:29]=[CH2:30])(=[O:28])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1.Cl.[CH:39]12[O:46][CH:43]([CH2:44][CH2:45]1)[CH2:42][NH2+:41][CH2:40]2.CCN(C(C)C)C(C)C>O1CCOCC1>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:21][CH2:22][N:23]([S:26]([CH2:29][CH2:30][N:41]4[CH2:40][CH:39]5[O:46][CH:43]([CH2:44][CH2:45]5)[CH2:42]4)(=[O:28])=[O:27])[CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1
Reactant: C=CS(=O)(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Reactant: C1CC2C[NH2+]CC1O2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCN3CC4CCC(C3)O4)CC2)n1
Temperature: 25 °C
Reaction time: 60 h
Yield: 64.9 %

Procedure:
A mixture of 2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole (Example 3) (150 mg, 0.280 mmol), 8-oxa-3-azoniabicyclo[3.2.1]octane hydrochloride (209 mg, 1.40 mmol), and DIPEA (0.49 mL, 2.80 mmol) in 1,4-dioxane was stirred at room temperature for 2.5 days. Additional 8-oxa-3-azoniabicyclo[3.2.1]octane hydrochloride (84 mg, 0.561 mmol) was added and the mixture refluxed for 1 hr. The solvent was removed under vacuum, and the residue was diluted with water. The resulting precipitate was dissolved in CH2Cl2 and dried (Na2SO4). The solvent was removed under vacuum. Chromatography on silica eluting with CH2Cl2/MeOH (98:2), followed by recrystallization from CH2Cl2/hexanes gave 3-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-8-oxa-3-azabicyclo[3.2.1]octane (118 mg, 87%): mp 219-221° C.; 1H NMR (CDCl3) δ 7.85 (dd, J=8.4, 0.5 Hz, 1H), 7.43 (t, JHF=53.5 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 6.82 (d, J=7.7 Hz, 1H), 4.26 (m, 2H), 4.05 (s, 3H), 4.01 (br s, 4H), 3.88 (br s, 4H), 3.79 (m, 4H), 3.38 (t, J=5.0 Hz, 4H), 3.07 (dd, J=8.1, 6.3 Hz, 2H), 2.79 (dd, J=8.1, 6.3 Hz, 2H), 2.55 (d, J=10.6 Hz, 2H), 2.38 (dd, J=10.9, 2.0 Hz, 2H), 1.83 (m, 4H); Anal. Calcd. for C28H37F2N9O5S: C, 51.8; H, 5.7; N, 19.4. Found: C, 51.8; H, 5.9; N, 19.3%.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10]C(C(O)=O)=[CH:5][CH:4]=1.C([O:15][C:16](=[O:18])[CH3:17])(=O)C.[C:19]([O-])(=[O:21])[CH3:20]>N1C=CC=CC=1>[C:19]([N:2]([C:3]1[CH:4]=[CH:5][C:17]([C:16]([OH:15])=[O:18])=[CH:10][CH:11]=1)[CH3:1])(=[O:21])[CH3:20]
Reactant: CNc1ccc(C(=O)O)cc1
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)[O-]
Solvent: c1ccncc1
Product: CC(=O)N(C)c1ccc(C(=O)O)cc1
Temperature: 25 °C

Procedure:
To a solution of N-methyl-4-aminobenzoic acid (2.0 g, 13.2 mmol) in anhydrous pyridine (13.2 mL) was added acetic anhydride (1.4 mL, 14.5 mmol). The reaction was stirred at ambient temperature until TLC indicatedcomplete reaction (~22 hours). The resultant solution was poured intoethyl acetate and the organic phase was washed (3×, 10% HCl; 1×, water; 1×, brine), dried (MgSO4), filtered and concentrated in vacuo to provide the amide as a colorless solid. Recrystallization (ethyl acetate/hexane) afforded 4-(N-acetyl-N-methylamino)benzoic acid (2.15 g, 84.0%). 1H NMR (300 MHz, CDCl3) d 8.18 (2H, br d, J=8.5 Hz), 7.33 (2H, br d, J=8.5 Hz), 3.33 (3H, s), 2.0 (3H, br s). MS m/e 194 (M+H)+, 211 (M+NH4)+.
Reaction SMILES: [NH2:1][C:2]([CH3:15])([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([OH:14])[CH:8]=1)[C:3]([OH:5])=[O:4].N([C:18](C)([CH2:22][C:23]1C=CC(O)=C(OC)C=1)[C:19](O)=O)N>>[NH2:1][C:2]([CH3:15])([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([OH:14])[CH:8]=1)[C:3]([O:5][CH2:19][CH2:18][CH2:22][CH3:23])=[O:4]
Reactant: COc1cc(CC(C)(NN)C(=O)O)ccc1O
Reactant: CC(N)(Cc1ccc(O)c(O)c1)C(=O)O
Product: CCCCOC(=O)C(C)(N)Cc1ccc(O)c(O)c1
Yield: 82 %

Procedure:
The procedure of Example 1 was repeated employing 2-amino-2-methyl-3-(3,4-dihydroxyphenyl)propionic acid rather than 2-hydrazino-2 -methyl-3-(4-hydroxy-3-methoxyphenyl)propionic acid. The butyl (±)-2-amino-2-methyl-3-(3,4-dihydroxyphenyl)propionate was obtained in a yield of 82%. The product was recrystallized from acetonitrile (77% yield) to give pure ester: mp 121.5 ° C. to 122.0° C.; HPLC analysis (C-18 column, 280 nm, tR =14.5 min) showed >99% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15].[I:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1>>[I:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])[N:6]([C@@H:11]3[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]3[O:13][C:14](=[O:16])[CH3:15])[CH:5]=2)=[O:40])=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C(=O)c3ccc(I)cc3)c3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
4-Chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indole obtained in Example 1-(3) and 4-iodobenzoyl chloride were treated in a manner similar to Example 2-(4) to give 4-chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indol-3-yl 4-iodophenyl ketone as a colorless powder. APCI-Mass m/Z 711/713 (M+H). 1H-NMR (DMSO-d6) δ 1.69 (s, 3H), 1.97 (s, 3H), 1.98 (s, 3H), 2.04 (s, 3H), 4.10 (d, J=4.0 Hz, 2H), 4.29 (m, 1H), 5.28 (t, J=9.8 Hz, 1H), 5.53 (t, J=9.6 Hz, 1H), 5.73 (t, J=9.2 Hz, 1H), 6.33 (d, J=9.0 Hz, 1H), 7.29 (d, J=7.7 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.57 (d, J=8.3 Hz, 2H), 7.79 (d, J=8.4 Hz, 1H), 7.94 (d, J=8.3 Hz, 2H), 8.17 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:23][C@H:24]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@H:25]([OH:30])[C:26]([O:28]C)=[O:27])=[O:22])[N:4]=1)#[N:2].O.CCOC(C)=O.Cl>CO.[OH-].[Na+]>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:23][C@H:24]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@H:25]([OH:30])[C:26]([OH:28])=[O:27])=[O:22])[N:4]=1)#[N:2]
Reactant: COC(=O)[C@@H](O)[C@@H](Cc1ccccc1)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: N#Cc1nc(C(=O)N[C@H](Cc2ccccc2)[C@H](O)C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(2S,3R)-Methyl 3-(1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxamido)-2-hydroxy-4-phenylbutanoate (4 mg, 0.01 mmol) was dissolved in MeOH (2 mL) and 2 N NaOH (2 mL). After stirring for 6 hours at room temperature, H2O (15 mL) and EtOAc (15 mL) were added. To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-30% MeOH/CH2Cl2) to give the title compound in 3 mg. MS: (−) m/z 482.30 (M−1).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:4]([CH:5]=[C:6]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:3]1[C:19]([O-:21])=[O:20].CO.Cl>O>[CH3:1][C:2]1([CH3:22])[CH:4]([CH:5]=[C:6]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[CH:3]1[C:19]([OH:21])=[O:20]
Reactant: CC(C)(C)OC(=O)C(=CC1C(C(=O)[O-])C1(C)C)OC(C)(C)C
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)C(=CC1C(C(=O)O)C1(C)C)OC(C)(C)C
Temperature: 20 °C
Reaction time: 6 h

Procedure:
A mixture of 590 mg Sof the product of Step B, 20 ml of methanol, 10 ml of acetane and 20 ml of aqueous N hydrochloric acid was stirred at 20° C. for 6 hours and was poured into water. The mixture was extracted with methylene chloride and the organic phase was evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 4-6 hexane-ethyl acetate mixture to obtain 364 mg of (1R,transΔZ) 2,2-dimethyl-3-[2-tert.-butoxy-2-tert.-butoxycarbonyl-ethenyl]-cyclopropane-carboxylic acid melting at 85° C.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([C:12]#[N:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:14][C:15]([F:25])([F:24])[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH2:20].[C:26]([O-:29])([O-])=[O:27].[K+].[K+]>C(O)(C)C>[F:14][C:15]([F:24])([F:25])[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH:20][C:2]1[C:11]2[C:6](=[C:7]([C:12]#[N:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:26]([OH:29])([C:15]([F:25])([F:24])[F:14])=[O:27]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cccc2c(Br)ccnc12
Reactant: NCc1cccc(C(F)(F)F)c1
Agent: [K+]
Solvent: CC(C)O
Product: N#Cc1cccc2c(NCc3cccc(C(F)(F)F)c3)ccnc12
Product: O=C(O)C(F)(F)F
Temperature: 110 °C

Procedure:
To a suspension of 4-bromoquinoline-8-carbonitrile (100 mg, 0.43 mmol) in 4 mL of isopropanol, 3-(trifluoromethyl)benzylamine (150 mg, 0.85 mmol, 2.0 equiv.) and K2CO3 (119 mg, 0.85 mmol, 2.0 equiv.) were added. The resulting mixture was stirred at 110° C. 2 days. After work-up, the crude was purified by preparative HPLC to yield the title compound as TFA salt in 20% yield. 1HNMR (in MeOD): 4.96 (s, 2H), 6.96 (d, J=7.0 Hz, 1H), 7.58-7.71 (m, 3H), 7.76 (s, 1H), 7.86 (dd, J=7.7 and 8.8 Hz, 1H), 8.39 (d, J=7.3 Hz, 1H), 8.44 (dd, J=1.1 and 7.3 Hz, 1H), 8.75 (dd, J=1.1 and 8.8 Hz, 1H). Mass: M+H+: 328.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[O:10][C:11]=2[C:12]([F:15])([F:14])[F:13])=[CH:3][CH:2]=1.ClCCl.[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>N1C=CC=CC=1>[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([NH:22][C:19]1[CH:20]=[CH:21][C:16]([C:9]2[O:10][C:11]([C:12]([F:15])([F:13])[F:14])=[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[N:8]=2)=[CH:17][CH:18]=1)=[O:30]
Reactant: Nc1ccc(-c2nc(-c3ccncc3)c(C(F)(F)F)o2)cc1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(-c2nc(-c3ccncc3)c(C(F)(F)F)o2)cc1)c1ccccc1Cl

Procedure:
to a stirred mixture of 4-(4-(pyridin-4-yl)-5-(trifluoromethyl)oxazol-2-yl)benzenamine (214 mg, 701 mop and pyridine, anhydrous (0.567 ml, 7011 μmol) in dichloromethane (5.00 ml, 77709 μmol) at room temperature was added 2-chlorobenzoyl chloride (0.0979 ml, 771 μmol) all at once by metered pipet. The reaction was stirred for an hour then concentrated under reduced pressure, taken up in heptane and concentrated under reduced pressure again. The residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic separation was dried over magnesium sulfate, filtered and filtrate concentrated under reduced pressure to afford a colorless solid. ESI+ m/z=444.1 [MH]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]([OH:20])=O)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O=S(Cl)[Cl:23]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]([Cl:23])=[O:20])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C(=O)O)ccc2C1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2cc(C(=O)Cl)ccc2C1

Procedure:
To a suspension of 3,4-dihydro-1H-isoquinoline-2,6-dicarboxylic acid 2-tert-butyl ester (96 mg, 0.348 mmol) in toluene (4 mL) is added SOCl2 (254 μL, 10 eq.). The mixture is heated to reflux for 3 hours. All the solvent is removed under reduced pressure. The residue is redissolved in toluene and evaporated to dryness twice to remove excess HCl and is dried under high vacuum for 2 hours to give crude 6-chlorocarbonyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3]1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl.O>[CH3:22][S:23]([O:1][C@@H:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:3]1)(=[O:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](OS(C)(=O)=O)C1
Temperature: 2.5 °C
Yield: 91.2 %

Procedure:
To a solution of tert-butyl N-[(1S,3R)-3-hydroxycyclopentyl]carbamate (3.0 g, 14.91 mmol, 1.00 equiv) and triethylamine (3.0 g, 29.65 mmol, 1.99 equiv) in dichloromethane (50 mL) was added methanesulfonyl chloride (2.2 g, 19.21 mmol, 1.29 equiv) dropwise with stirring at 0-5° C. After addition was completed, the reaction mixture was warmed to room temperature and stirred at room temperature for 2 h. The mixture was diluted with 50 mL of water and extracted with 2×50 mL of ethyl acetate. The combined organic layers was washed with 2×30 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 3.8 g (91%) of tert-butyl N-[(1S,3R)-3-(methane sulfonyloxy)cyclopentyl]carbamate as a white solid.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[S-:15][C:16]#[N:17].[NH4+].[CH2:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]2[O:28][CH2:29][O:30][C:24]=2[CH:23]=1)[CH3:20]>CC(C)=O.CN(C=O)C>[CH2:19]([N:21]([C:16]1[S:15][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:6])[N:17]=1)[C:22]1[CH:27]=[CH:26][C:25]2[O:28][CH2:29][O:30][C:24]=2[CH:23]=1)[CH3:20]
Reactant: CCNc1ccc2c(c1)OCO2
Reactant: O=C(O)c1cccnc1Cl
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCN(c1ccc2c(c1)OCO2)c1nc(=O)c2cccnc2s1
Yield: 57.9 %

Procedure:
The reaction procedure of Example 57 was followed except that 1.585 mg (10.08 mmol) of 2-chloronicotinic acid, 15 ml of thionyl chloride, two droplets of DMF, 844 mg of ammonium thiocyanate, 15 ml of acetone, 1.83 g of N-ethyl-3,4-methylenedioxyaniline and 10 ml of acetone were used. The resulting crude product was then recrystallized from a mixture of ethanol and ether to obtain 1.91 g of 2-[N-ethyl-N-(3,4-methylenedioxyphenyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[N:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C.[C:22]([O:28][CH2:29][CH2:30][CH2:31]Br)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C>[N:3]1[CH:8]=[CH:7][CH:6]=[N:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:31][CH2:30][CH2:29][O:28][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:11][CH2:10]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: CC(C)(C)C(=O)OCCCBr
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OCCCN1CCN(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 164.1 %

Procedure:
To a stirred solution of N-(2-pyrimidinyl)piperazine dihydrochloride (4.25 g, 0.0179 mol) and triethylamine (6.06 g, 0.06 mol) in DMF was added 3-bromopropyl pivalate (4.0 g, 0.0179 mol) and the solution was stirred overnight at room temperature. The solvent was evaporated and the residue dissolved in CH2Cl2. The CH2Cl2 extract was washed with water, dried (anhydrous Na2SO4) and evaporated to afford 9.0 g of crude title compound. Purification by HPLC and conversion to the dihydrochloride with ethereal HCl yielded the product, mp. 178°-180° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26](O)=[O:27])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[C:37](=[N:39]O)[NH2:38]>>[F:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[C:37]1[N:39]=[C:26]([CH:12]2[CH2:13][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:20][CH:21]=3)[CH2:15][N:10]([C:8]([N:5]3[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]3)=[O:9])[CH2:11]2)[O:27][N:38]=1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Reactant: NC(=NO)c1cc(F)ccc1F
Product: O=C(N1CCC(O)CC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3cc(F)ccc3F)no2)C1

Procedure:
100 mg (0.250 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 99A) and 47.3 (0.275 mmol) of 2,5-difluoro-N′-hydroxybenzenecarboximidamide (Example 74A) were reacted according to the General Method 1. Yield: 68.1 mg (51% of theory).
Reaction SMILES: Cl.Cl.[CH:3]([S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[N:17]=[C:18]([NH:26][CH:27]2[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]2)[NH:19][C:20](=[O:25])[C:21]=1[C:22]([NH2:24])=[O:23])(=[O:8])=[O:7])([CH3:5])[CH3:4].N1C=CC=CC=1.[S:39](Cl)([CH3:42])(=[O:41])=[O:40]>C(O)C>[CH:3]([S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[N:17]=[C:18]([NH:26][CH:27]2[CH2:32][CH2:31][CH2:30][N:29]([S:39]([CH3:42])(=[O:41])=[O:40])[CH2:28]2)[NH:19][C:20](=[O:25])[C:21]=1[C:22]([NH2:24])=[O:23])(=[O:8])=[O:7])([CH3:5])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(NC2CCCNC2)[nH]c(=O)c1C(N)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(NC2CCCN(S(C)(=O)=O)C2)[nH]c(=O)c1C(N)=O
Reaction time: 1 h

Procedure:
To a mixture of 4-{[2-(isopropylsulfonyl)phenyl]amino}-6-oxo-2-(piperidin-3-ylamino)-1,6-dihydropyrimidine-5-carboxamide dihydrochloride (Example 29) (67 mg) and pyridine (1.3 mL), mesyl chloride (0.10 mL) was added under ice cooling and stirred for 1 hour. After ethanol was added to the reaction system, the reaction system was concentrated. The resulting residue was partitioned using chloroform and saturated aqueous sodium hydrogen carbonate, and the organic layer was dried. The organic layer was concentrated, followed by an azeotropic process with toluene. The resulting residue was solidified with ethyl acetate-hexane. The resulting solid was recrystallized from ethanol to give 4-{[2-(isopropylsulfonyl)phenyl]amino}-2-{[1-(methylsulfonyl)piperidin-3-yl]amino}-6-oxo-1,6-dihydropyrimidine-5-carboxamide (43 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([CH2:13][OH:14])[CH2:5]1.[C:16]1(C)C=CC=CC=1.S(OC)(OC)(=O)=O>C1(C)C(C)=CC=CC=1.O>[CH3:3][C:4]1([CH3:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([CH2:13][O:14][CH3:16])[CH2:5]1
Reactant: Cc1ccccc1
Reactant: CC1(C)CC(CO)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Solvent: COS(=O)(=O)OC
Product: COCC1CC(C)(C)c2ccccc21
Reaction time: 5 h
Yield: 92 %

Procedure:
A solution of 17.25 g (0.43 mol) of 60% sodium hydride in 500 ml of xylene was heated to 100° C. To this was dropwise added over 2 hours a mixture of 69 g (0.39 mol) of 1,1-dimethyl-3-hydroxymethylindane (IX) and 250 ml of toluene. After stirring for 5 hours, 27.1 g (0.215 mol) of dimethyl sulfate was added dropwise to the reaction mixture over 2 hours. After the addition, the mixture was stirred for 3 hours to complete the reaction. 250 ml of water was added to the resulting reaction mixture to separate the water and organic layers. The organic layer was washed with water, an aqueous solution of sodium sulfate, and saturated brine, and dried over anhydrous magnesium sulfate. After removing the solvent, the residue was distilled under reduced pressure to produce 68.3 g (0.36 mol) of 1,1-dimethyl-3-methoxymethylindane at a yield of 92%. The product was a colorless, transparent liquid having a green, herbal, woody odor.