Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][NH:14][C:15]2[C:16](=[O:31])[N:17]([CH:28]([CH3:30])[CH3:29])[S:18](=[O:27])(=[O:26])[C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=O)=O)=CC=1.[CH3:32][S:33]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[OH:43])(=[O:35])=[O:34].C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH3:32][S:33]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[O:43][CH2:12][CH2:13][NH:14][C:15]1[C:16](=[O:31])[N:17]([CH:28]([CH3:29])[CH3:30])[S:18](=[O:26])(=[O:27])[C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)(=[O:35])=[O:34]
Reactant: Cc1ccc(S(=O)(=O)OCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)C)C2=O)cc1
Reactant: CS(=O)(=O)Oc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)N1C(=O)C(NCCOc2ccccc2OS(C)(=O)=O)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 15 %

Procedure:
2-[(2-Isopropyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]ethyl 4-methylbenzenesulfonate (200 mg, 0.431 mmol) was dissolved in dry MeCN (4 mL) under nitrogen atmosphere. 2-Hydroxyphenyl methanesulfonate (89 mg, 0.474 mmol) was added followed by potassium carbonate (297 mg, 2.152 mmol). The reaction mixture was heated in a microwave reactor for 15 mins at 120° C. Potassium carbonate was filtered off and the reaction mixture was concentrated and redissolved in EtOAc. The mixture was washed with NaHCO3, dried over Na2SO4, filtered and evaporated. The residue was purified on a Horizon TM flash system using Heptane and EtOAc as eluant and TEA as additative and then purified by column chromatography (ISOLUTE SI, (5 g)) using DCM as eluant to afford the title compound (31 mg, 15%). 1H NMR (CDCl3, 500 MHz): δ 1.59 (d, 6H), 3.22 (s, 3H), 3.31 (q, 2H), 3.96 (t, 2H), 4.38-4.46 (m, 1H), 5.88 (t, 1H), 6.89 (d, 1H), 7.02 (t, 1H), 7.23-7.30 (m, 2H), 7.46-7.48 (m, 3H), 7.53-7.56 (m, 2H); 13C NMR (CDCl3, 125 MHz): δ 20.38, 38.57, 43.36, 47.85, 67.23, 108.08, 114.71, 122.38, 124.59, 125.14, 128.55, 129.15, 130.09, 131.63, 135.62, 138.64, 150.55, 158.40; Mass Spectrum: M+H+ 481.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:19]=[N:20][CH:21]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([C:8]([O:10]C)=[O:9])[CH:7]=1.[OH-].[Na+].O.C(O)(=O)C>CO>[Cl:1][C:2]1[C:3]2[N:4]([CH:19]=[N:20][CH:21]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([C:8]([OH:10])=[O:9])[CH:7]=1
Reactant: COC(=O)c1cc(Cl)c2cncn2c1-c1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc(Cl)c2cncn2c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.9 %

Procedure:
Methyl 8-chloro-5-(3-fluorophenyl)imidazo[1,5-a]pyridine-6-carboxylate (0.60 g, 2.0 mmol) was stirred in methanol (40 mL) and a solution of 3 N sodium hydroxide in water (10 mL, 40 mmol) was added. The mixture was stirred for 16 hours at room temperature, and glacial acetic acid (5 mL) was added. Evaporation gave a precipitate which was filtered and washed with water to give the desired compound (0.29 g, 50%). LCMS calculated for C14H9ClFN2O2 (M+H)+: m/z=291.1. found: 290.9. 1H NMR (300 MHz, DMSO-d6): δ 7.77 (s, 1H), 7.60 (m, 2H), 7.40 (m, 4H).
Reaction SMILES: [NH:1]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:14]([N:16]1[CH2:30][CH2:29][CH2:28][C@H:17]1[C:18]([O:20]CC1C=CC=CC=1)=[O:19])=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:8])=[O:4]>C(O)(=O)C>[NH:1]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:14]([N:16]1[CH2:30][CH2:29][CH2:28][C@H:17]1[C:18]([OH:20])=[O:19])=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:8])=[O:4]
Reactant: CC(C)[C@H](NC(=O)CNC(=O)CNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Solvent: CC(=O)O
Product: CC(C)[C@H](NC(=O)CNC(=O)CNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
IV (6.2 g, 0.012 mole) in acetic acid was hydrogenated and worked up as for IIto obtain V quantitatively, no sharp m.p. 74°-83° C. Rf3, 0.25; Rf4, 0.15. Anal. Calcd. for C19H32N4O7 : C, 51.10: H, 7.67; N, 12.54%. Found: C, 51.28: H, 7.50 N, 12.38%.
Reaction SMILES: Cl[C:2]1[C:3]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:18]([NH2:21])(=[O:20])[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>C(O)(C)(C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O>[C:18]([NH:21][C:2]1[C:3]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])(=[O:20])[CH3:19]
Reactant: CC(N)=O
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(Cl)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cnc(OCC(F)(F)F)c(NC(C)=O)c1
Temperature: 110 °C
Reaction time: 3 h
Yield: 17.7 %

Procedure:
A mixture of methyl 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinate (3.08 g, 11.4 mmol, Step-1), acetamide (0.70 mL, 13.7 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.73 g, 0.80 mmol), potassium phosphate (7.27 g, 34.3 mmol) and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.34 g, 0.800 mmol) in tert-butyl alcohol (114 mL) is stirred for 3 hours at 110° C. The reaction mixture is poured into water and extricated with ethyl acetate and dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (3:1 to 1:1) to give 0.59 g (18% yield) of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([C:14](=[O:26])[NH:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)=[O:18])[CH:12]2[CH2:27][CH:9]1CC2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O:32]C(N1C(C(O)=O)C2CC1CC2)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:27][O:32][CH2:12][CH:13]1[C:14](=[O:26])[NH:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=1)=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)O
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)NCC(=O)c1ccc(Br)cc1
Product: CC(C)(C)OC(=O)N1CCOCC1C(=O)NCC(=O)c1ccc(Br)cc1

Procedure:
Title compound was prepared according to the method employed to prepare 3-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (Example AE), substituting Morpholine-3,4-dicarboxylic acid 4-tert-butyl ester for 2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH2:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[K+]>C1(C)C=CC=CC=1.O>[CH2:10]([O:17][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1ccc(OCc2ccccc2)nc1
Temperature: 70 °C
Reaction time: 7 h
Yield: 40.3 %

Procedure:
To a stirred solution of 6-chloronicotinonitrile (1 g, 7.2 mmol) and benzyl alcohol (780 mg, 7.2 mmol) in toluene (15 mL) was added KOH (729 mg, 12.99 mmol) and 18 crown ether (2.86 g, 10.8 mmol). The resulting mixture was stirred at 70° C. for 7 hrs. The mixture was diluted with cold water and the product was extracted with EtOAc. The organic layer was washed with saturated brine solution and dried over Na2SO4. The organic layer was then concentrated under reduced pressure. The obtained residue was purified by column chromatography (using neutral alumina and 5% MeOH: CHCl3 as eluent) to afford 610 mg (40.1% yield) of 6-benzyloxy-nicotinonitrile. LCMS Purity: 77.69%.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[N:11]=[C:10]2[N:5]([C:6](O)=[N:7][C:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[CH:9]2)[N:4]=1.P(Cl)(Cl)([Cl:27])=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>[Cl:27][C:6]1[N:5]2[N:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[N:11]=[C:10]2[CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:7]=1
Reactant: Oc1nc(-c2ccc(C(F)(F)F)cc2)cc2nc(C(F)(F)F)nn12
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Product: FC(F)(F)c1ccc(-c2cc3nc(C(F)(F)F)nn3c(Cl)n2)cc1
Temperature: 120 °C
Reaction time: 12 h

Procedure:
650 mg (1.9 mmol) of 2-(trifluoromethyl)-7-[4-(trifluoromethyl)phenyl][1,2,4]triazolo[1,5-c]-pyrimidin-5-ol (Example 131A) are introduced into phosphoryl chloride (10 ml), 1.28 g (5.6 mmol) of benzyltriethylammonium chloride are added, and the reaction mixture is stirred at 120° C. for 12 h. The reaction mixture is slowly poured, with vigorous stirring, into saturated sodium bicarbonate solution (50 ml) and ice, and solid sodium bicarbonate (approx. 1 g) is added until a pH of 8 is reached. The solid is filtered off with suction. 635 mg (93% of theory) of the crude product are obtained.
Reaction SMILES: CO[N:3]=[C:4]1[CH2:8][N:7]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:6][CH:5]1[C:19]([O:21]C)=O.B.C1COCC1.C([O-])([O-])=O.[K+].[K+].[O:35](C(OC(C)(C)C)=O)[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=O>C1COCC1.CCOC(C)=O.O>[C:39]([O:38][C:36]([NH:3][C@H:4]1[C@@H:5]([CH2:19][OH:21])[CH2:6][N:7]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:8]1)=[O:35])([CH3:42])([CH3:41])[CH3:40]
Reactant: CON=C1CN(C(=O)OCc2ccccc2)CC1C(=O)OC
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1CO
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 37.9 %

Procedure:
A solution of 1-benzyl 3-methyl 4-(methoxyimino)pyrrolidine-1,3-dicarboxylate (12.6 g, 41.1 mmol) in THF (100 mL) at −78° C. was added borane THF complex (1M in THF, 148 mL, 148 mmol) dropwise and stirred for 1.5 hrs, and then it was warmed to 0° C. and stirred for 2 hrs and further warmed up to RT and stirred for 16 hrs. The reaction was quenched with water at 0° C. until effervescence ceased, and to it was added K2CO3 (5.68 g, 41.1 mmol). The reaction mixture was warmed up to RT and stirred for 1 hr. (BOC)2O (11.46 mL, 49.4 mmol) was added. The reaction mixture was stirred at RT for 16 hrs. The reaction mixture was added 200 mL of water and 500 mL of EtOAc and stirred for 10 minutes. The organic phase was separated and washed with 200 mL of brine, dried over Na2SO4, and then it was filtered, concentrated and purified by silica gel chromatography, eluting with 0-70% ethyl acetate in hexanes, to give the racemic title compound (5.46 g, 38% yield). 1H NMR (400 MHz, chloroform-d) δ 7.41-7.30 (m, 5H), 5.15 (d, J=1.3 Hz, 2H), 4.86-4.72 (m, 1H), 4.30 (br. s., 1H), 3.94-3.85 (m, 1H), 3.66 (dd, J=11.9, 5.1 Hz, 2H), 3.59-3.44 (m, 3H), 2.96 (q, J=11.4 Hz, 1H), 2.57 (br. s., 1H), 1.50-1.44 (m, 9H). MS(ES+) m/z: 351.1 (M+H); HPLC retention time: 2.79 min (analytical HPLC Method B).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[S:5][C:6]=1[CH:7]([OH:10])[CH2:8][CH3:9].CC(C)([O-])C.[K+].[F:27][C:28]1[CH:35]=[C:34](F)[C:33]([F:37])=[CH:32][C:29]=1[C:30]#[N:31].O>O1CCCC1.C(O)(C)(C)C>[F:27][C:28]1[CH:35]=[C:34]([O:10][CH:7]([C:6]2[S:5][C:4]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=3)=[N:3][C:2]=2[CH3:1])[CH2:8][CH3:9])[C:33]([F:37])=[CH:32][C:29]=1[C:30]#[N:31]
Reactant: N#Cc1cc(F)c(F)cc1F
Reactant: CCC(O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CCC(Oc1cc(F)c(C#N)cc1F)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
To a solution of 900 mg of 1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propan-1-ol in 2 mL of tetrahydrofuran at 5° C. was slowly added 3.3 mL of a molar solution of potassium tert-butoxide in tert-butanol. After stirring at 5° C. for 30 minutes, the resulting solution was slowly added to a solution of 469 mg of 2,4,5-trifluoro-benzonitrile in 2 mL of tetrahydrofuran at −60° C. The resulting mixture was stirred for 1 h at −60° C. then stirred overnight allowing the temperature to warm up to room temperature. It was then poured into water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient from heptane 100 to heptane 80/ethyl acetate 20) to give 1.25 g of 2,5-difluoro-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-benzonitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:11]=[C:10]3[N:27]([CH2:30][C:31](O)=[O:32])[N:28]=[CH:29][C:9]=23)=[CH:4][CH:3]=1.[NH3:34]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)=[C:12]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[N:11]=[C:10]3[N:27]([CH2:30][C:31]([NH2:34])=[O:32])[N:28]=[CH:29][C:9]=23)=[CH:4][CH:3]=1
Reactant: N
Reactant: O=C(O)Cn1ncc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc21
Product: NC(=O)Cn1ncc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc21
Yield: 36 %

Procedure:
Following a similar procedure to that described in example 48, but using 2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1-yl]acetic acid (obtained in example 45) instead of 2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]acetic acid, and aqueous NH3 instead of morpholine, the title compound was obtained (yield: 36%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[OH:16][CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[F:13][C:12]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[N:19]1[CH2:20][CH2:21][CH:17]([OH:16])[CH2:18]1
Reactant: FC(F)(F)c1ccc(Br)c(C(F)(F)F)c1
Reactant: OC1CCNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: OC1CCN(c2ccc(C(F)(F)F)cc2C(F)(F)F)C1
Temperature: 25 °C
Yield: 79.6 %

Procedure:
A solution of 1-bromo-2,4-bis(trifluoromethyl)benzene (4.45 g), 3-hydroxypyrrolidine (1.2 g), palladium(II) acetate (156 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (846 mg) and cesium carbonate (13.6 g) in toluene (74 ml) was stirred under an argon gas atmosphere at 85° C. for 16 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 90:10-65:35) to give the title compound (3.28 g, yield 79%) as a brown oil.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][CH:17]([NH:21][C:22](=[O:29])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=CC=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH:10]1[C:11]2[C:20]3[CH2:19][CH2:18][CH:17]([NH:21][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:16][C:15]=3[CH:14]=[N:13][C:12]=2[NH:8][N:9]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CC(NC(=O)c2ccccc2)CC4)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(NC1CCc2c(cnc3[nH]ncc23)C1)c1ccccc1
Temperature: 65 °C
Yield: 24.4 %

Procedure:
To N-[3-(4-methoxy-benzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolin-7-yl]-benzamide (0.084 g, 0.21 mmol) was added trifluoroacetic acid (2 mL). The reaction mixture was heated at 65° C. for 16 hours. On completion of the reaction, toluene (5 mL) was added and the solvent removed under reduced pressure. The crude product was purified using reverse phase HPLC to give the desired product, N-(6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolin-7-yl)benzamide as a white solid (0.015 g, 25%). M.p.>300° C.; 400 MHz 1H NMR (DMSO-d6) δ: 13.31 (s, 1H), 8.49 (d, J=7.2 Hz, 1H), 8.00 (d, J=1.2 Hz, 1H), 7.92 (s, 1H), 7.86 (m, 2H), 7.48 (m, 3H), 4.28 (m, 1H), 3.22-2.91 (m, 4H), 2.13 (m, 1H), 1.96 (m, 1H); LCMS [M+H]: 293.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH:24]=[CH:25][C:26]([O:28]CC)=[O:27])[C:21]([O:31]COC)=[C:20]([C:35]([O:37]COC)=[O:36])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].Cl.[OH-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])[C:21]([OH:31])=[C:20]([C:35]([OH:37])=[O:36])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOC(=O)C=Cc1cc(-c2csc(-c3ccc(OCC)c(OCC)c3)n2)cc(C(=O)OCOC)c1OCOC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1ccc(-c2nc(-c3cc(C=CC(=O)O)c(O)c(C(=O)O)c3)cs2)cc1OCC
Temperature: 60 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
In 10 ml of ethanol was dissolved 350 mg of 2-(3,4-diethoxyphenyl)-4-[3-methoxymethoxycarbonyl-4-methoxymethoxy-5-(2-ethoxycarbonylvinyl)phenyl]thiazole. Thereto was added 0.2 ml of 10% hydrochloric acid. The mixture was stirred at 60° C. for 1 hour with heating. Thereto was added 1 ml of 10% sodium hydroxide. The mixture was refluxed for 4 hours with heating. The solvent was removed from the reaction mixture by distillation. The residue was mixed with 15 ml of water. The mixture was made weakly acidic with 10% hydrochloric acid and extracted with 40 ml of hot ethyl acetate. The organic layer was washed with 15 ml of a saturated aqueous sodium chloride solution, dried and subject to distillation to remove the solvent. The residue was recrystallized from ethyl acetate to obtain 170 mg of 2-(3,4-diethoxyphenyl)-4-[3-carboxy-4-hydroxy-5-(2-carboxyvinyl)phenyl]thiazole.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1.C(N(C(C)C)CC)(C)C.[CH3:31][O:32][CH2:33]/[CH:34]=[CH:35]/[C:36](Cl)=[O:37].C(=O)(O)[O-].[Na+]>>[Br:21][C:17]1[CH:16]=[C:15]([NH:14][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:36](=[O:37])[CH:35]=[CH:34][CH2:33][O:32][CH3:31])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]#[N:13])[CH:20]=[CH:19][CH:18]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: COC/C=C/C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COCC=CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Reaction time: 1.5 h

Procedure:
To a solution of 1.0 g (2.95 mmol) of of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile and 0.57 g (4.42 mmol) of diisopropylethyl amine at 0° C. with stirring was added 0.43 g (3.24 mmol) of 4-methoxycrotonyl chloride. After 1.5 hr at 0° C., the mixture was poured into a saturated solution of sodium bicarbonate and then extracted with ethyl acetate. The organic solution was dried over magnesium sulfate and the solvent was removed. The residue was recrystallized from 1-butanol giving 1.3 g of 4-Methoxy-but-2-enoic acid [4-(3-bromo-phenylamino)-3-cyano-quinolin-6-yl]-amide as a yellow solid: mass spectrum (electrospray, m/e,): M+H 436.4, 438.9.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([N+:20]([O-])=O)[CH:14]=1.CC(O)=O>C(O)C.O.[Fe]>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH:14]=1)[NH2:20]
Reactant: COc1ccc2nc(-c3ccc(C)c([N+](=O)[O-])c3)c(Br)n2n1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: COc1ccc2nc(-c3ccc(C)c(N)c3)c(Br)n2n1
Temperature: 80 °C
Yield: 97.6 %

Procedure:
To a stirred solution of 3-bromo-6-methoxy-2-(4-methyl-3-nitrophenyl)imidazo[1,2-b]pyridazine (0.190 g, 0.523 mmol) in ethanol (15 mL) and water (5 mL) containing AcOH (3.13 mmol) is added iron (0.146 g, 2.61 mmol). The reaction mixture is heated at 80° C. for 2 hours, cooled, concentrated under reduced pressure and sat. aqueous NaHCO3 (50 mL) is added. The mixture is extracted with EtOAc (3×25 mL). Organic layer is collected, dried over Na2SO4, filtered and concentrated to dryness. The crude product is purified via chromatography using a gradient of hexanes to EtOAc to afford the title compound (0.170 g, 89%) as an off-white solid: Rf 0.18 (1:1 EtOAc:hexanes); LCMS (m/z)=333.2, 335.2 [M+H]+, tR=2.22 min.
Reaction SMILES: [H-].[Na+].[NH2:3][C@H:4]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[CH2:5][OH:6].Cl[CH2:15][C:16](OCC)=[O:17]>C1COCC1>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C@H:4]2[NH:3][C:16](=[O:17])[CH2:15][O:6][CH2:5]2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)CCl
Reactant: N[C@@H](CO)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1COC[C@@H](c2ccc(F)cc2)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
To a stirring mixture of NaH (1.1 g, 45.7 mmol) in THF (30 mL) at room temperature under N2 atmosphere was added dropwise a solution of (R)-2-amino-2-(4-fluoro-phenyl)-ethanol (5.0 g, 32.2 mmol) in THF (50 mL). The reaction mixture was stirred at room temperature for 30 minutes, then cooled to 0° C. A solution of ethyl chloroacetate (4.0 g, 33 mmol) in THF (30 mL) was added dropwise, and the reaction mixture was stirred for 30 minutes at 0° C., then stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure, and water (50 mL) was added to the residue. The resulting mixture was pH adjusted to approximately 6.5 by addition of 1M aqueous HCl, and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was recrystallized from diethyl ether to give 2.87 g of (R)-5-(4-fluoro-phenyl)-morpholin-3-one. The mother liquor from the recrystallization was concentrated and purified via chromatography (50-70% ethyl acetate in hexanes) to give an additional 1.0 g of (R)-5-(4-fluoro-phenyl)-morpholin-3-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][C:10]=2[NH:11][C:12](=S)[CH2:13][N:14]=1.O.[NH2:22][NH2:23]>C(O)C>[NH:22]([C:12]1[CH2:13][N:14]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:9]2[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][C:10]=2[N:11]=1)[NH2:23]
Reactant: NN
Reactant: CCc1cc2c(s1)NC(=S)CN=C2c1ccccc1Cl
Solvent: O
Solvent: CCO
Product: CCc1cc2c(s1)N=C(NN)CN=C2c1ccccc1Cl

Procedure:
[d] 32.1 g of 5-o-chlorophenyl-7-ethyl-1,2-dihydro-3H-thieno[2,3-e][1,4] diazepine-2-thione obtained in the above example [a] is suspended in 200 ml of ethanol, and to the suspension is added 8 g of hydrazine hydrate. Several minutes stirring turns the suspension into a homogeneous, red, transparent solution. Then crystals begin to precipitate. After stirring at room temperature for 2 hours and subsequent ice-cooling, the crystals are collected by suction filtration and washed well with methanol to give 28.6 g of almost pure 2-hydrazino-5-o-chlorophenyl-7-ethyl-3H-thieno[2,3-e][1,4]diazepine as yellowish crystals. The crystals, when recrystallized from a mixture of ethanol and diemethylformamide, show a melting point of 214° - 216°C (decomposition).