Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[CH:16]=[C:15]([NH:25][C:26]2[CH:30]=[CH:29][NH:28][N:27]=2)[N:14]=1>>[CH3:24][O:23][C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[C:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1)=[N:14][C:15]([NH:25][C:26]1[CH:30]=[CH:29][NH:28][N:27]=1)=[CH:16]2
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: CC(=O)Nc1ccc(O)cc1
Product: COc1ccc2c(Oc3ccc(NC(C)=O)cc3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from N-(4-Hydroxy-phenyl)-acetamide and (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine to give N-{4-[6-methoxy-3-(1H-pyrazol-3-ylamino)-isoquinolin-1-yloxy]-phenyl}-acetamide. LC-MS m/e 390(MH+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(O)(=O)C.[Br:16]Br.C([O-])(O)=O.[Na+]>CCOCC>[Br:16][C:9]1[CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=1[OH:11]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(O)c(Br)c1
Temperature: -10 °C
Reaction time: 1 h
Yield: 43.8 %

Procedure:
To a solution of 4-(methylsulfonyl)phenol (5 g, 29.1 mmol) in ether (100 mL) at −15° C. was slowly added acetic acid (5 mL). To this cold solution was slowly added Br2 (5.1 g, 32.0 mmol) and the reaction was stirred at −10° C. for 1 h and then warmed to r.t. and stirred for further 10 h. After the reaction was completed, 100 mL of sat. NaHCO3 aq. was added and the mixture was extracted with EA (50 mL×3). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and evaporation of the solvent, 2-bromo-4-(methylsulfonyl)phenol (3.2 g, 43.6%) was obtained as a white solid.
Reaction SMILES: Cl.[C:2]([O:6][C:7]([N:9]1[CH2:12][C:11]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].C=O.[C:20](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[C:2]([O:6][C:7]([N:9]1[CH2:12][C:11]2([CH2:17][CH2:16][N:15]([CH3:20])[CH2:14][CH2:13]2)[CH2:10]1)=[O:8])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC2(CCNCC2)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CN1CCC2(CC1)CN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2,7-diaza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester hydrochloride (100 mg, 0.381 mmol) in DCE (10 mL) was added an aqueous solution of formaldehyde (37% w/w, 40 μL, 0.537 mmol). The mixture was stirred at RT for 10 min, then sodium triacetoxyborohydride (121 mg, 0.571 mmol) was added and stirring was continued for 1 h. Water was added to the reaction mixture before being loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH then eluted with 2 M NH3 in MeOH to give 7-methyl-2,7-diaza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester. To a solution of 7-methyl-2,7-diaza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester in DCM (5 mL) was added TFA (1 mL) and the resulting mixture was stirred at RT for 1 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to give the title compound as a colourless oil (45 mg, 84%).
Reaction SMILES: [CH2:1]([N:5]([CH2:42][CH2:43][CH2:44][CH3:45])[C:6]([C:8]1[N:9]=[C:10]([C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=2[C:30]([N:32]2[CH2:41][CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33]2)=[O:31])[N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C(Cl)CCl.[CH2:50](O)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[CH2:42]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:8]1[N:9]=[C:10]([C:21]2[CH:29]=[CH:28][C:24]([C:25]([O:27][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[O:26])=[CH:23][C:22]=2[C:30]([N:32]2[CH2:41][CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33]2)=[O:31])[N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=1)=[O:7])[CH2:43][CH2:44][CH3:45]
Reactant: OCc1ccccc1
Reactant: CCCCN(CCCC)C(=O)c1cn(COCC[Si](C)(C)C)c(-c2ccc(C(=O)O)cc2C(=O)N2CCc3ccccc3C2)n1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCCN(CCCC)C(=O)c1cn(COCC[Si](C)(C)C)c(-c2ccc(C(=O)OCc3ccccc3)cc2C(=O)N2CCc3ccccc3C2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.6 %

Procedure:
To a stirred solution of 4-(4-(dibutylcarbamoyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoic acid (320 mg, 0.96 mmol) in dry DCM (5.0 mL) was added EDC (932 mg, 4.81 mmol), benzyl alcohol (208 mg, 1.92 mmol) and DMAP (235 mg, 1.92 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirring was continued for 16 h. The reaction mixture was diluted with water and extracted with DCM (2×). The combined organic layer was dried over Na2SO4 and concentrated in vacuo to give crude product. The crude material was purified by flash chromatography (gradient 10 to 30% EtOAc/hexanes) to provide the title compound (400 mg, 92%). MS(ESI+) m/z 723.6 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1([O:30][CH2:31][CH3:32])[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[C@@H:6]([CH2:18][N:19]2C(=O)C3=CC=CC=C3C2=O)[CH2:5]1)[CH3:2].O.NN>C(O)C>[CH2:31]([O:30][C:4]1([O:3][CH2:1][CH3:2])[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[C@@H:6]([CH2:18][NH2:19])[CH2:5]1)[CH3:32]
Reactant: CCOC1(OCC)CCN([C@@H](C)c2ccccc2)[C@@H](CN2C(=O)c3ccccc3C2=O)C1
Agent: NN
Solvent: O
Solvent: CCO
Product: CCOC1(OCC)CCN([C@@H](C)c2ccccc2)[C@@H](CN)C1
Yield: 107.1 %

Procedure:
A mixture of 4,4-diethoxy-1-((S)-1-phenyl-ethyl)-(R)-2-phthalimidomethyl-piperidine (5.25 g, 12.0 mmol) and hydrazine hydrate (2.92 ml, 60 mmol) was stirred overnight in ethanol (100 ml) at room temperature. The solvent was removed in vacuo and the solid residue was extracted with refluxing diethyl ether. The diethyl ether fractions were combined and evaporated in vacuo, which afforded 3.94 g (94%) of 4,4-diethoxy-1-((S)-1-phenyl-ethyl)-(R)-2-aminomethyl-piperidine as an oil.
Reaction SMILES: [N:1]#[C:2]Cl.[CH2:4]([N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(#N)C>[C:5]1([CH2:4][N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[C:2]#[N:1])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: N#CCl
Reactant: c1ccc(Cn2ccnc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1nccn1Cc1ccccc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
In a 50 ml 4-neck flask with stirring bar, nitrogen bubbler, gas inlet tube, thermometer, septum and acetonitrile (20 ml) was bubbled cyanogen chloride (3.1 g, 50 mmol) (ice bath was used to avoid mild heat of solution). The reaction was cooled in an ice bath and a solution of 1-benzylimidazole (3.16 g, 20 mmol) in acetonitrile (ca. 5 ml) was added via syringe. The colorless solution turned yellow-orange and within a few minutes a yellow-orange crystalline solid started to form. After 1 hour, the thick slurry was cooled to -20° C. and triethylamine (7 ml, 50 mmol) was added at such a rate to prevent the temperature from rising above 0° C. The mixture was stirred 1 hour while warming to room temperature, poured into saturated aq NaHCO3 (100 ml) and extracted with ether (3×75 ml). The combined organic layers were dried (MgSO4), evaporated and purified by Kugelrohr distillation. After a forerun of diethylcyanamide, the desired product was collected at 130° C. (0.4 mm) (3.05 g, 83%) as a colorless liquid which crystallized on standing, mp 51°-52° C. (cyclohexane).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][S:4]([CH2:7][CH2:8][C:9]([OH:11])=O)(=[O:6])=[O:5].S(Cl)([Cl:14])=O>>[Cl:1][CH2:2][CH2:3][S:4]([CH2:7][CH2:8][C:9]([Cl:14])=[O:11])(=[O:6])=[O:5]
Reactant: O=C(O)CCS(=O)(=O)CCCl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CCS(=O)(=O)CCCl

Procedure:
50 grams of β-(β-chloroethanesulfonyl)propionic acid and 150 ml of thionyl chloride were heated under refluxing for about 2 hours, excess thionyl chloride distilled off under reduced pressure, and the residue recrystallized from anhydrous benzene to give 46 g of white β-(β-chloroethanesulfonyl)propionyl chloride, m.p. 73°-5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([O-:14])(=O)=[O:12].[Na+].S1(CCCC1)(=O)=O.P(Cl)(Cl)([Cl:25])=O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([Cl:25])(=[O:14])=[O:12]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)[O-])c1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1
Temperature: 25 °C

Procedure:
To a mixture of 104 g of commercially available sodium 2-chloro-5-nitrobenzenesulfonate, 200 ml of acetonitrile and 200 ml of sulfolane stirred at 25° C., was added 153 ml of phosphorus oxychloride over a period of 30 minutes. The temperature was not allowed to exceed 40° C. After completion of the addition, the reaction mixture was heated to 70° C. for 1.5 hours. On cooling to 0° C., the reaction mixture was poured over ice. The resulting solid product was washed with cold water, filtered and air-dried to give 77.6 g of the title compound with a melting point of 87°-89° C.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[C:19]1([S:29](Cl)(=[O:31])=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:17](=[N:16][CH:15]=[CH:14][CH:13]=4)[N:12]([S:29]([C:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=[CH:21][CH:20]=4)(=[O:31])=[O:30])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: c1cc2[nH]cc(C3CCN4CCCC4C3)c2cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)n1cc(C2CCN3CCCC3C2)c2cccnc21

Procedure:
from 3-(octahydro-7-indolizinyl)-1-H-5-azaindole (less polar isomer) (10 mg, 0.0415 mmol), 1-naphthalenesulfonyl chloride (17.2 mg, 0.0828 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([F:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[CH2:11][C:10]2([CH3:23])[CH3:22])=[O:4].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[F:24][C:7]1[CH:8]=[C:9]2[C:14](=[C:5]([C:3]([OH:2])=[O:4])[CH:6]=1)[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:16]=1)[CH2:11][C:10]2([CH3:23])[CH3:22]
Reactant: COC(=O)c1cc(F)cc2c1NC(c1cccc(Br)c1)CC2(C)C
Reactant: C1COCCN1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2c(C(=O)O)cc(F)cc21
Temperature: 25 °C
Yield: 61.4 %

Procedure:
A mixture solution of 2-(3-bromo-phenyl)-6-fluoro-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (5 g, 12.7 mmol), morpholine (11.1 mL, 125 mmol), copper(I) iodide (1.43 g, 7.5 mmol), N,N-dimethylglycine hydrochloride (1.4 g, 10 mmol), and potassium carbonate (5.2 g, 75 mmol) in dimethyl sulfoxide (20 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature. The reaction mixture was extracted with ethyl acetate (150 mL×2), washed with saturated aqueous ammonium chloride solution (50 mL×3) and brine (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 30-50% ethyl acetate in petroleum ether) to afford 6-fluoro-4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (3 g, 61%) as a white solid: MS (ESI) M+1=385.1.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[NH:16][C:17]([C@@H:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][N:20]1[C:29](=[O:38])[C@@H:30]([NH2:37])[CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:18].[C:39]([O:43][C:44]([N:46]([CH3:52])[C@@H:47]([CH3:51])[C:48](O)=[O:49])=[O:45])([CH3:42])([CH3:41])[CH3:40].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:39]([O:43][C:44](=[O:45])[N:46]([C@H:47]([C:48](=[O:49])[NH:37][C@@H:30]([CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1)[C:29]([N:20]1[CH2:21][CH2:22][C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@H:19]1[C:17](=[O:18])[NH:16][C:10]1[C:11]([F:15])=[CH:12][CH:13]=[CH:14][C:9]=1[F:8])=[O:38])[CH3:51])[CH3:52])([CH3:40])([CH3:41])[CH3:42]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: N[C@H](C(=O)N1CCc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1F)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](C(=O)N[C@H](C(=O)N1CCc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1F)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To a solution of (S)-2-((S)-2-amino-2-cyclohexyl-acetyl)-1,2,3,4-tetrahydro-isoquinoline-1-carboxylic acid (2,6-difluoro-phenyl)-amide trifluoroacetate (63.6 mg, 117 μmol, Eq: 1.00), (S)-2-(tert-butoxycarbonyl-methyl-amino)-propionic acid (22.2 mg, 117 μmol, Eq: 1.00), HATU (49.1 mg, 129 μmol, Eq: 1.1) in DMF (500 μL) at 0° C. was added DIEA (45.5 mg, 61.5 μL, 352 μmol, Eq: 3). The reaction was stirred at RT for 1 h diluted with water and extracted with EtOAc. The combined organics were washed with water, brine, dried with MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography to give ((S)-1-{(S)-1-cyclohexyl-2-[(S)-1-(2,6-difluoro-phenylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethylcarbamoyl}-ethyl)-methyl-carbamic acid tert-butyl ester (58 mg) as a white foam.
Reaction SMILES: [CH3:1][O:2][CH:3]1[S:7][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[N:5][CH2:4]1.Br[CH2:30][CH3:31].[OH-].[Na+].CN(C)C=O>O>[OH2:2].[CH2:30]([N:8]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[CH2:19][CH2:20]2)=[CH:11][CH:10]=1)[C:6]1[S:7][CH:3]([O:2][CH3:1])[CH2:4][N:5]=1)[CH3:31].[CH2:30]([N:8]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[CH2:19][CH2:20]2)=[CH:11][CH:10]=1)[C:6]1[S:7][CH:3]([O:2][CH3:1])[CH2:4][N:5]=1)[CH3:31]
Reactant: COc1ccc(N2CCN(c3ccc(NC4=NCC(OC)S4)cc3)CC2)cc1
Reactant: CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C1=NCC(OC)S1)c1ccc(N2CCN(c3ccc(OC)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.4 %

Procedure:
A mixture of 15 parts of 4,5-dihydro-5-methoxy-N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-2-thiazolamine, 5.8 parts of bromoethane, 3 parts of sodium hydroxide pellets and 207 parts of N,N-dimethylformamide was stirred for 16 hours at room temperature. The reaction mixture was diluted with water. The precipitated product was filtered off and purified by column chromatography over silica gel using a mixture of trichloromethane, ethyl acetate, hexane and methanol (49::30:20:1 by volume) as eluent. The second fraction was collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and dried, yielding 7.3 parts (44.4%) of N-ethyl-4,5-dihydro-5-methoxy-N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-2-thiazolamine hemihydrate; mp. 131.5° C. (int. 6).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH:5]=[N:6][C:7]=1[CH3:8].[Se](=O)=[O:21]>COCCOC>[Br:1][C:2]1[C:7]([CH:8]=[O:21])=[N:6][CH:5]=[C:4]([N:9]2[C:10](=[O:19])[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]2=[O:18])[CH:3]=1
Reactant: Cc1ncc(N2C(=O)c3ccccc3C2=O)cc1Br
Reactant: O=[Se]=O
Solvent: COCCOC
Product: O=Cc1ncc(N2C(=O)c3ccccc3C2=O)cc1Br
Temperature: 130 °C
Yield: 383.1 %

Procedure:
To 2-(5-bromo-6-methylpyridin-3-yl)isoindoline-1,3-dione (30A, 1.5 g, 4.73 mmol) and selenium dioxide (682 mg, 6.15 mmol) was added 14 mL of DME. The reaction mixture was heated in a 130° C. heating bath for 20 hours. The reaction was repeated on identical scale 4×. The combined reaction mixtures were cooled and the solids filtered off. The filtrate was concentrated to afford 6 g of the title compound. 1H NMR (400 MHz, DMSO) δ 10.04 (s, 1H), 8.95 (d, J=1.9 Hz, 1H), 8.41 (d, J=1.7 Hz, 1H), 8.07-7.84 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5].[C:12](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1c(F)cccc1Br
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1c(F)cccc1Br
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 99.3 %

Procedure:
To a solution 2-bromo-6-fluorobenzoic acid (50 g, 0.229 mol) and potassium carbonate (31.6 g, 0.229 mol) in N,N-dimethylformamide (250 mL) was added dropwise methyl iodide (51.83 g, 0.365 mol) over a 30 minute period. The reaction mixture was stirred at RT for 3.5 hours. The resulting mixture was diluted with water (500 mL) and extracted with EtOAc (3×300 mL). The combined organic layers were washed with 1M aqueous HCl (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (53 g, 99.7%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrC[C:45]1[CH:50]=[CH:49][CH:48]=C[C:46]=1[C:51]([F:54])([F:53])[F:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:48]=[CH:49][CH:50]=[CH:45][C:46]=3[C:51]([F:54])([F:53])[F:52])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: FC(F)(F)c1ccccc1CBr
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3ccccc3C(F)(F)F)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2-(trifluoromethyl)benzene and isolated as light-yellow gum (7.8 mg, 43%). MS (m/e): 441.4 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:15](=O)[CH2:14][CH2:13][C:12]1=O)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][CH2:14][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N1C(=O)CCC1=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccccc1N1CCCC1
Temperature: 25 °C
Yield: 79.7 %

Procedure:
To a solution of 1-(2-tert-butylphenyl)pyrrolidine-2,5-dione (500 mg, 2.16 mmol) in THF (10 mL) was added BH3 in toluene (350 mg, 1.72 mmol) dropwise and the reaction mixture was heated to reflux overnight. The reaction was cooled to room temperature and quenched with methanol (until the evolution of H2 ceased). The solvent was evaporated to obtain 1-(2-tert-butylphenyl)pyrrolidine (350 mg, 80%) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.30 (s, 1H), 7.28 (s, 1H), 7.15 (d, J=0.9 Hz, 1H), 7.07-7.01 (m, 1H), 2.90 (s, 4H), 1.88-1.78 (m, 4H), 1.35 (s, 9H). LC/MS: m/z 204.1 (M+H)+ at 0.88 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: CC([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[C:10]=1[C:15]([O:17][CH3:18])=[O:16])(=[O:8])=[O:7])(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.[Au]>[NH2:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[C:10]=1[C:15]([O:17][CH3:18])=[O:16])(=[O:8])=[O:7]
Reactant: COC(=O)c1c(S(=O)(=O)NC(C)(C)C)ccn1C
Agent: [Au]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c(S(N)(=O)=O)ccn1C

Procedure:
To a solution of 3.53 g of methyl 3-[[(1,1-dimethylethyl)amino]sulfonyl]-1-methyl-1H-pyrrole-2-carboxylate in 40 mL of methylene chloride under an nitrogen atmosphere was added 80 mL of trifluoroacetic acid (TFA). The gold solution was stirred at room temperature overnight ca. 16 hours. The gold solution was concentrated to an oily residue. Diethyl ether was added to the residue and removed by evaporation to remove residual TFA. The resulting solid was suspended in diethyl ether and filtered affording the title compound as a tan solid, m.p. 105°-107° C. 1H NMR (Acetone-d6, 200 MHz.) δ: 7.01(d,1H), 6.51(d,1H), 6.28(bs,2H), 3.95(s,3H), 3.93(s,3H).
Reaction SMILES: [CH3:1][C:2]1[NH:14][C:5]2=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=[C:4]2[C:3]=1[CH3:15].Cl[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]>>[CH3:1][C:2]1[N:14]=[C:5]2[N:6]([CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[CH:9]=[C:4]2[C:3]=1[CH3:15]
Reactant: O=C(CCl)c1ccccc1
Reactant: Cc1[nH]c2ncc(C(F)(F)F)cc2c1C
Product: Cc1nc2n(CC(=O)c3ccccc3)cc(C(F)(F)F)cc-2c1C

Procedure:
A solution of 0,1 g (0,47 mmol) 2,3-dimethyl-5-trifluoromethyl-pyrrolo[2,3-b]pyridine and 0,13g (0,84 mmol) 2-chloroacetophenone in 5 ml acetronitrile was refluxed for 48 h. The solvent was evaporated. Chromatography on silica gel eluting with methylene chloride and methanol (100:5) gave the desired product. (0,023 g 15%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][N:10](C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[O-]C#N.[Zn+2].[O-]C#N>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]#[N:10])=[N:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#C[O-]
Agent: [Zn+2]
Product: N#Cc1ccc(Br)cn1
Temperature: 135 °C

Procedure:
2,5-Dibromopyridine (10 mmol), Pd(Ph3P)4 (0.3 mmol) and zinc cyanate (10 mmol) are mixed in DMF (12 mL) and purged with N2. The mixture is heated in a microwave reactor at 135° C. for 15 minutes, poured into saturated NH4Cl solution, and extracted with EtOAc. The combined extracts are washed with saturated aqueous NaCl and dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (9:1 hexanes/EtOAc) to give 5-bromo-pyridine-2-carbonitrile.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-:3])=[O:2].[N:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:16]=[O:17].C(N(CC)CC)C>C(C(C)=O)C>[N+:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][C:16]([NH:15][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:17])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-:3])=[O:2]
Reactant: CCOC(=O)CN=C=O
Reactant: O=[N+]([O-])c1ccc(O)c2ncccc12
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Product: CCOC(=O)CNC(=O)Oc1ccc([N+](=O)[O-])c2cccnc12
Reaction time: 0.5 h

Procedure:
5-Nitro-8hydroxyquinoline (19.0 g) was added to a solution containing 13.6 g of ethyl isocyanatoacetate in 250 ml of methyl ethyl ketone. This mixture was then stirred at room temperature while triethylamine (1.0 g) was added. Stirring was continued at ambient temperature for about 30 minutes when a crystalline mass precipitated. This crystalline solid was collected by filtration, washed with carbon tetrachloride and subsequently dried leaving the desired ethyl N-(((5-nitro-8-quinolinyl)oxy)carbonyl)glycinate as cream colored crystals, m.p. 121°-122° C.