Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[Cl:16][C:17]1[C:21]([CH2:22][NH:23][CH3:24])=[CH:20][S:19][C:18]=1[C:25]([N:27]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[O:30][CH2:29][CH2:28]1)=[O:26].C(N(CC)CC)C>ClCCl>[Cl:16][C:17]1[C:21]([CH2:22][N:23]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=2)(=[O:10])=[O:9])[CH3:24])=[CH:20][S:19][C:18]=1[C:25]([N:27]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[O:30][CH2:29][CH2:28]1)=[O:26]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: CNCc1csc(C(=O)N2CCOc3ccccc32)c1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(Cc1csc(C(=O)N2CCOc3ccccc32)c1Cl)S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.5 %

Procedure:
4-Chloro-3-nitrobenzenesulfonyl chloride (0.46 g, 1.8 mmol) was added to a solution of 4-(3-chloro-4-(methylaminomethyl)thiophene-2-carbonyl)benzomorpholine hydrochloride (0.54 g, 1.49 mmol) and triethylamine (0.50 ml, 0.36 g, 3.6 mmol) in dichloromethane (20 ml) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature and stirred for 3 days. The mixture was reduced and chromatographed to afford 4-(3-chloro(N-(4-chloro-3-nitrobenzenesulphonyl)-N-methylaminomethyl)thiophene-2-carbonyl)benzomorpholine (0.61 g, 76%) as a white crystalline solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:17]([C:18](OCC)=[O:19])=[CH:16][O:15][N:14]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:17]([CH2:18][OH:19])=[CH:16][O:15][N:14]=3)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1conc1-c1ccc(-c2ccccc2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1conc1-c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
To a solution of ethyl 3-(4-phenylphenyl)isoxazole-4-carboxylate (10.00 g) in tetrahydrofuran (100 ml) was gently added diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 80 ml) at 0° C. and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 3-(4-phenylphenyl)-4-isoxazolylmethanol (8.32 g, yield 97%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 138–139° C.
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][NH:19][S:20]([CH2:23][CH:24]3[CH2:26][CH2:25]3)(=[O:22])=[O:21])[CH:16]=2)[CH2:11][CH2:10][CH:9]1[NH:27]C(=O)OC(C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:27][CH:9]1[CH:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:17]2[CH:16]=[C:15]([CH2:18][NH:19][S:20]([CH:23]3[CH2:25][CH2:26][CH2:24]3)(=[O:22])=[O:21])[CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(CNS(=O)(=O)CC3CC3)cc2C1Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCc2ccc(CNS(=O)(=O)C3CCC3)cc2C1Cc1ccccc1

Procedure:
tert-Butyl 1-benzyl-7-((cyclopropylmethylsulfonamido)methyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (0.602 g, 1.242 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (0.5 mL, 6.49 mmol) and stirred overnight at room temperature. The solution was evaporated and partitioned between saturated aqueous NaHCO3 and ethyl acetate. Water was extracted with ethyl acetate (2×30 mL). The collected organic extracts were dried on MgSO4 and evaporated under reduced pressure to give a brown oil. Product was obtained as a brown oil (0.470 g, 1.22, 98%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]2[NH:18][C:17](=O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:2]=1.S(Cl)([Cl:22])=O>CN(C)C=O>[Cl:22][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([CH:8]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:18]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]c(C=Cc2cccnc2)nc2ccccc12
Solvent: CN(C)C=O
Product: Clc1nc(C=Cc2cccnc2)nc2ccccc12

Procedure:
A suspension of the quinazolinone compound (2.9 g, prepared in Reference example 15) in thionyl chloride (25 mL) and a few drops of dimethylformamide was heated at reflux for three hours. The mixture was then concentrated, the concentrate poured into 150 mL portions of chloroform, dried over potassium carbonate and concentrated to obtain the title compound (1.1 g) as a red oil.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][N:8]1[C:18](=[O:19])[CH2:17][NH:16][C:15](=[O:20])[CH:14]=[C:9]12)(=[O:3])[CH3:2].[CH3:21][N:22]([CH:24](OC)OC)[CH3:23]>CN(C=O)C>[CH3:21][N:22]([CH3:24])[CH:23]=[CH:2][C:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][N:8]1[C:18](=[O:19])[CH2:17][NH:16][C:15](=[O:20])[CH:14]=[C:9]12)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cccc2c1CCN1C(=O)CNC(=O)C=C21
Solvent: CN(C)C=O
Product: CN(C)C=CC(=O)c1cccc2c1CCN1C(=O)CNC(=O)C=C21
Temperature: 100 °C
Reaction time: 1 h
Yield: 56.1 %

Procedure:
100-2. A mixture of 9-acetyl-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (200 mg, 0.74 mmol) in DMF (1.0 mL) was treated with DMF-DMA (0.12 mL, 0.89 mmol) and stirred at 100° C. for 1 h. The mixture was concentrated in vacuo and the crude product obtained was purified by flash chromatography (SiO2, DCM/MeOH 98:2 to 85:15) to give the title compound (135 mg) as a beige solid. UPLC-MS: MS 236.2 (M+H+), UPLC rt 0.54 min.
Reaction SMILES: C([N:5]1[C:12](=O)[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6]1)CCC.N#C[Br:20]>ClCCl>[Br:20][C:12]1[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6][N:5]=1
Reactant: N#CBr
Reactant: CCCCn1sc2nc3ccccc3n2c1=O
Solvent: ClCCl
Product: Brc1nsc2nc3ccccc3n12
Temperature: 25 °C
Reaction time: 26 h
Yield: 81.4 %

Procedure:
A mixture of 2-butyl-1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-one (5.0 g, 20.2 mmole) and cyanogen bromide (4.28 g, 40.4 mmole) in 100 mL of dichloromethane was stirred at room temperature for 26 h. The precipitate was filtered and washed with dichloromethane to yield 4.18 g (81%) of 3-bromo-1,2,4-thiadiazolo[4,5-a]benzimidazole as a white powder: mp 189°-190° C.; 1H NMR (CDCl3) δ8.23 (d, 1H), 7.82 (d, 1H), 7.52 (t, 1H), 7.42 (d, 1H)ppm; 13C NMR (1:1 CDCl3 :DMSO-d6): δ162.78, 149.67, 129.22, 125.53, 122.25, 119.48, 117.25, 111.27 ppm; IR (KBr): ν3025, 2925, 1601, 1493, 1451, 1028, 757, 701 cm-1 ; HRMS calcd for C8H4N3SBr 252.9309, found 252.9307. Anal. Calcd for C8H4N3SBr: C, 37.81; H, 1.59; N, 16.54. Found: C, 37.44; H, 1.33; N, 16.57.
Reaction SMILES: C(CC[S:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31])(C(C(C(C(C(F)(F)F)(F)F)(F)F)(F)F)(F)F)(F)F.[C:32]([CH2:51][CH2:52][S:53][CH2:54][CH2:55]OCCS)([C:35]([C:38]([C:41]([C:44]([C:47]([F:50])([F:49])[F:48])([F:46])[F:45])([F:43])[F:42])([F:40])[F:39])([F:37])[F:36])([F:34])[F:33].ClCCOCCOCCO>>[C:32]([CH2:51][CH2:52][S:53][CH2:54][CH2:55][S:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31])([C:35]([C:38]([C:41]([C:44]([C:47]([F:48])([F:49])[F:50])([F:45])[F:46])([F:43])[F:42])([F:40])[F:39])([F:37])[F:36])([F:34])[F:33]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCSCCOCCS
Reactant: OCCOCCOCCSCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: OCCOCCOCCCl
Product: OCCOCCOCCSCCSCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
By proceeding in the same manner, C6F13C2H4S(C2H4O)3H is prepared from C6F13C2H4SC2H4OC2H4SH and Cl(C2H4O)3H.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]#[C:13][CH2:14][CH2:15][NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:6]=[CH:5]2.[O:27]1[CH2:29][CH:28]1[CH2:30][OH:31].C(N(CC)CC)C>CCO>[OH:27][CH:28]([CH2:30][OH:31])[CH2:29][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]#[C:13][CH2:14][CH2:15][NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH:6]=[CH:5]2
Reactant: OCC1CO1
Reactant: O=C(NCCC#Cc1ccc2cc(O)ccc2c1)OCc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(NCCC#Cc1ccc2cc(OCC(O)CO)ccc2c1)OCc1ccccc1
Yield: 51.1 %

Procedure:
A solution of 4-(6-hydroxynaphthalen-2-yl)but-3-ynylcarbamate (30, 390 mg, 1.1 mmole), oxiran-2-ylmethanol (21, 0.1 mL, 1.4 mmole), and triethylamine (0.01 mL, 0.06 mmole) in absolute EtOH (8.8 mL) was subjected to microwave irradiation at 130° C. for 30 min. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (silical gel, 95:5 CH2Cl2/MeOH) to afford carbamate 31 (236 mg, 42%) as a white solid: 1H NMR (300 MHz, CD3OD) δ 7.80 (s, 1H), 7.68 (dd, J=8.7, 3.9 Hz, 2H), 7.38-7.16 (m, 8H), 5.10 (s, 2H), 4.18 (dd, J=9.6, 4.2 Hz, 1H), 4.11-4.01 (m, 2H), 3.76-3.67 (m, 2H), 3.39-3.31 (m, 4H), 2.63 (t, J=6.9 Hz, 2H).
Reaction SMILES: [F:1][C:2](=[CH2:6])[C:3]([OH:5])=[O:4].CN(C)C=O.S(Cl)(Cl)=O.C(N(CCCC)CCCC)CCC.[F:29][C:30]([F:38])([F:37])[CH:31](O)[C:32]([F:35])([F:34])[F:33]>C1(C)C(C)=CC=CC=1>[F:1][C:2](=[CH2:6])[C:3]([O:5][CH:31]([C:32]([F:35])([F:34])[F:33])[C:30]([F:38])([F:37])[F:29])=[O:4]
Reactant: C=C(F)C(=O)O
Reactant: OC(C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1C
Product: C=C(F)C(=O)OC(C(F)(F)F)C(F)(F)F
Temperature: 80 °C

Procedure:
107 g (1 mol) of the ammonium salt of α-fluoroacrylic acid are mixed with 14.5 g (0.2 mol) of dimethylformamide and 0.6 liter of xylene, and 131 g (1.1 mol) of thionyl chloride are added dropwise to the mixture in the course of one hour; the mixture is then warmed at a temperature of 80° C. for two hours. After cooling to a temperature of 0° C., a mixture of 204 g (1.1 mol) of tributylamine and 185 g (1.1 mol) of hexafluoroisopropanol is added to the reaction mixture in the course of 30 minutes. The mixture is then stirred at a temperature of 30° C. for a further hour and is finally filtered. The filtrate is distilled under a pressure of 270 mbar and hexafluoroisopropyl α-fluoroacrylate is obtained as a colorless liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:17]([C:18]([O:20]CC3C=CC=CC=3)=[O:19])=[C:16]([CH3:28])[C:15]([CH2:29][OH:30])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([C:18]([OH:20])=[O:19])=[C:16]([CH3:28])[C:15]([CH2:29][OH:30])=[CH:14][CH:13]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1c(CO)ccc(NS(=O)(=O)c2ccc(F)cc2)c1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Cc1c(CO)ccc(NS(=O)(=O)c2ccc(F)cc2)c1C(=O)O

Procedure:
A mixture of Example 234A (71 mg, 0.17 mmol) in methanol (8 mL) was treated with 10% Pd/C (0.15 g) for 1 hour under a hydrogen atmosphere. Filtration and solvent evaporation gave the desired compound. 1H NMR (DMSO-d6) δ 2.15 (s, 3H), 4.43 (s, 2H), 5.15 (br s, 1H), 6.77 (d, 1H), 7.28 (d, 1H), 7.30-7.41 (m, 2H), 7.75-7.79 (m, 2H), 9.62 (s, 1H), 13.05 (br s, 1H); MS (ESI(−)) m/e 338 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:12])[S:9][C:10]=1[NH2:11])=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.Br[C:56]1[CH:57]=[C:58]([S:62]([NH2:65])(=[O:64])=[O:63])[CH:59]=[CH:60][CH:61]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:12])[S:9][C:10]=1[NH:11][C:56]1[CH:61]=[CH:60][CH:59]=[C:58]([S:62](=[O:64])(=[O:63])[NH2:65])[CH:57]=1)=[O:5])[CH3:2]
Reactant: NS(=O)(=O)c1cccc(Br)c1
Reactant: CCOC(=O)c1nc(C)sc1N
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(C)sc1Nc1cccc(S(N)(=O)=O)c1
Yield: 23.7 %

Procedure:
A microwave vial was charged with 5-amino-2-methyl-thiazole-4-carboxylic acid ethyl ester (0.300 g, 1.61 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (0.28 g, 0.48 mmol) and palladium dibenzylideneacetone (Pd2dba3)-chloroform complex (0.17 g, 0.16 mmol). Degassed dioxane (15.00 ml) was added, followed by 3-bromobenzenesulfonamide (0.38 g, 1.61 mmol) and cesium carbonate (0.93 g, 2.87 mmol) The vial was then irradiated in a microwave oven at 150° C. for 15 min. The mixture was diluted with THF and the solids filtered, washing with THF. The filtrate was evaporated and the residue purified by flash chromatography (heptane ethyl acetate) to yield 2-methyl-5-(3-sulfamoyl-phenylamino)-thiazole-4-carboxylic acid ethyl ester (0.13 g, 24%) as an off-white solid, MS (ISP): m/e=342.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[I:13])[C:5]([N:7]=[C:8]=[O:9])=O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])=[CH:17][C:16]=1[NH:28][NH:29]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])=[CH:17][C:16]=1[N:28]1[C:8](=[O:9])[NH:7][C:5]([C:4]2[CH:10]=[CH:11][C:12]([I:13])=[C:2]([F:1])[CH:3]=2)=[N:29]1
Reactant: O=C=NC(=O)c1ccc(I)c(F)c1
Reactant: CC(C)C(=O)NCc1ccc(Cl)c(NNC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(I)c(F)c3)[nH]c2=O)c1
Yield: 74.7 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 3-fluoro-4-iodobenzoyl isocyanate (Intermediate-102, 1.0 g), tert-butyl 2-(2-chloro-5-{[(2-methylpropanoyl)amino]methyl}phenyl)hydrazinecarboxylate (Intermediate-97, 0.800 g), DCM (15 mL), and trifluoro acetic acid (3.0 mL) to afford 0.900 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.30 (s, 6H), 2.43-2.45 (m, 1H), 4.26 (m, 2H), 7.01 (m, 1H), 7.46-7.49 (m, 1H), 7.63-7.66 (m, 1H), 7.84-7.91 (m, 1H), 8.01-8.06 (m, 1H), 8.22 (s, 1H), 8.36 (br s, 1H), 12.66 (m, 1H); MS (m/z): 515.21 (M+H)+.
Reaction SMILES: C1COCC1.Br.[CH3:7][N:8]([CH2:10][CH2:11][CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:9].O=[C:33]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[CH2:40][CH2:39][C:38]2[CH:37]=[C:36]([CH:47]=[CH:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[S:35][C:34]1=2.[ClH:54].O1CCOCC1>O1CCOCC1>[ClH:54].[CH3:7][N:8]([CH3:9])[CH2:10][CH2:11]/[CH:12]=[C:33]1\[C:34]2[S:35][C:36](/[CH:47]=[CH:48]/[C:49]([O:51][CH2:52][CH3:53])=[O:50])=[CH:37][C:38]=2[CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]\1=2
Reactant: CCOC(=O)C=Cc1cc2c(s1)C(=O)c1ccccc1CC2
Reactant: CN(C)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Br
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cc2c(s1)/C(=C\CCN(C)C)c1ccccc1CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 6 %

Procedure:
A 1.6 mol/L n-butyllithium-hexane solution (42 mL) was added to a THF (100 mL) solution of dimethylaminopropyltriphenylphosphonium hydrobromide (23.5 g) under ice-cooling, and the mixed solution was stirred at room temperature for 1 hour. A THF (100 mL) solution of the compound obtained in Example 1 (6.11 g) was added to this solution, and the mixture was further stirred overnight. The solvent was distilled off under a reduced pressure, an aqueous saturated ammonium chloride solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution, and then dried over anhydrous sodium sulfate, and the solvent was distilled off under a reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol=9:1), the purified product obtained was dissolved in 1,4-dioxane (20 mL), a 4 mol/L hydrogen chloride-dioxane solution (1.1 mL) was thereto, and the mixture was stirred at room temperature for 1 hour. The solvents were distilled off under a reduced pressure, and the precipitated crystals were filtered off and dried, to give 0.51 g (6%) of the captioned compound as a mixture of E-form and Z-form.
Reaction SMILES: [CH3:1][N:2]1[C@@H:11]2[CH2:12][C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([OH:20])[C:14]=3[C:9]3[C:10]2=[C:5]([CH:6]=[CH:7][CH:8]=3)[CH2:4][CH2:3]1.O.[C:22]([OH:31])(=[O:30])[CH:23]([CH:25]([C:27]([OH:29])=[O:28])[OH:26])[OH:24]>>[CH3:1][N:2]1[C@@H:11]2[CH2:12][C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([OH:20])[C:14]=3[C:9]3[C:10]2=[C:5]([CH:6]=[CH:7][CH:8]=3)[CH2:4][CH2:3]1.[C:27]([CH:25]([CH:23]([C:22]([O-:31])=[O:30])[OH:24])[OH:26])([O-:29])=[O:28].[CH3:1][N:2]1[C@@H:11]2[CH2:12][C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([OH:20])[C:14]=3[C:9]3[C:10]2=[C:5]([CH:6]=[CH:7][CH:8]=3)[CH2:4][CH2:3]1
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: CN1CCc2cccc3c2[C@H]1Cc1ccc(O)c(O)c1-3
Solvent: O
Product: O=C([O-])C(O)C(O)C(=O)[O-]

Procedure:
Apomorphine tartrate solution was prepared by dissolving apomorphine base in 0.1M tartaric acid solution. Water was added to obtain solutions with a molar ratio of 1:1 or 1:0.5, apomorphine:tartaric acid, at a concentration of 2% apomorphine. The pH of each solution was 3.45 and 4.0, respectively.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[N:12][OH:13])[CH3:11])=[CH:6][CH:5]=1.[C:14]([OH:18])(=[O:17])[CH:15]=[CH2:16]>C(O)C.O>[CH3:11][C:10](=[N:12][O:13][CH2:16][CH2:15][C:14]([OH:18])=[O:17])[C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=1
Reactant: C=CC(=O)O
Reactant: CC(=NO)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=NOCCC(=O)O)c1ccc(Cl)cc1

Procedure:
A solution of 2.4 g of sodium hydroxide in 55 ml of 85% ethanol was mixed with 6,78 g of 4'-chloroacetophenone oxime and 2.88 g of acrylic acid. The mixture was then refluxed for 2.5 hours, subsequently diluted with 10 ml of water, and concentrated by evaporation in a vacuum after 2 hours. The residue was dissolved in 50 ml of ether and 50 ml of water, and the layers were separated. The water layer was extracted with 50 ml of ether and then acidified with 40 ml of 2 N hydrochloric acid. The acid solution was extracted with 100 ml of ether and the ethereal solution was dried over sodium sulfate. Then the solvent was distilled off and its last traces were removed together with higher boiling substances at a pressure of 0.01 mm and a temperature of 50° C. The residue was crystallized from petroleum ether. Melting point 80° C.-83° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]=[CH:14][N:15]([CH3:17])[CH3:16])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C=NS(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
0.325 g of 4-bromobenzenesulfonamide was admixed with 0.82 g of dimethylformamide dimethyl acetal in 1.6 ml of dry dimethylformamide and stirred at room temperature for 90 min. For workup, the reaction mixture was admixed with 10 ml of water, and the precipitate was filtered off with suction, filtered and dried under reduced pressure. 4-Bromo-N-[1-dimethylaminomethylidene]benzenesulfonamide was obtained in a yield of 85%. Molecular weight 289.97 (C9H11BrN2O2S); retention time Rt=1.3 min. [B]; MS (ESI): 290.96 (MH+).
Reaction SMILES: N=[C:2]1[C:6]2([CH2:9][CH2:8][CH2:7]2)[N:5]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[C:4](=[S:17])[N:3]1[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=1.C[OH:31].O>Cl>[O:31]=[C:2]1[C:6]2([CH2:9][CH2:8][CH2:7]2)[N:5]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[C:4](=[S:17])[N:3]1[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=1
Reactant: Cc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=N)C23CCC3)cc1
Reactant: CO
Agent: Cl
Solvent: O
Product: Cc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Temperature: 25 °C

Procedure:
A mixture of 7b (0.041 g, 0.1 mmol) in HCl aq., 2N (3 ml) and methanol (1 ml) was heated to reflux 2 h. After being cooled to room temperature, the reaction mixture was poured into cold water (5 ml) and extracted with ethyl acetate (6 ml). The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane) to yield 4-(8-oxo-6-thioxo-5-(4-methylphenyl)-5,7-diazaspiro[3.4]oct-7-yl)-2-trifluoromethylbenzonitrite, 4-(8-oxo-6-thioxo-5-(4-methylphenyl)-5,7-diazaspiro[3.4]oct-7-yl)-2-trifluoromethylbenzonitrile, 7c (0.04 g, 0.096 mmol, 96%) as a white powder.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH2:26][CH3:27])=[N:19][N:20]3[CH:23]([CH3:25])[CH3:24])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][C:29]1[N:33]=[C:32]([CH2:34][C:35](OC)=[O:36])[O:31][N:30]=1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH2:26][CH3:27])=[N:19][N:20]3[CH:23]([CH3:24])[CH3:25])=[CH:16][CH:15]=2)[CH2:11][CH2:12][N:13]1[C:35](=[O:36])[CH2:34][C:32]1[O:31][N:30]=[C:29]([CH3:28])[N:33]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1nc(C)no1
Reactant: CCc1nn(C(C)C)c2cc(N3CCN[C@@H](Cc4ccccc4)C3)ccc12
Product: CCc1nn(C(C)C)c2cc(N3CCN(C(=O)Cc4nc(C)no4)[C@@H](Cc4ccccc4)C3)ccc12
Yield: 64 %

Procedure:
Prepared by the method outlined for Example 275 using 6-((S)-3-benzyl-piperazin-1-yl)-1-isopropyl-3-ethyl-1H-indazole and methyl (3-methyl-1,2,4-oxadiazol-5-yl)acetate as starting materials. Product was obtained as a colorless solid (64%). LC/MS (Method B) 3.95 min, [M+1]+ 487.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[CH:5][C:6]2[NH:7][C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[I-].[Na+].Cl[Si](C)(C)C.C(O)(=O)C>CN(C)C=O.[Zn]>[CH3:2][C:3]1[N:4]=[CH:5][C:6]2[NH:7][C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: OCc1cc2c(cn1)[nH]c1ccccc12
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1cc2c(cn1)[nH]c1ccccc12
Temperature: 80 °C
Reaction time: 18 h

Procedure:
2 g of 3-hydroxymethyl-β-carboline, 3.7 g of sodium iodide and 2.5 ml of chlorotrimethylsilane are stirred in 50 ml of N,N-dimethylformamide at a bath temperature of 35° C. for 4 hours. 3 g of zinc powder and 10 ml of glacial acetic acid are added to the resulting yellow suspension and stirred for another 18 hours at 80° C. The reaction mixture is allowed to clarify on Celite and the filtrate is concentrated under vacuum. The resulting oil is chromatographed on silica gel (methylene chloride/ethanol: 9+1). 0.825 g of 3-methyl-β-carboline with a 255°-256° C. melting point was obtained.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].N1C=CC=CC=1.[Cl:17][CH2:18][C:19]([CH3:24])([CH3:23])[C:20](Cl)=[O:21].Cl>C1(C)C=CC=CC=1>[Cl:17][CH2:18][C:19]([CH3:24])([CH3:23])[C:20]([NH:5][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[F:1])=[O:21]
Reactant: CC(C)(CCl)C(=O)Cl
Reactant: NCc1ccc(F)cc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)(CCl)C(=O)NCc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
28.6 g (0.20 mol) of 2,4-difluorobenzylamine and 19.0 g (0.24 mol) of pyridine are dissolved in 100 ml of toluene. 34.1 g (0.22 mol) of chloropivaloyl chloride are added dropwise to this solution at 20°-25° C. over the course of 15 minutes with ice-bath cooling. A suspension forms and is stirred for a further 3 hours at room temperature until the reaction is complete (GC check). For work-up, the pH is adjusted to between 1 and 2 using 50 ml of 2N hydrochloric acid. The white emulsion produced is extracted three times with 100 ml of toluene. The extract is washed with 100 ml of water, dried using magnesium sulfate and evaporated on a vacuum rotary evaporator. 49.2 g (94% of theory) of a yellow oil are obtained.