Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@H:17]([C:19]4[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=4)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C@H:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:27][CH3:28])=[O:4].[Cl:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH2:39]Br>>[Cl:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH2:39][O:25][C:22]1[CH:23]=[CH:24][C:19]([C@H:17]2[CH2:16][O:15][C:11]3=[CH:12][C:13]4[CH2:14][C@@H:5]([C:3]([OH:2])=[O:4])[N:6]([C@H:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH2:27][CH3:28])[CH2:7][C:8]=4[CH:9]=[C:10]3[O:18]2)=[CH:20][CH:21]=1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)OC)OC[C@H](c1ccc(O)cc1)O3
Reactant: Clc1cccc(CBr)c1
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCc2cccc(Cl)c2)cc1)O3

Procedure:
(3S,8S)-3-(4-Hydroxy-phenyl)-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid methyl ester (20 mg) was reacted with 3-chloro-benzyl bromide according to General Procedure J and the resulting ester was hydrolyzed according to General Procedure AB to provide (3S,8S)-3-[4-(3-chloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (20 mg). The title compound (18 mg) was prepared from (3S,8S)-3-[4-(3-chloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (20 mg) and (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride according to General Procedures L and B. LCMS (m/z): 823.
Reaction SMILES: [N:1]([C@H:4]1[C@@H:8]([CH3:9])[CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.O>[NH2:1][C@H:4]1[C@@H:8]([CH3:9])[CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
To solution of (+/−)-(cis)-benzyl 3-azido-4-methylpyrrolidine-1-carboxylat (2.00 g, 7.68 mmol) in acetonitrile (30 mL) and water (3 mL) was added triphenylphosphine (2.42 g, 9.22 mmol) in one portion as solid and the resulting mixture was stirred at rt for 30 min then heated to 60° C. overnight. The resulting mixture was concentrated and taken up in diethyl ether (300 mL), extracted with aq 2N HCl (30 mL×4). The combined aqueous washes were washed with diethyl ether, then the aqueous portion was cooled with ice-bath and was made basic by slowly adding 2N aq NaOH to pH>10. The aqueous mixture was extracted with ether (80 mL×4) and the combined ether extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated to dryness to afford the title compound as a tan oil (1.67 g, 7.13 mmol, 93%). HPLC (method B) retention time=1.51 min. LCMS (m+1)=235.2. 1H NMR (400 MHz, METHANOL-d4) δ 7.42-7.32 (m, 4H), 5.14 (s, 2H), 3.65-3′50 (m, 2H), 3.43 (td, J=5.2, 3.4 Hz, 1H), 3.32-3.28 (m, 1H), 3.25-3.14 (m, 1H), 2.33 (dsxt, J=13.7, 7.0 Hz, 1H), 1.07 (dd, J=6.8, 3.3 Hz, 3H).
Reaction SMILES: [CH:1]1([N:7]([C:32]2[S:33][CH:34]=[CH:35][N:36]=2)[C:8](=[O:31])[CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12](C(=O)C3C=CC(Cl)=CC=3)[C:11]=2[CH3:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>ClCCl.CO.[OH-].[Na+]>[CH:1]1([N:7]([C:32]2[S:33][CH:34]=[CH:35][N:36]=2)[C:8](=[O:31])[CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[NH:12][C:11]=2[CH3:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc2c(c1)c(CC(=O)N(c1nccs1)C1CCCCC1)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2[nH]c(C)c(CC(=O)N(c3nccs3)C3CCCCC3)c2c1

Procedure:
A solution of 2.42 g (0.0045 mol) of N-Cyclohexyl-N-thiazol-2-yl-1-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetamide in 2.4 mL of dichloromethane, 48 mL of methanol and 24 mL of 1N aqueous NaOH solution was stirred at rt for 90 min. During this time, the title compound formed as a precipitate. It was filtered, washed with water and dried.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]([CH3:10])[C:5]([CH3:9])([CH3:8])[CH2:6][OH:7].Cl.[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15]Cl>C1(C)C=CC=CC=1>[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][O:7][CH2:6][C:5]([CH3:9])([N:4]([CH3:10])[CH3:3])[CH3:8]
Reactant: CN(C)CCCl
Reactant: CN(C)C(C)(C)CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN(C)CCOCC(C)(C)N(C)C
Temperature: 70 °C
Yield: 27 %

Procedure:
To toluene (100 ml), sodium hydroxide (16.7 g, 418 mmol) and 2-dimethylamino-2-methyl-1-propanol (23.4 g, 200 mmol) were added and the mixture was heated at reflux for 2 hours. After cooling to 70° C., β-dimethylaminoethyl chloride hydrochloride (28.8 g, 200 mmol) was added. Then, the mixture was heated at reflux for 5.5 hours. After cooling to room temperature, insolubles were separated by filtration and the organic phase was concentrated under reduced pressure. The residue was distilled under reduced pressure to obtain 10.3 g (in a yield of 27%) of the objective compound as a colorless liquid.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]([F:20])=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:23](I)[CH3:24].O>CN(C)C=O>[CH2:23]([N:9]([C:10]1[C:11]([F:20])=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:24]
Reactant: COC(=O)c1cccc(NC(=O)c2ccccc2)c1F
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(=O)c1ccccc1)c1cccc(C(=O)OC)c1F
Yield: 61.2 %

Procedure:
Methyl 3-benzamido-2-fluorobenzoate (3.10 g, 11.0 mmol) was dissolved in N,N-dimethylformamide (30 ml), and the solution was cooled. 60% Sodium hydride (0.53 g, 13.2 mmol) was added thereto, and the reaction mixture was agitated without heating or cooling. 10 minutes later, ethyl iodide (2.05 g, 13.0 mmol) was added to the mixture, and the mixture was agitated overnight at room temperature. Water was added dropwise to the reaction mixture, and the reaction mixture was extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The sodium sulfate was filtered away, and then the filtrate was concentrated under reduced pressure. The concentration residue was purified by silica gel column chromatography (developer solvent: ethyl acetate/n-hexane=1/5), as a result of which 2.03 g (yield: 61%) of the indicated compound was obtained.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[C:11]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl.C([O-])(O)=O.[Na+]>[Br:16][C:12]1[C:11]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][N:19]=2)=[C:10]([CH2:9][CH2:8][NH2:7])[CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCc1cccc(Br)c1Oc1ccc(C(F)(F)F)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCc1cccc(Br)c1Oc1ccc(C(F)(F)F)cn1
Reaction time: 8 h
Yield: 99.2 %

Procedure:
{2-[3-bromo-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (1.3 g, 2.818 mmol) was dissolved in dichloromethane (10 ml) and stirred at 0° C. for 5 min TFA (1.08 ml, 14.091 mmol, 5 eq) was added and stirring was continued overnight. Reaction mixture was diluted with 10 ml NaHCO3 (sat.) and extraction with DCM (3×20 ml) followed. Organic layers were combined and evaporated in vacuo to give 2-[3-bromo-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl]-ethylamine (1.01 g, 2.796 mmol, yield=99%, purity=100%). [M+H]+=361.17
Reaction SMILES: Br[C:2]1[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:3]=1[CH2:4][O:5][CH:6]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[CH:14][CH:13]=2)[CH2:10][CH2:9][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7]1.C(=[NH:57])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>[Cl-].[Na+].O>[NH2:57][C:2]1[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:3]=1[CH2:4][O:5][CH:6]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[CH:14][CH:13]=2)[CH2:10][CH2:9][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(C)cc2Br)cc1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(C)cc2N)cc1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
The mixture of 0.800 g of tert-butyl 3-(2-bromo-4-methylbenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate, 0.250 ml of benzophenone imine, 0.0037 g of dipalladiumtris(dibenzylidenacetone)-chloroform complex, 0.0051 g of (R)-(+)-2,2′-bis(diphenylphosphine)-1,1′-binaphthyl and 0.168 g of sodium tert-butoxide is admixed with 6.0 ml of toluene and stirred under argon at 80° C. over 72 hours. The reaction mixture is cooled, admixed with brine (20 ml) and extracted with ethyl acetate (2×80 ml). The organic phases are dried over sodium sulphate, filtered and concentrated by evaporation. The residue is dissolved in 6.0 ml of methanol, admixed with 0.090 g of 5% Pd/C and 1.15 g of ammonium formate, and stirred at 60° C. over 72 hours. The reaction mixture is diluted with methanol (20 ml) and clarified by filtration, and the filtrate is concentrated by evaporation. The residue is admixed with 0.1M NaOH (100 ml) and extracted with ethyl acetate (2×100 ml). The organic phases are washed successively with 0.1M NaOH (100 ml) and brine (100 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.30 (1:2 EtOAc-heptane); Rt=5.32.
Reaction SMILES: [C:1]([CH2:3][O:4][CH2:5][C@@H:6]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[N:13](COCC[Si](C)(C)C)[CH:12]=1)=[O:10])[CH3:7])#[N:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([CH2:3][O:4][CH2:5][C@@H:6]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[NH:13][CH:12]=1)=[O:10])[CH3:7])#[N:2]
Reactant: C[C@@H](COCC#N)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H](COCC#N)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.8 %

Procedure:
In a round-bottomed flask containing 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-cyanomethoxy-1-methyl-ethyl)-amide (55 mg, 0.102 mmol) dissolved in THF (1 ml) was added TBAF (1.0 M in THF, 1.0 ml, 1.0 mmol). The flask was backfilled with nitrogen then sealed and placed in an oil bath at 85° C. for 2 h. The reaction was cooled to room temperature, quenched with acetone (2 ml) and sat'd NaHCO3 (4 ml). The mixture was stirred for 1 h then diluted with water and extracted twice with EtOAc. The combined organics were washed with water and brine then dried over MgSO4, filtered and concentrated. The crude solid was purified by flash chromatography (4 g silicycle) with 0% to 10% MeOH in dichloromethane. The appropriate fractions were combined and concentrated. The solid was triturated with Et2O to afford 7 mg (16%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-cyanomethoxy-1-methyl-ethyl)-amide as a light brown solid. LC-MS (M+H)+=408; 1H NMR (300 MHz, DMSO-d6) δ: 12.95 (br. s., 1H), 9.17 (s, 1H), 8.47-8.62 (m, 2H), 8.26 (d, J=8.5 Hz, 1H), 7.76 (dd, J=9.8, 2.0 Hz, 1H), 7.25 (td, J=9.0, 2.3 Hz, 1H), 4.57 (s, 2H), 4.43-4.53 (m, 1H), 4.21 (s, 3H), 3.66-3.85 (m, 2H), 1.40 (d, J=6.8 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:26])=[C:11]([CH2:13][CH2:14][O:15]S(C3C=CC(C)=CC=3)(=O)=O)[N:12]=2)=[CH:4][CH:3]=1.[CH3:27][O:28][C:29](=[O:40])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][C:33]=1[CH3:39].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH3:27][O:28][C:29](=[O:40])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:15][CH2:14][CH2:13][C:11]2[N:12]=[C:8]([C:5]3[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[O:9][C:10]=2[CH3:26])=[CH:34][C:33]=1[CH3:39]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(Cl)nc3)oc2C)cc1
Reactant: COC(=O)CCc1ccc(O)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(OCCc2nc(-c3ccc(Cl)nc3)oc2C)cc1C
Temperature: 60 °C

Procedure:
A mixture of toluene-4-sulfonic acid 2-[2-(6-chloro-pyridin-3-yl)-5-methyl-oxazol-4-yl]-ethyl ester (0.4 g, 1.0 mmol, 3-(4-Hydroxy-2-methyl-phenyl)-propionic acid methyl ester (0.2 g, 1 mmol) and Cs2CO3 (0.49 g, 1.5 mmol) in DMF (5 mL) is heated at 60° C. overnight, cooled to room temperature, diluted with ethyl acetate, washed with water and dried. Column chromatography on silica gel gave the product (85 mg).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]([C:13]2[CH:17]=[CH:16][O:15][CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([CH3:18])=[CH:8][CH:9]=2)[N:4]=1)#[N:2].C1C(=O)N([Br:26])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:26][CH2:18][C:7]1[CH:6]=[C:5]2[C:10]([C:11]([C:13]3[CH:17]=[CH:16][O:15][CH:14]=3)=[CH:12][C:3]([C:1]#[N:2])=[N:4]2)=[CH:9][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(-c3ccoc3)cc(C#N)nc2c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(-c2ccoc2)c2ccc(CBr)cc2n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-cyano-4-(furan-3-yl)-7-methylquinoline (4.2 g) in refluxing CCl4 (400 mL) was added NBS (3.3 g) and AIBN (150 mg) portionwise. After 90 min., the mixture was cooled to r.t. filtered through a pad of silica gel washing with CH2Cl2. The filtrate was concentrated and swished with Et2O for 15 h. The solid precipitate was collected and was 85% of the title compound. This material was used as such in the subsequent reactions.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH3:13])[CH:7]=[CH:6]2.C1C(=O)N([Br:21])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>ClC1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH2:13][Br:21])[CH:7]=[CH:6]2
Reactant: COc1ccc2nc(C)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Product: COc1ccc2nc(CBr)ccc2c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 27.6 %

Procedure:
A mixture of 6-methoxy-2-methylquinoline (999 mg, 5.77 mmol), NBS (1.03 g, 5.77 mmol), AIBN (153 mg) and chlorobenzene (10 mL) was stirred at 120° C. for 2 hours, then added with AIBN (153 mg) again and further stirred for 4 hours with heating. The solvent was evaporated under reduced pressure, and then the residue was extracted with ether. The solvent was evaporated, and the residue was recrystallized from ethanol to obtain 6-methoxy-2-bromomethylquinoline as white powder (yield: 400 mg, 1.59 mmol, 28%).
Reaction SMILES: [CH3:1][N:2]([CH3:4])[CH3:3].[S:5]([C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1)([O-:8])(=[O:7])=[O:6].[C:16]1([CH3:22])C=CC=C[CH:17]=1>>[S:5]([C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1)([O-:8])(=[O:7])=[O:6].[OH:6][CH2:17][CH2:16][CH2:22][N+:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: Cc1ccccc1
Reactant: CN(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: C[N+](C)(C)CCCO
Reaction time: 72 h

Procedure:
7 ml of 18% trimethylamine in toluene was added to 2.0 g (9.2 mmole) of the above tosylate, and the mixture was allowed to stand at room temperature for 3 days. The crystals separated out were collected by filtration, washed with toluene and dried under reduced pressure to give 3-hydroxypropyltrimethylammonium tosylate as colorless needles. Melting point: 80° C. Yield: 2.3 g (yield: 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.[N+:25]([C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH2:30][NH:31][CH2:32]2)([O-:27])=[O:26].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[N+:25]([C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH2:30][N:31]([C:15]1[C:16]([F:18])=[C:17]3[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:13][C:14]=1[F:20])[CH2:32]2)([O-:27])=[O:26]
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Reactant: O=[N+]([O-])c1cccc2c1CNC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(N3Cc4cccc([N+](=O)[O-])c4C3)c(F)cc2c1=O
Yield: 35.7 %

Procedure:
200 mg of 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 176 mg of 4-nitroisoindoline, 164 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 102 mg of the target compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(N(C)C)=O.[Br:18][C:19]1[CH:20]=[N:21][C:22](Cl)=[N:23][CH:24]=1>O>[Br:18][C:19]1[CH:20]=[N:21][C:22]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[N:23][CH:24]=1
Reactant: c1cn[nH]c1
Reactant: Clc1ncc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Brc1cnc(-n2cccn2)nc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 126.1 %

Procedure:
Pyrazole (130 mg) and cesium carbonate (610 mg) were added to a DMAc (10 ml) solution containing 5-bromo-2-chloropyrimidine (300 mg), followed by stirring at 120° C. for 0.5 hours. The reaction mixture was adjusted to room temperature and water was added to the mixture. Next, the organic layers were collected, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure and a yellow solid of 5-bromo-2-(pyrazol-1-yl)pyrimidine (440 mg) was thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[S:30]1[CH:34]=[C:33]([CH2:35]O)[N:32]=[CH:31]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:35][C:33]5[N:32]=[CH:31][S:30][CH:34]=5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: OCc1cscn1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1Cc1cscn1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(1,3-thiazol-4-ylmethyl)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and thiazol-4-yl-methanol following General Procedure J.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][CH:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:6][CH:5]=1.[H-].[Na+].[Cl:20][C:21]([Cl:25])=[CH:22][CH2:23]Cl>CN(C)C=O>[Cl:20][C:21]([Cl:25])=[CH:22][CH2:23][C:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:16])([F:17])[F:1])=[CH:15][CH:14]=1)([C:12]#[N:13])[C:10]#[N:11]
Reactant: ClCC=C(Cl)Cl
Reactant: N#CC(C#N)Cc1ccc(OC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CC=C(Cl)Cl)Cc1ccc(OC(F)(F)F)cc1
Yield: 28 %

Procedure:
Using 0.20 g of (4-(trifluoromethoxy)benzyl)malononitrile, 5 ml of N,N-dimethylformamide, 50 mg of sodium hydride (60% in oil), and 0.17 ml of 1,1,3-trichloropropene, and according to the process described in the Production Example 1, there was obtained 80 mg of 2-(3,3-dichloro-2-propenyl)-2-(4-(trifluoromethoxy)benzyl)malononitrile (the present compound (28)).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:3]=1[C:4]([NH:6][C:7](=[O:24])[NH:8][C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=1[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[O:21])=[O:5].Cl>[Zn].C(O)(=O)C>[NH2:15][C:13]1[CH:12]=[CH:11][C:10]([CH:18]=[CH:19][C:20]([O:22][CH3:23])=[O:21])=[C:9]([NH:8][C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:2]=2[Cl:1])=[O:24])[CH:14]=1
Reactant: COC(=O)C=Cc1ccc([N+](=O)[O-])cc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: COC(=O)C=Cc1ccc(N)cc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
8.5 g (19.3 mmol) of methyl 3-{2-[3-(2-chloro-4,5-difluorobenzoyl)ureido]-4-nitro-phenyl}acrylate were suspended in 60 ml of a mixture of glacial acetic acid and concentrated hydrochloric acid (10:1) and heated to 70° C. Then 8.85 g (135.3 mmol) of zinc powder were added. After 30 minutes, the mixture was cooled, the solid was filtered off with suction, and the filtrate was concentrated. The residue was taken up in ethyl acetate and washed with a 10% strength sodium bicarbonate solution. The organic phase was dried and concentrated. 7.9 g (100%) of the desired product were obtained.
Reaction SMILES: [OH-].[Na+].C([N:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[C:8](=[C:18]([O:25][CH2:26][CH3:27])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]1=[O:28])(=O)C>C(Cl)Cl.CCO>[CH2:26]([O:25][C:18](=[C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[NH:6][C:7]1=[O:28])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH3:27]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Reaction time: 0.5 h

Procedure:
1.5 equivalents of 1N sodium hydroxide solution are added dropwise to a stirred mixture of 1-acetyl-3-{1-ethoxy-1-phenylmethylidene}-5-nitro-2-indolinone in methylene chloride (11 ml/g) and EtOH (8.5 ml/g) whilst cooling with ice so that the internal temperature does not exceed 14 to 17° C. Then stirring is continued for 0.5 hours at ambient temperature and the methylene chloride is eliminated by evaporation in vacuo at a bath temperature of 30° C. Water is added (11 ml/g) and the mixture is thoroughly stirred. The precipitate is filtered, washed with water, isopropanol and lastly with ether and dried at 100° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:36])([F:35])[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])=[CH:23][CH:22]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:36])([F:19])[F:35])=[CH:26][CH:25]=3)=[O:33])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccc(C(F)(F)F)cc1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3ccc(C(F)(F)F)cc3)n2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(4-trifluoromethyl-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 01b: tR=1.03 min; [M+H]+=445.11.