Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[N:8]=[CH:9][S:10][C:11]=1[CH3:12].[C:13]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)(=[O:15])[CH3:14]>C(OCC)C>[CH3:6][C:7]1[N:8]=[C:9]([C:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)([OH:15])[CH3:14])[S:10][C:11]=1[CH3:12]
Reactant: Cc1ncsc1C
Reactant: CC(=O)c1cccs1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1nc(C(C)(O)c2cccs2)sc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.5M solution in hexanes, 9.7 ml) was added dropwise to a stirred solution of 4,5-dimethylthiazole (2.5 g) in dry diethyl ether (30 ml) at -70° C. under an atmosphere of dry nitrogen. After 30 minutes, 2-acetylthiophene (3.1 g) in diethyl ether (20 ml) was added dropwise. After a further 1 hour the mixture was allowed to warm to room temperature and was then worked up in the normal fashion to yield the title compound.
Reaction SMILES: [CH2:1]([N:3](CC)CC)[CH3:2].[Cl:8][C:9]1[C:18]([C:19](Cl)=[O:20])=[C:17]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:8][C:9]1[C:18]([C:19]2[O:20][CH2:2][CH2:1][N:3]=2)=[C:17]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: CCN(CC)CC
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C(=O)Cl)c1Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C2=NCCO2)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 45.6 %

Procedure:
At room temperature, 41.8 g (0.41 mol) of triethylamine and then 31.1 g (0.10 mol) of methyl 2-chloro-3-chlorocarbonyl-4-methylsulfonylbenzoate in 150 ml of toluene were added dropwise to 26.6 g (0.13 mol) of I-amino-2-bromoethane hydrobromide in 500 ml of toluene. The mixture was heated under reflux for 5 hours and then stirred at room temperature for 12 hours, another 5.0 g (0.02 mol) of I-amino-2-bromoethane hydrobromide were added and the mixture was heated under reflux for 7.5 hours. The reaction mixture was allowed to cool, diluted with ethyl acetate, washed with water, dried and concentrated. The residue was then recrystallized from methyl tert-butyl ether/ethyl acetate. 14.5 g (46% of theory) of methyl 2-chloro-4-methylsulfonyl-3-(4,5-dihydrooxazol-2-yl)benzoate were obtained.
Reaction SMILES: C([O:5][C:6](=[O:20])/[CH:7]=[CH:8]/[C:9]1[CH:10]=[N:11][C:12]2[NH:13][C:14](=[O:19])[CH2:15][CH2:16][C:17]=2[CH:18]=1)(C)(C)C.[O:21]1CCOCC1.[OH-].[Na+].Cl>CO>[NH2:13][C:12]1[N:11]=[CH:10][C:9](/[CH:8]=[CH:7]/[C:6]([OH:5])=[O:20])=[CH:18][C:17]=1[CH2:16][CH2:15][C:14]([OH:19])=[O:21]
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ncc(/C=C/C(=O)O)cc1CCC(=O)O
Reaction time: 0.33 h
Yield: 78 %

Procedure:
A solution of (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)acrylic acid tert-butyl ester (0.86 g, 3.0 mmol) was stirred in methanol (10 mL), dioxane (10 mL) and aq. NaOH (15 mL of a 1 N solution, 15 mmol) for 4 days. The clear solution was neutralized with aq. HCl (15 mL of a 1 N solution, 15 mmol) and stirred for 20 min. The white precipitate was collected by filtration to give (E)-3-[6-amino-5-(2-carboxy-ethyl)pyridin-3-yl]acrylic acid (0.57 g, 78%): MS (ESI) m/e 237 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:10]([SH:21])=[N:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:13][CH:14]=1)=[O:8])[CH3:2].II>>[CH2:22]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:7](=[O:8])[C:9]2[C:10](=[N:11][C:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[N:13][CH:14]=2)[S:21]1)[CH3:23]
Reactant: CCN(CC)CCNC(=O)c1cnc(-c2ccccc2)nc1S
Agent: II
Product: CCN(CC)CCn1sc2nc(-c3ccccc3)ncc2c1=O
Yield: 68.5 %

Procedure:
Using the procedure of Example 20, 3.3 g (0.01 mol) of 4-mercapto-2-phenyl-pyrimidine-5-carboxylic acid (2-diethylamino-ethyl)-amide (from Preparation 36) and 2.54 g (0.01 mol) of iodine were reacted to give 2.25 g of the title compound after recrystallization from isopropanol, mp 106-107° C.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([C:17]([O:19][CH3:20])=[O:18])[C:10]3[NH:14][C:13](=O)[NH:12][C:11]=3[CH:16]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:32]>>[Cl:32][C:13]1[NH:14][C:10]2[C:9]([C:17]([O:19][CH3:20])=[O:18])=[CH:8][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:16][C:11]=2[N:12]=1
Reactant: COC(=O)c1cc(N2CCOCC2)cc2[nH]c(=O)[nH]c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: COC(=O)c1cc(N2CCOCC2)cc2nc(Cl)[nH]c12
Temperature: 103 °C
Yield: 23 %

Procedure:
To a solution of combined batches of methyl 6-(4-morpholinyl)-2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate (6.8 g, 24.5 mmol) in POCl3 (25 mL) was added N,N-Dimethylaniline (8.8 g, 73.5 mmol) and the mixture was heated to 103° C. for 12 h. When TLC analysis showed no starting material remaining, the mixture was cooled to room temperature, purified by chromatography (eluted with petroleum ether/EtOAc=1/1) on silica to afford the desired product as a off-white solid (1.6 g, 23%). 1H NMR (300 MHz, DMSO-d6): δ ppm 3.11 (t, 4H, J=4.5 Hz), 3.77 (t, 4H, J=4.5 Hz), 3.93 (s, 3H), 7.43 (d, 1H, J=1.8 Hz), 7.50 (d, 1H, J=1.8 Hz), 12.97 (s, 1H). LC-MS: m/e=296 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH:38]([C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41])[NH2:39]>C(N(CC)CC)C.C(Cl)Cl>[CH2:43]([O:42][C:40]([NH:38][NH:39][C:13]([C@@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15])=[O:41])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: NNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NNC(=O)OCc1ccccc1
Reaction time: 0.17 h
Yield: 81.5 %

Procedure:
(S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.076 g, 5.00 mmol) was stirred under an argon atmosphere at room temperature with dehydrated methylene chloride (16 mL). Then, N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC, 1.15 g), 1-hydroxybenzotriazole.monohydrate (HOBt.H2O, 0.918 g), and triethylamine (1.01 g) were added, followed by stirring for 10 minutes. Benzyl hydrazinecarboxylate (1.66 g) was added, followed by stirring for 18 hours. After completion of the reaction, the reaction solution was washed with 0.5M hydrochloric acid and saturated brine, then the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, after that, the resulting residue was subjected to silica gel column chromatography (hexane/ethyl acetate=4/1→0/1→ethyl acetate/methanol=30/1) to afford 1.48 g of the title compound (yield 81.6%).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8]C)=[C:6]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[C:5]([C:17]#[N:18])=[C:4]([CH3:19])[C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=1.BrB(Br)Br.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[Br:1][C:2]1[C:7]([OH:8])=[C:6]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:13])[CH3:14])[C:5]([C:17]#[N:18])=[C:4]([CH3:19])[C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=1
Reactant: COc1c(Br)c(-c2cccc([N+](=O)[O-])c2)c(C)c(C#N)c1NC(=O)C(C)(C)C
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1c(C#N)c(NC(=O)C(C)(C)C)c(O)c(Br)c1-c1cccc([N+](=O)[O-])c1
Temperature: -70 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
N-(2-Bromo-5-cyano-3-methoxy-6-methyl-3′-nitrobiphenyl-4-yl)-2,2-dimethylpropionamide (I-12) (630 mg, 1.41 mmol) was dissolved in dichloromethane (dewatered, 20 ml) under nitrogen atmosphere, cooled at −70° C. in a dry ice-methanol bath. 1 M tribromoborane (dichloromethane solution) (4.23 ml) was dropwise added to it at −70° C. to −68° C., followed by stirring for 2 hours with heating up to 0° C. The reaction liquid was diluted with cold water, followed by pH control at 6 to 7 by addition of aqueous 10% sodium carbonate solution. The organic matter was extracted with ethyl acetate, washed with saturated brine, dried on anhydrous magnesium sulfate, the solvent was evaporated away under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1→3:2) to obtain the entitled compound (503 mg, 82%) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[C:3]2[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[CH2:23]([O:25][C:26]1[CH:37]=[CH:36][C:29]([CH2:30][CH2:31][NH:32][CH2:33][CH2:34][NH2:35])=[CH:28][C:27]=1[O:38][CH3:39])[CH3:24].O>CN1C(=O)CCC1>[CH2:23]([O:25][C:26]1[CH:37]=[CH:36][C:29]([CH2:30][CH2:31][NH:32][CH2:33][CH2:34][NH:35][C:2]2[C:3]3[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]([C:14]4[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=4[CH3:22])[C:4]=3[N:5]=[C:6]([CH3:8])[N:7]=2)=[CH:28][C:27]=1[O:38][CH3:39])[CH3:24]
Reactant: CCOc1ccc(CCNCCN)cc1OC
Reactant: Cc1cc(C)c(-n2c(C)c(C)c3c(Cl)nc(C)nc32)c(C)c1
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOc1ccc(CCNCCNc2nc(C)nc3c2c(C)c(C)n3-c2c(C)cc(C)cc2C)cc1OC

Procedure:
Heat a solution of 4-chloro-2,5,6-trimethyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidine (340 mg, 1.1 mmol) and N-(4-ethoxy-3-methoxy-phenethyl)-ethylenediamine in NMP (2 mL) for 14 h at 130° C. Pour into water (5 mL) and extract with EtOAc (2×10 mL). Dry the combined organic extracts over Na2SO4, filter, and concentrate under reduced pressure. Purify by preparative TLC, eluting with 10% MeOH in CH2Cl2. Dissolve the residue in a minimum amount of MeOH then add HCl in EtOAc (2 mL) and triturate with Et2O to obtain the title compound as a solid (HCl salt).
Reaction SMILES: [OH-].[Na+:2].[CH:3]1([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][C:16]([O:18][C:19]4[N:24]=[C:23]([C:25]([O:27]C)=[O:26])[C:22]([C:29]([O:31]C)=[O:30])=[CH:21][CH:20]=4)=[CH:17][C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1>O.C(O)C>[CH:3]1([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][C:16]([O:18][C:19]4[N:24]=[C:23]([C:25]([O-:27])=[O:26])[C:22]([C:29]([O-:31])=[O:30])=[CH:21][CH:20]=4)=[CH:17][C:10]=3[CH2:9][CH2:8]2)[CH2:4][CH2:5][CH2:6]1.[Na+:2].[Na+:2]
Reactant: COC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C([O-])c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1C(=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium hydroxide (0.66 g) in water (3 ml) was added to a solution of dimethyl 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2,3-pyridinedicarboxylate (E231) (1.69 g, 4.12 mmol) in ethanol (20 ml) at room temperature. The mixture was vigorously stirred at room temperature for 4 h and the resulting precipitate filtered off to give the title compound as a colourless solid (E232); MS (ES+) m/e 383 [M+H]+.
Reaction SMILES: [N:1]([CH:4]([C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=1)[C:5]([O:7]C)=[O:6])=[N+:2]=[N-:3].[OH-].[Li+]>C1COCC1.O>[N:1]([CH:4]([C:9]1[CH:10]=[C:11]([F:16])[CH:12]=[C:13]([F:15])[CH:14]=1)[C:5]([OH:7])=[O:6])=[N+:2]=[N-:3]
Reactant: COC(=O)C(N=[N+]=[N-])c1cc(F)cc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: [N-]=[N+]=NC(C(=O)O)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 2-azido-2-(3,5-difluorophenyl)acetate in THF/H2O (2.6:1) cooled to 0° C. was added 1.7 eq. of lithium hydroxide. The reaction mixture was stirred at room temperature for 3 hours and then poured into a separatory funnel. The mixture was extracted into water and washed with ether. The aqueous layer was acidified with 1N HCl and extracted with ethyl acetate. The organic layer was then washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2-azido-2-(3,5-difluorophenyl)acetic acid.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[CH3:14]O>S(=O)(=O)(O)O.CCOC(C)=O>[NH2:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([O:10][CH3:14])=[O:9])(=[O:3])=[O:4]
Reactant: NS(=O)(=O)c1cccc(C(=O)O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(S(N)(=O)=O)c1
Yield: 98 %

Procedure:
3-(Aminosulfonyl)benzoic acid (603 mg, 3.0 mmol) was heated at 80° C. in CH3OH (3 mL) with 3 drops of concentrated sulfuric acid for 60 hours. The reaction mixture was diluted with EtOAc (20 mL), washed with water, brine, and dried (Na2SO4). The solvent was evaporated to afford the product (630 mg, 98%) as a white solid. MS (ES+) m/z 216 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([C:17]#[N:18])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:19][NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:17]([C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][CH2:2][N:20]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH3:19])#[N:18]
Reactant: CNCCc1ccc(F)cc1
Reactant: N#CC(CCBr)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCc1ccc(F)cc1)CCC(C#N)(c1ccccc1)c1ccccc1

Procedure:
A mixture containing 3-bromo-1-cyano-1,1-diphenylpropane (1.5 g)--see Preparation 4), N-methyl-4-fluorophenethylamine (0.766 g--see CA 80:PIZ0985y), anhydrous potassium carbonate (1.38 g) and acetonitrile (50 ml) was heated under reflux for 24 hours then concentrated in vacuo. The residue was dissolved in water (40 ml) and extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (Na2SO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with hexane containing dichloromethane (25% up to 100%) and then with dichloromethane containing methanol (0% up to 3%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a gum, yield, 0.51 g.
Reaction SMILES: [CH3:1][N:2]1[C:12]2[C:7](=[C:8]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)[CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:3]1=[O:4].[CH2:18]([CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CO.[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].CC(C)=O>CC(C)=O>[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].[CH3:1][N:2]1[C:12]2[C:7](=[C:8]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][N:28]3[CH2:29][CH2:30][CH:25]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)[CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:3]1=[O:4]
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: CN1C(=O)CCc2c(OCC3CO3)cccc21
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CC(C)=O
Product: CN1C(=O)CCc2c(OCC(O)CN3CCC(Cc4ccccc4)CC3)cccc21
Temperature: 25 °C
Yield: 78 %

Procedure:
2.4 Grams of 1-methyl-5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril and 2.0 g of 4-benzylpiperidine were mixed with 30 ml of methanol and the mixture was heated under refluxing condition for 3 hours. The reaction mixture was concentrated under a reduced pressure and the residue thus obtained was dissolved in 30 ml of acetone and a 5%-oxalic acid-acetone solution was added under stirring at a room temperature to adjust the pH to 4.5 and allowed to stand. The precipitates thus formed were collected by filtration, washed with acetone and recrystallized from ethanol-ether to obtain 3.9 g (yield: 78%) of 1-methyl-5-[2-hydroxy-3-(4-benzyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyril monooxalate as in the form of colorless powder. Melting point: 150°-152° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:17])[CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[F:18][C:19]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:20]=1[C:21](Cl)=[O:22]>C1(C)C=CC=CC=1>[CH3:8][N:9]([CH3:17])[CH:10]=[C:11]([C:21](=[O:22])[C:20]1[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:19]=1[F:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C=CN(C)C
Reactant: O=C(Cl)c1cc(F)c(F)cc1F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(F)c(F)cc1F
Temperature: 90 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a solution of triethylamine (107 mL, 771 mmol) and ethyl 3-(dimethylamino)acrylate (55.2 mL, 386 mmol) in toluene (250 mL) was added dropwise a toluene solution of 2,4,5-trifluorobenzoyl chloride (50 g, 257 mmol). The mixture was stirred at 90° C. for 3 h. LCMS showed completion of reaction. After cooling down, the reaction mixture was washed with water and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated to afford ethyl 3-(dimethylamino)-2-(2,4,5-trifluorobenzoyl)acrylate (65 g, 216 mmol, 84% yield) as a brown oil. LCMS: (M+H)+: 302.1.
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][C:13]2[N:14]=[C:15]([NH:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=3[C:29]([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])=[O:20])[S:16][CH:17]=2)=[CH:6][CH:5]=1>[Li+].[OH-]>[CH:31]1([C:29]([C:23]2[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=2[NH:21][C:19](=[O:20])[NH:18][C:15]2[S:16][CH:17]=[C:13]([CH2:12][CH2:11][O:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:36])=[O:2])=[CH:9][CH:8]=3)[N:14]=2)=[O:30])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COC(=O)c1ccc(OCCc2csc(NC(=O)Nc3ccc(C)cc3C(=O)C3CCCC3)n2)cc1
Agent: [Li+]
Agent: [OH-]
Product: Cc1ccc(NC(=O)Nc2nc(CCOc3ccc(C(=O)O)cc3)cs2)c(C(=O)C2CCCC2)c1
Yield: 96.2 %

Procedure:
4-(2-{2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}ethoxy) benzoic acid (19 mg, 96%) was prepared from 4-(2-{2-[3-(2-cyclopentanecarbonyl-4-methylphenyl)-ureido]-thiazol-4-yl}ethoxy) benzoic acid methyl ester (0.020 g, 0.04 mmol) and 2.5M LiOH (20 uL) following the general procedure J.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:20])=[N:4][C:5]([C:9]2[C:13]([Cl:14])=[C:12]([O:15][CH:16]([F:18])[F:17])[N:11]([CH3:19])[N:10]=2)=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29]([NH2:31])=[O:30]>>[Cl:1][C:2]1[C:3]([O:20][CH2:28][C:29]([NH2:31])=[O:30])=[N:4][C:5]([C:9]2[C:13]([Cl:14])=[C:12]([O:15][CH:16]([F:17])[F:18])[N:11]([CH3:19])[N:10]=2)=[C:6]([F:8])[CH:7]=1
Reactant: Cn1nc(-c2nc(O)c(Cl)cc2F)c(Cl)c1OC(F)F
Reactant: NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cn1nc(-c2nc(OCC(N)=O)c(Cl)cc2F)c(Cl)c1OC(F)F
Temperature: 50 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
20.0 g of 3-chloro-6-(4-chloro-5-difluoromethoxy-1-methyl-[1H]-pyrazol-3-yl)-5-fluoropyridin-2-ol (Example P27) are placed together with 18.9 g of potassium carbonate and 6.4 g of chloroacetamide at 22° C. and the mixture is stirred overnight at 50° C. The next day, the mixture is cooled to 22° C. and then introduced into 2 liters of ice-water. After subsequently stirring for 10 minutes at 22° C., the resulting slurry is filtered. The filtration residue is washed with cold water and then dried in vacuo at 60° C. 20.2 g of the desired title compound are obtained in the form of a white solid having a melting point of 178-180° C.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]([CH2:17][CH3:18])[CH:4]([C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[C:20]([S-:22])#[N:21].[K+].BrBr>CC(O)=O>[CH3:1][N:2]([CH3:19])[CH:3]([CH2:17][CH3:18])[CH:4]([C:10]1[CH:16]=[CH:15][C:13]2[N:14]=[C:20]([NH2:21])[S:22][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: CCC(C(c1ccc(N)cc1)n1ccnc1)N(C)C
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CCC(C(c1ccc2nc(N)sc2c1)n1ccnc1)N(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)aniline (600 mg, 2.32 mmol) and KSCN (508 mg, 5.22 mmol) in 15 mL AcOH was cooled to about 7° C. and treated with Br2 (125 μL, 2.43 mmol) in 2 mL AcOH added dropwise via syringe over 5 min. The reaction vessel was removed from the cooling bath and stirred at rt for 1 hr. The reaction was cooled in an ice bath and basified with 3N NaOH (100 mL) added portionwise over several minutes. This mixture was then extracted with DCM (4×75 mL). The combined organic extracts were dried over Na2SO4, decanted and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 6% MeOH (2N NH3)/DCM to give 6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine as a yellow foam. MS ESI: m/z 316.16 [M+1+].
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:31](Cl)(=[O:34])[CH:32]=[CH2:33]>C(Cl)Cl>[C:31]([N:21]1[CH2:22][CH2:23][CH:18]([N:4]([CH:1]2[CH2:3][CH2:2]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:19][CH2:20]1)(=[O:34])[CH:32]=[CH2:33]
Reactant: C=CC(=O)Cl
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
To a solution of N-cyclopropyl-N-piperidin-4-yl-3-trifluoromethyl-benzene sulfonamide (1045 mg, 3 mmol) in CH2Cl2 was added triethylamine (0.418 ml, 3 mmmol) and acryloyl chloride (0.244 ml, 3 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min. After quenching with water (5 ml), the mixture was extracted by CHCl3 (50 ml×2), washed with brine (50 ml×2). The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (AcOEt/n-hexane=4/1) to afford the title compound 1 (648 mg, yield 54%). LC: 100%. MS: m/z=402.39, 403.18 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[C:12](=[O:13])[CH:11]([CH3:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[C:8]2[C:19]([NH2:23])=[CH:20][CH:21]=[CH:22][C:7]1=2)=[O:5])[CH3:3].N1C=CC=CC=1.[CH2:30]([S:34](Cl)(=[O:36])=[O:35])[CH2:31][CH2:32][CH3:33]>CN(C=O)C>[CH2:30]([S:34]([NH:1][C@H:2]([C:4]([N:6]1[C:12](=[O:13])[CH:11]([CH3:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[C:8]2[C:19]([NH2:23])=[CH:20][CH:21]=[CH:22][C:7]1=2)=[O:5])[CH3:3])(=[O:36])=[O:35])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCS(=O)(=O)Cl
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCCCS(=O)(=O)N[C@@H](C)C(=O)N1C(=O)C(C)c2ccccc2-c2c(N)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 342.7 %

Procedure:
To 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7B) (0.1500 g, 0.0485 mmol) in DMF (4 ml) were added pyridine (0.059 ml, 0.728 mmol) and 1-butanesulfonyl chloride (Aldrich) (0.063 ml, 0.485 mmol), stirred at RT overnight. The reaction mixture was evaporated to dryness. Water was added, extracted with EtOAc, washed with brine, dried over MgSO4. Evaporation and flash chromatography (silica, 5% MeOH/CH2Cl2), gave the title compound (0.0714 g, 34%) as a yellow solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[N:9]1(C(OC(C)(C)C)=O)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>O>[N:9]1([C:2]2[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=2)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: O=Cc1ccc(Br)s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O
Product: O=Cc1ccc(N2CCNCC2)s1
Yield: 71.5 %

Procedure:
A suspension of 1.09 g (5.7 mmol) of 5-bromothiophene-2-carboxaldehyde and 3.19 g (17.1 mmol) of tert-butyl piperazine-1-carboxylate in 30 ml of water is heated under reflux for 48 h. The aqueous phase is extracted three times with methylene chloride. The organic phases are combined, dried over sodium sulfate, filtered, and evaporated. The residue is purified by chromatography on silica (MeOH gradient in dichloromethane: 5 to 10%) to yield 0.80 g (70%) of 5-(piperazin-1-yl)thiophene-2-carboxaldehyde in the form of a blue-grey solid.