Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[S:7]([NH2:10])(=[O:9])=[O:8].[CH2:11]([N:15]=[C:16]=[O:17])[CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([NH:15][C:16]([NH:10][S:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH3:1])(=[O:9])=[O:8])=[O:17])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCN=C=O
Reactant: Cc1ccsc1S(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)c1sccc1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 150 ml of acetone and 3-methyl-2-thiophenesulfonamide was added 11 g of n-butyl isocyanate and 14 g of anhydrous potassium carbonate. After stirring at ambient temperature for 24 hours, the mixture was concentrated to 2/3 of its volume and poured into ice-water. The pH was adjusted to 3 by the addition of hydrochloric acid and the solid thus obtained was filtered, air dried and triturated with 1-chlorobutane to yield 10.6 g of N-(butylaminocarbonyl)-3-methyl-2-thiophenesulfonamide melting at 144°-146°. It showed absorption peaks by NMR (60 MC) at 2.6 δ (singlet, CH3), 1-1.8 δ (mult., C3H7), 3.42 δ (trip., N-Ch2 - of butyl) and at 7.1 δ and 7.7 δ (2 doublets for CH's of thiophene) consistent for the desired structure.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:13]([C:14]#[N:15])=[CH:12][CH:11]=[CH:10][N:9]=1>O>[C:14]([C:13]1[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=[CH:11][CH:12]=1)#[N:15]
Reactant: C1CNCCN1
Reactant: N#Cc1cccnc1Cl
Solvent: O
Product: N#Cc1cccnc1N1CCNCC1
Temperature: 150 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
Piperazine (125 g) was melted by heating at 150° C. and 2-chloro-3-cyanopyridine (20.0 g) was added thereto. The mixture was stirred at 110° C. for 2 hr. Water was added to the reaction mixture and the mixture was extracted with chloroform. The extract was washed with brine, dried and concentrated under reduced pressure to give 1-(3-cyano-2-pyridyl)piperazine (24.2 g) as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH:19]([C:21]1[NH:22][C:23]2[CH2:24][CH2:25][CH2:26][CH2:27][C:28]=2[C:29]=1[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=O>N1CCCCC1.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([C:13](=[CH:19][C:21]4[NH:22][C:23]5[CH2:24][CH2:25][CH2:26][CH2:27][C:28]=5[C:29]=4[CH2:30][CH2:31][C:32]([OH:34])=[O:33])[C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc3c(c2)NC(=O)C3)cc1
Reactant: O=Cc1[nH]c2c(c1CCC(=O)O)CCCC2
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]c3c(c2CCC(=O)O)CCCC3)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
A mixture of 103 mg 6-(4-methoxyphenyl)-2-oxindole, 95 mg 3-(2-formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid and piperidine (3 drops) in ethanol (2 mL) was heated to 90° C. in a sealed tube and held there for 4 hrs. The reaction mixture was concentrated and acidified with 6 N hydrochloric acid. Ethyl acetate was added upon which a solid precipitated from the aqueous layer. The precipitate was collected by filtration, and washed with water and hexane to give 57 mg of 3-{2-[6-(4-Methoxyphenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-4,5,6,7-tetrahydro-1H-indol-3-yl}-propionic acid as a brown solid (30%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([OH:18])=[C:11]([N+:15]([O-])=O)[CH:12]=2)[CH2:7][N:6]1[C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([OH:18])=[C:11]([NH2:15])[CH:12]=2)[CH2:7][N:6]1[C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])=[O:4]
Reactant: COC(=O)[C@@H]1Cc2cc([N+](=O)[O-])c(O)cc2CN1C(=O)OC(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1Cc2cc(N)c(O)cc2CN1C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.8 %

Procedure:
(S)-7-Hydroxy-6-nitro-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-isopropyl ester 3-methyl ester (2.0 g) was dissolved in MeOH and 200 mg Pd/C added. The flask was evacuated and placed under balloon pressure of hydrogen. The reaction stirred at rt for 1.5 h and was filtered over a plug of celite. The celite plug was washed with EtOAc and DCM. The filtrates were combined and evaporated to provide (S)-6-amino-7-hydroxy-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-isopropyl ester 3-methyl ester (1.8 g). LC-MS (m/z) 310.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]>C1COCC1>[C:9]([C:8]([C:4]1[CH:3]=[C:2]([NH:1][C:20](=[O:21])[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:7]=[CH:6][CH:5]=1)([CH3:12])[CH3:11])#[N:10]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C#N)c1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(NC(=O)Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a solution of 2-(3-aminophenyl)-2-methylpropanenitrile (490 mg, 3.06 mmol) and potassium carbonate (552 mg, 4 mmol) in anhydrous THF (4.2 ml) was added dropwise phenyl chloroformate (0.81 ml, 6.4 mmol) as a solution in THF (2 ml). The reaction mixture was stirred at rt overnight. The solvent was removed and the residue taken in DCM, washed with water and brine and the organics combined, dried (MgSO4) and concentrated. The crude was purified by silica gel chromatography (hexane/ethyl acetate 15%) to afford phenyl 3-(2-cyanopropan-2-yl)phenylcarbamate (828 mg, 96%) as a solid. 1H NMR (300 MHz, CDCl3) δ 1.72 (s, 6H), 7.20-7.28 (m, 4H), 7.35-7.41 (m, 4H), 7.65 (s, 1H); LC-MS (ESI) m/z 281 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14](S(C)=O)=[N:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[NH2:27]>COCCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([NH:27][C:26]4[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:24]([O:23][CH3:22])[CH:25]=4)=[N:15]3)=[CH:10][CH:9]=2)[CH:7]=1
Reactant: COc1ccc(N)cc1OC
Reactant: COc1ccc(Cl)cc1-c1ccc2cnc(S(C)=O)nn12
Solvent: COCCO
Product: COc1ccc(Nc2ncc3ccc(-c4cc(Cl)ccc4OC)n3n2)cc1OC
Temperature: 180 °C
Yield: 34.1 %

Procedure:
[7-(5-Chloro-2-methoxy-phenyl)-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazine (75.0 mg, 0.000233 mol) and 3,4-dimethoxyaniline (71.4 mg, 0.000466 mol) were dissolved in 2-Methoxyethanol (1.64 mL) and the reaction was heated at 180° C. until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 32.66 mg of [7-(5-Chloro-2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(3,4-dimethoxy-phenyl)-amine as a lyophilized powder. (M+H)=411.12. 1H NMR (400 MHz, DMSO, d6) δ 9.24 (s, 1H), 8.95 (s, 1H), 7.93 (s, 1H), 7.48 (m, 1H), 7.31 (m, 2H), 6.97 (d, 1H, J=4.80 Hz), 6.82 (d, 1H, J=8.34 Hz), 6.26 (m, 1H), 6.05 (dd, 1H, J=2.52, 6.07 Hz), 3.79 (s, 3H), 3.69 (s, 3H), 3.65 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6](B(O)O)[CH:7]=1.Br[C:14]1[CH:19]=[CH:18][C:17]([C@H:20]([NH2:22])[CH3:21])=[CH:16][CH:15]=1>O.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C@H:20]([NH2:22])[CH3:21])=[CH:16][CH:15]=2)[CH:7]=1
Reactant: C[C@@H](N)c1ccc(Br)cc1
Reactant: COc1ccc(F)cc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CO
Product: COc1ccc(F)cc1-c1ccc([C@@H](C)N)cc1
Temperature: 200 °C
Yield: 94.8 %

Procedure:
Palladium acetate (56 mg, 0.25 mmol) was added to a mixture of 5-fluoro-2-methoxyphenylboronic acid (850 mg, 5.0 mmol) and (R)-1-(4-bromophenyl)ethylamine (500 mg, 2.5 mmol) in water (20 ml). This mixture was heated for 5 min at 200° C. in a Smithcreator microwave oven and then diluted with methanol (200 ml). The mixture was purified on a SCX column (20 g) using 2M ammonia in methanol to elute the intermediate amine. Evaporation of solvents under reduced pressure gave (R)-1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine as a gum (580 mg, 2.37 mmol, 96.6%). Triethylamine (41.1 μl, 0.295 mmol) and 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride (20.5 mg, 0.0984 mmol) were added to a solution of (R)-1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine (20 mg, 0.082 mmol) in dichloromethane (1 ml) and the resulting solution shaken at room temperature overnight. The reaction mixture was washed with saturated sodium bicarbonate solution (500 μl), the dichloromethane layer separated, dried over magnesium sulfate and the solvent evaporated. Purification by preparatory LCMS and removal of solvent under reduced pressure gave the title compound (13.8 mg, 0.033 mmol, 40%): 1H NMR (400 MHz, CDCl3): δ7.37, 7.14 (a/b, 4H), 7.02-6.87 (m, 3H), 4.68 (m, 1H), 4.48 (t, 1H), 3.78 (s, 3H), 3.55 (s, 3H), 2.35 (s, 3H), 2.22 (s, 3H), 1.50 (d, 3H) ppm; MS (ESI) m/z: 417 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11]C(CCC)CCC)[CH:5]=[C:4]([CH3:19])[N:3]=1.[Br:20][C:21]1[CH:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[CH:25]=[CH:24][C:22]=1[NH2:23]>C(Cl)Cl>[Br:20][C:21]1[CH:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[CH:25]=[CH:24][C:22]=1[N:23]([CH:21]([CH2:27][CH2:26][CH3:28])[CH2:22][CH2:24][CH3:25])[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=[C:4]([CH3:19])[N:3]=1
Reactant: CC(C)c1ccc(N)c(Br)c1
Reactant: CCCC(CCC)Nc1cc(C)nc(Cl)c1[N+](=O)[O-]
Solvent: ClCCl
Product: CCCC(CCC)N(c1ccc(C(C)C)cc1Br)c1nc(C)cc(N)c1[N+](=O)[O-]
Yield: 86.3 %

Procedure:
2-Chloro-6-methyl-3-nitro-N-(1-propylbuty)pyridin-4-amine (0.5 g, 1.75 mmol) and 2-bromo-4-isopropylaniline (0.74 g, 3.5 mmol) were heated at 140° C. for 4.5 h. After cooling it was dissolved in CH2Cl2 and filtered through a short column of silica gel. The filtrate was concentrated and chromatographed on silica gel (5% EtOAc/hexanes eluting solvent) to give the product (0.7 g).
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[N:6]([C:14]([CH3:19])([CH3:18])[C:15]([O-:17])=O)=[N:7][C:8]([CH3:13])([CH3:12])[C:9]([O-:11])=O.C[O-].[Na+].O>CO>[N:7]([C:8]([CH3:12])([CH3:13])[C:9]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:11])=[N:6][C:14]([CH3:19])([CH3:18])[C:15]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:17]
Reactant: CC(C)(N=NC(C)(C)C(=O)[O-])C(=O)[O-]
Reactant: CC(C)CN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)CNC(=O)C(C)(C)N=NC(C)(C)C(=O)NCC(C)C
Temperature: 10 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
34.9 Grams of isobutylamine is mixed with 50 g of 2,2'-azobis (2-methyl propionate), and 10 g of 28% sodium methoxide solution in methanol is dropwise added thereto with stirring, followed by conducting a reaction at room temperature with stirring for 6 hours and keeping standing overnight. 100 Milliliter of water is added to the reaction solution and cooled to 10° C. to precipitate crystals. The crystals are recovered by filtration and dried to give 56.4 g (yield 83%) of 2,2'-azobis [N-(2 -methylpropyl)-2-methyl propionamide] as pale yellow crystal. The solubility is shown in Table 1.
Reaction SMILES: C1(S(C2(SC)[CH2:15][C@H:14]3[C@:12]([C:16]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH:19]=[CH:18][CH:17]=4)([CH2:13]3)[CH2:11]2)(=O)=O)C=CC=CC=1.[CH3:28][OH:29].Cl>C(OCC)(=O)C.CCCCCC>[C:16]1([C@:12]23[CH2:13][C@H:14]2[CH2:15][C:28](=[O:29])[CH2:11]3)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CO
Reactant: CSC1(S(=O)(=O)c2ccccc2)C[C@@H]2C[C@]2(c2cccc3ccccc23)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1C[C@@H]2C[C@]2(c2cccc3ccccc23)C1
Yield: 99 %

Procedure:
(1S,5S)-3-Benzenesulfonyl-1-(1-naphthyl)-3-methylsulfanyl-bicyclo[3.1.0]hexane (3 g, 7.6 mmol), methanol (18 mL) and concentrated hydrochloric acid (5.4 mL) were heated to reflux for 7 hours. The reaction was monitored by TLC (ethyl acetate/hexane (20:80)).The reaction mixture was concentrated under reduced pressure to remove methanol. The pH of the reaction mass was adjusted to 8-9 with saturated sodium bicarbonate solution. The aqueous layer was extracted with diethyl ether (300 mL). The organic layer was washed with water, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to yield 3 g of crude oil, which was purified by preparative HPLC to give 1 g (62%) of 99% pure product. 1H NMR δ(300 MHz,CDCl3): 0.75-0.78 (1H,t, J=4 Hz), 1.37 (1H,m), 1.98-2.04 (1H,m), 2.49-2.55 (1H,d ,J=18 Hz), 2.77-2.79 (2H,d,J=6 Hz), 3.03-3.11 (2H,dd,J=18,6 Hz), 7.39-7.44 (1H,m), 7.48-7.57 (3H,m),7.76-7.78 (1H,d,J=6 Hz), 7.87-7.90 (1H,m), 8.12-8.15 (2H,d ,J=9 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15].C(O)(=O)C.[I:20]N1C(=O)CCC1=O.S(=O)(=O)(O)O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([I:20])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15]
Reactant: Oc1ccc(-c2ccccc2F)c(Cl)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(=O)O
Product: Oc1cc(Cl)c(-c2ccccc2F)cc1I
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
2-Chloro-2′-fluorobiphenyl-4-ol (Preparation 76, 430 mg, 1.93 mmol) was dissolved in DCM, and cooled to 0° C. Acetic acid (5 mL), N-iodosuccinimide (434 mg, 1.93 mmol) were added followed by concentrated sulphuric acid (0.2 mL). The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was purified by flash chromatography on silica gel eluting with heptane:ethyl acetate 7:3 to give the title compound (620 mg, 92%) as oil.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[O:19][CH:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:16]3)=[CH:10][CH:11]=1)=[O:4].[N-:29]=[N+:30]=[N-:31].[Na+]>C(#N)C>[N:29]([CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[O:19][CH:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:16]3)=[CH:10][CH:11]=1)=[O:4])=[N+:30]=[N-:31]
Reactant: O=C(CCl)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC#N
Product: [N-]=[N+]=NCC(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Temperature: 25 °C

Procedure:
2-Chloro-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]acetamide (500 mg), sodium azide (445 mg) and acetonitrile were mixed. Reaction mixture was refluxed for 3 hours. After cooling into room temperature, the reaction mixture was filtered and the filtrate was evaporated to the dryness. 1H-NMR (400 MHz; d6-DMSO) δ: 10.3 (s, 1H), 8.29 (d, 1H, J 2.7 Hz), 8.03 (dd, 1H, J 2.7, 8.8 Hz), 7.47-7.33 (m, 5H), 6.96 (d, 1H, J 8.8 Hz), 6.88-6.85 (m, 3H), 5.12 (dd, 1H, J 2.20, 10.1 Hz), 4.07 (s, 2H), 3.00-2.92 (m, 1H), 2.76-2.70 (m, 1H), 2.19-2.14 (m, 1H), 2.02-1.97 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[N:12]3[N:29]=[CH:30][C:31]([CH:32]=[C:33]4[C:37](=[O:38])[NH:36][C:35](=[O:39])[NH:34]4)=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:12]3[N:29]=[CH:30][C:31]([CH:32]=[C:33]4[NH:34][C:35](=[O:39])[NH:36][C:37]4=[O:38])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Nc3cccc(Cl)c3)nc3c(C=C4NC(=O)NC4=O)cnn23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NC(=O)C(=Cc2cnn3c(NC4CCNCC4)cc(Nc4cccc(Cl)c4)nc23)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl 4-(5-(3-chlorophenylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)piperidine-1-carboxylate (640 mg, 1.2 mmol) was dissolved in 10 mL of TFA/DCM (1:1) and stirred at room temperature for 1 hour then quenched by addition to ice cold 6N NaOH. The mixture was diluted with water then the aqueous layer was decanted. The organic layer was diluted with hexanes and filtered. The product, 5-((5-(3-chlorophenylamino)-7-(piperidin-4-ylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione, was collected as a solid in quantitative yield. LCMS (M+1=453)
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9](OCC)(=[O:18])[CH2:10][C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=O.[Na]>P(=O)(O)(O)O>[C:13]([C:11]1[C:8]2[C:1](=[CH:3][C:4]([OH:5])=[CH:6][CH:7]=2)[O:2][C:9](=[O:18])[CH:10]=1)([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Reactant: Oc1cccc(O)c1
Agent: O=P(O)(O)O
Agent: [Na]
Product: CCOC(=O)c1cc(=O)oc2cc(O)ccc12
Yield: 80 %

Procedure:
0.10 mole resorcinol and 0.12 mole sodium diethyl oxalacetate is heated to 80° C. for 1 hour in 60 ml concentrated phosphoric acid. 4-Carbethoxy-7-hydroxy-coumarin is thus obtained at an 80% yield in the form of a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([NH:13][C:14]([O:16]C2C=CC=CC=2)=O)[CH:3]=1.[C:23]1([N:29]2[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][O:37][C:38]3[CH:43]=[CH:42][C:41]([S:44]([NH2:47])(=[O:46])=[O:45])=[CH:40][CH:39]=3)[CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([N:29]2[CH2:30][CH2:31][N:32]([CH2:35][CH2:36][O:37][C:38]3[CH:43]=[CH:42][C:41]([S:44]([NH:47][C:14]([NH:13][C:4]4[CH:3]=[C:2]([Cl:1])[CH:12]=[CH:11][C:5]=4[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:16])(=[O:46])=[O:45])=[CH:40][CH:39]=3)[CH2:33][CH2:34]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Reactant: NS(=O)(=O)c1ccc(OCCN2CCN(c3ccccc3)CC2)cc1
Product: CCOC(=O)c1ccc(Cl)cc1NC(=O)NS(=O)(=O)c1ccc(OCCN2CCN(c3ccccc3)CC2)cc1

Procedure:
As the starting substances, ethyl 4-chloro-2-phenoxycarbonylaminobenzoate and 4-[2-(4-phenylpiperazin-1-yl)ethyloxy)benzenesulfonamide were used and the same method was applied as in Example 36 to obtain N-{4-[2-(4-phenylpiperazin-1-yl)ethyloxy] benzenesulfonyl}-N'-(2-ethyloxycarbonyl-5-chlorophenyl)urea and to obtain from 813 mg (1.39 mmol) of N-{4-(2-(4-phenylpiperazin-1-yl)ethyloxy] benzenesulfonyl}-N'-(2-carboxy-5-chlorophenyl)urea 115 mg of the above-identified compound (yield 15.3%). Properties: colorless crystal, Melting point: 177°-179° C., PMR (δppm, DMSO-d6):2.65 (4H,t), 2.80 (2H,t), 3.13 (4H,t), 4.26 (2H,t), 6.75 (1H,t), 6.90 (2H,d), 7.12 (1H,s), 7.17-7.22 (5H,m), 7.85 (1H,d), 8.10 (2H,d), 11.59 (1H,br).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[N:8]=[CH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:5].CO.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][N:25]=1.C([BH3-])#N.[Na+]>C(O)(=O)C>[Br:23][C:24]1[N:25]=[CH:26][C:27]([CH2:30][NH:1][C:2]2[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=2[C:4]([NH:6][C:7]2[N:8]=[CH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:5])=[CH:28][CH:29]=1
Reactant: Nc1ccccc1C(=O)Nc1cc2ccccc2cn1
Reactant: O=Cc1ccc(Br)nc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(Nc1cc2ccccc2cn1)c1ccccc1NCc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.3 %

Procedure:
3.46 g (13.17 mmol) of 2-amino-N-isoquinolin-3-yl-benzamide is introduced into 50 ml of methanol, mixed with 1.5 ml of glacial acetic acid as well as 2.45 g (13.17 mmol) of 2-bromopyridine-5-carbaldehyde and stirred for 24 hours under argon and in a moisture-free environment at room temperature. Then, it is mixed with 828 mg (13.17 mmol) of sodium cyanoborohydride and stirred for another 24 hours at room temperature. After concentration by evaporation under vacuum, the residue is taken up in dilute sodium bicarbonate solution and suctioned off. The residue that is obtained is absorptively precipitated in a little ethyl acetate and suctioned off repeatedly. The residue that is obtained in this case is chromatographed on silica gel with hexane:ethyl acetate=1:1 as an eluant. 3.27 g (57% of theory) of 2-[(6-bromo-pyridin-3-ylmethyl)-amino]-N-isoquinolin-3-yl-benzamide is obtained.
Reaction SMILES: [OH-].[Na+].[CH3:3][S:4][C:5]([NH2:7])=[NH:6].OS(O)(=O)=O.C([O:15][CH:16]=[C:17]([C:23](OCC)=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>C(O)C>[CH3:3][S:4][C:5]1[N:7]=[C:16]([OH:15])[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:23][N:6]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1cnc(SC)nc1O
Reaction time: 18 h
Yield: 60.7 %

Procedure:
To a 4N sodium hydroxide solution (200 mL) was added S-methylisothioureasulfate (55.6 g, 0.2 mol), and after stirring for 30 min, at room temperature a solution of diethyl ethoxymethylenemalonate (80.8 mL, 0.35 mol) in ethanol (100 mL) was dropwise added slowly over 1 h. After stirring for 18 h, the precipitated crystals were collected by filtration, washed several times with cold ethanol and the obtained crystals were added to 1N hydrochloric acid (300 mL). The mixture was stirred for 30 min and the precipitated crystals were collected by filtration, washed several times with cold water and dried with heating under vacuum to give the title compound (26 g, 61%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=O)=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:20]=[C:21]([NH2:26])[C:22]([NH2:25])=[CH:23][CH:24]=1.O.Cl>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:8]2[CH:16]=[CH:15][C:11]([C:12]3[NH:26][C:21]4[CH:20]=[C:19]([C:18]([F:17])([F:27])[F:28])[CH:24]=[CH:23][C:22]=4[N:25]=3)=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Reactant: O=C(O)c1ccc(-c2ncccc2Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: FC(F)(F)c1ccc2nc(-c3ccc(-c4ncccc4Cl)cc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.9 %

Procedure:
To a solution of 0.58 g (2.5 mmol) 4-(3-chloropyridin-2-yl)benzoic acid in 30 mL anhydrous pyridine was added 0.44 g (2.5 mmol) 4-trifluoromethylbenzene-1,2-diamine, followed by stirring for 6 hours in a heat flux condition. After cooling to room temperature, cold water (100 mL) containing HCl (10 mL) was added to the solution, which was then allowed to stand for 30 min to form precipitates. These were separated using column chromatography (developing solvent: chloroform/methanol=30/1) to produce 0.70 g of 2-[4-(3-chloropyridin-2-yl)phenyl]-6-trifluoromethyl-1H-benzoimidazole (yield 75%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([CH3:29])([CH3:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=1[O-].C1CCCCC=1>[Pd].CC(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([CH3:28])([CH3:29])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: CCOC(=O)CC(C)(C)Cc1ccc(OCCCNc2cccc[n+]2[O-])c(F)c1
Agent: [Pd]
Solvent: CC(C)O
Solvent: C1=CCCCC1
Product: CCOC(=O)CC(C)(C)Cc1ccc(OCCCNc2ccccn2)c(F)c1
Temperature: 25 °C
Yield: 61.1 %

Procedure:
A mixture of the product of STEP 7 (640 mg, 1.6 mmol), 10% Pd/C (400 mg, 0.36 mmol), cyclohexene (4.0 ml, 39.5 mmol), and 2-propanol (20 ml) was heated at reflux for 6 h. The reaction was allowed to cool to room temperature. An additional 10% Pd/C (250 mg, 0.23 mmol) and cyclohexene (2.0 ml, 19.8 mmol) were added. After 18 h of refluxing, the reaction was cooled to room temperature, filtered through a short column of Celite®, and washed with 100 ml 2-propanol. The filtrate was concentrated to give 380 mg oil. The NMR spectra were consistent for the proposed structure.