Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[C:2]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[C:3]([OH:5])=[O:4].[C:11](Cl)(=O)[CH3:12]>>[CH2:1]=[C:2]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([OH:5])=[O:4]
Reactant: C=C(CCC(=O)O)C(=O)O
Reactant: CC(=O)Cl
Product: C=C(CCC(=O)OCC)C(=O)O

Procedure:
A mixture of 2-methyleneglutaric acid [Ber. 34, 427 (1901)] (40 g.) and acetyl chlorine (80 ml.) is heated on the steam bath for 1.5 hours. The excess acetyl chloride is removed in vacuo (75°) and the residue is evaporated from toluene twice. Finally, the residue is dissolved in ethanol and heated on the steam bath for one hour. The reaction mixture is concentrated to dryness to yield 2-methylene-4-(ethoxycarbonyl)butyric acid.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[S:3]([N:6]1[C:10]2[CH:11]=[C:12]([Cl:20])[C:13]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:14][C:9]=2[N:8]=[C:7]1Cl)(=[O:5])=[O:4].[CH2:23]([O:25][C:26]([C:28]1[CH:29]=[N:30][NH:31][CH:32]=1)=[O:27])[CH3:24].C([O-])([O-])=O.[K+].[K+]>>[CH2:23]([O:25][C:26]([C:28]1[CH:29]=[N:30][N:31]([C:7]2[N:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:22])[CH3:1])[C:10]3[CH:11]=[C:12]([Cl:20])[C:13]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:14][C:9]=3[N:8]=2)[CH:32]=1)=[O:27])[CH3:24]
Reactant: CN(C)S(=O)(=O)n1c(Cl)nc2cc(OC(F)(F)F)c(Cl)cc21
Reactant: CCOC(=O)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1cnn(-c2nc3cc(OC(F)(F)F)c(Cl)cc3n2S(=O)(=O)N(C)C)c1
Temperature: 70 °C
Reaction time: 10 h

Procedure:
2,6-Dichloro-5-trifluoromethoxy-1H-benzoimidazole (160 g, 0.59 mol, 1.0 equiv.) was dissolved in dry DMF (1.5 L) and then K2CO3 (98 g, 0.71 mol, 1.2 equiv.) and dimethylsulfamoyl chloride (85 g, 0.59 mol, 1.0 equiv.) were added sequentially. The reaction mixture was stirred at room temperature for 16 hours to afford 2,6-dichloro-5-trifluoromethoxy-benzoimidazole-1-sulfonic acid dimethylamide. Without isolation of 2,6-dichloro-5-trifluoromethoxy-benzoimidazole-1-sulfonic acid dimethylamide, 1H-pyrazole-4-carboxylic acid ethyl ester (91 g, 0.65 mol, 1.1 equiv.) and K2CO3 (98 g, 0.71 mol, 1.2 equiv.) were added to the reaction mixture. The reaction mixture was stirred at 70° C. for 10 hours and cooled to room temperature, to afford 1-(6-chloro-1-dimethylsulfamoyl-5-trifluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester. To crude reaction mixture was added LiOH H2O (124 g, 2.95 mol, 5.0 equiv.) in 2.5 L water. The reaction solution was heated at 70° C. for 6 hours and then cooled to room temperature. Concentrated HCl was added to adjust pH=4.0. The precipitated solid was collected by filtration, washed with water and dried. The solid was recrystallized from hot EtOAc (˜3 L). After cooling to room temperature and filtration, the pure compound was obtained as a white solid (109 g, 0.31 mol, 54% over 3 steps). MS (ESI/CI): mass calcd. for C12H6ClF3N4O2, 346.0; m/z found, 347.0 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 13.79 (s, 1H), 13.06 (s, 1H), 8.91 (s, 1H), 8.33 (s, 1H), 7.79 (br d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24]Br)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:31][NH:32][CH2:33][CH2:34][OH:35]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24][N:32]([CH2:33][CH2:34][OH:35])[CH3:31])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCBr
Reactant: CNCCO
Solvent: CN(C)C=O
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN(C)CCO
Reaction time: 48 h
Yield: 74.1 %

Procedure:
4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide (250 mg, 0.51 mmol.) and 2-(methylamino)-ethanol(97 mg, 1.02 mmol.) were dissolved with stirring, under nitrogen, in 9 ml anhydrous dimethylformamide. After 48 hours, the mixture was partitioned between saturated sodium bicarbonate solution, and ethyl acetate. The organic phase was seperated, dried over magnesium sulfate, filtered, and evaporated to give a gum. It was chromatographed on silica gel, and eluted with 40/4/1 (ethyl acetate/methanol/triethylamine) producing 183 mg (74%) of the purified product as a yellow solid: mp 210-214° C.
Reaction SMILES: [CH:1]([NH:5][C:6]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[O:7])([CH2:3][CH3:4])[CH3:2].Cl.[CH3:14]O>>[CH:1]([NH:5][C:6]([CH:8]=[CH:9][C:10]([O:12][CH3:14])=[O:11])=[O:7])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)NC(=O)C=CC(=O)O
Reactant: CO
Agent: Cl
Product: CCC(C)NC(=O)C=CC(=O)OC
Reaction time: 2 h

Procedure:
To 3-(sec butylcarbamoyl)acrylic acid (20 g, 117 mmol) at room temperature was added 150 mL 1.2M HCl in methanol. The resulting mixture was stirred for two hours. Solvents were removed in vacuo to give the desired ester, which was used without further purification.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[C:10]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][C@@H:28]2[CH3:33])[C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[CH:20][C:21](F)=[C:22]([CH:25]=3)C#N)=[N:14][C:12]=2[N:13]=1.O.[NH2:35]N>CCO>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[C:10]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][C@@H:28]2[CH3:33])[C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:25]=[C:22]([NH2:35])[CH:21]=[CH:20][CH:19]=3)=[N:14][C:12]=2[N:13]=1
Reactant: NN
Reactant: C[C@H]1COCCN1c1nc(N2CCOC[C@@H]2C)c2ccc(-c3ccc(F)c(C#N)c3)nc2n1
Solvent: CCO
Solvent: O
Product: C[C@H]1COCCN1c1nc(N2CCOC[C@@H]2C)c2ccc(-c3cccc(N)c3)nc2n1

Procedure:
To a 0.3M solution of 5-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-fluoro-benzonitrile (example lay) (1 equiv) in EtOH was added hydrazine hydrate (5 equiv). The mixture was refluxed for 90 minutes whereupon it was cooled and partitioned between CH2Cl2 and water (1 reaction volume of each). The organic extract was removed. The aqueous phase was further extracted with CH2Cl2 (2×1 reaction volume). The combined organic extracts were then dried (MgSO4), filtered and concentrated in vacuo to give a yellow slurry which was further purified by flash chromatography (SiO2) using EtOAC/Hexanes as eluent to give the title compound as a yellow powder.
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:32])[F:31])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:34][C:35]([F:50])([F:49])[C:36]1[CH:37]=[C:38]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[C:39](O)=[O:40]>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:31])[F:32])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:39](=[O:40])[C:38]2[CH:42]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:44]=[C:36]([C:35]([F:34])([F:49])[F:50])[CH:37]=2)[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)Oc1cccc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)c1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](OCc2cccc(OC(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (27.7 mg) obtained in Example 27 and 3,5-bis(trifluoromethyl)benzoic acid (31.0 mg) were reacted and treated in the same manner as in the method described in Example 33 to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[N:16]3[C:11]([CH2:12][CH2:13][CH2:14][CH2:15]3)=[C:10]([C:17]#[N:18])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:19]N1C(=O)CCC1=O>>[Br:19][C:9]1[C:10]([C:17]#[N:18])=[C:11]2[N:16]([C:8]=1[C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1)[CH2:15][CH2:14][CH2:13][CH2:12]2
Reactant: N#Cc1cc(-c2cccnc2F)n2c1CCCC2
Reactant: O=C1CCC(=O)N1Br
Product: N#Cc1c(Br)c(-c2cccnc2F)n2c1CCCC2
Yield: 84.8 %

Procedure:
2-Bromo-3-(2-fluoro-3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carbonitrile is prepared as described in Example 9, from 1.6 g of 3-(2-fluoro-3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carbonitrile and 1.3 g of N-bromosuccinimide. 1.8 g of 2-bromo-3-(2-fluoro-3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carbonitrile are thus obtained in the form of beige powder melting at 172° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][CH:10]([CH2:14][O:15][C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)[CH2:9]2)=[CH:4][CH:3]=1.Cl.[NH2:26][C:27]1[C:28](=[O:41])[N:29]([CH2:38][CH2:39][CH3:40])[C:30](=[O:37])[N:31]([CH2:34][CH2:35][CH3:36])[C:32]=1[NH2:33].CCN=C=NCCCN(C)C>CO>[NH2:33][C:32]1[N:31]([CH2:34][CH2:35][CH3:36])[C:30](=[O:37])[N:29]([CH2:38][CH2:39][CH3:40])[C:28](=[O:41])[C:27]=1[NH:26][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([O:15][CH2:14][CH:10]2[CH2:11][C:12](=[O:13])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:9]2)=[CH:17][CH:18]=1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: O=C(O)c1ccc(OCC2CC(=O)N(c3ccc(F)cc3)C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Product: CCCn1c(N)c(NC(=O)c2ccc(OCC3CC(=O)N(c4ccc(F)cc4)C3)cc2)c(=O)n(CCC)c1=O
Temperature: 22.5 °C
Reaction time: 16 h
Yield: 89.5 %

Procedure:
To a stirred solution of 4-[1-(4-fluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethoxy]-benzoic acid obtained in step 2 (0.140 g, 0.426 mmol) and HCl salt of 5,6-diamino-1,3-dipropyl-1H-pyrimidine-2,4-dione (0.112 g, 0.426 mmol) in MeOH (5 mL) was added EDCI (0.0136 g, 0.593 mmol). After stirring at 20-25° C. for 16 hours, the reaction mixture was quenched with water (5 mL). The solid obtained was filtered and washed with water to provide the crude product which was purified by column chromatography to afford N-(6-amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-4-[1-(4-fluorophenyl)-5-oxo-pyrrolidin-3-ylmethoxy]-benzamide (0.205 g, 90%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]([CH2:20][CH3:21])[S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:22])=[CH:4][N:3]=1.[CH3:23][O:24][C:25]1[C:26]([NH2:40])=[CH:27][C:28]2[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][O:37][CH3:38])[CH2:31][CH2:30][C:29]=2[CH:39]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)([O-])[O-]>C(O)(C)C>[Cl:22][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]([CH2:20][CH3:21])[S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:40][C:26]2[C:25]([O:24][CH3:23])=[CH:39][C:29]3[CH2:30][CH2:31][N:32]([CH2:35][CH2:36][O:37][CH3:38])[CH2:33][CH2:34][C:28]=3[CH:27]=2)=[N:3][CH:4]=1
Reactant: CCN([C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl)S(C)(=O)=O
Reactant: COCCN1CCc2cc(N)c(OC)cc2CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: CCN([C@@H]1CCCC[C@H]1Nc1nc(Nc2cc3c(cc2OC)CCN(CCOC)CC3)ncc1Cl)S(C)(=O)=O

Procedure:
N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-N-ethyl-methanesulfonamide (99 mg, 0.27 mmol), 8-Methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (67 mg, 0.27 mmol), and 10-Camphorsulfonic acid (94 mg, 0.40 mmol) in Isopropyl alcohol (4 mL) was heated in a microwave vial for 90 min at 120° C. Upon cooling, the mixture was treated with MP-Carbonate (2.69 mmol/g loading; 0.35 g, 0.94 mmol) for 1 h, was filtered and was concentrated in vacuo onto Celite. Chromatography (ISCO, 12 g silica gel, 40-80% EtOAc:Hex) afforded N-((1R,2R)-2-{5-Chloro-2-[8-methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-N-ethyl-methanesulfonamide as an off white foam (70 mg, 40%). LCMS: 581 (M+H); 1H-NMR, CDCl3: 8.18 (s, 1H), 7.90 (s, 1H), 7.35 (s, 1H), 6.64 (s, 1H), 5.86 (s, 1H), 4.05 (m, 1H), 3.87 (s, 3H), 3.80 (m, 3H), 3.54 (m, 1H), 3.3 (s, 3H), 3.25 (m, 3H), 2.6-2.9 (m, 10H), 2.45 (m, 1H), 1.94 (m, 2H), 1.82 (m, 1H), 1.7 (m, 1H), 1.1-1.5 (m, 7H).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][C@H:5](O)[C:6]([O:8][CH3:9])=[O:7].Cl.O1CCOCC1.S(Cl)([Cl:20])=O>N1C=CC=CC=1>[ClH:20].[NH2:2][CH2:3][CH2:4][C@@H:5]([Cl:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)[C@@H](O)CCN
Agent: Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COC(=O)[C@H](Cl)CCN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To methyl (S)-4-amino-2-hydroxybutyrate hydrochloride (170.1 mg; 133.5 mg when calculated as methyl (S)-4-amino-2-hydroxybutyrate) was added 3 ml of 4 N-HCl/dioxane, followed by further addition of 189.1 mg of thionyl chloride. The mixture was stirred at room temperature for 1 hour. Thereafter, 2.5 mg of pyridine was added, and the mixture was further stirred at 50° C. for 6 hours. After confirmation of disappearance of the starting material by TLC, the solvent was distilled off under reduced pressure to give methyl (R)-4-amino-2-chlorobutyrate hydrochloride. To this were added 10 ml of chloroform and 5 ml of a saturated aqueous solution of sodium hydrogen carbonate, and the aqueous layer was further extracted six times with chloroform. The organic layer was dried over sodium sulfate and the solvent was distilled off to give 120.7 mg of (R)-3-chloro-2-pyrrolidinone (yield quantitative, optical purity 93.9% ee). The optical purity was determined by high performance liquid chromatography using a chiral column (Chiralcel OB-H (Daicel)).
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8]([C:10]2([NH:15][C:16]([CH:18]3[CH2:22][CH:21]([O:23][C:24]4[CH:29]=[CH:28][N:27]=[C:26](Cl)[N:25]=4)[CH2:20][CH:19]3[C:31]([N:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=[CH2:40])[CH3:34])=[O:32])=[O:17])[CH2:12][CH:11]2[CH:13]=[CH2:14])=[O:9])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[C:41]1(B(O)O)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]1([S:4]([NH:7][C:8]([C:10]2([NH:15][C:16]([CH:18]3[CH2:22][CH:21]([O:23][C:24]4[CH:29]=[CH:28][N:27]=[C:26]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[N:25]=4)[CH2:20][CH:19]3[C:31]([N:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=[CH2:40])[CH3:34])=[O:32])=[O:17])[CH2:12][CH:11]2[CH:13]=[CH2:14])=[O:9])(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: OB(O)c1ccccc1
Reactant: C=CCCCCN(C)C(=O)C1CC(Oc2ccnc(Cl)n2)CC1C(=O)NC1(C(=O)NS(=O)(=O)C2CC2)CC1C=C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: C=CCCCCN(C)C(=O)C1CC(Oc2ccnc(-c3ccccc3)n2)CC1C(=O)NC1(C(=O)NS(=O)(=O)C2CC2)CC1C=C
Temperature: 120 °C
Yield: 8.5 %

Procedure:
Compound 10f (43 mg, 72.4 mmol), phenylboronic acid (13 mg, 109 μmol) and (PPh3)2PdCl2 (5 mg, 7.2 umol) were mixed in a microwave reaction vial and heated in the microwave at 120° C. for 20 min. The reaction mixture was then quenched by addition of citric acid (20 ml) and extracted 2 times with DCM (10 ml). The combined organic phases were washed with water (2×10 ml) and brine (10 ml), dried over MgSO4 and filtered. The solvent was removed in vacuo and the crude product was purified by preparative LC-MS which gave the title compound (5.9 mg, 13%), (ESI+)=636 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13](O)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([CH:32]=[CH:33][CH:34]=1)[C:27]([O:29][CH2:30][CH3:31])=[O:28].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:13]([NH:23][C:24]2[CH:34]=[CH:33][CH:32]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:25]=2)=[O:14])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc(Br)cc1
Reactant: CCOC(=O)c1cccc(N)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)c1cccc(NC(=O)[C@H](Cc2ccccc2)NS(=O)(=O)c2ccc(Br)cc2)c1

Procedure:
The procedure described in Example 180 was repeated, except that (S)-2-(4-bromobenzenesulfonylamino)-3-phenylpropanoic acid (2 g) and ethyl 3-aminobenzoate were condensed in dichloromethane (100 ml) in the presence of N,N'-dicyclohexylcarbodiimide (1.29 g). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from ethanol to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-phenylpropanamide (812 mg).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1Cl)=[CH:8][C:7]([Cl:14])=[CH:6][CH:5]=2.[CH2:16]([OH:19])[CH2:17][OH:18].[Na]>O>[Cl:14][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3](=[O:15])[C:2]1[O:18][CH2:17][CH2:16][O:19][C:11]=1[C:10]2=[O:13]
Reactant: OCCO
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2cc(Cl)ccc21
Agent: [Na]
Solvent: O
Product: O=C1C2=C(OCCO2)C(=O)c2cc(Cl)ccc21
Temperature: 80 °C

Procedure:
2,3,6-Trichloronaphthoquinone (13.1 g) is added in small portions to a solution previously prepared from ethylene glycol (500 ml) and sodium metal (2.3 g) and heated to 80° C. under nitrogen. Upon completion of the addition, the reaction mixture is diluted with water (1 L) and cooled. The resulting precipitate is collected to afford 6-chloro-2,3-ethylenedioxy-1,4-naphthoquinone as an orange solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)[N:3]=2)=[CH:21][CH:20]=1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: Oc1ccc(F)cc1
Product: Fc1ccc(Oc2nc(Nc3cc[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-fluoro-phenol to give [1-(4-fluoro-phenoxy)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 321 (MH+).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][C:16](=[O:22])[N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])/[C:8]([O:10]CC)=[O:9])[N:6]=1.O.[OH-].[Na+]>CO>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][C:16](=[O:22])[N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)/C(=N\OCC(=O)N(CC)CC)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCN(CC)C(=O)CO/N=C(\C(=O)O)c1csc(N)n1
Yield: 402.7 %

Procedure:
68.1 g of ethyl 2-(2-amino-4-thiazolyl)-2-[(Z)-[(diethylcarbamoyl)methoxy]imino]-acetate are dissolved in 2.8 l of methanol and 240 ml of water and the solution is treated with 230 ml of 1N aqueous sodium hydroxide solution. The methanol is removed under reduced pressure after 48 hours and the aqueous solution is washed with ethyl acetate. After the addition of 230 ml of 1N aqueous hydrochloric acid, the crystallized acid is filtered off and dried. There are obtained 250.8 g of 2-(2-amino-4-thiazolyl)-2-[(Z)-[(diethylcarbamoyl)methoxy]imino]-acetic acid of melting point 180° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[C:4]([C:3]1[CH:8]=[C:9]([O:12][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([Cl:13])[CH:15]=2)[CH:10]=[CH:11][C:2]=1[OH:1])([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(O)ccc1O
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1cc(OCc2cccc(Cl)c2)ccc1O
Yield: 68.2 %

Procedure:
Eight grams (47.62 mmoles) of the above ester was treated with 6.3 ml (47.62 mmoles) of 3-chlorobenzyl bromide and 8 grams potassium carbonate in 70 ml acetonitrile under reflux for 4 hours. The mixture was diluted with 100 ml ethyl acetate, filtered, and stripped in vacuo. The residue was recrystallized from ethanol to give 9.5 g of 2-Carbomethoxy-4-(m-chlorophenylmethyloxy)-phenol (62% yield from 2,5-dihydroxybenzoic acid).
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[S:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:15]1([CH3:24])[CH:20]=[CH:19][CH:18]=[C:17]([C:21](Cl)=[O:22])[CH:16]=1.C1(C)C=CC=CC=1>[OH-].[Na+].O>[C:1]([N:5]([C:21]([C:17]1[CH:16]=[C:15]([CH3:24])[CH:20]=[CH:19][CH:18]=1)=[O:22])[NH:6][C:7](=[S:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: CC(C)(C)NNC(=S)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(C(=O)N(NC(=S)c2ccccc2)C(C)(C)C)c1
Reaction time: 3 h

Procedure:
N't-butyl-N-(thiobenzoyl)hydrazine (ca. 1 g), m-toluoyl chloride (approx. 0.7 g) and 50% aqueous sodium hydroxide (6 drops) were mixed in 1 ml water and 10 ml toluene at 23° C. After stirring for 3 hours, ether-hexane was added and the product was isolated by filtration (0.25 g). m.p. 165-168° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][CH2:15][CH:16]=O)=[CH:12][C:11]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:10]2)=[CH:5][CH:4]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][N:34]([CH2:16][CH2:15][CH2:14][C:13]2[N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:23])([F:22])[F:1])=[CH:4][CH:5]=3)[N:10]=[C:11]([CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=2)[CH2:33][CH2:32]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCCCc1cc(CCC=O)n(-c2ccc(C(F)(F)F)cc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2ccc(C(F)(F)F)cc2)n1

Procedure:
258.6 mg (84.7%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-(4-trifluoromethylphenyl)-3-butyl-1H-pyrazol-5-yl)propanal (202.6 mg, 0.625 mmol), 1-(2-fluorophenyl)piperazine (148 mL, 0.937 mmol), and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1>>[F:23][C:22]1[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[N:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)=[C:18]([O:24][CH3:25])[CH:19]=[CH:20][CH:21]=1
Reactant: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: Brc1ncccn1
Product: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)c3ncccn3)c2)c1

Procedure:
This compound is prepared by method C using compound 12g and 2-bromopyrimidine
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH:13]1([N:19]=[C:20]=[S:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH:12][C:20]([NH:19][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[S:21])(=[O:10])=[O:11]
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Reactant: S=C=NC1CCCCC1
Agent: Cl
Product: Nc1cc(Cl)sc1S(=O)(=O)NC(=S)NC1CCCCC1

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and cyclohexyl isothiocyanate by a procedure analogous to the procedure described in example 3-a (yield 78%); 1H-NMR (DMSO-d6): δ1.1-1.9 (m, 10H), 4.0 (m, 1H), 6.45 (br s, 2H), 6.66 (s, 1H), 8.05 (br d, 1H), 11.2 (br s, 1H).