Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.O>[CH2:30]([N:24]1[C:18]2[CH:17]=[CH:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:14][CH:13]=3)=[CH:29][C:19]=2[CH:20]=[C:21]([C:25]([O:27][CH3:28])=[O:26])[CH2:22][CH2:23]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
In 1,2-dichloroethane (7 ml) were dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.4 g) and benzaldehyde (0.43 g). To the solution was added sodium triacetoxyborohydride (0.43 g), and the mixture was stirred under nitrogen atmosphere at room temperature overnight, poured into water, neutralized with sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give methyl 1-benzyl-7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.49 g) as oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1>C1COCC1.C(Cl)(Cl)Cl.O=[Mn]=O>[O:12]=[C:9]1[NH:8][C:7]2[CH:13]=[C:3]([CH:2]=[O:1])[CH:4]=[CH:5][C:6]=2[S:11][CH2:10]1
Reactant: O=C1CSc2ccc(CO)cc2N1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc2c(c1)NC(=O)CS2
Temperature: 70 °C
Reaction time: 4 h
Yield: 57.5 %

Procedure:
To a solution of 6-hydroxymethyl-4H-benzo[1,4]thiazin-3-one (360 mg, 1.8 mmol) in THF/CHCl3 (2:1, 18 mL) was added MnO2 (1.6 g, 18 mmol) and the resulting suspension was heated to 70° C. and stirred for 4 h. The suspension was filtered through diatomaceous earth and the filtrate was concentrated. The resulting solid was triturated with EtOAc/hexanes (1:1) and a minimal amount of CH3OH to provide 200 mg (56%) of the title compound as a tan solid. MS (ESI): exact mass calculated for C9H7NO2S, 193.02; m/z found, 194.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 9.94 (s, 1H), 8.78 (br s, 1H), 7.54-7.49 (m, 2H), 7.37 (d, J=1.5, 1H), 3.52 (s, 2H).
Reaction SMILES: C([N:8]1[C@@H:20]([C:21]([O:23][CH3:24])=[O:22])[CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[C@@H:9]1[CH3:25])C1C=CC=CC=1>CO.[Pd]>[CH3:25][C@H:9]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[CH2:19][C@H:20]([C:21]([O:23][CH3:24])=[O:22])[NH:8]1
Reactant: COC(=O)[C@H]1Cc2c([nH]c3ccccc23)[C@H](C)N1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H]1Cc2c([nH]c3ccccc23)[C@H](C)N1
Yield: 98.6 %

Procedure:
Methyl (1RS,3SR)-trans-2-benzyl-1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylate (14.0 g) is dissolved in methanol (600 ml), and thereto is added 10% Pd-C (1.0 g). The mixture is subjected to catalytic reduction under atmospheric pressure. After the reaction, the catalyst is removed by filtration and washed with methanol. The filtrate and the washing liquid are combined and distilled to remove the solvent. The residue is recrystallized from methanol-isopropyl ether to give the title compound (10.08 g, 98.5%) as colorless prisms, m.p. 152°-154° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:17]O>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: CO
Reactant: O=C(O)c1cccc(Cl)c1Cl
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(Cl)c1Cl
Yield: 92 %

Procedure:
A solution of 2,3-dichlorobenzoic acid (100 g, 0.526 mol) in methanol (1 L), was added H2SO4 (20 mL). The solution was stirred under reflux overnight. The reaction mixture was cooled and concentrated. The resulting residue was diluted with water (100 mL) and ethyl acetate (1 L). Then the organic layer was washed with aq. NaHCO3 and brine, dried over Na2SO4, filtered and the filtrate was concentrated to provide the titled compound (99 g, 92%), as a white solid; 1H NMR (300 MHz, CDCl3) δ ppm 3.95 (s, 3H), 7.27 (t, J=7.8 Hz, 1H), 7.60 (dd, J=1.8, 7.8 Hz, 1H), 7.66 (dd, J=1.8, 7.8 Hz, 1H).
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:11]([CH2:23][CH3:24])=[N:12][N:13]3[C:18](Cl)=[C:17]4[CH2:20][CH2:21][CH2:22][C:16]4=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:25]>CO>[C:1]1([S:7]([C:10]2[C:11]([CH2:23][CH3:24])=[N:12][N:13]3[C:18]([NH2:25])=[C:17]4[CH2:20][CH2:21][CH2:22][C:16]4=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCc1nn2c(Cl)c3c(nc2c1S(=O)(=O)c1ccccc1)CCC3
Reactant: N
Solvent: CO
Product: CCc1nn2c(N)c3c(nc2c1S(=O)(=O)c1ccccc1)CCC3

Procedure:
In an analogous manner to that described in Example 4, from 3-benzenesulphonyl-8-chloro-2-ethyl-6,7-dihydro-5H-cyclopenta[d]pyrazolo[1,5-a]pyrimidine and NH3 in MeOH there was obtained 3-benzenesulphonyl-2-ethyl-6,7-dihydro-5H-cyclopenta[d]pyrazolo[1,5-a]pyrimidin-8-ylamine as colorless crystals, m.p.>230°.
Reaction SMILES: [CH2:1]([N:5]1[CH2:11][CH2:10][C:9](O[Si](C)(C)C)=[C:8](O[Si](C)(C)C)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].Br.Br.[NH2:24][CH2:25][C:26]([NH2:28])=[NH:27]>>[NH2:28][C:26]1[CH:25]=[N:24][C:9]2[CH2:10][CH2:11][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7][C:8]=2[N:27]=1
Reactant: N=C(N)CN
Reactant: CCCCN1CCC(O[Si](C)(C)C)=C(O[Si](C)(C)C)CC1
Agent: Br
Product: CCCCN1CCc2ncc(N)nc2CC1

Procedure:
This compound was prepared analogous to Example 3 from 1-butyl-2,3,6,7-tetrahydro-4,5-bis(trimethylsilyloxy)-azepine and 2-amino-acetamidine dihydrobromide.
Reaction SMILES: FC1C=C(F)C=CC=1N[S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH2:16][CH2:15][CH2:14]1)(=O)=O.[C:24]1([CH2:30]S)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1CCN2C(=NCCC2)CC1>CN(C)C=O.C(OCC)(=O)C>[CH2:30]([S:10][CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH2:16][CH2:15][CH2:14]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: SCc1ccccc1
Reactant: CCOC(=O)C1=CCCCC1S(=O)(=O)Nc1ccc(F)cc1F
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=CCCCC1SCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl 6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate (1 g, synthesized according to the method disclosed in JP-A-10-056492) and phenylmethanethiol (719 mg) in N,N-dimethylformamide (20 ml) was added dropwise under ice-cooling 1,8-diazabicyclo[5,4,0]-7-undecene (441 mg) and the mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate (100 ml), washed with water (70 ml×2) and saturated brine (70 ml), and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by flash silica gel column chromatography (eluent: toluene) to give ethyl 6-(benzylsulfanyl)-1-cyclohexene-1-carboxylate (673 mg) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16]CC=C)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[C:26]([O:35]C(OC(C)(C)C)=O)[C:25]([C:43]([F:46])([F:45])[F:44])=[CH:24][CH:23]=1>>[C:31]([O:30][C:28]([C:27]1[C:26]([OH:35])=[C:25]([C:43]([F:44])([F:45])[F:46])[CH:24]=[CH:23][C:22]=1[CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: C=CCOC(=O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)c1c(COc2ccc(-c3ccc(C(=O)O)cc3)cc2)ccc(C(F)(F)F)c1O
Yield: 80 %

Procedure:
According to a method similar to Example (40-2), Example (33-5) and Example (13-5), using allyl 4′-hydroxy-1,1′-biphenyl-4-carboxylate (190 mg, 0.75 mmol) obtained in Example (43-1) and tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (400 mg, 0.88 mmol) obtained in Example (28-5), the title compound was obtained as a colorless powder (293 mg, three-step total yield: 80%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:18]([CH:19]=[O:20])=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:21][CH3:22])[CH:15]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1>[CH2:1]([NH:8][C:9]1[C:18]([CH2:19][OH:20])=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:21][CH3:22])[CH:15]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2nc(NCc3ccccc3)c(C=O)cc2c1
Solvent: C1CCOC1
Product: COc1ccc2nc(NCc3ccccc3)c(CO)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a stirred solution of 2-(benzylamino)-6-methoxyquinoline-3-carbaldehyde SLA 41002 (0.40 g, 1.37 mmol) in THF (50 mL) in a 100 mL round-bottomed flask equipped with a magnetic stirrer was added sodium borohydride NaBH4 (0.24 g, 6.35 mmol) and the mixture was stirred overnight at RT then cooled in an ice bath before quenching by addition of a 1 N aq. HCl solution (15 mL). After stirring for 15 min at that temperature, the mixture was basified to pH=9 with a 2 N aq. NaOH solution. THF was then removed at 40° C. under vacuum and the solution was extracted with CH2Cl2 (200 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give (2-(benzylamino)-6-methoxyquinolin-3-yl)methanol SLA 41006 as a yellow solid (0.395 g, 98% yield).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.Br[C:10]1[CH:11]=[C:12]2[C:25]3[C:15]([CH2:16][C@@H:17]4[C@@H:22]([C:23]=3[CH:24]=1)[CH2:21][C@H:20]([NH:26][C:27](=[O:33])[N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH2:19][N:18]4[CH3:34])=[CH:14][N:13]2[Si](C(C)(C)C)(C)C>>[Cl:1][C:24]1[C:23]2=[C:25]3[C:12]([NH:13][CH:14]=[C:15]3[CH2:16][C@@H:17]3[C@@H:22]2[CH2:21][C@H:20]([NH:26][C:27](=[O:33])[N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH2:19][N:18]3[CH3:34])=[CH:11][CH:10]=1
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(Br)cc4c3c(cn4[Si](C)(C)C(C)(C)C)C[C@H]2N(C)C1
Reactant: O=C1CCC(=O)N1Cl
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c(Cl)ccc4[nH]cc(c34)C[C@H]2N(C)C1

Procedure:
With N-chlorosuccinimide and 3-(13-bromo-1-tert-butyldimethylsilyl-6-methyl-8α-ergolinyl)-1 1-diethylurea:
Reaction SMILES: [C:1]([N:5]([CH2:13][CH2:14][C:15]#[C:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[C:6](=[O:12])[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>O1CCOCC1.O>[C:1]([N:5]([CH2:13][CH2:14][C:15]#[C:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[C:6](=[O:12])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)N(CCC#Cc1cccs1)C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)N(CCC#Cc1cccs1)C(=O)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 100 mg of 1d in 1 ml of dioxane was mixed with a solution of 40 mg of KOH in 400 μl of water and stirred for 16 hr at RT. The mixture was diluted with 5 ml of water and acidified to pH3 with 0.5 N HCl. The product was extracted with ethyl acetate and the extracts were washed once with sat. NaCl, dried and concentrated, to provide 65 mg of essentially pure 1e as colorless oil; MS-ESI: [M+1] 280.16; NMR (CDCl3) δ 1.54 (s, 9, tertC4H9), 2.80 (m, 2, CH2), 4.10 (bm, 2, CH2), 6.94, 7.13, 7.20 (3×m, 3, thiophene-H).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[C:10]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:9]3[N:19]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:21]=[C:8]3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C.O1CCCC1>[N:1]1([C:6]2[CH:11]=[C:10]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:9]3[N:19]=[C:20]([C:22]([OH:24])=[O:23])[CH:21]=[C:8]3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cc2nc(N3CCCC3)cc(NC3CCOCC3)n2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cc2nc(N3CCCC3)cc(NC3CCOCC3)n2n1

Procedure:
To a solution of ethyl 5-pyrrolidin-1-yl-7-(tetrahydro-2H-pyran-4-ylamino)pyrazolo[1,5-a]pyrimidine-2-carboxylate (1.89 g, 5.26 mmol) in ethanol (25 mL) and tetrahydrofuran (25 mL) was added 1N aqueous sodium hydroxide (10.5 mL, 10.5 mmol) at room temperature. After being stirred for 23 h at same temperature, 6N aqueous hydrochloric acid (1.75 mL, 3.50 mmol), and then the reaction mixture was concentrated in vacuo. The residue was triturated with diisopropyl ether to give 5-pyrrolidin-1-yl-7-(tetrahydro-2H-pyran-4-ylamino)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid. MS (APCI): m/z 330 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:15])[C:9](=[CH2:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[F:16].C(N(CC)CC)C.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO>[CH2:24]([NH:31][CH2:14][CH:9]([CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:16])[CH:4]=1)[OH:15])[C:10]([O:12][CH3:13])=[O:11])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: C=C(C(=O)OC)C(O)c1ccc(Cl)c(F)c1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)C(CNCc1ccccc1)C(O)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-[(4-chloro-3-fluorophenyl)(hydroxy)methyl]prop-2-enoate (69.1 g) and triethylamine (47.3 mL) in methanol (706 mL) was added benzylamine (37.1 ml), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (58.2 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([Cl:15])[CH:10]=2)[C:3]=1[N+:16]([O-])=O>C(O)C.C(O)(=O)C.[Zn]>[Cl:15][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[C:3]([NH2:16])=[C:2]([Cl:1])[N:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][N:12]=1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Nc1ccnc(Cl)c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1c(Cl)ncnc1Nc1ccnc(Cl)c1
Reaction time: 1 h
Yield: 128.4 %

Procedure:
N-(6-Chloro-5-nitro-4-pyrimidinyl)-N-(2-chloro-4-pyridyl)amine (2.2 g, 7.6 mmol) was suspended in 44 ml ethanol and 4.4 ml acetic acid, and 2.2 g zinc powder was added little by little thereto at 0° C. The reaction solution was returned to room temperature and stirred for 1 hour, and then the insoluble matters were filtered off. The filtrate was concentrated and suspended in water, and the resulting solid was collected by filtration and air-dried, to give 2.5 g of the title compound in crude form.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.CC1(C)C(C)(C)OB([C:40]2[CH:48]=[C:47]3[C:43]([CH2:44][CH2:45][C:46]3=[O:49])=[CH:42][CH:41]=2)O1>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:16][C:6]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:2]([C:40]2[CH:48]=[C:47]3[C:43](=[CH:42][CH:41]=2)[CH2:44][CH2:45][C:46]3=[O:49])[N:3]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:5]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Reactant: CC1(C)OB(c2ccc3c(c2)C(=O)CC3)OC1(C)C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: COCCOC
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2c(c1)C(=O)CC2
Yield: 56.5 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.159 g; 0.5 mmol), tetrakis(triphenylphosphine) palladium(0) (0.059 mg; 0.05 mmol), N,N-diisopropylethylamine (0.345 mL; 2 mmol) and intermediate 18 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one (0.325 g; 1.25 mmol) in DME-water (2 mL) for 30 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.117 g (56%) of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.[CH3:9][NH:10][CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=2)=[O:20])[CH2:15][CH2:14]1>>[CH3:9][N:10]([CH2:11][CH2:12][CH:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][C:23]2[CH:24]=[C:25]([Cl:30])[CH:26]=[C:27]([Cl:29])[CH:28]=2)=[O:20])[CH2:17][CH2:18]1)[C:6]([C:4]1[N:3]=[N:2][NH:1][CH:5]=1)=[O:8]
Reactant: CNCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Reactant: O=C(O)c1c[nH]nn1
Product: CN(CCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)C(=O)c1c[nH]nn1

Procedure:
The title compound was prepared analogously to Example 34, step 3 from 1H-1,2,3-triazole-4-carboxylic acid and 3,5-dichlorobenzyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate (Example 1, step 3) (200 mg, 0.579 mmol);
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:16][CH:17]([C:21]1[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:22]=1[F:29])[C:18](=O)[CH3:19])[C:10](OC(C)C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([NH2:33])(C)C>CS(C)=O>[CH3:19][C@H:18]1[NH:33][C:10](=[O:11])[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:16][C@H:17]1[C:21]1[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:22]=1[F:29]
Reactant: CC(C)N
Reactant: CC(=O)C(CC(NC(=O)OC(C)(C)C)C(=O)OC(C)C)c1c(F)ccc(F)c1F
Solvent: CS(C)=O
Product: C[C@H]1NC(=O)C(NC(=O)OC(C)(C)C)C[C@H]1c1c(F)ccc(F)c1F
Temperature: 55 °C
Reaction time: 27.5 h

Procedure:
Crude keto ester 19 (23.6 g, 69 wt %, 16.3 g assay, 39 mmol) was dissolved in DMSO (163 mL) and the solution was added to the reactor over 5-10 min. Then the reaction was heated to 55° C. The pH was adjusted to 10.5 according to a handheld pH meter and controlled overnight with an automated pH controller using 8 M aqueous isopropylamine. The reaction was aged for 27.5 hours.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[N:2]=1.[C:16]1([C:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:16]1([C:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:8]([NH:7][C:3]4[N:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:15])[CH2:29][CH2:28]3)[S:25][CH:26]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1cccnn1)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1cccnn1)N1CCN(c2nc(-c3ccccc3)cs2)CC1
Yield: 44.3 %

Procedure:
A solution of 2,2,2-trichloroethyl pyridazin-3-ylcarbamate (200 mg, 0.793 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (181 mg, 0.739 mmol), diisopropylethylamine (0.129 ml, 0.739 mmol) and dimethylsulfoxide (3 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate to obtain the desired product (120 mg, 44.3%) as a solid.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH:21][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)=[N:4]1)[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Product: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)c3ccccc3)cc2)n1

Procedure:
Following the procedure described in Example 1 with 4-[1-ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline and benzoyl chloride provided the title compound. ESMS [M+H]+: 408.2
Reaction SMILES: [CH2:1]([C:8]1[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])O[C:9]=1[CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[NH3:17]>>[CH2:1]([C:8]1[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[NH:17][C:9]=1[CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCc1c(C)oc(C)cc1=O
Reactant: N
Product: CCCCCCCc1c(C)[nH]c(C)cc1=O
Temperature: 25 °C

Procedure:
Compound 1 (0.01 g, 30.6 mmol) was heated at 100° C. with aqueous ammonia in a high pressure tube for 18 h. After the mixture was cooled to room temperature, the crude was concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column. Elution with 5:1 ethyl acetate/methanol gave 3-heptyl-2,6-dimethylpyridin-4(1H)-one (3) as a brown solid: yield 0.083 g (81%); silica gel TLC Rf 0.25 (3:1 ethyl acetate/methanol); 1H NMR (CD3OD) δ 0.68-0.71 (m, 3H), 1.09-1.28 (m, 10H), 2.20 (s, 3H), 2.27 (s, 3H), 2.34-2.36 (m, 2H) and 6.29 (s, 1H).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([CH2:8][CH2:9][C:10]1[CH:31]=[CH:30][C:29]2[C:15]3[NH:16][C:17](=[O:28])[C:18]4[N:19]([CH:20]=[C:21]([C:23]([O:25]CC)=[O:24])[N:22]=4)[C:14]=3[CH2:13][C:12]=2[CH:11]=1)=[O:7])C.O1CCOCC1.Cl>O>[C:6]([CH2:8][CH2:9][C:10]1[CH:31]=[CH:30][C:29]2[C:15]3[NH:16][C:17](=[O:28])[C:18]4[N:19]([CH:20]=[C:21]([C:23]([OH:25])=[O:24])[N:22]=4)[C:14]=3[CH2:13][C:12]=2[CH:11]=1)([OH:7])=[O:5]
Reactant: CCOC(=O)CCc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nc(C(=O)OCC)cn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nc(C(=O)O)cn12
Reaction time: 6 h
Yield: 59.9 %

Procedure:
18 ml of 1N sodium hydroxide solution are added, under an argon blanket, to a stirred mixture, at a temperature in the region of 20° C., of 1.75 g of ethyl 8-(2-ethoxycarbonylethyl)-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylate, 220 ml of dioxane and 60 ml of water and stirring is continued for 6 hours. The reaction mixture is filtered, the solid is washed with 2×20 ml of dioxane and 30 ml of water are added to the solid. The solution obtained is acidified to pH 1 with 1N hydrochloric acid and the precipitate is filtered, washed with 2×30 ml of distilled water and then 2×30 ml of acetone and dried under vacuum (1 mm Hg; 0.13 kPa) in the region of 50° C. 0.9 g of 8-(2-carboxyethyl)-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-2-carboxylic acid is obtained in the form of a beige solid melting above 290° C. (1H NMR spectrum in d6-DMSO, T=300 K, δ in ppm (200 MHz): 2.60 (2H, t, J=6 Hz, CH2CO2H), 2.90 (2H, t, J=6 Hz, CH2), 4.00 (2H, s, CH2), 7.25 (1H, d, J=8 Hz, arom. CH), 7.45 (1H, s, arom. CH), 7.78 (1H, d, J=8 Hz, arom. CH), 8.50 (1H, s, imidazole H), 12.5 (3H, s, NHCO and 2CO2H)).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[Br:9][C:10]1[C:11]([Cl:28])=[CH:12][C:13](F)=[C:14]([S:16]([N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)(=[O:18])=[O:17])[CH:15]=1>CN(C=O)C>[Br:9][C:10]1[C:11]([Cl:28])=[CH:12][C:13]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])=[C:14]([S:16]([N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)(=[O:17])=[O:18])[CH:15]=1
Reactant: OCCCCO
Reactant: CN(c1ccccn1)S(=O)(=O)c1cc(Br)c(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1ccccn1)S(=O)(=O)c1cc(Br)c(Cl)cc1OCCCCO
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 96.8 %

Procedure:
To a solution of 1,4-butanediol (0.315 mL, 3.6 mmol) in DMF (2.5 mL) at ambient temperature was added sodium hydride (60%, 34 mg, 0.85 mmol) and the mixture was stirred for 15 minutes. A solution of 5-bromo-4-chloro-2-fluoro-N-methyl-N-pyridin-2-yl-benzenesulfonamide (0.268 g, 0.71 mmol) in DMF (2.5 mL) was added and the mixture heated at 50° C. for 2 h. The solvent was removed in vacuo and water and DCM were added. The mixture was extracted with DCM. The organic layer was washed with brine and was dried over anhydrous MgSO4. Concentration of the filtrate provided a residue that was purified by silica gel chromatography [eluent: 50% ethyl acetate in hexane] to afford 5-bromo-4-chloro-2-(4-hydroxy-butoxy)-N-methyl-N-pyridin-2-yl-benzenesulfonamide as a solid (0.309 g). MS: 451.0 (M+H)+; tR=2.59 min (method 1).