Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)=[CH:16][CH:15]=[C:14]([S:28]([CH3:31])(=[O:30])=[O:29])[N:13]=2)[CH2:8][CH2:7]1)C.O1CCCC1.CO.[OH-].[Li+]>O>[Cl:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:17]1[C:12]([N:9]2[CH2:10][CH2:11][CH:6]([CH2:5][C:4]([OH:32])=[O:3])[CH2:7][CH2:8]2)=[N:13][C:14]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:15][CH:16]=1)=[O:27]
Reactant: CCOC(=O)CC1CCN(c2nc(S(C)(=O)=O)ccc2NC(=O)c2cccc(Cl)c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc(NC(=O)c2cccc(Cl)c2)c(N2CCC(CC(=O)O)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
To a mixture of 0.055 g (0.11 mmol) of [3′-(3-chloro-benzoylamino)-6′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid ethyl ester in a 2:1 mixture of tetrahydrofuran:methanol (6 mL) is added 0.014 g (0.57 mmol) of lithium hydroxide as a solution in water (1 mL). The mixture is stirred overnight at room temperature then concentrated under reduced pressure. The residue is diluted with water and the pH of the mixture is adjusted to pH 2 by the addition of concentrated hydrochloric acid causing a solid to precipitate from solution. The formed precipitate is collected by filtration and dried to provide 0.023 g (44%) of [3′-(3-chloro-benzoylamino)-6′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:5][N:6]1[CH2:11][CH2:10][C:9]([C:12](OC)=[O:13])=[CH:8][C:7]1=[O:16].[BH4-].[Li+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:5][N:6]1[CH2:11][CH2:10][C:9]([CH2:12][OH:13])=[CH:8][C:7]1=[O:16]
Reactant: COC(=O)C1=CC(=O)N(Cc2ccc(F)c(Cl)c2)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1C=C(CO)CCN1Cc1ccc(F)c(Cl)c1
Reaction time: 24 h

Procedure:
A solution of methyl 1-(3-chloro-4-fluorobenzyl)-5,6-dihydropyridin-2(1H)-one-4-carboxylate (4.0 g, 13 mmol) from the previous step in THF (75 mL) was cooled to −78° C. with stirring. A solution of lithium borohydride in THF (15 mL of a 2.0 M solution, 30 mmol) was added and the mixture was stirred at −78° C. for 30 min and then at ambient temperature for 24 hours. The reaction was quenched by the careful addition of 1 N aqueous HCl. Enough HCl was added so that the solution measured pH 1. The solvent was removed under reduced pressure and the residue was partitioned between CH2Cl2 (100 mL) and water (50 mL). The organic layer was separated and the aqueous phase was extracted with more CH2Cl2 (2×100 mL). The organic phases were combined and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography eluting with 95:5 CH2Cl2:MeOH. Fractions containing product were concentrated under reduced pressure to give the title compound as a gum. HPLC RT=2.67 min (Method A); ES MS M+1=272.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:21](O)=[O:22])[S:5][C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH:9]=1.[NH2:24][CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:26][OH:27].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[OH:27][CH2:26][CH:25]([NH:24][C:21]([C:4]1[S:5][C:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[CH:9]=2)=[C:2]([CH3:1])[N:3]=1)=[O:22])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1nc(C(=O)O)sc1Cc1cccc(N2CCN(C)CC2)c1
Reactant: NC(CO)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(C(=O)NC(CO)c2ccccc2)sc1Cc1cccc(N2CCN(C)CC2)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 48.1 %

Procedure:
To a mixture of 4-methyl-5-(3-(4-methylpiperazin-1-yl)benzyl)thiazole-2-carboxylic acid (200 mg, 0.6 mmol), 2-amino-2-phenylethanol (99 mg, 0.7 mmol) and TEA (0.3 mL, 1.8 mmol) in DMF (2 mL), EDCI.HCl (175 mg, 0.9 mmol) and HOBT (95 mg, 0.7 mmol) were added. The mixture was stirred at 50° C. overnight, then cooled to RT, diluted with H2O (50 mL) and extracted with DCM/MeOH (10/1, 4×30 mL). The combined organic layers were washed with a saturated aqueous solution of LiCl (3×20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated to afford the crude product, which was purified by Combiflash reverse phase chromatography (50%˜60% MeCN/H2O containing 10 mM NH4HCO3) to afford N-(2-hydroxy-1-phenylethyl)-4-methyl-5-(3-(4-methylpiperazin-1-yl)benzyl)thiazole-2-carboxamide as a colorless oil (130 mg, 48%). MS (ES+) C25H30N4O2S requires: 450, found: 451 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:30])[C:8]4[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@H:23]5[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24]5)=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[S:31]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC(N(C)C)=O.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:29][C:25]1([CH3:28])[O:24][C@@H:23]([CH2:22][O:21][C:18]2[CH:19]=[CH:20][C:8]3[C:7](=[O:30])[C:6]4[C:5]5[C:13](=[CH:14][C:2]([C:33]6[CH:34]=[CH:35][S:31][CH:32]=6)=[CH:3][CH:4]=5)[NH:12][C:11]=4[C:10]([CH3:15])([CH3:16])[C:9]=3[CH:17]=2)[CH2:27][O:26]1
Reactant: CC1(C)OC[C@H](COc2ccc3c(c2)C(C)(C)c2[nH]c4cc(Br)ccc4c2C3=O)O1
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC1(C)OC[C@H](COc2ccc3c(c2)C(C)(C)c2[nH]c4cc(-c5ccsc5)ccc4c2C3=O)O1

Procedure:
3-Bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (20.0 mg, 0.043 mmol), thiophene-3-boronic acid (10.9 mg, 0.085 mmol), K3PO4 (40 mg) and Pd (PPh3)4 (9.9 mg, 0.0086 mmol) were dissolved in DMA (0.8 ml) and water (0.2 ml), and stirred at 140° C. for 10 min under microwave irradiation. The reaction solution was diluted with ethyl acetate and washed with saturated brine. The organic layer was concentrated under reduced pressure, and the resulting residues were purified by column chromatography (hexane/ethyl acetate) to obtain 8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy)-6,6-dimethyl-3-thiphen-3-yl-5,6-dihydro-benzo[b]carbazol-11-one.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[C-].[H-].[Na+].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:17]([C:22](=O)[C:23]2[CH:28]=[CH:27][N:26]=[C:25]([Cl:29])[CH:24]=2)=[CH:18][C:19]=1[O:20][CH3:21])[CH:15]=O.C(O)(=O)C>CN(C)C=O>[Cl:29][C:25]1[CH:24]=[C:23]([C:22]2[C:17]3[C:14](=[CH:13][C:12]([O:11][CH3:10])=[C:19]([O:20][CH3:21])[CH:18]=3)[CH:15]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[N:1]=2)[CH:28]=[CH:27][N:26]=1
Reactant: COc1cc(C=O)c(C(=O)c2ccnc(Cl)c2)cc1OC
Reactant: [C-]#[N+]CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)c1cc2cc(OC)c(OC)cc2c(-c2ccnc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl isocyanoacetate (18 ml) in dimethylformamide (85 ml) is added sodium hydride (7.85 g, 62.4% in oil) with ice-cooling under nitrogen atmosphere, and the mixture is stirred at room temperature for 30 minutes. To a solution of 3,4-dimethoxy-6-(2-chloroisonicotinoyl)benzaldehyde (52.0 g) in dimethylformamide (170 ml) is added dropwise the above solution at 40-50° C., and then the mixture is stirred at 50° C. for one hour. The mixture is neutralized with 10% acetic acid, concentrated, and extracted with chloroform. The extract is washed, and the insoluble materials are collected by filtration, and the filtrate is dried and concentrated. The resultant and the collected insoluble materials are combined, and recrystallized from ether-methanol to give 2-chloro-4-(3-methoxycarbonyl-6,7-dimethoxyisoquinolin-1-yl)pyridine (16.1 g).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[N+:18]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].O.[S-2].[Na+].[Na+]>CO>[CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[NH2:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(NCc2ccccc2)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1cc([N+](=O)[O-])ccc1NCc1ccccc1
Temperature: 25 °C
Yield: 73.2 %

Procedure:
A mixture of 2.0 g (7.3 mmol) N-benzyl-2,4-dinitroaniline, 1.50 g (28.0 mmol) ammonium chloride, 6.7 g (28.0 mmol) sodium sulfide hydrate and 100 ml methanol was refluxed for 3/4 h. After cooling to 25° C. the mixture was filtered and evaporated. The product was stirred with water to give 1.3 g (73%) N-benzyl-2-amino-4-nitroaniline. 1H-NMR (CDCl3): 8.1-6.5 (8H, m), 4.9-4.3 (3H, m), 3.4 (2H, broad s).
Reaction SMILES: [OH-].[K+].[CH2:3]([N:10]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[S:11]([C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([C:24]([O:26]C)=[O:25])=[CH:21]2)=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.O.C(Cl)Cl>[CH2:28]([N:10]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[S:11]([C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([C:24]([OH:26])=[O:25])=[CH:21]2)=[CH:16][CH:15]=1)(=[O:12])=[O:13])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)c1ccc2ccc(S(=O)(=O)N(Cc3ccccc3)Cc3ccccc3)cc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1ccc2ccc(S(=O)(=O)N(Cc3ccccc3)Cc3ccccc3)cc2c1
Yield: 108.5 %

Procedure:
A solution of KOH (720 mg, 12.8 mmol) in MeOH (5 mL) and H2O (2 mL) was added dropwise to a solution of 209 (1.90 g, 4.27 mmol) in MeOH (10 mL) and CH2Cl2 (15 mL). After 48 h at room temperature CH2Cl2 and H2O were added. The aqueous layer was separated and acidified to pH 2 with 2 M HCl. The resulting white precipitate was collected, dissolved in CH2Cl2, and the solution was washed with H2O and brine. The CH2Cl2 layer was dried, the solvent was evaporated, and the residue was dried in a vacuum desiccator. Recrystallization from CH2Cl2/petroleum ether gave 7-[(dibenzylamino)sulfonyl]-2-naphthoic acid (210) (2.00 g, 99%) as colorless crystals: mp 189-190° C.; 1H NMR (CDCl3) 8 (CO2H not observed) 8.76 (s, 1H), 8.47 (s, 1H), 8.29 (dd, J=8.6, 1.5 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.92 (dd, J=8.7, 1.8 Hz, 1H), 7.23-7.15 (m, 6H), 7.12-7.05 (m, 4H), 5.29 (s, 1H), 4.42 (s, 4H); 13C NMR δ 170.8, 139.0, 137.0, 135.4, 133.1, 131.4, 129.7, 129.3, 128.6, 128.5, 128.4, 128.2, 128.1, 127.8, 125.3, 50.7. Anal. (C25H21NO4S) C, H, N.
Reaction SMILES: OCC1C=C(CCCO)C=CC=1.[Si:13]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH2:31][OH:32])[CH:28]=[CH:29][CH:30]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>>[Si:13]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=1)[CH:31]=[O:32])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)OCCCCc1cccc(CO)c1
Agent: OCCCc1cccc(CO)c1
Product: CC(C)(C)[Si](C)(C)OCCCCc1cccc(C=O)c1

Procedure:
Prepared by the method of Aromatic Intermediate 18, step c using (3-(4-(tert-butyldimethylsilyloxy)butyl)phenyl)methanol [Aromatic Intermediate 19, step b] (0.72 g) in place of 3-(3-(hydroxymethyl)phenyl)propan-1-ol. Yield 0.64 g.
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]([OH:16])(=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:17]1(=[O:24])[NH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(O)(=O)C>[C:8]([CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:17]1=[O:24])(=[O:16])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)c1ccccc1
Reactant: O=C1CCCCCN1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C1NCCCCC1C(=O)c1ccccc1

Procedure:
heating acetic anhydride, benzoic acid, and caprolactam at a temperature of about 130° to about 170° C. to form volatile acetic acid and benzoyl caprolactam;
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1.[NH:21]1[C:25]([C:26]2[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=2)=[N:24][N:23]=[N:22]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:24]1[C:25]([C:26]2[CH:31]=[C:30]([C:2]3[C:10]4[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=4)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=3)[CH:29]=[CH:28][CH:27]=2)=[N:21][N:22]=[N:23]1
Reactant: OB(O)c1cccc(-c2nnn[nH]2)c1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)CCOCn1nc(-c2cccc(-c3nnn[nH]3)c2)c2ccc(C=O)cc21
Temperature: 125 °C
Reaction time: 4 h
Yield: 38 %

Procedure:
A mixture of 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (100 mg, 0.25 mmol), 3-(tetrazol-5-yl)phenylboronic acid (57 mg, 0.30 mmol), Pd(PPh3)4 (18 mg, 0.025 mmol) and 2M Na2CO3 (0.13 mL, 0.25 mmol) in DME/H2O/EtOH (2.8 mL/0.8 mL/0.4 mL) was degassed by evacuation and blanketed with Ar. The reaction mixture was sealed and heated with stirring under microwave irradiation at 125° C. for 4 hours. The crude reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using MeOH (5% to 10%) in DCM as the eluent to provide a white solid (40 mg, 38%). 1H NMR (400 MHz, CD3OD) δ ppm 10.10 (s, 1H), 8.59 (s, 1H), 8.25 (s, 1H), 8.21 (d, J=8.5 Hz, 1H), 8.11 (d, J=7.9 Hz, 1H), 8.04 (d, J=8.3 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.67 (t, J=7.8 Hz, 1H), 5.88 (s, 2H), 3.66 (t, J=8.1 Hz, 2H), 0.89 (t, J=8.0 Hz, 2H), −0.10 (s, 9H); MS ESI 421.1 (100) [M+H]+, calcd for [C21H24N6O2Si+H]+ 421.2.
Reaction SMILES: [CH:1]([N:4]1[C:32](=[O:33])[C:31]2[N:12]3[CH2:13][CH2:14][C:15]4[CH:16]=[C:17]([O:29][CH3:30])[C:18]([C:21]5[C:22]([CH3:28])=[N:23][N:24]([CH3:27])[C:25]=5[CH3:26])=[CH:19][C:20]=4[C:11]3=[C:10]([C:34]3[S:35][CH:36]=[CH:37][CH:38]=3)[C:9]=2[CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].[F:39][C:40]([F:47])([F:46])[CH2:41][CH2:42][C:43](O)=[O:44].C(N1CCOCC1)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(OCC)(=O)C.O>[CH:1]([N:4]1[C:32](=[O:33])[C:31]2[N:12]3[CH2:13][CH2:14][C:15]4[CH:16]=[C:17]([O:29][CH3:30])[C:18]([C:21]5[C:22]([CH3:28])=[N:23][N:24]([CH3:27])[C:25]=5[CH3:26])=[CH:19][C:20]=4[C:11]3=[C:10]([C:34]3[S:35][CH:36]=[CH:37][CH:38]=3)[C:9]=2[CH2:8][N:7]([C:43](=[O:44])[CH2:42][CH2:41][C:40]([F:47])([F:46])[F:39])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: O=C(O)CCC(F)(F)F
Reactant: COc1cc2c(cc1-c1c(C)nn(C)c1C)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCNC3
Agent: CCN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc2c(cc1-c1c(C)nn(C)c1C)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCN(C(=O)CCC(F)(F)F)C3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 26 mg of 10q, 10 mg of trifluorobutyric acid, 15 μl of N-ethyl morpholine and 20 mg of TBTU was stirred at RT for 1 hr. The turbid mixture readily became homogeneous. After one hour, water and ethyl acetate were added and the mixture was stirred for ½ hr. The organic layer was once washed with 1N NaOH and twice with 5% aq. NH4Cl, dried and concentrated. The residue was treated with diethyl ether, from which 25 mg of 10t crystallized, Mp: 256-258° C. Rf 0.25 (heptane/acetone). MS-ESI: [M+1] 654.18
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:17]=1)[C:7](=[NH:16])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:17]=[C:6]([C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]3[N:16]=2)[CH:5]=[N:4][CH:3]=1
Reactant: Cc1ccc(NC(=N)c2cncc(Br)c2)nc1
Solvent: Cc1ccccc1
Product: Cc1ccc2nc(-c3cncc(Br)c3)nn2c1
Temperature: 150 °C

Procedure:
Lead tetra acetate (2.28 g, 0.0051 mol) was added to a solution of 5-bromo-N-(5-methylpyridin-2-yl)nicotinimidamide (44-1; 1 g, crude 0.0034 mol) in toluene (40 mL) in a 80 mL microwave vial at RT. The reaction mixture was heated to 150° C. for 2.5 h under microwave irradiation. It was concentrated under vacuum to afford the crude product, which was purified by silica gel column chromatography to afford the title compound. MS (M+1): 290.1
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][C:10]1[S:11][C:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])C)=[O:16])=[CH:13][CH:14]=1.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].Cl.OC1C=[CH:39][C:35]([C:36]([NH2:38])=[NH:37])=[CH:34]C=1.CCN=C=NCCCN(C)C.Cl>N1C=CC=CC=1>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[CH3:1][O:2][C:3](=[O:22])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][C:10]1[S:11][C:12]([C:15]([O:17][C:18]2[CH:20]=[CH:39][C:35]([C:36](=[NH:37])[NH2:38])=[CH:34][CH:21]=2)=[O:16])=[CH:13][CH:14]=1
Reactant: N=C(N)c1ccc(O)cc1
Reactant: COC(=O)[C@@H]1CCCN1Cc1ccc(C(=O)OC(C)(C)C)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1CCCN1Cc1ccc(C(=O)Oc2ccc(C(=N)N)cc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
To the compound (0.55 g, 1.7 mmol) obtained in step 1 was added trifluoroacetic acid (10 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, pyridine (10 ml), 4-hydroxybenzamidine hydrochloride (0.35 g, 2.0 mmol), and WSC hydrochloride (0.48 g, 2.5 mmol) were added to the obtained residue, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by high performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to give the title compound (0.30 g, 0.49 mmol, 29%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=O)[CH2:11][C:10](=[O:15])[CH2:9]1.Cl.[NH2:17][CH2:18][C:19]#[C:20][CH3:21].O1CCCC1>C(N(CC)CC)C>[CH3:21][C:20]1[C:11]2[C:10](=[O:15])[CH2:9][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:13][C:12]=2[N:17]=[CH:18][CH:19]=1
Reactant: CC#CCN
Reactant: Cc1ccccc1C1CC(=O)CC(=O)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccccc1C1CC(=O)c2c(C)ccnc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.9 %

Procedure:
To a mixture of 5-(2-methylphenyl)cyclohexane-1,3-dione (1.5 g), 1-amino-2-butyne hydrochloride (0.86 g), molecular sieves 4A (2 g) and tetrahydrofuran (20 ml) was added triethylamine (0.74 g), and the mixture was stirred at room temperature for 1 hour and then refluxed for 17 hours and cooled. Insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and the residue was stirred at 220° C. for 4 hours, to which were added ethyl acetate and sodium hydrogen carbonate solution. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane). The resulting crystals were recrystallized from ethyl acetate-hexane to give colorless crystals of 4-methyl-7-(2-methylphenyl)-5,6,7,8-tetrahydroquinolin-5-one (0.52 g).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH:9]([CH2:11][O:12]CC2C=CC=CC=2)[O:8][CH:7]([CH2:20][O:21][CH2:22][C:23]([N:25]([CH2:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28])=[O:24])[CH2:6]1)[CH2:2][CH2:3][CH3:4]>C(O)(=O)C.C(Cl)(Cl)Cl.[Pd]>[CH2:1]([N:5]1[CH2:10][CH:9]([CH2:11][OH:12])[O:8][CH:7]([CH2:20][O:21][CH2:22][C:23]([N:25]([CH2:26][CH2:27][CH3:28])[CH2:29][CH2:30][CH3:31])=[O:24])[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CC(COCC(=O)N(CCC)CCC)OC(COCc2ccccc2)C1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCCCN1CC(CO)OC(COCC(=O)N(CCC)CCC)C1
Temperature: 25 °C
Reaction time: 28 h

Procedure:
To a solution of 10.86 g of 2-[[4-butyl-6-[(phenylmethoxy)methyl]-2-morpholinyl]methoxy]-N,N-dipropylacetamide (0.025 mole) in 125 ml of glacial acetic acid is added 4.0 g of 10% Pd/C and the mixture is hydrogenated at 50 psi at 60° over a period of 28 hours (debenzylation taking up 94% of the calculated theory). The mixture is cooled to room temperature and the Pd/C removed via filtration through a pad of "celite" filter aid. The acetic acid is removed in vacuo yielding a pale yellow oil. The oil is taken up in 200 ml of chloroform and washed with 100 ml of saturated NaHCO3 solution. The CHCl3 layer is separated, dried over anhydrous Na2SO4 and then the CHCl3 is removed in vacuo yielding 8.2 g (95%) of crude product as a dark brown oil. The oil is chromatographed on 150 g of neutral Alumina III to give 0.5 g of forerun (eluted with 100 ml of chloroform) and 7.6 g (88%) of the desired product (eluted with 400 ml of chloroform and 200 ml of 2% methanolic chloroform). The 7.6 g of product is dried in vacuo to give the desired product, a dense yellow-orange oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]1[C:17]2[N:16]([CH3:18])[C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[N:13]([C:23]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([OH:35])=O)=[C:27]([CH3:36])[CH:26]=3)=[O:24])[CH2:12][C:11]=2[CH:10]=[N:9]1.Cl.Cl.[CH3:39][C:40]([CH3:50])([CH3:49])[CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1.CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C>[CH3:39][C:40]([CH3:50])([CH3:49])[CH2:41][CH2:42][N:43]1[CH2:44][CH2:45][N:46]([C:33](=[O:35])[CH2:32][CH2:31][C:28]2[CH:29]=[CH:30][C:25]([C:23]([N:13]3[CH2:12][C:11]4[CH:10]=[N:9][N:8]([CH3:7])[C:17]=4[N:16]([CH3:18])[C:15]4[CH:19]=[CH:20][CH:21]=[CH:22][C:14]3=4)=[O:24])=[CH:26][C:27]=2[CH3:36])[CH2:47][CH2:48]1
Reactant: CC(C)(C)CCN1CCNCC1
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3N(C)c3ccccc32)ccc1CCC(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3N(C)c3ccccc32)ccc1CCC(=O)N1CCN(CCC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
Oxalyl chloride (0.018 ml, 0.20 mmol) was added to a solution of 3-[4-(3,4-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-phenyl]-propionic acid from Example E80.2 (40 mg, 0.10 mmol) in dichloromethane (5 ml) and a few drops of DMF. The mixture was stirred for 1 h at room temperature, concentrated in vacuo and azeotroped with toluene. The residue was dissolved in dichloromethane (5 ml) and 1-(3,3-dimethyl-butyl)-piperazine dihydrochloride from Example E4 (30 mg, 0.12 mmol) and DIEA (0.052 ml, 0.30 mmol) were added. The mixture was stirred for 20 h at room temperature, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white powder identified as the title compound (36 mg, 65%).