Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:9][CH:10]2[C:19]3[N:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:20]([Si:24]([CH3:32])([CH3:31])[O:25][CH2:26][CH2:27][CH2:28][CH:29]=O)([CH3:23])([CH3:22])[CH3:21].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:20]([Si:24]([CH3:31])([CH3:32])[O:25][CH2:26][CH2:27][CH2:28][CH2:29][N:9]([C:3]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=1)[CH:10]1[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:13][CH2:12][CH2:11]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: Cc1cnc(NC2CCCc3cccnc32)c(C)c1
Reactant: CC(C)(C)[Si](C)(C)OCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(N(CCCCO[Si](C)(C)C(C)(C)C)C2CCCc3cccnc32)c(C)c1

Procedure:
Using General Procedure B, reaction of (3,5-dimethyl-pyridin-2-yl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine, 4-(tert-butyl-dimethyl-silanyloxy)-butyraldehyde and NaBH(OAc)3 in CH2Cl2 gave [4-(tert-butyl-dimethyl-silanyloxy)-butyl]-(3,5-dimethyl-pyridin-2-yl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[C:5](=[O:14])[CH2:4]1.[C:16]1([Li])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+].O>C(OCC)C>[CH3:1][N:2]([CH3:15])[CH:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([OH:14])[CH2:4]1
Reactant: [Li]c1ccccc1
Reactant: CN(C)C1CCc2ccccc2C(=O)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: CN(C)C1CCc2ccccc2C(O)(c2ccccc2)C1
Reaction time: 2 h

Procedure:
A solution of 24.46 g of 7-dimethylamino-5-oxo-6,7,8,9-tetrahydro [5H] benzocycloheptene in 488 ml of ethyl ether was added over 75 minutes under a nitrogen atmosphee at 0° to 5° C to a solution of 1.2 M of phenyl lithium in ethyl ether and the mixture was stirred for 2 hours at 0° to 5° C. 120 ml of an aqueous saturated ammonium chloride solution and then 100 ml of water were slowly added thereto at 0° to 15° C and the mixture was decanted. The ether phase was washed with water and dried to obtain 29.4 g of raw 7-dimethylamino-5ξ-phenyl-5ξ-hydroxy6,7,8,9-tetrahydro [5H] benzocycloheptene which was used as is for the next step. The product was a mixture of the 2 isomers with substitution in the 5-position.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([NH2:17])[CH:5]=1.[N:19]([O-])=O.[Na+]>Cl.O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([NH:17][NH2:19])[CH:5]=1
Reactant: COC(=O)c1cc(N)cc(-c2ccc(C)cn2)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(NN)cc(-c2ccc(C)cn2)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 174.9 %

Procedure:
3-Amino-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester (1.0 g, 4 mmol) was suspended in 16 mL concentrated aqueous HCl, and the mixture was cooled to 0° C. A solution of sodium nitrite (0.30 g) in water (3 mL) was added, and the mixture was stirred at 0° C. for 45 minutes. A solution of SnCl2 hydrate (2.34 g) in 5 mL concentrated aqueous HCl was then added. The reaction mixture was stirred for one hour at room temperature, then filtered. The collected solid was washed with water and dried to give 1.80 g of 3-hydrazino-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester as a white powder.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH2:16][CH2:15][C:10]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:9][CH:8]=2)[CH2:3][CH2:2]1>[Pd].CO>[O:1]1[CH2:2][CH2:3][CH:4]([CH:7]2[CH2:16][CH2:15][C:10]3([O:11][CH2:12][CH2:13][O:14]3)[CH2:9][CH2:8]2)[CH2:5][CH2:6]1
Reactant: C1=C(C2=CCC3(CC2)OCCO3)CCOC1
Agent: [Pd]
Solvent: CO
Product: C1CC(C2CCC3(CC2)OCCO3)CCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a flask containing 8-(3,6-dihydro-2H-pyran-4-yl)-1,4-dioxaspiro[4.5]dec-7-ene (218 mg, 0.972 mmol), prepared in the Example 28 Step B, and Palladium on Carbon (157 mg, 0.074 mmol) was carefully added methanol (24 mL). The reaction flask was evacuated, backfilled with hydrogen via balloon and stirred at room temperature overnight. The catalyst was removed by filtration and the filtrate concentrated in vacuo to afford the product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([OH:14])[CH:8]=2)([O-:3])=[O:2].[H-].[Na+].[F:17][C:18]([F:28])([F:27])[C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Cl.S([O-])([O-])(=O)=O.[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=1[C:18]([F:17])([F:27])[F:28])[CH:8]=2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnc2cc(O)ccc2c1
Reactant: FC(F)(F)c1ccccc1CCl
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc2cc(OCc3ccccc3C(F)(F)F)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
In dimethylformamide (DMF, 9 mL) was dissolved 3-nitro-7-hydroxyquinoline (800 mg, 4.24 mmol.). To the solution were added subsequently sodium hydride (168 mg, 4.24 mmol.) and 2-trifluoromethylbenzyl chloride (816 mg, 4.24 mmol.) under chilling with ice. The resulting mixture was stirred overnight at room temperature. After the completion of reaction was confirmed, ethyl acetate and aqueous sodium sulfate were added. The ethyl acetate portion was recovered, washed with water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give 790 mg of the desired compound as a white crystalline product, yield 53%.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:22](=[O:24])=[O:23].O>O1CCCC1>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:22]([OH:24])=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cn2cnc3ccccc32)cc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nc2ccccc2n1Cc1ccccc1
Temperature: 0 °C
Yield: 80 %

Procedure:
A solution of 2.08 g (10 mmol) of 1-benzylbenzimidazole in 200 ml of dry tetrahydrofuran was cooled under N2 atmosphere to -78° C. and treated with 8.0 ml (20 mmol) of n-butyllithium. The resulting solution was warmed to 0° C. for 0.5 h, recooled to -78° C., and poured into a mixture of excess dry ice in 200 ml of tetrahydrofuran. After being allowed to warm, the solution was treated with 200 ml of water, washed with ether, neutralized, and washed with ether. The aqueous layer was concentrated in vacuo, after which the residue was triturated with 2% methanol in chloroform and filtered. The filtrate was dried over MgSO4 and concentrated to give 2.01 g (80%) of the desired compound as a white powder. Mass spectrum: (M-OH)+ =235.
Reaction SMILES: O.[OH-].[Li+:3].C[O:5][C:6]([C:8]1[CH:12]=[C:11]([C:13]2[N:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:10]([C:19]2[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[N:9]=1)=[O:7]>CO>[Li+:3].[CH3:26][O:25][C:22]1[N:21]=[CH:20][C:19]([N:10]2[C:11]([C:13]3[N:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:12][C:8]([C:6]([O-:7])=[O:5])=[N:9]2)=[CH:24][CH:23]=1
Reactant: COC(=O)c1cc(-c2cccnn2)n(-c2ccc(OC)nc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(-n2nc(C(=O)[O-])cc2-c2cccnn2)cn1

Procedure:
Lithium hydroxide monohydrate (42 mg) was added to the above-obtained 1-(6-methoxy-3-pyridyl)-5-(3-pyridazinyl)pyrazole-3-carboxylic acid methyl ester (309 mg) in methanol (20 mL), and the resultant mixture was refluxed under heat for 18 hours, and then cooled in air. The reaction solvent was removed under reduced pressure, to thereby give the title compound as an amorphous product (322 mg, >100%).
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:14]([O-])([O-:16])=[O:15].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([N+:14]([O-:16])=[O:15])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1c(F)c(F)cc(C(=O)O)c1F
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1c(F)c(F)c([N+](=O)[O-])c(C(=O)O)c1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 54.8 %

Procedure:
To 100 ml of conc. sulfuric acid was dissolved 31 g of 2,4,5-trifluoro-3-methylbenzoic acid, and to this solution was incrementally added 19.5 g of potassium nitrate on ice. The solution was stirred at room temperature for 3 days, and another 1.4 g of potassium nitrate was added on ice. After stirring for 6 hours, the solution was poured into ice water, and the solid precipitate was collected by filtration. The precipitate was dissolved in diethylether and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The solid precipitate was collected by filtration to obtain 21 g of the title compound.
Reaction SMILES: C(OC([N:11]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[C:26]1[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[C:28]([CH2:34][C:35]([OH:37])=[O:36])[CH:27]=1)[CH:12]1[CH2:14][CH2:13]1)=O)C1C=CC=CC=1>[Pd].CO>[CH:12]1([NH:11][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:19]=[CH:18][C:17]=2[C:26]2[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[C:28]([CH2:34][C:35]([OH:37])=[O:36])[CH:27]=2)[CH2:14][CH2:13]1
Reactant: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1CN(C(=O)OCc1ccccc1)C1CC1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1CNC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
{2′-[(Benzyloxycarbonyl-cyclopropyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (0.054 g, 0.10 mmol) and 10% palladium on carbon (17.5 g) were combined in MeOH (2 mL) and stirred under a balloon of H2 at room temperature for 1 hour. The mixture was filtered and concentrated to give the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[O:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.N.O>CO>[N:12]1([C:15]2[CH:21]=[CH:20][C:18]([NH:19][C:2]3[CH:3]=[C:4]([NH2:8])[N:5]=[CH:6][N:7]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10][O:9][CH2:14][CH2:13]1
Reactant: Nc1cc(Cl)ncn1
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: N
Solvent: O
Solvent: CO
Product: Nc1cc(Nc2ccc(N3CCOCC3)cc2)ncn1
Temperature: 25 °C

Procedure:
The title compound is prepared analogously as described in Example 105A from 6-chloro-pyrimidin-4-ylamine and 4-morpholinoaniline. The semi-solid reaction mixture received after cooling to room temperature is dissolved in warm methanol, basified with conc. aqueous ammonia solution and the mixture concentrated to half of its volume. The precipitate obtained after addition of H2O is filtered off, washed with H2O and dried in vacuo to afford the title compound. Faintly violet solid, ESI-MS: 272.3 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([CH2:8]O)[CH:5]=[CH:6][CH:7]=1.CN(C)C1C=CC=CC=1.S(Cl)([Cl:29])=O.Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][Cl:29])[C:3]=1[S:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(Cl)c1SCc1ccccc1
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: ClC(Cl)Cl
Product: ClCc1cccc(Cl)c1SCc1ccccc1
Temperature: 15 °C
Reaction time: 1 h

Procedure:
To a mixture of 54 g of the compound of Example 2 in 200 mL of chloroform (ethanol-free) and of N,N-dimethylaniline, a solution of 30 g of thionyl chloride in 50 mL of chloroform (ethanol-free) was added while maintaining the reaction temperature at 15° C. with an ice-water bath. The mixture was stirred at 25° C. for 1 hour, then refluxed for 3 hours. The mixture was acidified with 1 N aqueous hydrochloric acid and the organic layer was collected. The organic layer was washed once with 1 N aqueous hydrochloric acid, dried over magnesium sulfate, and filtered. The filtrate was passed through a silica gel column, eluted with methylene chloride, and after evaporation of the eluant, 54 g subject compound was obtained as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:13]([OH:28])[C:14]([NH:17][C:18](=[O:27])OCC2C=CC=CC=2)([CH3:16])[CH3:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].Br[CH2:34][C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][C:36]=1[C:45]1[CH:46]=[C:47]([C:53]2[CH:58]=[CH:57][C:56]([C:59]([O:61]C)=[O:60])=[CH:55][C:54]=2[CH3:63])[CH:48]=[CH:49][C:50]=1[O:51][CH3:52]>C1COCC1>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:13]2[O:28][C:18](=[O:27])[N:17]([CH2:34][C:35]3[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][C:36]=3[C:45]3[CH:46]=[C:47]([C:53]4[CH:58]=[CH:57][C:56]([C:59]([OH:61])=[O:60])=[CH:55][C:54]=4[CH3:63])[CH:48]=[CH:49][C:50]=3[O:51][CH3:52])[C:14]2([CH3:16])[CH3:15])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CBr)c2)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(C(=O)O)cc2C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)OC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1(C)C
Reaction time: 72 h

Procedure:
To a solution of benzyl {2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-1,1-dimethylethyl}carbamate (65 mg, 0.149 mmol) in THF (1.5 mL) was added NaH (13 mg, 0.542 mmol) and methyl 2″-(bromomethyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (91.1 mg, 0.185 mmol). The reaction was stirred for 72 hours, and then additional NaH (36.2 mg, 1.51 mmol) was added. After 6 more hours at room temperature, the reaction was quenched with saturated NH4Cl solution (10 mL) and diluted with EtOAc (20 mL). The aqueous layer was extracted with EtOAc (20 mL), and the combined organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. Purification of the residue by reverse-phase chromatography (C-18, 10 to 95% MeCN/water with 0.1% TFA) afforded 2″-({5-[3,5-bis(trifluoromethyl)phenyl]-4,4-dimethyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylic acid. LCMS=726.0 (M+1)+. 1H NMR (CDCl3, 500 MHz, rotamers present) a 8.03-8.02 (m, 1H), 7.80-7.96 (m, 1H), 7.89 (s, 1H), 7.79-7.76 (m, 2H), 7.62-7.59 (m, 1H), 7.42-7.31 (m, 3H), 7.22-7.08 (m, 3H), 5.26-5.28 (m, 1H), 4.81 (d, J=16.6 Hz), 4.44-4.42 (m, 1H), 4.02 (d, J=16.6 Hz), 3.85 (s, 3H), 2.37-2.35 (m, 3H), 1.24 (s), 1.06 (s), 0.56-0.54 (m, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:11][C:12](=O)[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[C:7]([Br:10])=[CH:8][CH:9]=1)=O.C([O-])(=O)C.[NH4+:28].O>C(O)(=O)C>[Br:10][C:7]1[N:6]2[CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[NH:28][C:3](=[O:2])[C:5]2=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(Br)n1CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c(-c2ccc(C(F)(F)F)cc2)cn2c(Br)ccc12
Temperature: 130 °C
Yield: 97.4 %

Procedure:
A mixture of 5-bromo-1-[2-oxo-2-(4-trifluoromethyl-phenyl)-ethyl]-1H-pyrrole-2-carboxylic acid methyl ester (0.09 g, 0.23 mmol) and ammonium acetate (90 mg, 1.17 mmol) in glacial acetic acid (3 mL) were heated to 130° C. overnight. At this time, the reaction was treated with water. The resulting precipitate was collected by filtration, washed with water and dried in vacuo to afford 6-bromo-3-(4-trifluoromethyl-phenyl)-2H-pyrrolo[1,2-a]pyrazin-1-one (80 mg, 97%) as light brown solid. 1H NMR (chloroform-d) δ ppm 7.75-7.83 (m, 7H), 7.68-7.74 (m, 2H), 7.27 (d, J=1.5 Hz, 1H), 7.23 (s, 1H), 7.20 (s, 1H). LC-MS calcd. for C14H7BrF3N2O [(M−H)−] 356, obsd. 354.9.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.[C:30](Cl)(Cl)=[O:31].C1(C)C=CC=CC=1>>[N:27]([C:26]1[CH:28]=[CH:29][C:23]([O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:24][CH:25]=1)=[C:30]=[O:31]
Reactant: Nc1ccc(OCCOCCOCCOCCOCCOC2CCCCO2)cc1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(OCCOCCOCCOCCOCCOC2CCCCO2)cc1
Reaction time: 3 h

Procedure:
To a stirred 0° C. solution of 29 (0.95 g, 2.30 mmol) in 5:1 DCM/TEA (30 mL) was added a 20% phosgene/toluene solution (2.43 mL, 4.59 mmol). After stirring for 3 h the reaction was concentrated under reduced pressure and carried on without further purification.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][N:18]([CH3:33])[CH2:19][CH2:20][NH:21][C:22]([C:24]1[C:28]([CH3:29])=[C:27]([CH:30]=O)[NH:26][C:25]=1[CH3:32])=[O:23]>>[CH3:17][N:18]([CH3:33])[CH2:19][CH2:20][NH:21][C:22]([C:24]1[C:28]([CH3:29])=[C:27]([CH:30]=[C:11]2[C:10]3[C:14](=[CH:15][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][CH:9]=3)[NH:13][C:12]2=[O:16])[NH:26][C:25]=1[CH3:32])=[O:23]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN(C)C
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Product: Cc1[nH]c(C=C2C(=O)Nc3cc(-c4ccccc4)ccc32)c(C)c1C(=O)NCCN(C)C
Yield: 37.9 %

Procedure:
6-Phenyl-1,3-dihydroindol-2-one (0.17 g, 0.8 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-dimethylaminoethyl)amide (0.2 g) to give 0.13 g (36%) of the title compound as a yellow-orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].[Br:17][CH2:18][CH2:19][CH2:20]Br>C(#N)C.O>[Br:17][CH2:18][CH2:19][CH2:20][O:10][C:4]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1cccc(C)c1O
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cccc(C)c1OCCCBr

Procedure:
The mixture of 2.50 g of 2-methoxy-6-methylphenol, 3.75 g of potassium carbonate and 18.3 ml of 1,3-dibromopropane in 50 ml of acetonitrile is stirred at reflux with stirring over 16 hours. The reaction mixture is cooled, diluted with 200 ml of water and extracted with tert-butyl methyl ether (2×200 ml). The organic phases are washed successively with water (200 ml) and brine (200 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.59 (1:1 EtOAc-heptane); Rt=5.10.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH3:10])=[CH:8][C:7]2[O:11][C:12]3([O:18][C:6]=2[C:5]=1[CH3:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[C:9]([CH3:10])=[CH:8][C:7]2[O:11][C:12]3([O:18][C:6]=2[C:5]=1[CH3:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3
Reactant: Cc1cc2c(c(C)c1[N+](=O)[O-])OC1(CCCCC1)O2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc2c(c(C)c1N)OC1(CCCCC1)O2
Yield: 90.3 %

Procedure:
Cyclohexanone 4-nitro-3,5-dimethyl-1,2-phenylene ketal (10.0 g) and 10% palladium on charcoal (1.0 g) in ethanol (200 ml) was shaken in a hydrogen atmosphere (50 p.s.i.) at 45° C. for 3 hours. The mixture was filtered through celite and evaporated to leave cyclohexanone 4-amino-3,5-dimethyl-1,2-phenylene ketal (8.0 g, 90%) as a brown oil.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CS(C)=O>[N:13]1([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: C1CNCCN1
Reactant: CCOC(=O)c1ccc(F)cc1
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2CCNCC2)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
Ethyl 4-fluorobenzoate (20.1 g) was dissolved in dimethyl sulfoxide (50 ml). Piperazine (31.1 g) was added to the solution, and the mixture was stirred at 120° C. for 2 hr. The reaction solution was poured into 1.2 liters of ice water. The precipitated crystal was washed with a mixed solution composed of hexane (500 ml) and diethyl ether (50 ml), was collected by filtration, and was dried under the reduced pressure to give 24.3 g (86.8%) of ethyl 4-(piperazin-1-yl)benzoate.
Reaction SMILES: C([N:4]([CH:7]([CH3:9])[CH3:8])CC)(C)C.[Cl:10][C:11]1[N:16]=[C:15]([C:17]2[S:21][C:20]3[CH:22]=[CH:23][CH:24]=[C:25]([C:26]([OH:28])=O)[C:19]=3[CH:18]=2)[C:14]([Cl:29])=[CH:13][N:12]=1.C1(N)CC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl.C(OCC)C>[CH:7]1([NH:4][C:26]([C:25]2[C:19]3[CH:18]=[C:17]([C:15]4[C:14]([Cl:29])=[CH:13][N:12]=[C:11]([Cl:10])[N:16]=4)[S:21][C:20]=3[CH:22]=[CH:23][CH:24]=2)=[O:28])[CH2:9][CH2:8]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Diisopropylethylamine (1.42 mL) is added to a stirred suspension of 2-(2,5-dichloro-pyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid (2.55 g, 7.84 mmol) in anhydrous dichloromethane (40 mL) at 0° C. under nitrogen to form a solution, followed by sequentially addition of cyclopropylamine (0.570 mL, 8.23 mmol) and powdered 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (3.64 g, 8.23 mmol). The resultant mixture is allowed to stir at 0° C. for 2 hours, then at ambient temperature for 3 hours. Diethyl ether (35 mL) is added in small portions to the mixture, the mixture is stirred for another 20 minutes before filtration. After drying, the crude title compound (2.45 g) is obtained as a tan solid. It is used without further purification.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]2[C@H:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:12][CH2:13][N:6]2[C:5](=[O:21])[CH2:4][CH2:3]1.CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+].[C:33](Cl)(=[O:42])[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>[Cl-].[Na+].O.O>[C:17]([O:16][C:14]([C@H:10]1[N:7]2[C:8](=[O:9])[C@@H:2]([NH:1][C:33]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:42])[CH2:3][CH2:4][C:5](=[O:21])[N:6]2[CH2:13][CH2:12][CH2:11]1)=[O:15])([CH3:18])([CH3:20])[CH3:19]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](N)C(=O)N12
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](NC(=O)OCc3ccccc3)C(=O)N12
Temperature: 0 °C
Reaction time: 6 h
Yield: 99.4 %

Procedure:
In a 20 mL pear-shaped flask, (1S,9S)-tert-butyl 9-amino-6,10-dioxooctahydro-1H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate (0.9 g, 3.03 mmol) was combined with DMF (8 ml) to give a colorless solution and cooled to 0° C. Sodium carbonate (385 mg, 3.63 mmol) and benzyl carbonochloridate (516 mg, 432 μl, 3.03 mmol) were added and stirred at room temperature for 6 hr. It was diluted with brine and H2O, extracted with EtOAc (2×60 ml). The combined organic layer was washed with brine and H2O, dried with MgSO4, filtered and concentrated in vacuo to afford (1S,9S)-tert-butyl-9-(benzyloxycarbonylamino)-6,10-dioxooctahydro-1H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate as an oil (1.3 g, 99.5%). ESI-LRMS m/e calcd for C18H21N3O6 [M+] 431. found 432 [M+H+]. The crude was used without further purification.