Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[O:13])[CH:5]=[CH:4][N:3]=1.[NH3:29]>C(O)(O)C.[Cu-]=O>[NH2:29][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[O:13])[CH:5]=[CH:4][N:3]=1
Reactant: N
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1ccccc1NCc1ccnc(Br)c1
Agent: O=[Cu-]
Agent: CC(O)O
Product: Nc1cc(CNc2ccccc2C(=O)Nc2cccc(C(F)(F)F)c2)ccn1
Yield: 51 %

Procedure:
8.747 g (19.4 mmol) of 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzamide is heated with 175 mg of copper(I) oxide in 150 ml of ethanediol for 23 hours under 10 bar of ammonia pressure to 80° C. in an autoclave. After the solvent is distilled off in a vacuum, the residue is purified on silica gel with a gradient of ethyl acetate:ethanol=100:0 to 0:100 as an eluant. 4.15 g (51% of theory) of 2-[(2-amino-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzamide with a melting point of 64° C. is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[N+:14]([O-])=O.[Cl:17][CH2:18][C:19](O)=O>CO.[Pd]>[Cl:17][CH2:18][C:19]1[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:3]=2[N:14]=1
Reactant: Nc1cccc(-c2ccccc2)c1[N+](=O)[O-]
Reactant: O=C(O)CCl
Agent: [Pd]
Solvent: CO
Product: ClCc1nc2c(-c3ccccc3)cccc2[nH]1
Yield: 92.7 %

Procedure:
A solution of 2-amino-6-phenyl-nitrobenzene (0.600 g, 2.80 mmol) in MeOH (28 mL) was hydrogenated (30 psi) over palladium, 10 wt. % on activated carbon (0.121 g). The resultant crude 3-phenyl-1,2-phenylenediamine was reacted with chloroacetic acid (0.537 g, 5.68 mmol) in refluxing 4 N Hl (6 mL) overnight. After normal workup, 0.63 g (92%) of 2-chloromethyl-4-phenyl-1H-benzimidazole was isolated as a brown solid, which was used without further purification.
Reaction SMILES: [CH2:1]([N:5]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:6](=[O:29])[C:7]([CH3:28])([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([NH:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:10]=1)[CH3:8])[CH:2]([CH3:4])[CH3:3]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]([CH3:8])([CH3:28])[C:6]([N:5]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:1][CH:2]([CH3:4])[CH3:3])=[O:29])=[CH:10][C:11]=1[NH:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(C)CN(CC(C)C)C(=O)C(C)(C)c1ccc([N+](=O)[O-])c(NCCCN2CCCCC2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)CN(CC(C)C)C(=O)C(C)(C)c1ccc(N)c(NCCCN2CCCCC2)c1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
N,N-diisobutyl-2-methyl-2-{4-nitro-3-[(3-piperidin-1-ylpropyl)amino]phenyl}propanamide (1.6 g) in solution in a mixture of ethyl acetate/ethanol 2:1 (100 ml) and 10% palladium on carbon (160 mg) are introduced into an autoclave. After stirring for 4 hours under a hydrogen atmosphere (3 bars) at a temperature of approximately 20° C., the catalyst is eliminated by filtration on celite and the filtrate is concentrated under reduced pressure at 40° C. in order to produce the expected compound in the form of an oil (1.4 g, 94% yield).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]([CH3:19])=[CH:18][C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:29][O:30]C(Cl)Cl.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH:29]([C:18]1[C:13]2[O:12][CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=3)[C:14]=2[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]=1[CH3:19])=[O:30]
Reactant: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reaction time: 0.33 h
Yield: 74.6 %

Procedure:
To a solution of N-(3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (650 mg, 1.71 mmol) obtained in Example 3 and 1,1-dichloromethyl methyl ether (237 mg, 2.06 mmol) in dichloromethane (5 mL) was added dropwise at 0° C. under an argon atmosphere and ice-cooling titanium tetrachloride (0.34 mL, 3.07 mmol), and the mixture was stirred at the same temperature for 20 minutes. Water was added to the reaction solution and the product was extracted with dichloromethane. The organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 520 mg (yield: 75%) of the title compound. Melting point: 177-178° C (ethyl acetate-hexane).
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:20][C:21]1[CH:34]=[CH:33][C:24]([C:25]([NH:27][N:28]2[NH:32][CH:31]=[CH:30][S:29]2)=[O:26])=[CH:23][C:22]=1B1OC(C)(C)C(C)(C)O1>>[CH3:17][O:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:18]=[CH:19][C:2]([C:22]2[CH:23]=[C:24]([C:25](=[O:26])[NH:27][N:28]3[NH:32][CH:31]=[CH:30][S:29]3)[CH:33]=[CH:34][C:21]=2[CH3:20])=[N:3][CH:4]=1
Reactant: Cc1ccc(C(=O)NN2NC=CS2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Product: COc1cccc(CNC(=O)c2ccc(-c3cc(C(=O)NN4NC=CS4)ccc3C)nc2)c1

Procedure:
N-(3-Methoxybenzyl)-6-[2-methyl-5-(thiadiazol-2-ylcarbamoyl)-phenyl]-nicotinamide was prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide (Intermediate 3) and 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide (Intermediate 12) using General Method B. LCMS: retention time 3.02 min, MH− 460. NMR: δH [2H6]-DMSO 13.14, (1H, b), 9.32, (1H, t), 9.24, (1H, s), 9.18, (1H, d), 8.40, (1H, dd), 8.26, (1H, s), 8.10, (1H, d), 7.84, (1H, d), 7.55, (1H, d), 7.27, (1H, t), 6.94, (2H, m), 6.84, (1H, d), 4.53, (2H, d), 3.75, (3H, s), 2.46, (3H, s).
Reaction SMILES: O[CH2:2][CH:3]1[CH2:7][C:6]2[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=[CH:11][C:5]=2[O:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:36]N1C(=O)CCC1=O>C(Cl)Cl>[Br:36][CH2:2][CH:3]1[CH2:7][C:6]2[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=[CH:11][C:5]=2[O:4]1
Reactant: CCOC(=O)c1ccc2c(c1)CC(CO)O2
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)CC(CBr)O2
Yield: 82.5 %

Procedure:
To a solution of 5.0 g (22.5 mmole) ethyl 2-hydroxymethyl-2,3-dihydrobenzofuran-5-carboxylate in 80 ml methylene chloride under nitrogen was added in one portion 6.5 (24.7 mmole) triphenylphosphine and the resulting solution was stirred for ten minutes. To this was added, in portions over twenty minutes, 4.39 g (24.7 mmole) N-bromosuccinimide and the resulting mixture was stirred overnight at room temperature. The mixture was diluted with methylene chloride, extracted with water, brine and dried (MgSO4). Evaporation in vacuo afforded an oil which was triturated with ethyl ether and filtered to remove insoluble triphenylphosphine oxide. Evaporation of the filtrate yielded 8.4 g of crude product which was charged to a column containing 200 g silica gel and eluted with methylene chloride to provide 5.29 g of purified product, TLC Rf 0.85. Mass spectrum (m/e) 286 (M+). 1H-NMR(CDCl3) ppm(delta): 3.2 (CH2Br), 3.6 (benzyl CH2).
Reaction SMILES: [C:1]([N:4]1[C:8]2([C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10](=[O:18])[N:9]2[CH3:19])[C:7](=[O:20])[N:6]([CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:5]1=[O:30])(=[O:3])[CH3:2].[CH2:31](I)[CH:32]([CH3:34])[CH3:33]>>[C:1]([N:4]1[C:8]2([C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:10](=[O:18])[N:9]2[CH3:19])[C:7](=[O:20])[N:6]([CH2:21][O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:5]1=[O:30])(=[O:3])[CH3:2]
Reactant: CC(C)CI
Reactant: CC(=O)N1C(=O)N(COCc2ccccc2)C(=O)C12c1ccccc1NC(=O)N2C
Product: CC(=O)N1C(=O)N(COCc2ccccc2)C(=O)C12c1ccccc1N(CC(C)C)C(=O)N2C

Procedure:
In the same manner as described in Example 36-(1), 3'-acetyl-1'-benzyloxymethyl-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione and isobutyl iodide are treated to give 3'-acetyl-1'-benzyloxymethyl-1-isobutyl-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][C:5]=1[CH3:14])(=[O:3])[CH3:2].[OH-].[Na+].[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][C:19]=1[CH3:26].Cl>CCO.O>[OH:17][C:18]1[CH:25]=[CH:24][C:21](/[CH:22]=[CH:2]/[C:1]([C:4]2[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][C:5]=2[CH3:14])=[O:3])=[CH:20][C:19]=1[CH3:26]
Reactant: Cc1cc(C=O)ccc1O
Reactant: CC(=O)Nc1ccc(C(C)=O)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1ccc(C(=O)/C=C/c2ccc(O)c(C)c2)c(C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of N-(4-acetyl-3-methylphenyl)acetamide (1.3 g, 7.0 mmol) and NaOH (1.4 g, 36 mmol) in 25 mL of absolute EtOH was added 4-hydroxy-3-methylbenzaldehyde (1.0 g, 7.3 mmol). The reaction mixture was stirred at room temperature for 18 hr. 5 mL of water was added and the reaction mixture was acidified with concentrated HCl to pH 5-6. The aqueous layer was extracted with two 25 mL portions of EOAc, and the layers were separated. The organic layer was dried with Na2SO4, filtered and concentrated under reduced pressure. The resulting product was submitted to the next step without further purification.
Reaction SMILES: Br[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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>[C:10]1([C:2]2[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: O=Cc1cnccc1Br
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: O
Solvent: C1COCCO1
Product: O=Cc1cnccc1-c1ccccc1
Temperature: 110 °C
Yield: 50.5 %

Procedure:
4-bromonicotinaldehyde (150 mg, 0.81 mmol), phenylboronic acid (98 mg, 0.81 mmol) and tetrakis(triphenylphosphine)palladium(0) (46.6 mg, 0.05 mmol) were mixed in dioxane (3.5 mL). Na2CO3 (2 M solution in water, 0.81 mL, 1.63 mmol) was added and the reaction mixture was stirred and heated in the microwave (110° C., 150 W) for 30 min. After addition of excess water followed by extraction with EtOAc, the combined organic layers were filtered (celite) and dried (MgSO4). Purification by flash chromatography (heptane/EtOAc, gradient 5-40% EtOAc) provided 4-phenylnicotinaldehyde (75 mg, 48%) as a dark yellow gum. ESI-MS [M+H]+=279.1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][N:6]=[CH:5][C:4]=2[C:3]=1[C:11]([O:13][CH3:14])=[O:12].F[B-](F)(F)F.[CH3:20][O+](C)C>C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:20])[N:7]=2)[C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1c(Br)ccc2[nH]ncc12
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1c(Br)ccc2nn(C)cc12
Reaction time: 2.5 h
Yield: 72.2 %

Procedure:
To a solution of methyl 5-bromo-1H-indazole-4-carboxylate (4.50 g, 17.6 mmol) in ethyl acetate (176 mL) was added trimethyloxonium tetrafluoroborate (3.38 g, 22.9 mmol) at room temperature, and the mixture was stirred for 2.5 hr. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→30/70) to give the title compound (3.42 g, yield 73%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12]([OH:14])=[O:13])[CH2:6][CH2:5]2.[CH3:15]O.S(=O)(=O)(O)O>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:6][CH2:5]2
Reactant: CO
Reactant: O=C(O)C1CCc2cc(O)ccc2C1
Agent: O=S(=O)(O)O
Product: COC(=O)C1CCc2cc(O)ccc2C1
Yield: 88.9 %

Procedure:
To a solution of 6-hydroxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (0.5 g, 3 mmol) in methanol (6 mL, 200 mmol) was added sulfuric acid (0.05 g, 0.5 mmol) and stirred over weekend. After concentration, the residue was dissolved in EtOAc and washed with water, brine and dried over Na2SO4 to give the pure product as a white solid (0.55 g, 100%). LCMS: Rt=1.17 min, m/z=207.00 [M+], 100%.
Reaction SMILES: [C:1]([C:9]1[CH:33]=[CH:32][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]=[CH:27][C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.O1CCOCC1.[Pd]>[C:1]([C:9]1[CH:33]=[CH:32][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:25]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C=Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)CCc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1
Temperature: 25 °C
Reaction time: 10.5 h

Procedure:
The compound obtained in Example 31 is dissolved in a methanol/dioxane mixture and then a catalytic amount of palladium-on-carbon is added. The reaction is stirred at ambient temperature under a hydrogen atmosphere for from 6 to 15 hours. The carbon is then filtered off and the solvents are removed by evaporation in vacuo. The resulting residue is recrystallised from methanol to yield the title product.
Reaction SMILES: [OH:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C@H:11]([OH:14])[CH2:12][CH3:13])[CH2:3][CH3:4].N1C=CC=CC=1.[C:21]1([P:27](Cl)(Cl)=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>CC(OC)(C)C>[CH2:3]([C@H:2]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C@H:11]([CH2:12][CH3:13])[O:14][P:27](=[O:28])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:1]1)[CH3:4]
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: CC[C@@H](O)c1ccccc1[C@@H](O)CC
Agent: Cl
Solvent: COC(C)(C)C
Solvent: c1ccncc1
Product: CC[C@@H]1OP(=O)(c2ccccc2)O[C@@H](CC)c2ccccc21
Temperature: 25 °C

Procedure:
A solution of (R,S)-1-[2-(1-Hydroxy-propyl)-phenyl]-propan-1-ol (4.0 g, 20.6 mmol) in pyridine (4.89 g, 61.7 mmol) was cooled with an ice-bath. Then phenyl phosphonic acid dichloride (4.03 g, 20.6 mmol) was added drop wise. The mixture was allowed to warm to ambient temperature, and stirred over night. To the mixture was then added HCl (ca. 20 ml 4N solution) and TBME (ca. 50 ml). The organic layer was separated, dried (sodium sulfate), and after removal of the solvent the product remained as a colourless oil. Yield: 5.88 g (90.3%). 1H/13C-NMR (CDCl3, HSQC/HMBC) δ/δ 1.05 (tr, J=7.4 Hz)/11.05 (CH3); 1.13 (tr, J=7.6 Hz)/10.48 (CH3); 2.05-2.21 (m)/27.82 (d, J=8.9 Hz), 30.61 (d, J=9.4 Hz) (2 CH2Me); 5.42 (ddd, J=4.7 Hz, J=5.8 Hz, J=8.5 Hz)/80.30 (d, J=7.6 Hz) (CHEt); 5.75 (ddd, J=3.8 Hz, J=5.3 Hz, J=7.4 Hz)/80.47 (d, J=7.3 Hz) (CHEt); 7.24/126.73 (Ar CH); 7.24/127.18 (Ar CH); 7.24/128.12 (Ar CH); 7.31/128.59 (Ar CH); 7.40/128.47 (d, J=15.2 Hz) (Ph meta-CH); 128.93 (d, J=192 Hz) (Ph ipso-C); 7.51/132.47 (d, J=3.1 Hz) (Ph para-CH); 7.73/131.74 (d, J=9.8 Hz) (Ph ortho-CH); 137.66, 138.92 (2 Ar ipso-C). 31P-NMR (CDCl3) δ 19.26.
Reaction SMILES: [CH3:1][N:2]([C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[S:21])[NH:3][C:4](=[O:19])[CH2:5][C:6]([NH:8][N:9]([CH3:18])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[S:11])=[O:7].[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)Cl>[C:28]([N:8]([C:6](=[O:7])[CH2:5][C:4]([NH:3][N:2]([CH3:1])[C:20]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[S:21])=[O:19])[N:9]([CH3:18])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[S:11])(=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: CN(NC(=O)CC(=O)NN(C)C(=S)c1ccccc1)C(=S)c1ccccc1
Solvent: ClCCl
Product: CC(=O)N(C(=O)CC(=O)NN(C)C(=S)c1ccccc1)N(C)C(=S)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of N′1,N′3-dimethyl-N′1,N′3-di(phenylcarbonothioyl)malonohydrazide (a, 2.0 mmol) in TEA (5 mL) and DCM (10 mL) was added dropwise acetyl chloride (4.0 mmol) and the mixture was stirred at rt for 12 h before quenching with aqueous 1N NaHCO3 (10 mL). The organic layer was separated and evaporated. The residue was purified by flash chromatography to give b as yellow solids (7 mg).
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13](F)[C:12]([F:16])=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[Cl:17][C:18]1[CH:19]=[C:20]([OH:32])[CH:21]=[N:22][C:23]=1[O:24][CH2:25][CH:26]1[CH2:29][C:28]([F:31])([F:30])[CH2:27]1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CS(C)=O>[Cl:17][C:18]1[CH:19]=[C:20]([O:32][C:13]2[C:12]([F:16])=[CH:11][C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[C:2]([F:1])[CH:14]=2)[CH:21]=[N:22][C:23]=1[O:24][CH2:25][CH:26]1[CH2:27][C:28]([F:30])([F:31])[CH2:29]1
Reactant: CC(C)(C)OC(=O)c1cc(F)c(F)cc1F
Reactant: Oc1cnc(OCC2CC(F)(F)C2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cc(F)c(Oc2cnc(OCC3CC(F)(F)C3)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.7 %

Procedure:
tert-Butyl 2,4,5-trifluorobenzoate (Preparation 6, 0.200 g, 0.86 mmol), 5-chloro-6-[(3,3-difluorocyclobutyl)methoxy]pyridin-3-ol (Preparation 5, 0.258 g, 1.03 mmol) and potassium carbonate (0.178 g, 1.29 mmol) were suspended in DMSO (5.0 mL). The mixture was stirred at room temperature under nitrogen for 16 hours. EtOAc (50 mL) was added and the mixture was washed with water (3×150 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (0.400 g, 101%):
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH3:7])[NH:5][CH:6]=1.CCN(C(C)C)C(C)C.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1.CN(C1C=CN=CC=1)C>[I:1][C:2]1[N:3]=[C:4]([CH3:7])[N:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:6]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1nc(I)c[nH]1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)n1cc(I)nc1C
Temperature: 0 °C
Yield: 95.2 %

Procedure:
To a solution of 4-iodo-2-methyl-1H-imidazole (162 mg, 0.78 mmol) in THF (2.6 mL, 0.3M) containing DIEA (0.33 mL, 1.95 mmol) and DMAP (47 mg, 0.039 mmol), cooled in a ice bath at 0° C., was added a solution of Ethyl chloroformate (211 mg, 1.95 mmol) in THF (2 mL, 1M). The reaction mixture was heated at 50° C. for 48 h and then concentrated. The residue was dissolved in DCM and the organic layer was washed with saturated NaCl, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (Prepacked column 10 g, DCM/MeOH: 97/3 as eluent) to afford 208 mg of ethyl 4-iodo-2-methyl-1H-imidazole-1-carboxylate (95%) as colorless oil.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([NH:25][C:26]([NH:28][C:29]3[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=3)[C:32]([O:34]C)=[O:33])=[O:27])[CH:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:39]([F:42])([F:41])[F:40])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>>[C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([NH:25][C:26]([NH:28][C:29]3[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=3)[C:32]([OH:34])=[O:33])=[O:27])[CH:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:39]([F:42])([F:40])[F:41])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(NC(=O)Nc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1
Agent: [Li+]
Agent: [OH-]
Product: O=C(Nc1cccc(C(=O)O)c1)Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from methyl 3-{[({3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amino) carbonyl]amino}benzoate and LiOH according to the procedure of Example 1. MS (ES) m/z 553.9.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:22]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:29])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2cccnc2)CC1
Reaction time: 2 h
Yield: 98.8 %

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with nicotinoyl chloride hydrochloride (0.028 g, 0.16 mmol) and triethylamine (0.058 mL, 0.41 mmol) in methylene chloride (1.0 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (39 mg, 95%). LCMS calculated for C21H20ClN4O2 (M+H)+: m/z=395.1; Found: 395.1.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]1[O:13][C:14](=[O:16])[CH3:15])(=[O:3])[CH3:2].[C:17]([O:20][C:21]1([C:37](=[O:39])[CH3:38])[CH2:30][C:29]2[C:28](=[O:31])[CH:27]=[CH:26][C:25](=[O:32])[C:24]=2[C:23]2([O:36][CH2:35][CH2:34][O:33]2)[CH2:22]1)(=[O:19])[CH3:18]>C1(C)C=CC=CC=1>[C:17]([O:20][C:21]1([C:37](=[O:39])[CH3:38])[CH2:30][C:29]2[C:28](=[O:31])[CH:27]3[CH:26]([CH:5]([O:4][C:1](=[O:3])[CH3:2])[C:8]4[C:7]([CH:6]3[O:13][C:14](=[O:16])[CH3:15])=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:25](=[O:32])[C:24]=2[C:23]2([O:36][CH2:35][CH2:34][O:33]2)[CH2:22]1)(=[O:19])[CH3:18]
Reactant: CC(=O)O[C@@H]1c2ccccc2[C@H]1OC(C)=O
Reactant: CC(=O)OC1(C(C)=O)CC2=C(C(=O)C=CC2=O)C2(C1)OCCO2
Solvent: Cc1ccccc1
Product: CC(=O)OC1c2ccccc2C(OC(C)=O)C2C(=O)C3=C(CC(OC(C)=O)(C(C)=O)CC34OCCO4)C(=O)C12
Yield: 42 %

Procedure:
A solution of 110 mg (0.5 mmol) of trans-1,2-diacetoxy-1,2-dihydrobenzocyclobutene and 112 mg (0.35 mmol) o rac-3-acetoxy-3-acetyl-1,1-ethylenedioxy-1,2,3,4,5,8-hexahydro-5,8-dioxonaphthalene in 10 ml of toluene was stirred and heated under reflux for 3 hours under an atmosphere of nitrogen. The solution was evaporated and the resulting yellow gum was crystallised from diethyl ether to yield 80 mg (42%) of rac-3,6,11-triacetoxy-3-acetyl-1,1-ethylenedioxy-1,2,3,4,5,5a,6,11,11a,12-decahydro-5,12-dioxonaphthacene in the form of a pale yellow solid of melting point 133°-143° C.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[C:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:6]1[CH3:22])[CH2:2][CH2:3][CH3:4].[CH2:23]([O:25][C:26](=[O:31])[C:27](Br)([CH3:29])[CH3:28])[CH3:24]>>[CH2:23]([O:25][C:26](=[O:31])[C:27]([O:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([CH3:22])=[C:7]2[C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)([CH3:29])[CH3:28])[CH3:24]
Reactant: CCCCn1c(C)c(-c2ccc(F)cc2)c2cc(O)ccc21
Reactant: CCOC(=O)C(C)(C)Br
Product: CCCCn1c(C)c(-c2ccc(F)cc2)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
The above compound was prepared from 1-butyl-3-(4-fluoro-phenyl)-2-methyl-1H-indole-5-ol and 2-bromo-2-methylpropanoic acid ethylester using a procedure analogous to that of Example 10.