Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([CH2:18][CH2:19]Br)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2)#[N:2].[ClH:21].[CH:22]12[CH2:29][CH2:28][CH:25]([CH2:26][CH2:27]1)[CH2:24][NH:23]2.C(=O)([O-])[O-].[K+].[K+].Cl>O.C(O)(C)C.C(OCC)C>[ClH:21].[C:1]([C:3]1([CH2:18][CH2:19][N:23]2[CH2:24][CH:25]3[CH2:28][CH2:29][CH:22]2[CH2:27][CH2:26]3)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2)#[N:2]
Reactant: C1CC2CCC1CN2
Reactant: N#CC1(CCBr)c2ccccc2CCc2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CC(C)O
Product: N#CC1(CCN2CC3CCC2CC3)c2ccccc2CCc2ccccc21

Procedure:
A mixture of 6.5 parts 5-cyano-5-(2-bromoethyl)10,11-dihydro-5H-dibenzo[a,d]cycloheptene, 4.0 parts 2-azabicyclo[2.2.2]octane hydrochloride and 4.0 parts potassium carbonate in 88 parts N,N-dimethylsulfoxide and 20 parts water is heated at reflux for about 4 hours. After cooling, the reaction mixture is diluted with water, resulting in the formation of an oil. The water layer is decanted and the oil dissolved in ethyl ether. The ethereal solution is washed twice with water, once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The solvent is removed to give an oil which is treated with a solution of hydrogen chloride in isopropanol. Addition of ethyl ether results in a precipitate that is separated, washed with ether and dried to afford-5-cyano-5[2-(2-azabicyclo[2.2.2]oct-2-yl)ethyl]-10,11-dihydro-5H-dibenzo[a,d]cycloheptene hydrochloride. This compound is represented by the following structural formula. ##STR14##
Reaction SMILES: [N+](C1C=CC([C:10]2[CH:22]=[C:21]([C:23]([O-])=[O:24])[C:20]3[C:19]4[C:14](=[C:15]([Cl:26])[CH:16]=[CH:17][CH:18]=4)[N:13]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C:12]=3[C:11]=2[O:35][CH3:36])=CC=1)([O-])=O.[Cl:37][C:38]1[CH:39]=[N:40][CH:41]=[C:42]([Cl:45])[C:43]=1[NH2:44].[H-].[Na+]>CN(C=O)C>[Cl:37][C:38]1[CH:39]=[N:40][CH:41]=[C:42]([Cl:45])[C:43]=1[NH:44][C:23]([C:21]1[C:20]2[C:19]3[C:14](=[C:15]([Cl:26])[CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:12]=2[C:11]([O:35][CH3:36])=[CH:10][CH:22]=1)=[O:24]
Reactant: Nc1c(Cl)cncc1Cl
Reactant: COc1c(-c2ccc([N+](=O)[O-])cc2)cc(C(=O)[O-])c2c3cccc(Cl)c3n(Cc3ccc(F)cc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c3cccc(Cl)c3n(Cc3ccc(F)cc3)c12
Reaction time: 1 h
Yield: 66.8 %

Procedure:
To a solution of 4-nitrophenyl-8-chloro-9-(4-Fluorobenzyl)-1-methoxy-9H-4-carbazole carboxylate (100 mg, 0.1982 mmoles) and 3,5-dichloro 4-amino pyridine (32.3 mg, 0.1982 mmoles) in dry DMF (7 mL), at 25° C. under nitrogen atmosphere, sodium hydride 55% (10.3 mg, 0.2576 mmoles) was added and stirred for 1 hr. The reaction mixtre was quenched in ice cold water (25 mL) and extracted with ethyl acetate (2×25 mL). The organic layer was washed with bicarbonate (2×25 mL), followed by 1N HCl (2×25 mL) and with brine (25 mL), dried over sodium sulphate and concentrated to give the 70 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=2[Cl:42])=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34][C:35]3[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=3[Cl:42])=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: Clc1ccc(Cl)c(Sc2ccc(Br)cc2)c1
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
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(Sc3cc(Cl)ccc3Cl)cc2)c1C
Yield: 28.6 %

Procedure:
A stirred solution of [6-chloro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.53 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol), crude 1-(4-bromo-phenylsulfanyl)-2,5-dichlorobenzene (0.334 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {6-chloro-4-[4-(2,5-dichloro-phenylsulfanyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.076 g, 28%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:18][C:16]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:12]=[CH:11][S:10][CH:9]=1.[CH:28]1[C:33]([C:34]([OH:36])=[O:35])=[CH:32][C:31]2[C:37]([O:39][C:40](=O)[C:30]=2[CH:29]=1)=[O:38]>>[C:22]1([C:19]2[CH:20]=[CH:21][C:15]3[O:14][C:13]([C:4]4[CH:5]=[CH:6][C:7]([C:8]5[CH:12]=[CH:11][S:10][CH:9]=5)=[C:2]([N:1]5[C:37](=[O:38])[C:31]6[C:30](=[CH:29][CH:28]=[C:33]([C:34]([OH:36])=[O:35])[CH:32]=6)[C:40]5=[O:39])[CH:3]=4)=[N:17][C:16]=3[CH:18]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: Nc1cc(-c2nc3cc(-c4ccccc4)ccc3o2)ccc1-c1ccsc1
Product: O=C(O)c1ccc2c(c1)C(=O)N(c1cc(-c3nc4cc(-c5ccccc5)ccc4o3)ccc1-c1ccsc1)C2=O

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-4-(3-thienyl)phenyl)-5-phenylbenzoxazole (61 mg, 0.16 mmol) and 1,2,4-benzenetricarboxylic anhydride (32 mg, 0.16 mmol) the title compound was obtained (66 mg, 75%). 1H NMR (DMSO) δ 8.50(d, 1H), 8.41(m, 2H), 8.30(s, 1H), 8.07(m, 2H), 7.90(m, 2H), 7.75(m, 3H), 7.62(m, 1H), 7.55(m, 1H), 7.50(m, 2H), 7.40(t, 1H), 7.11(dd, 1H). MS 540.7 m/z (M−H)−.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.Br[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]=1[B:32]1[O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]1.O>CN(C=O)C>[C:1]1([N:7]([CH2:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[B:32]2[O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]2)[C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1
Reactant: CC1(C)OB(c2c(CBr)ccc3ccccc23)OC1(C)C
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1ccc2ccccc2c1B1OC(C)(C)C(C)(C)O1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a suspension of 17.0 g (88.1 mmol) of tert-butyl phenylcarbamate in 150 ml of hexanes 35.2 ml (88.1 mmol) of 2.5 M nBuLi in hexanes was slowly added at gentle reflux for ca. 15 min. This mixture was stirred for additional 30 minutes and then evaporated to dryness. The resulting white powder was added to a solution of 30.6 g (88.1 mmol) of 2-[2-(bromomethyl)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in 300 ml of DMF. This mixture was stirred for 20 minutes at 75° C. and then poured into 1200 cm3 of cold water. The product was extracted with 3×200 ml of ethyl acetate. The combined organic extract was washed by 2×300 ml of water, dried over MgSO4, and then evaporated to dryness. The crude product was purified by flash chromatography on silica gel 60 (40-63 um, eluent: hexanes-ethyl acetate=20:1, vol. then 10:1, vol.). Yield 28.0 g (69%) of yellowish oil. 1H NMR (CDCl3): 8.19 (m, 1H, 8-H in naphthyl), 7.85 (d, J=8.6 Hz, 1H, 4-H in naphthyl), 7.77 (m, 1H, 5-H in naphthyl), 7.60 (d, J=8.6 Hz, 1H, 3-H in naphthyl), 7.45 (m, 1H, 7-H in naphthyl), 7.40 (m, 1H, 6-H in naphthyl), 7.20 (m, 2H, 3,5-H in Ph), 7.13 (m, 2H, 2,6-H in Ph), 7.08 (m, 1H, 4-H in Ph), 5.21 (s, 2H, CH2N), 1.42 (s, 9H, tBu), 1.38 (s, 12H, CMe2CMe2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)=[CH:12][C:11]([C:24]([O:26]CC)=[O:25])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C(O)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[CH:15]=3)=[CH:12][C:11]([C:24]([OH:26])=[O:25])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)c1cc(-c2cccc(C(F)(F)F)c2)n(-c2ccc(F)c(Cl)c2)n1
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Product: O=C(O)c1cc(-c2cccc(C(F)(F)F)c2)n(-c2ccc(F)c(Cl)c2)n1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 47A in analogy to the synthesis of the compound of Example 71A. 344 mg (97% of theory) of the title compound are obtained.
Reaction SMILES: [OH-].[Na+:2].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=[O:15])[C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1.[CH3:16]I.Cl>CO>[O:15]=[C:11]([CH:10]([C:7]1[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=1)[CH3:16])[C:12]([O-:14])=[O:13].[Na+:2]
Reactant: CI
Reactant: O=C(O)C(=O)Cc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C(=O)C(=O)[O-])c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A 3N aqueous solution of sodium hydroxide (5.0 ml, 15 mmoles) and 20 ml of methanol were added to p-fluorophenylpyruvic acid (0.92 g, 5.0 mmoles) to form a solution. Then, 2.0 ml of methyl iodide was added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was acidified with 1N hydrochloric acid, and extracted with three 30 ml portions of ether. The ether layers were dried over magnesium sulfate, and concentrated under reduced pressure to give a pale yellowish white solid. To the product was added 2 ml of a 3N aqueous solution of sodium hydroxide, and the mixture was concentrated under reduced pressure. Ether was added to the resulting semi-solid mixture, and the precipitated sodium 2-oxo-3-(p-fluorophenyl)butanoate was isolated by filtration as a white solid (yield 26 %).
Reaction SMILES: [CH:1]1([C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[NH2:8])[CH2:5][CH2:4][CH:3]=[CH:2]1.C(=O)(O)[O-].[Na+].[Cl:18][CH2:19][C:20](Cl)=[O:21]>C(Cl)Cl.O>[CH:1]1([C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[NH:8][C:20](=[O:21])[CH2:19][Cl:18])[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: O=C(Cl)CCl
Reactant: Nc1ccccc1C1C=CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(CCl)Nc1ccccc1C1C=CCC1
Temperature: 0 °C
Yield: 77 %

Procedure:
A solution of 10.00 g (62.8 mmol) of 2-(cyclopent-2-enyl)aniline from Example 1 in 150 mL of methylene chloride and 5.28 g (62.8 mmol) of sodium bicarbonate in 15 mL of water were combined with rapid stirring and cooled 0° C. with the aid of an ice bath. A solution of 7.099 (62.8 mmol) of chloroacetyl chloride in 25 mL of methylene chloride was then added dropwise through the course of 20 min. After an additional hour of vigorous stirring. the layers were separated and the organic layer was dried over anhydrous magnesium sulfate. Evaporation of the solvent in the organic layer and recrystallization of the precipitate with ether afforded 11.41 g (77% yield) of N-[2-(cyclopent-2-enyl)phenyl]-2-chloroacetamide: mp 101°-102° C.
Reaction SMILES: O1CCCC1.[F:6][CH2:7][CH2:8][OH:9].[H-].[Na+].[Br:12][C:13]1[N:30]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:16]2[CH:17]=[N:18][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20](=[O:21])[C:15]=2[C:14]=1[CH2:39]Br>O>[Br:12][C:13]1[N:30]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:16]2[CH:17]=[N:18][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20](=[O:21])[C:15]=2[C:14]=1[CH2:39][O:9][CH2:8][CH2:7][F:6]
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(CBr)c(Br)n2COCC[Si](C)(C)C)c1=O
Reactant: OCCF
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ncc2c(c(COCCF)c(Br)n2COCC[Si](C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To 15 ml of dehydrated tetrahydrofuran solution containing 1.02 g (16 mmol) of 2-fluoroethanol was added 0.32 g (8.0 mmol) of sodium hydride (60% dispersed material in mineral oil) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Then, 0.90 g (1.6 mmol) of 2-bromo-3-bromomethyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 25-(a) was further added to the mixture, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=7:3 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 802 mg of the title compound as a white solid. (Yield: 91%)
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[CH:39]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:39][C:30]3[CH:31]=[CH:32][C:33]4[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:29]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1ccc2ccccc2c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4ccc5ccccc5c4)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and naphthalene-2 carbaldehyde. MS (ESI) m/z 519.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Br:21][CH2:22][CH2:23][C:24](Cl)=[O:25].O>C(Cl)Cl>[Br:21][CH2:22][CH2:23][C:24]([NH:9][CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:25]
Reactant: O=C(Cl)CCBr
Reactant: CCOC(=O)C(N)C(=O)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(NC(=O)CCBr)C(=O)OCC
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
2(a) 2.8 ml of triethylamine were added to a suspension of 2.11 g of diethyl 2-aminomalonate hydrochloride in 50 ml of methylene chloride. 1.71 g of 3-bromopropionyl chloride were then added to the mixture, whilst ice-cooling, and then the mixture was stirred for 30 minutes. At the end of this time, the reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with a 5% w/v aqueous solution of sodium bicarbonate and with water, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to give 2.5 g of diethyl 2-(3-bromopropionamido)malonate.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].C(O)(=O)C.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:22](=[O:23])[NH:21][CH:20](SC)[NH:19][C:18]2=[O:26])=[CH:13][CH:12]=1>O>[CH3:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[C:18](=[O:26])[NH:19][CH:20]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])[NH:21][C:22]2=[O:23])=[CH:15][CH:16]=1
Reactant: CC(C)CN
Reactant: CSC1NC(=O)N(c2ccc(C)cc2)C(=O)N1
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(N2C(=O)NC(NCC(C)C)NC2=O)cc1
Reaction time: 5 h
Yield: 89.5 %

Procedure:
Isobutylamine (1.60 g.) was added to acetic acid (1.20 g.) at 20°-25° C. during 15 minutes. 3-(4-Methylphenyl)-6-methylthiotetrahydro-1,3,5-triazine-2,4-dione (4.98 g.) was then added, and the whole mixture stirred at 120°-125° C. for 5 hours and then cooled. Water (50 ml.) was added and the mixture stirred thoroughly. The solid produced was collected by filtration, washed with water and dried to give 3-(4-methylphenyl)-6-isobutylaminotetrahydro-1,3,5-triazine-2,4-dione (4.90 g., 89%), m.p. 297°-301° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[C-]#N.[K+].O.C(N)[CH2:14][NH2:15]>CC(N(C)C)=O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]#[N:15])=[N:3][CH:4]=1
Reactant: NCCN
Reactant: Fc1ccc(Br)nc1
Agent: [C-]#N
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: N#Cc1ccc(F)cn1
Temperature: 65 °C

Procedure:
2-Bromo-5-fluoropyridine (recrystallized from 0.3 volumes of pentane, 1240 g, 1 equivalent) was dissolved in dimethylacetamide (2 volumes), the mixture was heated to 60-70° C. and cuprous cyanide (0.4 equivalents) was added in one portion, giving a dark green solution. Heating was continued and potassium cyanide (1.2 equivalents) was added in portions above 90° C. After completion of the addition, the resulting brown suspension was heated to 145° C. for 5 hours. The reaction mixture was allowed to cool to room temperature and poured into cold water (14 volumes). Ethylene diamine (1.2 equivalents) was added and the solution extracted with methyl t-butyl ether (4×5 volumes). The combined extracts were dried filtered and evaporated in vacuo with a bath temperature no higher than 45° C. The crude solid was purified by silica pad chromatography (5 w/w silica; 10-33% methyl t-butyl ether in 40/60 petroleum ether). Product containing fractions were evaporated to give a white crystalline solid. Mp 40-41° C., 541 g, 62.9% theory.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.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>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
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: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COc1ccccc1-c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Yield: 83.7 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of 2-methoxyphenylboronic acid (139 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. 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 evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (180 mg, 83.7%) as an oil.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[N:27]=[C:26]([NH:28][C:29]4[C:34]([Cl:35])=[C:33]([F:36])[CH:32]=[C:31]([CH2:37][NH2:38])[C:30]=4[Cl:39])[NH:25][C:15]3=[N:16][C:17]=2[N:18]2[CH2:23][CH2:22][CH:21]([F:24])[CH2:20][CH2:19]2)=[O:11])[CH2:5][CH2:4]1.[C:42](Cl)(=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44].C1COCC1>CO>[F:41][C:2]([F:40])([F:1])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[N:27]=[C:26]([NH:28][C:29]4[C:34]([Cl:35])=[C:33]([F:36])[CH:32]=[C:31]([CH2:37][NH:38][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])[C:30]=4[Cl:39])[NH:25][C:15]3=[N:16][C:17]=2[N:18]2[CH2:19][CH2:20][CH:21]([F:24])[CH2:22][CH2:23]2)=[O:11])[CH2:5][CH2:4]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCc1cc(F)c(Cl)c(Nc2nc3cc(C(=O)N[C@H]4CC[C@H](C(F)(F)F)CC4)c(N4CCC(F)CC4)nc3[nH]2)c1Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C(=O)NCc1cc(F)c(Cl)c(Nc2nc3cc(C(=O)N[C@H]4CC[C@H](C(F)(F)F)CC4)c(N4CCC(F)CC4)nc3[nH]2)c1Cl
Reaction time: 0.33 h

Procedure:
A mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-2-{2,6-dichloro-5-fluoro-3-(aminomethyl)-phenylamino}-5-[4-fluoro-piperidinyl]-3H-imidazo[4,5-b]pyridine-6-carboxamide (130 mg, 0.210 mmol), pivaloyl chloride (26 μL, 0.21 mmol), TEA (75 mg, 0.74 mmol) and 5 mL THF is stirred for 20 min and diluted with MeOH. The crude product is purified via prep. HPLC (C-18 stable bond, eluent gradient: water(+0.15% HCOOH)/MeOH 9:1->MeOH).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4](=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:5]([N:7]1[CH2:14][CH2:13][CH2:12][C@H:8]1[C:9](O)=[O:10])=[O:6].S(Cl)(Cl)=O>C1C=CC=CC=1>[CH3:1][N:2]1[C:3]2[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=2[C:5](=[O:6])[N:7]2[CH2:14][CH2:13][CH2:12][CH:8]2[C:9]1=[O:10]
Reactant: CNc1ccccc1C(=O)N1CCC[C@H]1C(=O)O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CN1C(=O)C2CCCN2C(=O)c2ccccc21

Procedure:
A mixture of 24.8 g. of (-)-1-(N-methylanthraniloyl)-proline and 300 ml. of benzene is stirred and 12.0 g. of thionyl chloride is added dropwise. The mixture is heated at reflux temperature for 2 hours, cooled, washed twice with water and concentrated to recover the (+)-1,2,3,11a-tetrahydro-10-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5,11(10H)-dione.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][C:3]=1[O:14][CH3:15].Cl[C:17]([O:19][CH3:20])=[O:18].C(N(CC)CC)C>O1CCCC1>[CH3:20][O:19][C:17]([O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][C:3]=1[O:14][CH3:15])=[O:18]
Reactant: COC(=O)Cl
Reactant: COc1cc(OC)c2ccccc2c1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Oc1c(OC)cc(OC)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1.27 g of 1-hydroxy-2,4-dimethoxynaphthalene, prepared as shown in Preparations 7 and 8, in 50 ml of tetrahydrofuran was added 0.694 g of methyl chloroformate followed by 0.743 g of triethylamine. The mixture was stirred at room temperature for 16 hours, filtered, then the solvent removed under reduced pressure. The residue was dissolved in diethyl ether, washed with dilute hydrochloric acid and dried over anhydrous sodium sulfate. The ether was removed under reduced pressure and the residue chromatographed on silica gel, eluting with a 1:1 mixture of methylene chloride and hexane, to give 1-methoxycarbonyloxy-2,4-dimethoxynaphthalene, m.p. 128°-129° C.