Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Na+].C1(C)C=CC=CC=1.[CH:18]1([CH2:24][CH2:25][C:26]([N:28]2[C@@H:32]([CH:33]([CH3:35])[CH3:34])[CH2:31][O:30][C:29]2=[O:36])=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[C:37]([O:41][C:42](=[O:45])[CH2:43]Br)([CH3:40])([CH3:39])[CH3:38]>C1COCC1.Cl>[CH:18]1([CH2:24][CH:25]([C:26]([N:28]2[CH:32]([CH:33]([CH3:34])[CH3:35])[CH2:31][O:30][C:29]2=[O:36])=[O:27])[CH2:43][C:42]([O:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:45])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)CCC1CCCCC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)C1COC(=O)N1C(=O)C(CC(=O)OC(C)(C)C)CC1CCCCC1
Temperature: -10 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
A solution of sodium hexamethyldisilazide (92.4 mL of a 0.6M toluene solution, Aldrich) in THF (70 mL) was cooled to −78° C. and then treated with a solution of (S)-3-cyclohexylpropionyl-4-isopropyloxazolidin-2-one (10.5 g, 39.3 mmol) in THF (30 mL) added dropwise over 10 minutes. The mixture was stirred for 1 hour and then treated with a solution of tert-butylbromoacetate (9.75 mL, 50 mmol) in THF (20 mL) added dropwise. The mixture was stirred for 1 hour, while warming to −10° C. The mixture reaction was diluted with 1M hydrochloric acid (100 mL) and the dilution was extracted with ethyl acetate (200 mL). The extract was washed with saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL), dried (MgSO4), filtered and concentrated to dryness. The residue was dissolved in hexane and product was crystallized out to provide tert-butyl 3-cyclohexylmethyl-4-(4-isopropyl-2-oxooxazolidin-3-yl)-4-oxobutyrate (9.09 g, 61%). MS (M+1): 382.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:21][C:22]([C:24]2[C:33]([NH:34][C:35](=[O:44])[O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:32][C:31]3[C:26](=[CH:27][C:28]([CH:45]([OH:47])[CH3:46])=[CH:29][CH:30]=3)[N:25]=2)=[O:23])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:45]([C:28]1[CH:27]=[C:26]2[C:31]([CH:32]=[C:33]([NH:34][C:35]([O:36][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[O:44])[C:24]([C:22]([NH:21][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:15]=3[N:11]3[CH2:12][CH2:13][CH2:14][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10]3)=[O:23])=[N:25]2)=[CH:30][CH:29]=1)(=[O:47])[CH3:46]
Reactant: CC(O)c1ccc2cc(NC(=O)OCc3ccccc3)c(C(=O)Nc3cnccc3N3CCC[C@H](NC(=O)OC(C)(C)C)C3)nc2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(=O)c1ccc2cc(NC(=O)OCc3ccccc3)c(C(=O)Nc3cnccc3N3CCC[C@H](NC(=O)OC(C)(C)C)C3)nc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.4 %

Procedure:
A solution of benzyl [2-{[(4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}pyridin-3-yl)amino]carbonyl}-7-(1-hydroxyethyl)quinolin-3-yl]carbamate (0.100 g, 0.156 mmol) (from Example 15, step 7) in DCM (0.50 mL) was mixed with a solution of Dess-Martin periodinane (0.099 g, 0.23 mmol) in DCM (0.50 mL, 7.8 mmol). The reaction mixture was stirred at room temperature for 18 h. The crude mixture was diluted with DCM and washed with aq. NaOH. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the sub-title compound (100 mg, 100%). LCMS calc. for C35H39N6O6 (M+H)+: m/z=639.2. Found: 639.2.
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[Br:14]N1C(=O)CCC1=O>FC(F)(F)C(O)=O>[Br:14][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:4]=1[CH:1]1[CH2:2][CH2:3]1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C2CC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(C2CC2)c(Br)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
Into a 50-mL round-bottom flask, was placed a mixture of methyl 4-cyclopropylbenzoate (compound 10.1, 500 mg, 2.84 mmol), N-bromosuccinimide (500 mg, 2.81 mmol) and trifluoroacetic acid (20 mL). The mixture was stirred overnight at 50° C., then cooled and carefully quenched with water (10 mL). The mixture was extracted with ethyl acetate (3×30 mL) and the combined organic layers were washed with brine (3×30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether as the eluent to yield 0.5 g (69%) of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[O:17])=[C:12]([Cl:25])[CH:11]=1.[F:26][C:27]([F:34])([F:33])[CH2:28][S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])=[O:17])=[C:12]([Cl:25])[CH:11]=2)=[C:2]([NH:1][S:29]([CH2:28][C:27]([F:34])([F:33])[F:26])(=[O:31])=[O:30])[CH:7]=1
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2N)cc1Cl
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: c1ccncc1
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2NS(=O)(=O)CC(F)(F)F)cc1Cl
Reaction time: 4 h

Procedure:
The reaction was conducted as described in the preparation of compound 179 using {4-[(2-amino-4-bromophenyl)amino]-2-chlorophenyl}(2-methylphenyl)methanone (0.15 g, 0.35 mmol)(disclosed in WO 01/05744) in pyridine (0.47 mL) and trifluoroethanesulfonyl chloride (0.059 mL, 0.53 mmol). The reaction time was 4 h. Work up as described in the preparation of compound 179 afforded the title compound as brown crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22]=1[C:32](Cl)=[O:33]>O1CCCC1>[C:6]1([N:5]([CH2:4][CH2:3][N:2]([CH3:12])[CH3:1])[C:32]([C:22]2[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:24][O:25][C:21]=2[CH3:20])=[O:33])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(C)CCNc1ccccc1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1C(=O)N(CCN(C)C)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A mixture of 24.6 grams (0.15 mole) of N,N-dimethyl-N'-phenyl-ethylenediamine and 18.2 grams (0.18 mole) of triethylamine in 500 milliliters of tetrahydrofuran (THF) is cooled to 0° C. and 39.8 grams (0.18 mole) of 5-methyl-3-phenyl-4-isoxazole carbonyl chloride in 100 milliliters of tetrahydrofuran is added dropwise. After the addition is complete, the mixture is warmed to room temperature and stirred for 4 hours. The resulting suspension is filtered and the THF removed in vacuo. The residue is dissolved in methylene chloride and washed with 2N sodium hydroxide and water and then dried over magnesium sulfate. The mixture is filtered and the solvent removed by evaporation. The residue is then treated with hexane to yield crystals of N-phenyl-N-(2-dimethylaminoethyl)-5-methyl-3-phenyl-4-isoxazole carboxamide; M.P. 88°-89° C.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[CH2:11]([C:13]1([Mg]Br)[CH:18]=[C:17]([CH2:19][CH3:20])[CH:16]=[C:15]([CH2:21][CH3:22])[CH2:14]1)[CH3:12].S(=O)(=O)(O)O>O1CCCC1>[CH2:19]([C:17]1([C:2](=[O:4])[C:1]([O:8][CH2:9][CH3:10])=[O:7])[CH:18]=[C:13]([CH2:11][CH3:12])[CH:14]=[C:15]([CH2:21][CH3:22])[CH2:16]1)[CH3:20]
Reactant: CCC1=CC(CC)([Mg]Br)CC(CC)=C1
Reactant: CCOC(=O)C(=O)OCC
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C1(CC)C=C(CC)C=C(CC)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
On the other hand, to a 3 L volume four-necked flask, diethyl oxalate (295 g) and tetrahydrofuran (anhydrous) (350 ml) were added under a nitrogen atmosphere and cooled on ice-bath. The above mentioned solution of 1,3,5-triethylphenylmagnesium bromide in tetrahydrofuran was added thereto with keeping the temperature below 10° C. The resulting mixture was stirred at room temperature for 2 hours. The pH of the mixture was adjusted to less than 2 with 20 w/w % of sulfuric acid under ice-cooling. The mixture was extracted with toluene. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 495.3 g of ethyl 2-(1,3,5-triethylphenyl)-2-oxoacetate (9-b).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:13])/[CH:10]=N/O)=[CH:4][C:3]=1[O:14][CH3:15].[OH:16]S(O)(=O)=O>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[O:14][CH3:15])[NH:8][C:9](=[O:13])[C:10]2=[O:16]
Reactant: COc1cc(NC(=O)/C=N/O)ccc1Br
Reactant: O=S(=O)(O)O
Product: COc1cc2c(cc1Br)C(=O)C(=O)N2
Temperature: 80 °C

Procedure:
Concentrated H2SO4 (400 mL) was heated to 50° C. and portions of (2E)-N-[4-bromo-3-(methyloxy)phenyl]-2-(hydroxyimino)ethanamide (75 g, 275 mmol) were added while keeping the internal temperature below 70° C. After complete addition, the mixture was heated to 80° C. for 1 h, then poured into ice, filtered and washed with H2O to yield 5-bromo-6-(methyloxy)-1H-indole-2,3-dione (75 g) of a red solid. MS (m/z) 257.9 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[C:28]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)=[CH:27][CH:26]=[CH:25][C:24]=2[O:39][CH2:40][CH:41]2[CH2:43][CH2:42]2)[N:3]=1.CC[O:46][C:47]([CH:49](P(OCC)(OCC)=O)[F:50])=O.[Cl-].[Li+].N12CCCN=C1CCCCC2>C(#N)C>[CH:41]1([CH2:40][O:39][C:24]2[CH:25]=[CH:26][CH:27]=[C:28]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[C:23]=2[C:4]2[CH:5]=[C:6]([CH:10]3[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:11]3)[C:7]3[CH:8]=[C:49]([F:50])[C:47](=[O:46])[NH:1][C:2]=3[N:3]=2)[CH2:43][CH2:42]1
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c(C=O)c(N)n2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c3cc(F)c(=O)[nH]c3n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of tert-butyl 3-(2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-3-formyl-4-pyridinyl)-1-piperidinecarboxylate (0.500 g, 0.851 mmol), triethyl-2-fluoro-2-phosphonoacetate (0.350 mL, 1.701 mmol) and anhydrous lithium chloride (0.072 g, 1.701 mmol) in acetonitrile (20 mL) was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.250 mL, 1.701 mmol). The mixture was stirred at room temperature for 30 min and concentrated under reduced pressure. The residue was extracted with ethyl acetate and water. The separated organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue (liquid) was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1-1/1) to give tert-butyl 3-(2-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-6-fluoro-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)-1-piperidinecarboxylate as a form (0.261 g, 49%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:21][C:22]([Cl:27])([Cl:26])[C:23](Cl)=[O:24].[Cl-].[Na+]>C1C=CC=CC=1>[NH:7]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:23](=[O:24])[C:22]([Cl:27])([Cl:26])[Cl:21])=[CH:10][CH:9]=1)[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Nc1ccc(Nc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(Nc1ccc(Nc2ccccc2)cc1)C(Cl)(Cl)Cl

Procedure:
The following materials are charged to a reactor: 62.5 g (0.34 mole) 4-aminodiphenylamine, 39 g (0.37 mole) sodium carbonate and 500 ml benzene. To this stirred mixture, under nitrogen, is added a solution of 63.8 (0.35 mole) trichloroacetyl chloride in 100 ml benzene over a thirty minute period. Stirring is continued for another 31/2 hours. The crude product containing sodium chloride by-product is dried to remove solvent. The dried material is washed first with dilute HCl, then distilled water, air dried and the product is recrystallized from a methanol/benzene (1/2) solvent mixture. Melting point and elementary analysis are reported in Table I.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Br:16][C:17]1[CH:18]=[CH:19][C:20]([OH:31])=[C:21]([CH:30]=1)[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([O:31][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[C:21]([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:30]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(c1ccccc1)c1cc(Br)ccc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(Br)cc3C(=O)c3ccccc3)c2cc1OC
Temperature: 160 °C
Reaction time: 7 h
Yield: 94.5 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (56.1 mg), 5-bromo-2-hydroxybenzophenone (361 mg), and 4-dimethylaminopyridine (168 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160° C. for 7 hr. The reaction solution was cooled to room temperature, and the solvent was then removed therefrom by distillation under the reduced pressure. Chloroform was added to the residue, and mixture was washed with a 1 N aqueous potassium hydroxide solution and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform and by thin layer chromatography using acetone-hexane to give the title compound (110 mg, yield 94%).
Reaction SMILES: [ClH:1].[F:2][C:3]([F:21])([F:20])[C:4]1[CH:5]=[C:6]([C:10]2[O:14][C:13]([C:15](=[NH:19])OCC)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.[CH3:22][O:23][CH:24]([O:27][CH3:28])[CH2:25][NH2:26]>C(O)C>[ClH:1].[CH3:22][O:23][CH:24]([O:27][CH3:28])[CH2:25][N:26]=[C:15]([C:13]1[O:14][C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([F:2])([F:20])[F:21])[CH:5]=2)=[CH:11][CH:12]=1)[NH2:19]
Reactant: COC(CN)OC
Reactant: CCOC(=N)c1ccc(-c2cccc(C(F)(F)F)c2)o1
Agent: Cl
Solvent: CCO
Product: COC(CN=C(N)c1ccc(-c2cccc(C(F)(F)F)c2)o1)OC
Yield: 77.7 %

Procedure:
To a stirring mixture of 110 g (0.36 mole) of ethyl 5-(3-trifluoromethylphenyl)-2-furimidate hydrochloride and 1700 ml of absolute ethanol was added 38 g (0.36 mole) of aminoacetaldehyde dimethyl acetal with dissolution. The reaction solution was refluxed for 6 hours, the solvent was removed on the Calab evaporator, and the residual solid was washed in hexane and air dried to yield 106 g (78%) of N'-(2,2-dimethoxyethyl)-5-(3-trifluoromethylphenyl)-2-furamidine hydrochloride. A sample was recrystallized from acetonitrile and dried at room temperature to give a m.p. of 173°-174°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[F:10][CH:11]([F:17])[C:12]([F:16])([F:15])[CH2:13]I>>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([O:8][CH2:13][C:12]([F:16])([F:15])[CH:11]([F:17])[F:10])=[CH:6][N:7]=1
Reactant: FC(F)C(F)(F)CI
Reactant: Cc1cc(Cl)ncc1O
Product: Cc1cc(Cl)ncc1OCC(F)(F)C(F)F
Yield: 89 %

Procedure:
The title compound is prepared in 89% yield (7.97 g, pale yellow solid) from 6-chloro-4-methylpyridin-3-ol (5.00 g, 34.8 mmol) and 1,1,2,2-tetrafluoro-3-iodopropane (16.9 g, 69.7 mmol) in a similar manner to Step-1 of Amine-49.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.OS(O)(=O)=O.[N+:24]([O-])([OH:26])=[O:25]>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[O:9])=[CH:6][C:7]=1[N+:24]([O-:26])=[O:25]
Reactant: O=C(c1ccc(Br)cc1)c1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(Cl)Cl
Product: O=C(c1ccc([N+](=O)[O-])cc1)c1ccc(Br)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
The crude (4-Bromo-phenyl)-(4-nitro-phenyl)-methanone (15 g, 49 mmol) was dissolved in 45 mL of dichloroethane and added dropwise via addition funnel to a mixture of concentrated H2SO4(aq) (21 mL, 392 mmol) and fuming HNO3(aq) (15.7 mL, 392 mmol). The mixture was stirred at 60° C. overnight. Subsequently the mixture was poured over ice water and allowed to stir resulting in precipitation of the product. The product was filtered and dried affording 78% yield of the desired (4-Bromo-3-nitro-phenyl)-(-4-nitro-phenyl)-methanone (13.1 g, 38 mmol).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:29])[C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=3)[NH:20][C:19]2=[O:28])=[CH:13][CH:12]=1.CO.[Li+].[OH-].Cl>O>[F:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:28])[C:18]2=[CH:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:30])=[O:2])=[O:29])=[CH:12][CH:13]=1
Reactant: COC(=O)CCCCCNC(=O)c1ccc(C=C2C(=O)Nc3ccc(F)cc32)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCNC(=O)c1ccc(C=C2C(=O)Nc3ccc(F)cc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.9 %

Procedure:
6-(4-((5-fluoro-2-oxoindolin-3-ylidene)methyl)benzamido)hexanoic acid methyl ester (410 mg, 1 mmol) and 300 ml of CH3OH were stirred at room temperature while 25 ml of 4 N solution of LiOH in H2O was added. The mixture was stirred for 24 hours at room temperature. The mixture is neutralized with concentrated hydrochloric acid to pH 7 and evaporated under vacuum to remove methanol. The residue was adjusted to pH 3 with concentrated hydrochloric acid. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (305 mg, 77% yield) as a brown solid. LC-MS (m/z) 397 (M+1).
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12]2)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:20]([O:19][C:17](=[O:18])[CH:16]=[C:11]1[CH2:10][CH:9]2[NH:8][CH:13]([CH2:14][CH2:15]2)[CH2:12]1)[CH3:21]
Reactant: CCOC(=O)C=C1CC2CCC(C1)N2C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C=C1CC2CCC(C1)N2
Reaction time: 8 h

Procedure:
To 3-ethoxycarbonylmethylene-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (12.3 g, 41.8 mmol) in CH2Cl2 was added TFA (10 ml) and the reaction was stirred for 8 h. The solution was concentrated under reduced pressure, diluted with CH2Cl2, and washed first with 2 M NaOH and followed by brine. The water phases were thereafter back-extracted with EtOAc and the combined organic phase was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude title product was used without further purification (7.04 g, 37.9 mmol, 91%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].[CH:11](=O)/[CH:12]=[CH:13]/[CH3:14].[OH-].[NH4+]>Cl>[F:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[O:9][CH3:10])[N:6]=[C:13]([CH3:14])[CH:12]=[CH:11]2
Reactant: C/C=C/C=O
Reactant: COc1cc(N)ccc1F
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: COc1cc2nc(C)ccc2cc1F

Procedure:
To 4-fluoro-3-methoxyaniline (1.0 g, 7.1 mmol) in refluxing 6N HCl (20 mL) was added dropwise (E)-but-2-enal (0.99 g, 14 mmol) and the reaction was heated to reflux for 2 hours. After cooling, the reaction was neutralized with ammonium hydroxide and extracted with DCM. The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure to yield 6-fluoro-7-methoxy-2-methylquinoline as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)([CH3:11])[CH2:9][OH:10])[C:5](O)=[C:4]([CH3:22])[C:3]=1[CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>C1COCC1>[Br:1][C:2]1[C:3]([CH3:23])=[C:4]([CH3:22])[C:5]2[O:10][CH2:9][C:8]([C:12]3[CH:13]=[CH:14][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:17]=3)([CH3:11])[C:6]=2[CH:7]=1
Reactant: Cc1c(Br)cc(C(C)(CO)c2ccc(C(C)C)cc2)c(O)c1C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1c(Br)cc2c(c1C)OCC2(C)c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-6-(2-hydroxy-1-(4-isopropylphenyl)-1-methylethyl)-2,3-dimethylphenol obtained in Reference Example 22 (830 mg, 2.21 mmol) and triphenylphosphine (638 mg, 2.43 mmol) in THF (60 mL) was added diethyl azodicarboxylate (a 40% toluene solution, 1.06 g, 2.43 mmol) with ice-cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain oily 5-bromo-3-(4-isopropylphenyl)-3,6,7-trimethyl-2,3-dihydro-1-benzofuran 660 mg. To a solution of said compound (660 mg, 1.84 mmol) and benzylamine (0.24 mL, 2.21 mmol) in toluene (10 mL) were added palladium acetate (4 mg, 0.02 mmol) and BINAP (34 mg, 0.6 mmol) at room temperature, and the mixture was stirred under argon stream for 15 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C@H:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])[C:24]([Cl:38])=[CH:23][N:22]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C>[Cl:38][C:24]1[C:25]([NH:27][C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])=[N:26][C:21]([NH:1][C:2]2[CH:19]=[CH:18][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C@H:12]([OH:17])[C:13]([F:16])([F:14])[F:15])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:22][CH:23]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CCN(C[C@H](O)C(F)(F)F)CC2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(C[C@H](O)C(F)(F)F)CC3)ncc1Cl
Temperature: 120 °C
Yield: 53.9 %

Procedure:
(S)-3-(7-Amino-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,1,1-trifluoro-propan-2-ol (96 mg, 0.350 mmol, 1.0 eq), 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (115 mg, 0.385 mmol, 1.1 eq), and 10-camphorsulfonic acid (89 mg, 0.385 mmol, 1.1 eq) were dissolved in IPA (3 mL) and heated at 120° C. in a microwave for 40 minutes. The reaction was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (20 mL) and washed with sat. NaHCO3 (20 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by amine capped silica gel chromatography using a gradient of 0-100% EtOAc/hex as the eluting solvent to obtain 2-{5-chloro-2-[3-((S)-3,3,3-trifluoro-2-hydroxy-propyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide as a pale yellow solid (101 mg, 54%). LCMS (m/e) 535 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 11.09 (s, 1H), 8.67 (d, 1H, J=8.4 Hz), 8.11 (s, 1H), 7.51 (d, 1H, J=7.8 Hz), 7.48-7.42 (m, 1H), 7.40 (s, 1H), 7.31-7.26 (m, 1H), 7.14-7.08 (m, 1H), 7.05 (d, 1H, J=8.0 Hz), 6.91 (s, 1H), 6.21 (bs, 1H), 4.42 (bs, 1H), 4.10-4.02 (m, 1H), 3.05 (d, 3H, J=4.6 Hz), 3.00-2.80 (m, 7H), 2.78-2.64 (m, 3H).