Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH3:22])=[C:17]([N+:23]([O-])=O)[CH:16]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]([F:43])([F:42])[CH2:30][N:31]1[C:35]2=[N:36][CH:37]=[CH:38][CH:39]=[C:34]2[CH:33]=[C:32]1[CH:40]=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O>[C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([C:15]2[CH:20]=[CH:19][C:18]3[N:21]([CH3:22])[C:40]([C:32]4[N:31]([CH2:30][C:29]([F:43])([F:42])[F:28])[C:35]5=[N:36][CH:37]=[CH:38][CH:39]=[C:34]5[CH:33]=4)=[N:23][C:17]=3[CH:16]=2)=[O:26])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CNc1ccc(C(=O)N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)cc1[N+](=O)[O-]
Reactant: O=Cc1cc2cccnc2n1CC(F)(F)F
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cn1c(-c2cc3cccnc3n2CC(F)(F)F)nc2cc(C(=O)N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)ccc21
Temperature: 90 °C
Yield: 62.6 %

Procedure:
To a mixture of (R)-tert-butyl(1-(4-(methylamino)-3-nitrobenzoyl)piperidin-3-yl)carbamate (2.1 g, 5.55 mmol) and 1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (1.3 g, 5.70 mmol) in ethanol (55 ml) was added portionwise a solution of sodium hydrosulfite (3.41 g, 16.65 mmol) in water (25 ml). The mixture was flushed with nitrogen and heated at 90° C. overnight for 17 hours. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. DCM was added to the residue and the heterogeneous solution was dried over sodium sulfate. The solid was filtered off and the filtrate was concentrated under vacuo. The residue was loaded in dichloromethane and purified by SP4 SNAP on 2 silica (Si) 100 g columns using an initial gradient of 25-80% (15 CVs), followed by 80-100% (10 CVs) ethyl acetate/cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a pale yellow solid (1.934 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:22]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: Cc1ccccc1C(=O)Nc1ccc2[nH]c3c(c2c1)CC(N(C)C)CC3
Yield: 70.7 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 8.9 μL (0.051 mMol) 2-methylbenzoyl chloride, 11.3 mg (71%) of the title compound were recovered as a beige solid.
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[CH2:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][C:24]1=O>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][CH:24]2[CH2:23][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Reactant: O=C1Cc2ccccc2C1
Product: CCCC(NC1Cc2ccccc2C1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was reacted with 2-indanone to provide the title compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.5, 24.3, 26.6, 26.7, 36.4, 39.9, 40.6, 56.0, 59.0, 61.4, 67.3, 104.8, 124.9, 125.0, 126.7, 126.8, 131.2, 137.4, 141.2, 141.7, 172.2; MS m/z 424.4 (M+1).
Reaction SMILES: Br[CH:2]=[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH2:4]1.[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:11]([C:10]1[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:23]2[C:22](=[O:24])[C:21]3=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]3[C:19]2=[O:29])=[CH:4][CH:5]=1)([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccccc1C1=CCC(=CBr)C=C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccccc1-c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Yield: 7.4 %

Procedure:
Methyl 2-[4-(bromomethylene)phenyl]benzoate (1.22 g, 0.04 mole), phthalimide (0.59 g, 0.04 mole), and potassium carbonate (0.55 g, 0.04 mole) are combined in 120 mL acetonitrile. The mixture is heated at reflux for 24 hours. At that time the mixture is filtered through celite and rotovapped to a residue. The residue is crystallized from ethyl acetate to afford 1.1 g (71%) of the title compound as a tan solid mp 148°-150° C. 1H NMR (CDCl3) 7.9-7.1 (12H, m); 4.92 (2H, s); 3.63 (3H, s). Mass Spec. (DCl) m/z 372 (M+H). Analysis--calc'd for C23H17NO4.1/2 H2O: C, 72.62; H, 4.77: N, 3.68; found: C, 72.88; H, 4.55; N, 3.77.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)=[CH:12][CH:11]=3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[N:1]1([C:7]2[CH:8]=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:19][CH:18]=2)=[CH:12][CH:11]=3)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(-c2ccc3ncc(N4CCOCC4)nc3c2)cc1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(-c2ccc3ncc(N4CCOCC4)nc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
A mixture of 4-(3-morpholin-4-yl-quinoxalin-6-yl)-phenylamine [intermediate example 4.1] (100 mg) and pyridine (0.5 mL) was treated with a solution of methane sulfonyl chloride (75 mg, 0.65 mmol) in pyridine (0.6 mL) and stirred at room temperature overnight. The reaction was partitioned between dichloromethane and water, the phases separated and the organic layer concentrated in vacuo. The residue was triturated with dichloromethane and filtered to give the title compound (71 mg). UPLC-MS: RT=0.97 min; m/z (ES+) 385.19 [MH+]; required MW=384.46.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:22]2[CH:21]=[N:20][CH:19]=[C:18]([O:17][CH3:16])[CH:23]=2)[C:11]=1[CH3:12]
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1cncc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a stirred solution of 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.35 g, 1.411 mmol) in toluene (2.80 mL) was added 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.50 g, 2.12 mmol), potassium carbonate (0.585 g, 4.23 mmol) and palladium tetrakistriphenylphosphine (0.163 g, 0.141 mmol). The reaction was stirred at 100° C. and stirring continued for 15 h. The reaction mixture was cooled to rt and concentrated in vacuo. The crude material was purified by column chromatography on silica gel, eluting with (0-50% EtOAc in hexanes) to provide 4-chloro-5,7-difluoro-2-(5-methoxy-3-pyridinyl)-3-methylquinoline as a white solid. Mass Spectrum (ESI) m/e=321.1 (M+1).
Reaction SMILES: [N:1]1([CH2:6][C:7]2([CH2:10][NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]4[N:26]=[C:25]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[N:24]=[C:23]([NH:33][C:34]5([C:37]6[CH:47]=[CH:46][C:40]([O:41][CH2:42][C:43](O)=[O:44])=[CH:39][CH:38]=6)[CH2:36][CH2:35]5)[N:22]=4)=[CH:16][CH:15]=3)=[O:13])[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:48][CH:49]([S:51]([NH2:54])(=[O:53])=[O:52])[CH3:50].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:48][CH:49]([S:51]([NH:54][C:43](=[O:44])[CH2:42][O:41][C:40]1[CH:39]=[CH:38][C:37]([C:34]2([NH:33][C:23]3[N:24]=[C:25]([O:27][CH2:28][C:29]([F:32])([F:30])[F:31])[N:26]=[C:21]([NH:20][C:17]4[CH:16]=[CH:15][C:14]([C:12]([NH:11][CH2:10][C:7]5([CH2:6][N:1]6[CH2:2][CH2:3][CH2:4][CH2:5]6)[CH2:9][CH2:8]5)=[O:13])=[CH:19][CH:18]=4)[N:22]=3)[CH2:35][CH2:36]2)=[CH:47][CH:46]=1)(=[O:53])=[O:52])[CH3:50]
Reactant: O=C(O)COc1ccc(C2(Nc3nc(Nc4ccc(C(=O)NCC5(CN6CCCC6)CC5)cc4)nc(OCC(F)(F)F)n3)CC2)cc1
Reactant: CC(C)S(N)(=O)=O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NC(=O)COc1ccc(C2(Nc3nc(Nc4ccc(C(=O)NCC5(CN6CCCC6)CC5)cc4)nc(OCC(F)(F)F)n3)CC2)cc1
Yield: 21.2 %

Procedure:
2-(4-(1-(4-(4-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methylcarbamoyl)phenylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)cyclopropyl)phenoxy)acetic acid (20 mg, 0.031 mmol), propane-2-sulfonamide (4.88 mg, 0.040 mmol), PyBOP (23.81 mg, 0.046 mmol), and Hunig's Base (0.027 mL, 0.153 mmol) were stirred in DCM (Volume: 3 mL) for 3 days. The solvent was removed and the crude material was purified by Prep-HPLC (Column: Sunfire prep C18 OBO 5 uM, 30×100 mm by Waters Corp) using a gradient of 10-60% ACN/water w/0.1% TFA modifier to give 4-(4-(1-(4-(2-(1-methylethylsulfonamido)-2-oxoethoxy)phenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-N-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methyl)benzamide (5 mg). 1H NMR (500 MHz, MeOD) δ ppm 0.75 (s, 2H), 0.83 (s, 2H), 1.14-1.42 (m, 10H), 2.12-2.26 (m, 4H), 3.06-3.43 (m, 7H), 3.77-3.88 (m, 2H), 4.64 (s, 2H), 4.81-4.92 (m, 2H), 6.86-7.00 (m, 2H), 7.21-7.32 (m, 2H), 7.64-7.76 (m, 3H), 7.89 (s, 1H); LC-MS (Condition A), MS m/z (M++H) 761.2.
Reaction SMILES: [CH:1]1([N:4]([C@H:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[F:18])C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.Cl[C:20]1[N:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][N:21]=1>>[CH:1]1([NH:4][CH:12]2[CH2:17][CH2:16][N:15]([C:20]3[N:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][N:21]=3)[CH2:14][CH:13]2[F:18])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N(C1CC1)[C@H]1CCNC[C@H]1F
Reactant: CCc1cnc(Cl)nc1
Product: CCc1cnc(N2CCC(NC3CC3)C(F)C2)nc1

Procedure:
The title compound is prepared from tert-butyl N-cyclopropyl-N-[(3R,4S)-3-fluoropiperidin-4-yl]carbamate and 2-chloro-5-ethylpyrimidine following a procedure analogous to that described for Intermediate 87. LC (method 20): tR=1.80 min; Mass spectrum (APCI): m/z=265 [M+H]+.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:24]([S:27](Cl)(=[O:29])=[O:28])[CH2:25][CH3:26]>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][S:27]([CH2:24][CH2:25][CH3:26])(=[O:29])=[O:28])=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(C=C2c3ccccc3CCc3ccccc32)cc1
Reactant: CCCS(=O)(=O)Cl
Product: CCCS(=O)(=O)Nc1ccc(C=C2c3ccccc3CCc3ccccc32)cc1
Yield: 50.9 %

Procedure:
Following procedures essentially as described in Example 90, 4-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylamine (100 mg, 0.336 mmol) and 1-propanesulfonyl chloride (144 mg, 1.01 mmol) affords 69 mg (51%) of the title compound as a colorless oil. MS (ES) 426 (M+Na), 402 (M−H); HPLC shows 99% purity.
Reaction SMILES: [CH:1]1[N:5]([CH:6]2[O:10][CH:9]([CH2:11][OH:12])[CH:8]([OH:13])[CH:7]2[OH:14])[C:4]2[N:15]=[C:16]([Cl:20])[N:17]=[C:18]([NH2:19])[C:3]=2[C:2]=1[C:21]#[N:22].[OH:23]O>[OH-].[NH4+]>[NH2:19][C:18]1[C:3]2[C:2]([C:21]([NH2:22])=[O:23])=[CH:1][N:5]([C@@H:6]3[O:10][C@H:9]([CH2:11][OH:12])[C@@H:8]([OH:13])[C@H:7]3[OH:14])[C:4]=2[N:15]=[C:16]([Cl:20])[N:17]=1
Reactant: OO
Reactant: N#Cc1cn(C2OC(CO)C(O)C2O)c2nc(Cl)nc(N)c12
Agent: [NH4+]
Agent: [OH-]
Product: NC(=O)c1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2nc(Cl)nc(N)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Chlorotoyocamycin (6, 200 mg) was suspended in 40 ml of conc. ammonium hydroxide and 4 ml of 30% hydrogen peroxide were added. The mixture was stirred at room temperature for 2 hr and 2 more ml of 30% hydrogen peroxide were added. Stirring at room temperature was continued for 2 more hours and 2 more ml of 30% hydrogen peroxide were added and the solution was stirred at room temperature for an additional 12 hr. One more ml of hydrogen peroxide was added and stirring at room temperature was continued for an additional hour and the solution was evaporated to dryness in vacuo. The residue was coevaporated first with 40 ml of ethanol and then 40 ml of acetone. The residue was suspended in 50 ml of chloroform, the solid was collected by filtration, washed with 25 ml of chloroform and air dried. The product was then crystallized from 10 ml of absolute ethanol to yield, after drying the sample in an Abderhalden apparatus for 2 hr in vacuo at 110°, 100 mg (47%) of 8, mp 175° dec.
Reaction SMILES: [C:1]([NH:11][C:12]1[CH:17]=[C:16]([F:18])[C:15]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[C:14]([F:25])[CH:13]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[H-].[Na+].[Br-].[CH2:29]1[CH2:33]OC[CH2:30]1>>[CH2:33]([N:11]([C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[C:12]1[CH:13]=[C:14]([F:25])[C:15]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[C:16]([F:18])[CH:17]=1)[CH:29]=[CH2:30]
Reactant: O=C(Nc1cc(F)c(-c2cccnc2)c(F)c1)OCc1ccccc1
Reactant: C1CCOC1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Product: C=CCN(C(=O)OCc1ccccc1)c1cc(F)c(-c2cccnc2)c(F)c1
Reaction time: 0.5 h

Procedure:
A mixture of N-carbobenzyloxy-4-(3-pyridyl)-3,5-difluoroaniline (PREPARATION 3, 543 mg, 1.60 mmol) in anhydrous THF (40 ml) is treated with sodium hydride (60% dispersion in mineral oil, 128 mg, 3.19 mmol, 2 eq). The reaction is kept under an atmosphere of nitrogen at 20°-25° for 0.5 hr. After this time, ally bromide (691 pl, 7.99 mmol, 5 eq) is added. Stirring is continued at 20°-25° for 16 hr. After this time, the reaction is carefully quenched with water (20 ml). The layers are separated and the aqueous layer is extracted with ethyl acetate (3×25 ml). The combined organics phases are washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The concentrate is purified by silica gel chromatography (125 g of silica gel) eluting with acetonitrile/chloroform (3/97 - 11). The appropriate fractions are concentrated to give the title compound. An analytical sample is prepared by preparative TLC (SG, acetonitrile/chloroform -6/94), mp=92°-93°; FTIR (mull) cm-1 3068, 3061, 1710, 1705, 1643, 1635, 1412, 1263, 1024, 733; MS (EI) m/z: 380, 336, 309, 245, 91, 65; NMR (CDCl3) 8.72, 8.62, 7.99, 7.42-7.36, 7.03, 5.94, 5.23-5.18 and 4.34 δ.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.[N:40]1([C:48](=O)[CH2:49]Cl)[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[N:40]1([CH2:48][CH2:49][O:39][C:38]2[CH:37]=[CH:36][C:4]([CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]3[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=3[CH:16]3[CH2:25][CH2:24][C:23]4[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=4[CH2:17]3)=[CH:3][C:2]=2[F:1])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: O=C(CCl)N1CCCCCCC1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CCCCCCC3)c(F)c2)C(C)C)c1
Yield: 35.3 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 1-azocan-1-yl-2-chloroethanone (18 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (9.5 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:20][CH2:19]1.[Cl:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[OH:36]>>[Cl:29][C:30]1[CH:31]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)[CH2:20][CH2:19]2)[CH:33]=[CH:34][C:35]=1[OH:36]
Reactant: OB(O)c1ccc(O)c(Cl)c1
Reactant: O=C(c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](N2CCCC2)CC1)C1CC1
Product: O=C(c1cnc2ccc(-c3ccc(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](N2CCCC2)CC1)C1CC1

Procedure:
Following general procedure D, {6-bromo-4-[trans-4-(pyrrolidin-1-yl)cyclohexylamino]quinolin-3-yl}(cyclopropyl)methanone (24 mg, 0.054 mmol) was reacted with 3-chloro-4-hydroxyphenylboronic acid (26 mg, 0.150 mmol) to afford the desired product (22 mg, 83%) as a brown solid: 1H NMR (300 MHz, CD3OD) δ 9.14 (s, 1H), 8.34 (s, 1H), 8.01 (dd, J=8.8, 1.8 Hz, 1H), 7.92 (d, J=8.7 Hz, 1H), 7.70 (d, J=2.2 Hz, 1H), 7.52 (dd, J=8.5, 2.3 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 4.18 (s, 1H), 3.24 (s, 4H), 3.07 (s, 1H), 2.90-2.78 (m, 1H), 2.34 (d, J=14.5 Hz, 4H), 2.02 (s, 4H), 1.73-1.51 (m, 4H), 1.26-1.15 (m, 2H), 1.15-1.02 (m, 21-1); ESI MS m/z 490 [C29H32ClN3O2+H]+; HPLC 98.9% (AUC), tR=10.90 min.
Reaction SMILES: [F:1][C:2]1[C:3]([C:24]([F:27])([F:26])[F:25])=[N:4][N:5]([C:14]2[CH:15]=[CH:16][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[N:18][CH:19]=2)[C:6]=1[C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1.BrC1C=CC(C2N([C:40]3C=C[C:43]([S:46](N)(=O)=O)=[N:44][CH:45]=3)N=C(C(F)(F)F)C=2Cl)=CC=1>>[F:1][C:2]1[C:3]([C:24]([F:27])([F:26])[F:25])=[N:4][N:5]([C:14]2[CH:15]=[CH:16][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[N:18][CH:19]=2)[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:45]2[N:44]=[CH:43][S:46][CH:40]=2)=[CH:9][CH:8]=1
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(F)c2-c2ccc(Br)cc2)cn1
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(Cl)c2-c2ccc(Br)cc2)cn1
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(F)c2-c2ccc(-c3cscn3)cc2)cn1

Procedure:
The title compound was prepared according to the procedure of step 3 in the Example 4 using 5-[4-fluoro-5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide, instead of 5-[5-(4-bromophenyl)-4-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:43]=[CH:42][C:18]([O:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)=[O:28])[CH:21]=2)=[CH:17][CH:16]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1.C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:11][C:12](=[S:13])[NH:14][C:15]2[CH:16]=[CH:17][C:18]([O:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([N:29]4[CH2:30][CH2:31][CH:32]([N:35]5[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]5)[CH2:33][CH2:34]4)=[O:28])[CH:21]=3)=[CH:42][CH:43]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4)ccn3)CC2)CC1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4)ccn3)CC2)CC1
Reaction time: 3 h
Yield: 40 %

Procedure:
After adding a solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (0.25 M, 3.0 ml) to a solution of 4-(4-aminophenoxy)-2-{[4-(1-methylpiperazin-4-yl)piperidin-1-yl]carbonylamino}pyridine (149 mg) and (+)-10-camphorsulfonic acid (152 mg) in ethanol (4.0 ml) at room temperature, the mixture was stirred for 3 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine and dried over anhydrous sodium sulfate. The solvent was then distilled off, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:methanol=98:2 to 97:3) to provide the title compound (88.2 mg, 40%) as white powder.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([C:17]3[N:18]([CH3:23])[N:19]=[CH:20][C:21]=3[Br:22])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO>[Br:22][C:21]1[CH:20]=[N:19][N:18]([CH3:23])[C:17]=1[C:15]1[CH:14]=[CH:13][C:9]2[CH:10]([CH3:12])[CH2:11][NH:5][CH2:6][CH2:7][C:8]=2[CH:16]=1
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2cc(-c3c(Br)cnn3C)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1CNCCc2cc(-c3c(Br)cnn3C)ccc21
Reaction time: 8 h
Yield: 98.2 %

Procedure:
A solution of N-trifluoroacetyl-7-(4-bromo-2-Methyl-2H-pyrazol-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (37 mg, 0.089 mmol) in methanol (2 mL) was treated with of 15% aqueous NaOH (2 mL), and stirred overnight at 20 C. The product mixture was concentrated, extracted 3 times with CH2Cl2 (5 mL), dried with Na2SO4 and the solvent evaporated. Flash chromatography (0-15% MeOH in CH2Cl2, silica) resulted in 28 mg of a clear oil. 1H NMR (400 MHz, CDCl3) d 7.50 (s, 1 H), 7.25 (d, J=8 Hz, 1H), 7.17 (d, J=8 Hz, 1 H), 7.10 (s, 1 H), 3.83 (s, 3 H), 3.17 (m, 1 H), 3.1-2.9 (m, 8 H), 2.80 (dd, J=7, 13 Hz, 1 H), 2.48 (bs, 1 H), 1.40 (d, J=8 Hz, 3 H). MS calculated for C15H18BrN3+H: 320, observed: 320.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:25](Br)[C:26]#[CH:27]>CC(C)=O>[C:25]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9]2)=[CH:4][CH:3]=1)#[C:26][CH3:27]
Reactant: O=c1cc(-c2ccccc2)oc2cc(O)ccc12
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC#COc1ccc2c(=O)cc(-c3ccccc3)oc2c1

Procedure:
A mixture of 7-hydroxyflavone (2.38 g, 0.01 mol), K2CO3 (2.8 g, 0.02 mol), Kl (0.166 g, 0.001 mol), propargyl bromide (1.78 g, 0.015 mol) and acetone (100 mL) was refluxed 10 h and hot filtered. The solvent was evaporated and the residue was crystallized by toluene. This yields 2.58 g of a product with the following characteristics: m.p. 199-200° C.; 1H NMR (CDC13) δ: 2.6 (m, 1H), 4.8 (s, 2H), 6.75-8.18 (m, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[O:8][C:9]3[N:26]=[C:25]([C:27]4[CH:37]=[CH:36][C:30]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])=[CH:29][CH:28]=4)[CH:24]=[CH:23][C:10]=3[CH:11]([C:12]([CH3:22])([CH3:21])[C:13](=[O:20])[NH:14][C:15]3[S:16][CH:17]=[N:18][N:19]=3)[C:5]2=[CH:4][CH:3]=1.[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH3:21][C:12]([CH:11]1[C:5]2[C:6](=[N:7][C:2]([N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[CH:3][CH:4]=2)[O:8][C:9]2[N:26]=[C:25]([C:27]3[CH:37]=[CH:36][C:30]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])=[CH:29][CH:28]=3)[CH:24]=[CH:23][C:10]1=2)([CH3:22])[C:13](=[O:20])[NH:14][C:15]1[S:16][CH:17]=[N:18][N:19]=1
Reactant: C1CCNC1
Reactant: CN(C)C(=O)c1ccc(-c2ccc3c(n2)Oc2nc(Cl)ccc2C3C(C)(C)C(=O)Nc2nncs2)cc1
Product: CN(C)C(=O)c1ccc(-c2ccc3c(n2)Oc2nc(N4CCCC4)ccc2C3C(C)(C)C(=O)Nc2nncs2)cc1

Procedure:
Using conditions described for synthesis of Example 67, the acid from Step 4 of Example 54 was reacted with pyrrolidine and converted Example 70. 1H NMR (400 MHz, chloroform-d) δ ppm 8.90 (1H, s), 8.06 (2H, d, J=8.31 Hz), 7.56 (2H, s), 7.51 (2H, d, J=8.31 Hz), 7.42 (1H, d, J=8.81 Hz), 6.27 (1H, d, J=8.56 Hz), 4.43 (1H, s), 3.53-3.64 (4H, m), 3.19 (3H, s), 3.06 (3H, s), 2.00-2.16 (4H, m), 1.25 (3H, s), 1.23 (3H, s); MS (ES+) m/z: 570 (M+H); LC retention time: 3.88 min (analytical HPLC Method A).