Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Br[CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:14][C:13]([CH3:15])=[CH:12][CH2:11][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: CC(C)=CCBr
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCOc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
3-Hydroxybenzonitrile (1.19 g, 10 mmol) and 4-bromo-2-methyl-2-butene (1.66 g, 10 mmol) were dissolved in N,N-dimethylformamide (5 mL), potassium carbonate (1.66 g, 12 mmol) was added, and the solution was stirred at room temperature for 2 hours. Water (50 mL) was added to the reaction solution, which was then extracted with ethyl acetate (50 mL). The extract was washed, then, dried over anhydrous magnesium sulfate, and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5), and the title compound (1.71 g, 10 mmol, 99.4%) was obtained as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:38][C:39]1[CH:40]=[C:41]([S:45]([NH2:48])(=[O:47])=[O:46])[CH:42]=[CH:43][CH:44]=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]([NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([S:45]([NH2:48])(=[O:46])=[O:47])[CH:40]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: CC(C)(C)c1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(C(=O)Nc2cccc(S(N)(=O)=O)c2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 6-tert-butylpyridine-3-carboxylic acid (18 mg, 0.10 mmol) and HATU (38 mg, 0.10 mmol) in DMF (1 mL) was stirred at room temperature for 3 minutes. To this solution was added 3-amino-benzenesulfonamide (17 mg, 0. 10 mmol) and triethylamine (28 μL, 0.20 mmol). The reaction was stirred at room temperature for 16 h and purified by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to give 6-tert-butyl-N-(3-(aminosulfonyl)phenyl)pyridine-3-carboxamide. LC/MS: m/z 334.3 (M+H)+ at 1.99 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:5](=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.[H-].[Na+].I[CH3:15]>O1CCCC1>[CH3:15][O:11][C:7]1[C:5]2[N:6]=[C:2]([NH2:1])[O:3][C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Nc1nc2c(O)cccc2o1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc2oc(N)nc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
To a stirred solution of 10 g (66 mmol) 2-amino-benzooxazol-4-ol in 100 ml tetrahydrofuran at room temperature was added portionwise 3.49 g (79.9 mmol) sodium hydride (55% dispersion in oil), and the mixture was then stirred for 1 h at 50° C. A solution of 14.5 ml (233 mmol) iodomethane in 500 ml tetrahydrofuran was then added dropwise over 3 h, while the reaction mixture was maintained at 50° C. The mixture was then poured onto water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over sodium sulfate, and concentrated in vacuo. Flash chromatography (dichloromethane then 2/98 methanol/dichloromethane) afforded 7.5 g (69%) 4-methoxy-benzooxazol-2-yl-amine as a brown crystalline solid. EI-MS m/e (%): 164 (M+, 100), 149 ([M−CH3]+, 23), 135 (46).
Reaction SMILES: Cl.[C:2](=[NH:6])([NH2:5])[CH2:3][CH3:4].C[O-].[Na+].[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([C:30](=O)[CH2:31][CH2:32][CH2:33][CH3:34])[C:26](OC)=[O:27])=[CH:20][CH:19]=1)#[N:11]>CO>[CH2:31]([C:30]1[N:6]=[C:2]([CH2:3][CH3:4])[NH:5][C:26](=[O:27])[C:25]=1[CH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:13]2[C:12]([C:10]#[N:11])=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:23][CH:22]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CCC(=N)N
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCc1nc(CC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 79.6 %

Procedure:
A solution of propanimidamide hydrochloride (3.9 g), 28% sodium methoxide (11 mL) and methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (6.5 g) in methanol (65 mL) was stirred overnight. The solvent was evaporated under reduced pressure, and water and acetic acid were added. The precipitated solid was collected by filtration, and washed with water and diethyl ether to give the title compound (5.5 g, 83%) as a pale-yellow solid.
Reaction SMILES: [OH:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([N+]([O-])=O)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[H+].[B-](F)(F)(F)F.N([O-])=[O:28].[Na+].[OH-].[Na+]>O>[OH:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([OH:28])=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6]
Reactant: O=N[O-]
Reactant: CC(C)S(=O)(=O)NCC(C)(O)c1ccc([N+](=O)[O-])cc1
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: CC(C)S(=O)(=O)NCC(C)(O)c1ccc(O)cc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
Into a 50 mL-3 neck flask fitted with a stirrer and thermometer was placed 1.0 gm. Of [2-(4-aminophenyl)-2-hydroxypropyl][(methylethyl)sulfonyl]amine (prepared in example 19) and 4.06 gm of 48% HBF4 in H2O (20 mL) at 0° C. The reaction was then stirred at this temperature for 30 minutes. 0.26 gm of sodium nitrite was then added portion wise to the mixture and stirring at this temperature continued for an additional 30 minutes. The reaction was then slowly heated to 70° C. and stirred at this temperature for 3 hours. The mixture was cooled to room temperature and the solution was taken to pH 12 with 1 N NaOH and the solution was filtered. The filtrate was the taken to pH 3.0 with 1 N HCl and the desired product was extracted into ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced vacuum to yield 1.20 gm of a dark oil. This two spot material was purified via silica gel chromatography employing the Chromatotron and using a 4000 micron rotor while eluting with a solvent of methylene chloride/ethyl acetate 9:1. Collection of the bottom spot provided the intermediate title compound (200 mg, 20%) as a slowly crystallizing oil. Ion spray M.S. 272.4 (M*−1).
Reaction SMILES: C([O:5][C:6](=[O:34])[C:7]([CH3:33])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[N:14]=1)[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:33][C:7]([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[N:14]=1)([CH3:8])[C:6]([OH:34])=[O:5]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(-c3ccc([N+](=O)[O-])cc3)cc2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Sc1nc(CCOc2ccc(-c3ccc([N+](=O)[O-])cc3)cc2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a solution of 2-methyl-2-[(4-{2-[(4′-nitrobiphenyl-4-yl)oxy]ethyl}-1,3-thiazol-2-yl)thio]propionic acid tert-butyl ester (3.3 g) synthesized in Example 733-1 in dichloromethane (10 mL) was added trifluoroacetic acid (30 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, poured into water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure. Thereto was added diisopropyl ether, and the resulting crystals were collected by filtration to give the title compound (2.4 g) as yellow crystals.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([N:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:24][CH2:25][OH:26])[C:16]4[CH2:22][NH:21][CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.Cl.[CH3:41][N:42]([CH2:44][C:45](Cl)=[O:46])[CH3:43]>CO.ClCCl>[CH3:41][N:42]([CH3:43])[CH2:44][C:45]([N:21]1[CH2:20][CH2:19][C:17]2[N:18]=[C:13]([NH:12][C:9]3[CH:10]=[CH:11][C:6]([C:5]4[O:1][CH:2]=[N:3][CH:4]=4)=[CH:7][CH:8]=3)[N:14]=[C:15]([N:23]([CH2:24][CH2:25][OH:26])[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:16]=2[CH2:22]1)=[O:46]
Reactant: CN(C)CC(=O)Cl
Reactant: OCCN(c1ccccc1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CNCC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CN(C)CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCO)c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.1 %

Procedure:
2-((2-(4-(Oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (100 mg, 0.23 mmol, Example 1) was dissolved in methanol (0.5 mL) and dichloromethane (5 mL). Triethylamine (0.033 mL, 0.23 mmol) was added followed by dimethylaminoacetyl chloride hydrochloride (43.4 mg, 0.23 mmol). The reaction mixture was stirred at room temperature for 1 h and the solvent was evaporated under reduced pressure. The crude was dissolved in dimethylformamide filtered and purified by preparative HPLC yielding 2-(dimethylamino)-1-(4-((2-hydroxyethyl)(phenyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (27.3 mg, 20.39%).
Reaction SMILES: [CH:1]12[N:8]([C:9]3[C:14]([CH2:15][O:16][C:17]4[C:26]5[C:25](=O)[O:24]C(C)(C)[O:22][C:21]=5[CH:20]=[CH:19][CH:18]=4)=[CH:13][CH:12]=[CH:11][N:10]=3)[CH:5](CC1)[CH2:4][O:3][CH2:2]2.[CH3:30][CH:31](C[AlH]CC(C)C)C.CO.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C(Cl)Cl>[CH:4]12[O:3][CH:2]([CH2:30][CH2:31]1)[CH2:1][N:8]([C:9]1[C:14]([CH2:15][O:16][C:17]3[CH:18]=[CH:19][CH:20]=[C:21]([OH:22])[C:26]=3[CH:25]=[O:24])=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:5]2
Reactant: CC1(C)OC(=O)c2c(OCc3cccnc3N3C4CCC3COC4)cccc2O1
Reactant: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=Cc1c(O)cccc1OCc1cccnc1N1CC2CCC(C1)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
To a cooled (−78° C.) solution of 5-((2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyridin-3-yl)methoxy)-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (0.11 g, 0.28 mmol) in CH2Cl2 was added DIBAL-H (0.85 mL, 1M in CH2Cl2) and reaction mixture was allowed to warm to ambient temperature over 3 hours. The reaction mixture was then cooled (−78° C.) and MeOH was added followed by saturated potassium sodium tartrate solution (300 μL). This mixture was stirred for 2 hours at ambient temperature and filtered over Celite. The resulting solution was partitioned between EtOAc and saturated aqueous NaHCO3 and washed two times with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by preparatory HPLC resulted in 2-((2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)methoxy)-6-hydroxybenzaldehyde (0.025 g, 25% yield). 1H NMR (400 MHz, Chloroform-d) δ 11.95 (s, 1H), 10.39 (d, J=0.6 Hz, 1H), 8.32 (dd, J=4.8, 1.9 Hz, 1H), 7.74 (dd, J=8.0, 2.1 Hz, 1H), 7.40 (t, J=8.4 Hz, 1H), 7.00 (dd, J=7.5, 4.8 Hz, 1H), 6.56 (d, J=8.5 Hz, 1H), 6.39 (d, J=8.3 Hz, 1H), 5.15 (s, 2H), 4.47-4.40 (m, 2H), 3.33 (dd, J=12.5, 2.0 Hz, 2H), 3.03 (dd, J=12.3, 1.4 Hz, 2H), 2.13-1.94 (m, 4H). MS (ES) for C19H20N2O4: 341 (MH+).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[CH2:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:26]([F:29])([F:28])[F:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([O:37][CH3:38])=[O:36].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[CH2:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=1)[O:25][CH2:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([O:37][CH3:38])=[O:36])=[CH:15][CH:14]=[CH:13][C:12]=2[C:26]([F:28])([F:29])[F:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc(Cc2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1cccc(COc2cccc(Cc3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1
Yield: 50.9 %

Procedure:
3-{[3-Benzyl-8-(trifluoromethyl)quinolin-4-yl]methyl}phenol (0.100 g, 0.254 mmol), methyl 3-bromomethylbenzoate (0.058 g, 0.254 mmol) and Cs2CO3 (0.331 g, 1.02 mmol) in acetonitrile (4 mL) are stirred 18 h. The reaction is filtered and then purified using Prep HPLC (10 to 100% acetonitrile/water gradient) to afford 0.070 g of the title compound as a colorless oil. 1H NMR (CDCl3) δ 8.96 (s, 1H), 8.12 (d, J=8.6 Hz, 1H), 8.02 (m, 2H), 7.97 (d, J=7.7 Hz, 1H), 7.5 (m, 2H), 7.42 (m, 1H), 7.18 (m, 6H), 6.80 (dd, J=8.2 and 2.0 Hz, 1H), 6.63 (d, J=7.7 Hz, 1H), 6.51 (s, 1H), 4.96 (s, 2H), 4.45 (s, 2H), 4.19 (s, 2H), 3.92 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[S:8])[NH:6][C:5]2[CH:9]=[CH:10][N:11]=[CH:12][C:4]=2[S:3]1(=[O:14])=[O:13].[C:15](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[CH3:1][N:2]1[C:7]([S:8][CH3:15])=[N:6][C:5]2[CH:9]=[CH:10][N:11]=[CH:12][C:4]=2[S:3]1(=[O:14])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: CN1C(=S)Nc2ccncc2S1(=O)=O
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CSC1=Nc2ccncc2S(=O)(=O)N1C
Reaction time: 1 h

Procedure:
A solution of 2-methyl-3-thioxo-2,3-dihydro-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide (1.0 g) in acetonitrile (20 mL) was supplemented with potassium carbonate (1.0 g), then with methyl iodide (1 mL). After 1 h at room temperature, the solvent was removed by distillation under reduced pressure. The residue was dispersed in water (50 mL) and the suspension was adjusted to pH 5 with formic acid. The insoluble material was collected by filtration, washed with water and dried (yield: 0.8 g); m.p. 135°-138° C. (Compound V).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C@H:5]([OH:25])[CH2:6][C@H:7]([NH:16][C:17]([C:19]1[N:20]=[N:21][N:22]([OH:24])[CH:23]=1)=[O:18])[CH2:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=1)[CH3:2].[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.C([O-])([O-])=O.[K+].[K+].Cl.O1CCOCC1>[Pd].O.CCO>[CH2:1]([O:3][C:4](=[O:26])[C@H:5]([OH:25])[CH2:6][C@H:7]([NH:16][C:17]([C:19]1[N:20]=[N:21][N:22]([OH:24])[CH:23]=1)=[O:18])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:27])[CH:33]=2)=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](O)C[C@@H](Cc1ccc(Br)cc1)NC(=O)c1cn(O)nn1
Reactant: OB(O)c1cccc(Cl)c1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cn(O)nn1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
(2R,4R)-5-(4-Bromo-phenyl)-2-hydroxy-4-[(1-hydroxy-1H-1,2,3-triazole-4-carbonyl)-amino]-pentanoic acid ethyl ester (120 mg, 281 μmol) and 3-chlorophenylboronic acid, pinacol ester (120 mg, 506 μmol) were combined with K2CO3 (116 mg, 842 μmol), EtOH (3 mL), and water (0.8 mL). SilicaCat®DPP-Pd (280 μmol/g loading; 1 mg, 28 μmol) was then added and the mixture was heated at 90° C. and the reaction monitored by LC/MS. The reaction was stopped after 2 hours, and the mixture was filtered, concentrated and purified (C18 reverse phase column; 30-70% MeCN in water with 0.05% TFA). EtOH (5.0 mL, 86 mmol) and 4 M HCl in dioxane (1.5 mL, 6.0 mmol) was added and the resulting mixture was stirred at room temperature for 40 minutes, then concentrated and purified (C18 reverse phase column; 30-90% MeCN in water with 0.05% TFA) to yield the title compound (20 mg; purity 95%). MS m/z [M+H]+ calc'd for C22H23ClN4O5, 459.14. found 459.4.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:12]([NH2:14])=O>O>[Br:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:12][NH:14][C:4]2=[O:5]
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: NC=O
Solvent: O
Product: O=c1[nH]cnc2ccc(Br)cc12
Temperature: 180 °C
Yield: 90 %

Procedure:
2-Amino-5-Bromo-benzoic acid (10.817 g, 50 mmol) was suspended in 70 ml formamide. The mixture was heated at 180° C. for 7 hrs. The cooled solution was diluted with 100 ml cold water and filtered. The tan solid was washed with di water and used for the next step reaction without further purification. 10.2 g product was obtained. Yield: 90%. 1H NMR (500 MHz, DMSO-d6): δ 7.61430–7.63179(d, J=8.745 Hz, 1H), 7.94922–7.97149 (dd, J1=8.75 Hz, J2=2.385 Hz, 1H), 8.142421(s, 1H), 8.19136–8.19609(d, J=2.365 Hz, 1H); ESI-MS: m/z 225, 227(M++1)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[F:23][C:24]([F:39])([F:38])[C:25]1[CH:26]=[CH:27][C:28]([N:31]2[CH2:36][CH2:35][NH:34][C:33](=[O:37])[CH2:32]2)=[N:29][CH:30]=1>>[CH3:11][N:8]1[C:9]2[CH:10]=[C:2]([N:34]3[CH2:35][CH2:36][N:31]([C:28]4[CH:27]=[CH:26][C:25]([C:24]([F:38])([F:39])[F:23])=[CH:30][N:29]=4)[CH2:32][C:33]3=[O:37])[CH:3]=[CH:4][C:5]=2[C:6]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]1=2
Reactant: O=C1CN(c2ccc(C(F)(F)F)cn2)CCN1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Product: Cn1c2c(c3ccc(N4CCN(c5ccc(C(F)(F)F)cn5)CC4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 18.1 %

Procedure:
tert-Butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (300 mg, 0.821 mmol) and 4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-2-one (184 mg, 0.751 mmol) were reacted according to Example 2 (step f) to provide the title compound (72 mg, 18%): ESI MS m/z 530 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22](=[O:24])[CH3:23])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25]>O1CCOCC1>[ClH:25].[ClH:25].[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[CH:16]=[C:17]([NH:21][C:22](=[O:24])[CH3:23])[CH:18]=[CH:19][CH:20]=2)[CH2:12][CH2:13]1
Reactant: CC(=O)Nc1cccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(NC2CCNCC2)c1

Procedure:
A solution of 4-(3-acetylamino-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.21 g, 0.63 mmol) in 4 M HCl in dioxane (10 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 234.4 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:37])=[CH:21][N:20]=1>>[CH2:1]([O:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][C:19]3[N:24]=[C:23]([NH:25][C:26]4[C:27]([C:28](=[O:29])[NH:30][CH3:31])=[CH:32][CH:33]=[CH:34][C:35]=4[F:36])[C:22]([Cl:37])=[CH:21][N:20]=3)=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCCOc2cc(N)ccc21
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CCOC(=O)N1CCCOc2cc(Nc3ncc(Cl)c(Nc4c(F)cccc4C(=O)NC)n3)ccc21

Procedure:
3-[5-Chloro-4-(2-fluoro-6-methylcarbamoyl-phenylamino)-pyrimidin-2-ylamino]-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid ethyl ester was prepared from 3-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid ethyl ester and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 1410. Product isolated as a yellow foam (135 mg, 66%). LCMS (m/e) 515 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.95-8.72 (m, 1H), 8.09 (s, 1H), 7.44-7.17 (m, 4H), 7.15-6.84 (m, 3H), 6.30-6.10 (m, 1H), 4.32-3.95 (m, 4H), 3.87-3.60 (m, 2H), 3.00-2.85 (m, 3H), 2.13-1.98 (m, 2H), 1.41-1.11 (m, 3H); 19F-NMR (CDCl3, 400 MHz) δ −111.
Reaction SMILES: O(CC(O)=O)C1C=CC=CC=1.N[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][N:21]=1)[C:16]([NH2:18])=[O:17].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:16]([NH2:18])(=[O:17])[C:15]1[CH:19]=[CH:20][N:21]=[CH:13][CH:14]=1
Reactant: NC(=O)c1ccnc(N)c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)COc1ccccc1
Solvent: CO
Solvent: CN(C)C=O
Product: NC(=O)c1ccncc1
Temperature: 25 °C
Yield: 65.6 %

Procedure:
To solution of (phenoxy-acetic acid (100 mg, 0.65 mmol), 2-amino isonicotinamide (180 mg, 1.31 mmol) and DMAP (160 mg, 1.31 mmol) in DMF 5 ml was added PyBOP (684 mg, 1.31 mmol), and stirred room temperature. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by PLC (EtOAc:n-Hexanes:MeOH=1:2:1˜1:2:2) to afford 242-phenoxy-acetylamino)-isonicotinamide as a colorless solid (0.105 g, 58.9% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([N:30]4[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]4)[C:17]4[CH2:22][CH2:21][CH:20]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:43][CH3:44])[CH:6]=1.[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46]>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([N:30]4[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]4)[C:17]4[CH2:22][CH2:21][CH:20]([C:23]5[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:43][CH3:44])[CH:6]=1.[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46]
Reactant: COc1cc(Nc2nc3c(c(N4CCN(C(=O)OC(C)(C)C)CC4)n2)CCC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Nc2nc3c(c(N4CCNCC4)n2)CCC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (Intermediate 31-1) (167 mg, 0.270 mmol) in DCM (5 mL) was added TFA (500 μL, 6.49 mmol). The reaction mixture was stirred at RT for 1 h. The mixture was then concentrated in vacuo. Purification by prep HPLC (Waters Sunfire C18, 50×250 mm, MeOH/H2O/TFA) gave N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine, TFA (39 mg, 0.062 mmol, 22.78% yield) as a brown oil. LC-MS (M+H)+=520.3. 1H NMR (500 MHz, MeOD) δ ppm 7.83 (1H, br. s.), 7.28-7.46 (5H, m), 7.08-7.21 (3H, m), 4.41-4.53 (1H, m), 4.18-4.28 (4H, m), 3.80 (3H, s), 3.44 (5H, d, J=4.27 Hz), 3.24-3.31 (1H, m), 3.12-3.23 (1H, m), 2.69-2.82 (1H, m), 2.06-2.22 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[CH:12]1([C:18](Cl)=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([C:18]2[NH:11][S:8](=[O:9])(=[O:10])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: O=C(Cl)C1CCCCC1
Product: O=S1(=O)NC(C2CCCCC2)=Nc2ccccc21

Procedure:
2-Aminobenzenesulfonamide was transformed by Method E (using cyclohexanecarbonyl chloride).