Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C@@H:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4]2[CH:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:18]([CH3:20])=[CH:19][C:3]1=2.C1(P([N:39]=[N+:40]=[N-:41])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:39]([C@H:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4]2[CH:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:18]([CH3:20])=[CH:19][C:3]1=2)=[N+:40]=[N-:41]
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@H]2O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N=[N+]=[N-]
Yield: 84.2 %

Procedure:
Heat a mixture of (R)-tert-butyl 5-hydroxy-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (1.60 g, 4.65 mmol), diphenylphosphoryl azide (DPPA, 1.4 mL, 6.50 mmol) and DBU (1.0 mL, 6.50 mmol) in toluene (20 mL) at 65° C. under nitrogen for 12 h. Add silica gel to the cooled mixture and remove the solvents under reduced pressure. Purify the residue by column chromatography, eluting with ethyl acetate/hexanes (1:2), to provide the title compound as a colorless oil (1.45 g, 85%). APCI MS m/z 356 (M−N2)−.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][C:7]=1[CH:15]=O.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][C:19]1=[O:27].N1CCCCC1>C(O)C>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][C:7]=1[CH:15]=[C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:18][C:19]1=[O:27]
Reactant: O=C1Cc2ccccc2N1
Reactant: CN(C)CCCc1c(C=O)[nH]c2c1CCCC2
Solvent: CCO
Solvent: C1CCNCC1
Product: CN(C)CCCc1c(C=C2C(=O)Nc3ccccc32)[nH]c2c1CCCC2
Temperature: 25 °C
Yield: 68.6 %

Procedure:
3-(3-Dimethylaminopropyl)-2-formyl-4,5,6,7-tetrahydro-1H-indole (1.8 g), 1 g of 2-oxindole and 0.1 g of piperidine in 10 mL of ethanol was refluxed for 4 hours and then cooled to room temperature. The precipitate which formed was collected by vacuum filtration and washed with 4 mL of ethanol. The solids were slurry-washed with 8 mL of refluxing ethanol, cooled, collected by vacuum filtration, washed with 3 mL of ethanol and vacuum dried to give 1.8 g (70% yield) of 3-[3-(3-dimethylaminopropyl)-4,5,6,7-tetrahydro-1H-indol-2-ylmethylene]-1,3-dihydroindol-2-one as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])[CH:5]=[CH:4][N:3]=1.[N:27]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([NH:22][S:33]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)(=[O:35])=[O:34])[CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)N1CCOCC1
Reactant: Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)N1CCOCC1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline (150 mg, 0.383 mmol) and 4-morpholinesulfonyl chloride (142 mg, 0.766 mmol) the title compound of Step A was obtained as a yellow foam (96 mg, 46% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.78-10.01 (m, 1H), 8.34 (d, J=5.5 Hz, 1H), 7.58 (td, J=7.4, 2.4 Hz, 1H), 7.17-7.41 (m, 2H), 6.57-6.68 (m, 1H), 3.68 (t, J=4.7 Hz, 4H), 3.42-3.63 (m, 8H), 2.91-3.11 (m, 4H).
Reaction SMILES: [CH3:1][CH:2]([CH2:23][CH3:24])[CH:3]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20].[H][H]>[Pt]=O.C(O)(=O)C>[CH3:1][CH:2]([CH2:23][CH3:24])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: [H][H]
Reactant: CCC(C)C=CCCCCCCCCCCCCCCC(=O)OC
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CCC(C)CCCCCCCCCCCCCCCCC(=O)OC
Yield: 56.3 %

Procedure:
5.3 gm of methyl 18-methyl-16-eicosenoate charged into an autoclave together with 0.3 gm of platinum oxide and 30 ml of acetic acid were reduced under 100 atm hydrogen pressure at 100° C. for 5 hours. After the reaction, the catalyst was removed by filtration and the solvent was evaporated to obtain 3 gm of methyl 18-methyleicosanoate, which was purified by flash column chromatography (chloroform). The product was dissolved into 150 ml of a 5% sodium hydroxide-ethanol solution and stirred at room temperature for 8 hours. Then, 95 ml of 2N sulfuric acid was added to obtain a solid. The solid material was filtered and washed with water to obtain 3.1 gm of 18-methyleicosanoic acid (yield: 59% from methyl 18-methyl-16-eicosenoate).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)=O.[C:16]([NH:19][C:20]([NH2:22])=[S:21])(=[NH:18])[NH2:17]>C(O)C>[NH:19]([C:20]1[S:21][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]3)[N:22]=1)[C:16]([NH2:18])=[NH:17]
Reactant: N=C(N)NC(N)=S
Reactant: O=C1CCc2cc(C(=O)CCl)ccc2N1
Solvent: CCO
Product: N=C(N)Nc1nc(-c2ccc3c(c2)CCC(=O)N3)cs1

Procedure:
A mixture of 6-(chloroacetyl)-3,4-dihydrocarbostyril (7 g), amidinothiourea (3.8 g) and absolute ethanol (250 ml) is stirred under reflux for about 24 hours. The reaction mixture is cooled to ice bath temperature and the precipitate filtered, washed with ethanol, and dried. The solid is suspended in aqueous sodium hydroxide, filtered, the filtered solid washed with water, and dried in vacuo. The dried solid is recrystallized from 50% aqueous DMF, and dried in vacuo yielding the desired product, M.P. >250° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([C:8]1[CH:9]=[CH:10][C:11]([O:18][CH3:19])=[C:12]2[C:17]=1[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:7])[CH3:6].S(=O)(=O)(O)O>C(OC(=O)C)(=O)C>[C:5]([C:8]1[CH:9]=[C:10]([N+:1]([O-:4])=[O:2])[C:11]([O:18][CH3:19])=[C:12]2[C:17]=1[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:7])[CH3:6]
Reactant: COc1ccc(C(C)=O)c2c1CCCC2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: COc1c([N+](=O)[O-])cc(C(C)=O)c2c1CCCC2
Reaction time: 0.33 h
Yield: 59.4 %

Procedure:
A solution of 100% nitric acid (0.42 ml, 10 mmol) in 2 ml of acetic anhydride was added dropwise with stirring at <10° to <15° C. to a solution of 8-acetyl-1,2,3,4-tetrahydro5-methoxynaphthalene (2.1 g, 10 mmol) in 25 ml of acetic anhydride containing one drop of conc. sulfuric acid. Stirring was continued for 20 min. at the same temperature, then the reaction mixture was poured into 100 ml of icewater. The precipitated crystals were collected by filtration and washed with water and a small amount of cold ethanol to give 1.48 g (59%) of the title compound. M.p. 76°-77° C.; 1H-NMR (CDCl3) 1.60-1.93 (m, 4H, 2CH2), 2.57 (s, 3H, COCH3), 2.67-3.13 (m, 4H, 2CH2), 3.88 (s, 3H, OCH3), 7.97 (s, 1H, H-7).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:12])=[CH:5][CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1.[F:13][C:14]([F:19])([F:18])[C:15](O)=O.C(=O)(O)[O-]>Cl.C(Cl)Cl>[CH3:1][N:2]1[C:3]2[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=2[N:12]=[C:15]1[C:14]([F:19])([F:18])[F:13]
Reactant: CNc1cc([N+](=O)[O-])ccc1N
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)nc2ccc([N+](=O)[O-])cc21
Temperature: 70 °C
Yield: 20.4 %

Procedure:
A 250 ml round bottomed flask was charged with N1-methyl-5-nitrobenzene-1,2-diamine (29 g, 0.16 mol), trifluoroacetic acid (22 ml, 0.24 mol) and a few drops of concentrated HCl. A minimum amount of DCM (˜20 ml) was added so that the solid mixture was stirring. The reaction mixture was heated to 70° C. for 12 hours forming a dark brown liquid. The reaction mixture was allowed to cool to room temperature, basified by the slow addition of saturated bicarbonate solution, and extracted into ethyl acetate. The aqueous layer was further extracted twice with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The compound was purified by flash column chromatography (10 to 20% ethyl acetate/petrol) to afford the title compound (8 g, 20% yield). 1H NMR (DMSO D6, 400 MHz) 4.2 (3H, s), 8.05 (1H, d), 8.35 (1H, d), 8.55 (1H, s); MS (ES+) 246.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1.[CH3:16][C:17]1[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=[CH:19][N:18]=1.C([O-])([O-])=O.[Na+].[Na+]>O.COCCOC>[F:14][C:6]1[C:5]([CH3:15])=[C:4]2[C:9]([CH:10]=[C:11]([CH:12]=[O:13])[C:2]([C:22]3[C:17]([CH3:16])=[N:18][CH:19]=[CH:20][CH:21]=3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: Cc1c(F)ccc2cc(C=O)c(Cl)nc12
Reactant: Cc1ncccc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ncccc1-c1nc2c(C)c(F)ccc2cc1C=O
Temperature: 90 °C
Yield: 90.5 %

Procedure:
A mixture of 2-chloro-7-fluoro-8-methylquinoline-3-carbaldehyde (8.0 g, 35.77 mmol), 2-methylpyridin-3-ylboronic acid pinacol ester (9.58 g, 39.35 mmol), tetrakis-(triphenylphosphine)palladium(0) (207 mg, 18 mmol) and Na2CO3 (5.69 g, 53.66 mmol) in water (50 mL) and DME (100 mL) was degassed and flushed three times with nitrogen gas, then heated at 90° C. for 24 h. The mixture was allowed to cool to room temperature. The reaction mixture was diluted with DCM (150 mL) and washed with water (150 mL). The aqueous phase was extracted with DCM (2×100 mL) and the combined organic fractions were washed with brine (150 mL), then dried (phase separator) and evaporated in vacuo. The crude material was triturated in hexane (50 mL), then the solid was filtered off and dried under vacuum to give the title compound (9.07 g, 90%) as a pale yellow solid. δH (DMSO-d6) 9.94 (s, 1H), 9.09 (1H, s), 8.61 (dd, J 4.9, 1.7 Hz, 1H), 8.26 (dd, J 8.9, 6.4 Hz, 1H), 7.78 (dd, J 7.7, 1.7 Hz, 1H), 7.69 (t, J 9.2 Hz, 1H), 7.40 (dd, J 7.7, 4.9 Hz, 1H), 2.61 (d, J 2.4 Hz, 3H), 2.34 (s, 3H). LCMS (ES+) 281 (M+H)+, RT 2.26 minutes.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)=[O:6].[C-:14]#[N:15].[K+]>CO.C(OCC)(=O)C>[C:9]1([CH3:13])[CH:10]=[CH:11][CH:12]=[C:7]([C:5]2([C:14]#[N:15])[CH2:4][CH2:3][CH2:2][O:6]2)[CH:8]=1
Reactant: [C-]#N
Reactant: Cc1cccc(C(=O)CCCCl)c1
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cccc(C2(C#N)CCCO2)c1
Temperature: 35 °C

Procedure:
To a solution of Example 91B (1.56 g, 8 mmol) in MeOH (15 mL) was carefully added KCN (0.8 g, 12.3 mmol) and the mixture was warmed at 35° C. for 48 hours. The mixture was diluted with 50 mL ethyl acetate, washed with conccentrated aqueous NaHCO3 (20 mL) and brine (10 mL). The aqueous solution was oxidized with excessive NaC100. The organic phase was dried over MgSO4, filtered, and concentrated to give the title compound as an oil which was used directly for the next step (1.35 g, 90%). LC-MS: m/z (M+H): 161.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:3]=1.[Br:13]Br.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[Br:13][C:10]1[S:9][C:8]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=2)=[CH:12][CH:11]=1
Reactant: Clc1ccnc(-c2cccs2)c1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Clc1ccnc(-c2ccc(Br)s2)c1
Reaction time: 6 h

Procedure:
To a solution of 4-chloro-2-thiophen-2-yl-pyridine (195 mg, 0.55 mmol) in CH2Cl2 (2 mL) was added Br2 (1 M in CH2Cl2, 0.6 mL). After 6 h, the resulting mixture was treated with Na2S2O3 (1 M in water, 1 mL), stirred for 10 min, and extracted with CH2Cl2. The organic layer was dried and concentrated, and the resulting crude product was recrystallized from EtOH to yield 2-(5-bromo-thiophen-2-yl)-4-chloro-pyridine as a solid.
Reaction SMILES: ClC1C=CC(O[CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[N:21]([CH3:27])[N:22]=[C:23]([CH2:25][CH3:26])[CH:24]=3)=[O:18])[CH2:14][OH:15])[CH2:8]2)=CC=1.Cl.N[C@@H](CCN1CC([C:41](=[O:50])[C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([F:49])[CH:43]=2)C1)CO>>[Cl:48][C:45]1[CH:46]=[CH:47][C:42]([C:41]([CH:7]2[CH2:8][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[N:21]([CH3:27])[N:22]=[C:23]([CH2:25][CH3:26])[CH:24]=3)=[O:18])[CH2:14][OH:15])[CH2:10]2)=[O:50])=[CH:43][C:44]=1[F:49]
Reactant: N[C@H](CO)CCN1CC(C(=O)c2ccc(Cl)c(F)c2)C1
Reactant: CCc1cc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)cc3)C2)n(C)n1
Agent: Cl
Product: CCc1cc(NC(=O)N[C@H](CO)CCN2CC(C(=O)c3ccc(Cl)c(F)c3)C2)n(C)n1

Procedure:
This compound is prepared analogously to 1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-2-methyl-2H-pyrazol-3-yl)-urea in Example 88 except using (S)-2-amino-4-[3-(4-chloro-3-fluoro-benzoyl)-azetidin-1-yl]-butan-1-ol hydrochloride in place of (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol hydrochloride.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH:8]1[C:17](=O)[C:16]2[C:15]([C:19](OCC)=[O:20])=[CH:14][CH:13]=[CH:12][C:11]=2[NH:10][CH:9]1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[CH3:2].O.[NH2:32][NH2:33]>CO>[CH2:1]([N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH:8]1[C:17]2=[N:32][NH:33][C:19](=[O:20])[C:15]3[CH:14]=[CH:13][CH:12]=[C:11]([C:16]=32)[NH:10][CH:9]1[C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1CC)C(c1ccc(F)cc1)N2
Reactant: NN
Solvent: CO
Solvent: O
Product: CCn1ccnc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47 %

Procedure:
A mixture of ethyl 3-(1-ethyl-1H-imidazol-2-yl)-2-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (90 mg, 0.22 mmol) in 85% hydrazine monohydrate (4 mL) and methanol (10 mL) was stirred for 4 h at room temperature. Methanol was removed under reduced pressure. The mixture was filtered and washed with water to give the crude product. The crude product was purified by prep-HPLC to give the title compound (38.5 mg, yield: 47%). 1H-NMR (400 MHz, MeOD) δ (ppm): 1.06-1.09 (t, J=7.2 Hz, 3H), 3.74-3.78 (m, 2H), 4.60-4.62 (d, J=11.6 Hz, 1H), 4.98-5.01 (d, J=11.6 Hz, 1H), 6.91-7.02 (m, 4H), 7.19-7.21 (m, 1H), 7.39-7.43 (m, 2H), 7.56-7.64 (m, 2H); LC-MS (ESI) m/z: 376 (M+1)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:19](Cl)=[O:20])[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2.Cl.[F:23][C:24]([F:28])([F:27])[CH2:25][NH2:26].C(N(CC)CC)C>ClCCl>[F:23][C:24]([F:28])([F:27])[CH2:25][NH:26][C:19]([C:6]1([CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:20]
Reactant: NCC(F)(F)F
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
23 g (0.063 mol) of 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride are added dropwise to a solution of 9.35 g (0.069 mol) of 2,2,2-trifluoroethylamine-hydrochloride and 26 ml (0.188 mol) of triethylamine in 550 ml of dichloromethane at 0° C. under nitrogen and stirred for 2 hours at ambient temperature. The reaction mixture is extracted twice each with water, 1N hydrochloric acid and sodium hydrogen carbonate solution. The organic phase is dried over sodium sulphate and the solvent is distilled off. The product is purified by column chromatography on silica gel (eluant: cyclohexane/ethyl acetate=8:1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([OH:7])=O.Cl.[CH3:13][O:14][C:15](=[O:21])[C@H:16]([C@@H:18]([CH3:20])[OH:19])[NH2:17].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>ClCCl>[CH3:13][O:14][C:15](=[O:21])[C@H:16]([C@@H:18]([CH3:20])[OH:19])[NH:17][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([CH3:11])[CH:10]=[C:2]([CH3:1])[CH:3]=1
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Reactant: Cc1cc(C)cc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)c1cc(C)cc(C)c1)[C@@H](C)O
Reaction time: 0.17 h

Procedure:
1.00 g (6.66 mmol/1 eq) of 3,5-dimethylbenzoic acid and 1.13 g (6.66 mmol/1 eq) of L-threonine methyl ester hydrochloride are suspended in 50 ml dichloromethane. At 0° C., 2.04 ml (14.7 mmol/2.2 eq) of triethylamine are added dropwise. After 10 minutes' stirring, 2.55 g (13.3 mmol/2 eq) of N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (EDC) are added, and after a further 15 min 1-hydroxybenzotriazole (HOBt) is added. Stirring is carried out for twelve hours, the solution assuming room temperature. The organic phase is washed with 10 ml each of H2O, hydrochloric acid (2N), and NaHCO3 solution. After drying over magnesium sulfate, the solvent is removed in vacuo. 1.70 g (6.41 mmol/96%) of a white solid are obtained, which may, if desired, be recrystallised from absolute diethyl ether.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[F:23][C:24]1[CH:25]=[C:26]([NH2:31])[CH:27]=[CH:28][C:29]=1[F:30]>>[F:23][C:24]1[CH:25]=[C:26]([NH:31][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: Nc1ccc(F)c(F)c1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(Nc2ccc(F)c(F)c2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (3,4-difluorophenyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a light-yellow solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.05 (s, 3H), 2.32 (s, 3H), 4.70 (d, J=5.5 Hz, 2H), 5.87 (bs, 1H), 6.32 (bs, 1H), 6.95-7.05 (m, 2H), 7.16 (t, J=7.0 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.57-7.66 (m, 2H), 8.58 (d, J=3.6 Hz, 1H); MS (ESI) m/z 342.7 (M+1)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][C:21](=[O:33])[C:22]1[CH:31]=[C:30]([NH2:32])[CH:29]=[C:24]([C:25]([O:27][CH3:28])=[O:26])[CH:23]=1>C(Cl)Cl.N1C=CC=CC=1>[CH3:28][O:27][C:25](=[O:26])[C:24]1[CH:29]=[C:30]([NH:32][S:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH:31]=[C:22]([C:21]([O:20][CH3:19])=[O:33])[CH:23]=1
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc(OCc3ccccc3)cc2)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Benzyloxy-benzenesulfonyl chloride (7.35 g, 26.0 mmol) was added in small portions to a suspension of 5-amino isophtalic acid dimethyl ester (5.23 g, 25.0 mmol) in DCM (100 ml) and pyridine (10 ml). The resulting clear yellow solution was stirred for 2 hours at room temperature, the volatile solvents were removed under reduced pressure, the solid residue was suspended in MeOH (125 ml) and the mixture was heated to reflux for 10 minutes. The off white solid was filtered off, washed with water and cold MeOH and dried under high vacuum. Yield 10.93 g (96%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:10][C:8](=[O:9])[NH:7][C:5]=2[CH:6]=1.[CH2:11]([NH:13][CH2:14][CH3:15])[CH3:12]>>[OH:10][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[NH:7][C:8]([N:13]([CH2:14][CH3:15])[CH2:11][CH3:12])=[O:9]
Reactant: O=c1[nH]c2ccccc2o1
Reactant: CCNCC
Product: CCN(CC)C(=O)Nc1ccccc1O

Procedure:
Benzoxazolinone (1 mole) was stirred with 2 moles of diethylamine (dissolved in industrial alcohol) at 50° C. for 48 hours, then the alcohol and excess of diethylamine were distilled off under reduced pressure at below 60° C. The residue was taken up in acetone, the desired product was precipitated by adding water and then it was filtered off and dried under reduced pressure at 80° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[C:31]=1[CH2:32][NH2:33]>ClCCl>[CH3:39][O:38][C:34]1[CH:35]=[CH:36][CH:37]=[C:30]([O:29][CH3:28])[C:31]=1[CH2:32][NH:33][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: COc1cccc(OC)c1CN
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(OC)c1CNC(=O)c1ccccc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
4 g 2-nitrobenzoic acid (23.93 mmol) and 2.42 g triethylamine were dissolved in 100 mL dichloromethane, mixed with one equivalent isobutyl chloroformate (3.27 g) at 5° C. and stirring was continued for 1 hour at room temperature. Then the mixture was cooled again to 5° C., 4.02 g 2,6-dimethoxybenzylamine was added and the mixture was stirred at room temperature until the reaction was complete. For workup, the mixture was diluted with dichloromethane, washed twice each with 10% citric acid, saturated NaHCO3 and saturated NaCl solution, dried with MgSO4, filtered and concentrated, yielding 7.5 g beige solids that were reacted further directly without any further workup.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:17]=[C:16]2[C:8]([C:9]3[C:10](B4OC(C)(C)C(C)(C)O4)=[CH:11][CH:12]=[C:13]([C:18]([NH2:20])=[O:19])[C:14]=3[NH:15]2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].Br[C:31]1[C:32]([CH3:49])=[C:33]([NH:37][C:38]2[C:47]3[C:42](=[C:43]([F:48])[CH:44]=[CH:45][CH:46]=3)[N:41]=[CH:40][N:39]=2)[CH:34]=[CH:35][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[F:48][C:43]1[CH:44]=[CH:45][CH:46]=[C:47]2[C:42]=1[N:41]=[CH:40][N:39]=[C:38]2[NH:37][C:33]1[C:32]([CH3:49])=[C:31]([C:10]2[C:9]3[C:8]4[C:16](=[CH:17][C:5]([C:2]([OH:1])([CH3:4])[CH3:3])=[CH:6][CH:7]=4)[NH:15][C:14]=3[C:13]([C:18]([NH2:20])=[O:19])=[CH:12][CH:11]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: Cc1c(Br)cccc1Nc1ncnc2c(F)cccc12
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(B3OC(C)(C)C(C)(C)O3)c12
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: CCO
Solvent: Cc1ccccc1
Product: Cc1c(Nc2ncnc3c(F)cccc23)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(C(C)(C)O)ccc3c12
Temperature: 90 °C
Yield: 65.4 %

Procedure:
Step 2 A mixture of 7-(2-hydroxypropan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole-1-carboxamide (ca. 60% purity, 35 mg, 0.053 mmol), N-(3-bromo-2-methylphenyl)-8-fluoroquinazolin-4-amine (Intermediate 32-7, 17.69 mg, 0.053 mmol), and 2 M aqueous sodium carbonate (0.067 mL, 0.133 mmol) in toluene (0.8 mL) and ethanol (0.200 mL) was purged with argon, treated with tetrakis(triphenylphosphine)palladium (3.1 mg, 0.003 mmol) and heated at 90° C. in a sealed tube for 16.5 h. The mixture was cooled to rt and concentrated. The residue was purified by preparative HPLC and the appropriate effluent fractions were treated with NaHCO3 (aq) and partially concentrated at rt. The resulting aqueous suspension was filtered and the precipitate was washed with water and dried to provide 4-(3-(8-fluoroquinazolin-4-ylamino)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide as a white solid (18.0 mg, 61%). 1H NMR (400 MHz, DMSO-d6) δ 11.41 (1H, s), 10.08 (1H, s), 8.56 (1H, s), 8.35 (1H, d, J=8.4 Hz), 8.16 (1H, br. s.), 7.99 (1H, d, J=7.9 Hz), 7.87 (1H, s), 7.70 (1H, dd, J=10.2, 8.3 Hz), 7.60 (1H, td, J=8.1, 5.2 Hz), 7.42-7.54 (3H, m), 7.28 (1H, dd, J=7.3, 1.3 Hz), 7.11 (2H, s), 7.01 (1H, d, J=7.7 Hz), 5.00 (1H, s), 1.85 (3H, s), 1.49 (6H, s). Mass spectrum m/z 520.1 (M+H)+.