Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[NH:25][N:24]=[C:23]([CH:26]([OH:28])[CH3:27])[CH:22]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[C:29](OC(=O)C)(=[O:31])[CH3:30]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:29]([O:28][CH:26]([C:23]1[CH:22]=[C:21]([C:19](=[O:20])[NH:18][C@@H:16]([CH3:17])[CH2:15][N:12]2[CH:13]=[CH:14][C:10]([C:4]3[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[CH:3]=3)=[N:11]2)[NH:25][N:24]=1)[CH3:27])(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: CC(O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OC(C)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
A flask containing N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide (400 mg, 1.003 mmol) and DMAP (12.25 mg, 0.100 mmol) was put under nitrogen atmosphere. Pyridine (10 ml) was added, the reaction mixture cooled down to 0° C. and acetic anhydride (0.099 ml, 108 mg) was added dropwise. The mixture was allowed to warm to RT and stirred overnight. Next day the mixture was evaporated and purified by flash chromatography. Yield 58.9%. 1H-NMR (400 MHz; DMSO-d6): δ 1.15 (d, 3H), 1.51 (d, 3H), 2.02 (s, 3H), 4.25-4.37 (m, 2H), 4.39-4.49 (m, 1H), 5.88 (q, 1H), 6.64 (s, 1H), 6.90 (dd, 1H), 7.80 (dd, 1H), 7.91-7.96 (m, 2H), 8.04-8.07 (m, 1H), 8.15 (s, 1H), 13.24 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][C@H:14]3[CH2:18][OH:19])=[O:12])[S:10][C:3]=12.[C:20]([Si:24]([CH3:27])([CH3:26])Cl)([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][C@H:14]3[CH2:18][O:19][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:27])[CH3:26])=[O:12])[S:10][C:3]=12
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCC[C@H]1CO
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CCCN1C(=O)c1cc2nccc(Cl)c2s1
Reaction time: 16 h
Yield: 126.5 %

Procedure:
To a stirred solution of 7-chloro-2-[(S)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]thieno[3,2-b]pyridine 3a (4.50 g, 15 mmole) were added t-butyldimethylchlorosilane (3.18 g, 21 mmole) and triethylamine (3.4 ml, 2.47 g, 24 mmole). The resultant reaction mixture was stirred at ambient temperaure for 16 hours. The crude reaction mixture was poured into water (150 ml) and extracted with CH2Cl2 (150 ml). The combined organic extracts were washed with brine (150 ml), dried over Na2SO4 and concentrated, in vacuo, to give 7.8 g of an orange syrup, which was purified by silica gel chromatography. Elution with Et2O:hexane (67:33) and evaporation of the appropriate fractions gave 5.73 g (92%) of an off-white solid. 1H NMR (DMSO-d6): δ 8.72 (1H, d, J=5.0 Hz), 8.07 (1H, s), 7.68 (1H, d, J=5.0 Hz), 4.30–4.15 (1H, m), 3.94–3.67 (4H, m), 2.12–1.81 (4H, m), 0.85 (9H, s), 0.03 (3H, s), 0.00 (3H, s). Anal. Calcd. for C19H27N2O2SClSi: C, 55.52; H, 6.62; N, 6.82; S, 7.80; Cl, 8.63. Found: C, 55.49; H, 6.46; N, 6.92; S, 7.80; Cl, 8.88.
Reaction SMILES: [CH2:1]1[CH2:10][N:9]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=O)[CH2:8][C:7]2[CH:6]=[N:5][C:4]3[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=3[C:2]1=2.C(N(CC)CC)C.CCCP(=O)=O.[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[CH:39]=1>CN(C=O)C>[CH2:1]1[CH2:10][N:9]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[CH:39]=2)=[O:16])[CH2:8][C:7]2[CH:6]=[N:5][C:4]3[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=3[C:2]1=2
Reactant: O=C(O)c1cccc(N2CCc3c(cnc4ccccc34)C2)c1
Reactant: Cc1cccc(N)c1
Agent: CCCP(=O)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc(NC(=O)c2cccc(N3CCc4c(cnc5ccccc45)C3)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48.3 %

Procedure:
To a mixture of 3-(1,4-dihydrobenzo[c]-2,7-naphthyridin-3(2H)-yl)benzoic acid (0.20 mmol, 61 mg) and triethylamine (0.40 mmol, 0.056 mL) in 1.6 mL DMF at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.24 mmol, 0.143 mL). After 15 min at rt, meta-toluidine (0.30 mmol, 0.032 mL) was added and the reaction stirred at rt for 18 hours. The reaction was quenched into dilute aqueous Na2CO3 solution, extracted into EtOAc, the EtOAc layer washed with H2O, dilute aqueous Na2CO3 solution, brine, dried with anhydrous Na2SO4 and concentrated. The resulting solid was chromatographed eluting with CHCl3/EtOAc and then recrystallized from EtOAc/hexane to give the title compound as an off-white solid (38 mg, 48%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=4)[CH:11]=[C:10]([CH3:24])[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(Cl)n2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2)n1

Procedure:
The title compound was prepared from 2-chloro-4-[6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-pyrimidine (example E.83) (0.5 g, 1.432 mmol) and commercially available 3-(tert-butylsulfamoyl)-benzeneboronic acid (0.404 g, 1.575 mmol) according to the general procedure VI. Obtained as a white solid (0.10 g, 13%) and additional off-white solid (0.48 g, 64%). MS (ISP) 527.2 [(M+H)+]; mp 218° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7]C(=O)[C:5]2=[O:15].[OH:16]O.Cl>[OH-].[Na+]>[NH2:7][C:8]1[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]([F:1])=[CH:3][C:4]=1[C:5]([OH:15])=[O:16]
Reactant: O=C1Nc2c(cc(F)cc2[N+](=O)[O-])C1=O
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1c(C(=O)O)cc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.17 %

Procedure:
To a slurry of 5-fluoro-7-nitro-1H-indole-2,3-dione (3 g, 14.2 mmol) in aqueous 5N NaOH solution (30 mL) was added slowly an aq. solution of 33% hydrogen peroxide (3 mL) at 0° C. After completion of the addition, the reaction mixture was stirred at room temperature for 4 h. After completion of the reaction, the reaction mixture was acidified with 2N HCl and the resulting precipitate was filtered, washed with water (2-3 times) and dried under vacuum to obtain the title compound as yellow solid (2 g, 70.17%).
Reaction SMILES: C[O:2][C:3](=[O:42])[C@@H:4]([N:12]1[CH:17]=[C:16]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[CH:15]=[C:14]([NH:28][C:29](=[O:40])[C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[C:13]1=[O:41])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Li+].Cl>O1CCCC1>[C:18]1([C:16]2[CH:15]=[C:14]([NH:28][C:29](=[O:40])[C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:37])([F:38])[F:39])=[CH:32][CH:31]=3)[C:13](=[O:41])[N:12]([C@@H:4]([CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:3]([OH:42])=[O:2])[CH:17]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)n1cc(-c2cccc3ccccc23)cc(NC(=O)c2ccc(C(F)(F)F)cc2)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(Nc1cc(-c2cccc3ccccc23)cn([C@@H](Cc2ccccc2)C(=O)O)c1=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-2-[5-naphthalen-1-yl-2-oxo-3-(4-trifluoromethyl-benzoylamino)-2H-pyridin-1-yl]-3-phenylpropionic acid methyl ester from Step F (31 mg, 0.054 mmol) and 1N lithium hydroxide (2.0 mL) in tetrahydrofuran (2.0 mL) was stirred at room temperature for 1 h. 1N Hydrochloric acid (3 mL) was added and the mixture was extracted with dichloromethane (3×10 mL). The combined organic layer was dried with sodium sulfate, filtered and concentrated in vacuo to give a quantitative yield of the title compound. MS 557.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2](=[O:37])[C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=1.Br[C:39]1[CH:47]=[C:46]2[C:42]([CH2:43][N:44]([CH3:49])[C:45]2=[O:48])=[CH:41][CH:40]=1.C([O-])(=O)C.[K+]>C(#N)C.O>[NH2:1][C:2](=[O:37])[C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:39]2[CH:47]=[C:46]3[C:42](=[CH:41][CH:40]=2)[CH2:43][N:44]([CH3:49])[C:45]3=[O:48])=[CH:9][CH:10]=1
Reactant: CN1Cc2ccc(Br)cc2C1=O
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(N)=O)CCOCC1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CN1Cc2ccc(-c3ccc(C[C@H](NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)C(N)=O)cc3)cc2C1=O
Temperature: 25 °C
Yield: 64.3 %

Procedure:
(S)-tert-Butyl 4-(1-amino-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 16, step (i), 300 mg), 6-bromo-2-methylisoindolin-1-one (Example 30, step (i), 131 mg) and potassium acetate (171 mg) in a mixture of acetonitrile (15 mL) and water (5 mL) was stirred under nitrogen at 90° C. with 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (378 mg). After 4 h the reaction mixture was cooled to room temperature and diluted with water (50 mL). The products were extracted with ethyl acetate (3×50 mL) and the combined extracts dried over magnesium sulfate and concentrated to afford the sub-titled compound (200 mg).
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1B(O)O)[CH3:18]>>[CH2:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[C:2]1[C:3]2[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1)[CH3:18]
Reactant: CCOc1ccc(F)cc1B(O)O
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ncnc12
Product: CCOC(=O)c1c(C)[nH]c2c(-c3cc(F)ccc3OCC)ncnc12

Procedure:
Starting from ethyl 4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example A4) and commercially available 2-ethoxy-5-fluoro-phenyl-boronic acid the title compound is obtained as pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2]>C(Cl)(Cl)Cl.CO>[CH2:9]([C:8]1[NH:11][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=2[N:10]=1)[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCc1nc2ccc([N+](=O)[O-])cc2[nH]1
Yield: 78 %

Procedure:
Prepared from 4-nitrophenylenediamine in a manner similar to that of Example 4c. Yield: 78%; Rf (9/1 chloroform/methanol): 0.70; 1H-NMR (CDCl3) 10.2 (bs, 1H); 8.4 (d, J=1.5 Hz, 1H); 8.1 (dd, J=8.6 Hz, 1.53 Hz, 1H); 7.5 (d, J=8.6 Hz, 1H); 3.0 (t, 2H); 1.90 (m, 2H); 1.6-1.1 (m, 4H); 0.87 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:32]=[CH:31][C:11]3[N:12]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:13]([C:15]4[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=4[N:22]4[CH:26]=[N:25][CH:24]=[N:23]4)=[N:14][C:10]=3[CH:9]=2)=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:40][C:41]([CH3:48])([CH3:47])[C:42]([O:44][CH2:45][CH3:46])=[O:43]>CN(C=O)C>[CH2:45]([O:44][C:42](=[O:43])[C:41]([CH3:48])([CH3:47])[CH2:40][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[N:12]([C:27]([CH3:29])([CH3:28])[CH3:30])[C:11]3[CH:31]=[CH:32][C:8]([C:5]4[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=4)=[CH:9][C:10]=3[N:14]=2)=[C:16]([N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)[CH:17]=1)[CH3:46]
Reactant: CC(C)(C)n1c(-c2ccc(O)cc2-n2cncn2)nc2cc(-c3cnc(N)nc3)ccc21
Reactant: CCOC(=O)C(C)(C)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)COc1ccc(-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c(-n2cncn2)c1
Temperature: 90 °C
Yield: 51.5 %

Procedure:
To a stirred solution of 4-[5-(2-Amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzoimidazol-2-yl]-3-[1,2,4]-triazol-1-yl-phenol (300 mg, 0.7 mmol) in DMF (10 mL) is added cesium carbonate (687 mg, 2.1 mmol) followed by Ethyl 3-chloro-2,2-dimethylpropanoate (231 mg, 1.4 mmol) at room temperature. The solution is heated to 90° C. for 72 hours. The solution is cooled to room temperature and is extracted with H2O (10 mL) and EtOAc (3×10 mL). The combined organic layer is dried with Mg2SO4 (500 mg) and is filtered. The filtrate is concentrated and the residue is purified by silica gel flash column chromatography with 10% MeOH in CH2Cl2 as the eluent to afford the title compound (200 mg, 51%). LCMS (ESMS): m/z: 555.40 (M++1).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[CH2:25]([O:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)c1ccc(Cc2ccccc2O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cc2ccccc2OCc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a suspension of methyl 4-(2-hydroxybenzyl)benzoate (1.5 g) and potassium carbonate (0.94 g) in N,N-dimethylformamide (200 mL) was added benzyl bromide (0.81 mL), and the mixture was stirred at 50° C. for 5 hours. In soluble material was removed by filtration, and to the filtrate was added water and dilute hydrochloric acid. The mixture was extracted with ethylacetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=4/1) to give methyl 4-(2-benzyloxybenzyl)benzoate (2.1 g).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([Cl:18])[C:15]([I:17])=[CH:16][C:11]=2[N:10]=[C:9]1S(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([O:25][P:26]([C:31]1[CH:36]=[C:35]([OH:37])[CH:34]=[CH:33][C:32]=1[CH3:38])(=[O:30])[O:27][CH2:28][CH3:29])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:28]([O:27][P:26]([C:31]1[CH:36]=[C:35]([O:37][C:9]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:12]3[CH:13]=[C:14]([Cl:18])[C:15]([I:17])=[CH:16][C:11]=3[N:10]=2)[CH:34]=[CH:33][C:32]=1[CH3:38])(=[O:30])[O:25][CH2:23][CH3:24])[CH3:29]
Reactant: CCOP(=O)(OCC)c1cc(O)ccc1C
Reactant: CS(=O)(=O)c1nc2cc(I)c(Cl)cc2n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)c1cc(Oc2nc3cc(I)c(Cl)cc3n2Cc2ccccc2)ccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-benzyl-6-chloro-5-iodo-2-methanesulfonyl-1H-benzoimidazole (2.7 g, 6.0 mmol) in DMF (30 ml) was added (5-hydroxy-2-methyl-phenyl)-phosphonic acid diethyl ester (1.9 g, 8.4 mmol), followed by potassium carbonate (1.7 g, 12 mmol). After stirring overnight at rt the volatiles were removed by rotary evaporation. The residue thus obtained was partitioned between EtOAc and half-saturated ammonium chloride solution. The EtOAc layer was washed with H2O, brine, and then dried with MgSO4. The crude oil was then purified by flash chromatrography (SiO2, 80 g) using a gradient up to 65% EtOAc in hexane to yield the title compound.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:11][CH2:10]1)C1C=CC=CC=1>CO.[Pd]>[N:15]1([C@H:12]2[CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10][CH2:11]2)[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: c1ccc(CN(Cc2ccccc2)[C@H]2CC[C@H](N3CCCC3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: N[C@H]1CC[C@H](N2CCCC2)CC1

Procedure:
2.2 g (6.1 mmol) trans-dibenzyl-(4-pyrrolidin-1-yl-cyclohexyl)-amine are placed in 40 ml of methanol and 0.4 g palladium/charcoal (10%) are added. The mixture is hydrogenated at 5 bar and 20° C. Then the catalyst is suction filtered, the mother liquor is combined with conc. hydrochloric acid and concentrated by evaporation. The residue is stirred out with acetone.
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21]([OH:23])=O)[NH:3]1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:29]([NH2:32])([CH3:31])[CH3:30]>>[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:29]([NH:32][C:21]([C@H:11]1[CH2:10][CH2:9][C@H:8]2[C@H:7]3[C@H:16]([CH2:15][CH2:14][C@:12]12[CH3:13])[C@:17]1([CH3:20])[C:4]([NH:3][C:2](=[O:1])[CH2:19][CH2:18]1)=[CH:5][CH2:6]3)=[O:23])([CH3:31])[CH3:30]
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Reactant: CC(C)(N)c1cccs1
Product: CC(C)(NC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4NC(=O)CC[C@]4(C)[C@H]3CC[C@]12C)c1cccs1
Yield: 27 %

Procedure:
The title compound was prepared in a yield of 27% in a similar manner to that described in Example 2 by reacting 3-oxo-4-azaandrost-5-ene-17β-carboxylic acid and 1-(2-thienyl)-1-methylethylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)=[N:8][NH:9][C:10]2=O)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[N:8][N:9]=1
Reactant: COc1cccc(-c2n[nH]c(=O)c3cc(OC)ccc23)c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cccc(-c2nnc(Cl)c3cc(OC)ccc23)c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 7-methoxy-4-(3-methoxyphenyl)-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:30]2[CH2:34][CH2:33][CH2:32][C:31]2([F:36])[F:35])[C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:26]=[CH:27][C:28]=2[F:29])[CH2:15][C:16]2([C:19]([O:21]C(C)(C)C)=[O:20])[CH2:18][CH2:17]2)=[O:10])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:30]2[CH2:34][CH2:33][CH2:32][C:31]2([F:36])[F:35])[C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:26]=[CH:27][C:28]=2[F:29])[CH2:15][C:16]2([C:19]([OH:21])=[O:20])[CH2:17][CH2:18]2)=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C1(Cc2ccc(F)c(NC(=O)C(c3ccc(Cl)cc3)C3CCCC3(F)F)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(CC2(C(=O)O)CC2)ccc1F)C(c1ccc(Cl)cc1)C1CCCC1(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
750 mg (1.44 mmol) of tert-butyl 1-(3-{[(4-chlorophenyl)(2,2-difluorocyclopentyl)acetyl]amino}-4-fluorobenzyl)cyclopropanecarboxylate (as racemic diastereomer mixture) were dissolved in 1.6 ml of dichloromethane, and 5.5 ml of TFA were added at RT. The mixture was stirred at RT for 2 h and then concentrated under reduced pressure. The residue was dried under high vacuum and then triturated with acetonitrile. The precipitated solid was filtered off. The filtrate was concentrated, the residue obtained was once more triturated with acetonitrile and a further batch of solid was isolated. This procedure was repeated once more, and all solid batches were then combined. This gave a total of 553 mg (82.6% of theory) of the title compound as a mixture of four isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([O:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([CH3:18])[C:12]=2[F:19])[N:3]=1.C1C(=O)N([Br:27])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:27][CH2:18][C:13]1[C:12]([F:19])=[C:11]([O:10][C:4]2[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=[C:2]([Cl:1])[N:3]=2)[C:16]([Cl:17])=[CH:15][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Cl)c(Oc2cc(C#N)cc(Cl)n2)c1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(Cl)nc(Oc2c(Cl)ccc(CBr)c2F)c1
Yield: 57.2 %

Procedure:
2-chloro-6-[(6-chloro-2-fluoro-3-methylphenyl)oxy]-4-pyridinecarbonitrile (3.65 g, 12.28 mmol) and NBS (2.187 g, 12.28 mmol) were combined in carbon tetrachloride (100 mL) with a catalytic amount of AIBN (0.101 g, 0.614 mmol) and stirred at reflux for 16 h. The reaction mixture was washed with water, dried over MgSO4, filtered and concentrated to dryness. The residue was purified by chromatography on 120 g silica gel eluted with 0% to 10% Et2O in hexanes to give the desired product, 2-{[3-(bromomethyl)-6-chloro-2-fluorophenyl]oxy}-6-chloro-4-pyridinecarbonitrile (2.64 g, 7.02 mmol, 57.2% yield), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm (8.01 (s, 1H), 7.96 (s, 1H), 7.50-7.62 (m, 2H), 4.75 (s, 2H). LC-MS (ES+) m/z 374.98, 377.01, 379.03 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[C:4](=NN)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11].[OH-].[K+]>C(O)COCCO>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][C:3]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:2]=1[NH2:1]
Reactant: NN=C(c1cc(Cl)ccc1N)c1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Product: Nc1ccc(Cl)cc1Cc1ccccc1Cl

Procedure:
In the manner given in Preparation 11, 2-amino-2',5-dichlorobenzophenone hydrazone is refluxed with potassium hydroxide in diethylene glycol to give 2-(o-chlorobenzyl)-4-chloroaniline, melting point 64°-65° C.
Reaction SMILES: Cl[C:2]1[C:14]2[N:13]=[C:12]3[N:7]([CH2:8][CH2:9][O:10][C:11]3([CH3:16])[CH3:15])[C:6]=2[N:5]=[C:4]([Cl:17])[N:3]=1.[CH3:18][C@H:19]1[O:24][C@@H:23]([CH3:25])[CH2:22][NH:21][CH2:20]1.C(N(CC)CC)C>>[Cl:17][C:4]1[N:3]=[C:2]([N:21]2[CH2:20][C@H:19]([CH3:18])[O:24][C@H:23]([CH3:25])[CH2:22]2)[C:14]2[N:13]=[C:12]3[N:7]([C:6]=2[N:5]=1)[CH2:8][CH2:9][O:10][C:11]3([CH3:16])[CH3:15]
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: CC1(C)OCCn2c1nc1c(Cl)nc(Cl)nc12
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(c2nc(Cl)nc3c2nc2n3CCOC2(C)C)C[C@H](C)O1
Temperature: 140 °C
Yield: 99.4 %

Procedure:
A mixture of 1,3-dichloro-8,8-dimethyl-5,6-dihydro-8H-7-oxa-2,4,4b,9-tetraaza-fluorene (100 mg, 0.366 mmol), (2R,6S)-2,6-dimethyl-morpholine (84 mg, 0.732 mmol) and triethylamine (77 μL, 0.55 mmol) in IMS (2 mL) was heated at 140° C. for 20 mins in a microwave reactor, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, 10% ethyl acetate in cyclohexane) affording 3-Chloro-1-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-8,8-dimethyl-5,6-dihydro-8H-7-oxa-2,4,4b,9-tetraaza-fluorene as a white solid (128 mg, 99%). LCMS (method A): RT=3.62 min, [M+H]+=352.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][C:27]=2[NH2:28])[CH2:22][CH2:21]1.Cl.O1CCOCC1>CO>[N:23]1([C:26]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:29][C:27]=2[NH:28][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:3]=2[CH3:19])[CH2:24][CH2:25][O:20][CH2:21][CH2:22]1
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Reactant: Cc1c(-c2ccccn2)nc2ccc(F)cc2c1Cl
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2ccc(F)cc2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to general Procedure K using 4-chloro-6-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (100 mg, 0.37 mmol), 2,5-dimorpholinoaniline (97 mg, 0.37 mmol) and a 4.0M solution of HCl in dioxane (0.09 mL, 0.37 mmol) in MeOH (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification N-(2,5-di-4-morpholinylphenyl)-6-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine was obtained. 1H NMR (500 MHz, chloroform-d) δ ppm 8.67-8.81 (1H, m), 8.19 (1H, dd, J=9.0, 5.4 Hz), 7.83-7.94 (2H, m), 7.42-7.52 (2H, m), 7.39 (1H, ddd, J=7.3, 4.8, 1.6 Hz), 7.17 (1H, s), 7.12 (1H, d, J=8.6 Hz), 6.45 (1H, dd, J=8.7, 2.8 Hz), 5.99 (1H, d, J=2.7 Hz), 3.84-3.98 (4H, m), 3.65-3.79 (4H, m), 3.06 (4H, dd, J=3.4, 2.0 Hz), 2.83-2.95 (4H, m), 2.39 (3H, s). Mass Spectrum (ESI) m/e=500.2 (M+1).