Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[NH:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[Cl:24][C:25]([Cl:31])([Cl:30])[C:26](=N)OC>C(O)(=O)C>[C:20]([O:19][C:17]([NH:16][CH2:15][CH2:14][CH2:13][N:12]1[C:3]2[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=2[N:1]=[C:26]1[C:25]([Cl:31])([Cl:30])[Cl:24])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(N)c(NCCCNC(=O)OC(C)(C)C)c1
Solvent: CC(=O)O
Product: COC(=O)c1ccc2nc(C(Cl)(Cl)Cl)n(CCCNC(=O)OC(C)(C)C)c2c1
Reaction time: 3 h
Yield: 79.6 %

Procedure:
To a stirred solution of methyl 4-amino-3-({3-[(tert-butoxycarbonyl)amino]propyl}amino)benzoate (4.7 g, 14.5 mmol) in acetic acid (50 mL) is added methyl trichloroacetimidate (3.1 g, 17.4 mmol). After 3 h at room temperature, the solvent is evaporated, the residue is dissolved in EtOAc, and is washed with Na2CO3 and brine. The organic layer is dried (Na2SO4) and evaporated. The residue is triturated with hexanes to afford the title compound (5.2 g, 80%) as a fine powder. LCMS (Method T), 1.85 min, 450.63 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[S:10]([NH:13][C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=1)(=[O:12])=[O:11].O[Li].O>CCO.O>[NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[S:10]([NH:13][C:14]1[CH:24]=[CH:23][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)(=[O:11])=[O:12]
Reactant: CCOC(=O)c1ccc(NS(=O)(=O)c2ccc(F)c(N)c2N)cc1
Agent: [Li]O
Solvent: CCO
Solvent: O
Product: Nc1c(F)ccc(S(=O)(=O)Nc2ccc(C(=O)O)cc2)c1N
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of the compound 39E (350 mg, 1 mmol) in EtOH/H2O (10 mL/3 mL) was added LiOH.H2O (200 mg, 5 mmol) and the resulting suspension was stirred at 70° C. overnight. The solvent was concentrated and the residue was partitioned between aqueous 2 N HCl and EtOAc. The organic layer was separated and washed with water and brine, dried over Na2SO4 and concentrated to give the desired crude product 39F, which was confirmed by LCMS, and used in subsequent reaction without further purification. LC-MS: m/z 326.3 (M+H)+.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([CH2:17][CH2:18][N:19]3[C@H:24]4[CH2:25][CH2:26][C@@H:20]3[CH2:21][CH:22]([N:27]3[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=5[N:29]=[C:28]3[CH3:36])[CH2:23]4)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:7]=[C:8]([F:10])[CH:9]=1.C(N(CC)CC)C.[CH3:44][C:45]([CH3:50])([CH3:49])[C:46](Cl)=[O:47]>ClCCl>[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([CH2:17][CH2:18][N:19]3[C@H:24]4[CH2:25][CH2:26][C@@H:20]3[CH2:21][CH:22]([N:27]3[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=5[N:29]=[C:28]3[CH3:36])[CH2:23]4)[CH2:12][CH2:13][N:14]([C:46](=[O:47])[C:45]([CH3:50])([CH3:49])[CH3:44])[CH2:15][CH2:16]2)[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cc(F)cc(Cl)c2)CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cc(F)cc(Cl)c2)CCN(C(=O)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.2 %

Procedure:
A mixture of 1-((1R,5S)-8-{2-[4-(3-chloro-5-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole dihydrochloride (0.2 g, 0.39 mmol), triethylamine (0.11 mL, 0.78 mmol) and trimethylacetyl chloride (0.053 mL, 0.43 mmol) in dichloromethane (4 mL) was stirred at rt for 1 h before the reaction mixture was quenched with saturated sodium bicarbonate solution. The organic layer was separated, dried, concentrated and purified by two successive chromatographies on silica gel using a dichloromethane to methanol:dichloromethane 1:20 gradient to give 1-((1R,5S)-8-{2-[4-(3-chloro-5-fluorophenyl)-1-(2,2-dimethylpropanoyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole as a glass (0.06 g, 27%). 1H NMR (400 MHz, CDCl3) δ 7.67 (m, 1H), 7.29 (m, 1H), 7.17 (m, 2H), 7.09 (m, 1H), 7.00 (m, 1H), 6.93 (m, 1H), 4.72 (m, 1H), 3.90 (m, 2H), 3.37 (m; 4H), 2.61 (s, 3H), 2.47 (m, 2H), 1.89-2.11 (m, 8H), 1.78 (m, 6H), 1.27 (s, 9H). HRMS C33H42ClFN4O m/z 565.3109 (M+H)Cal., 565.3095 (M+H)Obs..
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](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:18][CH2:17]1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45].Cl>ClCCl.CO>[ClH:28].[Cl:44][C:31]1[CH:32]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:17][CH2:18][C@H:19]([CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:20][CH2:21]2)[CH:34]=[C:29]([Cl:28])[C:30]=1[OH:45]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CN2CCCC2)CC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](CN2CCCC2)CC1

Procedure:
Following general procedure F, 1-(6-bromo-4-(trans-4-(pyrrolidin-1-ylmethyl)cyclohexylamino)quinolin-3-yl)ethanone (6.0 g, 14.0 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (4.4 g, 15.0 mmol) to obtain the free base. The purified product was suspended in dichloromethane/methanol (1:1, 200 mL) after which HCl (35 mL, 1.25 M in methanol) was added to form a solution. The solution was concentrated to dryness and the resultant solid was triturated with dichloromethane. The mixture was filtered, washed with dichloromethane, and dried to obtain desired product (4.9 g, 60% over two steps) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ 9.10 (s, 1H), 8.47 (d, J=2.1 Hz, 1H), 8.26 (dd, J=8.8, 1.8 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.73 (s, 2H), 4.55-4.45 (m, 1H), 3.70 (br s, 2H), 3.20-3.04 (m, 4H), 2.74 (s, 3H), 2.45 (d, J=12.6 Hz, 2H), 2.17-1.94 (m, 7H), 1.89-1.70 (m, 2H), 1.46-1.27 (m, 2H); APCI MS m/z 512 [C28H31Cl2N3O2+H]+; HPLC>99% (AUC), tR=8.69 min.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.Cl.[CH3:20][NH2:21]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][CH3:20])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Reactant: CN
Agent: Cl
Product: CNc1nc(Cl)nc2c1CCC2c1ccc(F)cc1
Yield: 70.2 %

Procedure:
2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) (500 mg, 1.766 mmol) and methanamine hydrochloride (179 mg, 2.65 mmol) were combined and purified as per Preparation Ha to give 2-chloro-7-(4-fluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (344 mg, 1.239 mmol, 70.1% yield). LC-MS (M+H)+=278.0. 1H NMR (500 MHz, CDCl3) δ ppm 7.03-7.12 (2H, m), 6.91-7.03 (2H, m), 4.53-4.79 (1H, m), 4.19-4.29 (1H, m), 3.09 (3H, d, J=4.88 Hz), 2.56-2.80 (3H, m), 2.00-2.15 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[C:4](Cl)[N:3]=1.[NH2:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([NH:16][CH3:17])=[O:15].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([NH:16][CH3:17])=[O:15])[C:5]([C:8]#[N:9])=[CH:6][N:7]=1
Reactant: CNC(=O)c1ccccc1N
Reactant: N#Cc1cnc(Cl)nc1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C#N

Procedure:
In a similar fashion as outlined in Example 191a, 2,6-dichloro-5-cyanopyrimidine was reacted with 2-amino-N-methylbenzamide and N,N-diisopropylethylamine in isopropyl alcohol (no microwave −20° C., 10 minutes) to afford 2-(2-chloro-5-cyano-pyrimidin-4-ylamino)-N-methyl-benzamide as a yellow solid. Mp: 228-32° C. (dec); MS: 288.26 (M+H); 1H NMR (chloroform-d): δ 12.49 (s, 1H), δ 8.69 (d, J=8 Hz, 1H), δ 8.50 (s, 1H), δ 7.57 (m, 2H), δ 7.22 (t, J=8 Hz, 1H), δ 6.31 (br s, 1H), δ 3.08 (d, J=5 Hz, 3H).
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:9]=[C:10]([CH2:23][C:24]([OH:26])=O)[CH:11]=[CH:12][C:13]=2[NH:14][C:15]([NH:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[O:16])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH:1]1([C:6]([C:8]2[CH:9]=[C:10]([CH2:23][C:24]([N:31]3[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]3)=[O:26])[CH:11]=[CH:12][C:13]=2[NH:14][C:15]([NH:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[O:16])=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCNCC1
Reactant: O=C(O)Cc1ccc(NC(=O)Nc2nccs2)c(C(=O)C2CCCC2)c1
Product: CN1CCN(C(=O)Cc2ccc(NC(=O)Nc3nccs3)c(C(=O)C3CCCC3)c2)CC1
Yield: 60.1 %

Procedure:
1-{2-Cyclopentanecarbonyl-4-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-phenyl}-3-thiazol-2-yl-urea (137 mg, 60%) was prepared from [3-cyclopentanecarbonyl-4-(3-thiazol-2-yl-ureido)-phenyl]-acetic acid (186 mg, 0.5 mmol) and N-methyl piperazine (50 mg, 0.5 mmol) following the general procedure K.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13](/[CH:17]=[CH:18]/[CH:19]([OH:28])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:12]=2)[CH:5]=1.[OH-].[Na+]>CO>[OH:28][CH:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])/[CH:18]=[CH:17]/[C:13]1[N:12]=[C:11]([O:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:29])=[O:2])[CH:16]=[CH:15][CH:14]=1
Reactant: CCCCCCCCC(O)/C=C/c1cccc(Oc2cccc(C(=O)OC)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCC(O)/C=C/c1cccc(Oc2cccc(C(=O)O)c2)n1
Yield: 75.2 %

Procedure:
Under the conditions of example 2, 40 mg of 3-{6-[(1E)-(3RS)-3-hydroxy-1-undecenyl]-2-pyridyloxy)-benzoic acid methyl ester in 1 ml of methanol is saponified with 1 ml of 1 n sodium hydroxide solution and worked up. 29 mg of the title compound of melting point 85°-87° C. is obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:22])[CH:6]=[C:7]([CH2:20][CH3:21])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH3:2].[Cl:23][C:24]([Cl:28])=[CH:25][CH2:26]Cl.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:20]([C:7]1[CH:6]=[C:5]([O:22][CH2:26][CH:25]=[C:24]([Cl:28])[Cl:23])[CH:4]=[C:3]([CH2:1][CH3:2])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH3:21]
Reactant: ClCC=C(Cl)Cl
Reactant: CCc1cc(O)cc(CC)c1OCCCCOCC=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc(OCC=C(Cl)Cl)cc(CC)c1OCCCCOCC=C(Cl)Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.8 %

Procedure:
A reaction vessel was charged with 0.35 g of 3,5-diethyl-4-(4-(3,3-dichloro-2-propenyloxy)butyloxy)phenol, 0.16 g of 1,1,3-trichloro-1-propene, 0.15 g of potassium carbonate and 10 ml of N,N-dimethylformamide. After stirring at room temperature for 24 hours, the reaction mixture was poured into water and extracted twice with 50 ml of diethyl ether. The diethyl ether layers were combined, washed with water, dried over magnesium sulfate and then concentrated. The residue was subjected to silica gel chromatography, which afforded 0.33 g of 3,5-diethyl-1-(3,3-dichloro-2-propenyloxy)-4-(4-(3,3-dichloro-2-propenyloxy)butyloxy)benzene (yield, 72%), nD24.4 1.5311.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][C:14]1[NH:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.[H-].[Na+].Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][C:14]1[N:15]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: c1ccc(-c2ccccc2Sc2nc3ccccc3[nH]2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)n1c(Sc2ccccc2-c2ccccn2)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-[2-(2-Pyridyl)-phenyl thio]-benzimidazole (0.825 mmole) in anhydrous dimethylformamide (15 ml) was treated under nitrogen with sodium hydride (0.90 mmole). The mixture was stirred for 20 minutes at room temperature, cooled to 5° and benzyl chloroformate (0.90 mmole) was added. The mixture was allowed to attain room temperature, then stirred for 18 hours after which it was poured into ice/water and extracted with ethyl acetate (2×15 ml). The combined extracts were washed with water, dried (MgSO4), filtered and evaporated to an oil. The oil was flash chromatographed on silica gel using 10% ethyl acetate in dichloromethane as eluant to give the sub-title compound as a brown oil, MW 437 Base Peak 91.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:20])[C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[C:18]([Cl:19])[C:11]=12)[NH2:5].Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH2:28])[N:23]=1.Cl.[OH-].[Na+]>O.C(O)C>[Cl:19][C:18]1[C:11]2[C:12](=[N:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]2[C:7]([F:20])=[CH:6][C:4]([NH:5][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH2:28])[N:23]=3)=[CH:3][C:2]=2[F:1])[NH:16][CH:17]=1
Reactant: Nc1cc(F)c(Oc2ccnc3[nH]cc(Cl)c23)c(F)c1
Reactant: Nc1nccc(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1nccc(Nc2cc(F)c(Oc3ccnc4[nH]cc(Cl)c34)c(F)c2)n1

Procedure:
200 mg (0.67 mmol) of 3,5-difluoro-4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]aniline and 88 mg (0.67 mmol) of 4-chloropyrimidine-2-amine are suspended in 6 ml of water/ethanol 1:1. 69 μl (0.81 mmol) of 37% strength hydrochloric acid are added, and the mixture is heated at reflux for 3 h. Using 1N aqueous sodium hydroxide solution, the pH is adjusted to 7, and the mixture is extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is purified by preparative HPLC.
Reaction SMILES: [C:1]([CH:8]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3=[N:22][C:23]([C:27]([O:29][CH3:30])=[O:28])=[CH:24][C:25]([CH3:26])=[C:20]3[N:19]=[C:18]2[CH2:31][CH3:32])=[CH:12][C:11]=1[CH2:33][CH2:34][CH3:35])([O:3]C(C)(C)C)=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([CH:8]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3=[N:22][C:23]([C:27]([O:29][CH3:30])=[O:28])=[CH:24][C:25]([CH3:26])=[C:20]3[N:19]=[C:18]2[CH2:31][CH3:32])=[CH:12][C:11]=1[CH2:33][CH2:34][CH3:35])([OH:3])=[O:2]
Reactant: CCCc1cc(Cn2c(CC)nc3c(C)cc(C(=O)OC)nc32)ccc1OC(C(=O)OC(C)(C)C)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1cc(Cn2c(CC)nc3c(C)cc(C(=O)OC)nc32)ccc1OC(C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
To a solution of 21.4 mg (0.038 mmol) of the product of Step P in CH2Cl2 (1 mL) was added TFA (0.4 mL, 5.19 mmol) at rt. The solution was stirred at rt for 2 hours. The crude mixture was directly purified by flash chromatography eluted with CHCl3 /MeOH/NH4OH (100:10:1) to give 11 mg of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:14][O-:15].[Na+]>CO.O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([O:15][CH3:14])=[N:7]2
Reactant: Fc1ccc(Br)c2ccc(Cl)nc12
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2c(Br)ccc(F)c2n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-bromo-2-chloro-8-fluoroquinoline (1.08 g, 4.2 mmol) in anhydrous methanol (10 mL) at 50° C. was added NaOMe (30% w/w, 0.9 g, 5.0 mmol). The resulting mixture was stirred at 50° C. for one hour, then allowed to cool to room temperature. The mixture was diluted with water, then extracted with EtOAc. The combined organics were washed with water then saturated Nael (aq), dried over MgSO4, filtered, then concentrated. The residue was purified by silica gel chromatography eluting with 0-5% EtOAc/hexanes to afford the title compound as a white solid: 1H NMR (500 MHz, CDCl3): δ 8.33 (dd, J=9.1, 1.6 Hz, 1H); 7.55 (dd, J=8.4, 4.4 Hz, 1H); 7.22 (dd, J=10.2, 8.4 Hz, 1H); 7.04 (d, J=9.2 Hz, 1H); 4.13 (s, 4H). LC4 2.37 min. (M+H) 256.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].F[C:26]1[N:33]=[CH:32][CH:31]=[CH:30][C:27]=1[C:28]#[N:29]>CS(C)=O.CCOC(C)=O>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:26]2[N:33]=[CH:32][CH:31]=[CH:30][C:27]=2[C:28]#[N:29])=[CH:14][CH:13]=1
Reactant: N#Cc1cccnc1F
Reactant: Cn1c(Nc2ccc(O)cc2)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cn1c(Nc2ccc(Oc3ncccc3C#N)cc2)nc2ccccc21
Temperature: 80 °C

Procedure:
To a solution of 4-(1-methyl-1H-benzo[d]imidazol-2-ylamino)phenol (120 mg, 0.5 mmol) in DMSO (1 mL) was added cesium carbonate (196 mg, 0.6 mmol) and 2-fluoronicotinonitrile (61 mg, 0.5 mmol). The resulting mixture was heated to 80° C. for 16 h. After cooling to RT, the reaction mixture was diluted with EtOAc and washed with water and brine several times to remove DMSO. The aqueous layer was back extracted with EtOAc (3×) and the combined organic layer was dried (Na2SO4) and concentrated. The crude product was chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 0% to 5% of MeOH in CH2Cl2, followed by trituration with ether, to provide 2-(4-(1-methyl-1H-benzo[d]imidazol-2-ylamino)phenoxy)nicotinonitrile as off-white solid. MS (ESI, pos. ion) m/z: 342.2 (M+1). IC50 (uM) +++++.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:27][C:28]([CH3:30])=[CH2:29]>CC#N>[CH3:29][C:28](=[CH2:27])[CH2:30][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1
Reactant: COc1cccc(OCc2nc3ccccc3[nH]2)c1
Reactant: C=C(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=C(C)Cn1c(COc2cccc(OC)c2)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
To a solution of 51 (16.51 g, 0.065 mol) in CH3CN (150 mL) was added K2CO3 (17.94 g, 0.13 mol) followed by addition of 3-bromo-2-methylpropene (8.78 g, 0.065 mol) under Ar. The resulting mixture was stirred at rt overnight. The reaction mixture was filtered, and the filter cake was washed with CH3CN (100 mL). The filtrate was concentrated in vacuo to give an oil. The oil was chromatographed on 150 g of silica gel with 30 g of anhydrous Na2SO4 on top packed with hexanes. The column was eluted with 150 mL portions of 10% EtOAc in hexanes for fractions 1-5, 20% EtOAc in hexanes for fractions 6-14 and 25% EtOAc for fraction 15-16. The product was eluted in fractions 7-16 (TLC solvent: 50% EtOAc in hexanes) to give 19 g (95%) of Compound #3 as a viscous oil. HPLC analysis showed a purity of 99%. 1H NMR for HCl salt (300 MHz, CD3OD): δ 7.9 (m, 2H), 7.7 (m, 2H), 7.3 (t, 1H), 6.65-6.8 (m, 3H), 5.7 (s, 2H), 5.2 (s, 2H), 5.1 (s, 1H), 4.9 (s, 1H), 4.7 (s, 1H), 3.8 (s, 3H), 1.85 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.C(O)C.N>CO.[Ni]>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1
Reactant: N#Cc1ccc(Oc2ccccc2F)cc1
Agent: [Ni]
Agent: N
Solvent: CCO
Solvent: CO
Product: NCc1ccc(Oc2ccccc2F)cc1
Temperature: 60 °C
Yield: 78.9 %

Procedure:
Add 4-(2′-fluorophenoxy)-benzonitrile (1.5 g, 7.0 mmol) and ethanol wet Raney® activated nickel (0.4 g) to a Parr pressure vessel. Immediately add a 7N solution of ammonia in methanol (170 mL) and seal the vessel. Purge the reaction vessel with nitrogen, pressurize the reaction mixture with hydrogen (3400 KPa), seal the vessel, agitate the reaction and heat to 60° C. Continue the reaction for 18 h, turn off the heat and allow the reaction mixture to cool to ambient temperature. Vent the excess hydrogen from the vessel and purge the vessel with nitrogen. Filter the reaction mixture to remove the Raney® nickel. Concentrate in vacuo and purify by chromatography on silica gel eluting with DCM/2M ammonia in methanol (9:1) to obtain the title compound (1.2 g, 79%). MS (ES+) m/z: 201 (M+H—NH3)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[S:10][C:9]([NH:11][C:12]([N:14]2[C:30]3[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=3)[C:16]3([CH2:20][CH2:19][N:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17]3)[CH2:15]2)=[O:13])=[N:8][CH:7]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>>[Cl:31][C:27]1[CH:26]=[C:25]2[C:16]3([CH2:20][CH2:19][N:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17]3)[CH2:15][N:14]([C:12](=[O:13])[NH:11][C:9]3[S:10][C:6]([S:5][CH2:4][CH2:3][CH2:2][NH:1][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:7][N:8]=3)[C:30]2=[CH:29][CH:28]=1
Reactant: COC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(SCCCN)s1)c1ccc(Cl)cc12
Reactant: CS(=O)(=O)Cl
Product: COC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(SCCCNS(C)(=O)=O)s1)c1ccc(Cl)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Example 3, with the exceptions that the methyl 1-((5-((3-aminopropyl)thio)thiazol-2-yl)carbamoyl)-5-chlorospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate obtained in Example 176 was used instead of 5-bromo-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide, and that methanesulfonic acid chloride was used instead of acetyl chloride.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:31]=[CH:30][C:14]([CH2:15][NH:16][C:17]2[C:26]3[C:21](=[C:22]([C:27]([NH2:29])=[O:28])[CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[NH:7]([C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][NH:16][C:17]2[C:26]3[C:21](=[C:22]([C:27]([NH2:29])=[O:28])[CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:30][CH:31]=1)=[O:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)c1cccc2c(NCc3ccc(N)cc3)ncnc12
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1cccc2c(NCc3ccc(NC(=O)Nc4ccccc4)cc3)ncnc12
Reaction time: 8 h
Yield: 27 %

Procedure:
Phenyl isocyanate (240 μL, 0.5 M in anhydrous DCM, 0.11 mmol, 1.1 equiv.) was added to a solution of 4-[(4-aminobenzyl)amino]quinazoline-8-carboxamide (32 mg, 0.1 mmol, 1.0 equiv.) and triethylamine (40 μL, 0.3 mmol, 3.0 equiv.) in anhydrous DCM (2 mL). The resulting mixture was stirred at it overnight. The title compound was obtained by pre-HPLC in 27% yield. Mass: M+H+: 413.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([OH:8])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][CH2:18]Br>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[O:9][CH2:18][CH2:17][O:8][C:5]2=[N:6][CH:7]=1
Reactant: Oc1cc(Br)cnc1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cnc2c(c1)OCCO2
Temperature: 100 °C

Procedure:
To a suspension of 5-Bromo-pyridine-2,3-diol (10.0 g, 52.63 mmol, commercially available, CAS 34206-49-0) in DMF (150 mL) was added K2CO3 (21.78 g, 158 mmol) and 1,2-dibromo ethane (11.87 g, 63.2 mmol). The reaction mixture was heated to 100° C. for 5 h. The reaction mixture was cooled to rt and poured into ice cold water EtOAc was added and the phases were separated and the aq layer was extracted with more ethyl acetate. The combined organic layers was dried over anhydrous Na2SO4 and concentrated under vacuo to get the crude compound. The crude compound was purified by silica gel chromatography (eluent 10% ethyl acetate in petrol ether). Yield of 6-Bromo-[1,3]dioxolo[4,5-b]pyridine 2.2 g (18%) pure by 1H NMR (400 MHz, DMSO) δ 7.85 (d, 1H, J=2 Hz), 7.59 (d, 1H, J=2 Hz), 4.41 (m, 2H), 4.27 (m, 2H).