Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B1([O-])OO1.[OH2:5].[OH2:6].O.O.[Na+].[CH3:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[C:13]=1[OH:21].Cl.C(=O)(O)[O-].[Na+]>C(O)(=O)C.[Zn]>[NH2:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([S:11]([CH3:10])(=[O:6])=[O:5])[C:13]=1[OH:21]
Reactant: CSc1cccc([N+](=O)[O-])c1O
Reactant: O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CS(=O)(=O)c1cccc(N)c1O
Temperature: 55 °C
Yield: 21.4 %

Procedure:
Sodium perborate tetrahydrate (640 mg, 4.16 mmol) was added to a solution of 2-methylthio-6-nitrophenol (120 mg, 0.648 mmol) in acetic acid (6 ml) and the mixture was stirred at 55° C. for4 hours. The residue obtained by concentrating the reaction solution was purified by a silica gel column chromatography (50 g of silica gel; developing solvent, chloroform→chloroform:methanol=50:1→chloroform:methanol=4:1), the resulting residue was suspended in acetic acid (12 ml), under cooling with ice water then zinc (450 mg, 6.88 mmol) and concentrated hydrochloric acid (0.2 ml) were added thereto and the mixture was returned to room temperature and stirred for 20 minutes. The reaction solution was neutralized by adding a saturated sodium bicarbonate solution thereto and extracted with chloroform. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was purified by a preparative thin layer chromatography (developing solvent, chloroform:methanol=10:1) to provide 26 mg (yield 21%) of 2-amino-6-methanesulfonylphenol as brown oil.
Reaction SMILES: N[C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:9][C:10]([F:14])([F:13])[CH2:11][OH:12].CS(O)(=O)=O.N(OC(C)(C)C)=O.C1(C)C=C(C)C=C(C)C=1>>[Cl:8][C:3]1[C:2]([O:12][CH2:11][C:10]([F:14])([F:13])[F:9])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Nc1cccnc1Cl
Reactant: OCC(F)(F)F
Agent: CC(C)(C)ON=O
Agent: CS(=O)(=O)O
Solvent: Cc1cc(C)cc(C)c1
Product: FC(F)(F)COc1cccnc1Cl
Yield: 73 %

Procedure:
A reactor vessel is charged with 3-amino-2-chloropyridine (10 g, 77.8 mmol), 2,2,2-trifluoroethanol (55.6 g, 556 mmol), and after cooling in an ice bath, methanesulfonic acid (7.48 g, 77.8 mmol) is added. The solution is cooled to the range −5° C. to 0° C. and then the reagent t-butyl nitrite (2.51 g of a 96% solution, 23.4 mmol) is added drop-wise to the vessel while maintaining the temperature in the range −5° C. to 0° C. After stirring a few minutes the solution is transferred by Masterflex® pump to a reactor vessel containing 2,2,2-trifluoroethanol (74.1 g, 741 mmol) maintained at 65° C. to 70° C. The pump line is cleared into the second reactor with 2,2,2-trifluoroethanol (5 g, 50 mmol) and mesitylene (10 g). An additional 20 g mesitylene was charged to the reactor vessel and a distillation column is attached to the reactor. Impure 2,2,2-trifluoroethanol (114 g, 90% recovery) is distilled out of the vessel. After cooling the solution it is neutralized with aqueous saturated sodium bicarbonate solution and then extracted with MTBE. The volatiles were removed by evaporation to obtain 2-chloro-3-(2,2,2-trifluoroethoxy)pyridine as a crude oil (44 g) with an actual yield of 73%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[N:13]=[C:12]2[N:14]=[CH:15][CH:16]=[C:17]([O:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:21]([F:33])[CH:20]=3)[C:11]2=[N:10][CH:9]=1>>[F:33][C:21]1[CH:20]=[C:19]([O:18][C:17]2[C:11]3[C:12](=[N:13][C:8]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:9][N:10]=3)[N:14]=[CH:15][CH:16]=2)[CH:24]=[CH:23][C:22]=1[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc3nc(Cl)cnc23)cc1F
Reactant: C1COCCN1
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc3nc(N4CCOCC4)cnc23)cc1F

Procedure:
Method D6 was used with morpholine and tert-butyl 4-(3-chloropyrido[2,3-b]pyrazin-8-yloxy)-2-fluorophenylcarbamate to give the title compound as a white solid. Yield: 117 mg (89%).
Reaction SMILES: [Br-].[CH:2]1([Zn+])[CH2:4][CH2:3]1.Br[C:7]1[N:11]2[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]2=[N:9][C:8]=1[NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20]>O1CCCC1.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>[CH:2]1([C:7]2[N:11]3[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]3=[N:9][C:8]=2[NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:4][CH2:3]1
Reactant: [Zn+]C1CC1
Reactant: O=C(Nc1nc2ccc(F)cn2c1Br)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(Nc1nc2ccc(F)cn2c1C1CC1)C(F)(F)F

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.0797 g, 0.000069 mol) was added to a solution of 0.50 M of cyclopropylzinc bromide in tetrahydrofuran (4.1 mL) and N-(3-bromo-6-fluoro-imidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoro-acetamide (compound d, 0.225 g, 0.000690 mol) in tetrahydrofuran (20.0 mL) and the reaction was heated to reflux for 3 hours. An additional 0.50 M of cyclopropylzinc bromide (4.1 mL) in tetrahydrofuran and tetrakis(triphenylphosphine)palladium(0) (0.080 g) was added and the mixture was heated to reflux overnight. The reaction was concentrated in vacuo and crude product purified by column chromatography (50% ethyl acetate/hexanes) to give N-(3-cyclopropyl-6-fluoro-imidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoro-acetamide as a yellow solid. Rf 0.46, 50% ethyl acetate/hexanes; MS m/z 287 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=[O:13].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:33]([CH3:37])([CH3:36])[CH:34]=O)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32].C(O)(=O)C.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.[BH3-]C#N.[Na+]>ClCCCl>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:33]([CH3:37])([CH3:36])[CH2:34][NH:1][C:2]2[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=2[C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:18][CH:19]=2)=[O:13])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: COc1cc(N)c(C(=O)c2ccc(C(C)C)cc2)cc1OC
Reactant: COc1ccc(C(C)(C)C=O)cc1OC
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc(C(C)(C)CNc2cc(OC)c(OC)cc2C(=O)c2ccc(C(C)C)cc2)cc1OC
Reaction time: 1 h

Procedure:
After one hour stirring a mixture of 143 mg (0.476 mmol) (2-amino-4,5-dimethoxy-phenyl)-(4-isopropyl-phenyl)-methanone, 98 mg (0.476 mmol) 2-(3,4-dimethoxy-phenyl)-2-methyl-propionaldehyde, 1.1 g molecular sieves 4 Å pore size, 5 ml 1,2-dichloroethane and 31 μl (0.476 mmol) acetic acid 41 mg (0.666 mmol) NaCNBH3 are added. Over the duration of 4 days three additional portions of 31 μl acetic (0.476 mmol) and 41 mg NaCNBH3 (0.666 mmol) are added. Excess hydride is destroyed by addition of 1 M hydrochloric acid and the reaction mixture is basified by means of 1 M sodium hydroxide. {2-[2-(3,4-Dimethoxy-phenyl)-2-methyl-propylamino]-4,5-dimethoxy-phenyl}-(4-isopropyl-phenyl)-methanone is isolated by filtration followed by extraction with dichloromethane and reversed phase preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=4)[CH:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH2:17]O)[CH:14]=[CH:15][CH:16]=3)[N:6]2[N:5]=[CH:4][N:3]=1.O=S(Cl)[Cl:37].N1C=CC=CC=1>O1CCOCC1>[CH2:28]([N:24]1[CH:23]=[C:22]2[C:26]([CH:27]=[C:19]([C:8]3[CH:9]=[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][Cl:37])[CH:12]=4)[N:6]4[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)[CH:20]=[CH:21]2)=[N:25]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Nc1ncnn2c(-c3cccc(CO)c3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: O=S(Cl)Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: Nc1ncnn2c(-c3cccc(CCl)c3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reaction time: 1.5 h
Yield: 24.5 %

Procedure:
{3-[4-Amino-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-methanol (254 mg, 0.57 mmol) was suspended in 2 mL of dioxane and SOCl2 (83 μL, 1:1 mmol) was added followed by the dropwise addition of pyridine (0.14 mL, 1.7 mmol). The mixture was stirred for 1.5 hours and carefully quenched by the addition of 2M aqueous Na2CO3. The mixture was diluted with water and extracted with 3×10 mL of 10% MeOH/EtoAc. The combined organic fractions were washed with 1M aqueous H3PO4, brine, dried (Na2SO4), filtered and concentrated. The residue was purified by ISCO® Redi-sep 12, 80% to 100% EtOAc/hexanes to provide 65 mg (24%) of the title compound as a crusty solid. 1H-NMR (DMSO-d6) 8.55 (s, 1H), 8.19 (s, 1H), 8.08, (d, 1H) 7.99 (s, 1H) 7.83 (d, 1H) 7.70 (s, 1H), 7.46 (t, 1H), 7.40 (t, 1H), 7.38-7.26 (m, 4H), 7.24 (d, 1H), 7.22 (s, 1H), 5.72 (s, 2H), 4.60 (s, 2H); LC-MS [M+H]+=465.3, 467.2, RT=3.24 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH:15]=2)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([C:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH:15]=2)[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(C2=CCNCC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
Dissolve tert-butyl 4-(3-nitro-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (300 mg, 0.81 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (3 mL), stir at room temperature overnight. Adjust pH=8 with saturated NaHCO3 solution, extract with ethyl acetate, wash the organic extract with water and brine sequentially, dry over anhydrous sodium sulfate. Concentrate under reduced pressure to provide yellow oil (220 mg, 100%) which is used directly in next step.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]4[CH:29]=[N:30][C:31]5[C:36]([CH:37]=4)=[CH:35][CH:34]=[CH:33][CH:32]=5)[N:26]=3)[N:21]=[CH:20][C:19]=2[C:38]([O:40]C)=[O:39])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].C(O)C>O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]4[CH:29]=[N:30][C:31]5[C:36]([CH:37]=4)=[CH:35][CH:34]=[CH:33][CH:32]=5)[N:26]=3)[N:21]=[CH:20][C:19]=2[C:38]([OH:40])=[O:39])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cnc2ccc(-c3cnc4ccccc4c3)nc2c1NC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cnc2ccc(-c3cnc4ccccc4c3)nc2c1NC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
A mixture of compound 46 (8.2 g, 15 mmol) and lithium hydroxide (480 mg, 20 mmol) in 2:1 ethanol:water (150 mL) was heated to 75° C. resulting in a solution. After 2 hours, the solution was cooled to room temperature and concentrated. The residue was taken up in water (200 mL) and the solution was acidified with 1 N HCl (20 mL). The precipitate was collected by filtration and dried at 60° C. under vacuum to afford 4-({1-[(benzyloxy)carbonyl]piperidin-4-yl}amino)-6-quinolin-3-yl-1,5-naphthyridine-3-carboxylic acid (compound 47) (7.8 g, 98%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:8](=[O:17])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:6]=1[CH3:7].Br[CH2:19][CH:20]1[CH2:22][CH:21]1[CH3:23]>>[CH3:1][C:2]1[N:3]([CH2:19][CH:20]2[CH2:22][CH:21]2[CH3:23])[C:4]([C:8](=[O:17])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:6]=1[CH3:7]
Reactant: CC1CC1CBr
Reactant: Cc1cc(C(=O)CCc2ccccc2)[nH]c1C
Product: Cc1cc(C(=O)CCc2ccccc2)n(CC2CC2C)c1C
Yield: 99.1 %

Procedure:
The title compound was prepared as a yellow oil in 99.1% yield in a similar procedure to that described in Referential Example 97 by using 2,3-dimethyl-5-(3-phenylpropionyl)pyrrole and 1-bromomethyl-2-methylcyclopropane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=2)[C:10]([O:20][CH3:21])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[C:10]([O:20][CH3:21])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1nn(C(=O)OC(C)(C)C)c2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1nn(C(=O)OC(C)(C)C)c2ccc(N)cc12

Procedure:
3-Methoxy-5-nitroindazole-1-carboxylic acid tert-butyl ester (0.33 g, 1.11 mmol) and palladium (10% wt) on carbon (0.24 g, 20% wt) were dissolved in EtOAc (25 mL). The flask was evacuated and filled with N2 (×5), then evacuated and filled with hydrogen (×10) and left over a weekend. The mixture was filtered over celite and the solvents removed in vacuo. Purification by column chromatography on silica gel (Jones, 20 g) loading in DCM and eluting in 5:1 Hexanes:EtOAc stepwise to 7:3 Hexanes:EtOAc yielded the title compound as a white powder. 1H NMR (400 MHz, CDCl3): δ=1.69 (s, 9H), 3.73 (brs, 2H), 4.15 (s, 3H), 6.85 (d, J=2.0 Hz, 1H), 6.91 (dd, J=8.8, 2.4 Hz, 1H), 7.74 (brs, 1H). MS (ES+): m/z 164.3 (65) [MH+](fragment ion, loss of Boc group).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=O.CCN=C=NCCCN(C)C.Cl.[C:25]1([CH2:41][NH:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=2)[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][NH:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[CH:26]=1.O>CN(C=O)C.C1C=CC2N(O)N=NC=2C=1>[Cl:1][C:2]1[C:3]([OH:12])=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([N:32]([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=1)[CH2:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([CH2:41][NH:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=2)[CH:26]=1)=[O:7]
Reactant: Fc1ccc(CNCc2cccc(CNCc3ccc(F)cc3)c2)cc1
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1cc(Cl)cc(Cl)c1O)N(Cc1ccc(F)cc1)Cc1cccc(CNCc2ccc(F)cc2)c1
Yield: 21.4 %

Procedure:
To a solution of 3,5-dichloro-2-hydroxybenzoic acid (300 mg, 1.449 mmol) in DMF (5 mL) at rt was added EDCI.HCl (300 mg, 1.565 mmol) followed by N,N′-(1,3-phenylenebis(methylene))bis(1-(4-fluorophenyl)methanamine) (365 mg, 1.036 mmol) in 2 mL of DMF and hydrated HOBt.H2O (200 mg), and the reaction mixture was stirred at rt overnight. The mixture was directly purified by prep HPLC to provide a monoacylated product 3,5-dichloro-N-(4-fluorobenzyl)-N-(3-((4-fluorobenzylamino)methyl)benzyl)-2-hydroxybenzamide (0.12 g, 21.4%) and a diacylated product, N,N′-(1,3-phenylenebis(methylene))bis(3,5-dichloro-N-(4-fluorobenzyl)-2-hydroxybenzamide) (0.245 g, 32.4%). 1H NMR (CD3OD): δ 7.34˜6.80 (m, 16H), 4.59 (s, 4H), 4.24 (s, 4H); MS (ESI): (M+H)+=731.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15](F)=[CH:16][C:17]=3[O:19][CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:27][CH2:28][O:29][C:5]2=[CH:4][CH:3]=1.[OH-].[K+].[OH:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]1.Cl>COCCOCCOC>[Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:32][CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]4)=[CH:16][C:17]=3[O:19][CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:27][CH2:28][O:29][C:5]2=[CH:4][CH:3]=1
Reactant: Fc1cc(OC2CCOCC2)c2c(Nc3c(Cl)ccc4c3OCO4)ncnc2c1
Reactant: CN1CCN(CCO)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: COCCOCCOC
Product: CN1CCN(CCOc2cc(OC3CCOCC3)c3c(Nc4c(Cl)ccc5c4OCO5)ncnc3c2)CC1
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
4-(6-Chloro-2,3-methylenedioxyanilino)-7-fluoro-5-tetrahydropyran-4-yloxyquinazoline (0.5 g) was added to a stirred mixture of potassium hydroxide (0.168 g), 1-(2-hydroxyethyl)-4-methylpiperazine (0.69 g) and di-(2-methoxyethyl)ether (10 ml) that had been warmed to 120° C. and the resultant reaction mixture was heated to 120° C. for 12 hours. The reaction mixture was cooled to ambient temperature, acidified to pH 1 to 3 by the addition of 1M aqueous hydrochloric acid (9 ml) and washed with isopropyl acetate (20 ml). The aqueous solution was stirred and basified to pH 13 to 14 by the addition of 2M aqueous sodium hydroxide (5 ml). After 10 minutes, water (22 ml) was added and the mixture was stirred for 2 hours to allow precipitation of a solid to finish. The mixture was cooled to 10° C. and filtered. The resultant solid was washed with water (20 ml) and dried in vacuo at 40° C. There was thus obtained 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (0.47 g, 92.5% purity by HPLC using Method B, retention time 7.3 minutes); NMR Spectrum: (CDCl3) 1.65 (br s, 3H), 1.9-2.05 (m, 2H), 2.2-2.3 (m, 2H), 2.31 (s, 3H), 2.4-2.8 (m, 8H), 2.9 (m, 2H), 3.6-3.7 (m, 2H), 3.95-4.05 (m, 2H), 4.2-4.25 (m, 2H), 4.8 (m, 1H), 6.05 (s, 2H), 6.55 (s, 1H), 6.75 (d, 1H), 6.85 (s, 1H), 7.0 (d, 1H), 8.55 (s, 1H), 9.25 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:13]C(=O)OC(C)(C)C)[CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[CH:10][S:11][CH:12]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[C:4]([NH2:13])[CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[CH:10][S:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cscn2)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-c2cscn2)c(F)c1
Yield: 81.1 %

Procedure:
A solution of tert-butyl 3-fluoro-4-(thiazol-4-yl)phenylcarbamate (270 mg, 0.92 mmol) in CH2Cl2 (2 mL) and TFA (4 mL) was stirred at room temperature for 60 min. It was then concentrated in vacuo. The residue was dissolved in CH2Cl2 (20 mL), which was washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give 3-fluoro-4-(thiazol-4-yl)benzenamine (145 mg) as free base. MS 195.2 (M+H)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.CC(C)([O-])C.[K+].C(S[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[C:22]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[C:32]([F:42])[CH:31]=2)[N:21]=1)C.CO.ClCCl>CN(C)C=O>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)=[C:32]([F:42])[CH:31]=4)[N:21]=3)=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: CCSc1nc(-c2ccc(-c3ccccc3)c(F)c2)nc2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: Fc1cc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
A solution of 5-aminoindazole (0.020 g, 0.15 mmol) in dry N,N-dimethylformamide (4 mL) was added dropwise to a solution of potassium t-butoxide (0.017 g, 0.15 mmol) in dry N,N-dimethylformamide (1 mL). The reaction mixture went from green to red within a 20-minute period, and the contents were stirred at room temperature for 1 hour before the flask was treated with a solution of the compound of Example 37 (0.050 g, 0.14 mmol) in dry N,N-dimethylformamide (2 mL). The contents were stirred at room temperature for 2 hours, at which time TLC (silica gel 60, 5% methanol/dichloromethane, UV detection) analysis indicated complete consumption of starting quinazoline. The reaction mixture was poured into ethyl acetate (20 mL), and the organics were washed with brine (20 mL, 3×30 mL), dried over sodium sulfate and concentrated. The material was air-dried for 2 hours to give the product (0.031 g, 51%) as a pale-green solid. The NMR data was identical to that obtained in Example 5.
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=[O:34]>>[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33]([NH:1][C@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:12]=2)[CH2:7][CH2:6]1)=[O:34]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: O=C(Cl)c1cccc(Cl)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)c3cccc(Cl)c3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3-chlorobenzoyl chloride: ESMS m/e: 518.3 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:15]([Cl:16])=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[C:8]([Br:17])[CH:7]=1)(=O)C.O.[OH-].[Li+]>C1COCC1.CO.O>[Br:17][C:8]1[CH:7]=[C:6]([CH2:5][OH:4])[C:15]([Cl:16])=[CH:14][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: COC(=O)c1cc(Cl)c(COC(C)=O)cc1Br
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(Cl)c(CO)cc1Br
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.4 %

Procedure:
To a solution of acetate 27 (33.5 g, 104.1 mmol) in THF/MeOH/H2O (250 mL/250 mL/90 mL) was added lithium hydroxide monohydrate (13.1 g, 312 mmol). The mixture was stirred at room temperature for 15 h. The mixture was evaporated in vacuo to remove organic solvents. The residue was diluted with H2O, cooled to 0° C. and acidified with aq. 1 N HCl solution. The titled compound 28 was precipitated as a solid, filtered off and washed with H2O. The solid was dried under vacuum at 50° C. for 15 h to obtain the product (27.2 g, 96%). MH+265.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[N:8][CH:7]=[CH:6]2)=[O:2].[BH4-].[Na+].O>O1CCCC1.CO>[OH:2][CH2:1][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([NH:13][C:14](=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[N:8][CH:7]=[CH:6]2
Reactant: O=Cc1ccc2c(NC(=O)c3ccccc3)nccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(Nc1nccc2cc(CO)ccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 102.5 %

Procedure:
To a stirred suspension of 1.23 g of 1f in 40 mL of tetrahydrofuran and 15 mL of methanol was added 217 mg sodium borohydride in small portions. After stirring the mixture at ambient temperature for 5 min, 50 mL of water was added and tetrahydrofuran and methanol were removed in vacuo. Brine was added and the mixture was extracted with ethyl acetate. The ethyl acetate extract was dried (MgSO4) and concentrated under reduced pressure giving 1.27 g of 1g. 1H-NMR 200 MHz (CDCl3) δ: 4.75 (2H, s), 6.95 (1H, br.s), 7.30-7.55 (7H, m), 8.25-8.38 (2H, m), 8.69 (1H, br.s).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3O[C:36]([CH3:40])=[C:37]([CH3:39])[N:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[CH2:41]([NH:43]C=O)[CH3:42].C(N)C>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:43]([CH2:41][CH3:42])[C:36]([CH3:40])=[C:37]([CH3:39])[N:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCNC=O
Reactant: CCCc1nc2c(C)cc(-c3nc(C)c(C)o3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: CCN
Product: CCCc1nc2c(C)cc(-c3nc(C)c(C)n3CC)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 146 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-(4,5-dimethyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and N-ethylformamide/ethylamine.