Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:19])[C:5]([CH2:8][NH:9][C:10]([CH3:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH3:11])=[N:6][CH:7]=1.[CH3:20][O:21][C:22](=[O:33])[C:23]1[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:24]=1[CH2:31]Br.CCN(C(C)C)C(C)C>CC#N>[CH3:20][O:21][C:22](=[O:33])[C:23]1[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:24]=1[CH2:31][N:9]([CH2:8][C:5]1[C:4]([CH3:19])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)[C:10]([CH3:11])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH3:18]
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Reactant: Cc1cc(Cl)cnc1CNC(C)(C)c1ccccn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(C#N)ccc1CN(Cc1ncc(Cl)cc1C)C(C)(C)c1ccccn1

Procedure:
Using General Procedure A: Reaction of (5-chloro-3-methyl-pyridin-2-ylmethyl)-(1-methyl-1-pyridin-2-yl-ethyl)-amine in CH3CN with 2-bromomethyl-5-cyano-benzoic acid methyl ester, KI, and DIPEA gave 2-{[(5-chloro-3-methyl-pyridin-2-ylmethyl)-(1-methyl-1-pyridin-2-yl-ethyl)-amino]-methyl}-5-cyano-benzoic acid methyl ester as a pale yellow solid. 1H NMR (CDCl3) δ 1.60 (s, 6H), 2.17 (s, 3H), 3.80 (s, 2H), 3.91 (s, 3H), 4.24 (s, 2H), 7.10-7.12 (m, 2H), 7.47 (d, 1H, J=6.0 Hz), 7.63-7.65 (m, 1H), 7.77 (d, 2H, J=9.0 Hz), 7.88 (s, 1H), 8.03-8.09 (m, 2H), 8.56-8.57 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[C:6]=2[CH:18]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:30](B(O)O)=[CH:29][CH:28]=[N:27]2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[C:30]([C:2]3[CH:3]=[CH:4][C:5]4[N:9]=[CH:8][N:7]([C:10]5[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=5)[C:6]=4[CH:18]=3)=[CH:29][CH:28]=[N:27]2)=[CH:24][CH:25]=1
Reactant: COc1ccc(-n2cnc3ccc(Br)cc32)cc1
Reactant: OB(O)c1ccnn1-c1ccc(Cl)cc1
Product: COc1ccc(-n2cnc3ccc(-c4ccnn4-c4ccc(Cl)cc4)cc32)cc1

Procedure:
The title compound, off-white solid (16 mg, 12%), MS (ISP) m/z=401.5 [(M+H)+], mp 163° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-(4-methoxy-phenyl)-1H-benzo[d]imidazole (intermediate N) (100 mg, 330 μmol) and 1-(4-chloro-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate D) (88.1 mg, 396 μmol).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[CH2:21][CH2:20][NH:19][CH2:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:23]1[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[CH2:21][CH2:20][N:19]([C:23]4[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)c1cccnc1Cl
Reactant: CC(C)(C)c1ccc(Nc2ncnc3c2CCNC3)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)c1ccc(Nc2ncnc3c2CCN(c2ncccc2S(C)(=O)=O)C3)cc1
Temperature: 25 °C
Yield: 48 %

Procedure:
A mixture of N-(4-tert-butylphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine prepared as described in Example 3.A. (0.066 g, 0.23 mmol), 2-chloro-3-(methylsulfonyl)pyridine (Ponticello et al, J. Org. Chem., 44(17), 1979), (0.088 g, 0.47 mmol) and N,N-diisopropylethlamine (0.041 mL, 0.23 mmol) was heated in a sealed tube via microwave (Emrys Optimizer model, Personal Chemistry) for 30 min at 150° C. The reaction mixture was cooled to r.t. and poured into water (20 mL). The mixture was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated to leave an oil which was purified by silica gel chromatography (ethyl acetate/hexane gradient) to give the title compound as a white solid (0.049 g, 48%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[S:13][CH2:12][CH2:11][CH2:10]2)=[O:4].[OH-].[Na+]>C(O)C>[S:13]1[C:14]2[C:9](=[CH:8][CH:7]=[CH:6][C:5]=2[C:3]([OH:4])=[O:2])[CH2:10][CH2:11][CH2:12]1
Reactant: COC(=O)c1cccc2c1SCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cccc2c1SCCC2
Reaction time: 5 h
Yield: 76.5 %

Procedure:
Methylthiochroman-8-carboxylate (0.220 g, 1.05 mmol) was dissolved in ethanol (5 ml) and treated with 10% sodium hydroxide solution (10 ml). The mixture was then heated to reflux with stirring. After 5 h, the reaction mixture was allowed to cool. The ethanol present was then removed by evaporation under reduced pressure. The aqueous residue was then washed with CH2Cl2 (2×) before being acidified to pH1 using 5M HCl. The resultant pale yellow precipitate was then filtered off and dried in vacuo to give the title compound (0.156 g, 76%) (D6).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:14])[C:8](I)=[CH:9][O:10]2)=[CH:5][CH:4]=1.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[N:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:9]2[O:10][C:11]3[C:6]([C:7](=[O:14])[CH:8]=2)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)=[N:16]1
Reactant: c1ccc2[nH]ncc2c1
Reactant: COc1ccc2c(=O)c(I)coc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(=O)cc(-c3n[nH]c4ccccc34)oc2c1
Temperature: 0 °C
Yield: 27.7 %

Procedure:
A mixture of 7-methoxy-3-iodochromone (151 mg) prepared in Example 21, indazole (236 mg), potassium carbonate (1382 mg), and dimethylformamide (15 ml) was reacted at 80° C. for 2 hours with stirring. The reaction mixture was added to ice water and extracted from chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by the silica gel column chromatography, and recrystallized from benzene/hexane to give the titled compound (40.5 mg; yield=27.6%) as golden crystals. Melting point: 218°-220° C. 1H-NMR(CDCl3, δ ppm): 3.97 (s, 3H, CH3O), 6.83 (s, 1H, H3), 8.16 (dd, 1H, H5), 7.02 (s, 1H, H6), 7.01 (s, 1H, H8), 8.27 (s, H3'), 7.36 (d, 1H, H4'), 7.06 (d, 1H, H5'), 7.80 (d, 1H, H6').
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:12][C@H:13]1[C:17](=[O:18])[N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][C@H:14]1[C:25]([O:27]C(C)(C)C)=[O:26])=[O:11]>FC(F)(F)C(O)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:12][C@H:13]1[C:17](=[O:18])[N:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:15][C@H:14]1[C:25]([OH:27])=[O:26])=[O:11]
Reactant: CC(C)(C)OC(=O)[C@@H]1CN(c2ccccc2)C(=O)[C@@H]1NC(=O)c1cc2ccccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@H]1C(=O)N(c2ccccc2)C[C@H]1C(=O)O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 43.4 %

Procedure:
The tert-butyl ester of Example 5 (110 mg, 0.26 mmol) was dissolved in 3 ml of trifluoroacetic acid and the resulting solution was stirred for 2 days at room temperature. Concentration in vacuo gave an oil which was chromatographed on silica gel eluting with 5/91/1 EtOH/CH2Cl2 /HOAc to give the title compound (41 mg, 43%) as a colorless solid. MS calcd C20H17N3O4 363, found 363. DSC=214.2°-229.3° C. @48.7 J/g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[C:13]([F:15])([F:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:21][CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1>>[NH2:18][C:10]1[O:11][C:12]([CH3:16])([CH3:17])[C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30]([C:27]3[CH:26]=[CH:25][C:24]([O:23][CH2:22][F:21])=[CH:29][N:28]=3)=[O:31])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: CC1(C)OC(N)=N[C@](C)(c2cc(N)ccc2F)C1(F)F
Reactant: O=C(O)c1ccc(OCF)cn1
Product: CC1(C)OC(N)=N[C@](C)(c2cc(NC(=O)c3ccc(OCF)cn3)ccc2F)C1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-2) and 5-fluoromethoxy-pyridine-2-carboxylic acid (CAS1174321-03-9, WO2009091016) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=441.3 [M+H]+.
Reaction SMILES: [NH2-].[Na+].O1CCCC1.[C:8]([CH:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)#[N:9].[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27]Cl>O>[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27][C:10]1([C:8]#[N:9])[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: CN(C)CCCCl
Reactant: N#CC1c2ccccc2-c2ccccc21
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCCC1(C#N)c2ccccc2-c2ccccc21
Temperature: 25 °C

Procedure:
To a stirred solution of 2.6 g. of sodium amide in 200 ml. of tetrahydrofuran was added dropwise over thirty minutes a solution of 12.7 g. of 9-cyanofluorene in 300 ml. of tetrahydrofuran. The reaction mixture was next heated to reflux for three hours, and then cooled to room temperature. While the reaction mixture was being stirred at room temperature, a solution of 14.2 g. of 3-dimethylaminopropyl chloride in 500 ml. of tetrahydrofuran was added dropwise over one hour. Following complete addition, the reaction mixture was again heated to reflux and stirred for sixteen hours. After cooling the mixture to room temperature, it was added to 500 ml. of water. The product was extracted into diethyl ether, and the ethereal extracts were combined, washed with water and dried. Removal of the solvent by evaporation under reduced pressure afforded, after distillation, 2.3 g. of 9-(3-dimethylaminopropyl)-9-cyanofluorene. B.P. 195°-201° C.at 0.1 torr.
Reaction SMILES: [N:1]1([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH2:28][CH:29]([OH:32])[CH2:30][CH3:31])[CH:23]=5)[C:18]4=[O:33])=[CH:13][C:12]=3[F:34])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:35]I>>[N:1]1([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH2:28][CH:29]([O:32][CH3:35])[CH2:30][CH3:31])[CH:23]=5)[C:18]4=[O:33])=[CH:13][C:12]=3[F:34])[CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CI
Reactant: CCC(O)COc1ccc2c(=O)n(-c3ccc(N4CC[C@@H](N5CCCC5)C4)c(F)c3)ccc2c1
Product: CCC(COc1ccc2c(=O)n(-c3ccc(N4CC[C@@H](N5CCCC5)C4)c(F)c3)ccc2c1)OC

Procedure:
According to Method AA, 2-((R)-4-[1,3′]bipyrrolidinyl-1′-yl-3-fluorophenyl)-6-(2-hydroxy-butoxy)-2H-isoquinolin-1-one was reacted with methyl iodide. In this way the product was obtained with molecular weight 479.60 (C28H34FN3O3); MS (ESI): 480 (M+H+).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)=[O:12])[CH2:5][CH2:4]1.C(N(CC)CC)C.[O:32]([CH2:39][CH2:40][CH2:41][CH2:42]Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(O)C>[O:32]([CH2:39][CH2:40][CH2:41][CH2:42][N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)=[O:12])[CH2:5][CH2:4]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCCCCOc1ccccc1
Reactant: O=C(NCC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(NCC1CCN(CCCCOc2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1

Procedure:
To a solution of 0.58 g (1.5 mM) of N-(piperidin-4-ylmethyl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 1.0 ml (27.5 mM) of triethylamine in ethanol (6 ml) was added 0.45 g (1.96 mM) of 4-phenoxybutyl bromide at room temperature and the mixture was refluxed under nitrogen for 14 hours. To this reaction mixture was further added 0.23 g (1.0 mM) of 4-phenoxybutyl bromide and the mixture was refluxed for 6 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The resulting crude product was purified by column chromatography (methanol/chloroform=1/15-1/10-1/5) to provide the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[CH:19]=O)[CH:11]=1)[CH3:2].C([BH3-])#N.[Na+].[CH2:26]([NH2:28])[CH3:27].C(O)(=O)C>CO>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[CH2:19][NH:28][CH2:26][CH3:27])[CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cncc(-c2ccc(F)cc2C=O)c1
Reactant: CCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCNCc1cc(F)ccc1-c1cncc(CC(=O)OCC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To [5-(4-fluoro-2-formyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester (1.2 g, 4.18 mmol) in MeOH was added sodium cyanoborohydride (0.394 g, 6.26 mmol) and ethylamine (2M in THF; 3.13 mL, 6.26 mmol). Acetic acid (0.36 mL, 6.26 mmol) was added, and the reaction was stirred for 2 hours at room temperature. The mixture was concentrated, and the residue was dissolved in CH2Cl2 and washed with saturated aqueous NaHCO3 and H2O. The organic layer was dried over Na2SO4, filtered, and concentrated, and the residue was purified by silica gel chromatography (0-10% MeOH in CH2Cl2) to give [5-(2-ethylaminomethyl-4-fluoro-phenyl)-pyridin-3-yl]-acetic acid ethyl ester.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([CH:14]=C)[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].C[OH:19]>>[CH:14]([C:12]1[CH:11]=[C:5]([CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:19]
Reactant: C=Cc1cc(C(=O)OCC)cc(C(F)(F)F)c1
Reactant: CO
Product: CCOC(=O)c1cc(C=O)cc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
25.39 g (103.96 mmol) of ethyl 3-(trifluoromethyl)-5-vinylbenzoate 33 is dissolved in dry MeOH (200 mL) and reaction vessel Is cooled down to −78° C. Then O3 is bubbled through for 1.5 hours until the reaction mixture turned dark blue. Then ozone is turned off and nitrogen is bubbled through the reaction mixture to remove extra ozone from the solution. 9.6 g of dimethyl sufide (155.95 mmol, 1.5 eq) is added and the reaction mixture is stirred at −78° C. for 2 hours followed by at room temperature for another hour. All the solvents are removed and ethyl 3-formyl-5-(trifluoromethyl)benzoate 34 is isolated via flash column chromatography (5-10% EtOAc/Hex). MS: m/z [M+H+]) 247.18, 1H NMR 10.16 (s, 1H), 8.73 (s, 1H), 8.56, (s, 1H), 8.35 (s, 1H), 4.46-4.51 (q, 2H, J=7.21 Hz), 1.45-1.49 (t, 3H, J=7.21 Hz).
Reaction SMILES: [CH:1]1([CH:7]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:34])=[CH:29][CH:28]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][S:23][CH3:24])=[CH:15][CH:14]=3)[O:10][C:9]=2[CH3:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:43]OS([O-])=O.[K+]>CO.O>[CH:1]1([CH:7]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:34])=[CH:29][CH:28]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][S:23]([CH3:24])=[O:43])=[CH:17][CH:18]=3)[O:10][C:9]=2[CH3:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S([O-])OO
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2cc(-c3ccc(OCCCSC)cc3)oc2C)C2CCCCC2)cc1
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2cc(-c3ccc(OCCCS(C)=O)cc3)oc2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
Ethyl 3-{[(4-{[cyclohexyl(2-methyl-5-{4-[3-(methylsulfanyl)propoxy]phenyl}furan-3-yl)methyl]amino}phenyl)carbonyl]amino}propanoate (296 mg) was dissolved in methanol (9 mL) and water (1 mL), OXONE (277 mg) was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (0% methanol/ethyl acetate to 20% methanol/ethyl acetate) to give the title compound (278 mg, 91%) as an oil.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:13]=[C:14]([CH:16]=1)[NH2:15].CCCCCC>C1(C)C=CC=CC=1>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:17]([F:18])([F:19])[F:20])[CH:13]=[C:14]([NH:15][C:1](=[O:3])[CH3:2])[CH:16]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COc1cc(NC(C)=O)cc(C(F)(F)F)c1
Reaction time: 1.5 h

Procedure:
Acetic anhydride (1.22 ml, 12.8 mmol) is added during 10 min to a solution of 5-methoxy-3-trifluoromethyl-aniline (2.29 g, 12.0 mmol) in toluene (10 ml) at a temperature of 25-33° C. After 90 min at RT, hexane (10 ml) is added und the suspension is stirred for 20 min. Filtration, washing with toluene/hexane 2:1 and hexane gives the title compound: mp: 123-124° C.; API-MS: 234 [MH]+; TLC: Rf=0.27 (Hex/EtOAc, 1:1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:15].[O:16]=[C:17]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)[CH2:18][CH2:19][C:20](O)=[O:21].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O>[O:16]=[C:17]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)[CH2:18][CH2:19][C:20]([NH:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[NH:7][C:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[CH:14]2)=[O:21]
Reactant: O=C(O)CCC(=O)c1cccs1
Reactant: Nc1cccc2cc(-c3nccs3)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCC(=O)c1cccs1)Nc1cccc2cc(-c3nccs3)[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 220.3 %

Procedure:
To a mixture of 2-(1,3-thiazol-2-yl)-1H-indole-7-amine (0.31 g), 4-oxo-4-(2-thienyl)butanoic acid (0.89 g), 1H-1,2,3-benzotriazol-1-ol (0.75 g) and N,N-dimethylformamide (20 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1.06 g), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography and the title compound (1.21 g, yield. 69%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (3:1, volume ratio). melting point 140-141° C.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1F)[NH:18][CH:17]=[N:16][C:15]2=[O:23].O>CN(C)C=O>[CH2:1]([O:8][C:21]1[CH:20]=[C:19]2[C:14]([C:15](=[O:23])[N:16]=[CH:17][NH:18]2)=[CH:13][C:12]=1[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=c1nc[nH]c2cc(F)c(F)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1nc[nH]c2cc(OCc3ccccc3)c(F)cc12
Temperature: 60 °C
Yield: 83.2 %

Procedure:
Benzyl alcohol (4.27 g, 39.5 mmol) was added dropwise to a stirred suspension of sodium hydride (1.6 g of a 60% dispersion in mineral oil, 40.0 mmol) in dimethylformamide (50 ml) at 0° C. The reaction was stirred at 0° C. for 1 hour before addition of 6,7-difluoroquinazolin-4(1H)-one (3.60 g, 19.8 mmol) whereupon the reaction was heated to 60° C. for 2 hours. The reaction was cooled to ambient temperature, poured into water (200 ml) and the resultant solid collected by suction filtration. Drying of the solid in vacuo yielded 7-(benzyloxy)-6-fluoroquinazolin-4(1H)-one (4.45 g, 83% yield) as a pale brown solid:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[CH:11][C:10]([C:13]3[CH:26]=[CH:25][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)=[CH:15][CH:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.Br[C:28]1([CH2:37][CH2:38][O:39][CH2:40][CH3:41])[C:33](=[O:34])[NH:32][C:31](=[O:35])[NH:30][C:29]1=[O:36]>>[CH2:40]([O:39][CH2:38][CH2:37][C:28]1([O:24][C:21]2[CH:22]=[CH:23][C:18]([O:17][C:16]3[CH:15]=[CH:14][C:13]([C:10]4[CH:11]=[CH:12][N:8]([C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=5)[N:9]=4)=[CH:26][CH:25]=3)=[CH:19][CH:20]=2)[C:29](=[O:36])[NH:30][C:31](=[O:35])[NH:32][C:33]1=[O:34])[CH3:41]
Reactant: Oc1ccc(Oc2ccc(-c3ccn(-c4cccc(F)c4)n3)cc2)cc1
Reactant: CCOCCC1(Br)C(=O)NC(=O)NC1=O
Product: CCOCCC1(Oc2ccc(Oc3ccc(-c4ccn(-c5cccc(F)c5)n4)cc3)cc2)C(=O)NC(=O)NC1=O

Procedure:
By the same procedure as Example 1, Part C, 4-{4-[1-(3-fluorophenyl)-1H-pyrazol-3-yl]-phenoxy}phenol and 5-bromo-5-(2-ethoxyethyl)-pyrimidine-2,4,6-trione (from Preparation 3B) were converted to the title compound. MS m/z: ESI+545.4 (M+H)+, ESI-543.3 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1([CH2:5][OH:6])[CH2:4][CH2:3]1.[CH3:7][S:8](Cl)(=[O:10])=[O:9]>C(Cl)Cl>[CH3:7][S:8]([O:6][CH2:5][C:2]1([CH3:1])[CH2:4][CH2:3]1)(=[O:10])=[O:9]
Reactant: CC1(CO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC1(COS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
Treat a 0° C. solution of (1-methylcyclopropyl)methanol (1.0 g, 11.61 mmol) in DCM (50 mL) with TEA (1.29 g, 12.77 mmol), add methanesulfonyl chloride (1.46 g, 12.77 mmol) drop-wise and stir at 0° C. for 2 h. Warm the mixture to RT, wash with H2O, then brine, dry over Na2SO4 and concentrate to dryness to afford the title compound (1.85 g, 97%) as an oil. 1H NMR (400 MHz, DMSO-d6): δ 4.05 (s, 2H), 3.20 (s, 3H), 1.17 (s, 3H), 0.59 (m, 2H), 0.47 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:8](COCC[Si](C)(C)C)[CH:7]=[C:6]([C:29]#[N:30])[C:5]2=[O:31].N1C=CN=[CH:33]1>C(O)=O>[N:15]1([CH2:14][CH2:13][N:12]2[C:11]3[C:2](=[CH:3][C:4]4[C:5](=[O:31])[C:6]([C:29]#[N:30])=[CH:7][NH:8][C:9]=4[CH:10]=3)[N:1]=[CH:33]2)[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: c1c[nH]cn1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)c(=O)c2cc(N)c(NCCN3CCOCC3)cc21
Solvent: O=CO
Product: N#Cc1c[nH]c2cc3c(cc2c1=O)ncn3CCN1CCOCC1
Yield: 49.4 %

Procedure:
A mixture of 422 mg (0.95 mmol) of 6-amino-7-{[2-(4-morpholinyl)ethyl]amino}-4-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,4-dihydro-3-quinolinecarbonitrile, 258.7 mg (3.80 mmol) of imidazole in 6 mL of 96% formic acid is refluxed for 6.5 hours. After cooling, the mixture is concentrated under reduced pressure and the residue is diluted with water. Undissolved solid is filtered off and washed with water. The combined filtrate and water washes are brought to pH 8 with 28% ammonium hydroxide aqueous solution. The precipitate is collected by filtration and washed with water. After drying in vacuo, this yields 190.0 mg of the crude product as a yellow solid. The crude product is purified by flash chromatography (elution with methylene chloride, then a gradient of 99:1 to 88:12 methylene chloride/methanol) to give 151.6 mg (49.3%) of the pure product as an off-white solid, mp>270° C.
Reaction SMILES: [Cl-].[OH:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][CH:29]=1)[CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:30]([C:32]1[N:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]2)=[CH:34][CH:33]=1)=O>>[OH:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:30][C:32]2[N:37]=[CH:36][C:35]([N:38]3[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]3)=[CH:34][CH:33]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: OCc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)nc2)CC1
Agent: [Cl-]
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C=Cc3cccc(CO)c3)nc2)CC1
Yield: 70.3 %

Procedure:
By a method similar to Production Example 108, step 4, [3-(hydroxymethyl)benzyl](triphenyl)phosphonium chloride (1.675 g, 3.998 mmol) and tert-butyl 4-(6-formylpyridin-3-yl)piperazine-1-carboxylate (1.165 g, 4.000 mmol) were condensed to give tert-butyl 4-(6-{2-[3-(hydroxymethyl)phenyl]vinyl}pyridin-3-yl)piperazine-1-carboxylate (1.111 g, yield 70.2%, E/Z mixture) as a yellow solid.