Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:33])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[C:18]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:16])=[CH:10][CH:9]=1)[CH3:4].I[CH3:35].O>CN(C)C=O>[CH2:3]([O:5][C:6](=[O:33])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]([CH3:35])[C:15]([C:17]2[C:18]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:27][CH:28]=3)=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:16])=[CH:12][CH:13]=1)[CH3:4]
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(N(C)C(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
Sodium hydride (51 mg) was dissolved in dimethylformamide (5 mL), and the solution was cooled to 0° C. To the solution was added the 4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenylacetic acid ethyl ester (500 mg) obtained in Example 1e), and the mixture was stirred for one hour. After addition of iodomethane (183 mg), the mixture was stirred at room temperature for 3 hours and water was then added. The reaction solution was concentrated, diluted with ethyl acetate, and washed with water. The resulting solution was dried over sodium sulfate and purified by column chromatography on silica gel with hexane:ethyl acetate=4:1 to give the title compound (141 mg).
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14](Cl)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[NH2:18][C:19]1[CH:27]=[CH:26][C:25]2[NH:24][C:23]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:22][C:21]=2[C:20]=1[C:32]#[N:33].C(N(CC)CC)C>CN(C=O)C>[C:28]([C:23]1[NH:24][C:25]2[C:21]([CH:22]=1)=[C:20]([C:32]#[N:33])[C:19]([NH:18][C:14]([C:11]1([C:9]3[CH:8]=[CH:7][C:5]4[O:6][C:2]([F:17])([F:1])[O:3][C:4]=4[CH:10]=3)[CH2:13][CH2:12]1)=[O:15])=[CH:27][CH:26]=2)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)c1cc2c(C#N)c(N)ccc2[nH]1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc2c(C#N)c(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (26 mg, 0.1 mmol) was added to a solution of 5-amino-2-tert-butyl-1H-indole-4-carbonitrile (21 mg, 0.1 μmol) and triethylamine (41.7 μL, 0.3 mmol) in DMF (1 mL). The reaction was stirred at room temperature overnight, then filtered and purified by reverse-phase HPLC to yield the product, N-(2-tert-butyl-4-cyano-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 437.2, found 438.7 (M+1)+. Retention time 2.10 minutes. 1H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 8.88 (s, 1H), 7.52 (d, J=8.5 Hz, 2H), 7.41 (d, J=8.3 Hz, 1H), 7.32 (dd, J=1.5, 8.3 Hz, 1H), 7.03 (d, J=8.6 Hz, 1H), 6.21 (d, J=1.8 Hz, 1H), 1.51-1.49 (m, 2H), 1.36 (s, 9H), 1.18-1.16 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)N.N([O-])=[O:15].[Na+].O>Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:15])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1
Reactant: O=N[O-]
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1cc(O)cc(C(F)(F)F)c1
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
3-Methoxy-5-(trifluoromethyl)aniline. (5 g) was suspended in 20% HCl (200 mL), stirred for 30 min, cooled to 0-5° C. and diazotized with NaNO2 (2.17 g) added in small portions. The mixture was stirred for 30 min at that temperature and added dropwise to boiling water (200 mL). The mixture was refluxed for 15 min, allowed to cool to room temperature and extracted with AcOEt, dried (MgSO4), filtered and evaporated. The residue was then purified by column chromatography (silica gel; eluent: hexane and AcOEt) to give 3-methoxy-5-(trifluoromethyl)phenol (3.6 g)
Reaction SMILES: [CH2:1]([N:3]([CH2:38][CH3:39])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[C:34]([F:37])[C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:71]([NH2:75])([CH3:74])([CH3:73])[CH3:72]>CN(C=O)C>[CH2:38]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[C:34]([F:37])[C:35]=2[CH3:36])[C:30]([NH:75][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:39]
Reactant: CC(C)(C)N
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NC(C)(C)C)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.3 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-5-fluoro-4-methylbenzoic acid (30 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and t-butylamine (8.71 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (14.8 mg, 46%). LC-MS m/z 595 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[O:11][CH:12]=2)[CH:7]=1.C1COCC1.[OH-].[Na+:27]>CO>[Na+:27].[Na+:27].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O-:19])=[O:18])[O:11][CH:12]=2)[CH:7]=1.[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O-:19])=[O:18])[O:11][CH:12]=2)[CH:7]=1
Reactant: O=C(O)CCCCc1nc(-c2cc(Cl)ccc2O)co1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C([O-])CCCCc1nc(-c2cc(Cl)ccc2O)co1

Procedure:
Combine 5-[4-(5-Chloro-2-hydroxy-phenyl)-oxazol-2-yl]-pentanoic acid (2.71 g, 9.2 mmol) with THF (10 mL), MeOH (10 mL) and 1N NaOH (18.4 mL) and stir at RT for 2 h. Concentrate the mixture and dry the residue overnight in vacuo at 40-50° C. to allow for recovery of 5-[4-(5-Chloro-2-hydroxy-phenyl)-oxazol-2-yl]-pentanoic acid disodium salt (3.0 g, 96%). MS (ES): (M+1)+ 296.1, 298.1 m/z.
Reaction SMILES: C([O:3][C:4](=[O:39])[C@@H:5]([NH:15][C@H:16]([C:31](=[O:38])[NH:32][C:33]1[NH:37][N:36]=[N:35][N:34]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)=[CH:20][CH:19]=1)[CH2:6][O:7]CC1C=CC=CC=1)C>CCOC(C)=O.CCO.[Pd]>[Cl:30][C:26]1[CH:25]=[C:24]([C:21]2[CH:20]=[CH:19][C:18]([CH2:17][C@H:16]([NH:15][C@@H:5]([CH2:6][OH:7])[C:4]([OH:39])=[O:3])[C:31](=[O:38])[NH:32][C:33]3[NH:37][N:36]=[N:35][N:34]=3)=[CH:23][CH:22]=2)[CH:29]=[CH:28][CH:27]=1.[C:21]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:20]=[CH:19][C:18]([CH2:17][C@H:16]([NH:15][C@@H:5]([CH2:6][OH:7])[C:4]([OH:39])=[O:3])[C:31](=[O:38])[NH:32][C:33]2[NH:34][N:35]=[N:36][N:37]=2)=[CH:23][CH:22]=1
Reactant: CCOC(=O)[C@H](COCc1ccccc1)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)Nc1nnn[nH]1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)[C@H](CO)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)Nc1nnn[nH]1
Product: O=C(O)[C@H](CO)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)Nc1nnn[nH]1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
To a solution of (S)-3-benzyloxy-2-[(S)-2-(3′-chloro-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethylamino]-propionic acid ethyl ester (47 mg, 0.090 mmol) in EtOAc (1 mL) and EtOH (1 mL) was added 5% Pd—C (9.6 mg, 0.0045 mmol). H2 gas was loaded with a balloon and the reaction mixture was stirred at 50° C. for 6 hours. The reaction mixture was filtered through celite pad and the filtrate was concentrated. The residue was purified by reverse phase HPLC (Sunfire C-18 column, eluent: 0.1% TFA in H2O/CH3CN) to give (S)-2-[(S)-2-(3′-chloro-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethylamino]-3-hydroxy-propionic acid and (S)-2-[(S)-2-biphenyl-4-yl-1-(1H-tetrazol-5-ylcarbamoyl)-ethylamino]-3-hydroxy-propionic acid.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[C:4]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:5]=1[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.CCN(C(C)C)C(C)C.[C:52](Cl)(Cl)=[O:53].C1(C)C=CC=CC=1.N.[CH2:64]([OH:66])[CH3:65]>C(Cl)Cl>[CH2:64]([O:66][C:52]([N:40]1[CH2:39][CH2:38][CH:37]([CH:3]([C:4]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:5]=2[CH2:6][N:7]([CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[C:8]2[N:9]=[N:10][N:11]([CH3:13])[N:12]=2)[O:2][CH3:1])[CH2:42][CH2:41]1)=[O:53])[CH3:65]
Reactant: O=C(Cl)Cl
Reactant: CCO
Reactant: COC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCNCC1
Agent: N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(C(OC)c2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34 %

Procedure:
To a solution of N-(2-(methoxy(piperidin-4-yl)methyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine (19.4 mg, 0.032 mmol) in methylene chloride (0.5 mL) at room temperature was added Hunig's base (8.9 mg, 12 μL, 0.069 mmol) followed by phosgene in toluene (20%, 25 μL, 0.048 mmol). The mixture was stirred at room temperature for 3 hours. Ammonia in ethanol (1 mL) was added and the mixture was stirred at room temperature overnight. Solvent was removed in vacuo The residue was purified by chromatography over 12+S Biotage silica column (eluted with 0-50% ethyl acetate in hexane) to afford the title compound (7.4 mg, 34%). 1H NMR (400 MHz, CDCl3) δ ppm 1.11-1.18(m, 1H) 1.20-1.31 (m, 2H) 1.24(t, J=7.05 Hz, 3H) 1.61-1.71 (m, 1H) 1.85(d, J=12.86 Hz, 1H) 2.56 (q, J=14.94 Hz, 2H) 3.04 (s, 3H) 4.05-4.19 (m, 2H) 4.10 (q, J=7.05 Hz, 2H) 4.16 (d, J=7.05 Hz, 1H) 4.21 (s, 3H) 4.68 (d, J=15.77 Hz, 1H) 4.71 (s, 2H) 4.88 (d, J=15.77 Hz, 1H) 7.36 (s, 1H) 7.50 (d, J=7.88 Hz, 1H) 7.58 (d, J=8.71 Hz, 1H) 7.64 (s, 2H) 7.78 (s, 1H). MS (ES+) Calc: 682.6, Found: 683.6 (M+1)
Reaction SMILES: [C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11](Cl)=[O:12])=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2].[CH3:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>N1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([N:22]2[CH2:23][CH2:24][CH:19]([CH3:18])[CH2:20][CH2:21]2)=[O:12])=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2]
Reactant: CC1CCNCC1
Reactant: COc1cc(C=CC(=O)Cl)ccc1OC(C)=O
Solvent: c1ccncc1
Product: COc1cc(C=CC(=O)N2CCC(C)CC2)ccc1OC(C)=O

Procedure:
Using 5.09 g of 4-acetoxy-3-methoxycinnamoyl chloride, 2.4 ml of 4-methylpiperidine, and 100 ml of pyridine, a reaction similar to that conducted in Example 53 was carried out. As a result, 5.2 g of 1-(4-acetoxy-3-methoxycinnamoyl)-4-methylpiperidine (a compound of the present invention) was obtained as an orange-yellow oil, which had the following physiochemical properties:
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: BrCc1ccccn1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3ccccn3)C2=O)cn1
Yield: 50 %

Procedure:
Prepared as in Example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione and 2-(bromomethyl)pyridine. Yield: 50%. 1H NMR (CDCl3, 400 MHz): δ 2.19 (s, 3H), 2.41 (s, 3H), 4.12 (s, 2H), 4.71 (s, 2H), 5.05 (s, 2H), 7.72-7.23 (m, 4H), 7.92 (s, 1H) 8.08 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.68 μM.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[C:10]([CH:23]=[O:24])=[N:11][C:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[CH3:22])=[CH:13][N:14]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([NH:21][C:5](=[O:7])[CH3:6])[CH:18]=[CH:17][C:16]=2[CH3:22])=[N:11][C:10]=1[C:23]([C:27]1[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=1)=[O:24]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccncc1
Reactant: Cc1ccc(N)cc1-c1cnc(N)c(C=O)n1
Product: CC(=O)Nc1ccc(C)c(-c2cnc(N)c(C(=O)c3cccnc3)n2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (19.7 ml, 0.21 mmol) is added to solution of Example 110 (48.5 mg, 0.15 mmol) in pyridine (1.5 ml), and the resulting solution is stirred at room temperature for 2 hours. The solvent is removed in vacuo and trituration with methanol and diethyl ether yields the title compound as a yellow solid; MS m/z 348 [M+H]+
Reaction SMILES: [OH:1][C:2]1[C:10]2[O:9][C:8]([C:11]([O:13]CC)=[O:12])=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([CH3:17])[C:3]=1[CH3:18].[OH-].[Na+].Cl>CO.C1COCC1>[OH:1][C:2]1[C:10]2[O:9][C:8]([C:11]([OH:13])=[O:12])=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([CH3:17])[C:3]=1[CH3:18]
Reactant: CCOC(=O)c1oc2c(O)c(C)c(C)cc2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2c(C)c(C(=O)O)oc2c(O)c1C
Temperature: 0 °C

Procedure:
Ethyl 7-hydroxy-3,5,6-trimethylbenzofuran-2-carboxylate (90 g, 0.37 mole) (from Preparation 2, Step 3) was dissolved in 1:1 MeOH/THF (600 mL) and cooled to 0° C. Dropwise addition of 2N NaOH (750 mL) followed by warming to room temperature for a 2 hr period effected saponification of the ester. The reaction was acidified with conc. HCl (150 mL) and the product extracted into EtOAc, dried (Na2SO4) and the solvent evaporated to give the carboxylic acid used directly in the next step.
Reaction SMILES: CC([O-])(C)C.[K+].[NH:7]1[CH:11]=[CH:10][CH:9]=[N:8]1.Cl[C:13]1[C:30]2[C:17](=[C:18]3[C:27](=[CH:28][CH:29]=2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[S:20](=[O:32])(=[O:31])[NH:19]3)[N:16]=[CH:15][CH:14]=1>CS(C)=O>[N:7]1([C:13]2[C:30]3[C:17](=[C:18]4[C:27](=[CH:28][CH:29]=3)[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[S:20](=[O:31])(=[O:32])[NH:19]4)[N:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[N:8]1
Reactant: c1cn[nH]c1
Reactant: O=S1(=O)Nc2c(ccc3c(Cl)ccnc23)-c2ccccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=S1(=O)Nc2c(ccc3c(-n4cccn4)ccnc23)-c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28.5 %

Procedure:
KOtBu (76 mg, 0.68 mmol) was added to a solution of pyrazole (51 mg, 0.76 mmol) in DMSO (1 ml) at 0° C. in a sealed tube and the mixture was stirred at room temperature for 15 min. 1-Chloro-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide 305 (80 mg, 0.252 mmol) was added and the mixture was heated at 100° C. for 4 h. After cooling, the mixture was poured onto ice and the aqueous was extracted with iPA: chloroform (30:70). The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with chloroform/MeOH (98:2) to give the title compound (25 mg, 29%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[CH2:6][NH:7]C(=O)OC(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][NH2:7])[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1
Reactant: COc1ccc(COc2ccc(CNC(=O)OC(C)(C)C)cc2OC)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(COc2ccc(CN)cc2OC)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
To a stirred solution of tert-butyl 3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzylcarbamate (31.92 g, 85.25 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (75 mL, 973.5 mmol). The resulting yellow solution was allowed to stir at room temperature. After 2 h, the reaction mixture was concentrated to dryness, and the residue was dissolved in water (250 mL). The acidic solution was extracted with diethyl ether (2×125 mL; organic phases discarded). The aqueous phase was then made basic with concentrated ammonium hydroxide. The basic aqueous phase was then extracted with dichloromethane (2×200 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to provide 21.46 g (92%) of (3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)methanamine as an off-white solid.
Reaction SMILES: [C:1]([Si:5]([CH3:33])([CH3:32])[O:6][C@H:7]1[CH2:11][CH2:10][C@H:9]([N:12]2[C:17]3=[N:18][C:19](Cl)=[N:20][CH:21]=[C:16]3[CH2:15][N:14]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH3:30])=[CH:25][CH:24]=3)[C:13]2=[O:31])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C.ClCCl>[C:1]([Si:5]([CH3:33])([CH3:32])[O:6][C@H:7]1[CH2:11][CH2:10][C@H:9]([N:12]2[C:17]3=[N:18][C:19]([NH:39][C:38]4[CH:40]=[CH:41][C:35]([F:34])=[CH:36][CH:37]=4)=[N:20][CH:21]=[C:16]3[CH2:15][N:14]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH3:30])=[CH:25][CH:24]=3)[C:13]2=[O:31])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(F)cc1
Reactant: CCc1ccc(N2Cc3cnc(Cl)nc3N([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)C3)C2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CC(C)O
Solvent: O
Product: CCc1ccc(N2Cc3cnc(Nc4ccc(F)cc4)nc3N([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)C3)C2=O)cc1
Temperature: 160 °C

Procedure:
(±)-1-[trans-3-(tert-Butyl-dimethyl-silanyloxy)-cyclopentyl]-7-chloro-3-(4-ethyl-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (125 mg, 0.25 mmol) (from Example 39b supra) was suspended in 2-propanol (3 mL) (Fisher). 4-Fluoroaniline (0.036 mL, 0.38 mmol) (Aldrich) and p-toluenesulfonic acid mono-hydrate (12.5 mg, 0.05 mmol) (Aldrich) were added and the mixture was heated to 160° C. in a microwave synthesizer (SmithSynthesizer®) for 30 minutes. After cooling to room temperature, the heterogeneous reaction mixture was diluted with dichloromethane. The resulting solution was washed with 1 N aqueous hydrochloric acid. The layers were separated and the organic phase was dried over anhydrous sodium sulfate, filtered and then concentrated under reduce pressure to give (±)-1-[trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-3-(4-ethyl-phenyl)-7-(4-fluoro-phenylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a pale green solid. (Yield 123 mg, 85%).
Reaction SMILES: O1C2C=CC=CC=2C=C1C1CCCOC1[N:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25]([NH:27][CH:28]([CH3:30])[CH3:29])=[O:26])=[CH:22][CH:23]=2)[CH:18]=[N:17]1.Cl.O1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[O:35]1[C:36]2[CH:37]=[CH:18][CH:19]=[CH:20][C:21]=2[CH:33]=[C:34]1[C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[C:21]([C:25]([NH:27][CH:28]([CH3:29])[CH3:30])=[O:26])[CH:20]=2)[NH:16][N:17]=1
Reactant: C1COCCO1
Reactant: CC(C)NC(=O)c1ccc2c(cnn2C2OCCCC2c2cc3ccccc3o2)c1
Agent: Cl
Product: CC(C)NC(=O)c1ccc2[nH]nc(-c3cc4ccccc4o3)c2c1
Reaction time: 8 h
Yield: 7 %

Procedure:
(3-Benzo[d]furan-2-yl-1-perhydro-2H-pyran-2-yl(1H-indazol-5-yl))-N-(methylethyl)carboxamide (170 mg, 0.41 mmol) was taken up in a solution of 4 N HCl in dioxane and allowed to stir overnight. The reaction was neutralized to pH 7 and extracted with ethyl acetate. The organic layer was dried, filtered, and concentrated to yield the crude material which was purified by semi-preprative HPLC to yield the title compound (9 mg, 7% yield). 1H NMR (DMSO-d6) δ 13.8 (s, 1H), 8.7 (s, 1H), 8.4 (d, 1H), 8.0 (d, 1H), 7.6-7.8 (m, 4H), 7.4 (m, 2H), 4.2 (m, 1H), 3.2 (d, 1H), 1.2 (d, 6H)
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[C:13]([OH:25])(=[O:24])[CH2:14][C:15]([CH2:20][C:21]([OH:23])=[O:22])([C:17]([OH:19])=[O:18])[OH:16]>O>[C:13]([O-:25])(=[O:24])[CH2:14][C:15]([CH2:20][C:21]([O-:23])=[O:22])([C:17]([O-:19])=[O:18])[OH:16].[OH:1][NH+:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[OH:1][NH+:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[OH:1][NH+:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11]
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Product: CC1(C)CC(O)CC(C)(C)[NH+]1O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Reaction time: 0.5 h

Procedure:
To a glass 0.5 L reaction bottle are added 20.0 g (116 mmol) of 1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine, 7.39 g (38.5 mmol) citric acid, 200 mg 5% Pt on C and 100 mL water. Catalytic hydrogenation is carried out at 50 psi for 30 minutes at room temperature. Catalyst is removed by filtration through a pad of Celite. The aqueous salt solution has a pH of 5.56. Removal of water yields the product as a hygroscopic glassy solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22](O)[CH3:23])[C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[C:19]=1[C:20]#[N:21].CN(C)C=O.S(Cl)([Cl:32])=O.O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]([Cl:32])[CH3:23])[C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[C:19]=1[C:20]#[N:21]
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1cc(Cl)c(C#N)c2c1OCCN(C(=O)OC(C)(C)C)C2
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(Cl)c1cc(Cl)c(C#N)c2c1OCCN(C(=O)OC(C)(C)C)C2
Reaction time: 1 h

Procedure:
The tert-butyl 7-chloro-6-cyano-9-(1-hydroxyethyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (0.090 g, 0.26 mmol) was dissolved in methylene chloride (3 mL) and N,N-dimethylformamide (0.020 mL) and cooled in an ice bath. The thionyl chloride (0.037 mL, 0.51 mmol) was added slowly, and the reaction was stirred for 1 h and then diluted with methylene chloride (30 mL). The reaction mixture was cooled in an ice bath, and water saturated sodium bicarbonate was added. The organic layer was washed with water, brine, dried over magnesium sulfate, and concentrated to give tert-butyl 7-chloro-9-(1-chloroethyl)-6-cyano-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate as an oil. LCMS calculated for C17H20Cl2N2O3Na (M+Na)+: m/z=393.1; found: 393.0.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:31][CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([F:22])=[CH:28][CH:27]=3)[CH2:34][CH2:33]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: CCc1cc(NC(=O)N2CCN(c3ccc(F)cc3)CC2)c(OC)nc1C
Yield: 81 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin 3-yl)carbamate and 1-(4-fluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.