Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH3:21])[CH2:5][N:6]([C:11]1[C:16]([N+:17]([O-])=O)=[CH:15][N:14]=[C:13]([Cl:20])[N:12]=1)[CH:7]1[CH2:10][CH2:9][CH2:8]1>[Fe].C(O)(=O)C>[Cl:20][C:13]1[N:14]=[CH:15][C:16]2[NH:17][C:3](=[O:2])[CH:4]([CH3:21])[CH2:5][N:6]([CH:7]3[CH2:10][CH2:9][CH2:8]3)[C:11]=2[N:12]=1
Reactant: COC(=O)C(C)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCC1
Agent: [Fe]
Solvent: CC(=O)O
Product: CC1CN(C2CCC2)c2nc(Cl)ncc2NC1=O
Yield: 52.1 %

Procedure:
To a solution of 2.54 g (0.0077 mole) of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclobutyl-amino]-2-methyl-propanoic acid methyl ester (IV-52) and 40 mL of acetic acid was added 2.5 g (0.0448 g-atom) of iron powder. The mixture was heated at 80 degrees for 3 hours, then filtered through Celite while still hot. The filter cake was washed with 100 mL of ethyl acetate. The filtrate was washed successively with 100 mL of water, 100 mL of 7.4 M ammonium hydroxide, 100 mL of water and 100 mL of brine. The aqueous layers were back extracted with 100 mL of ethyl acetate. The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from dichloromethane—hexanes to give 1.07 g of (rac)-2-chloro-9-cyclobutyl-7-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-52) as white crystalline solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.CCN(CC)CC.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>C(Cl)Cl>[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:6][C@H:3]2[CH2:4][CH2:5][O:1][CH2:2]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: O[C@@H]1CCOC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)O[C@H]2CCOC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of (R)-tetrahydrofuran-3-ol (3 g, 34.1 mmole) and Et3N (6.9 g, 68.2 mmole) in DCM (40 mL) at 0° C. was added 4-methylbenzene-1-sulfonyl chloride (7.2 g, 37.5 mmole. The mixture was stirred at room temperature for 8 h. The mixture was washed with water, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 15% ethyl acetate in hexane) to give the title compound (6.8 g, 83% yield). MS (ESI) m/z: Calc. 242.1 (M+). Found: 243.1 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16](F)=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:34]=1.[N:35]1([C@@H:41]2[CH2:45][CH2:44][CH2:43][C@H:42]2[OH:46])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[N:35]1([C@@H:41]2[CH2:45][CH2:44][CH2:43][C@H:42]2[O:46][C:16]2[CH:17]=[CH:18][C:13]([C:11]([C:10]3[C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:34][C:7]=4[S:8][C:9]=3[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:22][CH:21]=3)=[O:12])=[CH:14][CH:15]=2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: O[C@@H]1CCC[C@H]1N1CCCCC1
Reactant: COc1ccc2c(C(=O)c3ccc(F)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Product: COc1ccc2c(C(=O)c3ccc(O[C@@H]4CCC[C@H]4N4CCCCC4)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Yield: 70 %

Procedure:
The title compound was prepared in 70% yield by essentially following the procedures outlined in Example 72, Part E, from 4-fluorophenyl 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl ketone (Example 59, Part A) and (±)-trans-2-(1-piperidyl)cyclopentanol (Part A).
Reaction SMILES: [CH3:1][C:2]1([CH2:8][O:9][C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([C:23]#[N:24])[N:21]=[CH:22][C:16]=4[N:15]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:14]=3[N:13]=[CH:12][CH:11]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:33](=O)[CH3:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH2:33]([N:5]1[CH2:4][CH2:3][C:2]([CH2:8][O:9][C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([C:23]#[N:24])[N:21]=[CH:22][C:16]=4[N:15]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:31])([CH3:30])[CH3:32])[C:14]=3[N:13]=[CH:12][CH:11]=2)([CH3:1])[CH2:7][CH2:6]1)[CH3:34]
Reactant: CC=O
Reactant: CC1(COc2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCN1CCC(C)(COc2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-((4-methylpiperidin-4-yl)methoxy)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (75 mg, 0.17 mmol) in methylene chloride (1.1 mL) was added acetaldehyde (14 uL, 0.25 mmol) and sodium triacetoxyborohydride (53 mg, 0.25 mmol), and the mixture was stirred at ambient temperature for 10 minutes. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (50 mL) and methylene chloride (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified flash chromatography (silica, 4 g, ISCO, 0-20% methanol in methylene chloride) to afford the title compound as a yellow solid, which was used in the next step without any further purification (58 mg, 73%).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][CH2:5][NH:6][C:7](=[O:12])[C:8]([F:11])([F:10])[F:9].[CH2:17]=O.S(=O)(=O)(O)O>C(O)(=O)C>[Br:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:3]=1[CH2:4][CH2:5][N:6]([C:7](=[O:12])[C:8]([F:10])([F:11])[F:9])[CH2:17]2
Reactant: C=O
Reactant: O=C(NCCc1ccccc1Br)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(N1CCc2c(Br)cccc2C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of N-(2-bromophenethyl)-2,2,2-trifluoroacetamide (8.88 g, 30 mmol) and paraformaldehyde (13.5 g, 0.45 mol) in 45 mL of glacial acetic acid at room temperature was slowly added 30 mL of sulfuric acid (96.6%). After stirring at room temperature overnight, the reaction mixture was quenched with ice water and extracted with EtOAc, washed with brine and Sat. NaHCO3 and dried over Na2SO4. After concentration, flash chomatography (SiO2, hexane/DCM=1:1) gave of 1-(5-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone as a white solid.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C@@H:8]([C:15]1[C:16]([CH3:44])=[N:17][C:18]([CH3:43])=[C:19]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)=[CH:29][CH:28]=2)[C:20]=1[N:21]1[CH2:24][C:23]([CH3:26])([CH3:25])[CH2:22]1)[C:9]([O:11]C(C)C)=[O:10])([CH3:6])([CH3:5])[CH3:4].Cl>C(O)C>[C:3]([O:7][C@@H:8]([C:15]1[C:16]([CH3:44])=[N:17][C:18]([CH3:43])=[C:19]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)=[CH:29][CH:28]=2)[C:20]=1[N:21]1[CH2:24][C:23]([CH3:26])([CH3:25])[CH2:22]1)[C:9]([OH:11])=[O:10])([CH3:6])([CH3:4])[CH3:5]
Reactant: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CC(C)(C)C2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CC(C)(C)C2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 74.8 %

Procedure:
The 0.60 mL of 1M sodium hydroxide (16.64 mg, 0.42 mmol) was added to a solution (S)-isopropyl 2-(tert-butoxy)-2-(4-(3,3-dimethylazetidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (60 mg, 0.10 mmol) in ethanol (2 mL) and stirred for 18 h at 90° C. The reaction mixture was neutralized with 1N HCl solution, extracted with EtOAc, and the organic layer was washed with brine, and dried (MgSO4). The crude material was purified by prep HPLC to give (S)-2-(tert-butoxy)-2-(4-(3,3-dimethylazetidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetic acid 40 mg (72%). 1H NMR (500 MHz, DMSO-d6) δ 7.40-7.37 (m, 2H), 7.26 (br. s, 1H), 7.14 (t, J=8.8 Hz, 2H), 7.0 (d, J=9.2 Hz, 1H), 6.96 (d, J=6.6 Hz, 1H), 6.86 (br. s, 1H), 5.04 (s, 1H), 4.21 (t, J=6.2 Hz, 2H) 3.47 (br. s, 4H), 3.05 (t, J=6.2 Hz, 2H), 2.01 (s, 3H), 1.91 (s, 3H), 1.10 (s, 9H), 1.02 (s, 6H). UPLC (M+H)=535.45.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[Br:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27]Br)[CH:22]=1>CC(C)=O>[C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][CH2:27][C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][Br:19])[CH:22]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2]
Reactant: BrCc1cccc(CBr)c1
Reactant: N#Cc1nc2ccc(O)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1nc2ccc(OCc3cccc(CBr)c3)cc2s1
Yield: 91.7 %

Procedure:
To a solution of 2-cyano-6-hydroxybenzothiazole (1.04 g) in 30 mL of acetone was added potassium carbonate (1.63 g), followed by α,α′-dibromo-m-xylene (4.7 g). The resultant solution was stirred at RT for 1 hour and the solvent was removed under reduced pressure. The residue was resuspended in dichloromethane and washed with water. The aqueous phase was extracted with more dichloromethane (2×) and the organic extracts were combined, dried over sodium sulfate, and purified by flash chromatography using dichloromethane. 1.945 g of product was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][CH2:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[CH2:17][CH2:18][N:10]([C:11]=23)[C:9]2[CH:19]=[CH:20][CH:21]=[CH:22][C:8]=2[NH:7]1.[CH3:24][N:25]=[C:26]=[O:27].[ClH:28]>C1(C)C=CC=CC=1.CCOCC.CCOCC.CO>[ClH:28].[CH3:23][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[CH2:17][CH2:18][N:10]([C:11]=23)[C:9]2[CH:19]=[CH:20][CH:21]=[CH:22][C:8]=2[N:7]1[C:26]([NH:25][CH3:24])=[O:27]
Reactant: CN(C)CCCC1Nc2ccccc2N2CCc3cccc1c32
Reactant: CN=C=O
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CNC(=O)N1c2ccccc2N2CCc3cccc(c32)C1CCCN(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6.26 g of N,N-dimethyl-1,2,6,7-tetrahydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine-6-propanamine in 125 ml of dry toluene was added 2.36 ml of methyl isocyanate, via syringe, under nitrogen. After stirring the mixture overnight at room temperature it was diluted with ether (500 ml) and the resulting solution was washed with water (2×250 ml) and saturated sodium chloride solution and thereafter dried over anhydrous sodium sulfate. Filtration and concentration in vacuo afforded a foam weighing 6.72 g. This material was dissolved in 5:1 ether/methanol solution (approx. 150 ml) and treated dropwise with hydrogen chloride-saturated ether solution with stirring. Crude salt formed as an insoluble oil on the side wall of the flask. After a few minutes of stirring, the liquid phase was decanted and fresh ether used to triturate the crude salt to a solid. Filtration and drying in vacuo afforded 6.72 g of solid. This material was combined with some crude salt prepared in an analogous manner and dissolved in 25 ml of boiling isopropanol. The hot solution was gravity-filtered, allowed to cool and stand at room temperature for a few minutes and then was refrigerated overnight. The recrystallized salt was filtered, washed twice with cold isopropanol, and ether and dried in vacuo to afford 4.7 g of crystalline solid, m.p. 233°-235° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH:8]1[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[CH:16][N:15]=1.C(N(CC)CC)C>CO>[C:1]([O:5][C:6](=[O:12])[NH:7][CH:8]1[CH2:11][N:10]([C:16]2[CH:17]=[CH:18][N:19]=[C:14]([Cl:13])[N:15]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CN(c2ccnc(Cl)n2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
A mixture of azetidin-3-yl-carbamic acid tert-butyl ester (635 mg, 3.4 mmol), 2,4-dichloropyrimidine (500 mg, 3.4 mmol) and triethylamine (0.5 ml, 3.6 mmol) in methanol (10 ml) was stirred at room temperature overnight. The mixture was concentrated and purified by column chromatography (0-40% ethyl acetate/petroleum ether) furnishing 561 mg title compound. MS: [M+H]+=283/285
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3S[CH2:17][CH2:16][C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][C:13]=3[CH:23]=2)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=O)C=1.[S:35]([O-:39])([O-])(=[O:37])=S.[Na+].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[S:35](=[O:39])(=[O:37])[CH2:17][CH2:16][C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][C:13]=3[CH:23]=2)=[CH:7][CH:8]=1
Reactant: O=S([O-])([O-])=S
Reactant: COC(=O)C1=Cc2cc(-c3ccc(OC)cc3)ccc2SCC1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1=Cc2cc(-c3ccc(OC)cc3)ccc2S(=O)(=O)CC1
Reaction time: 2 h

Procedure:
To a solution of methyl 7-(4-methoxyphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylate (0.60 g) in THF (10 ml) was added at 0° C. 70% 3-chloroperbenzoic acid (1.0 g), and the mixture was stirred at 0° C. for 30 minutes and then at room temperature for 2 hours. To the mixture was added an aqueous solution of sodium thiosulfate, and the mixture was stirred for a few minutes and extracted with dichloromethane. The organic layer was washed with sodium bicarbonate solution and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give solid, which was recrystallized from ethyl acetate/hexane to give colorless crystals of methyl 7-(4-methoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (584.5 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:10]([CH3:11])[C:9](=[O:12])[N:8]2[C:4](=[N:5][C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=32)[NH:3]1.[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19]>>[CH2:18]([NH:20][C:21]([N:5]1[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[N:8]2[C:9](=[O:12])[N:10]([CH3:11])[C:2]([CH3:17])([CH3:1])[N:3]=[C:4]12)=[O:22])[CH3:19]
Reactant: CCN=C=O
Reactant: CN1C(=O)n2c(nc3ccccc32)NC1(C)C
Product: CCNC(=O)N1C2=NC(C)(C)N(C)C(=O)N2c2ccccc21
Yield: 96 %

Procedure:
The title compound was prepared by reaction of 1,2-dihydro-2,2,3-trimethyl-1,3,5-triazino[1,2-a]benzimidazol-4(3H)-one (see Example 1 (B)) with ethyl isocyanate according to the general procedure of Example 10. The product, mp 127°-131° C., was obtained as a white solid in 96% yield. The confirmatory elemental analysis is shown in Table III.
Reaction SMILES: COC1C=CC(CN2CCN(CC3N=CC([NH:21][C:22]([C:24]4[CH:25]=[CH:26][C:27]([C:34]5[C:39]([Cl:40])=[C:38]([O:41][CH3:42])[CH:37]=[C:36]([O:43][CH3:44])[C:35]=5[Cl:45])=[C:28]5[C:33]=4[N:32]=[CH:31][CH:30]=[CH:29]5)=[O:23])=CC=3)CC2)=CC=1.[CH3:48][N:49]([CH3:59])[CH2:50][C:51]1[N:52]=[C:53]([N+]([O-])=O)[NH:54][CH:55]=1.CO.C1COCC1.CO>[Ni].C(Cl)Cl.CO>[CH3:48][N:49]([CH2:50][C:51]1[N:52]=[C:53]([NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:34]3[C:39]([Cl:40])=[C:38]([O:41][CH3:42])[CH:37]=[C:36]([O:43][CH3:44])[C:35]=3[Cl:45])=[C:28]3[C:33]=2[N:32]=[CH:31][CH:30]=[CH:29]3)=[O:23])[NH:54][CH:55]=1)[CH3:59]
Reactant: CN(C)Cc1c[nH]c([N+](=O)[O-])n1
Reactant: COc1ccc(CN2CCN(Cc3ccc(NC(=O)c4ccc(-c5c(Cl)c(OC)cc(OC)c5Cl)c5cccnc45)cn3)CC2)cc1
Agent: [Ni]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3nc(CN(C)C)c[nH]3)c3ncccc23)c1Cl

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but using 5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (6-piperazin-1-ylmethyl-pyridin-3-yl)-amide (Example 170), dimethyl-(2-nitro-1H-imidazol-4-ylmethyl)-amine (Step 22.1) instead of 2-nitroimidazole in Step 14.3, and Raney nickel and MeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2. The title compound: ESI-MS: 500.0 [M+H]+; tR=3.50 min (System 1); TLC: Rf=0.20 (DCM/MeOH, 9:1).
Reaction SMILES: [CH3:1][C:2]1[C:8]2[CH:9]=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:7]=2[O:6][C:5]2[CH:15]=[CH:16][C:17]([C:19]([O:21]CC)=[O:20])=[CH:18][C:4]=2[N:3]=1.[OH-].[Na+].Cl>CO>[CH3:1][C:2]1[C:8]2[CH:9]=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:7]=2[O:6][C:5]2[CH:15]=[CH:16][C:17]([C:19]([OH:21])=[O:20])=[CH:18][C:4]=2[N:3]=1
Reactant: CCOC(=O)c1ccc2c(c1)N=C(C)c1ccc(OC)cc1O2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(c1)Oc1ccc(C(=O)O)cc1N=C2C
Yield: 92.3 %

Procedure:
A mixture of 1 g of ethyl 11-methyl-3-methoxydibenz-[b,f][1,4]oxazepine-8-carboxylate, 10 ml of methanol and 10 ml of 1 N aqueous sodium hydroxide was refluxed for 1 hour. After cooling, the mixture was neutralized with diluted hydrochloric acid, and the precipitating crystal was filtered off and recrystallized from methanol to give 0.84 g of 11-methyl-3-methoxydibenz[b,f][1,4]oxazepine-8-carboxylic acid. Yield 92%, m.p. 247° C. (with decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][CH:10]([CH2:13][OH:14])[CH2:11][OH:12])[C:6]([N+:15]([O-:17])=[O:16])=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+].CO[C:25](OC)([CH3:27])[CH3:26]>ClCCl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:26][C:25]1([CH3:27])[O:12][CH2:11][CH:10]([NH:9][C:7]2[C:6]([N+:15]([O-:17])=[O:16])=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=2)[CH2:13][O:14]1
Reactant: COc1ccc([N+](=O)[O-])c(NC(CO)CO)n1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(NC2COC(C)(C)OC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
2-{[6-(Methyloxy)-3-nitro-2-pyridinyl]amino}-1,3-propanediol (53.93 g, 228.7 mmol) was stirred in 2,2-dimethoxypropane (900 ml) under argon and p-toluenesulphonic acid monohydrate (1.00 g) was added. The mixture was stirred at room temperature overnight. This was diluted with dichloromethane (1 L) and the resulting solution was treated with saturated aqueous sodium hydrogen carbonate (20 ml) and solid sodium hydrogen carbonate (20 g) with vigorous stirring (effervescence). The mixture was vigorously stirred for 20 minutes, then the remaining water was absorbed by addition of anhydrous sodium sulphate. The mixture was filtered with suction and the solids were washed with DCM (500 ml). The combined filtrate plus washings were evaporated under reduced pressure to give a yellow solid which was stirred with petroleum ether) (40-60°) over the weekend. The solid was isolated by filtration with suction, washed with petroleum ether) (40-60°) and air-dried to give the title compound as a bright yellow solid 57.83 g, 92%).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]([O:10][C:11]2[N:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:3]>CO.[Pd]>[CH3:3][CH:2]([C:4]1[CH:5]=[C:6]([O:10][C:11]2[N:16]=[CH:15][C:14]([NH2:17])=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:1]
Reactant: CC(C)c1cccc(Oc2ncc([N+](=O)[O-])cn2)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)c1cccc(Oc2ncc(N)cn2)c1
Reaction time: 3 h
Yield: 87 %

Procedure:
To a solution of 2-{[3-(1-methylethyl)phenyl]oxy}-5-nitropyrimidine (Intermediate 84, 520 mg) in methanol (50 mL) was added Pd/C (10% wt., 100 mg) and the mixture was stirred under H2 atmosphere for 3 hours. The resulting mixture was filtered through a pad of celite and the filtrate was concentrated under vacuum to afford the title compound (400 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:13]([CH:18]([CH3:20])[CH3:19])[C:14]([O:16][CH3:17])=[O:15])[C:7]2=[O:12].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C@H:28]([CH3:32])[C:29](O)=[O:30])=[CH:24][CH:23]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O>C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C@H:28]([CH3:32])[C:29]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]([C@H:13]([CH:18]([CH3:20])[CH3:19])[C:14]([O:16][CH3:17])=[O:15])[C:7]3=[O:12])=[O:30])=[CH:26][CH:27]=1
Reactant: C[C@H](C(=O)O)c1ccc(Cl)cc1
Reactant: COC(=O)[C@@H](C(C)C)n1ccc2c(N)cccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](C(C)C)n1ccc2c(NC(=O)[C@@H](C)c3ccc(Cl)cc3)cccc2c1=O

Procedure:
(R)-Methyl 2-(5-amino-1-oxoisoquinolin-2(1H)-yl)-3-methylbutanoate (0.3 g, 0.001 mol), (S)-2-(4-chlorophenyl)propanoic acid (0.4 g, 0.002 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.8 g, 0.002 mol), N,N-diisopropylethylamine (0.6 g, 0.004 mol) were stirred in N,N-dimethylformamide (3 mL, 0.04 mol) at room temperature over a weekend. The reaction mixture was diluted with CH2Cl2 (100 mL), washed with NaHCO3 (20 mL×3), dried over Na2SO4, purified via flash chromatography (12 g of silica gel, 0-90% EtOAc/Hexane) and then prep. HPLC gave a light yellow oil. MS m/z 441.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][CH3:12])[CH:5]=1)=[O:3].C([O-])([O-])=O.[K+].[K+].[Cl:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]Cl>C(#N)C>[Cl:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=1[O:11][CH3:12]
Reactant: ClC/C=C\CCl
Reactant: COc1cc(C(C)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OC/C=C\CCl
Yield: 106.8 %

Procedure:
A stirred mixture of 4-hydroxy-3-methoxyacetophenone (16.6 g, 10 mmole), K2CO3 (14 g, 100 mmol) and cis-1,4-dichloro-2-butene (Aldrich, 15 g, 120 mmol) in acetonitrile (250 ml) was heated at reflux for 2.5 hours. The mixture was filtered and concentrated to an oil. Purification was by flash chromatography. The fractions containing the purest product were combined and concentrated to give white crystals, 7.7 g, 30%. This was recrystallized from ether to give analytical pure (Z)-1-[4-[(4-chloro-2-butenyl)oxy]-3-methoxyphenyl]ethanone (2.72 g), m.p.=64°-66° C.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([C:60]5[CH:61]=[N:62][NH:63][CH:64]=5)[C:52]([O:58][CH3:59])=[CH:53][CH:54]=4)[O:49][C:48]=3[C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O>CO.O.Cl>[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([C:60]5[CH:64]=[N:63][NH:62][CH:61]=5)[C:52]([O:58][CH3:59])=[CH:53][CH:54]=4)[O:49][C:48]=3[C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)=[CH:45][CH:46]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: COc1ccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2c1-c1cn[nH]c1
Agent: Cl
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(=O)c(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)oc2c1-c1cn[nH]c1
Yield: 34.3 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, (1-{4-[7-methoxy-4-oxo-2-phenyl-8-(1H-pyrazol-4-yl)-4H-chromen-3-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester (50 mg, 0.088 mmol) was treated with TFA. The resultant free base was dissolved in a mixture of MeOH (7 mL), water (7 mL) and 1 M HCl (0.6 mL) and chromatographed on a 20 g C18 cartridge {gradient 30 to 80% MeOH in water+1 M HCl (60 μL in each 10 mL of eluent)} to yield the title compound as a white solid (14 mg, 32%). 1H NMR (300 MHz, DMSO-d6): δ 8.75 (s, 3H), 8.12-8.01 (m, 3H), 7.50-7.24 (m, 9H), 7.11 (s, 1H), 4.01 (s, 3H), 2.62-2.48 (m, 4H), 2.27-2.10 (m, 1H), 1.87-1.72 (m, 1H). LCMS (Method E): RT=2.99 min, [M+H]+=464.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.Cl.[F:23][C:24]([F:33])([F:32])[C:25]1[O:29][N:28]=[C:27]([CH2:30][NH2:31])[CH:26]=1>>[F:33][C:24]([F:23])([F:32])[C:25]1[O:29][N:28]=[C:27]([CH2:30][NH:31][C:14]([C:12]2[CH:11]=[CH:10][C:9]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:13]=2)=[O:16])[CH:26]=1
Reactant: O=C(O)c1ccc(OCC2CC2)c(-c2ccc(Cl)cc2)n1
Reactant: NCc1cc(C(F)(F)F)on1
Agent: Cl
Product: O=C(NCc1cc(C(F)(F)F)on1)c1ccc(OCC2CC2)c(-c2ccc(Cl)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 41 using 6-(4-Chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid (example AW) and 5-trifluoromethyl-isoxazol-3-methanamine hydrochloride (example BF) as starting materials, LC-MS (UV peak area/ESI) 97.8%, 452.4 (M+H)+.