Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:8]=[C:9]([CH2:23][N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[C:10]=1[N:11]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:12])=[O:4].[CH2:37](O)[C:38]#[C:39][CH3:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:8]=[C:9]([CH2:23][N:24]2[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]2)[C:10]=1[N:11]([S:13]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:37][C:38]#[C:39][CH3:40])=[CH:20][CH:21]=1)(=[O:15])=[O:14])[CH3:12])=[O:4]
Reactant: CC#CCO
Reactant: COC(=O)c1cc(-c2ccccc2)cc(CN2CCN(C)CC2)c1N(C)S(=O)(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)N(C)c2c(CN3CCN(C)CC3)cc(-c3ccccc3)cc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.9 %

Procedure:
To a solution of 0.810 g (1.59 mmol) of the product of Example 73 and 0.594 mL (7.95 mmol) of 2-butyn-1-ol in 8 mL of THF, was added 2.08 g (7.95 mmol) of triphenylphosphine and then 1.25 mL (7.95 mmol) of diethyl azodicarboxylate. The mixture was stirred at room temperature for 18 h, diluted with ethyl acetate, washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel with 2% methanol/dichloromethane to provide 0.830 g (93%) of the desired product as a beige solid. Electrospray Mass Spec 562.1 (M+H)+
Reaction SMILES: O=[C:2]1[CH2:11][N:10]2[C:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][C:13]=3[C:8]3[C:9]2=C([CH:5]=[CH:6][CH:7]=3)N1.[H-].[Na+].CI.[CH3:27][N:28]([CH:30]=[O:31])[CH3:29]>O>[CH3:2][CH:11]1[N:10]2[C:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][C:13]=3[C:8]3[C:9]2=[C:27]([CH:5]=[CH:6][CH:7]=3)[N:28]([CH3:29])[C:30]1=[O:31]
Reactant: CCOC(=O)N1CCc2c(c3cccc4c3n2CC(=O)N4)C1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCOC(=O)N1CCc2c(c3cccc4c3n2C(C)C(=O)N4C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To a solution of ethyl 2-oxo-2,3,9,10-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (from Example 211, StepA) (500 mg, 1.6 mmol) in DMF (20 mL) at rt was added NaH (147 mg, 3.6 mmol), MeI (0.25 mL, 4.0 mmol) and stirred at 25° C. for 3 hours. The solution was diluted with water (30 mL) and extracted with EtOAc (2×30 mL). The combined extracts were dried over magnesium sulfate, concentrated, and purified by flash chromatography to afford ethyl 1,3-dimethyl-2-oxo-2,3,9,10-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (350 mg, 64%) as an oil. MS [M+H]+328. 1H NMR (CDCl3, 300 MHz): δ 7.18 (d, 1H, J=7.7 Hz), 7.01 (t, 1H, J=7.7 Hz), 6.63 (d, 1H, J=7.7 Hz), 4.90 (m, 1H), 4.51 (m 1H), 3.20 (m, 5H), 3.49 (m, 1H), 3.42 (s, 3H), 2.91 (m, 1H), 2.80 (m, 1H), 1.61 (d, 3H, J=7.0), 1.28 (t, 3H, J=7.3 Hz) ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][C:16]2([CH2:20][CH3:21])[CH2:19][O:18][CH2:17]2)=[CH:4][CH:3]=1.C([Li])CCC.C(O[B:31]1[O:35][C:34]([CH3:37])([CH3:36])[C:33]([CH3:39])([CH3:38])[O:32]1)(C)C>C1COCC1>[CH2:20]([C:16]1([CH2:15][O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([B:31]3[O:35][C:34]([CH3:37])([CH3:36])[C:33]([CH3:39])([CH3:38])[O:32]3)=[CH:3][CH:4]=2)[CH2:19][O:18][CH2:17]1)[CH3:21]
Reactant: CCC1(COCCCCCCc2ccc(Br)cc2)COC1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC1(COCCCCCCc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)COC1
Yield: 70.6 %

Procedure:
To a stirred solution of 3-[6-(4-bromophenyl)hexyloxymethyl]-3-ethyl-oxetane (2.0 g, 5.63 mmol) in dry THF (20 ml) is added n-butyllithium (2.5 M in hexanes, 2.25 ml, 5.63 mmol) dropwise at −78° C. under nitrogen, with stirring. After complete addition, the mixture is stirred for another 20 min, followed by the addition of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.05 g, 5.64 mmol). The resultant mixture is stirred overnight at room temperature. The reaction is quenched with water, and the reaction mixture is extracted with ethyl acetate (3×50 ml). The combined organic extracts are washed with water, brine, and dried (Na2SO4). The solvent is removed under reduced pressure and the residue is purified by column chromatography on silica, eluting with petroleum ether/ethyl acetate (9:1 to 7:3), to give a brown oil (1.60 g, 71%). 1H NMR (300 MHz, CDCl3): δ(ppm) 7.72 (d, J=8.1 Hz, 2H, Ar—H), 7.17 (d, J=8.1 Hz, 2H, Ar—H), 4.43 (d, J=5.8 Hz, 2H, OCH2), 4.35 (d, J=5.8 Hz, 2H, OCH2), 3.48 (s, 2H, OCH2), 3.41 (t, J=6.4 Hz, 2H, OCH2), 2.60 (t, J=7.9 Hz, 2H, ArCH2), 1.72 (q, J=7.5 Hz, 2H, CH2), 1.56 (m, 4H, CH2), 1.32 (m, 14H, CH2 and CH3); 0.86 (t, J=7.5 Hz 3H, CH3); 13C NMR (75 MHz, CDCl3): δ (ppm) 146.1 (quat.), 134.8 (CH), 127.8 (CH), 83.5 (quat.), 78.5 (OCH2), 73.3 (OCH2), 71.5 (OCH2), 43.4 (quat.), 36.1 (CH2), 31.3 (CH2), 29.5 (CH2), 29.0 (CH2), 26.7 (CH2), 26.0 (CH2), 24.8 (CH3), 8.2 (CH3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:8]([Cl:16])[CH:7]=1)=O.Cl.[CH:19]1([O:25][NH2:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CO>[CH3:1][O:2][C:3](=[O:17])/[C:4](/[C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:8]([Cl:16])[CH:7]=1)=[N:26]/[O:25][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NOC1CCCCC1
Reactant: COC(=O)C(=O)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: Cl
Solvent: CO
Product: COC(=O)/C(=N/OC1CCCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
(3-Chloro-4-methanesulfonyl-phenyl)-oxo-acetic acid methyl ester (prepared as in Example 1, 1.2 g, 4.34 mmol) was stirred in methanol (9 mL) and warmed in a 70° C. oil bath. O-Cyclohexyl-hydroxylamine hydrochloride (0.811 g, 5.43 mmol) was added. After 2 h, the reaction mixture was allowed to cool and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 20% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) afforded (E)-(3-chloro-4-methanesulfonyl-phenyl)-cyclohexyloxyimino-acetic acid methyl ester as a white solid (552 mg, 34%): H1-NMR (400 MHz, CDCl3) δ=1.34 (3H, m), 1.51 (3H, m), 1.68 (2H, m), 1.96 (2H, m), 3.31 (3H, s), 3.91 (3H, s), 4.39 (1H, m), 7.51 (1H, dd, J=8.1 Hz, J=1.5 Hz), 7.62 (1H, d, J=1.5 Hz), 8.18 (1H, d, J=8.1 Hz).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([NH:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19]([C:24]([O:26]CC)=[O:25])=[CH:18]3)=[O:13])[O:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[OH-].[Li+]>>[CH:1]([C:4]1[CH:5]=[C:6]([C:12]([NH:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19]([C:24]([OH:26])=[O:25])=[CH:18]3)=[O:13])[O:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc2cc(NC(=O)c3cc(C(C)C)c(C(C)C)o3)ccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Product: CC(C)c1cc(C(=O)Nc2ccc3[nH]c(C(=O)O)cc3c2)oc1C(C)C
Yield: 93.6 %

Procedure:
This ester (38 mg, 99.5 μmol) was hydrolyzed with lithium hydroxide in a conventional manner, and then the residue was recrystallized to obtain the title compound (36, 33 mg, 94%) as colorless prisms.
Reaction SMILES: [C:1](=[NH:21])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH3:20])[CH:14]=2)=[CH:8][CH:7]=1)[NH2:2].[CH:22]([CH:24]([CH2:29][C:30]1[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=1)[C:25](OC)=O)=[O:23].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:25]=[C:24]([CH2:29][C:30]4[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=4)[C:22](=[O:23])[N:21]=3)=[CH:11][CH:10]=2)=[CH:14][C:15]=1[CH3:20]
Reactant: Cc1cc(Oc2ccc(CCOC(=N)N)cc2)ccc1Cl
Reactant: COC(=O)C(C=O)Cc1cnn(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1cc(Oc2ccc(CCOc3nc(=O)c(Cc4cnn(C)c4)c[nH]3)cc2)ccc1Cl
Temperature: 130 °C
Yield: 5.5 %

Procedure:
To the solution of 2-{4-[(4-chloro-3-methylphenyl)oxy]phenyl}ethyl imidocarbamate (50 mg, 0.120 mmol) and methyl 2-formyl-3-(1-methyl-1H-pyrazol-4-yl)propanoate (30 mg, 0.153 mmol) in NMP (2 mL), was added K2CO3 (50 mg, 0.362 mmol). The mixture was heated with a microwave reactor at 130° C. for 1 h. Purification via MDAP then afforded the title compound (3 mg, 5.56% yield). LCMS: rt=3.39 min, [M+H]=451
Reaction SMILES: CS(O[CH2:6][C:7]1[O:8][CH:9]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)[C:11](=[O:13])[CH:12]=1)(=O)=O.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>ClCCl>[F:33][C:31]([F:34])([F:32])[C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][CH:22]=[C:21]2[O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:10]1[C:11](=[O:13])[CH:12]=[C:7]([CH2:6][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[O:8][CH:9]=1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)OCc1cc(=O)c(OCCCCCOc2ccnc3ccc(C(F)(F)F)cc23)co1
Solvent: ClCCl
Product: O=c1cc(CN2CCOCC2)occ1OCCCCCOc1ccnc2ccc(C(F)(F)F)cc12
Temperature: 45 °C
Reaction time: 18 h
Yield: 35 %

Procedure:
Methanesulfonic acid 4-oxo-5-[5-(7-trifluoromethyl-quinolin-4-yloxy)-pentyloxy]-4H-pyran-2-ylmethyl ester 16 (100 mg, 0.20 mmol) was dissolved in dichloromethane (5 mL). Morpholine (44 μL, 0.50 mmol) was added via syringe. The mixture was stirred at 45° C. for 18 h. After cooling to room temperature CH2Cl2 (75 ml) was added and the mixture was washed with NaHCO3 10% (3×50 mL) and brine (3×50 mL). The organic layer was dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent CH2Cl2:MeOH=9:1. 5-(5-(6-(Trifluoromethyl)quinolin-4-yloxy)pentyloxy)-2-(morpholinomethyl)-4H-pyran-4-one EHT 1426 was obtained (37 mg, 35% yield) as an orange oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:29])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH:10]=2)[CH:8]=1.[OH:30][CH2:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](O)=[O:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[F:29][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:31]([C:32]2[CH:40]=[CH:39][CH:38]=[C:34]([CH2:35][OH:36])[CH:33]=2)=[O:30])=[CH:8][C:7]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:20][CH2:21]2)[CH:10]=1
Reactant: O=C(O)c1cccc(CO)c1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cc(CN)ccc3F)c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cc(CNC(=O)c4cccc(CO)c4)ccc3F)c2)CC1
Temperature: 25 °C
Reaction time: 21 h
Yield: 91.4 %

Procedure:
To a solution of 1,1-dimethylethyl 4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-1-piperazinecarboxylate (100 mg, 0.25 mmol) in DCM (2.5 mL) was added 3-(hydroxymethyl)benzoic acid (38 mg, 0.25 mmol), HBTU (0.104 g, 0.275 mmol), and Et3N (0.0351 mL, 0.25 mmol). The mixture was stirred at room temperature for 21 h. The reaction was quenched with H2O. The organic layer was separated, directly load onto silica gel cartridge and purified by CombiFlash chromatograph to afford the title compound 0.122 g (91%). LC-MS m/z 534 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:23]=[C:22]([C:24](=[O:30])[CH:25]=[CH:26][C:27]([OH:29])=O)[CH:21]=[CH:20][C:5]=1[O:6][CH2:7][C:8]([NH:10][C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)=[O:9])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>ClCCl>[CH:1]([C:4]1[CH:23]=[C:22]([C:24](=[O:30])[CH:25]=[CH:26][C:27]([N:50]2[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]2)=[O:29])[CH:21]=[CH:20][C:5]=1[O:6][CH2:7][C:8]([NH:10][C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)=[O:9])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(C(=O)C=CC(=O)O)ccc1OCC(=O)Nc1nc2ccccc2s1
Reactant: CN1CCNCC1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1cc(C(=O)C=CC(=O)N2CCN(C)CC2)ccc1OCC(=O)Nc1nc2ccccc2s1
Reaction time: 2.5 h

Procedure:
To a solution of 2-[2-isopropyl-4-(3-carboxyacryloyl)phenoxymethylcarbonylamino]benzothiazole (1.0 g) and triethylamine (0.4 ml) in dichloromethane (20 ml) is added dropwise isobutyl chloroformate (0.32 ml) under ice-cooling. To the mixture is added N-methylpiperazine (0.27 ml) at the same temperature, and the mixture is stirred for 2.5 hours. The reaction solution is washed with water, dried and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; dichloromethane→dichloromethane:methanol=30:1), and recrystallized from ethanol to give 2-{2-isopropyl-4-[3-(4-methyl-1-piperazinylcarbonyl)acryloyl]phenoxymethylcarbonylamino}benzothiazole (0.80 g).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].CC1(C)[O:17][C:16](=O)[CH:15]([CH3:19])[C:14](=[O:20])[O:13]1>C1(C)C=CC=CC=1>[C:14]([CH:15]([CH3:19])[C:16]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])=[O:17])([OH:20])=[O:13]
Reactant: Nc1ccccc1C(=O)O
Reactant: CC1C(=O)OC(C)(C)OC1=O
Solvent: Cc1ccccc1
Product: CC(C(=O)O)C(=O)Nc1ccccc1C(=O)O
Yield: 84.4 %

Procedure:
Anthranilic acid (1.00 g, 7.29 mmol) was added to a solution of 2,2,5-trimethyl-1,3-dioxane-4,6-dione (1.27 g, 8.02 mmol) in toluene (10 mL). The reaction flask was fitted with a Dean-Stark apparatus and the suspension was heated to reflux for 3 h. The suspension was cooled, filtered, washed with toluene and dried. 2-[(2-Carboxy-1-oxopropyl)amino]benzoic acid (1.46 g, 85%) was obtained as a colourless solid; δH (500 MHz, DMSO-d6) 1.31 (d, J=7.2 Hz, 3H, CH3), 3.52 (q, J=7.2 Hz, 1H, CH), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.59 (td, J4,5=J5,6=8.0, J3,5=1.5 Hz, 1H, H5), 7.98 (dd, J3,4=8.0, J3,5=1.5 Hz, 1H, H3), 8.46 (d, J5,6=8.0 Hz, 1H, H6), 11.36 (s, 1H, NH), 12.87 (br s, 1H, CO2H), 13.52 (br s, 1H, CO2H); δC (125 MHz, DMSO-d6) 13.6, 48.4, 116.7, 120.0, 122.9, 131.1, 134.1, 140.5, 168.2, 169.4, 171.6. νmax 1172, 1251, 1587, 1679, 2553, 2941, 2990, 3332 cm−1.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:12]([CH:14]1[O:16][CH2:15]1)Br>CN(C)C=O>[C:1]1([CH2:7][CH2:8][O:9][CH2:12][CH:14]2[CH2:15][O:16]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCC1CO1
Reactant: OCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(CCOCC2CO2)cc1

Procedure:
A procedure similar to that described in Preparation 46 was repeated, except that 4.28 g of 2-phenylethanol, 1.68 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 4.1 ml of epibromohydrin and 100 ml of anhydrous dimethylformamide were used. The resulting crude product was purified by silica gel column chromatography, using a 8:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 4.68 g of the title compound as a colorless oil having an Rf value of 0.77 (on silica gel thin layer chromatography, using a 2:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: C(OC(=O)[N:7]([CH2:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[S:27][C:26]3[C:21](=[N:22][CH:23]=[CH:24][C:25]=3[O:28][C:29]3[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:38][C:39]4[CH:44]=[CH:43][CH:42]=[C:41]([P:45]([CH3:48])([CH3:47])=[O:46])[CH:40]=4)=[O:37])=[CH:31][C:30]=3[F:49])[CH:20]=2)=[CH:17][CH:18]=1)[CH2:8][CH2:9][O:10][CH3:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:48][P:45]([C:41]1[CH:40]=[C:39]([NH:38][C:36]([NH:35][C:32]2[CH:33]=[CH:34][C:29]([O:28][C:25]3[CH:24]=[CH:23][N:22]=[C:21]4[CH:20]=[C:19]([C:16]5[CH:17]=[CH:18][C:13]([CH2:12][NH:7][CH2:8][CH2:9][O:10][CH3:11])=[CH:14][N:15]=5)[S:27][C:26]=34)=[C:30]([F:49])[CH:31]=2)=[O:37])[CH:44]=[CH:43][CH:42]=1)([CH3:47])=[O:46]
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)Nc5cccc(P(C)(C)=O)c5)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)Nc5cccc(P(C)(C)=O)c5)cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.1 %

Procedure:
To a solution of compound 288 (230 mg, 0.32 mmol) in dichloromethane (7 mL) under nitrogen at room temperature was added trifluoroacetic acid (2.5 mL, 32 mmol). The reaction mixture was stirred for 16 h at room temperature. The solvent was removed under reduced pressure and a saturated aqueous solution of sodium bicarbonate was added. The aqueous phase was extracted with ethyl acetate (3×), the combined organic layers were concentrated. The residue was purified via Biotage (linear gradient 0-20%, methanol/dichloromethane; 25M column) to afford compound 289 as an off-white solid (75.3 mg, 0.122 mmol, 38.0%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.15 (s, 1H), 9.06 (s, 1H), 8.57 (d, J=1.6 Hz, 1H), 8.53 (d, J=5.6 Hz, 1H), 8.31 (s, 1H), 8.23 (d, J=8.0 Hz, 1H), 7.92-7.83 (m, 2H), 7.76 (dd, J=13.2, 2.4 Hz, 1H), 7.67-7.62 (m, 1H), 7.49-7.42 (m, 2H), 7.41-7.33 (m, 1H), 7.32-7.26 (m, 1H), 6.67 (d, J=5.6 Hz, 1H), 3.78 (s, 2H), 3.54-3.34 (2H, hidden under water signal), 3.24 (s, 3H), 2.65 (t, J=5.6 Hz, 2H), 1.65 (d, J=13.2 Hz, 6H). MS (m/z): 620.4 (M+H).
Reaction SMILES: [C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([N:16](C)[C:17](=O)OC(C)(C)C)[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]=[CH:30][C:29]=2[CH:38]2[CH2:40][CH2:39]2)[C:6]2[CH:41]=[CH:42][CH:43]=[CH:44][C:5]1=2)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([NH:16][CH3:17])[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]=[CH:30][C:29]=2[CH:38]2[CH2:39][CH2:40]2)[C:6]2[CH:41]=[CH:42][CH:43]=[CH:44][C:5]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2N(Cc2c(C3CC3)cnc3ccccc23)C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@@H]1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(C3CC3)cnc3ccccc23)c2ccccc2N(C(C)=O)[C@H]1C
Reaction time: 2.5 h

Procedure:
To a rt solution of tert-butyl(S)-1-((2S,3S)-1-acetyl-5-((3-cyclopropylquinolin-4-yl)methyl)-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (65 mg, 108 μmol) in CH2Cl2 (434 μl) was added TFA (108 μl). The reaction was stirred for 2.5 h, then concentrated and purified by reverse phase preparative HPLC to provide, after extraction from sat. aq. NaHCO3 and lyophilzation, (S)-N-((2S,3S)-1-acetyl-5-((3-cyclopropylquinolin-4-yl)methyl)-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide (27.2 mg, 50%) as a white solid. MS m/z 500 (MH)+.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2)=[N+]=[N-]>CCOC(C)=O.[Pd]>[NH2:1][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2
Reactant: [N-]=[N+]=NCc1cccc2cccnc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NCc1cccc2cccnc12
Reaction time: 19 h

Procedure:
To a solution of 0.8432 g (4.58 mmol) 21 in 20 mL EtOAc was added 0.0880 g Pd (10% on C). After 19 h under H2 at atmospheric pressure, the reaction mixture was diluted with 25 mL EtOAc and filtered over celite. The celite was washed with 150 mL EtOAc, and the combined organics were dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (40×140 mm silica gel, linear gradient 5-15% (10% NH4OH:MeOH):CH2Cl2) gave 22. 1H NMR (CDCl3, 400 MHz) δ 8.936 (dd, 1H, J=1.78, 4.16 Hz, ArH); 8.165 (dd, 1H, J=1.69, 8.28 Hz, ArH); 7.730 (dd, 1H, J=1.10, 8.14 Hz, ArH); 7.652 (dd, 1H, J=0.64, 7.03 Hz, ArH); 7.497 (t, 1H, J=7.59 Hz, ArH); 7.421 (dd, 1H, J=4.22, 8.23 Hz, ArH); 4.433 (s, 2H, ArCH2); MS (FAB): m/z 159.09 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([O:11][CH3:12])=[C:9]([NH2:13])[C:8]([Cl:14])=[C:7]([Br:15])[N:6]=1)=[O:4].[OH-].[Na+]>CO>[NH2:13][C:9]1[C:8]([Cl:14])=[C:7]([Br:15])[N:6]=[C:5]([C:3]([OH:4])=[O:2])[C:10]=1[O:11][CH3:12]
Reactant: COC(=O)c1nc(Br)c(Cl)c(N)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c(C(=O)O)nc(Br)c(Cl)c1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.1 %

Procedure:
To methyl-4-amino-6-bromo-5-chloro-3-methoxypyridine-2-carboxylate (0.300 g, 1.02 mmol) in 10 mL of methanol was added 1 N NaOH (1.10 mL, 1.10 mmol). The reaction mixture was stirred at room temperature for 4 hr and was then concentrated to dryness in vacuo. The resulting aqueous layer was acidified with concentrated HCl. The white solid was collected by filtration and was rinsed with H2O. The solid was dried at 50° C. under vacuum to give 0.230 g of a white fluffy solid; mp 154-156° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.[CH:11]1[CH2:15][CH2:14][CH2:13][CH:12]=1>>[CH3:7][C:6]1([CH3:8])[CH2:5][C:4]2([CH3:10])[CH:3]([CH:11]3[CH:15]2[CH2:14][CH2:13][CH2:12]3)[C:2](=[O:1])[CH2:9]1
Reactant: C1=CCCC1
Reactant: CC1=CC(=O)CC(C)(C)C1
Product: CC1(C)CC(=O)C2C3CCCC3C2(C)C1

Procedure:
The second photochemical reaction consists in reacting isophorone with cyclopentene to yield 5,5,7-trimethyltricyclo[6.3.0.02,7 ]undecane-3-one: ##STR2##
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2N=CC=N2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[NH:16]1[CH:20]=[CH:19]N=[CH:17]1>>[N:11]1([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:6]=2[C:7]([OH:9])=[O:8])[CH:19]=[CH:20][N:16]=[CH:17]1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Reactant: c1c[nH]cn1
Product: Cc1ccc(-n2ccnc2)c(C(=O)O)c1

Procedure:
The title compound was synthesized following the same general protocol as described for 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid in Example A11, using imidazole. ESI-MS (m/z): 203 [M+1]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCCCCCOCc1ccccc1
Reactant: O=C1CCNCC1
Product: O=C1CCN(CCCCCOCc2ccccc2)CC1

Procedure:
1-(5-Benzyloxypentyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-5-benzyloxypentane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:19])=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[CH2:20]([O:22][C:23](=[O:35])[CH2:24][N:25]1[C:33]2[C:28](=[CH:29][C:30]([OH:34])=[CH:31][CH:32]=2)[CH:27]=[CH:26]1)[CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:20]([O:22][C:23](=[O:35])[CH2:24][N:25]1[C:33]2[C:28](=[CH:29][C:30]([O:34][CH2:2][C:3]3[C:4]([CH3:19])=[N:5][C:6]([C:9]4[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=4)=[N:7][CH:8]=3)=[CH:31][CH:32]=2)[CH:27]=[CH:26]1)[CH3:21]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ncc1CCl
Reactant: CCOC(=O)Cn1ccc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccc2cc(OCc3cnc(-c4ccc(C(F)(F)F)cc4)nc3C)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 44 %

Procedure:
To a solution of 300 mg (0.94 mmol) 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidine and 206 mg (0.94 mmol) (5-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 1 c]) in 3 ml DMF was added 375 mg (1.15 mmol) cesium carbonate. The reaction mixture was stirred for 3 h at RT and then partitioned between ether and water. The crude product was purified by chromatography over silica gel with AcOEt/heptane 1.2 to give 194 mg of pure {5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester.