Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:26](O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CCOC(C)=O>[CH2:26]([O:12][C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)=[O:13])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a solution of quinoline-6-carboxylic acid (2.0 g, 11.6 mmol) in EtOAc (30 mL) was added carbonyldiimidazole (2.15 g, 13.3 mmol). The resulting mixture was stirred at room temperature for 2 h at which time all solids had dissolved. Benzyl alcohol (1.4 mL) was added and the reaction was stirred overnight. The mixture was then extracted successively with aqueous 1 N HCl (25 mL), aqueous NaHCO3 and brine. Evaporation of the solvent gave a solid, which was triturated with cold 1:1 EtOAc/hexane to afford the title compound as a solid (1.9 g, 62%). 1H NMR (selected signals, CD3OD) δ=9.00 (dd, 1H), 8.61 (d, 1H), 8.34 (d, 1H), 8.29 (dd, 1H), 8.25 (d, 1H), 5.43 (s, 2H)
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[CH2:11][C:12]([OH:14])=O.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:28][O:29][C:30](=[O:36])[C@@H:31]1[CH2:35][CH2:34][CH2:33][NH:32]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:28][O:29][C:30](=[O:36])[C@@H:31]1[CH2:35][CH2:34][CH2:33][N:32]1[C:12](=[O:14])[CH2:11][CH:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C(O)CC1CCc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1C(=O)CC1CCc2ccccc2C1
Temperature: 25 °C
Yield: 66.8 %

Procedure:
To a solution of 3.4 g of 1,2,3,4-tetrahydronaphthalen-2-ylacetic acid in 50 ml of methylene chloride was added 14.1 g of WSC.HCl with stirring at room temperature. Then, 3.6 g of L-proline methyl ester hydrochloride and 2.2 g of triethylamine were added to the solution. The mixture was stirred for 17 hours at room temperature. The reaction mixture was washed with water, diluted hydrochloric acid, and saturated sodium hydrogen carbonate in this order. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 3.6 g of 1-(1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-proline methyl ester as a colorless oil.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].Br[CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30]>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:19][CH2:20][N:21]([CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH2:22][CH2:23]1
Reactant: CCC(Br)CC
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCNCC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCN(C(CC)CC)CC3)c2n1

Procedure:
Prepared similarly to Example 35 from 2-(butyloxy)-8-(methyloxy)-9-[3-(4-piperidinyl)propyl]-9H-purin-6-amine and 3-bromopentane.
Reaction SMILES: [O:1]=[S:2]1(=[O:20])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]12[CH2:16][CH:12]3[CH2:13][CH:14]([CH2:15]1)[C:10](C(O)=O)([CH2:11]3)[CH2:9]2.OS(O)(=O)=O.[N-:26]=[N+]=[N-].[Na+]>C(Cl)(Cl)Cl.O>[O:1]=[S:2]1(=[O:20])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]12[CH2:16][CH:12]3[CH2:13][CH:14]([CH2:15]1)[C:10]([NH2:26])([CH2:11]3)[CH2:9]2
Reactant: O=C(O)C12CC3CC1CC(CN1CCCS1(=O)=O)(C3)C2
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: NC12CC3CC1CC(CN1CCCS1(=O)=O)(C3)C2
Yield: 73.4 %

Procedure:
To a stirred solution of the acid obtained in step III (0.39 g, 1.31 mmol) in CHCl3 (7 mL) was added conc. H2SO4 (1.4 mL, 26 mmol). Solid NaN3 (0.26 g, 3.93 mmol) was added slowly in portions by keeping the reaction temperature below 40° C. The reaction mixture was stirred at r.t for 2, h then it was cooled to ice bath temperature, diluted with water, and extracted with EtOAc. The aqueous layer was basified by adding 50% NaOH solution and extracted with CHCl3. The combined organic layer was washed with brine, dried over Na2SO4, and the solvent was evaporated under reduced pressure to obtain 1-[(1,1-dioxidoisothiazolidin-2-yl) methyl]tricyclo[3.3.1.03,7]nonan-3-amine (0.26 g) as viscous liquid in 74% yield. m/z (M+1) 271; 1H NMR (CDCl3) 300 MHz δ 3.32 (t, J=6.8 Hz, 2H), 3.10 (t, J=7.4 Hz, 2H), 2.92 (s, 2H), 2.40-2.28 (m, 3H), 2.01-1.83 (m, 3H), 1.75-1.52 (m, 6H), 1.50-1.43 (m, 1H), 1.39-1.32 (m, 1H).
Reaction SMILES: [CH3:1][CH:2]1[C:7]2=[N:8][C:9]3[CH:10]=[N:11][C:12]4[C:17]([C:18]=3[N:6]2[C@@H:5]([CH3:19])[CH2:4][O:3]1)=[CH:16][CH:15]=[CH:14][CH:13]=4.ClC1C=C(C=CC=1)C(OO)=[O:25].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][CH:2]1[C:7]2=[N:8][C:9]3[CH:10]=[N+:11]([O-:25])[C:12]4[C:17]([C:18]=3[N:6]2[C@@H:5]([CH3:19])[CH2:4][O:3]1)=[CH:16][CH:15]=[CH:14][CH:13]=4
Reactant: CC1OC[C@H](C)n2c1nc1cnc3ccccc3c12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC1OC[C@H](C)n2c1nc1c[n+]([O-])c3ccccc3c12
Reaction time: 18 h
Yield: 99.9 %

Procedure:
A solution of (11S)-8,11-dimethyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline (80 mg, 0.316 mmol) and 5 mL of CHCl3 was treated with MCPBA (meta-chloroperoxybenzoic acid) (93 mg, 77% max). After 18 hours, the reaction was treated with ˜10 mL of CHCl3 and 5 mL of 2% Na2CO3 solution and the layers were separated. The aqueous layer was extracted with CHCl3 (5×10 mL). The organic layers were combined then washed with brine, dried over Na2SO4, filtered, and concentrated to give (11S)-8,11-dimethyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline 5-oxide (85 mg) as a light yellow solid.
Reaction SMILES: Cl[C:2]1(C#N)[CH2:7][CH:6]2[CH2:8][CH2:9][C:3]1([O:10][CH3:11])[CH:4]=[CH:5]2.[OH2:14]>C(O)C>[CH3:11][O:10][C:3]12[CH2:9][CH2:8][CH:6]([CH:5]=[CH:4]1)[CH2:7][C:2]2=[O:14]
Reactant: O
Reactant: COC12C=CC(CC1)CC2(Cl)C#N
Solvent: CCO
Product: COC12C=CC(CC1)CC2=O
Yield: 57 %

Procedure:
A solution of 2-chloro-1-methoxybicyclo[2.2.2]oct-5-ene-2-carbonitrile (14.0 g, 71 mmol) and Na2S.9H2O (34.0 g, 142 mmol) in ethanol (175 mL) was heated under reflux for 14 h. The solution was poured into H2O and extracted three times with ether. The combined extracts were washed with saturated aqueous NH4Cl solution, H2O, and brine. The organic layer was dried over Na2SO4, concentrated to the residue. The crude product was purified by column chromatography to afford 1-methoxybicyclo[2.2.2]oct-5-en-2-one (5.7 g, 57%). 1H NMR (CDCl3, 400 MHz) δ 6.46 (dd, 1H), 6.22 (d, 1H), 3.50 (s, 3H), 2.94 (m, 1H), 2.11 (m, 2H), 1.53-1.92 (m, 4H).
Reaction SMILES: Br[C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:13]2[C:4](=[C:5]([O:20][C@H:21]3[CH2:25][N:24]([C:26](=[O:44])[C@H:27]([CH:39]4[CH2:43][CH2:42][CH2:41][CH2:40]4)[NH:28][C:29]([O:31][CH2:32][C:33]([CH3:38])([CH3:37])[CH2:34][CH:35]=[CH2:36])=[O:30])[C@H:23]([C:45]([O:47][CH3:48])=[O:46])[CH2:22]3)[N:6]=[C:7]3[C:12]=2[CH:11]=[CH:10][C:9]([C:18]#[N:19])=[CH:8]3)[CH:3]=1.[CH:49]([Sn](CCCC)(CCCC)CCCC)=[CH2:50]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]([C:9]1[CH:10]=[CH:11][C:12]2[C:7]([CH:8]=1)=[N:6][C:5]([O:20][C@H:21]1[CH2:25][N:24]([C:26](=[O:44])[C@H:27]([CH:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[NH:28][C:29]([O:31][CH2:32][C:33]([CH3:37])([CH3:38])[CH2:34][CH:35]=[CH2:36])=[O:30])[C@H:23]([C:45]([O:47][CH3:48])=[O:46])[CH2:22]1)=[C:4]1[C:13]=2[CH:14]=[C:15]([O:16][CH3:17])[C:2]([CH:49]=[CH2:50])=[CH:3]1)#[N:19]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: C=CCC(C)(C)COC(=O)N[C@H](C(=O)N1C[C@H](Oc2nc3cc(C#N)ccc3c3cc(OC)c(Br)cc23)C[C@H]1C(=O)OC)C1CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCC(C)(C)COC(=O)N[C@H](C(=O)N1C[C@H](Oc2nc3cc(C#N)ccc3c3cc(OC)c(C=C)cc23)C[C@H]1C(=O)OC)C1CCCC1

Procedure:
To a degassed solution of the product mixture from Step 2, methyl (4R)-4-[(8-bromo-3-cyano-9-methoxyphenanthridin-6-yl)oxy]-1-[(2S)-2-cyclopentyl-2-({[(2,2-dimethylpent-4-en-1-yl)oxy]carbonyl}amino)acetyl]-L-prolinate (420 mg, 0.58 mmol) in PhMe (10 mL) was added vinyltributyltin (0.205 mL, 0.70 mmol) and tetrakis(triphenylphosphine)palladium (67 mg, 0.06 mmol). The mixture was then heated to reflux for 18 h. The solvent was then removed in vacuo and the crude material was purified on silica (gradient elution, 10-50% EtOAc/hex) to provide the title compound. LRMS (M+H)+=669.3.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[S:9]([OH:12])(=[O:11])=[O:10].[Na].[CH3:14][C:15](N(C)C)=O>[Cu].O>[Br:8][C:5]1[CH:4]=[C:3]([S:9]([OH:12])(=[O:11])=[O:10])[C:2]([C:2]2[C:3]([S:9]([OH:12])(=[O:11])=[O:10])=[CH:4][C:5]([Br:8])=[CH:14][CH:15]=2)=[CH:7][CH:6]=1
Reactant: CC(=O)N(C)C
Reactant: O=S(=O)(O)c1cc(Br)ccc1Br
Agent: [Cu]
Agent: [Na]
Solvent: O
Product: O=S(=O)(O)c1cc(Br)ccc1-c1ccc(Br)cc1S(=O)(=O)O
Temperature: 120 °C
Yield: 86 %

Procedure:
A modification of the published procedures of Courtot and Lin in Bull. Soc. Chim. Fr. 1931, 49, 1047 was used. Inside a glove box, a 500 mL round-bottom flask equipped with a reflux condenser, stirring bar, and gas inlet was charged with 2,5-dibromobenzenesulfonic acid, sodium salt (73 g, 0.216 moles), activated copper bronze (27 g, 0.43 moles), and DMAc (200 mL). The mixture was heated to 120° C. overnight under nitrogen. The mixture was poured into water (1 L) and the solid removed by vacuum filtration. The filtrate was evaporated and the residue dried at 100° C. under vacuum. The solids were recrystallized from acetonitrile/water (10:1) after treating with decolorizing carbon and dried under vacuum at 60-150° C. to give 48.13 g (86% yield) of 4,4′-dibromobiphenyl-2,2′-disulfonic acid, sodium salt. 1H NMR (DMSO-d6): 7.19 (d, 8.3 Hz, 2H), 7.42 (dd, 8.3 and 2.1 Hz, 2H), 7.96 (d, 2.1 Hz, 2H).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[N:14]1[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2>ClCCl>[CH:25]1[C:26]2[N:14]([C:8]3[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]=3[OH:6])[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]=2[CH:22]=[CH:23][CH:24]=1
Reactant: COc1ccc(C)cc1-n1c2ccccc2c2ccccc21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc(O)c(-n2c3ccccc3c3ccccc32)c1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
A 1.0 M boron tribromide solution in dichloromethane (90 mL, 90 mmol, 1.9 equiv) was added dropwise at −78° C., over 30 minutes, to a solution of compound 4 (13.5 g, 46.98 mmol, 1 equiv) in anhydrous dichloromethane (400 mL). The reaction was warmed to room temperature, when liquid chromatography-mass spectrometry (LCMS) indicated that the reaction was complete. The reaction was quenched with ice-water (200 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (2×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on an ANALOGIX 40-150 g column, eluting with a gradient of 0 to 20% ethyl acetate in heptanes to give compound 5 (12.3 g, 95% yield) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:20]=[CH:19][C:13]([O:14][CH:15]([CH3:18])[CH:16]=[O:17])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[S:21](=[O:24])([OH:23])[O-:22].[Na+:25]>CO.O>[Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:20]=[CH:19][C:13]([O:14][CH:15]([CH3:18])[CH:16]([OH:17])[S:21]([O-:24])(=[O:23])=[O:22])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Na+:25]
Reactant: CC(C=O)Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Reactant: O=S([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1)C(O)S(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 96 h
Yield: 72.7 %

Procedure:
A solution of 2-{p-[(3,5-dichloro-2-pyridyl)-oxy]phenoxy}propionaldehyde (25.38 g, 0.0813 mol) in methanol (300 mL) is added dropwise to a solution of sodium bisulfite (10.2 g, 0.0976 mol) in water (100 mL). The reaction mixture is stirred for 4 days at room temperature and filtered. The filter cake is dried in a vacuum oven overnight to obtain the title product as a white solid (24.6 g, mp 172°-173° C.).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C[N:8](C)C=O.[CH3:12][C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:15][C:14]=1[CH2:24][O:25][C:26]1[CH:46]=[CH:45][C:29]([CH2:30][O:31]/[N:32]=[C:33](/[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)\[CH2:34][CH2:35][C:36]([OH:38])=O)=[CH:28][CH:27]=1>O1CCCC1>[CH3:12][C:13]1[O:17][C:16]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:15][C:14]=1[CH2:24][O:25][C:26]1[CH:46]=[CH:45][C:29]([CH2:30][O:31]/[N:32]=[C:33](/[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)\[CH2:34][CH2:35][C:36]([NH2:8])=[O:38])=[CH:28][CH:27]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCC(=O)O)c2ccccc2)cc1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCC(N)=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
Oxalyl chloride (0.156 ml) and N,N-dimethylformamide (catalytic amount) were added to a solution of E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyric acid (700 mg) in tetrahydrofuran (10 ml) at room temperature, which was stirred at room temperature for 30 minutes and concentrated. The residue was dissolved in tetrahydrofuran (10 ml) and added dropwise to a mixture of a 25% aqueous ammonia (15 ml) and ethyl acetate (20 ml) at 0° C. After stirred at room temperature for 1 hour, water was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate to obtain E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyramide (315 mg, yield 45%) as colorless crystals. m.p. 164-165° C.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40]([C:43]2([C:46]#[N:47])[CH2:45][CH2:44]2)=[N:41][CH:42]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:38]=[CH:39][C:40]([C:43]4([C:46]#[N:47])[CH2:45][CH2:44]4)=[N:41][CH:42]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: N#CC1(c2ccc(Br)cn2)CC1
Product: C[C@@H](c1ccc(-c2ccc(C3(C#N)CC3)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 16 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 1-(5-bromo-pyridin-2-yl)-cyclopropanecarbonitrile following a procedure analogous to that described in Example 1. Yield: 16% of theory; Mass spectrum (ESI+): m/z=496 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 0.81 (s, 3H), 1.18 (s, 3H), 1.47 (d, J=7.0 Hz, 3H), 1.70-1.74 (m, 2H), 1.81-1.85 (m, 2H), 2.02 (s, 2H), 2.11-2.20 (m, 1H), 2.38-ca. 2.50 (m, 2H) superimposed by D3CSOCHD2 signal, 3.03 (mc, 1H), 4.23 (s, 1H), 5.44 (q, J=7.0 Hz, 1H), 6.98 (d, J=8.3 Hz, 2H), 7.26-7.39 (m, 5H), 7.44 (d, J=8.3 Hz, 2H), 7.60 (d, J=8.3 Hz, 1H), 8.03 (dd, J=8.3, 2.4 Hz, 1H), 8.73 (d, J=2.0 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.Br[CH:20]([CH3:27])[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C.C(OCC)C>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH:20]([CH3:27])[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[O:24])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: COC(=O)C=CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCC(C)=O
Product: COC(=O)C=CC(C)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 25 °C
Reaction time: 32 h
Yield: 83.8 %

Procedure:
In 50 ml of methyl ethyl ketone, 2.0 g (0.0078 mole) of 4-[5-(trifluoromethyl)-2-pyridinyloxy]phenol, 3.2 g of methyl 4-bromo-2-pentenoate, and 2.0 g of potassium carbonate were refluxed with constant stirring for 32 hours. Upon cooling to room temperature, the suspension was filtered through celite and the insoluble material washed with 75 ml of acetone. The filtrate was concentrated under reduced pressure to give an oily residue which was dissolved in 125 ml of ethyl ether and transferred to a separatory funnel. After washing with saturated sodium bicarbonate and water, the ether layer was dried over magnesium sulfate and charcoal filtered. Under reduced pressure, the solvent was evaporated and traces of volatile impurities removed at 0.4 mm Hg. (50° for 2 hours) to yield 2.4 g (84% ) of product, ND25 1.520.
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([C:19]#N)[CH:17]=[CH:18][C:4]1=2)[CH3:2].C(O)=[O:22]>[Ni]>[CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:11])([CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH:19]=[O:22])[CH:17]=[CH:18][C:4]1=2)[CH3:2]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(C#N)ccc21
Reactant: O=CO
Agent: [Ni]
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(C=O)ccc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile (1.0 g) and Raney nickel (3.0 g) were suspended in formic acid (10 ml), and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was filtered to remove insoluble matter, and the filtrate was condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50→20:80). The purified product was condensed under reduced pressure to give the title compound (0.92 g) as a yellowish-white solid (yield=92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C@H:10]1[CH2:19][CH2:18][C:13]2(OCC[O:14]2)[CH2:12][C@@H:11]1[NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O1CCOCC1.O>S(=O)(=O)(O)O>[O:14]=[C:13]1[CH2:12][C@H:11]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@@H:10]([C:3]2[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH2:19][CH2:18]1
Reactant: O=C(N[C@H]1CC2(CC[C@@H]1c1cc(F)c(F)cc1F)OCCO2)OCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: O=C1CC[C@H](c2cc(F)c(F)cc2F)[C@@H](NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of benzyl [(7S,8R)-8-(2,4,5-trifluorophenyl)-1,4-dioxaspiro[4.5]dec-7-yl]carbamate (315 mg, 0.75 mmol) in sulfuric acid (15 mL, 1:1 in water) was added 1,4-dioxane (30 mL). The mixture was stirred at room temperature for 1 h. The resulting mixture was poured into water (70 ml) and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and evaporated to yield the title compound. LC/MS 378.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[Br:11][C:12]1[CH:13]=[N:14][NH:15][CH:16]=1.CN(C=O)C>CCOC(C)=O>[Br:11][C:12]1[CH:13]=[N:14][N:15]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[NH:8][CH:9]=[CH:10][C:3]=23)[CH:16]=1
Reactant: Brc1ccnc2[nH]ccc12
Reactant: Brc1cn[nH]c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1cnn(-c2ccnc3[nH]ccc23)c1
Temperature: 150 °C

Procedure:
A mixture of 4-bromo-1H-pyrrolo[2,3-b]pyridine (1.10 g, 0.00558 mol) and 4-bromo-1H-pyrazole (1.2 g, 0.0084 mol) was heated neat to 150° C. for 2 h. DMF was added to dissolve the crude residue. This residue was taken up in EtOAc and washed with IN NaOH. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give a crude 4-(4-bromo-1H-pyrazol-1-yl)-1H-pyrrolo[2,3-b]pyridine residue, LC/MS (M+H)+: 263, 265.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:31]=[CH:30][C:10]([C:11]([NH:13][CH:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[C:15]([OH:17])=O)=[O:12])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[NH2:34][CH2:35][CH2:36][OH:37]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:31]=[CH:30][C:10]([C:11]([NH:13][CH:14]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][C:26]([F:27])([F:29])[F:28])=[CH:23][CH:24]=3)[C:15]([NH:34][CH2:35][CH2:36][OH:37])=[O:17])=[O:12])=[CH:9][CH:8]=2)=[CH:32][CH:33]=1
Reactant: NCCO
Reactant: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)O)c1ccc(Oc2ccc(Cl)cc2)cc1
Product: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)NCCO)c1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 82.6 %

Procedure:
A reaction similar to that described in Example 32 (32c) was conducted using 2-{[4-(4-chlorophenoxy)benzoyl]amino}-3-[4-(trifluoromethoxy)phenyl]propanoic acid (467 mg, 0.973 mmol) prepared in Example 48 (48a) and 2-aminoethanol (106 μL, 1.75 mmol) to give 420 mg of the title compound (white powder, yield: 83%).
Reaction SMILES: [O:1]([C:8]1[C:14]([CH3:15])=[CH:13][C:11]([NH2:12])=[C:10]([CH3:16])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:19](OC)[N:20]([CH2:22][CH3:23])[CH3:21]>C1(C)C=CC=CC=1.CO>[CH2:22]([N:20]([CH3:21])[CH:19]=[N:12][C:11]1[CH:13]=[C:14]([CH3:15])[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][C:10]=1[CH3:16])[CH3:23]
Reactant: CCN(C)C(OC)OC
Reactant: Cc1cc(Oc2ccccc2)c(C)cc1N
Solvent: Cc1ccccc1
Solvent: CO
Product: CCN(C)C=Nc1cc(C)c(Oc2ccccc2)cc1C
Temperature: 50 °C
Reaction time: 12 h
Yield: 96.6 %

Procedure:
0.18 g (0.8 mmol) of 4-phenoxy-2,5-dimethylaniline was dissolved in 2.5 ml of toluene and this solution was then admixed with 0.18 ml of a solution of N-ethyl-N-methylformamide dimethyl acetal in methanol (60%). After 12 h of stirring of the reaction mixture at 50° C., subsequent filtration and removal of the solvent under reduced pressure, 240 mg (94.8% purity, 96.6% yield) of the product were obtained; log P(HCOOH)=1.87.
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:4]([CH3:18])=[N:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([C:29]([CH3:33])([CH3:32])[CH2:30][Cl:31])=[O:28].C(Cl)Cl>C(C(C)=O)C>[CH3:1][N:2]1[C:6]([O:7][CH2:26][C:27](=[O:28])[C:29]([CH3:33])([CH3:32])[CH2:30][Cl:31])=[C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:4]([CH3:18])=[N:3]1
Reactant: Cc1nn(C)c(O)c1C(=O)c1ccc(Cl)cc1Cl
Reactant: CC(C)(CCl)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: Cc1nn(C)c(OCC(=O)C(C)(C)CCl)c1C(=O)c1ccc(Cl)cc1Cl
Yield: 47.8 %

Procedure:
Into a four necked flask was charged 1.0 g of 1,3-dimethyl-4-(2,4-dichlorobenzoyl)-5-hydroxypyrazole, and the contents were dissolved in 20 ml of methyl ethyl ketone. 0.54 g of anhydrous potassium carbonate was added thereto, and 0.75 g of 1,1-dimethyl-2-chloroethyl bromomethyl ketone was further dropwise added while stirring whereby the mixture was reacted for 2 hours under the reflux condition (80° C.). After completion of the reaction, the reaction product was collected by filtration, and the solvent (methyl ethyl ketone) was distilled off to obtain a crude product. The crude product was passed through a silica gel column (eluent: methylene chloride), and the eluent was distilled off to obtain 0.7 g of the titled compound having a melting point of 58° to 60° C.