Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:11])[CH2:2][CH3:3].[F:12][C:13]([F:23])([F:22])[C:14](=O)[CH2:15][C:16](OCC)=[O:17]>[Cl-].[Zn+2].[Cl-].O>[OH:11][C:5]1[C:4]([CH2:1][CH2:2][CH3:3])=[C:9]2[C:8]([C:14]([C:13]([F:23])([F:22])[F:12])=[CH:15][C:16](=[O:17])[O:10]2)=[CH:7][CH:6]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: CCCc1c(O)cccc1O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Product: CCCc1c(O)ccc2c(C(F)(F)F)cc(=O)oc12
Yield: 77 %

Procedure:
2-propylbenzene-1,3-diol (J. Med. Chem., 38, pp 4411-4432, 1995) (3.65 g, 24.0 mmol), zinc chloride (3.60 g, 26.4 mmol), and ethyl 4,4,4-trifluoroacetoacetate (4.86 g, 26.4 mmol) were stirred overnight at 110° C. The reaction solution was added with water and extracted with ethyl acetate. Subsequently, the organic layer was washed with saturated saline, dried using anhydrous sodium sulfate, and concentrated under vacuum. The obtained residue was purified using silica-gel chromatography (chloroform) and then recrystallized with chloroform, and 5.01 g of the title compound (yield 77%) was obtained as pale-brown crystalline powder.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=O.Cl.[NH2:32][OH:33].C[O-].[Na+].CO.Cl>O1CCOCC1>[OH:33][NH:32][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:11][CH2:12][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:14][CH2:15]2)=[N:7][CH:6]=1)=[O:2]
Reactant: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc(-c4ccccc4)cc3)CC2)s1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(NO)c1cnc(N2CCN(S(=O)(=O)c3ccc(-c4ccccc4)cc3)CC2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.2 %

Procedure:
To a solution of compound 12j (125 mg, 0.281 mmol) in 1,4-dioxane (2 mL) were added hydroxylamine hydrochloride (194 mg, 2.80 mmol) and a freshly prepared solution of sodium methoxide in methanol (96 mg, 4.20 mmol of sodium dissolved in 1 mL of methanol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to pH˜6 with 1M HCl and the formed precipitates were filtered off. The filtrate was diluted with ethyl acetate (5 mL) and water (2 mL) and the organic layer was separated. The aqueous layer was washed with ethyl acetate (5 mL) and the combined organic layers were dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 13j (9 mg, yield 7.2%). HPLC: 97.51% (Rt=14.61 min).
Reaction SMILES: N1([C:10]([CH:12]2[CH2:17][C:16]([CH3:19])([CH3:18])[O:15][C:14]([CH3:21])([CH3:20])[CH2:13]2)=[O:11])C2C=CC=CC=2N=N1.CCOCC.[Mg+2].[Br-].[Br-].[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37](=[O:39])[CH3:38])=[CH:33][CH:32]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37](=[O:39])[CH2:38][C:10]([CH:12]2[CH2:13][C:14]([CH3:20])([CH3:21])[O:15][C:16]([CH3:18])([CH3:19])[CH2:17]2)=[O:11])=[CH:33][CH:32]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: CC1(C)CC(C(=O)n2nnc3ccccc32)CC(C)(C)O1
Agent: [Br-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)CC(C(=O)CC(=O)c2ccc(Cl)cc2)CC(C)(C)O1
Reaction time: 8 h
Yield: 72.8 %

Procedure:
To a mixture of benzotriazol-1-yl-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-methanone (1.00 g, 3.13 mmol), magnesium bromide diethyl etherate (1.62 g, 6.26 mmol), and 1-(4-chloro-phenyl)-ethanone (0.39 mL, 2.98 mmol) in 10 mL of DCM at RT was added dropwise DIEA (1.74 mL, 9.40 mmol). The mixture was stirred overnight and then diluted with 50 mL of DCM and washed with 1N HCl (100 mL) and brine (100 mL). The organic layer was dried over Na2SO4, concentrated, and the residue purified by flash chromatography on silica gel to give 0.70 g (69%) of a white solid.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:22]([CH3:25])([CH3:24])[CH3:23])[S:8]/[C:9]/1=[N:10]\[C:11](=[O:21])[C:12]1[CH:17]=[C:16](I)[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])[CH2:2][CH2:3][CH3:4].[C:26]([Si:28]([CH3:31])([CH3:30])[CH3:29])#[CH:27].C(N(CC)CC)C>CN(C=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:1]([C:5]1=[CH:6][N:7]([C:22]([CH3:25])([CH3:24])[CH3:23])[S:8]/[C:9]/1=[N:10]\[C:11](=[O:21])[C:12]1[CH:17]=[C:16]([C:27]#[C:26][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])[CH2:2][CH2:3][CH3:4]
Reactant: C#C[Si](C)(C)C
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)c1cc(I)ccc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)c1cc(C#C[Si](C)(C)C)ccc1OC
Temperature: 50 °C
Yield: 96.8 %

Procedure:
A mixture of the product from Example 61 (330 mg, 0.7 mmol), ethynyltrimethylsilane (206 mg, 2.1 mmol), PdCl2(PPh3)2 (49 mg, 0.07 mmol), triethylamine (201 mg, 2.1 mmol) and CuI (33 mg, 0.18 mmol) in DMF (5 mL) was heated at 50° C. for 16 hrs, diluted with H2O and extracted with EtOAc (2×). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% Hexane in ethyl acetate) to afford 300 mg (97%) of the title compound. MS (DCI/NH4+) m/z 443 (M+H)+.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[N:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]5)=[CH:18][CH:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:35]=[CH:36][N:37]=[CH:38][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([N:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)=[CH:20][N:21]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:35]=[CH:36][N:37]=[CH:38][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc2c3cnc(Nc4ccc(N5CCNCC5)cn4)nc3n(C3CCCC3)c2cn1
Yield: 98.5 %

Procedure:
A solution of compound 6 (3.28 g, 6.37 mmol) in TFA/DCM (60, 1:1) was stirred at room temperature for 30 min. The reaction mixture was concentrated and the residue was purified by chromatography on silica gel eluting with CH2Cl2/methanol/NH4OH (200:10:1) to give the title compound (7) as an off-white solid (2.60 g, 98%). 1H NMR (400 MHz, DMSO-d6) δ 9.86 (1H, s), 9.28 (1H, s), 9.01 (1H, s), 8.68 (1H, br s), 8.45 (1H, d, J=4 Hz), 8.23 (1 H, d, J=8 Hz), 8.10 (1H, d, J=4 Hz), 8.04 (1H, d, J=8 Hz), 7.54 (1H, dd, J=8 Hz, J=4 Hz), 5.43 (1H, p, J=8 Hz), 3.35 (4H, m), 3.26 (4H, m), 2.40 (2H, m), 2.03-2.10 (4H, m), 1.78 (2H, m) ppm; LCMS-ESI (POS), M/Z, M+1: Found 415.1, Calculated 415.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:9](I)=[CH:10][C:3]=12.C([Li])CCC.[O:27]=[C:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:9]([C:28]3([OH:27])[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[CH2:32][CH2:33]3)=[CH:10][C:3]=12
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(Cl)ccnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(C3(O)CCN(C(=O)OC(C)(C)C)CC3)cc3c(Cl)ccnc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (200 mg, 0.462 mmol) in tetrahydrofuran (1.5 mL) at −78° C. was added 1.6 M n-butyllithium in hexanes (0.347 mL, 0.555 mmol) under nitrogen. The mixture was stirred for 10 minutes and tert-butyl 4-oxopiperidine-1-carboxylate (111 mg, 0.555 mmol) was added. The mixture was stirred at −78° C. for 1 hour and was slowly warmed to room temperature overnight. The mixture was quenched with water, extracted with ethyl acetate (2×5 mL) and the organic layer was dried over magnesium sulfate, filtered, and concentrated. Purification by flash chromatography (silica gel, 20-100% ethyl acetate/heptanes) afforded the title compound. MS (ESI+) m/z 506.0 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:15])[CH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1.[C:16](OCC)(=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.C(O[K])(C)(C)C.Cl>C1COCC1.O>[OH:23][C:16]([C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)=[C:4]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)[C:3]([NH:2][CH3:1])=[O:15]
Reactant: CCOC(=O)c1ccncc1
Reactant: CNC(=O)Cc1ccc2ccccc2c1
Agent: CC(C)(C)O[K]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)C(=C(O)c1ccncc1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Methyl-2-naphthalen-2-yl-acetamide (94 g, 470 mmol) and 71.3 g (71 ml) of ethyl isonicotinate (470 mmol) were partially dissolved in 800 mL of anhydrous THF in a 3 L, 3-necked r.b. flask equipped with a mechanical stir, temperature probe, and a 500-mL addition funnel. The flask was cooled to 0–5° C. in an ice-water bath. tBuOK (1M in THF, 470 mL) was added slowly into the heterogeneous mixture. After the addition, the resulting yellow-brown heterogeneous mixture was stirred overnight at RT. The resulting dark solution was cooled to 0–5° C. in an ice-water bath. Distilled water (800 mL) was added. The basic solution was neutralized to pH 7 using 37% HCl. The solvent was removed in vacuum at RT. The resulting solid was filtered off, washed by slurring in water (1 L) and toluene (1 L), respectively. The suspension was then filtered. The solid was dried under vacuum at 50° C. overnight and used crude in the next step.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=O)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([NH:12][CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[CH:3]=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([NH:12][CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCC(CCC)Nc1cc(C)[nH]c(=O)c1[N+](=O)[O-]
Product: CCCC(CCC)Nc1cc(C)nc(Cl)c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
6-Methyl-3-nitro-4-(1-propylbutylamino)pyridone (3.7 g, 13.84 mmol), was treated with POCl3 (14 mL) at 25° C. for 20 h. Then it was poured into ice/water (200 mL) and extracted with EtOAc (300 mL). The EtOAc was washed with water, brine, dried (MgSO4) and stripped in vacuo. The residue was chromatographed on silica gel (20% EtOAc/hexanes eluting solvent) to give the product (3.3 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.C(O)(=O)C.[N:21]([O-])=[O:22].[Na+]>O>[N:21]([C:5]1[C:6]([NH2:8])=[N:7][C:2]([NH2:1])=[N:3][C:4]=1[O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:22]
Reactant: O=N[O-]
Reactant: Nc1cc(OCc2ccccc2)nc(N)n1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(N)c(N=O)c(OCc2ccccc2)n1

Procedure:
To a solution of 16 g 2,4-diamino-6-benzyloxy-pyrimidine (7) in 250 mL of warm 30% acetic acid is added a solution of 7g sodium nitrite in 25 mL H2O. The sodium nitrite solution is held at 70°-80° C. and is added dropwise while being stirred continuously. The sodium nitrite solution is added until potassium-iodate starch paper shows a positive reaction. The violet-red precipitate is cooled, suctioned off and then recrystallized from ethanol or acetone to yield 8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.[CH3:25][O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34]Br)[CH:29]=1>>[CH3:25][O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][O:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:7]3[C:6]4[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=4)[N:10]=[N:9][C:8]=3[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:19]=2)[CH:29]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: Oc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Product: COC(=O)c1cccc(COc2cccc(-c3c(-c4ccccc4)nnc4c(Cl)cccc34)c2)c1

Procedure:
3-[3-(8-Chloro-3-phenyl-cinnolin-4-yl)-phenoxymethyl]-benzoic acid methyl ester was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenol and 3-bromomethyl-benzoic acid methyl ester according to the procedure of Example 14. MS (ES) m/z 480.8;
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[C:4]([CH3:18])([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH2:11])[CH2:3]1.F[C:20](F)(F)[C:21](O)=O.O1[CH2:31][CH2:30]OCC1>>[CH3:1][N:2]1[CH2:3][C:4]([CH3:18])([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH2:11])[C:5]2[NH:2][C:3]3[CH:4]=[CH:5][C:21]([CH3:20])=[CH:30][C:31]=3[C:6]=2[CH2:7]1
Reactant: C1COCCO1
Reactant: O=C(O)C(F)(F)F
Reactant: C=C(CC1(C)CN(C)CCC1=O)c1ccncc1
Product: C=C(CC1(C)CN(C)Cc2c1[nH]c1ccc(C)cc21)c1ccncc1
Temperature: 100 °C

Procedure:
P-Tolylhydrazinehydrochloride (150 mg, 0.94 mmol) and 1,3-dimethyl-3-(2-pyridin-4-yl-allyl)-piperidin-4-one (347 mg, 1.4 mmol) were dissolved in 1,4-dioxane (5 mL). Trifluoroacetic acid (0.3 mL) was added and the reaction mixture was heated to 100° C. for 16 h. The reaction mixture was concentrated under reduced pressure and residue was basified with saturated aqueous sodium bicarbonate. The product was extracted with EtOAc (3×30 mL), organic layer was washed with water (2×20 mL), dried over sodium sulfate and concentrated. The residue was purified by reverse phase chromatography to obtain 15 mg of 2,4,8-trimethyl-4-(2-pyridin-4-yl-allyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=2[O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[O:12])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.O>CN(C)C=O>[CH3:32][O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[O:33][CH3:34])[N:24]=[CH:23][CH:22]=[C:21]2[O:20][C:14]1[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=1[C:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[CH:6][CH:7]=1)=[O:12]
Reactant: C1COCCN1
Reactant: COc1cc2nccc(Oc3ccc(C)cc3C(=O)c3ccc(OCCCl)cc3)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(C)cc3C(=O)c3ccc(OCCN4CCOCC4)cc3)c2cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
[4-(2-Chloro-ethoxy)-phenyl]-[2-(6,7-dimethoxy-quinolin-4-yloxy)-5-methyl-phenyl]-methanone (compound 189) (51 mg) was dissolved in N,N-dimethylformamide to prepare a solution. Potassium carbonate (84 mg) and morpholine (46 mg) were then added to the solution, and the mixture was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, and water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (38 mg, yield 68%).
Reaction SMILES: [OH:1][CH2:2][C@:3]([C:6]1[CH:25]=[CH:24][C:9]([C:10]([NH:12][C:13]2[N:18]=[CH:17][C:16]3[CH:19]=[CH:20][N:21]([CH2:22][CH3:23])[C:15]=3[CH:14]=2)=[O:11])=[CH:8][CH:7]=1)([OH:5])[CH3:4].[Cl:26]N1C(=O)CCC1=O>CN(C=O)C>[Cl:26][C:19]1[C:16]2[CH:17]=[N:18][C:13]([NH:12][C:10](=[O:11])[C:9]3[CH:24]=[CH:25][C:6]([C@@:3]([OH:5])([CH3:4])[CH2:2][OH:1])=[CH:7][CH:8]=3)=[CH:14][C:15]=2[N:21]([CH2:22][CH3:23])[CH:20]=1
Reactant: CCn1ccc2cnc(NC(=O)c3ccc([C@](C)(O)CO)cc3)cc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CCn1cc(Cl)c2cnc(NC(=O)c3ccc([C@](C)(O)CO)cc3)cc21
Temperature: 60 °C
Yield: 23 %

Procedure:
In a 50 mL pear flask was added (S)-4-(1,2-dihydroxypropan-2-yl)-N-(1-ethyl-1H-pyrrolo[3,2-c]pyridin-6-yl)benzamide (92 mg, 0.27 mmol) in DMF (2 ml) to give a solution. At room temperature 1-chloropyrrolidine-2,5-dione (36 mg, 0.27 mmol) was added, and the mixture was heated to 60° C. for 4 hours, at which point the reaction seemed to have stalled. An additional 0.2 equivalence of 1-chloropyrrolidine-2,5-dione was added, and the mixture was heated to 60° C. for another hour. The mixture was then cooled, and partitioned between brine and EtOAc. The aqueous layer was further extracted with EtOAc, and the organic layers were combined, washed with brine, dried, filtered and concentrated in vacuo. The residue was then triturated with hot EtOAc, and the resulting precipitate was collected on a fritted-glass funnel. The collected solid was then recrystallized from EtOH to give the product (S)—N-(3-chloro-1-ethyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1,2-dihydroxypropan-2-yl)benzamide (23 mg, 0.062 mmol, 22% yield) as a pink solid. 1H NMR (DMSO-d6) δ 10.68 (s, 1H), 8.60 (s, 1H), 8.37 (s, 1H), 8.02 (s, 2H), 7.69 (s, 1H), 7.59 (s, 2H), 5.05 (s, 1H), 4.76 (t, J=5.8 Hz, 1H), 4.19 (q, J=7.1 Hz, 2H), 3.40-3.50 (m, 2H), 1.34-1.45 (m, 6H); m.p. 223.0-223.9° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH2:17]O)=[CH:14][C:13]=2[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH2:17][N:24]3[C:20](=[O:30])[C:21]4[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:23]3=[O:25])=[CH:14][C:13]=2[CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cc2cc(OCc3ccccc3)ccc2o1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1cc2cc(OCc3ccccc3)ccc2o1
Temperature: 25 °C
Reaction time: 9 h
Yield: 74.9 %

Procedure:
To a tetrahydrofuran (10 mL) solution of (5-benzyloxy-benzofuran-2-yl)-methanol (561 mg, 2.21 mmol) described in Production Example 7-1-4 were added phthalimide (358 mg, 2.43 mmol), triphenylphosphine (696 mg, 2.65 mmol) and diethylazodicarboxylate (1.21 mL, 2.65 mmol) at 0° C., which was stirred at room temperature for 9 hours. Water was added to the reaction solution at room temperature followed by extraction with ethyl acetate. The organic layer was washed with sat. NaCl followed by drying over anhydrous magnesium sulfate and filtering. The filtrate was concentrated under a reduced pressure and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=7:3) to obtain the title compound (635 mg, 75%) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:6]([CH3:23])=[N:5][CH:4]=1.CC(C)([O-])C.[K+].[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.[K]>O1CCCC1>[CH3:23][C:6]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:3]([CH2:2][N:34]2[C:30](=[O:40])[C:31]3[C:32](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:33]2=[O:35])=[CH:4][N:5]=1
Reactant: Cc1ncc(CCl)n1-c1ccc(Cl)cc1Cc1ccccc1F
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [K]
Solvent: C1CCOC1
Product: Cc1ncc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(Cl)cc1Cc1ccccc1F
Temperature: 10 °C

Procedure:
To a suspension of 89.4 g (0.232 mole) of 5-(chloromethyl)-2-methyl-1-[4-chloro-2-(2-fluorobenzyl)phenyl]-1H-imidazole in 900 ml of tetrahydrofuran cooled to 10° C. was added 26.2 g (0.232 mole) of potassium t-butoxide. The temperature was maintained at 20° C. by means of an ice water bath during this addition. The bath was removed. To this mixture was added 51.5 g (0.278 mole) of potassium phthalimide. The reaction mixture was stirred under reflux for 2 hr. The mixture was cooled to room temperature and poured onto 1.2 l of ice-water and extracted with 3×600 ml of methylene chloride. The organic phases were combined and dried over sodium sulfate. The solution was filtered free of drying agent and the filtrate concentrated to dryness giving an oil. The oil was crystallized from 180 ml of ether. The resulting crystals were collected and dried to give end product of m.p. 152°-156° C.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=O)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.S(O)(O)(=O)=O.C[NH:28][C:29](=[NH:31])[SH:30].[CH2:32](O)C>[Na]>[CH3:32][S:30][C:29]1[N:31]=[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:28]=1
Reactant: CNC(=N)S
Reactant: CCOC=C(C(=O)Cc1cccc(OC)c1)C(=O)OCC
Reactant: CCO
Agent: O=S(=O)(O)O
Agent: [Na]
Product: CCOC(=O)c1cnc(SC)nc1Cc1cccc(OC)c1

Procedure:
In ethanol in which sodium had been dissolved, ethyl 3-ethoxy-2-[(3-methoxyphenyl)acetyl]acrylate and methylisothiourea sulfate were reacted under heat reflux to obtain ethyl 2-methylsulfanyl-4-(3-methoxybenzyl)pyrimidine-5-carboxylate (yellow oil).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([C@H:16]1[C@H:21]([CH3:22])[CH2:20][C:19]([CH3:23])=[CH:18][CH2:17]1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[OH:26]>[Pd]>[CH3:22][C@@H:21]1[CH2:20][C@H:19]([CH3:23])[CH2:18][CH2:17][C@H:16]1[C:14]([OH:15])=[O:26].[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([C@@H:16]1[CH2:17][CH2:18][C@@H:19]([CH3:23])[CH2:20][C@H:21]1[CH3:22])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: CC1=CC[C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)[C@H](C)C1
Agent: [Pd]
Product: C[C@@H]1CC[C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)[C@H](C)C1
Product: C[C@@H]1CC[C@@H](C(=O)O)[C@H](C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-4-benzyl-3-((1R,6R)-4,6-dimethylcyclohex-3-ene-carbonyl)oxazolidin-2-one (1.5 g, 4.8 mmol) (J. Am. Chem. Soc. 110(4), 1988, 1238-1256) in EtOH (24 mL) and 10% Pd/C (500 mg) was stirred under a H2 atmosphere (1 atm) at room temperature overnight. The reaction mixture was filtered through a pad of diatomaceous earth and concentrated to give a 3:1 mixture of diastereomers which were separated by preparative chiral column chromatography: Chiral-Pak AD-H (20 cm×250 cm; semi prep): Retention time: 5.11 min, 6.25 min (80:20 heptane:ethanol), providing the desired compound (R)-4-benzyl-3-((1R,2R,4R)-2,4-dimethylcyclohexanecarbonyl)oxazolidin-2-one (0.65 g).
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[O:20][CH2:19][CH2:18][N:17]3[C:13](=[N:14][C:15]([C:21]4[N:22]([CH:26]([CH3:28])[CH3:27])[N:23]=[CH:24][N:25]=4)=[CH:16]3)[C:12]=2[CH:29]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:26]([N:22]1[C:21]([C:15]2[N:14]=[C:13]3[N:17]([CH2:18][CH2:19][O:20][C:11]4[CH:10]=[CH:9][C:8]([CH2:7][C:6]([OH:30])=[O:5])=[CH:29][C:12]=43)[CH:16]=2)=[N:25][CH:24]=[N:23]1)([CH3:28])[CH3:27]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(CC(=O)OC(C)(C)C)ccc1OCC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(CC(=O)O)ccc1OCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.4 %

Procedure:
To a solution of [2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-yl]acetic acid tert-butyl ester (930 mg, 2.27 mmol) in DCM (20 mL) was added TFA (10 mL) and the resulting mixture stirred at RT for 1 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was found to be acid and the corresponding methyl ester so was purified by column chromatography (Si-PCC, gradient 0-20% MeOH in DCM) affording [2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-yl]acetic acid as a white solid (164 mg, 21%). LCMS: RT 2.65 min [M+H]+ 354.3