Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)(O)=[O:2].C[CH2:21][N:22]=C=NCCCN(C)C.Cl.CN>C(Cl)Cl.[Ni].CN1CCOCC1>[CH3:21][NH:22][C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Agent: [Ni]
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CNC(=O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Reaction time: 72 h
Yield: 48.2 %

Procedure:
A mixture of 4-(3-carboxyphenoxy)-1-nitrobenzene (3.72 g, 14.4 mmol), EDCI.HCl (3.63 g, 18.6 mmol), Ni-methylmorpholine (1.6 mL, 14.5 mmol) and methylamine (2.0 M in THF 8 mL, 16 mmol) in CH2Cl2 (45 mL) was stirred at room temp. for 3 d, then concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and the resulting mixture was extracted with a 1M HCl solution (50 mL). The aqueous layer was back-extracted with EtOAc (2×50 mL). The combined organic phases were washed with a saturated NaCl solution (50 mL), dried (Na2SO4), and concentrated under reduced pressure to give 4-(3-(N-methylcarbamoyl)phenoxy)-1-nitrobenzene as an oil (1.89 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19](S(O)(=O)=O)=CC=1.C1(=O)CCCC1>C1(C)C=CC=CC=1>[N:13]1[CH:12]=[CH:11][C:10]([C:4]2[S:3][C:2]3[NH:1][C:19]4([CH2:20][CH2:21][CH2:16][CH2:26]4)[NH:9][C:7](=[O:8])[C:6]=3[CH:5]=2)=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NC(=O)c1cc(-c2ccncc2)sc1N
Solvent: Cc1ccccc1
Solvent: O=C1CCCC1
Product: O=C1NC2(CCCC2)Nc2sc(-c3ccncc3)cc21
Yield: 22.1 %

Procedure:
A mixture of 2-amino-5-(pyridin-4-yl)thiophene-3-carboxamide (300 mg, 1.29 mmol), p-toluenesulfonic acid (150 mg) and cyclopentan-1-one (10 mL) in toluene (30 mL) was heated to reflux for overnight. After removal of the solvent, the residue was purified by column chromatography on silica gel (MeOH: dichloromethane=1:9) to afford the crude title compound (90 mg), which was further purified by preparative TLC to give the title compound (55 mg, yield 15%) as a brown solid.
Reaction SMILES: Cl.[F:2][C@H:3]1[C@:8]([CH2:11][OH:12])([O:9][CH3:10])[CH2:7][CH2:6][NH:5][CH2:4]1.CCN(C(C)C)C(C)C.CN1C(=O)CCC1.Cl[C:30]1[N:38]2[C:34](=[N:35][C:36]3[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=32)[C:33]([C:43]([NH2:45])=[O:44])=[C:32]2[CH2:46][C:47]([CH3:50])([CH3:49])[CH2:48][C:31]=12>O>[F:2][C@H:3]1[C@:8]([CH2:11][OH:12])([O:9][CH3:10])[CH2:7][CH2:6][N:5]([C:30]2[N:38]3[C:34](=[N:35][C:36]4[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=43)[C:33]([C:43]([NH2:45])=[O:44])=[C:32]3[CH2:46][C:47]([CH3:50])([CH3:49])[CH2:48][C:31]=23)[CH2:4]1
Reactant: CO[C@]1(CO)CCNC[C@H]1F
Reactant: CC1(C)Cc2c(c(Cl)n3c(nc4ccccc43)c2C(N)=O)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: CO[C@]1(CO)CCN(c2c3c(c(C(N)=O)c4nc5ccccc5n24)CC(C)(C)C3)C[C@H]1F
Yield: 38.3 %

Procedure:
rel-[(3R,4S)-3-fluoro-4-methoxypiperidin-4-yl]methanol hydrochloride (399 mg) and DIPEA (523 μl) were added to an NMP (3 ml) solution of 11-chloro-2,2-dimethyl-2,3-dihydro-1H-cyclopenta[4,5]pyrido[1,2-a]benzimidazole-4-carboxamide (314 mg), and heating and stirring were performed at 200° C. for 60 minutes under microwave irradiation. After adding water to the reaction liquid, the resulting precipitate was collected by filtration and dried under reduced pressure. The resulting solid was purified by silica gel column chromatography (MeOH/chloroform). The resulting crude purified matter was washed with chloroform-EtOAc-hexane to obtain rel-11-[(3R,4S)-3-fluoro-4-(hydroxymethyl)-4-methoxypiperidin-1-yl]-2,2-dimethyl-2,3-dihydro-1H-cyclopenta[4,5]pyrido[1,2-a]benzimidazole-4-carboxamide (169 mg).
Reaction SMILES: C12(COC3C=CC(C(N)=O)=CC=3C3C(OC)=NC=CC=3)CC3CC(CC(C3)C1)C2.[C:30]12([CH2:40][O:41][C:42]3[C:50]([CH:51]4[CH2:53][CH2:52]4)=[CH:49][C:45]([C:46]([NH2:48])=[O:47])=[C:44]([F:54])[CH:43]=3)[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]3)[CH2:31]1)[CH2:37]2.CS(Cl)(=O)=O.[O:60]1[CH2:65][CH2:64][CH:63]([S:66](Cl)(=[O:68])=[O:67])[CH2:62][CH2:61]1>>[C:30]12([CH2:40][O:41][C:42]3[C:50]([CH:51]4[CH2:52][CH2:53]4)=[CH:49][C:45]([C:46]([NH:48][S:66]([CH:63]4[CH2:64][CH2:65][O:60][CH2:61][CH2:62]4)(=[O:68])=[O:67])=[O:47])=[C:44]([F:54])[CH:43]=3)[CH2:37][CH:36]3[CH2:38][CH:32]([CH2:33][CH:34]([CH2:35]3)[CH2:39]1)[CH2:31]2
Reactant: O=S(=O)(Cl)C1CCOCC1
Reactant: NC(=O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: COc1ncccc1-c1cc(C(N)=O)ccc1OCC12CC3CC(CC(C3)C1)C2
Agent: CS(=O)(=O)Cl
Product: O=C(NS(=O)(=O)C1CCOCC1)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 38 step 4 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-3-(2-methoxypyridin-3-yl)benzamide with 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamide and to replace methanesulfonyl chloride with tetrahydro-2H-pyran-4-sulfonyl chloride, the title compound was obtained as a colorless solid (0.15 g, 30%): 1H NMR (300 MHz, CDCl3) δ8.55-8.44 (m, 1H), 7.60-7.52 (m, 1H), 6.62-6.52 (m, 1H), 4.17-3.90 (m, 3H), 3.56 (s, 2H), 3.47-3.36 (m, 2H), 2.12-1.95 (m, 8H), 1.84-1.65 (m, 12H), 1.00-0.90 (m, 2H), 0.71-0.58 (m, 2H); MS (ES+) m/z 492.21 (M+1).
Reaction SMILES: Br[C:2]1[CH:12]=[N:11][C:5]2[N:6]=[C:7]([Cl:10])[N:8]=[CH:9][C:4]=2[CH:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:10][C:7]1[N:8]=[CH:9][C:4]2[CH:3]=[C:2]([C:17]3[CH:16]=[C:15]([O:14][CH3:13])[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=3)[CH:12]=[N:11][C:5]=2[N:6]=1
Reactant: Clc1ncc2cc(Br)cnc2n1
Reactant: COc1cc(OC)cc(B(O)O)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC)cc(-c2cnc3nc(Cl)ncc3c2)c1
Temperature: 85 °C
Yield: 46.2 %

Procedure:
A mixture of 6-bromo-2-chloropyrido[2,3-d]pyrimidine (800 mg, 3.3 mmol), 3,5-dimethoxyphenylboronic acid (655 mg, 3.6 mmol), bis(tri-tert-butylphosphine)palladium (83 mg, 0.16 mmol) and cesium carbonate (1.06 g, 3.3 mmol) in THF (30 mL) and water (6 mL) was degassed with nitrogen for three times and then heated at 85° C. for 0.5 hour. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/ethyl acetate=3/1) to get the title product as a yellow solid (460 mg, 47%) as a yellow solid. MS (ES+) C15H12ClN3O2 requires: 301, 302, found: 302, 304 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[S:17][C:18]4[C:28]5[C:23](=[CH:24][C:25]([CH:29]([OH:32])CO)=[CH:26][CH:27]=5)[CH2:22][CH2:21][C:19]=4[N:20]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O>[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[S:17][C:18]4[C:28]5[C:23](=[CH:24][C:25]([CH:29]=[O:32])=[CH:26][CH:27]=5)[CH2:22][CH2:21][C:19]=4[N:20]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC(O)c1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)sc1-2
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)sc1-2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 1-(2-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[2,1-d]thiazol-7-yl)ethane-1,2-diol (Example 83, 0.233 g, 0.508 mmol) in THF (3 mL) was added sodium periodate (0.163 g, 0.762 mmol) in 2 mL of water over a period of 2 min. at room temperature and the contents stirred at room temperature for 30 min. The reaction mixture was partitioned between EtOAc (60 mL) and water (20 mL). The EtOAc layer was concentrated, the yellow solid that was obtained was azeotroped with acetonitrile (20 mL), dried under a high vacuum. Yield: (183 mgs, 83%); LC/MS M+1=427.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1)([O-:14])=[O:13].Cl>C1COCC1>[CH3:6][O:5][C:3](=[O:4])[CH:2]([CH2:19][C:18]1[CH:21]=[CH:22][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=1)[C:1]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
To a solution of dimethyl malonate (5.53 g) in THF (100 mL) was added 60% sodium hydride (1.84 g) under ice-cooling, and the mixture was stirred for 30 min. 4-Nitrobenzyl bromide (9.04 g) was added to this mixture under ice-cooling, and the mixture was allowed to warm to room temperature while stirring for 4 hr. The reaction mixture was adjusted to pH=2-3 by the addition of dilute hydrochloric acid, the precipitate was removed by filtration, and the filtrate was extracted with ethyl acetate (200 mL). The organic layer was washed with saturated brine and concentrated under reduced pressure to give the title compound (7.66 g) as a pale-yellow solid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[O:11][C:12]1[C:13]2[N:14]([CH:18]=[C:19]([CH3:21])[N:20]=2)[CH:15]=[CH:16][CH:17]=1.[N:22](OCCCC)=[O:23]>O1CCCC1>[OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[O:11][C:12]1[C:13]2[N:14]([C:18]([N:22]=[O:23])=[C:19]([CH3:21])[N:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1cn2cccc(O[C@@H]3c4ccccc4C[C@H]3O)c2n1
Reactant: CCCCON=O
Solvent: C1CCOC1
Product: Cc1nc2c(O[C@@H]3c4ccccc4C[C@H]3O)cccn2c1N=O
Yield: 63.4 %

Procedure:
0.5 g 8-(2-(trans)-hydroxy-2,3-dihydro-1-indenyloxy)-2-methyl-imidazo[1,2-a]pyridine, dissolved in 50 ml tetrahydrofuran, are mixed with 0.6 g commercial butyl nitrite at 50° C. and left over night at this temperature. After evaporation of the volatile components in vacuo, residue is washed with few cold acetonitrile and, after the solvent is poured off, recrystallized from acetonitrile. 0.35 g yellow title compound of m.p. 178°-179° C. is obtained.
Reaction SMILES: [OH:1][C:2]1[C:6]2[CH2:7][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][CH2:10][CH2:11][C:5]=2[O:4][N:3]=1.[CH2:19](Br)[C:20]#[CH:21]>>[CH2:21]([O:1][C:2]1[C:6]2[CH2:7][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][CH2:10][CH2:11][C:5]=2[O:4][N:3]=1)[C:20]#[CH:19]
Reactant: C#CCBr
Reactant: CC(C)(C)OC(=O)N1CCCc2onc(O)c2C1
Product: C#CCOc1noc2c1CN(C(=O)OC(C)(C)C)CCC2
Yield: 58 %

Procedure:
The compound was synthezised from tert.butyl 3-hydroxy-5,6,7,8-tetrahydro-4H-isoxazolo [4,5-c]azepin-5-carboxylate (from Example 7) and 2-propynyl bromide, by the method described in Example 4. The title compound was isolated by using chromatography on silica gel (eluent: toluene-ethyl acetate (3:1)) in a yield of 58%. 1H NMR: δ4.83 (2 H, d), 4.20 (2 H, s), 3.60 (2 H, t), 2.83 (2 H, t), 2.52 (1 H, t), 1.86 (2 H, m), 1.43 (9 H, s).
Reaction SMILES: [CH3:1][O-:2].[Na+].[C:4]([N:11]1[C:16](=[O:17])[CH:15]2[CH2:18][CH:12]1[CH:13]=[CH:14]2)([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]>CO>[CH3:1][O:2][C:16]([C:15]1[CH2:18][C@@H:12]([NH:11][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH2:13][CH:14]=1)=[O:17]
Reactant: C[O-]
Reactant: CC(C)(C)OC(=O)N1C(=O)C2C=CC1C2
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1=CC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
Sodium methoxide (8.23 ml of a 25% wt solution in methanol, 0.05 mol eq) was added dropwise to a stirred solution of (−)-N-Boc 2-azabicyclo[2.2.1]hept-5-en-3-one (150 g, 0.72 mol) in methanol (750 ml) at 0° C. After 30 minutes, the reaction was warmed to room temperature. After 60 h, the reaction was quenched with acetic acid and concentrated to dryness. The residue was redissolved in dichloromethane (700 ml) and washed with water (300 ml), saturated sodium hydrogen carbonate (300 ml) and brine (300 ml). The combined aqueous washings were then back extracted with dichloromethane (300 ml), the organic extracts combined and dried over magnesium sulfate. Filtration and concentration under reduced pressure gave a white solid which was recrystallized from ethyl acetate/heptane to give the title compound as white crystals (130 g, 75%)
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C1(CN)CCCCC1.[O:17]=[C:18]1[C:26]2([CH2:30][O:29][C:28]3[CH:31]=[C:32]4[C:36](=[CH:37][C:27]2=3)[CH2:35][CH2:34][O:33]4)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]1[CH2:38][C:39]1[CH:47]=[CH:46][CH:45]=[CH:44][C:40]=1[C:41](O)=[O:42].O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[CH2:1]([NH:8][C:41](=[O:42])[C:40]1[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=1[CH2:38][N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26]2([CH2:30][O:29][C:28]3[CH:31]=[C:32]4[C:36](=[CH:37][C:27]2=3)[CH2:35][CH2:34][O:33]4)[C:18]1=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Reactant: CCCCCCCN
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: CCCCCCCNC(=O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using heptylamine to replace cyclohexanemethylamine, and 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-heptyl-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (75%) as a colorless solid: mp 196-198° C.; 1H NMR (300 MHz, DMSO-d6) δ8.53 (t, J=5.5 Hz, 1H), 7.46-7.27 (m, 3H), 7.23-7.06 (m, 3H), 6.99 (dd, J=7.5, 7.5 Hz, 1H), 6.84 (d, J=7.7 Hz, 1H), 6.51 (s, 1H), 6.40 (s, 1H), 5.10=-4.92 (m, 2H), 4.85 (d, J=9.4 Hz, 1H), 4.71 (d, J=9.4 Hz, 1H), 4.55-4.39 (m, 2H), 3.23 (q, J=6.8 Hz, 2H), 3.03-2.84 (m, 2H), 1.59-1.44 (m, 2H), 1.38-1.14 (m, 8H), 0.81 (t, J=6.6 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ177.8, 168.7, 161.6, 161.2, 142.8, 136.9, 134.1, 132.6, 130.4, 129.1, 128.1, 127.8, 126.8, 124.1, 123.6, 120.9, 120.3, 119.6, 109.6, 92.9, 80.4, 72.6, 57.4, 41.3, 31.7, 29.4, 28.9, 28.8, 26.9, 22.5, 14.4; MS (ES+) m/z 511.2 (M+1).
Reaction SMILES: [OH-].[Na+].[O:3]1[CH2:8][CH2:7][S:6][C:5]([CH2:9][C:10]([O:12]CC)=[O:11])=[CH:4]1>O.C(O)C>[O:3]1[CH2:8][CH2:7][S:6][C:5]([CH2:9][C:10]([OH:12])=[O:11])=[CH:4]1
Reactant: CCOC(=O)CC1=COCCS1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CC1=COCCS1
Temperature: 60 °C
Yield: 78 %

Procedure:
A solution of sodium hydroxide (3.2 g.) in water (18 cc.) is added to a solution of ethyl (5,6-dihydro-1,4-oxathiin-3-yl )acetate (13.4 g.) in ethanol (134 cc.). The reaction mixture is heated for one hour at 60° C. and is then concentrated to dryness under reduced pressure (20 mm.Hg). The resulting residue is taken up in water (250 cc.), and the mixture extracted with diethyl ether (200 cc.), decanted and the ether phase is discarded. The aqueous phase is acidified to pH 1 by addition of 4N hydrochloric acid and is then extracted three times with diethyl ether (total 600 cc.). The ether fractions are combined, washed twice with water (total 200 cc.), dried over sodium sulphate and treated with decolourizing charcoal. After filtration and concentration to dryness under reduced pressure (20 mm.Hg), (5,6-dihydro-1,4-oxathiin-3-yl )acetic acid (8.9 g.) is obtained in the form of an oil which is used as it is.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[I-].[K+].[C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Cl)(=[O:19])[CH3:18]>CN(C=O)C>[C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:4]([CH3:3])([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:19])[CH3:18]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: CC(=O)OCCCCCCl
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(CCCCCOC(C)=O)C(=O)OCC
Reaction time: 8 h

Procedure:
Sodium hydride (4.8 g., 0.2 mole) as a 50% suspension in mineral oil is washed with petroleum ether under nitrogen to remove the mineral oil, suspended in dry benzene (150 ml.), and the suspension cooled in an ice bath . Diethyl methylmalonate (34.8 g., 0.2 mole) dissolved in sieve dried DMF (150 ml.) is added to the suspension of sodium hydride dropwise. The mixture is allowed to stand overnight at room temperature. Potassium iodide (0.4 g.) and 5-acetoxypentyl chloride (32.9 g., 0.2 mole) are then added, and the mixture is heated for 24 hours at 125° in an oil bath. The reaction mixture is concentrated in vacuo, diluted with ether (200 ml.), and filtered to remove sodium chloride. The filtrate is washed with brine, dried over anhydrous magnesium sulfate and concentrated to yield 39.6 g. (66%) of oily product.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][CH2:15][CH2:14][CH:13]([N:17]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:18][C@H:19]([OH:28])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:12][C:11]=2[CH:36]=1)C.[OH-].[Na+].Cl>C(O)C>[C:32]([O:31][C:29]([N:17]([CH:13]1[CH2:12][C:11]2[CH:36]=[C:7]([O:6][CH2:5][C:4]([OH:37])=[O:3])[CH:8]=[CH:9][C:10]=2[CH2:16][CH2:15][CH2:14]1)[CH2:18][C@H:19]([OH:28])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: CCOC(=O)COc1ccc2c(c1)CC(N(C[C@H](O)COc1ccccc1)C(=O)OC(C)(C)C)CCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(C[C@H](O)COc1ccccc1)C1CCCc2ccc(OCC(=O)O)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of 2-[8-[N-tert-butoxycarbonyl-N-[(2S)-2-h ydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetic acid ethyl ester (3.60 g) in ethanol (20 ml) was added 1N sodium hydroxide (7 ml) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The resulting mixture was acidified with hydrochloric acid to pH 2 and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate) over silica gel to afford 2-[8-[N-tert-butoxycarbonyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetic acid (3.2 g).
Reaction SMILES: [F:1][C:2]([F:56])([F:55])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:46]=[CH:45][C:37]([C:38]([O:40]C(C)(C)C)=[O:39])=[CH:36][C:35]=5[CH3:47])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:48]4[CH2:51][C:50]([F:53])([F:52])[CH2:49]4)[N:21]=3)[C@H:14]2[CH3:54])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.FC(F)(F)C(O)=O>ClCCl>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:46]=[CH:45][C:37]([C:38]([OH:40])=[O:39])=[CH:36][C:35]=5[CH3:47])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:48]4[CH2:49][C:50]([F:52])([F:53])[CH2:51]4)[N:21]=3)[C@H:14]2[CH3:54])[CH:4]=[C:3]([C:2]([F:56])([F:55])[F:1])[CH:8]=1
Reactant: COc1ncc(-c2ccc(C(=O)OC(C)(C)C)cc2C)cc1-c1cnc(N2CC(F)(F)C2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ncc(-c2ccc(C(=O)O)cc2C)cc1-c1cnc(N2CC(F)(F)C2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
tert-Butyl 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(3,3-difluoroazetidin-1-yl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3-methylbenzoate (Step A, 639 mg, 0.805 mmol) was treated with 20 mL of a mixture of dichloromethane and trifluoroacetic acid (2 to 1 by volume) at room temperature for 0.5 hour, and purified on reverse phase HPLC to give the title compound as a white solid, after lyophilization. LCMS (M+H)+: 738.0. 1H NMR (CD3OD, 500 MHz): δ 8.26 (s, 1H), 8.22 (d, J=2.0 Hz, 1H), 8.00 (s, 1H), 7.96 (s, 1H), 7.93 (s, 2H), 7.90 (dd, J=1.5 Hz, 8.0 Hz, 1H), 7.71 (d, J=2.5 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 5.87 (d, J=9.0 Hz, 1H), 4.69 (d, J=16.0 Hz, 1H), 4.45 (m, 4H), 4.43 (m, 1H), 4.15 (d, J=16.0 Hz, 1H), 4.00 (s, 3H), 2.38 (s, 3H), 0.73 (d, J=6.5 Hz, 3H). RTA IC50: 9 nM
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[CH3:13]NOC.C[Mg]Br>>[Br:1][C:2]1[CH:10]=[C:6]([C:7](=[O:9])[CH3:13])[CH:5]=[N:4][C:3]=1[Cl:11]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Reactant: CNOC
Agent: C[Mg]Br
Agent: Cl
Product: CC(=O)c1cnc(Cl)c(Br)c1

Procedure:
5-Bromo-6-chloronicotinic acid and N,O-dimethylhydroxyamine hydrochloride were treated in the similar manner to Reference Example 7(5), and then the resulting compound and methylmagnesium bromide were treated in the similar manner to Reference Example 7(6) to give 1-(5-bromo-6-chloropyridin-3-yl)ethanone [REx(113-1)] as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[CH2:34][CH2:35][C:36]([OH:38])=[O:37]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: O=C(O)CCC1COCCN1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2CCC(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 47.3 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1 g, 2 mmol) was reacted with 3-(morpholin-3-yl)propanoic acid hydrochloride (0.39 g, 2 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.55 g, 47%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:35])[N:8]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])[CH:9]=[C:10]([C:11]3[CH:16]=[N:15][C:14]([O:17]CC4C=CC(OC)=CC=4)=[CH:13][N:12]=3)[C:5]=2[NH:4][N:3]=1.CO.O1CCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(N(CC)CC)C>[NH2:1][C:2]1[C:6]2[C:7](=[O:35])[N:8]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])[CH:9]=[C:10]([C:11]3[N:12]=[CH:13][C:14](=[O:17])[NH:15][CH:16]=3)[C:5]=2[NH:4][N:3]=1
Reactant: COc1ccc(COc2cnc(-c3cn(-c4c(F)cccc4F)c(=O)c4c(N)n[nH]c34)cn2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Nc1n[nH]c2c(-c3c[nH]c(=O)cn3)cn(-c3c(F)cccc3F)c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
To 3-amino-5-(2,6-difluorophenyl)-7-(5-((4-methoxybenzyl)oxy)pyrazin-2-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Example 151 (133 mg) were added methanol (2 mL), tetrahydrofuran (3 mL) and p-toluenesulfonic acid monohydrate (53 mg), and the reaction mixture was stirred at room temperature for 1 hr. p-Toluenesulfonic acid monohydrate (53 mg) was added thereto, and the reaction mixture was stirred at room temperature for 5 hr. To the reaction mixture were added triethylamine (97 μL) and silica gel, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/methanol). The obtained residue was crystallized from ethyl acetate/diethyl ether to give the title compound (92 mg).