Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][N:3]=1.[C:16](Cl)(=[O:26])[C:17]1[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:19](Cl)=[O:20]>N1C=CC=CC=1.CCOC(C)=O>[C:12]([O:11][C:9]([NH:8][C:5]1[CH:6]=[N:7][C:2]([N:1]2[C:19](=[O:20])[C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[C:16]2=[O:26])=[N:3][CH:4]=1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1cnc(N)nc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cnc(N2C(=O)c3ccccc3C2=O)nc1
Temperature: 45 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To a solution of N-(2-aminopyrimidin-5-yl)(tert-butoxy)carboxamide (0.237 g, 1.0 mmol) in pyridine (1 mL) was added phthaloyl dichloride (0.144 mL, 1.0 mmol). The resulting suspension was stirred at 45° C. for 2 hr, diluted with EtOAc, washed with water and brine, dried and concentrated in vacuo to give crude (tert-butoxy)-N-[2-(1,3-dioxobenzo[c]azolidin-2-yl)pyrimidin-5-yl]carboxamide (0.31 g). ES-MS (M+H)+=341; (M+H-tBu)+=285.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(=O)C.[CH2:11]([N:13]1[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[C:17](=[O:23])[N:16]([CH3:24])[C:15]2[CH:25]=[C:26]([CH2:29][N:30]([CH2:44][C:45]3[CH:52]=[CH:51][CH:50]=[CH:49][C:46]=3[CH:47]=O)[CH2:31][CH2:32][N:33]3[CH:38]=[CH:37][C:36]4[O:39][C:40]([CH3:42])=[CH:41][C:35]=4[C:34]3=[O:43])[CH:27]=[CH:28][C:14]1=2)[CH3:12].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O.ClCCCl>[CH2:11]([N:13]1[C:19](=[O:20])[C:18]([CH3:21])([CH3:22])[C:17](=[O:23])[N:16]([CH3:24])[C:15]2[CH:25]=[C:26]([CH2:29][N:30]([CH2:31][CH2:32][N:33]3[CH:38]=[CH:37][C:36]4[O:39][C:40]([CH3:42])=[CH:41][C:35]=4[C:34]3=[O:43])[CH2:44][C:45]3[CH:52]=[CH:51][CH:50]=[CH:49][C:46]=3[CH2:47][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:27]=[CH:28][C:14]1=2)[CH3:12]
Reactant: C1COCCN1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCn3ccc4oc(C)cc4c3=O)Cc3ccccc3C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCn3ccc4oc(C)cc4c3=O)Cc3ccccc3CN3CCOCC3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Morpholine (0.06 ml) and acetic acid (0.1 ml) were added to a 1,2-dichloroethane solution (7 ml) of 2-({N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)benzaldehyde (0.35 g), and the mixture was stirred for 30 minutes at room temperature. Sodium triacetoxy borohydride (0.20 g) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction liquid, followed by extraction by dichloromethane. The organic layer was dried by anhydrous sodium sulfate, and condensed under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:hexane=3:2). The purified product was condensed under reduced pressure to give the title compound (0.30 g) as a white amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH3:24])=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=2)[N:12]=1.[C:25]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])#[N:26].N1CCCCC1.N1C=CC=CC=1>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH3:24])=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[C:27]([C:25]#[N:26])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:18][CH:17]=2)[N:12]=1
Reactant: CCOC(=O)CC#N
Reactant: Cc1oc(-c2ccccc2Cl)nc1CCOc1ccc(C=O)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CCOC(=O)C(C#N)=Cc1ccc(OCCc2nc(-c3ccccc3Cl)oc2C)cc1
Reaction time: 2 h
Yield: 95.8 %

Procedure:
A mixture of 4-[2-[2-(2-chlorophenyl)-5-methyl-4-oxazolyl]ethoxy]benzaldehyde (2.0 g), ethyl cyanoacetate (0.795 g), piperidine (0.15 g) and pyridine (30 ml) was stirred for 2 hours at 100°-110° C. The reaction mixture was poured into water. Resulting crystalline precipitate was collected by filtration and recrystallized from dichloromethane-ethanol to give ethyl 4-[2-[2-(2-chlorophenyl)-5-methyl-4-oxazolyl]ethoxy]-α-cyanocinnamate (2.45 g, 96%) as colorless needles, m.p.120°-121° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](Cl)(=[O:47])[O:9][C@@:10]([CH3:46])([C:13](=[O:45])[C@@H:14]([NH:22][C:23](=[O:44])[C@@H:24]([NH:28][C:29](=[O:43])[C@@H:30]([NH:34][C:35]([C:37]1[S:41][C:40]([CH3:42])=[N:39][CH:38]=1)=[O:36])[CH2:31][O:32][CH3:33])[CH2:25][O:26][CH3:27])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:11][I:12]>>[C:8](=[O:47])([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[O:9][C@@:10]([CH3:46])([C:13](=[O:45])[C@@H:14]([NH:22][C:23](=[O:44])[C@@H:24]([NH:28][C:29](=[O:43])[C@@H:30]([NH:34][C:35]([C:37]1[S:41][C:40]([CH3:42])=[N:39][CH:38]=1)=[O:36])[CH2:31][O:32][CH3:33])[CH2:25][O:26][CH3:27])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:11][I:12]
Reactant: Oc1ccccc1
Reactant: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@@](C)(CI)OC(=O)Cl
Product: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@@](C)(CI)OC(=O)Oc1ccccc1

Procedure:
Prepared according to procedures described above, using phenol with the intermediate (2S,4S)-1-iodo-4-((S)-3-methoxy-2-((S)-3-methoxy-2-(2-methylthiazole-5-carboxamido)propanamido)propanamido)-2-methyl-3-oxo-5-phenylpentan-2-yl carbonochloridate. 1H NMR (CDCl3): δ 8.02 (s, 1H). 7.40 (t, J=8 Hz, 2H), 7.29-7.10 (m, 10H), 6.98 (d, J=7.2 Hz, 1H), 6.82 (d, J=6 Hz, 1H), 5.51-5.45 (m, 1H), 4.67-4.62 (m, 1H), 4.45-4.41 (m, 1H), 3.83-3.78 (m, 2H), 3.70-3.64 (m, 2H), 3.50 (t, J=4.8 Hz, 1H), 3.45 (s, 3H), 3.32-3.28 (m, 1H), 3.27 (s, 3H), 3.19-3.14 (m, 1H), 2.91-2.86 (m, 1H), 2.74 (s, 3H), 1.55 (s, 3H); MS for C32H37IN4O9S m/z: 782 (M+H)+.
Reaction SMILES: [F:1][C:2]([O:6][C:7]([F:10])([F:9])[F:8])=[C:3]([F:5])[F:4].[Cl:11][C:12]1[C:13]([N:18]2[C:22]([C:23]([O:25][CH2:26]C)=[O:24])=[CH:21][C:20]([OH:28])=[N:19]2)=[N:14][CH:15]=[CH:16][CH:17]=1.[OH-].[K+].CO>O.CS(C)=O>[Cl:11][C:12]1[C:13]([N:18]2[C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:20]([O:28][C:3]([F:5])([F:4])[CH:2]([F:1])[O:6][C:7]([F:10])([F:9])[F:8])=[N:19]2)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: FC(F)=C(F)OC(F)(F)F
Reactant: CCOC(=O)c1cc(O)nn1-c1ncccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(OC(F)(F)C(F)OC(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Trifluoromethyl trifluorovinyl ether was blown into a mixture of 1.0 g of ethyl 1-(3-chloro-2-pyridinyl)-3-hydroxy-1H-pyrazole-5-carboxylate, 0.042 g of potassium hydroxide, 10 ml of methanol and 10 ml of dimethyl sulfoxide under ice-cooling. The resulting mixture was stirred at room temperature for 4 days. Water was poured into the reaction mixture, and the mixture was extracted with diethyl ether two times. The organic layers were combined, washed with water and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 1.32 g of methyl 1-(3-chloro-2-pyridinyl)-3-[1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy]-1H-pyrazole-5-carboxylate of the formula:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:10])[CH:6]=[CH:7][C:8]=1[Br:9].Br[CH2:12][C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:10][CH2:12][C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[CH:7][C:8]=1[Br:9]
Reactant: CCOC(=O)C(=O)CBr
Reactant: COc1cc(S)ccc1Br
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)C(=O)CSc1ccc(Br)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.2 %

Procedure:
3-Methoxy-4-bromobenzenethiol (D2) (9.6 g, 44 mmoles) in pyridine (30 ml) was treated with ethyl bromopyruvate (5.9 ml, 46 mmoles) and stirred at room temperature for 1 hr. Dilute hydrochloric acid (100 ml) was added and the product extracted into diethyl ether. The organics were washed with dilute hydrochloric acid then brine and dried (Na2SO4). Evaporation of the solvent followed by flash chromatography on TLC silica gel eluting with dichloromethane gave the title compound (D3) (3.7 g, 25%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@:10]2([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH3:33])=[CH:27][CH:26]=4)[CH:18]=3)[O:16][C@@:7]([CH2:34][O:35][C:36](=[O:38])[CH3:37])([CH2:8][O:9]2)[C@H:6]1[O:39][C:40](=[O:42])[CH3:41])(=[O:3])[CH3:2].BrN1C(=[O:49])CCC1=O.O.ClCCl>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@:10]2([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH:24]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH3:33])=[CH:27][CH:26]=4)[OH:49])[CH:18]=3)[O:16][C@@:7]([CH2:34][O:35][C:36](=[O:38])[CH3:37])([CH2:8][O:9]2)[C@H:6]1[O:39][C:40](=[O:42])[CH3:41])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](COC(C)=O)(O3)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)ccc2Cl)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCOc1ccc(C(O)c2cc([C@]34OC[C@](COC(C)=O)(O3)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.4 %

Procedure:
To a solution of acetic acid (1R,2S,3S,4R,5S)-3,4-diacetoxy-1-acetoxymethyl-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6,8-dioxa-bicyclo[3.2.1]oct-2-yl ester (Example 2; 344 mg, 0.569 mmol) in carbon tetrachloride (8 mL) was added N-bromosuccinimide (159 mg, 0.893 mmol) followed by the addition of 2,2′-azobisisobutyronitrile (AIBN, 8 mg, 0.05 mmol) and the reaction mixture was heated at reflux under nitrogen. After 16 hours, the reaction mixture was cooled to room temperature, water (50 mL) and dichloromethane (25 mL) were added and the resulting mixture was stirred for 24 hours at room temperature. The layers were separated and the aqueous layer was extracted two additional times with dichloromethane (25 mL). The combined organic layers were washed with brine (20 mL), dried over magnesium sulfate, filtered through a pad of celite, and concentrated under reduced pressure. The crude material was chromatographed with the Biotage SP4 automated chromatography unit (SNAP 25 g silica gel column) eluting with a gradient of 0-80% ethyl acetate in heptane to produce 316 mg (89% yield) of acetic acid (1R,2S,3S,4R,5S)-3,4-diacetoxy-1-acetoxymethyl-5-{4-chloro-3-[(4-ethoxy-phenyl)-hydroxy-methyl]-phenyl}6,8-dioxa-bicyclo[3.2.1]oct-2-yl ester as a mixture of diastereoisomers at the bis-benzylic position.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11](N1C2C(=CC=CC=2)CCC1)=[O:12].Cl.Cl.[NH2:30][C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=1[N:38]([CH3:40])[CH3:39]>CCCCCCC.C(OCC)(=O)C>[Cl:37][C:35]1[CH:34]=[CH:33][C:32]([N:38]([CH3:40])[CH3:39])=[C:31]([NH:30][C:11](=[O:12])[C:6]2[C:5]([O:4][C:3]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:2]=3[Cl:1])=[CH:10][CH:9]=[N:8][CH:7]=2)[CH:36]=1
Reactant: CN(C)c1ccc(Cl)cc1N
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Agent: Cl
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CN(C)c1ccc(Cl)cc1NC(=O)c1cnccc1Oc1cc(Cl)ccc1Cl

Procedure:
The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate), (2-amino-4-chlorphenyl)dimethylamine dihydrochloride (commercially available, CAS RN 183251-88-9), using 5 mole equivalents of base and using a gradient of n-heptane:ethyl acetate (100:0 to 50:50) for the chromatographic purification. White solid (72%). MS (ESI): m/z=436.038 [M+H]+.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[F:31])[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O>CN(C=O)C>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([CH:11]([C:12]2[C:20]3[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:9][C:1]#[N:2])=[C:25]([F:31])[CH:26]=1
Reactant: CSCc1cccc2c(C(CCOS(C)(=O)=O)c3ccc(Cl)cc3F)c[nH]c12
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: CSCc1cccc2c(C(CCC#N)c3ccc(Cl)cc3F)c[nH]c12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
572 mg (8.78 mmol) of potassium cyanide were added to 1.94 g (4.39 mmol) of the compound from Example 54A in 26 ml of DMF. The mixture was stirred at 80° C. for 2 h and then concentrated, and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 1.30 g (79% of theory) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[S:9][CH2:10][C@@H:11]2[CH2:16][C@H:15]([O:17][CH3:18])[CH2:14][C@:12]2([C:19]2[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:20]=2[F:28])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].O.C(OCC)(=O)C>C(O)C.[Fe]>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[S:9][CH2:10][C@@H:11]2[CH2:16][C@H:15]([O:17][CH3:18])[CH2:14][C@:12]2([C:19]2[CH:24]=[C:23]([NH2:25])[CH:22]=[CH:21][C:20]=2[F:28])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CO[C@H]1C[C@H]2CSC(NC(=O)OC(C)(C)C)=N[C@@]2(c2cc([N+](=O)[O-])ccc2F)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CO[C@H]1C[C@H]2CSC(NC(=O)OC(C)(C)C)=N[C@@]2(c2cc(N)ccc2F)C1
Temperature: 25 °C
Yield: 75.7 %

Procedure:
A solution of tert-butyl[(4aR*,6S*,7aS*)-7a-(2-fluoro-5-nitrophenyl)-6-methoxy-4,4a,5,6,7,7a-hexahydrocyclopenta[d][1,3]thiazin-2-yl]carbamate (118 mg) and iron (133 mg) in ethanol (8 mL)-a saturated ammonium chloride solution (0.303 mL) was stirred at 87° C. for 30 minutes. The reaction solution was cooled to room temperature and then poured into water-ethyl acetate, followed by extraction with ethyl acetate. The extract was washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography to obtain the title compound (83 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([F:12])[C:3]=1[O:13][C:14]1[CH:18]=[C:17]([CH3:19])[N:16](C(OC(C)(C)C)=O)[N:15]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[C:4]([F:12])[C:3]=1[O:13][C:14]1[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=1
Reactant: Cc1cc(Oc2c(F)cc(C(F)(F)F)cc2Cl)nn1C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2c(F)cc(C(F)(F)F)cc2Cl)n[nH]1
Yield: 88.9 %

Procedure:
To an ethyl acetate (100 mL) solution of tert-butyl 3-(2-chloro-6-fluoro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxylate (49.7 g, 126 mmol) was added 3 mol/L of HCL (40 mL), and the mixture was refluxed under heating for 2 hours. After completion of the reaction, the reaction mixture was consecutively washed with water and a 1 mol/L sodium hydroxide aqueous solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off to give a white solid of 3-(2-chloro-6-fluoro-4-trifluoromethylphenyloxy)-5-methylpyrazole (33.0 g, yield: 89.0%). Melting point: 116˜117° C., 1H-NMR (CDCl3, TMS, ppm): δ2.24 (s, 3H), 5.69 (s, 1H), 7.36 (dd, J=1.8 Hz, JHF=9.4 Hz, 1H), 7.50-7.60 (m, 1H), 9.00-9.30 (brs, 1H).
Reaction SMILES: [C:1]([C:3]([C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14]C)=[O:13])([CH3:8])[CH2:4][CH:5]1[CH2:7][CH2:6]1)#[N:2].O.[OH-].[Li+]>O1CCCC1.CO.O>[C:1]([C:3]([C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([OH:14])=[O:13])([CH3:8])[CH2:4][CH:5]1[CH2:7][CH2:6]1)#[N:2]
Reactant: COC(=O)c1cccc(C(C)(C#N)CC2CC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C#N)(CC1CC1)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.6 %

Procedure:
To a solution of methyl 3-(1-cyano-2-cyclopropyl-1-methylethyl)benzoate (120 mg, 0.49 mmol) in tetrahydrofuran/methanol/water (=3.0 mL/1.0 mL/1.0 mL) was added lithium hydroxide monohydrate (40 mg, 0.99 mmol), and the reaction mixture was stirred at room temperature for 4 hr. The mixture was concentrated under reduced pressure, and the obtained aqueous solution was adjusted to pH 5 by adding 1N hydrochloric acid. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=50/50→100/0) to give the title compound (76 mg, 66%) as a colorless oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][Br:10].[CH2:11]([O:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[CH3:12].C([N-]C(C)C)(C)C.[Li+]>CN(C)P(N(C)C)(N(C)C)=O>[CH3:16][C:15]([CH3:17])([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][Br:10])[C:14]([O:13][CH2:11][CH3:12])=[O:18]
Reactant: BrCCCCCCCCBr
Reactant: CCOC(=O)C(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(C)(C)CCCCCCCCBr
Yield: 16.5 %

Procedure:
Using the method described in Example 5(i), 1,8-dibromooctane (27.2 g, 0.1 mol) and ethylisobutyrate (10.44 g, 0.09 mol) were reacted in the presence of lithium diisopropylamide (67 ml, 0.1 mol) and hexamethylphosphoramide (22 g) to give the title compound (4.56 g) as an oil.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.[OH-].[K+:10]>CS(C)=O>[NH2:7][C:6]1[CH:1]=[CH:2][C:3]([O-:8])=[CH:4][CH:5]=1.[K+:10]
Reactant: Nc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1ccc([O-])cc1

Procedure:
6.6 g (0.06 mol) of p-aminophenol in 4.0 g (0.06 mol) potassium hydroxide (purity 85%) and 80 ml of dimethylsulfoxide was heated under stirring. The water generated was distilled off under reduced pressure to obtain the potassium p-aminophenolate. To the solution, which was allowed to be cooled to room temperature, was added a solution of 10.9 g (0.06 mol) of 6-fluoro-2-chloroquinoxaline dissolved in 60 ml of dioxane. The mixture was reacted at 50°-60° C. for 3 hours. After the reaction was over, the reaction solution was poured onto ice and the separated solid was filtered off, and washed with 5% aqueous solution of sodium hydroxide and then washed with water. The substance thus obtained was recrystallized from ethanol to yield 8.2 g (yield 54%) of the intended compound (Compound No. 4) having a melting point of 174°-175.5° C. as light-yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([N+:23]([O-])=O)=[C:12]([N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:13]=2)=[CH:5][CH:4]=1>[Pd].CO>[NH2:23][C:11]1[CH:10]=[CH:9][C:8]([O:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:27][CH:26]=2)=[CH:13][C:12]=1[N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19]
Reactant: COc1ccc(Oc2ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c2)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(Oc2ccc(N)c(N(C)C(=O)OC(C)(C)C)c2)cc1
Yield: 94.1 %

Procedure:
In a similar manner to that described in Reference Example 7, a reaction was carried out using t-butyl N-[5-(4-methoxyphenoxy)-2-nitrophenyl]-N-methylcarbamate (7.2 g), palladium on carbon (10%, 0.5 g) and methanol (100 ml) and the reaction mixture was purified to give the title compound (6.23 g).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([O:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C:15]=1[O:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[C:10](O)=[O:11])[CH:2]=[C:3]([CH3:5])[CH3:4].[NH2:28][CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][N:31]1[CH2:35][CH3:36]>>[CH2:35]([N:31]1[CH2:32][CH2:33][CH2:34][CH:30]1[CH2:29][NH:28][C:10](=[O:11])[C:9]1[CH:8]=[C:7]([O:6][CH2:1][CH:2]=[C:3]([CH3:5])[CH3:4])[C:15]([O:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[C:14]([O:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH:13]=1)[CH3:36]
Reactant: CC(C)=CCOc1cc(C(=O)O)cc(OCC=C(C)C)c1OCC=C(C)C
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=O)c1cc(OCC=C(C)C)c(OCC=C(C)C)c(OCC=C(C)C)c1
Yield: 79 %

Procedure:
In a manner identical to Example 15, 3,4,5-triprenyloxybenzoic acid (0.94 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.35 g, thereby yielding 1.21 g (79%) of the aimed compound.
Reaction SMILES: [N:1]([C:4]1[C:5]([F:24])=[CH:6][C:7]2[C:17](=[O:18])[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][N:9]3[C@@H:10]([CH3:14])[CH2:11][O:12][C:13]=1[C:8]=23)=[N+]=[N-].C(O)C>CN(C)C=O.[Pd]>[NH2:1][C:4]1[C:5]([F:24])=[CH:6][C:7]2[C:17](=[O:18])[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][N:9]3[C@@H:10]([CH3:14])[CH2:11][O:12][C:13]=1[C:8]=23
Reactant: CCOC(=O)c1cn2c3c(c(N=[N+]=[N-])c(F)cc3c1=O)OC[C@@H]2C
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)c1cn2c3c(c(N)c(F)cc3c1=O)OC[C@@H]2C
Temperature: 0 °C
Yield: 78.6 %

Procedure:
A slurry of 701 g of ethyl (S)-10-azido-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate in 6.0 of dimethylformamide was charged to the five gallon autoclave. After placing the vessel under nitrogen, a slurry of 45 g of 10% palladium-on-carbon in 700 ml of dimethylformamide was added. The mixture was hydrogenated at 48-50 psi and 600 RPM. A 10° C. rise in temperature was observed during the first thirty minutes of reaction. The reaction mixture was filtered and washed with 2×3 L of dimethylformamide. Concentration of the filtrate under aspirator pressure gave a very thick, dark residue (volume~700 ml). Ethanol (1.2 L) was added and the suspension was refluxed briefly. After cooling to 0° C., the product was collected, washed with 3×300 ml of cold ethanol and dried for eighteen hours at 80° C. in vacuo to give 508 g of product which was shown to be 97.6% pure by HPLC.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([CH2:16][O:17][C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=3[CH3:28])=[O:15])[CH:5]=[CH:4][C:3]1=2.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:48]N1C(=O)CCC1=O.O>C(Cl)(Cl)(Cl)Cl.ClCCl>[CH3:1][C:2]1([CH3:29])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]([CH2:16][O:17][C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=3[CH2:28][Br:48])=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccc(OCC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(OCC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)c(CBr)c1

Procedure:
A solution of methyl 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoyl)methyloxy]-3-methylbenzoate (3.73 g, 9.5 mmol), benzoyl peroxide (0.02 g) and N-bromosuccinimide (1.74 g, 9.8 mmol) in carbon tetrachloride (200 ml) was heated to reflux and irradiated with a 1000 W lamp for fifteen minutes. 300 ml of water and 150 ml of dichloromethane were added. After separation of the phases once settling had taken place, the organic phase was washed twice, with 250 ml of water, and dried over magnesium sulfate. After concentration on a rotary evaporator at 40° C. under vacuum, the product obtained was purified by flash chromatography (10% CH2Cl2, 90% heptane). Its properties were as follows:
Reaction SMILES: C[CH:2]=[CH:3][SiH:4]([Cl:6])[Cl:5].[CH2:7](C(O)CCCCC)C.[CH3:16][SiH:17]([Cl:19])[Cl:18]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH3:7][Si:4]([Cl:6])([Cl:5])[CH2:3][CH2:2][Si:17]([CH3:16])([Cl:19])[Cl:18]
Reactant: CCCCCC(O)CC
Reactant: CC=C[SiH](Cl)Cl
Reactant: C[SiH](Cl)Cl
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Product: C[Si](Cl)(Cl)CC[Si](C)(Cl)Cl
Reaction time: 1 h
Yield: 97 %

Procedure:
A reactor was charged with 42.3 grams (0.30 mol) of methylvinyldichlorosilane and 0.1 ml of a 2.ethylhexyl alcohol solution containing 2% chloroplatinic acid. To the reactor was added dropwise 34.5 grams (0.30 mol) of methyldichlorosilane. After the completion of addition, stirring was continued for a further one hour. After cooling, the reaction solution was distilled, obtaining 74.5 grams (yield 97%) of 1,2-bis(methyldichlorosilyl)ethane having a boiling point of 109°-110° C./30 mmHg.