Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([NH2:17])(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:59]1[N:64]=[C:63]([S:65][CH2:66][C:67]2[CH:72]=[CH:71][CH:70]=[C:69]([F:73])[C:68]=2[F:74])[N:62]=[C:61]([O:75][CH2:76][CH2:77][CH2:78][OH:79])[CH:60]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:74][C:68]1[C:69]([F:73])=[CH:70][CH:71]=[CH:72][C:67]=1[CH2:66][S:65][C:63]1[N:64]=[C:59]([NH:17][S:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH2:10]2)(=[O:16])=[O:15])[CH:60]=[C:61]([O:75][CH2:76][CH2:77][CH2:78][OH:79])[N:62]=1
Reactant: OCCCOc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: CC(C)(C)OC(=O)N1CCN(S(N)(=O)=O)CC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)Nc2cc(OCCCO)nc(SCc3cccc(F)c3F)n2)CC1
Temperature: 100 °C

Procedure:
A mixture of 4-(aminosulfonyl)-1-piperazinecarboxylic acid-1,1-dimethylethyl ester (the product from example 15, step i), 0.4 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.43 g) and 3-({6-chloro-2-[(2,3-difluorobenzyl)thio]pyrimidin-4-yl}oxy)propan-1-ol (the product from step i), 0.4 g) in 1,4-dioxane (40 ml) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 3 h. The reaction mixture was then reduced in vacuo and the residue separated between DCM (150 ml) and H2O (150 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a yellow solid. Yield 0.83 g
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][Al](C)C.O.O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>O1CCCC1.CCCCCC>[Br:1][C:2]1[C:3]([CH3:10])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1nc(Cl)ncc1Br
Temperature: 25 °C
Yield: 35.1 %

Procedure:
5 g of 5-bromo-2,4-dichloropyrimidine was dissolved in 70 mL of tetrahydrofuran, and under stirring at room temperature, 15.8 g of trimethyl aluminum in 15% n-hexane and 1.77 g of tetrakis(triphenyl)phosphine were added, and stirred at 80° C., under nitrogen atmosphere for 7 hours. Under ice cooling, 70 mL of water was added little by little, followed by 46 g of potassium sodium tartrate tetrahydrate, and stirred at room temperature for 1 hour. Then the solution was extracted twice with ethyl acetate, and the resultant organic layer was washed with saturated brine. After drying over magnesium sulfate, the solvent was evaporated, and purification and isolation by silica gel column chromatography (ethyl acetate:n-hexane=1:8) were followed, to obtain 1.6 g of the title compound as a pale yellow syrup.
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[CH:5][S:4][CH:3]=1.C([Li])CCC.CN(OC)[C:15](=[O:18])[CH2:16][CH3:17]>CCOCC>[Br:7][C:6]1[C:2]([C:15](=[O:18])[CH2:16][CH3:17])=[CH:3][S:4][CH:5]=1
Reactant: Brc1cscc1Br
Reactant: CCC(=O)N(C)OC
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCC(=O)c1cscc1Br
Reaction time: 0.25 h
Yield: 38.3 %

Procedure:
A solution of 3,4-dibromothiophene (6.0 g, 24.8 mmol) in 10 mL of ether was cooled to -78° C. and trated with n-butyllithium (9.92 mL, 2.5M solution in hexanes, 24.8 mmol). While holding the temperature at -78° C., the reaction was stirred for 15 minutes, then 2.9 g (24.8 mmol) of N-methyl-N-methoxypropionamide was added and the reaction was stirred for 1 hour. The reaction was quenched with satd NH4Cl, and the mixture was diluted with ether. The ether layer was separated, washed with water and brine, dried over MgSO4 and concentrated. The residue was triturated with hexanes, and the mixture was filtered. The solvent was removed to give 2.08 g of a tan solid. MS 236, 238 (M+NH4)+. NMR (CDCl3) δ:7.99 (d, J=3 Hz, 1H), 7.32 (d, J=3 Hz, 1H), 2.98 (q, J=7 Hz, 2H), 1.21 (t, J=7 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH3:18])=[N:15][CH:16]=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[C:23]([F:29])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)[Cl:31].CO>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH3:18])=[N:15][C:16]([Cl:31])=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([F:29])[C:24]([F:28])=[C:25]([F:27])[CH:26]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: ClCCl
Reactant: CCc1ncc2n1CCN(C(=O)OC(C)(C)C)C2CCc1cc(F)c(F)c(F)c1
Solvent: CO
Product: CCc1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1cc(F)c(F)c(F)c1

Procedure:
Subsequent chlorination (70° C.; 3h30) of 3-ethyl-8-[2-(3,4,5-trifluoro-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (2.070 g; 5.056 mmol), and purification by FC (DCM/MeOH=25/1) afforded 1-chloro-3-ethyl-8-[2-(3,4,5-trifluoro-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow oil (1.220 g; 54%). LC-MS: tR=1.06 min.; [M+H]+=444.00 g/mol.
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][C@H:19]3[CH2:21][C@H:20]3[C:22]([O:24]C)=[O:23])=[C:8]2[CH3:26])=[CH:4][CH:3]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO>[Br:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][C@H:19]3[CH2:21][C@H:20]3[C:22]([OH:24])=[O:23])=[C:8]2[CH3:26])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1C[C@@H]1Cc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(C[C@H]1C[C@H]1C(=O)O)c(C)n2Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
To the ester from Step 2 (145 mg, 0.33 mmol) in 3 mL THF and 3 mL MeOH was added 2N NaOH (1 mL, 2 mmol) and the reaction mixture was stirred at r.t. for 16 h. Excess 0.5N citric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and evaporated. Purification by flash chromatogrpahy on silicic acid (20% to 40% ethyl acetate in hexane) provided 99 mg of the title compound.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][C:6]([Cl:16])=[C:7]([C:9](=[O:15])[C:10]([O:12]CC)=[O:11])[N:8]=1)=[O:2].Cl>[OH-].[K+]>[CH:1]([NH:3][C:4]1[S:5][C:6]([Cl:16])=[C:7]([C:9](=[O:15])[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2]
Reactant: CCOC(=O)C(=O)c1nc(NC=O)sc1Cl
Agent: CCOC(=O)C(=O)c1[nH]c(=NC=O)sc1Cl
Agent: Cl
Agent: [K+]
Product: O=CNc1nc(C(=O)C(=O)O)c(Cl)s1

Procedure:
Ethyl 2-(2-formylamino-5-chloro-1,3-thiazol-4-yl)-glyoxylate, which can be represented as ethyl 2-(2-formylimino-5-chloro-2,3-dihydro-1,3-thiazol-4-yl)glyoxylate, (1.3 g.) was dissolved in 1N potassium hydroxide aqueous solution (10 ml.) at room temperature with stirring and the solution was stirred for 5 minutes at the same temperature. After the reaction, the reaction mixture was cooled with ice and then adjusted to pH 1 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water and then dried to give 2-(2-formylamino-5-chloro-1,3-thiazol-4-yl)glyoxylic acid (0.91 g.), which can be represented as 2-(2-formylimino-5-chloro-2,3-dihydro-1,3-thiazol-4-yl)glyoxylic acid, mp. 148° to 152° C. (dec.). The remaining filtrate and washing were combined together and then extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and then the solvent was distilled off to give further the same object compound (0.23 g.).
Reaction SMILES: [OH:1][CH:2]([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14].ClCCl>C1(C)C=CC=CC=1>[N+:13]([C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:4][CH2:3][CH:2]([OH:1])[CH3:5])=[O:21])=[CH:23][CH:24]=1)([O-:15])=[O:14]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(O)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(O)COC(=O)c1ccc([N+](=O)[O-])cc1
Yield: 51 %

Procedure:
2-Hydroxypropanol (4.57 g) was dissolved in toluene (80 ml) by stirring and triethylamine (6.68 g) was dropped thereinto at 0° C. After stirring at the same temperature for 30 minutes, a solution of p-nitrobenzoyl chloride (11.4 g) dissolved in toluene (12 ml) was slowly added thereto. The resultant mixture was heated to room temperature and stirred for 2 hours. Next, dichloromethane (50 ml) was added and the crystals thus precipitated were dissolved. The solution was washed with an dilute aqueous solution of sodium hydrogencarbonate (100 ml) and then with an aqueous solution of hydrochloric acid (0.5 mol/l). The organic layer thus obtained was concentrated and the residue was dissolved in toluene (45 ml) by heating. Then it was cooled by allowed to stand at room temperature for crystallization. The crystals thus precipitated were collected by filtration and dried under reduced pressure to give 6.90 g (51%) of the title compound as yellow crystals.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:10]([CH2:11][C:12]([OH:14])=[O:13])[N:9]=[N:8][N:7]=2)=[CH:2]1.S(=O)(=O)(O)O.[CH2:20](O)[CH2:21][OH:22]>>[OH:22][CH2:21][CH2:20][O:13][C:12](=[O:14])[CH2:11][N:10]1[C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[N:7][N:8]=[N:9]1
Reactant: OCCO
Reactant: O=C(O)Cn1nnnc1-c1ccoc1
Agent: O=S(=O)(O)O
Product: O=C(Cn1nnnc1-c1ccoc1)OCCO
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 54.6 %

Procedure:
To a solution of 1 g (5.3 mM) of [5-(3-furyl)tetrazol-1-yl] acetic acid in 5 ml of ethylene glycol was aded 0.5 ml of sulfuric acid. After the addition, the mixture was stirred at 90° C. for 2.5 hrs. The mixture was then poured into ice-water and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatogrpahy (eluent: chloroform/methyl alcohol=50/1) for separation and purification to give 670 mg (yield 54.6%) of [5-(3-furyl)tetrazol-1-yl] acetic acid 2-hydroxyethyl ester.
Reaction SMILES: C1C=CC(C(N)CO)=CC=1.C[C@@H]([C@@H](OCC1C=CC=CC=1)C)C=O.[Si](C#N)(C)(C)C.[C:31]([C@H:33]([NH:45][C@H:46]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH2:47][OH:48])[C@@H:34]([CH3:44])[C@@H:35]([O:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][O:39]1)[CH3:36])#[N:32].C([C@@H](N[C@H](C1C=CC=CC=1)CO)[C@@H](C)[C@@H](OC1CCCCO1)C)#N>ClCCl.C(Cl)(Cl)Cl.CO>[C:31]([CH:33]([NH:45][C@H:46]([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[CH2:47][OH:48])[C@@H:34]([CH3:44])[C@@H:35]([O:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][O:39]1)[CH3:36])#[N:32]
Reactant: C[C@H]([C@H](C#N)N[C@@H](CO)c1ccccc1)[C@H](C)OC1CCCCO1
Agent: C[C@@H]([C@H](C)OC1CCCCO1)[C@@H](C#N)N[C@@H](CO)c1ccccc1
Agent: C[C@H](C=O)[C@H](C)OCc1ccccc1
Agent: C[Si](C)(C)C#N
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: C[C@H](OC1CCCCO1)[C@H](C)C(C#N)N[C@@H](CO)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(R)-phenylglycinol (115 mg, 0.84 mmol) was added at room temperature to a solution of (2S,3S)-2-methyl-3-tetrahydropyranyloxybutyraldehyde (6) (130 mg, 0.7 mmol) in dichloromethane (6 ml), and the stirring was continued for 2 hours at room temperature. The reaction mixture was cooled to 0° C., and methanol (2 ml) and TMSCN (104 mg, 140 μl, 1.05 mmol) were successively introduced. After stirring at 0° C. for 2 hours and then to room temperature for 22 hours, the reaction mixture was separated in saturated NaHCO3 and in ether. The aqueous phase was extracted with ether, the ether extracts were washed with brine, they were dried and filtered on a short disk of Celite and Na2SO4 and then evaporated. Flash chromatography on a silica gel column with, as eluent, a heptane/EtOAc=3:1 then 2:1 mixture produced a mixture of (1R,2R,3S)-1-cyano-2-methyl-3-tetrahydropyranyloxy-N-[(R)-1′-phenyl-2′-hydroxyethyl]butylamine (1R)-(19) and (1S,2R,3S)-1-cyano-2-methyl-3-tetrahydropyranyloxy-N-[(R)-1′-phenyl-2′-hydroxyethyl]butylamine (1S)-(19) (225 mg in total, 97%): IR (CHCl3) 3630, 3442, 3347, 3012, 2947, 2856, 1493, 1455, 1385, 1356, 1231, 1173 cm−1; 1H NMR (250 MHz, CDCl3) δ 7.37 to 7.27 (m, 5H); 4.72 to 4.39 (m, 1H); 4.14 to 3.39 (m, 7H); 2.30 (broad s, 2H, OH+NH); 2.05 to 1.20 (m, 7H); [1.17 (d, J=6.3 Hz), 1.08 (d, J=7.7 Hz), 1.05. (d, J=7.0 Hz), 6H]; 13C NMR (62.5 MHz, CDCl3) δ 140.6; 140.0; 138.7; 138.4; 128.6; 128.0; 127.8; 127.7; 127.3; 120.4; 119.8; 119.6; 119.2; 101.0; 100.1; 97.5; 95.6; 78.9; 76.3; 71.4; 71.2; 67.1; 66.9; 66.0; 65.6; 65.5; 63.2; 63.0; 62.8; 62.7; 53.0; 50.5; 50.1; 49.9; 42.7; 42.5; 42.3; 31.0; 30.8; 30.6; 25.2; 25.0; 21.6; 20.0; 19.6; 19.4; 18.3; 17.0; 16.1; 14.0; 12.7; 12.0; 11.7. MS (CI) m/z 333 [M+H]+. HRMS: calculated for C19H29N2O3 (M+H), 333.21780; found, 333.21668.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=1.C([Li])CCC.[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH:24]=[O:25])[CH3:19].C(O)(C)C>C1COCC1.O>[CH2:11]([O:10][C:4]1[CH:3]=[C:2]([CH:24]([C:23]2[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:21]([O:20][CH2:18][CH3:19])[CH:22]=2)[OH:25])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9])[CH3:12]
Reactant: CCOc1cc(Br)ccc1OC
Reactant: CCOc1cc(C=O)ccc1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: CCOc1cc(C(O)c2ccc(OC)c(OCC)c2)ccc1OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 103.6 %

Procedure:
A stirred mixture of 4-bromo-2-ethoxy-1-methoxy-benzene (6.52 g, 28.2 mmol) and dry THF (40 mL) was cooled to −78° C., evacuated and refilled with nitrogen for 10 cycles. To this clear solution was slowly added n-butyllithium (11.3 mL, 28.2 mmol) and stirred for 30 min. Then a mixture of 3-ethoxy-4-methoxy-benzaldehyde (4.62 g, 25.7 mmol) in dry THF (60 mL) was added and stirred for 1 h at −78° C. The mixture was quenched with isopropanol (11.7 mL, 154 mmol) and added water (30 mL). It was extracted with ether (3×50 mL). The combined organic phases were washed with water (2×50 mL), dried over MgSO4 and concentrated to an oil, which was purified by flash column chromatography (EtOAc/Hexane) to give bis-(3-ethoxy-4-methoxy-phenyl)-methanol as an oil (8.85 g, 100% yield): 1H NMR (CDCl3) δ 1.44 (t, J=7 Hz, 6H, 2CH2CH3), 2.12 (d, J=4 Hz, 1H, OH), 3-0.86 (s 6H, 2OCH3), 4.06 (q, J=7 Hz, 4H, 2CH2CH3), 5.74 (d, J=4 Hz, 1H, CH), 6.81-6.91 (m, 6H, Ar). The product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH2:10][C@@H:11]([C:20](O)=[O:21])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O>C(COC)OC>[C:16]([O:15][C:13]([NH:12][C@H:11]([CH2:20][OH:21])[CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:23])=[O:14])([CH3:18])([CH3:19])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: COCCOC
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@H](CO)CC(=O)OCc1ccccc1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
N-(tert-Butoxycarbonyl)-L-aspartic acid 4-benzyl ester (30 g) was dissolved in dimethoxyethane (90 mL) and the solution was cooled to −5° C. N-Methylmorpholine (10.32 mL) was added followed by a slow addition of isobutyl chloroformate (12.66 mL) such that the reaction temperature was kept below −10° C. The mixture was aged for 0.5 hour. The solids were quickly filtered and washed with dimethoxyethane (90 mL). The filtrate was cooled to −50° C. and a solution of sodium borohydride (4.4 g) in water (45 mL) was added slowly such that the reaction temperature was maintained between −30° C. and −15° C. Water (500 mL) was then added such that the reaction mixture temperature was maintained below −15° C. The suspension was filtered, the solid washed with water (400 mL) and dried to yield benzyl (3S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxybutanoate.
Reaction SMILES: C[O:2][C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2(O)[CH2:18][CH2:17][C:16]([CH3:20])([CH3:19])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)(OC)[CH3:4].[I-].[Na+].C(#N)C.[Cl-].Cl[Si](C)(C)C>ClCCl.C(O)(=O)C>[CH3:19][C:16]1([CH3:20])[CH2:17][CH2:18][C:13]([C:10]2[CH:9]=[CH:8][C:7]([C:3](=[O:2])[CH3:4])=[CH:12][CH:11]=2)=[CH:14][CH2:15]1
Reactant: COC(C)(OC)c1ccc(C2(O)CCC(C)(C)CC2)cc1
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [I-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(=O)c1ccc(C2=CCC(C)(C)CC2)cc1
Temperature: 30 °C
Reaction time: 12 h

Procedure:
99.32 g of 1-[4-(1,1-dimethoxyethyl)phenyl]-4,4-dimethylcyclohexanol in 300 ml of dichloromethane, and 151 g of sodium iodide are added to 600 ml of acetonitrile, under an inert atmosphere, and the reaction mixture is heated to 30° C. 102 ml of chlorotrimethylsilane chloride are added, followed, at 65° C., by portionwise addition of a mixture of 300 ml of acetonitrile and 47 ml of acetic acid, and the reaction mixture is stirred for 12 hours at room temperature. The reaction mixture is filtered and extracted with dichloromethane. The residue obtained is purified by chromatography on a column of silica gel, eluting with a 99/1 (v/v) cyclohexane/ethyl acetate mixture.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].CO.[BH4-].[Na+]>O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17]
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1ccc(C(O)c2ccccc2)cc1[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
(a-1) To a stirred and cooled (water-bath) mixture of 48.5 parts of (4-amino-3-nitrophenyl)phenylmethanone and 320 parts of methanol were added portionwise 11.4 parts of sodium tetrahydroborate. Upon completion, stirring was continued for 15 minutes at room temperature. 100 Parts of water were added and the methanol was evaporated. The precipitated product was filtered off, washed with water, dried, filtered and crystallized twice from a moisture of methanol and water, yielding 19.6 parts of 4-amino-3-nitro-α-phenylbenzenemethanol; mp. 125° C. (int. 124).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.[CH3:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[C:14]([O:21]C(=O)C)[CH:13]=1.Cl>CN(C)C1C=CC=CC=1.CC(C)=O.[OH-].[Na+]>[Cl:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([Cl:10])[C:5]=1[OH:9])[NH:1][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([CH3:11])=[CH:13][C:14]=1[OH:21]
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Reactant: CC(=O)Oc1cc(C)ccc1C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CN(C)c1ccccc1
Product: Cc1ccc(C(=O)Nc2cc(Cl)c(O)c(Cl)c2)c(O)c1
Yield: 72.5 %

Procedure:
4-Amino-2,6-dichlorophenol (16 g.) was put into solution in N,N-dimethylaniline (15 ml.) and acetone (200 ml.), to which the acetone solution of 4-methyl-2-acetoxybenzoyl chloride was added dropwise. After reaction for several hours, by condensing and then acidifying the solution with 4 N hydrochloric acid a precipitate was obtained, which was redissolved in 2 N sodium hydroxide solution. The solution was made acidic with dilute hydrochloric acid, thereby precipitating the product which was recrystallized from aqueous acetone to give white crystals (20.3 g.) of 3',5'-dichloro-2,4'-dihydroxy-4-methylbenzanilide. Yield: 72.5%. The melting point was 246°-247° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C@H:19]([C:23]([O:25][CH3:26])=[O:24])[CH:20]([CH3:22])[CH3:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[O:27]=[C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[C:30]([C:38](OCC)=[O:39])[NH:29]1>CCO>[O:27]=[C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[C:30]([C:38]([NH:1][CH2:2][C:3]2[CH:4]=[C:5]([C:9]3[CH:10]=[CH:11][C:12]([S:15]([NH:18][C@H:19]([C:23]([O:25][CH3:26])=[O:24])[CH:20]([CH3:21])[CH3:22])(=[O:17])=[O:16])=[CH:13][CH:14]=3)[CH:6]=[CH:7][CH:8]=2)=[O:39])[NH:29]1
Reactant: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2cccc(CN)c2)cc1)C(C)C
Solvent: CCO
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2cccc(CNC(=O)c3nc4ccccc4c(=O)[nH]3)c2)cc1)C(C)C
Yield: 86 %

Procedure:
A suspension of methyl N-{[3′-(aminomethyl)biphenyl-4-yl]sulfonyl}valinate obtained in Reference Example 94 (0.300 g, 0.797 mmol) and ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate obtained according to the methods described in Journal of Organic Chemistry (1978), 43(23), 4485-7 and the like (0.145 g, 0.664 mmol) in EtOH (9 mL) was stirred at 90° C. for 5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, washed with 0.1N hydrochloric acid and saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a colorless oil (0.375 g, 86%).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[C:6]([O:13][CH3:14])[CH:5]=[C:4]([O:15][CH3:16])[C:3]=1[C:17](=[O:19])[CH3:18].[H-].[Na+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25].Cl>CN(C)C=O>[CH2:8]([C:7]1[C:2]([O:1][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[C:3]([C:17](=[O:19])[CH3:18])[C:4]([O:15][CH3:16])=[CH:5][C:6]=1[O:13][CH3:14])[CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: COC(=O)CBr
Reactant: COc1cc(OC)c(C(C)=O)c(O)c1CCC(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1c(CCC(C)C)c(OC)cc(OC)c1C(C)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
To 16.7 g of the so-obtained 2'-hydroxy-3'-isopentyl-4',6'-dimethoxyacetophenone and 1.5 g of sodium hydride was added 130 ml of dimethylformamide, and 9.9 g of methyl α-bromoacetate was further added and the mixture was stirred for 1.5 hours at 0° C. and for 2 hours at room temperature to effect reaction. After the reaction, the reaction mixture was made acidic by dilute hydrochloric acid, extracted with diethyl ether and filtered. The solvent was removed from the filtrate by distillation. The obtained residue was subjected to the silica gel column chromatography [230-400 mesh silica gel, eluting solvent=n-hexane/ethyl acetate (4/1)] to obtain 14.9 g (yield=70.3%) of 3'-isopentyl-4',6'-dimethoxy-2'-methoxycarbonylmethoxyacetophenone.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=1[O:28][Si](C(C)(C)C)(C)C)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F.C(N(CC)CC)C>C(#N)C>[CH2:1]([O:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=1[OH:28])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cc([N+](=O)[O-])ccc1NC(=O)N[C@@H]1CCCC[C@H]1OCc1ccccc1
Agent: F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)N[C@@H]1CCCC[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
To a solution of trans-N-(2-Benzyloxycyclohexyl)-N'-(2-tert-butyldimethylsilyloxy-4-nitrophenyl) urea (100 mg, 0.2 mmol) in acetonitrile (2 mL), triethylamine hydrofluoride (0.1 mL, 0.6 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give product (73 mg, 95%). EI-MS m/z 386 (M+H)+.