Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[NH:10][CH:11]1[CH2:20][CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13][CH:12]1[CH2:21][S:22]([C:25]1[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)[CH3:34]>C1(C)C=CC=CC=1.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>[CH2:1]([O:8][C:9](=[O:32])[NH:10][C@H:11]1[CH2:20][CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13][C@H:12]1[CH2:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH:33]=[CH2:34])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1CCC2(CC1CS(=O)(=O)c1ccc(Br)cc1)OCCO2)OCc1ccccc1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(S(=O)(=O)C[C@@H]2CC3(CC[C@@H]2NC(=O)OCc2ccccc2)OCCO3)cc1

Procedure:
[7-(4-Bromo-benzenesulfonylmethyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-carbamic acid benzyl ester from example (3e) (1.0 g), was dissolved in toluene (15 ml) prior to the addition of PdCl2(PPh3)2 (66 mg) and Sn(vinyl)Bu3 (0.61 ml), and a few crystals of 2,6-di-tert-butyl-4-methylphenol. The resulting solution was heated to reflux for 4 h. After cooling, the solution was concentrated. Flash chromatography of the resulting residue gave (7R,8S) [7-(4-vinyl-benzenesulfonylmethyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-carbamic acid benzyl ester (668 mg). MS found: (M+H)+=460.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-])=O)=[CH:5][C:4]=1[C:13]([F:16])([F:15])[F:14]>CO.[C].[Pd]>[CH3:1][O:2][C:3]1[C:4]([C:13]([F:14])([F:16])[F:15])=[CH:5][C:6]([NH2:10])=[C:7]([CH3:9])[CH:8]=1
Reactant: COc1cc(C)c([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: COc1cc(C)c(N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 104 %

Procedure:
1-Methoxy-5-methyl-4-nitro-2-trifluoromethyl-benzene (10 g) is dissolved in methanol (100 ml), and thereto is added 10% palladium-carbon (1 g) and the mixture is stirred under hydrogen atmosphere at room temperature for 1 day. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure to give 4-methoxy-2-methyl-5-trifluoromethyl-phenylamine (9.07 g). MS (m/z): 206 [M+H]+
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[F:20][C:21]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=1[CH:23]=[O:24].[Cl-].[NH4+]>C(OCC)(=O)C.CCCCCC.O1CCCC1>[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH:23]([C:22]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:21]=1[F:20])[OH:24]
Reactant: Clc1cccnc1
Reactant: O=Cc1cc(F)ccc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(c1cc(F)ccc1F)c1ccncc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
To a tetrahydrofuran solution (14 ml) of diisopropylamine (1.4 ml, 10 mmol) was added n-butyl lithium (6.3 ml, a 1.59M hexane solution) at −78° C. After the resulting mixture was stirred for 10 minutes, 3-chloropyridine (1.13 g, 10 mmol) was added thereto. Thirty minutes later, 2,5-difluorobenzaldehyde (1.09 ml, 10 mmol) was added and the temperature of the resulting mixture was raised gradually to 0° C. Stirring was conducted for further 10 minutes. After addition of an aqueous solution of ammonium chloride, the resulting mixture was diluted with ethyl acetate (80 ml). The organic layer was separated, washed with brine and then dried. After filtration, the precipitate obtained by concentrating the resulting solution under reduced pressure was triturated with ethanol to give the title compound (1.33 g, 52%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([O:14][CH2:15][C:16]([O:18]CC2C=CC=CC=2)=[O:17])(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+]>CO.Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([O:14][CH2:15][C:16]([OH:18])=[O:17])(=[O:12])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(S(=O)(=O)OCC(=O)OCc2ccccc2)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)OCC(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.9 %

Procedure:
Benzyl 2-(3,4-dimethoxyphenylsulfonyloxy)acetate (400 mg, 1.092 mmol) was dissolved in MeOH (5 ml). NaOH 1M (2 ml) was added, and the reaction was stirred at RT for 6 hours to achieve completion. The reaction mixture was diluted with HCl 1N and extracted with EtOAc. The organic phase was washed with HCl 1N and brine, dried over Na2SO4 and concentrated under vacuum. The crude product was triturated in petroleum ether to give 2-(3,4-dimethoxyphenylsulfonyloxy)acetic acid (250 mg, 83% yield).
Reaction SMILES: [CH2:1]([N:10]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]1=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:17]([NH2:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(N(CC)CC)C>C(#N)C>[CH2:1]([N:10]1[C:11](=[O:16])[CH2:12][CH:13]([NH:26][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:14]1=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCN
Reactant: CCCCCCCCCN1C(=O)C=CC1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCCCCCNC1CC(=O)N(CCCCCCCCC)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of N-nonyl maleimide (0.01 M) prepared as described in Example 12 above, nonylamine (0.01 M), triethylamine [catalytic, 0.1 equivalent] in acetonitrile (25 ml) was stirred for 24 hours at room temperature. Acetonitrile was removed under vacuum to leave a residual liquid product which was flash chromatographed (25% ethyl acetate in petroleum ether) to yield a white solid as the desired product.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[C:10]([CH3:23])=[C:11]([CH3:22])[C:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14](=O)[C:13]=2[C:20]=1[CH3:21].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:7][O:8][C:9]1[C:10]([CH3:23])=[C:11]([CH3:22])[C:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14](=[CH2:1])[C:13]=2[C:20]=1[CH3:21]
Reactant: CC(C)(C)[O-]
Reactant: COc1c(C)c(C)c2c(c1C)C(=O)C(C)(C)O2
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C1c2c(C)c(OC)c(C)c(C)c2OC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
Potassium tert-butoxide (4 g, 35.5 mmol) is added portionwise at 0° C. and under nitrogen to a suspension of methyltriphenylphosphonium bromide (12.7 g, 35.5 mmol) in dry tetrahydrofuran (120 mL) and the reaction mixture is stirred for 1 hr at room temperature. The 5-methoxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-one (5.55 g, 23.7 mmol) in dry tetrahydrofuran (40 mL) is added dropwise at 0° C. to the yellow suspension and the reaction is stirred overnight at room temperature. Water (50 mL) is carefully added and most of the solvent is evaporated under reduced pressure. The residue is taken in ethyl acetate (200 mL), washed with brine, dried (magnesium sulfate) and evaporated to dryness. Purification through a small pad of silica gel using dichloromethane as a solvent gave 5.47 g 5-methoxy-3-methylene-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran (99%) as a yellow oil. Rf=0.48 (heptane/ethyl acetate 90:10).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[Cu](C#N)[C:12]#[N:13]>O.C(OCC)(=O)C>[C:12]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2)#[N:13]
Reactant: Brc1cccc2cc[nH]c12
Reactant: N#C[Cu]C#N
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cccc2cc[nH]c12
Temperature: 200 °C
Reaction time: 2.5 h
Yield: 54.8 %

Procedure:
Combine 7-bromoindole (4.72 g, 24.0 mmol) and copper cyanide (4.30 g, 48.1 mmol) in 1-methyl-2-pyrrolidine (40 mL). Heat to 200° C. After 2.5 hours, cool to room temperature, add water-ethyl acetate (200 mL, 1/1) to give a solid. Filter through the celite, extract the filtrate with ethyl acetate, combine the organic layers, wash with brine, dry over Na2SO4, filter and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with hexanes: ethyl acetate (10:1) to give (1.87 g) of the title compound as a yellow solid: 1H NMR (300 MHz, DMSO-d6)) 6.64–6.66 (m, 1H), 7.17 (t, 1H, J=7.6 Hz), 7.51–7.53 (m, 1H), 7.60–7.62 (m, 1H), 7.94 (d, 1H, J=8.0 H), 12.03 (br, 1H).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[F:14][C:15]1[C:16]2[CH2:27][CH2:26][C:25](=O)[C:17]=2[C:18]2[C:22]([CH:23]=1)=[N:21][N:20]([CH3:24])[CH:19]=2.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[F:14][C:15]1[C:16]2[CH2:27][CH2:26][C:25](=[CH:5][C:3]#[N:4])[C:17]=2[C:18]2[C:22]([CH:23]=1)=[N:21][N:20]([CH3:24])[CH:19]=2
Reactant: Cn1cc2c3c(c(F)cc2n1)CCC3=O
Reactant: CCOP(=O)(CC#N)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1cc2c3c(c(F)cc2n1)CCC3=CC#N
Reaction time: 0.25 h
Yield: 63.7 %

Procedure:
To a suspension of 60% sodium hydride (59.0 mg, 1.48 mmol) in tetrahydrofuran (8 mL) was added diethyl cyanomethylphosphonate (260 μL, 1.60 mmol) at room temperature, and the mixture was stirred for 15 min. A suspension of 5-fluoro-2-methyl-6,7-dihydrocyclopenta [e] indazol-8(2H)-one (252 mg, 1.23 mmol) in tetrahydrofuran (4 mL) was added thereto, and the mixture was stirred at room temperature for 4 hr. Saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained crystals were washed with diisopropyl ether to give the title compound (178 mg, yield 64%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[NH:8][CH:9]([CH2:12][O:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10][O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:33](N1C=CN=C1)(N1C=CN=C1)=[O:34]>C(Cl)Cl>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([S:14]([O:13][CH2:12][CH:9]2[N:8]3[C:33](=[O:34])[NH:1][C:2]4=[CH:3][CH:4]=[CH:5][C:6](=[C:7]34)[O:11][CH2:10]2)(=[O:16])=[O:15])=[CH:18][CH:19]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3cccc(N)c3N2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2COc3cccc4[nH]c(=O)n2c34)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
Toluene-4-sulfonic acid 5-amino-3,4-dihydro-2H-benzo[1,4]oxazin-3-ylmethyl ester (6.7 g , ˜10 mmole) was dissolved in methylene chloride (100 mL), N, N-diisopropylethylamine (5.22 mL, 30.0 mmole) was added, followed by carbonyldiimidazole (4.05 g, 25.0 mmole), and the mixture was stirred at room temperature under nitrogen overnight. The mixture was diluted with methylene chloride (100 mL), washed with water (2×200 mL), saturated sodium bicarbonate (200 mL) saturated sodium chloride (200 mL) and dried (Na2SO4). Filtration, evaporation in vacuum and column chromatography on silica gel with 1% methanol/methylene chloride as eluent gave 2.0 g of the title compound as an off white solid, m.p. 140-142° C. 1H NMR (DMSO-d6): δ 10.7 (s, 1H); 7.63 (d, 2H); 7.47 (d, 2H); 6.82 (t, 1H); 6.57 (d, 1H); 6.52 (d, 1H); 4.53 (m, 1H); 4.43 (dd, 1H); 4.34 (dd, 1H); 4.16 (dd, 1H); 4.10 (dd, 1H); 2.38 (s, 3H). MS (ESI) m/z359 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:28]2[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=2)[CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(Cc2ccc(Cl)cc2)c1
Yield: 47.8 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(4-Chlorobenzyl)benzamide was prepared according to method B with the N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.060 g; 0.173 mmol), 4-chlorophenylboronic acid (0.028 g; 0.181 mmol), tetrakis(triphenylphosphine)palladium(0) (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.345 mmol), sodium iodide (0.052 g; 0.345 mmol), in dimethoxyethane (3 mL) and water (1 mL), heated in a sealed tube at 130° C. for 18 hours. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.035 g (47%) of the title compound as a white solid.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.[NH:27]1[CH2:32][CH2:31][S:30][CH2:29][CH2:28]1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:15]2[C:14]([CH2:13][O:12][C:9]3[N:8]=[N:7][C:6]([C:4]([N:27]4[CH2:32][CH2:31][S:30][CH2:29][CH2:28]4)=[O:5])=[CH:11][CH:10]=3)=[C:18]([CH3:19])[O:17][N:16]=2)=[CH:21][CH:22]=1
Reactant: C1CSCCN1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C)nn1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)N2CCSCC2)nn1
Yield: 85 %

Procedure:
As described for example 59, 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid ethyl ester (143 mg, 0.4 mmol) was converted, using thiomorpholine instead of aminomethylcyclopropane, to the title compound (140 mg, 85%) which was obtained as an off-white solid. MS: m/e=415.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:30])[C:4]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:5]2[C:10](=[O:11])[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)[CH2:8][CH2:7][N:6]2[CH:21]=1.N1C=CC=CC=1.[C:37](Cl)(=[O:41])[CH:38]([CH3:40])[CH3:39].S([O-])(O)(=O)=O.[K+]>C(Cl)(Cl)Cl>[CH2:23]([O:22][C:4]1[C:3](=[O:30])[C:2]([NH:1][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])=[CH:21][N:6]2[CH2:7][CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)[C:10](=[O:11])[C:5]=12)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cn2c(c(OCc3ccccc3)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Reactant: CC(C)C(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cn2c(c(OCc3ccccc3)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 7-amino-9-benzyloxy-2-(3-chloro-4-fluorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (29 mg) in chloroform (0.6 ml) were added pyridine (0.0082 ml) and isobutyryl chloride (0.01 ml) at 0° C., and the mixture was stirred at room temperature for 1.5 hr. 5% Aqueous potassium hydrogen sulfate solution was added and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was dried, concentrated and purified by silica gel thin layer chromatography (chloroform:methanol=10:1) to give N-[9-benzyloxy-2-(3-chloro-4-fluorobenzyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl]isobutyramide (29 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[N:3]=1.C(NC(C)C)(C)C.[Li].[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[O:22]>C1COCC1>[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]([C:7]1[C:2]([F:1])=[N:3][C:4]([F:9])=[CH:5][C:6]=1[F:8])[OH:22]
Reactant: O=Cc1ccccc1Cl
Reactant: Fc1cc(F)nc(F)c1
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OC(c1ccccc1Cl)c1c(F)cc(F)nc1F
Temperature: -78 °C

Procedure:
2,4,6-Trifluoropyridine (7.5 g, 56.36 mmol) was taken up in 9 mL of dry THF, and the reaction mixture was cooled to −78° C. under argon with stirring. Lithium diisopropylamine (42.3 mL of 2M solution in THF) was added dropwise, and the solution was stirred for 10 minutes. 2-Chlorobenzaldehyde (9.5 mL, 1.5 equiv) was added dropwise via syringe, and the reaction mixture was stirred for 15 minutes. The reaction was quenched by addition of saturated ammonium chloride and water, and the aqueous mixture was extracted once with EtOAc. The combined organic layers were washed with saturated brine and water, dried over MgSO4, filtered and evaporated. The residue was purified by FLASH column chromatography using 5%-10% EtOAc/Hexanes to yield 8.02 g of (2-Chloro-phenyl)-(2,4,6-trifluoro-pyridin-3-yl)-methanol. Mass spec., M+1=275.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=13)[N:8]=[CH:7][N:6]([C@H:16]1[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]1[O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[C:5]2=[O:30].[H-].[Na+].IC>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=13)[NH:8][CH2:7][N:6]([C@H:16]1[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]1[O:22][Si:23]([C:26]([CH3:28])([CH3:27])[CH3:29])([CH3:24])[CH3:25])[C:5]2=[O:30]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1COCC[C@@H]1n1cnc2c(cc(Br)c3ccccc32)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)(C)[Si](C)(C)O[C@H]1COCC[C@@H]1N1CNc2c(cc(Br)c3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of crude 1,5-anhydro-3-(6-bromo-4-oxobenzo[h]quinazolin-3(4H)-yl)-2-O-[tert-butyl(dimethyl)silyl]-3,4-dideoxy-L-threo-pentitol (1.01 g, 2.06 mmol) in DMF (17 mL) was cooled at 0° C. Sodium hydride (95%, 62 mg, 2.58 mmol) was added and the resulting yellow mix was stirred for 5 minutes. Iodomethane (0.27 mL, 4.32 mmol) was added and the reaction was stored in the freezer overnight. LCMS showed the reaction was incomplete. It was put back in an ice bath and additional sodium hydride (50 mg) was added. After 20 minutes, the completed reaction was quenched with ammonium chloride and allowed to warm to room temperature. The reaction was diluted with water and extracted 2× with CH2Cl2. The organics were washed with brine, dried over MgSO4, filtered, concentrated, and dried. The residue was purified via silica gel chromatography, eluting with 10-55% ethyl acetate in hexanes to provide 1,5-anhydro-3-(6-bromo-4-oxo-1,4-dihydrobenzo[h]quinazolin-3(2H)-yl)-2-O-[tert-butyl(dimethyl)silyl]-3,4-dideoxy-L-threo-pentitol that gave a mass ion (ES+) of 506.9 for [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([CH3:3])=[CH2:2].N1C=CC=CC=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>CCOCC>[C:17]([O:10][C:6]1[CH:5]=[C:4]([C:1]([CH3:3])=[CH2:2])[CH:9]=[CH:8][CH:7]=1)(=[O:19])[CH3:18]
Reactant: C=C(C)c1cccc(O)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOCC
Product: C=C(C)c1cccc(OC(C)=O)c1
Yield: 94.6 %

Procedure:
250 g (1.86 mol) m-isopropenylphenol and 15 mL (0.19 mol) pyridine were placed in a four-neck flask equipped with a stirrer, reflux condenser, addition funnel, and thermometer. While stirring with cooling on a water bath, 200 mL (2.12 mol) acetic anhydride was dripped in. The reaction mixture was then diluted with ether and washed with water to neutrality. Drying and distillation afforded 310 g (1.76 mol) of the target material. The yield was 94%. The properties of this product are reported below.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.ClCCl.N1C=CC=CC=1.[C:32]([C:36]1[CH:41]=[CH:40][C:39]([CH:42]([OH:67])[C:43]2[C:44]([C:60]3[CH:65]=[CH:64][C:63]([F:66])=[CH:62][CH:61]=3)=[C:45]3[C:53](=[CH:54][C:55]=2[CH:56]([CH3:58])[CH3:57])[O:52][C:48]2([CH2:51][CH2:50][CH2:49]2)[CH2:47][C:46]3=[O:59])=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>C(OCC)(=O)C.[OH-].[Na+]>[C:32]([C:36]1[CH:37]=[CH:38][C:39]([C:42]([C:43]2[C:44]([C:60]3[CH:65]=[CH:64][C:63]([F:66])=[CH:62][CH:61]=3)=[C:45]3[C:53](=[CH:54][C:55]=2[CH:56]([CH3:58])[CH3:57])[O:52][C:48]2([CH2:51][CH2:50][CH2:49]2)[CH2:47][C:46]3=[O:59])=[O:67])=[CH:40][CH:41]=1)([CH3:34])([CH3:35])[CH3:33]
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(C(C)(C)C)cc1)C(=O)CC1(CCC1)O2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(=O)c1ccc(C(C)(C)C)cc1)C(=O)CC1(CCC1)O2
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
91 mg (0.21 mmol) of 1,1-dihydro-1,1,1-triacetoxy-1,2-benziodoxol-3(1H)-one are dissolved in 1.4 ml of abs. dichloromethane and cooled to −30° C. 12 μl (0.14 mmol) of pyridine are added, followed by the dropwise addition of 68 mg (0.14 mmol) of 6-[(4-tert-butylphenyl)(hydroxy)-methyl]-5-(4-fluorophenyl)-7-isopropylspiro[chromen-2,1′-cyclobutan]-4(3H)-one (Example 55A), dissolved in 0.6 ml of abs. dichloromethane. The mixture is slowly warmed to 0° C. and stirred at this temperature for 1.5 h. The mixture is diluted with ethyl acetate, 5 ml of 1 N aqueous sodium hydroxide solution are added and the mixture is then extracted twice with ethyl acetate. The combined organic phases are washed once with 1 N hydrochloric acid and twice with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude product is dried under high vacuum and then reacted without further purification. This gives 81 mg (>100% of theory) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Cl[C:12]1[N:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=1>>[Cl:18][C:15]1[CH:14]=[N:13][C:12]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)=[N:17][CH:16]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: OB(O)c1ccc(O)cc1
Product: Oc1ccc(-c2ncc(Cl)cn2)cc1
Yield: 29 %

Procedure:
The title compound was prepared according to the method described for Preparation 17 using 4-hydroxybenzene boronic acid and 2,5-dichloro-pyrimidine to afford the title compound as a pale yellow solid (1.91 g, 29%)
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][C@@H:12]([CH2:16][CH3:17])[CH2:13][CH2:14]O.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:14][CH2:13][CH:12]([CH3:11])[CH2:16][CH3:17])=[O:7])=[CH:4][CH:3]=1
Reactant: CC[C@H](C)CCO
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCC(C)CCOC(=O)c1ccc(O)cc1
Yield: 80.7 %

Procedure:
13.7 g of p-hydroxybenzoic acid and 11.4 g of (S)-(+)-3-methyl-1-pentanol were refluxed for 10 hours in toluene in the presence of sulfuric acid, while removing out the generated water from the reaction system. Subsequently, the reaction solution was washed with water to remove the sulfuric acid out. The reaction solution was then dried, concentrated, and purified by column chromatography, to obtain 17.8 g of the objective ester compound (liquid state at room temperature ([α]d23 =+7.8° (CHCl3)). (Yield: 80%)