Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[C:5]2I.[CH3:13][O:14][CH2:15][C:16]#[CH:17]>CN(C)C=O.C(N(CC)CC)C.O.[Cu]I.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>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[C:5]2[C:17]#[C:16][CH2:15][O:14][CH3:13]
Reactant: Cn1nc(I)c2cc(Br)ccc21
Reactant: C#CCOC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCC#Cc1nn(C)c2ccc(Br)cc12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 81.67 g of 5-bromo-3-iodo-1-methyl-1H-indazole in 750 ml of N,N-dimethylformamide and 335 ml of triethylamine is admixed at room temperature under argon with 25 ml of 3-methoxypropyne, 5.5 g of copper(I) iodide and 10 g of bis(triphenylphosphine)palladium(II) chloride, and subsequently heated to 60° C. After 1 hour, the reaction mixture is cooled to room temperature, diluted with water and extracted with ethyl acetate (4×). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.67 (2:1 EtOAc-heptane). Rt=4.42 (gradient I).
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1C=CC=CC=1.C(Cl)(=O)C(Cl)=O>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([O:20][CH3:21])[CH:17]=[CH:18][C:19]=1[C:5]([C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=1[OH:2])=[O:6]
Reactant: COc1cccc(OC)c1
Reactant: COc1ccccc1C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Solvent: c1ccccc1
Product: COc1ccc(C(=O)c2ccccc2O)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
To a solution 2.0 g (13.14 mmol) of 2-methoxybenzoic acid in 60 ml of dry benzene, 5 ml oxalyl chloride was added under stirring at room temperature. After 2 hours, solvent and excess reagents were removed at reduced pressure. The residual 2-methoxybenzoyl chloride was dissolved in 80 ml of anhydrous ether, and then 1.8 g (13.03 mmol) of 1,3-dimethoxybenzene and 5.0 g of aluminum chloride were added. After stirred at room temperature for 8 hours, the resulting mixture was hydrolyzed by 500 ml of ice water containing 45 ml of concentrated HCl and then extracted with chloroform. The solvent was removed to give a crude product. After purified by column chromatography, 2.20 g (8.53 mmol) of a yellow oily product was obtained and the yield was 65%. The data of the physical properties of the compounds were measured and are listed below.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[N:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.I[CH2:46][C:47]([NH2:49])=[O:48].O>CN(C)C=O>[NH2:49][C:47](=[O:48])[CH2:46][N:17]1[C:12](=[N:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:21][CH:20]=2)=[CH:16]1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3ccc(NC(=O)OCc4ccccc4)cc3)cn2)cc1
Reactant: NC(=O)CI
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3ccc(NC(=O)OCc4ccccc4)cc3)cn2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.5 %

Procedure:
To a solution of benzyl {4-[(6-{[(4-methylphenyl)sulfonyl]amino}pyridin-3-yl)oxy]phenyl}carbamate (23.8 g, 48.6 mmol) in N,N-dimethylformamide (238 mL) were added N,N-diisopropylethylamine (11.0 mL, 63.2 mmol) and iodoacetamide (11.7 g, 63.2 mmol), and the mixture was stirred at room temperature for 24 hr. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate/tetrahydrofuran. The combined organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with hexane/ethyl acetate and collected by filtration to give the title compound (20.6 g, 78%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][C:12]2[N:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]3=[N:14][CH:13]=2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[Ca+2].[Cl-]>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][C:12]2[N:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]3=[N:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(SCc2cnc3ccccn23)cc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: Nc1ccc(SCc2cnc3ccccn23)cc1
Temperature: 25 °C
Yield: 84.2 %

Procedure:
A mixture of 3-(4-nitrophenylthiomethyl)imidazo[1,2-a]pyridine (1.5 g), reduced iron (1.47 g) and calcium chloride (0.29 g) in 15% hydrous ethanol (45 ml) was heated to reflux for 5 hours. After cooling to room temperature, and the precipitates were removed by filtration. After concentrating the filtrate, water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The precipitated crystals were collected by filtration. The crystals were washed with diisopropylether, to give 3-(4-aminophenylthiomethyl)imidazo[1,2-a]pyridine (1.13 g) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1.[Cl:20][S:21](O)(=[O:23])=[O:22]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([S:21]([Cl:20])(=[O:23])=[O:22])[CH:14]=1
Reactant: Cc1ccc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1S(=O)(=O)Cl
Temperature: 0 °C
Yield: 81.1 %

Procedure:
6.7 g (22.0 mmol) of 4-(2,6-dichloro-4-trifluoromethylphenyl)toluene prepared in (a) was dissolved in 50 ml of chloroform, and 3.8 g (32.6 mmol) of chlorosulfonic acid was added dropwise at 0° C. with stirring. After further 3 hours of stirring at room temperature, the reaction mixture was poured into about 200 ml of ice-cold water for separation. The organic layer was washed with water twice and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 7.2 g of 5-(2,6-dichloro-4-trifluoromethylphenyl)-2-methylbenzenesulfonyl chloride (yield 81.0%).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.Cl[C:11]1[S:12][C:13]([C:16]#[N:17])=[CH:14][N:15]=1>C1COCC1>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH:3][C:11]1[S:12][C:13]([C:16]#[N:17])=[CH:14][N:15]=1
Reactant: Nc1ccccn1
Reactant: N#Cc1cnc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cnc(Nc2ccccn2)s1

Procedure:
A flame dried round-bottom flask under Ar was charged with NaH (60% dispersion 0.037 g, 0.91 mmol). Anhydrous THF, 2 mL, was added followed by the addition of 2-aminopyridine (0.032 g, 0.033 mmol). 2-Chloro-thiazole-5-carbonitrile (9-2, 0.044 g, 0.30 mmol) was added and the reaction was heated to reflux. After 2 h the reaction was cooled and quenched by the addition of water. The THF was removed in vacuo and the precipitate which formed was filtered and washed with water. The solid was recrystallized from DMSO to provide a pure sample of the desired product. 1H NMR (DMSO-d6) d 12.23 (s, 1H), 8.40 (m, 1H), 8.27 (s, 1h), 7.82 (m, 1H), 7.15 (d, 1H, J=8.3 Hz), 7.08 (m, 1H). MS [M+H]+=203.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Si:9]([CH3:12])([CH3:11])[CH3:10])[CH:5]=[C:6]([Br:8])[CH:7]=1.[Li]CCCC.[CH3:18][Si:19](Cl)([CH3:21])[CH3:20].Cl>CCOCC>[CH3:10][Si:9]([CH3:12])([CH3:11])[C:4]1[CH:5]=[C:6]([Br:8])[CH:7]=[C:2]([Si:19]([CH3:21])([CH3:20])[CH3:18])[CH:3]=1
Reactant: C[Si](C)(C)c1cc(Br)cc(Br)c1
Reactant: C[Si](C)(C)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: C[Si](C)(C)c1cc(Br)cc([Si](C)(C)C)c1
Temperature: -68 °C
Reaction time: 0.75 h
Yield: 94 %

Procedure:
17.18 g of 3,5-Dibromo-trimethylsilyl-benzene, 55.8 mmol, was dissolved in 380 ml Et2O. The solution was chilled to −68° C., and 22.3 mL of n-BuLi (2.5 M in hexanes), 55.8 mmol, were added within 18 minutes. The solution changed its color from clear to yellow, and was stirred for 45 minutes at −68° C. 7.5 mL TMSCl, 59 mmol, were added within six minutes. The temperature of solution rose within one hour to −33° C., and after another 30 minutes to −18° C. The solution was stirred overnight at room temperature. 60 mL of 2M HCl were added to the white suspension. Stirring for 30 minutes resulted in two clear phases. Et2O-phase was dried with MgSO4, filtered, and solvent evaporated. Raw product was distilled at a temperature of 70-76° C. and 0.1-0.2 mbar. All pure fractions were combined and gave 15.8 g of product (52.4 mmol, 94%). 1H-NMR (CHCl3=7.24 ppm): δ 7.56 (s, 2H), 7.50 (t, 1H), 0.25 (s, 6×3H).
Reaction SMILES: [N:1]1([C:6]2[CH:16]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]([OH:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][CH:20]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][CH:20]=[C:19]2[O:17][C:9]1[CH:8]=[CH:7][C:6]([N:1]2[CH:5]=[CH:4][CH:3]=[CH:2]2)=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CCOC(=O)c1cc(-n2cccc2)ccc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1cc(-n2cccc2)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 22.1 %

Procedure:
Ethyl 5-(pyrrol-1-yl)salicylate (170 mg), 4-chloro-6,7-dimethoxyquinoline (87 mg), and 4-dimethylaminopyridine (143 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (36 mg, yield 15%).
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:30]([C:31]([O:33]C)=[O:32])=[C:22]2[O:23][CH2:24][C@H:25]3[CH2:29][CH2:28][CH2:27][N:26]3[C:21]2=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:2].O.[OH-].[Li+].C(O)=O.C(OCC)(=O)C>O1CCOCC1.O.C(O)C.C1(C)C=CC=CC=1>[CH2:35]([N:3]([CH2:1][CH3:2])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:30]([C:31]([OH:33])=[O:32])=[C:22]2[O:23][CH2:24][C@H:25]3[CH2:29][CH2:28][CH2:27][N:26]3[C:21]2=[CH:20][CH:19]=1)(=[O:15])=[O:16])[CH3:36]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OC[C@H]1CCCN21
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OC[C@H]1CCCN21
Yield: 48 %

Procedure:
A mixture of methyl (R)-7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzene-sulfonylamino]-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-6-carboxylate (Intermediate 1, 0.640 g) and lithium hydroxide monohydrate (0.505 g) in dioxane (9.6 mL) and water (2.4 mL) was irradiated in the microwave at 135° C. for 45 minutes. After cooling, the mixture was acidified with formic acid, diluted with ethanol and toluene and concentrated in vacuo. The residue was triturated with methanol in DCM (10% solution) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-10%. The resultant solid was triturated with ethyl acetate to give a pale yellow solid which was treated with hot ethyl acetate and filtered while still hot. The filtrate was concentrated in vacuo and the residue was triturated with ethyl acetate to give (R)-7-[2-((Z)-3-diethylaminoprop-1-en-1-yl)-4-fluorobenzenesulfonyl-amino]-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-6-carboxylic acid (0.299 g) as a pale yellow solid.
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][N:3]2[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]#[N:20])=[CH:11][CH:10]=1.C(N(CC)C(C)C)(C)C.[CH3:30][O:31][CH2:32][C:33](Cl)=[O:34].O>ClCCl>[CH3:30][O:31][CH2:32][C:33]([N:6]1[CH2:7][C@@H:2]2[CH2:8][C@H:5]1[CH2:4][N:3]2[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]#[N:20])=[CH:11][CH:10]=1)=[O:34]
Reactant: N#Cc1ccc(N2C[C@@H]3C[C@H]2CN3)c2ccccc12
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COCC(=O)N1C[C@@H]2C[C@H]1CN2c1ccc(C#N)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
165RL09 (16.5 mg, 0.066 mmol) was dissolved in dichloromethane (1 mL). N,N-Diisopropylethylamine (DIPEA) (9.4 mg, 0.073 mmol) was added followed by methoxyacetyl chloride (7.9 mg, 0.073 mmol). The mixture was shaken in a vial at rt for 18 hours. Water (3 mL) was added and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×5 mL) and the combined organic layers were evaporated. The compound was further purified by column chromatography on silica gel using ethyl acetate/methanol (1:1) to give the title compound (21 mg, 97%).
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][CH:52]=[C:53]([O:58][C:59]([F:62])([F:61])[F:60])[CH:54]=4)[O:49][C:48]=3[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][CH:52]=[C:53]([O:58][C:59]([F:62])([F:60])[F:61])[CH:54]=4)[O:49][C:48]=3[C:63]3[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(OC(F)(F)F)cc4c3=O)cc2)CCC1
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(OC(F)(F)F)cc4c3=O)cc2)CCC1
Yield: 80 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(4-oxo-2-phenyl-6-trifluoromethoxy-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a white solid (54 mg, 80%). 1H NMR (400 MHz, DMSO-d6): δ 7.97-7.87 (m, 3H), 7.45-7.32 (m, 7H), 7.16-7.12 (m, 2H), 2.42-2.33 (m, 2H), 2.15-2.05 (m, 2H), 2.05-1.94 (m, 1H), 1.70-1.60 (m, 1H). LCMS (Method E): RT=4.06 min, [M+H]+=452.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)[CH2:8][N:9]([CH3:13])[CH2:10]2)=[CH:5][CH:4]=1.CC(O)=O>Br>[CH3:13][N:9]1[CH2:8][C@@H:7]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[C:6]2[C:11](=[CH:12][C:3]([OH:2])=[CH:4][CH:5]=2)[CH2:10]1
Reactant: COc1ccc2c(c1)CN(C)C[C@H]2c1ccc2ccccc2c1
Agent: Br
Solvent: CC(=O)O
Product: CN1Cc2cc(O)ccc2[C@H](c2ccc3ccccc3c2)C1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of Compound 7 (42.5 g, 140 mmol) in 48% HBr (200 mL) was added AcOH (100 mL) to give a light yellow suspension. The reaction was heated to give a light yellow solution and stirred at 120° C. for 6 hr (<1.5% starting material left by HPLC), then concentrated. Dichloromethane (500 mL) was added to the residue and the suspension was filtered. The filtrate was neutralized with ice water, 50% NaOH (added slowly) and Na2CO3 solution to pH of 10. The aqueous layer was extracted with dichloromethane twice. The solid was fully dissolved in dichloromethane and triethylamine (25 mL), and washed with Na2CO3 solution to pH of 10. The organic layers were combined and washed with NaHCO3 and brine, dried over Na2SO4 overnight, filtered and concentrated. The crude product Compound 8, as the free base, can be used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[C:4]([O:17][C:18]([F:21])([F:20])[F:19])[CH:3]=1.C([Li])CCC.C[O:28]B(OC)OC.C(O)(=O)C.OO>C1COCC1.O>[OH:28][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[C:4]([O:17][C:18]([F:21])([F:20])[F:19])[CH:3]=1
Reactant: COB(OC)OC
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Br)cc1OC(F)(F)F
Agent: OO
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(O)cc1OC(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-bromo-1-(tert-butyldimethylsilyloxymethyl)-2-trifluoromethoxybenzene (5.5 g, 15 mmol) from Step 3 above in THF (100 mL) at -78° C. was added n-butyllithium (6.6 mL of a 2.5 M solution in hexanes, 16.5 mmol) dropwise over a period of 10 min. The resulting pale yellow solution was stirred at -78° C. for 30 min and trimethylborate (1.75 g, 17 mmol) was added. The resulting solution was stirred at -78° C. for 5 min and then warmed to ambient temperature for 45 min. To the mixture was added acetic acid (0.90 mL, 15 mmol) and hydrogen peroxide (0.1.7 mL of a 30% solution in water, 17 mmol) and stirring was continued for 1 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (150 mL) and water (2×50 mL). The organic layer was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 10% EtOAc:hexanes as eluant to give 4-hydroxy-1-(tert-butyldimethylsilyloxymethyl)-2-trifluoromethoxy-benzene as a colorless oil (TLC Rf =0.40 (10% EtOAc:hexanes)).
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:26][CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[OH:38])(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH3:40][N:41]([CH2:43][CH2:44]O)[CH3:42].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6](=[O:39])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:26][CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[O:38][CH2:44][CH2:43][N:41]([CH3:42])[CH3:40])(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccccc1OCCc1c(O)ccc2ccccc12
Reactant: CN(C)CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccccc1OCCc1c(OCCN(C)C)ccc2ccccc12
Temperature: 25 °C
Yield: 37.5 %

Procedure:
3-{2-[2-(2-Hydroxy-naphthalen-1-yl)-ethoxy]-benzenesulfonylamino}-N-methoxy-N-methyl-succinamic acid tert-butyl ester (176 mg, 0.32 mmol) was combined with dimethylamino ethanol (0.063 mL, 0.63 mmol), triphenyl phosphine (165 mg, 0.63 mmol), and diethylazodicarboxylate (0.10 mL, 0.63 mmol) in freshly distilled THF (1.6 mL). The reaction was stirred at room temperature for eighteen hours. TLC analysis (silica, 50% EtOAc/hexanes) indicated consumption of the starting naphthol. The reaction mixture was concentrated and purified by gradient elution flash chromatography (SiO2, 30% EtOAc/hexanes to 50% EtOAc/hexanes to 80% EtOAc/hexanes to 100% EtOAc to 10% MeOH/CH2Cl2) to give 3-(2-{2-[2-(2-dimethylamino-ethoxy)-naphthalen-1-yl]-ethoxy}-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester (75 mg, 0.12 mmol) in 38% yield. MS (APCI) m/z 630.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([S:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[C:8]2[CH2:33][C:34]([CH3:40])([CH3:39])[C:35]([O:37][CH3:38])=[O:36])=[CH:4][CH:3]=1.[CH3:43][Si](C)(C)N[Si](C)(C)C.[K].IC.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH:17]([C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[CH3:43])=[CH:13][CH:14]=3)[C:9]([S:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[C:8]2[CH2:33][C:34]([CH3:40])([CH3:39])[C:35]([O:37][CH3:38])=[O:36])=[CH:41][CH:42]=1
Reactant: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Agent: [K]
Solvent: CI
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OC(C)c3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of methyl 3-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-yl methoxy) indol-2-yl]-2,2-dimethylpropanoate (420 mg) (EP 419,049, Ex. 1, Step D) in THF (10 mL) at -78° C. was added 0.6M potassium hexamethyldisilazane in toluene (1.75 mL) and stirred at -78° C. for 5 min. Then iodomethane (87 ml) was added followed 15 min later by more 0.6M KHMDS in toluene (1.75 mL). The mixture was finally stirred at -78° C. for 30 min. The reaction mixture was poured into 25% NH4OAc (100 mL), extracted with ethyl acetate (2×100 mL), washed with brine (100 mL), and dried (MgSO4). The filtrate was evaporated to dryness and the residue was chromatographed on flash silica gel using ethyl acetate:hexane (15:85) as eluant to give the title product as a foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9]O)[CH:5]=[CH:6][C:7]=1[F:8].P(Br)(Br)[Br:12]>C(Cl)Cl>[Br:12][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc(F)c(Cl)c1
Solvent: ClCCl
Product: Fc1ccc(CBr)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a solution of (3-chloro-4-fluoro-phenyl)-methanol (4.3 g, 26.8 mmol) in DCM (20 mL) was added PBr3 (1 mL) at 0° C. The resulting mixture was stirred at room temperature for 1 hour before it was quenched with satd. aq. NaHCO3 solution. The organic solution was washed with water, brine, dried over anhy. Na2SO4 and concentrated in vacuo to give the desired product (3.7 g, 61.9%). It was used directly in the next step, without further purification.