Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2](C)/[CH:3]=[C:4](\[CH3:10])/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH:12]([C:14]1[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][N:15]=1)N>CC(O)=O.CCO>[C:20]([C:18]1[CH:17]=[CH:16][N:15]=[C:14]([NH:12][NH:2]/[CH:3]=[C:4](\[CH3:10])/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:19]=1)#[N:21]
Reactant: N#Cc1ccnc(NN)c1
Reactant: CCOC(=O)/C(C)=C/N(C)C
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)/C(C)=C/NNc1cc(C#N)ccn1
Temperature: 90 °C
Yield: 62.1 %

Procedure:
A solution of ethyl (E)-3-(dimethylamino)-2-methylprop-2-enoate (668 mg, 4.25 mmol) and 2-hydrazinylpyridine-4-carbonitrile (570 mg, 4.25 mmol, PREPARATION 2) in 2 mL HOAc and 10 mL EtOH was charged to a flask and the mixture was heated to 90° C. for 30 min. Cooled to room temperature and removed the solvent. The residue was dissolved in ethylacetate and water, aqueous basified with NaHCO3 sat (pH=8), extracted with ethylacetate. The organic phase was washed with brine and dried with anhydrous sodium sulfate and then purified by silica gel chromatograph to give 0.65 g of the title compound (62%). [M+H] Calc'd for C12H14N4O2, 247. Found, 247.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.O.[C:12]([O:19][CH2:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=O)(=[O:18])[CH2:13][CH2:14][C:15]([CH3:17])=[O:16]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]=[C:21]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:20][O:19][C:12](=[O:18])[CH2:13][CH2:14][C:15]([CH3:17])=[O:16])=[CH:5][CH:4]=1
Reactant: CC(=O)CCC(=O)OCC(=O)OCc1ccccc1
Reactant: COc1ccc(NN)cc1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(NN=C(COC(=O)CCC(C)=O)OCc2ccccc2)cc1
Yield: 104.4 %

Procedure:
5.2 g of p-methoxyphenylhydrazine were suspended in 25 ml of glacial acetic acid and 90 ml of water and 10 g of benzyl levulinoyloxyacetate were slowly added at room temperature while stirring. After stirring for 1 hour, the mixture was extracted by shaking with toluene, the toluene solution was washed neutral with water, dried and concentrated. 15.1 g of benzyl levulinoyloxyacetate (p-methoxyphenyl)-hydrazone were obtained as a brownish oil, which was not purified but was dissolved in 25 ml of absolute pyridine, and then 100 ml of ether were added and mixed with a solution of 8.7 g of p-chlorobenzoyl chloride in 50 ml of ether at 0°C with the introduction of nitrogen. After boiling for 2 hours under nitrogen, the solution was cooled, washed neutral with water, dried and concentrated by evaporation. 19 g (crude yield) of N(2) -(p-chlorobenzoyl)-N(2) -(p-methoxyphenyl)-hydrazone of benzyl levulinoyloxyacetate were obtained. This product was further treated without purification, by taking it up in 75 ml of glacial acetic acid and heating for 5 hours at 80°C. After evaporating off the glacial acetic acid under vacuum, the further treatment was carried out as described in Example 1. The yield of [1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indoleacetoxy]-benzyl acetate amounted to 11% of the theoretical, based on the total amount of hydrazine.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[N:9]([C:10]2[CH:14]=[CH:13][S:12][C:11]=2[C:15]([O:17][CH3:18])=[O:16])[C:8](=[O:19])[N:7]([CH3:20])[N:6]=1>CO.C(COC)OC.CO>[CH3:1][O:2][C:5]1[N:9]([C:10]2[CH:14]=[CH:13][S:12][C:11]=2[C:15]([O:17][CH3:18])=[O:16])[C:8](=[O:19])[N:7]([CH3:20])[N:6]=1
Reactant: COC(=O)c1sccc1-n1c(Cl)nn(C)c1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CO
Product: COC(=O)c1sccc1-n1c(OC)nn(C)c1=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Sodium methoxide (16.5 mL of a 30% solution in methanol) was added to a solution of the title compound of Step C (7.9 g) in anhydrous dimethoxyethane/methanol (85 mL/35 mL). The resulting yellow solution was heated to 50° C. for 2 h under N2 and then left to stir overnight at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in methylene chloride. The resulting mixture was washed with water and then with saturated aqueous NaCl. The aqueous layer was filtered through Celite® and the filtrate was extracted three times with methylene chloride. The combined methylene chloride layers were dried (MgSO4), filtered, and concentrated under reduced pressure to give 5.4 g of an off-white solid. The crude product was purified by flash chromatography (20-100% ethyl acetate/hexane as eluent) to afford 3.9 g of the title compound of Step D as a white solid. 1H NMR (CDCl3): δ 7.58 (d,1H), 7.12 (d,1H), 3.93 (s,3H), 3.83 (s,3H), 3.44(s,3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([N:14]3[C:19](=[O:20])[C:18]([CH2:21][C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)=[N:17][C:16]4[CH:28]=[CH:29][CH:30]=[N:31][C:15]3=4)[CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[C:32]1(=[O:42])[O:37][C:35](=[O:36])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12>O1CCOCC1.O>[C:35]([C:34]1[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=1[C:32]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([N:14]3[C:19](=[O:20])[C:18]([CH2:21][C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)=[N:17][C:16]4[CH:28]=[CH:29][CH:30]=[N:31][C:15]3=4)[CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1)=[O:42])([OH:37])=[O:36]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1cccc(-c2cccc(-n3c(=O)c(Cc4cccnc4)nc4cccnc43)c2)c1
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccccc1C(=O)Nc1cccc(-c2cccc(-n3c(=O)c(Cc4cccnc4)nc4cccnc43)c2)c1
Yield: 80.6 %

Procedure:
A solution of 4-[3-(3-aminophenyl)phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (100 mg) and phthalic anhydride (48 mg) in dioxane (3 ml) was stirred overnight at room temperature. The reaction mixture was diluted with water, and precipitated crystals were collected to give 4-[3-[3-(2-carboxybenzoylamino)phenyl]phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (110 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]=[C:6]=[S:7])=[O:4].[F:8][C:9]([F:32])([F:31])[C:10]1[CH:11]=[C:12]([S:16]([O:19][C:20]2[CH:21]=[CH:22][C:23]([NH:27][C:28]([NH2:30])=[O:29])=[C:24]([CH:26]=2)[NH2:25])(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1.C(OC(C)C)(C)C>O1CCOCC1>[CH3:1][O:2][C:3]([NH:5][C:6]([NH:25][C:24]1[CH:26]=[C:20]([O:19][S:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([C:9]([F:8])([F:31])[F:32])[CH:11]=2)(=[O:18])=[O:17])[CH:21]=[CH:22][C:23]=1[NH:27][C:28]([NH2:30])=[O:29])=[S:7])=[O:4]
Reactant: COC(=O)N=C=S
Reactant: NC(=O)Nc1ccc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)cc1N
Solvent: C1COCCO1
Solvent: CC(C)OC(C)C
Product: COC(=O)NC(=S)Nc1cc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)ccc1NC(N)=O
Reaction time: 4 h

Procedure:
12 ml of methoxycarbonyl isothiocyanate are added dropwise, with stirring, to 18.7 g of 5-(3-trifluoromethylphenylsulfonyloxy)-2-ureidoaniline in 300 ml of dioxane, the temperature rising to about 40° C. The mixture is stirred for a further four hours without cooling, 60 ml of diisopropyl ether are added and the precipitate is filtered off with suction. After washing with diisopropyl ether, recrystallization is carried out from methanol/diisopropyl ether with the addition of active charcoal, melting point 190° C., decomposition.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[C:4]([C:14](=O)[C:15](Cl)=[O:16])=[CH:3]1.Cl.C([O:23][C:24](=[NH:39])[CH2:25][C:26]1[C:34]2[C:29](=[C:30]([N+:35]([O-:37])=[O:36])[CH:31]=[CH:32][CH:33]=2)[N:28]([CH3:38])[CH:27]=1)(C)C>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[C:4]([C:14]2[C:15](=[O:16])[NH:39][C:24](=[O:23])[C:25]=2[C:26]2[C:34]3[C:29](=[C:30]([N+:35]([O-:37])=[O:36])[CH:31]=[CH:32][CH:33]=3)[N:28]([CH3:38])[CH:27]=2)=[CH:3]1
Reactant: CC(C)OC(=N)Cc1cn(C)c2c([N+](=O)[O-])cccc12
Reactant: Cn1cc(C(=O)C(=O)Cl)c2ccc([N+](=O)[O-])cc21
Agent: Cl
Product: Cn1cc(C2=C(c3cn(C)c4c([N+](=O)[O-])cccc34)C(=O)NC2=O)c2ccc([N+](=O)[O-])cc21

Procedure:
ll) 3-(1-Methyl-6-nitro-1H-indol-3-yl)-4-(1-methyl-7-nitro-1H-indol-3-yl)-pyrrole-2,5-dione was prepared from (1-methyl-6-nitro-1H-indol-3-yl)-oxo-acetyl chloride and 2-(1-methyl-7-nitro-1H-indol-3-yl)-acetimidic acid isopropyl ester hydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[CH3:2].Cl[CH2:13][CH2:14][O:15][CH2:16][CH2:17]Cl>>[CH2:1]([O:3][C:4]([C:5]1([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11])[CH3:2]
Reactant: CCOC(=O)Cc1cccs1
Reactant: ClCCOCCCl
Product: CCOC(=O)C1(c2cccs2)CCOCC1

Procedure:
Thiophen-2-yl-acetic acid ethyl ester (1) was dialkylated as described in Example 1, Step 1, using 1-chloro-2-(2-chloroethoxy)ethane to obtain the title compound (37).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][NH2:9])=O.[CH2:10]([N:17]=[C:18]=[S:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1>>[CH2:10]([N:17]1[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:8][N:9]=[C:18]1[S:19][CH2:26][C:25]1[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NNC(=O)c1cccs1
Reactant: S=C=NCc1ccccc1
Reactant: COc1ccc(CBr)cc1
Product: COc1ccc(CSc2nnc(-c3cccs3)n2Cc2ccccc2)cc1

Procedure:
This compound was synthesized using the same methodology as described in Example 1 above, using 2-thiophencarboxylic acid hydrazide, benzyl isothiocyanate and 4-methoxybenzyl bromide as the starting materials. (M+H)+−394.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.O[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[C:27]([CH3:38])[C:26]=1[CH3:39]>>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:8]2[C:7]([CH2:6][O:5][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[C:27]([CH3:38])[C:26]=3[CH3:39])=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=2)=[CH:17][CH:18]=1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: COc1ccc(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)cc1
Product: COc1ccc(-c2nsc(C(F)(F)F)c2COc2ccc(CCC(=O)O)c(C)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (5-(trifluoromethyl)-3-(4-methoxyphenyl) isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ: 7.65 (d, J=6.9 Hz, 2H), 6.96-7.02 (m, 3H), 6.72 (d, J=8.4 Hz, 1H), 5.13 (s, 2H), 3.55 (s, 3H), 2.92 (t, J=8.4 Hz, 2H), 2.51 (t, J=8.1 Hz, 2H), 2.28 (s, 3H), 2.07 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C23H22F3NO4S, 466.1 (M+H). found 466.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[CH2:21][NH:22][CH2:23][CH3:24])[CH:10]=1.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][C:12]=2[CH2:21][N:22]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:23][CH3:24])[CH:10]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OC)c1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OC)c1)C(=O)OCc1ccccc1

Procedure:
[5-(2-Ethylaminomethyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester and benzyl chloroformate were reacted as described in Example 11, Step 2 to provide (5-{2-[(N-benzyloxycarbonyl-N-ethyl-amino)-methyl]-4-trifluoromethyl-phenyl}-pyridin-3-yl)-acetic acid methyl ester.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:26][CH:27]=[CH:28][CH3:29])=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:26][CH:27]=[CH:28][CH3:29])=[CH:7][CH:6]=1
Reactant: CC=CCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Sc1ccc(NC(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC=CCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Sc1ccc(N)cc1
Temperature: 25 °C

Procedure:
The mixture of 1.2 g of 4-(4-acetamidophenylmercapto)-3-(2-butenylamino)-5-sulfamoylbenzoic acid and 12 ml of 2N aqueous sodium hydroxide is refluxed for one hour under nitrogen. After cooling to room temperature it is filtered, the filtrate acidified with glacial acetic acid to a pH of 4-5 and the precipitate formed filtered off. It is washed with water and recrystallized from 50% aqueous ethanol, to yield the 4-(4-aminophenylmercapto)-3-(2-butenylamino)-5-sulfamoylbenzoic acid, melting at 242°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].O1CCCC1.C[O-].[Na+].[Cl:18][CH2:19][CH2:20]OS(C1C=CC(C)=CC=1)(=O)=O>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:20][CH2:19][Cl:18]
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: COc1ccccc1O
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccccc1OCCCl
Yield: 67.2 %

Procedure:
24.83 g (0.2 mole) of o-methoxyphenol and 100 ml of tetrahydrofuran were placed in a 500 ml-flask equipped with a stirring device and a cooling pipe. A solution in which sodium methoxide (0.2 mole) was dissolved in methanol was added to the flask while stirring the contents. Then tetrahydrofuran and methanol were eliminated at reduced pressure. 300 ml of tetrahydrofuran was added to the flask and then 46.94 g (0.2 mole) of 2-chloroethyl-p-toluene sulfonate was added thereto. The mixture was then stirred under heating reflux for 20 hours to promote reaction. After reaction, insoluble matters were eliminated by filtration, and the product was condensed at reduced pressure. The reaction mixture was then refined by column chromatography using silica gel, and 25.1 g of 2-(o-methoxyphenoxy)ethyl chloride was produced.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]([NH2:30])=[S:29])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][C:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=O>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]3[S:29][CH:38]=[C:39]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[N:30]=3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: NC(=S)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Fc1ccc(Cn2c(NC3CCN(CCNc4nc(-c5ccccc5)cs4)CC3)nc3ccccc32)cc1
Reaction time: 8 h

Procedure:
To a stirred mixture of 4.3 parts of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]thiourea, 2.1 parts of potassium carbonate and 40 parts of methanol was added dropwise a solution of 2 parts of 2-bromo-1-phenylethanone in methanol. Upon completion, stirring was continued for overnight at room temperature. The reaction mixture was filtered over Hyflo and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 2.5 parts of 1-[(4-fluorophenyl)methyl]-N-[1-[2-[(4-phenyl-2-thiazolyl)amino]ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 176.2° C. (compound 89).
Reaction SMILES: C([Li])(CC)C.[C:6]([Si:10]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].B(OC)(OC)[O:23]C.CC(O)=O.OO>C1COCC1.C(OCC)C>[Si:10]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([OH:23])[CH:16]=1)([C:6]([CH3:9])([CH3:7])[CH3:8])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(F)cc1
Reactant: COB(OC)OC
Agent: OO
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(F)c(O)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
sec-Butyllithium (20.7 mL, 29.0 mmol) was added dropwise to a solution of tert-butyl(4-fluorobenzyloxy)dimethylsilane (2) (6.33 g, 26.3 mmol) in THF (30 mL) over 30 min, at −78° C. Trimethyl borate (2.99 mL, 26.3 mmol) was added dropwise over 30 min while the temperature was maintained at −78° C. The reaction mixture was allowed to warm to 0° C. and AcOH (2.26 mL, 39.5 mmol) was added dropwise, followed by hydrogen peroxide (2.48 mL, 29.0 mmol). The mixture was stirred at 0° C. for 30 min then allowed to warm to RT and stirred for 1 h. The reaction mixture was diluted with diethyl ether (100 mL) and washed with 2M NaOH (100 mL) and brine (100 mL). The organic solution was dried over MgSO4, filtered and the solvent was removed in vacuo to give 5-((tert-butyldimethylsilyloxy)methyl)-2-fluorophenol (3) (4.0 g, 50%) as a colourless oil: m/z 255 [M−H]− (ES−).
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12](=[O:37])[CH:13](OS(C3C=CC(C)=CC=3)(=O)=O)[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:8]=2)[O:3]1.[F-:39].[K+]>C(#N)C.O>[CH3:1][C:2]1([CH3:38])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12](=[O:37])[CH:13]([F:39])[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:8]=2)[O:3]1
Reactant: COc1cc(C(OS(=O)(=O)c2ccc(C)cc2)C(=O)c2ccc3c(c2)CCC(C)(C)O3)cc(OC)c1OC
Reactant: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc(C(F)C(=O)c2ccc3c(c2)CCC(C)(C)O3)cc(OC)c1OC
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
To a solution of toluene-4-sulfonic acid 2-(2,2-dimethyl-chroman-6-yl)-2-oxo-1-(3,4,5-trimethoxy-phenyl)-ethyl ester (21.6 mg, 0.04 mmol) in anhydrous ACN (0.5 mL) is added KF (4.72 mg, 0.08 mmol) and Kryptofix (30.6 mg, 0.08 mmol). After completion of addition the reaction mixture is heated to 90° C. After 15 minutes, the reaction mixture is cooled down to room temperature and diluted with water. The aqueous layer is separated and extracted with ethyl acetate (3×). All combined organic layers are dried over Na2SO4, filtered, and concentrated to yield an oil. The crude material is purified using reverse phase to yield the desired compound.
Reaction SMILES: [C:1]1([CH3:26])[CH:6]=[CH:5][C:4]([C@H:7]([O:9][C:10](=[O:25])[NH:11][C:12]2[C:13]([CH3:24])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[CH3:8])=[CH:3][CH:2]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH3:24])[C:12]=4[NH:11][C:10]([O:9][C@@H:7]([C:4]4[CH:5]=[CH:6][C:1]([CH3:26])=[CH:2][CH:3]=4)[CH3:8])=[O:25])=[CH:18][CH:19]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1ccc([C@@H](C)OC(=O)Nc2c(C)noc2-c2ccc(Br)cc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)O[C@H](C)c4ccc(C)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 6, Step 3 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-p-tolyl-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](O)=[CH:4][CH:3]=1.[Cl:9][CH:10](C)[CH2:11]OS(C1C=CC(C)=CC=1)(=O)=O.[C:24]([O-:27])([O-])=O.[Cs+].[Cs+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:27][CH2:24][CH2:11][CH2:10][Cl:9])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)OCC(C)Cl)cc1
Reactant: Oc1ccc(Br)cc1
Agent: [Cs+]
Product: ClCCCOc1ccc(Br)cc1

Procedure:
4-Bromophenol was reacted with 2-chloropropyl-p-toluenesulfonate and Cs2CO3 to give 1-bromo-4-(3-chloropropoxy)benzene.
Reaction SMILES: Br[C:2]1[N:27]=[CH:26][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=5[Cl:25])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:28][NH:29][CH3:30]>>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:26]=[N:27][C:2]([N:29]([CH3:30])[CH3:28])=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1
Reactant: CNC
Reactant: Clc1ccccc1-n1ncnc1-c1cn2c(n1)-c1cnc(Br)cc1OCC2
Product: CN(C)c1cc2c(cn1)-c1nc(-c3ncnn3-c3ccccc3Cl)cn1CCO2

Procedure:
Following the procedures of Examples 413 and 420, 9-bromo-2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine and dimethylamine were reacted to give 422. LC/MS (ESI+): m/z 408.1 (M+H)
Reaction SMILES: I[C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1.CCCCCC.C([Li])CCC.[CH3:35][C:36]1[N:41]=[C:40]([CH:42]=[O:43])[CH:39]=[CH:38][CH:37]=1.O>O1CCCC1>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH3:22])[N:12]=[CH:11][CH:10]=[C:9]2[O:8][C:7]1[C:2]([CH:42]([C:40]2[CH:39]=[CH:38][CH:37]=[C:36]([CH3:35])[N:41]=2)[OH:43])=[N:3][C:4]([CH3:23])=[CH:5][CH:6]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: Cc1cccc(C=O)n1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(C)nc3C(O)c3cccc(C)n3)c2cc1OC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 73.8 %

Procedure:
4-(2-Iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxyquinoline (compound 116) (100 mg) was dissolved in tetrahydrofuran (7 ml) to prepare a solution which was then brought to −78° C. n-Butyllithium hexane solution (0.22 ml) was slowly added dropwise thereto, and the mixture was stirred at −78° C. for 20 min. 6-Methyl-2-pyridine-carbaldehyde (57 mg) was dissolved in tetrahydrofuran (7 ml) to prepare a solution which was then added dropwise to the reaction solution, followed by stirring at room temperature for 5 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give [3-(6,7-dimethoxy-quinolin-4-yloxy)-6-methyl-pyridin-2-yl]-(6-methyl-pyridin-2-yl)-methanol (73 mg, yield 73%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:11]1[C:24]2[C:23]3([CH2:26][N:27]4[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]4)[CH2:25][CH:16]([C:17]4[C:22]3=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:15]=2[CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:21]1[C:22]2[C:23]3([CH2:26][N:27]4[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]4)[CH2:25][CH:16]([C:15]4[C:24]3=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: OC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a cooled solution (-78° C.) of oxalyl chloride (3.06 mL, 35.1 mmol, 2 eq) in methylene chloride (100 mL) under nitrogen was added distilled dimethylsulfoxide (5.00 mL, 70.2 mmol, 4 eq). After 10 min 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl) piperidin-4-ol (described above) (17.5 mmol) was added as a methylene chloride solution (10 mL). The reaction was stirred at -78° C. for 30 min prior to the addition of triethylamine (19.6 mL, 140 mmol, 8 eq). The cooling bath was removed and the reaction warmed to room temperature over 1.5 h. The reaction mixture was poured into 2.5N NaOH (100 mL) and the aqueous phase extracted with methylene chloride (3×100 mL). Combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and reduced to an oil. The crude reaction mixture was purified by flash chromatography over silica gel (400 mL, eluent:20% ethyl acetate in hexane) to yield the title compound in 80% yield as a white solid. TLC analysis (Rf 0.31, 2% methanol in methylene chloride). MS (Cl, CH4) m/z 304 (M+1,100), 332 (M+29,21)