Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:3][C:4]([CH3:20])([CH3:19])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)=O.COCCO[AlH2-]OCCOC.[Na+].O.[ClH:34]>C1C=CC=CC=1.CCOCC>[ClH:34].[CH3:1][NH:3][C:4]([CH3:20])([CH3:19])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(NC=O)c1ccc(C#Cc2ccccc2)cc1
Agent: COCCO[AlH2-]OCCOC
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: c1ccccc1
Product: CNC(C)(C)c1ccc(C#Cc2ccccc2)cc1

Procedure:
A solution of 2.92 grams of N-formyl-α,α-dimethyl-4-(phenylethynyl)-benzylamine in 30 ml. of benzene is placed in a dry flask. The solution is stirred. A solution of 6.6 grams of a 70% "Red-Al" solution in benzene is diluted with 30 ml. of benzene; this solution is added dropwise over approximately 30 minutes to the solution of N-formyl-α,α-dimethyl-4-(phenylethynyl)-benzylamine. The reaction is hydrolyzed with water and is extracted thoroughly with a 1:1 benzene-ether solvent mixture. The combined extracts are dried over magnesium sulfate, filtered, and the solvent is evaporated to give 3.34 gm. of an oil. This oil is dissolved in ether and treated with ethanolic hydrogen chloride. The precipitate is collected and recrystallized from isopropanol to give N,α,α-trimethyl-4-(phenylethynyl)-benzylamine hydrochloride, m.p. 266°-268° C.
Reaction SMILES: FC(F)(F)C(O)=O.[I:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([NH:18]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[I:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2([NH2:18])[CH2:16][CH2:17]2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(I)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1(c2ccc(I)cc2)CC1
Reaction time: 24 h

Procedure:
3 mL (38.76 mmol) of trifluoroacetic acid are added to a solution of 1 g (2.78 mmol) of tert-butyl [1-(4-iodophenyl)cyclopropyl]carbamate in 40 mL dichloromethane and stirred for 24 h. Then the solvent is eliminated by rotary evaporation and the residue is combined with toluene and then again eliminated by rotary evaporation. This residue is then added to a solution of 0.39 g (2.8 mmol) of potassium carbonate in 20 mL of water and stirred for 30 minutes at RT. The aqueous phase is extracted with dichloromethane, the organic phase is dried with sodium sulfate and the solvent is eliminated by rotary evaporation. Yield: 0.7 g (97% of theory); C9H10IN (M=259.09); calc.: molecular ion peak (M+H)+: 260; found: molecular ion peak (M+H)+: 260.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH:18]=[O:19])=[CH:15][CH:16]=3)[N:11]=[C:10]([C:20]([NH2:22])=[O:21])[CH:9]=2)=[CH:4][CH:3]=1.CC(=CC)C.Cl([O-])=[O:29].[Na+].O.P([O-])(O)(O)=O.[Na+]>CC(O)(C)C.O>[NH2:22][C:20]([C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:17]2[C:12](=[CH:13][C:14]([C:18]([OH:29])=[O:19])=[CH:15][CH:16]=2)[N:11]=1)=[O:21]
Reactant: [O-][Cl+][O-]
Reactant: NC(=O)c1cc(-c2ccc(F)cc2)c2ccc(C=O)cc2n1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: NC(=O)c1cc(-c2ccc(F)cc2)c2ccc(C(=O)O)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a solution of 4-(4-fluorophenyl)-7-formylquinoline-2-carboxamide (5-2, 200.0 mg, 0.680 mmol, 1.0 equiv.) and 2-methyl-2-butene (3.96 mL, 37.4 mmol, 55 equiv.) in t-BuOH (14.0 mL, 0.05 M) was added a solution of sodium chlorite (553.0 mg, 6.12 mmol, 9 equiv.) and sodium dihydrogen phosphate monohydrate (559.0 mg, 4.08 mmol, 6 equiv.) in water (6.5 mL). The resulting mixture was stirred at room temperature for 1 hour. A white solid precipitated. Water (100.0 ml) was added and the mixture stirred for 30 minutes. The solid was collected via suction filtration, washed with water, dried in vacuo to give 2-(aminocarbonyl)-4-(4-fluorophenyl)quinoline-7-carboxylic acid (5-3, 150.0 mg, 71.1%) as a white solid. LRMS m/z (M+H)+ 311.1 found, 311.1 required.
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([O:22][CH3:23])[CH2:20][Br:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:24][N:25]([CH3:27])[CH3:26]>CC#N>[Br-:21].[CH2:1]([S:17][CH2:18][CH:19]([O:22][CH3:23])[CH2:20][N+:25]([CH3:27])([CH3:26])[CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CN(C)C
Reactant: CCCCCCCCCCCCCCCCSCC(CBr)OC
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCSCC(C[N+](C)(C)C)OC
Product: [Br-]
Temperature: 25 °C
Yield: 92 %

Procedure:
To a 100 milliliter heavy wall glass tube equipped with a magnetic stir bar, was added a solution of 2.0 grams (0.005 mole) of (±)-1-hexadecylthio-2-methoxy-3-bromopropane dissolved in 50 milliliters of CH3CN and the vessel was cooled to -10° Centigrade. An excess of condensed trimethylamine was added, the tube was sealed, and the vessel was heated to 60° Centigrade for 24 hours. The reaction mixture was then cooled to room temperature, resulting in a precipitate which was filtered. The precipitate was swirled with five 50 milliliter portions of ether, the ether decanted off, and dried under vacuum, resulting in 2.1 grams (92%) of pure product, (mp 197°-199° Centigrade). 1H-NMR (CDCl3): delta, 0.87(t, 3H, terminal methyl), 1.2-1.6[m, 28H, (CH2)14 ], 2.45-3.0(m, 4H, CH2S--CH2), 3.48[s, 12H, CH3 --O, N(CH3)3 ], 3.5-4.0(m, 3H, CH--CH2N). Anal. (C23H50NOSBr) C,H,N.
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[C:43]([CH3:44])=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][C:35]=5[CH3:45])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22](SC)[N:21]=3)[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.[S:52]([O-:57])(O[O-])(=O)=[O:53].[K+].[K+].[C:60](#N)C>>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[C:35]([CH3:45])=[CH:36][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:42][C:43]=5[CH3:44])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([S:52]([CH3:60])(=[O:57])=[O:53])[N:21]=3)[C@H:14]2[CH3:48])[CH:4]=[C:3]([C:2]([F:1])([F:50])[F:49])[CH:8]=1
Reactant: O=S(=O)([O-])O[O-]
Reactant: COC(=O)c1cc(C)c(-c2cnc(OC)c(-c3cnc(SC)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Reactant: CC#N
Agent: [K+]
Solvent: O
Product: COC(=O)c1cc(C)c(-c2cnc(OC)c(-c3cnc(S(C)(=O)=O)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Reaction time: 16 h

Procedure:
Methyl 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylthio)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3,5-dimethylbenzoate (INTERMEDIATE 43, 1.05 g, 1.457 mmol) was dissolved in acetonitrile (10.2 mL). Water (4.4 mL) was added, followed by potassium peroxymonosulfate (2.24 g, 3.64 mmol). The reaction was allowed to stir 16 hours, after which it was partitioned between ethyl acetate and brine. The organic was washed a second time with brine, dried over sodium sulfate, filtered and evaporated to give the title compound, which can be used without further purification. 1H NMR (CDCl3, 500 MHz): δ 8.75 (s, 1H), 8.16 (d, 1H), 7.89 (s, 1H), 7.83 (s, 2H), 7.77 (s, 2H), 7.42 (d, 1H), 5.88 (d, 1H), 4.92 (d, 1H), 4.62 (br, 1H), 4.25 (d, 1H), 4.04 (s, 3H), 3.94 (s, 3H), 3.41 (s, 3H), 2.17 (d, 6H), 0.81 (d, 3H).
Reaction SMILES: C[C:2]1[C:6](C)=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)O[N:3]=1.[C:17]1([C:23]2[N:27]=[C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:25][N:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH:34]([N:37](C(C)C)CC)(C)[CH3:35].O>CS(C)=O>[CH2:34]([N:37]1[C:5]([NH:8][C:9]([N:31]2[CH2:32][CH2:33][N:28]([C:26]3[S:25][N:24]=[C:23]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:27]=3)[CH2:29][CH2:30]2)=[O:16])=[CH:6][CH:2]=[N:3]1)[CH3:35]
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Solvent: CS(C)=O
Solvent: O
Product: CCn1nccc1NC(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 70 °C
Reaction time: 5 h
Yield: 36.9 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (256 mg, 0.893 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 g) and diisopropylethylamine (0.156 ml, 0.893 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 5 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 115 mg (36.8%) of the desired product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9]([NH:12]CC1C=CC(OC)=CC=1OC)(=[O:11])=[O:10].C[Li].[CH3:26][C:27]([CH3:29])=[O:28].FC(F)(F)C(O)=O>C1COCC1.C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([S:9]([NH2:12])(=[O:10])=[O:11])[C:27]([OH:28])([CH3:29])[CH3:26]
Reactant: COc1ccc(CNS(=O)(=O)Cc2ccccc2Cl)c(OC)c1
Reactant: CC(C)=O
Agent: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)C(c1ccccc1Cl)S(N)(=O)=O
Reaction time: 0.17 h

Procedure:
Under inert gas, 1.51 g of C-(2-chlorophenyl)-N-(2,4-dimethoxybenzyl)methanesulfonamide were initially charged in 30 ml of THF, and then, at a temperature of −78° C., 6.09 ml of a 1.6 N methyllithium solution in diethyl ether were added dropwise and the mixture was stirred at constant temperature for 10 minutes. Subsequently, 1.83 ml of acetone were added. After stirring for 10 minutes, the reaction solution was admixed with 2 ml of trifluoroacetic acid and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with saturated aqueous sodium hydrogencarbonate solution and water, dried over MgSO4 and concentrated by rotary evaporation. The residue was dissolved in 20 ml of dichloromethane, and 3 ml of trifluoroacetic acid were added. After stirring at room temperature for 2 hours, the reaction solution was concentrated by rotary evaporation and the residue was taken up in a mixture of water and dichloromethane. The solid which precipitates out was analyzed by LCMS and 1H NMR and subsequently discarded, since no product was present. Another solid precipitated out of the filtrate, which was identified by LCMS as product-containing (512 mg). Since further product was present in both phases of the filtrate, the aqueous phase was extracted with dichloromethane, the combined organic phases were concentrated by rotary evaporation and the residue was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation (707 mg). This gave the product with a molecular weight of 263.7 g/mol (C10H14ClNO3S); MS (ESI): m/e=283 (M+H2O+H+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH2:7][CH2:8][OH:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C1COCC1>[CH3:17][S:18]([O:9][CH2:8][CH2:7][C:6]1[S:5][CH:4]=[N:3][C:2]=1[CH3:1])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ncsc1CCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ncsc1CCOS(C)(=O)=O

Procedure:
The 4-methyl-5-thiazole ethanol (Aldrich, 0.18 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClC1C=C(N=C=S)C=C(Cl)C=1C#N.O=[C:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1.C(O)(=O)C>CO>[C:39]([O:38][C:36]([N:33]1[CH2:34][CH2:35][CH:30]([NH:15][C:13]2[NH:12][N:11]=[C:10]([NH:9][C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:14]=2)[CH2:31][CH2:32]1)=[O:37])([CH3:42])([CH3:40])[CH3:41]
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: N#Cc1c(Cl)cc(N=C=S)cc1Cl
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
To a stirred solution of N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (122 mg, 0.5 mmol) in 10 ml of methanol, tert-butyl 4-oxopiperidine-1-carboxylate (102 mg, 0.512 mmol), was added acetic acid (0.05 mL). The mixture was stirred at rt for 15 min, after which picolineborane (112 mg, 1.047 mmol) was added. The mixture was stirred at rt overnight. LCMS indicated 87% product and 13% SM. Additional picolineborane (50 mg, 0.467 mmol) was added and the mixture was stirred for an additional 24 hours. The solvent was removed under reduced pressure and the residue was dissolved in methylene chloride and treated with saturated sodium bicarbonate to pH=9. The organic layer was separated and the aqueous layer was extracted with methylene chloride (3×10 mL). The solvent was reduced to about 4 mL and the residue was loaded onto a silica gel column. Eluting with 5% methanol/methylene chloride gave 188 mg (88%) of desired product as white solid. MS +m/z: 427.0 (M+H)+
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][S:9][C:10]2[S:14][C:13]([S:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])=[N:12][N:11]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].[OH-].[Na+].C(OCC)(=O)C.Cl>CO>[C:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][S:9][C:10]2[S:14][C:13]([S:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[N:12][N:11]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2]
Reactant: CCCc1c(CSc2nnc(SCCCCC(=O)OCC)s2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCc1c(CSc2nnc(SCCCCC(=O)O)s2)ccc(C(C)=O)c1O
Temperature: 60 °C
Yield: 95.7 %

Procedure:
In 2 ml of 90% methanol was dissolved 0.20 g of ethyl 5-[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]thio]valerate obtained in Example 9 with heating at 60° C. Further 1.5 ml of a 1N aqueous sodium hydroxide solution was added to the solution followed by stirring at 60° C. for 30 minutes An aqueous sodium hydroxide solution and ethyl acetate were added to the reaction solution to fractionate. The aqueous phase was made acidic with 2N hydrochloric acid and extracted with ethyl acetate The extract was washed with, in sequence, water, a saturated aqueous sodium chloride solution and then water and, dried over anhydrous magnesium sulfate. The solvent was then distilled off to give 0.18 g of oily 5-[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol- 2-yl]thio]valeric acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[C:12]([CH3:25])=[N:13][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)[C:15]=3[CH3:16])=[CH:9][N:8]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=1.[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41](B2OC(C)(C)C(C)(C)O2)=[CH:40][C:39]=1[NH:53][S:54]([CH3:57])(=[O:56])=[O:55].C(=O)([O-])[O-].[Na+].[Na+]>>[F:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:14]1[C:15]([CH3:16])=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:41]4[CH:42]=[CH:43][C:38]([O:37][CH3:36])=[C:39]([NH:53][S:54]([CH3:57])(=[O:55])=[O:56])[CH:40]=4)[CH:3]=3)[N:8]([S:26]([C:29]3[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=3)(=[O:27])=[O:28])[CH:9]=2)[C:12]([CH3:25])=[N:13]1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(Br)cnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cccc(F)c4)c2C)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Yield: 95.8 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (300 mg, 0.542 mmol) was coupled with N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methane sulfonamide (intermediate-17) (212 mg, 0.650 mmol) in sodium carbonate (172 mg, 1.62 mmol), 1,2-methoxyethane (15 mL). This afforded 350 mg of the crude titled compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH2:10])=[CH:5][CH:4]=1.[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K]>CN(C=O)C.O>[CH:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:15]2[C:11](=[O:21])[C:12]3[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:14]2=[O:16])=[CH:4][CH:5]=1)=[CH2:10]
Reactant: C=Cc1ccc(CCl)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 70 °C
Yield: 46 %

Procedure:
To a stirred solution of 1-(chloromethyl)-4-vinylbenzene (10 g, 66 mmol) in DMF (100 mL) was added potassium phthalimide (13.3 g, 72.1 mmol), and the resultant reaction mixture was heated at 70° C. for 16 h. The reaction mixture was diluted with H2O and extracted with CHCl3. The combined CHCl3 layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Recrystallization from MeOH afforded the title compound as an off-white solid (8 g, 46%): 1H NMR (400 MHz, CDCl3) δ 7.83 (m, 2H), 7.71 (m, 2H), 7.39 (m, 4H), 6.65 (dd, J=17.6, 10.8 Hz, 1H), 5.72 (d, J=17.6 Hz, 1H), 5.21 (d, J=10.8 Hz, 1H), 4.82 (s, 2H); GCMS m/z 263.2 ([M]+); IR (thin film) 3420, 1133, 718 cm−1.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:11]1([S:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)=O.CC(C)=O.[F:32][C:33]([F:46])([F:45])[S:34]([O:37]S(C(F)(F)F)(=O)=O)(=[O:36])=[O:35]>>[F:32][C:33]([F:46])([F:45])[S:34]([O-:37])(=[O:36])=[O:35].[C:19]1([S+:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:6][CH:7]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COCOc1ccccc1
Reactant: O=S(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C=O
Solvent: CC(C)=O
Product: COCOc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 0 °C
Yield: 58.5 %

Procedure:
About 100 g of the methoxymethoxybenzene manufactured in the synthesis example 1 and about 133.1 g of phenyl sulfoxide were mixed and stirred in about 1,200 ml of an MC, and then a temperature was reduced to about −78° C. using a dry ice-aceton. Next, about 240 g of trifluoromethanesulfonic anhydride was gradually dropped and stirred for about three hours using a dropping funnel at about −78° C. to perform a synthesis reaction (See Equation 2 below). Next, the synthesis reaction was terminated when an initiator on a thin layer chromatography (TLC) disappeared. Next, about 200 g of calcium carbonate was dissolved in about 1.5 L of water, and the reaction mixed liquid was added in a solvent cooled to about 0° C. and strongly stirred for about 20 minutes. Next, an organic phase was extracted, and further stirred in a calcium carbonate aqueous solution. Next, the extracted organic phase was washed using brine, and dried using magnesium sulphate. Next, the organic was filtered and concentrated to obtain about 200 g (a yield: about 58.5%) of a diphenyl-4-methoxymethoxyphenylsulfonium trifluoromethanesulfonate salt, and a structure of the diphenyl-4-methoxymethoxyphenylsulfonium trifluoromethanesulfonate salt was observed by 1H-NMR (See FIG. 2):
Reaction SMILES: Br[C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:12])[CH:3]=1.C([Li])CCC.[CH3:18][N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1.[Cl-].[NH4+]>O1CCCC1.CCCCCC.O>[F:12][C:4]1[CH:3]=[C:2]([C:22]2([OH:25])[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)[C:10]([F:11])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1cc(F)c(Br)cc1F
Reactant: CN1CCC(=O)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC(O)(c2cc(F)c(C(=O)O)cc2F)CC1
Temperature: -30 °C
Reaction time: 0.33 h

Procedure:
A solution of 1.19 g (5 mmoles) of 4-bromo-2,5-difluorobenzoic acid in 20 ml of tetrahydrofuran at -75° C. was treated with 4.2 ml of 2.4 M n-butyl lithium in hexane. The mixture was stirred 20 minutes, treated with a solution of 0.58 g (5.1 mmoles) of 1-methyl-4-piperidone in 5 ml tetrahydrofuran, stirred a further 1.5 hours, let warm to -30° C., and treated with a solution of 0.55 g (10.3 mmoles) ammonium chloride in 20 ml water. The product, the title compound, crystallized on standing.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[OH:31])[N:15]=2)[CH2:10]1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>C1COCC1>[OH:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:16]1[N:15]=[C:14]([N:11]2[CH2:12][CH2:13][C@@H:9]([NH:8][C:33](=[O:34])[O:35][CH2:36][CH3:37])[CH2:10]2)[C:23]2[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=2)[N:17]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3ccccc3O)nc2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)N[C@@H]1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)C1
Temperature: -55 °C
Yield: 86.3 %

Procedure:
Under an N2 atmosphere at RT, triethylamine (174 μL, 1.25 mmol) was added to a solution of (R)-2-(4-(3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (200 mg, 0.62 mmol) in THF (6.0 mL). After cooling the mixture to −55° C., ethyl chloroformate (59 μL in 600 μL THF, 0.62 mmol) was slowly added, and the reaction was warmed to RT over a period of 30 minutes. The mixture was quenched with H2O and extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-20% EtOAc in a 1:1 mixture of CH2Cl2 and hexanes gave (R′)-ethyl 1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (compound 2) (210 mg, 86%). 1H NMR (400 MHz, DMSO-d6) δ 8.42 (dd, J=7.8, 1.5 Hz, 1H), 8.18 (d, J=8.7 Hz, 1H), 7.59-7.58 (m, 2H), 7.38-7.33 (m, 2H), 6.94-6.90 (m, 2H), 4.27-4.12 (m, 3H), 4.04-3.98 (m, 3H), 3.87-3.86 (m, 1H), 2.50 (s, 3H), 2.26-2.18 (m, 1H), 2.05-1.99 (m, 1H), 1.16 (t, J=7.3 Hz, 3H) ppm. LC/MS: m/z 393.3 (M+H)+ at 2.31 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Br[CH2:36][C:37]([C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1)=[O:38]>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)=[O:38])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(CC(=O)c2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48.1 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, 2-bromo-1-(4-methoxyphenyl)ethanone (0.77 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.68 g, 48%).