Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][OH:12])[CH:6]=[C:7]([CH2:9][OH:10])[CH:8]=1.C(N(CC)CC)C.[CH3:20][C:21]1([CH3:24])[CH2:23][S:22]1>CO>[SH:22][C:21]([CH3:24])([CH3:23])[CH2:20][S:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][OH:12])[CH:6]=[C:7]([CH2:9][OH:10])[CH:8]=1
Reactant: OCc1cc(CO)cc(CS)c1
Reactant: CC1(C)CS1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(S)CSCc1cc(CO)cc(CO)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.2 %

Procedure:
(5-(mercaptomethyl)-1,3-phenylene)dimethanol (0.163 g, 0.885 mmol) was dissolved in methanol (3 mL) in a small vial and a stir bar was added. To this solution was added triethylamine (0.016 mL, 0.118 mmol) followed by 2,2-dimethylthiirane (0.058 mL, 0.590 mmol) and the resulting mixture was capped and stirred overnight (16 hrs) at room temperature. The reaction was then concentrated, redissolved in dichloromethane, loaded onto a silica ptlc plate (1000 micron) and the plate was developed using 10% methanol in dichloromethane. The band corresponding to the product was scraped, filtered with neat ethyl acetate, and concentrated to give (5-((2-mercapto-2-methylpropylthio)methyl)-1,3-phenylene)dimethanol (0.095 g, 0.349 mmol, 59.1% yield). 1H NMR (400 Hz, CDCl3): δ 7.26 (s, 3H), 4.69 (s, 4H), 3.82 (s, 2H), 2.74 (s, 2H), 2.17 (s, 1H), 2.12 (br s, 2H), 1.43 (s, 6H); 13C NMR (400 Hz, CDCl3): δ 141.6, 138.9, 126.7, 124.3, 65.0, 49.0, 45.4, 38.4, 31.5; MS (m/z), expected: 272.4. found 295.0 (M+Na). See FIG. 30.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH:5]([OH:9])[CH:6]([CH3:8])[CH3:7])[CH2:3][OH:4].[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22])([O:13][CH3:14])=[O:12]>N1C=CC=CC=1>[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([O:4][CH2:3][C:2]([CH3:10])([CH3:1])[CH:5]([O:9][S:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:11]([O:13][CH3:14])=[O:12])(=[O:23])=[O:22])[CH:6]([CH3:8])[CH3:7])(=[O:23])=[O:22])([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)C(O)C(C)(C)CO
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1S(=O)(=O)OCC(C)(C)C(OS(=O)(=O)c1ccccc1C(=O)OC)C(C)C
Temperature: 0 °C

Procedure:
Into a one-liter, four-necked, round bottom flask equipped with stirrer, condenser, thermometer and addition funnel, 36.5 parts of 2,2,4-trimethyl-1,3-pentanediol and 632.0 parts of pyridine were mixed under a nitrogen blanket and cooled to 0° C. using an ice water bath. Subsequently, 117.3 parts of o-carbomethoxybenzenesulfonyl chloride were added in small portions over a two hour period while maintaining the temperature below 10° C. The aforesaid mixture was maintained at a temperature between 0° C. and 10° C. for a two hour period and then refrigerated at 15° C. for at least twenty-four hours prior to work-up. For work-up the reaction mixture was poured into 1000 parts of ice water and subsequently extracted with 500 parts of methylene chloride. The organic layer was washed successively with cold, dilute 6N sulfuric acid (twice with 500 part-portions), cold, dilute sodium bicarbonate (once with 500 parts), and water (until the water layer was neutral to pH paper). It was then dried over sodium sulfate, filtered, and the solvent removed in vacuo to yield the 2,2,4-trimethyl-1,3-pentanediyl bis-(ortho-carbomethoxybenzenesulfonate).
Reaction SMILES: [C:1]([C:5]1[N:14]=[CH:13][C:12]2[CH2:11][CH2:10][C:9]3[N:15]=[C:16]([NH2:18])[S:17][C:8]=3[C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:19]1[N:23]=[CH:22][N:21]([C:24](N2C=NC=C2)=[O:25])[CH:20]=1.C(Cl)Cl>CN(C=O)C>[C:1]([C:5]1[N:14]=[CH:13][C:12]2[CH2:11][CH2:10][C:9]3[N:15]=[C:16]([NH:18][C:24]([N:21]4[CH:20]=[CH:19][N:23]=[CH:22]4)=[O:25])[S:17][C:8]=3[C:7]=2[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ncc2c(n1)-c1sc(N)nc1CC2
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)c1ncc2c(n1)-c1sc(NC(=O)n3ccnc3)nc1CC2
Temperature: 4 °C

Procedure:
8-tert-Butyl-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-ylamine (Stage A.1, 0.319 g, 1.225 mmol) and CDI (278 mg, 1.715 mmol) were added to DCM (5 ml) and DMF (0.25 ml) under an argon atm. After 18 h the residue was cooled to 4° C. and the precipitate was collected by filtration. The solid was dried at 50° C. in high vacuo to give the title compound as a pale yellow solid. LCMS: tR 0.95 min and M+H 319.0 (method A2) for (8-tert-butyl-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl)-carbamic acid methyl ester; the product of the reaction of the title compound with MeOH during the preparation of the sample as MeOH solution.
Reaction SMILES: [ClH:1].[C:2]1([CH2:8][CH2:9][C:10]#[N:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][OH:13]>CCOCC>[ClH:1].[CH3:12][O:13][C:10](=[NH:11])[CH2:9][CH2:8][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCCc1ccccc1
Reactant: CO
Agent: Cl
Solvent: CCOCC
Product: COC(=N)CCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Hydrogen chloride is bubbled into a cold (0° C.) solution of 3-phenypropionitrile (5.43 g, 41.4 mmol) in methanol (2.5 mL, 62.1 mmol) for 5 min, and the mixture stirred at rt for 3 h. The solid that formed is suspended in Et2O and filtered to give 7.8 g of the product 242. 1H NMR (CDCl3) δ 12.65 (s, 1 H), 11.65 (s, 1 H), 7.40-7.15 (m, 5 H), 4.24 (s, 3 H), 3.08 (s, 4 H)
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])C.O.[CH3:7][O:8][P:9]([O-:13])([O:11][CH3:12])=[O:10].[CH3:14][NH+:15]1[CH2:19][CH2:18][N:17](C)[CH:16]1Cl>C(O)C>[CH3:7][O:8][P:9]([O-:13])([O:11][CH3:12])=[O:10].[CH3:1][NH+:3]1[CH2:4][CH2:5][N:17]([CH3:18])[CH:16]1[N:15]([CH3:19])[CH3:14]
Reactant: CN1CC[NH+](C)C1Cl
Reactant: CCNCC
Agent: COP(=O)([O-])OC
Solvent: CCO
Solvent: O
Product: CN(C)C1N(C)CC[NH+]1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.9 %

Procedure:
1.14 g (15.59 mmol) of diethylamine and 10 ml of water are added with stirring to 2.0 g (7.73 mmol) of 1,3-dimethyl-2-chloroimidazolidinium dimethylphosphate. The reaction mixture is stirred for 10 minutes at room temperature, and 10 ml of ethanol are subsequently added. The solution is extracted 5 times with 30 ml of dichloromethane. Water is distilled off from the aqueous phase. The residue is dried for 4 hours under a reduced pressure of 7 Pa at an oil-bath temperature of 70-80° C., giving 1.85 g of 1,3-dimethyl-2-dimethylaminoimidazolidinium dimethylphosphate, corresponding to a yield of 81%.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13]([CH3:28])[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16]([Cl:27])[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=[N:39][CH:38]=2)O1>>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13]([CH3:28])[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16]([Cl:27])[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13]([CH3:28])[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16]([C:37]2[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH:40]=[N:39][CH:38]=2)[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2cncc3ccccc23)OC1(C)C
Agent: Cn1c(CN2CCN(C(C)(C)C)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cn1c(CN2CCN(C(C)(C)C)CC2)nc2c(N3CCOCC3)nc(-c3cncc4ccccc34)nc21

Procedure:
4-(8-((4-tert-butylpiperazin-1-yl)methyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine was prepared following General Procedure E of amine SN2 alkylation. Following General Procedure A Suzuki coupling, 4-(8-((4-tert-butylpiperazin-1-yl)methyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline were reacted to give 445. LCMS: M+H+=501.3
Reaction SMILES: [CH2:1]([C:3]1([CH2:7][OH:8])[CH2:6][O:5][CH2:4]1)[CH3:2].C(OC1C(OC(=O)C)=C(I)C=CC=1)(=[O:11])C.CC1(C)N([O])C(C)(C)CCC1.[OH-].[Na+]>C(#N)C.O>[CH2:1]([C:3]1([C:7]([OH:11])=[O:8])[CH2:6][O:5][CH2:4]1)[CH3:2]
Reactant: CC(=O)Oc1cccc(I)c1OC(C)=O
Reactant: CCC1(CO)COC1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CCC1(C(=O)O)COC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.9 %

Procedure:
(3-Ethyloxetan-3-yl)methanol (0.58 g, 5.00 mmol) was dissolved in 10 mL of a 1:1 ACN-water mixture, and bis-acetoxyiodobenzene (BAIB, 3.54 g, 11.0 mmol) was added. The mixture was cooled in an ice bath, and TEMPO (0.156 g, 1.00 mmol) was added under argon flow. The mixture was stirred at room temperature for 1 hr, and then treated with 1 M aqueous sodium hydroxide (20 mL). The solution was washed twice with EtOAc and then acidified to pH 2. The aqueous solution was extract six times with EtOAc and these combined extracts were dried over sodium sulfate and concentrated to afford 0.37 g (57%) of Intermediate 55 as oil, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9](Br)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cu][C:15]#[N:16].CN1CCCC1=O>O>[NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([C:15]#[N:16])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: N#C[Cu]
Reactant: COC(=O)c1cc(Br)cc(C)c1N
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc(C#N)cc(C)c1N
Temperature: 120 °C

Procedure:
Methyl 2-amino-5-bromo-3-methylbenzoate (100 g, 0.393 mol, 96% of quantitative NMR), copper(I) cyanide (36.3 g, 0.401 mol) and N-methyl-2-pyrrolidinone (NMP) (206 g, 200 mL, 2.084 mol) are heated to 170° C. for 4 hours under agitation. The reaction batch is cooled down to 120° C., 350 mL of H2O (90° C.) are added dropwise in the course of 30 minutes and the suspension obtained is filtered. The solid obtained is washed twice with ammonia (200 g, 12% in H2O) and 2 times with 100 ml of water. Following drying in a vacuum drying cabinet at 50° C., methyl 2-amino-5-cyano-3-methylbenzoate is obtained as a grey solid. Yield: 69.0 g, 88.2% of theory, purity: 95.6% quantitative NMR, 1500 ppm Cu).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])=[CH:4][C:3]=1[S:17](Cl)(=[O:19])=[O:18].[CH2:21]([NH2:24])[C:22]#[CH:23]>O1CCCC1>[CH2:21]([NH:24][S:17]([C:3]1[CH:4]=[C:5]([NH:9][S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])[C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])(=[O:19])=[O:18])[C:22]#[CH:23]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)cc1NS(=O)(=O)C(F)(F)F
Reactant: C#CCN
Solvent: C1CCOC1
Product: C#CCNS(=O)(=O)c1cc(NS(=O)(=O)C(F)(F)F)c(C)cc1C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
2,4-Dimethyl-5-(trifluoromethanesulfonamido)benzenesulfonyl chloride (1.5 g) was added to tetrahydrofuran (20 ml) containing propargylamine (0.5 g), and the resultant mixture was allowed to stand overnight at room temperature. Upon completion of the reaction, the mixture was concentrated. A 5% aqueous solution of hydrochloric acid was added to the residue, whereby an oily substance was deposited. The oily substance was extracted with chloroform and washed with a 5% aqueous solution of hydrochloric acid and water in order. The extract was concentrated and recrystallized from toluene to give 1.05 g of N-propargyl-2,4-dimethyl-5-(trifluoromethanesulfonamido)benzenesulfonamide (Compound No. 35). M.P., 130.5°-132° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]34[CH2:21][CH2:20][C:17]([CH2:22][C:23]([O:25][CH3:26])=[O:24])([CH2:18][CH2:19]3)[O:16][CH2:15]4)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C=CC=CC=1.CCOC(C)=O.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]34[CH2:19][CH2:18][C:17]([CH2:22][C:23]([O:25][CH2:26][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[O:24])([CH2:20][CH2:21]3)[O:16][CH2:15]4)=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: OCc1ccccc1
Reactant: COC(=O)CC12CCC(c3ccc(-c4ccc(N)cc4)cc3)(CC1)CO2
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Nc1ccc(-c2ccc(C34CCC(CC(=O)OCc5ccccc5)(CC3)OC4)cc2)cc1
Temperature: 120 °C
Yield: 68.8 %

Procedure:
To a mixture of methyl 2-(4-(4′-amino-[1,1′-biphenyl]-4-yl)-2-oxabicyclo[2.2.2]octan-1-yl)acetate (0.323 g, 0.918 mmol) in toluene (35 ml) was added benzyl alcohol (2.377 ml, 22.95 mmol), titanium(IV) isopropoxide (0.807 ml, 2.75 mmol) and 4 A molecular sieves (5 g, 0.918 mmol). The reaction mixture was heated at 120° C. for 48 hours. The resulting mixture was taken up in EtOAc and filtered. The filtrate was subsequently washed with water, then brine. The organic portion dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (10 to 50% EtOAc/Heptane) to give the title compound after drying (270 mg, yield 68.8% yield). LC/MS, ESI-MS(+) m/z 428.1, RT 1.59 (Condition R).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:11]=1[C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:28][C:27]([Si:24]([CH3:26])([CH3:25])[O:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])=[C:11]([C:18](=[O:23])[C:19]([CH3:20])([CH3:22])[CH3:21])[CH:12]=1)([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2C(=O)C(C)(C)C)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(F)c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2C(=O)C(C)(C)C)c1
Reaction time: 16 h
Yield: 100.6 %

Procedure:
To a stirred solution of 66.13F (1.00 g, 3 mmol) in DCM (10.00 mL) at 23° C. was added tert-butyldimethylsilyl chloride (0.6 mL, 4 mmol), followed by TEA (0.5 mL, 4 mmol) and DMAP (0.04 g, 0.3 mmol). The reaction was stirred for 16 hours and then the reaction was concentrated in vacuo. The product was purified on silica gel (0-10% EtOAc in hexanes) to yield 66.30A as a colorless oil (1.30 g, 96% yield).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]#[N:13].[H-].[Na+].Br[CH2:17][CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1>C1COCC1.ClCCl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([CH2:17][CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)[C:12]#[N:13]
Reactant: N#CCc1ccc2ccccc2c1
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#CC(CCOC1CCCCO1)c1ccc2ccccc2c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 33.5 %

Procedure:
2-Napthylacetonitrile (3.3442 g, 20 mmol) in THF (50 mL) was added to sodium hydride (0.528 g, 22 mmol, 1.1 eq.) in THF (50 mL) at -78° C. under nitrogen. The slurry was allowed to warm to 20° C. and stir for 2 hours. The slurry was cooled to 0° C. and 2-(2-bromo-ethoxy)-tetrahydro-pyran (4.1786 g, 20 mmol, 1 eq.) was added. The solution was allowed to stir at 20° C. for 16 hours and then diluted with dichloromethane and washed with water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel with a gradient from 5% ethyl acetate in hexane to ethyl acetate to give 1.9774 g (66%) of the title compound. 12.2 Synthesis of 3-cyano-3-naphthalen-2-yl-5-(tetrahydro-pyran-2-yloxy)-pentanoic acid ethyl ester (003F143).
Reaction SMILES: [CH2:1]([N:3]([C:27](=O)[C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C@@H:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([O:20]C(=O)C(C)(C)C)[CH:14]=[CH:13][C:12]=2[CH2:11]1)[CH3:2].Cl[CH2:37][C:38]([N:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1)=O>>[CH2:1]([N:3]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:37][CH2:38][N:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:30][CH:29]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C@@H:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13][C:12]=2[CH2:11]1)[CH3:2]
Reactant: O=C(CCl)N1CCCC1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1ccccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN2CCCC2)cc1)c1ccccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 47.3 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]phenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (18 mg) and 2-chloro-1-pyrrolidin-1-ylethanone (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.5 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[C:9]1(=[O:13])[O:12][CH2:11][CH2:10]1.[H-].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:11][CH2:10][C:9]([OH:13])=[O:12])=[CH:4][CH:3]=1
Reactant: O=C1CCO1
Reactant: Fc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CCSc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
p-Fluorothiophenol (5 g, 40 mmol) and β-propiolactone (2.8 g, 40 mmol) were dissolved in THF (36 mL of freshly distilled) and then placed in an ice bath. 95% sodium hydride (1 g, 42.9 mmol) was added in small portions over 1 hour. The reaction was allowed to stir at 0° C. for 2 hours, then placed in the freezer overnight. The reaction was quenched with ice chips and then acidified with concentrated hydrogen chloride until a pH of 2. The product was extracted with ethyl acetate (1×200 mL) and dichloromethane (2×200 mL), dried (sodium sulfate) and concentrated to give 3-[(4-fluorophenyl)sulfanyl]propanoic acid (7.08 g, 89%). 1H NMR (CDCl3, 300 MHz): δ 7.42-7.35 (m, 2H), 7.02 (t, 2H, J=8.6 Hz), 4.35 (t, 1H, J=6.2 Hz), 3.10 (t, 2H, J=7.3 MHz), 2.63 (t, 2H, J=7.3 Hz) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH2:10][OH:11])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:13][C:14]([C@H:17]1[CH2:21][CH2:20][NH:19][C@H:18]1[CH3:22])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Li+].[Li+].O>CS(C)=O>[Cl:1][C:2]1[C:9]([CH2:10][OH:11])=[C:8]([N:19]2[CH2:20][CH2:21][C@H:17]([C:14]([OH:13])([CH3:16])[CH3:15])[C@@H:18]2[CH3:22])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Reactant: N#Cc1ccc(F)c(CO)c1Cl
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@H]1[C@@H](C(C)(C)O)CCN1c1ccc(C#N)c(Cl)c1CO
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 34.1 %

Procedure:
To a solution (2 mL) of 2-chloro-4-fluoro-3-(hydroxymethyl)benzonitrile (150 mg) in dimethyl sulfoxide were added (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (167 mg) and lithium carbonate (66 mg), and the mixture was stirred at 140° C. for 10 min in a microwave reaction apparatus. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=9:1→1:1) and recrystallized from ethyl acetate-isopropyl ether to give the compound as a pale-yellow solid (yield: 85 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH:3]=1.[CH:18]1([C:21](=O)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:20][CH2:19]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CCO>[CH2:26]([O:25][C:23]([C:22]1[C:21]([CH:18]2[CH2:20][CH2:19]2)=[N:8][C:5]2[C:4]([C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:24])[CH3:27]
Reactant: CCOC(=O)CC(=O)C1CC1
Reactant: Nc1ccc(Cl)cc1C#Cc1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(C2CC2)nc2ccc(Cl)cc2c1Cc1ccccc1Cl
Yield: 21.7 %

Procedure:
To a solution of 4-chloro-2-(2-chloro-phenylethynyl)-phenylamine (100 mg, 0.38 mmol, 1 eq) and ethyl 3-cyclopropyl-3-oxopropanoate (89.4 mg, 0.57 mmol, 1.5 eq) in anhydrous EtOH (5 ml), was added p-TsOH.H2O (72.6 mg, 0.38 mmol, 1 eq) and the mixture was refluxed for 16 h. After cooling, the reaction mixture was concentrated in vacuo and then diluted with ethyl acetate. The mixture was washed with saturated sodium bicarbonate solution, brine, dried over sodium sulfate and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (elution with 3% ethyl acetate in hexane) to give 6-chloro-4-(2-chloro-benzyl)-2-cyclopropyl-quinoline-3-carboxylic acid ethyl ester (33 mg, 22%) as a pale yellow solid. MS (ESI): 400.0 (M+H)+.
Reaction SMILES: Br.Br[CH:3]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[C:4]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)=O.C(N(CC)CC)C.[NH2:24][C:25]([NH2:27])=[S:26].C(=O)([O-])O.[Na+]>C(O)C>[NH2:27][C:25]1[S:26][C:3]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[C:4]([C:6]2[O:7][CH:8]=[CH:9][CH:10]=2)[N:24]=1
Reactant: NC(N)=S
Reactant: O=C(c1ccco1)C(Br)c1ccncc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1nc(-c2ccco2)c(-c2ccncc2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Bromo-1-(2-furyl)-2-(4-pyridyl)ethanone hydrobromide (7.59 g, 21.9 mmol) was suspended in ethanol (110 mL), and triethylamine (3.35 mL, 24.1 mmol) was added thereto, followed by stirring at room temperature for 30 minutes. Thiourea (1.83 g, 24.1 mmol) was added to the reaction mixture, followed by stirring under heating and reflux for 30 minutes. The reaction mixture was allowed to cool down to room temperature, and then a saturated aqueous solution of sodium hydrogencarbonate was added thereto, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=10:1) to afford the entitled Compound a (5.10 g, 96%) as pale yellow crystals.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7](=[O:28])[CH2:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:4]([C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]([NH:38][CH2:39][C@H:40]2[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]2)=[O:37])=[O:30])[CH2:3]1.[CH3:46][CH:47]([CH2:50][CH3:51])[CH:48]=O>>[OH:1][C@H:2]1[CH2:6][N:5]([C:7](=[O:28])[CH2:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:4]([C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]([NH:38][CH2:39][C@H:40]2[CH2:45][CH2:44][CH2:43][N:42]([CH2:46][CH:47]([CH3:48])[CH2:50][CH3:51])[CH2:41]2)=[O:37])=[O:30])[CH2:3]1
Reactant: CCC(C)C=O
Reactant: O=C(NC[C@H]1CCCNC1)[C@H]1CCCN1C(=O)[C@@H]1C[C@@H](O)CN1C(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCC(C)CN1CCC[C@H](CNC(=O)[C@H]2CCCN2C(=O)[C@@H]2C[C@@H](O)CN2C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1

Procedure:
The title compound was prepared by a method similar to Step 3 of Example 17, using (2R)-1-{(2S,4R)-4-hydroxy-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonyl-N-((3S)-3piperidylmethyl)pyrrolidine-2-carboxamide and 2-methylbutanal. The compound was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([NH2:24])[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.C([BH3-])#N.[Na+]>C1COCC1.C(O)(=O)C>[CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([NH:24][CH2:31][C:30]3[CH:33]=[CH:34][C:27]([F:26])=[CH:28][CH:29]=3)[CH:17]=2)[CH2:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13]1)=[O:4]
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(N)c2)Cc2ccccc2C1
Reactant: O=Cc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(NCc3ccc(F)cc3)c2)Cc2ccccc2C1
Temperature: 25 °C
Yield: 80 %

Procedure:
The compound of example 117, step 2 (0.042 g, 0.12 mmol) and 4-fluorobenzaldehyde (0.0115 g, 0.092 mmol) were dissolved in THF (3 ml) and acetic acid (0.5 ml). Resin-bound sodium cyanoborohydride (0.2 mmol) was added, and the mixture was stirred at room temperature until LC/MS analysis showed complete conversion. The resin was filtered off, the filtrate was subjected to preparative RP HPLC (water/ACN gradient), and the fractions containing the title compound freeze-dried to give 33 mg of the title compound.