Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[C:10](Cl)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1.[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:25]([C:10]1[CH:9]=[CH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:13][C:14]3[S:15][CH:16]=[CH:17][N:18]=3)[C:3]=2[N:11]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Reactant: Oc1ccccc1
Reactant: Nc1nccs1
Product: c1ccc(Oc2ccc3ncnc(Nc4nccs4)c3n2)cc1

Procedure:
The compound of Example 32 was manufactured by the same method as in Example 31, by a similar method thereto or by a combination of such a method with a conventional method using 4,6-dichloro-pyrido[3,2-d]pyrimidine, 2-aminothiazole and phenol.
Reaction SMILES: [CH2:1]([C@H:8]1[NH:23][C:22](=[O:24])[C@@H:21]([CH3:25])[NH:20][C:19](=[O:26])[CH2:18][C@@H:17](/[CH:27]=[CH:28]/[CH2:29][CH2:30][S:31]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:16][C:15](=[O:51])[CH2:14][NH:13][C:12](=[O:52])[C@@H:11]([CH:53]([CH3:55])[CH3:54])[NH:10][C:9]1=[O:56])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([C@H:8]1[NH:23][C:22](=[O:24])[C@@H:21]([CH3:25])[NH:20][C:19](=[O:26])[CH2:18][C@@H:17](/[CH:27]=[CH:28]/[CH2:29][CH2:30][SH:31])[O:16][C:15](=[O:51])[CH2:14][NH:13][C:12](=[O:52])[C@@H:11]([CH:53]([CH3:55])[CH3:54])[NH:10][C:9]1=[O:56])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H]1NC(=O)[C@@H](Cc2ccccc2)NC(=O)[C@@H](C)NC(=O)C[C@@H](/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)OC(=O)CNC1=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H]1NC(=O)[C@@H](Cc2ccccc2)NC(=O)[C@@H](C)NC(=O)C[C@@H](/C=C/CCS)OC(=O)CNC1=O
Reaction time: 0.25 h
Yield: 35.8 %

Procedure:
To a stirred solution of 15 (9 mg, 0.012 mmol) in CH2Cl2 (500 □L) Et3SiH (3.83 μL, 0.024 mmol) and TFA (60 μL) were added. After 15 minutes stirring the solvent was removed in vacuo and the residue was purified by flash column chromatography on silica gel (2-7% MeOH/CH2Cl2) to give thiol 16 (2.3 mg, 0.0043 mmol, 36%) as a white solid: Rf 0.58 MeOH/CH2Cl2 (1:9); LRMS (ES+) m/z 555.4 (100%, [M+Na]+).
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].IC.[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[NH:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([S:26][CH3:27])[N:19]=1.O>CN(C)C=O>[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[N:17]([CH3:1])[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([S:26][CH3:27])[N:19]=1
Reactant: CSc1nc(Nc2ccc(F)cc2F)ccc1C#N
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc(N(C)c2ccc(F)cc2F)ccc1C#N
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.9 %

Procedure:
3.05 mL (5.04 mmol) of potassium 2-methylpropan-2-olate and then 286 μL (1.8 eq) of iodomethane are added dropwise under nitrogen to a solution of 700 mg (2.52 mmol) of 6-(2,4-difluorophenylamino)-2-(methylthio)nicotinonitrile in 20 mL of N,N-dimethyl formamide. The reaction medium is stirred at room temperature for 24 hours and then 126 μL (0.8 eq, 2.02 mmol) of iodomethane is added. The reaction medium is stirred at room temperature for 2 additional hours. Water is added and the product is extracted with ethyl acetate. The organic phase is dried on anhydrous magnesium sulfate, filtered, and evaporated to yield 660 mg (90%) of 6-((2,4-difluorophenyl)(methyl)amino)-2-(methylthio)nicotinonitrile in the form of a brown solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)O1.Br[C:24]1[N:25]=[C:26]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[S:27][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>CS(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:38][C:35]1[CH:34]=[CH:33][C:32]([S:29]([C:26]2[S:27][CH:28]=[C:24]([C:9]3[CH:21]=[CH:20][C:12]4[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=4[CH:10]=3)[N:25]=2)(=[O:31])=[O:30])=[CH:37][CH:36]=1
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Reactant: O=S(=O)(c1ccc(F)cc1)c1nc(Br)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: CC(=O)Nc1nc2ccc(-c3csc(S(=O)(=O)c4ccc(F)cc4)n3)cc2s1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
A RBF was charged with N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.5 g, 1 mmol), 4-bromo-2-(4-fluorophenylsulfonyl)thiazole (0.4 g, 1 mmol), 2 M Na2CO3 (1 mL, 2 mmol), tetrakis(triphenylphosphine)palladium(0) (0.2 g, 0.2 mmol), and dioxane (6 mL). The flask was placed into a pre-heated (95° C.) bath and allowed to stir under an inert atmosphere overnight. The mixture was diluted with DMSO and filtered. The crude was purified by reverse-phase HPLC to give N-(6-(2-(4-fluorophenylsulfonyl)thiazol-4-yl)benzo[d]thiazol-2-yl)acetamide as an off-white solid. MS (ESI pos. ion) m/z: 434 (MH+). Calculated exact mass for C18H12FN3O3S3: 433. 1H NMR (400 MHz, DMSO-d6): 8.53 (s, 1H), 8.30 (s, 1H), 8.21 (s, 2H), 7.81 (s, 1H), 7.56 (s, 3H), 2.07 (s, 3H).
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1([CH2:20][OH:21])[CH2:15][CH2:14][C:13]2([O:19][CH2:18][CH2:17][O:16]2)[CH2:12][CH2:11]1>CN(C=O)C.C(OCC)(=O)C>[O:16]1[CH2:17][CH2:18][O:19][C:13]21[CH2:14][CH2:15][C:10]1([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:21][CH2:20]1)[CH2:11][CH2:12]2
Reactant: OCC1(c2ccccc2F)CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1ccc2c(c1)OCC21CCC2(CC1)OCCO2
Temperature: 110 °C
Reaction time: 6 h
Yield: 98.1 %

Procedure:
Sodium hydride (80% in mineral oil, 1.53 g, 51 mmol) was stirred in dry DMF (30 ml) as 4'-(2-fluorophenyl)-4'-(hydroxymethyl)spiro[[1,3]-dioxolane-2,1 '-cyclohexane] (D22, 5.44 g, 20 mmol) was added in dry DMF (70 ml). The mixture was stirred under Ar at 110° C. for 6 h, cooled, diluted with ethyl acetate (500 ml), washed with water and brine, dried (Na2SO4) and evaporated to give the title compound (4.83 g, 96%) as a straw-coloured solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:3][OH:4].[C:12]([N:16]=[C:17]=[S:18])([CH3:15])([CH3:14])[CH3:13]>C(O)C>[C:12]([NH:16][C:17]([NH:1][C@@H:2]([CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:3][OH:4])=[S:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: N[C@H](CO)CC1CCCCC1
Reactant: CC(C)(C)N=C=S
Solvent: CCO
Product: CC(C)(C)NC(=S)N[C@H](CO)CC1CCCCC1
Temperature: 20 °C
Reaction time: 72 h

Procedure:
The process is performed as in Example 3, starting with 8.1 g of (+)-(2S)-2-amino-3-cyclohexyl-1-propanol and 9.8 cm3 of tert-butyl isothiocyanate in 79 cm3 of ethanol. The reaction medium is stirred for 72 hours at a temperature in the region of 20° C. After concentration of the reaction mass under reduced pressure (5 kPa) at a temperature in the region of 50° C., the oil obtained is taken up in 110 cm3 of cold petroleum ether. The crystals are filtered off and dried under reduced pressure (10 Pa) at a temperature in the region of 60° C. 11.1 g of N-(tert-butyl)-N′-[(1S)-1-cyclohexylmethyl-2-hydroxyethyl]thiourea are obtained in the form of a white solid melting at 97° C.
Reaction SMILES: [C:1]([C:4]1[N:9]=[CH:8][C:7]([NH:10][C:11]2[N:16]=[C:15]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:25][C:26]([NH2:28])=[O:27])[C:14]([C:29]([F:32])([F:31])[F:30])=[CH:13][N:12]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]>CN(C=O)C.CCO.CCN(CC)CC.[Pd]>[C:1]([C:4]1[N:9]=[CH:8][C:7]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:25][C:26]([NH2:28])=[O:27])[C:14]([C:29]([F:30])([F:31])[F:32])=[CH:13][N:12]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(Nc2ncc(C(F)(F)F)c(C#Cc3ccccc3CC(N)=O)n2)cn1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(N)=O)n2)cn1
Reaction time: 20 h
Yield: 57.1 %

Procedure:
A solution of 2-(2-((2-((6-acetylpyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethynyl)phenyl)acetamide (A142) (0.347 g, 0.790 mmol) in DMF (20 mL), EtOH (3 mL) and Et3N (1 mL) containing 10% palladium on carbon (0.110 g) was stirred under a hydrogen atmosphere for 20 hours. The reaction mixture was filtered through a pad of Celite and the solvent was concentrated in vacuo. The crude material was adsorbed onto silica gel and purified by silica gel column chromatography (CombiFlash Rf, 24 g SiO2 Cartridge, 0-10% MeOH in DCM) to give the title compound (A143) as a white solid (0.200 g, 57%). LCMS-B: 6.80 min; m/z 444 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[C:4]([CH2:13][NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH:3]=1.[CH3:19][C:20]([O:23][C:24]([NH:26][CH2:27][CH2:28][C:29](O)=[O:30])=[O:25])([CH3:22])[CH3:21].Cl.C(N=C=NCCCN(C)C)C.CC1C=CN=C(N)C=1C>ClCCl>[Cl:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[C:4]([CH2:13][N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:29](=[O:30])[CH2:28][CH2:27][NH:26][C:24]([O:23][C:20]([CH3:21])([CH3:19])[CH3:22])=[O:25])[CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: CC(C)CNCc1cc(Cl)c2c(c1)OCCCO2
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccnc(N)c1C
Agent: Cl
Solvent: ClCCl
Product: CC(C)CN(Cc1cc(Cl)c2c(c1)OCCCO2)C(=O)CCNC(=O)OC(C)(C)C

Procedure:
A mixture of N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-2-methylpropan-1-amine (140 mg), 3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid (Boc-beta-alanine, 98 mg), of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (163 mg), and of dimethyl aminopyridine (113 mg) in dichloromethane (10 ml) was stirred overnight. The mixture was concentrated under reduced pressure. Desired compound [N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutyl 3-[(2-methylpropan-2-yl)oxycarbonylamino]propanamide] was isolated by flash chromatography on silica (100% dichloromethane) as a resin: MS (m+1)=441.3.
Reaction SMILES: [CH3:1][N:2]([CH3:40])[CH2:3][CH:4]([O:7][CH:8]([O:12][C@H:13]1[CH2:37][CH2:36][C@@:35]2([CH3:38])[C:15](=[CH:16][CH2:17][C@@H:18]3[C@@H:34]2[CH2:33][CH2:32][C@@:31]2([CH3:39])[C@H:19]3[CH2:20][CH2:21][C@@H:22]2[C@H:23]([CH3:30])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:14]1)[CH2:9][CH2:10][CH3:11])[CH2:5][OH:6].[H-].[Na+].S(O[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55]/[CH:56]=[CH:57]\[CH2:58]/[CH:59]=[CH:60]\[CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])(=O)(=O)C>C1(C)C=CC=CC=1>[CH3:40][N:2]([CH3:1])[CH2:3][CH:4]([O:7][CH:8]([O:12][C@H:13]1[CH2:37][CH2:36][C@@:35]2([CH3:38])[C:15](=[CH:16][CH2:17][C@@H:18]3[C@@H:34]2[CH2:33][CH2:32][C@@:31]2([CH3:39])[C@H:19]3[CH2:20][CH2:21][C@@H:22]2[C@H:23]([CH3:30])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:14]1)[CH2:9][CH2:10][CH3:11])[CH2:5][O:6][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55]/[CH:56]=[CH:57]\[CH2:58]/[CH:59]=[CH:60]\[CH2:61][CH2:62][CH2:63][CH2:64][CH3:65]
Reactant: CCCC(OC(CO)CN(C)C)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCC/C=C\C/C=C\CCCCCCCCOCC(CN(C)C)OC(CCC)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.7 %

Procedure:
3-Dimethylamino-2-(Cholest-5-en-3β-oxybutan-4-oxy)-1-propanol (2.6 g, 4.6 mmol) was weighed into a 200 mL round bottomed flask and co-evaporated with anhydrous toluene 2×20 mL). A stir bar was added to the flask, which was then sealed, flushed with argon and charged with anhydrous toluene (100 mL). Sodium hydride (0.7 g, 6 equiv) was added at once and the mixture was stirred, under argon, for 20 minutes. Linoleyl mesylate (4.6 g, 2.3 equiv.) was measured in a PP syringe and added slowly to the reaction mixture. The flask was fitted with a reflux condenser and the apparatus was flushed with argon. The reaction mixture was heated in an oil bath and allowed to stir at reflux overnight. The reaction mixture was then cooled to room temperature in a water bath and ethanol was added dropwise until gas evolution ceased. The reaction mixture was diluted with ethyl acetate (300 mL) and washed with aqueous 10% sodium carbonate (2×200 mL). The aqueous phases were combined and back extracted with ethyl acetate (2×100 mL). The organic phases were combined, dried over MgSO4, filtered and concentrated. The resultant oil was purified via column chromatography (10% EtOAc/Hexanes, 3% TEA) to afford 3.0 g (81%) of a colorless oil.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=1[C:14](=[O:16])[CH3:15])=[O:5].[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18].[ClH:22]>C1C=CC=CC=1.CCOCC>[ClH:22].[CH2:17]([N:19]([CH2:20][CH3:21])[CH2:2][CH2:3][C:4]([NH:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=1[C:14](=[O:16])[CH3:15])=[O:5])[CH3:18]
Reactant: CCNCC
Reactant: CC(=O)c1cccc(C)c1NC(=O)CCBr
Agent: Cl
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCN(CC)CCC(=O)Nc1c(C)cccc1C(C)=O

Procedure:
To a solution of 1.5 g of 3-bromo-2'-acetyl-6'-methylpropionanilide in 20 ml of benzene was added 0.8 g of diethylamine at room temperature. The resultant mixture was stirred at room temperature for 24 hours. The reaction mixture was washed with water, dried over anhydrous sodium sulfate and evaporated to give an oily residue. The residue was dissolved in ether and hydrogen chloride was added to the solution to give crystals. Recrystallization from ethanol gave 3-(diethylamino)-2'-acetyl-6'-methylpropionanilide hydrochloride having a melting point of 124° to 126° C.
Reaction SMILES: Br[C:2]1[C:10](Br)=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.[CH3:22][S:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[C:10]([C:27]3[CH:28]=[CH:29][C:24]([S:23][CH3:22])=[CH:25][CH:26]=3)=[CH:9][C:5]3[O:6][CH2:7][O:8][C:4]=3[CH:3]=2)=[CH:15][CH:14]=1
Reactant: Brc1cc2c(cc1Br)OCO2
Reactant: CSc1ccc(B(O)O)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CSc1ccc(-c2cc3c(cc2-c2ccc(F)cc2)OCO3)cc1
Yield: 142.6 %

Procedure:
Under nitrogen, 1 g of Pd(PPh3)4 was added to a stirred solution of 4 g (14.3 mmol) of 5,6-dibromo-1,3-benzodioxole (Lancaster), 2.4 g (17.2 mmol) of 4-fluorophenylboronic acid, and 2.87 g (17.2 mmol) of 4-methylthiophenylboronic acid (Example 1, Step 2) in 70 mL of toluene, 40 mL of ethanol, and 30 mL of 2M Na2C03. After vigorous stirring at reflux overnight, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate, washed with water, and dried over Na2SO4. Concentration in vacuo gave 6.9 g of 5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-1,3-benzodioxole as a semi-solid which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:11][CH2:12][CH2:13][CH2:14]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:14][CH2:13][CH2:12][Br:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: BrCCCBr
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1ccc(SCCCBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 50 ml of a 2-butanone solution containing 5.5 g of 4-nitrothiophenol and 28.3 g of 1,3-dibromopropane was added 9.0 g of anhydrous potassium carbonate, and the solution was then stirred for 30 minutes at room temperature.
Reaction SMILES: [Cl:1][C:2]1[C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][S:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[OH:28]O>>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([S:20]([CH2:19][CH2:18][CH2:17][CH2:16][O:15][C:14]2[C:2]([Cl:1])=[CH:3][C:4]3[NH:9][C:8](=[O:10])[O:7][C:6]([CH3:12])([CH3:11])[C:5]=3[CH:13]=2)=[O:28])=[CH:26][CH:25]=1
Reactant: CC1(C)OC(=O)Nc2cc(Cl)c(OCCCCSc3ccc(Cl)cc3)cc21
Reactant: OO
Product: CC1(C)OC(=O)Nc2cc(Cl)c(OCCCCS(=O)c3ccc(Cl)cc3)cc21

Procedure:
Prepared analogously to Example 2 from 7-chloro-6-[4-(4-chloro-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[C:13]([N:17]2[C:21](=[O:22])[NH:20][C:19]([C:23]3[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=3)=[N:18]2)=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8].[C:30]([CH:32]1[CH2:34][CH2:33]1)#[CH:31].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>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.CS(C)=O>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[C:13]([N:17]2[C:21](=[O:22])[NH:20][C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:31]#[C:30][CH:32]4[CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[N:18]2)=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)C(=O)NCc1cc(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c(Cl)cc1Cl
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: CC(C)(C)C(=O)NCc1cc(-n2nc(-c3ccc(C#CC4CC4)cc3)[nH]c2=O)c(Cl)cc1Cl
Yield: 369.4 %

Procedure:
The title compound was prepared according to the procedure described in Example-111 using N-(2,4-dichloro-5-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide (Intermediate-84, 0.150 g, 0.028 mmol), ethynylcyclopropane (0.038 g, 0.56 mmol), TBAF (0.268 g, 0.85 mmol), bis(triphenylphosphine)palladium(II) chloride (catalytic) and DMSO (3.0 mL) to afford 0.050 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 0.77 (m, 2H), 0.93 (m, 2H), 1.21 (s, 9H), 1.58 (m, 1H), 4.32 (d, J=6.3 Hz, 2H), 7.50-7.53 (m, 3H), 7.82-7.91 (m, 2H), 7.95 (s, 1H), 8.21 (m, 1H)
Reaction SMILES: ClC(Cl)(Cl)C([O:6][C:7]([N:9]1[CH:14]2[C:15]([C:36](O)=[O:37])=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=4[Cl:35])=[CH:20][CH:19]=3)[CH2:17][CH:10]1[CH2:11][N:12]([C:39](=[O:41])[CH3:40])[CH2:13]2)=[O:8])(C)C.[CH:44]1([NH:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([CH3:55])[C:50]=2[CH3:56])[CH2:46][CH2:45]1>>[CH:7]([OH:8])=[O:6].[CH:44]1([N:47]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([CH3:55])[C:50]=2[CH3:56])[C:36]([C:15]2[C@@H:14]3[NH:9][C@H:10]([CH2:17][C:16]=2[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=4[Cl:35])=[CH:20][CH:19]=2)[CH2:11][N:12]([C:39](=[O:41])[CH3:40])[CH2:13]3)=[O:37])[CH2:46][CH2:45]1
Reactant: CC(=O)N1CC2CC(c3ccc(OCCOc4cc(F)ccc4Cl)cc3)=C(C(=O)O)C(C1)N2C(=O)OC(C)(C)C(Cl)(Cl)Cl
Reactant: Cc1cccc(CNC2CC2)c1C
Product: CC(=O)N1C[C@H]2CC(c3ccc(OCCOc4cc(F)ccc4Cl)cc3)=C(C(=O)N(Cc3cccc(C)c3C)C3CC3)[C@@H](C1)N2
Product: O=CO

Procedure:
Synthesized according to typical procedures H and E from bicyclononene BN10 and cyclopropyl-(2,3dimethylbenzyl)amine. LC-MS: Rt=0.91; ES+: 632.31.
Reaction SMILES: C(S(C1C=C(C2C=CC(O)=C3C=2C2C=C(C)C=NC=2N3)C=CC=1)(=O)=O)C.[CH2:27]([S:29]([C:32]1[CH:33]=[C:34]([C:38]2[CH:46]=[CH:45][C:44]([O:47][C@H:48]([CH3:51])[CH2:49][OH:50])=[C:43]3[C:39]=2[C:40]2[CH:55]=[C:54]([CH3:56])[CH:53]=[N:52][C:41]=2[NH:42]3)[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30])[CH3:28]>>[CH2:27]([S:29]([C:32]1[CH:33]=[C:34]([C:38]2[CH:46]=[CH:45][C:44]([O:47][C@@H:48]([CH3:51])[CH2:49][OH:50])=[C:43]3[C:39]=2[C:40]2[CH:55]=[C:54]([CH3:56])[CH:53]=[N:52][C:41]=2[NH:42]3)[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30])[CH3:28]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O[C@H](C)CO)c3[nH]c4ncc(C)cc4c23)c1
Agent: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2ccc(O[C@@H](C)CO)c3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was synthesized from Compound 157 using an analogous procedure to that outlined in the preparation of Compound 211. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (t, J=7.45 Hz, 3 H) 1.36 (d, J=6.06 Hz, 3 H) 2.26 (s, 3 H) 3.40 (q, J=7.41 Hz, 2 H) 3.63-3.72 (m, 2 H) 4.63 (m, 1 H) 4.90 (t, J=6.19 Hz, 1 H) 7.07 (d, J=8.08 Hz, 1 H) 7.15-7.19 (m, 1 H) 7.56 (s, 1 H) 7.85 (t, J=7.71 Hz, 1 H) 7.97-7.99 (m, 2 H) 8.07-8.10 (m, 1 H) 8.27 (d, J=2.02 Hz, 1 H) 11.82 (s, 1 H); [M+H] calc'd for C23H25N2O4S, 425.2.; found, 425.3.
Reaction SMILES: N(OC(C)(C)C)=O.[CH3:8][C:9]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:10]=1N.[CH3:19][S:20]SC>[Cu]>[CH3:8][C:9]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:10]=1[S:20][CH3:19]
Reactant: CSSC
Reactant: Cc1cccc([N+](=O)[O-])c1N
Agent: [Cu]
Agent: CC(C)(C)ON=O
Product: CSc1c(C)cccc1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
160 g of copper powder and 500 ml of dimethyl disulfide were added to 357 g (3.12 mol) of tert-butyl nitrite. At 50–52° C., a solution of 316 g (2.08 mol) of 2-methyl-6-nitroaniline in 1600 ml of dimethyl disulfide was added dropwise, and the mixture was stirred at 50–55° C. for 4 hours. After cooling, the reaction mixture was filtered off with suction through kieselguhr, and dichloromethane was added to the filtrate. The organic phase was washed with dilute hydrochloric acid and then with water and subsequently dried over magnesium sulfate. Concentration under high vacuum gave 452 g of 2-methyl-6-nitrothioanisole as a red-black oil which was used for the next reaction step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([O:14][CH3:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.C(O)(O)=O>CC#N.O>[F:16][C:17]1[CH:22]=[C:21]([C:2]2[C:11]([CH:12]=[O:13])=[CH:10][C:9]3[C:4](=[C:5]([O:14][CH3:15])[CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COc1cccc2cc(C=O)c(Cl)nc12
Agent: O=C(O)O
Solvent: CC#N
Solvent: O
Product: COc1cccc2cc(C=O)c(-c3cccc(F)c3)nc12
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 2-chloro-8-methoxyquinoline-3-carbaldehyde (1.8583 g, 8.384 mmol), 3-fluorobenzeneboronic acid (1.290 g, 9.223 mmol), tetrakis(tri-phenylphosphine)palladium (0.4844 g, 0.4192 mmol), and sodium carbonate anhydrous (4.443 g, 41.92 mmol) in 76 mL of CH3CN—H2O (3:1) was stirred at 100° C. After 3 h, the mixture was cooled to room temperature and partitioned between EtOAc (200 mL) and water (100 mL). The organic layer was washed with brine (100 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give an orange solid. The orange solid was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and then 50% isocratic of EtOAc for 25 min as eluent to give 2-(3-fluorophenyl)-8-methoxyquinoline-3-carbaldehyde as a light-yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 10.09 (1 H, s), 8.94 (1 H, s), 7.80 (1 H, dd, J=8.2, 1.2 Hz), 7.66 (1 H, t, J=8.0 Hz), 7.53-7.64 (2 H, m), 7.47-7.53 (1 H, m), 7.36-7.44 (2 H, m), 4.00 (3 H, s); LC-MS (ESD m/z 282.1 [M+H]+.