Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)Cc1cc(F)cc(C(F)(F)F)c1
Reactant: OCc1ccccc1
Product: O=C(O)Cc1cc(OCc2ccccc2)cc(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using the following starting materials: 3-fluoro-5-(trifluoromethyl)phenylacetic acid and benzyl alcohol.
Reaction SMILES: C1C=CC=CC=1.[C:7]([C:11]1[CH:12]=[C:13]([C:22]2[N:23]=[C:24]([SH:27])[S:25][CH:26]=2)[CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])([CH3:10])([CH3:9])[CH3:8].Br[CH2:29][C:30]([OH:32])=[O:31]>C(N(CC)CC)C>[C:7]([C:11]1[CH:12]=[C:13]([C:22]2[N:23]=[C:24]([S:27][CH2:29][C:30]([OH:32])=[O:31])[S:25][CH:26]=2)[CH:14]=[C:15]([C:18]([CH3:20])([CH3:21])[CH3:19])[C:16]=1[OH:17])([CH3:8])([CH3:9])[CH3:10]
Reactant: O=C(O)CBr
Reactant: CC(C)(C)c1cc(-c2csc(S)n2)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)(C)c1cc(-c2csc(SCC(=O)O)n2)cc(C(C)(C)C)c1O
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To 20 ml of benzene were added 0.64 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-mercaptothiazole and 0.32 g of bromoacetic acid and then 0.5 g of triethylamine was added dropwise to the mixture with stirring. After one hour, triethylamine hydrobromide thus precipitated was filtered off and the benzene solution was extracted with 10 ml of a 2% sodium hydroxide solution. The aqueous extract was acidified by the addition of hydrochloric acid and extracted with ether. The ether solution was dried over anhydrous sodium sulfate and concentrated. The crystals thus obtained were recrystallized from benzene to provide 0.52 g of [4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-thiazolylthio]acetic acid.
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:24])[C:5]([CH3:23])([CH3:22])[CH2:6][O:7][C:8](=[O:21])[C@H:9]([CH:18]([CH3:20])[CH3:19])[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[I-:25].[Na+]>C(#N)C>[I:25][CH2:2][O:3][C:4](=[O:24])[C:5]([CH3:23])([CH3:22])[CH2:6][O:7][C:8](=[O:21])[C@H:9]([CH:18]([CH3:20])[CH3:19])[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: [I-]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(C)(C)C(=O)OCCl
Agent: [Na+]
Solvent: CC#N
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(C)(C)C(=O)OCI
Yield: 94.9 %

Procedure:
2,2-Dimethyl-3-(N-Boc-L-valyloxy)propionic acid chloromethyl ester (3.6 g, 10 mmole) was dissolved in acetonitrile (50 ml). Sodium iodide (2.1 g, 14 mmole) was added to the solution. After reaction at 70° C. for 2 hr, the reaction mixture was filtered and the residue was dissolved in methylene chloride (20 ml) and refiltered. The solution was dried and gave 4.34 g of the titled product.
Reaction SMILES: C([N:8]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:11][N:10]=[N:9]1)C1C=CC=CC=1>Cl.[Pd].C(O)C>[N:10]1[NH:9][N:8]=[C:12]([O:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:11]=1
Reactant: COC(=O)CCCOc1cnnn1Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COC(=O)CCCOc1cn[nH]n1
Reaction time: 16 h
Yield: 99.4 %

Procedure:
Add 5 drops of concentrated hydrochloric acid to a heterogeneous solution of methyl 4-[(1-benzyl-1H-1,2,3-triazol-5-yl)oxy]butanoate (0.50 g; 1.0 equiv; 1.82 mmoles) and 10% palladium on carbon (0.05 g; 0.025 equiv; 0.047 mmoles) in ethanol (7 mL). Evacuate and backfill with nitrogen (3×) then hydrogen (3×), and vigorously stir the reaction mixture for 16 hours under 50 psi hydrogen. Filter the contents and concentrate the filtrate to afford methyl 4-(2H-triazol-4-yloxy)butanoate (0.335 g; 99%). MS (m/z): 184(M−1).
Reaction SMILES: [H][H].[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([OH:27])/[CH:9]=[CH:10]/[C@@H:11]1[C@@H:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:14](=[O:15])[CH2:13][C@H:12]1O.C(O)(=O)C>O>[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([OH:27])/[CH:9]=[CH:10]/[C@@H:11]1[C@@H:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:14](=[O:15])[CH:13]=[CH:12]1
Reactant: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O
Reactant: [H][H]
Solvent: CC(=O)O
Solvent: O
Product: CCCCC[C@H](O)/C=C/[C@H]1C=CC(=O)[C@@H]1CCCCCCC(=O)O
Temperature: 60 °C

Procedure:
Refer to Chart E, wherein E is --CH=CH--, R2 is methyl, R4 is hydrogen, V is --(CH2)5 --, and W is 1-pentyl. A mixture of PGE1, 15-methyl ether, (0.4 g.), glacial acetic acid (9 ml.), and water (1 ml.) is heated under nitrogen at 60° C. for 18 hrs. The mixture is concentrated under reduced pressure, and the residue is subjected to silica gel chromatography, eluting with 25-100% ethyl acetate-Skellysolve B. The fractions shown by TLC to contain the desired product free of starting material and impurities are combined and concentrated to give the Formula-X PGA1 -type title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:13][NH2:14])=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[F:15][C:16]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:17]=1[CH:18]=O>Cl>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:13][N:14]=[CH:18][C:17]2[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:16]=2[F:15])=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=Cc1ccc(F)cc1F
Reactant: NNc1cc(N2CCCC2)c(Cl)nn1
Agent: Cl
Product: Fc1ccc(C=NNc2cc(N3CCCC3)c(Cl)nn2)c(F)c1

Procedure:
3-Chloro-6-hydrazino-4-(pyrrolidin-1-yl)pyridazine (1.06 g, 4.9 mmol) and 2,4-difluorobenzaldehyde (437 ml, 4.9 mmol) were stirred in 0.2M hydrochloric acid (30 ml) for 2 hours. The precipitated imine was then collected by filtration and dried (1.37 g, 92%). MS (ES+) 338 [MH]+, 340 [MH]+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[N:5][C:6]2[CH:7]([C:13]([NH2:15])=O)[CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>N1C=CC=CC=1.S>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[N:5][C:6]2[CH:7]([C:13](=[S:19])[NH2:15])[CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1
Reactant: NC(=O)C1CCCc2cc(C(F)(F)F)cnc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: S
Solvent: c1ccncc1
Product: NC(=S)C1CCCc2cc(C(F)(F)F)cnc21
Temperature: 0 °C

Procedure:
The amide (1 mol) is dissolved in dry pyridine saturated with H2S gas and treated with P2S5 (1 mol) then heated at reflux for 45 min. while maintaining a slow stream of H2S gas. The reaction mixture is evaporated to dryness in vacuo and cooled to 0° C, made alkaline with 10% sodium hydroxide and the solution extracted with chloroform (3 times). The combined extracts are washed with brine, dried and evaporated in vacuo to give the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:14][C:15]([C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[CH:18]=1)=[O:16].[OH-].[Na+]>CO>[CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9](/[CH:10]=[CH:14]/[C:15]([C:17]2[CH:18]=[C:19]([O:25][CH3:26])[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=2)=[O:16])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C=O)cc1
Reactant: COc1cc(OC)cc(C(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCOc1ccc(/C=C/C(=O)c2cc(OC)cc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a stirred solution of 4-butoxybenzaldehyde (0.5 g, 2.8 mmol) and 3,5-dimethoxyacetophenone (0.5 g, 2.8 mmol) in methanol (10 ml) was added 50% w/v of aqueous sodium hydroxide (2.24 ml, 0.028 mol). The reaction mixture was stirred for 2 h at room temperature and then extracted with ethyl acetate (3×20 ml), the combined organic layers were dried over magnesium sulphate and reduced in vacuo. The product was recrystallised from ethanol to give 0.925 g (97%) of off-white crystals. 1H-NMR (CDCl3) δ 7.8 (d, 1H), 7.6 (d, 2H), 7.35 (d, 1H), 7.1 (d, 2H), 6.9 (d, 2H), 6.7 (t, 1H), 4.0 (t, 2H), 3.85 (s, 6H), 1.75 (m, 2H), 1.5 (m, 2H), 1.0 (t, 3H). 13C-NMR (CDCl3) δ 191.1, 161.4, 160.8, 144.9, 140.8, 130.2, 127.3, 119.6, 114.9, 106.3, 104.8, 67.9, 55.6, 31.2, 19.2, 13.8. Mass Spectrum m/e (M+1) 341.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10](Cl)=[O:11])[CH:6]=[CH:7][CH:8]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CC(=O)Cl)c1
Reactant: Nc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cccc(CC(=O)Nc2ccccc2)c1
Reaction time: 3 h
Yield: 88.5 %

Procedure:
To a solution of 3-methoxyphenylacetyl chloride (2.3 g, 12.5 mmol) in ethyl acetate (30 mL) was added a solution of aniline (1.16 g, 12.5 mmol) in ethyl acetate (30 mL). After 3 hours, the reaction was poured into water (50 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated to provide the title compound (2.67 g, 89% yield): EI-MS (m/z) 241.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Cl:13])[CH:12]=1)(=O)=O.[C:16]1([CH2:22][SH:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH2:22]([S:23][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Cl:13])[CH:12]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Oc1cncc(Cl)c1)C(F)(F)F
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cncc(SCc2ccccc2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 104.6 %

Procedure:
To a solution of 5-chloropyridin-3-yl trifluoromethanesulfonate (1.73 g) in toluene (15 mL) were added phenylmethanethiol (861 mg), N,N-diisopropylethylamine (1.88 g), tris(dibenzylideneacetone)dipalladium(0) (121 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (153 mg), and the mixture was stirred under an argon atmosphere at 80° C. for 3 hr. The reaction mixture was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane→hexane-ethyl acetate=19:1) to give the title compound as a yellow oil (yield 1.63 g, quantitative).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:37](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:39])=[O:38])=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1>>[Cl:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:37]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=3)[C:9]3[S:10][CH:11]=[CH:12][N:13]=3)(=[O:39])=[O:38])=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Cl)nccc2c1
Reactant: COc1ccc(CNc2nccs2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a flask containing an ice cold suspension of N-(4-methoxybenzyl)thiazol-2-amine (0.423 g, 1.922 mmol) in 2Me-THF (7.04 ml) was added lithium bis(trimethylsilyl)amide (2.014 ml, 2.014 mmol) dropwise over 10 min. The mixture was stirred for 15 min prior to the addition of a solution of perfluorophenyl 1-chloroisoquinoline-6-sulfonate (see Example 73, Step 1) (0.750 g, 1.831 mmol) in 2Me-THF (3.5 ml). After 1 hr of stirring (ice melt) LC-MS indicated about 65% conversion to product with starting ester and amine present. The mixture was re-cooled to 0° C. and additional LiHMDS (0.5 eq) was added. The mixture was allowed to stir and slowly warm to room temperature overnight. LC-MS indicated about 90% conversion to desired product. The reaction was quenched by the addition of acetic acid (˜2 ml) and the resulting mixture (some precipitate formation) was dried under reduced pressure and purified with a 40 g silicycle HP column ramping EtOAc in heptane (0 to 50%) providing product 1-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate JJJ) (0.530 g, 1.188 mmol, 64.9% yield) as a white foam. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.71 (s, 3H) 5.11 (s, 2H) 6.69-6.76 (m, 2H) 7.04 (d, J=3.62 Hz, 1H) 7.26-7.33 (m, 2H) 7.42 (d, J=3.62 Hz, 1H) 7.59-7.64 (m, 1H) 7.85 (dd, J=8.95, 1.81 Hz, 1H) 8.21 (d, J=1.76 Hz, 1H) 8.33-8.41 (m, 2H). m/z (ESI) 446.1 (M+H)+.
Reaction SMILES: [CH2:1]([NH:4][CH3:5])[CH:2]=[CH2:3].Cl.[NH2:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13]Cl)[N:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([N:4]([CH2:13][C:11]1[N:12]=[C:8]([NH2:7])[S:9][CH:10]=1)[CH3:5])[CH:2]=[CH2:3]
Reactant: Nc1nc(CCl)cs1
Reactant: C=CCNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C=CCN(C)Cc1csc(N)n1

Procedure:
N-allyl-N-methylamine (7.0 mg, 0.1 mmol), 2-amino-4-chloromethylthiazole hydrochloride (18.5 mg, 0.1 mmol), and potassium carbonate (30 mg, 0.21 mmol) are shaken in ethanol (1 mL) at room temperature for 18 hours. The mixture is filtered and the filtrate was condensed under vacuum.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC1C2N=NNC=2C=CC=1.[CH2:19]([C:23]1[NH:24][C:25](=[O:32])[CH:26]=[C:27]([CH:31]=1)[C:28](O)=[O:29])[CH2:20][CH2:21][CH3:22].C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C>CN(C=O)C>[CH2:19]([C:23]1[NH:24][C:25](=[O:32])[CH:26]=[C:27]([C:28]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:29])[CH:31]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCc1cc(C(=O)O)cc(=O)[nH]1
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCc1cc(C(=O)OCc2ccccc2)cc(=O)[nH]1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
13.3 g (123 mmol) of benzyl alcohol and 4.7 g (31 mmol) of hydroxybenzotriazole are added to a solution of 6.0 g (31 mmol) of 6-butyl-2-oxo-1,2-dihydro-isonicotinic acid in 100 ml of DMF. The resulting clear solution is cooled to 0° C., followed by the addition of 7.0 g (34 mmol) of dicyclohexylcarbodiimide and 4.2 ml (31 mmol) of triethylamine. The mixture is allowed to thaw to 20° C., stirred for a further 2 hours and subjected to aqueous work-up. 6.8 g (77% of theory) of the title compound are obtained.
Reaction SMILES: [Br:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][O:5][C:6]2=[O:7].O.N>C(O)C.S([O-])([O-])(=O)=O.[Fe+2]>[Br:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][O:5][C:6]2=[O:7]
Reactant: O=C1OCc2c1ccc([N+](=O)[O-])c2Br
Agent: [Fe+2]
Agent: N
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1Br)COC2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
6.6 g of 4-bromo-5-nitrophthalide is dissolved in 45 ml of ethanol and added in drops to a mixture of 65 g of iron(II) sulfate, 220 ml of water and 65 ml of ammonia (33%) that is heated to 60° C. and stirred well. After 2 hours at 60° C., the mixture is absorptively precipitated five times with 200 ml of diethyl ether. The diethyl ether phases are concentrated by evaporation. As a residue, 4.1 g of 4-bromo-5-aminophthalide is obtained, melting point 176-180° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>>[CH2:18]([O:17][C:15](=[O:16])[NH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1nccs1
Solvent: CCN(CC)CC
Product: O=C(Nc1nccs1)OCc1ccccc1
Temperature: 25 °C
Yield: 70 %

Procedure:
To a stirred solution of 2-aminothiazole (AA1-A, 3.0 g, 30.0 mmol) and triethylamine (6.30 mL, 45.0 mmol) at 0° C. was added benzyl chloroformate (5 mL, 36 mmol). The reaction was stirred at RT O/N. The reaction mixture was washed with a saturated aqueous solution of NaHCO3, then water and concentrated to dryness under reduced pressure. The resulting yellow solid was crystallized from ethanol to afford AA1-2 in 70% yield.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][CH:8]([S:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:29][O:28][C:22]1[CH:21]=[C:20]([S:19][CH:8]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][C:6]([OH:30])=[O:5])[CH:25]=[CH:24][C:23]=1[O:26][CH3:27]
Reactant: COc1ccc(SC(CCCCc2ccccc2)CC(=O)OC(C)(C)C)cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(SC(CCCCc2ccccc2)CC(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.9 %

Procedure:
To a solution of t-butyl-3-(3,4-dimethoxyphenyl)sulfanyl-7-phenylheptanoate (14.9 g, 0.03 mol) in CH2Cl2 (150 mL) cooled to 0° C., is added trifluoroacetic acid (30 mL). The solution is allowed to warm to room temperature and stir overnight after which TLC analysis indicated complete reaction. The reaction mixture is concentrated in vacuo and the brown residue is chromatographed on silica gel (pet-ether/EtOAc, 1:1) to afford 11.9 g of (±) 3-(3,4-dimethoxyphenyl)sulfanyl-7-phenylheptanoic acid (91%) as a pale yellow oil. TLC analysis [pet-ether/EtOAc, 1:1, Rf (heptanoate)=0.95, Rf (acid)=0.15]. 1H NMR (300 MHz, CDCl3) δ 1.5-1.65 (m, 6H), 2.55 (m, 4H), 3.30 (t, 1H), 3.85, (d, 6H), 6.80 (d, 1H), 6.98-7.31 (m, 7H) ppm. Mass spectrum (FAB) m/z 374 M+.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([CH3:14])[CH:3]=1.N(OCCC(C)C)=O.[I:23]CI>>[I:23][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([CH3:14])[CH:3]=1
Reactant: Cc1cc(N)ccc1-c1ccccc1
Reactant: ICI
Agent: CC(C)CCON=O
Product: Cc1cc(I)ccc1-c1ccccc1
Temperature: 75 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
A stirred solution of 4-amino-2-methyl-1-phenylbenzene (10.49 gm, 57.2 mmol) in diiodomethane (100 mL) was treated with iso-amyl nitrite (27 mL, 200.2 mmol) over 5 mins. The mixture was heated to 75° C. for 45 mins, then at 65° C. for 1 h. After being cooled, the mixture was concentrated under reduced pressure (95° C./30 mmHg) and the residue was purified by flash chromatography (eluting with hexane) to give 4-iodo-2-methyl-1-phenylbenzene (11.6 gm, 66%) as an oil.
Reaction SMILES: COC1C=CC(C[NH:10][C:11]2[N:16]=[C:15]([C:17]3[N:22]=[CH:21][C:20]4[CH:23]=[N:24][N:25]([C:26]5[N:31]=[C:30]([N:32]6[CH2:38][CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]6)[CH:29]=[CH:28][CH:27]=5)[C:19]=4[CH:18]=3)[CH:14]=[N:13][CH:12]=2)=CC=1.Cl.OS(C(F)(F)F)(=O)=O>ClCCl.O1CCOCC1>[N:32]1([C:30]2[N:31]=[C:26]([N:25]3[C:19]4[CH:18]=[C:17]([C:15]5[N:16]=[C:11]([NH2:10])[CH:12]=[N:13][CH:14]=5)[N:22]=[CH:21][C:20]=4[CH:23]=[N:24]3)[CH:27]=[CH:28][CH:29]=2)[CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1
Reactant: COc1ccc(CNc2cncc(-c3cc4c(cn3)cnn4-c3cccc(N4CCCN(C(=O)OC(C)(C)C)CC4)n3)n2)cc1
Agent: Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3CCCNCC3)n2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 27.1 %

Procedure:
To a mixture of tert-butyl 4-[6-[6-[6-[(4-methoxyphenyl)methylamino]pyrazin-2-yl]pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-1,4-diazepane-1-carboxylate (0.4789 mmol; 291 mg) in Dichloromethane (5 mL) was added Hydrogen Chloride, 4.0 M in 1,4-Dioxane (5 mL), and TRIFLIC ACID (4.789 mmol; 733.3 mg; 0.4293 mL). The reaction mixture was stirred at room temperature for 3 days. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 247 as an off-white solid (50.3 mg, 27%). 1H NMR (400 MHz, DMSO) δ 9.45-9.41 (s, 1H), 9.26-9.22 (s, 1H), 8.76-8.73 (s, 1H), 8.64-8.58 (s, 1H), 7.99-7.96 (s, 1H), 7.73-7.67 (t, J=8.1 Hz, 1H), 7.16-7.12 (d, J=7.7 Hz, 1H), 6.63-6.58 (d, J=8.5 Hz, 1H), 6.33-6.25 (s, 2H), 3.89-3.82 (dd, J=11.0, 5.2 Hz, 4H), 3.03-2.98 (m, 2H), 2.73-2.66 (m, 2H), 1.91-1.84 (dd, J=11.5, 5.8 Hz, 2H); MS (ESI) m/z: 388.2 [M+H]+
Reaction SMILES: [CH2:1]([N:4]1[C:8]2[C:9]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:10][CH:11]=[C:12]([Cl:13])[C:7]=2[NH:6][C:5]1=O)[CH:2]=[CH2:3].P(Cl)(Cl)([Cl:22])=O>C(OCC)(=O)C>[CH2:1]([N:4]1[C:8]2[C:9]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:10][CH:11]=[C:12]([Cl:13])[C:7]=2[N:6]=[C:5]1[Cl:22])[CH:2]=[CH2:3]
Reactant: C=CCn1c(=O)[nH]c2c(Cl)ccc(C(CC)CC)c21
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: C=CCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Yield: 95 %

Procedure:
A solution of 1-allyl-4-chloro-7-(1-ethylpropyl)-1,3-dihydro-2H-benzimidazol-2-one (9.80 g, 35.1 mmol) in phosphoryl chloride (35 mL) was stirred at 100° C. for 2 hr. The mixture was concentrated in vacuo to give a residue which was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 5-20% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound (9.90 g, 33.3 mmol, 95%) as a colorless solid.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]([CH3:13])([C:10]([OH:12])=[O:11])[C:7](O)=[O:8].[CH3:14][S:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>C1COCC1>[CH3:14][S:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:7](=[O:8])[C:6]([CH3:13])([CH3:5])[C:10]([OH:12])=[O:11])=[CH:18][CH:17]=1
Reactant: CC(C)(C(=O)O)C(=O)O
Reactant: CSc1ccc(N)cc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CSc1ccc(NC(=O)C(C)(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (8.15 g, 5 ml, 0.069 mol) was added to a stirred solution of 2,2-dimethylmalonic acid (7.26 g, 0.055 mol) in dry THF (55 ml). The mixture was heated under reflux for 3 hr. The reaction mixture was cooled to room temperature and 4-methylthioaniline (15.3 g, 0.11 mol) in THF (30 ml) was then added dropwise over 30 mins to the solution. The mixture was stirred at room temperature for 2 hr. The reaction mixture was then concentrated in vacuo and then treated with hydrochloric acid (2N, 100 ml). The product was extracted with ethyl acetate (2×100 ml). The organic extracts were combined, then washed with water (100 ml) and saturated sodium hydrogen carbonate solution (5×80 ml). The organic layer was then acidified with hydrochloric acid (5N, 250 ml) and the resultant white crystalline precipitate was collected by filtration to afford N-(4-methylthiophenyl)-2,2-dimethylmalonamic acid. mp 130-132° C.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[C:19][CH2:20]OS(C)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:28][NH:29][CH3:30]>>[CH3:28][N:29]([CH3:30])[CH2:20][C:19]#[C:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:27])([F:26])[F:1])=[CH:4][CH:5]=3)=[N:10][S:11][C:12]=2[CH:17]=1
Reactant: CS(=O)(=O)OCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Reactant: CNC
Product: CN(C)CC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 17.1, Methanesulfonic acid 3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl ester and Dimethylamine were converted to yield Dimethyl-{3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-amine as light brown oil, MS: 361 (MH+).