Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[CH:11]=1.S(Cl)([Cl:14])=O>C(Cl)Cl>[Cl:14][CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cn2ccccc2n1
Solvent: ClCCl
Product: ClCc1cn2ccccc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
In a round bottomed flask containing 2-hydroxymethyl-imidazo[1,2-a]pyridine (800 mg, 5.4 mmol) in DCM (8 mL), was added at R.T. thionyl chloride (1.96 mL, 27 mmol). The solution became clear and 10 min later, a precipitated was formed. The reaction mixture was stirred at R.T. for 2 hours and the solvent was removed under reduced pressure to afford 1.10 g of a brownish solid as the chlorhydrate form of 2-(chloromethyl)-imidazo[1,2-a]pyridine (Yield: 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:13].[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][C:16]=1[F:24]>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.COCCOC>[Cl:13][C:3]1[CH:4]=[C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:7][C:2]=1[C:18]1[CH:19]=[CH:20][C:15]([Cl:14])=[C:16]([F:24])[CH:17]=1
Reactant: CS(=O)(=O)Nc1ccc(Br)c(Cl)c1
Reactant: OB(O)c1ccc(Cl)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CS(=O)(=O)Nc1ccc(-c2ccc(Cl)c(F)c2)c(Cl)c1

Procedure:
N-(4-bromo-3-chlorophenyl)methanesulfonamide (B, 100.0 mg, 0.351 mmol), 4-chloro-3-fluorophenylboronic acid (73.4 mg, 0.421 mmol, L2 equiv.) and Pd(PPh3)4 (20.3 mg, 0.0176 mmol, 0.05 equiv.) was placed in a 50 mL round bottomed flask under a nitrogen atmosphere. To the flask were added 2M-Na1CO3 (1.0 mL, 2.0 mmol, 5.7 equiv.) and DME (4 mL) subsequently at ambient temperature. The mixture was heated under reflux conditions for 1 hours. The mixture was filtered through Celite (3 g) and the Celite was washed with EtOAc (70 mL). The solvent was removed under a reduced pressure. Obtained crude mixture was purified by column chromatography (SiO2=80 g, EtOAc/hexane=1:3˜1:1, Rf=0.4) to give the desired product as colorless crystals (compound 5 (designated PT-017).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([CH:17]=[O:18])[N:13]=[CH:12][C:11]=2[C:10]([CH3:20])([CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]1[CH2:25]OC[CH2:22]1>>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([CH:17]([OH:18])[CH:21]([CH3:25])[CH3:22])[N:13]=[CH:12][C:11]=2[C:10]([CH3:20])([CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(C=O)cc21
Reactant: C1CCOC1
Product: CC(C)C(O)c1cc2c(cn1)C(C)(C)CN2C(=O)OC(C)(C)C
Temperature: -78 °C

Procedure:
To a stirred solution of 6-formyl-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (0.65 g, 2.36 mmol), in THF (20 mL) at −78° C. under nitrogen was added, dropwise over 0.1 h, a solution of isopropylmagnesium chloride-lithium chloride complex in THF (1.3 M, 2.7 mL, 3.53 mmol). Resulting solution was stirred at −78° C. then was quenched with aqueous citric acid (5%, 30 mL) and extracted with DCM (4×50 mL). Combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give a foam. Chromatography (SiO2; gradient elution with 0-100% EtOAc in 40-60 petroleum ether) gave the title compound (0.398 g). 1H NMR (Me-d3-OD): 8.15 (1H, s), 8.08-7.45 (1H, m), 4.41 (1H, d), 3.78 (2H, s), 2.10-1.97 (1H, m), 1.60 (9H, s), 1.40 (6H, d), 0.92 (6H, t).
Reaction SMILES: [CH2:1]([Li])CCC.[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:15]([CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH2:19][CH2:18]1)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CCCCCC>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][CH2:23][N:20]2[CH2:21][CH2:22][CH:17]([C:15]([C:7]3[S:6][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[N:8]=3)=[CH2:1])[CH2:18][CH2:19]2)=[CH:26][CH:27]=1
Reactant: COc1ccc(CCN2CCC(C(=O)c3nc4ccccc4s3)CC2)cc1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C(c1nc2ccccc2s1)C1CCN(CCc2ccc(OC)cc2)CC1
Reaction time: 2 h

Procedure:
Dissolve methyltriphenylphosphonium bromide (2.50 g, 6.99 mmol) in anhydrous tetrahydrofuran (50 mL). Add n-butyllithium (2.8 mL of a 2.5M solution in hexane, 6.99 mmol) and cool to -10° C. Add, by dropwise addition, a solution of [2-benzothiazolyl][1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]methanone (2.66 g, 6. 99 mmol) in anhydrous tetrahydrofuran (50 mL). Stir for 2 hours then quench with water. Separate the organic phase and extract the aqueous phase with ethyl ether. Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo. Purify by chromatography (50% ethyl ether/hexane) to give the title compound as a white powder; mp 84°-85° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][CH:9]2[C:14](=[C:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.F[C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1>O>[N+:37]([C:34]1[CH:35]=[CH:36][C:31]([N:10]2[CH2:11][CH2:12][CH2:13][C:14](=[C:15]([CH3:17])[CH3:16])[CH:9]2[CH2:8][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:19][CH:18]=2)=[CH:32][CH:33]=1)([O-:39])=[O:38]
Reactant: COc1ccc(CC2NCCCC2=C(C)C)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CC2C(=C(C)C)CCCN2c2ccc([N+](=O)[O-])cc2)cc1

Procedure:
A mixture of 1.0 g. of 2-(p-methoxybenzyl)-3-isopropylidenepiperidine hydrochloride, 1.1 g. of powdered potassium carbonate, 10 ml. of dimethyl sulfoxide, and 0.4 ml. of p-fluoronitrobenzene was stirred and heated on a steam bath for one hour. The reaction mixture was then poured into water and the water was decanted from the precipitated gum. The gum was washed with several portions of water and then taken up in diethyl ether, and the ether was washed with several portions of water. The ether was dried and filtered, and the filtrate was evaporated to dryness under reduced pressure to yield 1-(p-nitrophenyl)-2-(p-methoxybenzyl)-3-isopropylidenepiperidine as a residue. Neither the residue nor its hydrochloride could be induced to crystallize, although only one component could be observed on thin layer chromatographic analysis using several developing systems on both silica gel and alumina. The nuclear magnetic resonance spectrum (CDCl3) of the crude residue showed: 439 (A2B2), 410, (A2B2), 295 (t,1,J=7 cps), 222 (a,3), 172 (d,2, J=7 cps), 95, (s,3), 76 (d,3,J=1-2 cps). The ultraviolet spectrum (95% ethanol) showed: 272s (ε4100), 286s (ε3500), 400 m (ε16300); lit, p-methylanisole 277 (ε2100), 284 (ε1800); N,N-dimethyl-p-nitroaniline 395 (ε20000).
Reaction SMILES: [CH:1]([Li])([CH2:3]C)[CH3:2].[Cl:6][C:7]1[CH:8]=[C:9]([C@@H:13]2[C@:18]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:17]([CH:27]([CH3:29])[CH3:28])[C:16](=[O:30])[CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1.C(Br)C=C>C1COCC1>[CH2:3]([C@@H:15]1[CH2:14][C@H:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[CH:8]=2)[C@:18]([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)([CH3:19])[N:17]([CH:27]([CH3:28])[CH3:29])[C:16]1=[O:30])[CH:1]=[CH2:2]
Reactant: CC(C)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@@]1(C)c1ccc(Cl)cc1
Reactant: [Li]C(C)CC
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@](C)(c2ccc(Cl)cc2)N(C(C)C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.2 %

Procedure:
sec-Butyllithium (0.8N in cyclohexane, 0.274 mL, 0.219 mmol) was added over a period of one minute to a degassed (Argon bubbled through solution for 10 minutes at RT) solution of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-methylpiperidin-2-one (Example 418, Step H, 75 mg, 0.199 mmol) in THF (6 mL) cooled by an acetone-dry ice bath. The cold bath was removed and the reaction equilibrated to room temperature over fifteen minutes. The reaction was stirred at room temperature for 30 minutes. Allyl bromide (1M in THF, 0.219 mL, 0.219 mmol) was added over one minute at room temperature. After two hours the reaction was quenched by addition of saturated aqueous ammonium chloride solution. The organic layer was diluted with ethyl acetate and separated. The aqueous layer was extracted again with ethyl acetate. The combined organic layers were then dried with anhydrous magnesium sulfate and concentrated to afford a faintly orange glass. The diastereomeric products were isolated by chromatography on silica gel (12 g RediSep® pre-packed silica gel column (Teledyne Isco, Lincoln, Nebr.)) eluting with 20 to 80% ethyl acetate gradient in hexane to afford 25 mg of (3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-methylpiperidin-2-one as the product eluting first on silica gel TLC plate (Rf=0.52 in 3:1 hexane:ethyl acetate eluent) and 25 mg of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-methylpiperidin-2-one as the product eluting second on silica gel TLC plate (Rf=0.28 in 3:1 hexane:ethyl acetate eluent).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:8]=[C:7]([C:9]2[C:14]([F:15])=[CH:13][C:12]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:11][C:10]=2[F:20])[S:6][C:5]=1[NH:21][C:22]1[N:27]=[C:26]([C@@:28]2([OH:45])[CH2:33][CH2:32][N:31](C(OCC3C=CC=CC=3)=O)[CH2:30][C@@H:29]2[OH:44])[CH:25]=[CH:24][CH:23]=1)=[O:3].[H][H]>CO.[Pd]>[F:15][C:14]1[CH:13]=[C:12]([C:16]([OH:19])([CH3:18])[CH3:17])[CH:11]=[C:10]([F:20])[C:9]=1[C:7]1[S:6][C:5]([NH:21][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([C@@:28]3([OH:45])[CH2:33][CH2:32][NH:31][CH2:30][C@@H:29]3[OH:44])[N:27]=2)=[C:4]([C:2]([NH2:1])=[O:3])[CH:8]=1
Reactant: [H][H]
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc([C@@]4(O)CCN(C(=O)OCc5ccccc5)C[C@@H]4O)n3)s2)c(F)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc([C@@]4(O)CCNC[C@@H]4O)n3)s2)c(F)c1

Procedure:
Benzyl (3S,4S)-4-[6-({3-(aminocarbonyl)-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-thienyl}amino)pyridin-2-yl]-3,4-dihydroxypiperidine-1-carboxylate (100 mg, 0.16 mmol) was dissolved in methanol (4.6 mL) and subjected to the H-cube hydrogenator machine, where the solution passed through a palladium on carbon cartridge at 0.5 mL/min at a temperature of 35° C. and a hydrogen pressure of 40 PSI. Once complete, the solution was concentrated and the crude residue was purified by reverse phase HPLC to yield the title compound.
Reaction SMILES: S(O[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]OS(=O)(=O)O)(O)(=O)=O.[CH:16]1([NH2:19])[CH2:18][CH2:17]1>>[CH:16]1([N:19]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:18][CH2:17]1
Reactant: NC1CC1
Reactant: O=S(=O)(O)OCCNCCOS(=O)(=O)O
Product: C1CN(C2CC2)CCN1
Temperature: 50 °C

Procedure:
A carousel tube was charged with sulfuric acid mono-[2-(2-sulfooxy-ethylamino)-ethyl]ester (1 g) and D2O (3 mL). To the resulting stirred solution was added then added cyclopropylamin (0.7 mL). The resulting mixture was observed to form a stirrable thick slurry, which was heated at 50° C. overnight. Comparison of the 1H NMR of the title compound with the 1H NMR of the di-hydrochloride salt of the title compound confirmed that the title compound was prepared and present in the resulting solution.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][C:14](=[O:16])[CH3:15])[CH2:10][C@@H:9]1[C:17](=O)[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][C:14](=[O:16])[CH3:15])[CH2:10][C@@H:9]1[C:17](=[S:37])[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1C[C@H](C(=O)NCc2ccc(Cl)cc2)N(C(=O)OC(C)(C)C)C1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1C[C@H](C(=S)NCc2ccc(Cl)cc2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
A mixture of purified (2R,4R)-tert-butyl-2-((4-chlorobenzyl)carbamoyl)-4-acetoxypyrrolidine-1-carboxylate from Step B (4.1 g, 10.3 mmol) and Lawesson's reagent (2.1 g, 5.15 mmol) in toluene (80 ml) was refluxed for 2 h under argon. The mixture was cooled to room temperature and then diluted with EtOAc (80 ml), treated with 1N NaOH (2×40 ml), dried over Na2SO4 and concentrated in vacuo. Flash chromatography purification (Hex/EtOAc gradient, 10-100% EtOAc) provided the desired product as a foamy white solid (1.8 g, 43%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][C@H:11]([CH3:14])[CH2:12][Cl:13]>>[Cl:13][CH2:12][C@@H:11]([CH3:14])[CH2:10][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(Br)cc1
Reactant: C[C@H](CCl)CBr
Product: C[C@H](CCl)COc1ccc(Br)cc1

Procedure:
Prepared by Procedure U and Scheme AK using 4-bromophenol and (2R)-1-bromo-3-chloro-2-methylpropane.
Reaction SMILES: [ClH:1].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:14][S:13][C:12]3=[N:15][CH:16]=[C:17]([C:18]([OH:20])=O)[N:11]23)=[CH:6][CH:5]=1)#[N:3].[C:21]1([CH2:27][CH2:28][CH2:29][NH2:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>>[ClH:1].[C:21]1([CH2:27][CH2:28][CH2:29][NH:30][C:18]([C:17]2[N:11]3[C:12]([S:13][CH2:14][CH:10]3[C:7]3[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:9][CH:8]=3)=[N:15][CH:16]=2)=[O:20])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N#Cc1ccc(C2CSc3ncc(C(=O)O)n32)cc1
Reactant: NCCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(C2CSc3ncc(C(=O)NCCCc4ccccc4)n32)cc1
Reaction time: 0.25 h

Procedure:
The carboxylic acid from Step D, Example 1 (20.0 mg, 0.0625 mmol), 3-phenylpropylamine (0.0089 mL, 0.0625 mmol), EDC hydrochloride (14.4 mg, 0.0751 mmol), HOBT (10.1 mg, 0.0751 mmol), and N,N-diisopropylethylamine (0.044 mL, 0.250 mmol) were stirred in dry, degassed DMF (1 mL) at 25° C. for 16 hours. The crude product was purified by preparative HPLC using a gradient of 5%-95% acetonitrile/0.1% TFA; 95%-5%/0.1% aqueous TFA over 15 min. The title compound was isolated after conversion to the HCl salt. MS (es) m+1=389. 1H-NMR (CD3OD): δ7.72 (d, 2H, J=8.2 Hz); 7.71 (s, IH); 7.24 (d, 2H, J=8.2 Hz); 7.23 (t, 2H, J=7.9 Hz); 7.14 (t, 1H, J=7.6 Hz); 7.10 (d, 2H, J=7.3 Hz); 6.38 (bd, 1H, J=7.4 Hz); 4.70 (dd, 1H, J=11.6, 8.4 Hz); 3.81 (d, 1H, J=11.6 Hz); 3.14-3.22 (m, 2H); 2.53 (t, 2H, J=7.7 Hz), 1.73-1.80 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][C:14]1[CH:18]=[C:17]([C:19](Cl)=[O:20])[O:16][N:15]=1>CC(C)=O>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:19]([C:17]2[O:16][N:15]=[C:14]([CH3:13])[CH:18]=2)=[O:20])=[CH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: Cc1cc(C(=O)Cl)on1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(NC(=O)c2cc(C)no2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
To a stirred solution of 3.3 g of ethyl p-aminobenzoate in 60 ml of acetone was added 1.46 g of 3-methylisoxazole-5-carbonyl chloride. The mixture was stirred at room temperature for 1 hr. and then refluxed for 1 hr. The solvent was removed and the residue was washed with 5% hydrochloric acid, 5% potassium carbonate and water. Recrystallization from a mixture of benzene and n-hexane gave 1.6 g of pure product. Melting point: 160°-163° C. Yield: 58.4%.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:17][CH2:18][CH2:19][OH:20])=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[S:28](Cl)([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29].C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[C:9]2[C:4](=[CH:5][C:6]([O:17][CH2:18][CH2:19][O:20][S:28]([C:31]3[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=3)(=[O:30])=[O:29])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(N2CCCC2)c2ccc(OCCO)cc2n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(N4CCCC4)cc(C)nc3c2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 78.2 %

Procedure:
To a cooled (0° C.) solution of of 2-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxy)-ethanol (425 mg, 1.56 mmol) in dichloromethane (20 mL) was added triethylamine (0.9 mL, 6.49 mmol) and tosyl chloride (1115 mg, 5.85 mmol). The reaction mixture was stirred 22 h at room temperature. An aqueous solution of NaHCO3 was added. After separation, the organic layer was washed with brine. The brown gum was triturated with diethylether. After filtration, the solid was dried in a high vacuum to give 520 mg (78.1%) of toluene-4-sulfonic acid 2-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxy)-ethyl ester as a light yellow solid. ISP mass spectrum, m/e: 427.5 (M+1 calculated for C23H26N2O4S: 427.5).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:12][CH:11]=2)=[CH:4][N:3]=1.[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH3:28].CCN(C(C)C)C(C)C>CS(C)=O>[CH3:23][O:24][CH2:25][CH2:26][N:27]([CH3:28])[C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:12][CH:11]=2)=[CH:4][N:3]=1
Reactant: CC(=O)NC(C)Cc1ccc(C#Cc2cnc(Cl)nc2)cc1
Reactant: CNCCOC
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(C)c1ncc(C#Cc2ccc(CC(C)NC(C)=O)cc2)cn1
Temperature: 25 °C

Procedure:
28.2 mg (0.09 mmol) N-(1-(4-((2-chloropyrimidin-5-yl)ethynyl)phenyl)propan-2-yl)-acetamide (I69.1) in 1.5 mL DMSO are added to 12.0 mg (0.14 mmol) N-(2-methoxyethyl)-methylamine followed by 21.8 μl (0.14 mmol) DIPEA. The reaction mixture is stirred at r.t. over night and is directly purified by HPLC (MeOH/H2O/TFA).
Reaction SMILES: [CH3:1][C:2]([CH3:22])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:21])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:20])=[CH:11]/[CH2:12][S:13][CH2:14][C@H:15]([NH2:19])[C:16]([OH:18])=[O:17].C(=O)([O-])[O-].[K+].[K+].[N:29]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>C1COCC1>[N:29]1([C:35]([NH:19][C@@H:15]([CH2:14][S:13][CH2:12]/[CH:11]=[C:10](\[CH3:20])/[CH2:9][CH2:8]/[CH:7]=[C:6](\[CH3:21])/[CH2:5][CH2:4][CH:3]=[C:2]([CH3:22])[CH3:1])[C:16]([OH:18])=[O:17])=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](NC(=O)N1CCOCC1)C(=O)O
Temperature: 25 °C
Reaction time: 47 h
Yield: 27 %

Procedure:
In 100 mL round bottom flask, S-trans, trans-farnesyl-L-cysteine (325 mg, 1.0 mmole) and potassium carbonate (1.3 g, 10 mmole) were dissolved in THF (50 mL). 4-morpholine carbonyl chloride (160 mg, 1.2 mmole) was added. The reaction mixture was stirred at room temperature for 47 hours. THF was removed by rotary evaporation. The crude material was washed with water (10 mL) and 1N HCl solution (10 mL). The remaining crude material was purified by preparative HPLC (120 mg, 27% yield) to yield Compound H: 1H-NMR (500 MHz, CDCl3) δ 1.60 (bs, 6H), 1.66 (s, 3H), 1.67 (s, 3H), 1.95-2.12 (m, 8H), 2.94-3.02 (m, 2H), 3.10-3.20 (m, 2H), 3.40-3.44 (m, 4H), 3.71 (t, J=4.8 Hz, 4H), 4.55 (dd, J=6.3, 11.6 Hz, 1H), 5.09 (t, J=6.9 Hz, 2H), 5.19 (t, J=7.6 Hz, 1H). 13C-NMR (125 MHz, CDCl3): δ 16.0, 16.2, 17.7, 25.7, 26.4, 26.7, 29.9, 33.0, 39.6, 39.7, 44.0, 53.0, 66.3, 119.4, 123.7, 124.3, 131.3, 135.4, 140.2, 157.7, 174.1; ES-MS: mass calcd for Chemical Formula: C23H38N2O4S 438.3 (M+). Found (M+Na) m/z 461.4.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[S:10][C:11]=2[CH:12]=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][Mg+].[Br-]>C1COCC1.C(OCC)C>[C:1]1([C:7]2[C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[S:10][C:11]=2[CH:12]([OH:13])[CH3:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1sc2ccccc2c1-c1ccccc1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)c1sc2ccccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-phenylbenzo[b]thiophene-2-carbaldehyde (430 mg, 1.87 mmol) in THF (10 mL) cooled to −78° C. and under a nitrogen atmosphere was added 3.0M MeMgBr in diethyl ether (1.24 mL) and stirring was continued for 30 min. The reaction mixture was quenched with a saturated solution of NH4Cl (20 mL) and slowly warmed to RT. The mixture was extracted with EtOAc (×2) and the combined organic layers were washed with water, then dried (Na2SO4) and concentrated in vacuo affording 1-(3-phenylbenzo[b]thiophen-2-yl)ethanol as a white solid (472 mg, quantitative). 1H NMR (CDCl3, 400 MHz): δ 7.88-7.84 (1H, m), 7.52-7.28 (8H, m), 5.21 (1H, q, J=6.35 Hz), 2.03 (1H, s), 1.59 (3H, d, J=6.63 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[CH:10](O)=[O:11]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH:5][CH:10]=[O:11]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=CO
Solvent: O
Product: O=CNc1ccc(Cl)c(Cl)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
3,4-Dichloroaniline (1000.0 g, 6.172 mol) and formic acid (585 g, 12.7 mol) were charged, and the mixture was stirred at 90° C. for 1 hr. Water (1.5 L) was dropwise added with heating, and then the mixture was gradually cooled to allow precipitation of the crystals. The mixture was stirred at room temperature for 30 min., and the crystals were collected by filtration. The crystals were washed with water (1.2 L) and dried in vacuo at 40° C. for 8 hrs. to give the title compound (1160.8 g, yield 99.0%) as pale-brown crystals.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8](Cl)=[O:9])([CH3:4])([CH3:3])[CH3:2].[OH:16][CH2:17][C:18]1[S:22][C:21]([C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])=[CH:20][CH:19]=1>>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8]([O:16][CH2:17][C:18]1[S:22][C:21]([C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])=[CH:20][CH:19]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(=O)Cl)cc1C(C)(C)C
Reactant: C=CCOC(=O)c1ccc(CO)s1
Product: C=CCOC(=O)c1ccc(COC(=O)c2ccc(OC)c(C(C)(C)C)c2)s1

Procedure:
In a manner similar to Example 1(d), by reaction of 1.6 g (7 mmol) of 3-tert-butyl-4-methoxybenzoyl chloride with 1.4 g (7 mmol) of allyl 5-hydroxymethyl-2-thiophenecarboxylate, 1.5 g (55%) of allyl ester are obtained in the form of a slightly yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(N(CC)CC)C.CS(C)=O>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:13])([CH3:12])[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(CO)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C=O)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution 2-(tert-Butoxycarbonylamino)-2-methyl-1-propanol (5.7 g, 30.0 mmol) in triethylamine (42 mL) was added a mixture of sulfur trioxide pyridine complex (14.3 g, 90.0 mmol) in anhydrous DMSO (dimethylsulfoxide) (50 mL) at room temperature. The reaction was stirred for 1 hour under nitrogen and concentrated. The residue was dissolved in EtOAc (200 mL), washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, and concentrated to give crude 2-(tert-butoxycarbonylamino)-2-methyl propionaldehyde as yellow oil. Purification by distillation afforded 4.90 g (87%) of waxy, white solid: 1H NMR (CDCl3) δ 1.30 (s, 6H), 1.41 (s, 9H), 4.97 (br, 1 H), 9.40 (s, 1H).