Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([Mg]Br)=[CH:3][CH3:4].[CH2:7]([O:11][CH:12]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:13]1[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][N:14]=1)[CH2:8][CH2:9][CH3:10].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH2:7]([O:11][CH:12]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:13]1[N:14]=[CH:15][CH:16]=[C:17]2[C:3]([CH3:4])=[C:2]([CH3:1])[NH:19][C:18]=12)[CH2:8][CH2:9][CH3:10]
Reactant: CC=C(C)[Mg]Br
Reactant: CCCCOC(OCCCC)c1ncccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCOC(OCCCC)c1nccc2c(C)c(C)[nH]c12
Reaction time: 8 h
Yield: 65.7 %

Procedure:
1-Methyl-1-propenyl magnesium bromide (0.5M in tetrahydrofuran solution, 243 ml, 121 mmol) was slowly added at −78° C. to a solution of 2-dibutoxymethyl-3-nitropyridine (11.53 g, 40 mmol) prepared in Step 2 in tetrahydrofuran (100 ml). The reaction mixture was stirred overnight and a saturated ammonium chloride solution (50 ml) was added thereto. The reaction mixture was diluted with ethyl acetate (100 ml), washed with water, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 8 g of the titled compound as brown oil. The product was used in the subsequent step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([S:13][CH3:14])[NH:10][N:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([Cl:22])C(=O)C1>>[Cl:22][C:12]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:9][NH:10][C:11]=1[S:13][CH3:14]
Reactant: CSc1cc(-c2ccc(F)cc2)n[nH]1
Reactant: O=C1CCC(=O)N1Cl
Product: CSc1[nH]nc(-c2ccc(F)cc2)c1Cl

Procedure:
Following protocol L, 3-(4-fluoro-phenyl)-5-methylsulfanyl-1H-pyrazole was treated with NCS in to yield the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.OC1CCNC1.[OH:33][CH2:34][CH2:35][CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:39]3[CH2:40][CH2:41][CH:36]([CH2:35][CH2:34][OH:33])[CH2:37][CH2:38]3)[CH:7]=2)=[CH:9][C:10]=1[C:23]([F:26])([F:25])[F:24]
Reactant: OCCC1CCNCC1
Reactant: COc1ccccc1Sc1ccc(-c2ccnc(Cl)c2)cc1C(F)(F)F
Agent: OC1CCNC1
Product: COc1ccccc1Sc1ccc(-c2ccnc(N3CCC(CCO)CC3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 96 (0.039 g, 0.0985 mmol) and 3-hydroxypyrrolidine with 4-(2′-hydroxyethyl)piperidine. A yellow solid 108 was obtained (0.0308 g, 64%). 1H-NMR (CDCl3, 400 MHz) δ 1.34–1.43 (m, 2H), 1.58 (q, J=6.6 Hz, 2H), 1.84–1.93 (m, 1H), 1.96–2.02 (m, 2H), 3.21–3.29 (m, 2H), 3.74 (t, J=6.2 Hz, 2H), 3.83 (s, 3H), 4.33–4.39 (m, 2H), 6.91 (d, J=6.6 Hz, 1H), 6.96 (s, 1H), 7.00–7.07 (m, 3H), 7.45–7.52 (m, 3H), 7.84 (s, 1H), 8.24 (d, J=6.6 Hz, 1H); MS (APCI) m/z 489 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([F:10])=[C:4](Cl)[N:3]=1.C(O)C.[H][H]>[Pd].C(N(CC)CC)C>[NH2:9][CH2:8][C:7]1[CH:2]=[N:3][CH:4]=[C:5]([F:10])[CH:6]=1
Reactant: [H][H]
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: NCc1cncc(F)c1
Reaction time: 18 h

Procedure:
In a Parr Bottle add 2,6-dichloro-3-cyano-5-fluoropyridine (20 g, 0.105 mol), ethanol (336 mL), triethylamine (24 mL), and 5% Pd/C (4g). Place on a Parr Shaker Apparatus under 60 psi hydrogen for 1 h at ambient temperature. Filter the reaction mixture and bubble ammonia gas into filtrate for 10 min. Add Raney® nickel (5.2 g) and place on a Parr Shaker Apparatus under 500 psi hydrogen for 18 h at 60-70° C. Filter the reaction mixture and concentrate in vacuo. Dissolve in methanol and add 1N hydrogen chloride in ether until form a precipitate. Cool in an ice bath, filter off the precipitate, wash the solid several times with ether, and dry to give the title compound as the hydrochloride salt (12g, 70%). MS (ES+) m/z: 127 (M+H)+. Dissolve the hydrochloride salt in water, add 0.1 N aqueous NaOH to adjust to pH 10, extract with DCM, dry the organic layer over Na2SO4, filter and concentrate to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[C:14]([F:16])[C:13]([NH:17][C:18]([NH:20][C:21]3[CH:34]=[CH:33][C:24]4[O:25][C:26]([F:32])([F:31])[O:27][C:28]([F:30])([F:29])[C:23]=4[CH:22]=3)=[O:19])=[C:12]([F:35])[CH:11]=2)[CH:6]=[CH:5][N:4]=1)#[N:2].C([O-])([O-])=[O:37].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+]>CC(C)=O.O>[F:35][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([F:16])[C:13]=1[NH:17][C:18]([NH:20][C:21]1[CH:34]=[CH:33][C:24]2[O:25][C:26]([F:31])([F:32])[O:27][C:28]([F:29])([F:30])[C:23]=2[CH:22]=1)=[O:19])[O:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:1]([NH2:2])=[O:37])[CH:8]=1
Reactant: N#Cc1cc(Oc2cc(F)c(NC(=O)Nc3ccc4c(c3)C(F)(F)OC(F)(F)O4)c(F)c2)ccn1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: NC(=O)c1cc(Oc2cc(F)c(NC(=O)Nc3ccc4c(c3)C(F)(F)OC(F)(F)O4)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-{4-[(2-cyanopyridin-4-yl)oxy]-2,6-difluorophenyl}-N′-(2,2,4,4-tetra-fluoro-4H-1,3-benzodioxin-6-yl)urea (100 mg, 0.20 mmol) in acetone (2 ml) and water (1 ml) was treated with sodium percarbonate (contain 25% H2O2, 320 mg, 2.0 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (20 ml) and water (10 ml). The organic layer was washed with water (10 ml) and brine (5 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was crystallized from methanol providing 42 mg (41%) of title compound as a white solid. 1H-NMR (DMSO-d6) δ 9.48 (s, 1H), 8.56 (d, J=6.0 Hz, 1H), 8.31 (s, 1H), 8.15 (s, 1H), 8.07 (d, J=2.2 Hz, 1H), 7.74 (s, 1H), 7.68 (dd, J=9.2, 2.7 Hz, 1H), 7.46 (d, J=2.3 Hz, 1H), 7.41 (d, J=9.3 Hz, 1H), 7.25 (m, 2H); MS GC-MS M+=515.0, RT=3.63 min.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:4]=2[N:3]=1.[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)#[CH:22].CCN(CC)CC>CN(C=O)C.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.[Cu]I>[CH:16]1([N:5]2[C:4]3[N:3]=[C:2]([C:22]#[C:21][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:11]=[CH:10][C:9]=3[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]2[CH2:14][CH3:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@@H]1C(=O)N(C)c2cnc(C#Cc3ccccc3)nc2N1C1CCCC1

Procedure:
To a solution of Intermediate B (1.0 eq) in DMF, ethynylbenzene (compound III-139, 3.0 eq), Pd(PPh3)2Cl2 (0.2 eq), CuI (0.25 eq) and Et3N (5.0 eq) were added. The mixture was refluxed for 18 h under argon, extracted with EtOAc and purified by silica gel column to give (R)-8-cyclopentyl-7-ethyl-5-methyl-2-(phenylethynyl)-7,8-dihydropteridin-6(5H)-one (compound IV-139).
Reaction SMILES: CC([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1)=C.OO.[OH:19]S(O)(=O)=O.[O-]S([O-])=O.[Na+].[Na+]>C(O)(=O)C.O>[OH:19][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1
Reactant: C=C(C)c1ccc(OC(C)C(=O)OC)cc1
Reactant: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)C(C)Oc1ccc(O)cc1
Temperature: 10 °C
Reaction time: 0.03 h
Yield: 94 %

Procedure:
An 86.0 g-portion of methyl 2-(4-(1-methylethenyl)phenoxy)propanoate was dissolved in 360 ml glacial acetic acid. An equimolar portion of 30% aqueous H2O2 was added. The solution was cooled to 10° C. and 7.6 mol % of 98% H2SO4 was added. The solution was allowed to slowly warm to 35° C. over 11 minutes at which point the ice bath was put back on. The temperature peaked at 84° C. two minutes later. The reaction mixture was allowed to cool slowly to 36° C. over 25 minutes. A 26 g-portion of 20% aqueous Na2SO3 was added, followed by 900 ml water. The mixture was extracted with four 200 ml-portions of CH2Cl2. The combined organic layers were washed with two 200 ml-portions and one 400 ml-portion of 5% aqueous NaHCO3. The organic layer was dried with Na 2 SO4. Removal of solvent gave 74.8 of 94% pure methyl 2-(4-hydroxyphenoxy)propanoate, corresponding to a 92% yield. Distillation under reduced pressure gave 59.3 g of methyl 2-(4-hydroxyphenoxy)propanoate (b.p. 154°-155° C./4 torr) corresponding to a 77% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[S:14][C:15]([C:19]([O:21][CH3:22])=[O:20])=[C:16]([CH3:18])[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11]Cl.[CH3:23][CH:24]1[CH2:28][CH2:27][CH2:26][NH:25]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[S:14][C:15]([C:19]([O:21][CH3:22])=[O:20])=[C:16]([CH3:18])[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][N:25]1[CH2:26][CH2:27][CH2:28][CH:24]1[CH3:23]
Reactant: COC(=O)c1sc(-c2ccc(OCCCCl)c(Br)c2)nc1C
Reactant: CC1CCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: COC(=O)c1sc(-c2ccc(OCCCN3CCCC3C)c(Br)c2)nc1C
Temperature: 90 °C
Reaction time: 8 h
Yield: 8 %

Procedure:
A suspension of methyl 2-[3-bromo-4-(3-chloropropoxy)phenyl]-4-methyl-1,3-thiazole-5-carboxylate i91 (0.5 g, 1.24 mmol, 1 eq), 2-methylpyrrolidine (0.3 ml, 3.0 mmol, 2.5 eq), potassium carbonate (0.68 g, 5 mmol, 4 eq) and sodium iodide (20 μg, 0.12 mmol, 0.1 eq) in acetonitrile (10 ml) is stirred overnight at 90° C. The resulting mixture is taken up with dichloromethane, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The crude product is triturated in diethyl ether to afford 50 mg of methyl 2-{3-bromo-4-[3-(2-methyl-1-pyrrolidinyl)propoxy]phenyl}-4-methyl-1,3-thiazole-5-carboxylate 126.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[CH:4][N:3]=1.[Li]CCCC.CN([CH:25]=[O:26])C.[BH4-].[Na+]>CCOCC>[Si:10]([O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:25][OH:26])=[N:3][CH:4]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Br)nc1
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1ccc(CO)nc1

Procedure:
The reaction was carried out as described in Example 1, Step 3 using 2-bromo-5-(tert-butyldimethylsilyloxymethyl)pyridine (12 g, 39.7 mmol), BuLi (37 ml of a 1.6 M solution in hexanes, 59.6 mmol) DMF (9.2 ml, 0.12 mol) and NaBH4 (1.5 g, 39.7 mmol) to yield, after column chromatography on silica using Et2O as eluent, the title alcohol (6.66 g, 66%).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:14]1[N:15]=[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[N:17]2[C:26]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:13])=O)C1C=CC=CC=1.CSC>C(O)(C(F)(F)F)=O>[NH2:11][C@H:12]([C:14]1[N:15]=[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[N:17]2[C:26]=1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH3:13]
Reactant: COC(=O)c1cccc2nc([C@H](C)NC(=O)OCc3ccccc3)c(-c3ccccc3)n12
Solvent: CSC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc2nc([C@H](C)N)c(-c3ccccc3)n12
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.2 %

Procedure:
The mixture of (S)-methyl 2-(1-(((benzyloxy)carbonyl)amino)ethyl)-3-phenylimidazo[1,2-a]pyridine-5-carboxylate (600 mg, 1.3 mmol) and dimethylsulfide (0.4 mL) in TFA (1.2 mL) was stirred at 25° C. overnight. The mixture was concentrated in vacuo and the residue was dissolved in EtOAc. The organic layer was washed with satd. sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo to provide (S)-methyl 2-(1-aminoethyl)-3-phenylimidazo-[1,2-a]pyridine-5-carboxylate (400 mg): LC-MS (ESI) m/z 296.2 [M+H]+. The crude product was used without further purification.
Reaction SMILES: N[C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:13])=[N:7]2.N([O-])=O.[Na+].[OH-].[Na+].[ClH:20]>O>[Cl:20][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:13])=[N:7]2
Reactant: Cc1ccc2c(N)c(Cl)ccc2n1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2c(Cl)c(Cl)ccc2n1

Procedure:
5-Amino-6-chloroquinaldine (4 g) was dissolved in 40 ml of concentrated hydrochloric acid and the resulting solution was cooled with ice. Then, a solution of 2.1 g of sodium nitrite dissolved in 5 ml of water was added thereto dropwise while ice-cooling. After continuing the reaction at the same temperature as above, the reaction mixture was added to a solution of 7 g of cuprous chloride dissolved in 15 ml of concentrated hydrochloric acid and the resulting mixture was allowed to react on a water bath at a temperature of 50° C. for 1 hour, during which time vigorous formation of nitrogen gas was observed. Subsequently, the reaction mixture was cooled, rendered alkaline with 30% sodium hydroxide, and filtered and extracted using 300 ml of chloroform and Celite (diatomaceous earth). After drying over anhydrous sodium sulfate the chloroform fraction was concentrated and recrystallized from a mixture of isopropanol and water to give 3.5 g of 5,6-dichloroquinaldine as white needles having a melting point of 84° to 85° C.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>>[F:21][C:22]([F:32])([F:33])[C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:28])=[CH:25][CH:24]=1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Product: CCOC(=NC(=O)c1ccc(C(F)(F)F)cc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
In an analogous manner, starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and p-trifluoromethylbenzoyl chloride, there is obtained ethyl N-(p-trifluoromethylbenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 112°-113° C.;
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH2:10][C@@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([Cl:21])=[C:18](Br)[CH:19]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(CC)CC.[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31]>C1(C)C=CC=CC=1.[I+].[Cu+].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>[C:1]([N:8]1[CH2:11][CH2:10][C@@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([Cl:21])=[C:18]([C:34]#[C:33][Si:30]([CH3:32])([CH3:31])[CH3:29])[CH:19]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]1COc1cnc(Cl)c(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [I+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@@H]1COc1cnc(Cl)c(C#C[Si](C)(C)C)c1
Temperature: 100 °C
Yield: 62.2 %

Procedure:
To a solution of 3-(1-BOC-2-(R)-azetidinylmethoxy)-6-chloro-5-bromopyridine (660 mg, 1.75 mmol) in toluene (20 mL) was added NEt3 (0.7 mL), copper (I) iodine (33 mg), tetrakis(triphenylphosphine)palladium (0) (201 mg) and (trimethylsilyl)acetylene (0.30 mL, 2.10 mmol). The reaction mixture was stirred and heated at 100° C. for 16 h. Solvent was evaporated and the residue was chromatographed (silica gel; hexane/EtoAc, 5:1 to 2:1) to afford an oil (430 mg, 62%): 1H NMR (CDCl3, 300 MHz) δ 1.42 (s, 9H), 2.20-2.40 (m, 2H), 3.80-3.92 (m, 2H), 4.10 (m, 1H), 4.30 (m,1H), 4.50 (m, 1H), 7.37 (d, 1H, J=3.0 Hz), 8.05 (d, 1H, J=3.0 Hz); MS (CI/NH3) m/z 395 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([C:10]2[CH:11]=[N:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[CH:14][CH:15]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[SH:57][C:58]1[CH:67]=[CH:66][C:61]([C:62]([O:64][CH3:65])=[O:63])=[CH:60][CH:59]=1>C1COCC1.C1(C)C=CC=CC=1>[CH3:65][O:64][C:62](=[O:63])[C:61]1[CH:66]=[CH:67][C:58]([S:57][CH:8]([C:10]2[CH:11]=[N:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[CH:14][CH:15]=2)[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:59][CH:60]=1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: OC(CC1CCCCC1)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(SC(CC2CCCCC2)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-cyclohexyl-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethanol (300 mg, 0.88 mmol) in THF (2 mL) and toluene (4 mL) is added 1,1′-(azodicarbonyl)dipiperidine (ADDP, 325.0 mg, 1.29 mmol) at 0° C., followed by the addition of tributylphosphine (0.32 mL, 1.29 mmol) and methyl 4-mercaptobenzoate (173.3 mg, 1.03 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl acetate giving 4-{2-cyclohexyl-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethylsulfanyl}-benzoic acid methyl ester. The ester product is taken into ethanol (2 mL), treated with sodium hydroxide (5N aqueous, 1 mL) for 3 h at room temperature. The mixture is concentrated, diluted with ethyl acetate, acidified with 5 N HCl (1.1 mL), extracted with ethyl acetate. The organic layers are dried and concentrated giving 4-{2-cyclohexyl-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethylsulfanyl}-benzoic acid (190 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:29]([NH:31][CH2:32][CH:33]5[CH2:35][CH2:34]5)=[O:30])=[CH:19][N:20](COCC[Si](C)(C)C)[C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:29]([NH:31][CH2:32][CH:33]5[CH2:34][CH2:35]5)=[O:30])=[CH:19][NH:20][C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NCC2CC2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: ClCCl
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NCC4CC4)c3n2)c2ccc(Cl)cc21
Reaction time: 18 h
Yield: 92.7 %

Procedure:
To a stirred solution of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-N-(cyclopropylmethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (0.049 g, 0.096 mmol) in dichloromethane (5 mL) was added TFA (0.55 g, 0.36 mL, 4.78 mmol) at 20° C. After 18 h, the mixture was concentrated in vacuo. The residue was diluted with dichloromethane and concentrated again. The residue was then suspended in dichloromethane (5 mL) and ethylenediamine (0.29 g, 0.32 mL, 4.78 mmol) was added. The mixture was stirred for 18 h, then concentrated in vacuo. The residue was triturated with water and collected by filtration, washed with water and dried in a vacuum oven to give 2-(6-chloro-1-methyl-1H-indazol-3-yl)-N-(cyclopropylmethyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (0.034 g, 0.089 mmol, 93%) as a yellow solid. MS (M+H)+=381; 1H NMR (DMSO-d6) δ: 9.10 (s, 1H), 8.47 (d, J=8.7 Hz, 2H), 8.44 (s, 1H), 8.21 (t, J=5.4 Hz, 1H), 8.00 (d, J=1.3 Hz, 2H), 7.31 (dd, J=8.6, 1.8 Hz, 2H), 4.18 (s, 3H), 3.33-3.40 (m, 2H), 1.04-1.28 (m, 1H), 0.48-0.65 (m, 2H), 0.27-0.41 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:33])[CH:13]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[CH3:10][O:11][C:12](=[O:33])/[CH:13]=[CH:8]/[C:5]1[CH:6]=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Br)nc1
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5.045 g (27.12 mmol) of 6-bromopyridine-3-carbaldehyde were dissolved in 50 ml of THF. 9.068 g (27.12 mmol) of 2-(triphenylphosphoranylidene)acetic acid methyl ester were added and the mixture was stirred at RT for 4 hours. After evaporation, the residue stirred with methanol and the solid was filtered off. The filtrate was evaporated and the residue was purified by chromatography (silica gel, ethyl acetate/n-heptane 1:4). Yield: 5.01 g (76.3%)
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([C:33]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([F:43])[CH:36]=2)=O)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH3:23]>C1COCC1>[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([C:33]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([F:43])[CH:36]=2)=[CH:9][C:10]#[N:11])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH3:23]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CCOc1cc(C(=O)c2ccc(OC)c(F)c2)ccc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOc1cc(C(=CC#N)c2ccc(OC)c(F)c2)ccc1OC
Temperature: 0 °C
Yield: 66.2 %

Procedure:
To a stirred solution of cyanomethylphosphonic acid diethyl ester (0.38 mL, 2.4 mmol) in THF (8 mL) in an ice bath was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 2.3 mL, 2.3 mmol) dropwise. The mixture was stirred at room temperature for 40 min. (3-Ethoxy-4-methoxy-phenyl)-(3-fluoro-4-methoxy-phenyl)-methanone (0.35 mg, 1.2 mmol) was added to the mixture. The mixture was refluxed overnight. The solution was poured into ice water (30 ml). The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers was washed with water (50 mL), sodium hydrogen carbonate (50 mL, sat), brine (50 mL) and dried over magnesium sulfate. Removal of solvent and chromatography (Silica Gel) gave a mixture of (E/Z) 3-(3-ethoxy-4-methoxy-phenyl)-3-(3-fluoro-4-methoxy-phenyl)-acrylonitrile as an off-white solid (0.26 g, 69% yield) (isomer ratio is 1:0.8 by HNMR): mp: 122-124° C.; 1H NMR (DMSO-d6) δ 1.31 (t, J=7 Hz, 3H, CH3), 3.78 (s, 3H, CH3), [4.83 and 3.87 (2s)], 3.94 (s, 3H, CH3), 4.01 (q, J=7 Hz, 2H, CH2), [6.15 (s)], 6.21 (s, 1H, CH), 6.74 (dd, J=2, 8 Hz, 1H, Ar), 6.92-7.36 (m, 5H, Ar); 13C NMR (DMSO-d6) δ 14.56, 14.58, 55.49, 56.08, 56.16, 63.84, 93.60, 93.82, 111.39, 111.59, 112.07, 113.53, 113.65, 113.75, 115.34, 115.64, 116.69, 116.99, 118.56, 122.27, 122.33, 125.70, 125.74, 120.22, 126.27, 128.84, 129.59, 129.70, 130.12, 130.86, 130.96, 147.47, 147.89, 148.12, 148.28, 148.88, 149.04, 149.18, 150.27, 151.18, 152.79, 153.06, 159.99, 160.09; Anal. Calcd for C19H18NO3F: C, 69.71; H, 5.54; N, 4.28. Found: C, 69.55; H, 5.58; N, 4.25.
Reaction SMILES: C([C:3]([S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:5]=[CH:6][N:7](C)[CH3:8])#N.[ClH:16].O.[OH-].[Na+]>C(O)(C)C>[Cl:16][N:7]1[CH:6]=[CH:5][CH:4]=[C:3]([S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])[CH2:8]1
Reactant: CC(C)S(=O)(=O)C(C#N)=CC=CN(C)C
Reactant: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(C)S(=O)(=O)C1=CC=CN(Cl)C1
Reaction time: 20 h
Yield: 51.5 %

Procedure:
The 1-cyano-1-isopropylsulphonyl-4-dimethylamino-1,3-butadiene (34 g, 0.15 mol) obtained in (a) above was dissolved in isopropanol (350 ml). The solution was then heated to reflux and saturated with dry hydrogen chloride. After about 20 hours, the solution was cooled and poured into water and crushed ice. This solution was then neutralised with sodium hydroxide solution and extracted with toluene (5×100 ml). The combined extracts were then evaporated and the remaining brown syrup purified over silica using 1:1 toluene:ethyl acetate as eluant to leave an oil which yielded 7 g 1-chloro-3-isopropylsulphonylpyridine as yellow crystals, m.pt. 82°-84° C., after stirring with petroleum ether. Yield: 51.5% of the theoretical.