Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=O)[CH:3]=1.[C:12]([N:15]1[CH2:20][CH2:19]C(C2C=CC=CC=2)=[CH:17][CH2:16]1)(=[O:14])[CH3:13]>C(Cl)Cl>[C:12]([N:15]1[CH2:20][CH2:19][C:8]2([O:10][CH:17]2[CH2:16]1)[C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=1)(=[O:14])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)N1CC=C(c2ccccc2)CC1
Solvent: ClCCl
Product: CC(=O)N1CCC2(c3ccccc3)OC2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6.0 G. of 85% m-chloroperbenzoic acid was added portionwise to a solution of 5.8 g. of 1-acetyl-4-phenyl-1,2,5,6-tetrahydropyridine dissolved in 100 ml. of methylene chloride, the latter being cooled during the addition using an ice bath. The mixture was stirred 18 hours at room temperature, then washed with water, sodium bisulfite solution, sodium carbonate solution and, finally, again with water. After evaporation 4.8 g. of solid remained, which was recrystallised from ether to give 3.9 g. of the desired product which was found to have a melting point of 68°-71° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6].[I-:14].[Na+]>C(C(C)=O)C>[I:14][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6]
Reactant: [I-]
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: [Na+]
Solvent: CCC(C)=O
Product: O=C(CCCI)c1ccc(F)cc1
Yield: 96.2 %

Procedure:
20 g of 1-chloro-3-(p-fluorophenylcarbonyl)propane dissolved in 100 cm3 of methyl ethyl ketone are refluxed for 24 hours in the presence of 18.5 g of sodium iodide. After treatment, 28 g of the desired compound are isolated.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[NH:13][CH:14]=[CH:15][C:3]=12.[H-].[Na+].[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>CN(C=O)C>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([S:25]([C:22]3[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=3)(=[O:27])=[O:26])[CH:14]=[CH:15][C:3]=12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)c1cnc2[nH]ccc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 102.4 %

Procedure:
To a solution of ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1.32 g, 5.88 mmol) in DMF (39 mL) at about 0° C. was added sodium hydride (60% dispersion in mineral oil, 0.400 g, 10.00 mmol) and the reaction mixture was stirred at this temperature for about 15 min. A solution of 4-methylbenzene-1-sulfonyl chloride (2.24 g, 11.8 mmol) in DMF (17 mL) was added dropwise and the reaction mixture was allowed to warm to ambient temperature for about 2 h. The reaction mixture was concd under reduced pressure and the residue was partitioned between EtOAc and water (25 mL each). The aqueous layer was extracted with EtOAc (2×25 mL) and the combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The solid was triturated with heptane, and the precipitates were filtered to give ethyl 4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (2.28 g, 102%, 90% purity) as a white solid: LCMS (Table 1, Method c) Rt=1.64 min; MS m/z: 379 (M+H)+.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:22])[C:4]([S:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)([CH3:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH:23]O>CO>[OH:1][NH:2][C:3](=[O:22])[C:4]([S:13]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)=[O:23])([CH3:12])[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COc1ccc(SC(C)(Cc2ccccc2)C(=O)NO)cc1
Reactant: OO
Solvent: CO
Product: COc1ccc(S(=O)C(C)(Cc2ccccc2)C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N-hydroxy-2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionamide (400 mg, 1.26 mmol) (prepared in Example 1) was dissolved in methanol (100 ml) and 30% H2O2 (10 ml) was added. The reaction mixture was stirred for 48 hours at room temperature at which time it was cooled to 0° C. and quenched with saturated Na2SO3 (20 ml) solution. The reaction mixture became cloudy. It was stirred for 4 hours before it was concentrated in a room temperature water bath, diluted with water, extracted with CHCl3 and washed with H2O. The organic layer was dried over MgSO4, filtered and concentted. The title compound was isolated by silica gel column chromatography, eluting with 75% ethylacetate:hexane. Low melting solid. Yield: 220 mg (52%); MS: 334.1 (M+H)+; 1H NMR (300 Mz, CDCl3): d 1.11 (s, 2H), 1.22 (s, 3H), 3.84 (s, 3H), 7.00-7.61 (m, 9H).
Reaction SMILES: [BH4-].[Na+].C([O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:23])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)(=O)C>>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]([OH:23])[CH2:15][CH2:14]2)=[CH:11][CH:12]=1
Reactant: CC(=O)Oc1ccc(N2CCC(=O)c3ccccc32)cc1
Agent: [BH4-]
Agent: [Na+]
Product: Oc1ccc(N2CCC(O)c3ccccc32)cc1

Procedure:
Conventional sodium borohydride reduction of compound A [method see Example 2c), below] yields 1-p-hydroxyphenyl-4-hydroxy-1,2,3,4-tetrahydro-quinoline.
Reaction SMILES: C(C(=N[OH:14])C=C)CCCCCCCC.[CH2:15]([C:24](=[CH2:27])[C:25]#[N:26])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CC1C=CC=CC=1C>[CH2:15]([C:24](=[CH2:27])[C:25]([NH2:26])=[O:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: C=CC(CCCCCCCCC)=NO
Reactant: C=C(C#N)CCCCCCCCC
Solvent: Cc1ccccc1C
Product: C=C(CCCCCCCCC)C(N)=O
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 318.9 %

Procedure:
418.8 g of 94% pure α-nonylacrolein oxime, 1,030 g of o-xylene, 94.6 g of 95% pure α-nonylacrylonitrile and 13.9 g (2 mol %, based on oxime) of Cu(II) 2-ethylhexanoate were heated at 130° C. A vigorous exothermic reaction began; after this reaction had abated, stirring was continued for a further 1.5 hours at 110° C. Analysis by gas chromatography showed that 98.8% of the oxime used had been converted. 1.2 liters of petroleum ether were added to the reaction mixture, the latter was then cooled to -20° C., and the crude amide precipitated was filtered off under suction. Recrystallization from cyclohexane gave 332 g (84%) of α-nonylacrylamide as colorless crystals of melting point 80°-81° C.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[C:16]([S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH:17]=1>CN(C=O)C>[C:22]([NH:21][S:18]([C:16]1[CH:17]=[C:12]([NH:11][CH:1]=[O:3])[CH:13]=[CH:14][C:15]=1[S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])(=[O:19])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CCS(=O)(=O)c1ccc(N)cc1S(=O)(=O)NC(C)(C)C
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(NC=O)cc1S(=O)(=O)NC(C)(C)C
Temperature: 50 °C
Reaction time: 2 h

Procedure:
0.82 ml of formic acid is added dropwise to 1.85 ml of acetic anhydride. After the mixture has been stirred at 50° C. for 2 hours, a solution of 2.5 g of 5-amino-N-tert-butyl-2-ethylsulfonylbenzenesulfonamide in 10 ml of DMF is added dropwise at room temperature. This mixture is first stirred at 50° C. for 3 hours and then concentrated under a high vacuum. The residue is taken up in water and the mixture is extracted with ethyl acetate. After the organic phase been dried over magnesium sulfate, the solvent is distilled off. The residue (3.0 g) contains the desired product and is of adequate purity for further reactions.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].COCCOC.Br[C:14]1[N:19]=[C:18]([C@@H:20]([OH:25])[CH2:21][O:22][CH2:23][CH3:24])[CH:17]=[CH:16][CH:15]=1.[C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)#[N:27]>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.O>[CH2:23]([O:22][CH2:21][C@@H:20]([C:18]1[N:19]=[C:14]([C:31]2[CH:32]=[CH:33][C:28]([C:26]#[N:27])=[CH:29][CH:30]=2)[CH:15]=[CH:16][CH:17]=1)[OH:25])[CH3:24]
Reactant: CCOC[C@H](O)c1cccc(Br)n1
Reactant: N#Cc1ccc(B(O)O)cc1
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: COCCOC
Solvent: O
Product: CCOC[C@H](O)c1cccc(-c2ccc(C#N)cc2)n1
Temperature: 80 °C
Reaction time: 0.03 h
Yield: 130 %

Procedure:
Pd(PPh3)4 (187 mg, 0.162 mmol) and Na2CO3 (1.29 g, 12.2 mmol) was treated with DME (20 mL) and stirred under nitrogen for 2 min. Water (10 mL), (1R)-1-(6-bromo-2-pyridinyl)-2-(ethyloxy)ethanol (1.0 g, 4.1 mmol) and (4-cyanophenyl)boronic acid (656 mg, 4.47 mmol) were added and the stirred reaction mixture heated at 80° C. for 17 h. The mixture was then allowed to cool to ambient temperature and the residue partitioned between saturated NH4Cl (100 mL) and EtOAc (100 mL). The aqueous phase was extracted with EtOAc (2×100 mL) and the combined organic extracts washed with brine (100 mL), dried (Na2SO4) and evaporated to give a yellow oil (1.43 g). Purification by Biotage™ chromatography (silica, 40 g cartridge) eluting with cyclohexane:EtOAc (4:1) afforded the title compound as a pale yellow oil (945 mg).
Reaction SMILES: [CH2:1]([P:3]([CH2:10][CH:11]([CH3:14])[CH2:12][OH:13])(=[O:9])[O:4]CCCC)[CH3:2].O>C(O)CCC.O>[CH2:1]([P:3]([CH2:10][CH:11]([CH3:14])[CH2:12][OH:13])(=[O:4])[OH:9])[CH3:2]
Reactant: CCCCOP(=O)(CC)CC(C)CO
Solvent: O
Solvent: CCCCO
Product: CCP(=O)(O)CC(C)CO
Reaction time: 4 h
Yield: 99 %

Procedure:
444 g (2 mol) of butyl ethyl(2-methyl-3-hydroxypropyl)phosphinate (produced as in Example 13) are initially charged to a 1 l five-neck flask equipped with thermometer, reflux condenser, high-performance stirrer and dropping funnel. At 160° C., during 4 h, 500 ml of water are metered in and a butanol-water mixture is distilled off. The solid residue is recrystallized from acetone to obtain 329 g (99% of theory) of ethyl(2-methyl-3-hydroxypropyl)phosphinic acid as oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:11]([CH3:13])[CH3:12])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[Na+].[Na+].[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>COCCOC.C(OCC)(=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>[CH:11]([O:10][C:5]1[CH:4]=[CH:3][C:2]([C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)=[CH:9][C:6]=1[CH:7]=[O:8])([CH3:13])[CH3:12]
Reactant: CC(C)Oc1ccc(Br)cc1C=O
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
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(-c2ccc(F)cc2)cc1C=O
Reaction time: 2 h

Procedure:
To a solution of 5-bromo-2-isopropoxy-benzaldehyde (504 mg, 2.07 mmol) in 1,2-dimethoxyethane (5 mL) were added tetrakis(triphenylphosphine)palladium(0) (87 mg, 0.075 mmol), 2M aqueous sodium carbonate (2.5 mL), and 4-fluorobenzeneboronic acid (396 mg, 2.83 mmol). The reaction mixture was stirred for 2 hours at reflux temperature, cooled, diluted with ethyl acetate, washed with water, saturated brine solution, dried (Na2SO4), and evaporated. The title compound was purified by flash chromatography eluting with 4% diethyl ether in hexane; yield 347 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([CH2:14][CH:15]([C:21]([O:23]CC)=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][N:11]=[C:10]1[S:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[Na+].[Na+].C(O)C.Cl>O>[C:16]([CH:15]([CH2:14][C:13]1[N:9]([CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:10]([S:26][CH2:27][CH2:28][CH3:29])=[N:11][CH:12]=1)[C:21]([OH:23])=[O:22])([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCCSc1ncc(CC(C(=O)OCC)C(=O)OCC)n1Cc1ccccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCSc1ncc(CC(C(=O)O)C(=O)OCC)n1Cc1ccccc1Cl
Yield: 39.7 %

Procedure:
A solution of diethyl [1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]methylmalonate (0.62 g, 1.41 mmol), sodium carbonate (1.5 g, 14.2 mol), ethanol (10 mL) and water (10 mL) was stirred at 25° C. for 18 hours, then heated for 15 minutes on a steam bath. The mixture was cooled, neutralized with aqueous hydrochloric acid solution, and the product was extracted into methylene chloride, washed with water, dried and concentrated to 0.425 g of product. Crystallization from ethyl acetate/hexane provided 0.23 g (55%) of 2-carbethoxy-3-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]propanoic acid; mp 118°-120° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[CH2:14]([NH2:16])[CH3:15]>O>[CH2:14]([NH:16][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[CH3:15]
Reactant: CCN
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: O
Product: CCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
2-nitrobenzenesulfonyl chloride (10 g) is added portion-wise to 70% ethylamine in water at 0-5° C., maintaining the temperature. It is stirred for 15 minutes until completing the transformation. Water (80 mL) is added, maintaining the temperature. It is stirred for 30 minutes. It is filtered, washed and dried, obtaining 8.97 g of N-ethyl-2-nitrobenzenesulfonamide.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[O:13]=[S:14]1(=[O:24])[CH2:18][C:17]2[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:16]=2[CH2:15]1>>[O:13]=[S:14]1(=[O:24])[CH2:18][C:17]2[CH:19]=[CH:20][C:21]([NH:23][C:2]3[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=3)=[CH:22][C:16]=2[CH2:15]1
Reactant: Nc1ccc2c(c1)CS(=O)(=O)C2
Reactant: CSc1nc(C)c(C#N)c(Cl)n1
Product: CSc1nc(C)c(C#N)c(Nc2ccc3c(c2)CS(=O)(=O)C3)n1

Procedure:
The compound was prepared from 4-chloro-6-methyl-2-(methylthio)-5-pyrimidinecarbonitrile and (2,2-dioxido-1,3-dihydro-2-benzothien-5-yl)amine following a procedure similar to that described for Intermediate 23.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:14])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:13])[CH2:9][CH:10]([CH3:12])[CH3:11].[OH:15][C:16]1[CH:24]=[CH:23][C:19]2[CH2:20][CH2:21][O:22][C:18]=2[CH:17]=1>>[CH3:14][C:4]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:13])[CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:3][CH2:2][O:15][C:16]1[CH:24]=[CH:23][C:19]2[CH2:20][CH2:21][O:22][C:18]=2[CH:17]=1
Reactant: Oc1ccc2c(c1)OCC2
Reactant: CC(=CCBr)CCC=C(C)CC(C)C
Product: CC(=CCOc1ccc2c(c1)OCC2)CCC=C(C)CC(C)C

Procedure:
1-bromo-3,7,9-trimethyl-2,6-decadiene and 6-hydroxy-2,3-dihydrobenzofuran are reacted to form 6-[(3,7,9-trimethyl-2,6-decadienyl)-oxy]-2,3-dihydrobenzofuran of boiling point (bulb-tube) 112° C./0.03 mmHg; nD21 = 1.5271.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([Cl:11])[CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>>[Cl:11][C:4]1[CH:3]=[C:2]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]=12
Reactant: Clc1cc(Cl)c2c(n1)CCC2
Reactant: C1CCNC1
Product: Clc1cc(N2CCCC2)nc2c1CCC2
Yield: 38.7 %

Procedure:
Following general procedure B1, 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.150 g, 0.80 mmol) was reacted with pyrrolidine (0.085 g, 1.2 mmol) to afford the title compound (0.069 g, 38%) as a light yellow solid. MW=222.71. 1H NMR (CDCl3, 300 MHz) δ 6.13 (s, 1H), 3.46-3.36 (m, 4H), 2.97-2.81 (m, 4H), 2.13-1.94 (6H); APCI MS m/z 223 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([NH:1][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([Cl:15])=[CH:17][CH:18]=2)[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 27.7 %

Procedure:
4-Amino-1-N-Boc piperidine (1.80 g, 8.9 mmol) was dissolved in CH2Cl2 and 4-chlorobenzylbromide (1.84 g, 8.9 mmol) and triethylamine (1.25 mL, 8.9 mmol) were added. The solution was allowed to stir for 14 h at room temperature and evaporated in vacuo and partitioned between ether/1N NaOH. The aqueous layer was removed and the ether was washed with brine and dried over MgSO4, filtered and evaporated in vacuo, then purified by Biotage flash chromatography (5% methanol/95% methylene chloride) to yield the title compound (0.800 g, 27%). 1H-NMR (CDCl3): δ 1.26 (m, 1H), 1.44 (s, 9H), 1.83 (d, 2H), 2.63 (t, 1H), 2.78 (t, 2H), 3.46 (s, 2H), 3.78 (s, 2H), 4.00 (bs, 2H), 7.26 (bs, 4H). ESI-MS m/z: 325.1 (M+1), retention time 1.86.
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[CH2:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:18](O)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].C(N(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[C:18]([O:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: OCc1ccccc1
Reactant: CC(C)(C)C(=O)O
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: Cc1ccccc1
Solvent: CCCCN(CCCC)CCCC
Product: CC(C)(C)C(=O)OCc1ccccc1
Yield: 62 %

Procedure:
To a suspended toluene (2 ml) solution of 2-chloro-1-methylpyridinium iodide (306 mg, 1.2 mmol) was added a mixture of benzyl alcohol (108 mg, 1.0 mmol), pivalic acid (102 mg, 1.0 mmol) and tri-n-butylamine (444 mg, 2.4 mmol) in toluene (2 ml), and the resulting mixture was refluxed for 3 hours. After evaporation of the solvent, the residue was separated by silica gel column chromatography, and benzyl pivalate was isolated in 62% yield.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[O:15]CC=C)([CH3:4])([CH3:3])[CH3:2].[CH:19](OC(C)C)([CH3:21])[CH3:20]>>[CH2:21]([C:7]1[CH:8]=[C:9]([C:11]([CH3:12])([CH3:13])[CH3:14])[CH:10]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:6]=1[OH:15])[CH:19]=[CH2:20]
Reactant: CC(C)OC(C)C
Reactant: C=CCOc1ccc(C(C)(C)C)cc1C(C)(C)C
Product: C=CCc1cc(C(C)(C)C)cc(C(C)(C)C)c1O

Procedure:
10 g of 2,4-di-tert-butylallyloxybenzene are heated under nitrogen to 245° C. for 45 minutes. The yellow crude oil is taken up in diisopropyl ether. The ether phase is washed with 3 % sodium hydroxide and then with water. After drying and evaporation of the solvent, the oil obtained (7.6 g) is chromatographed on silica gel 60 (eluent: 80/20 heptane/CH2Cl2). A pale-yellow oil of 2-allyl-4,6-di-tert-butylphenol is obtained (5.4 g, yield =54 %).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[S:8][C:9]([I:22])=[C:10]([C:20]#[N:21])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])=O.C1(C)C=CC=CC=1.P(Cl)(Cl)(Cl)=O>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:11]1[C:10]([C:20]#[N:21])=[C:9]([I:22])[S:8][C:7]=1[C:5]1[NH:4][CH2:3][CH2:2][N:1]=1
Reactant: N#Cc1c(I)sc(C(=O)NCCN)c1-c1ccc(Cl)cc1Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: N#Cc1c(I)sc(C2=NCCN2)c1-c1ccc(Cl)cc1Cl
Temperature: 120 °C
Yield: 89.6 %

Procedure:
To a mixture of N-(2-aminoethyl)-4-cyano-3-(2,4-dichlorophenyl)-5-iodothiophene-2-carboxamide (1.16 g, 0.00249 mol) in Toluene (20 mL, 0.19 mol) in a pressure vessel was added Phosphoryl chloride (2.0 mL, 0.022 mol) and the mixture was heated at 120° C. for 3 hours. Solvent was evaporated and the residue was diluted with water, treated with 1N NaOH (10 mL) and extracted with DCM (5×50 mL). The combined DCM layers were washed with brine, dried with MgSO4, filtered and concentrated to afford the product (1.00 g, 89%). LCMS: (FA) ES+, 448, 450. 1H NMR (400 MHz, d6-DMSO) δ: 7.81-7.78 (m, 1H) 7.56-7.52 (m, 1H), 7.50-7.47 (m, 1H), 3.67-3.59 (m, 2H), 3.25-3.17 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[H][H]>[Pd].O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/c1ccc(-c2ccc(C)cn2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(-c2ccc(C)cn2)cc1

Procedure:
10% Palladium on charcoal (0.8 g) was added to a solution of the compound obtained from step b above (1.8 g) in tetrahydrofuran (15 mL) at room temperature, and hydrogen was supplied at 50 psi in a Paar apparatus for 4 hours. The reaction mixture was filtered through a celite pad and concentrated to afford the title compound (1.8 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44]>>[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]3[NH:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:25])[CH3:26])=[CH:21][CH:22]=2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44]
Reactant: CN(C)Cc1ccc(Nc2c(S(C)(=O)=O)cnc3ccc(Br)cc23)cc1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CN(C)Cc1ccc(Nc2c(S(C)(=O)=O)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)cc1
Yield: 61.4 %

Procedure:
Following general procedure D, 6-bromo-N-(4-((dimethylamino)methyl)phenyl)-3-(methylsulfonyl)quinolin-4-amine (43 mg, 0.10 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (53 mg, 0.183 mmol) to afford the desired product (31.7 mg, 61%) as a yellow solid. 1H NMR (500 MHz, MeOD) δ 9.00 (s, 1H), 8.06-7.97 (m, 2H), 7.74 (s, 3H), 7.46-7.38 (m, 2H), 7.21 (d, J=8.0 Hz, 2H), 7.13 (s, 2H), 3.86 (s, 2H), 3.27 (s, 3H), 2.45 (s, 6H). ESI MS m/z 516 [C25H23Cl2N3O2S+H]+; HPLC 94.5% (AUC), tR=11.57 min.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.Cl[C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][CH3:17])[N:12]=[C:11]([S:18]([CH3:21])(=[O:20])=[O:19])[N:10]=1.[CH:22]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)([CH3:24])[CH3:23]>C(COC)OC.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>[CH:22]([C:25]1[CH:30]=[C:29]([C:9]2[CH:14]=[C:13]([CH2:15][CH2:16][CH3:17])[N:12]=[C:11]([S:18]([CH3:21])(=[O:20])=[O:19])[N:10]=2)[CH:28]=[CH:27][CH:26]=1)([CH3:24])[CH3:23]
Reactant: CC(C)c1cccc(B(O)O)c1
Reactant: CCCc1cc(Cl)nc(S(C)(=O)=O)n1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: CCCc1cc(-c2cccc(C(C)C)c2)nc(S(C)(=O)=O)n1
Yield: 23.9 %

Procedure:
Potassium carbonate (0.850 g, 6 mmol), water (1 ml) and tetrakis(triphenylphosphine)palladium (0.695 g, 0.6 mmol) were successively added under a nitrogen atmosphere, to a mixture of 4-chloro-2-methanesulfonyl-6-propyl-pyrimidine (1.17 g, 5 mmol) and 3-isopropyl-phenylboronic acid (0.984 g, 6 mmol) in dimethoxyethane (40 mL). The mixture was refluxed for 18 hours then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was chromatographed over silica gel (eluent: Cyclohexane/Ethyl acetate 7/3) to afford a yellow oil which crystallised in pentane. After filtration, 4-(3-isopropyl-phenyl)-2-methanesulfonyl-6-propyl-pyrimidine (0.380 g) was obtained as an off white solid (mp=82° C.).