Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([CH:11]=1)=[C:9]([CH2:12][CH3:13])[CH:8]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]2=[O:19].[CH3:20][CH:21]1[CH2:26][NH:25][CH2:24][CH2:23][NH:22]1>N1C=CC=CC=1>[CH2:12]([C:9]1[CH:8]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:19])[N:5]2[C:10]=1[CH:11]=[C:2]([N:25]1[CH2:24][CH2:23][NH:22][CH:21]([CH3:20])[CH2:26]1)[CH:3]=[CH:4]2)[CH3:13]
Reactant: CCOC(=O)c1cc(CC)c2cc(Cl)ccn2c1=O
Reactant: CC1CNCCN1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(CC)c2cc(N3CCNC(C)C3)ccn2c1=O
Temperature: 65 °C
Yield: 100.5 %

Procedure:
Ethyl 8-chloro-1-ethyl-4H-quinolizin-4-one-3-carboxylate (558 mg, 2.0 mmol), the product of Step 3 of Example 62, was dissolved in 10 mL of dry pyridine under a nitrogen atmosphere. To the resultant solution was added 600 mg (6.0 mmol) of 2-methylpiperazine and the stirred reaction mixture was heated at 65° C. for 3 hours. The reaction mixture was allowed to cool to ambient temperature and then concentrated in vacuo in order to remove all of the pyridine. The residue was dissolved in 60 mL of methylene chloride and the methylene chloride solution was washed with 60 mL of water. The aqueous layer was extracted with 2×60 mL of methylene chloride and the combined methylene chloride solutions were dried over anhydrous sodium sulfate, filtered and concentrated and dried in vacuo to afford 690 mg of the title compound. The product was carried on to the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH:21]1[CH2:23][CH2:22]1>CN(C=O)C.C(OCC)(=O)C>[CH:21]1([CH2:20][O:10][C:9]2[C:8]([O:11][CH3:12])=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[F:1])[CH2:23][CH2:22]1
Reactant: BrCC1CC1
Reactant: COc1cc(C=O)cc(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C=O)cc(F)c1OCC1CC1
Temperature: 70 °C

Procedure:
To a solution of 3-fluoro-4-hydroxy-5-methoxybenzaldehyde (5.00 g) in DMF (50 mL) were added potassium carbonate (6.09 g) and (bromomethyl)cyclopropane (3.42 mL), and the mixture was stirred with heating at 70° C. for 1 hr. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, and washed with saturated brine. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (6.59 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].[C:16]([C:18]1[CH:19]=[C:20]([S:25]([N:28](CC2C=CC(OC)=CC=2OC)[C:29]2[S:33][N:32]=[CH:31][N:30]=2)(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=1F)#[N:17].Cl>CN(C)C(=O)C.O1CCOCC1.CS(C)=O>[C:16]([C:18]1[CH:19]=[C:20]([S:25]([NH:28][C:29]2[S:33][N:32]=[CH:31][N:30]=2)(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=1[S:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)#[N:17]
Reactant: Fc1ccc(S)cc1F
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Product: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1Sc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3,4-Difluorothiophenol (0.101 g, 0.690 mmol) and potassium carbonate (0.200 g, 1.45 mmol) were stirred in N,N-dimethylacetamide (3 mL). After 5 minutes, 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 1, 0.300 g, 0.690 mmol) was added to the reaction mixture and the mixture stirred at ambient temperature overnight. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with a 1M aqueous solution of sodium hydroxide, followed by brine, then dried over MgSO4, filtered and concentrated in vacuo to give a white solid. The solid was then dissolved in 1,4-dioxane and a 4M solution of hydrogen chloride in 1,4-dioxane (3 mL) added. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated in vacuo to give a residue. The residue was solubilised in dimethylsulfoxide (1 mL) and purified by the B-HPLC method to afford the title compound.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH:6]([OH:14])[CH2:7][NH:8][C:9](=[O:13])[C:10]([CH3:12])=[CH2:11])[CH:2]=[CH2:3].[CH3:15][Si:16]([CH3:30])([CH3:29])[O:17][SiH:18]([O:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[O:19][Si:20]([CH3:23])([CH3:22])[CH3:21].[Cl-]>C1(C)C=CC=CC=1>[OH:14][CH:6]([CH2:5][O:4][CH2:1][CH2:2][CH2:3][Si:18]([O:19][Si:20]([CH3:23])([CH3:22])[CH3:21])([O:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[O:17][Si:16]([CH3:29])([CH3:30])[CH3:15])[CH2:7][NH:8][C:9](=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: C=CCOCC(O)CNC(=O)C(=C)C
Reactant: C[Si](C)(C)O[SiH](O[Si](C)(C)C)O[Si](C)(C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)NCC(O)COCCC[Si](O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](C)(C)C
Temperature: 96 °C
Reaction time: 16 h

Procedure:
N-(3-Allyloxy-2-hydroxy-propyl)-2-methyl acrylamide made according to Example 9 (18 g, 0.09 mol), platinic chloride (4 mg, 100 ppm), BHT (36 mg, 2000 ppm) and toluene (90 mL) were charged into a 500 mL three-neck flask, equipped with a condenser with a nitrogen inlet and outlet, and a thermocouple connected to a temperature controller. Tris(trimethylsiloxy)silane (26.8 g, 0.09 mol) was added dropwise to the above mixture at 96-97° C. After stirred at about 96° C. for 16 hours, additional platonic chloride (4 mg, 100 ppm) was added to the reaction solution. The reaction was monitored by gas chromatography. After stirred for 47 hours, the reaction solution was washed with 0.5 N aqueous sodium hydroxide solution and twice with 2.5% aqueous sodium chloride solution. This was followed by washing with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate and filtered. The filtrate, inhibited with 4-methoxyphenol (0.02 g), was concentrated under reduced pressure at 30° C.-40° C. to give an oil (˜36 g). N-(2-hydroxy-3-(3-(tris(trimethylsilyloxy)silyl)propyloxy)propyl)-2-methyl acrylamide was purified by column chromatography.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH:6]=1.[C:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:18])/[CH:15]=[CH:16]/[CH3:17]>C(#N)C.O.O.O.O.O.O.[N+]([O-])([O-])=O.[Y+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:13]=[CH:12][C:10]([NH:11][CH:16]([CH3:17])[CH2:15][C:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])=[CH:9][CH:8]=2)[CH:6]=1
Reactant: Cc1cn(-c2ccc(N)cc2)cn1
Reactant: C/C=C/C(=O)NC(=O)OC(C)(C)C
Agent: O=[N+]([O-])[O-]
Agent: [Y+3]
Solvent: CC#N
Solvent: O
Product: Cc1cn(-c2ccc(NC(C)CC(=O)NC(=O)OC(C)(C)C)cc2)cn1
Temperature: 50 °C
Yield: 33 %

Procedure:
A mixture of 4-(4-methyl-1H-imidazol-1-yl)aniline (for a preparation see intermediate 64) (500 mg, 2.89 mmol), 1,1-dimethylethyl (2E)-2-butenoylcarbamate (for a preparation see intermediate 65) (615 mg, 3.32 mmol) and Yttrium(III) Nitrate hexahydrate (111 mg, 0.289 mmol) in acetonitrile (2 mL) was heated at 50° C. for 15 h. An extra portion of Yttrium(III) Nitrate hexahydrate (111 mg, 0.289 mmol) was added to the mixture which was stirred for 7 more hours before being cooled to room temperature. Half of the solvent was removed in vacuo and the residue was partitioned between AcOEt (40 mL) and a saturated NaHCO3 aqueous solution (20 mL). The layers were separated and the organic phase was washed with brine (15 mL). The combined aqueous phases were extracted with AcOEt (35 mL) and the combined organic were dried over MgSO4 and concentrated in vacuovacuo. Purification of the residue by flash chromatography on silica gel (gradient:4 to 8% MeOH in DCM) gave a residue which was further purified by flash chromatography on silica gel (gradient:60-95% AcOEt in Hexanes) to give 1,1-dimethylethyl (3-{[4-(4-methyl-1H-imidazol-1-yl)phenyl]amino}butanoyl)carbamate (343 mg, 0.956 mmol, 33%) as a colourless sticky solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(O[C:11](=[O:16])[C:12]([Br:15])([F:14])[F:13])C>C1COCC1>[Br:15][C:12]([F:13])([F:14])[C:11]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:16]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)C(F)(F)Br
Solvent: C1CCOC1
Product: CN1CCN(C(=O)C(F)(F)Br)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.2 %

Procedure:
1-Methyl-piperazine (1.23 g; 12.3 mmol; 5 eq.) was added to a solution of bromo-difluoro-acetic acid ethyl ester (500 mg; 2.46 mmol; 1 eq.) in THF (50 mL) and the reaction mixture was stirred at room temperature for 16 hours then concentrated in vacuo. The residue was taken up in EA, washed with water, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (450 mg, 71%) as a yellow oil.
Reaction SMILES: [Cl-].[CH3:2][Zn+].Br[C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12]=2[Cl:14])[N:7]([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH:6]=1>C1COCC1.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>[Cl:14][C:12]1[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][N:9]=[C:8]2[N:7]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:6]=[C:5]([CH3:2])[C:13]=12
Reactant: C[Zn+]
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2c(Cl)c(-c3ccccc3)cnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1cn(S(=O)(=O)c2ccccc2)c2ncc(-c3ccccc3)c(Cl)c12
Temperature: 80 °C
Yield: 87.8 %

Procedure:
Methyl zinc chloride (3.35 mL, 6.70 mmol) was added to 3-bromo-4-chloro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.00 g, 2.23 mmol) and Pd(PPh3)4 (0.129 g, 0.111 mmol) in THF (10 mL). The reaction was then heated to 80° C. for 2 hours, cooled to room temperature, and quenched with saturated NH4Cl. The resulting solids were filtered and discarded. The filtrate was diluted with DCM (500 mL) and was washed with water. The combined organic fractions were dried, filtered, and concentrated to give a crude solid that was purified by column chromatography (2:1 DCM:hexanes) to give 4-chloro-3-methyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.75 g, 87.7% yield).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C@:11]([OH:27])([CH3:26])[CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+].C(OCC)(=O)C.O>CN(C=O)C>[CH3:26][C@@:11]1([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[O:27][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@](C)(O)Cn2cc([N+](=O)[O-])nc2Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Reaction time: 2 h
Yield: 70.9 %

Procedure:
Tert-butyl (S)-4-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]-piperazine-1-carboxylate prepared in Example 365 (10.25 g, 25.4 mmol) was dissolved in DMF (30 ml). To the solution, sodium hydride (1.12 g, 27.9 mmol) was added followed by stirring for 2 hours with cooling on ice-bath. To the reaction mixture, ethyl acetate (10 ml) and water (70 ml) were added. The precipitates were filtered off, and washed with water. The crude solids were recrystallized from ethyl acetate (70 ml) to afford tert-butyl (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate (6.62 g, yield 71%) as a light yellow powder.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4](I)=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[CH2:13]([Sn](CCCC)(CCCC)C#C)[CH2:14]CC.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C(OCC)(=O)C>CN1CCCC1=O.[Cl-].[Na+].O.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].[Cl-].[Zn+2].[Cl-]>[NH2:1][C:2]1[S:3][C:4]([C:13]#[CH:14])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)c1nc(N)sc1I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: C#Cc1sc(N)nc1C(=O)OCC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
2-Amino-4-ethoxycarbonyl-5-iodothiazole (1.40 g) prepared in step a) in Example 1 was dissolved in 20 ml of N-methyl-2-pyrrolidinone. tri-n-butylethynyltin (1.63 ml), 127 mg of tri(2-furyl)phosphine, 127 mg of tris(dibenzylideneacetone)dipalladium(0), and 1.27 g of zinc chloride were added to the solution under an argon atmosphere, and the mixture was stirred at room temperature for 2.5 hr. Brine and ethyl acetate were added to the reaction solution. The insolubles were removed by filtration through Celite, and the filtrate was extracted twice with ethyl acetate. The organic layers were combined, were washed with brine, were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1) to give 597 mg of 2-amino-4-ethoxycarbonyl-5-ethynylthiazole.
Reaction SMILES: [OH-:1].[Na+].BrBr.[C:5]([C:8]1[C:12]2[CH:13]=[C:14]([C:17]#[N:18])[CH:15]=[CH:16][C:11]=2[O:10][C:9]=1[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:7])C.Cl>O.O1CCOCC1>[C:17]([C:14]1[CH:15]=[CH:16][C:11]2[O:10][C:9]([CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)=[C:8]([C:5]([OH:1])=[O:7])[C:12]=2[CH:13]=1)#[N:18]
Reactant: COc1ccc(CCc2oc3ccc(C#N)cc3c2C(C)=O)cc1
Reactant: [OH-]
Agent: BrBr
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CCc2oc3ccc(C#N)cc3c2C(=O)O)cc1
Yield: 34.6 %

Procedure:
5.2 g of sodiumhydroxide was dissolved in 30 ml of water, and the solution was cooled to a temperature of 0° C. or below. With stirring, to this were added dropwise 2.7 ml of bromine and then 40 ml of a dioxane solution containing 4.14 g of 3-acetyl-2-[2-(4-methoxyphenyl)ethyl]-5-benzofurancarbonitrile obtained in the above step d). The resulting mixture was stirred at 0° C. for 45 minutes with ice cooling for 1 hour. The resulting reaction solution was mixed with water, adjusted to pH 2 with concentrated hydrochloric acid, and then extracted with chloroform. The resulting organic layer was washed with water and dried to distill off the solvent. Thereafter, the resulting residue was purified by subjecting it to silica gel column chromatography using chloroform as an eluant, thereby obtaining 1.44 g of 5-cyano-2-[2-(4-methoxyphenyl)ethyl]-3-benzofurancarboxylic acid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH3:36])[CH:31]=[CH:30][C:29]=4[F:37])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH3:41]N>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:3]1([CH2:36][NH:35][CH2:34][C:32]2[CH:31]=[CH:30][C:29]([F:37])=[C:28]([C:25]3[CH:26]=[C:27]4[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=3)[NH:21][CH:20]=[C:19]4[CH:16]3[CH2:17][CH2:18][N:13]([S:10]([CH2:8][CH3:9])(=[O:11])=[O:12])[CH2:14][CH2:15]3)[CH:33]=2)[CH2:2][CH2:41]1
Reactant: CN
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CNC)ccc4F)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CNCC5CC5)ccc4F)cc23)CC1
Yield: 62.7 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole-7-carboxamide trifluoroacetate, substituting 2-methyl-1-butanamine (38 μL, 0.524 mmol) for methanamine to afford 16.2 mg of the title compound (62.7%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1.C(N(C(C)C)CC)(C)C.[C:27](Cl)(=[O:30])[CH:28]=[CH2:29]>C1COCC1.C(OCC)(=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH:17][C:27](=[O:30])[CH:28]=[CH2:29])[CH:14]=[CH:15][CH:16]=1
Reactant: Nc1cccc(-c2cnc3ccccc3n2)c1
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cccc(-c2cnc3ccccc3n2)c1
Reaction time: 24 h
Yield: 87.6 %

Procedure:
To a solution of (3-quinoxalin-2-ylphenyl)amine (100 mg, 0.452 mmol) and diisopropylethylamine (DIEA, 90 μL, 0.542 mmol) in THF (5 mL), acryloyl chloride (41 μL, 0.497 mmol) was added at room temperature and the reaction mixture was stirred for 24 hrs. Upon diluted with ethyl acetate (25 mL), the organic phase was washed with water (25 mL), dried over MgSO4, filtered and the solvent evaporated in vacuo to afford N-(3-(quinoxalin-2-yl)phenyl)acrylamide (109 mg, 87% yield). LCMS calculated for C17H13N3O (M+H): 276.31. found 276.17. 1H-NMR (DMSO-d6, 400 Mhz) δH: 10.49 (1H, br.), 9.52 (1H, s), 8.60 (1H, m), 8.13-8.16 (2H, m), 8.05-8.08 (1H, m), 7.80-7.95 (3H, m), 7.55-7.60 (1H, m), 6.48-6.58 (1H, dd, J=10 Hz and 16.5 Hz), 6.32 (1H, d, J=16.5 Hz), 5.80 (1H, d, J=10 Hz).
Reaction SMILES: [H+].[CH3:2][C@H:3]([NH2:12])[C@H:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl-].[OH-].[Na+].[I:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21]>CCOCC>[I:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([NH:12][CH:3]([CH3:2])[CH:4]([OH:11])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:21]
Reactant: O=C(Cl)c1cccc(I)c1
Reactant: C[C@H](N)[C@H](O)c1ccccc1
Agent: [Cl-]
Agent: [H+]
Agent: [Na+]
Solvent: CCOCC
Product: CC(NC(=O)c1cccc(I)c1)C(O)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 89.8 %

Procedure:
To a ice-cooled mixture of norephedrine hydrochloride (1) (7.02 g, 37.5 mmol) in Et2O (165 mL) and 55 NaOH aqueous solution (60 mL) was added dropwise a solution of 3-Iodobenzoyl chloride (2b, 10 g, 37.5 mmol) in Et2O (100 mL). After the addition had completed, the resulting mixture was stirred at 0° C. for 4 h. The solvent was removed in vacuo. The residue was washed with H2O, dried, the recrystallized from EtOH to provide a white solid (12.84 g, 90%). mp 139-140.5° C. 1H NMR (CDCl3) d 1.10 (d, J=) 6.9 Hz, 3 H, CH3), 3.51 (d, J=3.3 Hz, 1 H, --CHCH3), 4.42-4.52 (m, 1 H, --OH), 4.97 (bs, 1 H, --CHOH), 6.42 (d, J=7.8 Hz, 1 H, NH), 7.14 (t, J=7.8 Hz, 1 H, aromatic), 7.25-7.42 (m, 5 H, aromatic), 7.69 (d, J=7.8 Hz, 1 H, aromatic), 7.82 (d, J=8.1 Hz, 1 H, aromatic), 8.08 (s, 1 H, aromatic). 13C NMR (CDCl3) d 14.20 (q, CH3), 51.45 (d, --CHCH3), 76.18 (d, --CHOH), 94.24 (s, =CI--, aromatic), 126.14 (d, 2C, aromatic), 127.63 (d, aromatic), 128.26 (d, aromatic), 130.19 (d, aromatic), 136.00 (d, aromatic), 136.25 (s, aromatic), 140.41 (d, aromatic), 140.55 (s, aromatic), 166.26 (s, aromatic). Anal. Calcd. for C16H16INO2 : C, 50.41; H, 4.23; N, 3.67. Found: C, 50.48; H, 4.28; N, 3.62.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1)=[O:4].Br[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[N:18]1[CH:19]=[CH:20][C:15]([C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[C:3]([O:2][CH3:1])=[O:4])=[CH:16][CH:17]=1
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: Brc1ccncc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cccc(-c2ccncc2)c1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
A mixture of (3-(methoxycarbonyl)phenyl)boronic acid (600 mg, 3.33 mmol), 4-bromopyridine (583.5 mg, 3.0 mmol), K2CO3 (1.2 g, 9.0 mmol) and Pd(dppf)Cl2 (50 mg) in a solution of dioxane (10 mL) and H2O (2.5 mL) was stirred at 120° C. for 30 min with microwave heating. The catalyst was filtered and the filtrate concentrated. The residue was then purified by column chromatography to give the title product (630 mg Yield 90%).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[Cl:10][C:11]1[C:19]([S:20](Cl)(=[O:22])=[O:21])=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1>C(Cl)Cl>[Cl:10][C:11]1[C:19]([S:20](=[O:22])(=[O:21])[N:5]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1
Reactant: CCCCNCCCC
Reactant: O=C(O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Solvent: ClCCl
Product: CCCCN(CCCC)S(=O)(=O)c1cc(C(=O)O)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3.9 g. (0.03 mole) of di-n-butylamine in 15 ml. of methylene chloride is added 2.5 g. (0.01 mole) of 4-chloro-5-chlorosulfonylbenzoic acid (J. Pharm. Pharmacol., 683 (1962), and the resulting reaction mixture allowed to stir at room temperature for 3 hrs. The solvent is removed under reduced pressure and the residue partitioned between 1 N sodium hydroxide and diethyl ether. The aqueous phase is separated, acidified with 12 N hydrochloric acid and the precipitated solid filtered and dried, 3.0 g., m.p. 93°-96° C. Recrystallization from ether-hexane provides the pure product, 2.5 g., m.p. 94.5°-96.5° C.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]1[CH2:15][CH:14]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.B(F)(F)F.CC[O:29]CC.[OH-].[K+].OO>C(COC)OC.O.C(Cl)Cl>[CH2:3]([N:10]1[CH2:11][CH2:12][CH:13]([C:16]2[CH:17]=[CH:18][C:19]([Br:22])=[CH:20][CH:21]=2)[CH:14]([OH:29])[CH2:15]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Brc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Reactant: CCOCC
Agent: FB(F)F
Agent: OO
Agent: [BH4-]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: OC1CN(Cc2ccccc2)CCC1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57 %

Procedure:
16.9 g of sodium borohydride were added to a solution of 51.1 g (0.156 mol) of 1-benzyl-4-(4-bromo-phenyl)-1,2,3,6-tetrahydro-pyridine in 350 ml of dimethoxyethane and the reaction mixture was stirred at room temperature for 15 minutes. Thereafter, 95.2 ml of boron trifluoride etherate were added dropwise at 25-30° C. during 30 minutes, the reaction mixture was subsequently stirred at room temperature for 2 hours. Thereafter, firstly a solution of 98.4 g of potassium hydroxide in 530 ml of water was slowly added dropwise and thereafter within 15 minutes 80.7 ml of a 30% hydrogen peroxide solution were added. Subsequently, the mixture was boiled under reflux for 2 hours. For the working-up, the cooled reaction mixture was filtered over Dicalit and this was rinsed with methylene chloride. The solution obtained was treated with 700 ml of methylene chloride, the organic phase was separated and then the aqueous phase was back-extracted with 300 ml of methylene chloride. The combined organic phases were washed twice with 200 ml of water each time, dried over magnesium sulphate and evaporated under reduced pressure. Crystallization of the crude product from acetone yielded 31 g (57% of theory) of (3RS,4RS)-1-benzyl-4-(4-bromo-phenyl)-piperidin-3-ol as colourless crystals; m.p.: 125-129° C.