Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1.O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1)=[O:13])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(Br)cn1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 35.8 %

Procedure:
In 20 ml of pyridine was dissolved 2.19 g of N-t-butoxycarbonyl-L-alanine and the solution was added with 1 g of 2-amino-5-bromopyridine, 2.77 g of 1-(3-dimethyl(aminopropyl)-3-ethylcarbodimide hydrochloride and 1.41 g of 4-dimethylaminopyridine individually and stirred at room temperature for 15 hours. Water was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer thus separated was washed with brine, dehydrated, filtered, and concentrated in vacuo to give 0.713 g of 2-(N-t-butoxycarbonyl-L-alanylamino)-5-bromopyridine. This compound was dissolved, along with 0.714 g of (S)-[N-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide, in 20 ml of dimethylformamide. Reaction was conducted at 100° C. for 4 hours in the presence of 0.6 ml of triethyl amine with the catalytic aid of 0.36 g of dichlorobistriphenylphosphine palladium (II) with stirring after their addition at room temperature. Water was then added to the reaction mixture, followed by the extraction with ethyl acetate. The organic layer thus separated was washed with brine, dehydrated, filtered and concentrated in vacuo. Recrystallization of the concentrate gave 0.27 g of (S)-[N-3-(4-(2-(N-t-buxotycarbonyl-L-alanylaminopyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl)methyl acetamide. This compound was reacted with 0.15 ml of trimethylsilyl iodide in chloroform at room temperature for 30 min under a nitrogen atmosphere. Following the addition of chloroform, the organic layer thus separated was washed with brine, dehydrated, filtered, and concentrated in vacuo. The concentrate was subjected to column chromatography to produce the title compound. 50 mg.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10](=[O:21])[C:9]([C:22]([OH:24])=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:27])=O>>[C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10](=[O:21])[C:9]([C:22]([Cl:27])=[O:24])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1nn(-c2ccccc2)c(=O)n(Cc2ccccc2)c1=O
Product: O=C(Cl)c1nn(-c2ccccc2)c(=O)n(Cc2ccccc2)c1=O
Yield: 81 %

Procedure:
Intermediate k (3.0 g, 0.01 mol) was added to thionyl chloride (10V/W, 30 mL). The mixture was warmed up under stirring to react under reflux for 6 h. The solvent was evaporated off to produce a clear yellow crystal (2.8 g) in a yield of 81%.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([N:13]1[C:18](=[O:19])[CH2:17][C:16](=O)[NH:15][C:14]1=[O:21])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[CH2:6]([N:13]1[C:18](=[O:19])[CH:17]=[C:16]([Cl:3])[NH:15][C:14]1=[O:21])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1CC(=O)N(Cc2ccccc2)C(=O)N1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: O=c1cc(Cl)[nH]c(=O)n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To 16.8 ml of 50% ethanol, 78.7 ml (844 mmol) of phosphorus oxychloride was added dropwise, with stirring under ice cooling conditions. To this solution, 20.62 g (94.5 mmol) of 3-benzylpyrimidine-2,4,6(1H,3H)-trione was added portionwise. This mixture was stirred at 50° C. for 30 minutes and then at 100° C. for 90 minutes. After cooling, the reaction mixture was poured into ice water and stirred for 1 hour. The resulting precipitate was collected by filtration, washed with water and n-hexane and dried to yield 20.12 g (90.0%, white crystal) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH:9]1[CH2:15][NH:14][CH2:13][CH2:12][CH2:11][N:10]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH2:5].C(=O)(O)[O-].[Na+].[CH2:28]([O:35][C:36](Cl)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[CH2:28]([O:35][C:36]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([CH:9]2[CH2:15][NH:14][CH2:13][CH2:12][CH2:11][N:10]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[C:2]([F:1])[CH:3]=1)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1c1ccc(N)cc1F
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCNCC1c1ccc(NC(=O)OCc2ccccc2)cc1F
Reaction time: 18 h
Yield: 135.3 %

Procedure:
To 3-Fluoro-4-(N-tert-butoxycarbonylhomopiperazinyl)aniline (2.6 g, 8.4 mmol) in THF (25 ml) cooled to 5° C., sodium bicarbonate (0.85 g 10.1 mmol), was added and then benzylchloroformate (1.72 g, 10 mmol) was added dropwise. The reaction mixture was stirred for 18 hrs. at R.T. and then filtered. The filtrate was evaporated in vacuo. The residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate solution and brine water. The organic layer was dried over anhyd Na2SO4 and evaporated in vacuo to give 5.04 g of final product.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH2:27]([O:34][C:35]([NH:37][C:38]1[NH:39][C:40](=[O:51])[C:41]2[N:42]=[CH:43][N:44]([CH2:47][C:48](O)=[O:49])[C:45]=2[N:46]=1)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:48](=[O:49])[CH2:47][N:44]2[CH:43]=[N:42][C:41]3[C:40](=[O:51])[NH:39][C:38]([NH:37][C:35]([O:34][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:36])=[N:46][C:45]2=3)[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Reactant: O=C(O)Cn1cnc2c(=O)[nH]c(NC(=O)OCc3ccccc3)nc21
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1nc2c(ncn2CC(=O)N2CCN(S(=O)(=O)c3nc4ccccc4s3)C(=O)C2)c(=O)[nH]1)OCc1ccccc1

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [2-N-(benzyloxycarbonyl)-guanin-9-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 11.35 (bs, 2H), 8.34 (m, 1H), 8.25 (m, 1H), 7.81 (s, 0.6H), 7.77 (s, 0.4H), 7.71 (m, 2H), 7.45˜7.30 (m, 5H), 5.23 (s, 2H), 5.13 (s, 1.2H), 5.02 (s, 0.8H), 4.51 (s, 0.8H), 4.27 (s, 1.2H), 4.24 (t, 1.2H), 4.08 (t, 0.8H), 4.03 (t, 1.2H), 3.85 (t, 0.8H).
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=3)[CH:6]=[CH:5]2)[CH2:3][CH2:2]1.ClS([N:19]=[C:20]=O)(=O)=O>CN(C=O)C>[C:20]([C:6]1[C:7]2[C:12](=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:4]([CH:1]2[CH2:3][CH2:2]2)[CH:5]=1)#[N:19]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COc1ccc2ccn(C3CC3)c2c1
Solvent: CN(C)C=O
Product: COc1ccc2c(C#N)cn(C3CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
To a solution of 1-cyclopropyl-6-methoxylindole (3.29 g, 17.6 mmol) in dry DMF (30 mL), at 0° C., is added chlorosulfonyl isocyanate (3.11 g, 1.91 mL, 22.0 mmol). After the addition, the mixture is stirred at room temperature for 2 h, followed by aqueous work-up. Chromatography (silica gel, hexanes/EtOAc, 9/1) furnishes 3-cyano-1-cyclopropyl-6-methoxyindole (3.05 g, 82%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:8]CC=C)[CH:5]=[CH:6][CH:7]=1.CN(C)[C:14]1[CH:19]=CC=C[CH:15]=1>>[CH2:19]([C:3]1[C:2]([Br:1])=[CH:7][CH:6]=[CH:5][C:4]=1[OH:8])[CH:14]=[CH2:15]
Reactant: CN(C)c1ccccc1
Reactant: C=CCOc1cccc(Br)c1
Product: C=CCc1c(O)cccc1Br

Procedure:
The title compound was synthesized from allyl 3-bromophenyl ether by an ortho Claisen rearrangement in dimethylaniline as described in Helvetica Chemica Acta, 56(1), 14, (1973).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][OH:7])[CH3:2].[H-].[Na+].Cl[C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1.O>O1CCCC1>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][O:7][C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1)[CH3:2]
Reactant: CCOCCCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOCCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-ethoxy-1-propanol (940 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]2[CH:12]=[N:13][C:14]([N:17]3[CH2:22][CH2:21][C:20]([CH2:28][CH3:29])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]3)=[N:15][CH:16]=2)=[CH:4][C:3]=1Br.C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)CCC>CN(C=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>[NH2:1][C:2]1[C:3]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)=[CH:4][C:5]([C:11]2[CH:16]=[N:15][C:14]([N:17]3[CH2:18][CH2:19][C:20]([CH2:28][CH3:29])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:21][CH2:22]3)=[N:13][CH:12]=2)=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CCOC(=O)C1(CC)CCN(c2ncc(-c3cc(Br)c(N)c([N+](=O)[O-])c3)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CC)CCN(c2ncc(-c3cc(-c4ccccn4)c(N)c([N+](=O)[O-])c3)cn2)CC1
Temperature: 120 °C
Yield: 47.6 %

Procedure:
To a solution of ethyl 1-(5-(4-amino-3-bromo-5-nitrophenyl)pyrimidin-2-yl)-4-ethylpiperidine-4-carboxylate (1.5 g, 3.14 mmol) in DMF (10.0 mL) was added 2-(tributylstannyl)pyridine (1.73 g, 4.72 mmol) and the mixture degassed by purging N2 for 15 min followed by addition of tetrakis(triphenylphosphine)palladium(0) (0.36 g, 0.314 mmol). The reaction mixture was again degassed for 10 min then heated up to 120° C. for 5 h. After completion of reaction, 100 mL ice-cold water was added, extracted with EtOAc (4×100 mL) and the combined organic layer washed with ice-cold water, brine solution respectively, dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified over neutral alumina using 15% EtOAc:Hexane to obtain the desired product (0.712 g, 47%). 1H NMR (CDCl3): δ 8.68-8.69 (m, 1H), 8.63 (s, 2H), 8.38 (s, 1H), 7.89 (s, 1H), 7.84 (s, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.34-7.36 (m, 1H), 4.65-4.67 (m, 2H), 4.20-4.22 (m, 2H), 3.21-3.25 (m, 2H), 2.30-2.34 (m, 2H), 1.58-1.60 (m, 2H), 1.44-1.46 (m, 2H), 1.30 (t, J=7.20 Hz, 3H) and 0.86 (t, J=7.60 Hz, 3H). MS: 477.44 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]([OH:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.N1CCOCC1.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[C:24]1([CH:23]2[NH:1][C:2]3[C:15]4[CH:14]([CH2:13][CH2:12][CH2:11][C:10]=4[N:9]=[C:8]4[C:3]=3[CH:4]=[CH:5][CH:6]=[CH:7]4)[O:16]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1c2c(nc3ccccc13)CCCC2O
Reactant: O=Cc1ccccc1
Solvent: C1COCCN1
Solvent: Cc1ccccc1
Product: c1ccc(C2Nc3c4c(nc5ccccc35)CCCC4O2)cc1

Procedure:
9-Amino-1,2,3,4-tetrahydroacridine-1-ol (15.0 g) was refluxed in 1 liter of toluene that contained 12.28 g of morpholine and 9.29 g of benzaldehyde that had been freshly washed with K2CO3. The reaction mixture was refluxed overnight and allowed to cool. The crude product was then filtered off and purified by flash chromatography (20% isopropanol/ethyl acetate) to give 8.07 g of a 80:20 mixture of diastereomers after recrystallization from methanol/water. Recrystallization from dimethylformamide/water gave a 60:40 mixture of diastereomers, m.p. 225°-235° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]([C:10]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:11]=3[O:12][C:13]3[C:18]([Cl:19])=[CH:17][C:16]([S:20]([NH:23][C:24]4[N:25]=[CH:26][S:27][CH:28]=4)(=[O:22])=[O:21])=[C:15]([F:29])[CH:14]=3)=[CH:8][CH:7]=[N:6]2)[CH2:2]1.CO.C=O.[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:19][C:18]1[C:13]([O:12][C:11]2[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:10]=2[C:9]2[N:5]([CH:3]3[CH2:4][N:1]([CH3:39])[CH2:2]3)[N:6]=[CH:7][CH:8]=2)=[CH:14][C:15]([F:29])=[C:16]([S:20]([NH:23][C:24]2[N:25]=[CH:26][S:27][CH:28]=2)(=[O:21])=[O:22])[CH:17]=1
Reactant: O=S(=O)(Nc1cscn1)c1cc(Cl)c(Oc2ccc(F)cc2-c2ccnn2C2CNC2)cc1F
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CC(n2nccc2-c2cc(F)ccc2Oc2cc(F)c(S(=O)(=O)Nc3cscn3)cc2Cl)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-[2-(1-Azetidin-3-yl-1H-pyrazol-5-yl)-4-fluorophenoxy]-5-chloro-2-flouro-N-1,3-thiazol-4-ylbenzenesulfonamide (Example 808, 29 mg, 0.052 mmol) was stirred in dichloromethane (2 ml), methanol (0.2 ml), aqueous formaldehyde (0.015 ml of 37% wt/vol) added and the reaction stirred at room temperature for a further 30 minutes. Sodium triacetoxyborohydride (37 mg, 0.172 mmol) was added and the solution stirred for 3 hours. The solvents were removed in vacuo and the residue dissolved in ethyl acetate and extracted with saturated aqueous sodium hydrogencarbonate solution (2×10 ml) and brine (2×10 ml). The organic layer was separated, dried over sodium sulphate, filtered and evaporated to give a solid. The compound was purified using preparative HPLC to afford the title compound. Yield 15.9 mg 57%.
Reaction SMILES: [CH2:1]([C:3]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH3:26])[CH:20]=1)([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([OH:17])([CH3:16])[CH3:15])=[C:8]([CH3:18])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[F-].[Cs+].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:35]1[O:37][C@H:36]1[CH2:38][OH:39]>C(Cl)Cl.CN(C=O)C>[CH2:1]([C:3]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:35][C@@H:36]([OH:37])[CH2:38][OH:39])=[C:21]([CH3:26])[CH:20]=1)([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([OH:17])([CH3:15])[CH3:16])=[C:8]([CH3:18])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(CCC(C)(C)O)c(C)c1
Reactant: OC[C@H]1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCC(CC)(c1ccc(CCC(C)(C)O)c(C)c1)c1ccc(OC[C@@H](O)CO)c(C)c1
Temperature: 80 °C
Yield: 46.7 %

Procedure:
To a solution of 4-{1-ethyl-1-[4-(3-hydroxy-3-methylbutyl)-3-methyl-phenyl]propyl}-2-methylphenol (0.14 g, 0.40 mmol) in anhyd DMF (2 mL) was added CsF (67 mg, 0.44 mmol), Cs2CO3 (26 mg, 80 □ mol) and (S)-glycidol (29 μL, 0.44 mmol). The reaction mixture was heated at 80° C. for 4 h. After cooling, the mixture was diluted with DCM (40 mL), washed with H2O (2×40 mL), 1 N HCl (20 mL) and brine, then dried (Na2SO4) and concentrated under reduced pressure. The crude material was chromatographed (silica, EtOAc/DCM, 0:100 to 75:25) to provide the title compound (80 mg, 47%) as a white powdered solid: 1H-NMR (CD2Cl2) δ 7.01 (1H, d, J=8.1), 6.96 (1H, dd, J=2.3, 8.3), 6.88-6.94 (3H, m), 6.73 (1H, d, J=8.3), 3.97-4.11 (3H, m), 3.77-3.84 (1H, m), 3.69-3.76 (1H, m), 2.62 (2H, m), 2.53 (1H, d, J=5.1), 2.24 (3H, s), 2.16 (3H, s), 2.05 (4H, q, J=7.3), 1.99 (1H, t, J=6.1), 1.67 (2H, m), 1.27 (6H, s), 0.58 (6H, t, J=7.3); 13C-NMR (CD2Cl2) δ 155.0, 147.2, 142.0, 138.4, 135.7, 131.2, 130.4, 128.5, 126.9, 126.3, 126.2, 110.9, 71.4, 71.3, 70.1, 64.6, 49.3, 45.2, 29.8, 29.6, 28.3, 20.0, 17.0, 8.9.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[C:17]3[CH2:21][CH2:20][N:19]([C:22]4[CH:23]=N[CH:25]=[CH:26][CH:27]=4)[C:18]3=[O:28])[CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9]2)=[CH:4][CH:3]=1.[C:29]1(C)C=CC=CC=1>C(N(CC)CC)C.Cl[Pd]Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[C:17]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:29][CH:23]=4)[C:18]3=[O:28])[CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CC(=C2CCN(c3cccnc3)C2=O)c2ccc(Cl)cc2N1
Reactant: Cc1ccccc1
Agent: Cl[Pd]Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CC(=C2CCN(c3ccccc3)C2=O)c2ccc(Cl)cc2N1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of intermediate 4b (370 g) in toluene (5.2 lit), Triethylamine (248 ml), Triphenilphosphine (7.4 g) and PdCl2 (2.52 g) were added. The resulting solution was warmed to 100° C. and stirred for 2 h. The suspension was chilled to 20-25° C. and toluene (2.6 ml) was added. The reaction mixture was washed with NH4Cl 8% (3×5.2 lit) and water (52 lit). The organic layer was filtered over a celite pad and it was washed with toluene (1 lit); then it was distilled under vacuum (T=50° C.; P=60 mbar) to reach 6.3 lit. After cooling to T=20-25° C., isooctane (5.2 lit) was dropped over 30 min. The precipitate was stirred for 2 h 30 min then it was filtered and washed with a mixture toluene/isooctane 1/1 (1.85 lit). The yellow solid was dried in vacuum at T=40° C. for 18 h to obtain the title compound as a yellow solid 210 g.
Reaction SMILES: C([NH:3][C:4]([CH3:20])([CH3:19])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)=O.C(O)(=O)C.[ClH:25]>O>[ClH:25].[CH3:20][C:4]([NH2:3])([CH3:19])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(NC=O)c1ccc(C#Cc2ccccc2)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(N)c1ccc(C#Cc2ccccc2)cc1

Procedure:
A mixture of 0.50 gram of N-formyl-α,α-dimethyl-4-(phenylethynyl)-benzylamine, 10.7 ml. of glacial acetic acid, 6.7 ml. of water, and 1.07 ml. of concentrated hydrochloric acid is stirred and refluxed for 2.5 hours. The solution is evaporated to dryness and α,α-dimethyl-4-(phenylethynyl)-benzylamine hydrochloride is obtained as a light tan solid. The product is recrystallized from an isopropyl alcohol-methanol-ether mixture to give pure α,α-dimethyl-4-(phenylethynyl)-benzylamine hydrochloride, m.p. 275°-278° (decomp.).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.[CH:14]1N=CN(C(N2C=NC=C2)=O)C=1.CO>CN(C=O)C>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:8]=1
Reactant: CSc1ccc(CCC(=O)O)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)CCc1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 71.9 %

Procedure:
In a 100 mL round bottom flask, 3-(4-(methylthio)phenyl)propanoic acid (1.00 g, 5.10 mmol) was dissolved in DMF (17 mL) under N2(g). CDI (1.24 g, 7.65 mmol) was then added to the reaction mixture and the resulting mixture was allowed to stir at room temperature for ˜45 min. MeOH (6 μL) was then added in dropwise fashion to the reaction. The reaction was allowed to stir for an additional 1 h, after which time it was extracted with EtOAc (3×50 μL) and brine (3×50 mL). The combined organic extracts were dried over anhydrous Na2SO4(s), filtered and concentrated. The crude product was purified by column chromatography (silica gel, gradient elution mixture: 10% EtOAc in Hexanes to 100% EtOAc) to give the title compound (0.771 g, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[O:32]([CH2:39][CH2:40][NH2:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:31])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:41][CH2:40][CH2:39][O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:22])=[CH:17][C:9]1=2
Reactant: NCCOc1ccccc1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(NCCOc1ccccc1)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-phenoxyethylamine as in General Procedure 10 to give the title compound. LCMS: m/z=566.93 (M+H+); retention time=0.94 minutes.
Reaction SMILES: [CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH2:13])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][N:4]=1)[CH3:2].[CH3:20][CH:21]([CH3:26])[CH2:22][C:23](Cl)=[O:24]>>[CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH:13][C:23](=[O:24])[CH2:22][CH:21]([CH3:26])[CH3:20])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][N:4]=1)[CH3:2]
Reactant: CC(C)CC(=O)Cl
Reactant: CCc1noc(-c2sc(N)nc2-c2ccccc2)n1
Product: CCc1noc(-c2sc(NC(=O)CC(C)C)nc2-c2ccccc2)n1

Procedure:
Prepared from 5-(3-ethyl-[1,2,4]oxadiazol-5-yl)-4-phenyl-thiazol-2-ylamine and 3-methyl-butyryl chloride.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][CH2:10][CH2:11][Cl:12].C1COCC1>O>[Cl:12][CH2:11][CH2:10][CH2:9][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: ClCCCBr
Solvent: O
Solvent: C1CCOC1
Product: ClCCCSc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 112.5 %

Procedure:
A mixture of benzenethiol (0.550 g, 5.00 mmol), 1-bromo-3-chloropropane (106 mg, 5.50 mmol), TEA (1.01 g, 10.0 mmol) and THF (10.0 mL) was stirred for 12 h at 25° C. The resulting crude mixture was diluted with water (40 mL), the aqueous layer was extracted with CH2Cl2 (3×30 mL). The combined organic layers were concentrated in vacuo and the residue was purified by preparative TLC using hexane:EtOAc (10:1) to give the desired product [(3-chloropropyl)sulfanyl]benzene (1.05 g, 100%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([O:19][CH3:20])[C:14]=1[O:15][CH2:16][CH2:17][CH3:18])[CH:10]=O)(=[O:6])=[O:5].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:35]([SH:38])[CH2:36][SH:37])[CH:26]=[C:27]([O:33][CH3:34])[C:28]=1[O:29][CH2:30]OC.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1C=CC=CC=1>C1C=CC=CC=1.O>[OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:10]2[S:38][C@H:35]([C:25]3[CH:24]=[C:23]([O:22][CH3:21])[C:28]([O:29][CH3:30])=[C:27]([O:33][CH3:34])[CH:26]=3)[CH2:36][S:37]2)[CH:12]=[C:13]([O:19][CH3:20])[C:14]=1[O:15][CH2:16][CH2:17][CH3:18])(=[O:6])=[O:5]
Reactant: COCOc1c(OC)cc(C(S)CS)cc1OC
Reactant: CCCOc1c(OC)cc(C=O)cc1S(=O)(=O)CCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCOc1c(OC)cc([C@@H]2SC[C@@H](c3cc(OC)c(OC)c(OC)c3)S2)cc1S(=O)(=O)CCO

Procedure:
1-(3-(2-hydroxyethylsulfonyl)-5-methoxy-4-propoxybenzaldehyde (54) (FIG. 24) (0.88 g,2.91 mmole), 1-(3,4,5-trimethoxyphenyl)-1,2-ethanedithiol (39) (FIG. 19) (0.947 g, 3.64 mmole) and 0.365 g of pyridinium para-toluene sulfonate was added to 120 ml dry benzene and refluxed with Dean-Stark removal of the benzene- water azeotrope for 24 hours. The benzene was removed in vacuo, and the remaining oil redissolved in dichloromethane. The organic layer was washed with 10% NaHCO3 and H2O. The organic layer was dried over MgSO4, and evaporated in vacuo to an oil which was purified by flash column chromatography with 1:1 hex/ethyl acetate as eluent. The product mixture (white foam) contains a 1.0/1.0 cis/trans ratio (1.254 g, 79%).