Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[N:17]=[C:16](Cl)[CH:15]=[C:14]([Cl:19])[N:13]=1.[OH2:20]>O1CCCC1>[CH2:1]([O:8][C:12]1[N:17]=[C:16]([O:20][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:15]=[C:14]([Cl:19])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cc(OCc2ccccc2)nc(OCc2ccccc2)n1
Temperature: 50 °C

Procedure:
The reaction is carried out under an argon protective-gas atmosphere. 24.8 ml (0.24 mol) of absolute benzyl alcohol in 100 ml of THF are added dropwise at 25° C. to 9.6 g of NaH (0.24 mol, 60% suspension in paraffin) in 120 ml of tetrahydrofuran (THF). The reaction mixture is warmed at 50° C. for 0.5 hour, cooled and then added dropwise to a solution, cooled to 0° C., of 13.8 ml of 2,4,6-trichloropyrimidine in 100 ml of THF. The mixture is allowed to warm to 25° C. overnight, and is then poured into 200 ml of water. After extraction with toluene three times, the combined organic phases are washed with 100 ml of water, dried using MgSO4, filtered and evaporated on a rotary evaporator. Filtration through silica gel (eluent ethyl acetate:hexane 1:1) gives 39.9 g (100% of theory) of the title product.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][N:7]=1.[CH2:11]([C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[CH:22]([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])[NH2:18])[CH:12]([CH3:14])[CH3:13].[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[CH2:11]([C:15]1[CH:16]=[C:17]([NH:18][C:8]([C:3]2[C:2]([CH3:1])=[N:7][CH:6]=[CH:5][N:4]=2)=[O:10])[CH:19]=[CH:20][C:21]=1[CH:22]([C:27]([F:28])([F:29])[F:30])[C:23]([F:24])([F:25])[F:26])[CH:12]([CH3:14])[CH3:13]
Reactant: Cc1nccnc1C(=O)O
Reactant: CC(C)Cc1cc(N)ccc1C(C(F)(F)F)C(F)(F)F
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nccnc1C(=O)Nc1ccc(C(C(F)(F)F)C(F)(F)F)c(CC(C)C)c1
Yield: 69.2 %

Procedure:
3-Methylpyrazine-2-carboxylic acid (138 mg, 1 mmol), 3-isobutyl-4-[2,2,2-trifluoro-1-(trifluoromethyl)ethyl]aniline (299 mg, 1 mmol), 2-chloro-1-methylpyridinium iodide (255 mg, 1 mmol) and triethylamine (303 mg, 3 mmol) were dissolved in tetrahydrofuran (10 ml) and refluxed under heating for 3 hours. The reaction solution was diluted with ethyl acetate, followed by washing with water. The organic layer was dried over magnesium sulfate anhydride, and concentrated under reduced pressure, and then the residue was purified by using silica gel chromatography (hexane:ethyl acetate=2:1) to obtain 290 mg of the desired compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:18]=[C:17]([CH3:19])[O:16][N:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:20][O:21][C:22]1[C:29]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)=[CH:28][C:25]([CH:26]=O)=[C:24]([O:35][CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[CH:23]=1.C[O-].[Li+].[ClH:47]>CN(C)C=O.CO.O>[ClH:47].[CH3:20][O:21][C:22]1[C:29]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)=[CH:28][C:25](/[CH:26]=[CH:2]/[C:1]([C:4]2[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]3[CH:18]=[C:17]([CH3:19])[O:16][N:15]=3)(=[O:11])=[O:12])=[CH:8][CH:9]=2)=[O:3])=[C:24]([O:35][CH2:36][CH2:37][N:38]2[CH2:39][CH2:40][O:41][CH2:42][CH2:43]2)[CH:23]=1
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2cc(C)on2)cc1
Reactant: COc1cc(OCCN2CCOCC2)c(C=O)cc1-c1cccs1
Agent: C[O-]
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OCCN2CCOCC2)c(/C=C/C(=O)c2ccc(S(=O)(=O)Nc3cc(C)on3)cc2)cc1-c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
4-Acetyl-N-(5-methylisoxazole-3-yl)benzenesulfonamide (Ex-1B, 0.30 g, 0.86 mmol) and 4-methoxy-2-(2-morpholin-4-ylethoxy)-5-thien-2-ylbenzaldehyde (Ex-14A, 0.24 g, 0.86 mmol) were dissolved in a dimethylformamide-methanol solution (6.0 mL, 7:3). After complete dissolution, lithium methoxide (0.13 g, 3.4 mmol) was added and the resulting orange slurry was stirred in the dark at room temperature for 1 h. Upon completion, as determined by HPLC, the mixture was diluted with water (8.0 mL), acidified with a 1 N hydrochloric acid solution, and extracted with ethyl acetate:tetrahydrofuran (1:1, 3×20 mL). The combined organic extracts were evaporated to dryness. The crude oil was taken up in ethanol (10 mL) and warmed to 60° C. to obtain complete dissolution and allowed to cool to room temperature. The resulting precipitate was collected on filter paper and dried in vacuo to yield 0.46 g (88%) of the title compound as a pale orange solid, mp>260° C. 1H-NMR (300 MHz, DMSO-d6) 8.34 (d, 2H, J=9.0 Hz), 8.32 (s, 1H), 8.12 (d, 1H, J=15.9 Hz), 8.03 (d, 2H, J=9.0 Hz), 7.93 (d, 1H, J=15.9 Hz), 7.69 (d, 1H, J=3.3 Hz), 7.56 (d, 1H, J=5.4 Hz), 7.15 (dd, 1H, J=5.4, 3.3 Hz), 6.92 (s, 1H), 6.18 (s, 1H), 4.65 (brs, 2H), 4.03 (s, 3H), 3.97 (brs, 4H), 3.69 (brs, 2H), 3.50–3.23 (brs, 4H), 2.31 (s, 3H). Anal. Calcd. for C30H32ClN3O7S2.H2O: C, 54.25; H, 5.16; N, 6.33; S, 9.66; Found: C, 54.10; H, 4.91; N, 6.39; S, 9.68. HRMS (ESI) Calcd. for C30H32ClN3O7S2: 610.1681 (—HCl) (M+H)+. Found: 610.1673.
Reaction SMILES: [CH:1]1([NH:8][C:9]([NH2:11])=[S:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:13]1([C:19](OC)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:1]1([NH:8][C:9]2[S:10][C:13]3([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:19](=[O:20])[N:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=S)NC1CCCCCC1
Reactant: COC(=O)C1(Br)CCCCC1
Product: O=C1N=C(NC2CCCCCC2)SC12CCCCC2

Procedure:
Synthesis was performed from N-cycloheptylthiourea and methyl 1-bromocyclohexanecarboxylate according to Method D.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[C:7](=[O:13])[N:8]([CH3:12])[CH2:9][CH2:10][CH:11]=1.[NH2:15][O:16][K].C(O)(=O)C>CO.C(OCC)(=O)C>[OH:16][NH:15][C:3](=[O:2])[CH2:4][CH2:5][C:6]1[C:7](=[O:13])[N:8]([CH3:12])[CH2:9][CH2:10][CH:11]=1
Reactant: COC(=O)CCC1=CCCN(C)C1=O
Reactant: NO[K]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1CCC=C(CCC(=O)NO)C1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
50 mg of 3-(1-methyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid methyl ester prepared from the above Step 1 was dissolved in methanol (0.25 mM) and then 0.122 ml of 1.7M NH2OK suspension solution in methanol (0.207 mM) was added thereto at 0° C. and the resulting mixture was stirred for 3 hrs at room temperature. The resulting mixture was neutralized with 0.02 ml of acetic acid, diluted with 10 ml of ethyl acetate, filtered and concentrated in vacuo. The resulting compound was purified by column chromatography on Silica gel with methanol/chloroform (1:20) solvent mixture as an eluant to give 19 mg of the title compound (j2) (yield: 35%).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4].[CH3:15][N:16]([CH3:31])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CC(C)=O>[Br-:1].[C:5]12([C:3]([CH2:2][N+:16]([CH3:15])([CH3:31])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:4])[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2
Reactant: CCCCCCCCCCCCCCN(C)C
Reactant: O=C(CBr)C12CC3CC(CC(C3)C1)C2
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCC[N+](C)(C)CC(=O)C12CC3CC(CC(C3)C1)C2
Product: [Br-]

Procedure:
A mixture of 1.3g. (0.005 mole) 1-adamantyl bromomethyl ketone and 1.23g. (0.005 mole) dimethyltetradecylamine was solubilized by the addition of 30cc acetone. The next day the solidified mixture was washed with ether and recrystallized from ethyl acetate to yield 2.1g. white crystals, m.p. 134°-135.5°C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:12].[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:11])(=[O:9])=[O:10])=[CH:4][C:3]=1[CH3:12])(=[O:15])[CH3:14].[NH+:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cc(S(=O)(=O)O)ccc1N
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(S(=O)(=O)[O-])cc1C
Product: c1cc[nH+]cc1

Procedure:
For example, commercially available 2-aminotoluene-5-sulfonic acid was allowed to react with acetic anhydride in pyridine to afford pyridinium 4-(acetylamino)-3-methylbenzenesulfonate (Scheme V). The resulting salt was then allowed to react with sodium hydroxide to afford the corresponding sodium salt, sodium 4-(acetylamino)-3-methylbenzenesulfonate. The salt was then allowed to react with thionyl chloride to afford the intermediate sulfonyl chloride, followed by reaction with ammonia and subsequent deprotection by reaction with aqueous hydrochloric acid in ethanol to afford the desired sulfonamide.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:11]3[C:18]([C:19]([OH:21])=[O:20])=[CH:17][NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].[C:22](Cl)(=O)C([Cl:25])=O>C(Cl)Cl.CN(C=O)C>[ClH:25].[CH3:22][O:20][C:19]([C:18]1[C:11]2[C:10]([NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[CH:2])[CH:4]=3)=[N:15][CH:14]=[N:13][C:12]=2[NH:16][CH:17]=1)=[O:21]
Reactant: C#Cc1cccc(Nc2ncnc3[nH]cc(C(=O)O)c23)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C#Cc1cccc(Nc2ncnc3[nH]cc(C(=O)OC)c23)c1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.2 %

Procedure:
To 4-(3-ethynyl-phenylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (0.108 g, 0.39 mmol) in dry methylene chloride (2 ml) was added a solution of oxalyl chloride (0.17 ml, 1.9 mmol) in dry methylene chloride (4 ml) followed by 1 drop of dry DMF. The suspension was stirred at ambient temperature for 1 hour, then concentrated in vacuo. To the resulting solid was added dry acetone (2 ml) and dry methanol (1 ml). The solution was stirred at ambient temperature for 15 hours, then concentrated in vacuo. The residue was diluted with ethyl acetate and water, and the solid filtered and dried in vacuo to afford the title compound as a tan powder (40 mg, 35%). TS-MS: 293 (MH+); anal. RP18-HPLC RT: min.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]([F:21])([F:20])[F:19])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1.Cl>>[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([N:10]2[C:11]3[C:16](=[CH:15][C:14]([O:17][C:18]([F:21])([F:19])[F:20])=[CH:13][CH:12]=3)[C:8]([C:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=3)=[CH:9]2)=[O:29])=[CH:26][CH:25]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CN1CC=C(c2c[nH]c3ccc(OC(F)(F)F)cc23)CC1
Agent: Cl
Product: COc1ccc(C(=O)n2cc(C3=CCN(C)CC3)c3cc(OC(F)(F)F)ccc32)cc1

Procedure:
(22.2 mg, 67%); from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-trifluoromethoxy-1H-indole (Example 4h, 20 mg, 0.068 mmol) and 4-methoxybenzoyl chloride (18.3 mg, 0.107 mmol), HRMS-FAB+ for C23H21N2O3F3.HCl, calculated MH+ (--HCl): 431.15826; found: 431.15694.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([CH:14]3[O:19][CH2:18][CH2:17][NH:16][CH2:15]3)[NH:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[C:23]([NH2:28])[N:22]=1.CCN(C(C)C)C(C)C.O>C(O)C>[Cl:20][C:21]1[CH:26]=[C:25]([N:16]2[CH2:17][CH2:18][O:19][CH:14]([C:11]3[NH:12][CH:13]=[C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)[N:10]=3)[CH2:15]2)[N:24]=[C:23]([NH2:28])[N:22]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: COc1cccc(-c2c[nH]c(C3CNCCO3)n2)c1
Solvent: O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(-c2c[nH]c(C3CN(c4cc(Cl)nc(N)n4)CCO3)n2)c1
Reaction time: 8 h
Yield: 42.3 %

Procedure:
To a stirred solution of 2-{4-[3-(methyloxy)phenyl]-1H-imidazol-2-yl}morpholine (1.5 g, 5.07 mmol) and 4,6-dichloro-2-pyrimidinamine (0.832 g, 5.07 mmol) in ethanol (100 mL) was added Hunig's base (4.5 mL, 25.4 mmol), and the reaction mixture was stirred overnight at reflux. Water (150 mL) was added, and the resulting mixture was extracted with EtOAc (3×100 mL). The organic was dried (Na2SO4), filtered, and concentrated. Purification by silica gel chromatography, eluting with EtOAc in PE from 50% to 80% afforded the title compound (830 mg) as a brown solid. LC-MS (ES) m/z=387 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][NH:8]2)([O-:3])=[O:2].[Br:19]N1C(=O)CCC1=O>CC(O)=O>[Br:19][C:7]1[NH:8][C:9]2[C:5]([C:6]=1[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2
Reactant: CCOC(=O)Cc1c[nH]c2cccc([N+](=O)[O-])c12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: CCOC(=O)Cc1c(Br)[nH]c2cccc([N+](=O)[O-])c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl (4-nitro-1H-indol-3-yl)acetate from Step A (1.00 g, 4.03 mmol) in AcOH (40 mL) was added N-bromosuccinimide (789 mg, 4.43 mmol) in AcOH (40 mL) dropwise over 30 min. The resulting mixture was stirred at ambient temperature for 1 h, then concentrated to dryness under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of CHCl3:EtOAc—100:0 to 80:20, to give the title compound. MS: m/z=327 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:5][CH:4]=1.[CH3:16][CH2:17][CH:18](Br)[CH2:19][CH3:20]>>[CH2:17]([CH:18]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[N:8]=[N:7][C:6]=1[NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:19][CH3:20])[CH3:16]
Reactant: COc1ccc(NC(=O)C(C)(C)C)nn1
Reactant: CCC(Br)CC
Product: CCC(CC)c1cc(OC)nnc1NC(=O)C(C)(C)C
Yield: 65.5 %

Procedure:
Using a procedure analogous to Example 6a, from N-(6-methoxy-pyridazin-3-yl)-2,2-dimethyl-propionamide (6.09 g, 29.14 mmol) and a Grignard reagent prepared from 3-pentyl bromide (18.1 mL, 160.3 mmol) and Mg (3.84 g, 160.26 mmol) gives the title compound (5.32 g, 19.08 mmol, 65%). 1H NMR (CDCl3): δ. 0.84 (t, J=7.5 Hz, 6H), 1.36 (s, 9H), 1.50-1.72 (m, 4H), 3.50-3.70 (m, 1H), 4.07 (s, 3H), 6.96 (s, 1H). ES-MS (m/z): calcd for C15H25N3O2 (M+H)+: 280.4; found: 280.2.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[SH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17]O.Cl>ClCCl>[S:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][O:7][CH:6]1[C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: OCc1ccccc1S
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Solvent: ClCCl
Product: Oc1ccc(C2OCc3ccccc3S2)cc1

Procedure:
Following the same procedure as outlined in Example 1 step b), 4-hydroxybenzaldehyde (0.73 g, 5.95 mmol) and (2-mercaptophenyl)methanol (1 g, 7.14 mmol) in dichloromethane (30 ml) were treated with hydrogen chloride gas. After workup and chromatography, as in example 1 step b), the subtitle compound was obtained (0.91 g, 63%) as a white solid. 1H NMR (300 MHz, CDCl3, ppm) δ 5.04 (d, J=15 Hz, 1H); 5.10 (d, J=15 Hz, 1H); 5.19 (s, 1H); 6.02 (s, 1H); 6.76-6.81 (m, 2H); 6.96-7.03 (m, 1H); 7.04-7.19 (m, 3H); 7.35-7.42 (m, 2H): 13C NMR (75 MHz, CDCl3, ppm) δ 70.6; 82.8; 115.7; 125.1; 126.0, 127.5; 128.4; 129.9; 130.6; 133.1; 156.4; MS calculated for C14H12O2S+H 245 observed 245.
Reaction SMILES: Cl.[C:2]([O:5]CC)(=[O:4])C.[C:8]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([N:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21](C=O)[CH:20]([CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:19]2)=[O:17])=[CH:10][CH:9]=1.[CH3:42][OH:43]>>[C:2]([OH:5])(=[O:4])[C:42]([OH:17])=[O:43].[C:8]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]([N:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]([CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:19]2)=[O:17])=[CH:12][CH:13]=1
Reactant: CO
Reactant: CCOC(C)=O
Reactant: O=CN1c2ccccc2N(C(=O)CCc2ccc(-c3ccccc3)cc2)CC1CN1CCCC1
Agent: Cl
Product: O=C(CCc1ccc(-c2ccccc2)cc1)N1CC(CN2CCCC2)Nc2ccccc21
Product: O=C(O)C(=O)O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
4N Hydrochloric acid-ethyl acetate (2 ml) was added to a methanol (10 ml) solution of 4-(3-(4-biphenylyl)propanoyl)-1-formyl-2-(pyrrolidin-1-yl)methyl-1,2,3,4-tetrahydroquinoxaline (320 mg). The reaction mixture was stirred at 50° C. for one hour, then concentrated. 10% Aqueous potassium carbonate solution was added to the residue, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried and concentrated. The residue was purified by alumina column chromatography (eluent: hexane to hexane/ethyl acetate=7/1), which was converted into its oxalate. The obtained crystals were washed with methanol-IPE to give the entitled compound (250 mg).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[C:9]([CH3:16])=[CH:10][C:11]([CH:14]=O)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:19][C:20]([S@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>>[F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[C:9]([CH3:16])=[CH:10][C:11](/[CH:14]=[N:25]/[S@@:23]([C:20]([CH3:22])([CH3:21])[CH3:19])=[O:24])=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(C=O)ncc1OCc1ccc(F)cc1
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(/C=N/[S@](=O)C(C)(C)C)ncc1OCc1ccc(F)cc1
Yield: 67 %

Procedure:
The title compound is prepared in 67% yield (972 mg, pale yellow solid) from 5-((4-fluorobenzyl)oxy)-4-methylpicolinaldehyde (1.03 g, 4.19 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide (762 mg, 6.29 mmol) in a similar manner to Step-6 of Amine-49.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:24][OH:25])[CH2:4][C:5]1[CH:6]=[C:7]([CH:21]=[CH:22][CH:23]=1)[CH2:8][C:9]1[N:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:12][C:13]=1[CH3:14].[C:26]([O:31][CH3:32])(=[O:30])[C:27]([CH3:29])=O.B(F)(F)F.CCOCC.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:29][C:27]1([C:26]([O:31][CH3:32])=[O:30])[O:1][CH2:2][CH:3]([CH2:4][C:5]2[CH:23]=[CH:22][CH:21]=[C:7]([CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])[CH:6]=2)[CH2:24][O:25]1
Reactant: Cc1oc(-c2ccccc2)nc1Cc1cccc(CC(CO)CO)c1
Reactant: COC(=O)C(C)=O
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)C1(C)OCC(Cc2cccc(Cc3nc(-c4ccccc4)oc3C)c2)CO1
Temperature: 25 °C
Yield: 49.9 %

Procedure:
To 5 ml of acetonitrile, 297 mg of 4-{3-[2,2-bis-(hydroxymethyl)ethyl]benzyl}-5-methyl-2-phenyloxazole and 369 mg of methyl pyruvate were added. To the mixture was added 544 mg of boron trifluoride etherate (about 47% ) with stirring at room temperature, and stirred for 14 hours at room temperature. The reaction solution was poured into an ice-cold water solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=3:1) to provide 185 mg of a mixture (cis:trans=2.5:1, based on NMR integral value) as colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].Cl[CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]([NH2:30])=[O:29])[CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+].N>CO.C(Cl)Cl.CN(C=O)C>[CH3:3][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][CH:25]([C:28]([NH2:30])=[O:29])[CH2:26][CH2:27]3)=[CH:13][CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)[CH3:1]
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Reactant: NC(=O)C1CCN(CCCCl)CC1
Agent: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)CC1(c2ccc(OCCCN3CCC(C(N)=O)CC3)cc2)CCOCC1
Yield: 20.4 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (500 mg, 2.13 mmol), 1-(3-chloro-propyl)-piperidine-4-carboxylic acid amide (436 mg, 2,13 mmol), DMF (10 ml) and K2CO3 (1.18 g, 8.52 mmol) were reacted together according to general procedure B. The isolated material was subjected to chromatography on silica, eluant 95:4:1 (DCM:MeOH:NH3) to give the title compound as a white solid (175 mg, 20%). 1H NMR (400 MHz, CDCl3) δ7.21 (d, 2H), 6.86 (d, 2H), 5.44 (br s, 1H), 5.25 (br s, 1H), 4.00 (t, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 3.03-2.93 (m, 2H), 2.51 (t, 2H), 2.40 (s, 2H), 2.22-1.66 (m, 13H), 1.97 (s, 6H).
Reaction SMILES: O[C:2]1([CH:13]=[CH:12][CH:11]=[CH:10][CH2:9]1)[CH2:3][C:4]1[CH:8]=[CH:7][S:6][CH:5]=1.ClCCl>[Na]>[CH2:3]([C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)[C:2]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: OC1(Cc2ccsc2)C=CC=CC1
Agent: [Na]
Solvent: ClCCl
Product: c1ccc(Cc2ccsc2)cc1
Yield: 58.5 %

Procedure:
A solution containing P2I4 (3.42 g, 6 mmol) and 3-(1-hydroxybenzyl)thiophene (1.90 g, 10 mmol) in sodium-dried toluene (100 ml) was heated under nitrogen for one hour. The reaction mixture was cooled and then quenched with 10% aqueous sodium sulphite. The mixture was extracted with ether, and the combined organic phases were washed with water and brine then dried. Filtration and evaporation afforded a yellow oil, which on bulb-to-bulb distillation (110° C. at 0.05 mmHg) gave a pale-pink oil. Chromatography with dichloromethane gave 3-benzylthiophene as an oil (1.02 g, 53% yield); 1H nmr:delta 3.84 (2H,s), 7.0-7.2 (8H,m) ppm.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[C:40]([N+:48]([O-:50])=[O:49])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:51][C:52]1[S:53][CH:54]=[CH:55][N:56]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:45])=[O:46])=[C:40]([N+:48]([O-:50])=[O:49])[CH:39]=2)[C:35]([NH:51][C:52]2[S:53][CH:54]=[CH:55][N:56]=2)=[O:37])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1[N+](=O)[O-]
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 51.5 %

Procedure:
A solution of triphenylphosphine (138 mg, 0.53 mmol) in methylene chloride (2 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (94 mg, 0.53 mmol) in small portions. The reaction mixture was stirred at 0° C. for 10 min and then treated with 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (150 mg, 0.44 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C., where it was stirred for 25 min. The reaction mixture was then treated with 2-aminothiazole (97 mg, 0.97 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was directly purified by flash chromatography, (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate), to afford 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-thiazol-2-yl-propionamide (96 mg, 52%) as a pale yellow solid: mp 121-124° C.; FAB-HRMS m/e calcd for C18H21N3O5S2 (M+H)+ 424.1001, found 424.1000.