Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][NH2:27]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2[NH:27][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)CCN
Reactant: CC(C)(C)c1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Product: CN(C)CCNc1c(C=O)c2ccccc2n1-c1ccc(C(C)(C)C)cc1
Yield: 26 %

Procedure:
1-(4-tert-Butylphenyl)-2-chloro-1H-indole-3-carboxaldehyde is reacted with N,N-dimethylethylenediamine as described in Step 2 of Example 29 to afford 1-(4-tert-butylphenyl)-2-(2-dimethylaminoethylamino)-1H-indole-3-carboxaldehyde (26% yield) as a light tan solid. ESI/MS 364 (M+H); RT 3.39 min. NMR 9.94 (1H, s); 7.84 (1H, br s); 7.67 (2H, d); 7.48 (2H, d, J=9 Hz); 7.10 (1H, t); 6.98 (1H, t); 6.66 (1H, d, J=9 Hz); 3.05 (2H, br s); 2.30 (2H, BR t); 2.03 (6H, S); 1.36 (9H, s).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([C:12]2[C:13]3[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=3[S:15][C:16]=2[CH2:17][OH:18])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CS(Cl)(=O)=O>[CH3:1][S:2]([O:18][CH2:17][C:16]1[S:15][C:14]2[CH:19]=[CH:20][CH:21]=[CH:22][C:13]=2[C:12]=1[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1sc2ccccc2c1-c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCc1sc2ccccc2c1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 86.6 %

Procedure:
Methanesulfonyl chloride (127 μL, 1.63 mmol) was added dropwise to a solution of (3-phenylbenzo[b]thiophen-2-yl)methanol (356 mg, 1.48 mmol) and DIPEA (322 μL, 1.85 mmol) in anhydrous DCM (10 mL) at 0° C. Stirring at 0° C. was continued for 15 min, then the mixture was slowly warmed to RT. After 2.5 h stirring at RT, additional methanesulfonyl chloride (1 drop) was added and stirring was continued for 1 h. The reaction mixture was diluted with DCM and the organic layer was washed with water, then dried (Na2SO4) and concentrated in vacuo affording (3-phenylbenzo[b]thiophen-2-yl)methyl methanesulfonate as a yellow oil (408 mg, 87%). 1H NMR (DMSO, 400 MHz): δ 8.07-8.02 (1H, m), 7.62-7.56 (2H, m), 7.55-7.37 (6H, m), 4.96 (2H, s), 3.33 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH2:21]([O:23][C:24]([C:26]1[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=1[NH2:28])=[O:25])[CH3:22].C(N(CC)CC)C.Cl>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[C:24]([O:23][CH2:21][CH3:22])=[O:25])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: CCOC(=O)c1ccccc1N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccccc1NC(=O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
To a solution of 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (340 mg, 1 mmol), o-ethoxycarbonylaniline (150 μL, 1 mmol), and triethylamine (280 μL, 2 mmol) in dichloromethane (3 mL) was added N,N-bis(2-oxo-3-oxazolydinyl)phosphinic chloride (254 mg, 1 mmol) at 0° C. The mixture was stirred overnight at room temperature and 0.2N hydrochloric acid was added. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated. The residual solid was rinsed with diethyl ether and dried in vacuo to give 290 mg of the title compound (58%): mp>265°~267° C.; 1H NMR (270 MHz, DMSO-d6) δ12.05 (bs, 1H), 10.55 (s, 1H), 8.14 (d, 1H, J=8.1 Hz), 7.89 (d, 2H, J=8.1 Hz), 7.60 (t, 1H, J=8.1 Hz), 7.23 (d, 1H, J=2 Hz), 7.22 (t, 1H, J=8.1 Hz), 7.16 (d, 1H, J=2 Hz), 5.14~5.26 (m, 1H), 4.29 (q, 2H, J=7.2 Hz), 3.06 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.82 (dm, 1H, J=17.1 Hz), 2.62~2.76 (m, 2H), 2.18 (dm, 1H, J=13.5 Hz), 1.81~1.97 (m, 1H), 1.32 (t, 3H, J=7.2 Hz).
Reaction SMILES: C(=O)(O)[O-:2].[Na+].[I-].[K+].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)=[O:15].O>CS(C)=O>[O:2]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)=[O:15]
Reactant: O=C([O-])O
Reactant: O=C(CCCCCBr)Nc1ccc(C(F)(F)F)cc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=CCCCCC(=O)Nc1ccc(C(F)(F)F)cc1

Procedure:
A solution of sodium bicarbonate (0.250 g), potassium iodide (0.050 g), and 6-bromo-N-[4-(trifluoromethyl)phenyl]hexanamide (1.00 g) in dimethylsulfoxide (15 mL) was heated at 125°-130° C. for 3.5 hours while stirring under a nitrogen atmosphere. The reaction was treated with water (75 mL) and extracted with ether. The ether extract was washed with brine (50 mL), dried over sodium sulfate after adding dichloromethane (30 mL), filtered, and concentrated in vacuo. Chromatography using 50/50 ethyl acetate/hexane gave a white solid (Rf 32 0.2 in same solvent system, 0.326 g), identified as the title compound. m.p.: 129.5°-131.0° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.F[C:10]1[C:22]([F:23])=[C:21]([F:24])[C:20]([F:25])=[CH:19][C:11]=1[C:12]([C:14](=[CH2:18])[C:15]([O-:17])=[O:16])=[O:13]>C(O)C>[F:25][C:20]1[CH:19]=[C:11]2[C:10](=[C:22]([F:23])[C:21]=1[F:24])[N:6]([C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1)[CH:18]=[C:14]([C:15]([OH:17])=[O:16])[C:12]2=[O:13]
Reactant: Nc1ccc(F)cc1
Reactant: C=C(C(=O)[O-])C(=O)c1cc(F)c(F)c(F)c1F
Solvent: CCO
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Temperature: 0 °C

Procedure:
5.7 g of 4-fluoroaniline are added dropwise to a solution of 16 g of ethyl 3-ethoxy-2-(2,3,4,5-tetra-fluorobenzoyl-acrylate (5) (X1 -X4 =F) (Appln. Ser. No. 756,469, filed July 18, 1985, now U.S. Pat. No. 4,952,695) in 50 ml of ethanol, while cooling with ice and stirring. The mixture is stirred at room temperature for 1 hour, 50 ml of ice-water are added and the precipitate is filtered off cold with suction, rinsed with water and dried at 50° C. over calcium chloride in vacuo. 16.5 g of (6) (R=4-fluorophenyl, X1 -X4 =F) of melting point 93°-95° C. are obtained.
Reaction SMILES: [CH:1]1([NH:5][CH2:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:29]1([CH2:35][S:36](Cl)(=[O:38])=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl>[C:19]([N:16]1[CH2:15][CH2:14][N:13]([C:10]2[CH:9]=[CH:8][C:7]([CH2:6][N:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)[S:36]([CH2:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:38])=[O:37])=[CH:12][CH:11]=2)[CH2:18][CH2:17]1)(=[O:21])[CH3:20]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(=O)N1CCN(c2ccc(CNC3CCC3)cc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2ccc(CN(C3CCC3)S(=O)(=O)Cc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.9 %

Procedure:
To a solution of 1-(4-(4-((cyclobutylamino)methyl)phenyl)piperazin-1-yl)ethanone (185 mg, 0.64 mmol) in dichloromethane (1.5 mL) was added triethylamine (0.18 mL, 1.29 mmol), followed by phenylmethanesulfonyl chloride (185 mg, 0.96 mmol) and the reaction was stirred at ambient temperature for 16 hours. The reaction was then filtered through diatomaceous earth, concentrated and purified by preparative reverse phase HPLC to yield 62 mg of N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-cyclobutyl-C-phenyl-methanesulfonamide. 1H NMR (400 MHz, DMSO) δ 7.46-7.29 (m, 5H), 7.18 (d, J=8.6 Hz, 2H), 6.91 (d, J=8.7 Hz, 2H), 4.36 (s, 2H), 4.18 (s, 2H), 4.14-3.98 (m, 1H), 3.63-3.48 (m, 4H), 3.18-3.10 (m, 2H), 3.10-3.00 (m, 2H), 2.03 (s, 3H), 2.01-1.89 (m, 2H), 1.89-1.72 (m, 2H), 1.54-1.15 (m, 2H); LCMS (m/z) ES+ 442.2 [M+1]+.
Reaction SMILES: [ClH:1].C(OC([N:9]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[O:42][C:43]3[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][C:44]=3[N:45]=2)=[CH:37][CH:36]=1)[CH:10]1[CH2:19][CH2:18][CH2:17][C:16]2[N:15]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[CH:12][C:11]1=2)=O)(C)(C)C>O1CCOCC1>[ClH:1].[ClH:1].[CH3:50][C:47]1[CH:48]=[CH:49][C:43]2[O:42][C:41]([C:38]3[CH:37]=[CH:36][C:35]([CH2:34][O:33][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[CH2:26][CH2:25][NH:9][CH:10]4[CH2:19][CH2:18][CH2:17][C:16]5[N:15]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[CH:12][C:11]4=5)=[CH:40][CH:39]=3)=[N:45][C:44]=2[CH:46]=1
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccccc1OCc1ccc(-c2nc3cc(C)ccc3o2)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc2c(n1)CCCC2NCCc1ccccc1OCc1ccc(-c2nc3cc(C)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6.1 ml of a 4 N solution of hydrogen chloride in dioxane were added to 620 mg (0.94 mmol) of (−)-ethyl 5-{(tert-butoxycarbonyl)[2-(2-{[4-(5-methyl-1,3-benzoxazol-2-yl)benzyl]oxy}phenyl)-ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate (Example 26A), and the mixture was stirred at room temperature for 4 h. The reaction solution was then concentrated to dryness and the residue was dried under high vacuum overnight. This gave 604 mg (about 0.95 mmol, about 100% of theory) of the target product as a beige solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([F:18])[CH:9]=2)[CH:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[N:3]=1.[Br:23][C:24]1[N:25]=[CH:26][NH:27][CH:28]=1>>[Br:23][C:24]1[N:25]=[CH:26][N:27]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([F:18])[CH:9]=3)[CH:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[N:3]=2)[CH:28]=1
Reactant: Fc1cc(-c2cc(C(F)(F)F)nc(Cl)n2)ccc1C(F)(F)F
Reactant: Brc1c[nH]cn1
Product: Fc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(Br)c3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-chloro-4-(3-fluoro-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example A.6) (0.50 g, 1.45 mmol) and commercially available 4-bromo-imidazole (0.32 g, 2.18 mmol) according to the general procedure IVa. Obtained as a white solid (0.34 g, 51%). MS (EI) 455.1 [(M)+]; mp 164.5° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6](/[CH:11]=[CH:12]/[C:13]([N:15]2[CH2:20][CH2:19][CH:18]([CH:21]=[O:22])[CH2:17][CH2:16]2)=[O:14])[CH:7]=[C:8]([F:10])[CH:9]=1.[CH3:23]S(C)=O>>[F:10][C:8]1[CH:7]=[C:6](/[CH:11]=[CH:12]/[C:13]([N:15]2[CH2:16][CH2:17][CH:18]([CH:21]3[CH2:23][O:22]3)[CH2:19][CH2:20]2)=[O:14])[CH:5]=[C:4]([F:3])[CH:9]=1
Reactant: O=CC1CCN(C(=O)/C=C/c2cc(F)cc(F)c2)CC1
Reactant: CS(C)=O
Agent: [H-]
Agent: [Na+]
Product: O=C(/C=C/c1cc(F)cc(F)c1)N1CCC(C2CO2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
An oven dried 500-mL flask was charged with (CH3)3SOI (46.14 g, 210 mmol, 1.3 eq) and 250 mL dry DMSO. NaH (95%, 5.30 g, 210 mmol, 1.3 eq) was added in around 10 batches and solution was then cooled to 0° C. The resulting mixture was stirred at 0° C. for 30 min. The aldehyde (Intermediate 2, 45 g, 161 mmol, 1.0 eq) in 150 mL dry DMSO solution was added dropwise and the resulting solution was stirred at 0° C. for 30 min. LCMS showed completed reaction. The reaction was then quenched with 800 mL water and poured into 1200 mL diethyl ether. The organic layer was separated and washed with 2×150 mL water and dried over MgSO4 and concentrated. Crude LCMS showed >90% purity for the desired product in 58% yield as a light yellow oil which solidified to a yellow solid overnight. MS (ES) m/e 294 [M+H]+. 1HNMR (CDCl3) δ(ppm): 7.56 (d, 1H), 7.04 (dd, 2H), 6.91 (d, 1H), 6.80 (m, 1H), 4.74 (m, 1H), 4.11 (m, 1H), 3.05 (m, 1H), 2.77 (s, 2H), 2.61 (m, 1H), 1.95 (m, 1H), 1.70-1.80 (m, 1H), 1.30-1.60 (m, 4H).
Reaction SMILES: I[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][CH3:10])[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][N:13](C)C=O>>[OH:11][C:5]1[CH:4]=[CH:3][C:2]([C:12]#[N:13])=[N:7][C:6]=1[CH2:8][CH2:9][CH3:10]
Reactant: CN(C)C=O
Reactant: CCCc1nc(I)ccc1O
Product: CCCc1nc(C#N)ccc1O
Yield: 100 %

Procedure:
6-Iodo-2-propylpyridin-3-ol (2.0 g, 7.60 mmol) was dissolved in N,N-dimethylformamide (30 mL). Dinitrile zinc (1.34 g, 11.4 mmol) and tetrakis triphenylphosphine palladium (878 mg, 0.760 mmol) were added at room temperature, and the resultant mixture was stirred for 20 minutes under microwave irradiation. After completion of the reaction, the reaction solution was filtered using celite and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified using column chromatography (hexane/ethyl acetate) and 5-hydroxy-6-propyl picolinonitrile (1.75 g, yield >100%) was obtained as a yellow oil.
Reaction SMILES: CS(O[CH:6]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][CH2:8][C@@H:9]1[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:12](=[O:25])[CH2:11][CH2:10]1)(=O)=O.[S-:31][C:32]#[N:33].[K+]>CN(C)C=O>[O:25]=[C:12]1[CH2:11][CH2:10][C@H:9]([CH2:8][CH2:7][CH:6]([S:31][C:32]#[N:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C@H:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: N#C[S-]
Reactant: CCCCCC(CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC)OS(C)(=O)=O
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCC(CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC)SC#N

Procedure:
A solution of 1 g. of ethyl 15-methanesulfonyloxy-9-oxo-prostanoate (Example 90) and 1 g. of dry potassium thiocyanate in 30 ml. of N,N-dimethylformamide is heated on the steam bath for 18 hours. The resulting mixture is poured into 150 ml. of water and extracted with ether. The extract is washed with water, dried with anhydrous magnesium sulfate and taken to dryness. Silica gel chromatography of the residue gives 462 mg. of oil; λmax. 4.67 (thiocyanate group) and 5.78 μ (carbonyl groups).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([Mg]Br)C.[Cl:21][C:22]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:23]=1[C:24]#[N:25].O>C1COCC1>[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([NH:14][C:24](=[NH:25])[C:23]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:22]=2[Cl:21])=[CH:15][CH:16]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: N#Cc1ccc(Cl)cc1Cl
Agent: CC[Mg]Br
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: N=C(Nc1ccc(OCc2ccccc2)cc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.8 %

Procedure:
4-Benzyloxyaniline hydrochloride (5.0 g, 21.2 mmol) was dropwise added to a solution of ethylmagnesium bromide (44.5 ml, 1M in THF, 44.5 mmol) in 25 ml dry TIHF under nitrogen atmosphere. After stirring for 20 minutes a solution of 2,4-dichlorobenzonitrile (3.65 g, 21.2 mmol) in 25 ml THF was added. The reaction mixture was stirred for 20 hours at room temperature. Water (50 ml) was carefully added. Extraction with EtOAc (2×100 ml), drying (Na2SO4), filtration and evaporation to dryness afforded 7.7 g (98%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:14]SC)=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].O>C(O)C.[Ni]>[NH2:1][C:2]1[C:3]([CH3:14])=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1ccc(Cl)c(N)c1CSC
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc(Cl)c(N)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
A solution of ethyl 3-amino-4-chloro-2-(methylsulphenylmethyl)benzoate (50 g) in ethanol was added to a stirred suspension of Raney Nickel (300 g) in ethanol. After stirring overnight at room temperature, a further addition of Raney Nickel was made and the mixture stirred for 2 hours. Water was added, the mixture filtered and the residue washed with dichloromethane. The filtrate was evaporated, re-extracted with ethyl acetate, dried (magnesium sulphate) and evaporated to give ethyl 3-amino-4-chloro-2-methylbenzoate (29.7 g) as a brown oil, NMR (CDCl3) 1.25 (t,3H), 2.25 (s,3H), 4.3 (q,2H), 7.05 (m,2H).
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][S:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.[C:16]1([NH:22]N)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>CC(O)(C)C>[CH3:15][C:2]1[NH:22][C:16]2[C:21]([C:3]=1[S:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: CC(=O)CSc1cccc(CC(=O)O)c1
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CC(C)(C)O
Product: Cc1[nH]c2ccccc2c1Sc1cccc(CC(=O)O)c1
Temperature: 70 °C

Procedure:
[3-(2-Oxo-propylsulfanyl)-phenyl]-acetic acid (0.200 g, 1.12 mmol) was dissolved in t-BuOH (5 mL) then phenylhydrazine (121 μL, 1.232 mmol) was added followed by HCl (1.232 mL, 1.0M in ether). The reaction was heated to 70° C. for 1 hour then cooled and submitted to aqueous workup to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C@H:20]2[N:24]3[C:25](=[O:37])[C:26]([NH:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:27][N:28]=[C:23]3[CH2:22][CH2:21]2)=[O:19])=[CH:12][CH:11]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[C:39](OC(=O)NC(C1C=CC(CNC([C@H]2N3C(=O)C(N)=CN=C3CC2)=O)=CC=1)=N)(C)(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8](=[NH:9])[C:10]1[CH:11]=[CH:12][C:13]([CH2:16][NH:17][C:18]([C@H:20]2[N:24]3[C:25](=[O:37])[C:26]([NH:29][CH2:30][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:39]=4)=[CH:27][N:28]=[C:23]3[CH2:22][CH2:21]2)=[O:19])=[CH:14][CH:15]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NCc4ccccc4)c(=O)n32)cc1
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(N)c(=O)n32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NCCc4ccccc4)c(=O)n32)cc1
Yield: 54 %

Procedure:
Following a procedure similar to that for the preparation of 1k, intermediate 1j (60 mg, 0.14 mmol), phenylacetyladehyde (67.3 mg, 0.56 mmol) and NaBH(OAc)3 (326.4 mg, 1.54 mmol) yielded 40 mg (54%) of intermediate 2a. MS (ESI) 531.1 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl.Cl.[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[CH2:21][CH2:20]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(N(CC)CC)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][C:13]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=3)[CH2:21][CH2:20]2)=[O:15])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: CC(=O)c1ccc(OCCC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCCC(=O)NC2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)cc1
Reaction time: 12 h
Yield: 60.2 %

Procedure:
3-(4-Acetylphenyloxy)propionic acid (1.0 g) and 4-amino-1-(3,4-dichlorobenzyl)piperidine dihydrochloride (1.6 g) were suspended in DMF (50 mL), and triethylamine (1.3 mL), EDC hydrochloride (1.1 g) and HOBt (0.9 g) were added to the suspension. The suspension was stirred for 12 hrs. The reaction mixture was washed with water and then saturated brine and dried, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to crystallize to give the title compound (1.3 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][Cl:12])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:21])C=1>C(Cl)Cl.[O-]S([O-])=O.[Na+].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][CH2:10][CH2:11][Cl:12])=[O:21])=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1ccc(SCCCCl)cc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=S(CCCCl)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
A solution of 3-chloropropyl 4-fluorophenyl sulfide (77.5 mg, 0.380 mmol) in CH2Cl2 (2.00 mL) was cooled to 0° C. To this solution m-CPBA (78.7 mg, 0.460 mmol) was added. The reaction mixture was stirred at 0° C. for 30 min, then at 23° C. for 4 h. The resulting crude mixture was diluted with 10% aqueous Na2SO3 (10 mL), the aqueous layer was extracted with CH2Cl2 (2×15 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC using 2.5% of NH3 (2.0 M in methanol) in CH2Cl2 to give the desired product 3-chloropropyl 4-fluorophenyl sulfoxide (47.8 mg, 57.0%).
Reaction SMILES: [C:1]([N:3]=[C:4](OCC)[CH2:5][CH2:6][CH3:7])#[N:2].[C:11]([C:13]1[CH:26]=[CH:25][C:16]2[O:17][C:18]([CH3:24])([CH3:23])[C@@H:19]([OH:22])[C@H:20]([NH2:21])[C:15]=2[CH:14]=1)#[N:12]>C(OCC)(=O)C>[C:11]([C:13]1[CH:26]=[CH:25][C:16]2[O:17][C:18]([CH3:24])([CH3:23])[C@@H:19]([OH:22])[C@H:20]([NH:21][C:4](=[N:3][C:1]#[N:2])[CH2:5][CH2:6][CH3:7])[C:15]=2[CH:14]=1)#[N:12]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: CCCC(=NC#N)OCC
Solvent: CCOC(C)=O
Product: CCCC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Reaction time: 2 h

Procedure:
To 3.09 g of ethyl N-cyanobutyrimidate, 4.38 g of 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-amino-2H-benzo[b]pyran-3-ol was added, and the mixture was reacted under stirring at a temperature of from 100° to 120° C. for 2 hours. The reaction mixture was cooled, then dissolved in 100 ml of ethyl acetate, washed twice with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The residual oily substance was purified by silica gel column chromatography to obtain 3.54 g of the above identified compound in the form of crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:8]=[C:9]([C:11](=[O:17])[NH:12][C@@H:13]([CH3:16])[CH2:14][OH:15])[CH:10]=1)=[O:4].[OH-].[Li+].C1COCC1.Cl>O>[OH:15][CH2:14][C@@H:13]([NH:12][C:11]([C:9]1[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:8]=1)=[O:17])[CH3:16]
Reactant: COC(=O)c1cc(C(=O)N[C@@H](C)CO)cc(-c2ccc(C)cc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N[C@@H](C)CO)c2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of (S)-methyl5-(1-hydroxypropan-2-ylcarbamoyl)-4′-methylbiphenyl-3-carboxylate (105 mg, 0.321 mmol), lithium hydroxide (9.98 mg, 0.417 mmol), THF (3 mL), and water (1 mL) was stirred at room temperature for 12 h. LC-MS indicated completion of the reaction. The reaction mixture was diluted with water (5 mL) and acidified with 1N aq. HCl to pH=3 and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to yield a white solid. LC-MS: 314.4 [M+1]+.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.N1CCCCC1.[CH:15](=O)/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[C:18]1([CH:17]=[CH:16][CH:15]=[C:2]2[C:3](=[O:7])[CH2:4][CH2:5][CH2:6][C:1]2=[O:8])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1CCCC(=O)C1
Reactant: O=C/C=C/c1ccccc1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1CCCC(=O)C1=CC=Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 11.2 g (0.1 mol) of 1,3-cyclohexanedione in 110 mL of ethanol was stirred at room temperature while 1 mL of piperidine was added followed by the dropwise addition of 13 mL (0.103 mol) of trans-cinnamaldehyde over a 2 min period. The resulting mixture was stirred at room temperature for 2 hr and then in an ice-bath for 1 hr. The resulting yellow slurry was filtered with suction and the solid dried under high vacuum giving 13.9 g (61.5%) of the title dione. Recrystallization of a sample of this material from ethyl acetate gave yellow solid, mp 115.5°-118° C.