Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[C:14]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].O>ClC(Cl)C.ClCCl>[C:14]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:15]=[CH:16][C:17]([CH2:20][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C@@H:8]3[CH2:10][C@H:9]3[C:11]([OH:13])=[O:12])=[CH:6][CH:7]=2)=[CH:18][CH:19]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: Nc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(NCc2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
A suspension of racemic-(trans)-2-(4-aminophenyl)cyclopropanecarboxylic acid (I-1) (0.28 g, 1.58 mmol) and 4-biphenylcarbaldehyde (0.32 g, 1.74 mmol) in dichloroethane (20 mL) were heated to reflux until a clear solution formed. The solution was cooled to RT then NaB(OAc)3H (0.50 g, 2.37 mmol) was added and stirred for 2 h. Water (50 mL) and dichloromethane (50 mL) were added and the organic layer was separated, dried over Na2SO4, filtered and concentrated. The crude material was purified on silica gel eluting with an increasing gradient from hexanes to 40% ethyl acetate/hexanes to give the title compound as a white solid (0.33 g, 61%). 1H NMR (400 MHz, DMSO) δ 12.15 (s, 1H), 7.65-7.59 (m, 4H), 7.46-7.41 (m, 4H), 7.34 (t, J=7.3 Hz, 1H), 6.84 (d, J=8.6 Hz, 2H), 6.51 (d, J=8.4 Hz, 2H), 6.22 (s, 1H), 4.29 (s, 2H), 2.23-2.18 (m, 1H), 1.62-1.57 (m, 1H), 1.32-1.28 (m, 1H), 1.21-1.16 (m, 1H). ES-MS m/z 344.2 (MH+).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[C:8]([O:10][CH3:11])=[O:9].C(=O)(O)[O-].[Na+].[C:17](Cl)([O:19][CH2:20][CH:21]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18]>O1CCOCC1.O>[N:2]1([C:17]([O:19][CH2:20][CH:21]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[C:28]3[C:33]2=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:18])[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1COCCN1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C1COCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl morpholine-3-carboxylate hydrochloride (2.0 g, 11.01 mmol) in a mixture of 1,4-dioxane (10 mL) and water (20 mL) was added sodium bicarbonate (2.79 g, 33.2 mmol). The suspension was cooled in an ice-water bath and a solution of Fmoc chloride (2.93 g, 11.33 mmol) in 1,4-dioxane (30 mL) was added. The mixture was stirred at ambient temperature for 2 hours. The mixture was partitioned between ethyl acetate (150 mL) and water (150 mL). The phases were separated and the organic extract washed with 1 M aqueous HCl (150 mL) and brine (50 mL). The organic extract was dried (MgSO4), filtered and the solvent removed in vacuo to leave a colourless gum, 4.2 g. LCMS [LCMS4] Rt 3.10 min, m/z (ES+) 368 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH:13]([OH:15])[CH3:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:16](OC=C)(=[O:18])[CH3:17]>C1(C)C=CC=CC=1>[C:16]([O:15][C@@H:13]([C:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[O:12][N:11]=1)[CH3:14])(=[O:18])[CH3:17]
Reactant: C=COC(C)=O
Reactant: CC(O)c1cc(-c2cccc(Cl)c2)on1
Solvent: Cc1ccccc1
Product: CC(=O)O[C@H](C)c1cc(-c2cccc(Cl)c2)on1
Yield: 39.5 %

Procedure:
The title compound of Example 7.1 (106.5 g, 476 mmol) and Novozyme 435® (13 g) are taken up under Ar in dry toluene (1.5 L). After addition of vinyl acetate (66 mL, 716 mmol) the reaction was run at RT over night, followed by filtration over diatomaceous earth and washing with DCM. The solvent was evaporated in vacuo and the crude product was subjected to column chromatography on silica using dichloromethane/methanol (20:1) to give the title compound (50 g, 47%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:29])=[C:4]([NH:8][CH:9]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[CH3:28])[C:10]2[N:11]([CH:18]([CH3:20])[CH3:19])[CH:12]=[CH:13][C:14]=2[C:15]([OH:17])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]([F:29])=[C:4]([N:8]2[C:15](=[O:17])[C:14]3[CH:13]=[CH:12][N:11]([CH:18]([CH3:20])[CH3:19])[C:10]=3[CH:9]2[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[CH3:28])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(Cl)ccc1C(Nc1cccc(Cl)c1F)c1c(C(=O)O)ccn1C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(Cl)ccc1C1c2c(ccn2C(C)C)C(=O)N1c1cccc(Cl)c1F
Temperature: 80 °C

Procedure:
A mixture of 2-[(3-chloro-2-fluoro-phenylamino)-(4-chloro-2-methyl-phenyl)-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid (Step A2) (2.257 mmol), HATU (2.482 mmol) and NMM (6.77 mmol) in DMF (30 mL) was heated at 80° C. for 18 h. After cooling to rt, the reaction mixture was diluted with EtOAc and washed with a saturated aqueous solution of NaHCO3. The aqueous phase was extracted with EtOAc (2×). The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a white solid. tR: 5.31 min (HPLC 1); ESI-MS: tR=1.29 min, [M+H]+ 417/419 (LC-MS 1); TLC: Rf=0.13 (1:3 EtOAc/heptanes).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)C(=O)OC(C)(C)[O:13][C:12]2=O)=[CH:6][CH:5]=1.[O:30]1[C:35]2=[CH:36][CH:37]=[CH:38][C:34]2=[CH:33][CH:32]=[C:31]1[NH:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN1C(=O)CCC1.O>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH:11]([C:12](=[O:13])[N:39]([C:31]2[O:30][C:35]3=[CH:36][CH:37]=[CH:38][C:34]3=[CH:33][CH:32]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([Br:28])=[CH:26][CH:27]=2)=[CH:8][CH:9]=1
Reactant: c1ccc(Nc2ccc3cccc-3o2)cc1
Reactant: COC(=O)c1ccc(CC2(Cc3ccc(Br)cc3)C(=O)OC(C)(C)OC2=O)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1ccc(CC(Cc2ccc(Br)cc2)C(=O)N(c2ccccc2)c2ccc3cccc-3o2)cc1
Yield: 56.1 %

Procedure:
A solution of 4-[5-(4-Bromobenzyl)-2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-ylmethyl]-benzoic acid methyl ester (1.35 g, 2.93 mmol) and 4-benzofuran-2-ylphenylamine (736 mg, 3.52 mmol) in dry NMP (10 mL) was heated at 220° C. for 5 min in the microwave. The reaction mixture was diluted with water then extracted with EtOAc. After concentrating, the crude material was purified by flash chromatography on silica gel (ISCO cartridge, 40 g), eluting with a gradient of zero to 35% ethyl acetate in hexane over 30 minutes to afford 4-[2-(4-Benzofuran-2-ylphenylcarbamoyl)-3-(4-bromophenyl)-propyl]-benzoic acid methyl ester (935 mg, 56%). 1H NMR (300 MHz, DMSO-d6): δ 9.92 (s, 1H), 7.86 (d, J=8.4 Hz, 2H), 7.80 (d, J=8.7 Hz, 2H), 7.64-7.17 (m, 13H), 3.81 (s, 3H), 3.10-2.93 (m, 3H), 2.85-2.71 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.CS(C)=O.ClC[C:16]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:20][CH:19]=[CH:18][O:17]1.[C:27](=O)([O-])[O-].[Cs+].[Cs+]>O>[C:21]1([C:16]2[O:17][CH:18]=[C:19]([CH2:27][O:1][C:2]3[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=3)[N:20]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C([O-])[O-]
Reactant: ClCC1(c2ccccc2)NC=CO1
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccc(OCc2coc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.5 %

Procedure:
A mixture of 4-hydroxybenzaldehyde (1.9 g, 17.0 mmol), dimethyl sulfoxide (50 mL), 2-(chloromethyl)-2-phenyloxazole (3.3 g, 17.0 mmol) and cesium carbonate (11.0 g, 34.0 mmol) was stirred at room temperature for 16 hours. The mixture was poured into water (400 mL) and filtration of the resultant precipitate afforded the crude product. Crystallization of the solids from ethyl acetate gave the product as a light yellow solid in 90.5 % yield, m.p. 94°-96° C. MS (EI, m/e): 279 (M)+
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH:46]([NH2:48])[CH3:47]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:21])[NH:48][CH:46]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[F:39])[CH3:47])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:37])[CH3:38])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Reactant: CC(N)c1ccccc1F
Product: CC(C)c1ccc2c(Nc3cc(C(=O)NC(C)c4ccccc4F)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Yield: 84 %

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and (RS)-1-(2-fluorophenyl)ethylamine: yield 84%.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[NH2:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=2)[CH2:20][CH2:19][N:18]=1>C1(C)C=CC=CC=1>[CH3:28][O:27][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[C:17]1=[N:16][CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11](=[O:13])[N:18]1[CH2:19][CH2:20]2
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ccc2c(c1)CCN=C2N
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnc2n(c1=O)CCc1cc(OC)ccc1-2
Reaction time: 0.17 h
Yield: 69 %

Procedure:
Diethyl ethoxymethylenemalonate (10.72 g., 0.0496 mole) was added to a stirred mixture at 25° of 1-amino-3,4-dihydro-6-methoxyisoquinoline (8.75 g., 0.0496 mole) in toluene (330 ml.). Stirring was continued for 10 minutes after which the temperature of the resulting yellow solution was raised to the reflux point during ten minutes. The solution was refluxed for 5 minutes and cooled to give ethyl 6,7-dihydro-9-methoxy-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate, m.p. 158°-160° C. Successive recrystallizations from ethyl acetate and ethanol gave off-white flocculent needles: 10.3 g. (69% yield), m.p. 173°-175°.
Reaction SMILES: [H-].[Na+].[CH:3](=O)[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6].Cl[CH2:13][C:14]([NH:16][C:17]1[CH:18]=[N:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=1)=[O:15].C[O-].[Na+]>CN(C)C=O.O>[C:23]([C:20]1[N:19]=[CH:18][C:17]([NH:16][C:14]([C:13]2[O:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[CH:3]=2)=[O:15])=[CH:22][CH:21]=1)#[N:24]
Reactant: N#Cc1ccc(NC(=O)CCl)cn1
Reactant: O=Cc1ccccc1O
Agent: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(NC(=O)c2cc3ccccc3o2)cn1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (0.184 g, 7.6 mmol) in dry dimethyl formamide (20 mL), a solution of salicylaldehyde (0.947 g, 7.6 mmol) in dry dimethylformamide (20 mL) was added dropwise under stirring. Stirring was continued for 30 minutes, and compound of example 3 (1.5 g, 7.6mmol) was added to the reaction mixture and heated at 80° C. for 2 hours. To this reaction mixture was added a solution of sodium methoxide (0.044 g) and stirred for 1 hour at 80° C. The reaction mixture was cooled, diluted with water and extracted with chloroform (3×100 mL). Chloroform layer was dried over sodium sulfate and concentrated. The crude product was purified using repetitive column chromatography (silica gel, ethyl acetate/petroleum ether followed by chloroform as an eluent) to obtain the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:7][C:8]1[CH:21]=[CH:20][C:11]([C:12]([CH2:14][C:15](OCC)=[O:16])=O)=[CH:10][CH:9]=1.P(Cl)(Cl)[Cl:23].[ClH:26]>>[Cl:26][C:14](=[CH:12][C:11]1[CH:20]=[CH:21][C:8]([CH3:7])=[CH:9][CH:10]=1)[C:15]([Cl:23])=[O:16]
Reactant: Cl
Reactant: CCOC(=O)CC(=O)c1ccc(C)cc1
Reactant: ClP(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: Cc1ccc(C=C(Cl)C(=O)Cl)cc1

Procedure:
A one liter flask was fitted with a mechanical stirrer, CaCl2 drying tube, condenser and a sidearm addition funnel. 100 gms of PCl5 was placed in the flask. 39 gms of ethyl 4-methylbenzoylacetate and 100 gms of PCl3 were mixed and slowly added to the PCl5 at room temperature. The reaction mixture evolved HCl. After 30 minutes the mixture was cautiously refluxed for 2 hours. At this time PCl3 and POCl3 were distilled from the reaction mixture at reduced pressure. The residue was then distilled at 0.5 mm (bp=116°-121° C.) to provide 32 gms of -chloro-4-methylcinnamoyl chloride as a clear oil.
Reaction SMILES: C[N:2]([CH3:15])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)=O.Cl.NC1[N:19]=[CH:20][NH:21][C:22]=1[C:23]([NH2:25])=[O:24].C(#N)C.C(O)C>C(O)(=O)C>[CH3:14][O:13][C:9]1[CH:8]=[C:7]([C:5]2[N:19]3[CH:20]=[N:21][C:22]([C:23]([NH2:25])=[O:24])=[C:15]3[N:2]=[CH:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: COc1cccc(C(=O)C=CN(C)C)c1
Reactant: NC(=O)c1[nH]cnc1N
Agent: Cl
Solvent: CCO
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1cccc(-c2ccnc3c(C(N)=O)ncn23)c1
Yield: 65.2 %

Procedure:
A stirred mixture of 15.0 g of 3-dimethylamino-3'-methoxyacrylophenone (prepared as described in Example 5 and 9.2 g of 4-amino-5-imidazolecarboxamide hydrochloride in 150 ml of glacial acetic acid was heated at reflux for 24 hours. The solvent was evaporated in vacuo and the crystalline residue was treated with 100 ml of saturated sodium bicarbonate solution, filtered and washed with 200 ml of water to give yellow crystals. This material was treated with 400 ml of acetonitrile then with 600 ml of hot ethanol to give 9.9 g of the product of the example as yellow crystals, mp 249°-252° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH2:10].CN(C)C=O.[H-].[Na+].Cl[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1>O.CC1C=CC=CC=1>[F:26][C:22]1[CH:21]=[C:20]([CH2:19][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[C:2]2[NH2:10])[CH:25]=[CH:24][CH:23]=1
Reactant: Nc1nc2ccccc2[nH]1
Reactant: Fc1cccc(CCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1nc2ccccc2n1Cc1cccc(F)c1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a stirred and heated (60° C.) solution of 41.3 parts of 1H-benzimidazol-2-amine in 162 parts of N,N-dimethylformamide (DMF) were added portionwise during a 40 minutes period 12 parts of sodium hydride dispersion 60%. Upon completion, stirring at 60° C. was continued for 30 minutes. After cooling to 40° C., there was added dropwise during 25 minutes a solution of 50 parts of 1-(chloromethyl)-3-fluorobenzene in 9 parts of DMF and 36 parts of methylbenzene. After the addition was complete, the whole was stirred for 1.50 hours at 50°-65° C. The reaction mixture was cooled and water was added. The solid product was filtered off and crystallized from a mixture of 2,2'-oxybispropane, tetrahydrofuran and methanol. The product was filtered off and recrystallized from methylbenzene, yielding 34.8 parts of 1-[(3-fluorophenyl)methyl]-1H-benzimidazol-2-amine; mp. 188.1° C. (1).
Reaction SMILES: [S:1]1[CH2:5][C:4](=O)[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2.[C:11](#[N:15])[CH2:12][C:13]#[N:14].[N+](=[C:18]1CCCCCCCCC(C2CCCCCCCCCC=2)=C1)=[N-].C(OCC)(=O)C>C(O)C.O>[C:13]([CH:12]([C:11]#[N:15])[CH:18]=[C:4]1[CH2:5][S:1][C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]1=2)#[N:14]
Reactant: N#CCC#N
Reactant: [N-]=[N+]=C1C=C(C2=CCCCCCCCCC2)CCCCCCCC1
Reactant: O=C1CSc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#CC(C#N)C=C1CSc2ccccc21
Yield: 54 %

Procedure:
One (1) part of benzo[b]thiophen-3(2H)-one and 0.5 parts of malononitrile were dissolved in ethanol, and 0.8 parts of diazobicycloundecene was added dropwise to the solution for 10-hour reaction at room temperature. After the completion of the reaction, ethyl acetate and water were added to the reaction product to separate it into phases, the organic phase of which was concentrated to solid, thereby obtaining 0.7 parts of 3-dicyanoethylidenebenzo[b]thiophene (in a yield of 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:14][CH2:13][N:12](CC3C=CC=CC=3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.ClC(OC1C=CC=CC=1)=O.Br>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(SC2CCN(Cc3ccccc3)CC2)cc1
Agent: Br
Agent: O=C(Cl)Oc1ccccc1
Product: Cl
Product: Clc1ccc(SC2CCNCC2)cc1

Procedure:
Following the procedure of Intermediate 9, 4-[(4-chlorophenyl)thio]-1-(phenylmethyl)piperidine is reacted with phenyl chloroformate and the product is hydrolyzed with 48% hydrobromic acid to give the free base of the title compound which is then converted to the hydrochloride.
Reaction SMILES: Br[CH2:2][CH:3]1[O:7][CH2:6][CH2:5][O:4]1.[CH2:8]([NH2:12])[CH2:9][CH2:10][CH3:11].[OH-].[Na+]>O>[CH2:8]([NH:12][CH2:2][CH:3]1[O:7][CH2:6][CH2:5][O:4]1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCN
Reactant: BrCC1OCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCNCC1OCCO1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
2-Bromomethyl-1,3-dioxolane (20 grams) and n-butylamine (120 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at a temperature of about 100° C. for a period of about 3 hours. After this time sodium hydroxide (10 grams) dissolved in water (100 ml) was added and the resulting mixture was stirred for a period of about 30 minutes. The reaction mixture was then extracted with ether and the ether solution was separated and dried over magnesium sulfate. The dried solution was filtered and stripped of solvent to yield the desired product N-n-butyl-N-(1,3-dioxolan-2-ylmethyl)amine as an oil.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([C:17]2[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[NH:10][S@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])=[CH:5][CH:4]=1)=[O:2].[CH3:27][Mg]Br>C1COCC1>[OH:2][CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]([C:17]2[C:22]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[NH:10][S@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])=[CH:7][CH:8]=1)[CH3:27]
Reactant: CC(C)(C)[S@](=O)N[C@@H](c1ccc(C=O)cc1)c1ncccc1C(F)(F)F
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1ccc([C@H](N[S@@](=O)C(C)(C)C)c2ncccc2C(F)(F)F)cc1

Procedure:
(S)—N—((S)-(4-Formylphenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (0.200 g, 0.520 mmol) was dissolved in dry THF (30 mL) and cooled in an ice bath. Methylmagnesium bromide (3M in Et2O, 0.50 mL, 1.50 mmol) was added dropwise and the reaction stirred. The resulting mixture was stirred for 1 h and then quenched by addition of saturated aqueous NH4Cl (10 mL). H2O (100 mL) and EtOAc (100 mL) were added, and the phases were mixed and separated. The organic layer was dried with MgSO4 and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to EtOAc gradient) gave impure material which was further purified using reverse phase HPLC to give the desired (S)—N-((1S)-(4-(1-hydroxyethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1.[H-].[Na+].I[CH3:23]>C1COCC1>[CH3:23][N:6]1[CH2:5][CH2:4][N:3]([C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]2)[C:2]1=[O:1]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N2CCNC2=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN([C@@H]2CCCN(C(=O)OC(C)(C)C)C2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To a solution of (R)-tert-butyl 3-aminopiperidine-1-carboxylate (50 g, 250 mmol) and Et3N (50.5 g, 500 mmol) in DCM (500 mL) was added 2-chloroethyl isocyanate (31.65 g, 300 mmol) dropwise. The resulting mixture was stirred at RT for 4 hours before being quenched with water (100 mL). The layers were separated and the organic layer was washed with brine, dried, concentrated, and subjected to silica flash column using 0 to 50% EA in to isolate (R)-tert-butyl 3-(3-(2-chloroethyl)ureido)piperidine-1-carboxylate (364) (63.6 g, 81.5%) as a colorless oil. At 0° C., to a solution of (R)-tert-butyl 3-(3-(2-chloroethyl)ureido)piperidine-1-carboxylate (364, 31.0 g, 102 mmol) in anhydrous THF (350 mL) was added NaH (60% in mineral oil, 4.82 g, 122 mmol) in small portions slowly. The resulting mixture was stirred at RT for 6 hours before being quenched with water (50 mL). The layers were separated and the aqueous was extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried, concentrated and subjected to silica flash column using 0 to 5% MeOH in DCM to isolate (R)-tert-butyl 3-(2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (365) (25.4 g, 93%) as a white solid. At 0° C., to a solution of (R)-tert-butyl 3-(2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (365) (16.2 g, 60.2 mmol) in anhydrous THF (160 mL) was added NaH (60%, 3.6 g, 90.3 mmol) in small portions. The resulting mixture was stirred at RT for 30 min, cooled back to 0° C., and then iodomethane (12.9 g, 90.3 mmol) was added dropwise. After the addition, the mixture was stirred at RT for 3 hours. The reaction was quenched with water and extracted with DCM (50 mL×2). The combined organic layers were washed with brined, dried, concentrated, and purified by silica flash column using 0 to 3% MeOH in DCM to get (R)-tert-butyl 3-(3-methyl-2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (366) (13.0 g, 74%) as a light yellow oil. (R)-tert-butyl 3-(3-methyl-2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (366) (3.5 g, 12.37 mmol) was treated with 40 mL commercial 4N HCl in dioxane at RT for 2 hours. The solvent was removed in vacuo, and the residue was basified to pH 9 with ammonium hydroxide. The solvent was then removed in vacuo, and the residue was subjected to silica flash column using 0 to 10% MeOH in DCM to isolate (R)-1-methyl-3-(piperidin-3-yl)imidazolidin-2-one (367) (1.2 g, 53%) as an oil. LC-MS (ESI): m/z (M+1) 184.2. Proton NMR (CDCl3): δ 3.95-3.83 (2H, m), 3.75 (1H, s), 3.39-3.26 (5H, m), 3.08-2.97 (1H, m), 2.93-2.79 (1H, m), 2.78 (3H, s), 1.94-1.86 (2H, m), 1.82-1.56 (2H, m), 1.48-1.21 (1H, m) ppm.