Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:9][S:10][C:11](SC)=[CH:12][N+:13]([O-:15])=[O:14]>CN(C=O)C.C(N(CC)CC)C>[NH2:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:1][C:11]([S:10][CH3:9])=[CH:12][N+:13]([O-:15])=[O:14]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: Nc1ccncc1N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSC(=C[N+](=O)[O-])Nc1cnccc1N
Yield: 13.1 %

Procedure:
3,4-Diaminopyridine (6.00 g, 55.0 mmol) and 1,1-bis(methylthio)-2-nitroethylene (10.0 g, 60.5 mmol) were dissolved in 60 ml of DMF and 10 ml of triethylamine, followed by reaction at 70° C. for 5 hours. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: chloroform:methanol=2:1 (v/v)] to obtain 1.63 g of the intended product (yield: 13.1%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:34]([N+:37]([O-])=O)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>CO.C(O)(=O)C.[Fe]>[NH2:37][C:34]1[CH:35]=[CH:36][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([CH:33]=1)[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc([N+](=O)[O-])ccc1OCc1ccccc1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(N)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 49.2 %

Procedure:
Iron powder (43 mg) was added to a solution mixture of tert-butyl 2-(2-(benzyloxy)-5-nitrobenzamido)-4-phenylbenzoate (0.14 g) in methanol (1.4 mL) and acetic acid (1.4 mL), followed by heating to reflux for 1 hour. The reaction mixture was cooled to room temperature, and iron powder (14 mg) was added thereto, followed by heating to reflux for 30 minutes. The reaction mixture was cooled to room temperature, and a saturated aqueous solution of sodium bicarbonate and ethyl acetate were added thereto. The insoluble substance was removed by filtration. The organic layer was separated, washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride sequentially, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 90-50% hexane/ethyl acetate] to obtain 0.065 g of tert-butyl 2-(5-amino-2-(benzyloxy)benzamido)-4-phenylbenzoate as a yellow solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14]C)=O)[CH2:2]1.[CH3:19][C:20]#[N:21]>>[O:14]=[C:12]([C:11]1[CH:16]=[CH:17][CH:18]=[C:9]([O:8][CH2:7][CH:3]2[CH2:4][CH2:5][CH2:6][O:1][CH2:2]2)[CH:10]=1)[CH2:19][C:20]#[N:21]
Reactant: CC#N
Reactant: COC(=O)c1cccc(OCC2CCCOC2)c1
Product: N#CCC(=O)c1cccc(OCC2CCCOC2)c1

Procedure:
Reaction between methyl 3-((tetrahydro-2H-pyran-3-yl)methoxy)benzoate and CH3CN following the method used in Example 1 gave 3-oxo-3-(3-((tetrahydro-2H-pyran-3-yl)methoxy)phenyl)propanenitrile as a white solid. Yield (84%); 1H NMR (400 MHz, DMSO-d6) 87.52-7.45 (m, 2H), 7.43 (s, 1H), 7.29-7.26 (m, 1H), 4.75 (s, 2H), 3.93-3.87 (m, 3H), 3.75-3.71 (m, 1H), 3.39-3.36 (m, 1H), 3.28-3.25 (m, 1H), 2.01-1.98 (m, 1H), 1.86-1.83 (m, 1H), 1.60-1.58 (m, 1H), 1.53-1.49 (m, 1H), 1.42-1.39 (m, 1H).
Reaction SMILES: C([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH:5]([Cl:7])[Cl:6])C.C[C:12]1[CH:17]=[CH:16]C(S(O)(=O)=O)=CC=1.[CH2:22](O)CC>>[CH2:9]([O:8][CH:4]([O:3][CH2:16][CH2:17][CH3:12])[CH:5]([Cl:6])[Cl:7])[CH2:10][CH3:22]
Reactant: CCOC(OCC)C(Cl)Cl
Reactant: CCCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCOC(OCCC)C(Cl)Cl

Procedure:
A mixture of 5 g of dichloro-acetaldehyde diethyl-acetal, 30 ml of propanol and 0.1 g of 4-methyl-benzene-sulphonic acid is heated on a water-bath for 5 hours, then distilled.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]2[NH:8][CH2:9][C:10]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=2)[N:20]=[C:19]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:18]=1[CH3:34].[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]2[N:8]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=4)[N:20]=[C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:18]=3[CH3:34])[CH2:9][C:10]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Reactant: Brc1ccc2c(c1)NCC21CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2ccc(Br)cc21
Temperature: 130 °C

Procedure:
Prepared according to procedure M using 6-bromo-2′,3′,5′,6′-tetrahydrospiro-[indoline-3,4′-pyran] (98 mg, 367 μmol), 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (100 mg, 367 μmol) in DMF (4.5 mL) and sodium hydride (18 mg, 0.73 mmol) and heating the reaction mixture at 130° C. for 8 h. After purification 6-bromo-1-(7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yl)-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran] was obtained as a yellow film. 1H NMR (400 MHz, chloroform-d) δ ppm 8.74 (1H, d, J=5.1 Hz), 7.89-7.98 (2H, m), 7.85 (1H, dd, J=10.0, 2.5 Hz), 7.75 (1H, dd, J=9.2, 6.1 Hz), 7.41 (1H, ddd, J=6.7, 4.5, 2.5 Hz), 7.28-7.33 (1H, m), 7.07 (1H, d, J=7.8 Hz), 6.89 (1H, dd, J=7.8, 2.0 Hz), 6.11 (1H, d, J=2.0 Hz), 3.93-4.10 (4H, m), 3.45-3.60 (2H, m), 2.38 (3H, s), 2.08-2.25 (2H, m), 1.91 (1H, dd, J=13.9, 2.5 Hz), 1.81 (1H, dd, J=13.7, 2.3 Hz). Mass Spectrum (ESI) m/e 504 [(M+1) (79Br)] and 506 [(M+1) (81Br)].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:2]=1.[CH2:18]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:19][CH2:20][C:21]#[CH:22]>CCCCCCC.CCOC(C)=O>[C:23]1([CH2:18][CH2:19][CH2:20][C:21]#[C:22][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C#CCCCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccnc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: C(#Cc1cccnc1)CCCc1ccccc1

Procedure:
This product was prepared from toluene-4-sulfonic acid pyridin-3-yl ester and pent-4-ynyl-benzene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/EtOAc 8:2; yield (80 mg, 72%); 1H NMR δ (CDCl3): 8.62-8.63 (m, 1H), 8.48-8.46 (m, 1H), 7.68-7.64 (m, 1H), 7.21-7.17 (m, 6H), 2.76 (t, J=7.11 Hz, 2H), 2.4 (t, J=7.10 Hz, 2H), 1.91 (p, J=7.12 Hz, 2H); LCMS m/z: 221.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[C:13]([O:15][CH3:16])=[O:14])=[O:6])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:9][C@H:8]1[C:13]([O:15][CH3:16])=[O:14])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1C(=O)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-2-methoxycarbonyl-4-hydroxypyrrolidine (210.2 g) and triethylamine (150.2 ml) in dichloromethane (2 l) was added dropwise methanesulfonyl chloride (70.7 ml) at 0° C. After stirring for 1 hour at 0° C., the reaction mixture was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give (2S,4R)-1-allyloxycarbonyl-2-methoxycarbonyl-4-methanesulfonyloxypyrrolidine (281.8 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CN(C)C=O.CC1(C)C2CCC1(CS(O)(=O)=O)C(=O)C2.[NH:34]1[CH2:38][CH2:37][C@@:36]2([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[C:40](=[O:47])[O:39]2)[CH2:35]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([N:34]3[CH2:38][CH2:37][C@@:36]4([C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=5[C:40](=[O:47])[O:39]4)[CH2:35]3)=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Br)cc2)CC1
Reactant: O=C1O[C@]2(CCNC2)c2ccccc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(Br)cc4)CC3)C2)c2ccccc21
Reaction time: 17 h

Procedure:
To a stirred solution of 1-(4-bromophenyl)cyclopropanecarboxylic acid (1.616 g, 0.006704 mol) in anhydrous N,N-dimethylformamide (12.0 mL, 0.155 mol) at room temperature was added (7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonic acid-(1R)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (1:1) (2.569 g, 0.006095 mol, example 96, steps 1-2), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (3.057 g, 0.006704 mol), followed by N,N-diisopropylethylamine (4.27 mL, 0.0244 mol). The resulting clear solution was stirred at temperature for 17 hours. LCMS showed that the reaction was complete. The reaction was quenched with saturated aqueous NaHCO3 (50 mL), and the reaction mixture was extracted with EtOAc (2×).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([Br:12])=[CH:5][N:6]=[CH:7]2.[CH2:13]([CH:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:20](O)=[S:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[Br:12][C:4]1[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:20](=[S:21])[CH:19]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:7]=[N:6][CH:5]=1
Reactant: Nc1cccc2cncc(Br)c12
Reactant: CCCCCCCCC(CCCCCC)C(O)=S
Product: CCCCCCCCC(CCCCCC)C(=S)Nc1cccc2cncc(Br)c12

Procedure:
5-Amino-4-bromoisoquinoline (prepared according to the process described by Gordon et. al., J. Het. Chem., 4, 410 (1967)) was coupled with 2-hexylthiodecanoic acid (prepared by the procedures described in Examples 1 and 3) using the procedure described in Example 25 to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6][C:7]#[N:8])[CH3:2].Cl[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[Na+].O>CS(C)=O.CCOCC>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[CH:6]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:7]#[N:8])[CH3:2]
Reactant: CCCCCCl
Reactant: CCOc1ccccc1CC#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: CCCCCC(C#N)c1ccccc1OCC
Temperature: 25 °C
Yield: 47.7 %

Procedure:
A three neck 300 ml flask fitted with a reflux condenser, thermometer and dropping funnel was charged with 18.52 grams (0.15 moles) of commercially available 2-ethoxy benzylcyanide in 50 ml of dimethyl sulfoxide (DMSO). To the reaction was added 17.6 grams (0.165 moles, 1.1 ec.) of 1-chloropentane. While stirring at room temperature, 13.2 grams (0.165 moles) of 50% NaOH in 20 ml of DMSO was added over 20 minutes. A slight exotherm occurred and the reaction mixture was stirred at room temperature for 2 hours after which gas-liquid chromatoqraphy (GLC) indicated the reaction was 92% complete. The reaction was stirred for an additional 3 hours, then water was added followed by 200 ml of ether. After washing with acid and brine, the solvent was concentrated and gave an oil which was distilled under vacuum (160°-165° C. at 0.5 mm) and gave 15.82 grams (47.7% yield) of product.
Reaction SMILES: Cl[CH2:2][CH:3]([CH3:13])[CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[K].[CH2:15]([O:17][C:18]([O:20][NH:21][C:22](=[O:26])[O:23][CH2:24][CH3:25])=[O:19])[CH3:16].CN(C)C=O>C(OCC)(=O)C.O>[CH2:24]([O:23][C:22]([N:21]([CH2:2][CH:3]([CH3:13])[CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])[O:20][C:18]([O:17][CH2:15][CH3:16])=[O:19])=[O:26])[CH3:25]
Reactant: CCOC(=O)NOC(=O)OCC
Reactant: CCOP(=O)(CC(C)CCl)OCC
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)ON(CC(C)CP(=O)(OCC)OCC)C(=O)OCC
Reaction time: 3 h
Yield: 82 %

Procedure:
A mixture of diethyl 3-chloro-2-methylpropylphosphonate (22.8 g.), potassium salt of ethyl N-ethoxycarbonyloxycarbamate (21.5 g.) and dry N,N-dimethylformamide (114 ml.) was stirred at 80°-85° C. for 3 hours and then concentrated under reduced pressure to give an oily residue, to which was added a mixture of water (100 ml.) and ethyl acetate (100 ml.) The ethyl acetate layer was separated and the resultant aqueous layer was saturated with sodium chloride and extracted again with ethyl acetate (50 ml.). The combined ethyl acetate layer was washed with aqueous solution saturated with sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure to give oily diethyl 3-(N-ethoxycarbonyl-N-ethoxycarbonyloxyamino)-2-methylpropylphosphonate (30.2 g.).
Reaction SMILES: [H-].[Na+].[I-].[Na+].[CH3:5]N(C)P(N(C)C)(N(C)C)=O.Cl[CH2:17][S:18][CH2:19][O:20][CH2:21]SCCl.[CH2:25]1[CH2:29]O[CH2:27][CH2:26]1>>[CH3:17][S:18][CH2:19][O:20][C:21]1[CH:5]=[CH:29][CH:25]=[CH:26][CH:27]=1
Reactant: C1CCOC1
Reactant: ClCSCOCSCCl
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Product: CSCOc1ccccc1
Temperature: 0 °C
Yield: 89 %

Procedure:
N—BOC protected compound 22 (0.202 g 0.434 mmol) was dissolved in 2.0 mL of dry THF under argon and cooled to 0° C. Sodium hydride (0.018 g of a 60% dispersion, 0.46 mmol) was added and the reaction continued to stir at 0° C. for fifteen minutes. Sodium iodide (0.071 g 0.48 mmol), hexamethylphosphoramide (0.45 mL, 2.6 mmol), and chloromethylthiomethyl ether (36 μL, 0.48 mmol) were added in that order. After stirring for five minutes, the ice bath was removed and the reaction was warmed to room temperature. After stirring for another 45 minutes, water was added to the reaction mixture and it was extracted with ethyl acetate. The organics were combined and dried over sodium sulfate. Purification was accomplished using column chromatography eluting with 6:1 hexanes/ethyl acetate to provide methlythiomethylphenyl ether 23 (0.203 g 89%) as an oil, 1H-NMR (300 MHz, CDCl3) δ 7.07 (m, 2H), 6.86 (d, J=8.5 Hz, 2H), 5.11 (s, 2H), 4.84 (m, 1H), 4.33 (m, 1H), 3.91 (m, 1H), 3.35 (m, 3H), 2.83 (m, 1H), 2.24 (s, 3H), 2.06 (s, 3H), 1.48 (s, 9H), 0.81 (s, 9H), −0.02 (s, 6H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][C:14]1[CH:15]=[CH:16][C:17]2[CH2:18][C@H:19]3[C@@H:24]([C:25]=2[CH:26]=1)[CH2:23][CH2:22][CH2:21][NH:20]3>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:20]3[CH2:21][CH2:22][CH2:23][C@@H:24]4[C:25]5[CH:26]=[C:14]([CH3:13])[CH:15]=[CH:16][C:17]=5[CH2:18][C@H:19]34)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: Cc1ccc2c(c1)[C@H]1CCCN[C@H]1C2
Product: Cc1ccc2c(c1)[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1C2
Yield: 60 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-6-methyl-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1. Yield: 60% of theory; LC (method 1): tR=2.75 min; Mass spectrum (ESI+): m/z=332 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([CH:18]([OH:47])[CH2:19][NH:20][CH2:21][CH2:22][C:23]2[CH:46]=[CH:45][C:26]([NH:27][CH:28]3[CH2:33][CH2:32][N:31]([C:34]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[O:35])[CH2:30][CH2:29]3)=[CH:25][CH:24]=2)[CH:7]=[CH:8][C:9]=1[O:10]CC1C=CC=CC=1)=[O:3].[H][H]>C(O)C.[Pd]>[CH2:37]([NH:36][C:34]([N:31]1[CH2:32][CH2:33][CH:28]([NH:27][C:26]2[CH:45]=[CH:46][C:23]([CH2:22][CH2:21][NH:20][CH2:19][CH:18]([C:6]3[CH:7]=[CH:8][C:9]([OH:10])=[C:4]([C:2](=[O:3])[NH2:1])[CH:5]=3)[OH:47])=[CH:24][CH:25]=2)[CH2:29][CH2:30]1)=[O:35])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: [H][H]
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNCC(O)c3ccc(OCc4ccccc4)c(C(N)=O)c3)cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNCC(O)c3ccc(O)c(C(N)=O)c3)cc2)CC1

Procedure:
4-{4-[2-({2-[3-(Aminocarbonyl)-4-(benzyloxy)phenyl]-2-hydroxyethyl}-amino)ethyl]anilino}-N-octyl-1-piperidinecarboxamide was dissolved in ethanol (20 mL) and 10% palladium on carbon added (0.1 g). The mixture was shaken overnight on a Parr apparatus under 50 psi hydrogen, filtered through a Celite pad and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel Merck-60 (eluant: 5:1 chloroform-methanol) to yield the title compound (0.030 g, 0.05 mmol)
Reaction SMILES: [C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14](O)=[O:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([NH2:36])(=[O:35])=[O:34]>C1C=CC=CC=1>[C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33](=[O:35])(=[O:34])[NH2:36])=[O:15])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)c1ccc(COc2cccc(C(=O)O)c2)cc1
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)(C)c1ccc(COc2cccc(C(=O)Nc3ccccc3S(N)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.4 %

Procedure:
A benzene (30 ml) solution containing 4.00 g (14.0 mmol) of 3-(4-t-butylbenzyloxy)benzoic acid and 3 ml of thionyl chloride was heated under reflux for 2 hours and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in methylene chloride (30 ml), this solution was added dropwise under ice-cooling to a pyridine (50 ml) solution containing 2.42 g (14.0 mmol) of 2-aminobenzenesulfonamide, the mixture was stirred at room temperature for 18 hours and then methylene chloride was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with a 1 N hydrochloric acid aqueous solution, water and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The thus obtained crude crystals were recrystallized from an ether-hexane mixed solvent to obtain 4.2 g (yield: 68.0%) of the title compound.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)CC4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[CH3:45][N:46]([CH3:54])[C:47]1[CH:52]=CC(N)=[CH:49][CH:48]=1.NC1C=CC=CC=1>>[CH:9]12[O:12][CH:5]([CH2:11][CH2:10]1)[CH2:6][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:30]=[CH:52][C:47]([N:46]([CH3:54])[CH3:45])=[CH:48][CH:49]=4)=[O:27])=[CH:23][CH:24]=3)[N:16]=[C:15]3[N:31]([CH3:34])[N:32]=[CH:33][C:14]=13)[CH2:8]2
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: CN(C)c1ccc(N)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: CN(C)c1ccc(NC(=O)Nc2ccc(-c3nc(N4CC5CCC(C4)O5)c4cnn(C)c4n3)cc2)cc1

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing N,N-dimethyl-1,4-phenylenediamine as the aniline component. (24%, MS=499.2 (M+H))
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34](O)=[O:35])=[O:30])[CH:11]=1)=[O:9].C[N:46]([CH2:90][CH2:91][N:92]1[CH2:97][CH2:96][O:95][CH2:94][CH2:93]1)[C:47](=O)[C:48]1[CH:88]=CC=C(C(NC2C=CC(N3CCCCC3)=CC=2C2C=C(C(=O)NCC3C=CC=C(C(F)(F)F)C=3)C=CN=2)=O)C=1.Cl.O1CCN(CCNC2CC2)CC1>>[CH:47]1([N:46]([CH2:90][CH2:91][N:92]2[CH2:93][CH2:94][O:95][CH2:96][CH2:97]2)[C:34](=[O:35])[C:33]2[CH:37]=[CH:38][CH:39]=[C:31]([C:29]([NH:28][C:17]3[CH:18]=[CH:19][C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:21][C:16]=3[C:12]3[CH:11]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][C:5]4[CH:40]=[CH:41][CH:42]=[C:3]([C:2]([F:43])([F:44])[F:1])[CH:4]=4)[CH:15]=[CH:14][N:13]=3)=[O:30])[CH:32]=2)[CH2:48][CH2:88]1
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: C(CN1CCOCC1)NC1CC1
Agent: Cl
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(C(=O)N(CCN3CCOCC3)C3CC3)c2)c1

Procedure:
This compound was prepared from 3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzoic acid 4.1e using the procedure described for the preparation of N1-methyl-N1-(2-morpholinoethyl)-N3-(4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)isophthalamide 4.8. N-(2-morpholinoethyl)cyclopropanamine hydrochloride was used as the amine component in this coupling. MS (ES, m/z): 755 [M+H]+
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][Si:28]([C:31]#[CH:32])([CH3:30])[CH3:29].C(N(CC)CC)C.O>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.CCOCC>[Si:1]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:32]#[C:31][Si:28]([CH3:30])([CH3:29])[CH3:27])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OCc1ccc(Br)cc1)(c1ccccc1)c1ccccc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OCc1ccc(C#C[Si](C)(C)C)cc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A 25 mL round bottom flask was flame-dried under high vacuum. The vacuum was broken by the addition of dry argon, and the flask was allowed to cool to room temperature. The flask was charged with 2.0 g (4.70 mmol) of 4-bromobenzyl tert-butyldiphenylsilyl ether (Compound 1), 2.0 mL (14.1 mmol) of (trimethylsilyl)acetylene, and 16.5 mL of triethylamine. The solution was purged with argon for 15 minutes and bis(triphenylphosphine)palladium (II) chloride (83 mg, 0.12 mmol) and copper (I) iodide (22 mg, 0.12 mmol) were added and the solution stirred at ambient temperature for 3 days. The solution was poured into a separatory funnel containing water and ether. The layers were separated and the aqueous layer was extracted 3 times with ether. The combined ether layers were washed once with brine, and dried over magnesium sulfate, and the solvents were removed under reduced pressure. The residue was purified by distillation (bp=180° B 185° C., 1 torr) to give the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=3[N:10]=[C:9]2[C:18]([OH:21])([CH3:20])[CH3:19])[CH2:4][CH2:3]1.[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][CH:27]([CH:32]=O)[CH2:26]2>>[Cl:17][C:15]1[CH:14]=[CH:13][C:12]2[N:8]([C@H:5]3[CH2:4][CH2:3][C@@H:2]([NH:1][CH2:32][CH:27]4[CH2:26][C:25]5[C:29](=[CH:30][CH:31]=[C:23]([Cl:22])[CH:24]=5)[CH2:28]4)[CH2:7][CH2:6]3)[C:9]([C:18]([OH:21])([CH3:19])[CH3:20])=[N:10][C:11]=2[CH:16]=1
Reactant: O=CC1Cc2ccc(Cl)cc2C1
Reactant: CC(C)(O)c1nc2cc(Cl)ccc2n1[C@H]1CC[C@@H](N)CC1
Product: CC(C)(O)c1nc2cc(Cl)ccc2n1[C@H]1CC[C@@H](NCC2Cc3ccc(Cl)cc3C2)CC1

Procedure:
This compound was prepared from the hydrochloride salt of cis-2-[1-(4-amino-cyclohexyl)-5-chloro-1H-benzoimidazol-2-yl]-propan-2-ol and 5-chloro-indan-2-carbaldehyde. 1H-NMR is consistent with the assigned structure, LC-MS showed a single peak, C26H31Cl2N3O (m/e) calcd 471.1844, obsd 472.1 (M+H).