Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH2:10]([N:17]1[CH2:21][CH2:20][C:19](=O)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[CH2:10]([N:17]1[CH2:21][CH2:20][CH:19]([NH:1][C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CCN(Cc2ccccc2)C1
Reactant: Cc1cc(C)nc(N)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)nc(NC2CCN(Cc3ccccc3)C2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.2 %

Procedure:
A mixture of 2-amino-4,6-dimethylpyridine (2.0 g), 1-benzylpyrrolidin-3-one (2.9 g), acetic acid (2.9 mL), and chloroform (34 mL) was ice-cooled, followed by addition of sodium triacetoxyborohydride (4.9 g), and the mixture was stirred for 18 h while heating slowly to room temperature. To the reaction mixture was added 1 M aqueous sodium hydroxide to make it basic, and then the mixture was extracted with chloroform. The organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=65:35) to obtain 1-benzyl-3-(4,6-dimethylpyridin-2-ylamino)pyrrolidine (1.3 g). (2) 1-Benzyl-3-(4,6-dimethylpyridin-2-ylamino)pyrrolidine (1.3 g) was dissolved in methanol (13 mL), followed by addition of 20% Pd(OH)2/C (0.26 g), and the mixture was stirred at room temperature for 20 h under hydrogen atmosphere. The catalyst was removed by Celite filtration, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, chloroform/methanol=19:1) to obtain 3-(4,6-dimethylpyridin-2-ylamino)pyrrolidine (0.10 g). (3) A mixture solution of 3-(4,6-dimethylpyridin-2-ylamino)pyrrolidine (0.73 g), 4-trifluoromethoxyphenylacetic acid (0.12 g), EDC.HCl (0.12 g), HOBt.H2O (0.12 g), and chloroform (1.0 mL) was stirred at room temperature. After completion of the reaction, the reaction mixture was diluted with chloroform and washed with 1 M aqueous sodium hydroxide and brine. The organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=19:1) and then crystallized with hexane and diethyl ether to obtain the title compound (0.14 g).
Reaction SMILES: C(OCC=C)C=C.[Na].[C:9]([C:11]1[CH:12]=[N:13][N:14]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[C:36]=2[Cl:43])[C:15]=1[N:16](C(OC1C=CC=CC=1)=O)[C:17]([O:19][C:20]1C=CC=[CH:22][CH:21]=1)=[O:18])#[N:10].C(=O)=O>C(O)C=C.O1CCCC1>[C:9]([C:11]1[CH:12]=[N:13][N:14]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[C:36]=2[Cl:43])[C:15]=1[NH:16][C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])#[N:10]
Reactant: N#Cc1cnn(-c2ccc(Cl)c(Cl)c2Cl)c1N(C(=O)Oc1ccccc1)C(=O)Oc1ccccc1
Agent: C=CCOCC=C
Agent: O=C=O
Agent: [Na]
Solvent: C=CCO
Solvent: C1CCOC1
Product: C=CCOC(=O)Nc1c(C#N)cnn1-c1ccc(Cl)c(Cl)c1Cl
Reaction time: 0.25 h

Procedure:
A solution of sodium 2-propenyloxide in allyl alcohol [30 ml; prepared by dissolving sodium metal (1.0 g) in allyl alcohol (40 ml)] was added to a stirred solution of 4-cyano-5-di(phenoxycarbonyl)amino-1-(2,3,4-trichlorophenyl)pyrazole (15 g) in tetrahydrofuran (300 ml). The mixture was stirred for 15 minutes at laboratory temperature then solid carbon dioxide pellets added to adjust the pH of the solution to pH7. The neutralized solution was filtered through diatomaceous earth and then evaporated under reduced pressure and the residue crystallised from a mixture of ethyl acetate and hexane to give 4-cyano-5-(2-propenyloxycarbonylamino)-1-(2,3,4-trichlorophenyl)pyrazole, m.p. 154°-155° C., in the form of colourless crystals.
Reaction SMILES: [P:1]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:2]C1C=CC=CC=1.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[CH3:31][N:32]([CH3:37])[S:33]([NH2:36])(=[O:35])=[O:34]>ClC1C=CC=CC=1>[CH3:31][N:32]([CH3:37])[S:33]([NH:36][CH:23]([P:1](=[O:2])([O:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:35])=[O:34]
Reactant: O=Cc1ccccc1
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Reactant: CN(C)S(N)(=O)=O
Solvent: Clc1ccccc1
Product: CN(C)S(=O)(=O)NC(c1ccccc1)P(=O)(Oc1ccccc1)Oc1ccccc1
Temperature: 115 °C
Yield: 36 %

Procedure:
A mixture of 0.25 mole each of triphenyl phosphite, benzaldehyde, and N,N-dimethylsulfamide in 130g of chlorobenzene is warmed at 115° C. for 1.5 hrs. After the reaction mixture cools to room temperature, 41.0g (36% yield) of crude product is isolated by filtration. It is washed with water and recrystallized from chlorobenzene, giving a white solid: mp 193°-196°; 31P nmr (DMSO-d6) -14.0 ppm(d, J = 28Hz); 1H nmr δ8.8(d of d, 1, J = 2 and 11, NH), 6.8-7.8(m, 15, aryl), 5.2(d of d, 1, J = 10 and 25Hz, CH), 2.4(s, 6, CH3).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[CH:31]=[CH:30][N:29]=[C:28](Cl)[N:27]=3)[CH:21]=2)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:33][C:34]1[CH:35]=[C:36]([CH2:40][CH2:41][NH2:42])[CH:37]=[CH:38][CH:39]=1>>[Cl:33][C:34]1[CH:35]=[C:36]([CH2:40][CH2:41][NH:42][C:28]2[N:27]=[C:26]([C:22]3[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=3)[CH2:19][N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[S:15]([CH3:18])(=[O:16])=[O:17])[CH:31]=[CH:30][N:29]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(-c3ccnc(Cl)n3)c2)S(C)(=O)=O)CC1
Reactant: NCCc1cccc(Cl)c1
Product: CS(=O)(=O)N(Cc1cccc(-c2ccnc(NCCc3cccc(Cl)c3)n2)c1)C1CCNCC1

Procedure:
Intermediate 30 was coupled with 2-(3-chloro-phenyl)-ethylamine following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 500. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.3 (d, 1H), 8.1 (d, 1H) 7.7 (d, 1H) 7.5 (t, 1H), 7.3 (m, 2H), 7.25 (m, 3H), 7.20 (d, 1H), δ 4.6 (s, 2H), δ 3.3 (t, 2H), 3.09 (s, 3H), δ 3.04 (m, 7H), 2.0 (m, 4H).
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([O:30][CH3:31])=[O:29])=[CH:18][CH:17]=1.O>C1COCC1.C(O)(=O)C>[CH3:31][O:30][C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH:3]([C:2](=[O:1])[CH2:8][CH2:9][CH2:10][CH3:11])[C:4]([O:6][CH3:7])=[O:5])=[CH:21][CH:20]=1)=[O:29]
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCCCC(=O)C(Cc1ccc(-c2ccccc2C(=O)OC)cc1)C(=O)OC
Reaction time: 0.25 h
Yield: 93 %

Procedure:
Under nitrogen atmosphere, 2.3 of methyl 3-oxoheptanoate, dissolved into 10 ml of anhydrous THF were dropped into a suspension containing 0.22 g of 80% NaH in 30 ml g of anhydrous THF. After the effervescence was over, 2.22 g of 4-bromomethyl-2'-methoxycarbonylbiphenyl, dissolved in 10 ml of anhydrous THF, were slowly dropped into the clear solution. After 15 minutes, water was added and acetic acid was added till acidic pH. The reaction mixture was extracted with AcOEt. The organic phase was washed with a NaCl saturated solution, dried on Na2SO4 and evaporated to dryness. The residue was purified by FC (eluent: hexane/AcOEt 8:2). 2.6 g of a clear oil were obtained (yield 93%); 1H-NMR (200 MHz, CDCl3)δ: 0.86 (t, 3H), 1.15-1.62 (m, 4H), 2.25-2.65 (m, 2H), 3.20 (d, 2H), 3.63 (s, 3H), 3.71 (s, 3H), 3.84 (t, 1H), 7.12-7.58 (m, 7H), 7.78 (dd, 1H).
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[CH3:12][CH:13]([CH3:33])[CH2:14][C:15]([O:17][CH:18]([O:22][C:23](ON1C(=O)CCC1=O)=[O:24])[CH:19]([CH3:21])[CH3:20])=[O:16]>CC(OC)(C)C.CC(C)=O.O>[CH3:12][CH:13]([CH3:33])[CH2:14][C:15]([O:17][CH:18]([O:22][C:23]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:24])[CH:19]([CH3:20])[CH3:21])=[O:16]
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CC(C)CC(=O)OC(OC(=O)ON1C(=O)CCC1=O)C(C)C
Solvent: COC(C)(C)C
Solvent: O
Solvent: CC(C)=O
Product: CC(C)CC(=O)OC(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)C(C)C

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (472 mg, 3.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxyl]-2-methylpropyl 3-methylbutanoate (558 mg, 1.77 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 46 (75 mg, 12% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.82-0.94 (br. m, 14H), 1.17-1.37 (m, 3H), 1.65-1.73 (br. m, 2H), 1.83-2.01 (br. m, 4H), 2.09 (tt, J=12.4, 3.6 Hz, 1H), 2.17 (d, J=6.6 Hz, 2H), 2.74-2.87 (br. m, 2H), 6.45 (d, J=4.8 Hz, 1H), 7.40 (t, J=6.0 Hz, 1H), 11.97 (br. s, 1H). MS (ESI) m/z 380.23 (M+Na)+; 356.18 (M−H)−.
Reaction SMILES: C([N:9]1[CH2:14][CH2:13][C:12]2([CH2:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:20]=3)[O:15]2)[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.C(O)C.[ClH:33].CO>ClCCl>[ClH:33].[O:24]=[C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:20]=2)[O:15][C:12]2([CH2:11][CH2:10][NH:9][CH2:14][CH2:13]2)[CH2:23]1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CC1(CCN(C(=O)c3ccccc3)CC1)O2
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Temperature: 87.5 °C
Reaction time: 3.5 h
Yield: 114 %

Procedure:
N-(1′-Benzoyl-4-oxospiro[chroman-2,4′-piperidine]-6-yl)methanesulfonamide (10, 0.81 g, 1.95 mmol) was suspended in a mixture of absolute ethanol (10 mL) and 6 M aqueous hydrochloric acid (10 mL) and stirred at 85-90° C. in an oil bath. After 1 hour the oil bath temperature was increased to 95° C. After ˜3.5 hours at 95° C. the reaction was allowed to cool to room temperature. TLC (silica gel, 10% methanol in dichloromethane, UV visualization) showed no remaining starting material [Rf (10)=0.65−0.7]. Solvent was removed under reduced pressure on a rotary evaporator. Ethanol was added to the residue and then evaporated to dryness under reduced pressure on a rotary evaporator. The ethanol addition and evaporation to dryness was repeated two more times. The residue was dried in vacuo to afford 0.77 g (114% yield) of N-(4-oxospiro[chroman-2,4′-piperidine]-6-yl)methanesulfonamide hydrochloride (11) as a light yellow solid that was homogeneous by TLC [silica gel, 10% methanol in dichloromethane containing a small amount of concentrated aqueous ammonium hydroxide, UV visualization, Rf (11)=0.12−0.19]. Mass spec: m/z=311.2 [M+H]+
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C@H:8]2[O:12][C:11](=[O:13])[N:10]([CH2:14][C:15]3[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=3[C:25]3[CH:26]=[C:27]([C:33]4[CH:38]=[CH:37][C:36]([C:39]([O:41][CH3:42])=[O:40])=[CH:35][C:34]=4[CH3:43])[CH:28]=[CH:29][C:30]=3[O:31][CH3:32])[C@H:9]2[CH3:44])[CH:5]=[CH:4][N:3]=1.[CH3:45]B1OB(C)OB(C)O1>C1COCC1.C([O-])([O-])=O.[K+].[K+].O.CCOC(C)=O>[CH3:32][O:31][C:30]1[CH:29]=[CH:28][C:27]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([O:41][CH3:42])=[O:40])=[CH:35][C:34]=2[CH3:43])=[CH:26][C:25]=1[C:16]1[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:15]=1[CH2:14][N:10]1[C@@H:9]([CH3:44])[C@@H:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:45])[CH:7]=2)[O:12][C:11]1=[O:13]
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4ccnc(Cl)c4)[C@@H]3C)c2)c(C)c1
Reactant: CB1OB(C)OB(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4ccnc(C)c4)[C@@H]3C)c2)c(C)c1
Temperature: 80 °C

Procedure:
To a solution of methyl 2″-{[(4S,5R)-5-(2-chloropyridin -4-yl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (48 mg, 0.077 mmol) in THF (1 mL) and K2CO3 (1N) (1 mL) was added trimethylboroxine (0.107 mL, 0.768 mmol) and 1,1-bis(di-tert-butylphosphino)ferrocene palladium dichloride (7.1 mg, 0.011 mmol). The mixture was sealed and heated at 80° C. overnight. The mixture was diluted with water and EtOAc and filtered through Celite. The organic layer was separated and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with brine (1×), dried (Na2SO4), filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica gel to give methyl 4′-methoxy-2-methyl-2″-{[(4S,5R)-4-methyl-5-(2-methylpyridin-4-yl)-2-oxo-1,3-oxazolidin-3-yl]methyl}-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate. LCMS calc.=605.2; found=605.0 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers) δ 8.49 (t, J=4.3 Hz, 1H); 7.98 (t, J=6.6 Hz, 1H); 7.91 (t, J=10.0 Hz, 1H); 7.73 (s, 0.5H); 7.67 (s, 0.5H); 7.65 (s, 1H); 7.47-7.39 (m, 2H); 7.33-7.26 (m, 1H); 7.15 (dd, J=2.2, 5.7 Hz, 1H); 7.09 (dd, J=6.8, 8.4 Hz, 1H); 7.06 (s, 0.5H); 7.00 (s, 0.5H); 6-95 (d, J=4.8 Hz, 0.5H); 6.90 (d, J=4.7 Hz, 0.5H); 5.43 (d, J=8.2 Hz, 0.5H); 5.18 (d, J=8.1 Hz, 0.5H); 4.92 (d, J=15.8 Hz, 0.5H); 4.87 (d, J=15.8 Hz, 0.5H); 4.22 (d, J=15.8 Hz, 0.5H); 4.00 (d, J=15.8 Hz, 0.5H); 3.95 (s, 3H); 3.89 (s, 1.5H); 3.88 (s, 1.5H); 3.81-3.73 (m, 1H); 2.57 (s, 1.5H); 2.56 (s, 1.5H); 2.39 (s, 1.5H); 2.34 (s, 1.5H); 0.57 (d, J=6.6 Hz, 1.5H); 0.47 (d, J=6.6 Hz, 1.5H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]1[C:18]2[NH:17][C:16]3[C:11](=[CH:12][C:13]([F:23])=[CH:14][C:15]=3[S:19]([CH3:22])(=[O:21])=[O:20])[C:10]=2[CH2:9][CH2:8][CH2:7]1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:44][C:45]1[CH:50]=[CH:49][C:48]([C@H:51](O)[CH3:52])=[CH:47][CH:46]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]1[C:18]2[N:17]([C@H:51]([C:48]3[CH:49]=[CH:50][C:45]([Cl:44])=[CH:46][CH:47]=3)[CH3:52])[C:16]3[C:11](=[CH:12][C:13]([F:23])=[CH:14][C:15]=3[S:19]([CH3:22])(=[O:21])=[O:20])[C:10]=2[CH2:9][CH2:8][CH2:7]1)[CH3:2]
Reactant: C[C@@H](O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C[C@H]1CCCc2c1[nH]c1c(S(C)(=O)=O)cc(F)cc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@H]1CCCc2c1n([C@@H](C)c1ccc(Cl)cc1)c1c(S(C)(=O)=O)cc(F)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of the compound of Step 4 (1 eq), triphenylphosphine (1.5 eq) and (1R)-1-(4-chlorophenyl)ethanol (1.5 eq, prepared following the general procedure described in Reference Example 1) in THF (0.175M) was added a solution of di-tert-butyl azodicarboxylate (2.1 M in THF, 1.5 eq) over a 10 min period. The mixture was stirred at room temperature for 2 hr and concentrated. The residue was purified by silica gel flash chromatography, eluting with 7% EtOAc in toluene to give the desired product (˜90% pure) which was used as such for the next reaction.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7](Br)[CH:8]=[N:9][CH:10]=1)([CH3:3])[CH3:2].[CH3:12][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:14]([CH2:16][CH:17]=[CH2:18])[CH3:15].C(N(CC)CC)C.C(#N)C>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:12][N:13]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH:14]([CH2:16]/[CH:17]=[CH:18]/[C:7]1[CH:8]=[N:9][CH:10]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:6]=1)[CH3:15]
Reactant: CC(C)Oc1cncc(Br)c1
Reactant: C=CCC(C)N(C)C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CC(C)Oc1cncc(/C=C/CC(C)N(C)C(=O)OC(C)(C)C)c1
Temperature: 80 °C
Yield: 119 %

Procedure:
Under a nitrogen atmosphere, a mixture of 5-isopropoxy-3-bromopyridine (847.0 mg, 3.92 mmol), N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine (784.7 mg, 3.94 mmol), palladium(II) acetate (9.0 mg, 0.04 mmol), tri-o-tolylphosphine (50.0 mg, 0.16 mmol), triethylamine (0.73 g, 7.21 mmol), and anhydrous acetonitrile (2 mL) was stirred and heated under reflux at 80° C. for 20 h. The mixture, containing solids was cooled, diluted with water (10 mL), and extracted with CHCl3 (3×10 mL). The combined CHCl3 extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to give an oily residue (1.56 g). The crude product was purified by column chromatography on silica gel, eluting with 25–40% (v/v) ethyl acetate in hexane. Selected fractions containing the product were combined and concentrated to give 1.15 g (87.8%) of a light-amber oil.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]=3)=[CH:10][C:9]=2[CH3:22])=[O:7])=[CH:4][CH:3]=1.[CH3:25][N:26]=[C:27]=[S:28]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:27]([NH:26][CH3:25])=[S:28])=[CH:17][N:16]=3)=[CH:10][C:9]=2[CH3:22])=[O:7])=[CH:23][CH:24]=1
Reactant: CN=C=S
Reactant: Cc1cc(Cc2ccc(N)cn2)n(C)c1C(=O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=S)Nc1ccc(Cc2cc(C)c(C(=O)c3ccc(Cl)cc3)n2C)nc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
N-{2-[5-(4-Chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]pyridin-5-yl}amine (0.3 g, 0.88 mmol) and methylisothiocyanate (0.3 ml, 4.4 mmol) were dissolved in THF and the reaction mixture was stirred at 60° C. overnight. The mixture was diluted with ethyl acetate and washed with 1N HCl, 10% sodium bicarbonate, water, and brine. The solvents were removed in vacuo and the crude product was purified by flash chromatography (ethyl acetate-methanol, 97:3) to give 1-{2-[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]pyridin-5-yl}-3-methyl-2-thiourea (265 mg, 73%) as a solid, mp 135° C.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[N:16]([C:40]2[CH:45]=[CH:44][C:43]([C:46]([O:49][CH3:50])([CH3:48])[CH3:47])=[CH:42][CH:41]=2)[C:17](=[O:39])[C:18]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:27][CH:26]=2)=[C:19]([CH2:21][CH2:22][CH3:23])[N:20]=1)[CH3:14]>O>[CH2:13]([C:15]1[N:16]([C:40]2[CH:41]=[CH:42][C:43]([C:46]([O:49][CH3:50])([CH3:48])[CH3:47])=[CH:44][CH:45]=2)[C:17](=[O:39])[C:18]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:3][C:4](=[O:7])[O:5][N:38]=3)=[CH:27][CH:26]=2)=[C:19]([CH2:21][CH2:22][CH3:23])[N:20]=1)[CH3:14]
Reactant: [NH3+]O
Reactant: CCCc1nc(CC)n(-c2ccc(C(C)(C)OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCc1nc(CC)n(-c2ccc(C(C)(C)OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 22.4 %

Procedure:
A mixture of hydroxylammonium chloride (0.23 g), sodium hydrogen carbonate (0.33 g) and dimethyl sulfoxide (4 mL) was stirred at 40° C. for 30 min, 4′-({2-ethyl-1-[4-(1-methoxy-1-methylethyl)phenyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.1 g) was added, and the mixture was stirred at 90° C. for 24 hr. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (4 mL). N,N′-carbonyldiimidazole (0.05 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.05 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.025 g, 22%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([C:19]4[N:20]=[CH:21][N:22](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:23]=4)[C:11]3=[O:43])[CH2:9]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([C:19]4[N:20]=[CH:21][NH:22][CH:23]=4)[C:11]3=[O:43])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1N(c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c2ccccc2[C@]12C[C@H]2c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1N(c2c[nH]cn2)c2ccccc2[C@]12C[C@H]2c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of racemic (1S,2R) and (1R,2S)-2-(4-chlorophenyl)-1′-(1-trityl-1H-imidazol-4-yl)spiro[cyclopropane-1,3′-indolin]-2′-one (115 mg, 0.2 mmol) in DCM (2 mL) and water (0.5 mL) was added TFA (0.1 mL) dropwise at 0° C. The mixture was stirred for 14 hours at room temperature. The mixture was poured into the sat. aqueous NaHCO3 solution, extracted with DCM (3×10 mL), dried and concentrated to give the title product. The residue was dissolved in 2 mL of DMF. Purification by preparative HPLC gave the title compound as white powder (60 mg, 89%). LC/MS m/e calcd. for C19H14ClN3O: 335, observed (M+H)+: 336.1 1H NMR (400 MHz, DMSO-d6) δppm 2.13 (dd, J=9.09, 5.05 Hz, 1 H) 2.42 (dd, J=8.08, 4.80 Hz, 1 H) 3.23 (t, J=8.72 Hz, 1 H) 6.20 (d, J=7.58 Hz, 1 H) 6.81 (t, J=7.20 Hz, 1 H) 7.16 (t, J=7.83 Hz, 1 H) 7.30-7.45 (m, 5 H) 7.66 (s, 1 H) 8.27 (s, 1 H). MS calcd. for C19H14ClN3O 335, obsd. (ESI+) [(M+H)+] 336.3.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:27])[CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C[Si]([Cl:41])(C)C.CCOCC>CC(CC)=O>[ClH:41].[CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:27])[CH2:19][O:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Cl
Agent: O=C(COc1ccccc1)N1CCC2(CC1)N[C@@H](Cc1ccccc1)C(=O)N2Cc1ccccc1
Solvent: CCOCC
Solvent: O
Solvent: CCC(C)=O
Product: Cl
Reaction time: 8 h

Procedure:
1,3-(S)-dibenzyl-8-(2-phenoxyacetyl)-1,4,8-triazaspiro[4,5]decan-2-one (410 mg, 0.9 mmol) was dissolved in ethyl methyl ketone (3.3 mL), water (9 μL), TMSCl (121 μL), and ether (30 mL) were added and the mixture was stirred overnight. The solid matter was isolated by filtration, washed with ether, and dried in vacuo. The product 1,3-(S)-dibenzyl-8-(2-phenoxyacetyl)-1,4,8-triazaspiro[4,5]decan-2-one hydrochloride was obtained in a yield of 347 mg (79%).