Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@@H:4]([CH2:5][CH2:6][C:7]3[C:8]4[C@:19]([CH3:27])([CH2:20][CH2:21][C:22]=32)[C@@H:11]([C@H:12]([CH3:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:10][CH:9]=4)[C:3]1([CH3:29])[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:36](Cl)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C>[CH2:36]([O:16][C:15](=[O:17])[CH2:14][CH2:13][C@H:12]([C@@H:11]1[C@:19]2([CH3:27])[C:8]([C:7]3[CH2:6][CH2:5][C@@H:4]4[C@:23]([C:22]=3[CH2:21][CH2:20]2)([CH3:26])[CH2:24][CH2:25][C@H:2]([OH:1])[C:3]4([CH3:28])[CH3:29])=[CH:9][CH2:10]1)[CH3:18])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: C[C@H](CCC(=O)O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@H](CCC(=O)OCc1ccccc1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Temperature: 50 °C
Reaction time: 8 h

Procedure:
3β-Hydroxy-4,4-dimethyl-5α-chola-8,14-dien-24-oic acid (100 mg) is suspended in 5 ml of dry DMF. 811 mg of cesium carbonate and 0.29 ml of benzyl chloride is added and the mixture is stirred at 50° C. overnight. After aqueous work-up, column chromatography and crystallisation from acetone/water 55 mg of the title compound is obtained. Melting point: 118-119° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=1[O:14][CH3:15])(=O)=O.[C:18](=[N:31][NH2:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:15][O:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([CH3:13])[C:7]=1[NH:32][N:31]=[C:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1cccc(C)c1OS(=O)(=O)C(F)(F)F
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1cccc(C)c1NN=C(c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 97.7 %

Procedure:
A mixture of 2-methoxy-6-methylphenyl trifluoromethanesulfonate (3.0 g, 0.011 mol), benzophenone hydrazone (2.38 g, 0.012 mol), BINAP (0.691 g, 0.001 mol), and cesium carbonate (5.06 g, 0.016 mol) in toluene (50 mL) was degassed with nitrogen. Palladium (II) acetate (0.075 g, 0.33 mol) was added, and the mixture was heated to 100° C. for 16 h. Reaction completion was judged by TLC (Eluent—5% EtOAc/Hexanes). The mixture was cooled to rt, concentrated under vacuum, and purified by silica gel chromatography using a gradient of hexanes—10% EtOAc/hexanes to afford 3.40 g (97%) of diphenylmethanone (2-methoxy-6-methylphenyl)hydrazone. 1H NMR (400 MHz, CD2Cl2) δ 7.65 (m, 2H), 7.55 (m, 3H), 7.40 (m, 2H), 7.30 (m, 3H), 6.85 (m, 2H), 6.68 (m, 1H), 3.70 (s, 3H), 2.67 (s, 3H); ES-MS m/z 317.1 (MH+); HPLC RT (min) 4.23.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)([CH:10]([CH3:12])[CH3:11])[C:6]([O:8][CH3:9])=[O:7].[CH3:23][NH:24][CH2:25][CH2:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1>>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([C:5]([C:6]([O:8][CH3:9])=[O:7])([CH:10]([CH3:12])[CH3:11])[CH2:4][CH2:3][CH2:2][N:24]([CH3:23])[CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: CNCCc1ccc(C(=O)OC)cc1
Reactant: COC(=O)C(CCCCl)(c1ccc(OC)c(OC)c1)C(C)C
Product: COC(=O)c1ccc(CCN(C)CCCC(C(=O)OC)(c2ccc(OC)c(OC)c2)C(C)C)cc1

Procedure:
Reaction of 1e with 2b produced 3h. MS found M+H=486. The oxalate salt of 3h was recrystallized from ethyl acetate; mp 129-131° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](O)=[O:11].B.C1COCC1>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11]
Reactant: COC(=O)CCCCCCC(=O)O
Agent: B
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CCCCCCCO
Reaction time: 8 h

Procedure:
A solution of suberic acid monomethyl ester (15 g, 7.97 mmol, 1.0 equiv.) in tetrahydrofuran (THF) (32.0 mL, 0.25M) at -20° C. was treated ##STR1## dropwise with BH3.THF (1M solution in THF, 7.97 mL, 7.97 mmol, 1.0 equiv.). The reaction mixture was stirred overnight and was subsequently allowed to reach room temperature. The reaction mixture was then diluted with ethyl acetate (100 mL) and quenched with methanol (10 mL) and 10% HCl (10 mL). Extraction with NaHCO3 (1×20 mL), water (2×10 mL), and brine (1×10 mL), afforded methyl-8-hydroxy-octanoate (7) as a crude white solid.
Reaction SMILES: BrP([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[N+:30]([C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][CH2:41][CH:42]=O)=[CH:35][CH:34]=1)([O-:32])=[O:31]>C1COCC1>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH:21]=[CH:42][CH2:41][CH2:40][CH2:39][C:36]2[CH:37]=[CH:38][C:33]([N+:30]([O-:32])=[O:31])=[CH:34][CH:35]=2)=[CH:23][C:24]=1[Cl:29]
Reactant: O=CCCCc1ccc([N+](=O)[O-])cc1
Reactant: Clc1ccc(CP(Br)(c2ccccc2)(c2ccccc2)c2ccccc2)cc1Cl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CCCC=Cc2ccc(Cl)c(Cl)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
A solution of bromo[(3,4-dichlorophenyl)methyl]triphenylphosphine (3.95 g, 7.9 mmol) in dry THF (20 mL) was cooled to 0° C. LHDMS (1.0 M/THF, 9 ml, 9.0 mol) was added dropwise to maintain the temperature at 0° C. After stirring for 30 minutes, a solution of 4-(4-nitro-phenyl)butyraldehyde (1.45 g, 7.5 mmol) in TBF (5 mL) was added dropwise, and the mixture was allowed to warm to room temperature within 2 hours. The mixture was then quenched with H2O and extracted with EtOAc. The organic layers were washed with 0.1N HCl solution, H2O, brine, dried (Na2SO4), filtered, and concentrated in vacuo to give a lightly brown oil. Purification by flash chromatography (silica gel, 10% EtOAc/hexane) yielded 2.5 g (7.4 mmol, 99%) of the desired product.
Reaction SMILES: C(O)(C(F)(F)F)=O.CC(OC([N:15]([C:23]1[NH:24][C:25]([C:29]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([O:40][C:41]3[CH:46]=[C:45]([C:47]#[N:48])[CH:44]=[C:43]([Cl:49])[CH:42]=3)[C:34]=2[F:50])=[O:30])=[C:26]([Br:28])[N:27]=1)C(OC(C)(C)C)=O)=O)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[NH2:15][C:23]1[NH:24][C:25]([C:29]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([O:40][C:41]3[CH:46]=[C:45]([C:47]#[N:48])[CH:44]=[C:43]([Cl:49])[CH:42]=3)[C:34]=2[F:50])=[O:30])=[C:26]([Br:28])[N:27]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(Br)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(N)nc3Br)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.8 %

Procedure:
TFA (2 ml, 26.0 mmol) was added to a solution of bis(1,1-dimethylethyl)(4-bromo-5-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-imidazol-2-yl)imidodicarbonate (1.130 g, 1.616 mmol) in dichloromethane (10 mL). The mixture was stirred at RT overnight. The reaction mixture was stirred with saturated aqueous sodium bicarbonate for 1 hr and the resulting solid was isolated by filtration. A portion (0.100 g) was recrystallized from ethanol to give the title compound (0.071 g, 9%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.16 (br. s., 1H), 7.79-7.85 (m, 1H), 7.72-7.79 (m, 1H), 7.44-7.55 (m, 2H), 7.29-7.39 (m, 1H), 5.53 (br. s., 2H), 4.24-4.68 (m, 2H). ES MS: m/z 498, 500.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[N+:16]([C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([N+]([O-])=O)[C:20]=1[C:21]#[N:22])([O-:18])=[O:17].C(OC(C)(C)C)=O>>[C:21]([C:20]1[C:19]([N+:16]([O-:18])=[O:17])=[CH:26][CH:25]=[CH:24][C:23]=1[O:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)#[N:22]
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: CC(C)(C)OC=O
Product: CC(C)(C)OC(=O)N1CCCC(COc2cccc([N+](=O)[O-])c2C#N)C1
Yield: 58 %

Procedure:
Prepared as in Example 215c from tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate and 2,6-dinitrobenzonitrile in 58% yield. MS 263 [M+H-Boc]+.
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][C:4]([N:7]2[CH2:11][CH:10]([CH2:12][O:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)[CH2:9][C:8]2=[O:24])=[CH:3][CH:2]=1.[Br:26]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:26][CH2:25][C:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:11][CH:10]([CH2:12][O:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=3)[CH2:9][C:8]2=[O:24])=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(OCC2CC(=O)N(c3ccc(C)cc3)C2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(OCC2CC(=O)N(c3ccc(CBr)cc3)C2)cc1
Yield: 56.8 %

Procedure:
Methyl 4-[1-(4-tolyl)-2-pyrrolidon-4-yl]methoxybenzoate (3.00 g) and N-bromosuccinimide (1.81 g) are suspended in carbon tetrachloride (50 ml), and thereto is added benzoyl peroxide (0.21 g) and the mixture is stirred under refluxing for 5 hours. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is dissolved in ethyl acetate (60 ml), washed successively with aqueous sodium hydrogen carbonate solution and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily product is subjected to silica gel column chromatography and eluted with a mixed solvent of chloroform/n-hexane [1:1 (v/v)]to give the desired product (2.10 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][C@H:12]([NH2:14])[CH3:13])[CH:6]=[CH:7][C:8]=1Cl.[F:15][C:16]([F:25])([F:24])C1C=CC=CC=1O>>[ClH:2].[F:15][C:16]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][C@H:12]([NH2:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1
Reactant: Oc1ccccc1C(F)(F)F
Reactant: C[C@@H](N)CCc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: C[C@@H](N)CCc1cccc(C(F)(F)F)c1
Yield: 88 %

Procedure:
Intermediate 5 (55 mg, 0.25 mmol, 88% yield) was prepared as a white powder following the procedure described for Intermediate 4 by replacing 2,6-dichlorophenol with 2-trifluromethylphenol. LC-MS (ESI) 218.1 (M+H), RT=1.60 min (Method B).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C([C:9]1[CH:10]=[C:11](/[CH:15]=[CH:16]/[C:17]([OH:19])=O)[CH:12]=[CH:13][CH:14]=1)#N.C[N:21]([CH:23]=[O:24])C>ClCCl>[CH2:15]([C@H:16]1[CH2:17][O:19][C:23](=[O:24])[NH:21]1)[C:11]1[CH:10]=[CH:9][CH:14]=[CH:13][CH:12]=1
Reactant: N#Cc1cccc(/C=C/C(=O)O)c1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C1N[C@@H](Cc2ccccc2)CO1
Reaction time: 0.5 h

Procedure:
Oxalyl chloride was slowly added at room temperature to a mixture of (2E)-3-(3-cyanophenyl)acrylic acid, DMF and dichloromethane and stirred for 30 minutes. The reaction solution was concentrated under a reduced pressure, and the thus obtained residue was dissolved in THF and again concentrated under a reduced pressure. By repeating this operation, excess hydrogen chloride and oxalyl chloride were removed and crude (2E)-3-(3-cyanophenyl)acrylic acid chloride was obtained. The thus obtained crude product and (S)-4-benzyl-2-oxazolidinone were subjected to condensation reaction in the same manner as in Reference Example 1 to obtain 3-{(1E)-3-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-oxoprop-1-en-1-yl}benzonitrile. FP: 333, NMR 1: 3.02 (1H, dd, J=7.0, 13.5 Hz), 3.10 (1H, dd, J=3.5, 13.5 Hz), 4.25 (1H, dd, J=3.0, 8.5 Hz), 4.41 (1H, t, J=8.5 Hz), 4.75-4.85 (1H, m), 7.20-7.37 (5H, m), 7.68 (1H, t, J=8.0 Hz), 7.85 (2H, br.s), 7.90-7.95 (1H, m), 8.01-8.06 (1H, m), 8.20 (1H, br.s).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([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)=[O:6].C1(C)C=CC=CC=1.CO>C1COCC1.CCOC(C)=O>[OH:6][C@H:5]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:22]=[CH:21][CH:20]=1)[C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:8]1
Reactant: Cc1cccc(C(=O)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cccc([C@@H](O)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Temperature: -15 °C
Reaction time: 1 h
Yield: 11.9 %

Procedure:
To a solution of (R)-tert-butyl 3-(3-methylbenzoyl)piperidine-1-carboxylate (168 g, 0.55 mol) in anhydrous THF (600 mL) at −15° C. under nitrogen was added dropwise a solution of 1 M R-CBS-oxazaborolidine in toluene (82 mL, 82 mmol, 0.15 eq). After stirring for 1 hr at −15° C., a solution of 10 M BH3 in THF (60 mL, 0.60 mol, 1.1 eq) was added dropwise. After addition, the reaction mixture was stirred for 2 hr at −15° C. TLC indicated the starting material was disappeared. Methanol (400 mL) was added dropwise carefully at −15° C. The solvent was removed under reduced pressure, the residue was purified by column chromatography on silica gel eluting with EtOAc/hexane (1:30→1:15) to provide the light yellow oil (95 g, HPLC≧70%, ratio≧3:1). The mixture was dissolved in EtOAc until the alcohol was just dissolved (about 5 mL/1 g), the solvent was removed on the rotary evaporator until a few crystals appeared. The solution was cooled to rt slowly and stood for 1-2 hr. To the above solution was added hexane (about 300 mL) and then filtered, the crystals were washed with cool hexane and re-crystallized two more times to afford the pure isomer (R)-tert-butyl 3-((S)-hydroxy(m-tolyl)methyl)piperidine-1-carboxylate (20 g, ee≧99%).
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C[O:22][C:23](=[O:41])[C@H:24]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[NH2:25].[Li+].[OH-]>C1COCC1.O>[C:2]1([CH3:19])[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:25][C@H:24]([C:23]([OH:41])=[O:22])[CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2)C(=O)O)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to Nε-Cbz-L-lysine methyl ester hydrochloride using the procedure described in Method 3. The title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water.
Reaction SMILES: Cl[C:2]1[C:3]2[C@H:10]([CH3:11])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Br-].[CH2:13]([O:15][C:16]([C:18]1[S:22][C:21]([Zn+])=[CH:20][CH:19]=1)=[O:17])[CH3:14].C1COCC1.O>C(OCC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][C@H:10]1[C:3]2[C:2]([C:21]3[S:22][C:18]([C:16]([O:15][CH2:13][CH3:14])=[O:17])=[CH:19][CH:20]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH2:8][CH2:9]1
Reactant: CCOC(=O)c1ccc([Zn+])s1
Reactant: C[C@@H]1CCc2ncnc(Cl)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2ncnc3c2[C@H](C)CC3)s1
Temperature: 70 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
Pd(PPh3)4 (10 mg, 0.09 mmol) was added to a degassed solution of (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta-[d]-pyrimidine (300 mg, 1.78 mmol) and a 0.5M solution of 5-ethoxycarbonyl-2-thienylzinc bromide in THF (3.6 mL, 1.78 mmol). The reaction mixture was stirred at 70° C. for 16 hours and then it was cooled to room temperature and diluted with diethyl ether (10 mL). Water was added (5 mL) and a precipitate was formed and filtered. The solid was washed with more diethyl ether and the filtrate was concentrated. The resulting oil was purified on silica gel (0%-75% EtOAc/hexanes) to yield (R)-ethyl 5-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxylate as an oil (400 mg, 78%). m/z: 289 (MH+), 1H NMR (CDCl3): δ (ppm) 8.95 (s, 1H), 7.84-7.82 (m, 1H), 7.70-7.69 (m 1H), 4.39 (dq, 2H, J1=7.2 Hz, J2=1.2 Hz), 3.77 (quint., 1H, J=7.2 Hz), 3.23-1.14 (m, 1H), 3.001-2.95 (m, 1H), 2.42-2.31 (m, 1H), 1.98-1.92 (m, 1H), 1.40 (dt, 3H, J1=7.2 Hz, J2=1.2 Hz), 1.29 (d, 3H, J=7.2 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:33][NH:34][O:35][CH3:36]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH2:9][C:10]([N:34]([O:35][CH3:36])[CH3:33])=[O:11])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C(CC(=O)O)c1ccc(Br)cc1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccccc1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 89.2 %

Procedure:
To a suspension of 3-(4-bromophenyl)-3-o-tolylpropanoic acid (125.5 g, 393 mmol) in dichloromethane (600 mL) was added 1,1′-carbonyldiimidazole (79.7 g, 491 mmol) portionwise over 5 min. After gas evolution had ceased N,O-dimethylhydroxylamine hydrochloride (42.2 g, 432 mmol) was added in portions over 5 min. The reaction mixture was stirred for 17 h at room temperature, then washed with water. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. The crude product was chromatographed (SiO2; heptane/ethyl acetate 3:1) and the product triturated with heptane to produce the title compound (127 g, 88%). White solid, MS: 362.1 [M+H]+.
Reaction SMILES: [C:1]([C:5]([N:7]=[C:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[CH:11]=[C:10]([CH3:23])[S:9]1)=O)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:33]2)=CC=1>C1COCC1>[C:1]([C:5]([N:7]=[C:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[CH:11]=[C:10]([CH3:23])[S:9]1)=[S:33])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=NC(=O)C(C)(C)C)s1
Solvent: C1CCOC1
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=NC(=S)C(C)(C)C)s1
Yield: 57.3 %

Procedure:
A solution of 2-[(t-butylcarbonyl)imino]-3-[3-(trifluoromethyl)phenyl]-5-methylthiazoline (1 g) and 2,4bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4disulfide (2 g) in THF (10 ml) was refluxed for 2 days. After cooling and removal of the solvent under reduced pressure, the concentrated residue was added pottasium hydrogencarbonate. The obtained crystallines were recrystallized to give 0.6 g of 2-[t-butyl(thiocarbonyl)]imino-3-[3-(trifluoromethyl)phenyl]-5-methylthiazoline (Compound No. 3).
Reaction SMILES: [C:1]([CH2:5][N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@@H:9]([NH:17][C:18]([C:20]2[NH:21][C:22]3[C:27]([CH:28]=2)=[CH:26][C:25]([Cl:29])=[CH:24][CH:23]=3)=[O:19])[C:7]1=[O:8])([O:3]C)=[O:2].O.[OH-].[Li+].Cl>O1CCCC1.CO.O>[C:1]([CH2:5][N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@@H:9]([NH:17][C:18]([C:20]2[NH:21][C:22]3[C:27]([CH:28]=2)=[CH:26][C:25]([Cl:29])=[CH:24][CH:23]=3)=[O:19])[C:7]1=[O:8])([OH:3])=[O:2]
Reactant: COC(=O)CN1C(=O)[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CN1C(=O)[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
(R)-1-carbomethoxymethyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril (Example 7) (13 mg) was dissolved in a 2:2:1 mixture of tetrahydrofuran, methanol, and water (5 mL). Lithium hydroxide monohydrate (3 mg) was added, and the resulting mixture was stirred at room temperature for 2 h. Addition of 1.0 M aqueous hydrochloric acid (10 mL) was followed by extraction with ethyl acetate (20 mL twice). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and evaporated under vacuum to provide the title compound (12 mg). HPLC/MS [M+H]+, 398.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:30])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](Cl)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:1]([O:8][CH2:9][C:10]1([CH3:30])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:35]5[CH:36]=[CH:37][C:32]([CH3:31])=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Cl)cc4)CC3)n2CCS1
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)cc1
Yield: 42.6 %

Procedure:
A solution of the compound (324 mg, 0.7 mmol) obtained in Example 1-2), 4-methylphenylboronic acid (105 mg, 0.77 mmol), tris(dibenzylideneacetone)dipalladium(0) (32 mg, 0.04 mmol), tricyclohexylphosphine (24 mg, 0.08 mmol), and tripotassium phosphate (260 mg, 1.2 mmol) in dioxane (2 mL) and water (1 mL) was stirred at 140° C. for 2 h under microwave irradiation. The reaction mixture was purified by silica gel chromatography (Isco Combiflash, 12 g, hexane:ethyl acetate=0:100 to 100:0, gradient) to obtain the title compound (155 mg, 43%) as a brown oily substance.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][NH:25][C:26]1[N:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:29]5[CH:28]=[N:27][C:26]([NH:25][CH3:24])=[N:31][CH:30]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CNc1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CNc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cn1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and methyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-yl]-amine (Stage 80.1.1) to give the title compound as a white solid. (HPLC: tR 2.18 min (Method A); M+H=401 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.93 (s, 1H), 8.49-8.34 (s, br, 2H), 8.13-8.11 (m, 1H), 8.07-8.04 (m, 1H), 7.89-7.85 (m, 1H), 7.42-7.37 (m, 2H), 3.90 (s, 3H), 3.57 (s, 3H), 2.84 (d, 3H), 1.96 (s, 3H))
Reaction SMILES: C(O[CH:4](OCC)[N:5]1[CH2:9][CH2:8][NH:7][C:6]1=[N:10][N+:11]([O-:13])=[O:12])C.[NH2:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21].CN(C=O)C>CCOCC>[C:20]([C:19]1[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=1[N:17]=[CH:4][N:5]1[CH2:9][CH2:8][NH:7][C:6]1=[N:10][N+:11]([O-:13])=[O:12])#[N:21]
Reactant: CCOC(OCC)N1CCNC1=N[N+](=O)[O-]
Reactant: N#Cc1ccccc1N
Solvent: CCOCC
Solvent: CN(C)C=O
Product: N#Cc1ccccc1N=CN1CCNC1=N[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 85.4 %

Procedure:
0.05 g of boron trifluoride ether complex was added to a mixture of 2.0 g of 1-diethoxymethyl-2-nitroiminoimidazolidine, 1.02 g of o-aminobenzonitrile and 5 ml of DMF, followed by agitation at room temperature for 15 minutes. Ether was added to the reaction mixture, and the resultant crystals were collected by filtration and dried to give 1.9 g of 1-(2-cyanophenyliminomethyl)-2-nitroiminoimidazolidine.