Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1([C:16]([OH:18])=O)[CH2:12][CH:11]1[CH:13]([CH3:15])[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=[N:25]C=2C=1.CN1CCOCC1.C(Cl)CCl>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1([C:16](=[O:18])[NH2:25])[CH2:12][CH:11]1[CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CC(C)C1CC1(CNC(=O)OC(C)(C)C)C(=O)O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CC(C)C1CC1(CNC(=O)OC(C)(C)C)C(N)=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 100.3 %

Procedure:
To a solution of 1-(tert-butoxycarbonylamino-methyl)-2-isopropyl-cyclopropanecarboxylic acid (6.4 g, 24.9 mmol) in dry THF (190 mL) was added HOBt (4.7 g, 34.8 mmol), NMM (3.83 mL, 34.8 mmol) and EDC (6.7 g, 34.8 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 3 hours and quenched with concentrated ammonium hydroxide (16 mL). The reaction mixture was stirred at room temperature overnight. Excess of solvent was removed in vacuo and the residue was dissolved in EtOAc (200 mL). The organic layer was washed with 1N HCl, aqueous NaHCO3, brine and dried over Na2SO4. Evaporation of excess of solvent gave 6.4 g (100%) of (1-carbamoyl-2-isopropyl-cyclopropylmethyl)-carbamic acid tert-butyl ester as a colorless oil: 1H NMR (300 MHz, CD3OD) δ 0.62 (m, 1H), 1.00 (d, 3H), 1.05 (d, 3H), 1.25 (m, 3H), 1.45 (s, 9H), 3.05 (dd, 1H), 3.80 (dd, 1H), 6.70 (m, 1H); MS (APCI) m/z 257 [M+H]+
Reaction SMILES: [C:1]1([CH:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CC(C)=O>[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])[CH3:8]
Reactant: CC(O)c1ccccc1
Solvent: CC(C)=O
Product: CC(=O)c1ccccc1
Reaction time: 0.08 h
Yield: 96.5 %

Procedure:
There were weighed out 1-phenylethanol (122 mg, 1.00 mmol) and 4-benzoyloxy-2,2,6,6-tetramethylpiperidine-N-oxyl compound (3.0 mg, 0.01 mmol). Then, 2 ml of acetone was added to obtain a uniform solution. Added thereto was 500 mg of silica gel (product of Merck, grade 9385) and the mixture was vigorously agitated for 5 minutes. The acetone used was distilled off under reduced pressure. Added thereto was 7% aqueous solution of sodium bicarbonate (5 ml) containing 20 wt % of sodium bromide. Then, the mixture was thoroughly stirred. Two platinum electrodes (1.5×1.0 cm) were applied to the mixture which was then subjected to electrolytic oxidation reaction for 2 hours while being vigorously stirred at room temperature and maintaining the current at 30 mA (quantity of electricity being 2.2 F/mol). After completion of reaction, silica gel was filtered off from the reaction mixture, extraction was effected with 5 ml of acetone and acetone was distilled off. The obtained residue was passed through silica gel column to adsorb it on the column, and elution was performed with a solvent mixture of ethyl acetate/hexane=7/1, giving 116 mg of acetophenone in a yield of 96%.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]=[C:23]([S:25][NH2:26])[S:22][N:21]=2)=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C.ClCCl>COCCOC>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:24]=[C:23]([S:25]([NH2:26])=[O:6])[S:22][N:21]=2)=[CH:18][CH:19]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2nsc(SN)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(-c2nsc(S(N)=O)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.2 %

Procedure:
A solution of 23.9 g of 85% m-chloroperoxybenzoic acid in 125 ml of 1,2-dimethoxyethane (DME hereafter) was added dropwise over 1 hour to a solution of 14 g of 3-(4-methoxyphenyl)-1,2,4-thiadiazole-5-sulfenamide in 300 ml of DME at -5° (ice/methanol bath). The resulting solution was stirred at room temperature overnight. Concentration gave a solid mass which was stirred for 2 hours with 300 ml of saturated sodium bicarbonate solution, collected, washed with water and dried to give 14.8 g of crude product. Flash chromatography using a step gradient of 12 to 15% ethyl acetate/dichloromethane gave 1.37 g of solid, m.p. 144°-147°.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][N:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][O:48][C@H:49]1[CH2:53][CH2:52][NH:51][CH2:50]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][N:37]([CH2:40][C:41]([N:51]4[CH2:52][CH2:53][C@H:49]([O:48][CH3:47])[CH2:50]4)=[O:42])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CO[C@H]1CCNC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CC[C@H](OC)C2)CC1

Procedure:
In a manner analogous to the method described in example 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid was coupled with (S)-3-methoxy-pyrrolidine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C40H51Cl2N6O4 [(M+H)+] 749.3344, observed 749.3340.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12].[NH2:16][C:17]([NH2:19])=[S:18]>>[CH3:1][O:2][C:3]([C:4]1[N:16]=[C:17]([NH2:19])[S:18][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=[O:15]
Reactant: COC(=O)C(=O)C(Cl)c1ccccc1F
Reactant: NC(N)=S
Product: COC(=O)c1nc(N)sc1-c1ccccc1F

Procedure:
prepared by reaction of 3-chloro-3-(2-fluoro-phenyl)-2-oxo-propionic acid methyl ester with thiourea. LC-MS: tR=0.76 min; [M+H]+=253.2.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:12](=[O:16])[N:11]([C:17]2[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][CH2:26][C:25]5([CH2:31][CH2:30][NH:29][CH2:28]5)[CH2:24]4)=[C:19]([F:32])[CH:18]=2)[CH:10]=[CH:9]3)[CH2:3][CH2:2]1.[CH3:33][C:34]1([CH3:37])[CH2:36][O:35]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:12](=[O:16])[N:11]([C:17]2[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][CH2:26][C:25]5([CH2:31][CH2:30][N:29]([CH2:33][C:34]([OH:35])([CH3:37])[CH3:36])[CH2:28]5)[CH2:24]4)=[C:19]([F:32])[CH:18]=2)[CH:10]=[CH:9]3)[CH2:3][CH2:2]1
Reactant: O=c1c2ccc(OCC3CC3)cc2ccn1-c1ccc(N2CCC3(CCNC3)C2)c(F)c1
Reactant: CC1(C)CO1
Product: CC(C)(O)CN1CCC2(CCN(c3ccc(-n4ccc5cc(OCC6CC6)ccc5c4=O)cc3F)C2)C1

Procedure:
According to Method U, 6-cyclopropylmethoxy-2-[4-(2,7-diaza-spiro[4.4]non-2-yl)-3-fluorophenyl]-2H-isoquinolin-1-one was reacted with 2,2-dimethyl-oxirane. In this way the product was obtained with molecular weight 505.64 (C30H36FN3O3); MS (ESI): 506 (M+H+).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[C:5]([F:18])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:49]=[CH:48][C:31]([C:32](Cl)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)=[CH:30][CH:29]=1>C(Cl)Cl>[CH3:40][O:39][C:36]1[CH:35]=[CH:34][C:33]([C:32]([NH:16][C:10]2[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]3[C:5]([F:18])=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=3)([CH3:17])[N:9]=2)([C:31]2[CH:30]=[CH:29][C:28]([O:27][CH3:26])=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:38][CH:37]=1
Reactant: C[C@]1(c2nc(Br)ccc2F)N=C(N)OCC1(F)F
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(NC2=N[C@](C)(c3nc(Br)ccc3F)C(F)(F)CO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.2 %

Procedure:
(R)-4-(6-bromo-3-fluoro-pyridin-2-yl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazine-2-ylamine (5 g, 15.43 mmol, Example 1 intermediate h) was dissolved in DCM (154 ml) under argon, triethylamine (4.30 mL, 30.9 mmol) and 4,4′-dimethoxytrityl chloride (5.75 g, 16.97 mmol) were added and the reaction mixture was stirred at rt for 18 hours. The solvent was removed in vacuo and the residue was taken up in ethyl acetate. The organic layer was washed with aq 10% citric acid, water, aqueous saturated sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and concentrated. The crude product was chromatographed over silica gel (Redisep column 120 g, cyclohexane/ethyl) to give the title compound: 8.16 g (69.2% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[CH3:12][O:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Br)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC>[CH3:12][O:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:1][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CSc1ncc(C#N)c(N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)c1ccc(CNc2nc(SC)ncc2C#N)cc1
Temperature: 60 °C

Procedure:
To a solution of 4-amino-2-methylsulfanyl-pyrimidine-5-carbonitrile (229a) (200 mg, 1.2 mmol) in DME (10 ml) were added 4-bromomethyl-benzoic acid methyl ester (274 mg, 1.2 mmol) and K2CO3 (663 mg, 4.8 mmol) at room temperature. The reaction mixture was heated at 100° C. for 5 h, overnight at 60° C., cooled, filtered and concentrated in vacuo. The crude product was used in the next reaction without further purification. LRMS: 314.3(calc.); 315.3 (obt.) (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:26][C:25](=[O:27])[C:24]4[C:15](=[C:16]([CH3:32])[C:17]5[C:22]([CH:23]=4)=[N:21][C:20]([C:28]([F:31])([F:30])[F:29])=[CH:19][CH:18]=5)[N:14]=3)=[CH:11][C:10]([C:33]([F:36])([F:35])[F:34])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:37][NH2:38].CCCCCC.C(OCC)(=O)C>O1CCCC1>[CH3:37][NH:38][C:25]([C:24]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([C:28]([F:29])([F:30])[F:31])=[N:21]2)=[C:16]([CH3:32])[C:15]=1[NH:14][C:13]([C:12]1[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]=[C:10]([C:33]([F:34])([F:36])[F:35])[CH:11]=1)=[O:26])=[O:27]
Reactant: CN
Reactant: Cc1c2ccc(C(F)(F)F)nc2cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CNC(=O)c1cc2nc(C(F)(F)F)ccc2c(C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C

Procedure:
2-[2-(3-Chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-9-methyl-6-trifluoromethyl-3-oxa-1,5-diaza-anthracen-4-one (0.249, 0.456 mmol) in 20 ml of tetrahydrofurane is treated with methylamine (0.11 ml of 8M solution in ethanol, 0.9 mmol) and stirred at room temperature. TLC analysis (hexane:ethyl acetate 4:1) after 12 h shows reaction completion. The mixture is concentrated in vacuo, and then purified by flash column chromatography to give the title compound as white crystals.
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[C:30]([NH:34][C:35]([CH:37]3[CH2:39][CH2:38]3)=[O:36])[CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:23]1>>[C:12]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH3:11])[C:8]([NH:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35]([CH:37]4[CH2:39][CH2:38]4)=[O:36])[CH:31]=[CH:32][CH:33]=3)[CH2:24][CH2:23]2)=[O:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C(=O)O)(c1ccccc1)c1ccccc1
Reactant: NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1
Product: CC(C(=O)NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1)(c1ccccc1)c1ccccc1

Procedure:
Example 123 was prepared from 2,2-diphenylpropanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide according to the procedures described in Scheme 10: ESMS m/e: 510.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@@H:7](O)[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].Cl.[Cl:19][C:20]1[C:24]([Cl:25])=[C:23]([CH3:26])[NH:22][C:21]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.CCOCC>[Cl:19][C:20]1[C:24]([Cl:25])=[C:23]([CH3:26])[NH:22][C:21]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][N:33]([CH:7]2[CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:4]([C:3]([O:2][CH3:1])=[O:17])[CH2:8]2)[CH2:32][CH2:31]1)=[O:28]
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)[C@@H]1CC(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-BOC-trans-4-Hydroxy-L-proline methylester (0.20 g, 0.81 mM) and 3,4-dichloro-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide (free base of Intermediate 1), 0.16 g, 0.81 mM) were stirred in 1,2-dichloroethane (3.5 ml). Sodium triacetoxyborohydride (0.24 g, 1.1 mM) was added followed by acetic acid (0.05 ml). The reaction was stirred under nitrogen at room temperature overnight then diluted with ether and washed with 1 N sodium hydroxide. The organic phase was washed with brine, dried over MgSO4 and concentrated to give an orange oil. The oil was chromatographed using EtOAc to give the desired product as a light yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:36]=[CH:35][C:7]([O:8][CH2:9][CH:10]([OH:34])[CH2:11][O:12][C:13]2[CH:30]=[CH:29][C:16]3[C:17](=[O:28])[CH:18]=[C:19](/[CH:21]=[CH:22]/[C:23]([O:25]CC)=[O:24])[O:20][C:15]=3[C:14]=2[CH2:31][CH2:32][CH3:33])=[C:6]([CH2:37][CH2:38][CH3:39])[C:5]=1[OH:40])(=[O:3])[CH3:2].C(=O)([O-])O.[Na+].C(Cl)(Cl)(Cl)Cl>C(O)C>[C:1]([C:4]1[CH:36]=[CH:35][C:7]([O:8][CH2:9][CH:10]([OH:34])[CH2:11][O:12][C:13]2[CH:30]=[CH:29][C:16]3[C:17](=[O:28])[CH:18]=[C:19](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])[O:20][C:15]=3[C:14]=2[CH2:31][CH2:32][CH3:33])=[C:6]([CH2:37][CH2:38][CH3:39])[C:5]=1[OH:40])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCC(O)COc2ccc3c(=O)cc(/C=C/C(=O)OCC)oc3c2CCC)ccc(C(C)=O)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Product: CCCc1c(OCC(O)COc2ccc3c(=O)cc(/C=C/C(=O)O)oc3c2CCC)ccc(C(C)=O)c1O
Yield: 39.2 %

Procedure:
A solution of trans-ethyl 3-[7-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-2-hydroxypropyloxy]-4-oxo-8-n-propyl-4H-1-benzopyran-2-yl]acrylate (1.56 g) and sodium hydrogen carbonate (1.56 g) in aqueous ethanol was refluxed for 1 hour. Ethanol was removed by distillation and the residual aqueous solution cooled. Acidification afforded a gum which solidified on prolonged treatment with refluxing carbon tetrachloride. Crystallisation from acetone-carbon tetrachloride yielded trans-3[7-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-2-hydroxypropyloxy]-4-oxo-8-n-propyl-4H-1-benzopyran-2-yl]acrylic acid (0.58 g) mp 101°-103° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[CH3:8].C([O-])([O-])=O.[K+].[K+].[CH3:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:20]=1[CH2:21]Cl>CN(C=O)C.CCOC(C)=O>[CH3:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:20]=1[CH2:21][O:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cccc(C)c1CCl
Reactant: Cc1ccc(CC#N)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(CC#N)cc1OCc1c(C)cccc1C
Reaction time: 16 h

Procedure:
To a stirred solution of 2-(3-Hydroxy-4-methylphenyl)acetonitrile (Step A, 2.18 g, 14.8 mmol), K2CO3 (2.66 g, 19.2 mmol) in dry DMF (20 ml) was added 2,6-Dimethylbenzyl chloride (2.97 g, 19.2 mmol) at room temperature under argon. The reaction mixture was stirred for 16 hours, diluted with EtOAc (40 ml), washed with water (20 ml) and brine. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex: ethyl acetate 2:1) to give the title compound as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7]1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC>[C:12]1([N:8]2[CH2:7][CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:27]3[CH2:28][CH2:29][N:24]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=4)[CH2:25][CH2:26]3)[O:10][C:9]2=[O:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1OC(CCCCCl)CN1c1ccccc1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: O=C1OC(CCCCN2CCN(c3ccccn3)CC2)CN1c1ccccc1
Yield: 86 %

Procedure:
Following the procedure of Example 5, a mixture of 5-(4-chlorobutyl)-3-phenyl-2-oxazolidinone (3.0 g, 0.01186 mol), 1-(2-pyridinyl)piperazine (1.94 g, 0.01186 mol), potassium carbonate (4.92 g, 0.0356 mol), and potassium iodide (1.0 g) in n-butanol (75 mL) gave an oil, which crystallized upon standing (3.9 g, 86% yield). The solid was recrystallized from isopropanol/isopropyl ether and dried under high vacuum to give 1.80 g, mp 78°-81° C.
Reaction SMILES: C([CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]([C:16]#[N:17])=[CH:13][C:12]=2[C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:7][CH:6]=1)=O.Cl>CO.O1CCCC1>[CH3:3][NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:15][C:14]([C:16]#[N:17])=[CH:13][C:12]=2[C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:9][CH:10]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C#N)sc2-c2ccc(NCC=O)cc2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CNc1ccc(-c2sc(C#N)cc2-c2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 68.5 %

Procedure:
A mixture of 5-[4-(N-formylmethylamino)phenyl]-4-[4-(methylsulfonyl)phenyl]thiophene-2-carbonitrile (2.2 g) and concentrated hydrochloric acid (13 ml) in methanol (60 ml) and tetrahydrofuran (40 ml) was stirred at ambient temperature for 2.5 hours. The mixture was concentrated and the residue was triturated in a sodium bicarbonate solution to give a powder. The crude powder was purified by column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (4:1) to give a yellow powder of 5-[4-(methylamino)phenyl]-4-[4-(methylsulfonyl)phenyl]thiophene-2-carbonitrile (1.4 g).
Reaction SMILES: N[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.O=[C:13]([CH2:17][CH2:18]C(O)=O)[C:14]([OH:16])=[O:15]>C(O)(=O)C.Cl.O>[C:17]1([CH2:13][C:14]([OH:16])=[O:15])[C:10]2=[C:11]3[C:6](=[CH:7][CH:8]=[CH:9]2)[CH2:5][CH2:4][CH2:3][N:2]3[CH:18]=1
Reactant: NN1CCCc2ccccc21
Reactant: O=C(O)CCC(=O)C(=O)O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)Cc1cn2c3c(cccc13)CCC2
Yield: 42.9 %

Procedure:
17 g of 1-amino-1,2,3,4-tetrahydroquinoline (preparation see Example 1B) and 20 g of 2-ketoglutaric acid were heated under reflux at a temperature of 80° C. for 2 hours in a mixture of 160 ml of acetic acid and 11.4 ml of concentrated hydrochloric acid. To work up the reaction mixture the solid residue which remained was taken up in water and extracted with ethyl acetate. The organic phase was separated and extracted with 20% strength aqueous sodium hydroxide solution. The alkaline (pH=9) aqueous phase was separated and acidified to pH=4 by addition of aqueous 10% strength hydrochloric acid solution, and a precipitate formed. The solution was extracted with ethyl acetate. The organic phase was evaporated. 10.6 g of crude 5,6-dihydro- 4H-pyrrolo-[3,2,1-ij]quinoline-1-acetic acid were obtained as a solid residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6][OH:7].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:12][O:11][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[CH:10]=1)[CH:6]=[O:7]
Reactant: COc1cc(CO)cc(OC)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1cc(C=O)cc(OC)c1
Yield: 89.7 %

Procedure:
Alcohol 4 (17.5 g, 0.11 mol) in CH2Cl2 (50 mL) was added slowly to a dry stirred suspension of freshly prepared pyridinium chlorochromate (33.64 g 0.16 mol) in CH2Cl2 (100 mL) at 0.degree. C. The reaction mixture was stirred for 2 h at rt after which the solvent was removed under reduced pressure on a rotatory evaporator. The residue from the reaction mixture was washed with diethyl ether (3×150 mL) and then filtered. The organic filtrate was diluted with a saturated aq solution of NaHCO33 (250 mL) and extracted with EtOAc (3×250 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The crude oil was purified by FCC (10% ethyl acetate in hexane) to afford a yellow solid aldehyde 5 (16.4 g, 95%): 1H NMR (300 MHz, CDCl3) δ 9.92 (1H, s, HCO), 7.03 (2H, d, J=2.4 Hz HAr), 6.72 (1H, t, J=2.4 Hz, HAr), 3.87 (6H, s, H3 CO). The spectral data for 5 were in excellent accord with data previously reported on it (Seidel et al., 1990).1 This material was employed directly in the later step.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2].[N+:32]([C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37]Br)([O-:34])=[O:33]>>[C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:37][C:36]2[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=2[N+:32]([O-:34])=[O:33])[S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1
Product: COc1ccc2ccc(S(=O)(=O)N(Cc3ccccc3[N+](=O)[O-])[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1

Procedure:
The title compound is prepared as described in EXAMPLE 25, Part A using 7-methoxynaphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide as the starting material and o-nitrobenzyl bromide in place of methyl iodide. The crude product is triturated from 50% EtOAc/hexanes to afford the title compound as a solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:7]=[C:8]([CH:35]=[CH:36][CH:37]=1)[CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:19]([CH3:22])=[N:20][N:21]=3)[C:13]=2[CH:12]=[C:11]1[C:23]1[CH:27]=[CH:26][N:25]([C:28]2([CH2:32][C:33]#[N:34])[CH2:31][NH:30][CH2:29]2)[N:24]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([N:30]1[CH2:31][C:28]([CH2:32][C:33]#[N:34])([N:25]2[CH:26]=[CH:27][C:23]([C:11]3[N:10]([CH2:9][C:8]4[CH:35]=[CH:36][CH:37]=[C:6]([Cl:5])[CH:7]=4)[C:14]4[CH:15]=[CH:16][C:17]5[N:18]([C:19]([CH3:22])=[N:20][N:21]=5)[C:13]=4[CH:12]=3)=[N:24]2)[CH2:29]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1nnc2ccc3c(cc(-c4ccn(C5(CC#N)CNC5)n4)n3Cc3cccc(Cl)c3)n12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CC(CC#N)(n2ccc(-c3cc4c(ccc5nnc(C)n54)n3Cc3cccc(Cl)c3)n2)C1
Reaction time: 0.17 h
Yield: 61.7 %

Procedure:
Acetyl chloride (1.1 μL, 0.016 mmol, Aldrich) in DCM (0.35 mL) was added to (3-{3-[6-(3-chlorobenzyl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-7-yl]-1H-pyrazol-1-yl}azetidin-3-yl)acetonitrile (6.0 mg, 0.013 mmol, from Step 1). Triethylamine (3.7 μL, 0.026 mmol) was then added and the reaction was stirred for 10 minutes. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) afforded product (4.0 mg, 61%).