Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:13]([O:20][CH2:21][CH2:22][OH:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC(C)([O-])C.[K+].O>C1COCC1>[CH2:13]([O:20][CH2:21][CH2:22][O:23][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCCOCc1ccccc1
Reactant: CCOC(=O)c1ccnc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccnc(OCCOCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of ethyl 2-bromoisonicotinate (575 mg, MATRIX) in THF (25 ml) was added with ethylene glycol monobenzyl ether (710 μl, TCI), cooled to 0° C., and added with potassium t-butoxide (420 mg, TCI), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was added with purified water (15 ml), and extracted with ethyl acetate (30 ml×2). The organic layers were combined, washed with saturated brine, and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Flash, hexane:ethyl acetate=10:1) to obtain the title compound (Intermediate ii-01).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:13])[CH2:10][CH2:11]Cl)=[C:4]([Cl:14])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([Cl:14])[CH:3]=1)[NH:8][C:9](=[O:13])[CH2:10][CH2:11]2
Reactant: O=C(CCCl)Nc1ccc(Br)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1CCc2cc(Br)cc(Cl)c2N1
Temperature: 140 °C
Yield: 26.9 %

Procedure:
A flame-dried 500-mL flask equipped with a magnetic stirring bar was charged with N-(4-bromo-2-chloro-phenyl)-3-chloro-propionamide (29.7 g, 0.1 mol) and aluminium chloride (53.3 g, 0.4 mol). In a pre-heated oil bath, the flask was heated at 140° C. for 1 hr. After cooling to room temperature, the mixture was treated with ice-water slowly and extracted with EtOAc. The organic layer was washed with water and brine in sequence, dried over anhy. Na2SO4, filtered, and concentrated in vacuo. The resulting residue was then purified by flash chromatography (silica gel, 30% ethyl acetate in hexane) to afford the title compound (7.0 g, 27% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:14]1([C:20]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:28]3[CH:24]([CH2:25][NH:26][CH2:27]3)[C:23](=[O:29])[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[C:30]1([C:20]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:28]3[CH:24]([CH2:25][N:26]([C:10](=[O:12])[CH2:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH2:27]3)[C:23](=[O:29])[CH2:22][CH2:21]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COc1ccccc1CC(=O)O
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 0.25 h
Yield: 65.4 %

Procedure:
N,N'-Carbonyldiimidazole (1.13 g) is added to a solution of 2-methoxyphenylacetic acid (1.16 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 15 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.28 g) and triethylamine (1.96 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with water (2×150 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The meringue obtained is crystallized from a mixture of acetonitrile (30 cc) and isopropyl ether (30 cc). The crystals are drained, washed with isopropyl ether (25 cc) and dried. (3aRS,7aRS)-7,7-diphenyl-2-[(2-methoxyphenyl)acetyl]-4-perhydroisoindolone (2 g) is obtained in the form of white crystals melting at 163° C.
Reaction SMILES: [CH2:1]([N:5]([CH2:25][CH2:26][CH2:27][CH3:28])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=[CH:15][C:16]2[S:20][C:19]([CH:21]=O)=[CH:18][CH:17]=2)=[C:8]([O:23][CH3:24])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:29]([C:31]1[C:32](=[C:39]([C:42]#[N:43])[C:40]#[N:41])[O:33][C:34]([CH3:38])([CH3:37])[C:35]=1[CH3:36])#[N:30].C([O-])(=O)C.[NH4+]>C(O)C.O1CCCC1>[CH2:25]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=[CH:15][C:16]2[S:20][C:19]([CH:21]=[CH:36][C:35]3[C:34]([CH3:37])([CH3:38])[O:33][C:32](=[C:39]([C:40]#[N:41])[C:42]#[N:43])[C:31]=3[C:29]#[N:30])=[CH:18][CH:17]=2)=[C:8]([O:23][CH3:24])[CH:7]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCN(CCCC)c1ccc(C=CC=Cc2ccc(C=O)s2)c(OC)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=CC=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C)s2)c(OC)c1
Temperature: 50 °C
Yield: 68.3 %

Procedure:
In 7 ml of ethanol and 2 ml of tetrahydrofuran were dissolved 248 mg (0.62 mmol) of 5-[4-(4-dibutylamino-2-methoxyphenyl)-1,3-butadienyl]thiophene-2-carboaldehyde and 137 mg (0.61 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene) propanedinitrile. To this mixture was added 50 mg of ammonium acetate, and the mixture was stirred with heating at 50° C. for 4 hours. The product was separated by filtration, washed with ethanol, and purified by silica gel column chromatography to give 241 mg of a dark brown crystal (yield: 66.8%; mp: 185-187° C.)
Reaction SMILES: [NH2:1][CH:2]1[C:27](=[O:28])[N:4]2[C:5]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH2:7][S:8][C@:3]12[O:29][CH3:30].N1C=CC=CC=1.[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[CH2:42][C:43](Cl)=[O:44]>C(Cl)Cl>[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[CH2:42][C:43]([NH:1][CH:2]1[C:27](=[O:28])[N:4]2[C:5]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH2:7][S:8][C@:3]12[O:29][CH3:30])=[O:44]
Reactant: CO[C@]12SCC(COC(C)=O)=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N1C(=O)C2N
Reactant: O=C(Cl)Cc1cccs1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CO[C@]12SCC(COC(C)=O)=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N1C(=O)C2NC(=O)Cc1cccs1
Reaction time: 0.5 h

Procedure:
A solution of the major isomer of p-nitrobenzyl 7-amino-6-methoxy-3-acetoxymethyl-ceph-3-em-4-carboxylate (53 mg., 0.12 mMol) in anhydrous CH2Cl2 (1 ml.) is cooled in an ice-bath and treated with pyridine (10.7 μl, 0.13 mMol) and 2-thienylacetyl chloride (17.8 μl., 0.13 mMol). The resulting solution is stirred in the cold for 30 mins., and then diluted with CH2Cl2, washed with H2O (3x) and brine, dried with MgSO4, filtered, and evaporated in vacuo. Crystallization of the residual yellow oil (66 mg.) from CH2Cl2 - hexane affords p-nitrobenzyl 7-(2-thienylacetamido)-6-methoxy-3-acetoxymethyl-ceph-3-em-4-carboxylate as off-white crystals: mp 148°-151° C.; ir (neat) 3.04, 5.57, 5.74, 5.91, 6.54, 7.40, 8.1, 11.67, and 13.5μ; nmr (CDCl3) δ 2.05 (s, 3, COCH3), 3.23 (s, 3, OCH3), 3.38 (s, 2, SCH2), 3.82 (s, 2, thienyl-CH2), 4.75, 5.10 (ABq, 2, J=13Hz, CH2OAc), 5.32 (d, 1, J=9Hz, H7), 5.35 (s, 2, CH2Ar), 6.82 (d, 1, J=9Hz, NH), 6.95 (m, 2, thienyl-H), 7.23 (m, 1, thienyl-H), and 7.53, 8.17 (ABq, 4, J=9Hz, ArH); mass spectrum m/e 561 (M+), 381, 365, 321, and 200.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[CH3:8][N:9](C)[CH2:10]CO.C(Cl)(Cl)Cl.[OH-].[Na+]>C(O)(=O)C>[C:1]([O:4][CH2:5][CH2:6][N:9]([CH3:10])[CH3:8])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)CCO
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)OCCN(C)C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
With gentle cooling, 168.5 g of acetic anhydride are added dropwise to 133.6 g of 2-dimethylaminoethanol in the course of 20 minutes, whereupon the temperature rises from 20° C. to a maximum of 105° C. The reaction mixture is kept for 30 minutes at 100° C. and then cooled. Then 750 ml of CHCl3 are added and the acetic acid formed is neutralised with 380 ml of 20% sodium hydroxide solution at 30°-35° C. with cooling. The two phases are separated and the organic phase is washed with a small amount of H2O. Distillation of the residue affords 151.7 g (77.7%) of product with a boiling point of 114° C./225 torr.
Reaction SMILES: S(=O)(=O)(O)O.C([Si](C)(C)[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([CH3:40])([O:33]C3CCCCO3)[CH3:32])[CH:21]=2)[CH:13]=1)(C)(C)C>C1COCC1.O>[OH:33][C:31]([CH3:40])([CH3:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][C:22]1[CH:21]=[C:20]([CH:19]=[CH:18][C:14]2[CH:13]=[C:12]([OH:11])[CH:17]=[CH:16][CH:15]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(CCCCCc1cccc(C=Cc2cccc(O[Si](C)(C)C(C)(C)C)c2)c1)OC1CCCCO1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)CCCCCc1cccc(C=Cc2cccc(O)c2)c1

Procedure:
In a manner similar to Example 25(d), by reacting 0.133 ml of concentrated sulphuric acid with 1.25 g (2.39 mmol) of tert-butyldimethyl-[3-(2-{3-[6-methyl-6-(tetrahydropyran-2-yloxy)heptyl]phenyl}-vinyl)phenoxy]silane in 20 ml of THF and 10 ml of water, after crystallization from a heptane/ethyl acetate mixture, white crystals (m=697 mg; Y=90%) are obtained. m.p.=96-7° C.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([Cl:20])[C:17]([S:21][CH3:22])=[C:16]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:15]=2)=[CH:10][CH:9]=1)=[O:6].[OH-].[Na+].C1COCC1>O>[Cl:20][C:18]1[C:17]([S:21][CH3:22])=[C:16]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([N:7]3[CH2:2][CH2:3][NH:4][C:5]3=[O:6])=[CH:9][CH:10]=2)[N:19]=1
Reactant: CSc1c(Cl)nc(-c2ccc(NC(=O)NCCCl)cc2)nc1N1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CSc1c(Cl)nc(-c2ccc(N3CCNC3=O)cc2)nc1N1CCOCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(2-chloro-ethyl)-3-[4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea (20 mg, 0.045 mmol.), 10% NaOH (0.5 ml), THF (2.0 ml), and H2O (1.0 ml) was added to a vessel. The reaction mixture was stirred at 80° C. for 8 hr and then dried, and the solvent was evaporated. The reaction mixture was partitioned between EA and 0.1N HCl, the organic layer was washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The resulting residue was purified by flash chromatography on silica gel (Hexane/EtOAc 3:1) to give a gray solid of 11.4 mg (62.3%).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:14][C@@H:13]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH2:12][CH2:11][C@@H:10]1[NH:20][C:21]([C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([Cl:32])=[CH:27][CH:26]=2)=[O:22])=O)(C)(C)C.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[Cl:32][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([C:21]([NH:20][C@H:10]1[CH2:11][CH2:12][C@H:13]([C:15](=[O:19])[N:16]([CH3:17])[CH3:18])[CH2:14][C@H:9]1[NH2:8])=[O:22])=[CH:31]2
Reactant: CN(C)C(=O)[C@H]1CC[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](NC(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)[C@H]1CC[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](N)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
(1S,2R,4S)—N2-(tert-Butoxycarbonyl)-N1-[(5-chloroindol-2-yl)carbonyl]-4-(N,N-dimethyl-carbamoyl)-1,2-cyclohexanediamine (200 mg) was dissolved in dichloromethane (6 ml), trifluoroacetic acid (2 ml) was added, and the mixture was stirred at room temperature for 2.5 hours. The solvent was distilled off under reduced pressure to obtain (1S,2R,4S)—N1-[(5-chloroindol-2-yl)carbonyl]-4-(N,N-dimethylcarbamoyl)-1,2-cyclohexanediamine trifluoroacetate.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19](C3ON=CC=3)=[CH:18][CH:17]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[N:30]1(C2C=C(C=CC=2)N)[CH:34]=[N:33][CH:32]=[N:31]1>>[N:30]1([C:18]2[CH:17]=[C:16]([NH:15][C:13]3[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=[C:9]([NH:8][C@@H:3]4[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]4[NH2:1])[N:14]=3)[CH:21]=[CH:20][CH:19]=2)[CH:34]=[N:33][CH:32]=[N:31]1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Reactant: Nc1cccc(-n2cncn2)c1
Product: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc(-n2cncn2)c1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 3-(1H-1,2,4-triazol-1-yl)aniline in step 1. MS: 394.2 (M+H).
Reaction SMILES: C([N:3]1[C:7]2([CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]4[N:20]=[CH:21][C:22]5[S:27][C:26]([C:28](N)=[O:29])=[C:25]([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=6[O:37][CH3:38])[C:23]=5[N:24]=4)=[C:14]([O:39][CH:40]([CH3:42])[CH3:41])[CH:13]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4]1)=O.[OH-:43].[Na+].O>CO>[NH:3]1[C:7]2([CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]4[N:20]=[CH:21][C:22]5[S:27][C:26]([C:28]([OH:43])=[O:29])=[C:25]([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=6[O:37][CH3:38])[C:23]=5[N:24]=4)=[C:14]([O:39][CH:40]([CH3:42])[CH3:41])[CH:13]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4]1
Reactant: [OH-]
Reactant: COc1ccccc1-c1c(C(N)=O)sc2cnc(Nc3ccc(N4CCC5(CCCN5C=O)C4)cc3OC(C)C)nc12
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccccc1-c1c(C(=O)O)sc2cnc(Nc3ccc(N4CCC5(CCCN5)C4)cc3OC(C)C)nc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 76 mg of 2-{[4-(1-formyl-1,7-diazaspiro[4.4]non-7-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamide and 2 ml of 5N sodium hydroxide in 15 ml of methanol is stirred at ambient temperature for 3 hours, and then maintained at reflux for 1 h 30. The mixture is stirred at AT for 15 h and then again maintained at reflux for 5 h 30. The reaction medium is then run into 20 ml of water and then the methanol is eliminated by concentration under reduced pressure. The resulting aqueous phase is washed several times with dichloromethane (3 times 20 ml) and then acidified so as to obtain a pH with a value of about 7/8, and then the aqueous phase is extracted a further three times with 20 ml of dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and concentrated under vacuum, so as to obtain 72 mg of 2-{[4-(1,7-diazaspiro[4.4]non-7-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxylic acid in the form of a brown solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.[NH2:17][C:18]1[CH:23]=[C:22]([Br:24])[CH:21]=[CH:20][N:19]=1>>[Br:24][C:22]1[CH:21]=[CH:20][N:19]2[CH:2]=[C:3]([C:5]3[C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:7][O:8][C:9]=3[CH3:10])[N:17]=[C:18]2[CH:23]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Reactant: Nc1cc(Br)ccn1
Product: Cc1onc(-c2ccccc2)c1-c1cn2ccc(Br)cc2n1
Yield: 33 %

Procedure:
As described for Example 2, 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (2.0 g, 7.2 mmol) was converted, using 2-amino-4-bromopyridine instead of 2-amino-3-methylpyridine, to the title compound (824 mg, 33%) which was obtained as a light yellow foam. MS: m/e=354.1/355.9 [M+H]+.
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:6][CH:5]=1.[CH:29]1([NH2:32])[CH2:31][CH2:30]1>>[CH:29]1([NH:32][C:3]([C:4]2[CH:9]=[CH:8][C:7]([C:10]([N:12]3[CH2:13][CH2:14][N:15]([C:18]4[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=4)[CH2:16][CH2:17]3)=[O:11])=[N:6][CH:5]=2)=[O:28])[CH2:31][CH2:30]1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)nc1
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NC3CC3)cn2)CC1
Yield: 69 %

Procedure:
By the same procedure as described in the example 25, the synthesis was carried out starting with 6-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid methyl ester and using cyclopropylamine. And then, the product was recrystallized with ethanol and hexane to give a desired compound.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[NH:11][C:12]([CH:15]=O)=[C:13]([CH3:14])[C:7]=2[C:6]1=[O:17].[Cl:19][C:20]1[CH:21]=[C:22]([NH:27][C:28]2[C:29]3[CH2:36][C:35](=[O:37])[NH:34][C:30]=3[N:31]=[CH:32][N:33]=2)[CH:23]=[CH:24][C:25]=1[F:26]>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:27][C:28]2[C:29]3[C:36](=[CH:15][C:12]4[NH:11][C:8]5[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][N:2]([CH3:18])[CH3:1])[C:6](=[O:17])[C:7]=5[C:13]=4[CH3:14])[C:35](=[O:37])[NH:34][C:30]=3[N:31]=[CH:32][N:33]=2)[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CC2
Product: Cc1c(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)[nH]c2c1C(=O)N(CCN(C)C)CC2
Yield: 61.5 %

Procedure:
The title compound was prepared under the same conditions as described in Example 102 with 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (prepared according to Bioorganic & Medicinal Chemistry Letters, 12 (16), 2153-2157, 2002) as starting materials to give 4-(3-chloro-4-fluoro-phenylamino)-5-[5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (240 mg, 61.5%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:22][CH2:21]1)=[O:19])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.IC.[H-].[Na+].[CH3:40]N(C)C=O>O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:40])[C:13]([C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:22][CH2:21]1)=[O:19])=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)c2cc3cc(OCc4ccccc4)ccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cn1c(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
A mixture of 5-(benzyloxy)-2-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}-1H-indole obtained in Example 23 (880 mg), iodomethane (0.143 mL), sodium hydride (92 mg, 60% in oil dispersion), and N,N-dimethylformamide (5 mL) was stirred at room temperature for 16 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to provide the title compound (860 mg, 95%) as crystals.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[CH:5]([CH2:7][OH:8])[NH2:6].[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:20](O)=[O:21])=[CH:14]2>>[CH3:2][O:3][C:4](=[O:9])[CH:5]([NH:6][C:20]([C:15]1[NH:16][C:17]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:10])=[CH:19][CH:18]=2)=[O:21])[CH2:7][OH:8]
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: COC(=O)C(N)CO
Agent: Cl
Product: COC(=O)C(CO)NC(=O)c1cc2cc(Cl)ccc2[nH]1

Procedure:
D,L-Serine methyl ester hydrochloride (2.1 mmol) and 5-chloro-1H-indole-2-carboxylic acid (2.0 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, washed with acid first then with saturated NaHCO3) and the product purified by chromatography on silica gel eluted with 10, 20, 40 and 60% ethyl acetate in hexanes: Yield 565 mg, 95%; HPLC (60/40) 3.46 minutes (98%); mp 153-155° C.; TSPMS 297/299 (MH+, 100/40%);
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([O:26][CH:23]1[CH2:24][CH2:25][N:20]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:21][CH2:22]1)=[O:7])([O-:3])=[O:2]
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccccc1[N+](=O)[O-]
Yield: 59.7 %

Procedure:
1.55 g (0.00837 mol) of 2-nitro-benzoyl chloride were dissolved in 70 ml of toluene and treated with 2.0 g (0.0104 mol) of 1-benzyl-4-hydroxypiperidine and 2.6 ml (0.0184 mol) of triethylamine. After boiling under reflux for 18 hrs. the suspension was filtered, the filtrate was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:2->1:1) as the eluent. 1.7 g (60%) of 1-benzyl-piperidin-4-yl 2-nitro-benzoate were obtained as yellow crystals; m.p. 98°-99°.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[C:27]#[N:28]>CN(C)C=O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:23][C:24]4[CH:31]=[CH:30][CH:29]=[C:26]([C:27]#[N:28])[CH:25]=4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1csc(-c2cc3cc(O)ccc3o2)n1
Reactant: N#Cc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1csc(-c2cc3cc(OCc4cccc(C#N)c4)ccc3o2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 81 %

Procedure:
To a cooled solution of 4-tert-butyl 2-(5-hydroxybenzofuran-2-yl)thiazole (0.33 g) in N,N-dimethylformamide (5 ml), sodium hydride ((60% in mineral oil) 55 mg) was added below 10° C. After being stirred for 10 minutes, 3-bromomethylbenzonitrile (0.26 g) was added to the mixture. After being stirred at ambient temperature for 2 hours, the resulting mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was crystallized with diisopropyl ether and filtered to give crystals of 4-tert-butyl-2-[5-(3-cyanophenylmethoxy)benzofuran-2-yl]thiazole (0.38 g).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([C@H:14]2[C@H:19]3[CH2:20][CH2:21][C@H:16]([CH2:17][N:18]3[S:22]([C:25]3[N:26]=[CH:27][N:28]([CH3:30])[CH:29]=3)(=[O:24])=[O:23])[CH2:15]2)=[O:13])=[N:9][CH:10]=1)([CH3:3])[CH3:2].CCCCCC>C(O)C>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([CH:14]2[CH:19]3[CH2:20][CH2:21][CH:16]([CH2:17][N:18]3[S:22]([C:25]3[N:26]=[CH:27][N:28]([CH3:30])[CH:29]=3)(=[O:24])=[O:23])[CH2:15]2)=[O:13])=[N:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(NC(=O)[C@@H]2C[C@@H]3CC[C@H]2N(S(=O)(=O)c2cn(C)cn2)C3)nc1
Solvent: CCCCCC
Solvent: CCO
Product: CC(C)Oc1ccc(NC(=O)C2CC3CCC2N(S(=O)(=O)c2cn(C)cn2)C3)nc1
Yield: 20.6 %

Procedure:
The compound (561 mg, 1.29 mmol)synthesized in Example 48 was optically resolved using normal-phase chiral HPLC(CHIRALPAK OD 2 cm ø×25 cmL (Daicel Chemical Industries, Ltd.); mobile phase: hexane:ethanol=70:30; flow rate: 10 ml/min; isogradient), and (1R**,4S**,6R**)-N-(5-isopropoxypyridin-2-yl)-2-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-2-azabicyclo[2.2.2]octane-6-carboxamide (retention time: 22 min; 109 mg), and (1S**,4R**,6S**)-N-(5-isopropoxypyridin-2-yl)-2-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-2-azabicyclo[2.2.2]octane-6-carboxamide (retention time: 48.5 min; 115 mg) were obtained.