Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]1([C:12]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][NH:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:13]1[CH2:14][CH2:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]1([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: c1ccc(C2(c3ccccc3)NCCc3ccccc32)cc1
Reactant: O=C(Cl)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(CCl)N1CCc2ccccc2C1(c1ccccc1)c1ccccc1

Procedure:
Chloroacetyl chloride (0.151 mL) was added to a solution of 1,1-diphenyl-1,2,3,4-tetrahydroisoquinoline (339 mg) and p-toluenesulfonate monohydrate (11.3 mg) in toluene (5 mL). The mixture was heated under reflux for 3 hours. The solvent was evaporated under reduced pressure, and EtOAc and an aqueous 1 M HCl solution were added to the residue. The organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 2-(chloroacetyl)-1,1-diphenyl-1,2,3,4-tetrahydroisoquinoline (452 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]([C:13]#[N:14])=[C:8]([S:11][CH3:12])SC)([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[C:25]([F:26])=[CH:24][C:20]([C:21]([NH2:23])=O)=[C:19]([F:27])[CH:18]=1.[H-].[Na+].Cl.CN(C=[O:35])C>O>[C:1]([O:5][C:6]([C:7]1[C:13](=[O:35])[NH:14][C:21]([C:20]2[CH:24]=[C:25]([F:26])[C:17]([Cl:16])=[CH:18][C:19]=2[F:27])=[N:23][C:8]=1[S:11][CH3:12])=[O:15])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C=O
Reactant: NC(=O)c1cc(F)c(Cl)cc1F
Reactant: CSC(SC)=C(C#N)C(=O)OC(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CSc1nc(-c2cc(F)c(Cl)cc2F)[nH]c(=O)c1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 31 %

Procedure:
2-Cyano-3,3-bis-methylsulfanyl-acrylic acid tert-butyl ester (2.94 g, 12 mmol) and 4-chloro-2,5-difluorobenzamide (2.29 g, 12 mmol) were combined in 50 mL DMF and 60% sodium hydride (1.0 g, 25 mmol) was added in a single portion. After 1 hour, the reaction mixture was added to water and the neutralized with 2N HCl. The product was extracted with ether, dried, filtered and concentrated. The product was triturated with 30% diethyl ether/hexane to give 1.85 g of a white solid that was then heated in methanol overnight. The solid that formed when the reaction mixture cooled was filtered, rinsed with a small amount of cold methanol, and dried to give the title compound as a yellow solid (1.45 g, 31% yield for the two steps): 1H NMR (DMSO-d6): δ 13 (br s, 1H), 7.8-8.0 (m, 2H), 2.4 (s, 3H), 1.5 (s, 9H).
Reaction SMILES: [CH2:1]([CH:8]([CH2:13][S:14]([N:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)(=[O:16])=[O:15])[C:9]([O:11]C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Na+].C(O)(C)C>CC(C)=O>[CH2:1]([C@H:8]([CH2:13][S:14]([N:17]1[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]1)(=[O:16])=[O:15])[C:9]([OH:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(Cc1ccccc1)CS(=O)(=O)N1CCN(C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: CC(C)=O
Product: CN1CCN(S(=O)(=O)C[C@@H](Cc2ccccc2)C(=O)O)CC1
Temperature: 75 °C
Reaction time: 18 h
Yield: 19.7 %

Procedure:
The product of Example 4B (69 kg, 202 mol) in acetone (420 kg)/water (960 kg) was adjusted to pH 8.0 using 1N sodium hydroxide. Alcalase™ (Novo Industries, Denmark), (Subtilisin Carlsberg) (6.9 liters) was added and the pH was maintained between 7.9 and 8.4 by the addition of 1N sodium hydroxide. When 80% of the theoretical amount of sodium hydroxide had been consumed, the reaction was quenched by the addition of ethyl acetate. The reaction mixture was concentrated to half the original volume under reduced pressure and then washed with ethyl acetate (2×700 kg). The volume of the aqueous phase was concentrated by half and the pH adjusted to 5.2. The reaction mixture was treated with XAD-16 resin (50 kg), stirred for 18 hours, and applied to an XAD-16 resin column (50 kg). The column was eluted with water (500 kg) and then 35% ethanol in water (1,000 kg) to afford a residue which was treated with isopropanol (270 kg) and warmed to 75° C. Upon cooling to room temperature and subsequently to -5° C., crystalline material was obtained. The solid was removed by filtration, washed with cold isopropanol (30 kg) and dried at 50° C. to afford the title compound (13 kg, 49%). MS (DCI/NH3) m/e 327 (M+H)+. This compound can be recrystallized from 1:1 isopropanol/water.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:14])[C:10]=1[C:11]([OH:13])=O)=[O:5])[CH3:2].Cl.Cl.[CH3:17][N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:27][CH2:28][NH2:29]>>[CH3:14][N:9]1[C:10]([C:11](=[O:13])[NH:29][CH2:28][CH2:27][C:19]2[N:18]([CH3:17])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=2)=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=[N:8]1
Reactant: Cn1c(CCN)nc2ccccc21
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Agent: Cl
Product: CCOC(=O)c1cnn(C)c1C(=O)NCCc1nc2ccccc2n1C

Procedure:
The product was obtained starting from 4-(ethoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (150 mg, 757 μmol, prepared as described in US 2011/0071128) and 2-(1-methyl-1H-benzo[d]imidazol-2-yl)ethanamine dihydrochloride (225 mg, 908 μmol) according to the method described in example 8, step 3 as red viscous oil (80 mg, 225 μmol, 29.7%).
Reaction SMILES: [H-].[Na+].C(OP([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]=O.O>O1CCCC1>[CH3:17][C:11](=[CH:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: O=Cc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)=Cc1ccccn1
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
Sodium hydride (ca. 60%, 2.0 g, 50.0 mmol) was suspended in tetrahydrofuran (20 ml), and a solution of ethyl 2-(diethylphosphono)propionate (11.7 g, 49.1 mmol) in tetrahydrofuran (8 ml) was added thereto under ice cooling condition. The mixture was stirred for 0.5 hr. Successively, a solution of 2-pyridinecarbaldehyde (5.0 g, 46.7 mmol) in tetrahydrofuran (8 ml) was added to the mixture. The mixture was stirred at 0° C. for 14 hrs, combined with water, concentrated under reduced pressure to the half amount and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel (80 g) column chromatography. The fractions eluted with hexane-ethyl acetate (3:1, v/v) were collected and concentrated to give the titled compound (7.8 g, 87%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([OH:14])([CH3:13])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[N:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1.Cl.O1CCOCC1.C(N(CC)CC)C.[S:42]1[CH:46]=[CH:45][CH:44]=[C:43]1[S:47](Cl)(=[O:49])=[O:48]>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([OH:14])([CH3:13])[C:9]([F:10])([F:12])[F:11])[CH:5]=[CH:4][C:3]=1[N:15]1[CH2:16][CH2:17][N:18]([S:47]([C:43]2[S:42][CH:46]=[CH:45][CH:44]=2)(=[O:49])=[O:48])[CH2:19][CH2:20]1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(C)(O)C(F)(F)F)cc2Br)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)CC2)c(Br)c1)C(F)(F)F
Reaction time: 0.25 h
Yield: 67.5 %

Procedure:
A 250 mL round-bottomed flask was charged with tert-butyl 4-(2-bromo-4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-1-piperazinecarboxylate (3.70 g, 8.16 mmol), 25 mL of EtOAc, and 8 mL of 4M HCl in dioxane (32 mmol). After heating at reflux for 30 min, the mixture was cooled and concentrated. The resulting viscous oil was dissolved in 30 mL of CH2Cl2 and triethylamine (3.98 mL, 28.6 mmol). At 0° C., 2-thiophenesulfonyl chloride (1.49 g, 8.16 mmol, Sigma-Aldrich, St. Louis, Mo.) was added at 0° C. After 15 min, the mixture was concentrated then re-dissolved in 5 mL of CH2Cl2, filtered, and purified via column chromatography (120 g of silica, 0 to 50% EtOAc in hexanes) to give 2-(3-bromo-4-(4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1-trifluoro-2-propanol (2.75 g) as a white solid.
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[C:16]=1[NH:25][C:26]([CH:28]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:29](O)=[O:30])=[O:27].O[NH:39][C:40](=[NH:53])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]>C1COCC1>[CH2:41]([C:40]1[N:39]=[C:29]([CH:28]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]([NH:25][C:16]2[C:17]([O:23][CH3:24])=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:15]=2[O:14][CH3:13])=[O:27])[O:30][N:53]=1)[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]
Reactant: COc1cc(OC)c(NC(=O)C(C(=O)O)c2ccccc2)c(OC)c1
Reactant: CCCCCCCCCCCCC(=N)NO
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1noc(C(C(=O)Nc2c(OC)cc(OC)cc2OC)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.6 %

Procedure:
Carbonyl dimidazole (0.28 g, 1.71 mmol) was added to a solution of α-[[(2,4,6-trimethoxyphenyl)amino]carbonyl]-benzene acetic acid (0.56 g, 1.63 mmol) in dry THF (20 mL), and the resulting mixture was stirred at room temperature for 1 hour, then N-hydroxy-tridecane imidamide (0.37 g, 1.63 mmol) was added, and the mixture stirred for 1.5 hours, concentrated in vacuo, dissolved in glacial acetic acid, and refluxed for 1.5 hours. The solution was concentrated and azeotroped with benzene (2×25 mL), dissolved in ethyl acetate, and washed with NaHCO3, water, brine, dried with MgSO4, and recrystallized from ethanol/water to yield a white solid (0.093 g, 11%). (found): C, 69.25; H, 8.08; N, 7.68. ##STR13##
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[N:14])[CH:8]=1)[CH3:2].[CH2:16]=O.[CH:18]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30])(=[O:22])=[O:21])=[CH2:19]>>[CH2:1]([O:3][C:4]([CH:5]1[CH2:16][CH:18]([S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([F:30])([F:32])[F:31])(=[O:21])=[O:22])[CH2:19][N:6]1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[N:14])[CH:8]=1)=[O:15])[CH3:2]
Reactant: C=O
Reactant: CCOC(=O)CNc1cccc(C#N)c1
Reactant: C=CS(=O)(=O)c1ccccc1C(F)(F)F
Product: CCOC(=O)C1CC(S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cccc(C#N)c1

Procedure:
In analogy to the procedure described in example 343d, (3-cyano-phenylamino)-acetic acid ethyl ester (CAS Reg. No. 92316-76-2) was reacted with paraformaldehyde and 1-ethenesulfonyl-2-trifluoromethyl-benzene (example 243c) to give the title compound as brown oil. MS (ESI): m/z=453.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH:9]1[C:18]([OH:20])=O)=[O:7])([CH3:4])(C)C.CCN=C=NCCCN(C)C.Cl.[CH:33]1[CH:34]=[CH:35]C2N(O)N=N[C:37]=2[CH:38]=1.C(N(CC)CC)C.[NH2:50][C:51]1[C:59]([NH2:60])=[CH:58][CH:57]=[CH:56][C:52]=1[C:53]([NH2:55])=[O:54]>CN(C=O)C>[NH2:50][C:51]1[C:52]([C:53](=[O:54])[NH2:55])=[CH:56][CH:57]=[CH:58][C:59]=1[NH:60][C:18]([CH:9]1[CH2:10][CH2:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]1[C:6]([O:5][CH2:1][C:4]1[CH:35]=[CH:34][CH:33]=[CH:38][CH:37]=1)=[O:7])=[O:20]
Reactant: NC(=O)c1cccc(N)c1N
Reactant: CC(C)(C)OC(=O)N1c2ccccc2CCC1C(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)c1cccc(NC(=O)C2CCc3ccccc3N2C(=O)OCc2ccccc2)c1N
Temperature: 55 °C
Reaction time: 0.17 h

Procedure:
Step-1: To a solution of 1-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid (100 mg, 0.36 mmol) in anhydrous DMF (3 ml) was added EDC.HCl (207 mg, 1.08 mmol), HOBt (73.4 mg, 0.54 mmol) and triethylamine (0.08 ml, 0.54 mmol) at RT and the mixture was stirred for 10 min. To this reaction mixture, 2,3-diaminobenzamide (60 mg, 0.4 mmol) was added and heated to 55° C. over night. The reaction mixture was poured into ice cold water and stirred for 30 min. The precipitate formed was filtered and dried under vacuum to yield benzyl 2-((2-amino-3-carbamoylphenyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-carboxylate. MS (ES+): m/z 2411.30 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH:19]1(Br)[CH2:21][CH2:20]1>CN(C=O)C.O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH:19]2[CH2:21][CH2:20]2)=[CH:4][N:3]=1
Reactant: Oc1cnc(Cl)c2ccccc12
Reactant: BrC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ncc(OC2CC2)c2ccccc12
Temperature: 145 °C
Yield: 3.3 %

Procedure:
To a solution of 1-chloroisoquinolin-4-ol (1.0 g, 55.7 mmol) in DMF (20 m) was added Cs2CO3 (2.72 g, 8.35 mmol) followed by cyclopropylbromide (6.74 g, 55.7 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 145° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (0.4 g, 32.7%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ ppm 8.22-8.24 (m, 2H), 8.14 (s, 1H), 8.14-8.12 (m, 1H), 7.74-7.67 (m, 2H), 4.00-3.95 (m, 1H), 0.92-0.90 (m, 4H); MS: MS m/z 220.0 (M++1).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.O=[C:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10]1.[C-:19]#[N:20].C([Al+]CC)C>ClCCCl.ClCCl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:19]([C:9]1([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10]1)#[N:20]
Reactant: OC1CCNCC1
Reactant: CCOC(=O)N1CCC(=O)C1
Reactant: [C-]#N
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: CC[Al+]CC
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)N1CCC(C#N)(N2CCC(O)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
To a stirred solution of 4-hydroxypiperidine (464 mg, 4.58 mmol) and ethyl 3-oxopyrrolidine-1-carboxylate (610 mg, 3.82 mmol) in 1,2-dichloroethane (25 mL) was added titanium isopropoxide (1.09 g, 3.82 mmol), and the mixture was stirred at room temperature overnight. Then a 1.0 M solution of diethylaluminum cyanide (1.02 g, 9.17 mmol) was added at room temperature and the mixture was stirred for 24 h. Diluted with dichloromethane (25 mL) and quenched with saturated ammonium chloride solution (10 mL) at 0° C. Then mixture was filtered through a small pad of celite, and the resulting filtrate was concentrated in vacuo to afford the title compound as a yellow gum (1.0 g). 1H NMR (CDCl3, 400 MHz): δ 4.22 (q, 2H), 4.21-4.1 (dd, 1H), 3.79-3.62 (m, 3H), 3.38 (dd, 1H), 2.9 (brs, 1H), 2.7 (brs, 1H), 2.54-2.35 (m, 3H), 2.18-1.85 (brm, 3H), 1.68-1.45 (m, 3H), 1.25 (t, 3H). MS (M+1): 268.14.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]([C:11]1[N:16]=[C:15]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18]2)[N:14]=[C:13]([Cl:27])[CH:12]=1)[CH3:10]>CN(C)C=O>[ClH:27].[CH2:9]([C:11]1[N:16]=[C:15]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18]2)[N:14]=[C:13]([N:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH3:1])[CH:12]=1)[CH3:10]
Reactant: CNc1ccccc1
Reactant: CCc1cc(Cl)nc(N2CCc3ccccc3C2)n1
Solvent: CN(C)C=O
Product: CCc1cc(N(C)c2ccccc2)nc(N2CCc3ccccc3C2)n1
Product: Cl
Yield: 13.2 %

Procedure:
After N-methylaniline(0.10 ml, 9.22 mmol) was added to a mixture solution of 6-ethyl-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)-4-chloropyrimidine(1.20 g, 4.38 mmol) and dimethylformamide(10 ml), 0.22 g of the titled compound was obtained in accordance with the same procedure as in Step 4 of Example 57.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]#[C:13][CH2:14][CH2:15][NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:6]=[CH:5]2.[O:27]1[CH2:29][CH:28]1[CH2:30][OH:31].C(N(CC)CC)C>CCO>[OH:27][CH:28]([CH2:30][OH:31])[CH2:29][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]#[C:13][CH2:14][CH2:15][NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH:6]=[CH:5]2
Reactant: O=C(NCCC#Cc1ccc2cc(O)ccc2c1)OCc1ccccc1
Reactant: OCC1CO1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(NCCC#Cc1ccc2cc(OCC(O)CO)ccc2c1)OCc1ccccc1
Yield: 51.1 %

Procedure:
A solution of 4-(6-hydroxynaphthalen-2-yl)but-3-ynylcarbamate (30, 390 mg, 1.1 mmole), oxiran-2-ylmethanol (21, 0.1 mL, 1.4 mmole), and triethylamine (0.01 mL, 0.06 mmole) in absolute EtOH (8.8 mL) was subjected to microwave irradiation at 130° C. for 30 min. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (silical gel, 95:5 CH2Cl2/MeOH) to afford carbamate 31 (236 mg, 42%) as a white solid: 1H NMR (300 MHz, CD3OD) δ 7.80 (s, 1H), 7.68 (dd, J=8.7, 3.9 Hz, 2H), 7.38-7.16 (m, 8H), 5.10 (s, 2H), 4.18 (dd, J=9.6, 4.2 Hz, 1H), 4.11-4.01 (m, 2H), 3.76-3.67 (m, 2H), 3.39-3.31 (m, 4H), 2.63 (t, J=6.9 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[CH2:36][OH:37].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]2[CH2:36][OH:37])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: OCC1CCCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3CO)ccc21
Yield: 57.2 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (50.9 mg, 0.124 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with 2-piperidine methanol (63.8 mg, 0.554 mmol), acetic acid (0.284 mL, 4.96 mmol) and sodium triacetoxyborohydride (158 mg, 0.745 mmol). The reaction mixture was added with 1 mol/L hydrochloric acid and ethyl acetate, followed by extracting with 1 mol/L hydrochloric acid. The aqueous layer was added with sodium hydrogen carbonate to adjust the pH to 9. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-7-{1-(tert-butoxycarbonyl)-5-[2-(hydroxymethyl)piperidinomethyl]indol-2-yl}isoindolinone (36.2 mg, yield 57%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:20])[CH:14]([CH3:19])[CH:15]([CH3:18])[CH2:16][CH3:17])[CH:10]=2)[N:5]=[CH:4][N:3]=1.CO[CH:23]=[C:24]([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26].O>CN(C)C=O>[CH3:19][CH:14]([CH:15]([CH3:18])[CH2:16][CH3:17])[C:13]([NH:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:1][CH:23]=[C:24]([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26])=[O:20]
Reactant: CCC(C)C(C)C(=O)Nc1ccc2ncnc(N)c2c1
Reactant: COC=C(C(=O)OC)C(=O)OC
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)C(C)C(=O)Nc1ccc2ncnc(NC=C(C(=O)OC)C(=O)OC)c2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
A mixture of 4-amino-6-(2,3-dimethylpentanamido)-quinazoline (6.75 g) and dimethyl methoxymethylene-propanedioate (6.48 g) in N,N-dimethylformamide (20 ml) was stirred at 100° C. for 1 hour and cooled to ambient temperature. Water was added to the reaction mixture. The resulting solid was separated by filtration, washed with water, and dried. There was obtained dimethyl [[6-(2,3-dimethylpentanamido)-4-quinazolinylamino]methylene]propanedioate (6.58 g). A portion of the crude product was chromatographed on silica gel with chloroform and ethyl acetate (3:1) and recrystallized from ethyl acetate to give analytically pure dimethyl [[6-(2,3-dimethylpentanamido)-4-quinazolinylamino]methylene]propanedioate (0.45 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH2:9][CH2:8]2)(=[O:4])=[O:3].Br[C:15]1[N:16]=[C:17]([O:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[S:18][CH:19]=1>>[C:30]([O:29][C:27]([N:24]1[CH2:23][CH2:22][CH:21]([O:20][C:17]2[S:18][CH:19]=[C:15]([N:10]3[C:11]4[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=4)[CH2:8][CH2:9]3)[N:16]=2)[CH2:26][CH2:25]1)=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2nc(Br)cs2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2nc(N3CCc4cc(S(C)(=O)=O)ccc43)cs2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using 5-(methylsulfonyl)indoline (intermediate 26) and tert-Butyl 4-((4-bromothiazol-2-yl)oxy)piperidine-1-carboxylate (intermediate 46).
Reaction SMILES: CO.[NH2:3][CH:4]1[C:15](=[O:16])[N:6]2[CH:7]([C:12]([OH:14])=[O:13])[CH:8]([OH:11])[CH2:9][S:10][C@H:5]12.C(=O)(O)[O-].[Na+].[CH3:22][O:23][N:24]=[C:25]([C:29]([O:35][CH2:36][CH3:37])([O:32][CH2:33][CH3:34])[CH2:30][Cl:31])[C:26](Cl)=[O:27]>O.O1CCCC1>[CH3:22][O:23][N:24]=[C:25]([C:29]([O:35][CH2:36][CH3:37])([O:32][CH2:33][CH3:34])[CH2:30][Cl:31])[C:26]([NH:3][CH:4]1[C:15](=[O:16])[N:6]2[CH:7]([C:12]([OH:14])=[O:13])[CH:8]([OH:11])[CH2:9][S:10][C@H:5]12)=[O:27]
Reactant: CCOC(CCl)(OCC)C(=NOC)C(=O)Cl
Reactant: NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(CCl)(OCC)C(=NOC)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Yield: 132.9 %

Procedure:
Methanol (40 ml) was added to a solution of 7-amino-3-hydroxycepham-4-carboxylic acid (2 g) and sodium bicarbonate (0.57 g) in water (13.4 g) under ice-cooling. A solution of 2-methoxyimino-3,3-diethoxy-4-chlorobutyryl chloride (syn isomer, 1.34 g) in dry tetrahydrofuran (2 ml) was added to a solution while adjusting pH 6.5 to 7.8, then and stirred under ice-cooling for three hours. After adjusting the resultant mixture to pH 7.5, the solvent was removed in vacuo. The aqueous residue was adjusted to pH 7.5 under ice-cooling, and diisopropyl ether (10 ml) was added to the solution. After the aqueous solution was separated, ethyl acetate (20 ml) was added to the aqueous solution, and adjusted to pH 2.0 with 20% sulfuric acid. The ethyl acetate layer was separated and the aqueous solution was extracted with ethyl acetate (10 ml) twice. The ethyl acetate layer and the extract were combined, washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solution was concentrated in vacuo to give 7-(2-methoxyimino-3,3-diethoxy-4-chlorobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 2.97 g).
Reaction SMILES: [ClH:1].[F:2][C:3]([F:18])([F:17])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=CC=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.[S:19](C(C)C(=O)C)[C:20]#[N:21]>>[ClH:1].[CH3:16][C:11]1[N:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([F:2])([F:17])[F:18])=[CH:9][CH:8]=2)[C:20](=[NH:21])[S:19][C:12]=1[CH3:13]
Reactant: CC(=O)C(C)SC#N
Reactant: FC(F)(F)c1ccc(Nc2ccccc2)cc1
Agent: Cl
Product: Cc1sc(=N)n(-c2ccc(C(F)(F)F)cc2)c1C

Procedure:
The title compound was prepared from 4-trifluoromethylphenylaniline hydrochloride and 3-thiocyano-2-butanone as described for Example 160A.