Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:37](OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=[O:38])[C@H:2]([C:10]([NH:12][C@H:13]([C:34]([OH:36])=[O:35])[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[C:24]1[C:32](=[O:33])[CH2:31][C:28]([CH3:30])([CH3:29])[CH2:27][C:25]1=[O:26])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N1CCCC[CH2:55]1.N[C@H](C(N[C@H](C(O)=O)CCCCNC(=C1C(=O)CC(C)(C)CC1=O)CC(C)C)=O)CC1C=CC=CC=1.C(OC(=O)C)(=O)C>>[NH:1]([C:37]([CH3:55])=[O:38])[C@H:2]([C:10]([NH:12][C@H:13]([C:34]([OH:36])=[O:35])[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[C:24]1[C:25](=[O:26])[CH2:27][C:28]([CH3:29])([CH3:30])[CH2:31][C:32]1=[O:33])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C1CCNCC1
Reactant: CC(C)CC(NCCCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)=C1C(=O)CC(C)(C)CC1=O
Agent: CC(C)CC(NCCCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O)=C1C(=O)CC(C)(C)CC1=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCCNC(CC(C)C)=C1C(=O)CC(C)(C)CC1=O)C(=O)O

Procedure:
To the deprotected Lys-resin sample was added Fmoc-Phe (8.8 mg, 33.2 μmol) in DCM/DMF and 1,3-diisopropylcarbodiimide (DIC) (3 μL, 20 μmol). The coupling reaction was continued for 2 h and ninhydrin tests gave negative amino group readings. The Fmoc-Phe-Lys(ivDde) on resin was then treated with photogenerated piperidine as described above. Upon completion of the reaction, the resin was washed with DCM/DMF. Capping of the NH2-Phe-Lys(ivDde)-resin was carried out for 1 h with acetic anhydride (470 μL, 5 mmol) and TEA (700 μL, 5 mmol) in 1.5 mL DMW to give Ac-Phe-Lys(ivDde)-resin.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CCC2[C:40]([S:46][C:47](=O)N(C)C)=[C:41](Cl)[CH:42]=C(Cl)C=2CC1)=O)(C)(C)C.[OH-].[K+].ClCC1SC=CC=1>CO.CCOC(C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:47]3[S:46][CH:40]=[CH:41][CH:42]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: CN(C)C(=O)Sc1c(Cl)cc(Cl)c2c1CCN(C(=O)OC(C)(C)C)CC2
Agent: ClCc1cccs1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3cccs3)c2CC1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
To a 4:1 mixture of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 3-tert-butoxycarbonyl-7,9-dichloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-benzo[d]azepine (108 mg, 0.281 mmol) in methanol (3 ml), add potassium hydroxide pellets (504 mg, 9.0 mmol) and heat the mixture 2 h at 50° C. Cool the reaction to ambient temperature, add 2-chloromethylthiophene (186 μL, 1.406 mmol), and continue stirring for 30 min. Dilute with EtOAc and water. Separate the layers and extract the aqueous layer three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (19:1) to give 3-tert-butoxycarbonyl-7-chloro-6-(thiophen-2-ylmethylthio)-2,3,4,5-tetrahydro-benzo[d]azepine as a colorless oil (36 mg, 31%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[N:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[OH:28])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C[O:30][C:31](=[O:40])[CH:32](Br)[CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH:34]1([CH2:33][CH:32]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:28][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[CH:6]=[N:5]2)[C:31]([OH:30])=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Reactant: Oc1ccccc1N1CCOCC1
Reactant: COC(=O)C(Br)CC1CCCC1
Product: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2N2CCOCC2)cc1=O
Yield: 64 %

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 2-morpholin-4-yl-phenol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[4-(2-morpholin-4-yl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (8.5 g, 64%) as a white solid; LC-MS: 414 [M+H+]. HPLC: >99% (purity). 1H-NMR (300 MHz, DMSO-d6): δ 12.9 (s, 1H), 8.00 (s, 1H), 7.1-7.3 (m, 4H), 5.76 (s, 1H), 5.3 (m, 1H); 3.3 (m, 4H), 2.9 (m, 4H), 1.0-2.2 (m, 11H).
Reaction SMILES: [C:1]1([CH:7]2[CH2:15][C:14]3[C:9](=[C:10]([Cl:19])[C:11]([Cl:18])=[C:12]([O:16][CH3:17])[CH:13]=3)[C:8]2=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21]N(C=O)C.O(C)[Na].IC>O.C1C=CC=CC=1>[CH3:21][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:15][C:14]2[C:9](=[C:10]([Cl:19])[C:11]([Cl:18])=[C:12]([O:16][CH3:17])[CH:13]=2)[C:8]1=[O:20]
Reactant: CN(C)C=O
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(c1ccccc1)C2
Agent: CO[Na]
Solvent: CI
Solvent: O
Solvent: c1ccccc1
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccccc1)C2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Phenyl-5-methoxy-6,7-dichloro-1-indanone, 50.84 g. is dissolved in 700 ml. dry DMF and 700 ml. benzene in a 3-liter flask equipped with a nitrogen inlet, air condenser and hopper for NaOCH3. The reaction mixture is cooled in ice-water and 103 ml. of iodomethane is added. NaOCH3, 13.5 g., is added portion wise from the hopper over 3/4 of an hour. After stirring for 1/2 hour in an ice-water bath, the reaction mixture is added to water, (4 liters), and extracted with benzene. The benzene layer is separated dried over molecular sieves and concentrated to dryness to give 2-methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone, mp 164°-5°C. after recrystallization from benzene-cyclohexane, 1:2.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([OH:21])[C:19]4[C:14](=[CH:15][C:16]([C:22]([F:25])([F:24])[F:23])=[CH:17][CH:18]=4)[C:13]3=[O:26])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl[C:29]([N:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1)=[O:30].C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([O:21][C:29]([N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)=[O:30])[C:19]4[C:14](=[CH:15][C:16]([C:22]([F:24])([F:25])[F:23])=[CH:17][CH:18]=4)[C:13]3=[O:26])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1c2cc(C(F)(F)F)ccc2C(O)N1c1ccc2ccc(Cl)nc2n1
Reactant: CN1CCN(C(=O)Cl)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(C(=O)OC2c3ccc(C(F)(F)F)cc3C(=O)N2c2ccc3ccc(Cl)nc3n2)CC1
Yield: 73.5 %

Procedure:
Following the procedure of Example 28, but starting from 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-6-trifluoromethyl-1-isoindolinone (4.8 g.), 1-chlorocarbonyl-4-methyl-piperazine hydrochloride (15.1 g.), triethylamine (14.2 cc., equivalent to 10.2 g.) and pyridine (66 cc.) in methylene chloride (250 cc.), a crude product (7.8 g.) is obtained, which is triturated with water (50 cc.). The solid obtained is filtered off and washed with water (30 cc.). After recrystallisation from isopropanol (240 cc.), 2-(7-chloro1,8-naphthyridin-2-yl)-3-(4-methyl-piperazinyl)carbonyloxy-6-trifluoromethyl-1-isoindolinone (4.7 g.) melting at 219° C is obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][S:12][C:8]2[C:6]3[N:7]=[C:2]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:3]=[C:4]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:5]=3[N:11]=[CH:10][N:9]=2)=[CH:15][CH:16]=1
Reactant: C1CNCCN1
Reactant: Clc1ccc(CSc2ncnc3c(N4CCOCC4)nc(Cl)nc23)cc1
Product: Clc1ccc(CSc2ncnc3c(N4CCOCC4)nc(N4CCNCC4)nc23)cc1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(4-chlorobenzyl-thio)-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 135°-145° C.) and piperazine.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:10][NH:11][C@H:12]([C:14]([NH:16][C@H:17]([C:21]([NH:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH3:13])=O)(C)(C)C.FC(F)(F)C(O)=O.ClCCl>C(O)C>[NH2:8][C@@H:9]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:10][NH:11][C@H:12]([C:14]([NH:16][C@H:17]([C:21]([NH:23][CH2:24][CH:25]([CH3:26])[CH3:27])=[O:22])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH3:13]
Reactant: CC(C)CNC(=O)[C@@H](NC(=O)[C@H](C)NC[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)C
Solvent: ClCCl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CNC(=O)[C@@H](NC(=O)[C@H](C)NC[C@@H](N)Cc1ccccc1)C(C)C

Procedure:
N-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropyl]-L-alanyl-N1-isobutyl-L-valinamide (84 mg, 0.176 mmol) is stirred with 1 mL of trifluoroacetic acid and 3 mL of dichloromethane for 30 min. It is then concentrated on a rotary evaporator and then neutralized with several mL of saturated aqueous sodium bicarbonate. The product is taken up in 70 mL of ethyl ether, washed with several more mL of bicarbonate solution, and then dried over anhydrous sodium sulfate. Concentration from ethyl ether, and then from absolute ethanol, afforded 75 mg of a slightly yellow oil, whose NMR spectrum was consistent with the title compound, along with a small amount of residual ethanol. NMR (CDCl3) δ 7.96 (d, J=9 Hz, 1H), 7.3-7.17 (m, 5H), 6.88 (br t, 1H), 4.13 (m, 1H), 3.27 (m, 1H), 3.13 (m, 1H), 3.05 (m, 1H), 2.94 (m, 1H), 3.83 (m, 2H), 2.7 (dd, 1H), 2.57 (dd, 1H), 2.08 (m, 1H), 1.72 (m, 1H), 1.31 (d, J=7 Hz, 3H), 0.93-0.86 (overlapping d, 12H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:18]=2I)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[CH3:29][C:30]([CH3:41])=[CH:31]B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+].N#N>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:18]=2[CH:29]=[C:30]([CH3:41])[CH3:31])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C(F)(F)F)c2I)Cc2ccccc2C1
Reactant: CC(C)=CB1OC(C)(C)C(C)(C)O1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)C1(NC(=O)c2cccc(C(F)(F)F)c2C=C(C)C)Cc2ccccc2C1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 42-(2-Iodo-3-trifluoromethyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (A8) (500 mg, 1.10 mmol) and 2-methyl-1-propenyl boronic acid pinacol ester (400 mg, 2.20 mmol) in dioxane (20 mL) is added dichloro[1,1′-bis(diphenylphosphino)ferrocene]-palladium (II) DCM adduct (71.8 mg, 8.2% mmol) and 2M aqueous solution of K2CO3 (1.65 mL, 3.30 mmol). The resulting reaction mixture is filled in with N2, heated to 100° C. and stirred continuously overnight. Reaction mixture is filtered and concentrated in vacuo, and the resulting residue is purified by flash column chromatography (12 g silica gel, gradient elution: 0%-50% EtOAc in heptane) to give a pure product (396) as light brown oil (100 mg, 21%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[C:5]2[CH:20]=[C:21]([O:24][C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:23][C:4]=2[NH:3]1.[ClH:29]>CO.C(O)C>[ClH:29].[NH:10]1[CH2:11][CH2:12][CH:7]([N:6]2[C:5]3[CH:20]=[C:21]([O:24][C:25]([F:27])([F:26])[F:28])[CH:22]=[CH:23][C:4]=3[NH:3][C:2]2=[O:1])[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ccc(OC(F)(F)F)cc32)CC1
Agent: Cl
Solvent: CCO
Solvent: CO
Product: O=c1[nH]c2ccc(OC(F)(F)F)cc2n1C1CCNCC1
Reaction time: 1 h

Procedure:
A solution of 1,1-dimethylethyl 4-{2-oxo-6-[(trifluoromethyl)oxy]-2,3-dihydro-1H-benzimidazol-1-yl}-1-piperidinecarboxylate (D31) (1.54 g) in methanol (20 mL) was treated with a saturated solution of hydrogen chloride in ethanol (10 mL). The mixture was stirred for 1 hour when the solvent was removed to give the title compound as a white solid (1.28 g).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:14]1([NH:13][CH2:1][C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CNc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 55.3 %

Procedure:
Methyl 4-formylbenzoate (1 g, 6 mmol) and aniline (837 mg, 9 mmol) were dissolved in methanol (30 mL). The mixture was heated to 50° C., and acetic acid (two or three drop) was added to the reaction mixture. The resultant mixture was stirred at 50° C. for 1 hour. After the mixture was cooled to room temperature, sodium cyanoborohydride (1.13 g, 18 mmol) was added. The mixture was stirred at room temperature for 18 hours. The reaction was quenched with water (10 mL) and the mixture was extracted with dichloromethane (10 mL×3). The combined organic phase was separated, dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=8:1) to give methyl 4-((phenylamino)methyl)benzoate (0.8 g, 55%). LRMS (M+H+) m/z: cald. 241.08. found 241. LRMS (M+H+) m/z: calcd 241.08. found 241. 1H NMR (300 MHz, CD3OD): δ 7.95 (dd, J=7.2 Hz, J=2.1 Hz, 2H), 7.44 (d, J=7.8 Hz, 2H), 7.05 (t, J=6.0 Hz, 2H), 6.60-6.56 (m, 3H), 4.37 (s, 2H), 3.86 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([N-:16][CH2:17][C@H:18](O)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CS(OS(C)(=O)=O)(=O)=O.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>N1C=CC=CC=1.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[O:15][C@@H:18]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:17][N:16]=3)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C([N-]C[C@H](O)c1ccccc1)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Clc1ccc(-c2ccc(C3=NC[C@H](c4ccccc4)O3)cc2)cc1
Reaction time: 16 h

Procedure:
A solution of 1.24 g of 4'-chlorobiphenyl-4-carbonyl-[2(R)-hydroxy-2-phenylethyl]amide in 20 ml of pyridine is cooled in an ice bath and treated with a solution of 921 mg of methanesulfonic acid anhydride in dichloromethane. The reaction mixture is stirred for additional 16 hours at 5°, ethyl acetate and saturated aqueous sodium hydrogencarbonate are added, the organic layer is separated, dried and concentrated in vacuo. Vacuum flash chromatography on silica gel (toluene/ethyl acetate =3/1) yields the compound as pale yellow crystals; m.p.: 121.5° (recrystallized from ethanol); [α]D20 =+133.5° (c=1.3, methanol);
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[O:20][CH3:21])=[N:10][C:9]=1[CH3:22])(C)(C)C.Cl.O1CCOCC1.C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>CO>[NH2:7][C:8]1[S:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[O:20][CH3:21])=[N:10][C:9]=1[CH3:22]
Reactant: COc1cc(Cl)ccc1-c1nc(C)c(NC(=O)OC(C)(C)C)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc(Cl)ccc1-c1nc(C)c(N)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.8 %

Procedure:
In methanol (25 ml), [2-(4-chloro-2-methoxyphenyl)-4-methylthiazol-5-yl]carbamic acid tert-butyl ester (1.02 g, 2.87 mmol) prepared in the Step 28-1-1 was dissolved, and a 4-N hydrogen chloride-dioxane solution (25 ml) was added thereto. The mixture was stirred at a room temperature for 16 hours. Chloroform was added to the mixture, and the resulting mixture was neutralized with a saturated sodium bicarbonate solution. The resulting mixture was subjected to extraction with chloroform. The extract was dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (chloroform:methanol=20:1) to give the title compound (474 mg, 65%) as a light-brown powder.
Reaction SMILES: C([S:4][C:5]([S:26]C(=O)C)=[C:6]([N:20]1[CH:23](Cl)[CH2:22][C:21]1=[O:25])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:8])(=O)C.CO.CN>C(Cl)Cl.C(N(CC)CC)C>[S:4]=[C:5]1[CH:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[N:20]2[C:21](=[O:25])[CH2:22][C@H:23]2[S:26]1
Reactant: CC(=O)SC(SC(C)=O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1Cl
Agent: CN
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)C1C(=S)S[C@@H]2CC(=O)N12
Reaction time: 0.25 h

Procedure:
Following the procedure of Example 1(b), a carbon tetrachloride solution containing an equimolar amount of chlorine was added to a solution of p-nitrobenzyl 2-[bis(acetylthio)methylidene]-2-(4-methylthio-2-azetidinon-1-yl)acetate (144 mg, 0.306 mmole) in methylene chloride (2 ml) to give p-nitrobenzyl 2-[bis(acetylthio)methylidene]-2-(4chloro-2-azetidinon-1-yl)acetate. This crude 4-chloroazetidinone derivative was dissolved in methylene chloride (3 ml) and triethylamine (43 μl), and then 135 μl of a 30% methanol solution of methylamine were added thereto, after which the mixture was stirred for 15 minutes. The solvent was distilled off under reduced pressure. The residue was purified by column chromatography (eluent:ethyl acetate) to afford 60 mg of the desired compound.
Reaction SMILES: [CH3:1]/[C:2](/[NH2:6])=[CH:3]\[C:4]#[N:5].[C:7]([NH:11]N)(=O)[CH2:8][CH3:9].Cl.[OH2:14]>C(N)=O>[C:4]([C:3]1[C:9]([OH:14])=[CH:8][C:7]2[N:6]([N:5]=[C:4]([CH2:3][CH3:2])[N:11]=2)[C:2]=1[CH3:1])#[N:5]
Reactant: C/C(N)=C\C#N
Reactant: O
Reactant: CCC(=O)NN
Agent: Cl
Solvent: NC=O
Product: CCc1nc2cc(O)c(C#N)c(C)n2n1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
125 g of 3-aminocrotonitrile were dissolved in 500 ml of formamide and heated to 100° C. To this were added 155 g of N-cyanoacetyl-N,-propionylhydrazine in such a way that the exothermic reaction had subsided before the next addition. The mixture was then stirred at 120° to 125° C. for 6 hours and allowed to cool. It was then diluted with 1000 ml of water and acidified with concentrated hydrochloric acid. Filtration with suction, washing with water and drying at 100° C. resulted in 141 g of 6-cyano-2-ethyl-7-hydroxy-5-methyl[1,2,4]triazolo-[2,3-a]pyridine. A sample recrystallized from N-methylpyrrolidone melts at 346° to 348° C. and has the following analysis:
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[CH2:16]([C:23]1[NH:24][C:25](=O)[C:26]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28][C:27]=2[N:40]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:16]([C:23]1[N:24]=[C:25]([O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2])[C:26]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:29][CH2:28][C:27]=2[N:40]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Cc3ccccc3)[nH]c(=O)c2CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2nc(Cc3ccccc3)nc(OS(=O)(=O)C(F)(F)F)c2CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
Triflic anhydride (516 mg, 0.30 mL, 1.83 mmol) was added dropwise to a solution of the product of Step A (500 mg, 1.41 mmol) and pyridine (167 mg, 0.17 mL, 2.11 mmol) in CH2Cl2 (5.0 mL) at 0° C. The resulting solution was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was quenched by addition of water then partitioned between 5% citric acid and ethyl acetate. The organic layer was washed with sodium bicarbonate (sat.), dried over magnesium sulfate and concentrated under vacuum to yield the crude product as a yellow gum (670 mg). This material was taken on without further purification.
Reaction SMILES: [NH:1]([C:8]1[O:9][CH2:10][C:11](=O)[C:12]=1[C:13]([OH:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[NH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[C:2]1([NH:1][C:8]([C:12]2[C:13](=[O:15])[O:14][CH2:10][C:11]=2[NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1=C(Nc2ccccc2)OCC1=O
Reactant: Nc1ccccc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)C1=C(Nc2ccccc2)COC1=O

Procedure:
The title derivative was obtained by a procedure similar to that described in Example 8 starting with 2-anilino-4-oxo-3-furoic acid (7.01 grams, 0.032 mol), triethylamine (8.98 ml, 0.064 mol), BOP-Cl (8.15 grams, 0.032 mol) and aniline (2.95 ml, 0.32 mol) dissolved in 100 ml methylene chloride. Yield: 7.37 g, mp 175°-176° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=1)=O.[CH2:14]([C:18]1[N:19]([CH2:32][CH2:33][CH2:34][NH:35][CH:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[C:20]2[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:23]=[C:22]([NH2:30])[C:21]=2[N:31]=1)[CH2:15][CH2:16][CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CN1C(=O)CCC1.CO>[NH2:30][C:22]1[C:21]2[N:31]=[C:18]([CH2:14][CH2:15][CH2:16][CH3:17])[N:19]([CH2:32][CH2:33][CH2:34][N:35]([CH2:1][C:3]3[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=3)[CH:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)[C:20]=2[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N:23]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNC1CCN(C)CC1
Reactant: COC(=O)Cc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: CC(=O)O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN(Cc1cccc(CC(=O)OC)c1)C1CCN(C)CC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A solution of methyl 2-(3-formylphenyl)acetate (0.15 g) dissolved in NMP (10 mL) was added to a stirred solution of the product from step (i) (0.36 g) in NMP (10 mL) at rt. Sodium triacetoxyborohydride (0.90 g) was added to the mixture, the temperature was increased to 50° C. and the reaction mixture stirred for 24 h. The resulting solution was dissolved in methanol (0.5 mL), acidified with acetic acid (0.5 mL) and purified by SCX. The crude product was further purified by RPHPLC to give the title product, yield 22 mg.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[CH3:8].[C:9](OC(=O)C)(=[O:11])[CH3:10]>N1C=CC=CC=1>[C:9]([NH:1][CH2:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[CH3:8])(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccsc1CN
Solvent: c1ccncc1
Product: CC(=O)NCc1sccc1C

Procedure:
2-Aminomethyl-3-methylthiophene (H. D. Hartough, et al., J. Am. Chem. Soc., 70, 4018 [1948]) is dissolved in pyridine and treated with excess acetic anhydride overnight. The solvent is removed under pressure, the residue dissolved in ethyl acetate and washed with dilute hydrochloric acid and sodium bicarbonate solution. The organic extract is dried over magnesium sulfate and evaporated to yield the desired compound.