Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[C:8]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[CH:9]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=1.O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)[CH:7]=[C:8]([C:10](=[O:14])[CH:11]([CH3:12])[CH3:13])[CH:9]=1)=[O:4]
Reactant: Fc1ccc(CBr)cc1F
Reactant: COC(=O)c1cc(C(=O)C(C)C)c[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C(=O)C(C)C)cn1Cc1ccc(F)c(F)c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A mixture of 4-isobutyryl-1H-pyrrole-2-carboxylic acid methyl ester (B1-I) and cesium carbonate were stirred in dry DMF for 10 minutes at 40-50° C. To it 1-bromomethyl-3,4-difluorobenzene was added and the reaction was stirred for 18 hrs at 50° C. Water was added to the reaction and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 1-(3,4-difluoro-benzyl)-4-isobutyryl-1H-pyrrole-2-carboxylic acid methyl ester (B1-II).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:15]([CH:20]1[CH:24]([OH:25])[CH:23]=[CH:22][C:21]1=O)[CH2:16][CH2:17][CH2:18][CH3:19]>COC1C=CC2N=CC=C([C@@H](O)[C@H]3N4C[C@H](C=C)[C@@H](CC4)C3)C=2C=1.C1(C)C=CC=CC=1>[CH2:15]([C:20]1[C:24](=[O:25])[CH2:23][CH:22]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:21]=1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: Sc1ccccc1
Reactant: CCCCCC1C(=O)C=CC1O
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCC1=CC(Sc2ccccc2)CC1=O
Reaction time: 5 h
Yield: 104.5 %

Procedure:
Into the same flask as used in Example 1, thiophenol (10 g), triethylamine (2 g), quinine (0.2 g), 2-n-pentyl-3-hydroxy-4-cyclopentenone (16.8 g) and toluene (30 g) were charged, and the mixture was stirred under a nitrogen stream at a temperature of 40° to 70° C. for 5 hours. After completion of the reaction, the mixture was treated and purified in the same manner as in Example 50 to obtain 2-n-pentyl-4-phenylthio-2-cyclopentenone (24.7 g). Yield, 95%. nD20 1.5706.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:15]2[CH:16]=[N:17][CH:18]=[C:19]([CH2:21]CC(O)=O)[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].C1C[O:41]CC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:15]2[CH:16]=[N:17][CH:18]=[C:19]([CH2:21][OH:41])[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCC(=C(c2ccccc2)c2cncc(CCC(=O)O)c2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)(C)OC(=O)N1CCC(=C(c2ccccc2)c2cncc(CO)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a solution of 4-(1-phenyl-1-(5-carboxyethylpyridin-3yl)-methylene)-piperidine-1-carboxylic acid tert-butyl ester (0.058 g, 0.137 mmol) in dry THF (2 mL) was added LAH (0.334 mL, 0.949 mmol) portionwise over 10 min. The mixture was stirred at room temperature for an additional 30 min and then it was quenched with a saturated aqueous solution of Rochelle's salt (5 mL). The resulting mixture was filtered and the filtrate concentrated to dryness to give the title compound (0.046 g, 87%) as a clear brown oil:
Reaction SMILES: [F:1][C:2]([F:18])([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([O:16][CH3:17])=[CH:9]2)[C:3]([OH:5])=O.[Cl:19][C:20]1[CH:21]=[C:22]([F:28])[C:23]([NH:26][NH2:27])=[N:24][CH:25]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([F:28])[C:23]([NH:26][NH:27][C:3](=[O:5])[C:2]([F:1])([F:18])[C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[N:12]=[CH:11][C:10]([O:16][CH3:17])=[CH:9]3)=[N:24][CH:25]=1
Reactant: NNc1ncc(Cl)cc1F
Reactant: COc1cnc2ccc(C(F)(F)C(=O)O)cc2c1
Product: COc1cnc2ccc(C(F)(F)C(=O)NNc3ncc(Cl)cc3F)cc2c1

Procedure:
This compound was assembled from 2,2-difluoro-2-(3-methoxyquinolin-6-yl)acetic acid and 1-(5-chloro-3-fluoropyridin-2-yl)hydrazine according to General Method I. LRMS (ESI) ml: calcd for C17H13ClF3N4O2S (M+H) 397.1. found 397.2.
Reaction SMILES: C([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH3:14])[CH:8]=1)(=O)CCC.[Cl-].[Al+3].[Cl-].[Cl-].Cl>>[C:7]([C:12]1[C:11]([CH3:13])=[CH:10][C:9]([CH3:14])=[CH:8][C:7]=1[OH:6])(=[O:6])[CH2:8][CH2:9][CH3:10]
Reactant: CCCC(=O)Oc1cc(C)cc(C)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCCC(=O)c1c(C)cc(C)cc1O
Temperature: 70 °C
Reaction time: 4 h

Procedure:
180 g. of 1-butyryloxy-3,5-dimethyl-benzene are treated at room temperature with 340 g. of aluminium chloride. The mixture is strirred for 4 hours at 90°-95° C., then cooled at 70° C., poured onto ice and 3n aqueous hydrochloric acid and extracted with ether. The ether extract is washed with water to neutral reaction, dried over sodium sulfate and evaporated. There is obtained 2-butyryl-3,5-dimethyl-phenol, which melts at 48°-52° C. after recrystallization from petroleum ether.
Reaction SMILES: [C:1]([NH:8][CH2:9][C@H:10]([OH:17])[CH2:11][C:12](OCC)=[O:13])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.[NH2:19][NH2:20]>CO>[C:1]([NH:8][CH2:9][C@H:10]([OH:17])[CH2:11][C:12]([NH:19][NH2:20])=[O:13])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NN
Reactant: CCCCCC(=O)NC[C@H](O)CC(=O)OCC
Solvent: O
Solvent: CO
Product: CCCCCC(=O)NC[C@H](O)CC(=O)NN
Temperature: 65 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
A 6.50 g (24.9 mmol) of ethyl (R)-4-hexanoylamino-3-hydroxybutyrate (optical purity: 95%e.e.) was dissolved in 26 ml of methanol, and 1.87 g (37.3 mmol) of hydrazine monohydrate was added thereto dropwise at room temperature. After the addition, the mixture was heated to 65° C. and then stirred for 2 hours. After the mixture was cooled to room temperature, stirring was conducted overnight to give 4.09 g (66%) of the title compound as a crystal. Melting point: 172.5° C. Optical purity: >99.9%e.e.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[N:7]=[C:8]([NH2:14])[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.N(OC(C)(C)C)=O.C[Si]([N:28]=[N+:29]=[N-])(C)C>C(#N)C>[N:14]([C:8]1[S:9][C:10]2[CH2:11][CH2:12][O:13][C:4]3[CH:3]=[C:2]([Br:1])[CH:16]=[CH:15][C:5]=3[C:6]=2[N:7]=1)=[N+:28]=[N-:29]
Reactant: Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: [N-]=[N+]=Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-ylamine (2.38 g, 8 mmol) in acetonitrile at 0° C. was added tert-butyl nitrite (1.43 mL, 12 mmol) followed by trimethylsilyl azide (1.26 mL, 9.6 mmol) dropwise. The reaction mixture was stirred at 0° C. for 90 mins, allowed to warm up to RT and concentrated in vacuo. The resulting residue was purified by flash chromatography (SiO2, 10% ethyl acetate in cyclohexane) to yield the title compound as a red oil which solidified upon standing (956 mg, 37%). 1H NMR (CDCl3): 8.21 (1 H, d, J=8.6 Hz), 7.24 (1 H, dd, J=8.6, 2.1 Hz), 7.20 (1 H, d, J=2.1 Hz), 4.34 (2 H, t, J=5.1 Hz), 3.21 (2 H, t, J=5.1 Hz).
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([O:20]C([C@H](O)[C@@H](NC(C2C=CC=CC=2)=O)C2C=CC=CC=2)=O)[CH2:18][C@:14]2([OH:41])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([O:59][C:60]([CH3:62])=[O:61])[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@H:8]1[OH:57])=[O:6].CC1[C@@H](OC([C@H](O)[C@@H](NC(C2C=CC=CC=2)=O)C2C=CC=CC=2)=O)C[C@]2(O)C(C)(C)C=1[C@@H](OC(C)=O)C([C@@]1(C)[C@H]([C@@H]2OC(C2C=CC=CC=2)=O)[C@]2(OC(C)=O)CO[C@@H]2C[C@@H]1O)=O>>[CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([O:59][C:60]([CH3:62])=[O:61])[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6]
Reactant: CC(=O)O[C@H]1C(=O)[C@]2(C)[C@H](O)C[C@H]3OC[C@@]3(OC(C)=O)[C@H]2[C@H](OC(=O)c2ccccc2)[C@]2(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c3ccccc3)c3ccccc3)C(C)=C1C2(C)C
Agent: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Product: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](O)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O

Procedure:
Degradation products were formed in the same proportions as in the experiments conducted under room temperature but in significantly lower quantities. Again, 7-epi-taxol was the main degradation product of paclitaxel (10% at pH 8.0). Baccatin III and 10-deacethyltaxol were formed for about 5 to 6% at pH 8.0. Found unknown substances were the same.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Cl)=[CH:10][CH:9]=1.[NH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C(#N)C>[NH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:12][C:11]2[CH:14]=[CH:15][C:8]([Cl:7])=[CH:9][CH:10]=2)[CH2:20][CH2:19]1
Reactant: NCC1CCNCC1
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NCC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 68.8 %

Procedure:
K2CO3 (3.02 g) and 4-chlorobenzyl chloride (3.52 g, 21.8 mmol) were successively added to an acetonitrile (100 mL) solution of 4-(aminomethyl)piperidine (7.00 g, 61.3 mmol). The resulting reaction mixture was stirred at 60° C. for 16 hours, cooled to 25° C. and concentrated. The obtained residue was fractionated between dichloromethane (75 mL) and water (50 mL) and then washed with water (50 mL×2) and brine (50 mL×1). The organic layer was dried (over MgSO4), concentrated and then purified by chromatography (SiO2, 4% H2O-iPrOH) to provide 4-(aminomethyl)-1-(4-chlorobenzyl)piperidine (3.58 g, 69%).
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7][C:8](=[O:13])[CH2:9][CH2:10][S:11][CH3:12])=[CH:5][N:4]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1.[CH3:20][CH:21]([CH2:25][S:26][CH3:27])[C:22](Cl)=[O:23]>ClCCCl>[Cl:1][C:2]1[C:6]([N:7]([C:8](=[O:13])[CH2:9][CH2:10][S:11][CH3:12])[C:22](=[O:23])[CH:21]([CH3:20])[CH2:25][S:26][CH3:27])=[CH:5][N:4]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1
Reactant: CSCC(C)C(=O)Cl
Reactant: CSCCC(=O)Nc1cn(-c2cccnc2)nc1Cl
Solvent: ClCCCl
Product: CSCCC(=O)N(C(=O)C(C)CSC)c1cn(-c2cccnc2)nc1Cl
Reaction time: 3 h
Yield: 22.3 %

Procedure:
To a solution of N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-(methylthio)propanamide (0.216 g, 0.728 mmol) in DCE (2.91 ml) in a 10 mL vial was added 2-methyl-3-(methylthio)propanoyl chloride (0.244 g, 1.601 mmol). The vial was capped and placed in a Biotage Initiator microwave reactor for 3 hours at 100° C., with external IR-sensor temperature monitoring from the side of the vessel. The crude mixture was concentrated and purified using reverse phase C-18 column chromatography (0-100% acetonitrile/water) to yield the title compound as a pale yellow oil (67 mg, 22%): IR (thin film) 2916 and 1714 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.96-8.92 (d, J=2.7 Hz, 1H), 8.64-8.59 (dd, J=4.9, 1.4 Hz, 1H), 8.07-7.99 (m, 2H), 7.50-7.40 (dd, J=8.4, 4.8 Hz, 1H), 3.39-3.28 (m, 1H), 3.10-2.99 (td, J=7.2, 3.9 Hz, 2H), 2.96-2.86 (dd, J=13.2, 8.7 Hz, 1H), 2.86-2.79 (t, J=7.3 Hz, 2H), 2.58-2.48 (dd, J=13.1, 5.8 Hz, 1H), 2.14-2.12 (s, 3H), 2.09-2.06 (s, 3H), 1.30-1.26 (d, J=6.9 Hz, 3H); ESIMS m/z 413 ([M+H]+).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][NH:7][C:8]([C:10]1[C:11]2[CH:18]=[N:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:12]=2[CH:13]=[N:14][CH:15]=1)=[O:9].[I:31][CH3:32]>C1COCC1>[I-:31].[F:25][C:22]1[CH:23]=[CH:24][C:19]([N:16]2[C:12]3=[CH:13][N+:14]([CH3:32])=[CH:15][C:10]([C:8](=[O:9])[NH:7][CH2:6][C:5]4[CH:26]=[CH:27][CH:28]=[C:3]([C:2]([F:1])([F:29])[F:30])[CH:4]=4)=[C:11]3[CH:18]=[N:17]2)=[CH:20][CH:21]=1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1cncc2c1cnn2-c1ccc(F)cc1
Reactant: CI
Solvent: C1CCOC1
Product: C[n+]1cc(C(=O)NCc2cccc(C(F)(F)F)c2)c2cnn(-c3ccc(F)cc3)c2c1
Product: [I-]
Reaction time: 264 h

Procedure:
To a solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid 3-trifluoromethyl-benzylamide (0.060 g, 0.14 mmol) in THF (2 mL) was added iodomethane (0.50 mL, 4.0 mmol). The reaction was monitored by TLC (EtOAc-hexanes 4:6). After 11 days, the reaction afforded a white precipitate. The mixture was concentrated under a stream of nitrogen and the residue triturated with ether with a few drops of methanol and then hexanes was added. The solid was collected by filtration to afford the title compound as a yellow solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13](=O)[NH:14][CH:15]=[N:16]3)=[CH:11][C:10]=2[O:20][CH3:21])[CH:5]=[CH:4][N:3]=[CH:2]1.S(Cl)([Cl:24])=O.CN(C=O)C>C1(C)C=CC=CC=1>[Cl:24][C:13]1[C:12]2[C:17](=[CH:18][C:9]([O:8][CH2:7][CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[C:10]([O:20][CH3:21])[CH:11]=2)[N:16]=[CH:15][N:14]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCn1ccnc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCn1ccnc1
Temperature: 0 °C
Yield: 59 %

Procedure:
A mixture of 7-(2-(imidazol-1-yl)ethoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (412 mg, 1.44 mmol), thionyl chloride (5 ml) and DMF (0.2 ml) was heated at reflux for 1 hour. The mixture was diluted with toluene and the volatiles were removed by evaporation. The residue was suspended in methylene chloride, cooled to 0° C. and aqueous sodium hydrogen carbonate solution was added. The resulting precipitate was collected by filtration and dried under vacuum to give 4-chloro-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline (258 mg, 59%).
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][NH:11][CH2:10][C:9](=[O:13])[N:8]2[C:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:16][C:15]=2[C:25]([OH:27])=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:28][C:29]1[N:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.[OH-].[Na+].Cl>CC#N.CCOC(C)=O>[Cl:28][C:29]1[N:34]=[CH:33][C:32]([S:35]([N:11]2[CH2:10][C:9](=[O:13])[N:8]([C:14]3[CH:18]=[C:17]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[S:16][C:15]=3[C:25]([OH:27])=[O:26])[C@H:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:12]2)(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: O=C(O)c1sc(-c2ccccc2)cc1N1C(=O)CNCC1C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(O)c1sc(-c2ccccc2)cc1N1C(=O)CN(S(=O)(=O)c2ccc(Cl)nc2)C[C@H]1C1CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
To a solution of 3-(2-cyclohexyl-6-oxo-piperazin-1-yl)-5-phenyl-thiophene-2-carboxylic acid (0.80 g, 1.90 mmol, 1.0 equiv) in MeCN (20 mL) at room temperature, was added 6-chloro-pyridine-3-sulfonyl chloride (1.10 g, 5.20 mmol, 2.7 equiv) and followed by NaOH (6.94 mL, 1.5 N solution, 10.4 mmol, 5.5 equiv) dropwise. The mixture was stirred at room temperature for 10 minutes. The mixture was acidified with 3 N HCl (2.5 mL), and then diluted with EtOAc (50 mL). The mixture was washed water (25 mL), brine (25 mL), dried (over Na2SO4), filtered and concentrated to give crude product (1.0 g, 94%) as yellow-green solid. MS: 560 [M−H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18](=[O:39])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:22][C:21]=3[C:35]([O:37]C)=[O:36])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.C1COCC1.CO>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18](=[O:39])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH:27][C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])=[CH:22][C:21]=3[C:35]([OH:37])=[O:36])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: COC(=O)c1cc(CNC(=O)OC(C)(C)C)ccc1NC(=O)C[C@@H]1CCc2cc(Cl)cc3[nH]c(=O)c(=O)n1c23
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(NC(=O)C[C@@H]2CCc3cc(Cl)cc4[nH]c(=O)c(=O)n2c34)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 104.4 %

Procedure:
A solution of (S)-9-chloro-5-[p-tert-butoxycarbonylaminomethyl-o-(methoxycarbonyl)phenylcarbamoylmethyl]-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (445 mg) in a mixture of 1N sodium hydroxide (5 mL), THF (5 mL), and methanol (5 mL) was stirred for 3.5 h at room temperature and the solvent was concentrated to ca. 5 mL. To the residue was added 5% potassium hydrogen sulfate and the precipitates formed were collected by filtration, washed with water, and dried to give 453 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][S:6][C:7]1[S:11][C:10]([NH2:12])=[N:9][CH:8]=1)[CH3:2].[C:14](C1NC=CN=1)(C1NC=CN=1)=[O:15].[CH:26]1([NH:32][C@H:33]2[CH2:38][CH2:37][C@H:36]([CH2:39][O:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:35][CH2:34]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>CN(C)C1C=CN=CC=1.O1CCCC1>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:14]([N:32]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C@H:33]2[CH2:34][CH2:35][C@H:36]([CH2:39][O:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:37][CH2:38]2)=[O:15])=[N:9][CH:8]=1)[CH3:2]
Reactant: c1ccc(OC[C@H]2CC[C@H](NC3CCCCC3)CC2)cc1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CCOC(=O)CSc1cnc(N)s1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)CSc1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](COc3ccccc3)CC2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester (0.13 g), carbonyl diimidazole (0.11 g) and 4-dimethylaminopyridine (4 mg) in tetrahydrofuran (10 mL) and tetrahydrofuran (10 mL) was stirred at room temperature for 2 h. Cyclohexyl-(trans-4-phenoxymethyl-cyclohexyl)-amine was added and the reaction stirred overnight at room temperature. Purification by flash chromatography gave 80 mg {2-[3-cyclohexyl-3-(trans-4-phenoxymethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester
Reaction SMILES: [CH2:1]([O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6])[C:2]#[CH:3].CC[Mg+].[Br-].N#N.[C:18](=[O:20])=[O:19]>C1COCC1>[Si:5]([O:4][CH2:1][C:2]#[C:3][C:18]([OH:20])=[O:19])([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:6])[CH3:7]
Reactant: O=C=O
Reactant: C#CCO[Si](C)(C)C(C)(C)C
Agent: CC[Mg+]
Agent: N#N
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC#CC(=O)O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To an ice-cold solution of 13.71 g t-butyldimethylsilyl propargyl ether in 160 mL anhydrous THF was added dropwise 35 mL EtMgBr (3M in Et2O) in a N2 atmosphere. After completing the addition, the reaction was stirred 45 minutes at room temperature. Pellets of dry ice were then added slowly until the reaction became cold and carboxylate salt precipitated. Stirring at room temperature was continued overnight. The reaction was concentrated to dryness and the residue partitioned between H2O and Et2O and the organic extract discarded. The aqueous solution was acidified to pH 2 with 6N HCl and immediately extracted with EtOAc. The organic layer was washed with 10% NaHCO3, H2O, and brine and dried (MgSO4). Filtration and concentration provided 13.56 g of product which was used without purification. 1H-NMR (CDCl3) δ 10.6 (s, 1H), 4.3 (s, 2H), 0.80 (s, 9H), 0.03 (s, 6H). ##STR73##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6]([C:18]([NH:20][NH2:21])=[O:19])=[C:5]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[C:28](N1C=CN=C1)(N1C=CN=C1)=[S:29].C(N(CC)CC)C.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6]([C:18]1[O:19][C:28](=[S:29])[NH:21][N:20]=1)=[C:5]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: NNC(=O)c1c(N2CCCCC2)nc2ccc(Cl)cc2c1-c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: S=c1[nH]nc(-c2c(N3CCCCC3)nc3ccc(Cl)cc3c2-c2ccccc2)o1
Temperature: 50 °C
Yield: 80.1 %

Procedure:
6-Chloro-4-phenyl-2-piperidin-1-yl-quinoline-3-carboxylic acid hydrazide (prepared as described in example 77 step E) (35 mg, 82.7 μmol, Eq: 1.00) and 1,1′-thiocarbonyldiimidazole (17.7 mg, 99.2 μmol, Eq: 1.2) were dissolved in THF (1.00 ml). Then triethylamine (11.7 mg, 16.1 μl, 116 μmol, Eq: 1.4) was added and the mixture was warmed to 50° C. for 72 h. Water was added and the mixture was extracted with ethyl acetate (3×). The combined extracts were washed with water and brine, dried with Na2SO4 and evaporated. The remaining residue was purified by column chromatography (silica gel, DCM/EtOAc 97:3) to afford the title compound as yellow solid (28 mg). MS (ESI): 423.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5](I)=[CH:4][N:3]=1.[N:10]1([CH2:16][CH2:17][NH2:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.CC1(C)C(C)(C)OB([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)O1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:18][CH2:17][CH2:16][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)=[CH:4][N:3]=1
Reactant: NCCN1CCCCC1
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: CC1(C)OB(c2cccs2)OC1(C)C
Product: Clc1ncc(-c2cccs2)c(NCCN2CCCCC2)n1

Procedure:
Preparation according to procedures 2 and 3 with the use of 2,4-dichloro-5-iodopyrimidine, 2-piperidin-1-yl-ethylamine and 4,4,5,5-tetramethyl-2-(2-thienyl)-1,3,2-dioxaborolane.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:12]2[S:19][C:18]([CH3:20])=[C:17]3[C:13]=2[CH2:14][C@H:15]2[C:21]([CH3:23])([CH3:22])[C@H:16]23)=[O:11])=[CH:4][C:3]=1[CH3:24].[CH2:25]([CH:27]1[O:29][CH2:28]1)Cl>C(O)(C)C.[OH-].[Na+].C(O)(=O)C>[CH3:24][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][C:10]([C:12]2[S:19][C:18]([CH3:20])=[C:17]3[C:13]=2[CH2:14][C@H:15]2[C:21]([CH3:22])([CH3:23])[C@H:16]23)=[O:11])[CH:6]=[CH:7][C:2]=1[O:1][CH2:25][CH:27]1[CH2:28][O:29]1
Reactant: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)ccc1O
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)ccc1OCC1CO1
Reaction time: 1.5 h
Yield: 32.7 %

Procedure:
A solution of 3-(4-hydroxy-3-methyl-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (179 mg, 0.525 mmol, Intermediate 4) in isopropanol (10 mL) and 3 N aq. NaOH (4 mL) is treated with epichlorohydrine (197 mg, 1.58 mmol). The reaction mixture is stirred at 70 for 1.5 h. The mixture is diluted with acetic acid (0.3 mL) and the solvent is removed under reduced pressure. The residue is purified by prep. HPLC (Waters Xterra MS18, 75×30 mm ID, 10 μm, 10 to 95% acetonitrile in water containing 0.5% formic acid) to give 3-(3-methyl-4-oxiranylmethoxy-phenyl)-1-((1aS,5aR)1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (68 mg) as a pale brown oil; LC-MS: tR=1.15 min, [M+1]+=397.27.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:7]([N:19]=1)=[N:8][C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:10]([OH:12])[N:11]=2)[NH2:2].[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1.C(Cl)CCl.O>CN1C(=O)CCC1>[OH:12][C:10]1[N:11]=[C:6]2[CH:5]=[CH:4][C:3]([NH:1][NH:2][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=3)=[N:19][C:7]2=[N:8][C:9]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1cccnc1
Reactant: NNc1ccc2nc(O)c(-c3ccccc3)nc2n1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: ClCCCl
Product: O=C(NNc1ccc2nc(O)c(-c3ccccc3)nc2n1)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 6-hydrazino-3-phenylpyrido[2,3-b]pyrazin-2-ol (3-3) (3.7 g, 14.5 mmol) and nicotinic acid (2.1 g, 17.4 mmol) in NMP (50 mL) was added EDC (3.1 g, 16.0 mmol), and stirred at room temperature for overnight. To the mixture was added water, and the resulting solid was collected by filtration to yield N-(2-hydroxy-3-phenylpyrido[2,3-b]pyrazin-6-yl)nicotinohydrazide (3-4).