Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH:6]([N:9]([CH2:13][CH2:14][CH2:15][C:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:12])[CH3:11])([CH3:8])[CH3:7].Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:15][CH2:14][CH2:13][N:9]([CH:6]([CH3:8])[CH3:7])[C:10](=[O:12])[CH3:11])=[S:4]
Reactant: CC(=O)N(CCCC(=O)c1ccccc1)C(C)C
Reactant: NNC(N)=S
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(=O)N(CCCC(=NNC(N)=S)c1ccccc1)C(C)C
Yield: 100.2 %

Procedure:
Thiosemicarbazide (6.1901 g, 67.9 mmol) was added to a solution of N-isopropyl-N-(4-oxo-4-phenyl-butyl)-acetamide (11.20 g, 45.3 mmol), prepared in the previous step, in 160 ml of methanol plus 12.2 ml of 1 N HCl, plus 12.2 ml of water and the reaction stirred at room temperature for 22 hours (overnight). The reaction was concentrated under reduced pressure to remove the methanol. The residue was partitioned between methylene chloride and water. The organic layer was separated, washed five times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 14.54 g of a yellow foam. The foam was crystallized from ethyl acetate to give 10.28 g (71%) of the title compound as a white solid, mp 141-147° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:15]([Br:16])=[C:14]([Br:17])[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[C:27]([Cu])#[N:28]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:15]([Br:16])=[C:14]([Br:17])[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:9]2=[C:10]([C:27]#[N:28])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2c(c1O)c(Br)c(Br)n2Cc1ccccc1F
Reactant: N#C[Cu]
Product: CCOC(=O)c1nc(C#N)c2c(c1O)c(Br)c(Br)n2Cc1ccccc1F

Procedure:
Prepared in analogy to that of Example 105(a) from 2,3,7-tribromo-1-(2-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester and CuCN. The title compound, ESI MS (m/z): 496 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].[NH2:20][C:21](=[N:41]O)[C:22]1[CH:31]=[C:30]2[C:25]([CH2:26][CH2:27][N:28]([CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29]2)=[CH:24][CH:23]=1>CCOC(C)=O>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:12][N:20]=[C:21]([C:22]3[CH:31]=[C:30]4[C:25]([CH2:26][CH2:27][N:28]([CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29]4)=[CH:24][CH:23]=3)[N:41]=2)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19]
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Reactant: CC(C)(C)OC(=O)CCN1CCc2ccc(C(N)=NO)cc2C1
Solvent: CCOC(C)=O
Product: COCc1cc(-c2nc(-c3ccc4c(c3)CN(CCC(=O)OC(C)(C)C)CC4)no2)ccc1-c1ccccc1C

Procedure:
Title compound was prepared following general procedure 2 starting from Intermediate 14 (154 mg; 0.6 mmol) and Intermediate 25 (182 mg; 0.6 mmol). The reaction mixture was diluted with EtOAc, washed with water and brine and evaporated under vacuum. Purification by silica column chromatography (c-Hex/(DCM/EtOAc 1:1), 90/10 to 50/50) afforded the title compound as a yellow oil. 1H NMR (DMSO-d6) δ 8.32 (d, J=1.6 Hz, 1H), 8.16 (dd, J=8.0, 2.0 Hz, 1H), 7.87 (dd, J=8.0, 1.6 Hz, 1H), 7.82 (d, J=1.4 Hz, 1H), 7.42 (d, J=7.9 Hz, 1H), 7.38-7.26 (m, 4H), 7.15 (d, J=7.2 Hz, 1H), 4.25-4.14 (m, 2H), 3.71 (s, 2H), 3.25 (s, 3H), 2.91-2.86 (m, 2H), 2.78-2.70 (m, 4H), 2.53-2.46 (m, 2H), 2.04 (s, 3H), 1.40 (s, 9H). LC/MS (method B): 540.1 (M+H)+. HPLC (Method A) Rt 4.81 min (Purity: 97.4%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7][CH2:8][C:9]([OH:11])=O.[NH2:12][C:13]1[C:22]2[N:23]=[C:24]([CH2:31][CH2:32][CH2:33][CH3:34])[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[C:21]=2[C:20]2[N:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1>>[NH2:12][C:13]1[C:22]2[N:23]=[C:24]([CH2:31][CH2:32][CH2:33][CH3:34])[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:9](=[O:11])[CH2:8][S:7][C:2]3[N:1]=[CH:6][CH:5]=[CH:4][N:3]=3)[C:21]=2[C:20]2[N:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Reactant: O=C(O)CSc1ncccn1
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)CSc1ncccn1

Procedure:
Using the general method of Example 105 (2-pyrimidinylthio)acetic acid (0.11 g, 64 mmol) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.2 g, 0.64 mmol) to provide N1-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-2-(2-pyrimidinylsulfanyl)acetamide as a white solid, m.p. 156-160° C. (dec.).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6](=[O:17])(=[O:16])[C:5]=2[CH:4]=[C:3]([CH:18]=O)[CH:2]=1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>C1(C)C=CC=CC=1>[C:21]1([N:20]=[CH:18][C:3]2[CH:2]=[CH:1][C:11]3[CH:10]=[CH:9][C:8]4[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=4[S:6](=[O:17])(=[O:16])[C:5]=3[CH:4]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1ccc2c(c1)S(=O)(=O)c1ccccc1C=C2
Reactant: Nc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=S1(=O)c2ccccc2C=Cc2ccc(C=Nc3ccccc3)cc21
Reaction time: 0.17 h

Procedure:
Heat a mixture of 675 mg (2.5 mmoles) of dibenzo[b,f]thiepin-3-carboxaldehyde-5,5-dioxide and 465 mg of aniline (5 mmoles) in 20 ml of toluene, under reflux, with azetropic removal of water for 21 hours. Cool the mixture and filter the insoluble product. Stir the solid in 10 ml of ether containing a few drops of THF for 10 minutes then filter to obtain the pure product, 704 mg, mp: 184°-185°.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:56]=[CH:55][C:27]([CH2:28][P:29](=[O:54])([O:33][CH2:34][C:35]4([CH2:39][N:40]5[CH:44]=[C:43]([B:45]6[O:49][C:48]([CH3:51])([CH3:50])[C:47]([CH3:53])([CH3:52])[O:46]6)[CH:42]=[N:41]5)COC4)[O:30][CH2:31][CH3:32])=[CH:26][C:25]=3[O:57][CH3:58])[N:14]=2)=[CH:4][CH:3]=1.BrC1N=C(C(=O)NC)C(NC2C(C(F)(F)F)=CN=C(NC3C(OC)=CC(CP(=O)(O)OCC)=C([Cl:97])C=3)N=2)=CC=1.CC1(C)C(C)(C)OB(C2C=NN(CCCO)C=2)O1>>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:20])([F:21])[F:22])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[C:25]([O:57][CH3:58])=[CH:26][C:27]([CH2:28][P:29](=[O:54])([O:33][CH2:34][CH2:35][CH2:39][N:40]4[CH:44]=[C:43]([B:45]5[O:49][C:48]([CH3:50])([CH3:51])[C:47]([CH3:53])([CH3:52])[O:46]5)[CH:42]=[N:41]4)[O:30][CH2:31][CH3:32])=[C:55]([Cl:97])[CH:56]=3)[N:14]=2)=[CH:4][CH:3]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1)OCC1(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)COC1
Reactant: CCOP(=O)(O)Cc1cc(OC)c(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)cc1Cl
Agent: CC1(C)OB(c2cnn(CCCO)c2)OC1(C)C
Product: CCOP(=O)(Cc1cc(OC)c(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)cc1Cl)OCCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1

Procedure:
Prepared analogously to Compound 44A using ethyl hydrogen (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-2-chloro-5-methoxybenzyl)phosphonate (Compound 56B, 200 mg, 0.306 mmol) and 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-1-ol (Compound 3E, 81 mg, 0.321 mmol) to afford 181 mg of the title compound as a racemic mixture (67%). MS (ESI): m/z=887.59/889.59 [M+H]+. UPLC: tR=1.74 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][C:12]([Br:17])=[CH:11][CH:10]=3.[CH2:18]([CH:20]1[O:22][CH2:21]1)Br>CN(C=O)C>[Br:17][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:18][CH:20]3[CH2:21][O:22]3)[C:7]3[C:15]([C:14]=2[CH:13]=1)=[CH:16][C:4]([Br:3])=[CH:5][CH:6]=3
Reactant: BrCC1CO1
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)c1cc(Br)ccc1n2CC1CO1
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
Following a literature procedure (Asso, V.; Ghilardi, E.; Bertini, S.; Digiacomo, M.; Granchi, C.; Minutolo, F.; Rapposelli, S.; Bortolato, A.; Moro, S. Macchia, M. Chem Med Chem, 2008, 3, 1530-1534) powdered KOH (0.103 g, 1.85 mmol) was added to a solution of 3,6-dibromocarbazole (0.500 g, 1.54 mmol) in DMF (1.5 mL) at ambient temperature and stirred for 30 min until dissolved. Epibromohydrin (0.32 mL, 3.8 mmol) was added via syringe and the reaction was stirred at room temperature overnight. Upon completion, the solution was partitioned between EtOAc and H2O. The aqueous layer was washed 3× with EtOAc, and the combined organics were washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was recrystallized from EtOAc/Hexane to afford the desired product (389 mg, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:35])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([OH:17])[C:11]=2[NH:18][C:19]([C:21]2[S:22][CH:23]=[C:24]([CH2:27][N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)[C:25]=2[Cl:26])=[O:20])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:42][O:43][CH2:44][CH2:45]Br>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:35])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][CH2:45][CH2:44][O:43][CH3:42])[C:11]=2[NH:18][C:19]([C:21]2[S:22][CH:23]=[C:24]([CH2:27][N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)[C:25]=2[Cl:26])=[O:20])=[N:6][CH:7]=1
Reactant: CN1CCN(Cc2csc(C(=O)Nc3c(O)cc(Cl)cc3C(=O)Nc3ccc(Cl)cn3)c2Cl)CC1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCOc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(CN2CCN(C)CC2)c1Cl
Yield: 60.2 %

Procedure:
E, In a manner similar to that described in Paragraph B above, N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide (7.0 g, 13 mmol) reacted with cesium carbonate (29 g, 89 mmol) and 2-bromoethyl methyl ether (2.6 g, 19 mmol) in DMF (100 mL) at 60° C. Purification by flash chromatography on silica gel afforded 4.8 g (62% yield) of N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-methoxyethoxy)-5-chlorobenzamide, as a yellow solid; NMR (DMSO-d6 /TFA) 10.9 (s, 1), 9.4 (s, 1), 8.4 (s, 1), 8.1 (d, 2), 7.9 (d, 1), 7.4 (s, 1), 7.3 (s, 1), 4.2 (s, 2), 4.2 (br, 2), 3.6 (s, 2), 3.8-3.0 (br, 8), 3.2 (s, 3), 2.9 (s, 3) ppm.
Reaction SMILES: C(N(CC)CC)C.Cl.[C:9]([O:13][C:14](=[O:21])[C@H:15]([CH2:17][CH:18]([CH3:20])[CH3:19])[NH2:16])([CH3:12])([CH3:11])[CH3:10].[CH:22](OCC#N)=[O:23]>ClCCl>[C:9]([O:13][C:14](=[O:21])[C@H:15]([CH2:17][CH:18]([CH3:19])[CH3:20])[NH:16][CH:22]=[O:23])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Reactant: N#CCOC=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@H](NC=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The preparation was carried out analogously to W. Duczek et al., Synthesis, 37-38 (1996). A solution of 4.04 g (40 mmol) of triethylamine in 10 mL of dichloromethane was added at 0° C. to a solution of 8.94 g (40 mmol) of L-leucine tert-butyl ester hydrochloride and 3.4 g (40 mmol) of cyanomethyl formate in 60 mL of dichloromethane. The reaction solution was allowed to warm to room temperature, stirred overnight at room temperature and then washed twice with saturated NaCl solution. The phases were separated and the organic phase was dried over magnesium sulfate. After filtration and removal of the solvent in vacuo, the residue obtained was distilled in vacuo. Yield: 7.5 g (87%). Boiling point: 118° C./2.7 Pa (0.02 torr).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:43].C(Cl)CCl.C1[CH:49]=[CH:50][C:51]2N(O)N=[N:54][C:52]=2C=1.C1(CN)CC1>C(Cl)Cl>[CH:51]1([CH2:52][NH:54][C:22]([C:21]2[CH:25]=[CH:26][C:27]([CH3:28])=[C:19]([C:18]3[C:13]4[CH2:12][NH:11][C:10](=[O:43])[N:9]([C:3]5[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])[C:14]=4[N:15]=[C:16]([N:29]4[CH2:30][CH2:31][CH:32]([NH:35][C:36](=[O:37])[O:38][C:39]([CH3:41])([CH3:42])[CH3:40])[CH2:33][CH2:34]4)[N:17]=3)[CH:20]=2)=[O:23])[CH2:49][CH2:50]1
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(NC(=O)OC(C)(C)C)CC2)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: On1nnc2ccccc21
Agent: NCC1CC1
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1ccc(C(=O)NCC2CC2)cc1-c1nc(N2CCC(NC(=O)OC(C)(C)C)CC2)nc2c1CNC(=O)N2c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-{8-(2,6-Difluorophenyl)-2-[4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1-piperidinyl]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methylbenzoic acid (250 mg) in methylenechloride (100 mL) were added EDC (100 mg), HOBt (70 mg) and cyclopropylmethylamine (110 uL). The reaction was stirred at r.t. overnight and evaporated in vacuo. Flash chromatography then provided the title compound as a white solid. LC-MS m/z 648 (M+H)+, 2.33 min (ret. time).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH:7]1[C:16]2[N:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:10][CH2:9][CH2:8]1.[Cl-].[Na+]>O>[N:1]1([CH:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:10][CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClC1CCCc2cccnc21
Reactant: C1CCNC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: c1cnc2c(c1)CCCC2N1CCCC1
Reaction time: 0.12 h

Procedure:
Over a period of 7 minutes with stirring and while allowing it to heat up, 50 ml of pyrrolidine were added to a solution of 20 g of 8-chloro-5,6,7,8-tetrahydroquinoline in 50 ml of water. The temperature reached 57° C. at the end of the introduction and stirring was continued for 1 hour at this temperature. The temperature was then allowed to return to 20° C. and the reaction medium was saturated with sodium chloride and then was extracted with ether. The combined organic phases were dried and the solvents were eliminated under reduced pressure to obtain 20.22 g of 8-pyrrolidinyl-5,6,7,8-tetrahydroquinoline in the form of an oil.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[CH3:13].[Li]CCCC.[C:19](=[O:21])=[O:20].Cl>C1COCC1>[CH:10]([O:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([C:19]([OH:21])=[O:20])=[C:3]([CH3:13])[CH:4]=1)([CH3:12])[CH3:11]
Reactant: O=C=O
Reactant: Cc1cc(OC(C)C)c(C)cc1I
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)c(C)cc1OC(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
A solution of 1-iodo-4-isopropoxy-2,5-dimethylbenzene (450 mg, 1.6 mmol) in THF (7.8 mL) was cooled to −78° C. before nBuLi (620 mL, 2.5 M, 1.6 mmol) was added dropwise. The mixture was allowed to warm to 0° C., then it was cooled to −78° C. before it was added dropwise to a flask containing crushed, dry CO2. The mixture was allowed to warm to room temperature and was stirred overnight. The mixture was poured over ice and was acidified with 1N HCl. The mixture was extracted with ethyl acetate (3×) and the combined organics were washed with brine, dried over sodium sulfate, and concentrated to give 4-isopropoxy-2,5-dimethylbenzoic acid (67 mg, 10%). ESI-MS m/z calc. 208.1. found 209.1 (M+1)+; Retention time: 1.55 minutes (3 min run).
Reaction SMILES: NN.[F:3][CH2:4][C:5]1[CH:6]=[C:7]([N:11]([CH2:13][C:14]([O:16]C)=O)[NH2:12])[CH:8]=[CH:9][CH:10]=1.[O-:18][C:19]#[N:20].[Na+].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[F:3][CH2:4][C:5]1[CH:6]=[C:7]([N:11]2[CH2:13][C:14](=[O:16])[NH:20][C:19](=[O:18])[NH:12]2)[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)CN(N)c1cccc(CF)c1
Reactant: N#C[O-]
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C1CN(c2cccc(CF)c2)NC(=O)N1
Reaction time: 2.25 h
Yield: 78 %

Procedure:
The hydrazine (Intermediate 55, 1.5 g, 7.1 mmol) was dissolved in dry toluene (30 ml) under nitrogen at room temperature. Sodium cyanate (1.6 g, 24.6 mmol) was added followed by trifluoroacetic acid (1.7 ml, 22,1 mmol). The reaction was stirred for 2.25 h after which the reaction was poured into saturated sodium bicarbonate solution (100 ml) and extracted with ethyl acetate (4×(100 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give a white solid. The crude material was triturated with ether (2×100 ml) to give the title compound (Intermediate 56, 1.41 g, 78%) as a colourless powder, m.p. 169°-70°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([CH2:10][CH3:11])=[CH:8][C:7]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:6][CH:5]=1.ClC1C=C(C=CC=1)C(OO)=[O:28]>C(Cl)Cl.CCOCC>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([CH2:10][CH3:11])=[CH:8][C:7]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N+:6]([O-:28])[CH:5]=1
Reactant: CCc1cc(-c2c(CC)cccc2CC)ncc1C(=O)OC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOCC
Solvent: ClCCl
Product: CCc1cc(-c2c(CC)cccc2CC)[n+]([O-])cc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-(2,6-diethyl-phenyl)-4-ethyl-nicotinic acid methyl ester (2.1 g, 7.1 mmol) and 3-chloroperoxybenzoic acid (77%, 1.9 g) in CH2Cl2 (50 mL) is stirred at room temperature overnight. The mixture is diluted with ether (600 mL) and washed with saturated Na2CO35 then brine, and dried. Concentration at reduced pressure gives 6-(2,6-diethyl-phenyl)-4-ethyl-nicotinic acid methyl ester N-oxide. 1H NMR (CDCl3) 8.89 (s, 1H), 7.26 (t, 1H), 7.19 (m, 3H), 3.95 (s, 3H), 3.02 (q, 2H), 2.04 (m, 2H), 2.30 (m, 2H), 1.26 (t, 3H), 1.11 (t, 6H).
Reaction SMILES: [CH3:1][S:2]SC.C(P(CCCC)CCCC)CCC.[F:18][C:19]([F:53])([F:52])[C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]2[O:29][CH:30]=[C:31]([CH2:33][O:34][C:35]3[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][CH2:43][CH2:44][N:45]4[CH:49]=[CH:48][N:47]=[C:46]4[CH2:50]O)=[CH:37][CH:36]=3)[N:32]=2)=[CH:22][CH:21]=1.[OH-].[Na+]>ClCCl.N1C=CC=CC=1>[CH3:1][S:2][CH2:50][C:46]1[N:45]([CH2:44][CH2:43][CH2:42][CH2:41][C:38]2[CH:39]=[CH:40][C:35]([O:34][CH2:33][C:31]3[N:32]=[C:28](/[CH:27]=[CH:26]/[C:23]4[CH:24]=[CH:25][C:20]([C:19]([F:53])([F:52])[F:18])=[CH:21][CH:22]=4)[O:29][CH:30]=3)=[CH:36][CH:37]=2)[CH:49]=[CH:48][N:47]=1
Reactant: CSSC
Reactant: OCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CSCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Pyridine (0.600 ml), dimethyl disulfide (0.217 ml) and tributylphosphine (0.600 ml) were added to a solution of [1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]methanol (400 mg) in dichloromethane (8 ml) at room temperature, and the mixture was stirred at room temperature for 6 hr. The reaction mixture was combined with 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1 to ethyl acetate), and recrystallized from ethyl acetate-diethyl ether-hexane to give the titled compound (213 mg) as a colorless crystal powder.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]([CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([N+:21]([O-:23])=[O:22])=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8])=[O:4].N1C=CC=CC=1.[CH3:30][Si:31]([CH3:36])([CH3:35])[CH2:32][CH2:33]O.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[CH3:30][Si:31]([CH3:36])([CH3:35])[CH2:32][CH2:33][O:8][C:7](=[O:9])[CH:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([N+:21]([O-:23])=[O:22])=[CH:13][CH:12]=1
Reactant: COC(=O)NC(Cc1ccc([N+](=O)[O-])c2ccccc12)C(=O)O
Reactant: C[Si](C)(C)CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: CC#N
Product: COC(=O)NC(Cc1ccc([N+](=O)[O-])c2ccccc12)C(=O)OCC[Si](C)(C)C
Reaction time: 1 h

Procedure:
To a mixture of 2-methoxycarbonylamino-3-(4-nitro-naphthalen-1-yl)-propionic acid (0.35 g, 1.1 mmol), pyridine (0.78 mL) and 2-trimethylsilylethanol (0.18 mL, 1.25 mmol, 1.1 eq) in acetonitrile (1.1 mL) cooled in an ice bath was added dicyclohexylcarbodiimide (0.25 g, 1.21 mmol). The mixture was stirred cold for 1 hour, placed in the refrigerator for 14 hours. The reaction mixture was filtered, concentrated under reduced pressure and purified on silica gel eluting with heptane/ethyl acetate (4:1) to provide the titled compound. MS ESI(−)) m/e 417 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([C:13]1[S:20][C:19]([CH3:21])=[C:18]2[C:14]=1[CH2:15][C@H:16]1[C:22]([CH3:24])([CH3:23])[C@H:17]12)=[O:12].[CH2:25]([CH:27]1[O:29][CH2:28]1)Cl>C(O)(C)C.[OH-].[Na+].C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:25][CH:27]2[CH2:28][O:29]2)[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([C:13]1[S:20][C:19]([CH3:21])=[C:18]2[C:14]=1[CH2:15][C@H:16]1[C:22]([CH3:24])([CH3:23])[C@H:17]12)=[O:12]
Reactant: ClCC1CO1
Reactant: Cc1sc(C(=O)CCc2ccc(O)cc2Cl)c2c1[C@H]1[C@@H](C2)C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOCC
Product: Cc1sc(C(=O)CCc2ccc(OCC3CO3)cc2Cl)c2c1[C@H]1[C@@H](C2)C1(C)C
Reaction time: 18 h
Yield: 48 %

Procedure:
A solution of 3-(2-chloro-4-hydroxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (400 mg, 1.11 mmol, Intermediate 18) in isopropanol (10 mL) and 3 N aq. NaOH (6 mL) is treated with epichlorohydrine (554 mg, 4.43 mmol). The dark red reaction mixture is stirred at rt for 6 h before another portion of epichlorohydrine (554 mg, 4.43 mmol) is added. Stirring is continued for 18 h. The mixture is diluted with diethyl ether (150 mL) and washed with sat. aq. NaHCO3 followed by water. The organic layer is dried over MgSO4 and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 7:3 to give 3-(2-chloro-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 (222 mg) as a pale yellow oil; LC-MS: tR=1.16 min, [M+1]+=417.20.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:30][O:31][C:32]1[C:33](=[O:56])[C:34]([CH3:55])=[C:35]([CH2:41][C:42]2[C:43]([O:51][C:52](=[O:54])[CH3:53])=[C:44]([CH:48]=[CH:49][CH:50]=2)[C:45](O)=[O:46])[C:36](=[O:40])[C:37]=1[O:38][CH3:39]>C(Cl)Cl>[CH3:30][O:31][C:32]1[C:33](=[O:56])[C:34]([CH3:55])=[C:35]([CH2:41][C:42]2[C:43]([O:51][C:52](=[O:54])[CH3:53])=[C:44]([CH:48]=[CH:49][CH:50]=2)[C:45]([NH:11][C:10]2[CH:12]=[CH:13][C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:8][CH:9]=2)=[O:46])[C:36](=[O:40])[C:37]=1[O:38][CH3:39]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2OC(C)=O)=C(C)C1=O
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)Nc3ccc(N4CCOCC4)cc3)c2OC(C)=O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 50.6 %

Procedure:
4-Morpholinoaniline (0.214 g, 1.203 mmol), triethylamine (0.122 g, 1.203 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.203 g, 1.203 mmol) were added to a methylene chloride solution (40 ml) of 3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.150 g, 0.401 mmol) and the resulting solution was stirred at room temperature for 10 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (ethyl acetate) and then recrystallized from ether to obtain the titled compound (0.109 g, 0.203 mmol, 51%).