Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:8]=[C:9]([N+:17]([O-:19])=[O:18])[C:10]([Cl:16])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].[CH3:20]O>>[CH3:20][O:13][C:12](=[O:14])[C:11]1[CH:15]=[C:7]([Br:6])[CH:8]=[C:9]([N+:17]([O-:19])=[O:18])[C:10]=1[Cl:16]
Reactant: CO
Reactant: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1Cl
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1Cl

Procedure:
20 ml of concentrated sulfuric acid are added dropwise to 51.0 g (0.182 mol) of 5-bromo-2-chloro-3-nitrobenzoic acid and 500 ml of methanol. The mixture is then boiled under reflux for 16 hours and subsequently cooled with an ice bath and the resulting precipitate is isolated by filtration. The mother liquor is concentrated, water is added and the resulting precipitate is isolated by filtration.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[CH:21][C:20]=3[O:31][CH3:32])=[N:16]2)=[CH:11][CH:10]=1.[CH2:33]1[O:36][C@@H:34]1[CH3:35]>O1CCCC1>[CH3:32][O:31][C:20]1[CH:21]=[C:22]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:33][C@H:34]([OH:36])[CH3:35])[CH2:27][CH2:26]2)[CH:23]=[CH:24][C:19]=1[NH:18][C:15]1[N:14]=[CH:13][C:12]2=[CH:11][CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:17]2[N:16]=1
Reactant: C[C@@H]1CO1
Reactant: COc1cc(C2CCNCC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Solvent: C1CCOC1
Product: COc1cc(C2CCN(C[C@@H](C)O)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(2-methoxy-4-piperidin-4-yl-phenyl)-amine (70.00 mg, 0.163 mmol) was dissolved in tetrahydrofuran (0.300 mL) and the reaction mixture was placed in a sealed tube. (R)-(−)-Propylene oxide (14.2 mg, 0.244 mmol) was then added at room temperature and the reaction was next stirred overnight at 50° C. The solvent was evaporated under reduced pressure and the product was isolated by flash column chromatography (Silicagel, methanol/dichloromethane 0-10% gradient) to afford (R)-1-(4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-propan-2-ol as a tan solid (39 mg, 49%). MP: 67-74° C.; 1H-NMR (CDCl3) δ 8.69 (s, 1H), 8.29 (d, J=8.1 Hz, 1H), 7.99 (d, J=7.7 Hz, 1H), 7.43 (m, 2H), 7.14 (m, 1H), 7.07 (d, J=8.4 Hz, 1H), 7.02 (d, J=4.4 Hz, 1H), 6.83 (d, J=4.4 Hz, 1H), 6.73 (s, 1H), 6.71 (d, J=8.1 Hz, 1H), 3.90 (s, 3H), 3.89 (m, 1H), 3.84 (s, 3H), 3.15 (m, 1H), 2.94 (m, 1H), 2.35 (m, 4H), 2.06 (m, 1H), 1.79 (m, 4H), 1.30 (br s, 1H), 1.16 (d, J=5.8 Hz, 3H); LC/MS (ESI+): 488.2 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)[CH2:9][CH2:10][C:11]2[CH:25]=[CH:24][C:14]([O:15][C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=2)=[N:6][CH:7]=1.[CH2:38]([OH:41])[C:39]#[CH:40]>CCN(CC)CC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[OH:41][CH2:38][C:39]#[C:40][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:29][CH:28]=2)[CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:24][CH:25]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(OC(F)(F)F)cc2)c2ccc(Br)cn2)cc1
Reactant: C#CCO
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(OC(F)(F)F)cc2)c2ccc(C#CCO)cn2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of ethyl 2-[4-(2-{(5-bromopyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (500 mg; 0.86 mmol) in 3 ml of Et3N was treated under nitrogen with tetrakis(triphenylphosphine)palladium (0) (99 mg; 0.086 mmol) and copper (I) iodide (16 mg; 0.086 mmol). After stirring at rt for 5 minutes, propargyl alcohol (72 mg; 1.29 mmol) was added and the mixture heated at 65C for 7 hr. Upon cooling the reaction mixture was concentrated and the residue was partitioned between ethyl acetate and 0.1N HCl. The organic phase was washed with 0.1N HCl and brine, dried over sodium sulfate and concentrated. Purification by radial chromatography using ethyl acetate-hexane mixtures (5–50% gradient) afforded ethyl 2-[4-(2-{[5-(3-hydroxyprop-1-ynyl)pyridin-2-yl][4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33]OS(C)(=O)=O>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Reactant: CS(=O)(=O)OCc1ccccn1
Product: O=C(c1cn(Cc2ccccn2)c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (prepared according to example 69) with methanesulfonic acid pyridin-2-ylmethyl ester (described in WO 9955318) gave the title compound. ES-MS m/e (%): 458.3(M+H+).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=1.[CH2:8]([C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[CH3:7][N:4]1[CH:5]=[CH:6][C:2]([C:11]#[C:10][CH2:9][CH2:8][C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)=[N:3]1
Reactant: Cn1ccc(Br)n1
Reactant: C#CCCc1nc2ccccc2s1
Product: Cn1ccc(C#CCCc2nc3ccccc3s2)n1
Yield: 21 %

Procedure:
The title compound was prepared in accordance with the general method of Example 108(C), from 3-bromo-1-methyl-1H-pyrazole (100 mg, 0.62 mmol) and 2-but-3-ynyl-benzo[d]thiazole (233 mg, 1.24 mmol, Example 35(A)). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 7:3) to yield 35 mg (0.13 mmol, 21%) of 2-(4(1-methyl-1H-pyrazol-3-yl)but-3-ynyl)benzo[d]thiazole as a brown semi-solid.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.C([Li])CCC.[F:12][C:13]([F:20])([F:19])[C:14](OCC)=[O:15].Cl>C(OCC)C>[F:12][C:13]([F:20])([F:19])[C:14]([C:2]1[CH:6]=[CH:5][O:4][CH:3]=1)=[O:15]
Reactant: CCOC(=O)C(F)(F)F
Reactant: Brc1ccoc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(c1ccoc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Bromofuran (20 g) was added to a solution of n-butyllithium (2.5M in hexanes, 60 ml) in diethyl ether (200 ml) at -70° C. After 30 minutes, ethyl trifluoroacetate (28.6 g) was added slowly. After a further 1 hour the mixture was allowed to warm to room temperature and was then left to stir overnight. 1M Hydrochloric acid (100 ml) was added and the mixture stirred for 5 minutes. The organic layer was separated,
Reaction SMILES: [CH2:1]([C:3]1[C:7](=[O:8])[O:6][NH:5][C:4]=1[CH2:9][CH2:10][CH3:11])[CH3:2].O=C(Cl)[O:14][C:15](Cl)(Cl)[Cl:16]>ClCCl>[CH2:1]([C:3]1[C:7](=[O:8])[O:6][N:5]([C:15]([Cl:16])=[O:14])[C:4]=1[CH2:9][CH2:10][CH3:11])[CH3:2]
Reactant: CCCc1[nH]oc(=O)c1CC
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCc1c(CC)c(=O)on1C(=O)Cl
Temperature: 0 °C
Reaction time: 6 h

Procedure:
At 0° C., 15 g (96.65 mmol) of 4-ethyl-3-propyl-5(2H)-isoxazolone in 150 ml of dichloromethane are admixed with 27.81 g (144.98 mmol) of diphosgene, and the mixture is then stirred at 0° C. for 6 h. To remove excess phosgene, argon was passed through the reaction mixture at RT for 1 h, the exhaust gas being neutralized by sodium hydroxide. The solution was concentrated and the product was distilled under reduced pressure. B.p.mbar 125-30° C.
Reaction SMILES: [N:1]#[C:2]Br.[Cl:4][C:5]1[CH:6]=[C:7]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[O:8][C:9]1[C:10]([CH2:21][CH3:22])=[N:11][N:12]([CH2:16][C:17]([NH:19][NH2:20])=[O:18])[C:13]=1[CH2:14][CH3:15]>C(O)C>[Cl:4][C:5]1[CH:6]=[C:7]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[O:8][C:9]1[C:10]([CH2:21][CH3:22])=[N:11][N:12]([CH2:16][C:17]2[O:18][C:2]([NH2:1])=[N:20][N:19]=2)[C:13]=1[CH2:14][CH3:15]
Reactant: CCc1nn(CC(=O)NN)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Reactant: N#CBr
Solvent: CCO
Product: CCc1nn(Cc2nnc(N)o2)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Yield: 44.2 %

Procedure:
Cyanogen bromide (49 mg, 0.462 mmol) was added to a stirred solution of the hydrazide of Example 11 (150 mg, 0.420 mmol) in ethanol (30 ml), at room temperature, under nitrogen and the resulting solution was heated to reflux for 2.5 hours. After cooling, the mixture was concentrated under reduced pressure to leave a brown oil. The crude product was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:ammonia (98:1.75:0.25, by volume) to provide the title compound (71 mg) as a white powder, m.p. 226–228° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([SH:20])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30](Br)[CH3:31])=[CH:26][CH:25]=1.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH:30]([C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)[CH3:31])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(S)c2CC1
Reactant: CC(Br)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2)c1ccc(F)cc1
Temperature: 45 °C
Reaction time: 0.08 h
Yield: 83.8 %

Procedure:
Dissolve 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (415 mg, 1.08 mmol) in methanol (20 mL) and add potassium hydroxide (1.938 g, 34.53 mmol). Heat at 60° C. for 4 h. Cool the reaction mixture to ambient temperature, add aqueous saturated ammonium chloride and concentrate in vacuo. Partition the residue between EtOAc and water. Dry the organic phase over anhydrous Na2SO4 and concentrate in vacuo to give 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.34 g, 1.086 mmol). Dissolve the crude 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.34 g, 1.086 mmol) in anhydrous DMF (10 mL), add sodium hydride (65 mg, 1.63 mmol, 60% in mineral oil) and stir the mixture for 5 min. Add a solution of (±)-1-(4-fluorophenyl)ethyl bromide (332 mg, 1.63 mmol) in anhydrous DMF (5 mL) and heat the solution at 45° C. overnight. Cool to ambient temperature, add water and extract the aqueous phase twice with EtOAc. Dry the combined organic extracts over anhydrous Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1 and 9:1) to give (±)-3-tert-butoxycarbonyl-7-chloro-6-[1-(4-fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as oil (397 mg, 84%). MS (ES+) m/z: 336 (M+H-Boc)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18](Br)[CH:17]=2)[C@@H:9]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:33][N:34]1[C:38]([Sn](CCCC)(CCCC)CCCC)=[CH:37][N:36]=[N:35]1>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:38]3[N:34]([CH3:33])[N:35]=[N:36][CH:37]=3)[CH:17]=2)[C@@H:9]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](OCc2cc(Br)cc(C(F)(F)F)c2)[C@@H]1c1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnnn1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: Cn1nncc1-c1cc(CO[C@H]2CCCN(C(=O)OC(C)(C)C)[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
Bis(triphenylphosphine)palladium dichloride (5.0 mg) was added to a degassed solution of [2S,3S]-1-tert-butoxycarbonyl-2-phenyl-3-[3-bromo-5-(trifluoromethyl)phenylmethoxy]piperidine (330 mg), and 1-methyl-5-tributylstannanyl-1H-[1,2,3]triazole (713 mg) in dry toluene (15.0 ml) under a dry nitrogen atmosphere. The resulting solution was warmed to reflux for 4 hours. After this time the reaction was cooled to room temperature and the solvent removed under reduced pressure. The residue was partitioned between aqueous NaHCO3 solution (10 ml, satd.) and ethyl acetate. The organic layer was washed with brine (10 ml), dried over MgSO4, filtered and the solvent removed under pressure. Purification by MPLC (1:1 ethyl acetate/n-hexane) afforded [2S,3S]-1-tert-butoxycarbonyl-2-phenyl-3-[3-(1-methyl-1H-[1,2,3]triazol-5-yl)-5-(trifluoromethyl)phenylmethoxy]piperidine as a yellow foam (330 mg). 1H NMR (360 MHz,CDCl3) δ 1.45 (9H, s), 1.74 (2H, m), 2.00 (2H, m), 2.75 (1H, t d, J=7.2, 3.0 Hz), 3.91 (2H,m), 4.03 (3H, s), 4.74 (2H, s), 5.71 (1H, br s), 7.27-7.33 (3H, m), 7.44-7.62 (5H, m), 7.75 (1H, s).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16](Cl)=[O:17].S(O)(O)(=O)=O.[NH2:24][C:25]1[NH:26][CH:27]=[CH:28][N:29]=1>>[NH:26]1[CH:27]=[CH:28][N:29]=[C:25]1[NH:24][C:16]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([F:15])([F:14])[F:13])=[O:17]
Reactant: Nc1ncc[nH]1
Reactant: O=C(Cl)c1cnc2c(C(F)(F)F)cccc2c1O
Agent: O=S(=O)(O)O
Product: O=C(Nc1ncc[nH]1)c1cnc2c(C(F)(F)F)cccc2c1O
Yield: 39.7 %

Procedure:
Using the procedure of Example 1, 11.57 g of 4-hydroxy-8-trifluoromethyl-quinoline-3-carboxylic acid chloride were reacted with 5.52 g of 2-aminoimidazole sulfate to obtain 3.9 g of N-(1H-imidazol-2-yl)-4-hydroxy-8-trifluoromethyl-quinoline-3-carboxamide melting at 211° C.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([CH2:23][C@@H:24]5[CH2:28][C@@H:27]([OH:29])[CH2:26][NH:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.[CH2:37]=O>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([CH2:23][C@@H:24]5[CH2:28][C@@H:27]([OH:29])[CH2:26][N:25]5[CH3:37])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@@H]1C[C@@H](O)CN1
Reactant: C=O
Product: CN1C[C@H](O)C[C@H]1CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{[(2S,4R)-4-hydroxy-1-methylpyrrolidin-2-yl]methyl}-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{[(2S,4R)-4-hydroxypyrrolidin-2-yl]methyl}-1,3-thiazolidine-2,4-dione and formaldehyde following General Procedure R.
Reaction SMILES: Br[CH2:2][C:3]1[O:7][C:6]2[C:8]([O:14]C(=O)C)=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:5]=2[C:4]=1[C:18](=[O:31])[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=1.[CH3:32][NH:33][CH3:34]>C1COCC1>[CH3:32][N:33]([CH:2]=[C:3]1[O:7][C:6]2[C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:5]=2[CH:4]1[C:18](=[O:31])[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=1)[CH3:34]
Reactant: CNC
Reactant: COc1cc(C(=O)c2c(CBr)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Solvent: C1CCOC1
Product: COc1ccc2c(c1O)OC(=CN(C)C)C2C(=O)c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 71 %

Procedure:
To a stirred solution of 2-bromomethyl-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7-acetoxy-benzo[b]furan (Example 33) (25 mg, 0.051 mmol) in dry THF (0.5 mL) was added solution of dimethylamine (0.5 mL, excess, 2M solution in THF) and the mixture was stirred for 6 hours at room temperature (tlc). The solvent was distilled and the crude was purified over silica gel to afford the title compound as a light yellow solid (15 mg, 71%). 1H NMR (300 MHz, CDCl3) δ-7.14 (s, 2H, benzoyl Hs), 6.85 (s, 2H, Ar—Hs), 3.93 (s, 3H, OMe), 3.92 (s, 3H, OMe), 3.81 (s, 6H, 2×OMe), 3.75 (s, 2H), 2.31 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH2:6][CH:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=2[CH3:16])[CH2:4][C:3]1=[O:17].CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>>[CH3:21][N:22](/[CH:24]=[C:4]1/[CH:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=2[CH3:16])[CH2:6][CH2:7][C:2]([CH3:18])([CH3:1])[C:3]/1=[O:17])[CH3:23]
Reactant: COC(OC)N(C)C
Reactant: Cc1cc(C#N)ccc1C1CCC(C)(C)C(=O)C1
Product: Cc1cc(C#N)ccc1C1CCC(C)(C)C(=O)/C1=C\N(C)C
Temperature: 25 °C
Yield: 27 %

Procedure:
4-(4,4-Dimethyl-3-oxo-cyclohexyl)-3-methyl-benzonitrile (0.6 g, 2.49 mmol) in N,N-dimethylformamide dimethylacetal (50 mL) is stirred at 90° C. for two days. The mixture is cooled to room temperature and concentrated in vacuo. The residue is diluted with ethyl acetate (50 mL) and water (50 mL). The organic phase is separated and the aqueous phase is extracted with ethyl acetate (3×50 mL). The combined organic phase is washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue is purified by silica gel flash chromatography, eluting with pet ether:EtOAc 1:1 to MeOH:DCM=1:30 to give 4-[(2Z)-2-(dimethylaminomethylene)-4,4-dimethyl-3-oxo-cyclohexyl]-3-methyl-benzonitrile (0.2 g, 27%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][C:23]2([C:26]([O:28]C)=O)[CH2:25][CH2:24]2)=[O:21])=[CH:15][CH:14]=1.CN(C=O)C>>[OH:28][C:26]1[C:23]2([CH2:25][CH2:24]2)[O:22][C:20](=[O:21])[C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)C1(OC(=O)Cc2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Solvent: CN(C)C=O
Product: O=C1OC2(CC2)C(O)=C1c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.5 %

Procedure:
To a 0° C. solution of methyl 1-(2-(4-(quinolin-2-ylmethoxy)phenyl)acetoxy)cyclopropanecarboxylate (2.0 g, 6.825 mmol) in DMF (20 mL) NaH (49 mg, 20.477 mol) was added and the mixture stirred at RT for 12 h. After complete consumption of the starting material (by TLC), the reaction mixture was quenched with ice water (3 mL) and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (30 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford crude 7-hydroxy-6-(4-(quinolin-2-ylmethoxy)phenyl)-4-oxaspiro[2.4]hept-6-en-5-one (2.0 g, 83%) as a light yellow color solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:7][O:6][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C@:17]([OH:38])([CH2:18][C@@H:19]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:20][C@@H:21]3[OH:29])[CH:16]=[CH:15]4)[CH2:12][CH2:11]2)[CH3:9])[O:4][CH2:3]1.[O:40]1[CH2:44]CO[CH:41]1C([C@@H]1[C@]2(C)[C@H]([C@H]3[C@H](CC2)[C@]2(C)[C@](O)(C[C@@H](O)C[C@@H]2O)C=C3)CC1)C>>[CH3:39][C:2]1([CH3:1])[CH2:7][O:6][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C@:17]([OH:38])([CH2:18][C@@H:19]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:20][C@@H:21]3[O:29][CH2:41][O:40][CH3:44])[CH:16]=[CH:15]4)[CH2:12][CH2:11]2)[CH3:9])[O:4][CH2:3]1
Reactant: CC(C1OCCO1)[C@H]1CC[C@H]2[C@@H]3C=C[C@@]4(O)C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3C=C[C@@]4(O)C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Product: COCO[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@]2(O)C=C[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]12C
Yield: 74.2 %

Procedure:
The reaction and workup procedures of Example 110 were repeated except that 400 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-3β-(tert-butyldimethylsilyl)oxypregn-6-ene-1α,5α-diol was used in lieu of 400 mg of 20-(1,3-dioxolan-2-yl)pregn-6-ene-1α,3β,5α-triol to give 320 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-3β-(tertbutyldimethylsilyl)oxy-1α-(methoxymethyl)oxypregn-6-en-5α-ol showing the following physical properties.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=2)[C:3]1=[O:18].[CH3:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][C:27]([S:31](Cl)(=[O:33])=[O:32])=[CH:28]2)=[CH:23][CH:22]=1>C(Cl)Cl>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][S:31]([C:27]3[CH:26]=[CH:25][C:24]4[C:29](=[CH:30][C:21]([O:20][CH3:19])=[CH:22][CH:23]=4)[CH:28]=3)(=[O:33])=[O:32])[C:3]2=[O:18])=[CH:9][C:10]=1[N+:15]([O-:17])=[O:16]
Reactant: COc1ccc2ccc(S(=O)(=O)Cl)cc2c1
Reactant: Nc1ccc(CN2CC[C@H](N)C2=O)cc1[N+](=O)[O-]
Solvent: ClCCl
Product: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4ccc(N)c([N+](=O)[O-])c4)C3=O)cc2c1

Procedure:
The title compound is prepared in CH2Cl2 instead of CH3CN as described in EXAMPLE 1, Part K using 3-(S)-amino-1-(4-amino-3-nitrobenzyl)-pyrrolidin-2-one in place of 7-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-1-chloro-isoquinoline hydrochloride and 7-methoxynaphthalene-2-sulfonyl chloride as prepared in EXAMPLE 1, Part J. The crude product is purified by column chromatography eluting with a gradient of 20% EtOAc/CH2Cl2 to 50% EtOAc/CH2Cl2 to afford the title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[Cl:12]N1C(=O)CCC1=O.FC(F)(F)S(O)(=O)=O>C(#N)C.C(OCC)C>[Cl:12][C:6]1[CH:5]=[CH:4][C:3]([OH:11])=[C:2]([CH3:1])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1c(O)cccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC#N
Solvent: CCOCC
Product: Cc1c(O)ccc(Cl)c1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 1.5 h

Procedure:
2-Methyl-3-nitrophenol (25.5 g), N-chlorosuccinimide (44.5 g), and trifluormethanesulfonic acid (50.0 g) were combined in dry acetonitrile (500 mL) and allowed to stir under an atmosphere of nitrogen at 75° C. for 1.5 hr. The reaction mixture was cooled to room temperature, diluted with ethyl ether (650 mL), washed with water, 10% sodium bisulfite solution, water, and finally saturated sodium chloride solution. Evaporation of the solvent afforded a crude material which was flash chromatographed on silica and eluted with acetone:hexane (1:9) to afford 16.8 g as a yellow solid.
Reaction SMILES: Cl.Cl[C:3]1[CH:4]=[CH:5][C:6]2[CH2:15][C@H:14]3[C@@H:9]([CH2:10][CH2:11][CH2:12][N:13]3[CH2:16][CH2:17][CH3:18])[CH2:8][C:7]=2[N:19]=1.Cl.[CH3:21][NH:22][CH3:23].[OH-].[Na+]>O>[CH3:21][N:22]([CH3:23])[C:3]1[CH:4]=[CH:5][C:6]2[CH2:15][C@H:14]3[C@@H:9]([CH2:10][CH2:11][CH2:12][N:13]3[CH2:16][CH2:17][CH3:18])[CH2:8][C:7]=2[N:19]=1
Reactant: CNC
Reactant: CCCN1CCC[C@H]2Cc3nc(Cl)ccc3C[C@@H]21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCN1CCC[C@H]2Cc3nc(N(C)C)ccc3C[C@@H]21
Temperature: 200 °C
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
A mixture of (±)-trans-2-chloro-6-propyl-5,5a,6,7,8,9,9a,10-octahydropyrido[2,3-g]quinoline hydrochloride (1.00 g, 3.32 mmol) and dimethylamine hydrochloride (15 g) was heated to 200° C. to form a homogeneous molten semi-solid. After 30 minutes, the molten semi-solid was poured into water, made basic with dilute NaOH solution, and extracted with methylene chloride. The extract was dried (Na2SO4) and concentrated to give the crude product as a brown solid. Purification by flash chromatography (10% methanol in methylene chloride, NH4OH) provided (±)-trans-2-dimethylamino-6-propyl-5,5a,6,7,8, 9,9a,10-octahydropyrido[2,3-g]quinoline (Rf =0.54, 568 mg, 63% yield) as an orange oil.