Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:16][C:17](=[O:31])[CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=2[Cl:30])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13].[C:32](OC(=O)C)(=[O:34])[CH3:33]>>[C:32]([NH:1][C:2]1[CH:3]=[C:4]([NH:16][C:17](=[O:31])[CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][C:21]=2[Cl:30])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])(=[O:34])[CH3:33]
Reactant: CCN(CC)CCOc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1N
Reactant: CC(=O)OC(C)=O
Product: CCN(CC)CCOc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1NC(C)=O

Procedure:
A solution of 100 mg (0.217 mmol) N-[3-amino-4-(2-diethylamino-ethoxy)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Example 160) in 10 mL acetic anhydride was stirred for 3 h at 100° C. and then evaporated down i. vac. The residue was combined with saturated aqueous sodium bicarbonate and exhaustively extracted with EtOAc. The combined org. phases were dried over sodium sulphate, evaporated down i. vac. and the residue was stirred with ether. The precipitate was filtered off, washed with ether and dried in a HV.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:1]2[CH:5]=[CH:4][N:3]=[C:2]2[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1ncc[nH]1
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nccn1Cc1ccc(Cl)cc1

Procedure:
Ethyl 1H-imidazole-2-carboxylate (4 g, 28.5 mmol), p-chlorobenzylchloride (4.38 mL, 34.3 mmol), and sodium carbonate (3.63 g, 34.3 mmol), was dissolved in DMF (8 mL). The solution was stirred at rt for 24 h, at which time water was added and material was extracted with EtOAc. The organic phase was collected, dried over magnesium sulfate, and decanted. Purification accomplished via silica gel flash chromatography (150 g silica, 10% EtOAc/Hexanes to 80% EtOAc/Hexanes.) The title compound was obtained as a clear, yellow-tinted oil. (Yield: 7.28 g, 27.5 mmol, 96%) 1H NMR (400 MHz, CDCl3) 7.25, 7.15, 7.10-7.00, 5.55, 4.34, 1.36
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[C:27]1([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:36]2[CH2:37][CH2:38][N:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:34][CH2:35]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccccc3)CC2)c2ccccc2-c2ccccc21
Temperature: 80 °C
Reaction time: 10 h

Procedure:
A suspension of 0.4 g (0.93 mmol) of 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide, 0.153 ml (1 mmol) of 1-phenylpiperazine, 0.8 g of potassium carbonate and 1 ml water in 30 ml dimethylformamide is stirred for 10 hours at 80° C. The reaction mixture is then poured onto water, extracted with ethyl acetate and the organic phase is dried over sodium sulphate. Purification is by column chromatography on silica gel (eluant: dichloromethane/methanol=15:1).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:13]2[CH3:25])=[N:4][N:3]=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[CH3:25])=[N:4][N:3]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1nnc(Cl)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CNCCN1c1nnc(Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(R)-tert-butyl 4-(4-chlorophthalazin-1-yl)-3-methylpiperazine-1-carboxylate (1.20 g, 3.31 mmol) was dissolved in dry dichloromethane (40 mL). Trifluoroacetic acid (8 mL) was added dropwise and allowed to stir at RT for 2 hours. The reaction was added to saturated NaHCO3 (200 mL) and the aqueous phase was extracted with 3×100 mL of dichloromethane. The combined organics were dried (MgSO4) and evaporated to give a pale yellow solid. MS (M+H)+=263.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:26][CH:25]([NH2:27])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:26][CH:25]([NH:27][CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Product: CC(C)(C)OC(=O)N1CC(NCc2cccc(-c3ccnc(Cl)n3)c2)C1

Procedure:
Intermediate 1 was coupled with 3-Amino-azetidine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 375.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[CH2:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O)[CH3:32]>>[CH2:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([N:9]1[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]1)[NH:20][C:19]2=[O:29])[CH3:32]
Reactant: CCc1ccccc1B(O)O
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Product: CCc1ccccc1-c1ccc2nc(-n3cc(C(=O)O)cn3)[nH]c(=O)c2c1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E, using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 69 product from step B) and 2-ethylphenylboronic acid in step C. MS (ESI): mass calcd. for C20H16N4O3, 360.1; m/z found, 361.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.01 (br s, 1H), 12.91 (br s, 1H), 8.99 (s, 1H), 8.28 (s, 1H), 7.99 (s, 1H), 7.81 (dd, J=8.2, 1.8 Hz, 1H), 7.77 (s, 1H), 7.40-7.36 (m, 2H), 7.32-7.29 (m, 1H), 7.25 (d, J=7.2 Hz, 1H), 2.59 (q, J=7.5 Hz, 2H), 1.05 (t, J=7.5 Hz, 3H).
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[F:17][C:18]1[CH:19]=[C:20](/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28])[CH:21]=[CH:22][C:23]=1[F:24].FC(F)(F)C(O)=O>C1COCC1>[CH2:10]([N:4]1[CH2:3][CH:25]([C:20]2[CH:21]=[CH:22][C:23]([F:24])=[C:18]([F:17])[CH:19]=2)[CH:26]([C:27]([OH:29])=[O:28])[CH2:5]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)/C=C/c1ccc(F)c(F)c1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1CN(Cc2ccccc2)CC1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (48.3 g, 204 mmol) and (E)-3-(3,4-difluoro-phenyl)-acrylic acid (15 g, 81.5 mmol) in THF (200 mL) was added trifluoroacetic acid (0.312 mL, 0.0041 mol) at 0° C. The mixture was gradually warmed to room temperature and stirred overnight. It was then concentrated in vaccuo and the residue was diluted with n-heptane (500 mL) followed by vigorous stirring for 1 hour. The resulted white precipitation was collected and washed with heptane affording 26 g (100%) of the title compound as a white solid. MS m/e: 318.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([I:30])[CH:27]=[CH:26][C:25]=3[O:31][CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[C:5]2=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:47][C:48]([O:50][CH3:51])=[O:49]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([I:30])[CH:27]=[CH:26][C:25]=3[O:31][CH:32]3[CH2:33][CH2:34][N:35]([CH2:47][C:48]([O:50][CH3:51])=[O:49])[CH2:36][CH2:37]3)[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2OC2CCNCC2)N1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)CN1CCC(Oc2ccc(I)cc2C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)CC1
Temperature: 80 °C
Yield: 53 %

Procedure:
To a solution of racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-iodo-2-(4-piperidinyloxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.36 g, 0.54 mmol) prepared in example 5a in ethanol (2 mL) was added triethylamine (0.15 mL, 1.08 mmol) and methyl bromoacetate (0.124 g, 0.81 mmol) (Aldrich). The reaction mixture was heated at 80° C. for 2 h, then cooled to room temperature. The mixture was partitioned between dichloromethane and water. The organic layer was separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (MeOH:EtOAc=7:93) to give racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-iodo-2-(1-methoxycarbonylmethyl-4-piperidinyloxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a light yellow solid (Yield 0.21 g, 53%)
Reaction SMILES: [CH:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4].C(N(CC)CC)C.[CH3:13][Si:14](Cl)([CH3:16])[CH3:15]>C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-].C1(C=CC(O)=CC=1)O>[CH3:13][Si:14]([CH3:16])([CH3:15])[O:5][CH:1]=[CH:2][CH:3]=[CH2:4]
Reactant: C/C=C/C=O
Reactant: C[Si](C)(C)Cl
Agent: Oc1ccc(O)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CC=CO[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To a solution of crotonaldehyde (31.8 g, 0.454 mole) and triethylamine (51.4 g, 1.1 eq) in benzene at 25° C., was added hydroquinone (0.95 g) and zinc chloride (0.75 g) rapidly with efficient stirring. This was followed by the addition of freshly distilled trimethylsilyl chloride (46 ml, 0.9 eq) over 1-2 minutes, whereupon a white precipitate rapidly formed. After stirring the mixture for 30 minutes at 25° C., a further 0.2 eq of trimethylsilyl chloride were added. The reaction was then warmed to 70° C. and stirred at this temperature for 12 hours. It was then cooled to 0° C., quenched by addition of saturated aq. NaHCO3 (75 ml), poured into a separatory funnel, and the organic layer separated. The aqueous layer was extracted with further portions of benzene (3×50 ml), the organic extracts combined, washed with 10% KHSO4, and the benzene removed in vacuo to leave a dark brown liquid. Distillation through a short Vigreaux column yielded 28.4 g (46%) of pure 1-trimethylsilyloxy-1,3-butadiene as a colorless liquid (bp 78°-80° C./68 mm Hg). 1H NMR (200 MHz, CDCl3): δ 6.66(1H,d,J=11.9 Hz), 6.35(1H,dt,J=17.1, 10.6Hz), 5.84(1H,t,J=11.4 Hz), 5.11(1H,dd,J=16.8, 1.8 Hz), 4.94(1H,dd,J=10.3, 1.8 Hz), 0.37(9H, s).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:2]=1.[CH2:17]([N:19]([CH2:34][CH3:35])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=O)[NH:27][C:26]=1[CH3:33])=[O:24])[CH3:18]>>[CH2:34]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=[C:11]2[C:10]3[C:14](=[CH:15][C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[CH:8][CH:9]=3)[NH:13][C:12]2=[O:16])[NH:27][C:26]=1[CH3:33])=[O:24])[CH3:35]
Reactant: O=C1Cc2ccc(-c3cccnc3)cc2N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cc(-c4cccnc4)ccc32)c1C
Yield: 33.6 %

Procedure:
6-Pyridin-3-yl-1,3-dihydroindol-2-one (40 mg, 0.19 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (50 mg) give, 29 mg (33%) of the title compound as a light orange solid.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[BrH:14].N([O-])=O.[Na+].[Br-]>O.C(OCC)C>[Br:14][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Br
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1
Agent: O=N[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 70 °C

Procedure:
To the solution of 7.92 g (43 mmol) 3-amino-5-nitro-benzoic acid in 4 ml water in an ice bath 48.8 ml (434 mmol, 10 eq) of aq 48% HBr are added. A saturated aqueous solution of 4.05 g (59 mmol, 1.35 eq) sodium nitrit is added over 10 min. The obtained solution is added to the solution of 9.36 g (65 mmol, 1.5 eq) cupper bromide in 48.8 ml (434 mmol, 10 eq) of aq 48% HBr at 70° C. The mixture is heated for 45 min at 70° C. After cooling to rt diethylether is added and the organic layer is washed with water until neutral pH is reached. Drying over sodium sulfate and evaporation of the solvent at reduced pressure to give the product as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:24]1([CH:27](O)[CH3:28])[CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:20])([F:19])[F:21])[N:13]([CH3:22])[C:12]2=[O:23])=[CH:7][C:3]=1[C:4]([O:6][CH:27]([CH:24]1[CH2:26][CH2:25]1)[CH3:28])=[O:5]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C(=O)O)c2)c1=O
Reactant: CC(O)C1CC1
Product: CC(OC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl)C1CC1

Procedure:
In an analogous manner, starting from 2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl]-benzoic acid via its acid chloride and 1-cyclopropylethanol there is obtained 1-cyclopropylethyl 2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl]-benzoate, m.p. 118°-119° C.;
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[O:7][C:6]2[CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]3[CH:29]=[CH:28][C:17]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])=[CH:16][CH:15]=3)=[CH:11][C:5]=2[C:4](=[O:30])[O:3]1.CCN(C(C)C)C(C)C.[CH:41]1([CH2:46][CH2:47][C:48](Cl)=[O:49])[CH2:45][CH2:44][CH2:43][CH2:42]1.Cl>C(Cl)Cl>[CH:41]1([CH2:46][CH2:47][C:48]([N:12]([CH2:13][C:14]2[CH:29]=[CH:28][C:17]([C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])=[CH:16][CH:15]=2)[C:10]2[CH:9]=[CH:8][C:6]3[O:7][C:2]([CH3:31])([CH3:1])[O:3][C:4](=[O:30])[C:5]=3[CH:11]=2)=[O:49])[CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: CC1(C)OC(=O)c2cc(NCc3ccc(C(=O)OCc4ccccc4)cc3)ccc2O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)OC(=O)c2cc(N(Cc3ccc(C(=O)OCc4ccccc4)cc3)C(=O)CCC3CCCC3)ccc2O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a cold (0° C.) solution of benzyl 4-{[(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-6-yl)amino]methyl}benzoate (430 mg) and DIEA (146 mg) in anhydrous DCM (5 nm) was added a solution of 3-cyclopentylpropanoyl chloride (182 mg, 1 M in DCM). The mixture was stirred 1 h at 0° C. then 3 h at rt. An aqueous solution of HCl (1N, 50 mL) was added and the resulting mixture was extracted with Et2O (3×50 mL). The combined organic layers were washed with brine (1×50 mL), dried over MgSO4, filtered and evaporated under vacuum to give a light orange oil. Purification by chromatography (SiO2, DCM/c-Hex) gave the title compound as a colorless oil (499 mg, 89%). 1H NMR (CDCl3) δ 8.00 (d, J=8.3 Hz, 2H), 7.69 (d, J=2.3 Hz, 1H), 7.49-7.32 (m, 5H), 7.27 (d, J=7.5 Hz, 2H), 7.11-7.03 (m, 1H), 6.91 (d, J=8.6 Hz, 1H), 5.37 (s, 2H), 4.93 (s, 2H), 2.13-2.05 (m, 2H), 1.85 (s, 6H), 1.71-1.37 (m, 9H), 1.06-0.89 (m, 2H). M+(ESI): 542.3.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH3:14])=[CH:9][C:8]=1[F:15].CC([O-])(C)C.[K+].[C:22](=[O:24])=[O:23]>C1COCC1.O>[Cl:6][C:7]1[C:8]([F:15])=[C:9]([C:10]([NH:13][CH3:14])=[CH:11][CH:12]=1)[C:22]([OH:24])=[O:23]
Reactant: O=C=O
Reactant: CNc1ccc(Cl)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CNc1ccc(Cl)c(F)c1C(=O)O
Temperature: -75 °C
Reaction time: 0.08 h
Yield: 11 %

Procedure:
n-Butyllithium solution (1.6 M in hexane, 4.95 mL, 8.0 mmol) was added at −78° C. to THF (10 ml) under nitrogen. A solution of (4-chloro-3-fluoro-phenyl)-methyl-amine (575 mg, 4.0 mmol) in THF (3 mL) was added dropwise keeping the temperature below −70° C. The solution was stirred for 5 min at −75° C. Potassium tert-butylate (889 mg, 8 mmol) dissolved in THF (2 ml) was added within 15 min. The reaction was stirred at −75° C. for 2 h and treated with a large excess of dry ice. Within 30 min the reaction was warmed to RT. Water was added and the reaction was extracted twice with diethyl ether. The aqueous layer was acidified to pH1 with 1N aq. HCl solution and extracted twice with diethyl ether. The combined organic layers were washed with sat. aq. NaCl solution, dried over sodium sulfate, filtered and the solvent was removed in vacuo to yield 3-chloro-2-fluoro-6-methylamino-benzoic acid (83 mg, 11%). Light brown solid, 1HNMR (DMSO-d6, 300 MHz): δ 81 (s, 3H), 6.52 (d, J=9.2 Hz, 1H), 7.45 (t, J=9.1 Hz, 1H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]1[CH2:16][C:17]1[S:18][CH:19]=[C:20](/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25])[N:21]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:27](I)[CH2:28][CH2:29][CH3:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]1[CH2:16][C:17]1[S:18][CH:19]=[C:20](/[CH:22]=[CH:23]/[C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])[N:21]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CCCCI
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CCC(=O)N1Cc1nc(/C=C/C(=O)O)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOC(=O)/C=C/c1csc(CN2C(=O)CC[C@@H]2CO[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound 72 (980 mg) in dimethylformamide (3.00 mL) was added n-butyl iodide (570 μL) at room temperature and then thereto was added potassium carbonate (691 mg) at 0° C. The solution was stirred at room temperature overnight. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed water and brine, dried over anhydrous sodium sulfate and concentrated. The organic residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=78:22→50:50) to give the title compound (960 mg) having the following physical data.
Reaction SMILES: C(O[CH2:5][C:6]1[NH:10][C:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:8]([CH3:21])[C:7]=1[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(=O)C.[CH2:28]([C:30]1[C:34]([CH2:35][CH3:36])=[CH:33][NH:32][CH:31]=1)[CH3:29]>>[CH2:14]([O:13][C:11]([C:9]1[NH:10][C:6]([CH2:5][C:31]2[NH:32][C:33]([CH2:5][C:6]3[NH:10][C:9]([C:11]([O:13][CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[O:12])=[C:8]([CH3:21])[C:7]=3[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:34]([CH2:35][CH3:36])[C:30]=2[CH2:28][CH3:29])=[C:7]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:8]=1[CH3:21])=[O:12])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCc1c[nH]cc1CC
Reactant: CCOC(=O)Cc1c(COC(C)=O)[nH]c(C(=O)OCc2ccccc2)c1C
Product: CCOC(=O)Cc1c(Cc2[nH]c(Cc3[nH]c(C(=O)OCc4ccccc4)c(C)c3CC(=O)OCC)c(CC)c2CC)[nH]c(C(=O)OCc2ccccc2)c1C

Procedure:
condensing two molecular equivalents of benzyl 5-(acetoxymethyl)-4-ethoxycarbonylmethyl-3-methylpyrrole-2-carboxylate with 3,4-diethyl pyrrole under acidic conditions to produce 2,5-bis(5-benzyloxycarbonyl-3-ethoxycarbonylmethyl-4-methylpyrrol-2-ylmethyl)-3,4-diethylpyrrole;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16]S(C3C=CC(C)=CC=3)(=O)=O)=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:37]1([CH2:42][CH2:43]O)[CH2:41][CH2:40][CH2:39][CH2:38]1>O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:43][CH2:42][CH:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OCCC1CCCC1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)c(F)c3)c2=O)cc1
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2OCCC2CCCC2)cc1

Procedure:
The title compound was prepared according to the method of Example 178, starting with 2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 2-cyclopentyl-1-ethanol in place of 2-ethyl-1-hexanol (yield: 115 mg, 60%). mp 100–101° C. 1H NMR (300 MHz, DMSO-d6) δ 1.00 (m, 2H), 1.38 (m, 2H), 1.57 (m, 7H), 3.30 (s, 3H), 4.42 (t, J=7 Hz, 2H), 7.52 (m, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 7.90 (d, J=9 Hz, 2H), 8.08 (d, J=9 Hz, 2H), 8.22 (s, 1H). MS (APCI+) m/z 475 (M+H)+; (APCI−) m/z 509 (M+Cl)−. Anal. calc. for C24H24F2N2O4S.0.25 H2O: C, 60.17; H, 5.15; N, 5.84. Found: C, 60.12; H, 5.14; N, 5.76.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]1[C:15]([CH3:24])=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>>[Cl:13][C:14]1[C:15]([CH3:24])=[C:16]([S:20]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cccc(Cl)c2C)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 3-chloro-2-methylbenzenesulfonyl chloride according to METHOD A at 30° C., using a Quest 210 apparatus. This procedure gave 2.05 g (34%) of an off-white solid: mp 154° C.; MS (Ionspray, [M+H]+) m/z 375; Anal. Calcd (found) for C14H15ClN2O4S2: C, 44.9 (45.0)%, H, 4.0 (3.7)%, N, 7.5 (7.1)%.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[CH3:22][O:23][C:24]1[CH:32]=[C:31]2[C:27]([CH2:28][C:29](=[O:33])[NH:30]2)=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:32]=[C:31]2[C:27]([C:28](=[CH:20][C:3]3[NH:4][C:5]4[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]5[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]5)[C:7](=[O:19])[C:6]=4[C:2]=3[CH3:1])[C:29](=[O:33])[NH:30]2)=[CH:26][CH:25]=1
Reactant: COc1ccc2c(c1)NC(=O)C2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Product: COc1ccc2c(c1)NC(=O)C2=Cc1[nH]c2c(c1C)C(=O)N(CCN1CCCCC1)CC2
Yield: 61.8 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 6-methoxy-1,3-dihydro-indol-2-one (prepared according to Journal of Organic Chemistry, 70(5), 1828-1834, 2005) starting materials to give 2-(6-methoxy-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (51 mg, 61.8%) as an orange solid.