Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH:4]1[N:9]([CH2:10][CH:11]=[C:12]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7][N:6]([CH2:27][C:28]([NH:30][C:31]2[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:38])=[O:29])[CH2:5]1)=[O:3].[H][H]>[Pd].CO>[NH2:1][C:2]([CH:4]1[N:9]([CH2:10][CH2:11][CH:12]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7][N:6]([CH2:27][C:28]([NH:30][C:31]2[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:38])=[O:29])[CH2:5]1)=[O:3]
Reactant: [H][H]
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(CC=C(c2ccc(F)cc2)c2ccc(F)cc2)C(C(N)=O)C1
Agent: [Pd]
Solvent: CO
Product: Cc1cccc(C)c1NC(=O)CN1CCN(CCC(c2ccc(F)cc2)c2ccc(F)cc2)C(C(N)=O)C1

Procedure:
A mixture of 4 parts of 3-(aminocarbonyl)-4-[3,3-bis(4-fluorophenyl)-2-propenyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide and 120 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and dissolved in acetonitrile. The solution was filtered and the filtrate was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 2.21 parts of 3-(aminocarbonyl)-4-[3,3-bis(4-fluorophenyl)propyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide; mp. 143.2° C. (compound 170).
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[OH:36])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:47][C:48]#[CH:49].Cl>CN(C=O)C>[F:37][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:15][CH2:16][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[O:36][CH2:49][C:48]#[CH:47])[O:27][N:26]=4)[N:24]=3)[CH2:18][CH2:19]2)=[O:13])[N:4]=1
Reactant: C#CCBr
Reactant: O=C(Cn1nc(C(F)F)cc1C(F)F)N1CCC(c2nc(C3=NOC(c4ccccc4O)C3)cs2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: C#CCOc1ccccc1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Temperature: 80 °C
Reaction time: 9 h
Yield: 62.3 %

Procedure:
To a solution of 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (60 mg) and potassium carbonate (23 mg) in DMF (3 ml) are added, at room temperature, potassium iodide (10 mg) and 3-bromoprop-1-yne (21 mg). The reaction mixture is stirred at 80° C. for 9 h. Then the mixture is admixed with dilute hydrochloric acid and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated. Purification by column chromatography gives 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-(prop-2-yn-1-yloxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone (40 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:7]([CH:12]=1)[C:8]([O:10]C)=[O:9])#[N:2].[OH-].[Na+].Cl>CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:7]([CH:12]=1)[C:8]([OH:10])=[O:9])#[N:2]
Reactant: COC(=O)c1cc(C#N)ccc1NC1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc(NC2CCCC2)c(C(=O)O)c1
Yield: 99.2 %

Procedure:
A mixture of methyl 5-cyano-2-(cyclopentylamino)benzoate (2.30 g), methanol (100 mL) and 1N-sodium hydroxide solution (20 mL) was heated for 2 hours under reflux. The reaction mixture was acidified with 1N-hydrochloric acid to pH 4 and the organic solvent was removed by evaporation. The aqueous layer was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over magnesium sulfate. Then, the resultant was evaporated in vacuo to give 5-cyano-2-(cyclopentylamino)benzoic acid (2.15 g) as pale yellow powders.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[C:15]1[N:19]2[C:20]3[CH:26]=[CH:25][N:24](S(C4C=CC(C)=CC=4)(=O)=O)[C:21]=3[N:22]=[CH:23][C:18]2=[CH:17][N:16]=1.[OH-].[Na+].CC(O)=O>O1CCOCC1>[C:15]1([CH:3]2[CH:2]([CH3:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4]2)[N:19]2[C:20]3[CH:26]=[CH:25][NH:24][C:21]=3[N:22]=[CH:23][C:18]2=[CH:17][N:16]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnc(C4CN(C(=O)OC(C)(C)C)CCC4C)n23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CC1CCN(C(=O)OC(C)(C)C)CC1c1ncc2cnc3[nH]ccc3n12
Temperature: 60 °C
Yield: 92.8 %

Procedure:
To a solution of tert-butyl 4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate (19.0 g, 37.3 mmol) in 1,4-dioxane (100 mL) was added aqueous NaOH (1N, 74.6 mL, 74.6 mmol). The reaction was heated at about 60° C. for about 30 min and allowed to cool to ambient temperature followed by the addition of 10% aqueous AcOH (250 mL). The mixture was extracted with EtOAc (2×250 mL) and the combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography (330 g) eluting with a gradient of 10-70% EtOAc in heptane to provide tert-butyl 3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carboxylate (12.3 g, 93%) as a white foam: LC/MS (Table 2, Method a) Rt=1.96 min; MS m/z: 356 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[C:11]([C:38](=[O:40])[CH3:39])[C:12]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[C:27]([OH:34])[C:26]=3[CH2:35][CH2:36][CH3:37])=[CH:13][CH:14]=2)[CH:9]=1.[OH-].[Na+]>CO>[C:38]([C:11]1[C:12]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[C:27]([OH:34])[C:26]=2[CH2:35][CH2:36][CH3:37])=[CH:13][CH:14]=[C:15]2[C:10]=1[CH:9]=[C:8]([O:7][CH2:6][CH2:5][CH2:4][C:3]([OH:41])=[O:2])[CH:17]=[CH:16]2)(=[O:40])[CH3:39]
Reactant: CCCc1c(OCCOCCOc2ccc3ccc(OCCCC(=O)OC)cc3c2C(C)=O)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCOCCOc2ccc3ccc(OCCCC(=O)O)cc3c2C(C)=O)ccc(C(C)=O)c1O
Yield: 84.4 %

Procedure:
A solution of 1.7 g of 4-[[8-acetyl-7-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-naphthalenyl]oxy]butanoic acid methyl ester and 30 ml of 1N sodium hydroxide in 60 ml of methanol was stirred at reflux for 1 hour. The methanol was removed in vacuo and the aqueous solution was acidified to pH 3. The gummy precipitate was extracted with methylene chloride, the extract was washed with water, dried (magnesium sulfate) and concentrated in vacuo to an oil. The oil was triturated with hexane-ether to yield 1.4 g, m.p. 71°-75° C. (85%) of 4-[[8-acetyl-7-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-naphthalenyl]oxy]butanoic acid.
Reaction SMILES: [C:1]([C:5]1[C:10]2[O:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([C:16]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1(C)C=CC=CC=1>[C:1]([C:5]1[C:10]2[O:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([C:16]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)=[S:32])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)c1cc(C(=O)c2ccco2)cc2c1OCC2(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(C(=S)c2ccco2)cc2c1OCC2(C)C
Yield: 159.6 %

Procedure:
7-tert-Butyl-2,3-dihydro-3,3-dimethyl-5-(2-furoyl)benzo[b]furan (600 mg, 2 mmol) and Lawesson's reagent (404 mg, 1 mmol) in dry toluene (10 mL) is refluxed in an argon atmosphere. The mixture is cooled and the toluene evaporated. The resulting solid was purified by flash chromatography on silica gel to give 502 mg (80%) of the title compound as a yellowish crystals.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CC(C)([O-])C.[Na+].[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].Br[C:43]1[C:48]2[O:49][CH:50]=[CH:51][C:47]=2[CH:46]=[CH:45][CH:44]=1>C1(C)C=CC=CC=1.[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[O:49]1[CH:50]=[CH:51][C:47]2[CH:46]=[CH:45][CH:44]=[C:43]([N:39]3[CH2:40][CH2:41][N:36]([C:34]([O:33][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:35])[CH2:37][CH2:38]3)[C:48]1=2
Reactant: Brc1cccc2ccoc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3ccoc23)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 19.9 %

Procedure:
Tri-o-tolylphosphine (1.42 g) was added to a stirred suspension of bis (dibenzylideneacetone) palladium (O) (1.4 g) in toluene (480 ml) at ambient temperature under nitrogen. Sodium tert-butoxide (16.1 g) was added, followed by N-tert-butoxycarbonylpiperazine (26.6 g) and stirring was continued at ambient temperature for 5 minutes. 7-Bromobenzo[b]furan (23.3 g) was added and the stirred mixture was heated under reflux for 20 hours and then cooled to ambient temperature. The organic solution was decanted from the palladium residues, then washed with brine (500 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by flash column chromatography over silica using a 1:9 mixture of ether and petroleum ether (b.p. 60-80° C.) as eluant to give tert-butyl 4-(7-benzo[b]furanyl)piperazine-1-carboxylate (7.12 g) as a pale yellow solid, m.p. 98-100° C.
Reaction SMILES: Br[CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:3].[CH3:10][O:11][C:12](=[O:22])[C:13]1[CH:21]=[CH:20][C:18]([OH:19])=[C:15]([O:16][CH3:17])[CH:14]=1>>[CH3:10][O:11][C:12](=[O:22])[C:13]1[CH:21]=[CH:20][C:18]([O:19][CH:2]([CH3:3])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])=[C:15]([O:16][CH3:17])[CH:14]=1
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: CC(C)CCCC(C)Br
Product: COC(=O)c1ccc(OC(C)CCCC(C)C)c(OC)c1

Procedure:
By the procedure described in Example 1, 2 -bromo-6-methylheptane is reacted with vanillic acid methyl ester to produce 4-[(1,5-dimethyl-hexyl)-oxy]-m-methoxy-benzoic acid methyl ester (boiling point = 198°-200° C/0.1 mmHg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.Cl.[NH2:16][C@@H:17]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18]([O:20][CH3:21])=[O:19].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:16][C@@H:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]([O:20][CH3:21])=[O:19])=[C:8]([C:11](=[O:12])[NH2:13])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: COC(=O)[C@@H](N)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](Nc1c(C(N)=O)cnn2cc(Br)cc12)c1ccccc1
Yield: 44.9 %

Procedure:
6-Bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 2.0 g, 7.29 mmol), (S)-methyl 2-amino-2-phenylacetate hydrochloride (2.20 g, 10.93 mmol) and DIPEA (3.82 mL, 21.86 mmol) in NMP (10 mL) were heated in the CEM microwave at 80° C. for 1 hr. The reaction was then quenched with ice-water and the resulting precipitate filtered. The crude solid was purified by column chromatography using hexane:ethyl acetate as eluent to give the title compound (1.32 g, 3.27 mmol, 44.9% yield) as a white solid. HPLC (condition B): retention time=0.93 min. LCMS (condition B): m/z 403.2, 405.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (1 H, d, J=7.48 Hz), 8.31 (1 H, s), 7.88 (1 H, d, J=1.54 Hz), 7.11-7.72 (3H, m), 6.93 (2 H, d, J=1.76 Hz), 6.12 (1 H, d, J=7.70 Hz), 3.31 (3 H, s).
Reaction SMILES: [C:1](C1C=C(C)C=C(C)N=1)(=O)C.[Br:12][CH2:13][C:14]([C:16]1[CH:21]=[C:20]([CH2:22]C)[CH:19]=[CH:18][N:17]=1)=[O:15]>>[Br:12][CH2:13][C:14]([C:16]1[C:21]([CH3:1])=[C:20]([CH3:22])[CH:19]=[CH:18][N:17]=1)=[O:15]
Reactant: CCc1ccnc(C(=O)CBr)c1
Reactant: CC(=O)c1cc(C)cc(C)n1
Product: Cc1ccnc(C(=O)CBr)c1C

Procedure:
* 2-Bromoacetyl-3,4-dimethylpyridine was prepared from 2-acetyl-4,6-dimethylpyridine (Sundberg et al., J. Am. Chem. Soc., 1969, 91, 658) according to the procedure for preparing 2-bromoacetyl-4-ethylpyridine described in Example 57.
Reaction SMILES: [N:1]1([S:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH:18]([CH3:24])[CH:19]([N:21]=[N+]=[N-])[CH3:20])[C:13](=[O:25])[C:12]23[O:30][CH2:29][CH2:28][CH2:27][O:26]2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[N:1]1([S:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH:18]([CH3:24])[CH:19]([NH2:21])[CH3:20])[C:13](=[O:25])[C:12]23[O:30][CH2:29][CH2:28][CH2:27][O:26]2)(=[O:7])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(N=[N+]=[N-])C(C)N1C(=O)C2(OCCCO2)c2cc(S(=O)(=O)N3CCCC3)ccc21
Agent: [Pd]
Solvent: CO
Product: CC(N)C(C)N1C(=O)C2(OCCCO2)c2cc(S(=O)(=O)N3CCCC3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-[5′-{[pyrrolidin-1-yl]sulfonyl}-2′-oxospiro[1,3-dioxane-2,3′-indol]-1′(2′H)-yl]-2-azidobutane (0.16 g, 0.37 mmoles) and 10% Pd/C in methanol (5 ml) was stirred under a H2 atmosphere (1 atmosphere) overnight at room temperature. The reaction mixture was filtered, and concentrated. The crude product was purified by flash chromatography on silica gel using 40% EtOAc/hexane followed by 1% CH3OH/EtOAc to give the title compound as an off white solid (0.06 g, 40% yield). NMR (400 MHz, DMSO-d6): consistent. MS: (API-ES+) m/z 410 [M+H].
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[CH:22]=[C:21]([OH:25])[CH:20]=[CH:19][C:18]=2[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][C@@H:16]2[F:26])([CH3:14])[C@@H:12]([OH:27])[CH2:11][CH2:10]1.[I-:28].[Na+].O>C(C(C)=O)C>[F:26][C@H:16]1[CH2:15][C@@:13]2([CH3:14])[C@@H:9]([CH2:10][CH2:11][C@@H:12]2[OH:27])[C@H:8]2[C@H:17]1[C:18]1[CH:19]=[CH:20][C:21]([OH:25])=[CH:22][C:23]=1[CH2:24][C@H:7]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][I:28]
Reactant: [I-]
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCl)[C@H]3[C@@H]1CC[C@@H]2O
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: O
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCI)[C@H]3[C@@H]1CC[C@@H]2O
Temperature: 90 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
4.29 g of 7α-(5-chloropentyl)-11β-fluor-estra-1,3,5(10)-triene-3,17β-diol is dissolved in 60 ml of ethylmethylketone, mixed with 4.91 g of sodium iodide and stirred overnight at 90° C. For working-up, the reaction mixture is cooled to room temperature, stirred into water, extracted 3 times with ethyl acetate, washed with thiosulfate solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. 5.16 g of 11β-fluor-7α-(5-iodopentyl)-estra-1,3,5(10)-triene-3,17β-diol is obtained as a crude product, which is used without further purification in the next stage.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([O:13]C)=[O:12])=[N:3]1.[OH-].[Na+].Cl>CO.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=[O:12])=[N:3]1
Reactant: COC(=O)c1nn(C)c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1nc(C(=O)O)c2ccccc21
Yield: 92 %

Procedure:
A solution of 1-methylindazole-3-carboxylic acid, methyl ester (1.00 g, 0.0053 mole; was stirred in a mixture of methanol (10 ml)/2N NaOH solution (120 ml) at reflux temperature for 2 hours. After cooling, the mixture was diluted with water (100 ml) and acidified with 6N HCl solution. The white solid that formed was collected by filtration and dried under ambient conditions for 6 days to give 0.86 g (92% yield) of the product; mp 215°-216° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH2:10])=[O:4]>C(CC(OC)=O)#N>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][C:3](=[O:2])[CH2:5][C:9]#[N:10])=[O:4]
Reactant: COC(=O)c1sccc1N
Agent: COC(=O)CC#N
Product: COC(=O)c1sccc1NC(=O)CC#N
Yield: 100.3 %

Procedure:
A solution of methyl-3-amino-thiophene-2-carboxylate (13 g, 82.70 mmol) in neat methyl cyanoacetate (40 mL) was heated at 210° C. for 10 h. The solution was cooled and excess methyl cyanoacetate was distilled off under vacuum. The residue was taken in methanol, sonicated briefly, and filtered. The solids were washed by cold methanol and dried to yield 9.3 g (50%) of 3-(2-cyano-acetylamino)-thiophene-2-carboxylic acid methyl ester as white solids. MP 146° C.; 1H NMR (400 MHz, DMSO-d6) δ 4.18 (s, 2H), 7.86 (d, J=5.2 Hz, 1H), 7.93 (d, J=5.2 Hz, 1H), 10.25 (s, 1H) ppm; MS m/z=225 amu (M++1).
Reaction SMILES: Br[CH2:2][N:3]1[C:7](=[O:8])[C:6]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]2[C:4]1=[O:13].[P:14]([O:19]C)([O:17][CH3:18])[O:15][CH3:16].BrCCN1C(=O)C2=CC=CC=C2C1=O.P(OCC)(OCC)OCC>>[C:7]1(=[O:8])[N:3]([CH2:2][P:14](=[O:19])([O:17][CH3:18])[O:15][CH3:16])[C:4](=[O:13])[C:5]2=[CH:12][CH:11]=[CH:10][CH:9]=[C:6]12
Reactant: COP(OC)OC
Reactant: O=C1c2ccccc2C(=O)N1CBr
Agent: CCOP(OCC)OCC
Agent: O=C1c2ccccc2C(=O)N1CCBr
Product: COP(=O)(CN1C(=O)c2ccccc2C1=O)OC

Procedure:
Reaction of N-bromomethylphthalimide with trimethyl phosphite as described in Example 18 for N-(2-bromoethyl)phthalimide and triethyl phosphite gives dimethyl phthalimidomethylphosphonate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:26][CH2:25][C:15]3([O:20][CH2:19][C:18](=[O:21])[N:17]([CH:22]4[CH2:24][CH2:23]4)[CH2:16]3)[CH2:14][CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:44]=[C:43]3[C:38]([CH:39]=[CH:40][CH:41]=[N:42]3)=[CH:37][CH:36]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:22]1([N:17]2[CH2:16][C:15]3([CH2:25][CH2:26][N:12]([CH:8]([C:5]4[CH:6]=[CH:7][C:2]([C:35]5[CH:44]=[C:43]6[C:38]([CH:39]=[CH:40][CH:41]=[N:42]6)=[CH:37][CH:36]=5)=[CH:3][CH:4]=4)[C:9](=[O:11])[CH3:10])[CH2:13][CH2:14]3)[O:20][CH2:19][C:18]2=[O:21])[CH2:24][CH2:23]1
Reactant: CC1(C)OB(c2ccc3cccnc3c2)OC1(C)C
Reactant: CC(=O)C(c1ccc(Br)cc1)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)C(c1ccc(-c2ccc3cccnc3c2)cc1)N1CCC2(CC1)CN(C1CC1)C(=O)CO2

Procedure:
A solution of the crude 9-(1-(4-bromophenyl)-2-oxopropyl)-4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one from Example 24b in 1,4-dioxane (1.5 mL) was treated with 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (0.245 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.0113 mmol), and 2M aq potassium carbonate (0.668 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture irradiated in a Biotage
Reaction SMILES: C([CH2:3][CH2:4][NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[CH:8][C:7]=1[CH3:23])#N.Cl.[C:25]([O-:28])(O)=[O:26].[Na+]>[OH-].[Na+]>[C:25]([CH2:3][CH2:4][NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]([OH:22])([C:14]([F:17])([F:15])[F:16])[C:18]([F:19])([F:20])[F:21])=[CH:8][C:7]=1[CH3:23])([OH:28])=[O:26]
Reactant: O=C([O-])O
Reactant: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1NCCC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1NCCC(=O)O

Procedure:
Combine N-(2-cyanoethyl)-2,6-dimethyl-4-(hexafluoro-2-hydroxy-2-propyl)aniline (4.0 g, 12 mmol) with 350 ml 1.0 N NaOH. Reflux 2 hours, allow to cool, add concentrated HCl, and then solid NaHCO3. Extract with ether, dry and concentrate. Recrystallize from ether-hexane to give title compound as a solid product, m.p. 175°-176° C.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)[CH2:3]1.CCN(CC)CC.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[C:23]([N:7]1[CH2:6][CH2:5][N:4]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH:2]1[CH3:1])(=[O:25])[CH3:24]
Reactant: CC1CN(c2ccc(C=O)cc2)CCN1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2ccc(C=O)cc2)CC1C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 73.1 %

Procedure:
A solution of 4-(3-methylpiperazin-1-yl)benzaldehyde (1.0 g, 4.89 mmol) in methylene chloride (15 mL) was cooled to 0° C. and treated with Et3N (0.68 mL, 4.89 mmol), followed by acetyl chloride (0.34 mL, 4.89 mmol). The resulting solution was stirred at 0° C. for 20 minutes and then concentrated in vacuo. The material was purified by flash chromatography on silica gel, eluting with 0% to 5% of EtOAc/CH2Cl2, to afford 4-(4-acetyl-3-methylpiperazin-1-yl)benzaldehyde (0.88 g, 73%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:19]([N:21]=[C:22]=NCCCN(C)C)C.CN(CCCN=C=NCC)C.ON1C2C=CC=CC=2N=N1.CNC>CN(C)C=O>[CH3:19][N:21]([CH3:22])[C:15]([CH2:14][CH2:13][CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:17]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)CCCNC(=O)OCc1ccccc1
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN(C)C(=O)CCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.5 %

Procedure:
4-(Benzyloxycarbonylamino)butyric acid (0.74 g, 3.12 mmol) was dissolved in N,N-dimethylformamide, then 1-(dimethylaminopropyl)-3-ethylcarbodiimide 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.60 g, 3.13 mmol), 1-hydroxybenzotriazole (0.48 g, 3.13 mmol) and dimethylamine (2.0 M tetrahydrofuran solution, 2.40 ml, 4.80 mmol) were added, followed by stirring at room temperature for 3 days. The reaction liquid was concentrated under reduced pressure, diluted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=70:1 to 40:1) to obtain a yellow solid (0.68 g, 82%).
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([S:14]([NH2:16])=[O:15])([CH3:13])[CH3:12]>C(Cl)Cl.S([O-])([O-])(=O)=O.[Cu+2]>[I:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[N:16]/[S:14]([C:11]([CH3:13])([CH3:12])[CH3:10])=[O:15])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(I)cc1
Reactant: CC(C)(C)S(N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)S(=O)/N=C/c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 4-(iodo)benzaldehyde (2.00 g, 8.62 mmol) (BioNet Research) in DCM (20 mL) was added 2-methylpropane-2-sulfinamide (2.09 g, 17.2 mmol) (AK Scientific) and copper (II) sulfate (2.75 g, 17.2 mmol) (Fluka). The suspension was stirred at rt under N2 for 17 h. The suspension was then filtered through Celite® brand filter agent, and the solids were washed with DCM (2×20 mL). The filtrates were concentrated and purified by ISCO (80 g, SiO2, 0-100% EtOAc/hexanes) to give the title compound as a yellow solid.