Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:13][CH:12]=2)=[C:6]([NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)[CH:5]=1.[Li+].[OH-]>C1COCC1>[C:21]([O:20][C:18]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([S:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:39])=[O:2])=[CH:5][C:6]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:16][CH:15]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(Nc2ncnc3nc(C(C)C)ccc23)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Temperature: 25 °C
Reaction time: 26 h
Yield: 96.9 %

Procedure:
To a solution of 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid methyl ester (3.25 g, 6.0 mmol) in THF (32.5 mL) was added aqueous LiOH [prepared from LiOH monohydrate (1.02 g, 24 mmol) and H2O (10 mL)] dropwise at room temperature. The mixture was stirred at room temperature for 26 hours, and then evaporated. The aqueous mixture was diluted with 100 mL of H2O, washed with AcOEt (50 mL), and then carefully acidified to pH 4-5 with 10% HCl at 5° C. under stirring. The resulting solid was collected by filtration, washed with H2O, and dried at 60° C. overnight under reduced pressure to give the title compound as pale yellow crystal (3.09 g, 98%). 1H-NMR (300 MHz, DMSO-d6) δ ppm: 1.34 (d, J=7.0 Hz, 6H), 1.48 (s, 9H), 3.22 (septet, J=7.0 Hz, 1H), 6.93 (d, J=8.5 Hz, 1H), 7.36 (d, J=8.8 Hz, 2H), 7.54 (d, J=8.8 Hz, 2H), 7.63 (d, J=8.5 Hz, 1H), 7.75 (dd, J=8.5, 1.8 Hz, 1H), 7.89 (d, J=1.8 Hz, 1H), 8.58 (s, 1H), 8.84 (d, J=8.5 Hz, 1H), 9.61 (s, 1H), 10.16 (s, 1H), 12.98 (br-s, 1H)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([CH2:23][CH3:24])[CH:3]=1.[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[CH2:23]([C:4]1[CH:3]=[C:2]([C:28]2[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=2)[CH:7]=[CH:6][C:5]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=2[C:13]=1[CH3:22])(=[O:10])=[O:11])[CH3:24]
Reactant: CCc1cc(Br)ccc1NS(=O)(=O)c1sc2ccc(F)cc2c1C
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CCc1cc(-c2ccncc2)ccc1NS(=O)(=O)c1sc2ccc(F)cc2c1C
Yield: 25.1 %

Procedure:
This product was prepared in analogy to Example 2 starting from 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-ethyl-phenyl)-amide (0.10 g) and 4-pyridineboronic acid (0.043 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0.25 ml) and 2 M aqueous sodium carbonate solution (0.9 ml) with tetrakis(triphenylphosphine)palladium (0.013 g) to obtain the title compound (0.025 g) as a yellowish foam. MS (ISP): 427.3 (M+H)+
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[N:25]=[C:6]2[CH:7]=[C:8]([NH:11][C:12]([C:14]3[N:18]([CH3:19])[N:17]=[CH:16][C:15]=3[C:20]([O:22]CC)=[O:21])=[O:13])[CH:9]=[CH:10][N:5]2[N:4]=1.O.[OH-].[Li+]>CO.O>[CH3:1][N:2]([CH3:26])[C:3]1[N:25]=[C:6]2[CH:7]=[C:8]([NH:11][C:12]([C:14]3[N:18]([CH3:19])[N:17]=[CH:16][C:15]=3[C:20]([OH:22])=[O:21])=[O:13])[CH:9]=[CH:10][N:5]2[N:4]=1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(N(C)C)nc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1
Temperature: 50 °C
Reaction time: 4 h
Yield: 95.4 %

Procedure:
A mixture of ethyl 5-(2-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylate (1.24 g, 3.47 mmol) and lithium hydroxide monohydrate (291 mg, 6.94 mmol) in methanol (20 ml) and water (5 ml) is stirred for 4 hours at 50° C. The solvent is evaporated. The brown oily residue is dissolved in water and acidified to pH=5 with 2N aqueous hydrochloric acid (3.47 ml). The precipitated off-white solid is collected by filtration, dissolved in methanol and evaporated affording 5-(2-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (1.09 g, 95.3%) as an off-white solid. Mp.: >250° C. MS: m/z=328.0 (M−H+).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:18]=[CH:17][C:12]2[C:13](Cl)=[N:14][S:15][C:11]=2[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:20][CH2:21][CH2:22][CH2:23][NH2:24]>>[NH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:13]1[C:12]2[CH:17]=[CH:18][C:9]([S:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:8])=[O:7])=[CH:10][C:11]=2[S:15][N:14]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc2c(Cl)nsc2c1
Reactant: NCCCN
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1ccc2c(NCCCN)nsc2c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of N-tert-butyl-3-chlorobenzo[d]isothiazole-6-sulfonamide (278 mg, 0.9 mmol) in 1,3-diaminopropane (1 mL) was allowed to stir at room temperature for 3.5 h. The reaction mixture was then poured over water (10 mL), extracted with ethyl acetate and the combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give, upon trituration with ethyl ether, 3-(3-aminopropylamino)-N-t-butylbenzo[d]isothiazole-6-sulfonamide (242 mg). 1H NMR (300 MHz, CD3OD): 8.54 (dd, 1H), 7.95 (d, 1H), 7.94 (d, 1H), 3.58 (t, 2H), 2.80 (t, 2H), 1.91 (q, 2H), 1.20 ppm (s, 9H). MW=342 confirmed by LC-MS, tr=8.14 min (Method Y) MH+=343.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=2)[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].C[OH:28].[OH-].[Na+]>O1CCCC1>[C:14]([O:13][C:11]([N:8]1[CH2:7][CH2:6][C:5]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:28])[NH2:26])=[CH:21][CH:20]=2)([C:3]([OH:2])=[O:4])[CH2:10][CH2:9]1)=[O:12])([CH3:16])([CH3:15])[CH3:17]
Reactant: COC(=O)C1(Cc2ccc(C#N)cc2)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(C(N)=O)cc2)(C(=O)O)CC1

Procedure:
To a solution of 4-(4-cyanobenzyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (23.04 mmol; 8.26 g) (prepared as in Example 1, but substituting 4-cyanobenzylbromide for 4-biphenylmethyl bromide), in tetrahydrofuran (50 mL) and methanol (50 mL) was added an aqueous 1M NaOH solution (46.1 mmol; 46.1 mL), and the resulting solution was heated to reflux for 48 hours. The mixture was then evaporated and an aqueous 1N HCl solution (50 mL) was added, resulting in the formation of a precipitate. The solid was separated via filtration and dried under vacuum to yield 4-(4-carbamoylbenzyl)-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester. MS (ESI) m/z 384.89 [M+Na]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C)(C)C.Cl[CH2:16][CH:17]([OH:21])[CH2:18][CH2:19][Cl:20].[OH-].[Na+]>O>[Cl:20][CH2:19][CH2:18][CH:17]([OH:21])[CH2:16][O:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(O)ccc1Cl
Reactant: OC(CCl)CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1cc(OCC(O)CCCl)ccc1Cl
Temperature: 40 °C
Reaction time: 10 h

Procedure:
To a mixture of 286 g. (2 moles) of 3-methyl-4-chlorophenol, 700 ml. of tertiary butanol, 700 ml. of water and 3.0 moles of 1,4-dichloro-2-butanol, sodium hydroxide (2.9 moles, 230 g. in 700 ml. water) was added with stirring at 40° C. to maintain a pH of 9.5-10.0 as the reaction progressed. The addition was 10 hr.; the reaction was stirred at 40° C. for 48 hr. The resulting reaction mixture was extracted with chloroform sodium hydroxide at 25° C. The chloroform extract was washed with sodium sulfate. The dried chloroform solution was concentrated and the residue was distilled under reduced pressure to give 110.9 g. of the product which distilled at 135°-143° C./0.007 mm. and melted at 87°-89° C. after recrystallization with isopropanol and pet. ether (30.60°)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.Br[CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: CC(C)CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)CCn1c2c(c(=O)n1-c1ccc(F)cc1F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 120 °C
Yield: 27.7 %

Procedure:
A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 600 mg, 1.97 mmol), tetrabutylammonium iodide (770 mg, 2.1 mmol) and 1-bromo-3-methyl-butane (2 mL, 16.7 mmol) in dimethylformamide (6 mL) was heated in an oil-bath at 120° C. for 18 h. The solvent was evaporated and dichloromethane (75 mL) was added. The solution was washed with water (5×20 mL) and aqueous sodium thiosulfate (20 mL), dried (magnesium sulfate), filtered, and evaporated. The residue was purified using an ISCO 40 g column, eluting with 20-90% ethyl acetate/hexanes to give (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1-(3-methyl-butyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (204 mg, 28%) as a white solid. ES(+)-MS (M+H) 375.
Reaction SMILES: [S:1]1[C:8]2[CH:7]=[C:6]([C:9]([OH:11])=[O:10])[NH:5][C:4]=2[CH:3]=[CH:2]1.[CH3:12][Si](C=[N+]=[N-])(C)C>CO>[S:1]1[C:8]2[CH:7]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[NH:5][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(O)c1cc2sccc2[nH]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1cc2sccc2[nH]1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 86 %

Procedure:
4H-thieno[3,2-b]pyrrole-5-carboxylic acid (3.0 g, 17.9 mmol) was dissolved in anhydrous MeOH (50.0 mL) and cooled to 0° C. A solution (45.0 mL, 2 M in hexanes) of trimethylsilyldiazomethane (45 mL) was added in portions and the yellow color of the TMSCH2N2 remained. Stirring was continued for 10 min and then the excess TMSCH2N2 was quenched with acetic acid (5.0 mL). The solvent was removed with N2 stream, and the residue was chromatographed over silica gel (5%-40%, 30 min, EtOAc in heptane) to give methyl 4H-thieno[3,2-b]pyrrole-5-carboxylate (2.8 g, 86% yield). 1H NMR (400 MHz, CD3Cl) δ ppm 3.90 (s, 3H) 6.95 (dd, J=5.32, 0.78 Hz, 1H) 7.13 (dd, J=1.88, 0.76 Hz, 1H) 7.33 (d, J=5.37 Hz, 1H) 9.02 (br. s, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:32]=[CH:31][NH:30][C:29](=[O:33])[CH:28]=7)=[C:24]([C:34]([NH:36][CH3:37])=[O:35])[C:23]=6[CH:38]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1.[C:45]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:32]=[CH:31][N:30]([CH3:45])[C:29](=[O:33])[CH:28]=7)=[C:24]([C:34]([NH:36][CH3:37])=[O:35])[C:23]=6[CH:38]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CNC(=O)c1c(-c2cc[nH]c(=O)c2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccn(C)c(=O)c2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.1 %

Procedure:
To a suspension of 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)-2-(2-oxo-1,2-dihydropyridin-4-yl)benzofuran-3-carboxamide (20 mg, 0.03 mmol) and K2CO3 (10 mg, 0.06 mmol) in DMF (1 mL) was added CH3I (5 mg, 0.03 mol) at 0° C. under N2, and then the mixture was stirred for 12 hours at room temperature. After being concentrated in vacuo, the resulting residue was suspended in H2O and extracted with DCM. The combined organic layer was washed with H2O and dried over Na2SO4. After concentration, the residue was purified by prep-HPLC to give the product of 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-N-methyl-2-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (10 mg, yield: 49%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.7˜28.74 (m, 1H), 8.10 (s, 1H), 7.84˜7.86 (m, 2H), 7.70˜7.72 (m, 1H), 7.59˜7.62 (m, 1H), 7.50˜7.53 (m, 1H), 7.24˜7.28 (m, 1H), 7.23 (s, 1H), 6.96˜7.09 (m, 2H), 6.67˜6.91 (m, 1H), 6.27 (s, 2H), 3.48 (s, 3H), 3.31 (s, 3H), 2.97 (s, 3H), 2.85 (d, J=4.4 Hz, 3H). MS (M+H)+: 628.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][C@@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.C([O:33][CH2:34][C:35](Cl)=[O:36])(=O)C>C(Cl)Cl.C(N(C(C)C)CC)(C)C>[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][C@@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[C:34](=[O:33])[CH2:35][OH:36])[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1C(=O)CO
Temperature: 4 °C
Reaction time: 2 h
Yield: 38.1 %

Procedure:
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(2S)-pyrrolidin-2-ylmethoxy]quinazoline hydrochloride (0.25 g, 0.57 mmole; prepared as described in Example 31-starting materials) was dissolved in a mixture of methylene chloride (5 ml) and diisopropylethylamine (0.3 ml). The solution was cooled in an ice/water bath to 4° C. and acetoxyacetyl chloride (0.064 ml, 0.6 mmol) added. The reaction mixture was stirred cold for two hours and then partitioned between methylene chloride and saturated aqueous NaHCO3. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and evaporated. The residue was dissolved in methanol (5 ml) containing anhydrous powdered potassium carbonate (0.2 g). After stirring overnight the solvent was evaporated and the residue purified by column chromatography eluting with methylene chloride/isopropanol (96/4)(containing 0.5% triethylamine). The fractions containing the expected product were evaporated and the residue was triturated with diethylether to give the title product as a white solid (0.1 g, 38%); 1H NMR Spectrum: (CDCl3) 1.95-2.29 (m, 4H); 3.29 (m, 1H); 3.46 (m, 2H); 4.03 (s, 3H); 4.07-4.18 (m, 3H); 4.55 (d, 1H); 4.69 (t, 1H); 7.13-7.16 (m, 2H); 7.26 (s, 1H); 8.26 (m, 1H); 8.35 (s, 1H); 8.48 (s, 1H); 8.66 (s, 1H); Mass Spectrum: (M+H)+ 461.
Reaction SMILES: O[CH:2]1[O:26][C:10]2=[CH:11][C:12]([O:14][CH:15]([CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:16])=[CH:13][C:8]3=[C:9]2[CH:4]([CH2:5][C:6]([CH3:28])([CH3:27])[O:7]3)[CH2:3]1.C(O)C.[CH3:32][O:33][NH2:34]>N1C=CC=CC=1>[CH3:32][O:33][NH:34][CH:2]1[O:26][C:10]2=[CH:11][C:12]([O:14][CH:15]([CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:16])=[CH:13][C:8]3=[C:9]2[CH:4]([CH2:5][C:6]([CH3:27])([CH3:28])[O:7]3)[CH2:3]1
Reactant: CC(CCCc1ccccc1)Oc1cc2c3c(c1)OC(C)(C)CC3CC(O)O2
Reactant: CON
Solvent: CCO
Solvent: c1ccncc1
Product: CONC1CC2CC(C)(C)Oc3cc(OC(C)CCCc4ccccc4)cc(c32)O1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 102.6 %

Procedure:
In a stirred flask, under nitrogen, was placed (0.045 mole) 2-hydroxy-5,5-dimethyl-8-(5-phenyl-2-pentyloxy)-3,3a,4,5-tetrahydro-2H-pyrano[4,3,2-de]benzopyran, 250 ml ethanol and 250 ml pyridine. The solution was cooled to 0° C. and 3.94 g (0.047 mole) methoxyamine was added. The resulting mixture was stirred at 0° C. for 2.5 hours, the solvent evaporated in vacuo, the residue taken up in 500 ml ethyl ether and washed twice with water. The aqueous phase was backwashed with ether and the combined ether layers washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo to obtain 19 g of residual oil. The structure of the product was verified by 1H-NMR. Mass spectrum (m/e): 411 (M+), 380 (M-OCH3), 364 (M-NH2OCH3).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@H:11]3[C@@H:15]4[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]4[C@@H:13]([CH2:21]O)[CH2:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1C=CC(OP(OC2C=CC=CC=2)([N:65]=[N+:66]=[N-:67])=O)=CC=1>C1COCC1>[N:65]([CH2:21][C@@H:13]1[C@H:14]2[O:18][C:17]([CH3:19])([CH3:20])[O:16][C@H:15]2[C@H:11]([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=3[CH:10]=[CH:9]2)[CH2:12]1)=[N+:66]=[N-:67]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](n3ccc4c(Cl)ncnc43)[C@@H]2O1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2[C@@H](CN=[N+]=[N-])C[C@@H](n3ccc4c(Cl)ncnc43)[C@@H]2O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.6 %

Procedure:
((3aR,4R,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol (2.68 g, 8.28 mmol) was dissolved in THF (32 mL), treated with PPh3 (3.05 g, 11.6 mmol), and the reaction vessel was cooled in an ice-brine bath. Diisopropyl azodicarboxylate [DIAD] (2.3 mL, 12 mmol) was added dropwise via syringe and the mixture was stirred for 10 min. A solution of diphenylphosphonic azide [DPPA] (2.50 mL, 11.6 mmol) in THF (7.8 mL) was added dropwise via syringe to afford a off-white mixture, which was stirred for 21 h, allowing the ice bath to warm to rt; HPLC/LC MS indicated complete consumption of starting material and formation of product. At 22.5 h the reaction mixture was concentrated in vacuo and purified by column chromatography (4×22 cm silica; 0-25% EtOAc/Hex) to afford the title compound (2.27 g, 78%) as a clear, colorless oil: MS (ESI+) for C15H17ClN6O2 m/z 349.2 (M+H)+; MS (ESI−) for C15H17ClN6O2 m/z 393.2 (M+HCO2)−; HPLC purity>95% (ret. time, 4.169 min).
Reaction SMILES: [I:1][C:2]1[C:10]([I:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].B#B>O1CCCC1>[I:1][C:2]1[C:10]([I:11])=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1cccc(I)c1I
Agent: B#B
Solvent: C1CCOC1
Product: OCc1cccc(I)c1I

Procedure:
2,3-Diiodobenzoic acid is treated with diborane in tetrahydrofuran to give 2,3-diiodobenzyl alcohol which is oxidized to 2,3-diiodobenzaldehyde with activated manganese dioxide in methylene chloride.
Reaction SMILES: Br[CH:2]([C:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:18][C:19]([NH2:21])=[S:20]>C(O)C>[NH2:21][C:19]1[S:20][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[N:18]=1
Reactant: CCOC(=O)C(Br)C(=O)c1ccc(Cl)cc1Cl
Reactant: NC(N)=S
Solvent: CCO
Product: CCOC(=O)c1sc(N)nc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of ethyl 2-bromo-3-(2,4-dichlorophenyl)-3-oxopropanoate (5.14 g, 15.1 mmol) in ethanol (90 mL) was added thiourea (1.26 g, 16.6 mmol) and the solution was stirred at reflux for 2 hours. The reaction was allowed to cool to room temperature, then the solvent was evaporated in vacuo. Column chromatography was performed to yield the title compound (4.79 g, 99%). LCMS: (AA) ES+, 319. 1H NMR (300 MHz, d1-chloroform) δ: 8.11 (br s, 2H), 7.52-7.33 (m, 3H), 4.24-4.16 (m, 2H), 1.23-1.17 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[O:17])[CH:11]=[CH:12][C:13]=1[OH:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:47][CH2:48][N:49]1[CH2:53][CH2:52][CH2:51][CH2:50]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[O:17])[CH:11]=[CH:12][C:13]=1[O:14][CH2:47][CH2:48][N:49]1[CH2:53][CH2:52][CH2:51][CH2:50]1
Reactant: OCCN1CCCC1
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)Nc2ccc(F)cc2F)ccc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)Nc2ccc(F)cc2F)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
To a solution of 1-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-hydroxy-phenyl]-3-(2,4-difluoro-phenyl)-urea (0.35 g, 0.09 mmol) in anhydrous THF (2 mL), triphenyl phosphine (70.8 mg, 0.27 mmol) and 1-(2-hydroxyethyl)-pyrrolidine (0.032 mL, 0.27 mmol) were added followed by dropwise addition of diisopropyl azodicarboxylate (DIAD) (0.052 mL, 0.27 mmol). The reaction mixture was stirred at room temperature for 2 hours, concentrated to give a crude product that was subjected to purification by preparative HPLC. The proper fractions were collected, neutralized with 1N NaOH and extracted with EtOAc four times. The solution was evaporated under reduced pressure to afford Compound 13 as an off-white solid in 52.8% yield. LCMS m/z (%)=476 (M+H 35Cl, 100), 478 (M+H 37Cl, 40). 1H NMR (400 MHz, DMSO-d6) δ: 9.10 (s, 1H), 8.55 (s, 1H), 8.17-8.09 (m, 1H), 7.69 (s, 1H), 7.61 (dd, J=8.97 and 2.72 Hz, 1H), 7.47 (d, J=2.70 Hz, 1H), 743-7.36 (m, 1H), 7.26 (d, J=9.04 Hz, 1H), 7.16-7.09 (m, 1H), 4.25-4.08 (m, 2H), 3.73 (s, 3H), 2.58-2.45 (m, 2H), 2.45-2.29 (m, 4H), 1.75-1.69 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10]C)=[O:9])#[N:2].O.[OH-].[Li+].Cl>O1CCCC1.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([OH:10])=[O:9])#[N:2]
Reactant: COC(=O)c1cc(C#N)ccc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C#N)cc1C(=O)O
Yield: 99.1 %

Procedure:
A mixture of Example 25A (6.1 g, 31.9 mmol) and lithium hydroxide monohydrate (5.36 g, 128 mmol) in tetrahydrofuran (100 mL) and H2O (50 mL) was stirred at room temperature for 3 h. The reaction pH was adjusted to pH=3 with 3N HCl, and the mixture was extracted twice with isopropanol/CH2Cl2 (1:3). The organics were combined, dried (MgSO4), filtered and concentrated to afford 5.6 g (99%) of the title compound. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 4.15 (s, 3H) 7.17 (d, J=8.85 Hz, 1H) 7.86 (dd, J=8.85, 2.44 Hz, 1H) 8.47 (d, J=2.14 Hz, 1H).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)#[N:2].C(C1CC([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)(C#N)CCC1=O)(OC)=O.S(=O)(=O)(O)O>C(O)(=O)C>[Cl:28][C:25]1[CH:26]=[CH:27][CH:22]=[CH:23][C:24]=1[C:3]1([C:1]#[N:2])[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1
Reactant: COC(=O)C1CC(C#N)(c2ccc(Cl)cc2)CCC1=O
Reactant: N#CC1CCC(=O)CC1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: N#CC1(c2ccccc2Cl)CCC(=O)CC1
Yield: 80 %

Procedure:
Following the procedure of Example 1, Part C, but substituting 33.4 gm. (0.115 mole) of 2-carbomethoxy-4-chlorophenyl)-4-cyanocyclohexanone (prepared in Part B, above) for the 29.8 gm. of the 2-carbomethoxy-4-(p-chlorophenyl)-4-cyanocyclohexanone, using 730 ml. glacial acetic acid and 365 ml. 10 percent aqueous sulfuric acid instead of the 660 ml. and 330 ml., respectively, and heating for 48 hours instead of 24 hours there is obtained a residual solid that is recrystallized from a mixture of methylene chloride and technical hexane thus affording 20.54 gm. (80% yield) of 4-(o-chlorophenyl)-4-cyanocyclohexanone having a melting point at 106° to 108° C.