Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]([NH2:17])=[O:16])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([C:18](N(OC)C)=[O:19])[CH2:8][C:9]=1[NH:10]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>C1COCC1>[Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]([NH2:17])=[O:16])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([CH:18]=[O:19])[CH2:8][C:9]=1[NH:10]2
Reactant: CON(C)C(=O)C1CCc2c([nH]c3c(C(N)=O)ccc(Br)c23)C1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: NC(=O)c1ccc(Br)c2c3c([nH]c12)CC(C=O)CC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.6 %

Procedure:
Step 2 A suspension of 5-bromo-N2-methoxy-N2-methyl-2,3,4,9-tetrahydro-1H-carbazole-2,8-dicarboxamide (1.73 g, 4.55 mmol) in THF (40 mL) was treated with lithium aluminum hydride (0.259 g, 6.82 mmol) portionwise over 30 min at 0° C. After 20 min, more lithium aluminum hydride (120 mg) was added portionwise, and the mixture was stirred at rt for 20 min. The reaction mixture was cooled to 0° C. and treated dropwise with 0.5 M hydrochloric acid, and the resulting mixture was extracted three times with DCM. The combined organic phases were washed with NaHCO3 (aq) and water, dried and concentrated to provide 5-bromo-2-formyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide as a yellow solid (1.31 g, 90%), used without further purification. Mass spectrum m/z 321, 323 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4](Cl)=[O:5].[CH2:12]([NH:14][CH2:15][C:16]([CH2:22][NH:23][C:24]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]2[C:25]=1[CH:26]=[N:27][N:28]2[C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)([OH:21])[C:17]([F:20])([F:19])[F:18])[CH3:13]>>[CH2:12]([N:14]([CH2:15][C:16]([CH2:22][NH:23][C:24]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]2[C:25]=1[CH:26]=[N:27][N:28]2[C:34]1[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=1)([OH:21])[C:17]([F:19])([F:20])[F:18])[C:4](=[O:5])[C:3]1[C:2]([CH3:1])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:11])[CH3:13]
Reactant: CCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Reactant: Cc1cccc(C)c1C(=O)Cl
Product: CCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1c(C)cccc1C

Procedure:
Prepared similarly to Example 48 from 2,6-dimethylbenzoyl chloride and 3-(ethylamino)-1,1,1-trifluoro-2-({[1-(4-fluorophenyl)-6-methyl-1H-indazol-4-yl]amino}methyl)-2-propanol.
Reaction SMILES: C1(C(=[N:14][CH:15]([CH2:23][CH2:24][C:25]([F:28])([F:27])[F:26])[C:16]([O:18]C(C)(C)C)=[O:17])C2C=CC=CC=2)C=CC=CC=1.[ClH:29]>>[ClH:29].[NH2:14][CH:15]([CH2:23][CH2:24][C:25]([F:26])([F:27])[F:28])[C:16]([OH:18])=[O:17]
Reactant: CC(C)(C)OC(=O)C(CCC(F)(F)F)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Product: NC(CCC(F)(F)F)C(=O)O
Temperature: 100 °C
Yield: 90 %

Procedure:
A stirred solution of tert-butyl 2-((diphenylmethylene)amino)-5,5,5-trifluoropentanoate (800 mg, 2.023 mmol) in 50% aqueous hydrochloric acid (0.123 mL, 2.023 mmol) was heated to reflux at 100° C. for 8 h. The reaction mixture was cooled to rt and washed with ethyl acetate (10 mL). The aqueous layer was concentrated under reduced pressure to afford 2-amino-5,5,5-trifluoropentanoic acid hydrochloride (400 mg, 1.82 mmol, 90% yield) as white solid. LCMS (ESI) m/e 171.7 [(M+H)+, calcd for C5H7F3O2, 172.1]; LC/MS retention time (method H): tR=0.80 min.
Reaction SMILES: Cl[C:2]1[N:10]([CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C:9]2[C:8](=[O:16])[N:7]([CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:6](=[O:25])[N:5]([CH2:26][O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[C:4]=2[N:3]=1.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].C12CCCCC1CCCNN=2>CN1CCCC1=O>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][N:44]([C:2]2[N:10]([CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C:9]3[C:8](=[O:16])[N:7]([CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:22])[CH3:23])[C:6](=[O:25])[N:5]([CH2:26][O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[C:4]=3[N:3]=2)[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)=CCn1c(Cl)nc2c1c(=O)n(COC(=O)C(C)(C)C)c(=O)n2COC(=O)C(C)(C)C
Agent: C1CCC2CCCNN=C2C1
Solvent: CN1CCCC1=O
Product: CC(C)=CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(COC(=O)C(C)(C)C)c(=O)n2COC(=O)C(C)(C)C
Temperature: 150 °C
Reaction time: 6.5 h
Yield: 45 %

Procedure:
2,2-Dimethylpropionic acid [8-chloro-3-(2,2-dimethylpropionyloxymethyl)-7-(3-methylbut-2-enyl)-2,6-dioxo-2,3,6,7-tetrahydropurin-1-yl]methyl ester (470 mg) and 1-piperazinecarboxylic acid tert-butyl ester (218 mg) were dissolved in N-methylpyrrolidone (4 ml), and diazabicyclo[5.4.0]undecene (160 μl) was added to the solution. The mixture was stirred at 150° C. for 6.5 hours. The reaction mixture was filtered through Celite, diluted with chloroform, washed with water, and dried over anhydrous magnesium sulfate. After the solvent was removed by distillation from the organic layer, the residue was purified by silica gel column chromatography to give 277 mg of the title compound from the elution fraction of hexane-ethyl acetate (2:1)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O:25][C:26](=[O:37])[CH2:27][S:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:30]=1[CH3:36])C.CC(C)(C(=O)CC(=O)C(C)(C)C)C.C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Na+]>CN1C(=O)CCC1.CO.[Cu]Cl>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][C:4]2[CH:3]=[C:2]([CH:22]=[CH:21][CH:20]=2)[O:35][C:32]2[CH:33]=[CH:34][C:29]([S:28][CH2:27][C:26]([OH:37])=[O:25])=[C:30]([CH3:36])[CH:31]=2)=[C:7]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1
Reactant: CCOC(=O)CSc1ccc(O)cc1C
Reactant: Clc1ccc(Oc2cccc(Br)c2)c(Oc2ccccc2)c1
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cc1cc(Oc2cccc(Oc3ccc(Cl)cc3Oc3ccccc3)c2)ccc1SCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
A solution of 1-(3-bromo-phenoxy)-4-chloro-2-phenoxy-benzene (0.15 g, 0.4 mmol), (4-hydroxy-2-methyl-phenylsulfanyl)-acetic acid ethyl ester (99 mg, 0.44 mmol), copper(I) chloride (20 mg, 0.2 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (0.02 mL, 0.1 mmol), and cesium carbonate (156 mg, 0.48 mmol) in NMP (3 mL) is heated to 120° C. The reaction is stirred overnight and cooled to rt. The reaction is quenched with 1N aqueous HCl and extracted with ethyl ether. The organic is washed with brine, dried over sodium sulfate, and filtered. The solvent is removed to afford the crude ester intermediate. The intermediate is treated with 5N NaOH (0.4 mL, 2.2 mmol) in MeOH (5 mL) and heated to reflux. The reaction is stirred at reflux for 2 hours and then cooled. The reaction is quenched with 1N aqueous HCl to give pH=4. The aqueous layer is extracted with ethyl ether. The organic layer is washed with brine, dried over sodium sulfate, and filtered. The solvent is removed to afford the crude product. The crude is purified by prep HPLC to afford 78 mg (40%) of desired product. 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C27H21ClO5S 492, found 493 and 495 (M+1 and M+3, 100%).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:38])[C:22]([C:24]4[N:25]=[C:26]([NH:29]C(OC(CC)(C)C)=O)[S:27][CH:28]=4)=[O:23])[C:18](=[O:39])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:4][N:3]=1>C(O)=O>[CH3:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:38])[C:22]([C:24]4[N:25]=[C:26]([NH2:29])[S:27][CH:28]=4)=[O:23])[C:18](=[O:39])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:4][N:3]=1
Reactant: CCC(C)(C)OC(=O)Nc1nc(C(=O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnc(C)s4)CS[C@H]23)cs1
Agent: CCC(C)(C)OC(=O)N=c1[nH]c(C(=O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnc(C)s4)CS[C@H]23)cs1
Solvent: O=CO
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)C(=O)c4csc(N)n4)[C@H]3SC2)s1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
A solution of 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, (8.56 g.) in formic acid (180 ml.) was stirred for 5.5 hours at room temperature. After the reaction, the reaction mixture was post-treated in the similar manners as in Examples 16 to 17 to give 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-(2-amino-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, (2.6 g.), mp. 156° to 160° C. (dec.).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[N:3]1.[NH2:10][C:11]1[N:16]=[CH:15][C:14]2[C:17]([CH3:25])([CH3:24])[C:18](=[O:23])[N:19]([CH:20]3[CH2:22][CH2:21]3)[C:13]=2[CH:12]=1>>[CH:20]1([N:19]2[C:13]3[CH:12]=[C:11]([NH:10][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=4)=[O:9])[N:16]=[CH:15][C:14]=3[C:17]([CH3:24])([CH3:25])[C:18]2=[O:23])[CH2:22][CH2:21]1
Reactant: CC1(C)C(=O)N(C2CC2)c2cc(N)ncc21
Reactant: Cn1nccc1C(=O)O
Product: Cn1nccc1C(=O)Nc1cc2c(cn1)C(C)(C)C(=O)N2C1CC1

Procedure:
Prepared in analogy to example 26 from 1-methyl-1H-pyrazole-5-carboxylic acid and 6-amino-1-cyclopropyl-3,3-dimethyl-1H-pyrrolo[3,2-c]pyridin-2(3H)-one (example 79c). The title compound was obtained as white foam.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[C:17]([N:25]=[C:26]=[O:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[C:17]([NH:25][C:26]([NH:16][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:3]2[N:4]([CH3:7])[N:5]=[CH:6][C:2]=2[Br:1])[CH:9]=1)=[O:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)NC(=O)c2ccccc2)cc1-c1c(Br)cnn1C
Yield: 66.7 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.033 g, 0.12 mmol) was treated with benzoyl isocyanate (0.020 g, 0.12 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.2 to afford Compound 73 (0.036 g, 0.08 mmol, 72%) as a white solid. LCMS m/z (%)=429 (M+H79Br, 99), 431 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 10.92 (s, 1H), 9.85 (s, 1H), 8.12 (d, J=7.4 Hz, 2H), 7.76 (dd, J=2.6, 9.0 Hz, 1H), 7.68 (t, J=7.3 Hz, 1H), 7.62 (d, J=2.6 Hz, 1H), 7.57 (t, J=7.8 Hz, 2H), 7.51 (s, 1H), 7.21 (d, J=9.0 Hz, 1H), 3.86 (s, 3H), 3.71 (s, 3H).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=O.S(Cl)(Cl)=O.Cl.NC(CS)C[N:18]1[C:24]2[CH:25]=[CH:26][C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:28][C:23]=2[CH2:22][N:21]([C:35]([C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=[CH:39][CH:38]=2)=[O:36])[CH2:20][CH2:19]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.N1C=CC=CC=1>[C:37]1([C:35]([N:21]2[CH2:22][C:23]3[CH:28]=[C:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:26]=[CH:25][C:24]=3[N:18]([C:7]([CH:2]3[CH2:3][CH2:4][C:5](=[O:6])[NH:1]3)=[O:9])[CH2:19][CH2:20]2)=[O:36])[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: NC(CS)CN1CCN(C(=O)c2cccc3ccccc23)Cc2cc(-c3ccccc3)ccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: O=C1CCC(C(=O)N2CCN(C(=O)c3cccc4ccccc34)Cc3cc(-c4ccccc4)ccc32)N1
Reaction time: 2 h
Yield: 28.9 %

Procedure:
To a stirred solution of pyroglutamic acid (400 mg, 3.1 mmol) in methylene chloride (6 mL), was added thionyl chloride (4 mL) along with a drop of pyridine at room temperature. The reaction mixture was allowed to stir for 2 h and concentrated. The residue was dissolved in 2 mL methylene chloride. To this stirred solution, was added the compound E of Example 2 (40 mg, 0.106 mmol) and diisopropylethylamine (0.5 mL, 3 mmol) in methylene chloride (5 mL). The mixture was allowed to stir for 16 h, and concentrated. The residue was dissolved in ethyl acetate (50 mL). The resultant solution was washed successively with 1N aqueous potassium bisulfate, saturated aqueous sodium bicarbonate and brine. The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by preparative HPLC (aqueous methanol with 0.1% TFA) to give 15 mg of the title compound as a white solid. MS (M+NH4): 507.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][N:4]=1.Br[C:14]1[O:18][C:17]([C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[C:22]#[N:23])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.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>[C:9]([C:6]1[CH:7]=[CH:8][C:3]([C:14]2[O:18][C:17]([C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22]#[N:23])=[CH:16][CH:15]=2)=[N:4][CH:5]=1)#[N:10]
Reactant: C[Sn](C)(C)c1ccc(C#N)cn1
Reactant: N#Cc1cccc(-c2ccc(Br)o2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-c2ccc(-c3cccc(C#N)c3)o2)nc1
Temperature: 110 °C
Reaction time: 15 h
Yield: 23 %

Procedure:
In a similar fashion, Pd(PPh3)4 (10 Mg, 0.009 mmol) was added to a solution of 2-trimethylstannyl-5-cyano-pyridine (22.7 mg, 0.085 mmol) and 3-(5-bromofuran-2-yl)-benzonitrile (31 mg, 0.125 mmol) in toluene (1 mL) under argon. The resulting solution was stirred at 110° C. for 15 h. After cooling to room temperature, the solvent was removed in vacuo. Chromatography (5g silica gel SPE tube, 50% chloroform in hexane to 20% ethyl acetate in 1:1 chloroform:hexane) followed by triturating with 50% dichloromethane in hexane afforded 5.3 mg (23%) of 3-(5-(5-cyano-2-pyridyl)-2-furyl)-benzonitrile (91% pure by GC/MS, contaminated by 9% dimer). 1H-NMR (CDCl3), δ (ppm): 8.85 (s, 1H), 7.87-8.05 (m, 5H), 7.52-7.63 (m, 3H), 7.36 (d, 1H), 6.95 (d, 1H), dimer impurity caused peak intensity to increase in region 8.00, 7.92, 7.49-7.57, plus 2 peaks additional peaks exactly overlapping with pure dimer @ δ (ppm): 6.87 (d) & 6.80 (d).
Reaction SMILES: C[Al](C)C.[CH2:5]([NH:8][CH2:9][CH2:10][CH3:11])[CH2:6][CH3:7].[Cl:12][C:13]1[CH:33]=[CH:32][C:16]2[C:17](=[O:31])[C:18]3[C:25]([C:26]([O:28]CC)=O)=[N:24][NH:23][C:19]=3[C:20](=[O:22])[NH:21][C:15]=2[CH:14]=1>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:33]=[CH:32][C:16]2[C:17](=[O:31])[C:18]3[C:25]([C:26](=[O:28])[N:8]([CH2:9][CH2:10][CH3:11])[CH2:5][CH2:6][CH3:7])=[N:24][NH:23][C:19]=3[C:20](=[O:22])[NH:21][C:15]=2[CH:14]=1
Reactant: CCOC(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Reactant: CCCNCCC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CCCN(CCC)C(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Reaction time: 45 h
Yield: 31 %

Procedure:
To a solution of trimethylaluminum in toluene (4.68 mL 9.38 mmol) was added dipropylamine (1.29 mL, 9.38 mmol) and the solution was stirred for 45 hours. A portion (1.9 30 mL) of this solution was added to a solution of 7-chloro-3-(ethoxycarbonyl)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (500 mg, 1.56 mmol) in toluene (2 mL). Additional toluene (7 mL) was added. The solution was stirred for 70 minutes at room temperature and then quenched with 1N hydrochloric acid (9.3 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organics were washed with 1N hydrochloric acid and water (25 mL) and concentrated by rotary evaporation. The crude residue was purified by chromatography eluting with hexanes:ethyl acetate (95:5-50:50) to give the title compound (31% yield, m.p. 270° C.).
Reaction SMILES: [OH:1][CH:2]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([O:30]C)=[O:29])[CH:23]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6](/[CH:10]=[CH:11]/[CH:12]([OH:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[N:5]=1.[OH-].[Na+]>CO>[OH:1][CH:2]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([OH:30])=[O:29])[CH:23]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6](/[CH:10]=[CH:11]/[CH:12]([OH:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[N:5]=1
Reactant: CCCCCCCCC(O)/C=C/c1cccc(CC(O)c2cccc(C(=O)OC)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCC(O)/C=C/c1cccc(CC(O)c2cccc(C(=O)O)c2)n1
Yield: 62 %

Procedure:
Under the conditions of example 2, 30 mg of 2-[(2RS)-2-hydroxy-2-(3-methoxycarbonylphenyl)-ethyl]-6-[(1E)-(3RS)-3-hydroxy-1-undecenyl]-pyridine in 2 ml of methanol is saponified with 1 ml of 1 n sodium hydroxide solution and worked up. 18 mg of the title compound is obtained as oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[C:6]([C:7](OC)=[O:8])=[CH:5][N:4]=1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([CH2:7][OH:8])=[C:11]([C:13]([F:16])([F:14])[F:15])[CH:12]=1
Reactant: COC(=O)c1cnc(OC)cc1C(F)(F)F
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: COc1cc(C(F)(F)F)c(CO)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 78.7 %

Procedure:
To a cooled (−78° C.) solution of methyl 6-methoxy-4-trifluoromethylnicotinate (300 mg, 1.35 mmol) in toluene (10 mL) was added diisobutylaluminum hydride (DIBAL, 1 M/toluene, 1.35 mL). The mixture was warmed slowly to room temperature and stirred for 2 days. Additional DIBAL (1 M/toluene, 2 mL) was added to complete the reaction. After stirring for 4 hours, the mixture was quenched with saturated aqueous ammonium chloride solution (1 mL), dried over anhydrous magnesium sulfate, filtered through a pad of celite, and concentrated under reduced pressure to give 6-methoxy-4-trifluoromethyl-3-pyridinemethanol (220 mg, 78.6%). The crude product was used directly in the following Swern oxidation.
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([CH2:21][O:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H-].[Na+].[CH3:44]I>C1COCC1.O>[CH2:1]([S:17][CH2:18][CH:19]([CH2:21][O:22][C:23]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[O:20][CH3:44])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCSCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCSCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.9 %

Procedure:
A solution of 6.0 grams (0.01 mole) (±)-1-S-hexadecyl-3-O-tritylthioglycerol in 250 milliliters of THF was added to a slurry of 0.4 grams (0.014 mole) 80% NaH (oil dispersion) in 50 milliliters of THF and the reaction mixture stirred at room temperature for one hour. Then 1.4 gram (0.13 mole) of CH3I was added and the reaction allowed to proceed at room temperature for 24 hours. The reaction mixture was then diluted with 300 milliliters of distilled water and extracted twice with 200 milliliter portions of ether. The nonaqueous extracts were combined, dried over anhydrous sodium sulfate, filtered and removed in vacuo to provide 6.0 grams of crude product as an oil. 1H-NMR (CDCl3): delta, 0.7-1.7[m, 31H, (CH2)14CH3 ], 2.3-2.8(m, 4H, CH2 --S--CH2), 3.25(m, 5H, CH3O, CH--CH2 --O), 3.6-4.0(m, 1H, CH), 7.6-7.0[m, 15H, C(C6H5)3 ].
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[C:8]([C:9]([NH2:11])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1.C(N)(=O)C1C(=CC=CC=1)O.Br[CH:25]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26]1>CN(C)C=O.O>[OH2:10].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:13][CH:25]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26]2)=[C:8]([CH:12]=1)[C:9]([NH2:11])=[O:10].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:13][CH:25]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26]2)=[C:8]([CH:12]=1)[C:9]([NH2:11])=[O:10]
Reactant: CN1CCC(Br)C1
Reactant: NC(=O)c1cc(Cl)ccc1O
Agent: NC(=O)c1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCC(Oc2ccc(Cl)cc2C(N)=O)C1
Yield: 34.1 %

Procedure:
To a cooled suspension of 2.4 g (0.41 mole) sodium hydride in 50 ml of dimethylformamide was added dropwise 17 g (0.1 mole) of 5-chlorosalicylamide dissolved in 50 ml of dimethylformamide at a rate such that the temperature did not exceed 20° C. After addition of the salicylamide was complete, 16.7 g (0.1 mole) of 3-bromo-1-methylpyrrolidine dissolved in 50 ml of dimethylformamide was added dropwise. The reaction mixture was stirred and heated at reflux for 19 hr. The cooled solution was diluted with 250 ml of water and extracted twice with 250 ml portions of chloroform. The chloroform was extracted thrice with 500 ml portions of 3N hydrochloric acid. The aqueous extracts were made alkaline with 50% sodium hydroxide and extracted with ethyl acetate. Drying over magnesium sulfate and evaporation of the ethyl acetate under reduced pressure gave 6 g (23%) of product as a beige solid. The solid was recrystallized from ethyl acetate, m.p. 126°-128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[CH:4][C:3]=1[N:14]=[C:15]=[S:16].[NH2:17][C:18]1[CH:19]=[C:20]([CH:31]=[CH:32][C:33]=1[NH:34][CH3:35])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=1)=[O:22]>CN(C=O)C>[C:11]([NH:10][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([NH:14][C:15](=[S:16])[NH:17][C:18]2[CH:19]=[C:20]([CH:31]=[CH:32][C:33]=2[NH:34][CH3:35])[C:21]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([Br:30])=[CH:28][CH:29]=2)=[O:22])[CH:4]=1)[CH3:9])(=[O:13])[CH3:12]
Reactant: CNc1ccc(C(=O)Nc2ccc(Br)cc2)cc1N
Reactant: CC(=O)NC(C)c1ccc(Cl)c(N=C=S)c1
Solvent: CN(C)C=O
Product: CNc1ccc(C(=O)Nc2ccc(Br)cc2)cc1NC(=S)Nc1cc(C(C)NC(C)=O)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[1-(4-Chloro-3-isothiocyanatophenyl)ethyl]acetamide in DMF (2 mL) was added to a mixture of 3-amino-N-(4-bromophenyl)-4-methylaminobenzamide (87 mg, 0.2 mmol, crude material from the step above) in DMF (2 mL) at rt. The mixture was stirred at rt overnight and concentrated. The residue was purified by chromatography to give the sub-title compound. Yield: 130 mg.
Reaction SMILES: C([O-])(=O)/C=C\[C:4]([O-:6])=[O:5].C[O:10][C:11](=[O:39])[C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17](=[O:38])[C@H:18]([CH3:37])[NH:19][C@H:20](OCC)[C:21](=C=O)[S:22][CH:23]1[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24]1>>[C:4]([C@@H:20]([NH:19][C@H:18]([C:17]([N:13]1[CH2:14][CH2:15][CH2:16][C@H:12]1[C:11]([OH:10])=[O:39])=[O:38])[CH3:37])[CH2:21][S:22][CH:23]1[CH2:24][C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:31]1)([OH:6])=[O:5]
Reactant: O=C([O-])/C=C\C(=O)[O-]
Reactant: CCO[C@@H](N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC)C(=C=O)SC1Cc2ccccc2C1
Product: C[C@H](N[C@@H](CSC1Cc2ccccc2C1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
Following the general procedure of Example 59, the title compound was prepared as white crystals from 300 mg of the maleate of β-isomer of N-[(R)-1-ethoxy-carbonyl-2(2-indanyl)thioethyl]-alanyl-(S)-proline methyl ester prepared in Example 58. Yield 165 mg.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:17][CH2:16][N:15]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:14]2=[O:24])=[CH:9][CH:8]=1)=[O:4].Br.C(S[C:29](=[NH:31])[NH2:30])C.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:29]([N:21]1[CH2:22][CH2:23][CH:18]([N:15]2[CH2:16][CH2:17][N:13]([C:10]3[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[CH:8][CH:9]=3)[C:14]2=[O:24])[CH2:19][CH2:20]1)(=[NH:30])[NH2:31]
Reactant: CCSC(=N)N
Reactant: COC(=O)CCc1ccc(N2CCN(C3CCNCC3)C2=O)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(N2CCN(C3CCN(C(=N)N)CC3)C2=O)cc1

Procedure:
Prepared from 1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3-(4-piperidinyl)-imidazolidin-2-one and S-ethylisothiourea-hydrobromide by heating to 100° C. for four hours in dimethylformamide in the presence of sodium carbonate.