Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([C:18]2[N:19]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[C:20]([CH2:23][OH:24])=[N:21][N:22]=2)[N:9]=[N:8]1.O>CS(C)=O>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:38])([F:37])[F:39])[CH:35]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([C:18]2[N:19]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[C:20]([CH:23]=[O:24])=[N:21][N:22]=2)[N:9]=[N:8]1
Reactant: OCc1nnc(-c2nnn(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2-c2ccccc2)n1Cc1ccccc1Cl
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1nnc(-c2nnn(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2-c2ccccc2)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve [5-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-4-(2-chloro-benzyl)-4H-[1,2,4]triazol-3-yl]methanol in DMSO. Add sulfur trioxide pyridine complex (4 eq) and add TEA (10 eq). Stir overnight at RT. Pour into water and extract with CH2Cl2. Purify via silica gel chromatography using a gradient of 4:1 to 1:1 hexanes:EtOAc to give the title compound. MS (IS) 589.0 (M−1). Rf=0.43 (1:1 hexanes:EtOAc)
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23](=[O:35])[NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:26]=4)=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)C>C1COCC1.O>[C:31]([C:27]1[CH:26]=[C:25]([NH:24][C:23]([C:20]2[CH:21]=[CH:22][C:17]([N:14]3[CH2:13][CH2:12][N:11]([C:8]4[CH:7]=[CH:6][C:5]([C:4]([OH:36])=[O:3])=[CH:10][CH:9]=4)[CH2:16][CH2:15]3)=[N:18][CH:19]=2)=[O:35])[CH:30]=[CH:29][CH:28]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CCOC(=O)c1ccc(N2CCN(c3ccc(C(=O)Nc4cccc(C(C)(C)C)c4)cn3)CC2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)nc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 13 %

Procedure:
4-{4-[5-(3-tert-Butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid ethyl ester (50 mg, 0.11 mmol) in THF (10 mL) and water (2 mL) was treated with LiOH monohydrate (8.6 mg, 0.22 mmol). After stirring at rt for 4 h the mixture was treated with another portion of LiOH monohydrate (9 mg, 0.22 mmol) and the mixture was stirred at 50° C. for 16 h. The mixture was then cooled and partitioned between EtOAc and water. The acidity of the water layer was adjusted to pH 5 with 1N aqueous HCl. The water layer was extracted twice more with EtOAc and the combined EtOAc layer was dried, filtered and concentrated. The residue was chromatographed on a silica gel column with 0-3% MeOH in CH2Cl2 gradient to afford the product (6 mg; Yield: 13%). HRMS m/z calcd for C27H30N4O3 [M+H]+: 459.2391. Found: 459.2388.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6](=[O:26])[CH2:7][CH2:8][NH:9][C:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=3[Cl:19])[NH:12][C:11]=2[C:21]([O:23]CC)=[O:22])=[CH:4][CH:3]=1.[OH-].[Li+].C(OCC)(=O)C>O1CCCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:26])[CH2:7][CH2:8][NH:9][C:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=3[Cl:19])[NH:12][C:11]=2[C:21]([OH:23])=[O:22])=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCCC(=O)c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCNc1c(C(=O)O)[nH]c2cc(Cl)cc(Cl)c12)c1ccc(F)cc1
Yield: 86.4 %

Procedure:
Dissolve 3-[(p-fluorophenacyl)methylamino]-2-carbethoxy-4,6-dichloroindole (660 mg, 1.61 mmol) in tetrahydrofuran (5 mL) and water (5 mL). Add lithium hydroxide (203 mg, 4.8 mmol) and stir for 24 hours at room temperture. Dilute the reaction with water(20 mL) and ethyl acetate (50 mL) and acidify. Separate the layers and dry the organic phase over magnesium sulfate, filter and dilute the filtrate with hexane (100 mL). Recrystallize from this solution to yield the title compound as a white powder (550 mg, 90%).
Reaction SMILES: [CH2:1]([C:4]1[C:17]2[O:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:18])[C:8]=2[CH:7]=[C:6]([CH3:19])[C:5]=1[OH:20])[CH:2]=C.ClC1C=CC=C(C(OO)=O)C=1.C(Cl)(Cl)Cl.[C:36](=[O:39])([O-])[O-:37].[K+].[K+]>O>[CH3:19][C:6]1[C:5]2[O:20][CH:2]([C:36]([OH:37])=[O:39])[CH2:1][C:4]=2[C:17]2[O:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9](=[O:18])[C:8]=2[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: C=CCc1c(O)c(C)cc2c(=O)c3ccccc3oc12
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(=O)c3ccccc3oc2c2c1OC(C(=O)O)C2
Temperature: 25 °C
Reaction time: 5 h
Yield: 65.2 %

Procedure:
A mixture of 4-allyl-3-hydroxy-2-methyl-9-oxo-9H-xanthene (12 g), m-chloroperbenzoic acid (12 g) and chloroform (700 ml) was stirred at room temperature for 5 hours and thereafter left to stand overnight. To the mixture, 20 g of potassium carbonate and 400 ml of water were added and the resulting mixture was extracted with chloroform. The chloroform layer was dried and the solvent was distilled off. The residue was dissolved in acetone (2,000 ml) and, to the stirred solution, a mixture of chromium trioxide (34 g), water (70 ml) and concentrated sulfuric acid (30 ml) was added dropwise at room temperature. After standing overnight, the mixture was filtered and the filtrate was evaporated to dryness under vacuum. After addition of water, the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from a mixed solvent of ethanol and DMF gave 8.7 g of 1,2-dihydro-4-methyl-6-oxo-6H-furo[2,3-c]xanthene-2-carboxylic acid. m.p. 292°-295° C. This compound produced a mass spectrum having a molecular ion peak at m/e 296.
Reaction SMILES: [CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:8]1[N:13]2[N:14]=[CH:15][C:16](I)=[C:12]2[N:11]=[C:10]([CH2:18][CH:19]2[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH:9]=1.[Cl:40][C:41]1[N:46]=[CH:45][C:44](B2OC(C)(C)C(C)(C)O2)=[CH:43][CH:42]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl>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].O.O1CCOCC1>[CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:44]3[CH:45]=[N:46][C:41]([Cl:40])=[CH:42][CH:43]=3)=[C:12]2[N:11]=[C:10]([CH2:18][CH:19]2[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH:9]=1
Reactant: CC1(C)OB(c2ccc(Cl)nc2)OC1(C)C
Reactant: CCOC(=O)C1CCC(Cc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1CCC(Cc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(Cl)nc4)c3n2)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a 10-20 mL microwave vessel was charged ethyl 4-((7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)methyl)cyclohexanecarboxylate (Int-4j, 2.94 g, 4.27 mmol), 6-chloropyridine-3-boronic acid pinacol ester (1.07 g, 4.48 mmol), K3PO4 (2.72 g, 12.81 mmol), and PdCl2(dppf)2.CH2Cl2 (349 mg, 0.43 mmol). To this was added 9:1 1,4-dioxane:H2O. The vial was flushed with argon, sealed, and stirred at 100° C. overnight. After 18 hours, the reaction was cooled to room temperature and diluted with DCM. The reaction was washed with water and the aqueous phase was extracted again with DCM. The combined organics were dried over Na2SO4 and the residue purified via silica gel chromatography to yield title compound as yellowish oil that crystallizes over time. Yield=1.93 g.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1)=[O:2].[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C@:26]([OH:41])([C@H:33]([S:35][CH:36]([CH2:39]O)[CH2:37][OH:38])[CH3:34])[CH2:27][N:28]1[CH:32]=[N:31][CH:30]=[N:29]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C@@:26]([OH:41])([CH2:27][N:28]1[CH:32]=[N:31][CH:30]=[N:29]1)[C@H:33]([S:35][C@@H:36]1[CH2:37][O:38][C@@H:1]([C:3]2[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=3)=[O:8])=[CH:16][CH:17]=2)[O:2][CH2:39]1)[CH3:34]
Reactant: O=Cc1ccc(C(=O)Nc2ccncc2)cc1
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: C[C@@H](S[C@H]1CO[C@H](c2ccc(C(=O)Nc3ccncc3)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In the same manner as that described in Example 3(3), a reaction was carried out using 4-formyl-N-(4-pyridyl)benzamide (200 mg, 0.88 mmol), (2R,3R)-2-(2,4-difluorophenyl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol (318 mg, 0.88 mmol) and p-toluenesulfonic acid monohydrate (469 mg, 2.5 mmol) and the reaction mixture was treated according to a similar procedure to that described in Example 3(3) to give the trans isomer of the title compound (187 mg, yield 37%) as a white solid and the cis isomer (86 mg, yield 17%) as a colorless oil. The trans isomer was recrystallized from ethyl acetate-hexane to give white powdery crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:36])[C:19](=[O:35])[NH:20][N:21]=2)[C@H:10]([CH3:37])[CH2:9]1)=O)(C)(C)C.[ClH:38]>>[ClH:38].[F:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:27]1[CH:26]=[C:25]2[C:16]([N:17]3[C:22]([CH2:23][O:24]2)=[N:21][NH:20][C:19](=[O:35])[C@H:18]3[CH3:36])=[CH:15][C:14]=1[C@H:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]1[CH3:37]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1cc2c(cc1-c1ccccc1F)OCC1=NNC(=O)[C@@H](C)N12
Agent: Cl
Product: C[C@@H]1CNCC[C@@H]1c1cc2c(cc1-c1ccccc1F)OCC1=NNC(=O)[C@@H](C)N12
Temperature: 20 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
A mixture of (3S,4S)-4-[(R)-7-(2-fluoro-phenyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (0.035 g, 0.069 mmol) in HCl (4 M in EtOAc, 10 mL) was stirred at 20° C. for 2 h. The reaction mixture was concentrated in vacuo to give (R)-7-(2-fluoro-phenyl)-4-methyl-6-((3S,4S)-3-methyl-piperidin-4-yl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloride acid as a colorless solid (0.015 g, 53%). 1H NMR (400 MHz, MeOD) δ 7.52-7.41 (m, 1H), 7.35-7.18 (m, 3H), 6.93 (s, 1H), 6.86 (s, 1H), 4.90 (m, 1H), 4.65 (s, 2H), 3.47 (m, 1H), 3.22-2.94 (m, 4H), 2.84 (d, J=9.8 Hz, 1H), 2.55-2.27 (m, 2H), 2.00-1.80 (m, 3H), 1.51 (d, J=6.4 Hz, 3H), 1.00-0.80 (m, 3H). SFC (Table 1, Method 43), Rt=3.789 min., LC/MS (Table 1, Method 4) Rt=1.748 min.; MS m/z: 409 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19])#[N:2].[C:22]1([C@@H:28]([NH2:30])[CH3:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:10][C:11]([NH:30][C@H:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:29])=[O:13])=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19])#[N:2]
Reactant: N#Cc1ccc(N(CC(=O)O)CC2CC2)cc1C(F)(F)F
Reactant: C[C@H](N)c1ccccc1
Product: C[C@H](NC(=O)CN(CC1CC1)c1ccc(C#N)c(C(F)(F)F)c1)c1ccccc1

Procedure:
Synthesized as described for Example 91C using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(cyclopropylmethyl)glycine and (1S)-1-phenylethanamine: MS (APCI) m/z 402 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:18])=[C:7]([CH3:19])[CH:6]=1)=[O:4].[OH-].[Na+].Cl>O1CCCC1>[CH3:19][C:7]1[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=[CH:9][C:8]=1[C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:18]
Reactant: COC(=O)c1ccc(-c2c(C)cccc2C)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)ccc1-c1c(C)cccc1C
Temperature: 90 °C
Yield: 86.3 %

Procedure:
A solution of 2,2′,6′-trimethyl-biphenyl-4-carboxylic acid methyl ester of Step A (18.5 g, 75.4 mmole) in tetrahydrofuran was treated with 1 N sodium hydroxide (250 mL) and heated at 90° C. for 20 hours. The mixture was acidified to pH ˜1 with concentrated hydrochloric acid, extracted with dichloromethane, dried over anhydrous magnesium sulfate, and concentrated to give the title compound as a white powder (15.63 g). Recrystallization from aqueous ethanol provided white plates, m.p. 172-173° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[H-].[Na+].[Br:12][C:13]1[CH:14]=[C:15]([N+]([O-])=O)[C:16]([C:19]#[N:20])=[N:17][CH:18]=1.[NH4+].[Cl-]>O.CN(C=O)C>[Br:12][C:13]1[CH:14]=[C:15]([O:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Br:1])[C:16]([C:19]#[N:20])=[N:17][CH:18]=1
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: Oc1ccc(F)cc1Br
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ncc(Br)cc1Oc1ccc(F)cc1Br
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.2 %

Procedure:
A 1 L flask was charged with 2-bromo-4-fluorophenol (20.5 g, 107 mmol) and DMF (500 mL). The reaction was cooled to 0° C. and NaH (2.84 g, 118 mmol) was added slowly and stirred for 15 minutes. 5-Bromo-3-nitropicolinonitrile (24.5 g, 107 mmol) was added and reaction stirred at 0° C. for 20 minutes. Saturated NH4Cl (300 mL) was added and poured into 1L water and stirred. The resultant solids were filtered and dried in a vacuum oven overnight to afford 5-bromo-3-(2-bromo-4-fluorophenoxy)picolinonitrile (38.3 g, 95.8% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)[C:7]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:6]1.Cl[C:27]1[N:32]=[C:31]([NH2:33])[C:30]([N+:34]([O-:36])=[O:35])=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[NH2:33][C:31]1[N:32]=[C:27]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=3)[C:7]([NH:18][C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])=[CH:6]2)[CH:28]=[CH:29][C:30]=1[N+:34]([O-:36])=[O:35]
Reactant: CCc1ccc(-c2cn(CCCN)cc2NC(=O)OC(C)(C)C)cc1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCc1ccc(-c2cn(CCCNc3ccc([N+](=O)[O-])c(N)n3)cc2NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 75 %

Procedure:
N-[1-(3-aminopropyl)-4-(4-ethylphenyl)pyrrol-3-yl] (tert-butoxy)carboxamide (1 eq) and 6-chloro-3-nitro-2-pyridylamine (1.2 eq) were dissolved in DMA with stirring under argon at rt. Hünig's Base (1.5 eq) was added to the clear dark brown solution which was heated to 60° C. for 12 hours until completion was determined by LC/MS and TLC, eluting with EtOAc/Hexane (3:2, v/v) (Rf=0.3). EtOAc was added to the reaction mixture which was then washed with water, brine, dried (Na2SO4), filtered, and concentrated to dryness to give the crude brown product. The brown residue was purified by silica column chromatography eluting with EtOAc/Hexane (24:26, v/v). After collecting the purified fractions and concentrating, the product was isolated as a light yellow solid (75% yield).
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].C(OC(=O)C)(=O)C.[N+:24]([O-])([OH:26])=[O:25]>C(O)(=O)C>[C:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][C:16]=1[N+:24]([O-:26])=[O:25])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C(=O)Nc1ccc(C#N)cc1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(=O)Nc1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a mixture of 1.0 g (4.0 mmol) 4-ethoxalylaminobenzonitril in 4 ml glacial acetic acid was added 4 ml acetic anhydride. At 0° C. a solution of 1 ml 100% nitric acid in 2 ml glacial acetic acid was added dropwise, and after 15 min. further 1 ml 100% nitric acid was added. Stirring was continued at 0° C. for 1 h. The reaction mixture was poured into 50 ml ice-water to give 0.95 g (81%) of 4-ethoxalylamino-3-nitrobenzonitril. M.p. 151.8° C.
Reaction SMILES: S([CH2:11][N+:12]#[C-:13])(C1C=CC(C)=CC=1)(=O)=O.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:24]([O:26][C:27](=[O:46])[CH:28]=[CH:29][C:30]1[C:35]([CH2:36][N:37]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH3:38])=[CH:34][CH:33]=[CH:32][N:31]=1)[CH3:25]>C1COCC1>[CH2:24]([O:26][C:27]([C:28]1[C:29]([C:30]2[C:35]([CH2:36][N:37]([CH2:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH3:38])=[CH:34][CH:33]=[CH:32][N:31]=2)=[CH:13][NH:12][CH:11]=1)=[O:46])[CH3:25]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)C=Cc1ncccc1CN(C)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c[nH]cc1-c1ncccc1CN(C)Cc1ccccc1
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
A solution of 2.3 g (11.6 mmol) of tosylmethyl isocyanide in 25 mL of anhydrous THF is cooled to −50° C. under a nitrogen atmosphere. To this solution is added dropwise 23 mL (11.6 mmol) of potassium bis(trimethylsilyl) amide (0.5M solution in toluene) keeping the temperature <−50° C. After addition is complete this mixture is stirred for a 0.5 hour. To this mixture a solution of 1.8 g (5.8 mmol) of 3-{3-[[benzyl-methyl-amino]-methyl]-pyridin-2-yl}-acrylic acid ethyl ester dissolved in 10 mL of anhydrous THF is added dropwise maintaining a temperature <−50° C. After addition is complete the reaction mixture is quenched with 10 mL of water and extracted with ethyl acetate. The organic extracts are dried (Na2SO4) and evaporated. The residue is redissolved in approximately 100 mL of ethyl acetate and 100 mL of water. The pH of the mixture is adjusted to 2.0 with 1N HCL. The ethyl acetate layer is separated from the water layer. An additional 100 mL of ethyl acetate is added to the water layer and the pH adjusted to 9.0 with 1N NaOH. The ethyl acetate layer is separated from the water layer, dried (Na2SO4) and evaporated to yield 1.9 grams of 4-{3-[[benzyl-methyl-amino]-methyl]-pyridin-2-yl}-1H-pyrrole-3-carboxylic acid ethyl ester. 1H NMR (CDCl3) δ 8.5 (m, 1H), 8.0 (m, 1H), 7.35 (s, 6H), 7.30 (m, 5H), 7.20 (m, 1H), 6.60 (s, 1H), 4.0 (q, 2H), 3.42 (s, 2H), 3.38 (s, 2H), 2.0 (s, 3H), 1.0 (t, 3H). Mass spectrum: m/e=350.3 (p+1). TLC (10/1 chloroform/methanol) Rf=0.35. Step 9:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:11]([C:18]([F:21])([F:20])[F:19])=[N:10]2)=[CH:5][CH:4]=1.[CH2:22]([NH:24][C:25](=[O:27])[CH3:26])[CH3:23]>>[CH2:22]([N:24]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:11]([C:18]([F:21])([F:20])[F:19])=[N:10]2)=[CH:5][CH:4]=1)[C:25](=[O:27])[CH3:26])[CH3:23]
Reactant: CCNC(C)=O
Reactant: FC(F)(F)c1nn(-c2ccc(CCl)cc2)c2c1CCCC2
Product: CCN(Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1)C(C)=O

Procedure:
The title compound was prepared from 1-[4-(chloromethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole and N-ethylacetamide using a similar procedure to that described for Description 15.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].N12CCCN=C1CCCCC2.[C@@H:16]1([N:25]2[C:34]3[N:33]=[CH:32][N:31]=[C:29]([OH:30])[C:28]=3[N:27]=[CH:26]2)[O:24][C@H:21]([CH2:22][OH:23])[C@@H:19]([OH:20])[C@H:17]1[OH:18]>CC(N(C)C)=O.C(Cl)(Cl)Cl.CO>[CH2:1]([N:31]1[CH:32]=[N:33][C:34]2[N:25]([C@@H:16]3[O:24][C@H:21]([CH2:22][OH:23])[C@@H:19]([OH:20])[C@H:17]3[OH:18])[CH:26]=[N:27][C:28]=2[C:29]1=[O:30])[C:2]#[CH:3]
Reactant: C#CCBr
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: CO
Product: C#CCn1cnc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1=O

Procedure:
Propargyl bromide (11.8 ml, 105.9 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (20.62 ml, 135.2 mmol) were added to a suspension of inosine (27.56 g, 102.8 mmol) in dimethylacetamide (590 ml). The reaction mixture was stirred at room temperature overnight under argon, at which time TLC in chloroform/methanol (85:15) demonstrated disappearance of starting material. The reaction was terminated by addition to the suspension 3.5 L of ether/hexane (1:1) with storage at about -20 degrees C. overnight. While still chilled, solvent was decanted from the resulting gum, which was then dissolved in methanol and evaporated in vacuo (oil pump) onto silica gel. The product was isolated by silica gel chromatography using chloroform/methanol (95:5). The product was then characterized using mass spectrometry and proton NMR data. The mass spectrometer gave the following results: FABMS(glycerol), m/z 307 (MH+). The NMR data gave the following results: 1H-NMR (DMSO-d6): 8.50 (1H, s, H2); 8.39 (1H, s, H8); 5.87, 5.84 (1H, d, H1'); 5.51, 5.49 (1H, d, 2--OH); 5.23, 5.20 (1H, d, 3'--OH); 5.05 (1H, t, 5'--OH); 4.84, 4.83 (2H, d, CH2); 4.44 (1H, m, H2); 4.11, (1H, m, H3'), 3.92 (1H, m, H4'); 3.62 (1H, m, H5'); 3.57 (1H, m, H5'); 3.41 (1H, t, CH). Characterization with mass spec. and NMR yielded data consistent with the structure of 1-propargylinosine.
Reaction SMILES: NC(N)=O.[CH2:5]([N:7]=[C:8]=[O:9])[CH3:6].[CH3:10][O:11][C:12]([C:14]1[S:33][C:17]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([NH:25][CH2:26][CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[C:23]=3[S:24][C:16]=2[C:15]=1[O:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:13]>CN(C1C=CN=CC=1)C.ClCCCl>[CH3:10][O:11][C:12]([C:14]1[S:33][C:17]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([N:25]([CH2:26][CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[C:8]([NH:7][CH2:5][CH3:6])=[O:9])[C:23]=3[S:24][C:16]=2[C:15]=1[O:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:13]
Reactant: CCN=C=O
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1c(NCC3CCCCC3)cccc12
Agent: CN(C)c1ccncc1
Agent: NC(N)=O
Solvent: ClCCCl
Product: CCNC(=O)N(CC1CCCCC1)c1cccc2c1sc1c(OCC(=O)OCC)c(C(=O)OC)sc12
Yield: 43.3 %

Procedure:
Step B Urea Formation: Addition of ethyl isocyanate (0.5 mL, 6.5 mmol) to 7-(Cyclohexylmethyl-amino)-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester (60 mg, 0.13 mmol) was carried out following a procedure similar to that delineated in Step B, Example 27, with the following exceptions: co-solvent (DCE), addition of catalytic DMAP, temperature (70° C. vs. ambient), and total reaction time (100+ hours), affording 30 mg of 7-(1-Cyclohexylmethyl-3-ethyl-ureido)-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester (43% yield).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH:4]=[C:3]1[C:12](Cl)=[O:13].[OH-].[NH4+:16]>>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH:4]=[C:3]1[C:12]([NH2:16])=[O:13]
Reactant: O=C(Cl)c1coc2ccccc2c1=O
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)c1coc2ccccc2c1=O
Yield: 48.8 %

Procedure:
A quantity of 0.9 g (0.0043 mol) of 4-oxo-4H-1-benzopyran-3-carbonylchloride was added gradually to a stirred quantity of 15 ml of conc. ammonium hydroxide at room temperature. All solid went into solution when crystals gradually separated. After 15 min. the solid was filtered and washed with water; wt 0.4 g (48.8% yield); mp 220°-225°. Two recrystallizations from 2-propanol gave pure material melting at 250°-252°C.