Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([N:18]2[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]2)[CH:9]=1)=[O:6].C(N(CC)C(C)C)C.[C:36]([C:38]1[N:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]2=[N:40][CH:39]=1)#[CH:37]>CN(C=O)C.[Cu]I>[N:40]1[CH:39]=[C:38]([C:36]#[C:37][C:2]2[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=2[CH3:27])[C:5]([NH:7][C:8]2[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[CH:11]=[C:10]([N:18]3[CH2:22][CH:21]([CH3:23])[N:20]=[CH:19]3)[CH:9]=2)=[O:6])[N:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=12
Reactant: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(I)c3)cc(C(F)(F)F)c2)cn1
Reactant: C#Cc1cnc2ccccn12
Agent: [Cu]I
Agent: CCN(CC)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2cc(N3C=NC(C)C3)cc(C(F)(F)F)c2)cc1C#Cc1cnc2ccccn12
Temperature: 25 °C
Reaction time: 28 h

Procedure:
To a solution of 3-iodo-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide (0.11 g, 0.22 mmol.) in DMF (1 mL) in a sealed tube was added Pd[(PPh3)4] (0.013 g, 0.011 mmol), CuI (3 mg, 0.016 mmol), diethylisopropylamine (0.057 mL, 0.33 mmol.), followed by 3-ethynylimidazo[1,2-a]pyridine (0.040 g, 0.28 mmol.). The mixture was purged with argon for 15 minutes, sealed and stirred at rt for 28 h. The solvent was concentrated and the residue was taken up in methylene chloride (50 mL). The organic layer was washed with water, dried (Na2SO4) and evaporated to leave a brown residue which was purified by combiflash (hexane/ethyl acetate/methanol) to yield the desired material: MS (M+H)+ 500.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:5][N:4]=1.[C:26](Cl)([CH3:28])=[O:27].C([O-])(O)=O.[Na+]>C1COCC1>[C:26]([NH:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[O:5][N:4]=1)(=[O:27])[CH3:28]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN)no1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)NCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
A solution of tert-butyl (3R)-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoate (preparation 18) (219 mg, 0.62 mmol) in THF (10 ml) was treated with AcCl (53 μl, 0.75 mmol) and stirred at room temperature for 1 hour. More AcCl (200 μl) was added and stirred for a further hour. Sat. NaHCO3 solution was added and the layers separated. The organic extract was washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure to afford the title compound as a colourless oil (247 mg, 100%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[C:7]([F:15])[CH:6]=1)(=[O:3])[CH3:2].[CH3:16][NH2:17]>ClCCl.C1COCC1>[F:15][C:7]1[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=[CH:9][C:8]=1[S:11](=[O:13])(=[O:12])[NH:17][CH3:16]
Reactant: CN
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)c(F)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(NC(C)=O)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
The above prepared 4-acetylamino-2-fluorobenzenesulfonyl chloride (2 g, 7.9 mmol) was dissolved in dichloromethane and methylamine (9.9 mL of a 2M solution in THF, 19.9 mmol) was added. The reaction was stirred at room temperature for 2 hrs. The solvent was then evaporated under reduced pressure and the resulting solid was suspended in 50 mL of water. The solid was isolated by filtration and dried to yield 1.55 g (79%) of N-(3-fluoro-4-methylsulfamoylphenyl)acetamide which was used in the subsequent step without further purification.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([NH2:14])[CH2:8]2)([O-:4])=[O:3].C(N(CC)CC)C.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C=O)C>[ClH:1].[N+:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([NH:14][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:8]2)([O-:4])=[O:3]
Reactant: BrCc1ccccc1
Reactant: NC1Cc2ccc([N+](=O)[O-])cc2C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc2c(c1)CC(NCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 5-nitro-2-aminoindane hydrochloride (3.00 g, 14.00 mmol) in DMF (60 ml) was added triethylamine (4.07 ml, 29.40 mmol) followed by benzyl bromide (1.74 ml, 14.68 mmol). The mixture was warmed to room temperature, stirred for 1 hr, dumped into water (200 ml), and extracted with ethyl acetate (3×50 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered through a small plug of silica gel and reduced to a syrup. The sub-titled compound was isolated as the hydrochloride salt: (2.29 g, 54%); m.p. dec 266° C.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.BrC[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:21]([O-])([O-])=O.[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O.CCCCCC.C(OCC)(=O)C>[C:15]1([C:14](=[CH2:13])[CH2:21][N:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:10])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1NCc2ccccc21
Reactant: O=C([O-])[O-]
Reactant: BrCC=Cc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Cs+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: C=C(CN1Cc2ccccc2C1=O)c1ccccc1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A mixture of 2,3-dihydroisoindol-1-one (0.066 g, 0.5 mmol), 3-bromo-propenyl-benzene (0.118 g, 0.6 mmol), Cs2CO3 (0.408 g, 1.25 mmol), and 18-crown-6 (0.013 g, 0.05 mmol) in acetone (3 mL) was stirred at 70° C. for 16 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(2-phenyl-allyl)-2,3-dihydro-isoindol-1-one. 1H NMR (300 MHz, CDCl3): δ (ppm) 4.42 (m, 4H), 6.22 (m, 1H), 6.60 (d, 1H), 7.22-7.60 (m, 8H), 7.88 (d, 1H). GC-MS: m/z 249 (M)+.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[F:8][C:9]1[CH:10]=[C:11]([N+:16]([O-])=O)[CH:12]=[CH:13][C:14]=1F.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[F:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=1[S:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)[NH2:16]
Reactant: Sc1ccncc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(Sc2ccncc2)c(F)c1
Yield: 80.3 %

Procedure:
A solution of 4-mercaptopyridine (4.2 g, 35.6 mmol), 3,4-difluoronitrobenzene (5.7 g, 35.7 mmol), and potassium carbonate (12.4 g, 89.7 mmol) in anhydrous DMF (40 mL) was stirred at 40° C. and under argon for 3 h. TLC showed complete reaction. The mixture was diluted with ethyl acetate (100 mL) and water (100 mL) and the aqueous layer was back-extracted with ethylacetate (2×100 mL). The organic layers were washed with a saturated NaCl solution (100 mL), dried (MgSO4), and concentrated under reduced pressure. The crude product was purified by column chromatography with 50% ethyl acetate/50% hexanes. It afforded the desired product as a yellow solid (6.3 g, 71%). TLC (50% EtOAc/50% hexane) Rf 0.53; 1H-NMR (DMSO-d6) δ 7.27 (dd, J=0.76, 4.2 Hz, 2H), 7.78 (dt, J=0.76, 7.2 Hz, 1H), 8.11-8.15 (m, 1H), 8.28-8.33 (m, 1H), 8.5 (dd, J=1.4, 4.6 Hz, 2H), MS [M+H]+=251. Step2. Preparation of 3-fluoro-4-(4-pyridinylsulfanyl)aniline.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH3:23][NH:24][CH2:25][CH2:26][OH:27]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:24]([CH3:23])[CH2:25][CH2:26][OH:27])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: CNCCO
Reactant: Clc1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1
Product: CN(CCO)CCCCOc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
According to the method in example 7, 6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole and 2-(Methylamino)Ethanol were converted to yield 2-({4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-methyl-amino)-ethanol, MS: 391 (MH+, 1Cl).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:21]([CH3:23])[CH3:22])[C:6]2[O:10][C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:20]=1)#[N:2].[CH2:24]1[C:28]2([CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)[CH2:27][CH2:26][NH:25]1>>[C:37]([O:36][C:34]([N:31]1[CH2:32][CH2:33][C:28]2([CH2:24][N:25]([C:15](=[O:16])[C:14]3[CH:13]=[CH:12][C:11]([C:9]4[O:10][C:6]5[C:5]([CH:21]([CH3:23])[CH3:22])=[CH:4][C:3]([C:1]#[N:2])=[CH:20][C:7]=5[N:8]=4)=[CH:19][CH:18]=3)[CH2:26][CH2:27]2)[CH2:29][CH2:30]1)=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2)CC1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)O)cc3)oc12
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)N4CCC5(CCN(C(=O)OC(C)(C)C)CC5)C4)cc3)oc12

Procedure:
The title compound was synthesized from 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoic acid (INTERMEDIATE 2) and tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate following the procedure described in EXAMPLE 120. Mass spectrum (ESI) 529.2 (M+1).
Reaction SMILES: [NH:1]1C=N[C:3]([C:6]([OH:8])=[O:7])=[N:2]1.S1[CH:14]=[CH:13]C=[C-]O1.[CH:15]([NH:17]N)=[O:16]>>[CH:15]([NH:17][NH:1][N:2]=[CH:3][C:6]([O:8][CH2:13][CH3:14])=[O:7])=[O:16]
Reactant: [C-]1=CC=CSO1
Reactant: O=C(O)c1nc[nH]n1
Reactant: NNC=O
Product: CCOC(=O)C=NNNC=O

Procedure:
In Latvijas PSR Zinatnu Akad. Vestis, Khim. Ser., (2), 204-208(1965), there is described obtaining 1,2,4-triazole-3-carboxamide starting from acetyl chloride through the six reaction steps described below: ##STR3## In Czechoslovakia Pat. No. 175,118, there is disclosed a process for preparing ethyl ester of 1,2,4-triazole-3-carboxylic acid, in which ethyl ester of thioxamide acid and formylhydrazine are subjected to reaction with each other at 50° to 60° C. to obtain ethyl (2-formylhydrazino)iminoacetate, which is then heated at 160° C. to form a closed ring by dehydration. Since ethyl ester of thioxamide acid can be synthesized by subjecting ethyl ester of oxamide acid, which is available from a reaction between ethyl oxalate and ammonia, to reaction with phosphorus pentasulfide,1,2,4-triazole-3-carboxamide can be prepared from an oxalate through the five reaction steps described below. ##STR4## In this case, hydrogen sulfide is formed as a by-product and a complicated apparatus is required for deodorization thereof.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@@H:8]([OH:9])[C@H:7]([OH:10])[C@H:6]([OH:11])[C@@H:5]([O:12][CH3:13])[O:4]1.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([O:9][C@H:8]1[C@H:7]([O:10][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:6]([O:11][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:5]([O:12][CH3:13])[O:4][C@@H:3]1[CH2:2][O:1][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a stirred solution of (2R,3S,4S,5S,6S)-2-(hydroxymethyl)-6-methoxytetrahydro-2H-pyran-3,4,5-triol (15.0 g, 77.2 mmol, 1.0 equiv., commercially available Sigma Aldrich) in dry DMF (250 mL) was added sodium hydride (14.8 g, 309 mmol, 4.0 equiv) at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 30 minutes and then benzylbromide (38 mL, 309 mmol, 4.0 equiv) was added dropwise. The reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with MeOH (50 mL) at 0° C. and concentrated in vacuo. Ice cold water (80 mL) was added, the mixture was extracted with EtOAc (2×250 mL), and the combined organic layers were washed with saturated NaHCO3 solution (3×60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The material thus obtained was purified by silica gel chromatography, eluting with 20% EtOAc in petroleum ether to afford (2R,3R,4S,5S,6S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-methoxytetrahydro-2H-pyran as a pale yellow oil (28 g, 65%). 1H NMR (400 MHz, CDCl3) δ 7.47-7.24 (m, 18H), 7.25-7.15 (m, 2H), 4.92 (d, J=10.8 Hz, 1H), 4.79 (dd, J=17.2, 2.2 Hz, 3H), 4.70 (d, J=12.1 Hz, 1H), 4.67-4.50 (m, 4H), 4.01 (t, J=9.1 Hz, 1H), 3.92 (dd, J=9.3, 3.1 Hz, 1H), 3.86-3.72 (m, 4H), 3.36 (s, 3H). ESI (M+H2O) 572.0, calc for C35H38O6 554.3.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.[OH-:19].[K+]>O>[OH:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:19][C:5]2[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][CH:4]=2)=[CH:4][CH:3]=1
Reactant: BrCCCCCCCCBr
Reactant: Oc1ccc(O)cc1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: Oc1ccc(OCCCCCCCCOc2ccc(O)cc2)cc1
Reaction time: 1.5 h
Yield: 99 %

Procedure:
A five neck five liter round bottom flask equipped with a mechanical stirrer, two condensers, and a dropping funnel is purged with nitrogen then charged under a nitrogen blanket with 1.1 kg (10.0 moles) hydroquinone, 350 grams deionized water, and 272.0 grams (1.0 moles) 1,8-dibromooctane. The reaction mass becomes a stirable slurry as it is slowly heated to reflux under a slow nitrogen purge. A solution of 184 grams (2.7 moles) 85% KOH pellets in 184 grams water is added dropwise under a nitrogen blanket over a period of 75 minutes. After about one third of the KOH has been added, the slurry has converted to a tea colored solution; then, after most of the KOH has been added, a white material precipitates in increasing amounts as the refluxing is continued an additional 90 minutes. The reaction mixture is quenched with one liter of water then poured into 4 liters of water. The water slurry is acidified with 30% sulfuric acid and filtered under reduced pressure. The filter cake is slurried in warm (50°-70° C.) water, filtered again and washed with several portions of boiling water. It is then dried in a vacuum oven at 120° C. and 310 grams of crude white product is recovered. The product is treated with 8 liters of boiling ethanol and filtered to remove oligomers. The filtrate yields a total of 134 grams (41% Yield based on the dibromide) of white, shiny, "mica-like" crystals more than 95% pure by HPLC peak area nd GPC analysis. A final crystallization form 1.1 liters boiling ethanol gives product more than 99% pure by HPLC peak area (m.p. 151°-153.5° C.) for use in preparation of the copolymer epoxy resin, examples 12, 14, 15, 23 and 24. The ultraviolet absorption spectrum is 30/70 (by volume) methanol/dimethylformamide (DMF) shows a maximum absorption at 297 nm and in 30/70 (by volume) 1.0N KOH in methanol/DMF at 315 nm.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]1[CH2:13][CH2:14][NH:15][CH2:16][CH:8]1[C:7](=[O:17])[NH:6]2.[CH:20]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)=[CH2:21].Cl.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(O)C.CO.C(O)(=O)C>[N:25]1[CH:26]=[CH:27][C:22]([CH2:20][CH2:21][N:15]2[CH2:14][CH2:13][N:9]3[C:10]4[C:5]([NH:6][C:7](=[O:17])[CH:8]3[CH2:16]2)=[CH:4][C:3]([C:2]([F:18])([F:1])[F:19])=[CH:12][CH:11]=4)=[CH:23][CH:24]=1
Reactant: C=Cc1ccncc1
Reactant: O=C1Nc2cc(C(F)(F)F)ccc2N2CCNCC12
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CO
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1Nc2cc(C(F)(F)F)ccc2N2CCN(CCc3ccncc3)CC12

Procedure:
A solution of 9.0 g. of 2,3,4,4a-tetrahydro-8-trifluoromethyl-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one, 18 ml. of 4-vinylpyridine and 7 ml. of acetic acid was refluxed in 250 ml. of methanol overnight. The solvent was removed and the residue was precipitated with water. The precipitate was filtered and recrystallized from ethanol-water to yield 9.2 g. of the free base, m.p. 204°-206° C. 4 G. of this free base was dissolved in ethanol and treated with dry hydrogen chloride saturated ethanol. The product hydrogen chloride salt was filtered and recrystallized once from i-propanol and once from ethanol to yield 3.4 g. of the dihydrochloride salt of the title compound, m.p. 218°-221° C.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:44])[CH2:14][CH2:15][N:16]([CH2:28][CH2:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][C@@H:33]1[C:37]([O:39]C(C)(C)C)=[O:38])=[O:31])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1)=[O:7])(C)(C)C.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>ClCCl.CCOCC>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[C:37]([C@H:33]1[CH2:34][CH2:35][CH2:36][N:32]1[C:30](=[O:31])[CH2:29][CH2:28][N:16]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][CH:19]=1)[CH2:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:44])([OH:39])=[O:38]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)CCN(CCC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C)Cc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H]1CCCN1C(=O)CCN(CCC(=O)N1CCC[C@@H]1C(=O)O)Cc1ccc(C(F)(F)F)cc1
Reaction time: 16 h
Yield: 75 %

Procedure:
To a stirred solution of 200 mg (0.32 mmol) (R)-1-[3-[[3-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-(4-trifluoromethyl-benzyl)-amino]-propionyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 5 ml dichloromethane at 0° C. was added dropwise 1.0 ml trifluoroacetic acid and stirring continued for 16 h at room temperature. Concentration in vacuo and azeotroping three times with chloroform on a rotary evaporator afforded, after trituration in ether, 150 mg (75%) of the title compound as a yellow crystalline solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]2[CH:9](CC)[CH2:10][O:11][C:12]3[CH:19]=[C:18]([F:20])[C:17]([Br:21])=[CH:16][C:13]=3[C:14]=2[N:15]=1)=[O:5])C.O1CCCC1.[Li+].[OH-].Cl>O>[Br:21][C:17]1[C:18]([F:20])=[CH:19][C:12]2[O:11][CH2:10][CH2:9][C:8]3[S:7][C:6]([C:4]([OH:5])=[O:3])=[N:15][C:14]=3[C:13]=2[CH:16]=1
Reactant: CCOC(=O)c1nc2c(s1)C(CC)COc1cc(F)c(Br)cc1-2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nc2c(s1)CCOc1cc(F)c(Br)cc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.3 %

Procedure:
Into a 10-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of argon was placed ethyl 9-Bromo-8-fluoro-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid ethyl ester (350 g, 940.33 mmol, 1.00 equiv), tetrahydrofuran (1.3 L), water (2.6 L), and LiOH (62 g, 2.59 mol, 2.73 equiv). The resulting solution was stirred at room temperature for 3 h, cooled to <10° C. and adjusted to pH=2-3 with hydrochloric acid. The precipitates were collected by filtration, washed with 4×1 L of water and dried to afford 260 g (80%) of 9-Bromo-8-fluoro-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid as a brown solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]1([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]4[N:23]([CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[N:22]=[CH:21][CH:20]=4)[CH:17]=3)[C:12]([CH2:30][CH3:31])=[N:11]2)[CH2:9][CH2:8][CH2:7][CH2:6]1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([N:27]1[CH2:28][CH2:29][CH:24]([N:23]2[C:19]([C:16]3[CH:17]=[C:18]4[C:13]([C:12]([CH2:30][CH3:31])=[N:11][N:10]4[CH:5]4[CH2:9][CH2:8][CH2:7][CH2:6]4)=[CH:14][CH:15]=3)=[CH:20][CH:21]=[N:22]2)[CH2:25][CH2:26]1)(=[O:3])[CH3:2]
Reactant: CCc1nn(C2CCCC2)c2cc(-c3ccnn3C3CCNCC3)ccc12
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nn(C2CCCC2)c2cc(-c3ccnn3C3CCN(C(C)=O)CC3)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.7 %

Procedure:
Acetyl chloride (7.8 μL, 0.11 mmol) was slowly added to a mixture of 1-cyclopentyl-3-ethyl-6-(1-piperidin-4-yl-1H-pyrazol-5-yl)-1H-indazole (20 mg, 0.055 mmol), triethylamine (15 μL, 0.11 mmol) in methylene chloride (2 mL), and the reaction was stirred for 16 hours at room temperature. Methylene chloride was added and the organic layer was washed with saturated sodium bicarbonate, water, then brine, dried, filtered and concentrated. The residue was dissolved in ethyl acetate and purified by silica gel column chromatography using 100% ethyl acetate as the eluent to afford 18 mg (81%) of 6-[1-(1-acetylpiperidin-4-yl)-1H-pyrazol-5-yl]-1-cyclopentyl-3-ethyl-1H-indazole. LC/MS (EI) tR 4.29 (Method C), m/z 406.3 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH:8]1[CH2:13][CH:6]([CH2:7]1)[C:5]2=[N:14]O.S(Cl)(Cl)=[O:17]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([CH:8]3[CH2:13][CH:6]([NH:14][C:5]2=[O:17])[CH2:7]3)=[CH:10][C:11]=1[F:12]
Reactant: O=S(Cl)Cl
Reactant: ON=C1c2cc(Br)c(F)cc2C2CC1C2
Solvent: C1COCCO1
Product: O=C1NC2CC(C2)c2cc(F)c(Br)cc21
Yield: 88.6 %

Procedure:
Into a 100-mL round-bottom flask was placed a solution of 6-Bromo-7-fluoro-2,3-dihydro-1H-1,3-methano-naphthalen-4-one oxime (3.5 g, 12.96 mmol, 1.00 equiv) in 1,4-dioxane (30 mL) and thionyl chloride (24.7 g, 207.56 mmol, 16.00 equiv). The resulting solution was heated to reflux for 6 h, cooled, concentrated under vacuum, and quenched by the addition of 50 mL of water/ice. The solids were collected by filtration, washed with 2×50 mL of saturated aqueous NaHCO3 and 2×50 mL of water to afford 3.1 g (89%) of 5-bromo-4-fluoro-9-azatricyclo[8.1.1.0[2,7]]dodeca-2,4,6-trien-8-one as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:6]([CH:22]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]2NN=NN=2)=[CH:13][CH:12]=1)[CH2:9][CH3:10].[OH-:29].[Na+].CC[O:33]CC>O.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH2:24][CH:25]2[CH2:28][CH2:27][CH2:26]2)=[C:6]([CH:22]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([OH:33])=[O:29])=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: CCOCC
Reactant: CCN(Cc1cc(Cl)ccc1OC1CCCC1)c1ccc(-c2nnn[nH]2)nn1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCN(Cc1cc(Cl)ccc1OCC1CCC1)c1ccc(C(=O)O)nn1

Procedure:
The title compound was prepared from using a similar method to that of example 18 by treating 6-[N-(5-Chloro-2-cyclobutylmethoxybenzyl)-N-ethylamino]-3-cyanopyridazine (reference example 27) (2.3 g, 6.46 mmol) with sodium hydroxide (2.6 g, 65 mmol) in water (20 ml) and ethanol (100 ml) to give a gum which solidified on trituration with ether (1.15 g, 47%).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.Cl.NO.[N:16]1C=CC=CC=1.CCO>CC(OC(C)=O)=O.O>[Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]#[N:16])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Reactant: c1ccncc1
Agent: Cl
Agent: NO
Solvent: O
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Product: N#Cc1c(Cl)[nH]c2ccccc12
Yield: 58 %

Procedure:
A mixture of 2-chloroindole -3-carboxaldehyde (7.0 g, 36 mmol) was reacted with a slight excess of hydroxylamine hydrochloride and pyridine in refluxing EtOH for 1 hour, to give the crude oxime (Latrell R, Bartmann W, Musif J, Granzer E, German Patent 2,707,268, 31 Aug. 1978, Chem. Abstr. 1978;89:179858y). A solution of this in Ac2O (100 mL) was heated under reflux for 1 hour, cooled, and stirred with water (700 mL). The precipitated solid was collected, washed with water, and crystallized from aqueous MeOH to give 2-chloro-1H-indole-3-carbonitrile (3.7 g, 58%); mp 177°-180° C.