Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].S(=O)(=O)(O)O>>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][C:8]=1[CH2:9][CH3:10])[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]2)[CH3:2]
Reactant: CCc1ccc(CCCC(=O)O)cc1CC
Agent: O=S(=O)(O)O
Product: CCc1cc2c(cc1CC)C(=O)CCC2

Procedure:
Alternatively 4-(3',4'-diethylphenyl) butanoic acid (23.3 g; 0.106 mole) maybe cyclised by stirring at 100° C with 80% sulphuric acid (115 ml) for 11/2 hours. After dilution, extraction into ether, and distillation 15.83 g (74%) of the tetralone was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[S:12](Cl)(=[O:14])=[O:13].[OH-].[NH4+:17]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[S:12]([NH2:17])(=[O:14])=[O:13]
Reactant: [NH4+]
Reactant: COc1cccc([N+](=O)[O-])c1S(=O)(=O)Cl
Agent: [OH-]
Product: COc1cccc([N+](=O)[O-])c1S(N)(=O)=O

Procedure:
A mixture of 2-methoxy-6-nitro-benzenesulfonyl chloride (12.8 g, 50.87 mmol) and 25% ammonium hydroxide is swirled at 65° C. on a rotavap. After 15 min the volume of the resulting solution is reduced to half by evaporation of volatiles at reduced pressure. Collecting the precipitate by filtration after cooling gives 2-methoxy-6-nitro-benzenesulfonamide.
Reaction SMILES: [Br:1][C:2]1[C:15](=[O:16])[N:14]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1.[OH-].[NH4+:23]>O1CCOCC1>[NH2:23][C:7]1[N:8]=[C:9]([CH3:10])[C:4]2[CH:3]=[C:2]([Br:1])[C:15](=[O:16])[N:14]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:5]=2[N:6]=1
Reactant: [NH4+]
Reactant: Cc1nc(S(C)=O)nc2c1cc(Br)c(=O)n2C1CCCC1
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nc(N)nc2c1cc(Br)c(=O)n2C1CCCC1
Temperature: 110 °C
Yield: 93 %

Procedure:
To a solution of 6-bromo-8-cyclopentyl-4-methyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one (0.80 g, 2.16 mmol) in dioxane (5 mL) was added ammonium hydroxide (30%, 2.6 mL). The mixture was then heated at 110° C. in a sealed tube for 30 minutes. The solution was concentrated in vacuo and extracted with ethyl acetate (3×30 mL). The combined organics were washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered and concentrated to dryness to give the title compound as a brown crystalline solid (0.65 g, 93%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:13][C:14]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:15]=1[C:16](O)=[O:17].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:16](=[O:17])[C:15]3[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:14]=3[F:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: Cc1ccc(F)c(C(=O)O)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(F)c(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)c1
Yield: 62.9 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H), 2-fluoro-5-methylbenzoic acid (281 mg, 1.83 mmol), BOP-Cl (465 mg, 1.83 mmol), and triethylamine (0.606 mL, 4.35 mmol) in DCM (5 mL) was processed as described in Example 62, Step A, to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-fluoro-5-methylbenzamide (200 mg, 63% yield).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[O:11]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(C)(C)C.[K+]>CS(C)=O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:22][C:21]1[CH:20]=[CH:19][C:18]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:24][CH:23]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccccc1Nc1ccc(Oc2ccccc2)cc1

Procedure:
The product (2.03 g) is obtained according to the method of stage 1 of Example 4, by using 3.7 mL of 2-fluoro-nitrobenzene and 7.88 g of 4-phenoxyaniline in the presence of 6.36 g of potassium tert-butanolate in 34 mL of DMSO.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:15]2[C:14](=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:19])[C:6]=2[C:5]=1[N+]([O-])=O)([O-:3])=[O:2].[N+:23]([O-:26])([OH:25])=O>>[N+:23]([C:9]1[C:8]2[C:7](=[O:19])[C:6]3[C:15](=[CH:16][CH:17]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14](=[O:18])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([O-:26])=[O:25]
Reactant: O=C1c2ccccc2C(=O)c2c1ccc([N+](=O)[O-])c2[N+](=O)[O-]
Reactant: O=[N+]([O-])O
Product: O=C1c2ccc([N+](=O)[O-])cc2C(=O)c2c1cccc2[N+](=O)[O-]
Yield: 1.8 %

Procedure:
5.00 kg of this dinitroanthraquinone mixture (consisting of 41.2% of 1,5-dinitroanthraquinone, 39.6% of 1,8-dinitroanthraquinone, 8.9% of 1,6-dinitroanthraquinone and 9.5% of 1,7-dinitroanthraquinone) together with 49.04 kg of 97 percent strength by weight nitric acid (molar ratio 45) continuously flow, per hour, onto the fourth tray of a 5-tray rectifying column at about 55° C. 29.65 kg/hour of 99 percent strength by weight nitric acid is taken off at the head of the column at a reflux ratio of reflux/take-off of 0.4. The column is operated under a head pressure of 200 mm Hg, a head temperature of about 50° C. being set up. 19.29 kg/hour of 70 percent strength by weight nitric acid are continuously added to the sump of the column at a temperature of about 70° C. The dinitro-anthraquinone mixture to be crystallised, in which the molar ratio of nitric acid to organic products is 30:1 and the nitric acid concentration is 82 percent by weight (weight ratio 7.7), is removed at the sump of the column at a temperature of about 70° C. 3.8 kg per hour of a dinitroanthraquinone mixture having a composition of 53.2% of 1,5-dinitroanthraquinone, 44.6% of 1,8-dinitroanthraquinone, 0.3% of 1,6-dinitroanthraquinone and 1.8% of 1,7-dinitroanthraquinone is isolated from the mixture thus obtained, by cooling to room temperature (25° to 30° C.), separating off by filtration the solid which has precipitated and then drying it.
Reaction SMILES: [OH-].[K+].[C:3](=[N:16][OH:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CS(O[C@H:23]1[CH2:27][CH2:26][N:25](OC(C)(C)C)[C:24]1=C=O)(=O)=O.O>CS(C)=O>[NH:25]1[CH2:26][CH2:27][C@@H:23]([O:17][N:16]=[C:3]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:24]1
Reactant: ON=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)ON1CC[C@H](OS(C)(=O)=O)C1=C=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc(C(=NO[C@@H]2CCNC2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of KOH powder (4.86 g) in DMSO (250 ml) under vigorous stirring, benzophenone oxime (7.86 g) was added. After stirring at RT for 30 min, a solution of N-tert-butoxy-carbonyl-3-(S)-pyrrolidinyl methanesulfonate (10.0 g) in DMSO (70 ml) was added. After 18 h at RT the reaction was poured into iced water (900 ml) and extracted with Et2O. The combined organic layers were washed with water, brine, dried and the solvent was evaporated. Benzophenone O-[(R)-3-pyrrolidinyl]oxime was obtained (13.0 g, 96%) as a white solid and used without any further purification in the next step.
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]1[C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH2:14]([N:16]([CH2:18][CH3:19])[OH:17])[CH3:15]>CCOCC>[C:2]([O:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[C:11]([O:17][N:16]([CH2:18][CH3:19])[CH2:14][CH3:15])=[O:12])(=[O:3])[CH3:1]
Reactant: CCN(O)CC
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Solvent: CCOCC
Product: CCN(CC)OC(=O)c1ccccc1OC(C)=O
Yield: 84 %

Procedure:
To 9.1 g (0.0455 mol) of aspirin chloride dissolved in 100 ml of ether was added 8.1 g (0.09 mol) of N,N-diethylhydroxylamine dissolved in 100 ml of ether. The resulting suspension was filtered and the filtrate was diluted with 800 ml of heptane and filtered again. The ether-heptane filtrate was then concentrated in vacuo to give the desired compound (E) as a light yellow oil in 84% yield: TLC (silica gel, ehter) Rf =0.39; IR (neat) broad band 1760-1730 cm-1 (s) (C=O); NMR (CDCl1)δ8.1.7.0 (m, 4, aromatic-H), 3.0 (q, 4, J=7 Hz, CH3CH2 --N), 2.33 (s, 3, CH3C--O2) and 1.18 (t, 6, J=7 Hz, CH3CH2 --N).
Reaction SMILES: Cl[C:2]([CH:4]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:3].[CH2:17]([NH2:25])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN1CCOCC1>C(OCC)(=O)C>[CH:11]1([CH2:10][CH:4]([C:2]([NH:25][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:3])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCOC(=O)C(CC1CCCCC1)C(=O)Cl
Reactant: NCCc1ccccc1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC1CCCCC1)C(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.7 %

Procedure:
A mixture of ethyl 2-chlorocarbonyl-3-cyclohexylpropionate (2.65 mmol), phenethylamine (0.376 mL, 3 mmol) and N-methylmorpholine (0.44 mL, 4 mmol) in ethyl acetate (6 mL) was cooled to between −20 and −10° C. and stirred for 15 minutes. The mixture was allowed to warm to room temperature, stirred for approximately 12 hours and then diluted with ethyl acetate (5 mL) and ice (5 mL). The organic layer was separated, washed with cold 0.05 N hydrochloric acid, sodium bicarbonate solution and brine, dried (MgSO4) and concentrated to provide ethyl 2-cyclohexylmethyl-N-phenethylmalonamate (366 mg, 1.106 mmol).
Reaction SMILES: [NH:1]1[C:10](N)=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[N:4][C:2]1=S>C(O)CC.[Ni]>[N:1]1[CH:10]=[C:9]2[C:5](=[N:6][CH:7]=[N:8]2)[NH:4][CH:2]=1
Reactant: Nc1[nH]c(=S)nc2nc[nH]c12
Agent: [Ni]
Solvent: CCCO
Product: c1nc2cnc[nH]c-2n1
Yield: 140.8 %

Procedure:
4.39 g (11 mmoles) of thioisoguanine and 7.10 g (121 mmoles) of neutral Raney-nickel are refluxed in 50 ml of 1-propanol for 4.5 hours. The nickel was filtered off and the filtrate evaporated to dryress. The residue (3.79 g/93.8%) was dissolved in 20 ml of chloroform and 0.4 ml methanol and filtered through 24 g of silicagel in a column also with 2% methanol. The combined fractions were washed with 1N NaOH and the organic phase evaporated to dryness. The residue (2.69 g/66.6%) was dissolved in 30 ml of dichloromethane and 0.6 ml methanol and again filtered through 30 g of silicagel. A total of 1.86 g (46.0%) of 3H-purine was isolated, which was dissolved in 20 ml of methanol, treated with 5.4 ml of 1N methanolic HCl, and evaporated in vacuo to dryness. Crystallization and recrystallization from dichloromethane and ethyl acetate gave 1.75 g (39.4%) of 3H-purine hydrochloride with mp 170-85° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[Cl:26])[C:20]([OH:22])=[O:21]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[Cl:26])[C:20]([OH:22])=[O:21])=[O:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)O
Reactant: Nc1cc(C(=O)O)ccc1Cl
Product: CC(C)(C)OC(=O)NCCCCC(=O)Nc1cc(C(=O)O)ccc1Cl

Procedure:
For the preparation of the starting material, 5-[1-(t-butoxy)formamido]valeric acid and 3-amino-4-chlorobenzoic acid are coupled to give 3-[5-(1-t-butoxyformamido)valeramido]-4-chlorobenzoic acid, m.p. 203° C., and the latter is coupled with β-alanine t-butyl ester to give N-[3-[5-(1-t-butoxyformamido)valeramido]-4-chlorobenzoyl]-β-alanine t-butyl ester, MS: 498 (60, M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:16]([CH2:17][OH:18])=[N:15][O:14][N:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].N1C(C)=CC=CC=1C.O([Si:35]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])S(C(F)(F)F)(=O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:16]([CH2:17][O:18][Si:35]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])=[N:15][O:14][N:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(Nc1ccc(F)c(Cl)c1)c1nonc1CO
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)[Si](OCc1nonc1C(=O)Nc1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a stirred solution of N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-1,2,5-oxadiazole-3-carboxamide (3.2 g, 0.012 mol) in dichloromethane (DCM) (23 mL) at 0° C. was added 2,6-lutidine (3.4 mL, 0.029 mol) followed by triisopropylsilyl triflate (4.1 mL). The solution was stirred at 0° C. for 30 min and then the reaction was warmed to rt overnight. The reaction was concentrated and chromatographed on a silica column eluting with 15% ethyl acetate/hexane to yield a colorless oil (4.59 g, 91%). 1H NMR (400 MHz, DMSO-d6) δ: 11.03 (s, 1H), 8.01 (dd, J=6.7, 2.6 Hz, 1H), 7.67 (ddd, J=9.1, 4.3, 2.6 Hz, 1H), 7.44 (dd, J=9.1, 9.1 Hz, 1H), 5.2 (s, 2H), 1.09 (m, 3H), 0.99 (d, J=7.1 Hz, 18H); MF=C19H27ClFN3O3Si; LCMS calculated for C19H28ClFN3O3Si(M+H)+: m/z=428.157.
Reaction SMILES: CO[C:3](=[O:38])[N:4]=[C:5](SC)[C:6]([C:20]1[CH:25]=[C:24]([CH2:26][CH3:27])[CH:23]=[C:22]([O:28][CH2:29][C:30](=[O:34])[N:31]([CH3:33])[CH3:32])[C:21]=1[F:35])=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.Cl.[NH:40]([C:42]1[CH:50]=[CH:49][CH:48]=[CH:47][C:43]=1[C:44]([OH:46])=[O:45])[NH2:41]>>[CH3:32][N:31]([CH3:33])[C:30]([CH2:29][O:28][C:22]1[C:21]([F:35])=[C:20]([CH:6]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:18]=[C:17]([CH3:19])[O:16][N:15]=3)=[CH:12][CH:13]=2)[C:5]2[NH:4][C:3](=[O:38])[N:40]([C:42]3[CH:50]=[CH:49][CH:48]=[CH:47][C:43]=3[C:44]([OH:46])=[O:45])[N:41]=2)[CH:25]=[C:24]([CH2:26][CH3:27])[CH:23]=1)=[O:34]
Reactant: NNc1ccccc1C(=O)O
Reactant: CCc1cc(OCC(=O)N(C)C)c(F)c(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)c1
Agent: Cl
Product: CCc1cc(OCC(=O)N(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ccccc3C(=O)O)c(=O)[nH]2)c1
Yield: 60.2 %

Procedure:
The same procedure was carried out as in Example (2f), except that 0.409 g of {2-(3-dimethylcarbamoylmethoxy-5-ethyl-2-fluorophenyl)-2-[4-(5-methyl -[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester was used instead of the [2-(4-cyanophenylimino)-2-(2-fluoro-3,5-dimethoxyphenyl)-1-methylsulfanylethylidene]carbamic acid methyl ester in Example (2f), and 0.160 g of 2-hydrazinobenzoic acid hydrochloride was used instead of (1-oxypyridin-2-yl)hydrazine, to give the title compound (0.280 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:19](=[O:20])[C:18](=[O:21])[C:17]=3[O:22]CC)[CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[CH2:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH3:40])[CH2:30][CH:29]1[C:41]([NH2:43])=[O:42])=[O:27].[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:17](=[O:22])[C:18](=[O:21])[C:19]=3[OH:20])[CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[CH2:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH3:40])[CH2:30][CH:29]1[C:41]([NH2:43])=[O:42])=[O:27]
Reactant: CCOc1c(N2CCC(Oc3ccc(CC(=O)N4CCN(c5ccccc5C)CC4C(N)=O)c(OC)c3)CC2)c(=O)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(OC2CCN(c3c(O)c(=O)c3=O)CC2)ccc1CC(=O)N1CCN(c2ccccc2C)CC1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2-Methoxy-4-(1-(3-ethoxy-3-cyclobutene-1,2-dion-4-yl)-4-piperidyloxy)phenylacetyl)-4-(2-methylphenyl)piperazine-2-carboxamide (87 mg, 0.147 mmole) was dissolved in 3 ml of ethanol, treated with one equivalent of 1N sodium hydroxide solution, and stirred at ambient temperature overnight. All volatiles were removed under reduced pressure and the residual material was applied directly to precoated silica gel plates (0.5 mm thickness). Multiple elutions with a chloroform-methanol-acetic acid solvent mixture (80:20:2) afforded the title compound as a white solid: m.p. 144°-148° C.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)[N:5]=[C:4]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)[C:3]1=[O:38]>C(O)(C(F)(F)F)=O.ClCCl>[NH2:30][C@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:4]2[C:3](=[O:38])[N:2]([CH3:1])[CH:7]=[C:6]([N:8]3[C:16]4[CH:15]=[C:14]([C:17]5[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=5)[N:13]=[CH:12][C:11]=4[CH:10]=[N:9]3)[N:5]=2)[CH2:25]1
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2cn(C)c(=O)c(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2cn(C)c(=O)c(N3CCC[C@H](N)C3)n2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.2 %

Procedure:
A mixture of tert-butyl N-[(3S)-1-[4-methyl-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-3-oxo-pyrazin-2-yl]-3-piperidyl]carbamate (0.3505 mmol; 181.4 mg) in TFA (1 mL) and dichloromethane (4 ml) was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 241 as an off-white solid (28.1 mg, 18%). 1H NMR (400 MHz, DMSO) δ 9.47-9.40 (s, 1H), 9.36-9.30 (s, 1H), 8.66-8.57 (s, 2H), 8.48-8.40 (s, 1H), 7.96-7.90 (d, J=2.5 Hz, 1H), 6.96-6.90 (d, J=2.5 Hz, 1H), 3.69-3.61 (d, J=6.6 Hz, 2H), 3.58-3.52 (s, 3H), 2.83-2.72 (t, J=9.7 Hz, 1H), 2.63-2.58 (s, 3H), 2.30-2.23 (m, 1H), 1.88-1.81 (d, J=9.0 Hz, 1H), 1.74-1.68 (d, J=13.3 Hz, 1H), 1.63-1.53 (d, J=12.8 Hz, 1H), 1.18-1.06 (m, 1H); MS (ESI) m/z: 418.2 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][C:28]2[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=2)=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[F:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]([CH2:32][C:31]2[CH:30]=[CH:29][C:28]([C:27]#[C:26][C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=3)=[CH:35][CH:34]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CCCCCCNc1ccc(F)c(C(=O)OC)c1
Reactant: O=Cc1ccc(C#Cc2ccc(F)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(F)cc2)cc1)c1ccc(F)c(C(=O)OC)c1
Temperature: 50 °C
Yield: 32 %

Procedure:
To a solution of methyl 2-fluoro-5-(hexylamino)benzoate (270 mg; 1.07 mmol) and 4-[(4-fluorophenyl)ethynyl]benzaldehyde (358 mg; 1.60 mmol, intermediate which may be obtained according to methods disclosed in EP03103780.7) in anhydrous DCE (15 mL) was added sodium triacetoxyborohydride (678 mg; 3.20 mmol) at rt. The reaction mixture was then heated at 50° C. for 14 h. It was then poured into a solution of saturated NaHCO3 and extracted twice with DCM. The combined organic phases were then washed with brine, dried over MgSO4, filtrated and concentrated. The crude brown oil (652 mg) was purified by preparative HPLC using a X-Terra column to give 158 mg (32%) of the title compound as a beige powder. HPLC, Rt: 6.01 min (purity: 96.5%), LC/MS, M+(ESI): 462.2, 1H NMR: (CDCl3) δ: 7.46 (m, 2H), 7.41 (d, J=8.3 Hz, 2H), 7.37 (m, 1H), 7.13 (d, J=7.9 Hz, 2H), 6.94-7.05 (m, 4H), 4.52 (s, 2H), 3.90 (s, 3H), 3.42 (t, J=7.7 Hz, 2H), 1.56 (m, 2H), 1.26 (m, 6H), 0.85 (t, J=6.6 Hz, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:6]([OH:8])=O)=[O:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:35]([C:37]1[CH:38]=[C:39]([CH:44]=[C:45]([CH3:48])[C:46]=1[OH:47])[C:40]([NH:42]O)=[NH:41])[CH3:36]>CN(C=O)C>[CH2:35]([C:37]1[CH:38]=[C:39]([C:40]2[N:41]=[C:6]([C:5]3[CH:4]=[C:3]([CH:11]=[C:10]([CH3:12])[CH:9]=3)[CH:1]=[O:2])[O:8][N:42]=2)[CH:44]=[C:45]([CH3:48])[C:46]=1[OH:47])[CH3:36]
Reactant: CCc1cc(C(=N)NO)cc(C)c1O
Reactant: Cc1cc(C=O)cc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCc1cc(-c2noc(-c3cc(C)cc(C=O)c3)n2)cc(C)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.6 %

Procedure:
A solution of 3-formyl-5-methyl-benzoic acid (3.80 g, 23.2 mmol), HOBt (4.17 g, 27.8 mmol) and EDC HCl (4.44 g, 23.2 mmol) in DMF (200 mL) was stirred at rt for 5 min before 3-ethyl-4,N-dihydroxy-5-methyl-benzamidine (4.50 g, 23.2 mmol) was added. The mixture was stirred at rt for 1 h. The mixture was heated to 75° C. and stirring was continued for 3 h. The mixture was concentrated to about 40 mL, acidified by adding formic acid (0.6 mL), diluted with a small amount of acetonitrile/water and separated by prep. HPLC (Waters XBridge Prep C18, 50×50 mm+50×100 mm, 10 μm, 80% to 10% water (containing 0.5% of formic acid) in MeCN) to give the title compound as a white solid (2.14 g). LC-MS**: tR=0.82 min; [M+1]+=323.15, 1H NMR (D6-DMSO): δ 1.20 (t, J=7.3 Hz, 3H), 2.28 (s, 3H), 2.55 (s, 3H), 2.69 (q, J=7.5 Hz, 2H), 7.71 (d, J=2.0 Hz, 2H), 8.05 (s, 1H), 8.32 (s, 1H), 8.49 (s, 1H), 8.95 (s, 1H), 10.14 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10]2([C:13]([OH:15])=O)[CH2:12][CH2:11]2)=[CH:4][C:3]=1[CH3:16].[O-:17][C:18]#[N:19].[K+].C(=O)([O-])O.[Na+]>C(O)(=O)C.ClCCl>[Br:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]([N:9]2[C:18](=[O:17])[NH:19][C:13](=[O:15])[C:10]32[CH2:11][CH2:12]3)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(NC2(C(=O)O)CC2)cc(C)c1Br
Reactant: N#C[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(N2C(=O)NC(=O)C23CC3)cc(C)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.7 %

Procedure:
To a mixture of 1-((4-bromo-3,5-dimethylphenyl)amino)cyclopropane carboxylic acid (198 mg, 0.697 mmol) in acetic acid (3 mL) and dichloromethane (1.5 mL), potassium cyanate (424 mg, 5.23 mmol) was added at room temperature. The mixture was stirred at room temperature for one hour, and then stirred at 60° C. for two hours. A saturated aqueous sodium hydrogen carbonate solution was added to adjust pH to 8, and this mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to afford 4-(4-bromo-3,5-dimethylphenyl)-4,6-diazaspiro[2.4]heptane-5,7-dione (49 mg, 23%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si](C)(C)C)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+]>CO>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)#[CH:9]
Reactant: C[Si](C)(C)C#Cc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(I)cc1
Reaction time: 48 h
Yield: 64.8 %

Procedure:
To a solution of ((4-iodophenyl)ethynyl)trimethylsilane (5) (2.07 g, 6.23 mmol) in methanol (40 mL) was added K2CO3 (8.0 g, 57.9 mmol) and the reaction was allowed to stir for 48 hours. The volatiles were then removed in vacuo and the residue partitioned between ethyl acetate and H2O. The layers were separated and the aqueous phase re-extracted with ethyl acetate (2×). The combined organic layers were washed (H2O, brine), dried (Na2SO4), and filtered. The solvent was removed in vacuo and the residue was crystallized from hexane at −20° C. (in 2 crops) to give 1-ethynyl-4-iodobenzene (6) as a colorless solid (0.92 g, 64%). 1H NMR (400 MHz, DMSO-d6) δ 7.66 (app d, J=8.6 Hz, 2H), 7.20 (app d, J=8.5 Hz, 2H), 1.54 (s, 1H).