Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]#[C:22][Si](C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>ClCCl>[Br:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:16])([F:15])[F:17])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]#[CH:22]
Reactant: C[Si](C)(C)C#Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: O
Product: C#Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1Br
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-bromo-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trimethylsilylethynylpyrazole (43 mg, the compound of Example C1) in dichloromethane (1 ml) was added dropwise over five minutes tetra-n-butylammonium fluoride (0.098 ml). Stirring was continued at room temperature for 30 minutes. The reaction mixture was then poured into dichloromethane (10 ml) and water (10 ml). The organic layer was separated, dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel (10 g) eluted with dichloromethane : hexane (1:2) to provide the title compound as a pale yellow solid m.p. 134-5° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])OC(C)(C)C)[CH2:4][CH2:3]1.[C:16](OC(=O)C)(=O)C.[ClH:23].O1CCOCC1>C(Cl)Cl>[ClH:23].[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[CH3:16])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)N[C@H]1CC[C@H](N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl trans-4-aminocyclohexylcarbamate (500 mg, 2.333 mmol) in DCM (20 mL) was added acetic anhydride (0.231 mL, 2.450 mmol). The solution was stirred overnight at RT. After 16 hours, 4 M HCl in dioxane (2.333 mL, 9.33 mmol) was added, and the reaction was stirred at RT for 3 days. The resulting white solid was collected by vacuum filtration and dried in vacuo to generate N-(trans-4-aminocyclohexyl)acetamide hydrochloride as a white powder (0.49 g, 109% yield).
Reaction SMILES: C[O:2][C:3](=O)[C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH3:14][NH:15][NH2:16]>CO.O>[F:12][C:9]1[CH:10]=[CH:11][C:6]([C:5]2[N:15]([CH3:14])[NH:16][C:3](=[O:2])[CH:4]=2)=[CH:7][CH:8]=1
Reactant: CNN
Reactant: COC(=O)C#Cc1ccc(F)cc1
Solvent: CO
Solvent: O
Product: Cn1[nH]c(=O)cc1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 36.4 %

Procedure:
A suspension of (4-fluorophenyl)propynoic acid methyl ester (1.6 g, 9.0 mmol) in MeOH (10 mL) and H2O (10 mL) was heated at 60° C. and MeNHNH2 (0.5 mL, 9.4 mmol) was added. The reaction mixture was stirred at 60° C. for 20 min. then filtered. The residue was washed with H2O (10 mL) and MeOH (5 mL) and dried to give 5-(4-fluorophenyl)-1-methyl-1,2-dihydro-pyrazol-3-one (0.63 g, 36%). The filtrate was then concentrated under reduced pressure and the residue dissolved in EtOAc (20 ml) and washed with H2O (3×15 mL). The aqueous layer was acidified to pH 5.5 with 2 M citric acid solution (3×15 mL) and extracted with EtOAc (3×20 mL). The extracts were dried (MgSO4) and concentrated under reduced pressure to give 5-(4-fluoro-phenyl)-2-methyl-1,2-dihydro-pyrazol-3-one (0.2 g, 12%).
Reaction SMILES: CN(C)C1C=CC=CC=1.[C:10]([O:13][CH2:14][C:15]1[CH:20]=[C:19](O)[N:18]2[N:22]=[C:23]([CH3:25])[N:24]=[C:17]2[N:16]=1)(=[O:12])[CH3:11].C(Cl)(Cl)[Cl:27]>P(Cl)(Cl)(Cl)=O>[C:10]([O:13][CH2:14][C:15]1[CH:20]=[C:19]([Cl:27])[N:18]2[N:22]=[C:23]([CH3:25])[N:24]=[C:17]2[N:16]=1)(=[O:12])[CH3:11]
Reactant: ClC(Cl)Cl
Reactant: CC(=O)OCc1cc(O)n2nc(C)nc2n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CC(=O)OCc1cc(Cl)n2nc(C)nc2n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
In 300 ml of phosphorus oxychloride was added dropwise 40 ml of N,N-dimethylaniline, and 35 g of 5-acetoxymethyl-7-hydroxy-2-methyl-s-triazolo[1,5-a]pyrimidine was added to the mixture and the mixture was stirred at 50° C. for one hour. An oily residue obtained by removing phosphorus oxychloride was dissolved in 500 ml of chloroform and ice-cooled. After addition of crushed ice and water to the mixture and stirring thereof, a chloroform layer was separated, washed with water and dried over anhydrous magnesium sulfate. Then, removing a solvent, an oily product was obtained. This was applied to a silica gel column chromatography (eluent: chloroform) and fractions containing the title compound were condensed to obtain an oily product. This was allowed to stand to cool and crystallized to obtain 31 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]2[CH2:14][CH2:15][C@:10]([CH2:16][CH2:17]O)([CH:11]=[CH:12]2)[O:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C(C(O)=O)(O)C(C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1.[CH3:45][C@@H:46]1[C@@H:51]([O:52][C:53](=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:50][CH2:49][NH:48][CH2:47]1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)CC)(C)C>C(#N)CC>[C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][C:10]([CH2:16][CH2:17][N:48]3[CH2:49][CH2:50][C@H:51]([O:52][C:53](=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55])[C@@H:46]([CH3:45])[CH2:47]3)([CH2:11][CH2:12]2)[O:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H]1CNCC[C@@H]1OC(=O)C(C)(C)C
Reactant: CC(C)(C)OC(=O)N1O[C@@]2(CCO)C=C[C@@H]1CC2
Agent: C[P+](C)(C)CC#N
Agent: O=C(O)C(O)(C(=O)c1ccccc1)C(O)(C(=O)O)C(=O)c1ccccc1
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(CCC23CCC(CC2)N(C(=O)OC(C)(C)C)O3)CC[C@@H]1OC(=O)C(C)(C)C
Temperature: 120 °C
Reaction time: 16 h

Procedure:
(1S,4S)-1-(2-Hydroxy-ethyl)-2-oxa-3-aza-bicyclo[2.2.2]oct-5-ene-3-carboxylic acid tert-butyl ester (11) (620 mg, 2.41 mmol) is dissolved in 24 ml of propionitrile and after addition of amine 6 (480 mg, 2.41 mmol), cyanomethyl-trimethyl-phosphonium iodide (796 mg, 6 mmol) and diisopropyl ethyl amine (2 ml, 12 mmol) the mixture is stirred for 16 h at 120° C. Then the mixture is evaporated under reduced pressure. The residue is diluted with ethyl acetate, washed 10% K2CO3- and NaCl-solution, and dried over Na2SO4. The crude product is purified by Flash-chromatography (ethyl acetate/hexanes (9.5:0.5), silicagel).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][C@H:22]1[CH2:26][CH2:25][C@H:24]([CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23]1)=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][C@H:22]1[CH2:26][CH2:25][C@H:24]([CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:23]1)=[O:19]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)C1
Reaction time: 1 h
Yield: 111.5 %

Procedure:
A mixture of tert-butyl {trans-3-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]cyclopentyl}methylcarbamate 117 (0.90 mmol) and Pd/C (0.50 g) in methanol (20 mL) was hydrogenated at 30 psi at room temperature for 1 hour. The mixture was filtered through a Celite pad and concentrated to provide 118 (0.40 g) as a white foam.
Reaction SMILES: O=[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][NH:5][CH:4]=[C:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(CC([Cl:28])=O)C=CC=CC=1>P(Cl)(Cl)(Cl)=O>[Cl:28][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCOC(=O)c1c[nH]cc(-c2ccccc2)c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cncc(-c2ccccc2)c1Cl
Yield: 90 %

Procedure:
A mixture of ethyl 1,4-dihydro-4-oxo-3-phenyl-5-pyridinecarboxylate (prepared from phenylacetyl chloride according to the procedures described in J. Org. Chem. 1978, 43, 2087-2088 and J. Heterocyclic Chem. 1980, 17, 359-368) (3.82 g, 15.7 mmol) and phosphorus oxychloride (50 ml) was heated at reflux overnight. The excess solvent was removed in vacuo. The residue was partitioned between ice-cold aqueous Na2CO3 and ethyl acetate, and the organic layer was evaporated in vacuo to afford 3.72 g (90%) of the title compound as a brown solid; 1H NMR (250 MHz, CDCl3) δ1.44 (3H, t, J 7.2 Hz), 4.47 (2H, q, J 7.2 Hz), 7.40-7.54 (5H, m), 8.62 (1H, s), 8.91 (1H, s); MS (ES+) m/z 262/264 [MH]30 .
Reaction SMILES: [C:1]([O:13][CH3:14])(=[O:12])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[C:6]([O:8][CH2:9][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])(=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([C:1]([O:13][CH2:14][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])=[O:12])=[CH:3][CH:4]=1
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Product: CCCCCCCCCCCCCCCCCCOC(=O)c1ccc(C(=O)OCCCCCCCCCCCCCCCCCC)cc1
Temperature: 130 °C
Yield: 96.2 %

Procedure:
To a 2L Buchi reactor equipped with a double turbine agitator and distillation apparatus was charged Dimethyl terephthalate (315.8 grams), Stearyl Alcohol (879.7 grams) and heated to 130° C. under Nitrogen purge for 1 hour, after which stirring was commenced followed by the addition of Tyzor catalyst (3.0 grams, available from Dupont). The reaction mixture was then heated to 145° C., followed by slowly ramping the temperature to 190° C. over a 3-4 hour period such that the evolution of methanol is distilled in a controlled manner. The reaction temperature was maintained at 190° C. for an additional 16 hours until >96% conversion to the product was achieved as determined by 1H NMR spectroscopy. The product was discharged as a low viscosity liquid which solidified on cooling to give a 1050 gram of a white solid (96.2% yield). The product was shown to be pure by 1H NMR spectroscopy with trace amounts of the mono-ester. Physical properties of this compound are shown in Table 2.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12](=O)[CH3:13])=[CH:2]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:21].[Na+]>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH:12]([NH2:21])[CH3:13])=[CH:2]1
Reactant: [BH3-]C#N
Reactant: CC(=O)CCc1c[nH]c2ccccc12
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)CCc1c[nH]c2ccccc12
Reaction time: 64 h
Yield: 62.3 %

Procedure:
To a solution of 4-(1H-indol-3-yl)-butan-2-one (1.0 g, 5.3 mmol) in methanol (20 mL is added ammonium acetate (4.45 g, 57.73 mmol) and sodium cyanoborohydride (0.37 g, 5.9 mmol) at room temperature. The resulting mixture is allowed to stir for 64 hours at the same temperature. The reaction mixture is quenched by addition of 1 N hydrochloric acid and adjusted to pH ˜2. The mixture is concentrated and extracted with dichloromethane (50 mL). Then the aqueous phase is adjusted to pH ˜12 using 4 N aqueous sodium hydroxide and extracted with dichloromethane (3×50 mL). The combined organic phases are dried with sodium sulfate and concentrated in vacuo. The resulting residue is subjected to flash column chromatography (5%-30% methanol in dichloromethane) to afford 3-(1H-indol-3-yl)-1-methyl-propylamine (622 mg, 62%) as an oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Cl:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31]>>[Cl:26][C:27]1[CH:28]=[C:29]([C:30]([N:20]2[CH2:21][CH2:22][CH:17]([N:15]3[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=4)=[N:16]3)[CH2:18][CH2:19]2)=[O:31])[CH:33]=[CH:34][CH:35]=1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cccc(Cl)c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 3-chlorobenzoyl chloride as starting compounds. The crude product is purified by crystallization from EA to yield the title compound.
Reaction SMILES: F[C:2](F)(F)C(O)=O.ICI.[F:11][C:12]([F:21])([CH2:18][CH:19]=[CH2:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14].Cl>ClCCl.[Cu].[Zn]>[CH:19]1([CH2:18][C:12]([F:21])([F:11])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:2][CH2:20]1
Reactant: O=C(O)C(F)(F)F
Reactant: C=CCC(F)(F)C(=O)OCC
Agent: [Cu]
Agent: Cl
Agent: [Zn]
Solvent: ICI
Solvent: ClCCl
Product: CCOC(=O)C(F)(F)CC1CC1
Temperature: 2.5 °C

Procedure:
Zinc-copper (Zn—Cu) couple (1.6 Kg, 800 mol %) and dichloromethane (7.5 L) was charged into a dry 20.0 L, 4-neck round bottomed flask, fitted with an over head stirrer, a thermo socket and a condenser under a nitrogen atmosphere. Trifluoroacetic acid (235 mL, 100 mol %) was added to the above Zn—Cu couple at ambient temperature via addition funnel over 30 minutes. Diiodomethane (860 mL; 2.86 Kg; 10.7 mol; 352 mol %) was added to above the Zn—Cu couple at ambient temperature via addition funnel over 1.5 hours. The reaction temperature was raised to reflux and then ethyl 2,2-difluoropent-4-enoate (500 g; 3.05 mol) in dichloromethane (500 mL) was added slowly via addition funnel over 30 minutes at reflux. The reaction temperature was maintained for 40-60 hours at reflux. Progress of the reaction was monitored by GC analysis which showed about 93% conversion to product based on relative area % of the peaks corresponding to product and starting material. The reaction mass was cooled to 0-5° C. and 5% dilute hydrochloric acid (500 mL) was added then the solution was filtered and washed with dichloromethane (1500 mL). The filtrate was washed with a solution of 5% aqueous hydrochloric acid (500 mL), water (1000 mL) followed by a solution of brine (1000 mL). The organic layer was concentrated under vacuum at 35° C./260-360 mm Hg to provide crude ethyl 3-cyclopropyl-2,2-difluoropropanoate (740 g), which was 79% pure by GC analysis. The crude product was then subjected to an oxidative work-up as described below to remove residual starting material (5% by area as determined by GC analysis).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][S:7][C:8]=1[O:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)([O-])=O.O.C([O-])(O)=O.[Na+].[O-]S(S([O-])=O)=O.[Na+].[Na+]>CO.C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[N:6][S:7][C:8]=1[O:9][CH:10]1[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2sncc2[N+](=O)[O-])CC1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2sncc2N)CC1
Temperature: 35 °C
Reaction time: 3 h
Yield: 40.3 %

Procedure:
To a solution of tert-butyl 4-(4-nitroisothiazol-5-yloxy)piperidine-1-carboxylate (1C3) (213 mg, 0.67 mmol) in methanol (4 mL) at room temperature was added water (3 mL), saturated NaHCO3 solution (3 mL) and Na2S2O4 (340 mg, 2 mmol). The mixture was stirred at 35° C. for 3 hours, cooled to room temperature, diluted with ethyl acetate (100 mL), washed with brine, dried over Na2SO4, and concentrated in vacuo at room temperature (25° C.). The residue was purified with flash column (eluent: 10-30% ethyl acetate/petroleum ether) to afford the product tert-butyl 4-(4-aminoisothiazol-5-yloxy)piperidine-1-carboxylate (1D4) (80 mg, 0.27 mmol).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]([CH2:9][C:10]([OH:13])([CH3:12])[CH3:11])=[CH:7][C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:5]1.[H-].[Na+].I[CH3:22]>C1COCC1>[OH:13][C:10]([CH3:12])([CH3:11])[CH2:9][C:8]1[N:4]([CH2:3][CH2:2][O:1][CH3:22])[N:5]=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=1
Reactant: CCOC(=O)c1cc(CC(C)(C)O)n(CCO)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(CC(C)(C)O)n(CCOC)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of ethyl 1-(2-hydroxyethyl)-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carboxylate (24.6 g, 95.9 mmol) in THF (191 mL) was cooled to 0° C. Sodium hydride (4.6 g of a 60% dispersion in mineral oil, 110 mmol) was added, and iodomethane (6.6 mL, 105 mmol) was added dropwise over a period of ten minutes. The reaction was allowed to warm to ambient temperature and stirred for six hours. The work-up procedure described in Part B of Example 1255 was followed to provide ethyl 5-(2-hydroxy-2-methylpropyl)-1-(2-methoxyethyl)-1H-pyrazole-3-carboxylate as a light brown oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N+:28]([O-])=O)=[N:4][CH:5]=[CH:6][CH:7]=1>CO.[Pd]>[CH3:20][C:19]1[C:14]([CH:10]2[CH2:11][CH2:12][CH2:13][CH:8]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]2[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[NH2:28])=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1ccccc1N
Yield: 15.7 %

Procedure:
To a solution of 3,3″-dimethyl-1′-(2-nitro-benzyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.55 g, 1.37 mmol) in MeOH (20 mL) was added palladium (50% wet with water), 10 wt.% on activated carbon (0.113 g). The resultant mixture was hydrogenated at 30 psi on a Parr shaker for 3 hours. The mixture was vacuum filtered through celite and the cake was washed with MeOH. The solvent was removed from the filtrate under reduced pressure and the thus obtained oil was purified by radial chromatography on silica gel (2 mm plate, 100:1:1 CH2Cl2—CH3OH—NH4OH) and provided 80 mg (16%) of COMPOUND 65 as a white solid. 1H NMR (CDCl3) δ 1.49-1.72 (m, 3H), 1.88-1.95 (m, 1H), 2.06-2.20 (m, 2H), 2.36 (s, 6H), 3.33 (s, 2H), 3.75 (dd, 2H, J=11.7, 3.0 Hz), 4.47 (br s, 2H), 6.07 (dd, 2H, J=7.5, 6.0 Hz), 6.42-6.45 (m, 1H), 6.54 (td, 1H, J=7.5, 1.2 Hz), 6.87 (dd, 2H, J=7.5, 4.8 Hz), 7.15 (d, 2H, J=7.5 Hz), 8.33 (d, 2H, J=3.9 Hz); ES-MS m/z 373 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)[C:10]([CH:11]=[O:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>ClCCl>[Br:18][C:15]1[O:14][C:13]([C:9]2[C:10]([CH:11]=[O:12])=[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]3[N:8]=2)=[CH:17][CH:16]=1
Reactant: O=Cc1c(-c2ccco2)nn2c(Cl)cccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: O=Cc1c(-c2ccc(Br)o2)nn2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 7-chloro-2-(2-furyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (2.0 g, 8.06 mmol) in dichloromethane was added N-bromosuccinimide (2.01 g, 11.28 mmol). After stirring at room temperature for 2 hours, the reaction mixture was diluted with dichloromethane, washed with water and brine and dried over magnesium sulfate. Filtration and concentration followed by recrystallization with ethyl acetate gave 2-(5-bromo-2-furyl)-7-chloropyrazolo[1,5-a]pyridine-3-carbaldehyde (2.1 g, 80%) as a white solid. 1H NMR (CDCl3): δ 10.50 (s, 1H), 8.37 (dd, 1H), 7.47 (t, 1H), 7.20–7.18 (m, 2H), 6.54 (d, 1H). MS m/z 325 (M+1).
Reaction SMILES: C([Li])CCC.[S:6]1[C:10]([C:11]2[C:12]3[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:9][N:8]=[CH:7]1.C(Br)(Br)(Br)[Br:29]>CCCCCC.C1COCC1>[Br:29][C:7]1[S:6][C:10]([C:11]2[C:12]3[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:9][N:8]=1
Reactant: BrC(Br)(Br)Br
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cncs3)ncnc21
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnc(Br)s3)ncnc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 58.8 %

Procedure:
2.5 M n-Butyllithium in hexane (0.860 mL) was added dropwise to a −78° C. solution of 4-(1,3-thiazol-5-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (550 mg, 0.0016 mol) in THF (20 mL). The mixture was stirred for 30 minutes at −78° C., followed by the slow addition of carbon tetrabromide (658 mg, 0.00198 mol) as a solution in THF (10 mL). After 30 minutes, the mixture was quenched with a small amount of saturated ammonium chloride, diluted with ether, and dried over sodium sulfate. The residue obtained after filtration and concentration was purified by flash column chromatography (ethyl acetate/hexanes) to afford the desired product (387 mg, 57%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][O:10][CH3:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][O:16][C:17]([N:19]=[C:20]=[S:21])=[O:18]>CC(C)=O>[CH3:15][O:16][C:17]([NH:19][C:20](=[S:21])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][O:10][CH3:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])=[O:18]
Reactant: COC(=O)N=C=S
Reactant: COCSc1ccc(N)c([N+](=O)[O-])c1
Solvent: CC(C)=O
Product: COCSc1ccc(NC(=S)NC(=O)OC)c([N+](=O)[O-])c1

Procedure:
1 G. of 1-amino-2-nitro-4-methoxymethylthiobenzene, prepared according to Example VIII, in 50 ml. acetone is treated with 3 g. methoxy carbonyl isothiocyanate at room temperature for several days. The solution is concentrated and the residue triturated with methanol and recrystallized from acetone to afford 1-(3-methoxycarbonyl-2-thioureido)-2-nitro-4-methoxymethylthiobenzene. This latter compound is treated for four hours in a refluxing mixture of 160 ml. methanol and 40 ml. water with 4 g. iron powder (added in two portions) and 1 g. ferrous sulfate. The mixture is filtered, and the filtrate concentrated. The residue is dissolved in chloroform, washed with water, then the solvent is evaporated to afford 2-amino-1-(3-methoxycarbonyl-2-thioureido)-4-methoxymethylthiobenzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:21])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH:13]([CH2:17][O:18][CH3:19])[CH2:14][O:15][CH3:16])[CH2:9][CH2:8][C:7]=2[CH:20]=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([NH:35][C:36]2[C:41]([Cl:42])=[CH:40][N:39]=[C:38](Cl)[N:37]=2)=[C:27]([S:29]([N:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])[CH:28]=1>>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([NH:35][C:36]2[C:41]([Cl:42])=[CH:40][N:39]=[C:38]([NH:21][C:4]3[C:3]([O:2][CH3:1])=[CH:20][C:7]4[CH2:8][CH2:9][N:10]([CH:13]([CH2:14][O:15][CH3:16])[CH2:17][O:18][CH3:19])[CH2:11][CH2:12][C:6]=4[CH:5]=3)[N:37]=2)=[C:27]([S:29]([N:32]([CH3:34])[CH3:33])(=[O:30])=[O:31])[CH:28]=1
Reactant: CN(C)S(=O)(=O)c1cc(Cl)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COCC(COC)N1CCc2cc(N)c(OC)cc2CC1
Product: COCC(COC)N1CCc2cc(Nc3ncc(Cl)c(Nc4ccc(Cl)cc4S(=O)(=O)N(C)C)n3)c(OC)cc2CC1

Procedure:
The title compound was prepared from 8-Methoxy-3-(2-methoxy-1-methoxymethyl-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 5-Chloro-2-(2,5-dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide in an analogous manner to Example 61e. Product isolated as a tan foam (0.072 g, 54%). MP: 66-79° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 9.23 (s, 1H), 8.49 (d, 1H, J=8.8 Hz), 8.14 (s, 1H), 7.91 (s, 1H), 7.87-7.85 (m, 1H), 7.52-7.46 (m, 2H), 6.65 (s, 1H), 3.87 (s, 3H), 3.59-3.53 (m, 2H), 3.49-3.43 (m, 2H), 3.33 (s, 6H), 3.08-3.01 (m, 1H), 2.88-2.80 (m, 6H), 2.77 (s, 6H), 2.73-2.68 (m, 2H). MS: 639.19 (MH)+.