Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH2:4][OH:5].[N:11]1[S:12][N:13]=[C:14]2[CH:19]=[C:18]([CH2:20]Cl)[CH:17]=[CH:16][C:15]=12.Cl[C:23]([N:25]1[C@H:30]([CH3:31])[CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][C@@H:26]1[CH3:39])=[O:24]>>[CH3:39][C@H:26]1[CH2:27][NH:28][CH2:29][C@@H:30]([CH3:31])[N:25]1[C:23]([O:5][CH2:4][C:3]1[CH:6]=[C:7]([O:10][CH2:20][C:18]2[CH:17]=[CH:16][C:15]3=[N:11][S:12][N:13]=[C:14]3[CH:19]=2)[CH:8]=[CH:9][C:2]=1[F:1])=[O:24]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)Cl
Reactant: OCc1cc(O)ccc1F
Reactant: ClCc1ccc2nsnc2c1
Product: C[C@@H]1CNC[C@H](C)N1C(=O)OCc1cc(OCc2ccc3nsnc3c2)ccc1F

Procedure:
5-(5-[2,1,3]Benzothiadiazolylmethyl)oxy-2-fluorobenzyl cis-2,6-dimethylpiperazine-1-carboxylate was prepared from 2-fluoro-5-hydroxybenzyl alcohol, 5-[2,1,3]benzothiadiazolylmethyl chloride and 1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butoxycarbonylpiperazine according to the procedures described for Examples 121 and 54 to give the product as a yellow oil: δH (400 MHz, DMSO-d6) 1.25 (6H, d, J 7.0 Hz), 2.78–2.95 (4H, m), 4.10 (2H, br), 5.20 (2H, s), 5.22 (2H, s), 6.90–7.08 (3H, m), 7.65 (1H, m) and 8.03 (2H, m), NH not observed; HPLC (XTERRA, 50/80%, 220 nm) 90.7% (4.84 min).
Reaction SMILES: C1(O)C=CC=CC=1.[NH:8]([C:15]1[CH:24]=[N:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:25]C)[CH:21]=2)[N:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Na].C(S)C>CN(C=O)C>[NH:8]([C:15]1[CH:24]=[N:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([OH:25])[CH:21]=2)[N:16]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COc1ccc2nc(Nc3ccccc3)cnc2c1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCS
Solvent: Oc1ccccc1
Product: Oc1ccc2nc(Nc3ccccc3)cnc2c1
Temperature: 110 °C

Procedure:
By the method of Feutrill, G. I.; Mirrington, R. N. Tet. Lett. 1970, 1327; the aryl methyl ether is converted to the phenol derivative. To 2-anilino-6-methoxy-quinoxaline (0.27 g, 1.07 mmol) under argon in DMF is added the sodium salt of ethanethiol (0.19 g, 2 mmol). The reaction mixture is heated to 110° C. overnight. The mixture is concentrated and partitioned between EtOAc and H2O/5% tartaric acid such that the pH of the aqueous layer is approximately 4. The organic layer is washed with H2O (4×), then with 2.5% NaOH (4×). The basic layers combined, washed with EtOAc (2×), re-acidified with 5% tartaric acid, and washed with multiple portions of EtOAc. The organic layers are combined, washed with brine, dried (Na2SO4), and concentrated. The resulting solid is chromatographed (50% EtOAc/hexanes). An analytical sample is obtained by triturating the product with Et2O to provide a yellow powder (m.p. 211-213° C.). Anal. Calcd. for C14H11N3O: C, 70.88; H, 4.67; N, 17.71; Found: C, 70.64; H, 4.85; N, 17.58.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29]([NH2:32])(=[O:31])=[O:30].[C:33](=[O:36])([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([CH:15]=[CH:11][CH:10]=1)[C:33]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29]([NH:32][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][CH:17]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)(=[O:30])=[O:31])=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: O=C(O)c1cccc(OCc2ccccc2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Solvent: c1ccccc1
Product: O=C(Nc1ccccc1S(=O)(=O)NC(=O)c1cccc(OCc2ccccc2)c1)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.3 %

Procedure:
A benzene (10 ml) solution containing 600 mg (2.3 mmol) of 3-benzyloxybenzoic acid and 1.5 ml of thionyl chloride was heated under reflux for 2 hours and then the solvent was evaporated. A dioxane (10 ml) solution of the resulting residue was added dropwise to a water-dioxane 1:1 (10 ml) solution containing 248 mg (1.44 mmol) of 2-amino-benzenesulfonamide and 726 mg (5.2 mmol) of potassium carbonate, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, dioxane was evaporated, the resulting residue was acidified by adding 1 N HCl under ice-cooling and extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. By recrystallizing the resulting residue from acetonitrile, 200 mg (yield: 90%) of the title compound was obtained.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C(=O)=O.C([O:15][C:16]([C:18]1[C:19]([CH:34]2[CH2:36][CH2:35]2)=[N:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[N:22][CH:23]=1)=O)C>C1(C)C=CC=CC=1.C1COCC1.CCOCC>[CH:34]1([C:19]2[C:18]([CH2:16][OH:15])=[CH:23][N:22]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:26][CH:25]=3)[N:20]=2)[CH2:36][CH2:35]1
Reactant: CCOC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C=O
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Within 10 min 31.6 ml (37.9 mmol) of a 1.2 M DIBALH solution in toluene were added dropwise to a dry ice cooled (−50° C.) solution of 4.25 g (12.64 mmol) 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl ester in 50 ml of THF. The reaction mixture was stirred 30 min at −50° C. and after letting rise the temperature to RT, for 1 h at RT. The reaction mixture was taken up in ether and washed with 1N HCl and water. The solvent was removed under reduced pressure to give 3.72 g of pure [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-methanol.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C@@H:17]([NH2:19])[CH3:18])=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:9]=2)[CH:4]=[CH:3]1.[Cl:20][C:21]1[C:26]([C:27]#[N:28])=[C:25](Cl)[N:24]=[C:23]([S:30][CH3:31])[N:22]=1.CCN(CC)CC>C1COCC1.C(OCC)(=O)C>[Cl:20][C:21]1[C:26]([C:27]#[N:28])=[C:25]([NH:19][C@H:17]([C:7]2[N:6]=[C:5]3[CH:4]=[CH:3][N:2]([CH3:1])[C:10]3=[CH:9][C:8]=2[N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[CH3:18])[N:24]=[C:23]([S:30][CH3:31])[N:22]=1
Reactant: CSc1nc(Cl)c(C#N)c(Cl)n1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1N1CCOCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1nc(Cl)c(C#N)c(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
(S)-1-(1-Methyl-6-morpholino-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (200 mg, 0.768 mmol) was dissolved in THF (5 mL) along with 4,6-dichloro-2-(methylthio)pyrimidine-5-carbonitrile (169 mg, 0.768 mmol) and Et3N (0.118 mL, 0.845 mmol) to give an orange suspension. The reaction mixture was stirred at room temperature for 2 h, then diluted with ethyl acetate and washed saturated aq NH4Cl (3×15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was then loaded onto an ISCO® silica gel cartridge (12 g) and eluted using an EtOAc/Hexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a white solid (200 mg, 59%). ESI-MS m/z [M+H]+ calc'd for C20H22ClN7OS, 443.95; found 444.3.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4](O)=[O:5].O.Cl>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(Cl)c1Cl
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(Cl)c(Cl)c(CO)c1
Reaction time: 20 h
Yield: 80.6 %

Procedure:
In a flask under a nitrogen atmosphere, 81.60 grams (0.346 mole) of 2,3-dichloro-5-nitrobenzoic acid was dissolved in 325 mL of tetrahydrofuran, and this solution was cooled to below 10° C. To this solution was slowly added 400 mL (0.400 mole) of a 1.0M solution of borane-tetrahydrofuran complex in tetrahydrofuran. Upon completion of addition, the temperature of the reaction mixture was allowed to rise to ambient conditions, at which it was stirred for about 20 hours. At the conclusion of this period, 40 mL of water was slowly added to the reaction mixture. This was followed by the addition of 220 mL of 10% aqueous hydrochloric acid. Addition of the water had caused the mixture to become cloudy, but addition of the acid restored the clarity of the solution. The solvent was concentrated under reduced pressure, leaving a residue which was then dissolved in approximately 1500 mL of ethyl acetate. This solution was washed in succession three times with water, four times with an aqueous solution of sodium bicarbonate, once with water, and finally with a saturated aqueous solution of sodium chloride. The solution was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure, leaving 61.90 grams of 2,3-dichloro-5-nitrophenylmethanol as a solid residue. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C=O.[BH3-][C:4]#N.[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]([CH2:38][NH:39][CH:40]([CH3:42])[CH3:41])[C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:27][N:26]=[C:25]4[NH:35][CH:36]=[CH:37][C:24]=34)[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1.C([O-])(O)=O.[Na+]>CO>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]([CH2:38][N:39]([CH:40]([CH3:42])[CH3:41])[CH3:4])[C:15]([N:17]2[CH2:18][CH2:19][N:20]([C:23]3[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:27][N:26]=[C:25]4[NH:35][CH:36]=[CH:37][C:24]=34)[CH2:21][CH2:22]2)=[O:16])=[CH:10][CH:9]=1
Reactant: [BH3-]C#N
Reactant: CC(C)NC[C@@H](C(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)N(C)C[C@@H](C(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 26.2 %

Procedure:
Formaldehyde (0.0712 mL, 0.957 mmol) and NaCNBH3 (0.0120 g, 0.191 mmol) were added to (S)-2-(4-chlorophenyl)-3-(isopropylamino)-1-(4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)propan-1-one (0.055 g, 0.096 mmol, see Example 13) in MeOH (0.5 mL). The mixture was stirred at room temperature for 20 minutes. Saturated NaHCO3 (5 mL) was added, the aqueous layer was extracted with DCM (20 mL), and the combined organic phases were dried over sodium sulfate. After removal of the solvent, the residue was purified by chromatography (20:1:0.1 DCM:ethyl acetate:ammonium hydroxide) to give (S)-2-(4-chlorophenyl)-3-(isopropyl(methyl)amino)-1-(4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)propan-1-one (0.013 g, 23%) as a solid. MS ESI (+) m/z 516 detected.
Reaction SMILES: [CH3:1][C:2]1[N:38]=[C:5]2[N:6]([CH:33]([CH3:37])[C:34](=O)[CH3:35])[C:7](=[O:32])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][C:29](=[O:31])[O:28][N:27]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.Cl.[NH2:40][O:41][CH2:42][CH3:43].N1C=CC=CC=1.Cl>O.C(OCC)(=O)C>[CH2:42]([O:41]/[N:40]=[C:34](\[CH3:35])/[CH:33]([N:6]1[C:7](=[O:32])[C:8]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][C:29](=[O:31])[O:28][N:27]=3)=[CH:18][CH:19]=2)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=[C:2]([CH3:1])[N:38]=[C:5]12)[CH3:37])[CH3:43]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C(C)C(C)=O)c2nc(C)nn12
Reactant: CCON
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C(C)/C(C)=N/OCC)c2nc(C)nn12
Temperature: 100 °C
Reaction time: 48 h
Yield: 64.6 %

Procedure:
A mixture of 2-methyl-4-(1-methyl-2-oxopropyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.2 g), (aminooxy)ethane hydrochloride (0.76 g) and pyridine (5 mL) was stirred at 100° C. for 48 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 N hydrochloric acid. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.14 g, 66%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[N:16]4[N:17]=[CH:18][C:19]([C:20](O)=[O:21])=[C:15]4[N:14]=[CH:13][C:12]=3[C:23]([N:25]3[CH2:30][CH2:29][CH:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:27][CH2:26]3)=[O:24])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38]>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[N:16]4[N:17]=[CH:18][C:19]([C:20]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:21])=[C:15]4[N:14]=[CH:13][C:12]=3[C:23]([N:25]3[CH2:26][CH2:27][CH:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:29][CH2:30]3)=[O:24])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1cnn2c(Nc3ccc4[nH]ccc4c3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccc4[nH]ccc4c3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 35 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(5-indolylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.05 g, 0.10 mmol) obtained in step 2 and ethanesulfonamide (0.092 g, 0.84 mmol), the title compound (0.020 g, 35%) was obtained. ESI-MS m/z: 572 (M+H)+; 1H-NMR (CDCl3, δ): 1.15-1.82 (m, 4H), 1.46 (t, J=7.3 Hz, 3H), 2.40-2.59 (m, 2H), 2.60-4.15 (m, 3H), 3.62 (q, J=7.3 Hz, 2H), 6.61 (s, 1H), 7.00-7.37 (m, 7H), 7.47 (d, J=8.4 Hz, 1H), 7.58 (s, 1H), 8.33 (s, 1H), 8.37 (s, 1H), 8.63 (s, 1H), 8.64 (s, 1H), 10.58 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][C:6]1=[O:11].C(N(CC)C(C)C)(C)C.[F:21][C:22]1[CH:23]=[C:24]([N+:29]([O-:31])=[O:30])[CH:25]=[CH:26][C:27]=1F.FC(F)(F)C(O)=O.C(N(CC)C(C)C)(C)C>C(#N)C>[F:21][C:22]1[CH:23]=[C:24]([N+:29]([O-:31])=[O:30])[CH:25]=[CH:26][C:27]=1[N:8]1[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:6](=[O:11])[CH2:7]1
Reactant: COCCN1CCNCC1=O
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COCCN1CCN(c2ccc([N+](=O)[O-])cc2F)CC1=O

Procedure:
1-(2-Methoxyethyl)-2-oxopiperazine (4TFA salt, 13.5 g) was dissolved in acetonitrile (200 ml), and N,N-diisopropylethylamine (22.6 ml) followed by 3,4-difluoronitrobenzene (2.2 ml) were added. The mixture was heated to reflux for 18 hours. Solvent was evaporated, and the residue chromatographed on silica, using as eluant a gradient increasing in polarity from 0 to 4% methanol in dichloromethane. Relevant fractions were combined and evaporated to give a solid containing some N,N-diisopropylethylamine trifluoroacetate. The solid was purified by dissolving in ethyl acetate and washing well with water. Evaporation of the organic layer gave 3-fluoro-4-(4-{2-methoxyethyl}-3-oxopiperazin-1-yl)nitrobenzene as a solid (4.07 g).
Reaction SMILES: [CH3:1][S:2]C1C=C2C(=CC=1)C=NCC2.N[C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=[O:18].O(CC)C([S-])=S.[Na+].S(OC)(OC)(=O)=O>>[CH3:1][S:2][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=[O:18]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: CSc1ccc2c(c1)CCN=C2
Agent: CCOC(=S)[S-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Product: CSc1cccc(C(=O)O)c1

Procedure:
Scheme 3 depicts the synthesis of 6-methylsulfanyl-3,4-dihydro-isoquinoline (XII). 3-Amino-benzoic acid (IV) is diazotized, reacted with sodium ethyl xanthate, followed by saponification, and is alkylated with dimethyl sulfate to give 3-methylsulfanyl-benzoic acid (V). This acid is reduced with Red-Al® (sodium bis (2-methoxyethoxy) aluminum hydride in toluene, Aldrich, Milwaukee, Wis., USA) to yield the alcohol (VI) which is converted to a benzyl chloride (VII) using thionyl chloride. The benzyl nitrile compound (VIII) is synthesized by treating (VII) with potassium cyanide in the presence of 18-crown-6. Standard reduction conditions (e.g., Raney nickel) gives phenethyl carbamate (IX), and deprotection yields the phenethylamine (X). (XI) is obtained by treating (X) with ethyl formate, followed by ring closure using phosphorus oxychloride to give the desired dihydroisoquinoline (XII).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH3:8])([CH3:7])[CH:5]=O.Cl.[NH2:10][OH:11].C([O-])(=O)C.[Na+].O>C(O)C>[CH3:1][O:2][CH2:3][C:4]([CH3:8])([CH3:7])[CH:5]=[N:10][OH:11]
Reactant: NO
Reactant: COCC(C)(C)C=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COCC(C)(C)C=NO
Temperature: 40 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
116 parts of methoxypivalaldehyde were dissolved in 600 parts of ethanol, and a solution of 76.5 parts of hydroxylamine hydrochloride and 86 parts of sodium acetate in 500 parts of water was added dropwise to the above, vigorously stirred solution, the temperature increasing temporarily to 40° C. Stirring was continued for 24 hours at room temperature, after which the mixture was poured into 4,000 parts of water and then saturated with sodium chloride and extracted with eight times 400 parts of ether. The combined extracts were dried over sodium sulfate, the solvent was stripped off, and the residue was distilled, giving 90.4 parts of methoxypivalaldoxime as a colourless liquid at 48°-49° C./0.1 mbar. Yield: 69% of theory.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:18][OH:19].Cl.N1C=CC=CC=1>CO>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[N:18][OH:19])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)COc1cccc(C=O)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)(C)OC(=O)COc1cccc(C=NO)c1
Reaction time: 2 h

Procedure:
To a solution of (3-formyl-phenoxy)-acetic acid tert-butyl ester prepared of Preparation 20, Step A (2.05 g, 8.68 mmol) in MeOH (30 mL) was added NH2OH.HCl (0.66 g, 9.54 mmol) and pyridine (3.5 mL, 43.4 mmol) and the reaction was stirred for 2 hours. The MeOH was removed in vacuo and the residue was diluted with EtOAc and 1N HCl. The layers were separated and the aqueous solution was washed with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to afford the title compound of Step B (1.99 g). 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.23-7.28 (m, 2H), 7.12 (m, 1H), 6.93 (d, 1H), 4.51 (s, 2H), 1.46 (s, 9H).
Reaction SMILES: [CH2:1]([N:3](CC)[CH2:4][CH3:5])[CH3:2].C[Al](C)C.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[N:24]=[C:23]2[O:25][C:26]([C:35](OCC)=[O:36])=[C:27]([NH:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[C:22]2=[CH:21][C:20]=1[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[N:24]=[C:23]2[O:25][C:26]([C:35]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:36])=[C:27]([NH:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[C:22]2=[CH:21][C:20]=1[C:40]1[CH:41]=[CH:42][C:43]([Cl:46])=[CH:44][CH:45]=1
Reactant: CCOC(=O)c1oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc2c1NC(=O)C(F)(F)F
Reactant: CCN(CC)CC
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)c1oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc2c1NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a magnetically stirred solution of 0.119 mL (1.15 mmol) of triethylamine in 5 mL toluene was added 0.575 mL (1.15 mmol) of a 2.0 M solution of trimethylaluminum in toluene at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred for 30 min. A solution of 0.300 g (0.57 mmol) of the product of Example 181 in 1 mL CH2Cl2 was added to the reaction mixture and when the addition was complete the reaction mixture was heated at 60° C. for 2 h. The reaction mixture was allowed to cool again to room temperature and was partitioned between EtOAc and 10% aq. NaHSO4. The organic extracts were combined, washed with water and brine, dried (Na2SO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 0–30% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded the titled compound. HPLC/MS: 550.0 (M+1), 551.8 (M+3); Rt=4.74 min.
Reaction SMILES: [CH2:1]1[CH:8]2[N:4]([C:5](=[O:9])[CH2:6][CH2:7]2)[C:3](=[O:10])[CH2:2]1.Cl.[CH2:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:19][C:5](=[O:9])[CH2:6][CH2:7][CH:8]1[CH2:1][CH2:2][C:3](=[O:10])[NH:4]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCc1ccccc1
Reactant: O=C1CCC2CCC(=O)N12
Agent: Cl
Product: O=C1CCC(CCC(=O)OCc2ccccc2)N1
Temperature: 98 °C

Procedure:
Twenty-eight grams of dihydro 1H-pyrrolizine-3,5 (2H, 6H) dione is dissolved in 76 g of benzyl alcohol and 0.2 ml of concentrated hydrochloric acid is added. The solution is heated at 98° C. for 104 hours. The mixture is cooled and excess benzyl alcohol is distilled at 0.1 mm pressure to a maximum bath temperature of 100° C. The residual oil is dissolved in 1 l of anhydrous diethylether, 1 g of activated charcoal is added and the resulting suspension is filtered through filter aid. The filtrate is concentrated at reduced pressure and the resulting crystals are isolated by filtration. Recrystallization from cyclohexane containing 12% methylene chloride yields 5-oxo-2-pyrrolidinepropanoic acid benzyl ester with a melting point of 79°-80° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]([NH:15][CH2:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:14].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:30][CH2:31][N:32]1[CH2:37][C@H:36]([CH3:38])[O:35][C@H:34]([CH3:39])[CH2:33]1.CC#N>CC(C)=O>[CH3:39][C@H:34]1[O:35][C@@H:36]([CH3:38])[CH2:37][N:32]([CH2:31][CH2:30][N:20]2[CH2:21][CH2:22][CH:17]([CH2:16][NH:15][C:13]([C:7]3[C:6]4[C:10](=[CH:11][CH:12]=[C:4]([O:3][CH3:2])[CH:5]=4)[NH:9][N:8]=3)=[O:14])[CH2:18][CH2:19]2)[CH2:33]1
Reactant: C[C@@H]1CN(CCCl)C[C@H](C)O1
Reactant: COc1ccc2[nH]nc(C(=O)NCC3CCNCC3)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(C)=O
Product: COc1ccc2[nH]nc(C(=O)NCC3CCN(CCN4C[C@@H](C)O[C@@H](C)C4)CC3)c2c1
Yield: 48.3 %

Procedure:
A mixture of compound 7b (8 g, 24.6 mmoles) and potassium carbonate (17 g, 123 mmoles) in acetone (250 mL) was refluxed for 1 hour, then (2R,6S)-4-(2-chloroethyl)-2,6-di methyl morpholine (25.9 mmoles) was added dropwise. The mixture was refluxed overnight then was cooled and filtered. The resulting solid was dried and purified via preparative HPLC (channel A=CH3CN+0.1% formic acid; channel B=H2O+0.1% formic acid: flow=40 ml/min; gradient=10%-45% of eluent A in 15 minutes) providing N-[(1-{2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]ethyl}piperidin-4-yl)methyl]-5-methoxy-1H-indazole-3-carboxamide 25 (48.3% yield)
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:9]=[C:8]([Cl:10])[C:7]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:6][C:4]=1[NH2:5].[CH3:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[CH2:18][C:19]#N.C>CO>[Cl:10][C:8]1[C:7]([S:11](=[O:13])(=[O:14])[NH2:12])=[CH:6][C:4]2[NH:5][C:19]([CH2:18][C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[CH3:15])=[N:2][C:3]=2[CH:9]=1
Reactant: Cc1ccccc1CC#N
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1N
Agent: Cl
Solvent: CO
Product: Cc1ccccc1Cc1nc2cc(Cl)c(S(N)(=O)=O)cc2[nH]1
Reaction time: 0.08 h

Procedure:
To 50 ml of 6 N hydrochloric acid was added 11.8 g of 2-amino-4-chloro-5-sulfamylaniline and 10.4 g of 2-methylbenzyl cyanide. The reaction was refluxed for 22 hours and then concentrated in vacuo to a solid which was then added with stirring to 200 ml of 38% ammonium hydroxide. Filtration provided the free base as a semi-gum which was dissolved in 500 ml of methanol. The methanol solution was brought to a boil, charcoal added, and boiling continued for five minutes. Upon cooling, the suspension was filtered through Celite and the filtrate concentrated in vacuo to yield a solid, m.p. 226°-230°.