Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([O:14][CH2:15][C@@H:16]3[CH2:19][CH2:18][NH:17]3)[CH:10]=[N:11][C:12]=2[Cl:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[CH:22](O)=O.[BH3-]C#N.[Na+]>CCO.O.C([O-])([O-])=O.[K+].[K+]>[C:1]1([C:7]2[CH:8]=[C:9]([O:14][CH2:15][C@@H:16]3[CH2:19][CH2:18][N:17]3[CH3:22])[CH:10]=[N:11][C:12]=2[Cl:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ncc(OC[C@@H]2CCN2)cc1-c1ccccc1
Reactant: O=CO
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Solvent: CCO
Solvent: O
Product: CN1CC[C@H]1COc1cnc(Cl)c(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 5-phenyl-6-chloro-3-(2-(S)-azetidinylmethoxy)pyridine from Example 67 (100 mg, 0.36 mmol) in EtOH (3 mL) was added formalin (37%, 0.5 mL) and formic acid (0.25 mL), and the pH was adjusted to 6. Then NaCNBH3 (70 mg) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and saturated with K2CO3. The mixture was extracted with CHCl3. The solvent was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with CH2Cl2:MeOH 10:1 to afford the free base of the title compound. MS (CI/NH3) m/z 289 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 2.05-2.14 (m, 2H), 2.40 (s, 3H), 2.32-2.44 (m, 1H), 3.34-3.51 (m, 2H), 4.44 (d, J=7.5 Hz, 2H), 7.26 (d, J=3 Hz, 1H), 8.09 (d, J=3Hz, 1H). The salt was prepared by treatment with HCl in Et2O, as described above, to give the title compound. mp 187-188° C. MS (CI/NH3) m/z 289 (M+H)+. 1H NMR (D2O, 300 MHz) δ: 2.60-2.71 (m, 2H), 2.99 (s, 3H), 3.94-4.12 (m, 1H), 4.18-4/33 (m, 1H), 4.47-4.55 (m, 3H), 7.57 (m, 5H), 7.60 (d, J=3.0 Hz, 1H), 8.18 (d, J=3.0 Hz, 1H). Anal. Calcd for C16H17N2OCl.HCl.0.5 H2O: C, 57.50; H, 5.73; N, 8.38. Found: C, 57.38; H, 5.53; N, 8.35. [α]25D=+15° (c 0.11, MeOH).
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([OH:19])[CH:3]=1.Br[CH2:21][CH2:22][O:23][C:24](=[O:26])[CH3:25]>C(#N)C>[C:24]([O:23][CH2:22][CH2:21][O:19][C:4]1[CH:3]=[C:2]([NH2:1])[C:17]([Cl:18])=[CH:16][C:5]=1[C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[O:7])(=[O:26])[CH3:25]
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Reactant: CC(=O)OCCBr
Solvent: CC#N
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCOC(C)=O
Yield: 85.5 %

Procedure:
A solution of the tetrabutylammonium salt of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide (5.27 g, 10 mmoles) (prepared in Preparation No. 3) in acetonitrile (100 ml) and 2-bromoethylacetate (2 g, 12 mmoles) was stirred for 48 hours. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic layer was washed with ice-cold 0.4N sodium hydroxide solution, water, dried and the solvent evaporated. The residue was chromatographed over deactivated silica using methylene chloride (100 ), methanol (2), ammonia (0.5) solvent system. The appropriate fractions were combined and the solvent evaporated to leave a residue of 3.18 g (85%) of the title compound. Crystallization from toluene gave a sample, mp. 101°-102° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[CH:5][NH:4][N:3]=1.[CH2:8]=[O:9]>CO>[OH:9][CH2:8][N:4]1[CH:5]=[C:6]([CH3:7])[C:2]([CH3:1])=[N:3]1
Reactant: C=O
Reactant: Cc1c[nH]nc1C
Solvent: CO
Product: Cc1cn(CO)nc1C
Yield: 95 %

Procedure:
96 g (1.0 mol) of 3,4-dimethylpyrazole in 50 ml of methanol were dissolved in 100 g (1.0 mol) of formalin solution (30%) at room temperature. Water and methanol were then evaporated. The title compound remained as a white solid (yield 95%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:23][CH3:24])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Cl:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([Cl:39])[C:31]=1[C:32](=O)[C:33]([O:35]CC)=O.CC(O)=O>COCCO>[Cl:39][C:30]1[CH:29]=[N:28][CH:27]=[C:26]([Cl:25])[C:31]=1[C:32]1[C:33](=[O:35])[N:23]([CH3:24])[C:3]2[N:4]=[C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]([CH2:19][CH3:20])[CH2:21][CH3:22])=[CH:11][CH:10]=3)[N:6]=[CH:7][C:2]=2[N:1]=1
Reactant: CCN(CC)CCOc1ccc(Nc2ncc(N)c(NC)n2)cc1
Reactant: CCOC(=O)C(=O)c1c(Cl)cncc1Cl
Solvent: CC(=O)O
Solvent: COCCO
Product: CCN(CC)CCOc1ccc(Nc2ncc3nc(-c4c(Cl)cncc4Cl)c(=O)n(C)c3n2)cc1
Yield: 15.3 %

Procedure:
A mixture of 0.465 g (1.4 mmol) of 5-amino-2-[[4-[2-(diethylamino)-ethoxy]-phenyl]amino]-4-(methylamino)pyrimidine, 0.69 g (2.8 mmol) of ethyl 2-(3,5-dichloropyridin-4-yl)-2-oxoacetate, and 0.5 mL of HOAc in 15 mL of 2-methoxyethanol is heated under reflux for 18 hours, and the reaction is worked up as above in 6 to give 0.11 g (15%) of the title compound (Compound 20): mp (MeOH) 179–180.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:7]([NH2:9])[CH:8]=1.[OH:20][C:21]1[CH:22]=[C:23]([C:30](O)=[O:31])[C:24](=[CH:28][CH:29]=1)[C:25](O)=[O:26]>>[OH:20][C:21]1[CH:22]=[C:23]2[C:24](=[CH:28][CH:29]=1)[C:25](=[O:26])[N:9]([C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[C:30]2=[O:31]
Reactant: O=C(O)c1ccc(O)cc1C(=O)O
Reactant: COc1ccc(CCc2ccc(OC)cc2N)cc1
Product: COc1ccc(CCc2ccc(OC)cc2N2C(=O)c3ccc(O)cc3C2=O)cc1
Yield: 110.6 %

Procedure:
Synthesized from 5-methoxy-2-[2-(4-methoxyphenyl)ethyl]phenylamine (1.5 g) and 4-hydroxyphthalic acid (1.6 g) according to an analogous synthetic method to Preparation Example 112, the title compound (2.6 g) was obtained.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15](=[O:23])[NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:13])([CH3:12])[CH3:11].[CH3:24][O:25][C:26](=[O:38])[C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][C:28]=1[F:37]>C(Cl)Cl>[CH3:24][O:25][C:26](=[O:38])[C:27]1[CH:32]=[CH:31][C:30]([S:33]([N:20]2[CH2:21][CH2:22][CH:17]([NH:16][C:15]([O:14][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:23])[CH2:18][CH2:19]2)(=[O:34])=[O:35])=[CH:29][C:28]=1[F:37]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(S(=O)(=O)N2CCC(NC(=O)OC(C)(C)C)CC2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
Diisopropylethylamine (3.2 ml, 18.5 mmol) was added in one portion to a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester (0.5 g, 2.5 mmol) in DCM (10 ml) at room temperature. To this mixture was added 4-chlorosulfonyl-2-fluoro-benzoic acid methyl ester (0.6 g, 2.5 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time the mixture was diluted with DCM (50 ml) and washed sequentially with HCl (1M solution, 10 ml), NaOH (1M solution, 10 ml) and brine (10 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated. The resulting residue was purified by flash column chromatography (elution: 98% DCM, 2% Methanol) to give the title compound (0.98 g, 87% yield) as a white solid. Tr=2.08 min m/z (ES+) (M+Na+) 439.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11]COCC)[CH:3]=1.[C:16]1(OB(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:3][C:4]=1[OH:11])([O-:10])=[O:9]
Reactant: OB(O)Oc1ccccc1
Reactant: CCOCOc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(-c2ccccc2)cc1O
Temperature: 80 °C

Procedure:
9.3 g (40 mmol) of 4-chloro-2-(ethoxymethoxy)-1-nitrobenzene from step A and 7.3 g (60 mmol) of phenylboric acid were dissolved in 170 mL of toluene under nitrogen. Then, 0.1 g (0.5 mmol) of palladium acetate, 0.35 g (1 mmol) of 2-(dicyclohexylphosphino)biphenyl and 15 g of tripotassium phosphate were added, and the reaction mixture was heated to 80° C. At the end of the reaction, the reaction mixture was poured into 100 mL of ethyl acetate and the organic phase was extracted with dilute sodium hydroxide solution and then dried over magnesium sulfate. The solvent was distilled off in a rotary evaporator, and the residue was purified on silica gel with hexane/ethyl acetate (9:1). The resulting product dissolved in 50 mL of ethanol was heated to 50° C. 80 mL of a 2.9-molar ethanolic hydrochloric acid solution was then added dropwise after which the reaction mixture was cooled to 0° C. The precipitate was filtered off, washed twice with 20-mL portions of ethanol and then dried. This gave 9.35 g of 4-nitro-1,1′-biphenyl-3-ol.
Reaction SMILES: [CH:1]1([N:6]2[C:10](=[O:11])[C:9]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=4)=[CH:15][C:8]=3[S:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[CH3:37])[C:31]([OH:33])=[O:32].C([O-])([O-])=O.[Na+].[Na+].N#N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH:1]1([N:6]2[C:10](=[O:11])[C:9]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:19]=[C:20]([C:28]5[C:36]([CH3:37])=[CH:35][CH:34]=[C:30]([C:31]([OH:33])=[O:32])[CH:29]=5)[CH:21]=[CH:22][CH:23]=4)=[CH:15][C:8]=3[S:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)O)cc1I
Reactant: O=c1c2ccc(OCc3cccc(B(O)O)c3)cc2sn1C1CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Cc1ccc(C(=O)O)cc1-c1cccc(COc2ccc3c(=O)n(C4CCCC4)sc3c2)c1
Temperature: 25 °C
Yield: 35.7 %

Procedure:
A mixture of 3-((2-cyclopentyl-3-oxo-2,3-dihydrobenzo[d]isothiazol-6-yloxy)methyl)phenylboronic acid (0.050 g, 0.14 mmol), 3-iodo-4-methylbenzoic acid (0.053 g, 0.20 mmol) and tetrakistriphenylphosphinepalladium(0) (0.016 mg, 0.014 mmol) were taken 2 mL of DME. To this 1M Na2CO3 (0.48 mmol) solution was added and the resulting solution was refluxed in an atmosphere of N2 for 12 h. The reaction mixture cooled to room temperature and the solvent was removed under vacuum. The solvent was evaporated and the residue was dissolved in water and neutralized using 1M HCl. The aqueous layer was extracted with ethyl acetate and the organic layer was dried over anhydrous Na2SO4. The solvent was evaporated in vacuum to obtain the crude acid as a yellow solid. The crude residue was purified using automated prep-HPLC to yield the desired compound as a pale yellow solid (0.023 g, 36%). 1H NMR (400 MHz, CDCl3): δ 8.01 (s, 1H), 7.90 (d, 1H, J=8.5 Hz), 7.65-7.23 (m, 7H), 7.03 (s, 1H), 5.23 (s, 2H), 4.64-4.59 (m, 1H), 2.34 (s, 3H), 2.16-2.14 (m, 2H), 1.88-1.68 (m, 6H). LC-MS (ESI) Calcd for C27H25NO4S [M+H]+: 460.15. Found: 460.00.
Reaction SMILES: [CH2:1]([NH:5][C:6](=O)[CH2:7][CH2:8][N:9]([CH2:13][CH2:14][C:15](=O)[NH:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:10][CH2:11][SH:12])[CH2:2][CH2:3][CH3:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>COCCOC.C(Cl)Cl>[CH2:17]([NH:16][CH2:15][CH2:14][CH2:13][N:9]([CH2:8][CH2:7][CH2:6][NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH2:10][CH2:11][SH:12])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCNC(=O)CCN(CCS)CCC(=O)NCCCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: CCCCNCCCN(CCS)CCCNCCCC

Procedure:
Dissolve N-butyl-3-[(2-butylcarbamoyl-ethyl)-(2-mercapto-ethyl)-amino]-propionamide (10 mmol) prepared in Scheme VIII, step A in 1,2-dimethoxyethane (50 mL) and treat with lithium aluminum hydride (20 mmol). Heat the reaction to reflux for 18 hours. After cooling the reaction is worked up by consecutive addition of water (0.8 mL), 10% sodium hydroxide (1.2 mL) and water (2.2 mL). Then dilute with methylene chloride (200 mL), rinse with water (100 mL), brine (100 mL), dry over anhydrous sodium sulfate, filter and concentrate under vacuum. Purify the residue by flash chromatography (silica gel, methanol/methylene chloride) to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].I[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu].C(OCC)(=O)C>[C:13]1([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Ic1ccccc1
Reactant: COC(=O)c1ccccc1N
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1Nc1ccccc1
Temperature: 180 °C
Yield: 90 %

Procedure:
A mixture of methyl 2-aminobenzoate (7 g), iodobenzene (3.9 ml), potassium carbonate (6.4 g), and copper powder (0.46 g) was heated at 180° C. for 17 hours. The reaction solution was allowed to cool to room temperature, and ethyl acetate was added thereto. The resulting mixture was stirred and filtered with celite. The filtrate was washed with ethyl acetate and concentrated under reduced pressure. The thus-obtained residue was purified by silica gel column chromatography (developing solvent, ethyl acetate: hexane=1:30) to obtain methyl 2-phenylaminobenzoate (7.13 g; yield, 90%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[C:7]2[CH:14]=[CH:13][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11][C:8]=2[S:9][CH:10]=1)[CH3:2].Br[C:26]1[CH:49]=[CH:48][C:29]([O:30][CH2:31][C:32]2[N:36]([C:37]3[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][C:38]=3[Cl:44])[N:35]=[CH:34][C:33]=2[CH:45]([CH3:47])[CH3:46])=[CH:28][C:27]=1[CH3:50].N#N.C1(P(C2CCCCC2)C2(OC)CC=CC(OC)=C2C2C=CC=CC=2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[C:7]2[CH:14]=[CH:13][C:12]([C:26]3[CH:49]=[CH:48][C:29]([O:30][CH2:31][C:32]4[N:36]([C:37]5[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][C:38]=5[Cl:44])[N:35]=[CH:34][C:33]=4[CH:45]([CH3:46])[CH3:47])=[CH:28][C:27]=3[CH3:50])=[CH:11][C:8]=2[S:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)Cc1csc2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Reactant: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COC1=C(c2ccccc2)C(OC)(P(C2CCCCC2)C2CCCCC2)CC=C1
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1csc2cc(-c3ccc(OCc4c(C(C)C)cnn4-c4c(Cl)cccc4Cl)cc3C)ccc12
Temperature: 100 °C
Reaction time: 15 h
Yield: 11.8 %

Procedure:
A solution of [6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo[b]thiophen-3-yl]-acetic acid ethyl ester (267 mg, 0.770 mmol) and 5-(4-bromo-3-methyl-phenoxymethyl)-1-(2,6-dichloro-phenyl)-4-isopropyl-1H-pyrazole (280 mg, 0.616 mmol) in toluene (10 mL) is evacuated and refilled with N2 three times. Pd(OAc)2 (5.5 mg, 0.024 mmol), 2-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl (20 mg, 0.049 mmol), and potassium phosphate, tribasic, N-hydrate (262 mg, 1.23 mmol) are added. The mixture is stirred at 100° C. for 15 hours. The reaction mixture is cooled to room temperature and filtered through a pad of celite. The filtrate is concentrated, and the residue is purified by flash chromatography (eluted with 25% EtOAc/Hexanes) and the appropriate fractions are concentrated. The material is dried in vacuo to afford (6-{4-[2-(2,6-dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-benzo[b]thiophen-3-yl)-acetic acid ethyl ester (43 mg, 12% yield). ES/MS m/e 592.8; 594.8 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][NH2:14])=[C:9]([Cl:15])[CH:8]=1)[CH3:6])[CH3:2].C(O[CH:20]([CH3:31])[C:21](OCC)(OCC)OCC)C.Cl>C(O)C>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:31]=[CH:20][CH:21]=[N:14]2)=[C:9]([Cl:15])[CH:8]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)c1ccc(NN)c(Cl)c1
Reactant: CCOC(C)C(OCC)(OCC)OCC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(C)c1ccc(-n2cccn2)c(Cl)c1
Yield: 82.8 %

Procedure:
2.11 g (8.7 mmoles) of 2-(3-chloro-4-hydrazinophenyl)propionic acid ethyl ester and 1.91 g of tetra-ethoxypropane are dissolved in 2 ml of absolute ethanol. The solution is saturated with hydrochloric acid gas and left to stand for half an hour. The solvent is evaporated off; the residue is distilled. 2 g (83%) of 2-[3-chloro-4-(pyrazol-1-yl) phenyl] propionic acid ethyl ester (b.p. 120° C./10-2 mm Hg) are obtained.
Reaction SMILES: [CH3:1][S:2]([N:5]([S:7]([NH:10][C:11](=[O:15])OCC)(=[O:9])=[O:8])[CH3:6])(=[O:4])=[O:3].[NH2:16][C:17]1[N:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[N:18]=1>ClC1C=CC=CC=1>[CH3:1][S:2]([N:5]([S:7]([NH:10][C:11]([NH:16][C:17]1[N:18]=[C:19]([O:25][CH3:26])[CH:20]=[C:21]([O:23][CH3:24])[N:22]=1)=[O:15])(=[O:8])=[O:9])[CH3:6])(=[O:3])=[O:4]
Reactant: CCOC(=O)NS(=O)(=O)N(C)S(C)(=O)=O
Reactant: COc1cc(OC)nc(N)n1
Solvent: Clc1ccccc1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)N(C)S(C)(=O)=O)n1
Temperature: 80 °C
Yield: 98.5 %

Procedure:
52.0 g of ethyl (N-methylsulfonyl-N-methylamino)sulfonylcarbamate are dissolved in 500 ml of chlorobenzene, 31.0 g of 2-amino-4,6-dimethoxypyrimidine are added at room temperature with stirring, and the mixture is heated at 80° C. for 3 hours. After cooling to 0° C., the precipitate is filtered off and washed with 100 ml of chlorobenzene. 72.7 g of the desired product of a purity of 98.5% are obtained, which corresponds to a yield of 97.2% of theory. The melting point of the product is 185°-186° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=O)[C:11]([N:13]2[CH2:18][CH2:17][CH:16]([O:19][C:20]3[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)[CH2:15][CH2:14]2)=O)=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:22]1([CH3:26])[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH:16]2[CH2:15][CH2:14][N:13]([CH2:11][CH2:10][C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[CH2:18][CH2:17]2)[CH:21]=1
Reactant: Cc1cccc(OC2CCN(C(=O)C(=O)c3c[nH]c4ccccc34)CC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccc(OC2CCN(CCc3c[nH]c4ccccc34)CC2)c1

Procedure:
A solution of 10.0 of 1-(indol-3ylglyoxyloyl)-4-(m-tolyloxy)piperidine in 205 ml. of tetrahydrofuran is added dropwise to a stirred suspension of 4.8 g of lithium aluminum hydride in 140 ml. of tetrahydrofuran. After the addition is complete, the mixture is stirred and refluxed for 3 hours under nitrogen, cooled, and the excess hydride is carefully destroyed with water. The inorganic precipitate is filtered off and washed with tetrahydrofuran. The filtrate is concentrated, under reduced pressure, to a clear oil which crystallizes to a white solid. The solid is recrystallized from acetonitrile to give white needles of 3-{2-[4-(m-tolyloxy)piperidyl]ethyl}indole, m.p. 145°-146° C.
Reaction SMILES: [H-].[Na+].C(OC([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][OH:18])[CH2:12][CH2:11]1)=O)(C)(C)C.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1>C1COCC1>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][O:18][CH2:17][CH2:16][CH:13]2[CH2:12][CH2:11][NH:10][CH2:15][CH2:14]2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: COc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COCCC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.7 %

Procedure:
NaH (60% dispersion in oil, 98 mg, 2.4 mmol, 1.2 equiv.) was added to a solution of 1-(tert-butoxycarbonyl)-4-(2-hydroxyethyl)piperidine (468 mg, 2.0 mmol) in THF (10 mL) at 0° C. under Ar protection. The mixture was warmed to room temperature and stirred at that temperature for 3 h. 1-(Bromomethyl)-4-methoxybenzene (353 μL, 2.4 mmol, 1.2 equiv.) was added at room temperature. After stirring for 20 h, the reaction was quenched with saturated aqueous NH4Cl solution. The mixture was extracted three times with EtOAc, and the combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed, and the residue was purified by CC (SiO2, hexane/EtOAc 10:1 to 4:1) to afford the product (268 mg, 38%) as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 7.22 (d, 2H, J=8.4 Hz), 6.85 (d, 2H, J=8.8 Hz), 4.40 (s, 2H), 4.05 (m, 2H), 3.76 (m, 4H), 3.45 (t, 2H, J=6.0 Hz), 2.65 (m, 2H), 1.62-1.50 (m, 5H), 1.44 (s, 9H), 1.08 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][C:15](OC)=[O:16])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][CH2:15][OH:16])=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1cnoc1-c1ccc(Cl)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCc1cnoc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To a solution of methyl 3-[5-(4-chlorophenyl)-4-isoxazolyl]propionate (6.00 g) in tetrahydrofuran (100 ml) was gently added diisobutylaluminum hydride (1.0 M hexane solution, 50 ml) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 3-[5-(4-chlorophenyl)-4-isoxazolyl]propan-1-ol (4.89 g, yield 91%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 58–59° C.
Reaction SMILES: C(OC([N:8]1[CH2:31][CH2:30][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:12]2=[O:29])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C.CCOCC>[CH2:22]([N:13]1[C:12](=[O:29])[C:11]2([CH2:30][CH2:31][NH:8][CH2:9][CH2:10]2)[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(Cc1ccccc1)CN2c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C1N(Cc2ccccc2)CN(c2ccccc2)C12CCNCC2

Procedure:
A solution of 2.16 g (5.12 mmol) 3-benzyl-4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester in 43 ml ethyl acetate and 25 ml of a saturated solution of HCl in ether was stirred at ambient temperature for 90 min. The resulting suspension was filtered, the filtrate was dissolved in water and treated with saturated NaHCO3 and extracted with dichloromethane. The combined organic extracts were washed with brine, dried over MgSO4, filtered and evaporated to provide 3-benzyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one as a brown solid; MS (ISP): 322.5 MH+.