Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[C:18]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.C([Li])CCC.[CH2:24]([N:31]1[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[CH2:24]([N:31]1[CH2:36][CH2:35][C:34]([OH:37])([C:9]2[C:18]3[O:17][CH2:16][CH2:15][O:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH2:33][CH2:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Brc1cccc2c1OCCO2
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: OC1(c2cccc3c2OCCO3)CCN(Cc2ccccc2)CC1

Procedure:
A toluene solution (10 ml) of 5-bromo-2,3-dihydrobenzo[1,4]dioxin (10 mmol) was stirred under argon at 0° C. and was treated with the dropwise addition of n-butyllithium (10 mmol) over ten minutes. After stirring for a further twenty minutes a solution of 1-benzyl-4-piperidone in toluene (10 mmol in 10 ml) was added dropwise over five minutes. Stirring was continued for two hours, at which point water (100 ml) was added and the product extracted into ethyl acetate (4×50 ml). The combined organics were washed with water (2×50 ml), brine (75 ml) and dried (MgSO4). Filtration and concentration in vacuo gave an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[C:5]([CH3:9])([CH3:8])[CH2:6][NH2:7])[CH3:2].[C:11]1(=O)[CH2:15][CH2:14][CH2:13][CH2:12]1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:10])[C:5]([CH3:9])([CH3:8])[CH2:6][NH:7][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[CH3:2]
Reactant: O=C1CCCC1
Reactant: CCOC(=O)C(C)(C)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)CNC1CCCC1

Procedure:
Reaction of 3-amino-2,2-dimethyl-propionic acid ethyl ester with cyclopentanone, sodium acetate and sodium triacetoxyborohydride in DCM gave 3-Cyclopentylamino-2,2-dimethyl-propionic acid ethyl ester
Reaction SMILES: [CH2:1]([N:4]([CH2:28][CH2:29][CH3:30])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][NH:20][CH2:21][C:22]3[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=3)[CH:15]=2)[CH2:10]1)[CH2:2][CH3:3].N1C=CC=CC=1.Cl.[NH:38]1[CH:42]=[CH:41][N:40]=[C:39]1[S:43](Cl)(=[O:45])=[O:44].[OH-].[Na+]>ClCCl>[CH2:28]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][N:20]([CH2:21][C:22]3[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=3)[S:43]([C:39]3[NH:38][CH:42]=[CH:41][N:40]=3)(=[O:45])=[O:44])[CH:15]=2)[CH2:10]1)[CH2:29][CH3:30]
Reactant: CCCN(CCC)CCCCN1CCc2cc(CNCc3nccn3C)ccc2C1
Reactant: O=S(=O)(Cl)c1ncc[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCN(CCC)CCCCN1CCc2cc(CN(Cc3nccn3C)S(=O)(=O)c3ncc[nH]3)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
In a solution of the compound 23-a (100 mg) and pyridine (59 mL) in dichloromethane (3 mL), the compound 36 (74 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. To the reaction mixture, an aqueous 1N sodium hydroxide solution (15 mL) was added. The aqueous layer was extracted twice with dichloromethane (30 mL). The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel chromatography (ethyl acetate:methanol:triethylamine=10:1:0→10:1:0.5) to obtain the title compound (119 mg) having the following physical properties.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[CH:11]([NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1)([CH3:13])[CH3:12].[ClH:26]>C(=O)([O-])[O-].[Na+].[Na+].C(COC)OC.C(OCC)(=O)C>[ClH:26].[CH:11]([NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:21][CH:20]=1)([CH3:13])[CH3:12]
Reactant: Cc1ccccc1B(O)O
Reactant: CC(C)NCCCOc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1ccccc1-c1ccc(OCCCNC(C)C)cc1
Temperature: 80 °C

Procedure:
2-Methylphenyl boronic acid (0.42 g) was added to a solution of N-isopropyl-3-(4-bromophenoxy)propylamine (1.0 g) and tetrakis triphenylphosphine palladium (100 mg) in aqueous 2M sodium carbonate (8.4 ml) and dimethoxyethane (5 ml). The mixture was heated at 80° C. for 18 hours, cooled to ambient temperature and diluted with ethyl acetate. The reaction mixture was washed with dilute sodium hydroxide solution, brine, dried (MgSO4) and evaporated. The residue was purified by dry flash column chromatography on silica gel (Merck 60H, Art No 7736) using a 5:95 v/v mixture of methanol and dichloromethane to give an oil. This oil was treated with ethereal hydrogen chloride to give a solid which was recrystallised from isopropyl alcohol to give N-isopropyl-3-[4-(2-methylphenyl)phenoxy]propylamine hydrogen chloride (0.38 g) as a solid, m.p. 157°-158° C.; microanalysis, found: C, 71.6; Hi 8.2; N, 4.4; Cl, 10.8%; C19H25NO. HCl requires: C, 71.3; H, 8.19; N, 4.38; Cl, 11.1%; NMR([CD3 ]2SO): 1.27(6H,d), 2.14(2H,m), 2.22(3H,s), 3.05(2H,t), 3.29(1H,m), 4.13(2H,t), 7.01(2H,d) and 7.12-7.30(6H,m); m/z 284(M+H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(Cl)[Cl:17].S(Cl)(Cl)=O>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([Cl:17])=[O:15])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: ClCCl
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 25 °C

Procedure:
To an oven-dried round bottom flask containing 1-(benzo[d][1,3]dioxol-5-yl)-cyclopropanecarboxylic acid (A-8) (618 mg, 3.0 mmol) and CH2Cl2 (3 mL) was added thionyl chloride (1.07 g, 9.0 mmol) and N,N-dimethylformamide (0.1 mL). The reaction mixture was stirred at ambient temperature under an Ar atmosphere until the gas evolution ceased (2-3 h). The excess thionyl chloride was removed under vacuum and the resulting residue dissolved in CH2Cl2 (3 mL). The mixture was used without further manipulation.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[CH:30]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][C:34]1=[O:39])([CH3:32])[CH3:31].CO.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:36]4[CH2:37][CH2:38][N:33]([CH:30]([CH3:32])[CH3:31])[C:34](=[O:39])[CH2:35]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: CC(C)N1CCNCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)C)C(=O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 21.8 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.15 g, 0.39 mmol), 1-isopropylpiperazin-2-one (0.082 g, 0.58 mmol) and 4 Å molecular sieves (0.718 g) in DCE (5 mL) and MeOH (1 mL) was stirred for 5 h at room temperature. Sodium triacetoxyborohydride (0.163 g, 0.77 mmol) was added and the reaction mixture was stirred for 72 h at room temperature. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:EtOAc, gradient 0:100 to 5:95) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to give 469 as an off-white solid (0.044 g, 22%). LCMS (Method I): RT=3.31 min, [M+H]+ 518.3. 1H NMR (400 MHz, DMSO-d): δ 8.04-8.00 (m, 1 H); 7.65-7.61 (m, 1 H); 7.28-7.21 (m, 2 H); 4.64-4.58 (m, 1 H); 4.28-4.25 (m, 4 H); 3.86 (s, 2 H); 3.81 (s, 3 H); 3.80-3.77 (m, 4 H); 3.27 (q, 7.5 Hz, 2 H); 3.17 (t, J=5.3 Hz, 2 H); 3.13 (s, 2 H); 2.73 (t, J=5.3 Hz, 2 H); 1.34 (t, J=7.5 Hz, 3 H); 1.05 (d, J=6.8 Hz, 6 H)
Reaction SMILES: [C:1]1([CH:7]2[N:11]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:10][CH:9]([CH2:16][OH:17])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.O>C(N(CC)CC)C>[C:1]1([CH:7]2[N:11]([C:12]([CH3:13])([CH3:14])[CH3:15])[CH2:10][CH:9]([CH2:16][O:17][S:24]([C:21]3[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=3)(=[O:26])=[O:25])[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)N1CC(CO)OC1c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2CN(C(C)(C)C)C(c3ccccc3)O2)cc1

Procedure:
To a solution of dl-2-phenyl-3-t-butyl-5-hydroxymethyloxazolidine (12.05 g.) in triethylamine (120 ml.) 13 is added p-toluenesulfonylchloride (14.5 g.). After 6 days at room temperature the mixture is added to water (500 ml.) and extracted with ether (2×200 ml.). The ether solution is washed with water, dried with anhydrous magnesium sulfate and evaporated to dryness. The residue is recrystallized from hexane to afford 2-phenyl-3-t-butyl-5-p-toluenesulfonyloxymethyloxazolidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([CH3:34])=[C:32]([CH:35]=O)[NH:31][C:30]=2[CH3:37])=[O:28])[CH:23]=[CH:22][N:21]=[N:20]1>C(O)C.N1CCCCC1>[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([CH3:34])=[C:32]([CH:35]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)[NH:13][C:12]3=[O:18])[NH:31][C:30]=2[CH3:37])=[O:28])[CH:23]=[CH:22][N:21]=[N:20]1
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cccc(-c2cccc3c2C(=Cc2[nH]c(C)c(C(=O)NCCn4ccnn4)c2C)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 14.9 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (18 mg, 15%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:8]([O:10]C)=[O:9])([CH3:4])([CH3:3])[CH3:2].CO.O.Cl>[OH-].[Na+]>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:8]([OH:10])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(OC)c(C(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)O)cc1C(C)(C)C
Yield: 93.6 %

Procedure:
Preparation C11, Step 2: Methyl 3-tert-butyl-4-methoxybenzoate (1.12 g, 5.03 mmol, 1 eq) was dissolved in 1N NaOH in methanol (50.38 mL, 50.3 mmol, 10 eq) at room temperature then refluxed for 4 hours. Worked up stripping off the methanol. Added H2O (10 mL) then adjusted the pH to 3 with 6N HCl. Solids precipitated. Extracted the suspension 3 times with methylene chloride (20 mL). The organic layers were combined, dried (sodium sulfate) and stripped to give 3-tert-butyl-4-methoxybenzoic acid (0.98 g) as a white solid. Yield=93%. LCMS detects (M+H)+=208.25.
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:12]3[C:19]([C:20](=[O:36])[C:21]4[C:26]([F:27])=[CH:25][CH:24]=[C:23]([NH:28][S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30])[C:22]=4[F:35])=[CH:18][NH:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:6][CH:5]=1.CO.[OH-].[Na+].Cl>O1CCCC1>[F:35][C:22]1[C:23]([NH:28][S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30])=[CH:24][CH:25]=[C:26]([F:27])[C:21]=1[C:20]([C:19]1[C:12]2[C:11]([NH:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:37])=[O:2])=[CH:9][CH:8]=3)=[N:16][CH:15]=[N:14][C:13]=2[NH:17][CH:18]=1)=[O:36]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncnc(Nc4ccc(C(=O)OC)cc4)c23)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncnc(Nc4ccc(C(=O)O)cc4)c23)c1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 97 %

Procedure:
4-{5-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-benzoic acid methyl ester (P-1162, 26 mg, 0.05 mmol) is combined with 1 mL of methanol is added, 0.5 mL of tetrahydrofuran, and 0.5 mL of 2 M sodium hydroxide. The reaction is stirred at room temperature for 48 hours, then neutralized with 1 M hydrochloric acid and the volatile solvents are removed under vacuum. The remaining aqueous suspension is filtered to collect the solids, which are dried under vacuum to provide the desired compound (P-1163, 25 mg). MS (ESI) [M+H+]+=516.0.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[N:6][CH:7]=1.C([Li])CCC.CCCCCC.CON(C)[C:26](=[O:28])[CH3:27].[NH4+].[Cl-]>C1COCC1>[CH:9]([O:8][C:5]1[N:6]=[CH:7][C:2]([C:26](=[O:28])[CH3:27])=[CH:3][CH:4]=1)([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(Br)cn1
Reactant: CON(C)C(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OC(C)C)nc1
Temperature: -66 °C
Reaction time: 0.25 h
Yield: 77.3 %

Procedure:
A round-bottomed flask was charged with 5-bromo-2-iso-propoxypyridine (IM1) (5.00 g, 23.1 mmol) in THF (100) under N2 and cooled in an acetone/dry-ice bath to −66° C. (internal temperature). A solution of 2.5 M n-butyllithium in hexane (10.1 mL, 25.3 mmol) was added drop wise over 10 minutes at keeping the internal temperature below −55° C. The mixture was stirred at −65° C. for 15 minutes. N-methoxy-N-methylacetamide (3.07 mL, 28.9 mmol) dissolved in THF (10 mL) was then added drop wise over 10 minutes while keeping the internal temperature below −65° C. After stirring for 1 h the mixture was allowed to reach room temperature. The mixture was poured into saturated aqueous NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and evaporated to dryness. Flash chromatography (silica, heptanes/EtOAc 4:1) gave the title compound as a colorless oil (3.20 g, 77%) sufficiently pure for the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:9]([CH3:17])([CH2:11][CH2:12][C:13]([CH3:16])(Cl)[CH3:14])[CH3:10].[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:13]([CH3:16])([CH3:14])[CH2:12][CH2:11][C:9]([CH3:17])([CH3:10])[C:4]=2[CH:3]=1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: Brc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.4 %

Procedure:
To a solution of 2-bromobenzene (40 g, 255 mmol) and 2,5-dichloro-dimethyl hexane (52.7 g, 280 mmol) in 600 mL anhydrous CH2Cl2 at 5° C. was added, portionwise, AlCl3 (10.2 g, 76 mmol). Upon addition of AlCl3, HCl gas evolution was observed. The solution changed from yellow to reddish orange. The reaction solution was kept at 5-20° C. for two hours and then allowed to stir at room temperature overnight. The reaction mixture was poured into 600 g of ice and extracted with CHCl3 (2×700 mL). The organic phase was washed with water, aqueous saturated NaHCO3, saturated NaCl and dried (Na2SO4). The organic solution was then concentrated in vacuo and chromatographed (hexane) to provide 50 g of 2-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene as a yellow gummy solid in 73% yield. 1H NMR (400 MHz, CDCl3) δ7.41 (d, J=2.0 Hz, 1H, aromatic), 7.22 (dd, J=8.0 and 1.9 Hz, 1H, aromatic), 7.18 (d, J=8.0 Hz, 1H, aromatic), 1.68 (s, 4H, 2CH2), 1.27 (s, 6H, 2CH3), 1.24 (s, 6H, 2CH3).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]([CH2:30][CH2:31][CH3:32])[CH:9]2[CH2:18][C:17]3[CH:16]=[C:15]([O:19][S:20]([C:23]4[C:24]([CH3:29])=[N:25][O:26][C:27]=4[CH3:28])(=[O:22])=[O:21])[CH:14]=[CH:13][C:12]=3[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.C(OC([N:40]1[CH2:45][CH2:44][CH:43]([C:46](O)=[O:47])[CH2:42][CH2:41]1)=O)(C)(C)C.CCN=C=NCCCN(C)C.C(N(CC)CC)C>ClCCl>[NH:40]1[CH2:45][CH2:44][CH:43]([C:46]([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][N:8]([CH2:30][CH2:31][CH3:32])[CH:9]3[CH2:18][C:17]4[CH:16]=[C:15]([O:19][S:20]([C:23]5[C:24]([CH3:29])=[N:25][O:26][C:27]=5[CH3:28])(=[O:22])=[O:21])[CH:14]=[CH:13][C:12]=4[CH2:11][CH2:10]3)[CH2:3][CH2:2]2)=[O:47])[CH2:42][CH2:41]1
Reactant: CCCN(CC1CCNCC1)C1CCc2ccc(OS(=O)(=O)c3c(C)noc3C)cc2C1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(CC1CCN(C(=O)C2CCNCC2)CC1)C1CCc2ccc(OS(=O)(=O)c3c(C)noc3C)cc2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.7 %

Procedure:
Under an inert atmosphere 3,5-dimethyl-isoxazole-4-sulfonic acid 7-(piperidin-4-ylmethyl-propyl-amino)-5,6,7,8-tetrahydro-naphthalen-2-yl ester (400 mg, 0.87 mmol), piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (199 mg, 0.87 mmol, 1 eq.), EDCI (166 mg, 0.87 mmol, 1 eq.), triethylamine (0.25 mL, 1.79 mmol, 2 eq.), and dichloromethane (35 mL) were combined. The mixture was stirred at room temperature for 48 h and then concentrated in vacuo. The residue was taken up in EtOAc (50 mL) and washed with water (30 mL), 1N NaOH (30 mL), brine (30 mL), and then dried (MgSO4). The solution was filtered and concentrated to afford a yellow oil. The oil was flash chromatographed on silica gel eluting with 20% acetone in hexanes to afford the protected amine as a foam (447 mg), which was deprotected with trifluoroacetic acid, as described herein, to afford 3,5-dimethyl-isoxazole-4-sulfonic acid 7-{[1-(piperidine-4-carbonyl)-piperidin-4-ylmethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-yl ester (320 mg), 114M+H]+=609.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:7]([CH3:8])[N:6]=[C:5]([OH:9])[CH:4]=1.[Cl:12]N1C(C)(C)C(=O)N(Cl)C1=O>CCOCC>[F:11][C:2]([F:1])([F:10])[C:3]1[N:7]([CH3:8])[N:6]=[C:5]([OH:9])[C:4]=1[Cl:12]
Reactant: Cn1nc(O)cc1C(F)(F)F
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Solvent: CCOCC
Product: Cn1nc(O)c(Cl)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 4 h
Yield: 171.4 %

Procedure:
1907 g (11.48 mol) of 5-trifluoromethyl-3-hydroxy-1-methylpyrazole was stirred with 8 kg of ether and cooled to 0° C. 1222 g (6.2 mol) of 1,3-dichloro-5,5-dimethylhydantoin was added in three equal portions and the mixture was allowed to cool to 0° C. after each addition. The mixture was stirred for 4 hours, washed with water, brine and water. All washes were extracted with ether and the combined ether solutions were dried with MgSO4 filtered, evaporated on a rotary evaporator and recrystallized from methylcyclohexane to give 2131 g of a tan solid, m.p. 136°-140° C.
Reaction SMILES: [C:1]1([C:7]2([C:13]#[N:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)[CH2:17][C:18](=[O:20])C.C1OC1>C(O)C>[OH:20][CH2:18][CH2:17][N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:13]#[N:14])[CH2:12][CH2:11]1
Reactant: CC(=O)CC(C)C
Reactant: N#CC1(c2ccccc2)CCNCC1
Solvent: C1CO1
Solvent: CCO
Product: N#CC1(c2ccccc2)CCN(CCO)CC1
Temperature: 60 °C

Procedure:
A mixture of 8.0 parts of 4-phenylisonipecotonitrile, 41.8 parts of 4-methyl-2-pentanone, 4.3 parts of ethylene oxide and 79.2 parts of ethanol is heated in a sealed citric bottle at about 60° C. for 7 days. The resulting solution is cooled, the solvent is evaporated under reduced pressure and the residual material is partitioned between diluted sodium hydroxide and ether. The ether layer is then separated and extracted with diluted HCl. The acid layer is then made alkaline with aqueous sodium hydroxide and the resulting mixture is extracted with ether. The ether layer is dried over sodium sulfate and potassium carbonate and evaporated in vacuum. The residue is crystallized from a mixture of ether and n-pentane to give 1-(2-hydroxyethyl)-4-phenylisonipecotonitrile.
Reaction SMILES: [CH3:1][C@H:2]([O:5][C:6]1[CH:7]=[C:8]([CH:18]=[C:19]([O:21]CC2C=CC=CC=2)[CH:20]=1)[C:9]([NH:11][C:12]1[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=1)=[O:10])[CH2:3][CH3:4]>C1COCC1.C(O)C.[Pd]>[OH:21][C:19]1[CH:18]=[C:8]([CH:7]=[C:6]([O:5][C@@H:2]([CH3:1])[CH2:3][CH3:4])[CH:20]=1)[C:9]([NH:11][C:12]1[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=1)=[O:10]
Reactant: CC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C)n2)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reaction time: 8 h
Yield: 99.5 %

Procedure:
A solution of 3-{[(1S)-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide (900 mg) in THF (5 mL) and ethanol (5 mL) containing 10% palladium on carbon was stirred under an atmosphere of hydrogen overnight. The palladium on carbon was removed by filtration and the filtrate evaporated under reduced pressure to give the required compound as a white solid (683 mg). 1H NMR δ (CDCl3): 0.95 (t, 3H), 1.27 (d, 3H), 1.54-1.80 (m, 2H), 3.79 (s, 3H), 4.31 (q, 1H), 6.57 (t, 1H), 6.81 (d, 1H), 6.96 (s, 1H), 6.98 (s, 1H), 7.30 (s, 1H), 7.57 (s, 1H), 8.84 (s, 1H); m/z 290 (M+H)+
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[O:11][CH3:12]>[Fe]>[Br:1][C:8]1[C:7]([CH3:10])=[CH:6][C:5]([O:11][CH3:12])=[C:4]([CH3:3])[CH:9]=1
Reactant: COc1cc(C)ccc1C
Reactant: BrBr
Agent: [Fe]
Product: COc1cc(C)c(Br)cc1C

Procedure:
Bromine (291.5 g, 1835 mmol) was added dropwise to a mixture of 2,5-dimethylanisole (250 g, 1835 mmol) and Fe powder (3.25 g) while stirring. The commencement of the reaction could be observed by means of the evolution of gas. The remaining bromine was then added dropwise over a period of 30-40 minutes at room temperature while cooling on a water bath. The reaction mixture was stirred further for about 4 hours. The solution was subsequently separated from the Fe powder, a little chloroform was added and the mixture was shaken with water, leading to the solution becoming lighter in color. After shaking with 50 ml of saturated aqueous Na2SO3 solution, the solution had become completely decolorized. It was shaken once more with dilute aqueous NaOH and twice with H2O and, after drying, the solvent was taken off. The crude product was fractionally distilled under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][C:6](=[N:8][OH:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1.[C:13]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43]Br)=[CH:39][CH:38]=1)(=[O:34])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32]Br)=[CH:28][CH:27]=1)=[O:23]>>[C:13]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][N:8]([CH:6]2[CH2:7][C:2]([CH3:12])([CH3:1])[NH:3][C:4]([CH3:11])([CH3:10])[CH2:5]2)[OH:9])=[CH:39][CH:38]=1)(=[O:34])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:8]([CH:6]2[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3][C:2]([CH3:12])([CH3:1])[CH2:7]2)[OH:9])=[CH:28][CH:27]=1)=[O:23]
Reactant: CC1(C)CC(=NO)CC(C)(C)N1
Reactant: O=C(CCCCCCCCC(=O)OCc1ccc(CBr)cc1)OCc1ccc(CBr)cc1
Product: CC1(C)CC(N(O)Cc2ccc(COC(=O)CCCCCCCCC(=O)OCc3ccc(CN(O)C4CC(C)(C)NC(C)(C)C4)cc3)cc2)CC(C)(C)N1

Procedure:
from 2,2,6,6-tetramethylpiperidin-4-one oxime and di-(4-bromomethylbenzyi) sebacate