Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([C@@H:17]1[C@@H:21]([CH2:22][CH3:23])[CH2:20][CH2:19][NH:18]1)[N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[CH3:39][O:40][C:41](=[O:48])[C@H:42]([CH2:44][CH2:45][S:46][CH3:47])[NH2:43]>CCOC(C)=O>[CH3:39][O:40][C:41](=[O:48])[C@H:42]([CH2:44][CH2:45][S:46][CH3:47])[NH:43][C:11](=[O:13])[C@@H:10]1[CH2:14][CH2:15][CH2:16][N:9]1[CH:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C@@H:17]1[C@@H:21]([CH2:22][CH3:23])[CH2:20][CH2:19][NH:18]1
Reactant: CC[C@H]1CCN[C@@H]1C(C(=O)OC(C)(C)C)N1CCC[C@H]1C(=O)O
Reactant: COC(=O)[C@@H](N)CCSC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC[C@H]1CCN[C@@H]1C(C(=O)OC(C)(C)C)N1CCC[C@H]1C(=O)N[C@@H](CCSC)C(=O)OC
Temperature: 23 °C
Reaction time: 18 h
Yield: 75.7 %

Procedure:
N-[(tert-Butyloxy)carbonyl-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-proline (0.238 mmol), HOBT (0.048 g, 0.262 mmol), EDC (0.068 g, 0.0357 mmol), and methionine methyl ester hydrochloride (0.048 g, 0.238 mmol) were dissolved in CH2CL2 (10 mL) and stirred at 23° C. for 18 h. EtOAc (100 mL) was added, and the mixture washed with satd NaHCO3 solution, H2O, brine, and dried (MgSO4). Filtration and concentration to dryness gave 0.085 g of title compound. 1H NMR (CD3OD) δ(major rotamer) 4.63 (t, 1H, J=7 Hz), 3.73 (s, 3H), 3.55-3.7 (m, 1H), 3.0-3.5 (m,4H), 2.3-2.7 (m, 5H), 1.9-2.2 (m, 3H), 2.08 (s, 3H), 1.6-1.9 (m, 4H), 1.46 (s, 9H), 1.3-1.45 (m, 2H), 0.92-1.02 (m, 3H).
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:21]=[CH:20][C:17]([CH2:18]O)=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[Cl:24][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([O:13][CH2:12][C:10]2[N:11]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:8][CH:9]=2)=[CH:15][CH:16]=1
Reactant: OCc1ccc(OCc2coc(-c3ccccc3)n2)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: ClCc1ccc(OCc2coc(-c3ccccc3)n2)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A mixture of 4-(2-phenyl-4-oxazolylmethoxy)benzylalcohol (2.39 g), thionyl chloride (0.69 ml) and toluene (50 ml) was stirred at 40° C. overnight, and then the reaction mixture was concentrated. Saturated aqueous sodium bicarbonate solution was added to the residue, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain 4-(4-chloromethylphenoxymethyl)-2-phenyloxazole (2.34 g, yield 92%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 129–130° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=O)[CH2:9]2)[CH:7]=1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].[ClH:26].Cl.O>C(O)C>[ClH:26].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:9]2)[CH:7]=1
Reactant: Cc1ccc(F)cc1C1CC(=O)c2c(C)ccnc2C1
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc(F)cc1C1CC(=NNC(=N)N)c2c(C)ccnc2C1
Yield: 94.7 %

Procedure:
To a solution of 7-(5-fluoro-2-methylphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.1 g) and aminoguanidine hydrochloride (0.54 g) in ethanol (30 ml) were added concentrated hydrochloric acid (1.0 ml) and water (1.0 ml), and the mixture was refluxed for 6 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The mixture was washed with ethyl acetate, and to the aqueous layer was added sodium hydrogen carbonate solution to make it alkaline. The solution was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol, and to the mixture was added 1N hydrochloric acid (10 ml). The mixture was concentrated, and precipitated crystals were recrystallized from ethanol to give 7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 165) (1.4 g) as colorless crystals.
Reaction SMILES: BrC[CH2:3][C:4]1([CH3:17])[CH2:8][C:7]2[C:9]([CH3:16])=[C:10]([NH2:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:6]=2[O:5]1.[CH2:18]([N:25]([CH2:32][CH2:33][CH:34]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[NH2:15][C:10]1[C:11]([CH3:14])=[C:12]([CH3:13])[C:6]2[O:5][C:4]([CH2:3][N:29]3[CH2:30][CH2:31][CH:26]([N:25]([CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:32][CH2:33][CH:34]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH2:27][CH2:28]3)([CH3:17])[CH2:8][C:7]=2[C:9]=1[CH3:16]
Reactant: c1ccc(CN(CCC(c2ccccc2)c2ccccc2)C2CCNCC2)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CCBr)O2
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(N(CCC(c3ccccc3)c3ccccc3)Cc3ccccc3)CC1)O2
Yield: 60 %

Procedure:
Using 2-bromoethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine and N-benzyl-N-(3,3-diphenylpropyl)-4-piperidinamine, the procedure of Example 1 was otherwise repeated to provide 1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl)methyl]-N-benzyl-N-(3,3-diphenylpropyl)-4-piperidinamine. Yield 60%.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[C:16]=1[N:24]=[C:25]=[O:26])([CH3:14])[CH3:13].N1C=CC=CC=1>ClCCl>[CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:22])[CH3:23])[C:16]=1[NH:24][C:25]([NH:11][CH:8]1[CH2:7][CH2:6][CH:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10][CH2:9]1)=[O:26])([CH3:13])[CH3:14]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CC(C)(C)C1CCC(N)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NC1CCC(C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.5 %

Procedure:
To a solution of 1.6 g of 4-tert-butylcyclohexylamine in 15 ml of dichloromethane was added a solution of 2.2 g of 2,6-diisopropylphenylisocyanate in dichloromethane dropwise in the presence of pyridine at 0° C. Thereafter the mixture was stirred for 1.5 hours at room temperature and concentrated. The residue was partitioned between isopropyl ether and water, and the organic layer was successively washed with 0.5N hydrochloric acid, water and sodium sulfate solution. The organic layer was dried over magnesium sulfate and then distilled away. The resulting residue was crystallized from ethyl acetate to give 2.2 g of N-(2,6-diisopropylphenyl)-N'-(4-tert-butylcyclohexyl)urea, melting at 270° C.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10]1[C:15]([F:16])=[CH:14][C:13]([F:17])=[CH:12][N:11]=1)[CH3:9])(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[F:16][C:15]1[C:10]([CH:8]([NH2:7])[CH3:9])=[N:11][CH:12]=[C:13]([F:17])[CH:14]=1
Reactant: CC(NC(=O)OC(C)(C)C)c1ncc(F)cc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(N)c1ncc(F)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
To tert-butyl-1-(3,5-difluoropyridin-2-yl)ethylcarbamate (Method 16; 0.10 g, 0.39 mmol) in DCM (2 ml) was added HCl (0.8 ml, 3.12 mmol) in dioxane. The reaction was stirred at room temperature for 3 hours. The solvent was removed and 10 ml of saturated sodium bicarbonate was added. The resulting aqueous solution was extracted with ether (5×30 ml), dried over sodium sulfate and concentrated to give the title compound (0.06 g, 95%) as pale yellow oil. MS: Calcd.: 158. Found: [M+H]+ 159.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([N:1]2[CH2:5][CH2:4][CH2:3][CH:2]2[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1cncc(C2CCCN2)c1
Product: Cc1ccc(S(=O)(=O)N2CCCC2c2cccnc2)cc1

Procedure:
The title compound, white solid, m.p. 112° C., and MS: m/e=302 (M+) was prepared in accordance with the general method of example 1e from 3-(pyrolidin-2-yl)-pyridine and toluene-4-sulfonyl chloride.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][CH2:9][CH:10]([OH:20])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:5][CH:4]=1)#[N:2].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:23][S:24]([O:20][CH:10]([CH2:11][NH:12][C:13]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:19])[CH2:9][CH2:8][O:7][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:22][CH:21]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCC(O)CCOc1ccc(C#N)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCC(CCOc1ccc(C#N)cc1)OS(C)(=O)=O
Temperature: 0 °C
Yield: 58.5 %

Procedure:
tert-Butyl 4-(4-cyanophenoxy)-2-hydroxybutylcarbamate (38.1 g, 120 mmol; from step (f) above) and 4-(dimethylamino)pyridine (10 mol %) was dissolved in pyridine (200 mL). The mixture was cooled to 0° C. Methanesulfonyl chloride (10.7 mL, 0.136 mol) was added dropwise at 0° C. The mixture was allowed to reach r.t before the pyridine was evaporated. DCM was added, the solution was washed with 2 M HCl and water, dried and then evaporated. The compound was purified by chromatography on silica, eluting with DCM:ethyl acetate (95:5) to give 27 g of the sub-title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][NH:11]1.[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17].O>O1CCCC1>[C:15]([N:14]1[CH2:13][CH2:12][NH:11][C:10]1=[N:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])(=[O:19])[CH:16]([CH3:18])[CH3:17]
Reactant: Clc1ccc(N=C2NCCN2)c(Cl)c1
Reactant: CC(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(=O)N1CCNC1=Nc1ccc(Cl)cc1Cl

Procedure:
A mixture of 11.5 g 2-(2,4-dichlorophenylimino)imidazolidine 1.7 g sodium hydride (80 percent dispersion in oil) and 80 ml dry tetrahydrofuran was stirred and refluxed for one and a half hours, and a solution of 5.9 g isobutyryl chloride in 20 ml dry tetrahydrofuran was then added dropwise. The mixture was stirred and refluxed for five hours and then cooled and poured into iced water to give a solid which was dried over phosphorus pentoxide. Recrystallisation with charcoal from ethanol gave the novel compound 1-isobutyryl-2-(2,4-dichlorophenylimino)imidazolidine, melting point 147°-148° C.
Reaction SMILES: N[C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.P(=O)(O)(O)O.[N+]([O-])(O)=O.N([O-])=O.[Na+].[BrH:26]>O>[Br:26][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1
Reactant: Br
Reactant: CCOC(=O)c1sc(N)nc1C
Agent: O=N[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O
Solvent: O=[N+]([O-])O
Product: CCOC(=O)c1sc(Br)nc1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
Ethyl 2-amino-4-methylthiazole-5-carboxylate (1.20 g, 6.44 mmoles) was added to a solution of 85% phosphoric acid (18 mL) and 70% nitric acid (9 mL) at 0° C. Aqueous sodium nitrite(1.38 g (20 mmol) in water (9 mL) was immediately added dropwise over 20 minutes. After stirring at 0° C. for 15 minutes, cuprous bromide (930 mg, 6.44 mmoles) in hydrobromic acid (9 mL) was added. After stirring for 10 minutes, water (30 mL) was added. The mixture was filtered and the crude solid purified via silica gel chromatography (10% ethyl acetate/hexane) to afford 1.15 g (4.6 mmoles) of the product as a yellow solid (71%). H1 NMR (CDCl3) δ 4.35 (2H, q, J=7.1 Hz), 2.73 (3H, s), 1.38 (3H, t, J=7.1 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][C:6]([CH3:13])=[CH:7][CH:8]=2)[NH:3]1.[H][H]>[Rh]>[CH3:1][C:2]1([CH3:14])[CH2:11][CH:10]([CH3:12])[CH:9]2[CH:4]([CH2:5][CH:6]([CH3:13])[CH2:7][CH2:8]2)[NH:3]1
Reactant: CC1=CC(C)(C)Nc2cc(C)ccc21
Reactant: [H][H]
Agent: [Rh]
Product: CC1CCC2C(C)CC(C)(C)NC2C1
Reaction time: 24 h

Procedure:
2,2,4,7-tetramethyldecahydroquinoline was prepared by reacting 125 grams of 2,2,4,7-tetramethyl-1,2-dihydroquinoline with hydrogen using 3 grams of rhodium at 5% by weight on charcoal as the catalyst and operating at 185° C., a 1000 psig pressure, for 24 hours. The desired product was confirmed by NMR spectral analysis and its carbon, hydrogen, nitrogen content (calculated contents for C13H25N is the same as above and analyzed contents were 78.95% carbon, 13.30% hydrogen, and 6.80% nitrogen). The product was 95% pure as determined by vapor pressure chromotography and boiled at about 65° C. at 1 mm of Hg.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])=[N:4][CH:5]=[C:6](Cl)[N:7]=1.[CH3:15][S-:16].[Na+]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]([C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])=[N:4][CH:5]=[C:6]([S:16][CH3:15])[N:7]=1
Reactant: CON(C)C(=O)c1ncc(Cl)nc1Cl
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1ncc(SC)nc1Cl
Reaction time: 5 h

Procedure:
To a solution of 55B (2 g, 8.47 mmol) in DMF (10 mL), 1 eq. of sodium methanethiolate was added to the solution. After 5 hours, 0.5 eq. of sodium methanethiolate was added to the suspension. The reaction was stirred overnight then diluted with EtOAc and washed with NaHCO3 (aq) and brine. The organic layer was concentrated and purified by flash chromatography to provide the title compound. MS (m/z) 248 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH:6]=[O:7].[I-].[K+]>CN(C=O)C.O>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:14]1[CH2:2][C:3]2[CH:4]=[C:5]([CH:6]=[O:7])[CH:8]=[CH:9][C:10]=2[O:11][CH2:12][CH2:13]1
Reactant: O=Cc1ccc(OCCNc2ccccn2)c(CCl)c1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc2c(c1)CN(c1ccccn1)CCO2
Temperature: 130 °C

Procedure:
To a solution of 3-chloromethyl-4-[2-(pyridin-2-yl-amino)-ethoxy]-benzaldehyde [compound of step II] (7.45 g, 25.7 mmol) in 340 mL DMF, was added potassium iodide (8.53 g, 51.4 mmol) and the reaction mixture was heated to 130° C. for 1 hour. The reaction mixture was cooled, diluted with 1 L water and extracted with 2×500 mL of ethyl acetate. The ethyl acetate extract was washed with 250 mL brine, dried over anhydrous sodium sulfate and concentrated under vacuum at 40° C. to give 5.9 g crude material. This crude material was purified by silica chromatography using 15% ethyl acetate in petroleum ether to give 4-pyridin-2-yl-2,3,4,5-tetrahydro-benzo [f][1,4]oxazepine-7-carbaldehyde.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=3)[C:10]([C:18]([N:20]([CH3:22])[CH3:21])=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])#[CH:24].N1CCCCC1>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.[Cu]I>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:24]#[C:23][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:15]=3)[C:10]([C:18]([N:20]([CH3:22])[CH3:21])=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: CN(C)C(=O)c1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CN(C)C(=O)c1nn(-c2ccnc(N)n2)c2cc(C#C[Si](C)(C)C)ccc12
Temperature: 65 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
To a mixture of 1-(2-aminopyrimidin-4-yl)-6-bromo-N,N-dimethylindazole-3-carboxamide (61-b) (500 mg, 1.27 mmol), tetrakis(triphenylphosphine)palladium (118 mg, 0.102 mmol), copper(I) iodide (19.4 mg, 0.102 mmol) and ethynyl(trimethyl)silane 0.39 ml, 2.54 mmol) was added piperidine (3.1 mL). The mixture was purged with nitrogen for 2 minutes and then stirred at 65° C. for 4 hr. The reaction mixture was concentrated in vacuo, DCM (5 mL) was added and the concentration repeated (×2). The crude product was purified by flash chromatography (Biotage, 2-8% methanol in DCM) to give the title intermediate (250 mg): LC-MS: m/z=+379.45 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26]([C:27]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:6][CH:5]=1)=[CH:2][CH3:3]>C1C=CC=CC=1.[Pd]>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26]([C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[C:7]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CC=Cc1ccc(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Solvent: c1ccccc1
Product: CCCc1ccc(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.4 %

Procedure:
A solution of (cis- and trans-) ethyl 5-(1-propenyl)-1-[2'-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl-methyl]pyrrole-2-carboxylate (350 mg, 0.53 mmol) in benzene (35 ml) containing 5% Pd/C (35 mg) in a Paar bottle was placed on a Paar apparatus under 40 psi H2 and shaken for about 4 hours at room temperature. The mixture was suction filtered through Celite and concentrated to leave 350 mg of a white solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:18][CH2:17][C:12]3(OCC[O:13]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.CO>CO.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH2:11][C:12](=[O:13])[CH2:17][CH2:18]2)=[CH:7][CH:8]=1
Reactant: Fc1ccc(C2CCC3(CC2)OCCO3)cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: O=C1CCC(c2ccc(F)cc2)CC1
Yield: 87 %

Procedure:
Hydrochloric acid (0.75 ml) was added to a solution 8-(4-fluorophenyl)-1,4-dioxaspiro[4.5]decane (10 mmole) in methanol-water (2-1,100 ml). After stirring for 2 hr the methanol was removed in vacuo and the residue extracted with methylene chloride. Removal of the methylene chloride in vacuo gave the product as an oil (87%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:12]=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:13][CH2:12][C:3]1[C:2]([CH3:1])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: Cc1cc2ccccc2cc1C=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc2ccccc2cc1CO
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 71.7 %

Procedure:
To a stirred solution of 3-methylnaphthalene-2-carboxaldehyde (3.40 g, 20 mmol) in dry THF (200 mL) cooled to 0° C. was added lithium aluminum hydride (LAH, 380 mg, 10 mmol), in portions over 10 minutes. The resulting solution was stirred at 0° C. for 1.5 hours. Excess LAH was quenched by the addition of H2O (50 mL) and the THF was removed in vacuo. The residue was diluted with 1N HCl (150 mL) and extracted with Et2O (3×200 mL). The organics were dried (MgSO4) and concentrated in vacuo to give the crude product as a tan solid. This material was purified by preparative HPLC (SiO2 : 1:1 CH2Cl2 /hexane) to afford the title compound as a white solid (2.47 g, 72%).
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C.Cl>C(#N)C>[O:25]=[C:19]1[CH:18]([N:12]2[CH2:11][C:10]3[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][NH:6][C:26](=[O:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:9]=3)[C:13]2=[O:17])[CH2:23][CH2:22][C:21](=[O:24])[NH:20]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccccc1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3cc(CNC(=O)c4ccccc4)ccc3C2=O)C(=O)N1
Reaction time: 1 h
Yield: 63.3 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.50 g, 1.80 mmol) and benzoyl chloride (0.25 g, 1.80 mmol) in acetonitrile (20 mL), was added triethylamine (0.51 mL, 3.60 mmol) at room temperature under nitrogen. After 1 h, 1N aq. HCl (20 mL) was added and the mixture was stirred for 10 min. The product was isolated by filtration, washed with 1N aq. HCl (20 mL), acetonitrile (20 mL) and dried overnight in vacuo to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-benzamide as a white solid (0.43 g, 64% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 3.17 min (99.25%); mp: 266-268° C.; 1H NMR (DMSO-d6) δ 1.93-2.06 (m, 1H), 2.27-2.47 (m, 1H), 2.53-2.68 (m, 1H), 2.79-3.05 (m, 1H), 4.31 (d, J=17.4 Hz, 1H), 4.45 (d, J=17.4 Hz, 1H), 4.60 (d, J=5.9 Hz, 2H), 5.11 (dd, J=5.0, 13.1 Hz, 1H), 7.42-7.62 (m, 5H), 7.70 (d, J=7.7 Hz, 1H), 7.91 (d, J=7.0 Hz, 2H), 9.16 (t, J=5.9 Hz, 1H), 10.99 (s, 1H); 13C NMR (DMSO-d6) δ 22.5, 31.2, 42.7, 47.1, 51.6, 122.1, 122.9, 127.1, 127.2, 128.3, 130.3, 131.3, 134.2, 142.4, 144.0, 166.3, 167.9, 171.0, 172.8; LCMS: MH=378; Anal Calcd for C21H19N3O4: C, 66.83; H, 5.07; N, 11.13. Found: C, 66.75; H, 5.08; N, 11.18.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C.[Cl-].[NH4+]>[Fe].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Temperature: 80 °C
Yield: 16.3 %

Procedure:
4-(4-Nitro-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (10.0 g, 27 mmol) was suspended in a 5:1 mixture of ethanol and water (80 ml). To this solution was added iron powder (3.9 g, 70.2 mmol) and saturated ammonium chloride solution (8 ml), the mixture was heated to 80° C. for three hours. After this time, the reaction mixture was cooled to room temperature and filtered through a pad of celite, the celite was washed with ethanol (10 ml) and ethyl acetate (50 ml) and the solution was concentrated under vacuum. The resulting residue was partitioned between DCM (50 ml) and water (20 ml), the organic layer was separated, dried with MgSO4, filtered and concentrated to afford the title compound (1.5 g, 89% yield) as a white solid. δH (500 MHz, CDCl3) 7.53 (2H, d), 6.73 (2H, d), 4.36 (2H, br s), 3.56-3.49 (4H, m), 2.98-2.91 (4H, m), 1.42 (9H, s). Tr=1.81 min, m/z (ES+) ([(M−100)+H]+) 242.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].CCCCCCC>C(OCC)(=O)C>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]1=[O:1])[CH3:16]
Reactant: CCOC(=O)CBr
Reactant: COc1cccnc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCOC(=O)Cn1cccc(OC)c1=O
Yield: 92 %

Procedure:
As described for example 320a, 2-hydroxy-3-methoxy-pyridine was reacted with ethyl bromoacetate and potassium carbonate. Extractive workup followed by chromatography (SiO2, heptane:ethyl acetate=100:0 to 0: 100) afforded the title compound as a white solid (yield: 92%). MS: m/e=212.3[M+H]+.