Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]=2[CH:17]=1)#[N:2].[Cl-].[NH4+].[N-:20]=[N+:21]=[N-:22].[Na+].CN(C)C=O>O>[C:11]1([C:8]2[C:7]3[CH:17]=[C:3]([C:1]4[NH:22][N:21]=[N:20][N:2]=4)[CH:4]=[CH:5][C:6]=3[O:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#Cc1ccc2occ(-c3ccccc3)c2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(-c2coc3ccc(-c4nnn[nH]4)cc23)cc1
Temperature: 20 °C

Procedure:
A mixture of 61.4 g. (0.28 mole) of 5-cyano-3-phenylbenzofuran (described in U.S. Pat. No. 4,067,993, Example 1), 16.5 g. (0.31 mole) of ammonium chloride and 20.2 g. (0.31 mole) of sodium azide in 250 ml. of N,N-dimethylformamide is stirred at 110°-120° C. for 16 hours. The mixture is cooled to about 20° C. and poured into about 1 liter of water. A light brown solid forms which is collected by filtration, washed with water, and then recrystallized from ethanol to provide brown crystals of 3-phenyl-5-(1H-tetrazol-5-yl)benzofuran.
Reaction SMILES: [C:1]([CH:5]([CH2:8][OH:9])[CH2:6][OH:7])([CH3:4])([CH3:3])[CH3:2].[C:10]1([CH3:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:16]([O:7][CH2:6][CH:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:8][OH:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccccc1
Reactant: CC(C)(C)C(CO)CO
Product: CC(C)(C)C(CO)COCc1ccccc1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-t-butylpropane-1,3-diol (11.0 g.) (E.L. Eliel et al J. Amer Chem Soc. 1968, 90, 3444) was stirred in dry toluene (200 ml), at 20° C. Sodium hydride (2.4 g., 80% dispersion in oil), previously washed with hexane, was added carefully to the stirred mixture. The mixture was stirred at 120° C. for 30 minutes and cooled. Benzyl bromide (9.5 ml) was added dropwise and the mixture heated at 130°, with stirring for 6 hours. The mixture was cooled, water was added and the mixture extracted with diethyl ether. The ethereal extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was purified by chromatography on silica, eluting with 1:4 diethyl ether: hexane. 2-Benzyloxymethyl-3,3-dimethyl-butan-1-ol (8.0 g) was obtained as a colourless
Reaction SMILES: [C:1]([N:9]1[C:13]2([CH2:18][CH2:17][CH:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[S:12][CH2:11][C@H:10]1[C:29](O)=[O:30])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36].O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:1]([N:9]1[C:13]2([CH2:18][CH2:17][CH:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[S:12][CH2:11][C@H:10]1[C:29]([NH:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])=[O:30])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(OC2CCC3(CC2)SC[C@@H](C(=O)O)N3C(=O)c2ccccc2)cc1
Reactant: NCCC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1ccc(OC2CCC3(CC2)SC[C@@H](C(=O)NCCC(=O)OCc2ccccc2)N3C(=O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
In 10 ml of anhydrous tetrahydrofuran was dissolved 0.50 g of (3R)-4-benzoyl-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid. Then, at 0-5° C., 0.22 g of benzyl 3-aminopropionate, 0.19 g of 1-hydroxybenzotriazole monohydrate and 0.26 g of dicyclohexyl carbodiimide were added successively. After stirring the resulting mixture at the same temperature as above for 30 minutes and then at ambient temperature for 5 hours, the insoluble matter was filtered off. The filtrate was poured into a mixture of water and ethyl acetate, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer thus obtained was washed successively with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluent: hexane:ethyl acetate=2:1] gave 0.55 g of benzyl 3-{[(3R)-4-benzoyl-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]decan-3-yl]carbonyl}amino-propionate as a colorless oily product.
Reaction SMILES: CO[C:3]1([O:10]C)[CH:8]=[CH:7][C:6](=[O:9])[CH:5]=[CH:4]1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([N:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[C:23]2[C:3]2([OH:10])[CH:4]=[CH:5][C:6](=[O:9])[CH:7]=[CH:8]2)(=[O:20])=[O:21])=[CH:17][CH:18]=1
Reactant: COC1(OC)C=CC(=O)C=C1
Reactant: O=S(=O)(c1ccc(F)cc1)n1ccc2ccccc21
Product: O=C1C=CC(O)(c2cc3ccccc3n2S(=O)(=O)c2ccc(F)cc2)C=C1
Yield: 14 %

Procedure:
The title compound was prepared from 4,4-dimethoxy-cyclohexa-2,5-dienone and 1-(4-fluoro-benzenesulfonyl)-1H-indole, according to Method C, described above. Yield 14%; mp 165-166° C.; 1H NMR (CDCl3) δ 7.82-7.93 (m, 3H), 7.49 (d, J=10 Hz, 2H), 7.35 (d, J=8 Hz, 1H), 7.12-7.28 (m, 2H), 6.99-7.05 (m, 2H), 6.73 (s, 1H), 6.25 (d, J=10 Hz, 2H), 5.31 (s, 1H);13C NMR (CDCl3) δ 185.2, 170.9, 170.5, 147.7, 141.0, 138.6, 133.6, 130.1, 129.9, 128.8, 128.1, 126.8, 125.2, 122.2, 117.3, 116.9, 115.6, 114.5, 69.5, 67.9; MS (AP+) m/z 384.04 (M++1).
Reaction SMILES: COC[N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)[OH:10].C(O)(=O)C.Cl>O>[C:21]1([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)([C:5]2[NH:4][CH:8]=[CH:7][N:6]=2)[OH:10])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COCn1ccnc1C(O)(c1ccccc1)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: OC(c1ccccc1)(c1cccc(C(F)(F)F)c1)c1ncc[nH]1

Procedure:
A mixture of 13 g. (0.037 mol) of 1-methoxymethyl-α-phenyl-α-(m-trifluoromethyl-phenyl)imidazole-2-methanol, 100 ml. of glacial acetic acid, 10 ml. of concentrated hydrochloric acid and 10 ml. of water was refluxed for three hours. After cooling, the liquid was distilled off and the residue was dissolved in a small amount of ethanol. The solution was made alkaline with 2 N sodium hydroxide solution and the alcohol was evaporated. The remaining aqueous phase was then extracted with diethyl ether. The extract was dried over sodium sulphate and the ether was distilled off. The residue was crystallised from toluene, the toluenic solution being decolorised with active charcoal. There was obtained α-phenyl-α-(m-trifluoromethyl-phenyl)imidazole-2-methanol. Melting point 151.5°-152.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[O:6][CH2:7][CH:8]([OH:14])[CH2:9][NH:10][CH2:11][CH2:12][NH2:13])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:25][N:26]1[C:31](=[O:32])[C:30]([Cl:33])=[C:29](Cl)[CH:28]=[N:27]1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[O:6][CH2:7][CH:8]([OH:14])[CH2:9][NH:10][CH2:11][CH2:12][NH:13][C:29]1[CH:28]=[N:27][N:26]([CH3:25])[C:31](=[O:32])[C:30]=1[Cl:33])[CH3:2]
Reactant: Cn1ncc(Cl)c(Cl)c1=O
Reactant: CCOc1ccccc1OCC(O)CNCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOc1ccccc1OCC(O)CNCCNc1cnn(C)c(=O)c1Cl
Temperature: 25 °C
Yield: 84 %

Procedure:
5.1 g of N-[3-(o-ethoxyphenoxy)-2-hydroxy-propyl]-ethylenediamine ##STR19## are dissolved in 50 ml of toluene, and 3 g of potassium carbonate are added to the solution. A solution of 3.6 g of 2-methyl-4,5-dichloro-pyridazin-3-one ##STR20## in 50 ml of toluene is then added to the above solution at room temperature, while stirring, and the mixture is then heated under reflux for 17 hours, while stirring. The mixture is then allowed to cool to room temperature and is filtered off under suction from the inorganic residue, and the filtrate is concentrated in vacuo. The residual oil, which solidifies after a short time, is recrystallised from ethyl acetate. The N-[3-(o-ethoxyphenoxy)-2-hydroxy-propyl]-N'-[2-methyl-3-oxo-4-chloro-pyridaz-5-yl]-ethylenediamine ##STR21## is thus obtained.
Reaction SMILES: [CH3:1][N:2]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:3][CH:4]([OH:26])[CH2:5][O:6][C:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C=CC=CC=1.[CH3:51][N:52]=[C:53]=[O:54]>C1C=CC=CC=1>[CH3:1][N:2]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:3][CH:4]([O:26][C:53](=[O:54])[NH:52][CH3:51])[CH2:5][O:6][C:7]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CN=C=O
Reactant: CCCCCCCCCCCCCCCCCCN(C)CC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCN(C)CC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC(=O)NC
Yield: 80 %

Procedure:
A solution of 3-(N-methyl octadecylamino) 1-trityloxypropan-2-ol 6b (6 10-3M), pyridine (1 ml) and methylisocyanate (1.2 ml) in dry benzene (45 ml), was heated at 40° C. for three days. After elimination of the solvent, the residue was purified by column chromatography with CH2Cl2 as eluent, to give 7b.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]2[N:11]=[C:12]([CH3:23])[C:13]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=3[CH3:22])=[C:9]2[N:8]=[C:7]([CH3:24])[CH:6]=1.[C:25]1(=O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[CH:25]1([NH:1][CH2:2][CH2:3][NH:4][C:5]2[N:10]3[N:11]=[C:12]([CH3:23])[C:13]([C:14]4[C:15]([CH3:22])=[CH:16][C:17]([Cl:21])=[CH:18][C:19]=4[CH3:20])=[C:9]3[N:8]=[C:7]([CH3:24])[CH:6]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: Cc1cc(NCCN)n2nc(C)c(-c3c(C)cc(Cl)cc3C)c2n1
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Cc1cc(NCCNC2CCCCC2)n2nc(C)c(-c3c(C)cc(Cl)cc3C)c2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dissolve 7-(2-aminoethylamino)-2,5-dimethyl-3-(4-chloro-2,6-dimethylphenyl)-pyrazolo [1,5-a] pyrimidine (0.183 g, 5.4×10−4 mol, 339.2 g/mol) in dichloroethane (5 mL) and add cyclohexanone (100.12 g/mol) and sodium triacetoxyborohydride (0.172 g, 211.94 g/mol). To the resultant slurry, add glacial acetic acid (0.032 mL, 5.4×10−4 mol) and stir at ambient temperature under N2 for 3 h. Partition between CH2Cl2 (3 mL) and 1.0 N NaOH (10 mL), then separate the layers and chromatograph the CH2Cl2 layer using [10% (2.0M NH3 in MeOH)/90% CH2Cl2] as eluent. Obtained 0.16 g white solid-foam upon evaporation.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:23]=[CH:22][C:8]([NH:9][CH:10]=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25].C1(C)C=CC=CC=1.P([O-])([O-])([O-])=O>C(OCC)(=O)C>[O:25]=[C:24]1[N:4]([C:5]2[CH:6]=[CH:7][C:8]([NH:9][CH:10]=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:22][CH:23]=2)[CH2:3][CH2:2][O:1]1
Reactant: CCOC(=O)C(=CNc1ccc(NCCO)cc1)C(=O)OCC
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=CNc1ccc(N2CCOC2=O)cc1)C(=O)OCC
Yield: 88.7 %

Procedure:
To a flask containing diethyl 2-({4-[(2-hydroxyethyl)amino]anilino}methylene)-malonate (0.48 g) and 1,1'-carbonyldiimidazole (0.32 g) is added toluene (15 mL). The reaction mixture is heated to reflux under an argon atmosphere overnight. The reaction mixture is cooled to room temperatue and partioned between ethyl acetate and phosphate buffer (pH=7, 1M). The phases are separated and the aqueous layer is extracted with two additional portions of ethyl acetate. The combined organic layers are washed with buffer, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is chromatographed on silica eluting with ethyl acetate. The product-containing fractions are evaporated to give 0.46 g of diethyl 2-{[4-(2-oxo-1,3-oxazolidin-3-yl)anilino]methylene}malonate as a creme solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10](OS(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:17][C:18]1[CH:19]=[N:20][NH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:20]2[CH:19]=[C:18]([I:17])[CH:22]=[N:21]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Ic1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(n2cc(I)cn2)C1
Temperature: 85 °C

Procedure:
A mixture of 3-methanesulfonyloxyazetidine-1-carboxylic acid tert-butyl ester (4.00 g, 15.9 mmol), 4-iodopyrazole (3.1 g, 15.9 mmol), potassium carbonate (2.85 g, 20.6 mmol) and 18-crown-6 (400 mg) in dry DMF (15 mL) was heated at 85° C. for 24 h. The reaction mixture was cooled to RT, poured into water and extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with hexanes/dichloromethane/ethyl acetate (8:1:1) to give the pure title compound. 1H NMR (300 MHz, CDCl3): δ=1.47 (s, 9H), 4.29 (m, 2H), 4.36 (m, 2H), 5.05 (m, 1H), 7.59 (s, 1H), 7.60 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][O:36][C:35]1=[O:39]>O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:12][CH2:13][N:14]([CH2:32][CH2:33][N:34]4[CH2:38][CH2:37][O:36][C:35]4=[O:39])[CH2:15][CH2:16]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)CC(N1CCNCC1)c1ccccc1S2
Reactant: O=C1OCCN1CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1OCCN1CCN1CCN(C2Cc3cc(Cl)ccc3Sc3ccccc32)CC1

Procedure:
7.8 g of 1-(2-chloro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-piperazine are treated, together with 11.6 g of powdered potassium carbonate, 0.2 g of potassium iodide and 100 ml of toluene, with 8.22 g of N-(β-chloroethyl)-oxazolidinone and the mixture is heated under reflux for 22 hours. Then the mixture is poured on to water and the organic phase washed with saturated soda solution and water, dried over sodium sulphate and concentrated under reduced pressure. There is obtained crude liquid 3-[2-[4-(2-chloro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl]-2-oxazolidinone. The maleate is prepared by treatment with maleic acid in ethanol/ether; melting point 173°-175° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:24]=[C:23]([NH:25][C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[N:30]=[CH:29]4)[C:22]3[C:17](=[CH:18][C:19]([O:47][CH3:48])=[C:20]([O:42][CH2:43][CH2:44][O:45][CH3:46])[CH:21]=3)[N:16]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.N#N>CO.COCCOC.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:15]2[N:24]=[C:23]([NH:25][C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31]([C:35]([O:37][C:38]([CH3:40])([CH3:41])[CH3:39])=[O:36])[N:30]=[CH:29]4)[C:22]3[C:17](=[CH:18][C:19]([O:47][CH3:48])=[C:20]([O:42][CH2:43][CH2:44][O:45][CH3:46])[CH:21]=3)[N:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: COCCOc1cc2c(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)nc(-c3cccc(OCc4ccccc4)c3)nc2cc1OC
Agent: [Pd]
Agent: N#N
Solvent: COCCOC
Solvent: CO
Product: COCCOc1cc2c(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)nc(-c3cccc(O)c3)nc2cc1OC
Reaction time: 8 h
Yield: 96.9 %

Procedure:
A suspension of tert-butyl 5-(2-(3-(benzyloxy)phenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (2.70 g, 4.17 mmol) in MeOH (400 mL) and DME (200 mL) was added Pd/C (10%, wet, 0.500 g) under an atmosphere of N2. The N2 was exchanged for H2 and the mixture was stirred under an atmosphere of H2 (balloon pressure) overnight. The mixture was filtered through a pad of Celite® and the filtrate was concentrated in vacuo to give tert-Butyl 5-(2-(3-hydroxyphenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (2.25 g, 4.04 mmol, 97%). MS 558 (M+1). HPLC retention time 6.44 mins.
Reaction SMILES: C[Mg]Br.[CH3:4]COCC.[CH3:9][C:10]1([CH3:18])[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]1=[O:17].[Cl-].[NH4+]>CCOCC>[CH3:4][C:11]1([OH:17])[C:12]([CH3:16])([CH3:15])[CH2:13][CH2:14][C:10]1([CH3:18])[CH3:9]
Reactant: CC1(C)CCC(C)(C)C1=O
Reactant: CCOCC
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Product: CC1(C)CCC(C)(C)C1(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 ml of a 3M methylmagnesium bromide/ether solution was added to a solution of 30 g of 2,2,5,5-tetramethylcyclopentanone in 50 ml of ether under a nitrogen gas atmosphere, and the mixture was stirred at room temperature overnight. Then, 65 ml of aqueous saturated ammonium chloride solution was added dropwise thereto and the mixture was stirred for 10 minutes. The ether layer was subjected to decantation and the residue was extracted with ether. The ether layers were dried over anhydrous sodium sulfate, and concentrated under reduced pressure, whereby 30 g of 1,2,2,5,5-pentamethylcyclopentanol was obtained.
Reaction SMILES: [C:1]1([CH:7]2[O:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=1>ClC(Cl)C.C(Cl)Cl>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([N:9]2[CH2:10][CH2:11][O:12][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8]2)[CH3:21])=[CH:16][CH:15]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: c1ccc(C2CNCCO2)cc1
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CC(c1ccc(Br)cc1)N1CCOC(c2ccccc2)C1

Procedure:
The above compound could be made the following way: 1 eq. of 2-Phenylmorpholine (Array) in dichloroethane could be combined with 1.2 eq. 4′-Bromoacetophenone (Aldrich) and stirred overnight at room temperature. 1.5 eq. borane-pyridine complex could be added and the reaction stirred for several hours. The reaction mixture could be diluted with methylene chloride and washed with water and brine. The organics could be dried over sodium sulfate and purified by column chromatography.
Reaction SMILES: [CH2:1]1[CH:8]([N:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10]2=[O:11])C(=O)O[C:3](=O)[CH2:2]1.[CH2:20](N)[CH2:21][C:22]1C=CC=C[CH:23]=1>>[CH2:8]([N:9]1[C:10](=[O:11])[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:17]2[C:18]1=[O:19])[CH2:1][C:2]1[CH:3]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)O1
Reactant: NCCc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCc1ccccc1
Temperature: 177 °C

Procedure:
With reference to Scheme 3 below, a mixture of N-phthaloyl-DL-glutamic anhydride and phenethylamine was heated in a 177° C. oil bath. The reaction mixture was purified by chromatography on a silica gel column to afford N-phenethylthalidomide (8) and N-phenethylphthalimide (9).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH:7]([CH3:9])[CH3:8])C.[ClH:23].[OH:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[OH:34])[CH2:28][CH2:29][NH2:30].C(O)CCC>O>[ClH:23].[CH2:13]([O:12][C:10]([N:6]([CH2:5][CH:4]1[C:26]2[C:27](=[CH:31][CH:32]=[C:33]([OH:34])[C:25]=2[OH:24])[CH2:28][CH2:29][NH:30]1)[CH:7]([CH3:8])[CH3:9])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NCCc1ccc(O)c(O)c1
Reactant: CCOC(CN(C(=O)OCc1ccccc1)C(C)C)OCC
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: CC(C)N(CC1NCCc2ccc(O)c(O)c21)C(=O)OCc1ccccc1
Yield: 16.6 %

Procedure:
N-benzyloxycarbonyl-N-isopropylaminoacetaldehyde diethyl acetal (9 g) and 3,4-dihydroxyphenethylamine hydrochloride (4.5 g) were added to a mixture of n-butyl alcohol (100 ml) and water (15 ml) and then the mixture was refluxed for 6 hours. The above-mentioned acetal (2 g) was added thereto and the resultant mixture was refluxed for 1.5 hours. The solvent was distilled off from the reaction mixture. To the residue was added a mixed solvent of isopropyl alcohol, methanol and ether. The crystals obtained were recrystallized from the same mixed solvent to give 1-(N-benzyloxycarbonyl-N-isopropylaminomethyl)-7,8-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.6 g), mp 200° to 205° C. (dec). The mother liquor was concentrated and allowed to stand to give 1-(N-benzyloxycarbonyl-N-isopropylaminomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (4.4 g), colorless crystals, mp 207° to 210° C. (dec).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=O.[CH3:12][O:13][C:14](=[O:17])[CH2:15][SH:16]>CS(C)=O>[Br:1][C:2]1[C:3]([F:11])=[CH:4][C:5]2[S:16][C:15]([C:14]([O:13][CH3:12])=[O:17])=[CH:7][C:6]=2[CH:9]=1
Reactant: COC(=O)CS
Reactant: O=Cc1cc(Br)c(F)cc1F
Solvent: CS(C)=O
Product: COC(=O)c1cc2cc(Br)c(F)cc2s1
Yield: 4.8 %

Procedure:
Using analogous reaction condition and reagents as described in Example 25 for the preparation of I-25a above, 5-bromo-2,4-difluorobenzaldehyde (I-28a: 475 mg, 2.149 mmol) was reacted with TEA (0.748 mL, 5.372 mmol), mercapto-acetic acid methyl ester (0.211 mL, 2.36 mmol) and DMSO (4 mL) to afford crude product. Purification by column chromatography on silica gel (1.5% ethyl acetate in hexane) afforded 30 mg of the product (5% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([Cl:18])[CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Br:19]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=2)=[CH:12][C:13]=1[Cl:18]
Reactant: Cc1ccc(Oc2ccc(C#N)c(Cl)c2)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(Oc2ccc(CBr)c(Cl)c2)cc1Cl
Temperature: 25 °C
Yield: 17.7 %

Procedure:
To a stirred solution of 2-chloro-4-(3-chloro-4-methyl-phenoxy)-benzonitrile (14.41 g) in CCl4 (100 ml) under argon were added N-bromosuccinimide (9.5 g) and dibenzoylperoxide (1.38 g). The mixture was heated to reflux for 2.5 h. After cooling to room temperature, the mixture was filtered. The filter cake was washed with cyclohexane. The combined filtrate was concentrated to dryness to give the crude product (19.75 g) as a light orange solid. Part of the product was purified by repeated chromatography (SiO2, cyclohexane/ethyl acetate 1:0=>4:1) to give the title compound as an off-white solid (3.27 g).