Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=4[C:15](=[O:23])[N:14]4[CH2:24][CH2:25][C@H:13]4[C:12]=23)[O:5][N:4]=1.[CH2:26](Br)[CH:27]=[CH2:28].N12CCCN=C1CC[CH2:33][CH2:32][CH2:31]2>CN(C)C=O>[CH2:26]([N:1]([CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=4[C:15](=[O:23])[N:14]4[CH2:24][CH2:25][C@H:13]4[C:12]=23)[O:5][N:4]=1)[CH2:33][CH:32]=[CH2:31])[CH:27]=[CH2:28]
Reactant: NCc1noc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c(Cl)cccc2-3)n1
Reactant: C=CCBr
Reactant: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: C=CCN(CC=C)Cc1noc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c(Cl)cccc2-3)n1
Yield: 32.2 %

Procedure:
5.02 g (14 mmol) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-chloro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, 75 ml of N,N-dimethylformamide, 21 g (173.8 mmol) of allyl bromide and 29.4 g (193 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5) were stirred at 75° for 60 hours. The solution was concentrated and the residue was purified by chromatography on 350 g of silica gel while eluting with ethyl acetate. There were obtained 1.97 g (35%) of (S)-1-(3-diallylaminomethyl-1,2,4-oxadiazol-5-yl)-8-chloro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride of m.p. 190°-192°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:17][CH:18]([CH2:21][CH3:22])[CH2:19]O.S(=O)(=O)(O)O>C1C=CC=CC=1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH:18]([CH3:19])[CH2:21][CH3:22])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCC(C)CO
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CCC(C)COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Yield: 78.2 %

Procedure:
10.6 g of 4'-hydroxybiphenyl-4-carboxylic acid and 18.7 g of (+)-2-methylbutanol were heat-refluxed for 20 hours in benzene together with 1 ml of sulfuric acid. The mixture was subjected to filtration, condensation acid recrystallization to obtain 11.0 g of the objective product (yield: 83%).
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.CN(C)CCN(C)C.CCCCCC.CN(C)[CH:32]=[O:33].[NH4+].[Cl-]>CCOCC>[CH:32]([CH:7]1[N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4][C:3]2([CH2:2][CH2:1]2)[CH2:8]1)=[O:33]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC2
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC2(CC2)CC1C=O
Temperature: -60 °C
Reaction time: 0.17 h

Procedure:
tert-butyl 6-azaspiro[2.5]octane-6-carboxylate (Intermediate 2, 1 g, 4.73 mmol) dissolved in 20 ml of Et2O was cooled to −60° C., then N,N,N′,N′-tetramethyl ethylendiamine (0.71 ml, 4.73 mmol) and secBuLi 1.4M in hexane (4.05 ml, 5.68 mmol) were added. After 10 minutes at −60° C., the temperature was raised to −20° C. for 30 minutes, then the reaction was cooled to −78° C. and dimethylformamide (0.55 ml, 7.09 mmol, dissolved in 5 ml of Et2O) was added. After 30 minutes a saturated aqueous solution of NH4Cl (8 ml) was slowly added, then reaction was allowed to reach room temperature. Reaction was extracted with Et2O (3×50 ml), the organic solvent was dried (Na2SO4) and evaporated to obtain a crude that was purified by silica gel chromatography (petroleum ether/ethylacetate from 95/5 to 85/15). (±) tert-butyl 5-formyl-6-azaspiro[2.5]octane-6-carboxylate was obtained as light yellow solid (400 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[NH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>C(#N)C.O>[C:15]([O:14][C:13](=[O:19])[NH:12][CH2:11][CH2:10][NH:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)([CH3:18])([CH3:16])[CH3:17].[C:15]([O:14][C:13](=[O:19])[NH:12][CH2:11][CH2:10][NH:9][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Clc1ccnc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)NCCNc1ccnc(Cl)n1
Product: CC(C)(C)OC(=O)NCCNc1nccc(Cl)n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 58 %
Yield: 15 %

Procedure:
2,4-Dichloropyrimidine (1.0 g, 6.7 mmol), tert-butyl N-(2-aminoethyl)carbamate (1.06 mL, 6.71 mmol) and triethylamine (1.12 mL, 8.05 mmol) were partially dissolved in acetonitrile (22.5 mL). The mixture was stirred at room temperature for 14 hours before diluting with water and extracting with DCM. The DCM extract was dried over Na2SO4, filtered and concentrated to dryness. The crude mixture was purified by FCC to give tert-butyl-(2-((2-chloropyrimidin-4-yl)amino)ethyl)carbamate (1.07 g, 58%) and tert-butyl-(2-((4-chloropyrimidin-2-yl)amino)ethyl)carbamate (280 mg, 15%).
Reaction SMILES: O[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[CH2:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[CH:9]1[CH:8]=[CH:7][CH:6]=[C:3]2[C:2]=1[CH2:10][C@H:11]1[C@@H:4]2[O:5][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12]1
Reactant: OCc1ccccc1O
Reactant: C1=Cc2ccccc2C1
Product: c1ccc2c(c1)C[C@H]1Cc3ccccc3[C@H]1O2

Procedure:
2-Hydroxybenzyl alcohol (15.0 g) and indene (75 g.) were heated at 210° for 1.5 hr. The unchanged indene was distilled off under reduced pressure and the residue chromatographed on silica gel, eluting with toluene. The product thus obtained, was recrystallised from cyclohexane to yield cis-4b,10,10a,11-tetrahydrobenz(b)indeno(2,1-e)pyran, 2.54 g., m.pt. 59°-60°. The product was characterised by its 1H-n.m.r spectrum. Isomeric purity was established by 13C-n.m.r spectroscopy
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](NC)=[N:6][CH:7]=1.[CH3:10][C:11]([CH3:13])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:28](#[N:30])C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:28][NH:30][CH:11]([CH3:13])[CH3:10])=[N:6][CH:7]=1
Reactant: CC#N
Reactant: CC(C)=O
Reactant: CNc1ccc(Br)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC(C)NCc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (5-Bromo-pyridin-2-yl)-methylamine (0.350 g, 1.871 mmol) in dry acetonitrile (7.0 mL) is added acetone (119 mg, 2.05 mmol) at room temperature. After stirring for 1 hour at room temperature, sodium Triacetoxy borohydride (595 mg, 2.807 mmol) is added then stir at room temperature for 16 hours. The volatiles are removed under reduced pressure, diluted with saturated aqueous bicarbonate solution and ethyl acetate. The organic layer separated and aqueous layer is extracted with ethyl acetate. Combined organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and crude is purified by column chromatography eluting in 6% methanol in CH2Cl2 to afford the title compound (160 mg). 1H-NMR (400 MHz, DMSO-d6) δ: 0.98 (d, J=6.24 Hz, 6H), 2.66-2.73 (m, 1H), 3.76 (s, 2H), 7.44 (d, J=8.36 Hz, 1H), 7.97-7.80 (dd, J1=8.4 Hz, J2=2.4 Hz, 1H), 8.59 (d, J=2.32 Hz, 1H). LC-MS (m/z): [M+H]=230.9.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[NH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][C:14]([Cl:20])=[CH:15][CH:16]=2)[N:11]=1.C(O)C>O>[Cl:20][C:14]1[N:13]=[C:12]2[C:17]([CH:18]=[CH:19][C:10]([NH:9][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:8])=[N:11]2)=[CH:16][CH:15]=1
Reactant: O=C(O)c1cccs1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: CCO
Solvent: O
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1cccs1
Temperature: 4 °C
Yield: 48.9 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 2-thiophenecarboxylic acid (9 g), N,N'-carbonyldiimidazole (11.3 g) and 2-amino-7-chloro-1,8-naphthyridine (9.5 g). The product produced by precipitation in water (9.6 g; m.p. 242° C.) is dissolved in boiling ethanol (700 cc). After 1 hour's cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (2×25 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)-2-thiophenecarboxamide (7.5 g) is produced, m.p. 244° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]4[CH2:27][N:26]([CH2:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[CH2:25][CH2:24][CH2:23][C:22]=4[CH:36]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+].O.CCOCC>C(O)C>[C:31]([OH:33])(=[O:32])[CH3:30].[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]4[CH2:27][N:26]([CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH2:25][CH2:24][CH2:23][C:22]=4[CH:36]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:11])[CH3:12])#[N:2]
Reactant: CCOC(=O)CCCN1CCCc2cc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)ccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: CC(=O)O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCCN(CCCC(=O)O)C4)no2)cc1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
Ethyl 4-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl]butanoate (preparation 11) (90 mg, 0.184 mmol) dissolved in ethanol (20 ml) was treated with sodium hydroxide (0.184 ml, 0.368 mmol) (2N (aq)) solution followed by water (5.00 ml). This mixture was stirred at RT for 3 hours and left standing overnight. 2N NaOH (aq) (150 p1) was added and the reaction mixture stirred for 3 hours. Then ethanol was removed by evaporation and the aqueous layer acidified using AcOH. The product was extracted into EtOAc (50 ml) and dried over MgSO4. Solvent removal by evaporation yielded a white precipitate. Ether was added and the solid filtered off and washed with ether to yield the title compound (44 mg) on drying. δH (400 MHz, d6DMSO) 1.39 (6H, d), 1.91-1.95 (4H, m), 2.30 (2H, t), 2.96 (2H, m), 3.13 (2H, m), 3.53 (2H, m), 4.60 (2H, s), 4.94-5.03 (1H, m), 7.57 (1H, d), 7.68 (1H, d), 7.97-8.00 (2H, m), 8.41 (1H, dd), 8.52 (1H, d) 10.6 (1H, v. broad s), 12.3 (1H, v. broad s); MS (ES) C26H28N4O4 requires 460; found 461.0 [M+H]+.
Reaction SMILES: Cl[CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][N:17]([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])=[CH:10][CH:9]=1)[C:3]([O:5]C)=O.[NH2:24][C:25](N)=[S:26].C([OH:32])CCC>>[CH:18]([N:17]([CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH:2]2[S:26][C:25](=[O:32])[NH:24][C:3]2=[O:5])=[CH:9][CH:10]=1)[CH:21]([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: NC(N)=S
Reactant: CCCCO
Reactant: COC(=O)C(Cl)Cc1ccc(OCCN(C(C)C)C(C)C)cc1
Product: CC(C)N(CCOc1ccc(CC2SC(=O)NC2=O)cc1)C(C)C
Temperature: 100 °C
Yield: 65.2 %

Procedure:
A mixture of 9.0 g methyl 2-chloro-3-{4-[2-(N,N-diisopropylamino)ethyloxy]phenyl}propionate and 2.4 g thiourea is heated in the presence of 100 ml of n-butanol at 100° C. for 15 hours. After cooling, the n-butanol is distilled off under reduced pressure, 100 ml of 2 N-HCl is added to the residue and the mixture is heated at 100° C. for 6 hours. After cooling, the reaction mixture is neutralized with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The extract is washed with water, dried (over Na2SO4) and distilled to remove the ethyl acetate, whereupon 6.0 g (65.2%) of 5-{4-[2-(N,N-diisopropylamino)ethyloxy]benzyl}thiazolidine-2,4-dione is obtained as crystals. These crystals are recrystallized from ethanol. Colorless prisms, m.p. 134°-135° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][C@@H:23]([CH2:27][OH:28])[CH2:22]2)[NH:12][C:11]([C:29]2[N:33]=[CH:32][NH:31][N:30]=2)=[N:10]1.[C:34](O)(=[O:38])[CH:35]([CH3:37])[CH3:36]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][C@@H:23]([CH2:27][O:28][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH2:22]2)[NH:12][C:11]([C:29]2[N:33]=[CH:32][NH:31][N:30]=2)=[N:10]1
Reactant: CC(C)C(=O)O
Reactant: CCOC(=O)C1=C(CN2CCO[C@@H](CO)C2)NC(c2nc[nH]n2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CN2CCO[C@@H](COC(=O)C(C)C)C2)NC(c2nc[nH]n2)=NC1c1ccc(F)cc1Br
Yield: 35 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(((R)-2-(hydroxymethyl)morpholino)methyl)-2-(1H-1,2,4-triazol-3-yl)-1,4-dihydropyrimidine-5-carboxylate (2 g, 3.8 mmol) was reacted with isobutyric acid (0.44 g, 5 mmol) according to the procedure as described in Example 49 to give the title compound as yellow oil (0.79 g, 35%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:9]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[NH:10][C:11](=[O:20])[CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH:6]=[CH:7][CH:8]=1.[CH3:29][O:30][C:31]1[C:32](=O)[C:33](=[O:37])[C:34]=1[O:35]C>>[CH3:29][O:30][C:31]1[C:34](=[O:35])[C:33](=[O:37])[C:32]=1[NH:2][C:3]1[CH:4]=[C:5]([CH:9]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[NH:10][C:11](=[O:20])[CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(C(NC(=O)C(C)c2ccccc2)c2cccc(N)c2)cc1
Reactant: COc1c(OC)c(=O)c1=O
Agent: Cl
Product: COc1ccc(C(NC(=O)C(C)c2ccccc2)c2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1
Yield: 64.6 %

Procedure:
In a similar manner to that described in Example (46e) N-[(3-aminophenyl)-(4-methoxyphenyl)methyl]-2-phenylpropionamide hydrochloride (555 mg) [prepared as described in step (b) above] and 3,4-dimethoxy-3-cyclobutene-1,2-dione (398 mg) were reacted, to afford the title compound (425 mg) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH:22][C@@H:23]1[CH2:27][CH2:26][NH:25][CH2:24]1>CO>[ClH:1].[CH2:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21][N:12]1[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([N:25]2[CH2:26][CH2:27][C@@H:23]([OH:22])[CH2:24]2)[CH:11]=1
Reactant: Clc1cc(N2CCc3ccccc3C2)c2ccccc2n1
Reactant: O[C@@H]1CCNC1
Solvent: CO
Product: Cl
Product: O[C@@H]1CCN(c2cc(N3CCc4ccccc4C3)c3ccccc3n2)C1

Procedure:
The title compound, m.p. 270-274° C., [α]D20 =−34° (c=0.54, methanol) and MS: m/e=346.3 (M+H+), was prepared from 2-chloro-4-(3,4-dihydro-1H-isoquinolin-2yl)-quinoline and (R)-3-hydroxypyrrolidine
Reaction SMILES: C([O:8][C:9]1[C:14]2[N:15]([CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)[C:16]([CH3:18])=[N:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.C(O)(=O)C.[Pd]>[CH3:18][CH:16]1[NH:17][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([OH:8])[C:14]=2[N:15]1[CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1
Reactant: Cc1nc2cccc(OCc3ccccc3)c2n1Cc1ccc2ccccc2c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC1Nc2cccc(O)c2N1Cc1ccc2ccccc2c1

Procedure:
7-Benzyloxy-2-methyl-1-naphthalen-2-ylmethyl-1H-benzoimidazole (211 mg) in methanol (12 mL) and acetic acid (1.0 mL) was hydrogenated in presence of 10% Pd—C at 45 psi for 20 h. Reaction mixture was filtered through a pad of celite. The filtrate was concentrated to afford 2-methyl-3-naphthalen-2-ylmethyl-1H-benzoimidazol-4-ol, I-111 (211 mg).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([C:7](O)=[O:8])[N:6]=1.CN(C=O)C.C(Cl)(=O)C([Cl:24])=O>C(Cl)Cl>[CH3:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([C:7]([Cl:24])=[O:8])[N:6]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)s1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)Cl)c(-c2ccccc2)s1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a suspension of 2-methyl-5-phenyl-1,3-thiazole-4-carboxylic acid (1.47 g, 6.70 mmol) in CH2Cl2 (30 mL) cooled at 0° C. was added DMF (26 μL, 0.34 mmol) and oxalyl chloride (0.73 mL, 8.38 mmol). The reaction was allowed to warm to ambient temperature and stirred for 4 h. The solution was concentrated in vacuo to provide 2-methyl-5-phenyl-1,3-thiazole-4-carbonyl chloride as a yellow-orange oil which gave a mass ion (ES+) of 236.3. 1H NMR δ (ppm) (CDCl3): 7.42-7.46 (5H, m), 2.78 (3H, s).
Reaction SMILES: [C:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:19](Cl)(Cl)=[S:20]>ClCCl>[C:1]1([N:11]=[C:19]=[S:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1cccc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: S=C=Nc1cccc2ccccc12
Temperature: 25 °C

Procedure:
To the mixture of 1-naphthylamine (21.48 g), triethylamine (33.39 g), and dichloromethane (250 mL) was added a dicholomethane (50 mL) solution of thiophosgen (18.97 g) at bleow 20° C. over 30 minutes, and the mixture was stirred at room temperature. The reaction mixture was added into ice-water (1000 mL), extracted with diethyl ether (1000 mL). The extract was washed two times with brine (1000 mL), dried over anhydrous magnesium sulfate, evaporated under reduced pressure to obtain crude (1-naphthyl)isothiocyanate.
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]/[C:4]([CH:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH:8]=[C:7]1[CH3:14])=[O:5].[SH:15][CH2:16][CH2:17][CH2:18][Si:19]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22].C1CCN2C(=NCCC2)CC1.Cl>C1COCC1>[CH2:21]([O:20][Si:19]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])[CH2:18][CH2:17][CH2:16][S:15][CH:2]([CH3:1])[CH2:3][C:4]([CH:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH:8]=[C:7]1[CH3:14])=[O:5])[CH3:22]
Reactant: CCO[Si](CCCS)(OCC)OCC
Reactant: C/C=C/C(=O)C1C(C)=CCCC1(C)C
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCO[Si](CCCSC(C)CC(=O)C1C(C)=CCCC1(C)C)(OCC)OCC
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
A solution of α-damascone (9.60 g; 50.0 mmol) and 3-mercaptopropyltriethoxysilane (95% pure, 12.52 g, 50.0 mmol) in THF (40 ml) was treated with DBU (1.52 g, 10.0 mmol) and stirred at 40° C. for 90 min. The reaction solution was treated with 5% HCl, extracted twice with ether, washed with water, saturated aqueous NaHCO3 and then with saturated aqueous NaCl, dried over Na2SO4 and concentrated at 70° C./0.01 mbar. The reaction yielded 21.2 g (99%). of crude product:
Reaction SMILES: [CH:1]1([C:4]([NH:6][NH2:7])=[O:5])[CH2:3][CH2:2]1.[I:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[CH3:20])[C:12](=[NH:16])OCC>CO>[NH:16]=[C:12]([C:11]1[CH:17]=[CH:18][C:19]([CH3:20])=[C:9]([I:8])[CH:10]=1)[NH:7][NH:6][C:4]([CH:1]1[CH2:3][CH2:2]1)=[O:5]
Reactant: CCOC(=N)c1ccc(C)c(I)c1
Reactant: NNC(=O)C1CC1
Solvent: CO
Product: Cc1ccc(C(=N)NNC(=O)C2CC2)cc1I
Temperature: 75 °C
Reaction time: 1.5 h

Procedure:
Cyclopropanecarbohydrazide (0.36 g, 2.7 mmol) was added to a stirred solution of ethyl 3-iodo-4-methylbenzimidate (preparation 51b, 0.70 g, 2.4 mmol) in methanol (6 mL) and the mixture was stirred at 75° C. After 1.5 hours, the mixture was cooled to give a suspension. Methanol was added to the suspension and the precipitate was filtered and dried to give the desired compound in quantitative yield. The crude material was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8](O)[CH3:9])[C:3]=1[OH:11]>CO.[Pd]>[CH2:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[OH:11])[CH3:9]
Reactant: CC(O)c1cccc(F)c1O
Agent: [Pd]
Solvent: CO
Product: CCc1cccc(F)c1O
Reaction time: 6 h

Procedure:
A mixture of 2-fluoro-6-(1-hydroxy-ethyl)-phenol (1.7 g, 10.9 mmol) and 10 wt % Pd/C (0.85 g, Degussa type) in MeOH (30 mL) was stirred under a balloon of H2 for 6 hours. The reaction mixture was filtered through a pad of celite washing with EtOAc. The filtrate was concentrated to a yellow oil (1.35 g, 87%). 1H NMR (400 MHz, CDCl3): δ 1.22 (t, J=7.6 Hz, 3H), 2.68 (q, J=7.3 Hz, 2H), 5.12 (s, 1H), 6.76 (m, 1H), 6.92 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:6]2[C:7](Cl)=[N:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[NH4+:12].[OH-]>O1CCOCC1>[Br:1][C:2]1[C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1
Reactant: [NH4+]
Reactant: Clc1nccc2scc(Br)c12
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1nccc2scc(Br)c12
Temperature: 150 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
A mixture of 3-bromo-4-chlorothieno[3,2-c]pyridine (prepared according to the procedure described in Bull. Soc. Chim. Belges 1970, 79, 407–414, 3 g, 12 mmol), concentrated aqueous NH4OH (100 mL), and p-dioxane (100 mL) was sealed in a stainless steel, high-pressure reactor and stirred for 18 hours at 150° C. The mixture was concentrated to half its original volume, diluted with water, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated to provide 2.6 g (94%) of the desired product. 1H NMR (DMSO-d6, 400 MHz) δ 7.83 (d, 1H), 7.77 (s, 1H), 7.26 (d, 1H), 6.48 (br s, 2H); MS m/e 229 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5]1[C:10]([Cl:11])=[CH:9][C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:7]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:6]=1)C.O1CCCC1.[OH-].[Na+].Cl>C(O)C>[Cl:11][C:10]1[C:5]([C:4]([OH:32])=[O:3])=[CH:6][C:7]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[C:8]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH:9]=1
Reactant: CCOC(=O)c1cc(OCc2ccc(OC)cc2)c(OCc2ccc(OC)cc2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(COc2cc(Cl)c(C(=O)O)cc2OCc2ccc(OC)cc2)cc1
Yield: 91.3 %

Procedure:
A solution of 6-chloro-3,4-bis(p-methoxybenzyloxy)benzoic acid ethyl ester (110 g: 240 mMol.) in a mixture of ethanol (800 ml), pg,64 tetrahydrofuran (150 ml), and aqueous 2N -sodium hydroxide (264 ml: 2.2 Eq.) is heated at 70° C. for 2 hours. The reaction mixture is cooled and acidified with hydrochloric acid. The resulting precipitate is collected by filtration and washed with ethanol and water to give 6-chloro-3,4-bis(p-methoxybenzyloxy)benzoic acid (94 g). Yield: 99%.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[CH2:14]([OH:19])[CH:15]([OH:18])[CH:16]=[CH2:17]>>[Si:1]([O:19][CH2:14][CH:15]([OH:18])[CH:16]=[CH2:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CC(O)CO
Agent: c1c[nH]cn1
Product: C=CC(O)CO[Si](C)(C)C(C)(C)C
Reaction time: 2 h

Procedure:
t-Butyl dimethylsilylchloride (4.28 g, 28.4 mmol) and imidazole (4.83 g, 70.9 mmol) were added to a flask purged with N2 and dichloromethane (50 mL) was added. 3-Butene-1,2-diol (2.50 g, 28.4 mmol) was then added to the flask and the mixture was stirred for 2 hours. The solvent was removed and the titled product (2.71 g, 47.9%) was purified by column chromatography (5% ethyl acetate in hexanes).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([I:13])[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[C:8]([I:13])[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Oc1ccc(-n2ccnc2)cc1I
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc(-n4ccnc4)cc3I)c2cc1OC
Temperature: 140 °C
Reaction time: 7.5 h
Yield: 45.2 %

Procedure:
4-(Imidazol-1-yl)-2-iodophenol (123 mg), 4-chloro-6,7-dimethoxyquinoline (288 mg), and 4-dimethylaminopyridine (158 mg) were suspended in o-dichlorobenzene (3 ml), and the suspension was stirred at 140° C. for 7.5 hr. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure. The residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (92 mg, yield 45%).