Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[C:14]([N:22]3[CH:26]=[CH:25][N:24]=[N:23]3)[CH:13]=2)[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].[OH-].[Na+].Cl.O>O1CCCC1.CO>[CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[C:14]([N:22]3[CH:26]=[CH:25][N:24]=[N:23]3)[CH:13]=2)[S:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1sc(-c2ccc(OC(C)C)c(-n3ccnn3)c2)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(OC(C)C)c(-n3ccnn3)c2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
A reaction mixture solution prepared by dissolving 501 mg of ethyl 4-methyl-2-[4-(propan-2-yloxy)-3-(1H-1,2,3-triazol-1-yl)phenyl]-1,3-thiazole-5-carboxylate in 10 mL of a mixed solution of tetrahydrofuran/methanol=1/1 and adding 1.35 mL of 2 M sodium hydroxide aqueous solution was stirred at room temperature for 3 hours. After the addition of 1.35 mL of 2 M hydrochloric acid to the reaction mixture solution under stirring, 8 mL of water was added and extraction was performed using 20 mL of ethyl acetate. The organic phase was concentrated, followed by purifying by a conventional method to obtain 415 mg of 4-methyl-2-[4-(propan-2-yloxy)-3-(1H-1,2,3-triazol-1-yl)phenyl]-1,3-thiazole-5-carboxylic acid.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25]O)[C:5]1=[O:29])[CH:2]=[CH2:3].[CH:31]1([S:35]([NH2:38])(=[O:37])=[O:36])[CH2:34][CH2:33][CH2:32]1>>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][NH:38][S:35]([CH:31]2[CH2:34][CH2:33][CH2:32]2)(=[O:37])=[O:36])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Reactant: NS(=O)(=O)C1CCC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNS(=O)(=O)C2CCC2)C1=O
Temperature: 40 °C

Procedure:
The title compound was prepared from (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (Example 91, Step B, 250 mg, 0.560 mmol) and cyclobutanesulfonamide (Example 271G, 256 mg, 1.894 mmol) using the general procedure described in Step A of Example 272, albeit with an oil bath heated at 40° C. The crude product was purified by silica gel chromatography eluting with a gradient of EtOAc in hexanes. The product was obtained as a white powder (220 mg, 70%). LCMS (ESI): m/z=563.2 (M+H).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([CH3:25])=[CH:22][CH:23]=2)[C:18]([N:26]2[CH:30]=[N:29][N:28]=[C:27]2[SH:31])=[CH:17][CH:16]=1.CN(C=O)C>C1COCC1.O>[CH3:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([CH3:25])=[CH:22][CH:23]=2)[C:18]([N:26]2[CH:30]=[N:29][N:28]=[C:27]2[S:31][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:17][CH:16]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc2c(C)ccc(-n3cnnc3S)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CSc1nncn1-c1ccc(C)c2ccc(C)cc12
Temperature: 60 °C
Yield: 86.4 %

Procedure:
Ethyl 2-bromoacetate (87 μL, 0.783 mmol) and Potassium carbonate (0.216 g, 1.57 mmol) were added to a solution of 4-(4,7-Dimethylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol (0.2 g, 0.783 mmol) in THF (3.1 mL). The resulting mixture was then heated to 60° C. for 1 hour. Additional DMF (1 mL) was added and the mixture heated at 60° C. for 18 hours. Water (3 mL) was added and the mixture extracted with ethyl acetate (3×3 mL). The combined organic extracts were dried over sodium sulfate, filtered, concentrated and Purified by SGC (0-100% EtOAc/Hexanes) to afford ethyl 2-(4-(4,7-dimethylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate as a clear oil (0.231 g, 86%).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[N:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH2:14][CH2:13][CH:12]=2)[NH:6]1)([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[C:30]#[CH:31]>C1(C)C=CC=CC=1.O>[C:1]([N:5]1[C:9](=[O:10])[N:8]([CH2:31][C:30]#[CH:29])[C:7]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1[nH]c(C2=CCCC=C2)nc1=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: C#CCn1c(-c2ccccc2)nn(C(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of crude 345 g (1.2 mol) of 1-t-butyl-4-H-3-phenyl-1,2,4-triazol-5-one and 3.5 L of ethyl acetate containing 0.03% water was stirred at room temperature and 190 g (1.67 mol) of solid potassium carbonate (K2CO3) was added. The mixture was heated at reflux for 0.5 h and 248 g (1.67 mol) of an 80% weight solution of propargyl bromide in toluene was added dropwise over 30 minutes. Refluxing was continued for an additional 3 h. The mixture was allowed to cool to room temperature, diluted with 2 L of water and stirred for 15 min. The organic layer was separated, washed with brine and dried over magnesium sulfate (MgSO4). Removal of the solvent left 300 g of an oil which was crystallized from 500 mL of ether and 1500 mL of hexanes to furnish 180 g of the desired compound, mp 82°-83° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:19]C)[CH2:12][C:11]([N:21]([CH3:23])[CH3:22])=[N:10]2)=[CH:5][CH:4]=1.[BrH:24]>>[OH2:19].[BrH:24].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[OH:19])[CH2:12][C:11]([N:21]([CH3:23])[CH3:22])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COc1cccc2c1C(c1ccc(Cl)cc1)N=C(N(C)C)C2
Agent: Br
Agent: Cl
Product: CN(C)C1=NC(c2ccc(Cl)cc2)c2c(O)cccc2C1
Product: O

Procedure:
A solution of 1-(4-chlorophenyl)-3-dimethylamino-8-methoxy-1,4-dihydroisoquinoline hydrochloride (0.9 g) in 48% aqueous hydrobromic acid (100 ml) was heated at 115°-120° C. for 2.5 h. The solution was evaporated to dryness in vacuo and recrystallised from methanol-water to afford the title compound, (0.66 g), m.p. 185°-187° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([O:18][CH2:19][CH2:20][CH2:21][CH:22]=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCOCCCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCCCCCCOCCCC=O
Temperature: -45 °C
Yield: 77.4 %

Procedure:
A solution of oxalyl chloride (42 mL) in dry methylene dichloride (750 mL) was cooled under a nitrogen atmosphere to −75° C. Dimethylsulfoxide (72 mL) was added dropwise with stirring, followed after 10 minutes by a solution of 4-(n-heptyloxy)butan-1-ol (75.2 g from below) in methylene dichloride (75 mL). The mixture was stirred and allowed to warm to −45° C., then was again cooled to −75° C. and treated dropwise with triethylamine (292 mL). After the addition was complete, the cooling bath was removed and the mixture was allowed to slowly warm to room temperature and stir one hour. Ice was added, and the product was partitioned between water and methylene dichloride. The solvent was removed with a rotary evaporator, and the residue was dissolved in petroleum ether (500 mL) and the solution was rinsed in water, cold aqueous hydrochloric acid, water, and saturated aqueous sodium bicarbonate. After drying over magnesium sulfate, the solvent was stripped in vacuo, and the residue was distilled to give 57.6 g (77%) of 4-(n-heptyloxy)butanal, b.p. 60° C., 0.26 Torr.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([N:10]2[C:14]([CH3:15])=[C:13]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[C:21](=[O:25])[CH:20]([O:26][C:27]([CH3:29])=[O:28])[CH2:19]4)[N:12]=[N:11]2)=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:30]N(C)C=O>CI>[F:3][C:4]1[C:9]([N:10]2[C:14]([CH3:15])=[C:13]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[C:21](=[O:25])[C:20]([CH3:30])([O:26][C:27]([CH3:29])=[O:28])[CH2:19]4)[N:12]=[N:11]2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CC(=O)OC1Cc2cc(-c3nnn(-c4cccnc4F)c3C)ccc2C1=O
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CC(=O)OC1(C)Cc2cc(-c3nnn(-c4cccnc4F)c3C)ccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At room temperature, 3 mg of 60% of sodium hydride was added to 1 ml solution of dimethylformamide with 10 mg of 1-(2-fluoropyridine-3-yl)-4-(1-oxo-2-methylcarbonyloxy-indane-5-yl)-5-methyl-1H-[1,2,3]triazole, obtained in Example 45. After stirring 30 min at room temperature, 5 drops of methyl iodide was added and the mixture was further stirred for 1 hour at room temperature.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:38])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:37])[CH:17]([NH:18][C:19](=[O:36])[CH2:20][N:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:22]([O:24][CH:25]([CH:27]3[CH2:29][CH2:28]3)[CH3:26])=[O:23])[C@H:5]2[S:4]1.C(=O)(O)[O-].[Na+].[CH3:44][C:45]1[S:49][C:48]([SH:50])=[N:47][N:46]=1.O>C(N)=O>[CH3:44][C:45]1[S:49][C:48]([S:50][CH2:2][C:3]2([CH3:38])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]3[C:16](=[O:37])[CH:17]([NH:18][C:19](=[O:36])[CH2:20][N:21]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:22]([O:24][CH:25]([CH:27]4[CH2:29][CH2:28]4)[CH3:26])=[O:23])[C@H:5]3[S:4]2)=[N:47][N:46]=1
Reactant: Cc1nnc(S)s1
Reactant: CC(OC(=O)N(CC(=O)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)C(C)(CBr)S[C@H]12)c1ccccc1)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: NC=O
Solvent: O
Product: Cc1nnc(SCC2(C)S[C@@H]3C(NC(=O)CN(C(=O)OC(C)C4CC4)c4ccccc4)C(=O)N3C2C(=O)OCC(Cl)(Cl)Cl)s1
Reaction time: 4.5 h
Yield: 10.8 %

Procedure:
A solution of 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-[N-(1-cyclopropylethoxy)carbonylphenylglycyl]aminopenam-3-carboxylate (3.6 g) in formamide (40 ml) was added to a solution of sodium bicarbonate (0.66 g) and 5-methyl-1,3,4-thiadiazole-2-thiol (1.1 g) in formamide (60 ml) under ice-cooling, after which the mixture was stirred for 4.5 hours at the same temperature. After the reaction was completed, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with 5% sodium bicarbonate aqueous solution and then with water, dried, after which the solvent was distilled off. The oily residue was subjected to column chromatography on silica gel (110 g) and eluted with chloroform. The eluate was separated into fractions of each 50 ml and after collecting the fractions of the fifteenth and sixteenth, the solvent was distilled off to give oily 2,2,2-trichloroethyl 2-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-2-methyl-6-[N-(1-cyclopropylethoxy)carbonylphenylglycyl]aminopenam-3-carboxylate (0.42 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:17][CH:18]=[CH2:19])[CH3:16])[CH:5]=[CH:4][C:3]=1[C:20]([C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)=[O:21].[CH:29](O)=[O:30]>C(N)=O>[CH2:17]([N:15]([CH3:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([C:20](=[O:21])[C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)=[C:2]([NH:1][CH:29]=[O:30])[CH:7]=1)[CH:18]=[CH2:19]
Reactant: C=CCN(C)CCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)c(N)c1
Reactant: O=CO
Solvent: NC=O
Product: C=CCN(C)CCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)c(NC=O)c1

Procedure:
A solution of 230 mg of [2-amino-4-[6-(allyl-methyl-amino)-hexyloxy]-phenyl]-(4-bromo-phenyl)-methanone (Ex. 36) in 0.5 ml of formic acid and 2 ml of formamide is boiled at 165° C. for 5 min., concentrated at 170° C./0.1 Torr in a bulb-tube and converted into the free amine with methylene chloride/saturated sodium bicarbonate solution. After purification over silica gel with methylene chloride/methanol (2.5%) as the eluent there are obtained 30 mg of N-[5-[6-(allyl-methyl-amino)-hexyloxy]-2-(4-bromo-benzoyl)-phenyl]-formamide, MS: m/e 473 (M+H+, 1Br).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>>[I:8][C:5]1[CH:6]=[CH:7][C:2]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:3][CH:4]=1
Reactant: Clc1ccc(I)cn1
Reactant: C1COCCN1
Product: Ic1ccc(N2CCOCC2)nc1

Procedure:
Prepared from 2-chloro-5-iodopyridine and morpholine by the method of Example 9 (d).
Reaction SMILES: [NH2:1][C@H](C(O)=O)CCCCN.[NH2:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][C:14](=O)[OH:15].N[C@H](C(O)=O)CCC(=O)O>>[NH2:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][C:14](=[O:15])[NH2:1]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: N[C@@H](CCC(=O)O)C(=O)O
Product: NC(=O)C[C@H](N)C(=O)O

Procedure:
N Lys: K Asp: D Glu: E
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][C:10]([C:15]1[N:20]=[CH:19][N:18]3[CH:21]=[CH:22][CH:23]=[C:17]3[CH:16]=1)=[CH:9][C:8]2=[N:24][O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:4].O.[OH-].[Li+]>O1CCCC1.CO.O>[C:26]([O:25][N:24]=[C:8]1[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)[O:11][C:10]([C:15]2[N:20]=[CH:19][N:18]3[CH:21]=[CH:22][CH:23]=[C:17]3[CH:16]=2)=[CH:9]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: COC(=O)c1ccc2oc(-c3cc4cccn4cn3)cc(=NOC(C)(C)C)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(C(=O)O)cc12
Temperature: 60 °C
Yield: 83.2 %

Procedure:
A suspension of 4-(tert-Butoxyimino)-2-pyrrolo[1,2-c]pyrimidin-3-yl-4H-chromene-6-carboxylic acid methyl ester (example 115B) (170 mg, 0.43 mmol) in a mixture of tetrahydrofuran/methanol/water (2.0 ml/0.5 ml/0.5 ml) was treated with lithium hydroxide monohydrate (55 mg, 1.29 mmol) and heated at 60° C. for 2 hours. The solvents were removed and the residue was diluted with water, neutralized to pH 5-6 with a 1N solution of hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated to dryness to give 4-(tert-Butoxyimino)-2-pyrrolo[1,2-c]pyrimidin-3-yl-4H-chromene-6-carboxylic acid (135 mg, 84%) as a green solid. A solution of the previous carboxylic acid, (3-Dimethylamino-propyl)-ethyl-carbodiimide, hydrochloride (90 mg, 0.47 mmol), 1-Hydroxybenzotriazole hydrate (68 mg, 0.50 mmol) and triethylamine (250 μl, 1.80 mmol) in dimethylformamide (6.0 ml) was stirred at 0° C. for 1 hour then 4-(2-aminoethyl)-morpholine (52 μl, 0.40 mmol) was added. The mixture was stirred at room temperature for 18 hours. The volatiles were removed under vacuum and the residue taken into ethyl acetate, washed several times with a saturated solution of sodium hydrogenocarbonate, brine, dried over sodium sulfate and concentrated to dryness. The residue was purified by silica gel flash chromatography (gradient ethyl acetate/methanol 0-8%) to yield the title compound as a yellow solid (137 mg, 78%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[OH:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27]Br)=[CH:24][CH:23]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:27][CH2:26][C:25]4[CH:29]=[CH:30][C:22]([OH:21])=[CH:23][CH:24]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: Oc1ccc(CCBr)cc1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(CCc3ccc(O)cc3)C2=O)cn1
Yield: 31 %

Procedure:
Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 4-hydroxyphenethyl bromide. Yield: 31%. MS M+H calculated 396.16; found 396.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.41 μM.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:13][CH:14]=O)=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[O:16]1[C:20]2([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[O:16]1[C:20]2([CH2:25][CH2:24][N:23]([CH2:14][CH2:13][C:4]3[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[C:10]4[C:5]=3[CH:6]=[CH:7][CH:8]=[N:9]4)[CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1
Reactant: COc1ccc2ncccc2c1CC=O
Reactant: C1CC2(CCN1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc2ncccc2c1CCN1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
0.72 g of (6-methoxyquinolin-5-yl)acetaldehyde and 0.75 g of 1,4-dioxa-8-azaspiro[4.5]decane were dissolved in 30 ml of methylene chloride. Then, 0.50 ml of acetic acid and 0.89 g of sodium triacetoxyborohydride were added to the reaction solution, and the obtained mixture was then stirred at room temperature overnight. Thereafter, a saturated sodium bicarbonate aqueous solution was added to the reaction solution, followed by extraction with methylene chloride. The extract was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate), so as to obtain 1.01 g of the subject compound.
Reaction SMILES: C1C=CC=CC=1.[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH2:30]C)[C:25](=[C:32]([S:35][CH2:36][CH:37]([OH:45])[CH2:38][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)[C:33]#[N:34])[NH:24][CH2:23][CH2:22]2)C>C(N(CC)CC)C>[CH3:16][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH3:30])[C:25](=[C:32]([S:35][CH2:36][CH:37]([O:45][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:38][N:39]1[CH2:40][CH2:41][O:42][CH2:43][CH2:44]1)[C:33]#[N:34])[NH:24][CH2:23][CH2:22]2
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOc1cc2c(cc1OCC)C(=C(C#N)SCC(O)CN1CCOCC1)NCC2
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1cc2c(cc1OC)C(=C(C#N)SCC(CN1CCOCC1)OC(=O)c1ccccc1)NCC2

Procedure:
After adding 40 ml of benzene, 1.0 g of triethylamine and 1.5 g of benzoyl chloride to 4.06 g of 2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[2-hydroxy-3-(4-morpholinyl)propyl]mercaptoacetonitrile, the reaction mixture is refluxed for 45 minutes, then cooled down and filtered. After evaporating the filtrate, the residue crystallizes out on adding ethyl acetate to obtain the named product in a yield of 3.25 g, m.p.: 144° C. (from isopropanol).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:32])=[C:4]([CH:29]=[CH:30][CH:31]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:26])[CH2:24]Cl)[CH2:19][CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[I-].[Na+].[CH3:35][NH:36][CH3:37]>>[Cl:1][C:2]1[C:3]([F:32])=[C:4]([CH:29]=[CH:30][CH:31]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:26])[CH2:24][N:36]([CH3:37])[CH3:35])[CH2:19][CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)CCl)CC1
Reactant: CNC
Agent: [I-]
Agent: [Na+]
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)CN(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 4-(3-chloro-2-fluoroanilino)-6-[1-(chloroacetyl)piperidin-4-yloxy]-7-methoxyquinazoline (0.14 g) and sodium iodide (0.1 g) in an ethanolic solution of dimethylamine (33%) (10 ml) was stirred at ambient temperature for 2 hours. The mixture was evaporated under vacuum and the residue dissolved in methylene chloride and purified by column chromatography on silica eluting with increasingly polar mixtures of methylene chloride/methanol (saturated with ammonia) (100/0 to 85/15). The fractions containing the title product were combined and evaporated under vacuum and the residue triturated with diethyl ether and filtered to give the title product as a crystalline solid (0.085 g); 1H NMR Spectrum: (DMSO d6) 1.56-1.78 (m, 2H), 1.92-2.08 (m, 2H), 2.20 (s, 6H), 3.05-3.18 (m, 2H), 3.30-3.48 (m, 2H), 3.79-3.90 (m, 2H), 3.94 (s, 3H), 4.75 (m, 1H), 7.21 (s, 1H), 7.28 (t, 1H), 7.44-7.56 (m, 2H), 7.86 (s, 1H), 8.37 (s, 1H), 9.53 (s, 1H); Mass Spectrum: (M+H)+ 488.
Reaction SMILES: [C:1](Cl)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl-:11].[Al+3].[Cl-].[Cl-].[CH:15]#[CH:16]>C(Cl)(Cl)(Cl)Cl>[Cl:11]/[CH:15]=[CH:16]/[C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: [Cl-]
Reactant: CCCCCCCC(=O)Cl
Reactant: C#C
Agent: [Al+3]
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCC(=O)/C=C/Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 200 ml of octanoyl chloride (A6R1 =C2H5) in 750 ml of carbon tetrachloride is cooled on an ice bath and treated with 214 g of aluminum chloride in three portions over a 1 hour period while acetylene is bubbled through the solution. The ice bath is removed and the reaction mixture stirred at room temperature for 3 hours with additional acetylene being added. At the end of this period, the reaction mixture is poured into 4 kg of ice. The organic layer is separated and the aqueous layer extracted twice with 500 ml of chloroform. The combined organic extracts are washed once with 500 ml of water, dried over anhydrous sodium sulfate and concentrated in vacuo. Distillation of the residue yields 142 g of trans-1-chloro-dec-1-en-3-one, (A5R1 =C2H5).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:10]2[C:5](=[CH:6][C:7]([OH:14])=[C:8]([N+:11]([O-])=O)[CH:9]=2)[NH:4][C:3]1=[O:15].[H][H].[C:19](O)(=O)[CH3:20]>[Pd]>[N:4]1[CH:5]=[CH:6][C:19]([C:20]2[O:14][C:7]3[CH:6]=[C:5]4[NH:4][C:3](=[O:15])[C:2]([CH3:16])([CH3:1])[C:10]4=[CH:9][C:8]=3[N:11]=2)=[CH:2][CH:3]=1
Reactant: CC1(C)C(=O)Nc2cc(O)c([N+](=O)[O-])cc21
Reactant: CC(=O)O
Reactant: [H][H]
Agent: [Pd]
Product: CC1(C)C(=O)Nc2cc3oc(-c4ccncc4)nc3cc21
Reaction time: 72 h
Yield: 49 %

Procedure:
4 g. 1,3-Dihydro-3,3-dimethyl-6-hydroxy-5-nitro-2H-indol-2-one in 100 ml. glacial acetic acid were hydrogenated in the presence of 1 g. 10% palladium/charcoal at ambient temperature and normal pressure until 1.3 liters of hydrogen had been taken up. The catalyst was filtered off and 2.1 ml. 4-pyridinecarbaldehyde were poured into the filtrate, the solution thereby becoming yellow-orange coloured. While stirring, air was passed through the solution for 3 days, whereafter it was evaporated to dryness in a vacuum, the residue was digested with an aqueous solution of ammonia and water and purified by column chromatography (800 ml. silica gel; elution agent dichloromethane:methanolic ammonia=20:1 v/v). The appropriate fractions were evaporated in a vacuum and the crystalline residue was digested with ethanol and filtered off with suction to give 4.0 g. of beige crystals which were recrystallised from ethanol with treatment with fullers' earth. There were obtained 2.5 g. of the title compound in the form of colourless crystals; m.p. 336°-338° C. Yield 49% of theory.