Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]2[N:15]=[C:16]([CH3:21])[C:17]([C:18]([OH:20])=O)=[C:13]2[CH:12]=[C:11]([CH3:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[C:54]([O:58][C:59](=[O:68])[NH:60][C:61]([CH2:66][NH2:67])([CH3:65])[CH2:62][CH2:63][CH3:64])([CH3:57])([CH3:56])[CH3:55]>O1CCCC1>[C:54]([O:58][C:59](=[O:68])[NH:60][C:61]([CH3:65])([CH2:62][CH2:63][CH3:64])[CH2:66][NH:67][C:18]([C:17]1[C:16]([CH3:21])=[N:15][N:14]2[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]([CH3:22])=[CH:12][C:13]=12)=[O:20])([CH3:57])([CH3:56])[CH3:55]
Reactant: Cc1cc(OCc2ccccc2)n2nc(C)c(C(=O)O)c2c1
Reactant: CCCC(C)(CN)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3ccccc3)cc(C)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
A solution of 240 mg (0.81 mmol) of 7-benzyloxy-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid (Example 139A) in 12 ml of tetrahydrofuran was admixed with 132 mg (0.97 mmol) of 1-hydroxy-7-azabenzotriazole and 186 mg (0.97 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The reaction mixture was stirred at room temperature for 10 minutes. The resulting mixture was admixed with 0.422 ml (2.43 mmol) of N,N-diisopropylethylamine and 210 mg (0.97 mmol) of rac-(1-aminomethyl-1-methylbutyl)carbamic acid tert-butyl ester from Example 152A. The mixture was stirred at room temperature for a further 18 hours, and the contents were then concentrated under reduced pressure. The residue was partitioned between dichloromethane and water. The organic phase was removed and washed with water and aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using a prepacked silica gel cartridge (mobile phase: cyclohexane/ethyl acetate, gradient 0% to 50%), which gave 370 mg (65% yield, 71% pure) of the target compound, which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:14][C:15]1([F:19])[CH2:18][NH:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:17]2[CH2:18][C:15]([F:19])([F:14])[CH2:16]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: FC1(F)CNC1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(N2CC(F)(F)C2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.8 %

Procedure:
A 25 mL round-bottomed flask was charged with a solution of 3-oxoazetidine-1-carboxylic acid tert-butyl ester (0.4 g, 2.34 mmol), 3,3-difluoroazetidine hydrochloride (0.364 g, 2.80 mmol) and 4 Å molecular sieves (2.43 g) in DCE (10 mL). The reaction mixture was stirred for 3 h at room temperature. Sodium triacetoxyborohydride (0.99 g, 4.67 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 10:90) to give the title compound as a colourless oil (0.33 g, 57%). 1H NMR (300 MHz, CDCl3): δ 4.02-3.69 (m, 4 H), 3.65 (t, J=12.15 Hz, 4 H), 3.55-3.48 (m, 1 H), 1.43 (s, 9 H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[CH3:8].[N:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:34])[C:18]2[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:20][C:19]=2[OH:33])=[CH:12][CH:11]=1.O>CN(C)C=O>[N:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:34])[C:18]2[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])=[CH:20][C:19]=2[O:33][CH2:7][CH3:8])=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccncc2)c(O)c1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(CNC(=O)OC(C)(C)C)ccc1C(=O)Nc1ccncc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.5 %

Procedure:
Potassium carbonate (40 mg) and ethyl bromide (56 mg) were added to a solution of N-(4- pyridyl)-4-tert-butoxycarbonylaminomethyl-2-hydroxybenzamide (100 mg) in dimethylformamide (10 ml), and the mixture was stirred at room temperature for 4 hours. After the reaction, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, and concentrated under reduced pressure. The obtained crystals were recrystallized form ethyl acetate-hexane to give 60 mg of N-(4- pyridyl)-4-tert-butoxycarbonylaminomethyl-2-ethoxybenzamide.
Reaction SMILES: O.[NH2:2][NH2:3].[CH:4](=O)[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CC(O)(C)C>[C:7]1([CH:6]2[NH:3][N:2]=[CH:4][CH2:5]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=CC=Cc1ccccc1
Reactant: NN
Solvent: O
Solvent: CC(C)(C)O
Product: C1=NNC(c2ccccc2)C1

Procedure:
Under N2 atmosphere, hydrazine hydrate (9.2 mL) was added to a solution of cinnamaldehyde (10.0 g) in t-BuOH (20 mL). The mixture was refluxed overnight, followed by concentration under reduced pressure. Water was added to the residue, and the aqueous phase was extracted twice with DCM. The combined organic layers were washed with water, dried over Na2SO4 and concentrated under reduced pressure. This gave 10.46 g of a yellow oil containing 85% of the desired product, which was used in subsequent steps without further purification. 1H NMR (200 MHz, CDCl3) δ 2.61-2.80 (m, 1H), 3.04-3.23 (m, 1H), 4.72 (dd, J=8 and 10 Hz, 1H), 5.60-6.10 (br s, 1H), 6.77-6.87 (m, 1H), 7.18-7.47 (m, 5H).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]3)=[O:18])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.[OH-].[Li+].C1COCC1.O>CO>[CH:25]([N:22]1[CH2:21][CH2:20][N:19]([C:17]([C@H:14]2[CH2:13][CH2:12][C@H:11]([O:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:28])=[O:2])=[CH:9][CH:8]=3)[CH2:16][CH2:15]2)=[O:18])[CH2:24][CH2:23]1)([CH3:27])[CH3:26]
Reactant: COC(=O)c1ccc(O[C@H]2CC[C@H](C(=O)N3CCN(C(C)C)CC3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(C(=O)O)cc3)CC2)CC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a mixture 3.5 g (13.8 mmol) of cis-(4-Isopropyl-piperazin-1-yl)-(4-hydroxycyclohexyl)-methanone, 2.35 g (15.4 mmol) of methyl 4-hydroxybenzoate, 4.47 g (17.0 mmol) of triphenylphosphine in 12 ml of THF, a mixture of 3.88 g (16.9 mmol) of di-tert-butyl azodicarboxylate in 13 ml of THF was added dropwise at 0° C., and stirred for 24 h at room temperature. After evaporation, the residue was purified by column chromatography on silica gel eluting with CH2Cl2 and methanol=from 98:2 to 9:1. After evaporation of the combined products, the residue was purified by column chromatography on silica gel eluting with CH2Cl2 and MeOH=from 100:0 to 19:1. The combined product fractions were evaporated to dryness to yield 1.34 g (25%) of trans-4-[4-(4-Isopropyl-piperazine-1-carbonyl)-cyclohexyloxy]-benzoic acid methyl ester. A mixture of 0.6 g (1.5 mmol) of trans-4-[4-(4-Isopropyl-piperazine-1-carbonyl)-cyclohexyloxy]-benzoic acid methyl ester, 42 mg (1.8 mmol) of lithium hydroxide, 6 ml of THF, 3 ml of water, and 1 ml of methanol was stirred at 80° C. for 16 h. After evaporation, the residue was acidified with 2N hydrochloric acid solution and evaporated. The precipitate was washed with water and dried to yield 0.56 g (97%) of the titled compound. MS (m/e): 375 (MH+).
Reaction SMILES: C([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[S:11][CH:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([OH:15])=O)(O)=O.[C:20]([O-])(=[O:22])[CH3:21].[Na+].C(OC(=O)C)(=O)C>O>[C:20]([O:15][C:13]1[C:6]2[CH:7]=[C:8]([Cl:10])[CH:9]=[CH:4][C:5]=2[S:11][C:12]=1[CH2:16][CH2:17][CH2:18][CH3:19])(=[O:22])[CH3:21]
Reactant: CC(=O)[O-]
Reactant: CCCCC(Sc1ccc(Cl)cc1C(=O)O)C(=O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCCCc1sc2ccc(Cl)cc2c1OC(C)=O
Temperature: 80 °C

Procedure:
A mixture of 2-(2'-carboxy-4'-chlorophenylthio)hexanoic acid (2.3 g, 7.6 mmol), anhydrous sodium acetate (1.0 g), and acetic anhydride (5 ml) was heated at 80° C. for 30 minutes. After gas evolution had ceased, the temperature was gradually raised to 120° C. which was maintained for 30 minutes. The cooled reaction mixture was then poured into water and extracted with diethyl ether. The combined ethereal extracts were washed with 1% aqueous sodium hydroxide solution, water, and saturated aqueous sodium chloride solution, dried (sodium sulfate) and evaporated. The residue was vacuum filtered through a pad of silica gel (Merck No. 7734) eluting with 25:1 hexane-ether to give 3-acetoxy-2-butyl-5-chlorobenzo[b]thiophene as a colorless oil; yield 1.1 g (40% overall from the 2-step sequence), m/z 282 (M+.).
Reaction SMILES: C(C1C=CC(I)=C(C=1)C(O)=O)#N.[NH2:13][CH2:14][C@@H:15]1[C@H:20]([CH3:21])[CH2:19][CH2:18][CH2:17][N:16]1[C:22]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[C:32]1[N:37]=[CH:36][CH:35]=[CH:34][N:33]=1)[C:27]#[N:28])=[O:23].Cl[C:39]1[N:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][N:40]=1>>[CH3:21][C@@H:20]1[CH2:19][CH2:18][CH2:17][N:16]([C:22]([C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=2[C:32]2[N:33]=[CH:34][CH:35]=[CH:36][N:37]=2)[C:27]#[N:28])=[O:23])[C@@H:15]1[CH2:14][NH:13][C:39]1[N:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][N:40]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(C#N)ccc2-c2ncccn2)[C@@H]1CN
Agent: N#Cc1ccc(I)c(C(=O)O)c1
Product: C[C@@H]1CCCN(C(=O)c2cc(C#N)ccc2-c2ncccn2)[C@@H]1CNc1ncc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A230 using 5-cyano-2-iodobenzoic acid to make 3-((2S,3R)-2-(aminomethyl)-3-methylpiperidine-1-carbonyl)-4-(pyrimidin-2-yl)benzonitrile and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 482 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[O:12][CH3:13].S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:19][CH3:20])=[O:10])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: CCO
Reactant: COc1cc(CC(=O)O)ccc1O
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(O)c(OC)c1
Yield: 90 %

Procedure:
A mixture of (4-hydroxy-3-methoxyphenyl)acetic acid (15.00 g), conc. sulfuric acid (5 mL) and anhydrous ethanol (100 mL) was heated under reflux for 17 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1:9 to 7:3, v/v) to give ethyl (4-hydroxy-3-methoxyphenyl)acetate as a colorless oil (14.55 g, yield 90%).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].Cl.[C:14]([O:18][C:19](=[O:22])[CH2:20][NH2:21])([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C>C(O)C>[C:14]([O:18][C:19](=[O:22])[CH2:20][NH:21][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)CN
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CNc1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 74.7 %

Procedure:
To a solution of 4-chloro-3-nitrobenzonitrile (33.87 g) and glycine tert-butyl ester hydrochloride (55.98 g) in ethanol (400 ml) was added triethylamine (77.6 ml), and the mixture was stirred at room temperature for 15 hours and then at 50° C. for 3 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was extracted with ethyl acetate. The extract was washed with 10% aqueous citric acid solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The obtained residue was washed with diisopropyl ether and collected by filtration to give the title compound (38.419 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)(=[O:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OCC)(=O)C>CN(C=O)C.O>[OH:1][CH2:2][CH2:3][N:4]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: COc1ccc(S(=O)(=O)NCCO)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(CCO)Cc2ccccc2)cc1
Reaction time: 24 h
Yield: 65.1 %

Procedure:
Part A: To a solution of 10.04 g (43 mmol) of N-(2-hydroxyethyl)-4-methoxybenzenesulfonamide from Example 1 in 85 mL of anhydrous DMF, was added 17.8 g (128 mmol) of powdered potassium carbonate and then 8.2 g (48 mmol) of benzyl bromide. After 24 hours, ethyl acetate and water was added, the organic layer separated and washed 3×s with brine, dried with sodium sulfate, filtered and stripped to afford 14.3 g of crude product. This was recrystallized from tert-butylmethyl ether/hexane to afford 9.0 g of the desired N-(hydroxyethyl)-N-(phenylmethyl)-4-methoxybenzenesulfonamide.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.F[C:21]1[CH:22]=[CH:23][C:24]([N+:29]([O-:31])=[O:30])=[C:25]([CH:28]=1)[CH:26]=[O:27]>CS(C)=O>[CH:26]([C:25]1[CH:28]=[C:21]([N:10]2[CH2:11][CH2:12][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:9]2)[CH:22]=[CH:23][C:24]=1[N+:29]([O-:31])=[O:30])=[O:27]
Reactant: O=Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(C=O)c2)CC1
Reaction time: 8 h
Yield: 86.6 %

Procedure:
15 ml of dimethylsulfoxide, 4.2 g (30.4 mmol) of potassium carbonate and 5.66 g (30.4 mmol) of tert-butyl piperazine-1-carboxylate, respectively, are added to 5 g (29.6 mmol) of 5-fluoro-2-nitrobenzaldehyde. The solution is carried at 90° C. under stirring for 8 h. After cooling, the reaction mixture is poured over crushed ice. The yellow precipitate formed is filtered, rinsed with water, and then dried to yield 8.6 g (88%) of tert-butyl 4-(3-formyl-4-nitrophenyl)piperazine-1-carboxylate in the form of a yellow solid.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].[CH2:17]([NH2:20])[CH:18]=[CH2:19].C(=O)([O-])O.[Na+]>CN1CCN(C)C1=O>[CH2:17]([NH:20][C:7]1[N:6]=[C:5]([NH:4][CH2:1][CH:2]=[CH2:3])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[N:8]=1)[CH:18]=[CH2:19]
Reactant: C=CCNc1nc(Cl)nc2ccc(Cl)cc12
Reactant: C=CCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Product: C=CCNc1nc(NCC=C)c2cc(Cl)ccc2n1
Temperature: 100 °C
Reaction time: 10 h
Yield: 87.3 %

Procedure:
In 1 ml of 1,3-dimethyl-2-imidazolidinone was dissolved 300 mg (1.18 mmol) of 4-allylamino-2,6-dichloroquinazoline, and after 110 mg (1.87 mmol) of allylamine was added to the resulting solution, the mixture was stirred in a sealed tube at 100° C. for 10 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 283 mg (yield: 87.3%) of the title compound.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[H][H].[CH3:18][O:19][CH2:20]Cl>O.CN(C)C=O>[NH2:1][CH:2]([C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:18][O:19][CH3:20])=[CH:11][CH:12]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: [H][H]
Reactant: COC(=O)C(N)c1ccc(O)cc1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(C(N)C(=O)OC)cc1
Temperature: 60 °C

Procedure:
In this preparation 1.81 g. of methyl α-amino-α-(4-hydroxyphenyl)acetate is dissolved in 10 ml. of dimethylformamide under nitrogen and 0.24 g. of sodium hydride is then added. The solution is stirred at room temperature under nitrogen until hydrogen evolution ceases and then 0.80 g. of chloromethyl methyl ether is added. The resulting mixture is warmed at 60° C for 1 hour and then cooled and diluted with water. The aqueous mixture is extracted with ether and the ether extract is dried and evaporated to afford methyl α-amino-α-(4-methoxymethoxyphenyl)acetate.
Reaction SMILES: [Mg].CCOCC.BrBr.ClC1C=CC(C[O:15][C:16]2[C:23]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[CH:22][CH:21]=[CH:20][C:17]=2[CH:18]=[O:19])=CC=1>C1C=CC=CC=1>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][O:24][C:23]2[C:16]([OH:15])=[C:17]([CH:20]=[CH:21][CH:22]=2)[CH:18]=[O:19])=[CH:27][CH:28]=1
Reactant: O=Cc1cccc(OCc2ccc(Cl)cc2)c1OCc1ccc(Cl)cc1
Agent: BrBr
Agent: [Mg]
Solvent: CCOCC
Solvent: c1ccccc1
Product: O=Cc1cccc(OCc2ccc(Cl)cc2)c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To magnesium (0.098 g, turnings, 4.0 mmol) in a mixture of anhydrous ether (20 mL) and benzene (20 mL) at 0° C., bromine (0.10 mL, 2.0 mmol) was added dropwise. When the reaction had started, stirring was commenced and the addition of bromine continued until complete. The ice bath was removed and the reaction mixture was heated until the solution was almost colorless. After cooling down, the reaction mixture was slowly added to a solution of 2,3-bis-(4-chloro-benzyloxy)-benzaldehyde (627, 0.78 g, 2.0 mmol) in benzene (60 mL) at room temperature while stirring vigorously. Upon completion of the addition, the reaction mixture was stirred at room temperature overnight, then refluxed for 36 hours. After the reaction mixture was cooled down to room temperature, a solid was collected by filtration and washed with benzene, then boiled in hydrochloric acid (100 mL, 1.0 M) for 30 minutes. After cool down, the solution was extracted with dichloromethane. The organic layer was washed with brine and dried over magnesium sulfate. An off-white solid was obtained after removal of the solvent (628, 0.32 mg, 60%). MS (ESI) [M−H−]=261.25.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:14]1([CH:13]2[C:5]3[NH:6][C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]=3[CH2:3][CH2:2][NH:1]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.1 %

Procedure:
A solution of tryptamine (15 g, 94.0 mmol) and benzaldehyde (10.9 g, 1.1 eq.) in CH2Cl2 (800 mL) was treated with TFA (15 mL, 2 eq.). The resulting mixture was stirred at room temperature (rt) for one day and then neutralized to pH 7 with a saturated aqueous solution of sodium carbonate (Na2CO3). After filtration and concentration to dryness, the residue was recrystallized from 2-propanol to give the title compound (11.0 g, 47%) as white crystals (m.p.:175-177° C.).
Reaction SMILES: B(Br)(Br)[Br:2].ClCCl.[S:8]1[CH:12]=[CH:11][C:10]2[C:13]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][CH2:26][N:27]4[CH:36]=[CH:35][C:34]5[C:29](=[CH:30][C:31]([O:37]C)=[CH:32][CH:33]=5)[C:28]4=[O:39])[CH2:19][CH2:18]3)=[CH:14][CH:15]=[CH:16][C:9]1=2>O>[BrH:2].[S:8]1[CH:12]=[CH:11][C:10]2[C:13]([N:17]3[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][CH2:26][N:27]4[CH:36]=[CH:35][C:34]5[C:29](=[CH:30][C:31]([OH:37])=[CH:32][CH:33]=5)[C:28]4=[O:39])[CH2:21][CH2:22]3)=[CH:14][CH:15]=[CH:16][C:9]1=2
Reactant: BrB(Br)Br
Reactant: COc1ccc2ccn(CCCCN3CCN(c4cccc5sccc45)CC3)c(=O)c2c1
Solvent: O
Solvent: ClCCl
Product: Br
Product: O=c1c2cc(O)ccc2ccn1CCCCN1CCN(c2cccc3sccc23)CC1

Procedure:
Boron tribromide (2M dichloromethane solution, 1.0 ml) was added to a dichloromethane (50 ml) solution of 2-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-7-methoxy-2H-isoquinolin-1-one (0.16 g) while being stirred under ice-cooling and stirred at room temperature for 3 days. Water was added to the reaction solution, which was then stirred at room temperature for 0.5 hour. Precipitated crystals were separated by filtration, recrystallized from ethyl acetate and thereby 2-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-7-hydroxy-2H-isoquinolin-1-one hydrobromide (0.13 g) was obtained in the form of a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:9](=O)[CH2:8][S:7][CH2:6]1)=[O:4].Cl.[NH2:12][OH:13]>>[CH3:1][O:2][C:3]([CH:5]1[C:9](=[N:12][OH:13])[CH2:8][S:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CSCC1=O
Reactant: NO
Agent: Cl
Product: COC(=O)C1CSCC1=NO

Procedure:
Compounds of structure (II) were prepared by using 4-amino-thiophene-3-carboxylic acid methyl ester, as depicted by formula (21), as a starting material. To make this compound, methyl thioglycolate was reacted with methyl acrylate to yield intermediate 3-methoxycarbonylmethylsulfanyl-propionic acid methyl ester, depicted by formula (18), which was cyclized to 4-oxo-tetrahydro-thiophene-3-carboxylic acid methyl ester, depicted by formula (19). This intermediate was reacted with hydroxylamine hydrochloride to yield 4-hydroxyimino-tetrahydro-thiophene-3-carboxylic acid methyl ester, depicted by formula (20), which yielded 4-amino-thiophene-3-carboxylic acid methyl ester hydrochloride, depicted by formula (21), as shown in Scheme 10.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.O1C2C=CC(C3(C(NC4C=CC(Br)=CN=4)=O)CC3)=CC=2OC1.[Cl-].[Cl:52]C1C=CC=CC=1C[Zn+]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[Cl:52])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Nc1ccc(Cc2ccccc2)cn1)C1(c2ccc3c(c2)OCO3)CC1
Reactant: Clc1ccccc1C[Zn+]
Agent: O=C(Nc1ccc(Br)cn1)C1(c2ccc3c(c2)OCO3)CC1
Agent: [Cl-]
Product: O=C(Nc1ccc(Cc2ccccc2Cl)cn1)C1(c2ccc3c(c2)OCO3)CC1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-(2-chlorobenzyl)pyridin-2-yl)cyclopropanecarboxamide was synthesized using the procedure of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-benzylpyridin-2-yl)cyclopropanecarboxamide by reacting 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-bromopyridin-2-yl)cyclopropanecarboxamide with (2-chlorobenzyl)zinc(II) chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].[O:11]1CCOCC1>>[NH2:4][C:3]1[C:5]([CH3:10])=[CH:6][C:7]([CH:9]=[O:11])=[CH:8][C:2]=1[CH3:1]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: C1COCCO1
Product: Cc1cc(C=O)cc(C)c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.2 %

Procedure:
To a solution of 2,4,6-trimethylaniline (29.8 g, 0.22 mol) in dioxane (300 mL) DDQ (49.9 g, 0.22 mol) is added. The brown suspension is stirred at rt for 18 h before it is filtered. The solvent of the filtrate is evaporated and the crude product is purified by CC on silica gel eluting with hexane:EA 1:1 to give 4-amino-3,5-dimethyl-benzaldehyde (5.0 g) as a beige solid; LC-MS: tR=0.78 min, [M+1]+=150.26.