Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[NH:5]2.[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1>C1C=CC=CC=1>[CH:16]1([C:19]([N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[NH:8][C:9](=[O:11])[C:10]3=[CH:1][S:2][CH:3]=[C:4]23)=[O:20])[CH2:18][CH2:17]1
Reactant: O=C1Nc2ccccc2Nc2cscc21
Reactant: O=C(Cl)C1CC1
Solvent: c1ccccc1
Product: O=C1Nc2ccccc2N(C(=O)C2CC2)c2cscc21

Procedure:
To a mixture of 10.0 g. of 4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one in 100 ml. of benzene is added 11 g. of cyclopropanecarbonyl chloride. The mixture is refluxed for 3 hours and then filtered. The filtrate is washed four times with aqueous sodium bicarbonate, the organic layer is dried over magnesium sulfate and then is filtered. The filtrate is evaporated to give the desired product as pale pink crystals, mp. 245°-247° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].Cl[CH2:9][C:10]([O-:12])=O.[Na+].Cl.[C:15](=[S:17])=[S:16]>O>[S:17]1[CH2:9][C:10](=[O:12])[N:1]([CH2:2][C:3]([OH:5])=[O:4])[C:15]1=[S:16]
Reactant: S=C=S
Reactant: O=C([O-])CCl
Reactant: NCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CN1C(=O)CSC1=S

Procedure:
Glycine (19 g) and sodium hydroxide (20 g) were dissolved in water (50 g), and the resultant solution was cooled to 10° C. Carbon disulfide (19 g) was added dropwise to the solution over 30 minutes with stirring, and then the mixture was allowed to react at 20° C. for three days. Subsequently, a solution of sodium chloroacetate (29 g) in water (60 g) was added dropwise to the reaction mixture over 15 minutes, and the resultant mixture was allowed to react at room temperature for 24 hours. Concentrated hydrochloric acid (90 g) and water (32 g) were added to the reaction mixture, and the resultant mixture was allowed to react at 80° C. for five hours. After completion of reaction, precipitated target crystals were separated through filtration, washed with cold water, and dried to 50° C. for one day, to thereby yield 24 g of the crystals. The purity of the product, as obtained through liquid chromatography, was 98%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:30]([O:31][CH3:32])=[CH:29][C:6]2[CH2:7][C:8](=[O:28])[N:9]([CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:39](Br)[CH:40]=[CH2:41].C(Cl)(Cl)[Cl:44]>>[ClH:44].[CH3:1][O:2][C:3]1[C:30]([O:31][CH3:32])=[CH:29][C:6]2[CH2:7][C:8](=[O:28])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH2:41][CH:40]=[CH2:39])[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: C=CCBr
Reactant: ClC(Cl)Cl
Reactant: COc1ccc(CCNCCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCN(CCCN1CCc2cc(OC)c(OC)cc2CC1=O)CCc1ccc(OC)c(OC)c1
Product: Cl

Procedure:
3.1 gm (0.007 mol) of 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[N-(2-{3,4-dimethoxy-phenyl}-ethyl)-amino]-propane were refluxed for 21 hours with 1.0 gm (0.007 mol) of potassium carbonate and 0.6 ml (0.007 mol) of allyl bromide in 100 ml of chloroform. Subsequently, the organic phase was extracted with water, dried, evaporated in vacuo, and the residue was purified on an aluminum oxide column (300 gm neutral, activity III) with methylene chloride containing 2% of acetone as the eluant. Subsequently the hydrochloride was precipitated.
Reaction SMILES: [CH3:1][C:2]1([CH2:8][O:9]C2C=CC(C=C3SC(=O)NC3=O)=CC=2[N+]([O-])=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][C:2]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC1(COc2ccc(C=C3SC(=O)NC3=O)cc2[N+](=O)[O-])CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(CO)CCCCC1
Temperature: 80 °C

Procedure:
General Procedure C for compounds 7a-m: A mixture of compound 3 (0.5 mmol), compounds 6a-m (0.6 mmol) and K2CO3 (0.65 mmol) were stirred in 3 mL DMF. The solution was heated to 80° C. for 4 hr. the solution was poured into water, extracted with ethyl acetate (10 ml * 3), and concentrated. The residue was purified by chromatography.
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH3:17])[C:11]=1[C:18]1[N:23]=[CH:22][C:21]([CH:24]=[O:25])=[C:20]([O:26][CH3:27])[CH:19]=1)[CH3:9].[NH4+].[Cl-]>CCOCC>[CH2:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH3:17])[C:11]=1[C:18]1[N:23]=[CH:22][C:21]([CH:24]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[OH:25])=[C:20]([O:26][CH3:27])[CH:19]=1)[CH3:9]
Reactant: CCc1cccc(CC)c1-c1cc(OC)c(C=O)cn1
Reactant: [Li]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCc1cccc(CC)c1-c1cc(OC)c(C(O)c2ccccc2)cn1
Reaction time: 2 h

Procedure:
Phenyllithium (1M in THF, 0.26 mL) is added dropwise to a solution of 6-(2,6-diethyl-phenyl)-4-methoxy-pyridine-3-carbaldehyde (70 mg, 0.26 mmol) in ether (4 mL) at room temperature. The mixture is stirred for 2 hours, then treated with aqueous NH4Cl solution (4 mL) and diluted with ether (10 mL). The organic layer is separated, dried and concentrated. The crude is purified by PTLC (4:1 hexane/EtOAc) to give [6-(2,6-diethyl-phenyl)-4-methoxy-pyridin-3-yl]-phenyl-methanol. 1H NMR (CDCl3) 8.51 (s, 1H), 7.26-7.43 (m, 6H), 7.15 (d, 2H), 6.76 (s, 1H), 6.06 (s, 1H), 3.82 (s, 3H), 3.21 (s, 1H), 2.32 (m, 4H), 1.05 (m, 6H).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:31][CH:32]([CH3:35])[CH2:33][OH:34]>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH:31][CH:32]([CH3:35])[CH2:33][OH:34])=[O:16])[CH2:6][CH2:5]2
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: CC(N)CO
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NC(C)CO)O2
Yield: 79.4 %

Procedure:
Following the amide coupling procedure described in protocol A, 500 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.00 mmol), 365 mg CDI (2.25 mmol) and 165 mg 2-amino-1-propanol (2.2 mmol) produced 488 mg of 6-hydroxy-N-(1-hydroxypropan-2-yl)-2,5,7,8-tetramethylchroman-2-carboxamide as a pale brown foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].N1CCCC1>C(O)C>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][CH:6]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Clc1ccc2[nH]ccc2c1
Solvent: C1CCNC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc(Cl)cc23)CC1
Yield: 75.3 %

Procedure:
A stirred solution of 5-chloroindole (455 mg, 3.0 mmol), t-butyl-4-oxo-1-piperidinecarboxylate (650 mg, 3.3 mmol), and pyrrolidine (0.62 mL, 7.4 mmol) in ethanol (10 mL) was heated at reflux for 16 hours. Solvent was evaporated and the residue subjected to chromatography on silica gel with 20% ethyl acetate/hexanes to afford a yellow solid (752 mg, 75%).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:49]1[C:54]2[CH:55]=[CH:56][C:57]([C:59]3[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=3)=[CH:58][C:53]=2[O:52][CH2:51][CH2:50]1>CN(C=O)C>[O:49]1[C:54]2[CH:55]=[CH:56][C:57]([C:59]3[CH:60]=[C:61]([NH:65][C:22]([C:17]4[C:18](=[O:21])[O:19][C:20]5[C:15]([CH:16]=4)=[CH:14][CH:13]=[CH:12][C:11]=5[OH:10])=[O:24])[CH:62]=[CH:63][CH:64]=3)=[CH:58][C:53]=2[O:52][CH2:51][CH2:50]1
Reactant: Nc1cccc(-c2ccc3c(c2)OCCO3)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2ccc3c(c2)OCCO3)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 39.5 %

Procedure:
DIEA (0.013 mL, 0.072 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.067 mmol) and HATU (0.028 g, 0.072 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-phenylamine (0.015 g, 0.067 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and lyophilized for 48 hours to give 0.011 g of product in 39% yield: LCMS (ESI) m/z 416 (MH+).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[NH:16][C:17](=[O:20])[O:18][CH3:19]>C1(C)C=CC=CC=1>[Br-:1].[CH2:2]([N+:13]1[CH:14]=[CH:15][C:10]([CH3:9])=[C:11]([NH:16][C:17]([O:18][CH3:19])=[O:20])[CH:12]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)Nc1cnccc1C
Solvent: Cc1ccccc1
Product: COC(=O)Nc1c[n+](Cc2ccccc2)ccc1C
Product: [Br-]
Temperature: 110 °C
Reaction time: 16 h
Yield: 101.8 %

Procedure:
1-(Bromomethyl)benzene (19 g, 111 mmol, 1.10 equiv.) was added to a solution of methyl 4-methylpyridin-3-ylcarbamate (17 g, 102 mmol, 1.00 equiv.) in toluene (500 mL). The solution was stirred at about 110° C. for about 16 hours. After cooling to ambient temperature, the solids were collected by filtration and washed with toluene to afford the title product as a light brown solid (35 g; yield=97%).
Reaction SMILES: [CH2:1]([NH:5][C:6](=S)[NH:7][NH2:8])[CH2:2][CH2:3][CH3:4].Cl.[Cl:11][C:12]1[CH:26]=[CH:25][C:15]([C:16]([CH:18](Cl)[CH2:19][C:20]([O:22][CH3:23])=[O:21])=O)=[CH:14][CH:13]=1.[CH2:27](O)[CH2:28][CH2:29]C>O>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][C:18]1[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[N:7][NH:8][C:16]=1[C:15]1[CH:25]=[CH:26][C:12]([Cl:11])=[CH:13][CH:14]=1)[CH2:27][CH2:28][CH3:29]
Reactant: COC(=O)CC(Cl)C(=O)c1ccc(Cl)cc1
Reactant: CCCCO
Reactant: CCCCNC(=S)NN
Agent: Cl
Solvent: O
Product: CCCCNc1n[nH]c(-c2ccc(Cl)cc2)c1CC(=O)OCCCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 5.9 g (0.04 mole) of 4-butyl-3-thiosemicarbazide, 3.3 ml (0.04 mole) of 37% hydrochloric acid and 10.5 g (0.04 mole) of methyl 3-(4-chlorobenzoyl)-3-chloropropionate in 150 ml of 1-butanol was stirred at ambient temperature for 4 hours and heated at reflux for 40 hours. The reaction mixture was diluted with 50 ml of water, filtered to remove the inorganic sulfur, then concentrated in vacuo (19 g). The residue was placed on a 400 g Florisil column and eluted with benzene then with an acetone:benzene gradient (0.5 to 10%). The product fractions were combined and concentrated in vacuo to give 15.2 g of pale yellow solid. Recrystallization from 2-propanol yielded 2 g (14%) of fluffy white crystals, mp 130°-130.5° C.
Reaction SMILES: [N+]([O-])([O-])=[O:2].[Tl+].[CH2:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][CH2:8]1>CO.C(Cl)(Cl)Cl>[CH3:18][O:17][CH:14]1[CH2:13][CH2:12][C:11]2=[CH:10][CH:9]=[CH:8][C:6](=[O:2])[CH2:7][CH:16]2[CH2:15]1
Reactant: O=[N+]([O-])[O-]
Reactant: C=C1CCCc2ccc(OC)cc21
Agent: [Tl+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC1CCC2=CC=CC(=O)CC2C1
Reaction time: 0.02 h
Yield: 70.7 %

Procedure:
To a solution of thallium nitrate (2.4 g) in methanol (24 ml) was added 1-methylene-7-methoxy-1,2,3,4-tetrahydronaphthalene (1.0 g) in methanol (7 ml) in one portion. The mixture was stirred for 1 minute and diluted with chloroform (24 ml). The resulting precipitate was filtered off and the filtrate was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution; 8:1, n-hexane-ethyl acetate) to give 3-methoxy-1,2,3,4-tetrahydro-5H-benzocyclohepten-6-one (0.78 g).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH:11]([OH:14])[CH2:12]Br.[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[NH:23][C:24]([CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:25].CCCCCC>C(O)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH:11]([OH:14])[CH2:12][N:30]1[CH2:31][CH2:32][N:27]([CH2:26][C:24]([NH:23][C:17]2[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:16]=2[CH3:15])=[O:25])[CH2:28][CH2:29]1
Reactant: OC(CBr)C1COc2ccccc2O1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCNCC1
Solvent: CCO
Solvent: CCCCCC
Product: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)C2COc3ccccc3O2)CC1
Yield: 106.6 %

Procedure:
1-(1,4-Benzodioxan-2-yl)-2-bromoethanol (formula H) (12 g) prepared according to J. Med. Chem. 13, 169, (1970), is treated with 1-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine (14 g) in 500 ml of ethanol. The remainder of the procedure is described in Example 1 above and 21 g of the 1-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine is obtained from hexane. The dihydrochloride salt has a melting point of 175°-176° C.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:9]=3[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:18]1([O:23][C:24]2[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([O:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([C:11]3[S:10][C:9]4[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:8]=4[C:7]=3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:29])=[CH:31][CH:32]=2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: O=C(Cl)c1ccc(OC2CCCC2)cc1
Reactant: COc1ccc2c(-c3ccccc3)csc2c1
Product: COc1ccc2c(-c3ccccc3)c(C(=O)c3ccc(OC4CCCC4)cc3)sc2c1

Procedure:
3-Phenyl-6-methoxybenzo[b]thiophene and p-cyclopentyloxybenzoyl chloride were converted to the title compound by the procedure of Example 1 to yield 6 g of crude product.
Reaction SMILES: [OH-:1].[K+].[C:3](=[O:6])([O-])[O-].[Na+].[Na+].[C:9]1([C:19]2[CH:24]=[CH:23]C(S(O)(=O)=O)=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:12](S(O)(=O)=O)=[CH:11][CH:10]=1.Cl>O>[OH:1][C:12]1[CH:13]=[CH:14][C:9]([C:19]2[CH:24]=[CH:23][C:3]([OH:6])=[CH:21][CH:20]=2)=[CH:10][CH:11]=1
Reactant: [OH-]
Reactant: O=S(=O)(O)c1ccc(-c2ccc(S(=O)(=O)O)cc2)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: Oc1ccc(-c2ccc(O)cc2)cc1
Temperature: 320 °C
Yield: 92 %

Procedure:
400 g (6.1 moles) of potassium hydroxide having a water content of 15% by weight and 40 g (0.38 mole) of sodium carbonate were initially taken in a stirred 1 1 V2A stainless steel kettle and 195 g (0.5 mole) of the dipotassium salt of biphenyl-4,4'-disulfonic acid were introduced at 280° C. The temperature was then increased to 320° C., this temperature was maintained for 3 hours and the melt was cooled by constantly metering in water and simultaneously reducing the heating bath temperature. The reaction mixture was diluted with water and acidified with concentrated hydrochloric acid at 90° C. to a pH of 6.5. The resulting precipitate was filtered off under suction, and 4,4'-dihydroxybiphenyl was extracted by means of acetone. The extracting agent was removed to give 85.5 g (92%) of 4,4'-dihydroxybiphenyl, which had a purity of >99% (HPLC).
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][C:6]1[C:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[N:8][N:9]2[CH:14]=[CH:13][CH:12]=[N:11][C:10]=12)C.[OH-].[Na+].C(O)C.C(O)(=O)C>O>[CH3:21][C:18]1[CH:17]=[CH:16][C:15]([C:7]2[C:6]([CH2:5][C:4]([OH:22])=[O:3])=[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)Cc1c(-c2ccc(C)cc2)nn2cccnc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(-c2nn3cccnc3c2CC(=O)O)cc1
Reaction time: 8 h
Yield: 91.8 %

Procedure:
A stirred mixture of 32.5 g (0.11 mole) of 2-(4-methylphenyl)pyrazolo[1,5-a]pyrimidine-3-acetic acid ethyl ester and 4.5 g (0.11 mole) of sodium hydroxide in 150 mL of 190 ethanol was heated until the material dissolved. After cooling, the reaction mixture was diluted with an equal volume of water, heated until a clear dark brown solution was obtained, then cooled by stirring overnight. The reaction mixture was diluted with an additional 300 mL of water and acidified to pH 6 with glacial acetic acid. The milky solution yielded 27 g (90%) of brown crystalline product, mp 170°-171°. An analytical sample recrystallized from acetonitrile-water yielding pale yellow crystals, mp. 172°-173° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([CH2:15][OH:16])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24]C([O-])(C)C.[K+].I[CH2:31][C:32]1[N:33]=[C:34]([C:38]2[CH:43]=[CH:42][C:41](C)=[CH:40][CH:39]=2)[O:35][C:36]=1[CH3:37].O>C1(Cl)C=CC=CC=1.CC(OC)(C)C>[CH2:17]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([CH2:15][O:16][CH2:31][C:32]2[N:33]=[C:34]([C:38]3[CH:39]=[C:40]([CH3:24])[CH:41]=[CH:42][CH:43]=3)[O:35][C:36]=2[CH3:37])[CH2:10]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCC1CCCC(N(Cc2ccccc2)Cc2ccccc2)C1
Reactant: CC(C)(C)[O-]
Reactant: Cc1ccc(-c2nc(CI)c(C)o2)cc1
Agent: [K+]
Solvent: O
Solvent: Clc1ccccc1
Solvent: COC(C)(C)C
Product: Cc1cccc(-c2nc(COCC3CCCC(N(Cc4ccccc4)Cc4ccccc4)C3)c(C)o2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.3 %

Procedure:
5.0 g of 3-dibenzylaminocyclohexylmethanol and 1.72 g of KOtBu were initially charged in PhCl, and 7.59 g of 4-iodomethyl-5-methyl-2-p-tolyloxazole were added a little at a time. At room temperature and under an atmosphere of argon, the mixture was stirred for 2 days. Another 1.0 g of KOtBu was added, and stirring of the mixture was continued. The reaction was then complete. For work-up, water and MTBE were added, the phases were separated and the organic phase was washed with water and sat. NaCl solution, dried over MgSO4 and concentrated. Chromatography of the residue on silica gel (heptane/ethyl acetate 10:1→3:1) gave 7.0 g of dibenzyl-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxymethyl)cyclohexyl]amine as a brown oil.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](Cl)=[O:9])(=[O:4])=[O:3].[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:41]1[NH:46][CH2:45][CH2:44][N:43]2[CH2:47][CH2:48][CH2:49][C@@H:42]12>ClCCl.CO>[F:34][C:31]1[CH:32]=[CH:33][C:28]([CH:21]([C:18]2[CH:17]=[CH:16][C:15]([F:14])=[CH:20][CH:19]=2)[N:22]2[CH2:23][CH2:24][N:25]([C:8]([C:7]3[CH:6]=[C:5]([S:2]([N:46]4[CH2:45][CH2:44][N:43]5[CH2:47][CH2:48][CH2:49][C@H:42]5[CH2:41]4)(=[O:4])=[O:3])[CH:13]=[CH:12][CH:11]=3)=[O:9])[CH2:26][CH2:27]2)=[CH:29][CH:30]=1
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Reactant: C1C[C@H]2CNCCN2C1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C(c1cccc(S(=O)(=O)N2CCN3CCC[C@H]3C2)c1)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(chlorosulfonyl)benzoyl chloride (0.474 g, 1.981 mmol) in anhydrous dichloromethane (40 mL) was added 1-(bis(4-fluorophenyl)methyl)piperazine (0.571 g, 1.981 mmol) in dichloromethane (4 mL) slowly over 10 minutes at room temperature. Then sodium carbonate (0.64 g, 6 mmol) was added. The mixture was stirred at room temperature overnight. Then (S)-octahydropyrrolo[1,2-α]pyrazine (0.250 g, 1.981 mmol) was added. The mixture was stirred at reflux for 20 minutes and then at room temperature for 3 days. Methanol (5 mL) was added, the mixture was stirred for 20 minutes, then filtered, and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/methanol=20:1) to give the titled compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07 (m, 1H), 1.55 (m, 2H), 1.71 (m, 1H), 1.95 (m, 4H), 2.08 (m, 1H), 2.28 (m, 3H), 2.39 (m, 3H), 2.85 (m, 1H), 2.92 (m, 1H), 3.57 (m, 2H), 3.74 (m, 2H), 4.45 (s, 1H), 7.13 (m, 4H), 7.45 (m, 4H), 7.66 (s, 1H), 7.70 (m, 2H), 7.80 (m, 1H); MS (ESI) m/z 581 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][C:5]1[C:6]2[CH2:27][NH:26][CH2:25][CH2:24][C:7]=2[N:8]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])=[CH:14][CH:13]=2)[N:10]=1.[CH2:32]=O>>[F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][C:5]1[C:6]2[CH2:27][N:26]([CH3:32])[CH2:25][CH2:24][C:7]=2[N:8]=[C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])=[CH:16][CH:17]=2)[N:10]=1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccccc4F)n2)CNCC3)cc1
Reactant: C=O
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccccc4F)n2)CN(C)CC3)cc1
Yield: 4 %

Procedure:
4-(2-Fluorobenzyl)-6-methyl-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (3.8 mg, 4%) was synthesised from 4-(2-fluorobenzyl)-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and formaldehyde according to the general procedure for reductive amination. MS (ES+) m/z 429.3 (M+H)+
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][O:13][CH2:14][CH2:15][CH2:16][NH2:17]>>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:17][CH2:16][CH2:15][CH2:14][O:13][CH3:12])[CH:7]=1
Reactant: COCCCN
Reactant: O=[N+]([O-])c1ccc(Br)cc1Br
Product: COCCCNc1cc(Br)ccc1[N+](=O)[O-]
Reaction time: 48 h

Procedure:
A solution of 26.49 g of 2,4-dibromo-1-nitrobenzene [51686-78-3] and 70 ml of 3-methoxypropylamine is stirred at room temperature for 4 hours and subsequently left to stand at 3° C. for 2 days. The reaction mixture is concentrated by evaporation. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60 F). Rf=0.4 (1:3 EtOAc-heptane). Rt=4.99 (gradient I).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.Br[C:13](C)(C)[C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O-])([O-])=O.[K+].[K+].O>CC#N>[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][CH:6]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)COc1ccc(NC(C)=O)cc1

Procedure:
To a solution of N-(4-hydroxyphenyl)acetamide (500 mg, 3.31 mmol) in CH3CN (10 mL) was added ethyl 2-bromo-2-methylpropanoate (663 mg, 3.97 mmol) and K2CO3 (3 g, 21.7 mmol) at 25° C. The mixture was heated at reflux for 16 h. The mixture had water (100 mL) added and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give the title compound which was used in next step without further purification.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[O:7]([CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C(C)Oc1ccccc1
Reaction time: 12 h
Yield: 61.5 %

Procedure:
A mixture consisting of 34.8 gm (0.37 mol) of phenol, 111 gm (0.81 mol) of potassium carbonate, 89 ml (0.69 mol) of ethyl 2-bromo-propionate and 200 ml of ethanol was boiled for 12 hours, while stirring. Thereafter, the reaction mixture was filtered, and the filtrate was distilled, yielding 44.2 gm of ethyl 2-phenoxy-propionate, b.p. 93°-94° C. at 0.1 mm Hg.