Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH:11]([CH2:13][N:14]3[CH2:19][CH2:18][CH:17]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[NH2:27])[CH2:16][CH2:15]3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[C:28](=S)=[S:29].[OH-].[K+].[ClH:33]>O.C(O)C>[ClH:33].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH:11]([CH2:13][N:14]3[CH2:15][CH2:16][CH:17]([N:20]4[C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=5[NH:27][C:28]4=[S:29])[CH2:18][CH2:19]3)[CH2:10][O:9]2)=[CH:4][CH:3]=1
Reactant: Nc1ccccc1NC1CCN(CC2COC(c3ccc(F)cc3)C2)CC1
Reactant: S=C=S
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Fc1ccc(C2CC(CN3CCC(n4c(=S)[nH]c5ccccc54)CC3)CO2)cc1
Reaction time: 3.5 h

Procedure:
A mixture of 13.7 g of 1-[2-(4-fluorophenyl)-tetrahydro-4-furylmethyl]-4-(2-aminoanilino)piperidine, 18 g of carbon disulfide and 4.2 g of potassium hydroxide is heated under reflux with stirring for 3.5 hours and then cooled. To the mixture are added 200 ml of ethanol, 126 ml of water and 32 ml of concentrated hydrochloric acid, and the whole is heated under reflux for 20 minutes. The solvent is then distilled off under reduced pressure. The residue is made alkaline with aqueous ammonia and extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by column chromatography on silica gel with chloroform eluant. To the thus obtained oil is added ethanolic hydrochloric acid. The crystals precipitated are collected by filtration and recrystallized from methanol-isopropyl ether to give 1-[1-(2-(4-fluorophenyl)-tetrahydro-4-furylmethyl)-4-piperidyl]benzimidazoline-2-thione hydrochloride as colorless needles, melting at 269°-270° C. with decomposition.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH:13]([CH3:15])[CH2:12][C:11]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[NH2:22])=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:23][C:24]1[N:29]=[C:28]([C:30](O)=[O:31])[CH:27]=[CH:26][C:25]=1[F:33]>CCOC(C)=O>[Br:23][C:24]1[N:29]=[C:28]([C:30]([NH:22][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:16]=2[C:11]2[CH2:12][CH:13]([CH3:15])[CH2:14][CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[CH:10]=2)=[O:31])[CH:27]=[CH:26][C:25]=1[F:33]
Reactant: O=C(O)c1ccc(F)c(Br)n1
Reactant: CC1CC(c2ccncc2N)=CC(O[Si](C)(C)C(C)(C)C)C1
Solvent: CCOC(C)=O
Product: CC1CC(c2ccncc2NC(=O)c2ccc(F)c(Br)n2)=CC(O[Si](C)(C)C(C)(C)C)C1

Procedure:
Following Method 9, 4-(3-(tert-butyldimethylsilyloxy)-5-methylcyclohex-1-enyl)pyridin-3-amine and 6-bromo-5-fluoropicolinic acid were coupled and following addition of EtOAc and washing with H2O, NaCl(sat.) and drying over MgSO4, 6-bromo-N-(4-(3-(tert-butyldimethylsilyloxy)-5-methylcyclohex-1-enyl)pyridin-3-yl)-5-fluoropicolinamide was obtained. LCMS (m/z): 455.3 (MH+); LC Rt=2.09 min.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[CH2:19]([N:3]1[N:4]=[C:5]([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[NH:1][NH:2]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(-c2nn[nH]n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Oc1ccc(C2=NN(Cc3ccccc3)NN2)cc1
Temperature: 50 °C
Yield: 72.3 %

Procedure:
A 20 mL round bottomed flask equipped with a Teflon coated magnetic stirring bar, a rubber septum and a reflux condenser was charged with acetone (25 mL), 4-(2H-tetrazol-5-yl)phenol (50 mg, 0.31 mmol) and K2CO3 (213 mg, 1.54 mmol). The reaction mixture was treated with benzylbromide (37 μL, 0.31 mmol) and heated at 50° C. for 18 h. The reaction mixture was cooled to ambient temperature and filtered to remove the K2CO3 and the filtrate was concentrated to dryness. The resulting residue was triturated with 3 M aqueous NaOH and extracted with ethyl acetate. The aqueous phase was separated and treated with HCl (conc.). The precipitate was collected and subjected to flash chromatography (SiO2, 30% ethyl acetate/hexane) to afford the title product as a white solid (57 mg, 74%). This procedure was repeated on a 3 g scale in 50% yield.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH:9]([C:12]#[N:13])[C:10]#[N:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]([F:21])([F:20])[CH2:16][CH2:17][CH2:18]Br.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[C:1]([O:5][C:6]([CH2:8][C:9]([CH2:18][CH2:17][CH2:16][C:15]([F:21])([F:20])[F:14])([C:12]#[N:13])[C:10]#[N:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)CCCBr
Reactant: CC(C)(C)OC(=O)CC(C#N)C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC(C#N)(C#N)CCCC(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.9 %

Procedure:
0.48 g of 2-(tert-butoxycarbonylmethyl)malononitrile and 0.32 g of 1,1,1-trifluoro-4-bromobutane were dissolved in 2 ml of N,N-dimethylformamide, and to the solution was added 0.40 g of potassium carbonate followed by stirring for 5 hours at room temperature. Then, to the reaction mixture was added dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography to give 0.33 g of 2-(tert-butoxycarbonylmethyl)-2-(4,4,4-trifluorobutyl)malononitrile (hereinafter referred to as the present invention compound (51)).
Reaction SMILES: [C:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:10]([C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[CH:29]=[C:28]([OH:33])[CH:27]=[CH:26]4)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:35][C:36]([O:38][CH3:39])=[O:37].C(=O)([O-])[O-].[Cs+].[Cs+]>>[C:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=3)[C:10]([C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[CH:29]=[C:28]([O:33][CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH:27]=[CH:26]4)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)COc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccc(C(F)(F)F)cc3)ccc2c1
Yield: 93.2 %

Procedure:
In a similar manner as described in step 1 of Example 3, the title compound was prepared from 6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthol (0.250 g, 0.564 mmol), prepared in step 2 of Example 8, methyl bromoacetate (0.103 g, 0.676 mmol) and cesium carbonate (0.920 g, 2.82 mmol). Purification on a Biotage FlashElute™ system with a KP-Sil Flash 40+M column (90 g Silica Gel, 60 Å) using 50% methylene chloride in hexane as the eluent gave methyl [(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]acetate as an off-white solid (0.271 g, 93%), mp 90–91° C. Elemental Analysis for C31H24F3NO3.0.09 C6H14 Calc'd: C, 72.39; H, 4.87; N, 2.68. Found: C, 72.26; H, 4.68; N, 2.28.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([C:9]([Cl:11])=[O:10])[CH2:5][CH2:4]1.[F:12][C:13]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=1[C:20]1[CH:21]=[C:22]2[C:28]([NH2:29])=[N:27][NH:26][C:23]2=[CH:24][N:25]=1>N1C=CC=CC=1>[ClH:11].[ClH:1].[F:12][C:13]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=1[C:20]1[CH:21]=[C:22]2[C:28]([NH:29][C:9]([CH:6]3[CH2:7][CH2:8][N:3]([CH3:2])[CH2:4][CH2:5]3)=[O:10])=[N:27][NH:26][C:23]2=[CH:24][N:25]=1
Reactant: Nc1n[nH]c2cnc(-c3cccc(F)c3F)cc12
Reactant: CN1CCC(C(=O)Cl)CC1
Agent: Cl
Solvent: c1ccncc1
Product: CN1CCC(C(=O)Nc2n[nH]c3cnc(-c4cccc(F)c4F)cc23)CC1

Procedure:
1-Methyl-4-piperidinecarbonyl chloride hydrochloride (400 mg, 2.02 mmol) was added to a solution of 5-(2,3-difluorophenyl)-1H-pyrazolo[3,4-c]pyridin-3-ylamine (100 mg, 0.41 mmol) in pyridine (4.5 mL). The reaction mixture was stirred at reflux for 48 hours, allowed to cool and concentrated. Purification by column chromatography using 20% v/v of a 2M methanolic ammonia solution in chloroform as eluent, and subsequent treatment of the product with 1M hydrogen chloride in ether afforded the title compound as a solid.
Reaction SMILES: O1CCOCC1.[OH-].[Na+].C([O:12][C:13]1[CH:42]=[CH:41][C:40]([N:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)=[CH:39][C:14]=1[C:15]([NH:17][C:18]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][CH3:38])[CH:28]=[CH:27][C:19]=1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:16])(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C>[OH:12][C:13]1[CH:42]=[CH:41][C:40]([N:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)=[CH:39][C:14]=1[C:15]([NH:17][C:18]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][CH3:38])[CH:28]=[CH:27][C:19]=1[C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])=[O:16]
Reactant: COc1ccccc1-c1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2cc(N3CCCCC3)ccc2OC(C)=O)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccccc1-c1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2cc(N3CCCCC3)ccc2O)c1
Temperature: 52.5 °C
Reaction time: 2 h
Yield: 24.6 %

Procedure:
Dioxane (4.0 mL) and a 4 mol/L aqueous solution of sodium hydroxide (0.25 mL) were added to the obtained tert-butyl 2-(2-acetoxy-5-(piperidin-1-yl)benzamido)-4-(2-methoxyphenyl)benzoate (0.11 g), followed by stirring at 50 to 55° C. for 2 hours. The reaction mixture was cooled to room temperature, and a 10% aqueous solution of citric acid and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 95-60% hexane/ethyl acetate] to obtain 0.025 g of tert-butyl 2-(2-hydroxy-5-(piperidin-1-yl)benzamido)-4-(2-methoxyphenyl)benzoate as a yellow solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[C:19]2[C:10](=[CH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:8][CH:7]=1.[C:20](Cl)(=[O:24])[C:21](Cl)=[O:22].Cl>C(=S)=S>[Cl:5][C:6]1[C:19]2[C:10]3[C:9]([C:20](=[O:24])[C:21](=[O:22])[C:11]=3[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Clc1cccc2cc3ccccc3cc12
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C1C(=O)c2c3ccccc3cc3c(Cl)ccc1c23
Temperature: 0 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
Anhydrous aluminum chloride (3.5 g, 26.2 mmol) was added to a cold (0° C.) mixture of 1-chloroanthracene (3 g, 14.1 mmol) and oxalyl chloride (10 g, 78.8 mmol) in 30 ml of dry carbon disulfide. After stirring the reaction mixture under an argon atmosphere for two hours at 0° C., additional portions of anhydrous carbon disulfide (30 ml) and dry aluminum chloride (2.25 g, 18.7 mmol) were added. Stirring at 0° C. was continued for an additional two hours. Thereafter, an additional portion of anhydrous carbon disulfide (10 ml) was added, and stirring was continued overnight at room temperature. At the end of the reaction, the mixture was cooled to 0° C. and dilute hydrochloric acid was slowly added. An orange precipitate was collected, washed with water, and treated with 5% sodium hydroxide solution (150 ml). The insoluble solid was collected, washed with water, and air-dried. The crude material was purified by short-column filtration using silica gel and chloroform. Yield was 53%.
Reaction SMILES: [OH:1][C@@:2]12[CH2:8][C@@H:7]1[CH2:6][C@H:5]1[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:3]21[CH3:4])[C:17]1[CH2:16][CH2:15][C:14](=[O:21])[CH2:13][C:12]=1[CH2:11][CH2:10]3>N1C=CC=CC=1>[OH:1][C@@:2]12[CH2:8][C@@H:7]1[CH2:6][C@H:5]1[C@H:9]3[C:18]([CH2:19][CH2:20][C@:3]21[CH3:4])=[C:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3
Reactant: C[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1C[C@H]1C[C@]12O)CC(=O)CC4
Solvent: c1ccncc1
Product: C[C@]12CCC3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1C[C@H]1C[C@]12O

Procedure:
2.3 g of 17beta-hydroxy-16alpha,17alpha-methylene-estr-5(10)-en-3-one is dissolved in 20 ml of pyridine dried on KOH and is mixed at -30° C. with stirring in an inert gas atmosphere with 2.88 g of pyridine hydrobromide perbromide. Then, it is stirred for about 15 minutes at a temperature of about -5° C. and then the excess bromation agent is destroyed by addition of dihydropyrane. Then, it is stirred for 4 hours at room temperature, the reaction mixture is mixed with water and the steroid is extracted with methylene chloride. After the concentration of the extracts by evaporation, the remaining residue is chromatographed on silica gel. A benzene/ethyl acetate mixture (5:1 to 2:1) is used as mobile phase. 1.6 g of dienone, which can be crystallized from aqueous methanol, is obtained.
Reaction SMILES: [CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[Cl:23])[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=[O:5])[OH:4])[CH3:2].[CH3:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32]Cl)=[O:30].C(N(CC)CC)C.CN(C)C=O>C(Cl)Cl>[CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:15][C:14]=2[Cl:23])[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=[O:4])[O:5][CH2:32][O:31][C:29](=[O:30])[C:28]([CH3:35])([CH3:34])[CH3:27])[CH3:2]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CCP(=O)(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCP(=O)(OCOC(=O)C(C)(C)C)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinic acid (0.33 g, 0.80 mmol), chloromethyl 2,2-dimethylpropanoate (0.24 g, 1.60 mmol), triethylamine (0.22 ml) and dimethylformamide (DMF) (3 ml) is stirred at RT for 2 days. The reaction is then diluted with methylene chloride, washed, dried and evaporated to dryness, followed by purification by preparative thin layer chromatography (prep. TLC) (silica gel, eluting with 40% ethyl acetate/hexane) to yield 2,2-dimethylpropionyloxymethyl P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinate.
Reaction SMILES: Br[C:2]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]=[C:15]3[S:19][C:18]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[N:17][C:16]3=[O:27])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[CH:36]1(B(O)O)[CH2:38][CH2:37]1>>[CH:36]1([C:2]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:3]=2[CH2:4][N:5]2[C:13]3[C:8](=[CH:9][C:10]([CH:14]=[C:15]4[S:19][C:18]([N:20]5[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]5)=[N:17][C:16]4=[O:27])=[CH:11][CH:12]=3)[CH:7]=[N:6]2)[CH2:38][CH2:37]1
Reactant: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4Br)c3)S2)CC1
Reactant: OB(O)C1CC1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C4CC4)c3)S2)CC1

Procedure:
5-[1-(2-Cyclopropyl-4-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one was prepared from 5-[1-(2-bromo-4-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one and cyclopropyl boronic acid following General Procedure G.
Reaction SMILES: C(Cl)Cl.[CH2:4]([O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([F:16])[C:8]=1[F:17])[CH3:5].[F:18][CH:19]1[C:24]([F:26])([F:25])[C:23]2([CH2:29][CH2:30][CH3:31])[CH2:27][CH2:28][C:20]1(O)[CH2:21][CH2:22]2.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.O>[F:18][CH:19]1[C:24]([F:25])([F:26])[C:23]2([CH2:29][CH2:30][CH3:31])[CH2:22][CH2:21][C:20]1([O:12][C:11]([C:10]1[CH:14]=[CH:15][C:7]([O:6][CH2:4][CH3:5])=[C:8]([F:17])[C:9]=1[F:16])=[O:13])[CH2:28][CH2:27]2
Reactant: CCOc1ccc(C(=O)O)c(F)c1F
Reactant: CCCC12CCC(O)(CC1)C(F)C2(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCC12CCC(OC(=O)c3ccc(OCC)c(F)c3F)(CC1)C(F)C2(F)F

Procedure:
Methylene chloride solution containing 4-ethoxy-2,3-difluorobenzoic acid (7) (52.6 mg) and 2,3,3-trifluoro-1-hydroxy-4-n-propylbicyclo[2.2.2]octane (4) (39.0 mg) was added with N,N′-dicyclohexyl carbodiimide (53.0 mg) and 4-dimethylamino pyridine (7.0 mg), and the mixture was refluxed under heating for 11 hours. The mixture was then added with water to terminate the reaction, the organic layer was extracted three times with ethyl acetate, the organic layers were combined, and the combined organic layer was washed with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then vaporized off under reduced pressure to thereby obtain a crude product. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate=8:2), to thereby obtain 2,3,3-trifluoro-1-(4′-ethoxy-2′,3′-difluorophenyl)carbonyloxy-4-n-propylbicyclo[2.2.2]octane (8) (yield=20.0 mg, yield ratio=28%) as a colorless clear crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16]>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6](/[CH:7]=[N:11]/[C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COC(=O)c1cccc(N)c1
Solvent: CO
Product: COC(=O)c1cccc(/N=C/c2ccc(OC)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
4-Methoxybenzaldehyde (2.72 g, 19.98 mmol, 1.00 equiv), methyl 3-aminobenzoate (3 g, 19.85 mmol, 1.00 equiv), and methanol (30 mL) were placed in a 50-mL round-bottom flask and allowed to react, with stirring, at room temperature overnight. The resulting solids were collected by filtration and dried in an oven under reduced pressure, yielding 3 g (56%) of (E)-methyl 3-(4-methoxybenzylideneamino)benzoate as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Cl:11])=[O:3].C(O[CH:15](OCC)[N:16]([CH3:18])[CH3:17])C>>[Cl:11][C:5]1[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:4]=1[C:2]([CH:1]=[CH:15][N:16]([CH3:18])[CH3:17])=[O:3]
Reactant: CC(=O)c1ccc(Cl)cc1Cl
Reactant: CCOC(OCC)N(C)C
Product: CN(C)C=CC(=O)c1ccc(Cl)cc1Cl

Procedure:
Part D. A mixture of 2,4-dichloroacetophenone (10.0 g, 52.9 mmol) and dimethylformamide diethyl acetal (10.0 mL, 58.3 mmol) was heated to reflux for 12 hours, then cooled and evaporated under high vacuum. The residual oil was separated by column chromatography (silica gel, 1:1 ethyl acetate-hexane) to afford the product, 1-(2,4-dichlorobenzoyl)-2-(N,N-dimethylamino)ethene, as a viscous oil (12.11 g, 49.6 mmol, 94%). TLC RF 0.05 (20:80 ethyl acetate-hexane). Spectral data: 1H NMR (300 MHz, CDCl3): δ 7.40 (1H, d, J=2.2 Hz), 7.38-7.23 (3H, m), 5.33 (1H, d, J=12.4 Hz), 3.11 (3H, br s), 2.89 (3H, br s). MS (NH3—CI): m/e 249 (1), 248 (10), 247 (8), 246 (64), 245 (16), 244 (100).
Reaction SMILES: Cl.Cl.[I:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[N:10][C:11]=2[NH2:13])[N:6]([CH:14]2[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]2)[N:5]=1.[CH:20]1[C:32]2[CH:31]([CH2:33][O:34][C:35]([N:37]([CH3:44])[C:38]([CH3:43])([CH3:42])[C:39](O)=[O:40])=[O:36])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2N=CC=CC=2N=N1>ClCCl>[NH2:13][C:11]1[N:10]=[CH:9][N:8]=[C:7]2[N:6]([CH:14]3[CH2:19][CH2:18][CH2:17][N:16]([C:39](=[O:40])[C:38]([N:37]([CH3:44])[C:35](=[O:36])[O:34][CH2:33][CH:31]4[C:30]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:24]5[C:32]4=[CH:20][CH:21]=[CH:22][CH:23]=5)([CH3:43])[CH3:42])[CH2:15]3)[N:5]=[C:4]([I:3])[C:12]=12
Reactant: CN(C(=O)OCC1c2ccccc2-c2ccccc21)C(C)(C)C(=O)O
Reactant: Nc1ncnc2c1c(I)nn2C1CCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)OCC1c2ccccc2-c2ccccc21)C(C)(C)C(=O)N1CCCC(n2nc(I)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 11.9 %

Procedure:
A mixture of 3-iodo-1-(3-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (0.17 g, 0.00042 mol), 2-[[(9H-9-fluorenylmethoxy)carbonyl]-(methyl)amino]-2-methylpropanoic acid (0.175 g, 0.00052 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.1 g, 0.00052 mol), N,N-diisopropylethylamine (0.23 g, 0.0018 mol) and 1-hydroxy-7-azabenzotriazole (0.057 g, 0.00042 mol) in anhydrous dichloromethane (7 mL) was stirred for 18 hours at room temperature. Additional 2-[[(9H-9-fluorenylmethoxy)carbonyl](methyl)amino]-2-methylpropanoic acid (0.044 g, 0.00013 mol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.025 g, 0.00013 mol) were added to the reaction and stirred for 16 hours. The solvent was removed under reduced pressure. The residue was partitioned between brine and ethyl acetate. The aqueous layer was extracted with ethyl acetate, and the combined organic solvent was removed under reduced pressure, and the residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 20 min with 0.1 M ammonium acetate, 21 mL/min) to yield 9H-9-fluorenylmethyl N-{2-[3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidino]-1,1-dimethyl-2-oxoethyl}-N-methylcarbamate (0.030 g, 0.00005 mol).
Reaction SMILES: ClC1C2N=C(C3C=CC(F)=CC=3)C=CC=2N=CN=1.[O:19]([C:26]1[C:27]2[N:35]=[C:34]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[CH:33]=[CH:32][C:28]=2[N:29]=[CH:30][N:31]=1)[C:20]1C=CC=C[CH:21]=1>C(O)C>[CH2:20]([O:19][C:26]1[C:27]2[N:35]=[C:34]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[CH:33]=[CH:32][C:28]=2[N:29]=[CH:30][N:31]=1)[CH3:21]
Reactant: Fc1ccc(-c2ccc3ncnc(Oc4ccccc4)c3n2)cc1
Agent: Fc1ccc(-c2ccc3ncnc(Cl)c3n2)cc1
Solvent: CCO
Product: CCOc1ncnc2ccc(-c3ccc(F)cc3)nc12
Yield: 87 %

Procedure:
This compound was synthesized from 4-chloro-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine and ethanol in 87% yield, using the procedure described for the synthesis of 4-phenoxy-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine. The mass spectrum characterising data was as follows: MS (m/z): 270 ([M+H]+, 100).
Reaction SMILES: [C:1]1(C=O)[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].[BH4-].[Na+].[CH2:26](O)C>>[OH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:17][CH2:26][C:6]1[C:5]2[C:14]([CH:13]=[C:12]3[C:7]=1[CH:8]=[CH:9][CH:10]=[CH:11]3)=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: O=Cc1cccc2cc3ccccc3cc12
Reactant: NCCCCCO
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Product: OCCCCCNCc1c2ccccc2cc2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.2 %

Procedure:
A solution of anthraldehyde (9.595 g, 0.0465 mol) and 5-amino-1-pentanol (15.00 g, 0.116 mol) dissolved in 500 mL ethanol at 0° C. was stirred for 3 h. After warming to room temperature the solvent was removed under reduced pressure, and 150 mL of ethanol containing NaBH4 (4.65 g, 0.1229 mol) was added slowly with stirring. The resulting mixture was allowed to stir overnight. The ethanol was removed under reduced pressure and to the brown oil/solid mixture was added 150 mL diethyl ether. Water was added dropwise to this solution until the evolution of hydrogen ceased, followed by the addition of 500 mL water. The ether phase was isolated, washed with 2×50 mL water, dried over sodium sulfate and filtered on a sintered-glass frit. Removal of the solvent afforded 12.17 g (89.2% yield) of 5 as a golden solid; 1H NMR (300.13 MHz, CD3CN) δ 1.51 (m, 6H), 2.81 (t, 2H), 3.49 (t, 2H), 4.68 (s, 2H), 7.52 (m, 4H), 8.05 (d, 2H), 8.44 (m, 3H); 13C-{1H} NMR (75.4 MHz, CDCl3) δ 133.1, 132.0, 131.7, 130.4, 128.6, 127.4, 126.2, 125.1, 62.9, 51.1, 45.8, 33.5, 30.3, 24.8.