Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:17]([CH:20]=[CH2:21])=[CH:16][C:10]=1[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C12BC(CCC1)CCC2.[OH-:31].[Na+].OO>O1CCCC1.O>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:31])=[CH:16][C:10]=1[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: C=Cc1ccc(OCc2ccccc2)c(C(=O)N(C)C)c1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc(CCO)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 14.5 h

Procedure:
To a stirred solution of 2-benzyloxy-N,N-dimethyl-5-vinylbenzamide (560 mg) in tetrahydrofuran (5 ml) was added dropwise a solution of 9-borabicyclo[3.3.1]nonane (255 mg) in tetrahydrofuran (8 ml) at −20° C. under an argon atmosphere, and the mixture was stirred for 14.5 hours at room temperature. To the stirred reaction mixture were added 2N aqueous sodium hydroxide solution (3.0 ml) and 30% aqueous hydrogen peroxide solution (2.4 ml) under ice-cooling, and the resulting mixture was stirred for 5 hours at room temperature. To the reaction mixture was added water, and the resulting mixture was extracted with dichloromethane. The extract was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, purification of the residue by flash column chromatography on silica gel (eluent:hexane/diethyl ether/dichloromethane=1/2/2 and methanol/diethyl ether/dichloromethane=1/10/10) gave 2-benzyloxy-5-(2-hydroxyethyl)-N,N-dimethylbenzamide (300 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([S:16](Cl)(=[O:18])=[O:17])[CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13].[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl.N1C=CC=CC=1>[CH2:25]([NH:32][S:16]([C:7]1[CH:8]=[CH:9][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]([O:4][C:3]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:2]=2[Cl:1])[CH:6]=1)(=[O:18])=[O:17])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CS(=O)(=O)Nc1ccc(S(=O)(=O)Cl)cc1Oc1ccc(Cl)cc1Cl
Reactant: NCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(S(=O)(=O)NCc2ccccc2)cc1Oc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-(2,4-Dichlorophenoxy)-4-methylsulphonylaminobenzene-sulphonic acid chloride (1.08 g, 2.51 mmol) was dissolved in CH2Cl2 (5 ml) and at 0° C. added dropwise to a solution of benzylamine (0.35 ml, 3.2 mmol) in pyridine (20 ml). The mixture was stirred for 2 hours at 0° C. and then evaporated down. The residue was dried in vacuo and purified by chromatography (silica gel, CHCl3 /MeOH 19/1). Yield: 0.18 g=15% 13C (100 MHz, DMSO-d6) δ 149.94, 147.70, 137.38, 137.26, 132.04, 130.41, 129.55, 129.19, 128.30, 127.71, 127.28, 126.23, 123.52, 122.87, 122.67, 114.71, 46.23, 40.92
Reaction SMILES: [F:1][CH:2]([F:49])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]([CH2:34][CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH:21]3[CH2:26][CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]3)[N:9]=2)[C:6]2[CH:43]=[CH:44][CH:45]=[C:46]([O:47][CH3:48])[C:5]=2[N:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:49][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]([CH2:34][CH2:35][CH2:36][N:37]3[CH2:38][CH2:39][O:40][CH2:41][CH2:42]3)[CH:21]3[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]3)[N:9]=2)[C:6]2[CH:43]=[CH:44][CH:45]=[C:46]([O:47][CH3:48])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN2CCOCC2)C2CCCN(C(=O)OC(C)(C)C)C2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN2CCOCC2)C2CCCNC2)n1

Procedure:
Reaction of tert-butyl 3-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl][3-(4-morpholinyl)propyl]amino}-1-piperidinecarboxylate with TFA in CH2Cl2 gave 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-[3-(4-morpholinyl)propyl]-N-(3-piperidinyl)-1,3,5-triazin-2-amine, which was treated with methanesulfonyl chloride in CH2Cl2 to give 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-3-piperidinyl]-6-(4-morpholinyl)-N-[3-(4-morpholinyl)propyl]-1,3,5-triazin-2-amine in 78% yield.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][O:7][CH:8]1[CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]1.[ClH:19]>C(OCC)C>[ClH:19].[NH:10]1[CH2:11][CH:8]([O:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(OCc2nccs2)C1
Agent: Cl
Solvent: CCOCC
Product: c1csc(COC2CNC2)n1
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 3-(1,3-thiazol-2-ylmethoxy)azetidine-1-carboxylate (193 mg, 0.71 mmol; which may be prepared as described in Step 2) dissolved in diethyl ether (2.6 mL) at room temperature was added HCl 2N in diethyl ether (7.1 mL). The reaction mixture was stirred for 1.5 h then concentrated to dryness. The resulting solid was triturated with diethyl ether, collected and dried to give the title compound (138 mg, quantitative) as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([Cl:30])[CH:23]=2)[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([Cl:30])[CH:23]=3)[C:11]3[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc([N+](=O)[O-])cc23)cc1Cl
Reactant: Cc1ncc[nH]1
Product: COc1ccc(CNc2nc(-n3ccnc3C)nc3sc([N+](=O)[O-])cc23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-nitro-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-nitro-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:22][C:23](=[O:28])[C:24]([NH:26][NH2:27])=[O:25])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C1C[O:32][CH2:31]C1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:22][C:23]([C:24]3[O:25][C:31](=[O:32])[NH:27][N:26]=3)=[O:28])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)C(=O)NN
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1n[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (R)-ethyl 4-(3′-chlorobiphenyl-4-yl)-3-(2-hydrazinyl-2-oxoacetamido)butanoate, intermediate 12, (289 mg, 0.72 mmol) in THF (8.5 mL) is added CD (139 mg, 0.86 mmol) at room temperature. After stirring for 18 hour at room temperature, the reaction is quenched with H2O and 1M HCl, and the crude is diluted with EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O (0.1% TFA)/CH3CN) and then lyophilized to give (R)-ethyl 4-(3′-chlorobiphenyl-4-yl)-3-(5-oxo-4,5-dihydro-1,3,4-oxadiazole-2-carboxamido)butanoate (100 mg). HPLC retention time=1.67 minutes (condition A); MS (m+1)=430.2; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (t, J=7.1 Hz, 3 H) 2.52-2.70 (m, 2 H) 2.84 (dd, J=13.7, 8.4 Hz, 1 H) 2.90 (dd, J=13.7, 8.4 Hz, 1 H) 4.02 (q, J=7.1 Hz, 2 H) 4.42-4.58 (m, 1 H) 7.30 (d, J=8.1 Hz, 2 H) 7.37-7.43 (m, 1 H) 7.47 (t, J=7.8 Hz, 1 H) 7.57-7.66 (m, 3 H) 7.70 (t, J=1.9 Hz, 1 H) 8.98 (d, J=8.8 Hz, 1 H) 12.94 (s, 1 H).
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[C:9]([OH:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=O.P(Cl)(Cl)(Cl)=O>C(OCC)(=O)C>[OH:1][C:2]1[C:10]([OH:11])=[C:9]([OH:12])[CH:8]=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: NC(=O)c1ccc(O)c(O)c1O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: N#Cc1ccc(O)c(O)c1O
Temperature: 95 °C
Yield: 57 %

Procedure:
Eighteen and five tenths grams of 2,3,4-trihydroxybenzamide were refluxed with 20 ml. of phosphorusoxychloride and 100 ml. of ethyl acetate for 2.5 hours. The volatile constituents were removed in vacuo and the residue poured into 150 ml. of an ice-water mixture. The resulting suspension was heated to 95° C. and then filtered through activated carbon. The filtrate was concentrated to about 50 ml. whereupon 2,3,4-trihydroxybenzonitrile precipitated and was collected by filtration. 2,3,4-Trihydroxybenzonitrile monohydrate thus prepared melted at 172° C. after recrystallization from a methanol-benzene solvent mixture; yield=57%
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:23])([C:7]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:24].[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CN(C)CCCN=C=NCC>ClCCl>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:23])([C:7]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:25](=[O:32])[C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH:17]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:24]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccc(N)c4)cc3CC[C@@H]12
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccc(NC(=O)c5ccccc5)c4)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.6 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)(10bR)-4-methyl-8-(3-aminophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (50 mg, 0.16 mmol), N,N-dimethylaminopyridine (3 mg, 0.024 mmol), benzoic acid (21 mg, 0.18 mmol), and 0.4 mL of dichloromethane. 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (EDCl) hydrochloride (120 mg, 0.64 mmol) was added in one portion, and the mixture was stirred at room temperature for 10 min. The mixture was diluted with dichloromethane, and the organic phase was washed with water followed by brine. The organic phase was dried over sodium sulfate, concentrated, and chromatographed on silica gel (0-50% methanol/ethyl acetate eluent gradient) to give 50 mg (76%) of the title compound as an amorphous foam. mp 257°-262° (decomp.) FDMS m/e=424. α[D]589 =+62.50 (c=0.61, chloroform).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H-].[Na+].[CH2:13]([O:15][C:16](=[O:27])[CH:17](Cl)[C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]>C1COCC1.C(O)C>[CH2:13]([O:15][C:16]([CH:17]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[F:1])[C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:27])[CH3:14]
Reactant: CCOC(=O)C(Cl)C(=O)c1ccccc1
Reactant: O=C(O)c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(OC(=O)c1ccccc1F)C(=O)c1ccccc1
Temperature: 0 °C
Yield: 37.5 %

Procedure:
2-Fluorobenzoic acid (6 g, 42.8 mmole) was dissolved in 300 mL of anhydrous THF and the resulting reaction solution was cooled to 0° C. To this solution was added sodium hydride (1.88 g of a 60% oil dispersion, 47.1 mmole). The reaction mixture was allowed to warm to room temperature over 1 h. The THF was removed by evaporation before addition of 2-chloro-3-oxo-3-phenyl-propionic acid ethyl ester (9.7 g, 42.8 mmole) in 250 mL of ethanol. Reaction solution was warmed at reflux for 24 h. The ethanol was removed by evaporation and the resulting product was dissolved in water and extracted with toluene. The toluene was washed with 2 N aqueous Na2CO3, and saturated NaCl. The resulting toluene layer was concentrated and purified by chromatography (5-8% ethyl acetate in hexanes gradient) providing 2-fluoro-benzoic acid 1-ethoxycarbonyl-2-oxo-2-phenyl-ethyl ester (Intermediate XVIIb, 5.3 g, 38% yield)
Reaction SMILES: [Na].[NH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:18][C:19](=[O:22])[NH:20][OH:21])[CH:9]=[CH:10]2)[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl[CH2:29][C:30]([N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31].[I-].[Na+]>CO>[NH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:18][C:19](=[O:22])[NH:20][O:21][CH2:29][C:30](=[O:31])[N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[CH:9]=[CH:10]2)[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)c1c2ccc(CC(=O)NO)ccc-2c(C(=O)OCC)c1N
Reactant: O=C(CCl)N1CCCCC1
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CCOC(=O)c1c2ccc(CC(=O)NOCC(=O)N3CCCCC3)ccc-2c(C(=O)OCC)c1N

Procedure:
A mixture of 0.96 g (2.5 mmol) of diethyl 2-amino-6-[(hydroxycarbamoyl)-methyl]-azulene-1,3-dicarboxylate sodium, 50 ml of methanol, 0.4 g (2.5 mmol) of N-chloroacetyl-piperidine and 20 mg of sodium iodide is heated at reflux for 20 hours. Thereafter, the mixture is concentrated and the residue is chromatographed on silica gel. Elution with isohexane: ethyl acetate 1:1 gives 0.42 g (35% of theory) of the title compound of m.p. 153-155° C.
Reaction SMILES: O[CH:2]([CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][C:4](O)=O.O[CH:17]([CH2:22][CH2:23][CH2:24]COC1C=CC=CC=1)[CH2:18][C:19]([OH:21])=[O:20]>>[O:9]([CH2:8][CH2:7][CH2:2][CH2:3][CH2:4][CH2:24][CH2:23][CH2:22][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)CC(O)CCCCOc1ccccc1
Reactant: O=C(O)CC(O)CCOc1ccccc1
Product: O=C(O)CCCCCCCCCCOc1ccccc1

Procedure:
Also, in Macromolecules, 29, 3432-3435 (1996), it is reported that using Pseudomonas oleovorans, PHA containing 3-hydroxy-4-phenoxybutyric acid and 3-hydroxy-6-phenoxyhexanoic acid as units is produced from 6-phenoxyhexanoic acid, PHA containing 3-hydroxy-4-phenoxybutyric acid, 3-hydroxy-6-phenoxyhexanoic acid and 3-hydroxy-8-phenoxyoctanoic acid as units is produced from 8-phenoxyoctanoic acid, and PHA containing 3-hydroxy-5-phenoxyvaleric acid and 3-hydroxy-7-phenoxyheptanoic acid as units is produced from 11-phenoxyundecanoic acid. Yields of polymers in this report are extracted and are shown in the following.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[CH3:13][CH:14]([CH3:32])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[N:21]=[N:22][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:24][CH:25]=1)=[O:19]>>[CH3:13][CH:14]([CH3:32])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[N:21]=[N:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([C:6](=[O:7])[C:5]3[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=3[N+:1]([O-:3])=[O:2])[CH2:28][CH2:27]2)=[CH:24][CH:25]=1)=[O:19]
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3[N+](=O)[O-])CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 2-nitrobenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white solid (72% yield). 1H NMR (500 MHz, CDCl3) δ 8.24, 8.07, 7.84, 7.76, 7.63, 7.44, 7.01, 4.12-4.26, 3.75-3.95, 3.50, 3.41, 1.65-1.76, 1.52, 0.94. MS (ES+) m/z 427 (M+1).
Reaction SMILES: I[CH2:2][I:3].[CH2:4]([O:6][C:7]([C:9]1[N:10]([CH3:17])[CH:11]=[C:12](C#N)[C:13]=1[NH2:14])=[O:8])[CH3:5].C(ON=O)CC(C)C>C(#N)C>[CH2:4]([O:6][C:7]([C:9]1[N:10]([CH3:17])[CH:11]=[C:12]([C:13]#[N:14])[C:2]=1[I:3])=[O:8])[CH3:5]
Reactant: ICI
Reactant: CCOC(=O)c1c(N)c(C#N)cn1C
Agent: CC(C)CCON=O
Solvent: CC#N
Product: CCOC(=O)c1c(I)c(C#N)cn1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Add diiodomethane (22.15 mL, 274.97 mmol) to 3-amino-4-cyano-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (14.75 g, 76.34 mmol, prepared in preparation 33) in acetonitrile with stirring at room temperature. Next, add isoamylnitrite (25.65 mL, 190.92 mmol) while heating the reaction to 35° C. After complete addition, the reaction is heated to 65° C. After 10 minutes; cool the reaction mixture to room temperature and concentrate under reduced pressure. Purify the residue by filtering over silica gel with methylene chloride and triturating the filtrate with hexane to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21]#[N:22]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:20][C:21]#[N:22])=[C:4]([CH:3]=1)[NH:9][C:10](=[O:12])[CH3:11]
Reactant: N#CCCl
Reactant: CC(=O)Nc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Nc1cc(Cl)ccc1OCC#N
Reaction time: 48 h

Procedure:
To a solution of 25.0 grams of 4-chloro 2-acetamidophenol (0.135 mole) in 500 ml of acetone is added 18.7 grams of potassium carbonate (0.135 mole). To the resulting suspension is added 10.20 grams of chloroacetonitrile (0.135 mole). The suspension is stirred for 48 hours at reflux. The reaction mixture is then filtered and the solvent removed under reduced pressure to yield a dark solid residue. Recrystallization of the residue from methylene chloride-petroleum ether (1:1) followed by recrystallization twice more from methanol yields refined 5'-chloro 2'-(cyanomethoxy) acetanilide mp; 146°-149° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1[N:21]=[C:20]([CH:22]=O)[CH:19]=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClC(Cl)C.C(O)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:22][C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:15])[N:21]=2)[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Cc1cccc(C=O)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1cccc(CN2CCC(NC(=O)OC(C)(C)C)CC2)n1
Yield: 112.4 %

Procedure:
In 15 ml of dichloroethane, 315 mg of 4-t-butoxycarbonylaminopiperidine, 320 mg of 6-methyl-2-pyridinecarbaldehyde and 100 mg of acetic acid were dissolved. To the solution 575 mg of sodium triacetoxyborohydride was added at room temperature, followed by an hour's stirring at the same temperature. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and removed of the solvent by reduced pressure distillation. The residue was purified by silica gel column chromatography (chloroform/methanol=100/1 to 50/1), to give 540 mg of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][CH:3]=1.[CH3:13][C:14]([C:16]1[CH:21]=[CH:20][C:19](F)=[CH:18][CH:17]=1)=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:19]2[CH:20]=[CH:21][C:16]([C:14](=[O:15])[CH3:13])=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: Oc1ccc(Cl)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(=O)c1ccc(Oc2ccc(Cl)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 35.6 g of 4-chloro-1-naphthol, 27.62 g of 4-fluoroacetophenone, and 55.2 g of potassium carbonate in 250 ml of N,N-dimethylacetamide are heated under Argon with vigorous stirring at 150°-155° C. overnight. After cooling to room temperature, 500 ml of water is added and the mixture is extracted with three 150 ml portions of benzene. The combined extracts are washed with two 150 ml portions of 5% NaOH, three 150 ml portions of 10% HCl, two 150 ml portions of water, 150 ml of saturated NaHCO3, 150 ml of saturated brine, and dried over MgSO4. Evaporation of the solvent at reduced pressure affords a light brown solid, which is extracted with 800 ml of hot hexane to give the product as a tan solid, mp 98°-105° C. Recrystallization from 15:1 hexane-chloroform gives cream colored plates, mp 100°-104.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C1COCC1.[H-].[Na+].Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[C:38]([C:39]4[CH:44]=[CH:43][N:42]=[C:41]([NH:45][CH3:46])[N:40]=4)=[CH:37][CH:36]=[CH:35][N:34]=3)=[CH:28][CH:27]=2)=[N:17][N:16]=1>O>[CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]4[C:38]([C:39]5[CH:44]=[CH:43][N:42]=[C:41]([NH:45][CH3:46])[N:40]=5)=[CH:37][CH:36]=[CH:35][N:34]=4)=[CH:28][CH:27]=3)=[N:17][N:16]=2)[CH:6]=1
Reactant: Cc1cn[nH]c1
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(Cl)c4ccccc34)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CNc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(-n4cc(C)cn4)c4ccccc34)cc2)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A dry resealable pressure bottle, under nitrogen, was charged with 4-methylpyrazole (0.086 ml, 1.05 mmol). To this was added THF (1.3 ml, 0.2 M) and reaction mixture cooled to 0° C. 60% wt sodium hydride in mineral oil (44.0 mg, 1.10 mmol) was added slowly. Reaction mixture stirred at 0° C. for 15 minutes and 4-chloro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amine (120 mg, 0.260 mmol) added slowly. Reaction kept at 0° C. for 10 minutes, then warmed up slowly to room temperature and placed in an oil bath. Reaction heated to 65° C. and stirred at this temperature overnight. Reaction mixture was cooled to 0° C. and diluted with water, and extracted with EtOAc. The organic layer was collected, dried over Na2SO4 and concentrated to afford an orange residue, which was purified by Gilson reverse phase chromatography (10% to 90% CH3CN/H2O/0.1% TFA). The product-containing fractions were combined, basified by addition of aq. NaHCO3 and extracted with ethyl acetate. The organic portion was dried with Na2SO4, filtered, and concentrated to afford pure 4-(4-methyl-1H-pyrazol-1-yl)-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amine as a yellow solid. MS m/z=502 [M+H]+. Calc'd for C28H23N9O: 501.54.
Reaction SMILES: O.NN.[Cl:4][C:5]1[CH:6]=[C:7]([CH:11]([N:19]2C(=O)C3=CC=CC=C3C2=O)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:8]=[CH:9][CH:10]=1>C(O)C>[Cl:4][C:5]1[CH:6]=[C:7]([CH:11]([NH2:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C1c2ccccc2C(=O)N1C(Cc1ccccn1)c1cccc(Cl)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: NC(Cc1ccccn1)c1cccc(Cl)c1

Procedure:
150 ml of a solution of 5.25 g of hydrazine hydrate in ethanol was added to 12.7 g of the N-{1-(3-chlorophenyl)-2-(pyridin-2-yl)ethyl}phthalimide prepared in the Preparative Example 22. The obtained mixture was heated under reflux for 2 hours. The precipitated crystals were filtered out and the filtrate was concentrated, followed by the addition thereto of ethyl acetate. The precipitated impurities were filtered out and the filtrate was concentrated to give the title compound. Yield: 7.9 g.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])=[O:6].Cl.[NH2:19]O>C(O)C>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:5]1[O:6][N:19]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:4]=1
Reactant: COc1ccccc1C(=O)CC(=O)C(F)(F)F
Reactant: NO
Agent: Cl
Solvent: CCO
Product: COc1ccccc1-c1cc(C(F)(F)F)no1
Temperature: 25 °C

Procedure:
A mixture of 4,4,4-trifluoro-1-(2-methoxyphenyl)butane-1,3-dione (C9) (933 mg, 3.79 mmol) and hydroxylamine hydrochloride (798 mg, 11.4 mmol) in ethanol (10 mL) was refluxed under nitrogen for 3 hours, then cooled to room temperature. The reaction was concentrated in vacuo, treated with water (30 mL) and extracted with dichloromethane (3×10 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 20% ethyl acetate in heptanes) afforded the title compound as a yellow oil. Yield: 502 mg, 2.06 mmol, 54%. GCMS m/z 243 (M+). 1H NMR (400 MHz, CDCl3) δ 4.00 (s, 3H), 7.01 (s, 1H), 7.05 (dd, J=8.4, 0.9 Hz, 1H), 7.11 (ddd, J=7.8, 7.4, 1.1 Hz, 1H), 7.48 (ddd, J=8.4, 7.4, 1.8 Hz, 1H), 8.00 (dd, J=7.8, 1.7 Hz, 1H).