Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])=[CH:4][C:3]=1[Br:19].[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1C=CC=CC=1.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1>ClCCl>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([O:18][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:10]([F:11])([F:12])[F:13])[C:14]([F:17])([F:15])[F:16])=[CH:4][C:3]=1[Br:19]
Reactant: Nc1c(Cl)cc(C(O)(C(F)(F)F)C(F)(F)F)cc1Br
Reactant: O=C(O)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Nc1c(Cl)cc(C(OC(=O)c2ccccc2)(C(F)(F)F)C(F)(F)F)cc1Br
Temperature: 25 °C
Yield: 42 %

Procedure:
To a solution of 2-(4-amino-3-bromo-5-chlorophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (Example 3.3) (3.725 g, 10.0 mmol) and benzoic acid (1.28 g, 10.5 mmol) in dichloromethane (30 ml) was added pyridine (4.18 ml, 30 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (“BOP-Cl”) (2.80 g, 11 mmol). The reaction mixture was heated to reflux for 24 hours. The reaction mixture was cooled to ambient temperature and quenched by addition of aqueous hydrochloric acid (1N) (50 ml). The mixture was then extracted three times with dichloromethane. The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (Buchi fraction collector C-660, prepacked cartridges Silicagel 60, particle size: 40-63 μm, D 40×150 mm, Gradient 99 to 1% methanol in toluene over 15 min, 60 mL/min, fraction 20 mL) to give benzoic acid 1-(4-amino-3-bromo-5-chlorophenyl)-2,2,2-trifluoro-1-trifluoromethylethyl ester (2 g, 42% yield). 1H NMR (400 MHz, CDCl3): 8.18 (d, 1H), 8.11 (d, 1H), 7.68 (m, 1H), 7.53 (m, 2H), 7.41 (s, 1H), 7.29 (s, 1H), 4.74 (bs, 2H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10](=[O:33])[C@@H:11]([CH2:18][C:19]1[C:20]([CH2:28][O:29]C(=O)C)=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][N:23]=[CH:22]2)[CH2:12][C:13]([O:15][CH2:16]C)=[O:14])C>CO>[CH3:7][O:9][C:10](=[O:33])[C@@H:11]([CH2:18][C:19]1[C:20]([CH2:28][OH:29])=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][N:23]=[CH:22]2)[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: CCOC(=O)C[C@H](Cc1ccc2[nH]ncc2c1COC(C)=O)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)C[C@H](Cc1ccc2[nH]ncc2c1CO)C(=O)OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
Potassium carbonate (1.6 g, 11.6 mmol) was added to a solution of 2-(S)-(4-acetoxymethyl-1H-indazol-5-ylmethyl)-succinic acid diethyl ester (2.0 g, 5.5 mmol) in methanol (60 mL). Mixture was stirred at room temperature for 1.5 hours. Reaction was quenched with the addition of 1N hydrochloric acid (30 mL). Methanol was removed from the mixture in vacuo. Remaining aqueous was basified with sodium bicarbonate. Mixture was extracted with ethyl acetate (2×40 mL). Combined organic layers were washed successively with water (30 mL) and brine (30 mL). Organic was dried (magnesium sulfate), filtered then concentrated in vacuo. Desired product was obtained in 92% yield as an amber oil. 1H NMR (300 MHz, CDCl3): δ=8.21 ((s, 1H), 7.34 (d, J=9.2, 1H), 7.17 (d, J=8.8, 1H), 5.02 (dd, J1=12.4, J2=17.9, 1H) 3.63 (s, 6H), 3.23 (m, 1H), 2.98 (m, 1H), 2.77 (dd, J1=7.7, J2=16.8, 1H), 2.53 (dd, J1=6.4, J2=16.7, 1H). MS m/e (M+H)+=307.0.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[C:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)#[N:22]>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([C:27]3[CH:28]=[C:23]([CH:24]=[CH:25][CH:26]=3)[C:21]#[N:22])[C:11]3[C:6]([CH:5]=2)=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[CH:19]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: COc1cccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc12
Product: COc1cccc2c(-c3cccc(C#N)c3)nc(Nc3cc(C)[nH]n3)cc12

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-cyano-phenylboronic acid to give 3-[3-(5-methyl-1H-pyrazol-3-ylamino)-5-methoxy-isoquinolin-1-yl]-benzonitrile LC-MS m/e 356(MH+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([OH:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>O1CCCC1>[S:14]([O:12][CH:10]([CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:11])(=[O:16])(=[O:15])[CH3:13]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)CCCc1ccccc1
Solvent: C1CCOC1
Product: CC(CCCc1ccccc1)OS(C)(=O)=O
Temperature: 25 °C
Yield: 95 %

Procedure:
To a stirred solution of 5-phenyl-2-pentanol (482 g.; 2.94 moles) in tetrahydrofuran (2250 ml.) at 0° C. was added methanesulfonyl chloride (300 ml.) at such a rate that the internal temperature does not rise above 10° C. (total addition time 4.5 hours). After addition is complete, the reaction mixture was allowed to warm to room temperature and stirring was continued for an additional hour. The reaction mixture was filtered and the supernate concentrated to a light yellow oil (2800 g.) which was dissolved in chloroform (2 liters) and washed with water (4×1 liter), brine (1×1 liter), charcoal treated (50 g.), dried (MgSO4), filtered through diatomaceous earth and concentrated to a light orange oil (687 g., 95% yield). This material was suitable for use without further purification.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][CH:22]([CH3:32])[CH2:23][CH:24]([C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[NH2:25]>>[CH3:21][CH:22]([CH3:32])[CH2:23][CH:24]([NH:25][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[C:26]1[N:27]=[CH:28][CH:29]=[CH:30][N:31]=1
Reactant: CC(C)CC(N)c1ncccn1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Product: CC(C)CC(NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)c1ncccn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and 3-methyl-1-(pyrimidin-2-yl)butan-1-amine (CAN 1178500-15-6) as starting materials, MS (EI): m/e=432.4 [M+H]+.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH2:5]([O:7][C:8](=[O:12])[C:9](Cl)=[O:10])[CH3:6].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20][CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>C(Cl)Cl>[CH2:5]([O:7][C:8](=[O:12])[C:9]([C:18]1[CH:17]=[CH:16][C:15]([S:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:14]([Cl:13])[CH:19]=1)=[O:10])[CH3:6]
Reactant: Clc1ccccc1SC1CCCC1
Reactant: CCOC(=O)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1ccc(SC2CCCC2)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a round bottom flask is placed methylene chloride (100 mL) and aluminum trichloride (1.39 equiv) and it is cooled to 0° C. in an ice bath. To this solution is then added dropwise chloro-oxo-acetic acid ethyl ester (1.09 equiv.) keeping the temperature of the solution below 5° C. and it is then stirred for 30 min at 0° C. After this time a solution of 1-chloro-2-cyclopentylsulfanyl-benzene (50.0 mmol) in methylene chloride (5 mL) is added dropwise while keeping the temperature of the solution below 5° C. The ice bath is then removed and the reaction is allowed to warm up to 25° C. and is stirred for 3 h. The reaction is then cooled back down to 0° C. in an ice bath and ice water (20 mL) is then added dropwise keeping the temperature of the solution below 20° C. It is then stirred for 15 min and then transferred to a separatory funnel and separated. The organic phase is then washed with water (2×25 mL), saturated aqueous sodium bicarbonate solution (2×25 mL) and water (25 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo to afford (3-chloro-4-cyclopentylsulfanyl-phenyl)-oxo-acetic acid ethyl ester.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[N:3]1[CH2:12][C:13]([CH3:17])=[CH:14][C:15]#[N:16]>C(O)C.CN(C)C=O.[Pd]>[O:1]=[S:2]1(=[O:18])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[N:3]1[CH2:12][CH:13]([CH3:17])[CH2:14][C:15]#[N:16]
Reactant: CC(=CC#N)CN1C(=O)c2ccccc2S1(=O)=O
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(CC#N)CN1C(=O)c2ccccc2S1(=O)=O
Reaction time: 12 h
Yield: 47.8 %

Procedure:
10.0 g (38 millimoles) of 3-(2,3-dihydro-1,1-dioxido-3-oxo-1,2-benzisothiazol-2-yl)-1-cyano-2-methylprop-1-ene (Example 1) were dissolved in 200 ml of ethanol and 100 ml of dimethylformamide, 1 g of palladium on active carbon (10%) was added and hydrogenation was carried out for 12 hours at room temperature and under atmospheric pressure. The mixture was filtered, the filtrate was evaporated down under reduced pressure and the resulting greenish oil was purified by column chromatography (silica gel, mobile phase 85:15 mixture of toluene and methanol) to give 4.8 g (48%) of 3-(2,3-dihydro-1,1-dioxido-3-oxo-1,2-benzisothiazol-2-yl)-1-cyano-2-methylpropane in the form of an oil which slowly crystallized through. Mp 83°-84° C.
Reaction SMILES: [F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]([O-:5])=O.[Na+].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[C:42]([NH2:44])=[O:43]>CN(C=O)C>[F:13][C:2]([F:1])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]([NH:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[C:42]([NH2:44])=[O:43])=[O:5]
Reactant: O=C([O-])C(F)(F)c1ccc(F)cn1
Reactant: NC(=O)c1ccccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1NC(=O)C(F)(F)c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To a mixture of sodium 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetate (100 mg, 0.47 mmol), HATU (213 mg, 0.56 mmol) and 2-aminobenzamide (77 mg, 0.56 mmol) was added DMF (2 mL) and the mixture was stirred overnight at rt. The mixture was partitioned between saturated aq ammonium chloride and EtOAc, and the organic layer was concentrated. The residue was purified by silica gel chromotography eluting with 2-10% MeOH/DCM to afford 2-(2,2-difluoro-2-(5-fluoropyridin-2-yl)acetamido)benzamide as an oil (110 mg, 74%). LC-MS (ESI) m/z 332 (M+Na)+.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)#[CH:12].N>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[N:8][CH:9]=3)[CH:12]=2)=[CH:14][CH:15]=1
Reactant: ON=C(Cl)c1cncnc1
Reactant: C#Cc1ccc(F)cc1
Agent: N
Product: Fc1ccc(-c2cc(-c3cncnc3)no2)cc1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 44B (79 mg, 0.5 mmol) and 1-ethynyl-4-fluorobenzene (Aldrich, 60 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.40-7.57 (m, 2H), 7.76 (s, 1H), 7.90-8.06 (m, 2H), 9.32 (s, 2H), 9.35 (s, 1H) ppm; MS (DCI/NH3) m/z 242 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][C:6]([CH3:31])([CH3:30])[CH2:7][N:8]1[C:27](=[S:28])[N:11]2[C:12]3[CH:13]=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=4)[O:15][C:16]=3[CH:17]=[C:10]2[C:9]1=[O:29])C.O>FC(F)(F)C(O)=O>[CH3:30][C:6]([CH3:31])([CH2:7][N:8]1[C:27](=[S:28])[N:11]2[C:12]3[CH:13]=[C:14]([C:18]4[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=4)[O:15][C:16]=3[CH:17]=[C:10]2[C:9]1=[O:29])[CH2:5][C:4]([OH:32])=[O:3]
Reactant: CCOC(=O)CC(C)(C)CN1C(=O)c2cc3oc(-c4ccc([N+](=O)[O-])cc4)cc3n2C1=S
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(CC(=O)O)CN1C(=O)c2cc3oc(-c4ccc([N+](=O)[O-])cc4)cc3n2C1=S
Temperature: 90 °C
Yield: 82.9 %

Procedure:
Compound 7 (300 mg, 0.66 mmol) was dissolved in trifluoroacetic acid (TFA, 9 ml). Water (3 ml) was added and the resulting mixture was heated at 90° C. for 16 hours. The reaction mixture was then filtered, washed with ethanol and the solvents were evaporated under reduced pressure to give Compound 8 (234 mg, 83% yield) as an orange solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:20])(C)(C)C.[Cl:22][C:23]1[CH:24]=[C:25]([C:29]2OC(C)(C)O[C:31](=[O:37])[CH:30]=2)[CH:26]=[CH:27][CH:28]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:22][C:23]1[CH:24]=[C:25]([C:29]2[CH2:30][C:31](=[O:37])[NH:20][C:9]3[CH:10]=[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:12]=[CH:13][C:8]=3[N:7]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: CC1(C)OC(=O)C=C(c2cccc(Cl)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(Cl)c2)=Nc2ccc(-c3ccccc3)cc2N1
Yield: 54.2 %

Procedure:
Prepared from (3-amino-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G9) (284 mg, 1.0 mmol) and 6-(3-Chloro-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J6) (358 mg, 1.2 mmol) according to the general procedure K. The obtained material (339 mg) was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (188 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[N:25]=1.[NH2:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][C:28]=1[O:36][CH3:37]>C(O)C.O.Cl>[F:14][C:9]1([F:15])[CH2:8][N:7]([CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]2[N:25]=[C:2]([NH:26][C:27]3[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][C:28]=3[O:36][CH3:37])[N:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10]1=[O:13]
Reactant: CN1C(=O)C(F)(F)CN(CCCc2ccccc2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(CCCc1ccccc1)CC(F)(F)C(=O)N2C
Yield: 76.1 %

Procedure:
A mixture of 0.50 g (0.0014 mole) of 2-chloro-7,7-difluoro-5-methyl-9-(3-phenyl-propyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-281) and 0.27 g (0.0017 mole) of 4-amino-3-methoxy-benzoic acid in 3.2 mL of ethanol-water-hydrochloric acid (20:80:1) was refluxed for 18 hours, then cooled and partially concentrated under reduced pressure. The resulting solid was collected by filtration, washed with water and dried to give 0.53 g of 4-[7,7-difluoro-5-methyl-6-oxo-9-(3-phenyl-propyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-benzoic acid (I-281).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([CH2:17][C:18](NC1N=NN(CCCCCCCCCCCC)N=1)=[O:19])(=[O:16])=[O:15])([CH3:3])[CH3:2].[CH2:38]([NH:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>>[CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[NH:13][S:14]([CH2:17][C:18]([N:46]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[O:19])(=[O:16])=[O:15])([CH3:11])[CH3:12]
Reactant: CCCCCCCCCCCCn1nnc(NC(=O)CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Reactant: CCCCCCCCNCCCCCCCC
Product: CCCCCCCCN(CCCCCCCC)C(=O)CS(=O)(=O)Nc1c(C(C)C)cccc1C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 2, except that 2-DAT was replaced with N,N-dioctylamine, mp 107°-109° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:11]=[C:10]([CH3:12])[C:9](=[O:13])[NH:8][C:7]1=[O:14].[Cl:15][C:16]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:17]=1[CH2:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.[Br-].[Na+].C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[Cl:15][C:16]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:17]=1[CH2:18][N:19]1[CH2:20][CH2:21][N:22]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH:11]=[C:10]([CH3:12])[C:9](=[O:13])[NH:8][C:7]2=[O:14])[CH2:23][CH2:24]1
Reactant: Clc1ccc(CN2CCNCC2)c(Cl)c1
Reactant: Cc1cn(CCCCCl)c(=O)[nH]c1=O
Agent: [Br-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(CCCCN2CCN(Cc3ccc(Cl)cc3Cl)CC2)c(=O)[nH]c1=O
Yield: 33.4 %

Procedure:
1-(4-Chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione (0.69 mmol, 0.15 g), 1-(2,4-dichlorobenzyl)piperazine (0.62 mmol, 0.15 g), sodium bromide (3.46 mmol, 0.36 g) and diisopropylethylamine (6.92 mmol, 0.89 g) were heated in N-methylpyrrolidinone (0.6 ml) at 120° C. for 5 hours. The reaction mixture was then allowed to cool, the suspension was filtered with suction, and the filtrate was concentrated. The residue was then then taken up in ethyl acetate and washed with saturated brine. The organic layer was dried, filtered to remove the desiccant and evaporated in vacuo. The resulting residue was purified by chromatography on silica gel (eluent: methyl tert-butyl ether/methanol (0-100%), resulting in 88.0 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6](O)[C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([Cl:19])[C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: O=S(Cl)Cl
Solvent: O
Product: Fc1ccc(C(Cl)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
To 15.0 g (68.1 mmol) of 4,4'-difluorobenzhydrol was added 14.9 ml (204 mmol) of thionyl chloride in the atmosphere of argon, and the mixture was stirred at room temperature for 30 minutes. To the resulting mixture was added water followed by extraction with benzene. The organic layer was successively washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was subjected to column chromatography on silica gel. There was yielded 14.32 g (60 mmol) of 4,4'-difluorobenzhydryl chloride from the fraction eluted with benzene.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[N:14]=[N:15]NN=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](Cl)(=[O:28])[C:19]1[CH:27]=[CH:26][CH:25]=[C:21]([C:22](Cl)=[O:23])[CH:20]=1.O.[OH-].[Na+]>N1C=CC=CC=1>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[O:28][C:18]([C:19]4[CH:27]=[CH:26][CH:25]=[C:21]([C:22]5[O:23][C:13]([C:9]6[N:8]=[C:7]([C:1]7[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=7)[CH:12]=[CH:11][CH:10]=6)=[N:14][N:15]=5)[CH:20]=4)=[N:15][N:14]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Reactant: c1ccc(-c2cccc(-c3nn[nH]n3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: c1ccc(-c2cccc(-c3nnc(-c4cccc(-c5nnc(-c6cccc(-c7ccccc7)n6)o5)c4)o3)n2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
5.0 g of 2-phenyl-6-(2H-tetrazol-5-yl)pyridine was dissolved in 125 ml of dehydrated pyridine. Temperature was elevated to 120° C., and 75 ml was dehydrated by azeotropy. After cooling to 50° C., 2.28 g of isophthaloyl dichloride was added. Temperature was elevated to 100° C., and stirring was conducted for 1 hour. After cooling to room temperature, the reaction solution was poured into 300 ml water, and after adjusting pH to 12 with 20% sodium hydroxide aqueous solution, stirring was conducted for 1 hour. A precipitated brown solid was taken out by suction filtration, and washed with water. The solid obtained was vacuum dried at 70° C. for 20 hours, and purified with column chromatography (carrier: NH silica gel, eluting solution: chloroform) to obtain 4.27 g (yield 73%) of PhpyOXDm. The product was identified with NMR analysis. The result of NMR analysis (CDCl3) was as follows. 9.07 ppm (1H), 8.46 ppm (2H), 8.28 ppm (2H), 8.17 ppm (4H), 7.92-8.15 ppm (4H), 7.78 ppm (1H), 7.46-7.55 ppm (6H).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([NH:23][NH2:24])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[C:2]1([C:1](=[N:24][NH:23][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccncc1
Reactant: NNC(=O)c1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(NN=C(c1ccccc1)c1ccncc1)c1cccnc1
Temperature: 25 °C
Yield: 54.3 %

Procedure:
A mixture of 9.16 gm (0.05 mole) of 4-benzoyl pyridine, 6.86 gm (0.05 mole) of nicotinic acid hydrazide, 100 ml of ethanol and 4.4 ml of concentrated hydrochloric acid was refluxed 16 hr. The reaction mixture was cooled to room temperature. An equal volume of water was added containing 5.4 gm (0.05 mole) of sodium carbonate. The mixture was placed in the refrigerator. The product which separated was collected, washed with water and dried to give 8.21 gm (54%) of the title compound having a melting point of 74.0° C.
Reaction SMILES: [C:1]([CH:9]([CH3:13])C(O)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[O:15]1CCC[CH2:16]1>>[C:2]1([CH:1]([OH:8])[CH2:9][CH2:13][CH2:16][OH:15])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)C(=O)c1ccccc1
Reactant: C1CCOC1
Agent: Cl
Product: OCCCC(O)c1ccccc1
Reaction time: 60 h

Procedure:
A solution of 35.6 g (0.20 mole) of benzoylpropionic acid in 100 ml of tetrahydrofuran was added dropwise to 300 ml of a 1 molar solution of borane tetrahydrofuran complex in tetrahydrofuran. The mixture was stirred at ambient temperatures for 60 hr, giving a gel. This was treated with 100 ml of 2N hydrochloric acid solution and the mixture stirred for 15 min. Most of the tetrahydrofuran was removed on a rotary evaporator and the residue partitioned between methylene chloride and water. The aqueous layer was extracted again with methylene chloride. The combined extract was washed with water, dried (sodium sulfate), and concentrated to yield 24.30 g of 1-phenyl-1,4-butanediol. This intermediate was dissolved in acetone and heated at reflux temperature for 5 hr while 30 g of manganese dioxide was added in five portions. The reaction mixture was filtered and concentrated to a brown oil that was chromatographed on silica gel using 15% ethyl acetate-85% methylene chloride to elute the fraction identified by 1H nmr as the title compound. The fraction weighed 11.20 g, after concentration and was shown to have a purity greater than 90%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([NH2:12])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[C:18](Cl)=[O:19].C(N(CC)CC)C>O1CCCC1>[CH3:27][O:26][C:22]1[CH:21]=[C:17]([CH:16]=[C:15]([O:14][CH3:13])[C:23]=1[O:24][CH3:25])[C:18]([NH:12][C:5]1[C:6](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:7]([O:9][CH3:10])=[O:8])=[O:19]
Reactant: COC(=O)c1cc(Cl)ccc1N
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)ccc1NC(=O)c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
To a solution of 1.3 g of methyl 5-chloroanthranilate and 1.8 g of 3,4,5-trimethoxybenzoylchloride in 30 ml of tetrahydrofuran is added 1.5 g of triethylamine under cooling, and the mixture is stirred at room temperature for 2 hours and then heated under reflux for 1 hour. The reaction mixture is concentrated under reduced pressure and to the residue is added water. The precipitated crystals are collected by filtration and recrystallized from a mixture of chloroform and ether to obtain 1.4 g of methyl N-(3,4,5-trimethoxybenzoyl)-5-chloroanthranilate as colorless prisms.