Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[CH2:25]([O:27][C:28]([CH:30]1[NH:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]1)=[O:29])[CH3:26].C(N(CC)CC)C>C(O)C>[CH2:25]([O:27][C:28]([CH:30]1[N:35]([C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[N:6]3[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:31]1)=[O:29])[CH3:26]
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(Cl)ncnc32)cc1
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1c1ncnc2c1nc(-c1ccccc1Cl)n2-c1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
6-Chloro-9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H-purine I-(4A-7)c (103 mg, 0.27 mmol), piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (Chiu, C. K.-F. and Griffith, D. A., EP 1004583 A2; 156 mg, 0.60 mmol), and triethylamine (95 μl, 0.68 mmol) were combined in ethanol (1.5 ml) and heated at 60° C. until complete by TLC (3 days). The reaction mixture was concentrated under reduced pressure and then purified on a Biotage™ Flash 12M column using 20 to 30% ethyl acetate in hexanes as eluant to afford title compound I-(8A-1)a (78 mg, 48%): +ESI MS (M+1) 597.3; 1H NMR (400 MHz, CD3OD) δ 8.298 (br s, 1H), 7.57 (br s, 1H), 7.48–7.25 (m, 7H), 5.60 (v br s, 1H), 4.67 (d, J=13.7 Hz, 1H), 4.23–4.05 (br m, 3H), 3.43–3.00 (br m, 2H), 1.46 (s, 9H), 1.22 (t, J=7.1 Hz, 3H).
Reaction SMILES: COC1C=CC2N=CCOC=2C=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[OH:22].[Cl:23][CH2:24][C:25](Cl)=[O:26]>CC(C)=O>[Cl:23][CH2:24][C:25]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[OH:22])=[O:26]
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(N)c(O)c1
Agent: COc1ccc2c(c1)OCC=N2
Solvent: CC(C)=O
Product: COc1ccc(NC(=O)CCl)c(O)c1

Procedure:
Hill and Ramage reported at J. Chem. Soc., 3709 (1964) a convenient synthesis of 7-methoxy-1,4-benzoxazine from 2-amino-5-methoxyphenol 9a. Compound 9a reacted with chloroacetyl chloride in acetone to give 2-chloroacetamido-5-methoxy phenol 10a. An intramolecular cyclization of 10a with aqueous sodium hydroxide produced 7-methoxy-3-oxo-1,4-benzoxazine 11a, which upon reduction with lithium aluminum hydride in THF resulted in the formation of 7-methoxy-3,4-dihydro-2H-1,4-benzoxazine 12a. ##STR4##
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>C(OCC)(=O)C>[CH3:26][S:27]([O:1][CH2:2][CH2:3][CH2:4][O:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(OCCCO)CC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(OCCCOS(C)(=O)=O)CC1

Procedure:
To a solution of 4-(3-hydroxypropyloxy)-N-t-butyloxycarbonylpiperidine (3.82 g) in ethyl acetate (40 ml) were added triethylamine (4.1 ml) and methanesulfonyl chloride (1.37 ml) with stirring under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture were added water (50 ml) and ethyl acetate (50 ml) with stirring. The organic layer was separated, washed twice with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (150 ml) eluting with a mixture of n-hexane and ethyl acetate (1:1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give 4-[3-(methanesulfonyloxy)propyloxy]-N-t-butyloxycarbonylpiperidine (3.77 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][C:15]1[C:19]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]([CH3:30])[NH:25][CH2:24][CH2:23]3)=[C:18]([CH3:31])[O:17][N:16]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:25]3[CH2:24][CH2:23][C:22]4[C:27](=[CH:28][CH:29]=[C:20]([C:19]5[C:15]([CH3:14])=[N:16][O:17][C:18]=5[CH3:31])[CH:21]=4)[CH:26]3[CH3:30])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: Cc1noc(C)c1-c1ccc2c(c1)CCNC2C
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: Cc1noc(C)c1-c1ccc2c(c1)CCN(C(=O)c1cc3ncc(Br)cn3n1)C2C

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-(3,5-Dimethyl-isoxazol-4-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: N([O-])=O.[Na+].[Br:5][C:6]1[CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:7]=1N.Cl.[C-:19]#[N:20].[K+]>O.S([O-])([O-])(=O)=O.[Cu+2]>[Br:5][C:6]1[CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:7]=1[C:19]#[N:20]
Reactant: Nc1ccc(OC(F)(F)F)cc1Br
Reactant: [C-]#N
Agent: [Cu+2]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Product: N#Cc1ccc(OC(F)(F)F)cc1Br
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of sodium nitrite (2.76 g, 40 mmol) in water (15 ml) was added dropwise to a suspension of 2-bromo-4-(trifluoromethoxy)aniline (10.2 g, 40 mmol) in a mixture of concentrated hydrochloric acid (20 ml) and water (50 ml) at 0° C. The mixture was stirred at 0° C. for 45 min., then added dropwise to a mixture of potassium cyanide (11.4 g, 176 mmol) and copper (II) sulfate (6.4 g, 40 mmol) in water (80 ml) at 65° C. The mixture was stirred at 65° C. for 30 min., cooled to room temperature and filtered through a pad of Hyflo™ washing with dichloromethane (2×200 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (100 ml). The combined organic fractions were dried and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica, eluting with hexane/EtOAc (75:25), to give the title compound as an oil. 1H NMR (360 MHz, CDCl3) δ7.12-7.15 (1 H, m), 7.56 (1 H, s), and 7.72 (1 H, d, J 8.6 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2].[CH2:23]([Sn](CCCC)(CCCC)CCCC)[C:24](=[CH2:26])[CH3:25]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([CH2:25][C:24]([CH3:26])=[CH2:23])[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2nc(-c3ccccc3)sc2c1O
Reactant: C=C(C)C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: C=C(C)Cc1nc(C(=O)OCC)c(O)c2sc(-c3ccccc3)nc12
Temperature: 130 °C
Reaction time: 0.75 h
Yield: 45.1 %

Procedure:
A mixture of 4-bromo-7-hydroxy-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (301.5 mg, 0.80 mmole), methallyltri-n-butyltin (529 μl, 1.60 mmole) and bis(triphenylphosphine)palladium(II) dichloride (56 mg, 0.08 mmole) in dimethylformamide (4 ml) was stirred at 130° C. for 45 min before it was cooled to room temperature, quenched with water, filtered. The filtrate was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a white solid (128 mg). MS: (+) m/z 355.02 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:14]([C:18]([F:21])([F:20])[F:19])[O:15]3)=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.[SiH](CC)(CC)CC>C(O)(C(F)(F)F)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:14]([C:18]([F:21])([F:20])[F:19])[O:15]3)=[CH:10][CH:9]=2)=[CH:27][CH:28]=1
Reactant: CCOC(=O)C1=Cc2ccc(C(=O)c3ccc(C)cc3)cc2OC1C(F)(F)F
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1=Cc2ccc(Cc3ccc(C)cc3)cc2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The ester from Step 1 was dissolved in TFA (18 mL). Et3SiH was added dropwise at room temperature. The reaction was stirred at room temperature overnight. The reaction was quenched with NaHCO3 and extracted with ether. The organic layer was dried over MgSO4. The filtrate was concentracted to give yellow oil, which was purified by Biotage with 3-5% EtOAc in hexane to give clear oil quantity: LCMS m/z 377.15 (M+H). 1H NMR (CDCl3/400 MHz) 7.68 (s, 1H), 7.08 (m, 4H), 6.79 (d, 1H, J=6.4 Hz), 5.68 (q, 1H, J=7.2 Hz), 4.29 (m, 2H), 3.89 (s, 2H), 2.31 (s, 3H), 1.35 (t, 3H, J=7.2 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[C:3]=1[C:4]#[N:5].[CH:11]1(B(O)O)[CH2:13][CH2:12]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:11]2[CH2:13][CH2:12]2)[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(N)cccc1Br
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1c(N)cccc1C1CC1
Temperature: 25 °C
Yield: 62.6 %

Procedure:
A 2-5 mL microwave vial containing 2-amino-6-bromobenzonitrile (1.0 eq., 1.0 mmol, 197 mg), cyclopropylboronic acid (1.3 eq., 1.3 mmol, 112 mg), and K3PO4 (3.5 eq., 3.5 mmol, 743 mg) was flushed with nitrogen. To this vial was added toluene (4 mL, Sure-Seal), water (200 μL), tricyclohexylphosphine (0.018 eq., 18.1 mmol, 88% pure, 20% in hexanes, 32 μL), and palladium (II) acetate (0.05 eq. “Pd,” trimer, 0.0167 mmol, 12 mg), all under nitrogen. The reaction vial was flushed with nitrogen, capped with a crimp-top septum, and microwaved for 30 minutes at 130° C. The reaction mixture was cooled to room temperature, partitioned between EtOAc (3 mL) and water (1 mL). The layers were separated, the water layer extracted EtOAc (2×3 mL), the combined organic layers dried over sodium sulfate. The EtOAc was filtered through a 0.45 μm PTFE frit to remove finely divided solids and concentrated on a rotary evaporator. The crude product was purified on silica gel (SiliaPrep 80 g cartridge, gradient elution from 10% EtOAc/hexanes to 40% EtOAc/hexanes, loaded in solution in 1:1 hexanes:DCM). The fractions containing product were concentrated on a rotary evaporator to give 2-amino-6-cyclopropylbenzonitrile (99 mg, 62.7%) as a waxy yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 0.668 (m, 2H), 0.979 (m, 2H), 1.978 (m, 1H), 5.882 (br. s, 2H), 6.128 (d, J=8 Hz, 1H), 6.546 (d, J=8 Hz, 1H), 7.129 (t, J=8 Hz, 1H).
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.Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([NH:23][C:24]2[CH:28]=[CH:27][NH:26][N:25]=2)[N:14]=1>>[NH:26]1[CH:27]=[CH:28][C:24]([NH:23][C:15]2[N:14]=[C:13]([O:1][C:2]3[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=3)[C:22]3[C:17]([CH:16]=2)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:25]1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: CC(=O)Nc1ccc(O)cc1
Product: CC(=O)Nc1ccc(Oc2nc(Nc3cc[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 10 was used, starting from N-(4-hydroxy-phenyl)-acetamide and (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine to give N-{4-[3-(1H-pyrazol-3-ylamino)-isoquinolin-1-yloxy]-phenyl}-acetamide. LC-MS m/e 360(MH+).
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=C[CH:2]=1.[C:12]([C:15]12[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2)([OH:14])=[O:13]>C(O)C>[CH2:1]([O:13][C:12]([C:15]12[CH2:24][CH:19]3[CH2:18][CH:17]([CH2:23][CH:21]([CH2:20]3)[CH2:22]1)[CH2:16]2)=[O:14])[CH3:2]
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)C12CC3CC(CC(C3)C1)C2

Procedure:
In the presence of an acid catalyst (p-toluenesulfonic acid), 1-carboxyadamantane obtained in Example 2 was allowed to react with an excess amount of ethanol to give 1-ethoxycarbonyladamantane.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[CH:13]=C[O:15][C:11]=2[CH:10]=[C:9]2[C:4]=1[C:5](=[O:18])[CH2:6][C:7]([CH3:17])([CH3:16])[O:8]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:38]=[O+][O-]>ClCCl>[OH:15][C:11]1[CH:10]=[C:9]2[C:4]([C:5](=[O:18])[CH2:6][C:7]([CH3:17])([CH3:16])[O:8]2)=[C:3]([O:2][CH3:1])[C:12]=1[CH:13]=[O:38]
Reactant: COc1c2c(cc3occc13)OC(C)(C)CC2=O
Reactant: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1c(C=O)c(O)cc2c1C(=O)CC(C)(C)O2
Temperature: -78 °C
Reaction time: 2 h

Procedure:
500 mg (2.03 mmol) of 4-methoxy-7,7-dimethyl-6,7-dihydro-5H-furo[3,2-g]chromen-5-one (Example 1A) and 666 mg (2.54 mmol) of triphenylphosphine are initially charged, and 50 ml of dichloromethane are added. The mixture is cooled to −78° C., and ozone is then introduced for about 5 min. Once the color of the solution has turned to blue, excess ozone is flushed out with oxygen. The solution is stirred for another two hours and slowly warmed to room temperature. The mixture is concentrated and the residue that remains is purified on a silica gel column (mobile phase: cyclohexane/ethyl acetate 5:1) This gives 370 mg (72% of theory) of the title compound.
Reaction SMILES: ClS([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=O)=O>N1C=CC=CC=1.C(Cl)Cl>[C:9]([OH:11])(=[O:10])[C:8]1[CH:12]=[CH:13][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.07 h

Procedure:
To a stirred solution of compound 757-A (4.99 g, 25.0 mmol) in pyridine (50 mL) and methylene chloride (25 mL), cooled on an ice bath, was added 4-(chlorosulfonyl)benzoic acid (5.52 g, 25.0 mmol), portion-wise, for 4 min, and the reaction was allowed to stir at ambient temperature for 4 days. The reaction mixture was concentrated under reduced pressure, the residue stirred with 1N HCl (100 mL), the resulting solid filtered, washed with 1N HCl and air dried. The crude product was triturated with MeOH (15 mL), filtered, rinsed with MeOH (2×5 mL) and air-dried to afford crude benzoic acid (not shown). The benzoic acid was suspended in MeOH (100 mL), treated with concentrated H2SO4 (0.1 mL) and the reaction mixture refluxed for 5 days. The reaction mixture was cooled, the solvent evaporated under reduced pressure, and the residue was triturated with MeOH (15 mL), filtered, washed with methanol (2×5 mL) and once with another portion of methanol (10 mL). The solid was dried to afford 6.31 g of compound 398-A as a tan-yellow powder. 1H-NMR (DMSO-d6) δ: 2.02 (s, 3H), 3.89 (s, 3H), 7.40-7.29 (m, 2H), 7.67-7.61 (m, 1H), 7.83-7.77 (m, 1H), 7.89 (d, 2H), 8.14 (d, 2H), 10.66 (s, 1H); MS: m/z 360.2 (M-H+).
Reaction SMILES: ClCCl.[NH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[N:10]1[S:11][N:12]=[C:13]2[CH:18]=[C:17]([C:19](OC)=[O:20])[CH:16]=[CH:15][C:14]=12>C1(C)C=CC=CC=1>[N:10]1[S:11][N:12]=[C:13]2[CH:18]=[C:17]([C:19]([N:4]3[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]3)=[O:20])[CH:16]=[CH:15][C:14]=12
Reactant: COC(=O)c1ccc2nsnc2c1
Reactant: C1CCNCC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(c1ccc2nsnc2c1)N1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
Trimethylaluninum (2M in toluene; 3.0 mL, 6.0 mmol) was diluted into 30 mL dichloromethane to which piperidine (0.55 g, 6.5 mmol) and methyl benzo-2,1,3-thiadiazole-5-carboxylate (1.16 g, 6.00 mmol) were added. The reaction was stirred at room temperature for 2 hours and concentrated to one-half the volume by rotary evaporation. Dry toluene (25 mL) was added and the reaction solution was heated to 80° C. for 1 hour. Additional piperidine (about 0.2 g) was added and the temperature was increased to 100° C. for 1 hour. The solution was allowed to cool to room temperature and stirred overnight, at which time it was quenched with 10% citric acid and hydrochloric acid. The solution was diluted with ethyl acetate and sequentially washed with 10% citric acid, saturated sodium hydrogen phosphate and saturated sodium chloride, and subsequently dried over anhydrous sodium sulfate. The solution was concentrated onto silica and product was eluted with hexane/ethyl acetate (3:1). Purification by distillation in a kugelrohr at 180° C. and 0.5 mmHg yielded 1-(benzo-2,1,3-thiadiazole-5-ylcarbonyl)piperidine, 1 (1.29 g, 87%) as a pale yellow oil. IR: 2920, 2855, 1633, 1478, 1439, 1280, 1223, 1001, 816, and 748 cm−1. 1H NMR (500 MHz): δ8.06 (1H, d, J=9.1 Hz); 8.02 (1H, s); 7.63 (1H, t, J=9.0 and 1.5 Hz); 3.77 (2H, br s); 3.40 (2H, br s); 1.72 (4H, br s); and 1.57 ppm (2H, br s).
Reaction SMILES: [OH:1][CH:2]([CH3:20])[CH2:3][N:4]1[C:12]2[C:7](=[C:8]([C:15]([F:18])([F:17])[F:16])[C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[CH:6]=[C:5]1[CH3:19].[F:21][C:22]1[N:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1>>[F:21][C:22]1[N:27]=[CH:26][C:25]([O:1][CH:2]([CH3:20])[CH2:3][N:4]2[C:12]3[C:7](=[C:8]([C:15]([F:18])([F:16])[F:17])[C:9]([C:13]#[N:14])=[CH:10][CH:11]=3)[CH:6]=[C:5]2[CH3:19])=[CH:24][CH:23]=1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(C)O
Reactant: Oc1ccc(F)nc1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(C)Oc1ccc(F)nc1

Procedure:
Synthesized as described in Example 139C using 1-(2-hydroxypropyl)-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 335) and 6-fluoro-3-pyridinol: 1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.49 (d, J=8.6 Hz, 1H), 6.94 (m, 1H), 6.71 (m, 1H), 6.56 (s, 1H), 4.57 (m, 1H), 4.40 (m, 1H), 4.30 (m, 1H), 2.54 (s, 3H), 1.43 (d, J=6.1 Hz, 3H); MS (ES) m/z 400 (M+Na).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:28]#[N:29])=[C:10]2[C:14]=1[N:13]=[C:12]1[N:15]([C:19]3[C:24]([CH3:25])=[CH:23][C:22]([Cl:26])=[CH:21][C:20]=3[Cl:27])[CH2:16][CH2:17][CH2:18][N:11]21.[BH4-].[Na+]>O1CCCC1.CC(O)C.O>[Cl:5][C:6]1[C:14]2[N:13]=[C:12]3[N:15]([C:19]4[C:24]([CH3:25])=[CH:23][C:22]([Cl:26])=[CH:21][C:20]=4[Cl:27])[CH2:16][CH2:17][CH2:18][N:11]3[C:10]=2[C:9]([CH:28]([NH2:29])[CH2:1][CH3:2])=[CH:8][CH:7]=1
Reactant: Cc1cc(Cl)cc(Cl)c1N1CCCn2c1nc1c(Cl)ccc(C#N)c12
Reactant: CC[Mg]Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: CCC(N)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)cc(Cl)cc1Cl
Yield: 106.5 %

Procedure:
Ethylmagnesium bromide (3 M solution in diethyl ether, 4.50 mL, 13.5 mmol) was added to a stirred suspension of 9-chloro-1-(2,4-dichloro-6-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbonitrile (530 mg, 1.35 mmol) in tetrahydrofuran (14 mL) at room temperature. After the resultant mixture was refluxed for 3 hr, a suspension of sodium tetrahydroborate (1.02 g, 27.0 mmol) in 2-propanol (14 mL) was added at room temperature. The resultant mixture was stirred at 50° C. for 30 min, diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude 1-[9-chloro-1-(2,4-dichloro-6-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-amine (609 mg), which was used for the next step without further purification. To a mixture of crude 1-[9-chloro-1-(2,4-dichloro-6-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-amine (120 mg) and triethylamine (0.0742 mL, 0.532 mmol) in tetrahydrofuran (2.7 mL) was added acetic anhydride (0.0302 mL, 0.319 mol) at 0° C. The resultant mixture was stirred at room temperature for 10 min, diluted with aqueous sodium bicarbonate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-100% ethyl acetate/n-hexane gradient mixture and preparative HPLC eluting with a 10-40% acetonitrile/water gradient mixture to give the two title compounds as colorless solids.
Reaction SMILES: [Na:1].C(C1(C[CH2:15][O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([CH2:23][S:24]([C:26]3[NH:30][C:29]4[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=4[N:27]=3)=[O:25])[C:18]=2[CH3:35])OCC2(OCCO2)CO1)C.ClC1C=CC=C(C(OO)=O)C=1.[O:47]1[C:51]2([CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]2)[O:50][CH2:49][CH:48]1CO>>[Na:1].[O:47]1[C:51]2([CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]2)[O:50][CH2:49][C@@H:48]1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([CH2:23][S:24]([C:26]2[NH:27][C:28]3[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=3[N:30]=2)=[O:25])[C:18]=1[CH3:35]
Reactant: OCC1COC2(CCCCC2)O1
Reactant: CCC1(CCOc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)OCC2(CO1)OCCO2
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na]
Product: Cc1c(OC[C@H]2COC3(CCCCC3)O2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 16.8 %

Procedure:
The same procedure as in the steps (4f) to (4j) of Example 4 (a reprecipitation operation was not performed in oxidation step with 3-chloroperbenzoic acid) was repeated using (+)-1,4-dioxaspiro[4.5]decane-2-methanol to obtain the title compound (500 mg, total 16.8% yield) as a white solid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.Cl.[Cl:26][CH2:27][CH2:28][CH2:29][CH:30]([C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[C:37]([F:43])[CH:36]=1)[C:31]([NH:33][NH2:34])=[O:32].[F:44][C:45]1[CH:46]=[C:47](/[CH:57]=[CH:58]/[C:59](O)=[O:60])[CH:48]=[CH:49][C:50]=1[N:51]1[CH:55]=[C:54]([CH3:56])[N:53]=[CH:52]1.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[F:44][C:45]1[CH:46]=[C:47](/[CH:57]=[CH:58]/[C:59]([NH:34][NH:33][C:31](=[O:32])[CH:30]([C:35]2[CH:36]=[C:37]([F:43])[C:38]([F:42])=[C:39]([F:41])[CH:40]=2)[CH2:29][CH2:28][CH2:27][Cl:26])=[O:60])[CH:48]=[CH:49][C:50]=1[N:51]1[CH:55]=[C:54]([CH3:56])[N:53]=[CH:52]1
Reactant: NNC(=O)C(CCCCl)c1cc(F)c(F)c(F)c1
Reactant: Cc1cn(-c2ccc(/C=C/C(=O)O)cc2F)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cn(-c2ccc(/C=C/C(=O)NNC(=O)C(CCCCl)c3cc(F)c(F)c(F)c3)cc2F)cn1

Procedure:
IPEA (0.14 mL) and BOPCl (100 mg) were added to a solution of 5-chloro-2-(3,4,5-trifluorophenyl)pentanoic acid hydrazide hydrochloride (83 mg) and (E)-3-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (CAS No. 870839-63-7, 65 mg) in methylene chloride (5 mL), and the reaction solution was stirred at room temperature for 18 hours. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane:ethyl acetate=1:1->ethyl acetate->ethyl acetate:methanol=9:1) to obtain 103 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [Cl:1]C1C(C([O-])=O)=NC2C(C=1)=CC=CC=2OC.O[C:18]1[C:27]2[C:22](=[C:23]([O:28][CH3:29])[CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([C:30]([O:32][CH3:33])=[O:31])[CH:19]=1.O=P(Cl)(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>>[Cl:1][C:18]1[C:27]2[C:22](=[C:23]([O:28][CH3:29])[CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([C:30]([O:32][CH3:33])=[O:31])[CH:19]=1
Reactant: COc1cccc2cc(Cl)c(C(=O)[O-])nc12
Reactant: COC(=O)c1cc(O)c2cccc(OC)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc(Cl)c2cccc(OC)c2n1
Temperature: 80 °C
Yield: 69 %

Procedure:
Methyl 4™chloro-8-methoxyquinoline-2-carboxylate compound of the formula V, R5 =CH3O, R6 =H, R8 =CH3 57.6 g (247 mmol) of methyl 4-hydroxy-8-methoxyquinolinecarboxylate were introduced a little at a time into 113 ml of POCl3 at room temperature to 40° C., and the mixture was heated at 80° C. for 2 hours. The dark reaction mixture was poured onto ice and adjusted to pH 6 with concentrated K2CO3 solution. The precipitate was filtered off with suction and recrystallized from DMF/water. 42.7 g (=69%) of methyl 4-chloro-8-methoxyquinoline-2-carboxylate of melting point 139-141° C. were obtained.