Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]([NH:12][C:13]([O:15]C(C)(C)C)=O)[C:6]1=[O:20])=[O:4].C(O)(C(F)(F)F)=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+].[Cl:45][C:46]1[CH:55]=[C:54]2[C:49]([C:50]([N:57]3[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]3)=[CH:51][C:52]([NH2:56])=[N:53]2)=[CH:48][CH:47]=1>>[NH2:56][C:52]1[CH:51]=[C:50]([N:57]2[CH2:58][CH2:59][N:60]([C:13]([NH:12][C@H:7]3[CH2:8][CH2:9][CH2:10][CH2:11][N:5]([C:3]([O:2][CH3:1])=[O:4])[C:6]3=[O:20])=[O:15])[CH2:61][CH2:62]2)[C:49]2[C:54](=[CH:55][C:46]([Cl:45])=[CH:47][CH:48]=2)[N:53]=1
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Reactant: COC(=O)N1CCCC[C@@H](NC(=O)OC(C)(C)C)C1=O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1CCCC[C@H](NC(=O)N2CCN(c3cc(N)nc4cc(Cl)ccc34)CC2)C1=O

Procedure:
As described for example 213, (3R)-3-[[(1,1-dimethylethoxy)carbonyl]amino]hexahydro-2-oxo-1H-azepine-1-carboxylic acid-methyl ester, TFA, triphosgene, NaHCO3 (sat.), and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the title product as a light yellow solid. LC-MS: 475 (M++1). 1H NMR (CDCl3): δ 1.45–2.05 (m, 5H), 2.15 (m, 1H), 3.12 (m, 4H), 3.42 (dd, 1H), 3.66 (m, 4H), 3.90 (s, 3H), 4.45 (m, 1H), 4.75˜4.85 (m, 3H), 5.95 (d, 1H), 6.15 (s, 1H), 7.19 (dd, 1H), 7.62 (d, 1H), 7.74 (d, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH3:24])[CH2:3][CH:4]([C:8]1[CH:9]=[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=[C:12](C(F)(F)F)[CH:13]=1)[C:5]([OH:7])=[O:6].[F:25][C:26]([F:41])([F:40])[C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:30]([NH2:32])=[O:31]>>[F:25][C:26]([F:40])([F:41])[C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:35]=1)[C:30]([NH:32][C:12]1[CH:13]=[C:8]([CH:4]([CH2:3][CH:2]([CH3:1])[CH3:24])[C:5]([OH:7])=[O:6])[CH:9]=[C:10]([C:18]2[CH:23]=[CH:22][C:21]([C:26]([F:41])([F:40])[F:25])=[CH:20][CH:19]=2)[CH:11]=1)=[O:31]
Reactant: NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)CC(C(=O)O)c1cc(-c2ccccc2)cc(C(F)(F)F)c1
Product: CC(C)CC(C(=O)O)c1cc(NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
The title compound was prepared by a Buchwald coupling reaction of 4-methyl-2-(5-trifluoromethyl-biphenyl-3-yl)pentanoic acid (intermediate compound 1g) with 3,5-bis(trifluoromethyl)-benzamide under the conditions described in Example 1; 1H NMR (400 MHz, MeOD) δ ppm 0.97 (dd, J=6.60, 2.45 Hz, 6 H), 1.56 (dt, J=13.27, 6.69 Hz, 1 H), 1.75 (ddd, J=13.88, 7.21, 7.03 Hz, 1 H), 2.02 (ddd, J=13.57, 7.70, 7.58 Hz, 1 H), 3.78 (t, J=7.70 Hz, 1 H), 7.47 (s, 1 H), 7.75-7.85 (m, 5 H), 8.08 (s, 1 H), 8.21 (s, 1 H), 8.60 (s, 2 H); Calcd for C28H22F9NO3 (M+H) 592.15, Found 592.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.CCN(CC)CC.Cl[C:34]([O:36][CH3:37])=[O:35].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:25][C:21]1[CH:20]=[C:19]([C@H:5]([O:4][CH2:3][CH2:2][NH:1][C:34]([O:36][CH3:37])=[O:35])[C@@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:7]2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cccc(Cl)c2)C1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chlorophenyl)methyl)piperidine-1-carboxylate (70 g, crude, 0.1 mol) and DMAP (1.83 g, 15 mmol, 0.15 eq) in dry CH2Cl2 (150 mL), Et3N (12.1 g, 15.8 mL, 120 mmol) was added. The resulting mixture was cooled to 0-5° C. using a ice-water bath, a solution of methyl chloroformate (11.28 g, 120 mmol, 1.2 eq) in dry CH2Cl2 (100 mL) was added drop wise. After addition, the reaction mixture was stirred for 3 h at 0-5° C. TLC showed the starting material had disappeared. Water (80 mL) was added. The aqueous layer was extracted with CH2Cl2 (3×00 mL), the combined organic layers were washed with 10% citric acid (2×150 mL) and brine (100 mL), then dried over Na2SO4, filtered and concentrated to the crude product, which was purified by preparative HPLC to afford (R)-tert-butyl 3-((R)-(3-chlorophenyl)(2-(methoxycarbonylamino)ethoxy)-methyl)piperidine-1-carboxylate (10.7 g, the total yield for three steps is 25%). 1H NMR (400 MHz, CDCl3): 1.12-1.40 (m, 4H), 1.43 (s, 9H), 1.64 (m, 2H), 2.82 (m, 2H), 3.25 (m, 2H), 3.61 (s, 3H), 3.74 (m, 1H), 4.05 (m, 1H), 4.16 (m, 1H), 7.22 (m, 1H), 7.32 (m, 3H).
Reaction SMILES: [CH3:1][C:2]12[CH2:13][CH2:12][CH:5]([C:6](=[N:10][OH:11])[C:7]1=[N:8][NH2:9])[CH:4]([CH3:14])[O:3]2.CO[C:17](OC)(OC)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([C:17]2[N:9]=[N:8][C:7]3[C:2]4([CH3:1])[CH2:13][CH2:12][CH:5]([CH:4]([CH3:14])[O:3]4)[C:6]=3[N+:10]=2[O-:11])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC1OC2(C)CCC1C(=NO)C2=NN
Reactant: COC(OC)(OC)c1ccccc1
Product: CC1OC2(C)CCC1c1c2nnc(-c2ccccc2)[n+]1[O-]

Procedure:
A solution of 1.97 g. (0.01 mole) 1,3-dimethyl-2-oxabicyclo[2,2,2]octan-5,6-dione-5-oxime-6-hydrazone in 10 ml. trimethylorthobenzoate is refluxed under nitrogen for 18 hours at a bath temperature of 140° C. during which time all distillate is removed. The resulting mixture is cooled and evaporated to dryness in vacuo. After filtering the residue dissolved in 2% methanol-chloroform through silica gel, and evaporation of the filtrate gives 3-phenyl-5,8-dihydro-6,8-dimethyl-5,8-ethano-6H-pyrano[4,3-e]-as-triazine-4-oxide.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:32])[C:19]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[CH:20][O:21][CH:22]([F:24])[F:23])=[CH:11][C:10]=1[O:33][CH3:34])C1C=CC=CC=1.Br>C(O)(=O)C>[F:23][CH:22]([F:24])[O:21][CH:20]=[C:19]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)[C:18]([NH:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([O:33][CH3:34])[CH:11]=1)=[O:32]
Reactant: COc1cc(CCNC(=O)C(=COC(F)F)c2ccc(C)cc2)ccc1OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: COc1cc(CCNC(=O)C(=COC(F)F)c2ccc(C)cc2)ccc1O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 60 %

Procedure:
9.40 g of N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-3-difluoromethoxy-2-(4-methylphenyl)acrylamide (20.1 mmol), 3.72 g (22.1 mmol) of 48% hydrobromic acid and 95 ml of acetic acid were mixed and stirred at 80° C. for 1.5 hours. The solvent was distilled off from the reaction mixture under reduced pressure and the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=2:1) to give 4.55 g of 3-difluoromethoxy-N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-2-(4-methylphenyl)acrylamide (the present compound 1452).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])C1C=CC=CC=1.Cl.Cl[CH2:39][CH2:40][N:41]([CH3:43])[CH3:42].[H-].[Na+]>CN(C)C=O>[CH3:42][N:41]([CH3:43])[CH2:40][CH2:39][N:25]1[CH:24]=[C:23]([CH2:22][N:21]([C:28]2[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=2)[C:19]([CH:14]2[C:15]3[C:10](=[C:9]([OH:8])[CH:18]=[CH:17][CH:16]=3)[CH2:11][CH2:12][CH2:13]2)=[O:20])[CH:27]=[N:26]1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1ccc(N(Cc2cnn(CCN(C)C)c2)C(=O)C2CCCc3c(O)cccc32)cc1
Reaction time: 24 h
Yield: 53.6 %

Procedure:
To a solution of 5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.35 g) in dimethylformamide were added 2-chloro-N,N-dimethylethylamine hydrochloride (0.12 g) and sodium hydride (0.035 g), and the mixture was stirred for one day. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the obtained residue was reacted and treated in the same manner as in Example 17 to give N-({1-[2-(dimethylamino)ethyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.18 g). melting point: 92° C.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:16][CH:15]2[CH:11]([CH2:12][NH:13][CH2:14]2)[CH2:10]1)=[O:8].Cl[C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1>>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:10][CH:11]2[CH2:12][N:13]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)[CH2:14][CH:15]2[CH2:16]1)=[O:8]
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNCC2C1
Reactant: Clc1ccc2ccccc2n1
Product: O=C(c1ccccc1-c1ccccc1)N1CC2CN(c3ccc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 17 and 2-chloro-quinoline. MS (ESI) mass calcd. for C28H25N3O, 419.53; m/z found, 420.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:31])[C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=3)=[C:12]([N+:28]([O-])=O)[CH:11]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.C(O)C.O.[Fe]>[NH2:28][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=1)[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)=[O:31]
Reactant: CS(=O)(=O)Nc1ccc(Oc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)Nc1ccc(Oc2ccc(C(=O)Nc3ccc(Br)cc3)cc2N)cc1
Temperature: 25 °C
Yield: 93 %

Procedure:
A suspension of the product of Example 91B (223 mg, 0.4404 mmol) and iron powder (98 mg, 1.762 mmol) in acetic acid (5 mL) and ethanol (5 mL) was heated at reflux under a nitrogen atmosphere for 30 minutes. The reaction was cooled to room temperature, diluted with water (50 mL), and treated with solid sodium carbonate until the pH was 6. Extracted with ethyl acetate (100 mL), washed the organic with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation under vacuum. Co-evaporating the resulting oil with methylene chloride/hexanes gave the title compound as a light tan solid (195 mg, 93%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]=1I.F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>Cl[Pd]Cl.[Pd].C([O-])([O-])=O.[Na+].[Na+]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[C:11]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Fc1ccccc1
Reactant: Fc1cc(Br)ccc1I
Agent: Cl[Pd]Cl
Agent: [Pd]
Agent: O=C([O-])[O-]
Product: Fc1ccccc1-c1ccccc1-c1ccccc1
Yield: 12 %

Procedure:
3 g of 2-fluoro-4-bromoiodobenzene, about 0.4 g of PdCl2 and 0.2 g or 5% Pd on carbon, 20 ml of fluorobenzene, and 10 ml of 2M Na2CO3, were added to a 3-neck round bottom flask equipped with a slow nitrogen purge. The mixture was vigorously stirred and 1.21 g of phenylboronic acid in about 5 g of concentrated ethanol was added. The solution was then refluxed at 70°-72° C. The resulting solution was then analyzed by gas chromatography (corrected for sensitivity factors) and it was determined that the desired product, 2-fluoro-4-bromobiphenyl, was produced in 55% yield with about 12% fluoroterphenyl.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:47]([O:48]C(=O)C)[C@H:46]([O:52]C(=O)C)[C@@H:45]([C:56]([O:58]C)=[O:57])[O:44][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:17]([CH2:18][CH2:19][C@H:20]([O:28]C(=O)C)[C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:16](=[O:32])[N:15]2[C:33]2[CH:38]=[CH:37][C:36]([C:39]#[C:40][C:41]([OH:43])=[O:42])=[CH:35][CH:34]=2)=[CH:10][CH:9]=1)(=O)C.[C-]#N.[Na+]>CO>[O:7]([C:8]1[CH:9]=[CH:10][C:11]([C@@H:14]2[C@@H:17]([CH2:18][CH2:19][C@@H:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[OH:28])[C:16](=[O:32])[N:15]2[C:33]2[CH:34]=[CH:35][C:36]([C:39]#[C:40][C:41]([OH:43])=[O:42])=[CH:37][CH:38]=2)=[CH:12][CH:13]=1)[C@@H:6]1[O:44][C@H:45]([C:56]([OH:58])=[O:57])[C@@H:46]([OH:52])[C@H:47]([OH:48])[C@H:5]1[OH:4]
Reactant: COC(=O)[C@H]1O[C@@H](Oc2ccc([C@@H]3[C@@H](CC[C@H](OC(C)=O)c4ccc(F)cc4)C(=O)N3c3ccc(C#CC(=O)O)cc3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Product: O=C(O)C#Cc1ccc(N2C(=O)[C@H](CC[C@H](O)c3ccc(F)cc3)[C@H]2c2ccc(O[C@@H]3O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]3O)cc2)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of 4-{(2S,3R)-3-[(3S)-3-(acetyloxy)-3-(4-fluorophenyl)propyl]-1-[4-(carboxyethynyl)phenyl]-4-oxoazetidin-2-yl}phenyl methyl 2,3,4-tri-O-acetyl-β-D-glucopyranosiduronate (10d) and sodium cyanide (˜1 mg, 0.020 mmol) in methanol (3 mL) was heated to 45° C. After 22 h, the reaction mixture was concentrated under reduced pressure and dissolved in methanol/water/triethylamine (1:7:2, 1 mL). After stirring at room temperature for approximately 1 h, the volatiles were evaporated in vacuo and the crude residue purified by preparative reversed phase high performance liquid chromatography on YMC Pack Pro C18 phase (gradient elution; 10-60% acetonitrile/water as eluent, 0.1% TFA modifier) to give the title compound (10e), m/z (ES) 442.0 (M-sugar-OH)+, 618.0 (M−OH)+; HRMS (ES) m/z calcd. for C33H31FNO11 (MH+) 636.1881, found 636.1889
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:12]1[O:29][C@H:28]([CH2:30][O:31]C(=O)C)[C@@H:23]([O:24]C(=O)C)[C@H:18]([O:19]C(=O)C)[C@H:13]1[O:14]C(=O)C.[CH2:35]([O:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=O)=[CH:40][CH:39]=1)[CH3:36]>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:42][C:41]1[CH:45]=[CH:46][C:38]([O:37][CH2:35][CH3:36])=[CH:39][CH:40]=1)=[CH:5][N:6]2[C@@H:12]1[O:29][C@H:28]([CH2:30][OH:31])[C@@H:23]([OH:24])[C@H:18]([OH:19])[C@H:13]1[OH:14]
Reactant: CCOc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Cl)c(F)ccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CCOc1ccc(Cc2cn([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3ccc(F)c(Cl)c23)cc1

Procedure:
4-Chloro-5-fluoro-1-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyl)indole obtained in Example 34-(3) and 4-ethoxybenzoyl chloride were treated in a manner similar to Example 27 to give the titled compound as a colorless powder. APCI-Mass m/Z 483/485 (M+NH4). 1H-NMR (DMSO-d6) δ 1.30 (t, J=6.9 Hz, 3H), 3.15-3.50 (m, 4H), 3.64 (m, 2H), 3.96 (q, J=6.9 Hz, 2H), 4.18 (s, 2H), 4.54 (t, J=5.4 Hz, 1H), 5.11 (t, J=5.3 Hz, 1H), 5.17 (d, J=5.0 Hz, 1H), 5.23 (d, J=5.8 Hz, 1H), 5.39 (d, J=9.1 Hz, 1H), 6.82 (d, J=8.5 Hz, 2H), 7.12 (d, J=8.5 Hz, 2H), 7.16 (t, J=9.4 Hz, 1H), 7.30 (s, 1H), 7.56 (dd, J=8.9, 3.9 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[N:9][S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:13][CH2:14][CH:15]([OH:18])[CH2:16]Cl>O.C(Cl)Cl>[S:10]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([O:1][CH2:16][CH:15]([OH:18])[CH2:14][Cl:13])[C:7]=2[CH:8]=[N:9]1
Reactant: OC(CCl)CCl
Reactant: Oc1cccc2sncc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: OC(CCl)COc1cccc2sncc12
Reaction time: 4 h

Procedure:
30.0 g of 4-hydroxy-1,2-benzisothiazole are suspended in 26.0 g of 1,3-dichloro-propan-2-ol and a solution of 8.5 g of sodium hydroxide in 60 ml of water is added in the course of 4 hours at 60°-80° C. After reacting for a further four hours at the same temperature, the organic phase is taken up in methylene chloride, dried over magnesium sulfate and evaporated to dryness. The residue left (35 g) is recrystallized from methanol. The 1-(1,2-benzisothiazol-4-yloxy)-3-chloropropan-2-ol thus obtained is identical with the sample prepared as described in (a). Preparation of compounds according to the invention
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:5](O)=O.CN1CCOCC1.ClC(OCC(C)C)=O.[Br:31][C:32]1[CH:33]=[C:34]([NH2:39])[C:35]([NH2:38])=[CH:36][CH:37]=1.C(O)(=O)C>C(#N)C>[Br:31][C:32]1[CH:37]=[CH:36][C:35]2[NH:38][C:5]([C@@H:4]([NH:8][C:9](=[O:10])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:3][CH2:2][CH3:1])=[N:39][C:34]=2[CH:33]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CC(=O)O
Solvent: CC#N
Product: CCC[C@H](NC(=O)OC(C)(C)C)c1nc2cc(Br)ccc2[nH]1
Temperature: -20 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
To a solution of Boc-NVA-OH (4.5 g, 21 mmol) in acetonitrile (68 mL) and 4-methylmorpholine (2.41 mL, 21.9 mmol) cooled to −20° C. was added isobutyl chloroformate (2.7 mL, 21 mmol) dropwise. The mixture was stirred for 120 minutes at −20° C. and then 4-bromo-1,2-benzenediamine (3.87 g, 20.7 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The solvent was evaporated, redissolved in ethyl acetate, washed with water, saturated aqueous solution of sodium hydrogen carbonate, and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in acetic acid (20 mL, 400 mmol) and stirred at 70° C. for 6 hours. The acetic acid was removed in vacuo and the mixture was redissolved in ethyl acetate, washed with saturated aqueous solution of sodium hydrogen carbonate, and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was redissolved in dichloromethane, treated with activated carbon and filtered through a plug of celite. Purification by silica gel column chromatography eluting with a 0-100% ethyl acetate/hexanes gradient to afford the title compound (5.95 g, 78%) as a white solid.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:7]1(C)[CH:12]=CC(S(O)(=O)=O)=[CH:9][CH:8]=1>C(O)CCC>[C:1]([O:6][CH2:12][CH2:7][CH2:8][CH3:9])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Product: C=C(C)C(=O)OCCCC

Procedure:
Butyl methacrylate was prepared by reacting methacrylic acid and n-butyl alcohol. Butyl alcohol and methacrylic acid were mixed at the ratio of 1.2 (mole), and para-toluene sulfonic acid was added to be 0.75% (by weight) to the mixture as esterification catalyst. The mixture was charged into the reactor, and heated by steam. The reaction temperature was kept at 100° C. by adjusting the pressure in the reactor. Heating was continued until the reaction was completed by distilling all the water formed by the reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:14])[C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[O:15]1[CH2:18][C:17](=O)[CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:14])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH:17]2[CH2:18][O:15][CH2:16]2)[CH2:10][CH2:9]1
Reactant: O=C1COC1
Reactant: Fc1cncc(Cl)c1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Fc1cncc(Cl)c1N1CCN(C2COC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 1-(3-chloro-5-fluoropyridin-4-yl)piperazine (900 mg, 4.173 mmol) in THF (9.000 mL) was added 3-oxetanone (601.4 mg, 8.346 mmol). To this mixture, under N2, was added sodium triacetoxyborohydride (2.034 g, 9.598 mmol) portionwise over 5 min and the reaction mixture was stirred at RT overnight. MeOH (2 ml) was added to the flask before the mixture was concentrated in vacuo. The residue was partitioned between water (50 ml) and EtAOc (50 ml). The aqueous phase was basified to pH 7-8 with NH4OH. Combined organics washed with brine (30 ml), dried over Na2SO4, filtered and concentrated in vacuo to afford 1-(3-chloro-5-fluoro-4-pyridyl)-4-(oxetan-3-yl)piperazine as a cream solid that was used in next step without further purification. MS (ES+) 272.1.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH2:11]([O:13][C:14]([C:16]1[C:17]([CH3:40])=[C:18]2[C:23](=[CH:24][C:25]=1[CH3:26])[N:22]=[C:21]([CH2:27][OH:28])[N:20]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([F:38])([F:37])[F:36])[C:19]2=[O:39])=[O:15])[CH3:12]>N1C=CC=CC=1>[CH2:11]([O:13][C:14]([C:16]1[C:17]([CH3:40])=[C:18]2[C:23](=[CH:24][C:25]=1[CH3:26])[N:22]=[C:21]([CH2:27][O:28][C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3])[N:20]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([F:38])([F:37])[F:36])[C:19]2=[O:39])=[O:15])[CH3:12]
Reactant: CCOC(=O)c1c(C)cc2nc(CO)n(-c3ccccc3C(F)(F)F)c(=O)c2c1C
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C)cc2nc(COC(=O)Oc3ccccc3)n(-c3ccccc3C(F)(F)F)c(=O)c2c1C
Temperature: 80 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
Phenyl chloroformate (470 mg) was added to a solution of 420 mg of 6-ethoxycarbonyl-2-hydroxymethyl-5,7-dimethyl-3-[2-(trifluoromethyl)phenyl]-4(3H)-quinazolinone in 5 ml of pyridine. The reaction mixture was stirred at 80° C. for 3 hours, and the solvent was then evaporated off in vacuo. The residue was taken up with ethyl acetate, and the solution was washed successively with 1N aqueous hydrochloric acid and water, and dried over anhydrous sodium sulfate. The ethyl acetate was evaporated off to give 400 mg of crude 6-ethoxycarbonyl-5,7-dimethyl-2-(phenoxycarbonyloxymethyl)-3-[2-(trifluoromethyl)phenyl]-4(3H)-quinazolinone.
Reaction SMILES: [Li+:1].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)(=[O:13])[CH3:12].[C:19](OC(C)(C)C)(=[O:27])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>CCOCC>[C:23]([O:22][C:20](=[O:21])[C:19]([O-:27])=[CH:12][C:11]([C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)=[O:13])([CH3:26])([CH3:25])[CH3:24].[Li+:1]
Reactant: CC(C)(C)OC(=O)C(=O)OC(C)(C)C
Reactant: CC(=O)c1ccco1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C([O-])=CC(=O)c1ccco1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 83 %

Procedure:
Part A. A 1-L flame-dried flask was charged with 130 mL of LiHMDS (130 mmol; 1.0 M in THF) and 410 mL of ethyl ether. The resulting solution was cooled to −78° C. and 2-acetylfuran (14 g, 12 m mmol) was added in one portion. After 5 min, di-tert-butyl oxalate was added dropwise over 1 h as a solution in 100 mL of ether. The resulting mixture was warmed to 23° C. over a period of 3 h and was maintained at rt for 20 h. The mixture was then filtered, and the resulting beige precipitate was washed with 100 mL of ether. The filter cake was then dried in a vacuum oven for 1 h to afford lithium 1-tert-butoxy-4-(2-furyl)-1,4-dioxo-2-buten-2-olate (25 g, 83%) as a cream colored solid. 1H NMR (DMSO-d6) δ 7.75 (t, 1H), 6.96 (m, 1H), 6.56 (m, 1H), 3.34 (s, 2H), 1.46 (s, 9H).
Reaction SMILES: Br[C:2]([CH3:14])([CH3:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])=[O:4].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:13][C:2]1([CH3:14])[C:3](=[O:4])[NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:12]1
Reactant: CC(C)(Br)C(=O)Nc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)Oc2ccccc2NC1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 84.5 %

Procedure:
To a stirred solution of 2-Bromo-N-(2-hydroxy-phenyl)-2-methyl-propionamide (21.8 g, 84.4 mmol) in DMF (85 mL) at 25° C. was added potassium carbonate (23.32 g, 168.99 mmol) and stirred the reaction mixture at 80° C. for 4 h. After TLC reaction mixture was filtered through celite and diluted with ethyl acetate 500 mL and then washed with water (100 mL×3), brine (100 mL), dried over anhydrous sodium sulfate, concentrated to give 2,2-dimethyl-4H-benzo[1,4]oxazin-3-one (12.64 g) as brown solid which was purified by column chromatography to furnish 8.5 g pure compound.