Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[N:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:30])=[C:24]([CH:29]=1)[C:25]([O:27][CH3:28])=[O:26].C(Cl)Cl.CO>CN(C=O)C>[F:30][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[CH:3]=[N:2]2)=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: O=c1cn[nH]c2ccccc12
Reactant: COC(=O)c1cc(CBr)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cn2ncc(=O)c3ccccc32)ccc1F
Temperature: 100 °C

Procedure:
To a solution of cinnolin-4(1H)-one in DMF (0.1 M) was added K2CO3 (1.2 eq) and methyl 5-(bromomethyl)-2-fluorobenzoate (prepared as described in US 2007/0021427 A1, 1 eq). The mixture was stirred and heated to 100° C. for 1 h. After cooling to RT the solvent was removed under reduced pressure and the residue was partitioned between DCM and H2O. The organic phase was washed with brine, dried (Na2SO4) and filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography on silicagel, using a gradient of DCM/MeOH (from 0% to 10% MeOH in 10 CV). The 2-[4-fluoro-3-(methoxycarbonyl)benzyl]cinnolin-2-ium-4-olate was eluted after the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1)[C:6](O)=[O:7].O.[NH2:19][NH2:20]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1)[C:6]([NH:19][NH2:20])=[O:7]
Reactant: COc1cc(C(=O)O)ccc1-n1cnc(C)c1
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)NN)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzoic acid (5 g) in THF (60 mL) was added N,N′-carbonyldiimidazole (6.98 g) at room temperature, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was cooled to −10° C., hydrazine monohydrate (10.44 mL) was added, and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, and water was added. The precipitated solid was collected by filtration to give the title compound (0.70 g).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[O:8][C:9]4[CH:20]=[C:19]([O:21]C)[CH:18]=[C:17]([O:23]C)[C:10]=4[C:11](=[O:16])[C:12]=3[O:13][C:14]=2[CH:15]=1.N1C(=O)CC[C@H]1C(O)=O.Cl>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[O:8][C:9]4[CH:20]=[C:19]([OH:21])[CH:18]=[C:17]([OH:23])[C:10]=4[C:11](=[O:16])[C:12]=3[O:13][C:14]=2[CH:15]=1
Reactant: COc1cc(OC)c2c(=O)c3oc4cc(OC)ccc4c3oc2c1
Agent: Cl
Agent: O=C1CC[C@@H](C(=O)O)N1
Solvent: O
Product: O=c1c2oc3cc(O)ccc3c2oc2cc(O)cc(O)c12

Procedure:
Example 33 (0.90 g, 2.8 mmol) and Pyr-HCl (5 g) were heated together at 200° C. for 2 h. The reaction was cooled and diluted with water and the resultant solid filtered off. The solid thus obtained was triturated with MeOH, filtered, and triturated with EtOAc and then CH2Cl2. The resulting pink solid was dissolved in CH3OH/EtOAc (200 mL) and silica gel added. The solution was filtered and concentrated and the resulting solid triturated with CH3OH and then CH2Cl2. The product 36 was isolated as an off-white solid (0.35 g): Mp>300° C.; 1H NMR (DMSO-d6) δ 12.71 (s, 1H), 10.88 (s, 1H), 10.71 (s, 1H), 7.85 (d, 1H, J=8.7 Hz), 7.12 (d, 1H, J=1.8 Hz), 7.0 (dd, 1H, J=8.7 Hz, 1.9 Hz), 6.56 (d, 1H, J=2.1 Hz), 6.27 (d, 1H, J=2.0 Hz); MS 283 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C([O:19][CH:20]=[C:21]([C:27](OCC)=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])C.CN(C)C=O>O>[O:19]=[C:20]1[N:3]2[CH:4]=[N:5][C:6]3[CH:7]=[CH:8][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:10][C:11]=3[C:2]2=[N:1][CH:27]=[C:21]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CS(=O)(=O)Nc1ccc2ncnc(N)c2c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c3cc(NS(C)(=O)=O)ccc3ncn2c1=O
Temperature: 155 °C
Reaction time: 2.5 h
Yield: 55 %

Procedure:
A mixture of 4-amino-6-methanesulfonamidoquinazoline (6.89 g), diethyl ethoxymethylenepropanediate (15.5 g) and N,N-dimethylformamide (55 ml) was stirred at 155° C. for 2.5 hours. The reaction mixture was cooled to ambient temperature. To the mixture was added water to give precipitates, which were separated by filtration and washed with water. To the crystals was added a mixture of methanol and chloroform (1:4) (400 ml). After stirring under heating, insoluble materials (6.95 g) were filtered off and recrystallized from N,N-dimethylformamide to give crystalline ethyl 4-oxo-10-methanesulfonamido-4H-pyrimido [1,2-c]quinazoline-3-carboxylate (5.76 g).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[Si]([O:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)(C(C)(C)C)(C)C.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([C:40]2[CH:39]=[CH:38][CH:37]=[C:36]([OH:35])[CH:41]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(B(O)O)c1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCCCc1nc(C)n(-c2cccc(O)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (5.0 g), (3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)boronic acid (9.0 g), triethylamine (10.0 mL), pyridine (5.0 mL) and molecular sieves 4 A (10.0 g) in methylene chloride (100 mL) was added copper(II) acetate (5.0 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was dissolved in tetrahydrofuran (20 mL), tetrabutylammonium fluoride (1.7 g) was added, and the mixture was stirred for 15 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.71 g, 21%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:11]([OH:14])([CH3:13])[CH3:12])[NH:8]2)=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.I[CH3:22]>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:11]([OH:14])([CH3:13])[CH3:12])[N:8]2[CH3:22])=[C:4]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[N:3]=1
Reactant: CC(C)(O)c1nc2c(N3CCOCC3)nc(Cl)nc2[nH]1
Reactant: CI
Product: Cn1c(C(C)(C)O)nc2c(N3CCOCC3)nc(Cl)nc21

Procedure:
2-(2-Chloro-6-morpholino-9H-purin-8-yl)propan-2-ol (100 mg) was treated with iodomethane via General Procedure C to give crude intermediate 2-(2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)propan-2-ol which was treated with 2-aminopyrimidine-5-boronic acid, pinacol ester via General Procedure A and purified via reverse phase HPLC to give 44 mg of 130 as a white solid. MS (Q1) 371.2 (M)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[C:3]=1[CH:12]([CH3:14])[CH3:13].C(Br)C.[Mg].[CH3:19][C:20]([CH:27]=[O:28])=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl>C1COCC1>[OH:28][CH:27]([C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[C:3]=1[CH:12]([CH3:14])[CH3:13])[C:20]([CH3:19])=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C=C(C)C=O
Reactant: COc1ccc(Br)c(C(C)C)c1OC
Agent: Cl
Agent: [Mg]
Solvent: CCBr
Solvent: C1CCOC1
Product: CCOC(=O)C=C(C)C(O)c1ccc(OC)c(OC)c1C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
Compound 7 (10.0 g, 38.6 mmol) and ethyl bromide (0.60 g, 5.5mmol) were added to magnesium turnings (1.20 g, 49.4 mg atom) in 100 mL of dry THF in a 520 mL round bottom flask equipped with a reflux condenser and magnetic stirrer. The mixture was refluxed with stirring under a static nitrogen atmosphere for 1 h. The reaction mixture was cooled to 0° C. and 7a (6.90 g, 48.5mmol) in 25 mL of dry THF at 0° C. was added. The mixture was stirred at ambient temp for 1 h and poured into 100 g of ice and 25 ml of 6M HCl. The organic layer was extracted into ether and the ether was washed with water and brine and dried over MgSO4. The ether was evaporated and the byproducts distilled bulb to bulb (120° C./1 torr) to leave 9.8 g (30.4 mmol, 79%) of 8 as a residual oil: IR 3440 (alcohol), 1722 (ester), 1655 (alkene) cm-1 ; 1H NMR δ1.31 (t, J=7.1 Hz, 3H), 1.37 (d, J=7.0 Hz, 6H), 1.99 (s, 3H), 3.40 (br s, 1H), 3.75-3.85 (m, 1H), 3.847 (s, 3H), 3.853 (s, 3H), 4.19 (q, J+7.1 Hz, 2H), 5.39 (s, 1H), 6.26 (s, 1H), 6.75 (d, J=8.6 Hz, 1H), 6.94 (d, J=7.1 Hz, 1H). Anal. (C18H26O5) C,H.
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.ClC[C:18]#[N:19]>[OH-].[Na+].C(Cl)Cl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:10][C:4]=1[S:3][CH2:2][C:18]#[N:19]
Reactant: N#CCCl
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#CCSc1cc(OC(F)(F)F)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.6 %

Procedure:
A suspension of 2-amino-6-trifluoromethoxybenzothiazole (1.8 g, 7.7 mmol) in 10 N NaOH (30 ml) is refluxed, under a current of nitrogen, for 2 hours, after which time the suspension becomes a clear solution, and to which chloroacetonitrile (0.48 ml, 7.7 mmol) in CH2Cl2 (50 ml) and tetrabutylammonium hydrogensulphate (0.26 g, 0.77 mmol) are added. The resulting reaction mixture is stirred for 18 hours at room temperature, then the organic phase is separated, washed with water and dried over Na2SO4. The solvent is evaporated and the residue chromatographed through silica, eluting with petroleum ether/AcOEt (1:1) to give the product as a dark oil (1.1 g, 58% yield). 1H-NMR (CDCl3): 3.45 (s, 2H), 4.44 (br s, 2H), 6.74 (d, J=8.8, 1H), 7.10 (m, 1H), 7.39 (m, 1H). MS (ESI): m/z 249 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:9]([O:10]C)=[CH:8][CH:7]=[C:6]([F:12])[C:3]=1[C:4]#[N:5].B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([F:12])[C:3]=1[C:4]#[N:5]
Reactant: COc1ccc(F)c(C#N)c1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1c(F)ccc(O)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,6-difluoro-3-methoxybenzonitrile (4.42 g, 26.1 mmol) was dissolved in DCM (10 mL) at 0° C. then 1 M BBr3 (52.2 mL, 52.2 mmol) was added. The reaction mixture was then warmed up to RT and stirred overnight. The reaction mixture was poured into ice water and extracted with more DCM. The organic layer was separated, dried over Na2SO4, filtered, and evaporated to dryness to yield 2,6-difluoro-3-hydroxybenzonitrile: LC-MS: M+1=156.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:32][CH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:32][CH:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Reactant: BrCC1CCOCC1
Product: Cc1nc2c(ccn2CC2CCOCC2)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 4-(bromomethyl)tetrahydro-2H-pyran. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.49-7.43 (m, 1 H), 7.20-7.11 (m, 2 H), 6.98 (t, J=8.3 Hz, 1 H), 6.45-6.39 (m, 1 H), 5.53 (d, J=4.3 Hz, 1 H), 4.51-4.41 (m, 1 H), 4.32 (t, J=5.2 Hz, 2 H), 4.24 (dd, J=7.9, 14.5 Hz, 1 H), 4.03-3.93 (m, 2 H), 3.45-3.33 (m, 2 H), 2.97-2.82 (m, 5 H), 2.29 (br. s., 1 H), 2.17-2.07 (m, 2 H), 1.64-1.55 (m, 1 H), 1.54-1.33 (m, 3 H), 1.00-0.90 (s, 9 H); LC/MS (m/z) ES+=493.38 (M+1).
Reaction SMILES: O.[OH-].[Li+].[C:4]1(/[C:10](=[N:17]/[O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)=[CH:22][CH:21]=2)/[CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.Cl>O1CCCC1.CO>[C:4]1(/[C:10](=[N:17]/[O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)=[CH:22][CH:21]=2)/[CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)CC/C(=N\OCc1ccc(OCc2ccc3ccccc3n2)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CC/C(=N\OCc1ccc(OCc2ccc3ccccc3n2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
Lithium hydroxide monohydrate (108 mg) was added to a solution of methyl E-4-phenyl-4-[4-(2-quinolinylmethoxy)benzyloxyimino]butyrate (585 mg) in tetrahydrofuran (6 ml)-water (4 ml)-methanol (4 ml) and stirred at room temperature for 2 hours. 1N hydrochloric acid (2.6 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4-phenyl-4-[4-(2-quinolinylmethoxy)benzyloxyimino]butyric acid (469 mg, yield 83%) as colorless crystals. m.p. 133-134° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C@@H](C2C=CC=CC=2)C)[C@@H:10]([C:23]([OH:25])=[O:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[OH-].[Pd+2].[OH-].CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[C@@H:10]([C:23]([OH:25])=[O:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H](N[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@@H]1C(=O)O)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@@H](C(=O)O)C1
Reaction time: 42 h
Yield: 89.3 %

Procedure:
In a dry 500-mL Paar flask charged with Palladium hydroxide (20 wt % Pd, dry basis, on carbon, 0.22 g) was added methanol (50 mL) and (3S,4R)-4-[(R)-1-Phenyl-ethylamino]-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (2.11 g, 6.05 mmol). The reaction mixture was hydrogenated at 53 psi for 42 hours with vigorous shaking. The reaction mixture was filtered through a plug of celite. The plug was washed with 20 mL of ethanol and the combined filtrates were concentrated in vacuo to give a colorless oil (1.32 g, 89%). 1H NMR (300 MHz, CDCl3), δ: 4.38 (bd, J=12, 1H), 4.16 (m, 1H), 3.30 (m, 1H), 2.70 (m, 2H), 1.90-2.40 (m, 5H), 1.45 (s, 9H). MS (ESI), m+/z: (M+H)+=245.1.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:19])=[C:4]([CH3:18])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH:7]([C:12]([O:14]C)=[O:13])[C:6]=2[C:16]=1[CH3:17]>CO.[OH-].[Na+]>[OH:1][C:2]1[C:3]([CH3:19])=[C:4]([CH3:18])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH:7]([C:12]([OH:14])=[O:13])[C:6]=2[C:16]=1[CH3:17]
Reactant: COC(=O)C1c2c(C)c(O)c(C)c(C)c2OC1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1O)C(C(=O)O)C(C)(C)O2
Yield: 77.5 %

Procedure:
Refluxing 22.36 g of the above material (see Step C) in 100 ml of methanol and 100 ml of 2N sodium hydroxide for 24 hours is followed by acidification with 120 ml of 2N hydrochloric acid, evaporation of methanol, and extraction with ethyl acetate (twice). The extract is washed with water and acidic product is extracted into a sodium bicarbonate solution, which upon acidification is reextracted with ethyl acetate. The extract is dried over sodium sulfate, filtered and evaporated. The resulting solid is recrystallized from ethyl acetate/heptane to give 16.40 g (77%) of 2,3-dihydro-5-hydroxy-2,2,4,6,7-pentamethyl-1-benzofuran-3-carboxylic acid, m.p. 161°-164° C. Elemental analysis, IR, UV, and 1H-NMR spectra confirm the structure.
Reaction SMILES: O=P(Cl)(Cl)Cl.FC(F)(F)[C:8]([O-])=[O:9].C[NH2+]CC1C=CC(C2N=CC3N4C(NC(=O)CC=3)CCC=24)=CC=1.[C:36]([C:38]1[CH:43]=[CH:42][C:41]([C:44]2[N:45]=[C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([O:54][CH3:55])=[O:53])[N:47]3[CH:56]=2)=[CH:40][CH:39]=1)#[N:37]>CN(C=O)C>[C:36]([C:38]1[CH:43]=[CH:42][C:41]([C:44]2[N:45]=[C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([O:54][CH3:55])=[O:53])[N:47]3[C:56]=2[CH:8]=[O:9])=[CH:40][CH:39]=1)#[N:37]
Reactant: COC(=O)c1cccc2nc(-c3ccc(C#N)cc3)cn12
Reactant: O=C([O-])C(F)(F)F
Agent: C[NH2+]Cc1ccc(C2=C3CCC4NC(=O)CC=C(C=N2)N34)cc1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cccc2nc(-c3ccc(C#N)cc3)c(C=O)n12
Yield: 58 %

Procedure:
POCl3 (5.0 eq.) was added to a solution of Example 1, A2 in DMF (0.1 M) at RT. The reaction mixture was heated to reflux for 1 h. After cooling down, the reaction mixture was quenched by the addition of ice water, then, the aqueous phase was separated and extracted several times with DCM. The combined organic extracts were washed with brine and dried (Na2SO4). Evaporation of the solvent gave a residue which was purified by flash column on silica using a gradient of EtOAc/Petroleum ether from 40:60 to 70:30 to yield (58%) the title compound as a yellow powder. 1H NMR (400 MHz, DMSO-d6, 300K) δ 9.80 (1H, s), 8.22-8.15 (3H, m), 8.04 (2H, d, J=8.4 Hz), 7.87 (1H, dd, J=8.8, 7.0 Hz), 7.70 (1H, d, J=7.0 Hz), 3.92 (3H, s). MS (ES+) C17H11N3O3 requires: 305, found: 306 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[N+:34]([O-])=O)=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4]>C1COCC1.Cl>[NH2:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:6]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9][N:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:16]([F:19])([F:18])[F:17])[C:7]2=[O:20])=[CH:23][CH:24]=1
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Agent: Cl
Solvent: C1CCOC1
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2N)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46.5 %

Procedure:
To a solution of 217 mg (0.438 mmole) of 5-n-butyl-2,4-dihydro-4-[(2'-nitrobiphenyl-4-yl)methyl]-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Step C) in 2.2 ml of THF stirred at 0° C. under N2 was added dropwise a solution of 692 mg (3.07 mmole) of stannous chloride dihydrate in 1.2 ml of concentrated hydrochloric acid. After 15 minutes, the ice bath was removed, and the mixture was allowed to warm to room temperature. After 2 hours at room temperature, by which time TLC (98:2 CH2Cl2 --MeOH) indicated complete disappearance of starting material, the reaction mixture was added to a mixture of 10.6 g of ice, 3 ml of 50% NaOH, and 6 ml of ether. The resulting mixture was stirred at 0° C. for about 1 hour and then extracted with 2×10 ml of ether and 1×10 ml of ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was flash chromatographed twice on silica gel (first elution with a gradient of 0.5-5% MeOH in CH2Cl2, second elution with 0.5% MeOH in CH2Cl2). Concentration of the product fractions afforded 95 mg (47%) of the title compound as a sticky foam; satisfactory purity by TLC (98:2 CH2Cl2 --MeOH) for use in the next step; mass spectrum (FAB) m/e 467 (M+1)+.
Reaction SMILES: F[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].Cl.[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>C(#N)C>[S:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[CH2:7][O:6][C:5]1[CH:17]=[CH:18][C:2]([NH:29][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([Br:23])=[CH:25][CH:26]=2)=[C:3]([N+:19]([O-:21])=[O:20])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(OCc2nc3ccccc3s2)ccc1F
Reactant: NCc1ccc(Br)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(OCc2nc3ccccc3s2)ccc1NCc1ccc(Br)cc1
Temperature: 0 °C

Procedure:
A solution of 2-((4-fluoro-3-nitrophenoxy)methyl)benzo[d]thiazole (1.9 g, 6.4 mmol), 4-bromobenzylamine hydrochloride (2.1 g, 9.6 mmol), DIPEA (5.5 mL, 31.9 mmol) and acetonitrile (10 mL) was added to a sealed tube and heated to reflux for 16 h. The reaction was cooled to 0° C. and solid product precipitated. Solids were collected by vacuum filtration, washed with cold acetonitrile (10 mL) and dried in vacuum oven at 60° C. This material was used without purification. MS (ESI): mass calcd. for C21H16BrN3O3S, 469.10; m/z found, 470.1 [M+H]+. 1H-NMR (500 MHz, DMSO-d6) δ 8.67-8.53 (m, 1H), 8.12 (d, J=7.9, 1H), 8.02 (d, J=8.1, 1H), 7.74 (d, J=3.1, 1H), 7.56-7.52 (m, 2H), 7.48-7.43 (m, 1H), 7.37-7.34 (m, 1H), 7.31 (d, J=8.4, 2H), 6.89 (d, J=9.5, 1H), 5.58 (s, 2H), 4.60 (d, J=6.2, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)[NH:11][C:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:9]2)=O)C.[Li+].[BH4-].O>CO>[OH:3][CH2:4][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)[NH:11][C:10]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[CH:9]2
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c2[nH]c(-c3ccccc3)cc2c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1cc(CO)cc2cc(-c3ccccc3)[nH]c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Phenyl-7-nitro-1H-indole-5-carboxylic acid ethyl ester (10 g, 29 mmol) prepared in Step A of Example 28 was dissolved in methanol (100 mL), and LiBH4 (1M THF solution, 4 mL) was added thereto at 0° C. After warming to room temperature, the mixture was stirred for 3 h. A small amount of water was added to quench the reaction. Methanol was removed under reduced pressure. 1N HCl was added to the residue, which was then extracted with EtOAc, dried, and used in the next reaction without further purification.