Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][N:14]([CH2:27][C:28]([F:31])([F:30])[F:29])[C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)=[CH:7][CH:6]=1)=[O:4].[F:34][C:35]([Si](C)(C)C)([F:37])[F:36].[F-].[Cs+].Cl>COCCOC.O>[F:31][C:28]([F:30])([F:29])[CH2:27][N:14]([CH2:13][CH2:12][O:11][C:8]1[CH:7]=[CH:6][C:5]([C:3]([OH:4])([C:35]([F:37])([F:36])[F:34])[C:2]([F:32])([F:33])[F:1])=[CH:10][CH:9]=1)[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:16]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: N#Cc1ccc(N(CCOc2ccc(C(=O)C(F)(F)F)cc2)CC(F)(F)F)cc1C(F)(F)F
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Product: N#Cc1ccc(N(CCOc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.8 %

Procedure:
To a solution of 4-[(2-{[4-(trifluoroacetyl)phenyl]oxy}ethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (0.106 g, 0.22 mmol, example 37) and (trifluoromethyl)trimethylsilane (0.040 mL, 0.26 mmol) in dry DME at rt, under N2, was added anhydrous CsF (0.0020 g, 0.011 mmol). The mixture was stirred 3 h at rt and an additional portion of (trifluoromethyl)trimethylsilane (0.040 mL, 0.26 mmol) was added, and the mixture stirred another 2 h. 2N HCl (5 mL) was added, and the mixture was stirred for 60 h at rt. The mixture was diluted with water and the whole extracted with EtOAc (×2). Combined organics were washed (water, brine, dried over Na2SO4 and concentrated in vacuo, affording 0.051 g of the title compound as a pale yellow solid: MS (ESI) m/z 553 (M−1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][N:8]([CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:9][CH:10](O)[CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].O=S(Cl)[Cl:30]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:27])[CH2:7][N:8]([CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:9][CH:10]([Cl:30])[CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCC(O)CN(CC(=O)OC(C)(C)C)C(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCC(Cl)CN(CC(=O)OC(C)(C)C)C(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of [benzhydryl-(2-hydroxybutyl)amino]acetic acid tert-butyl ester (7.4 g, 20 mmol, 1 eq.) in dry CHCl3 (50 mL) at 0° C. was added SOCl2 (3.13 mL, 43 mmol, 2.15 eq.) dropwise. After 30 min, the solvent was removed in vacuo to afford [benzhydryl-(2-chlorobutyl)amino]acetic acid tert-butyl ester (99% crude yield), which was used without further purification. ESMS: 388.3 [M+H].
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[Li]CCCC.[F:14][C:15]([F:20])([F:19])[C:16](=[O:18])[CH3:17]>CCOCC>[Cl:8][C:5]1[N:4]=[CH:3][C:2]([C:16]([OH:18])([CH3:17])[C:15]([F:20])([F:19])[F:14])=[CH:7][N:6]=1
Reactant: CC(=O)C(F)(F)F
Reactant: Clc1ncc(Br)cn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(O)(c1cnc(Cl)nc1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 17 %

Procedure:
A 500-mL round-bottomed flask was charged with 5-bromo-2-chloropyrimidine (8.53 g, 44.1 mmol, Combi-Blocks, San Diego, Calif.) and 100 mL of ether. After cooling to −78° C., n-BuLi (2.5 M in hexanes, 27.6 mL, 44.1 mmol) was added. This mixture was stirred at −78° C. for 10 min, then 1,1,1,tri-fluoro-2-propanone (14.82 g, 132 mmol, Sigma-Aldrich, St. Louis, Mo.) was added. After stirring for an additional 10 min at −78° C., the reaction was quenched with saturated aqueous NH4Cl. The solution was extracted with EtOAc, dried (MgSO4), filtered, and concentrated. Purification via column chromatography on silica gel (0 to 85% EtOAc in hexanes) gave 2-(2-chloro-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (1.70 g) as a white solid.
Reaction SMILES: C(S[C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[N:8][CH:9]=1)C.F[C:12](F)(F)[C:13](O)=O.ClC1C=CC=C(C(OO)=O)C=1.[S:29]([O-:32])([O-])=[O:30].[Na+].[Na+]>ClCCl>[CH2:12]([S:29]([C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[N:8][CH:9]=1)(=[O:32])=[O:30])[CH3:13]
Reactant: O=S([O-])[O-]
Reactant: CCSc1ccc(N)nc1
Reactant: O=C(O)C(F)(F)F
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(N)nc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of 5-(ethylthio)pyridin-2-amine (Step A, 1.23 g, 7.96 mmol) in dichloromethane (30 mL) were added trifluoroacetic acid (1.2 mL, 15.9 mmol) and m-chloroperbenzoic acid (4.3 g, 17.5 mmol) at 0° C. The mixture was stirred at 0° C. for 2 h. Aqueous sodium sulfite (20 mL) was added. The mixture was extracted with dichloromethane (30 mL×3) and washed with aqueous sodium hydrogencarbonate (15 mL×2). The organic extracts were dried over sodium sulfate and concentrated to afford the title compound (1.43 g, 97%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=O)=[CH:4][CH:3]=1.C(O)(=O)C>[Zn].O>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]2[C:8]3[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=[O:12])[O:11]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)cc1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: O=C1OC(c2ccc(Cl)cc2)c2ccccc21
Temperature: 105 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A five-liter, 3-neck flask fitted with a reflux condensor and drying tube, an air-driven stirring blade, and thermometer and temperature controller was charged with 2-(4'-chlorobenzoyl)benzoic acid (130.3 grams; 0.5 mol), zinc dust (490.3 g; 7.5 gram-atom), glacial acetic acid (2500 milliliters (ml)), and water (500 ml). The resulting mixture was heated, with stirring, under reflux temperatures (about 105° C.) for about 2 hours. The acetic acid solution was then decanted from the zinc and poured into 4 liters of cold water and the resulting white, fluffy needles were collected by filtration and dried at 60° C. at 10 mm of pressure for 14 hours. As a result of such operations, the desired 3-(4'-chlorophenyl)phthalide compound of Formula I was obtained in a yield of about 88%. Recrystallization from ethanol gave a purified product having an m.p. of 123.5°-124° C. as compared to a literature reference (Rec. Trav. Chim., 82, 801-805 (1963)) of 122°-125° C.
Reaction SMILES: [F:1][C:2]1([F:44])[CH2:7][CH2:6][C@H:5]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([S:16]([N:19](CC3C=CC(OC)=CC=3OC)[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:18])=[O:17])=[C:11]([F:37])[CH:10]=2)[C@@H:4]([C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)[CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:44][C:2]1([F:1])[CH2:7][CH2:6][C@H:5]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([S:16]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:17])=[O:18])=[C:11]([F:37])[CH:10]=2)[C@@H:4]([C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)[CH2:3]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCC(F)(F)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CC(F)(F)CC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 85.5 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the crude 4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (150 mg, 0.236 mmol) prepared in Example 88h, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield the title compound (98 mg, 80%, 2 steps) as a colorless solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH3:13])=[CH:7][N:8]=2)[N:3]=1.C(O[C:19](=[O:30])[NH:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][OH:29])[CH2:23][CH2:22]1)(C)(C)C.[O:31]=[C:32]1[NH:37][C:36]2[CH:38]=[C:39](C(O)=O)[CH:40]=[CH:41][C:35]=2[S:34][CH2:33]1>>[CH3:13][O:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([O:29][CH2:28][CH2:27][N:24]3[CH2:23][CH2:22][CH:21]([NH:20][C:19]([C:39]4[CH:40]=[CH:41][C:35]5[S:34][CH2:33][C:32](=[O:31])[NH:37][C:36]=5[CH:38]=4)=[O:30])[CH2:26][CH2:25]3)=[N:3]2)=[N:8][CH:7]=1
Reactant: COc1cnc2ccc(Cl)nc2c1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Product: COc1cnc2ccc(OCCN3CCC(NC(=O)c4ccc5c(c4)NC(=O)CS5)CC3)nc2c1

Procedure:
The title compound is prepared as an off-white lyophilizated powder following Scheme 1 and in analogy to Example 1 using 2-chloro-7-methoxy-[1,5]naphthyridine, [1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[C:7]([NH:22][C:23]([NH:25][C:26]2[C:31]([CH:32]([CH3:34])[CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=2[CH:35]([CH3:37])[CH3:36])=[O:24])[C:6]1=[O:38])[CH2:2][CH2:3][CH3:4].Br[CH2:40][CH2:41][CH2:42][Cl:43].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:40][CH2:41][CH2:42][Cl:43])[CH:16]=2)=[C:7]([NH:22][C:23]([NH:25][C:26]2[C:27]([CH:35]([CH3:37])[CH3:36])=[CH:28][CH:29]=[CH:30][C:31]=2[CH:32]([CH3:33])[CH3:34])=[O:24])[C:6]1=[O:38])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(O)c2)c2cccnc21
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OCCCCl)c2)c2cccnc21
Reaction time: 6 h
Yield: 88.7 %

Procedure:
To a solution of N-{1-butyl-4-(3-hydroxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl}-N'-(2,6-diisopropylphenyl)urea (1000 mg, 1.95 mmol) and 1-bromo-3-chloropropane (460 mg, 2.93 mmol) in DMF (10 ml) was added potassium carbonate (673 mg, 4.88 mmol), and the mixture was stirred at 50°-60° C. for 6 hours. After allowed to stand for cooling, the mixture was poured into water, extracted with ethyl acetate, washed with water, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The residue was concentrated under reduced pressure, purified by silica gel column chromatography (ethyl acetate:hexane=50:50), and crystallized from hexane to give the title compound (1020 mg, 1.73 mmol) as a colorless powder.
Reaction SMILES: Br[C:2]1[S:6][C:5]2[CH:7]=[C:8](Br)[S:9][C:4]=2[CH:3]=1.[C:11]([Si:15]([CH3:43])([CH3:42])[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[S:27][C:26]([C:28]2[S:29][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:32]=2)=[CH:25][CH:24]=1)([CH3:14])([CH3:13])[CH3:12].[C:44](=[O:47])([O-])[O-].[K+].[K+]>C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[S:27][C:26]([C:28]2[S:29][C:30]([C:2]3[S:6][C:5]4[CH:7]=[C:8]([C:30]5[S:29][C:28]([C:26]6[S:27][C:23]([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:44][O:47][Si:15]([C:11]([CH3:12])([CH3:14])[CH3:13])([CH3:43])[CH3:42])=[CH:24][CH:25]=6)=[CH:32][CH:31]=5)[S:9][C:4]=4[CH:3]=3)=[CH:31][CH:32]=2)=[CH:25][CH:24]=1)([C:11]([CH3:14])([CH3:12])[CH3:13])([CH3:43])[CH3:42]
Reactant: CC1(C)OB(c2ccc(-c3ccc(CCCCCCO[Si](C)(C)C(C)(C)C)s3)s2)OC1(C)C
Reactant: Brc1cc2sc(Br)cc2s1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCCCc1ccc(-c2ccc(-c3cc4sc(-c5ccc(-c6ccc(CCCCCCO[Si](C)(C)C(C)(C)C)s6)s5)cc4s3)s2)s1
Reaction time: 0.33 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.05 g) was added to a solution 2,5-dibromothieno[3,2-b]thiophene (0.10 g, 0.34 mmol) in dry THF (30 ml), with stirring, under nitrogen. After 20 min, 2-{5′-[6-(tert-butyl-dimethyl-silanyloxy)-hexyl]-[2,2′]bithiophenyl-5-yl}-4,4,5,5-tetramethyl-[1,3,2}dioxaborolane (0.51 g, 1.01 mmol) and a solution of potassium carbonate (0.28 g, 2.03 mmol) in water (10 ml) were added. The resultant mixture was heated at reflux for 1.5 h. After cooling, water (100 ml) was added and the precipitate filtered off, washed with water and diethyl ether, to give a yellow solid, which was recrystallised with toluene to offer yellow crystals (0.17 g, 57%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([CH:19]([OH:28])[CH2:20][Si](OC(C)C)(C)C)=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([Cl:29])[CH:3]=1.[F-].[K+].[OH:32]O>CO.C1COCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([CH:19]([OH:28])[CH2:20][OH:32])=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([Cl:29])[CH:3]=1
Reactant: OO
Reactant: CC(C)O[Si](C)(C)CC(O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: [F-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: OCC(O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 34 %

Procedure:
To the crude 1-[6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-2-(isopropoxy-dimethyl-silanyl)-ethanol 10v in MeOH-THF (5 mL-5 mL) is added KHCO3 (54 mg, 0.54 mmol), and KF (74 mg, 1.27 mmol), and 30% aqueous H2O2 (0.20 mL) at rt. After stirring for 3.5 hours at room temperature, the reaction mixture is diluted with water, and extracted with EtOAc. The organic layer is dried over MgSO4, filtered, concentrated in vacuo, and purified by flash chromatography (8% to 10% MeOH in CH2Cl2) to give the desired product (74 mg, 34%): MS APCI (+) m/z 400, 402 (M+, Br pattern) detected; 1H NMR (400 MHz, CD3OD) δ 8.20 (s, 1H), 7.62 (broad s, 1H), 7.47 (d, 1H), 7.14 (dd, 1H), 6.30 (d, 1H), 4.96 (t, 1H), 3.64 (m, 2H); 19F NMR (376 MHz, CD3OD) −136.87 (s).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:23][CH2:22]3)[C:10]3[C:15]([O:16][C:17]=2[CH:18]=1)=[C:14]([O:19][CH3:20])[CH:13]=[CH:12][CH:11]=3)=[O:4].[OH-].[Na+].O.Cl>O1CCOCC1>[CH2:27]([N:24]1[CH2:23][CH2:22][CH:21]([N:9]2[C:8]3[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:18][C:17]=3[O:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[O:19][CH3:20])[CH2:26][CH2:25]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc2c(c1)Oc1c(OC)cccc1N2C1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc2c1Oc1cc(C(=O)O)ccc1N2C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 94 %

Procedure:
To a solution of 10-(1-benzyl-piperidin-4-yl)-6-methoxy-10H-phenoxazine-3-carboxylic acid methyl ester, 2d (270 mg, 0.7 mmol) in dioxane (15 mL) was added sodium hydroxide (31 mg, 0.77 mmol) and the mixture was heated to reflux for 4 h. The mixture was allowed to cool to rt, water (15 mL) was added, and the solution was acidified with 1N HCl to pH 2. The mixture was extracted with methylene chloride, the organic phase was separated, dried, and evaporated to yield 245 mg (94%) of title compound 10-(1-benzyl-piperidin-4-yl)-6-methoxy-10H-phenoxazine-3-carboxylic acid, 3d.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:8]2[C:9]3[CH:15]=[C:14]([CH3:16])[NH:13][C:10]=3[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1.[CH3:17][CH2:18][O:19][C:20]([CH:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]>CN(C=O)C.CCOC(C)=O.O>[CH3:3][C:4]1[N:8]2[C:9]3[CH:15]=[C:14]([CH3:16])[N:13]([CH:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:20]([O:19][CH2:18][CH3:17])=[O:21])[C:10]=3[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: Cc1cc2c(ccc3nnc(C)n32)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(c1ccccc1)n1c(C)cc2c1ccc1nnc(C)n12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (110 mg, 2.7 mmol, 60% in mineral oil) was added to a solution of 1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (0.500 g, 2.68 mmol, from Example 2, Step 5) in DMF (50 mL). After 15 minutes, a solution of ethyl-alpha-bromophenyl acetate (0.70 mL, 4.0 mmol, Aldrich) in DMF (10 mL) was added dropwise. The mixture was stirred for 15 minutes at room temperature and then was poured into pH 7 buffer and diluted with EtOAc and water. The layers were separated and the aqueous was extracted again with EtOAc. The combined organic extracts were washed with water, then brine, dried over sodium sulfate, filtered and concentrated. The product was purified by flash chromatography, eluting with a gradient from 5-10% MeOH in DCM (187 mg, 20%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=1.C([Li])CCC.[O:18]1[C:22]2[CH:23]=[CH:24][C:25]([CH:27]=[O:28])=[CH:26][C:21]=2[CH:20]=[CH:19]1.C(O)(C)C>C1COCC1.O>[O:18]1[C:22]2[CH:23]=[CH:24][C:25]([CH:27]([C:2]3[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=3)[OH:28])=[CH:26][C:21]=2[CH:20]=[CH:19]1
Reactant: CCOc1cc(Br)ccc1OC
Reactant: O=Cc1ccc2occc2c1
Agent: [Li]CCCC
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(C(O)c2ccc3occc3c2)ccc1OC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 116.3 %

Procedure:
A stirred mixture of 4-bromo-2-ethoxy-1-methoxy-benzene (1.74 g, 7.5 mmol) and dry THF (15 mL) was cooled to −78° C., evacuated and refilled with nitrogen for 10 cycles. To this clear solution was slowly added n-butyllithium (3.0 mL, 7.5 mmol) and stirred for 20 min. Then a mixture of benzofuran-5-carbaldehyde (1.0 g, 6.8 mmol) in dry THF (10 mL) was added and stirred for 1 hour at −78° C. The mixture was quenched with isopropanol (3.1 mL, 41 mmol) and added water (10 mL). The mixture was extracted with EtOAc (3×50 mL). The combined organic phases were washed with water (2×50 mL), dried over MgSO4 and concentrated to give benzofuran-5-yl-(3-ethoxy-4-methoxy-phenyl)-methanol as an oil (2.36 g, 115% yield). The product was used in the next step without further purification.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:23][CH2:22][CH2:21][C:20]2=[O:24])=[CH:15][CH:14]=1.CN(C)C1C=CC=CC=1.C(OCC)(=O)C>O1CCCC1>[O:24]=[C:20]1[CH2:21][CH2:22][CH2:23][N:19]1[C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:2](=[O:3])[O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:14][CH:15]=1
Reactant: Nc1ccc(N2CCCC2=O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CN(C)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(N2CCCC2=O)cc1)OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
4.27 g (25.03 mmol) of benzyl chloroformate are slowly added to 4 g (22.7 mmol) of 1-(4-aminophenyl)pyrrolidin-2-one and 3.6 ml (28.4 mmol) of N,N-dimethylaniline in 107 ml of tetrahydrofuran at −20° C. The mixture is stirred at −20° C. for 30 minutes and then allowed to reach room temperature. 0.5 l of ethyl acetate is added, and the organic phase is washed with 0.5 l of saturated NaCl solution. The removed organic phase is dried with MgSO4, and the solvent is evaporated in vacuo. The residue is triturated with diethyl ether and filtered off with suction. 5.2 g (73.8% of theory) of benzyl 4-(2-oxo-1-pyrrolidinyl)phenylcarbamate are obtained as pale beige crystals with a melting point of 174° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.[H-].[Na+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].Cl>CN(C=O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:3]=1
Reactant: O=[N+]([O-])c1ccc2c(Cl)n[nH]c2c1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1nc(Cl)c2ccc([N+](=O)[O-])cc21
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 56.6 %

Procedure:
3-chloro-6-nitroindazole (20 g) was dissolved in dry DMF (180cm3) and the solution cooled to 5° C. 50% sodium hydride (4.86 g) was added portionwise with stirring and cooling between 5° and 10° C. and then for an additional 15 minutes. Ethyl bromoacetate (16.91 g) was added slowly at 5° C., the reaction mixture warming to 30° C. The reaction mixture was then stirred at 20° C. for four hours. Water (lL) was added and the mixture acidified with diluted hydrochloric acid, shaken with ethyl acetate and filtered through hyflo. The organic phase was separated from the filtrate and the aqueous phase extracted (×2) with ethyl acetate. The combined organic phase was washed with water, dried (MgSO4) filtered and the solvent removed from the filtrate under vacuum. The residue was purified by flash chromatography (SiO2 ; hexane: TBME, 7:3 and then chloroform:ethyl acetate 95:5) to give ethyl 3-chloro-6-nitroindazol-1-ylacetate (16.25 g) as a pale yellow solid m.pt 109.1°-110.3° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:36][O:37][CH3:38])[C:4]([CH3:35])=[C:5]([C:26]([O:28][CH2:29][O:30][C:31](=[O:34])[CH2:32][CH3:33])=[O:27])[CH:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:7]=1[C:8]([O:10]COC(=O)CC)=[O:9]>C(OC(C)C)(C)C.O>[CH3:1][C:2]1[N:3]([CH2:36][O:37][CH3:38])[C:4]([CH3:35])=[C:5]([C:26]([O:28][CH2:29][O:30][C:31](=[O:34])[CH2:32][CH3:33])=[O:27])[C@@H:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CCC(=O)OCOC(=O)C1=C(C)N(COC)C(C)=C(C(=O)OCOC(=O)CC)C1c1cccc([N+](=O)[O-])c1
Solvent: O
Solvent: CC(C)OC(C)C
Product: CCC(=O)OCOC(=O)C1=C(C)N(COC)C(C)=C(C(=O)O)[C@@H]1c1cccc([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 69.2 %

Procedure:
In 20 ml of isopropyl ether saturated with water was dissolved 267 mg of bis(propionyloxymethyl) 1,4-dihydro -2,6-dimethyl-1-methoxymethyl-4-(3-nitrophenyl) -3,5-pyridinedicarboxylate obtained in Example 12, and 50 mg of Lipase B was added thereto, followed by stirring at 0° to 5° C. for 8 hours. Any insoluble matter was removed by filtration and washed with dichloromethane. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate/hexane=1/2) to obtain 155 mg (yield: 71%) of (S)-1,4-dihydro-2,6-dimethyl-1-methoxymethyl-4-(3-nitrophenyl)-5-propionyloxymethoxycarbonyl -3-pyridinecarboxylic acid as a pale yellow crystal.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([C@@H:14]([OH:28])[C@@H:15]([N+:25]([O-])=O)[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C@@H:10]([O:29][CH2:30][CH3:31])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>CO.[Ni](Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH:13]([C@@H:14]([OH:28])[C@@H:15]([NH2:25])[CH2:16][C:17]2[CH:18]=[C:19]([F:24])[CH:20]=[C:21]([F:23])[CH:22]=2)[CH2:12][O:11][C@@H:10]([O:29][CH2:30][CH3:31])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCO[C@H]1CN(C(=O)OC(C)(C)C)C([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)[N+](=O)[O-])CO1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCO[C@H]1CN(C(=O)OC(C)(C)C)C([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)CO1
Reaction time: 0.5 h

Procedure:
To a solution of (R)-5-[(1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-2-nitropropyl]-2-ethoxymorpholine-4-carboxylic acid tert-butyl ester (0.145 g, 0.325 mmol) in methanol (5 mL) at room temperature add nickel (II) chloride (0.063 g, 0.487 mmol) and then sodium borohydride (0.061 g, 1.62 mmol) portionwise. Stir 30 minutes, add water (˜3 mL) and concentrate. Dilute with ethyl acetate and filter through Celite®. Partition the filtrate between ethyl acetate and water. Dry the ethyl acetate layer (magnesium sulfate), filter and concentrate to give the desired compound as a white solid.