Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:32])=[C:8]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]=[C:11]([CH2:17][CH2:18][C:19]([O:21]CC)=O)[N:10]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30])[C:9]2=[O:31])=[O:5])[CH3:2].C(OC(=O)C1C(C)=C[C:43]([NH:47]C(=O)CCC(OCC)=O)=[C:39](C(O)=O)C=1C)C.ClC1C=CC=CC=1N.P(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:32])=[C:8]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]=[C:11]([CH2:17][CH2:18][C:19](=[O:21])[NH:47][CH2:43][CH3:39])[N:10]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30])[C:9]2=[O:31])=[O:5])[CH3:2]
Reactant: CCOC(=O)CCc1nc2cc(C)c(C(=O)OCC)c(C)c2c(=O)n1-c1ccccc1Cl
Reactant: CCOC(=O)CCC(=O)Nc1cc(C)c(C(=O)OCC)c(C)c1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Nc1ccccc1Cl
Solvent: Cc1ccccc1
Solvent: ClP(Cl)Cl
Product: CCNC(=O)CCc1nc2cc(C)c(C(=O)OCC)c(C)c2c(=O)n1-c1ccccc1Cl
Temperature: 130 °C

Procedure:
3-(2-Chlorophenyl)-2-(2-ethoxycarbonylethyl)-5,7-dimethyl-4-oxo-3,4-dihydroquinazoline-6-carboxylic acid ethyl ester: A stirred mixture of 4-(3-ethoxycarbonylpropionylamino)-2,6-dimethylisophthalic acid 1-ethyl ester (0.327 g, 0.89 mmol), 2-chloroaniline (0.28 mL, 2.66 mmol) and phosphorus trichloride (0.74 g, 5.4 mmol) in toluene (6 mL) is heated at 130° C. for 3 h. Upon cooling to room temperature, the reaction mixture is poured onto saturated sodium hydrogen carbonate solution and extracted with chloroform. The chloroform extracts are combined, washed with brine and dried over anhydrous MgSO4. The solvent is removed under reduced pressure and the residue is purified by flash chromatography over silica gel (initial eluent: 19:1 cyclohexane:ethyl acetate; final eluent: 7:3 cyclohexane:ethyl acetate) to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].I[CH2:13][CH2:14][O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18]>>[CH3:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([O:7][CH2:13][CH2:14][O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])=[O:6])=[CH:3][C:2]=1[O:1][CH2:13][CH2:14][O:15][Si:16]([CH:20]([CH3:21])[CH3:22])([CH:17]([CH3:19])[CH3:18])[CH:23]([CH3:24])[CH3:25]
Reactant: CC(C)[Si](OCCI)(C(C)C)C(C)C
Reactant: Cc1ccc(C(=O)O)cc1O
Product: Cc1ccc(C(=O)OCCO[Si](C(C)C)(C(C)C)C(C)C)cc1OCCO[Si](C(C)C)(C(C)C)C(C)C

Procedure:
Analogously to Example 12d, 5.0 g of 3-hydroxy-4-methylbenzoic acid and 24.3 g of (2-iodoethoxy)triisopropylsilane are reacted. The title compound is obtained as a yellowish oil. Rf=0.66 (1:4 EtOAc-heptane); Rt=6.30.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][C:10](=[O:12])[CH3:11])=[C:4]([CH3:13])[CH:3]=1.C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].C1OCCOCCOCCOCCOCCOC1.[N:44](OCCC(C)C)=O>C(Cl)(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[F:8])[N:9]([C:10](=[O:12])[CH3:11])[N:44]=[CH:13]2
Reactant: CC(C)CCON=O
Reactant: CC(=O)Nc1cc(F)c(Br)cc1C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)n1ncc2cc(Br)c(F)cc21
Temperature: 25 °C

Procedure:
A solution of N-(4-bromo-5-fluoro-2-methylphenyl)acetamide (29B, 10.00 g, 40.64 mmol) in chloroform (100 mL) was treated with acetic anhydride (11.5 mL, 122.0 mmol), potassium acetate (8.00 g, 81.5 mmol), and 18-Crown-6 (540.00 mg, 2.0430 mmol) and then with isoamyl nitrite (12.3 mL, 871 mmol) and heated at 65° C. for 12 hours. The reaction mixture was cooled to room temperature and treated with EtOAc (500 mL), washed with water, dried (MgSO4), filtered, and then concentrated in vacuo. A pale yellow solid of 1-(5-bromo-6-fluoro-1H-indazol-1-yl)ethanone (29C) precipitated out. The initial filtrate was concentrated and the residue was purified using chromatography (SiO2, EtOAc/Hexanes) to yield more of product 29C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:37])[C:13]([CH3:15])([CH3:14])[O:12][C:11]([NH:16][C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[CH2:18][CH2:19][O:20][Si](C(C)(C)C)(C)C)=[N:10][S:9]2(=[O:36])=[O:35])[CH:5]=[CH:6][CH:7]=1.Cl>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:37])[C:13]([CH3:15])([CH3:14])[O:12][C:11]([NH:16][C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[CH2:18][CH2:19][OH:20])=[N:10][S:9]2(=[O:36])=[O:35])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c2ccccc2F)=NS(=O)(=O)C1(C)c1cccc(Br)c1
Agent: Cl
Solvent: CO
Product: CC1(C)OC(N[C@@H](CCO)c2ccccc2F)=NS(=O)(=O)C1(C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 62.7 %

Procedure:
To detach the protecting group, 20 mg of [5-(3-bromophenyl)-5,6,6-trimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-1,4,3-oxathiazin-2-yl]-[(S)-3-(tert-butyldimethylsilanyloxy)-1-(2-fluorophenyl)propyl]amine were dissolved in 1 ml of methanol and, after addition of 0.05 ml of concentrated hydrochloric acid, the mixture was stirred at room temperature for 2.5 hours. The reaction solution was concentrated by rotary evaporation and the residue purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined, the acetonitrile was removed under reduced pressure, and the aqueous residue was basified with saturated aqueous sodium hydrogencarbonate solution. Subsequently, this aqueous residue was extracted with ethyl acetate, and the combined organic phases were dried over MgSO4 and concentrated by rotary evaporation. The residue was taken up again in a mixture of acetonitrile and water and lyophilized. This gave the product (10.2 mg) with a molecular weight of 499.4 g/mol (C21H24BrFN2O4S); MS (ESI): m/e=500 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15](O)=[O:16])=[C:10]3[C@@H:9]3[CH2:18][CH2:19][CH2:20][N:8]3[C:7](=[O:21])[C:6]=2[CH:22]=1.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([N:11]4[CH:10]=[CH:14][N:13]=[CH:12]4)=[O:16])=[C:10]3[C@@H:9]3[CH2:18][CH2:19][CH2:20][N:8]3[C:7](=[O:21])[C:6]=2[CH:22]=1
Reactant: O=C(O)c1ncn2c1[C@@H]1CCCN1C(=O)c1cc(F)ccc1-2
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2cc(F)ccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
14.53 g (89.6 mmol) of N,N'-carbonyldiimidazole are introduced portion wise into a suspension of 20 g (66.4 mmol) of (S)-7-fluoro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylic acid in 70 ml of N,N-dimethylformamide. The solution obtained is stirred at room temperature and at 50°, in each case for 1 hour, and is then poured into about 300 ml of water. After stirring for 20 minutes the suspension obtained is suction filtered and the residue is washed with water. After drying at 90° for 16 hours in a water-jet vacuum there is obtained 1-[[(S)-7-fluoro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl]carbonyl]imidazole of melting point 206°-207°.
Reaction SMILES: [Cl:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[C:12]2[CH:17]=[C:16](I)[C:15]([N:19]3[CH2:22][CH:21]([CH2:23][OH:24])[CH2:20]3)=[N:14][CH:13]=2)=[CH:6][CH:5]=1.[F:28][C:29]1[CH:30]=[N:31][NH:32][C:33]=1[Sn](CCCC)(CCCC)CCCC.CCOC(C)=O>CS(C)=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>[Cl:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[C:12]2[CH:17]=[C:16]([C:33]3[NH:32][N:31]=[CH:30][C:29]=3[F:28])[C:15]([N:19]3[CH2:22][CH:21]([CH2:23][OH:24])[CH2:20]3)=[N:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC(CO)C2)c(I)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1[nH]ncc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC(CO)C2)c(-c2[nH]ncc2F)c1
Temperature: 100 °C
Reaction time: 21 h

Procedure:
A mixture of N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-(hydroxymethyl)azetidin-1-yl)-5-iodonicotinamide (Stage 92.1, 200 mg, 0.392 mmol), 4-fluoro-5-(tributylstannyl)-1H-pyrazole (147 mg, 0.392 mmol), Pd(PPh3)4 (22.67 mg, 0.02 mmol) in DMSO (2 mL) was stirred at 100° C. under argon atmosphere for 21 h. The RM was treated with EtOAc, washed with sat. aq. NaHCO3 and brine dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The residue was purified by flash chromatography on silica gel, dissolved in MeOH (3 mL), filtered through a SPE PL-Thiol cartridge (StratoSphere™, 500 mg 1.5 mmol), the cartridge was washed with MeOH and the solvent was evaporated off under reduced pressure to give a residue which was further purified by preparative SFC (Column Diol, from 21% to 26% in 6 min) to give the title product as a white solid. HPLC (Condition 7) tR=5.701 min, UPLC-MS (Condition 8) tR=0.95 min, m/z=468.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.58-2.73 (m, 1H) 3.43-3.51 (m, 2H) 3.51-3.60 (m, 2H) 3.75-3.85 (m, 2H) 4.68-4.77 (m, 1H) 7.30-7.38 (m, 3H) 7.83-7.91 (m, 2H) 7.99-8.07 (m, 1H) 8.73-8.83 (m, 1H) 10.21 (s, 1H) 12.92-13.18 (m, 1H).
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:24][C:25]([OH:27])=[O:26])[C:19](=[O:28])[CH2:18]3)[S:11]([CH3:14])(=[O:13])=[O:12])[CH2:4][CH2:3]1.[Cl:29][C:30]1[CH:31]=[N+:32]([O-:55])[CH:33]=[C:34]([Cl:54])[C:35]=1[CH2:36][C@@H:37]([C:39]1[CH:44]=[CH:43][C:42]([O:45][CH:46]([F:48])[F:47])=[C:41]([O:49][CH2:50][CH:51]2[CH2:53][CH2:52]2)[CH:40]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:29][C:30]1[CH:31]=[N+:32]([O-:55])[CH:33]=[C:34]([Cl:54])[C:35]=1[CH2:36][C@@H:37]([C:39]1[CH:44]=[CH:43][C:42]([O:45][CH:46]([F:48])[F:47])=[C:41]([O:49][CH2:50][CH:51]2[CH2:53][CH2:52]2)[CH:40]=1)[O:26][C:25](=[O:27])[CH2:24][N:20]1[C:21]2[C:17](=[CH:16][C:15]([N:10]([CH2:9][CH2:8][N:5]3[CH2:6][CH2:7][O:2][CH2:3][CH2:4]3)[S:11]([CH3:14])(=[O:13])=[O:12])=[CH:23][CH:22]=2)[CH2:18][C:19]1=[O:28]
Reactant: CS(=O)(=O)N(CCN1CCOCC1)c1ccc2c(c1)CC(=O)N2CC(=O)O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CS(=O)(=O)N(CCN1CCOCC1)c1ccc2c(c1)CC(=O)N2CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 40 %

Procedure:
A mixture of 2-(5-(N-(2-morpholinoethyl)methylsulfonamido)-2-oxoindolin-1-yl)acetic acid hydrochloride (0.105 g, 0.242 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.092 g, 0.220 mmol), EDC (0.127 g, 0.660 mmol), and DMAP (0.054 g, 0.440 mmol) in DCM (15 ml) was stirred at room temperature for 24 hours. The mixture was diluted with DCM and washed with aqueous sat. NH4Cl and aqueous 5% NaHCO3; the organic phase was dried over sodium sulfate and the solvent was removed. The crude was purified by flash chromatography on silica gel column (DCM:MeOH=99:1 to 96:4) affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-(N-(2-morpholinoethyl)-methylsulfonamido)-2-oxoindolin-1-yl)acetoxy)ethyl)pyridine 1-oxide (0.070 g, 0.088 mmol, 39.8% yield, MS/ESI+ 799.46 [MH]+, [αD]=−40.88, c=0.25, MeOH). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.44 (s, 2H), 7.32 (s, 1H), 7.26 (dd, 1H), 7.19 (d, 1H), 7.11 (d, 1H), 6.97 (dd, 1H), 6.83 (d, 1H), 7.07 (t, 1H), 6.03 (dd, 1H), 4.61 (d, 1H), 4.50 (d, 1H), 3.95 (d, 2H), 3.70 (t, 2H), 3.67 (s, 2H), 3.48-3.57 (m, 4H), 3.39 (dd, 1H), 3.22 (dd, 1H), 3.07 (s, 3H), 2.30-2.43 (m, 6H), 1.14-1.34 (m, 1H), 0.50-0.69 (m, 2H), 0.25-0.46 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.[CH:12]1([C:17](Cl)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([C:17]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=2)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Nc1ccc(C(=O)O)c(O)c1
Reactant: O=C(Cl)C1CCCC1
Product: O=C(O)c1ccc(NC(=O)C2CCCC2)cc1O

Procedure:
4-Cyclopentanecarbonylamino-2-hydroxy-benzoic acid was prepared as described in Example 3 from 8 g (0.0379 mol) of 4-amino-2-hydroxy-benzoic acid (sodium salt, with 2 moles of H2O) and 5.28 g (0.0398 mol) of cyclopentanecarboxylic acid chloride.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1>CC(O)=O>[Br:1][C:9]1[CH:8]=[CH:7][C:6]([N:11]2[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]2)=[C:5]([O:4][CH3:3])[CH:10]=1
Reactant: COc1ccccc1N1CCN(C)CC1
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1cc(Br)ccc1N1CCN(C)CC1
Temperature: 25 °C

Procedure:
A bromine solution (1.24 ml, 24.2 mmol) in 9.7 ml AcOH is added dropwise to a cooled solution (ca. 5° C.) of 1-(2-Methoxy-phenyl)-4-methyl-piperazine (as obtained in preparation 71, 5 g, 24.2 mmol) in AcOH (87 ml). After complete addition, the cooling bath is removed and reaction mixture allowed to warm up to RT. The dark violet solution is concentrated in vacuo, 20 ml de-ionized water is added and the pH is adjusted basic with a 20% NaOH solution. The mixture is extracted several times with CH2Cl2 and the combined organic layers are washed with brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography on a 120 g silica gel column on a Combiflash Companion™ (Isco Inc.) apparatus (gradient CH2Cl2/CH2Cl2:EtOH:NH3 90:9:1 from 1:0=>0:1) to afford the title compound as a dark brown oil, Rt=0.767 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 285 (M+1, 79Br)+.
Reaction SMILES: [OH:1][CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=1[C:38]1[C:42]([C:43](Cl)=[O:44])=[C:41]([CH3:46])[O:40][N:39]=1>>[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=1[C:38]1[C:42]([C:43]([O:1][CH:2]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:3][CH2:4][CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:13]=3)[CH2:10][CH2:11]2)=[O:44])=[C:41]([CH3:46])[O:40][N:39]=1
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(O)c3ccccc3)CC2)c1
Product: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)OC(CCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1

Procedure:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3-[1-(4-hydroxy-4-phenylbutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazolecarbonyl chloride: Anal. Calcd for C36H39ClFN3O4+0.54CHCl3: C, 63.0; H, 5.72; N, 6.03. Found: C, 63.0; H, 5.54; N, 6.05; ESMS m/e: 632.2 (M+H)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1[N:18]=[C:17]([CH3:19])[CH:16]=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]=1[C:10](OCC)=[O:11].O.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[CH3:7][C:8]1[C:9]([CH2:10][OH:11])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[C:17]([CH3:19])[N:18]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)cc(C)nc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccccc2)c(CO)c(C)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 102.4 %

Procedure:
LiAlH4 (1 M solution in THF, 8.93 mL, 8.93 mmol) was added dropwise to a solution of ethyl 2,6-dimethyl-4-phenylnicotinate (940 mg, 3.57 mmol) in THF (38 mL) at 0° C. After stirring for 45 min, the reaction mixture was allowed to warm to room temperature and the stirring was continued for 75 min Water (0.2 mL) was added at 0° C. followed by NaOH (2 M, 0.2 mL) and water (0.2 mL). After the addition of excess EtOAc and filtration, the solvent was removed in vacuo providing (2,6-dimethyl-4-phenylpyridin-3-yl)methanol as a pale yellow gum (780 mg, >99%). ESI-MS [M+H]+=214.1.
Reaction SMILES: [Cl:1][C:2]1[C:6]2[C:7]([F:13])=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:5]=2[S:4][C:3]=1C(O)=O.[N+](=C1CCCCCCCCCC1C1CCCCCCCCCC1)=[N-]>CC(N(C)C)=O.C(OCC)C>[Cl:1][C:2]1[C:6]2[C:7]([F:13])=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:5]=2[S:4][CH:3]=1
Reactant: COc1ccc(F)c2c(Cl)c(C(=O)O)sc12
Agent: [N-]=[N+]=C1CCCCCCCCCC1C1CCCCCCCCCC1
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: COc1ccc(F)c2c(Cl)csc12
Temperature: 25 °C
Yield: 57.3 %

Procedure:
A mixture of 3-chloro-4-fluoro-7-methoxy-1-benzothiophene-2-carboxylic acid (1.09 g, 4.19 mmol) and diazobicycloundecane (DBU) (2 mL) in dimethylacetamide (15 mL) was heated in a sealed vessel in a microwave (300 W, 100%) for 1 h. After cooling to room temperature the mixture was diluted with diethyl ether (100 mL) and washed with brine (2×100 mL). The organic phase was dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography eluting silica gel with hexane:diethyl ether [10:1] to yield a white solid (520 mg, 57%); δH (300 MHz, CDCl3) 7.24 (1H, s, Ar), 7.05–6.92 (1H, m, Ar), 6.70–6.60 (1H, dd, Ar), 3.96 (3H, s, OCH3).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21](Br)[N:20]=3)[CH:17]=2)[N:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1B(O)O.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1.C(O)C>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:28]4[C:27]([F:26])=[CH:32][CH:31]=[CH:30][C:29]=4[F:33])[N:20]=3)[CH:17]=2)[N:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(-c2ccc3nccc(OCc4ccccc4)c3c2)n1
Reactant: OB(O)c1c(F)cccc1F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Fc1cccc(F)c1-c1cccc(-c2ccc3nccc(OCc4ccccc4)c3c2)n1
Yield: 74 %

Procedure:
A solution of 4-(benzyloxy)-6-(6-bromopyridin-2-yl)quinoline (1.0 equiv.), 2,6 difluorophenylboronic acid (3.0 equiv.), diisopropylethylamine (3.0 equiv) and tetrakis(triphenylphospine)palladium (0.1 equiv.) in 1:1 toluene/ethanol was heated in a microwave at 120° C. for 20 minutes. Upon cooling, the solution was partitioned between EtOAc and H2O. Upon separation, the organic layer was washed with NaCl(sat.), dried over MgSO4, concentrated and purified by silica gel chromatography (60-75 EtOAc/hexanes eluant) to yield 4-(benzyloxy)-6-(6-(2,6-difluorophenyl)pyridin-2-yl)quinoline (74%). LC/MS=425.1 (M+H), LC=3.59 min.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:26])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=2)=[CH:12][C:11]=1[N+:23]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.NN>[Pd].C(O)C>[NH2:23][C:11]1[CH:12]=[C:13]([C:16]2[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=2)[CH:14]=[CH:15][C:10]=1[O:9][CH2:8][CH:7]([OH:26])[CH2:6][NH:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NCC(O)COc1ccc(C2=NNC(=O)CC2)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)NCC(O)COc1ccc(C2=NNC(=O)CC2)cc1N

Procedure:
6-[4-(3-t-Butylamino-2-hydroxypropoxy)-3-nitrophenyl]-4,5-dihydro-3(2H)-pyridazinone was reduced over 10% palladium on charcoal with excess hydrazine hydrate in ethanol to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@@H:10]3[O:19][C@@H:9]3[C:8]=2[CH:20]=1)([O-:3])=[O:2].[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][CH2:31][C:32]1[N:33]=[N:34][N:35]([CH3:37])[N:36]=1)([CH3:23])[CH3:22]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@H:10]([OH:19])[C@@H:9]([N:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH:21]([CH3:23])[CH3:22])[CH2:31][C:32]3[N:33]=[N:34][N:35]([CH3:37])[N:36]=3)[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: CC(C)c1ccccc1NCc1nnn(C)n1
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2nnn(C)n2)c2ccccc2C(C)C)[C@H]1O
Yield: 35 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using the epoxide compound (300 mg, 1.07 mmol) obtained in step 1 of example 2 and N-(2-isopropylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=2:1), to give desired compound (192 mg, yield: 35%).
Reaction SMILES: Br.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C@H:8]2[CH2:13][CH2:12][C@@H:11]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[CH2:10][C@H:9]2[CH2:19][CH3:20])[C:4]1=[O:21].C(N(CC)CC)C.Cl[C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C:40]([F:43])([F:42])[F:41])[CH:38]=2)[N:33]=[CH:32][N:31]=1>CCO>[CH2:19]([C@@H:9]1[CH2:10][C@H:11]([N:14]([CH:16]([CH3:17])[CH3:18])[CH3:15])[CH2:12][CH2:13][C@@H:8]1[N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([C:40]([F:42])([F:43])[F:41])[CH:38]=3)[N:33]=[CH:32][N:31]=2)[C:4]1=[O:21])[CH3:20]
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Reactant: CC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Agent: Br
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Temperature: 80 °C

Procedure:
A sample of the bis-HBr salt of (S)-3-amino-1-((1S,2R,4R)-2-ethyl-4-(isopropyl(methyl)amino)cyclohexyl)pyrrolidin-2-one (147 mg) was dissolved in EtOH (5 mL) and the resulting solution was charged with triethylamine (0.55 mL) and 4-chloro-6-trifluoromethylquinazoline (183 mg) before being heated at 80° C. for 14 h. The reaction was cooled and concentrated under reduced pressure, and the residue was partitioned between diethyl ether and water. The organic phase was extracted twice with water. The combined aqueous extracts were lyophilized and the resultant powder was purified by RP-HPLC to afford (S)-1-((1S,2R,4R)-2-ethyl-4-(isopropyl(methyl)amino)-cyclohexyl)-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-2-one. MS found: (M+H)+=478.4.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].C(=O)=O.[CH3:17][C:18](C)=O.C([N-]C(C)C)(C)C.[Li+].CN1CCCN(C)C1=O.C(I)C>O1CCCC1>[CH2:17]([CH:3]([C:2]([CH3:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:1])[C:4]([OH:6])=[O:5])[CH3:18]
Reactant: CC(C)(CC(=O)O)c1ccccc1
Reactant: CC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Solvent: CCI
Product: CCC(C(=O)O)C(C)(C)c1ccccc1
Temperature: 25 °C
Yield: 30 %

Procedure:
In accordance with a modified literature procedure (Pfeffer, P. E.; Silbert, L. S.; Chirinko, J. M. J. Org. Chem. 37(3), 1972, 451-458), a solution of 3,3-dimethyl-3-phenyl propionic acid (0.47 g, 2.6 mmol, from Reference Example 22) in tetrahydrofuran (4.5 mL) is cooled to −40° C. (dry ice/acetone) while stirring under a nitrogen atmosphere. Lithium diisopropylamide (Aldrich, 2.0 M solution in tetrahydrofuran/ethylbenzene/heptane, 2.9 mL, 5.8 mmol) is added dropwise via syringe, followed by 1,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone (DMPU, 0.35 mL, 2.9 mmol). The reaction mixture is then allowed to warm to room temperature and to stir for 30 minutes before being re-cooled to 0° C. (ice water bath). Ethyl iodide (0.31 mL, 3.9 mmol) is then added neat via syringe and the reaction mixture is allowed to stir overnight while warming to room temperature. The reaction is quenched by the addition of 10% aqueous hydrochloric acid solution and extracted thrice with ethyl acetate. The combined extracts are washed twice with 10% aqueous hydrochloric acid solution and once with saturated sodium chloride solution, dried over anhydrous sodium sulfite, and concentrated under reduced pressure. The crude solid is recrystallized from hexanes to afford pure material as a white solid (0.16 g, 30%). MS (ES−): (M−H)=205.0