Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[C:13]([Cl:21])=[C:14]([Cl:20])[C:15]([O:18]C)=[C:16]([Cl:17])[C:11]=2[O:10][N:9]=1.Cl.N1C=CC=CC=1.Cl>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[C:13]([Cl:21])=[C:14]([Cl:20])[C:15]([OH:18])=[C:16]([Cl:17])[C:11]=2[O:10][N:9]=1
Reactant: COc1c(Cl)c(Cl)c2c(-c3ccccc3F)noc2c1Cl
Agent: Cl
Solvent: c1ccncc1
Product: Oc1c(Cl)c(Cl)c2c(-c3ccccc3F)noc2c1Cl

Procedure:
To 12.5 g of 3-(2-fluorophenyl)-6-methoxy-4,5,7-trichloro-1,2-benzisoxazole is added 80.0 g of pyridine hydrochloride. The mixture is immersed in an oil bath at 200° C. for thirty minutes with stirring. The melt is poured into one liter of iced-hydrochloric acid solution, stirred for thirty minutes, and the resultant precipitate collected and dried to yield 3-(2-fluorophenyl)-6-hydroxy-4,5,7-trichloro-1,2-benzisoxazole, mp 110° C. (dec). To 50 ml of dry dimethylformamide is added 12 g of 3-(2-fluorophenyl)-6-hydroxy-4,5,7-trichloro-1,2-benzisoxazole, 4.4 ml of ethyl bromoacetate and 20 g of potassium carbonate. The reaction is stirred at 70° C. for 2 hrs, filtered and solvent evaporated to afford an oil, which is stirred with 500 ml water for ten minutes and then extracted with ether/ethyl acetate. The organic extract is washed with water (2X), saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Evaporation of the filtrate followed by recrystallization from 95% ethanol yields ethyl{[3-(2-fluorophenyl)-4,5,7-trichloro-1,2-benzisoxazol-6-yl]oxy}acetate, mp 140°-3° C.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[CH:30]=[CH:29][C:24]3[NH:25][C:26](=[O:28])[O:27][C:23]=3[CH:22]=2)[CH2:17][CH2:16]1.[OH-].[Na+].[BH-](OC(C)=O)(OC(C)=O)O[C:35](C)=O.[Na+]>CO>[CH3:35][N:14]([CH2:13][C:3]1[N:4]=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[S:6][C:2]=1[CH3:1])[C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[CH:30]=[CH:29][C:24]3[NH:25][C:26](=[O:28])[O:27][C:23]=3[CH:22]=2)[CH2:17][CH2:16]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1sc(-c2ccccc2)nc1CN[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1sc(-c2ccccc2)nc1CN(C)[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1
Reaction time: 3 h

Procedure:
A mixture of trans-6-{4-[(5-methyl-2-phenyl-thiazol-4-ylmethyl)-amino]-cyclohexyl}-3H-benzoxazol-2-one of formula 42 (510 mg, 1.12 mmol), 2N NaOH (1 mL), and p-formaldehyde (168 mg, 5.60 mmol) in MeOH (10 mL) was stirred for 3 hours, NaBH(OAc)3 (332 mg, 1,56 mmol) was added, and the mixture was stirred overnight. The reaction was quenched by addition of MeOH. Concentration under reduced pressure followed by purification by flash chromatography (silica gel, 95:5:1 CH2Cl2:MeOH:NH4OH) gave trans-6-{4-[methyl-(5-methyl-2-phenyl-thiazol-4-ylmethyl)-amino]-cyclohexyl}-3H-benzoxazol-2-one (43) (345 mg, 71%), as a white solid: mp 246-248° C.; IR (KBr): 2927, 1773 cm−1: 1H NMR (500 MHz, DMSO-d6) δ 7.88 (dd, J=8, 2 Hz, 1H), 7.44 (m, 5H), 7.15 (s, 1H), 6.98 (m, 1H), 3.75 (s, 2H), 2.53 (m, 1H), 2.48 (m, 1H), 2.48 (s, 3H), 2.24 (s, 3H), 1.86 (m, 4H), 1.47 (m, 4H); CI-MS (methane) (m/z): 434 [M+H]+; HRMS-API (m/z): [M+H]+ calcd for C25H27N3O2S, 434.1902; found, 434.1903; HPLC: method A, 12.46 minutes (99.0%); method B, 14.05 minutes (98.7%); Anal. Calcd for C25H27N3O2S.0.25H2O: C, 68.54; H, 6.33; N, 9.59. Found: C, 68.21; H, 6.07; N, 9.59.
Reaction SMILES: [CH2:1]([C:5]1[NH:10][C:9](=[O:11])[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=1)[CH2:2][CH2:3][CH3:4].[F:16][C:17]1[CH:24]=[C:23]([I:25])[CH:22]=[CH:21][C:18]=1[CH2:19]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC>[CH2:1]([C:5]1[N:10]([CH2:19][C:18]2[CH:21]=[CH:22][C:23]([I:25])=[CH:24][C:17]=2[F:16])[C:9](=[O:11])[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Fc1cc(I)ccc1CBr
Reactant: CCCCc1cc(C(=O)OC)cc(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CCCCc1cc(C(=O)OC)cc(=O)n1Cc1ccc(I)cc1F

Procedure:
A solution of 2.09 g (10 mmol) of the compound from Example VIII, 3.14 g (10 mmol) of 2-fluoro-4-iodobenzyl bromide and 2.11 g (11 mmol) of caesium carbonate in 40 ml of DME is stirred at 20° C. under argon for 16 hours. The solvent is then removed in vacuo, the residue is taken up in methylene chloride/water, the aqueous phase is extracted once with methylene chloride and the combined organic phases are dried over sodium sulphate and concentrated. The residue is purified on silica gel using petroleum ether/ethyl acetate (5:1 and 3:1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[CH3:16][N:17]([CH2:19][C@@H:20]1[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]1)[CH3:18]>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:26][C@H:23]1[CH2:24][CH2:25][C@@H:20]([CH2:19][N:17]([CH3:18])[CH3:16])[CH2:21][CH2:22]1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: CN(C)C[C@H]1CC[C@@H](N)CC1
Product: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@@H](CN(C)C)CC1

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (500 mg, 2.1 mmol) was reacted with cis-4-[(dimethylamino)methyl]cyclohexanamine (300 mg, 2.0 mmol) to afford the desired product (400 mg, 55%) as a yellow solid: ESI MS m/z 361 [M+H]+;
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=C[CH:7]=[CH:6][C:3]=1C=O.[CH3:11][O:12][C:13]([O:16][CH3:17])(C)[CH3:14]>>[CH3:11][O:12][CH:13]([O:16][CH3:17])[C:14]1[CH:7]=[CH:6][CH:3]=[C:2]([F:1])[C:9]=1[F:10]
Reactant: COC(C)(C)OC
Reactant: O=Cc1cccc(F)c1F
Product: COC(OC)c1cccc(F)c1F

Procedure:
The title compound b.p. 58°-62° C. (1 mm Hg) was prepared from 2,3-difluorobenzaldehyde and 2,2-dimethoxypropane by an analogous procedure to that described in Example X19.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:29][O:30][C:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)=[O:32]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH3:29][O:30][C:31](=[O:32])[C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)[CH:38]=1
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: COC(=O)c1cccc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)c1

Procedure:
In analogy to Example 5, 6-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 56, step 4) was reacted with 3-methoxycarbonyl-phenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a white solid. MS (m/e, ISP neg. ion)=548.2 [M−H+]
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][N:8]1[C:20]2[CH:19]=[CH:18][C:17]([CH:21]=O)=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2.[Cl-:23].[OH:24][CH2:25][CH2:26][N+:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1.N1CCCCC1>C(O)C>[Cl-:23].[OH:24][CH2:25][CH2:26][N+:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:21]/[C:17]2[CH:18]=[CH:19][C:20]3[N:8]([CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:9]4[C:14]([C:15]=3[CH:16]=2)=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:29][CH:28]=1
Reactant: COCCOCCn1c2ccccc2c2cc(C=O)ccc21
Reactant: Cc1cc[n+](CCO)cc1
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCNCC1
Product: COCCOCCn1c2ccccc2c2cc(/C=C/c3cc[n+](CCO)cc3)ccc21
Temperature: 25 °C
Yield: 53 %

Procedure:
A solution mixture of 3a (0.13 g, 0.75 mmol), 9 (0.27 g, 0.9 mmol) and piperidine (0.1 mL) in ethanol (30 mL) was heated to reflux overnight. After cooling down to room temperature, the organic solvent was removed by rotary evaporation. The residue was purified by recrystallization from methanol affording SPOH (0.18 g) as pale red solid in 53% yield. 1H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J=6.8 Hz, 2H), 8.55 (s, 1H), 8.19 (m, 4H), 7.84 (d, J=8 Hz, 1H), 7.65 (m, 2H), 7.49 (m, 2H), 7.25 (t, J=7.2 Hz, 1H), 5.66 (s, 1H), 4.57 (m, 4H), 3.79 (m, 4H), 3.43 (m, 2H), 3.27 (m, 2H), 3.08 (s, 3H). 13C NMR (400 MHz, DMSO-d6) δ 153.4, 144.4, 142.4, 141.7, 140.8, 126.4, 126.3, 126.2, 122.7, 122.6, 122.1, 121.1, 120.3, 120.0, 119.7, 110.4, 110.2, 71.2, 69.8, 68.8, 61.6, 600.1, 58.1, 42.8. HRMS (MALDI-TOF) m/z Calcd for C26H29N2O3 417.2172 Found 417.2184 [M+].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[Na+].[Na+].O.[C:18]1(B2OC(C)(C)C(C)(C)O2)[CH2:22][CH2:21][CH2:20][CH:19]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[C:18]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:22][CH2:21][CH2:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1ccccc1C1=CCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
To a mixture of 1-chloro-2-nitrobenzene (0.5 g, 3.2 mmol) and sodium carbonate (0.34 g, 3.2 mmol) in a 100 mL roundbottom flask equipped with a magnetic stir bar and nitrogen inlet were added water (3.2 mL), dioxane (13 mL) and 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.77 mL, 3.8 mmol). The reaction flask was evacuated and purged with nitrogen (2×) prior to the addition of bis(triphenylphosphine)palladium(II) chloride (0.18 g, 0.25 mmol), and then evacuated and purged (3×) following the addition of the catalyst. The reaction was heated to 80° C. and stirred overnight. The reaction was cooled and filtered through a pad of Celite® which was subsequently washed with water and ethyl acetate. The phases were separated and the organic phase was dried by passing it through a phase separator cartridge and concentrated. The residue was purified by flash column chromatography providing the title compound (0.56 g, 3.0 mmol, 93% yield) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.78-7.71 (m, 1H), 7.54-7.47 (m, 1H), 7.40-7.32 (m, 2H), 5.86-5.82 (m, 1H), 2.63-2.55 (m, 2H), 2.55-2.47 (m, 2H), 2.09-1.98 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 148.77, 139.96, 133.58, 132.08, 130.87, 130.52, 127.55, 123.70, 35.31, 33.49, 24.05; ESIMS m/z 190 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][CH:13]3[CH2:15][CH2:14]3)[C:7](=[O:16])[C@H:6]3[CH2:17][O:18][CH:19]([CH3:21])[CH2:20][N:5]3[C:4]=2[N:3]=1.IC.[CH3:24]C([O-])(C)C.[Na+]>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][CH:13]3[CH2:14][CH2:15]3)[C:7](=[O:16])[C@@:6]3([CH3:24])[CH2:17][O:18][CH:19]([CH3:21])[CH2:20][N:5]3[C:4]=2[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: CC1CN2c3nc(Cl)ncc3N(CC3CC3)C(=O)[C@H]2CO1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CI
Product: CC1CN2c3nc(Cl)ncc3N(CC3CC3)C(=O)[C@@]2(C)CO1
Temperature: 0 °C
Reaction time: 14 h

Procedure:
To (R)-2-chloro-5-(cyclopropylmethyl)-9-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (124 mg, crude) was added iodomethane (0.25 mL, 4 mmol) and DMSO (2 mL). The mixture was cooled to 0° C. and then −78° C. and sodium 2-methylpropan-2-olate (0.154 g, 1.6 mmol) was added, followed by more DMSO (0.7 mL). The cooling bath was removed and the mixture was stirred at room temperature for 14 hours and then diluted with EtOAc and water, extracted with EtOAc and dried over Na2SO4. Solvent was removed to give crude (R)-2-chloro-5-(cyclopropylmethyl)-6a,9-dimethyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one. MS [M+H] found 323.3.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH2:18]([NH:20][CH2:21][CH:22]([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])[CH3:19].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:18]([N:20]([CH2:21][CH:22]([O:23][CH2:24][CH3:25])[O:26][CH2:27][CH3:28])[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16])[CH3:19]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Reactant: CCNCC(OCC)OCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(CN(CC)c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-])OCC

Procedure:
4-Chloro-3,5-dinitrobenzotrifluoride (5.4 grams; 0.02 mole) dissolved in toluene (50 ml) and a solution of N-ethyl-N-(2,2-diethoxyethyl)amine (3.2 grams; 0.02 mole) and triethylamine (2.02 grams; 0.02 mole in toluene (50 ml) were charged into a glass reaction vessel equipped with stirrer, thermometer and reflux condenser. The mixture was heated at reflux overnight resulting in the formation of a precipitate. The reaction mixture was then filtered and the filtrate was washed with water, dried and stripped of solvent to yield the desired product N-ethyl-N-(2,2-diethoxyethyl)-2,6-dinitro-4-trifluoromethylaniline.
Reaction SMILES: C([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:50]2[N:51]=[C:52]([NH:55]C(OC(C)(C)C)=O)[S:53][CH:54]=2)\[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([OH:34])(=[O:33])=[O:32])[C@@H:27]2[CH2:35][N:36]2[CH:40]=[C:39]([CH2:41][NH:42]C(OC(C)(C)C)=O)[N:38]=[N:37]2)=[O:24])[CH2:19][CH2:18]1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:42][CH2:41][C:39]1[N:38]=[N:37][N:36]([CH2:35][C@@H:27]2[C@H:26]([NH:25][C:23](=[O:24])/[C:22](=[N:21]\[O:20][C:17]3([C:15]([OH:16])=[O:14])[CH2:19][CH2:18]3)/[C:50]3[N:51]=[C:52]([NH2:55])[S:53][CH:54]=3)[C:29](=[O:30])[N:28]2[S:31]([OH:34])(=[O:33])=[O:32])[CH:40]=1
Reactant: CC(C)(C)OC(=O)NCc1cn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CC3)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)nn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1cn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)nn1
Temperature: 0 °C
Reaction time: 3 h
Yield: 13.6 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-(((tert-butoxycarbonyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-4-oxoazetidine-1-sulfonic acid (1.74 g, 1.94 mmol), DCM (19.4 mL) and TFA (8.95 mL, 116 mmol). After 3 h at rt, it was cooled to 0° C. and more TFA (200 μL, 2.6 mmol) was added whereupon it was allowed to warm to rt. After another 1 h at rt, it was cooled to 0° C. and more TFA (200 μL, 2.6 mmol) was added, again allowing to warm to rt. After an additional 1 h at rt it was diluted with DCM and concentrated in vacuo. Half of the crude residue was purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (140 mg, ca 23%) as a white powder. LCMS: Rt=0.27 min, m/z=530.1 (M+1) Method 2m_acidic; 1H NMR (400 MHz, D2O) δ 8.07 (s, 1H), 7.08-6.99 (m, 1H) 5.42-5.31 (m, 1H), 4.88-4.74 (m, 2H assumed; partially obscured by solvent residual peak), 4.74-4.68 (m, 1H), 4.20 (s, 2H), 1.36-1.23 (m, 2H), 1.23-1.07 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:13])[CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:14]([NH2:16])=O>O>[CH3:12][N:11]([CH3:13])[C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:14][NH:16][C:4]2=[O:6]
Reactant: CN(C)c1ccc(N)c(C(=O)O)c1
Reactant: NC=O
Solvent: O
Product: CN(C)c1ccc2nc[nH]c(=O)c2c1
Temperature: 25 °C

Procedure:
A mixture of 14.6 g. of 2-amino-5-dimethylaminobenzoic acid and 75 ml. of formamide is refluxed for 40 minutes, cooled to room temperature, 100 ml. of water added, the crystals broken up and recovered by filtering. After washing several times with water, the solids are dried to obtain 6-dimethylamino-quinazolin-4(3H)one, m.p. 233°-236° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([OH:30])[C:11]1[CH:29]=[CH:28][C:14]([O:15][C:16]2[C:21]([C:22]3[CH2:26][CH2:25][CH:24]([OH:27])[CH:23]=3)=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:13][CH:12]=1.[H][H]>O1CCCC1.[Pd]>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([OH:30])[C:11]1[CH:29]=[CH:28][C:14]([O:15][C:16]2[C:21]([CH:22]3[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23]3)=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:13][CH:12]=1
Reactant: OC1C=C(c2cccnc2Oc2ccc(C(O)c3nc4ccccc4[nH]3)cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: OC1CCC(c2cccnc2Oc2ccc(C(O)c3nc4ccccc4[nH]3)cc2)C1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
A solution of 3-(2-(4-((1H-benzo[d]imidazol-2-yl)(hydroxy)methyl)phenoxy)pyridin-3-yl)cyclopent-2-enol (780 mg, 1.953 mmol) in Tetrahydrofuran (50 mL) was treated with palladium, 10% wt. on activated carbon (208 mg, 0.195 mmol) under nitrogen. The reaction flask was equipped with a hydrogen balloon and cycled through vacuum-hydrogen cycles (3×). The reaction was heated to 40° C. under hydrogen. After 5 h, the reaction was cooled to 23° C., and filtered through celite. The filter cake was washed with tetrahydrofuran (200 mL), the filtrates combined and concentrated, affording the product as a white solid. MS (ESI, pos. ion) m/z: 402.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:7][C:6](=[O:8])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:18]=O)[O:16][CH:17]=3)=[CH:12][C:3]1=2.Cl.[NH2:22][OH:23].C([O-])(=O)C.[Na+]>C(O)C>[CH3:1][C:2]1([CH3:20])[C:3]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[N:22][OH:23])[O:16][CH:17]=3)[CH:10]=[CH:9][C:4]=2[NH:5][C:6](=[O:8])[O:7]1
Reactant: NO
Reactant: CC1(C)OC(=O)Nc2ccc(-c3coc(C=O)c3)cc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC1(C)OC(=O)Nc2ccc(-c3coc(C=NO)c3)cc21

Procedure:
A mixture of 4-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-furan-2-carbaldehyde (2.7 g, 10 mmol), hydroxylamine hydrochloride (0.75 g, mmol) and sodium acetate (0.87 g, 10.6 mmol) was heated at reflux in 80% ethanol (25 mL) for 2 hours. The title compound crystallized from the cooled reaction mixture as tan crystals (1.5 g, 52.4%): mp 236-238° C. 1H NMR (DMSO-d6) δ 11.97 (s, 1H), 10.26 (s, 1H), 8.2 (s, 1H), 7.63 (s, 1H), 7.56-7.52 (m, 3H), 6.91-6.88 (d, 1 H, J=8.1 Hz), 1.66 (s, 6H). MS ESI m/z 285 [M−H]−. Anal. Calcd. For C15H14N2O4: C, 62.93; H, 4.93; N, 9.79. Found C, 62.77; H, 5.00; N, 9.79.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:35][C@H:36]([OH:43])[C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25]C)=[O:24])=[C:19]([O:27][CH:28]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH2:35][C@H:36]([OH:43])[C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[C:19]([O:27][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)[CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(-c2ccc(CCN(C[C@H](O)c3cccnc3)C(=O)OC(C)(C)C)cc2)cc1OC1CCCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(C(=O)O)c(OC3CCCCCC3)c2)cc1)C[C@H](O)c1cccnc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.5 %

Procedure:
To a solution of methyl 4′-[2-[(tert-butoxycarbonyl)-[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-3-(cycloheptyloxy)-4-biphenylcarboxylate (813 mg) in methanol (8.1 ml) and tetrahydrofuran (2.4 ml) was added 1N sodium hydroxide (4.14 ml) and the mixture was stirred at room temperature for 24 hours. The mixture was quenched by the addition of 1N hydrochloric acid (4.14 ml) and the solvent was removed by evaporation. The residue was chromatographed on silica gel (eluent: hexane/ethyl acetate) to give 4′-[2-[(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-3-(cycloheptyloxy)-4-biphenylcarboxylic acid (575 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:13])[C@H:10]([CH3:12])O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:14]([O:21][CH2:22][C@@H:23]1[C@@H:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][NH:25][CH2:24]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>>[Si:14]([O:21][CH2:22][C@@H:23]1[C@@H:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][N:25]([C@H:10]([CH3:12])[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:13])[CH2:24]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1ccccc1
Reactant: C[C@H](O)C(=O)OCc1ccccc1
Product: C[C@H](C(=O)OCc1ccccc1)N1C[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](c2ccccc2)C1
Yield: 66.3 %

Procedure:
The title compound was prepared from 242 mg (1.3 mmol) of (S)-lactic acid, benzyl ester (from EXAMPLE 7, Step A) and 310 mg (1.0 mmol) of 3-(R)-(t-butyldimethylsilyloxymethyl)-4-(S)-phenylpyrrolidine (from EXAMPLE 1, Step E) using a procedure analogous to that described in EXAMPLE 1, Step G to provide 301 mg (62%) of the title compound: RF: 0.47 (4:1 v/v hexanes/EtOAc). 1H NMR (300 MHz) δ 0.0 (s, 6H), 0.85 (s, 9H), 1.41 (d, J=6.0 Hz, 3H), 2.41-3.62 (m, 9H), 5.17 (s, 2H), 7.16-7.38 (m, 10H).
Reaction SMILES: [C-:1]#[N:2].[K+].[CH3:4][S:5]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH2:19]O)=[C:9]1[CH3:21])(=[O:7])=[O:6]>CS(C)=O.O1CCCC1>[CH3:4][S:5]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH2:19][C:1]#[N:2])=[C:9]1[CH3:21])(=[O:7])=[O:6]
Reactant: [C-]#N
Reactant: COc1ccc2c(c1)c(CO)c(C)n2S(C)(=O)=O
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(CC#N)c(C)n2S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of potassium cyanide (3.0 g, 46.1 mmol) in methyl sulfoxide (16 ml) and tetrahydrofuran (4 ml) at 0° C. was added a solution of (1-methanesulfonyl-5-methoxy-2-methyl-1H-indol-3-yl)-methanol (0.26 g,) in tetrahydrofuran (20 ml) at 0° C. The reaction mixture was stirred at room temperature for 8 hours and then kept at 4° C. for 72 hours. The mixture was partitioned between ethyl acetate and water, and the organic extract was washed with brine, dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel eluting with 50 to 70% ethyl acetate in hexane) to give (1-methanesulfonyl-5-methoxy-2-methyl-1H-indol-3-yl)-acetonitrile as a white solid, (0.2 g, 13% in 2 steps). 1H NMR (CDCl3) δ: 2.58 (s, 3H), 3.03 (s, 3H), 3.71 (s, 2H), 3.88 (s, 3H), 6.93-6.99 (m, 2H), 7.91 (dd, 1H, J=8.9 Hz, 0.6 Hz).
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][CH2:10][NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>O1CCCC1>[O:13]=[C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:12][CH2:11][CH2:10][N:9]1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: O=C1NCCCC1(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of the product of Example 1C (2.51 g, 10.00 mmol) in tetrahydrofuran (100 mL) was added potassium tert-butoxide (1.35 g, 12.00 mmol) under nitrogen followed by ethyl 2-bromoacetate (1.22 mL, 11.00 mmol). The reaction mixture was heated to 80° C. and stirred overnight. The reaction mixture was cooled to room temperature, concentrated and then diluted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (20:80) gave the title compound. MS (DCI+) m/z 338 (M+H)+.