Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][O:11][C:12]=2[CH3:13])[N:7]=1.[CH3:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][OH:35])=[CH:32][CH:31]=1>CN(C=O)C>[CH3:13][C:12]1[O:11][N:10]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]=1[C:6]1[N:7]=[C:3]([CH2:2][O:35][CH2:34][C:33]2[CH:36]=[CH:37][C:30]([CH3:29])=[CH:31][CH:32]=2)[N:4]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:5]=1
Reactant: Cc1ccc(CO)cc1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(CCl)n1
Solvent: CN(C)C=O
Product: Cc1ccc(COCc2nc(-c3c(-c4ccccc4)noc3C)cn2-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.6 %

Procedure:
A solution of 4-[2-chloromethyl-1-(4-nitro-phenyl)-1H-imidazol-4-yl]-5-methyl-3-phenyl-isoxazole (50 mg, 0.13 mmol) in DMF (0.5 mL) was added to a suspension on NaH (55% in oil, 5.5 mg, 0.13 mmol) in DMF (0.5 mL) containing 4-methylbenzyl alcohol (15.5 mg, 0.13 mmol) in DMF (0.5 mL) and the resulting mixture stirred at room temperature for 2 h. The mixture was then poured onto water and extracted with ethyl acetate. The combined organic layers were then washed with brine and water and then dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 80:20) afforded the title compound (11.6 mg, 19%) which was obtained as a yellow gum. MS: m/e=481.3 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:11]2[N:6]([C:7]3[CH:15]=[CH:14][C:13]([N:16]4[CH:20]=[CH:19][O:18][C:17]4=[O:21])=[CH:12][C:8]=3[O:9][CH2:10]2)[C:5](=[O:22])[O:4]1.[Cl:23][C:24]1[S:28][C:27]([C:29](O)=[O:30])=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[S:28][C:27]([C:29]([NH:1][CH2:2][C@H:3]2[C@H:11]3[N:6]([C:7]4[CH:15]=[CH:14][C:13]([N:16]5[CH:20]=[CH:19][O:18][C:17]5=[O:21])=[CH:12][C:8]=4[O:9][CH2:10]3)[C:5](=[O:22])[O:4]2)=[O:30])=[CH:26][CH:25]=1
Reactant: NC[C@@H]1OC(=O)N2c3ccc(-n4ccoc4=O)cc3OC[C@@H]12
Reactant: O=C(O)c1ccc(Cl)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC[C@@H]1OC(=O)N2c3ccc(-n4ccoc4=O)cc3OC[C@@H]12)c1ccc(Cl)s1
Yield: 76.9 %

Procedure:
Using compound (3S,3aS)-3-(aminomethyl)-7-(2-oxooxazol-3-yl)-3a,4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-1 (3H)-one, 5-chlorothiophene-2-carboxylic acid (0.12 g, 0.737 mmol), HATU (0.38 g, 0.982 mmol), and Et3N (0.15 g, 1.473 mmol) as starting materials, DCM (10 ml) and DMF (2 ml) as a mixed solvent, preparation following the method as described in Example 11 (g) afforded white solid 0.17 g, yield 76.9%.
Reaction SMILES: [CH3:1][C:2]([CH3:37])([CH3:36])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:13]=2[O:25][CH3:26])[CH:7]=[CH:6][C:5]=1[C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[F:35]>C1COCC1.C(OCC)(=O)C.[Pd]>[CH3:36][C:2]([CH3:1])([CH3:37])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:13]=2[O:25][CH3:26])[CH:7]=[CH:6][C:5]=1[C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[F:35]
Reactant: CCOC(=O)/C=C/c1ncnc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1OC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ncnc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a solution of ethyl (2E)-3-(6-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-5-methoxypyrimidin-4-yl)acrylate (1.13 g) in THF (10 mL) and ethyl acetate (10 mL) was added 10% palladium-activated carbon (113 mg) and, under a hydrogen atmosphere, the mixture was stirred at room temperature for 2 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (1.13 g) as a pale-yellow solid. This compound was used for the next step without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].[CH2:6]([O:13][C:14]([NH:16][C@@H:17]([CH3:21])[C:18]([OH:20])=O)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>[OH-].[Na+].C(#N)C>[CH3:2][O:3][N:4]([CH3:5])[C:18](=[O:20])[C@@H:17]([NH:16][C:14](=[O:15])[O:13][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:21]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CNOC
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CC#N
Product: CON(C)C(=O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.1 %

Procedure:
To a solution of N-methoxy-N-methylamine hydrochloride 21.95 g (225 mmol) in 1N sodium hydroxide 225 ml, a solution of (S)-2-(benzyloxycarbonylamino)propanoic acid 33.48 g (150 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride 62.26 g (225 mmol) in acetonitrile 225 ml was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate 600 ml and washed with water 300 ml and brine 300 ml. The organic phase was dried over magnesium sulfate and filtered and the mother solution was concentrated in vacuo to obtain the title compound 42 g (93%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][CH2:22]Cl)[CH:14]=3)=[CH:11][C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][CH2:22][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:14]=3)=[CH:11][C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1CCNC1
Reactant: CCOC(=O)c1cc(-c2cccc(OCCCCl)c2)n(-c2cccc(Cl)c2)n1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2cccc(OCCCN3CCCC3)c2)n(-c2cccc(Cl)c2)n1
Yield: 40.3 %

Procedure:
41.5 mg (0.10 mmol) of the compound of Example 68A and 83 μl (0.99 mmol) of pyrrolidine in 3 ml of ethanol are stirred at 80° C. overnight. The reaction mixture is subsequently purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). 18.3 mg of the title compound are obtained.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][C:7]1[N:11]=[C:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][N:8]=1)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCO>[C:13]1([CH2:12][C:10]2[O:9][N:8]=[C:7]([CH2:6][CH2:5][CH:4]=[O:3])[N:11]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(CCc1noc(Cc2ccccc2)n1)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: O=CCCc1noc(Cc2ccccc2)n1
Yield: 89.9 %

Procedure:
Crude 3-[3,3-bis(ethyloxy)propyl]-5-(phenylmethyl)-1,2,4-oxadiazole (5.63 g, 19.4 mmol) in EtOH (75 ml) was stirred with p-toluenesulphonic acid (0.738 g, 3.9 mmol) for 21 h and the mixture partitioned between EtOAc and water. The organics were isolated washed with water and brine, dried and concentrated to a red oil. This material contained significant amounts of acetal, therefore the oil was dissolved in THF (15 ml) and treated with 2M HCl solution for 2 h then partitioned between EtOAc and water. The organics were isolated washed with brine, dried and concentrated to yield 3-[5-(phenylmethyl)-1,2,4-oxadiazol-3-yl]propanal as a red/brown oil (3.77 g) which was used crude in the next stage.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH2:22][C:23](=[O:39])[NH:24][C:25]4[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[C:29]([N:36]([CH3:38])[CH3:37])=[CH:28][C:26]=4[N:27]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH3:37][N:36]([CH3:38])[C:29]1[C:30]([C:32]([F:35])([F:33])[F:34])=[CH:31][C:25]2[NH:24][C:23](=[O:39])[CH2:22][C:21]([C:17]3[CH:16]=[C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:10]=4)[CH:20]=[CH:19][CH:18]=3)=[N:27][C:26]=2[CH:28]=1
Reactant: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c1)=N2
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccc(S(N)(=O)=O)c3)c1)=N2

Procedure:
) The title compound was prepared from the above described 3′-(8-dimethylamino-4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-biphenyl-3-sulfonic acid tert-butylamide (130 mg) and TFA (3 mL) according to the general procedure I step 2. Obtained as a light yellow solid (40 mg, 16%). MS (ISN) 501.4 [(M−H)−]; mp 258° C. (dec).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:17]2[C:11]([CH2:12][C:13](=[O:35])[N:14]([CH2:22][C:23]([N:25]([CH:32]([CH3:34])[CH3:33])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:24])[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=32)=[N:10][N:9]=1.[NH:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]([CH:45]=O)=[CH:37]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:17]2[C:11]([CH:12]([CH2:45][C:38]3[C:39]4[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=4)[NH:36][CH:37]=3)[C:13](=[O:35])[N:14]([CH2:22][C:23]([N:25]([CH:32]([CH3:33])[CH3:34])[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:24])[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=32)=[N:10][N:9]=1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: CC(C)N(C(=O)CN1C(=O)Cc2nnc(-c3ccccc3F)n2-c2ccccc21)c1ccccc1
Product: CC(C)N(C(=O)CN1C(=O)C(Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3F)n2-c2ccccc21)c1ccccc1

Procedure:
Following the procedure described for Example 6(A), Step A; 2-(1-(2-fluorophenyl)-5-oxo-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-isopropyl-N-phenyl-acetamide (Preparation 7(B)) was condensed with 1H-indole-3-carbaldehyde. This intermediate was carried forward according to Example 6(A) Step B to afford 2-[1-(2-fluoro-phenyl)-4-(1H-indol-3-ylmethyl)-5-oxo-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-phenyl-acetamide. 1H NMR (CD2Cl2) δ 8.26 (s, 1H), 7.71-7.74 (m, 1H), 7.60-7.67 (m, 2H), 7.40-7.59 (m, 6H), 7.34-7.38 (m, 2H), 7.23-7.32 (br. m, 2H), 7.14-7.20 (m, 1H), 7.05-7.12 (m, 3H), 6.81-6.83 (m, 1H), 4.98-5.03 (m, 1H), 4.28 (d, 1H), 3.93 (d, 1H), 3.83-3.84 (m, 3H), 1.12 (d, 6H); MS 599 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O-:19])=[O:18])=[CH:12][CH:11]=1)=[O:5])C.[OH-].[K+]>>[C:4]([C:6]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:7]=1[CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:14][CH:15]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(OC)cc1COc1ccc(CC(=O)[O-])cc1
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(C(=O)O)c(COc2ccc(CC(=O)O)cc2)c1

Procedure:
Reaction of 4-(2-ethoxycarbonyl-5-methoxybenzyloxy)phenylacetate with potassium hydroxide as described in Example 1c provides 4-(2-carboxy-5-methoxybenzyloxy)phenylacetic acid as colorless crystals, m.p. 198°-200° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CN(CCN(C)C)C.[Li]CCCC.[Cl:28][CH2:29][CH2:30][CH2:31]I>C1COCC1.CCCCCCC.CCOC(C)=O>[Cl:28][CH2:29][CH2:30][CH2:31][C:12]1[O:11][C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:14][CH:13]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccco1
Reactant: ClCCCI
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(CCCCl)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A solution of 2-(t-butyldimethylsilyloxymethyl)furan (5 g, 0.023 mol) in THF (48 mL) was dried over 3 Å molecular sieves. After the sieves were removed, an additional 10 mL THF was added along with TMEDA (3.47 mL, 0.023 mol), and the solution was cooled to 0° C. in an ice bath. A solution of BuLi (10.1 mL of 2.5M in hexane, 0.025 mol) was added dropwise over 25 minutes. The mixture was allowed to stir for 1 hour. 1-chloro-3-iodopropane (5.64 g, 0.028 mol) was injected rapidly. After 2 hours TLC indicated completion. The solvent was evaporated, and the material was partitioned between ether (100 mL) and 5% citric acid (100 mL). The ether layer was washed with water (50 mL) and then brine (50 mL). The ether solution was dried with sodium sulfate, filtered, and evaporated. The resulting material was flashed on silica using 20/1 heptane/EtOAc. Appropriate fraction were combined and evaporated to yield 4.9 g (75% yield). TLC: Rf 0.6 (Heptane/EtOAc 5/1) 1H NMR: (CDCl3) δ 0.00 (s, 6H), 0.83 (s, 9H), 2.01 (p, 2H), 2.71 (t, 2H), 3.48 (t, 2H), 4.51 (s, 2H), 5.88 (d, 1H), 6.04 (d, 1H)
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:40])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Br:32].[CH3:41][C:42]1[S:43][CH:44]=[C:45]([CH:47]=O)[N:46]=1>O1CCCC1>[CH3:9][O:10][C:11](=[O:40])/[C:12](/[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Br:32])=[CH:47]/[C:45]1[N:46]=[C:42]([CH3:41])[S:43][CH:44]=1
Reactant: Cc1nc(C=O)cs1
Reactant: COC(=O)C(NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Br)P(=O)(OC)OC
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1csc(C)n1)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Br
Temperature: -40 °C
Reaction time: 0.08 h
Yield: 91.8 %

Procedure:
1,1,3,3-Tetramethylguanidine (50 μL, 0.397 mmol) was added to a solution of rac.-N-[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 130; 100 mg, 0.189 mmol) in tetrahydrofuran (2 mL) at −40° C. The solution was stirred at −40° C. for 5 min and then 2-methylthiazole-4-carboxaldehyde (Example 41; 48 mg, 0.378 mmol) was added. The solution was stirred at −40° C. for 1 h and then allowed to stir at room temperature for 4 h. The solution was quenched with pH 6 phosphate buffer, diluted with ethyl acetate (15 mL) and the separated organic layer was washed with pH 6 phosphate buffer (10 mL) and brine (10 mL). The organic phase was dried (MgSO4), filtered, evaporated and triturated with diethyl ether to give (Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(2-methylthiazol-4-yl)propenoic acid methyl ester (92 mg, 49% yield) as a brown solid.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Br[CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][OH:17]>O.C(OCC)C>[F:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:18][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17]
Reactant: CC(Br)CCCCO
Reactant: Oc1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: OCCCCCCOc1cccc(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1 M NaOH (17.8 mL) was added to a refluxing mixture of 3-fluorophenol (2 g, 17.8 mmol) and 5-bromo-1-hexanol (3.23 g, 17.8 mmol) in water (20 mL). After 3 h, the resulting mixture was cooled to room temperature and diluted with diethyl ether. The layers were separated, the organic layer was washed sequentially with 1N NaOH and water, then dried (Na2SO4) and concentrated to yield 6-(3-fluorophenoxy)hexan-1-ol as an oil. A solution of 6-(3-fluorophenoxy)hexan-1-ol (2.9 g, 13.67 mmol) was added dropwise to a mixture of 1,1,1-tris(acetyloxy)1,1-dihydro-1,2-benziodoxol-3-(1H)-one (7.0 g, 16.4 mmol) with ice-bath cooling. The resulting solution was stirred for 2.5 h at room temperature, then poured into a solution of sodium thiosulfate in saturated aqueous sodium bicarbonate. After 0.5 h, the layers were separated and the aqueous layer was extracted with CH2Cl2. The organic phase was dried (Na2SO4) filtered and concentrated to yield 6-(3-fluorophenoxy)hexanal. A solution of 6-(3-fluorophenoxy)hexanal (2.9 g, 13.8 mmol) in ethyl acetate (20 mL) and water (20 mL) containing NaCN (2 g, 41.4 mmol) was stirred vigorously overnight. After 20 h, the phases were separated and the aqueous layer was extracted twice with ethyl acetate. The combined ethyl acetate layers were washed with water, dried (Na2SO4) and concentrated to yield 7-(3-fluorophenoxy)-2-hydroxyheptanenitrile, which was dissolved in methanol (40 mL) and cooled to −78° C. The solution was saturated with HCl (g) and stored at −10° C. for 18 h. The resulting mixture was concentrated, diluted with ethyl acetate (40 mL) and water (40 mL), then stirred overnight. The layers were separated and the organic phase was dried (Na2SO4) and concentrated to yield the corresponding methyl ester which was dissolved in 9:1 dioxane:water (20 mL) and treated with a solution of LiOH (1.4 g, 58 mmol). The resulting solution was stirred for 4 h then acidified to pH˜3 with 1N HCl. The mixture was then extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed with water, dried (Na2SO4) and concentrated to yield 7-(3-fluorophenoxy)-2-hydroxyheptanoic acid as a white solid. (MS m/z=257 MH+).
Reaction SMILES: OCCN1C=NC(C2C=CC(C3C=NN4C=CC(N5[C@@H](C(C)C)COC5=O)=NC=34)=CC=2)=N1.[OH:33][CH2:34][CH2:35][N:36]1[C:40]([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:48]=[N:49][N:50]4[CH:55]=[CH:54][C:53]([N:56]5[CH:60]([CH:61]([CH3:63])[CH3:62])[CH2:59][O:58][C:57]5=[O:64])=[N:52][C:51]=34)=[CH:43][CH:42]=2)=[N:39][CH:38]=[N:37]1>C(#N)C.O>[OH:33][CH2:34][CH2:35][N:36]1[C:40]([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:48]=[N:49][N:50]4[CH:55]=[CH:54][C:53]([N:56]5[C@@H:60]([CH:61]([CH3:62])[CH3:63])[CH2:59][O:58][C:57]5=[O:64])=[N:52][C:51]=34)=[CH:43][CH:42]=2)=[N:39][CH:38]=[N:37]1
Reactant: CC(C)C1COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncnn4CCO)cc3)c2n1
Agent: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(CCO)n4)cc3)c2n1
Solvent: CC#N
Solvent: O
Product: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncnn4CCO)cc3)c2n1
Yield: 11 %

Procedure:
A crude mixture of (S)-3-(3-(4-(1-(2-hydroxyethyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-isopropyloxazolidin-2-one and S)-3-(3-(4-(1-(2-hydroxyethyl)-1H-1,2,4-triazol-5-yl)phenyl)pyrazolo[1,5-a]pyrimidin -5-yl)-4-isopropyloxazolidin-2-one was prepared as described in Example 58. (S)-3-(3-(4-(1-(2-hydroxyethyl)-1H-1,2,4-triazol-5-yl)phenyl)pyrazolo[1,5-a]pyrimidin -5-yl)-4-isopropyloxazolidin-2-one (6 mg, 11%) was isolated as the minor product by reverse phase preparative HPLC (5%-95% acetonitrile/water) as described in Example 58. LCMS (APCI+) m/z 434.6 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][CH3:21])[C:7]2[C:16]3[CH:15]=[C:14]([OH:17])[CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:18]=1)[CH3:2].I[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]>>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][CH3:21])[C:7]2[C:16]3[CH:15]=[C:14]([O:17][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:18]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCCCCI
Reactant: CCCn1c(COCC)nc2cnc3ccc(O)cc3c21
Product: CCCn1c(COCC)nc2cnc3ccc(OCCCCCCNC(=O)OC(C)(C)C)cc3c21

Procedure:
The synthesis of 2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol is described in Parts A-I of Example 2. The general method described in Part L of Example 2 was followed. 2-(Ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol (4.43 g, 15.5 mmol) was treated with tert-butyl 6-iodohexylcarbamate (prepared as described in Part F of Example 45, 6.1 g, 18.6 mmol). After the work up, the crude product was not purified to yield 9.9 g of tert-butyl 6-{[2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}hexylcarbamate as a tan waxy solid that contained DMF and dichloromethane.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N+:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([O-])=O>[Cu]>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:7][CH:2]=[C:3]([N:21]([C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=3)[CH:13]=[CH:12][CH:11]=2)[C:24]2[CH:29]=[CH:28][C:27]([C:27]3[CH:28]=[CH:29][C:24]([N:21]([C:10]4[CH:9]=[C:8]([C:5]5[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=5)[CH:13]=[CH:12][CH:11]=4)[C:3]4[CH:4]=[C:5]([C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=5)[CH:6]=[CH:7][CH:2]=4)=[CH:25][CH:26]=3)=[CH:26][CH:25]=2)[CH:4]=1
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Reactant: O=[N+]([O-])c1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(-c2cccc(N(c3ccc(-c4ccc(N(c5cccc(-c6ccccc6)c5)c5cccc(-c6ccccc6)c5)cc4)cc3)c3cccc(-c4ccccc4)c3)c2)cc1
Yield: 55.7 %

Procedure:
A 500-ml reactor was charged with 44.5 g (0.139 mol) of di(3-biphenyl)amine, 27.6 g (0.0680 mol) of 4,4'-diiodobiphenyl, 34.3 g (0.249 mol) of potassium carbonate, 2.3 g of copper powder, and 180 ml of nitrobenzene. In an argon stream, the contents were heated under reflux for 24 hours. At the end of reaction, the insoluble was removed by filtration and the filtrate was distilled of the solvent. The still residue was purified through a silica gel column with a 3/1 mixture of n-hexane and toluene, obtaining 30 g of N,N,N',N'-tetra(3-biphenylyl)benzidine of primary purity grade (yield 55.7%). It was further purified by recrystallization from toluene, obtaining 6.0 g of a 99.58% pure fraction and 5.0 g of a 99.23% pure fraction (combined yield 20.496). Further purification by sublimation yielded 8.0 g of a 99.99% pure product.
Reaction SMILES: [CH2:1]([N:8]([CH3:16])[CH2:9][C:10](N(OC)C)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([Mg]Cl)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH2:1]([N:8]([CH3:16])[CH2:9][C:10](=[O:11])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)CN(C)Cc1ccccc1
Reactant: Cl[Mg]CCc1ccccc1
Solvent: C1CCOC1
Product: CN(CC(=O)CCc1ccccc1)Cc1ccccc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
2-(Benzyl-methyl-amino)-N-methoxy-N-methyl-acetamide (2.0 g, 9.0 mmol, 1.0 equiv) was dissolved in 30 mL of dry THF under argon. The solution was cooled to −78° C. and a 1 M solution of phenethyl magnesium chloride (12.6 mL, 12.6 mmol, 1.4 equiv) was added dropwise of a period of 1 min. The resulting mixture was stirred at −78° C. for 3 h, warmed to 0° C. for 20 min and recooled to −78° C. at which time the reaction was quenched by the addition of 5 mL of saturated sodium bicarbonate. The reaction solution was diluted with 200 mL of EtOAc and 200 mL of water. The layers were separated and the organic layer was dried over Na2SO4, decanted and concentrated to an oil (2.4 g, ˜100%) which was used without further purification; MS, m/z 268=M+1.