Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([O:10][C@H:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])[CH:3]=1.[CH3:16]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOC(C)=O>[CH3:16][C:7]1[CH:2]=[CH:3][C:4]([O:10][C@H:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])=[C:5]([CH:6]=1)[CH:8]=[O:9]
Reactant: C=CC[C@H](C)Oc1cc(C)ccc1CO
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CC[C@H](C)Oc1ccc(C)cc1C=O
Yield: 90.8 %

Procedure:
A mixture (S)-(4-methyl-2-(pent-4-en-2-yloxy)phenyl)methanol (100 mg, 0.485 mmol), Dess-Martin periodinane (247 mg, 0.582 mmol) in DCM (5 mL) was stirred at rt for 1 h. It was then diluted with EtOAc and washed with sat. NaHCO3 and water. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 10% EtOAc/hexane to isolate (S)-5-methyl-2-(pent-4-en-2-yloxy)benzaldehyde (90 mg, 91%) as an oil. 1H NMR (400 MHz, CDCl3) δ 10.44 (s, 1H), 7.75 (d, J=8.1 Hz, 1H), 6.87-6.78 (m, 2H), 5.88 (ddt, J=17.1, 10.1, 7.1 Hz, 1H), 5.21-5.10 (m, 2H), 4.59 (sxt, J=6.1 Hz, 1H), 2.63-2.51 (m, 1H), 2.51-2.42 (m, 1H), 2.40 (s, 3H), 1.40 (d, J=6.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH:18]4[CH2:20][O:19]4)[C:12](=[O:21])[N:11]([CH3:22])[C:10]=3[N:9]=[C:8]2[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=2)=[CH:4][CH:3]=1.Cl.[CH3:38][NH:39][CH3:40].Cl([O-])(=O)(=O)=O.[Li+]>C1COCC1.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH:18]([OH:19])[CH2:20][N:39]([CH3:40])[CH3:38])[C:12](=[O:21])[N:11]([CH3:22])[C:10]=3[N:9]=[C:8]2[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:33])([F:32])[F:34])[CH:25]=2)=[CH:35][CH:36]=1
Reactant: CNC
Reactant: Cn1c(=O)n(CC2CO2)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)CC(O)Cn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.9 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-3-methyl-1-(oxiran-2-ylmethyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (100 mg, 0.192 mmol, example 13, step 1) in THF (10 mL) was added dimethylamine hydrochloride (160 mg, 1.98 mmol) and lithium perchlorate (20 mg, 0.189 mmol). The mixture was stirred at 25° C. in a sealed tube for 2 h. The mixture was diluted with ethyl acetate and water. The phases were separated and the organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give crude product. This crude material was purified via preparative HPLC to give 7-(4-chlorobenzyl)-1-(3-(dimethylamino)-2-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (50 mg, 46.2% yield) as white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[S:19]1[CH:23]=[CH:22][C:21]([C:24](Cl)=[O:25])=[CH:20]1>>[S:19]1[CH:23]=[CH:22][C:21]([C:24]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:25])=[CH:20]1
Reactant: CCN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccsc1
Product: CCN1CCC(c2c[nH]c3ccc(NC(=O)c4ccsc4)nc23)CC1

Procedure:
Beginning with 0.015 gm (0.061 mMol) 5-amino-3-(1-ethylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.012 mL (0.080 mMol) 3-thiophenecarbonyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([NH:12][CH3:13])[C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:20][O:21][CH:22]([O:25][CH3:26])[CH2:23]Br>CN(C=O)C>[CH3:20][O:21][CH:22]([O:25][CH3:26])[CH2:23][O:5][C:4](=[O:6])[C:3]1[C:7]([NH:12][CH3:13])=[CH:8][C:9]([F:11])=[CH:10][C:2]=1[F:1]
Reactant: COC(CBr)OC
Reactant: CNc1cc(F)cc(F)c1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNc1cc(F)cc(F)c1C(=O)OCC(OC)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
A mixture of example 12a (3.83 g, 20.5 mmol) and potassium carbonate (2.0 g, 14.4 mmol) in DMF (20 mL) was heated at 90° C. After stirring for 1 h, the mixture was cooled to r.t. Bromoacetaldehyde dimethyl acetal (3.74 g, 21.52 mmol) was added dropwise. After addition, the reaction mixture was heated to 130° C. for 11 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in diethyl ether and passed through a silica plug, and concentrated under reduced pressure to yield 3.64 g (65%) of clean desired product as an orange oil. 1H NMR (400 MHz, DMSO-d6): δ 7.52 (bs, 1H), 6.31-6.46 (m, 2H), 4.66 (t, 1H, J=5.2 Hz), 4.23 (d, 2H, J=5.2 Hz), 3.34 (s, 6H), 2.81 (d, 3H, J=4.8 Hz). MS (ES) [m+H] calc'd for C12H15F2NO4, 276; found 276.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:17]=[C:16]([O:18][CH:19]3[CH2:36][CH:35]4[CH:21]([C:22](=[O:42])[N:23]([CH3:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH:30]5[C:32]([C:38]([OH:40])=O)([NH:33][C:34]4=[O:37])[CH2:31]5)[CH2:20]3)[C:15]3[C:10](=[C:11]([CH3:45])[C:12]([O:43][CH3:44])=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:58]1([S:61]([NH2:64])(=[O:63])=[O:62])[CH2:60][CH2:59]1.C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:17]=[C:16]([O:18][CH:19]3[CH2:36][CH:35]4[CH:21]([C:22](=[O:42])[N:23]([CH3:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH:30]5[C:32]([C:38]([NH:64][S:61]([CH:58]6[CH2:60][CH2:59]6)(=[O:63])=[O:62])=[O:40])([NH:33][C:34]4=[O:37])[CH2:31]5)[CH2:20]3)[C:15]3[C:10](=[C:11]([CH3:45])[C:12]([O:43][CH3:44])=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3cccc(C)n3)nc2c1C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3cccc(C)n3)nc2c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.6 %

Procedure:
A mixture of the acid 17-[2-(6-methyl-2-pyridyl)-7-methoxy-8-methylquinolin-4-yl-oxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (102, 28 mg, 0.046 mmol) and CDI (15 mg, 0.092 mmol) in dry THF (3 mL) was heated at reflux for 2 h under nitrogen. The activation was monitored by LC-MS. The reaction mixture was cooled at room temperature and cyclopropylsulfonamide (17 mg, 0.137 mmol) was added. Then, DBU (16 μL, 0.105 mmol) was added and the reaction was heated at 55° C. After 24 h, the pH of the reaction mixture was adjusted to 3 with citric acid (5%). Then, the solvent was evaporated, and the residue partitioned between AcOEt and water. The crude material was purified by preparative HPLC to give 17 mg (52%) of the target compound 103: m/z=716 (M+H)+.
Reaction SMILES: P(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.[Mg+2].[Cl-].[Cl-].[C@@H:35]1([N:73]2[C:82]3[N:81]=[CH:80][N:79]=[C:77]([NH2:78])[C:76]=3[N:75]=[CH:74]2)[O:72][C@H:44]([CH2:45][O:46][P:47]([O:50][P:51]([O:54][CH2:55][C:56]([C@H:59]([C:61]([NH:63][CH2:64][CH2:65][C:66]([NH:68][CH2:69][CH2:70][SH:71])=[O:67])=[O:62])[OH:60])([CH3:58])[CH3:57])([OH:53])=[O:52])([OH:49])=[O:48])[C@@H:38]([O:39][P:40]([OH:43])([OH:42])=[O:41])[C@H:36]1[OH:37].[OH:83][C@H:84]([CH2:89][CH2:90][CH2:91][CH2:92][CH3:93])[CH2:85][C:86]([O-])=[O:87]>C(O)C(N)(CO)CO.Cl>[OH:83][C@H:84]([CH2:89][CH2:90][CH2:91][CH2:92][CH3:93])[CH2:85][C:86]([S:71][CH2:70][CH2:69][NH:68][C:66](=[O:67])[CH2:65][CH2:64][NH:63][C:61](=[O:62])[C@H:59]([OH:60])[C:56]([CH3:58])([CH3:57])[CH2:55][O:54][P:51]([OH:53])(=[O:52])[O:50][P:47]([OH:49])(=[O:48])[O:46][CH2:45][C@H:44]1[O:72][C@@H:35]([N:73]2[C:82]3[N:81]=[CH:80][N:79]=[C:77]([NH2:78])[C:76]=3[N:75]=[CH:74]2)[C@H:36]([OH:37])[C@@H:38]1[O:39][P:40]([OH:43])([OH:42])=[O:41])=[O:87]
Reactant: CC(C)(COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O)[C@@H](O)C(=O)NCCC(=O)NCCS
Reactant: CCCCC[C@@H](O)CC(=O)[O-]
Agent: Cl
Agent: NC(CO)(CO)CO
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Product: CCCCC[C@@H](O)CC(=O)SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O

Procedure:
(R)-3-hydroxyoctanoyl-CoA was synthesized according to Rehm B. H. A., Kruger N., Steinbuchel A., Journal of Biological Chemistry, 273, p. 24044-24051, 1998 with slight changes as described below. Acyl-CoA synthetic enzyme (available from Sigma Co.) was dissolved in a Tris-HCl buffer (50 mM, pH 7.5) containing 2 mM ATP, 5 mM MgCl2, 2 mM coenzyme A, and 2 mM (R)-3-hydroxyoctanoate to concentration of 0.1 mU/μl. The mixture was retained in a warm bath at 37° C. and was sampled suitably to analyze progress of a reaction by HPLC. After the enzyme reaction was terminated by adding sulfuric acid to the sampled reaction solution to concentration of 0.02 N, the unreacted substrate (R)-3-hydroxyoctanoate was removed by extraction with n-heptane. The HPLC analysis employed RP18 column (nucleosil C18, 7 μm, Knauser), and elusion was conducted under a linear concentration slope of acetonitrile, using a 25 mM phosphoric acid buffer (pH 5.3) as a moving phase. A thioester compound produced through the enzymatic reaction was detected by monitoring an absorption spectrum of 200 to 500 nm using a diode array detector. (R)-3-hydroxy-5-phenylvaleryl CoA and (R)-3-hydroxy-5-(4-fluorophenyl)valeryl CoA were synthesized in a similar manner.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:15]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=2[O:13][CH:12]=[C:11]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(C)C>[CH2:1]([O:8][C:9]1[C:15]2[C:14](=[CH:19][CH:18]=[C:17]([F:20])[CH:16]=2)[C:12]([OH:13])=[C:11]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc2c(c1)C(OCc1ccccc1)=NC(c1ccc(Br)cc1)=CO2
Solvent: CC(C)O
Product: Oc1c(-c2ccc(Br)cc2)nc(OCc2ccccc2)c2cc(F)ccc12
Temperature: 140 °C
Yield: 90 %

Procedure:
5-Benzyloxy-3-(4-bromo-phenyl)-7-fluoro-benzo[f][1,4]oxazepine (830 mg, 1.96 mmol) was dissolved in isopropanol, degassed under reduced pressure and purged with argon. The reaction mixture was heated at 140° C. under microwave irradiation for 1 h. The solvent was then evaporated to dryness to afford the title compound as a solid, which was used without any further purification (750 mg, 90% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[N:3]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.C(Cl)(Cl)Cl>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH2:10][CH2:9][O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:3]=2)=[CH:12]1
Reactant: Clc1cncc(OCCc2c[nH]c3ccccc23)n1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: c1ccc2c(CCOc3cncc(N4CCNCC4)n3)c[nH]c2c1
Temperature: 110 °C
Yield: 23 %

Procedure:
A mixture of the product from Step 1 above (1.07 g, 3.90 mmol), piperazine (0.98 g, 11.3 mmol) and K2CO3 (0.54 g, 3.9 mmol) in acetonitrile (11 mL) was heated at 85° C. for 5 h and at 110° C. for 8 h in a sealed pyrex flask. The reaction mixture was diluted with CHCl3, filtered, and concentrated in vacuo. The semi-solid residue was purified by chromatography on silica gel (11×4 cm) using CHCl3/MeOH (9:1) as eluent. The resulting oil was redissolved in CHCl3 and filtered through a short plug of alumina, covered by K2CO3, using CHCl3 as eluent. Solvent removal in vacuo furnished 0.50 g (23%) of the title compound as an oil that solidified upon standing: mp 133-135° C. HRMS m/z calcd for C18H21N5O (M)30 323.1746, found 323.1763. Anal. (C18H21N5O) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:13])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][CH:10]=[N:9]1.[Br-:14].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>O1CCCC1.CCOCC>[Br:14][C:5]1[CH:6]=[C:7]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[C:2]([F:1])=[CH:3][C:4]=1[NH2:13]
Reactant: [Br-]
Reactant: Nc1ccc(-n2cccn2)c(F)c1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Nc1cc(F)c(-n2cccn2)cc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-fluoro-4-(pyrazol-1-yl)phenylamine (2.56 g, 14.5 mmol) in tetrahydrofuran (50 ml) was added dropwise a solution of pyridinium tribromide (5.09 g, 15.9 mmol) in tetrahydrofuran (50 ml). The mixture was stirred for 1 h at room temperature then diluted with ether (250 ml). After stirring for a further 30 min the precipitate was filtered and washed with ether (50 ml×2). The white solid was dissolved in water (200 ml) and extracted with ethyl acetate (100 ml×3). The combined organic phases were dried over magnesium sulphate, filtered and the solvent removed to leave an orange oil. Purification by chromatography on silica gel eluting with dichloromethane gave 2-bromo-5-fluoro-4-(pyrazol-1-yl)phenylamine as a white solid: m/z (ES+) 256 and 258 (M++H).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[O:11][C:12]4[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO.C1COCC1>[CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[O:11][C:12]4[CH:18]=[CH:17][C:16]([CH2:19][N:21]5[CH2:25][CH2:24][CH2:23][CH2:22]5)=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: O=Cc1ccc2oc(N3CCN(C4CC4)CC3)nc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: c1cc2oc(N3CCN(C4CC4)CC3)nc2cc1CN1CCCC1
Yield: 39.9 %

Procedure:
To a solution of 2-(4-cyclopropylpiperazin-1-yl)benzooxazole-5-carboxaldehyde (400 mg, 1.48 mmol) and pyrrolidine (210 mg, 2.96 mmol) in CH3OH/THF (36 mL, 1:3) was added acetic acid (142 mg, 2.37 mmol), followed by NaCNBH3 (137 mg, 2.37 mmol). The mixture was heated at reflux for 12 h. The volatiles were removed and the residue was diluted with water (5 mL). The resulting mixture was extracted with CH2Cl2 (3×10 mL) and the combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel (elute: 2% dichloromethane in methanol) to give 193 mg (40%) of 2-(4-cyclopropylpiperazin-1-yl)-5-pyrrolidin-1-ylmethylbenzooxazole.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][CH3:14].[CH3:15][O:16][CH2:17][CH2:18]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][O:13][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[O:1][CH2:18][CH2:17][O:16][CH3:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(OCCOC)c(OC)c1
Yield: 88.9 %

Procedure:
A mixture of ethyl 4-hydroxy-3-methoxybenzoate (9.8 g, 50 mmol), 2-bromoethyl methyl ether (8.46 ml, 90 mmol) and potassium carbonate (12.42 g, 90 mmol) in acetone (60 ml) was heated at reflux for 30 hours. The mixture was allowed to cool and the solids removed by filtration. The volatiles were removed from the filtrate by evaporation and the residue triturated with hexane to give ethyl 3-methoxy-4-(2-methoxyethoxy)benzoate (11.3 g, 89%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.Br[C:20]1[CH:36]=[CH:35][C:23]([C:24]([C@@H:26]2[CH2:30][CH2:29][CH2:28][C@H:27]2[C:31]([O:33]C)=[O:32])=[O:25])=[CH:22][CH:21]=1.FC1C=C(C2C=CC(C([C@@H]3CCC[C@H]3C(O)=O)=O)=CC=2)C=CC=1NC1SC2C=C(OC(F)(F)F)C=CC=2N=1>>[CH3:18][C:15]1[CH:16]=[CH:17][C:11]2[O:10][C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([C:20]4[CH:21]=[CH:22][C:23]([C:24]([C@@H:26]5[CH2:30][CH2:29][CH2:28][C@H:27]5[C:31]([OH:33])=[O:32])=[O:25])=[CH:35][CH:36]=4)=[CH:3][CH:4]=3)=[N:13][C:12]=2[CH:14]=1
Reactant: Cc1ccc2oc(Nc3ccc(Br)cc3)nc2c1
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(Br)cc1
Agent: O=C(O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(OC(F)(F)F)cc4s3)c(F)c2)cc1
Product: Cc1ccc2oc(Nc3ccc(-c4ccc(C(=O)[C@@H]5CCC[C@H]5C(=O)O)cc4)cc3)nc2c1
Yield: 17 %

Procedure:
This compound was prepared from N-(4-bromophenyl)-N-(5-methyl-1,3-benzoxazol-2-yl)amine (0.50 g, 1.65 mmol), methyl (1R,2R)-2-(4-bromobenzoyl)cyclopentanecarboxylate (0.57 g, 1.83 mmol, 94.5% ee) in a similar manner to the method described for (1R,2R)-2-({3′-fluoro-4′-[(6-trifluoromethoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylic acid. Yield: 17%. 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.05 (d, 2H), 7.75-7.90 (m, 6H), 7.35 (d, 1H), 7.25 (s, 1H), 6.95 (d, 1H), 4.05 (q, 1H), 3.20 (s, 1H), 2.40 (s, 3H), 2.15 (m, 1H), 2.00 (m, 1H), 1.55-1.80 (m, 4H). LC-MS m/z 441.3 (MH+), ret. time 3.48 min.
Reaction SMILES: I[C:2]1[N:23](S(C2C=CC(C)=CC=2)(=O)=O)[C:5]2[N:6]=[CH:7][N:8]=[C:9]([C:10]3[S:14][C:13]([C:15]4([O:19]COC)[CH2:18][CH2:17][CH2:16]4)=[N:12][CH:11]=3)[C:4]=2[CH:3]=1.[CH3:34][N:35]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[N:36]1.C(=O)(O)[O-]>CN(C)C=O.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>[CH3:34][N:35]1[CH:39]=[C:38]([C:2]2[NH:23][C:5]3[N:6]=[CH:7][N:8]=[C:9]([C:10]4[S:14][C:13]([C:15]5([OH:19])[CH2:16][CH2:17][CH2:18]5)=[N:12][CH:11]=4)[C:4]=3[CH:3]=2)[CH:37]=[N:36]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COCOC1(c2ncc(-c3ncnc4c3cc(I)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc3c(-c4cnc(C5(O)CCC5)s4)ncnc3[nH]2)cn1
Temperature: 70 °C

Procedure:
To a stirred ambient solution of 5-(6-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-(1-(methoxymethoxy)cyclobutyl)thiazole (Example 160C) (60 mg, 0.10 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (25.0 mg, 0.120 mmol) in N,N-dimethylformamide (2.0 mL) was added saturated aqueous bicarbonate solution (1.0 mL) followed by bis(triphenylphosphine)palladium dichloride (7.02 mg, 10.0 μmol). The mixture was heated to 70° C. for 3 hours and was then quenched by the addition of water and ethyl acetate. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate. The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in methanol (1 mL), and 4 molar aqueous HCl solution (0.5 mL) was added. The reaction was heated to 60° C. for 2 hours and was then cooled to room temperature. 4 Normal aqueous sodium hydroxide solution (1 mL) was added, and the reaction heated to 80° C. for 1 hour. The reaction was cooled to room temperature, and the pH adjusted to ˜7 with 10% aqueous HCl solution. The aqueous layer was extracted with ethyl acetate (3×). The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The solid was triturated with diethyl ether to give the title compound. 1H NMR (500 MHz, DMSO-d6) ppm 1.76-2.08 (m, 2H) 2.31-2.45 (m, 2H) 2.54-2.66 (m, 2H) 3.93 (s, 3H) 6.62 (s, 1H) 7.24 (s, 1H) 8.11 (s, 1H) 8.29 (s, 1H) 8.65 (s, 1H) 8.69 (s, 1H) 12.58 (s, 1H); MS ESI(+) m/z 353 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][C@H:19]([C:23]4[CH:32]=[CH:31][C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH:24]=4)[C@@H:20]([NH2:22])[CH3:21])=[CH:15][CH:16]=3)[CH:11]=[N:10]2)=[CH:5][CH:4]=1.CN(C)C(N(C)C)=N.[F:41][C:42]([F:49])([F:48])[C:43](OCC)=[O:44]>CO>[F:41][C:42]([F:49])([F:48])[C:43]([NH:22][C@@H:20]([CH3:21])[C@H:19]([O:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:9]([C:6]1[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=1)[N:10]=[CH:11]2)[C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)=[O:44]
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc2ccccc2c1
Reactant: CCOC(=O)C(F)(F)F
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CO
Product: C[C@H](NC(=O)C(F)(F)F)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc2ccccc2c1

Procedure:
(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(naphthalen-2-yl)propan-2-amine hydrochloride (50 mg, 0.11 mmol), 1,1,3,3-tetramethylguanidine (100 μl, 0.79 mmol) and Ethyl trifluoroacetate (200 μl, 1.68 mmol) in MeOH (2.5 mL) was stirred at r.t. for 1 h. The reaction mixture was concentrated by evaporation. The residual material was purified by HPLC. Yield 37 mg (65%)
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][CH:7]=[C:6]3[C:12](=[O:21])[N:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:14]=[C:5]3[C:4]=2[CH:3]=1.[CH3:22][O:23]C1C=CC(NN)=CC=1>>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][CH:7]=[C:6]3[C:12](=[O:21])[N:13]([C:15]4[CH:20]=[CH:19][C:18]([O:23][CH3:22])=[CH:17][CH:16]=4)[N:14]=[C:5]3[C:4]=2[CH:3]=1
Reactant: COc1ccc(NN)cc1
Reactant: O=c1c2c[nH]c3ccc(F)cc3c-2nn1-c1ccccc1
Product: COc1ccc(-n2nc3c4cc(F)ccc4[nH]cc-3c2=O)cc1

Procedure:
The title compound was prepared following procedure for 23a using 4-methoxy phenylhydrazine instead of phenyl hydrazine. 1H-NMR (DMSO-d6) δ (ppm): 7.05 (3H, m), 7.52 (1H, dt, J=8.52, 3.02 Hz), 7.80 (1H, dd, J=9.07, 4.94 Hz), 7.88 (1H, dd, J=9.06, 2.75 Hz), 8.05 (2H, m), 8.74 (1H, d, J=5.49 Hz). m/z 310.3 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](O)=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCCCCCCCC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCCCCCCCCCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
Compound 1 (29.0 g, 96.2 mmol) was dissolved in anhydrous tetrahydrofuran (500 mL). The solution was cooled to 0° C. under a dry inert atmosphere. Borane-tetrahydrofuran complex (1.0 M, 144 mL, 144 mmol) was added dropwise with stirring over 1 hour. The cooling bath was removed and the reaction was allowed to warm to room temperature and stirred an additional 2 hours. The reaction was then quenched by the slow, careful addition of saturated aqueous sodium bicarbonate solution (100 mL). The mixture was diluted with water (400 mL), and the tetrahydrofuran was removed in vacuo. The resulting mixture was extracted three times with ethyl acetate (200 mL portions), and the organic extracts were combined. The ethyl acetate solution was washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo. A white waxy solid was obtained (27.1 g, 98% yield), which was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6): δ 1.23 (m, 14H), 1.30–1.43 (m, 13H), 2.88 (q, J=6.7 Hz, 2H), 3.36 (q, J=6.3 Hz, 2H), 4.31 (t, J=5.1 Hz, 1H), 6.74 (t, J=5.2 Hz, 1H). 13C NMR (75 MHz, DMSO-d6): δ 25.13, 26.27, 28.25, 28.74, 28.98, 29.03, 29.11, 29.48, 32.56, 60.72, 77.21, 155.55. HRMS (ESI-pos): calcd for C16H34NO3 288.2539, obsd 288.2535.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][C:15]1[N:24]([C:25]2[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=2)[C:23](=[O:32])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1>>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:28]2[CH:27]=[CH:26][C:25]([N:24]3[C:23](=[O:32])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[C:15]3[CH3:14])=[CH:30][CH:29]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2ccccc2c(=O)n1-c1ccc(O)cc1
Reactant: OC1CCN(Cc2ccccc2)C1
Product: Cc1nc2ccccc2c(=O)n1-c1ccc(OC2CCN(Cc3ccccc3)C2)cc1

Procedure:
1-benzyl-3-pyrrolidinol and 2-methyl-3-(4-hydroxyphenyl)-4-(3H) quinazolinone synthesized according to Example 1-(1) and -(2) were etherated by the Mitsunobu reaction according to Example 117-(2), and the target compound was thus obtained.