Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][O:5][C:4]2[CH:8]=[C:9]([OH:12])[CH:10]=[CH:11][C:3]1=2.O1C2C(=CC=C(O)C=2)CCC1.[O:24]1[CH2:28][CH2:27][CH2:26][C@@H:25]1[CH2:29][N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](=[O:39])[C:31]1=[O:40].C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(=O)C2=O)C=CC=CC=1>>[OH:39][C:32]1([C:10]2[C:9]([OH:12])=[CH:8][C:4]3[O:5][CH2:6][CH2:7][N:2]([CH3:1])[C:3]=3[CH:11]=2)[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:30]([CH2:29][C@H:25]2[CH2:26][CH2:27][CH2:28][O:24]2)[C:31]1=[O:40]
Reactant: O=C1C(=O)N(C[C@H]2CCCO2)c2ccccc21
Reactant: CN1CCOc2cc(O)ccc21
Agent: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: Oc1ccc2c(c1)OCCC2
Product: CN1CCOc2cc(O)c(C3(O)C(=O)N(C[C@H]4CCCO4)c4ccccc43)cc21

Procedure:
Following the procedure as described in PREPARATION 13A, and making non-critical variations using 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-ol to replace chroman-7-ol, and 1-[(2R)-tetrahydrofuran-2-ylmethyl]-1H-indole-2,3-dione to replace 1-(diphenylmethyl)indoline-2,3-dione, 3-hydroxy-3-(7-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-one was obtained (91%) as a pale grey solid: 1H NMR (300 MHz, CDCl3) (diastereomers) δ 8.94 (s, 0.4H), 8.80 (s, 0.6H), 7.52-7.48 (m, 1H), 7.41-7.34 (m, 1H), 7.20-7.08 (m, 2H), 6.52 (s, 1H), 6.16 (s, 1H), 4.51 (s, 0.4H), 4.44 (s, 0.6H), 4.29-4.17 (m, 3H), 3.90-3.64 (m, 4H), 3.17-2.99 (m, 2H), 2.58 (s, 3H), 2.04-1.78 (m, 3H), 1.74-1.60 (m, 1H); 13C NMR (diastereomers) (75 MHz, CDCl3) δ179.4, 179.2, 149.4, 149.3, 146.2, 143.2, 143.0, 130.2, 130.1, 129.8, 129.6, 125.9, 125.7, 123.6, 123.5, 117.6, 112.7, 112.4, 110.4, 110.3, 107.4, 79.3, 79.2, 76.9, 76.7, 68.3, 68.2, 65.3, 49.5, 44.7, 44.6, 39.5, 29.3, 29.1, 25.7, 25.6; MS (ES+) m/z 419.1 (M+23).
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:11][C:10]=1[CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([O:5][C:6](=[O:45])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:43])([F:44])[F:42])=[CH:37][CH:36]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1COc1ccc(C(F)(F)F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCc1ccc(O)cc1COc1ccc(C(F)(F)F)cc1
Reaction time: 1.5 h
Yield: 76.7 %

Procedure:
A 100 mL round bottomed flask was charged with 3-[4-(tert-butyldiphenylsilanyloxy)-2-(4-trifluoromethylphenoxymethyl)phenyl]propionic acid tert-butyl ester (0.65 g, 1.02 mmol), anhydrous THF (40 mL), and then tetrabutylammonium fluoride (3.1 mL, 3.1 mmol, 1.0 M in THF). The reaction was stirred under a nitrogen atmosphere for 1.5 h and was concentrated. The residue was diluted with EtOAc (100 mL). The organic layer was washed with brine (2×), dried (Na2SO4), and concentrated to an orange oil. The crude oil was purified using radial chromatography (EtOAc:hexanes 15:85) to give a white solid (0.31 g, 77%). MS (ES) m/e 395 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH:7]=O.[C:11]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:13][CH2:14][CH3:15])=[O:12]>C1COCC1>[Br:1][C:2]1[CH:9]=[C:6](/[CH:7]=[CH:16]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([Cl:10])=[N:4][CH:3]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc(Br)cnc1Cl
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
A vial was charged with 5-bromo-2-chloronicotinaldehyde (500 mg, 2.268 mmol, Small Molecules, Inc.) and THF (9072 μl). (Carbethoxymethylene)triphenylphosphorane (830 mg, 2.381 mmol) was added to the solution, and the mixture was stirred at RT for 1.5 h. The crude mixture was loaded onto silica gel and purified using a gradient of 0-50% EtOAc/heptane to provide (E)-ethyl 3-(5-bromo-2-chloropyridin-3-yl)acrylate (660 mg, 2.272 mmol, 100% yield) as a white solid. m/z (ESI) 291.8 (M+H)+.
Reaction SMILES: O[C:2]1C=C(O)C=C2C=1C(=O)CCN2.[CH3:14][O:15][C:16]1[CH:21]=[C:20]([CH2:22][NH:23][CH2:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][CH2:33][CH2:34][CH2:35][NH2:36])[CH:19]=[CH:18][C:17]=1[OH:37].[OH:38][N:39]1[C:48]2[C:43](=[CH:44][CH:45]=[C:46]([O:49][CH:50]([CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH3:51])[CH:47]=2)[C:42](=[O:57])[CH2:41][CH2:40]1>>[CH3:14][O:15][C:16]1[CH:21]=[C:20]([CH2:22][NH:23][CH2:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][CH2:33][CH2:34][CH2:35][NH2:36])[CH:19]=[CH:18][C:17]=1[OH:37].[OH:38][N:39]1[C:48]2[C:43](=[CH:44][CH:45]=[C:46]([O:49][CH:50]([CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH3:51])[CH:47]=2)[C:42](=[O:57])[CH2:41][CH:40]1[CH3:2]
Reactant: CCCCCC(C)Oc1ccc2c(c1)N(O)CCC2=O
Reactant: O=C1CCNc2cc(O)cc(O)c21
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Product: CCCCCC(C)Oc1ccc2c(c1)N(O)C(C)CC2=O

Procedure:
In like manner, 5,7-dihydroxy-4-oxo-1,2,3,4-tetrahydroquinoline converted to dl-5-hydroxy-7-(2-heptyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline, an oil.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([C:7]2[C:17]3[CH:18]=[CH:19][C:20]([O-:22])=[CH:21][C:16]=3[O:15][C:14]3[C:8]=2[CH:9]=[CH:10][C:11]([CH:13]=3)=[O:12])[C:4]([C:23]([O-:25])=[O:24])=[CH:3][CH:2]=1.[Na+:26].[Na+].C1C=C2C(OC3(C4C(=C(I)C(O)=C(I)C=4)OC4C3=CC(I)=C(O)C=4I)C2=CC=1)=O.C1C=C(C2C3C(=C(I)C([O-])=C(I)C=3)OC3C=2C=C(I)C(C=3I)=O)C(C([O-])=O)=CC=1.[Na+].[Na+]>>[CH:2]1[CH:3]=[C:4]2[C:23]([O:25][C:7]3([C:8]4[CH:9]=[CH:10][C:11]([O-:12])=[CH:13][C:14]=4[O:15][C:16]4[CH:21]=[C:20]([O-:22])[CH:19]=[CH:18][C:17]3=4)[C:5]2=[CH:6][CH:1]=1)=[O:24].[Na+:26].[Na+:26]
Reactant: O=C([O-])c1ccccc1-c1c2ccc(=O)cc-2oc2cc([O-])ccc12
Agent: O=C([O-])c1ccccc1-c1c2cc(I)c(=O)c(I)c-2oc2c(I)c([O-])c(I)cc12
Agent: O=C1OC2(c3ccccc31)c1cc(I)c(O)c(I)c1Oc1c2cc(I)c(O)c1I
Agent: [Na+]
Product: O=C1OC2(c3ccc([O-])cc3Oc3cc([O-])ccc32)c2ccccc21

Procedure:
##STR2## is an adsorption indicator dyestuff C.I. 45350. Erthrosin B (tetra-iodo-fluorescein) is an adsorption indicator dyestuff. C.I. 45430. all available from B.D.H. (Aust.) Pty. Ltd.
Reaction SMILES: [Br:1][CH:2]([CH3:14])[C:3]([C:5]1[CH:6]=[N:7][C:8]([O:12][CH3:13])=[CH:9][C:10]=1C)=[O:4].BrC1C(C)=C[C:19]([O:22]C)=NC=1>>[Br:1][CH:2]([CH3:14])[C:3]([C:5]1[C:6]([O:22][CH3:19])=[N:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=1)=[O:4]
Reactant: COc1cc(C)c(C(=O)C(C)Br)cn1
Reactant: COc1cc(C)c(Br)cn1
Product: COc1ccc(C(=O)C(C)Br)c(OC)n1

Procedure:
This compound is prepared analogously to 2-bromo-1-(6-methoxy-4-methyl-pyridin-3-yl)-propan-1-one (Intermediate DA) by replacing 5-bromo-2-methoxy-4-methyl-pyridine with the appropriate starting compound. MS: m/z 274 [M+H]+
Reaction SMILES: C([O:5][C:6](=[O:45])[CH2:7][C:8]1([C:38]([O:40]C(C)(C)C)=[O:39])[O:12][N:11]=[C:10]([C:13]2[CH:18]=[C:17]([O:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH2:30])=[NH:29])=[CH:23][CH:22]=3)[CH:16]=[CH:15][C:14]=2[CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:9]1)(C)(C)C.[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47]>>[F:49][C:48]([F:51])([F:50])[C:46]([OH:52])=[O:47].[NH:27]([C:24]1[CH:23]=[CH:22][C:21]([C:20]([O:19][C:17]2[CH:16]=[CH:15][C:14]([CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]3)=[C:13]([C:10]3[CH2:9][C:8]([CH2:7][C:6]([OH:45])=[O:5])([C:38]([OH:40])=[O:39])[O:12][N:11]=3)[CH:18]=2)=[O:31])=[CH:26][CH:25]=1)[C:28]([NH2:30])=[NH:29]
Reactant: CC(C)(C)OC(=O)CC1(C(=O)OC(C)(C)C)CC(c2cc(OC(=O)c3ccc(NC(=N)N)cc3)ccc2C2CCCCC2)=NO1
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)Nc1ccc(C(=O)Oc2ccc(C3CCCCC3)c(C3=NOC(CC(=O)O)(C(=O)O)C3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 5-(2-tert-butoxy-2-oxoethyl)-3-(5-((4-carbamimidamidobenzoyl)oxy)-2-cyclohexylphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (12.7 mg) and TFA (1 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and then, the residue was washed with diethyl ether to obtain the title compound (5.8 mg).
Reaction SMILES: Br[C:2]1[C:7]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:6][N:5]=[CH:4][N:3]=1.[F:13][C:14]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:15]=1[C:16]([N:18]=[C:19]=[S:20])=[O:17]>O1CCOCC1>[CH2:9]([N:8]1[C:7]2[CH:6]=[N:5][CH:4]=[N:3][C:2]=2[S:20]/[C:19]/1=[N:18]\[C:16](=[O:17])[C:15]1[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:14]=1[F:13])[CH2:10][CH2:11][CH3:12]
Reactant: O=C(N=C=S)c1cc(C(F)(F)F)ccc1F
Reactant: CCCCNc1cncnc1Br
Solvent: C1COCCO1
Product: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)sc2ncncc21
Temperature: 60 °C
Yield: 81.5 %

Procedure:
A mixture of product from Example 3A (270 mg, 1.17 mmol) and 2-fluoro-5-(trifluoromethyl)benzoyl isothiocyanate (322 mg, 1.29 mmol) in dioxane was heated at 60° C. for 12 hours. The mixture was then concentrated under reduced pressure and the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was washed with brine, dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (hexanes-EtOAc 1:2) to afford 380 mg of the title compound. MS (ESI) m/z 399 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:11]=[C:10]3[NH:27][N:28]=[C:29]([CH3:30])[C:9]=23)=[CH:4][CH:3]=1.I[CH3:32]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:11]=[C:10]3[N:27]([CH3:32])[N:28]=[C:29]([CH3:30])[C:9]=23)=[CH:4][CH:3]=1
Reactant: CI
Reactant: Cc1n[nH]c2nc(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)c12
Product: Cc1nn(C)c2nc(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)c12

Procedure:
Following a similar procedure to that described in examples 6 and 7, but using 4,6-bis(4-fluorophenyl)-3-methyl-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (obtained in example 4) instead of 4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine and iodomethane instead of iodoethane, the title compounds were obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I-:25].[C:26]([O:30][C:31]([NH:33][C@@H:34]([CH2:39]O)[C:35]([O:37][CH3:38])=[O:36])=[O:32])([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl>[C:26]([O:30][C:31]([NH:33][C@@H:34]([CH2:39][I:25])[C:35]([O:37][CH3:38])=[O:36])=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: COC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Reactant: [I-]
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)[C@H](CI)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
A mixture of triphenylphosphine (131 g, 0.500 mol) and imidazole (34 g, 0.50 mol) in DCM (600 mL) was cooled to 0° C. and iodide (127 g, 0.50 mol) was added in small portions over 0.5 h. The cooling bath was removed and the mixture was stirred for 0.5 h. After the mixture was re-cooled to 0° C., a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoate (73 g, 0.33 mol) in DCM (300 mL) was added dropwise. After the addition, the cooling bath was removed and the mixture was allowed to warm to ambient temperature and stirred for 1.5 h. The mixture was filtered and the filtrate was concentrated to remove most of the solvent. MTBE (400 mL) was added to the residue and the mixture was filtered to remove triphenylphosphine oxide. The filtrate was concentrated and the residue was purified by flash column chromatography on silica gel to afford (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (74.0 g, 68% yield) as a colorless solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]2[N:11]=[CH:12][NH:13][C:9]=2[CH:8]=[CH:7][CH:6]=1)=O.O.[NH2:15][NH2:16].O>CCO>[N:11]1[C:10]2[C:5]([C:3]([NH:15][NH2:16])=[O:2])=[CH:6][CH:7]=[CH:8][C:9]=2[NH:13][CH:12]=1
Reactant: NN
Reactant: COC(=O)c1cccc2[nH]cnc12
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cccc2[nH]cnc12
Temperature: 25 °C

Procedure:
Benzimidazole ester 3 (1.65 g, 9.36 mmol), hydrazine monohydrate (10 mL), and water (3 mL) were refluxed in EtOH (60 mL) for 24 hs. Reaction mixture was cooled to room temperature and solid formed was filtered, washed with EtOH and dried to give 1.13 g (68%) of pure 4: 1H NMR (DMSO-d6) δ 12.31 (br.s, 1H), 10.59 (s, 1H), 8.44 (s, 1H), 7.86 (d, 1H, J=6.5 Hz), 7.76 (d, 1H, J8.0 Hz), 7.34 (t, 1H, J=8.0 Hz), 4.68 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O[C:13]1[CH:18]=CC(C(C2C=CC(O)=CC=2)(C)C)=C[CH:14]=1>>[OH:11][C:8]1[CH:7]=[C:6]2[C:5](=[CH:10][CH:9]=1)[C:1]([CH3:4])([CH3:2])[CH2:3][C:13]2([CH3:18])[CH3:14]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CC(C)(C)c1ccc(O)cc1
Product: CC1(C)CC(C)(C)c2cc(O)ccc21
Yield: 35.2 %

Procedure:
172 g (1.15 mol) of 4-tert.-butylphenol, 57.5 g (0.25 mol) of 2,2-bis-(4-hydroxyphenyl)-propane and 20 g of an ion exchanger are heated with stirring for 5 hours to about 170° C. in an autoclave. The ion exchanger is then filtered off while still hot, leaving 208.5 g of a reaction mixture from which 16.7 g (0.088 mol) of 5-hydroxy-1,1,3,3-tetramethyl indane are isolated by fractional distillation.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.CC#N.C(=O)=O.C([Li])CCC.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][N:21]=1>C1COCC1>[CH3:1][N:2]1[C:6]([CH:24]([C:23]2[CH:22]=[N:21][C:20]([C:19]([F:29])([F:18])[F:28])=[CH:27][CH:26]=2)[OH:25])=[CH:5][N:4]=[N:3]1
Reactant: Cn1ccnn1
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC#N
Product: Cn1nncc1C(O)c1ccc(C(F)(F)F)nc1
Temperature: -40 °C
Reaction time: 0.67 h

Procedure:
A 50 mL flask containing 1-methyl-1H-1,2,3-triazole (0.47 g, 5.71 mmol) in dry THF (3 mL) was cooled to −43° C. (CH3CN—CO2 bath). n-Butyllithium (2.5 M in THF, 2.43 mL, 6.08 mmol) was then added dropwise resulting in a light blue suspension. The suspension was stirred at −40° C. for 40 minutes, and then a homogeneous solution of 6-(trifluoromethyl)nicotinaldehyde (1 g, 5.71 mmol) in THF (7 mL) was introduced at −40° C. The resulting homogeneous colorless solution was allowed to warm gradually to room temperature, and after 30 minutes, LC/MS showed that the reaction was complete. The mixture was quenched with water and aqueous NH4Cl and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to provide the title compound as a semi-solid which was carried on to the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:20][C@H:21](CS([O-])(=O)=O)[CH2:22][CH3:23].S(=O)(=O)(O)O>CN(C=O)C.O>[CH3:20][C@@H:21]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=1)[CH2:22][CH3:23]
Reactant: COC(=O)COc1ccc(O)cc1
Reactant: CC[C@H](C)CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@@H](C)Oc1ccc(OCC(=O)OC)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A mixture of methyl 4-hydroxyphenoxyacetate (25.50 g, 140.0 mmol) and potassium carbonate (18.67 g, 135.0 mmol) in 70 ml of DMF is heated to 75°, with stirring, for 40 min. The above methanesulfonate (10.66 g, 70.0 mmol) in 5 ml of DMF is added slowly over 5 min. The reaction mixture is allowed to stand at 60° overnight. To the cooled reaction mixture is added ice water, followed by cold sulfuric acid to bring it to pH 4-5. Additional water is added and the mixture is extracted with ether (3×). The combined ether extracts are washed with 1% sulfuric acid/1% potassium dihydrophosphate, with 1% potassium dihydrophosphate (2×), then hexane is added and the organic layer is washed with 10% sodium hydroxide (5×), with water and with brine; dried; filtered and the filtrate evaporated to give methyl (R)-(-)-4-(1-methylpropoxy)phenoxyacetate, [α]D20 - 20.672.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10]O)[CH:5]=[N:6][C:7]=1[CH2:8][CH3:9].S(Cl)([Cl:14])=O>>[Cl:1][C:2]1[C:7]([CH2:8][CH3:9])=[N:6][CH:5]=[C:4]([CH2:10][Cl:14])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCc1ncc(CO)cc1Cl
Product: CCc1ncc(CCl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
5-Chloro-6-ethyl-pyridin-3-yl-methanol (4.00 g, 23.3 mmol) is treated with thionyl chloride (50 mL, 685 mmol) and stirred at room temperature for 3 h. The excess SOCl2 is removed under reduced pressure. Water (300 mL) is added and the mixture is neutralized with solid Na2CO3. The precipitated product is filtered, washed with H2O (200 mL) and dried in vacuo to provide 3-chloro-5-chloromethyl-2-ethyl-pyridine as a light brown oil (4.3 g, 97%): Rf 0.54 (30% ethyl acetate in n-heptane), 1H NMR (CDCl3, 300 MHz) δ 8.42 (d, J=1.9 Hz 1 H), 7.70 (d, J=1.9 Hz, 1 H), 4.55 (s, 2 H), 2.97 (q, J=7.4 Hz, 2 H), 1.30 (t, J=7.4 Hz, 3 H). ESI-LCMS m/z calcd for C8H9Cl2N: 189.0; found 190.0 (M+1)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[CH3:13][C:14]1[N:18]=[CH:17][NH:16][N:15]=1.[OH-].[K+].Cl>CS(C)=O.O>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:16]1[CH:17]=[N:18][C:14]([CH3:13])=[N:15]1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: Cc1nc[nH]n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc([N+](=O)[O-])ccc1-n1cnc(C)n1
Reaction time: 0.75 h
Yield: 6.3 %

Procedure:
A solution of 2-chloro-5-nitroanisole (1.0 g, 5.2 mmol), 3-methyl-1H-1,2,4-triazole (1.74 g, 20.9 mmol) and potassium hydroxide (0.44 g, 7.8 mmol) in dimethyl sulfoxide (5 ML) was heated to 80° C. under an atmosphere of nitrogen for two days. Water and 1M aqueous hydrogen chloride solution was added and the reaction was stirred for 45 minutes. The precipitate was filtered off, washed with water, dissolved in dichloromethane. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with water, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by reversed preparative HPLC using acetonitril/water (0.1% formic acid) to yield the title compound as a yellow solid (77 mg, 6%). MS ISP (m/e): 235.2 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.88 (s, 1H), 8.10 (d, 1H), 7.96-8.02 (m, 2H), 4.10 (s, 3H), 2.51 (s, 3H).
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:23][C:24]1[CH:25]=[CH:26][C:27]([CH3:42])=[C:28]([CH:41]=1)[C:29]([NH:31][C:32]1[N:37]=[CH:36][C:35]([C:38](Cl)=[O:39])=[CH:34][CH:33]=1)=[O:30]>ClCCl.O>[CH:1]1[C:6]2[CH2:7][N:8]([C:38]([C:35]3[CH:34]=[CH:33][C:32]([NH:31][C:29](=[O:30])[C:28]4[CH:41]=[C:24]([F:23])[CH:25]=[CH:26][C:27]=4[CH3:42])=[N:37][CH:36]=3)=[O:39])[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)CNc1ccccc1O2
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Oc3ccccc32)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.4 %

Procedure:
To a stirred solution of 0.39 g of 10,11-dihydrodibenz[b,f][1,4]-oxazepine, 1.1 ml of triethylamine in 5 ml of dichloromethane is added 1.17 g of 6-[(5-fluoro-2-methylbenzoyl)amino]-pyridine-3-carbonyl chloride. The mixture is stirred under argon at room temperature for 16 hours, and diluted with 50 ml of dichloromethane and 20 ml of water. The organic layer is separated, washed with 20 ml each of 1M NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate is concentrated to dryness under vacuum. The residue is chromatographed on silica gel with ethyl acetate-hexane (1:1) as solvent to give a solid. Crystallization from ethyl acetate gives 0.335 g of off-white crystals, m.p. 180°-186° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([CH3:34])=[CH:31][CH:32]=4)[NH:27][N:26]=3)=[CH:23][N:24]=[C:19]2[N:18]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:17]=1)=[O:15])([CH3:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[CH2:55][C:56]([N:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1)=[O:57].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[Si:1]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([CH3:34])=[CH:31][CH:32]=4)[N:27]([CH2:55][C:56]([N:58]4[CH2:63][CH2:62][O:61][CH2:60][CH2:59]4)=[O:57])[N:26]=3)=[CH:23][N:24]=[C:19]2[N:18]([C:35]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:17]=1)=[O:15])([CH3:11])[CH3:12])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: O=C(CCl)N1CCOCC1
Reactant: Cc1ccc2c(-c3cnc4c(n3)c(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)cn4C(c3ccccc3)(c3ccccc3)c3ccccc3)n[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc2c(-c3cnc4c(n3)c(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)cn4C(c3ccccc3)(c3ccccc3)c3ccccc3)nn(CC(=O)N3CCOCC3)c2c1
Temperature: 90 °C

Procedure:
A mixture of N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-methyl-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (100 mg, 0.139 mmol), 2-chloro-1-morpholinoethanone (27 mg, 0.166 mmol) and K2CO3 (58 mg, 0.417 mmol) in dry DMF (20 mL) was heated to 90° C. for 3 hours. After cooling to room temperature, ethyl acetate (100 mL) was added, and the solution was washed with water (3×10 mL) and brine (2×10 mL). The combined organic layers were dried over Na2SO4, concentrated to give the residue which was used into the next step without further purification. LCMS: (M+H)+=848.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11](OCC)=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CCOC(=O)c1ccc2nc(N)sc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1nc2ccc(CO)cc2s1
Reaction time: 6.5 h
Yield: 46.4 %

Procedure:
To a solution of ethyl 2-aminobenzo[d]thiazole-6-carboxylate (5.05 g, 22.7 mmol, 1.0 eq.) in THF (60 mL) under nitrogen at 0° C. was added LAH (1M, THF; 100 mL, 100 mmol, 4.4 eq.) over 20 min. After 6.5 h, ice was added, and the solution was stirred overnight. The precipitate was filtered and rinsed with EtOAc. The filtrate was concentrated in vacuo to give a solid which was triturated with Et2O to give (2-aminobenzo[d]thiazol-6-yl)methanol as a yellow solid (1.90 g, 46% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=[O:8].[OH-].[Na+:11]>C(=O)([O-])[O-].[Zn+2].O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O-:9])=[O:8].[Na+:11]
Reactant: O=C(O)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])c1ccccn1

Procedure:
An aqueous solution of sodium picolinate was prepared from 12.3 grams (100 mmol) of picolinic acid, about 4 grams of sodium hydroxide, and 50 ml of water while adjusting the solution to pH 7.2 with an amount of NaOH. With stirring, 2.84 grams (25 mmol of Zn2+) of basic zinc carbonate, 3Zn(OH)2.2ZnCO3.H2O was added to the solution. The resulting mixture indicated pH 13.8.