Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:20])=[N:4][C:5]([C:9]2[C:13]([Cl:14])=[C:12]([O:15][CH:16]([F:18])[F:17])[N:11]([CH3:19])[N:10]=2)=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29]([NH2:31])=[O:30]>>[Cl:1][C:2]1[C:3]([O:20][CH2:28][C:29]([NH2:31])=[O:30])=[N:4][C:5]([C:9]2[C:13]([Cl:14])=[C:12]([O:15][CH:16]([F:17])[F:18])[N:11]([CH3:19])[N:10]=2)=[C:6]([F:8])[CH:7]=1
Reactant: NC(=O)CCl
Reactant: Cn1nc(-c2nc(O)c(Cl)cc2F)c(Cl)c1OC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cn1nc(-c2nc(OCC(N)=O)c(Cl)cc2F)c(Cl)c1OC(F)F
Temperature: 50 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
20.0 g of 3-chloro-6-(4-chloro-5-difluoromethoxy-1-methyl-[1H]-pyrazol-3-yl)-5-fluoropyridin-2-ol (Example P27) are placed together with 18.9 g of potassium carbonate and 6.4 g of chloroacetamide at 22° C. and the mixture is stirred overnight at 50° C. The next day, the mixture is cooled to 22° C. and then introduced into 2 liters of ice-water. After subsequently stirring for 10 minutes at 22° C., the resulting slurry is filtered. The filtration residue is washed with cold water and then dried in vacuo at 60° C. 20.2 g of the desired title compound are obtained in the form of a white solid having a melting point of 178-180° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.Br[C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][N:25]=[CH:26]2)=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:19]3[CH:28]=[C:27]4[C:22]([CH:23]=[CH:24][N:25]=[CH:26]4)=[CH:21][CH:20]=3)[C:6]3[CH:11]4[CH2:12][CH2:13][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:17]4
Reactant: Fc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Reactant: Brc1ccc2ccncc2c1
Product: Fc1ccc2c(c1)c1c(n2-c2ccc3ccncc3c2)C2CCN(CC2)C1

Procedure:
The reaction of 9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (78 mg, 0.34 mmol; Example 161) and 7-bromoisoquinoline (106 mg, 0.51 mmol; Frontier) was performed as described in Example 68 to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.94-2.22 (m, 4H) 2.88-2.96 (m, 1H) 3.08-3.29 (m, 4H) 4.31 (s, 2H) 6.85 (td, J=9, 2 Hz, 1H) 7.06 (dd, J=9, 4 Hz, 1H) 7.12 (dd, J=10, 2 Hz, 1H) 7.74 (dd, J=9, 2 Hz, 1H) 7.96 (d, J=6 Hz, 1H) 8.13 (d, J=2 Hz, 1H) 8.17 (d, J=8 Hz, 1H) 8.55 (d, J=6 Hz, 1H) 9.35 (s, 1H); MS (DCI/NH3) m/z 358 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[N:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:31][C:32]=1[CH3:33])[CH2:6][O:7][C:8]1[CH:12]=[C:11]([C:13]([O:15]C)=[O:14])[N:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:9]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[N:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:31][C:32]=1[CH3:33])[CH2:6][O:7][C:8]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[N:10]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:9]=1
Reactant: COC(=O)c1cc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)c(OC)c2)nn1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(COc2cc(C(=O)O)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 60 °C
Reaction time: 5 h
Yield: 89.5 %

Procedure:
A mixture of methyl 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazole-5-carboxylate (700 mg), 1N aqueous sodium hydroxide solution (3 mL), tetrahydrofuran (5 mL) and ethanol (3 mL) was stirred at 60° C. for 5 hrs. 1N Hydrochloric acid (3 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained colorless crystals were collected by filtration to give 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazole-5-carboxylic acid (610 mg, yield 90%). The crystals were recrystallized from tetrahydrofuran-hexane. melting point: 192-193° C.
Reaction SMILES: [N:1]1[N:2]([C:10]2[N:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]([NH:14][CH:15]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]([OH:20])[C:17](O)=[O:18])=[O:13])[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2.[CH2:32]([NH2:34])[CH3:33]>>[CH2:32]([NH:34][C:17](=[O:18])[CH:16]([OH:20])[CH:15]([NH:14][C:12](=[O:13])[C:11]1[CH:28]=[CH:29][CH:30]=[N:31][C:10]=1[N:2]1[CH:3]=[C:4]2[C:9]([CH:8]=[CH:7][CH:6]=[CH:5]2)=[N:1]1)[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH3:33]
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1cc2ccccc2n1
Reactant: CCN
Product: CCNC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc2ccccc2n1

Procedure:
The reaction was carried out in analogy to reaction step 1.4 by reacting 3-(2-(2H-indazol-2-yl)nicotinamido)-2-hydroxy-4-phenylbutanoic acid and ethylamine.
Reaction SMILES: C([O:5]O)(C)(C)C.C1(C)C=CC=CC=1.[Cl:14][C:15]1[CH:22]=[C:21]([O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[C:20]([O:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])=[CH:19][C:16]=1[CH:17]=[CH2:18].O>C(Cl)Cl.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.O=[V]>[Cl:14][C:15]12[O:5][C:16]1([CH:19]=[C:20]([O:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[C:21]([O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:22]2)[CH:17]=[CH2:18]
Reactant: C=Cc1cc(OCOCCOC)c(OCOCCOC)cc1Cl
Reactant: CC(C)(C)OO
Agent: O=[V]
Agent: CC(=O)/C=C(/C)O
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: C=CC12C=C(OCOCCOC)C(OCOCCOC)=CC1(Cl)O2
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
19 g of vanadylacetylacetonate in solution of 50 ml of methylene chloride were cooled to 0° C. and 3.5 ml of terbutyl hydroperoxide in a toluene solution (3M/l) were added over 30 minutes. The mixture was stirred for 20 minutes at 0° C. and 2.6 g of the product of Stage D in solution in 10 ml of methylene chloride were added. The reaction mixture was stirred for 3 hours at ambient temperature and 30 ml of water were added. The organic phase was separated and the solvent was eliminated under reduced pressure. The residue was chromatographed on silica (eluant: methylene chloride—acetone 8-2) to obtain 21.8 g of the expected product with a Rf=0.35 (CH2Cl2-acetone 8-22).
Reaction SMILES: Cl.[CH3:2][O:3][CH:4]1[CH2:7][NH:6][CH2:5]1.[F:8][C:9]([F:53])([F:52])[C:10]1[CH:11]=[C:12]([C@H:20]2[O:24][C:23](=[O:25])[N:22]([CH2:26][C:27]3[C:32]([C:33]4[CH:34]=[C:35]([CH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44])[CH:36]=[CH:37][C:38]=4[O:39][CH3:40])=[CH:31][N:30]=[C:29](S(C)(=O)=O)[N:28]=3)[C@H:21]2[CH3:51])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1.C(N(CC)CC)C>C1COCC1>[F:53][C:9]([F:8])([F:52])[C:10]1[CH:11]=[C:12]([C@H:20]2[O:24][C:23](=[O:25])[N:22]([CH2:26][C:27]3[C:32]([C:33]4[CH:34]=[C:35]([CH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44])[CH:36]=[CH:37][C:38]=4[O:39][CH3:40])=[CH:31][N:30]=[C:29]([N:6]4[CH2:7][CH:4]([O:3][CH3:2])[CH2:5]4)[N:28]=3)[C@H:21]2[CH3:51])[CH:13]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:15]=1
Reactant: COC1CNC1
Reactant: COC(=O)CCc1ccc(OC)c(-c2cnc(S(C)(=O)=O)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(OC)c(-c2cnc(N3CC(OC)C3)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methoxy-azetidine hydrochloride (60.4 mg, 0.488 mmol) was added into a stirred mixture of methyl 3-{3-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylsulfonyl)pyrimidin-5-yl]-4-methoxyphenyl}propanoate (66 mg, 0.098 mmol) and triethylamine (0.068 mL, 0.488 mmol) in THF (1 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The yellow reaction crude was concentrated in vacuo. The resulting pot residue was purified by preparative HPLC (reverse phase, SunFire Prep C18 OBD 5 um 19×150 mm) eluting with acetonitrile/water+0.05% HCOOH (20% to 100% organic in 10 min, hold 100% for 2 min, 20 mL/min) to give a colorless glass as the titled compound. LCMS calc.=682.22. found=683.27 (M+H)+. 1H-NMR (CDCl3, 500 MHz) δ 8.12 (s, 1H), 7.86 (s, 1H), 7.73 (s, 2H), 7.20 (dd, J=8.5, 2.0 Hz, 1H), 6.97 (d, J=1.5 Hz, 1H), 6.88 (d, J=8.5 Hz, 1H), 5.59 (br d, J=8.0 Hz, 1H), 4.73 (br d, J=17 Hz, 1H), 4.41-4.32 (m, 3H), 4.28 (br s, 1H), 4.11-4.03 (m, 2H), 3.91 (br s, 1H), 3.77 (s, 3H), 3.64 (s, 3H), 3.37 (s, 3H), 2.92 (t, J=7.5 Hz, 2H), 2.62 (t, J=7.5 Hz, 2H), 0.66 (br s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16](I)=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)[O:22][B:21](B2OC(C)(C)C(C)(C)O2)[O:20]1.C([O-])(=O)C.[K+].C(Cl)Cl>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([B:21]([OH:22])[OH:20])=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-n2ncc3c(I)ccnc32)cc1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: OB(O)c1ccnc2c1cnn2-c1ccc(F)cc1
Temperature: 84 °C

Procedure:
To a 16×100 mm reaction vial was added Intermediate 2A (61.8 mg, 0.182 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (85.5 mg, 0.337 mmol), potassium acetate (77 mg, 0.785 mmol), and DMSO (1 mL). Argon was bubbled into the reaction mixture for 5 minutes. Next, PdCl2(dppf).CH2Cl2 (10 mg, 0.012 mmol) was added and the reaction mixture was heated at 84° C. for 18 h. The desired product was confirmed to be present by LC/MS (Condition B): 88.0%; ret. T=3.4 min; (M+H)+ 258.04.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH2:18][C:19](=[O:35])[NH:20][C:21]4[CH:27]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=5)[CH:25]=[CH:24][C:22]=4[N:23]=3)[CH:12]=2)[S:9][CH:10]=1)=[O:5])C>NCCO>[OH:5][CH2:4][CH2:6][NH:7][C:4]([C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH2:18][C:19](=[O:35])[NH:20][C:21]4[CH:27]=[C:26]([C:28]5[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=5)[CH:25]=[CH:24][C:22]=4[N:23]=3)[CH:12]=2)[S:9][CH:10]=1)=[O:5]
Reactant: CCOC(=O)c1csc(-c2cccc(C3=Nc4ccc(-c5ccc(F)cc5)cc4NC(=O)C3)c2)n1
Solvent: NCCO
Product: O=C1CC(c2cccc(-c3nc(C(=O)NCCO)cs3)c2)=Nc2ccc(-c3ccc(F)cc3)cc2N1
Yield: 83.9 %

Procedure:
A solution of 2-{3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo [b][1,4]diazepin-2-yl]-phenyl}-thiazole-4-carboxylic acid ethyl ester (Example 153) (49 mg, 0.1 mmol) in 2-amino-ethanol was heated to 40° C. for 40 min. The cooled solution was partitioned between ethyl acetate and H2O and the organic layer was dried over Na2SO4 and evaporated in vacuum. The residue was triturated with ethyl acetate to give to give the title compound as light yellow solid (21 mg).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([C:14]1[CH:36]=[CH:35][C:17]([CH2:18][N:19]2[CH:34]=[C:22]3[C:23](=[O:33])[N:24]([CH3:32])[C:25]4[N:26]([CH2:27][C:28]([CH3:31])([CH3:30])[N:29]=4)[C:21]3=[N:20]2)=[CH:16][CH:15]=1)(=[O:13])[CH3:12].[Cl:37]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.C(Cl)Cl>[C:11]([C:14]1[CH:36]=[CH:35][C:17]([CH2:18][N:19]2[C:34]([Cl:37])=[C:22]3[C:23](=[O:33])[N:24]([CH3:32])[C:25]4[N:26]([CH2:27][C:28]([CH3:31])([CH3:30])[N:29]=4)[C:21]3=[N:20]2)=[CH:16][CH:15]=1)(=[O:13])[CH3:12]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CC(=O)c1ccc(Cn2cc3c(n2)N2CC(C)(C)N=C2N(C)C3=O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)c1ccc(Cn2nc3c(c2Cl)C(=O)N(C)C2=NC(C)(C)CN23)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
1.0M LiHMDS (2.5 mL, 2.5 mmol) in THF is added dropwise into a solution of 7,8-dihydro-2-(4-acetylbenzyl)-5,7,7-trimethyl-[2H]-imidazo-[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one (580 mg, 1.65 mmol) and hexachloroethane (782 mg, 3.32 mmol) in methylene chloride (8 mL) at −20° C. The reaction mixture is stirred at −20° C. for 30 min, and then quenched with acetic acid (60 μL). Solvents are removed under reduced pressure and the obtained residue is purified on a basic alumina oxide column to give 273 mg of product (yield: 43%). MS (ESI) m/z 386.2 [M+H]+.
Reaction SMILES: C(C1C=NC(C2C=CC(O)=CC=2)=NC=1)CCCCCCCCCC.FC1C=C(C(O)=O)SC=1CCC.[CH2:37]([C:40]1[S:44][C:43]([C:45]([O:47][CH3:48])=[O:46])=[CH:42][CH:41]=1)[CH2:38][CH3:39].[N+:49]([O-])([OH:51])=[O:50].OS(O)(=O)=O>>[N+:49]([C:41]1[CH:42]=[C:43]([C:45]([O:47][CH3:48])=[O:46])[S:44][C:40]=1[CH2:37][CH2:38][CH3:39])([O-:51])=[O:50]
Reactant: O=[N+]([O-])O
Reactant: CCCc1ccc(C(=O)OC)s1
Agent: CCCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: CCCc1sc(C(=O)O)cc1F
Agent: O=S(=O)(O)O
Product: CCCc1sc(C(=O)OC)cc1[N+](=O)[O-]

Procedure:
4.9 g of 4-(5-undecyl-pyrimidin-2-yl)phenol, 2.0 g of 4-fluoro-5-propyl-thiophene-2-carboxylic acid (prepared in accordance with Scheme 1 by nitrating methyl 5-propyl-thiophene-2-carboxylate in HNO3/H2SO4 to form methyl 4-nitro-5-propyl-thiophene-2-carboxylate, followed by reduction of the latter by means of Sn/HCl to give the corresponding amino compound, conversion of the latter into the diazonium tetrafluoroborate, thermolysis and, finally, hydrolysis) and 2.1 g of dicyclohexylcarbodiimide are stirred for 24 h in 50 ml of dichloromethane at room temperature. Filtration, removal of the dichloromethane by distillation, purification by chromatography (silica gel; dichloromethane/heptane) and recrystallization from acetonitrile affords the target compound as colorless crystals.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)[C:14]([NH2:17])=[N:15][CH:16]=1.O>C1COCC1>[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:22][CH:23]=2)[C:14]2[N:15]([CH:16]=1)[CH2:4][CH2:5][S:6](=[O:8])(=[O:7])[N:17]=2
Reactant: Nc1ncc(Cl)cc1-c1ccc(Oc2ccccc2)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=C(Cl)C=C(c3ccc(Oc4ccccc4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
To a mixture of NaH (60%, 2.59 g) and 2-chloroethanesulfonyl chloride (6.33 g) in THF (dry) (50 mL) was added a solution of 5-chloro-3-(4-phenoxyphenyl)pyridin-2-amine (3.84 g) in THF (dry) (50 mL) at room temperature. The mixture was stirred at room temperature overnight. Water and NH silica gel were added and the mixture was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (3.07 g) as a pale yellow solid. The solid was crystallized from DMSO (15 mL)-EtOH (90 mL) to give a white solid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[C:19]2[C:20]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:21]3[N:26]([C:18]=2[N:17]=[CH:16][N:15]=1)[CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]3.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:8][S:9]([O:27][CH:24]1[CH2:23][CH2:22][C:21]2[N:26]([C:18]3[N:17]=[CH:16][N:15]=[C:14]([NH2:13])[C:19]=3[C:20]=2[C:28]2[CH:29]=[N:30][C:31]3[C:36]([CH:37]=2)=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:25]1)(=[O:11])=[O:10]
Reactant: Nc1ncnc2c1c(-c1cnc3ccccc3c1)c1n2CC(O)CC1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OC1CCc2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2C1
Reaction time: 0.25 h

Procedure:
Triethylamine (0.157 ml) and methanesulfonyl chloride (0.074 ml) were added to a solution of 4-amino-5-(quinolin-3-yl)-6,7,8,9-tetrahydropyrimido[5,4-b]indolizin-8-ol (288 mg) obtained in Step 8 in THF (5 ml) under ice-cooling. After stirring at the same temperature for 15 minutes, the mixture was poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a light-brown solid (615 mg).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:20])=[O:19])=[CH:16][C:3]1=2.[CH3:21][CH:22](O)[CH3:23]>>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([O:20][CH:22]([CH3:23])[CH3:21])=[O:19])=[CH:16][C:3]1=2
Reactant: CC(C)O
Reactant: O=C(O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Product: CC(C)OC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2

Procedure:
Reaction of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid with 2-propanol as described in Example 4 provides isopropyl 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetate as colorless crystals, m.p. 67°-68.5° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]([O:14]C)=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-].[Li+]>C1COCC1.O>[O:1]=[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: COC(=O)c1cc2ccncc2[nH]c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2ccncc2[nH]c1=O
Temperature: 65 °C
Yield: 88.6 %

Procedure:
A mixture of methyl 2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxylate (prepared as described in WO 2010/016846)(4.22 g, 20.67 mmol) and lithium hydroxide (2.475 g, 103 mmol) in THF (50 mL) and water (50 mL) was heated at 65° C. for 1 hour. The white precipitate was filtered, washed with water, and dried to afford a white solid. The filtrate was concentrated, dissolved in water and neutralized to pH=7 with concentrated HCl to afford a white solid. The white precipitate was filtered, washed with water, and dried. The solids were combined to afford 2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxylic acid (3.482 g, 18.31 mmol, 89% yield) as an off-white solid. m/z (ESI) 191.2 (M+H)+.
Reaction SMILES: O[CH2:2][C@H:3]1[N:8]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)=[O:11])[CH2:7][CH2:6][N:5]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:4]1.C([SiH](CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(Cl)Cl.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>[N+:18]([C:14]1[CH:13]=[C:12]([CH:10]2[O:11][CH2:2][C@@H:3]3[CH2:4][N:5]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:6][CH2:7][N:8]3[CH2:9]2)[CH:17]=[CH:16][CH:15]=1)([O-:20])=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)c2cccc([N+](=O)[O-])c2)[C@H](CO)C1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCN2CC(c3cccc([N+](=O)[O-])c3)OC[C@@H]2C1
Reaction time: 2 h

Procedure:
(S)-tert-butyl 3-(hydroxymethyl)-4-(2-(3-nitrophenyl)-2-oxoethyl)piperazine-1-carboxylate (1.5 g, 3.95 mmol) was dissolved in mixture of DCM (10 mL)/TFA (5 ml) then added triethylsilane (3.16 mL, 19.8 mmol) and stirred at room temperature overnight. The reaction mixture was concentrated. The residue was dissolved in DCM (15 mL) with saturated aqueous NaHCO3 (15 ml) and di-tert-butyl dicarbonate (2.157 g, 9.88 mmol) was added then stirred for 2 hrs. The reaction was extracted with DCM (2×). The combined DCM was washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The product was chromatographed through 120 g ISCO Redi-sep column and eluted with 10-70% ethyl acetate/hexane to yield the title compound; the product was almost exclusively the trans isomer.
Reaction SMILES: C[C:2]([CH3:5])([O-])C.[K+].[N:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][C:11]=12.O>O1CCCC1>[CH3:11][N:7]1[CH:8]=[CH:9][N:10]=[C:2]1/[CH:5]=[CH:16]/[C:13]1[CH:14]=[CH:15][N:10]2[CH:9]=[CH:8][N:7]=[C:11]2[CH:12]=1
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1ccn2ccnc2c1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1ccnc1/C=C/c1ccn2ccnc2c1
Reaction time: 2 h

Procedure:
To a stirred solution of 2-triphenylphosphonium-1-methyl-1H-imidazole chloride (656 mg, 1.6 mmol, 1 equiv) in tetrahydrofuran (5 ml) at room temperature was added dropwise a solution of potassium tert-butoxide in tetrahydrofuran (1M, 3.3 ml, 3.3 mmol, 2 equiv). This brightly orange mixture was stirred thus for 2 hours and then a solution of imidazo[1,2-a]pyridine-7-carbaldehyde (245 mg, 1.7 mmol, 1 equiv) in tetrahydrofuran (8 ml) was added and the lightly coloured mixture was stirred at room temperature overnight. To the reaction was added water and the mixture was extracted with ethyl acetate. The organic liquors were washed with water and brine and then dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (0-20% methanol/ethyl acetate) furnishing 7-[(E)-2-(1-methyl-1H-imidazol-2-yl)-vinyl]-imidazo[1,2-a]pyridine (87 mg). MS:
Reaction SMILES: C(OCC)(=O)[CH2:2][C:3]([O-])=[O:4].[K+].[Cl-].[Mg+2].[Cl-].[C:14]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C@@:26]([OH:34])([CH:31]([CH3:33])[CH3:32])[CH2:27][C:28]([OH:30])=O)=[CH:20][CH:19]=1)(=[O:16])[CH3:15].C(C1NC=CN=1)(C1NC=CN=1)=O>O1CCCC1.C(#N)C>[C:14]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][C@:26]2([CH:31]([CH3:33])[CH3:32])[O:34][C:3](=[O:4])[CH:2]=[C:28]([OH:30])[CH2:27]2)=[CH:22][CH:23]=1)(=[O:16])[CH3:15]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CC(=O)Nc1ccc(CC[C@](O)(CC(=O)O)C(C)C)cc1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(CC[C@@]2(C(C)C)CC(O)=CC(=O)O2)cc1
Temperature: 15 °C
Reaction time: 3 h
Yield: 74.2 %

Procedure:
Potassium ethyl malonate (12.9 g) and magnesium chloride (7.6 g) are added to a flask followed by acetonitrile (70 mL) and tetrahydrofuran (45 mL) and the resulting mixture stirred at 15° C. for 3 hours under an inert atmosphere. To a second flask is added (S)-3-[2-(N-acetylaminophenyl)ethyl]-3-hydroxy-4-methylpentanoic acid (23a) (9.6 g, 31 mmol correcting for 4.9% water content) and tetrahydrofuran (296 mL) followed by carbonyl diimidazole (8.0 g) and the resulting solution stirred at ambient temperature for 3 hours. The latter solution is then added over a 2 hour period to the potassium ethyl malonate-magnesium chloride complex in the first flask and the resulting mixture stirred overnight at 20° C. The mixture was concentrated under vacuum to remove solvent while maintaining the temperature below 40° C. Cold ethyl acetate (116 mL) and water (60 mL) are added to the residue followed by 37% hydrochloric acid (7 g) with agitation while maintaining the temperature below 10° C. The layers are allowed to settle and the aqueous layer separated. The organic layer is extracted twice with a solution of 37% hydrochloric acid (2.5 g) in water (22 mL) followed by a solution of sodium bicarbonate (2 g) in water (20 mL). The remaining organic layer is concentrated under vacuum to remove solvent. The residue is dissolved in methanol (10 mL) and a solution of sodium hydroxide pellets (3.0 g) dissolved in methanol (25 mL) is added and the resulting solution stirred at ambient temperature for 3 days. The solution was concentrated under vacuum to remove solvent. Water (60 mL) was added to the residue and then removed by concentrating under vacuum while maintaining the temperature below 45° C. The remaining oil is dissolved in water (60 mL) and the resulting solution added over 45 minutes to a solution of 3.9 g acetic acid in methanol (10 mL) and water (10 mL). The mixture is stirred overnight at ambient temperature and then cooled to 5° C. and filtered and the solid washed with water (100 mL) and vacuum dried at 60° C. to give 8.0 g (23 mmol; 74% correcting for HPLC purity and water content) of (S)-6-[2-(4-acetylamino-phenyl)ethyl]-4-hydroxy-6-isopropyl-5,6-dihydropyran-2-one (24a): HPLC: 95.1 %; Water (KF): 4.4%.