Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1([Cl:15])[C:10]([Cl:11])=[C:9]([Cl:12])[C:8]1([Cl:14])[Cl:13].S(=O)(=O)=O.[Cl-].[Na+]>>[Cl:6][C:7]([Cl:15])=[C:10]([Cl:11])[C:9]([Cl:12])=[C:8]([Cl:14])[Cl:13]
Reactant: ClC1=C(Cl)C(Cl)(Cl)C1(Cl)Cl
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Agent: [Cl-]
Product: ClC(Cl)=C(Cl)C(Cl)=C(Cl)Cl
Temperature: 80 °C
Yield: 2.4 %

Procedure:
In a 500 cc flask, 105.7 g of 29% strength fuming sulphuric acid were poured onto 102.5 g of 97.6% pure hexachlorocyclobutene [100 g (0.383 mole) of hexachlorocyclobutene; remainder hexachloro-1,3-butadiene], with stirring (molar ratio of hexachlorocyclobutene:sulphuric acid:sulphur trioxide=1:2:1). The mixture was heated at 80° C. for 1 hour. After cooling, the reaction product was poured slowly into a mixture of ice and sodium chloride, with vigorous stirring, and the organic phase was then separated immediately from the aqueous phase. A mixture of 41.1 g of tetrachlorocyclobutenone, 9.5 g of hexachlorocyclobutene and 2.4 g of hexachloro-1,3-butadiene was obtained. The selectivity of the reaction was thus 72% of theory with a conversion of 91% of theory.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:15][C:14]=1[Cl:24].[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1>[Cl:24][C:14]1[CH:15]=[C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:17]=[CH:18][C:13]=1[O:12][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([S:33]([C:27]3[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=3[Cl:25])(=[O:35])=[O:34])[C:8]([CH3:11])=[N:9][C:10]=2[C:2]=1[NH:1][S:33]([C:27]1[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=1[Cl:25])(=[O:35])=[O:34]
Reactant: COC(=O)Cc1ccc(Oc2ccc3[nH]c(C)nc3c2N)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Product: COC(=O)Cc1ccc(Oc2ccc3c(nc(C)n3S(=O)(=O)c3ccc(Cl)cc3Cl)c2NS(=O)(=O)c2ccc(Cl)cc2Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under an N2 atmosphere, methyl 2-(4-(4-amino-2-methyl-1H-benzo[d]imidazol-5-yloxy)-3-chlorophenyl)acetate (0.171 g, 0.495 mmol) was dissolved in pyridine (1.5 mL) and 2,4-dichlorobenzenesulfonyl chloride (0.267 g, 1.09 mmol) was added. The reaction was allowed to stir at room temperature for 3 h and then concentrated in vacuo. Flash column chromatography of the residue, eluting 0% to 50% ethyl acetate in hexanes, afforded the title compound. LC-MS ESI (pos.) m/z: 763.7 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:23][CH2:22][C:21]2[C:20]([C:24]3[N:28](C4CCCCO4)[N:27]=[CH:26][CH:25]=3)=[N:19][CH:18]=[N:17][C:16]=2[CH2:15]1)=[O:13].Cl.[OH-].[Na+]>CO.O>[NH:28]1[C:24]([C:20]2[C:21]3[CH2:22][CH2:23][N:14]([C:12]([C:3]4[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:10])([F:9])[F:11])[C:2]=4[Cl:1])=[O:13])[CH2:15][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:25][CH:26]=[N:27]1
Reactant: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2c(ncnc2-c2ccnn2C2CCCCO2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2c(ncnc2-c2ccn[nH]2)C1
Reaction time: 3 h
Yield: 80.5 %

Procedure:
To a solution of Example 17 (224 mg, 0.46 mmol) in MeOH (2 mL) was added 6 M HCl (0.30 mL). The mixture was aged for 3 h and then neutralized with solid NaOH (74 mg, 1.84 mmol) dissolved in a minimum amount of water. The mixture was then concentrated in vacuo. The material was dissolved in DCM and stirred overnight. Filtration removed the inorganic solids and the filtrate was concentrated in vacuo. Chromatography on SiO2 EtOAc/Hex afforded the desired compound as a colorless foam (151 mg, 81%). MS (ESI) mass calcd. C18H13ClF3N5O, 407.08. m/z found 408.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 9.10-8.95 (m, 1H), 7.83-7.77 (m, 1H), 7.76-7.69 (m, 1H), 7.58-7.45 (m, 2H), 7.05-6.89 (m, 1H), 5.18-4.98 (m, 1H), 4.60-4.41 (m, 1H), 4.25-4.04 (m, 1H), 3.64-3.51 (m, 1H), 3.43-3.09 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:27]=[CH:28][CH:29]=2)[C:15]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)=[O:16])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.F[C:31]1C=C(S(Cl)(=O)=O)C=C[CH:36]=1>>[CH2:31]([O:23][C:22](=[O:24])[C:21]1[CH:25]=[CH:26][C:18]([NH:17][C:15](=[O:16])[C:14]2[CH:27]=[CH:28][CH:29]=[C:12]([NH:11][S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)(=[O:9])=[O:10])[CH:13]=2)=[CH:19][CH:20]=1)[CH3:36]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: O=C(O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3cccc(F)c3)c2)cc1
Product: CCOC(=O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3cccc(F)c3)c2)cc1

Procedure:
4-[3-(3-Fluoro-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=413.1 (M−H), was prepared in analogy to example 1, steps A to D. Step C was performed using 3-fluoro-benzensulfonyl chloride and yielded 4-[3-(3-fluoro-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH3:25])[N:5]2[C:10]=1[C:9]([N:11]1[CH:15]=NC=N1)=[N:8][C:7]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1)=[N:6]2.[CH3:26][O:27][C:28]1[CH:29]=C([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])N.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][C:2]1[N:3]=[C:4]([CH3:25])[N:5]2[C:10]=1[C:9]([NH:11][C:15]1[CH:29]=[C:28]([O:27][CH3:26])[C:34]([O:35][CH3:36])=[C:33]([O:37][CH3:38])[CH:32]=1)=[N:8][C:7]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1)=[N:6]2
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: Cc1nc(C)n2nc(-c3cccc([N+](=O)[O-])c3)nc(-n3cncn3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Nc2nc(-c3cccc([N+](=O)[O-])c3)nn3c(C)nc(C)c23)cc(OC)c1OC
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 350 mg (1.04 mmol) of 5,7-dimethyl-2-(3-nitrophenyl)-4-(1H-1,2,4-triazol-1-yl)imidazo[5,1-f][1,2,4]triazine from example 12A in DMF is treated with 290 mg (1.56 mmol) of 3,4,5-trimethoxyaniline and 220 mg (1.56 mmol) of potassium carbonate. The reaction mixture is stirred overnight at 90° C. After cooling, the solvent is removed on a rotary evaporator, the residue is treated twice more with toluene and the solvent is removed in vacuo. The product is extracted by stirring with a little methanol and filtered off with suction.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:10][CH2:9][N:8]([C:11](=[O:24])[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:7]1)C.[Li+].[OH-]>CO>[Cl:32][C:27]1[CH:26]=[C:25]([C:6]2([CH2:5][CH2:4][OH:3])[CH2:10][CH2:9][N:8]([C:11](=[O:24])[C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)[CH2:7]2)[CH:30]=[CH:29][C:28]=1[Cl:31]
Reactant: CCOC(=O)CC1(c2ccc(Cl)c(Cl)c2)CCN(C(=O)c2cc(OC)c(OC)c(OC)c2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)N2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
(+)-Ethyl-2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-acetate (670 mg, 1.351 mmol, 99% ee) was dissolved in methanol (15 mL) and treated with LiOH (4.2 mL, 1N, 3.1 eq.) at ambient temperature for 3.5 h. The organics were concentrated in vacuo. The residue was dissolved in dichloromethane and washed with 1N HCl (50 mL), 5% NaHCO3 (50 mL), dried over MgSO4, filtered, and concentrated in vacuo to obtain a residue. The residue was dried under high vacuum for 18 h to give the title compound:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23](Cl)=[N:24][C:17]=2[N:16]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C:15]1=[O:34])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:24][C:17]=2[N:16]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[C:15]1=[O:34])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=c1c2cc(F)c(Cl)nc2n(-c2ccc(F)cc2)c(=O)n1OCc1ccccc1
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=c1c2cc(F)c(N3CCCC3)nc2n(-c2ccc(F)cc2)c(=O)n1OCc1ccccc1
Yield: 79.3 %

Procedure:
Pyrrolidine (0.04 mL, 0.52 mmol) was added to a solution of 3-benzyloxy-7-chloro-6-fluoro-1-(4-fluorophenyl)-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example Q-2, 0.17 g, 0.42 mmol) and triethylamine (0.36 mL, 2.6 mmol) in 20 mL of acetonitrile. The solution was warmed to reflux for 17 hours, cooled, and concentrated to a solid. The solid was dissolved in chloroform, washed with 1N HCl, saturated NaHCO3, brine, and dried over magnesium sulfate. The solution was concentrated to give 0.15 g of the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Li]CCCC.CC([O-])(C)C.[K+].[CH2:22]([O:24][C:25](=O)[O:26]CC)[CH3:23]>CCOCC>[NH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[C:2]1[CH2:1][C:25]([O:24][CH2:22][CH3:23])=[O:26]
Reactant: Cc1cc2ccccc2[nH]1
Reactant: CCOC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCOC(=O)Cc1cc2ccccc2[nH]1

Procedure:
2-Methylindole (1.7 g, 13 mmol) in 130 mL Et2O was treated with nBuLi (1.6M in hexane, 24.4 mL, 39 mmol) and KOtBu (1.0M in THF, 26 mL, 26 mmol) at RT for 40 min, then diethylcarbonate (3.15 mL, 26 mmol) was added. After 1 h the reaction was quenched with water, adjusted to pH 7 with 6N HCl, extracted with EtOAc, then the organic layer was washed with water and brine, dried (MgSO4), and concentrated. Flash chromatography (silica 10% then 20% EtOAc/hexane) provided 4-1 as a brown oil. Rf 0.33 (silica, 20% EtOAc/hexane).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[NH:11][C:10](=[O:19])[C:9]([C:20]([OH:22])=O)=[CH:8]2)(=[O:3])[CH3:2].S(Cl)([Cl:25])=O>CN(C)C=O.C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[NH:11][C:10](=[O:19])[C:9]([C:20]([Cl:25])=[O:22])=[CH:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc2cc(C(=O)O)c(=O)[nH]c2cc1OC(C)=O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(=O)Oc1cc2cc(C(=O)Cl)c(=O)[nH]c2cc1OC(C)=O

Procedure:
A mixture of 6,7-diacetoxy-1,2-dihydro-2-oxoquinoline-3-carboxylic acid (100 mg), thionyl chloride (70 μL), and dimethylformamide (one drop) was heated under reflux for 4.5 hours in 50 mL of benzene, and the solvent was distilled off. Benzene (30 mL) was added to the residue and the benzene was distilled off again, followed by vacuum drying, to yield 6,7-diacetoxy-1,2-dihydro-2-oxoquinoline-3-carbonyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[C:12]([C:14](O)=[O:15])[C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N+:23]([O-])=O)=[N:10]2)[CH:6]=[CH:7][CH:8]=1.CO>[Pd].O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[C:12]3[C:14](=[O:15])[NH:23][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[C:11]3=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-n2cc(C(=O)O)c(-c3ccccc3[N+](=O)[O-])n2)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(-n2cc3c(=O)[nH]c4ccccc4c3n2)c1
Temperature: 25 °C
Yield: 82.2 %

Procedure:
A mixture of 1-(3-methoxyphenyl)-3-(2-nitrophenyl)-1H-pyrazole-4-carboxylic acid (500 mg), 10% palladium/active carbon (50% water, 50 mg), tetrahydrofuran (30 ml) and methanol (50 ml) was stirred under hydrogen atmosphere, at room temperature for one night. To the reaction mixture was added tetrahydrofuran to dissolve the precipitated solid and the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. To the residue was added ethanol-ethyl acetate, and the solid was collected by filtration. The solid was washed with ethyl acetate and dried to obtain the target compound (353 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:3]=1[CH2:4][N:5]([CH3:7])[CH3:6].[Br:14]Br>C(Cl)Cl>[NH2:1][C:2]1[C:11]([Br:14])=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:3]=1[CH2:4][N:5]([CH3:7])[CH3:6]
Reactant: COc1ccc(N)c(CN(C)C)c1
Reactant: BrBr
Solvent: ClCCl
Product: COc1cc(Br)c(N)c(CN(C)C)c1

Procedure:
2-Amino-3-bromo-N,N-dimethyl-5-methoxy-benzylamine was prepared from 2-amino-N,N-dimethyl-5-methoxy-benzylamine and bromine analogous to Example 9. Proof of structure by IR-, UV- and NMR-spectra, IR-spectrum (methylenechloride): 3250 cm-1NH2 ; 3410 cm-1NH2 ; 2780 cm-1N(CH3)2 ; 2830 cm-1OCH3 ; 1590 cm-1C=C; 1600 cm-1C=C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[O:13]=[S:14]1(=[O:24])[CH2:18][C:17]2[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:16]=2[CH2:15]1>>[O:13]=[S:14]1(=[O:24])[CH2:18][C:17]2[CH:19]=[CH:20][C:21]([NH:23][C:2]3[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=3)=[CH:22][C:16]=2[CH2:15]1
Reactant: CSc1nc(C)c(C#N)c(Cl)n1
Reactant: Nc1ccc2c(c1)CS(=O)(=O)C2
Product: CSc1nc(C)c(C#N)c(Nc2ccc3c(c2)CS(=O)(=O)C3)n1

Procedure:
The compound was prepared from 4-chloro-6-methyl-2-(methylthio)-5-pyrimidinecarbonitrile and (2,2-dioxido-1,3-dihydro-2-benzothien-5-yl)amine following a procedure similar to that described for Intermediate 23.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.Cl.[CH:16]1([C@H:19]([NH2:21])[CH3:20])[CH2:18][CH2:17]1.CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:21][C@@H:19]([CH:16]3[CH2:18][CH2:17]3)[CH3:20])=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: C[C@@H](N)C1CC1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(Br)cc12)C1CC1
Reaction time: 0.17 h
Yield: 82.5 %

Procedure:
A solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 500 mg, 1.821 mmol), (R)-1-cyclopropylethanamine HCl salt (277 mg, 2.277 mmol) and DIPEA (0.795 mL, 4.55 mmol) in NMP (5 mL) was heated to 100° C. for 4 hr. The reaction mixture was added 10 mL of water and stirred for 10 minutes. The solid was collected by vacuum filtration and dried to afford the title compound (485.4 mg, 79%). HPLC (condition G): retention time=2.29 min. LCMS (condition B): m/z 324.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.70 (1 H, d, J=8.1 Hz), 8.22 (1 H, s), 7.84 (1 H, d, J=1.8 Hz), 6.99 (1 H, d, J=1.8 Hz), 3.78-3.91 (1H, m), 1.29 (3 H, d, J=6.2 Hz), 0.99-1.11 (1 H, m), 0.42-0.53 (2 H, m), 0.33-0.40 (1H, m), 0.22-0.29 (1 H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C@@H:8]([O:10]C(=O)[C@H](NC(OC(C)(C)C)=O)C(C)C)[CH3:9])=[N:6][CH:7]=1>CO>[Br:1][C:2]1[CH:3]=[N:4][C:5]([CH:8]([OH:10])[CH3:9])=[N:6][CH:7]=1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O[C@@H](C)c1ncc(Br)cn1
Solvent: CO
Product: CC(O)c1ncc(Br)cn1
Yield: 75.2 %

Procedure:
Amberlite® basic ion exchange resin and ii (15.4 g, 38.3 mmol) were stirred in MeOH (50 mL) overnight at RT. The suspension was filtered through a pad of silica using 1:1 MeOH/DCM and the filtrate concentrated in vacuo. Crystallisation from hot heptane gave Precursor 82 (5.85 g). (1S)-1-(5-bromopyrimidin-2-yl)ethanol (Precursor 83) was similarly prepared using Boc-L-valine. Mitsunobu inversion of one enantiomer to the desired enantiomer may also be employed.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:11]([C:12]([OH:14])=O)[C:10]=2[C:18]([OH:20])=O)=[CH:5][CH:4]=1.Cl.[NH2:24][CH:25]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:26]1=[O:27]>N1C=CC=CC=1>[O:27]=[C:26]1[CH:25]([N:24]2[C:18](=[O:20])[C:10]3[C:11](=[CH:15][CH:16]=[CH:17][C:9]=3[O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:22][CH:21]=3)[C:12]2=[O:14])[CH2:31][CH2:30][C:29](=[O:32])[NH:28]1
Reactant: COc1ccc(COc2cccc(C(=O)O)c2C(=O)O)cc1
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(COc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1
Yield: 40.5 %

Procedure:
A stirred mixture of 3-(4-methoxy-benzyloxy)-phthalic acid (1.5 g, 5.2 mmol), alpha-amino-glutarimide hydrochloride (0.90 g, 5.4 mmol) in pyridine was refluxed overnight. The mixture was evaporated in vacuo, and the residue was purified by flash column chromatography (Silica Gel, methanol/methylene chloride, 0% gradient to 10% 30 min) to give 2-(2,6-dioxo-piperidin-3-yl)-4-(4-methoxy-benzyloxy)-isoindole-1,3-dione as a white solid (0.83 g, 40% yield); HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 50/50 CH3CN/0.1% H3PO4, RT=4.17 min (98.6%); mp, 178-180° C.; 1HNMR (DMSO-d6) δ1.99-2.06 (m, 1H, CHH), 2.51-2.82 (m, 2H, CHHCH2), 3.76 (s, 3H, CH3), 5.08 (dd, J=6, 12 Hz, 1H, CH), 5.29 (s, 2H, CH2), 6.95-7.84 (m, 7H, Ar), 11.11 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.96, 30.91, 48.72, 55.08, 69.92, 113.88, 115.41, 116.55, 120.29, 127.93, 129.21, 133.25, 136.92, 155.57, 159.10, 165.28, 166.77, 169.90, 172.75. Anal Calcd For C21H18N2O6: C, 63.96; H, 4.60; N, 7.10. Found: C, 63.86; H, 4.30; N, 6.92.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1>C(OCC)(=O)C>[N+:8]([C:7]1[C:2]([NH:11][C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: Cc1cccc(N)c1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CCOC(C)=O
Product: Cc1cccc(Nc2ncccc2[N+](=O)[O-])c1
Temperature: 100 °C
Yield: 36.4 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (1.59 g) and m-toluidine (1.07 g) was heated at 100° C. for 20 minutes. The mixture was cooled and dissolved in ethyl acetate. The organic solution was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate, 4:1) to afford 3-nitro-2-[(m-tolyl)amino]pyridine (834 mg) as an orange solid.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3Br)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][C:42]([C:45]([O:47][CH3:48])=[O:46])=[CH:41][C:40]=2[CH3:49])=[CH:35][C:34]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O>O.CCO.C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCC>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[C:34]3[CH:35]=[C:36]([C:39]4[CH:44]=[CH:43][C:42]([C:45]([O:47][CH3:48])=[O:46])=[CH:41][C:40]=4[CH3:49])[CH:37]=[CH:38][C:33]=3[O:32][CH3:31])[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(Cl)ccc1Br
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(B3OC(C)(C)C(C)(C)O3)c2)c(C)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(Cl)cc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1

Procedure:
A mixture of the title compound from Step B (0.068 g, 0.13 mmol), methyl 4′-methoxy-2-methyl-3′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-carboxylate (INTERMEDIATE 11) (0.075 g, 0.19 mmol), tetrakis(triphenylphosphine) palladium (15 mg, 5% mol) and sodium carbonate (0.07 g, 0.65 mmol) in 7 ml of water/EtOH/toluene (1:2:4) was heated to reflux for 5 h. TLC (EtOAc:hexane/1:3) showed that the reaction was over. The solvents were removed. Water (10 ml) was added. The organic was extracted with methylene chloride (3×20 ml). The combined methylene chloride layers were washed with brine, and dried over sodium sulfate. The title compound was obtained after purification with preparative TLC using 10% EtOAc in hexane as the eluant. 1H NMR (CDCl3, 500 MHz): δ 1:1 mixture of atropisomers 7.96 (d, J=9 Hz, 1H), 7.88 (m, 2H), 7.72 (s, 1H), 7.65 (s, 1H), 7.49 (d, J=2 Hz, 0.5H), 7.39 (m, 2H), 7.36 (d, J=2 Hz, 0.5H), 7.24-7.28 (m, 2H), 7.15 (m, 1H), 7.70 (m, 1H), 5.62 (d, J=8 Hz, 0.5H), 5.52 (d, J=8 Hz, 0.5H), 4.91 (t, J=16 Hz, 1H), 4.08 (d, J=15.5 Hz, 0.5H), 3.95 (s, 3H), 3.88 (s, 3H), 3.87 (d, J=16 Hz, 0.5H), 3.84 (m, 1H), 2.39 (s, 1.5H), 2.33 (s, 1.5H), 0.56 (d, J=7 Hz, 1.5H), 0.43 (d, J=6.5 Hz, 1.5H).
Reaction SMILES: [C:1](Cl)(=O)C.[OH:5][C:6]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]>CO>[OH:5][C:6]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([O:10][CH3:1])=[O:9]
Reactant: O=C(O)c1cccc(O)c1O
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1cccc(O)c1O
Temperature: 25 °C
Yield: 99 %

Procedure:
Prepare a reaction flask with 300 mL methanol and add 30 mL of acetyl chloride, under argon, in an ice bath. Add 2,3-dihydroxy-benzoic acid (21.70 g, 0.1418 mole) and stir while heating at reflux overnight. Chill in an ice bath and bubble through hydrogen chloride gas for about 10 minutes. Heat the mixture and stir at reflux overnight. Cool to ambient temperature, then concentrate to an off-white solid. Dissolve and separate into diethyl ether and water. Isolating the ether portion and extract twice with 250 mL 5% sodium bicarbonate. Separate, wash with brine and dry over magnesium sulfate. Filter and condense on a rotary evaporator to give the title compound as an off-white solid (21.1 g, 99%). m.p. 79°-81° C.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[O:34])[CH:7]([CH:13]([C:20]1[CH:21]=[N:22][C:23]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]([O:10]CC)=[O:9])[CH3:4]>C(O)C.C(Cl)Cl>[CH2:3]([O:5][C:6](=[O:34])[CH:7]([CH:13]([C:20]1[CH:21]=[N:22][C:23]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]([OH:10])=[O:9])[CH3:4]
Reactant: CCOC(=O)C(C(=O)OCC)C(c1ccccc1)c1ccc(NC(=O)OC(C)(C)C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(C(=O)O)C(c1ccccc1)c1ccc(NC(=O)OC(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
A solution of KOH (0.266 g, 4.11 mmol) in ethanol (14 mL) was added to a solution of 2-[(6-tert-butoxycarbonylamino-pyridin-3-yl)-phenyl-methyl]-malonic acid diethyl ester (1.82 g, 4.11 mmol) in ethanol (12 mL) and methylene chloride (13 mL) at 0° C. The mixture was stirred overnight at room temperature. More KOH (80 mg dissolved in 3 mL ethanol) was added at 0° C. The reaction mixture was stirred for additional 18 h. The mixture was concentrated under reduced pressure and ethyl acetate, and 0.5 M HCl were added to the residue. The organic layer was washed with brine and dried. After filtration and evaporation in vacuo, the residue was suspended in hexane. Filtration of the crystals gave 2-[(6-tert-butoxycarbonylamino-pyridin-3-yl)-phenyl-methyl]-malonic acid monoethyl ester (1.7 g, 98%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]([CH3:31])([CH3:30])[CH2:28][OH:29]>>[OH:29][CH2:28][C:27]([CH3:31])([CH3:30])[CH2:26][NH:25][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:22]
Reactant: CC(C)(CN)CO
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)O)n(C)n1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)NCC(C)(C)CO)n(C)n1
Yield: 70 %

Procedure:
As described for example 55, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.3 mmol) was converted, using 3-amino-2,2-dimethyl-1-propanol instead of 2-amino-2-methyl-1-propanol, to the title compound (88 mg, 70%) which was obtained as a white solid. MS: m/e=417.2 [M+H]+.