Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:6][N:7]([C:28]1[N:33]=[CH:32][C:31]([C:34]2[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=2)=[CH:30][N:29]=1)[C@@H:8]1[CH2:12][N:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23](O)[CH3:24])[C@H:10]([CH2:26][CH3:27])[CH2:9]1.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O.ClCCCl>[F:45][C:43]([F:44])([F:46])[C:41]1[CH:40]=[C:5]([CH:4]=[C:3]([C:2]([F:48])([F:47])[F:1])[CH:42]=1)[CH2:6][N:7]([C@H:8]1[CH2:9][C@@H:10]([CH2:26][CH3:27])[N:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:14]=2[CH2:23][CH3:24])[CH2:12]1)[C:28]1[N:29]=[CH:30][C:31]([C:34]2[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=2)=[CH:32][N:33]=1
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1c1ccc(C(F)(F)F)cc1C(C)O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CCc1cc(C(F)(F)F)ccc1N1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)C[C@H]1CC
Temperature: 80 °C
Reaction time: 4 h
Yield: 7.5 %

Procedure:
To a mixture of 1-[2-((2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidin-1-yl)-5-trifluoromethyl-phenyl]-ethanol (29 mg, 0.04 mmol) in TFA (1 mL) and DCE (1 mL) is added triethylsilane (1 mL, 6.3 mmol) The reaction mixture is stirred at 80° C. for 4 hours. After removal of solvent and triethylsilane, the mixture is washed with brine and extracted with EtOAc. The combined organic layer is dried over MgSO4 then concentrated under reduced pressure to give (3,5-bis-trifluoromethyl-benzyl)-[(3S,5R)-5-ethyl-1-(2-ethyl-4-trifluoromethyl-phenyl)-pyrrolidin-3-yl]-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine as a colorless oil (2 mg, 7%) after purification by silica gel column chromatography (eluent: n-hexane/EtOAc);
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][OH:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([CH2:34][O:35][S:44]([CH3:43])(=[O:46])=[O:45])[C@H:11]([CH2:13][N:14]([CH:31]([CH3:32])[CH3:33])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CO)C(C)C)ccc1OC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2COS(C)(=O)=O)C(C)C)ccc1OC
Reaction time: 0.33 h

Procedure:
To a solution of (3S,4R)-3-hydroxymethyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (2.32 g, 4.69 mmol; Example 10, reaction step H) is subsequently added at −20° C. with stirring NEt3 (1.95 mL, 14.1 mmol) and in a dropwise fashion methane sulfonylchloride (0.423 mL, 5.39 mmol). Stirring is continued for 20 min at −20° C., the mixture is then diluted with CH2Cl2 and the organic layer is washed with 2N HCl, dried (Na2SO4) and evaporated to dryness to give the crude title compound as yellowish oil. TLC, Rf (hexane/AcOEt 1:3)=0.13.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[CH2:11](O)[CH3:12]>[Ni]>[CH2:11]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1)[CH3:12]
Reactant: Nc1ccc2c(c1)CCO2
Reactant: CCO
Agent: [Ni]
Product: CCNc1ccc2c(c1)CCO2
Temperature: 25 °C

Procedure:
A mixture of 148 g. (1.09 moles) of 5-amino-2,3-dihydrobenzofuran and 93 g. of W2 Raney nickel in 850 ml. of ethanol was heated to reflux for 24 hours. The reaction was cooled to 25° C., filtered and evaporated to give a quantitative yield of the desired intermediate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10]C(C)C)=[CH:4][C:3]=1[C:14](=[O:16])[CH3:15].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([OH:10])=[CH:4][C:3]=1[C:14](=[O:16])[CH3:15]
Reactant: COc1cc(Br)c(C(C)=O)cc1OC(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(Br)c(C(C)=O)cc1O
Temperature: 18 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
A solution of ketone 38 (220 mg, 0.766 mmol) in dry CH2Cl2 (2.0 mL) was treated with AlCl3 (306 mg, 2.29 mmol) and the resulting mixture stirred at 18° C. under a nitrogen atmosphere for 2 h. The ensuing mixture was partitioned between H2O (5 mL) and CH2Cl2 (5 mL) then the separated aqueous phase extracted with CH2Cl2 (1×15 mL). The combined organic fractions were dried (MgSO4), filtered and concentrated under reduced pressure and the ensuing residue subjected to flash chromatography (15:85 v/v ethyl acetate/hexane elution) to afford the title compound 39 (184 mg, 98%) as a pale-yellow solid, m.p. 109.7-111.4° C., Rf 0.4 in 1:1 v/v ethyl acetate/hexane.
Reaction SMILES: [C:1]([NH:9][CH:10]1[C:16](=[O:17])[N:15]2[CH:18]([C:22]([NH:24][CH:25]([C:34](=[O:38])[CH:35]=[N+:36]=[N-:37])[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:39])[CH2:12][CH2:11]1)(=[O:8])[C:2]1C=CC=CC=1.[K+].[Br-]>C(Cl)Cl>[C:1]([NH:9][CH:10]1[C:16](=[O:17])[N:15]2[CH:18]([C:22]([NH:24][CH:25]([C:34](=[O:38])[CH:35]=[N+:36]=[N-:37])[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28])=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:39])[CH2:12][CH2:11]1)(=[O:8])[CH3:2]
Reactant: CC(C)(C)OC(=O)CC(NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12)C(=O)C=[N+]=[N-]
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)NC1CCC(=O)N2CCCC(C(=O)NC(CC(=O)OC(C)(C)C)C(=O)C=[N+]=[N-])N2C1=O

Procedure:
was prepared by a similar method as compound 506a. 81%: [α]D28 −146.7° (c 0.4, CH2Cl2); IR (KBr) 3438, 2904, 2113, 1728, 1669, 1523, 1368, 1328, 1155; 1H NMR (CDCl3) δ7.32 (1H, d), 6.43 (1H, d), 5.50 (1H, s), 5.22 (1H, m), 4.94 (1H, m), 4.77 (1H, m), 4.60 (1H, m), 3.24 (1H, m), 3.03-2.52 (4H, m), 2.36 (1H, m), 2.10-1.64 (5H, m), 2.02 (3H, s), 1.45 (9H, s). Anal. Calcd for C21H20N6O7: C, 52.69; H, 6.32; N, 17.05. Found: C, 52.51; H, 6.27; N, 17.36. MS (ES+) 477(M+−1, 100%).
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:8](=[O:21])[NH:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:31]=[CH:30][C:26]2[O:27][CH2:28][O:29][C:25]=2[C:24]=1[NH2:32].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC([O-])(C)C.[Na+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:22][C:23]1[CH:31]=[CH:30][C:26]2[O:27][CH2:28][O:29][C:25]=2[C:24]=1[NH:32][C:2]1[C:11]2[CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:8](=[O:21])[NH:7][C:6]=2[N:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN2Cc3c(Cl)ccnc3NC2=O)cc1
Reactant: Nc1c(Cl)ccc2c1OCO2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: COc1ccc(CN2Cc3c(Nc4c(Cl)ccc5c4OCO5)ccnc3NC2=O)cc1
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 35 %

Procedure:
1 (69 mg, 0.23 mmol), 5-chloro-1,3-benzodioxol-4-amine (47 mg, 0.27 mmol), Pd(OAc)2 (2.5 mg, 0.01 mmol), X-Phos (11 mg, 0.02 mmol), and NaOtBu (65 mg, 0.68 mmol) were suspended in anhydrous dioxane (2 mL), and stirred in a microwave at 120° C. for 150 min. The crude product was purified directly via HPLC to provide 101 (35% yield). LC-MS (M+H=439, obsd.=439).
Reaction SMILES: I[CH2:2][I:3].N(OCCC(C)C)=O.NC1[C:14]2[C:39]([CH3:41])([CH3:40])[C:38](=[O:42])[NH:37][C:15]=2[N:16]=[C:17]([C:19]2[C:27]3[C:22](=[N:23][C:24]([CH3:28])=[N:25][CH:26]=3)[N:21]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[F:36])[N:20]=2)[N:18]=1>C(#N)C>[F:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH2:29][N:21]1[C:22]2=[N:23][C:24]([CH3:28])=[N:25][CH:26]=[C:27]2[C:19]([C:17]2[N:18]=[C:2]([I:3])[C:14]3[C:39]([CH3:41])([CH3:40])[C:38](=[O:42])[NH:37][C:15]=3[N:16]=2)=[N:20]1
Reactant: ICI
Reactant: Cc1ncc2c(-c3nc(N)c4c(n3)NC(=O)C4(C)C)nn(Cc3ccccc3F)c2n1
Agent: CC(C)CCON=O
Solvent: CC#N
Product: Cc1ncc2c(-c3nc(I)c4c(n3)NC(=O)C4(C)C)nn(Cc3ccccc3F)c2n1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
3.770 g (14.08 mmol) of diiodomethane and 411 mg (3.51 mmol) of isopentyl nitrite were added to 70 mg (0.17 mmol) of 4-amino-2-[1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one. The mixture was stirred for 8 h at 85° C. After cooling, it was diluted with acetonitrile and the mixture was purified by preparative HPLC (eluent: acetonitrile/water, gradient 30:70→95:5). 35 mg (24% of theor.) of the target compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]=[O:13])[C:8]([C@@H:14]([N:16]1[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]1=[O:26])[CH3:15])=[CH:7]2.[OH:27]P([O-])(O)=O.[K+].Cl([O-])=O.[Na+]>CC(=CC)C.CC(O)(C)C.C(Cl)Cl.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([OH:27])=[O:13])[C:8]([C@@H:14]([N:16]1[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]1=[O:26])[CH3:15])=[CH:7]2
Reactant: O=P([O-])(O)O
Reactant: C[C@@H](c1cc2cccc(Cl)c2nc1C=O)N1C(=O)c2ccccc2C1=O
Agent: CC=C(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: C[C@@H](c1cc2cccc(Cl)c2nc1C(=O)O)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-8-chloro-3-(1-(1,3-dioxoisoindolin-2-yl)ethyl)-quinoline-2-carbaldehyde (110 mg, 0.30 mmol) and potassium phosphate monobasic (41.0 mg, 0.30 mmol) in 2-methyl-2-butene (2 mL), tBuOH (2 mL), DCM (1.0 mL) and water (2.0 mL) was added sodium chlorite (27.3 mg, 0.30 mmol) in water (2.0 mL). The reaction was stirred at room temperature. for 2 hours and then it was treated with additional potassium phosphate monobasic (41.0 mg, 0.30 mmol) and sodium chlorite (27.3 mg, 0.30 mmol) in water (2.0 mL). The reaction was stirred for 2 hours and then it was diluted with 1.0 M citric acid (40 mL) and ethyl acetate (60 mL). The separated aqueous layer was extracted withy ethyl acetate (2×60 mL) and the combined organic layers were washed with brine (40 mL), dried (MgSO4), filtered and evaporated in vacuo to give (S)-8-chloro-3-(1-(1,3-dioxoisoindolin-2-yl)ethyl)quinoline-2-carboxylic acid. 1H NMR (400 MHz, CDCl3) δ ppm 8.62 (1H, s), 7.72-7.84 (6H, m), 7.65 (1H, dd, J=5.3, 2.9 Hz), 6.80 (1H, q, J=7.0 Hz), 1.96 (3H, d, J=7.0 Hz). Mass Spectrum (ESI) m/e=381.0 (M+1).
Reaction SMILES: [Si](O[CH2:9][CH2:10][CH2:11][C:12](=[CH2:29])[C:13]([C:15]1[CH:20]=[C:19]([C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)[C:18]([F:27])=[CH:17][C:16]=1[F:28])=[O:14])(C(C)(C)C)(C)C.[NH2:30][C:31]([NH2:33])=[S:32].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CC(O)=O.C1COCC1>[F:28][C:16]1[CH:17]=[C:18]([F:27])[C:19]([C:21]2[CH:26]=[N:25][CH:24]=[N:23][CH:22]=2)=[CH:20][C:15]=1[C@@:13]12[O:14][CH2:9][CH2:10][CH2:11][C@@H:12]1[CH2:29][S:32][C:31]([NH2:33])=[N:30]2
Reactant: C=C(CCCO[Si](C)(C)C(C)(C)C)C(=O)c1cc(-c2cncnc2)c(F)cc1F
Reactant: NC(N)=S
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: NC1=N[C@]2(c3cc(-c4cncnc4)c(F)cc3F)OCCC[C@@H]2CS1
Temperature: 25 °C
Reaction time: 12 h
Yield: 2.3 %

Procedure:
To a solution of 5-((tert-butyldimethylsilyl)oxy)-1-(2,4-difluoro-5-(pyrimidin-5-yl)phenyl)-2-methylenepentan-1-one (Preparation 16, 606 mg, 1.448 mmol) in HOAc (7239 μL) was added thiourea (441 mg, 5.79 mmol), and a suspension was formed. The reaction mixture was stirred at rt for 12 h, and a clear yellowish solution was formed. TBAF (2172 μL, 2.172 mmol) in THF was added, and the reaction mixture was stirred at rt for 5 h, followed by heating at 60° C. for 12 h. This crude reaction mixture was purified by reverse phase preparative HPLC on a Luna C18 column (10 μM, 30×100 mm) eluting with 0-100% B (A: 10% MeOH/90% water/0.1% TFA; B: 90% MeOH/10% water/0.1% TFA) over 12 min to give a mixture of two isomers. This mixture was purified by preparative TLC on silica gel (0.50 mm thickness) eluting with 90% DCM/9% MeOH/1% ammonium hydroxide to give (4aS,8aS)-8a-(2,4-difluoro-5-(pyrimidin-5-yl)phenyl)-4,4a,5,6,7,8a-hexahydropyrano[2,3-d][1,3]thiazin-2-amine (13 mg, 0.034 mmol, 2.354% yield) as a white solid. 1H NMR (500 MHz, CHLOROFORM-d) δ 9.22 (s, 1H), 8.91 (d, J=1.4 Hz, 2H), 7.43 (t, J=8.5 Hz, 1H), 7.02 (dd, J=10.8, 10.2 Hz, 1H), 5.0-4.5 (broad s, 2H), 4.00-3.92 (m, 1H), 3.88-3.80 (m, 1H), 2.95 (dd, J=12.6, 4.0 Hz, 1H), 2.81-2.71 (m, 1H), 2.67 (dd, J=12.6, 2.8 Hz, 1H), 2.01-1.83 (m, 2H), 1.75-1.57 (m, 2H). MS (M+H)+: 363.03.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[C:10](=[O:19])[NH:9][N:8]=1.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][CH2:32][CH2:33][CH2:34]Br.C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[C:10](=[O:19])[N:9]([CH2:34][CH2:33][CH2:32][O:31][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][O:25]2)[N:8]=1
Reactant: BrCCCOC1CCCCO1
Reactant: COc1ccc(CNc2n[nH]c(=O)c3ccc(C#N)cc23)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(CNc2nn(CCCOC3CCCCO3)c(=O)c3ccc(C#N)cc23)cc1Cl
Temperature: 50 °C
Reaction time: 4 h
Yield: 70.6 %

Procedure:
4-(3-Chloro-4-methoxybenzyl)amino-6-cyano-1(2H)-phthalazinone (0.20 g) prepared in Example 21 was dissolved in 5 ml of N-methyl-2-pyrrolidinone, followed by the addition of 0.24 g of 3-bromopropyl 2-tetrahydropyranyl ether and 0.24 g of potassium carbonate. The obtained mixture was stirred at 50° C. for 4 hours and poured into water, followed by extraction with ethyl acetate. The organic phase was washed with water twice and with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and freed from the solvent by vacuum distillation. The residue was purified by silica gel column chromatography [solvent: n-hexane/ethyl acetate (1:1)] to give 0.20 g of the title compound as a yellow crystal.
Reaction SMILES: O.CC(C)=[O:4].OS(O)(=O)=O.O=[Cr](=O)=O.[F:15][C:16](=[C:20]([F:22])[F:21])[CH2:17][CH2:18][OH:19]>CC(C)=O>[F:15][C:16](=[C:20]([F:22])[F:21])[CH2:17][C:18]([OH:4])=[O:19]
Reactant: OCCC(F)=C(F)F
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)CC(F)=C(F)F
Yield: 65 %

Procedure:
A mechanically stirred 12 L glass reactor clad with a jacket cooled with tap water was charged with 100 mL of acetone and 100 mL of Jones reagent. A solution of 3,4,4-trifluoro-3-buten-1-ol (850 g, 6.75 mol) diluted to a total volume of 5.0 L in acetone was added simultaneously with 5.0 L of Jones reagent via a twin head peristaltic pump capable of of a pump rate ca. 120 mL/min. A reaction temperature of 51°-54° C. was maintained by adjusting the pump rate and the tap water cooling flow. Following the addition (45 min), the mixture was allowed to cool to 35°-40° C. over 30-60 min. The reaction mixture was transferred to a separatory funnel and layers separated. The upper layer was washed once with brine and concentrated. The lower layer was diluted with water (500 mL) and extracted with dichloromethane (3 L). The dichloromethane extract was combined with the above residue, washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave 613 g (65%) of the desired product as a green oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[N:14]([CH2:15][C:16]([O:18]CC)=O)[N:13]=[C:12]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:27]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[N:14]([CH2:15][C:16]([NH:32][CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:18])[N:13]=[C:12]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: NC1CCCC1
Reactant: CCOC(=O)Cn1nc(-c2ccncc2)nc1-c1ccc(OC)c(Cl)c1
Product: COc1ccc(-c2nc(-c3ccncc3)nn2CC(=O)NC2CCCC2)cc1Cl
Temperature: 25 °C
Yield: 75 %

Procedure:
A mixture of ethyl {5-[3-chloro-4-(methyloxy)phenyl]-3-pyridin-4-yl-1H-1,2,4-triazol-1-yl}acetate (0.2 mmol) and cyclopentylamine (4 mL) were heated to reflux for 2 h. The mixture was cooled to room temperature and the excess cyclopentylamine was removed in vacuo. The crude solid was then triturated with methanol to afford the pure product (0.061 g, 75%). 1H NMR (400 MHz, d6-DMSO): δ 8.68 (dd, 2H), 7.92 (22, 2H), 7.82 (m, 1H), 7.75 (dd, 1H), 7.33 (d, 1H), 4.95 (s, 2H), 4.00 (m, 1H), 3.94 (s, 3H), 1.80 (m, 2H), 1.64 (m, 2H), 1.51 (m, 2H), 1.40 (m, 2H). MS (EI) for C21H23ClN5O2: 412 (MH+).
Reaction SMILES: [C:1]1([CH3:10])[C:2]([C:7]([OH:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:11][CH2:10][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=[O:8]
Reactant: Cc1ccccc1C(=O)O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: O=C(O)c1ccccc1CBr
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 53.7 %

Procedure:
In a 1 L round bottom flask fitted with a reflux condenser, a stirred suspension of 10.00 g of o-toluic acid and 19.56 g (1.5 eq.) N-bromosuccinimide in 735 mL chloroform was sparged for 0.5 h with nitrogen. The sparging was discontinued, and the suspension was stirred and irradiated under nitrogen atmosphere using a 500 W quartz halogen lamp at 75% power, causing the solids to dissolve and the chloroform to reflux. The red color of the reaction mixture disappeared after 1.5 h, and 6.52 g (0.5 eq.) of N-bromosuccinimide was added. The reaction mixture was stirred and irradiated under nitrogen atmosphere with a 500 W quartz halogen lamp at 75% power for another 1.5 h, at which time the solution became colorless. The solvent volume was reduced in vacuo to about 100 mL, and then cooled to −20° C. The resultant suspension was vacuum filtered through a 1 cm bed of dry silica in a 150 mL fritted funnel. The silica was washed with 2.5 L of chloroform. The chloroform filtrate was reduced in vacuo to about 1 L, washed in a separatory funnel with 3×1 L volumes of water followed by one 3×1 L volume of brine to remove traces of succinimide, then dried with magnesium sulfate and vacuum filtered. The chloroform was reduced by rotary evaporation at reflux at 1 atmosphere to 250 mL and cooled at −20° C. for 3 days. The resultant crystals were vacuum filtered, washed with 30 mL of chloroform followed by 50 mL of hexanes, then dried in a vacuum oven at room temperature overnight, providing 8.48 g (54%) 2-bromomethylbenzoic acid as a white crystalline power.
Reaction SMILES: [ClH:1].[CH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[CH:6][C:5]=1[N+:14]([O-])=O)=O.[C:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)[CH3:18].[OH-].[K+]>CCO.[Fe].O>[ClH:1].[C:20]1([C:17]2[CH:18]=[CH:2][C:4]3[C:5](=[CH:6][C:7]([C:8]([OH:10])=[O:9])=[CH:12][CH:13]=3)[N:14]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[ClH:1]
Reactant: COC(=O)c1ccc(C=O)c([N+](=O)[O-])c1
Reactant: CC(=O)c1ccccc1
Agent: [Fe]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc2ccc(-c3ccccc3)nc2c1
Temperature: 95 °C
Reaction time: 1.5 h

Procedure:
Iron powder (21.05 g, 377 mmol), water (8 mL), and concentrated hydrochloric acid (0.63 mL, ˜7.5 mmol) were added consecutively to a solution of methyl 4-formyl-3-nitrobenzoate (8.04 g, 38.4 mmol) in EtOH (100 mL). The mixture was stirred at 95° C. for 1.5 h. Acetophenone (4.4 mL, 37.7 mmol) and solid KOH (6.344 g, 113 mmol) were then added with caution. This mixture was stirred at 95° C. for another 5 h. The inorganic solids were filtered off when still warm and the filtrate was acidified to pH =˜1.0 with 4 N HCl (aq). The solvents were removed and water (10 mL) was added. The product was extracted into THF (100 mL×3), dried over MgSO4, filtered, concentrated to afford the desired product as HCl salt; 1H-NMR (CD3OD, 400 MHz) δ 7.73-7.80 (m, 3H), 8.17-8.20 (m, 2H), 8.40-8.48 (m, 3H), 9.02 (d, J=0.8 Hz, 1H), 9.17 (d, J=8.8 Hz, 1H). MS (ES+): m/z 250 [MH+]. HPLC: tR=3.18 min (OpenLynx, polar—5 min).
Reaction SMILES: CC(C1C=CC=CC=1)C(O)=O.[CH3:12][C@@H:13]([NH:22][CH3:23])[C@@H:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.COC(C1C=CC=CC=1)C(O)=O.[S:36](=[O:40])(=[O:39])([OH:38])[OH:37].[Cl-].[Na+]>C(O)C.ClCCl.CO>[CH3:12][C@H:13]([NH:22][CH3:23])[C@H:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[S:36](=[O:38])(=[O:37])([OH:40])[OH:39]
Reactant: CN[C@H](C)[C@@H](O)c1ccccc1
Agent: CC(C(=O)O)c1ccccc1
Agent: COC(C(=O)O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: CN[C@@H](C)[C@H](O)c1ccccc1
Temperature: 25 °C

Procedure:
Heat 40.0 g. (0.241 moles) of racemic (+)-α-methyl-α-phenylacetic acid [D. G. Neilson et al. J. Chem. Soc., (1962), 1519] with 40.0 g. (0.242 moles) of d-ephedrine (available from Aldrich) in 180 mL of 95% ethanol under reflux on a steam bath. Cool the resulting solution to room temperature slowly and leave undisturbed overnight (16 hrs.). Filter the resulting crystallized solid and wash same with 95% ethanol (20 mL) and ethyl ether to give 35.6 g. Recrystallize (twice) the solid from 95% ethanol to give 26.5 g. of salt of d-ephedrine and (+)-α-methoxy-α-phenylacetic acid [(+)-(S)-O-methylmandelic acid], m.p. 185°-188°, [α]D21 +72.8° (c, 4.64, MeOH). Acidify 26.3 g. of the solid with 90 mL of ice-cooled sulfuric acid, with stirring to give a solution. Add sodium chloride (31 g.) and stir the resulting mixture. Add 100 mL of dichloromethane to the mixture to give a voluminous precipitate (ephedrine, sulfuric acid salt). Add another 100 mL portion of dichloromethane to the mixture and filter the mixture through a glass filter. Wash the solid with 100 mL of dichloromethane. Shake the filtrate and separate the organic and aqueous layers. Extract the aqueous layer with 100 ml of dichloromethane. Dry the combined organic layers over anhydrous magnesium sulfate. Evaporate the solvent to give an oil which solidifies on cooling to yield 13.2 g. of the title compound as a solid: m.p. 60.5°-62.0°, [α]D22 +149° (C, 5.61, MeOH).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=2[C:17]2[C:18]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([NH:29][CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[O:28])[C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:4][CH2:3]1.C([O:39][C@@H:40]([CH3:44])[C:41](Cl)=[O:42])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:15])([F:14])[F:16])=[CH:9][C:8]=2[C:17]2[C:18]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([NH:29][CH:30]4[CH2:31][CH2:32][N:33]([C:41](=[O:42])[C@@H:40]([OH:39])[CH3:44])[CH2:34][CH2:35]4)=[O:28])[C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:3][CH2:4]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCN(C(=O)[C@H](C)O)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(trifluoromethyl)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f31) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.