Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[N:3]1.Cl[C:13]1[N:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16]>CS(C)=O.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:13]3[N:20]=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]#[N:16])=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: N#Cc1cccnc1Cl
Reactant: Cn1ncc2cc(O)ccc21
Solvent: CS(C)=O
Solvent: O
Product: Cn1ncc2cc(Oc3ncccc3C#N)ccc21
Temperature: 110 °C
Yield: 89.3 %

Procedure:
1-Methyl-1H-indazol-5-ol (1n) (synthesized as described in Example 94) (0.10 g, 0.68 mmol) and 2-chloro-nicotinonitrile (2n) (0.11 g, 0.81 mmol) were suspended in DMSO (2 mL). The reaction mixture was heated to 110° C. for 18 hours. The reaction mixture was diluted with water and extracted into EtOAc. The combined organics were dried, Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification by flash column chromatography (20-100% EtOAc/Hexanes) furnished the desired product (3n), (0.152 g, 90% yield). 1H NMR (400 mHz, CD3OD) δ 8.27-8.25 (m, 1H), 8.23-8.20 (m, 1H), 8.01 (s, 1H), 7.62 (d, J=8.6 Hz, 1H), 7.57 (d, J=2.3 Hz, 1H), 7.28-7.26 (m, 1H), 7.23-7.20 (m, 1H), 4.10 (s, 3H); MS (ESI+) m/z 251 (M+H) detected.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([C:19]3[O:20][C:21]([C:24]4[N:29]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:26][CH:25]=4)=[CH:22][N:23]=3)=[O:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=O.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[N:34]1([CH2:1][C:3]2[CH:4]=[CH:5][C:6]([C:9]3[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]([C:19]4[O:20][C:21]([C:24]5[N:29]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:26][CH:25]=5)=[CH:22][N:23]=4)=[O:18])=[CH:13][CH:14]=3)=[CH:7][CH:8]=2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: C1CCNCC1
Reactant: COC(=O)c1cccc(-c2cnc(C(=O)CCc3ccc(-c4ccc(C=O)cc4)cc3)o2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COC(=O)c1cccc(-c2cnc(C(=O)CCc3ccc(-c4ccc(CN5CCCCC5)cc4)cc3)o2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.9 %

Procedure:
Methyl 6-(2-(3-(4′-formylbiphenyl-4-yl)propanoyl)oxazol-5-yl)pyridine-2-carboxylate (19 mg, 0.043 mmol) and piperidine (0.007 mL, 0.07 mmol) were dissolved in dichloroethane (2 mL) and NaBH(OAc)3 (18 mg, 0.086 mmol) was added. The reaction solution was stirred under an atmosphere of Ar at ambient temperature for 1 h and then quenched with saturated aqueous NaHCO3. The crude product was extracted with EtOAc and the solvent was removed in vacuo. The crude product was purified by flash chromatography (SiO2, 5% MeOH/EtOAc) to furnish methyl 6-(2-(3-(4′-(piperidin-1-ylmethyl)biphenyl-4-yl)propanoyl)oxazol-5-yl)pyridine-2-carboxylate as a clear pale yellow oil (14 mg, 64%): 1H NMR (CDCl3, 600 MHz) δ 8.11 (d, 1H, J=7.7 Hz), 8.02 (d, 2H, J=9.0 Hz), 7.97 (t, 1H, J=7.8 Hz), 7.52 (dd, 4H, J=7.9, 6.4 Hz), 7.37 (d, 2H, J=7.9 Hz), 7.33 (d, 2H, J=7.8 Hz), 4.03 (s, 3H), 3.52-3.50 (m, 4H), 3.15 (t, 2H, J=7.6 Hz), 2.42 (bs, 4H), 1.61-1.58 (m, 4H), 1.44 (bs, 2H); 13C NMR (CDCl3, 150 MHz) δ 187.3, 165.1, 157.4, 152.4, 148.5, 146.5, 139.5, 139.2, 139.1, 138.3, 129.7, 128.8, 128.0, 127.1, 126.7, 125.2, 123.3, 63.4, 54.4, 53.1, 40.6, 29.3, 25.9, 24.3; HR ESI-TOF m/z 510.2385 (M+H+, C31H31N3O4, requires 510.2387).
Reaction SMILES: C(=O)([O-])OCC[C:5](=[O:18])[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[C:8]([O:16][CH3:17])[CH:7]=1>[Pd]>[CH3:17][O:16][C:8]1[CH:7]=[C:6]([CH:11]=[C:10]([O:12][CH3:13])[C:9]=1[O:14][CH3:15])[CH:5]=[O:18]
Reactant: COc1cc(C(=O)CCOC(=O)[O-])cc(OC)c1OC
Agent: [Pd]
Product: COc1cc(C=O)cc(OC)c1OC

Procedure:
It was found that the catalyst for the hydrogenation of the mixed anhydride to aldehyde is palladium 10% deposited on barium sulfate for instance (10% Pd/BaSO4ENGELHARD) preferably at the ratio of 50% in respect to the amount of 3,4,5-trimethoxy-benzoyl-ethyl carbonate used. In order to have high yields of 3,4,5-trimethoxy-benzaldehyde, it is necessary to partially poison the catalyst with a very dilute solution of sulfur and quinoline.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12].O>N1C=CC=CC=1>[N+:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:11](=[O:13])[CH3:12])[CH:7]=1)([O-:10])=[O:9]
Reactant: Nc1cc([N+](=O)[O-])ccn1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1cc([N+](=O)[O-])ccn1
Temperature: 25 °C
Reaction time: 30 h
Yield: 101.2 %

Procedure:
To a solution of 2-amino-4-nitropyridine (3.0 g, 0.018 mol) in pyridine (40 mL) was added acetic anhydride (5.2 mL 0.055 mol). The reaction mixture was allowed to stir for 30 h at rt. Water was added to the solution and the resulting solid was collected and washed with water and dried under vacuum to give N-(4-nitropyridin-2-yl)acetamide as a brown solid (3.3 g, 99%). 1HNMR (300 MHz, CDCl3) δ: 8.90 (s, 1H), 8.50 (d, 1H), 8.30 (br s, 1H), 7.8 (dd, 1H), 2.3 (s, 3H); LCMS: (FA) ES+ 182.2.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]2)=[C:4]([C@H:10]([OH:17])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]>C(Cl)Cl>[Br:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]2)=[C:4]([C@H:10]([O:17][C:4]([CH3:10])([CH3:5])[CH3:3])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(C)c([C@H](O)C(=O)OC(C)C)c(N2CCC(C)CC2)c1Br
Solvent: ClCCl
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(C)CC2)c1Br
Temperature: 25 °C
Reaction time: 72 h
Yield: 142 %

Procedure:
The isobutylene gas was bubbled into a nitrogen purged, cooled (0° C.) solution of (S)-isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-methylpiperidin-1-yl)pyridin-3-yl)-2-hydroxyacetate (2.25 g, 5.63 mmol) and 0.53 mL of 70% HClO4 in DCM (30 mL) for 20 min. The reaction mixture was allowed to warm to rt and stirred for 72 h in a pressure sealed vessel. The reaction was then diluted with DCM, washed with 1M Na2CO3 solution, and dried over MgSO4. The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient elution (0-12% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-methylpiperidin-1-yl)pyridin-3-yl)-2-(tert-butoxy)acetate 1.82 g (71%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 6.16 (s, 1H), 4.93-4.90 (m, 1H), 3.82-3.77 (m, 1H), 3.24 (t, J=10.6 Hz 1H), 2.98 (d, J=9.9 Hz, 1H), 2.74 (br. s, 1H), 2.51 (s, 3H), 2.41 (s, 3H), 1.73 (br. s, 1H), 1.62 (br. s, 1H), 1.49 (br. s, 1H), 1.28-1.23 (m, 2H), 1.16-1.14 (m, 12H), 1.07 (d, J=6.2 Hz, 3H), 0.97 (d, J=6.2 Hz, 3H). UPLC (M+H)=457.3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[CH:19]#[C:20][CH:21]([OH:25])[CH2:22][CH2:23][CH3:24]>>[F:14][C:13]([F:16])([F:15])[C:12]([NH:11][CH2:10][CH2:9][CH:8]([OH:18])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:19]#[C:20][CH:21]([OH:25])[CH2:22][CH2:23][CH3:24])[CH:3]=1)=[O:17]
Reactant: O=C(NCCC(O)c1cccc(Br)c1)C(F)(F)F
Reactant: C#CC(O)CCC
Product: CCCC(O)C#Cc1cccc(C(O)CCNC(=O)C(F)(F)F)c1

Procedure:
Sonogashira reaction of 25 (3 g, 9.2 mmol) with hex-1-yn-3-ol yielded 2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxyhex-1-ynyl)phenyl)propyl)acetamide as yellow oil. Yield (2.31 g, 73%): 1H NMR (400 MHz, CDCl3) δ 7.42 (s, 1H), 7.26-7.38 (m, 3H), 4.86 (m, 1H), 4.61 (dd, J=2.0, 5.6 Hz, 1H), 3.67-3.71 (m, 1H), 3.37-3.46 (m, 1H), 2.38 (d, J=2.0 Hz, 1H), 1.95-1.99 (m, 2H), 1.75-1.88 (m, 2H), 1.53-1.57 (m, 2H), 0.97 (t, J=7.2 Hz, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:13][CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.C(N(CC)CC)C>C(Cl)Cl.O>[CH2:14]([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)[CH2:13][C:12](=[O:11])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCC(O)CCn1ccnc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: CCCCCC(=O)CCn1ccnc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (3.0 ml) in methylene chloride (75 ml) was placed in a flask and cooled to -50° C. to -60° C. Dimethyl sulfoxide (5.1 ml) in 15 ml of methylene chloride was then added followed by 5.88 g of 1-(3-hydroxyoctyl)imidazole dissolved in 30 ml of methylene chloride. The reaction mixture was stirred for 30 minutes at the initial temperature. Triethylamine (21 ml) was added to the reaction mixture which was then allowed to warm to room temperature. Water (100 ml) was added, the organic layer separated and the aqueous layer extracted with methylene chloride (2×50 ml). The organic layers were dried over MgSO4 and the solvent removed to give 1-(octan-3-on-1-yl)imidazole as an oil.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][C:25]([O:29][CH2:30][C:31](=[O:35])[N:32]([CH3:34])[CH3:33])=[CH:26][CH:27]=5)[C:22]([CH2:36][C:37]([O:39]C)=[O:38])=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>CO>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][C:25]([O:29][CH2:30][C:31](=[O:35])[N:32]([CH3:34])[CH3:33])=[CH:26][CH:27]=5)[C:22]([CH2:36][C:37]([OH:39])=[O:38])=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1cn(Cc2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)c2ccc(OCC(=O)N(C)C)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CN(C)C(=O)COc1ccc2c(c1)c(CC(=O)O)cn2Cc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
A mixture of methyl 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-(N',N'-dimethylcarbamoylmethoxy)indole-3-acetate (0.15 g) and 1N-lithium hydroxide (0.52 ml) in methanol (2 ml) was stirred at room temperature for 8 hours. After removal of solvent, the residue was dissolved into water and the solution was acidified with diluted hydrochloric acid. The resulting precipitates were collected by filtration and washed with water to give 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-(N',N'-dimethylcarbamoylmethoxy)indole-3-acetic acid (80 mg).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[OH:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C(Cl)(Cl)Cl>[C:1]([O:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH2:12][CH2:11]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Cl
Reactant: OCCN1CCNCC1
Solvent: ClC(Cl)Cl
Product: CCCC(=O)OCCN1CCN(C(=O)CCC)CC1
Reaction time: 8 h
Yield: 86.8 %

Procedure:
Butyryl chloride (11.83 g, 0.11 mol) was added dropwise to a cooled solution of 4.84 g (0.04 mol) of 1-(2-hydroxyethyl)-piperazine in 20 ml of chloroform. Cooling was maintained for 2 h, and a white precipitate formed. Chloroform (15 ml) was added and the mixture was stirred overnight, washed with 210 ml of cold 0.6 N sodium hydroxide solution, then washed twice with 50 ml of cold water. The organic fraction was dried over anhydrous sodium sulfate, filtered and, concentrated in vacuo to yield 9.39 g (94%) of a clear yellow liquid. This was distilled: bp 144–146° C., (0.5 mm Hg) to give 6.08 g (65%) of MEB. 1H NMR (CDCl3) δ 0.897 (t, 3H, J=7.4, CH3), 0.901 (t, 3H, J=7.4, CH3), 1.59 (m, 2H, CH3CH2), 1.61 (m, 2H, CH3CH2), 2.24 (t, 2H, J=7.4 CH2CO), 2.25 (t, 2H, J=7.4, CH2CO), 2.42–2.43 (app t, 2H, J=5.2, axial CH ester end of ring), 2.43–2.44 (app t, 2H, J=5.2, equatorial CH ester end of ring), 2.59 (t, 2H, J=5.8, N—CH2—CH2—O), 3.41 (app t, 2H, axial CH amide end of ring), 3.57 (app t, 2H, equatorial CH amide end of ring), 4.16 ( t, 2H, N—CH2—CH2—O); MS m/z 270 (M+), 255, 242, 227, 199, 182, 169 (Base Peak).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.[NH:10]1[CH:14]=[CH:13][CH:12]=[N:11]1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[N:10]1([C:2]2[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=2)[CH:14]=[CH:13][CH:12]=[N:11]1
Reactant: c1cn[nH]c1
Reactant: OCc1ccnc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: OCc1ccnc(-n2cccn2)c1
Temperature: 25 °C
Yield: 74.2 %

Procedure:
A mixture of (2-bromopyridin-4-yl)methanol [118289-16-0] (370 mg, 2.00 mmol), 1H-pyrazole (204 mg, 3.00 mmol), Cu powder (26 mg, 0.40 mmol) and Cs2CO3 (1.30 g, 4.00 mmol) in acetonitrile (4 mL) was heated under reflux for 16 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed with water and brine, dried over anhydrous sodium sulfate, filtered and the organic layer was evaporated under reduced pressure. The residue was purified by flash-column chromatography over silicagel (eluent: 50% ethyl acetate in hexane) to yield the title compound (260 mg, 74%). [LCMS RtF=0.31 min, [M+H]+=176.1].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:31][CH2:32][C:33](=[O:43])[CH2:34][C:35](=[O:42])[CH2:36][C:37]([O:39]CC)=O)[C:10]([CH:28]([CH3:30])[CH3:29])=[C:11]([C:19](=[O:27])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.FC1C=CC([C:51]2[N:52](CC[C@@H](O)CC(O)CC(OC)=O)[C:53](C(C)C)=C(C(=O)NC3C=CC=CC=3)C=2C2C=CC=CC=2)=CC=1>>[CH3:51][N:52]([CH3:53])[C:37](=[O:39])[CH2:36][CH:35]([OH:42])[CH2:34][C@H:33]([OH:43])[CH2:32][CH2:31][N:9]1[C:10]([CH:28]([CH3:30])[CH3:29])=[C:11]([C:19](=[O:27])[NH:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1
Reactant: CCOC(=O)CC(=O)CC(=O)CCn1c(-c2ccc(F)cc2)c(-c2ccccc2)c(C(=O)Nc2ccccc2)c1C(C)C
Reactant: COC(=O)CC(O)C[C@H](O)CCn1c(-c2ccc(F)cc2)c(-c2ccccc2)c(C(=O)Nc2ccccc2)c1C(C)C
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H](O)CC(O)CC(=O)N(C)C

Procedure:
In a process analogous to Step 6 METHOD A, using alternative Ru(II)-chiral diphosphine complexes in place of RuCl2(DMF)n[(R)-Cl-MeO-BIPHEP)] as the hydrogenation catalyst, one can obtain the identical products with varying enantiomeric excess at C-5. For example, in the reduction of 7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dioxo-heptanoic acid, ethyl ester to (5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid, methyl ester proceeded as follows:
Reaction SMILES: [CH3:1][CH:2]([CH3:10])[CH2:3][CH2:4][C:5](=[O:9])[C:6](O)=[O:7].C(Cl)(=O)C([Cl:14])=O>>[CH3:1][CH:2]([CH3:10])[CH2:3][CH2:4][C:5](=[O:9])[C:6]([Cl:14])=[O:7]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)CCC(=O)C(=O)O
Product: CC(C)CCC(=O)C(=O)Cl

Procedure:
The 5-methyl-2-oxohexanoic acid is reacted with at least a 10% excess over the stoichiometric amount of oxalyl chloride to form 5-methyl-2-oxohexanoyl chloride [reaction (4)]. ##EQU6## Oxalyl chloride is a suitable solvent for reaction (4), and theoretically can be present in an unlimited excess over stoichiometry. Solvents such as diethyl ether, petroleum ether, benzene, CH2Cl2, and hexane are also suitable solvents for the reaction. The use of solvents is preferred but is not necessary. Reaction (4) must be run under anhydrous conditions in an inert atmosphere and requires from 40 to 60 hours at a temperature of from 25° to 60° C. for completion.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.Cl.[NH2:14][OH:15].C(O)(=O)C>O>[Cl:1][C:2]1[C:7]([CH:8]=[N:14][OH:15])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: NO
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CSc1nc(Cl)c(C=NO)c(Cl)n1
Temperature: 60 °C

Procedure:
4,6-Dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde (7.34 g, 33.09 mmol), hydroxylamine hydrochloride (2.31 g, 33.33 mmol), acetic acid (49.6 mL), and water (3.3 mL) were mixed, and heated to 60° C. for 2 hours. The reaction mixture was diluted with water and cooled under ice bath. The precipitate was collected and dried (Yield=6.41 g, 82%). MS (m/z): 238 (M+H).
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH:19]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=3)=[CH:22][CH:21]=2)[CH2:18][C:17]([C:32]([C:38]([F:41])([F:40])[F:39])([C:34]([F:37])([F:36])[F:35])[OH:33])=[N:16]1.C(N(CC)CC)C.C(Cl)(=O)C.ClCCl>O>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH:19]([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH2:27][CH2:28][N:29]([C:3](=[O:4])[CH3:2])[CH2:30][CH:31]=3)=[CH:24][CH:25]=2)[CH2:18][C:17]([C:32]([C:38]([F:41])([F:39])[F:40])([C:34]([F:35])([F:36])[F:37])[OH:33])=[N:16]1
Reactant: O=C(O)C(F)(F)F
Reactant: OC(C1=NN(c2ccccc2Cl)C(c2ccc(C3=CCNCC3)cc2)C1)(C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: CC(=O)N1CC=C(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.9 %

Procedure:
1-(2-Chloro-phenyl)-5-[4-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole trifluoroacetate (15.0 mg, 0.02 mmol) prepared in Example 292, triethylamine (9.3 uL, 0.07 mmol) and acetyl chloride (3.6 uL, 0.03 mmol) were added at 0° C. to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 2 hours and then distilled water was added thereto. The reaction mixture was extracted with dichloromethane two times. The combined extract was washed with 1N hydrochloric acid, a saturated solution of sodium carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3) to give 4.9 mg of the titled compound as a yellow liquid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:32])([CH3:31])[C@@H:11]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]([O:14][CH2:15][O:16][C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])=[O:13])(=[O:7])=[O:6].[N-:33]=[N+:34]=[N-:35].[Na+]>CS(C)=O>[N:33]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:32])([CH3:31])[C@@H:11]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]([O:14][CH2:15][O:16][C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])=[O:13])(=[O:7])=[O:6])=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)OC(=O)OCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)OC(=O)OCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-]

Procedure:
Following the general procedure for the preparation of azides of Description 16, (methylethoxycarbonyloxy)methyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoate (27a) (0.14 g, 0.28 mmol) dissolved in 3 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 45 mg (0.7 mmol) of sodium azide (NaN3). After work-up, the crude title compound (27) was used in the next step without further purification. MS (ESI) m/z 524.06 (M+Na)+.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[La+3:4].[Li].C([Li])CCC.[CH:11]1[CH:16]=[C:15]2[CH:17]=[CH:18][C:19]([OH:32])=[C:20]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][C:22]=3[OH:31])[C:14]2=[CH:13][CH:12]=1.CC(C)([O-])C.[Na+].O>C1COCC1.CCCCCC>[La:4].[CH:27]1[CH:26]=[C:25]2[CH:24]=[CH:23][C:22]([OH:31])=[C:21]([C:20]3[C:14]4[C:15](=[CH:16][CH:11]=[CH:12][CH:13]=4)[CH:17]=[CH:18][C:19]=3[OH:32])[C:30]2=[CH:29][CH:28]=1
Reactant: [La+3]
Agent: CC(C)(C)[O-]
Agent: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Agent: [Cl-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: [La]
Reaction time: 8 h

Procedure:
To a suspension of 122.6 mg (0.50 mmol) of anhydrous lanthanum trichloride in 6.0 ml of THF were added, in an argon atmosphere and at room temperature, a lithium binaphthoxide solution in THF [prepared by adding 0.625 ml (1.0 mmol) of a 1.6N n-butyllithium solution in hexane to a solution of 143.2 mg (0.50 mmol) of (R)-1,1'-bi-2-naphthol in 2.5 ml of THF], 48.1 mg (0.50 mmol) of sodium t-butoxide and 99 μl (5.5 mmol) of water in that order. The resultant mixture was stirred at room temperature for 15 hours. The insoluble matter was caused to precipitate by allowing the mixture to stand overnight, and the supernatant was submitted to the reaction proper as a lanthanum/(R)-1,1'-bi-2-naphthol complex solution (0.05 mol/l).
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.Cl.[CH3:24][C:25]1([NH2:28])[CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>>[CH3:22][C:3]1[C:2]([NH:28][C:25]2([CH3:24])[CH2:27][CH2:26]2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: CC1(N)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1(C)CC1
Temperature: 100 °C
Yield: 25 %

Procedure:
Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 48 mg, 0.162 mmol), 1-methylcyclopropanamine hydrochloride (34.9 mg, 0.324 mmol, ChemBridge, San Diego, Calif.), and DIPEA (141 μl, 0.810 mmol), heating at 100° C. for 2 h. Purification by silica gel (100% DCM to 6% MeOH/DCM) provided 2-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (25% yield). 1H NMR (400 MHz, MeOH-d4) δ ppm 0.93-1.00 (m, 2H) 1.01-1.07 (m, 2H) 1.66 (s, 3H) 2.53 (s, 3H) 3.03 (t, J=7.04 Hz, 2H) 3.64 (t, J=7.04 Hz, 2H) 7.11 (s, 1H) 7.39 (t, J=7.92 Hz, 1H) 7.61 (d, J=8.02 Hz, 1H) 8.00 (d, J=7.63 Hz, 1H). MS (ESI, pos. ion) m/z: 348.2 (M+1).
Reaction SMILES: [I-].[CH2:2]([O:4][C:5]([C@@:7]1([NH:12][C:13](N2C=C[N+](C)=C2)=[O:14])[CH2:9][C@H:8]1[CH:10]=[CH2:11])=[O:6])[CH3:3].[CH2:21]([N:29]([CH3:38])[C:30]([C@@H:32]1[CH2:36][C@@H:35]([OH:37])[CH2:34][NH:33]1)=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[CH:27][CH3:28].C(OC([C@@]1(NC(N2C[C@H](O)C[C@H]2C(=O)N(CCCCC=C)C)=O)C[C@@H]1C=C)=O)C>>[CH2:2]([O:4][C:5]([C@@:7]1([NH:12][C:13]([N:33]2[CH2:34][C@H:35]([OH:37])[CH2:36][C@H:32]2[C:30](=[O:31])[N:29]([CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH2:27][CH3:28])[CH3:38])=[O:14])[CH2:9][C@@H:8]1[CH:10]=[CH2:11])=[O:6])[CH3:3]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)n1cc[n+](C)c1)C(=O)OCC
Reactant: CC=CCCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1
Agent: C=CCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)N[C@]1(C(=O)OCC)C[C@@H]1C=C
Agent: [I-]
Product: C=C[C@H]1C[C@]1(NC(=O)N1C[C@H](O)C[C@H]1C(=O)N(C)CCCCC=CCC)C(=O)OCC
Yield: 48 %

Procedure:
Compound 72b was synthesized from compounds 34 and 71b as a beige solid in 48% yield, following the procedure as described for compound 50.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10]C)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(C=O)c(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=Cc1ccc(O)cc1F
Temperature: 0 °C
Yield: 94.6 %

Procedure:
To a 2000 mL dry round bottom flask were added 2-fluoro-4-methoxybenzaldehyde (25.0 g, 162.2 mmol), anhydrous AlCl3 (64.8 g, 486.8 mmol) and anhydrous CH2Cl2 (1000 mL). The mixture was stirred and refluxed for 3 days. The reaction mixture was cooled in an ice-water bath, then ice (100 g) was added very carefully into the reaction mixture to quench the excess AlCl3. Another 800 mL of cold water was added. The organic layer was separated, and the aqueous solution was extracted with MTBE (300 mL×2). The combined organic layer was concentrated, and the residual solid was dissolved in 400 mL of cold 2N aqueous NaOH and 200 mL of water. The resulting aqueous solution was extracted with MTBE (200 mL×2). The basic aqueous solution then was acidified with concentrated HCl. After filtration and drying, 2-fluoro-4-hydroxybenzaldehyde (21.5 g) was obtained as a white solid. Yield: 95%. 1H NMR (Acetone-d6, 300 MHz): δ=10.12 (s, 1H), 9.87 (s, 1H), 7.74 (t, J=8.4 Hz, 1H), 6.83 (dd, J=8.4, 1.8 Hz, 1H), 7.70 (dd, J=12.3, 2.1 Hz, 1H).