Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:3]=1[C:4]([NH:6][C:7]1[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[O:12])=[CH:9][C:8]=1[O:39][CH3:40])=[O:5].[SH:46][CH2:47][C:48](O)=O>C(Cl)(Cl)Cl>[CH3:40][O:39][C:8]1[CH:9]=[C:10]([CH:37]=[CH:38][C:7]=1[NH:6][C:4]([C:3]1[C:2]2[N:1]=[C:48]([CH2:47][SH:46])[NH:45][C:44]=2[CH:43]=[CH:42][CH:41]=1)=[O:5])[C:11]([N:13]([CH3:36])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1)=[O:28])=[O:12]
Reactant: O=C(O)CS
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc(N)c1N
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(CS)nc12
Yield: 55 %

Procedure:
A solution of 4-(2,3-diaminobenzoyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (100 mg) and mercaptoacetic acid (448 mg) was heated at 80° C. for 5 hours. The reaction mixture was diluted with chloroform and washed with aqueous sodium hydrogen carbonate. The extract was dried over sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (10% methanol in chloroform) to give 3-methoxy-4-(2-mercaptomethyl-1H-benzimidazol-4-yl)carbonylamino-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (60 mg).
Reaction SMILES: [C:1]([C:3]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[CH2:48][CH2:49][C:50](O)=[O:51])[CH2:8][CH2:7][N:6]([C:9]([C@:11]2([O:32][C:33]3[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[S:35][CH:34]=3)[CH2:16][CH2:15][CH2:14][N:13]([C:17](=[O:28])[C:18]3[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[N:20][CH:19]=3)[C@@H:12]2[CH2:29][CH2:30][CH3:31])=[O:10])[CH2:5][CH2:4]1)#[N:2].B.C1COCC1>C1COCC1>[OH:51][CH2:50][CH2:49][CH2:48][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=1[C:3]1([C:1]#[N:2])[CH2:4][CH2:5][N:6]([C:9]([C@:11]2([O:32][C:33]3[CH:37]=[C:36]([C:38]([F:41])([F:39])[F:40])[S:35][CH:34]=3)[CH2:16][CH2:15][CH2:14][N:13]([C:17](=[O:28])[C:18]3[C:23]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:21]=[N:20][CH:19]=3)[C@@H:12]2[CH2:29][CH2:30][CH3:31])=[O:10])[CH2:7][CH2:8]1
Reactant: CCC[C@H]1N(C(=O)c2cnccc2C(F)(F)F)CCC[C@@]1(Oc1csc(C(F)(F)F)c1)C(=O)N1CCC(C#N)(c2ccccc2CCC(=O)O)CC1
Agent: B
Solvent: C1CCOC1
Product: CCC[C@H]1N(C(=O)c2cnccc2C(F)(F)F)CCC[C@@]1(Oc1csc(C(F)(F)F)c1)C(=O)N1CCC(C#N)(c2ccccc2CCCO)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Acid A136 3-(2-(4-cyano-1-((2R,3S)-2-propyl-1-(4-(trifluoromethyl)nicotinoyl)-3-(5-(trifluoromethyl)thiophen-3-yloxy)piperidine-3-carbonyl)piperidin-4-yl)phenyl)propanoic acid (10 mg, 13.3 μmol) was dissolved in THF (0.5 mL). The mixture was cooled to 0° C. and BH3.THF (30 μL, 27.9 μmol) was added dropwise under Ar. The reaction was warmed to 23° C. and was stirred overnight. The reaction mixture was quenched with 1 M NaOH and was concentrated. The crude residue was purified by reverse phase preparative HPLC to yield 4-(2-(3-hydroxypropyl)phenyl)-1-((2R,3S)-2-propyl-1-(4-(trifluoromethyl)nicotinoyl)-3-(5-(trifluoromethyl)thiophen-3-yloxy)piperidine-3-carbonyl)piperidine-4-carbonitrile A138. LC/MS RT (10 min method)=6.04 min. Mass observed: 737.25 (M+H).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:36][CH2:37][N:38]([CH:41]([CH3:43])[CH3:42])[C:39](=[O:40])[C:10]=12)C1C=CC=CC=1.OC1C(=O)N=C(CC2(C3C=CC(C(F)(F)F)=CC=3)CCCC2)N2CCN(C(C)C)C(=O)C=12>>[F:34][C:32]([F:33])([F:35])[C:24]1[CH:23]=[C:22]([C:17]2([CH2:16][C:12]3[N:11]4[CH2:36][CH2:37][N:38]([CH:41]([CH3:43])[CH3:42])[C:39](=[O:40])[C:10]4=[C:9]([OH:8])[C:14](=[O:15])[N:13]=3)[CH2:18][CH2:19][CH2:20][CH2:21]2)[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=1
Reactant: CC(C)N1CCn2c(CC3(c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: CC(C)N1CCn2c(CC3(c4ccc(C(F)(F)F)cc4)CCCC3)nc(=O)c(O)c2C1=O
Product: CC(C)N1CCn2c(CC3(c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CCCC3)nc(=O)c(O)c2C1=O

Procedure:
6-((1-(3,5-Bis(trifluoromethyl)phenyl)cyclopentyl)methyl)-9-hydroxy-2-isopropyl-3,4-dihydro-1H-pyrazino[1,2-c]pyrimidine-1,8(2H)-dione (466) was synthesized as a white solid from 9-(benzyloxy)-6-((1-(3,5-bis(trifluoromethyl)phenyl)cyclopentyl)methyl)-2-isopropyl-3,4-dihydro-1H-pyrazino[1,2-c]pyrimidine-1,8(2H)-dione (465) following the procedure described for 6-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-9-hydroxy-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (248).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)=[O:10].Cl[C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1>>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]([N:2]1[CH2:3][CH:4]2[CH2:8][N:7]([C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)[CH2:6][CH:5]2[CH2:1]1)=[O:10]
Reactant: O=C(c1ccccc1-c1cccs1)N1CC2CNCC2C1
Reactant: Clc1ccc2ccccc2n1
Product: O=C(c1ccccc1-c1cccs1)N1CC2CN(c3ccc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 37 and 2-chloro-quinoline. MS (ESI) mass calcd. for C26H23N3OS, 425.56; m/z found, 426.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.Cl[Ni]Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1OCc1ccccc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Nc1ccccc1OCc1ccccc1
Yield: 99.7 %

Procedure:
To a stirred solution of 2-benzyloxynitrobenzene (9.92 g, 43.3 mmol) and NiCl2 (20.3 g, 157 mmol) in MeOH (350 mL) was added portionwise NaBH4 (8.09 g, 214 mmol) at 0° C. After disappearing of the starting material (monitored by TLC), the mixture was evaporated off. The black precipitate was dissolved in 1 N HCl, then acidic solution was alkalified by the addition of 1 N NaOH and extracted with EtOAc. The extracts were washed brine, dried over Na2SO4, and concentrated to dryness. Chromatography of the residue with CHCl3 as eluent gave 2-benzyloxy aniline (8.60 g, 100%) as a reddish oil. 1H-NMR (CDCl3) δ 3.71 (broad s , 2H), 5.06 (s, 2H), 6.68–6.86 (m, 4H), 7.32–7.44 (m, 51); FAB-MS m/z 200 (M++1).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1.[Li+].CC([N-]C(C)C)C>C1COCC1>[N:4]12[CH2:9][CH2:8][C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: CCOC(=O)C1CCN(CCCl)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C12CCN(CC1)CC2
Temperature: 25 °C
Yield: 95.7 %

Procedure:
A solution of ethyl 1-(2-chloroethyl)-4-piperidinecarboxylate (20.42 g, 92.9 mmol) in THF (600 mL) was cooled to −50° C. under Ar. LDA (2.0 M in heptane/THF/ethyl benzene, 70 mL, 140 mmol) was slowly added to the solution at −50° C. over 25 min. The reaction was allowed to warm up to room temperature over 16 h. The reaction was quenched with K2CO3 (saturated aqueous) (500 mL) and extracted with Et2O (3×500 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The resulting orange oil was co-evaporated three times with DCM to remove excess ethyl benzene, resulting in the title compound (16.29 g, 95.7%). EI-MS m/z 184 (M+H+) Rt (1.08 min).
Reaction SMILES: [CH2:1]([O:17][CH:18]([CH3:23])[CH:19]([OH:22])[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:24](Cl)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N1C=CC=CC=1.Cl>O>[CH2:1]([O:17][CH:18]([CH3:23])[CH:19]([OH:22])[CH2:20][O:21][C:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOC(C)C(O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCOC(C)C(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 48 h
Yield: 97.8 %

Procedure:
A mixture of 27.5 g of 3-(hexadecyloxy)-1,2-butanediol, 34.79 g of trityl chloride and 125 ml of pyridine was allowed to stand 48 hours and then poured into water. A mixture of ether-petroleum ether was added, followed by dilute hydrochloric acid. The organic layer was separated, washed with dilute hydrochloric acid, then brine, dried and the solvent removed. The residue was mixed with petroleum ether and allowed to stand several days. After filtration, the filtrate was evaporated, giving 46.6 g of the desired compound as an oil, which was used in Example 9 without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.C(O)C>Cl>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[CH:19][CH:18]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3cccnc3)cc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(Cc2ccc(OCc3cccnc3)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-[4-(3-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (340 mg), 1 N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml), and ethanol (4 ml) was stirred at room temperature for two hours, diluted with 1 N hydrochloric acid (2 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[3-ethoxy-1-[4-(3-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (260 mg, yield: 82%) was obtained. This was recrystallized from ethanol-hexane. Melting point: 120–121° C.
Reaction SMILES: N#N.[CH3:3][S:4]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])=[O:5].[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][S:4]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])=[O:5]
Reactant: CS(=O)(=O)c1ccc(Cn2ncc([N+](=O)[O-])n2)o1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(Cn2ncc(N)n2)o1
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 2-(5-methanesulfonyl-furan-2-ylmethyl)-4-nitro-2H-[1,2,3]triazole (62 mg, 0.23 mmol), iron powder (39 mg, 0.68 mmol) and NH4Cl (62 mg, 1.14 mmol) in a mixture of EtOH (1.0 mL) and water (0.5 mL) was stirred at 85° C. for 30 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (10 mL) was added followed by water (10 mL). The aq. layer was extracted with CH2Cl2 (2×10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 02: tR=0.63 min; [M+H]+=243.27.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:28][CH:29]([F:31])[F:30])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[Cl:27])[C:10]([CH2:17][CH3:18])=[N:11]2.[OH-].[Li+]>O1CCCC1>[Cl:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[CH2:19][C:9]1[C:10]([CH2:17][CH3:18])=[N:11][C:12]2[C:7]([C:8]=1[O:28][CH:29]([F:30])[F:31])=[C:6]([O:5][CH2:4][C:3]([OH:32])=[O:2])[CH:15]=[CH:14][C:13]=2[F:16]
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(F)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1nc2c(F)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of [3-(2-chloro-4-fluorobenzyl)-4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy]acetic acid methyl ester (1.2 g), tetrahydrofuran (10 mL) and 1.0 M aqueous lithium hydroxide solution (3.0 mL) was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the pH of the residue adjusted to 4 by the addition of sodium dihydrogenphosphate. The mixture was extracted with ethyl acetate and the combined extracts dried over magnesium sulfate. The solvent was removed under reduced pressure to afford title compound, 1.1 g.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:7][N:8]([C:13](=[O:21])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:9][CH2:10][C:11]=1[NH2:12])=[O:5])[CH3:2].N1C=CC=CC=1.[C:28](Cl)(=[O:36])[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH2:7][N:8]([C:13](=[O:21])[C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[CH2:9][CH2:10][C:11]=1[NH:12][C:28]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:36])=[O:5])[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCOC(=O)C1=C(N)CCN(C(=O)c2ccc(Cl)cc2)C1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1=C(NC(=O)Oc2ccccc2)CCN(C(=O)c2ccc(Cl)cc2)C1

Procedure:
Ethyl-4-amino-1-(4-chlorobenzoyl)-1,2,5,6-tetrahydropyridine-3-carboxylate (7.0 g) was dissolved in methylene chloride (140 ml), pyridine (6.0 ml) and phenyl chlorocarbonate (6.0 ml) were added under ice cooling, and the resultant mixture was stirred at room temperature for 2 hours. To the reaction solution, water was added and the mixture was extracted with methylene chloride. After the organic layer was washed with citric acid solution and a saturated saline solution, the organic layer was dried over sodium sulfate, filtrated and concentrated. The resultant residue was subjected to medium-pressure column fractionation (solvent; ethyl acetate:hexane=20:80 to 60:40). The titled compound (8.35 g) was obtained as a white powder.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[C:13]([CH:16]2[CH2:18][CH2:17]2)=[CH:12][N:11]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH3:28])=[CH:21][CH:20]=2)[CH:10]=1)C1C=CC=CC=1.CC(O)=O>[Pd].CO>[CH2:25]([C:22]1[CH:21]=[CH:20][C:19]([N:11]2[CH:10]=[C:9]([OH:8])[C:14](=[O:15])[C:13]([CH:16]3[CH2:18][CH2:17]3)=[CH:12]2)=[CH:24][CH:23]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCc1ccc(-n2cc(OCc3ccccc3)c(=O)c(C3CC3)c2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCc1ccc(-n2cc(O)c(=O)c(C3CC3)c2)cc1

Procedure:
A suspension of 3-(benzyloxy)-1-(4-butylphenyl)-5-cyclopropylpyridin-4(1H)-one (27 mg, 0.07 mmol) and 10% Pd/C (1 mg, 0.001 mmol) in a 1:50 mixture of AcOH:MeOH was stirred under H2 (1 atm) for 18 h. The reaction mixture was filtered (0.5μ), concentrated under reduced pressure and purified by reversed phase HPLC (2 cm×5 cm C18, acetonitrile-water gradient, 0.05% TFA added) to provide 1-(4-butylphenyl)-3-cyclopropyl-5-hydroxypyridin-4(1H)-one. 1H NMR (499 MHz, DMSO): δ 7.73 (s, 1 H); 7.55 (d, J=2.7 Hz, 1 H); 7.48 (d, J=8.1 Hz, 2 H); 7.35 (d, J=8.1 Hz, 2 H); 2.64 (t, J=7.7 Hz, 2 H); 2.04-1.95 (m, 1 H); 1.61-1.52 (m, 2 H); 1.37-1.27 (m, 2 H); 0.94-0.87 (m, 3 H); 0.84-0.75 (m, 4 H). HRMS (ES) Calc (M+H)+=284.1645. Found 284.1643.
Reaction SMILES: [CH2:1]([C:4]1[CH:44]=[C:43]([F:45])[C:42]([F:46])=[CH:41][C:5]=1[CH2:6][O:7][CH2:8][C:9]1[CH:40]=[C:12]2[N:13]=[C:14]([CH3:39])[C:15]([C@H:28]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:16]([N:17]3[CH2:22][CH2:21][C:20]([O:24][CH2:25][CH:26]=[CH2:27])([CH3:23])[CH2:19][CH2:18]3)[N:11]2[N:10]=1)C=C.[BH4-].[Na+]>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.C(Cl)Cl>[C:35]([O:34][C@@H:28]([C:15]1[C:14]([CH3:39])=[N:13][C:12]2=[CH:40][C:9]3=[N:10][N:11]2[C:16]=1[N:17]1[CH2:18][CH2:19][C:20]([CH3:23])([O:24][CH2:25][CH2:26][CH2:27][CH2:1][C:4]2[CH:44]=[C:43]([F:45])[C:42]([F:46])=[CH:41][C:5]=2[CH2:6][O:7][CH2:8]3)[CH2:21][CH2:22]1)[C:29]([O:31][CH2:32][CH3:33])=[O:30])([CH3:37])([CH3:36])[CH3:38]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(COCc4cc(F)c(F)cc4CC=C)nn23)CC1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCCc1cc(F)c(F)cc1COC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
A mixture of (S)-ethyl 2-(2-(((2-allyl-4,5-difluorobenzyl)oxy)methyl)-7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (100 mg, 0.156 mmol) and Grubbs II catalyst (13.25 mg, 0.016 mmol) in DCM (100 mL) was refluxed for 2 h. It was then concentrated and the residue was dissolved in MeOH (2 mL). Sodium borohydride (5.90 mg, 0.156 mmol) was added and stirred at rt for 1 h. It was then quenched with NH4Cl, extracted with EtOAc. The organic layer was washed with water, dried over MgSO4, filtered and concentrated. The residue was purified by biotage, eluting with 20% EtOAc/hexane to isolate ethyl (2S)-2-(tert-butoxy)-2-{15,16-difluoro-4,24-dimethyl-11,23-dioxa-1,5,7,8-tetraazapentacyclo[22.2.2.16,9.02,7.013,18]nonacosa-2,4,6(29),8,13(18),14,16-heptaen-3-yl}acetate (60 mg, 0.098 mmol, 62.5% yield) as a white solid. LCMS (M+1)=615.3.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2].C(O)C>[Pd].C(OCC)(=O)C>[NH2:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]([C:5]2[N:6]3[C:15]4[C:10]([CH:9]=[CH:8][C:7]3=[C:3]([C:1]#[N:2])[CH:4]=2)=[CH:11][CH:12]=[CH:13][CH:14]=4)=[O:26])=[CH:22][CH:21]=1
Reactant: N#Cc1cc(C(=O)c2ccc([N+](=O)[O-])cc2)n2c1ccc1ccccc12
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#Cc1cc(C(=O)c2ccc(N)cc2)n2c1ccc1ccccc12
Yield: 13.1 %

Procedure:
A solution of 3-cyano-1-(4-nitro-benzoyl)-pyrrolo[1,2-a]quinoline (44.3 mg, 0.130 mmol), 5 wt % Palladium on Carbon (23.4 mg), ethanol (12.0 mL), and ethyl acetate (90.0 mL) was agitated under hydrogen (30 PSI) for 1.5 h. The solution was filtered through Celite and purified by flash column chromatography (9:1 dichloromethane/ethyl acetate) to yield 5.3 mg (13%) of a light brown solid. 1H NMR (DMSO-d6): 8.04 (d, J=6.86 Hz, 1H), 7.88 (d, J=9.34 Hz, 1H), 7.81 (d, J=8.79 Hz, 2H), 7.75 (d, J=9.07 Hz, 2H), 7.55–7.70 (m, 3H), 6.66 (d, J=8.79 Hz, 2H), 6.42 (s, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]([OH:13])=[O:12])[C:8]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].CI.[C:24](=O)([O-])O.[Na+].O>CN(C=O)C>[C:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]([O:13][CH3:24])=[O:12])[C:8]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(OCc2ccccc2)c(C(=O)O)n1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1nc(NC(C)=O)ccc1OCc1ccccc1
Yield: 90 %

Procedure:
1.5 g (5.2 mmol) of the obtained 6-acetylamino-3-benzyloxypicolinic acid and 1.0 g (7 mmol) of methyl iodide were dissolved in 100 ml of DMF, and 20 ml of an aqueous solution of 0.53 g (6.3 mmol) of sodium hydrogen carbonate was added thereto. The mixture was reacted at 60° C. for 3 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The crystals thereby obtained was washed with diisopropyl ether to obtain methyl 6-acetylamino-3-benzyloxypicolinate.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:30][C:31]([F:34])([F:33])[CH3:32])[C:5]([C:7]1[C:11]([O:12]C(=O)C)=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[N:8]=1)=[O:6].C([O-])([O-])=O.[K+].[K+].Cl>CO>[Cl:1][CH2:2][CH2:3][N:4]([CH2:30][C:31]([F:34])([F:33])[CH3:32])[C:5]([C:7]1[C:11]([OH:12])=[C:10]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)[N:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[N:8]=1)=[O:6]
Reactant: CC(=O)Oc1c(C(=O)N(CCCl)CC(C)(F)F)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(F)(F)CN(CCCl)C(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1O
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
Acetic acid 3-[(2-chloroethyl)-(2,2-difluoropropyl)-carbamoyl]-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1-H-pyrazol-4-yl-ester I-6f (3.55 g, 6.69 mmol) was dissolved in 90 ml of methanol with warming in a 40° C. waterbath to give a clear colorless solution. The resulting solution was cooled to 0° C. (still a clear, colorless solution), followed by addition of K2CO3 (1.02 g, 7.31 mmol) in one portion as a solid (reaction mixture goes from colorless to yellow). Reaction stirred for 30 minutes at 0° C., followed by addition of concentrated hydrochloric acid (1.2 ml of 12.1 M, 14.5 mmol). Note: upon neutralization, reaction turns colorless and clear, then product begins to precipitate. The reaction was warmed to room temperature, then 45 ml of water was added, followed by stirring for 2.5 hours. The precipitated solids were collected by filtration and the resulting filtercake was washed with 50 ml of room temperature 2:1, methanol:water. Collected solids were dried at 50° C. and 10 mm for 1 hour to give 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-hydroxy-1H-pyrazole-3-carboxylic acid (2-chloroethyl)-(2,2-difluoropropyl)-amide I-6g (2.86 g, 87%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5]2.[OH2:19]>C(Cl)Cl.CC#N>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[C:8](=[O:19])[N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5]2
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Cl)ncc2C1
Reactant: O
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc(Cl)ncc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a solution of NaIO4 (9.56 g, 44.7 mmol) and RuCl3 (927 mg, 4.47 mmol) in water (50 mL), DCM (50 mL) and MeCN (2 mL) was added a solution of tert-butyl 6-chloro-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (4.0 g, 14.9 mmol) in DCM (25 mL). This reaction was stirred at room temperature for 2 h. At completion, the reaction was and was quenched with isopropanol (10 mL), filtered over celite and the filter cake was washed with DCM (20 mL). The filtrate was partitioned in a separatory funnel and the layers were separated. The organic layer was extracted with DCM (2×20 mL) and the combined organics were dried over Na2SO4, then filtered and concentrated. The residue was purified by flash chromatography over silica gel (20-50% EtOAc/hexane eluent) to give tert-butyl 6-chloro-1-oxo-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (3.0 g, 71% yield) as a yellow crystalline solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.92 (s, 1H), 7.47 (s, 1H), 4.03 (t, J=6.3 Hz, 2H), 3.09 (t, J=6.1 Hz, 2H), 1.54-1.62 (m, 9H); MS (EI) m/z=283.7 [M+1]+.