Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([NH:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:9]([O:11][C:12](=[O:24])[C:13](=[CH:20]N(C)C)[C:14](=O)[C:15]([F:18])([F:17])[F:16])[CH3:10].C([O-])(=O)C.[Na+]>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[CH:20]=[N:8][N:7]([CH:2]2[CH2:6][CH2:5][CH2:4][CH2:3]2)[C:14]=1[C:15]([F:16])([F:17])[F:18])=[O:24])[CH3:10]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)C(F)(F)F
Reactant: NNC1CCCC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnn(C2CCCC2)c1C(F)(F)F
Temperature: 70 °C
Yield: 52.6 %

Procedure:
Cyclopentyl-hydrazine hydrochloride (0.250 g, 1.83 mmol, Example 64, Step 2), 2-dimethylaminomethylene-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester (0.403 g, 1.68 mmol) and anhydrous sodium acetate (0.163 g, 1.99 mmol) were combined in ethanol (2.5 mL) and heated at 70° C. for 17 hours. After cooling to room temperature, the reaction mixture was partitioned between methylene chloride and water. The organic phase was washed with water and brine. Each aqueous phase was back extracted with a second portion of methylene chloride. The two organic phases were combined, dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography, eluting with a 10-40% ethyl acetate-hexanes gradient, yielded 1-cyclopentyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.244 g, 52%). Mass spectrum: m/z: 277.1 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=1[C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:20]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(c1ccccc1)c1ccccc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccccc3C(=O)c3ccccc3)c2cc1OC
Temperature: 160 °C
Reaction time: 4 h

Procedure:
4-Chloro-6,7-dimethoxyquinoline (58 mg), 2-hydroxybenzophenone (271 mg), and 4-dimethylaminopyridine (166 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160° C. for 4 hr. The reaction solution was cooled to room temperature, and the solvent was then removed therefrom by distillation under the reduced pressure. Chloroform was added to the residue, and the mixture was washed with a 1 N aqueous potassium hydroxide solution and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform and by thin layer chromatography using acetone-hexane to quantitatively give 110.4 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH2:24][C@@H:25]1[CH2:29][CH2:28][C@H:27]([C:30]([OH:32])=[O:31])[CH2:26]1.[OH-].[K+]>O1CCOCC1>[Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[N:10]=2)=[CH:4][C:5]([NH:24][C@@H:25]2[CH2:29][CH2:28][C@H:27]([C:30]([OH:32])=[O:31])[CH2:26]2)=[N:6][CH:7]=1
Reactant: N[C@@H]1CC[C@H](C(=O)O)C1
Reactant: Fc1cccc(CNc2cccc(-c3cc(F)ncc3Cl)n2)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)[C@H]1CC[C@@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)C1
Temperature: 100 °C
Reaction time: 18 h
Yield: 7.5 %

Procedure:
To 5′-chloro-2′-fluoro-N-(3-fluorobenzyl)-2,4′-bipyridin-6-amine (100 mg, 0.301 mmol), was added (1S,3R)-3-aminocyclopentanecarboxylic acid (117 mg, 0.904 mmol), powdered potassium hydroxide (85 mg, 1.507 mmol) and dioxane (1 ml). The reaction mixture was stirred at 100° C. for 18 hr in a sealed vessel and followed by LCMS. The crude reaction mixture was partitioned between 30 mL saturated ammonium chloride and 30 mL ethyl acetate. The organic layer was removed, dried over sodium sulfate, and reduced. This was redissolved in 1.5 mL DMSO, filtered, and purified through prep LC. The product fractions were combined and extracted with 50 mL ethyl acetate, which was dried over sodium sulfate, and concentrated to constant mass. 10 mg of the desired compound was obtained. LCMS (m/z): 441.2 (MH+), retention time=0.68 min. 1H NMR (400 MHz, CHLOROFORM-d, 25° C.) δ ppm 1.59 (m, 2H) 1.83 (m, 2H) 1.99 (m, 1H) 2.72 (m, 1H) 3.40 (br. s., 1H) 3.78 (br. s., 1H) 4.42 (br. s., 1H) 5.48 (br. s., 1H) 6.29 (d, J=8.22 Hz, 1H) 6.50 (s, 1H) 6.80-6.92 (m, 2H) 6.95-7.10 (m, 2H) 7.16-7.25 (m, 1H) 7.38 (t, J=8.02 Hz, 1H) 7.89 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH:10](O)[CH2:11][CH:12](C)[CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][CH:5]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[Br:51][C:52]1[CH:57]=[CH:56][C:55]([SH:58])=[CH:54][CH:53]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:5]=[CH:6][C:7]([CH:10]([S:58][C:55]2[CH:56]=[CH:57][C:52]([Br:51])=[CH:53][CH:54]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:8][CH:9]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CCCCC(C)CC(O)c1ccc(C(=O)OC)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCCCCCC(Sc1ccc(Br)cc1)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1-hydroxy-3-methyl-heptyl)-benzoic acid methyl ester (1760 mg, 7.04 mmol) in toluene (70 mL) is added 1,1′-(azodicarbonyl)dipiperidine (ADDP, 2664 mg, 10.56 mmol) at 0° C., followed by the additions of tributylphosphine (2.63 mL, 8.38 mmol) and 4-bromo-benzenethiol (1597 mg, 8.45 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl acetate giving 4-[1-(4-bromo-phenylsulfanyl)-heptyl]-benzoic acid methyl ester. 1700 mg of the ester product is taken into ethanol (5 mL), treated with sodium hydroxide (5N aqueous, 2 mL) for 3 h at room temperature. The mixture is concentrated, diluted with ethyl acetate, acidified with 5 N HCl (2 mL), and extracted with ethyl acetate. The organic layers are dried and concentrated giving 4-[1-(4-bromo-phenylsulfanyl)-3-methyl-heptyl]-benzoic acid (1700 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](Cl)=[C:7]3[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:8]3=[N:9][C:10]=2[CH:11]=1.[CH2:19]([N:21]([CH2:30][CH3:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH2:29])[CH3:20].C1(O)C=CC=CC=1.[ClH:39]>CC(C)=O>[ClH:1].[ClH:39].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([NH:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:30][CH3:31])[CH2:19][CH3:20])=[C:7]3[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:8]3=[N:9][C:10]=2[CH:11]=1
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2n1
Reactant: CCN(CC)CCCCCCCN
Agent: Cl
Solvent: CC(C)=O
Solvent: Oc1ccccc1
Product: CCN(CC)CCCCCCCNc1c2ccc(Cl)cc2nc2ccc(OC)nc12

Procedure:
A mixture of 2.8 g. of 7,10-dichloro-2-methoxypyrido [3,2-b]quinoline, 2.0 g. of 7-diethylaminoheptylamine and 6.5 g. of phenol is stirred on a steam bath for 3 hours. The reaction is cooled, 20 ml. of 95% alcohol is added and this mixture is poured into a mixture of 200 ml. of acetone and 2.5 ml. of concentrated hydrochloric acid. The resulting solution is cooled in ice. The solid is collected and recrystallized from n-propanol:ethyl acetate (50:50), giving the desired product as yellow crystals, mp. 170°-174° C. (dec.).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]([F:14])=[C:12]([O:15][CH3:16])[CH:11]=[C:10]([O:17][CH3:18])[C:9]=1[F:19])(C)(C)C>FC(F)(F)C(O)=O>[F:14][C:13]1[C:12]([O:15][CH3:16])=[CH:11][C:10]([O:17][CH3:18])=[C:9]([F:19])[C:8]=1[NH2:7]
Reactant: COc1cc(OC)c(F)c(NC(=O)OC(C)(C)C)c1F
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(F)c(N)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
To 34.6 g (0.12 mol) of (2,6-difluoro-3,5-dimethoxy-phenyl)-carbamic acid tert-butyl ester, 120 mL of trifluoroacetic acid was added to give a homogeneous solution which was stirred at room temperature for 30 minutes. After 30 min., the reaction mixture was concentrated in vacuo. To the residue, a saturated solution of sodium bicarbonate was carefully added to pH 8. The resulting suspension was extracted twice with diethylether. Combined diethylether layers were washed once with brine, dried over sodium sulfate, filtered and evaporated to give 22 g (97%) of title compound. MS (APCI) (m+1)/z 190.1.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([C:2]2[O:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(Br)o1
Reactant: OB(O)c1ccccc1
Product: O=Cc1ccc(-c2ccccc2)o1
Yield: 101.9 %

Procedure:
The title compound (2.0 g, 95%) was prepared from 5-bromo-2-furaldehyde (2.0 g, 11.4 mmol) and phenylboronic acid (1.5 g, 12 mmol) using the procedure of Example 159, step 1.
Reaction SMILES: [C:1]([C@@:3]1([CH:31]2[CH2:33][CH2:32]2)[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[N:17][N:18]([C:20]([CH3:29])([CH3:28])[C:21]([O:23]C(C)(C)C)=[O:22])[CH:19]=3)[N:9]=2)[C:4]1=[O:30])#[N:2].[ClH:34]>C(OCC)(=O)C>[ClH:34].[C:1]([C@@:3]1([CH:31]2[CH2:32][CH2:33]2)[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[N:17][N:18]([C:20]([CH3:29])([CH3:28])[C:21]([OH:23])=[O:22])[CH:19]=3)[N:9]=2)[C:4]1=[O:30])#[N:2]
Reactant: CC(C)(C)OC(=O)C(C)(C)n1cc(Nc2nccc(N3CC[C@@](C#N)(C4CC4)C3=O)n2)cn1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(C(=O)O)n1cc(Nc2nccc(N3CC[C@@](C#N)(C4CC4)C3=O)n2)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 2-(4-((4-((3S)-3-cyano-3-cyclopropyl-2-oxopyrrolidin-1-yl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-2-methylpropanoate (1.0 g) obtained in Step C of Example 108 in ethyl acetate (10 mL) was added a solution of 4 M hydrogen chloride in ethyl acetate (10 mL), and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure, and the residue was recrystallized (diisopropyl ether/ethanol) to give the crude title compound (1.1 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]2[CH2:18][C@@H:17]([C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)=[O:11])=[C:4]([NH:39][CH2:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45])[CH:3]=1.C(OCC)(=O)C.[ClH:52]>C(O)(=O)C>[ClH:52].[ClH:52].[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:9]([C:10]([N:12]([CH2:34][CH:35]([CH3:36])[CH3:37])[C@H:13]3[CH2:18][C@@H:17]([C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[O:20])[CH2:16][NH:15][CH2:14]3)=[O:11])[N:39]([CH2:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45])[C:4]=2[CH:3]=1
Reactant: COCCCCNc1cc(F)ccc1NC(=O)C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)N3CCOCC3)C2)nc2ccc(F)cc21
Temperature: 80 °C
Reaction time: 72 h

Procedure:
tert-Butyl (3S,5R)-3-{[({4-fluoro-2-[(4-methoxybutyl)amino]phenyl}amino)(oxo)acetyl](2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (294 mg) was dissolved in acetic acid (5 ml), and the mixture was stirred at 80° C. for 3 days. The reaction mixture was cooled to room temperature, 4M hydrogen chloride-ethyl acetate (5 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, and the residue was diluted with aqueous sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate-methanol (85:15) was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, 4M hydrogen chloride-ethyl acetate (1 ml) was added, and the mixture was concentrated again to give the object product (113 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][NH:10][C:3]=12.[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[OH:21].C([O-])([O-])=O.[K+].[K+]>O(C1C=CC=CC=1)C1C=CC=CC=1>[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[O:21][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][NH:10][C:3]=12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Clc1ccnc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc[nH]c23)c(F)c1
Temperature: 170 °C
Yield: 26.1 %

Procedure:
A mixture of 266 (180 mg, 1.18 mmol), 2-fluoro-4-nitrophenol (558 mg, 3.55 mmol) and K2CO3 (981 mg, 7.10 mmol) in Ph2O (4 mL) was heated at 170° C. for 8 hours, cooled to room temperature and partitioned between EtOAc and water. Organic phase was collected, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography with gradient elution of hexane, to hexane/EtOAc (1:1), to afford the title compound 267 (84 mg, 26% yield) as a yellowish solid. MS (m/z): 274.1(M+H) (found).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:12]=[C:11]([C:21]([OH:23])=O)[CH:10]=[CH:9]2)[CH2:2][CH2:3][CH3:4].[ClH:24].Cl.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[CH2:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(N(CC)CC)C.P(C#N)(=O)(OCC)OCC>CN(C)C=O>[ClH:24].[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:12]=[C:11]([C:21]([N:35]1[CH2:34][CH2:33][N:32]([CH2:31][C:30]3[CH:38]=[C:39]([O:43][CH3:44])[C:40]([O:41][CH3:42])=[C:28]([O:27][CH3:26])[CH:29]=3)[CH2:37][CH2:36]1)=[O:23])[CH:10]=[CH:9]2)[CH2:2][CH2:3][CH3:4]
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Reactant: CCCCOc1cc2ccc(C(=O)O)cc2cc1OCCCC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCOc1cc2ccc(C(=O)N3CCN(Cc4cc(OC)c(OC)c(OC)c4)CC3)cc2cc1OCCCC
Yield: 84.2 %

Procedure:
Using 6,7-dibutoxy-2-naphthoic acid (0.25 g), 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (0.31 g), triethylamine (0.35 g), N,N-dimethylformamide (10 ml) and diethyl phosphorocyanidate (0.5 ml), an amidation as that described in Example 6 is carried out. The reaction mixture is purified by gel column chromatography (hexane:acetone=1:1) and converted to the hydrochloride in ethyl acetate to give 1-(6,7-dibutoxy-2-naphthoyl)-4-(3,4,5-trimethoxybenzyl)piperazine hydrochloride (0.4 g) as colorless prisms, m.p. 182°-185° C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:13][N:12]([C:14]2[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=2)[C:11](=[O:20])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N+:21]([O-])([OH:23])=[O:22].C(=O)([O-])O.[Na+]>C(OC(=O)C)(=O)C>[Si:1]([O:8][C@@H:9]1[CH2:13][N:12]([C:14]2[C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]([CH3:19])[N:15]=2)[C:11](=[O:20])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: Cn1ccc(N2C[C@@H](O[Si](C)(C)C(C)(C)C)CC2=O)n1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cn1cc([N+](=O)[O-])c(N2C[C@@H](O[Si](C)(C)C(C)(C)C)CC2=O)n1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of (4S)-4-((tert-butyl(dimethyl)silyl)oxy)-1-(1-methyl-1H-pyrazol-3-yl)pyrrolidin-2-one (2.07 g) in acetic anhydride (21 mL) was added a solution of fuming nitric acid (0.58 mL) in acetic anhydride (21 mL), and the mixture was stirred under for 1.5 hr under ice-cooling. To the reaction mixture were added ice water and saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.9 g).
Reaction SMILES: [F:1][C@@H:2]1[CH2:7][CH2:6][N:5](C(OCC2C=CC=CC=2)=O)[CH2:4][C@@H:3]1[NH:18][C:19]1[CH:24]=[N:23][CH:22]=[C:21]([C:25]2[CH:26]=[N:27][N:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=23)[N:20]=1.Cl.O>CO>[F:1][C@@H:2]1[CH2:7][CH2:6][NH:5][CH2:4][C@@H:3]1[NH:18][C:19]1[CH:24]=[N:23][CH:22]=[C:21]([C:25]2[CH:26]=[N:27][N:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=23)[N:20]=1
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](F)[C@@H](Nc2cncc(-c3cnn4ccccc34)n2)C1
Agent: Cl
Solvent: O
Solvent: CO
Product: F[C@@H]1CCNC[C@@H]1Nc1cncc(-c2cnn3ccccc23)n1
Temperature: 100 °C
Yield: 96 %

Procedure:
Benzyl (3s,4r)-4-fluoro-3-[(6-pyrazolo[1,5-a]pyridin-3-ylpyrazin-2-yl)amino]piperidine-1-carboxylate (Preparation 41a, 229 mg, 0.51 mmol) was added to a 3N hydrochloric acid solution in methanol (45 mL) and the resulting mixture was heated overnight at 100° C. in a sealed tube. A 37% aqueous hydrochloric acid solution (10 mL) was then added and the reaction mixture was stirred at 100° C. for four additional hours. After cooling to ambient temperature, water was added and the organic solvent was evaporated under reduced pressure. The resulting aqueous phase was washed with methylene chloride, basified by addition of an aqueous 2N sodium hydroxide solution until a basic pH was reached and washed again with methylene chloride (×3). The combined organic phases were washed with brine, dried (MgSO4) and the solvent was evaporated in vacuo to yield the title compound (153 mg, 95%) as an oil.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][OH:11])[CH2:5][CH2:4]1.F[C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][N:14]=1>C1COCC1.O>[I:19][C:16]1[CH:17]=[CH:18][C:13]([O:11][CH2:10][CH2:9][N:6]2[CH2:7][CH2:8][O:3][CH2:4][CH2:5]2)=[N:14][CH:15]=1
Reactant: OCCN1CCOCC1
Reactant: Fc1ccc(I)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Ic1ccc(OCCN2CCOCC2)nc1
Temperature: 60 °C
Yield: 60 %

Procedure:
To a suspension of sodium hydride (2.15 g, 60% dispersion in mineral oil, 54.0 mmol) in THF (100 mL) at 0° C. was added 2-morpholinoethanol (5.43 mL, 44.8 mL). After 30 min 2-fluoro-5-iodopyridine (10.0 g, 44.8 mmol) was added and the reaction mixture was heated to 60° C. for 16 hr and was then cooled and diluted with water (75 mL). The resulting mixture was extracted with EtOAc (2×75 mL) and the combined organic extracts were dried and evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, 120 g, 20-60% EtOAc in isohexane, gradient elution) to afford 4-(2-(5-iodopyridin-2-yloxy)ethyl)morpholine as a yellow oil (9.35 g, 60%); Rt 0.94 min (Method 2, acidic); m/z 335 (M+H)+, (ES+).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[N:6][NH:5][C:4](=S)[NH:3]1>CCO.[Ni]>[O:1]=[C:2]1[C:7]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[N:6][N:5]=[CH:4][NH:3]1
Reactant: O=C1c2ccccc2C(=O)N1Cc1n[nH]c(=S)[nH]c1=O
Agent: [Ni]
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1Cc1nnc[nH]c1=O

Procedure:
A slurry of 2-(5-oxo-3-thioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylmethyl)-isoindole-1,3-dione (1.0 g, 3.47 mmol) in EtOH (40 mL) was charged with excess Raney Nickel (3 spatula) and heated to reflux for 2 h. The reaction mixture was filtered hot through a small pad of celite and washed with a hot mixture of EtOH/THF (1:1) (100 mL) and the filtrate was concentrated in vacuo resulting in the title compound as an off-white solid; 1H NMR (DMSO-d6, 400 MHz) δ 4.75 (s, 2H), 7.84-7.98 (m, 4H), 8.66 (s, 1H); MS (ES+): m/z 257.22 (100) [MH+], HPLC: tR=2.08 min (MicromassZQ, polar—5 min).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:11])([CH3:10])[CH2:8][OH:9].[C:12](OC)(=[O:34])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C[O-].C[N+](C)(C)CC1C=CC=CC=1>[C:12]([CH:8]([OH:9])[C:7]([OH:11])([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH3:10])(=[O:34])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CC(O)(CO)C1CCCCO1
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)OC
Agent: C[N+](C)(C)Cc1ccccc1
Agent: C[O-]
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)C(O)C(C)(O)C1CCCCO1
Temperature: 70 °C
Yield: 44.1 %

Procedure:
2-Tetrahydropyranyl propylene glycol (16.0 grams, 0.1 mole) is interesterified with 39 grams methyl behenate using 4 ml. of 40% trimethyl benzyl ammonium methoxide as a catalyst. The reactants are stirred in a 250 ml. flask heated at 60-80° C. under a reduced pressure of 200 mm. Hg for 6 hours. The reactants are poured into 600 ml. of hexane and the hexane solution washed with 400 ml. of 1% potassium bicarbonate solution. The washed hexane layer is diluted with 200 ml. ethanol and 75 grams urea are added to the sample, Adduct formation with urea is accomplished by stirring the sample initially at 40° C. and allowing the mixture to cool at 25° C. during a 2 hour interval. The urea adduct is removed by filtration and discarded. The adduction with urea is repeated using 60 grams urea. The filtrate from the second urea adduction is water-washed three times and the hexane layer is evaporated to dryness. The residue is dissolved in 300 ml. hexane and the solution is crystallized at -18° C. Filtration at -18° C yields 21.3 grams of 1-behenoyl-2-tetrahydropyranyl propylene glycol. 1-Behenoyl-2-tetrahydropyranyl propylene glycol (8 grams, 0.0l65 mole) is cleaved by reaction with 11 ml. of 1.6 molar boric acid in trimethyl borate. The reactants are heated in a boiling water bath with application of vacuum. Heating is continued for 15 minutes with a vacuum of 2-5 mm. Hg pressure during the final 10 minutes. The residue is cooled to room temperature and dissolved in 200 ml. ethyl ether and water-washed three times. The ether phase is dried with sodium sulfate, and evaporated to dryness on an evaporator without warming above 30° C. The residue is dissolved in 100 ml. petroleum ether and crystallized at 70° F. The crystals recovered at 70° F. are recrystallized from 200 ml. petroleum ether at 50° F. to yield ca. 5 grams of 1-propylene glycol monobehenate.
Reaction SMILES: O.O.[Sn](Cl)Cl.[C:6]([C:8]1[N:9]=[CH:10][C:11]([NH:14][C:15]2[CH:20]=[C:19]([O:21][CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)[C:18]([N+:36]([O-])=O)=[CH:17][N:16]=2)=[N:12][CH:13]=1)#[N:7]>C(O)C>[NH2:36][C:18]1[C:19]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[CH:20][C:15]([NH:14][C:11]2[CH:10]=[N:9][C:8]([C:6]#[N:7])=[CH:13][N:12]=2)=[N:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cc(Nc3cnc(C#N)cn3)ncc2[N+](=O)[O-])CC1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(COc2cc(Nc3cnc(C#N)cn3)ncc2N)CC1
Temperature: 78 °C
Yield: 89 %

Procedure:
Tin (II) chloride dihydrate (745 mg, 3.3 mmol) was added to a solution of crude tert-butyl 4-((2-(5-cyanopyrazin-2-ylamino)-5-nitropyridin-4-yloxy)methyl)piperidine-1-carboxylate (301 mg, 0.66 mmol) in ethanol. After heating at 78° C. for 2 hours the mixture was cooled to room temperature and concentrated. The residue was diluted with ethyl acetate and water and the resulting precipitate was removed by filtration. The biphasic filtrate was separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to give a brown solid (250 mg). A portion of the crude material was purified by preparative HPLC to give tert-butyl 4-((2-(5-cyanopyrazin-2-ylamino)-5-nitropyridin-4-yloxy)methyl) piperidine-1-carboxylate (16 mg) as a yellow powder.