Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:17][CH:16]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[N:25]1([CH2:24][CH2:23][CH2:22][O:21][C:18]2[CH:17]=[CH:16][C:15]([N:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH:14]=[C:6]3[CH2:4][OH:3])=[CH:20][CH:19]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCOC(=O)c1cc2ccccc2n1-c1ccc(OCCCN2CCCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc2ccccc2n1-c1ccc(OCCCN2CCCC2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 0.8 %

Procedure:
(1-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]-1H-indole-2-carboxylic acid ethyl ester (0.5 g, 1.27 mmol) was dissolved in THF (10 mL) and added dropwise to lithium aluminum hydride (1.53 mL, 1 M solution in THF, 1.53 mmol) in THF (10 mL). The reaction was stirred at 60° C. for 2 hours. Water (0.3 mL), 2 N NaOH (0.3 mL), and water (0.9 mL) were added, and the solvent was evaporated. The resulting residue was diluted with water and extracted with dichloromethane. The dichloromethane extracts were dried over MgSO4 and concentrated to give a white solid, 0.36 g. A small amount of the product was purified by semi-prep LC-MS to give 3.5 mg of pure desired product. LC-MS (C22H26N2O2 calc'd 350) m/z 351 (M+H); 1H NMR (300 MHz, CDCl3) δ 7.65-7.61 (m, 1H), 7.35 (d, J=8.7 Hz, 2H), 7.16-7.08 (m, 3H), 7.01 (d, J=8.7 Hz, 2H), 6.65 (s, 1H), 4.64 (s, 2H), 4.10 (t, J=6 Hz, 2H), 2.93-2.86 (m, 6H), 2.21-2.12 (m, 2H), 1.94-1.90 (m, 4H).
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:2](C=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.[Br-].[C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:18])=[O:17].C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1.B(F)(F)F.CCOCC>O1CCCC1.O>[C:9]1([C:1]2[CH:6]=[CH:5][C:4](/[CH:23]=[CH:22]/[CH2:21][CH2:20][CH2:19][C:16]([OH:18])=[O:17])=[CH:3][CH:2]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)CCCCC[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1-c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: FB(F)F
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: O=C(O)CCC/C=C/c1ccc(-c2ccccc2)cc1
Yield: 59 %

Procedure:
Six grams biphenylcarboxaldehyde, 10.23 g 5-carboxypentyl triphenylphosphorane bromide, 5.8 g anhydrous K2CO3 and 130 mg 18-Crown-6 were suspended in 240 mL dry tetrahydrofuran. The mixture was heated and stirred at reflux for 7 days, diluted with 200 mL H2O, extracted with EtOAc (5×200 mL). The EtOAc extract was dried (Na2SO4) and concentrated, the residue was taken up in methanol (200 mL) treated with 1 equivalent BF3.OEt2 and the methyl esters of the cis and trans acids separated by chromatography (yield 59%). The esters were hydrolyzed upon dissolving in MeOH (100 mL) and treatment with 1N NaOH (50 mL). Acidification resulted in precipitation of the corresponding acids cis-6-(4'-biphenyl)hex-5-enoic acid, m.p. 107°-109° and trans-6-(4'-biphenylyl)hex-5-enoic acid, m.p. 116°-118°.
Reaction SMILES: O.[C:2]1(=[O:8])O[C:5](=[O:6])[CH:4]=[CH:3]1.[CH2:9]([NH2:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].P(=O)(O)(O)O>C1(C)C(C)=CC=CC=1>[CH2:9]([N:21]1[C:5](=[O:6])[CH:4]=[CH:3][C:2]1=[O:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=C1C=CC(=O)O1
Reactant: CCCCCCCCCCCCN
Agent: O=P(O)(O)O
Solvent: O
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCCN1C(=O)C=CC1=O
Temperature: 215 °C

Procedure:
A glass flask having an inner volume of 3 liters was fitted with a thermometer, a stirrer, and a water separator. In this reactor, 240 g of a solution containing 120 g of maleic anhydride in xylene was placed. Then, a solution containing 220 g of dodecylamine in 1880 g of xylene was added gradually and piecemeal over a period of 120 minutes at 40° C. to the reactor. After the addition was completed, the mixture in the reactor and 65.4 g of orthophosphoric acid (purity 89% by weight) added thereto were heated at 215° C. for 1 hour under 4.4 kg/cm2G. to effect reaction. The resultant reaction mixture was cooled to 30° C., washed with 400 ml of water, and separated into a water layer and a xylene layer. The xylene layer was separated by filtration to effect removal of insolubles. The xylene layer was distilled to expel xylene. Consequently, there was obtained 258 g of slightly impure N-dodecyl maleimide. This product was found to have purity of 85.3% by weight, indicating the yield to be 69.9 mol% based on dodecylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:64]=[CH:63][C:53]2[NH:54][C:55]([C@@H:57]([NH2:62])[CH2:58][CH2:59][S:60][CH3:61])=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([NH:62][C@H:57]([C:55]1[NH:54][C:53]2[CH:63]=[CH:64][C:50]([Cl:49])=[CH:51][C:52]=2[N:56]=1)[CH2:58][CH2:59][S:60][CH3:61])=[O:7]
Reactant: CSCC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(O)c1ccc(C(=O)N2CCCC2)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSCC[C@H](NC(=O)c1ccc(C(=O)N2CCCC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 62 %

Procedure:
Prepared analogously to Example 1g from 3-chloro-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-(methyl-sulfanyl)propylamine in tetrahydrofuran. Yield: 62%; Rf value: 0.50 (silica gel; dichloromethane/ethanol=9:1); C23H24Cl2N4O2S (491.44); mass spectrum: (M+H)+=391/393/395 (chlorine isotope).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][C:37]([F:41])([F:40])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[F:41][C:37]1([F:40])[CH2:38][CH2:39][N:34]([S:31]([C:26]2[CH:25]=[CH:30][CH:29]=[CH:28][C:27]=2[C:6]2[CH:5]=[CH:4][C:3]([C:17]3[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=3)=[C:2]([F:1])[CH:7]=2)(=[O:33])=[O:32])[CH2:35][CH2:36]1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(c1ccccc1Br)N1CCC(F)(F)CC1
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCC(F)(F)CC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 1-((2-bromophenyl)sulfonyl)-4,4-difluoropiperidine. MS (ESI): mass calcd. for C21H19F3N4O2S, 448.12; m/z found, 449.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.35 (s, 1H), 8.27 (d, J=1.4, 1H), 8.12 (d, J=8.0, 1H), 7.98 (m, 1H), 7.75-7.67 (m, 1H), 7.63 (m, 1H), 7.43 (d, J=7.6, 1H), 7.32 (d, J=10.6, 2H), 3.02-2.93 (m, 4H), 1.90-1.73 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[F:10][C:11]1[CH:12]=[C:13](/[CH:18]=[CH:19]/[C:20]([N:22]2[C@H:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][O:24][C:23]2=[O:33])=[O:21])[CH:14]=[C:15]([F:17])[CH:16]=1>C1COCC1>[F:10][C:11]1[CH:12]=[C:13]([C@H:18]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:19][C:20]([N:22]2[C@H:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][O:24][C:23]2=[O:33])=[O:21])[CH:14]=[C:15]([F:17])[CH:16]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: O=C(/C=C/c1cc(F)cc(F)c1)N1C(=O)OC[C@H]1c1ccccc1
Solvent: C1CCOC1
Product: O=C(C[C@@H](c1ccc(F)cc1)c1cc(F)cc(F)c1)N1C(=O)OC[C@H]1c1ccccc1
Temperature: -40 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-fluorophenylmagnesium bromide (29 mL of a 2.0 M solution in THF, 58 mmol) and copper(I) bromide-dimethylsulfide complex (12 g, 59 mmol) in THF (100 mL) under an atmosphere of nitrogen was cooled to −40° C. in a dry ice-acetonitrile bath. To the stirred solution was added a solution of (4R)-3-[(2E)-3-(3,5-difluorophenyl)prop-2-enoyl]-4-phenyl-1,3-oxazolidin-2-one (7.7 g, 23 mmol) in 100 mL of THF dropwise over 15 min. The resulting mixture was stirred at −40° C. for 1.5 h, then the cooling bath was removed and the stirred mixture was allowed to warm to ambient temperature. The reaction was quenched by the addition of aqueous NH4Cl solution. The resulting mixture was stirred for 15 min then extracted with two portions of EtOAc. The combined organic phases were washed with water and brine, then dried (MgSO4), filtered, and the solvents were removed in vacuo. The residue was chromatographed on a 330 g SiO2 column using a gradient elution of 0-50% EtOAc:A, where A=1:1 hexanes:CHCl3. Fractions containing product were combined and the solvents were removed in vacuo to give a solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[NH:17][C:16](=O)[CH2:15]2)=[C:10]([CH2:19][O:20][Si](C(C)C)(C(C)C)C(C)C)[CH:9]=1.Cl>CCOCC>[ClH:7].[NH:17]1[CH2:16][CH2:15][CH:14]1[C:11]1[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][C:10]=1[CH2:19][OH:20]
Reactant: CC(C)[Si](OCc1cc(Cl)ccc1C1CC(=O)N1)(C(C)C)C(C)C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: OCc1cc(Cl)ccc1C1CCN1
Temperature: 0 °C
Yield: 200 %

Procedure:
LAH (1 M solution in ether, 7.74 mL) was added to a stirred solution of 4-(4-chloro-2-{[(triisopropylsilyl)oxy]methyl}phenyl)azetidin-2-one (0.7122 g, 1.935 mmol) in ether (2 mL) at 0° C. The solution was heated to reflux and after 2 h was cooled to 0° C. and quenched with water (0.294 mL), 15% sodium hydroxide solution (0.294 mL) and water (0.881 mL). The mixture was sonicated to give a uniform precipitate, filtered and evaporated in vacuo to an oil. The oil was dissolved in ethanol (10 mL) and concentrated HCl (0.167 mL, 2 mmol) was added with stirring at 0° C. The reaction was warmed to ambient temperature and after 30 min was evaporated in vacuo, azeotroping with ethanol to give (2-azetidin-2-yl-5-chlorophenyl)methanol hydrochloride (0.453 g) as a crystalline solid: 1H NMR (CD3OD, 400 MHz) δ 2.79 (m, 1H), 3.14 (m, 1H), 3.87 (dt, J=4.5 and 10.0 Hz, 1H, 4.18 (q, J=9.3 Hz, 1H), 4.61 (d, J=13.1 Hz, 1H), 4.68 (d, J=13.1 Hz, 1H), 5.93 (t, J=9.0 Hz, 1H), 7.49 (m, 2H), 7.69 (d, J=8.2 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[O:8])=[CH:5][N:6]=1.[Cl:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[C:21]([CH3:26])[N:20]=1.CC(C)([O-])C.[Na+].Cl>C1COCC1>[Cl:18][C:19]1[N:20]=[C:21]([CH3:26])[N:22]=[C:23]([NH:1][C:2]2[S:3][C:4]([C:7]([NH:9][C:10]3[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:17])=[O:8])=[CH:5][N:6]=2)[CH:24]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: Cc1cccc(Cl)c1NC(=O)c1cnc(N)s1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc(Nc2ncc(C(=O)Nc3c(C)cccc3Cl)s2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.1 %

Procedure:
To a stirring solution of compound 5C (5.00 g, 18.67 mmol) and 4,6-dichloro-2-methylpyrimidine (3.65 g 22.4/mmol) in THF (65 mL) was added a 30% wt. solution of sodium t-butoxide in THF (21.1 g, 65.36 mmol) slowly with cooling to keep the temperature at 10-20° C. The mixture was stirred at room temperature for 1.5 h and cooled to 0-5° C. Hydrochloric acid, 2N (21.5 mL) was added slowly and the mixture stirred 1.75 h at 0-5° C. The solid was collected by vacuum filtration, washed with water (15 mL) and dried to give 6.63 g (86.4% yield) of compound 5D. 1H NMR (400 MHz, DMSO-d6) δ 2.23 (s, 3H), 2.58 (s, 3H), 6.94 (s, 1H), 7.18-7.34, (m, 2H, J=7.5), 7.34-7.46 (d, 1H, J=7.5), 8.31 (s, 1H), 10.02 (s, 1H), 12.25 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[CH2:14]([Mg]Br)[CH3:15].[NH4+].[Cl-]>C1COCC1>[F:1][C:2]([F:12])([F:13])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]([OH:9])[CH2:14][CH3:15])=[CH:6][CH:5]=1
Reactant: CC[Mg]Br
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A cooled (0° C.) solution of 4-(trifluoromethoxy)benzaldehyde (5.000 g; 26.29 mmol) in anh. THF (50 ml) was treated dropwise with a solution of ethylmagnesium bromide (3 M in Et2O; 10.50 ml; 31.50 mmol), and the resulting mixture was stirred at rt, under nitrogen, for 17 h. The resulting reaction mixture was cooled to 0° C., and aq. sat. NH4Cl (30 ml) was added dropwise. The separated aq. layer was further extracted with AcOEt (3×20 ml), and the mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=60/1) afforded 1-(4-(trifluoromethoxy)phenyl)propan-1-ol as a colorless oil. LC-MS (conditions A): tR=0.79 min.; no ionisation.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[O:38])[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27][C:28]([CH3:37])([CH3:36])[C:29]([O:31]C(C)(C)C)=[O:30])=[CH:23][CH:22]=1)[CH2:14][C:15]1[O:16][CH:17]=[CH:18][CH:19]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[O:38])[CH2:12][N:13]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([S:27][C:28]([CH3:36])([CH3:37])[C:29]([OH:31])=[O:30])=[CH:25][CH:26]=1)[CH2:14][C:15]1[O:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1ccc(NC(=O)CN(Cc2ccc(SC(C)(C)C(=O)OC(C)(C)C)cc2)Cc2ccco2)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(NC(=O)CN(Cc2ccc(SC(C)(C)C(=O)O)cc2)Cc2ccco2)c(C)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
200 mg of tert-butyl 2-[[4-[[[2-[(2-methyl-4-methoxyphenyl)amino]-2-oxoethyl](2-furanyl-methyl)amino]methyl]phenyl]thio]-2-methyl-propanoate are dissolved in 5 ml of dichloromethane and reacted with I ml of trifluoroacetic acid. The mixture is stirred at room temperature for 20 h and then concentrated and purified chromatographically (dichloromethane/methanol 50+1). This gives 174 mg of the title compound as a solid foam.
Reaction SMILES: [CH:1]1([CH:7]([NH:24][C:25]2[N:30]=[CH:29][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])=[O:32])=[CH:27][CH:26]=2)[C:8]2[CH:9]=[N:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)=[N:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Li+]>CO>[CH:1]1([CH:7]([NH:24][C:25]2[N:30]=[CH:29][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:32])=[CH:27][CH:26]=2)[C:8]2[CH:9]=[N:10][C:11]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=3)=[N:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2cnc(-c3ccc(C(F)(F)F)cc3)nc2)C2CCCCC2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)c1ccc(NC(c2cnc(-c3ccc(C(F)(F)F)cc3)nc2)C2CCCCC2)nc1
Temperature: 50 °C

Procedure:
In two separate reaction vessels, (+) and (−)-ethyl N-({6-[(cyclohexyl{2-[4-(trifluoromethyl)phenyl]pyrimidin-5-yl}methyl)amino]pyridin-3-yl}carbonyl)-beta-alaninate (0.050 g, 0.090 mmol) were separately dissolved in methanol (0.2 ml) and tetrahydrofuran (0.10) and treated with aqueous lithium hydroxide (0.090 ml, 0.36 mmol, 2.0M aq.). The reactions were heated to 50° C. for 12 hours. The reactions were concentrated in vacuo, then diluted with water and acidified with aqueous 1.0M hydrochloric acid. The precipitated solids were collected for both acids and dried in vacuo to give the products as single enantiomers. 1H NMR (400 MHz, CD3OD, δ): 8.91 (s, 2H), 8.60 (d, J=8.2 Hz, 2H), 8.34 (s, 1H), 8.18 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.2 Hz, 2H), 7.10 (d, J=9.4 Hz, 1H), 4.79 (d, J=8.0 Hz, 2H), 3.58 (t, J=6.7 Hz, 2H), 2.60 (t, J=6.7 Hz, 2H), 1.92-2.09 (m, 2H), 1.66-1.90 (m, 3H), 1.53 (d, J=12.3 Hz, 1H), 1.05-1.43 (m, 7H). MS (M+1): 528.4.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[C:17]([O:19][CH3:20])=[O:18])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1Cl.[CH3:21][O:22][C:23]1[C:24](=O)[C:25](=[O:29])[C:26]=1[O:27]C>CO>[CH3:21][O:22][C:23]1[C:26](=[O:27])[C:25](=[O:29])[C:24]=1[NH:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[C:17]([O:19][CH3:20])=[O:18])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(OC)c(=O)c1=O
Reactant: COC(=O)[C@H]1CCCN1S(=O)(=O)c1ccc(Cl)c(N)c1
Solvent: CO
Product: COC(=O)[C@H]1CCCN1S(=O)(=O)c1cccc(Nc2c(OC)c(=O)c2=O)c1
Temperature: 60 °C
Yield: 29.3 %

Procedure:
A mixture of 2.54 g of methyl (R)-1-(3-amino-4-chlorobenzenesulfonyl)pyrrolidine-2-carboxylate and 5.68 g of 3,4-dimethoxycyclobut-3-ene-1,2-dione in 50 ml of methanol was heated at 60° C. overnight. The solvent was evaporated off and the residue was chromatographed on silica gel eluted with heptane/ethyl acetate (4:1, 2:1, and pure ethyl acetate). 0.92 g of methyl (R)-1-[3-(2-methoxy-3,4-dioxocyclobut-1-enylamino)benzenesulfonyl]pyrrolidine-2-carboxylate was obtained. Yield=23%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][NH2:6].[CH2:11]([O:18][NH:19][C:20]([C:22]1[N:27]=[CH:26][C:25]2[C:28](=[O:31])[O:29][CH2:30][C:24]=2[C:23]=1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][NH:19][C:20]([C:22]1[C:23]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:24]([CH2:30][OH:29])[C:25]([C:28]([NH:6][CH2:5][C:4]2[CH:3]=[C:2]([F:1])[CH:9]=[C:8]([F:10])[CH:7]=2)=[O:31])=[CH:26][N:27]=1)=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1cc(F)cc(F)c1
Reactant: O=C1OCc2c1cnc(C(=O)NOCc1ccccc1)c2OCc1ccccc1
Product: O=C(NCc1cc(F)cc(F)c1)c1cnc(C(=O)NOCc2ccccc2)c(OCc2ccccc2)c1CO
Yield: 26.8 %

Procedure:
3,5-difluorobenzylamine (0.02 g, 0.154 mmol, 2.5 eq) and N,7-bis(benzyloxy)-3-oxo-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide (0.030 g, 0.077 mmol, 1 eq) were heated neat at 70° C. for 30 min. The crude product was purified by silica gel (100% ethyl acetate) yielding 0.011 g of N2,3-bis(benzyloxy)-N5-(3,5-difluorobenzyl)-4-(hydroxymethyl)pyridine-2,5-dicarboxamide (15% yield) as a white solid; MS-ESI m/z 534 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]([CH2:15][CH:16]1[CH2:19][CH:18]([C:20]([N:22]([O:24][CH3:25])[CH3:23])=[O:21])[CH2:17]1)=O>C(O)(=O)C>[C:8]([C:6]1[CH:5]=[CH:4][C:3]2[NH:12][C:13]([CH2:15][CH:16]3[CH2:19][CH:18]([C:20]([N:22]([O:24][CH3:25])[CH3:23])=[O:21])[CH2:17]3)=[N:1][C:2]=2[CH:7]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CON(C)C(=O)C1CC(CC(=O)Nc2ccc(C(C)(C)C)cc2N)C1
Solvent: CC(=O)O
Product: CON(C)C(=O)C1CC(Cc2nc3cc(C(C)(C)C)ccc3[nH]2)C1
Yield: 116.1 %

Procedure:
A stirred solution of 3-{[(2-amino-4-tert-butylphenyl)carbamoyl]methyl}-N-methoxy-N-methylcyclobutane-1-carboxamide (70%, 2.62 g, 5.28 mmol) in acetic acid (25 ml) was heated to reflux for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue partitioned between sat. NaHCO3 (aq) (25 ml) and EtOAc (25 ml), and the layers separated. The aqueous layer was extracted with EtOAc (2×25 ml), the combined organics were washed with brine (50 ml), dried (MgSO4) and concentrated. The crude material was purified by silica flash column chromatography, eluting with 1-10% 2M NH3 in MeOH in DCM to afford the title compound (2.02 g, 93%) as a yellow gum: MS (ESI+) for C19H27N3O2 m/z 330.5 [M+H]+; LC purity 80% (UV), 100% (ELS), (ret. time, 1.51 min); 1H NMR (500 MHz, CHLOROFORM-d) δH ppm 7.56 (br. s., 1H), 7.48 (d, J=8.5 Hz, 1H), 7.30 (dd, J=8.5, 1.7 Hz, 1H), 3.80-3.90 (m, 1H), 3.65 (s, 3H), 3.47-3.57 (m, 1H), 3.20 (s, 3H), 2.94-3.13 (m, 2H), 2.88 (dt, J=16.1, 8.1 Hz, 1H), 2.32-2.60 (m, 2H), 2.01-2.17 (m, 2H), 1.38 (s, 9H).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][CH2:11][CH:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH:18](CCCC(CCCC(C)C)C)[CH3:19])C)C)C>O>[CH3:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:12][CH2:11][CH2:10][CH2:9][CH2:7][CH2:6][CH2:5][CH2:4][CH2:2][CH3:1]
Reactant: CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C
Solvent: O
Product: CCCCCCCCCCCCCCCC

Procedure:
The formulations of SLP in an emulsion of squalane in water, soybean oil in water and hexadecane in water were prepared according to the method described in Example 1.
Reaction SMILES: [N:1]1(C(=O)C)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[OH-].[Na+].Cl>C1COCC1.CO.O>[NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(=O)n1ncc2ncccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: c1cnc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
Pyrazolo[4,3-b]pyridin-1-yl-ethanone (973 mg, 6.04 mmol) was dissolved in THF/MeOH (1:1, 16 mL) and 10% NaOH (1.8 mL) was added. The reaction mixture was stirred at room temperature for 30 min then neutralized with 1.0 M HCl, diluted with water and extracted with EtOAc (2×). The combined organics were washed with brine then dried over MgSO4 and concentrated to afford 687 mg (96%) of 1H-pyrazolo[4,3-b]pyridine as a light yellow solid. 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 13.29 (br. s., 1H), 8.50 (d, J=4.5 Hz, 1H), 8.27 (s, 1H), 8.00 (d, J=8.7 Hz, 1H), 7.34 (dd, J=8.7, 4.5 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([CH3:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[N:37][CH:36]=[C:35]([CH3:39])[N:34]=2)[CH:28]=1)=[O:26])(C)(C)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([CH3:15])=[CH:10][C:9]=1[NH:16][C:23](=[O:22])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[N:37][CH:36]=[C:35]([CH3:39])[N:34]=2)[CH:28]=1)=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cncc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)n1
Reactant: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1Cl
Product: Cc1cncc(-c2cccc(C(=O)CC(=O)Nc3cc(C)c(Cl)cc3NC(=O)OC(C)(C)C)c2)n1

Procedure:
The title compound was prepared from (2-amino-5-chloro-4-methyl-phenyl)-carbamic acid tert-butyl ester (Example J21) (257 mg, 1.0 mmol) and 3-[3-(6-methyl-pyrazin-2-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K16) (312 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (400 mg, 81%).
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][C:7]([F:11])=[C:6]([F:12])[C:3]=1[C:4]#N.C[OH:14].O>[Ni].C(O)(=O)C>[F:1][C:2]1[C:9]([F:10])=[CH:8][C:7]([F:11])=[C:6]([F:12])[C:3]=1[CH:4]=[O:14]
Reactant: N#Cc1c(F)c(F)cc(F)c1F
Reactant: CO
Agent: [Ni]
Solvent: O
Solvent: CC(=O)O
Product: O=Cc1c(F)c(F)cc(F)c1F
Temperature: 60 °C

Procedure:
Into a 500 ml-volume glass-made reactor equipped with a condenser tube, 5.00 g of 2,3,5,6-tetrafluorobenzonitrile, 51.00 g of methanol, 52.00 g of water, 45.00 g of acetic acid and 0.50 g of sponge nickel were charged. After purging the vapor phase moiety with hydrogen gas, the mixed solution was stirred at 60° C. under atmospheric pressure while continuously supplying hydrogen. As the time passed, the reaction solution was sampled and analyzed by means of a gas chromatograph. As a result, it was confirmed that 2,3,5,6-tetrafluorobenzyl alcohol was produced together with 2,3,5,6-tetrafluorobenzaldehyde. The yields in the reaction solution are shown in the table below.