Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:12][O:13][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OCC1(c2ccc(Cl)cc2)CCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)COCC1(c2ccc(Cl)cc2)CCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74.6 %

Procedure:
A solution of (1-(4-chlorophenyl)cyclobutyl)methanol (1.5 g, 7.63 mmol) in toluene (21 mL) was cooled to 0° C. and treated with a 33% aq. NaOH solution (7.43 mL) followed by tetrabutylammonium hydrogen sulfate (647 mg, 1.91 mmol). The mixture was stirred at 0° C. for 10 min and tert-butyl bromoacetate (1.11 mL, 7.63 mmol) was added. The ice bath was removed, and stirring was continued at room temperature for 50 min. Additional tert-butyl bromoacetate (1.11 mL, 7.63 mmol) was added and the mixture was stirred at room temperature for 16 h. Additional tert-butyl bromoacetate (1.11 mL, 7.63 mmol) was added and the mixture was stirred at room temperature for additional 24 h. The reaction mixture was diluted with EtOAc and water. The organic layer was separated, washed with water, brine, dried (Na2SO4), and concentrated. The crude oil was chromatographed on silica gel (Teledyne-Isco RediSep 80 g silica gel column) and eluted with hexanes, followed by 1% and 2% EtOAc in hexanes to obtain tert-butyl 2-((1-(4-chlorophenyl)cyclobutyl)methoxy)acetate (1.77 g, 75% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ ppm 7.25-7.28 (2 H, m), 7.06-7.19 (2 H, m), 3.85 (2 H, s), 3.64 (2 H, s), 2.22-2.49 (4 H, m), 1.98-2.18 (1 H, m), 1.73-1.93 (1 H, m), 1.45 (9 H, s).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH:4]=[C:5]1[CH2:10][CH2:9][O:8][C:6]1=[O:7]>C(O)C.[C].[Pd]>[OH:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][CH:5]1[CH2:10][CH2:9][O:8][C:6]1=[O:7]
Reactant: O=C1OCCC1=Cc1ccccc1O
Agent: [Pd]
Solvent: CCO
Product: O=C1OCCC1Cc1ccccc1O
Reaction time: 6 h
Yield: 99 %

Procedure:
α-(2′-Hydroxybenzylidene)-γ-butyrolactone (5.0 g) was dissolved in ethanol (400 ml) and 10% palladium carbon (0.5 g) was added. The reaction mixture was reduced for 6 hr at 50 atm. The reaction mixture was filtered and the organic solvent was concentrated to give the title compound (5.0 g).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:32][CH2:31][NH:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:32][CH2:31][N:30]([C:36](=[O:37])[CH2:35][O:34][CH3:33])[CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c(C)[nH]c23)c(OCC2CC2)c1
Agent: Cl
Product: COCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f21) and commercially methoxyacetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: CO[C:3]1[C:4]([N:53]=[C:54]=[O:55])=[C:5]([CH:32]=[CH:33][C:34]=1C1C2N=C(CNC(OC(C)(C)C)=O)NC=2C=CC=1)[C:6]([N:8](C)C1C=CC(C)=CC=1OCCCCCC(N1CCC(=O)CC1)=O)=[O:7].[BH4-].[Na+]>CO.C(Cl)(Cl)Cl>[C:54](=[N:53][C:4]1[CH:3]=[CH:34][CH:33]=[CH:32][C:5]=1[C:6]([NH2:8])=[O:7])=[O:55]
Reactant: COc1c(-c2cccc3[nH]c(CNC(=O)OC(C)(C)C)nc23)ccc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCC(=O)CC2)c1N=C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: NC(=O)c1ccccc1N=C=O
Reaction time: 1 h
Yield: 464.3 %

Procedure:
To a solution of 3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-oxopiperidin-1-yl)carbonylpent-1-yloxy]phenyl]-4-[2-(tert-butoxycarbonyl)aminomethyl-1H-benzimidazol-4-yl]-carbonylaminobenzamide (150 mg) in methanol (5 ml) was added sodium borohydride (7.52 mg) under an ice bath cooling and the mixture was stirred at the same temperature for 1 hour. The mixture was diluted with chloroform and the solution was washed with water and brine. The organic phase was dried over magnesium sulfate and the solvent was evaporated in vacuo to give N-[2-[5-(4-hydroxypiperidin-1-yl)carbonylpent-1-yloxy]-4-methylphenyl]-3-methoxy-N-methyl-4-[2-tert-butoxycarbonyl)aminomethyl-1H-benzimidazol-4-yl]carbonylaminobenzamide (150 mg).
Reaction SMILES: [CH3:1][C:2]1[C:10](Br)=[C:9]2[C:5]([C:6]([CH2:12][CH2:13][NH2:14])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(O)C>C(N(CC)CC)C>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:12][CH2:13][NH2:14])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(CCN)c[nH]c2c1Br
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc2c(CCN)c[nH]c2c1

Procedure:
A sample of 6-methyl-7-bromo-1 H-indole-3-ethanamine was contacted with Pd/C H2 in the presence of ethanol and triethylamine. The resulting material was evaporated and partitioned between base/CHCl3. The organic phase was dried, concentrated, and dried. The resulting material was taken up into methanol and added to ethereal HCl. The resulting material was washed and vacuum dried.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]([C:33](=[CH:36][C:37]([N:40]4[CH2:43][CH:42]([O:44][Si](C(C)(C)C)(C5C=CC=CC=5)C5C=CC=CC=5)[CH2:41]4)([CH3:39])[CH3:38])[C:34]#[N:35])=[O:32])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]([C:33](=[CH:36][C:37]([N:40]4[CH2:43][CH:42]([OH:44])[CH2:41]4)([CH3:39])[CH3:38])[C:34]#[N:35])=[O:32])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CC(C)(C=C(C#N)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1)N1CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1)N1CC(O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-((R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(3-(tert-butyldiphenylsilyloxy)azetidin-1-yl)-4-methylpent-2-enenitrile (300 mg, 0.36 mmol, 1.0 equiv) in THF (8 mL) was added a solution of 1 M TBAF in THF (0.432 mL, 0.432 mmoL). The resulting mixture was stirred at rt overnight. The mixture was concentrated and the crude product was purified by prep-HPLC eluting with CH3CN/H2O (0.05% TFA). The organic phase was removed under reduced pressure and the resulting aqueous solution was diluted with sat.Na2CO3 solution and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. This resulted in 18.1 mg of 2-((R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(3-hydroxyazetidin-1-yl)-4-methylpent-2-enenitrile as a white solid. LCMS (ESI, pos. ion) m/z: 597 (M+1).
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([O:15][CH3:16])=[C:7]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:6]=1.[P:21]([O-:26])(OC)OC.Cl>C1COCC1.C1(C)C=CC=CC=1.O>[C:17]([C:7]1[CH:6]=[C:5]([PH:21](=[O:26])[C:5]2[CH:10]=[C:9]([C:11]([CH3:13])([CH3:14])[CH3:12])[C:8]([O:15][CH3:16])=[C:7]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:6]=2)[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]=1[O:15][CH3:16])([CH3:20])([CH3:19])[CH3:18]
Reactant: COc1c(C(C)(C)C)cc(Br)cc1C(C)(C)C
Reactant: COP([O-])OC
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1c(C(C)(C)C)cc([PH](=O)c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)cc1C(C)(C)C
Temperature: 5 °C
Reaction time: 1 h
Yield: 27.2 %

Procedure:
Under argon atmosphere, a solution of magnesium (4.0 g, 0.95 equivalents) and a small amount of iodine in THF (50 mL) was stirred at room temperature for 1 hour. After 4-bromo-2,6-di-tert-butylanisole (52 g, 0.175 mol) synthesized in Reference Example 2 was added at 46° C. to 53° C. thereto, the mixture was stirred at 5° C. for 1 hour. Then, dimethyl phosphite (11.4 g, 0.52 equivalents) was added and the mixture was stirred at 5° C. for 1 hour. After water (50 mL) was added at 3° C. and toluene (50 mL) and 6M-HCl (20 mL) were then added, the mixture was stirred at room temperature for 30 minutes. The reaction solution was allowed to separate into layers. An organic layer was washed successively with water (20 mL), a 5% NaHCO3 aqueous solution (20 mL) and a 5% NaCl aqueous solution (20 mL), dried over anhydrous magnesium sulfate and then naturally filtered. The filtrate was concentrated under reduced pressure. The residue was recrystallized from heptane to obtain the title compound (11.6 g, pale yellowish white crystal). Yield 20.5%, mp. 166.1° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12](O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:27][C:28]1[CH:29]=[C:30]([NH2:35])[C:31]([NH2:34])=[CH:32][CH:33]=1>CN(C=O)C.N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[NH:34][C:31]3[CH:32]=[CH:33][C:28]([CH3:27])=[CH:29][C:30]=3[N:35]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N)c(N)c1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1ccc2[nH]c(C3CN(C(=O)OC(C)(C)C)C3)nc2c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
To the mixture of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (4.94 g, 24.6 mmol) in DMF (30 mL) and pyridine (30 mL) was added CDI (4.38 g, 27 mmol) at 45° C. and the mixture was stirred for another 2 h at this temperature. Then 4-methyl-benzene-1,2-diamine (3 g, 24.6 mmol) was added and the mixture was stirred at RT overnight. Solvents were removed in vacuo and the residue was dissolved in HOAc (30 mL) and heated for 1 h at 100° C. Then the reaction mixture was concentrated and the residue was partitioned between DCM and aqueous of Na2CO3. The organic layer was dried over Na2SO4 and concentrated to give the crude product which was purified by column chromatography (ethyl acetate:petroleum ether=1:2) to give the compound (4.6 g, yield 61%) as yellow solid.
Reaction SMILES: [S:1]1[C:5]2[S:6][CH2:7][CH2:8][C:4]=2[CH:3]=[C:2]1[C:9]([O:11]C)=[O:10].[OH-].[Na+]>C1COCC1.O>[S:1]1[C:5]2[S:6][CH2:7][CH2:8][C:4]=2[CH:3]=[C:2]1[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1cc2c(s1)SCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2c(s1)SCC2
Reaction time: 8 h
Yield: 87 %

Procedure:
Methyl 4,5-dihydrothieno[2,3-b]thiophene-2-carboxylate (9.5 g, 50 mmol) was dissolved in 200 mL THF followed by treatment with 100 mL of 20% sodium hydroxide and stirred overnight. THF was removed in vacuo to give a dark residue. The residue was taken up in water and extracted with ethyl acetate two times. The aqueous phase was then acidified to pH<1 with conc. HCl and extracted 3×200 mL ethyl acetate. The combined extracts were washed with: 1× water, 2× brine followed by drying over magnesium sulfate. The solution was filtered and the solvent evaporated to give the title compound as a solid (8.1 g). 1H NMR (300 MHz,DMSO-d6) d 2.5(t,2H), 2.8(t,2H), 7.5(s,1H), 12.8(bs,1H exch).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=3)[N:12]=[C:11]([CH3:21])[CH:10]=2)[CH:6]=[CH:5][N:4]=1.Br.O.[OH-].[NH4+]>C(O)(=O)C>[CH3:20][C:16]1[CH:15]=[C:14]([N:13]2[C:9]([C:7]3[CH:6]=[CH:5][NH:4][C:3](=[O:2])[CH:8]=3)=[CH:10][C:11]([CH3:21])=[N:12]2)[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc(-c2cc(C)nn2-c2cccc(C)c2)ccn1
Agent: Br
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccc(-n2nc(C)cc2-c2cc[nH]c(=O)c2)c1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
To a solution of 2-methoxy-4-[1-(3-methylphenyl)-3-methyl-1H-pyrazol-5-yl]pyridine (Example 22; 0.56 g, 0.002 mol) in 5 mL of acetic acid was added 5 mL of hydrobromic acid. The reaction mixture was heated at reflux for 3 hours and then cooled to room temperature. Water was added and the solution was basified with ammonium hydroxide. The aqueous phase was extracted with ethyl acetate and the organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 0.45 g (85%) of product as a white solid: mp: 182-183° C.; Anal. Calc'd. for C16H15N3O: C, 72.43; H, 5.70; N, 15.84. Found: C, 72.37; H, 5.66; N, 15.97.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[CH3:8][S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]=[C:17]=[S:18].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:3]1[CH2:4][C:5](=[O:7])[N:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9][CH3:8])[C:17]1=[S:18])[CH3:2]
Reactant: CSc1ccccc1N=C=S
Reactant: CCNCC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(c2ccccc2SC)C1=S
Yield: 48.6 %

Procedure:
A mixture of N-ethyl glycine (9.23 g), 2-(methylthio)-phenyl-isothiocyanate (9.1 g), triethylamine (10.1 g) and methylene chloride (150 mL) was heated at reflux for 3 hours. The mixture was evaporated to dryness. The residue was recrystallized from ethanol to give the title compound (6.5 g) as a creamy solid, m.p. 128°-131° C. Anal. Calcd. for. C12H14N2S2O: C, 52.11; H, 5.30; N, 10.52. Found: C, 52.28; H, 5.26; N, 10.54. Mass spectrum (EI, M.+) m/z 266.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1C(OC(C)(C)C)=O)=O.O=P(Cl)(Cl)Cl.[NH2:25][C:26]1[CH:34]=[C:33]([Br:35])[CH:32]=[CH:31][C:27]=1[C:28]([OH:30])=O>>[Br:35][C:33]1[CH:34]=[C:26]2[C:27]([C:28](=[O:30])[N:5]([CH2:6][CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][NH:8]3)[C:3]([CH2:2][Cl:1])=[N:25]2)=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CNC(=O)CCl
Reactant: Nc1cc(Br)ccc1C(=O)O
Solvent: O=P(Cl)(Cl)Cl
Product: O=c1c2ccc(Br)cc2nc(CCl)n1CC1CCCCN1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
A solution of tert-butyl 2-((2-chloroacetamido)methyl)piperidine-1-carboxylate (590 mg, 2.02 mmol) and POCl3 (5 mL) was stirred at room temperature for 30 min. Then 2-amino-4-bromobenzoic acid (442 mg, 1.94 mmol) was added to the mixture and stirred for another 20 min. After warming slowly to 100° C., the mixture was maintained at 100° C. for 1.5 h. Then the reaction mixture was poured into ice water, adjusted pH to 8 and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the crude product was directly used for the next reaction. MS (ESI): 370, 372 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)[CH:7]=1.[H-].[Na+].[CH2:16]1[O:19][CH:17]1[CH3:18]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:19][CH:17]([CH3:18])[CH2:16][N:9]3[CH:10]=[CH:11][N:12]=[C:8]3[C:6]=2[CH:7]=1
Reactant: Fc1ccc(Br)cc1-c1ncc[nH]1
Reactant: CC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1Cn2ccnc2-c2cc(Br)ccc2O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.9 %

Procedure:
To a solution of 2-(5-bromo-2-fluoro-phenyl)-1H-imidazole (250 mg, 1.0371 mmol) in dimethylformamide (3.0 mL) was added sodium hydride (1.1 equiv., 45.6 mg, 1.1408 mmol) at 0° C. The reaction was stirred at this temperature for 10 minutes, then (+/−)-propylene oxide (1.2 equiv., 0.09 mL, 1.2445 mmol) was added and the mixture was allowed to warm up to room temperature. The reaction was then heated to 95° C. for 6 h. The reaction mixture was cooled to room temperature and quenched with saturated aqueous ammonium chloride. The solution was extracted 3× with methylene chloride. The organic layers were combined, dried with sodium sulfate, and concentrated in vacuo. The crude was purified by flash chromatography (5-100% EtOAc in heptanes) to afford 188 mg (65% yield) of an orange solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22](O)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O.CO>[O:21]=[C:20]1[C:4]2[C:5]3[C:6](=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]=3[CH:10]=[C:2]([NH:1][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=3)[CH:3]=2)[CH:17]=[N:18][NH:19]1
Reactant: O=C(O)c1cccnc1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O)c1cccnc1
Yield: 68.4 %

Procedure:
Preparation of example 22 from the title compound of Example 7 (hydrochloride) (21 mg, 0.076 mmol), nicotinic acid (7 mg, 0.076 mmol), triethylamine (0.014 mL, 0.10 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (32 mg, 0.084 mmol) in CH2Cl2 (0.3 mL) and N,N-dimethylformamide (0.3 mL) was carried out analogously to Example 11. Silica gel chromatography (9:1 CH2Cl2:methanol), also in an analogous manner, afforded the title compound (20 mg, 0.052 mmol) as a yellow powder in 69% yield.
Reaction SMILES: [ClH:1].[C:2]([C:6]1ON=[C:8]([NH:11][C:12](=[O:36])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[CH:24][N:23]=3)=[CH:16][CH:15]=2)[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].C(OC(N1CCC(OC2C=CN=C(C(O)=O)C=2)CC1)=O)(C)(C)C.Cl.NC1C=CC(NC(NC2[O:76][N:75]=C(C(C)(C)C)C=2)=O)=CC=1.NC1C=CC(NC(NC2C=C(C(C)(C)C)ON=2)=O)=CC=1>>[ClH:1].[C:2]([C:6]1[CH:7]=[C:8]([NH:11][C:12](=[O:36])[NH:13][C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]4[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]4)=[CH:24][N:23]=3)=[CH:18][CH:19]=2)[O:76][N:75]=1)([CH3:4])([CH3:5])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCNCC4)cn3)cc2)no1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(N)cc2)on1
Agent: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(C(=O)O)c2)CC1
Agent: CC(C)(C)c1cc(NC(=O)Nc2ccc(N)cc2)no1
Agent: Cl
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCNCC4)cn3)cc2)on1

Procedure:
N-(4-(3-(3-tert-Butylisoxazol-5-yl)ureido)phenyl)-5-(piperidin-4-yloxy)picolinamide hydrochloride was prepared as a yellow solid (500 mg) using procedures analogous to those described in Steps 3-4 of Example 1, substituting 541-(tert-butoxycarbonyl)piperidin-4-yloxy)picolinic acid from Example 6 for 4-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)picolinic acid, and 1-(4-aminophenyl)-3-(3-tert-butylisoxazol-5-yl)urea hydrochloride from Step 1 of this example for 1-(4-aminophenyl)-3-(5-tert-butylisoxazol-3-yl)urea used in Example 1. LC-MS (ESI) m/z 479 (M+H)+.
Reaction SMILES: [C:1]([C:3](=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C([O-])([O-])=O.[Na+].[Na+]>CC1(C)CC(C)CC(O)C1>[C:1]([C:3](=[C:9]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]([O:6][CH:7]1[CH2:11][CH:10]([CH3:15])[CH2:9][C:3]([CH3:4])([CH3:1])[CH2:8]1)=[O:5])#[N:2]
Reactant: CCOC(=O)C(C#N)=C(c1ccccc1)c1ccccc1
Agent: CC1CC(O)CC(C)(C)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC1CC(OC(=O)C(C#N)=C(c2ccccc2)c2ccccc2)CC(C)(C)C1
Reaction time: 5 h
Yield: 77.6 %

Procedure:
55.4 g (0.2 mol) of ethyl 2-cyano-3,3-diphenylacrylate (Uvinul 3035), 100 ml of 3,3,5-trimethylcyclohexanol and 4 g of Na2CO3 were reacted with one another at 181-184° C. with distillative removal of the ethanol formed, assisted by a stream of nitrogen. After about 5 h, the reaction mixture was filtered hot in order to remove the Na2CO3. After the filtrate had been cooled, the precipitate which had formed was filtered off, washed with cyclohexane and dried, giving 29 g (39%) of 3,3,5-trimethylcyclohexyl 2-cyano-3,3-diphenylacrylate [λmax=301 nm, E11=344] as a colorless solid.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.O.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CC(O)=O>[C:1]([NH:5][S:6]([C:9]1[CH:13]=[CH:12][NH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)n2ccc(S(=O)(=O)NC(C)(C)C)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1cc[nH]c1
Temperature: 60 °C
Yield: 68.7 %

Procedure:
To a solution of compound 27c (665 mg, 1.87 mmol) in a mixture of THF (12 mL), MeOH (12 mL) and water (3 mL) was added K2CO3 (3.1 g, 22 mmol) and then the solution was heated at 60° C. overnight, cooled, acidified to pH=5 with AcOH and extracted with EA twice. The combined organic layers were washed with water (3×) and brine, concentrated and purified by CC (PE/EA=2/1) to give compound 27d (260 mg, 69%) as a solid.
Reaction SMILES: C([Li])CCC.[CH:6]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])([CH3:8])[CH3:7].[CH3:19][O:20][CH:21]([O:28][CH3:29])[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[O:25].P(O)(O)([O-])=O.[Na+]>C1CCCCC1.O1CCCC1>[C:15]1([CH3:18])[CH:16]=[CH:17][C:12]([S:9]([C:6]([CH3:7])([CH3:8])[CH:22]([CH:21]([O:28][CH3:29])[O:20][CH3:19])[CH2:23][C:24]([O:26][CH3:27])=[O:25])(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: COC(=O)C=CC(OC)OC
Reactant: Cc1ccc(S(=O)(=O)C(C)C)cc1
Agent: O=P([O-])(O)O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: COC(=O)CC(C(OC)OC)C(C)(C)S(=O)(=O)c1ccc(C)cc1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 49.2 %

Procedure:
3.4 ml of a 1.95M butyllithium in cyclohexane solution were slowly added at -70° C. to a solution of 1.24 g of p-tolyl isopropyl sulfone in 13 ml of tetrahydrofuran and the mixture was stirred at -70° C. for 15 minutes. Then, a solution of 1 g of methyl 4,4-dimethoxy-2-butenoate in 20 ml of tetrahydrofuran was slowly added to the mixture which was stirred at -70° C. for one hour and poured into a aqueous monosodium phosphate solution. The mixture was extracted with methylene chloride and the organic phase was dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 1--1 ether-petroleum ether (b.p.=40°-70° C.) mixture to obtain 1.1 g of methyl 4-p-toluenesulfonyl-4-methyl-3-dimethoxymethyl-pentanoate melting at 110° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([NH:12][C:13](=O)[CH2:14][CH2:15][O:16][CH3:17])[CH:3]=1.[OH-].[Na+].O1CCOCC1>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6](=[O:7])[N:8]([CH3:9])[C:13]([CH2:14][CH2:15][O:16][CH3:17])=[N:12]2)=[CH:10][CH:11]=1
Reactant: CNC(=O)c1ccc(Br)cc1NC(=O)CCOC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COCCc1nc2cc(Br)ccc2c(=O)n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 124.9 %

Procedure:
The mixture of 4-bromo-2-(3-methoxypropanamido)-N-methylbenzamide (0.05 g, 0.159 mmol), 2.5 N NaOH (1 mL) and dioxane (1 mL) was stirred for 3 h at room temperature, then diluted with water, and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (3×10 mL), dried over Na2SO4, filtered, and evaporated to give 59 mg of the target compound. MS (ESI): 297, 299 (MH+).