Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[C:5]([NH:8][C:9]2[C:14]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)[S:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].O>CN(C=O)C>[CH3:2][C:3]1[N:4]=[C:5]([NH:8][C:9]2[C:14]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[O:23][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:13][CH:12]=[CH:11][N:10]=2)[S:6][CH:7]=1
Reactant: Cc1csc(Nc2ncccc2OCc2cccc(O)c2)n1
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1csc(Nc2ncccc2OCc2cccc(OCC(=O)OC(C)(C)C)c2)n1
Reaction time: 3 h
Yield: 55.4 %

Procedure:
3-((2-(4-Methylthiazol-2-ylamino)pyridin-3-yloxy)methyl)phenol (prepared according to Example 22; 900 mg, 2.87 mmol), potassium carbonate (992 mg, 7.18 mmol), and tert-butyl 2-bromoacetate (0.424 mL, 2.87 mmol) were added to a 100 mL round bottom flask and dissolved in DMF (10 mL). The reaction mixture was stirred for 3 hours, then water (90 mL) was added and the reaction mixture was stirred at room temperature for 1 hour. The resultant solids were filtered and purified over silica gel (20% ethyl acetate in hexanes) to afford tert-butyl 2-(3-((2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)methyl)phenoxy)acetate (680 mg, 55.4% yield) as a white foam. 1H NMR (CDCl3) δ 8.60 (bs, 1H), 7.94 (dd, 1H), 7.32 (t, 1H), 7.07 (dd, 1H), 7.03 (m, 1H), 6.95 (m, 1H), 6.89 (dd, 1H), 6.80 (dd, 1H), 6.39 (q, 1H), 5.08 (s, 2H), 4.53 (s, 2H), 2.33 (s, 3H), 1.48 (s, 9H). Mass spectrum (apci) m/z=372 (100), 428 (20).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:32])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][C:25]=3C#N)[CH2:20][CH2:19]2)=[N:6][CH:7]=1.C([N:35]([CH2:38]C)CC)C.Cl.[NH2:41][OH:42]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:32])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([C:38](=[NH:35])[NH:41][OH:42])[CH:25]=3)[CH2:20][CH2:19]2)=[N:6][CH:7]=1
Reactant: NO
Reactant: N#Cc1cnccc1N1CCC(CNc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CCO
Product: N=C(NO)c1cc(N2CCC(CNc3ccccc3C(=O)Nc3ccc(Cl)cn3)CC2)ccn1
Reaction time: 16 h
Yield: 75.8 %

Procedure:
A solution of N-(5-chloropyridin-2-yl)-2-[1-(3-cyanopyridin-4-yl)piperidin-4-ylmethylamino]benzamide (50 mg, 0.11 mmol) and triethylamine (22 mg, 0.22 mmol) in ethanol (5 mL) was treated with hydroxylamine hydrochloride (12 mg, 0.17 mmol). After 16 h, the mixture was concentrated and the residue was purified by column chromatography (SiO2; 5% methanol in methylene chloride) yielding 40 mg (75%) of the title compound.
Reaction SMILES: [CH2:1]([N:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:23][O:24][C:25](=[O:28])[O:26]C>CO>[CH3:23][O:24][C:25](=[O:26])[O-:28].[CH3:12][N+:11]([CH3:23])([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: COC(=O)OC
Reactant: CCCCCCCCCCN(C)CCCCCCCCCC
Solvent: CO
Product: CCCCCCCCCC[N+](C)(C)CCCCCCCCCC
Product: COC(=O)[O-]
Reaction time: 12 h

Procedure:
Into an autoclave equipped with a stirrer, didecylmethylamine (1 mol), dimethylcarbonate (1.5 mol) and methanol (2.0 mol) as a solvent were introduced, and a reaction was carried out at a reaction temperature of 110° C. for 12 hours to obtain a methanol solution of dimethyldidecyl ammonium methylcarbonate. To this solution, octylic acid (1 mol) was added, and by removing carbon dioxide and methanol, which were formed as byproducts, dimethyl didecylammonium/octylate (quaternary ammonium salt (B1)) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH:20]=O>C1(C)C=CC=CC=1>[C:12]([NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:1]=[CH:20][C:19]2[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:17]([F:16])[CH:18]=2)=[CH:3][CH:4]=1)(=[O:10])=[O:9])([CH3:15])([CH3:14])[CH3:13]
Reactant: COc1ccc(C=O)cc1F
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(N)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(C=Nc2ccc(S(=O)(=O)NC(C)(C)C)cc2)cc1F
Yield: 99.6 %

Procedure:
A mixture of 4-amino-N-tert-butylbenzenesulfonamide (52.3 g, 0.23 mol, obtained in example 1), 3-fluoro-4-methoxybenzaldehyde (35.3 g, 0.23 mol) and toluene (2.5 L) is heated at reflux in a Dean-Stark for 24 h. The solvent is removed, yielding 83.5 g of the title compound (yield: quantitative).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][NH:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15].C([O-])([O-])=O.[Na+].[Na+].[Cl:23][C:24]1[C:32]([O:33][CH3:34])=[C:31]([O:35][CH3:36])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>C(OCC)(=O)C.CC(C)=O.O>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][N:11]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:26]([C:25]1[CH:29]=[CH:30][C:31]([O:35][CH3:36])=[C:32]([O:33][CH3:34])[C:24]=1[Cl:23])=[O:27]
Reactant: CC(C)CCNCc1nc2ccccc2[nH]1
Reactant: COc1ccc(C(=O)Cl)c(Cl)c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(C(=O)N(CCC(C)C)Cc2nc3ccccc3[nH]2)c(Cl)c1OC
Temperature: 25 °C
Yield: 49.5 %

Procedure:
A solution of 3.0 g (13.8 mmole) of (benzimidazol-2-ylmethyl) (3-methylbutyl)amine in 150 mL of 1:1:1 ethyl acetate, acetone, water is treated with 3.66 g (34.5 mmole) Na2CO3 and a solution of 3.22 g (13.7 mmole) of 2-chloro-3,4-dimethoxybenzoyl chloride in 50 mL of acetone at 0° C. The resulting mixture is allowed to warm to room temperature for 1 hour. The reaction solution is diluted with 300 mL of ethyl acetate and then washed with 2×60 mL water, 1×60 mL sat. NaHCO3, and 1×60 mL of brine. The resulting organic layer is dried over anhydrous Na2SO4 and the solvent removed in vacuo. The residue is treated with 150 mL of methanol and 1.1 g of NaOH at reflux for 2 hours and then allow to cool to room temperature for 2 hours. The resulting solution is evaporated under reduced pressure and partioned between ethyl acetate 200 mL and water 100 mL. The ethyl acetate extracts are dried over anhydrous Na2SO4 and the solvent removed in vacuo. The resulting residue is flash chromatographed (1:1 ethyl acetate/hexanes) to afford 2.82 g (49%) of N-(benzimidazol-2-ylmethyl)(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carboxamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH:23]([CH3:25])[CH3:24])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:26])[CH:3]=1.[NH2:27][CH2:28][CH2:29][OH:30]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH:23]([CH3:25])[CH3:24])[C:10]=3[N:11]=[C:12]([NH:27][CH2:28][CH2:29][OH:30])[N:13]=2)=[C:4]([CH3:26])[CH:3]=1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2C(C)C
Reactant: NCCO
Product: Cc1cc(F)ccc1-c1nc(NCCO)nc2c1ccc(=O)n2C(C)C

Procedure:
The product of Example 56 and 2-aminoethanol were reacted by the procedure of Example 60 to afford the title compound 4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-ethylamino)-8-isopropyl-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3): δ 1.78 (m, 6H), 2.29 (s, 3H), 3.70 (br s, 2H), 3.89 (br s, 3H), 5.81 (m 1H), 6.02 (br s, 1H), 6.23 (d, 1H, J=9.7 Hz), 7.00 (m, 2H), 7.11 (d, 1H, J=9.7 Hz), 7.19 (m, 1H), LC MS (m/e)=357.2 (MH+). Rt=1.80 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(Cl)c4)c32)c(C)c1C(=O)NCCN1CCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.3 %

Procedure:
To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (68.5 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH —CH2Cl2 5:95 to provide pure product 5-[4-(3-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (75 mg, 61%).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[Cl:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:21]1[N:22]([CH:27]2[CH2:30][CH2:29][CH2:28]2)[N:23]=[C:24]([CH3:26])[CH:25]=1)=[O:4].[OH-].[Li+]>CO>[Cl:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[S:10]([C@H:8]1[CH2:7][N:6]([C:21]2[N:22]([CH:27]3[CH2:30][CH2:29][CH2:28]3)[N:23]=[C:24]([CH3:26])[CH:25]=2)[C@H:5]([C:3]([OH:4])=[O:2])[CH2:9]1)(=[O:12])=[O:11]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)CN1c1cc(C)nn1C1CCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)O)n(C2CCC2)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-1-(2-cyclobutyl-5-methyl-2H-pyrazol-3-yl)-pyrrolidine-2-carboxylic acid methyl ester (example 375c) was saponified in the presence of lithium hydroxide avoiding methanol as a cosolvent to give the title compound as yellow oil which was used in the next step without further purification. MS (ESI): m/z=442.2 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([O:14][CH2:15][CH3:16])[C:11]([CH3:18])([CH3:17])[C:10]=2[CH:19]=1)(=[O:4])=[O:3].C(OC(=O)C)(=[O:22])C.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([O:14][C:15](=[O:22])[CH3:16])[C:11]([CH3:18])([CH3:17])[C:10]=2[CH:19]=1)(=[O:3])=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC1Oc2ccc(OS(C)(=O)=O)cc2C1(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)OC1Oc2ccc(OS(C)(=O)=O)cc2C1(C)C
Reaction time: 2 h

Procedure:
2-ethoxy-2,3-dihydro-3,3-dimethylbenzofuran-5-yl methanesulphonate (7 parts) was treated with a mixture of acetic anhydride (20 parts) and sulphuric acid (0.6 parts) and left at 50° C. for two hours. The solution was then poured into an excess of ice and sodium bicarbonate. An oil precipitated which solidified and was filtered off and recrystallised from 90% aqueous ethanol to give 2-acetoxy-2,3-dihydro-3,3-dimethylbenzofuran-5-yl methanesulphonate (6.6 parts), melting point 83°-85° C.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[C:19]([CH2:26][S:27][C:28]1[N:29]([CH3:33])[CH:30]=[CH:31][N:32]=1)[C:18]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:17]2[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([O:47][CH3:48])[CH:40]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[C:19]([CH2:26][S:27]([C:28]1[N:29]([CH3:33])[CH:30]=[CH:31][N:32]=1)=[O:9])[C:18]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:17]2[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([O:47][CH3:48])[CH:40]=1
Reactant: CCOC(=O)c1c(CSc2nccn2C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)c1c(CS(=O)c2nccn2C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 69.4 %

Procedure:
m-Chloroperbenzoic acid (85%, 830 mg) was added in small portions under ice-cooling to a solution of ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-[(l-methylimidazol-2-yl)thiomethyl]quinoline-3-carboxylate (3.0 g) in dichloromethane (75 ml). The reaction mixture was stirred at room temperature for 2.5 hours, washed successively with 5% aqueous NaHSO3 solution, saturated aqueous sodium bicarbonate solution and water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate/methanol (10/1, v/v) gave ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-[(1-methylimidazol-2-yl)sulfinylmethyl]quinoline-3-carboxylate (1.8 g, 58%) which was then recrystallized from acetone-ethyl ether.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:12]([O-:14])=[O:13])[C:7](=[O:11])[NH:6][CH2:5]2
Reactant: Cc1ccc2c(c1)CNC2=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc2c(cc1[N+](=O)[O-])C(=O)NC2
Temperature: 0 °C
Reaction time: 12 h

Procedure:
5-Methyl-2,3-dihydro-isoindol-1-one (1.00 g, 6.79 mmol) was taken up in sulfuric acid and cooled to 0° C. One equivalent of nitric acid was added to the solution and the mixture was allowed to slowly warm to room temp and stir for 12 h. The reaction mixture was poured into ice water and the aqueous layer was extracted four times with ethyl acetate and the combined organic layers were washed with water, brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed under reduced pressure. Two products were isolated by flash chromatography. (10% methanol-ethyl acetate) Yield 813.40 mg of the 4-nitro and 100 mg of the 6-nitro. 1H NMR (300 MHz, d6-DMSO): 4-nitro δ 7.76 (s, 1H), 8.19 (s, 1H), 8.98 (bs, 1H); 6-nitro δ 7.69 (d, J=9 Hz, 1H), 7.84 (d, J=9 Hz), 8.91 (bs, 1H).
Reaction SMILES: Cl.[CH3:2][CH:3]1NC[C:6]2[CH:9]=[CH:10]SC=2[CH2:4]1.C[O:13][C:14]([C:16]1[CH:23]=CC=CC=1CBr)=O.C(=O)([O-])[O-:25].[Na+].[Na+]>CN(C)C=O>[CH:3]([OH:13])([CH3:4])[CH3:2].[CH:16]([O:25][CH:9]([CH3:6])[CH3:10])([CH3:14])[CH3:23]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccccc1CBr
Reactant: CC1Cc2sccc2CN1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)O
Product: CC(C)OC(C)C
Temperature: 80 °C
Reaction time: 3 h
Yield: 53 %

Procedure:
A mixture of 6-methyl-4,5,6,7-tetrahydro-thieno[3,2-c]-pyridine hydrochloride (7.05 g; 37.2 mmoles), o-methoxycarbonylbenzyl bromide (9 g; 39.3 mmoles) and sodium carbonate (6.05 g; 57 mmoles) in dimethylformamide (100 cc) is stirred during 3 hours at 80° C. After cooling, the inorganic salts are filtered off and the filtrate is evaporated to dryness. The residue is dissolved in ether and the ether solution is washed with water and dried over sodium sulfate, after which the ether is evaporated off. The resulting yellow oil is treated with an equivalent amount of hydrogen chloride gas in ether solution. The hydrochloride is filtered off and recrystallized from isopropyl alcohol-diisopropyl ether (M.p. = 166° C. Yield: 53%).
Reaction SMILES: [F:1][C:2]1[C:10]([CH:11]=[CH2:12])=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:13][Si](C=[N+]=[N-])(C)C.CCOCC.C(O)(=O)C>CO>[F:1][C:2]1[C:10]([CH:11]=[CH2:12])=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C=Cc1nccc(C(=O)O)c1F
Solvent: CCOCC
Solvent: CO
Solvent: CC(=O)O
Product: C=Cc1nccc(C(=O)OC)c1F

Procedure:
To a solution of 3-fluoro-2-vinylisonicotinic acid (1.3 g, 7.8 mmol, from Step 1) in methanol (20 mL) cooled to 0° C., was added dropwise 2.0M trimethylsilyldiazomethane in ether (21.6 mL, 44 mmol). When the reaction was complete, acetic acid was added dropwise to quench excess reagent and the volume of solvent was reduced in vacuo. The mixture was partitioned between saturated sodium bicarbonate solution and DCM. The aqueous portion was extracted with a total of three portions of DCM. The combined extracts were dried over sodium sulfate, decanted and concentrated and The product was used without further purification (1.4 g, 100%). 1H NMR (300 MHz, CDCl3): δ 8.47 (d, 1H), 7.62 (dd, 1H), 7.08 (ddd, 1H), 6.48 (dd, 1H), 5.65 (dd, 1H), 3.97 (s, 3H); LCMS (M+H)+: 182.0.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH2:48][CH2:49][C:50]1([CH3:63])[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][CH2:51]1>CN(C)C=O.O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:48][CH2:49][C:50]2([CH3:63])[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][CH2:51]2)=[O:15])[CH:3]=1
Reactant: CCOc1nc(C(=O)O)cc(N)c1C#N
Reactant: CC1(CN)CCN(C(=O)OC(C)(C)C)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1nc(C(=O)NCC2(C)CCN(C(=O)OC(C)(C)C)CC2)cc(N)c1C#N
Reaction time: 0.25 h

Procedure:
A solution of 4-amino-5-cyano-6-ethoxypicolinic acid (0.100 g) in N,N-dimethylformamide (2.5 mL) was treated with 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.102 g), 1-hyroxybenzotriazole hydrate (0.0813 g), followed by diisopropylethylamine (0.252 mL) at room temperature. After stirring for 15 minutes, the compound prepared in Example 416 (0.116 g) was added. Stirring was continued overnight, the mixture diluted with water, organic layer separated and washed with brine, dried, evaporated in vacuo to a beige paste that was triturated in ether and solids collected by filtration (0.584 g) with the following physical data.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[C:12]([CH:14]=[C:15]([O-])[CH3:16])#[N:13].[Na+].[NH2:19][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][C:22]#[N:23].C(O)(=O)C>C(O)CCCC.C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]3[C:21]([C:22]#[N:23])=[C:20]([C:24]([F:27])([F:26])[F:25])[NH:19][C:15]([CH3:16])=[C:14]3[C:12]#[N:13])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: N#CC=C(N)C(F)(F)F
Reactant: CC([O-])=CC#N
Reactant: O=Cc1ccc2[nH]ncc2c1
Agent: [Na+]
Solvent: CCCCCO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC1=C(C#N)C(c2ccc3[nH]ncc3c2)C(C#N)=C(C(F)(F)F)N1

Procedure:
A mixture of 250 mg (1.71 mmol) 1H-indazole-5-carbaldehyde, 180 mg (1.71 mmol) sodium 1-cyanoprop-1-en-2-olate and 931 mg (6.84 mmol) 3-amino-4,4,4-trifluorobut-2-enenitrile [preparation: A. W. Lutz, U.S. Pat. No. 3,635,977; C. G. Krespan, J. Org. Chem. 34, 42 (1969)] in 1-pentanol (2.5 ml) and acetic acid (0.15 ml) was heated to 105° C. overnight. After cooling, the reaction mixture was diluted with THF and directly purified by preparative RP-HPLC (acetonitrile/water+0.1% TFA gradient) yielding 131 mg (23% of th.) of the racemic title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH:27]([F:29])[F:28])=[N:24][CH:25]=1>>[F:29][CH:27]([F:28])[O:26][C:23]1[N:24]=[CH:25][C:20]([CH2:19][N:16]2[CH:11]([C:4]3[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]2=[O:17])=[CH:21][CH:22]=1
Reactant: FC(F)Oc1ccc(CBr)cn1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(OC(F)F)nc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with 5-(bromomethyl)-2-(difluoromethoxy)pyridine. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions D): tR=1.03 min.; [M+H]+: 393.53 g/mol.
Reaction SMILES: [CH2:1]([OH:9])/[CH:2]=[CH:3]/[CH:4]=[CH:5][CH2:6][CH2:7][CH3:8].[C:10](OC)(=[O:14])[C:11]([CH3:13])=[CH2:12].C1C2NC3C(=CC=CC=3)SC=2C=CC=1>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[C:10]([O:9][CH2:1]/[CH:2]=[CH:3]/[CH:4]=[CH:5][CH2:6][CH2:7][CH3:8])(=[O:14])[C:11]([CH3:13])=[CH2:12]
Reactant: C=C(C)C(=O)OC
Reactant: CCCC=C/C=C/CO
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: C=C(C)C(=O)OC/C=C/C=CCCC

Procedure:
The method of Example 1 was substantially repeated with trans, trans-2,4-octadien-1-ol (50.0 g, 0.40 mol), methyl methacrylate (170 mL, 1.6 mol), phenothiazine (1.0 g) and tetraisopropyl titanate (2.0 mL). After a 2-h reaction time the methyl methacrylate was distilled at 70 mm, and the product, at 73° C./0.25 mm, to give 60.3 g (78%) of clear, colorless liquid trans, trans-2,4-octadienyl methacrylate. IR (film): ν 2985, 1712, 1631, 1449, 1310, 1287, 1149, 985, 962, 935, 811 cm-1. UV (isooctane): λmax 230 nm, ε=33,000. 90 MHz 1H NMR: δ 6.4-5.4 (6H, m, vinyl), 4.6 (2H, d, J=7, OCH2 --), 2.05 (2H, q, J=7, allylic CH2), 1.92 (3H, m, allylic CH3), 1.4 (2H, hextet, J=7, CH3CH2CH2 --), 0.90 (3H, t, J=7, CH3CH2 --). 22.63 MHz 13C NMR: δ 166.9, 136.6, 136.2, 134.8, 129.6, 125.2, 124.3, 65.1, 34.8, 22.4, 18.3, 13.6.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@H:10]([OH:14])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:23]1[C:27]2C=CC=C[C:26]=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N)C>CN(C=O)C.CCOC(C)=O>[CH3:4][C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:10]([OH:14])[C:11]([NH:23][CH2:27][CH3:26])=[O:13])([CH3:2])[CH3:3]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O
Agent: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCNC(=O)C(O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 85.7 %

Procedure:
(5)(3S)-3-(tert-Butoxycarbonylamino)-2-hydroxy-4-phenylbutanoic acid (6.3 g, 21 mmol) and 1-hydroxybenzotriazole (HOBt) (3.0 g, 22.4 mmol) were dissolved in DMF (45 mL) and cooled in an ice bath. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (4.6 g, 24 mmol) was added, followed by aqueous ethylamine solution (3.0 mL). The solution was stirred for 18 hours. The solution was diluted into EtOAc (200 mL) and washed with 1M HCl, saturated aqueous NaHCO3, and saturated aqueous NaCl. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo to yield ((1S)-1-benzyl-3-ethylamino-2-hydroxy-3-oxo-propyl)carbamic acid 1,1-dimethylethyl ester (5.8 g, 84%) as a white solid.