Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[C:17](I)=[CH:16][CH:15]=1)=[CH:10][C:9]([O:24][CH3:25])=[C:8]([O:26][CH3:27])[CH:7]=2)#[N:2].CN(C)[CH:30]=[O:31]>>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[C:17]([CH:18]=[CH:19][C:20]([O:31][CH3:30])=[O:21])=[CH:16][CH:15]=1)=[CH:10][C:9]([O:24][CH3:25])=[C:8]([O:26][CH3:27])[CH:7]=2)#[N:2]
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(I)c4ccoc34)c2cc1OC
Reactant: CN(C)C=O
Product: COC(=O)C=Cc1ccc(Nc2c(C#N)cnc3cc(OC)c(OC)cc23)c2occc12
Temperature: 115 °C

Procedure:
The 3-cyano-6,7-dimethoxy-4-(4-iodobenzofuran-7-ylamino)quinoline (0.275 g) was suspended in N,N-dimethylformamide (15 ml) in a nitrogen-flushed vessel, then palladium (II) acetate (16 mg) was added, followed by methyl acrylate (1.1 ml) and triethylamine (0.6 ml). The reaction was heated to 115° C. for 5 hours before filtration and evaporation of solvents under reduced pressure. The residue was purified by column chromatography on silica using increasingly polar mixtures of iso-hexane with ethyl acetate as eluent The resulting product was triturated with diethyl ether and filtered. There was thus obtained the title compound (0.203 g), as a yellow solid; NMR Spectrum: (DMSOd6) 3.77 (s, 3H), 3.94 (s, 3H), 3.99 (s, 3H), 6.73 (d, 1H), 7.31 (d, 1H), 7.40(s, 1H), 7.47 (d, 1H), 7.76 (d, 1H), 7.86 (s, 1H), 7.97 (d, 1H), 8.08 (d, 1H), 8.56 (s, 1H), 10.02 (br s, 1H); Mass Spectrum: M+H+ 430.
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[CH:5][C:4]=1[C:14]([O:16]CC)=[O:15])#[N:2].[OH-:19].[K+]>C(O)C>[C:14]([C:4]1[CH:5]=[N:6][N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[C:1]([NH2:2])=[O:19])([OH:16])=[O:15]
Reactant: CCOC(=O)c1cnn(-c2ccccc2)c1C#N
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: NC(=O)c1c(C(=O)O)cnn1-c1ccccc1

Procedure:
A 4 g. portion of ethyl 5-cyano-1-phenyl-4-pyrazolecarboxylate was reacted with 2 g. of potassium hydroxide in 60 ml. of denatured ethanol substantially as described in Example 2, to obtain 2.7 g. of the desired product, m.p. 234°-235°, having the following elemental analysis.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.Cl.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](=[NH:28])[NH2:27].CCN(C(C)C)C(C)C>>[O:8]=[C:6]1[C:5](=[CH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[S:4][C:3]([NH:28][C:26]([C:22]2[S:21][CH:25]=[CH:24][CH:23]=2)=[NH:27])=[N:7]1
Reactant: N=C(N)c1cccs1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: N=C(NC1=NC(=O)C(=Cc2ccc3ncccc3c2)S1)c1cccs1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, thiophene-2-carboximidamide hydrochloride and DIEA to give N-(4-oxo-5-quinolin-6-ylmethylene-4,5-dihydro-thiazol-2-yl)-thiophene-2-carboxamidine. LC-MS m/e 365 (MH+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[N:19]=[C:20]([C:23](=O)[CH3:24])[CH:21]=[CH:22][C:17]5=[N:16][N:15]=4)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[CH3:30][N:31]([C:33]([NH2:35])=[O:34])[NH2:32]>CO>[CH3:30][N:31]([C:33]([NH2:35])=[O:34])/[N:32]=[C:23](/[C:20]1[CH:21]=[CH:22][C:17]2[N:18]([C:14]([C:11]3([C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)[CH2:12][CH2:13]3)=[N:15][N:16]=2)[N:19]=1)\[CH3:24]
Reactant: CC(=O)c1ccc2nnc(C3(c4ccc5ncccc5c4)CC3)n2n1
Reactant: CN(N)C(N)=O
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\N(C)C(N)=O)c1ccc2nnc(C3(c4ccc5ncccc5c4)CC3)n2n1
Yield: 40.9 %

Procedure:
A solution of 1-[3-(1-quinolin-6-yl-cyclopropyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-ethanone (30 mg, 0.091 mmol), acetic acid (0.1 mL) and 1-methylhydrazinecarboxamide (16.2 mg, 0.18 mmol) in methanol (5 mL) was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was diluted with DCM, washed with sat. aqueous NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography in silica gel eluting with a CH2Cl2/MeOH gradient to afford the title compound (14.9 mg, 41%) as yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.84 (dd, 1H), 8.30 (d, 1H), 8.22 (d, 1H), 8.13 (d, 1H), 7.94-7.92 (m, 2H), 7.70 (dd, 1H), 7.49 (dd, 1H), 6.64 (s, 2H), 3.21 (s, 3H), 2.16 (s, 3H), 1.78-1.75 (m, 2H), 1.68-1.65 (m, 2H). LCMS (method A): [MH]+=401, tR=4.11 min.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH2:12][C:13]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:15]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:14]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].I[CH3:32].O>O1CCCC1.CN(C)C=O>[CH3:3][N:4]([CH2:12][C:13]1[CH:17]=[C:16]([N:18]([CH3:32])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:15]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:14]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:8])[CH3:9]
Reactant: CI
Reactant: CN(Cc1cc(Nc2ccccc2)n(-c2ccccc2)n1)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cc(N(C)c2ccccc2)n(-c2ccccc2)n1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
To a suspension of sodium hydride (16 mg) in tetrahydrofuran (2 mL) and N,N-dimethylformamide (0.5 mL) was added tert-butyl methyl{[1-phenyl-5-(phenylamino)-1H-pyrazol-3-yl]methyl}carbamate (100 mg). After stirring at room temperature for 30 min, iodomethane (75 mg) was added, and the mixture was further stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→4:1) to give the title compound as a pale-brown oil (yield 67 mg, yield 65%).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:30])[C@H:15]([CH2:26][CH2:27][CH2:28]O)[C@H:16]([OH:25])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([C@@H:15]1[CH2:26][CH2:27][CH2:28][O:25][C@@H:16]1[CH:17]=[CH:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OC[C@@H](Cc2ccccc2)N1C(=O)[C@H](CCCO)[C@H](O)C=Cc1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: O=C1OC[C@@H](Cc2ccccc2)N1C(=O)[C@@H]1CCCO[C@@H]1C=Cc1ccccc1
Reaction time: 0.08 h
Yield: 63.3 %

Procedure:
To a stirring solution of (4R)-4-benzyl-3-[(2R,3R)-3-hydroxy-2-(3-hydroxy-propyl)-5-phenyl-pent-4-enoyl]-oxazolidin-2-one (3.88 g, 9.49 mmol) in anhydrous methylene chloride (100 mL) in a flame-dried round bottom flask under N2 at −78° C. was added 2,6-lutidine (2.76 mL, 23.7 mmol). Trifluoromethanesulfonic anhydride (1.68 mL, 9.96 mmol) was then added dropwise; after 5 min, the reaction was quenched with saturated aqueous sodium bicarbonate (50 mL), the layers were separated, and the aqueous layer was washed with methylene chloride (2×50 mL). The combined organic layers were dried over sodium sulfate, concentrated in vacuo, and purified by flash chromatography (SiO2, 20-30% ethyl acetate in hexanes) to yield a pale yellow oil. The resulting oil was diluted with ethyl acetate (50 mL), the organic layer was washed once with 1N aqueous hydrogen chloride (50 mL) to remove residual 2,6-lutidine, and the ethyl acetate was concentrated in vacuo to yield the desired tetrahydropyran (2.35 g, 63.3%) as a pale yellow oil. MS (APCI), m+/z: (M+H)+=392.4.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:11](O)[CH2:12][OH:13]>C1(C)C=CC=CC=1.CCOC(C)=O.S(O)(C1C=CC(C)=CC=1)(=O)=O.O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:9])[O:13][CH2:12][CH2:11][O:10]2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(I)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(c2ccc(I)cc2)OCCO1
Yield: 99.1 %

Procedure:
1-(4-Iodophenyl)ethanone (15.0 g, 61 mmol) and ethylene glycol (7.17 g, 122 mmol) in toluene (120 mL) were treated with TsOH—H2O (0.290 g, 1.52 mmol). The flask was equipped with a Dean-Stark apparatus and condenser and heated to reflux for about 4 h. The mixture was cooled and concentrated under reduced pressure to give a material. The material was dissolved in EtOAc (120 mL) then washed with saturated aqueous NaHCO3 (25 mL) then saturated aqueous NaCl (30 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give 2-(4-iodophenyl)-2-methyl-1,3-dioxolane (17.54 g, 99%): LC/MS (Table 2, Method a) Rt=2.80 min; MS m/z 291 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16](OC)=[O:17])[N:13]=2)=[N:6][CH:7]=1.O.[NH2:28][NH2:29]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]([NH:28][NH2:29])=[O:17])[N:13]=2)=[N:6][CH:7]=1
Reactant: COC(=O)CCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)CCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Temperature: 75 °C
Yield: 83.1 %

Procedure:
To a mixture of methyl 3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanoate (1.00 g, 2.303 mmol) (Example 315) in 15 mL EtOH was added hydrazine monohydrate (8.835 mL, 11.51 mmol) and the mixture heated at 75° C. for 4 hours. The reaction was cooled to ambient temperature and quenched with water and the solids were filtered to give the title compound (0.831 g, 83.10% yield) as off white solids there were used without further purification.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH:16]([NH:18][C:19]1[S:20][CH:21]=[C:22]([C:24](=[N:40][O:41][CH3:42])[C:25]([NH:27][CH:28]2[C:38](=[O:39])[N:30]3[C:31]([C:35]([OH:37])=[O:36])=[CH:32][CH2:33][S:34][C@H:29]23)=[O:26])[N:23]=1)=[O:17].[C:43]([O:53][CH2:54][CH:55]([CH2:57][O:58][C:59](=[O:68])[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])O)(=[O:52])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51].N1C=CC=CC=1>O1CCCC1>[CH:16]([NH:18][C:19]1[S:20][CH:21]=[C:22]([C:24](=[N:40][O:41][CH3:42])[C:25]([NH:27][CH:28]2[C:38](=[O:39])[N:30]3[C:31]([C:35]([O:37][CH:55]([CH2:54][O:53][C:43](=[O:52])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:57][O:58][C:59](=[O:68])[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])=[O:36])=[CH:32][CH2:33][S:34][C@H:29]23)=[O:26])[N:23]=1)=[O:17]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Reactant: CCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCCCC(=O)OCC(COC(=O)CCCCCCCC)OC(=O)C1=CCS[C@@H]2C(NC(=O)C(=NOC)c3csc(NC=O)n3)C(=O)N12
Temperature: 0 °C
Reaction time: 4 h
Yield: 28.9 %

Procedure:
Dicyclohexylcarbodiimide (6.5 g) was added to a stirred solution of 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 8.6 g) and 2-n-nonanoyloxy-1-n-nonanoyloxymethylethanol (7.8 g) in a mixture of dry pyridine (80 ml) and dry tetrahydrofuran (25 ml) at 3° C., and then stirred at 0° to 5° C. for 4 hours and allowed to stand at room temperature overnight. The resultant mixture was poured into ice water (450 ml) and extracted with ethyl acetate (450 ml). Water (50 ml) was added to the extract and adjusted to pH 2 to 3 with 20% sulfuric acid. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride (100 ml×2) and an aqueous solution of sodium bicarbonate in turn, and dried over anhydrous magnesium sulfate. After removing the solution in vacuo, the residue was subjected to column chromatography on silica gel (370 g) with a mixture of chloroform and acetone (5:1). The eluate was evaporated in vacuo to give powder (4.62 g) of 2-n-nonanoyloxy-1-n-nonanoyloxymethylethyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:25]([C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>O1CCCC1>[C:25]([C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:37])=[CH:31][CH:30]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 4-tert-butylphenyl isocyanate (0.214 ml, 1.22 mmol), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 235 mg (68.7%) of the desired product as a solid.
Reaction SMILES: [CH:1]12[O:10][CH:2]1[CH2:3][C:4]1[C:9]2=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH3:11]>>[NH2:11][C@@H:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[OH:10]
Reactant: N
Reactant: c1ccc2c(c1)CC1OC21
Product: N[C@@H]1c2ccccc2C[C@H]1O

Procedure:
The trans amide can be made from the epoxide either (1) by treating the indene oxide with ammonia or a primary amine to produce a trans-1-amino-2-indanol and reacting the trans-1-amino-2-indanol with an acylating agent, or (2) by treating the epoxide with an amide anion to produce the trans hydroxy amide directly. In one embodiment the indene is oxidized with aqueous hypochlorite in the presence of a chiral salen catalyst to produce a partially resolved epoxide, which is converted to the partially resolved trans-1-amino-2-indanol by treating with ammonia or a primary amine followed by acylating with benzoyl chloride. The resulting benzamide is recrystallized to yield substantially optically pure trans-1-benzamido-2-indanol. In two preferred embodiments, the cis-1-amino-2-indanols are (1S,2R)-1-amino-2-indanol and (1R,2S)-1-amino-2-indanol, produced by oxidation of indene in the presence of an R,R or S,S-salen catalyst respectively.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][CH:15]=O)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]1=[O:17].OC1C=C2C(=CC=1)N(C)C(=O)C=C2.[NH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH:39]=[CH:38][N:37]=[CH:36]1.[BH4-].[Na+]>CO.O>[N:35]1([CH2:34][CH2:33][CH2:32][NH:31][CH2:15][CH2:14][CH2:13][O:12][C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[N:2]([CH3:1])[C:3](=[O:17])[CH:4]=[CH:5]3)[CH:39]=[CH:38][N:37]=[CH:36]1
Reactant: NCCCn1ccnc1
Reactant: Cn1c(=O)ccc2cc(OCCC=O)ccc21
Agent: Cn1c(=O)ccc2cc(O)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cn1c(=O)ccc2cc(OCCCNCCCn3ccnc3)ccc21
Temperature: 25 °C
Reaction time: 7 h
Yield: 11.2 %

Procedure:
3-(1-Methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propionaldehyde (127.5 mg) prepared from 6-hydroxy-1-methylquinolin-2(1H)-one and N-(3-aminopropyl)imidazole (82.9 mg) were added to methanol (10 ml). The mixture was stirred at room temperature for 7 hours. The mixture was cooled to 0° C., and sodium borohydride(31.4 mg) was added thereto. The mixture was further stirred at room temperature overnight. Water was added to the reaction mixture and methanol was distilled off under reduced pressure. The residue was subjected to extraction using dichloromethane. The organic layer was washed with saturated saline, dried with anhydrous sodium sulfate, and was condensed under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: methanol=10:0→4:1). The purified product was condensed under reduced pressure to give the title compound(21 mg) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1)=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([OH:19])=O)[CH:13]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[CH3:68][O:69][C:70](=[O:74])[CH2:71][CH2:72][NH2:73].Cl>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1)=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:73][CH2:72][CH2:71][C:70]([O:69][CH3:68])=[O:74])=[O:19])[CH:13]=2)[CH:7]=1
Reactant: Cc1cccc(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2F)c1
Reactant: COC(=O)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cccc(C)c4)c(F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (Example 75) (1.50 g, 3.36 mmol), HATU (1.41 g, 3.70 mmol) and N,N-diisopropylethylamine (1.29 g, 10 mmol) in anhydrous DMF (15 ml) was stirred at room temperature for 10 minutes, followed by addition of β-alanine methyl ester hydrochloride (558 mg, 4.0 mmol). The mixture was stirred for another 10 minutes and poured into 200 ml of water with vigorous stirring. 2M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 3% of methanol in chloroform to give methyl 3-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propanoate as off-white solid. Yield: 1.18 g, 66%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=3)[C:12](=[O:26])[CH:11]=2)=[N:6][CH:7]=1.[C:27]([O-])([O-])=O.[Na+].[Na+].CB(O)O>O1CCOCC1>[OH:25][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][N:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][C:5]3[CH:4]=[CH:3][C:2]([CH3:27])=[CH:7][N:6]=3)=[CH:11][C:12]2=[O:26])=[CH:19][CH:20]=1
Reactant: O=c1cc(OCc2ccc(Br)cn2)ccn1CCc1ccc(CO)cc1
Reactant: O=C([O-])[O-]
Agent: CB(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc(COc2ccn(CCc3ccc(CO)cc3)c(=O)c2)nc1

Procedure:
To 300 mg (0.72 mmol) 4-(5-bromo-pyridin-2-ylmethoxy)-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (example 12.1a) is added 25 mg (0.04 mmol) bis(triphenylphosphan)palladium(II)-chloride, 1.08 mL (2.17 mmol) 2 M aqueous Na2CO3-solution and a solution of 65 mg (1.08 mmol) methyl-boronic acid in 10 mL 1,4-dioxane/5 mL MeOH. The reaction mixture is refluxed for 48 h. The solvent is evaporated and the residue is dissolved in water/DCM. The layers are separated and the aqueous phase is extracted with DCM. The combined organic phase is dried over MgSO4, filtered and the solvent is evaporated. The residue is purified via reverse HPLC chromatography (Waters symmetry, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([C:12]#[CH:13])([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.N1CCCCC1.[H][H]>[Ni].O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C.CO>[F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([CH:12]=[CH2:13])([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C#CC(O)(c1ccccc1)c1ccccc1F
Reactant: [H][H]
Agent: [Ni]
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: CO
Solvent: O
Solvent: C1CCNCC1
Product: C=CC(O)(c1ccccc1)c1ccccc1F

Procedure:
22.6 g. 2-fluoro-α-ethynyl-benzhydrol and 0.74 g. of zinc acetate dihydrate are dissolved in a mixture of 260 ml. of methanol and 10 ml. of piperidine, and 4.4 g. of Raney-nickel catalyst are added to the mixture. The reaction mixture is hydrogenated at room temperature under atmospheric pressure until the uptake of the calculated amount of hydrogen. Thereafter the catalyst is filtered off, and the solvent is evaporated in vacuo. The residue is dissolved in benzene, and the solution is washed with water in order to remove zinc acetate. The benzene phase is dried over anhydrous magnesium sulfate, filtered, and evaporated. The residual oil is distilled at 0.05 mmHg. 21.4 g. of colorless, oily 2-fluoro-α-vinyl-benzhydrol are obtained; b.p.: 91°-93° C/0.05 mmHg.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:30])/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=CC=1)([O-])=O.[CH3:31][C:32]([CH3:43])([NH2:42])[CH2:33][CH2:34][CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1>O1CCCC1>[F:29][C:25]1[CH:24]=[C:23]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:42][C:32]([CH3:43])([CH3:31])[CH2:33][CH2:34][CH2:35][C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)=[O:30])[CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(N)CCCc1cccnc1
Reactant: O=C(/C=C/C=C(c1cccc(F)c1)c1cccc(F)c1)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: CC(C)(CCCc1cccnc1)NC(=O)/C=C/C=C(c1cccc(F)c1)c1cccc(F)c1

Procedure:
As in Example 134, a solution of (E)-5,5-bis(3-fluorophenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (1.63 g) and alpha,alpha-dimethyl-3-pyridinebutanamine (0.9 mL) in tetrahydrofuran (20 mL) was stirred for 29 hours at reflux and was then worked up in the usual manner. The crude amide was crystallized from ethyl acetate-hexane to furnish 1.6 g of (E)-5,5-bis(3-fluorophenyl)-N-[1,1-dimethyl-4-(3-pyridinyl)butyl]-2,4-pentadienamide mp 135°-136° C. Anal. Calculated for C28H28F2N2O : C, 75.32: H, 6.32; F, 8.51; N, 6.27 Found: C, 75.30; H, 6.49; F, 8.21; N, 6.30.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=2[S:14]([N:17]2[CH2:23][CH:22]([OH:24])[CH2:21][O:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])[CH2:3][CH2:2]1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:32]=1[F:33])[NH2:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:25][C:26]1[CH:27]=[C:28]([NH:29][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][C:5]([O:4][CH:1]3[CH2:3][CH2:2]3)=[C:6]([S:14]([N:17]3[CH2:23][CH:22]([OH:24])[CH2:21][O:20][CH2:19][CH2:18]3)(=[O:15])=[O:16])[CH:7]=2)[CH:30]=[CH:31][C:32]=1[F:33]
Reactant: O=C(O)c1ccc(OC2CC2)c(S(=O)(=O)N2CCOCC(O)C2)c1
Reactant: Nc1ccc(F)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)c(Cl)c1)c1ccc(OC2CC2)c(S(=O)(=O)N2CCOCC(O)C2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.8 %

Procedure:
To a solution of 4-(cyclopropoxy)-3-[(6-hydroxy-1,4-oxazepan-4-yl)sulfonyl]benzoic acid (170.00 mg, 475.68 umol, 1.00 eq) and 3-chloro-4-fluoro-aniline (69.24 mg, 475.68 umol, 1.00 eq) in DMF (5.00 mL) were added HATU (180.87 mg, 475.68 umol, 1.00 eq) and DIPEA (122.95 mg, 951.36 umol, 2.00 eq). The mixture was stirred at 25° C. for 16 hr. TLC detected the reaction was complete, the mixture was poured into water, extracted with EA, the combined organic layer was dried over anhydrous Na2SO4, concentrated, the residue was purified by prep-HPLC (FA) to afford product N-(3-chloro-4-fluoro-phenyl)-4-(cyclopropoxy)-3-[(6-hydroxy-1,4-oxazepan-4-yl)sulfonyl]benzamide (94.10 mg, 194.05 umol, 40.79% yield) as white solid. 1H NMR (400 MHz, MeOD) δ 8.48 (d, J=2.01 Hz, 1H), 8.23 (dd, J=8.66, 2.13 Hz, 1H), 7.96 (dd, J=6.78, 2.51 Hz, 1H), 7.70 (d, J=8.78 Hz, 1H), 7.59-7.65 (m, 1H), 7.27 (t, J=8.91 Hz, 1H), 4.07-4.13 (m, 1H), 4.03 (t, J=6.53 Hz, 1H), 3.77-3.97 (m, 4H), 3.61-3.73 (m, 2H), 3.21-3.30 (m, 1H), 3.11 (dd, J=14.56, 7.53 Hz, 1H), 0.84-1.04 (m, 4H). LCMS: 485/487 [M+1].