Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15](O)=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.CCN=C=NCCCN(C)C.[F:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1>>[F:31][C:32]1[CH:38]=[CH:37][C:35]([NH:36][C:15](=[O:16])[CH2:14][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:19][CH2:18][C:5]2=3)=[CH:34][CH:33]=1
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)O)CCN(C)C1
Reactant: Nc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Product: Cc1ccc2c(c1)c1c(n2CC(=O)Nc2ccc(F)cc2)CCN(C)C1
Reaction time: 16 h

Procedure:
2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetic acid (CD58) was mixed with EDCI and 4-fluoroaniline and the reaction mixture was stirred for 16 h to obtain N-(4-fluorophenyl)-2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetamide after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:21][CH:20]=[CH:19][N:5]2[C:6](=[O:18])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.[CH2:22]([O:26][C:27]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]=O)[CH2:23][CH2:24][CH3:25].[O-]CC.[Na+]>C(O)C>[CH2:22]([O:26][C:27]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:28]=1/[CH:29]=[CH:1]/[C:2]1[N:3]=[C:4]2[S:21][CH:20]=[CH:19][N:5]2[C:6](=[O:18])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][CH:9]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCOc1c(C=O)cccc1OC
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(C(F)(F)F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCOc1c(/C=C/c2nc3sccn3c(=O)c2-c2ccc(C(F)(F)F)cc2)cccc1OC
Yield: 42 %

Procedure:
The title compound was prepared by condensation of Intermediate 5 (400 mg, 1.289 mmol) with 2-butoxy-3-methoxybenzaldehyde (400 mg, 1.922 mmol) in presence of sodium ethoxide (175 mg, 2.578 mmol) in ethanol (15 ml) according to the procedure described in Example 24 to afford 271 mg of the desired product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.95 (t, J=6.3 Hz, 3H), 1.42-1.48 (m, 4H), 3.77 (s, 3H), 3.79-3.85 (m, 2H), 6.91-7.01 (m, 4H), 7.52 (d, J=4.8 Hz, 1H), 7.58 (d, J=7.8 Hz, 2H), 7.82 (d, J=8.4 Hz, 2H), 8.01 (d, J=4.8 Hz, 1H), 8.08 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 501.18 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([CH2:15][O:16][N:17]=[C:18]([C:45]1[N:49]=[CH:48][S:47][N:46]=1)[C:19]([NH:21][CH:22]1[C:43](=[O:44])[N:24]2[C:25]([C:40]([OH:42])=[O:41])=[C:26]([CH2:29][S:30][C:31]3[CH:32]=[CH:33][C:34]4[N:35]([N:37]=[N:38][N:39]=4)[N:36]=3)[CH2:27][S:28][C@H:23]12)=[O:20])=[O:14])(C)(C)C.C(OC(C)C)(C)C>C(Cl)Cl.C1(OC)C=CC=CC=1>[C:13]([CH2:15][O:16][N:17]=[C:18]([C:45]1[N:49]=[CH:48][S:47][N:46]=1)[C:19]([NH:21][CH:22]1[C:43](=[O:44])[N:24]2[C:25]([C:40]([OH:42])=[O:41])=[C:26]([CH2:29][S:30][C:31]3[CH:32]=[CH:33][C:34]4[N:35]([N:37]=[N:38][N:39]=4)[N:36]=3)[CH2:27][S:28][C@H:23]12)=[O:20])([OH:14])=[O:12]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3ccc4nnnn4n3)CS[C@H]12)c1ncsn1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: O=C(O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3ccc4nnnn4n3)CS[C@H]12)c1ncsn1
Reaction time: 1.5 h
Yield: 21.1 %

Procedure:
Trifluoroacetic acid (12 ml) was added to a suspension of 7-[2-t-butoxycarbonylmethoxyimino-2-(1,2,4-thiadiazol-3-yl)acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (4 g) in methylene chloride (8 ml) and anisole (4 ml) at ambient temperature and the solution was stirred for 1.5 hours at the same temperature. To the resulting solution was added diisopropyl ether under stirring. The precipitates were collected by filtration, washed with diisopropyl ether. The precipitates were added to the mixture of ethyl acetate and water, and the mixture was adjusted to pH 7.5 with 20% aqueous solution of sodium carbonate. The separated aqueous layer was adjusted to pH 5.0 with 10% hydrochloric acid. The resulting solution was subjected to column chromatography on macroporous non-ionic adsorption resin "Diaion HP-20" (Trademark: prepared by Mitsubishi Chemical Industries Ltd.) and eluted with water. The fractions containing the object compound were adjusted to pH 2.0 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide in vacuo to give 7-[2-carboxymethoxyimino-2-(1,2,4-thiadiazol-3-yl)acetamido]3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.77 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[Cl:11][C:12]1[C:13]([C:29]([F:32])([F:31])[F:30])=[N:14][N:15]([CH2:18][C:19]([N:21]2[CH2:28][CH:27]3[CH:23]([CH2:24][NH:25][CH2:26]3)[CH2:22]2)=[O:20])[C:16]=1[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl-].[NH4+]>C1COCC1.CCOC(C)=O>[Cl:11][C:12]1[C:13]([C:29]([F:32])([F:30])[F:31])=[N:14][N:15]([CH2:18][C:19]([N:21]2[CH2:28][CH:27]3[CH:23]([CH2:24][N:25]([CH2:4][C:3]4[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=4[Cl:1])[CH2:26]3)[CH2:22]2)=[O:20])[C:16]=1[CH3:17]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CC2CNCC2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CC2CN(Cc3ccc(Cl)cc3Cl)CC2C1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
A solution of 2,4-dichlorobenzaldehyde (18 mg) and compound 7 (17 mg) in THF (1 mL) was stirred at room temperature for 1 hour and then sodium triacetoxyborohydride (42 mg) was added in one portion. The mixture was stirred at room temperature for another hour and EtOAc (1 mL) was added followed by the addition of saturated aqueous ammonium chloride (1 mL). The aqueous phase was extracted by EtOAc (3×1 mL) and the combined organic extractants was dried, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to afford the title compound 9 as a white solid (15 mg, 80%). LCMS: Rf: 3.605 min, M+H+: 495.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][NH:9][C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)([O-:16])=[O:15]>>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([CH2:21][C:20]3[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=3)[C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Product: COC(=O)c1cccc2c1ccn2Cc1ccc([N+](=O)[O-])cc1

Procedure:
1-(4-Nitro-benzyl)-1H-indole-4-carboxylic acid methyl ester was prepared from 1H-indole-4-carboxylic acid methyl ester and 4-nitrobenzyl bromide followed the procedure of Example 3 Step 1 as a yellow powder: 1H NMR (DMSO-d6) δ 3.90 (s, 3H), 5.69 (s, 2H), 7.05(dd, J=3.1, 0.9 Hz, 1H), 7.22 (t, J=7.6 Hz, 1H), 7.36 (d, J=8.9 Hz, 2H), 7.75 (td, J=7.6, 3.1 Hz, 3H), 8.18 (d, J=8.9 Hz, 2H); MS (ESI) m/z 311 (MH+), 309 ([M−H]−); Anal. calcd for C17H14N2O4: C, 65.80; H, 4.55; N, 9.03. Found: C, 65.81; H, 4.50; N, 8.98.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C:19]([CH3:26])([CH:23]([CH3:25])[CH3:24])[C:20]([NH2:22])=[O:21]>>[NH2:22][C:20](=[O:21])[C:19]([NH:18][C:15](=[O:17])[C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)([CH3:26])[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)C(C)(N)C(N)=O
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Product: CC(C)C(C)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and 2-amino-2,3-dimethyl-butanamide (CAN 40963-14-2) as starting materials, LC-MS (UV peak area/ESI) 96%, 346.2136 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C@H:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C@@H:5]2[N:4]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:3]1=[O:17].O=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.C([BH3-])#N.[Na+]>CO.[Cl-].[Cl-].[Zn+2]>[CH3:1][N:2]1[C@H:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C@@H:5]2[N:4]([CH:11]2[CH2:16][CH2:15][N:14]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[CH2:13][CH2:12]2)[C:3]1=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CN1C(=O)N(C2CCNCC2)[C@H]2CCCC[C@@H]21
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CN1C(=O)N(C2CCN(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)[C@H]2CCCC[C@@H]21
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
(3aS,7aS)-1-methyl-3-piperidin-4-yloctahydro-2H-benzimidazol-2-one (1.13 g, 4.75 mmol) was dissolved in MeOH (10 mL) and tert-butyl 4-oxopiperidine-1-carboxylate (1 g, 5.02 mmol) was then added. A solution containing sodium cyanoborohydride (0.49 g, 7.10 mmol) and ZnCl2 (0.38 g, 2.79 mmol) in MeOH (2 mL) was added and the mixture and stirred at room temperature overnight. The solvent was then removed under reduced pressure and the residue was dissolved in dichloromethane (150 mL). Organic layer was washed with 1N NaOH (10 mL) and brine (5 mL), dried and concentrated in vacuo. The residue was purified by column chromatography (dichloromethane-MeOH gradient) to provide the title compound as a white solid (1.6 g, 80%). MS (M+1): 421.4.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[N:16]=[C:6]2[N:7]=[C:8]3[CH2:15][CH2:14][CH2:13][S:12][C:9]3=[C:10](Cl)[N:5]2[N:4]=1.C(O)(C)C.[CH2:22]([CH2:24][NH2:25])[OH:23]>O>[CH3:1][N:2]([C:3]1[N:16]=[C:6]2[N:7]=[C:8]3[CH2:15][CH2:14][CH2:13][S:12][C:9]3=[C:10]([NH:25][CH2:24][CH2:22][OH:23])[N:5]2[N:4]=1)[CH3:17]
Reactant: CN(C)c1nc2nc3c(c(Cl)n2n1)SCCC3
Reactant: NCCO
Solvent: CC(C)O
Solvent: O
Product: CN(C)c1nc2nc3c(c(NCCO)n2n1)SCCC3

Procedure:
A mixture of 1.35 g (0,005 mole) of 2-dimethylamino-5-chloro-7,8-dihydro-9H-thiopyrano[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidine, 5 ml of isopropanol and 0.61 g (0.01 mole) of ethanolamine is boiled for half an hour under stirring. 10 ml of water are added to the warm solution. The mixture is cooled, then the separated product is filtered and washed with water and cold isopropanol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([Br:11])=[CH:8][C:9]=1[NH2:10])=[O:4].[CH2:12]1[O:22][C:15]2([CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]2)[O:14][CH2:13]1.C1([SiH3])C=CC=CC=1>C1COCC1.C([Sn](Cl)(Cl)CCCC)CCC>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([Br:11])=[CH:8][C:9]=1[NH:10][CH:18]1[CH2:19][CH2:20][C:15]2([O:22][CH2:12][CH2:13][O:14]2)[CH2:16][CH2:17]1)=[O:4]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: COC(=O)c1sc(Br)cc1N
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1sc(Br)cc1NC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91.5 %

Procedure:
A suspension of 3-amino-5-bromo-thiophene-2-carboxylic acid methyl ester (17.0 g, 72.0 mmol) in dry THF (21 ml) was treated with 1,4-cyclohexanedione monoethylene ketal (11.3 mg, 72.0 mmol), followed by dibutyltin dichloride (1.098 gr, 3.6 mmol). After 5 min, phenyl silane (9.74 ml, 79.2 mmol) was added and the reaction mixture was stirred overnight at room temperature. After concentration, the residue was dissolved in EtOAc washed with NaHCO3 then brine. The organic layer was separated, dried on Na2SO4, filtered and concentrated. The crude material was diluted in hexane (500 ml). After filtration, the mother liquor was evaporated to dryness to give 5-Bromo-3-(1,4-dioxa-spiro[4.5]dec-8-ylamino)-thiophene-2-carboxylic acid methyl ester (24.79 g, 92% yield). 1H NMR (CDCl3, 400 MHz): 6.90 (br s, 1H), 6.65 (s, 1H), 3.95 (s, 4H), 3.78 (s, 3H), 3.35 (m, 1H), 2.00 (m, 2H), 1.80 (m, 2H), 1.65 (m, 4H).
Reaction SMILES: N#N.[Li]CCCC.Br[C:9]1[S:10][C:11]([C:14]([CH3:22])([CH3:21])[O:15][SiH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:12][N:13]=1.CN(C)[C:25](=[O:27])[CH3:26].[NH4+].[Cl-]>CCOCC>[C:17]([SiH2:16][O:15][C:14]([CH3:22])([CH3:21])[C:11]1[S:10][C:9]([C:25](=[O:27])[CH3:26])=[N:13][CH:12]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(=O)N(C)C
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cnc(Br)s1
Agent: N#N
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(=O)c1ncc(C(C)(C)O[SiH2]C(C)(C)C)s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of n-BuLi (4.3 mL of a 2.5 M solution in hexanes, 10.75 mmol) in dry Et2O (15 mL) was added a solution of 2-bromo-5-(tert-butyl-dimethyl-silanyloxymethyl)-thiazole (3.03 g, 9.83 mmol) in dry Et2O (10 mL) at −78° C. The reaction mixture was then stirred for 30 min at −78° C. before N,N-dimethylacetamide (1.9 mL, 20.43 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 1 h. Sat. aq. NH4Cl (20 mL) was added, the layers separated and the aq. layer extracted with Et2O (2×30 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to give the title compound as an orange oil. TLC:rf (2:1 hept-EA)=0.60. LC-MS-conditions 02: tR=1.14 min; [M+H]+=272.32.
Reaction SMILES: [F-:1].[K+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[N+]([O-])=O)[C:9]([NH:11][CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:10])([O-:5])=[O:4].C1OCCOCCOCCOCCOCCOC1>CS(C)=O>[F:1][C:25]1[CH:24]=[CH:23][C:8]([C:9]([NH:11][CH2:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[O:10])=[CH:7][C:6]=1[N+:3]([O-:5])=[O:4]
Reactant: O=C(CNC(=O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)OCc1ccccc1
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(CNC(=O)c1ccc(F)c([N+](=O)[O-])c1)OCc1ccccc1
Temperature: 115 °C
Reaction time: 0.17 h
Yield: 56.8 %

Procedure:
A mixture of spray-dried KF (80 mg, 1.39 mmol), intermediate 3 (100 mg, 0.27 mmol) and catalytic amount of 18-crown-6 in dry DMSO (4 mL) was stirred at 110-120° C. for 10 min. Work-up of the reaction mixture as described in example 1 gave the product as a pale yellow color solid (51 mg, 55%), mp 84-86° C. 1H NMR (400 MHz, CDCl3): δ 8.50 (1H, dd, J=6.8, 1.6 Hz), 8.10-8.13 (1H, m), 7.34-7.39 (6H, m), 6.90 (1H, br s), 5.23 (2H, s), 4.28 (2H, d, J=5.2 Hz); LC-MS (negative ion mode): m/z 331 (M−H)−.
Reaction SMILES: [P:1]([O-:38])([O:34][CH2:35][CH2:36]Br)([O:3][CH2:4][CH:5]([O:28][C:29]1[CH:33]=[CH:32][O:31][N:30]=1)[CH2:6][O:7][C:8](=[O:27])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:2].[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[P:1]([O-:38])([O:34][CH2:35][CH2:36][N+:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([O:3][CH2:4][CH:5]([O:28][C:29]1[CH:33]=[CH:32][O:31][N:30]=1)[CH2:6][O:7][C:8](=[O:27])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:2]
Reactant: c1ccncc1
Reactant: CCCCCCCCCCCCCCCCCNC(=O)OCC(COP(=O)([O-])OCCBr)Oc1ccon1
Product: CCCCCCCCCCCCCCCCCNC(=O)OCC(COP(=O)([O-])OCC[n+]1ccccc1)Oc1ccon1

Procedure:
0.800 g of (2RS)-3-(N-heptadecylcarbamoyloxy)-2-(3-isoxazolyloxy)propyl 2-bromoethyl phosphate [prepared as described in Example 11(a)] was reacted with pyridine in a similar manner to that described in Example 3, to afford 0.549 g of the title compound as a viscous resinous material.
Reaction SMILES: [F:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([OH:14])=[O:13])[O:8][B:7]([OH:15])[C:6]=2[CH:5]=[C:4]([OH:16])[CH:3]=1.[OH-].[Na+].Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl>O>[CH2:23]([O:22][C:20]([O:16][C:4]1[CH:3]=[C:2]([F:1])[C:10]2[CH:9]([CH2:11][C:12]([OH:14])=[O:13])[O:8][B:7]([OH:15])[C:6]=2[CH:5]=1)=[O:21])[CH3:24]
Reactant: O=C(O)CC1OB(O)c2cc(O)cc(F)c21
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)Oc1cc(F)c2c(c1)B(O)OC2CC(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14.1 %

Procedure:
To a mixture of 2-(4-fluoro-1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)-acetic acid (113 mg, 0.5 mmol) and sodium hydroxide (0.06 g, 1.5 mmol) in water (3 mL) was added ethyl chloroformate (59 mg, 0.55 mmol). The reaction mixture was stirred at room temperature for 15 min and then acidified to pH=2 with 1N HCl. The mixture was extracted with ethyl acetate (2×15 mL) and the combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by HPLC to give the title compound as a white solid (21 mg, Yield: 14%). 1H NMR (400 MHz, DMSO-d) δ9.57 (s, 1H), 7.32-7.37 (m, 2H), 5.59-5.62 (m, 1H), 4.25-4.30 (m, 2H), 2.95-3.00 (m, 1H), 2.36-2.42 (m, 1H), 1.29-1.32 (t, J=6.8 Hz, 3H). MS (ESI) m/z=299 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:30][CH3:31])=[C:6]([C:8]([CH3:29])([CH3:28])[CH2:9][C:10]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[CH:14]=[CH:13]2)[CH:7]=1.[CH:32]([O:34]CCCC)=[CH2:33].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].O>[C:32]([C:2]1[CH:3]=[CH:4][C:5]([O:30][CH3:31])=[C:6]([C:8]([CH3:29])([CH3:28])[CH2:9][C:10]([OH:27])([C:23]([F:25])([F:26])[F:24])[CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[CH:14]=[CH:13]2)[CH:7]=1)(=[O:34])[CH3:33]
Reactant: COc1ccc(Br)cc1C(C)(C)CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(C)=O)cc1C(C)(C)CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F
Reaction time: 0.5 h
Yield: 27.1 %

Procedure:
A mixture of 1-[4-(5-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one (200 mg, 0.4 mmol), 1-vinyloxybutane (0.26 mL, 2.0 mmol), Pd(OAc)2 (5 mg, 0.02 mmol), 1,3-bis(diphenylphosphino) propane (DPPP) (10.5 mg, 0.03 mmol), K2CO3 (66.34 mg, 0.48 mmol), and water (0.1 mL) in DMF (1 mL) was microwaved for 1 hour at 122° C. After cooling, the mixture was poured into 5 mL of 5% HCl, stirred for 30 minutes and extracted with three 10 mL portions of ethyl acetate. The combined organic layers were washed with 10% aqueous K2CO3 and dried. The residue was purified silica gel chromatography and then by reverse phase HPLC to yield 50 mg (27% yield) of 1-[4-(5-acetyl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one as white solid.
Reaction SMILES: C(=O)=O.CCO.[Cl:7][C:8]([F:38])([F:37])[O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:36])[C:18]2[CH:23]=[C:22]([C:24]3[NH:28][N:27]=[CH:26][CH:25]=3)[C:21]([NH:29][CH2:30][CH2:31][CH:32]([OH:35])[CH2:33][OH:34])=[N:20][CH:19]=2)=[CH:12][CH:11]=1>>[Cl:7][C:8]([F:37])([F:38])[O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:36])[C:18]2[CH:23]=[C:22]([C:24]3[NH:28][N:27]=[CH:26][CH:25]=3)[C:21]([NH:29][CH2:30][CH2:31][C@H:32]([OH:35])[CH2:33][OH:34])=[N:20][CH:19]=2)=[CH:12][CH:11]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(NCCC(O)CO)c(-c2ccn[nH]2)c1
Agent: O=C=O
Solvent: CCO
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(NCC[C@H](O)CO)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared by chiral separation (Preparative chiral SFC, ChiralPak® AD-H, 250×30 mm, mobile phase: CO2/EtOH (3:2), flow rate: 50 mL/min, back pressure: 100 bar, column temperature: 38° C., wavelength: 220 nm, cycle time: 6.0 min) of a racemic mixture of N-(4-(chlorodifluoromethoxy)phenyl)-6-((3,4-dihydroxybutyl)amino)-5-(1H-pyrazol-5-yl)nicotinamide (Example 100), faster eluting isomer (Peak 1). Or alternatively in an analogous fashion to that described in Example 97 using (S)-benzyl(3,4-dihydroxybutyl)carbamate (Stage 101.1) as chiral starting material. Analytical chiral SFC (ChiralPak® AD-H, 250×4.6 mm, 5 μm, eluent: CO2/EtOH+0.05% DEA (3:2), flow rate: 2.4 mL/min, back pressure: 100 bar, temperature: 35° C., 220 nm): tR=3.18 min.
Reaction SMILES: C[OH:2].O.C(OC(O[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[CH2:15])=[CH:12][CH:11]=1)C)C>C1C2=C3C(=CC=C2)C=CC=C3C=1.CC1C=CC(C=C)=CC=1.N(C(C)(C)C(OC)=O)=NC(C)(C)C(OC)=O.COCC(O)C.O.O.C(O)(=O)C(O)=O>[OH:2][CH:15]=[CH:14][C:13]1[CH:16]=[CH:17][CH:10]=[CH:11][CH:12]=1
Reactant: C=Cc1ccc(OC(C)OCC)cc1
Reactant: CO
Agent: C1=Cc2cccc3cccc1c23
Agent: C=Cc1ccc(C)cc1
Agent: COC(=O)C(C)(C)N=NC(C)(C)C(=O)OC
Solvent: O
Solvent: COCC(C)O
Product: OC=Cc1ccccc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 136.9 %

Procedure:
In a 500-mL dropping funnel under nitrogen blanket, a solution was prepared by dissolving 76.0 g of 4-(1-ethoxyethoxy)styrene, 8.6 g of acenaphthylene, 12.7 g of 4-methylstyrene, 2.7 g of Monomer Z-1, and 10.4 g of dimethyl 2,2′-azobis(2-methylpropionate) (V601, Wako Pure Chemical Industries, Ltd.) in 112 g of propylene glycol monomethyl ether (PGME) as a solvent. A 500-mL polymerization flask was purged with nitrogen, charged with 75 g of PGME, and heated at 80° C., after which the solution was added dropwise to the flask over 4 hours. After the completion of dropwise addition, stirring was continued for 20 hours to effect polymerization while maintaining the temperature of 80° C. The polymerization solution was then cooled down to room temperature. To the solution were added 25 g of methanol and 1.25 g of oxalic acid dihydrate. The mixture was stirred for 3 hours at 50° C. The reaction solution was added dropwise to a mixture of 2,000 g of water and 50 g of methanol for precipitation. The copolymer precipitate was collected by filtration, washed twice with a mixture of 500 g of water and 10 g of methanol, and dried, yielding 65.0 g of a white hydroxystyrene copolymer, designated Polymer 3, having Mw=4,940 and Mw/Mn=1.63.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]#[CH:27]>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:27]#[C:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[Cl:19])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: C#Cc1ccccc1Cl
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2Cl)cc1[N+](=O)[O-]
Yield: 96.6 %

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) (1.82 g, 5.0 mmol) and 2-chlorophenylacetylene (1.02 g, 7.5 mmol) according to the general procedure F. Obtained as a yellow solid (1.8 g).
Reaction SMILES: [C:1]([C:5]1[CH:42]=[CH:41][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=2)[CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=2)=[C:7]([Cl:43])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N:48]=[N+:49]=[N-:50])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:42]=[CH:41][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([C:39]3[NH:50][N:49]=[N:48][N:40]=3)=[CH:37][CH:38]=2)[CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=2)=[C:7]([Cl:43])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2Cl)CCc2ccc(C#N)cc2)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2Cl)CCc2ccc(-c3nnn[nH]3)cc2)cc1
Temperature: 80 °C

Procedure:
A solution of 478 mg (0.81 mmol) of methyl 4-{(3E)-4-{2-[(4-tert-butyl-2-chlorobenzyl)oxy]-phenyl}-2-[2-(4-cyanophenyl)ethyl]but-3-en-1-yl}benzoate in 10 ml of toluene is mixed with 1116 mg (9.69 mmol) of trimethylsilyl azide and 351 mg (1.21 mmol) of di-n-butyltin oxide and then heated at 80° C. for 12 h. After cooling to room temperature, the mixture is washed with saturated sodium bicarbonate solution. The organic phase is separated off, washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the filtrate is concentrated to dryness. The resulting crude product is purified by chromatography on a silica gel column (mobile phase: cyclohexane/ethyl acetate 2:1→1:2). 144 mg (0.23 mmol, 28% of theory) of a white foam are obtained.