Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]1[C:10]([NH2:11])=[N:9][C:7]([NH2:8])=[N:6][C:4]=1[NH2:5].[C:12](=[O:27])([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)OC1C=CC=CC=1.Cl>CN(C)C=O>[O:20]([C:12]([NH:5][C:4]1[N:6]=[C:7]([NH:8][C:12]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:27])[N:9]=[C:10]([NH:11][C:12]([O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:27])[N:3]=1)=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Reactant: Nc1nc(N)nc(N)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1nc(NC(=O)Oc2ccccc2)nc(NC(=O)Oc2ccccc2)n1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.5 %

Procedure:
1 g of 95% sodium hydride was placed in a two-neck flask equipped with a magnetic stirring bar, a reflux condenser with an argon inlet and a rubber septum. To it was added 40 ml of dimethylformamide (DMF) followed by 1.26 g of melamine. The contents were stirred at room temperature for 15 minutes and then 8.56 g of diphenyl carbonate was added to the flask. The reaction mixture was stirred at room temperature for 4 hours and then poured, with stirring, into 500 ml of 5% aq HCl. A white precipitate was formed which was filtered, washed with water, and dried under reduced pressure to give 4.4 g of crude 2,4,6-tris-phenoxycarbonylamino-1,3,5-triazine. The structure was confirmed by thin layer chromatography (TLC), 1H NMR and mass spectroscopy.
Reaction SMILES: CN1CCOCC1.[N:8]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3([C:22]([OH:24])=O)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[N:9]1.Cl.Cl.[NH:27]1[CH2:31][CH2:30][C:29]2([C:39]3[CH:38]=[CH:37][N:36]=[CH:35][C:34]=3[C:33](=[O:40])[O:32]2)[CH2:28]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(O)(C(F)(F)F)=O>CN(C=O)C>[N:8]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]3([C:22]([N:27]4[CH2:31][CH2:30][C@@:29]5([C:39]6[CH:38]=[CH:37][N:36]=[CH:35][C:34]=6[C:33](=[O:40])[O:32]5)[CH2:28]4)=[O:24])[CH2:20][CH2:21]3)=[CH:17][CH:18]=2)[CH:12]=[CH:11][CH:10]=[N:9]1
Reactant: O=C(O)C1(c2ccc(-n3cccn3)cc2)CC1
Reactant: O=C1OC2(CCNC2)c2ccncc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(-n5cccn5)cc4)CC3)C2)c2ccncc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
4-Methylmorpholine (55 μL, 0.50 mmol) was added to a mixture of 1-[4-(1H-pyrazol-1-yl)phenyl]cyclopropanecarboxylic acid (0.10 mmol), 3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one dihydrochloride (0.026 g, 0.10 mmol), and BOP (0.057 g, 0.11 mmol) in DMF (1 mL). The mixture was stirred at room temperature for 2 hours, then adjusted to be acidic (PH=2.0) with TFA, and then diluted with DMF (0.8 mL). The resulting solution was purified by a prep-LCMS followed by chiral HPLC to give (1R)-1′-({1-[4-(1H-pyrazol-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one (30%). MS (ESI): (M+H)+=401.1
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)#[N:4].Cl[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]2)=[CH:18][N+:17]=1[O-].P(Cl)(Cl)Cl>CN(C)C=O.C(OCC)(=O)C>[OH:14][C:9]1[NH:10][C:11]2[C:7]([C:8]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]3)=[CH:18][N:17]=1)=[CH:6][C:5]([C:3]#[N:4])=[CH:13][CH:12]=2
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Reactant: CC1CCN(Cc2ccc(Cl)[n+]([O-])c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClP(Cl)Cl
Product: CC1CCN(Cc2ccc(-c3c(O)[nH]c4ccc(C#N)cc34)nc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 1.7 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 54 mg, 1.35 mmol) in N,N-dimethylformamide (1 mL) was added 5-cyanooxindole (161 mg, 1.02 mmol), and the mixture was stirred at ambient temperature for 10 min. To the obtained brownish solution was added a solution of 2-chloro-5-[(4-methylpiperidin-1-yl)methyl]pyridine 1-oxide (163 mg, 0.677 mmol) in N,N-dimethylformamide (1.5 mL). The reaction mixture was heated at 130° C. for 25 min, and was then allowed to cool. The solvent was removed in vacuo, and is to the residue was added 2 M HCl(aq). The obtained precipitate was partitioned between a saturated aqueous NaHCO3 solution and ethyl acetate. The aqueous layer was extracted with another two portions of ethyl acetate. The combined organic layers were dried (Na2SO4), and the solvent was removed in vacuo affording a crude product. The material was dissolved in ethyl acetate (25 mL), and phosphorus trichloride (0.24 mL, 2.71 mmol) was added. An orange precipitate was immediately formed. The mixture was heated at reflux for 30 min, and was then allowed to cool. The mixture was partitioned between ethyl acetate and a saturated aqueous NaHCO3 solution. The aqueous layer was extracted with another portion of ethyl acetate. The combined organic layers were dried (Na2SO4), and the solvent was evaporated. The crude product was purified on a silica gel column using chloroform/methanol, (95:5), as the eluent followed by preparative HPLC (column: Xterra, C8, 7 μm, 19×300 mm; eluent: 0.1 M NH4OAc buffer/acetonitrile, 8:2 to 4:6) affording 4 mg (2% yield) of the title compound as an orange solid: 1H NMR (acetone-d6, 400 MHz) δ 9.88 (br s, 1 H), 8.11 (d, J=1 Hz, 1 H), 7.90 (dd, J=9, 2 Hz, 1 H), 7.85 (d, J=9 Hz, 1 H), 7.82 (d, J=1 Hz, 1 H), 7.26 (dd, J=8, 2 Hz, 1 H), 7.11 (d, J=8 Hz, 1 H), 3.44 (s, 2 H), 2.91-2.86 (m, 2 H), 2.10-1.98 (m, 2 H), 1.65-1.59 (m, 2 H), 1.40-1.35 (m, 1 H), 1.28-1.16 (m, 2 H), 0.92 (d, J=7 Hz, 3 H); MS (ES) m/z 347 (M++1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][C:8](=[O:12])[NH:9][C:10]=2[N:11]=1.[C:13]1(/[CH:19]=[CH:20]/B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(Cl)(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:20](/[C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][C:8](=[O:12])[NH:9][C:10]=2[N:11]=1)=[CH:19]\[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1COc2ccc(Br)nc2N1
Reactant: OB(O)/C=C/c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: O=C1COc2ccc(/C=C/c3ccccc3)nc2N1
Temperature: 25 °C
Yield: 57.7 %

Procedure:
6-Bromo-4H-pyrido[3,2-b][1,4]oxazin-3-one (10.0 g, 44 mmole) and trans-2-phenylvinylboronic acid (9.0 g, 61 mmole) were dissolved in 1,4-dioxane (200 mL) and the solution was degassed with argon. (Ph3P)4Pd (2.5 g, 2.2 mmole) was added, followed by a solution of potassium carbonate (15 g, 109 mmole) in H2O (100 mL). The reaction was heated at reflux under argon overnight, then was cooled to room temperature and diluted with CHCl3 (400 mL). The solution was washed sequentially with H2O and brine, dried (Na2SO4), and concentrated in vacuo. The solid residue was recrystallized from hot EtOAc to afford the title compound (6.4 g, 57.5%): MS (ES) m/e 253.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[N:12]=[C:11]([NH2:13])[S:10][N:9]=1)[C:5]([OH:7])=O.P(Cl)(Cl)(Cl)=O.[NH2:19][CH:20]1[C:38](=[O:39])[N:22]2[C:23]([C:35]([OH:37])=[O:36])=[C:24]([CH:27]([S:29][C:30]3[NH:34][N:33]=[N:32][N:31]=3)[CH3:28])[CH2:25][S:26][C@H:21]12.C[Si](CC(N)=O)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C)C=O>[CH3:1][O:2][N:3]=[C:4]([C:8]1[N:12]=[C:11]([NH2:13])[S:10][N:9]=1)[C:5]([NH:19][CH:20]1[C:38](=[O:39])[N:22]2[C:23]([C:35]([OH:37])=[O:36])=[C:24]([CH:27]([S:29][C:30]3[NH:31][N:32]=[N:33][N:34]=3)[CH3:28])[CH2:25][S:26][C@H:21]12)=[O:7]
Reactant: CON=C(C(=O)O)c1nsc(N)n1
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)CC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(C)Sc3nnn[nH]3)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.3 %

Procedure:
A mixture of 2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) (100 mg) and phosphorus oxychloride (306 mg) in methylene chloride (5 ml) was stirred for 30 minutes at ambient temperature. To the mixture was added N,N-dimethylformamide (0.2 ml) under cooling in an ice-bath, followed by stirring for 30 minutes. A mixture of 7-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (300 mg) and trimethylsilylacetamide (0.9 g) in methylene chloride (9 ml) was warmed to make a clear solution. The solution was cooled in an ice-bath and added to the above obtained solution, followed by stirring for 30 minutes at 0° C. The reaction mixture was poured into a cold aqueous solution of sodium bicarbonate. The aqueous layer was separated, adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was triturated with diethyl ether to give a crude product of the title compound (120 mg). The crude material was dissolved in an aqueous solution of sodium bicarbonate and reprecipitated with diluted hydrochloric acid to give the pure title compound (60 mg), mp. 170° to 175° C. (dec.).
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH:14]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH2:15][NH:16]3)=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>C1COCC1.O>[C:37]([N:16]1[C:17]2[C:12](=[CH:11][CH:10]=[C:9]([O:8][CH2:7][C:4]3[CH:3]=[CH:2][C:1]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:6][CH:5]=3)[CH:18]=2)[CH2:13][CH:14]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH2:15]1)(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: CN(C)CCC1CNc2cc(OCc3ccc(-c4ccccc4)cc3)ccc2C1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CC(CCN(C)C)Cc2ccc(OCc3ccc(-c4ccccc4)cc3)cc21
Reaction time: 1 h

Procedure:
To a solution of 7-(4-biphenylyl)methoxy-3-[2-(N,N-dimethylamino) ethyl]-1,2,3,4-tetrahydroquinoline (250 mg) in THF (17 ml) was added triethylamine (0.33 ml) followed by addition of acetyl chloride (0.09 ml) at 0° C. After stirring in an ice bath for one hr, the reaction mixture was further stirred at room temperature for one hr. The reaction mixture was diluted with water and extracted with ethyl acetate. oil The organic layer was washed with saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by alumina column chromatography (eluent:ethyl acetate: hexane=1:20 to 1:6) and the resulting precipitated crystals were washed with diisopropyl ether to obtain the titled compound (210 mg).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[N:7]([CH3:14])[C:8](=[O:13])[N:9]([CH3:12])[C:10](=[O:11])[C:5]=2[NH:4]N=1.Br[CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[C:29]([F:31])[C:28]([O:32][CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[C:27]([F:38])[CH:26]=2)[N:24]=1)=[O:18].[H-].[Na+].[CH3:41]N(C=O)C>>[F:38][C:27]1[CH:26]=[C:25]([C:23]2[N:24]=[C:20]([NH:19][C:17](=[O:18])[CH2:16][N:4]3[C:5]4[C:10](=[O:11])[N:9]([CH3:12])[C:8](=[O:13])[N:7]([CH3:14])[C:6]=4[C:2]([CH3:41])=[CH:1]3)[S:21][CH:22]=2)[CH:30]=[C:29]([F:31])[C:28]=1[O:32][CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35]
Reactant: Cc1n[nH]c2c(=O)n(C)c(=O)n(C)c12
Reactant: CN(C)C=O
Reactant: CC(C)(C)COc1c(F)cc(-c2csc(NC(=O)CBr)n2)cc1F
Agent: [H-]
Agent: [Na+]
Product: Cc1cn(CC(=O)Nc2nc(-c3cc(F)c(OCC(C)(C)C)c(F)c3)cs2)c2c(=O)n(C)c(=O)n(C)c12

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 3 (50 mg, 0.258 mmol) with 2-bromo-N-{4-[3,5-difluoro-4-(2,2-dimethylpropoxy)phenyl]-1,3-thiazol-2-yl}acetamide (130 mg, 0.310 mmol) in the presence of NaH (15 mg, 0.375 mmol) in dry DMF (5.0 mL) to give 75 mg of the product as a white solid; 1H-NMR (δ ppm, DMSO-d6, 300 MHz) 1.01 (s, 9H), 2.29 (s, 3H), 3.16 (s, 3H), 3.59 (s, 3H), 3.80 (s, 2H), 5.25 (s, 2H), 7.12 (s, 1H), 7.63 (d, J=9.6 Hz, 2H), 7.76 (s, 1H), 12.63 (br s, 1H, exchangeable with D2O); ESI-MS (m/z) 532.18 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([O:22][CH2:23][CH:24]3[CH2:26][CH2:25]3)[CH2:13][CH2:12][C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:14]#N)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-:27].[K+].[OH2:29].S([O-])(O)(=O)=O.[Na+]>C(O)CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([O:22][CH2:23][CH:24]3[CH2:26][CH2:25]3)[CH2:13][CH2:12][C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:14]([OH:29])=[O:27])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: N#CC1(c2ccccc2)CCC(OCC2CC2)(c2cccc(Br)c2)CC1
Reactant: O
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: OCCO
Product: O=C(O)C1(c2ccccc2)CCC(OCC2CC2)(c2cccc(Br)c2)CC1
Temperature: 195 °C
Reaction time: 16 h

Procedure:
2.3 g of 4-(3-bromophenyl)-4-cyclopropylmethoxy-1-phenylcyclohexanecarbonitrile were suspended in 10 ml of ethylene glycol, 0.94 g of potassium hydroxide was added and the mixture was heated for 4 h at 195° C. The reaction mixture was then allowed to stand for 16 h at room temperature, poured onto 100 ml of water and adjusted to pH=3 with saturated aqueous sodium hydrogensulfate solution. The precipitated product was filtered off with suction and purified by preparative HPLC (column: Waters X-Terra MS C18 prep, 200×50 mm, 10 μm; eluent A: water+0.2% TFA, eluent B: acetonitrile; gradient and flow: 90% A+10% B and 50 ml/min for 2.2 min, then to 90% A+10% B and 150 ml/min in 1.3 min, then 90% A+10% B and 150 ml/min for 0.5 min, then to 80% A+20% B and 150 ml/min in 0.5 min, then to 5% A+95% B and 150 ml/min in 19.5 min, then 5% A+95% B and 150 ml/min for 6 min, then to 90% A+10% B and 150 ml/min in 1 min, then 90% A+10% B and 150 ml/min for 4 min). 215 mg of the title compound were obtained as a colorless oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[OH:18].[Cl:19][C:20]1[CH:25]=[C:24]([N+]([O-])=O)[CH:23]=[CH:22][N:21]=1>CN(C)C=O>[Cl:19][C:20]1[CH:25]=[C:24]([O:18][C:9]2[CH:10]=[CH:11][C:12]([C:14]([F:16])([F:17])[F:15])=[CH:13][C:8]=2[Cl:7])[CH:23]=[CH:22][N:21]=1
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(Oc2ccnc(Cl)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.48 gm (0.018 mol) of potassium carbonate were added in portions to a stirred solution of 2.95 gm (0.015 mol) of 2-chloro-4-trifluoromethyl-phenol and 2.2 gm (0.015 mol) of 2-chloro-4-nitro-pyridine in 10 ml of dimethylformamide, and the mixture was stirred first for 1 hour at room temperature and then for 11/2 hours at 80° C. Thereafter, the reaction mixture was poured into ice water, and the aqueous mixture was extracted with chloroform. The organic phase was separated, washed with 2N sodium hydroxide and with water, dried with sodium sulfate and evaporated, yielding the title compound as a colorless oil.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[N:28]1([CH2:33][C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[CH:32]=[CH:31][N:30]=[N:29]1>>[N:28]1([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([NH:38]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:39][CH:40]=2)[CH:32]=[CH:31][N:30]=[N:29]1
Reactant: Nc1ccc(Cn2ccnn2)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(Cn2ccnn2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(1,2,3-triazol-1-yl-methyl)-aniline Rf value: 0.4 (silica gel, methylene chloride/methanol=9:1) C26H21N5O3
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:13](Cl)=[O:14]>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:6]=[C:13]=[O:14])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Product: O=C=NC(=O)c1ccc(Cl)cc1Cl

Procedure:
2,4-Dichlorobenzamide was dissolved in dichloromethane, after which 1.5 eq. of oxalyl chloride were added and the mixture was heated to reflux for 16 hours. The reaction mixture was then concentrated under high vacuum and reacted in step b without any further purification.
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:22])=[O:4].[NH2:23][CH:24]([CH2:27][OH:28])[CH2:25][OH:26]>C1(C)C=CC=CC=1>[OH:26][CH2:25][CH:24]([NH:23][C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:22])=[O:4])[CH2:27][OH:28]
Reactant: NC(CO)CO
Reactant: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)OC)s1
Solvent: Cc1ccccc1
Product: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)NC(CO)CO)s1
Yield: 55 %

Procedure:
To a stirred solution of 2-[2-(3-butyl-5-methyl-isoxazol-4-yl)-ethyl]-4-methyl-thiazole-5-carboxylic acid methyl ester (100 mg, 0.31 mmol) in toluene (1.0 mL) was added 2-amino-1,3-propandiol (57 mg, 0.62 mmol) and TBD (13 mg, 0.09 mmol). After 15 h the reaction mixture was concentrated in vacuo then purified by chromatography (silica, 0 to 7.5% methanol in dichloromethane) to give the title compound (65 mg, 55%) as an off white oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:29]=[CH:28][CH:27]=[CH:26][C:16]=1[O:17][C:18]1[CH:19]=[C:20]([CH2:24]O)[CH:21]=[CH:22][CH:23]=1.C1(C)C(O)=CC=CC=1.BrC1C=C(C=CC=1)C=O>>[CH3:14][C:15]1[CH:29]=[CH:28][CH:27]=[CH:26][C:16]=1[O:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: Cc1ccccc1Oc1cccc(CO)c1
Agent: Cc1ccccc1O
Agent: O=Cc1cccc(Br)c1
Product: COC(=O)CCc1ccc(OCc2cccc(Oc3ccccc3C)c2)cc1

Procedure:
The title compound was synthesized in the same manner as in Example 277 from methyl 3-(4-hydroxyphenyl)propanoate and [3-(2-methylphenoxy)phenyl]methanol (synthesized in the same manner as in Reference Example 201 from o-cresol and 3-bromobenzaldehyde (mixture with side product)) (preparative HPLC (gradient cycle A) was used for purification). colorless oil (yield 28%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:30]([C:32]1[CH:33]=[C:34]([C:37](O)=[O:38])[S:35][CH:36]=1)#[N:31]>>[C:30]([C:32]1[CH:33]=[C:34]([C:37]([NH:21][C@@H:19]([CH3:20])[C@H:18]([O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=[CH:10]3)[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)=[O:38])[S:35][CH:36]=1)#[N:31]
Reactant: N#Cc1csc(C(=O)O)c1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2cc(C#N)cs2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 70 mg, 0.18 mmol) and 4-cyanothiophene-2-carboxylic acid (32.9 mg, 0.21 mmol).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][C:12]([CH3:16])([CH3:15])[CH:13]=O.[NH:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N:17]1([CH:13]([NH:10][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:12]([CH3:16])([CH3:15])[CH3:11])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1
Reactant: CC(C)(C)C=O
Reactant: NC(=O)Cc1ccccc1
Reactant: c1ccc2[nH]nnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)C(NC(=O)Cc1ccccc1)n1nnc2ccccc21
Temperature: 25 °C
Yield: 87.5 %

Procedure:
A suspension of phenylacetamide (2.9 g, 21.45 mmol), trimethylacetaldehyde (5.42 g, 63.00 mmol), and 1H-1,2,3-benzotriazole (2.56 g, 21.45 mmol) in toluene (75 mL) was treated with p-toluenesulfonic acid (0.200 g, 1.00 mmol). The solution was heated at reflux under Dean-Stark conditions for 10 hours, cooled gradually to ambient temperature. The mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel (sequential elution with 10, 15, and 20% of ethyl acetate in methylene chloride) to provide 6.05 g of the title compound. MS (ESI+) m/z 323 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[O:10][C:3]=12.[CH3:19][C:20]1[C:28]([NH2:29])=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[CH:23][NH:24]2>>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[O:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[NH:29][C:28]3[C:20]([CH3:19])=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]=[CH:22]4)[CH:8]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(-c2cc3nccc(Cl)c3o2)cc1
Reactant: Cc1c(N)ccc2[nH]ccc12
Product: COc1ccc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4C)c3o2)cc1

Procedure:
The title compound was prepared by procedure E using 7-chloro-2-(4-methoxyphenyl)furo[3,2-b]pyridine (30.10 mg; 0.12 mmol; 1.00 eq.) instead of 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine, and 4-methyl-1H-indol-5-ylamine (17.79 mg; 0.12 mmol; 1.05 eq.) instead of 6-amino-2,2-difluoro-4H-benzo[1,4]oxazin-3-one, and was obtained as a beige solid (27 mg, 64%). (HPLC (method F): 93%, RT: 4.07 min); 1H NMR (500 MHz, DMSO-d6) δ[ppm] 11.14 (s, 1H), 8.49 (s, 1H), 7.92 (d, J=5.5, 1H), 7.90 (d, J=8.8, 2H), 7.38 (t, J=2.7, 1H), 7.30 (d, J=8.4, 1H), 7.27 (s, 1H), 7.06 (d, J=8.9, 2H), 7.00 (d, J=8.5, 1H), 6.52 (s, 1H), 6.06 (d, J=5.5, 1H), 3.83 (s, 3H), 2.36 (s, 3H); MS (m/z) 370 [M+H]+, RT: 3.9 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C:3]2([CH2:11][CH:10]3[CH2:12][CH:7]2[CH2:8][CH2:9]3)[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([CH:21]1[O:23][CH2:22]1)[Cl:20]>C(O)C>[ClH:20].[Cl:20][CH2:19][CH:21]([OH:23])[CH2:22][N:1]1[CH2:6][CH2:5][CH2:4][C:3]2([CH2:11][CH:10]3[CH2:12][CH:7]2[CH2:8][CH2:9]3)[CH2:2]1
Reactant: C1CNCC2(C1)CC1CCC2C1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cl
Product: OC(CCl)CN1CCCC2(CC3CCC2C3)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
24.9 g (0.15 mole) of (1RS,2RS,4SR)-spiro[norbornane-2,3'-piperidine] and 25 g of potassium carbonate are suspended in 100 ml of ethanol; an addition of 15.0 g (0.11 mole) of epichlorohydrin (1-chloro-2,3-epoxypropane) is subsequently made, whereupon the mixture heats up to 40°. It is stirred for 16 hours at room temperature and then concentrated in vacuo (ca. 12 Torr). The residue is suspended in 150 ml of water, and extracted three times with 50 ml of chloroform each time. The chloroform extracts are washed separately three times with 50 ml of water each time, dried over sodium sulphate and concentrated by evaporation. The residue is dissolved in 200 ml of 2N hydrochloric acid; this solution is extracted once with 50 ml of chloroform and concentrated in vacuo (ca. 12 Torr). The obtained reddish crystals are recrystallised from acetone/ether to obtain α-(chloromethyl)-(1RS,2RS,4SR)-spiro[norbornane-2,3'-piperidine]-1' -ethanol-hydrochloride, M.P. 199°-201°.