Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][NH:9]2)=[CH:5][CH:4]=1.N1C=CC=CC=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1>CC(O)C>[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][N:9]2[C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[CH:5][CH:4]=1
Reactant: Clc1ccc2c(c1)NCC2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCc4ccc(Cl)cc43)c2cc1OC

Procedure:
To 6-chloroindoline hydrochloride (1 00 mg, 0.526 mmol) and pyridine (0.957 mmol, 77 μL) in dry i-PrOH (8 mL) was added 4-chloro-6,7-dimethoxyquinazoline (107 mg, 0.478 mmol). The mixture was refluxed for 2 hours under an atmosphere of dry N2(g) and then the solvent was removed in vacuo. The residue was partitioned between CHCl3 and 1M NaOH, and the organic phase was washed with brine, dried over Na2SO4(g) and concentrated in vacuo. The residue (171 mg) was purified by flash chromatography on silica using 80%EtOAc/CH2 Cl2 to yield 4-(6-chloro-2,3-dihydro-indol-1-yl)-6,7-dimethoxy-quinazoline as its free base (148 mg) (M.P. 229°-230° C.; LC-MS: 342 (MH+); anal. RP18-HPLC RT: 4.38 min.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@@H:4]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH2:10][CH2:9]1)[CH2:5][CH:6]=O.Cl.[CH2:28]1[C:30]2([CH2:35][CH2:34][NH:33][CH2:32][C@H:31]2[OH:36])[CH2:29]1>>[CH3:1][O:2][C:3](=[O:26])[C@@H:4]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=2)[CH2:10][CH2:9]1)[CH2:5][CH2:6][N:33]1[CH2:34][CH2:35][C:30]2([CH2:29][CH2:28]2)[C@H:31]([OH:36])[CH2:32]1
Reactant: O[C@@H]1CNCCC12CC2
Reactant: COC(=O)[C@H](CC=O)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Agent: Cl
Product: COC(=O)[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Yield: 70 %

Procedure:
In analogy to the procedure described in example 1K, (S)-4-oxo-2-[7-oxo-4-(3-trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-butyric acid methyl ester and (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2) gave the pure title compound in 70% yield as light yellow foam. MS: 484.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH3:13])=[C:8]([N+:10]([O-])=O)[CH:9]=1)=[O:4]>CO.[Ni]>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH3:13])=[C:8]([NH2:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C)s1
Agent: [Ni]
Solvent: CO
Product: COC(=O)c1cc(N)c(C)s1
Yield: 98.4 %

Procedure:
Sponge nickel (1.0 g water wet) was added to a solution of 5-methyl-4-nitro-thiophene-2-carboxylic acid methyl ester (1.79 g, 8.9 mmol) in methanol (50 mL), and the mixture was hydrogenated at room temperature under a hydrogen atmosphere at a starting pressure of 50 psi. After a reaction time of 25 hours, the pressure was released and the mixture filtered. The slurry was rinsed with methanol, and the filtrate was stripped of solvent under reduced pressure to afford 1.5 g of 5-methyl-4-amino-thiophene-2-carboxylic acid methyl ester. A sample was dissolved in ethyl acetate and filtered through a short column of silica gel. Evaporation of the effluent under reduced pressure gave product with a mp 90-91° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.I[C:24]1[CH:25]=[C:26]([C:31]([F:34])([F:33])[F:32])[C:27]([NH2:30])=[N:28][CH:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:24]4[CH:25]=[C:26]([C:31]([F:34])([F:33])[F:32])[C:27]([NH2:30])=[N:28][CH:29]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Nc1ncc(I)cc1C(F)(F)F
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Product: Nc1ncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)cc4)nc23)cc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.4) (322 g, 1.0 mmol) and 5-iodo-3-trifluoromethyl-pyridin-2-ylamine (example B.48) (288 mg, 1.0 mmol) according to general procedure II. Obtained as an orange solid (290 mg, 60%). MS (ISP) 482.3 [(M+H)+], 484 [(M+2+H)+]; mp 209° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7](Cl)[C:8]=1Cl)[NH2:5].[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[Cl:19])[NH2:15]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[Cl:19])[NH2:15]
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1
Agent: Nc1ccc(Cl)c(Cl)c1
Product: Nc1cccc(Cl)c1

Procedure:
Example 9 is repeated, the 3,4,5-trichloroaniline being replaced by 3,4-dichloroaniline. After a reaction time of 7 hours under the same conditions, 3-chloroaniline is obtained with a yield of 100% for a degree of conversion of 100% of the 3,4-dichloroaniline. The degree of hydrodechlorination of the solvent is 0.09%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[Cl:11][C:12]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][N:13]=1>>[Cl:11][C:12]1[CH:17]=[C:16]([O:18][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[F:1])[CH:15]=[CH:14][N:13]=1
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: Oc1ccnc(Cl)c1
Product: O=Cc1ccc(Oc2ccnc(Cl)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-difluorobenzaldehyde and 2-chloropyridin-4-ol.
Reaction SMILES: [C:1]([O:4][CH:5]([C@@H:8]1[CH2:12][C@H:11](OS(C(F)(F)F)(=O)=O)[C@H:10]([N:21]2[C:25]3[N:26]=[C:27]([NH2:31])[NH:28][C:29](=[O:30])[C:24]=3[S:23][C:22]2=[O:32])[O:9]1)[CH2:6][CH3:7])(=[O:3])[CH3:2].[CH3:33][S-:34].[Na+]>CN(C=O)C.CCOC(C)=O>[C:1]([O:4][CH:5]([C@@H:8]1[CH2:12][C@@H:11]([S:34][CH3:33])[C@H:10]([N:21]2[C:25]3[N:26]=[C:27]([NH2:31])[NH:28][C:29](=[O:30])[C:24]=3[S:23][C:22]2=[O:32])[O:9]1)[CH2:6][CH3:7])(=[O:3])[CH3:2]
Reactant: CCC(OC(C)=O)[C@@H]1C[C@H](OS(=O)(=O)C(F)(F)F)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(OC(C)=O)[C@@H]1C[C@@H](SC)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1-[(2S,4S,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-(trifluoromethylsulfonyloxy)tetrahydrofuran-2-yl]propyl acetate (compound 22d, 420 mg, 0.83 mmol) in DMF (7 mL) was added sodium thiomethoxide (84 mg, 1.2 mmol). After being stirred at room temperature for 2 hours, the resulting solution was diluted with EtOAc, washed with brine, dried over Na2SO4 and concentrated in vacuo to afford crude product of 1-[(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-methylsulfanyl-tetrahydrofuran-2-yl]propyl acetate (compound 22e), which was used in next step without further purification. MS obsd. (ESI−) [(M−H)−]: 399.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([NH:8][C:9]2[C:14](=[O:15])[N:13]([CH3:16])[CH:12]=[C:11]([C:17]3[C:22]([CH:23]=[O:24])=[C:21]([N:25]4[CH:37]=[CH:36][C:35]5[N:34]6[C:29]([CH2:30][CH2:31][CH2:32][CH2:33]6)=[CH:28][C:27]=5[C:26]4=[O:38])[N:20]=[CH:19][CH:18]=3)[CH:10]=2)=[N:3]1.[BH4-].[Na+]>CO>[CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([NH:8][C:9]2[C:14](=[O:15])[N:13]([CH3:16])[CH:12]=[C:11]([C:17]3[CH:18]=[CH:19][N:20]=[C:21]([N:25]4[CH:37]=[CH:36][C:35]5[N:34]6[C:29]([CH2:30][CH2:31][CH2:32][CH2:33]6)=[CH:28][C:27]=5[C:26]4=[O:38])[C:22]=3[CH2:23][OH:24])[CH:10]=2)=[N:3]1
Reactant: Cc1cc(Nc2cc(-c3ccnc(-n4ccc5c(cc6n5CCCC6)c4=O)c3C=O)cn(C)c2=O)nn1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Nc2cc(-c3ccnc(-n4ccc5c(cc6n5CCCC6)c4=O)c3CO)cn(C)c2=O)nn1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.5 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 246a (38 mg, 0.074 mmol, 1.0 eq.), NaBH4 (29 mg, 0.37 mmol, 5.0 eq.), and methanol (5 mL). The resulting mixture was stirred at room temperature for 20 min. It was then filtered and the filtrate was concentrated. The residue was purified by reverse-phase prep-HPLC to afford the title compound (18 mg, 48%) as a white solid. MS-ESI: [M+H]+ 512.3. 1H NMR (500 MHz, CDCl3) δ 8.58 (d, J=5.0 Hz, 1H), 7.98 (d, J=2.5 Hz, 1H), 7.78 (d, J=2.5 Hz, 1H), 7.52 (d, J=5.0 Hz, 1H), 7.37 (s, 1H), 7.17 (d, J=7.0 Hz, 1H), 6.58-6.57 (m, 2H), 5.74 (s, 1H), 5.41-5.39 (m, 1H), 4.42-4.32 (m, 2H), 4.08 (t, J=6.5 Hz, 2H), 3.72 (s, 3H), 3.70 (s, 3H), 2.98 (t, J=6.5 Hz, 2H), 2.25 (s, 3H), 2.13-2.09 (m, 2H), 1.97-1.92 (m, 2H).
Reaction SMILES: [C:1]1([CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[K+].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:30])(=O)=O)=CC=1.O>CCOCC>[C:1]1([C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[F:30])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Agent: [H-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C(F)(C(=O)OCC)c1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
1 millimole of diethyl phenylmalonate was stirred with potassium hydride in 2 milliliters ether for 30 minutes at -25° C. 1.2 molar equivalents N-fluorobenzenesulfonimide prepared according to Example 1 above in 2 milliliters ether were dropped into the mixture which was stirred for 1 hour at -20° C. The mixture was allowed to warm up to room temperature and water was added. The product was extracted into ether which was dried and evaporated. Purification was carried out on a silica gel column. C6H5CF(COOCH2CH3)2 was obtained in 47% yield.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:14])[CH2:11][CH2:12]Cl)=[CH:5][CH:4]=1.CN(C)C(=O)C.Cl[Al](Cl)Cl>>[OH:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:10](=[O:14])[CH2:11][CH2:12]2
Reactant: COc1ccc(NC(=O)CCCl)cc1
Agent: Cl[Al](Cl)Cl
Solvent: CC(=O)N(C)C
Product: O=C1CCc2cc(O)ccc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
N-(4-methoxyphenyl)-3-chloropropionamide (300 g, 1.4 mol.) and N,N-dimethylacetamide (165 ml, d=0.937, 1.3 eq.) were added to a three-necked, three-liter flask. Trichloroaluminum (760 g, 4 eq.) was slowly added over two hours. An exotherm raised the temperature of the mixture from about 25° C. to 140° C. over the course of the addition. The reaction mixture was a slightly cloudy colorless solution. The solution was stirred and held at 150-160° C. for two hours. At the end of the two hours the reaction mixture had become a stirrable slurry. The mixture was then cooled to ambient temperature and quenched by pouring into water (5.5 L) in a fume hood with good circulation and a trap between the inlet and the exhaust to capture evolved HCl gas. Next, sodium borohydride (30 g) was added, which caused the mixture color to turn from gray to white. The mixture was then cooled to ambient temperature and filtered. The collected solids were washed with water (2 L) and dried overnight in a vacuum-oven at 60° C. to give 6-hydroxy-3,4-dihydroquinolinone (212.8 g, 92.9%) in 99.2% purity based on HPLC analysis.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][C@H:14]1[C@@H:17]([NH:18][C:19](=[O:28])[CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16](=[O:29])[NH:15]1.C(O)(=O)C(C)O.CCCCCC>N1C=CC=CC=1.C(OCC)(=O)C>[O:29]=[C:16]1[NH:15][C@@H:14]([CH2:13][O:12][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[C@H:17]1[NH:18][C:19](=[O:28])[CH2:20][O:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(COc1ccccc1)N[C@H]1C(=O)N[C@H]1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CC(O)C(=O)O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2NC(=O)[C@@H]2NC(=O)COc2ccccc2)cc1
Reaction time: 3 h

Procedure:
To a solution of 4.30 g (0.022 mole) of 98% p-toluenesulfonyl chloride in 24 ml of anhydrous pyridine at 0° (ice bath) was added 2.64 g (0.011 mole) of cis-2-hydroxymethyl-4-oxo-3-phenoxyacetylaminoazetidine in one portion. The solution was stirred at 0° for 3 hours then was stored at -25° overnight. After warming to 0°, 1.0 ml of 85% lactic acid was added and stirring was continued for 1 hour. The reaction mixture was poured into ethyl acetate and extracted successively with water, dilute aqueous hydrochloric acid, aqueous sodium bicarbonate and brine and was dried (MgSO4). Filtration followed by removal of the solvent in vacuo resulted in a yellow solid. Clarification of a hot solution of this material in ethyl acetate (375 ml), followed by the addition of hexane (200 ml) and recrystallization afforded cis-4-oxo-3-phenoxyacetylamino-2-p-toluenesulfonyloxymethyl-azetidine; tlc: ethyl acetate, silica gel GF, Rf = 0.47; mp 136°(dec.).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:28](=[O:29])[N:13]3[CH:14]([C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21])[C:15]([CH3:19])([CH3:18])[S:16](=[O:17])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:30]N1C(=O)CCC1=O>C1(C)C=CC=CC=1>[CH3:18][C:15](=[CH2:19])[CH:14]([N:13]1[C:28](=[O:29])[CH:11]([NH:10][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:12]1[S:16]([Cl:30])=[O:17])[C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC1(C)C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2S1=O
Solvent: Cc1ccccc1
Product: C=C(C)C(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)Cc2ccccc2)C1S(=O)Cl

Procedure:
A solution of 500 mg. of 2,2,2-trichloroethyl 6β-phenylacetamido-2,2-dimethylpenam-3-carboxylate-1-oxide and 134 mg. of N-chlorosuccinimide in 40 ml. of dry toluene was refluxed for 90 minutes. The mixture was cooled, washed with H2O and brine, dried over MgSO4, and the solvent was evaporated on a rotavapor. The title compound was recovered as a colorless foam.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20](/[CH:21]=[CH:22]\[CH2:23][CH:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)=[C:19]([O:37][CH3:38])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20](/[CH:21]=[CH:22]\[CH2:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[C:19]([O:37][CH3:38])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1/C=C\CC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc2c(c1/C=C\CC1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.5 %

Procedure:
A solution of tert-butyl 4-((Z)-3-{(Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}allyl)piperidine-1-carboxylate (0.0724 g, 0.140 mmol) in methylene chloride (2 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the precipitated solid was collected by filtration. The solid was washed with water, and then dried under reduced pressure to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-[(Z)-3-(piperidin-4-yl)prop-1-enyl]benzofuran-3(2H)-one (0.0253 g, 43%).
Reaction SMILES: N[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:28][CH2:29][CH2:30][OH:31])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:18][C:17]3=[O:32])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N([O-])=[O:34].[Na+].[OH-].[Na+]>OS(O)(=O)=O>[OH:31][CH2:30][CH2:29][CH2:28][C@@:19]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:18][C:17](=[O:32])[N:16]([C@H:14]([C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][C:2](=[O:34])[NH:7][CH:6]=3)=[CH:13][CH:12]=2)[CH3:15])[CH2:21][CH2:20]1
Reactant: C[C@@H](c1ccc(-c2ccc(N)nc2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: C[C@@H](c1ccc(-c2ccc(=O)[nH]c2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
(R)-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (40 mg, 0.09 mmol.) was dissolved in 3.5 M H2SO4 (10 mL), and 2 M NaNO2 (10 mL) was added at 0° C. The reaction mixture was stirred at rt for 2 h and treated with NaOH solution. The mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated to afford the residue, which was purified by preparative HPLC to give (R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (10 mg, 20%). LC-MS Method 2 tR=1.66, min, m/z=433, 455; 1H NMR (CDCl3): 1.36 (m, 2H), 1.50 (m, 3H), 1.68 (m, 2H), 1.92 (m, 2H), 2.10-2.30 (m, 3H), 2.84 (m, 1H), 3.50 (m, 2H), 5.12 (m, 1H), 6.62 (m, 1H), 6.86 (m, 2H), 7.08 (m, 2H), 7.18-7.32 (m, 5H), 7.46 (m, 1H), 7.62 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>[Pt].C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:11][CH:10]=[CH:9][CH:8]=2
Reactant: CCOC(=O)CCCNc1c([N+](=O)[O-])cnc2cccnc12
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCNc1c(N)cnc2cccnc12

Procedure:
A mixture of ethyl 4-(3-nitro[1,5]naphthyridin-4-ylamino)butanoate (5.0 g, 16 mmol), 5% platinum on carbon (0.50 g), and ethyl acetate (80 mL) was added to a Parr vessel, and the reaction was placed under hydrogen pressure (30 psi, 2.1×105 Pa) for 2.5 hours. The reaction mixture was filtered through a layer of CELITE filter agent, and the filter cake was washed with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure to provide ethyl 4-(3-amino[1,5]naphthyridin-4-ylamino)butanoate as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]=1[CH2:15][N:16]1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][C:4]=1[CH2:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1
Reactant: COc1cc(-c2ccccc2)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2ccccc2)ccc1CN1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl 4-[(2-methoxy-4-phenylphenyl)methyl]piperazine-1-carboxylate (850 mg, 2.22 mmol, 1.00 equiv), dichloromethane (15 mL), trifluoroacetic acid (1.50 mL). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure to provide 600 mg (crude) of 1-[(2-methoxy-4-phenylphenyl)methyl]piperazine as yellow oil. LCMS (ESI, m/z): 283 [M+H]+.
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[CH:15]2.[OH-].[NH4+]>C(O)(=O)C>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[C:6]1[CH2:5][CH2:4][NH:3][CH2:8][CH:7]=1
Reactant: O=C1CCNCC1
Reactant: COc1ccc2[nH]ccc2c1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2[nH]cc(C3=CCNCC3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
44 g of the hydrochloride of 4-piperidone monohydrate were added at 100° C. to a solution of 12.6 g of 5-methoxy-indole in 240 ml of acetic acid and the mixture was held at 100° C. for 30 minutes and was then cooled and poured into ice water containing 400 ml of concentrated ammonium hydroxide solution. The mixture was extracted with ethyl acetate and the organic phase was washed with aqueous sodium chloride solution, was dried over magnesium sulfate and was evaporated to dryness to obtain 20 g of raw product. The latter was chromatographed over silica gel and elution with a 7-2-1 chloroform-methanol-triethylamine mixture yielded 5.26 g of 5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole in the form of a resin.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:12]([O:14][C:15](=[O:25])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:25])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[F:11])[CH:19]=1)[CH3:13]
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Reactant: O=C(O)c1cc(Br)ccc1F
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2cc(Br)ccc2F)c1

Procedure:
5-Bromo-2-fluoro-benzoic acid (250 mg, 1.14 mmol) was coupled to aniline (60)(240 mg, 1.26 mmol) using Method D. The residue was purified by column chromatography eluting with a stepped gradient of 10-15% EtOAc in heptane to give the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([CH2:10][C:11]([CH3:13])=[CH2:12])[CH:4]=1)[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]2[O:9][C:11]([CH3:13])([CH3:12])[CH2:10][C:5]=2[CH:4]=1)[CH3:2]
Reactant: C=C(C)Cc1cc(CC)ccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCc1ccc2c(c1)CC(C)(C)O2

Procedure:
A solution of 4-ethyl-2-(2-methylallyl)phenol (812) (4 g, 22.7 mmol), p-toluenesulfonic acid monohydrate (400 mg, 2.10 mmol), and chloroform (120 mL) was stirred overnight at room temperature. The reaction was concentrated in vacuo, and purified by flash column chromatography on silica gel eluting with hexanes and ethyl acetate to give 5-ethyl-2,2-dimethyl-2,3-dihydrobenzofuran (813).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]O.NC(N)=S.Cl.C(=O)([O-])[O-].[K+].[K+].C[S:26]([C:29]1[CH2:33][C:32]([CH3:35])([CH3:34])[O:31][N:30]=1)(=O)=O>O.O1CCOCC1>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][S:26][C:29]1[CH2:33][C:32]([CH3:35])([CH3:34])[O:31][N:30]=1
Reactant: OCc1ccccc1OC(F)(F)F
Reactant: CC1(C)CC(S(C)(=O)=O)=NO1
Agent: Cl
Agent: NC(N)=S
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)CC(SCc2ccccc2OC(F)(F)F)=NO1
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 15.7 %

Procedure:
2-(Trifluoromethoxy)benzyl alcohol (200 mg, 1.04 mmol), thiourea (100 mg, 1.31 mmol), aqueous hydrochloric acid (2M) (1.6 ml) and 1,4-dioxane (3 ml) were mixed and the mixture heated in a sealed vessel in the microwave at 140° C. for 10 minutes. Potassium carbonate (620 mg, 4.5 mmol) and 3-methanesulfonyl-5,5-dimethyl-4,5-dihydroisoxazole (220 mg, 1.24 mmol) were added and the mixture was stirred in an open vessel for 10 minutes. The mixture was heated in a sealed vessel in the microwave at 150° C. for 10 minutes. The mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with water, dried over magnesium sulfate and concentrated. The crude material was purified by chromatography on silica gel (eluent: ethyl acetate/hexane) to give the product as a white solid (50 mg, 15% yield). 1H-NMR (400 MHz, CDCl3): 1.41 (6H, s, Me), 2.78 (2H, s, CH2), 4.32 (2H, s, CH2), 7.2-7.4 (2H, m, CH), 7.57 (1H, m, CH).