Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:5]1[CH:12]2[CH2:13][CH:9]3[CH2:10][CH:11]2[CH:7]([CH2:8]3)[O:6]1)(=O)C.[C:14]([OH:19])(=[O:18])[C:15]([CH3:17])=[CH2:16]>C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)C1C(O)=C(C(C)(C)C)C=C(C)C=1>[C:14]([O:19][CH:5]1[CH:12]2[CH2:13][CH:9]3[CH2:10][CH:11]2[CH:7]([CH2:8]3)[O:6]1)(=[O:18])[C:15]([CH3:17])=[CH2:16]
Reactant: CC(=O)OC1OC2CC3CC2C1C3
Reactant: C=C(C)C(=O)O
Agent: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Product: C=C(C)C(=O)OC1OC2CC3CC2C1C3
Temperature: 50 °C
Yield: 93 %

Procedure:
A mixture of 16 g of 4-oxatricyclo[4.2.1.03,7]non-5-yl acetate, 40 g of methacrylic acid, and 16 mg of 2,2′-methylenebis(6-t-butyl-p-cresol) was heated at 50° C. under atmospheric pressure for 30 minutes, after which under a reduced pressure of 0.20 kPa, the reaction mixture was heated for 18 hours for distilling off the acetic acid formed. The reaction mixture was purified by distillation, obtaining 17 g (yield 91%) of the target compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([OH:18])([CH2:14][CH2:15][CH:16]=[CH2:17])[C:10]([F:13])([F:12])[F:11].[C:19](N1C=CN=C1)(N1C=CN=C1)=[O:20].C1COCC1>CCOC(C)=O>[F:12][C:10]([C:9]1([CH2:14][CH2:15][CH:16]=[CH2:17])[C:3]2[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=2[NH:1][C:19](=[O:20])[O:18]1)([F:13])[F:11]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C=CCCC(O)(c1cc(Cl)ccc1N)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCCC1(C(F)(F)F)OC(=O)Nc2ccc(Cl)cc21
Temperature: 60 °C
Yield: 61.4 %

Procedure:
To a 200 mL round bottomed flask with a stirring bar, argon inlet and a reflux condenser was added (+/-) 2-(2-Amino-5-chlorophenyl)-1,1,1-trifluoro-5-hexen-2-ol (4.80 g, 17.16 mmol), 1,1'-carbonyldiimidazole (13.91 g, 85.81 mmol) and dry THF (75 mL). This mixture was heated at 60° C. for 18 h. The cooled reaction mixture was diluted with EtOAc and washed with H2O (3×200 mL) and brine (250 mL). Drying (MgSO4), filtration, removal of the solvent in vacuo, followed by recrystallization from boiling EtOAc-hexane gave 3.22 g of (+/-) 4-(1,1,1,-trifluoromethyl)-4(1-buten-4-yl)-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white crystalline solid, mp: 165°-166° C. 1H NMR (CDCl3): δ 1.99 (m, 1H), 2.09-2.40 (m, 3H), 5.00 (d, 1H, J=1.4 Hz), 5.03 (dd, 1H, J=1.4, 7.9), 5.78 (m, 1H), 6.85 (d, 1H, J=8.6 Hz), 7.21 (br s, 1H), 7.35 (dd, 1H, J=2.2, 8.6 Hz), 9.63 (br s, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[N+:18]([O-])=O.CN(C)C=O.[CH3:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][C:33]=1[CH3:34])[NH2:30]>>[NH2:18][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:9]=1[O:8][CH3:7])[C:13]([NH:30][C:29]1[CH:31]=[CH:32][C:33]([CH3:34])=[C:27]([CH3:26])[CH:28]=1)=[O:15]
Reactant: Cc1ccc(N)cc1C
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccc(C)c(C)c2)cc1N
Yield: 87.4 %

Procedure:
Prepared according to the procedure described for Example 1 using oxalyl chloride (3.0 mL, 34.4 mmol), 4-methoxy-3-nitrobenzoic acid (5.00 g, 25.36 mmol), dimethylformamide (1.0 mL, 12.92 mmol), and 3,4-dimethylaniline (6.2 g, 51 mmol) to afford the product (5.99 g), m.p. 138-142° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].I[CH2:18][CH3:19].C(OCC)(=O)C>CC(C)=O.CCCCCC>[CH2:18]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2)[CH3:19]
Reactant: CCI
Reactant: Oc1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CCOc1ccc2[nH]ncc2c1

Procedure:
A solution of 5-hydroxy-1H-indazole[0.5 g, Reference Example 38] in acetone (10 ml) was treated with potassium carbonate (2.56 g) then with iodoethane (0.296 ml). The mixture was refluxed for 4 hours then cooled and then evaporated. The residue was partitioned between ethyl acetate and water and the aqueous layer was further extracted twice with ethyl acetate. The combined organic fractions were dried over magnesium sulfate and then evaporated to yield a brown residue which was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (1:1, v/v) to give 5-ethoxy-1H-indazole (0.38 g) as an off-white solid. LC-MS (METHOD B): RT=2.68 minutes; 163 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]2[C:14]3[N:15]=[C:16]([NH:19][C:20]4[CH:21]=[C:22]([CH2:26][CH2:27]OS(C)(=O)=O)[CH:23]=[CH:24][CH:25]=4)[N:17]=[CH:18][C:13]=3[CH:12]([CH3:33])[N:11]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[C:10]2=[O:42])[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH3:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>C(OCC)(=O)C>[CH3:41][O:40][C:37]1[CH:36]=[CH:35][C:34]([N:11]2[CH:12]([CH3:33])[C:13]3[C:14](=[N:15][C:16]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH2:27][N:47]5[CH2:48][CH2:49][N:44]([CH3:43])[CH2:45][CH2:46]5)[CH:21]=4)=[N:17][CH:18]=3)[N:9]([C:5]3[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=3)[C:1]#[N:2])[C:10]2=[O:42])=[CH:39][CH:38]=1
Reactant: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Nc4cccc(CCOS(C)(=O)=O)c4)ncc3C2C)cc1
Reactant: CN1CCNCC1
Solvent: CCOC(C)=O
Product: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Nc4cccc(CCN5CCN(C)CC5)c4)ncc3C2C)cc1
Temperature: 110 °C

Procedure:
A mixture of (±)-methanesulfonic acid (2-{3-[8-(3-cyano-phenyl)-6-(4-methoxy-phenyl)-5-methyl-7-oxo-5,6,7,8-tetrahydro-pyrimido[4,5-d]pyrimidin-2-ylamino]-phenyl}-ethyl)-ester (0.10 g; 0.16 mmol) (from Example 5a supra) and 1-methylpiperazine (0.25 mL; 2.23 mmol) (Aldrich) and heated at 110° C. for 1 hour. Upon cooling, the mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography (Biotage 12S; 100:0 to 40:60 ethyl acetate-methanol gradient) and then crystallized from ethyl acetate-hexanes to give (±)-3-(3-(4-methoxy-phenyl)-4-methyl-7-{3-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenylamino}-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl)-benzonitrile. (Yield 60.6 mg; 64.1%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8]C(=O)OC(C)(C)C)=[C:4]([C:16]#[C:17][CH:18]2[CH2:21][CH2:20][CH2:19]2)[CH:3]=1.CC([O-])(C)C.[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:16]=[C:17]([CH:18]3[CH2:21][CH2:20][CH2:19]3)[NH:8][C:5]2=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1C#CC1CCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cc2cc(C3CCC3)[nH]c2cn1
Temperature: 90 °C
Reaction time: 2 h
Yield: 51.2 %

Procedure:
To the solution of tert-butyl 6-chloro-4-(cyclobutylethynyl)pyridin-3-ylcarbamate (2.6 g, 8.5 mmol) in DMF (50 mL) was added t-BuOK (1.9 g, 16 mmol). The reaction mixture was stirred at 90° C. for 2 h. The mixture was diluted with water and extracted with dichloromethane (3×50 mL). The extract was washed with brine, dried, concentrated in vacuo and purified by chromatography on silica gel (5-10% ethyl acetate in petroleum ether as eluant) to afford the pure product of 5-chloro-2-cyclobutyl-1H-pyrrolo[2,3-c]pyridine (0.9 g, 53% yield). 1H NMR (300 MHz, CDCl3) δ: 8.66 (br, s, 1H), 8.45 (s, 1H), 7.44 (s 1H), 6.27 (s, 1H), 3.75-3.52 (m, 1H), 2.52-1.90 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[CH:16](N)=[NH:17]>C(O)C>[I:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:16][NH:17][C:4]2=[O:5]
Reactant: N=CN
Reactant: Nc1ccc(I)cc1C(=O)O
Solvent: CC(=O)O
Solvent: CCO
Product: O=c1[nH]cnc2ccc(I)cc12
Temperature: 0 °C
Yield: 80.9 %

Procedure:
A solution of 2-amino-5-iodobenzoic acid (26.3 g, 100 mmol) and formamidine acetate (13.5 g, 130 mmol) in ethanol (400 mL) was refluxed for 20 hours. After cooling to 0° C., the solid product was collected by filtration. Further drylng in vacuo provided 6-iodo-4-quinazolinone (22.0 g, 81%) as a grey crystalline solid. 1H NMR (400 MHz; DMSO-d6) δ: 12.38 (br. s, 1H), 8.35 (d, 1H), 8.05-8.10 (m, 2H), 7.43 (dd, 1H). LRMS: 272.9 (MH+).
Reaction SMILES: [N:1]1([CH2:5][CH2:6][CH2:7][N:8]2[C:16]([O:17][CH3:18])=[N:15][C:14]3[C:9]2=[N:10][C:11]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[N:12][C:13]=3[NH2:19])[CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[CH2:32](OC1NC(N)=C2C(N=1)=NC(OC)=N2)[CH2:33][CH2:34]C.BrCCCBr.N1CCCCCC1>>[CH2:21]([O:20][C:11]1[N:10]=[C:9]2[C:14]([N:15]=[C:16]([O:17][CH3:18])[N:8]2[CH2:7][CH2:6][CH2:5][N:1]2[CH2:4][CH2:3][CH2:34][CH2:33][CH2:32][CH2:2]2)=[C:13]([NH2:19])[N:12]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCN3CCC3)c2n1
Agent: BrCCCBr
Agent: C1CCCNCC1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCN3CCCCCC3)c2n1

Procedure:
Prepared similarly to Intermediate 20 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate, 1,3-dibromopropane and hexahydro-1H-azepine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[S:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([S-:20])=[S:19])[CH2:14][CH2:13]1.[Na+].[CH3:22]I>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[S:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([S:20][CH3:22])=[S:19])[CH2:14][CH2:13]1
Reactant: CI
Reactant: S=C([S-])N1CCC(Sc2c[nH]c3ccc(Br)cc23)CC1
Agent: [Na+]
Solvent: CCO
Product: CSC(=S)N1CCC(Sc2c[nH]c3ccc(Br)cc23)CC1

Procedure:
A solution of sodium 4-[(5-bromo-1H-indol-3-yl)thio]piperidine-1-carbodithioate (3 g, prepared in the previous Example) and methyl iodide (0.5 ml) in 95% ethanol (15 ml) is refluxed for one hour. The orange reaction mixture is concentrated, taken up with ether and washed with water. The organic phase is dried over sodium sulfate and concentrated. After chromatography on silica gel (eluent: cyclohexane/AcOEt 70/30), methyl 4-[(5-bromo-1H-indol-3-yl)thio]piperidine-1-carbodithioate (13 g) is obtained in the form of an oil, which is taken up with pentene to give a white solid.
Reaction SMILES: O(P(O[C:18]1[CH2:19][C@@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[SH:42][C@@H:43]1[CH2:47][N:46]([C:48]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=2)=[O:49])[C@H:45]([CH:61]2[CH2:65][CH2:64][N:63]([C:66]([O:68][CH2:69][C:70]3[CH:75]=[CH:74][C:73]([N+:76]([O-:78])=[O:77])=[CH:72][CH:71]=3)=[O:67])[CH2:62]2)[CH2:44]1>>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[C:18]([S:42][C@@H:43]3[CH2:47][N:46]([C:48]([O:50][CH2:51][C:52]4[CH:53]=[CH:54][C:55]([N+:58]([O-:60])=[O:59])=[CH:56][CH:57]=4)=[O:49])[C@H:45]([CH:61]4[CH2:65][CH2:64][N:63]([C:66]([O:68][CH2:69][C:70]5[CH:71]=[CH:72][C:73]([N+:76]([O-:78])=[O:77])=[CH:74][CH:75]=5)=[O:67])[CH2:62]4)[CH2:44]3)[CH2:19][C@H:20]12)[CH3:39]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)C[C@H]12
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC([C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)C[C@H]12
Yield: 76.7 %

Procedure:
The same procedure as in Example 1-1 was carried out by using p-nitrobenzyl (5R,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (255 mg, 0.45 mmol) and (2S,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-[N-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-yl]pyrrolidine (240 mg, 0.45 mmol, compound of Reference Example 5) to obtain p-nitrobenzyl (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[(2S,4S)-N-(p-nitrobenzyloxycarbonyl)-2-[N-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-yl]pyrrolidin-4ylthio]-1-carbapen-2-em-3-carboxylate (297 mg, yield: 78.6%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH:17]=O)=[C:12]3[C:16]=2[O:15][CH:14]=[CH:13]3)=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21].CO.N1C=CC=CC=1>CCOCC>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH:17]=[N:20][OH:21])=[C:12]3[C:16]=2[O:15][CH:14]=[CH:13]3)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(-c2ccc(O)cc2)c2occc12
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: CCOCC
Product: ON=Cc1ccc(-c2ccc(O)cc2)c2occc12
Temperature: 68 °C

Procedure:
To a 15 ml round bottom flask was added 7-(4-hydroxyphenyl)-benzofuran-4-carbaldehyde (250 mg, 1.05 mmol), hydroxylamine hydrochloride (146 mg, 2.10 mmol), anhydrous MeOH (6.5 ml), and anhydrous pyridine (0.17 ml, 2.10 mmol). The flask was then sealed and heated to 68° C. for 1 h, cooled to room temperature, dilute with ether, and the layers separated. The ether layer was washed with water, dried over anhydrous Na2SO4, passed through a silica plug, and concentrated to 250 mg (94%) clean product as a yellow solid. Further purification was done by chromatography (1:1 EtOAc/hexanes) for analytical analysis: mp 216–217° C.; 1H NMR (300 MHz, DMSO-d6): δ 6.92 (2H, d, J=8.7 Hz), 7.36 (1H, d, J=2.1 Hz), 7.49 (2H, app s), 7.74 (2H, d, J=8.6 Hz), 8.14 (1H, d, J=2.1 Hz), 8.42 (1H, s), 9.73 (1H, s) 11.36 (1H, s); MS (ESI) m/z 254 ([M+H]+).
Reaction SMILES: [CH2:1]([CH:3]([O:6][CH2:7][C:8]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12][C:13]2=[O:19])[CH2:4][CH3:5])[CH3:2].[N:20]1([CH2:25][C@@H:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)O)[CH:24]=[CH:23][N:22]=[CH:21]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N+](C(OCC)=O)(C(OCC)=O)=[N-]>O1CCCC1>[CH2:1]([CH:3]([O:6][CH2:7][C:8]1[C:17]([O:18][C@@H:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:25][N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12][C:13]2=[O:19])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)OCc1c(O)ccc2c1CCCC2=O
Reactant: O[C@@H](Cn1ccnc1)c1ccccc1
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(CC)OCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 60.6 %

Procedure:
According to step 2 in the method of example 19, 5-(1-Ethyl-propoxymethyl)-6-hydroxy-3,4-dihydro-2H-naphthalen-1-one (0.123 g, 0.53 mmol), (R)-2-Imidazol-1-yl-1-phenyl-ethanol (0.131 g, 0.7 mmol), triphenylphosphine resin (0.620 g, loading 1.24 mmol/g, Argonaut Technologies), diethyl diazodicarboxylate (0.121 ml, 0.77 mmol, Aldrich Chemical) and freshly distilled tetrahydrofuran (5 ml, Aldrich Chemical) were combined in a 2 dram screw topped vial with a teflon lined cap. After mixing on an inverting mixer at 25° C. for 16 hrs., the resin was removed by gravity filtration and mixture concentrated in vacuo to a yellow-brown syrup. The residue was dissolved in methanol (5 ml) and macroporous polystyrene sulfonic acid resin (0.583 g, loading 1.5 mmol/g, Argonaut Technologies) added. After mixing for 2 hrs. at 25° C., the resin was collected by gravity filtration, washed with methanol (2×5 ml). Elution of product from the resin with 2.0 M ammonia in methanol (5 ml, Aldrich) and concentration in vacuo yielded 139 mg brown glass compound. Low resolution mass spectroscopy m/z (APCI) 433 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([C:21]3[NH:29][C:28]4[CH:27]([CH3:30])[CH2:26][NH:25][C:24](=[O:31])[C:23]=4[CH:22]=3)[CH:15]=[CH:16][CH:17]=2)[N:12]=1.C(O)(C(F)(F)F)=O>CN(C=O)C.CS(C)=O>[CH3:30][CH:27]1[CH2:26][NH:25][C:24](=[O:31])[C:23]2[CH:22]=[C:21]([C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:13]=3[N:12]=[C:11]([O:9][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:20]=[CH:19]4)[NH:29][C:28]1=2
Reactant: Oc1ccccc1
Reactant: CC1CNC(=O)c2cc(-c3cccc4ccc(Cl)nc34)[nH]c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CC1CNC(=O)c2cc(-c3cccc4ccc(Oc5ccccc5)nc34)[nH]c21
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 63.3 %

Procedure:
To a slurry of NaH (60% in mineral oil; 0.036 g, 0.898 mmol) in 0.5 mL DMF was added phenol (0.085 g, 0.898 mmol). After 10 min, 2-(2-chloroquinolin-8-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 27; 0.040 g, 0.128 mmol) was added and the reaction was heated to 80° C. for 2 h. The reaction was cooled, treated with DMSO and TFA (0.069 ml, 0.898 mmol), filtered, and purified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 15-100% ACN/H2O with 0.1% TFA); product-containing fraction was treated with saturated aq. NaHCO3 and DCM. The organic layer was separated, and the aq. layer was extracted 3×DCM. The combined organic layers were then dried over Na2SO4, filtered, and concentrated in vacuo to give rac-7-methyl-2-(2-phenoxyquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.030 g, 0.081 mmol, 63% yield) as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.10 (1H, br. s), 8.50 (1H, d, J=9.0 Hz), 8.13 (1H, dt, J=7.5, 0.7 Hz), 7.80 (1H, dt, J=7.9, 0.7 Hz), 7.55-7.65 (2H, m), 7.49 (1H, t, J=7.7 Hz), 7.33-7.45 (4H, m), 6.83-6.99 (2H, m), 3.44 (1H, ddt, J=12.3, 5.6, 0.6, 0.6 Hz), 2.92-3.06 (1H, m), 2.55-2.60 (1H, m), 0.90 (3H, d, J=6.8 Hz). m/z (ESI, +ve) 370.1 (M+H)+.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][CH:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:22]([OH:25])[CH2:23][N:24]=2)=[CH:15][CH:14]=1)[CH3:11]>ClCCCl>[CH2:10]([O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[O:20][CH:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:22]([O:25][C:8](=[O:9])[NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:23][N:24]=2)=[CH:17][CH:18]=1)[CH3:11]
Reactant: CCOc1ccc(C2=NCC(O)C(c3ccccc3)O2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCCl
Product: CCOc1ccc(C2=NCC(OC(=O)Nc3ccccc3)C(c3ccccc3)O2)cc1
Temperature: 80 °C
Yield: 31.2 %

Procedure:
Phenyl isocyanate (0.38 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (5RS, 6SR)-2-(4-ethoxyphenyl)-6-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (0.8 g) in 1,2-dichloroethane (10 cc). The solution obtained is heated to 80° C. for 3 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is purified by chromatography on silica (0.063-0.2 mm; 100 g), contained in a column 2 cm in diameter, collecting 20-cc fractions. Fractions 3 and 4, eluted with a mixture of cyclohexane and ethyl acetate (6:4 by volume), are concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The solid obtained is then purified again by chromatography on silica (0.063-0.2 mm; 100 g), contained in a column 2 cm in diameter, collecting 20-cc fractions. Fractions 5 to 10, eluted with a mixture of cyclohexane, ethyl acetate and triethylamine (65:30:5 by volume), are concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in ethyl acetate, (5RS, 6SR)-2-(4-ethoxyphenyl)-6-phenyl-5-phenylcarbamoyloxy-5,6-dihydro-4H-1,3-oxazine (0.35 g), m.p. 80° C., is obtained.
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[CH3:12][C:13]1[CH:17]=[CH:16][NH:15][N:14]=1.[N+]([O-])(OC(=O)C)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.ClC(Cl)=C(Cl)Cl>[CH3:12][C:13]1[CH:17]=[C:16]([N+:8]([O-:11])=[O:9])[NH:15][N:14]=1
Reactant: Cc1cc[nH]n1
Reactant: O=[N+]([O-])O
Agent: CC(=O)O[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: ClC(Cl)=C(Cl)Cl
Product: Cc1cc([N+](=O)[O-])[nH]n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Acetic anhydride (96.2 mL, 104.58 g, 1.02 mol) was cooled to −15° C. with an ice/NaCl bath and to this was dropwise, very slowly, added red fuming HNO3 (40.7 mL, 61.8 g, 0.98 mmol). The reaction is strongly exothermic and care must be taken to keep the temperature below 0° C. (inside temperature). This solution was then rapidly transferred with a teflon tube of sufficient diameter (to prevent warming on transfer) to an addition funnel with a cooling mantle. This solution was kept <0° C. at all times and the addition funnel mounted on a flask containing methylpyrazole (35 g, 0.427 mol) in glacial acetic acid (40 mL) at −5° C. The chilled (−15° C.) acetyl nitrate solution was then dropwise added to the methylpyrazole 8 solution at 0° C. The reaction was highly exothermic until ca. 1 eq. acetyl nitrate had been added and it must not be allowed to warm above 5° C. After 3 hours stirring at 0° C. the mixture was poured into ice/water (500 mL) and neutralized to ca. pH 7 with sodium carbonate. Extraction with DCM (3×200 mL), drying (sodium sulfate) and evaporation in vacuo afforded a 90:10 mixture of N-nitro intermediates (42.8 g, 0.337 mol, 79%), which was dissolved in perchloroethylene (4 L), heated at 140° C. ext. temperature for 18 hours and for 5 hours at 165° C. Evaporation of the solvent and drying in vacuo gave pure 9 (39.0 g, 0.307 mol, 72% both steps).
Reaction SMILES: O=S(Cl)Cl.[NH2:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:17]O>>[CH3:17][O:15][C:14](=[O:16])[C@H:6]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:5]
Reactant: CO
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H](N)Cc1ccccc1
Yield: 88.3 %

Procedure:
6.61 mL of SOCl2 and 40 mL of methanol were thoroughly mixed in an ice bath for 30 minutes, followed by mixing with 10 g of L-phenylalanine. The mixture was subjected to a reflux reaction at 70° C. for 24 hours, followed by evaporating, re-crystallizing in ether, filtering and drying to obtain a product of 11.5 g (88.3%) of L-phenylalanine methyl ester 2. The analytic data of the product are as follows: 1H-NMR (D2O, 400 MHz), δ(ppm): 7.36-7.20 (m, 5H, Ar), 4.36-4.34 (t, 1H, J=6, H2NHCH), 3.75 (s, 3H, OCH3), 3.30-3.12 (m, 2H, CH2Ar); 13C-NMR (D2O, 100 MHz), δ(ppm): 170.2, 133.9, 129.5, 129.4, 129.3, 128.3, 128.1, 54.2, 53.7, 35.7; ESI-MS (m/z): calcd. 179.22, found 180.13 [M+H]+; Anal. Calcd (Found) for C10H13NO2.HCl: C, 55.69 (55.32); H, 6.45 (6.54); N, 6.49 (6.35).
Reaction SMILES: C([NH:4][C:5]1[C:6]([N+:20]([O-:22])=[O:21])=[C:7]2[C:11](=[CH:12][C:13]=1[Br:14])[CH:10](CCC(O)=O)[CH2:9][CH2:8]2)(=O)C.[C:23]([OH:26])(=[O:25])C>Cl>[NH2:4][C:5]1[C:6]([N+:20]([O-:22])=[O:21])=[C:7]2[C:11](=[CH:12][C:13]=1[Br:14])[CH2:10][CH:9]([C:23]([OH:26])=[O:25])[CH2:8]2
Reactant: CC(=O)Nc1c(Br)cc2c(c1[N+](=O)[O-])CCC2CCC(=O)O
Reactant: CC(=O)O
Agent: Cl
Product: Nc1c(Br)cc2c(c1[N+](=O)[O-])CC(C(=O)O)C2
Temperature: 100 °C

Procedure:
A mixture of 5-acetamido-6-bromo-2-carboxyethyl-4-nitroindane (7.1 g, 19 mmol) in acetic acid (25 mL) and 3N HCl (100 mL) was heated at 100° C. for 18 h. The mixture was concentrated by rotoevaporation, and the resulting orange solid was collected by filtration, washed with ether and dried to give the product (5.5 g).
Reaction SMILES: Cl[CH2:2][CH:3]=O.C(=O)(O)[O-].[Na+].[NH2:10][C:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][N:12]=1>[Na+].[Cl-]>[N:10]1[CH:14]=[CH:13][N:12]2[CH:3]=[CH:2][CH:15]=[C:16]([NH2:17])[C:11]=12
Reactant: O=CCCl
Reactant: Nc1cccnc1N
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Product: Nc1cccn2ccnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
To a solution of 50% aqueous chloroacetaldehyde (4.14 mL, 32.6 mmol) were added sodium bicarbonate (3.19 g, 40.0 mmol) and 2,3-diaminopyridine (3.56 g, 32.6 mmol). The reaction mixture was stirred at rt overnight, then diluted with saturated aqueous NaCl (100 mL) and extracted with n-butanol (3×200 mL). The organic layers were combined, dried (MgSO4), and concentrated. The crude residue was purified (FCC, 2 N NH3 in MeOH/DCM) to give imidazo[1,2-a]pyridin-8-ylamine (2.18 g, 51%). MS (ESI+): calcd for C7H7N3 m/z 133.06, found 134.1 (M+H)+. 1H NMR (d6-DMSO): 7.79-7.75 (m, 2H), 7.40 (d, J=1.1, 1H), 6.60 (s, 1H), 6.21 (dd, J=7.3, 1.1, 1H), 5.53 (br s, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(OCCO)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:18][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:7]=1
Reactant: NC1CCCCC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Solvent: CCOCCO
Product: O=[N+]([O-])c1ccc(Cl)cc1NC1CCCCC1

Procedure:
A mixture consisting of 19.4 g of 2,4-dichloro-1-nitrobenzene, 40 g of cyclohexylamine and 100 ml of 2-ethoxyethanol is maintained at reflux for 12 hours.