Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[CH3:23].CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]([CH2:38][NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH:35]=[CH:36][CH:37]=2)O1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.O.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>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([CH3:23])=[C:2]([C:32]4[CH:33]=[C:34]([CH2:38][NH:39][C:40](=[O:46])[O:41][C:42]([CH3:44])([CH3:43])[CH3:45])[CH:35]=[CH:36][CH:37]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(C)sc2n1
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: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3cccc(CNC(=O)OC(C)(C)C)c3)c(C)sc2n1
Temperature: 100 °C
Yield: 47.3 %

Procedure:
Under nitrogen, N-(3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 61) (85 mg, 0.197 mmol) was dissolved in 1,4-dioxane (1.5 mL) and water (0.5 mL). 1,1-Dimethylethyl {[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}carbamate (98 mg, 0.295 mmol), tetrakis(triphenylphosphine)palladium(0) (22.75 mg, 0.020 mmol) and potassium carbonate (54.4 mg, 0.394 mmol) were added and the mixture heated in a microwave at 100° C. for 10 min (×2). Ethyl acetate (10 mL) was then added and the mixture washed with water (2×5 mL). The organic layer was then dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by normal phase chromatography, eluting with a gradient of 0-30% ethyl acetate in cyclohexane and then further purified by normal phase chromatography, eluting with ethyl acetate and cyclohexane (0-30%), to give the title compound (52 mg). LCMS (A) m/z: 558 [M+1]+, Rt 1.47 min (acidic).
Reaction SMILES: [ClH:1].Cl.[NH:3]1[CH:7]=[C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[C:17]([N+:20]([O-])=O)[CH:18]=[CH:19][C:14]=3[CH2:13][N:12]([C:23]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)=[O:24])[CH2:11][CH2:10]2)[N:5]=[CH:4]1.[OH-].[Na+].C([O-])(O)=O.[Na+].Cl.Cl.Cl.N1C=C(CN2C3C=C(NC(=O)C)C=CC=3CN(C(C3C4C(=CC=CC=4)C=CC=3)=O)CC2)N=C1>CC(O)=O.O.CCOCC>[ClH:1].[ClH:1].[NH:3]1[CH:7]=[C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[C:17]([NH2:20])[CH:18]=[CH:19][C:14]=3[CH2:13][N:12]([C:23]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)=[O:24])[CH2:11][CH2:10]2)[N:5]=[CH:4]1
Reactant: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2cc([N+](=O)[O-])ccc2C1
Agent: CC(=O)Nc1ccc2c(c1)N(Cc1c[nH]cn1)CCN(C(=O)c1cccc3ccccc13)C2
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc2c(c1)N(Cc1c[nH]cn1)CCN(C(=O)c1cccc3ccccc13)C2
Reaction time: 0.25 h

Procedure:
16% aqueous TiCl3 (2 mL) was added to a solution of Example 25 (0.10 g, 0.23 mmol) in AcOH/H2O (2 mL, 1:1). After stirring for 15 min, the reaction was made basic with 1N NaOH and NaHCO3 and stirred for 30 min. The layers were separated and the aqueous layer was reextracted with CHCl3 /CH3OH (9/1). The combined organic layers were dried over MgSO4, filtered and concentrated to afford 0.92 g. (73%) of Example 26. A 20 mg. sample of this material was treated with 1M HCl in ether (2 mL). A light yellow solid was formed which was triturated several times with ether and dried under vacuum to afford Example 26 (23 mg.) as a light yellow solid. (Example 26 is also Compound G of Example 22.)
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][C:6]=2[CH:17]=1.[CH3:18][S:19]SC.C(OCC)(=O)C.O>C(#N)C>[CH3:18][S:19][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][C:6]=2[CH:17]=1
Reactant: CCOC(=O)C1=Cc2cc(N)ccc2OCC1
Reactant: CSSC
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C1=Cc2cc(SC)ccc2OCC1
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
The mixture of ethyl 2,3-dihydro-7-amino-1-benzoxepin-4-carboxylate (2.0 g), dimethyl disulfide (2.3 ml) and t-butylnitrile (1.2 ml) in acetonitrile (4 ml) was stirred at 50° C. for 2.5 hours. The mixture was poured into a mixture of ethyl acetate and water. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of hexane and toluene (1:1) as an eluent. The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl 2,3-dihydro-7-methylthio-1-benzoxepin-4-carboxylate (1.24 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[O:13][C:14]3[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:15]=3[N:16]=2)[C:5]([NH:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:7]=1.[CH:22]1[C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]2[C:31]([O:33][C:34](=O)[C:24]=2[CH:23]=1)=[O:32]>>[CH3:21][C:19]1[CH:18]=[CH:17][C:15]2[N:16]=[C:12]([C:4]3[CH:3]=[C:2]([N:1]4[C:31](=[O:32])[C:25]5[C:24](=[CH:23][CH:22]=[C:27]([C:28]([OH:30])=[O:29])[CH:26]=5)[C:34]4=[O:33])[CH:7]=[CH:6][C:5]=3[NH:8][CH2:9][CH2:10][CH3:11])[O:13][C:14]=2[CH:20]=1
Reactant: CCCNc1ccc(N)cc1-c1nc2ccc(C)cc2o1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: CCCNc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2ccc(C)cc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-propylaminophenyl)-6-methylbenzoxazole (100 mg, 0.33 mmol) and 1,2,4-benzenetricarboxylic anhydride (73 mg, 0.38 mmol) the title compound was obtained (87 mg, 58%). 1H NMR (DMSO) δ 8.47–8.40(m, 2H), 8.30(s, 1H), 8.08–8.06(m, 2H), 7.68(d, 1H), 7.56(s, 1H), 7.44(dd, 1H), 7.23(d, 1H), 7.01(d, 1H), 3.34(m, 2H), 2.46(s, 3H), 1.74(m, 2H), 1.05(t, 3H). MS 454.1 m/z (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([C:41]#[N:42])[CH:36]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([C:41]#[N:42])[CH:36]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(C#N)c2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(C#N)c2)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-[3-(2-cyano-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K24) (242 mg, 0.75 mmol) according to the general procedure M. Obtained as an orange foam (314 mg, 80%).
Reaction SMILES: C(SC1C=C(O)C(=O)NC=1)C1C=CC=CC=1.COC[O:20][C:21]1[C:22](=[O:38])[N:23](COC)[CH:24]=[C:25]([S:27][CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH:26]=1>>[OH:20][C:21]1[C:22](=[O:38])[NH:23][CH:24]=[C:25]([S:27][CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH:26]=1
Reactant: COCOc1cc(SCc2cccnc2)cn(COC)c1=O
Agent: O=c1[nH]cc(SCc2ccccc2)cc1O
Product: O=c1[nH]cc(SCc2cccnc2)cc1O

Procedure:
Prepared as described for 5-(benzylsulfanyl)-3-hydroxypyridin-2(1H)-one (Example 12) from 3-(methoxymethoxy)-1-(methoxymethyl)-5-[(pyridin-3-ylmethyl)sulfanyl]pyridin-2(1H)-one (Intermediate 27).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[NH:12][C:11]2=[NH:19])=[CH:4][CH:3]=1.[Cl:22][C:23]1[S:24][CH:25]=[C:26]([CH2:28]Cl)[N:27]=1.[Br-].[K+]>CC(=O)CC>[Cl:22][C:23]1[S:24][CH:25]=[C:26]([CH2:28][N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:10]([CH2:9][CH2:8][CH2:7][O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:21][CH:20]=3)[C:11]2=[NH:19])[N:27]=1
Reactant: N=c1[nH]c2ccccc2n1CCCOc1ccc(F)cc1
Reactant: ClCc1csc(Cl)n1
Agent: [Br-]
Agent: [K+]
Solvent: CCC(C)=O
Product: N=c1n(CCCOc2ccc(F)cc2)c2ccccc2n1Cc1csc(Cl)n1
Temperature: 95 °C
Reaction time: 22 h
Yield: 61 %

Procedure:
To a solution of 1-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine (2.89 g, 10.1 mmol) in 2-butanone (58 ml) at rt was added 2-chloro-4-chloromethyl-thiazole (2.55 g, 15.2 mmol) followed by potassium bromide (1.20 g, 10.1 mmol). The reaction mixture was heated to 95° C. where it was maintained for 32 h. After this time, the reaction was cooled to rt and additional potassium bromide (0.30 g, 2.52 mmol) was introduced. The reaction was stirred for a further 22 h at 90° C. and then it was cooled to rt and filtered. The collected solid was partitioned between dichloromethane and a saturated solution of NaHCO3 (50 ml) and the organic layer was separated. The aqueous phase was extracted with additional dichloromethane (×1) and the combined organic fractions were washed with H2O, brine, dried (Na2SO4), filtered and concentrated under reduced pressure to give 1-(2-chloro-thiazol-4-ylmethyl)-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine as a brown oil (2.57 g, 61%). HPLC-MS 417 [M+1]+.
Reaction SMILES: [NH:1]1[CH:5]([C:6]([OH:8])=[O:7])[CH2:4][CH:3]=[N:2]1.CCN(C(C)C)C(C)C.[CH:18]1([CH2:23][C@@H:24]([C:33](F)=[O:34])[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1.C(O)(=O)C.[Cl-].[NH4+]>ClCCl>[CH:18]1([CH2:23][C@H:24]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:33]([N:1]2[CH:5]([C:6]([OH:8])=[O:7])[CH2:4][CH:3]=[N:2]2)=[O:34])[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: O=C(O)C1CC=NN1
Reactant: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.4 %

Procedure:
To a solution of 4,5-dihydro-1H-pyrazole-5-carboxylic acid (1.44 g, 8.8 mmol) in dichloromethane (DCM) (62 ml) at 0° C. was added Hunig's base (9.25 ml, 53.0 mmol) followed by 1,1-dimethylethyl (3R)-3-(cyclopentylmethyl)-4-fluoro-4-oxobutanoate (3.8 g, 8.8 mmol) in 10 mL DCM. The resulting mixture was allowed to warm to room temperature and stirred for 4 hours. The mixture was then cooled to 0° C. and acetic acid (2.5 ml, 44.1 mmol) was added, followed by sat. aq ammonium chloride (15 mL). The phases were separated and the aqueous phase was extracted once with DCM (20 mL). The combined organics were washed with brine (15 mL), dried over sodium sulfate, and concentrated to yield a yellow oil. This crude product was purified by Combiflash automated silica gel chromatography (0-100% EtOAc in hex) to afford 1-{(2R)-2-(cyclopentylmethyl)-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoyl}-4,5-dihydro-1H-pyrazole-5-carboxylic acid (1.78 g, 5.05 mmol, 57% yield) as a clear oil. MS: 353 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[OH:9].C([O-])([O-])=O.[K+].[K+].[CH2:16](I)[CH3:17]>CN(C=O)C.CCOCC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:9][CH2:16][CH3:17])[CH:4]=1
Reactant: CCI
Reactant: Oc1cc(Br)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOc1cc(Br)ccc1Cl
Temperature: 55 °C
Yield: 99 %

Procedure:
To a solution of 2-chloro-5-bromophenol (WO98/003464 which is incorporated herein by reference, 3.43 g, 16.5 mmol) and K2CO3 (4.57 g, 33.0 mmol) in DMF (20 mL) was added ethyl iodide (1.78 mL, 22.3 mmol) at rt. The mixture was heated at 55° C. for 3.0 h. After cooling to rt, the reaction was diluted with ether, washed with water and brine, and dried over MgSO4. The crude residue was purified by flash column chromatography to give 3.85 g (99%) of 31A as viscous oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (t, J=7.03 Hz, 3H) 4.08 (d, J=7.03 Hz, 2H) 7.03 (m, 2H) 7.22 (d, J=6.15 Hz, 2H).
Reaction SMILES: [O:1]=[S:2]1(=[O:32])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:31])[N:14]([N:23]=[C:24]3[CH2:29][CH2:28][CH2:27][C@@H:26]([CH3:30])[CH2:25]3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:32]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:31])[N:14]([NH:23][CH:24]3[CH2:29][CH2:28][CH2:27][C@@H:26]([CH3:30])[CH2:25]3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1
Reactant: C[C@@H]1CCCC(=Nn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3ccccc32)C1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H]1CCCC(Nn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3ccccc32)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 239A (0.045 g, 0.10 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.010 mL, 0.28 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.075 mL, 0.15 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of approximately 2-4, diluted with water, and the resulting precipitate was collected by filtration and dried to give the title compound. The crude product was chromatographed on silica gel with dichloromethane to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.83 (m, 3 H) 1.22 (m, 3 H) 1.73 (m, 3 H) 2.99 (m, 1 H) 5.67 (d, J=4.04 Hz, 1 H) 7.04 (t, J=6.99 Hz, 1 H) 7.28 (t, J=8.27 Hz, 2 H) 7.53 (m, 2 H) 7.66 (d, J=7.72 Hz, 1 H) 7.74 (d, J=8.09 Hz, 1 H) 8.06 (m, 1 H). MS (ESI−) m/z 451 (M−H)−.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[NH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[CH2:11][CH2:10][CH2:9]2.C(=O)([O-])[O-].[K+].[K+]>Cl>[NH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[NH:1][CH2:11][CH2:10][CH2:9][C:8]=2[CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc2c(c1)CCCC2=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Nc1ccc2c(c1)CCCNC2=O
Temperature: 40 °C
Reaction time: 15 h
Yield: 50.3 %

Procedure:
With cooling with ice, 890 mg of sodium azide was added to a concentrated hydrochloric acid (30 mL) solution of 2 g of 6-amino-1,2,3,4-tetrahydronaphthalen-1-one, and stirred at 40° C. for 15 hours. The reaction liquid was poured into ice water, and neutralized with potassium carbonate. This was extracted with chloroform, and the organic layer was washed with saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the crude product was purified through basic silica gel column chromatography (chloroform/methanol) to obtain 1.1 g of the entitled compound as a colorless solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]1.[OH-].[Na+].Cl[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:12]([Cl:19])[N:11]=1>C1COCC1>[Cl:19][C:12]1[N:11]=[C:10]([O:6][C@H:3]2[CH2:4][CH2:5][O:1][CH2:2]2)[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=1
Reactant: O[C@H]1CCOC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Cl)nc1O[C@H]1CCOC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
A mixture of THF and 320 mg (3.6 mmol) (3S)-tetrahydrofuran-3-ol is cooled to 0° C. and 145 mg (3.6 mmol) NaOH are added and the mixture stirred for 1 h. 700 mg (3.6 mmol) 2,6-dichloro-3-nitro-pyridine are slowly added and the mixture is stirred at RT for 3 days. The reaction mixture is filtered and evaporated The residual is purified by FC, giving rise to 600 mg (68%) 6-chloro-3-nitro-2-[(3S)-tetrahydrofuran-3-yl]oxy-pyridine.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][C:12]([OH:14])=[O:13])[CH2:7][CH2:6]2)OCC1.Cl>CC(C)=O>[O:1]=[C:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]([OH:14])=[O:13])[CH2:7][CH2:6]1
Reactant: O=C(O)CC1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC(C)=O
Product: O=C(O)CC1CCC(=O)CC1

Procedure:
A solution of 1,4-dioxaspiro[4,5]decane-8-acetic acid (36.54 g) (Example G) in 750 ml of a 1:1 mixture of a 10% solution of hydrochloric acid:acetone is refluxed under nitrogen for four hours. The mixture is concentrated in vacuo and the residue extracted with chloroform. The organic extract is dried (magnesium sulfate) and evaporated to leave the title compound as a yellow oil which can be used without further purification.
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[CH2:10][CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>>[C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[C:10](=[CH:21][N:22]([CH3:24])[CH3:23])[CH2:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(OC)N(C)C
Reactant: O=C1CCN=C(c2ccccc2)c2ccccc21
Product: CN(C)C=C1CN=C(c2ccccc2)c2ccccc2C1=O

Procedure:
A mixture of 5.2 g (22 mmole) of 3,4-dihydro-1-phenyl-5H-2-benzazepin-5-one and 43 ml of dimethylformamide dimethyl acetal was refluxed for 4 hr. The mixture was concentrated at reduced pressure to dryness. The residue was crystallized with ether to give a yellow solid, mp 131°-133° C. Recrystallization from ether gave yellow prisms, mp 131°-132° C.
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[C:4]([CH3:14])([CH3:13])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.CC1(C)C(C)(C)OB([C:24]2[CH:41]=[CH:40][C:27]([O:28][CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=3)=[CH:26][CH:25]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(C)C=CC=CC=1.O>[CH3:13][C:4]1([CH3:14])[C:3](=[O:15])[C:2]([C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=3)=[CH:40][CH:41]=2)=[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[O:5]1
Reactant: CC1(C)OC(c2ccncc2)=C(Br)C1=O
Reactant: CC1(C)OB(c2ccc(OCc3ccc4ccccc4n3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)OC(c2ccncc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Yield: 73.8 %

Procedure:
A mixture of 4-bromo-2,2-dimethyl-5-(pyridin-4-yl)-furan-3(2H)-one (0.25 g, 0.93 mmol), 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline (0.37 g, 1.026 mmol), and Cs2CO3 (1.52 g, 4.664 mmol) in 5:1 toluene/water (12 mL) was degassed. Pd(dppf)Cl2(152.2 mg, 0.18 mmol) was then added under an inert atmosphere and the mixture was again degassed. The reaction mixture was refluxed for 3 h, filtered through a pad of Celite® and the filtrate was diluted with EtOAc (100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 2,2-dimethyl-5-(pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (0.29 g, 74%) as a solid. 1H NMR (500 MHz, CDCl3): δ 8.78 (d, J=7.2 Hz, 1 H), 8.56-8.50 (m, 2 H), 8.15-8.05 (m, 2 H), 7.78-7.72 (m, 1 H), 7.63-7.59 (m, 1 H), 7.56-7.47 (m, 2 H); 7.18-7.09 (m, 2 H), 7.02-6.96 (m, 3 H), 5.40 (s, 2 H), 1.50 (s, 6 H). MS: M+H: m/z=423.1. LC MS: 98%, Column: Eclipse XDB-C18, 150×4.6 mm, 5 um. Mobile Phase: 0.1% TFA in Water (A), AcN (B), Flow rate: 1.5 ml/min (Gradient)
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([OH:13])(=[O:12])[C:9]([CH3:11])=O.OS(O)(=O)=O>O>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([C:9]([C:4]2[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=2)([CH3:11])[C:8]([OH:13])=[O:12])=[CH:3][CH:2]=1
Reactant: CC(=O)C(=O)O
Reactant: Oc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C(=O)O)(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 25 °C
Yield: 48 %

Procedure:
To a cooled mixture of phenol (9.4 g, 0.1 mol), pyruvic acid (4.4 g, 0.05 mol), and water was added concentrated H2SO4 (4.5 mL, 18.0 g) dropwise with stirring. After 15 minutes the ice bath was removed and the reaction was warmed to room temperature and stirred for 18 hours. The reaction mixture was diluted with ethyl ether/water (200 ml 1:1) and the layers were separated. The organic layer was extracted with saturated aqueous NaHCO3. The aqueous extract was then acidified, extracted with ethyl ether, dried over MgSO4, filtered, and concentrated in vacuo to give 2,2-bis(4-hydroxyphenyl)propionic acid (6.2 g) as a colorless sticky oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:19](OC)=[O:20])=[N:4][N:5]2[CH:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[CH2:9][N:8]([CH3:17])[C:7](=[O:18])[C:6]=12.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>CO>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:19]([C:3]2[C:2]([OH:1])=[C:6]3[C:7](=[O:18])[N:8]([CH3:17])[CH2:9][CH:10]([C:11]4[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=4)[N:5]3[N:4]=2)=[O:20])=[CH:26][CH:25]=1
Reactant: COC(=O)c1nn2c(c1O)C(=O)N(C)CC2c1cccnc1
Reactant: NCc1ccc(F)cc1
Solvent: CO
Product: CN1CC(c2cccnc2)n2nc(C(=O)NCc3ccc(F)cc3)c(O)c2C1=O

Procedure:
Methyl 3-hydroxy-5-methyl-4-oxo-7-pyridin-3-yl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (40 mg, 0.13 mmol) and 4-fluorobenzylamine (130 mg, 1.06 mmol) were combined in MeOH (0.5 mL) and the mixture was heated to reflux, allowing the solvent to slowly evaporate over 18 hours. The residue was purified by preparative HPLC (Waters Nova Pak column (100×40 mm I.D. cartridge, C18, 6 μM pore size) eluting with 95-5% water (0.1% TFA)/acetonitrile (0.1% TFA) at 35 mL/minute.). The appropriate fractions were combined and the solvent was removed to give the title compound as a gum. 1H NMR (400 MHz, d6-DMSO) δ 8.77 (t, J=6 Hz, 1H), 8.67 (s, 1H), 8.53 (s, 1H), 7.6-7.7 (m, 2H), 7.33 (dd, J=5.7, 8.6 Hz, 2H), 7.13 (t, J=9.0 Hz, 2H), 5.90 (t, J=4.6 Hz, 1H), 4.39 (ABX, J=15, 6.1 Hz, 2H), 4.19 (dd, J=13, 4.6 Hz, 1H), 3.91 (dd, J=13, 4.5 Hz, 1H), 2.91 (s, 3H); ES MS (M+1)=396.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C@@H:9]3[O:13][C:12](=[O:14])[NH:11][C@@H:10]3[C:15]=2[CH:16]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C@@H:9]3[O:13][C:12](=[O:14])[NH:11][C@@H:10]3[C:15]=2[CH:16]=1
Reactant: O=C1N[C@@H]2c3cc([N+](=O)[O-])ccc3C[C@@H]2O1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)[C@H]1NC(=O)O[C@H]1C2
Reaction time: 2 h
Yield: 69.5 %

Procedure:
(3aR,8aS)-5-Nitro-3,3a,8,8a-tetrahydroindeno[1,2-d]oxazol-2-one (1.3 g, 5.45 mmol) was dissolved in EtOH (50 mL), transferred to par hydrogenation flask. Pd/C (450 mg) transferred to above flask and subjected to hydrogenation at 30 PSI for 2 h. Reaction mixture filtered through Celite and washed the filter cake with EtOH. Filtrate was concentrated and purified by silica gel column chromatography (50-100% EtOAc:hexanes) to provide (3aR,8aS)-5-amino-3,3a,8,8a-tetrahydroindeno[1,2-d]oxazol-2-one (720 mg, 69%) as a white solid. 1H NMR (DMSO-d6): δ 8.23 (s, 1H), 6.90 (d, 1H, J=8.2 Hz), 6.52-4.49 (m, 2H), 5.20 (app t, 1H, J=6.1 and 7.0 Hz), 5.04 (br s, 2H), 4.91 (d, 1H, J=7.0 Hz), 3.13 (dd, 1H, J=6.7 and 17.0 Hz), 2.89 (d, 1H, J=17.0 Hz). LCMS: purity: 99%; MS (m/e): 191 (MH+).