Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:26])[C:5]([C:24]#[N:25])=[CH:6][NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:12][CH:13]=1)C>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[OH:26][C:4]1[C:9]2[C:8](=[CH:13][CH:12]=[C:11]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[N:10]=2)[N:7]=[CH:6][C:5]=1[C:24]#[N:25]
Reactant: CCOC(=O)C(C#N)=CNc1ccc(OCCCN2CCOCC2)nc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: N#Cc1cnc2ccc(OCCCN3CCOCC3)nc2c1O
Temperature: 260 °C

Procedure:
A solution of 2-cyano-3-[6-(3-morpholin-4-yl-propoxy)-pyridin-3-ylamino]-acrylic acid ethyl ester (10 g) in Dowtherm (200 ml) was heated at 260° C. (internal temperature) under argon. During the first 8 hrs of heating, ethanol was removed through distillation head attached to apparatus. Then, the reaction mixture was heated at 260° C. for an additional 5 hrs. After cooling, the mixture was poured into hexanes. The solid was collected, and suspended in a mixture of CH2Cl2 and MeOH (ca 5:1). The black undissolved solid was removed, and the filtrate was diluted with ether. The yellowish brown solid was precipitated, collected, and dried to give the title compound mass spectrum (electrospray, m/e): 315.0 (M+H); IR cm-1: 2227, 1666, 1630; H-NMR δ(DMSO-d6): 1.88-1.90 (2H, m), 2.26-2.29 (6H, m), 2.51 (2H, m), 3.49 (2H,m), 4.34 (2H, m), 6.852 (1H, d, C7-H), 8.147 (1H, d, C8-H) 8.715 (1H, s, C2-H), 11.2 (1H, bs, OH).
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][C:2]1=[O:12].[N+:13]([O-])([OH:15])=[O:14].S(=O)(=O)(O)O>O>[N+:13]([C:10]1[CH:9]=[CH:8][C:7]2[NH:1][C:2](=[O:12])[CH2:3][CH2:4][CH2:5][C:6]=2[CH:11]=1)([O-:15])=[O:14]
Reactant: O=C1CCCc2ccccc2N1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1CCCc2cc([N+](=O)[O-])ccc2N1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2 g of 1,3,4,5-tetrahydro-2H-1-benzazepin-2-one are added to a solution of 25 ml of nitric acid at 70% in water and of 35 ml of sulfuric acid cooled to 0° C. The reaction medium is stirred for 15 minutes at 0° C. and then poured into water (250 ml) and extracted with ethyl acetate. The organic phase is washed with a saturated aqueous sodium bicarbonate solution and with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is taken up with diisopropyl ether and the insoluble material is filtered off and dried under vacuum, so as to give 1.04 g of 7-nitro-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in the form of a beige solid.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:22][CH:5]2[C:6](=[O:21])[N:7]([C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)[C:8](=[O:9])[CH:4]2[CH2:3]1.[BH4-].[Na+].O>CCO.ClCCl>[OH:9][CH:8]1[N:7]([C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=2)[C:6](=[O:21])[CH:5]2[CH2:22][C:2](=[CH2:1])[CH2:3][CH:4]12
Reactant: C=C1CC2C(=O)N(c3ccc(OC(F)(F)F)cc3)C(=O)C2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: C=C1CC2C(=O)N(c3ccc(OC(F)(F)F)cc3)C(O)C2C1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a cooled (−20° C.) solution of 5-Methylene-2-(4-trifluoromethoxy-phenyl)-tetrahydro-cyclopenta[c]pyrrole-1,3-dione (0.7 g, 2.25 mmol) in EtOH/dichloromethane (15/10 mL) were sequentially added CeCl3. 7H2O (1.0 g, 2.7 mmol) and NaBH4 (0.84 g, 22.5 mmol). The mixture was stirred for 0.5 h at −20° C., then poured into cold water (20 mL) and extracted with dichloromethane (2×15 mL). The solvent was removed by reduced pressure and the residue was purified by silica gel column (petroleum ether/ethyl acetate=5:1) to yield the title compound (0.55 g, 78%). H NMR (300 MHz, CDCl3): δ 7.64-7.60 (m, 2H), 7.25-7.22 (m, 2H), 5.67-5.61 (m, 1H), 5.07 (s, 1H), 4.98 (s, 1H), 3.21-3.09 (m, 2H), 2.81-2.56 (m, 5H); LC-MS: [M+1]+ 314.1.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:11][C@H:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[N:14]=[C:13]2[O:21]C)[CH2:9]1)(C)(C)C.[ClH:24]>>[ClH:24].[ClH:24].[NH2:7][C@H:8]1[CH2:11][C@H:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[NH:14][C:13]2=[O:21])[CH2:9]1
Reactant: COc1nc2cccnc2n1[C@H]1C[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Product: N[C@H]1C[C@H](n2c(=O)[nH]c3cccnc32)C1
Reaction time: 1.25 h
Yield: 92.8 %

Procedure:
Tert-butyl(trans-3-(2-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)cyclobutyl)carbamate (0.9680 g, 3.04 mmol) and hydrogen chloride (4.0M solution in 1,4-dioxane, 7.60 ml, 30.4 mmol) were combined at room temperature and stirred for 75 minutes. The mixture was evaporated to dryness under reduced pressure and the crude 3-(trans-3-aminocyclobutyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one dihydrochloride (0.780 g, 2.82 mmol, 93.5% yield) used without further purification.
Reaction SMILES: C(O)C.[NH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])[CH2:7][CH2:6]1.[ClH:17]>C(OCC)(=O)C>[ClH:17].[NH2:4][C@@H:5]1[CH2:6][CH2:7][C@H:8]([N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])[CH2:9][CH2:10]1
Reactant: NC1CCC(N2CCNC2=O)CC1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: N[C@H]1CC[C@@H](N2CCNC2=O)CC1

Procedure:
A mixture of 9500 ml of anhydrous ethyl alcohol and 2323 g of 1-(4-aminocyclohexyl)-2-imidazolidinone is heated with mixing to effect solution. The solution is cooled to room temperaure and 3200 ml of a saturated solution of anhydrous hydrogen chloride gas in ethyl acetate is added to pH 1. The temperature of the mixture rises to 60° and the product crystallizes. The mixture is cooled to 10°. The crude product is filtered off, washed with 3500 ml of anhydrous ethyl alcohol and dried at 50°-60° in vacuo for 2 days. The crude hydrochloride salt is recrystallized twice from anhydrous methanol-ethyl ether (ca 1:1) to give cis 1-(4-aminocyclohexyl)-2-imidazolidinone monohydrochloride, m.p. 327°-8°.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[N:16]=[CH:15][CH:14]=[C:13]([C:17]([OH:19])=O)[CH:12]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[O:41]=[C:42]([N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1)[CH2:43][NH:44][C:45]([C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:49][CH:48]=1)=[O:46]>CN(C=O)C.O>[Cl:10][C:11]1[CH:12]=[C:13]([C:17]([N:62]2[CH2:61][CH2:60][N:59]([C:42](=[O:41])[CH2:43][NH:44][C:45]([C:47]3[CH:52]=[CH:51][C:50]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)=[CH:49][CH:48]=3)=[O:46])[CH2:64][CH2:63]2)=[O:19])[CH:14]=[CH:15][N:16]=1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccnc(Cl)c2)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 40.9 %

Procedure:
DIPEA (179.7 mg, 0.24 mL, 1.39 mmol) was added to a stirred solution of 6-chloro-pyridine-4-carboxylic acid (48.6 mg, 0.37 mmol) in DMF (3 mL). HOBT (45.9 mg, 0.34 mmol) and EDCI (148.1 mg, 0.77 mmol) were then added at room temperature. After 2 minutes, Biphenyl-4-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide (120 mg, 0.37 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 80% EtOAc in Hexane as eluent) to afford 70 mg (49.2% yield) of biphenyl-4-carboxylic acid {2-[4-(2-chloro-pyridine-4-carbonyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 99.47, 1H NMR (DMSO-d6-D2O): δ 8.5 (s, 1H), 7.96-7.86 (d, 2H), 7.8-7.64 (m, 4H), 7.6-7.34 (m, 5H), 4.2-4.06 (dd, 2H), 3.72-3.42 (m, 6H), 3.38-3.2 (m, 2H).
Reaction SMILES: [Cl-:1].[CH2:2]([O:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH:15]([C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23]2[C:32]([CH2:33]O)=[CH:31][C:30]3[C:25](=[CH:26][C:27]([F:36])=[C:28]([F:35])[CH:29]=3)[N:24]=2)[CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:2]([O:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH:15]([C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23]2[C:32]([CH2:33][Cl:1])=[CH:31][C:30]3[C:25](=[CH:26][C:27]([F:36])=[C:28]([F:35])[CH:29]=3)[N:24]=2)[CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [Cl-]
Reactant: OCc1cc2cc(F)c(F)cc2nc1N1CCC[C@@H]1C1CCC(CCOCc2ccccc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1cc2cc(CCl)c(N3CCC[C@@H]3C3CCC(CCOCc4ccccc4)CC3)nc2cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methaneslufonyl chloride (5.5 mL, 71 mmol) is added dropwise to a mixture of [2-((R)-2-{4-[2-(benzyloxy)ethyl]cyclohexyl}pyrrolidin-1-yl)-6,7-difluoroquinolin-3-yl]methanol (13.7 g, 28.5 mmol) and N,N-diisopropylethylamine (DIPEA, 12.4 mL, 71 mmol) in toluene (150 mL) at 5° C., and the reaction mixture is stirred at ambient temperature for 2 hours. To the mixture, water and ethyl acetate are added and the organic layer is washed with sat. NaHCO3 aq, brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give crude 2-((R)-2-{4-[2-(benzyloxy)ethyl]cyclohexyl}pyrrolidin-1-yl)-3-(chloromethyl)-6,7-difluoroquinoline. To a mixture of 2-((R)-2-{4-[2-(benzyloxy)ethyl]cyclohexyl}pyrrolidin-1-yl)-3-(chloromethyl)-6,7-difluoroquinoline and N-[3,5-bis(trifluoromethyl)benzyl]-N-(2-methyl-2H-tetrazol-5-yl)amine (13.9 g, 43 mmol) in DMF (120 mL) is added potassium tert-butoxide (4.80 g, 43 mmol) at 5° C. The resulting mixture is stirred for 1 hour at the same temperature. After adding sat. NH4Cl aq., the mixture is extracted with ethyl acetate. The combined organic layer is washed with water, brine, dried over magnesium sulfate, filtrated, and concentrated. The resulting mixture is purified by silica gel column chromatography to give trans-N-[2-((R)-2-{-4-[2-(benzyloxy)ethyl]cyclohexyl}pyrrolidin-1-yl)-6,7-difluoroquinolin-3-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amine as a yellow amorphous.
Reaction SMILES: [CH3:1][CH:2]([CH2:17][CH3:18])[CH:3]([N:7]1[C:11](=[O:12])[C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[S:8]1)[C:4]([OH:6])=[O:5].C(N[C@H:23]([C:26]([OH:28])=[O:27])[CH2:24][SH:25])(=O)C>CO>[C:11]([NH:7][SH:25]([CH2:24][CH2:23][C:26]([OH:28])=[O:27])[S:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[C:11]([NH:7][CH:3]([CH:2]([CH3:1])[CH2:17][CH3:18])[C:4]([OH:6])=[O:5])=[O:12])(=[O:12])[CH3:10]
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Reactant: CCC(C)C(C(=O)O)n1sc2ccccc2c1=O
Solvent: CO
Product: CCC(C)C(NC(=O)c1ccccc1S[SH](CCC(=O)O)NC(C)=O)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 0.58 g (2.2 mmol) of [S-(R*,R*)]-3-methyl-2-(3-oxo-3H-benzo[d]isothiazol-2-yl)pentanoic acid in 20 mL of methanol was treated with 0.36 g (2.2 mmol) of N-acetyl-L-cysteine and the reaction was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was triturated with 100 mL of 60° C. water. The water was decanted and the solid was dissolved in 50 mL of ethyl acetate. The organic solution was dried (MgSO4), filtered and evaporated in vacuo to give the title compound as a white, solid foam, mp 85°-90° C.
Reaction SMILES: C([O:3][C:4](=[O:22])[C:5]([NH:7][C:8]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]2[C:9]=1[C:10](=[O:21])[CH2:11][CH:12]2[CH2:18][CH2:19][CH3:20])=[O:6])C.[OH-].[Na+]>CO>[CH3:17][C:14]1[CH:15]=[CH:16][C:8]([NH:7][C:5](=[O:6])[C:4]([OH:22])=[O:3])=[C:9]2[C:13]=1[CH:12]([CH2:18][CH2:19][CH3:20])[CH2:11][C:10]2=[O:21]
Reactant: CCCC1CC(=O)c2c(NC(=O)C(=O)OCC)ccc(C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC1CC(=O)c2c(NC(=O)C(=O)O)ccc(C)c21

Procedure:
A solution of 1.6 g N-(7-methyl-3-oxo-1-propyl-4-indanyl)oxamic acid ethyl ester in 100 ml methanol is heated at reflux with 5.28 ml of 1 M aqueous NaOH for 30 minutes. The solution is concentrated, diluted with water, filtered through a filtering aid such as Hyflo (Registered Trade Mark), and made acid with 2 N HCL. The title compound is filtered off and dried. M.Pt. 157°-158°.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:36]3[C:27](=[CH:28][C:29]4[O:34][CH2:33][CH2:32][O:31][C:30]=4[CH:35]=3)[O:26][CH2:25]1)[C:5](=[O:24])[N:6]2[CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[N:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[C:39](B(O)O)[CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.CN(C)C=O>[C:12]1([CH:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:6]2[C:7]3[C:3](=[C:2]([C:39]4[CH:38]=[N:37][C:46]5[C:41]([CH:40]=4)=[CH:42][CH:43]=[CH:44][CH:45]=5)[CH:10]=[CH:9][CH:8]=3)[C:4]3([C:36]4[C:27](=[CH:28][C:29]5[O:34][CH2:33][CH2:32][O:31][C:30]=5[CH:35]=4)[O:26][CH2:25]3)[C:5]2=[O:24])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Br)c2C12COc1cc3c(cc12)OCCO3
Reactant: OB(O)c1cnc2ccccc2c1
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: [Na+]
Solvent: CN(C)C=O
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(-c3cnc4ccccc4c3)c2C12COc1cc3c(cc12)OCCO3
Yield: 35.2 %

Procedure:
A 10 mL microwave reaction vessel was charged with 4′-bromo-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.38 g, 1.40 mmol), tetrakis(triphenylphosphine)palladium (0.080 g, 0.14 mmol), quinolin-3-ylboronic acid (0.20 g, 2.3 mmol), 2 M aqueous sodium carbonate (1.8 mL) and N,N-dimethylformamide (3.mL). The reaction mixture was irradiated at 150° C. for 15 min in a microwave reactor. The reaction was repeated and both reaction mixtures were combined, poured into distilled water (75 mL) and extracted with ethyl acetate (150 mL). The combined organic extracts were washed with water (3×50 mL) and brine (100 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 20% to 50% gradient of ethyl acetate in hexanes to afford 1′-(diphenylmethyl)-4′-quinolin-3-yl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.29 g, 35%) as a light yellow solid: MS (ES+) m/z 589.0 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([OH:12])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>CN(C=O)C>[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:10](=[O:12])[CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=2)[CH:19]=1
Reactant: COC(=O)c1cccc(N)c1
Reactant: O=C(O)COc1ccc([N+](=O)[O-])cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(NC(=O)COc2ccc([N+](=O)[O-])cc2)c1
Yield: 90.8 %

Procedure:
To a solution of the 4-nitrophenoxy acetic acid (100 mg, 0.5 mmol), 3-amino benzoic acid methyl ester (115 mg, 0.76 mmol), HOBt (102.81 mg, 0.76 mmol) and DIPEA (98.34 mg, 0.76 mmol) in DMF (4.0 mL) were added EDC (145.86 mg, 0.76 mmol) at room temperature. After reaction terminated, the reaction mixture in cool water was diluted with Ethyl acetate. The organic phase was washed with aqueous sodium bicarbonate and dried (anhydrous MgSO4), and concentrated. Purification by silica gel column chromatography (Ethyl acetate:Hexane=1:9˜1:1) gave 3-[2-(4-nitro-phenoxy)acetyl-amino]-benzoic acid methyl ester as a white solid (150 mg, 89% yield).
Reaction SMILES: C(O[C:9]([N:11]1[CH2:16][CH2:15][O:14][CH:13]2[CH2:17][C:18]3[C:23]([CH2:24][CH:12]12)=[C:22]([O:25][CH3:26])[CH:21]=[CH:20][CH:19]=3)=O)C1C=CC=CC=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].CO.CCOC(C)=O>C1COCC1>[CH3:9][N:11]1[CH2:16][CH2:15][O:14][CH:13]2[CH2:17][C:18]3[C:23]([CH2:24][CH:12]12)=[C:22]([O:25][CH3:26])[CH:21]=[CH:20][CH:19]=3
Reactant: COc1cccc2c1CC1C(C2)OCCN1C(=O)OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc2c1CC1C(C2)OCCN1C
Yield: 74 %

Procedure:
To a solution of 6-methoxy-3,4,4a,5,10,10a-hexahydro-2H-naphtho-[2,3-b][1,4]oxazine-4-carboxylic acid benzyl ester (0.40 g, 1.1 mmol) in THF was added 2.8 ml of LiAlH4 solution (1.0 M) in THF. The resulting solution was stirred at reflux for 3 h. The reaction mixture was quenched with ice, diluted with EtOAc and filtered through Celite. The organic layer was dried over Na2SO4 and concentrated in vacuo, yielding an oily residue which was subjected to column chromatography (5% MeOH-EtOAc) to yield 0.19 g (75%) of the desired product. 1H NMR (300 MHz, CDCl3): δ 2.07 (m, 1H), 2.28 (m, 1H), 2.37 (s, 3H), 2.49 (m, 1H), 2.77 (m, 2H), 2.97 (dd, 1H, J=5.5, 16.1 Hz), 3.28 (dd, 1H, J=5.5, 17.0 Hz), 3.55 (m, 1H), 3.79 (s, 3H), 3.86 (m, 2H), 6.67 (m, 2H), 7.09 (t, 1H, J=7.8 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][C:11]([CH2:15][C:16]([O:18][CH3:19])=[O:17])([CH3:14])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[C:28](=[O:33])[C:29]([O:31][CH3:32])=[O:30]>C(Cl)Cl>[CH3:19][O:18][C:16](=[O:17])[CH2:15][C:11]1([CH3:14])[CH2:12][CH2:13][N:8]([C:5]2[N:6]=[CH:7][C:2]([NH:1][C:28](=[O:33])[C:29]([O:31][CH3:32])=[O:30])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1
Reactant: COC(=O)CC1(C)CCN(c2ccc(N)cn2)CC1
Reactant: COC(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC1(C)CCN(c2ccc(NC(=O)C(=O)OC)cn2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a solution of methyl [1-(5-aminopyridin-2-yl)-4-methylpiperidin-4-yl]acetate (3.29 g, 13.20 mmol) in DCM (100 mL) was added triethylamine (2.2 mL, 15.84 mmol) followed by methyl chlorooxoacetate (1.6 mL, 17.15 mmol) and the reaction mixture was allowed to stir at ambient temperature for 1.5 hrs. The reaction mixture was washed brine (2×100 mL), the aqueous layer was re extracted with DCM (50 mL) the organic washings were combined, dried and concentrated to leave the title compound as a brown gum (4.4 g, 13.2 mmol, 100%). 1H NMR δ 1.06 (s, 3H), 1.40-1.46 (m, 2H), 1.53-1.57 (m, 2H), 2.36 (s, 3H), 3.46-3.52 (m, 2H), 3.59 (s, 3H), 3.67-3.73 (m, 2H), 3.78 (s, 3H), 6.90 (d, 1H), 7.56 (d, 1H), 8.06 (s, 1H); MS m/e MH+ 350.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[F:21][C:22]([F:29])([F:28])[C:23]1[CH:27]=[CH:26][NH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:21][C:22]([F:29])([F:28])[C:23]1[CH:27]=[CH:26][N:25]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=3[N:12]=2)[N:24]=1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: FC(F)(F)c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3-n3ccc(C(F)(F)F)n3)nc2c1
Temperature: 60 °C
Yield: 86 %

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.18 g of 3-trifluoromethylpyrazole, 0.55 g of potassium carbonate and 3 ml of DMF was stirred while heating at 60° C. for one hour. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.34 g of 2-[3-(3-trifluoromethylpyrazole-1-yl)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 60”).
Reaction SMILES: C(OC(N1CCC(N[C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: O=C(c1sccc1Nc1ccnc2[nH]ccc12)N1CCCC1

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using pyrrolidine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 313 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 12.40 (1H, br. s.) 10.62 (1H, s) 8.07 (1H, d, J=6.83 Hz) 7.88 (1H, d, J=5.27 Hz) 7.39 (1H, d, J=3.51 Hz) 7.29 (1H, d, J=5.47 Hz) 6.72 (1H, d, J=3.32 Hz) 6.70 (1H, d, J=6.64 Hz) 3.42 (1H, br. s.) 2.47 (4H, dt, J=3.66, 1.78 Hz) 1.75 (4H, br. s.)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[S:26][C:25]([NH:27]C(=O)OC(C)(C)C)=[N:24][C:23]=2[CH3:35])=[C:20]2[C:15]([N:16]([CH2:39][CH:40]3[CH2:42][CH2:41]3)[C:17](=[O:38])[N:18]([CH3:37])[C:19]2=[O:36])=[N:14]1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:27][C:25]1[S:26][C:22]([C:21]2[N:13]([CH2:12][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=4)[N:8]=[CH:7][CH:6]=3)[N:14]=[C:15]3[C:20]=2[C:19](=[O:36])[N:18]([CH3:37])[C:17](=[O:38])[N:16]3[CH2:39][CH:40]2[CH2:42][CH2:41]2)=[C:23]([CH3:35])[N:24]=1
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(N)sc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12

Procedure:
This compound was synthesized by treating tert-butyl 5-[2-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]4-methyl-1,3-thiazol-2-ylcarbamate with 10% TFA in dichloromethane at room temperature for 5 hours. Mass: 508.13 (M+H).