Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C:12]1[O:13][C:14]2[C:19]([C:20](=[O:28])[C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:18][C:17](Br)=[CH:16][CH:15]=2.[H][H].ClCCl>CO.[Pd]>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C:12]1[O:13][C:14]2[C:19]([C:20](=[O:28])[C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: [H][H]
Reactant: Nc1ncnc2c1ncn2Cc1oc2ccc(Br)cc2c(=O)c1-c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Nc1ncnc2c1ncn2Cc1oc2ccccc2c(=O)c1-c1ccccc1
Yield: 36.9 %

Procedure:
To a solution of Example 1 (0.1 g, 0.22 mmoles) in methanol (10 ml), palladium on carbon (10 mg) was added and the solution was hydrogenated at RT under 5 kg/cm2 pressure of hydrogen for 3 h. The solution was filtered through celite and concentrated. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as pale yellow solid (0.030 g, 37% yield). MP: 173-175° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 8.10 (d, J=12.5 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.77 (t, J=7.7 Hz, 1H), 7.48-7.41 (m, 6H), 7.22 (s, 2H), 5.34 (s, 2H). Mass: 370.05 (M++1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:17]([O:19]CC)=[O:18])=[N:4][O:5][C:6]=1[C:7]1[CH2:16][CH2:15][C:10]2([CH2:14][O:13][CH2:12][CH2:11]2)[CH2:9][CH:8]=1.C1COCC1.[OH-].[Na+].Cl>CO.CCOC(C)=O>[CH3:1][C:2]1[C:3]([C:17]([OH:19])=[O:18])=[N:4][O:5][C:6]=1[C:7]1[CH2:16][CH2:15][C:10]2([CH2:14][O:13][CH2:12][CH2:11]2)[CH2:9][CH:8]=1
Reactant: CCOC(=O)c1noc(C2=CCC3(CCOC3)CC2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)O)noc1C1=CCC2(CCOC2)CC1
Temperature: 25 °C

Procedure:
[Ethyl 4-methyl-5-(2-oxaspiro[4.5]dec-7-en-8-yl)isoxazole-3-carboxylate] (170 mg, 0.584 mmol) in MeOH (3.60 mL) and THF (6 mL) was treated at room temperature with 2M NaOH (aq) (0.584 mL, 1.167 mmol). The resulting mixture was stirred at room temperature and treated with 2M HCl (aq) (0.2 mL) and EtOAc. The combined organic layers were dried over MgSO4 and filtered and the solvent was removed under reduced pressure to afford the title compound;
Reaction SMILES: F[C:2]1[N:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=[O:5].[ClH:19].Cl.[NH:21]1[C:25]2=[N:26][CH:27]=[CH:28][C:29]([O:30][C:31]3[CH:36]=[CH:35][C:34]([NH:37]C4N=CC=CC=4C(NC4C=CC=CC=4C)=O)=[CH:33][C:32]=3[F:54])=[C:24]2[CH:23]=[CH:22]1>>[ClH:19].[ClH:19].[NH:21]1[C:25]2=[N:26][CH:27]=[CH:28][C:29]([O:30][C:31]3[CH:36]=[CH:35][C:34]([NH:37][C:2]4[N:18]=[CH:17][CH:16]=[CH:15][C:3]=4[C:4]([NH:6][CH2:7][C:8]4[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=4)=[O:5])=[CH:33][C:32]=3[F:54])=[C:24]2[CH:23]=[CH:22]1
Reactant: Cc1ccccc1NC(=O)c1cccnc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Reactant: O=C(NCc1ccc(F)cc1)c1cccnc1F
Agent: Cl
Product: O=C(NCc1ccc(F)cc1)c1cccnc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Yield: 35 %

Procedure:
2-Fluoro-N-(4-fluorobenzyl)nicotinamide (0.050 g, 0.20 mmol) was converted to the title compound (0.035 g, 35%) in a manner similar to the preparation of 2-(4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenylamino)-N-o-tolylnicotinamide (Step B of Example 8). 1H NMR (DMSO-d6) δ 12.63 (s, 1H), 11.17 (s, 1H), 9.44 (t, 1H, J=5.8 Hz), 8.10-8.40 (m, 4H), 7.50-7.60 (m, 1H), 7.30-7.45 (m, 4H), 7.08-7.10 (m, 2H), 6.90-6.95 (m, 1H), 6.66 (d, 1H, J=6.3 Hz), 6.43-6.46 (m, 1H), 4.44 (d, 2H, J=5.7 Hz); HRMS(ESI+), 472.1585 (M+H)+ calc, 472.1587 (M+H)+ found.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15]1.[S:21]1[C:25]2[CH:26]=[CH:27][C:28](B(O)O)=[CH:29][C:24]=2[CH:23]=[CH:22]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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]>[S:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:2]3[CH:3]=[C:4]4[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=3)[NH:7][CH:6]=[C:5]4[CH:14]3[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15]3)=[CH:29][C:24]=2[CH:23]=[CH:22]1
Reactant: OB(O)c1ccc2sccc2c1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)C3)c[nH]c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)c1cc(-c2ccc3sccc3c2)cc2c(C3CCS(=O)(=O)C3)c[nH]c12
Temperature: 100 °C
Yield: 63.8 %

Procedure:
5-Bromo-3-(1,1-dioxidotetrahydro-3-thienyl)-1H-indole-7-carboxamide (0.06 g, 0.168 mmol) and 1-benzothien-5-ylboronic acid (0.036 g, 0.202 mmol) was dissolved in a 6:1 solution of 1,4 dioxane/water in a 20 mL microwave reaction vessel. Potassium carbonate (0.113 g, 0.816 mmol) was added and the solution was degassed with Argon. PdCl2(dppf) (0.025 g, 0.034 mmol) was added and the reaction was heated in a microwave at 100° C. for 20 min. The solution was passed through a StratoSphere SPE PL-Thiol MP SPE column to remove palladium and purified on Gilson preparative HPLC using Acetonitrile/Water with 0.1% TFA. The desired fractions were concentrated, giving 0.044 g (67%) of the title compound.
Reaction SMILES: Br[C:2]1[C:3]([C:20]2[S:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1.[C:26]([NH:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:28])[CH3:27]>>[Cl:25][C:22]1[S:21][C:20]([C:3]2[C:2]([C:34]3[CH:35]=[C:30]([NH:29][C:26](=[O:28])[CH3:27])[CH:31]=[CH:32][CH:33]=3)=[CH:7][N:6]=[C:5]([NH:8][CH2:9][CH2:10][N:11]3[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]3=[O:19])[N:4]=2)=[CH:24][CH:23]=1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2ccc(Cl)s2)n1
Product: CC(=O)Nc1cccc(-c2cnc(NCCN3C(=O)NC(=O)C3(C)C)nc2-c2ccc(Cl)s2)c1

Procedure:
The title compound was prepared from 1-{2-[5-bromo-4-(5-chlorothiophen-2-yl)pyrimidin-2-ylamino]ethyl}-5,5-dimethylimidazolidine-2,4-dione and 3-acetamidophenylboronic acid in a manner analogous to Example 269. MS (M+H)+ 499.
Reaction SMILES: [O:1]=[C:2]([C:4]1[CH:8]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[O:6][N:5]=1)[CH3:3].[BH4-].[Na+].O>CO>[OH:1][CH:2]([C:4]1[CH:8]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[O:6][N:5]=1)[CH3:3]
Reactant: CC(=O)c1cc(-c2ncccn2)on1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(O)c1cc(-c2ncccn2)on1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-(3-(1-oxo-ethyl)-isoxazol-5-yl)-pyrimidine (1.2 gm) in methanol (20 ml) was added sodium borohydride (0.485 gm) in lots at 0° C. It was stirred at 30° C. over a period of 2 h. The reaction mixture was evaporated under vacuum to provide a residue. The residue was stirred with water and extracted with ethyl acetate (25 ml X3). Combined organic layers was washed with aqueous sodium bicarbonate solution followed by water and concentrated under vacuum to provide title compound in 1.1 gm quantity (91%). It as used as without purification for the next reaction.
Reaction SMILES: [OH-].[K+].O.[C:4]1([CH2:10][O:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])[CH2:16][CH2:15]2)=[O:13])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[C:4]1([CH2:10][O:11][C:12]([N:14]2[CH2:15][CH2:16][CH:17]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH2:18][CH2:19]2)=[O:13])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)CCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred and cooled (15° C.) mixture of 11.1 parts of potassium hydroxide and 96 parts of water was added dropwise a solution of 31.8 parts of ethyl 1-[(phenylmethoxy)carbonyl]-4-piperidinepropanoate in 38 parts of ethanol during 20 minutes. Upon complete addition, stirring was continued overnight at room temperature. The reaction mixture was evaporated at <50° C. The reaction mixture was poured into crushed ice and treated with concentrated hydrochloric acid. The separated aqueous layer was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 29 parts (100%) of 1-[(phenylmethoxy)carbonyl]-4-piperidinepropanoic acid as a residue (int. 33).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]2=[N:4][C:3]=1[CH2:17][CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.CC1(C)C(C)(C)OB([C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH:47]=[N:46][C:45](=[O:48])[N:44]3[CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])=[CH:39][CH:38]=2)O1>>[O:14]1[CH2:15][CH2:16][N:11]([C:10]2[C:5]3[N:6]([C:2]([C:37]4[CH:38]=[CH:39][C:40]([N:43]5[CH:47]=[N:46][C:45](=[O:48])[N:44]5[CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])=[CH:41][CH:42]=4)=[C:3]([CH2:17][CH2:18][C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)[N:4]=3)[N:7]=[CH:8][CH:9]=2)[CH2:12][CH2:13]1
Reactant: Brc1c(CCc2ccc3ccccc3n2)nc2c(N3CCOCC3)ccnn12
Reactant: CC1(C)OB(c2ccc(-n3cnc(=O)n3COCC[Si](C)(C)C)cc2)OC1(C)C
Product: C[Si](C)(C)CCOCn1c(=O)ncn1-c1ccc(-c2c(CCc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1

Procedure:
Compound 46a was subjected to Suzuki coupling conditions with compound 52d using the procedures described in Example 38, step A, to obtain compound 52e as a white solid. Mass Spectrum (LCMS, ESI pos.) Calcd. For C34H39N9O3Si: 649.3 (M+H). Found 649.2.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]3[N:14]=[C:15]([CH2:17][O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:16]=[C:10]3[C:9]2=[O:25])[CH:5]=[CH:4][CH:3]=1.B1([C:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=2)OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CN(C=O)C.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>[C:44]([O:43][C:41]([N:38]1[CH2:37][CH:36]=[C:35]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([N:8]3[CH2:13][CH2:12][N:11]4[N:14]=[C:15]([CH2:17][O:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH:16]=[C:10]4[C:9]3=[O:25])[N:7]=2)[CH2:40][CH2:39]1)=[O:42])([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=C1c2cc(COc3ccccc3)nn2CCN1c1cccc(Br)n1
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: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(N3CCn4nc(COc5ccccc5)cc4C3=O)n2)CC1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 81.3 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (7 mg, 0.006 mmol) was added to a stirred suspension of 5-(6-bromo-pyridin-2-yl)-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (50 mg, 0.125 mmol), (N-tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (97 mg, 0.31 mmol) and potassium carbonate in a mixture of 1,4-dioxane (0.5 mL) and DMF (0.5 mL) in a sealed tube and under nitrogen. The mixture was stirred at 150° C. for 15 minutes under microwave irradiation. The mixture was diluted with water and extracted with AcOEt. The organic layer was separated, washed with brine, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 100/0). The desired fractions were collected and the solvents evaporated in vacuo to yield 6-(4-oxo-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (51 mg, 81%) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C@H:10]([C:12]1[CH:16]=[CH:15][O:14][CH:13]=1)[OH:11])([CH3:4])[CH3:3].[Cl:18][C:19]1[C:26]([F:27])=[CH:25][C:22]([C:23]#[N:24])=[C:21](F)[CH:20]=1.[H-].[Na+]>CN(C)C=O>[CH3:4][C:2]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C@@H:10]([O:11][C:21]1[CH:20]=[C:19]([Cl:18])[C:26]([F:27])=[CH:25][C:22]=1[C:23]#[N:24])[C:12]1[CH:16]=[CH:15][O:14][CH:13]=1)([CH3:1])[CH3:3]
Reactant: N#Cc1cc(F)c(Cl)cc1F
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1ccoc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC[C@@H](Oc1cc(Cl)c(F)cc1C#N)c1ccoc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
The product of step (b) (277 mg, 1.15 mmol) and 4-chloro-2,5-difluorobenzonitrile (199 mg, 1.15 mmol) were dissolved in dimethylformamide (10 ml) and sodium hydride (60%, 48 mg, 1.2 mmol) added in one portion. The reaction was stirred for 2 h at room temperature then quenched with aqueous saturated ammonium chloride solution (30 ml) and extracted with ethyl acetate (3×60 ml). The combined organic extracts were washed with water (3×20 ml), dried (sodium sulphate) and evaporated iii vacuo. The residue was chromatographed on flash silica, eluting with hexane:ethyl acetate (3:1), to give the title compound as a white crystalline solid (330 mg, 73%).
Reaction SMILES: [N:1]([C@@H:4]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:5]([OH:24])[CH2:6][N:7]1[C@H:16]([C:17]([NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][C@H:14]2[C@H:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8]1)=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][C@@H:4]([CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C@H:5]([OH:24])[CH2:6][N:7]1[C@H:16]([C:17]([NH:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:15][C@H:14]2[C@H:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8]1
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)N=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@@H](N)Cc1ccccc1
Yield: 99.6 %

Procedure:
(A)(iii) A solution of 17 mg (0.04 mmol) of 2-[3(S)-azido-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide (prepared as described in Example 2 or Example 3) in 5 ml of ethanol was hydrogenated at about 3.4 atmospheres and at room temperature for 2 hours over 10 mg of 10% palladium-on-charcoal. The catalyst was filtered off and washed twice with ethanol. The combined filtrate and washings were evaporated to give 16 mg of 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS, 8aS)-isoquinoline-3(S)-carboxamide; MS: m/e 402 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:37])[N:32]([C:38]1([CH3:46])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45])[C:31]2=[O:47].O>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:26][CH2:27][C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[C:33](=[O:37])[N:32]([C:38]2([CH3:46])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]2=[O:45])[C:31]3=[O:47])=[O:10])=[CH:6][N:5]=1)[CH3:2]
Reactant: CCOc1ccc(C(=O)O)cn1
Reactant: CC1(N2C(=O)c3ccc(CN)cc3C2=O)CCC(=O)NC1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2(C)CCC(=O)NC2=O)C3=O)cn1
Temperature: 40 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
A stirred mixture of 6-ethoxy-nicotinic acid (0.33 g, 2.00 mmol) and CDI (0.36 g, 2.20 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 1 h, 5-aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.68 g, 2.00 mmol) was added and the mixture was heated at 40° C. for 1.5 h. The mixture was cooled to rt and water (40 mL) was added. The solvent was removed in vacuo and the crude product was purified by column chromatography (80/20, EtOAc/hexanes). The product fractions were combined, concentrated and the residue was triturated in Et2O. The product was isolated by filtration and dried in vacuo to give 6-ethoxy-N-[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-nicotinamide as a white solid (0.77 g, 86% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.56 min (99.14%); mp: 174-176° C.; 1H NMR (DMSO-d6) δ 1.33 (t, J=6.9 Hz, 3H), 1.89 (s, 3H), 2.02-2.08 (m, 1H), 2.54-2.73 (m, 3H), 4.34 (dd, J=7.2, 14.1 Hz, 2H), 4.62 (d, J=6.0 Hz, 2H), 6.88 (d, J=8.7 Hz, 1H), 7.77-7.83 (m, 3H), 8.14 (dd, J=2.4, 8.7 Hz, 1H), 8.70 (d, J=2.1 Hz, 1H), 9.20 (t, J=6.0 Hz, 1H), 11.01 (s, 1H); 13C NMR (DMSO-d6) δ 14.40, 21.00, 28.60, 29.10, 42.50, 58.70, 61.80, 110.30, 121.60, 123.00, 123.20, 129.60, 131.40, 133.40, 138.10, 147.10, 147.30, 164.70, 165.00, 167.70, 167.90, 172.10, 172.20; LCMS: MH=451; Anal Calcd for C23H22N4O6+0.3H2O: C, 60.60; H, 5.00; N, 12.29. Found: C, 60.24; H, 4.86; N, 12.15.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]2[C:9](=[C:11]([C:15]([OH:17])=O)[CH:12]=[CH:13][CH:14]=2)[N:10]=1.Cl.Cl.[NH2:20][CH:21]1[CH2:28][CH:27]2[N:29]([CH3:30])[CH:23]([CH2:24][CH2:25][CH2:26]2)[CH2:22]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[CH3:30][N:29]1[CH:23]2[CH2:24][CH2:25][CH2:26][CH:27]1[CH2:28][CH:21]([NH:20][C:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:8]3[O:7][C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)=[N:10][C:9]=13)=[O:17])[CH2:22]2
Reactant: O=C(O)c1cccc2oc(-c3ccco3)nc12
Reactant: CN1C2CCCC1CC(N)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1C2CCCC1CC(NC(=O)c1cccc3oc(-c4ccco4)nc13)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
A mixture of 2-furan-2-ylbenzoxazole-4-carboxylic acid (51 mg, 0.22 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (59 mg, 0.26 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (59 mg, 0.31 mmol) and 1-hydroxybenzotriazole (84 mg, 0.62 mmol) in DMF (5 mL) was stirred for 10 min at room temperature, then triethylamine (0.14 mL, 1.1 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (20 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×50 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-furan-2-ylbenzoxazole-4-carboxamide (49 mg, 61%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 8.94 (d, J=6.0 Hz, 1H), 8.22 (dd, J=7.5, 1.0 Hz, 1H), 7.74 (d, J=1.5 Hz, 1H), 7.68 (dd, J=8.0, 1.0 Hz, 1H), 7.46 (t, J=4.0 Hz, 1H), 7.35 (d, J=4.0 Hz, 1H), 6.79-6.66 (m, 1H), 4.58-4.53 (m, 1H), 3.12 (d, J=10.0 Hz, 2H), 2.66-2.59 (m, 2H), 2.55 (s, 3H), 2.18-1.98 (m, 3H), 1.68-1.49 (m, 3H), 1.22-1.17 (m, 2H); MS (ESI+) m/z 366 (M+H); HPLC>99% (AUC), tR=12.12 mm.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:17]1[O:20][CH:18]1[CH3:19]>C1(C)C=CC=CC=1>[OH:20][CH:18]([CH3:19])[CH2:17][N:14]1[CH2:15][CH2:16][CH:11]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[NH:8][N:7]=2)[CH2:12][CH2:13]1
Reactant: CC1CO1
Reactant: Fc1ccc2c(C3CCNCC3)n[nH]c2c1
Solvent: Cc1ccccc1
Product: CC(O)CN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Temperature: 50 °C
Yield: 54.9 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1H-indazole (500 mg, 2.3 mmol) and propylene oxide (1g, 17 mmol) in 25 ml toluene was heated to 50° C. in an autoclave for 7 days. The cooled reaction was concentrated in vacuo and purified by chromatography on silica gel 60 eluting with ethyl acetate:methanol (4:1, v/v). Concentration of the appropriate fractions afforded 350 mg (54.9%) of 3-[1-(2-hydroxyprop-1-yl)-4-piperidinyl]-6-fluoro-1 H-indazole as a foam.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[Cl:10][C:11]1[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=1.C(N(CC)CC)C>C1COCC1>[N:4]1([CH2:3][CH2:2][NH:1][S:16]([C:14]2[S:15][C:11]([Cl:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: NCCN1CCOCC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(NCCN1CCOCC1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.5 %

Procedure:
To a stirred solution of 4-(2-aminoethyl)-morpholine (1.80 g, 13.8 mmol) in THF (20 mL) was added at 0° C. (ice water bath) commercially available 5-chloro-thiophene-2-sulfonyl chloride (1.0 g, 4.61 mmol) and triethylamine (0.71 mL, 5.07 mmol). The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (ethyl acetate/heptane) to yield the title compound (1.34 g, 93%) as a colorless oil. MS (ISN) 309.0 [(M−H)−].
Reaction SMILES: [OH:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[C:5]([CH2:12][CH2:13][NH:14][CH2:15][CH2:16][N:17]([CH2:31][CH:32]2[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]2)[C:18](=[O:30])[CH2:19][CH2:20][O:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[OH:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[C:5]([CH2:12][CH2:13][NH:14][CH2:15][CH2:16][N:17]([CH2:31][CH:32]2[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]2)[C:18](=[O:30])[CH2:19][CH2:20][O:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN(CCNCCc2ccc(O)c3[nH]c(=O)sc23)C(=O)CCOCCc2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCOCCc1ccccc1)N(CCNCCc1ccc(O)c2[nH]c(=O)sc12)CC1CCNCC1
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
To a solution of 4-{[{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-ethyl}-(3-phenethyloxy-propionyl)-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (Example 1, 0.2 g) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL) and the reaction mixture was stirred for 30 minutes and then concentrated. The residue was dissolved in methanol (5 mL) and purified by reverse phase HPLC eluting with 5% to 95% acetonitrile in 0.2% trifluoroacetic acid. The fractions containing the product were concentrated and dissolved in methanol where 4N hydrogen chloride in 1,4-dioxane was added. The mixture was concentrated and the residue was triturated with ether, the ether was decanted and further concentration afforded the titled compound (0.13 g) as a hygroscopic solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](O)(=[O:13])=[O:12])=[CH:7][C:6]=1[N:15]=[N:16][CH:17]([C:27]([CH3:29])=[O:28])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])(=[O:3])[CH3:2].S(Cl)([Cl:32])=O>CN(C)C=O>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([Cl:32])(=[O:13])=[O:12])=[CH:7][C:6]=1[N:15]=[N:16][CH:17]([C:27]([CH3:29])=[O:28])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1ccc(S(=O)(=O)O)cc1N=NC(C(C)=O)C(=O)Nc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(S(=O)(=O)Cl)cc1N=NC(C(C)=O)C(=O)Nc1ccccc1

Procedure:
α-(2-Acetoxy-5-sulfophenylazo)acetoacetanilide (20 g) was added to thionyl chloride (100 ml). After the addition of dimethylformamide (4 ml), solution was complete, then followed by precipitation of the product. It was filtered off and dried in the vacuum oven at 40° C. Yield: 16.7 g, m.p. 225° to 226° C.
Reaction SMILES: [C:1]1([S:7]([C:10]2[S:11][CH:12]=[CH:13][C:14]=2[CH:15]=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19](=[O:32])[CH2:20][N:21]1[C:29]2[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=2)[CH:23]=[C:22]1[CH3:31]>>[CH3:17][O:18][C:19](=[O:32])[CH2:20][N:21]1[C:29]2[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=2)[C:23]([CH2:15][C:14]2[CH:13]=[CH:12][S:11][C:10]=2[S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:8])=[O:9])=[C:22]1[CH3:31]
Reactant: O=Cc1ccsc1S(=O)(=O)c1ccccc1
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Product: COC(=O)Cn1c(C)c(Cc2ccsc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 1c using 2-phenylsulfonylthiophene-3-carbaldehyde and (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.