Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10](CC(OCC)=O)[N:9]=1.[CH3:26][NH2:27].[CH2:28]([OH:30])[CH3:29]>>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:29][C:28]([NH:27][CH3:26])=[O:30])[N:9]=1
Reactant: CCOC(=O)Cn1nc(-c2ccccc2O)nc1-c1ccccc1O
Reactant: CN
Reactant: CCO
Product: CNC(=O)Cn1nc(-c2ccccc2O)nc1-c1ccccc1O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
2.0 g of ethyl [3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate (Example 2) are dissolved in 15 ml of ethanol and treated with 0.8 ml of 8M methylamine in ethanol. The mixture is stirred at 60° C. for 3 h and then cooled. The crystals precipitating in the course of this are filtered off and washed with ethanol. After drying, 2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-N-methylacetamide remains as colorless crystals m.p. 247-249° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.[CH2:16]([C:23]1([OH:29])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[CH2:16]([C:23]1([OH:29])[CH2:28][CH2:27][N:26]([C:13]([C:9]2[CH:10]=[N:11][O:12][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[O:14])[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1ccc(-c2oncc2C(=O)Cl)cc1
Reactant: OC1(Cc2ccccc2)CCNCC1
Solvent: ClCCl
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(O)(Cc3ccccc3)CC2)cc1
Reaction time: 1 h

Procedure:
To 5-(4-methylphenyl)isoxazole-4-carbonyl chloride (10 mg, 0.045 mmol) in dichloromethane (1 mL) was added 4-benzylpiperidin-4-ol (9.5 mg, 0.050 mmol, 1.1 eq.), and the reaction mixture was stirred for 1 h. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC to give the title compound. HRMS (ESI, pos. ion) m/z calcd for C23H24N2O3: 376.1787, found 376.1790.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:17]=1>C(#N)C.C(OCC)(=O)C>[CH2:7]([O:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:17]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1cc(O)c2ccccc2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1cc(OCc2ccccc2)c2ccccc2c1
Yield: 98.1 %

Procedure:
Potassium carbonate (19.2 g) and benzyl bromide (19.0 g) were added to a solution of ethyl 4-hydroxy-2-naphthoate (20 g) in acetonitrile (200 ml) and the mixture was heated to reflux for 2 hours. After being cooled, the reaction solution was diluted with ethyl acetate and insoluble materials were filtered through Celite. The filtrate was concentrated in vacuo and the resulted residue was purified with a silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=100/1) to give ethyl 4-(benzyloxy)-2-naphthoate (27.8 g) as a pale yellow oil.
Reaction SMILES: [Mg].II.Br[CH2:5][CH:6]1[CH2:9][CH2:8][CH2:7]1.[C:10]1([S:16]([N:19]2[C:23]3=[N:24][CH:25]=[C:26]([F:28])[CH:27]=[C:22]3[CH:21]=[C:20]2[C:29]([C:31]2[CH:36]=[CH:35][C:34]([S:37][CH3:38])=[CH:33][CH:32]=2)=[O:30])(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1>[C:10]1([S:16]([N:19]2[C:23]3=[N:24][CH:25]=[C:26]([F:28])[CH:27]=[C:22]3[CH:21]=[C:20]2[C:29]([C:31]2[CH:32]=[CH:33][C:34]([S:37][CH3:38])=[CH:35][CH:36]=2)([OH:30])[CH2:5][CH:6]2[CH2:9][CH2:8][CH2:7]2)(=[O:17])=[O:18])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: BrCC1CCC1
Reactant: CSc1ccc(C(=O)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CSc1ccc(C(O)(CC2CCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reaction time: 1 h
Yield: 26.8 %

Procedure:
To a stirred suspension of magnesium powder (1.6 g, 67.5 mmol) and iodine (3 pieces) in dry tetrahydrofuran (8 mL) was added (bromomethyl)cyclobutane (1.1 mL, 7.5 mmol) dropwise at room temperature. After the reaction initiated, a solution of (bromomethyl)cyclobutane (5.5 mL, 37.5 mmol) in dry tetrahydrofuran (30 mL) was added dropwise and then heated at reflux for 30 min. The resulting Grignard reagent was added to a solution of (1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-(4-methylsulfanyl-phenyl)-methanone (1.9 g, 4.5 mmol) at 0° C. and stirred for 1 h. The reaction was quenched with water, extracted with ethyl acetate (300 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 15% ethyl acetate/hexanes) afforded 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclobutyl-1-(4-methylsulfanyl-phenyl)-ethanol (600 mg, 26.9%) as a light yellow solid; LC/MS m/e calcd for C26H25FN2O3S2 [M+H]+ 497.63, observed 496.8.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@@H:8]([NH:17][C:18]([C@@H:20]2[CH2:25][CH2:24][CH2:23][N:22]([C:26](=[O:42])[CH2:27][CH2:28][CH:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)[CH2:21]2)=[O:19])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:5]=[N:6][CH:7]=1.[C:43]([C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([O:51][CH2:52][CH2:53][F:54])[CH:46]=1)#[CH:44]>CN(C=O)C.C(N)CCC.CS(C)=O.[Cu](I)I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:13]([O:12][C:10](=[O:11])[CH2:9][C@H:8]([NH:17][C:18]([C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26](=[O:42])[CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:31][CH2:30]2)[CH2:21]1)=[O:19])[C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:44]#[C:43][C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([O:51][CH2:52][CH2:53][F:54])[CH:46]=2)[CH:3]=1)([CH3:14])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(Br)c1
Reactant: C#Cc1cccc(OCCF)c1
Agent: I[Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(C#Cc2cccc(OCCF)c2)c1
Yield: 39.5 %

Procedure:
To a degassed solution of tert-butyl 4-[3-((3R)-3-{[(1S)-1-(5-bromopyridin-3-yl)-3-tert-butoxy-3-oxopropyl]carbamoyl}piperidin-1-yl)-3-oxopropyl]piperidine-1-carboxylate (example 27c, 100 mg, 15 mmol), copper iodide (4.4 mg, 23 μmol) and tetrakis(triphenylphosphine) palladium(0) (18 mg, 15 μmol) in DMF (0.4 mL) and n-butyl amine (0.23 mL) was added a solution of 1-ethynyl-3-(2-fluoroethoxy)benzene (50 mg, 0.31 mmol) in DMF (0.6 mL) over 60 minutes at 100° C. After additional 20 minutes at 100° C. the mixture was diluted with DMSO and purified by preparative HPLC to yield 90 mg of tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-(5-{[3-(2-fluoroethoxy)phenyl]ethynyl}pyridin-3-yl)-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][C@H:21]3[CH2:23][O:22]3)[N:9]=2)=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CCO.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][C@H:21]([OH:22])[CH2:23][N:35]3[CH2:34][CH2:33][N:32]([C:26]4[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=4[CH3:24])[CH2:37][CH2:36]3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(Br)cc3)nn2C[C@H]2CO2)C1
Reactant: Cc1ccc(Cl)cc1N1CCNCC1
Solvent: ClCCl
Solvent: CCO
Product: CC(=O)N1CCc2c(c(-c3ccc(Br)cc3)nn2C[C@H](O)CN2CCN(c3cc(Cl)ccc3C)CC2)C1
Temperature: 70 °C
Reaction time: 18 h
Yield: 35.1 %

Procedure:
(S)-1-[3-(4-Bromo-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (37 mg, 0.98 mmol) and 4-(2-methyl-5-chlorophenyl)piperazine (36 mg, 0.17 mmol) were combined in EtOH (0.4 mL) and heated to 70° C. After 18 h the mixture was allowed to cool, diluted with CH2Cl2 and purified by preparative TLC (silica, 8% MeOH/CH2Cl2) to give 35 mg (61%) the title compound. HPLC (reverse phase conditions): tR=4.41 min. MS (electrospray): m/z calculated for C28H3435Cl79BrN5O2 [M++H], 586.16, found 586.2. 1H NMR (CDCl3, 400 MHz, a mixture of amide rotamers): 7.56 (d (partially obscured), J=8.5, Hz, 2H), 7.53 (s, 4H), 7.48 (d, J=8.5 Hz, 2H), 7.08 (br d, J=8.5 Hz, 1H), 6.95 (m, 2H), 4.85 and 4.73 (A and B of AB quartet, Jab=15.6 Hz, 1H), 4.62 (s, 1H), 4.20 (m, 2H), 4.04 (m, 2H), 3.90-3.71 (m, 2H), 2.92-2.53 (m, 11H), 2.21 (s, 1.5H), 2.16 (s, 1.5H).
Reaction SMILES: C([O:4][CH:5](OC(=O)C)[C:6]1[CH:18]=[C:17]2[C:9]([C:10]3[CH:11]=[C:12]([Br:20])[CH:13]=[CH:14][C:15]=3[C:16]2=[O:19])=[CH:8][CH:7]=1)(=O)C.C[O-].[Na+].P([O-])([O-])([O-])=O>CO.C1COCC1.C(OCC)(=O)C>[Br:20][C:12]1[CH:13]=[CH:14][C:15]2[C:16](=[O:19])[C:17]3[C:9]([C:10]=2[CH:11]=1)=[CH:8][CH:7]=[C:6]([CH:5]=[O:4])[CH:18]=3
Reactant: CC(=O)OC(OC(C)=O)c1ccc2c(c1)C(=O)c1ccc(Br)cc1-2
Agent: C[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: O=Cc1ccc2c(c1)C(=O)c1ccc(Br)cc1-2
Temperature: 25 °C
Reaction time: 22.5 h
Yield: 105.4 %

Procedure:
7-Diacetoxymethyl-3-bromo-9-fluorenone (61.1 mg) was suspended in methanol (4.4 ml) and THF (1.0 ml). To this suspension was added 0.054M NaOMe (0.56 ml). The reaction mixture was stirred at room temperature for 22.5 hours. It was then neutralized with 0.2M pH 7 phosphate buffer. The THF and methanol were removed under reduced pressure. Reaction mixture was then diluted with ethyl acetate, washed with water and brine, dried and evaporated gave the crude product (47.5 mg).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]4[N:25]=[CH:26][N:27](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:28]=4)=[O:23])=[CH:17][CH:16]=3)[NH:10][C:9]=2[C:8](=[O:48])[N:7]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[F:56])[C:6]1=[O:57])[CH2:2][CH2:3][CH3:4].[F:58][C:59]([F:64])([F:63])[C:60]([OH:62])=[O:61].C([SiH](CC)CC)C>ClCCl>[F:58][C:59]([F:64])([F:63])[C:60]([OH:62])=[O:61].[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([NH:21][C:22]([C:24]4[N:25]=[CH:26][NH:27][CH:28]=4)=[O:23])=[CH:19][CH:20]=3)[NH:10][C:9]=2[C:8](=[O:48])[N:7]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[F:56])[C:6]1=[O:57])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NC(=O)c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)cn4)cc3)nc21
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NC(=O)c4c[nH]cn4)cc3)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
A solution of 1-trityl-1H-imidazole-4-carboxylic acid {4-[3-butyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-amide (46 mg, 0.06 mmol) in dichloromethane (1.0 mL) at 25° C. was treated with trifluoroacetic acid (1.0 mL). The reaction was stirred at 25° C. for 30 min. At this time, the reaction was treated with triethylsilane (20 μL, 0.12 mmol) and then concentrated in vacuo. The resulting residue was purified by HPLC (20–95% acetonitrile/water (0.075% trifluoroacetic acid in both solvents) over 20 min). Fractions with the desired product were freeze dried to afford 1H-imidazole-4-carboxylic acid {4-[3-butyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-amide; compound with trifluoro-acetic acid (27.8 mg, 74%) as a white solid: EI-HRMS m/e calcd for C27H26N7O3F (M+) 515.2081, found 515.2083.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([C:11]([O:13]CC)=[O:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O[Li].O>CO.C1COCC1.O>[Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([C:11]([OH:13])=[O:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1coc2c(Br)cccc12
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1coc2c(Br)cccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 7-bromo-1-benzofuran-3-carboxylate (1.0 g, 3.7 mmol) in 20 mL of MeOH/THF/H2O (2/211) was added LiOH H2O (777 mg, 18.5 mmol), and the mixture was stirred at ambient temperature overnight. The solvents were removed under vacuum, and the residue was added 10 mL of water and extracted with ether (100 mL). The aqueous layer was then acidified with 4 N HCl to pH=3 in ice bath, and extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated to give 7-bromo-1-benzofuran-3-carboxylic acid.
Reaction SMILES: [Na].F[C:3]1[N:8]=[C:7]([C:9]2([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[CH3:15][OH:16]>>[CH3:15][O:16][C:3]1[N:8]=[C:7]([C:9]2([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1
Reactant: CO
Reactant: N#CC1(c2cccc(F)n2)CCC1
Agent: [Na]
Product: COc1cccc(C2(C#N)CCC2)n1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To stirred 6.0 mL of anhydrous methanol at 0° C. under nitrogen was added sodium metal (˜1 g) and the mixture stirred for 30 minutes. To this was added 1-(6-fluoropyridin-2-yl)cyclobutanecarbonitrile (1.6 g, 9.1 mmol) and the resulting mixture heated to 75° C. for 45 minutes. The solution was cooled to room temperature and partitioned between water and EtOAc. The layers were separated, the aqueous phase was extracted with EtOAc, and the combined organic phases were washed with saturated NaCl, dried over Na2SO4 and concentrated in vacuo to give the desired product (1.7 g, 97%) as a colorless oil.
Reaction SMILES: [OH:1][CH:2]([CH3:17])[C:3]([NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15])([CH3:5])[CH3:4].C(N(CC)CC)C.O>CS(C)=O>[O:1]=[C:2]([CH3:17])[C:3]([NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15])([CH3:4])[CH3:5]
Reactant: CC(O)C(C)(C)NC(=O)c1ccc(F)cc1F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(=O)C(C)(C)NC(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.9 %

Procedure:
To a solution of N-(2-hydroxy-1,1-dimethylpropyl)-2,4-difluorobenzamide obtained in Example 33 (0.30 g, 1.2 mmol) and triethylamine (0.37 g, 3.7 mmol) in DMSO (3 ml) was added pyridine sulfur trioxide complex (0.59 g, 3.7 mmol) portionwise and stirred at room temperature for 3 hours. The reaction mixture was added to a mixture of ice and water and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, saturated aqueous NaHCO3 and brine, successively dried over Na2SO4 and concentrated under a reduced pressure. The residue was crystallized from hexane/ethyl acetate to give the title compound (0.24 g; 81%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]1[C:22](=[O:27])[O:23][C:24](=[O:26])[CH2:25][C:5]2=1.[CH2:28]([NH2:32])[CH2:29][CH2:30][CH3:31]>C(Cl)Cl>[CH2:28]([NH:32][C:24]([CH2:25][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[N:7]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:6]=1[C:22]([OH:23])=[O:27])=[O:26])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCN
Reactant: O=C1Cc2c(n(Cc3cccc4ccccc34)c3ccc(F)cc23)C(=O)O1
Solvent: ClCCl
Product: CCCCNC(=O)Cc1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccc(F)cc12

Procedure:
To a solution of 6-fluoro-9-naphthalen-1-ylmethyl-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione (1.0 mmole) in CH2Cl2 (3 ml) was added n-butylamine (5 mmole) and stirring was continued at 60° C. until completion of the reaction. The mixture was evaporated and the residue partitioned between aqueous HCl and AcOEt. The organic layer was dried, evaporated and the residue triturated with diethylether to give 3-butylcarbamoylmethyl-5-fluoro-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid as a white solid. MS: 431.4 ([M−H]−).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40]O)=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[CH3:46][N:47]([CH3:64])[CH2:48][CH2:49][CH2:50][NH:51]S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O.CC(NS(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)(C)C(N)=O>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][NH:51][CH2:50][CH2:49][CH2:48][N:47]([CH3:64])[CH3:46])=[CH:33][C:32]=3[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CN(C)CCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCO)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CC(C)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])C(N)=O
Product: Cc1cc(OCCCNCCCN(C)C)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 51 using 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and N,N-dimethyl-N′-(2-nitrobenzenesulfonyl)-1,3-diaminopropane instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-methyl-2-(2-nitrobenzenesulfonylamino)propionamide, respectively.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH:5]([NH2:11])[CH2:4]2.[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1/[CH:21]=[CH:22]/[C:23](O)=[O:24])([O-:14])=[O:13]>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH:5]([NH:11][C:23](=[O:24])/[CH:22]=[CH:21]/[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N+:12]([O-:14])=[O:13])[CH2:4]2
Reactant: O=C(O)/C=C/c1ccccc1[N+](=O)[O-]
Reactant: NC1CN2CCC1CC2
Agent: Cl
Product: O=C(/C=C/c1ccccc1[N+](=O)[O-])NC1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (RS)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(2-nitrophenyl)propenoic acid as a solid; MS (ES+) 302 (MH+).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11](=[O:24])[C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH2:25]([O:27][C:28]([C:30]1[CH:31]=[CH:32][C:33](Cl)=[N:34][CH:35]=1)=[O:29])[CH3:26].C(N(C(C)C)CC)(C)C>C1COCC1>[CH2:25]([O:27][C:28](=[O:29])[C:30]1[CH:31]=[CH:32][C:33]([N:21]2[CH2:22][CH2:23][N:18]([C:15]3[CH:14]=[CH:13][C:12]([C:11](=[O:24])[NH:10][C:6]4[CH:5]=[C:4]5[C:9](=[CH:8][CH:7]=4)[CH2:1][CH2:2][CH2:3]5)=[CH:17][CH:16]=3)[CH2:19][CH2:20]2)=[N:34][CH:35]=1)[CH3:26]
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: O=C(Nc1ccc2c(c1)CCC2)c1ccc(N2CCNCC2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccc5c(c4)CCC5)cc3)CC2)nc1
Temperature: 170 °C
Yield: 52.9 %

Procedure:
To a solution of N-indan-5-yl-4-piperazin-1-yl-benzamide (80 mg) and 2-chloropyridine-5-carboxylic acid ethyl ester (220 mg) in THF (4 mL) was added diisopropylethylamine (0.1 mL). The solution was heated in a microwave at 170° C. for 2 hrs. The crystalline precipitate was filtered and washed with THF to give 6-{4-[4-(indan-5-ylcarbamoyl)-phenyl]-piperazin-1-yl}-nicotinic acid ethyl ester (62 mg, Yield: 53%). LCMS calc for C28H30N4O3 (m/e) 470, obsd 471 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C=Cc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1cccc(N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
A mixture of ethyl 3-(3-nitrophenyl)acrylate (63 g, 284 mmol) and Pd/C (6.3 g) in MeOH (800 ml) were stirred under 40 psi of H2 at room temperature for 2 hr, then filtered through celite to give the product ethyl 3-(3-aminophenyl)propanoate (48 g, yield 89%). 1H NMR MeOD 400 MHz. δ 7.00-6.51 (m, 4H), 4.10-4.04 (m, 2H), 2.79-2.76 (m, 2H), 2.56-2.52 (m, 2H), 1.20-1.17 (m, 3H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([CH3:28])[O:11][C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([OH:27])[CH:26]=1)[C:15]([NH:17][C:18]1[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=1)=[O:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:29][N:30]1[C:38]2[C:33](=[CH:34][C:35](B(O)O)=[CH:36][CH:37]=2)[CH:32]=[CH:31]1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Si:1]([O:8][CH2:9][C@H:10]([CH3:28])[O:11][C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([O:27][C:35]2[CH:34]=[C:33]3[C:38](=[CH:37][CH:36]=2)[N:30]([CH3:29])[CH:31]=[CH:32]3)[CH:26]=1)[C:15]([NH:17][C:18]1[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=1)=[O:16])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: Cn1ccc2cc(B(O)O)ccc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc3c(ccn3C)c2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.9 %

Procedure:
A solution of 3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyloxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (202 mg, 0.5 mmol), 1-methylindole-5-boronic acid (131 mg, 0.75 mmol), copper (II) acetate (138 mg, 0.75 mmol), triethylamine (0.35 mL, 2.5 mmol) and freshly activated 4A molecular sieves (1 g) in DCM (10 mL) was stirred at ambient temperature and under ambient atmosphere for 2 days. The reaction mixture was filtered through Celite, washed with DCM (2×10 mL), the DCM removed in vacuo and the residual oil partitioned between ethyl acetate (25 mL) and water (25 mL). The ethyl acetate layer was separated, washed with aqueous sodium hydrogen carbonate solution, brine, dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with 40% ethyl acetate in iso-hexane, to give the desired compound (128 mg).
Reaction SMILES: [CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[NH:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:18]=1[CH2:19]Br>>[CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[N:10]2[CH2:19][C:18]2[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:17]=2[Cl:16])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)NN(C2CCCCCCC2)C1=O
Reactant: Clc1ccc(Cl)c(CBr)c1
Product: CC1(C)C(=O)N(C2CCCCCCC2)N1Cc1cc(Cl)ccc1Cl

Procedure:
2-Cyclooctyl-4,4-dimethyl-1,2-diazetidin-3-one and 2,5-dichlorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:29])[C:10]([C:26]([OH:28])=[O:27])=[CH:11][N:12]3CC3C=CC(OC)=CC=3OC)=[C:7]([CH3:30])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.O>FC(F)(F)C(O)=O>[N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:29])[C:10]([C:26]([OH:28])=[O:27])=[CH:11][NH:12]3)=[C:7]([CH3:30])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(Cn2cc(C(=O)O)c(=O)c3c(C)cc(N4CCC4)nc32)c(OC)c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N2CCC2)nc2[nH]cc(C(=O)O)c(=O)c12

Procedure:
A solution of Example 18B (0.230 g) in trifluoroacetic acid (5.6 mL) was heated at 60° C. for 1.5 hours then cooled, poured into water, and filtered. NMR (300 MHz, DMSO-d6) δ 12.88 (m, 1H), 8.33 (m, 1H), 6.32 (m, 1H), 4.14 (m, 4H), 2.72 (s, 3H), 2.38 (m, 2H). (C(O)OH not observed).