Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[C:6](O)=[O:7].COC1N=C(N)C=C(OC)[N:16]=1>>[CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[C:6]([NH2:16])=[O:7]
Reactant: CNc1cc(C(=O)O)ccc1O
Reactant: COc1cc(N)nc(OC)n1
Product: CNc1cc(C(N)=O)ccc1O
Yield: 67 %

Procedure:
Using 3-methylamino-4-hydroxylbenzoic acid and 2,6-dimethoxy-4-aminopyrimidine as materials, compound 3 is synthesized following a similar method as in Example 28. Yield: 67%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([OH:20])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[NH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[N:30]=[CH:29][CH:28]=[CH:27]2>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:20])[NH:21][C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[C:31]=3[N:30]=[CH:29][CH:28]=[CH:27]4)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: Nc1cccc2cccnc12
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: O=C(CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)Nc1cccc2cccnc12
Yield: 77.4 %

Procedure:
A procedure similar to that described in Example 52 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (170 mg, 0.5 mmol) and 8-aminoquinoline (150 mg, 1.04 mmol) to give 180 mg of the title compound (77%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.08 (bs, 1H), 10.25 (s, 1H), 8.90 (dd, 1H, J=1.8, 4.5 Hz), 8.61 (d, J=6.6 Hz), 8.41 (d, 8.3 Hz), 7.56 7.70 (m, 3H), 7.24 (s, 1H), 7.18 (s, 1H), 5.25~5.34 (m, 1H), 3.18 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 3.03 (dd, 1H, J=14.5, 8.9 Hz), 2.78~2.85 (m, 2H), 2.17 (dm, 1H, J=13.5 Hz), 1.85~1.99 (m, 1H).
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH2:11]([C:21]1[NH:22][CH:23]=[CH:24][CH:25]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Cl.O.O.O.C([O-])(=O)C.[Na+]>ClCCCl.O>[CH2:11]([C:21]1[NH:22][C:23]([CH:3]=[O:4])=[CH:24][CH:25]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CN(C)C=O
Reactant: CCCCCCCCCCc1ccc[nH]1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCCCc1ccc(C=O)[nH]1
Temperature: 25 °C
Yield: 82.3 %

Procedure:
To an ice cooled 4 g (56 mmol) of dimethylformamide was added 8.6 g (56 mmol) of phosphorous oxychloride over a period of 15 minutes while stirring under a nitrogen atmosphere. The mixture was stirred 15 minutes and then 15 mL of 1,2-dichloroethane was added. To this mixture was added a solution of 10.5 g (50.6 mmol) of 2-decylpyrrole, 35, in 15 mL of 1,2-dichloroethane while cooling in an ice bath. The reaction mixture was then heated under reflux for 15 minutes, during which time there was copious evolution of hydrogen chloride gas. After cooling to room temperature, a solution of sodium acetate trihydrate (38.1 g, 280 mmol) in 50 mL of water was added to the mixture. After heating at reflux for 15 minutes, the mixture was cooled and the 1,2-dichloroethane layer was separated. The aqueous layer was extracted with chloroform. The combined organic extracts were washed with saturated aqueous sodium carbonate solution and dried over anhydrous sodium carbonate. Following evaporation of solvent under vacuum, the crude product was purified by silica gel column chromatography with 1:9 ethyl acetate/hexanes as eluant, giving 9.8 g (82%) of compound 38 as a white solid.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][CH2:10][C:6]2=[N:5][CH:4]=[C:3]1[C:11]([O:13]CC)=O.[OH-].[NH4+:17]>>[C:11]([C:3]1[C:2](=[O:1])[N:7]2[CH2:8][CH2:9][CH2:10][C:6]2=[N:5][CH:4]=1)(=[O:13])[NH2:17]
Reactant: [NH4+]
Reactant: CCOC(=O)c1cnc2n(c1=O)CCC2
Agent: [OH-]
Product: NC(=O)c1cnc2n(c1=O)CCC2
Yield: 96.6 %

Procedure:
10.4 g of ethyl 4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine-3-carboxylate are dissolved in 30 ml of 30% by weight of ammonium hydroxide solution. The precipitated crystals are filtered after 2 hours. 8.7 g of 3-carbamoyl-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine are obtained with a yield of 96.6%, which melts at 293° C. after recrystallization from dimethyl formamide.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:40])[N:24]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH:20]=[C:19]([Cl:41])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]>ClCCl>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[Cl:41][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=1)[C:23]([N:24]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)=[O:40]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCOc2ccccn2)c2ccccc2)c1)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1cc(Cl)cc(OCCNc2ccncc2)c1)N(CCOc1ccccn1)c1ccccc1

Procedure:
A solution of {2-[3-chloro-5-(phenyl-2-(pyridin-2-yloxy)-ethyl-carbamoyl)-phenoxy]-ethyl}-pyridin-4-yl-carbamic acid tert-butyl ester (0.065 g) and trifluoroacetic acid (0.75 ml) in dichloromethane (0.75 ml) was stirred at room temperature for 2 h then concentrated under vacuum, co-evaporating with dichloromethane to give the title compound as a yellow oil (0.086 g).
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:18])=O.N#N>C(Cl)Cl.CN(C=O)C>[C:1]1([CH2:11][C:12]([Cl:18])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1cccc2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Agent: N#N
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)Cc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 12 h
Yield: 99.6 %

Procedure:
1-Naphthylacetylchloride was synthesized from 1-naphthylacetic acid (20.0 g, 107.4 mmol) which was dissolved in CH2Cl2 (200 mL) and the solution was cooled to 0° C. Oxalylchloride (11.20 mL, 128.90 mmol) was added to the solution dropwise over 20 min. under the atmosphere of N2 then followed by one drop of DMF. The mixture was then allowed to warm to room temperature where it was stirred for 12 hours. The reaction mixture was concentrated under vacuum, the resulting residue was redissolved in CH2Cl2 (200 mL) and the solvents were evaporated in vacuo to give 1-naphthylacetylchloride 21.90 g (99%) as a dark oil: 1H-NMR (400 MHz, CDCl3) δ 7.92-7.84 (m, 3H), 7.61-7.42 (m, 4H), 4.58 (s, 2H).
Reaction SMILES: CC[O:3]C(C[NH3+])=O.[Cl-].C([O-])(=O)C.[Na+].[OH:14][C:15]1[N:20]=[CH:19][NH:18][C:17]2=[C:21]([C@@H:24]3[NH:31][C@H:28]([CH2:29]O)[C@@H:26]([OH:27])[CH2:25]3)[CH:22]=[N:23][C:16]=12>CO>[OH:14][C:15]1[N:20]=[CH:19][NH:18][C:17]2=[C:21]([C@@H:24]3[NH:31][C@H:28]([CH3:29])[C@@H:26]([OH:27])[C@H:25]3[OH:3])[CH:22]=[N:23][C:16]=12
Reactant: OC[C@H]1N[C@@H](c2cnc3c(O)nc[nH]c2-3)C[C@@H]1O
Reactant: CCOC(=O)C[NH3+]
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: C[C@H]1N[C@@H](c2cnc3c(O)nc[nH]c2-3)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Glycine hydrochloride ethyl ester (0.76 g) and sodium acetate (0.9 g) were added to a stirred solution of the product from Example 1.3 (0.51 g) in methanol (10 ml). The mixture was stirred at room temperature for 16 h and then concentrated to dryness. Chromatography of the residue gave the (1S)-N-tert-butoxycarbonyl-5-O-tert-butyldimethylsilyl-1-C-[1-cyano-2-(ethoxycarbonylmethylamino) ethenyl]-1,4-dideoxy-1,4-imino-2,3-O-isopropylidene-D-ribitol (4) (0.48) g as a diastereomeric mixture.
Reaction SMILES: [C:1]([C:3](=[C:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([OH:27])[CH2:18][CH2:19]2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH2:4][C:5]([O-:7])=[O:6])#[N:2].[Na+].Cl>O>[C:1]([C:3](=[C:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([OH:27])[CH2:18][CH2:19]2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH2:4][C:5]([OH:7])=[O:6])#[N:2]
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=C(C#N)CC(=O)[O-])CC[C@@H]12
Agent: Cl
Agent: [Na+]
Solvent: O
Product: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=C(C#N)CC(=O)O)CC[C@@H]12

Procedure:
A solution of 20 parts of sodium 20-cyano-3β-hydroxypregna-5,17(20)-diene-21-carboxylate in 1000 parts of warm water is acidified with 100 parts of 4% hydrochloric acid. Approximately 1 hour later, the precipitate which has formed is separated by filtration, washed with water, dried in vacuo, and recrystallized from methanol to give 20-cyano-3β-hydroxypregna-5,17(20)-diene-21-carboxylic acid melting at 245°-250°. The product has the formula ##STR3##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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:23][C:24]1[CH:29]=[C:28]([C:18]2[CH:19]=[CH:20][C:15]([C:14]([NH:13][CH2:12][CH2:11][C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[NH:7][CH:6]=3)=[O:22])=[CH:16][CH:17]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Reactant: OB(O)c1cccc(Cl)c1
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: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(-c2cccc(Cl)c2)cc1
Yield: 65.2 %

Procedure:
3′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 3-chlorophenylboronic acid (0.029 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.047 g (65%) of 3′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].N1C=CC=CC=1.[C:18](Cl)(=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>ClC(Cl)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18](=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCCCCCCCC(=O)Cl
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCC(=O)Nc1ccc(Cl)c([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
4-chloro-3-nitroaniline, 10.1 g (0.058 mole), is dissolved in 100 ml dichloroethane, containing 25 ml pyridine. The solution is stirred at room temperature while nonanoylchloride, 10.5 g (0.067 mole), is added slowly. The solution is stirred for 2 hours. Excess pyridine is removed by washing the product with 4N hydrochloric acid. The product is then passed through a florisil column. The product does not crystallize from dichloroethane which was removed. The product was crystallized from 80% ethanol. There is obtained N-(4-Chloro-3-nitrophenyl) nonanamide (M.P. 44.5-45.0). Analysis shows 8.9% nitrogen and 11.26% chlorine as against calculated values of 8.96% and 11.33% respectively for C15H21ClN2O3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=O)=[CH:5][CH:4]=1.[NH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.C1CCC(N=C=NC2CCCCC2)CC1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6](/[CH:7]=[CH:8]/[C:9]([NH:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[O:11])=[CH:12][CH:13]=1
Reactant: Nc1ccncc1
Reactant: COc1ccc(C=CC(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: COc1ccc(/C=C/C(=O)Nc2ccncc2)cc1
Yield: 14.2 %

Procedure:
Reaction of 4-methoxycinnamic acid (0.89 g, 5.00 mmol) with 4-aminopyridine (0.47 g, 5.00 mmol) was conducted according to the general amide coupling procedure using DCC to obtain the product as a white solid (0.18 g, 14%). EIMS m/z: 255 ([M]+).
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]([C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=[C:12]4[C:28]3[CH:33]=[N:32][CH:31]=[C:30]([CH:34]4[CH2:36][CH2:35]4)[N:29]=3)=[N:7][N:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>O1CCOCC1>[CH:1]1([C:4]2[O:5][C:6]([C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[NH:14][CH:13]=[C:12]4[C:28]3[CH:33]=[N:32][CH:31]=[C:30]([CH:34]4[CH2:36][CH2:35]4)[N:29]=3)=[N:7][N:8]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(C4CC4)n3)c3cc(-c4nnc(C5CC5)o4)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: c1cc2[nH]cc(-c3cncc(C4CC4)n3)c2cc1-c1nnc(C2CC2)o1
Temperature: 25 °C
Yield: 49.8 %

Procedure:
A yellow solution of 2-cyclopropyl-5-(3-(6-cyclopropylpyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazole (206.8 mg, 0.416 mmol) and NaOH (3.0 M, aq; 2.0 mL, 6.00 mmol) in dioxane (5.0 mL) was heated at 100° C. for 40 min. The reaction was cooled to RT and partitioned between DCM (50 mL) and H2O (30 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (30 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-100% (10% MeOH-EtOAc)/Hex) furnished 2-cyclopropyl-5-(3-(6-cyclopropylpyrazin-2-yl)-1H-indol-5-yl)-1,3,4-oxadiazole (71.0 mg, 0.207 mmol, 50%) as a yellow solid: MS (ESI, pos. ion) m/z: 344.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.03 (1H, br. s.), 9.06 (1H, d, J=1.4 Hz), 8.93 (1H, s), 8.41 (1H, s), 8.38 (1H, s), 7.82 (1H, dd, J=8.5, 1.7 Hz), 7.61 (1H, d, J=8.6 Hz), 2.29-2.38 (1H, m), 2.20-2.29 (1H, m), 1.13-1.25 (8H, m).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][C:9]3[N:11]=[C:12]([N:18]4[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]4)[CH:13]=[C:14]([CH2:15][CH2:16][CH3:17])[C:8]=3[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:25][CH2:26][C@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[OH:28].C([BH3-])#N>CN(C=O)C.C(O)(=O)C>[NH2:1][C:2]1[C:3]2[S:10][C:9]3[N:11]=[C:12]([N:18]4[CH2:19][CH2:20][CH:21]([NH:25][CH2:26][C@H:27]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[OH:28])[CH2:22][CH2:23]4)[CH:13]=[C:14]([CH2:15][CH2:16][CH3:17])[C:8]=3[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCCc1cc(N2CCC(=O)CC2)nc2sc3c(N)ncnc3c12
Reactant: NC[C@@H](O)c1ccccc1
Agent: [BH3-]C#N
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCCc1cc(N2CCC(NC[C@@H](O)c3ccccc3)CC2)nc2sc3c(N)ncnc3c12
Reaction time: 16 h
Yield: 56.2 %

Procedure:
1-(4-Amino-9-propyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-7-yl)-piperidin-4-one (Example 4) (341 mg, 1.00 mmol) and (S)-2-amino-1-phenylethanol (142 mg, 1.00 mmol) was dissolved in 10 mL of dry DMF. MP-Cyanoborohydride (0534 mg, 1.20 mmol) was added followed by 10 drops of glacial acetic acid. This mixture was shaken for 16 h. The resin was removed by filtration and washed with MeOH and dichloromethane. The filtrate was evaporated. The residue was treated with 2 M sodium carbonate solution. The resulting solid was collected by filtration and recrystalized from MeOH/acetonitrile to give the title compound as a pale-colored solid (0.260 g, 56%).
Reaction SMILES: C(O[C:4](=[O:16])[C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[CH2:14]Br)C.[CH3:17][O:18][C:19](=[O:29])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1.NC1C=CC=CC=1>>[CH3:17][O:18][C:19](=[O:29])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:14][C:6]3[C:5](=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[CH:8][CH:7]=3)[C:4]2=[O:16])=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1CBr
Reactant: COC(=O)CCc1ccc(N)cc1
Solvent: Nc1ccccc1
Product: COC(=O)CCc1ccc(N2Cc3ccc([N+](=O)[O-])cc3C2=O)cc1

Procedure:
By using 2-bromomethyl-5-nitrobenzoic acid ethyl ester and 3-(4-amino-phenyl)propionic acid methyl ester instead of 2-bromomethyl-6-nitro-benzoic acid methyl ester and aniline in Example 25, synthesis was performed in the same manner as that of Example 25 to obtain 3-[4-(6-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-phenyl]-propionic acid methyl ester as yellow crystals.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH2:9]1[CH2:19]CN2C(=NCCC2)C[CH2:10]1.C(Br)(C)C.C(O)(=O)C>C1COCC1>[CH:9]([O:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][CH:8]=1)([CH3:19])[CH3:10]
Reactant: Oc1cccc(O)c1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CC(C)Br
Product: CC(C)Oc1cccc(O)c1

Procedure:
In 10 ml of THF, 1.5 g of resorcinol was dissolved and 2.24 ml of DBU was added under ice cooling. The resultant mixture was stirred for 10 min at room temperture. To the mixture, 1.92 ml of isopropyl bromide was added and refluxed for 2 hr. The reaction mixture was neutralized with acetic acid and evaporated under reduced pressure. The evaporated residue was redissolved in ethyl acetate and washed with 5% aqueous citric acid solution and saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure and the residue was subjected to a silica gel column chromatography (chloroform:methanol=40:1) to give 466 mg of the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]3[N:22]4[C@@H:23]([C:27]([F:30])([CH3:29])[CH3:28])[CH2:24][O:25][CH2:26][C:21]4=[N:20][C:14]=3[C:15]([NH2:19])=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:19][C:15]1[C:14]2[N:20]=[C:21]3[CH2:26][O:25][CH2:24][C@H:23]([C:27]([F:30])([CH3:29])[CH3:28])[N:22]3[C:13]=2[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[CH:10][CH:11]=2)[N:16]=1
Reactant: CC(C)(F)[C@H]1COCc2nc3c(N)nc4cc(OCc5ccccc5)ccc4c3n21
Agent: [Pd]
Solvent: CCO
Product: CC(C)(F)[C@H]1COCc2nc3c(N)nc4cc(O)ccc4c3n21
Reaction time: 8 h
Yield: 26.1 %

Procedure:
(11R)-3-(Benzyloxy)-11-(1-fluoro-1-methylethyl)-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (310 mg, 0.763 mmol) was dissolved in ethanol (50 mL) and the solution was placed in a pressure bottle. Palladium on carbon (10%, 140 mg) was added and the reaction mixture was shaken under H2 at 48 PSI (3.3×105 Pa) overnight. The reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with 1:1 CH2Cl2/ethanol and the combined filtrates were concentrated under reduced pressure to give an off white solid. Chromatography (SiO2, 30-50% CMA/CHCl3) followed by recrystallization from 1,2-dichloroethane gave (11R)-6-amino-11-(1-fluoro-1-methylethyl)-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-3-ol (63 mg) as a white powder, mp 219-221° C.
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)=[CH:22][C:4]=1[O:5][CH:6]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[CH3:21])[CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])#[N:2].[OH-].[Na+].Cl>CO>[C:1]([C:3]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)=[CH:22][C:4]=1[O:5][CH:6]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[CH3:21])[CH2:7][CH2:8][C:9]([OH:11])=[O:10])#[N:2]
Reactant: CCOC(=O)CCC(Oc1cc(OCc2ccsc2)ccc1C#N)c1cc(C)ccc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C)c(C(CCC(=O)O)Oc2cc(OCc3ccsc3)ccc2C#N)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.3 %

Procedure:
A solution of ethyl (RS)-4-(2-cyano-5-(3-thienylmethoxy)phenoxy)-4-(2,5-dimethylphenyl)butanoate (500 mg) in methanol (20 mL) containing 1 N sodium hydroxide (5 mL) is stirred at ambient temperature for 16 hours. The reaction mixture is poured into 0.5 N HCl (20 mL) and extracted three times with ethyl acetate (20 mL). The combined organic phases are washed with brine (20 mL), dried over magnesium sulphate, filtered and concentrated under reduced pressure to leave a brown oil. Crystallisation with cyclohexane gives (RS)-4-(2-cyano-5-(3-thienylmethoxy)phenoxy)-4-(2,5-dimethylphenyl) butanoic acid, (170 mg) in the form of an off-white solid, m.p. 135-136° C. [Elemental analysis:- C,68.4, H, 5.46, N, 3.33%. Calculated:- C,68.7, H, 5.57, N, 3.00%]
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:8][CH:9]=2)[C:4](=[O:17])[C:3]=1[C:18]([NH:20][CH2:21][C:22]([O:24]CC)=[O:23])=[O:19].[Br:27][C:28]1[CH:36]=[C:35]2[C:31]([C:32]([OH:47])=[C:33]([C:38]([NH:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:39])[C:34]2=[O:37])=[CH:30][CH:29]=1>>[OH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:8][CH:9]=2)[C:4](=[O:17])[C:3]=1[C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19].[Br:27][C:28]1[CH:36]=[C:35]2[C:31]([C:32]([OH:47])=[C:33]([C:38]([NH:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:39])[C:34]2=[O:37])=[CH:30][CH:29]=1
Reactant: CCOC(=O)CNC(=O)C1=C(O)c2ccc(-c3ccccc3)cc2C1=O
Agent: CCOC(=O)CNC(=O)C1=C(O)c2ccc(Br)cc2C1=O
Product: O=C(O)CNC(=O)C1=C(O)c2ccc(-c3ccccc3)cc2C1=O

Procedure:
ethyl 2-(3-hydroxy-1-oxo-6-phenyl-1H-indene-2-carboxamido)acetate. The title compound was prepared by a method analogous to Method 2(a) using ethyl 2-(6-bromo-3-hydroxy-1-oxo-1H-indene-2-carboxamido)acetate as starting material. Ethyl 2-(6-bromo-3-hydroxy-1-oxo-1H-indene-2-carboxamido)acetate was prepared by Method 1, as in Example 2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[C:13]([O:18][CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:6]2[C:10]=1[C@@H:9]([OH:11])[CH2:8][CH2:7]2.O[C:25]1[CH:38]=[CH:37][C:28]2[C@H:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:30][O:31][C:27]=2[CH:26]=1.BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[C:13]([O:18][CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:25]1[CH:38]=[CH:37][C:28]3[C@H:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:30][O:31][C:27]=3[CH:26]=1)[CH2:8][CH2:7]2
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Reactant: CC(C)(C)COc1ncccc1-c1ccc(F)c2c1CC[C@@H]2O
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccnc5OCC(C)(C)C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from (1S)-7-fluoro-4-(2-(neopentyloxy)pyridin-3-yl)-2,3-dihydro-1H-inden-1-ol and (S)-methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate following a procedure analogous to that described in Step 3 of Intermediate 1. LC (method 15): tR=1.32 min.
Reaction SMILES: C(C1C(C(O)=O)=CC(N2CCC(N3C4C(=NC=CC=4)NC3=O)CC2)=NC=1)#N.[C:28]([C:30]1[C:31]([N:39]2[CH2:44][CH2:43][CH:42]([N:45]3[C:53]4[C:48](=[N:49][CH:50]=[CH:51][CH:52]=4)[NH:47][C:46]3=[O:54])[CH2:41][CH2:40]2)=[CH:32][C:33]([C:36](O)=[O:37])=[N:34][CH:35]=1)#[N:29].Cl.Cl.[CH3:57][C:58]1([CH3:67])[CH2:63][NH:62][CH2:61][C:60]2[CH:64]=[N:65][NH:66][C:59]1=2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:57][C:58]1([CH3:67])[CH2:63][N:62]([C:36]([C:33]2[N:34]=[CH:35][C:30]([C:28]#[N:29])=[C:31]([N:39]3[CH2:40][CH2:41][CH:42]([N:45]4[C:53]5[C:48](=[N:49][CH:50]=[CH:51][CH:52]=5)[NH:47][C:46]4=[O:54])[CH2:43][CH2:44]3)[CH:32]=2)=[O:37])[CH2:61][C:60]2[CH:64]=[N:65][NH:66][C:59]1=2
Reactant: CC1(C)CNCc2cn[nH]c21
Reactant: N#Cc1cnc(C(=O)O)cc1N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC1(C)CN(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)c(C#N)cn2)Cc2cn[nH]c21
Temperature: 25 °C

Procedure:
0.11 mg (0.29 mmol) of an isomer mixture of 5′-cyano-4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-carboxylic acid and 5′-cyano-4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-2′-carboxylic acid, 65 mg (0.29 mmol) 7,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine dihydrochloride and 0.17 mL (1.2 mmol) TEA were placed in 1.5 mL DMF. 0.10 g (0.32 mmol) TBTU were added. The reaction mixture was stirred over the weekend at RT. The purification and separation of the isomers were carried out by HPLC-MS. The product-containing fractions were combined and freeze-dried.