Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:20]([CH2:27][CH2:28][O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[O:38][C:39]3[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=3[N:41]=2)=[CH:33][CH:32]=1)[CH2:21][CH2:22][O:23][CH2:24][C:25]#[CH:26])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:47]1[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=1>C(N)CCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([N:20]([CH2:27][CH2:28][O:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]2[O:38][C:39]3[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=3[N:41]=2)=[CH:35][CH:36]=1)[CH2:21][CH2:22][O:23][CH2:24][C:25]#[C:26][C:47]1[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(I)cc1
Reactant: C#CCOCCN(CCOCc1ccc(-c2nc3ccccc3o2)cc1)C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCN
Product: Cc1ccc(C#CCOCCN(CCOCc2ccc(-c3nc4ccccc4o3)cc2)C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 75 °C

Procedure:
N-trityl-N-[2-(4-(benzoxazol-2-yl)benzyloxy)ethyl]-2-(prop-2-ynyloxy)ethanamine (0.517 g; 0.87 mmol), 4-iodotoluene (0.262 g; 1.2 mmol) and copper (I) iodide (3.5 mg; 2% /wt) are dissolved in BuNH2 (4 ml) in an inert atmosphere (argon). To this is added (PPh3)2PdC12, [bis(triphenylphosphine)palladium chloride], (6 mg; 1% /wt) and the reaction is heated at 75° C. for 1 hour. The mixture is then concentrated in vacuo and purified by column chromatography using 10 Et3N/10 CH2Cl2 /PE to obtain N-trityl-N-[2-(4-(benzoxazol-2yl)benzyloxy)ethyl]-2-[3-(4-methylphenyl)prop-2-ynyloxy]ethanamine which is used directly in Step G.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH:16]([CH2:20][C@H:21]3[CH2:41][CH2:40][C:23]4([O:27][C@H:26]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C@@H:25]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[O:24]4)[CH2:22]3)[C:17](O)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1.CC(C)(C)C(Cl)=O.[CH2:49]([C@@H:56]1[CH2:60][O:59][C:58](=[O:61])[NH:57]1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.C([Li])CCC.CCCCCC.[OH-].[Na+]>C1COCC1.C(N(CC)CC)C>[CH2:49]([C@@H:56]1[CH2:60][O:59][C:58](=[O:61])[N:57]1[C:17](=[O:18])[CH:16]([C:6]1[CH:7]=[CH:8][C:9]([S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[C:4]([CH:1]2[CH2:2][CH2:3]2)[CH:5]=1)[CH2:20][C@H:21]1[CH2:41][CH2:40][C:23]2([O:27][C@H:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C@@H:25]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:24]2)[CH2:22]1)[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: O=C(O)C(C[C@H]1CCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: O=C1OC[C@@H](Cc2ccccc2)N1C(=O)C(C[C@H]1CCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
To a solution of 2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]propionic acid (70.8 g) in THF (350 mL) were added triethylamine (21 mL) and 2,2-dimethylpropanoyl chloride (19 mL) at an internal temperature of 11° C. or lower under ice-cooling, followed by stirring at room temperature for 1 hour. In another vessel, to a solution of (4R)-4-benzyl-1,3-oxazolidin-2-one (26.3 g) in THF (200 mL) was added 2.64 M n-butyl lithium/hexane solution (54.8 mL) at an internal temperature of −50° C. or lower, followed by warming to room temperature, stirring for 1 hour, and then cooling to an internal temperature of −60° C. To this reaction mixture was added dropwise the acid anhydride/THF mixture, which had been prepared previously, at an internal temperature of −50° C. or lower, followed by stirring at room temperature for 4 hours. 1 M Sodium hydroxide (600 mL) was added thereto under ice-cooling and the organic solvent was evaporated under reduced pressure, followed by extraction with ethyl acetate/hexane (1/3, 200 mL×3). The organic layer was sequentially washed with a saturated aqueous ammonium chloride solution (200 mL) and saturated brine (200 mL), and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure to obtain (4R)-4-benzyl-3-{2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]propanoyl}-1,3-oxazolidin-2-one (72 g) as a brown oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](O)=[O:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2].[CH3:34][C:35]([CH3:40])([CH3:39])[C:36]([NH2:38])=[O:37]>C(OCC)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH:38][C:36](=[O:37])[C:35]([CH3:40])([CH3:39])[CH3:34])=[O:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Reactant: CC(C)(C)C(N)=O
Solvent: CCOC(C)=O
Product: CCCCCC(CC(=O)Nc1cc(C(=O)NC(=O)C(C)(C)C)ccc1C(C)(C)C)c1ccc(OC)cc1OC

Procedure:
Following a similar procedure to that described in Example 139, but using N-(2-t-butyl-5-carboxyphenyl)-3-(2,4-dimethoxyphenyl)octanamide (prepared as described in Preparation 7) and 2,2-dimethylpropanamide, the title compound was obtained as crystals, melting at 170-172° C. (from ethyl acetate).
Reaction SMILES: Cl.[N:2]1[C:10]2[CH2:9][CH:8]([C:11]([OH:13])=[O:12])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:14]O>S(=O)(=O)(O)O>[CH3:14][O:12][C:11]([CH:8]1[CH2:9][C:10]2[N:2]=[CH:3][CH:4]=[CH:5][C:6]=2[CH2:7]1)=[O:13]
Reactant: O=C(O)C1Cc2cccnc2C1
Reactant: CO
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)C1Cc2cccnc2C1

Procedure:
A solution 6,7-dihydro-5H-[1]pyrindine-6-carboxylic acid hydrochloride (Example 88; 0.640 g, 3.21 mmol) and concentrated sulphuric acid (3 drops) in methanol (100 ml) is heated to reflux for 3 hours. The solvent is evaporated, the residue is treated with saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic phases are washed with brine, dried (MgSO4) and evaporated to afford 6,7-dihydro-5H-[1]pyrindine-6-carboxylic acid methyl ester, MH+178.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH2:22][C@@H:23]([CH3:26])[CH2:24][OH:25]>>[OH:25][CH2:24][C@@H:23]([NH:22][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21])[CH3:26]
Reactant: C[C@H](N)CO
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: C[C@@H](CO)Nc1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Yield: 61 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with (S)-2-amino-propan-1-ol according to the GPA affording 21.4 mg (61%) of a red powder. Rt=3.20 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:22])=[O:21])[C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([O:17]CC)=[O:16])=[CH:11]2.[OH-].[Na+].O1CCCC1>CO>[CH3:1][O:2][CH2:3][CH2:4][N:5]([S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:21])=[O:22])[C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11]2
Reactant: CCOC(=O)c1cc2cccc(N(CCOC)S(=O)(=O)c3cccs3)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COCCN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 50 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
A mixture of ethyl 7-[(2-methoxyethyl)(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (0.54 g), 2N aqueous sodium hydroxide solution (2.2 mL), tetrahydrofuran (4 mL) and methanol (4 mL) was stirred at 50° C. for 1 hr. The reaction mixture was concentrated, and water was added to the residue. The mixture was acidified with 10% aqueous citric acid solution, and the resulting crystals were filtrated, washed with water, and dried to give the title compound (0.46 g, yield 92%) as colorless crystals. melting point 216-217° C.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:4]1=[O:21].[CH2:22]([O:29][C:30](Cl)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.ClC(Cl)C.C(=O)([O-])O.[Na+]>O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:4](=[O:21])[CH:3]2[NH:2][C:30]([O:29][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:31]
Reactant: COc1ccc2c(c1)C(N)C(=O)N2c1ccc(F)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Product: COc1ccc2c(c1)C(NC(=O)OCc1ccccc1)C(=O)N2c1ccc(F)cc1
Yield: 93.9 %

Procedure:
A mixture of 30.0 g (0.0972 mole) of 3-amino-1-(4-fluorophenyl)-5-methoxy-2,3-dihydro-1H-indol-2-one hydrochloride, 18.2 g of benzyloxycarbonyl chloride, 200 ml of anhydrous dichloroethane and 200 ml of water was cooled in an ice-salt bath, and to the mixture was added 27.0 g of sodium hydrogen carbonate over 10 minutes under argon atmosphere while stirring. After the mixture was stirred at the same temperature for 20 minutes and at the room temperature for 20 minutes, the reaction mixture was washed with a 10% hydrochloric acid aqueous solution, water and then a saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and ethyl acetate to obtain 37.1 g of the title compound as colorless needle crystals. Melting point: 154.5° to 156° C.
Reaction SMILES: COC1C=CC([CH2:7][N:8](C)[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:22]4[C:23]([F:39])=[CH:24][C:25]([F:38])=[C:26]([NH:28][C:29]([NH:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[O:30])[CH:27]=4)[C:15](=[O:21])[N:16]3[CH2:19][CH3:20])=[CH:11][N:10]=2)=CC=1.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O>[CH2:19]([N:16]1[C:17]2[C:12](=[CH:11][N:10]=[C:9]([NH:8][CH3:7])[CH:18]=2)[CH:13]=[C:14]([C:22]2[C:23]([F:39])=[CH:24][C:25]([F:38])=[C:26]([NH:28][C:29]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:30])[CH:27]=2)[C:15]1=[O:21])[CH3:20]
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2F)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2F)cc2cnc(NC)cc21
Yield: 50.4 %

Procedure:
A solution of 1-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-phenylurea (219 mg, 0.384 mmol) in TFA (2.0 mL) was stirred at RT for 1 h. The mixture was concentrated in vacuo, dissolved in EtOAc, washed with satd. NaHCO3 and brine, dried (Na2SO4), warmed to reflux in MeOH (5 mL) with the drying agent, filtered free of drying agent (while hot), concentrated in vacuo and treated with 4M HCl/dioxane (0.2 mL). The mixture was evaporated at reduced pressure and then triturated with Et2O. The solid was collected by filtration, purified by reverse phase chromatography (MeCN/water with 0.1% TFA) and concentrated in vacuo to give an aqueous residue. The aqueous solution was treated with satd. NaHCO3 and allowed to precipitate. The solid was collected by filtration, washed with water and dried in vacuo to give 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-phenylurea (87 mg, 50% yield). 1H NMR (400 MHz, DMSO-d6), δ 9.01 (s, 1H), 8.52 (s, 1H), 8.42 (s, 1H), 8.12 (m, 1H), 7.81 (s, 1H), 7.42-7.24 (m, 5H), 7.05-6.94 (m, 2H), 6.23 (s, 1H), 4.13 (m, 2H), 2.85 (s, 3H), 1.20 (m, 3H); MS (ES-API) m/z: 450.1 [M+H]+.
Reaction SMILES: [Na:1].[CH3:2][CH2:3][C@@H:4]([C:23]([C@H:25]([C@@H:27]([OH:43])[C@@H:28]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([OH:39])[C:33]=1[C:40]([OH:42])=[O:41])[CH3:29])[CH3:26])=[O:24])[C@H:5]1[O:9][C@@:8]([C@@H:12]2[O:17][C@@H:16]([CH3:18])[C@@:15]([OH:21])([CH2:19][CH3:20])[CH2:14][CH2:13]2)([CH2:10][CH3:11])[CH2:7][C@@H:6]1[CH3:22].[Br:44]Br>C(=S)=S>[Br:44][C:37]1[C:32]([CH2:31][CH2:30][CH:28]([CH3:29])[CH:27]([OH:43])[CH:25]([CH3:26])[C:23](=[O:24])[CH:4]([CH2:3][CH3:2])[CH:5]2[CH:6]([CH3:22])[CH2:7][C:8]([CH2:10][CH3:11])([CH:12]3[CH2:13][CH2:14][C:15]([CH2:19][CH3:20])([OH:21])[CH:16]([CH3:18])[O:17]3)[O:9]2)=[C:33]([C:40]([OH:42])=[O:41])[C:34]([OH:39])=[C:35]([CH3:38])[CH:36]=1.[Na:1]
Reactant: BrBr
Reactant: CC[C@@H](C(=O)[C@@H](C)[C@@H](O)[C@H](C)CCc1ccc(C)c(O)c1C(=O)O)[C@H]1O[C@](CC)([C@H]2CC[C@](O)(CC)[C@H](C)O2)C[C@@H]1C
Agent: [Na]
Solvent: S=C=S
Product: CCC(C(=O)C(C)C(O)C(C)CCc1c(Br)cc(C)c(O)c1C(=O)O)C1OC(CC)(C2CCC(O)(CC)C(C)O2)CC1C

Procedure:
To a solution of 1.53 g of the sodium salt of antibiotic X-537A in 30 ml carbon disulfide was added dropwise a solution of 0.14 ml bromine 10 ml carbon disulfide at -5° over 10 minutes. The solvent was removed under a stream of nitrogen at room temperature (approximately 2 hours). The residue was purified by dissolving it in ethyl acetate and the solution washed successively with aqueous sodium bisulfite and sodium carbonate. After drying (Na2SO4), the solution was evaporated under reduced pressure and the residue crystallized from ethyl acetate to give 5-bromo-3-methyl-6-{7-ethyl-4-hydroxy-3,5-dimethyl-6-oxo-7-[5-ethyl-3-methyl-5-(5-ethyl-5-hydroxy-6-methyl-2-tetrahydropyranyl)-2-tetrahydrofuryl]heptyl} salicylic acid, sodium salt as colorless cubes, m.p. 185°, [α]D25 -7.36° (1% in methanol).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10](=[O:11])[NH:9][C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[CH:16][C:7]=12)=[O:5])[CH3:2].[Na].[CH3:18][O:19][C:20](=[O:28])[CH:21](Br)[CH2:22][C:23]([O:25][CH3:26])=[O:24]>CN(C=O)C.O>[CH3:18][O:19][C:20](=[O:28])[CH:21]([N:9]1[C:10](=[O:11])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=[C:8]12)[CH2:22][C:23]([O:25][CH3:26])=[O:24]
Reactant: CCOC(=O)c1c2cccccc-2[nH]c1=O
Reactant: COC(=O)CC(Br)C(=O)OC
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c2cccccc-2n(C(CC(=O)OC)C(=O)OC)c1=O
Temperature: 100 °C

Procedure:
A mixture of 1,2-dihydro-2-oxocyclohepta[b]pyrrole-3-carboxylic acid ethyl ester, sodium salt (12.5 g, described in example 1) and 2-bromobutanedioic acid dimethyl ester (14.5 g) in DMF (14.5 g) was heated at 100° C. for 48 hr. The mixture was cooled, diluted with water and extracted with chloroform. The chloroform extract was passed through a column of silica gel. Subsequent elution of the column with chloroform-methanol (97:3) gave 2.0 g of 2-(3-ethoxycarbonyl-1,2-dihydro-2-oxocyclohepta[b]pyrrol-1-yl) butanedioic acid dimethyl ester, nmr (CDCl3) δ1.4 (t, 3H), 3.35 (m, 2H), 3.6 and 3.7 (2s, 6H), 4.4 (q, 2H), 5.6 (t, 1H), 7.45 (m, 4H), 9.05 (d, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1C=O.[CH:13]1([NH2:16])[CH2:15][CH2:14]1.C(O)(=O)C>CO>[CH:13]1([NH:16][C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:15][CH2:14]1
Reactant: NC1CC1
Reactant: Cn1c(C=O)cc2ccccc21
Solvent: CC(=O)O
Solvent: CO
Product: Cn1c(NC2CC2)cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
To a solution of 1-methylindole-2-carboxaldehyde (1.5 g, 10 mmole), cyclopropylamine (1.14 g, 20 mmole), and glacial acetic acid (0.6 mL, 10 mmole) in MeOH (30 mL) was added NaB3CN (0.69 g, 11 mmole). The reaction was stirred at RT overnight, then was concentrated in vacuo. The residue was diluted with 10% NaOH and extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated. Flash chromatography on silica gel (3% MeOH/CH2Cl2) gave the title compound (1.3 g, 65%) as a semi-solid: MS (ES) m/e 201 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][CH:5]1[C:9](=[O:10])[N:8]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]2([CH2:23][CH2:22][N:21]([C:24](=[O:30])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:20][CH2:19]2)[S:6]1)([OH:3])=[O:2].[OH-].[Na+:32].C(OCC)(=O)C>C(O)C>[C:1]([CH2:4][CH:5]1[C:9](=[O:10])[N:8]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]2([CH2:23][CH2:22][N:21]([C:24](=[O:30])[CH2:25][CH2:26][C:27]([O-:29])=[O:28])[CH2:20][CH2:19]2)[S:6]1)([OH:3])=[O:2].[Na+:32].[Na+:32].[C:1]([CH2:4][CH:5]1[C:9](=[O:10])[N:8]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]2([CH2:23][CH2:22][N:21]([C:24](=[O:30])[CH2:25][CH2:26][C:27]([O-:29])=[O:28])[CH2:20][CH2:19]2)[S:6]1)([OH:3])=[O:2]
Reactant: O=C(O)CCC(=O)N1CCC2(CC1)SC(CC(=O)O)C(=O)N2CCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C([O-])CCC(=O)N1CCC2(CC1)SC(CC(=O)O)C(=O)N2CCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In 1.4 ml of ethanol was dissolved 0.31 g of 4-[2-(carboxymethyl)-3-oxo-4-phenethyl-1-thia-4,8-diazaspiro[4.5]decan-8-yl]-4-oxobutanoic acid. After adding 1.36 ml of 1 mol/L aqueous solution of sodium hydroxide at 0-5° C., the resulting mixture was stirred at ambient temperature for 5 hours. The reaction mixture was poured into a mixture of ice water and ethyl acetate, and the aqueous layer was separated. The aqueous layer thus obtained was concentrated under reduce pressure to obtain 0.32 g of disodium 4-[2-(carboxymethyl)-3-oxo-4-phenethyl-1-thia-4,8-diazaspiro[4.5]decan-8-yl]-4-oxobutanoate as a colorless solid product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[N:8]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:11]1[CH2:10][CH2:9][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][CH2:12]1
Reactant: Brc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccccn2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A solution of 2-bromopyridine (1.0 g, 6.33 mmol, 1.00 equiv), t-butyl piperazine-1-carboxylate (2.35 g, 12.62 mmol, 2.00 equiv), BINAP (196 mg, 0.63 mmol, 0.10 equiv), Pd2(dba)3 (290 mg, 0.32 mmol, 0.05 equiv), and NaOt-Bu (1.89 g, 18.90 mmol, 3.00 equiv) in toluene (20 mL) was placed in a 100-mL round bottom flask under an inert atmosphere and stirred overnight at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. Purification by silica gel column (ethyl acetate/petroleum ether (1:40)) yielded 1.4 g (84%) of t-butyl 4-(pyridin-2-yl)piperazine-1-carboxylate as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.[C:22]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:29]4[CH:30]=[CH:31][C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:27][CH:28]=4)=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)=[CH:13][CH:14]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(Cn2ccc3cc(Br)ccc32)cc1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: CC(C)(C)c1ccc(Cn2ccc3cc(-c4ccc(C(C)(C)C)cc4)ccc32)cc1

Procedure:
The title compound was prepared from 5-bromo-1-[4-(tert-butyl)benzyl]-1H-indole (Step 1 of Example 34) and 4-(tert-butyl)phenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an off-white solid, mp: 167-168° C. Mass spectrum (ESI, [M+H]+) m/z 396. 1 HNMR (400 MHz, DMSO-d6): δ 7.77 (d, 1H, J=1.38 Hz), 7.55 (d, 2H, J=8.56 Hz), 7.52-7.51 (m, 2H), 7.43 (d, 1H, J=8.40 Hz), 7.36 (d, 1H, J=8.55 Hz), 7.31 (d, 2H, J=8.40 Hz), 7.14 (d, 2H, J=8.40 Hz), 6.51 (d, 1H, J=3.05 Hz), 5.38 (s, 2H), 1.30 (s, 9H), and 1.21 ppm (s, 9H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[C:10]([CH2:15][CH:16]3[S:20][C:19](=[O:21])[N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:17]3=[O:41])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:42].[CH:43]1[C:48](O)=[CH:47][CH:46]=[C:45]([CH3:50])[CH:44]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(N=NC(OCC)=O)=O>C(OCC)(=O)C.C1COCC1>[CH3:50][C:45]1[CH:46]=[CH:47][C:48]([O:1][CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[C:9](=[C:10]([CH2:15][CH:16]4[S:20][C:19](=[O:21])[NH:18][C:17]4=[O:41])[CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7][C:6]2=[O:42])=[CH:43][CH:44]=1
Reactant: O=C1CCc2c(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cccc2N1CCCO
Reactant: Cc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(OCCCN2C(=O)CCc3c(CC4SC(=O)NC4=O)cccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
A THF solution (2 ml) of 100 mg (0.18 mmol) of 5-[1-(3-hydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl]-3-trityl thiazolidine-2,4-dione, 0.0363 ml (0.347 mmol) of p-cresol, and 91.1 mg (0.35 mmol) of triphenylphosphine was cooled with ice. 0.158 ml of azodicarboxylic acid diethyl (2.2 M toluene solution) was added to the solution in an argon atmosphere. The mixture was stirred at room temperature for two hours, and ethyl acetate was added to the reaction liquid. After washing with water, the organic layer was concentrated under reduced pressure, and the residue was purified by preparative silica gel thin layer chromatography (n-hexane:ethyl acetate=1:1). The purified product was concentrated under reduced pressure, and 2 ml of a solution of 4N-hydrogen chloride/ethyl acetate was added to the residue. The mixture was stirred at room temperature overnight, and further stirred at 70° C. for 1.5 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative silica gel thin layer chromatography (n-hexane:ethyl acetate=1:1). The purified product was concentrated under reduced pressure and evaporated to dryness, giving 27.1 mg (34.4% yield) of 5-{1-[3-(4-methylphenoxy)propyl]-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl}thiazolidine-2,4-dione as a colorless amorphous solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C:15]1[CH:20]=[N:19][C:18]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)=[C:17]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[N:16]=1)(C)(C)C>>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([C:17]2[N:16]=[C:15]([NH2:14])[CH:20]=[N:19][C:18]=2[O:21][CH:22]2[CH2:23][CH2:25][CH2:24]2)=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)n1
Solvent: O=C(O)C(F)(F)F
Product: Nc1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.3 %

Procedure:
TFA (14.8 g, 10 mL, 130 mmol) was added to [6-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyrazin-2-yl]-carbamic acid tert-butyl ester (example 50b, 1.365 g, 3.63 mmol). The resulting yellow solution was stirred at room temperature for 1 h. The solvent was evaporated and the residue was partitioned between ethyl acetate and 1M Na2CO3 solution; the organic phases were combined, dried with MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 100g, 10% to 50% ethyl acetate in heptane; then ethyl acetate/methanol 9/1 to give 0.133 g (13%) of the title compound (by rearrangement) as yellow oil; MS (EI) 276.1 (M+H)+.