Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=O)[C:13]=2[C:14]([O:16][CH3:17])=[O:15])[N:4]=1.Cl.[OH:25][NH2:26].C([O-])(=O)C.[K+]>CO>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=[N:26][OH:25])[C:13]=2[C:14]([O:16][CH3:17])=[O:15])[N:6]=1
Reactant: COC(=O)c1c(C=O)cccc1Oc1nc(OC)cc(OC)n1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: COC(=O)c1c(C=NO)cccc1Oc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.6 %

Procedure:
2.0 g of methyl 2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-formylbenzoate, 0.8 g of hydroxyamine hydrochloride, 1.1 g of potassium acetate and 10 ml of methanol were placed in a 50 ml eggplant type flask, and were stirred for 10 minutes at room temperature. Methanol was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The organic layer was washed with water, 5% hydrochloric acid and a saturated salt aqueous solution, and was dried with magnesium sulfate anhydride. After filtering, a small amount of Florisil was added to the resultant product, and was stirred for 5 minutes. The Florisil was filtered out, and ethyl acetate was distilled off under reduced pressure to obtain 1.5 g of the aimed compound (refractive index=1.5558) at a yield of 72%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14]C)[N:9]=[C:8]1[N:16]=[C:17]([C:21]([O:23]CC)=[O:22])[NH:18][C:19](=[O:20])[C:7]1=[CH:6]2.COC1C=C(C([N+]([O-])=O)=CC=1OCC)C=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]1[N:16]=[C:17]([C:21]([OH:23])=[O:22])[NH:18][C:19](=[O:20])[C:7]1=[CH:6]2
Reactant: CCOC(=O)c1nc2nc3cc(OCC)c(OC)cc3cc2c(=O)[nH]1
Agent: CCOc1cc([N+](=O)[O-])c(C=O)cc1OC
Product: COc1cc2cc3c(=O)[nH]c(C(=O)O)nc3nc2cc1OC

Procedure:
Ethyl 7-methoxy-8-ethoxypyrimido[4,5-b]quinoline-4(3H)-one-2-carboxylate is similarly prepared according to procedures A-C, beginning with 3-methoxy-4-ethoxy-6-nitrobenzaldehyde. It melts at 264°-265° C. (dec.)
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[C:7]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]=1>O1CCCC1.C(N(CC)C(C)C)(C)C>[Cl:11][C:9]1[N:8]=[C:7]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]=[C:5]([N:2]([CH3:3])[CH3:1])[CH:10]=1
Reactant: CNC
Reactant: Clc1cc(Cl)nc(Nc2ccccc2)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1cc(Cl)nc(Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Dimethylamine in tetrahydrofuran (2M, 15 mL) was added to a solution of 4,6-dichloro-N-phenyl-2-pyrimidinamine (0.715 g, 2.97 mmol) in tetrahydrofuran (30 mL) and N,N-diisopropylethylamine (0.52 mL). The resulting mixture was stirred at room temperature overnight. The solvent was removed and the crude material was purified by flash chromatography on silica gel, eluting with ethyl acetate/hexane (1:9). The eluent was removed, giving 6-chloro-N4,N4-dimethyl-N2-phenyl-2,4-pyrimidinediamine (0.592 g, 2.39 mmol, 80%, Rf=0.3).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH3:29][NH:30][CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:29][N:30]([CH2:25][C:24]1[CH:27]=[CH:28][C:21]([NH:20][C:18]2[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=[C:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=4)[N:16]3[N:17]=2)=[CH:22][CH:23]=1)[CH3:31]
Reactant: CS(=O)(=O)c1cccc(-c2cccc3nc(Nc4ccc(C=O)cc4)nn23)c1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)Cc1ccc(Nc2nc3cccc(-c4cccc(S(C)(=O)=O)c4)n3n2)cc1
Temperature: 24 °C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
To a solution of 4-(5-(3-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzaldehyde (150 mg, 0.38 mmol) in dichloromethane (50 mL) was added dimethylamine (1 M in THF) (3.6 g, 28 mmol). The resulting mixture was stirred at 24° C. for 1 h. Sodium triacetoxyborohydride was then added to the reaction mixture. After 16 h, the mixture was quenched with saturated aqueous sodium bicarbonate solution. The collected organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by preparative thin layer chromatography afforded the desired product (61 mg, 37% yield). LCMS (ESI) m/z: 421.9.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]1COCC1>>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:15])([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: C1CCOC1
Product: CC1(O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 59 %

Procedure:
To a solution of 1-benzyl-4-piperidone (5.6 mL, 30.0 mmol) in 50 mL THF was added a solution of methyl]ithium in THF (24.0 mL, 36 mmol) dropwise at 0° C. over 15 min. The reaction mixture was allowed to warm to room temperature over 3 h and then quenched with 30 mL of sat. NH4Cl solution. The organic layer was extracted with diethyl ether (2×100 mL) and the combined organic layer was washed with brine (100 mL). The organic layer was separated, dried over Na2SO4, filtered and the solvent was removed in vacuo to obtain yellow gum. It was purified by column chromatography over silica gel with 9:1 EtOAc-MeOH as the eluting system to obtain 1-benzyl-4-methyl-4-piperidinol as a yellow thick oil (3.6 g, 59% yield).
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:24])=[CH:9][C:10](OC)=[CH:11][C:12]=3[C@@:13]32[CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)=[CH:4][CH:3]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1.[O:34]1[CH2:39][CH2:38][CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH2:35]1>>[O:34]1[CH2:39][CH2:38][CH:37]=[C:36]([C:10]2[CH:9]=[C:8]([F:24])[C:7]3[O:6][C:5]4[C:14](=[CH:15][C:2]([C:27]5[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=5)=[CH:3][CH:4]=4)[C@@:13]4([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]4)[C:12]=3[CH:11]=2)[CH2:35]1
Reactant: CC1(C)OB(C2=CCCOC2)OC1(C)C
Reactant: COc1cc(F)c2c(c1)[C@]1(CCOC(N)=N1)c1cc(Br)ccc1O2
Reactant: OB(O)c1cccnc1
Product: NC1=N[C@@]2(CCO1)c1cc(-c3cccnc3)ccc1Oc1c(F)cc(C3=CCCOC3)cc12

Procedure:
The title compound was synthesized by steps analogous to those described in method A7 above, but using intermediate 20B, pyridin-3-ylboronic acid and 2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: C([O:3][C:4]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)=O)C.[BH4-].[Na+].O1CCCC1.C(O)C>CO>[OH:3][CH2:4][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)=[CH:12][CH:13]=1
Reactant: CCOC(=O)COc1ccc(-c2ccc(C(=O)OCC)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2ccc(OCCO)cc2)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl 4′-hydroxybiphenyl-4-carboxylate (2.262 g), ethyl bromoacetate (1.871 g) and potassium carbonate (1.940 g) in N,N-dimethylformamide (50 mL) was stirred at 60° C. for 1 hr. Diethylamine (6.820 g) was added to the reaction mixture. After being stirred at room temperature for 30 minutes, the mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford ethyl 4′-ethoxycarbonylmethoxybiphenyl-4-carboxylate (3.06 g) as a crude product. A mixture of the crude ethyl 4′-ethoxycarbonylmethoxybiphenyl-4-carboxylate, sodium borohydride (0.706 g), tetrahydrofuran (40 mL) and ethanol (10 mL) was stirred at 60° C. for 1 hr. Methanol (10 mL) was added to the reaction mixture, and stirred at room temperature for additional 30 minutes. The solvent was evaporated under reduced pressure, and the residue was partitioned between ethyl acetate and 1 mol/L hydrochloric acid. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford the title compound (3.000 g)
Reaction SMILES: B1([O-])OO1.[OH2:5].O.O.O.[Na+].[C:10]([O:14][C:15]([NH:17][C@@H:18]([CH2:22][S:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([N:37]3[C:45]4[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=4)[CH:39]=[CH:38]3)=[CH:33][CH:32]=2)=[CH:27][CH:26]=1)[C:19]([OH:21])=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11]>C(O)(=O)C.C(OCC)(=O)C>[C:10]([O:14][C:15]([NH:17][C@@H:18]([CH2:22][S:23]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]=[CH:33][C:34]([N:37]3[C:45]4[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=4)[CH:39]=[CH:38]3)=[CH:35][CH:36]=2)=[CH:27][CH:26]=1)=[O:5])[C:19]([OH:21])=[O:20])=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: O
Reactant: CC(C)(C)OC(=O)N[C@@H](CSCc1ccc(-c2ccc(-n3ccc4ccccc43)cc2)cc1)C(=O)O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CS(=O)Cc1ccc(-c2ccc(-n3ccc4ccccc43)cc2)cc1)C(=O)O
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Sodium perborate tetrahydrate (151 mg, 0.95 mmol) was added as a solid to a stirred solution of (2R)-tert-Butoxycarbonylamino-3-(4′-indol-1-ylbiphen-4-ylmethylsulfanyl)-propionic acid (380 mg, 0.76 mmol) in acetic acid (10 mL) at 40° C. This solution was stirred at 40° C. for 2 hours (HPLC control) and then diluted with ethyl acetate (50 mL), washed with water, brine (2×), dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by trituration of the product with diethyl ether afforded the title compound as a 2:1 mix of diastereoisomers as an off-white solid (372 mg, 95%): mp. 169-170° C. Rf 0.65 (20% methanol in dichloromethane). 1H NMR (DMSO-d6, 300 MHz): δ 7.88 (2H, d, J=8 Hz, Ar—H), 7.62-7.78 (7H, m, Ar—H), 7.44 (2H, d, J=8 Hz, Ar—H), 7.36 (1H, d, J=8 Hz, NH), 7.11-7.22 (2H, m, Ar—H), 6.72 (1H, d, J=3.5 Hz, Ar—H), 4.06-4.26 (3H, m, CHN+PhCH2), 2.96-3.04 (2H, m, CH2CHN), 1.39 (3H, s, CMe3, minor isomer), 1.36 (6H, s, CMe3, major isomer), ESI-LCMS e/z calcd for C29H30N2O5S: 518.631, found 519 (M+H)+, 541 (M+Na)+.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:9][C:8]=2[CH3:22])=[N:5][N:6]=1.[C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[F:31])#[N:24].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[C:23]([C:25]1[CH:26]=[C:27]([N:6]2[N:5]=[C:4]([C:7]3[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:9][C:8]=3[CH3:22])[S:3][CH2:2]2)[CH:28]=[CH:29][C:30]=1[F:31])#[N:24]
Reactant: N#Cc1cc(B(O)O)ccc1F
Reactant: Cc1cc(C=CC(=O)OC(C)(C)C)ccc1-c1nnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C=CC(=O)OC(C)(C)C)ccc1C1=NN(c2ccc(F)c(C#N)c2)CS1
Temperature: 80 °C
Yield: 30.3 %

Procedure:
tert-Butyl 3-(4-(2-Bromo-1,3,4-thiadiazol-5-yl)-3-methylphenyl)propenoate (0.15 g, 0.39 mmol, from Step A), 3-cyano-4-fluorophenyl boronic acid (0.097 g, 0.59 mmol, from Step B) and sodium carbonate (0.21 g, 1.95 mmol) were dissolved in DMF (6 mL) and water (0.2 mL). The reaction mixture was degassed for 5 min with a balloon of argon after which tetrakis(triphenylphosphine) palladium (0.1 g) was added. The reaction was heated at 80° C. for 3 h. The reaction was diluted with water and extracted with ethyl acetate (2×100 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel chromatography eluting with 10% ethyl acetate/hexane afforded 0.05 g of product: ESI-MS (m/z) 422.2; HPLC A: 4.21 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([N:21]=[CH:22][C:23]=2[C:24](=[O:34])[NH:25][C:26]2([C:32]#[N:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.CS(O)(=O)=[O:37].C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[C:32]([C:26]1([NH:25][C:24]([C:23]2[CH:22]=[N:21][N:12]3[C:13]([C:14]4[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=4)=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[CH:9]=[N:10][C:11]=23)=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)(=[O:37])[NH2:33]
Reactant: N#CC1(NC(=O)c2cnn3c(-c4ccc(Cl)cc4)c(-c4ccccc4Cl)cnc23)CCCCC1
Reactant: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: NC(=O)C1(NC(=O)c2cnn3c(-c4ccc(Cl)cc4)c(-c4ccccc4Cl)cnc23)CCCCC1
Temperature: 35 °C
Reaction time: 4 h
Yield: 25 %

Procedure:
To a solution of the compound obtained in Example A1 (70 mg) in methylene chloride (1.0 mL) were added methanesulfonic acid (84 μL) and a few drops of water, and the mixture was stirred at room temperature overnight and at 35° C. for 4 hours. To the reaction mixture was added successively an aqueous saturated sodium hydrogencarbonate solution and methylene chloride. After stirring, the organic layer was separated and concentrated in vacuo. The resultant crude product was purified by column chromatography on silica gel (solvent; chloroform/methanol=100/0 to 95/5) to give 3-[N-(1-carbamoylcyclohexyl)carbamoyl]-6-(2-chlorophenyl)-7-(4-chlorophenyl)-pyrazolo[1,5-a]pyrimidine (18 mg; yield: 25%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.O.[C:23](OCC)(=[O:25])C>O1CCCC1>[CH3:14][C:10]1[N:9]=[C:8]([O:7][CH2:6][C:5]2[CH:15]=[CH:16][C:2]([CH:23]=[O:25])=[CH:3][CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(C)=O
Reactant: Cc1cccc(OCc2ccc(Br)cc2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(OCc2ccc(C=O)cc2)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of 2-(4-bromo-benzyloxy)-6-methyl-pyridine (7.30 g, 26.2 mmol) described in Manufacturing Example 3-1-1 in anhydrous tetrahydrofuran (200 mL) was added dropwise n-butyl lithium (2.67 M n-hexane solution, 11.8 mL, 31.4 mmol) on a dry ice-ethanol bath (−78° C.), which was stirred for 30 minutes at −78° C. N,N-dimethylfornamide (4.04 mL, 52.4 mmol) was added to this mixture at −78° C., and stirred for 5 minutes. Water and ethyl acetate were added to the reaction mixture, which was stirred for 10 minutes at room temperature, and the organic layer was then s separated. This organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:3) to obtain the title compound (4.19 g, 70%).
Reaction SMILES: [Br:1][CH:2](O)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.Cl.[CH3:13][O:14][NH2:15].C[OH:17]>>[CH3:13][O:14][N:15]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:17])[CH2:2][Br:1]
Reactant: CO
Reactant: CON
Reactant: O=C(c1ccccc1)C(O)Br
Agent: Cl
Product: CON=C(CBr)c1ccccc1O
Temperature: 0 °C
Yield: 52 %

Procedure:
107.5 g (0.5 mol) of ω-bromo-2-hydroxy-acetophenone in 500 ml of methanol together with 41.75 g (0.5 mol) of O-methylhydroxylamine hydrochloride are heated under reflux for 4 hours. The methanol is distilled off under reduced pressure and the residue is admixed with 500 ml of water and extracted with 4 times 100 ml of ethyl acetate. The organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. At 0° C. , the residue is stirred with petroleum ether, affording 74 g (52% of theory) of crystalline 2-bromo-1-(2-hydroxy-phenyl)-ethanone O-methyl-oxime as a mixture of two stereoisomers (53% of isomer B and 33% of isomer A).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:23][C@@H:22]([C:24]3[CH:35]=[CH:34][C:27]4[O:28][C:29]([CH3:33])([CH3:32])[O:30][CH2:31][C:26]=4[CH:25]=3)[O:21][C:20]2=[O:36])[CH:5]=[CH:6][CH:7]=1.[S:37]1[CH2:41][CH2:40][N:39]2[CH:42]=[C:43]([CH:45]=O)[N:44]=[C:38]12.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].P([O-])([O-])([O-])=O>ClCCl>[S:37]1[CH2:41][CH2:40][N:39]2[CH:42]=[C:43]([CH2:45][NH:1][C:2]3[CH:3]=[C:4]([CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]4[CH2:23][C@@H:22]([C:24]5[CH:35]=[CH:34][C:27]6[O:28][C:29]([CH3:32])([CH3:33])[O:30][CH2:31][C:26]=6[CH:25]=5)[O:21][C:20]4=[O:36])[CH:5]=[CH:6][CH:7]=3)[N:44]=[C:38]12
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(N)c4)C(=O)O3)ccc2O1
Reactant: O=Cc1cn2c(n1)SCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NCc5cn6c(n5)SCC6)c4)C(=O)O3)ccc2O1
Reaction time: 1.5 h
Yield: 67.3 %

Procedure:
A solution of (5R)-3-{6-[2-{[(3-aminophenyl)methyl]oxy}ethoxy]hexyl}-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (200 mg) and 2,3-dihydroimidazo[2,1-b][1,3]thiazole-6-carboxaldehyde (62 mg) (WO94/10178) in dichloromethane (10 ml) was treated under nitrogen with sodium triacetoxy borohydride (340 mg) and stirred at 20° for 1.5 h. The mixture was cooled to 0°, phosphate buffer solution (pH6.5, 20 ml) was added and the mixture was extracted with EtOAc (3×30 ml). The combined organic extracts were dried (Na2SO4) and the solvent evaporated in vacuo to give a residue which was purified by SPE. Elution with dichloromethane, dichloromethane-EtOH-ammonia (400:8:1) then (225:8:1) gave the title compound (172 mg). LCMS RT=3.16 min, ES+ve 637 (MH)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:18]=[CH:17][C:16]2[O:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:19][CH2:20][CH2:21][CH2:22][O:23][C:24]4[CH:29]=[C:28]([OH:30])[C:27]([C:31](=[O:33])[CH3:32])=[CH:26][C:25]=4[CH2:34][CH3:35])[CH:13]=3)[C:8](=[O:36])[C:7]=2[CH:6]=1)=[O:4].[OH-:37].[Na+:38].Cl>CO.O1CCCC1>[OH2:2].[Na+:38].[Na+:38].[C:31]([C:27]1[C:28]([OH:30])=[CH:29][C:24]([O:23][CH2:22][CH2:21][CH2:20][O:19][C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:36])[C:7]2[CH:6]=[C:5]([C:3]([O-:4])=[O:2])[CH:18]=[CH:17][C:16]=2[O:15]3)=[C:25]([CH2:34][CH3:35])[CH:26]=1)(=[O:33])[CH3:32].[OH2:37].[OH2:2].[C:31]([C:27]1[C:28]([OH:30])=[CH:29][C:24]([O:23][CH2:22][CH2:21][CH2:20][O:19][C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:36])[C:7]2[CH:6]=[C:5]([C:3]([O-:4])=[O:2])[CH:18]=[CH:17][C:16]=2[O:15]3)=[C:25]([CH2:34][CH3:35])[CH:26]=1)(=[O:33])[CH3:32].[C:31]([C:27]1[C:28]([OH:30])=[CH:29][C:24]([O:23][CH2:22][CH2:21][CH2:20][O:19][C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:36])[C:7]2[CH:6]=[C:5]([C:3]([O-:4])=[O:2])[CH:18]=[CH:17][C:16]=2[O:15]3)=[C:25]([CH2:34][CH3:35])[CH:26]=1)(=[O:33])[CH3:32].[C:31]([C:27]1[C:28]([OH:30])=[CH:29][C:24]([O:23][CH2:22][CH2:21][CH2:20][O:19][C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:36])[C:7]2[CH:6]=[C:5]([C:3]([O-:4])=[O:2])[CH:18]=[CH:17][C:16]=2[O:15]3)=[C:25]([CH2:34][CH3:35])[CH:26]=1)(=[O:33])[CH3:32].[Na+:38].[Na+:38]
Reactant: [OH-]
Reactant: CCc1cc(C(C)=O)c(O)cc1OCCCOc1ccc2c(=O)c3cc(C(=O)OC)ccc3oc2c1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cc(C(C)=O)c(O)cc1OCCCOc1ccc2c(=O)c3cc(C(=O)[O-])ccc3oc2c1
Product: O
Temperature: 25 °C
Reaction time: 24 h
Yield: 35 %

Procedure:
A mixture of 6-[3-(4-acetyl-2-ethyl-5-hydroxyphenoxy)propoxy]-9-oxo-9H-xanthene-2-carboxylic acid methyl ester (380 mg) and 5N aqueous sodium hydroxide solution (4 mL) in 1:1 methanol/tetrahydrofuran (20 mL) was stirred at room temperature for 24 hours. The mixture was acidified with aqueous 5N hydrochloric acid solution and the resulting precipitate was collected via vacuum filtration. This material was dissolved in a minimum of aqueous 1N sodium hydroxide solution and purified on MCI HP-20™ resin using a water/acetonitrile gradient. Lyophilization of the appropriate fractions provided 120 mg (35%) of the title product as a fluffy white solid: 1H-NMR (DMSO-d6) 8.64 (d, J=2 Hz, 1H), 8.27 (dd, J=9, 2 Hz, 1H), 8.05 (d, J=9 Hz, 1H), 7.59 (s, 1H), 7.44 (d, J=9 Hz, 1H), 7.13 (d, J= 2 Hz, 1H), 7.01 (dd, J=9, 2 Hz, 1H), 6.54 (s, 1H), 4.32 (t, J=5 Hz, 2H), 4.21 (t, J=6 Hz, 2H), 2.51 (m, 5H), 2.25 (quintet, J=5 Hz, 2H), 1.10 (t, J=8 Hz, 3H); MS-FAB (m/e) 521 (p+1, 35), 500 (22), 499 (63), 477 (18); IR (CHCl3, cm-1) 3450 (b), 2976, 1620, 1401, 1268, 1162, 1049. Anal. (C27H22O8Na2 . 1.5 H2O):
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([O:27]CC)=[O:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Li+].[OH-].Cl>O.O1CCOCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([OH:27])=[O:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOC(=O)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Temperature: 100 °C
Yield: 82.9 %

Procedure:
Ethyl 5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indole-2-carboxylate (392 mg, 1.0 mmol) and LiOH (126 mg, 3 mmol) were dissolved in H2O (5 mL) and 1,4-dioxane (3 mL). The mixture was heated in an oil bath at 100° C. for 24 hours before it was cooled to room temperature. The mixture was acidified with 1N HCl and it was extracted with three 20 mL portions of dichloromethane. The organic extracts were dried over Na2SO4 and evaporated to yield 5-(1-(benzo[d][1,3]-dioxol-5-yl)cyclopropanecarboxamido)-1H-indole-2-carboxylic acid (302 mg, 83%). A small amount was further purified by reverse phase HPLC. ESI-MS m/z calc, 364.1, found 365.1(M+1)+; retention time 2.70 minutes.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:11]2[C:16](=[O:17])[NH:15][C:14](=[O:18])[C:13](C(O)=O)=[N:12]2)[CH:7]=[CH:8][C:9]=1[CH3:10])([OH:3])=[O:2].[OH-].[Na+].SCC(O)=O>C(OCC)(=O)C.C1(C)C=CC=CC=1.O>[O:17]=[C:16]1[NH:15][C:14](=[O:18])[CH:13]=[N:12][N:11]1[C:6]1[CH:7]=[CH:8][C:9]([CH3:10])=[C:4]([CH:5]=1)[C:1]([OH:3])=[O:2]
Reactant: Cc1ccc(-n2nc(C(=O)O)c(=O)[nH]c2=O)cc1C(=O)O
Agent: O=C(O)CS
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2ncc(=O)[nH]c2=O)cc1C(=O)O
Temperature: 102.5 °C
Yield: 73.9 %

Procedure:
2-(3-Carboxy-4-methyl-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic acid (110 gm) was added to 8 volumes of water with 2.4 equivalents of sodium hydroxide and 1.1 equivalents of mercaptoacetic acid. The reaction mixture was heated to reflux (100-105° C.) for approximately 18 hours at which point the reaction was complete by HPLC. 30% Sodium hydroxide and toluene were added and the resulting mixture was stirred. Upon settling a large interface was noted. More water, toluene and some ethyl acetate were added. The interface was minimized. The water layer was separated and treated with 2N HCl. At pH 2 solids precipitated out and the slurry was cooled to <10° C. The solids were filtered off in a slow filtration and dried in a vacuum oven to give 69 gm of the title compound.