Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[OH:12][CH2:13][C@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1>CC(N(C)C)=O>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([N:16]3[CH2:17][CH2:18][C@H:14]([CH2:13][OH:12])[CH2:15]3)=[N:3][N:4]=2)[CH:7]=1
Reactant: Fc1ccc2nnc(Cl)n2c1
Reactant: OC[C@H]1CCNC1
Solvent: CC(=O)N(C)C
Product: OC[C@H]1CCN(c2nnc3ccc(F)cn23)C1
Yield: 100.2 %

Procedure:
A solution of Intermediate 24b (485 mg, 2.83 mmol) and (S)-3-(hydroxymethyl)pyrrolidine (1.00 g, 9.90 mmol) in DMA (10 mL) was heated in the microwave at 175° C. for 2.5 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-20% [2M NH3 in MeOH] in DCM, to give the title compound as a brown gum (670 mg, quant.). LCMS (Method 3): Rt 0.44 min, m/z 237 [MH+].
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:21])([F:20])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([OH:7])[CH3:6].[Br:22][C:23]1[S:27][C:26]([S:28](Cl)(=[O:30])=[O:29])=[CH:25][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:22][C:23]1[S:27][C:26]([S:28]([N:17]2[CH2:18][CH2:19][N:14]([C:11]3[CH:10]=[CH:9][C:8]([C:5]([OH:7])([CH3:6])[C:4]([F:3])([F:20])[F:21])=[CH:13][CH:12]=3)[CH2:15][CH2:16]2)(=[O:30])=[O:29])=[CH:25][CH:24]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: CC(O)(c1ccc(N2CCNCC2)cc1)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3ccc(Br)s3)CC2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
A 250-mL round-bottomed flask was charged with 1,1,1-trifluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride (2.66 g, 7.65 mmol), 5-bromothiophenesulfonyl chloride (2.00 g, 7.65 mmol, Sigma-Aldrich, St. Louis, Mo.), 25 mL of CH2Cl2, and triethylamine (3.73 mL, 26.8 mmol). After stirring at room temperature for 15 min, the mixture was diluted with CH2Cl2 (50 mL) and filtered. The filtrate was concentrated and purified by column chromatography on silica gel (0 to 50% EtOAc in hexanes) to give 2-(4-(4-((5-bromo-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (2.10 g) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](C(OC)=O)[C:9]([O:11]C)=[O:10])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1.C(OCC)(=O)C.CCCCCC>Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1
Reactant: COC(=O)C(C(=O)OC)c1ccc(F)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(O)Cc1ccc(F)cc1[N+](=O)[O-]
Yield: 89.9 %

Procedure:
Dimethyl 4-fluoro-2-nitrophenylmalonate (5.0 g) was refluxed in 20 mL of 6N hydrochloric acid for 24 hours. The reaction was cooled and the white solid collected by vacuum filtration, washed with water and dried to give 3.3 g (87% yield) of 4-fluoro-2-nitrophenylacetic acid, Rf 0.6 on thin layer chromatography (ethyl acetate:hexane 1:2, silica gel).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]#[N:11])[CH2:6][CH2:5]1.S(C)C.O.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[NH2:11][CH2:10][CH:7]1[CH2:6][CH2:5][N:4]([CH2:3][CH2:2][OH:1])[CH2:9][CH2:8]1
Reactant: N#CC1CCN(CCO)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CSC
Product: NCC1CCN(CCO)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 47.4 %

Procedure:
To the solution of compound 1-(2-hydroxyethyl)piperidine-4-carbonitrile (300 mg, 2 mmol) in dry THF (5 mL) at 0° C., BH3.SMe2 (220 mg, 2.4 mmol) was added dropwise. The mixture was stirred at 0° C. for 2 hrs. Water was added then K2CO3. The mixture was filtered and concentrated to give compound 2-(4-(aminomethyl)piperidin-1-yl)ethanol (150 mg, 47%).
Reaction SMILES: [N:1]1([CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:13]=2[CH:14]=[O:15])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[I-].[CH3:22][S+](C)C>C(Cl)Cl.[OH-].[Na+].[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:20][C:17]1[CH:18]=[CH:19][C:12]([O:11][CH2:10][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[N:2]2)=[C:13]([CH:14]2[CH2:22][O:15]2)[CH:16]=1
Reactant: C[S+](C)C
Reactant: O=Cc1cc(Cl)ccc1OCn1nnc2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Product: Clc1ccc(OCn2nnc3ccccc32)c(C2CO2)c1
Yield: 114.8 %

Procedure:
98 (15.5 g, 54 mmol) is dissolved in 150 ml of DCM and 150 ml of 40% aqueous sodium hydroxide solution. After addition of trimethylsulfonium iodide (14.3 g, 70.2 mmol) and tetrabutylammoniumiodide (1.4 g, 3.8 mmol), the mixture is refluxed for 18 h. The reaction mixture is diluted with DCM, washed with water and the organic layers are dried over Na2SO4. Evaporation gave 18.7 g of a yellow oil, which is further purified by flash-chromatography (silicagel, ethyl acetate/hexanes 3:7)
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O>>[CH:1]1([NH:4][CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[C:7]([O:6][CH3:5])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: COc1cccc(C=O)c1
Product: COc1cccc(CNC2CC2)c1

Procedure:
prepared by reaction of cyclopropylamine with 3-methoxy-benzaldehyde
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10](Cl)(=[O:13])[CH:11]=[CH2:12].[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]([C:25]2[C:26]3[C:38]([NH2:39])=[N:37][CH:36]=[N:35][C:27]=3[N:28]3[C:33]=2[CH2:32][CH2:31][CH:30]([NH2:34])[CH2:29]3)[CH:16]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[NH2:39][C:38]1[C:26]2[C:25]([C:17]3[CH:16]=[N:15][C:24]4[C:19]([CH:18]=3)=[CH:20][CH:21]=[CH:22][CH:23]=4)=[C:33]3[N:28]([C:27]=2[N:35]=[CH:36][N:37]=1)[CH2:29][CH:30]([NH:34][C:10](=[O:13])[CH:11]=[CH2:12])[CH2:31][CH2:32]3
Reactant: C=CC(=O)Cl
Reactant: Nc1ncnc2c1c(-c1cnc3ccccc3c1)c1n2CC(N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)NC1CCc2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2C1
Reaction time: 0.25 h

Procedure:
N,N-diisopropylethylamine (0.033 ml) and acryloyl chloride (0.0154 ml) were added to a solution of 5-(quinolin-3-yl)-6,7,8,9-tetrahydropyrimido[5,4-b]indolizine-4,8-diamine (68 mg) obtained in Step 11 in chloroform (2.5 ml) under ice-cooling. After stirring at the same temperature for 15 minutes, the mixture was poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: chloroform/methanol) to obtain the title compound as a yellow solid (35.4 mg).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5].[CH3:18][N:19]([CH3:26])[CH:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1.Cl.C(N=C=NCCCN(C)C)C>>[CH3:18][N:19]([CH3:26])[CH:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])=[CH:14]3)=[O:17])[CH2:21]1
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Reactant: CN(C)C1CCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CCOC(=O)c1cc2cc(C(=O)N3CCCC(N(C)C)C3)ccc2[nH]1

Procedure:
The title compound was synthesized in analogy to Example 1, Intermediate 1a), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester, 3-dimethylamino-piperidine and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, to afford the product as a light-brown solid (63%).
Reaction SMILES: [Cl-].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([I+:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH3:23][O:24][C:25]1[C:26]2[C:31]([C:32]([O:44][CH3:45])=[C:33]3[C:38]=1[CH:37]=[C:36]([S:39]([O:42]C)(=[O:41])=[O:40])[CH:35]=[CH:34]3)=[CH:30][CH:29]=[CH:28][CH:27]=2>C(#N)C>[CH3:23][O:24][C:25]1[C:26]2[C:31]([C:32]([O:44][CH3:45])=[C:33]3[C:38]=1[CH:37]=[C:36]([S:39]([O-:42])(=[O:40])=[O:41])[CH:35]=[CH:34]3)=[CH:30][CH:29]=[CH:28][CH:27]=2.[C:19]([C:16]1[CH:17]=[CH:18][C:13]([I+:12][C:9]2[CH:8]=[CH:7][C:6]([C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:11][CH:10]=2)=[CH:14][CH:15]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1c2ccccc2c(OC)c2cc(S(=O)(=O)OC)ccc12
Agent: CC(C)(C)c1ccc([I+]c2ccc(C(C)(C)C)cc2)cc1
Agent: [Cl-]
Solvent: CC#N
Product: COc1c2ccccc2c(OC)c2cc(S(=O)(=O)[O-])ccc12
Yield: 78 %

Procedure:
Acetonitrile (90 ml) was added to bis(p-tert-butylphenyl)iodonium chloride (6.4 g; 15 mmol) and methyl 9,10-dimethoxyanthracene-2-sulfonate (6.48 g; 19.5 mmol). The resultant mixture was heated at 82° C.-85° C. and refluxed for 20 hours while being stirred. The reaction mixture was cooled, and precipitated solid was separated through filtration. The solid was washed with ethyl acetate, and dried under vacuum, to thereby yield 8.32 g of bis(p-tert-butylphenyl)iodonium 9,10-dimethoxyanthracene-2-sulfonate (yield: 78%). The chloride anion content of the resultant solid was 110 ppm, as determined by silver nitrate titration.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[C:11]([C:15]([O:17]CC)=[O:16])[CH:12]=[N:13][CH:14]=2)[CH2:3]1.[OH-].[Li+]>O1CCCC1>[CH3:8][C@H:6]1[NH:7][C@@H:2]([CH3:1])[CH2:3][N:4]([C:9]2[CH:10]=[C:11]([C:15]([OH:17])=[O:16])[CH:12]=[N:13][CH:14]=2)[CH2:5]1
Reactant: CCOC(=O)c1cncc(N2C[C@@H](C)N[C@@H](C)C2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2cncc(C(=O)O)c2)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of ethyl 5-[(3R,5S)-3,5-dimethyl-1-piperazinyl]-3-pyridinecarboxylate (D32) (800 mg, 3 mmol) in tetrahydrofuran (5 ml) was treated with 0.5M lithium hydroxide (12 ml, 6 mmol). The mixture was stirred at room temperature for 2 hours. The reaction was quenched with acetic acid (1 ml). The solvent was evaporated and the residue purified on SCX eluting with 2M ammonia in methanol to give the title compound (D33). MS (ES+) m/e 236 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([CH:20]1[CH2:25][CH2:24][CH:23]=[CH:22][CH2:21]1)=[CH:13][CH:12]=3)=[O:5])C.[OH-].[K+].C(O)(=O)C.O>C(O)C>[CH:23]1[CH2:24][CH2:25][CH:20]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9]2[CH:8]=[N:7][C:6]([C:4]([OH:5])=[O:3])=[C:18]([CH3:19])[C:17]3=2)[CH2:21][CH:22]=1
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(C4CC=CCC4)cc3c2c1C
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Cc1c(C(=O)O)ncc2[nH]c3ccc(C4CC=CCC4)cc3c12
Yield: 94.2 %

Procedure:
440 mg (1.31 mmol) of 6-(1-cyclohexen-4-yl)-4-methyl-β-carboline-3-carboxylic acid ethyl ester is heated under reflux for one hour in 20 ml of ethanol with 3.25 ml of 1N potassium hydroxide solution. After neutralizing with acetic acid and addition of 10 ml of water, the precipitated product is suctioned off, washed with water, and dried under vacuum over potassium hydroxide, thus obtaining 378 mg (94% of theory) of 6-(1-cyclohexen-4-yl)-4-methyl-β-carboline-3-carboxylic acid, mp 284°-285° C.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]([N:15]2[CH:21]3[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]3)[CH2:17][CH2:16]2)=[CH:11][C:3]=1[C:4]([NH:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5].[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O>C(O)C.C(O)(=O)C.CO.[O-2].[O-2].[Mn+4]>[N:18]12[CH2:23][CH2:22][CH:21]([CH2:20][CH2:19]1)[N:15]([C:12]1[CH:11]=[C:3]3[C:2](=[CH:14][CH:13]=1)[N:1]=[C:28]([C:27]1[CH:30]=[CH:31][CH:32]=[C:25]([Cl:24])[CH:26]=1)[N:6]([CH2:7][C:8]([OH:10])=[O:9])[C:4]3=[O:5])[CH2:16][CH2:17]2
Reactant: O=Cc1cccc(Cl)c1
Reactant: Nc1ccc(N2CCN3CCC2CC3)cc1C(=O)NCC(=O)O
Agent: [Mn+4]
Agent: [O-2]
Solvent: CO
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)Cn1c(-c2cccc(Cl)c2)nc2ccc(N3CCN4CCC3CC4)cc2c1=O
Temperature: 85 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
2-(2-Amino-5-(1,4-diazabicyclo[3.2.2]nonan-4-yl)benzamido)acetic acid (85.3 mg, 0.27 mmol) (Intermediate 9A) was dissolved in ethanol (3 mL). 3-Chlorobenzaldehyde (56.5 mg, 0.046 mL, 0.40 mmol) was added followed by 2 drops of acetic acid. The reaction mixture was refluxed at 85° C. overnight. The reaction mixture was diluted with methanol and purified directly using a 1 g SCX cartridge. The crude material was concentrated to dryness before re-dissolving in dichloromethane and manganese dioxide (18.8 mg, 0.32 mmol) added. The solution was then stirred overnight before filtering and concentrated under reduced pressure to give 2-(6-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-(3-chlorophenyl)-4-oxoquinazolin-3(4H)-yl)acetic acid (54 mg, 0.12 mmol).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[N:4][N:3]=1.[NH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:22][CH2:21]1>>[CH2:26]([N:23]1[CH2:24][CH2:25][CH:20]([NH:19][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[C:5]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[N:4][N:3]=2)[CH2:21][CH2:22]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COc1ccc2c(-c3cccs3)nnc(Cl)c2c1
Reactant: NC1CCN(Cc2ccccc2)CC1
Product: COc1ccc2c(-c3cccs3)nnc(NC3CCN(Cc4ccccc4)CC3)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 1-chloro-7-methoxy-4-(thiophen-2-yl)phthalazine with 4-amino-1-benzylpiperidine.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)C(O)=O>N1C2C(=CC=CC=2)C=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:4][C:3]=1[OH:13]
Reactant: COc1ccc(Br)c(O)c1C(=O)O
Solvent: c1ccc2ncccc2c1
Product: COc1ccc(Br)c(O)c1

Procedure:
3-Bromo-2-hydroxy-6-methoxybenzoic acid [T. de Paulis el. al., J. Med. Chem., (1985), 28, 1263-1269] (5 g, 0.02 mol) was heated in quinoline (200 mL) at 160° C. for 1 h. On cooling, the product was partitioned between Et2O and 3M HCl. The organic extract was washed with water and brine then dried (MgSO4), filtered and evaporated to give the title compound which was recrystallized from 5% ethyl acetate/hexane (4 g, 97%); m.p. 40°-42° C. Anal. Calc. for C7H7 BrO2 : C, 41.41; H, 3.48. Found C, 41.39; H, 3.37.
Reaction SMILES: C([Li])CCC.[C:6]1([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:28]([O:33][CH3:34])(=[O:32])[C:29]([CH3:31])=[O:30]>C1COCC1>[OH:30][C:29]([CH3:31])([CH:16]([S:17]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)(=[O:19])=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:28]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)C(C)=O
Reactant: COc1ccc(S(=O)(=O)CCCCCc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)C(C)(O)C(CCCCc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 33.7 %

Procedure:
A solution of n-butyl lithium in hexanes (1.9 mL, 4.4 mmol) is added dropwise to a solution of 1-(5-phenylpentane-1-sulfonyl)-4-methoxybenzene (1.35 g, 4.24 mmol) in THF (15 mL) at -78° C. The reaction is stirred at -78° C. for 15 minutes, raised to -30° C. for 15 minutes and then returned to -78° C. This solution is then cannulated into a solution of methyl pyruvate (0.82 g, 7.2 mmol) in THF (5 mL) precooled to -78° C. After 15 minutes the reaction is slowly warmed to -30° C. and stirred 15 minutes before quenching with a solution of NH4Cl (15 mL). The reaction is partitioned between ether (150 mL) and water (50 mL), and the layers are separated. The ether layer is washed with brine (50 mL), dried (MgSO4) and concentrated in vacuo. The crude product is purified by gradient elution chromatography (silica, CH2Cl2 to 1% MeOH in CH2Cl2) to yield a diastereomeric mixture (2:3 ratio) of methyl 2-hydroxy-3-(4-methoxybenzenesulfonyl)-2-methyl-7-phenylheptanoate products (0.60 g, 35%). An analytical sample of each isomer is obtained by additional chromatography using identical conditions; upper isomer, methyl 2-hydroxy-3-(4-methoxybenzenesulfonyl)-2-methyl-7-phenylheptanoate: 1H NMR (300 MHz, CDCl3) δ 7.78 (d, J=8.7 Hz, 2H), 7.28-7.23 (m, 2H), 7.19-7.14 (m, 1H), 7.06 (d, J=7.6 Hz, 2H), 6.99-6.94 (m, 2H), 4.0-3.7 (br,1H), 3.87 (s, 3H), 3.78 (s, 3H), 3.34-3.30 (m, 1H), 2.45 (t, J=7.5 Hz, 2H), 1.98-1.75 (m, 2H), 1.61 (s, 3H), 1.48-1.38 (m, 2H), 1.29-1.10 (m, 2H); MS (FAB) m/e 421 (M+H)+ ; lower isomer methyl 2-hydroxy-3-(4-methoxybenzenesulfonyl)-2-methyl-7-phenylheptanoate: 1H NMR (300 MHz, CDCl3) δ 7.77-7.74 (m, 2H), 7.28-7.23 (m, 2H), 7.20-7.15 (m, 1H), 7.09 (d, J=7.6 Hz, 2H), 6.99-6.94 (m, 2H), 3.87 (s, 3H), 3.84 (s, 3H), 3.64 (bs, 1H), 3.52 (t, J=6.5 Hz, 1H), 2.51 (t, J=7.5 Hz, 2H), 1.92-1.86 (m, 2H), 1.52-1.33 (m, 4H), 1.41 (s, 3H); MS (FAB) m/e 421 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([Br:26])[CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[C:9]2[C:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH:18]=1)=[O:3]>C(O)C.[Pt]=O>[NH2:1][C:2]([C:4]1[CH:5]=[C:6]([Br:26])[CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[C:9]2[CH:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:17][CH2:18]1)=[O:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: O=[Pt]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reaction time: 16 h
Yield: 48.3 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-bromo-1H-indol-3-yl]-3,6-dihydro-1(2H)-pyridinecarboxylate (7.41 g, 17.64 mmol) in ethanol (600 mL), platinum oxide (200 mg, 5%) was added. The reaction mixture was hydrogenated under an atmosphere of H2 for 16 hours. The resulting mixture was filtered through celite and the filtrate was concentrated. The resulting residue was purified by flash column chromatography (Ethyl acetate/hexanes, 1:4 to 2:1 v/v) to give the desired product (3.6 g, 48%).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5].[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[C:21]=1[Mg]Br.[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1>[C:15]([O:14][C:12]([NH:7][C@H:6]([CH2:10][CH2:9][C:8](=[O:11])[C:21]1[C:20]([F:19])=[CH:25][C:24]([F:26])=[CH:23][C:22]=1[F:27])[C:4]([O:3][CH2:2][CH3:1])=[O:5])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: Fc1cc(F)c([Mg]Br)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](CCC(=O)c1c(F)cc(F)cc1F)NC(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 12 h

Procedure:
To a solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (CAS No. 128811-48-3; 5.7 g) in tetrahydrofuran (30 mL), 2,4,6-trifluorophenylmagnesium bromide (0.24 M solution in THF; 100 mL) was added dropwise at −40° C. over one hour, and the reaction solution was stirred at −40° C. for 12 hours. Saturated aqueous ammonium chloride and ethyl acetate were added to the solution. The reaction solution was heated to room temperature, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane->heptane:ethyl acetate=1:1) to obtain 6.2 g of ethyl (R)-2-tert-butoxycarbonylamino-5-oxo-5-(2,4,6-trifluorophenyl)pentanoate. A solution of 4 N hydrochloric acid in ethyl acetate (30 mL) was added to a solution of the resulting ethyl (R)-2-tert-butoxycarbonylamino-5-oxo-5-(2,4,6-trifluorophenyl)pentanoate in ethyl acetate (30 mL), and the solution was stirred for 12 hours. The reaction solution was concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. 10% palladium-carbon (100 mg) was added to a solution of the residue in ethyl acetate (20 mL) and ethanol (10 mL), and the reaction solution was stirred in a hydrogen atmosphere at 1 atm for 21 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain 4.34 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:24])[C:6]1[C:17]([I:18])=[C:16]([N:19]=[C:20]=[O:21])[C:15]([I:22])=[C:8]([C:9]([NH:11][CH2:12][CH:13]=[CH2:14])=[O:10])[C:7]=1[I:23])[CH:2]=[CH2:3].[CH2:25]([OH:28])[CH2:26][OH:27]>ClCCl>[CH2:12]([N:11]([CH2:14][CH:13]=[CH2:12])[C:9]([C:8]1[C:15]([I:22])=[C:16]([NH:19][C:20]([O:27][CH2:26][CH2:25][O:28][C:20](=[O:21])[NH:19][C:16]2[C:17]([I:18])=[C:6]([C:5](=[O:24])[N:4]([CH2:15][CH:8]=[CH2:9])[CH2:1][CH:2]=[CH2:3])[C:7]([I:23])=[C:8]([C:9](=[O:10])[N:11]([CH2:3][CH:2]=[CH2:1])[CH2:12][CH:13]=[CH2:14])[C:15]=2[I:22])=[O:21])[C:17]([I:18])=[C:6]([C:5](=[O:24])[N:4]([CH2:7][CH:6]=[CH2:5])[CH2:1][CH:2]=[CH2:3])[C:7]=1[I:23])=[O:10])[CH:13]=[CH2:14]
Reactant: C=CCNC(=O)c1c(I)c(N=C=O)c(I)c(C(=O)NCC=C)c1I
Reactant: OCCO
Solvent: ClCCl
Product: C=CCN(CC=C)C(=O)c1c(I)c(NC(=O)OCCOC(=O)Nc2c(I)c(C(=O)N(CC=C)CC=C)c(I)c(C(=O)N(CC=C)CC=C)c2I)c(I)c(C(=O)N(CC=C)CC=C)c1I
Reaction time: 18 h

Procedure:
To a solution of N,N′-Diallyl-2,4,6-triiodo-5-isocyanatoisophthalamide in dichloromethane was added ethylene glycol (0.5 equivalent). The reaction mixture was stirred for 18 hours and then purified by column chromatography to give (3,5-Bis-diallylcarbamoyl-2,4,6-triiodo-phenyl)-carbamic acid 2-(3,5-bis-diallylcarbamoyl-2,4,6-triiodo-phenylcarbamoyloxy)-ethyl ester. A cis-dihydroxylation using OsO4 and NMMO was performed and the crude mixture was purified by preparative HPLC to give 1,3-bis-(N,N,N′,N′-tetrakis-(2,3-dihydroxypropyl))-2,4,6-triiodo-5-ureido-isophthalamide]-2-hydroxypropane as a white powder after freeze drying.
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH:15]([CH2:18][CH3:19])[CH2:16][CH3:17].CCN(CC)CC.[CH2:27]([O:29][C:30]1[C:31]([C:58]([OH:60])=O)=[N:32][C:33]([C:42]2[CH:47]=[CH:46][C:45]([NH:48][C:49]([NH:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[O:50])=[CH:44][CH:43]=2)=[N:34][C:35]=1[N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)[CH3:28]>CN(C=O)C>[CH2:16]([N:15]([CH2:18][CH3:19])[C:58]([C:31]1[C:30]([O:29][CH2:27][CH3:28])=[C:35]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[N:34]=[C:33]([C:42]2[CH:47]=[CH:46][C:45]([NH:48][C:49]([NH:51][C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)=[O:50])=[CH:44][CH:43]=2)[N:32]=1)=[O:60])[CH3:17]
Reactant: CCOc1c(C(=O)O)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)nc1N1CCOCC1
Reactant: CCNCC
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCOc1c(C(=O)N(CC)CC)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)nc1N1CCOCC1
Yield: 48 %

Procedure:
EDC (50 mg, 1.5 eq.), HOBT (40 mg, 1.5 eq.), Et2NH (0.0275 ml, 1.5 eq.) and Et3N (0.05 ml, 2.0 eq.) were added to a stirred solution of 5-ethoxy-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylic acid (80 mg, 1 eq.) in dry DMF (2 ml) and the mixture reacted overnight at r.t. The mixture was quenched with H2O, extracted with EA, and washed with brine. The crude was purified by chromatography to give a product (43 mg, 48%).
Reaction SMILES: [F:1][C@:2]12[C@@H:26]([OH:27])[CH2:25][C@@:24]3([CH3:28])[C@@H:12]([CH2:13][CH:14]=[C:15]3[C:16](=[O:23])[CH2:17]OS(C)(=O)=O)[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:30])[CH:4]=[CH:5][C:6](=[O:29])[CH:7]=1.[Cl-:31].[Li+].O>CN(C)C=O>[Cl:31][CH2:17][C:16](=[O:23])[C:15]1[C@:24]2([CH3:28])[C@H:12]([C@H:11]3[C@:2]([F:1])([C@@H:26]([OH:27])[CH2:25]2)[C@:3]2([CH3:30])[C:8](=[CH:7][C:6](=[O:29])[CH:5]=[CH:4]2)[CH2:9][CH2:10]3)[CH2:13][CH:14]=1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3CC=C(C(=O)COS(C)(=O)=O)[C@@]3(C)C[C@H](O)[C@@]12F
Reactant: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3CC=C(C(=O)CCl)[C@@]3(C)C[C@H](O)[C@@]12F

Procedure:
To a solution of 17.5g of 9-fluoro-11β-hydroxy-21-methanesulfonyloxypregna-1,4,16-triene-3,20-dione in dry dimethylformamide (250 ml) is added lithium chloride (30g). The mixture is heated, with stirring, from 30° to 100° C. over a 30-minute period. It is cooled and poured into cold water (1.51) and the precipitated solid is isolated and crystallized from methanol to afford 12g of the title compound, melting point 258°-260° C.(dec.).