Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:26]=[C:25]([C:27]([NH:29][CH2:30][C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH:33]=[N:34][N:35]3[CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][O:41]2)=[O:28])[CH:24]=[CH:23][C:5]=1[C:6]([NH:8][C@H:9]([C:19]([O:21]C)=[O:20])[CH2:10][NH:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)=[O:13])=[O:7]>CO>[Cl:3][C:4]1[CH:26]=[C:25]([C:27]([NH:29][CH2:30][C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH:33]=[N:34][N:35]3[CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][O:41]2)=[O:28])[CH:24]=[CH:23][C:5]=1[C:6]([NH:8][C@H:9]([C:19]([OH:21])=[O:20])[CH2:10][NH:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)=[O:13])=[O:7]
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1ccc(C(=O)NCc2cccc3c2cnn3C2CCCCO2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NCc1cccc2c1cnn2C1CCCCO1)c1ccc(C(=O)N[C@@H](CNC(=O)c2cccs2)C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 97 %

Procedure:
An aqueous solution of sodium hydroxide (1M, 190 μL, 0.19 mmol) was added to a solution of N-[2-chloro-4-[[[[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]methyl]amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine, methyl ester (108 mg, ˜0.169 mmol) in methanol (1 mL). The solution was allowed to stir at room temperature for 2 days, then it was concentrated and held under high vacuum for 1 h to give N-[2-chloro-4-[[[[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]methyl]amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine (100 mg, 97%) as a yellow solid.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10])[N:6]2[C:17](=[O:20])[CH:18]([NH2:19])[C@H:5]2[S:4]1.CN(C)C1C=CC=CC=1.[S:30]1[CH:34]=[N:33][N:32]=[C:31]1[S:35][CH2:36][C:37](O)=[O:38].C1(N=C=NC2CCCCC2)CCCCC1.Cl>ClCCl.C(N(CC)CC)C>[Cl:15][C:13]([Cl:16])([Cl:14])[CH2:12][O:11][C:9]([C:7]1[N:6]2[C:17](=[O:20])[CH:18]([NH:19][C:37](=[O:38])[CH2:36][S:35][C:31]3[S:30][CH:34]=[N:33][N:32]=3)[C@H:5]2[S:4][CH:3]([CH3:2])[CH:8]=1)=[O:10]
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(N)[C@H]2S1
Reactant: O=C(O)CSc1nncs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)CSc3nncs3)[C@H]2S1
Yield: 89.3 %

Procedure:
2,2,2-Trichloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride (3.82 g) was suspended in dried dichloromethane (80 ml) and dissolved by adding under stirring and ice-cooling a solution of triethylamine (0.9 g) and dimethylaniline (0.15 g) in dichloromethane (20 ml). To the solution were added (1,3,4-thiadiazol-2-ylthio)acetic acid (1.8 g) and dicyclohexylcarbodiimide (2.25 g) under stirring and ice-cooling, and the mixture was stirred for 1 hour under ice-cooling. To the reaction mixture, was added 5% hydrochloric acid (50 ml), and the mixture was stirred for 30 minutes, after which the organic layer was separated, washed in turn with 5% hydrochloric acid, a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution, and then dried over magnesium sulfate. The solvent was distilled off to give pale brown powder of 2,2,2-trichloroethyl2-methyl-7-[2-(1,3,4-thiadiazol-2-ylthio)acetamido]-3-cephem-4-carboxylate (4.5 g), mp 130° to 140° C. (dec.).
Reaction SMILES: [C:1](=[C:3]1[CH:8]=[C:7]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[C:11]([CH3:23])=[C:12]([C:18]([O:20]CC)=[O:19])[NH:13]3)[CH:6]=[CH:5][CH2:4]1)=[O:2].C1COCC1.[Li+].[OH-].Cl>C(OCC)(=O)C.O>[C:1](=[C:3]1[CH:8]=[C:7]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[C:11]([CH3:23])=[C:12]([C:18]([OH:20])=[O:19])[NH:13]3)[CH:6]=[CH:5][CH2:4]1)=[O:2]
Reactant: CCOC(=O)c1[nH]c2cccc(C3=CC(=C=O)CC=C3)c2c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)O)[nH]c2cccc(C3=CC(=C=O)CC=C3)c12
Reaction time: 6 h

Procedure:
To a solution of ethyl 5-carbonylphenyl-3-methyl-indole-2-carboxylate (10 mg, 0.034 mmol) and THF (0.5 mL) was added a solution of LiOH (3.6 mg, 0.15 mmol) and water (0.2 mL). The solution was stirred for 6 h, poured into a mixture of 1 N HCl (1 mL) and ethyl acetate (2 mL). The organic layer was separated, the aqueous layer extracted with ethyl acetate and the combined organic layers was washed with water (1 mL). The solution was dried (MgSO4), filtered and concentrated to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][N:36]([CH2:40][CH3:41])[CH2:35]1>O1CCCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([NH:33][CH:34]3[CH2:39][CH2:38][CH2:37][N:36]([CH2:40][CH3:41])[CH2:35]3)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCN1CCCC(N)C1
Reactant: O=C(O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCN1CCCC(NC(=O)Cn2c(-c3cccc(Cl)c3)nc3cccnc32)C1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
A solution of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.76 g, 0.020 mole), 1,1'-carbonyldiimidazole (3.24 g, 0.020 mole), and anhydrous tetrahydrofuran (250 ml) was stirred at room temperature with a stream of nitrogen bubbling through it for 21/2 hrs. The nitrogen flow was stopped and a solution of 3-amino-N-ethylpiperidine (2.56 g, 0.020 mole) in dry tetrahydrofuran (50 ml) was added. The solution was stoppered and stirred at room temperature for 2 hrs. The reaction was concentrated in vacuo and partitioned between ethyl acetate (150 ml) and potassium bicarbonate solution (50 ml). The layers were separated and the organic portion was washed with potassium bicarbonate solution (2×50 ml), water (50 ml), brine (25 ml), dried over sodium sulfate, and concentrated in vacuo. The solid residue (3.4 g) was converted to the hydrochloride salt and twice recrystallized from acetone-tetrahydrofuran-ethanol to give 2.7 g (31%) of a white solid, mp. 275°-276° C. with decomposition.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].[OH-].[K+].Cl.Cl[CH2:22][C:23]1[CH:24]=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[C:28]([O:33][CH3:34])[CH:27]=2>C1(C)C=CC=CC=1.C(Cl)Cl.O>[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([CH2:22][C:23]2[CH:24]=[N:25][C:26]3[C:31]([CH:32]=2)=[CH:30][CH:29]=[C:28]([O:33][CH3:34])[CH:27]=3)=[C:5]([OH:17])[N:4]=1)[CH3:2]
Reactant: COc1ccc2cc(CCl)cnc2c1
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1nc(O)c(Cc2cnc3cc(OC)ccc3c2)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 2 h

Procedure:
To a solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (121 mg, 519 μmol) in toluene (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.57 mL, 1.14 mmol) at RT followed by 3-(chloromethyl)-7-methoxyquinoline hydrochloride MDE 32012 (136 mg, 557 μmol) and the mixture was stirred at 150° C. for 2 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2 (50 mL) and H2O (10 mL). The organic phase was isolated and the aqueous phase was further extracted with CH2Cl2 (50 mL). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) gave 34 mg of 1-ethyl-6,7-dimethoxy-4-((7-methoxyquinolin-3-yl)methyl)isoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.09 M HCl solution in MeOH (3.0 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 1-ethyl-6,7-dimethoxy-4-((7-methoxyquinolin-3-yl)methyl)isoquinolin-3-ol dihydrochloride 31 as a brown solid (40 mg, 16% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([NH2:11])[CH2:5][C@H:6]1[CH2:9][C@@H:8]([CH3:10])[CH2:7]1.C(#N)C.C(N(CC)C(C)C)(C)C.[Cl:25][C:26]1[CH:59]=[CH:58][CH:57]=[CH:56][C:27]=1[O:28][C:29]1[CH2:33]N([C@@H](CC2CCCCC2)C(NC2C=CN(CC(O)(C)C)N=2)=O)[C:31](=[O:55])[CH:30]=1>ClCCl>[CH3:1][O:2][C:3](=[O:12])[CH:4]([N:11]1[CH2:33][C:29]([O:28][C:27]2[CH:56]=[CH:57][CH:58]=[CH:59][C:26]=2[Cl:25])=[CH:30][C:31]1=[O:55])[CH2:5][C@H:6]1[CH2:7][C@@H:8]([CH3:10])[CH2:9]1
Reactant: COC(=O)C(N)C[C@H]1C[C@@H](C)C1
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3ccccc3Cl)=CC2=O)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C(C[C@H]1C[C@@H](C)C1)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 80 °C

Procedure:
In a small pressure bottle was placed a mixture 2-amino-3-(cis-3-methyl-cyclobutyl)-propionic acid methyl ester (133 mg, 0.78 mmol), acetonitrile (10 mL) and N,N-diisopropylethylamine (200 μL, 0.94 mmol) and the resulting mixture heated to 80° C. To this mixture was added (E)-4-bromo-3-(2-chloro-phenoxy)-but-2-enoic acid ethyl ester (prepared as in Example 61, 250 mg, 0.78 mmol) in dichloromethane (5 mL) and the tube sealed and heated at 100° C. overnight. The mixture was then cooled and concentrated in vacuo with silica gel (2 g). Purification by Biotage flash chromatography (40S column, 20% ethyl acetate/hexanes to 40% ethyl acetate/hexanes) afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(cis-3-methyl-cyclobutyl)-propionic acid methyl ester (103 mg, 36%) as an amber gum: HR-ES-MS m/z calculated for C19H22NO4Cl [M+Na]+ 386.1129, observed 386.1130.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:4].[CH:25]1([CH:28]=O)C[CH2:26]1.[CH:30]1C=CC=CC=1>>[CH:25]1(/[CH:30]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4])[CH2:28][CH2:26]1
Reactant: O=CC1CC1
Reactant: c1ccccc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COC(=O)/C=C/C1CC1
Temperature: 55 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To a suspension of 85.8 g of methoxycarbonylmethylenetriphenylphosphorane in 550 ml of benzene is added dropwise a solution of 15.0 g of cyclopropanecarbaldehyde in 50 ml of benzene at room temperature under argon atmosphere. The mixture is stirred at 55° C. overnight. After the reaction mixture is cooled to room temperature, the reaction mixture is poured into 800ml of ice water. The aqueous mixture is extracted with 600 ml of chloroform twice. The chloroform layer is washed with brine. The organic layer is dried and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; hexane:ethyl acetate=12:1) to give 17.4 g of methyl trans-3-cyclopropylacrylate.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][O:36][C:35]1=[O:39]>C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:12][CH2:13][N:14]([CH2:32][CH2:33][N:34]4[CH2:38][CH2:37][O:36][C:35]4=[O:39])[CH2:15][CH2:16]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1OCCN1CCCl
Reactant: Cc1ccc2c(c1)CC(N1CCNCC1)c1ccccc1S2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)CC(N1CCN(CCN3CCOC3=O)CC1)c1ccccc1S2
Temperature: 0 °C

Procedure:
2.7 g of 1-(10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)-piperazine are treated, together with 4.3 g of powdered potassium carbonate, 200 mg of potassium iodide and 90 ml of toluene, with 3.2 g of N-(β-chloroethyl)-oxazolidinone and the mixture is heated for 24 hours under reflux. Then the mixture is poured on to ice-water, diluted with benzene and the organic phase washed with saturated soda solution and water, dried over sodium sulphate and concentrated under reduced pressure. There is obtained 3-[2-[4-(10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl]-2-oxazolidinone which is recrystallised from acetone/petroleum ether. The maleate melts at 159°-161° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][N:6]=1.Cl>CO>[CH3:1][O:2][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][N:6]=1
Reactant: C[O-]
Reactant: Brc1ccc(Br)nc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Br)cn1
Yield: 83.6 %

Procedure:
Sodium methylate (4.05 g, 21 mmol) was added to a methanol solution (20 mL) of 2,5-dibromopyridine (1 g, 4.2 mmol), followed by refluxing for 13 hours. The reaction solution was poured into dilute hydrochloric acid for neutralization and the mixture was extracted with a chloroform/methanol mixed solvent (chloroform/methanol=9/1). The extract was washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluted with chloroform/methanol=99/1) to obtain 2-methoxy-5-bromopyridine (660 mg; yield: 87%).
Reaction SMILES: C[Si](I)(C)C.[CH3:6][C@H:7]([O:11][C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([O:27][C:28]2[CH:40]=[CH:39][C:31]3[C:32](=[O:38])[N:33]([CH3:37])[CH2:34][CH2:35][O:36][C:30]=3[CH:29]=2)[CH:26]=1)[C:15]([NH:17][C:18]1[S:22][N:21]=[C:20]([CH3:23])[N:19]=1)=[O:16])[CH2:8][O:9]C.C(=O)([O-])O.[Na+]>C(#N)C>[OH:9][CH2:8][C@@H:7]([O:11][C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([O:27][C:28]2[CH:40]=[CH:39][C:31]3[C:32](=[O:38])[N:33]([CH3:37])[CH2:34][CH2:35][O:36][C:30]=3[CH:29]=2)[CH:26]=1)[C:15]([NH:17][C:18]1[S:22][N:21]=[C:20]([CH3:23])[N:19]=1)=[O:16])[CH3:6]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCCN(C)C3=O)cc(C(=O)Nc2nc(C)ns2)c1
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Cc1nsc(NC(=O)c2cc(Oc3ccc4c(c3)OCCN(C)C4=O)cc(O[C@@H](C)CO)c2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.4 %

Procedure:
Trimethylsilyl iodide (0.95 mL, 6.7 mmol) was added to a solution of 3-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-5-[(4-methyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepin-8-yl)oxy]-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide (335 mg, 0.67 mmol) in acetonitrile (20 mL) under an atmosphere of argon and the mixture stirred at RT for 18 hours. The mixture was poured onto saturated sodium hydrogen carbonate solution (50 mL), the acetonitrile removed in vacuo, and the aqueous layer extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with sodium thiosulphate solution, brine, dried (MgSO4) and evaporated in vacuo to a residue which was chromatographed on silica, eluting with ethyl acetate then with 2% methanol in DCM, to give the desired compound as a colourless solid (50 mg). 1H NMR δ (CDCl3): 1.3 (d, 3H), 2.5 (s, 3H), 3.2 (s, 3H), 3.6 (t, 2H), 3.75 (m, 2H), 4.4 (t, 2H), 4.55 (m, 1H), 6.55 (d, 1H), 6.7 (dd, 1H), 6.8 (d, 1H), 7.2 (s, 1H), 7.25 (s, 1H), 7.85 (d, 1H); m/z 485 (M+H)+
Reaction SMILES: Cl.Cl.[CH2:3]([O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(=O)(O)[O-].[K+].F[C:28]1[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=1.O>CS(C)=O.C(OCC)(=O)C>[CH2:3]([O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: CCCCCCOc1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCOc1ccc(N2CCN(c3ccc(C(=O)OCC)cc3)CC2)cc1
Temperature: 150 °C
Reaction time: 10 h

Procedure:
To a suspension of 1-(4-hexyloxyphenyl)piperazine dihydrochloride (0.914 g) and potassium bicarbonate (0.564 g) in dimethylsulfoxide (5 ml) was added ethyl p-fluorobenzoate (0.2 ml) and stirred for 10 hours at 150° C. The reaction mixture was added to a mixture of water and ethyl acetate. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give ethyl 4-[4-(4-hexyloxyphenyl)piperazin-1-yl]benzoate (0.347 g).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:33][C:32]([CH3:34])=[CH:31][C@@H:30]([CH2:35][CH:36]=[CH2:37])[C:28](=[O:29])[CH2:27][C@H:26]([OH:38])[C@@H:25]([CH3:39])[C@@H:24](/[C:40](/[CH3:51])=[CH:41]/[C@H:42]2[CH2:47][C@@H:46]([O:48][CH3:49])[C@H:45]([OH:50])[CH2:44][CH2:43]2)[O:23][C:21](=[O:22])[C@H:20]2[N:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[C:13](=[O:14])[C:11](=[O:12])[C@:9]2([OH:52])[O:10][C@@H:5]([C@@H:6]([O:54][CH3:55])[CH2:7][C@H:8]2[CH3:53])[C@@H:4]([O:56][CH3:57])[CH2:3]1.[C:58]1(=[O:64])[O:63][C:61](=[O:62])[CH2:60][CH2:59]1.C(OCC)(=O)C>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH2:35]([CH:30]1[CH:31]=[C:32]([CH3:34])[CH2:33][CH:2]([CH3:1])[CH2:3][CH:4]([O:56][CH3:57])[CH:5]2[O:10][C:9]([OH:52])([CH:8]([CH3:53])[CH2:7][CH:6]2[O:54][CH3:55])[C:11](=[O:12])[C:13](=[O:14])[N:15]2[CH:20]([CH2:19][CH2:18][CH2:17][CH2:16]2)[C:21](=[O:22])[O:23][CH:24]([C:40]([CH3:51])=[CH:41][CH:42]2[CH2:43][CH2:44][CH:45]([O:50][C:58](=[O:64])[CH2:59][CH2:60][C:61]([OH:63])=[O:62])[CH:46]([O:48][CH3:49])[CH2:47]2)[CH:25]([CH3:39])[CH:26]([OH:38])[CH2:27][C:28]1=[O:29])[CH:36]=[CH2:37]
Reactant: C=CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Reactant: O=C1CCC(=O)O1
Agent: C=CC[C@@H]1/C=C(\C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OC(=O)CCC(=O)O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of the FR-900506 substance (248 mg) in pyridine (7 ml) were added succinic anhydride (145 mg) and 4-(N,N-dimethylamino)pyridine (7 mg), and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was subjected to chromatography on pressure and the residue was subjected to chromatography on silica gel (20 g) with ethyl acetate to give 17-allyl-12-[2-[4-(3-carboxypropionyloxy)-3-methoxycyclohexyl]-1-methylvinyl]-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16,-tetraone (90 mg).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH:8]2[CH2:10][CH:5]1[CH2:6][NH:7]2)([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:36]=[C:35]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=[C:33]2[C:28]=1[CH2:29][N:30]([CH2:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=1)[C:31](=[O:49])[N:32]2[C:41]1[C:46]([Cl:47])=[CH:45][CH:44]=[CH:43][C:42]=1[Cl:48]>C1COCC1>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:36]=[C:35]([S:37]([N:7]2[CH2:6][CH:5]3[CH2:10][CH:8]2[CH2:9][N:4]3[CH:1]([CH3:3])[CH3:2])(=[O:39])=[O:38])[CH:34]=[C:33]2[C:28]=1[CH2:29][N:30]([CH2:50][C:51]1[CH:52]=[CH:53][C:54]([O:57][CH3:58])=[CH:55][CH:56]=1)[C:31](=[O:49])[N:32]2[C:41]1[C:42]([Cl:48])=[CH:43][CH:44]=[CH:45][C:46]=1[Cl:47]
Reactant: CC(C)N1CC2CC1CN2
Reactant: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(S(=O)(=O)Cl)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(S(=O)(=O)N4CC5CC4CN5C(C)C)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-isopropyl-2,5-diazabicyclo[2.2.1]heptane (INTERMEDIATE ABA2) (35 μL, ca. 0.249 mmol) and diisopropylethylamine (32 mg, 0.249 mmol) were added to a mixture of 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinazoline-7-sulfonyl chloride (103 mg, 0.166 mmol) (COMPOUND CCC8) in 2 mL THF at 0° C. The mixture was warmed to rt, stirred at this temperature for 0.5 h, and concentrated under reduced pressure. The residue was diluted with ethyl acetate and added to 6 mL of 1M aqueous HCl The phases were separated and the aqueous was extracted with 3×15 mL of ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The product was purified by preparative thin-layer chromatography, eluting with 93:7 CH2Cl2-methanol to yield the 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-[(5-isopropyl-2,5-diazabicyclo[2.2.1]hept-2-yl)sulfonyl]-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one. Mass spectrum (ESI) 725 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=O)=[C:4]2[CH:3]=1.[CH3:14][O:15][C:16]1[CH:32]=[CH:31][C:19]([CH2:20][NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1.CCN=C=NCCCN(C)C.CN(C=O)C>CN(C1C=CN=CC=1)C.O>[I:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([N:21]([CH2:20][C:19]3[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:32][CH:31]=3)[CH2:22][C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)=[O:13])=[C:4]2[CH:3]=1
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Reactant: O=C(O)c1cnn2ccc(I)cc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2cnn3ccc(I)cc23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 22 L round bottom flask was charged with 5-iodopyrazolo[1,5-a]pyridine-3-carboxylic acid (I-42) (200 g, 694.3 mmol), bis(4-methoxybenzyl)amine (182.2 g, 708.3 mmol), DMAP (42.4 g, 347.2 mmol), EDCI (146.4 g, 763.8 mmol) and DMF (3500 mL). The suspension was stirred at room temperature over 16 hours and a dark solution was obtained. HPLC showed no (I-42) remaining. 2-MethylTHF (4 L) and water (7 L) were added to the reaction mixture while keeping the batch temperature <25° C. The aqueous layer was separated and extracted with 2-methylTHF (4 L). The combined 2-methylTHF layers were washed with 0.25 N HCl (2×4 L), aqueous saturated NaHCO3 (4 L) and 10% brine (4 L). The 2-methylTHF layer was treated with carbon (20 g) and Na2SO4 (80 g). The solution was passed through a silica gel pad (400 g of silica gel 240-400 mesh) and the pad was washed with 2-MeTHF (3 L). The filtrate was concentrated under vacuum to give 5-iodo-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (I-43) as a solid. 1H NMR (500 MHz, CDCl3) δ 8.73 (d, 1 H), 8.17 (d, 1H), 7.86 (s, 1H), 7.22 (d, 4 H), 7.14 (dd, 1 H), 6.92 (d, 4 H), 4.68 (s, 4 H), 3.83 (s, 6 H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7](Cl)=[O:8].[NH2:10][C:11]1[C:12]([I:29])=[C:13]([C:22]([NH:24][CH2:25][CH:26]([OH:28])[CH3:27])=[O:23])[C:14]([I:21])=[C:15]([C:19]=1[I:20])[C:16]([OH:18])=[O:17].CC(N(C)C)=O>O>[OH:28][CH:26]([CH3:27])[CH2:25][NH:24][C:22](=[O:23])[C:13]1[C:14]([I:21])=[C:15]([C:19]([I:20])=[C:11]([NH:10][C:7](=[O:8])[CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:12]=1[I:29])[C:16]([OH:18])=[O:17]
Reactant: COCCOCC(=O)Cl
Reactant: CC(O)CNC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Solvent: CC(=O)N(C)C
Solvent: O
Product: COCCOCC(=O)Nc1c(I)c(C(=O)O)c(I)c(C(=O)NCC(C)O)c1I
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At a maximum of 10° C. (ice cooling), 16.5 ml. of methoxyethoxyacetyl chloride is added dropwise within 30 minutes with agitation to 30.8 g. (50 mmol) of 5-amino-(2-hydroxypropyl)2,4,6-triiodoisophthalamic acid in 60 ml. of dimethylacetamide. The mixture is stirred for 1 hour at 0° C. and then for 16 hours at room temperature. Thereafter, another 2 ml. of the acid chloride is added thereto, and the mixture is stirred at room temperature for 4 hours. Then, 10 ml. of water is added and the mixture is concentrated under vacuum. The residue is dissolved in 350 ml. of water and neutralized with 32% sodium hydroxide solution. The mixture is combined with another 5 ml. of 32% sodium hydroxide solution and then stirred for some time after adding 5 g. of active carbon. After the carbon has been removed, the mixture is acidified with concentrated hydrochloric acid, allowed to stand for a period of time and vacuum-filtered. The resulting precipitate is dried under vacuum. Yield: 21.3 g. (58%), m.p. 275° C., with decomposition.