Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=[O:17])[NH:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH:28]([N:30]([CH2:39][C@@H:40]([CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:41](F)=[O:42])[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:29].CC(O)=O>CN(C=O)C>[CH:28]([N:30]([CH2:39][C@@H:40]([CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:41]([N:12]1[C@H:13]([C:16]([OH:18])=[O:17])[CH2:14][CH2:15][N:11]1[C:9]([O:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:10])=[O:42])[O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:29]
Reactant: CCCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)F
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.7 %

Procedure:
To a 50 mL round-bottomed flask was added 1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (3.00 g, 8.23 mmol) and Hunig's base (DIPEA) (4.41 mL, 25.3 mmol) in DMF (15 mL). To this mixture was added (2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl)heptanoyl fluoride (1.87 g, 6.33 mmol) in DMF (5 mL) dropwise. The reaction mixture was stirred at room temperature overnight, then was stored in refrigerator for two days. HOAc (3 ml) was added to neutralize the excess Hunig's base. The resulting solution was purified by RP-HPLC to provide (3S)-2-[(2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl)heptanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid as a white solid (1.153 g, 35%). LCMS: (M+H)+: 526.0.
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[Na+].[Na+].S(O)(O)(=O)=O.[NH2:21]O>O>[NH2:9][C:8]1[CH:7]=[C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])[O:6][N:21]=1
Reactant: NO
Reactant: CC(C)(C)C(=O)CC#N
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1cc(N)no1
Yield: 124.4 %

Procedure:
A suspension of pivaloylacetonitrile (12.52 g), sodium carbonate (8.74 g) and water (200 ml) is stirred and mixed with hydroxylamine sulfate (9.03 g) at 25° C. pH 7.11. The reaction mixture is treated as in Example 2 to give 3-amino-5-t-butylisoxazole (12.01 g). Yield, 85.7%. Purity, 95.8%.
Reaction SMILES: CCCCCCCCCC([O:12][CH2:13][CH:14]([O:28][C:29]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:30])[CH2:15][O:16]C(CCCCCCCCC)=O)=O.P([O-])([O-])([O-])=O>C(O)CCC>[C:29]([O:28][CH:14]([CH2:13][OH:12])[CH2:15][OH:16])(=[O:30])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCC(=O)OCC(COC(=O)CCCCCCCCC)OC(=O)CCCCCCCCC
Agent: O=P([O-])([O-])[O-]
Solvent: CCCCO
Product: CCCCCCCCCC(=O)OC(CO)CO
Temperature: 37 °C
Reaction time: 3 h

Procedure:
Tridecanoin (45.0 mmole, 25.0 g) is dissolved in petroleum ether, b.p. 35° C.-60° C., (600 ml) and n-butanol (110 ml). This solution is mixed with 0.05 M phosphate buffer (110 ml) containing lipolase (Novo) 100L (9.0 g) and stirred at 37° C. for 3 hours. After separation of phases, the organic solution is evaporated at reduced pressure and temperature (below 30° C.) to a volume of about 100 ml. This solution is diluted with hexane (500 ml) and cooled to -78° C. using a dry ice-isopropanol bath. The precipitate is filtered below 0° C. and dried. Yield of 2-decanolyl glycerol is 7.2 g (65%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:20][C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)=[CH:15][C:14]=2[N+:28]([O-])=O)=[CH:7][CH:6]=1)=[O:4].C(O)(=O)C.CO.C(=O)([O-])O.[Na+]>[Fe].C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:20][C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)=[CH:15][C:14]=2[NH2:28])=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1ccc(CNc2ccc(-c3nc4ccccc4o3)cc2[N+](=O)[O-])cc1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(CNc2ccc(-c3nc4ccccc4o3)cc2N)cc1
Yield: 18.2 %

Procedure:
To 2-(2-(4-methoxycarbonylphenylmethyl)aminonitrobenzen-5-yl)benzoxazole (see Working Example 113-2) (367 mg, 0.910 mmol) was added iron powder (102 mg, 1.82 mmol), 10% aqueous acetic acid (5 mL) and methanol (7 mL), and this was heated to reflux for 16 hours. After the reaction solution was cooled, saturated aqueous sodium hydrogen carbonate solution and chloroform were added, this was filtered through Celite, and the filtrate obtained was extracted. After the organic layer obtained was dried over anhydrous sodium sulfate, it was filtered and concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (61.8 mg, 18% yield).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[CH:14][CH:13]=1.[C:20](=O)([O:23]C)[O:21][CH3:22].C(OCC)(=O)C>C1COCC1.CCCCCC>[C:18]([C:17]1[CH:16]=[N:15][CH:14]=[CH:13][C:12]=1[CH2:11][C:20]([O:21][CH3:22])=[O:23])#[N:19]
Reactant: COC(=O)OC
Reactant: Cc1ccncc1C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccncc1C#N
Temperature: -78 °C
Reaction time: 1 h
Yield: 14.1 %

Procedure:
1M LiHMDS (45 mL, 44.794 mmol) was added to a solution of 4-methylnicotinonitrile (2.52 g, 21.33 mmol) in THF (15 mL) at −78° C. and the resulting reaction mass was stirred at −78° C. for 1 hour. This was followed by the addition of dimethyl carbonate (1.98 mL, 23.464 mmol) and stirred the resulting reaction mass at −78° C. for 1 hour and further at 0° C. for 2 hours. The reaction was monitored by TLC (30% ethyl acetate in hexane). The reaction mass was quenched with saturated NH4Cl solution and extracted using ethyl acetate. The organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (25% ethyl acetate in hexane) afforded 530 mg of the product (14.10% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.CC(C)([O-])C.[K+].Br[CH2:24][CH2:25][CH2:26][Cl:27].O>CS(C)=O>[CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[N:9]([CH2:24][CH2:25][CH2:26][Cl:27])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: ClCCCBr
Reactant: COc1cc2c(cc1OC)CC(=O)NCC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1.1 gm (0.005 mol) of 7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one were suspended in 15 ml of absolute dimethylsulfoxide, and the suspension was mixed with 0.67 gm (0.006 mol) of potassium tert. butoxide, while stirring. After 10 minutes, the suspension thus obtained was added dropwise to 0.64 ml (0.006 mol) of 1-bromo-3-chloro-propane in 10 ml of dimethylsulfoxide, while cooling with ice water. After one hour the mixture was poured into water. After a short time the viscous precipitate began to crystallize. The precipitate was suction-filtered off, dissolved in acetone, precipitated again with water, and then suction-filtered off and dried
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]3[N:20]([CH:29]([CH3:31])[CH3:30])[C:21]([C:24](OCC)=[O:25])=[N:22][N:23]=3)=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].[NH:36]([CH3:38])[CH3:37].CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]3[N:20]([CH:29]([CH3:31])[CH3:30])[C:21]([C:24]([N:36]([CH3:38])[CH3:37])=[O:25])=[N:22][N:23]=3)=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:34])([F:33])[F:35]
Reactant: CNC
Reactant: CCOC(=O)c1nnc(-c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)n1C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)n1c(C(=O)N(C)C)nnc1-c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 7 %

Procedure:
To a vial containing ethyl 5-(3-(4-chloro-3-(trifluoromethyl) benzenesulfonamido)-5-chloropyridin-2-yl)-4-isopropyl-4H-1,2,4-triazole-3-carboxylate (57 mg, 0.1 mmol) was added Me2NH in THF (1.0 mL of a 2.0M solution). The solution was stirred at room temperature for 16 h. EtOAc (30 mL) was added. The organic phase washed with water (2×10 mL) and dried over Na2SO4. The volatiles were removed in vacuo. The resulting residue was purified by preparative HPLC (20→95% gradient of MeCN—H2O with 0.1% TFA) and the pure fractions lyophilized to afford the title compound (3.7 mg, 7% yield). HPLC retention time=2.91 minutes. 1H NMR (400 MHz, CDCl3) δ 8.36 (d, J=2.0, 1H), 8.17 (d, J=2.4, 1H), 8.10 (d, J=2.4, 1H), 7.93 (dd, J=2.4, 8.4, 1H), 7.57 (d, J=8.4, 1H), 5.65 (sept, J=7.2, 1H), 3.20 (s, 3H), 3.12 (s, 3H), 1.52 (d, J=7.2, 6H). MS (ES) [M+H]+ expected 551.1. found 551.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[CH2:21]([NH:13][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(CCN)cc1OC
Reactant: BrCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CCNCc2ccccc2)cc1OC
Reaction time: 0.04 h

Procedure:
N-benzyl-2-(3,4-dimethoxyphenyl)ethylamine was prepared using a system (FRX200, Syrris Limited) including a microflow reactor. For this purpose, 83 μl (0.5 mmol) of 2-(3,4-dimethoxyphenyl)ethylamine and 5 ml of tetrahydrofuran were added to the first storage unit of the system including the microflow reactor, and then 70 μl (0.5 mmol) of triethylamine was added thereto. Meanwhile, 60 μl (0.5 mmol) of benzyl bromide and 5 ml of tetrahydrofuran were added to the second storage unit of the system. The reactants included in the first and second storage units were transferred through the first and second flow channels to the mixing unit, and then transferred through the third flow channel into the microflow reactor including microchannels. The first and second flow channels could transfer 360 μl (180 μl for each flow channel) of the reactants to the microflow reactor. The microflow reactor was set at a capacity of 250 μl, a temperature of 100° C. and a pressure of 8 bar. The reactants in the first and second storage units were set such that they were passed through the first to third flow channels at a flow rate of 0.05 ml/min and introduced into the microflow reactor. Also, the residence time of the reactants in the microflow reactor was set at 2.5 minutes.
Reaction SMILES: C(OC([N:8]1[CH:12]2[CH2:13][CH2:14][CH2:15][CH:11]2[N:10]([CH2:16][CH3:17])[C:9]1=[O:18])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:16]([N:10]1[CH:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[NH:8][C:9]1=[O:18])[CH3:17]
Reactant: CCN1C(=O)N(C(=O)OC(C)(C)C)C2CCCC21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN1C(=O)NC2CCCC21
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.6 %

Procedure:
To a solution of (3aSR,6aRS)-3-methyl-2-oxo-hexahydro-cyclopentaimidazole-1-carboxylic acid tert-butyl ester (Example 1, step 2) (1.60 g, 6.29 mmol) in 15 ml of dichloromethane was added trifluoroacetic acid (5.74 g, 3.9 ml, 50.3 mmol, 8 equiv.) and the yellow solution was stirred for 15 h at room temperature. The reaction mixture was quenched by addition of saturated sodium bicarbonate solution and the pH of the aqueous phase was set to 9. After workup with dichloromethane/water, the organic phases were dried, filtered and concentrated in vaccuo to yield 0.801 g of a yellow oil, which directly used in the next step without further characterization.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][C:15]=2[OH:24])=[C:4]([CH3:25])[N:3]=1.[N:26]1([CH2:31][CH2:32][CH2:33][CH2:34]O)[CH2:30][CH2:29][CH2:28][CH2:27]1>>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:34][CH2:33][CH2:32][CH2:31][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:22])=[CH:16][C:15]=2[OH:24])=[C:4]([CH3:25])[N:3]=1
Reactant: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1O
Reactant: OCCCCN1CCCC1
Product: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)OCCCCN2CCCC2)cc1O

Procedure:
The title compound was prepared using the product of step (i) (50 mg), 4-(pyrrolidin-1-yl) butan-1-ol (64.2 mg) and the method of example 74 step (iii) to give a tan solid, 9 mg.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl-].[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>CCOCC.CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[CH2:12]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)c1ccc(F)cc1
Yield: 60.4 %

Procedure:
A mixture of 4-fluorobenzoic acid (1.0 g, 7.13 mmol) in Et2O was treated with oxallyl chloride (760 mL, 8.55 mmol) and a catalytic amount of DMF. The mixture was then stirred until the evolution of gas stopped. The mixture was then filtered and concentrated under reduced pressure. The residue was dissolved in a small volume of CH2Cl2 and the solution was added in a drop wise manner to a mixture of benzyl alcohol (770 mg, 7.13 mmol), diisopropyl ethyl amine (2.49 mL, 14.3 mmol) and a catalytic amount of DMAP in CH2Cl2 (20 mL). After stirring overnight the reaction mixture was concentrated and the residue was passed through a silica gel plug with 10% Et2O in hexanes to afford the product (991 mg, Yield: 60%). FIRMS m/z calcd for C14H11O2F [M+H]+: 230.0743. Found: 230.0742.
Reaction SMILES: [CH:1]1([N:4]([C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][C:21](OC)=[O:22])[CH2:16][CH2:15]2)[C:5](=[O:13])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[F:12])[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH:1]1([N:4]([C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]2)[C:5](=[O:13])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[F:12])[CH2:2][CH2:3]1
Reactant: COC(=O)C[C@H]1CC[C@H](N(C(=O)c2ccccc2F)C2CC2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1F)N(C1CC1)[C@H]1CC[C@H](CCO)CC1

Procedure:
To a solution of methyl 2-(trans-4-(N-cyclopropyl-2-fluorobenzamido)cyclohexyl)acetate (0.100 g, 0.30 mmol) in THF (3 mL) was added lithium aluminum hydride (1.0 M solution in THF) (0.33 ml, 0.33 mmol) at 0° C. The reaction was quenched with saturated NH4Cl (10 mL) after 30 minutes. The mixture was extracted with EtOAc twice. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by prep TLC eluting with 5% MeOH—CH2Cl2, 50% EtOAc-hexane. The alcohol product was obtained as a sticky white solid (74 mg). MS: 306 (M+1), C18H24FNO2.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[NH:13][C:14]1[N:19]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:18](=[O:26])[CH:17]=[C:16]([C:27]([F:30])([F:29])[F:28])[N:15]=1.S(Cl)([Cl:36])(=O)=O>>[F:32][C:2]([F:31])([F:1])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:11])([F:10])[F:12])=[CH:5][C:4]=1[NH:13][C:14]1[N:19]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:18](=[O:26])[C:17]([Cl:36])=[C:16]([C:27]([F:28])([F:29])[F:30])[N:15]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: O=c1cc(C(F)(F)F)nc(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)n1C1CCCCC1
Product: O=c1c(Cl)c(C(F)(F)F)nc(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)n1C1CCCCC1
Yield: 93 %

Procedure:
In accordance with the method of Example 25, chlorination of 2-{2,5-bis(trifluoromethyl)phenyl}amino-3-cyclohexyl-6-trifluoromethyl-4(3H)-pyrimidinone (80 mg, 0.18 mmol) was carried out using sulfuryl chloride to obtain white solid of 2-{2,5-bis(trifluoromethyl)phenyl}amino-5-chloro-3-cyclohexyl-6-trifluoromethyl-4(3H)-pyrimidinone [Compound No. 65].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C[O:15][C:16]([CH:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[S:27](Cl)(=[O:29])=[O:28])[CH2:19]1)=[O:17]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:27]([C:24]3[CH:23]=[CH:22][CH:21]=[C:20]4[C:25]=3[CH2:26][CH:18]([C:16]([OH:17])=[O:15])[CH2:19]4)(=[O:29])=[O:28])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C1Cc2cccc(S(=O)(=O)Cl)c2C1
Reactant: Clc1ccc(N2CCNCC2)cc1
Product: O=C(O)C1Cc2cccc(S(=O)(=O)N3CCN(c4ccc(Cl)cc4)CC3)c2C1

Procedure:
The compound 4-[4-(4-chloro-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylic acid was prepared from 1-(4-chloro-phenyl)-piperazine and 4-chlorosulfonyl-indan-2-carboxylic acid methyl ester following the procedure outlined in Example 79. 1H NMR (400 MHz, DMSO-d6): δ 7.58 (d, 1H), 7.56 (d, 1H), 7.43 (t, 1H), 7.23 (d, 2H), 6.92 (d, 2H), 3.50-3.41 (m, 2H), 3.40-3.29 (m, 1H), 3.28-3.13 (m, 6H), 3.12-3.04 (m, 4H); MS (ESI): 420.9 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH:9]1[CH:15]([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:21][C:22]1[N:23]([CH3:48])[C:24]2[C:29]([N:30]=1)=[C:28]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[N:27]=[C:26]([N:37]1[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[N:39]=[C:38]1[CH2:46][CH3:47])[N:25]=2>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:21][C:22]2[N:23]([CH3:48])[C:24]3[C:29]([N:30]=2)=[C:28]([N:31]2[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)[N:27]=[C:26]([N:37]2[C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=4[N:39]=[C:38]2[CH2:46][CH3:47])[N:25]=3)[C:10](=[O:14])[CH:9]1[CH:15]([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: CC(C)C1C(=O)NCCN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(=O)OC(C)(C)C)C(C(C)C)C3=O)n(C)c2n1
Reaction time: 19 h
Yield: 76.5 %

Procedure:
To a solution of 2-isopropyl-3-oxopiperazine-1-carboxylic acid tert-butyl ester (58 mg, 0.24 mmol) in DMF (1.5 mL) at 0° C. was added NaH (11 mg, 0.29 mmol, 60% dispersion in mineral oil) and the resulting mixture stirred at r.t. for 30 min before the addition of 8-bromomethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (100 mg, 0.22 mmol) in DMF (1.5 mL). The resulting mixture was allowed to stir for 19 h then partitioned between EtOAc and H2O. The organic phase was dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-10%) affording the title compound as a yellow oil (104 mg, 77%). LCMS (method H): RT 3.03 min [M+H]+ 618.4
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2=[CH:17][C:18]([Cl:27])=[C:19]([N:20]3[CH2:25][CH2:24][NH:23][CH:22]([CH3:26])[CH2:21]3)[C:12]3=[C:13]2[N:8]([CH:9]([CH3:28])[CH:10]=[CH:11]3)[CH:7]=1)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[Cl:27][C:18]1[CH:17]=[C:14]2[C:13]3[N:8]([CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:15]2=[O:16])[CH:9]([CH3:28])[CH:10]=[CH:11][C:12]=3[C:19]=1[N:20]1[CH2:25][CH2:24][NH:23][CH:22]([CH3:26])[CH2:21]1
Reactant: CCOC(=O)c1cn2c3c(c(N4CCNC(C)C4)c(Cl)cc3c1=O)C=CC2C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1CN(c2c(Cl)cc3c(=O)c(C(=O)O)cn4c3c2C=CC4C)CCN1
Reaction time: 2 h
Yield: 77.3 %

Procedure:
To 4.02 g (0.01 mole) of 9-chloro-5-methyl-8-(3-methyl-1-piperazinyl)-1-oxo-1H, 5H-benzo[ij]quinolizine-2-carboxylic acid ethyl ester was added 120 ml of a mixture of 1N aqueous sodium hydroxide and ethanol (with a volume ratio of 5:1). This mixture was stirred at 20°-25° C. for 2 hours to hydrolyze the starting material. The resulting reaction solution was adjusted to pH 6-7 by the addition of 1N hydrochloric acid under cooling with ice. This solution was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography [using a chloroform-methanol mixture (with a volume ratio of 2:1) as the developing solvent], and the fraction containing the desired product was collected. This fraction was evaporated to dryness under reduced pressure and the resulting residue was recrystallized from ethanol to obtain 2.89 g (77.3% yield) of 9-chloro-5-methyl-8-(3-methyl-1-piperazinyl)-1-oxo-1H, 5H-benzo[ij] quinolizine-2-carboxylic acid in the form of pale-yellow crystals. These crystals had a melting point of 200°-205° C. (dec.).
Reaction SMILES: [CH:1]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]([C:10]2[C:20]3[CH:21]=[CH:22][C:23]([OH:25])=[CH:24][C:19]=3[O:18][C:17]3[C:11]=2[CH:12]=[CH:13][C:14]([CH:16]=3)=[O:15])=[C:3]([C:26]([OH:28])=[O:27])[CH:2]=1.[OH:29][N:30]1[C:34](=[O:35])[CH2:33][CH2:32][C:31]1=[O:36].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[OH:29][N:30]1[C:34](=[O:35])[CH2:33][CH2:32][C:31]1=[O:36].[CH:1]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]2[C:10]3([O:27][C:26](=[O:28])[C:3]=2[CH:2]=1)[C:11]1[CH:12]=[CH:13][C:14]([OH:15])=[CH:16][C:17]=1[O:18][C:19]1[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:20]3=1
Reactant: O=C(O)c1ccc(C(=O)O)c(-c2c3ccc(=O)cc-3oc3cc(O)ccc23)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2c(c1)C1(OC2=O)c2ccc(O)cc2Oc2cc(O)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 83 mg (0.22 mmol) of 6-carboxyfluorescein dissolved in 2 ml of dimethylformamide was added 28 mg (0.24 mmol) of N-hydroxysuccinimide and 55 mg (0.27 mmol) of N,N'-dicyclohexylcarbodiimide. The reaction mixture was stirred at 0° C. under argon atmosphere for one hour and then maintained at 4° C. for 16 hours to yield a N-hydroxysuccinimide active ester of carboxyfluorescein having the formula: ##STR6##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:22][O:23][C:24](=[O:35])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=1>>[CH3:22][O:23][C:24](=[O:35])[CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:33][N:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:10])=[O:9])[C@@H:12]2[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])=[CH:31][CH:32]=1
Reactant: CC1(C)CCNC(=O)[C@H](NS(=O)(=O)c2ccc(Cl)cc2)C1
Reactant: COC(=O)CCc1ccc(CBr)cc1
Product: COC(=O)CCc1ccc(CN([C@@H]2CC(C)(C)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
4-Chloro-N-((R)-5,5-dimethyl-2-oxo-azepan-3-yl)-benzenesulfonamide was alkylated using 3-(4-bromomethyl-phenyl)-propionic acid methyl ester analogous to Example 2c to yield 3-(4-{[(4-chloro-benzenesulfonyl)-((R)-5,5-dimethyl-2-oxo-azepan-3-yl)-amino]-methyl}-phenyl)-propionic acid methyl ester: MS: m/e=507.6 (MH+).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)/[C:6](=[C:13](/[NH:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][S:28]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:30])=[O:29])=[CH:23][CH:22]=2)\[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)/[C:5]1=[O:38])(=O)C.[CH3:39][N:40]([CH3:45])[C:41](=[O:44])[CH2:42]Br.CC(C)([O-])C.[K+].[OH-].[Na+]>CS(C)=O.CO>[CH3:39][N:40]([CH3:45])[C:41]([CH2:42][N:27]([C:24]1[CH:25]=[CH:26][C:21]([NH:20]/[C:13](=[C:6]2\[C:5](=[O:38])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:22][CH:23]=1)[S:28]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:30])=[O:29])=[O:44]
Reactant: CC(=O)N1C(=O)/C(=C(\Nc2ccc(NS(=O)(=O)Cc3ccccc3)cc2)c2ccccc2)c2ccccc21
Reactant: CN(C)C(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: CN(C)C(=O)CN(c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1)S(=O)(=O)Cc1ccccc1

Procedure:
Prepared analogously to Examples 1 and 187 from (Z)-1-acetyl-3-[1-(4-benzylsulphonylamino-phenylamino)-1-phenyl-methylidene]-2-indolinone, bromoacetic acid-N,N-dimethylamide and potassium tert.butoxide in DMSO and subsequent treatment with sodium hydroxide solution in methanol.