Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[S:10])[S-:9].C([NH+](CC)CC)C.[C:18]1([C:24](=[O:27])[CH:25]=[CH2:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C.C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[S:9])[S:10][CH2:26][CH2:25][C:24](=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C=CC(=O)c1ccccc1
Reactant: S=C([S-])Nc1ccccn1
Agent: CC[NH+](CC)CC
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: O=C(CCSC(=S)Nc1ccccn1)c1ccccc1
Reaction time: 4 h
Yield: 28.3 %

Procedure:
The procedure of Example 4 is followed but a suspension of triethylammonium pyrid-2-yldithiocarbamate (81 g) in acetonitrile (400 cc) and a solution of 1-phenylprop-2-en-1-one (40 g) in acetonitrile (100 cc) are used as the starting materials at a maximum temperature of 25° C. The reaction is allowed to proceed for 4 hours at between 20° and 25° C. Triethylammonium pyrid-2-yldithiocarbamate (21 g) is filtered off. The acetonitrile is evaporated off under reduced pressure (20 mmHg) at 45° C. The residue is dissolved in chloroform (500 cc) and the chloroform solution is washed three times with distilled water (total 300 cc), dried over sodium sulphate and evaporated to dryness. The product obtained (60 g) is dissolved in chloroform (400 cc); the solution is chromatographed on silica (0.063-0.2 mm; 600 g) distributed in a column of diameter 6 cm. Elution is carried out with chloroform (1,600 cc), this eluate being discarded, and then with chloroform (3,000 cc), this eluate being collected and evaporated to dryness under reduced pressure (20 mmHg) at 40° C. The chromatographed product (35.2 g) is purified by recrystallisation from diisopropyl ether (105 cc). 3-Oxo-3-phenylpropyl pyrid-2-yldithiocarbamate (25.5 g) (structure determined by IR spectroscopy in petroleum jelly), which melts at 120° C., is obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:11]=2[C:12]([O:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:13]2[C:17](=[O:18])[N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:15][C:14]=12)=[O:4].C1COCC1.CO.[Li+].[OH-]>O>[CH:28]([O:27][C:12]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([C:3]([OH:4])=[O:2])=[C:14]2[CH2:15][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:17](=[O:18])[C:13]=12)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
A solution of 9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid methyl ester 212 (54 mg, 0.10 mmol) in 1.0 mL of a 1:1:1 mixture of THF:MeOH: H2O was stirred with LiOH (9.7 mg, 0.41 mmol) overnight when the starting materials were completely consumed as judged by TLC (DPM=benzhydryl, Ph2CH—). The reaction mixture was dried under reduced pressure and the residue was dissolved in EtOAc. The organic layer was stirred with saturated aqueous NH4Cl for 30 minutes. The aqueous layer was checked by TLC to assure complete transfer of the products to the organic layer. The organic layer was dried in vacuo to yield 45.5 mg (87%) of 9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid 213 as a white solid. The product was carried on without purification. MS (m/z) 519.2 [M+H]+, 541.2 [M+Na]+.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([O:24][CH3:25])[C:22](Br)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([O:24][CH3:25])[C:22]([N:31]3[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]3)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: COc1cc2c3c(cccc3c1Br)C(=O)N(OCc1ccccc1)C2=O
Product: COc1cc2c3c(cccc3c1N1CCN(C)CC1)C(=O)N(OCc1ccccc1)C2=O

Procedure:
2-Benzyloxy-6-bromo-5-methoxy-benzo[de]isoquinoline-1,3-dione (0.5 g, from Example Z) was reacted with N-methylpiperazine (30 mL) following the procedure of Example 18 to give 0.5 g of 2-benzyloxy-5-methoxy-6-(4-methyl-piperazin-1-yl)-benzo[de]isoquinoline-1,3-dione. Hydrogenation of 2-benzyloxy-5-methoxy-6-(4-methyl-piperazin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.3 g) at 40 psi in the presence of Pd/C (10%) in DMA (20 mL) afforded 0.2 g of the title compound as the free base. A solution of acetyl chloride (0.03 mL) in ethanol (1 mL) was added to a solution of 2-hydroxy-5-methoxy-6-(4-methyl-piperazin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.12 g, 0.4 mmol) in ethanol (5 mL). The solution was stirred for 30 minutes, and the precipitate was filtered, washed with ether, and dried to give 0.13 g of the title compound as the HCl salt, mp 296-300° C.;
Reaction SMILES: CC(C1C(OC)=C(C(C)(C)C)C=C(P(C2C=C(C(C)(C)C)C(OC)=C(C(C)(C)C)C=2)[C:18]2[CH:23]=[CH:22][C:21]3OCO[C:20]=3[C:19]=2[C:27]2C3OCOC=3C=[CH:29][C:28]=2P(C2C=C(C(C)(C)C)C(OC)=C(C(C)(C)C)C=2)C2C=C(C(C)(C)C)C(OC)=C(C(C)(C)C)C=2)C=1)(C)C.[F-].C([O:88][SiH](OCC)OCC)C.C(=O)C1C=CC=CC=1.C([Si](OC)(OC)OC)=C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O.CN(C=O)C>[C:19]1([CH:27]([OH:88])[CH:28]=[CH2:29])[CH:20]=[CH:21][CH:22]=[CH:23][CH:18]=1
Reactant: CCO[SiH](OCC)OCC
Reactant: COc1c(C(C)(C)C)cc(P(c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c2ccc3c(c2-c2c(P(c4cc(C(C)(C)C)c(OC)c(C(C)(C)C)c4)c4cc(C(C)(C)C)c(OC)c(C(C)(C)C)c4)ccc4c2OCO4)OCO3)cc1C(C)(C)C
Agent: C=C[Si](OC)(OC)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O=Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: C=CC(O)c1ccccc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a DMF (0.3 mL) solution of Cu(O-Bu-t) (20 mg, 0.02 mmol) as synthesized according to the method described in the publication Inorg. Chim. Acta, 1981, 20, 2728, (R)-DTBM-SEGPHOS (35 mg, 0.03 mmol) and triethoxysilane fluoride (4.0 μL, 0.02 mmol), benzaldehyde (0.020 mL, 0.20 mmol) and vinyltrimethoxysilane (62 μL, 0.40 mmol) were added at room temperature under an argon atmosphere, the temperature was then raised to 40° C., and the mixture was stirred for 30 minutes. Thereafter, the reaction mixture was allowed to stand for cooling to room temperature, to which was then added tetrabutylammonium fluoride (TBAF) (1M/THF, 0.5 mL), and the mixture was stirred for 10 minutes. After adding water, the mixture was extracted with ethyl acetate, and the resulting organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After drying, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (ethyl acetate/hexane: 1/9 to 1/4), thereby obtaining desired 1-phenyl-2-propen-1-ol as an (S)-form in a yield of 65% and an optical purity of 94% ee.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[C:12]([CH3:17])[CH:11]=1>CC(N(C)C)=O>[CH3:8][O:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:1](=[O:3])[CH3:2])=[C:12]([CH3:17])[CH:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(N)c(C)c1
Solvent: CC(=O)N(C)C
Product: COc1ccc(NC(C)=O)c(C)c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 88 %

Procedure:
Acetic anhydride (50 ml) was added dropwise to a solution of 4-methoxy-2-methylaniline (49.7 g, 360mmol) in DMA (200 ml) at 5° C. and the mixture stirred for 4.5 hours at ambient temperature. The solvent was removed by evaporation and the resulting solid washed with water and dried under vacuum to give N-(4-methoxy-2-methylphenyl)acetamide (57.3 g, 88%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[N:11]1([CH2:17][CH2:18][NH2:19])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(NC(C)C)(C)C>O1CCOCC1.ClCCl>[N:11]1([CH2:17][CH2:18][NH:19][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: NCCN1CCOCC1
Solvent: C1COCCO1
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(NCCN2CCOCC2)cc1
Temperature: 105 °C

Procedure:
A mixture of 7.5 mL of p-fluoronitrobenzene, 10.25 mL 2-morpholin-4-yl-ethylamine and 15 mL N,N-diisopropylamine in 36 mL dioxane is heated at 105° C. for 2 days. The reaction mixture is cooled to room temperature, diluted with dichloromethane (360 mL) and washed with water (3×290 mL). Upon evaporation to dryness, the dichloromethane layer yields the (2-morpholin-4-yl-ethyl)-(4-nitro-phenyl)-amine product, which is recrystallized from methanol.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]([N:8]1[CH2:44][C:10]2([C:18]3[C:13](=[CH:14][C:15]([C:19]4[CH2:23][C:22]([C:28]5[CH:33]=[C:32]([Cl:34])[C:31]([Cl:35])=[C:30]([Cl:36])[CH:29]=5)([C:24]([F:27])([F:26])[F:25])[N:21](C(OC(C)(C)C)=O)[N:20]=4)=[CH:16][CH:17]=3)[CH2:12][O:11]2)[CH2:9]1)=[O:7])(=[O:4])=[O:3]>O1CCOCC1>[ClH:34].[CH3:1][S:2]([CH2:5][C:6]([N:8]1[CH2:9][C:10]2([C:18]3[C:13](=[CH:14][C:15]([C:19]4[CH2:23][C:22]([C:28]5[CH:29]=[C:30]([Cl:36])[C:31]([Cl:35])=[C:32]([Cl:34])[CH:33]=5)([C:24]([F:26])([F:27])[F:25])[NH:21][N:20]=4)=[CH:16][CH:17]=3)[CH2:12][O:11]2)[CH2:44]1)=[O:7])(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)N1N=C(c2ccc3c(c2)COC32CN(C(=O)CS(C)(=O)=O)C2)CC1(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Solvent: C1COCCO1
Product: CS(=O)(=O)CC(=O)N1CC2(C1)OCc1cc(C3=NNC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)ccc12
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
by dissolving tert-butyl 3-(1-(2-(methylsulfonyl)acetyl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-5′-yl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazole-1-carboxylate in dioxane (0.2M) and purged with HCl gas at 0° C. for 30 minutes. Reaction mixture was then stirred for 30 minutes at room temperature. After consumption of starting material, reaction mixture reaction mixture was concentrated in vacuo to get an orange semisolid. Crude was triturated with Chloroform:hexane (1:8) to afford title compound as off white solid. Yield: 105 mg (35%). 1H NMR (400 MHz, CDCl3) δ: 3.18 (s, 3H), 3.38 (d, J=17.2 Hz, 1H), 3.85-3.89 (m, 3H), 4.33 (d, J=9.8 Hz, 1H), 4.43 (d, J=11.08 Hz, 1H), 4.65 (s, 2H), 5.14 (s, 2H), 6.42 (s, 1H), 7.50-7.54 (m, 4H), 7.60-7.62 (d, J=7.8 Hz, 1H). LC-MS (m/z):=593.8 (M−H). HPLC 87.81%.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([N:7]=[N:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:16])=[CH:13][C:14]=2[NH2:15])=[CH:5][CH:6]=1.Cl.[Cl:18][S:19]([OH:22])(=O)=[O:20].C1C=CC(N=NC2C=CC(N)=CC=2N)=CC=1.Cl.S(Cl)(O)(=O)=O.[CH2:45]([NH2:63])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62]>>[CH:1]1[CH:6]=[CH:5][C:4]([N:7]=[N:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:16])=[CH:13][C:14]=2[NH2:15])=[CH:3][CH:2]=1.[ClH:18].[CH2:45]([NH:63][SH:19](=[O:22])=[O:20])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62]
Reactant: O=S(=O)(O)Cl
Reactant: CCCCCCCCCCCCCCCCCCN
Agent: Cl
Agent: Nc1ccc(N=Nc2ccccc2)c(N)c1
Product: CCCCCCCCCCCCCCCCCCN[SH](=O)=O
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A mixture of 4 g of chrysoidine and 20 g of chlorosulfonic acid was stirred at a temperature lower than 20° C. for 2 hours and poured in ice water to salt out chrysoidine sulfochloride. Then 5 g of chrysoidine sulfochloride were reacted with 20 g of stearyl amine molten at 70° C. The reaction product was extracted with benzene and benzene was evaporated yield the intended chrysoidine-N-stearylsulfonamide. A liquid developer was prepared by dispersing 0.1 g of the resulting product in 1 liter of Shellsol 71 (product of Shell Petroleum Co.), which is an isoparaffin hydrocarbon, by effecting ultrasonic vibration for 2 minutes. This liquid developer was excellent in dispersibility and gave a yellow visible negative image of good fixing property.
Reaction SMILES: [CH3:1][C:2]1[N:3]2[CH:9]=[C:8]([CH2:10][OH:11])[N:7]=[C:4]2[S:5][CH:6]=1.[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl.C(O)(C)C>[ClH:12].[CH3:1][C:2]1[N:3]2[CH:9]=[C:8]([CH2:10][O:11][C:17](=[O:18])[C:16]3[CH:20]=[CH:21][C:13]([Cl:12])=[CH:14][CH:15]=3)[N:7]=[C:4]2[S:5][CH:6]=1
Reactant: Cc1csc2nc(CO)cn12
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: Cc1csc2nc(COC(=O)c3ccc(Cl)cc3)cn12
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5 g of 3-methyl-6-hydroxymethyl-imidazo-(2,1-b)thiazole in 100 ml of dry chloroform is dropped at room temperature into a solution of 20 ml of p-chlorobenzoyl chloride and 12 ml of pyridine in 75 ml of dry chloroform. The solution is stirred for 30 minutes at room temperature and filtered. The filtrate is concentrated under vacuum; the residue obtained is dissolved in isopropanol and a stream of dry hydrogen chloride is bubbled into the solution to yield 6 g of 3-methyl-6-p-chlorobenzoyloxymethyl-imidazo-(2,1-b)thiazole hydrochloride; m.p. 198°-199°.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:17])[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N1C2C(=CC=CC=2)C(=O)C1=O)CCCC.O1C2C=CC(O)=CC=2OC1.[Br:44][C:45]1[CH:46]=[C:47]([OH:51])[CH:48]=[CH:49][CH:50]=1>>[Br:44][C:45]1[CH:50]=[CH:49][C:48]([C:4]2([OH:17])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][CH:2]=3)[N:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]2=[O:16])=[C:47]([OH:51])[CH:46]=1
Reactant: CCCCCN1C(=O)C(=O)c2c(Br)cccc21
Reactant: Oc1cccc(Br)c1
Agent: CCCCCN1C(=O)C(=O)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCCCCN1C(=O)C(O)(c2ccc(Br)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1C, and making non-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dione with 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with 3-bromophenol, the title compound was obtained (48%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 9.66 (br, 1H), 7.50-7.38 (m, 2H), 7.24-7.16 (m, 2H), 6.98-6.86 (m, 2H), 6.64 (d, 1H), 4.15 (br, 1H), 3.80-3.55 (m, 2H), 1.75-1.62 (m, 2H), 1.40-1.34 (m, 4H), 0.89 (t, 3H); MS (ES+) m/z 391.4 (M+1), 393.4 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:4]=1[C:5]([NH:7][C@H:8]([C:10]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:13][NH:12][CH2:11]1)[CH3:9])=[O:6].CCN(C(C)C)C(C)C.[CH2:34]([S:37](Cl)(=[O:39])=[O:38])[CH2:35][CH3:36]>C(Cl)Cl>[Cl:2][C:3]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:4]=1[C:5]([NH:7][C@H:8]([C:10]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:13][N:12]([S:37]([CH2:34][CH2:35][CH3:36])(=[O:39])=[O:38])[CH2:11]1)[CH3:9])=[O:6]
Reactant: C[C@H](NC(=O)c1ccc(Cl)cc1Cl)C1(c2ccccn2)CNC1
Reactant: CCCS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCS(=O)(=O)N1CC(c2ccccn2)([C@H](C)NC(=O)c2ccc(Cl)cc2Cl)C1
Reaction time: 3 h

Procedure:
A sample of tert-butyl 3-{(1S)-1-[(2,4-dichlorobenzoyl)amino]ethyl}-3-pyridin-2-ylazetidine-1-carboxylate (I-4, 1.35 g, 3.5 mmol) was treated with HCl (40 mL of a 4.0 M solution in dioxane) and stirred at room temperature for 2 h before being concentrated under reduced pressure to afford 2,4-dichloro-N-[(1S)-1-(3-pyridin-2-ylazetidin-3-yl)ethyl]benzamide hydrochloride (1.54 g, 86%) which was used without further purification. A suspension of 2,4-dichloro-N-[(1S)-1-(3-pyridin-2-ylazetidin-3-yl)ethyl]benzamide hydrochloride (1.54 g, 4.4 mmol) in CH2Cl2 (45 mL) at 0° C. was treated with i-Pr2NEt (3.1 mL, 18 mmol) and n-PrSO2Cl (0.75 mL, 6.6 mmol) dropwise. After 3 h, the reaction was quenched with the addition of 1 M aqueous NaOH (50 mL) and stirred 1 h before being extracted with CH2Cl2 (3×50 mL). The combined organic extracts were dried (Na2SO4), concentrated under reduced pressure, and purified by reverse phase HPLC to afford 2,4-Dichloro-N-{(1S)-1-[1-(propylsulfonyl)-3-pyridin-2-ylazetidin-3-yl]ethyl}benzamide (I-5) as a white amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14]2)[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:23][C:24]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>ClCCl.CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14]2)[CH2:10][CH2:11][N:27]2[CH2:28][CH2:29][C:24]([OH:23])([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:25][CH2:26]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=CCC(c1ccc(Cl)c(Cl)c1)C1NC(=O)c2ccccc21
Reactant: OC1(c2ccccc2)CCNCC1
Solvent: ClCCl
Solvent: CO
Product: Cl
Product: O=C1NC(C(CCN2CCC(O)(c3ccccc3)CC2)c2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 67 %

Procedure:
3-(3,4-dichlorophenyl)-3-(3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.75 g) was coupled to 4-hydroxy-4-phenyl-piperidine (0.34 g) as described in Example 1. After chromatography, using dichloromethane:methanol (20:1) as eluent, the free amine was converted to the hydrochloride salt, to give the title compound as a white solid (0.4 g); mp 190° C.(dec); MS: m/z=495(M+1); NMR (CDCl3): 2.02 (broad,4), 2.70 (broad,4), 4.92 (broad,1), 6.95-7.73 (m,12). Analysis for C28H28Cl2N2O2.HCl.0.5 H2O: Calculated: C, 62.17; H, 5.59; N, 5.18; Found: C, 62.01; H, 5.54; N, 4.98.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:7][NH:6]1)=[O:4].[C:19](OC(C)(C)C)(=[O:24])[CH2:20][C:21]([CH3:23])=[O:22]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:11])=[O:12])[CH2:7][N:6]1[C:19](=[O:24])[CH2:20][C:21](=[O:22])[CH3:23])=[O:4]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)CN1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)CN1C(=O)CC(C)=O

Procedure:
In analogy to the procedure described in example 192f, (2S,4R)-4-benzenesulfonyl-pyrrolidine-2-carboxylic acid methyl ester was reacted with tert-butyl acetoacetate to give the title compound as yellow solid.
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](Cl)=[O:6].[N+:10]([C:13]1[CH:14]=[C:15]([NH2:22])[C:16](=[CH:20][CH:21]=1)[C:17]([OH:19])=[O:18])([O-:12])=[O:11].N1C=CC=CC=1>ClCCl>[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[C:15]([NH:22][C:5]([O:4][CH2:3][C:2]([Cl:9])([Cl:8])[Cl:1])=[O:6])[CH:14]=1)([O-:12])=[O:11]
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cc([N+](=O)[O-])ccc1C(=O)O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 2,2,2-trichloroethylchloroformate (Troc—Cl) (1.66 mL, 12.1 mmol) in dry dichloromethane (25 mL) was added drop wise to a solution of 4-nitroanthranilic acid 144 (2 g, 11 mmol) and pyridine (1.78 mL, 22 mmol) in dichloromethane (25 ml) at 0° C. The solution was allowed to stir at 25° C. for 5 hours. The reaction mixture was washed with dilute HCl (1N, 2×50 mL), water (1×50 mL), brine (1×2 5 mL) and dried over MgSO4. Removal of excess solvent by rotary evaporation under reduced pressure afforded the crude product which was used in the subsequent reaction without further purification.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:49][CH:50]1[CH2:55][CH2:54][CH2:53][NH:52][CH2:51]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:52]3[CH2:53][CH2:54][CH2:55][CH:50]([F:49])[CH2:51]3)=[O:25])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: FC1CCCNC1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc2[nH]c(C(=O)N3CCCC(F)C3)cc2c1)N1CCN(C2CCCC2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 3-fluoropiperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([Cl:12])=[C:6](O)[CH:5]=1.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[CH2:23][CH2:24][OH:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([Cl:12])=[C:6]([O:25][CH2:24][CH2:23][C:17]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=2[Cl:15])[CH:5]=1
Reactant: OCCc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1cc(O)c(Cl)c(OC)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC)c(Cl)c(OCCc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
500 mg (2.31 mmol) of 4-Chloro-3-hydroxy-5-methoxy-benzoic acid methyl ester was dissolved in 15 ml of anhydrous tetrahydrofuran. To this solution was added 485 mg (2.54 mmol) of 2-(2,4-Dichlorophenyl)-ethanol, 2.3 g (equivalent to 6.92 mmol PPh3) of triphenylphosphine derivatized polystyrene and 1.2 g (6.92 mmol) of DEAD. The solution was shaken for 16 h at RT. The polymer was filtered off and washed with ethyl acetate. The solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate/n-heptane (1/5).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:24][N:25]=[C:20]2[C@H:19]([NH2:31])[CH2:18][CH2:17]1.Cl[C:33](OC1C=CC([N+]([O-])=O)=CC=1)=[O:34].[Cl-].[Cl-].[F:47][C:48]1[CH:49]=[C:50]2[N:56]([CH:57]3[CH2:62][CH2:61][NH2+:60][CH2:59][CH2:58]3)[C:55](=[O:63])[NH:54][C:51]2=[NH+:52][CH:53]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:28])[F:29])=[CH:24][N:25]=[C:20]2[C@H:19]([NH:31][C:33]([N:60]2[CH2:59][CH2:58][CH:57]([N:56]3[C:50]4[C:51](=[N:52][CH:53]=[C:48]([F:47])[CH:49]=4)[NH:54][C:55]3=[O:63])[CH2:62][CH2:61]2)=[O:34])[CH2:18][CH2:17]1
Reactant: O=c1[nH]c2[nH+]cc(F)cc2n1C1CC[NH2+]CC1
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21)N1CCC(n2c(=O)[nH]c3ncc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.7 %

Procedure:
Triethylamine (19 μL, 0.135 mmol) was added to a solution of the hydrochloride salt of (6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-amine (18.8 mg, 0.045 mmol) and 4-nitrophenyl chloroformate (9.0 mg, 0.045 mmol) in tetrahydrofuran (2 mL) at 0° C. After 1 h, 6-fluoro-2-oxo-1-piperidinium-4-yl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-4-ium dichloride (14 mg, 0.045 mmol) and triethylamine (19 μL, 0.135 mmol) were added and the mixture allowed to warm to ambient temperature. After 1 h, saturated aqueous sodium carbonate was added and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate (3×), saturated brine, dried over sodium sulfate, filtered and concentrated. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (12.5 mg). MS 608.2229 (M+1).