Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[K+].[CH2:3]([O:5][C:6](=[O:15])[CH:7]([CH2:13][CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([I:27])[CH:25]=2)[N:20]=[CH:19][C:18]=1[C:28]#[N:29]>CCCCCC.O1CCCC1>[CH2:3]([O:5][C:6](=[O:15])[C:7]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([I:27])[CH:25]=2)[N:20]=[CH:19][C:18]=1[C:28]#[N:29])([CH2:13][CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4]
Reactant: CCOC(=O)C(CC)C(=O)OCC
Reactant: N#Cc1cnc2ccc(I)cc2c1Cl
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C(CC)(C(=O)OCC)c1c(C#N)cnc2ccc(I)cc12
Reaction time: 0.17 h
Yield: 83.8 %

Procedure:
Potassium hydride (35% oil dispersion, 220 mg, 1.91 mmol) was washed with newly opened hexane for two times under Argon. Then anhydrous tetrahydrofuran (55 mL) was added, followed by addition of 2-ethyl-malonic acid diethyl ester (480 mg, 2.54 mmol). The reaction mixture was stirred at about room temperature for 10 min. Then 4-chloro-6-iodo-quinoline-3-carbonitrile (example 14c, 200 mg, 0.64 mmol) in anhydrous tetrahydrofuran (3 mL) was added to the above reaction mixture, and then reaction continued at room temperature for another 30 min. The reaction was quenched with ice water, and then extracted with ethyl acetate. The organic layers were collected, washed with brain, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 20% ethyl acetate in hexane in 25 min) afforded 2-(3-cyano-6-iodo-quinolin-4-yl)-2-ethyl-malonic acid diethyl ester (250 mg, 85%) as colorless viscous oil. LC-MS m/e 467 (MH+).
Reaction SMILES: [I:1]NC(=O)CCC(N)=O.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:20][CH2:21][NH2:22])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].FC(F)(F)C(O)=O>C(#N)C>[I:1][C:15]1[CH:16]=[C:17]([O:18][CH3:19])[C:12]([O:11][CH3:10])=[CH:13][C:14]=1[CH2:20][CH2:21][NH2:22]
Reactant: COc1ccc(CCN)cc1OC
Reactant: NC(=O)CCC(=O)NI
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1cc(I)c(CCN)cc1OC
Yield: 70 %

Procedure:
To a solution of N-iodosuccinamide (NIS) (4.95 g, 22 mmol) in dry acetonitrile (50 mL) was added 2-(3,4-dimethoxyphenyl)ethanamine (3.32 mL, 20 mmol) and trifluoroacetic acid (3.85 mL, 50 mmol) with stirring. The mixture was stirred at room temperature in a 250 mL round bottom flask for two hours. The acetonitrile was removed and the remaining solid was taken up in water. The water solution was treated with saturated sodium bisulfite aqueous solution until the purple color disappeared. The pH was adjusted to 8 and the aqueous solution was extracted with dichloromethane (3×50 mL) The organic layers were combined and dried over sodium sulfate. The solvent was evaporated to yield 2-(2-iodo-4,5-dimethoxyphenyl)ethanamine (4.3 g, 70%). The crude product was dried under dynamic vacuum overnight and was sufficiently pure for subsequent steps.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:17]C)[CH:5]=[C:6]([C:8]2([C:13]([O:15][CH3:16])=[O:14])[CH2:12][CH:11]=[CH:10][CH2:9]2)[CH:7]=1.B(Br)(Br)Br.C[Si](C=[N+]=[N-])(C)C.CCCCCC>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[C:6]([C:8]2([C:13]([O:15][CH3:16])=[O:14])[CH2:9][CH:10]=[CH:11][CH2:12]2)[CH:7]=1
Reactant: COC(=O)C1(c2cc(F)cc(OC)c2)CC=CC1
Agent: BrB(Br)Br
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: ClCCl
Product: COC(=O)C1(c2cc(O)cc(F)c2)CC=CC1
Reaction time: 1 h
Yield: 86.1 %

Procedure:
To a stirred solution of methyl 1-(5-fluoro-3-methoxyphenyl)cyclopent-3-ene-1-carboxylate (495 mg, 2.0 mmol) in dry dichloromethane (10 ml) was added a 1.0M solution of boron tribromide in dichloromethane (10 ml, 10 mmol) at -78° C. and the mixture stirred for 1 hr at the same temperature. The reaction mixture was quenched by the addition of water (20 ml) and the resulted mixture acidified with 1.0N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was washed with brine, dried and concentrated under reduced pressure. The residue was dissolved in a mixture of methanol (5 ml) and toluene (15 ml) and a 2.0M solution of trimethylsilyldiazomethane in hexane (2 ml, 4 mmol) was added at ambient temperature with stirring. After 0.5 hr, the reaction mixture was partitioned between ethyl acetate and water, the organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with brine, dried with MgSO4 and concentrated in vacuo. The resultant oil was purified by column chromatography (SiO2, 150g; hexane/ethyl acetate (4/1)) to afford 407 mg (87%) of methyl 1-(5-fluoro-3-hydroxyphenyl)cyclopent-3-ene-1-carboxylate white crystals.
Reaction SMILES: [CH:1]1[C:2](Cl)=[CH:3][C:4]([N+:19]([O-])=O)=[C:5]([OH:18])[C:6]=1[C:7]1[CH:8]=[C:9](Cl)[CH:10]=[C:11]([N+:14]([O-])=O)[C:12]=1[OH:13]>O1CCCC1.C(N(CC)CC)C.[Pd]>[OH:13][C:12]1[C:11]([NH2:14])=[CH:10][CH:9]=[CH:8][C:7]=1[C:6]1[CH:1]=[CH:2][CH:3]=[C:4]([NH2:19])[C:5]=1[OH:18]
Reactant: O=[N+]([O-])c1cc(Cl)cc(-c2cc(Cl)cc([N+](=O)[O-])c2O)c1O
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1cccc(-c2cccc(N)c2O)c1O
Reaction time: 40 h

Procedure:
10 g of niclofolan (1) are dissolved in 100 ml of tetrahydrofuran (THF) and 17.6 g of triethylamine. After addition of 4 g of palladium on carbon 5% and a further 4 g after 40 hours, hydrogenation is carried out to saturation over a total period of about 88 hours. The solution is filtered through Hyflo and is immediately processed further without evaporation. Assumed yield of (2): 100%. Rf 0.11 (CH2Cl2/methanol/NH4OH 25% (60:10:1))
Reaction SMILES: C1O[CH:5]([CH:6]2[CH2:11][CH2:10][CH:9]([C:12]3[CH:17]=[C:16]([F:18])[C:15]([I:19])=[C:14]([F:20])[CH:13]=3)[CH2:8][CH2:7]2)[O:4]C1C.C(O)=O>C1(C)C=CC=CC=1>[F:18][C:16]1[CH:17]=[C:12]([CH:9]2[CH2:8][CH2:7][CH:6]([CH:5]=[O:4])[CH2:11][CH2:10]2)[CH:13]=[C:14]([F:20])[C:15]=1[I:19]
Reactant: CC1COC(C2CCC(c3cc(F)c(I)c(F)c3)CC2)O1
Solvent: Cc1ccccc1
Solvent: O=CO
Product: O=CC1CCC(c2cc(F)c(I)c(F)c2)CC1
Yield: 96.4 %

Procedure:
To 50 ml of toluene were added 23 g (56 mmol) of 4-(3,5-difluoro-4-iodophenyl)cyclohexanecarboaldehyde propylene ketal obtained above and 39 g (848 mmol) of formic acid, and the mixture was refluxed for 2 hours. The reaction solution was washed with water, further with a saturated aqueous sodium bicarbonate and then with water and dried over magnesium sulfate. The solvent was distilled off to afford 19 g (54 mmol) of 4-(3,5-difluoro-4-iodophenyl)cyclohexanecarboaldehyde.
Reaction SMILES: C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:9])C=CC=CC=1.[N+:27]([C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1)([O-:29])=[O:28]>>[CH3:9][C:8](=[CH:34][C:33]1[CH:36]=[CH:37][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)C(C)=Cc1ccc([N+](=O)[O-])cc1
Yield: 56 %

Procedure:
The title compound was prepared from triphenyl(1-[ethoxycarbonyl]ethylidene)phosphorane and 4-nitrobenzaldehyde, substantially according to Preparation 5. The product was obtained in 56% yield, as an orange-yellow solid, m.p. 70.5°-73° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[NH:37]1[CH2:42][CH2:41][CH:40]([N:43]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH2:39][CH2:38]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH2:11][C@@H:12]([NH:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:31][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[NH:27][C:26]2=[O:36])[CH2:21][CH2:20]1)=[O:18])[C:13](=[O:14])[N:37]1[CH2:42][CH2:41][CH:40]([N:43]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH2:39][CH2:38]1)[CH3:2]
Reactant: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Reactant: C1CCCN(C2CCNCC2)CC1
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCCCCC3)CC2)cc1CC

Procedure:
Prepared analogously to Example 9i) from 400 mg (0.81 mmol) (R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 180 mg (0.99 mmol) 1-piperidin-4-yl-azepan.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([O:8][C:9]([NH:11][CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:31])[C:27]([O:29]C)=O)=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>CCO>[NH:2]([C:27](=[O:29])[C:26]([NH:25][C:22]1[CH:21]=[CH:20][C:19]([C@H:16]2[CH2:17][CH2:18][C@H:13]([CH2:12][NH:11][C:9](=[O:10])[O:8][C:4]([CH3:6])([CH3:7])[CH3:5])[CH2:14][CH2:15]2)=[CH:24][CH:23]=1)=[O:31])[NH2:3]
Reactant: NN
Reactant: COC(=O)C(=O)Nc1ccc([C@H]2CC[C@H](CNC(=O)OC(C)(C)C)CC2)cc1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1

Procedure:
Prepared using hydrazine hydrate in EtOH from methyl {[4-(trans-4-{[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)phenyl]amino}(oxo)acetate as described for Intermediate 18.1 1H NMR δ 0.99-1.06 (2H, m), 1.37-1.42 (12H, m), 1.77-1.80 (4H, m), 2.39-2.49 (1H, m), 2.81 (2H, t), 4.60 (2H, s), 6.80 (1H, t), 7.19 (2H, d), 7.68 (2H, d), 10.21 (1H, s), 10.45 (1H, s)
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:13]=[CH:12][NH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCC1CCCCC1
Reactant: CC(C)(C)NS(=O)(=O)c1cc[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)NS(=O)(=O)c1ccn(CC2CCCCC2)c1
Yield: 40.9 %

Procedure:
To a solution of compound 27d (29.4 g, 146 mmol), bromocyclohexylmethane (30.9 g, 175 mmol), K2CO3 (40.2 g, 291 mmol) in dry DMF (300 mL) was heated at 85° C. overnight, quenched with water and extracted with EA twice. The combined organic layers were washed with water (3×) and brine, concentrated and purified by CC (PE/EA=2/1) to give compound 27e (17.8 g, 41%) as a solid.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:35]=[CH:34][CH:33]=[CH:32][C:5]=1[CH2:6][O:7][C:8]1[CH:17]=[C:16]([C:18](=[O:30])[NH:19][C:20]2[S:21][C:22]([C:25]([O:27]CC)=[O:26])=[CH:23][N:24]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:31])[CH:14]=2)[N:9]=1.Cl>C1COCC1.O>[Cl:3][C:4]1[CH:35]=[CH:34][CH:33]=[CH:32][C:5]=1[CH2:6][O:7][C:8]1[CH:17]=[C:16]([C:18](=[O:30])[NH:19][C:20]2[S:21][C:22]([C:25]([OH:27])=[O:26])=[CH:23][N:24]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:31])[CH:14]=2)[N:9]=1
Reactant: CCOC(=O)c1cnc(NC(=O)c2cc(OCc3ccccc3Cl)nc3ccc(C)cc23)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2nc(OCc3ccccc3Cl)cc(C(=O)Nc3ncc(C(=O)O)s3)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.7 %

Procedure:
Sodium hydroxide solution (0.3 ml of 2M, 0.6 mmol) was added to a stirred suspension of 2-(2-chlorobenzyloxy)-4-[N-(5-ethoxycarbonylthiazol-2-yl)carbamoyl]-6-methylquinoline (Method 1; 0.097 g, 0.202 mmol) in THF (5 ml) and water (2 ml), and the reaction mixture stirred at ambient temperature for 4 hrs. The reaction mixture was adjusted to pH 4–5 with aqueous hydrochloric acid (1M), and concentrated in vacuo. The solid thus precipitated was filtered, washed with water and dried to give the title compound as a colourless solid (0.030 g, 33%). NMR: 2.45 (3H, s), 5.60 (2H, s), 7.40 (3H, m), 7.50 (1H, m), 7.60 (1H, d), 7.65 (1H, m), 7.80 (2H, t), 7.90 (1H, d), 8.15 (1H, s); m/z
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:16](OC(=O)C)(=[O:18])[CH3:17]>ClCCl>[C:16]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1cccc(Br)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-bromophenol was dissolved in dichloromethane. Triethylamine (1 eq) and acetic anhydride (2 eq) were added and the mixture was stirred at room temperature for 5 hours. The solvent was eliminated by vacuum evaporation.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][NH:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24](O)[CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:20][C:19]=1[CH3:32].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][NH:6][C:7](=[O:15])[C:8]1[CH:9]=[CH:10][C:11]([O:14][CH:24]([C:21]2[CH:22]=[CH:23][C:18]([Br:17])=[C:19]([CH3:32])[CH:20]=2)[CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:12][CH:13]=1
Reactant: COC(=O)CCNC(=O)c1ccc(O)cc1
Reactant: Cc1cc(C(O)CCCC(C)C)ccc1Br
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)CCNC(=O)c1ccc(OC(CCCC(C)C)c2ccc(Br)c(C)c2)cc1
Temperature: 25 °C
Yield: 63 %

Procedure:
A solution of 3-(4-hydroxy-benzoylamino)-propionic acid methyl ester (805 mg, 3.61 mmol) and 1-(4-Bromo-3-methyl-phenyl)-5-methyl-hexan-1-ol (824 mg, 2.89 mmol) in toluene (15.0 mL) was degassed and filled with nitrogen for 3 times. Tributylphosphine (1.1 mL, 4.33 mmol) was added to the reaction mixture under nitrogen at 0° C., followed by addition of 1,1′-(azodicarbonyl)-dipiperidine (1.1 g, 4.33 mmol). The reaction mixture was allowed to warm to room temperature and stirred over night, the mixture was loaded on silica gel column. Chromatography gave the title compound (890 mg, 1.82 mmol).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([Cl:44])([CH2:11][C:12]([F:43])([F:42])[CH2:13][C@H:14]([C@@H:16]1[C@:33]2([CH3:34])[C@H:19]([C@H:20]3[C@H:30]([CH2:31][CH2:32]2)[C@:28]2([CH3:29])[C:23]([CH2:24][C@@H:25]([O:35]C4CCCCO4)[CH2:26][CH2:27]2)=[CH:22][CH2:21]3)[CH2:18][CH2:17]1)[CH3:15])[C:6](OCC)=[O:7])C>CCOCC>[Cl:44][C:5]([CH2:11][C:12]([F:42])([F:43])[CH2:13][C@H:14]([C@@H:16]1[C@:33]2([CH3:34])[C@H:19]([C@H:20]3[C@H:30]([CH2:31][CH2:32]2)[C@:28]2([CH3:29])[C:23]([CH2:24][C@@H:25]([OH:35])[CH2:26][CH2:27]2)=[CH:22][CH2:21]3)[CH2:18][CH2:17]1)[CH3:15])([CH2:6][OH:7])[CH2:4][OH:3]
Reactant: CCOC(=O)C(Cl)(CC(F)(F)C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C)C(=O)OCC
Solvent: CCOCC
Product: C[C@H](CC(F)(F)CC(Cl)(CO)CO)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
To a solution of the chlorodiester (10) (730 mg, 1.1 mmol) in ether (15 ml) lithium aluminium hydride (48 mg) was added and the mixture was stirred at 0° C. for 1 hr. and then stirred at room temperature for 2 hr. The usual work-up (ether for extraction) gave a crude product, which was applied to a column of silica gel (50 g). Elution with dichloromethane provided the chlorodiol (11) (250 mg, 39%) mp 152°-153° C. (n-hexane-ether). 1H-NMR δ(CDCl3 -acetone d6 -DMSO d6): 0.77 (3H, s, 18-H3), 1.00 (3H, s, 19-H3), 1.10 (3H, d, J=6 Hz, 21-H3), 3.50-4.50 (7H, m, 3-H, 26-H2, 27-H2, and THP), 4.77 (3H, m, 26-OH, 27-OH, and THP), 5.38 (1H, m, 6-H); δ(CDCl3 -acetone d6 -DMSOd6 -D2O): 3.60 (2H, m, THP), 3.77 (4H, s, 26-H2 and 27-H2), 4.77 (1H, m, THP). MS m/z: 434, 416, 404.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([NH:13][NH:14]C(OC(C)(C)C)=O)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([NH:13][NH2:14])=[O:12])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)C1(c2ccc(Br)cc2)CC1
Agent: Cl
Solvent: CO
Product: NNC(=O)C1(c2ccc(Br)cc2)CC1
Yield: 73.4 %

Procedure:
A solution of the compound (855 g, 2.41 mol) obtained in Example 16-2) and 4 M hydrochloric acid (1,4-dioxane solution, 1.25 L) in methanol (6.0 L) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, a 5 M aqueous sodium hydroxide solution (500 mL) was added to the residue at 0° C., the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, diisopropyl ether was added to the residue, and the white precipitate was collected by filtration and dried under reduced pressure to obtain the title compound (451 g, 73%) as a white solid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][C@H:24]([OH:44])[CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([OH:43])=[C:31]([NH:33][S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH:32]=1>>[CH2:18]([S:15]([NH:14][C:11]1[CH:12]=[CH:13][C:8]([N:5]2[CH2:6][CH2:7][CH:2]([NH:22][CH2:23][C@H:24]([OH:44])[CH2:25][O:26][C:27]3[CH:28]=[CH:29][C:30]([OH:43])=[C:31]([NH:33][S:34]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)(=[O:35])=[O:36])[CH:32]=3)[CH2:3][CH2:4]2)=[CH:9][CH:10]=1)(=[O:17])=[O:16])[CH2:19][CH2:20][CH3:21]
Reactant: NC[C@H](O)COc1ccc(O)c(NS(=O)(=O)c2ccccc2)c1
Reactant: CCCCS(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Product: CCCCS(=O)(=O)Nc1ccc(N2CCC(NC[C@H](O)COc3ccc(O)c(NS(=O)(=O)c4ccccc4)c3)CC2)cc1

Procedure:
The title compound was prepared from butane-1-sulfonic acid [4-(4-oxo-piperidine-1-yl)-phenyl]-amide (which was obtained in Example 228) and N-[5-((2S)-3-amino-2-hydroxy-propoxy)-2-hydroxy-phenyl]-benzenesulfonamide (which was obtained in Example 21) according to the procedure of Example 278 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.83 (t, J=7.3 Hz, 3H), 1.20-1.40 (m, 4H), 1.55-1.70 (m, 2H), 1.80-1.95 (m, 2H), 2.50-2.80 (m, 5H), 2.92 (t, J=7.6 Hz, 2H), 3.50-3.90 (m, 5H), 6.39 (d, J=8.7, 2.9 Hz, 1H), 6.57 (d, J=8.7 Hz, 1H), 6.72 (d, J=2.9 Hz, 1H), 6.90 (d, J=9.0 Hz, 2H), 7.05 (d, J=9.0 Hz, 2H), 7.40-7.60 (m, 3H), 7.74 (d, J=7.7 Hz, 2H); MS (ES) m/z: 633.1 (MH+); HRMS Calcd. for C30H41N4O7S2 (MH+): 633.2411. Found: 633.2409.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:34]=[C:35]([S:40](Cl)(=[O:42])=[O:41])[CH:36]=[CH:37][C:38]=1[Cl:39]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:35]4[CH:36]=[CH:37][C:38]([Cl:39])=[C:33]([Cl:32])[CH:34]=4)(=[O:42])=[O:41])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccc(Cl)c(Cl)c4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 3,4-dichloro-benzenesulfonyl chloride. Purity (ELSD, based on MW=630.5)=100%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]([F:13])([F:12])[F:11])=[CH2:9])[CH:5]=[C:4]([Cl:14])[C:3]=1[F:15].[CH2:16]([N:23]([CH2:29]OC)[CH2:24][Si](C)(C)C)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:16]([N:23]1[CH2:29][CH2:9][C:8]([C:6]2[CH:5]=[C:4]([Cl:14])[C:3]([F:15])=[C:2]([Cl:1])[CH:7]=2)([C:10]([F:13])([F:12])[F:11])[CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=C(c1cc(Cl)c(F)c(Cl)c1)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1c(Cl)cc(C2(C(F)(F)F)CCN(Cc3ccccc3)C2)cc1Cl
Temperature: 0 °C
Reaction time: 5 h
Yield: 40.3 %

Procedure:
To a stirred solution of 1,3-dichloro-2-fluoro-5-(1-trifluoromethyl-vinyl)-benzene (10 g, 38.61 mmol) in DCM (150 mL) was added benzyl-methoxymethyl-trimethylsilanylmethyl-amine (36.6 g, 154.44 mmol) at room temperature and reaction mixture was cooled to 0° C. followed by slow addition of TFA (0.29 mL, 3.861 mmol). Resulting reaction mixture was stirred at room temperature for 5 hours. After complete consumption of starting material, the reaction mixture was quenched with aqueous Na2CO3 and extracted with DCM (3×100 mL). Combined organic layer was dried over Na2SO4 and concentrated under vacuum to afford brown oil (9.7 g, crude). Crude compound was purified by column chromatography using 100-200 mesh silica gel. Desired product was eluted in 4% ethyl acetate in hexane to afford product as brownish solid (6.1 g, impure). Impure compound was used as such for next reaction. 1H-NMR (400 MHz, CDCl3) δ: 2.24-2.31 (m, 1H), 2.53-2.59 (m, 1H), 2.68-2.78 (m, 1H), 2.80-2.83 (m, 1H), 3.01-3.08 (m, 2H), 3.61-3.69 (m, 2H), 7.29-7.34 (m, 7H). (m/z): 280.4 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].CC1(C)[O:17][C:16](=O)[CH:15]=[C:14]([CH3:19])[O:13]1.CC(C)=O>C1(C)C(C)=CC=CC=1>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:16](=[O:17])[CH2:15][C:14](=[O:13])[CH3:19])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CC1=CC(=O)OC(C)(C)O1
Solvent: CC(C)=O
Solvent: Cc1ccccc1C
Product: CC(=O)CC(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 52.4 %

Procedure:
13.8 g (0.1 mol) of 4-nitroaniline were suspended in 20 ml of dry xylene and 14,22 g (0.1 mol) of 2,2,6-trimethyl-4H-1,3-dioxin-4-one were added. The reaction mixture was heated in an oil-bath at 150° C. for 30 minutes while the acetone formed in the reaction was removed by distillation. The reaction mixture was cooled to room temperature, filtered and the residue was washed thoroughly with ethyl acetate. The filtrate was evaporated to obtain 11.65 g (52%) of N-(4-nitrophenyl)-3-oxobutanamide as a white crystalline solid melting at 119°-21° C. (from ethyl acetate-petroleum ether (40°-60° C.)) (lit.* melting at 120°-122° C.).
Reaction SMILES: [CH2:1]([N:3]([CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)=[NH:28])[CH:24]=3)[NH:19][CH:18]=2)[CH2:12]1)C(=O)OC(C)(C)C)[CH3:2].C(O)(C(F)(F)F)=O.[NH4+].[OH-]>ClCCl>[CH2:1]([NH:3][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)=[NH:28])[CH:24]=3)[NH:19][CH:18]=2)[CH2:12]1)[CH3:2]
Reactant: CCN(C(=O)OC(C)(C)C)C1CCCC(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)C1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNC1CCCC(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 378.9 %

Procedure:
tert-Butyl ethyl(3-(5-(thiophene-2-carboximidamido)-1H-indol-3-yl)cyclohexyl)carbamate (0.17 g, 0.36 mmol) was treated with 20% TFA solution (20 mL) in dichloromethane at 0° C. and the mixture left to stir for 2 hours at 0° C. The solution then was neutralized with 10% NH4OH solution, the organic layer separated and evaporated. The crude was purified by column chromatography (20% 2N NH3 in MeOH: 80% CH2Cl2) to give the final product as a yellow solid (0.50 g, 85%). 1H-NMR (DMSO-d6) δ 1.11 (t, 3H, J=6.9 Hz), 1.21-1.53 (m, 4H), 1.81-2.11 (m, 3H), 2.27-2.37 (m, 1H), 2.82-2.88 (m, 3H), 2.99-3.07 (m, 1H), 6.22 (s, 2H, NH), 6.64 (d, 1H, J=8.4 Hz), 7.01-7.03 (m, 2H), 7.10 (dd, 1H, J=3.6, 5.1 Hz), 7.28 (d, 1H, J=8.7 Hz), 7.59 (d, 1H, J=5.1 Hz), 7.71 (d, 1H, J=3.0 Hz), 10.62 (s, 1H, NH); ESI-MS (m/z, %) 367 (MH+, 50), 322 (100), ESI-HRMS calc. for C21H27N4S (MH+) 367.1950 found 367.1968.