Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([CH2:31][CH3:32])[C:26]=1[Cl:33].O>O1CCOCC1>[Cl:33][C:26]1[C:27]([CH2:31][CH3:32])=[N:28][CH:29]=[CH:30][C:25]=1[NH:24][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: CCc1nccc(N)c1Cl
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Solvent: O
Product: CCc1nccc(NC(=O)Cc2ccc(O)cc2)c1Cl
Temperature: 5 °C
Yield: 48.2 %

Procedure:
0.76 g (5.0 mmol) of 4-hydroxyphenyl acetic acid was dissolved in 20 ml of 1,4-dioxane, and the solution was stirred at 5° C. Then, 0.97 g (6.0 mmol) of 1,1'-carbonyldiimidazole was added thereto, and the mixture was stirred for one hour at 5° C. Then, 0.76 g (5.0 mmol) of 4-amino-3-chloro-2-ethylpyridine was added thereto, and the mixture was refluxed under heating for 20 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate) and then recrystallized from ethanol to obtain 0.7 g of the desired product as a white powder (melting point: 158° to 161° C.).
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:4](=[O:12])[O:3]1.Cl.[Na+].[Cl-]>C1COCC1>[CH3:11][O:10][C:8]([CH2:7][C@@H:5]([OH:6])[C:4]([OH:12])=[O:3])=[O:9]
Reactant: COC(=O)C[C@H]1OC(C)(C)OC1=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C[C@@H](O)C(=O)O

Procedure:
Methyl 2-((R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (17.1 g, 90.9 mmol) was stirred in a 1:1 mixture of THF: 1 M HCl (200 mL) for 1 h at room temperature. After addition of NaCl to nearly saturate the aqueous layer, the mixture was extracted with EtOAc, and the extracts were dried over Na2SO4 and concentrated to obtain (R)-3-(methoxycarbonyl)-2-hydroxypropanoic acid as an oil. 1H NMR (400 MHz, CDCl3) δ 4.58-4.55 (m, 1H), 3.75 (s, 3H), 2.98-2.84 (m, 2H) ppm.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3](=[CH:9][CH:10]=[C:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]([O:6][CH2:7][CH3:8])=S.F[B-](F)(F)F.CN(C)C(C(OCC)=[O:38])=CC=[N+](C)C.CC[O-].[Na+].C1(CC(OCC)=O)C=CC=CC=1>C(O)C>[CH3:1][N:2]([CH3:23])[C:3](=[CH:9][CH:10]=[C:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]([O:6][CH2:7][CH3:8])=[O:38]
Reactant: CCOC(=O)C(=CC=[N+](C)C)N(C)C
Reactant: CCOC(=O)C(=CC=C(C(=S)OCC)N(C)C)c1ccccc1
Agent: CCOC(=O)Cc1ccccc1
Agent: CC[O-]
Agent: F[B-](F)(F)F
Solvent: CCO
Product: CCOC(=O)C(=CC=C(C(=O)OCC)N(C)C)c1ccccc1

Procedure:
The procedure is as in Example 2 for the preparation of diethyl 2-dimethylamino-5-phenylthio-2,4-hexadienedioate, starting with N-(3-dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (10 g), a 2M ethanolic solution of sodium ethylate (21 cc) and ethyl phenylacetate (5.6 cc) in ethanol (100 cc). After purification by chromatography on a silica column, with a mixture of cyclohexane and ethyl acetate (80:20 by volume) as eluent, diethyl 2-dimethylamino-5-phenyl-2,4-hexadienedioate (4.6 g) is obtained, and is used in the crude state in the subsequent phases.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH3:10])[CH:5]=[CH:6][C:7]=1[OH:8].Cl.[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([CH2:20][O:21][NH2:22])=[CH:18][CH:17]=1)([O-:15])=[O:14].N1C=CC=CC=1>C(O)C>[N+:13]([C:16]1[CH:17]=[CH:18][C:19]([CH2:20][O:21][N:22]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([F:1])[CH:3]=2)[CH3:10])=[CH:23][CH:24]=1)([O-:15])=[O:14]
Reactant: CC(=O)c1ccc(O)c(F)c1
Reactant: NOCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=NOCc1ccc([N+](=O)[O-])cc1)c1ccc(O)c(F)c1
Temperature: 25 °C

Procedure:
A solution of 3′-fluoro-4′-hydroxyacetophenone (0.063 g, 0.411 mmol), O-(4-nitrobenzyl)hydroxylamine hydrochloride (0.100 g, 0.491 mmol) and pyridine (0.13 ml, 1.61 mmol) in ethanol (5 ml) was stirred at reflux under nitrogen for 5h and cooled to room temperature. The solution was concentrated to a pale yellow oil which was diluted with dichloromethane/water. The resultant mixture was extracted with dichloromethane (×3). The combined organic phases were washed with water and brine, dried over magnesium sulphate, filtered and concentrated to an off-white solid. The crude product was purified by column chromatography (SiO2), eluting with 8:2 petrol/ethyl acetate, to give a 3′-fluoro-4′-hydroxyacetophenone-O-4-nitrobenzyloxime (CP9-132) as light yellow solid (0.081 g, 65%),
Reaction SMILES: C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.P([O-])([O-])(O)=O.[K+].[K+].P([O-])(O)(O)=O.[K+].NC1C=CC(C(O)=O)=CC=1.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].Cl.[CH3:56][NH:57][CH:58]([CH3:67])[C:59]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:60].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[CH3:67][C@H:58]([NH:57][CH3:56])[C@@H:59]([OH:60])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: CNC(C)C(=O)c1ccccc1
Agent: Cl
Agent: Nc1ccc(C(=O)O)cc1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CN[C@@H](C)[C@@H](O)c1ccccc1
Temperature: 30 °C
Reaction time: 48 h
Yield: 7 %

Procedure:
Rhodococcus erythropolis MAK-34 was inoculated to 5 ml of a medium (pH 7.0) containing 1.0% saccharose, 0.5% corn steep liquor, 0.1% dipotassium hydrogenphosphate, 0.3% potassium dihydrogenphosphate, 0.01% p-aminobenzoic acid and each inducer; and shake-culturing was carried out at 30° C. for 48 hours. After the culture was centrifuged to give bacterial cells, they were placed into a test tube and suspended by adding 1.0 ml of 0.2 M sodium phosphate buffer (pH 7.0) thereto. To this were added dl-2-methylamino-1-phenyl-1-propanone hydrochloride (10 mg) and glucose (20 mg) and reaction was allowed to take place under shaking at 30° C. for 16 hours. After the reaction, the reaction solution was centrifuged to remove bacterial cells, and the supernatant was subjected to HPLC, producing optically active pseudoephedrine (μ Bondaspherephenyl manufactured by Waters Inc.; diameter of 4 mm; length of 150 mm; eluent—7% acetonitrile-0.05 M sodium phosphate buffer (pH 6.5); flow rate of 0.8 ml/min; detection wavelength at 220 nm). As shown in Table 12, the production displayed remarkably higher values than does the case without the addition of inducer.
Reaction SMILES: S([C:5]1[CH:6]=[C:7]([C:14]([O-:16])=[O:15])[CH:8]=[C:9]([CH:13]=1)[C:10]([O-:12])=[O:11])(O)(=O)=O.[Na+].[Na+].[Na+].[OH-:20].[Na+].C1(C(C2C=CC=C(C)C=2C)C)C=CC=CC=1>O>[OH:20][C:5]1[CH:6]=[C:7]([C:14]([OH:16])=[O:15])[CH:8]=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11]
Reactant: O=C([O-])c1cc(C(=O)[O-])cc(S(=O)(=O)O)c1
Reactant: [OH-]
Agent: Cc1cccc(C(C)c2ccccc2)c1C
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(O)cc(C(=O)O)c1
Temperature: 280 °C
Yield: 94.8 %

Procedure:
Trisodium 5-sulfoisophthalate (312 g) was added to 170 g of a 50% aqueous solution of sodium hydroxide, and the mixture was stirred. Then, 1980 g of 1-phenyl-1-(2,3-dimethylphenyl)-ethane was mixed, and the resulting mixture was heated to 280° C. in a nitrogen stream and dehydrated with stirring. The dehydrated mixture was stirred at 280° C. for 1.5 hours. After cooling, 1 liter of water was added to the reaction mixture to separate the reaction medium. The aqueous layer was decolorized with activated carbon, and precipitated with dilute sulfuric acid to give 172.5 g (yield 94.8%) of 5-hydroxyisophthalic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:21][CH3:22])=[CH:5][C:6]2[NH:12][C:11](=[O:13])[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1.CI.[CH2:25](I)[CH3:26]>>[CH2:25]([N:12]1[C:6]2[CH:5]=[C:4]([O:21][CH3:22])[C:3]([O:2][CH3:1])=[CH:20][C:7]=2[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:9][CH2:10][C:11]1=[O:13])[CH3:26]
Reactant: CCI
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)=NCC(=O)N2
Solvent: CI
Product: CCN1C(=O)CN=C(c2ccccc2)c2cc(OC)c(OC)cc21
Yield: 62 %

Procedure:
By replacing 5-(4-bromophenyl)-7,8-dimethoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIaf) in example IIba by 7,8-dimethoxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIaa), and MeI by ethyl iodide, and proceeding in the same manner, the abovenamed product is obtained. Yield: 62%. M: 86–88° C. 1H-NMR (CDCl3, 200 MHz): d 1.15 (t, 3H, CH3), 3.80 (s, 3H, OCH3), 4.01 (s, 3H, OCH3), 4.03 (AB system, ? d=0.61, JAB=13.9, 2H, —NCH2), 4.30 (AB system, ? d=1.00, JAB=9.98, 2H, CH2), 6.71 (s, 1H Ar), 6.88 (s, 1H Ar), 7.40–7.69 (m, 5H Ar).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([N:19]3[C:24]([CH3:26])([CH3:25])[CH2:23][C:22](=[O:27])[CH2:21][C:20]3([CH3:29])[CH3:28])[N:8]=2)[CH2:3][CH2:2]1>O1CCCC1.[Ni]>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:10]=[C:9]([N:19]3[C:20]([CH3:28])([CH3:29])[CH2:21][CH:22]([OH:27])[CH2:23][C:24]3([CH3:26])[CH3:25])[N:8]=2)[CH2:5][CH2:6]1
Reactant: CC1(C)CC(=O)CC(C)(C)N1c1nc(N2CCOCC2)nc(N2CCOCC2)n1
Agent: [Ni]
Solvent: C1CCOC1
Product: CC1(C)CC(O)CC(C)(C)N1c1nc(N2CCOCC2)nc(N2CCOCC2)n1

Procedure:
5 g of 2,4-dimorpholino-6-(4-oxo-2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine (product from Example 21) are hydrogenated in 100 ml of tetrahydrofuran at 60° and a pressure of 100 bar until the reaction stops using Raney nickel as the catalyst. The reaction mixture is filtered, the solution is evaporated and the residue is recrystallized from 20 ml of toluene. The above substance is produced as white crystals which melt at 202°-204°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:14]([N:15]([CH3:30])[C:16]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)=[O:17])[CH2:13][CH2:12][N:11]([C:31]([CH:33]3[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]3)=[O:32])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]>Cl.CC(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:14]([N:15]([CH3:30])[C:16](=[O:17])[C:18]3[CH:19]=[CH:20][C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:22][CH:23]=3)[CH2:13][CH2:12][N:11]([C:31]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[O:32])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C(=O)c1ccc(N2CCOCC2)cc1)[C@@H]1CCN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CC(C)O
Product: CN(C(=O)c1ccc(N2CCOCC2)cc1)[C@@H]1CCN(C(=O)C2CCNCC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 213.3 %

Procedure:
To tert-butyl 4-{[(3R,4R)-3-(3,4-dichlorophenyl)-4-{methyl[(4-morpholin-4-ylphenyl)carbonyl]amino}piperidin-1-yl]carbonyl}piperidine-1-carboxylate (800 mg) obtained in Example 620 was added 2N hydrogen chloride/2-propanol (10 mL), and the mixture was stirred at 50° C. for 4 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (771 mg, 100%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:10][NH:11][C:7]=2[CH:6]=[CH:5][N:4]=1.F[C:25]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:26]=1[C:27]#[N:28].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:33][C:32]1[C:25]([N:11]2[C:7]3[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[C:8]=3[C:9]([C:12]3[CH:13]=[CH:14][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:17]=3)=[N:10]2)=[C:26]([CH:29]=[CH:30][CH:31]=1)[C:27]#[N:28]
Reactant: COc1nccc2[nH]nc(-c3ccc(N4CCOCC4)cc3)c12
Reactant: N#Cc1cccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nccc2c1c(-c1ccc(N3CCOCC3)cc1)nn2-c1c(F)cccc1C#N
Yield: 77.4 %

Procedure:
A solution of 4-methoxy-3-(4-(morpholin-4-yl)phenyl)-1H-pyrazolo[4,3-c]pyridine (355 mg), 2,3-difluorobenzonitrile (180 mg) and potassium carbonate in DMF (5 mL) was stirred at 100° C. for 2.5 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting solid was washed with petroleum ether to give the title compound (380 mg).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])=[N:8][CH:9]=1.[F:16][C:17]([F:23])([F:22])[S:18](Cl)(=[O:20])=[O:19]>C(OCC)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([O:15][S:18]([C:17]([F:23])([F:22])[F:16])(=[O:20])=[O:19])[C:11]([F:12])([F:13])[F:14])=[N:8][CH:9]=1
Reactant: OC(c1ccc(Br)cn1)C(F)(F)F
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: O=S(=O)(OC(c1ccc(Br)cn1)C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a stirred suspension of sodium hydride (765 mg, 60% dispersion in mineral oil) in dry diethyl ether (20 ml) under an argon atmosphere at 0° C. was added dropwise a solution of (RS)-1-(5-bromo-pyridin-2-yl)-2,2,2-trifluoro-ethanol (3.06 g) in diethyl ether (10 ml) and the resulting mixture was stirred at room temperature for 30 min. Trifluoromethanesulfonyl chloride (1.4 ml) was added and stirring was continued for a further 15 min at room temperature. The reaction mixture was quenched by addition of 10% aq. sodium bicarbonate solution and the mixture was extracted with diethyl ether. The phases were separated and the organic phase was washed with saturated brine. The organic phase was separated, dried over sodium sulphate, and concentrated in vacuo. The reside was purified by Kugelrohr distillation (60° C. oven temperature, 0.3 mbar) to give (RS)-trifluoro-methanesulfonic acid 1-(5-bromo-pyridin-2-yl)-2,2,2-trifluoro-ethyl ester (3.6 g, 78%) as a white solid. MS (EI): 389 ([{81Br}M]+), 387 ([{79Br}M]+), 320 ([{81Br}M−CF3]+), 318 ([{79Br}M−CF3]+), 256 ([{81Br}M−CF3—SO2]+), 254 ([{79Br}M−CF3—SO2]+), 240 ([{81Br}M−OSO2CF3]+), 238 ([{79Br}M−OSO2CF3]+).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C:9]([CH:11]2[C:16](=O)[CH2:15][CH2:14][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12]2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][C:26]1[N:27]([C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:38]([NH2:40])=[NH:39])=[CH:33][CH:32]=2)[CH:28]=[CH:29][N:30]=1>>[CH:1]1([CH2:7][CH2:8][C:9]2[C:11]3[CH2:12][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:15][C:16]=3[N:40]=[C:38]([NH:37][C:34]3[CH:35]=[CH:36][C:31]([N:27]4[CH:28]=[CH:29][N:30]=[C:26]4[CH3:25])=[CH:32][CH:33]=3)[N:39]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nccn1-c1ccc(NC(=N)N)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C(=O)CCC2CCCCC2)C1
Product: Cc1nccn1-c1ccc(Nc2nc(CCC3CCCCC3)c3c(n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Yield: 45 %

Procedure:
tert-Butyl 4-(2-cyclohexyl ethyl)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (393 mg, 45%) was synthesised from tert-Butyl 3-(3-cyclohexylpropanoyl)-4-oxopiperidine-1-carboxylate and 1(4-(2-methyl-1H-imidazol-1-yl)phenyl)guanidine (Example 41c) according to the general procedure for the synthesis of pyrimidines. MS (ES+) m/z 517.1 (M+H)+
Reaction SMILES: C([O:3][C:4](=[O:6])[CH3:5])C.[CH2:7]([N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]1[NH2:24])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O.CO>[C:4]([OH:6])(=[O:3])[CH3:5].[CH2:7]([N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]1[NH2:24])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(C)=O
Agent: Cl
Agent: NC1c2ccccc2C(=O)N1Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: O
Product: CC(=O)O

Procedure:
To a solution of compound 25 (300 mg, 0.92 mmol) in water (2 mL) and methanol (4 mL) was added potassium carbonate (509 mg, 3.7 mmol) and the resulting reaction mixture was allowed to stir at reflux for 2 hours. The reaction mixture was poured onto 3N HCl and extracted with dichloromethane (3×20 mL). The combined dichloromethane extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to provide 110 mg of 26 as a white solid (272 mg theoretical, 40% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[S:9]([CH2:12][C:13](=[O:15])[CH3:14])(=[O:11])=[O:10])=[CH:4][CH:3]=1.C1C=C[NH+]=CC=1.[Br:29][Br-]Br>C(O)(=O)C.ClCCl.C(OCC)(=O)C>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[S:9]([CH2:12][C:13](=[O:15])[CH2:14][Br:29])(=[O:10])=[O:11])=[CH:21][CH:20]=1
Reactant: CC(=O)CS(=O)(=O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(CBr)CS(=O)(=O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.9 %

Procedure:
To a solution of 1-[bis-(4-chloro-phenyl)-methanesulfonyl]-propan-2-one (Example 1, 0.63 g, 1.7 mmol) in a mixture of 10 mL of acetic acid and 60 mL of dichloromethane was added pyridine hydrobromide perbromide (0.62 g, 1.9 mmol) using a procedure such as those described in Grossert J. S. et al., Can. J. Chem. 1984; 62:798. The reaction mixture was stirred at room temperature for 18 hours and then evaporated to give an oil. The oil was dissolved in 200 mL of ethyl acetate, washed with three 50 mL portions of 5% aqueous sodium bicarbonate and then with 50 mL of brine. The organic layer was separated, dried (sodium sulfate), filtered, and then evaporated to afford an oil, which was chromatographed (silica gel, eluting with 30% ethyl acetate in hexane) to give 0.37 g (48%) of a white solid with mp 122–123° C.; 1H NMR (deuterochloroform): δ 4.03 (s, 2H), 4.09 (s, 2H), 5.64 (s, 1H), 7.33–7.41 (m, 4H), 7.51–7.58 (m, 4H); ms: m/z 435 (m−1) APCI-.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=[O:4].[S-:15][C:16]#[N:17].[K+]>C(O)C.O>[O:4]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)[CH2:2][S:15][C:16]#[N:17]
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Reactant: N#C[S-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CSCC(=O)c1cccc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 76.2 %

Procedure:
A solution of 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone (20 g) in ethanol (100 mL) was heated to 60-70° C., and aqueous solution (10 mL) of potassium thiocyanate (8 g) was added dropwise. The reaction mixture was heated at 80° C. for 10 min, and the mixture was stirred at room temperature for 4 hr and diluted with water. The precipitate was collected by filtration, dissolved in ethyl acetate and dried over anhydrous sodium sulfate. The solvent was evaporated to give 2-oxo-2-[3-(trifluoromethyl)phenyl]ethyl thiocyanate (14 g) as a solid. This solid (10 g) was dissolved in acetic acid (50 mL), and 48% hydrogen bromide-acetic acid solution (10 mL) was added. The reaction mixture was heated at 70-80° C. for 3 hr, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and water, sodium bicarbonate was added, and the mixture was adjusted to pH 7. The ethyl acetate layer was separated, washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (4.2 g) as a colorless solid.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.[C:11]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:10])[CH3:1])[CH:4]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CN(C)c1cccc(N)c1
Product: CN(C)c1cccc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1

Procedure:
prepared by reaction of N,N-dimethyl-benzene-1,3-diamine with 4-tert-butyl-benzenesulfonyl chloride
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:5]([NH:7][C@H:8]([C:19]([O:21]C)=[O:20])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)=[O:6])[CH2:3][OH:4].O>CC(O)(C)C>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])[C@H:2]([C:5]([NH:7][C@H:8]([C:19]([OH:21])=[O:20])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)=[O:6])[CH2:3][OH:4]
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(N[C@@H](CO)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1

Procedure:
In a second step, enzymatic hydrolysis of Z-Ser-Trp-OMe was accomplished using Alcalase 2.5 L DX (Int. J. Peptide Protein Res. 1990, 52) and subsequent catalytic hydrogenolysis provided the desired peptide as an off-white solid. To that end the purified Z-Ser-Trp-OMe was dissolved in tBuOH and water and Alcalase 2.5 L DX (Novozymes, Bagsvaerd, Denmark) was added. The mixture was stirred until (almost) all starting material was consumed. The mixture was then concentrated in vacuo and the residue taken up in water of pH 7. The aqueous mixture was extracted with ethyl acetate to remove any remaining starting material and subsequently the aqueous phase was acidified. The desired product, i.e. Z-Ser-Trp-OH, was isolated by extraction with ethyl acetate; the extract was dried over sodium sulphate and concentrated in vacuo.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C>[N:20]1([CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][N:30]([C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[NH:8][C:7](=[O:15])[C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:29]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: C1CCN(CCC2CCCNC2)CC1
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ncccc21
Solvent: CC#N
Product: O=C1Nc2ccccc2N(C(=O)N2CCCC(CCN3CCCCC3)C2)c2ncccc21
Yield: 50 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one and 3-[2-(1-piperidinyl)ethyl]piperidine in a yield of 50% of theory. Colourless crystals, m.p. 168°-169° C. (acetonitrile).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[Cl:14])[N:10]([CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)[CH:9]=[CH:8]2)=O.[H-].C([Al+]CC(C)C)C(C)C.C([O-])(O)=O.[Na+].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.CO>[C:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][CH:18]([CH2:17][CH2:16][CH2:15][N:10]2[C:11]3[C:7](=[CH:6][C:5]([CH2:3][OH:2])=[C:13]([Cl:14])[CH:12]=3)[CH:8]=[CH:9]2)[CH2:19][CH2:20]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: COC(=O)c1cc2ccn(CCCC3CCN(C(=O)OC(C)(C)C)CC3)c2cc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: O=C([O-])O
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(CCCn2ccc3cc(CO)c(Cl)cc32)CC1
Reaction time: 1 h
Yield: 53.4 %

Procedure:
To a 0° C. solution of 1-[3-(1-tert-butoxycarbonyl-piperidin-4-yl)-propyl]-6-chloro-1H-indole-5-carboxylic acid methyl ester (1.10 g, 2.53 mmol) in toluene (20 mL) was added diisobutylaluminum hydride (1 M in hexanes; 5.06 mL, 5.06 mmol) dropwise. The mixture was stirred for 1 h. Additional diisobutylaluminum hydride (1 M in hexanes; 5.06 mL, 5.06 mmol) was added. After 1 h, the mixture was diluted at rt with satd. aq. NaHCO3 (2 mL), MeOH (5 mL), CHCl3 (10 mL), and satd. aq. sodium potassium tartrate (10 mL). The mixture was stirred vigourously until the layers separated. The organic layer was dried and concentrated to give the crude product (117 mg), which was purified by FCC (EtOAc/hexanes) to give 550 mg (27%) of a white solid. 1H NMR (400 MHz, CDCl3): 7.65 (s, 1H), 7.34 (s, 1H), 7.07 (d, J=3.1, 1H), 6.45 (d, J=3.1, 1H), 4.85-4.80 (m, 2H), 4.04 (t, J=7.1, 2H), 2.69-2.55 (m, 2H), 2.30-2.21 (m, 2H), 1.85-1.76 (m, 2H), 1.62-1.54 (m, 2H), 1.44 (s, 9H), 1.40-1.18 (m, 3H), 1.03 (dq, J=12.6, 4.4, 2H).