Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]2[C:15](I)=[CH:16][N:17]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:12]2=[CH:11][CH:10]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[C:39]([NH:43][CH:44]3[CH2:49][CH2:48][CH2:47][N:46]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:45]3)[CH:40]=[N:41][CH:42]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]2[C:15]([C:37]3[CH:38]=[C:39]([NH:43][CH:44]4[CH2:49][CH2:48][CH2:47][N:46]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:45]4)[CH:40]=[N:41][CH:42]=3)=[CH:16][N:17]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:12]2=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2cncc(B3OC(C)(C)C(C)(C)O3)c2)C1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(-c4c(F)cccc4F)ccc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(NC4CCCN(C(=O)OC(C)(C)C)C4)c3)c3nc(-c4c(F)cccc4F)ccc32)cc1
Temperature: 100 °C
Reaction time: 15 h
Yield: 35 %

Procedure:
A suspension of 5-(2,6-difluorophenyl)-3-iodo-1-tosyl-1H-pyrrolo[3,2-b]pyridine (73 mg, 0.143 mmol) and crude tert-butyl 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-ylamino)piperidine-1-carboxylate (113 mg, 0.279 mmol) in toluene (1.000 mL) and EtOH (1 mL) was treated with Na2CO3, 2.0 M (0.143 mL, 0.286 mmol) and Pd(PPh3)4 (16.53 mg, 0.014 mmol, Strem). The reaction mixture was degassed, backfilled with argon and heated to 100° C. under N2. After 15 h, the reaction was cooled to 23° C., filtered through celite, and purified by silica gel chromatography (eluent: 0.5-10% MeOH/DCM), affording tert-butyl 3-(5-(5-(2,6-difluorophenyl)-1-tosyl-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-ylamino)piperidine-1-carboxylate (Rf=0.5 in 10% MeOH/DCM, desired product) (33 mg, 35%); along with a byproduct, tert-butyl 3-(5-(5-(2,6-difluorophenyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-ylamino)piperidine-1-carboxylate (Rf=0.2 in 10% MeOH/DCM, de-tosylated product) (31 mg, 43%). MS (ESI, pos. ion) m/z: 660.3 (M+1)
Reaction SMILES: FC1C=CC([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]2CCC2C(F)=CC=C(F)C=2F)=CC=1.FC1C=CC(N2C(C(OCC)=O)=CN=C2C#C[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[C:54]([F:57])([F:56])[F:55])=CC=1>[Pd].C(OCC)(=O)C.C(O)C>[F:55][C:54]([F:57])([F:56])[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[CH2:17][CH2:16][O:15][C:13]([C:12]1[NH:8][CH:9]=[N:10][CH:11]=1)=[O:14]
Reactant: CCOC(=O)c1cnc(CCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Reactant: CCOC(=O)c1cnc(C#Cc2ccccc2C(F)(F)F)n1-c1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(OCCc1ccccc1C(F)(F)F)c1cnc[nH]1

Procedure:
Ethyl 1-(4-fluorophenyl)-2-((2-(trifluoromethyl)phenethyl)-1H-imidazole-5-carboxylate (47) was prepared in a similar manner as that described for the synthesis of compound 18 using ethyl 1-(4-fluorophenyl)-2-((2-(trifluoromethyl)phenyl)ethynyl)-1H-imidazole-5-carboxylate (46) (651 mg, 1.62 mmol), Pd/C (10% Degussa type, 65 mg), and ethyl acetate/ethanol (1:2) (61 mL).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-:12].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>C(#N)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][Br:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCc1ccccc1
Reactant: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CC#N
Product: BrCCCCc1ccccc1
Reaction time: 0.17 h
Yield: 106.3 %

Procedure:
To a solution of 4-phenyl-1-butanol (21.75 g) in acetonitrile (300 mL) was added triphenylphosphine dibromide (67.23 g) in portions with stirring over 10 min. After stirring over night under nitrogen, methanol (4 mL) was added and after 1.5 h, the solvent was removed under reduced pressure. Hexanes (200 mL) and ˜75 g silica gel were added to the residue and the mixture was filtered and the filter cake was eluted with hexanes. The clear filtrate was concentrated to give 32.8 g of clear colorless liquid. This product was again eluted through silica gel using 1.5 L hexanes to give the title compound (24.7 g) as a colorless liquid.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][O:30][CH3:31])=[CH:25][CH:24]=3)=[N:21][CH:20]=[CH:19][N:18]=2)[CH2:13][CH2:12]1)C)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:31][O:30][CH2:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]2[C:17]([N:14]3[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][NH:7][CH3:6])[CH2:16][CH2:15]3)=[N:18][CH:19]=[CH:20][N:21]=2)=[CH:28][CH:27]=1
Reactant: COCc1ccc(-c2nccnc2N2CCN(CCN(C)C(=O)OC(C)(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCN1CCN(c2nccnc2-c2ccc(COC)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
Dissolve {2-[3′-(4-methoxymethyl-phenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl]-ethyl}-methyl-carbamic acid tert-butyl ester (1.01 g, 2.3 mmol, 1 eq.) in dichloromethane (20 mL). Add trifluoroacetic acid (10.5 g, 7.1 mL, 92 mmol, 40 eq.). Stir at room temperature for 1.5 hr. Partition the reaction mixture between aqueous 5N NaOH (pH aqueous layer=14) and dichlormethane. Separate the layers. Extract the aqueous layer with dichloromethane (2×50 mL). Combine the organic layers, dry over anhydrous Na2SO4, filter and concentrate to afford the title preparation (0.76 g, 97% yield). MS (loop): m/z=342.3 [M+H].
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:40])[C@@H:15]([O:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)[C@@H:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24]CC2C=CC=CC=2)=[CH:20][CH:19]=1)[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:40])[C@@H:15]([O:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)[C@H:16]([OH:17])[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(O[C@H](C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)[C@H](O)c2ccc(OCc3ccccc3)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(O[C@H](C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)[C@H](O)c2ccc(O)cc2)cc1
Yield: 111.6 %

Procedure:
To a solution of (S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxyphenyl)-3-hydroxy-2-(4-methylphenoxy)propionyl]oxazolidin-2-one (9.80 g) obtained from Reference example 20(b) in ethanol (150 ml) was added 5% palladium-charcoal (1.00 g), and the reaction solution was stirred at 50° C. for 4 hours in an atmosphere of hydrogen. After the catalyst was removed by filtration, the filtrate was concentrated under reduced pressure. Water was added to the residue, and the resulting solution was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and then the target compound (9.10 g) was obtained as a foam.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][S:9]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](O)=[O:16])(=[O:11])=[O:10].B.C1COCC1.Cl.O>C1COCC1>[OH:16][CH2:15][C:14]1[CH:13]=[C:12]([S:9]([NH:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)(=[O:11])=[O:10])[CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)NCc2ccccn2)c1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(NCc1ccccn1)c1cccc(CO)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To solution of 3-[(Pyridin-2-ylmethyl)-sulfamoyl]-benzoic acid (840 mg, 2.87 mmol) in THF (5 ml) was added BH3.THF (1M, 14.4 ml, 14.4 mmol) dropwise. After the addition, the reaction mixture was allowed to stir for 18 h at room temperature, and 5 N HCl (8 ml) was carefully added, resulting in the evolution of H2. Upon heating to 70° C. for 2 h, a clear solution was obtained. Water (30 ml) was added, and the resulting solution was extracted with diethyl ether (3×20 ml). The aqueous phase was cooled to 0° C., neutralized with solid NaOH, and then solid NaHCO3 and extracted with CHCl3 (6×20 ml). The combined organic extracts were dried over MgSO4, and concentrated under reduced pressure. The crude material was used without further purification in the next reaction.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][C@@H:11](O)[CH2:10][N:9]1[S:14]([C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)(=[O:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC([C@@H]1C[C@H](OS(C)(=O)=O)CN1S(C1C=CC2C(=CC=CC=2)C=1)(=O)=O)=O)(C)(C)C.[C:57]([O-:60])(=[S:59])[CH3:58].[K+]>>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:59][C:57](=[O:60])[CH3:58])[CH2:10][N:9]1[S:14]([C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)(=[O:15])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@H](O)CN1S(=O)(=O)c1ccc2ccccc2c1
Reactant: CC([O-])=S
Agent: CC(C)(C)OC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)CN1S(=O)(=O)c1ccc2ccccc2c1
Agent: [K+]
Product: CC(=O)S[C@@H]1C[C@@H](C(=O)OC(C)(C)C)N(S(=O)(=O)c2ccc3ccccc3c2)C1

Procedure:
(2S,4R)-4-Hydroxy-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid tert-butyl ester via (2S,4S)-4-Methanesulfonyloxy-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid tert-butyl ester which was treated with potassium thioacetate at 100° C. to give (2S,4R)-4-Acetylsulfanyl- 1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as light yellow solid, MS: 359 (M-HSCOCH3).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14](OS(C(F)(F)F)(=O)=O)[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[N:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.COCCOC>O>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([C:35]3[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=3)[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccncc1
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(OS(=O)(=O)C(F)(F)F)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1c(C(=O)OC(C)(C)C)oc2cccc(-c3ccncc3)c12
Temperature: 85 °C
Reaction time: 5 h
Yield: 74.2 %

Procedure:
3-Methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid tert-butyl ester (258 mg, 0.68 mmol) was mixed with K2CO3 (207 mg, 2.2 eq), pyridine-4-boronic acid (110 mg, 1.3 eq), Pd(Ph3)4 (43 mg, 0.05 eq), 3 mL of 1,2-dimethoxyethane and 0.5 mL of water. The mixture was heated and stirred in an 85° C. oil bath for 5 h. The reaction mixture was poured into water and was extracted with ethyl acetate. The organic extract was washed with water and dried over sodium sulfate. Removal of solvent gave the crude product, which was purified by column chromatography to give 156 mg of 3-methyl-4-pyridin-4-yl-benzofuran-2-carboxylic acid tert-butyl ester, obtained as white solid.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].C[O-].[Na+].[C:8]([C:11]1[CH:21]=[CH:20][C:14]([O:15][CH2:16][CH2:17][CH2:18]Br)=[C:13]([CH2:22][CH2:23][CH3:24])[C:12]=1[OH:25])(=[O:10])[CH3:9]>>[C:8]([C:11]1[CH:21]=[CH:20][C:14]([O:15][CH2:16][CH2:17][CH2:18][S:1][CH2:2][CH2:3][OH:4])=[C:13]([CH2:22][CH2:23][CH3:24])[C:12]=1[OH:25])(=[O:10])[CH3:9]
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Reactant: OCCS
Agent: C[O-]
Agent: [Na+]
Product: CCCc1c(OCCCSCCO)ccc(C(C)=O)c1O

Procedure:
4.68 g. (60 mMole) 2-mercaptoethanol are stirred for 10 minutes at ambient temperature with 60 ml. 1 M sodium methylate solution. Subsequently, 9.39 g. 3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-propyl bromide are added thereto and the reaction mixture is boiled under reflux for 5 hours. The reaction mixture is thereafter evaporated and the residue mixed with water and ethyl acetate. The ethyl acetate phase is successively shaken with 2 M aqueous sodium hydroxide solution and with 2 M hydrochloric acid and then dried and evaporated. After recrystallising the residue from diethyl ether/ligroin, there are obtained 6.4 g. (68% of theory) of the title compound; m.p. 72-74° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[C:16]2[CH2:17][NH:18][CH2:19][CH2:20][S:21][C:15]=2[CH:14]=[CH:13][CH:12]=1.Cl.C(N(CC)CC)C>ClCCl>[C:1]([N:18]1[CH2:17][C:16]2[C:11]([Cl:10])=[CH:12][CH:13]=[CH:14][C:15]=2[S:21][CH2:20][CH2:19]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Clc1cccc2c1CNCCS2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1CCSc2cccc(Cl)c2C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of benzoyl chloride (3.93 g) in dichloromethane (50 ml) was added dropwise at room temperature to a stirred solution of 6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (4.5 g, prepared in a similar manner to its hydrochloride, Example 1 above) and triethylamine (2.82 g) in dichloromethane (100 ml). The reaction mixture was stirred at room temperature for 15 minutes, washed with water, dried and the solvent was removed by evaporation. Purification of the residue by flash chromatography using dichloromethane as eluent gave 4-benzoyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was recrystallised from ethanol/water. Yield 5.93 g (m.p. 64°-72° C.).
Reaction SMILES: [CH3:1][C:2]1O[CH:7]=[CH:6][C:4](=[O:5])[C:3]=1[OH:9].[NH2:10][CH3:11]>>[CH3:1][C:2]1[N:10]([CH3:11])[CH:7]=[CH:6][C:4](=[O:5])[C:3]=1[OH:9]
Reactant: CN
Reactant: Cc1occc(=O)c1O
Product: Cc1c(O)c(=O)ccn1C
Temperature: 25 °C

Procedure:
Deferiprone was synthesized as described previously. (Gale et al, Res Comun Chem Pathol Pharmacol Vol. 73, No. 3, September 1991) An aqueous suspension of 3-hydroxy-2-methyl-pyrone, maltol, (Aldrich Chemical Co., Milwaukee, Wis., 50 gm, 396 nmol) and NH2CH3 (Aldrich Chemical Co., Milwaukee, Wis., 3 eq, 92 ml, 1.18 mol, 12.88 M) in distilled, degassed H2O was heated under reflux for 12 hours. The solution was allowed to cool to room temperature. The excess methyl amine was removed under reduced pressure and the brown mixture was carefully concentrated to a volume of approximately 200 ml. Reagent grade acetone (50 ml) was added to this brown suspension and the solid recovered by filtration. The solid was washed with 1200 ml of acetone and briefly allowed to dry. To this crude solid was added 2 g of Norite and 2 g of Celite 545 (fisher Scientific, Pittsburgh, Pa.) and the crude solid was dissolved in a minimal amount of hot water. The Celite/Norite matrix was removed from the solution by filtration. The pure crystalline compound was recovered by filtration to give 29.8 g (54%) of the title compound. All recovery and transfer procedures were performed with a porcelain spatula rather than stainless steel equipment due to the potent iron chelating property of 1,2-dimethyl-3-hydroxypyrid-4-one. Analytically pure 1,2-dimethyl-3-hydroxypyrid-4-one was obtained by a single recrystallization from H2O. Other alkyl-substituted pyridones can be prepared by similar measures.
Reaction SMILES: [N:1]([CH:4]1[N:10]=[C:9]([S:11][CH2:12][CH3:13])[C:8]2[CH:14]=[CH:15][CH:16]=[CH:17][C:7]=2[N:6]([CH3:18])[C:5]1=[O:19])=[N+]=[N-].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[NH2:1][CH:4]1[N:10]=[C:9]([S:11][CH2:12][CH3:13])[C:8]2[CH:14]=[CH:15][CH:16]=[CH:17][C:7]=2[N:6]([CH3:18])[C:5]1=[O:19]
Reactant: CCSC1=NC(N=[N+]=[N-])C(=O)N(C)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCSC1=NC(N)C(=O)N(C)c2ccccc21
Temperature: 25 °C

Procedure:
A solution of 1.90 mmol of azide (see Step B above) in 13 mL of tetrahydrofuran to which had been added 1 mL of water is treated with an excess of triphenyphospine (2.8 equivalents) added in one portion as a solid. The reaction is stirred at room temperature under nitrogen cover for twenty hours and then diluted with ethyl acetate. The solution is extracted with 1N HCl three times, and the combined extracts are rendered basic by the addition of 5N NaOH. This is extracted three times with ethyl acetate and the combined extracts washed once with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo on a rotary evaporator at 20° C. The resulting oil is used immediately.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][N:11]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]([C:32]3([CH3:35])[CH2:34][CH2:33]3)=[O:31])[CH2:26][CH2:25]2)=[O:23])[CH2:10]1)C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Cl:21][C:16]1[CH:15]=[C:14]([CH:13]2[CH:9]([NH:7][CH3:6])[CH2:10][N:11]([C:22]([CH:24]3[CH2:29][CH2:28][N:27]([C:30]([C:32]4([CH3:35])[CH2:33][CH2:34]4)=[O:31])[CH2:26][CH2:25]3)=[O:23])[CH2:12]2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: CN(C(=O)OC(C)(C)C)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 20 h
Yield: 72.8 %

Procedure:
Under an atmosphere of nitrogen was added to a solution of {(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid tert-butyl ester (3.02 g, 5.61 mmol) in dichloromethane (30 mL) at ambient temperature trifluoroacetic acid (4.3 mL, 56 mmol) and stirred for 20 h at this temperature. The reaction mixture was added slowly onto an aqueous solution of sodium carbonate (1M, 60 mL). The organic layer was separated and washed with brine (50 mL). The aqueous layers were extracted with dichloromethane (30 mL) and the combined organic layers were dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate:methanol=50:50:0 to 0:90:10) afforded the title compound (1.79 g, 73%) as a light brown oil. MS m/e: 438.3 [M]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@@H:6]1[CH2:10][CH2:9][N:8]([CH:11]2[CH2:16][CH2:15][C:14]([OH:23])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:13][CH2:12]2)[CH2:7]1)=[O:4].CCN(CC)CC.Cl[C:32]1[S:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1>C(O)(C)C>[S:33]1[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=[C:32]1[NH:1][CH2:2][C:3]([NH:5][C@@H:6]1[CH2:10][CH2:9][N:8]([CH:11]2[CH2:12][CH2:13][C:14]([OH:23])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:15][CH2:16]2)[CH2:7]1)=[O:4]
Reactant: NCC(=O)N[C@@H]1CCN(C2CCC(O)(c3ccccn3)CC2)C1
Reactant: Clc1nc2ccccc2s1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=C(CNc1nc2ccccc2s1)N[C@@H]1CCN(C2CCC(O)(c3ccccn3)CC2)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
The mixture of 2-amino-N-[(3R)-1-(4-hydroxy-4-pyridin-2-ylcyclohexyl)pyrrolidin-3-yl]acetamide (0.080 g, 0.25 mmol), Et3N (0.35 mL, 2.5 mmol) and 2-chloro-benzothiazole (0.424 g, 2.5 mmol) in isopropanol was stirred overnight at 90° C. The reaction mixture was concentrated and chromatographed to provide 55 mg of the title compound in 49% yield. MS (EI) calculated: (M+H)+=452.2. Found: 452.2.
Reaction SMILES: S1C2C=CC=CC=2N=C1N(COCC[Si](C)(C)C)C(C1C=CC=C2C=1CN(C1SC(C3C=CC(CO)=CC=3)=C(C(OCC)=O)N=1)CC2)=O.OCC1C=CC(B(O)O)=CC=1.Cl[C:61]1[N:66]=[CH:65][C:64]([O:67][CH2:68][CH2:69][N:70]([CH3:72])[CH3:71])=[CH:63][N:62]=1.CC1(C)C(C)(C)OB([C:81]2[CH:86]=[CH:85][C:84]([OH:87])=[CH:83][CH:82]=2)O1>>[CH3:71][N:70]([CH3:72])[CH2:69][CH2:68][O:67][C:64]1[CH:63]=[N:62][C:61]([C:81]2[CH:86]=[CH:85][C:84]([OH:87])=[CH:83][CH:82]=2)=[N:66][CH:65]=1
Reactant: CN(C)CCOc1cnc(Cl)nc1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(CO)cc1
Agent: OCc1ccc(B(O)O)cc1
Product: CN(C)CCOc1cnc(-c2ccc(O)cc2)nc1

Procedure:
Compound 112C was prepared in a similar manner to the synthesis of compound 34D by substituting compound 34C and 4-(hydroxymethyl)phenylboronic acid with compound 112B and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, respectively: 1H NMR (DMSO-d6): δ 9.80 (s, 1H), 8.56 (s, 2H), 8.12-8.15 (m, 1H), 6.83-6.86 (m, 2H), 4.23 (t, J=5.8 Hz, 2H), 2.65 (t, J=5.65 Hz, 2H), 2.22 (s, 6H); ESI (+)/MS: 259 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])nc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)Cc1ccc(N)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl (6-nitropyridin-3-yl)acetate (0.9 g, 4.28 mmol), Pd/C (10%, 0.1 g) in MeOH (50 mL) was stirred for 2 hours under H2 atmosphere at room temperature. The mixture was filtered and concentrated to give ethyl (6-aminopyridin-3-yl)acetate. 1H-NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.38 (dd, J=2.4 Hz, 8.4 Hz, 1H), 6.4 6(d, J=8.4 Hz, 1H), 4.48 (br, 2H), 4.13 (q, J=7.2 Hz, 2H), 3.44 (s, 2H), 1.23 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH:16]1([NH:22][C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[S:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[BrH:1].[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2([OH:4])[CH2:2][S:24][C:23](=[N:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[N:22]2[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:6][C:7]=1[S:12](=[O:15])(=[O:14])[NH2:13]
Reactant: S=C(NCc1ccccn1)NC1CCCCC1
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Product: Br
Product: NS(=O)(=O)c1cc(C2(O)CSC(=NCc3ccccn3)N2C2CCCCC2)ccc1Cl

Procedure:
4.7 g of 2-bromo-4'-chloro-3'-sulfamoylacetophenone and 3.75 g of 1-cyclohexyl-3-(2-pyridylmethyl)-thiourea were reacted according to the prescription given in Example 23 and the crystals were filtered off. Colorless solid body, melting point: 249° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([NH:19]C(OCC)=O)[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:25])[CH2:10][CH:9]=1.C[O-].[K+].CO.C(O)C>O>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[NH:12][C:11](=[O:25])[CH2:10][CH:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:14]=2[CH:15]=1
Reactant: CCOC(=O)Nc1ccc2c(c1)C(c1ccccc1Cl)=CCC(=O)N2
Agent: C[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CO
Product: Nc1ccc2c(c1)C(c1ccccc1Cl)=CCC(=O)N2

Procedure:
13.0 g of ethyl 5-(2-chlorophenyl)-2,3-dihydro-2-oxo-1H-1-benzazepine-7-carbamate are heated to boiling under reflux for 13 hours together with 39 g of potassium methylate in a mixture of in each case 215 ml of methanol, ethanol and water. After evaporation of the organic solvents, the residue is extracted with chloroform. The residue from the chloroform extract is crystallized from ethyl acetate. There is obtained 7-amino-5-(2-chlorophenyl)-1,3-dihydro-2H-1-benzazepin-2-one of melting point 192°.
Reaction SMILES: OC1C(OS(C2C=CC(C)=CC=2)(=O)=O)=C(I)C=CC=1.[F:20][C:21]([F:29])([F:28])[C:22](=O)[CH2:23][C:24](=[O:26])[CH3:25].[NH2:30][C:31]([NH2:33])=[S:32]>C(#N)C>[C:24]([C:23]1[S:32][C:31]([NH2:33])=[N:30][C:22]=1[C:21]([F:29])([F:28])[F:20])(=[O:26])[CH3:25]
Reactant: NC(N)=S
Reactant: CC(=O)CC(=O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)Oc2c(O)cccc2I)cc1
Solvent: CC#N
Product: CC(=O)c1sc(N)nc1C(F)(F)F
Reaction time: 8 h

Procedure:
Hydroxy(tosyloxy)iodobenzene (78.5 g) was added to a solution of 1,1,1-trifluoropentane-2,4-dione in acetonitrile (500 ml). The mixture was heated under reflux for 45 minutes, then cooled, and thiourea (15.2 g) was added. The mixture was heated under reflux for 4 hours and then left to stand overnight. Evaporation and crystallisation of the residue from dichloromethane gave the title compound.