Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH:26]([CH3:28])[CH3:27])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1)=[O:32]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH:26]([CH3:28])[CH3:27])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=[O:32])=[CH:4][CH:3]=1
Reactant: CN1CCN(C(=O)CCl)CC1
Reactant: CC(C)Oc1ccccc1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Product: CC(C)Oc1ccccc1C1CCN(C(=O)c2cn(CC(=O)N3CCN(C)CC3)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-isopropoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-1-(4-methyl-piperazin-1-yl)-ethanone gave the title compound.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:19][C:20]1[CH:32]=[CH:31][C:30]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][C:22]=2[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:8][NH:9][C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:19][C:20]1[CH:32]=[CH:31][C:30]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][C:22]=2[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCCCCBr)NOCc1ccccc1
Reactant: Oc1ccc2c(c1)[nH]c1ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCCCCCOc1ccc2c(c1)[nH]c1ccccc12)NOCc1ccccc1

Procedure:
In a manner analogous to that of example 1 (b), 7-bromo-heptanoic acid benzyloxy-amide (1.8 g, 5.7 mmol) was reacted with 2-hydroxycarbazole (1.05 g, 5.7 mmol) in the presence of potassium carbonate (1.2 g, 8.6 mmol) in dimethyl formamide to give 7-(9H-carbazol-2-yloxy)-heptanoic acid benzyloxyamide as an almost colorless wax (yield 0.53 g, 22%; purified by column chromatography using silica gel and ethyl acetate: heptane 4:6 to 6:4 as an eluent). MS (M−H+)=415.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:5]([NH2:17])=[C:4]([Cl:18])[N:3]=1.C(O)(=O)C.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O>CO>[NH2:1][C:2]1[N:7]=[C:6]2[C:5]([N:17]=[C:27]([C:26]3[CH:29]=[CH:30][CH:31]=[C:24]([F:23])[CH:25]=3)[N:8]2[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[C:4]([Cl:18])[N:3]=1
Reactant: N#Cc1cccc(Nc2nc(N)nc(Cl)c2N)c1
Reactant: O=Cc1cccc(F)c1
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1cccc(-n2c(-c3cccc(F)c3)nc3c(Cl)nc(N)nc32)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Crude crystals (3.2 g) of 3-[(2,5-diamino-6-chloro-4-pyrimidinyl)amino]benzonitrile were dissolved in 64 ml of methanol, then 3.2 ml of acetic acid and 1.7 ml of 3-fluorobenzaldehyde were added thereto and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated and was subjected to an azeotropy with toluene for two times. The resulting residue after concentration was dissolved in ethanol, a solution of 1.72 g of ferric chloride in 10 ml of ethanol was added and the mixture was heated under reflux for 1 hour. The reaction solution was returned to room temperature, concentrated to dryness and added to ice-water and the resulting crystals were collected by filtration to give 2.6 g of the title compound, i.e. 3-[2-amino-6-chloro-8-(3-fluorophenyl)-9H-9-purinyl]benzonitrile.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[NH:10][C:4]=2[CH:3]=1.[C:26](O)(=[O:28])[CH3:27].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([N:18]3[CH2:23][CH2:22][N:21]([C:26](=[O:28])[CH3:27])[CH2:20][CH2:19]3)[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[NH:10][C:4]=2[CH:3]=1
Reactant: CC(=O)O
Reactant: Fc1ccc2c(c1)Nc1sc3ccccc3c1C(N1CCNCC1)=N2
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(C2=Nc3ccc(F)cc3Nc3sc4ccccc4c32)CC1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
8-Fluoro-12-(piperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine (260 mg) was dissolved in toluene (5 ml) and anhydrous acetic acid (230 mg) and triethylamine (375 mg) were added. The mixture was stirred at 80° C. for 30 minutes. The reaction mixture was allowed to cool to room temperature, and extracted with chloroform, washed with water and dried over anhydrous magnesium sulfate. After natural filtration, the solvent was evaporated under reduced pressure and the residue was recrystallized from methanol to give 8-fluoro-12-(4-acetylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine.1/4 hydrate (97 mg).
Reaction SMILES: [OH-].[Li+].C([O:6][CH2:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([F:24])([F:23])([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:11]=[N:10][N:9]=1)(=O)C>C(O)C.O>[F:24][S:19]([F:20])([F:21])([F:22])([F:23])[C:16]1[CH:17]=[CH:18][C:13]([N:12]2[C:8]([CH2:7][OH:6])=[N:9][N:10]=[N:11]2)=[CH:14][CH:15]=1
Reactant: CC(=O)OCc1nnnn1-c1ccc(S(F)(F)(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCc1nnnn1-c1ccc(S(F)(F)(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
Lithium hydroxide (553 mg, 22.2 mmol) was added to a solution of {1-[4-(pentafluoro-λ6-sulfanyl)phenyl]-1H-tetrazol-5-yl}methyl acetate (Intermediate 43, 5.30 g, 15.3 mmol) in ethanol:water (2:1), at 0° C. The reaction mixture was stirred for 3 hr at room temperature. The solvent was removed by under reduced pressure and the residue was diluted with DCM, washed with ice-water, saturated aq NaHCO3 and brine solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. This was purified by column chromatography (100-200 mesh silica gel), eluting with 30%-40% EtOAc/pet-ether gave the title compound (3.98 g).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:18][CH3:19])=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11](O)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(Cl)(=O)C([Cl:23])=O>ClCCl.C1(C)C=CC=CC=1>[Cl:23][C:11]1[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]([CH2:18][CH3:19])[N:8]=[C:7]2[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=12
Reactant: CCOC(=O)c1c(CC)nc2c(cnn2CC)c1O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(CC)nc2c(cnn2CC)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
Ethyl 1,6-diethyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (0.10 g, 0.38 mmol, 1 equivalent, e.g. which can be as prepared in Intermediate 2C) was dissolved in dichloromethane (1.5 ml). Oxalyl chloride (0.07 ml, 0.10 g, 0.76 mmol, 2.0 equivalents) was added in one portion to the stirred solution. The reaction mixture, a solution, was stirred at room temperature for 2 hours, then was heated to 39° C. and stirred for 22.5 hours at this temperature, and then allowed to cool. The reaction mixture was diluted with toluene and then the solvent was removed in vacuo to give a brown oil which solidified on standing at room temperature to yield the title compound as a brown solid (0.086 g, about 80% theory yield). HPLC (5 min generic solvent gradient): TRET about 3.43. Mass Spectrum: Found: MH+ 282.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:16](=[O:17])[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8]2)[CH2:3][CH2:2]1.Cl[C:19]1[C:27]2[NH:26][N:25]=[CH:24][C:23]=2[C:22]2[CH2:28][N:29]([CH2:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C:30](=[O:53])[C@@H:31]([CH2:33][C:34](=[O:52])N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)[CH2:32][C:21]=2[CH:20]=1>>[CH2:54]([N:29]1[C:30](=[O:53])[C@H:31]([CH2:33][C:34](=[O:52])[N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[C:16](=[O:17])[CH2:15][C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:8]3)[CH2:3][CH2:2]2)[CH2:32][C:21]2[CH:20]=[CH:19][C:27]3[NH:26][N:25]=[CH:24][C:23]=3[C:22]=2[CH2:28]1)[C:55]([CH3:58])([CH3:57])[CH3:56]
Reactant: O=C1Cc2ccccc2CN1C1CCNCC1
Reactant: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Product: CC(C)(C)CN1Cc2c(ccc3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4CC3=O)CC2)C1=O
Yield: 40 %

Procedure:
2-(Piperidin-4-yl)-1,2-dihydroisoquinolin-3(4H)-one (105 mg, 0.46 mmol) and [9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]acetic acid (110 mg, 0.33 mmol) were combined in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Title compound was obtained as a white solid in 40% yield. High resolution MS m/e (M+H)+=541.3111.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:5][N:4]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.[S:42](N)([NH2:45])(=[O:44])=[O:43]>O1CCOCC1>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[N:17]2[CH:18]=[CH:19][N:20]([S:42]([NH2:45])(=[O:44])=[O:43])[CH:21]=[CH:22]2)=[CH:5][N:4]([C:23]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1
Reactant: NS(N)(=O)=O
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCNCC3)c2c1
Solvent: C1COCCO1
Product: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3C=CN(S(N)(=O)=O)C=C3)c2c1
Yield: 73.1 %

Procedure:
A mixture of 54 mg 6-(3-methyl-1-trityl-1H-4-pyrazolyl)-4-piperazin-1-yl-quinoline obtained in Example 187, 96 mg sulfamide, and 5 mL dioxane was heated for 4 hours under reflux. The reaction solution was evaporated, then ethyl acetate and water were added to the residue, and the organic layer was separated, then washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 45 mg of the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:13]([CH3:14])=[C:12](O)[C:11]2[C:6](=[C:7]([F:20])[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=2)[N:5]=1.[CH3:21][O:22][CH2:23][C:24](Cl)=[O:25]>O1CCCC1>[CH3:3][C:4]1[C:13]([CH3:14])=[C:12]([C:24](=[O:25])[CH2:23][O:22][CH3:21])[C:11]2[C:6](=[C:7]([F:20])[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=2)[N:5]=1
Reactant: Cc1nc2c(F)cc(C(C)(C)C)cc2c(O)c1C
Reactant: COCC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC(=O)c1c(C)c(C)nc2c(F)cc(C(C)(C)C)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In tetrahydrofuran (10 ml) was suspended 60% sodium hydride (165 mg). The compound 1 (680 mg) was added to the suspension under ice cooling, and the mixture was stirred for 30 min. Further, methoxyacetyl chloride (200 μl) was added thereto, and the mixture was stirred for 3 hr. The reaction solution thus obtained was poured into ice water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was then removed under the reduced pressure. The crude product was purified by chromatography on silica gel (Wako Gel C-200, elution solvent: n-hexane-ethyl acetate (3:1)) to give 2,3-dimethyl-6-t-butyl-8-fluoro-4-methoxyacetylquinoline (compound 10, 390 mg). 1H-NMR data on this compound in deutro-chloroform were as shown below.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=[C:3]1[CH2:16][C:17]([OH:19])=[O:18].[Br:20]Br>C(O)(=O)C>[Br:20][C:4]1[CH:5]=[C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[O:8])[N:2]([CH3:1])[C:3]=1[CH2:16][C:17]([OH:19])=[O:18]
Reactant: Cc1ccc(C(=O)c2ccc(CC(=O)O)n2C)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)c2cc(Br)c(CC(=O)O)n2C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2.0g. (0.0078 moles) of 1-methyl- 5-(p-toluoyl)pyrrole-2-acetic acid in 40 ml. of glacial acetic acid is added dropwise a solution of 1.2g (0.0078 moles) of bromine in 3 ml. of glacial acetic acid. The mixture is stirred at room temperature for two hours, after which it is poured into 300 ml. of water, and the solid which forms is filtered off. Recrystallization from ether-hexane yields 3-bromo-1-methyl-5-(p-toluoyl) pyrrole-2-acetic acid as a white solid; m.p. 162°-164° C.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([NH2:10])=[O:9])[C:3]1=[O:11].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[C:37]1([CH2:43][O:44][C:45]2[C:50]([O:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[CH:49][N:48]=[C:47]([C:59](O)=[O:60])[CH:46]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C)C=O>[C:37]1([CH2:43][O:44][C:45]2[C:50]([O:51][CH2:52][C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)=[CH:49][N:48]=[C:47]([C:59]([NH:1][N:2]3[CH2:7][CH2:6][CH2:5][N:4]([C:8]([NH2:10])=[O:9])[C:3]3=[O:11])=[O:60])[CH:46]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: NC(=O)N1CCCN(N)C1=O
Reactant: O=C(O)c1cc(OCc2ccccc2)c(OCc2ccccc2)cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: NC(=O)N1CCCN(NC(=O)c2cc(OCc3ccccc3)c(OCc3ccccc3)cn2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
To a solution of 3-aminotetrahydro-2-oxo-1(2H)-pyrimidinecarboxamide (10 g, 63.2 mmol) in 350 ml N,N-dimethylformamide were added dicyclohexylcarbodiimide (15.7 g, 75.9 mmol), N-hydroxybenzotriazole (0.97 g, 6.32 mmol) and 4,5-bis(phenylmethoxy)-2-pyridinecarboxylic acid (21.2 g, 63.2 mmol) and the mixture was stirred overnight at room temperature. Dicyclohexylurea (13.6 g) was filtered off and the solvent was removed in vacuo. Trituration of the residue with ether gave 27.5 g of the desired product, melting point 192°-195° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])=[CH:6][CH:5]=1)[CH3:2].CN(C)C(=N)N(C)C.[F:24][C:25]([F:32])([F:31])[C:26](OCC)=[O:27]>CO>[CH2:1]([O:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH:10][C:26](=[O:27])[C:25]([F:32])([F:31])[F:24])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CCOc1ccc(C[C@H](N)C(=O)O)cc1
Agent: CN(C)C(=N)N(C)C
Solvent: CO
Product: CCOc1ccc(C[C@H](NC(=O)C(F)(F)F)C(=O)O)cc1
Reaction time: 48 h

Procedure:
O-Ethyl-L-tyrosine (IV, EXAMPLE 3, 20.9 g, 100 mmol) is suspended in methanol (100 mL), tetramethylguanidine (TMG) (12.5 mL, 100 mmol) is added, followed by ethyl trifluoroacetate (14 mL, 120 mmol). The mixture is stirred at 20-25 deg for 48 hr and the resulting mixture is concentrated to remove most of the methanol and excess ethyl trifluoroacetate. The residue is dissolved in water (40 mL), added hydrochloric acid (100 mL of 1.0 M) to adjust the pH<3. The mixture is stirred at 20-25° for at least 2 hr, then filtered. The precipitate is suspended in water (50 mL), stirred for 0.5 hr, then filtered. This wash process is repeated once. Then the precipitate is dried in oven at 55° for 48 hr to give the title compound, NMR (DMSO-d6) δ12.9, 9.72, 7.15, 6.82, 4.46, 3.98, 3.15, 2.92 and 1.31; CMR (DMSO-d6) δ171.8, 157.6, 157.7, 130.3, 129.0, 116.1, 63.2, 54.6, 35.1 and 15.0; FMR (DMSO-d6) δ-74.7; HRMS (FAB) calculated for C13H14F3NO4 [M+1]=306.0953, found=306.0952.
Reaction SMILES: [CH3:1][C:2](C)([O-:4])C.[K+].[C:7]([C:10]1[CH:11]=[CH:12][C:13]([O:34][CH2:35][C:36]2[CH:41]=[C:40](Cl)[CH:39]=[CH:38][N:37]=2)=[C:14]([C:16]2[CH:33]=[CH:32][C:19]3[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24][C:18]=3[CH:17]=2)[CH:15]=1)(=[O:9])[CH3:8].O>C(O)C>[C:7]([C:10]1[CH:11]=[CH:12][C:13]([O:34][CH2:35][C:36]2[CH:41]=[C:40]([O:4][CH2:2][CH3:1])[CH:39]=[CH:38][N:37]=2)=[C:14]([C:16]2[CH:33]=[CH:32][C:19]3[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24][C:18]=3[CH:17]=2)[CH:15]=1)(=[O:9])[CH3:8]
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)c1ccc(OCc2cc(Cl)ccn2)c(-c2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOc1ccnc(COc2ccc(C(C)=O)cc2-c2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c1
Reaction time: 1.5 h

Procedure:
Potassium tert-butoxide (0.132 g) in ethanol (4 ml) was stirred for 15 min before adding 1,1-dimethylethyl 7-(5-acetyl-2-{[(4-chloro-2-pyridinyl)methyl]oxy}phenyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate, (0.4 g) and this was heated in a microwave at 110 C. for 1.5 h. Water (20 ml) was added to the cooled mixture and this was extracted with DCM (2×30 ml). The combined organics were washed with brine, dried over sodium sulphate and concentrated in vacuo. The crude product was purified through silica eluting with 0-45% ethyl acetate in hexane to give the title compound, 0.16 g
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[C:9]([N:11]1[CH2:16][CH2:15][C:14]([C:23](=[O:27])[CH2:24][CH2:25][CH3:26])([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=[O:10])(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[NH2:7][C@H:8]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[C:9]([N:11]1[CH2:16][CH2:15][C:14]([C:23](=[O:27])[CH2:24][CH2:25][CH3:26])([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:13][CH2:12]1)=[O:10]
Reactant: CCCC(=O)C1(C2CCCCC2)CCN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC(=O)C1(C2CCCCC2)CCN(C(=O)[C@H](N)Cc2ccc(OC)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.8 %

Procedure:
1.4 g (2.7 mmol) of tert-butyl[(R)-2-(4-butyryl-4-cyclohexylpiperidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]carbamate are placed in a mixture composed of 40 mL of DCM and 8 mL of trifluoroacetic acid. The reaction medium is stirred for 2 hours at room temperature and the reaction is then stopped by adding aqueous 1N sodium hydroxide solution. After extracting with dichloromethane, the organic phase is dried over sodium sulfate and then filtered and concentrated. 1.24 g of 1-{1-[(R)-2-amino-3-(4-methoxyphenyl)propionyl]-4-cyclohexylpiperidin-4-yl}butan-1-one in the form of a colourless oil are obtained in a yield of 100%.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[NH2:24][CH:25]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[CH2:26][OH:27]>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:15]=3[C:16]([NH:24][CH:25]([CH2:26][OH:27])[CH2:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)=[O:17])(=[O:11])=[O:12])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: Cc1ccc(C(=O)O)c(NS(=O)(=O)c2cccc3nsnc23)c1
Reactant: NC(CO)Cc1ccc(Cl)cc1
Product: Cc1ccc(C(=O)NC(CO)Cc2ccc(Cl)cc2)c(NS(=O)(=O)c2cccc3nsnc23)c1

Procedure:
2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-methyl-benzoic acid was coupled with (±)-2-amino-3-(4-chloro-phenyl)-propan-1-ol as in EXAMPLE 1, Part C. HPLC: RT=9.31 min. MS (ESI−): mass calcd. for C23H21ClN4O4S2, 516.07; m/z found, 515 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.52 (s, 1H), 8.33 (dd, J=7.0, 1.0, 1H), 8.19 (dd, J=8.8, 1.0, 1H), 7.68 (dd, J=8.8, 7.0, 1H), 7.48 (s, 1H), 7.32-7.27 (m, 2H), 7.21-7.17 (m, 2H), 7.09 (d, J=8.0, 1H), 6.75 (d, J=8.0, 1H), 6.28 (br d, J=7.4, 1H), 4.32-4.23 (m, 1H), 3.72 (dd, J=10.8, 3.6, 1H), 3.65 (dd, J=10.8, 4.5, 1H), 2.91 (d, J=7.4, 2H), 2.75 (br s, 1H), 2.27 (s, 3H).
Reaction SMILES: [C:1]([NH:5][S:6]([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14](OC(=O)C)(=[O:16])[CH3:15]>N1C=CC=CC=1>[C:1]([NH:5][S:6]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14](=[O:16])[CH3:15])(=[O:7])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)NS(=O)(=O)CCCCO
Solvent: c1ccncc1
Product: CC(=O)OCCCCS(=O)(=O)NC(C)(C)C
Reaction time: 1 h

Procedure:
A crude product (1.17 g) of N-tert-butyl-4-hydroxybutane-sulfonamide was dissolved in pyridine (3.0 ml) and acetic anhydride (1.5 ml) was added, and the mixture was left standing at room temperature for 1 hr. The reaction mixture was concentrated to dryness under reduced pressure and the residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed once with water and once with saturated brine, dried over magnesium sulfate and concentrated to dryness under reduced pressure to give N-tert-butyl-4-acetoxybutanesulfonamide (425 mg) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[NH2:17][C:18]1[N:19]=[CH:20][NH:21][C:22]=1[C:23]#[N:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:19]3[CH:20]=[N:21][C:22]([C:23]#[N:24])=[C:18]3[N:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)cc1
Reactant: N#Cc1[nH]cnc1N
Product: N#Cc1ncn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Yield: 38.4 %

Procedure:
Reaction of 1-(4-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (251 mg, 1.0 mmol), prepared from commercially available 4-chloro-acetophenone according to general procedure A, and 4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (124 mg, 38%). MS (ISP) 323.1 [(M+H)+]; mp 205° C.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[C:29]([O:37][CH2:38][C:39]([F:42])([F:41])[F:40])[CH:28]=4)[CH:24]=[C:23]([C:43]([F:46])([F:45])[F:44])[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:42][C:39]([F:40])([F:41])[CH2:38][O:37][C:29]1[CH:28]=[C:27]([C:25]2[CH:24]=[C:23]([C:43]([F:45])([F:46])[F:44])[N:22]=[C:21]([C:17]3[CH:16]=[C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:10]=4)[CH:20]=[CH:19][CH:18]=3)[N:26]=2)[CH:32]=[CH:31][C:30]=1[C:33]([F:34])([F:35])[F:36]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)cc(C(F)(F)F)n3)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)cc(C(F)(F)F)n3)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.6 %

Procedure:
To a cooled and stirred solution of 3′-{4-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-6-trifluoromethyl-pyrimidin-2-yl}-biphenyl-3-sulfonic acid tert-butylamide (0.45 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into saturated NaHCO3 solution (20 ml) and extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated. Further purification by crystallization (dischloromethane/MeOH/hexane) yielded the title compound as a white solid (0.25 g, 59%). MS (ISP) 622.2 [(M+H)+]; mp 188° C.