Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:7][CH2:6][CH2:5][O:4][C:3]=1[C:8](=[O:13])C(F)(F)F.[OH-:14].[K+].Cl>C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:7][CH2:6][CH2:5][O:4][C:3]=1[C:8]([OH:13])=[O:14]
Reactant: CC1=C(C(=O)C(F)(F)F)OCCO1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC1=C(C(=O)O)OCCO1
Yield: 69.4 %

Procedure:
A mixture of 1-(5,6-dihydro-3-methyl-1,4-dioxin-2-yl)-2,2,2-trifluoroethanone (12 g, 0.06 mole) and powdered potassium hydroxide (6 g, 0.1 mole) was refluxed in toluene (200 ml) for 7 hours. The mixture was cooled, acidified with 6N hydrochloric acid, and the solid precipitate, crude 5,6-dihydro-3-methyl-1,4-dioxin-2-carboxylic acid (6 g, 60% yield) collected.
Reaction SMILES: [CH2:1]([CH:3]([CH2:13][CH3:14])[C:4]([N:6]1[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl.[NH2:16][C@H:17]([C:22]([NH2:24])=[O:23])[CH2:18][CH2:19][S:20][CH3:21].C(N(CC)CC)C>CCO>[CH2:1]([CH:3]([CH2:13][CH3:14])[C:4]([N:6]1[CH2:11][CH2:10][C:9]2([NH:24][C:22](=[O:23])[C@H:17]([CH2:18][CH2:19][S:20][CH3:21])[NH:16]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCC(CC)C(=O)N1CCC(=O)CC1
Reactant: CSCC[C@H](N)C(N)=O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCC(CC)C(=O)N1CCC2(CC1)NC(=O)[C@H](CCSC)N2

Procedure:
A solution of 1-(2-ethylbutyryl)-piperidin-4-one (1.6 g, 8.1 mmol), (S)-methioninamide hydrochloride (1.5 g, 8.1 mmol), and triethylamine (820 mg, 8.1 mmol) in EtOH (66 mL) was heated under reflux over a period of 16 h. Following removal of the solvent, water (50 mL) and CH2Cl2 (50 mL) were added to the residue and the mixture was basified with concentrated sodium hydroxide solution. The aqueous phase was extracted with CH2Cl2 (3×20 mL) and the combined organic phases were dried over Na2SO4. Following removal of the solvent and vacuum drying, there was obtained the product 8-(2-ethylbutyryl)-3-(S)-(2-methylsulfanylethyl)-1,4,8-triazaspiro[4,5-]-decan-2-one in a yield of 1.8 g (69%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][NH:10][C:4]=2[CH:3]=1.[CH3:15][O:16][CH2:17][C@@H:18]([NH:25][C:26]([NH2:28])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:15][O:16][CH2:17][C@@H:18]([NH:25][C:26]([NH:28][C:2]1[N:7]=[CH:6][C:5]2[C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][NH:10][C:4]=2[CH:3]=1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC[C@@H](NC(N)=O)c1ccccc1
Reactant: FC(F)(F)c1n[nH]c2cc(Cl)ncc12
Product: COC[C@@H](NC(=O)Nc1cc2[nH]nc(C(F)(F)F)c2cn1)c1ccccc1

Procedure:
In a manner similar to that described in Example 30 (Step 1), 6-chloro-3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine was reacted with (S)-1-(2-methoxy-1-phenylethyl)urea (BrettPhos precatalyst, KOtBu, dioxane, 90° C., overnight) to provide 1-[(1S)-2-methoxy-1-phenylethyl]-3-[3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl]urea. MS ESI calc'd. for C17H16F3N5O2[M+1]+ 380, found 380.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([C:19]3[N:20]=[N:21][N:22]([CH3:24])[N:23]=3)=[CH:14][C:13]=2[CH3:25])[N:7]=1.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[S:28]>C(#N)C.CN(C1C=CN=CC=1)C>[O:29]([C:27]([O:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[C:13]([CH3:25])=[CH:14][C:15]([C:19]3[N:20]=[N:21][N:22]([CH3:24])[N:23]=3)=[CH:16][C:17]=2[CH3:18])[N:7]=1)=[S:28])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: S=C(Cl)Oc1ccccc1
Reactant: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCn1cnc(CO)n1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCn1cnc(COC(=S)Oc2ccccc2)n1
Temperature: 20 °C
Reaction time: 7 h

Procedure:
To a mixture of 5-hydroxymethyl-2-[3-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethyl-phenoxy]-propyl]-1,2,4-triazole (343 mg, 1 mmol) in 15 ml of acetonitrile was added DMAP (244 mg, 2 mmol) and phenyl chlorothioformate (381 mg, 2.2 mmol). The mixture was stirred at 20° C. for 7 h, an additional phenyl chlorothioformate (1 equiv) was added, and the mixture was stirred for 15 h. The solvent was removed in vacuo and 5-phenoxythiocarbonyloxymethyl-2-[3-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-propyl]-1,2,4-triazole was isolated and used without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:14])=[C:4]([O:12][CH3:13])[C:5]([C:8](=[CH2:11])[CH2:9][CH3:10])=[CH:6][CH:7]=1.[F:15][C:16]([F:25])([F:24])[C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>ClCCl.FC(F)(F)CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:9][CH3:10])[CH2:11][C@:17]([OH:23])([C:16]([F:24])([F:25])[F:15])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:4]([O:12][CH3:13])[C:3]=1[CH3:14]
Reactant: CCOC(=O)C(=O)C(F)(F)F
Reactant: C=C(CC)c1ccc(F)c(C)c1OC
Agent: [Pd]
Solvent: ClCCl
Solvent: OCC(F)(F)F
Product: CCOC(=O)[C@](O)(CC(CC)c1ccc(F)c(C)c1OC)C(F)(F)F
Temperature: 0 °C
Reaction time: 16 h
Yield: 34.1 %

Procedure:
5.7 g (29.3 mmol) of 3-fluoro-2-methyl-6-(1-methylenepropyl)anisole, 7.7 ml (170 mmol) of ethyl trifluoropyruvate and 15 g of molecular sieve are admixed dropwise at 0° C. over 30 minutes with 0.76 g (0.88 mmol) of [Cu(R,R)-2,2-bis(4,5-dihydro-4-tert-butyloxazolin-2-yl)propane)(H2O)2]((SbF6)2, in 38 ml of dichloromethane. The reaction mixture is stirred at 0° C. for 16 hours and the reaction mixture is purified by means of column chromatography on silica gel (hexane/ethyl acetate 0-20%). This gives 8.7 g of ethyl (R)-4-(4-fluoro-2-methoxy-3-methylphenyl)-2-hydroxy-2-(trifluoromethyl)hex-4-enoate as an E/Z mixture with an enantiomeric excess of greater than 80%, and in this way 13.9 of crude E/Z-4-(4-fluoro-2-methoxy-3-methylphenyl)-2-(trifluoromethyl)hex-4-ene-1,2-diol. 4.0 g (11 mmol) of ethyl (2R,4E/Z)-4-(4-fluoro-2-methoxy-3-methylphenyl)-2-hydroxy-2-(trifluoromethyl)hex-4-enoate are dissolved in 180 ml of 2,2,2-trifluoroethanol and the solution is admixed with 400 mg of palladium on carbon (10%). The suspension is shaken under a hydrogen atmosphere at 100 bar until reaction is complete. The mixture is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. The concentrated crude product is purified by column chromatography on silica gel (hexane/ethyl acetate 15%) to give 3.7 g (10 mmol) of ethyl (2R,4R/S)-4-(4-fluoro-2-methoxy-3-methylphenyl)-2-hydroxy-2-(trifluoromethyl)hexanoate as a diastereomer mixture. 3.7 g (10 mmol) of ethyl (2R,4R/S)-4-(4-fluoro-2-methoxy-3-methylphenyl)-2-hydroxy-2-(trifluoromethyl)hexanoate are cooled to −15° C. in 132 ml of diethyl ether and admixed over 10 minutes with solid lithium aluminum hydride, 1.03 g (27.3 mmol), in portions. The mixture is stirred at −10° C. for 3 hours, and ethyl acetate and water are added cautiously. The suspension is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1.[CH3:22][NH:23][CH2:24][C:25]([O:27][CH3:28])=[O:26].C(NC(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([N:23]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH3:22])(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1NC(=O)c1cc(Cl)ncn1
Reactant: CNCC(=O)OC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)CN(C)S(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-(6-chloropyrimidine-4-carboxamido)-3-methylbenzene-1-sulfonyl chloride (Intermediate 30, 1.2g; 3.47 mmol) in THF (100 ml) was treated with methyl 2-(methylamino)acetate (666 mg; 4.77 mmol) and diisopropylamine (2 ml; 14.3 mmol). After stirring at RT for 18 hours the solvent was removed in vacuo and the residue redissolved in DCM and washed with water. The organic extracts were passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc. The title product was obtained as a white solid.
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:8]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=[C:14]([CH3:26])[CH:13]=2)(=[O:10])=[O:9])=[C:5]([CH3:7])[N:6]=1.[C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)#[N:28].C(=O)([O-])[O-].[Cs+].[Cs+]>C(COC)OC.O>[C:27]([C:29]1[CH:34]=[CH:33][C:32]([C:2]2[S:3][C:4]([S:8]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=[C:14]([CH3:26])[CH:13]=3)(=[O:10])=[O:9])=[C:5]([CH3:7])[N:6]=2)=[CH:31][CH:30]=1)#[N:28]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(NS(=O)(=O)c2sc(Br)nc2C)c1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(NS(=O)(=O)c2sc(-c3ccc(C#N)cc3)nc2C)c1
Temperature: 80 °C
Yield: 33.1 %

Procedure:
A solution of tert-butyl (6-{[(2-bromo-4-methyl-1,3-thiazol-5-yl)sulfonyl]amino}-4-methylpyridin-2-yl)carbamate (0.96 g, 2.08 mmol, 1 equiv), 4-cyanophenylboronic acid (0.336 g, 2.29 mmol, 1.1 equiv), and cesium carbonate (2.03 g, 6.24 mmol, 3 equiv) in 2:1 dimethoxyethane/water (30 mL) was purged with nitrogen for 15 minutes. Dichloro[1,1′-bis(diphenylphosphine)ferrocene] palladium (II) chloride (0.068 g, 0.08 mmol, 0.04 equiv) was then added, and the resulting mixture was purged with nitrogen for another 15 minutes. The reaction was heated to 80° C. for 1 h. After cooling to 24° C., the solution was concentrated in vacuo (˜25 mm Hg). The resulting aqueous mixture was extracted ethyl acetate (60 mL). The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by high performance flash chromatography (0→10% ethyl acetate in hexanes) provided the intermediate (0.334 g, 33%). 1H NMR (400 MHz, CDCl3), δ: 7.97 (d, J=8.3 Hz, 2H), 7.73 (d, J=8.3 Hz, 2H), 7.63 (br s, 1H), 7.43 (s, 1H), 6.90 (s, 1H), 2.65 (s, 3H), 2.32 (s, 3H), 1.50 (s, 9H); LRMS (ESI) m/z: 486.1.
Reaction SMILES: [CH2:1]([NH:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([O:14][CH:15]([CH3:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]([CH3:24])([CH3:23])[CH2:7]1)[CH2:2][CH2:3][CH3:4].Cl[P:26]1[O:31][CH2:30][C:29]([CH3:33])([CH3:32])[CH2:28][O:27]1>>[CH3:22][CH:15]([O:14][N:9]1[C:8]([CH3:23])([CH3:24])[CH2:7][CH:6]([N:5]([P:26]2[O:31][CH2:30][C:29]([CH3:33])([CH3:32])[CH2:28][O:27]2)[CH2:1][CH2:2][CH2:3][CH3:4])[CH2:11][C:10]1([CH3:13])[CH3:12])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCCCNC1CC(C)(C)N(OC(C)c2ccccc2)C(C)(C)C1
Reactant: CC1(C)COP(Cl)OC1
Product: CCCCN(C1CC(C)(C)N(OC(C)c2ccccc2)C(C)(C)C1)P1OCC(C)(C)CO1

Procedure:
The title compound is prepared as a colorless glass from 4-n-butylamino-1-alpha-methylbenzyloxy-2,2,6,6-tetramethylpiperidine and 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphorinane according to the procedure of Example 11C.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([CH3:23])[CH:14]=3)[CH:10]=[C:9]([C:24]([F:27])([F:26])[F:25])[N:8]=2)[CH:6]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[CH3:23][C:15]1[CH:14]=[C:13]([C:11]2[CH:10]=[C:9]([C:24]([F:27])([F:26])[F:25])[N:8]=[C:7]([N:5]3[CH:6]=[C:2]([C:32]4[CH:33]=[CH:34][C:29]([NH2:28])=[N:30][CH:31]=4)[N:3]=[CH:4]3)[N:12]=2)[CH:18]=[CH:17][C:16]=1[C:19]([F:22])([F:21])[F:20]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(Br)c3)n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4ccc(N)nc4)c3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-(3-methyl-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example E.48) (0.23 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a yellow solid (0.084 g, 36%). MS (ISP) 465.3 [(M+H)+]; mp 290° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[Cl:43][C:44]1[CH:49]=[C:48]([Cl:50])[CH:47]=[CH:46][C:45]=1[CH2:51][CH2:52]O>O1CCCC1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:52][CH2:51][C:45]2[CH:46]=[CH:47][C:48]([Cl:50])=[CH:49][C:44]=2[Cl:43])[CH:5]=1
Reactant: OCCc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1cccc(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(OCCc2ccc(Cl)cc2Cl)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
2 g (13.1 mmol) of 3-hydroxybenzoic acid methyl ester and 4.75 g (18.1 mmol) of triphenylphosphine were dissolved in 48 ml of anhydrous tetrahydrofuran. The solution was cooled to 0° C. and a solution of 3.04 g (17.5 mmol) DEAD in 7 ml of anhydrous tetrahydrofuran was added dropwise over 20 min. The solution was stirred at RT for 45 min. and a solution of 2.76 g (14.5 mmol) of 2-(2,4-Dichlorophenyl)-ethanol in 3 ml anhydrous tetrahydrofuran was added. The reaction was stirred for 16 h at RT. The solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate/n-heptane (4/1).
Reaction SMILES: [Br:1][C:2]1[C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:12]([F:15])=[CH:13][C:14]=3[C:6]=2[C:5](=O)[NH:4][CH:3]=1.[OH-].[Na+].O=P(Cl)(Cl)[Cl:21]>>[Br:1][C:2]1[C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:12]([F:15])=[CH:13][C:14]=3[C:6]=2[C:5]([Cl:21])=[N:4][CH:3]=1
Reactant: O=c1[nH]cc(Br)c2[nH]c3ccc(F)cc3c12
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Fc1ccc2[nH]c3c(Br)cnc(Cl)c3c2c1
Temperature: 175 °C

Procedure:
4-Bromo-8-fluoro-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (1 gram) was suspended in 10 mL POCl3 and heated to 175° C. for 15 minutes in a microwave. The crude reaction mixture was poured over ice, neutralized with 12 M NaOH, extracted with EtOAc, washed with brine, dried over MgSO4, filtered, concentrated to dryness. The title compound was used without further purification.
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH2:19][CH3:20])[CH2:5][CH2:6][O:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=1)[CH3:3].Cl>>[ClH:1].[CH2:19]([N:4]([CH2:2][CH3:3])[CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:17][CH:18]=1)[CH3:20]
Reactant: CCOC(=O)c1ccc(OCCN(CC)CC)cc1
Agent: Cl
Product: CCN(CC)CCOc1ccc(C(=O)O)cc1

Procedure:
Hydrolysis of ethyl 4-(2-diethylaminoethoxy)benzoate hydrochloride with aqueous concentrated hydrochloric acid at 100° for two hours gives 4-(2-diethylaminoethoxy)benzoic acid hydrochloride, m.p. 166°-168°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].Cl>C1COCC1>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][NH:12][C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1ccc(NC(=O)Cc2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(NCCc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
N-(4-Ethoxycarbonylphenyl)-(4-chlorophenyl)-acetamide (8.91 g., 0.03 mole) was dissolved in dry THF (70 ml) under nitrogen and borane-dimethyl sulphide complex (3.8 ml; 0.03 mole) was added at room temperature. The mixture was stirred for 30 minutes at room temperature, boiled under reflux with stirring for 4 hours, cooled and 1 N hydrochloric acid (70 ml) was added. The organic phase was separated, the aqueous layer extracted with dichloromethane (2×80 ml), the combined organic phases washed with water (100 ml) and dried over anhydrous magnesium sulphate. Evaporation of the solvent gave an oil which was chromatographed on silica-gel (120 g.) in dichloromethane to give ethyl 4-[2-(4-chlorophenyl)ethylamino]benzoate (4.02 g, 44%) melting at 75°-77° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.[Br:14][CH2:15][CH2:16][CH2:17]Br.[H-].[Na+]>CN(C=O)C>[Br:14][CH2:15][CH2:16][CH2:17][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2
Reactant: BrCCCBr
Reactant: COc1cc2c(cc1O)CCC2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OCCCBr)CCC2=O

Procedure:
A mixture of 5-Hydroxy-6-methoxy-indan-1-one (Intermediate H) (5.0 g, 0.028 mole), 1,3-dibromopropane (5.7 mL, 0.056 mole) and sodium hydride (1.2 g, 0.028 mole) were stirred in 50 mL of DMF at room temperature overnight under Argon. The reaction mixture was quenched with water (150 mL), extracted with ethyl acetate, then washed with 1N HCl and brine. The extract was dried over sodium sulfate and the solvent removed in vacuo to yield the title compound, 5-(3-Bromo-propoxy)-6-methoxy-indan-1-one. MS m/z 297 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:19])([CH3:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])[C:24]([Cl:38])=[CH:23][N:22]=1>>[Cl:38][C:24]1[C:25]([NH:27][C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])=[N:26][C:21]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][C:2]([F:1])([F:19])[CH3:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:22][CH:23]=1
Reactant: COc1cc2c(cc1N)CCN(CC(C)(F)F)CC2
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1ccccc1Nc1nc(Nc2cc3c(cc2OC)CCN(CC(C)(F)F)CC3)ncc1Cl

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-propyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide in an analogous manner to Example 61e. Product isolated as a pale yellow solid (0.019 g, 21%). MP: 162-165° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 11.00-10.97 (m, 1H), 8.68-8.64 (m, 1H), 8.11 (d, 1H, J=1.8 Hz), 8.09-8.07 (m, 1H), 7.54-7.39 (m, 3H), 7.11-7.06 (m, 1H), 6.64 (s, 1H), 6.18 (br s, 1H), 3.87 (d, 3H, J=1.5 Hz), 3.06-3.02 (m, 3H), 2.90-2.72 (m, 10H), 1.75-1.61 (m, 3H). MS: 531.17 (MH)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:24])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(=O)([O-])O.[K+].O>ClCCl>[CH2:29]([O:28][C:26]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:24])[CH2:10][CH2:9]1)=[O:27])[CH3:30]
Reactant: CCOC(=O)Cl
Reactant: Cc1cccc([N+](=O)[O-])c1NC1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)N1CCC(Nc2c(C)cccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
1-Benzyl-4-[(2-methyl-6-nitrophenyl)amino]piperidine (45.2 mg) was dissolved in dichloromethane (0.9 ml), added with ethyl chloroformate (27 μl) and potassium hydrogencarbonate (28 mg) and stirred at room temperature for 30 minutes. The reaction mixture was added with water (2 ml) and extracted twice with ethyl acetate (2 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer silica gel column chromatography (developing solvent: hexane:ethyl acetate=2:1) to obtain 38.3 mg of the title compound. Yield: 90%.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C([O-])(O)=O.[Na+].[Cl:15][CH2:16][C:17](Cl)=[O:18]>CCOCC>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:17](=[O:18])[CH2:16][Cl:15]
Reactant: Cc1cccc(C)c1N
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: Cc1cccc(C)c1NC(=O)CCl
Temperature: 25 °C

Procedure:
2,6-dimethylaniline (9.8 g, 81.2 mmol) was dissolved in ether (100 mL) and saturated aqueous NaHCO3 (100 mL) and the reaction mixture was cooled in an ice/water bath. To the cold solution was added chloroacetyl chloride 2 (9.17 g, 81.2 mmol) dropwise over a period of 2 h. The mixture was allowed to warm to RT over 14 h. The mixture was diluted with 100 mL ether and the organic layer was separated, dried over MgSO4, filtered and concentrated to afford compound 3 as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:8][C:9]=1[N:10]1[C:15](=[O:16])[CH2:14][C:13](=O)[CH2:12][CH:11]1[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:4].[BH3-]C#[N:32].[Na+].CC(O)=O>CO>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:8][C:9]=1[N:10]1[C:15](=[O:16])[CH2:14][CH:13]([NH2:32])[CH2:12][CH:11]1[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:4]
Reactant: [BH3-]C#N
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N1C(=O)CC(=O)CC1C1CCCCC1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1sc(-c2ccccc2)cc1N1C(=O)CC(N)CC1C1CCCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-(2-cyclohexyl-4,6-dioxo-piperidin-1-yl)-5-phenyl-thiophene-2-carboxylic acid methyl ester (400 mg, 0.98 mmol, 1.0 equiv) in MeOH (2.0 mL) was added NH4OAc (375 mg, 4.86 mmol, 5 equiv) and the resulting solution was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved MeOH. To the solution was added NaCNBH3 (247 mg, 1.16 mmol, 1.2 equiv) and HOAc (56 mg, 0.97 mmol, 1 equiv). The resulting mixture was stirred at room temperature for 18 hours. The solvent was then removed in vacuo. To the residue was added sat. aq. NaHCO3 solution until pH>8. The mixture was extracted with DCM. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was continued to the next step with no further purification.
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[N:40]1([C:45]2[CH:53]=[CH:52][C:48]([C:49](Cl)=[O:50])=[CH:47][CH:46]=2)[CH:44]=[CH:43][CH:42]=[N:41]1>>[N:40]1([C:45]2[CH:53]=[CH:52][C:48]([C:49]([O:1][CH:2]3[CH2:20][CH:19]4[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]5[C:16]([C:22]([NH:24][S:25]([CH:28]6[CH2:30][CH2:29]6)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]4=[O:21])[CH2:15]5)[CH2:3]3)=[O:50])=[CH:47][CH:46]=2)[CH:44]=[CH:43][CH:42]=[N:41]1
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Reactant: O=C(Cl)c1ccc(-n2cccn2)cc1
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3ccc(-n4cccn4)cc3)CN2C1=O
Yield: 7.7 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 4-(1-pyrazolyl)benzoyl chloride (183 mg, 0.88 mmol). The final trituration (diethyl ether/hexane) and filtration gave 10 mg (7.7%) of 18-(4-[1-pyrazolyl]benzoyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 99.9% pure (HPLC), MS m/z 737 (M−H)−, HRMS: calcd. 739.3125 and found 739.3109 (M+H)+, mp 167-169° C.