Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][N:2]=1.[Br:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[Br-:11].[CH2:12]([N+:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:1]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1cc2c(cn1)CCCC2
Reactant: BrCCc1ccccc1
Solvent: CN(C)C=O
Product: [Br-]
Product: c1ccc(CC[n+]2ccc3c(c2)CCCC3)cc1
Reaction time: 4 h
Yield: 67 %

Procedure:
A mixture of 2.05 g of 5,6,7,8-tetrahydroisoquinoline, 4.30 g of 2-bromoethylbenzene, and 5 mL of dimethylformamide was stirred in a 75°-80° oil bath for 4 hours. The solvent was removed under vacuum, the residue was dissolved in 4 mL of acetonitrile and 8 mL of 1-chlorobutane were added. The precipitate was collected after 1 hour to give 3.28 g of 2-phenethyl-5,6,7,8-tetrahydroisoquinolinium bromide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1.ClC(Cl)(O[C:30](=[O:36])OC(Cl)(Cl)Cl)Cl.[CH2:38]([N:45]1[CH2:49][CH2:48][C@H:47]([NH2:50])[CH2:46]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)(Cl)Cl>[CH2:38]([N:45]1[CH2:49][CH2:48][C@H:47]([NH:50][C:30]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:17][C:18]=2[N+:23]([O-:25])=[O:24])=[O:36])[CH2:46]1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Reactant: COc1cc2ncnc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)N[C@H]4CCN(Cc5ccccc5)C4)c([N+](=O)[O-])c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
Chloroform (27 ml) and triethylamine (4 ml) were added to 4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-2-nitroaniline (200 mg) to prepare a solution. Triphosgene (192 mg) was added to the solution, and the mixture was stirred at room temperature for 30 min. (3S)-(+)-1-Benzyl-3-aminopyrrolidine (77 mg) was then added thereto, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/acetone for development. Diethyl ether was added to the purification product, and the precipitated crystal was collected by filtration and was washed to give the title compound (153 mg, yield 48%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25])(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2].[N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1CCO.[C:40]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:41]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6](=[O:26])[CH2:7][C@H:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:40][CH2:41][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:31]=1[CH:30]=[CH:29][CH:28]=[N:27]2)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCc1ccc2ccccc2n1
Reactant: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccccc1O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: CON(C)C(=O)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccccc1OCCc1cccc2ncccc12
Temperature: 25 °C
Reaction time: 17 h
Yield: 126.8 %

Procedure:
To a solution of S)-3-(2-hydroxy-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester (2.0 g, 5.15 mmol), quinoline ethanol (0.892 g, 5.15 mmol) and triphenylphospine (2.02 g, 7.73 mmol) in 80 mL of THF at 0° C. was slowly added DEAD (1.22 mL, 7.73 mmol). The reaction was stirred for 17 h with slow warming to RT before removing the solvent. The residue was chromatographed (250 g SiO2-50% EtOAC/Hex) to afford 3.55 g of (S)—N-methoxy-N-methyl-3-[2-(2-quinolin-5-yl-ethoxy)benzenesulfonylamino]-succinamic acid tert-butyl ester (contaminated with some triphenylphosphine oxide). 1H NMR (400 MHz, CDCl3) 8.90(d, 1H, J=4 Hz), 8.61(d, 1H, J=8 Hz), 8.04(d, 1H, J=8 Hz), 7.81(d, 1H, J=8 Hz), 7.69(t, 1H, J=8 Hz), 7.65(t, 1H, J=8 Hz), 7.51(t, 1H, J=8 Hz), 7.49(d, 1H, J=8 Hz), 6.95(t, 1H, J=8 Hz), 6.85(d, 1H, J=8 Hz), 5.90(d, 1H, J=10 Hz), 4.38(m, 1H), 3.90-3.65(m, 2H), 3.45(s, 3H), 2.80(s, 3H), 2.40(ABX, AB portion, 2H, JAB=15, JAX=6, JBX=7, ΔνAB=50.3 Hz), 1.41(s, 9H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[CH:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O=[Pt]=O.CCO>[C:8]1([CH2:7][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccccc1
Reactant: NCCCCO
Agent: O=[Pt]=O
Solvent: CCO
Product: OCCCCNCc1ccccc1

Procedure:
Combine 4-amino-butan-1-ol (8.9 gm-0.1 mol), benzaldehyde (10.6 gm-0.1 mol), EtOH (100 ml) and PtO2 (0.3 gm), and hydrogenate the mixture at 45 lbs./sq.in. until H2 is no longer taken up. Filter, evaporate the solvent (in vacuo) to yield 17.7 gm of the desired compound. Rf is 0.70 (eluted from silica gel with 10% conc. NH3 /CH3OH).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[N:8][CH:9]=1)([O-:3])=[O:2].[C:11]([CH:14]1[CH2:18][CH2:17][O:16][C:15]1=O)(=O)[CH3:12].P(Cl)(Cl)([Cl:22])=O>CC1C=CC=CC=1>[Cl:22][CH2:17][CH2:18][C:14]1[C:15](=[O:16])[N:8]2[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]2=[N:10][C:11]=1[CH3:12]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)C1CCOC1=O
Reactant: Nc1ccc([N+](=O)[O-])cn1
Solvent: Cc1ccccc1
Product: Cc1nc2ccc([N+](=O)[O-])cn2c(=O)c1CCCl
Temperature: 25 °C

Procedure:
A mixture of 90 parts of 5-nitro-2-pyridinamine, 90 parts of 3-acetyl-4,5-dihydro-2(3H)-furanone and 810 parts of methylbenzene was stirred at room temperature. 510 Parts of phosphoryl chloride were added dropwise during a 1 hour-period: the temperature rose to 40° C. The reaction mixture was heated slowly to reflux and the whole was stirred and refluxed for 5 hours. The solvent was evaporated. The hot residue was poured onto a mixture of crushed ice and ammonium hydroxide. After stirring for 30 minutes, the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane, yielding 54.8 parts of 3-(2-chloroethyl)-2-methyl-7-nitro-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 170° C. (intermediate 8).
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH2:8][C@H:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[CH:19][C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[CH3:10].C([O:35][N+:36]([O-])=[O:37])C(C)C.C(O)(=O)C>C(O)(C)(C)C.ClCCl>[OH:7][CH2:8][C@H:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[C:19]([N+:36]([O-:37])=[O:35])[C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[CH3:10]
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)CO[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C([N+](=O)[O-])C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Potassium tert-butoxide (7.6 g, 67.8 mM), (20S)-20-hydroxymethylpregn-4-en-3-one (6.6 g, 20 mM) in tert-butanol is heated at reflux temperature for 60 minutes under an argon atmosphere. Isobutylnitrate (2.34 ml, 20 mM) is then added in one continuous portion. After 20 minutes of further refluxing, the reaction vessel is cooled to room temperature. Acetic acid (10 ml) is then added, and the reaction vessel stirred for 18 hours, after which the combination is diluted with dichloromethane (200 mL). The solids are removed, washed, and recombined with the washing residue and subsequently purified as described in Example 1 to give crystallized (20S)-20-hydroxymethyl-4-nitropregn-4-en-3-one.
Reaction SMILES: P(OCC)(OCC)(OCC)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:26]1(=[O:33])[CH2:31][CH2:30][CH2:29][C:28](=O)[CH2:27]1.[Br:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[C:37]([S:43]([CH3:46])(=[O:45])=[O:44])[CH:36]=1.[F:47][C:48]([F:60])([F:59])[C:49]1[CH:50]=[C:51]([NH:55][C:56]([NH2:58])=[O:57])[CH:52]=[CH:53][CH:54]=1>COC(C)(C)C>[Br:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]2[C:27]3[C:26](=[O:33])[CH2:31][CH2:30][CH2:29][C:28]=3[N:55]([C:51]3[CH:52]=[CH:53][CH:54]=[C:49]([C:48]([F:59])([F:60])[F:47])[CH:50]=3)[C:56](=[O:57])[NH:58]2)=[C:37]([S:43]([CH3:46])(=[O:45])=[O:44])[CH:36]=1
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: O=C1CCCC(=O)C1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: COC(C)(C)C
Solvent: CCOP(=O)(OCC)OCC
Product: CS(=O)(=O)c1cc(Br)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Temperature: 50 °C

Procedure:
A mixture of triethyl phosphate (400 μL, 428 mg, 2.35 mmol) and phosphorous pentoxide (216 mg, 1.52 mmol) is heated at 50° C. over night and dilutet with tert-butyl methyl ether (10 mL). Cyclohexane-1,3-dione (320 mg, 2.85 mmol), 4-bromo-2-(methylsulfonyl)benz-aldehyde (500 mg, 1.90 mmol) and 1-(3-(trifluoromethyl)phenyl)urea (388 mg, 1.90 mmol) are added, and the mixture is heated at reflux over night and concentrated under reduced pressure. The residue is purified by reversed phase HPLC (Agilent ZORBAX™+SB-C18, gradient of acetonitrile in water, 0.15% formic acid). Yield: 80 mg; ESI mass spectrum [(79Br)-M+H]+=543, [(81Br)-M+H]+=545, Retention time HPLC: 1.06 min (Z017_S04).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[NH:10]N.C[CH2:13][O:14][C:15]([CH2:17][CH:18]1[C:23](=O)[CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:16]>>[Cl:1][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:10]2[C:23]3[CH:18]([CH2:17][C:15]([O:14][CH3:13])=[O:16])[CH2:19][CH2:20][CH2:21][C:22]=3[C:5]3[C:4]2=[C:3]([CH3:2])[CH:8]=[C:7]([CH3:9])[CH:6]=3)=[CH:4][CH:5]=1
Reactant: Cl
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: Cc1ccc(NN)c(C)c1
Product: COC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1c(C)cc(C)cc21

Procedure:
Following the procedure of Example 30, but using 1-(2,4-dimethylphenyl) hydrazine hydrochloride and ethyl 2-cyclohexanone acetate in Step I, as starting materisl, the title compound is prepared.
Reaction SMILES: Cl.[CH2:2]([NH:6][C:7](=[O:15])[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH3:5].[H][H]>C(O)C.O.[Rh]>[CH2:2]([NH:6][C:7](=[O:15])[NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH2:3][CH2:4][CH3:5]
Reactant: [H][H]
Reactant: CCCCNC(=O)Nc1ccncc1
Agent: [Rh]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCCNC(=O)NC1CCNCC1
Yield: 19.4 %

Procedure:
A solution of 3-n-butyl-1-(4-pyridyl)urea hydrochloride (37.4 g) in ethanol-water (1:1, 400 ml) containing 5% rhodium/alumina catalyst (10 g) was hydrogenated (50°, 750 psi) until no further uptake of hydrogen occurred. The catalyst was then removed by filtration and the solvent evaporated to leave an oil which partially solidified on storage at 0°. The solid was separated, treated with base, extracted with chloroform/n-butanol, the extracts evaporated and the residue recrystallized twice from ethyl acetate to give 3-n-butyl-1-(4-piperidyl)urea, (6.3 g), m.p. 132°-134°.
Reaction SMILES: C(C1COC(=O)N1[C:14](=[O:32])[CH:15]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:18])C1C=CC=CC=1.[OH:33]O.[Li+].[OH-]>C1COCC1.O>[CH:26]1([CH2:25][CH:15]([CH2:16][C:17]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)=[O:18])[C:14]([OH:32])=[O:33])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: OO
Reactant: O=C(CC(CC1CCCCC1)C(=O)N1C(=O)OCC1Cc1ccccc1)N1CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(CC(=O)N1CCOCC1)CC1CCCCC1

Procedure:
A 0.05 M solution of 1-(4-benzyl-2-oxo-oxazolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-butane-1,4-dione (1 g) in 3:1 —THF/H2O was treated at 0° C. with 8 equivalents of 30% H2O2 followed by 2.0 equivalents of LiOH. The resulting mixture was stirred at 0–25° C. until the substrate had been consumed (approximately 1 hour). The excess peroxide was quenched at 0° C. with a 10% excess of 1.5 N aqueous Na2SO3. After buffering to pH 9–10 with aqueous NaHCO3 and evaporation of the THF, the oxazolidone chiral auxiliary was recovered by MeCl2 extraction. The carboxylic acid was isolated by EtOAc extraction of the acidified (pH 1–2) aqueous phase, then recrystallized from EtOAc and hexane to yield 0.58 g of 2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid; H1NMR (DMSO-δ): 12(1H, s, COOH), 3.6–3.3(8H, m), 2.8–2.3(3H, m), 1.8–1.1(l 1H, m), 0.9–0.7(2H, m); MS: 282.2(M−1), 284.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9]Cl)=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17]C)[CH:12]=2)[N:5]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1.[CH3:25][S:26]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27].COC1C=C(C2C3CCN(C4C=CC=C(S(C)(=O)=O)C=4)C=3N=C(N3CCOCC3)N=2)C=CC=1>>[CH3:25][S:26]([C:29]1[CH:35]=[CH:34][C:32]([N:33]2[C:2]3[N:3]=[C:4]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:5]=[C:6]([C:11]4[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=4)[C:7]=3[CH2:8][CH2:9]2)=[CH:31][CH:30]=1)(=[O:27])=[O:28]
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Agent: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2cccc(S(C)(=O)=O)c2)c1
Product: CS(=O)(=O)c1ccc(N2CCc3c(-c4cccc(O)c4)nc(N4CCOCC4)nc32)cc1

Procedure:
In the same manner as Example 1-A-01, from 4-[4-chloro-5-(2-chloroethyl)-6-(3-methoxyphenyl)-pyrimidin-2-yl]-morpholine and 4-methanesulfonylaniline, 4-(3-methoxy-phenyl)-7-(3-methanesulfonylphenyl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine was obtained, and subsequently, further in the same manner as Example 1-A-09, the desired compound was obtained.
Reaction SMILES: [C:1]([C:7]1[CH:8]=[CH:9][C:10]([O:15][CH3:16])=[C:11]([CH:14]=1)[CH2:12][OH:13])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[OH-].[K+].[O-:19][Mn](=O)(=O)=O.[K+]>O1CCOCC1.O>[C:1]([C:7]1[CH:8]=[CH:9][C:10]([O:15][CH3:16])=[C:11]([CH:14]=1)[C:12]([OH:19])=[O:13])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: COc1ccc(C(=O)C(C)(C)C)cc1CO
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(C(=O)C(C)(C)C)cc1C(=O)O
Temperature: 25 °C
Yield: 83.9 %

Procedure:
5-Pivaloyl-2-methoxy benzyl alcohol (1.19 g, 5.35 mmol) was dissolved in dioxane (20 ml). A solution of KOH (0.449 g, 8.025 mmol in water (5 ml) was added followed by KMnO4 (1.69 g, 10.7 mmol). The mixture was allowed to stir at room temperature over the weekend. The solution was filtered through Celite and extracted with ether. The aqueous phase was acidified with dil. HCl and extracted with ether (3×50 ml). The organic layer was dried over magnesium sulphate and concentrated in vacuo to afford the title compound as a white solid (1.06 g).
Reaction SMILES: C(OCC)(=O)C.[OH:7][C:8]1[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=1)[NH:11][C:12](=[O:16])[C:13]([CH3:15])=[CH2:14].[C:20]1([N:26]=[C:27]=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(N(CC)CC)C>[C:20]1([NH:26][C:27]([O:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[NH:11][C:12](=[O:16])[C:13]([CH3:15])=[CH2:14])=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C=Nc1ccccc1
Reactant: C=C(C)C(=O)Nc1cccc(O)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=C(C)C(=O)Nc1cccc(OC(=O)Nc2ccccc2)c1
Temperature: 65 °C

Procedure:
A reaction vessel is charged with 100 parts of ethyl acetate and 17.7 parts of 3'-hydroxy-2-methylacrylanilide and heated with stirring to about 65°C. Phenyl isocyanate, 12 parts, is added. No apparent reaction occurs until one part of triethylamine is added to the reaction mixture. After a slight exothermic increase in temperature, the reaction mixture is heated at reflux for one-half hour, cooled and filtered. The solids are washed with ethyl acetate and air dried to give 22.8 parts of 3'-(phenylcarbamoyloxy)-2-methylacrylanilide, m.p. 177°-178°C.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].CS(O[CH2:18][C@H:19]1[O:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]1)(=O)=O.O>CN(C=O)C>[O:6]=[C:4]1[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:1](=[O:11])[N:5]1[CH2:18][C@H:19]1[O:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:20]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](COS(C)(=O)=O)C1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@H](CN2C(=O)c3ccccc3C2=O)C1
Temperature: 112.5 °C
Reaction time: 16 h
Yield: 86388.6 %

Procedure:
Potassium phthalimide (28.4 g 0.15 mol) was added to a solution of (S)-tert-butyl 2-((methylsulfonyloxy)methyl)morpholine-4-carboxylate (37.7 g, 0.13 mmol) in DMF (256 mL). The resulting mixture was stirred at 110-115° C. for 16 hr, and then cooled to room temperature and poured into water (500 mL). The aqueous layer was extracted with CH2Cl2 (3×250 mL). The combined organic layers were then washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was diluted in hexanes (200 mL) and then stirred vigorously while adding slowly Et2O (100 mL). The oil turned into a solid, which was filtered on a Buchner funnel. The filter cake was washed with hexanes and dried under reduced pressure. The mother liquor was concentrated, and the crude residue purified by silica gel flash chromatography (10-60% EtOAc in hexanes) to produce a second crop of solid. Both solids were combined to provide the title compound (38.9 g, 88%). 1H NMR (300 MHz, CDCl3) δ ppm 1.45 (s, 9 H), 2.68-2.82 (m, 1H), 2.91-3.04 (m, 1H), 3.44 (dt, J=11.45, 2.81 Hz, 1H), 3.63-3.79 (m, 3H), 3.82-4.03 (m, 3H), 7.70-7.78 (m, 2H), 7.84-7.88 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C@H:10]2[C:23](=[O:29])[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:30](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C@H:10]2[C:23](=[O:29])[N:24]([CH3:30])[S:25]([CH3:28])(=[O:27])=[O:26])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](C(=O)NS(C)(=O)=O)C1
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
To a solution of tert-butyl (6R,7R)-7-(3,4-dichlorophenyl)-6-[(methylsulfonyl)carbamoyl]-1,4-oxazepane-4-carboxylate (246 mg) in DMF (3 mL) were added potassium carbonate (109 mg) and methyl iodide (0.049 mL) at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (174 mg).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:30][C:31]([F:43])([F:42])[O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:35]=[CH:34][C:33]([O:32][C:31]([F:30])([F:42])[F:43])=[CH:38][CH:37]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccc(OC(F)(F)F)cc2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 4-trifluoromethoxybenzene boronic acid. The title compound was obtained in 84% yield as white foam. MS (m/e): 566.4 (MH+, 100%).
Reaction SMILES: [S:1]([Cl:5])(=[O:4])(=[O:3])[NH2:2].[N:6]1([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[O:14][CH2:15][CH2:16][OH:17])[CH:10]=[CH:9][N:8]=[CH:7]1.Cl>C(#N)C>[ClH:5].[N:6]1([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[O:14][CH2:15][CH2:16][O:17][S:1](=[O:4])(=[O:3])[NH2:2])[CH:10]=[CH:9][N:8]=[CH:7]1
Reactant: OCCOc1cccc(-n2ccnc2)c1
Reactant: NS(=O)(=O)Cl
Agent: Cl
Solvent: CC#N
Product: NS(=O)(=O)OCCOc1cccc(-n2ccnc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 50 %

Procedure:
A solution of sulfamoyl chloride (0.0275 mole) in 60 ml of acetonitrile was treated dropwise with a solution of 5.1 g (0.025 mole) of 2-[3-(1H-imidazol-1-yl)phenoxy]ethanol in 100 ml of acetonitrile. The mixture was stirred at ambient temperature under nitrogen for 20 hr. The mixture was concentrated under vacuum, and the residue was partitioned between ethyl acetate and dilute potassium carbonate solution. The organic fraction was again concentrated under vacuum to a crystalline residue. This residue was dissolved in warm 95% ethanol and treated with 1 equivalent of anhydrous hydrogen chloride. The solution was chilled and the precipitate was collected and dried to give 4.0 g (50%) of the title compound as a pink powder, mp 149.0°-150.0° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl[O:10][C:11](C)(C)[CH3:12].CSCC(OCC)=O.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][CH:3]=1)[NH:6][C:11](=[O:10])[CH2:12]2
Reactant: Nc1ccc(F)cc1
Reactant: CC(C)(C)OCl
Agent: CCOC(=O)CSC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1Cc2cc(F)ccc2N1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 11.1 g (0.1 mol) of 4-fluoroaniline in 200 ml of dichloromethane, at -60° to -65° C., was added, dropwise, a solution of 10.8 g (0.1 mol) of t-butyl hypochlorite in 25 ml of dichloromethane. Stirring was continued for 10 minutes at -60° to -65° C., and then was added, dropwise, a solution of 13.4 g (0.1 mol) of ethyl 2-(methylthio)acetate in 25 ml of dichloromethane. Stirring was continued at -60° C. for 1 hour and then was added, dropwise, at -60° to -65° C., a solution of 11.1 g (0.11 mol) of triethylamine in 25 ml of dichloromethane. The cooling bath was removed, and when the reaction mixture had warmed to room temperature, 100 ml of water was added. The phases were separated, and the organic phase was washed with saturated sodium chloride solution, dried (Na2SO4) and evaporated in vacuo. The residue was dissolved in 350 ml of diethyl ether, to which was added 40 ml of 2N hydrochloric acid. This mixture was stirred at room temperature overnight. The phases were separated and the ether phase was washed