Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([O:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)=[CH:4][N:3]=1.[F-:18].[Cs+]>CS(C)=O.O>[F:18][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([O:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)=[CH:4][N:3]=1
Reactant: Fc1ccc2c(OCC3CC3)cnc(Cl)c2c1
Reactant: [F-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Fc1ccc2c(OCC3CC3)cnc(F)c2c1
Temperature: 145 °C
Yield: 65.8 %

Procedure:
To a solution of 1-Chloro-4-(cyclopropylmethoxy)-7-fluoroisoquinoline (0.7 g, 2.78 mmol) in DMSO (5 mL) was added cesium fluoride (1.0 g, 6.95 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 145° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (0.43 g, 65%) as white solid. 1H NMR (400 MHz, CD3OD): δ ppm 8.35-8.33 (m, 1H), 7.77-7.74 (d, J=12 Hz, 1H) 7.73 (t, J=8 Hz, 1H), 7.52-7.51 (d, J=4 Hz, 1H), 4.10-4.08 (d, J=8 Hz, 2H), 1.42-1.40 (m, 1H), 0.74-0.69 (m, 2H), 0.49-0.46 (m, 2H); MS: MS m/z 237.0 (M++1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=3)[CH:11]=[C:10]([C:22]([F:25])([F:24])[F:23])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:26]([NH:30][S:31]([C:34]1[S:35][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:38]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][S:31]([C:34]1[S:35][C:36]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([C:22]([F:23])([F:25])[F:24])[CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=4)[N:13]=3)[CH:3]=2)=[CH:37][CH:38]=1)(=[O:32])=[O:33])([CH3:29])([CH3:27])[CH3:28]
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cc1F
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)c2)s1

Procedure:
N-tert-Butyl-5-{3-[6-(3,4-difluoro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromo-phenyl)-4-(3,4-difluoro-phenyl)-6-trifluoromethyl-pyrimidine (example E.101) (0.415 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.414 g, 1.2 mmol) according to the general procedure VI. Obtained as white foam (0.37 g), which was subsequently deprotected.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:23]=[CH:22][N:21]=[C:20]3[NH:24][N:25]=[C:26]([O:27][CH2:28][CH2:29]O)[C:19]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.CN(C=O)C.S(Cl)([Cl:38])=O>>[Cl:38][CH2:29][CH2:28][O:27][C:26]1[C:19]2[C:20](=[N:21][CH:22]=[N:23][C:18]=2[NH:17][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=3)=[C:2]([Cl:1])[CH:3]=2)[NH:24][N:25]=1
Reactant: OCCOc1n[nH]c2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Fc1cccc(COc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2Cl)c1

Procedure:
2-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]oxy}ethanol (prepared as described in Example 1/550 mg, 1.28 mmol) was dissolved in thionyl chloride (4 ml). DMF (20 μl) was added and the mixture refluxed for 2 hours under a dry atmosphere. After evaporation of the solvent under reduced pressure, the solid residue was triturated in ether, filtered and dried under vacuum to provide the title compound as a hydrochloride salt (551 mg, 89%); NMR Spectrum: 4.03 (t, 2H), 4.58 (t, 2H), 5.28 (s, 2H), 7.18 (t, 1H), 7.29-7.34 (m, 3H), 7.45-7.53 (m, 2H), 7.83 (s, 1H), 8.32 (s, 1H), 9.25 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N+:15]([O-:17])[CH3:16])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:29]=[CH:28][C:22]([CH2:23][O:24][CH2:25][CH:26]=[CH2:27])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][O:24][CH2:25][CH:26]2[O:17][N:15]([CH3:16])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([CH2:9][N:10]3[CH:14]=[CH:13][N:12]=[CH:11]3)[CH2:27]2)=[CH:28][CH:29]=1
Reactant: C[N+]([O-])=C(Cn1ccnc1)c1ccc(Cl)cc1
Reactant: C=CCOCc1ccc(Cl)cc1
Product: CN1OC(COCc2ccc(Cl)cc2)CC1(Cn1ccnc1)c1ccc(Cl)cc1

Procedure:
Derivative 3 (R1 =4-Cl, R2 =CH2C6H4Cl-4 is prepared by a procedure similar to that described in Example 1 by reacting 1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)-N-methylethanimine N-oxide (1: R1 =4-Cl) with allyl 4-chlorobenzyl ether (2: R2 =CH2C6H4Cl-4). The resulting cis-/trans-diastereomeric mixture of the title compound (3: R1 =4-Cl, R2 =CH2C6H4Cl-4) is flash-chromatographed on neutral silica gel using chloroform-methanol (98:2 by volume) as eluent.
Reaction SMILES: [Si]([C:8]1([OH:28])[C:21]2[O:22][C@@H:18]3[C@@:19]45[CH2:23][CH2:24][N:25]([CH3:26])[C@@H:13]([C@@H:14]4[CH:15]=[CH:16][C@@H:17]3[OH:27])[CH2:12][C:11]([C:20]5=2)=[CH:10][CH2:9]1)(C(C)(C)C)(C)C.[CH3:29][N:30]1[C@@H:47]2[CH2:48][C:35]3[CH:36]=[CH:37][C:38]([O:50][CH3:51])=[C:39]4[O:40][C@H:41]5[C:42]([CH2:44][CH2:45][C@:46]2([OH:49])[C@:33]5([C:34]=34)[CH2:32][CH2:31]1)=[O:43].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([C@@]12OC3=C(O[SiH](C)C)C=CC4C[C@H]5N(CC[C@]1([C@H]5C=C[C@@H]2O)C=43)C)CCC>C1COCC1>[CH:10]1[C:11]2[CH2:12][C@H:13]3[N:25]([CH2:24][CH2:23][C@@:19]45[C@H:14]3[CH:15]=[CH:16][C@H:17]([OH:27])[C@@H:18]4[O:22][C:21]([C:20]=25)=[C:8]([OH:28])[CH:9]=1)[CH3:26].[CH3:29][N:30]1[C@@H:47]2[CH2:48][C:35]3[CH:36]=[CH:37][C:38]([O:50][CH3:51])=[C:39]4[O:40][C@H:41]5[C:42]([CH2:44][CH2:45][C@:46]2([OH:49])[C@:33]5([C:34]=34)[CH2:32][CH2:31]1)=[O:43]
Reactant: CN1CC[C@]23C4=C5O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1CC4=CCC5(O)[Si](C)(C)C(C)(C)C
Agent: CCCC[C@@]12Oc3c(O[SiH](C)C)ccc4c3[C@@]13CCN(C)[C@H](C4)[C@@H]3C=C[C@@H]2O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Solvent: C1CCOC1
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5

Procedure:
To a solution of 3-tert-butyldimethylsilylmorphine (1 eq.) and the oxycodone-linker oxime from step 1 (1 eq.) in an anhydrous solvent such as THF (approximately 0.1 M) is added 2 equivalents of diethyl azodicarboxylate (DEAD) and 2 equivalents of triphenylphosphine. The resulting mixture is stirred at ambient temperature until the 3 -ten-butyldimethylsilylmorphine and/or the oxycodone-linker oxime is consumed, as monitored by TLC or HPLC. The resulting mixture is then subjected to an aqueous work up, and the product is purified by silica gel column chromatography or preparatory HPLC to provide the protected hybrid morphine-oxycodone compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]3[C:11]([CH2:12][C:13](=[O:35])[N:14]([CH2:22][C:23]([N:25]([CH:32]([CH3:34])[CH3:33])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:24])[C:15]4[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=43)=[N:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]([CH:45]=O)=[CH:37]1>>[OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]3[C:11]([C:12](=[CH:45][C:38]4[C:39]5[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=5)[NH:36][CH:37]=4)[C:13](=[O:35])[N:14]([CH2:22][C:23]([N:25]([CH:32]([CH3:33])[CH3:34])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:24])[C:15]4[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=43)=[N:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N(C(=O)CN1C(=O)Cc2nnc(-c3cccc(O)c3)n2-c2ccccc21)c1ccccc1
Reactant: O=Cc1c[nH]c2ccccc12
Product: CC(C)N(C(=O)CN1C(=O)C(=Cc2c[nH]c3ccccc23)c2nnc(-c3cccc(O)c3)n2-c2ccccc21)c1ccccc1
Yield: 57.3 %

Procedure:
Following the procedure described for Example 1(A), Step A, 2-[1-(3-hydroxy-phenyl)-5-oxo-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-phenyl-acetamide (Preparation 12) (244 mg, 0.522 mmol) was condensed over 48 hours with 1H-indole-3-carbaldehyde (105 mg, 0.723 mmol). Purification by medium pressure chromatography eluting with a solvent gradient (EtOAc to 5% MeOH in EtOAc to 10% MeOH in EtOAc) yielded 177.9 mg of 2-[1-(3-hydroxy-phenyl)-4-(1H-indol-3-ylmethylene)-5-oxo-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-phenyl-acetamide. 1H NMR (CD3OD) δ 8.23 (d, 1H), 7.90 (s, 1H), 6.90-7.63 (m, 16H), 4.95 (m, 1H), 3.68-4.50 (m, 3H), 1.11 (m, 6H); MS 595.3 (M+1), 593.3 (M−1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-])=O)=[O:8]>[Pd].CO>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16])=[O:8]
Reactant: NCCCCCC(=O)Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: NCCCCCC(=O)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4 (6.40 g, 25.7 mmol), 10% Pd—C (0.5 g), and methanol (200 mL) was stirred under a hydrogen balloon at room temperature for 3 hours. The catalyst was filtered off and washed with additional methanol. Solvent was removed in vacuo to give 5.8 g of Template 1 as an off white solid LC-MS (M++1) 222. 1H NMR (DMSO-d6) δ 1.34 (m, 4H), 1.57 (m, 2H), 2.29 (t, J=5.4 Hz, 2H), 2.49 (br, s, 2H), 2.54 (t, J=5.4 Hz, 2H), 4.32 (br, s, 2H), 6.52 (dd, J=6 Hz, J=6 Hz, 1H), 6.70 (d, J=6 Hz, 1H), 6.87 (dd, J=6 Hz, J=6 Hz, 1H), 7.15 (d, J=6 Hz, 1H), 9.14 (br, s, 1H).
Reaction SMILES: C(SC1C=C(O)C(=O)NC=1)C1C=CC=CC=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][S:25][C:26]2[CH:27]=[C:28]([O:36]COC)[C:29](=[O:35])[N:30](COC)[CH:31]=2)=[N:22][CH:23]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][S:25][C:26]2[CH:27]=[C:28]([OH:36])[C:29](=[O:35])[NH:30][CH:31]=2)=[N:22][CH:23]=1
Reactant: COCOc1cc(SCc2ccc(Cl)cn2)cn(COC)c1=O
Agent: O=c1[nH]cc(SCc2ccccc2)cc1O
Product: O=c1[nH]cc(SCc2ccc(Cl)cn2)cc1O

Procedure:
Prepared as described for 5-(benzylsulfanyl)-3-hydroxypyridin-2(1H)-one (Example 12) from 5-{[(5-chloropyridin-2-yl)methyl]sulfanyl}-3-(methoxymethoxy)-1-(methoxymethyl)pyridin-2(1H)-one (Intermediate 24).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5]([CH2:7]Cl)=[CH2:6])[CH3:2].[CH2:10]([O:12][P:13]([CH2:18][CH:19]([CH2:29][OH:30])[CH2:20][P:21](=[O:28])([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24])(=[O:17])[O:14][CH2:15][CH3:16])[CH3:11].C(N(CC)CC)C>C1COCC1>[CH2:23]([O:22][P:21]([CH2:20][CH:19]([CH2:29][O:30][CH2:7][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:9])=[CH2:6])[CH2:18][P:13](=[O:17])([O:14][CH2:15][CH3:16])[O:12][CH2:10][CH3:11])(=[O:28])[O:25][CH2:26][CH3:27])[CH3:24]
Reactant: C=C(CCl)C(=O)OCC
Reactant: CCOP(=O)(CC(CO)CP(=O)(OCC)OCC)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(COCC(CP(=O)(OCC)OCC)CP(=O)(OCC)OCC)C(=O)OCC
Temperature: 70 °C
Reaction time: 45 h
Yield: 47.5 %

Procedure:
Ethyl-2-(chloromethyl)-acrylate (3.86 g, 26.0 mmol, 1.5 eq.) was added to a solution of 2-hydroxymethyl-1,3-propylene-bisphosphonic acid tetraethylester (6.0 g, 17.3 mmol) and triethylamine (3.62 ml, 26 mmol, 1.5 eq.) in anhydrous THF (30 ml), and the reaction mixture was stirred for 45 h at 70° C. After concentrating in vacuo deionized water (50 ml) was added and the obtained solution was extracted with ethylacetate (3×50 ml). The combined organic phases were dried with anhydrous sodium sulphate. After removal of the solvent under reduced pressure the obtained crude product was purified by column chromatography (eluent: ethylacetate/methanol 98:2). 3.77 g (48% yield) of the product was obtained as a yellowish oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[N:9]=[N:10][C:11](Cl)=[C:12]([CH3:15])[C:13]=1[CH3:14]>>[Cl:7][C:8]1[N:9]=[N:10][C:11]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[C:12]([CH3:15])[C:13]=1[CH3:14]
Reactant: C1CNCCN1
Reactant: Cc1c(Cl)nnc(Cl)c1C
Product: Cc1c(Cl)nnc(N2CCNCC2)c1C

Procedure:
Compound 55 is prepared as described above from piperazine and 3,6-dichloro-4,5-dimethyl-pyridazine.
Reaction SMILES: [OH:1][C:2]([CH3:23])([CH3:22])[CH:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]1[CH3:21])[CH3:4].[H-].[Na+].I[CH3:27]>C1COCC1>[CH3:27][O:1][C:2]([CH3:22])([CH3:23])[CH:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]1[CH3:21])[CH3:4]
Reactant: Cc1c(C(=O)OC(C)(C)C)c2ccccc2n1C(C)C(C)(C)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)(C)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2ccccc21
Temperature: 45 °C
Yield: 95.2 %

Procedure:
To a solution of (±)-tert-butyl 1-(3-hydroxy-3-methylbutan-2-yl)-2-methyl-1H-indole-3-carboxylate (0.2594 g, 0.817 mmol) and THF (8 mL), in a 50 mL round bottom flask, cooled to 0° C. was added sodium hydride (0.065 g, 1.634 mmol). The reaction was then heated at 45° C. for 2 h then iodomethane (0.102 ml, 1.634 mmol) was added and the reaction was heated at that temperature overnight. The reaction was quenched with 1N HCl and brine, extracted with EtOAc, dried over Na2SO4, filtered, concentrated, deposited onto silica gel with aid of DCM, and purified by column chromatography using 5% EtOAc in Hex as eluent to provide (±)-tert-butyl 1-(3-methoxy-3-methylbutan-2-yl)-2-methyl-1H-indole-3-carboxylate (257.8 mg, 95%). LRMS (M+H+) m/z: calcd 332.45. found 332.2.
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH2:18][CH:19]([OH:24])[CH2:20][C:21]([OH:23])=O)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C([O-])=O.[Na+]>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[N:1]1([C:8]2[CH:9]=[CH:10][C:11]([S:14]([N:17]3[CH2:18][CH:19]([OH:24])[CH2:20][C:21]3=[O:23])(=[O:16])=[O:15])=[CH:12][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CC(O)CNS(=O)(=O)c1ccc(N2CCCCCC2)cc1
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C1CC(O)CN1S(=O)(=O)c1ccc(N2CCCCCC2)cc1
Reaction time: 3 h

Procedure:
6.3 g of the product obtained in Stage A above, 30 cm3 of trifluoroacetic anhydride and 6.3 g of sodium trifluoro-acetate are agitated under reflux for 12 hours. The mixture is evaporated to dryness, cooled down and the residue is taken up immediately in 120 cm3 of a 5% solution of sodium bicarbonate then in 350 cm3 of methanol. Agitation is carried out for 3 hours at ambient temperature, the mixture is concentrated to a reduced volume at 30° C. then extracted with methylene chloride, the extracts are dried and evaporated. The residue is chromatographed on silica (eluant: ethyl acetate - hexane (8-2)) after crystallization from ethanol, 2.1 g of desired product, M.p.=170-172° C., and 0.3 g of the corresponding delta-3,4 derivative are obtained.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)(=[O:13])=[O:12].Cl[C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=1>>[Cl:27][C:26]1[C:21]([N:17]2[CH2:18][CH2:19][CH:14]([S:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)(=[O:12])=[O:13])[CH2:15][CH2:16]2)=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=S(=O)(c1ccc2ccccc2c1)C1CCNCC1
Reactant: Clc1cccnc1Cl
Product: O=S(=O)(c1ccc2ccccc2c1)C1CCN(c2ncccc2Cl)CC1
Yield: 48.8 %

Procedure:
Using the procedure from Example 7A, Step 7E, 4-(2-naphthylsulfonyl)piperidine (Example 11, Step 3, 175 mg, 0.63 mmol) was reacted with 2,3-dichloropyridine (188 mg, 1.3 mmol) to afford the title compound (119 mg), a white solid, in 48% yield.
Reaction SMILES: Cl.[NH:2]=[C:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH3:8].C1C=CC=CC=1.[OH-].[Na+].[C:17]1([CH3:26])[C:18]([N:23]=[C:24]=[O:25])=[CH:19][CH:20]=[CH:21][CH:22]=1>O>[CH3:8][N:4]1[CH2:5][CH2:6][CH2:7][C:3]1=[N:2][C:24]([NH:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH3:26])=[O:25]
Reactant: Cc1ccccc1N=C=O
Reactant: CN1CCCC1=N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: Cc1ccccc1NC(=O)N=C1CCCN1C

Procedure:
A 6.73 g. (0.05 mole) sample of 2-imino-1-methylpyrrolidine HCl is treated with 50 ml. of benzene and 2 ml. of water. With stirring, 10 ml. of 50% sodium hydroxide is added. After stirring about one minute, the benzene layer is decanted onto anhydrous K2CO3 and the extraction repeated twice with 50 ml. portions of benzene. The dried, combined extracts are filtered from the drying agent and the filtrate is treated with 6.66 g. (0.05 mole) of o-tolylisocyanate. After stirring overnight, the mixture is filtered from a small amount of insoluble material and the solvent removed in vacuo. Recrystallization from ethyl acetate and finally from ether gives the pure product, 1-(1-methyl-2-pyrrolidylidene)-3-o-tolyl urea. m.p. = 91°-93° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:18](=[O:20])[NH2:19])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1(C)C=CC(S(O)(=O)=O)=C[CH:22]=1>C(O)C>[CH2:21]([O:16][C:15](=[O:17])[CH2:14][CH2:13][C@@H:12]([C:18](=[O:20])[NH2:19])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[CH3:22]
Reactant: NC(=O)[C@H](CCC(=O)O)NC(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(N)=O

Procedure:
A suspension of 15.98 g of N-Benyloxycarbonyl-L-isoglutamine in 500 mL of absolute ethanol containing 0.54 g of p-toluenesulfonic acid is refluxed for 12 hours until TLC indicated that the reaction is complete. The solution is concentrated to a small volume and addition f ether gave a solid. The solid is filtered and recrystallized to give 16.0 of N-Benyloxycarbonyl-L-isoglutamine ethyl ester, 16.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]OS(C)(=O)=O)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[CH3:23])=[O:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[Cl-:35].[K+].CS(C)=O>O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][Cl:35])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[CH3:23])=[O:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(CN(CCCCCCOS(C)(=O)=O)C(=O)Nc2ccc(Cl)cc2C)cc1
Reactant: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCc1ccc(CN(CCCCCCCl)C(=O)Nc2ccc(Cl)cc2C)cc1
Yield: 85 %

Procedure:
A mixture of 2.0 g of 1-[(4-butylphenyl)methyl]-3-(4-chloro-2-methylphenyl)-1-[6-[(methylsulfonyl)oxy]-hexyl]urea, 0.74 g of potassium chloride, and 3.0 ml of dimethyl sulfoxide was heated at an oil bath temperature of 60°-80° C. for 16 hours. The mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with three 40 ml portions of brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated in vacuo to yield 1.5 g of a brown oil. The oil was purified by chromatography to yield 1.5 g of the desired product as a light yellow oil in 86% yield.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[NH2:19][CH:20]([CH:30]([CH3:32])[CH3:31])[CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]>C(O)C>[Br:1][C:2]1[C:3]([NH:19][CH:20]([CH:30]([CH3:32])[CH3:31])[CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CC(C)C(N)CNC(=O)OC(C)(C)C
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(CNC(=O)OC(C)(C)C)Nc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 5-bromo-2,4-dichloro-pyrimidine 7.11 g (0.0312 mole) in ethanol (100 mL) was added diisopropylethyl amine 5.45 mL (1.0 eq) and tert-butyl N-(2-amino-3-methyl-butyl)carbamate 6.31 g (0.0312 mole). The reaction mixture was stirred at room temperature for 20 hrs. After concentration under vacuum, ethyl acetate and water was added. The organic layer was separated, dried with magnesium sulfate and then concentrated under vacuum. The crude product was purified by column chromatography using hexane/ethyl acetate (0-30%) over silica gel to afford tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate. 1H NMR (600 MHz, DMSO-d6) δ ppm 0.77-0.85 (d, J=6.5 Hz, 3H) 0.87 (d, J=6.73 Hz, 3H) 1.31-1.39 (m, 9H) 1.82-1.93 (m, 1H) 2.94 (d, J=5.56 Hz, 1H) 3.08-3.22 (m, 2H) 3.98 (d, J=8.20 Hz, 1H) 6.96 (d, J=8.78 Hz, 1H) 8.21 (s, 1H). LCMS (ESI) 393 (M+H).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[F:28][C:29]1([F:35])[CH2:31][CH:30]1[C:32](O)=[O:33]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32]([CH:30]5[CH2:31][C:29]5([F:35])[F:28])=[O:33])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)C1CC1(F)F
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)C1CC1(F)F

Procedure:
The title compound, white solid (92 mg, 85%), MS (ISP) m/z=435.4 [(M+H)+], mp 184.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 2,2-difluorocyclopropane-carboxylic acid.
Reaction SMILES: N1C2C(=CC(C(OCC3C=CC=CC=3)=O)=CC=2)C=C1.Br[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[O:32][CH3:33].[I-:34].[K+]>CN(C)C=O>[I:34][CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[O:32][CH3:33]
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: [I-]
Agent: O=C(OCc1ccccc1)c1ccc2[nH]ccc2c1
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CI)c(OC)c1
Yield: 26.3 %

Procedure:
A solution of benzyl indole-5-carboxylate (86.8 g), methyl 4-bromomethyl-3-methoxybenzoate (89.5 g) and potassium iodide (57.4 g) in N,N-dimethylformamide (900 mL) was heated to 80° C. for 10 hours. The reaction mixture was evaporated and partitioned between diethyl ether and water. The organic layer was separated and washed with water. The aqueous washes were combined and extracted with diethyl ether. The combined organic extract was dried (MgSO4) and evaporated. The residue was purified by flash chromatography, eluting sequentially with 0:1:1, 2:48:50, 4:46:50, 5:45:50, and 10:40:50 ethyl acetate:hexane:methylene chloride, to afford methyl 4-iodomethyl-3-methoxybenzoate (27.8 g), recovered benzyl indole-5-carboxylate (29.6 g), and the crude product as a tan solid (50.6 g). Treatment of the recovered benzyl indole-5-carboxylate (29.6 g) in N,N-dimethylformamide (250 mL) with methyl 4-iodomethyl-3-methoxybenzoate (29.8 g) at 80° C. for 12 hours, followed by evaporation, gave a dark residue, which was dissolved in diethyl ether and washed with water (3 times). The aqueous washes were combined and extracted with diethyl ether. The combined organic extract was dried (MgSO4) and evaporated. The residue was purified by flash chromatography, eluting sequentially with 0:1:1, 2:48:50, 5:45:50, and 10:40:50 ethyl acetate:hexane:methylene chloride, to give further crude product as a tan solid (31.9 g). The combined crude product (82.5 g) was suspended in diethyl ether (400 mL), heated to reflux for 30 min, cooled and filtered to obtain methyl 4-(5-benzyloxycarbonylindol-3-ylmethyl)-3-methoxybenzoate as an ivory solid (46.1 g, 31%); partial NMR (250 MHz, CDCl3): 3.84 (s, 3H, CO2CH), 3.88 (s, 3H, OCH3), 4.14 (s, 2H, CH2), 5.35 (s, 2H, OCH2), 6.97 (d, 1H, indole-H(2)), 8.15 (br, 1 H, NH), 8.37 (s, 1H, indole-H(4)).