Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]([N:9]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:11][CH:10]1[C:20]([O:22]CC)=[O:21])=[O:8])(=O)C.[OH-].[K+].C>CO.O.ClCCl>[SH:4][CH2:5][CH2:6][C:7]([N:9]1[N:13]=[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:11][CH:10]1[C:20]([OH:22])=[O:21])=[O:8]
Reactant: CCOC(=O)C1OC(c2ccccc2)=NN1C(=O)CCSC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: O=C(O)C1OC(c2ccccc2)=NN1C(=O)CCS
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.8 %

Procedure:
A solution of the product from step (c) (1.44 g) in methanol (40 ml) was cooled to 15° under nitrogen and treated dropwise with a solution of potassium hydroxide (0.69 g) in water (40 ml). The mixture was stirred at room temperature for 2 hours and then the solvents were evaporated. The residue was taken up in water and washed with ether. The aqueous phase was acidified with 2N HCl and extracted with ethyl acetate. The separated organic phase was washed with water, dried and evaporated. The residue was purified by flash chromatography to give a pale yellow solid. The solid was taken up in dichloromethane, treated with charcoal, filtered and the filtrate evaporated to give the title product (0.24 g) as an off-white solid. mp 106°-9°.
Reaction SMILES: N1CCCCC1.[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][C:8]1=[O:16].[N:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([CH:34]=O)[CH:32]=3)[N:27]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:26]=2)=[CH:19][CH:18]=1>CCO>[N:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([CH:34]=[C:9]4[C:10]5[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=5)[NH:7][C:8]4=[O:16])[CH:32]=3)[N:27]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:26]=2)=[CH:19][CH:18]=1
Reactant: C[Si](C)(C)CCOCn1nc(/C=C/c2ccncc2)c2cc(C=O)ccc21
Reactant: O=C1Cc2ccccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: C[Si](C)(C)CCOCn1nc(/C=C/c2ccncc2)c2cc(C=C3C(=O)Nc4ccccc43)ccc21
Temperature: 75 °C

Procedure:
A solution of piperidine (0.2M in EtOH, 0.10 mL, 0.02 mmol) was added to a suspension of oxindole (16.5 mg, 0.12 mmol) and (E)-3-(2-(pyridin-4-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-carbaldehyde (42.5 mg, 0.11 mmol) in EtOH (4 mL). The reaction was then heated to 75° C. for 15 hrs. The solvent was evaporated in vacuo. MeOH was added and the resulting suspension was sonicated, but the solution was still cloudy even after EtOAc was added. The solid was removed by filtration and the solvent evaporated in vacuo. Chromatography (5 g silica SPE tube, Silicycle, 2% MeOH in CH2Cl2) gave a yellow solid (35 mg, 64%, 55:45 mixture of E/Z isomers). 1H NMR (400 MHz, CDCl3 plus a drop of CD3OD) δ 9.77 (s, 0.45H), 8.63 (m, 1.9H), 8.42 (s, 0.55H), 8.18 (s, 0.45H), 8.14 (dd, J=8.8, 1.2 Hz, 0.45H), 8.00 (s, 1H), 7.83-7.42 (m, 7H), 7.26 (t, J=7.6 Hz, 1H), 7.09 (t, J=7.6 Hz, 0.45H), 6.94-6.88 (m, 1.6H), 5.80 (s, 0.55H), 5.77 (s, 0.45H), 3.64 (m, 2H), 0.95 (m, 2H), −0.02 (s, 5H), −0.03 (s, 4H).
Reaction SMILES: [CH:1]([C:3]1[N:8]=[N:7][C:6]2[O:9][CH2:10][CH2:11][CH2:12][C:5]=2[CH:4]=1)=C.O.I([O-])(=O)(=O)=[O:15].[Na+]>O1CCOCC1.[Os](=O)(=O)(=O)=O>[N:7]1[C:6]2[O:9][CH2:10][CH2:11][CH2:12][C:5]=2[CH:4]=[C:3]([CH:1]=[O:15])[N:8]=1
Reactant: C=Cc1cc2c(nn1)OCCC2
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1cc2c(nn1)OCCC2
Temperature: 25 °C
Reaction time: 4.75 h
Yield: 54.3 %

Procedure:
A solution of 3-ethenyl-6,7-dihydro-5H-pyrano[2,3-c]pyridazine (100 mg, 0.617 mmol) in 1,4-dioxane (5.5 ml)/water (1.1 ml) was cooled in ice/water and treated with sodium periodate (306 mg, 1.43 mmol) and a 4% aqueous solution of osmium tetroxide (0.55 ml). The mixture was allowed to warm to RT after an hour, and after a total of 4.75 hours stirring, the solvent was evaporated. 1,4-Dioxane was added and evaporated, a few ml of dichloromethane were added and the mixture briefly held in an ultrasonic bath. The whole mixture was applied to a silica column and eluted with ethyl acetate to give the product (55 mg, 54%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([C:34]([O:36]CC)=[O:35])[CH:28]=[CH:27]4)=[C:20]([CH3:39])[CH:19]=2)=[C:14]([CH:40]([CH3:42])[CH3:41])[O:13][N:12]=1.Cl.O>O1CCCC1.CO>[Cl:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[C:5]=1[C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([C:34]([OH:36])=[O:35])[CH:28]=[CH:27]4)=[C:20]([CH3:39])[CH:19]=2)=[C:14]([CH:40]([CH3:42])[CH3:41])[O:13][N:12]=1
Reactant: CCOC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3C)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(OCc2c(-c3c(Cl)cccc3Cl)noc2C(C)C)ccc1-c1ccc2nc(C(=O)O)ccc2c1
Temperature: 90 °C
Yield: 98.2 %

Procedure:
A 1 N solution of sodium hydroxide (187.7 μL, 187.7 μmol) was added to ethyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-2-methylphenyl]-2-quinolinecarboxylate (54.0 mg, 93.8 μmol) in tetrahydrofuran and methanol (1:1, 1.9 mL) and the mixture was heated in the microwave at 90° C. for 10 minutes. After cooling, the mixture was neutralized with 1 N hydrochloric acid (187.7 μL), water was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, then dried over anhydrous magnesium sulfate, filtered and concentrated to give 50.4 mg (98%) of 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-2-methylphenyl]-2-quinolinecarboxylic acid as a solid. 1H NMR (400 MHz, d6-DMSO): δ 13.41 (br s, 1H), 8.54 (d, J=9 Hz, 1H), 8.14 (d, J=9 Hz, 1H), 8.12 (d, J=9 Hz, 1H), 7.96 (s, 1H), 7.79 (dd, J=9.2 Hz, 1H), 7.66-7.60 (m, 2H), 7.56 (dd, J=9, 7 Hz, 1H), 7.19 (d, J=9 Hz, 1H), 6.78 (d, J=2 Hz, 1H), 6.73 (dd, J=8, 2 Hz, 1H), 4.86 (s, 2H), 3.47 (septet, J=7 Hz, 1H), 2.21 (s, 3H), 1.35 (d, J=7 Hz, 6H). HRMS C30H24Cl2N2O4 m/z 547.1191 (M+H)+Cal; 547.1188 (M+H)+Obs.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29](=[N:31][OH:32])[NH2:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C1CCN2C(=NCCC2)CC1.[C:44](N1C=CN=C1)(N1C=CN=C1)=[O:45]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:22][CH3:23])[CH2:24][CH3:25])[C:11](=[O:26])[C@:10]([CH2:28][C:29]3[NH:30][C:44](=[O:45])[O:32][N:31]=3)([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CC)N1C(=O)[C@@](C)(CC(N)=NO)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: CCC(CC)N1C(=O)[C@@](C)(Cc2noc(=O)[nH]2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a solution of 385 mg (0.81 mmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)-N′-hydroxyacetimidamide (Example 82, Step C) in dioxane (12.5 mL) was added 211 μL (1.41 mmol) of DBU and 262 mg (1.62 mmol) of 1,1′-carbonyldiimidazole. The resulting colorless solution was heated at 100° C. for 25 min, and then was quenched with water and extracted with EtOAc. The organic layer was washed with saturated aqueous sodium chloride, and then was dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by reversed phase prep. HPLC (Sunfire™ Prep C18 OBD 10 μm column (Waters, Mlford, Mass.), gradient elution of 55% MeCN in water to 80% MeCN in water over a 35 min period, where both solvents contain 0.1% TFA) provided the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]1[N:17]([CH3:18])[C:16]2[CH:19]=[CH:20][C:21]([O:23][C:24]3(C(O)=O)[CH:29]=[CH:28][CH:27]=[CH:26][NH:25]3)=[CH:22][C:15]=2[N:14]=1.[N:33]1([CH2:38][CH2:39][NH2:40])[CH2:37][CH2:36][CH2:35][CH2:34]1.CN([C:44]([O:48]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]1[N:17]([CH3:18])[C:16]2[CH:19]=[CH:20][C:21]([O:23][C:24]3([CH:36]4[CH2:37][N:33]([CH2:38][CH2:39][NH:40][CH:44]=[O:48])[CH2:34][CH2:35]4)[CH:29]=[CH:28][CH:27]=[CH:26][NH:25]3)=[CH:22][C:15]=2[N:14]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: NCCN1CCCC1
Reactant: Cn1c(Nc2cc(C(F)(F)F)ccc2F)nc2cc(OC3(C(=O)O)C=CC=CN3)ccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2cc(C(F)(F)F)ccc2F)nc2cc(OC3(C4CCN(CCNC=O)C4)C=CC=CN3)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 4-(2-{[2-fluoro-5-(trifluoromethyl)phenylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylic acid (1 eq) in tetrahydrofuran was added 2-pyrrolidinylethylamine (2 eq), HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir at ambient temperature for 16 h. The mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was concentrated and preparative chromatography yielded [4-(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino-1-methylbenzimidazol-5-yloxy)-(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide. MS: MH+=542.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23](C(OC(C)(C)C)=O)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.Cl>CO.CCOCC>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:24]=[N:23][NH:22][CH:21]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)cn1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
To a solution of tert-butyl 4-(6-fluoro-1-(phenylsulfonyl)-1H-indol-3-yl)-1H-pyrazole-1-carboxylate (Intermediate 4; 310 mg; 0.70 mmol) in methanol (2 mL) was added saturated HCl in Et2O (10 mL). The resulting mixture was stirred for 30 minutes. The reaction was concentrated to dryness under reduced pressure, diluted with water (10 mL), neutralized with saturated aqueous NaHCO3, and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford 234 mg (89%) of the title compound as a yellow solid.
Reaction SMILES: [Br-:1].C1(C(O)(C2C=CC=CC=2)C(O[C@@H]2C3CC[N+](CC(=O)NC4C=NC=CN=4)(CC3)C2)=O)CCCC1.[Br-].O[C@@H]1C2CC[N+](CC(=O)NC3C=NC=CN=3)(CC2)C1.[Br-].[OH:57][C@@H:58]1[CH:63]2[CH2:64][CH2:65][N+:60]([CH2:66][C:67](=[O:75])[NH:68][C:69]3[CH:74]=[CH:73][N:72]=[CH:71][N:70]=3)([CH2:61][CH2:62]2)[CH2:59]1.[CH:76]1([C:82]([OH:92])([C:86]2[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=2)[C:83](O)=[O:84])[CH2:81][CH2:80][CH2:79][CH2:78][CH2:77]1>>[Br-:1].[CH:86]1([C:82]([OH:92])([C:76]2[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=2)[C:83]([O:57][C@@H:58]2[CH:63]3[CH2:64][CH2:65][N+:60]([CH2:66][C:67](=[O:75])[NH:68][C:69]4[CH:74]=[CH:73][N:72]=[CH:71][N:70]=4)([CH2:61][CH2:62]3)[CH2:59]2)=[O:84])[CH2:91][CH2:90][CH2:89][CH2:88][CH2:87]1
Reactant: O=C(O)C(O)(c1ccccc1)C1CCCCC1
Reactant: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1ccncn1
Agent: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1cnccn1
Agent: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)C1CCCC1)C2)Nc1cnccn1
Agent: [Br-]
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)C1CCCCC1)C2)Nc1ccncn1

Procedure:
This compound is prepared analogously to (R)-3-(2-Cyclopentyl-2-hydroxy-2-phenyl-acetoxy)-1-(pyrazin-2-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide (Example 15) by replacing (R)-3-Hydroxy-1-(pyrazin-2-ylcarbamoylmethyl)-1-azonia-bicyclo-[2.2.2]octane bromide (Intermediate H) with (R)-3-Hydroxy-1-(pyrimidin-4-ylcarbamoyl-methyl)-1-azonia-bicyclo[2.2.2]octane bromide (Intermediate Q) and by replacing cyclopentyl-hydroxy-phenyl-acetic acid with cyclohexyl-hydroxy-phenyl-acetic acid, yielding the titled compound as a diastereomeric mixture. (M+ 479.5).
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Br:16])[CH:15]=1)[C:5]([O:7]CC)=O.[NH:18]([C:20]1[N:25]=[CH:24][N:23]=[C:22]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:21]=1)N.C1(C)C=CC(S(O)(=O)=O)=CC=1.[ClH:43]>C(O)C.O1CCOCC1>[ClH:43].[Br:16][C:14]1[CH:15]=[C:10]([C:4]2[C:5](=[O:7])[N:18]([C:20]3[CH:21]=[C:22]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[N:23]=[CH:24][N:25]=3)[NH:2][CH:3]=2)[CH:11]=[N:12][CH:13]=1
Reactant: NNc1cc(N2CCOCC2)ncn1
Reactant: CCOC(=O)C(=CN(C)C)c1cncc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: O=c1c(-c2cncc(Br)c2)c[nH]n1-c1cc(N2CCOCC2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 100° C., 500 mg (1.7 mmol) of the compound from Example 11A, 326 mg (1.7 mmol) of the compound from Example 9A and 58 mg (0.3 mmol) of p-toluenesulfonic acid are stirred in 4 ml of ethanol for 16 h. After cooling to RT, 0.5 ml of a 4 N solution of hydrogen chloride in dioxane is added, and the mixture is stirred at RT for 30 min. The precipitate is filtered off, washed first with ethanol and then with diethyl ether and dried under reduced pressure.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:30][O:31][C:32]1[N:37]=[C:36]([O:38][CH3:39])[C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=1>>[CH3:30][O:31][C:32]1[N:37]=[C:36]([O:38][CH3:39])[C:35]([C:2]2[N:3]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][CH:15]([N:18]5[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]5)[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:34][N:33]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCC(N4CCCCC4)CC3)cc2n1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)c(OC)n1
Product: COc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCC(N5CCCCC5)CC4)cc3n2)c(OC)n1

Procedure:
1′-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-[1,4′]bipiperidinyl (Example 24) was reacted with 2,4-dimethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine in General Procedure A. Purification on silica yielded 134. NMR (CDCl3): 1.46 (m, 2H, CH2), 1.60-1.69 (m, 6H, 3×CH2), 1.83 (m, 2H, Ch2), 2.12 (t, 2H, CH2, J=10.91 Hz), 2.28 (m, H, CH), 2.53 (m, 4H, 2×CH2), 3.04 (d, 2H, CH2, J=11 Hz), 3.82 (s, 2H, CH2), 3.87-3.89 (m, 4H, 2×CH2), 4.02-4.04 (m, 4H, 2×CH2), 4.08 (s, 3H, CH3), 4.11 (s, 3H, CH3), 7.30 (s, H, ArH), 8.93 (s, H, ArH). MS: (ESI+): MH+=540.51
Reaction SMILES: ClNCl.[ClH:4].[CH3:5][CH:6]([CH2:18][CH3:19])[CH2:7][O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1>C(O)(=O)C>[CH3:5][CH:6]([CH2:18][CH3:19])[CH2:7][O:8][C:9](=[O:17])[C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[C:14]([Cl:4])[CH:15]=1
Reactant: Cl
Reactant: CCC(C)COC(=O)c1ccc(O)cc1
Agent: ClNCl
Solvent: CC(=O)O
Product: CCC(C)COC(=O)c1ccc(O)c(Cl)c1
Reaction time: 8 h

Procedure:
On the other hand, dichloroamine T (28.0 g, 0.12 mol) was dissolved in acetic acid (450 ml), and hydrochloric acid (1.5 ml) was added. The resulting solution was dropwise added to a solution of the above p-hydroxybenzoic acid 2-methyl-butyl ester (50 g, 0.24 mol) dissolved in acetic acid (450 ml), followed by refluxing the mixture, allowing to stand overnight, distilling off acetic acid and filtering off deposited crystals to obtain 3-chloro-4-hydroxy-benzoic acid 2-methyl-butyl ester (42 g) (b.p. 135°~138° C./4 mmHg).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1.[O:31]1[C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=[N:32]1>>[O:29]=[C:27]1[NH:26][C:25](=[O:30])[CH:24]([CH2:23][C:20]2[CH:19]=[CH:18][C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][N:9]([CH3:8])[C:36]([C:35]4[O:31][N:32]=[CH:33][CH:34]=4)=[O:37])[CH:12]=3)=[CH:22][CH:21]=2)[S:28]1
Reactant: CNCc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Reactant: O=C(Cl)c1ccno1
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1)C(=O)c1ccno1

Procedure:
In a manner similar to that of Example 37(e), by reacting 500 mg (1.1 mmol) of 5-(3′-methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4-dione trifluoroacetate with 170 mg (1.3 mmol) of 5-isoxazolecarboxylic acid chloride, and after purification, 120 mg (26%) of N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylisoxazole-5-carboxamide are obtained in the form of a white solid with a melting point of 160° C.
Reaction SMILES: NN=CC1C=CC(N[C:11]([CH:13]2[CH2:15][CH:14]2[C:16]([OH:18])=[O:17])=[O:12])=CC=1.CN(C=O)C.[CH3:24][C:25](C)(C)C(Cl)=O.CN1CC[O:35]CC1>N1C=CC=CC=1>[CH2:24]([O:18][C:16]([CH:14]1[CH2:15][CH:13]1[C:11]([OH:12])=[O:35])=[O:17])[CH3:25]
Reactant: NN=Cc1ccc(NC(=O)C2CC2C(=O)O)cc1
Reactant: CN1CCOCC1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CC1C(=O)O
Temperature: 55 °C
Reaction time: 8 h

Procedure:
t-Butyl-β(S)-[[[2-[[[4-(aminoiminomethyl)phenyl]amino]carbonyl]cyclopropyl]carbonyl]amino]-phenylpropanoate 0.90 g (0.0036 mol) of 2-[[[4-(aminoiminomethyl)phenyl]amino]carbonyl]cyclopropyl-carboxylic acid was treated with 50 mL dry DMF and the solvent removed at 55° C. To the remaining solid was added 60 mL DMF, 6 mL pyridine and 0.43 g (0.44 mL, 0.0036 mol) trimethylacetyl chloride. After 0.5 hr at room temperature the reaction mixture was heated at 55° C. for 0.5 hr then 0.93 g (0.004 mol) tert-butyl-3-amino-3-phenyl propionate and 0.36 g (0.40 mL, 0.004mol) N-methylmorpholine were added and the reaction allowed to proceed overnight. At this point volatiles were removed and the desired product isolated by preparative RPHPLC and lyophilized to give a diastereomeric mixture of t-butyl-β(S)-[[[2-[[[4-(aminoiminomethyl)phenyl]amino]carbonyl]cyclopropyl]carbonyl]amino]-3-phenylpropanoate as a white powder (150 mg); 1H HMR (300 MHz) (d6DMSO) δ1.19 (m, 2H), 1.28 (s), 1.31 (s, 9H), 2.21 (m, 2H), 2.65 (d, J=7.9 Hz), 2.66 (d, J=7.7 Hz, 2H), 5.2 (m, 1H), 7.32 (m, 5H), 7.78 (m, 4H), 8.86 (d, 1H, J=8.6 Hz), 8.95 (bs, 2H), 9.10 (bs, 2H), 10.74 (s), 10.80 (s, 1H); MS (FAB) 451.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.C(OCC)(OCC)[O:13][CH2:14][CH3:15].[CH3:22][CH2:23]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:13][CH2:14][CH3:15])([O:11][CH2:22][CH3:23])[CH2:9][CH3:10])=[CH:6][CH:7]=1
Reactant: CCC(=O)c1ccc(Cl)cc1
Reactant: CCO
Reactant: CCOC(OCC)OCC
Product: CCOC(CC)(OCC)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 88 %

Procedure:
A solution of 15.0 g of p-chloropropiophenone and 7.8 mL of dry EtOH was treated with 22.0 mL of triethyl orthoformate. Gaseous HCl was bubbled through the solution until saturation and the reaction mixture heated to reflux overnight. An additional 14.8 mL of triethyl orthoformate was added and the reaction mixture allowed to cool to room temperature. The cooled mixture was washed with 10 % Na2CO3, extracted with diethyl ether and concd in vacuo to afford 19.0 g (88%) of a crude orange/yellow oil. The oil was distilled and a fraction collected (75°-96° C., 100 mtorr) which contained 13.4 g of 1-chloro-4-(1,1-diethoxypropyl)benzene: μ (23,D) 1.5612; 1HNMR (CDCl3) a 0.56 (t, 3H, 7.5 Hz), 1.19 (t, 6H, 7.0 Hz), 1.89 (q, 2H, 7.5 Hz), 3.36 (m, 4H), 7.28 (d, 2H, 8.5 Hz), 7.42 (d, 2H, 8.5 Hz). Anal. Calcd for C13H19O2Cl: C, 64.32;H, 7.89. Found: C, 64.09; H, 7.81.
Reaction SMILES: [Br:1][C:2]1[C:11]([F:12])=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([CH2:13]Br)[CH:3]=1.[CH:15]([NH2:18])([CH3:17])[CH3:16]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][C:11]=1[F:12])[C:6](=[O:8])[N:18]([CH:15]([CH3:17])[CH3:16])[CH2:13]2
Reactant: CC(C)N
Reactant: COC(=O)c1cc(F)c(Br)cc1CBr
Product: CC(C)N1Cc2cc(Br)c(F)cc2C1=O

Procedure:
This compound was prepared using procedures analogous to those described for the synthesis of Example 52, Step 6 starting from methyl 4-bromo-2-(bromomethyl)-5-fluorobenzoate and isopropylamine. LC/MS: (M+H)+=271.9/273.9.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:22]=[CH:21][C:6]2[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C@H:16]([CH2:18][CH:19]=[CH2:20])[NH2:17])=[N:8][O:9][C:5]=2[CH:4]=1>CO>[ClH:2].[O:9]1[C:5]2[CH:4]=[CH:3][CH:22]=[CH:21][C:6]=2[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C@H:16]([CH2:18][CH:19]=[CH2:20])[NH2:17])=[N:8]1
Reactant: C=CC[C@H](N)c1ccccc1-c1noc2cc(Cl)ccc12
Agent: Cl
Solvent: CO
Product: C=CC[C@H](N)c1ccccc1-c1noc2ccccc12

Procedure:
(S)-(−)-2-(6-chloro-1,2-benzisoxazol-3-yl)-a-2-propenyl-benzenemethanamine hydrochloride, melting at 169-178° C., a (c=0.9 in methanol) −7.8.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[OH-].[K+].[Cl:13][C:14]1[CH:22]=[C:21]2[C:17]([CH:18]=[C:19]([CH3:23])[NH:20]2)=[CH:16][CH:15]=1.ClCCN1CCOCC1>CS(C)=O>[Cl:13][C:14]1[CH:22]=[C:21]2[C:17]([CH:18]=[C:19]([CH3:23])[N:20]2[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)=[CH:16][CH:15]=1
Reactant: Cc1cc2ccc(Cl)cc2[nH]1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1cc2ccc(Cl)cc2n1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-chloroethylmorpholine HCl (134 mg, 0.72 mmol) in 0.3 mL DMSO was added pulverized KOH (102 mg, 1.81 mmol), then after 10 min, a solution of 6-chloro-2-methylindole (100 mg, 0.60 mmol) in 0.2 mL DMSO was added and the reaction stirred at room temperature overnight. Additional 2-chloroethylmorpholine (22 mg, 0.12 mmol) and KOH (17 mg, 0.3 mmol) added and stirred overnight. The reaction mixture was partitioned between H2O and toluene, and the organic extract washed two times with H2O, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography using a gradient from 0 to 50% ethyl acetate in hexane to give a final yield of 149 mg (0.54 mmol). 1H NMR (500 MHz, CDCl3, δ): 2.44 (s, 3H), 2.49 (t, J=4.4 Hz, 4H), 2.62 (t, J=7.2 Hz, 2H), 3.73 (t, J=4.5 Hz, 4H), 4.11 (t, J=7.2 Hz, 2H), 6.23 (s, 1H), 7.06 (dd, J=8.4 Hz, 1.7 Hz, 1H), 7.28 (s, 1H), 7.42 (d, J=8.3 Hz, 1H). 13C NMR (500 MHz, CDCl3, δ): 12.79, 41.18, 54.11, 57.83, 67.5, 100.30, 108.95, 119.90, 120.53, 126.40, 126.70, 137.06, 137.37. MS m/z 279.3 [M+H]+.
Reaction SMILES: [H-].[Na+].C([CH:5]1[CH2:9][CH2:8][C:7](=[O:10])[C:6]1([CH3:12])[CH3:11])#N.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.CCCCCC.[CH3:28][N:29](C)C=O>>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][C:8]2([C:28]#[N:29])[C:7](=[O:10])[C:6]([CH3:11])([CH3:12])[CH2:5][CH2:9]2)=[CH:16][CH:15]=1
Reactant: CN(C)C=O
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC1(C)C(=O)CCC1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: CC1(C)CCC(C#N)(Cc2ccc(Cl)cc2)C1=O
Reaction time: 5 h
Yield: 72.6 %

Procedure:
A 60% mineral oil suspension of sodium hydride (12.7 g, 0.31 mole) in dimethylformamide under nitrogen, is treated with cyano-2,2-dimethylcyclopentanone over a 50 minute period at ice-bath temperatures, then with a solution of 4-chloro-benzyl chloride (50.2 g, 0.31 mole) over a 30 minute period, stirred for 5 hours and quenched with water. The resultant mixture is extracted with ethyl acetate. The extracts are combined, washed with water and concentrated in vacuo to afford a solid residue. The residue is titurated with hexane to afford the title product as white crystals, 59.3 g (72.6% yield), mp 101°-103° C., identified by gas chromatography.