Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH:18]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:19]([O:21]CC3C=CC=CC=3)=[O:20])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH:18]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:19]([OH:21])=[O:20])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)CC(CS(=O)(=O)N1CCN(c2ccc(F)cc2)CC1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)CC(CS(=O)(=O)N1CCN(c2ccc(F)cc2)CC1)C(=O)O
Yield: 90.7 %

Procedure:
A solution of benzyl 3-[4-(4-fluorophenyl)piperazine-1-sulfonyl]-2-isobutylpropionate (630 mg) in methanol (10 ml) was hydrogenated under 40 PSI pressure for 18 hours in the presence of palladium on charcoal (63 mg, 10%). The catalyst was removed by filtration and the solvents were removed in vacuo to give 3-[4-(4-fluorophenyl)piperazine-1-sulfonyl]-2-isobutylpropionic acid (460 mg).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]3[C:13]([C:17]([NH:19][CH2:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[O:18])=[C:12](Cl)[CH:11]=[CH:10][C:9]=3[N:8]=2)[CH2:3]1.C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]3[C:13]([C:17]([NH:19][CH2:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[O:18])=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=2)[CH2:3]1
Reactant: [H][H]
Reactant: N[C@H]1CCN(c2ccc3c(C(=O)NCC4CCCCC4)c(Cl)ccc3n2)C1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: N[C@H]1CCN(c2ccc3c(C(=O)NCC4CCCCC4)cccc3n2)C1
Yield: 54.9 %

Procedure:
A suspension of 2-[(5)-3-amino-1-pyrrolidinyl]-6-chloro-N-(cyclohexylmethyl)-5-quinolinecarboxamide (Example 44) (0.10 g) and triethylamine (0.04 mL) in ethanol (20 mL) was treated with 5% palladium on charcoal (0.05 g) and stirred under 2 atmospheres of hydrogen at ambient temperature for 16 hours. The reaction mixture was filtered through Celite and the liquors concentrated to dryness. Recrystallisation from methanol/ethyl acetate afforded to title compound (0.05 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:40]=[C:41]([F:43])[CH:42]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([CH:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)=[C:22]([F:39])[CH:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1>C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:40]=[C:41]([F:43])[CH:42]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([CH:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[C:22]([F:39])[CH:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cc(F)cc(F)c6)c5)c4c3)cc2F)CC1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc(F)cc(Cn2cc(-c3c[nH]c4ncc(-c5ccc(C6CCNCC6)c(F)c5)cc34)cn2)c1
Yield: 28 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-fluorophenyl)piperidine-1-carboxylate (64 mg, 0.109 mmol) was deprotected in TFA/toluene (5/5 mL) to afford 14.9 mg (28.3% yield) of the titled compound after purification by preparative TLC using 6% methanol in chloroform as eluent. 1H NMR (CD3OD, 300 MHz): δ 8.48-8.47 (d, 1H), 8.38-8.37 (d, 1H), 8.25 (s, 1H), 7.96 (s, 1H), 7.66 (s, 1H), 7.53-7.39 (m, 3H), 6.92-6.86 (m, 3H), 5.44 (s, 2H), 3.24-3.20 (d, 2H), 3.09-3.07 (m, 1H), 2.87-2.80 (td, 2H), 1.89-1.77 (m, 4H). MS: m/z=488.3 (M+1), HPLC: 95.30% in method A.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]([CH3:31])([CH3:30])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=O)[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:23])[CH3:22])[CH:15]=2)[CH:8]=1)[CH3:2].[CH2:33]([SH:37])[CH2:34][CH2:35][SH:36].B(F)(F)F.CCOCC.[OH-].[Na+]>ClCCl>[CH2:1]([O:3][C:4](=[O:32])[C:5]([CH3:31])([CH3:30])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:23])[CH3:22])[CH:15]=3)[S:37][CH2:33][CH2:34][CH2:35][S:36]2)[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(C)Cc1cccc(C(=O)c2cccc(CC(C)(C)C(=O)OCC)c2)c1
Reactant: SCCCS
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Cc1cccc(C2(c3cccc(CC(C)(C)C(=O)OCC)c3)SCCCS2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
To a solution of 3-{3-[3-(2-ethoxycarbonyl-2-methyl-propyl)-benzoyl]-phenyl}-2,2-dimethyl-propionic acid ethyl ester (6.2 g, 14 mmol) in dichloromethane (100 mL) was added 1,3-propanedithiol (1.9 g, 17.5 mmol) and borontrifluoride etherate (0.52 mL) solution was stirred at room temperature overnight and 5% sodium hydroxide solution (17.5 mL) was added. The organic layer was separated, washed with water (50 mL), dried over sodium sulfate, and evaporated to afford 3-(3-{2-[3-(2-ethoxycarbonyl-2-methyl-propyl)-phenyl]-[1,3]dithian-2-yl}-phenyl)-2,2-dimethyl-propanoic acid ethyl ester (6.5 g, 86%) as an oil. 1H NMR (300 MHz, CDCl3): δ (ppm): 7.58-6.96 (m, 8H), 4.10 (q, J=7.2 Hz, 4H), 2.85 (s, 4H), 2.76 (t, J=5.6 Hz, 4H), 1.98 (m, 2H), 1.25-1.14 (m, 18H). 13C NMR (75 MHz, CDCl3): δ (ppm): 177.2, 142.2, 138.1, 131.1, 129.3, 127.8, 127.3, 60.4, 46.2, 43.5, 29.4, 24.9, 24.5, 14.1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17](Cl)=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1(B(O)O)[CH2:24][CH2:23][CH2:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([C:20]3[CH2:24][CH2:23][CH2:22][CH:21]=3)=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)C1=CCCC1
Reactant: Clc1cnc2c(n1)OCCN(Cc1ccccc1)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: C1=C(c2cnc3c(n2)OCCN(Cc2ccccc2)C3)CCC1
Temperature: 100 °C
Yield: 68 %

Procedure:
A solution of 8-benzyl-3-chloro-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (559 mg), cyclopent-1-en-1-ylboronic acid (273 mg), tetrakis(triphenylphosphine)palladium(0) (118 mg) and aqueous sodium carbonate solution (2M, 2 mL) in DME (10 mL) was stirred under an argon atmosphere with heating at 100° C. for 2 hr. Water was added to the reaction mixture, the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (solvent gradient: 5→50% ethyl acetate/hexane) to give the title compound (424 mg, 68%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:20][CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[C:6]([CH:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)O)[CH:7]=1.[SH:26][CH:27]([CH2:31][C:32]([OH:34])=[O:33])[C:28](O)=[O:29].C(O)(=O)CC>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:20]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:28](=[O:29])[CH:27]([CH2:31][C:32]([OH:34])=[O:33])[S:26][CH:8]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:7]=1
Reactant: O=C(O)CC(S)C(=O)O
Reactant: CC(C)(C)CNc1ccc(Cl)cc1C(O)c1cccc2ccccc12
Solvent: CCC(=O)O
Solvent: O
Product: CC(C)(C)CN1C(=O)C(CC(=O)O)SC(c2cccc3ccccc23)c2cc(Cl)ccc21
Temperature: 130 °C
Reaction time: 48 h
Yield: 92.2 %

Procedure:
A stirred mixture of 50.0 g (141 mmol) of (5-chloro-2-neopentylamino-phenyl)-naphthalen-1-yl-methanol, 27.58 g (184 mmol, 1.3 equivalents) of mercaptosuccinic acid, and 340 mL of propionic acid was heated to 130° C. with a nitrogen purge. After 48 hours, the reaction mixture was cooled to room temperature giving a precipitate, treated with 200 mL of water, cooled to -5° C. with stirring, and filtered giving 60.83 g (92% yield) of the title compound as an off white solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][C:5]=1[N+:17]([O-])=O)([CH3:3])[CH3:2].Cl.C(=O)([O-])O.[Na+]>C(O)C.[Fe]>[NH2:17][C:5]1[CH:6]=[C:7](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: CCOC(=O)/C=C/c1ccc(C(C)C)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Product: CCOC(=O)/C=C/c1ccc(C(C)C)c(N)c1
Yield: 85.5 %

Procedure:
13.2 g of ethyl (E)-3-(4-isopropyl-3-nitrophenyl)acrylate was dissolved in 330 ml of 80% ethanol. Thereto were added 27.9 g of an iron powder and 4.17 ml of concentrated hydrochloric acid at room temperature. The mixture was refluxed for 1.5 hours. The reaction mixture was neutralized with sodium hydrogencarbonate. The resulting insolubles were removed by filtration and the filtrate was subjected to distillation under reduced pressure to remove the solvent. To the residue were added 100 ml of water and 200 ml of diethyl ether. The mixture was adjusted to pH 1.0 with concentrated hydrochloric acid. The resulting crystals were filtered. The crystals obtained and the separated aqueous layer obtained from the filtrate were combined and neutralized with sodium hydrogencarbonate. Then, the mixture was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous sodium chloride solution in this order and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 10.0 g of brown oily ethyl (E)-3-(3-amino- 4-isopropylphenyl)acrylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](F)=[N:6][C:5]=1[F:11].[F:13][C:14]([F:24])([F:23])[C:15]1[N:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=1.O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH:22][CH2:21][C:18]2[CH:19]=[N:20][C:15]([C:14]([F:24])([F:13])[F:23])=[CH:16][CH:17]=2)=[N:6][C:5]=1[F:11]
Reactant: NCc1ccc(C(F)(F)F)nc1
Reactant: COC(=O)c1ccc(F)nc1F
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(NCc2ccc(C(F)(F)F)nc2)nc1F
Temperature: -40 °C

Procedure:
To 2,6-difluoro-nicotinic acid methyl ester (60, 1.82 g, 0.0105 mol, prepared as described in Example 22, Scheme 24, Step 2) in N,N-dimethylformamide (20.0 mL), under an atmosphere of nitrogen at −40° C., C-(6-trifluoromethyl-pyridin-3-yl)-methylamine (561, 1.00 g, 5.68 mmol) was added. The reaction was stirred at −40° C., then allowed to warm to room temperature for 2 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 35% to 100% ethyl acetate in hexane to give a white solid (562, 1.40 g, 74.9). MS (ESI) [M+H+]+=330.1.
Reaction SMILES: [C@@H:1]12[CH2:6][C@@H:5]1[CH2:4][NH:3][CH2:2]2.[I-].[Na+].Cl[CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=1>>[C@@H:1]12[CH2:6][C@@H:5]1[CH2:4][N:3]([CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=1)[CH2:2]2
Reactant: C1NC[C@H]2C[C@@H]12
Reactant: NC(=O)c1ccc(OCCCCl)cc1
Agent: [I-]
Agent: [Na+]
Product: NC(=O)c1ccc(OCCCN2C[C@H]3C[C@H]3C2)cc1
Reaction time: 16 h

Procedure:
0.004 mole of (1R,5S)-3-azabicyclo[3.1.0]hexane and 0.002 mole of sodium iodide are added to the reaction mixture of Step 1 at ambient temperature. Refluxing is then resumed for 16 hours. The precipitate is filtered off and rinsed with acetonitrile. The filtrate is concentrated to dryness. The residue is taken up in dichloromethane. The resulting solution is extracted with sodium hydroxide solution and then with water, before being dried over magnesium sulphate and concentrated to dryness. The residue is purified by a preparative chromatography technique on a Lichroprep RP-18 phase.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:9]=O)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21](=O)[CH2:22][C:23]([O:25][CH3:26])=[O:24])(=[O:14])=[O:13].O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-]>CO>[F:8][C:6]1[CH:7]=[C:2]2[C:3]([CH:9]=[C:22]([C:23]([O:25][CH3:26])=[O:24])[C:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[S:12]([CH3:11])(=[O:14])=[O:13])=[N:1]2)=[N:4][CH:5]=1
Reactant: Nc1cc(F)cnc1C=O
Reactant: COC(=O)CC(=O)c1ccccc1S(C)(=O)=O
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc2ncc(F)cc2nc1-c1ccccc1S(C)(=O)=O
Temperature: 100 °C

Procedure:
A mixture of 3-amino-5-fluoropicolinaldehyde (930 mg, 6.63 mmol), methyl 3-(2-(methylsulfonyl)phenyl)-3-oxopropanoate (1.7 g, 6.63 mmol) and cerium chloride heptahydrate (435 mg, 1.32 mmol) was heated to 100° C. for 3 h. The residue was dissolved in MeOH and purified by column chromatography on neutral alumina using 0-30% EtOAc in hexane to give methyl 7-fluoro-2-(2-(methylsulfonyl)phenyl)-1,5-naphthyridine-3-carboxylate: LC-MS (ESI) m/z 361.0 [M+H]+.
Reaction SMILES: O1CCOCCOCCOCCOCCOCC1.CC(C)([O-])C.[K+].[CH3:25][C:26]([CH3:46])([CH3:45])[CH2:27][C:28]([NH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:34]2)=[O:29].[F:47][C:48]([F:58])([F:57])[C:49]1[CH:56]=[CH:55][CH:54]=[CH:53][C:50]=1[CH2:51]Br>C1COCC1>[CH3:25][C:26]([CH3:45])([CH3:46])[CH2:27][C:28]([NH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([CH2:51][C:50]1[CH:53]=[CH:54][CH:55]=[CH:56][C:49]=1[C:48]([F:47])([F:57])[F:58])[C:35]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:34]2)=[O:29]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: CCOC(=O)c1cc2cc(NC(=O)CC(C)(C)C)ccc2[nH]1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(NC(=O)CC(C)(C)C)ccc2n1Cc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under argon, 35 mg (0.13 mmol) of 1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown-6) are initially charged in 7 ml of THF, and 1.98 ml (1.98 mmol) of a 1-molar potassium tert-butoxide solution in THF and 400 mg (1.32 mmol) of ethyl 5-[(3,3-dimethylbutanoyl)amino]-1H-indole-2-carboxylate from Example LXII are added. The mixture is stirred at RT for 15 minutes and cooled to 0° C. A solution of 474 mg (1.98 mmol) of 2-trifluoromethylbenzyl bromide in 12 ml of THF is slowly added dropwise. The ice-bath is removed and the mixture stirred at RT for 1 hour. For work-up, the mixture is diluted with water and the THF is removed under reduced pressure using a rotary evaporator. The aqueous residue is extracted with ethyl acetate and the organic phase is washed with sat. sodium chloride solution, dried with sodium sulphate, filtered and dried under reduced pressure. The residue is purified by column chromatography (mobile phase: cyclohexane:ethyl acetate 5:1).
Reaction SMILES: [NH2:1][N:2]1[C:6]([CH3:7])=[CH:5][CH:4]=[C:3]1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9].[C:17]([O:21][C:22]([NH:24][C@@H:25]([CH3:29])[C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[CH3:7][C:6]1[N:2]([NH:1][C:26](=[O:27])[C@@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH3:29])[C:3]([C:8](=[O:9])[NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:5]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1ccc(C(=O)Nc2ccccc2)n1N
Product: Cc1ccc(C(=O)Nc2ccccc2)n1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Yield: 73.1 %

Procedure:
The title compound was prepared following the experimental procedure described in preparation 20a from 380 mg (1.77 mmol) of 1-amino-5-methyl-N-phenyl-1H-pyrrole-2-carboxamide and 334 mg (1.77 mmol) of (S)-2-(tert-butoxycarbonylamino)propanoic acid (purchased from Aldrich). The crude product was purified by flash chromatography in hexane/ethyl acetate to afford 500 mg (59% yield) of the title compound.
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][CH2:12][O-].[Na+].O1CCOCC1.S(OCC)(OCC)(=O)=O>O>[O:1]([CH2:8][CH2:9][O:10][CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCOc1ccccc1
Reactant: CC[O-]
Agent: CCOS(=O)(=O)OCC
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOCCOc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
143.0 g (1.04 mol) of 2-phenoxyethanol, 81.0 g (1.19 mol) of sodium ethylate and 291 g of 1,4-dioxane are placed in a 1-liter four-necked flask equipped with a stirrer, a thermometer, a distillating column and a nitrogen-inlet tube. The solution is heated to 90° to 105° C., and then 200 g of the solvent is removed in a period of 2 hours. The distillating column is then replaced by a dropping funnel, and 183.5 g (1.19 mol) of diethyl sulfate is added thereto dropwise at 45° C. over a period of 30 minutes. After stirring the reaction mixture at 60° C. for 1 hour, the reaction product is placed in water and extracted with ether. The solvent is removed using an evaporator, and further distilled under reduced pressure to yield 160 g of ethyl 2-phenoxyethyl ether.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([N:29]([CH3:31])[CH3:30])=[O:28])=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[ClH:2].[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([N:29]([CH3:30])[CH3:31])=[O:28])=[CH:24][CH:25]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CN(C)C(=O)Cc1ccc(N)cc1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: CN(C)C(=O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 150 °C
Yield: 32.9 %

Procedure:
A mixture of 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.100 g, 0.33 mmol) and 2-(4-aminophenyl)-N,N-dimethylacetamide (0.178 g, 1.0 mmol) was heated for 3 h at 150° C., then toluene added and the mixture continued heating for an additional 7 h. After this time, the mixture was purified by silica gel chromatography eluting with methylene chloride and methanol. The resulting solid was converted to the HCl salt to afford the title compound (0.048 g, 33%) as a white solid. MW=405.92. 1H NMR (DMSO-d6, 500 MHz) δ 14.2 (br s, 1H), 9.88 (s, 1H), 7.91-7.90 (m, 1H), 7.72-7.66 (m, 2H), 7.61-7.58 (m, 1H), 7.37-7.32 (m, 1H), 7.01 (s, 1H), 3.73 (s, 2H), 3.17 (t, J=7.7 Hz, 2H), 3.04 (s, 3H), 2.93 (t, J=7.2 Hz, 2H), 2.84 (s, 3H), 2.27-2.21 (m, 2H); ESI MS m/z 406 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14]([NH:16][S:17](Cl)(=[O:19])=[O:18])=[O:15])[CH3:3].[CH2:21]([OH:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(N(CC)CC)C>C1COCC1>[CH2:21]([O:27][S:17](=[O:18])(=[O:19])[NH:16][C:14]([NH:13][C:5]1[C:6]([CH:10]([CH3:11])[CH3:12])=[CH:7][CH:8]=[CH:9][C:4]=1[CH:2]([CH3:3])[CH3:1])=[O:15])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)NS(=O)(=O)Cl
Reactant: CCCCCCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCOS(=O)(=O)NC(=O)Nc1c(C(C)C)cccc1C(C)C
Reaction time: 16 h
Yield: 25.8 %

Procedure:
A solution of [[[2,6-bis(1 methylethyl)phenyl]amino]carbonyl]sulfamoyl chloride (5.0 g, 15.7 mmoles) in 80 mL THF was added dropwise to a solution of n-hexanol (1.60 g, 15.7 mmoles) and excess triethylamine (~3 mL) in 150 mL THF at room temperature under an atmosphere of N2. This was stirred for 16 hours and then concentrated in vacuo. The residue was partitioned between IN HCl and EtOAc and the organic layer was dried with MgSO4, filtered, and evaporated to give an oily tan solid. Trituration with acetone/hexanes (9:1) gave 1.56 g of the title compound as a white solid, mp 148-151° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:14](#[N:18])[CH:15]([CH3:17])[CH3:16].[Cl-].[Al+3].[Cl-].[Cl-]>>[O:11]1[CH2:12][CH2:13][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:14](=[NH:18])[CH:15]([CH3:17])[CH3:16])[CH2:9][CH2:10]1
Reactant: CC(C)C#N
Reactant: Nc1ccccc1N1CCOCC1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)C(=N)Nc1ccccc1N1CCOCC1

Procedure:
A mixture of 4-(2-aminophenyl)morpholine (5.34 g), isobutyronitrile (6 g) and anhydrous aluminium chloride (12 g) was heated at 160°-170° C. for 6 hours to give N-(2-morpholinophenyl)isobutyramidine (m.p. 138° C.) which was recrystallised from a 1:1 mixture of ethylacetate and hexane.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][Mg]Cl)=[CH:4][CH:3]=1.[Br:11][C:12]1[C:13]([CH3:32])=[N:14][O:15][C:16]=1[NH:17][S:18]([C:21]1[CH:25]=[CH:24][S:23][C:22]=1[C:26](N(C)OC)=[O:27])(=[O:20])=[O:19]>C1COCC1>[Br:11][C:12]1[C:13]([CH3:32])=[N:14][O:15][C:16]=1[NH:17][S:18]([C:21]1[CH:25]=[CH:24][S:23][C:22]=1[C:26](=[O:27])[CH2:6][C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:19])=[O:20]
Reactant: CON(C)C(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Br
Reactant: Cc1ccc(C[Mg]Cl)cc1
Solvent: C1CCOC1
Product: Cc1ccc(CC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Br)cc1
Yield: 78 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenyl)acetyl]thiophene-3-sulfonamide was prepared in the same manner as described in Example 93B by reacting 4-methylbenzylmagnesium chloride with N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-methoxy(methylaminocarbonyl)]thiophene-3-sulfonamide in THF (see Example 93A) at -78° C. to room temperature, resulting in 78% yield. m.p. 146-150° C.8
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[N:5]=[C:6]([NH:9][C:10]2[N:15]=[CH:14][C:13]([S:16][CH2:17][C:18]3[C:23]([OH:24])=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:12][C:11]=2[O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:7][CH:8]=1.[H-].[Na+].[CH3:34]I>CN(C=O)C>[ClH:1].[CH3:34][O:24][C:23]1[C:18]([CH2:17][S:16][C:13]2[CH:12]=[C:11]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:10]([NH:9][C:6]3[S:7][CH:8]=[C:4]([CH3:3])[N:5]=3)=[N:15][CH:14]=2)=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1csc(Nc2ncc(SCc3ncccc3O)cc2Oc2ccccc2)n1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccnc1CSc1cnc(Nc2nc(C)cs2)c(Oc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 4.2 %

Procedure:
Placed 2-((6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)methyl)pyridine-3-ol (prepared in Example 69) (0.180 g, 0.426 mmol) in DMF (5 mL) and cooled to 0° C. Sodium hydride (0.0307 g, 1.28 mmol) was added and stirred for 10 minutes then MeI (0.0605 g, 0.426 mmol) was added stirred at ambient temperature for 30 minutes. Added water and extracted with CH2Cl2. The organic layer was concentrated and purified by silica gel. The product was still impure. Mixture was purified by medium pressure reverse phase followed by two high pressure reverse phase purifications. Combined all clean fractions' then dissolved in CH2Cl2 and added HCl in ether, then concentrated to give the title compound (0.0085 g, 4.22% yield). 1H NMR (d6-DMSO) δ 8.14 (m, 1H), 8.10 (d, 1H), 7.65 (m, 1H), 7.55 (m, 1H), 7.34-7.27 (m, 3H), 7.03 (m, 1H), 6.85 (d, 2H), 6.36 (s, 1H), 4.24 (s, 2H), 3.17 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.[OH:8][CH2:9][C@H:10]1[O:15][C:14]([CH3:17])([CH3:16])[O:13][C@@H:12]([CH2:18][C:19](O)=[O:20])[CH2:11]1.C(=O)(O)[O-].[Na+]>CO>[OH:8][CH2:9][C@H:10]1[O:15][C:14]([CH3:17])([CH3:16])[O:13][C@@H:12]([CH2:18][C:19]([O:6][CH3:7])=[O:20])[CH2:11]1
Reactant: COS(=O)(=O)OC
Reactant: CC1(C)O[C@H](CO)C[C@H](CC(=O)O)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Temperature: 27.5 °C
Reaction time: 12 h

Procedure:
Dimethyl sulfate (195 grams) was added to a mixture of 2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetic acid (200 grams), methanol (800 ml) and sodium bicarbonate (50 grams) at 0° C. and stirred for 12 hours at 25-30° C. After completion of the reaction, reaction mixture was quenched with water and extracted into methylene chloride. The methylene chloride was distilled off from the reaction mixture under reduced pressure to get the title compound.