Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([OH:21])[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1>>[Cl:10][C:11]1[CH:12]=[C:13]([CH:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:16]=1)[O:21][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1
Reactant: O=Cc1ccc(F)nc1
Reactant: Oc1cc(Cl)cc(C(F)(F)F)c1
Product: O=Cc1ccc(Oc2cc(Cl)cc(C(F)(F)F)c2)nc1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 6-fluoronicotinaldehyde and 3-chloro-5-(trifluoromethyl) phenol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[Cl:20][CH2:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26]>>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([NH:1][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][CH:30]=[C:22]([CH2:21][Cl:20])[CH:23]=3)[CH:3]=2)=[O:19])=[CH:12][CH:13]=1)#[N:18]
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: Cc1ccc(NC(=O)c2ccc(C#N)cc2)cc1N
Product: Cc1ccc(NC(=O)c2ccc(C#N)cc2)cc1NC(=O)c1cccc(CCl)c1

Procedure:
Using an analogous procedure to that described in Example 10, N-(3-amino-4-methylphenyl)-4-cyanobenzamide was reacted with 3-(chloromethyl)benzoyl chloride to give the title compound as a solid (0.267 g); NMR Spectrum: (DMSOd6) 2.2 (s, 3H), 4.84 (s, 2H), 7.25 (d, 1H), 7.55 (m, 2H), 7.64 (m, 1H), 7.83 (s, M1), 7.99 (m, 4H), 8.1 (d, 2H), 9.97 (s, 1H), 10.46 (s, 1H); Mass Spectrum: M−H− 402.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:17])[C:14](O)=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(Cl)(=O)C([Cl:21])=O>C(Cl)Cl.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:17])[C:14]([Cl:21])=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C(=O)C(=O)O)cc(OC)c1OC
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)C(=O)Cl)cc(OC)c1OC

Procedure:
A stirred suspension of 3,4,5-trimethoxyphenyl-2-oxoacetic acid (1.60 g, 6.66 mmoles) in dry methylene chloride (26 mL) at room temperature was treated with 2M oxalyl chloride in methylene chloride (14 mL, 4 equiv.) and dry dimethylformamide (1 drop). After 3 h the solvents were evaporated. The residue was flushed with dry methylene chloride (3×50 mL) and dried in vacuo for 2 h during which time a solid formed. The crude acid chloride was carried on without further purification.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:53]=[CH:52][C:29]3[N:30]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:31]=[N:32][C:28]=3[CH:27]=2)=[CH:22][C:21]=1[CH:54]=O.[CH3:56][Si:57]([CH3:71])([CH3:70])[CH2:58][CH2:59][O:60][C:61]([N:63]1[CH2:68][CH2:67][CH:66]([NH2:69])[CH2:65][CH2:64]1)=[O:62].C(=O)([O-])[O-].[Na+].[Na+]>ClC(Cl)C.ClCCl>[CH3:56][Si:57]([CH3:71])([CH3:70])[CH2:58][CH2:59][O:60][C:61]([N:63]1[CH2:64][CH2:65][CH:66]([NH:69][CH2:54][C:21]2[CH:22]=[C:23]([C:26]3[CH:53]=[CH:52][C:29]4[N:30]([C:33]([C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=5)([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)[C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[N:31]=[N:32][C:28]=4[CH:27]=3)[CH:24]=[CH:25][C:20]=2[F:19])[CH2:67][CH2:68]1)=[O:62]
Reactant: C[Si](C)(C)CCOC(=O)N1CCC(N)CC1
Reactant: O=Cc1cc(-c2ccc3c(c2)nnn3C(c2ccccc2)(c2ccccc2)c2ccccc2)ccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: C[Si](C)(C)CCOC(=O)N1CCC(NCc2cc(-c3ccc4c(c3)nnn4C(c3ccccc3)(c3ccccc3)c3ccccc3)ccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
Sodium triacetoxyborohydride (890 mg, 4.2 mmol) and acetic acid (126 mg, 4.2 mmol) were added to a solution of 5-(4-fluoro-3-formylphenyl)-1-trityl-1H-benzotriazole (1.0 mg, 2.1 mmol) and 4-amino-piperidine-1-carboxylic acid 2-trimethylsilanyl-ethyl ester (760 mg, 3.1 mmol) in dichloroethane. The mixture was stirred at ambient temperature overnight, and then it was diluted with dichloromethane, and neutralized with careful addition of 1 M sodium carbonate solution. The layers were separated and the aqueous phase extracted with dichloromethane. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated to leave the crude product. Chromatography provided 980 mg of product. LC/MS: Retention time, 3.27 and 3.34 min; (M+H)=712.
Reaction SMILES: [C:1]1(=[N:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([OH:17])=[C:9]([C:18]3[NH:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[S:20](=[O:29])(=[O:28])[N:19]=3)[C:8]2=[O:30])[CH2:5][CH2:4][CH2:3][CH2:2]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[CH:1]1([NH:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([OH:17])=[C:9]([C:18]3[NH:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[S:20](=[O:28])(=[O:29])[N:19]=3)[C:8]2=[O:30])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1N=C1CCCC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1NC1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 235A (0.030 g, 0.071 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.010 mL, 0.28 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.060 mL, 0.12 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water, and the resulting precipitate was collected by filtration and dried to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.61 (m, 8 H) 3.70 (m, 1 H) 5.68 (d, J=4.41 Hz, 1 H) 7.05 (t, J=7.35 Hz, 1 H) 7.28 (t, J=8.27 Hz, 2 H) 7.54 (m, 2 H) 7.69 (dd, J=15.81, 8.09 Hz, 2 H) 8.06 (dd, J=8.09, 1.47 Hz, 1 H) 16.28 (s, 1 H). MS (ESI−) m/z 423 (M−H)−.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([NH2:10])=[S:9].Br[CH2:13][C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[C:1]1([CH3:11])[C:2]([NH:7][C:8]2[S:9][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:10]=2)=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1NC(N)=S
Reactant: CCOC(=O)C(=O)CBr
Product: CCOC(=O)c1csc(Nc2ccccc2C)n1

Procedure:
Following a procedure similar to that described in Preparation 42, the desired compound was prepared from 20 g of o-tolylthiourea, 23 g of ethyl bromopyruvate and 200 ml of giving the desired compound as pale yellow prismatic crystals having the following physical properties.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)=[C:6]([CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:7]=1.Br[CH2:37][C:38]1[CH:39]=[C:40]([F:56])[C:41]([O:45][Si](C(C)C)(C(C)C)C(C)C)=[C:42]([F:44])[CH:43]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.C(OCC)(=O)C.O>[F:44][C:42]1[CH:43]=[C:38]([CH:39]=[C:40]([F:56])[C:41]=1[OH:45])[CH2:37][N:10]([CH2:9][CH2:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:31]=2)=[CH:22][CH:21]=1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: O=C(O)CCCCNCCc1cc(F)ccc1OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: CC(C)[Si](Oc1c(F)cc(CBr)cc1F)(C(C)C)C(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C(O)CCCCN(CCc1cc(F)ccc1OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)Cc1cc(F)c(O)c(F)c1

Procedure:
A solution of 40 mg (0.08 mmol) of 5-{[2-(5-fluoro-2-{[4′-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}pentanoic acid in 5 ml of acetone is mixed with 54.5 mg (0.09 mmol) of [4-(bromomethyl)-2,6-difluorophenoxy]triisopropyl)silane (Example 16A), 22.6 mg (0.16 mmol) of potassium carbonate and 20.3 mg (0.12 mmol) of potassium iodide and heated under reflux for 12 h. Cooling is followed by addition of water to the mixture and extraction with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and the solvent is distilled off in vacuo. The resulting residue is purified by preparative HPLC. 15.3 mg (0.024 mmol, 30% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:21]([O:23]CC)=[O:22])[S:5][C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH:9]=1.O[Li].O>C1COCC1.O>[CH3:1][C:2]1[N:3]=[C:4]([C:21]([OH:23])=[O:22])[S:5][C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]2)[CH:9]=1
Reactant: CCOC(=O)c1nc(C)c(Cc2cccc(N3CCN(C)CC3)c2)s1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(C(=O)O)sc1Cc1cccc(N2CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.3 %

Procedure:
A solution of ethyl 4-methyl-5-(3-(4-methylpiperazin-1-yl)benzyl)thiazole-2-carboxylate (270 mg, 0.72 mmol) was treated with LiOH.H2O (61 mg, 1.45 mmol) in THF (4 mL) and H2O (1 mL), and stirred at RT for 2 h. The solvents were removed under reduced pressure and the residue was purified by Combiflash (20% MeCN/H2O) to afford 4-methyl-5-(3-(4-methylpiperazin-1-yl)benzyl)thiazole-2-carboxylic acid as a yellow solid (70 mg, 29%). MS (ES+) C17H21N3O2S requires: 331, found: 332[M+H]+.
Reaction SMILES: O[N:2]=[CH:3][C:4]1[CH:8]=[CH:7][N:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:5]=1>C(OC(=O)C)(=O)C>[C:3]([C:4]1[CH:8]=[CH:7][N:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:5]=1)#[N:2]
Reactant: COC(=O)c1cccc(-n2ccc(C=NO)c2)c1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cccc(-n2ccc(C#N)c2)c1
Yield: 74.4 %

Procedure:
The mixture of methyl 3-(3-hydroxyiminomethylpyrrol-1-yl)benzoate (9.0 g) in acetic anhydride (45 ml) was heated under reflux for 3 hours under stirring and then the reaction mixture was concentrated in vacuo. To the residue was added a mixture of ethyl acetate and water, and the whole was adjusted to pH 8 with potassium carbonate. The separated organic layer was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with chloroform. The eluted fractions containing the desired product were combined and evaporated in vacuo. The residue was triturated with a mixture of diisopropyl ether and n-hexane to give methyl 3-(3-cyanopyrrol-1-yl)benzoate (6.20 g).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:15]1([C:21]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:29]3[CH:25]([CH2:26][NH:27][CH2:28]3)[S:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[CH3:13][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([N:27]1[CH2:28][CH:29]2[C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:22][CH2:23][S:24][CH:25]2[CH2:26]1)=[O:12]
Reactant: CN(C)c1ccccc1CC(=O)O
Reactant: c1ccc(C2(c3ccccc3)CCSC3CNCC32)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1ccccc1CC(=O)N1CC2SCCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
1.18 g of N,N'-carbonyldiimidazole are added to a solution of 1.16 g of 2-dimethylaminophenylacetic acid in 20 cm3 of dry dichloromethane. The mixture is stirred for 30 minutes at +5° C. and then a solution of 2.0 g of (4aRS,7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole hydrochloride and 1.83 cm3 of triethylamine in 20 cm3 of dichloromethane is added. The reaction mixture is stirred for 1 hour at 20° C. and is then washed twice with 50 cm3 of water and dried over magnesium sulphate. The solution is filtered and concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is chromatographed on a silica gel column (0.04 mm-0.06 mm, diameter 2.8 cm, height 26 cm), eluting under a nitrogen pressure of 0.6 bar with a cyclohexane and ethyl acetate mixture of (60/40 by volume) and collecting fractions of 60 cm 3 . Fractions 6 to 20 are pooled and concentrated to dryness under reduced pressure (2.7 kPa) and the residue is crystallized from an acetonitrile and diisopropyl oxide mixture. The crystals are drained and dried. 2.16 g of (4aRS,7aRS)-6-[(2-dimethylaminophenyl)acetyl]-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole are obtained in the form of a white solid; melting point 163° C.
Reaction SMILES: [OH:1][C@@H:2]1[C:8]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:7][S:6](=[O:15])(=[O:14])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[C@H:3]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl.CCCCCCCC(C([NH3+])(C(CCCCCCC)=O)C(CCCCCCC)=O)=O.[Cl-]>[OH:1][C@@H:2]1[C:8]2([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:7][S:6](=[O:15])(=[O:14])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[C@@H:3]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S1(=O)CC2(CCCCC2)[C@@H](O)[C@H](c2ccccc2)c2ccccc21
Agent: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: [Cl-]
Solvent: ClCCl
Product: O=S1(=O)CC2(CCCCC2)[C@@H](O)[C@@H](c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 10 h
Yield: 62.6 %

Procedure:
To a solution of 0.2 g (0.56 mmole) of 59 in 20 ml of CH2Cl2, was added 8 g of 50% NAOH and one drop of Aliquat-336 (methyltricaprylylammonium chloride) phase transfer catalyst. The reaction mixture was stirred for 10 h at room temperature. Twenty g of ice was added to the mixture and the mixture was extracted with CH2Cl2 (3×10 ml) washed with water, brine and dried over MgSO4 and concentrated in vacuo to recover 0.15 g of crude product. This was recrystallized from Hexane/EtOAc to give 125 mg of white crystal, mp 209-210° C. Proton and carbon NMR and mass spectra were consistent with the product.
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]>C(N(CC)CC)C.C(O)C>[Br:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[N:7]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[CH:8]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: O=c1ncc(Br)c[nH]1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Cn1cc(Br)cnc1=O)c1ccccc1

Procedure:
A solution of 5-bromopyrimidin-2-one hydrobromide (512 mg) and α-bromoacetophenone (398 mg) in triethylamine (2 ml) and ethanol (10 ml) was stirred at ambient temperature for three and a half hours. After evaporation of solvents, the residue was triturated with water. The product was filtered off and recrystallised from ethanol to give the title pyrimidinone: yield 253 mg: m.p. 161°-163°, λmaxEtOH 241.5 nm (ε 18810), 285 nm (ε 1690), 334.5 nm (ε 3190).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([CH2:33][OH:34])[CH:27]=1)[CH2:10][NH:11][C:12]([CH3:25])([CH3:24])[CH2:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21](O)=[O:22])[CH:17]=[CH:18][CH:19]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N:35]1([CH2:40][CH2:41][CH2:42][NH2:43])[CH2:39][CH2:38][CH2:37][CH2:36]1>>[Si:1]([O:8][C@H:9]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([CH2:33][OH:34])[CH:27]=1)[CH2:10][NH:11][C:12]([CH3:25])([CH3:24])[CH2:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([NH:43][CH2:42][CH2:41][CH2:40][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:22])[CH:17]=[CH:18][CH:19]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(Cc1cccc(CC(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Reactant: NCCCN1CCCC1
Product: CC(C)(Cc1cccc(CC(=O)NCCCN2CCCC2)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Yield: 16 %

Procedure:
The title compound was prepared from {3-[2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetic acid (preparation 154) and 1-pyrrolidinepropanamine, using a similar method to that of preparation 38, in 16% yield.
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]1[CH2:19][CH2:18][CH2:17][CH:16]([NH:20][C:21](=[O:39])[C@@H:22]([NH:27][C:28]([C:30]2[O:31][C:32]3[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=3[CH:34]=2)=[O:29])[CH2:23][CH:24]([CH3:26])[CH3:25])[CH:15]([OH:40])[CH2:14]1)(=[O:12])=[O:11].CO.O>>[O:31]1[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[CH:34]=[C:30]1[C:28]([NH:27][C@@H:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:21]([NH:20][CH:16]1[CH2:17][CH2:18][CH2:19][N:13]([S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:41])=[O:2])(=[O:11])=[O:12])[CH2:14][CH:15]1[OH:40])=[O:39])=[O:29]
Reactant: COC(=O)c1ccccc1S(=O)(=O)N1CCCC(NC(=O)[C@H](CC(C)C)NC(=O)c2cc3ccccc3o2)C(O)C1
Solvent: O
Solvent: CO
Product: CC(C)C[C@H](NC(=O)c1cc2ccccc2o1)C(=O)NC1CCCN(S(=O)(=O)c2ccccc2C(=O)O)CC1O
Yield: 27.2 %

Procedure:
2-(4-{(S)-2-[(benzofuran-2-carbonyl)-amino]-4-methyl-pentanoylamino}-3-hydroxy-azepane-1-sulfonyl)-benzoic acid methyl ester (compound 83a, 180 mg, 0.309 mmol) was dissolved in 5:1 MeOH/water (6 ml) LiOH (14 mg, 0.34 mmol) was added and the reaction mixture was stirred and refluxed for 6 h. The reaction mixture was then quenched with water and 6 N HCl (adjusted to pH=2), extracted with EtOAc (3×10 ml), dried with MgSO4, filtered, concentrated, and chromatographed (silica gel, 1% acetic acid/4% MeOH/CH2Cl2) to yield the title compound as a white solid (48 mg, 27%): M+H+=572.2
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([Br:24])[CH:22]=3)[N:17]=[CH:16][C:15]=2[C:25]([CH:27]2[CH2:29][CH2:28]2)=[O:26])[CH2:9][CH2:8]1)(=O)=O.[CH3:30][NH2:31]>>[Br:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][C:15]([C:25]([CH:27]1[CH2:28][CH2:29]1)=[O:26])=[C:14]2[NH:13][C@H:10]1[CH2:11][CH2:12][C@H:7]([CH2:6][NH:31][CH3:30])[CH2:8][CH2:9]1
Reactant: CS(=O)(=O)OC[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: CN
Product: CNC[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Temperature: 120 °C

Procedure:
A suspension of (trans-4-((6-bromo-3-(cyclopropanecarbonyl)quinolin-4-yl)amino)cyclohexyl)methyl methanesulfonate (175 mg, 0.36 mmol) in methylamine (2.0 M solution in THF, 4.0 mL, 8.0 mmol) in a sealed vessel was heated under microwave irradiation conditions to 120° C. for 2 h. The solution was cooled to room temperature and concentrated. The resultant residue was purified by preparative HPLC (C18 silica, 10-90% methanol/water with 0.05% TFA). The residue was eluted through an ion-exchange column (using methanol and 7 N methanol in ammonia) to obtain the desired product (42 mg, 28%) a white solid. ESI MS m/z 416 [C21H26BrN3O+H]+
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:11])=[C:4]([F:12])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]([O:11][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1cc(O)c(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(OCc2ccccc2)c(F)cc1Br
Temperature: 25 °C
Yield: 90.6 %

Procedure:
A mixture of 4-bromo-2-fluoro-5-nitrophenol (prepared according to WO2004/014361, 10 g, 42.3 mmol) and cesium carbonate (16.42 g, 50.4 mmol) in DMF (80 mL), was stirred at room temperature and treated with benzyl bromide (5.5 g, 46.5 mmol) and the mixture was stirred/sonicated at room temperature for 2 hours (˜30 mins sonication). The DMF was evaporated and water and ethyl acetate were added and the product was extracted into ethyl acetate. The combined extracts were washed with sodium bicarbonate solution, dried (Na2SO4) and concentrated. Trituration of the solid with diethyl ether (3×) and drying gave the title compound (D4), (12.50 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=[O:11].[CH3:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](=[O:22])[CH2:19][C:20]#[N:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](=[O:22])[CH:19]([C:10](=[O:11])[NH:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8])[C:20]#[N:21]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: Cn1cccc1C(=O)CC#N
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cn1cccc1C(=O)C(C#N)C(=O)Nc1c(Cl)cccc1Cl
Reaction time: 8 h

Procedure:
To the filtered solution of 4.4 g of 2,6-dichlorophenylisocyanate in 30 ml of toluene is added 2.5 g of 1-methyl-β-oxo-2-pyrrolpropionitrile and 2.1 g of triethylamine while stirring. The mixture is allowed to stand overnight at room temperature, whereupon it is filtered. The solids are washed with toluene and diethyl ether, taken up in 50 ml of methanol and the solution poured into the mixture of 6 ml of 5 N hydrochloric acid and 300 ml of water. The crystals formed are collected, washed with water, dried, triturated with ethanol, and recrystallized from methanol, to yield the 1-methyl-β-oxo-α-(2,6-dichlorophenylcarbamoyl)-2-pyrrolpropionitrile melting at 196°-199°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[Cl:20][C:21]1[C:22]([NH:30][CH2:31][CH2:32][OH:33])=[N:23][CH:24]=[C:25]([CH:29]=1)[C:26](O)=[O:27]>>[Cl:20][C:21]1[C:22]([NH:30][CH2:31][CH2:32][OH:33])=[N:23][CH:24]=[C:25]([CH:29]=1)[C:26]([NH:19][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)=[CH:7][C:2]=1[CH3:1])=[O:27]
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: O=C(O)c1cnc(NCCO)c(Cl)c1
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1cnc(NCCO)c(Cl)c1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 5-chloro-6-(2-hydroxy-ethylamino)-nicotinic acid. MS: 458.4 (M+H).
Reaction SMILES: C[N:2]([CH3:11])[C:3]1C=[C:5]([CH2:9][OH:10])[CH:6]=[CH:7][CH:8]=1.[Br:12][C:13]1C=N[NH:16][CH:17]=1.CC1(C)C(C)(C)OB(C2C=NNC=2)O1>>[Br:12][C:13]1[CH:17]=[N:16][N:2]([CH2:3][CH:8]2[CH2:7][CH2:6][CH2:5][CH2:9][O:10]2)[CH:11]=1
Reactant: Brc1cn[nH]c1
Reactant: CN(C)c1cccc(CO)c1
Agent: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: Brc1cnn(CC2CCCCO2)c1

Procedure:
The title compound was prepared by substituting (tetrahydro-2H-pyran-2-yl)methanol for (3-(dimethylamino)phenyl)methanol and 4-bromo-1H-pyrazole for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE 34A.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[CH:5]=1)[CH3:2].C([N-]C(C)C)(C)C.[Li+].CN(C)P(N(C)C)(N(C)C)=O.Br[CH2:31][CH2:32][CH:33]=[CH2:34].O>O1CCCC1>[CH2:34]([CH:7]1[C:6](=[O:10])[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH2:9][CH2:8]1)[CH2:33][CH:32]=[CH2:31]
Reactant: CCOC1=CC(=O)CCC1
Reactant: C=CCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: O
Product: C=CCCC1CCC(OCC)=CC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
A solution of 25 g. (0.178 mole) of 3-ethoxy-2-cyclohexen-1-one in 25 ml. of tetrahydrofuran was added dropwise over a 30 minute period to a -78° C. solution of 0.196 mole of lithium diisopropylamide (from 27.4 ml., 0.196 mole, of diisopropylamine and 85 ml., 0.187 moles of 2.2M n-butyllithium in hexane) in 125 ml. of tetrahydrofuran. The reaction was then stirred for 30 minutes and 65 ml. (0.374 mole) of hexamethylphosphoramide added followed by 38.9 ml. (0.383 mole) of 4-bromo-1-butene. The reaction was then allowed to warm to room temperature, stirred for 1.5 hours and then quenched by addition of 5 ml. (0.277 mole) of water. Most of the solvent was removed on a rotovapor and the residue diluted with 1000 ml. ice water and 500 ml. ether. The ether phase was separated, washed with two 300 ml. portions of water, dried over magnesium sulfate and evaporated on a rotovapor. Distillation of the resulting crude oil gave 10.1 g. (29%) of the title product.