Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28]>>[CH:18]1([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])=[O:24])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: COC(=O)c1ccc(OCc2c(C3CCCCC3)noc2C)nc1
Reactant: CC(C)(N)CO
Product: Cc1onc(C2CCCCC2)c1COc1ccc(C(=O)NC(C)(C)CO)cn1
Yield: 58 %

Procedure:
As described for example 31e, 6-(3-cyclohexyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (708 mg, 1.5 mmol) was converted, using 2-amino-2-methyl-1-propanol instead of isopropylamine, to the title compound (340 mg, 58%) which was obtained as a white solid after purification by chromatography (silica, 0 to 4% methanol in dichloromethane). MS: m/e=388.4 [M+H]+.
Reaction SMILES: CN(C(ON1N=[N:16][C:11]2[CH:12]=[CH:13][CH:14]=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[N:27]=[C:28]([C:45]2[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=2)[S:29][C:30]=1[CH2:31][NH:32][C:33]1[CH:38]=[CH:37][C:36]([C@@H:39]2[CH2:41][C@H:40]2[C:42](O)=[O:43])=[CH:35][CH:34]=1.C1(N)CCC1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH:11]1([NH:16][C:42]([C@@H:40]2[CH2:41][C@H:39]2[C:36]2[CH:37]=[CH:38][C:33]([NH:32][CH2:31][C:30]3[S:29][C:28]([C:45]4[CH:50]=[CH:49][C:48]([C:51]([F:52])([F:54])[F:53])=[CH:47][CH:46]=4)=[N:27][C:26]=3[CH3:25])=[CH:34][CH:35]=2)=[O:43])[CH2:12][CH2:13][CH2:14]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CNc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCC1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CNc1ccc([C@@H]2C[C@H]2C(=O)NC2CCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
HATU (0.154 g, 0.41 mmol) and (+)-(trans)-2-{4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)amino]phenyl}cyclopropanecarboxylic acid (III-3c) (0.135 g, 0.31 mmol) in DMF (10 mL) were stirred at RT for 15 min, then cyclobutylamine (0.50 g) was added. The solution was stirred at RT for 1 h, then saturated NaHCO3 solution (20 mL) was added. The resulting solid was filtered, washed with water (10 mL) and dissolved in ethyl acetate (50 mL). The organic layer was dried over MgSO4, filtered and concentrated to give the title compound as a white powder (0.116 g, 77%). 1H NMR (400 MHz, DMSO) δ8.23 (d, J=7.5 Hz, 1H), 8.01 (d, J=8.1 Hz, 2H), 7.76 (d, J=8.0 Hz, 2H), 6.81 (d, J=8.3 Hz, 2H), 6.51 (d, J=8.4 Hz, 2H), 6.20 (t, J=5.8 Hz, 1H), 4.38 (d, J=5.5 Hz, 2H), 4.19-4.13 (m, 1H), 2.42 (s, 3H), 2.10-2.06 (m, 2H), 2.04-1.99 (m, 1H), 1.85-1.75 (m, 2H), 1.59-1.50 (m, 3H), 1.18-1.13 (m, 1H), 1.01-0.96 (m, 1H).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[Br:8][C:9]1[N:14]=[C:13]([CH:15]=O)[CH:12]=[CH:11][CH:10]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[Br:8][C:9]1[N:14]=[C:13]([CH2:15][N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])[CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: CCCNCCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1cccc(Br)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
Dipropylamine (7.4 mL, 54 mmol) and 6-bromopyridine-2-carbaldehyde (5.0 g, 27 mmol) were dissolved in 1,2-dichloroethane (50 mL). 2 drops of glacial acetic acid was added followed by sodium triacetoxyborohydride (11.4 g, 54 mmol). The reaction was stirred at 50° C. for 1 h. The reaction was cooled and quenched with water. The solution was diluted with saturated sodium bicarbonate and extracted with ethyl acetate (3 times). The organic layers were dried over magnesium sulfate, filtered and concentrated. Flash chromatography gave 5.34 g (73% yield) of product.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([CH:8]([CH3:22])[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([F:21])[CH:10]=2)[O:5][N:4]=1.C(N(CC)CC)C.C1COCC1.[Br:35][CH:36]([CH3:40])[C:37](Br)=[O:38]>O>[Br:35][CH:36]([CH3:40])[C:37]([NH:1][CH2:2][C:3]1[N:7]=[C:6]([CH:8]([CH3:22])[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[C:11]([F:21])[CH:10]=2)[O:5][N:4]=1)=[O:38]
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CN)no1
Reactant: CC(Br)C(=O)Br
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(Br)C(=O)NCc1noc(C(C)c2ccc(-c3ccccc3)c(F)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
To a mixture of 4.13 g of 3-aminomethyl-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole, 1.56 g of triethylamine and 60 ml of THF was added dropwise with stirring 3.3 g of α-bromopropionyl bromide at 0°-5° C. After stirring for 1 hour at room temperature, the reaction mixture was diluted with water and extracted with benzene. The organic phase was successively washed with sodium bicarbonate solution and water, dried over sodium sulfate and evaporated. The residue was chromatographed over silica gel using benzene-ethyl acetate (5:1, v/v). Crystallization of the clean fractions from diisopropyl ether yielded 4.88 g of 3-(2-bromopropionylaminomethyl)-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole as colorless needles, m.p. 98°-99° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[C@@H:7]([NH:13][C:14]([NH:16][C@@H:17]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([I:37])[CH:32]=1)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15])[CH2:8][CH2:9][C:10]([OH:12])=O)([CH3:4])([CH3:3])[CH3:2].[S:40]([NH2:50])(=[O:49])([C:42]1[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=1)=[O:41].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:39])[C@@H:7]([NH:13][C:14](=[O:15])[NH:16][C@@H:17]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([I:37])[CH:32]=1)[C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:8][CH2:9][C:10](=[O:12])[NH:48][C:45]1[CH:46]=[CH:47][C:42]([S:40](=[O:49])(=[O:41])[NH2:50])=[CH:43][CH:44]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@H](CCCCNC(=O)c1cccc(I)c1)NC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](CCCCNC(=O)c1cccc(I)c1)NC(=O)N[C@@H](CCC(=O)Nc1ccc(S(N)(=O)=O)cc1)C(=O)OC(C)(C)C

Procedure:
(S)-2-(3-((S)-1-carboxy-4-oxo-4-(4-sulfamoylphenylamino)butyl) reido)-6-(3-iodobenzamido)hexanoic acid. A solution of (S)-5-tert-butoxy-4-(3-((S)-1-tert-butoxy-6-(3-iodobenzamido)-1-oxohexan-2-yl)ureido)-5-oxopentanoic acid (98 mg, 0.148 mmol), sulfanilamide (34.4 mg, 0.20 mmol), HATU (76 mg, 0.20 mmol), and DIPEA (0.50 mL) in DMF (5 mL) was stirred at 50° C. overnight. The solvents were evaporated under reduced pressure to give a residue, which was purified utilizing a Biotage SP4 with a gradient of 10-100% EtOAc in hexane to give (S)-tert-butyl 2-(3-((S)-1-tert-butoxy-1,5-dioxo-5-(4-sulfamoylphenylamino)pentan-2-yl)ureido)-6-(3-iodobenzamido)hexanoate. A solution of the above isolated material was dissolved in a mixture of TFA (2.0 mL)/DCM (2.0 mL) and stirred at room temperature for 3 h. The solvents were removed under reduced pressure to give a residue, which was purified by HPLC to give the title compound (20 mg, 19% over 2 steps) as a white solid. ESMS m/z: 704.2 (M+H)+.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][SiH:10]([CH2:12][SiH:13]([Cl:15])[Cl:14])[Cl:11]>C1C=CC=CC=1>[Cl:9][Si:10]([Cl:11])([CH2:12][SiH:13]([Cl:15])[Cl:14])[CH:8]=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: Cl[SiH](Cl)C[SiH](Cl)Cl
Solvent: c1ccccc1
Product: Cl[SiH](Cl)C[Si](Cl)(Cl)C=Cc1ccccc1
Reaction time: 2 h
Yield: 18.9 %

Procedure:
Hydrosilation of phenylacetylene with bis(dichlorosilyl)methane in the presence of Pt((CH2 =CHSiMe2)2O)2. Into the same apparatus as described in Example 1 were added 0.99 g of bis(dichlorosilyl)methane, 20 μl Pt((CH2 =CHSiMe2)2O)2 in 1,1,3,3-tetramethyl-1,3-divinyl-1,3-disiloxane (4 weight percent Pt), and 20 ml of dried benzene. The flask content was heated to reflux and 0.52 ml of phenylacetylene was added over a 10 minute period. The flask content was refluxed, with stirring, for another 2 hours and then the solvent removed at atmospheric pressure. The products were vacuum distilled at 67 Pa to give a mixture comprising 1.05 g of 3,3,5,5-tetrachloro-1-phenyl-3,5-disilapent-1-ene (TCD-GC area 18.9%) and 3,3,5,5-tetrachloro-1,7-diphenyl-3,5-disilahepta-1,6-diene (TCD-GC area 74.1%).
Reaction SMILES: CN(C)C=O.CS([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:16])[F:15])(=O)=O.[CH:18]1([O:23][C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][N:25]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1.C(=O)([O-])O.[Na+]>O>[CH:18]1([O:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:16])[F:15])=[O:29])=[CH:26][N:25]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(CCOS(C)(=O)=O)=C(F)F
Reactant: O=C(O)c1ccc(OC2CCCC2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(CCOC(=O)c1ccc(OC2CCCC2)nc1)=C(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 70.7 %

Procedure:
To 5 ml of N,N-dimethylformamide were dissolved 0.42 g (2.1 mmol) of 4,4-difluoro-3-methyl-3-butenyl methanesulfonate and 0.42 g (2.0 mmol) of 6-cyclopentyloxynicotinic acid, followed by the addition of 0.35 g (4.2 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (diisopropyl ether: hexane=1:7) to obtain 0.44 g (yield: 70%) of 4,4-difluoro-3-methyl-3-butenyl 6-cyclopentyloxynicotinate.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Na+].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O-:20])=[O:19])=[CH:14][CH:13]=1>CS(C)=O.O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([C:2]2[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=Cc1cccnc1Cl
Reactant: O=S([O-])c1ccc(Cl)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1cccnc1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 100 °C
Yield: 46.9 %

Procedure:
2-Chloro-3-pyridinecarboxaldehyde (5.0 g, 35.0 mmol) and 4-chlorobenzenesulfinic acid sodium salt (7.75 g, 38.8 mmol) were dissolved in DMSO (120 ml) and the mixture was heated at 100° C. for 72 h under nitrogen. Upon cooling to ambient the mixture was diluted with water (500 ml) and extracted with EtOAc (3×). The combined organics were washed with water, brine, dried (MgSO4) and evaporated to dryness to afford 8.1 g of crude material. The crude compound was pre-absorbed onto silica and purified by dry pad suction column chromatography, eluting with heptane using an EtOAc gradient, to afford 4.62 g (61%) of the desired product as a white powdery solid (MP=100.5-101° C.; IR=1698 cm−1; HPLC=8.00 min>99%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:54][N:55]2[CH:59]=[N:58][CH:57]=[N:56]2)[O:13][CH:12]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[C:38](=[O:39])[N:37]([CH:40]([CH3:53])[CH:41]([NH:43][CH:44]([C:47]6[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=6)[C:45]#[N:46])[CH3:42])[N:36]=[CH:35]5)=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH2:11][O:10]1.[H][H]>CO.N.[Ni]>[NH2:46][CH2:45][CH:44]([NH:43][CH:41]([CH3:42])[CH:40]([N:37]1[C:38](=[O:39])[N:34]([C:31]2[CH:32]=[CH:33][C:28]([N:25]3[CH2:24][CH2:23][N:22]([C:19]4[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:12]5[CH2:11][O:10][C:9]([C:3]6[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=6[F:1])([CH2:54][N:55]6[CH:59]=[N:58][CH:57]=[N:56]6)[O:13]5)=[CH:21][CH:20]=4)[CH2:27][CH2:26]3)=[CH:29][CH:30]=2)[CH:35]=[N:36]1)[CH3:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CC(NC(C#N)c1ccccc1)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(NC(CN)c1ccccc1)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O
Yield: 15.4 %

Procedure:
A mixture of compound 122 (0.003 mol) in CH3OH NH3 (200 ml) was hydrogenated overnight with Raney Nickel (1 g) as a catalyst. After uptake of hydrogen (2 equivalents), the catalyst was filtered off and the filtrate was evaporated. The residue was triturated in DIPE and 2-propanol, filtered off and dried. The residue was purified by HPLC (eluent: (ammonium acetate 0.5% in H2O/CH3CN 90/10)/CH3CN 90/10 to 0/100; column: HYPERPREP C18 BDS 8 μm). Two pure fractions were collected and their solvents were evaporated. The residue was triturated in DIPE, filtered off and dried, yielding 0.45 g [2S-[2α,4α[(S*,R*)(A)]]]-2-[2-[(2-amino-1-phenylethyl)amino]-1-methylpropyl]-4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihyro-3H-1,2,4-triazol-3-one (18.7%) (compound 174) and 0.37 g [2S-[2α,4α[(S*,R*)(B)]]]-2-[2[(2-amino-1-phenylethyl)amino]-1-methylpropyl]-4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]-phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (15.4%) (compound 178).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][CH2:13][CH:14]([OH:17])[CH2:15][CH3:16])=[CH:7][CH:6]=1.[C:19]([C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29](O)=[O:30])(=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:2][O:3][C:4](=[O:18])[C:5]1[CH:6]=[CH:7][C:8]([CH2:11][N:12]2[C:13]([C:14](=[O:17])[CH2:15][CH3:16])=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:27]3[C:28](=[CH:32][CH:33]=[C:34]([Cl:36])[CH:35]=3)[C:29]2=[O:30])=[CH:9][CH:10]=1
Reactant: CCC(O)CNCc1ccc(C(=O)OC)cc1
Reactant: O=C(O)c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: Cl
Product: CCC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(C(=O)OC)cc1

Procedure:
In the same manner as in Example 458, Step 2, the title compound was synthesized from 4-[(2-hydroxybutylamino)methyl]benzoic acid methyl ester hydrochloride and 2-benzoyl-4-chlorobenzoic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13])([CH3:4])([CH3:3])[CH3:2].Br[CH2:16][C:17]1[CH:18]=[C:19]([C:22]#[N:23])[S:20][CH:21]=1.[H-].[Na+]>C1COCC1.CN(C=O)C>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:16][C:17]2[CH:18]=[C:19]([C:22]#[N:23])[S:20][CH:21]=2)[C:9]1=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1cc(CBr)cs1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2csc(C#N)c2)C1=O
Reaction time: 2 h
Yield: 86.3 %

Procedure:
To a solution of (2-oxo-pyrrolidin-3-(S)-yl)-carbamic acid tert-butyl ester (3.2 g, 16 mmol), prepared as described in EXAMPLE 1, Part A in 80 mL of THF:DMF (10:1) at 0° C. is added 4-bromomethyl-thiophene-2-carbonitrile (3.23 g, 16 mmol) and sodium hydride (60% dispersion in oil, 0.67 g, 16.8 mmol). After addition, the solution was allowed to warm to ambient temperatures. After 2 h, the solution is quenched by the addition of sat. NH4Cl. The solution is diluted with H2O and EtOAc. The layers are separated. The organic layer is washed with H2O and sat. NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with gradient of 20% EtOAc/CH2 Cl2 to 30% EtOAc/CH2Cl2 to afford the title compound (4.0 g, 13.8 mmol) as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)[C:3]([O:5]C)=[O:4].[Li+].[OH-].C(Cl)(Cl)Cl.CO.N.C([O-])(O)=O.[Na+].[CH:27]1[C:39]2[CH:38]([CH2:40][O:41][C:42](Cl)=[O:43])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]=2[CH:30]=[CH:29][CH:28]=1>O1CCOCC1>[CH:27]1[C:39]2[CH:38]([CH2:40][O:41][C:42]([NH:1][C@@H:2]([CH2:7][C:8]3[O:9][CH:10]=[CH:11][CH:12]=3)[C:3]([OH:5])=[O:4])=[O:43])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]=2[CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)[C@@H](N)Cc1ccco1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: N
Agent: O=C([O-])O
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(N[C@@H](Cc1ccco1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reaction time: 8 h

Procedure:
Methyl (S)-2-amino-3-(2-furyl)propionate (1 g, 6.5 mmol) was mixed with 2M LiOH (3.27 ml, 6.5 mmol) and dioxane (3.27 ml ) at 0° C. and stirred overnight under N2. The next day a TLC control (CHCl3 /MeOH/NH3 aq 1/1/0.1) of the reaction mixture showed no ester present. 1M NaHCO3 (9.75 ml, 9.75 mmol) and 9-fluorenylmethyloxycarbonyl chloride (2.5 g, 9.75 mmol) dissolved in dioxane (10 ml) were added to the above solution and the stirring continued for a further 1 hour. Dioxane was removed under reduced pressure and the aqueous solution acidified with a 10% KHSO4 solution to pH 2. The solution was extracted with CHCl3 (3×20 ml), dried (MgSO4), evaporated and purified by flash chromatography (Hexane/ethyl acetate/acetic acid 10/10/1).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[C:10]([CH3:12])[N:11]=1)=O.C1COCC1>>[F:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:2]([F:1])[C:3]=1[CH2:4][NH:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[CH:14]=2)=[C:10]([CH3:12])[N:11]=1
Reactant: Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: Cc1nc(NCc2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Temperature: 60 °C
Yield: 34.2 %

Procedure:
Into solution of Compound 9 (75.0 mg, 0.19 mmol) at room temperature was added a solution of 1.0M borane-dimethylsulfide complex in THF (1.0 mL, 1.0 mmol). The mixture was heated to 60° C. overnight, cooled to room temperature, quenched by addition of water, extracted with CH2Cl2. The extracts were dried (Na2SO4), filtered and concentrated. The residue was purified on silica to give Compound 115 (25.0 mg).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][C@@H:13]2[CH2:26][NH:27][CH:28]([CH3:30])[CH3:29])=[CH:8][CH:7]=1)([OH:5])[CH3:4].CCN(C(C)C)C(C)C.[CH3:42][N:43]([CH3:48])[S:44](Cl)(=[O:46])=[O:45]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:42][N:43]([CH3:48])[S:44]([N:27]([CH:28]([CH3:29])[CH3:30])[CH2:26][C@H:13]1[CH2:14][N:15]([S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])[CH2:16][CH2:17][N:12]1[C:9]1[CH:8]=[CH:7][C:6]([C:3]([OH:5])([CH3:4])[C:2]([F:1])([F:31])[F:32])=[CH:11][CH:10]=1)(=[O:46])=[O:45]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CC(C)NC[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: CC(C)N(C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1)S(=O)(=O)N(C)C
Temperature: 80 °C
Yield: 8.2 %

Procedure:
To a solution of 1,1,1-trifluoro-2-(4-((2S)-2-(((1-methylethyl)amino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.100 g, 0.203 mmol, Example 195, Step 1) in pyridine (3.0 mL) was added 4-dimethylaminopyridine (5.0 mg, 0.040 mmol), Hünig's base (0.1 mL, 0.6 mmol), and dimethylsulfamoyl chloride (0.05 mL, 0.4 mmol, Aldrich, St. Louis, Mo.). The resulting mixture was heated at 80° C. for 6 h. The reaction mixture was allowed to cool to room temperature and then partitioned between EtOAc (30 mL) and water (20 mL). The aqueous layer was extracted with EtOAc (2×20 mL) and the combined organic extracts were dried over MgSO4, filtered, and concentrated. The crude product was purified by column chromatography (24 g of silica, 10% to 40% EtOAc in hexanes) to afford N,N-dimethyl-N′-(1-methylethyl)-N′-(((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)sulfamide (0.010 g) as a mixture of two isomers:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:41])=[C:9]([CH2:11][O:12][C:13]2[CH:38]=[CH:37][C:16]([CH2:17][O:18][C:19]3[CH:23]=[C:22](/[CH:24]=[CH:25]/[C:26]([O:28]CC)=[O:27])[N:21]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:20]=3)=[CH:15][C:14]=2[O:39][CH3:40])[N:10]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:41])=[C:9]([CH2:11][O:12][C:13]2[CH:38]=[CH:37][C:16]([CH2:17][O:18][C:19]3[CH:23]=[C:22](/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27])[N:21]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:20]=3)=[CH:15][C:14]=2[O:39][CH3:40])[N:10]=1
Reactant: CCOC(=O)/C=C/c1cc(OCc2ccc(OCc3nc(-c4ccco4)oc3C)c(OC)c2)nn1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(COc2cc(/C=C/C(=O)O)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccco2)oc1C
Yield: 93.8 %

Procedure:
To a mixture of ethyl (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-5-yl}-2-propenoate (0.73 g), tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (5 mL), and the mixture was heated under reflux for 1 hr. 1N Hydrochloric acid (5 mL) and water were added to neutralize the reaction mixture, and the precipitated crystals were collected by filtration to give (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-5-yl}-2-propenoic acid as colorless crystals (0.65 g, yield 94%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 191-192° C.
Reaction SMILES: C1(C(C2C=CC=CC=2)=[N:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=3[F:23])=[C:11]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:10]=2)C=CC=CC=1.Cl.[OH-].[Na+]>C1COCC1>[F:23][C:16]1[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:15]=1[C:12]1[CH:13]=[CH:14][C:9]([NH2:8])=[CH:10][C:11]=1[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: COc1ccc(F)c(-c2ccc(N=C(c3ccccc3)c3ccccc3)cc2CC(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(N)cc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a solution of a mixture (1.90 g) of N-(diphenylmethylene)-2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-amine in THF (42 mL) was added 3N hydrochloric acid (14.0 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 8N aqueous sodium hydroxide solution at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (970 mg) as a pale-yellow solid.