Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([C:19]2[S:23][C:22]([C:24]([OH:30])([CH3:29])[C:25]([F:28])([F:27])[F:26])=[N:21][CH:20]=2)[CH:15]=[C:16]([CH3:18])[CH:17]=1.C(O)(=O)C>O1CCOCC1>[CH3:18][C:16]1[CH:17]=[C:12]([NH:11][C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=2)[CH:13]=[C:14]([C:19]2[S:23][C:22]([C:24]([OH:30])([CH3:29])[C:25]([F:28])([F:27])[F:26])=[N:21][CH:20]=2)[CH:15]=1
Reactant: Cc1cc(N)cc(-c2cnc(C(C)(O)C(F)(F)F)s2)c1
Reactant: O=C(O)c1ccnc(Cl)n1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cc1cc(Nc2nccc(C(=O)O)n2)cc(-c2cnc(C(C)(O)C(F)(F)F)s2)c1
Temperature: 100 °C

Procedure:
To 2-chloropyrimidine-4-carboxylic acid (175 mg, 1.104 mmol) in dioxane (2.201 mL) was added 2-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-1,1,1-trifluoropropan-2-ol (INTERMEDIATE 17, (334 mg, 1.104 mmol) and acetic acid (69.5 μL, 1.214 mmol). The reaction was heated to 100° C. overnight and was complete by LCMS analysis. The reaction was cooled to room temperature and the solvent was removed under reduced pressure. Remaining acetic acid was azeotroped with toluene (2×5 mL) to yield 2-({3-methyl-5-[2-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-1,3-thiazol-5-yl]phenyl}amino)pyrimidine-4-carboxylic acid as a tan powder. MS ESI: [M+H]+ m/z 425.1. 1H NMR (500 MHz, dmso) δ 13.79-13.63 (m, 10.05 (s, 1H), 8.73 (d, J=5.0, 1H), 8.22-8.14 (m, 1H), 8.10 (s, 1H), 7.65 (s, 1H), 7.56 (s, 1H), 7.32 (d, J=5.0, 1H), 7.12 (s, 1H), 2.31 (s, 3H), 1.76 (s, 3H). rhSYK activity=+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10].[Br:21]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:9]([O:11][CH3:12])=[O:10])=[CH:15][CH:16]=1
Reactant: COC(=O)C(Oc1ccc(C)cc1)c1ccccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Oc1ccc(CBr)cc1)c1ccccc1Cl
Yield: 76.5 %

Procedure:
To a solution of 0.200 g (0.69 mmol) of the product of Step C dissolved in 2 mL of carbon tetrachloride was added 0.117 g (0.95 eq) of N-bromosuccinimide and ca. 10 mg (catalytic amount) of AIBN. The reaction mixture was stirred and refluxed under a nitrogen atmosphere for 30 minutes, then cooled and concentrated in vacuo. The residual oil was purified on a silica gel flash chromatography column eluted with 5% ethyl acetate/hexane to afford 0.186 g (73%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2O[CH:9]=[N:10][N:11]=2)[CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:13].C1(C)C(C)=CC=CC=1>O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:13][CH:9]=[N:10][N:11]=2)[CH:2]=1
Reactant: c1cncc(-c2nnco2)c1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1C
Solvent: O
Product: c1cncc(-c2nncs2)c1
Reaction time: 16 h

Procedure:
A mixture of 5.5 g of the above prepared 2-(3-pyridyl)-1,3,4-oxadiazole, 8.5 g of phosphorus pentasulfide and 70 ml of xylene is stirred for 16 hours at 150°-160° C. To the cooled reaction mixture are added 50 ml of water and stirring is continued for another 5 minutes. The reaction mixture is then filtered. The filter residue is taken up in 100 ml of 10% sodium hydroxide solution. After extraction with chloroform, the organic phase is washed with water, dried and concentrated. After purification by column chromatography over silica gel with a 95:5 mixture of chloroform/ethanol as eluant, the crude 2-(3-pyridyl)-1,3,4-thiadiazole (compound 1) of the formula ##STR8## with a melting point of 64°-67° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([CH2:8]Cl)=[CH:6][CH:7]=1.[C-:10]#[N:11].[K+].C(OCC)(=O)C>CS(C)=O.O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([CH2:8][C:10]#[N:11])=[CH:6][CH:7]=1
Reactant: ClCc1ccc(Cl)nn1
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#CCc1ccc(Cl)nn1
Temperature: 80 °C

Procedure:
3-Chloro-6-chloromethyl-pyridazine (1.50 g) dissolved in dimethyl sulfoxide (7.5 mL) was added to a solution of potassium cyanide (0.90 g) in water (1 mL) and dimethyl sulfoxide (7.5 mL) stirred at 80° C. The solution was stirred at this temperature for 30 min and then cooled to room temperature. Water and ethyl acetate were added and the resulting mixture was filtered over Celite. The aqueous phase of the filtrate was separated and extracted twice with ethyl acetate. The extracts and the organic phase of the filtrate were combined and washed with brine and dried (Na2SO4). The solvent was evaporated and the residue was chromatographed on silica gel (cyclohexane/ethyl acetate 1:1→0:1) to give the title compound as a solid. Yield: 0.23 g (16% of theory); LC (method 2): tR=0.76 min; Mass spectrum (ESI+): m/z=154/156 (Cl) [M+H]+.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:41])[C:6]([N:26]1[C@H:29]([SH:30])[C@@H:28]([C@H:31]([O:33][C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])[CH3:32])[C:27]1=[O:40])=[P:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH2:3].N1C=CC=CC=1.[F:48][C:49]1[CH:59]=[CH:58][C:52]([O:53][CH2:54][C:55](Cl)=[O:56])=[CH:51][CH:50]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1.[Ag]>[CH2:1]([O:4][C:5](=[O:41])[C:6]([N:26]1[C@H:29]([S:30][C:55](=[O:56])[CH2:54][O:53][C:52]2[CH:58]=[CH:59][C:49]([F:48])=[CH:50][CH:51]=2)[C@@H:28]([C@H:31]([O:33][C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])[CH3:32])[C:27]1=[O:40])=[P:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH2:3]
Reactant: O=C(Cl)COc1ccc(F)cc1
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N(C(C(=O)OCC=C)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1S
Agent: [Ag]
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N(C(C(=O)OCC=C)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1SC(=O)COc1ccc(F)cc1

Procedure:
1.74 g of the silver salt of 2-[(3S,4R)-3-[(1R)-1allyloxycarbonyloxyethyl]-4-mercapto-2-oxo-azetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester are reacted in 30 ml of methylene chloride with 0.41 ml of pyridine, 20 mg of 4-dimethylaminopyridine and 0.7 g of 4-fluorophenoxyacetyl chloride. After working up analogously to Example 1, 2-[(3S,4R)-3-[(1R)-1-allyloxycarbonyloxyethyl]-4-(4-fluorophenoxyacetylthio)-2-oxo-azetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester is obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[C:12]1=[O:23])(=[O:3])[CH3:2].[CH2:24]([Br:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[Br-:31].[C:1]([C:4]1[CH:5]=[N+:6]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[C:12]1=[O:23])(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: COc1ccc2c(c1)CCC(Cc1ccncc1C(C)=O)C2=O
Product: COc1ccc2c(c1)CCC(Cc1cc[n+](Cc3ccccc3)cc1C(C)=O)C2=O
Product: [Br-]

Procedure:
The title compound 119 is prepared according to the procedure reported in Example 38.1 with compound 103 (67 mg, 0.2 mmol) and benzyl bromide as reactants. White solid. (Yield 34.5 mg, 80%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]=[CH:11]C(O)=O)=[CH:5][CH:4]=1.C([N:19]([CH2:22]C)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:31])C=CC=CC=1>C1(C)C=CC=CC=1>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:22](=[O:31])[NH:19][CH:11]=[N:10]2)=[CH:7][CH:8]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)C=NNc1ccc(C(F)(F)F)cc1
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1[nH]cnn1-c1ccc(C(F)(F)F)cc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
4-(trifluoromethyl)phenylhydrazonoacetic acid (6.26 g, 27 mmol) was suspended in 176 ml of toluene, and 4.0 ml of triethylamine (28.7 mmol) and 6.1 ml of diphenylphosphorylazide (28.3 mmol) were added and the resulting mixture was stirred for one hour at 120° C. After cooling, the reaction solution was extracted with 200 ml of an aqueous solution of pottasium hydroxide (10%). The aqueous extract was acidified with concentrated hydrochloric acid to adjust pH to 1, and the crystals thus separated out were washed with water and hexane successively and dried over phosphorus pentoxide to give 4.48 g of 2-(4-trifluoromethylphenyl)-3(2H,4H)-1,2,4-triazolone (72%) as a colorless powder.
Reaction SMILES: C(O[C:4]([C:6]1[S:10][C:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[N:8][C:7]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:5])C.O[NH:26][C:27](=[NH:30])[CH2:28][CH3:29]>>[C:15]([O:14][C:12](=[O:13])[NH:11][C:9]1[S:10][C:6]([C:4]2[O:5][N:30]=[C:27]([CH2:28][CH3:29])[N:26]=2)=[C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:8]=1)([CH3:16])([CH3:17])[CH3:18]
Reactant: CCOC(=O)c1sc(NC(=O)OC(C)(C)C)nc1-c1ccccc1
Reactant: CCC(=N)NO
Product: CCc1noc(-c2sc(NC(=O)OC(C)(C)C)nc2-c2ccccc2)n1

Procedure:
Prepared from 2-tert-butoxycarbonylamino-4-phenyl-thiazole-5-carboxylic acid ethyl ester and N-hydroxy-propionamidine.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[C:5](O)[CH:4]=1)#[N:2].[Li+].[BH4-].Cl.C1C[O:20]CC1>>[OH:8][CH2:7][C:6]1[CH:11]=[CH:12][C:3]([C:1]#[N:2])=[C:4]([OH:20])[CH:5]=1
Reactant: COC(=O)c1ccc(C#N)cc1O
Reactant: C1CCOC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Product: N#Cc1ccc(CO)cc1O
Temperature: 25 °C

Procedure:
Methyl 4-cyano-2-hydroxybenzoate (0.50 g, 2.82 mmol) was dissolved in dry THF (30 mL), treated with LiBH4 (2.0M solution in THF) (5.64 mL, 11.28 mmol), and heated at reflux for 18 hr. The reaction mixture was cooled to room temperature, poured into 1N HCl solution and extracted with EtOAc (2×). Organics combined and dried (MgSO4), filtered and concentrated to dryness to give the title compound which was used without further purification.
Reaction SMILES: C([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:51]2[N:52]=[C:53]([NH:56]C(OC(C)(C)C)=O)[S:54][CH:55]=2)\[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([O-:34])(=[O:33])=[O:32])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]([CH2:41][S:42][CH:43]3[CH2:50][N:46]4[CH:47]=[N:48][CH:49]=[N+:45]4[CH2:44]3)[CH:38]=[N:37]2)=[O:24])[CH2:19][CH2:18]1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:56][C:53]1[S:54][CH:55]=[C:51](/[C:22](=[N:21]/[O:20][C:17]2([C:15]([OH:16])=[O:14])[CH2:19][CH2:18]2)/[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([O-:34])(=[O:33])=[O:32])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]([CH2:41][S:42][CH:43]3[CH2:44][N:45]4[CH:49]=[N:48][CH:47]=[N+:46]4[CH2:50]3)[CH:38]=[N:37]2)=[O:24])[N:52]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)[O-])[C@@H]2Cn2ncc(CSC3Cn4cnc[n+]4C3)n2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: Nc1nc(/C(=N/OC2(C(=O)O)CC2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)[O-])[C@@H]2Cn2ncc(CSC3Cn4cnc[n+]4C3)n2)cs1
Yield: 9.2 %

Procedure:
Prepared in analogous manner to example 138, step 3 using (2R,3S)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-(((6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazol-4-ium-6-yl)thio)methyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidine-1-sulfonate (23 mg, 0.025 mmol), anisole (5.5 μL, 0.050 mmol), TFA (116 μL, 1.50 mmol) and DCM (300 μL). The crude residue purified by reverse phase prep HPLC (Xselect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (1.5 mg, 8%). LCMS: Rt=0.60 min, m/z=654.4 (M+1) Method 2m_acidic; 1H NMR (400 MHz, D2O) δ 9.02 (d, J=4.8 Hz, 2H), 7.84 (s, 1H), 7.17 (s, 1H), 5.65 (d, J=5.8 Hz, 1H), 5.12-4.97 (m, 3H), 4.94-4.89 (m, 1H), 4.64-4.50 (m, 4H), 4.09 (s, 2H), 1.48-1.36 (m, 2H), 1.32-1.24 (m, 2H).
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[CH:11]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([S:21](Cl)(=[O:23])=[O:22])[C:15]=2[CH:14]=[CH:13][N:12]=1>C([O-])(O)=O.[Na+].C(OCC)C.O>[CH:11]1[C:20]2[C:15](=[C:16]([S:21]([O:5][C:4]3[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=3)(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(O)cc(OS(=O)(=O)c2cccc3cnccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
Orcinol monohydrate (1.42 g, 10.0 mmol) and 5-isoquinolinesulfonyl chloride (2.64 g, 10.0 mmol), as prepared in the preceding step, were mixed in saturated NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at room temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was triturated with ether/hexane to give the title compound as a pale yellow solid (1.15 g, 37%). 1H-NMR (300 MHz, CDCl3) δ9.67 (s, 1H), 9.60 (s, 1H), 8.86 (d, J=6.1 Hz, 1H), 8.63 (d, J=8.2 Hz, 1H), 8.37 (t, J=6.1 Hz, 2H), 7.86 (t, J=7.8 Hz, 1H), 6.46 (s, 1H), 6.23 (s, 1H), 5.97 (3, 1H), 2.08 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:12][CH:13]=O)[CH:8]=[N:9]2)=[N:4][CH:3]=1.C(O)(=O)C.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[C:7]([CH2:12][CH2:13][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH:6]=2
Reactant: O=CCc1cnc2cc(Br)cnc2c1
Reactant: C1CCNC1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: Brc1cnc2cc(CCN3CCCC3)cnc2c1

Procedure:
To a stirred solution of the product from Example 153D (0.1 g, 0.4 mmol), acetic acid (0.4 mmol, 0.025 g) and pyrrolidine (0.44 mmol, 0.031 g) in dry THF (5 ml) NaBH(OAc)3 was added (0.6 mmol, 0.127 g). After 12 hr at room temperature the mixture was diluted with 50 mL of CH2Cl2 and washed successively with a saturated solution of sodium bicarbonate, brine and water. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified over silica using 10% MeOH in CH2Cl2. The desired compound was obtained in 40%. 1H NMR (CDCl3, 300 MHz) δ 1.60 (m, 4H), 2.20 (m, 4H), 2.75 (m, 4H), 8.30 (m, 1H), 8.40 (m, 1H), 8.90 (m, 1H), 9.05 (m, 1H). MS (ESI) [M+H]+ at 307.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH2:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][C:11]#[CH:12]>>[Cl:1][C:2]1[N:7]=[C:6]([C:12]#[C:11][CH2:10][CH2:9][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C#CCCc1ccccc1
Reactant: Clc1ccnc(Cl)n1
Product: Clc1nccc(C#CCCc2ccccc2)n1
Yield: 68.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2,4-dichloropyrimidine (250 mg, 1.68 mmol) and 1-(but-3-ynyl)benzene (218 mg, 1.68 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 280 mg (1.15 mmol, 69%) of 2-chloro-4-(4-phenylbut-1-ynyl)pyrimidine as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C:9]1([CH2:18][CH:19]2[O:23][CH2:22][CH2:21][O:20]2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].IC.[CH3:27][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:24])[N:7]([CH2:8][C:9]1([CH2:18][CH:19]2[O:23][CH2:22][CH2:21][O:20]2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)[CH3:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1(CC2OCCO2)CCc2ccccc21
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(CC1(CC2OCCO2)CCc2ccccc21)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A solution of tert-butyl[1-(1,3-dioxolan-2-ylmethyl)-2,3-dihydro-1H-inden-1-yl]methylcarbamate (13.50 g, 38.9 mmole) in THF was cooled to 0° C. To this was added iodomethane (7.27 ml, 117 mmole) followed by 1M NaHMDS in THF (58 ml, 58 mmole). The reaction was then warmed to room temperature and stirred until no U16370/185/2 remained by TLC. The THF was evaporated and the residue dissolved in Et2O. The ether was washed with water and evaporated to afford 14.33 g of tert-butyl[1-(1,3-dioxolan-2-ylmethyl)-2,3-dihydro-1H-inden-1-yl]methyl(methyl)carbamate as a crude oil, which was used, with no further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.[CH3:42][CH:43]([NH2:53])[CH2:44][CH2:45][CH2:46][C:47]1[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=1>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([NH:53][CH:43]([CH3:42])[CH2:44][CH2:45][CH2:46][C:47]3[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=3)=[O:17])=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2ccc(C(=O)O)cc2)cc1C
Reactant: CC(N)CCCc1cccnc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc(C(=O)NC(C)CCCc3cccnc3)cc2)cc1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.2 %

Procedure:
A solution of 50 g of 3',4'-dimethyl[1,1'-biphenyl]-4-carboxylic acid in 200 mL of DMF was cooled in an ice bath and 5.2 mL of diphenylphosphoryl azide was added. After 20 minutes, 3.9 mL of triethylamine was added, and after a further hour, 4.0 g of rac. alpha-methyl-3-pyridinebutanamine was added and the mixture was allowed to warm to room temperature over night. The solvent was evaporated, the residue was taken up in dichloromethane and washed with water and bicarbonate, dried (MgSO4), and purified by preparative hPlc eluting with 95:5 dichloromethane-methanol to give 4.1 g (65%) of rac.-3',4'-dimethyl-N-[1-methyl-4-(3-pyridinyl)butyl][1,1'-biphenyl]4-carboxamide, mp 118°-120° C. after recrystallization from ethyl acetate-hexane. The analytical sample was obtained from ethyl acetate. mp 120°-121° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH3:14][Si](C)(C)[N-][Si](C)(C)C.[Li+].C(Br)[CH2:25][CH:26]([CH3:28])[CH3:27]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:14])([CH2:13][CH2:25][CH:26]([CH3:28])[CH3:27])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)CCBr
Reactant: COC(=O)C(C)c1ccc(F)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C)(CCC(C)C)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of the compound of Example 22A (10.0 g, 55 mmol) in tetrahydrofuran (30 mL) was added dropwise over 30 min to a −78° C. solution of lithium hexamethyldisilazide (prepared from hexamethyldisilazane (14.5 mL, 68.7 mmol) and n-butyllithium in hexane (2.5 M, 26.4 mL, 65.9 mmol)). The solution was stirred at −78° C. for 1 h. The solution was then treated with neat isoamyl bromide (9.9 mL, 82.4 mmol) followed by stirring at −78° C. for 30 min, and then warming to ambient temperature for 48 h. The solution was quenched by addition of saturated ammonium chloride solution (6 mL) and diluted with water. The mixture was concentrated in vacuo to remove tetrahydrofuran, and then extracted with ethyl acetate. The organic layer was extracted with water (2×) and saturated NaCl solution. Drying (Na2SO4) and concentration in vacuo afforded a brown oil, which was distilled under reduced pressure (90-93° C./0.3 mm Hg) to afford the title compound (11.8 g, 85%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 0.87 (m, 6 H) 1.03 (m, 2 H) 1.51 (m, 4 H) 1.95 (m, 2 H) 3.65 (s, 3 H) 7.01 (m, 2 H) 7.28 (m, 2 H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[N:5]=[C:4]([NH:23][C:24]2[CH:28]=[CH:27][N:26]([CH2:29][C:30]([OH:32])=O)[N:25]=2)[CH:3]=1.[CH3:33][NH:34][CH3:35].CN(C(O[N:44]1[N:52]=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.NN>>[NH2:9][C:8]1[C:7]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:12][CH:11]=3)=[N:5][C:4]([NH:23][C:24]3[CH:28]=[CH:27][N:26]([CH2:29][C:30]([N:34]([CH3:35])[CH3:33])=[O:32])[N:25]=3)=[CH:3][C:2]=2[NH:52][N:44]=1
Reactant: N#Cc1c(Cl)cc(Nc2ccn(CC(=O)O)n2)nc1-c1ccc(Oc2ccccc2)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CNC
Agent: F[P-](F)(F)(F)(F)F
Agent: NN
Product: CN(C)C(=O)Cn1ccc(Nc2cc3[nH]nc(N)c3c(-c3ccc(Oc4ccccc4)cc3)n2)n1

Procedure:
The acid from Step 2 of Example 248 and dimethylamine were coupled with HATU and subsequently reacted with hydrazine following conditions in Step 3 of Example 248 to give Example 249. 1H NMR (400 MHz, methanol-d4) δ ppm 7.91-7.97 (2H, m), 7.65 (1H, d, J=2.51 Hz), 7.47-7.54 (2H, m), 7.31 (1H, t, J=7.40 Hz), 7.18-7.24 (4H, m), 6.78 (1H, s), 6.05 (1H, d, J=2.26 Hz), 5.09 (2H, s), 3.03 (3H, s), 2.86 (3H, s); MS (ES+) m/z: 469.5 (M+H); LC retention time: 3.238 min (analytical HPLC
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:65])([CH3:64])[C@H:42]([N:50]1[CH2:54][CH2:53][N:52]([CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([CH3:62])[N:57]=2)[C:51]1=[O:63])[C:43](OC(C)(C)C)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:65])([CH3:64])[C@H:42]([N:50]1[CH2:54][CH2:53][N:52]([CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([CH3:62])[N:57]=2)[C:51]1=[O:63])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: Cc1cccc(CN2CCN([C@H](C(=O)OC(C)(C)C)C(C)(C)C)C2=O)n1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2cccc(C)n2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
A solution containing the product from Example 2C (1.0 g, 1.88 mmol) in THF (19 mL) was treated with the product from Example 10B (0.83 g, 1.98 mmol), DEPBT (0.84 g, 2.8 mmol), and N,N-diisopropylethylamine (1.6 mL, 9.2 mmol), stirred at 25° C. for 16 hours, and partitioned between a mixture of dichloromethane and ethyl acetate (2:1, respectively) and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane, followed by elution with 0-5% methanol in ethyl acetate to give the title compound (1.15 g, 75% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.83 (s, 9 H), 0.90 (s, 9 H), 1.55 (m, 2 H), 2.38 (q, J=9.44 Hz, 1 H), 2.46 (s, 3 H), 2.57 (m, 1 H), 2.67 (d, J=7.35 Hz, 2 H), 2.79 (m, 1 H), 2.97 (m, 1 H), 3.09 (q, J=8.95 Hz, 1 H), 3.21 (m, 1 H), 3.50 (s, 3 H), 3.67 (m, 1 H), 3.85 (d, J=9.93 Hz, 1 H), 4.12 (m, 3 H), 4.35 (m, 2 H), 4.54 (d, J=7.72 Hz, 1 H), 6.63 (d, J=9.56 Hz, 1 H), 7.09 (m, 7 H), 7.22 (d, J=8.09 Hz, 2 H), 7.31 (m, 1 H), 7.49 (d, J=9.56 Hz, 1 H), 7.69 (t, J=7.54 Hz, 1 H), 7.86 (m, 5 H), 8.63 (d, J=4.78 Hz, 1 H).