Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5].[CH:14]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[C:30]3=[N:31][CH:32]=[N:33][C:34](Cl)=[C:29]3[C:28]([CH3:36])=[N:27]2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])[CH3:15].[Cl-].[NH4+]>CN(C)C=O>[CH:14]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[C:30]3=[N:31][CH:32]=[N:33][C:34]([O:13][C:10]4[CH:11]=[CH:12][C:7]([S:4]([CH3:3])(=[O:5])=[O:6])=[CH:8][CH:9]=4)=[C:29]3[C:28]([CH3:36])=[N:27]2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])[CH3:15]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: Cc1nn(C2CCN(C(=O)OC(C)C)CC2)c2ncnc(Cl)c12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1nn(C2CCN(C(=O)OC(C)C)CC2)c2ncnc(Oc3ccc(S(C)(=O)=O)cc3)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.9 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 7 mg, 0.18 mmol) was added to a solution of 4-(methylsulfonyl)phenol (20 mg, 0.12 mmol) in dimethylformamide (1 mL) and the mixture was stirred at room temperature for 15 min. A solution of 4-(4-chloro-3-methyl-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid isopropyl ester (Intermediate 21; 40 mg, 0.12 mmol) in dimethylformamide (1 mL) was added, and the reaction mixture was allowed to stir at room temperature overnight. Saturated aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate (3×25 mL). The organic layer was washed with water (3 times) and brine, dried (sodium sulfate), filtered, evaporated and purified on a flash silica column (20 mm×3″) eluting with 75-80% ethyl acetate/hexanes to give 4-[4-(4-methanesulfonyl-phenoxy)-3-methyl-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid isopropyl ester (38 mg, 68%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.20 (d, 6H, J=6.3 Hz), 1.93-2.02 (m, 4H), 2.62 (s, 3H), 3.03-3.09 (m, 2H), 3.32 (s, 3H), 4.08-4.12 (m, 2H), 4.77-4.81 (m, 1H), 4.85-4.95 (m, 1H), 7.59-7.62 (m, 2H), 8.01-8.04 (m, 2H), 8.46 (s, 1H). Mass spectrum (ES) MH+=474.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C@@H:12]([C:14]([OH:16])=[O:15])[NH2:13].[OH-].[Na+].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>O>[CH2:23]([O:22][C:20]([NH:13][C@H:12]([C:14]([OH:16])=[O:15])[CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(N[C@@H](Cc1ccc2ccccc2c1)C(=O)O)OCc1ccccc1
Reaction time: 2 h

Procedure:
5 g of 3-(2-naphthyl)-L-alanine and 0.93 g of sodium hydroxide in 12 ml of water were cooled to 0° C. and stirred while a solution of 1.4 g of sodium hydroxide in 9 ml of water and 5 ml of benzyl chloroformate were added simultaneously during 10 minutes. Stirring was continued for 2 hours and the mixture was allowed to come to room temperature. The mixture was diluted with water and then extracted with diethyl ether. The aqueous layer was acidified with 4 ml of concentrated hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extracts were back-washed with water. The combined ethyl acetate extracts were dried over sodium sulphate, filtered, evaporated and triturated with petroleum ether (boiling point 40°-60° C.) to give 7.5 g of N-(benzyloxycarbonyl)-3-(2-naphthyl)-L-alanine of melting point 109°-111° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH3:14][NH:15][C@H:16]1[CH2:35][N:20]2[C:21]3[C:26]([C:27]([CH2:28][C:29]([O:31]CCC)=[O:30])=[C:19]2[CH2:18][CH2:17]1)=[CH:25][CH:24]=[CH:23][CH:22]=3>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([N:15]([CH3:14])[C@H:16]2[CH2:35][N:20]3[C:21]4[C:26]([C:27]([CH2:28][C:29]([OH:31])=[O:30])=[C:19]3[CH2:18][CH2:17]2)=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:11])=[CH:6][CH:7]=1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: CC(C)(C(=O)O)c1ccc(F)cc1
Product: CN(C(=O)C(C)(C)c1ccc(F)cc1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from 2-(4-fluorophenyl)-2-methylpropanoic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 423.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:15]([NH2:19])=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)=[CH:4][CH:3]=1.[CH:20]1([S:23](Cl)(=[O:25])=[O:24])[CH2:22][CH2:21]1>N1C=CC=CC=1>[CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[NH:19][S:23]([CH:20]3[CH2:22][CH2:21]3)(=[O:25])=[O:24])[N:10]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Cc1ccc(CNc2ccc3c(N)cccc3n2)o1
Solvent: c1ccncc1
Product: Cc1ccc(CNc2ccc3c(NS(=O)(=O)C4CC4)cccc3n2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N2-(5-Methyl-furan-2-ylmethyl)-quinoline-2,5-diamine (200 mg, 0.79 mmol) was dissolved in 2 mL pyridine and cyclopropane sulfonylchloride (118 mg, 0.79 mmol) was added. The reaction mixture was stirred at room temperature overnight and quenched by addition of 50 mL water and acetic acid until pH 5. The mixture was extracted three times with ethyl acetate (50 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->50:50 gradient). The title compound was obtained as a yellow oil (234 mg, 78%), MS: m/e=358.4 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])[N+:5]([O-:13])=[C:4]([NH:14][C:15]([O:17][CH3:18])=[O:16])[CH:3]=1.[NH:19]1[CH2:24][CH2:23][CH:22]=[CH:21][CH2:20]1>C(Cl)Cl>[N:19]1([C:2]2[N:7]=[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])[N+:5]([O-:13])=[C:4]([NH:14][C:15]([O:17][CH3:18])=[O:16])[CH:3]=2)[CH2:20][CH:21]=[CH:22][CH2:23][CH2:24]1
Reactant: COC(=O)Nc1cc(Cl)nc(NC(=O)OC)[n+]1[O-]
Reactant: C1=CCNCC1
Solvent: ClCCl
Product: COC(=O)Nc1cc(N2CC=CCC2)nc(NC(=O)OC)[n+]1[O-]

Procedure:
A suspension of 10 g. of dimethyl 6-chloro-2,4-pyrimidinedicarbamate-3-oxide in 40 ml. of methylene chloride is treated with 20 ml. of 1,2,5,6-tetrahydropyridine and stirred at room temperature under an argon atmosphere for 16 hours. The precipitate formed is filtered off and recrystallized from a mixture of methylene chloride and methanol, there being obtained pure dimethyl 6-[3,6-dihydro-1(2H)-pyridyl]-2,4-pyrimidinedicarbamate-3-oxide having a melting point of 203° C.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:4]3[CH2:5][CH:6]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:7][CH2:8][C:9]=3[S:10][C:11]=2[N:12]=[CH:13][N:14]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1>[OH:1][C:2]1[C:3]2[C:4]3[CH:5]=[C:6]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:7]=[CH:8][C:9]=3[S:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: CCOC(=O)CC1CCc2sc3ncnc(O)c3c2C1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc2sc3ncnc(O)c3c2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 67.6 %

Procedure:
A mixture of ethyl 2-[3-hydroxy-8-thia-4,6-diazatricyclo[7.4.0.0^[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl]acetate (3.00 g, 10.26 mmol, 1.00 equiv) and DDQ (5.83 g, 25.68 mmol, 2.50 equiv) in 1,4-dioxane (30 mL) was stirred for 2 h at 90° C. in an oil bath under nitrogen. The reaction mixture was cooled to room temperature and quenched with saturated aqueous Na2CO3, extracted with 3×40 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:1) to provide the desired ethyl 2-[3-hydroxy-8-thia-4,6-diazatricyclo[7.4.0.0^[2,7]]trideca-1(9),2(7),3,5,10,12-hexaen-12-yl]acetate (2.00 g, 68%) as a yellow solid. LCMS (ES, m/z): 289 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.[CH3:31][N:32](C=O)C>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[OH:29][C@@H:24]1[C@@H:23]([N:13]2[C:12](=[O:30])[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]4=[C:9]([CH2:8][C:5]4[CH:4]=[CH:3][C:2]([C:31]#[N:32])=[N:7][CH:6]=4)[CH:10]=3)[N:15]=[CH:14]2)[CH2:28][CH2:27][O:26][CH2:25]1
Reactant: CN(C)C=O
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Cc2cc3c(=O)n([C@H]4CCOC[C@@H]4O)cnc3c3ccccc23)cn1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a solution of 6-[(6-chloropyridin-3-yl)methyl]-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one (0.100 g, 0.237 mmol) in 1 mL of DMF under an atmosphere of nitrogen was added zinc cyanide (Example 1, 0.084 g, 0.71 mmol) and tetrakis(triphenylphosphine)palladium(0) (13.7 mg, 0.012 mmol). The mixture was heated to 100° C. for 8 h, then at 140° C. for another 15 h. The reaction was cooled to rt, diluted with ethyl acetate, washed 3× with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 413.1603 for [M+H]+ [Calc'd for C24H21N4O3, [M+H]+=413.1608]: 1H NMR (400 MHz, CDCl3) δ 8.96-8.94 (m, 1H), 8.56 (s, 1H), 8.29 (s, 1H), 7.98 (s, 1H), 7.78-7.75 (m, 1H), 7.64-7.59 (m, 2H), 7.50 (s, 2H), 4.72-4.69 (m, 1H), 4.49 (s, 2H), 4.11-4.05 (m, 2H), 4.04-3.98 (m, 1H), 3.50-3.47 (m, 1H), 3.29-3.20 (m, 2H), 2.17-2.13 (m, 1H), 2.00-1.95 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([OH:15])[CH2:9][CH2:10][C:11]([O:13]C)=[O:12])=[CH:4][C:3]=1[CH3:16].[OH-].[K+]>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([OH:15])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[CH3:16]
Reactant: COC(=O)CC[C@@H](O)c1ccc(F)c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc([C@H](O)CCC(=O)O)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-Methyl 4-(4-fluoro-3-methylphenyl)-4-hydroxybutanoate (181 mg, 0.80 mmol) in 5 mL dioxane was added 5 mL aqueous 5% KOH at 25° C. The mixture was stirred for 30 min at room temperature and then the reaction quenched by the addition of 10 mL of 1M HCl and the resulting mixture extracted with ethyl acetate (2×10 mL). The combined organic layers were extracted with 5% K2CO3 (3×5 mL) and the aqueous extracts acidified with 1M HCl to pH3. The resulting white colloidal suspension was extracted with ethyl acetate (3×20 mL) and the combined organic layers washed with brine (2×15 mL) before being dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude product (233 mg) was used in the next step without further purification.
Reaction SMILES: OCCCN1C=C(C2C=CC(N[C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=C3C=2CN(C)C3=O)C=N1.C(OP1(=O)CC2C=CC(=CC=2)NC2=NC(=C(C(F)(F)F)C=N2)NC2C=CC(=NC=2C(NC)=O)C2=CN(N=C2)CCCCO1)C.[NH2:94][C:95]1[C:96]([C:112]([NH:114][CH3:115])=[O:113])=[N:97][C:98]([C:101]2[CH:102]=[N:103][N:104]([CH2:108][CH2:109][CH2:110][OH:111])[C:105]=2[C:106]#[N:107])=[CH:99][CH:100]=1>>[C:106]([C:105]1[N:104]([CH2:108][CH2:109][CH2:110][OH:111])[N:103]=[CH:102][C:101]=1[C:98]1[N:97]=[C:96]([C:112](=[O:113])[NH:114][CH3:115])[C:95]([NH:94][C:26]2[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:22][N:23]=[C:24]([NH:32][C:33]3[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=3[O:48][CH3:49])[N:25]=2)=[CH:100][CH:99]=1)#[N:107]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: CNC(=O)c1nc(-c2cnn(CCCO)c2C#N)ccc1N
Agent: CCOP1(=O)Cc2ccc(cc2)Nc2ncc(C(F)(F)F)c(n2)Nc2ccc(nc2C(=O)NC)-c2cnn(c2)CCCCO1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4C#N)nc3C(=O)NC)n2)c(OC)c1)OCC
Yield: 55 %

Procedure:
Prepared analogously to Compound 1B using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 1 E, 218 mg, 0.480 mmol) and 3-amino-6-[5-cyano-1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-N-methylpyridine-2-carboxamide (Compound 53C, 151 mg, 0.504 mmol) to afford 191 mg of the title compound (55%). 1H NMR (400 MHz, CD3OD) δ 9.19 (br. s., 1H), 8.47 (s, 1H), 8.38 (s, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.69 (br. s., 1H), 7.08 (s, 1H), 6.98 (d, J=7.8 Hz, 1H), 4.52 (t, J=6.9 Hz, 2H), 4.01-4.14 (m, 3H), 3.88 (s, 2H), 3.61 (t, J=6.1 Hz, 2H), 3.36 (s, 2H), 2.99 (s, 3H), 2.17 (quin, J=6.5 Hz, 2H), 1.18-1.31 (m, 8H). MS (ESI): m/z=718.56 [M+H]+. UPLC: tR=1.36 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([CH:16]1[O:18][CH2:17]1)Br.[H-].[Na+]>CN(C)C=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH:16]2[CH2:17][O:18]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCCc1ccccc1
Reactant: BrCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(CCCCCCOCC2CO2)cc1

Procedure:
A procedure similar to that described in Preparation 46 was repeated, except that 5 g of 6-phenyl-1-hexanol, 4.6 ml of epibromohydrin, 1.23 g of sodium hydride (as a 55% by weight dispersion in mineral oil) and 80 ml of anhydrous dimethylformamide were used. The resulting crude product was purified by silica gel column chromatography, using a 1:7 by volume mixture of ethyl acetate and hexane as the eluent, to give 4.35 g of the title compound as a colorless oil having an Rf value of 0.60 (on silica gel thin layer chromatography, using a 1:5 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [C:1]12([C:11]3[N:12]([CH2:17][CH3:18])[C:13]([SH:16])=[N:14][N:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C[O-].[Na+].[CH2:22](I)[CH3:23]>CO>[C:1]12([C:11]3[N:12]([CH2:17][CH3:18])[C:13]([S:16][CH2:22][CH3:23])=[N:14][N:15]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CCn1c(S)nnc1C12CC3CC(CC(C3)C1)C2
Reactant: CCI
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCSc1nnc(C23CC4CC(CC(C4)C2)C3)n1CC

Procedure:
5-(1 -Adamantyl)-4-ethyl-4H-1,2,4-triazole-3-thiol (D, Arzneim.-Forsch. 1991, 41, 1260-1264) (40 mg, 0.15 mmol) and 0.5 M methanolic NaOMe (0.3 mL, 0.15 mmol) in methanol (1 mL) was heated under reflux for 10 min. Ethyl iodide (12 μl, 0.15 mmol) was added, and the mixture was heated under reflux for 2 h. The methanol was removed in vacuo, and the residue was partitioned between CH2Cl2 and water. The organic layer was dried (MgSO4) and evaporated in vacuo. The residue was purified by chromatography on silica gel with 10% MeOH in CH2Cl2 to give 3-(1-adamantyl)-4-ethyl-5-(ethylthio)-4H-1,2,4-triazole (2), MS: 278 (M+1).
Reaction SMILES: [CH3:1][C:2]([NH:11][C:12](=[O:21])[C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=1)([CH3:10])[C:3]([CH2:5][O:6]C(=O)C)=[O:4].C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:10][C:2]([NH:11][C:12](=[O:21])[C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=1)([CH3:1])[C:3]([CH2:5][OH:6])=[O:4]
Reactant: CC(=O)OCC(=O)C(C)(C)NC(=O)c1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(NC(=O)c1cc(Cl)cc(Cl)c1)C(=O)CO
Yield: 91.6 %

Procedure:
N-(1',1'-dimethyl-3'-acetoxyacetonyl)-3,5-dichlorobenzamide (5.0 gm, 0.15 m) was treated with potassium carbonate (0.21 gm, 0.0015 m) in 250 ml methanol at room temperature for 12 hours. The methanol was removed by a vacuum, the residue was taken up in ether and washed successively with saturated sodium bicarbonate, water and brine. Drying of the ether solution followed by removing the solvent yielded 4.0 gm (98%) of pure product.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@@:8]1([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])=[CH:19][CH:18]=2)[CH3:16])[CH2:10][CH2:9]1)(=O)=O.[NH:38]1[CH:42]=[CH:41][N:40]=[C:39]1[NH2:43].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[NH:38]1[CH:42]=[CH:41][N:40]=[C:39]1[NH:43][CH2:6][CH2:7][C@@:8]1([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])=[CH:21][CH:22]=2)[CH3:16])[CH2:10][CH2:9]1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCOS(C)(=O)=O)(c2ccc(F)cc2)OC1=O
Reactant: Nc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCNc2ncc[nH]2)(c2ccc(F)cc2)OC1=O
Yield: 19.2 %

Procedure:
A mixture of 2-((S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl methanesulfonate (40 mg, 0.07 mmol), 1H-imidazol-2-amine (18 mg, 0.21 mmol), K2CO3 (29 mg, 0.21 mmol) in acetonitrile (4 mL) was heated to reflux overnight. The solvent was removed and the residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product. It was purified by preparative HPLC to give (R)-6-(2-(1H-imidazol-2-ylamino)ethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (7 mg, 17%). LC-MS Method 3 tR=1.15, min, m/z=521; 1H NMR (CDCl3): 1.55 (m, 3H), 2.16-2.33 (m, 7H), 2.94 (m, 1H), 3.56 (m, 1H), 4.02 (m, 1H), 5.66 (m, 1H), 6.25 (m, 1H), 6.52 (m, 1H), 6.90 (m, 2H), 7.04 (m, 4H), 7.18 (m, 2H), 7.26 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3](Br)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:13]([C@@:15]1([CH3:30])[CH2:19][CH2:18][CH2:17][N:16]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])#[CH:14].O>C1(C)C=CC=CC=1.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.[Cu]I>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[C:14]#[C:13][C@@:15]1([CH3:30])[CH2:19][CH2:18][CH2:17][N:16]1[C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21]
Reactant: COC(=O)c1cccc(N)c1Br
Reactant: C#C[C@@]1(C)CCCN1C(=O)OCc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(N)c1C#C[C@@]1(C)CCCN1C(=O)OCc1ccccc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 58.9 %

Procedure:
To a suspension of tetrakis(triphenylphosphine)palladium(0)(1.72 g, 1.5 mmol) and CuI (0.29 g, 1.5 mmol) in 54 mL of toluene were added methyl 3-amino-2-bromobenzoate (2.3 g, 10 mmol), (R)-benzyl 2-ethynyl-2-methylpyrrolidine-1-carboxylate (3.0 g, 12 mmol), and TEA (7 mL, 50 mmol). The mixture was stirred for 18 h at 100° C. under nitrogen atmosphere. After cooling, water (20 mL) was added. The mixture was extracted with EtOAc (3×20 mL) and the combined organic layers were washed with brine (20 mL) and dried over MgSO4. The mixture was filtered, and the filtrate was evaporated to dryness. The residue was purified by column chromatography on silica gel using CH2Cl2 as eluent to provide 2.31 g of (R)-benzyl 2-((2-amino-6-(methoxycarbonyl)phenyl)ethynyl)-2-methylpyrrolidine-1-carboxylate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20]>[Pd]>[F:16][C:15]([F:18])([F:17])[O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([C:24]3[CH:25]=[CH:26][C:21]([CH:19]=[O:20])=[CH:22][CH:23]=3)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: FC(F)(F)Oc1ccc(-c2cc(Cl)ncn2)cc1
Agent: [Pd]
Product: O=Cc1ccc(-c2cc(-c3ccc(OC(F)(F)F)cc3)ncn2)cc1

Procedure:
The compound was prepared by palladium-catalyzed arylation of the product of step 1 with 4-formylphenyl boronic acid: 1H NMR (400 MHz, CDCl3) δ 10.15 (s, 1H), 9.38 (d, J=0.9 Hz, 1H), 8.33 (d, J=8.4 Hz, 2H), 8.23 (d, J=8.5 Hz, 2H), 8.16 (d, J=0.8 Hz, 1H), 8.08 (d, J=8.8 Hz, 2H), 7.40 (d, J=8.1 Hz, 2H); EIMS m/z 344 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([Cl:10])[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]1=[O:24].C(N(CC)CC)C.[F:32][C:33]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>>[Cl:10][C:6]1[CH:5]=[C:4]([F:11])[C:3]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[C:2]([NH:1][C:35](=[O:36])[C:34]2[CH:38]=[CH:39][C:40]([F:42])=[CH:41][C:33]=2[F:32])[C:7]=1[O:8][CH3:9]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1N
Solvent: CCN(CC)CC
Product: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1NC(=O)c1ccc(F)cc1F
Yield: 80.2 %

Procedure:
3-(2-Amino-4-chloro-6fluoro-3-methoxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)pyrimidinedione (2.0 g, 5.4 mmol) and triethylamine (0.66 g, 6.5 mmol) were dissolved in anhydrous tetrahydrofiuran (30 ml) and stirred under ice cooling. To this solution was slowly added 2,4-difluorobenzoyl chloride (0.96 g, 5.4 mmol) and solution refluxed for 2 hr. Another batch of 2,4-difluorobenzoyl chloride (0.19 g, 1.1 mmol) was added and solution refluxed for 2 hr. Solvent was removed in vacuo and the product purified by column chromatography on silica gel using hexane-ethyl acetate (3:1) as the eluent to afford the title compound (2.2 g).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[N:25]([CH3:26])[CH:24]=[CH:23][C:10]3=[N:11][C:12]=2[C@@H:13]([NH:15]C(=O)OC(C)(C)C)[CH3:14])=[C:5]([CH3:27])[O:4][N:3]=1.[ClH:28].O1CCOCC1>C(Cl)Cl>[ClH:28].[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[N:25]([CH3:26])[CH:24]=[CH:23][C:10]3=[N:11][C:12]=2[C@@H:13]([NH2:15])[CH3:14])=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1cc2c(ccn2C)nc1[C@H](C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1noc(C)c1-c1cc2c(ccn2C)nc1[C@H](C)N
Temperature: 20 °C
Reaction time: 21 h

Procedure:
To a solution of tert-butyl ((1S)-1-(6-(3,5-dimethylisoxazol-4-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)carbamate (105 mg, 0.283 mmol) in anhydrous DCM (3.0 mL) was added 4 N HCl in dioxane (0.40 mL, 1.6 mmol). The solution was stirred at 20° C. for 21 hours and then concentrated in vacuo to give an HCl salt of the title compound as a white solid, which was used without further purification. ESI-MS m/z [M+H]+ calc'd for C15H18N4O, 271; found 271.