Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:8][N:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=4)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=3)=[CH:11][CH:10]=2)[CH2:6]1)=[O:4].[OH-].[Li+]>C1COCC1.CO.O>[Cl:32][C:26]1[CH:25]=[C:24]([C:18]2([C:20]([F:21])([F:23])[F:22])[O:17][N:16]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([N:7]4[CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:8]4)=[CH:10][CH:11]=3)[CH2:19]2)[CH:29]=[C:28]([Cl:30])[C:27]=1[Cl:31]
Reactant: COC(=O)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.4 %

Procedure:
To a stirred suspension of 1-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-azetidine-3-carboxylic acid methyl ester (Preparation 11, 1.91 g, 3.77 mmol) in THF:MeOH:H2O (1:1:1, 60 mL) was added lithium hydroxide (0.791 g, 18.87 mmol) at room temperature and stirred at room temperature for 24 hours. After consumption of starting material, reaction mixture was concentrated in vacuo; suspension was diluted with water (20 mL) and acidified with 1N HCl up to pH ˜4. Acidified aqueous layer was extracted with ethyl acetate (5×50 mL). Combined organic layer washed with brine (150 mL), dried over sodium sulphate and evaporated under reduced pressure to afford yellow semi solid, which was triturated with chloroform:n-pentane (1:9) to afford yellow solid (1.57 g, 85%). 1H NMR (400 MHz, DMSO) δ: 3.49-3.52 (m, 1H), 3.90 (t, 2H, J=6.7 Hz), 4.04 (t, 2H, J=8.12 Hz), 4.13-4.25 (m, 2H), 6.46 (d, 2H, J=8.64 Hz), 7.48 (d, 2H, J=8.6 Hz), 7.79 (s, 2H); LC-MS (M+H): =492.60.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[C:10]([NH2:14])([CH3:13])([CH3:12])[CH3:11]>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([NH:14][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CC(C)(C)N
Solvent: CCO
Product: CC(C)(C)Nc1cc(Cl)nc(N)n1
Reaction time: 1 h
Yield: 75.6 %

Procedure:
10 g of 2-amino-4,6-dichloropyrimidine are suspended in 100 ml of ethanol. 44.50 g of tert-butylamine are added. The reaction mixture is refluxed for 48 hours. It is evaporated to dryness. The residue is taken up in 50 ml of water. The mixture is stirred for 1 hour and the precipitate is then filtered off on sintered glass. It is recrystallized from 60 ml of a 50/50 ethanol-water mixture. 9.25 g of 2-amino-4-tert-butylamino-6-chloro-pyrimidine are obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[C:24]([CH3:25])=[CH:23][S:22][CH:21]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:26])[N:3]=1.B([C:30]1[CH:41]=[CH:40][C:33]([CH2:34][C@@H:35]([C:37]([OH:39])=[O:38])[NH2:36])=[CH:32][CH:31]=1)(O)O.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:36][C@@H:35]([CH2:34][C:33]1[CH:40]=[CH:41][C:30]([C:2]2[CH:7]=[C:6]([O:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[C:24]([CH3:25])=[CH:23][S:22][CH:21]=3)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:26])[N:3]=2)=[CH:31][CH:32]=1)[C:37]([OH:39])=[O:38]
Reactant: Cc1cscc1-c1ccccc1C(Oc1cc(Cl)nc(N)n1)C(F)(F)F
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1cscc1-c1ccccc1C(Oc1cc(-c2ccc(C[C@H](N)C(=O)O)cc2)nc(N)n1)C(F)(F)F
Temperature: 150 °C
Yield: 38.1 %

Procedure:
In a microwave vial, 4-chloro-6-{2,2,2-trifluoro-1-[2-(4-methyl-thiophen-3-yl)-phenyl]-ethoxy}-pyrimidin-2-ylamine (30 mg, 0.075 mmol), 4-borono-L-phenylalanine (19 mg, 0.09 mmol), 1 ml of actonitrile and 0.7 ml of water were mixed. 0.3 ml of 1N aqueous sodium carbonate was added to mixture, followed by 5 mole percent of dichlorobis-(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, and then was purified by Prep HPLC to give 15.1 mg of (S)-2-amino-3-(4-{2-amino-6-[2,2,2-trifluoro-1-(2-(4-methyl-thiophen-3-yl)-phenyl]-ethoxy}-pyrimidin-4-yl}-phenyl)-propionic acid. 1H NMR (400 MHz, CD3OD) δ (ppm) 7.94 (d, J=8 Hz, 2H), 7.80 (s, 1H), 7.50 (m, 5H), 7.25 (m, 2H), 7.03 (s, 1H), 6.94 (s, 1H), 4.31 (t, J=5.6, 1H), 3.48 (m, 1H), 3.26 (m, 1H), 1.98 (s, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[C:19]([C:20](O)=[O:21])=[C:18]([CH3:23])[N:17]=[C:16]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:15]=1.[CH2:30]([NH:37][CH:38]([CH3:40])[CH3:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C=O)C>[CH2:30]([N:37]([CH:38]([CH3:40])[CH3:39])[C:20]([C:19]1[C:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[F:7])=[N:15][C:16]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)=[N:17][C:18]=1[CH3:23])=[O:21])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1nc(N2CCOCC2)nc(-c2ccccc2F)c1C(=O)O
Reactant: CC(C)NCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(N2CCOCC2)nc(-c2ccccc2F)c1C(=O)N(Cc1ccccc1)C(C)C
Reaction time: 0.25 h
Yield: 39.6 %

Procedure:
A solution of 2 M oxalyl chloride in CH2Cl2 (0.070 mL, 0.14 mmol) was added to a stirred solution of 4-(2-fluorophenyl)-6-methyl-2-morpholin-4-yl-pyrimidine-5-carboxylic acid (0.03 g, 0.09 mmol) in CH2Cl2 (2 mL) and DMF (0.030 mL) at room temperature, and stirring continued for 15 min. A solution of N-benzylisopropylamine (0.013 g, 0.1 mmol) in CH2Cl2(1 mL) and diisopropylethylamine(0.044 mL,0.25 mmol) were added and stirred for 24 hr. The solvent was removed under reduced pressure, and the residue was purified by Biotage SP1 on packed silica gel column (10%-80% EtOAc/Hexanes gradient) to give 4-(2-fluorophenyl)-6-methyl-2-morpholin-4-yl-pyrimidine-5-carboxylic acid benzyl-isopropyl-amide (0.016 g,40%).
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]2[C:10]([C:11]=1[OH:12])=[CH:9][CH:8]=[CH:7][N:6]=2.[CH3:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>N1C=CC=CC=1>[OH-:12].[OH:12][C:11]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3](=[O:19])[C:2]=1[N+:21]1([CH3:20])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CN1CCCC1
Reactant: O=c1c(Br)c(O)c2cccnc2n1-c1ccccc1
Solvent: c1ccncc1
Product: C[N+]1(c2c(O)c3cccnc3n(-c3ccccc3)c2=O)CCCC1
Product: [OH-]
Reaction time: 33 h

Procedure:
In dry pyridine (30 mL), 3-bromo-4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one (10 g) was suspended. N-methyl pyrrolidine (20 mL) was added to the suspension. The mixture was heated to 95°-100° C. with stirring, and was kept there for about 33 hours. The product was evaporated under high vacuum to provide a dark oil. This oil was slurried with 200 mL of CH3CN(40): H2O(60): CH3CO2H(1) and filtered. The solid residue on the filter was rinsed with water and the filtrate was evaporated to remove most of the CH3CN. Reversed phase chromatography through an E. Merck RP-8 LoBar column, eluting with increasing concentrations of CH3CN in H2O (containing 1% CH3CO2H) gave a moderately pure product which was subjected to a second chromatographic separation using the same conditions as above. Fractions containing the product were combined and evaporated to yield a solid which was recrystallized from CH2Cl2 /isopropanol to yield the desired product, m.p. 245°-250° C.
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8].[CH3:10][C:11]1[N:12]=[C:13]([Sn](CCCC)(CCCC)CCCC)[S:14][CH:15]=1>>[CH3:10][C:11]1[N:12]=[C:13]([C:2]2[S:3][CH:4]=[CH:5][C:6]=2[N+:7]([O-:9])=[O:8])[S:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccsc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(C)cs1
Product: Cc1csc(-c2sccc2[N+](=O)[O-])n1

Procedure:
4-Methyl-2-(3-nitrothiophen-2-yl)thiazole was prepared from 2-chloro-3-nitrothiophene (219 mg, 1.34 mmol) and 4-methyl-2-(tributylstannyl)thiazole (520 mg, 1.34 mmol) according to protocol E. Retention time (min)=2.462, method [1], MS(ESI) 227.0 (M+H).
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=1)[CH3:3].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:14][S:15]([O:1][CH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=1)[CH3:3])(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(C(C)O)nc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(C(C)OS(C)(=O)=O)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
To a 0° C. solution of methyl 6-(1-hydroxyethyl)nicotinate (0.100 g, 0.552 mmol) and 4-dimethylaminopyridine (152 mg, 1.32 mmol) in dichloromethane (10 mL) was added methanesulfonyl chloride (75.9 mg, 0.662 mmol) dropwise. The resulting mixture was stirred at room temperature for 1 hour. Additional methanesulfonyl chloride (75.9 mg, 0.662 mmol) was added and the mixture stirred at room temperature for an additional 2 hours. The mixture was quenched with water and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give crude methyl 6-(1-(methylsulfonyloxy)ethyl)nicotinate (134 mg) as an oil which was used in the next step directly.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH:18]1([C@@H:23]([N:27]2[CH:31]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:29]=[N:28]2)[CH2:24][C:25]#[N:26])[CH2:22][CH2:21][CH2:20][CH2:19]1.O1CCOCC1.O.C(=O)([O-])[O-].[K+].[K+]>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>[CH:18]1([C@@H:23]([N:27]2[CH:31]=[C:30]([C:2]3[C:3]4[CH:10]=[CH:9][N:8]([CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[C:4]=4[N:5]=[CH:6][N:7]=3)[CH:29]=[N:28]2)[CH2:24][C:25]#[N:26])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC1(C)OB(c2cnn([C@@H](CC#N)C3CCCC3)c2)OC1(C)C
Reactant: CCOC(OCC)n1ccc2c(Cl)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(OCC)n1ccc2c(-c3cnn([C@@H](CC#N)C4CCCC4)c3)ncnc21
Temperature: 95 °C
Reaction time: 21 h
Yield: 78 %

Procedure:
Into a 100 ml round bottom flask equipped with a stir bar, condenser and 3-way valve connected to nitrogen and vacuum was charged 4-chloro-7-(diethoxymethyl)-7H-pyrrolo[2,3-c]pyrimidine (3b, 3.30 g, 0.0129 mol), (3S)-3-cyclopentyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile ((S)-24, 5.12 g, 0.0146 mol, 1.13 equiv), 1,4-dioxane (33.4 mL, 0.428 mol), water (16.7 mL, 0.929 mol) and potassium carbonate (K2CO3, 8.03 g, 0.0581 mol, 4.5 equiv) at room temperature. The resulting reaction mixture was degassed three times back filling with nitrogen each time before being charged tetrakis(triphenylphosphine)palladium(0) (1.49 g, 0.00129 mol, 0.10 equiv). The mixture was degassed four times back filling with nitrogen each time and then warmed to 95° C. The reaction mixture was stirred at 95° C. for 21 hours. When the reaction was deemed complete, the reaction mixture was cooled to room temperature before being diluted with ethyl acetate (45 mL) and water (20 mL). The resulting mixture was stirred until the majority of solids had gone into solution. The two layers were separated, and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic fractions were washed with 20% aqueous brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 0% to 50% ethyl acetate/hexane gradient elution) afford (3S)-3-cyclopentyl-3-{4-[7-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-1H-pyrazol-1-yl}propanenitrile ((S)-25, 4.11 g, 5.27 g theoretical, 78% yield) as colorless oil, which was solidified upon standing at room temperature. For (S)-25: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.84 (s, 1H), 8.74 (s, 1H), 8.38 (s, 1H), 7.71 (d, 1H, J=3.8 Hz,), 7.12 (d, 1H, J=3.8 Hz), 6.76 (s, 1H), 4.53 (td, 1H, J=19.4, 4.3 Hz), 3.68 (m, 2H), 3.52 (m, 2H), 3.26 (dd, 1H, J=9.6, 17.3 Hz), 3.19 (dd, 1H, J=4.3, 17.2 Hz), 2.41 (m, 1H), 1.80 (m, 1H), 1.63-1.09 (m, 13H); C22H28N6O2 (MW, 408.50), LCMS (EI) m/e 409 (M++H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1([NH:14][C:15]2[C:16](=[O:34])[N:17]([C:21]3[CH:22]=[C:23]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:24]([NH:26][CH:27]3[CH2:29][CH2:28]3)=[O:25])[CH:18]=[CH:19][N:20]=2)[CH2:13][CH2:12]1.[CH3:35][NH2:36].C(OCC)C>O1CCOCC1.O>[CH:27]1([NH:26][C:24](=[O:25])[C:23]2[CH:30]=[CH:31][C:32]([CH3:33])=[C:21]([N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][C:11]4([C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[O:4][CH2:3][CH2:2][NH:36][CH3:35])[CH2:13][CH2:12]4)[C:16]3=[O:34])[CH:22]=2)[CH2:29][CH2:28]1
Reactant: CN
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCCl)CC2)c1=O
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: O
Product: CNCCOc1ccccc1C1(Nc2nccn(-c3cc(C(=O)NC4CC4)ccc3C)c2=O)CC1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
3-(3-(1-(2-(2-Chloroethoxy)phenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-4-methylbenzamide (Example 167e, 5.00 g) dissolved in dioxane (15 mL) was treated with methylamine (15 mL of a 40 wt % solution in water). The resulting suspension was stirred at 100° C. for 4 h in an autoclave. The solution was evaporated to dryness. The crude product was purified (SiO2 chromatography, eluting with a 5:1:94 (v/v) mixture of methanol:triethylamine:dichloromethane respectively). The product containing fractions were evaporated in vacuo and re-purified by RPHPLC (Xterra column, 95-5% gradient of aqueous 0.2% ammonia in acetonitrile as mobile phase). The product containing fractions were combined and freeze dried to leave a solid. Trituration with diethyl ether followed by drying in vacuo overnight gave the title compound as a white powder (3.14 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH2:6])[CH3:5].C(N(C(C)C)C(C)C)C.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.O>C(Cl)Cl>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:6][C@@H:4]([CH3:5])[CH2:3][O:2][CH3:1])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: COC[C@H](C)N
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](C)NS(=O)(=O)c1ccc(Br)cc1
Reaction time: 1 h
Yield: 94 %

Procedure:
(1S)-2-Methoxy-1-methylethylamine (7.34 g, 82.4 mmol) and N-ethyl-N,N-diisopropylamine (19.1, 110 mmol) was added dropwise over 20 min to a cooled (0° C.) solution of 4-bromobenzenesulfonyl chloride (14.0 g, 55 mmol) in methylene chloride (200 mL). The reaction mixture was allowed to stir for 1 h. Water was added and the mixture was washed, twice, with HCl (1 M) and once with saturated aqueous sodium hydrogen carbonate. The organic phase was dried over sodium sulfate and evaporated to give 15.1 g, (94% yield) of the title compound: 1H NMR (CDCl3, 400 MHz) δ 7.76 (d, J=8 Hz, 2H), 7.65 (d, J=8 Hz, 2H), 4.97 (m, 1H), 3.46 (m, 1H), 3.23 (m, 5H), 1.12 (d, J=7 Hz, 3H); MS (ESI) m/z 308 and 310 (M++1)
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:24][C:25](C)([O-:27])[CH3:26].[K+].[Br:30][C:31]1[CH:32]=[CH:33][C:34]([F:58])=[C:35]([C@:37]23[CH2:46]O[C@@H](C=O)C[C@H:42]2[CH2:41][S:40][C:39]([NH:49][C:50](=[O:57])[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[N:38]3)[CH:36]=1>O1CCCC1>[Br:30][C:31]1[CH:32]=[CH:33][C:34]([F:58])=[C:35]([C@:37]23[CH2:46][O:27][C@@H:25](/[CH:26]=[CH:2]/[O:3][CH3:4])[CH2:24][C@H:42]2[CH2:41][S:40][C:39]([NH:49][C:50](=[O:57])[C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)=[N:38]3)[CH:36]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cc(Br)ccc2F)CO1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CO/C=C/[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cc(Br)ccc2F)CO1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A suspension of oven-dried (methoxymethyl)triphenylphosphonium chloride (2.56 g, 7.46 mmol) in tetrahydrofuran (41 mL) was cooled to 0° C. To this solution was added potassium tert-butoxide (1.0 M in tetrahydrofuran, 6.41 mL, 6.41 mmol) at a very slow rate such that the internal temperature did not exceed 5° C. The resulting bright orange solution was left stirring at the same temperature for 5 minutes. It was then allowed to warm up to room temperature and was left stirring for another 30 minutes. The reaction mixture was cooled down to 0° C. and a solution of N-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-formyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C42) (1.00 g, 2.10 mmol) in tetrahydrofuran (18 mL) was then added slowly. Once the addition was completed, the resulting solution was stirred at 0° C. for 30 minutes. The reaction mixture was quenched by addition of a saturated aqueous solution of sodium bicarbonate (100 mL). The mixture was extracted with ethyl acetate (3×150 mL). The combined organics were then washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated. Purification via silica gel chromatography (Gradient: 0% to 50% ethyl acetate in heptane) afforded the product as a white solid. Yield: 540 mg, 51%. 1H NMR (400 MHz, CD3OD) characteristic peaks: δ 8.13 (br d, J=7.4 Hz, 2H), 7.44-7.57 (m, 4H), 7.13 (dd, J=12.1, 8.6 Hz, 1H), 6.05 (dd, J=6.3, 1.0 Hz, 1H), 4.58-4.63 (m, 1H), 4.48 (dd, J=7.9, 6.4 Hz, 1H), 4.12-4.15 (m, 1H), 3.85 (d, J=11.9 Hz, 1H), 3.63 (s, 3H), 3.20 (br s, 1H), 2.93 (dd, J=13.1, 4.1 Hz, 1H), 2.72 (J=13.2, 2.8 Hz, 1H), 1.84-1.90 (m, 1H), 1.71-1.75 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:15]([CH3:41])([CH3:40])[CH2:14]2)[N:5]=[C:4]([NH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH:47]2[CH2:52][C:51]([CH3:54])([CH3:53])[N:50]([O:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])[C:49]([CH3:75])([CH3:74])[CH2:48]2)[N:3]=1.[CH2:76]([CH2:78][NH2:79])[OH:77]>>[OH:77][CH2:76][CH2:78][NH:79][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:19])([CH3:20])[N:16]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:15]([CH3:40])([CH3:41])[CH2:14]2)[N:5]=[C:4]([NH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH:47]2[CH2:48][C:49]([CH3:74])([CH3:75])[N:50]([O:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])[C:51]([CH3:53])([CH3:54])[CH2:52]2)[N:3]=1
Reactant: CCCCCCCCCCCCCCCCCCON1C(C)(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OCCCCCCCCCCCCCCCCCC)C(C)(C)C3)n2)CC1(C)C
Reactant: NCCO
Product: CCCCCCCCCCCCCCCCCCON1C(C)(C)CC(CCCCNc2nc(NCCO)nc(NCCCCC3CC(C)(C)N(OCCCCCCCCCCCCCCCCCC)C(C)(C)C3)n2)CC1(C)C

Procedure:
The title compound is prepared from the reaction of 2-chloro-4,6-bis[N-(1-octadecyloxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazine and ethanolamine according to the procedure of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[CH:12]=[O:13].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][C:16]=1O.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[C:12]1[O:13][C:16]2[CH:17]=[C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:20][C:15]=2[N:14]=1
Reactant: Cn1cc(C=O)c2cc(Cl)ccc21
Reactant: COC(=O)Cc1ccc(N)c(O)c1
Solvent: Ic1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc2nc(-c3cn(C)c4ccc(Cl)cc34)oc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
In EtOH (9.0 ml), 5-chloro-1-methylindole-3-carbaldehyde (534 mg, 2.76 mmol) and methyl 4-amino-3-hydroxyphenylacetate (500 mg, 2.76 mmol) were stirred for hours. After iodobenzene diacetate (2.03 g, 6.31 mmol) was added to the reaction mixture and the mixture was stirred at room temperature for 1 hour, the solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column, whereby from n-hexane-ethyl acetate (1:1, v/v) eluate fractions, a mixture (594 mg) of methyl (2-(5-chloro-1-methyl-3-indolyl)-6-benzoxazolyl)acetate and 5-chloro-1-methylindole-3-carboxaldehyde was obtained. To the resulting mixture were added THF (17 ml) and 0.25N NaOH (10.0 ml, 2.50 mmol) and the mixture was stirred at room temperature for 23 hours. The reaction mixture was distilled under reduced pressure to remove the solvent. To the residue was added 1N HCl (10 ml), followed by extraction with chloroform-methanol (4:1, v/v). The extract was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent to give (2-(5-chloro-1-methyl-3-indolyl)-6-benzoxazolyl)acetic acid (88 mg, 9%) as a brown solid.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)(O)=[O:2].S(Cl)([Cl:14])=O.CN(C=O)C>C1(C)C=CC=CC=1>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([Cl:14])=[O:2])=[CH:5][CH:6]=1)=[O:9]
Reactant: O=S(Cl)Cl
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(C(=O)Cl)cc1
Temperature: 100 °C

Procedure:
A solution of 4-carboxybenzaldehyde (30.0 g, 0.200 mol) in toluene (300 mL) was treated with thionyl chloride (28.6 g, 0.240 mol) and DMF (1.0 mL). The reaction mixture was heated at 100° C. for 2 h, during which time the solids dissolved to yield a pale yellow colored solution. The reaction mixture was cooled to 0° C. to yield a solution of the title compound in toluene, which was used without further manipulation.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:39]1[CH:44]=[CH:43][C:42]([CH:45]([NH2:47])[CH3:46])=[CH:41][CH:40]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:22])[NH:47][CH:45]([C:42]3[CH:43]=[CH:44][N:39]=[CH:40][CH:41]=3)[CH3:46])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(N)c1ccncc1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)NC(C)c4ccncc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Yield: 41 %

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and (RS)-1-pyridin-4-yl-ethylamine: yield 41%.