Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CCCCCC.[CH2:20]1[O:22][CH2:21]1.CCOCC>C1COCC1>[CH:1]1[C:13]2[CH:12]([CH2:20][CH2:21][OH:22])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C1CO1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCCC1c2ccccc2-c2ccccc21
Reaction time: 5 h

Procedure:
2-(9-Fluorenyl) ethanol was prepared from a solution of fluorene (116.35 g, 0.7 mmol) in 800 ml of dry THF at -20° C. which was added n-Buli in hexane (0.7 mol) keeping the temperature below -10° C. To the clear solution was rapidly added 357 ml of 1.4M ethylene oxide in ether (0.5 mol) keeping the temperature below 5° C. The reaction mixture was stirred for 5 hours, then quenched with 50 ml of saturated ammonium chloride solution. The THF was removed at a rotary evaporator. The residue was partitioned between water and ethyl acetate. The organic layer was separated, dried with MgSO4 and concentrated in vacuo until crystallization began. The solution was allowed to stand overnight and the crystals were collected and dried (mp 97° C.) (85.5 g, (81%)).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([OH:14])=O)=[CH:4][N:3]=1.C(Cl)(=O)C([Cl:18])=O>CN(C=O)C.ClCl>[F:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([Cl:18])=[O:14])=[CH:4][N:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cnc(F)nc1C(F)(F)F
Agent: ClCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cnc(F)nc1C(F)(F)F
Yield: 75 %

Procedure:
The title compound was prepared as described in Example 25, but employing a solution of 2-fluoro-4-trifluoromethylpyrimidine-5-carboxylic acid (1.5 g, 7.1 mmol) and oxalyl chloride (1.0 g, 8 mmol), DMF (2 drops) in CH2 Cl2 (30 mL) resulted in a 75% yield (1.2 g); 1H NMR (CDCl3) δ 9.42 (s, 1H).
Reaction SMILES: [CH3:1][S:2]([Cl:5])(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([O:27][CH:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:23][CH2:22]1)[C:12](=[O:41])[NH:11][C:10]2=[O:42]>>[ClH:5].[O:41]=[C:12]1[NH:11][C:10](=[O:42])[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=2)[N:13]1[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([O:27][CH:28]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:23][CH2:22]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)c(=O)[nH]c(=O)n2CCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Product: CS(=O)(=O)Nc1ccc2c(c1)c(=O)[nH]c(=O)n2CCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Product: Cl
Yield: 54.2 %

Procedure:
Using the method similar to that in Example 43 and methanesulfonyl chloride (190 ml, 2.45 mmol) instead of ethylmalonyl chloride and starting from 6-amino-2,4-dioxo-1-[4-(4-diphenylmethoxypiperidino)butyl]-1,2,3,4-tetrahydroquinazoline (1.02 g, 2.05 mmol) obtained in Example 40, a free salt of the title compound (681 mg, 58%) was synthesized. Recrystallization from ethyl acetate yielded a colorless crystal having a melting point of 204 to 205° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([C:9]1[O:13][C:12]([CH2:14][CH2:15][C:16](OC)=[O:17])=[CH:11][CH:10]=1)[CH3:8]>C1COCC1>[CH2:7]([C:9]1[O:13][C:12]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=1)[CH3:8]
Reactant: CCc1ccc(CCC(=O)OC)o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1ccc(CCCO)o1
Temperature: 0 °C
Yield: 84.7 %

Procedure:
To a mixture of 3.42 g (90.1 mol) of LAH in THF under nitrogen and stirring at 0° C., was added dropwise 14.9 g (81.9 mmol) of methyl 3-(5-ethyl-2-furyl)propanoate in THF. The reaction mixture was quenched with 3.4 mL of water, 3.4 mL of sodium hydroxide solution, and 10.2 mL of water. Magnesium sulfate was added to the mixture with stirring, filtered and concentrated in vacuo. The residue was passed through silica gel and eluted with ethyl acetate/hexane (2:8) to yield 10.7 g (85%) of the desired product as a clear colorless oil, used in the next preparation without further purification.
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]1[NH:7][CH:6](O)[C@H:5]([OH:9])[C@@H:4]([OH:10])[C@@H:3]1[OH:11].[CH2:13]=O.[H][H]>O.[Ni]>[CH3:13][N:7]1[C@H:2]([CH2:1][OH:12])[C@@H:3]([OH:11])[C@H:4]([OH:10])[C@@H:5]([OH:9])[CH2:6]1
Reactant: OC[C@H]1NC(O)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: [H][H]
Reactant: C=O
Agent: [Ni]
Solvent: O
Product: CN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO

Procedure:
179 mg of nojirimycin is dissolved in 20 ml of water, followed by adding 1 ml of formalin, adding about 0.5 ml of Raney nickel catalyst and stirring in a hydrogen stream, at ordinary temperature, under atmospheric pressure, for 3 hours. After completion of the reaction, the catalyst is separated by filtration; the resulting filtrate is passed through a column containing about 100 ml of Dowex 50 W×4 (H); and after washing the column, the resulting adsorbed substances are eluted with 1% aqueous ammonia. The resulting elute is brought to dryness under reduced pressure, and the remaining colorless crystal is recrystallized from ethanol to obtain N-methyl moranoline.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:44])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]5[CH2:32][CH2:33][N:34](C(OC(C)(C)C)=O)[CH2:35][CH:36]=5)=[CH:27][CH:26]=3)[CH:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[ClH:45]>CO.O1CCOCC1>[ClH:45].[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:44])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]5[CH2:32][CH2:33][NH:34][CH2:35][CH:36]=5)=[CH:27][CH:26]=3)[CH:17]=[CH:16]4)[CH:12]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)cc3)ccc2c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(C4=CCNCC4)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of Example 6 step (iii) (0.2 g) in methanol (10 mL) was treated with 4.0M HCl in 1,4-dioxane (10 mL) and the solution stirred at room temperature for 2 hours. The volatiles were then removed under reduced pressure and the residue triturated with diethyl ether to give the product, after filtration as a solid (80 mg).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[CH3:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1C=O.O1CCC[CH2:24]1>>[CH3:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[C:3](=[CH2:24])[C:1]#[N:2]
Reactant: Cc1ccccc1C=O
Reactant: CCOP(=O)(CC#N)OCC
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: C=C(C#N)c1ccccc1C
Reaction time: 0.5 h

Procedure:
Diethyl cyanomethylphosphonate (5.0 ml, 30.9 mmol) was added to a stirring suspension of sodium hydride (60% oily suspension, 1.24 g, 31 mmol) in tetrahydrofuran (50 ml) under argon. After 30 min, 2-methylbenzaldehyde (3.6 ml, 31.1 mmol) was added and stirring continued for 1 h. The reaction was quenched by the addition of water and extracted with dichloromethane followed by drying and evaporation of the organic solution. Column chromatography (hexane; hexane:ethylacetate=3:1) provided 2-(2-methylphenyl)acrylonitrile as an oil. This material (3.8 g), 10% palladium on carbon (3.8 g) and 12 N hydrochloric acid (11.8 ml, 142 mmol) in methanol (125 ml) were hydrogenated with hydrogen at atmospheric pressure for 2 d. The catalyst was removed by filtration and the solvent was evaporated. The resultant material was partitioned between dichloromethane and water. The aqueous layer was made basic with 10 N sodium hydroxide and extracted with dichloromethane, followed by drying and evaporation. The resultant material was purified on a silica gel column (chloroform:methanol:triethylamine=85:10:5) to provide the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[CH3:11][O:12][C:13]([C:15]1[S:16][C:17](Br)=[CH:18][C:19]=1[N:20]([CH:30]([CH3:32])[CH3:31])[C:21]([CH:23]1[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]1)=[O:22])=[O:14].C1(C)C=CC=CC=1.CO.C([O-])([O-])=O.[Na+].[Na+]>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>[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[CH:18][C:19]=1[N:20]([CH:30]([CH3:32])[CH3:31])[C:21]([CH:23]1[CH2:24][CH2:25][CH:26]([CH3:29])[CH2:27][CH2:28]1)=[O:22])=[O:14]
Reactant: COC(=O)c1sc(Br)cc1N(C(=O)C1CCC(C)CC1)C(C)C
Reactant: OB(O)c1cccc(F)c1
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: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1sc(-c2cccc(F)c2)cc1N(C(=O)C1CCC(C)CC1)C(C)C
Temperature: 70 °C
Yield: 99.8 %

Procedure:
To the mixture of 3-fluorobenzeneboronic acid (25.0 mg, 0.180 mmol) and 5-Bromo-3-[isopropyl-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (24 mg, 0.060 mmol) in 5:1 mixture of toluene/MeOH (1.0 mL) was added a solution of Pd(PPh3)4 (7.0 mg, 0.006 mmol, 10 mol %) in toluene (0.5 mL) followed by aqueous 2M Na2CO3 solution (0.06 mL, 0.120 mmol). The resultant reaction mixture was heated at 70° C. for 18 h, cooled to room temperature, filtered off through MgSO4 and washed with EtOAc. Evaporation of the solvent and purification of the residue over preparative TLC using ethyl acetate/hexane (20:80) as an eluent furnished (25.0 mg, 99% yield) of 5-(3-Fluoro-phenyl)-3-[isopropyl-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]([CH:10]([CH3:12])[CH3:11])=[C:3]([Cl:9])[C:4](OCC)=[O:5].[CH:13]([NH2:15])=O.C[O-].[Na+]>CO>[Cl:9][C:3]1[C:4]([OH:5])=[N:15][CH:13]=[N:1][C:2]=1[CH:10]([CH3:12])[CH3:11]
Reactant: NC=O
Reactant: CCOC(=O)C(Cl)=C(N)C(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)c1ncnc(O)c1Cl

Procedure:
45.1 g (0.24 mol) of ethyl 3-amino-2-chloro-4-methyl-2-pentenoate are reacted with 36.8 g (0.59 mol) of formamide and 109 ml of sodium methylate solution in 130 ml of methanol and worked up in analogy to Example 9. Yield: 34.5 g (83.3%)
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[Cl:14][C:15]1[C:20]([C:21](O)=[O:22])=[CH:19][N:18]=[CH:17][CH:16]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>O.N1C=CC=CC=1>[CH3:1][NH:2][C:3]1[C:8]([NH:9][C:21]([C:20]2[CH:19]=[N:18][CH:17]=[CH:16][C:15]=2[Cl:14])=[O:22])=[CH:7][C:6]([C:10]([F:13])([F:11])[F:12])=[CH:5][N:4]=1
Reactant: CNc1ncc(C(F)(F)F)cc1N
Reactant: O=C(O)c1cnccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: c1ccncc1
Product: CNc1ncc(C(F)(F)F)cc1NC(=O)c1cnccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.3 %

Procedure:
A mixture of 524 mg of N2-methyl-5-trifluoromethylpyridine-2,3-diamine, 500 mg of 4-chloronicotinic acid, 790 mg of EDCI hydrochloride, 37 mg of HOBt and 4 ml of pyridine was stirred at room temperature for 4 hours. Water was poured to the reaction mixture, and the precipitated solid was filtered. The resulting solid was washed with water and n-hexane and then dried to obtain 828 mg of 4-chloropyridine-3-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide. 4-chloropyridine-3-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([O:8][CH3:9])[CH:7]=1.C(O[CH:18](N(C1C(C(C)C)CCC(C)C1)C1C(C(C)C)CCC(C)C1)[N:19]([CH:30]1C(C(C)C)CCC(C)C1)[CH:20]1C(C(C)C)CCC(C)C1)(C)(C)C>>[CH3:18][N:19]([CH3:30])[CH:20]=[CH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: CC1CCC(C(C)C)C(N(C2CC(C)CCC2C(C)C)C(OC(C)(C)C)N(C2CC(C)CCC2C(C)C)C2CC(C)CCC2C(C)C)C1
Reactant: COc1cc(C)ccc1[N+](=O)[O-]
Product: COc1cc(C=CN(C)C)ccc1[N+](=O)[O-]

Procedure:
83.5 of 5-methyl-2-nitroanisole and 162.0 g of tert-butoxybis(dimenthylamino)methane is heated for 8 hours to 100° C. After cooling, 111.0 g of N,N-dimenthyl-N-[2-(3-methoxy-4-nitrophenyl)ethenyl]amine is crystallized, mp 57°-58.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[C:16]([C:19]1C=C([N+]([O-])=O)C=C2[C:28]=1N=CC=C2)(O)=O>>[C:6]([C:5]1[CH:11]=[C:12]2[C:2](=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=1)[N:1]=[CH:28][CH:19]=[CH:16]2)([OH:8])=[O:7]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc2cccnc12
Reactant: CCOC(=O)c1ccc(N)c([N+](=O)[O-])c1
Product: O=C(O)c1cc([N+](=O)[O-])c2ncccc2c1
Yield: 61 %

Procedure:
6-Carboxy-8-nitroquinoline was prepared from ethyl 4-amino-3-nitrobenzoate using the method described for 8-carboxy-6-nitroquinoline in example 1. (Yield: 61%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([OH:16])=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10](=[O:16])[N:11]([CH3:17])[CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ncc(Br)cc1OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(Br)cc(OCc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
To a solution of 3-(benzyloxy)-5-bromopyridin-2-ol ((5.8 g, 20.7 mmol) in DMF (75 mL) was added Cs2CO3 (8.8 g, 26.9 mmol). A solution of MeI (1.62 mL, 25.9 mmol) in DMF (10 mL) was added dropwise to this mixture. After stirring at room temperature for 3 h, the reaction mixture was concentrated. The residue was taken up in H2O and the aqueous solution was extracted with CH2Cl2 (3×). Combined organic solutions washed with brine (1×), dried over Na2SO4 and concentrated. Purification by flash chromatography (250 g silica gel, 50% EtOAc in hexanes) afforded 4.02 g (66%) of 3-(benzyloxy)-5-bromo-1-methylpyridin-2(1H)-one as a white solid. 1H NMR (500 MHz, CDCl3): δ 7.43-7.32 (m, 5H), 7.05 (s, 1H), 6.91 (s, 1H), 5.11 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10]([N:12]([O:14][CH3:15])[CH3:13])=[O:11])=[CH:4][CH:3]=1.B([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)(O)O>>[CH3:15][O:14][N:12]([CH3:13])[C:10]([CH2:9][C@H:8]([C:5]1[CH:6]=[CH:7][C:2]([C:26]2[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=2)=[CH:3][CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])=[O:11]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CON(C)C(=O)C[C@H](c1ccc(Br)cc1)c1ccccc1C
Product: CON(C)C(=O)C[C@H](c1ccc(-c2ccc(C(=O)O)cc2)cc1)c1ccccc1C

Procedure:
In analogy to example 74, step 6, from (R)-3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (example 142, step 1) and 4-boronobenzoic acid was prepared the title compound as a light brown foam, MS (ESI+): m/z=404.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35](B(O)O)[CH:36]=2)[CH:31]=[CH:30]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:35]1[CH:36]=[C:37]2[C:32]([CH:31]=[CH:30][NH:29]2)=[CH:33][CH:34]=1
Reactant: OB(O)c1ccc2cc[nH]c2c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3ccc4cc[nH]c4c3)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 18 h
Yield: 97.2 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (120 mg, 0.27 mmol) were added (1H-indol-6-yl)boronic acid (65 mg, 0.41 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(11)dichloride dichloromethane complex (22 mg, 0.03 mmol) and 272 μl of a 2M aqueous solution of cesium carbonate in dioxane (2 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude was purified using SP1® Purification System (50% to 100%, hexane-ethyl acetate) to obtain 125 mg (94% yield) of the title compound as a white solid. Purity 98%.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[C:12]([C:19]2[N:24]=[C:23]([NH:25][C@:26]([CH3:32])([CH2:30][CH3:31])[C:27](O)=[O:28])[CH:22]=[CH:21][N:20]=2)=[CH:11]1.CCCP(=O)=O.[F:39][C:40]([F:44])([F:43])[CH2:41][NH2:42]>O.ClCCl>[NH:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[C:12]([C:19]2[N:24]=[C:23]([NH:25][C@:26]([CH3:32])([CH2:30][CH3:31])[C:27]([NH:42][CH2:41][C:40]([F:44])([F:43])[F:39])=[O:28])[CH:22]=[CH:21][N:20]=2)=[CH:11]1
Reactant: NCC(F)(F)F
Reactant: CC[C@@](C)(Nc1ccnc(-c2c[nH]c3ncccc23)n1)C(=O)O
Agent: CCCP(=O)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@@](C)(Nc1ccnc(-c2c[nH]c3ncccc23)n1)C(=O)NCC(F)(F)F
Temperature: 0 °C

Procedure:
Diisopropylethylamine (DIEA) (3.61 kg, 28.1 moles, 2.5 equiv.) was added to (R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoic acid (4a) (3.5 kg, 11.24 moles, 1.0 equiv.) in 7 volumes (32.6 kg) of dichloromethane (CH2Cl2 or DCM) while keeping the temperature at ≦30° C. Water (0.103 kg) was added to make 5.5±0.5% total water content for the reaction system, and the mixture was stirred at ≦30° C. for at least 30 minutes. The reaction mixture was cooled to 0±5° C. Propylphosphonic anhydride solution (17.9 kg, 28.1 moles, 2.5 equiv.) was added to the mixture while maintaining the temperature below 20° C. The mixture was agitated for at least an hour keeping the temperature at 20±5° C., then 2,2,2-trifluoroethylamine (1.68 kg, 16.86 moles, 1.5 equiv.) was added while maintaining the temperature below 20° C. The reaction mixture was warmed to 25±5° C. and agitated for 5 hours while holding the temperature. A 1.0 mL aliquot was removed and the reaction was determined to be 100% complete. Water (17.5 kg, 5 volumes) was added to the reaction mixture, and the resultant mixture was agitated for at least 30 minutes while maintaining the temperature below 30° C.
Reaction SMILES: [CH:1]([Si:4]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[CH2:16][CH2:17][OH:18])([CH3:3])[CH3:2].[C:25]([O:29][C:30](=[O:50])[CH2:31][C@H:32]([NH:39][S:40]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1O)(=[O:42])=[O:41])[C:33]([N:35]([O:37][CH3:38])[CH3:36])=[O:34])([CH3:28])([CH3:27])[CH3:26].CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:25]([O:29][C:30](=[O:50])[CH2:31][CH:32]([NH:39][S:40]([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:48]=1[O:18][CH2:17][CH2:16][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:6]=1[O:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:19]([CH3:21])[CH3:20])[CH:22]([CH3:24])[CH3:23])(=[O:42])=[O:41])[C:33]([N:35]([O:37][CH3:38])[CH3:36])=[O:34])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)[Si](Oc1ccc2ccccc2c1CCO)(C(C)C)C(C)C
Reactant: CON(C)C(=O)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccccc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccccc1OCCc1c(O[Si](C(C)C)(C(C)C)C(C)C)ccc2ccccc12
Yield: 69.8 %

Procedure:
2-(2-Triisopropylsilanyloxy-naphthalen-1-yl)-ethanol (1.0 g, 2.91 mmol) was mixed with (S)-3-(2-hydroxy-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester (1.13 g, 2.91 mmol), diethylazodicarboxylate (0.92 mL, 5.8 mmol), and triphenyl phosphine (1.52 g, 5.82 mmol) in THF (18.6 mL) at room temperature for 16 h. The reaction mixture was concentrated onto SiO2 (˜3 g) and then was chromatographed over SiO2 with 20% EtOAc/hexane to give N-methoxy-N-methyl-3-{2-[2-(2-triisopropylsilanyloxy-naphthalen-1-yl)-ethoxy]-benzenesulfonylamino}-succinamic acid tert-butyl ester (1.45 g, 2.03 mmol) as an oil in 69% yield. MS (APCI) m/z 715.4 (M+1).
Reaction SMILES: [C:1]1(=[O:26])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[CH2:7][C:8](O)=[O:9])[C:4](=[O:21])[C:3]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]12.[CH2:27]([NH2:29])[CH3:28]>>[CH2:27]([NH:29][C:8](=[O:9])[CH2:7][CH:6]([N:5]1[C:4](=[O:21])[C:3]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]2[C:1]1=[O:26])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[CH3:28]
Reactant: COc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1OC
Reactant: CCN
Product: CCNC(=O)CC(c1ccc(OC)c(OC)c1)N1C(=O)c2ccccc2C1=O
Reaction time: 1 h
Yield: 77 %

Procedure:
The procedure of Example 46 was followed utilizing 3-phthalimido-3-(3,4-dimethoxyphenyl)propionic acid and ethylamine (1.0 equiv). After the reaction mixture was concentrated, the residue was diluted with 20 mL of water and 1 mL of ether. The mixture was stirred for 1 hour to afford a slurry. The slurry was filtered and the solid dried in vacuo to afford 0.66 g (77%) of 3-phthalimido-3-(3,4-dimethoxyphenyl)propionic ethyl-amide compound as a white powder: mp 131.0-132.5° C.; 1H NMR (DMSO-d6, 250 MHz) δ 8.08 (t, 1H, J=5 Hz), 7.78-7.95 (m, 4H), 7.03 (s, 1H), 6.85-7.00 (m, 2H), 5.69 (t, 1H, J=8 Hz), 3.74 (s, 3H), 3.72 (s, 3H), 3.18 (d, 2H, J=8 Hz), 2.98 (m, 2H), 0.88 (t, 3H, J=7 Hz); 13C NMR (DMSO-d6)δ 168.8, 167.7, 148.5, 148.2, 134.5, 131.6, 131.2, 123.1, 119.4, 111.6, 111.1, 55.5, 50.5, 37.3, 33.2, 14.5; Anal. Calcd. for C21H22N2O5. Theoretical: C, 65.96; H, 5.80; N, 7.33. Found: C, 65.85; H, 5.84; N, 7.24.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:14]([CH3:31])[C:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)[S:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2].N1C=NN=N1.C(N(C(C)C)[P:41]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)(C)C.[OH:61]O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[P:41]([O:22][C:15]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30])([CH:14]([C:11]1[S:12][CH:13]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[N:10]=1)[CH3:31])[CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)([O:42][CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)([O:50][CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)=[O:61]
Reactant: OO
Reactant: CC(C)N(C(C)C)P(OCc1ccccc1)OCc1ccccc1
Reactant: CC(c1nc(-c2ccc(C#N)cc2)cs1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: CN(C)c1ccncc1
Agent: c1nnn[nH]1
Solvent: ClCCl
Product: CC(c1nc(-c2ccc(C#N)cc2)cs1)C(Cn1cncn1)(OP(=O)(OCc1ccccc1)OCc1ccccc1)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
3-[4-(4-Cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (Example 88, EP 0667346, 900 mg, 2.06 mmol), 1H-tetrazole (432 mg, 6.18 mmol), 4-dimethylaminopyridine (100 mg, 0.82 mmol) and dibenzyl diisopropylphosphoramidite (1.42 g, 4.12 mmol) in methylene chloride (10 ml) were refluxed under a nitrogen atmosphere for 20 hours. The mixture was then cooled to 0° C., and hydrogen peroxide (2.5 ml, 30% solution in water) was added dropwise maintaining the temperature below 20° C. The resulting mixture was stirred at 20° C. for 30 minutes before separating the organic layer, which was washed with water, dried (MgSO4) and the solvent evaporated. The resulting pale yellow oil was purified by column chromatography (silica gel, eluting with ethyl acetate/hexane) to give the subtitle compound as a viscous syrup (732 mg, 51%).