Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])CCC.C[Si](C)(C)N[Si](C)(C)C.[C:15]([O:19][C:20]([N:22]1[C@@H:26]([CH2:27][C:28]([CH:31]=O)([CH3:30])[CH3:29])[CH2:25][O:24][C:23]1([CH3:34])[CH3:33])=[O:21])([CH3:18])([CH3:17])[CH3:16]>CCCCCC.O1CCCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:15]([O:19][C:20]([N:22]1[C@@H:26]([CH2:27][C:28]([CH3:30])([CH3:29])[CH:31]=[CH2:1])[CH2:25][O:24][C:23]1([CH3:34])[CH3:33])=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: [Li]CCCC
Reactant: CC(C)(C=O)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CC(C)(C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 30 °C
Reaction time: 0.25 h

Procedure:
255 ml of a 1.6M butyllithium solution in hexane are added to a solution of 85 ml of hexamethyldisilazane in 800 ml of tetrahydrofuran at -40° C. After 15 min, 140 g of methyltriphenylphosphonium bromide are added at 0° C. and the reaction mixture is stirred at 30° C. for 30 min. 77 g of 3-tert-butoxycarbonyl-2,2-dimethyl-4(S)-(2-formyl-2-methylpropyl)-1,3-oxazolidine, dissolved in 200 ml of tetrahydrofuran, are then added to the reaction solution at -30° C. The reaction mixture is stirred at room temperature for 1 h, and 600 ml of hexane are then added at 0° C. The triphenylphosphinoxide which has precipitated out is filtered off and, after dilution with 400 ml of saturated ammonium chloride solution, the filtrate is extracted with diethyl ether. The crude product is purified by means of FC (400 g of silica gel, mobile phase G): Rf (D)=0.55, Rf (ethyl acetate)=0.44; [α]D =+4.2 (c=1.25 in CHCl3); MS: (M)+ =283.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([NH:20][C:21]([C@@H:23]2[N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30][C:29]3[N:28]=[C:27]([O:40][CH3:41])[CH:26]=[CH:25][C:24]2=3)=[O:22])[CH:12]=[C:13]2[C:17]=1[C:16]([CH3:19])([CH3:18])[CH2:15][CH2:14]2.C(=O)([O-])[O-].[K+].[K+]>C(=O)([O-])O.[Na+]>[F:8][C:9]1[CH:10]=[C:11]([NH:20][C:21]([C@@H:23]2[NH:32][CH2:31][CH2:30][C:29]3[N:28]=[C:27]([O:40][CH3:41])[CH:26]=[CH:25][C:24]2=3)=[O:22])[CH:12]=[C:13]2[C:17]=1[C:16]([CH3:18])([CH3:19])[CH2:15][CH2:14]2
Reactant: COc1ccc2c(n1)CCN(C(=O)OC(C)(C)C)[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(n1)CCN[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97.1 %

Procedure:
TFA (13 mL) was added to tert-butyl (R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (957 mg, 2.04 mmol) at room temperature, and the mixture was stirred at room temperature for 20 min. The reaction mixture was poured into ice-cooled saturated aqueous sodium hydrogencarbonate solution (110 mL), and the pH of the mixture was adjusted to 8 with potassium carbonate. Then, the mixture was extracted with ethyl acetate (×3). The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give (R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide (732 mg, 1.981 mmol, 97%) as an off-white amorphous solid.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C(C[CH2:14][CH:15]1[CH:20]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:19][C:18](=[O:28])[NH:17][CH2:16]1)(O)=O.[O:29]1CCCC1>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH:20]2[CH2:19][C:18](=[O:28])[NH:17][CH2:16][CH:15]2[CH:14]=[O:29])=[CH:22][CH:23]=1
Reactant: O=C(O)CCC1CNC(=O)CC1c1ccc(F)cc1
Reactant: C1CCOC1
Agent: CC(C)C[AlH]CC(C)C
Product: O=CC1CNC(=O)CC1c1ccc(F)cc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
DIBAL-H (4.03 ml, 6 mmol) was added gradually at a rate of 5.6 ml/hour, by means of a syringe pump, to a solution of 3-carboxyethyl-4-(4-fluorophenyl)-piperidine-6-one (0.53 g, 2 mmol) in 4 ml tetrahydrofuran at −70° C. under an argon atmosphere. The reaction mixture was stirred for 1 hour at −70° C. then quenched with a solution of methanol (0.24 ml) in toluene (2 ml) at −70° C., followed by 0.12 ml water at 0° C. After 30 minutes stirring at ambient temperature, the gel which formed was destroyed by the addition of 1.5 ml brine and the reaction mixture was extracted with diethyl ether (50 ml). The organic phase was separated, dried with anhydrous sodium sulphate, filtered and evaporated to yield the title compound (0.2 g) as a yellow oil. The aqueous layer was basified with 10% aqueous sodium hydroxide and extracted with dichloromethane (20 ml). A further 0.08 g product was isolated from the dichloromethane extract.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:26]([O:25][C:23]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=2)[C:5]([OH:7])=[O:6])[CH2:19][CH2:18]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1cc(Br)cc(S(F)(F)(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cc(C(=O)O)cc(S(F)(F)(F)(F)F)c2)CC1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
3.0 g (9.2 mmol) of the compound of Example 15A and 2.05 g (11.0 mmol) of tert-butyl piperazine-1-carboxylate were initially charged in 80 ml of toluene and the mixture was degassed with argon. 135 mg (0.18 mmol) of [2-(2-aminoethyl)phenyl](chloro)palladiumdicyclohexyl-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphane/tert-butyl methyl ether adduct, 87.5 mg (0.18 mmol) of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphane and 2.1 g (22.0 mmol) of sodium tert-butoxide were added successively to this solution. The mixture was stirred at 110° C. for 3 h. After this, another 67.8 mg (0.09 mmol) of [2-(2-aminoethyl)phenyl](chloro)palladiumdicyclohexyl-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphane/tert-butyl methyl ether adduct and 43.8 mg (0.09 mmol) of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphane were added and the mixture was stirred at 110° C. for a further 3 h. The hot mixture was then filtered through kieselguhr, and the mother liquor was concentrated on a rotary evaporator. The residue was suspended in 50 ml of pH 7 buffer solution and the precipitated solid was filtered off. The filter cake was washed with water and dried under reduced pressure. The residue was triturated with 20 ml of methylene chloride, the suspension was filtered again and the filter cake was once more dried under reduced pressure. This gave 2.98 g (72% of theory) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[S:4][CH:3]1[CH2:12][C:13]([NH:15][NH2:16])=[O:14].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH:22]=O.ClCCCl.C(O)C>C(O)C.C(O)(=O)C>[O:1]=[C:2]1[CH:3]([CH2:12][C:13]([NH:15]/[N:16]=[CH:22]/[C:21]2[CH:24]=[C:25]([O:29][CH3:30])[C:26]([O:27][CH3:28])=[C:19]([O:18][CH3:17])[CH:20]=2)=[O:14])[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[NH:7]1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: NNC(=O)CC1Sc2ccccc2NC1=O
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CCO
Product: COc1cc(/C=N/NC(=O)CC2Sc3ccccc3NC2=O)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a round-bottom glass flask equipped with a magnetic stir bar (3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl)-acetic acid hydrazide (1 eq. 0.063 mmol; 15 mg) was dissolved in ethanol (3 mL) at room temperature. To this well stirred solution, acetic acid (˜3 drops) and 3,4,5-trimethoxy-benzaldehyde solution (0.063 mmol; 12.4 mg dissolved in 0.5 mL of ethanol) were added, and the reaction mixture was stirred for another 5 hours at ambient temperature and monitored by TLC (typically with 1,2-dichloroethane-ethanol 5:1). The mixture was then concentrated under vacuum using a rotary evaporator. The crude product was diluted with hexanes and triturated. The precipitated solid product was transferred to a glass fiber funnel, the supernatant was removed by vacuum filtration and the solid was washed thoroughly with n-hexane twice to yield: 16 mg (61%) of 1-1.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][CH:32]([O:35][CH2:36][CH:37]=C)[CH2:31][CH2:30]1.I([O-])(=O)(=O)=[O:40].[Na+].CC(C)=O.C(#N)C>C(OCC)(=O)C.O.[Os]=O>[OH:40][CH2:37][CH2:36][O:35][CH:32]1[CH2:33][CH2:34][CH:29]([N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:11][CH:10]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)[CH2:30][CH2:31]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCOC1CCC(n2c(=O)c(Cc3ccc(-c4ccccc4C#N)cc3)c(CCC)n3ncnc23)CC1
Agent: O=[Os]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(OCCO)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
A mixture of 4′-({5-oxo-4-[4-(prop-2-en-1-yloxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.5 g), osmium oxide (7% immobilized catalyst, 0.5 g), sodium periodate (1.1 g), acetone (5 mL), acetonitrile (5 mL) and water (5 mL) was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate and water, and the insoluble material was filtered off through celite. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), sodium borohydride (0.045 g) was added, and the mixture was stirred at room temperature for 1 hr. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.4 g, 79%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH3:14][Si:15]([CH3:32])([CH3:31])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br.C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[CH3:14][Si:15]([CH3:31])([CH3:32])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)Cc1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1

Procedure:
A solution of 8.2 g. of 4-aminophenylacetic acid, 150 ml. of absolute ethanol, and 3 ml. of boron trifluoride etherate is heated to reflux for 15 hours. The solution is concentrated by distillation and then evaporated to dryness in vacuo. The residue is dissolved in ethyl ether, washed with aqueous sodium bicarbonate, dried, and evaporated to yield ethyl 4-aminophenylacetate. A mixture of 5.0 g. of this amine, 9.7 g. of 14-(trimethylsilyl)tetradecyl bromide, 4.2 g. of anhydrous potassium carbonate and 40 ml. of hexamethylphosphoramide is heated at 80° C. for 7 hours. The mixture is then cooled, diluted with water, and extracted with ethyl ether. The ether extracts are washed with water, dried and evaporated. The residue is recrystallized yielding ethyl 4-[14-(trimethylsilyl)tetradecylamino]phenylacetate. A mixture of 6.0 g. of this ester, 7.0 g. of potassium hydroxide and 100 ml. of ethanol-water is heated to reflux for 4 hours. While hot, the mixture is adjusted to pH 7 with concentrated hydrochloric acid.. The mixture is diluted with water, cooled and filtered. Recrystallization of the precipitate yields the title product as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[CH:7]=1.[Na].[CH3:20][OH:21]>>[CH3:20][O:21][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[CH:7]=1
Reactant: Cc1cccc(Nc2cc(Cl)ccc2[N+](=O)[O-])c1
Reactant: CO
Agent: [Na]
Product: COc1ccc([N+](=O)[O-])c(Nc2cccc(C)c2)c1
Temperature: 0 °C

Procedure:
39 g of 5-chloro-2-nitrophenyl-m-tolylamine was added to a solution of 9 g of sodium in 670 ml of methanol, and it was refluxed for 72 hours. Then, it is cooled to 0° C., and the crystalline product is suctioned off.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12](I)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:25][CH:22]3[CH2:23][CH2:24][O:19][CH2:20][CH2:21]3)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(I)cc2C1
Reactant: OC1CCOCC1
Product: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(OC3CCOCC3)cc2C1

Procedure:
Prepared in analogy to Example A6(a) from 5-chloro-6-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A3(c)) and tetrahydro-4H-pyran-4-ol. Off-white solid. MS (m/e): 300.1 ([{37Cl}M+H—Me2C═CH2]+, 36%), 298.3 ([{35Cl}M+H-Me2C═CH2]+, 100%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C:15]([CH3:16])=[C:14]([CH3:17])[C:13](=[O:18])[CH2:12][N:11]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si](OC[C@@H]1C=C(C)[C@H](O)CN1C(OC(C)(C)C)=O)(C(C)(C)C)(C)C>>[Si:1]([O:8][CH2:9][C@@H:10]1[C:15]([CH3:16])=[C:14]([CH3:17])[C@H:13]([OH:18])[CH2:12][N:11]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC1=C(C)[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)CC1=O
Agent: CC1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C[C@H]1O
Product: CC1=C(C)[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C[C@H]1O
Yield: 72 %

Procedure:
The title compound was prepared from (S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-3,4-dimethyl-5-oxo-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 190, 2.39 g, 6.47 mmol) following the procedure described for Intermediate 8. Silica gel chromatography (0%-20% ethyl acetate/hexanes) afforded the desired product as a colorless oily solid (1.73 g, 72%).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:22]=[C:21](Br)[CH:20]=[CH:19][C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:1]([NH:9][C:10]1[CH:22]=[C:21]([O:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([O:25][CH3:24])[CH:27]=2)[CH:20]=[CH:19][C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Reactant: COc1cccc(O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cccc(Oc2ccc(C(=O)OC(C)(C)C)c(NC(=O)c3ccccc3)c2)c1
Temperature: 25 °C

Procedure:
6.0 mg of palladium acetate was added to 5 mL of toluene suspension containing 0.50 g tert-butyl 2-(benzamido)-4-bromobenzoate, 0.18 mL of 3-methoxyphenol, 17 mg of 2-(di-tert-butylphosphino)-2′,4′,6′-triisopropylbiphenyl and 0.57 g of tripotassium phosphate at room temperature, and the resulting mixture was heated to reflux under nitrogen atmosphere for 5 hours. After the reaction mixture was cooled no room temperature, ethyl acetate and 10% citric acid aqueous solution were added and insoluble were removed by filtration. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 10% citric acid aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=6:1]to obtain 0.32 g of tert-butyl 2-(benzamido)-4-(3-methoxyphenoxy)benzoate as white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:15][CH3:16])[CH:6]=1)(=[O:3])[CH3:2].[N+:17]([O-])([OH:19])=[O:18]>C(OC(=O)C)(=O)C>[C:1]([NH:4][C:5]1[C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:15][CH3:16])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(NC(C)=O)cc1OC
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc([N+](=O)[O-])c(NC(C)=O)cc1OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84 %

Procedure:
To methyl 4-acetamido-2-methoxybenzoate (299 mg, 1.34 mmol) in acetic anhydride (3 ml) stirred under nitrogen at −10° C. was added concentrated nitric acid (0.35 ml) dropwise. After then stirring at 0° C. for 10 min the reaction mixture was partitioned between ethyl acetate (20 ml) and water (20 ml). The aqueous layer was further extracted with ethyl acetate (2×10 ml) and the combined organic extract washed with saturated sodium bicarbonate solution (2×10 ml), brine (2×10 ml), dried (MgSO4) and evaporated to give methyl 4-acetamido-2-methoxy-5-nitrobenzoate (301 mg, 84%) as a dull orange powder.
Reaction SMILES: IC.[C:3](=O)([O-])[O-].[K+].[K+].[Br:9][C:10]1[CH:24]=[N:23][C:13]2[NH:14][C:15](=[S:22])[N:16]([CH2:19][CH2:20][CH3:21])[C:17](=[O:18])[C:12]=2[CH:11]=1.C([O-])(O)=O.[Na+]>CN(C)C=O>[Br:9][C:10]1[CH:24]=[N:23][C:13]2[N:14]=[C:15]([S:22][CH3:3])[N:16]([CH2:19][CH2:20][CH3:21])[C:17](=[O:18])[C:12]=2[CH:11]=1
Reactant: CCCn1c(=S)[nH]c2ncc(Br)cc2c1=O
Reactant: O=C([O-])[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCCn1c(SC)nc2ncc(Br)cc2c1=O
Yield: 75.2 %

Procedure:
A mixture of iodomethane (1.33 g, 0.58 mL), 8.7 g potassium carbonate and 1.88 g of the title compound of Step B was stirred at room temperature in 50 mL of dimethylformamide for 3 h. A 1 mL portion of saturated aqueous NaHCO3 was added and the reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was partitioned between 200 mL each of methylene chloride and water, and the organic layer was removed. Further washing of the organic phase with water and saturated aqueous NaCl followed by drying (Na2SO4) and concentration under reduced pressure delivered 1.8 g of the crude product. This material was then subjected to silica gel chromatography using 70:30 hexane:ethyl acetate as eluant to afford 1.48 g of the title compound of Step C, a compound of the invention, as a white solid melting at 124-127° C. 1H NMR (400 MHz, CDCl3): δ 1.03 (t,3H), 1.76-1.90 (m,2H), 2.7 (s,3H), 4.1 (t,2H), 8.63 (s,1H), 8.89 (s,1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:20][C:21]2[CH:25]=[C:24]([CH:26]3[CH2:28][CH2:27]3)[NH:23][N:22]=2)=[N:4][C:5]([NH:9][C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:11][OH:12])=[N:6][C:7]=1[CH3:8].[C:29](O)(=O)C.C(N)=N>CCO>[CH:26]1([C:24]2[NH:23][N:22]=[C:21]([N:20]3[CH:29]=[N:1][C:2]4[C:3]3=[N:4][C:5]([NH:9][C@H:10]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:11][OH:12])=[N:6][C:7]=4[CH3:8])[CH:25]=2)[CH2:28][CH2:27]1
Reactant: CC(=O)O
Reactant: Cc1nc(N[C@@H](CO)c2ccc(F)cc2)nc(Nc2cc(C3CC3)[nH]n2)c1N
Agent: N=CN
Solvent: CCO
Product: Cc1nc(N[C@@H](CO)c2ccc(F)cc2)nc2c1ncn2-c1cc(C2CC2)[nH]n1
Yield: 35 %

Procedure:
A mixture of (R)-2-[5-amino-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6-methylpyrimidin-2-ylamino]-2-(4-fluorophenyl)ethanol (Method 40; 0.3 g, 0.8 mmol) and formamidine acetate (0.2 g, 1.6 mmol) in EtOH (8 ml) was heated to reflux for 12 hours. The reaction was then concentrated, dissolved in DCM (50 ml), and washed with saturated NaHCO3 solution (50 ml). The organic layer was then dried, filtered, and concentrated. The resulting solid was purified by column chromatography (DCM:MeOH=20:1) to give the title compound (0.11 g, 35%). NMR (400 MHz, CD3OD) 8.32 (s, 1H), 7.46-7.43 (m, 2H), 7.06-7.02 (m, 2H), 6.24 (s, 1H), 5.10-5.02 (m, 1H), 3.87-3.75 (m, 2H), 2.61 (s, 3H), 1.99-1.96 (m, 1H), 1.10-1.08 (m, 2H), 0.80-0.75 (m, 2H). MS: Calcd.: 393; Found: [M+H]+ 394.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH:11]([C:13]1[S:14][C:15]([CH:18]=[CH:19][C:20]2[C:21]3[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=3[S:23][CH:24]=2)=[CH:16][CH:17]=1)[OH:12])[C:6](OCC)=[O:7])(=[O:3])[CH3:2].[BH4-].[Li+]>O1CCCC1>[S:23]1[CH:24]=[C:20]([CH:19]=[CH:18][C:15]2[S:14][C:13]([CH:11]([OH:12])[CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6][OH:7])=[CH:17][CH:16]=2)[C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]1=2
Reactant: CCOC(=O)C(NC(C)=O)C(O)c1ccc(C=Cc2csc3ccccc23)s1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)NC(CO)C(O)c1ccc(C=Cc2csc3ccccc23)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
A stirred, chilled (-5° C.) suspension of ethyl 2-acetamido-3-[5-[2-(benzo[b]-thiophen-3-yl)ethenyl]thiophen-2-yl]-3-hydroxypropionate (4.0 g) and tetrahydrofuran (40 ml) was treated with lithium borohydride (5.8 ml of a 2.0M solution in tetrahydrofuran) over 3 mins. After stirring overnight at ambient temperature, the mixture was sequentially quenched with methanol (5 ml), water (20 ml), and 10% hydrochloric acid (5 ml). The organic solvent was removed in vacuo, and the aqueous phase was basified with 10% sodium hydroxide solution and extracted with dichloromethane and ether. The combined dried over anhydrous sodium sulfate organic phase was filtered and evaporated. The residue was purified by high performance liquid chromatography (silica gel, sample loaded in dichloromethane, eluted with 10% methanol in dichloromethane). The appropriate fractions were combined and evaporated to yield 2.23 g (62%) of product, mp 144°-145° C.
Reaction SMILES: FC(F)(F)C1C=C(C=CC=1)C=O.[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][NH:24][CH2:25]2)[CH2:21][CH2:20]1)=[O:17].C1(C(C2CCCCC2)C(N[C@@H]2[C@H:51]3[C@H:47]([CH2:48][NH:49][CH2:50]3)[CH2:46][CH2:45]2)=O)CCCCC1>>[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][N:24]([CH2:48][C:47]3[CH:51]=[CH:50][N:49]=[CH:45][CH:46]=3)[CH2:25]2)[CH2:21][CH2:20]1)=[O:17]
Reactant: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21)c1ccccc1
Agent: O=Cc1cccc(C(F)(F)F)c1
Product: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccncc3)C[C@@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting isonicotinaldehyde for 3-(trifluoromethyl)benzaldehyde and 3-methyl-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]-2-phenylbutanamide from Example 83 Step A for 2,2-dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide in the procedure described for Example 54: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.70 (d, J=5.9, 2H), 8.62 (s, 1H), 7.64 (dd, J=3.0, 7.5, 2H), 7.36-7.30 (m, 2H), 7.25 (dd, J=7.0, 12.4, 3H), 4.39-4.30 (m, 1H), 3.51 (d, J=14.2, 0.5H), 3.41 (dd, J=11.5, 14.2, 1H), 3.28 (d, J=14.3, 0.5H), 3.23 (dd, J=1.8, 10.5, 1H), 2.94 (dd, J=2.6, 9.2, 0.5H), 2.69-2.60 (m, 1H), 2.57 (dd, J=2.9, 9.2, 1H), 2.52-2.46 (m, 0.5H), 2.42 (dd, J=7.2, 8.8, 1H), 2.38-2.31 (m, 0.5H), 2.28 (dd, J=2.7, 9.0, 0.5H), 2.24-2.18 (m, 1H), 2.17-2.11 (m, 1H), 1.95-1.82 (m, 1H), 1.77 (dt, J=5.8, 12.3, 0.5H), 1.73-1.64 (m, 0.5H), 1.49-1.25 (m, 2H), 1.23-1.17 (m, 3H), 0.70 (d, J=6.5, 3H); MS (ESI+) m/z 378 (M+H)+.