Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[H][H].F[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1.[ClH:30]>C(O)(C)C.CN(C)C=O>[ClH:30].[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: [H][H]
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(OC2CCN(Cc3ccccc3)CC2)cc1
Reaction time: 16 h

Procedure:
A solution of 40.0 g of 1-benzyl-4-piperidinol in 75 ml. of dimethylformamide is added slowly to a stirred suspension of 6.7 g of a 50% oil dispersion of sodium hydride in 300 ml. of dimethylformamide at 60°-70° C. After addition is complete, heating is continued until no more hydrogen gas is liberated. A solution of 39.5 g of 1-fluoro-4-trifluoromethylbenzene in 50 ml. of dimethylformamide is added slowly while maintaining the reaction temperature at 60°-70° C. After addition is complete, stirring and heating at 70°-75° C. is continued for 16 hours. The mixture is poured into 1 l. of water and extracted with benzene. The combined benzene extracts are washed with water, dried, and solvent is removed under reduced pressure, leaving an oil. The oil is taken up in isopropanol and treated with ethereal-HCl, giving a white solid of 1-benzyl-4-(p-trifluoromethylphenoxy)piperidine hydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[H-].[Na+].Br[C:15]1[C:19]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:18]=2[S:17](=[O:26])[C:16]=1[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>CN(C=O)C>[CH3:25][O:24][C:22]1[CH:21]=[CH:20][C:19]2[C:15]([O:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=3)=[C:16]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[S:17](=[O:26])[C:18]=2[CH:23]=1
Reactant: COc1ccc(C2=C(Br)c3ccc(OC)cc3S2=O)cc1
Reactant: COC(=O)c1ccc(O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC2=C(c3ccc(OC)cc3)S(=O)c3cc(OC)ccc32)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
To a solution of methyl 5-hydroxypyridine-2-carboxylate (0.273 g, 1.78 mmol) in DMF (6.84 mL) at room temperature was added sodium hydride (60% suspension in oil, 0.043 g, 1.78 mmol) and the resulting mixture was stirred at room temperature for 30 mins. After 30 min at room temperature 3-bromo-6-methoxy-2-(4-methoxyphenyl)benzothiophene 1-oxide (0.5 g, 1.37 mmol) was added and the reaction was heated to 80° C. for 18 h. Upon completion the reaction was cooled to room temperature, quenched with water and extracted with DCM. The organic layers were combined, passed through a phase separator and concentrated in vacuo to give the crude product, which was purified by column chromatography (SiO2, 0-75% EtOAc/heptane) to afford methyl 5-((6-methoxy-2-(4-methoxyphenyl)-1-oxidobenzo[b]thiophen-3-yl)oxy)picolinate (314 mg, 0.72 mmol, 52% yield). 1H NMR (400 MHz, CDCl3) δ ppm=3.73 (s, 3H), 3.84 (s, 3H), 3.90-3.92 (m, 3H), 6.79-6.86 (m, 2H), 6.91 (dd, J=8.59, 2.53 Hz, 1H), 7.03 (d, J=8.59 Hz, 1H), 7.30 (dd, J=8.59, 3.03 Hz, 1H), 7.48 (d, J=2.53 Hz, 1H), 7.55-7.60 (m, 2H), 7.95 (d, J=8.59 Hz, 1H), 8.55 (d, J=2.02 Hz, 1H). LC/MS (m/z, MH+): 438.2.
Reaction SMILES: C([O:3][C:4](=[O:43])[CH:5]([OH:42])[CH2:6][NH:7][C:8](=[O:41])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=2)=[O:28])[C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)C.[OH-].[Na+].Cl>C(O)C>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([CH:15]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:38])([F:39])[F:40])=[CH:32][CH:31]=2)=[O:28])[C:12]2[CH:13]=[CH:14][C:9]([C:8]([NH:7][CH2:6][CH:5]([OH:42])[C:4]([OH:43])=[O:3])=[O:41])=[CH:10][CH:11]=2)=[CH:21][CH:20]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CCOC(=O)C(O)CNC(=O)c1ccc(C(NC(=O)Nc2ccc(OC(F)(F)F)cc2)c2ccc(C(C)(C)C)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1ccc(C(NC(=O)Nc2ccc(OC(F)(F)F)cc2)c2ccc(C(=O)NCC(O)C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 43 %

Procedure:
A solution of 3-{4-[1-(4-tert-butylphenyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid ethyl ester was stirred in absolute ethanol (20 mL) and 1 M sodium hydroxide (6 mL) was added. Stirring was continued for 17 hours and the solution was acidified with aqueous hydrochloric acid. The solvent was decanted and the remaining oil was dissolved in acetonitrile (20 mL) by heating. Water (20 mL) was added dropwise under vigorous stirring and the mixture was allowed to cool to room temperature. The precipitate was filtered off, washed with water and dried to afford 0.51 g (43%) of the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:8](=O)[CH2:7][CH:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[CH2:5][C:4]=2[N:3]=1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].[ClH:26].Cl.O>C(O)C>[ClH:26].[NH:24]([N:25]=[C:8]1[CH2:7][CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:5][C:4]2[N:3]=[C:2]([CH3:1])[CH:11]=[C:10]([CH3:12])[C:9]1=2)[C:21]([NH2:23])=[NH:22]
Reactant: N=C(N)NN
Reactant: Cc1cc(C)c2c(n1)CC(c1ccccc1C)CC2=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c2c(n1)CC(c1ccccc1C)CC2=NNC(=N)N
Yield: 89.6 %

Procedure:
A mixture of 2,4-dimethyl-7-(2-methylphenyl)-5,6,7,8-tetrahydroquinolin-5-one (0.48 g), aminoguanidine hydrochloride (0.21 g), concentrated hydrochloric acid (0.19 ml), water (0.19 ml) and ethanol (50 ml) was refluxed for 4 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with diethylether, and to the solution was added sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated. The residue was dissolved in ethanol, and to the solution was added 1N hydrochloric acid. Under reduced pressure, the solvent was evaporated to give 5-guanidinoimino-2,4-dimethyl-7-(2-methylphenyl)-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 84) (0.58 g) as amorphous.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl.CN(C=O)C>[Cl:23][C:17]([CH:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][CH2:13]1)=[O:19]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 3 h
Yield: 80.5 %

Procedure:
To a solution of 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid (4.50 g, 17.1 mmol, Preparation #5, Step A) in DCM (40 mL) at ambient temperature was added oxalyl chloride (3.00 mL, 34.2 mmol) followed by DMF (0.10 mL, 1.3 mmol). After about 3 h, the reaction was concentrated under reduced pressure to constant weight to afford benzyl 4-(chlorocarbonyl)piperidine-1-carboxylate as a yellow oil (3.88 g, 81%): 1H NMR (CDCl3) δ 7.44-7.35 (m, 5H), 5.16 (s, 2H), 4.20-4.10 (m, 2H), 3.03-2.89 (m, 3H), 2.15-2.05 (m, 2H), 1.81-1.76 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.CN([CH:17]=[O:18])C>C1COCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([CH:17]=[O:18])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1cccnc1Cl
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccnc(Cl)c1Cl
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2,3-dichloropyridine (10 g, 67.57 mmol) [C.A.S. 2402-77-9] in dry THF (200 ml) cooled at −78° C. under a nitrogen atmosphere, n-butyllithium (37.165 ml, 74 mmol, 2 M in hexanes) was dropwise added. The resulting reaction mixture was stirred at −78° C. for 20 min. Then dry DMF (6.28 ml, 81.087 mmol) was added dropwise. After 15 min stirring at −78° C., the mixture was allowed to warm to room temperature, quenched with water and extracted with DCM. The combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The crude residue was purified by short open column chromatography (DCM as eluent). The desired product fractions were collected and evaporated in vacuo to give a residue that was further purified by column chromatography (silica gel; DCM/heptane up to 50% as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate compound D41 (4.15 g, 34.9%) as a white solid.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:15]([CH3:16])[C:14](=[O:17])[C@H:13]([CH3:18])[N:12]=[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:10]=2[C:26]=1[Cl:27].C(N(CC)CC)C.[NH2:35][CH2:36][CH2:37][OH:38]>ClCCCl>[Cl:27][C:26]1[C:10]2[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[N:12][C@@H:13]([CH3:18])[C:14](=[O:17])[N:15]([CH3:16])[C:9]=2[CH:8]=[CH:7][C:6]=1[NH:5][C:1]([NH:35][CH2:36][CH2:37][OH:38])=[O:2]
Reactant: O=C(Cl)Cl
Reactant: C[C@@H]1N=C(c2ccccc2F)c2c(ccc(N)c2Cl)N(C)C1=O
Reactant: NCCO
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1N=C(c2ccccc2F)c2c(ccc(NC(=O)NCCO)c2Cl)N(C)C1=O
Temperature: 0 °C

Procedure:
A solution of 2g of phosgene in 20 ml of ice-cold 1,2-dichloroethane is placed in a sulphonation flask. There is added dropwise thereto a solution of 4 g (0.012 M) of (S)-7-amino-6-chloro-5-(o-fluorophenyl)-1,3-dihydro-1,3-dimethyl-2H-1,4-benzodiazepin-2-one in 40 ml of 1,2-dichloroethane while cooling with ice and stirring in such a manner that the temperature does not exceed 10° C. The mixture is then stirred at room temperature for 45 minutes. The resulting solution of (S)-[6-chloro-5-(o-fluorophenyl)-2,3-dihydro-1,3-dimethyl-2-oxo-1H-1,4-benzodizepin-7-yl]isocyanate is cooled with ice and slowly made alkaline with 6 ml of triethylamine. A solution of 2 ml of 2-aminoethanol in 20 ml of 1,2-dichloroethane is treated with the foregoing pre-prepared solution, the mixture is stirred at room temperature for 30 minutes and then concentrated. The residue is purified on a 300 g silica gel column using methylene chloride and then methylene chloride/ethanol (20:1) as the eluting agent and crystallised from a small amount of ethyl acetate/n-hexane. There is obtained (S)-1-[6-chloro-5-(o-fluorophenyl)-2,3-dihydro-1,3-dimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-3-(2-hydroxyethyl)urea which melts above 147° C. with decomposition; [α]25D =+192.2° (in dioxan; 1%).
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[C:3]([CH2:16][CH3:17])([CH2:14][CH3:15])[O:4][C:5]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][C:6]=12.[C:18]([N:20]=[C:21]1[NH:25][CH2:24][CH2:23][S:22]1)#[N:19].O>CN(C)C=O.C(N(CC)CC)C>[C:18]([N:20]=[C:21]1[N:25]([C@@H:7]2[C:6]3[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:5]=3[O:4][C:3]([CH2:16][CH3:17])([CH2:14][CH3:15])[C@H:2]2[OH:1])[CH2:24][CH2:23][S:22]1)#[N:19]
Reactant: N#CN=C1NCCS1
Reactant: CCC1(CC)Oc2ccc(C#N)cc2C2OC21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCC1(CC)Oc2ccc(C#N)cc2[C@@H](N2CCSC2=NC#N)[C@@H]1O
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 28.9 %

Procedure:
A mixture of 3,4-epoxy-2,2-diethyl-3,4-dihydro-2H-1-benzopyran-6-carbonitrile (1.07 g) and 2-cyanoiminothiazolidine (0.89 g) in N,N-dimethylformamide-triethylamine (2:1, 7.5ml) was heated at 100° C. with stirring for 8 hours and 20 minutes. The reaction mixture was poured into water, extracted with ethyl acetate, washed with brine, and then dried over anhydrous magnesium sulfate. After the solution was evaporated in vacuo, the residue was purified with silica gel column chromatography using a mixture of ethyl acetate and n-hexane (1:1) as an eluent. The fractions containing the object compound were concentrated in vacuo and the residue was recrystallized from 50% aqueous acetonitrile to give trans-4-(2-cyanoiminothiazolidin-3-yl)-2,2-diethyl-3,4-dihydro-3-hydroxy-2H-1-benzopyran-6carbonitrile (0.48 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[N:6]2OCOC.Cl.O1CCCC1.C(O)C>C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:13])=[O:14])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[NH:6]2
Reactant: COCOn1c(-c2nccs2)cc2c(F)ccc(N(C)S(=O)(=O)c3cccs3)c21
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(c1ccc(F)c2cc(-c3nccs3)[nH]c12)S(=O)(=O)c1cccs1
Yield: 51 %

Procedure:
A mixed solution of N-[4-fluoro-1-(methoxymethoxy)-2-(1,3-thiazol-2-yl)-1H-indol-7-yl]-N-methylthiophene-2-sulfonamide (165 mg), 6N hydrochloric acid (6 mL), tetrahydrofuran (2 mL) and ethanol (4 mL) was stirred at 80° C. for 7 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:9-3:7), and the obtained crystals were recrystallized from ethyl acetate-hexane to give the title compound (73 mg, yield 49%) as colorless needle crystals. melting point 197-198° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:27])(=[N:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])[CH:14]=2)=[CH:5][C:4]=1[N:28]=[CH:29]N(C)C)#[N:2].[NH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1.CCCCCC.ClCCl.CO>CO>[CH2:25]([O:24][C:22]([N:21]=[S:19]([CH3:27])([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][O:11][C:6]2[CH:5]=[C:4]3[C:3]([C:1]([NH:33][C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)=[N:2][CH:29]=[N:28]3)=[CH:8][C:7]=2[O:9][CH3:10])[CH:14]=1)=[O:20])=[O:23])[CH3:26]
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc(N=CN(C)C)c(C#N)cc2OC)c1
Reactant: Nc1cccnc1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CO
Product: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc3ncnc(Nc4cccnc4)c3cc2OC)c1
Yield: 55 %

Procedure:
According to GWP 5, the reaction of N′-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzyloxy}-4-methoxyphenyl)-N,N-dimethylformimidamide (76 mg, 0.17 mmol) with 3-aminopyridine (19 mg, 0.20 mmol) and chromatographic purification (silica gel, amino column, hexane, dichloromethane/methanol: 0→5% methanol) gives the desired product in 55% yield (46 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C@H:11]2[O:16][CH2:15][C@@H:14]3[CH2:17][NH:18][CH2:19][CH2:20][N:13]3[CH2:12]2)=[CH:4][CH:3]=1.OS(C(F)(F)F)(=O)=O.C1C(=O)N([I:36])C(=O)C1>>[F:1][C:2]1[C:3]([I:36])=[CH:4][C:5]([C@H:11]2[O:16][CH2:15][C@@H:14]3[CH2:17][NH:18][CH2:19][CH2:20][N:13]3[CH2:12]2)=[C:6]([CH3:10])[C:7]=1[C:8]#[N:9]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1c([C@@H]2CN3CCNC[C@H]3CO2)ccc(F)c1C#N
Agent: O=S(=O)(O)C(F)(F)F
Product: Cc1c([C@@H]2CN3CCNC[C@H]3CO2)cc(I)c(F)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-fluoro-2-methyl-3-((3R,9aS)-octahydropyrazino[2,1-c][1,4]oxazin-3-yl)benzonitrile (600 mg, 2.18 mmol) was dissolved in triflic acid (5.80 mL, 65.4 mmol), and NIS (1226 mg, 5.45 mmol) was added at 0° C. The reaction mixture was stirred at rt overnight and quenched into ice water and basified with 5 N NaOH. The aqueous layer was extracted with DCM. The organic layer was washed with aqueous NaS2O3, NaHCO3, brine, dried and evaporated to give crude title compound, which was used without further purification. LC/MS: [(M+1)]+=402.1;
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=1.O1CCOCC1.CCN(C(C)C)C(C)C.[C:49]1([SH:55])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[C:49]1([S:55][C:2]2[CH:3]=[C:4]([CH:8]([N:12]3[CH:16]=[C:15]([C:17]4[C:18]5[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=5[N:20]=[CH:21][N:22]=4)[CH:14]=[N:13]3)[CH2:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=2)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cncc(Br)c4)c3)ncnc21
Reactant: Sc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cncc(Sc5ccccc5)c4)c3)ncnc21
Yield: 80.1 %

Procedure:
To the 3-(5-bromopyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (0.130 g, 0.000248 mol) from Example 429 Step 2, in dry 1,4-dioxane (1.60 mL, 0.0205 mol) was added DIPEA (0.085 mL, 0.00049 mol). The solution was degassed with nitrogen, followed by addition of (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.007 g, 0.00001 mol), bis(dibenzylideneacetone)palladium(0) (0.0036 g, 0.0000062 mol), and benzenethiol (0.025 mL, 0.00025 mol). Again the solution was purged with nitrogen. The reaction mixture in a sealed tube was heated to reflux for 3 h. The reaction mixture was diluted with ethyl acetate, washed with water (2×), brine (1×), dried over magnesium sulfate, filtered, and the solvent was evaporated in vacuo. The crude product was triturated with hexane-ethyl acetate 9:1 to yield 3-[5-(phenylthio)pyridin-3-yl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (110 mg, 80%). LC/MS (M+H)+: m/z=554.2.
Reaction SMILES: [C:1](O)(=O)/C=C\[C:4]([OH:6])=[O:5].[CH3:9][O:10][C:11]1[C:31]([O:32][CH3:33])=[CH:30][C:14]2[CH:15]([O:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)[CH2:16][NH:17][CH2:18][CH2:19][C:13]=2[CH:12]=1.O.[C:35](=[O:38])([O-:37])[O-].[Na+].[Na+]>C(O)=O.C=O>[C:4]([OH:6])(=[O:5])[C:35]([OH:37])=[O:38].[CH3:9][O:10][C:11]1[C:31]([O:32][CH3:33])=[CH:30][C:14]2[CH:15]([O:20][C:21]3[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=3)[CH2:16][N:17]([CH3:1])[CH2:18][CH2:19][C:13]=2[CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)/C=C\C(=O)O
Reactant: COc1cc2c(cc1OC)C(Oc1ccc([N+](=O)[O-])cc1)CNCC2
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: COc1cc2c(cc1OC)C(Oc1ccc([N+](=O)[O-])cc1)CN(C)CC2
Product: O=C(O)C(=O)O
Yield: 74 %

Procedure:
A solution of 7,8-dimethoxy-1-(4-nitrophenoxy)-2,3,4,5-tetrahydro-3-benzazepine of Example 49, (6 g, 17.4 mmole) in 25 ml 95% formic acid and 25 ml 37% aqueous formaldehyde solution was stirred at 75° C. for 1.5 hours. After cooling, the reaction mixture was stirred with water, basified with sodium carbonate and was extracted with dichloromethane. The organic extract was washed with water and saturated sodium chloride and was dried (anhydrous MgSO4), filtered and evaporated to 6.2 g of an oil. This oil was purified by high pressure liquid chromatography (silica gel, ethyl acetate) to give 4.6 g (74%) of an oil. This oil was converted to the oxalate salt as in Example 1 and was twice recrystallized from isopropanol-methanol to give 3.4 g (44%) of 7,8-dimethoxy-3-methyl-1-(4-nitrophenoxy)-2,2,4,5-tetrahydro-3-benzazepine oxalate, d 158°-159° C.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:31])([CH3:30])[CH:8]1[O:13][C:12]2=[CH:14][S:15][C:16]([CH:17]=[CH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:21][CH:20]=3)=[C:11]2[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.CN(C)[CH:39]=[O:40]>O1CCCC1>[C:1]([SiH2:5][O:6][C:7]([CH3:30])([CH3:31])[CH:8]1[CH2:9][O:10][C:11]2=[C:16]([CH:17]=[CH:18][C:19]3[CH:20]=[CH:21][C:22]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:23][CH:24]=3)[S:15][C:14]([CH:39]=[O:40])=[C:12]2[O:13]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C)C=O
Reactant: CCN(CC)c1ccc(C=Cc2scc3c2OCC(C(C)(C)O[SiH2]C(C)(C)C)O3)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCN(CC)c1ccc(C=Cc2sc(C=O)c3c2OCC(C(C)(C)O[SiH2]C(C)(C)C)O3)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
60 mL of dry tetrahydrofuran is added via syringe to 3.4 g (0.0074 mole) of 4 contained in a nitrogen purged round bottom flask. The solution is cooled to 0° C. The solution is stirred at 0° C. for 60 minutes, at which point 3.2 mL of 2.5 M BuLi in hexanes is added dropwise. The solution is allowed to stir for 15 min at 0° C., followed by the addition of 0.697 mL (0.009 mole) of anydrous dimethylformamide. The solution is warmed to room temperature, where it was stirred overnight. The tetrahydrofuran is removed under reduced pressure, and the resulting material is taken up in 500 mL of chloroform. The organic layer is washed with water three times, dried over MgSO4, and solvent is then removed under reduced pressure. The compound is purified on a silica column with a hexane/ethyl acetate mobile phase.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][OH:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH2:24][C@@H:25]([C:29]([OH:31])=[O:30])[C@H:26]([CH3:28])[OH:27].CCN(CC)CC>CN(C=O)C.O>[OH:27][C@@H:26]([CH3:28])[C@@H:25]([NH:24][C:6]([O:23][CH2:22][CH2:21][CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])[C:29]([OH:31])=[O:30]
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Reactant: OCCCCc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](O)[C@@H](NC(=O)OCCCCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.7 %

Procedure:
In a four necked round bottom flask, CDI (10.6 g, 65.5 mmol) was added to a solution of 4-phenylbutan-1-ol (5 mL, 32.8 mmol) in anhydrous DMF (70 mL) under argon. After stirring 2 h at rt, D-threonine (3.90 g, 32.8 mmol) dissolved in water (70 mL) and Et3N (6.8 mL, 49.1 mmol) were added. The mixture was heated at 50° C. for 16 h then allowed to cool. Water (700 mL) was added and the mixture washed with Et2O (3×300 mL). The aqueous phase was acidified with 2M HCl solution then extracted with AcOEt (3×500 mL). The collected organic phases were dried over Na2SO4, filtered and the solvent removed under vacuum. The crude was further co-evaporated with toluene to give a pale yellow oil (5.2 g, 54%), which was used in the next step without further purification. MS (ESI) m/z: 296[M+H]+; 294[M−H]−. Rf=0.34 (Cy/AcOEt 2:8+1% CH3COOH). FTIR (cm−1): 3332 (br), 3027, 2978, 2938, 2863, 1719 (br), 1525, 1253, 1069, 779, 748, 699.