Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[C:14](OC(=O)C)(=[O:16])C>C(O)=O.O>[CH:14]([NH:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:16]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: O=CO
Product: O=CN[C@@H](Cc1ccc(O)cc1)C(=O)O
Temperature: 10 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
L-Tyrosine (60 g; 0.33 mol) was dissolved in 98% formic acid (400 ml) and cooled to 10° C. Acetic anhydride, (192 ml; 1.73 mol) was added in four stages for five minutes, while at the same time maintaining a temperature of 10° C. The mixture was then stirred for 60 min at 10° C. and then kept at room temperature for 30 min. Water (192 ml) was added with stirring at 10 to 15° C. for 30 min, and then the mixture was subjected to evaporation under reduced pressure at 70° C., until a dry residue was obtained. The residual oily solid was dissolved in a minimal volume of boiling water, and then cooled to produce fine white crystals of N-formyl-L-tyrosine (60.6 g; 88%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)=O.[Cl:25][CH2:26][C:27](=O)[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(N(CC)CC)C>C(O)C>[Cl:25][CH2:26][C:27]1[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=2)[C:4]2[C:3](=[CH:20][C:19]([O:21][CH3:22])=[C:18]([O:23][CH3:24])[CH:17]=2)[N:2]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
2-Amino-3',4,4',5-tetramethoxybenzophenone hydrochloride (36.0 g) and ethyl 4-chloroacetoacetate (21.4 g) were stirred in ethanol (350 ml) under reflux for 7 hours. After completion of the reaction, triethylamine (10.6 g) was added dropwise at a temperature not over 20° C. and the mixture was stirred at 5° C. for 1 hour. The crystals were collected by filtration, washed twice with 50 ml each of ethanol and dried under reduced pressure to provide ethyl 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (41.0 g; yield 92%).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[S:15][C:16]([C:20]([OH:22])=O)=[C:17]([CH3:19])[N:18]=3)[C:10](=[O:23])[CH:9]=2)=[CH:4][CH:3]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][NH2:33])[CH:27]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[S:15][C:16]([C:20]([NH:33][CH2:32][C:28]4[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=4)=[O:22])=[C:17]([CH3:19])[N:18]=3)[C:10](=[O:23])[CH:9]=2)=[CH:24][CH:25]=1
Reactant: Cc1nc(-n2ccc(OCc3ccc(F)cc3)cc2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Product: Cc1nc(-n2ccc(OCc3ccc(F)cc3)cc2=O)sc1C(=O)NCc1cccnc1
Yield: 52 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-(4-(4-fluorobenzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a colorless solid in 52% yield: mp 231-233° C. (dichloromethane/methanol); 1H NMR (300 MHz, DMSO-d6) δ 8.83 (t, J=5.6 Hz, 1H), 8.60 (d, J=8.1 Hz, 1H), 8.50 (s, 1H), 8.43 (d, J=4.2 Hz, 1H), 7.69 (d, J=7.9 Hz, 1H), 7.51-7.47 (m, 2H), 7.37-7.29 (m, 1H), 7.22 (t, J=8.8 Hz, 2H), 6.41-6.35 (m, 1H), 6.23 (s, 1H), 5.13 (s, 2H) 4.40 (d, J=4.2 Hz, 2H), 2.53 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 167.4, 164.1, 162.0, 161.6, 160.9, 154.0, 150.6, 149.3, 148.5, 135.6, 132.1, 131.0, 130.9, 123.9, 116.0, 115.7, 104.4, 97.5, 70.1, 42.2, 17.5; MS (ES+) m/z 451.3 (M+1).
Reaction SMILES: C(=O)(O)[O-].[Na+].O.[C:7]1([C:13]2[NH:18][C:17](=[S:19])[NH:16][C:15](=[O:20])[CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(O)C>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][S:19][C:17]1[N:16]=[C:15]([OH:20])[CH:14]=[C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:18]=1)[CH3:27]
Reactant: O=c1cc(-c2ccccc2)[nH]c(=S)[nH]1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CSc1nc(O)cc(-c2ccccc2)n1

Procedure:
To a stirred solution of 8.4 g of sodium bicarbonate in 450 ml. of water and 100 ml. of ethanol was added 20.4 g of 6-phenyl-2-thiouracil. The mixture was heated on a hot plate until a clear solution was obtained then 16.7 g of ethyl bromoacetate was added. A precipitate was deposited which was removed by filtration and washed with water. The dried product amounted to 28.1 g, mp. 214°-218°C. decomp. The analytical sample of (4-hydroxy-6-phenyl-2-pyrimidinylthio)acetic acid ethyl ester was obtained by recrystallization from dimethyl formamide, mp. 217°-219°C.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[CH:8]=[C:7]([C:17]3[CH:18]=[N:19][CH:20]=[C:21]([C:23]#[C:24][Si](C)(C)C)[CH:22]=3)[CH:6]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>CO.CCOC(C)=O>[CH:1]1([NH:4][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[CH:8]=[C:7]([C:17]3[CH:18]=[N:19][CH:20]=[C:21]([C:23]#[CH:24])[CH:22]=3)[CH:6]=2)[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)C#Cc1cncc(-c2cc(NC3CC3)nc(-c3ccccn3)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#Cc1cncc(-c2cc(NC3CC3)nc(-c3ccccn3)c2)c1

Procedure:
Cyclopropyl-(5″-trimethylsilanylethynyl-[2,2′;4′,3″]terpyridin-6′-yl)-amine (Example 2.128, step1) (1 eq, 0.127 mmol, 49 mg) is dissolved in MeOH (2 ml) and potassium carbonate is added (2 eq, 0.255 mmol, 35 mg). The reaction mixture is dissolved in EtOAc and washed with water. The organic layer is washed with brine, dried over drying agent MgSO4, filtered and the organic solvent is reduced in vacuo. The crude residue is purified by reverse phase column chromatography (Isolute™ C18, 0-20% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 313.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][C:10]=2[C:20]([F:23])([F:22])[F:21])[CH2:4][CH2:3]1.[OH-].[Na+]>O.CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=2[C:20]([F:23])([F:21])[F:22])[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(CN2CCN(C)CC2)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1CCN(Cc2ccc(C(=O)O)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of ethyl 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzoate (330 mg, 0.96 mmol) and sodium hydroxide solution (1.5 M) in water/methanol (15/5 mL) were stirred at room temperature for 5 hours. The mixture was concentrated and acidified with aqueous hydrochloric acid until a white solid formed. The mixture was lyophilized to give a white solid (600 mg, contains salt).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4](P(O)(O)=O)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].N12CCCN=C1CCCCC2.[CH3:32][CH:33]1[CH2:36][CH:35]([CH:37]=O)[CH2:34]1>ClCCl>[CH3:1][O:2][C:3](=[O:20])/[C:4](/[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])=[CH:32]/[CH:33]1[CH2:36][CH:35]([CH3:37])[CH2:34]1
Reactant: CC1CC(C=O)C1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)/C(=C/C1CC(C)C1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 37.4 %

Procedure:
In a round bottom flask under argon was placed N-(benzyloxycarbonyl)-α-phosphonoglycine methyl ester (3.04 g, 9.16 mmol) in dichloromethane (10 mL) and cooled to 0° C. This mixture was treated dropwise with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.20 mL, 7.94 mmol) and stirred at 0° C. for 20 min. A solution of 3-methyl-cyclobutanecarbaldehyde (600 mg, 6.11 mmol) in dichloromethane (5 mL) was then added. After the addition was complete the reaction was warmed to 25° C. and stirred overnight. The mixture was then concentrated in vacuo and dissolved in ethyl acetate (100 mL). The ethyl acetate layer was washed with a saturated aqueous ammonium chloride solution (2×50 mL), a saturated aqueous solution of sodium chloride (50 mL), dried over sodium sulfate and concentrated in vacuo with silica gel (3 g). Purification by Biotage flash chromatography (40M column, 20% ethyl acetate/hexanes) afforded (Z)-2-benzyloxycarbonylamino-3-(3-methyl-cyclobutyl)-acrylic acid methyl ester (693 mg, 38%) as a yellow viscous oil.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][C@@H:6]([CH2:8][OH:9])[CH:5]=[CH:4]1.OC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)C=C1.[NH2:25][C:26]1[C:27]([Cl:33])=[N:28][CH:29]=[N:30][C:31]=1Cl.C(N(CC)CC)C.[OH-].[Na+]>C(O)CCC>[NH2:25][C:26]1[C:31]([NH:2][C@H:3]2[CH2:7][C@@H:6]([CH2:8][OH:9])[CH:5]=[CH:4]2)=[N:30][CH:29]=[N:28][C:27]=1[Cl:33]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: N[C@@H]1C=C[C@H](CO)C1
Agent: CC(C)(C)OC(=O)N[C@@H]1C=C[C@H](CO)C1
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Nc1c(Cl)ncnc1N[C@@H]1C=C[C@H](CO)C1

Procedure:
A solution of (+)-(1R,cis)-4-amino-2-cyclopentene-1-methanol hydrochloride (from deblocking of 10.66 g, 50.0 mmoles of (+)-(1S,cis)-tert-butyl N-[4-(hydroxymethyl)-2-cyclopenten-1-yl]carbamate as described in part c of this example), 5-amino-4,6-dichloropyrimidine (Aldrich, 16.40 g, 0.100 mole), and triethylamine (15.2 g, 0.150 mole) in 1-butanol (25 mL) was refluxed under nitrogen for 18 hours. The solution was cooled and 1 N sodium hydroxide (100 mL) was added. Volatiles were evaporated under reduced pressure and the residual solid was chromatographed on silica gel. Title compound eluted with 5% methanol-chloroform as a pale yellow glass (10.8 g). Crystallization of such a sample from ethyl acetate gave title compound as white needles, m.p. 144–146° C.; 1H-NMR (DMSO-d6) δ 7.75 (s, 1H), 6.76 (d, J=6.8 Hz, 1H), 5.93 and 5.82 (two m, 2H), 5.11 (m, 3H), 4.66 (t, J=5.3 Hz, 1H), 3.40 (br t, J=6.1 Hz, 2H), 2.75 (m, 1H), 2.20 (m, 1H), 1.38 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:21][C:22]1[CH:23]=[C:24]([OH:29])[CH:25]=[C:26]([CH3:28])[CH:27]=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>[CH3:21][C:22]1[CH:23]=[C:24]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[O:29][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1
Reactant: CC(=O)c1c(C)cc(Cl)cc1C
Reactant: Cc1cc(C)cc(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
Product: CC(=O)c1c(C)cc(Oc2cc(C)cc(C)c2)cc1C
Temperature: 100 °C
Yield: 85.7 %

Procedure:
To a solution of 1-(4-chloro-2,6-dimethylphenyl)ethanone (5.0 g, 27.4 mmol), K3PO4 (11.6 g, 54.7 mmol), 3,5-dimethylphenol (4.01 g, 32.8 mmol) in toluene (54.8 mL), was added 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (349 mg, 0.82 mmol), Pd(OAc)2 (259 mg, 1.15 mmol). The reaction was heated at 100° C. overnight under N2. The solution was cooled to room temperature and filtered through a small pad of Celite. The cake was washed with ethyl acetate (50 mL) and combined filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 1-(4-(3,5-dimethylphenoxy)-2,6-dimethylphenyl)ethanone (6.3 g) as yellow solids in 86% yield: 1H NMR (500 MHz, CDCl3) δ 6.76 (s, 1H), 6.63 (s, 2H), 6.62 (s, 2H), 2.48 (s, 3H), 2.29 (s, 6H), 2.22 (s, 6H).
Reaction SMILES: Br[C:2](Br)=[CH:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[Li]CCCC.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[O:27][CH2:28][C:29](N(OC)C)=[O:30].[NH4+].[Cl-]>C1COCC1>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[O:27][CH2:28][C:29](=[O:30])[C:2]#[C:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=C(Br)Br
Reactant: COc1ccc(OCC(=O)N(C)OC)cc1OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(OCC(=O)C#C[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1OC
Temperature: 25 °C
Yield: 50.2 %

Procedure:
To a THF (120 mL) solution of (S)-t-butyl 2-(2,2-dibromovinyl)pyrrolidine-1-carboxylate (5.326 g), n-BuLi (11.6 mL, 2.64 N hexane solution) was added dropwise at −78° C. and the mixture was stirred at the same temperature for an hour; thereafter, a THF (50 mL) solution of the compound (4.00 g) obtained in Example 14-(1) was added dropwise and temperature was raised to room temperature over an hour. The reaction mixture was added to a saturated aqueous solution of NH4Cl (400 mL) and the organic layer extracted with AcOEt (400 mL×2) was dried (MgSO4), filtered and concentrated to give a crude product, which was further purified by neutral silica gel chromatography (AcOEt/hexane) to give the titled compound (2.934 g, pale yellow oil.)
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[C:7](=[O:14])[C:8]([CH:12]=C)=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH2:3][CH3:4].I([O-])(=O)(=O)=[O:31].[Na+].C(#N)C.O>CC(C)=O.[Os](=O)(=O)(=O)=O>[CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)[C:7](=[O:14])[C:8]([CH:12]=[O:31])=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C=Cc1c(C)nc(CCCC)n(Cc2ccc(-c3ccccc3C#N)cc2)c1=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CC#N
Product: CCCCc1nc(C)c(C=O)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 4 h
Yield: 72.2 %

Procedure:
To a solution of 4′-[(2-butyl-4-methyl-6-oxo-5-vinylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.91 g) and sodium periodate (2.56 g) in acetone (10 mL)-acetonitrile (10 mL)-water (10 mL) was added osmium tetroxide (0.9 g, 7% polymer-bound catalyst), and the mixture was stirred for 4 hr. The insoluble material was filtered off through celite, and the filtrate was diluted with ethyl acetate, washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow oil (0.66 g, 71%).
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[C:10]2[C:5](=[CH:6][C:7]([N+:25]([O-])=O)=[C:8]([NH:11][C:12](=[O:24])/[CH:13]=[CH:14]/[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N+:21]([O-])=O)[CH:9]=2)[N:4]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:3]1=[O:33].Cl[Sn]Cl.O>CCOC(C)=O>[NH2:25][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH3:1])([CH3:34])[C:3](=[O:33])[N:4]2[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:9][C:8]=1[NH:11][C:12](=[O:24])/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21]
Reactant: CCCCCN1C(=O)C(C)(C)c2cc(NC(=O)/C=C/c3ccccc3[N+](=O)[O-])c([N+](=O)[O-])cc21
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCN1C(=O)C(C)(C)c2cc(NC(=O)/C=C/c3ccccc3N)c(N)cc21

Procedure:
(E)-N-(3,3-Dimethyl-6-nitro-2-oxo-1-pentyl-2,3-dihydro-1H-indol-5-yl)-3-(2-nitrophenyl)-acrylamide is dissolved in EtOAc (70 ml). SnCl2.H2O (5.44 g; 24.1 mmol) is added and the resulting mixture is heated under reflux for 20 h. After re-cooling the mixture is filtered over basic Al2O3 (120 g) and concentrated in vacuo. The residue is taken-up in EtOAc and saturated K2CO3 solution. After an aqueous work-up the compound (0.82 g) is obtained as a yellow solid.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I/[CH:10]=[CH:11]/[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[C:1]1([C:7]#[C:8]/[CH:10]=[CH:11]/[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCC/C=C/I
Reactant: C#Cc1ccccc1
Product: CCCCCC/C=C/C#Cc1ccccc1

Procedure:
The general procedure was used to convert phenylacetylene and (E)-1-iodooctene to the title product in 24 hours. Purification by flash chromatography (light petroleum ether as eluent) gave the analytically pure product as a clear oil (423 mg, 99% yield). 1H NMR (400 MHz, CDCl3) δ 7.40 (m, 2H), 7.28 (m, 3H), 6.24 (m, 1H), 5.68 (d, J=15.84, 1H), 2.15 (q, 2H), 1.41-1.28 (m, 8H), 0.89 (t, 3H). 13C NMR (100 MHz, CDCl3) δ 145.08, 131.24, 128.07, 127.67, 123.49, 109.32, 88.23, 87.68, 33.08, 31.52, 28.66, 28.59, 22.45, 13.94. Anal. Calc'd. for C16H20: C, 90.51; H, 9.49; Found C, 90.65; H, 9.58.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([N:22]5[C:29](=[O:30])[CH2:28][C@@H:27]6[NH:31][C@@H:24]([CH2:25][CH2:26]6)[CH2:23]5)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:37][S:38](Cl)(=[O:40])=[O:39].C(N(C(C)C)CC)(C)C.C(Cl)Cl>CCOC(C)=O>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([N:22]5[C:29](=[O:30])[CH2:28][C@@H:27]6[N:31]([S:38]([CH3:37])(=[O:40])=[O:39])[C@@H:24]([CH2:25][CH2:26]6)[CH2:23]5)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@@H]5CC[C@H](CC4=O)N5)cn3)nc2n1C1CCCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@@H]5CC[C@H](CC4=O)N5S(C)(=O)=O)cn3)nc2n1C1CCCC1
Reaction time: 16 h
Yield: 43.3 %

Procedure:
A sample of 7-Cyclopentyl-N,N-dimethyl-2-(5-((1S,6R)-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (50 mg, 0.102 mmol), methanesulfonyl chloride (12.3 mg, 0.107 mmol) and diisopropyl ethylamine (0.027 ml, 0.154 mmol) were combined into 1 ml DCM in a crew cap vial along with a stir bar and allowed to stir for 16 hr. The reaction was then taken up into EtOAc, and extracted with saturated Na2CO3 solution, then with brine and the organic layer dried over Na2SO4. The crude product was purified by normal phase chromatography (0-75% ethyl acetate in Heptane) which gave 7-cyclopentyl-N,N-dimethyl-2-(5-((1S,6R)-9-(methylsulfonyl)-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (25 mg) in 44% yield. 1H NMR (400 MHz, CDCl3) δ ppm 8.66 (s, 2H), 8.47 (d, J=9.09 Hz, 2H), 8.07 (d, J=2.53 Hz, 1H), 7.46 (m, 1H), 6.40 (s, 1H), 4.73 (m, 1H), 4.42 (m, 1H), 4.31 (m, 1H), 4.20 (d, 1H), 3.64 (s, 2H), 3.09 (s, 6H), 3.00 (d, J=4.04 Hz, 1H), 2.90 (s, 3H), 2.49 (m, 2H), 2.00 (m, 4H), 1.66 (br. s., 4H). MS m/z 566.9 (M+H).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[C:9](/[CH:10]=[CH:11]/[C@@H:12]([OH:24])[CH2:13][C@@H:14]([OH:23])[CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])=[C:8]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[N:7]=[C:6]([N:32]([S:34]([CH3:37])(=[O:36])=[O:35])[CH3:33])[N:5]=1)[CH3:3].[OH-].[Na+:39]>C1COCC1.O>[CH3:3][CH:2]([C:4]1[C:9]([CH:10]=[CH:11][CH:12]([OH:24])[CH2:13][CH:14]([OH:23])[CH2:15][C:16]([O-:18])=[O:17])=[C:8]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[N:7]=[C:6]([N:32]([S:34]([CH3:37])(=[O:36])=[O:35])[CH3:33])[N:5]=1)[CH3:1].[Na+:39]
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/[C@@H](O)C[C@@H](O)CC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1C=CC(O)CC(O)CC(=O)[O-]
Temperature: 30 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
Rosuvastatin tert-butyl ester (3.0 g, 5.6 mmol) is dissolved in 25 mL of a 4:1 mixture of THF/water. The clear solution is warmed to 30° C. and 8.0 M NaOH (0.75 mL, 6.0 mmol) was added portionwise. The reaction mixture is stirred at 30° C. for 2 hours giving a clear yellow solution. Then THF is removed completely under the reduced pressure (20 mbar) at 40° C. The remaining aqueous solution is diluted with water to 25 mL and washed with AcOEt (2×10 mL). After separation from the organic layer aqueous phase is distilled under the reduced pressure (20 mbar) at 40° C. to completely remove the dissolved AcOEt. The remaining clear solution of sodium rosuvastatinate is diluted with water to 25 mL and liophylized to afford 2.81 g (100%) of rosuvastatin sodium salt as white powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7](O)[CH2:8][CH2:9][CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:32]>C1COCC1>[Br:32][CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCC(O)c1ccccn1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(Br)c1ccccn1
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
To a mixture of 1-(pyridin-2-yl)butan-1-ol (0.35 g, 2.3 mmol; Example 231, Step A) and triphenylphosphine (1.1 g, 4.2 mmol) in THF (15 mL) at 0° C. under N2 atmosphere was added CBr4 (1.2 g, 3.5 mmol). The mixture was stirred at 0° C. for 2 min, and then was allowed to warm to rt and stirred for 25 min. The precipitate was filtered off through a pad of Celite® (J. T. Baker, Phillipsberg, N.J., diatomaceous earth), the solid was washed with cold THF (10 mL). The filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel with 0-5-15% EtOAc/Hexanes provided the title compound as colorless oil. Mass Spectrum (ESI) m/z=214.0 and 216.0 (M+1).
Reaction SMILES: CI.[CH3:3][C:4]1([CH3:42])[NH:9][CH2:8][CH2:7][N:6]([CH2:10][C:11]2[N:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[C:21]4[N:22]=[CH:23][CH:24]=[N:25][C:26]=4[C:27]([C:30]4[C:35]([Cl:36])=[C:34]([O:37][CH3:38])[CH:33]=[C:32]([O:39][CH3:40])[C:31]=4[Cl:41])=[CH:28][CH:29]=3)=[O:19])=[CH:13][CH:12]=2)[CH2:5]1.[C:43](=O)([O-])[O-].[K+].[K+]>CC#N>[CH3:3][C:4]1([CH3:42])[N:9]([CH3:43])[CH2:8][CH2:7][N:6]([CH2:10][C:11]2[N:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[C:21]4[N:22]=[CH:23][CH:24]=[N:25][C:26]=4[C:27]([C:30]4[C:31]([Cl:41])=[C:32]([O:39][CH3:40])[CH:33]=[C:34]([O:37][CH3:38])[C:35]=4[Cl:36])=[CH:28][CH:29]=3)=[O:19])=[CH:13][CH:12]=2)[CH2:5]1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCNC(C)(C)C4)nc3)c3nccnc23)c1Cl
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)C(C)(C)C4)nc3)c3nccnc23)c1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 22.7 %

Procedure:
Methyl iodide (15 μL, 0.24 mmol, 1.2 equiv) was added to a mixture of 8-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid [6-(3,3-dimethyl-piperazin-1-ylmethyl)-pyridin-3-yl]-amide (Example 112) (115 mg, 0.2 mmol) and potassium carbonate (33 mg, 0.24 mmol, 1.2 equiv) in CH3CN (4 mL). The reaction mixture was stirred for 72 h at rt, quenched by addition of a saturated aqueous solution of NaHCO3 and extracted with EtOAc. The organic layer was washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/NH3aq, 99:1→DCM/MeOH/NH3aq, 96:3:1) followed by trituration id Et2O to afford 27 mg of the title compound as a yellow solid. Title compound: ESI-MS: 595.1/596.6 [M+H]+; tR=3.54 min (System 1); TLC: Rf=0.17 (DCM/MeOH, 9:1).