Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1)(=[O:19])=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.COCCOC.[C:36]1([C:42]#[CH:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cu]I.C(N(CC)CC)C>[C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([C:43]#[C:42][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1ccccc1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(Br)cc1
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: COCCOC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C#Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a magnetically stirred mixture of the N-(2-Benzoyl-4-chloro-phenyl)-4-bromo-benzenesulfonamide (450 mg, 1.0 mmol), [1,1′ Bis-(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (30 mg, 0.037 mmol) and copper (I) iodide (100 mg, 0.52 mmol) was added DME (6 mL) and dry triethylamine (3 mL) under dry nitrogen. To this stirred mixture was added tetrabutylammonium iodide (250 mg), followed by the addition of phenylacetylene (0.240 mL). The dark green mixture was stirred at ambient temp overnight. The reaction was worked up by addition to crushed ice and extracted with ethyl acetate (3×75 mL), and the organic layer was dried (MgSO4), filtered and concentrated. The crude product was chromatographed on silica gel using 10-30% EtOAc/Hexane. 1H NMR (CDCl3) δ 9.64 (br s, 1H, NH), 7.75 (d, 1H, J=Hz), 7.75 (d, 1H, J=8.8 Hz), 7.48 (m, 8H), 7.36 (m, 7H). MS: m/z 472 (M+1).
Reaction SMILES: [OH-].[Na+].C1(C)C=CC=CC=1.Cl[CH2:11][CH:12]([NH:29][C:30](=[O:39])[C:31]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=1[F:38])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25][CH:26]([F:28])[F:27])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C>[F:27][CH:26]([F:28])[S:25][C:22]1[CH:23]=[CH:24][C:19]([C:16]2[CH:17]=[CH:18][C:13]([CH:12]3[CH2:11][O:39][C:30]([C:31]4[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=4[F:38])=[N:29]3)=[CH:14][CH:15]=2)=[CH:20][CH:21]=1
Reactant: O=C(NC(CCl)c1ccc(-c2ccc(SC(F)F)cc2)cc1)c1c(F)cccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: Fc1cccc(F)c1C1=NC(c2ccc(-c3ccc(SC(F)F)cc3)cc2)CO1
Reaction time: 0.75 h
Yield: 76.1 %

Procedure:
To a well-stirred mixture of 0.6 g of 25% aqueous NaOH, 70 mg of tetrabutylammonium bromide (TBAB) and 10 mL of toluene was added 1.0 g of (+/-)-N-[2-chloro -1-[4'-[(difluoromethyl)thio][1,1'-biphenyl]-4-yl]ethyl]-2,6-difluorobenzamide as a solid. After 45 min, 2 mL of water was added along with 10 mL of diethyl ether. The organic phase was washed with water, dried (MgSO4), filtered, and concentrated to dryness. The residue was triturated with hexanes, filtered, and suction-dried to afford 0.70 g of product, m.p. 75-77° C. The 1H-NMR (CDCl3) spectrum was the same as that the product of Example 6.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[NH:13][C:14]1[C:15]2[O:22][CH:21]=[C:20]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:16]=2[N:17]=[CH:18][N:19]=1.Cl[C:30]1[N:35]=[CH:34][C:33]([Cl:36])=[CH:32][N:31]=1.C(N(CC)C(C)C)(C)C.O>CN(C)C=O>[Cl:36][C:33]1[CH:32]=[N:31][C:30]([N:26]2[CH2:27][CH2:28][CH:23]([C:20]3[C:16]4[N:17]=[CH:18][N:19]=[C:14]([NH:13][C:4]5[CH:5]=[CH:6][C:7]([S:9]([CH3:12])(=[O:10])=[O:11])=[CH:8][C:3]=5[F:2])[C:15]=4[O:22][CH:21]=3)[CH2:24][CH2:25]2)=[N:35][CH:34]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc3c(C4CCNCC4)coc23)c(F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(Nc2ncnc3c(C4CCN(c5ncc(Cl)cn5)CC4)coc23)c(F)c1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 19 %

Procedure:
N-[2-fluoro-4-(methylsulfonyl)phenyl]-7-(piperidin-4-yl)furo[3,2-d]pyrimidine-4-amine hydrochloride (9.8 mg, 0.023 mmol), 2,5-dichloropyrimidine (5.1 mg, 0.035 mmol) and N,N-diisopropylethylamine (9.0 mg, 0.069 mmol) were dissolved in N,N-dimethylformamide (0.5 mL) and stirred at 80° C. for 2.5 hours. Water was added to the reaction liquid, and the reaction liquid was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under a reduced pressure, and the obtained residue was purified by silica gel preparative thin layer chromatography (chloroform:methanol=25:1) to give the titled compound (2.2 mg, 19%) as a yellow solid.
Reaction SMILES: CS(O[C@@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[CH2:7]1)(=O)=O.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C)C=O>[N:24]([C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[CH2:7]1)=[N+:25]=[N-:26]
Reactant: CS(=O)(=O)O[C@@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 100 °C
Reaction time: 2 h
Yield: 101.5 %

Procedure:
To a solution of (3R)-3-methanesulfonyloxy-1-(p-nitrobenzyloxycarbonyl)-pyrrolidine (4.00 g, 11.6 mmol) (obtained as described in Reference Example 52(2)) in dimethylformamide (120 ml) was added sodium azide (831 mg, 12.8 mmol), and the mixture was stirred in an oil bath (100° C.) for 2 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (3:1→1:2) as the eluant to afford (3S)-3-azido-1-(p-nitrobenzyloxycarbonyl)pyrrolidine (3.43 g, yield 100%) as a pale yellow solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][C:29]([NH:31][CH2:32][C:33](O)=[O:34])=[O:30])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[Cl:36][CH2:37][CH2:38][NH:39][CH2:40][CH2:41][Cl:42].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][C:29]([NH:31][CH2:32][C:33]([N:39]([CH2:40][CH2:41][Cl:42])[CH2:38][CH2:37][Cl:36])=[O:34])=[O:30])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: ClCCNCCCl
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)NCC(=O)O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)NCC(=O)N(CCCl)CCCl)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 6 h
Yield: 54.5 %

Procedure:
To a solution of N-(cholest-5-en-3β-oxycarbonyl)glycine (160.8 mg) in dry tetrahydrofuran (50 ml) was added said bis(2-chloroethyl)amine (85.2 mg) and dicyclohexylcarbodiimide (61.9 mg) at 0° C. under blowing nitrogen gas and the mixture was stirred for 6 hours. After standing overnight (17 hours) at refrigerator, the reaction mixture was filtered and the solvent was evaporated under reduced pressure. The residue was solved in a mixture of chloroform and methanol (50:1) and was subjected to preparation column chromatography (PLC) eluting with a mixture of chloroform and methanol (50:1). The desired parts were gathered, extracted with a mixture of chloroform and methanol (4:1), filtered and concentrated under reduced pressure to give N-[N-(cholest-5-en-3β-oxycarbonyl)glycyl]bis(2-chloroethyl)amine (110 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:6]2.[OH-].[Na+].[I:19]I>C(O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[C:4]([I:19])=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:6]2
Reactant: II
Reactant: CCOC(=O)c1cc2c(Cl)cc(Cl)cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1I
Reaction time: 1 h

Procedure:
Combine 4,6-dichloro-indole-2-carboxylic acid, ethyl ester (5.2 g, 20.0 mmol) and sodium hydroxide (0.80 g, 20 mmol) in ethanol (250 mL). Add iodine (5.1 g, 20.0 mmol) as a solution in ethanol (100 mL). After 1 hour, concentrate the reaction mixture in vacuo to obtain a residue. Dissolve the residue in ethyl acetate and extract with 1M hydrochloric acid solution and then with saturated sodium chloride solution. Dry the organic layer over magnesium sulfate and evaporate in vacuo. Chromatograph on silica gel eluting with 25% ethyl acetate/hexane. Combine the product containing fractions and evaporate in vacuo. Recrystallize form ethyl acetate/hexane to give the title compound as a solid; mp: 218°-220° C. Elem. Anal. calculated for C11H8Cl2INO2 : C, 34.41; H, 2.10; N, 3.65. Found: C, 34.67; H, 2.09; N, 3.68.
Reaction SMILES: [C:1]([NH2:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH:13]([CH3:21])[C:14](=O)[CH2:15][C:16]([O:18][CH3:19])=[O:17].C(OC(=O)C)C>CN(C)C=O>[CH3:21][C:13]1[O:10][C:1]([CH:2]=[CH:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[N:11][C:14]=1[CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: NC(=O)C=Cc1ccccc1
Reactant: COC(=O)CC(=O)C(C)Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cc1nc(C=Cc2ccccc2)oc1C
Temperature: 100 °C
Reaction time: 15 h
Yield: 11.4 %

Procedure:
Cinnamamide (0.5 g) and methyl 4-bromo-3-oxopentanoate (0.71 g) were dissolved in N,N-dimethylformamide (2.5 ml) and the mixture was stirred 100° C. for 15 h. Ethylacetate (50 ml) was added, and the mixture was washed with water (100 ml) and then with saturated brine (100 ml), and dried (Na2SO4). Ethyl acetate was evaporated under reduced pressure and the obtained residue was purified by column chromatography to give the title compound (0.1 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([C:6](O)=[O:7])[C:4]=1[OH:12].N1C=CC=CC=1.C(Cl)(=O)C.CC[O:25][C:26]([CH3:28])=[O:27]>C(Cl)Cl>[CH3:1][S:2][CH2:3][C:4]([C:5]1[CH:9]=[CH:10][CH:11]=[C:28]([C:26]([OH:25])=[O:27])[C:6]=1[OH:7])=[O:12]
Reactant: CSc1cccc(C(=O)O)c1O
Reactant: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: CSCC(=O)c1cccc(C(=O)O)c1O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 20 %

Procedure:
To solution of 18 (46 mg, 0.25 mmol) in 1 mL of CH2Cl2 was added dry pyridine (20 mg, 50 μL, 0.3 mmol) at 0° C. (FIG. 2D). The solution was stirred at 0° C. for 10 minutes followed by the addition of acetyl chloride (~30 μL, 0.4 mmol). The reaction mixture was stirred overnight at 0° C. and then the solvent was removed under vacuo. The residue was partioned between water and EtOAc. The organic solution was washed with 1 M HCl (10 mL), water (50 mL), and then dried (MgSO4). The solvent was evaporated to afford a oil which was chromatographed on silica gel and eluted with hexanes:EtOAc (initially 70:30, then 50:50) to afford the desired product as a white solid (11 mg, 20% yield). 1H NMR (CDCl3) δ 7.86-7.89 (d, 1H, ArH), 7.46-7.44 (d, 1H, ArH), 7.32-7.36 (t, 1H, ArH), 2.45 (s, 3H, SCH3), 2.38 (s, 3H, CH3); FAB-MS 227 (MH+, 15) 226 (MH+ -1, 10), 167 (50), 157 (30), 102 (100).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:7][N:8]([CH3:12])[CH2:9][CH2:10]Cl>O>[C:1]([NH:5][CH2:10][CH2:9][N:8]([CH3:12])[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)CCCl
Reactant: CC(C)(C)N
Agent: Cl
Solvent: O
Product: CN(C)CCNC(C)(C)C
Yield: 59.4 %

Procedure:
Into a 50 mL-volume flask equipped with a stirrer, a thermometer and a dropping funnel were placed 16 g (0.22 mol) of t-butylamine, 5.0 g (35 mmol) of 2-(dimethylamino)ethyl chloride hydrochloride and 1 ml of water. And then, the mixture was reacted at 70° C. for 10 hours. After the completion of the reaction, the reaction solution was subjected to extraction with 25 ml of hexane twice, and the hexane layer was concentrated under reduced pressure. The resultant concentrate was distilled under reduced pressure (60° C., 2.4 kPa), to provide 3.0 g of 1-(t-butylamino)-2-dimethylaminoethane. (Isolation yield: 60%)
Reaction SMILES: Cl.[CH2:2]([C:4]1[N:8]([C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[N:15]3[CH3:18])=[C:11]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:10]=2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1)[CH3:3].Br[CH2:36][C:37]([NH2:39])=[O:38].[I-].[Na+].C([O-])([O-])=O.[K+].[K+]>CC#N.CCOC(C)=O>[CH2:2]([C:4]1[N:8]([C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([CH:19]4[CH2:20][CH2:21][N:22]([CH2:36][C:37]([NH2:39])=[O:38])[CH2:23][CH2:24]4)[N:15]3[CH3:18])=[C:11]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:10]=2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1)[CH3:3]
Reactant: NC(=O)CBr
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3CCNCC3)n(C)c2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3CCN(CC(N)=O)CC3)n(C)c2n1
Temperature: 50 °C
Yield: 76.2 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-8-piperidin-4-yl-9H-purine hydrochloride (150 mg, 0.31 mmol), 2-bromoacetamide (45 mg, 0.33 mmol), sodium iodide (5 mg, 0.03 mmol) and K2CO3 (90 mg, 0.65 mmol) in MeCN (3 mL) was heated to 50° C. for 2 h in a sealed tube. The reaction mixture was diluted with EtOAc, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-30%) affording 677 (119 mg, 76%). LCMS (method I): RT 2.40 min, [M+H]+ 504.2. 1H NMR (DMSO, 400 MHz): δ 8.02-7.98 (1 H, m), 7.64-7.63 (1 H, m), 7.25-7.24 (4 H, m), 4.27 (4 H, brd s), 3.82-3.72 (7 H, m), 3.35-3.30 (2 H, m), 3.26 (2 H, q, J=7.45 Hz), 3.11-2.90 (4 H, m), 2.38-2.31 (1 H, m), 1.97 (4 H, s), 1.33 (3 H, t, J=7.44 Hz)
Reaction SMILES: [OH-].[K+].[CH3:3][SH:4].O.Cl[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[CH:20]=[O:21])=[CH:9][CH:8]=1>C(O)C>[F:19][C:17]1[CH:16]=[CH:15][C:14]([CH:20]=[O:21])=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([S:4][CH3:3])=[CH:8][CH:9]=2)[CH:18]=1
Reactant: O=Cc1ccc(F)cc1-c1ccc(Cl)cc1
Reactant: CS
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1ccc(-c2cc(F)ccc2C=O)cc1
Temperature: 25 °C

Procedure:
85% potassium hydroxide solution (66 g) is dissolved in ethanol (700 ml) and cooled to room temperature. To this with stirring is added methyl mercaptan subsurface (50 g), water (2ml) and a solution of 4-chloro-5'-fluoro-2'-formylbiphenyl (234.5 g) in ethanol (300 ml). A slow stream of methyl mercaptan is continuously fed in while the reaction mixture is held at reflux for 3 hours. The reaction is poured into water (1 liter), and the solid is filtered off. The solid is recrystallized from benzene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]2[CH2:15][CH2:16][N:17]([C:19](=[O:32])[CH2:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[C:23]([OH:31])[CH:22]=3)[CH2:18][C:7]1=2.[OH-].[Na+].O>COC.CO>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]2[CH2:15][CH2:16][N:17]([C:19](=[O:32])[CH2:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[C:23]([OH:31])[CH:22]=3)[CH2:18][C:7]1=2
Reactant: COC(=O)c1ccc(CC(=O)N2CCc3c(n(Cc4cccc(F)c4)c4ncccc34)C2)cc1O
Agent: COC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(CC(=O)N2CCc3c(n(Cc4cccc(F)c4)c4ncccc34)C2)cc1O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 89.3 %

Procedure:
To 3.0 mL of a solution of the compound (53.8 mg) produced in Example 64 in dimethyl ether/methanol (1:1) was added a 1N aqueous sodium hydroxide solution (1.5 mL), the mixture was stirred at room temperature for 2.5 hours, and at 50° C. for 3 hours, and allowed to stand at room temperature overnight. On the next day, the resultant was stirred again at 50° C. for 5 hours, and water was added to the reaction solution. After washed with tert-butyl methyl ether, 1N hydrochloric acid was added to the aqueous layer to make the solution acidic (pH 3), and the resultant was extracted two times using ethyl acetate. The extracted organic layer was washed with an aqueous saturated sodium chloride solution, and dried with anhydrous magnesium sulfate, and the solution obtained by filter filtration was concentrated under reduced pressure to obtain the title compound (46.6 mg) having the following physical property values.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:13][CH:12]=1.Cl>>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:13][CH:12]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2F)cc1
Agent: Cl
Product: Nc1ccc(-c2ccc(CCCC(=O)O)cc2)c(F)c1

Procedure:
Prepared analogous to Example 7 from 4-(2'-fluoro-4'-nitro-4-biphenylyl)-4-oxo-butyric acid. Melting point of the hydrochloride: 170° C. (decomp.). C. C.
Reaction SMILES: C([C@@]1(C2C=CC(F)=CC=2)CCN([C@H](C2C=CC(C3C=CC(F)=CC=3)=CC=2)C)C(=O)N1)C=C.[OH:33][CH:34]([CH2:65][OH:66])[CH2:35][C@@:36]1([C:58]2[CH:63]=[CH:62][C:61]([F:64])=[CH:60][CH:59]=2)[CH2:41][CH2:40][N:39]([C@H:42]([C:44]2[CH:49]=[CH:48][C:47]([C:50]3[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=3)=[CH:46][CH:45]=2)[CH3:43])[C:38](=[O:57])[NH:37]1>>[OH:33][CH:34]([CH2:65][OH:66])[CH2:35][C:36]1([C:58]2[CH:59]=[CH:60][C:61]([F:64])=[CH:62][CH:63]=2)[CH2:41][CH2:40][N:39]([C@H:42]([C:44]2[CH:45]=[CH:46][C:47]([C:50]3[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=3)=[CH:48][CH:49]=2)[CH3:43])[C:38](=[O:57])[NH:37]1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@@](CC(O)CO)(c2ccc(F)cc2)NC1=O
Agent: C=CC[C@@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3)cc2)C(=O)N1
Product: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CCC(CC(O)CO)(c2ccc(F)cc2)NC1=O

Procedure:
Treatment of (S)-4-allyl-1-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-4-(4-fluorophenyl)tetrahydropyrimidin-2(1H)-one with AD-mix 13 following a procedure analogous to that described in Example 8 afforded (4R)-4-(2,3-dihydroxypropyl)-1-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-4-(4-fluorophenyl)tetrahydropyrimidin-2(1H)-one isomers 3 and 4 which were separated by prep HPLC. Isomer 3: LC-MS Method 1 tR=1.337 min, m/z=467.2; 1H NMR (CDCl3) 1.31 (d, 3H), 1.84-2.03 (m, 5H), 2.52 (m, 1H), 2.68 (m, 1H), 3.33 (m, 1H), 3.42 (m, 1H), 3.79 (s, 1H), 5.66 (m, 1H), 6.79 (s, 1H), 7.03 (m, 4H), 7.29 (m, 4H), 7.44 (m, 4H). Isomer 4: LC-MS Method 1 tR=1.382 min, m/z=467.2; 1H NMR (CDCl3) 1.33 (d, 3H), 1.76-1.88 (m, 2H), 2.04 (m, 2H), 2.57 (m, 1H), 2.71 (m, 1H), 3.52 (m, 3H), 5.76 (m, 1H), 7.12 (m, 4H), 7.33 (m, 4H), 7.52 (m, 4H), 7.61 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:11]1(B(O)O)[CH2:13][CH2:12]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[NH2:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([CH:11]2[CH2:13][CH2:12]2)[CH:9]=1
Reactant: N#Cc1ccc(N)cc1Cl
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(N)cc1C1CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
269 mg of palladium acetate were added under an argon atmosphere to a suspension of 916 mg of 2-chloro-4-aminobenzonitrile, 773 mg of cyclopropylboronic acid, 5.094 g of potassium phosphate and 673 mg of tricyclohexylphosphine in a mixture of 10.5 ml of toluene and 1.74 ml of water. The mixture was stirred at 80° C. overnight. The cooled reaction mixture was admixed with water and ethyl acetate and filtered, and the filtrate was extracted three times with a mixture of ethyl acetate with toluene. The organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography (method [PR1]) and afforded 4-amino-2-cyclopropylbenzonitrile. 1H NMR: 7.3, d, 1H; 6.4, d, 1H, 6.1, d, 1H, 4.0, s (broad), 2H, 2.0, m, 1H, 1.0, m, 2H, 0.65, m, 2H.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[CH:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)=[O:33]>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([C:37]2[CH:38]=[CH:39][C:34]([CH:32]=[O:33])=[CH:35][CH:36]=2)[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:31]
Reactant: COC(=O)c1cc(Br)cc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: O=Cc1ccc(B(O)O)cc1
Product: COC(=O)c1cc(-c2ccc(C=O)cc2)cc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 97.8 %

Procedure:
In the same manner as described in Example 241, 505.4 mg (1.0 mmol) of the product from Example 89 and 165 mg (1.1 mmol) of 4-formylbenzene boronic acid provided 519 mg (98%) of the desired product as a pale yellow solid. Electrospray Mass Spec 531 (M+H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][OH:19])=[CH:13][C:12]=1[CH3:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:21]1([CH2:24]Br)[CH2:23][CH2:22]1>CS(C)=O>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][O:19][CH2:24][CH:21]2[CH2:23][CH2:22]2)=[CH:13][C:12]=1[CH3:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCC1CC1
Reactant: Cc1cc(CCO)ccc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(CCOCC2CC2)ccc1OCc1ccccc1
Temperature: 75 °C
Reaction time: 48 h
Yield: 59 %

Procedure:
To a flask charged with redistilled dimethylsulphoxide (100 ml) and sodium hydride (50% dispersion, 4.28 g), at 60°-65° C. was added 2-(4-benzyloxy-3-methylphenyl)ethanol (18.0 g) followed by the dropwise addition of cyclopropylmethyl bromide (12.04 g). The reaction mixture was stirred at about 75° C. for 48 hours, poured on to ice-water (1000 ml) and extracted with vigorous stirring into diethyl ether (1000 ml). The ether layer was dried (MgSO4) and evaporated under reduced pressure to afford an oily residue. This residue was chromatographed on preparative high pressure liquid chromatography using petroleum ether (40°-60°) and petroleum ether/diethyl ether (5:1) as eluants. The desired fractions were collected and evaporated under reduced pressure to give 1-benzyloxy-2-methyl-4-[2-(cyclopropylmethoxy)ethyl]-benzene (13.0 g) as an oil.
Reaction SMILES: Br.C(O)(=[O:4])C.C([O:9][C:10]1[C:18]2[C:17]([C:19]3[CH:20]=[N:21][N:22]([CH:24]([CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[CH2:25][C:26]#[N:27])[CH:23]=3)=[N:16][C:15]([O:33]C)=[N:14][C:13]=2[NH:12][CH:11]=1)(=O)C>>[CH:28]1([C@H:24]([N:22]2[CH:23]=[C:19]([C:17]3[C:18]4[C:10](=[O:9])[CH2:11][NH:12][C:13]=4[N:14]=[C:15]([OH:33])[N:16]=3)[CH:20]=[N:21]2)[CH2:25][C:26]([NH2:27])=[O:4])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CC(=O)O
Reactant: COc1nc(-c2cnn(C(CC#N)C3CCCC3)c2)c2c(OC(C)=O)c[nH]c2n1
Agent: Br
Product: NC(=O)C[C@H](C1CCCC1)n1cc(-c2nc(O)nc3c2C(=O)CN3)cn1
Reaction time: 1 h

Procedure:
4 M of HBr in acetic acid (2 mL, 8 mmol) was added to 4-[1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl]-2-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl acetate (0.050 g, 0.13 mmol) and the reaction was stirred for 1 h. Volatiles were removed in vacuo. The residue was reconstituted and preparative HPLC-MS (eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) was used to afford purified product (12 mg, 26%). 1H NMR (500 MHz, d6-DMSO): δ 9.20 (s, 1H), 8.69 (s, 1H), 7.34 (s, 1H), 6.75 (s, 1H), 4.49 (dt, 1H), 3.89 (s, 2H), 2.80 (dd, 1H), 2.64 (dd, 1H), 2.36-2.26 (m, 1H), 1.83-1.74 (m, 1H), 1.63-1.36 (m, 4H), 1.32-1.20 (m, 2H), 1.15-1.05 (m, 1H); LCMS (M+H)+: 357.0.