Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([CH2:15][C@H:16]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17]2)[C:12](O)=[O:13])=[CH:7][C:6]=1[CH3:22])(=[O:4])=[O:3].C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[N:31]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[OH:38][C:36]([CH3:39])([CH3:37])[CH2:35][N:32]1[CH:33]=[CH:34][C:30]([NH:29][C:12](=[O:13])[C@@H:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[C:6]([CH3:22])[CH:7]=2)[CH2:15][C@H:16]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17]2)=[N:31]1
Reactant: Cc1cc([C@@H](C[C@H]2CCC(=O)C2)C(=O)O)ccc1S(C)(=O)=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc([C@@H](C[C@H]2CCC(=O)C2)C(=O)Nc2ccn(CC(C)(C)O)n2)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
(R)-2-(4-Methanesulfonyl-3-methyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionic acid (prepared in Example 122, 65 mg, 0.20 mmol) was dissolved in methylene chloride (2 mL) and N,N-dimethylformamide (two drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 110 μL, 0.21 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (2 mL) and added dropwise into a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 31 mg, 0.20 mmol), 2,6-lutidine (46 μL, 0.40 mmol) and methylene chloride (2 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 1 h. After this time, the reaction was quenched with a small amount of methanol and diluted with methylene chloride and then concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 50% ethyl acetate/hexanes to 100% ethyl acetate) to afford (R)—N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(4-methanesulfonyl-3-methyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionamide (71 mg, 77%) as a white foam: [α]32589=−63.3° (c=0.15, methanol); ES-HRMS m/e calcd for C23H31N3O5S (M+H)+ 462.2057, observed 462.2058; 1H NMR (300 MHz, DMSO-d6) δ 1.03 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.50 (m, 1H, CH), 1.76-2.30 (m, 8H, 4×CH2), 2.62 (s, 3H, ArCH3), 3.18 (s, 3H, SO2CH3), 3.86 (s, 2H, NCH2), 3.91 (m, 1H, ArCHCO), 4.65 (s, 1H, OH), 6.45 (d, J=2.2 Hz, 1H, Ar), 7.46 (brs, 1H, Ar), 7.47 (brd, 1H, Ar), 7.50 (d, J=2.2 Hz, 1 H, Ar), 7.85 (d, Jo=8.5 Hz, 1H, Ar), 10.79 (s, 1H, NH).
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[NH:3]1.[CH3:29][O:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38].C(N(CC)CC)C.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:13][CH:14]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Reactant: COc1ccc(B(O)O)cc1OC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OC)c(OC)c2)c2ncnn12
Reaction time: 16 h
Yield: 84.8 %

Procedure:
To a suspension (15 mL) of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.5 g), (3,4-dimethoxyphenyl)boronic acid (0.49 g), triethylamine (0.5 mL), pyridine (1 mL) and molecular sieves 4A (1 g) in dichloromethane was added copper(II) acetate (0.49 g), and the mixture was stirred for 16 hr. The reaction mixture was diluted with ethyl acetate, insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.58 g, 85%).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1.[H-].[Na+].O>CN(C)C=O>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:17][CH:16]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: BrCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(CN(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.7 %

Procedure:
In an argon atmosphere, diphenylamine (338 mg, 2.00 mmol) and 4-bromobenzyl bromide (500 mg, 2.00 mmol) were dissolved in dimethylformamide (8 mL), and to the solution was added sodium hydride (88 mg, 2.2 mmol) under ice -cooling, followed by stirring at room temperature for 4 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (14:1 hexane/acetone) to obtain N-(4-bromobenzyl)diphenylamine (478 mg, 71%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:24][CH3:25])=[C:4]([C:10]([CH2:13][S:14]([C:17]2[CH:22]=C[C:20](F)=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].BrC1C(OC)=C(C(CSC2C=CC=CC=2)=CC=1)C(OCC)=O.[N:48]1C=CC=C(S([O-])(=O)=O)C=1.[Na+]>>[Br:1][C:2]1[C:3]([O:24][CH3:25])=[C:4]([C:10]([CH2:13][S:14]([C:17]2[CH:22]=[N:48][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=S(=O)([O-])c1cccnc1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccc(F)cc2)ccc(Br)c1OC
Agent: CCOC(=O)c1c(CSc2ccccc2)ccc(Br)c1OC
Agent: [Na+]
Product: CCOC(=O)c1c(CS(=O)(=O)c2cccnc2)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 85, starting from ethyl 3-bromo-6-bromomethyl-2-methoxybenzoate (Intermediate 87) and sodium 3-pyridinesulphonate (prepared according to Crowell et al, J. med. Chem., 1989, 32, 2436).
Reaction SMILES: [C:1]([C:4]1[C:5]([O:14][CH3:15])=[CH:6][C:7]([Cl:13])=[C:8](B(O)O)[CH:9]=1)([OH:3])=[O:2].Br[C:17]1[C:22]([C:23]#[N:24])=[CH:21][C:20]([C:25]([F:28])([F:27])[F:26])=[N:19][CH:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[H+].[B-](F)(F)(F)F>C(OCC)(=O)C.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:7]1[C:8]([C:17]2[CH:18]=[N:19][C:20]([C:25]([F:27])([F:28])[F:26])=[CH:21][C:22]=2[C:23]#[N:24])=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[C:5]([O:14][CH3:15])[CH:6]=1
Reactant: COc1cc(Cl)c(B(O)O)cc1C(=O)O
Reactant: N#Cc1cc(C(F)(F)F)ncc1Br
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Product: COc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.4 %

Procedure:
N2 was bubbled through a solution of THF (8 mL) and water (2 mL) containing 5-carboxy-2-chloro-4-methoxy-phenylboronic acid (460.8 mg, 2.0 mmol) and 5-bromo-2-trifluoromethyl-isonicotinonitrile 1-1 (478 mg, 1.9 mmol) for 10 minutes. K3PO4 (1.2 g, 5.7 mmol), t-Bu3P.HBF4 (82.7 mg, 0.28 mmol), and Pd2 dba3 (91.0 mg, 0.1 mmol) were added under N2 atmosphere. The mixture was sealed, stirred at rt for 3 hrs, and diluted with ethyl acetate. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified via silica gel flash column chromatography eluting with 10% MeOH in dichloromethane to give 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-benzoic acid (301 mg).
Reaction SMILES: S(Cl)(Cl)=O.O[C@@H:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8].CN(C)C=O.[ClH:22]>O1CCCC1.C1(C)C=CC=CC=1.O>[Cl:22][C@H:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)[C@@H](O)Cc1ccccc1
Reactant: Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)[C@H](Cl)Cc1ccccc1
Temperature: 37.5 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
Thionyl chloride (43.8 g, 368.4 mmol) was added dropwise to a solution of 20.4 g (122.8 mmol) of (2S)-2-hydroxy-3-phenylpropionic acid (optical purity 100% ee (S)) in 200 ml of tetrahydrofuran, and the mixture was stirred at 35 to 40° C. for 2 hours. To that solution was added 1.8 g (24.6 mmol) of dimethylformamide, and the mixture was stirred at 42 to 44° C. for 6 hours. This reaction mixture was cooled and, while maintaining the temperature at 20° C., 70 ml of water was added dropwise and, after about an hour of stirring, the mixture was extracted with 200 ml of toluene. Water (70 ml) was added to the organic phase and, after pH adjustment to 9.0 with a 30% aqueous solution of sodium hydroxide, the organic phase was removed by phase separation. To the aqueous phase obtained was added 200 ml of toluene, the pH was adjusted to 1.0 with 35% aqueous hydrochloric acid, and the aqueous phase was removed by phase separation. The toluene was distilled off under reduced pressure from the thus-obtained toluene phase to give 21.1 g (114.3 mmol, yield 93%) of (2R)-2-chloro-3-phenylpropionic acid. The optical purity of the product as determined by the same method as in Example 12 was 99.8% ee (R) (rate of configurational inversion 99.8%).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][O:7][C:8]([C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([O:19][CH3:20])[CH:13]=2)=[O:9].CN([CH:24]=[O:25])C>>[CH:24]([C:18]1[C:17]2[C:12](=[CH:13][C:14]([O:19][CH3:20])=[CH:15][CH:16]=2)[NH:11][C:10]=1[C:8]([O:7][CH3:6])=[O:9])=[O:25]
Reactant: COC(=O)c1cc2ccc(OC)cc2[nH]1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1[nH]c2cc(OC)ccc2c1C=O
Reaction time: 0.5 h

Procedure:
General Procedure I. POCl3 (2.94 ml, 32.2 mmol) was added dropwise to anhydrous DMF (10 ml) at 0° C. under argon. After stirred for 30 min, this solution was added dropwise to a solution of methyl6-methoxy-1H-indole-2-carboxylate (Aldrich, 2.2 g, 10.7 mmol) in anhydrous DMF (20 ml) at 0° C. under argon. The reaction was stirred for 20 h at room temperature, quenched with ice, diluted with EtOAc, a precipitate formed and was filtered and washed with H2O (×3) to give the title compound as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18](=[N:26][C:27]#[N:28])OC4C=CC=CC=4)[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:29]([NH2:33])([CH3:32])([CH3:31])[CH3:30]>N1C=CC=CC=1>[C:29]([NH:33][C:18](=[N:26][C:27]#[N:28])[N:15]1[CH2:14][CH2:13][N:12]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[CH:8][CH:7]=2)[CH2:17][CH2:16]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)N
Reactant: N#CN=C(Oc1ccccc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Solvent: c1ccncc1
Product: CC(C)(C)NC(=NC#N)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
7-Chloro-4-[4-(cyanimino(phenoxy)methyl)piperazin-1-yl]quinoline (53 mg, 0.14 mmol) and tert-butylamine (2.0 mL, 19 mmol) are heated in pyridine (10 mL) for 6 h at reflux. The solvent is removed, and the residue purified by column chromatography with CH2Cl2-MeOH giving the title product as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[K+]>CC(C)=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=1[Cl:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: ClCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC(C)=O
Product: Nc1ccc(OCc2ccccc2)c(Cl)c1
Yield: 79.6 %

Procedure:
To 4-amino-2-chlorophenol (7.23 g, 50 mmol) dissolved in acetone (250 mL), was added potassium carbonate (6.94 g, 50 mmol), followed by the addition of benzyl chloride (5.8 mL, 50 mmol), tetrabutylammonium bromide (TBAB) (1.66 g, 5 mmol), and potassium hydroxide (2.84 g, 50 mmol). The reaction mixture was allowed to stir at reflux overnight under nitrogen. The reaction mixture was extracted three times using dichloromethane; the combined organic layers were washed with brine and dried over potassium carbonate. The sample was concentrated and the resulting oil was dried overnight under vacuum. The material was purified by silica gel flash column chromatography eluting with 50:50 v:v hexanes:ethyl acetate and the collected fractions were concentrated in vacuo to give E1 (9.3 g, 80%); mp 54° C.; HPLC: Inertsil ODS 3V C18, 40:30:30 [KH2PO4 (0.01 M, pH 3.2):CH3OH:CH3CN], 264 nm, Rt 14.8 min, 98.7% purity; MS (TOF ES+) m/z 234 (M+H, 100).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4](S([O-])=O)=[CH:3][CH:2]=1.[Na+].Br[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1.[O-2].[Ca+2]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN1CCCC1=O>[CH3:10][C:1]1[CH:6]=[CH:5][C:4]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(Br)cc1
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Ca+2]
Solvent: CN1CCCC1=O
Product: Cc1ccc(-c2ccc(C)cc2)cc1
Yield: 85.5 %

Procedure:
3.56 g (20 mmol) of sodium p-toluenesulfinate, 3.42 g (20 mmol) of p-bromotoluene, 0.0225 g (0.1 mmol) of palladium acetate, 0.0478 g (0.12 mmol) of 1,2-bis(diphenylphosphino)-ethane, 6.73 g (120 mmol) of calcium oxide and 60 ml of N-methyl-2-pyrrolidone were placed in a 100 ml round bottom flask and reacted at 150° C. in a nitrogen gas stream for 8 hours. After the completion of the reaction, the reaction mixture was analyzed by means of high performance liquid chromatography. The analysis showed that 17.1 mmol (yield: 86%) of 4,4'-dimethylbiphenyl was formed in the reaction mixture solution.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.S(Cl)(Cl)=O.[CH3:10][C:11]1[S:12][C:13]([C:17](O)=[O:18])=[C:14]([CH3:16])[N:15]=1>O1CCCC1>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:17]([C:13]1[S:12][C:11]([CH3:10])=[N:15][C:14]=1[CH3:16])=[O:18]
Reactant: Cc1nc(C)c(C(=O)O)s1
Reactant: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cc1nc(C)c(C(=O)c2ncc[nH]2)s1
Reaction time: 0.5 h

Procedure:
To a solution of imidazole (2.72 g; 40 mmol) in dry tetrahydrofuran (60 ml) was added dropwise thionyl chloride (1.20 g; 10 mmol) under ice-cooling while stirring. After the resultant mixture was turned to room temperature, 2,4-dimethyl-5-thiazolecarboxylic acid (1.57 g; 10 mmol) was added thereto at once, and stirring was continued for 30 minutes, whereby 5-imidazolylcarbonyl-2,4-dimethylthiazole was produced. To the mixture was added dropwise a solution of 2-(2-furyl)aminoacetonitrile (1.46 g; 12 mmol) in dry tetrahydrofuran under ice-cooling, and the resultant mixture was stirred at room temperature for 1 hour. After completion of the reaction, tetrahydrofuran was removed under reduced pressure to separate the residue. Water was added to the residue, which was extracted with ethyl acetate. The ethyl acetate layer was washed twice with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crude crystals. Recrystallization from ethanol gave 2.0 g of 2-(2,4-dimethylthiazole-5-carboxamido)-2-(2-furyl)acetonitrile as colorless crystals. m.p., 108° -109° C. Yield, 74%.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[N:5]2[C:10]3[CH:11]=[CH:12][N:13](S(C4C=CC(C)=CC=4)(=O)=O)[C:9]=3[N:8]=[CH:7][C:6]=12.[CH3:30][S:31]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)(=[O:33])=[O:32].C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Na+].[NH4+].[Cl-]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)Cl.O.CCO>[CH:24]1([C:4]2[N:5]3[C:10]4[CH:11]=[CH:12][NH:13][C:9]=4[N:8]=[CH:7][C:6]3=[C:2]([C:37]3[CH:38]=[CH:39][C:34]([S:31]([CH3:30])(=[O:33])=[O:32])=[CH:35][CH:36]=3)[N:3]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2c(Br)nc(C4CCCCC4)n23)cc1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-c2nc(C3CCCCC3)n3c2cnc2[nH]ccc23)cc1
Temperature: 120 °C
Yield: 39.2 %

Procedure:
A microwave vial was charged with 3-bromo-1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.050 g, 0.11 mmol, Preparation #MM.1), 4-(methylsulfonyl)phenylboronic acid (0.023 g, 0.12 mmol, Acros), cesium carbonate (0.086 g, 0.26 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.0066 g, 0.0000094 mmol), and 1,4-dioxane (0.42 mL), EtOH (0.42 mL), and water (0.21 mL). The vial was capped and the mixture was heated to about 120° C. for about 20 min (5 min ramp time, 300 Watts max power, 250 psi max pressure) in a microwave. The reaction mixture was concd under reduced pressure to give a solid that was dissolved in 1,4-dioxane (1.0 mL) and transferred to a microwave vial. Aqueous 2 N NaOH (0.11 mL, 0.21 mmol) was added and the vial was capped. The solution was heated to about 100° C. for about 15 min in a microwave (300 W max power, 250 psi max pressure, 5 min ramp time). DCM (10 mL) and saturated aqueous NH4Cl (5 mL) were added to the reaction solution. The layers were separated and the aqueous solution was extracted with additional DCM (5 mL). The combined extracts were dried over anhydrous MgSO4, filtered, and concentrated to dryness under reduced pressure to give a light brown solid. Upon addition of DCM (1 mL), a yellow precipitate formed that was collected by vacuum filtration and dried overnight on a Buchner funnel to give 1-cyclohexyl-3-(4-(methylsulfonyl)phenyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.017 g, 41%): LC/MS (Table 1, Method a) Rt=2.39 min; MS m/z: 395 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([NH:10][CH2:11][CH2:12][N:13]([CH2:26][CH2:27][C:28]12[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2)[C:14]([NH:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=[O:15])(=O)[CH3:8].C(OCC)(=O)C.[OH-].[Na+]>C(OCC)C.O1CCCC1>[C:28]12([CH2:27][CH2:26][N:13]([CH2:12][CH2:11][NH:10][CH2:7][CH3:8])[C:14]([NH:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[O:15])[CH2:35][CH:34]3[CH2:33][CH:32]([CH2:31][CH:30]([CH2:36]3)[CH2:29]1)[CH2:37]2
Reactant: CC(=O)NCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)NCCCc1ccncc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)NCCCc1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.8 %

Procedure:
Lithium aluminum hydride (890 mg, 23.5 mmol) was suspended in anhydrous diethyl ether (10 ml) under a nitrogen atmosphere, and a solution of 1-[2-(acetylamino)ethyl]-1-[2-(1-adamantyl)ethyl]-3-[3-(4-pyridyl)propyl]urea (Compound No. 1-103) (4.86 g, 11.4 mmol) in anhydrous tetrahydrofuran (60 ml) was added dropwise to the suspension under ice-cooling with stirring over two hours. The temperature was raised to room temperature, and the mixture was stirred for 70 hours. Ethyl acetate (25 ml) was added to the reaction mixture under ice-cooling, then a 1 N aqueous sodium hydroxide solution (25 ml) was added thereto, and the whole was filtered with Celite to remove an insoluble matter. The filtrate was distributed with ethyl acetate (25 ml) and water (25 ml), and the organic layer was washed with a saturated aqueous sodium chloride solution (20 ml). The organic layer was 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 titled compound (2.33 g, colorless crystals, 49.8%).
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2C=C[C:17]([CH3:20])=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1C=CC=CC=1.C/C(/C(C)=O)=N\[OH:24].CC1OC(C=O)=CC=1>>[I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[O:24][C:17]([CH3:20])=[CH:16][CH:15]=2)[O:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Reactant: CC(=O)/C(C)=N/O
Agent: Cc1ccc(C=O)o1
Product: Cc1ccc(-c2nc(CI)c(C)o2)o1

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole, diacetylmonoxime and 5-methylfuran-2-carbaldehyde gave 4-iodomethyl-5-methyl-2-(5-methylfuran-2-yl)oxazole.
Reaction SMILES: [CH:1]1(Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(C)C.[Si:10]([O:17][CH2:18][CH:19]1[CH2:21][N@@:20]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>C1COCC1.CCOCC>[CH:1]1([CH2:21][C@H:19]([NH:20][C:22](=[O:23])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][O:17][Si:10]([C:13]([CH3:15])([CH3:16])[CH3:14])([CH3:12])[CH3:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CC1CO[Si](C)(C)C(C)(C)C
Reactant: BrC1CCCC1
Solvent: CCOCC
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)CC1CCCC1
Reaction time: 2 h
Yield: 81.1 %

Procedure:
A 100 mL, three-neck flask was charged with Mg powder (720 mg, 30 mmol), and a solution of cyclopentylbromide (3.73 g, 25 mmol) in THF (25 mL) was added dropwise while the flask was heated with a heat gun. After stirring for about 2 h, most of the Mg had been consumed. The Grignard reagent was added to a suspension of CuBr.SMe2 (307.5 mg, 1.5 mmol) in THF (80 mL) at −78° C., the cuprate was stirred for 30 min and a solution of (S)-tert-butyl 2-(t-butyldimethylsilyloxymethyl)aziridine-1-carboxylate (2.87 g, 10 mmol) in ether (30 mL) was added. The mixture was stirred for 2 h, washed with sat'd aq NaHCO3 (2×20 mL) and brine (30 mL), dried over MgSO4, and evaporated. The residue was purified by silica chromatography to obtain tert-butyl (S)-3-cyclopentyl-1-(t-butyldimethylsilyloxy)propan-2-ylcarbamate (2.9 g, 81%) as an oil. 1H NMR (CDCl3, 400 MHz) δ 0.04 (s, 6H), 0.89 (s, 9H), 1.10 (m, 2H), 1.44 (s, 9H), 1.50 (m, 3H), 1.60 (m, 3H), 1.81 (m, 3H), 3.58 (m, 3H), 4.60 (brs, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C-:18]#[N:19].[Na+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH3:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][C:18]#[N:19])=[C:4]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=1
Reactant: Cc1ccc(CBr)c(OCc2ccccc2)c1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(CC#N)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A two-phase mixture of crude 1-bromomethyl-4-methyl-2-phenylmethoxybenzene (21.84 g, 75 mmol), NaCN (11.0 g, 0.22 mol), tetrabutylammonium bromide (2.4 g, 7.5 mmol), water (25 ml) and CH2Cl2 (50 ml) was stirred at room temperature for 1 hour and the layers were separated. The organic layer was washed well with water to remove tetrabutylammonium salts and after drying (CaCl2) the solvent was removed to give (4-methyl-2-phenylmethoxyphenyl)acetonitrile (17.8 g, 100% crude yield) as an oil.