Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([OH:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[OH:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20]>CN(C)C=O>[CH3:1][C:2]1[CH:8]=[C:7]([O:9][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:6]=[C:5]([CH3:10])[C:3]=1[OH:4]
Reactant: Cc1cc(O)cc(C)c1O
Reactant: C[Si](C)(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(OC[Si](C)(C)C)cc(C)c1O
Temperature: 25 °C

Procedure:
Mix 2,6-dimethylhydroquinone (1.4 g, 10 mmol), potassium carbonate (1.4 g, 10 mmol), chloromethyltrimethylsilane (1.9 g, 10 mmol) and dimethylformamide (50 mL). Stir at room temperature under inert atmosphere until the reaction is complete. Dilute the mixture with ice-water and extract with ethyl ether. Wash the ethereal layer with water, then brine and filter through fluorosil-Na2SO4. Evaporate to give the title compound and purify by silica gel chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5]2.ClS([N:20]=[C:21]=O)(=O)=O.N1C2C(=CC=CC=2)C=C1.CN(C)C=O>C(#N)C.C(OCC)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]([F:13])([F:15])[F:14])=[C:5]2[C:21]#[N:20]
Reactant: Cn1c(C(F)(F)F)cc2cc(Cl)ccc21
Reactant: O=C=NS(=O)(=O)Cl
Agent: c1ccc2[nH]ccc2c1
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: Cn1c(C(F)(F)F)c(C#N)c2cc(Cl)ccc21
Yield: 49.7 %

Procedure:
A solution of 5-chloro-1-methyl-2-(trifluoromethyl)indole (1.79 g, 7.7 mmole) in acetonitrile is cooled to 0° C., treated with chlorosulfonylisocyanate (CSI) (1.0 mL 11.5 mmole) stirred until starting indole cannot be observed by thin layer chromatography, treated with 5 mL of dimethylformamide (DMF), stirred for 0.5 hour and diluted with diethyl ether and water. The phases are separated. The organic phase is washed with water, dried over Na2SO4 and concentrated in vacuo. The resultant residue is chromatographed using silica gel and 4:1 hexanes:ethyl acetate as eluent to give the title product as a white solid, 0.99 g (49.7% yield) mp 166°-167.5° C., identified by IR, 1HNMR, 13CNMR, 19FNMR and mass spectral analyses.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[O:7][CH:8]=[C:9]([C:11](=[O:31])[NH:12][C@@H:13]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])[CH2:14]3)[N:10]=2)[CH2:3]1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>C(Cl)Cl>[CH3:32][S:33]([O:1][CH:2]1[CH2:3][N:4]([C:6]2[O:7][CH:8]=[C:9]([C:11](=[O:31])[NH:12][C@@H:13]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])[CH2:14]3)[N:10]=2)[CH2:5]1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(N[C@@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1coc(N2CC(O)C2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)N[C@@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)co2)C1
Reaction time: 0.17 h
Yield: 92.4 %

Procedure:
To a solution of 3-hydroxy-1-{4-[(3R)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-oxazol-2-yl}azetidine (500 mg, 1.16 mmol) (obtained as described in Reference Example 77(2)) in methylene chloride (25 ml) were added methanesulfonyl chloride (269 μl, 3.48 mmol) and triethylamine (488 μl, 3.48 mmol) in an ice bath and the mixture was stirred for 10 minutes and then at room temperature for 3 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. 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 ethyl acetate→ethyl acetate:methanol (96:4) as the eluant to afford 3-methanesulfonyloxy-1-{4-[(3R)-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-ylcarbamoyl]-1,3-oxazol-2-yl}azetidine (546 mg, yield 92%) as a pale yellow solid.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]([CH2:19][O:20][CH3:21])[NH:7][C:8]=2[C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12](O)=[O:13])[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH:47]1[CH2:52][CH2:51][CH:50]([C:53]2[CH:60]=[CH:59][C:56]([C:57]#[N:58])=[CH:55][CH:54]=2)[CH2:49][CH2:48]1.C(N(CC)CC)C>ClCCl>[CH:1]1([C:4]2[N:5]=[C:6]([CH2:19][O:20][CH3:21])[NH:7][C:8]=2[C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([N:47]2[CH2:52][CH2:51][CH:50]([C:53]3[CH:60]=[CH:59][C:56]([C:57]#[N:58])=[CH:55][CH:54]=3)[CH2:49][CH2:48]2)=[O:13])[CH2:2][CH2:3]1
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: COCc1nc(C2CC2)c(-c2cc(C(=O)O)ccc2C)[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCc1nc(C2CC2)c(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)ccc2C)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13 %

Procedure:
Into a round-bottom flask, was placed a solution of 3-(4-cyclopropyl-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 4.10, 30 mg, 0.10 mmol) in dichloromethane (5 mL). HBTU (76 mg, 0.20 mmol), 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2, 35 mg, 0.15 mmol, 1.50 equiv) and triethylamine (28 μL, 0.20 mmol) were added and the mixture was stirred overnight at room temperature. The mixture was diluted with DCM (30 mL) and washed with water (3×15 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (25.0% CH3CN up to 38.0% in 7 min, up to 100.0% in 3 min, down to 25.0% in 1 min); Detector, Waters 2489, 254 & 220 nm. The fractions containing pure compound were combined and lyophilized to yield the title compound as a white solid (5.9 mg, 12%). m/z (ES+) 455 (M+H)+. 1H NMR (400 MHz, CDCl3): δ 7.69 (d, J=8.0 Hz, 2H), 7.59-7.53 (m, 2H), 7.53-7.47 (m, 3H), ˜4.9-4.75 (m, 1H partially obscured by water peak), 4.72 (s, 2H), 3.99-3.85 (m, 1H), 3.52 (s, 3H), ˜3.3 (m, 1H overlapped with methanol solvent peak), 3.08-2.93 (m, 2H), 2.37 (s, 3H), 2.08-1.93 (m, 1H), 1.93-1.65 (m, 4H), 1.02-0.94 (m, 2H), 0.74-0.68 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=S)=[N:8][CH:9]=[CH:10][CH:11]=1.[NH3:29]>>[F:1][C:2]1[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[NH:29])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: Fc1ccc(F)c(COc2cccnc2NC(=S)Nc2ccc(Cl)cc2)c1F
Reactant: N
Product: N=C(Nc1ccc(Cl)cc1)Nc1ncccc1OCc1c(F)ccc(F)c1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of yellow mercuric oxide (1.23g, 0,056 mol), N-[3-(2,3,6-trifluorobenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea (2.00g 0.0047mol) and methanolic ammonia solution (40 ml) was stirred for 1 day at room temperature. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent, trituration with ether and recrystallisation from acetonitrile gave the desired product. Yield 1.20 g (63%), m.p. 153°-156 ° C.
Reaction SMILES: I[C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:11]2[CH2:14][O:13][CH2:12]2)[CH:3]=1.[C:15]1([C:21](=[N:28][C:29]2[CH:30]=[N:31][CH:32]=[C:33]([CH:40]=2)[C:34](N(OC)C)=[O:35])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([C:21](=[N:28][C:29]2[CH:40]=[C:33]([C:34]([C:2]3[C:10]4[CH:9]=[N:8][CH:7]=[N:6][C:5]=4[N:4]([CH:11]4[CH2:14][O:13][CH2:12]4)[CH:3]=3)=[O:35])[CH:32]=[N:31][CH:30]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Ic1cn(C2COC2)c2ncncc12
Reactant: CON(C)C(=O)c1cncc(N=C(c2ccccc2)c2ccccc2)c1
Product: O=C(c1cncc(N=C(c2ccccc2)c2ccccc2)c1)c1cn(C2COC2)c2ncncc12

Procedure:
The title compound was prepared according to the method described for Preparation 94 using 5-iodo-7-oxetan-3-yl-7H-pyrrolo[2,3-d]pyrimidine (Preparation 98) and 5-[(diphenylmethylene)amino]-N-methoxy-N-methylnicotinamide (Preparation 23) to afford the title compound as a yellow solid in 55% yield, 253 mg.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:9]=3[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([C:11]1[S:10][C:9]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:8]=2[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:24]
Reactant: COc1ccc2c(-c3ccccc3)csc2c1
Reactant: COc1cccc(C(=O)Cl)c1
Product: COc1cccc(C(=O)c2sc3cc(OC)ccc3c2-c2ccccc2)c1
Yield: 82 %

Procedure:
3-Phenyl-6-methoxybenzo[b]thiophene and 3-methoxybenzoyl chloride were converted to the title compound by the procedure of Example 1 in 82% yield, after crystallization from methanol.
Reaction SMILES: C(=O)([O-])[O-].[Na+:5].[Na+].B([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)(O)O.Cl.Br[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>O.C(O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Na+].[Na+].[Na+].P(C1C=C(S([O-])(=O)=O)C=CC=1)(C1C=C(S([O-])(=O)=O)C=CC=1)C1C=C(S([O-])(=O)=O)C=CC=1>[N:24]1[CH:25]=[CH:26][C:21]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([O-:16])=[O:15])=[CH:12][CH:11]=2)=[CH:22][CH:23]=1.[Na+:5]
Reactant: Brc1ccncc1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C([O-])c1ccc(-c2ccncc2)cc1
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 99.5 %

Procedure:
A solution of sodium carbonate (830 g, 7834.20 mmol) in water (6800 mL) was added dropwise over 30 minutes to a stirred suspension of 4-boronobenzoic acid (520 g, 3133.68 mmol), 4-bromopyridine hydrochloride (622 g, 3196.35 mmol) and palladium(II) acetate (1.407 g, 6.27 mmol) in ethanol (2600 mL) and water (3600 mL) at 20° C. The reaction was stirred for 10 minutes then 3,3′,3″-phosphinidynetris(benzenesulfonic acid) trisodium salt (30% w/w solution in water) (36.8 g, 18.80 mmol) was added and the mixture was heated to 85° C. for 4 hours. The reaction mixture was cooled to 55° C. and stirred for 2 hours, then the resulting suspension was stirred at 20° C. for 16 hours. The solid was collected by filtration, washed with acetone (3×1250 mL), and dried in a vacuum oven at 60° C. to afford sodium 4-(pyridin-4-yl)benzoate (690 g, 99%) as a solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[N:7][CH:8]=1.[H][H]>[Pt](=O)=O.[Rh].C(O)(=O)C>[F:18][C:2]([F:1])([F:17])[CH:3]1[CH2:8][NH:7][CH2:6][CH:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])[CH2:4]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)Nc1cncc(C(F)(F)F)c1
Agent: O=[Pt]=O
Agent: [Rh]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1CNCC(C(F)(F)F)C1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
In a 50 mL hastalloy metal reactor, tert-butyl (5-(trifluoromethyl)pyridin-3-yl)carbamate (600 mg, 2.29 mmol) was treated with glacial acetic acid (10 mL), platinum (IV) oxide (250 mg, 1.10 mmol) and rhodium (5 wt. % (dry) on carbon, degussa type, 250 mg, 2.43 mmol) and hydrogenated at 200 psi hydrogen at 70° C. for 23 h. The reaction mixture was cooled to RT and filtered through a 0.45 um acrodisc, washed with MeOH and concentrated under reduced pressure. The residue was treated with EtOAc and 2N NaOH and extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine and dried over MgSO4, filtered and concentrated to afford rac-tert-butyl (5-(trifluoromethyl)piperidin-3-yl)carbamate (490 mg, 1.83 mmol, 80%). MS (ESI, pos. ion) m/z: 269.1 (M+1). The crude material was used in the subsequent step without further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10](=[NH:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.C([Li])CCC.Cl[P:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][NH:9][C:10](=[N:17][P:24]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5][CH2:6]1
Reactant: N=C(NCCN1CCOCC1)c1ccccc1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Product: c1ccc(C(=NP(c2ccccc2)c2ccccc2)NCCN2CCOCC2)cc1
Yield: 63.7 %

Procedure:
Procedure as described for NP Amidine XVII using the following amounts: 1.17 g of N1-(2-morpholinoethyl)benzamidine (Amidine XV, 5.0 mmol), 2.50 mL of 2.0 M butyllithium (5.0 mmol), 0.93 mL chlorodiphenylphosphine (5.0 mmol). After filtration to remove lithium chloride and removal of solvent, the oily product was treated with 20 mL of pentane. Removal of the pentane yielded 1.33 g of off-white solid (64%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([C:24]([OH:26])=O)=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([C:24]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:26])=[CH:12][N:11]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CCNC1
Reactant: COc1cc2c(C(=O)O)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Product: COc1cc2c(C(=O)N3CCCC3)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Yield: 64 %

Procedure:
As described in example 1E, 100 mgs of 1-(tert-butoxycarbonylamino-methyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid was coupled with pyrrolidine to give 74 mgs (64%) of [6,7-dimethoxy-4-(pyrrolidine-1-carbonyl)-isoquinolin-1-ylmethyl]-carbamic acid tert-butyl ester: 1H NMR (CDCl3) δ 1.51 (s, 9H), 1.83-1.92 (m, 2H), 2.02-2.07 (m, 2H), 3.20-3.29 (m, 2H), 4.03 (m, 6H), 4.92 (br s, 2H), 6.17 (br s, 2H), 7.23-7.24 (m, 1H), 7.38 (br s, 1H), 8.31-8.33 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].ClCCl.C(OC(=O)[NH:17][CH2:18][C@@H:19]1[O:23][C:22](=[O:24])[N:21]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[S:32][CH2:33][C:34](=[S:37])[NH:35][N:36]=3)=[C:27]([F:38])[CH:26]=2)[CH2:20]1)(C)(C)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:17][CH2:18][C@@H:19]1[O:23][C:22](=[O:24])[N:21]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[S:32][CH2:33][C:34](=[S:37])[NH:35][N:36]=3)=[C:27]([F:38])[CH:26]=2)[CH2:20]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc(C3=NNC(=S)CS3)c(F)c2)C(=O)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC[C@H]1CN(c2ccc(C3=NNC(=S)CS3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
20% Trifluoroacetic acid/dichloromethane (2 ml) is added to {3-[3-fluoro-4-(5-thioxo-5,6-dihydro-4H-[1,3,4]thiadiazin-2-yl)-phenyl]-2-oxo-oxazolidin-5(S)-ylmethyl}-carbamic acid tert-butyl ester and the mixture is stirred at room temperature for 30 minutes. The reaction is evaporated to dryness and the trifluoroacetate salt is used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH2:16]([C:23]1[CH:53]=[C:52]([Cl:54])[CH:51]=[CH:50][C:24]=1[O:25][CH2:26][CH2:27][CH2:28][N:29]([CH:33]([C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=1)[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)[CH2:30][CH2:31][NH2:32])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(CC)CC>C(Cl)Cl>[CH2:16]([C:23]1[CH:53]=[C:52]([Cl:54])[CH:51]=[CH:50][C:24]=1[O:25][CH2:26][CH2:27][CH2:28][N:29]([CH:33]([C:42]1[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=1)[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)[CH2:30][CH2:31][NH:32][S:12]([C:7]1[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:11]=2[CH:10]=[CH:9][CH:8]=1)(=[O:14])=[O:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1cccc2c(Cl)nccc12
Reactant: COc1ccc(C(c2ccc(OC)cc2)N(CCN)CCCOc2ccc(Cl)cc2Cc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(c2ccc(OC)cc2)N(CCCOc2ccc(Cl)cc2Cc2ccccc2)CCNS(=O)(=O)c2cccc3c(Cl)nccc23)cc1
Reaction time: 1 h
Yield: 78.2 %

Procedure:
Powdered 1-chloro-isoquinoline-5-sulfonyl chloride (124 mg, 0.473 mmol) is added to a stirred solution of N1-[3-(2-benzyl-4-chloro-phenoxy)-propyl]-N1-[bis-(4-methoxy-phenyl)-methyl]-ethane-1,2-diamine (258 mg, 0.473 mmol) and NEt3 (0.198 mL, 1.42 mmol) in anhydrous CH2Cl2 (5 mL) at ambient temperature under nitrogen. The resultant mixture is allowed to stir for 1 hour. The mixture is chromatographed on silica gel (gradient 0-4% EtOAc in CH2Cl2) to give 285 mg (0.370 mmol, 78% yield) of the title compound as foam. ESIMS: m/z 768 [(M−H)−, 35C, 35Cl], 770 [(M−H)−, 35Cl, 37Cl], 772 [(M−H)−, 37Cl, 37Cl. Analysis for C42H41Cl2N3O5S: calcd: C, 65.45; H, 5.36; N, 5.45; found: C, 65.43; H, 5.27; N, 5.42.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:3]2[N:4]=[C:5]3[CH:10]=[N:9][CH:8]=[CH:7][N:6]3[C:2]=2[C:21]2[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=2)=[CH:12][CH:13]=1
Reactant: Fc1ccc(-c2nc3cnccn3c2Br)cc1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: Fc1ccc(-c2nc3cnccn3c2-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 27.8 %

Procedure:
To a 25 mL round bottom flask charged with 3-bromo-2-(4-fluorophenyl)-imidazo[1,2-a]pyrazine (Preparation #5, 0.090 g, 0.31 mmol), 4-pyridineboronic acid (0.045 g, 0.37 mmol), Pd(PPh3)4 (0.018 g, 0.015 mmol) and Cs2CO3 (0.250 g, 0.77 mmol) was added DME (10 mL) followed by water (1 mL). The reaction was allowed to stir at ambient temperature for about 3 minutes followed by submersion into an oil bath which was at about 90° C. After about 16 h, the reaction was concentrated in-vacuo and then purified by RP-HPLC (Table 1, Method d). The pure fractions were combined, concentrated, and lyophilized for about 12 h to give the title compound as a white solid (0.025 g, 23%): LC/MS (Table 1, Method b) Rt=1.54 min; MS m/z: 291.2 (M+H)+.
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[C:27]([CH2:31]I)([F:30])([F:29])[F:28].[F-].[Cs+].O>CS(C)=O>[CH2:1]([C@@:4]1([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:31][C:27]([F:30])([F:29])[F:28])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(O)cc2)C(=O)O1
Reactant: FC(F)(F)CI
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Solvent: O
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(OCC(F)(F)F)cc2)C(=O)O1
Temperature: 120 °C
Yield: 58 %

Procedure:
A mixture of (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-hydroxyphenyl)ethyl)-1,3-oxazinan-2-one (700 mg, 1.97 mmol), CF3CH2I (621 mg, 2.96 mmol) and CsF (360 mg, 2.37 mmol) in DMSO (10 mL) was heated under 120° C. overnight. The mixture was poured into water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by preparative TLC to give (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1,3-oxazinan-2-one (500 mg, 58%).
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:12](=[CH2:14])=[N-:13]>CCOCC>[C:1]([NH:9][C:10]1[S:11][N:13]=[N:12][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: O=C(Nc1cnns1)c1ccccc1
Reaction time: 1 h
Yield: 36.6 %

Procedure:
To a stirred solution of benzoylisothiocyanate (50.6 g., 310 mmoles) in commercial anhydrous ether (400 ml.), maintained at 0° and in a nitrogen atmosphere, was added dropwise with vigorous stirring, 0.685 N ethereal diazomethane (453 ml., 310 mmoles). When the addition was completed, the mixture was stirred for 1 hour at 0°, the solid was collected by filtration and dried in vacuo. The melting point of the crude material (23.3 g.) thus obtained was observed somewhere in the region 232° to 257°. Goerdler reported M.p. 267° for the pure material. A small second crop (2.1 g.) was obtained by evaporation of the mother liquor in vacuo. The total yield was therefore 40%.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:15][N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1B(O)O.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[CH3:15][N:16]1[C:20]2[CH:21]=[C:22]([C:2]3[C:3]([C:8]4[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=4)=[N:4][CH:5]=[CH:6][CH:7]=3)[CH:23]=[CH:24][C:19]=2[N:18]=[CH:17]1
Reactant: Cc1cccc(-c2ncccc2Cl)c1
Reactant: Cn1c(B(O)O)nc2ccccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cccc(-c2ncccc2-c2ccc3ncn(C)c3c2)c1
Temperature: 150 °C

Procedure:
1,4-Dioxane (3 mL) was transferred to a microwave vial (Smith Creator®) containing 3-chloro-2-(3-methylphenyl)pyridine (100 mg, 0.49 mmol), 1-methyl-1H-benzimidazole boronic acid (95 mg, 0.54 mmol), PdCl2(dppf)2.CH2Cl2 (35 mg, 0.042 mmol) and 2M aq. Na2CO3 (0.6 mL, 1.2 mmol). Slow stream of argon was bubbled through the heterogeneous red solution while stirring the reaction mixture. The vial was capped and heated in a microwave at 150° C. for 50 min. Progress of the reaction was analyzed by LC/MS. The reaction mixture was passed through a pad of Celite® and washed the pad with EtOAc (10 mL). The filtrate was concentrated and purified by preparative HPLC. Subsequently, product fractions were concentrated, diluted with water, neutralized with aq. NaHCO3 and extracted with EtOAc. Organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The concentrate was dissolved in acetonitrile/water (1:1, 15 mL) and allowed to freeze by external cooling in dry ice/acetone. Lyophilization of the frozen residue resulted in an off-white solid of 1-methyl-6-(2-m-tolylpyridin-3-yl)-1H-benzo[d]imidazole. 1H NMR (DMSO-d6): δ 8.64 (dd, 1H, J=1.7 and 4.7 Hz), 8.16 (s, 1H), 7.87 (dd, 1H, J=1.7 and 7.6 Hz), 7.51 (d, 1H, J=1.5 Hz), 7.47-7.43 (m, 2H), 7.27 (s, 1H), 7.03-6.97 (m, 2H), 6.90 (app d, 1H, J=6.7 Hz), 6.85 (dd, 1H, J=8.5 Hz), 3.76 (s, 3H), 2.19 (s, 3H). 19F NMR (DMSO-d6): δ −114.29 (s).LCMS: rt 3.16 min (A), purity 97%, MS (m/e) 300 (MH