Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[F-].[Cs+].[CH3:8][O:9][C:10](=[S:32])[NH:11][CH2:12][C:13]1[N:14]=[N:15][N:16]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]3)=[C:20]([F:31])[CH:19]=2)[CH:17]=1>C(O)C.C(OCC)(=O)C>[CH3:8][O:9][C:10](=[S:32])[NH:11][CH2:12][C:13]1[N:14]=[N:15][N:16]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][C:27](=[C:2]([C:1]#[N:5])[C:3]#[N:4])[CH2:26][CH2:25]3)=[C:20]([F:31])[CH:19]=2)[CH:17]=1
Reactant: N#CCC#N
Reactant: COC(=S)NCc1cn(-c2ccc(N3CCC(=O)CC3)c(F)c2)nn1
Agent: [Cs+]
Agent: [F-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=S)NCc1cn(-c2ccc(N3CCC(=C(C#N)C#N)CC3)c(F)c2)nn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of malononitrile (22 mg, 0.33 mmol) and CsF (42 mg, 0.28 mmol) in ethanol (5 ml) was added {1-[3-Fluoro-4-(4-oxo-piperidin-1-yl)-phenyl]-1H-[1,2,3]triazol-4-ylmethyl}-thiocarbamic acid O-methyl ester (100 mg, 0.28 mmol), obtained in Example 82. The reaction mixture was allowed to stir at room temperature for 2 h and then diluted with ethyl acetate (100 ml). The organic portion was washed with water followed by brine and dried over sodium sulfate. Removal of volatiles and purification of the resulting residue by silica gel column chromatography (ethyl acetate/pet. ether, 1:1), the title compound was obtained as white solid (45 mg, 40%). Mp. 198° C.
Reaction SMILES: [C:1]([S@@:5]([NH2:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]=[C:18]([CH:20]=O)[N:17]=[CH:16]2)=[CH:11][CH:10]=1.CCOC(C)=O.CCCCCCC>ClCCCl.[O-]S([O-])(=O)=O.[Cu+2]>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH:19]=[C:18](/[CH:20]=[N:7]/[S@:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[O:6])[N:17]=[CH:16]2)=[CH:13][CH:14]=1
Reactant: O=Cc1cn(-c2ccc(Cl)cc2)cn1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCCCCCC
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)[S@](=O)/N=C/c1cn(-c2ccc(Cl)cc2)cn1
Temperature: 60 °C
Yield: 28.1 %

Procedure:
To a suspension of (S)-(−)tert-Butanesulfinamide (2.35 g, 19.4 mmol) and 1-(4-chlorophenyl)-1H-imidazole-4-carbaldehyde (4 g, 19.4 mmol) in DCE (39 mL) was added CuSO4 (4.63 g, 29.0 mmol). The reaction mixture was heated at 60° C. for 18 hours in a oil bath. A dark brown suspension resulted. The reaction mixture was then cooled to room temperature, filtered through a pad of celite, rinsed with DCM. The solution was then concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 100%) provided (S,E)-N-((1-(4-chlorophenyl)-1H-imidazol-4-yl)methylene)-2-methylpropane-2-sulfinamide (1.69 g, 5.45 mmol, 28.2% yield) as a light brown solid. LCMS m/z 310.0 (M+H)+, Rt 0.75 min.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([O:4][C:5]([NH:7][CH:8]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH:9]([C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)[OH:10])=[O:6])[CH3:3].CO[C:26](OC)([CH3:28])[CH3:27].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH:17]1([CH2:16][C@H:8]2[C@H:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[O:10][C:26]([CH3:28])([CH3:27])[N:7]2[C:5]([O:4][C:2]([CH3:23])([CH3:1])[CH3:3])=[O:6])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: COC(C)(C)OC
Reactant: CC(C)(C)OC(=O)NC(CC1CCCCC1)C(O)c1ccco1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H](c2ccco2)OC1(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
[R-(R*,S*)]-β-[[(1,1-Dimethylethoxy)carbonyl]amino]-α-(2-furanyl)cyclohexanepropanol (41.63 g., 128.9 mmole, 1 eq.) was dissolved in distilled dichloromethane (1 l., 0.129M) under an argon atmosphere. 2,2-Dimethoxypropane (158.5 ml., 1289 mmole, 10 eq.) was added. The solution was cooled in an ice bath and pyridinium toluene-4-sulfonate (3.24 g., 12.89 mmole, 0.1 eq.) was added. The cooling bath was removed and the mixture was stirred at room temperature for 24 hours. Additional 2,2-dimethoxypropane (50 ml., 407 mmole, 3.2 eq.) and pyridinium toluene-4-sulfonate (1.5 g., 6.0 mmole, 0.05 eq.) were added and stirring at room temperature was continued for 20 hours. Solid sodium bicarbonate was added and the solvent was removed in vacuo. The residue was dissolved in ether (1 l.) and washed with saturated sodium bicarbonate solution (300 ml.) and saturated sodium chloride solution (300 ml.), dried (MgSO4) and freed of solvent in vacuo leaving a yellow oil (47.04 g.). This was chromatographed on silica gel (Merck, 1300 g.) eluting with ether:hexane (1:9) to give (4S-trans)-4-(cyclohexylmethyl)-5-(2-furanyl)-2,2-dimethyl-3-oxazolidinecarboxylic acid, 1,1-dimethylethyl ester as a colorless oil which crystallized on standing (36.66 g., 78.3%), m.p. 52°-56°. [α]D =-46.9° (c=1.6, methanol). TLC (silica gel, 1:3, ether:hexane) Rf =0.58.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([C:12]([O:14][CH3:15])=[O:13])[N:7]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:6][CH2:5]2.Br[CH2:24][C:25]1[C:30]([F:31])=[C:29]([Cl:32])[CH:28]=[CH:27][C:26]=1[F:33].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[Cl:32][C:29]1[C:30]([F:31])=[C:25]([C:26]([F:33])=[CH:27][CH:28]=1)[CH2:24][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([C:12]([O:14][CH3:15])=[O:13])[N:7]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:6][CH2:5]2
Reactant: COC(=O)[C@H]1c2ccc(O)cc2CCN1C(=O)OC(C)(C)C
Reactant: Fc1ccc(Cl)c(F)c1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)[C@H]1c2ccc(OCc3c(F)ccc(Cl)c3F)cc2CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 96.7 %

Procedure:
To a solution of (R)-2-tert-butyl 1-methyl 6-hydroxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (1.1 g, 3.58 mmol) in acetone (10 mL) was added 2-(bromomethyl)-4-chloro-1,3-difluorobenzene (0.95 g, 3.94 mmol) followed by the addition of Cs2CO3 (1.28 g, 3.94 mmol). The reaction was stirred at room temperature for 3.5 h and filtered. The solid was rinsed by CH2Cl2 several times. The combined organic layers and filtrate were concentrated and purified by column chromatography on ISCO (40 g) with 0-30% ethyl acetate in hexanes over 25 minutes to yield (R)-2-tert-butyl 1-methyl 6-(3-chloro-2,6-difluorobenzyloxy)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate as a white foam (1.62 g, 97%). HPLC retention time (Method C)=4.18 min. LC/MS (ESI) (M+H−Boc)+=368.1. 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (d, J=9.67 Hz, 9H), 2.71-2.88 (m, 1H), 2.88-3.07 (m, 1H), 3.70 (s, 4H), 3.72-3.85 (m, 2H), 5.10 (s, 2H), 6.78 (s, 1H), 6.86 (dd, J=8.79, 2.64 Hz, 1H), 6.89-6.97 (m, 1H), 7.33-7.46 (m, 2H).
Reaction SMILES: [C:1](O)(=O)C#C.[C:6]1([C:12]#[C:13][C:14]([OH:16])=[O:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CI.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:6]1([C:12]#[C:13][C:14]([O:16][CH3:1])=[O:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)C#Cc1ccccc1
Reactant: C#CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
Typical Procedure for Methylation of Propiolic Acid with Iodomethane (1b as Example) CH3I (2.2 mmol) and K2CO3 (2.2 mmol) were added to the solution of Propiolic acid (1b, 2 mmol) in acetonitrile and the obtained mixture was stirred at room temperature. The reaction was monitored by TLC until the starting 1b disappeared. After 3 hours, the mixture was extracted with ether (3×5 mL). The combined ether part was purified by column chromatography on silica gel (dichloromethane:hexane=1:3) to give pure methyl 3-phenylpropiolate in 98% yield. GC/Ms: m/z: 160. Data for 1H and 13C NMR of methyl 3-phenylpropiolate was conducted in CDCl3 and consistent with the data in reported literature.
Reaction SMILES: C[N:2]([CH3:21])[CH:3]=[C:4]([C:10](=[O:20])[C:11]1[CH:16]=[C:15]([F:17])[C:14]([Cl:18])=[CH:13][C:12]=1[Cl:19])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:22]1(N)C[CH2:23]1>C1(C)C=CC=CC=1>[CH:21]1([NH:2][CH:3]=[C:4]([C:10](=[O:20])[C:11]2[CH:16]=[C:15]([F:17])[C:14]([Cl:18])=[CH:13][C:12]=2[Cl:19])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:23][CH2:22]1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(F)c(Cl)cc1Cl
Reactant: NC1CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(Cl)cc1Cl
Yield: 93.9 %

Procedure:
33.4 g of ethyl 3-dimethylamino-2-(2,4-dichloro-5-fluorobenzoyl)acrylate are heated to boiling under reflux with 7 g of cyclopropylamine and 120 ml of toluene for 1 hour. The gas evolution, the onset of which is initially violent, is then finished. The toluene is removed by distillation in vacuo, and the solid residue is recrystallized from light petroleum. 32.5 g of ethyl 3-cyclopropylamino-2-(2,4-dichloro-5-fluorobenzoyl)acrylate of melting point 89°-91° C. are obtained.
Reaction SMILES: C([O-])(=O)C.[Na+].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[CH:14]=[CH:13][CH2:12][CH2:11]2.I[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28]>CC(N(C)C)=O.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>[N+:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:12]1[CH2:13][CH2:14][C:15]2[CH:16]=[C:17]([O:18][CH3:19])[C:8]([O:7][CH3:6])=[CH:9][C:10]=2[CH:11]=1)([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1ccccc1I
Reactant: COc1cc2c(cc1OC)CCC=C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(cc1OC)CCC(c1ccccc1[N+](=O)[O-])=C2
Temperature: 140 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
Pd(PPh3)2Cl2 (840 mg, 1.2 mmol) and sodium acetate (200 mg, 2.4 mmol) were added to a solution of 6,7-dimethoxy-3,4-dihydronaphthalene (2, 700 mg, 3.7 mmol) and 1-iodo-2-nitrobenzene (925 mg, 3.7 mmol) in dimethylacetamide (50 mL). The mixture was stirred under nitrogen at 140° C. overnight, and then concentrated in vacuo. Ethyl acetate (60 mL) was added to the residue and washed with distilled water (50 mL). The organic layer was separated and passed through a celite bed. The organic layer was then washed with brine, dried (anhydrous Na2SO4) and concentrated in vacuo. The residue was chromatographed to give compound 3 (330 mg) in 29% yield; 1H NMR (CDCl3) d 2.51(2H, t, J=8.1), 2.92(2H, t, J=8.1), 3.87(3H, s), 3.90(3H, s), 6.45(1H, s), 6.67(1H, s), 6.73(1H, s), 7.38˜7.45 (2H, m), 7.54˜7.62(1H, m), 7.88˜7.93(1H, m); 13C NMR d 28.5, 28.5, 56.6, 111.0, 111.7, 124.9, 127.0, 127.1, 128.1, 128:3, 131.3, 133.3, 135.7, 138.7, 147.9, 148.9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]([OH:13])=O)[C:6]=2[C:14]=1[F:15].[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:29])([CH3:28])[C:26]#[N:27])=[CH:21][C:20]=1[CH3:30])[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C.[OH-].[Na+]>[C:26]([C:25]([C:22]1[CH:23]=[CH:24][C:19]([CH:17]([NH:16][C:11](=[O:13])[CH2:10][N:7]2[C:6]3[C:14]([F:15])=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)[CH3:18])=[C:20]([CH3:30])[CH:21]=1)([CH3:28])[CH3:29])#[N:27]
Reactant: O=C(O)Cn1cnc2ccc(F)c(F)c21
Reactant: Cc1cc(C(C)(C)C#N)ccc1C(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cc(C(C)(C)C#N)ccc1C(C)NC(=O)Cn1cnc2ccc(F)c(F)c21
Yield: 74.8 %

Procedure:
To a solution of (6,7-difluoro-1H-benzimidazol-1-yl)acetic acid (250 mg, 1.18 mmol) prepared according to scheme 2, 2-[4-(1-aminoethyl)-3-methylphenyl]-2-methylpropanenitrile (202 mg 1.18 mmol) prepared according to scheme 15 and DMAP (285 mg, 2.35 mmol) stirred in anhydrous DMF (4.0 mL) is added HATU (448 mg, 1.18 mmol) after 18 hours of stirring, the mixture is diluted with 1N NaOH (40.0 mL) and then extracted 4 times with EtOAc (4×40.0 mL). The organic phases are combined and dried over MgSO4. The mixture is filtered and concentrated. The product is purified on a preparative LCMS system equipped with a Synergi Polar (4u) 21.2×50 mm column, mobile phase: A=water (ammonium carbonate buffer 0.01 M), B=MeCN using a short 40 to 60% B 10 min. gradient high pH method. The pure fractions are combined then extracted with ethyl acetate which is separated dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the expected product N-{1-[4-(1-cyano-1-methylethyl)-2-methylphenyl]ethyl}-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide (350 mg, 75%) as a white solid. 1H NMR (400 MHz, METHANOL-D4) d ppm 1.44 (d, J=6.84 Hz, 3H) 1.66 (s, 6H) 2.36 (s, 3H) 5.06 (d, J=16.99 Hz, 1H) 5.11 (d, J=16.99 Hz, 1H) 5.20 (q, J=7.03 Hz, 1H) 7.14 (ddd, J=11.38, 8.84, 7.52 Hz, 1H) 7.26 (d, J=2.15 Hz, 1H) 7.32 (dd, J=6.05, 2.15 Hz, 1H) 7.37-7.43 (m, 2H) 8.09 (s, 1H). MS [M+H], calcd: 397.2. found: 397.3. The enantiomers are separated on a chiral OD column, using methanol and CO2 as the mobile phase.
Reaction SMILES: CC([O:4][C@@H:5]([CH2:10][N+:11]([CH3:14])([CH3:13])[CH3:12])[CH2:6][C:7]([O-:9])=[O:8])=O.[As:15](=[O:19])([OH:18])([OH:17])[OH:16].[CH2:20]([OH:22])[CH3:21]>>[As:15](=[O:16])([OH:19])([OH:18])[OH:17].[C:20]([C@@:5]([CH2:6][C:7](=[O:8])[O-:9])([CH2:10][N+:11]([CH3:12])([CH3:13])[CH3:14])[OH:4])(=[O:22])[CH3:21]
Reactant: CC(=O)O[C@H](CC(=O)[O-])C[N+](C)(C)C
Reactant: CCO
Agent: O=[As](O)(O)O
Product: CC(=O)[C@@](O)(CC(=O)[O-])C[N+](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
Acetyl L-carnitine (35.3 g) was weighted and put in a flask (250 ml), into which 80 ml ethanol was added. The mixture was heated to dissolve completely. An ethanol solution containing 31.0 g arsenic acid was slowly and dropwise added into the solution of acetyl L-carnitine, continued to stir for a further 1 h after the addition, cooled to room temperature, and white crystals were precipitated. After grinding, 64.4 g of white powder was obtained. Yield: 97.1%. Melting temperature: 150.6° C.-152.1° C. 1H-NMR (DMSO, 500 MHz), δ 2.28 (m, 2H), 3.16 (m, 9H), 3.35 (m, 2H), 4.36 (m, 1H), 9.51 (s, 3H); IR: 3423 cm−1, 2975 cm−1, 2399 cm−1, 1723 cm−1, 1477 cm−1, 1302 cm−1, 1191 cm−1, 1106 cm−1, 879 cm−1, 769 cm−1.
Reaction SMILES: C[C@H]1CN[C@H](C)CN1C(OC(C)(C)C)=O.[F:16][C:17]([F:63])([F:62])[C:18]([C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:35]([CH3:36])[CH2:34][N:33]([C:37](=[O:57])[CH2:38][N:39]3[C:43](=[O:44])[C@@:42]([C:46]4[CH:51]=[CH:50][C:49]([O:52][CH:53]([CH3:55])[CH3:54])=[CH:48][CH:47]=4)([CH3:45])[NH:41][C:40]3=[O:56])[C@H:32]([CH3:58])[CH2:31]2)=[C:26](/[CH:59]=[CH:60]\[CH3:61])[CH:25]=1)([OH:23])[C:19]([F:22])([F:21])[F:20]>>[F:22][C:19]([F:20])([F:21])[C:18]([C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:35]([CH3:36])[CH2:34][N:33]([C:37](=[O:57])[CH2:38][N:39]3[C:43](=[O:44])[C@:42]([C:46]4[CH:51]=[CH:50][C:49]([O:52][CH:53]([CH3:54])[CH3:55])=[CH:48][CH:47]=4)([CH3:45])[NH:41][C:40]3=[O:56])[C@@H:32]([CH3:58])[CH2:31]2)=[C:26](/[CH:59]=[CH:60]\[CH3:61])[CH:25]=1)([OH:23])[C:17]([F:63])([F:62])[F:16]
Reactant: C/C=C\c1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1C[C@@H](C)N(C(=O)CN2C(=O)N[C@@](C)(c3ccc(OC(C)C)cc3)C2=O)CC1C
Agent: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1
Product: C/C=C\c1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1C[C@H](C)N(C(=O)CN2C(=O)N[C@](C)(c3ccc(OC(C)C)cc3)C2=O)CC1C

Procedure:
(2S,5R)-tert-butyl 2,5-dimethylpiperazine-1-carboxylate was used in place of (2R,5S)-tert-butyl 2,5-dimethylpiperazine-1-carboxylate for a similar reaction and treatment as the preparation (2R,5S,Z)-3-(2-{4-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-(prop-1-en-1-yl)phenyl]-2,5-dimethylpiperazin-1-yl}-2-oxoethyl)-5-[4-(1-methylethoxy)phenyl]-5-methylimidazolidine-2,4-dione of Example 14-1, and the title compound was obtained as a yellow oil.
Reaction SMILES: [CH3:1][CH:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:3][CH2:4][Si:5]([Cl:8])([Cl:7])Cl.[CH2:15]([Mg]Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>O1CCCC1>[CH3:1][CH:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:13])[CH3:14])[CH2:3][CH2:4][Si:5]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])([Cl:7])[Cl:8]
Reactant: CCCCCC[Mg]Br
Reactant: CC(C)CCCC(C)CC[Si](Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCCCCC[Si](Cl)(Cl)CCC(C)CCCC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
Tetrahydrofuran (50 ml) and 3,7-dimethyloctyl trichlorosilane (11.0 g, 40.0 mmol) were placed in a 200 mL four-necked flask in a nitrogen atmosphere, and cooled to −20° C. n-hexyl magnesium bromide (Sigma-Aldrich Co. LLC., 2.0 M, 21 ml) was added dropwise, and the mixture was agitated for 1 hour at 10° C. or less. The temperature was raised gradually to room temperature over the course of about 1 hour, and the mixture was left standing overnight. The precipitated salt was filtered out, the tetrahydrofuran was removed by concentration under reduced pressure, and the mixture was distilled under reduced pressure to obtain the target 3,7-dimethyloctyl-n-hexyl-dichlorosilane (Compound E24) (127-130° C./0.26 Torr, 9.5 g, yield 73%).
Reaction SMILES: [C:1]([CH2:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=2[N:5]=1)#[N:2].[C:19]([N:21]=[C:22]([NH2:24])[NH2:23])#[N:20].[OH-].[K+]>COCCO>[NH2:20][C:19]1[N:21]=[C:22]([NH2:24])[N:23]=[C:1]([CH2:3][C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:7]3[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]=2)[N:2]=1
Reactant: N#CN=C(N)N
Reactant: N#CCc1nc2ccccc2n1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: COCCO
Product: Nc1nc(N)nc(Cc2nc3ccccc3n2-c2ccccc2)n1
Yield: 73.5 %

Procedure:
A mixture of 2-cyanomethyl-1-phenyl-1H-benzimidazole (1.8 g), dicyanodiamide (785 mg) and potassium hydroxide (87 mg) in methyl cellosolve was refluxed for 2 hours. After the mixture was cooled, the resultant precipitates were filtered off and washed with water and methanol in turn to give 2,4-diamino-6-(1-phenyl-1H-benzimidazol-2-yl)methyl-1,3,5-triazine (1.8 g).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]#[N:9].[N+](C1C=CC([O:19][C:20]([C:22]2[C:30]3[S:29][C:28]([CH:31]4[CH2:33][CH2:32]4)=[N:27][C:26]=3[C:25]([O:34][CH3:35])=[CH:24][CH:23]=2)=O)=CC=1)([O-])=O>CN(C)C=O.C[Si](C)(C)[N-][Si](C)(C)C.[Na+]>[C:8]([C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[NH:1][C:20]([C:22]1[C:30]2[S:29][C:28]([CH:31]3[CH2:33][CH2:32]3)=[N:27][C:26]=2[C:25]([O:34][CH3:35])=[CH:24][CH:23]=1)=[O:19])#[N:9]
Reactant: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2sc(C3CC3)nc12
Reactant: Cn1ncc(C#N)c1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2c(C#N)cnn2C)c2sc(C3CC3)nc12
Yield: 49.8 %

Procedure:
Starting from 5-amino-1-methyl-1H-pyrazole-4-carbonitrile (90 mg) in dimethyl formamide (30 ml), sodium hexamethyldisilazide in tetrahydrofbran (1.08 ml, 1.0 M), and 2-cyclopropyl-4-methoxybenzothiazole-7-carboxylic acid 4-nitrophenyl ester (200 mg). Purification by flash chromatography (eluent 10% methanol in dichloromethane) to yield the title compound as an off-white solid (95 mg). TLC Rf 0.30 (10% methanol in dichloromethane); Mpt 259-260° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH3:17][C:18]1[S:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>>[CH3:23][C:21]1[S:22][C:18]([CH:17]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[NH:11][C:10]2=[O:16])=[CH:19][CH:20]=1
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Reactant: Cc1ccc(C=O)s1
Product: Cc1ccc(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)s1

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 5-methylthiophene-2-carbaldehyde to give the title compound.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])C1C=CC=CC=1.[H][H]>CCO.[Pd]>[N:27]1([CH:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8])[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: [H][H]
Reactant: CCCCCCCCC(CCCCCCCCCOCc1ccccc1)n1ccnc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCC(CCCCCCCCCO)n1ccnc1
Yield: 81 %

Procedure:
1-(18-(benzyloxy)octadecan-9-yl)-1H-imidazole (1.5 g, 3.52 mmol) was dissolved in EtOH, then 10% Pd on carbon (200 mg) was added and the reaction mixture hydrogenated under hydrogen balloon at reflux for 2 days. The reaction was filtered off to remove Pd carbon, then the filtrate was concentrated. The crude product was purified by silica gel column (3% MeOH in DCM) to give 10-(1H-imidazol-1-yl)octadecan-1-ol as a gummy liquid (0.96 g, 81%).
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[C:26]([F:34])[CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[F:34][C:26]1[CH:25]=[C:24]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C@@H:3]([CH3:14])[C@H:2]([OH:1])[CH2:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:6][CH:7]=2)[CH:29]=[CH:28][C:27]=1[S:30]([NH2:33])(=[O:31])=[O:32]
Reactant: NS(=O)(=O)c1ccc(Br)cc1F
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
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: [Na+]
Solvent: CCO
Product: C[C@H](Oc1ccc(-c2ccc(S(N)(=O)=O)c(F)c2)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C
Yield: 38.5 %

Procedure:
Prepared according to the method described in Example 12b) from 4-[(2S,3R)-5-(pyridin-3-yl)-3-hydroxypent-2-yloxy]benzeneboronic acid (0.20 g, Example 33), 4-bromo-2-fluorophenylsulfonic acid amide (0.20 g), ethanol (3 ml), 2M aqueous sodium carbonate (1.0 ml) and tetrakis(triphenylphosphine)palladium (0) (0.03 g) with heating at 90° C. for 3 hours. After work-up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane, followed by recrystalisation from aqueous ethanol, to give the title compound as a solid (0.11 g).
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:18]([CH:19]4[CH2:24][O:23][CH2:22][CH2:21][O:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)C=CC=CC=1.FC(F)(F)C(O)=O.[C@H:35]12[CH2:41][C@H:38]([NH:39][CH2:40]1)[CH2:37][O:36]2.N1C=CC=CC=1>C(Cl)(Cl)Cl>[O:20]1[CH2:21][CH2:22][O:23][CH2:24][CH:19]1[C:18]1[C:12]2[S:11][C:10]([NH:9][C:8]([N:39]3[CH2:40][C@@H:35]4[CH2:41][C@H:38]3[CH2:37][O:36]4)=[O:27])=[N:14][C:13]=2[C:15]([O:25][CH3:26])=[CH:16][CH:17]=1
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)Oc3ccccc3)nc12
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)N3C[C@@H]4C[C@H]3CO4)nc12

Procedure:
From (+)-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-carbamic acid phenyl ester with (1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]heptane trifluoroacetate and pyridine in chloroform. [α]D20=−11.9° (c=0.51, CHCl3), ES-MS m/e (%): 392 (M+H+, 100).