Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][CH2:31][C@@H:32]([CH3:35])[CH2:33][OH:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30][NH:29][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:26])([F:28])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: C[C@@H](CO)CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](CO)CCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 46.5 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ((R)-4-hydroxy-3-methyl-butyl)-amide (45 mg) was prepared by following General Procedure F starting 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (80 mg), (R)-4-amino-2-methyl-butan-1-ol (25 mg), HBTU (80 mg), and DIEA (70 uL) in DMF (1 mL). LC/MS: m/z 493.6.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[O:15])=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19]([C:21]1([C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)[CH2:23][CH2:22]1)=[O:20])[CH3:17].C(=O)(O)[O-].[Na+]>COCCOC.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>[CH2:16]([O:18][C:19]([C:21]1([C:24]2[CH:29]=[CH:28][C:27]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]=[O:15])=[CH:4][CH:3]=3)=[CH:26][CH:25]=2)[CH2:22][CH2:23]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C=O)cc3)cc2)CC1
Temperature: 85 °C

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (0.5 g, 1.88 mmol) was mixed with 1-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester (0.72 g, 2.07 mmol) and sodium bicarbonate (0.553 g, 6.58 mmol) in DME (5 mL) and H2O (2.5 mL). The reaction was purged with N2 (g) then bis(triphenylphosphine)palladium(II) dichloride (0.066 g, 0.094 mmol) was added and the reaction was heated to 85° C. overnight. After cooling to room temperature the reaction was submitted to standard aqueous workup the purified by silica gel chromatograph (0-20% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8](=[O:12])SCC)[CH:5]=[CH:4][N:3]=1.[I-].[C:14]([C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Zn+])#[N:15]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=2[C:14]#[N:15])=[O:12])[CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1c(F)cccc1[Zn+]
Reactant: CCSC(=O)c1ccnc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [I-]
Solvent: Cc1ccccc1
Product: N#Cc1c(F)cccc1C(=O)c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.9 %

Procedure:
To a degassed solution of S-ethyl 2-bromopyridine-4-carbothioate (5.0 g, 20.3 mmol) in anhydrous toluene (50 mL), Pd(OAc)2 (0.82 g, 3.66 mmol) was added followed by dropwise addition of 2-cyano-3-fluorophenylzinc iodide (0.5M in THF, 36.6 mL, 18.3 mmol). The reaction mixture was stirred at room temperature for 2 hours with continued bubbling of nitrogen. Water (50 mL) and saturated aqueous NH4Cl (100 mL) were added and the resulting mixture was extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography using a gradient of 25% to 100% ethyl acetate in hexanes to afford 3.4 g of the title compound (1.5 g, 27%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH:9]2[C:12]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13]2)=[CH:4][C:3]=1[O:25][CH3:26].C=O.[C:29]([BH3-])#N.[Na+].[BrH:33]>CC(O)C.CO>[BrH:33].[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH3:29])[CH:9]2[C:12]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13]2)=[CH:4][C:3]=1[O:25][CH3:26]
Reactant: COc1cc2c(cc1O)C(C1(c3ccccc3Cl)CC(C)(C)C1)NCC2
Reactant: [BH3-]C#N
Agent: Br
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(C)O
Product: COc1cc2c(cc1O)C(C1(c3ccccc3Cl)CC(C)(C)C1)N(C)CC2
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
A mixture of 7-hydroxy-6-methoxy-[1-(2-chlorophenyl)-3,3-dimethylcyclobutyl]-1,2,3,4-tetrahydroisoquinoline (3.7 g), methanol (50 ml) and 37-40% aqueous formaldehyde solution was cooled to 5° C. Sodium cyanoborohydride (1.4 g) was added and the mixture stirred for 1.5 hours. The solvents were removed by evaporation and the residue partitioned between water and dichloromethane. The organic layer was washed with aqueous ammonia solution and then brine, dried and the solvent removed by evaporation to give a gum which was dissolved in propan-2-ol. Addition of 48% aqueous hydrobromic acid gave 7-hydroxy-6-methoxy-2-methyl-1-[1-(2-chlorophenyl)-3,3-dimethylcyclobutyl]-1,2,3,4-tetrahydroisoquinoline hydrobromide, m.p. 202°-204° C. (dec).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([Br:15])=[C:11](Br)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:17].[K+]>CN(P(N(C)C)(N(C)C)=O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([Br:15])=[C:11]([OH:17])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c(Br)c(Br)cnn1Cc1ccccc1
Reactant: [OH-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=c1c(Br)c(O)cnn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
The residue from step 1 was dissolved in HMPA (50 mL) and 8N KOH (65 mL) was added. The mixture was warmed to 120°-125° C. and stirred vigourously for 16 h. The mixture was cooled to r.t., the aqueous layer was separated, diluted with H2O (500 mL) and acidified to pH 6 with 6N HCl under vigourous stirring. After cooling in an ice bath, the solid was collected and air dried. It was dissolved in warm IN NaOH and washed once with ETOAc. The aqueous layer was acidified to pH 6 with 6N HCl and cooled again in an ice bath. The solid was filtered and air dried to yield the title compound (4.4 g, 40 %).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:15]3[C@@H:14]4[CH2:16][C@@H:13]4[CH2:12][C:11]=3[C:10]([C:17]([OH:19])=O)=[N:9]2)[CH:3]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:51][C@@H:52]([C:55]([CH3:58])([CH3:57])[CH3:56])[CH2:53][OH:54]>CN(C=O)C>[OH:54][CH2:53][C@@H:52]([NH:51][C:17]([C:10]1[C:11]2[CH2:12][C@H:13]3[CH2:16][C@H:14]3[C:15]=2[N:8]([C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][N:5]=2)[N:9]=1)=[O:19])[C:55]([CH3:58])([CH3:57])[CH3:56]
Reactant: O=C(O)c1nn(-c2cc(Br)ccn2)c2c1C[C@H]1C[C@@H]21
Reactant: CC(C)(C)[C@H](N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[C@@H](CO)NC(=O)c1nn(-c2cc(Br)ccn2)c2c1C[C@H]1C[C@@H]21
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 94.6 %

Procedure:
To a solution of (1aR,5aR)-2-(4-bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2.00 g, 6.25 mmol) and triethylamine (1.741 mL, 12.49 mmol) in DMF (15 mL) was added HATU (2.423 g, 6.37 mmol). The reaction was stirred at 23° C. for 5 min, then was added (S)-2-amino-3,3-dimethylbutan-1-ol (0.805 g, 6.87 mmol). The reaction was stirred at 23° C. for 1 h then concentrated. The residue was purified by silica gel column chromatography to give the title compound as a white solid (2.48 g). LCMS m/z=419.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.44 (td, J=4.6, 3.4 Hz, 1H), 1.05 (s, 9H), 1.24 (td, J=7.8, 4.9 Hz, 1H), 2.23-2.29 (m, 1H), 2.46 (t, J=5.5 Hz, 1H), 2.78-2.83 (m, 1H), 2.91 (d, J=16.7 Hz, 1H), 3.01 (dd, J=16.6, 6.3 Hz, 1H), 3.66-3.72 (m, 1H), 3.93-4.01 (m, 2H), 7.01 (d, J=8.8 Hz, 1H), 7.37 (dd, J=5.3, 1.6 Hz, 1H), 8.09 (d, J=1.6 Hz, 1H) 8.28 (d, J=5.3 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][C:16](=[O:18])[CH3:17])[C:12]2[C:7](=[C:8](Br)[CH:9]=[CH:10][C:11]=2[F:19])[CH:6]=1)=[O:4].C(N(CC)CC)C>C(OCC)(=O)C.[C].[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][C:16](=[O:18])[CH3:17])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[F:19])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(OC(C)=O)c2c(F)ccc(Br)c2c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OC(C)=O)c2c(F)cccc2c1
Reaction time: 1 h

Procedure:
To a solution of 4-acetoxy-8-bromo-5-fluoronaphthalene-2-carboxylic acid methyl ester (2.0 g) and triethylamine (0.72 g) in ethyl acetate (60 mL) was added palladium-carbon (600 mg) at room temperature, and the mixture was stirred for 1 hour at the same temperature under a hydrogen atmosphere. The insoluble material was removed by filtering through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:38])[C:18]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]=[C:25]([O:30][CH:31]([CH3:33])[CH3:32])[CH:24]=[C:23]4[C:34]([F:37])([F:36])[F:35])=[O:19])=[C:13]([Cl:39])[CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:40][C:41]([Si](C)(C)C)([F:43])[F:42].[F-].C[N+](C)(C)C>>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:38])[C:18]([OH:19])([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]=[C:25]([O:30][CH:31]([CH3:33])[CH3:32])[CH:24]=[C:23]4[C:34]([F:35])([F:37])[F:36])[C:41]([F:43])([F:42])[F:40])=[C:13]([Cl:39])[CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C)Oc1cc(C(F)(F)F)c2cc(C(=O)C(C)c3ccc(Oc4ccc(C#N)c(Cl)c4)cc3Cl)ccc2n1
Agent: C[N+](C)(C)C
Agent: [F-]
Product: CC(C)Oc1cc(C(F)(F)F)c2cc(C(O)(C(C)c3ccc(Oc4ccc(C#N)c(Cl)c4)cc3Cl)C(F)(F)F)ccc2n1

Procedure:
In analogy to Example 1, step 3, 2-chloro-4-{3-chloro-4-[2-(2-isopropoxy-4-trifluoromethyl-quinolin-6-yl)-1-methyl-2-oxo-ethyl]-phenoxy}-benzonitrile was reacted with (trifluoromethyl)trimethylsilane and tetramethylammonium fluoride to give the title compound as an off-white gum. MS (m/e, ISP neg. ion)=641.1 [M−H+].
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[C:22]=1[CH2:31][C:32]([O:34][CH3:35])=[O:33].CCN(C(C)C)C(C)C.[CH2:45]([Si:47]([C:52]#[CH:53])([CH2:50][CH3:51])[CH2:48][CH3:49])[CH3:46]>CN(C=O)C.[Cu]I.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>[CH2:48]([Si:47]([C:45]#[C:46][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[C:22]=1[CH2:31][C:32]([O:34][CH3:35])=[O:33])([CH2:52][CH3:53])[CH2:50][CH3:51])[CH3:49]
Reactant: C#C[Si](CC)(CC)CC
Reactant: COC(=O)Cc1c(Br)cccc1C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[Si](C#Cc1cccc(C(F)(F)F)c1CC(=O)OC)(CC)CC
Temperature: 90 °C

Procedure:
A mixture of CuI (0.005 g, 0.03 mmol), PdCl2(PPh3)2 (0.009 g, 0.01 mmol), PPh3 (0.017 g, 0.065 mmol) and methyl 2-(2-bromo-6-(trifluoromethyl)phenyl)acetate (A91) (0.213 g, 0.717 mmol) in DMF (2.0 mL) was degassed with nitrogen for several minutes before the addition of DIPEA (2.00 mL, 11.5 mmol) and (triethylsilyl)acetylene (0.50 mL, 2.8 mmol). The resulting mixture was then degassed with nitrogen before heating under microwave irradiation at 90° C. for 2×20 minutes. The volatiles were evaporated under reduced pressure and the residue purified using silica gel column chromatography (0-10% EtOAc in petroleum benzine 40-60° C.) to give a mixture of product and starting material. To this material, CuI (0.013 g, 0.068 mmol), PdCl2(PPh3)2 (0.013 g, 0.019 mmol), PPh3 (0.030 g, 0.114 mmol), DMF (4.0 mL), DIPEA (2.00 mL, 11.5 mmol) and (triethylsilyl)acetylene (0.50 mL, 2.8 mmol) were added. The resulting mixture was heated at 100° C. for 30 minutes then concentrated under reduced pressure and the residue purified using silica gel column chromatography (Biotage Isolera, SiO2 cartridge, 5-10% EtOAc in petroleum benzine 40-60° C.) to give the title compound A92 (0.175 g, 69%); 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J=7.7 Hz, 1H), 7.62 (d, J=7.9 Hz, 1H), 7.35 (m, 1H), 4.09 (m, 2H), 3.68 (s, 3H), 1.03 (t, J=7.9 Hz, 9H), 0.67 (q, J=7.9 Hz, 6H).
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1(S)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Br.BrCCN.C(CC(=O)C)C(C)=O>C(O)(=O)C.C(N(CC)CC)C>[C:1]1([S:7][CH2:8][CH2:9][N:10]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:16]2[CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCSc1ccccc1
Reactant: Sc1ccccc1
Agent: Br
Agent: CC(=O)CCC(C)=O
Agent: NCCBr
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: Cc1ccc(C)n1CCSc1ccccc1
Yield: 70 %

Procedure:
Phenylthioethylamine (5.00 g, 32.68 mmoles) prepared by reacting thiophenol and β-bromoethylamine hydrobromide in the presence of triethylamine and 3.74 g (32.68 mmoles) of acetonylacetone were heated under reflux for 4 hours in 80 ml of acetic acid. The acetic acid was distilled off under reduced pressure, and toluene was added to the residue. The mixture was distilled under reduced pressure. The resulting crude product was chromatographed on a column of silica gel using hexane/benzene as an eluent to afford 2,5-dimethylpyrrol-1-yl-ethyl phenyl sulfide (5.32 g, 22.88 mmoles, 70%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10].C([O-])([O-])=O.[K+].[K+].F[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>CN(C=O)C.CCOC(C)=O>[F:12][C:2]([F:1])([F:11])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: FC(F)(F)Oc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Sc2ccccc2OC(F)(F)F)cc1
Temperature: 120 °C
Yield: 73.5 %

Procedure:
To a solution of 2-(trifluoromethoxy)benzenethiol (1.035 g, 5.33 mmol) in DMF (15 mL) at 0° C. was added K2CO3 (921 mg, 6.66 mmol). The solution was warmed to ambient temperature over 10 min before 4-fluorobenzonitrile (613 mg, 5.06 mmol) was added at once. The mixture was heated to 120° C. for 16 hours, then was then cooled and poured onto ice. The mixture was diluted with EtOAc, the layers separated, and the organics were washed successively with sat. NaHCO3 and brine (2×). The organics were dried (MgSO4), filtered, and purified by Biotage SP1 (DCM/hexanes gradient) to afford 4-((2-(trifluoromethoxy)phenyl)thio)benzonitrile (1.098 g, 74%) as a golden oil.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1.C[Si]([N:16]=[C:17]=[S:18])(C)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([C:17](=[S:18])[NH2:16])[C:6]=2[N:5]=[CH:4][CH:3]=1
Reactant: Cc1ccnc2c1CCCC2
Reactant: C[Si](C)(C)N=C=S
Solvent: Cc1ccccc1
Product: Cc1ccnc2c1CCCC2C(N)=S
Yield: 70.9 %

Procedure:
1.55M n-Butyl lithium in hexane (35.5 ml. 55mM) at 0° C. under argon was heated with a solution of N-benzylidine-tert-butylamine (8.85 g, 50mM) in toluene (40 ml) to form lithium N-t-butyl-N-(1-phenylpentyl) amide. After 2 hours a solution of 4-methyl-5,6,7,8-tetrahydroquinoline (7.35 g, 50mM) in toluene (10 ml) was added and after a further 0.5 hours the mixture was heated with a solution of trimethylsilyl isothio-cyanate (7.7 g, 55mM) in toluene (10 ml). After 0.5 hours the reaction was quenched with water, acidified (pH1) with sulphuric acid and the layers separated. The aqueous phase was mixed with an equal volume of cyclohexane and the pH adjusted to 10 with sodium hydroxide solution. The resultant precipitate was removed by filtration, washed with water and cyclohexane and dried in vacuo to give the title compound (7.3 g, 71%) identical with authentic material. (See Example 11 UK Patent Specification No. 1463666).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].CO[C:16](OC)([CH3:18])[CH3:17].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:17][C:16]1([CH3:18])[O:13][C:12]2[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=2[O:1]1
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc2c(c1)OC(C)(C)O2
Yield: 48.5 %

Procedure:
Ethyl 3,4-dihydroxybenzoate (910.9 mg, 5 mmol) was combined with 2,2-dimethoxypropane (1.23 mL, 10 mmol) and a catalytic amount of p-toluene sulfonic acid in toluene. The mixture was heated to reflux using a Dean-Stark trap for 20 hours. After solvent removal under reduced pressure, the crude was dissolved in ethyl acetate and washed successively with a saturated aqueous solution of sodium bicarbonate, water, and brine. The organic layer was dried over anhydrous sodium sulfate. Purification by chromatography on silica gel using a gradient hexane:ethyl acetate, 90:10 to 75:25, afforded a white powder (539.1 mg, 49%). 1H NMR (CDCl3): 1.36 (t, 3H, J=7.2 Hz), 1.69 (s, 6H), 4.32 (q, 2H, J=7.1 Hz, J=14.2 Hz), 6.74 (d, 1H, d, J=8.2 Hz), 7.38 (d, Ih, J=1.7 Hz), 7.61 (dd, 1H5 J=1.8 Hz, J=8.3 Hz).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=1B(O)O.CC(C)([O-])C.[K+]>COCCOC.C(O)(C)(C)C.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:11]1([CH3:10])[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=1[C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(B(O)O)c(C)c1
Reactant: OCc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: COCCOC
Product: Cc1cc(C)c(-c2cccc(CO)n2)c(C)c1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 68.4 %

Procedure:
(6-Bromopyridin-2-yl)-methanol (4.23 g, 22.5 mmol) was dissolved in 1,2-dimethoxyethane. Tetrakis(triphenylphosphine)palladium(0) (1.30 g, 1.12 mmol) was added and the reaction stirred for 15 minutes at 50° C. Upon cooling, 2,4,6-trimethylbenzeneboronic acid (3.69 g, 22.5 mmol) in 20 mL 1,2-dimethoxyethane was added to the reaction followed by potassium t-butoxide (5.05 g, 50.0 mmol) in 20 mL of t-butanol. The reaction was heated at 90° C. for 0.5 hr. The solution was cooled and filtered through paper. Flash chromatography (30% ethyl acetate/hexanes) gave the desired product as a white solid (3.50 g, 68% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4].[H-].[Na+].Cl[C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]([N+:23]([O-:25])=[O:24])=[CH:16][C:15]=1[C:26]([F:29])([F:28])[F:27].Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Cl:10])[C:3]=1[NH:4][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]([N+:23]([O-:25])=[O:24])=[CH:16][C:15]=1[C:26]([F:27])([F:29])[F:28]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Reactant: Nc1c(Cl)cc(Cl)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2c(Cl)cc(Cl)cc2Cl)c(C(F)(F)F)c1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
2,4,6-trichloroaniline (3.9 g.) was dissolved in dimethylformamide (20 ml.) and carefully added to sodium hydride (obtained by washing sodium hydride in mineral oil (2.0 g; 50%) with petrol) suspended in dimethylformamide (10 ml.) at 10° C. When the addition was complete the temperature of the mixture was allowed to rise to the ambient temperature over a period of 30 minutes, before being cooled to 10° C. A solution of 2-chloro-3,5-dinitrobenzotrifluoride (5.4 g.) in dimethylformamide (20 ml.) was slowly added, and the mixture stirred at the ambient temperature for 5 hours, and allowed to stand for further 16 hours. The mixture was poured into iced water and the resultant mixture acidified with concentrated hydrochloric acid. The precipitate was collected by decanting off the supernatant liquid and recrystallised from methylated spirit to yield 2(2,4,6-trichloroanilino)-3,5-dinitrobenzotrifluoride, melting point 105° C.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[C@H:7]([NH:15][CH:16]=[O:17])[CH2:6][C@@H:5]1[CH2:18][CH3:19])(=[O:3])[CH3:2].[N:20]1([CH2:26][C:27]2[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>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.C1(C)C=CC=CC=1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:30]3[CH:29]=[CH:28][C:27]([CH2:26][N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:32][CH:31]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:15][CH:16]=[O:17])[CH2:6][C@@H:5]1[CH2:18][CH3:19])(=[O:3])[CH3:2]
Reactant: OB(O)c1ccc(CN2CCCCC2)cc1
Reactant: CC[C@H]1C[C@@H](NC=O)c2cc(Br)ccc2N1C(C)=O
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC[C@H]1C[C@@H](NC=O)c2cc(-c3ccc(CN4CCCCC4)cc3)ccc2N1C(C)=O
Temperature: 110 °C
Reaction time: 3 h

Procedure:
((cis)-1-acetyl-6-bromo-2-ethyl-1,2,3,4-tetrahydro-4-quinolinyl)formamide (for a preparation see Intermediate 44) (1 g, 3.08 mmol) and [4-(1-piperidinylmethyl)phenyl]boronic acid (1.572 g, 6.15 mmol, Intermediate 1) were mixed with Ethanol (8 mL), Toluene (8.00 mL). potassium carbonate (1.402 g, 10.15 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.355 g, 0.308 mmol) were added and the mixture was stirred under nitrogen, at reflux at 110° C. After 3 hours, another sample of tetrakis(triphenylphosphine)palladium(0) (0.355 g, 0.308 mmol) was added and the reaction was left to stir overnight. The reaction was evaporated to dryness. The residue was diluted with DCM (150 mL), washed (water (150 mL), sat. sodium bicarbonate (200 mL), brine (200 mL)), dried (sodium sulfate), filtered and evaporated to dryness to give a black solid which was loaded onto an 20 g SCX-column, eluting with MeOH (120 mL) followed by MeOH/NH3 (300 mL). Product-containing fractions were evaporated to dryness to give a dark red solid which was purified on a 40+S Biotage silica column, eluting with DCM:2M MeOH/NH3 (1:0 to 19:1). Product-containing fractions were evaporated to dryness to give a yellow/orange solid (1.00 g).