Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25](O)=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21](=[O:23])[NH2:22])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:28]1([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=2)[CH2:30][CH2:29]1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([CH2:24][C:25](=[O:26])[N:31]([CH:28]2[CH2:30][CH2:29]2)[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([NH2:22])=[O:23])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cccc(CNC2CC2)c1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccccc2C(N)=O)cc1
Product: COc1cccc(CN(C(=O)CN(c2ccccc2C(N)=O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)C2CC2)c1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(2-carbamoyl-phenyl)-amino]-acetic acid with cyclopropyl-(3-methoxy-benzyl)-amine
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C.[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]Br.[Br-]>C(#N)C.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:34][C:33]1[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=1[Cl:31])[C:6](=[O:11])[C:5]2=[O:12]
Reactant: Clc1ccccc1CBr
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: [Br-]
Solvent: CC#N
Solvent: CO
Product: O=C1C(=O)N(Cc2ccccc2Cl)c2ccc(Br)cc21
Reaction time: 18 h
Yield: 102.7 %

Procedure:
Partially dissolve 5-bromoisatin (45 mg, 0.20 mmol) in acetonitrile (2 mL) and add 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine on polysteyrene (95 mg, 0.21 mmol, 2.2 mmol/g, Fluka) followed by adding 2-chlorobenzyl bromide (0.026 mL, 0.20 mmol). Stir 18 h and add additional base (50 mg) and bromide (0.010 mL) to drive reaction to completion after another 3 h. Dilute with MeOH and warm with heat gun to insure soluability. Filter off beads and concentrate the filtrate in vacuo to obtain 72 mg of the title compound as a dark orange solid. Use material in subsequent reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([C@@H:24]([CH3:26])[OH:25])[NH:5][C:6](=[O:23])[C@H:7]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH:8]C(OCC1C=CC=CC=1)=O.CCN(C(C)C)C(C)C.[N+](C1C=CC(O[C:47](=[O:63])[C@H:48]([CH:60]([CH3:62])[CH3:61])[NH:49][C:50]([O:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[O:51])=CC=1)([O-])=O.C1C=CC2N(O)N=NC=2C=1.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>CCO.Cl.[Pd]>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([C@@H:24]([CH3:26])[OH:25])[NH:5][C:6](=[O:23])[C@H:7]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH:8][C:47](=[O:63])[C@H:48]([CH:60]([CH3:61])[CH3:62])[NH:49][C:50]([O:52][CH2:53][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)=[O:51]
Reactant: COC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)[C@@H](C)O
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Agent: O=C1c2ccccc2C(=O)C1(O)O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)[C@@H](C)O

Procedure:
Benzyloxycarbonyl-L-leucyl-L-threonine methyl ester (I, 3.8 g, 10 mmole) was dissolved in a mixture of 95% EtOH (50 ml) and 1 N HCl (10 ml) and hydrogenated in the presence of a 10% Pd on charcoal catalyst (0.8 g). After removal of the catalyst and the solvent the residue was dissolved in DMF (35 ml), treated with DIEA (1.6 ml, 10 mmole), benzyloxycarbonyl-L-valine p-nitrophenyl ester (4.3 g, 12 mmole) and HOBt (1.5 g, 10 mmole). After a negative spot test with ninhydrin indicated the completion of the reaction, the solvent was removed in vacuo and the residue triturated with CHCl3 (40 ml). The resulting solid was washed with CHCl3 (20 ml) and dried: 4.5 g (94%, mp 217°-8° C.,) unchanged after extraction with solvents, [α]D24 -11.7° (c 1.5, DMF); RfC 0.75; Thr 1.08; Val 0.98; Leu 1.0.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1.C(N(CC)C(C)C)(C)C.O>CN1CCCC1=O>[F:8][C:4]1[N:3]=[C:2]([NH:16][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccc(CN)cc1
Reactant: Fc1cccc(F)n1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2cccc(F)n2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
To 2,6-difluoro-pyridine (20, 100 g, 869 mmol) in 500 mL of N-methylpyrrolidone, 4-methoxy-benzylamine (60, 136 mL, 1.043 mol) and N,N-diisopropylethylamine (304 mL, 1.738 mol) were added. The reaction was stirred at 90° C. overnight, then poured into 8 L of water. The precipitate was collected by filtration and washed with water, then taken up in ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was triturated with heptane and collected by filtration to provide the desired compound (61, 151 g, 650 mmol, 74.8% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([CH2:9][C:10]1[CH:15]=[C:14]([CH2:16][N:17]2[CH2:22][CH2:21][NH:20][C:19](=[O:23])[CH2:18]2)[CH:13]=[CH:12][C:11]=1[O:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH:37]([CH3:39])[CH3:38]>CN(C=O)C>[C:1]([O:5][C:6](=[O:33])[N:7]([CH2:9][C:10]1[CH:15]=[C:14]([CH2:16][N:17]2[CH2:22][CH2:21][N:20]([CH:37]([CH3:39])[CH3:38])[C:19](=[O:23])[CH2:18]2)[CH:13]=[CH:12][C:11]=1[O:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(Cc1cc(CN2CCNC(=O)C2)ccc1Oc1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(Cc2ccc(Oc3ccc(Cl)c(Cl)c3)c(CN(C)C(=O)OC(C)(C)C)c2)CC1=O
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
To a solution of [2-(3,4-dichloro-phenoxy)-5-(3-oxo-piperazin-1-ylmethyl)-benzyl]-methyl-carbamic acid tert-butyl ester 79 mg, 0.16 mmol) in DMF (3.2 mL) at 0° C. was added NaH (90%, 7.6 mg). After 30 min, 2-bromopropane (15 μL, 0.16 mmol) was added and the reaction was allowed to come to rt and stir overnight. The mixture was quenched with satd. aq. NaHCO3 and extracted with DCM. The combined organic layers were dried (Na2SO4) and concentrated. The crude product was purified by FCC to provide the title compound (35 mg, 41%). MS (ESI): mass calcd. for C27H35Cl2N3O4, 535.20; m/z found, 536.2 [M+H].
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH2:20])=[N:8][C:6]=2[N:7]=1.[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25]N>>[NH2:20][C:9]1[C:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[CH:11][C:5]2[CH:4]=[N:3][C:2]([NH:1][CH2:25][CH2:24][CH2:23][N:22]([CH3:27])[CH3:21])=[N:7][C:6]=2[N:8]=1
Reactant: CN(C)CCCN
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Product: CN(C)CCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1

Procedure:
The title compound was prepared as in Example 20 by reacting 3.0 g of 2,7-diamino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidine from Example 1 and 60 mL of 3-(dimethylamino)propylamine to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][OH:6].[CH2:12](Br)[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:14]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][OH:6])[CH:13]=[CH2:12]
Reactant: COc1ccc(CO)cc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1cc(CO)ccc1OC
Reaction time: 18 h
Yield: 99.5 %

Procedure:
A mixture of 3-hydroxy-4-methoxybenzylalcohol (0.80 g, 7.79 mmol.), allyl bromide (0.45 ml, 5.9 mmol.), acetonitrile (20 ml), and potassium carbonate (1.08 g, 7.8 mmol.) was reluxed for 18 hours, then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried (MgSO4) and evaporated to give the product as a yellow oil (1.14 g, 57%). 1H NMR (300 MHz, CDCl3) δ 1.90 (s, 1H), 3.79 (s, 3H), 4.52-4.54 (m, 4H), 5.2 (d, 1H, J=12 Hz), 5.32 (d, 1H, J=17.25 Hz), 6.0 (m, 1H), 6.77 (s, 2H), 6.85 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 56.3, 65.6, 70.3, 111.2, 113.6, 118.4, 119.7, 133.7, 134.4, 147.8, 149.9.
Reaction SMILES: [I:1]/[CH:2]=[CH:3]/[CH:4]([OH:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11]1([C:17](Br)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[I:1]/[CH:2]=[CH:3]/[CH:4]([O:10][C:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC(O)/C=C/I
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: CCCCCC(/C=C/I)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Treatment of 7.62 g. (0.03 mole) of 1-iodo-trans-1-octen-3-ol (Example 23) with 10.67 g. (0.033 mole) of triphenylmethyl bromide in pyridine in the manner described in Example 22 gave 13.448 g. (90%) of a colorless oil.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>C(Cl)Cl>[C:29]([NH:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]2)[CH2:9]1)=[O:6])(=[O:31])[CH3:30]
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (140 mg, 0.42 mmol) in DCM (10 ml), were sequentially added triethylamine (175 μl, 1.26 mmol) and acetyl chloride (35.8 μl, 0.50 mmol). The reaction was stirred at RT for 2 hours, and then the solvent was evaporated. The residue was taken up with little EtOAc, and the insoluble was filtered off. The organic phase was evaporated to dryness achieving (R)-quinuclidin-3-yl 2-acetamido-2-phenylacetate (127 mg; quantitative yield).
Reaction SMILES: [C:1]([N:11]1[CH2:32][CH2:31][N:14]2[C:15]3[C:20]([NH:21][C:22](=[O:23])[CH:13]2[CH2:12]1)=[CH:19][C:18]([NH:24]C(=O)C(F)(F)F)=[CH:17][CH:16]=3)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[OH-].[Na+]>O>[NH2:24][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]1[CH2:31][CH2:32][N:11]([C:1]([O:3][CH2:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)=[O:2])[CH2:12][CH:13]1[C:22](=[O:23])[NH:21]2
Reactant: O=C1Nc2cc(NC(=O)C(F)(F)F)ccc2N2CCN(C(=O)OCc3ccccc3)CC12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc2c(c1)NC(=O)C1CN(C(=O)OCc3ccccc3)CCN21

Procedure:
A mixture of 2.8 g. of 3-carbobenzoxy-2,3,4,4a-Tetrahydro-8-(2,2,2-trifluoroacetamido)-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one, 0.5 g. sodium hydroxide and 200 ml. of water is boiled for 15 minutes, then cooled. The mixture is then extracted with methylene chloride. The organic portion is then extracted with dilute hydrochloric acid. The aqueous acid phase is then basified with dilute sodium hydroxide and extracted with methylene chloride. The organic phase is dried and concentrated to give 1.6 g. of pale yellow solid product, m.p. 130°-135°.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[CH:12])[CH:4]=[CH:5][N:6]=1.[Br:13][C:14]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:15]=1[O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23](OS(C(F)(F)F)(=O)=O)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1>>[Br:13][C:14]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:15]=1[O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([C:12]#[C:11][CH2:10][CH2:9][CH2:8][CH2:7][N:3]3[CH:4]=[CH:5][N:6]=[C:2]3[CH3:1])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1
Reactant: C#CCCCCn1ccnc1C
Reactant: COc1cc2c(Oc3ccc(F)cc3Br)ncnc2cc1OS(=O)(=O)C(F)(F)F
Product: COc1cc2c(Oc3ccc(F)cc3Br)ncnc2cc1C#CCCCCn1ccnc1C

Procedure:
Using an analogous procedure to that described in the second last paragraph of Note [115] above, 6-(2-methylimidazol-1-yl)-1-hexyne was reacted with 4-(2-bromo-4-fluorophenoxy)-6-methoxy-7-trifluoromethanesulphonyloxyquinazoline to give 4-(2-bromo-4-fluorophenoxy)-6-methoxy-7-[6-(2-methylimidazol-1-yl)-1-hexynyl]quinazoline; NMR Spectrum: (DMSOd6) 1.56 (m, 2H), 1.85 (m, 2H), 2.28 (s, 3H), 2.56 (m, 2H), 3.9 (m, 2H), 3.98 (s, 3H), 6.75 (br m, 1H), 7.1 (br m, 1H), 7.36-7.82 (m, 3H), 7.63 (s, 1H), 7.98 (s, 1H), 8.61 (s, 1H); Mass Spectrum: M+H+ 509 and 511.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C@H:8]([N:13]1[CH2:18][CH2:17][C:16]3([CH2:23][C@@H:22]([OH:24])[C:21]4[CH:25]=[C:26]([NH2:29])[CH:27]=[CH:28][C:20]=4[O:19]3)[CH2:15][CH2:14]1)[CH2:7][CH2:6]2)#[N:2].[CH3:30][Si:31](C1NC=CN=1)([CH3:33])[CH3:32]>C(#N)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C@H:8]([N:13]1[CH2:18][CH2:17][C:16]3([CH2:23][C@@H:22]([O:24][Si:31]([CH3:33])([CH3:32])[CH3:30])[C:21]4[CH:25]=[C:26]([NH2:29])[CH:27]=[CH:28][C:20]=4[O:19]3)[CH2:15][CH2:14]1)[CH2:7][CH2:6]2)#[N:2]
Reactant: N#Cc1ccc2c(c1)CC[C@@H](N1CCC3(CC1)C[C@@H](O)c1cc(N)ccc1O3)C2
Reactant: C[Si](C)(C)c1ncc[nH]1
Solvent: CC#N
Product: C[Si](C)(C)O[C@@H]1CC2(CCN([C@@H]3CCc4cc(C#N)ccc4C3)CC2)Oc2ccc(N)cc21
Reaction time: 1.5 h
Yield: 98.1 %

Procedure:
To a solution of N-[1′-(6-cyano-1,2,3,4-tetrahydro-2(R)-naphthalenyl)-3,4-dihydro-4(R)-hydroxyspiro[2H-1-benzopyran-2,4′-piperidin]-6-yl]amine (50 mg, 0.128 mmole) in acetonitrile under argon was added trimethylsilylimidazole (0.36 gm, 2.5 mmole) and the reaction warmed to 60 C. for 1.5 hrs. The reaction was concentrated in vacuo and purified by flash chromatography using 95/5/0.1 dichloromethane/methanol/triethylamine to give N-[1′-(6-cyano-1,2,3,4-tetrahydro-2(R)-naphthalenyl)-3,4-dihydro-4(R)-trimethylsilyloxyspiro[2H-1-benzopyran-2,4′-piperidin]-6-yl]amine as a foam (58 mg, 98%). MS m/z 462 (M+), 1H NMR (CDCL3) δ 0.09 (9 H, s), 1.4-2.1 (8 H, m), 2.4-2.9 (9 H, m), 3.2 (2 H, br, s), 4.65 (1 H, t), 6.41(1 H, dd, J=9.2 and 3.3 Hz), 6.49 (1 H, d, J=3.3 Hz), 6.52 (1 H, d, J=9.2 Hz), 7.03 (1 H, d, J=9.2 Hz), 7.22 (2 H, m).
Reaction SMILES: C[Si](C)(C)[O-].[K+].[CH:7]1([S:10]([N:13]2[C:17]3[C:18]4[O:22][CH:21]=[CH:20][C:19]=4[C:23]([F:26])=[C:24]([F:25])[C:16]=3[N:15]([C:27]3[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=3[F:34])C2=O)(=[O:12])=[O:11])[CH2:9][CH2:8]1.C(OCC)(=O)C>C1COCC1.CCCCCC.C(Cl)Cl>[F:26][C:23]1[C:19]2[CH:20]=[CH:21][O:22][C:18]=2[C:17]([NH:13][S:10]([CH:7]2[CH2:8][CH2:9]2)(=[O:12])=[O:11])=[C:16]([NH:15][C:27]2[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=2[F:34])[C:24]=1[F:25]
Reactant: O=c1n(-c2ccc(I)cc2F)c2c(F)c(F)c3ccoc3c2n1S(=O)(=O)C1CC1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCCCCC
Product: O=S(=O)(Nc1c(Nc2ccc(I)cc2F)c(F)c(F)c2ccoc12)C1CC1
Temperature: 27.5 °C
Reaction time: 4 h
Yield: 65.7 %

Procedure:
Potassium trimethyl silanolate (0.019 g, 0.1498 mmol) was added to a solution of 1-(cyclopropylsulfonyl)-4,5-difluoro-3-(2-fluoro-4-iodophenyl)-1H-benzofuro[6,7-d]imidazol-2(3H)-one (0.04 g, 0.0749 mmol) in THF (5 mL) at 0° C. The reaction mass was stirred for 4 hours at 20-35° C. The reaction was monitored by TLC (25% ethyl acetate in hexane). The reaction mass was diluted with DCM (50 mL) and partitioned between water and DCM. The organic layer was washed with water, brine solution and concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (20% ethyl acetate in hexane) afforded 0.025 g of the product (66% yield). 1H NMR (CDCl3, 300 MHz): δ 7.72 (d, 1H), 7.40 (dd, 1H), 7.28 (d, 1H), 6.99 (d, 1H), 6.95 (bs, 1H), 6.38-6.641 (t, bs, 2H), 2.58-2.62 (m, 1H), 1.11-1.19 (m, 2H), 0.83-0.98 (m, 2H). LCMS: 96.54%, m/z=506.7 (M−1). HPLC: 96.31%
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:14]([C:15]([C:22]4[CH:27]=[CH:26][C:25]([CH:28]=[C:29]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:24][CH:23]=4)=[C:16]4[C:21]=2[CH:20]=[CH:19][CH:18]=[CH:17]4)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.[C:42]1([NH:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:49]1([N:48]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C:9]4[C:14]([C:15]([C:22]5[CH:27]=[CH:26][C:25]([CH:28]=[C:29]([C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)[C:30]6[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=6)=[CH:24][CH:23]=5)=[C:16]5[C:21]=3[CH:20]=[CH:19][CH:18]=[CH:17]5)=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:4][CH:3]=2)[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: Clc1ccc(-c2c3ccccc3c(-c3ccc(C=C(c4ccccc4)c4ccccc4)cc3)c3ccccc23)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: C(=C(c1ccccc1)c1ccccc1)c1ccc(-c2c3ccccc3c(-c3ccc(N(c4ccccc4)c4ccccc4)cc3)c3ccccc23)cc1

Procedure:
Under an atmosphere of argon, 9-(4-chlorophenyl)-10-(4-(2,2-diphenylvinyl)phenyl)anthracene (2.4 g, 4.4 mmole), diphenylamine (0.9 g, 5.3 mmole, 1.2 eq), tris(dibenzylideneacetone)dipalladium(0) (0.1 g, 0.11 mmole, 5% Pd), a toluene solution of tri-t-butylphosphine (66% by weight, 0.05 ml, 0.16 mmole, 0.7 eq to Pd) and sodium t-butoxide (0.6 g, 6.3 mmole, 1.4 eq) were suspended in anhydrous toluene (20 ml). The resultant suspension was refluxed for 8 hours. The reaction mixture was filtered and washed with toluene, water and methanol, and a green solid substance was obtained. The obtained solid substance was suspended in boiling toluene (40 ml). After the suspension was cooled while being left standing, the suspension was filtered, and a green solid substance (2.4 g, 81%) was obtained. The result of examination of the obtained product in accordance with 1H-NMR was as follows:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:12]([OH:17])[CH2:13][CH2:14][C:15]#[CH:16]>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:16]#[C:15][CH2:14][CH2:13][CH2:12][OH:17])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: C#CCCCO
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Product: CS(=O)(=O)c1ccc(C#CCCCO)cc1

Procedure:
Preparation of the title compound with 4-bromophenyl methyl sulphone (5.87 g, 25 mmol) and 4-pentyn-1-ol (2.1 g, 25 mmol) according to the procedure in Example 18 yielded 5.12 g (87%) of yellow oil which was characterized as 5-(4-Methanesulfonylphenyl)pent-4-yn-1-ol: NMR (CDCl3) δ 1.88-1.93 (m, 2H), 2.56-2.60 (t, J=6.99, 2H), 3.04 (s, 3H), 3.80-3.84 (t, J=6.15, 2H), 7.56 (d, J=5.1, 2H), 7.85 (d, J=4.8, 2H). MS m/z 239 (M+H cald. for C12H14O3S 238.3)
Reaction SMILES: Cl.C[Si](C)(C)CCOC[N:8]1[C:12]2=[N:13][CH:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][N:20]([C:22]4([CH2:26][C:27]#[N:28])[CH2:25][NH:24][CH2:23]4)[CH:21]=3)=[C:11]2[CH:10]=[CH:9]1.Br[C:32]1[CH:33]=[CH:34][C:35]([C:38]([NH:40][C:41]2([C:44]([F:47])([F:46])[F:45])[CH2:43][CH2:42]2)=[O:39])=[N:36][CH:37]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:27]([CH2:26][C:22]1([N:20]2[CH:21]=[C:17]([C:16]3[CH:15]=[CH:14][N:13]=[C:12]4[NH:8][CH:9]=[CH:10][C:11]=34)[CH:18]=[N:19]2)[CH2:25][N:24]([C:32]2[CH:33]=[CH:34][C:35]([C:38]([NH:40][C:41]3([C:44]([F:47])([F:45])[F:46])[CH2:43][CH2:42]3)=[O:39])=[N:36][CH:37]=2)[CH2:23]1)#[N:28]
Reactant: O=C(NC1(C(F)(F)F)CC1)c1ccc(Br)cn1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ccnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: N#CCC1(n2cc(-c3ccnc4[nH]ccc34)cn2)CN(c2ccc(C(=O)NC3(C(F)(F)F)CC3)nc2)C1
Temperature: 105 °C
Reaction time: 8 h
Yield: 8.4 %

Procedure:
A mixture of {3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile HCl salt (40 mg, 0.08 mmol), 5-bromo-N-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carboxamide 26 mg, 0.083 mmol), cesium carbonate (81 mg, 0.25 mmol), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (5.2 mg, 0.0083 mmol) and palladium acetate (1.9 mg, 0.0083 mmol) in toluene (1 mL) was stirred at 105° C. overnight. After the reaction mixture was cooled to room temperature, the solid was separated, and washed with ethyl acetate twice. The combined organic solution was concentrated under reduced pressure. The residue was dissolved in a solution of trifluoroacetic acid (1 mL) in methylene chloride (1:1, 1 mL). After stirred at room temperature for 1.5 h., the mixture was concentrated under reduced pressure. The residue was dissolved in methanol (1 mL). To the solution was added ethylenediamine (0.6 mL). The mixture was stirred at room temperature for 2 h. The product was purified with RP-HPLC (pH=2) to afford the desired product (3.4 mg) as TFA salt. LCMS (M+H)+: m/z=507.2. 1H NMR (500 MHz, DMSO-d6): δ 11.98 (s, 1H), 9.04 (s, 1H), 8.89 (s, 1H), 8.39 (s, 1H), 8.26 (d, J=5.3 Hz, 1H), 7.93 (d, J=2.6 Hz, 1H), 7.88 (d, J=8.6 Hz, 1H), 7.63-7.57 (m, 1H), 7.45 (d, J=5.3 Hz, 1H), 7.09 (dd, r=8.5, 2.7 Hz, 1H), 6.99 (dd, J=3.2, 1.4 Hz, 1H), 4.68 (d, J=8.9 Hz, 2H), 4.42 (d, J=8.9 Hz, 2H), 3.75 (s, 2H), 1.32-1.23 (m, 2H), 1.22-1.12 (m, 2H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[H-].[Na+].[CH2:11](Br)[CH:12]=[CH:13][CH3:14]>CN(C=O)C>[CH2:11]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[I:1])[CH:12]=[CH:13][CH3:14]
Reactant: Oc1ccccc1I
Reactant: CC=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC=CCOc1ccccc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
An ice-cold solution of 2-iodophenol (10.0 g, 45.4 mmol) in DMF (100 mL) was added dropwise to a solution of NaH (2.16 g, 90.8 mmol) in DMF at 0° C. Crotylbromide (7.97 g, 59.0 mmol) was then added. The mixture was warmed to room temperature and stirred overnight. The reaction was quenched with water (50 mL) and the mixture was extracted with CH2Cl2 (3×). The combined organics were washed with brine and dried over Na2SO4 to give the title compound (12.2 g, 99%) as a yellow oil: 1H NMR (500 MHz, DMSO-d6) δ 7.76 (dd, J=7.8, 1.5 Hz, 1H), 7.27-7.22 (m, 1H), 6.80 (dd, J=8.4, 1.2 Hz, 1H), 6.70-6.65 (m, 1H), 5.95-5.80 (m, 1H), 5.75-5.65 (m, 1H), 4.55-4.45 (m, 2H), 1.76-1.70 (m, 3H); ESI MS m/z 275 (M+H)+.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH3:6][C:7]1[N:8]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][S:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11](OC3C=CC=CC=3)[C:10]=2[N:24]=1.[OH-].[Na+]>O>[CH3:6][C:7]1[N:8]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][S:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH2:5])[C:10]=2[N:24]=1
Reactant: Cc1nc(Oc2ccccc2)c2nc(C)n(CCCCCSc3ccccc3)c2c1C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc(N)c2nc(C)n(CCCCCSc3ccccc3)c2c1C
Temperature: 160 °C

Procedure:
Ammonium acetate (25 g) and 2,6,7-trimethyl-4-phenoxy-1-[5-(phenylthio)pentyl]-1H-imidazo[4,5-c]pyridine (2.50 g, 5.80 mmol) were combined and heated at 160° C. in a sealed tube for 2 days. The reaction mixture was cooled to ambient temperature and diluted with water (100 mL). Sodium hydroxide (15%) was added and the mixture was extracted with chloroform (2×150 mL). The combined extracts were dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel eluting with 2% methanol in chloroform) followed by recrystallization from methanol/dichloromethane/hexanes to provide 2,6,7-trimethyl-1-[5-(phenylthio)pentyl]-1H-imidazo[4,5-c]pyridin-4-amine as an off white powder, m.p. 181–183° C.