Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:15])=[CH:4][C:5]([C:8](O)(O)[C:9]([F:12])([F:11])[F:10])=[N:6][CH:7]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.C(O)(=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([CH3:15])=[CH:4][C:5]([CH:8]([N:23]=[CH:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[C:9]([F:12])([F:11])[F:10])=[N:6][CH:7]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1cc(C(O)(O)C(F)(F)F)ncc1Br
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc(C=NC(c2cc(C)c(Br)cn2)C(F)(F)F)cc1
Temperature: 110 °C
Yield: 74.4 %

Procedure:
A solution of 1-(5-bromo-4-methylpyridin-2-yl)-2,2,2-trifluoroethane-1,1-diol (163.1 mg; 0.5702 mmol) in 2.0 mL toluene was added at room temperature to a solution of 4-methoxybenzylamine (118 μL; 0.858 mmol) and acetic acid (49 μL; 0.854 mmol) in 2.0 mL toluene. A scoop of oven-dried 3A molecular sieves was added, and the reaction mixture heated at 110° C. for 3 days. The mixture was poured into saturated aqueous sodium bicarbonate and extracted twice with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The crude product was purified via flash chromatography on silica gel (24 g silica, solvent gradient: 0-100% ethyl acetate in dichloromethane) to yield 164.2 mg of the title compound. LCMS (ESI): M-(4-methoxybenzaldehyde)+H=269.2; 1H NMR (400 MHz, DMSO) δ 8.69 (s, 1H), 8.57 (s, 1H), 7.80 (d, J=8.7 Hz, 2H), 7.66 (s, 1H), 7.05 (d, J=8.7 Hz, 2H), 5.28 (q, J=8.0 Hz, 1H), 3.82 (s, 3H), 2.41 (s, 3H).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[Cl:12].[C:13]([O:17][C:18](=[O:41])[NH:19][C:20]([C:22]1[S:23][C:24]([S:39][CH3:40])=[C:25]([S:27]([C:30]2[CH:35]=[CH:34][C:33](O)=[C:32](B)[C:31]=2O)(=[O:29])=[O:28])[CH:26]=1)=[NH:21])([CH3:16])([CH3:15])[CH3:14].C(O)C.C1(C)C=CC=CC=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.CCOC(C)=O>[C:13]([O:17][C:18](=[O:41])[NH:19][C:20]([C:22]1[S:23][C:24]([S:39][CH3:40])=[C:25]([S:27]([C:30]2[CH:31]=[C:32]([C:2]3[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=3[Cl:12])[CH:33]=[CH:34][CH:35]=2)(=[O:29])=[O:28])[CH:26]=1)=[NH:21])([CH3:16])([CH3:15])[CH3:14]
Reactant: Cc1cc([N+](=O)[O-])cc(Cl)c1Br
Reactant: Bc1c(O)ccc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1O
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: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc([N+](=O)[O-])cc2Cl)c1
Temperature: 80 °C
Yield: 29 %

Procedure:
2-Bromo-1-chloro-3-methyl-5-nitro-benzene (45 mg, 0.219 mmol), {[4-(3-Boranyl-dihydroxy-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (50 mg, 0.11 mmol, Example 140: step a) and Pd(PPh3)4 (25 mg, 0.02 mmol) were combined in aqueous Na2CO3 (2M, 500 μL), ethanol (500 μL) and toluene (1 mL). The reaction was heated to 80° C. overnight. The resulting residue was dissolved into EtOAc and washed with brine. The organic layers were dried (MgSO4) and the solvent was removed in vacuo followed by preparative TLC purification (30% EtOAc/hexanes) that yielded the title compound (20 mg, 29%). ESI-MS (m/z): Calcd. for C24H24CIN3O6S3: 582.1 (M+1); found: 582.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:10][CH2:11][C@H:12]([CH2:16][N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][CH:20]=[N:21][C:22]=3[NH:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:13]([OH:15])[CH3:14])=[CH:5][CH:4]=1.N1[C-]=NN=N1.C([NH2+]C(C)C)(C)C.[CH:61]([N:64]([CH:78]([CH3:80])[CH3:79])[P:65](N(C(C)C)C(C)C)[O:66][CH2:67][CH2:68][C:69]#[N:70])([CH3:63])[CH3:62]>ClCCl>[CH:78]([N:64]([CH:61]([CH3:63])[CH3:62])[P:65]([O:66][CH2:67][CH2:68][C:69]#[N:70])[O:15][C@H:13]([CH3:14])[C@@H:12]([CH2:16][N:17]1[CH:25]=[N:24][C:23]2[C:18]1=[N:19][CH:20]=[N:21][C:22]=2[NH:26][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:11][O:10][C:9]([C:41]1[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=1)([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([CH3:80])[CH3:79]
Reactant: COc1ccc(C(OC[C@H](Cn2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@@H](C)O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)N(C(C)C)P(OCCC#N)N(C(C)C)C(C)C
Agent: CC(C)[NH2+]C(C)C
Agent: [c-]1nnn[nH]1
Solvent: ClCCl
Product: COc1ccc(C(OC[C@H](Cn2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@@H](C)OP(OCCC#N)N(C(C)C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.7 %

Procedure:
To a stirred solution of 53 (0.7 g, 1.08 mmol) in 20 ml of anhydrous dichloromethane was added diisopropylammonium tetrazolide (0.18 g) followed b) 0.52 g (1.72 mmol) of 2-cyanoethyl N,N,N′,N′-tetraisopropylphosphordiamidite. After being stirred at room temperature for 20 hrs the reaction was concentrated, and the residue portioned between ethyl acetate and saturated NaHCO3. The organic phase was washed with saturated NaCl, dried over Na2SO4 and concentrated in vacuo. The crude phosphoramidite was p twice by re-dissolving in small (˜10 ml) amount of ethyl acetate, diluting with hexane (100 ml), allowing precipitate as an oil and decanting the liquid. Drying in vacuo afforded 0.9 g (99%) of 54 as an amorphous white solid. 31P NMR (DMSO-d6): δ 145.96, 145.03.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[C:11]([Br:12])=[CH:10][S:9][CH:8]=1.Cl[C:14]([O:16][CH3:17])=[O:15]>C1COCC1>[CH3:17][O:16][C:14]([C:7]1[C:11]([Br:12])=[CH:10][S:9][CH:8]=1)=[O:15]
Reactant: COC(=O)Cl
Reactant: Brc1cscc1Br
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COC(=O)c1cscc1Br
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 54.5 %

Procedure:
A solution of isopropylmagnesium chloride (1.0 g, 9.7 mmol, 1.2 eq.) in THF (5 mL) was added to a solution of 3,4-dibromo-thiophene (2 g, 8.3 mmol, 1.0 eq.) in THF (15 mL), and stirred for 3 hours while the temperature was maintained at 0-5° C. in an ice/salt bath. Methyl chloroformate (1.6 g, 16.9 mmol, 2 eq.) was added dropwise with stirring. The resulting solution was stirred for an additional 16 hours at room temperature. The reaction was then quenched with water (1 mL). The resulting mixture was concentrated under vacuum, then diluted with EtOAc (50 mL). The resulting mixture was washed 1N HCl (1×100 mL) and saturated aqueous NaCl (2×100). The organic layer was concentrated to provide a crude residue, which was applied onto a silica gel column and eluted with EtOAc/PE (1:50) to yield 4-bromothiophene-3-carboxylic acid methyl ester (1.0 g) as a light yellow solid.
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([NH:28]C(=O)OC(C)(C)C)([CH2:8][N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:18]=[CH:19][C:12]=3[CH2:11][CH2:10]2)[CH2:4][O:3]1.CC1(C)OCC(NC(=O)OC(C)(C)C)(CNC2C=CC(CCCCCCCC)=CC=2)CO1>>[NH2:28][C:5]([CH2:8][N:9]1[CH2:15][CH2:14][C:13]2[CH:16]=[C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:18]=[CH:19][C:12]=2[CH2:11][CH2:10]1)([CH2:6][OH:7])[CH2:4][OH:3]
Reactant: CCCCCCCCc1ccc2c(c1)CCN(CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1)CC2
Agent: CCCCCCCCc1ccc(NCC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1
Product: CCCCCCCCc1ccc2c(c1)CCN(CC(N)(CO)CO)CC2
Yield: 48 %

Procedure:
When the product of Step F was substituted for tert-butyl 2,2-dimethyl-5-((4-octylphenylamino)methyl)-1,3-dioxan-5-yl-carbamate in Example 1, Step B, the identical process afforded the title compound in 48% yield., as creamy paste. 1H-NMR (CDCl3) 0.87 (tr, 3H, J=6.93 Hz); 1.12-1.28 (m, 12H); 2.5 (tr, 2H, J=7.77 Hz); 2.59 (s, 2H); 2.76-2.83 (m, 8H); 3.52 (s, 4H); 6.78-6.94 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[C:10]3[C:15]([CH:16]=[CH:17][C:7]=2[C:6]=1[OH:18])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:4].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[C:10]3[C:15]([CH:16]=[CH:17][C:7]=2[C:6]=1[O:18][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:4]
Reactant: CCOC(=O)CBr
Reactant: COC(=O)c1sc2c(ccc3ccccc32)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1c(C(=O)OC)sc2c1ccc1ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an oven-dried 50 mL round bottom flask under a nitrogen atmosphere was added 3-hydroxy-naphtho[1,2-b]thiophene-2-carboxylic acid methyl ester (0.134 g, 052 mmol), ethyl bromoacetate (0.06 mL, 052 mmol), potassium carbonate (0.072 g, 052 mmol) and 20 mL DMF. The resulting mixture was allowed to stir for 16 hours at room temperature. 30 mL water was added to the mixture, at which point a precipitate formed. The solids were collected by filtration and dried in vacuo. 3-ethoxycarbonylmethoxy-naphtho[1,2-b]thiophene-2-carboxylic acid methyl ester was isolated as a white solid (0.116 g, 65%).
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.[CH:27]1([CH:33]=O)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:33][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN)CC1
Reactant: O=CC1CCCCC1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCC2CCCCC2)CC1
Yield: 95.9 %

Procedure:
4-Amino-N-(1-(5-aminopentyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (1 g) as starting compound and cyclohexanecarboxaldehyde (0.32 g) were reacted and treated in the same manner as in Example 121 to give 1.2 g of 4-amino-5-chloro-N-((1-(5-(cyclohexylmethylamino)pentyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:25][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[C:15]([O:20][CH2:21][CH:22]([F:24])[CH3:23])=[N:16][CH:17]=[CH:18][CH:19]=3)[C:7]=2[C:6]=1[CH3:26])=[O:4].[OH-].[Li+].Cl>C1COCC1>[F:24][CH:22]([CH3:23])[CH2:21][O:20][C:15]1[C:14]([NH:13][C:12]2[C:7]3[C:6]([CH3:26])=[C:5]([C:3]([OH:4])=[O:2])[S:25][C:8]=3[N:9]=[CH:10][N:11]=2)=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: COC(=O)c1sc2ncnc(Nc3cccnc3OCC(C)F)c2c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OCC(C)F)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl-4-(2-(2-fluoropropoxy)pyridin-3-ylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylate (333 mg) in THF (10 ml) was added lithium hydroxide (1M; 8 ml) and the reaction stirred at room temperature overnight. The mixture was neutralized with HCl (1M; 8 ml) and concentrated in vacuo. The crude product was purified by chromatography.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[S:31][C:30]4[CH:32]=[C:33](Br)[S:34][C:29]=4[CH:28]=3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].C(OC([N:44]1[C:48]([Sn](CCCC)(CCCC)CCCC)=[CH:47][N:46]=[C:45]1[C@@H:62]1[CH2:66][CH2:65][CH2:64][N:63]1[C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])=O)(C)(C)C>C1(C)C=CC=CC=1.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:70]([O:69][C:67]([N:63]1[CH2:64][CH2:65][CH2:66][C@H:62]1[C:45]1[NH:46][C:47]([C:33]2[S:34][C:29]3[CH:28]=[C:27]([C:24]4[CH:25]=[CH:26][C:21]([C:18]5[NH:17][C:16]([C@@H:12]6[CH2:13][CH2:14][CH2:15][N:11]6[C:9](=[O:10])[C@@H:5]([NH:4][C:3]([O:2][CH3:1])=[O:36])[CH:6]([CH3:8])[CH3:7])=[N:20][CH:19]=5)=[CH:22][CH:23]=4)[S:31][C:30]=3[CH:32]=2)=[CH:48][N:44]=1)=[O:68])([CH3:73])([CH3:71])[CH3:72]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3cc4sc(Br)cc4s3)cc2)[nH]1)C(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc([C@@H]2CCCN2C(=O)OC(C)(C)C)n1C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3cc4sc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4s3)cc2)[nH]1)C(C)C
Yield: 43 %

Procedure:
A mixture of compound 62 (0.131 mmol), compound 61 (0.141 mmol), and Pd(PPh3)4 (0.017 mmol) was refluxed in dry toluene under nitrogen overnight. Solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (eluent: DCM to DCM/MeOH 5%) to give compound 63 as an orange solid in 43% yield. MS (ESI, EI+) m/z=744.6 (MH+).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=2)=[CH:6][CH:5]=1)#[N:2].O1CCCC1>[Ni].CO>[NH2:2][CH2:1][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=2)=[CH:8][CH:9]=1
Reactant: N#CCc1ccc(Nc2ccc(C(N)=O)cn2)cc1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: NCCc1ccc(Nc2ccc(C(N)=O)cn2)cc1
Yield: 103.9 %

Procedure:
Combine 6-(4-cyanomethyl-phenylamino)-nicotinamide (1.8 g), raney nickel (350 mg), tetrahydrofuran (50 mL), and methanol (100 mL) then hydrogenated at 60 PSIG at 40° C. overnight. Filter off catalyst then concentrate on a rotary evaporator to yield 6-[4-(2-amino-ethyl)-phenylamino]-nicotinamide (1.9 g).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:32]([CH3:33])=[CH:31][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:48][CH3:49]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:32]([CH3:33])=[CH:31][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:25]4[CH2:26][CH2:27][N:28]([CH2:48][CH3:49])[CH2:29][CH2:30]4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCI
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCNCC4)c3)sc2c1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN(CC)CC4)c3)sc2c1-c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
To a solution of crude (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(piperazin-1-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)acetate (˜0.144 mmol) in DMF (1.5 mL) was added cesium carbonate (0.094 g, 0.288 mmol), followed by iodoethane (12.6 μL, 0.158 mmol). Reaction mixture was stirred for 1 h, then more iodoethane (5 μL) was added and reaction mixture stirred for 2 h. LC/MS showed incomplete reaction, so more iodoethane (5 μL) was added and reaction mixture stirred overnight. Reaction mixture was diluted with ethyl acetate, washed with 5% lithium chloride solution (2×), brine, dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 10% MeOH/CH2Cl2) to give product. LCMS-ESI+: calc'd for C33H40ClN4O3S: 607.2 (M+H+); Found: 607.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: CCOC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(O)c(Cl)c1
Solvent: C1CCOC1
Product: CCOC(=O)C(C)=Cc1ccc(O)c(Cl)c1
Temperature: 60 °C
Yield: 92.2 %

Procedure:
The mixture of 3-chloro-4-hydroxybenzaldehyde (0.783 g, 5 mmol) and ethyl 2-(triphenylphosphoranylidene)propionate (2.72 g, 7.5 mmol) in anhydrous tetrahydrofuran (25 mL) was heated at 60° C. under nitrogen for 4 hours. The solvent was removed in vacuo and purified by silica gel chromatography (40% EtOAc in hexanes) to provide ethyl 3-(3-chloro-4-hydroxyphenyl)-2-methylacrylate (515) (1.11 g, 95.2%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14](B4OC(C)(C)C(C)(C)O4)[CH:15]=3)[CH:10]=2)[O:3]1.Br[C:30]1[CH:51]=[CH:50][C:33]2[NH:34][C:35]([C@@H:37]3[CH2:42][C@@H:41]4[C@@H:39]([CH2:40]4)[N:38]3[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[N:36][C:32]=2[CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:7][C:6]1([CH3:8])[C:2]([CH3:1])([CH3:28])[O:3][B:4]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([C:30]2[CH:51]=[CH:50][C:33]4[N:34]=[C:35]([C@@H:37]5[CH2:42][C@@H:41]6[C@@H:39]([CH2:40]6)[N:38]5[C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])[NH:36][C:32]=4[CH:31]=2)[CH:13]=[CH:12]3)[O:5]1
Reactant: CC1(C)OB(c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2cc(Br)ccc2[nH]1
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: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2ccc(-c3ccc4cc(B5OC(C)(C)C(C)(C)O5)ccc4c3)cc2[nH]1
Temperature: 100 °C
Yield: 50 %

Procedure:
Pd(Ph3P)4 (0.382 g, 0.330 mmol) was added to a degassed solution of 2,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene (2.51 g, 6.61 mmol), (1R,3S,5R)-tert-butyl 3-(5-bromo-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (2.5 g, 6.6 mmol) and sodium carbonate (2.78 g, 33.0 mmol) in DME (52.9 mL) and water (13.2 mL) at 80° C. The reaction was backfilled with nitrogen, sealed and heated at 100° C. overnight. The volatiles were removed under vacuum and the residue was taken in EtOAc, washed with water, and the water layer was extracted with EtOAc. The combined organic layers were filtered through a pad of diatomaceous earth (CELITE®) and dried over Na2SO4, concentrated and purified on a BIOTAGE® (dry loaded on silica gel, charged to a 90 g silica gel cartridge and eluted with a gradient of 0 to 70% ethyl acetate in hexanes, then flushed with 10% MeOH/DCM) to yield (1R,3S,5R)-tert-butyl 3-(6-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (1.8 g, 3.3 mmol, 49% yield) as yellowish solid. LC-MS retention time 1.905 min; m/z 552.47 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 10% MeOH/90% H2O/0.1% TFA and Solvent B was 10% H2O/90% MeOH/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3](=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[Na].[Cl:11][C:12]1[C:22]([Cl:23])=[C:21]([C:24](=O)[C:25](=[CH2:28])[CH2:26][CH3:27])[CH:20]=[CH:19][C:13]=1[O:14][CH2:15][C:16]([OH:18])=[O:17]>C(O)C>[Cl:11][C:12]1[C:22]([Cl:23])=[C:21]([C:24]2[CH:25]([CH2:26][CH3:27])[CH2:28][CH:4]([C:3]([N:2]([CH3:9])[CH3:1])=[O:8])[C:5](=[O:6])[CH:7]=2)[CH:20]=[CH:19][C:13]=1[O:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: CC(=O)CC(=O)N(C)C
Reactant: C=C(CC)C(=O)c1ccc(OCC(=O)O)c(Cl)c1Cl
Agent: [Na]
Solvent: CCO
Product: CCC1CC(C(=O)N(C)C)C(=O)C=C1c1ccc(OCC(=O)O)c(Cl)c1Cl

Procedure:
N,N-Dimethylacetoacetamide (13.7 g, 0.1062M) was added at 65° to a solution of sodium (2.44 g, 0.1062M) dissolved in ethanol (200 ml). After 3-5 minutes [2,3-dichloro-4-(2-methylenebutyryl)phenoxy]acetic acid (15.2 g, 0.05M) was added and the suspension was stirred at reflux for 4 hours, cooled and concentrated. The residue was taken up in water, acidified with hydrochloric acid and extracted with chloroform. The organic extracts were washed with water and concentrated. The residue was recrystallized from acetonitrile and then from a mixture of water and acetic acid to obtain 2,3-dichloro-4-[4-(dimethylaminocarbonyl)-6-ethyl-3-oxo-1-cyclohexen-1-yl]phenoxy-acetic acid, m.p. 211° (d).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[O:17][C:18]([CH3:24])=[C:19]([CH2:21][CH2:22][OH:23])[N:20]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].O[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC([N+](C(OCC)=O)=[N-])=O)C>O1CCCC1>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[O:17][C:18]([CH3:24])=[C:19]([CH2:21][CH2:22][O:23][C:26]3[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=3)[N:20]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=Cc1ccc(O)cc1
Reactant: Cc1oc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)nc1CCO
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1oc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)nc1CCOc1ccc(C=O)cc1
Temperature: -5 °C
Yield: 74.1 %

Procedure:
The compound of Step C 3.61 g (10.9 mmole), 1.53 g (12.5 mmole) 4-hydroxybenzaldehyde, and 3.29 g (12.5 mmole) triphenylphosphine were dissolved in 30 ml tetrahydrofuran with stirring, under nitrogen. The solution was chilled to −5° C. and a solution of 1.97 ml (12.5 mmole) diethyldiazodicarboxylate in 10 ml. tetrahydrofuran was added over 10 minutes, with stirring. The reaction exothermed to +3° C. The bath was removed and the reaction stirred under nitrogen for 3 days. The reaction was stripped, dissolved in methylene chloride and placed in the freezer. The diethoxycarbonylhydrazine was then filtered off and the filtrate was chromatographed on 400 ml silica, eluting with a 5% isopropyl alcohol/hexane. The appropriate fractions were bulked and stripped to give 3.52 g (74%) product which was used without further purification.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[Cl:21])[C:15](O)=O.N>>[Cl:11][C:12]1[CH:13]=[C:14]([C:15]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Clc1ccc(-c2nc(-c3cccnc3)no2)cc1Cl

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3,4-dichlorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.64 (ddd, J=8.0, 5.1, 0.8 Hz, 1H), 7.82 (d, J=8.3 Hz, 1H), 8.14-8.19 (m, 1H), 8.40 (d, J=2.0 Hz, 1H), 8.56 (dt, J=7.9, 2.0 Hz, 1H), 8.75 (dd, J=5.2, 1.6 Hz, 1H), 9.29 (dd, J=2.2, 1.0 Hz, 1H) ppm; MS (DCI/NH3) m/z 292 (M+H)+.