Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][C:3]=1[F:18].[Zn](CC)[CH2:20][CH3:21].CCCCCCC.C(=O)(O)[O-].[Na+]>O1CCOCC1.O>[CH2:20]([C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][C:3]=1[F:18])[CH3:21]
Reactant: CC[Zn]CC
Reactant: CC(C)(C)OC(=O)n1ccc2cc(F)c(Br)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCCCCCC
Solvent: O
Product: CCc1cc2c(ccn2C(=O)OC(C)(C)C)cc1F
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 6-bromo-5-fluoro-1H-indole-1-carboxylate (1.57 g, 5.0 mmol) in dioxane (10 mL) was added a solution of Et2Zn in heptane (3.5 mL, 1.0M, 3.5 mmol) at room temperature. The mixture was kept stirring for 30 min at 90° C. and then cooled down to 0° C., into which saturated sodium bicarbonate was added dropwise. The mixture was then treated with water and extracted with CH2Cl2. The organic layer was dried over Na2SO4 and evaporated. The resulting oil was passed through a silica plug and eluted with 10% ethyl acetate in hexane. The eluent was evaporated to give tert-butyl 6-ethyl-5-fluoro-1H-indole-1-carboxylate as an oil which was solidified upon standing (1.25 g, 95%).
Reaction SMILES: C([NH:8][N:9]1[C:15](=[O:16])[CH2:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]1=2)(OC(C)(C)C)=O.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:31][CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>CN(C=O)C.C(Cl)Cl>[ClH:31].[NH2:8][N:9]1[C:15](=[O:16])[CH:14]([CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C:13]2[CH:12]=[CH:20][CH:19]=[CH:18][C:17]=2[C:24]2[CH:23]=[CH:22][CH:21]=[CH:11][C:10]1=2
Reactant: CC(C)(C)C(=O)CCl
Reactant: CC(C)(C)OC(=O)NN1C(=O)Cc2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)C(=O)CC1C(=O)N(N)c2ccccc2-c2ccccc21
Product: Cl
Temperature: 60 °C
Reaction time: 17 h

Procedure:
A solution of 5-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (0.2 g, 0.617 mmol) (Example 3) in DMF was treated with Cs2CO3 (0.3 g, 0.925 mmol) and warmed to 60° C. To this reaction mixture was added 1-chloro-3,3-dimethyl-2-butanone (0.096 mL, 0.74 mmol) (Aldrich) and stirring was continued for 17 h. After cooling to 23° C., the mixture was diluted with CH2Cl2, washed with several portions of brine and dried over Na2SO4. The title compound was isolated as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[S:11][CH:12]=1.[NH:25]1[CH:29]=[C:28]([CH2:30][CH2:31]O)[CH:27]=[N:26]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:31][CH2:30][C:28]3[CH:29]=[N:25][NH:26][CH:27]=3)=[CH:15][CH:14]=2)[S:11][CH:12]=1
Reactant: COC(=O)Cc1c(-c2ccccc2Cl)csc1-c1ccc(O)cc1
Reactant: OCCc1cn[nH]c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)Cc1c(-c2ccccc2Cl)csc1-c1ccc(OCCc2cn[nH]c2)cc1
Reaction time: 8 h
Yield: 92.4 %

Procedure:
To a solution of methyl [4-(2-chlorophenyl)-2-(4-hydroxyphenyl)thien-3-yl]acetate (0.485 g, 1.35 mmol), 2-(1H-pyrazol-4-yl)-ethanol (0.166 g, 1.48 mmol), and PPh3 (0.388 g, 1.4 mmol) in THF (3 mL) was added at 0° C. diethyl azo-dicarboxylate (DEAD) (0.265 g, 0.24 mL, 1.52 mmol). The solution was stirred overnight and the solvent removed. The product was purified directly by flash chromatography (20:1 CHCl3:MeOH) to yield methyl (4-(2-chlorophenyl)-2-{4-[2-(1H-pyrazol-4-yl)ethoxy]phenyl}thien-3-yl)acetate (0.565 g). This material was reacted as in Example 1, Steps 7 and 8 to yield 2-(4-(2-chlorophenyl)-2-{4-[2-(1H-pyrazol-4-yl)ethoxy]phenyl}thien-3-yl)-N-(diaminomethylene)acetamide (0.151 g) as a white solid. mp 71-72° C.; 1H NMR (500 MHz, DMSO-d6) δ: 2.90 (t, 2H, J=6.7 Hz), 3.50 (s, 2H), 4.15 (t, 2H, J=6.9 Hz), 7.05 (m, 2H), 7.44 (m, 6H), 7.55 (m, 2H), 7.70 (s, 1H). MS (ES) m/z 478.1 ([M−H]−). MS (ES) m/z 538.1 ([M+CH3COO]−). MS (ES) m/z 957.3 ([2M−H]−). Anal. Calcd for C24H22ClN5O2S.H2O: C, 57.88; H, 4.86; N, 14.06. Found: C, 55.49; H, 5.37; N, 14.80. A description of 2-(1H-pyrazol-4-yl)-ethanol can be found in Jones and Mann, J. Am. Chem. Soc., 75, 4048-52; 1953.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@H:4]([NH:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([F:18])=[C:13]([CH3:19])[CH:12]=1)[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][C:23]=1[CH3:30].C(N(CC)CC)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[F:18][C:14]1[C:15]([CH3:17])=[CH:16][C:11]([NH:10][C@H:4]([CH2:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([F:21])=[C:23]([CH3:30])[CH:24]=2)[C:3]([O:2][CH3:1])=[O:20])=[CH:12][C:13]=1[CH3:19]
Reactant: Cc1cc(C=O)ccc1F
Reactant: COC(=O)[C@@H](CCCCN)Nc1cc(C)c(F)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: COC(=O)[C@@H](CCCCNCc1ccc(F)c(C)c1)Nc1cc(C)c(F)c(C)c1
Temperature: 25 °C
Reaction time: 63 h
Yield: 87.5 %

Procedure:
To a solution of (R)-6-amino-2-(4-fluoro-3,5-dimethyl-phenylamino)-hexanoic acid methyl ester (0.400 g, 1.009 mmol), 4-fluoro-3-methylbenzaldehyde (0.139 g, 1.009 mmol), and triethylamine (0.204 g, 2.018 mmol) in 10 mL of dichloroethane, was added NaBH(OAc)3 (0.299 g, 1.413 mmol). After stirring at room temperature for 63 h, the reaction was quenched with 30 mL of saturated NaHCO3 solution and the reaction mixture was extracted with ethyl acetate (30 mL×3). The combined organic extracts dried (Na2SO4), filtered, and concentrated under reduced pressure. The product was isolated by Flash column chromatography (silica gel column) eluting with 0-10% methanol/dichloromethane to give the title compound as brown oil (0.357 g, 87% yield). GC-MS: tR=7.5 min; m/z 404 (M+).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[C:9]([NH:10][C:11]2[C:16]3[CH2:17][C:18]([CH3:21])([CH3:20])[CH2:19][C:15]=3[N:14]=[C:13]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=3[F:29])[N:12]=2)=[CH:8][CH:7]=[N:6][CH:5]=1.[OH-].[Na+].Cl>O1CCOCC1>[Cl:28][C:26]1[CH:25]=[CH:24][C:23]([F:29])=[C:22]([C:13]2[N:12]=[C:11]([NH:10][C:9]3[C:4]([C:3]([OH:30])=[O:2])=[CH:5][N:6]=[CH:7][CH:8]=3)[C:16]3[CH2:17][C:18]([CH3:20])([CH3:21])[CH2:19][C:15]=3[N:14]=2)[CH:27]=1
Reactant: COC(=O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1CC(C)(C)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC1(C)Cc2nc(-c3cc(Cl)ccc3F)nc(Nc3ccncc3C(=O)O)c2C1
Temperature: 60 °C
Yield: 79 %

Procedure:
To a solution of 4-[2-(5-Chloro-2-fluoro-phenyl)-6,6-dimethyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino]-nicotinic acid methyl ester (178 mg, 0.42 mmol) in dioxane (10 mL) was added NaOH (aq.) (451 μL, 0.44 mmol, 0.97N solution). The mixture was heated at 60° C. for 1 h, then cooled, and HCl (aq.) (425 μL, 0.44 mmol, 1.03N solution) was added. On addition, the acid precipitated from solution and was filtered and dried in vacuo, to give 137 mg of product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5](Br)[CH:4]=1.C([Li])CCC.C[O:22][C:23]([CH:25]1[CH2:31][CH2:30][C:29]2([C:33]3([CH3:38])[O:37][CH2:36][CH2:35][O:34]3)[CH2:32][CH:26]1[C:27](=[O:39])[O:28]2)=O>O1CCCC1>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([C:23]([CH:25]2[CH2:31][CH2:30][C:29]3([C:33]4([CH3:38])[O:37][CH2:36][CH2:35][O:34]4)[CH2:32][CH:26]2[C:27](=[O:39])[O:28]3)=[O:22])[CH:4]=1
Reactant: COc1cc(Br)c(OC)c2ccccc12
Reactant: COC(=O)C1CCC2(C3(C)OCCO3)CC1C(=O)O2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C(=O)C2CCC3(C4(C)OCCO4)CC2C(=O)O3)c(OC)c2ccccc12
Yield: 65 %

Procedure:
Following the method described in Example 4, a solution of 3.2 g of 1,4-dimethoxy-3-bromo-naphthalene in anhydrous tetrahydrofuran was treated at -78° C. with n-butyllithium and then added to a solution in anhydrous tetrahydrofuran of 2.7 g of the compound prepared in Example 3. After silica gel column purification 2.8 g of the title compound was obtained (65% yield) m/z 426 (M+.): IR (film): 1780 cm-1 (C=O, five membered ring lactone), 1670 cm-1 (C=O, benzylic ketone); PMR (CDCl3): inter alia: δ 1.4 (s, CH3), 3.85 (s, two OCH3), 3.9 (s, --O--CH2 --CH2 --O--), 6.9 (s, aromatic H) and 7.4-8.4 (m, four aromatic H).
Reaction SMILES: C[C:2]1[CH:7]=[CH:6]C(S(OC)(=O)=O)=CC=1.CCO/C=[C:17]1\[C:18]([O:20][C:21]([C:23]2[CH:28]=CC=CC=2)=[N:22]\1)=O>C(#N)C>[CH3:28][CH2:23][CH:21]1[O:20][CH2:18][CH2:17][N:22]1[C:2]1([CH2:7][CH3:6])[O:20][CH2:18][CH2:17][N:22]1[C:21]1([CH2:23][CH3:28])[O:20][CH2:18][CH2:17][NH:22]1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CCO/C=C1/N=C(c2ccccc2)OC1=O
Solvent: CC#N
Product: CCC1OCCN1C1(CC)OCCN1C1(CC)NCCO1

Procedure:
Loading amount: acetonitrile (30 mL), methyl p-tosylate (1 mmol, 0.15 mL), EtOx (88.4 mmol, 8.92 mL), Yield: 8 g, Degree of polymerization (DP)=93, Polydispersity index (PDI: Mw/Mn)=1.1)
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH2:33][CH2:34][O:35][CH3:36])[CH:30]=2)[N:25]=[CH:24][N:23]=1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH2:33][CH2:34][O:35][CH3:36])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Reactant: COCCOc1ccc2ncnc(Cl)c2c1
Product: COCCOc1ccc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2c1
Yield: 18.8 %

Procedure:
The title compound was prepared from 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea from Example 1A (138 mg, 0.5 mmol) and 4-chloro-6-(2-methoxyethoxy)quinazoline from Example 40A Step 5 (119 mg, 0.5 mmol) using the procedure of Example 16C. The crude product was purified by column chromatography (25-100% EtOAc/hexanes) to give 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea (45 mg, 0.094 mmol, 20%). 1H NMR (300 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.01 (s, 1H), 8.62 (s, 1H), 7.94 (d, 1H), 7.74-7.64 (m, 3H), 7.60 (s, 1H), 7.42 (t, 1H), 7.27 (d, 1H), 6.99 (d, 1H), 6.48 (s, 1H), 4.37-4.31 (m, 2H), 3.78-3.71 (m, 2H), 3.34 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 478 (M+H)+.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[BrH:14].N([O-])=O.[Na+].[Br-]>O.C(OCC)C>[Br:14][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Br
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1
Agent: O=N[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 70 °C

Procedure:
To the solution of 7.92 g (43 mmol) 3-amino-5-nitro-benzoic acid in 4 ml water in an ice bath 48.8 ml (434 mmol, 10 eq) of aq 48% HBr are added. A saturated aqueous solution of 4.05 g (59 mmol, 1.35 eq) sodium nitrit is added over 10 min. The obtained solution is added to the solution of 9.36 g (65 mmol, 1.5 eq) cupper bromide in 48.8 ml (434 mmol, 10 eq) of aq 48% HBr at 70° C. The mixture is heated for 45 min at 70° C. After cooling to rt diethylether is added and the organic layer is washed with water until neutral pH is reached. Drying over sodium sulfate and evaporation of the solvent at reduced pressure to give the product as yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:35][CH2:36][CH2:37][CH3:38])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23](Br)[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClCCl.C(N(CC)CC)C.[CH3:49][OH:50].CN([CH:54]=[O:55])C>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:35][CH2:36][CH2:37][CH3:38])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23]([C:49]([O:55][CH3:54])=[O:50])[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO
Reactant: CN(C)C=O
Reactant: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(Br)c1
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(C(=O)OC)c1
Temperature: 90 °C

Procedure:
A mixture of 4-[5-(3-bromo-4-cyclohexyloxy-phenyl)-6-butyl-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (Example 65, 0.816 mmol, 480 mg), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (0.163 mmol, 133 mg), 1,1′-bis(diphenylphosphino)ferrocene (0.163 mmol, 90.4 mg), triethyl amine (1.63 mL), MeOH (16.3 mL) and DMF (16.3 mL) was heated at 90° C. under carbon monoxide atmosphere (24 psi) overnight. The reaction mixture was partitioned between ethyl acetate (200 mL) and saturated aq. sodium bicarbonate solution (200 mL). The ethyl acetate layer was washed again with saturated aq. sodium bicarbonate solution (2×200 mL) and dried over sodium sulfate. Purification by column chromatography on silica gel using 20-50% ethyl acetate in hexanes gave 4-[6-butyl-5-(4-cyclohexyloxy-3-methoxycarbonyl-phenyl)-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester as light yellow, thick oil (428 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH2:13][CH2:14][CH2:15][CH3:16])=[CH:10]/[CH:11]=O)=[CH:5][CH:4]=1.[C:17]([CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:19][CH3:20])=[O:18]>C(Cl)(Cl)(Cl)Cl.ClCCl>[CH3:20][O:19][C:17](=[O:18])/[CH:21]=[CH:11]/[CH:10]=[C:9](/[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)\[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCC/C(=C\C=O)c1ccc(OC)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCC/C(=C\C=C\C(=O)OC)c1ccc(OC)cc1

Procedure:
As described in Example 99, (E)-3-(4-methoxyphenyl)-2-heptenal (10 g) was treated with (carbomethoxymethylene)triphenylphosphorane (17 g) in carbon tetrachloride (70 mL) and dichloromethane (15 mL) for 4 days at room temperature. The ester was isolated in the normal way and purified by HPLC (ether-hexane; 1:9) to furnish 8 g of (E,E)15-(4-methoxyphenyl)-2,4-nonadienoic acid methyl ester, as an oil.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:20]([F:28])[CH:19]=[CH:18][C:17]=1B(O)O>O1CCCC1.C(=O)([O-])[O-].[Na+].[Na+].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>[F:28][C:20]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:16]([F:15])[CH:17]=[CH:18][C:19]=1[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: OB(O)c1ccc(F)c(-c2cccnc2)c1F
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
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: C1CCOC1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cccnc4)c3F)cnc2n1
Temperature: 65 °C

Procedure:
A mixture of 2-(3-bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol (256 mg, 1.0 mmol) and 2,4-difluoro-3-(pyridin-3-yl)benzeneboronic acid (352 mg, 1.5 mmol) in tetrahydrofuran (3 ml) and sodium carbonate (1.25 ml of a 2M solution in water, 2.5 mmol) was degassed with nitrogen for 10 min. Tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol) was added and this mixture was heated at 65° C. for 24 h. The reaction was cooled to ambient temperature then partitioned between dichloromethane and saturated aqueous sodium hydrogencarbonate. The organics were dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification by chromatography on silica gel eluting with dichloromethane (containing 1% conc. ammonia) on a gradient of methanol (1-5%) gave 2-[3-(2,4-difluoro-3-(pyridin-3-yl)phenyl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol as a pale yellow oil which solidified on standing (200 mg, 44%). Bis-hydrochloride salt (from ethyl acetate/ethanol): δH (360 MHz, d6-DMSO) 1.56 (6H, s), 7.62 (1H, t, J 9), 7.79-7.84 (1H, m), 7.86 (1H, s), 7.88 (1H, s), 8.32 (1H, d, J 8), 8.54 (1H, s), 8.80 (1H, d, J 5), 8.98 (1H, s), 9.27 (1H, dd, J 7 and 3).
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:20])[C:9]([S:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)([CH3:11])[CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I[CH2:22][CH3:23].[H-].[Na+].O>CN(C=O)C.CCOC(C)=O>[CH:1]1([NH:7][C:8](=[O:20])[C:9]([S:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:22][CH3:23])=[CH:17][CH:18]=2)([CH3:11])[CH3:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(Sc1ccc(O)cc1)C(=O)NC1CCCCC1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(SC(C)(C)C(=O)NC2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
N-Cyclohexyl-2-[(4-hydroxyphenyl)thio]-2-methylpropanamide (prepared as example 67) was dissolved in DMF and to the solution was added iodoethane. The solution was cooled in an ice-water bath and treated with NaH (60% in mineral oil). After stirring in the ice-water bath for half an hour and at rt for 2 h, water was added followed by EtOAc. After stirring for 10 min., the layers were separated and the organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (silica, hexanes:EtOAc, 6:1) to provide the desired product as a white solid. LCMS: (M+H)+=322.2.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[NH:23]1[CH2:27][CH2:26][CH2:25][C@@H:24]1[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([N:23]5[CH2:27][CH2:26][CH2:25][C@@H:24]5[CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=5)=[O:20])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: c1ccc(C[C@H]2CCCN2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCC[C@@H]1Cc1ccccn1

Procedure:
Following Example 103, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50 mg, 0.20 mmol) in DMF at room temperature was added (R)-2-(pyrrolidin-2-ylmethyl)pyridine (0.24 mmol), followed by the addition of DIPEA (0.056 ml, 0.32 mmol). Finally, HATU (0.067 grams, 0.18 mmol) was added and the reaction mixture was heated as a slurry at 50 C for 4 hours. The reaction mixture was conc. in vacuo and taken into a large volume of EtOAc and the organic phase was washed with dilute aqueous bicarb, water and then saline and dried (Na2SO4), then concentrated to a residue. The crude material was purified by preparative RP-HPLC to give 216 as a lyophilized solid. MS: (ESI+)=458.5
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([S:9][CH3:10])[S:4][N:3]=1.[CH:11]1([CH2:17]O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CN=2)C=CC=CC=1.CN1CCN(C(N=NC(N2CCN(C)CC2)=O)=O)CC1>C1COCC1.O>[CH:11]1([CH2:17][O:1][C:2]2[C:6]([C:7]#[N:8])=[C:5]([S:9][CH3:10])[S:4][N:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CSc1snc(O)c1C#N
Reactant: OCC1CCCCC1
Agent: CN1CCN(C(=O)N=NC(=O)N2CCN(C)CC2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccn2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CSc1snc(OCC2CCCCC2)c1C#N
Reaction time: 72 h
Yield: 46.9 %

Procedure:
3-hydroxy-5-methylsulfanyl-isothiazole-4-carbonitrile (10 g, 58 mmol) is dissolved in anhydrous THF (200 mL). Cyclohexylmethanol (11 mL, 87.1 mmol) and diphenyl-2-pyridyl-phosphine (30.5 g, 116 mmol) are added to the solution. Diazenedicarboxylic acid bis(N′-methylpiperazide) (32.7 g, 116 mmol) is slurried in anhydrous THF (200 mL) and added dropwise over 1 hour to the reaction. The reaction is stirred at room temp. for 3 days and then diluted with water and extracted with EtOAc (100 mL×3). The combined organics are then dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography (20% EtOAc/hexane) followed by a second chromatography (10% EtOAc/hexane) provides 3 (7.3 g, 52%). 1H NMR (d6 DMSO): δ 4.18 (2H, d, J=6.3 Hz), 2.76 (3H, s), 1.64–1.81 (6H, m), 1.16–1.27 (3H, m), 1.00–1.13 (2H, m).
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:27]([Cl:28])=[CH:26][C:10]3[N:11]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:12](S(C)(=O)=O)=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.[OH:35][CH:36]1[CH2:40][CH2:39][CH:38]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:37]1>CN(C=O)C.CCOC(C)=O>[C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:27]([Cl:28])=[CH:26][C:10]3[N:11]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:12]([O:35][CH:36]4[CH2:40][CH2:39][CH:38]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:37]4)=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1
Reactant: CCOC(=O)C1CCC(O)C1
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCC(Oc2nc3cc(-c4ccc(-c5ccccc5)cc4)c(Cl)cc3n2COCC[Si](C)(C)C)C1
Temperature: 80 °C

Procedure:
To a solution of 5-(biphenyl-4-yl)-6-chloro-2-(methylsulfonyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (Intermediate 3, 0.350 g, 0.682 mmol) and ethyl 3-hydroxycyclopentanecarboxylate (Intermediate 9, 0.647 mL, 4.09 mmol) in 2.3 mL DMF was added DSU (0.514 mL. 3.41 mmol) dropwise via syringe. The reaction was heated overnight at 80° C., then diluted with EtOAc, and washed with H2O and brine. The aqueous layer was further extracted with EtOAc, and the combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification of the resulting residue by preparative TLC (25% EtOAc/hexanes) furnished the desired compound as a pale yellow oil. LCMS: calculated for C33H39ClN2O4Si 591.21, observed m/e 591.04 M+ (Rt 3.06/4 min).