Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[C@H:16]([CH2:20][C:21]([O:23]CC)=[O:22])[CH2:15][CH2:14]3)[CH:5]=[CH:4][CH:3]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].[CH3:53][NH:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1.[Li+].[OH-]>C1COCC1.O.CCO.CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[CH3:53][N:54]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[C@H:16]([CH2:20][C:21]([OH:23])=[O:22])[CH2:15][CH2:14]3)[CH:5]=[CH:4][CH:3]=1
Reactant: CNc1ccccc1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCc3cccc(Cl)n3)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CN(c1ccccc1)c1cccc(CCOc2ccc3c(c2)CC[C@H]3CC(=O)O)n1
Temperature: 100 °C
Reaction time: 18 h
Yield: 46.1 %

Procedure:
An oven-dried flask charged with ethyl {(1S)-5-[2-(6-chloro-2-pyridinyl)ethoxy]-2,3-dihydro-1H-inden-1-yl}acetate (Example 471, 100 mg, 0.277 mmol), Pd(OAc)2 (1.3 mg, 0.01 mmol), 2-(di-t-butylphosphino)biphenyl (3.3 mg, 0.02 mmol), and sodium tert-butoxide (37.4 mg, 0.39 mmol) was purged with argon. Toluene (1 mL) and N-methyl aniline (59.6 mg, 0.56 mmol) were added, and the mixture was stirred at 100° C. for 18 h. The reaction mixture was then cooled to rt, loaded on an ion-exchange resin column (SCX sorbent, Varian, strong cation exchange), and eluted with MeOH followed with NH3 (1N solution in MeOH). The fractions containing the desired product were combined and then concentrated under reduced pressure. The crude ester was then dissolved in a mixture of THF (2 mL), H2O (2 mL), and EtOH (1 mL), to which LiOH (26.8 mg, 1.12 mmol) was added. The reaction mixture was stirred at rt for 18 h, concentrated under reduced pressure, and then purified by preparative HPLC. The fractions containing the desired fractions were concentrated under reduced pressure, and then dissolved in a mixture of CH2Cl2 and a saturated aqueous solution of NaHCO3. The aqueous phase was brought to pH 4 using HCl (1N aqueous solution), the organic layer separated, dried, and then concentrated to give the product (51.4 mg, 46%). 1H NMR (400 MHz, CDCl3) δ 1.70-1.75 (m, 1H), 2.34-2.43 (m, 2H), 2.70-2.87 (m, 3H), 3.43-3.50 (m, 3H), 3.71 (s, 3H), 4.32 (t, 2H), 6.41 (d, 1H), 6.66 (d, 1H) 6.75 (s, 1H), 6.79 (d, 1H), 7.03 (d, 1H), 7.25 (d, 1H), 7.27 (d, 1H), 7.43 (t, 1H), 7.49-7.53 (m, 3H); LC-MS: RT=2.32 min, (M+H)+ 403.3.
Reaction SMILES: C([O:8][NH:9][C:10]([CH2:12][N:13]([CH3:32])[C:14]([C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH2:30][CH3:31])=[N:21][N:22]2[CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:18][CH:17]=1)=[O:15])=[O:11])C1C=CC=CC=1>[OH-].[OH-].[Pd+2]>[OH:8][NH:9][C:10]([CH2:12][N:13]([CH3:32])[C:14]([C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH2:30][CH3:31])=[N:21][N:22]2[CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:18][CH:17]=1)=[O:15])=[O:11]
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)N(C)CC(=O)NOCc3ccccc3)ccc12
Agent: [Pd+2]
Agent: [OH-]
Product: CCc1nn(C2CCCC2)c2cc(C(=O)N(C)CC(=O)NO)ccc12
Yield: 78.1 %

Procedure:
This compound was prepared according to the method of Example 38, using 126 mg (0.290 mmol, 1.0 equiv) 1cyclopentyl-3ethyl-1H-indazole-6-carboxylic acid (benzyloxycarbamoyl-methyl)-methyl amide as starting material and 40 mg of Pd(OH)2/C (Pearlman's catalyst) as catalyst, to give 78 mg (78%) of a light tan powder: mp 63° C. (dec); HRMS calcd for C18H24N4O3+H: 345,19285. Found: 345.1912.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].Br[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C>[CH:15]1([O:8][C:7]2[C:2]([OH:1])=[C:3]([C:11](=[O:13])[CH3:12])[CH:4]=[CH:5][C:6]=2[O:9][CH3:10])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1ccc(C(C)=O)c(O)c1O
Reactant: BrC1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C(C)=O)c(O)c1OC1CCCC1
Temperature: 110 °C

Procedure:
A mixture of 1-(2,3-dihydroxy-4-methoxyphenyl)ethanone (10 g, 55 mmol), bromocyclopentane (6.0 mL, 56 mmol), potassium carbonate (15.5 g, 112 mmol), and anhydrous DMF (100 mL) was heated at 110° C. under N2 for 17 h and then allowed to cool to rt. The mixture was poured into 0.5N HCl (600 mL) and extracted with diethyl ether (250 mL×2). The combined extracts were dried, filtered, concentrated, and purified by silica gel chromatography (1:0→17:3; hexanes:ethyl acetate) to give 1-[3-(cyclopentyloxy)-2-hydroxy-4-methoxyphenyl]ethanone: MS (ESI): 251.2.
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=CC=C[CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:29](=[O:34])[CH2:30][CH:31](C)C.C(O[C@H]1CC[C@H](N)CC1)CC.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:28][CH:23]([CH3:24])[CH2:22][CH2:21][N:7]([CH:1]1[CH2:2][CH2:3][CH:4]([O:34][CH2:29][CH2:30][CH3:31])[CH2:5][CH2:6]1)[C:8](=[O:20])[NH:9][C:10]1[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=1
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Reactant: CC(C)CC=O
Agent: CCCO[C@H]1CC[C@H](N)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: CCCOC1CCC(N(CCC(C)C)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
{2-[3-(3-Methyl-butyl)-3-(4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid was prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid using isovaleraldehyde, trans-4-propoxy-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:14])[C@H:6]([CH2:8][C:9]1[N:13]=[CH:12][NH:11][CH:10]=1)[NH2:7].C(N(CC)CC)C.[CH3:22][O:23][C:24]1[CH:36]=[CH:35][C:27]([CH2:28][O:29][C:30](N=[N+]=[N-])=[O:31])=[CH:26][CH:25]=1>C(Cl)(Cl)Cl>[CH3:3][O:4][C:5](=[O:14])[C@H:6]([CH2:8][C:9]1[N:13]=[CH:12][NH:11][CH:10]=1)[NH:7][C:30]([O:29][CH2:28][C:27]1[CH:35]=[CH:36][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1)=[O:31]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: COc1ccc(COC(=O)N=[N+]=[N-])cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 79.9 %

Procedure:
To a suspension of 10.0 g of L-histidine methyl ester dihydrochloride in 200 ml of dry chloroform were added 18.4 ml of a triethylamine and 10.2 g of 4-methoxybenzyloxycarbonylazide under cooling, and the mixture was stirred for 16 hours at 0° C. The reaction mixture was concentrated under reduced pressure, and a 5% aqueous sodium bicarbonate solution was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: chloroform/methanol=10/1 by volume) to obtain 11.0 g of N-(4-methoxybenzyloxycarbonyl)-L-histidine methyl ester as a yellow oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:29])=[C:8]([N:10]2[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[C:12]([Cl:27])[C:11]2=[O:28])[CH:9]=1.C([O:33][CH2:34][C:35](Cl)=[O:36])(=O)C.C(N(CC)CC)C.[OH-].[Na+]>CO.O1CCCC1>[Cl:27][C:12]1[C:11](=[O:28])[N:10]([C:8]2[CH:9]=[C:4]([CH:5]=[CH:6][C:7]=2[F:29])[CH2:3][NH:2][C:34](=[O:33])[CH2:35][OH:36])[C:15]([CH3:16])=[CH:14][C:13]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[F:26]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(CN)ccc1F
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(CNC(=O)CO)ccc1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A 10 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with 1-[5-(aminomethyl)-2-fluorophenyl]-3-chloro-4-[(2,4 difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one hydrochloride (250 mg, 0.56 mmol), acetoxyacetyl chloride (66 μL, 0.62 mmol), triethylamine (195 μL, 1.4 mmol) and tetrahydrofuran (4.0 mL). After stirring at 25° C.for 5 min the reaction was completed by LC-MS. NaOH (2.5M, 2.24 mmol, 1.0 mL) and MeOH (2.0 mL) was added and stirred for 10 min to give the title compound. The reaction mixture was acidified with concentrated HCl and extracted with ethyl. The organic phase was dried with Na2SO4 and concentrated in vacuo to obtain (217 mg, 78%) of the desired product as a yellow solid. 1H NMR (400 MHz, (CD3OD) δ 7.6 (q, J=7.6 and 6.9 Hz, 1H), 7.44 (m, 1H), 7.34 (m, 2H), 7.22 (m, 2H), 6.63 (s, 1H), 5.35 (s, 2H), 4.41 (s, 2H), 4.0 (s, 2H), 2.05 (s, 3H) ppm. ES-HRMS m/z 467.0957 (M+H calcd for C22H19ClF3N2O4 requires 467.0980).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C@H:12]([OH:14])[CH3:13])=[CH:7][CH:6]=2.[CH2:15]([Sn](CCCC)(CCCC)C=C)[CH2:16]CC>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.O1CCOCC1>[CH:15]([C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C@H:12]([OH:14])[CH3:13])=[CH:7][CH:6]=2)=[CH2:16]
Reactant: C[C@@H](O)c1ccc2cnc(Cl)cc2c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C=Cc1cc2cc([C@@H](C)O)ccc2cn1
Temperature: 150 °C
Yield: 50.2 %

Procedure:
1,4-Dioxane (5 mL) was degassed with nitrogen, (R)-1-(3-chloro-isoquinolin-6-yl)-ethanol (208 mg, 1 mmol), tributyl(vinyl)tin (951 mg, 0.9 mL, 3 mmol) and bis(triphenylphosphine)palladium(II) dichloride (70 mg, 0.1 mmol) were added and the reaction mixture was heated at 150° C. in a microwave reactor for 1 hour. Additional tributyl(vinyl)tin (0.3 mL, 1 mmol) and bis(triphenylphosphine)palladium(II) dichloride (70 mg, 0.1 mmol) was added and the reaction mixture was heated at 150° C. in a microwave reactor for 1 hour. The reaction mixture was cooled to room temperature and the mixture was filtered thorough filter aid and the filter pad was washed with ethyl acetate. The filtrate was evaporated and the residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 4:1 to 2:1 followed by silica gel chromatography using iso-hexanes/ethyl acetate 3:1 to afford the title compound (100 mg, 50%) as a white solid. 1H NMR (300 MHz, CDCl3) δ1.60 (d, J=6.5 Hz, 3H), 2.11 (br s, 1H), 5.10 (q, J=6.5 Hz, 1H), 5.52 (dd, J=10.6, 1.6 Hz, 1H), 6.40 (dd, J=17.2, 1.6 Hz, 1H), 6.95 (dd, J=17.2, 10.7 Hz, 1H), 7.57 (s, 1H), 7.58 (dd, J=8.5, 1.6 Hz, 1H), 7.78 (br s, 1H), 7.94 (d, J=8.5 Hz, 1H), 9.19 (s, 1H). LCMS (m/z) 200 [M+H], Tr=1.50 min.
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[CH:9][N:4]2[N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1>ClCCl>[F:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:2]2[S:6][C:5]3=[N:7][CH:8]=[CH:9][N:4]3[N:3]=2)=[CH:13][CH:12]=1
Reactant: Brc1nn2ccnc2s1
Reactant: Oc1ccc(F)cc1
Solvent: ClCCl
Product: Fc1ccc(Oc2nn3ccnc3s2)cc1
Temperature: 135 °C
Yield: 52.9 %

Procedure:
A mixture of 2-bromo-imidazo[2,1-b][1,3,4]thiadiazole (1.0 g, 4.90 mmol) and 4-fluorophenol (2.2 g, 19.60 mmol) was heated under microwave irradiation at 135° C. for 3.5 hours. On cooling, the mixture was diluted with dichloromethane (7 mL), adsorbed in silica and purified by column chromatography (Biotage™/Flash, silica, methanol:dichloromethane 0.2:9.8 to 2:8) to give 2-(4-fluoro-phenoxy)-imidazo[2,1-b][1,3,4]thiadiazole as a white solid (610 mg, 53% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][C:4]1[S:5][CH:6]=[CH:7][N:8]=1.[O:10]1[C:14]2([CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)[O:13][CH2:12][CH2:11]1>CCOCC>[CH3:1][N:2]([CH2:3][C:4]1[S:5][C:6]([C:17]2([OH:20])[CH2:18][CH2:19][C:14]3([O:13][CH2:12][CH2:11][O:10]3)[CH2:15][CH2:16]2)=[CH:7][N:8]=1)[CH3:9]
Reactant: CN(C)Cc1nccs1
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: CCOCC
Product: CN(C)Cc1ncc(C2(O)CCC3(CC2)OCCO3)s1

Procedure:
The title compound was prepared as a white solid from dimethyl-thiazol-2-ylmethyl-amine, as prepared in the previous step, and 1,4-dioxa-spiro[4.5]decan-8-one in ether using the procedure described in Step A of Example 33.
Reaction SMILES: [CH3:1][C:2]([NH:25]C(=O)OC(C)(C)C)([CH3:24])[CH2:3][C:4]1[C:12]2[C:7](=[C:8]([O:13][C@@H:14]([CH3:23])[C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.Cl.C(=O)([O-])O.[Na+]>C(Cl)Cl.O1CCOCC1>[CH3:1][C:2]([NH2:25])([CH3:24])[CH2:3][C:4]1[C:12]2[C:7](=[C:8]([O:13][C@@H:14]([CH3:23])[C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: C[C@H](Oc1cccc2c(CC(C)(C)NC(=O)OC(C)(C)C)c[nH]c12)C(=O)N1CCOCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@H](Oc1cccc2c(CC(C)(C)N)c[nH]c12)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
To a solution of tert-butyl (1,1-dimethyl-2-{7-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethoxy]-1H-indol-3-yl}ethyl)carbamate (166 mg, 0.373 mmol) in methylene chloride (2 mL) is added a 4N hydrogen chloride solution in dioxane (0.5 mL), and the mixture is stirred at room temperature for 3 hours. The reaction solution is poured into a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate, and the solvent is evaporated. The obtained crude product is purified by silica gel column chromatography (a saturated ammonia solution in chloroform ) a saturated ammonia solution in chloroform-methanol=50:1) to give the title compound (68.4 mg, yield: 53%).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[S:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>>[S:26]1[CH:30]=[CH:29][N:28]=[C:27]1[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5]
Reactant: c1cscn1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3C#N)c2)cn1
Product: N#Cc1ccccc1-c1cccc(-n2cnc(C(=O)c3nccs3)c2)c1

Procedure:
This compound is prepared by method C using compound 12d and thiazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH:11]1[C:19]2[N:14]([CH:15]=[CH:16][C:17](=O)[CH:18]=2)[CH2:13][CH:12]=1>>[CH2:11]1[CH:19]2[N:14]([CH2:15][CH:16]=[C:17]([C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[NH:7][CH:6]=3)[CH2:18]2)[CH2:13][CH2:12]1
Reactant: O=c1ccn2c(c1)C=CC2
Reactant: Clc1ccc2[nH]ccc2c1
Product: Clc1ccc2[nH]cc(C3=CCN4CCCC4C3)c2c1

Procedure:
The 5-chloro-1H-indole (1.00 g, 6.63 mmol) and 7-indolizinone (1.39 g, 9.95 mmol) were converted to product by the procedure of Example 2 to give 595 mg. (33.1%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:12])[O:9][CH2:8][CH:7]([CH2:10][OH:11])[CH2:6][O:5]1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH2:13]([O:11][CH2:10][CH:7]1[CH2:8][O:9][C:4]([CH3:12])([CH3:3])[O:5][CH2:6]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)OCC(CO)CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)OCC(COCc2ccccc2)CO1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.8 %

Procedure:
To a stirred suspension of sodium hydride (2.0 g, 42.02 mmol, 50% dispersion in oil) in tetrahydrofuran (20.0 ml) was added dropwise a solution of (2,2-dimethyl-[1,3]dioxan-5-yl)-methanol (4.09 g, 28.01 mmol) in tetrahydrofuran (10 ml) at 0° C. it was then stirred at 0° C. for 10 min and at 25° C. for 20 min. After that time, the reaction was cooled back to 0° C. and benzyl bromide (4.7 ml, 39.22 mmol) and tetrabutylammonium iodide (0.1 g, 0.27 mmol) were added. The reaction was stirred overnight at 25° C. After such time, the reaction was diluted with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate, filtered and then concentrated in vacuo. Purification on an AnaLogix Intelliflash system (120 g column, 15% ethyl acetate/hexanes to 25% ethyl acetate/hexanes) afforded 5-benzyloxymethyl-2,2-dimethyl-[1,3]dioxane (5.28 g, 80%) as a clear oil: 1H NMR (300 MHz, CDCl3) δ ppm 1.40 (s, 3H, CH3), 1.43 (s, 3H, CH3), 1.97-2.09 (m, 1H, CH), 3.53 (d, J=6.8 Hz, 2H, OCH2), 3.79 (dd, Jgem=11.9 Hz, J=6.4 Hz, 2H, 2×OCH of 2×OCH2), 3.98 (dd, Jgem=11.9 Hz, J=4.3 Hz, 2H, 2×OCH of 2×OCH2), 4.52 (s, 2H, OCH2Ar), 7.27-7.39 (m, 5H, Ar).
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([C:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[C:21]([CH3:33])[CH:20]=3)([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4].[BH4-].[Na+]>>[CH3:34][N:2]([CH3:1])[C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([C:14]([CH2:15][CH3:16])([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]([OH:32])[C:28]([CH3:30])([CH3:31])[CH3:29])=[C:21]([CH3:33])[CH:20]=3)[CH2:17][CH3:18])[CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)N(C)C)sc2c1
Agent: [BH4-]
Agent: [Na+]
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)N(C)C)sc2c1
Yield: 97.4 %

Procedure:
6-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzo[b]thiophene-2-carboxylic acid dimethylamide (235 mg, 0.490 mmol) is reduced by NaBH4 (37 mg, 0.980 mmol) as in Step F11 to afford the title compound (230 mg, 100%).
Reaction SMILES: O[C:2]1[N:7]=[C:6]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[C:4]([CH3:16])[CH:3]=1.[OH-].[Na+].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:2]1[N:7]=[C:6]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[C:4]([CH3:16])[CH:3]=1
Reactant: Cc1cc(O)nc(C=Cc2ccccc2)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(Cl)nc(C=Cc2ccccc2)n1

Procedure:
212 mg (1 mmol) of 6-hydroxy-4-methyl-2-(2-phenylethenyl)-pyrimidine in 1 ml of phosphorus oxychloride are boiled under reflux for 35 minutes under nitrogen. When cool, the reaction mixture is poured onto ice, and the aqueous solution is neutralised with sodium hydroxide solution and extracted several times with ether. The ether extracts are washed with water and saturated sodium chloride solution, dried over CaCl2, filtered with suction and concentrated. Purification is effected by sublimation in a bulb tube oven at 150° oven temperature and in vacuo (0.1 mm Hg ≠0.13 mbar). Colourless crystals of m.p. 71°-73° are obtained.
Reaction SMILES: [P:1]([OH:39])([OH:38])([O:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:13]=[C:8]2[C:7]([C:21](=[O:37])[C:22]2[C:27]([F:28])=[CH:26][CH:25]=[C:24]([NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31])[C:23]=2[F:36])=[CH:6]1)=[O:2].[OH-].[Na+:41]>C1COCC1.O>[P:1]([O-:38])([O-:39])([O:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:13]=[C:8]2[C:7]([C:21](=[O:37])[C:22]2[C:27]([F:28])=[CH:26][CH:25]=[C:24]([NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31])[C:23]=2[F:36])=[CH:6]1)=[O:2].[Na+:41].[Na+:41]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(COP(=O)(O)O)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(COP(=O)([O-])[O-])c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.4 %

Procedure:
To a solution of (5-(4-chlorophenyl)-3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)methyl dihydrogen phosphate (396 mg, 0.66 mmol) in THF (20 mL) was added dropwise a solution of NaOH (58 mg, 1.45 mmol) in 0.3 mL of H2O and 4 mL of THF at rt. The reaction was stirred at rt for 4 h, and then filtered to give the title compound as a white solid (401 mg, 94.4%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C:9]2([CH3:22])[CH3:21])=[CH:4][CH:3]=1.Br[C:24]1[C:25](=[O:32])[N:26]([CH3:31])[CH:27]=[C:28]([Br:30])[CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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].O1CCOCC1>[Br:30][C:28]1[CH:29]=[C:24]([NH:1][C:2]2[N:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C:9]3([CH3:22])[CH3:21])=[CH:4][CH:3]=2)[C:25](=[O:32])[N:26]([CH3:31])[CH:27]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)C(C)(C)C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3(C)C)cn2)c1=O
Temperature: 25 °C
Yield: 79.3 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with tert-butyl 4-(6-aminopyridin-3-yl)-3,3-dimethylpiperazine-1-carboxylate 190b (950 mg, 3.1 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (1240 mg, 4.6 mmol), 1,4-dioxane (30 mL), and cesium carbonate (2015 mg, 6.2 mmol). After bubbling nitrogen through the resulting solution for 5 min, Xantphos (179 mg, 0.31 mmol) and tris(dibenzylideneacetone)dipalladium(0) (283 mg, 0.31 mmol) were added. The reaction mixture was subjected to three cycles of vacuum/argon flush and heated at reflux for 10 h. After this time the reaction was cooled to room temperature and filtered. The filtrate was partitioned between ethyl acetate (50 mL) and water (10 mL). The aqueous layer was separated and extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with brine (30 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 4:1 petroleum ether/ethyl acetate to afford 190c (1.21 g, 79%). LCMS: [M+H]+ 492.1.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][N:13]=[C:12]2[CH2:17]C(OCC)=O)=[O:5].[OH-].[Na+]>C(O)C.O>[Cl:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][N:13]=[C:12]2[CH3:17])=[O:5]
Reactant: CCOC(=O)Cc1ncnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ncnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Yield: 94.7 %

Procedure:
A mixture of 8-(2,6-dichlorobenzoylamino)-4-ethoxycarbonylmethylquinazoline (90 mg) and 1N sodium hydroxide solution (1 ml) in ethanol (5 ml) was refluxed for 30 minutes. The mixture was diluted with water, and the resulting precipitate was collected by filtration and washed with water to give 8-(2,6-dichlorobenzoylamino)-4-methylquinazoline (70 mg).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]2[CH:14]=1)[CH2:2][C:3]#[CH:4].Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[Cl:13][C:12]1[C:7]2[N:8]([CH:14]=[C:5]([CH2:1][CH2:2][C:3]#[C:4][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:6]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Brc1ccccn1
Reactant: C#CCCc1cn2cccc(Cl)c2n1
Product: Clc1cccn2cc(CCC#Cc3ccccn3)nc12

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-(but-3-ynyl)-8-chloro-imidazo[1,2-a]pyridine (500 mg, 2.44 mmol) and 2-bromopyridine (405 mg, 2.57 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 293 mg (1.04 mmol, 43%) of 8-chloro-2-(4-(pyridin-2-yl)but-3-ynyl)H-imidazo[1,2-a]pyridine as a white solid (M.P.=106-107° C.).