Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.Cl[C:11]([O:13][CH2:14][C:15]1[C:27]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1)=[O:12]>>[CH:23]1[C:24]2[CH:15]([CH2:14][O:13][C:11]([NH:1][C:2]3([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]3)=[O:12])[C:16]3[C:26](=[CH:27][CH:19]=[CH:18][CH:17]=3)[C:25]=2[CH:20]=[CH:21][CH:22]=1
Reactant: NC1(C(=O)O)CCCC1
Reactant: O=C(Cl)OCc1cccc2c1Cc1ccccc1-2
Product: O=C(NC1(C(=O)O)CCCC1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.6 %

Procedure:
To a chilled (ice bath) suspension of aminocyclopentanecarboxylic acid (1.05 g, 8.13 mmol) in alumina-filtered dioxane (8 mL) was added 10% Na2CO3 (16.5 mL). The reaction mixture became clearer (but not completely clear) after 10% Na2CO3 was added. A solution of a fluorenylmethyl chloroformate (2.11 g, 8.16 mmol in 12 mL dioxane) was then slowly added to the reaction mixture, which became (and remained) cloudy. The reaction mixture was allowed to warm to room temperature (~20° C.) and was stirred overnight under N2. The reaction mixture was poured into ice water (~150 mL) and extracted three times with anhydrous ether. (Some product went into the ether layer). The aqueous layer was chilled in an ice bath, acidified with concentrated HCl to pH of about 2, and extracted three times with ethyl acetate (3×50 mL). The combined ethyl acetate layers were washed with 0.1N HCl and H2O. The ether and ethyl acetate layers were dried over MgSO4, combined and concentrated. Flash chromatography (40-50% ethyl acetate/hexane) gave the title compound as a white foam in a yield of 16.6% (0.476 g (1.35 mmol). DEI m+@m/z 351.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[OH:29][CH2:30][C:31]([CH3:36])([CH3:35])[C:32](O)=[O:33].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[OH:33][CH2:32][C:31]([CH3:36])([CH3:35])[C:30]([O:19][C@H:18]1[CH2:20][CH2:21][C@@:22]2([CH3:23])[C:16](=[CH:15][CH2:14][C@@H:13]3[C@@H:24]2[CH2:25][CH2:26][C@@:27]2([CH3:28])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH2:17]1)=[O:29]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)(CO)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)C(C)(C)CO)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 4 h
Yield: 13 %

Procedure:
A solution of 11.6 g of cholesterol and 3.6 g of hydroxypivalic acid in 80 ml of toluene is treated with 1 g of p-toluenesulphonic acid and boiled for 4 hours. The reaction mixture is treated with water and extracted with ether. The organic phase is dried and concentrated and the residue is purified over silica gel with petroleum ether/ether (4:1). There are obtained 1.9 g of cholest-5-en-3β-yl 3-hydroxy-2,2-dimethyl-propionate, m.p. 174°-176° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]([C:13]([NH:15][C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:34])[C:24]4[CH:29]=[C:28](Cl)[CH:27]=[CH:26][C:25]=4[N+:31]([O-:33])=[O:32])[CH:19]=[CH:20][CH:21]=3)=[O:14])[CH:10]=[CH:9][N:8]=2)[CH2:3][CH2:2]1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]([C:13]([NH:15][C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:34])[C:24]4[CH:29]=[C:28]([N:39]5[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]5)[CH:27]=[CH:26][C:25]=4[N+:31]([O-:33])=[O:32])[CH:19]=[CH:20][CH:21]=3)=[O:14])[CH:10]=[CH:9][N:8]=2)[CH2:3][CH2:2]1
Reactant: CN1CCNCC1
Reactant: O=C(Nc1cccc(NC(=O)c2cc(Cl)ccc2[N+](=O)[O-])c1)c1ccnc(N2CCOCC2)c1
Product: CN1CCN(c2ccc([N+](=O)[O-])c(C(=O)Nc3cccc(NC(=O)c4ccnc(N5CCOCC5)c4)c3)c2)CC1
Yield: 89 %

Procedure:
In an analogous procedure to that described in the fifth paragraph of the portion of Note c) which is concerned with the preparation of starting materials, N-[3-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-5-chloro-2-nitrobenzamide was reacted with 1-methylpiperazine to give N-[3-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-5-(4-methylpiperazin-1-yl)-2-nitrobenzamide in 89% yield; NMR Spectrum: (DMSOd6) 2.2 (s, 3H), 2.41 (m, 4H), 3.5 (m, 8H), 3.71 (t, 4H), 7.07 (m, 3H), 7.31 (m, 3H), 7.48 (d, 1H), 8.03 (d, 1H), 8.16 (s, 1H), 8.26 (d, 1H), 10.35 (broad s, 1H), 10.44 (broad s, 1H); Mass Spectrum: M+H+ 546.
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]([F:27])([F:26])[O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[N:16][C:15]([C:18]3[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=3)=[N:14]2)=[CH:9][CH:8]=1>CCO.O>[N:2](=[CH:22]/[C:21]1[CH:24]=[CH:25][C:18]([C:15]2[N:16]=[CH:17][N:13]([C:10]3[CH:11]=[CH:12][C:7]([O:6][C:5]([F:27])([F:26])[F:4])=[CH:8][CH:9]=3)[N:14]=2)=[CH:19][CH:20]=1)\[NH2:3]
Reactant: O=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: N/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 0 °C

Procedure:
To a 250 mL round-bottomed flask containing hydrazine hydrate (64% aq solution; 7.27 mL, 15.0 mmol) in EtOH (100 mL) at 80° C. was added 4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-benzaldehyde (5.00 g, 1.50 mmol) portionwise over 5 min. The solution was stirred at reflux for an additional 3 h before being diluted with H2O (300 mL) and cooled to 0° C. The precipitated product was collected by vacuum filtration as a white solid (4.89 g, 93%) mp 222-226° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.22 (d, J=8.2 Hz, 2H), 7.84-7.79 (m, 2H), 7.66 (d, J=8.3 Hz, 2H), 7.41 (d, J=8.2 Hz, 2H), 7.29 (s, 1H), 5.63 (br s, 2H); ESIMS m/z 348 (M+H).
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48](=[O:68])[C:49]4[C:50]([O:60][C:61]=3[C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)=[C:51]([C:55]3[CH:56]=[N:57][NH:58][CH:59]=3)[N:52]=[CH:53][CH:54]=4)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O.[ClH:77]>CO.O>[ClH:77].[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:48](=[O:68])[C:49]4[C:50]([O:60][C:61]=3[C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=3)=[C:51]([C:55]3[CH:56]=[N:57][NH:58][CH:59]=3)[N:52]=[CH:53][CH:54]=4)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(-c5cn[nH]c5)nccc4c3=O)cc2)CCC1
Agent: Cl
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: O
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(-c5cn[nH]c5)nccc4c3=O)cc2)CCC1
Yield: 81 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, (1-{4-[4-oxo-2-phenyl-8-(1H-pyrazol-4-yl)-4H-pyrano[2,3-c]pyridin-3-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was dissolved in a mixture of MeOH (0.75 mL), water (4.25 mL) and 1 M HCl (0.1 mL) and then chromatographed on a 2 g C18 cartridge {gradient 15 to 50% MeOH in water+1 M HCl (60 μL in each 5 mL of eluent)} to give the title compound as a white solid (12.1 mg, 81%, 2 steps). 1H NMR (400 MHz, DMSO-d6): δ 8.66 (d+br s, J=5.1 Hz, 4H), 8.29 (s, 2H), 7.80 (d, J=5.0 Hz, 1H), 7.55-7.41 (m, 7H), 7.30 (d, J=8.2 Hz, 2H), 2.59-2.51 (m, 4H), 2.23-2.12 (m, 1H), 1.85-1.74 (m, 1H). LCMS (Method E): RT=2.79 min, [M+H]+=435.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[N:10]=[C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[S:12][CH:13]=1)(=O)=O.[NH:26]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:25][O:24][C:16]1[CH:15]=[C:14]([C:11]2[S:12][CH:13]=[C:9]([CH2:8][CH2:7][CH2:6][N:26]3[CH2:32][CH2:31][CH2:30][N:29]([CH2:6][CH2:7][CH2:8][C:9]4[N:10]=[C:11]([C:14]5[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=5)[S:12][CH:13]=4)[CH2:28][CH2:27]3)[N:10]=2)[CH:19]=[C:18]([O:20][CH3:21])[C:17]=1[O:22][CH3:23]
Reactant: COc1cc(-c2nc(CCCOS(C)(=O)=O)cs2)cc(OC)c1OC
Reactant: C1CNCCNC1
Product: COc1cc(-c2nc(CCCN3CCCN(CCCc4csc(-c5cc(OC)c(OC)c(OC)c5)n4)CC3)cs2)cc(OC)c1OC

Procedure:
4-(3-Methanesulfonyloxypropyl)-2-(3,4,5-trimethoxy-phenyl)thiazole (152 mg) and homopiperazine (20 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[C:7]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=3)[C:15]([O:17][CH3:18])=[O:16])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[Na].N1C2C(=CC=CC=2)C=[CH:24]1.CI>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:24][N:3]1[C:11]2[C:6](=[C:7]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=3)[C:15]([O:17][CH3:18])=[O:16])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: COC(=O)c1cccc(-c2cccc3[nH]ccc23)c1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CI
Product: COC(=O)c1cccc(-c2cccc3c2ccn3C)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a suspension of sodium hydride (0.20 g) in anhydrous toluene (23 ml) was added a hot solution of methyl 3-(indol-4-yl)benzoate (1.16 g) in toluene (5.8 ml). Since a sodium salt did not form, N,N-dimethylformamide (0.5 ml) was introduced. An evolution of gas occurred with the formation of the orange sodium salt of the indole. After being stirred for 20 minutes methyl iodide was added thereto and the mixture was stirred at 60° C. for four hours. Then the sodium iodide was filtered off and washed with toluene. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with a mixture of hexane and acetone (20:1) to afford methyl 3-(1-methylindol-4-yl)benzoate (0.35 g).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH:6]([N:19]1[C@H:22]([CH2:23][CH2:24][C:25](=[O:31])[C@@H:26]2[CH2:30][CH2:29][CH2:28][O:27]2)[C@H:21]([N:32]2[C:36](=[O:37])[C:35]3=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]3[C:33]2=[O:42])[C:20]1=[O:43])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:8].N1C(C)=CC=CC=1C>C1COCC1>[Cl:3][CH:6]([N:19]1[C@H:22]([CH2:23][CH2:24][C:25](=[O:31])[C@@H:26]2[CH2:30][CH2:29][CH2:28][O:27]2)[C@H:21]([N:32]2[C:36](=[O:37])[C:35]3=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]3[C:33]2=[O:42])[C:20]1=[O:43])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:8]
Reactant: COc1ccc(COC(=O)C(O)N2C(=O)[C@@H](N3C(=O)c4ccccc4C3=O)[C@H]2CCC(=O)[C@@H]2CCCO2)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: COc1ccc(COC(=O)C(Cl)N2C(=O)[C@@H](N3C(=O)c4ccccc4C3=O)[C@H]2CCC(=O)[C@@H]2CCCO2)cc1
Reaction time: 1 h

Procedure:
A solution of thionyl chloride (530 μl, 7.27mmol) in THF (3 ml) was added to 4-methoxybenzyl (RS)-2-hydroxy-2-[(3S, 4R)-4-[3-oxo-3-[(S)-tetrahydrofuran-2-yl]propyl]-3-phthalimidoazetidin-2-on-1-yl]acetate (2.59 g, 4.84 mmol) and 2,6-lutidine (850 μl, 7.30 mmol) in THF (50 ml) at -20° C. After stirring for 1 h, the reaction mixture was filtered through a pad of celite, and the filtrate evaporated in vacuo. Toluene was added and re-evaporated to yield 4-methoxybenzyl (RS)-2-chloro-2-[(3S,4R)-4-[3-oxo-3-[(S)-tetrahydrofuran-2-yl]propyl]-3-phthalimidoazetidin-2-on-1-yl]acetate.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[C:5]([C:7]([O:9]C)=[O:8])[N:6]=1.[OH-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[S:3][C:4]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1
Reactant: COC(=O)c1nc(Cl)sc1CCc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nc(Cl)sc1CCc1cccc(Cl)c1

Procedure:
The product from step (ii) (3.46 g) was treated with sodium hydroxide (0.7 g) in tetrahydrofuran (15 ml) and water (15 m) at room temperature. After 3 h the mixture was partitioned between 2M HCl and ethyl acetate. The organic phase was collected, dried (MgSO4) and solvent evaporated under reduced pressure to leave a colourless solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=O.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=2)[N:8]=[CH:7][N:6]=1
Reactant: O=c1[nH]cnc2ccc(I)cc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2ccc(I)cc12

Procedure:
6-Iodoquinazolin-4(3H)-one (10 g, 37 mmol) was refluxed in POCl3 (100 mL) overnight. Then POCl3 was removed in vacuo. The residue was dissolved in CH2Cl2 (500 mL). The organic phase was washed with water (100 mL) and dried (MgSO4). Then CH2Cl2 was removed in vacuo and 1404-174 was obtained (5.7 g, 53%): LC-MS: 291 [M+1]+, 1H NMR (CDCl3): δ 7.81 (d, J=9.0 Hz, 1H), 8.21 (dd, J1=9.0 Hz, J2=1.8 Hz, 1H), 8.65 (d, J=1.8 Hz, 1H), 9.06 (s, 1H).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][C:9]=1[CH2:16][OH:17].[C:18](=[O:21])([O-])O.[Na+]>ClCCl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:7][C:8]1[CH:13]=[C:12]([CH2:14][O:15][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)[CH:11]=[CH:10][C:9]=1[CH2:16][O:17][CH:5]1[CH2:4][CH2:3][CH2:2][CH2:18][O:21]1
Reactant: C1=COCCC1
Reactant: OCc1ccc(CO)c(Br)c1
Reactant: O=C([O-])O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Brc1cc(COC2CCCCO2)ccc1COC1CCCCO1
Reaction time: 1 h
Yield: 88 %

Procedure:
3,4-Dihydro(2H)pyran (7.22 g, 84.9 mmol) was added dropwise to a solution of 2-bromo-1,4-benzenedimethanol (7.76 g, 35.8 mmol) obtained from Example 1-(1) and p-toluenesulfonic acid monohydrate (340.2 mg, 1.80 mmol) in dichloromethane (180 ml) with stirring at 0° C. The mixture was stirred for 1 hour, and then 3,4-dihydro(2H)pyran (0.8 g, 9.3 mmol) was further added thereto. After the mixture was stirred for 40 minutes, a saturated aqueous solution of sodium hydrogen carbonate (100 ml) was added thereto, then the resulting mixture was stirred for 5 minutes, and the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to chromatography on a silica gel (250 g) column (eluent; ethyl acetate:hexane=1:10) to give the title compound (12.07 g, 88% yield) as an oil.
Reaction SMILES: [S:1]1[C:5]([C:6](=[O:10])[CH:7](Br)[Br:8])=[CH:4][C:3]2[CH:11]=[CH:12][C:13]3[C:18]([C:2]1=2)=[CH:17][CH:16]=[C:15]([C:19](=[O:23])[CH:20](Br)[Br:21])[CH:14]=3.P([O-])(OCC)OCC.C(N(CC)CC)C>C1COCC1>[S:1]1[C:5]([C:6](=[O:10])[CH2:7][Br:8])=[CH:4][C:3]2[CH:11]=[CH:12][C:13]3[C:18]([C:2]1=2)=[CH:17][CH:16]=[C:15]([C:19](=[O:23])[CH2:20][Br:21])[CH:14]=3
Reactant: O=C(c1ccc2c(ccc3cc(C(=O)C(Br)Br)sc32)c1)C(Br)Br
Agent: CCOP([O-])OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc2c(ccc3cc(C(=O)CBr)sc32)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
1,1′-(naphtho[1,2-b]thiophene-2,7-diyl)bis(2,2-dibromoethanone) (10b) (180 g, 310 mmol) obtained as above was dissolved in 500 ml of THF and the solution was cooled to 0° C. A mixture of diethyl phosphite (80 ml, 620 mmol) and triethylamine (86 ml, 210 mmol) in 50 ml THF was added dropwise to the solution which was kept on an ice bath. After the addition, the ice bath was removed and the reaction mixture was stirred at room temperature for 2 hr. The volume of THF was reduced by rotary evaporation to obtain a solid residue which was washed with pentane to afford 1,1′-(naphtho[1,2-b]thiophene-2,7-diyl)bis(2-bromoethanone) as a brown solid (10c) (110 g, 84%).
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].C([Li])CCC.CCCCCC.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]C>C1COCC1.C(O)C>[CH2:10]([O:9][C:3](=[O:8])[CH2:4][C:5](=[O:6])[CH2:7][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH3:24])[CH3:11]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCCCCCCCCCCCCCCCBr
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCCC(=O)CC(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of sodium hydride (1.2 g, 50 mmol) in THF, distilled ethyl acetoacetate (4.16 g, 32 mmol) was added dropwise. The resulting mixture was stirred for 30 min at room temperature and then cooled at −78° C. A solution of n-butyllithium in hexane (16.1 mL, 35.2 mmol) was added dropwise. After stirring for an additional 1 h at 0° C., 1-bromohexadecane (19.1 mmol) in THF was added and the mixture was stirred for 12 h. Ethanol (15 mL) was added slowly at room temperature. The resulting solution was filtered through a Celite pad, concentrated in vaccum and purified by chromatography on silica gel to give the 3-oxo-nonadecanoic acid ethyl ester as a solid. Anal. C21H40O3: Calcd: C, 74.07; H, 11.84; O, 14.09. Found: C, 73.98; H, 11.59; O, 14.25. MS (ESIMS): m/z: 340.3.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]=[O:13]>>[CH:12]([C:11]1[CH:10]=[C:5]([CH:4]=[CH:3][C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7])=[O:13]
Reactant: C=O
Reactant: COC(=O)c1ccc(O)cc1
Product: COC(=O)c1ccc(O)c(C=O)c1
Yield: 46.3 %

Procedure:
Proceeding as in Reference 8, but substituting methyl 4-hydroxybenzoate (30.4 g, 0.20 mol, 1.0 eq.) and paraformaldehyde (42.0 g, 1.40 mol, 7.0 eq.), gave methyl 3-formyl-4-hydroxybenzoate (16.7 g) as a white solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[C:6]([O:25][CH3:26])=[C:7]([CH:13]([NH:15][C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][NH:20]4)[CH3:14])[CH:8]=[C:9]([Cl:12])[C:10]=2[Cl:11])[CH2:2]1.C(N(CC)CC)C.[F:34][C:35]([F:45])([F:44])S(O[CH2:40][CH:41]([F:43])[F:42])(=O)=O.CN([CH:49]=[O:50])C>>[F:34][C:35]([F:45])([F:44])[C:49]([OH:50])=[O:25].[F:34][C:35]([F:45])([F:44])[C:49]([OH:50])=[O:25].[Cl:11][C:10]1[C:9]([Cl:12])=[CH:8][C:7]([CH:13]([NH:15][C:16]2[N:24]=[CH:23][N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][NH:20]3)[CH3:14])=[C:6]([O:25][CH3:26])[C:5]=1[CH:3]1[CH2:2][N:1]([CH2:40][CH:41]([F:43])[F:42])[CH2:4]1
Reactant: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(Cl)c1C1CNC1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(Cl)c1C1CN(CC(F)F)C1
Product: O=C(O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 46 %

Procedure:
A solution of N-[1-(3-azetidin-3-yl-4,5-dichloro-2-methoxyphenyl)ethyl]-9H-purin-6-amine (15 mg, 0.038 mmol, from Example 194, Step 8) in DMF (1 mL) was treated with triethylamine (13 μL, 0.095 mmol), cooled to 0° C., treated with 2,2-difluoroethyl trifluoromethanesulfonate (12 mg, 0.058 mmol) and stirred at 0° C. for 20 minutes. The reaction mixture was purified by preparative LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) to give the desired product (12 mg, 46%). 1H NMR (300 MHz, DMSO-d6) δ 8.61 (br s, 1H), 8.40-8.11 (m, 2H), 7.76 (s, 1H), 5.89-5.55 (m, 1H), 4.66-4.33 (m, 7H), 3.90-3.65 (m, 4H), 1.49 (d, J=6.1 Hz, 3H). LCMS for C19H21Cl2F2N6O (M+H)+: m/z=457.1, 459.1. Found: 457.1, 459.1.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[F:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[CH:21]=3)=[O:32])=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3ccc(N)n3)n2)OCCO1
Reactant: O=C(O)c1ncoc1-c1cccc(F)c1
Product: CC(=O)c1csc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(F)c3)n2)n1

Procedure:
Following general procedure B followed by C, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-fluoro-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05: tR=0.84 min; [M+H]+=412.07.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[CH:12][C:3]=12.[CH2:21]([Mg]Br)[CH3:22].O1CCCC1.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[C:7]([CH:8]([OH:9])[CH2:21][CH3:22])=[CH:6][N:5]=[C:4]2[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[CH:12][C:3]=12
Reactant: CC[Mg]Br
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)c(C=O)cnc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)c1cnc2c(ccn2COCC[Si](C)(C)C)c1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.6 %

Procedure:
4-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (117 mg, 0.360 mmol) in tetrahydrofuran (2 mL) was mixed with ethylmagnesium bromide-tetrahydrofuran solution (1.0 M, 1.0 mL, 1.0 mmol) under cooling with ice and stirred at room temperature for one day. After addition of saturated aqueous ammonium chloride, the reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1 (v/v)) to give the title compound as a colorless oil (75.6 mg, yield 62%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].C(N(C(C)C)CC)(C)C.[C:28](Cl)(=[O:30])[CH3:29]>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][N:8]([CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[C:28](=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCCNCCC1OCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(CCO[Si](C)(C)C(C)(C)C)CCC1OCCO1
Temperature: 0 °C
Reaction time: 18 h
Yield: 65.2 %

Procedure:
To an ice-cooled solution of N-(2-(1,3-dioxolan-2-yl)ethyl)-2-((tert-butyldimethylsilyl)oxy)ethanamine (0.85 g, 3.09 mmol) and di-iso-propylethylamine (0.82 mL, 4.63 mmol) was added acetyl chloride (0.26 mL, 3.71 mmol). The reaction mixture was stirred with ice-cooling for 1 hour, then the coolant was removed and stirring continued at RT for 18 hours. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate and the organic phase poured through a hydrophobic frit. The solvent was evaporated at reduced pressure to afford the title compound (0.64 g, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH:23]([F:25])[F:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH3:20])[C:17](O)=[O:18])[C:10](=[O:21])[CH:9]=2)[CH:7]=1.[NH2:26][C:27]1[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH:23]([F:24])[F:25])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH3:20])[C:17]([NH:26][C:27]3[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])=[CH:29][CH:28]=3)=[O:18])[C:10](=[O:21])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(C)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1OC(F)F
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: COc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1OC(F)F

Procedure:
220 mg of crude product of 2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}propanoic acid (racemate) and 89 mg (0.46 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 48 mg (21% of theory)