Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1([C:12]([F:15])([F:14])[F:13])[C:7](F)([F:8])[O:6]C(F)=C(F)[O:3]1.[F:16][C:17]([F:21])=[C:18]([F:20])[F:19]>FC(F)(C(F)(F)F)C(OOC(=O)C(F)(F)C(F)(F)F)=O.C(C(Cl)(F)F)(Cl)(Cl)F>[F:16][C:17]1([F:21])[C:18]([F:20])([F:19])[O:3][C:2]([C:12]([F:15])([F:14])[F:13])=[C:7]([F:8])[O:6]1
Reactant: FC1=C(F)OC(F)(C(F)(F)F)C(F)(F)O1
Reactant: FC(F)=C(F)F
Agent: O=C(OOC(=O)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Solvent: FC(F)(Cl)C(F)(Cl)Cl
Product: FC1=C(C(F)(F)F)OC(F)(F)C(F)(F)O1
Reaction time: 0.03 h

Procedure:
A 240 mL s.s-lined tube was charged with 5.0 g (21 mmol) of monomer 14, 50 mL of CFCl2CF2Cl, 5 mL of cold 3% perfluoropropionyl peroxide catalyst in CFCl2CF2Cl, and 30 g (0.30 mol) of tetrafluoroethylene. The tube was agitated as the mixture warmed; at 20° C., a rapid exotherm carried to 55° C. while the pressure fell to 0 psig. The solid, white polymeric product was heated under vacuum to constant weight, 29.2 g. Analysis of the volatiles by GC indicated the presence of about 1.5 g (30%) of recovered monomer 14. For the polymer, DSC on reheat showed a broad mp, Tonset 271° C., Tpeak 297° C. TGA: 2% weight loss to 400° C., 3.5% weight loss to 440° C. Thus, copolymerization of 14 with TFE occurs readily to give very stable copolymer. A film pressed at 330° C. and 1800 psi for 2 min was clear and tough. ##STR36##
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:44]=[CH:43][C:9]2[N:10]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23]3[CH:28]=[C:27]([C:29]([N:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)=[O:30])[CH:26]=[CH:25][C:24]=3I)[CH:17]=[CH:16]4)=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[F:45][C:46]1[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1.C([O-])(O)=O.[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>[CH2:1]([O:3][C:4]([C:6]1[CH:44]=[CH:43][C:9]2[N:10]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23]3[C:24]([C:49]5[CH:50]=[CH:51][C:46]([F:45])=[CH:47][CH:48]=5)=[CH:25][CH:26]=[C:27]([C:29]([N:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)=[O:30])[CH:28]=3)[CH:17]=[CH:16]4)=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4I)ccc3c1)n2C1CCCCC1
Reactant: OB(O)c1ccc(F)cc1
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+]
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc(F)cc4)ccc3c1)n2C1CCCCC1
Temperature: 90 °C

Procedure:
A mixture of 200 mg (0.29 mmol) Compound 419d 62 mg (0.44 mmol) 4-fluorophenyl-boronic acid, 32 mg (0.029 mmol) Pd(PPh3)4 and 2 mL sat. NaHCO3 in 16 mL degassed MeOH was heated at 90° C. under Ar overnight. The mixture was evaporated to dryness, the residue was taken up in CH2Cl2 and purified on silica gel using CH2Cl21MeOH as eluent to yield 197 mg orange solid.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2.[C:23](OC(=O)C)(=[O:25])[CH3:24].O>N1C=CC=CC=1>[C:23]([O:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
19-Hydroxyandrost-4-ene-3,17-dione (50 g) dissolved in 100 ml of pyridine and 250 ml of acetic anhydride was swirled while being warmed on a steam bath. When solution was complete, the reaction was allowed to stand at room temperature. After two hours ice and water were added and the resultant oil was extracted into ethyl acetate. The organic phase was washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo to give 58 g of the title compound as an amorphous solid. The product, homogeneous by thin-layer chromatography using 1:1 ethyl acetate/Skellysolve B on silica gel, was employed for subsequent reactions without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]([N:12]([CH3:14])[CH3:13])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[O:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1.C(O)CCC>CN(C=O)C.CO>[CH3:13][N:12]([CH3:14])[C:11]1[CH:15]=[CH:16][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:27][C:26]3[CH:25]=[CH:24][C:23]([N:20]4[CH2:21][CH2:22][O:17][CH2:18][CH2:19]4)=[CH:29][CH:28]=3)[N:7]=2)=[CH:9][CH:10]=1
Reactant: CN(C)c1ccc(-c2ccnc(Cl)n2)cc1
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: CO
Solvent: CCCCO
Solvent: CN(C)C=O
Product: CN(C)c1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Temperature: 25 °C

Procedure:
A flask was charged with C3 (500 mg, 2.1 mmol), 4-morpholinoaniline (573 mg, 3.2 mmol) and nBuOH (10 mL). The flask was immersed in a 180° C. oil bath for 30 minutes. The reaction mixture was cooled to ambient temperature and the black residue dissolved in DMF and MeOH. The product 67 was purified by HPLC with TFA/ACN as eluent. The TFA salt was removed by extracting with sodium hydroxide and ethylacetate to afford the free base of 67.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(N(CC)CC)C>C1COCC1>[Si:10]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1cccc(O)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of 3-hydroxybenzaldehyde (12.21 g, 100 mmol) in 600 mL THF was added tert-butyldimethylsilyl chloride (TBDMSCl, 18.84 g, 125 mmol). The solution was cooled to 0° C. and triethylamine (12.65 g, 17.4 mL, 125 mmol) was added dropwise. The reaction mixture was brought to room temperature and stirred 5 h. The mixture was filtered and the THF removed under reduced pressure. The oil was repeatedly dissolved in 200 mL portions of THF and evaporated, until no more triethylamine hydrochloride precipitated. The oil was then dissolved in 150 mL diethyl ether, filtered through a plug of neutral alumina and activated charcoal to remove the salt and the yellow color, and evaporated. The colorless, mobile oil was dried in vacuo overnight. Yield: 21.43 g (91%). IR: 1703, 1583, 1482, 1278, 1145, 840 cm-1. 1H NMR (CDCl3, TMS) δ 9.927 (s, 1H), 7.447 (d, J) 7.50 Hz, 1H), 7.379-7-335 (m, 2H), 7.096-7.074 (m, 1H), 0.994 (s, 9H), 0.215 (s, 6H). 13C NMR (CDCl3, TMS) δ 191.60, 156.34, 138.03, 130.03, 126.34, 123.46, 119.70, 25, 59, 18.12, −4.52. Anal. Calcd. for Cl3H20O2Si: C, 66.05; H, 8.53. Found: C, 66.13; H, 8.53.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[CH:20][CH:19]=3)[N:9]=2)[CH2:3]1.[CH:32]1([C:35]2[S:39][C:38]([NH:40][C:41](=O)[O:42]C3C=CC=CC=3)=[N:37][N:36]=2)[CH2:34][CH2:33]1.CCN(CC)CC>C(Cl)Cl>[CH:32]1([C:35]2[S:39][C:38]([NH:40][C:41](=[O:42])[NH:1][C@@H:2]3[CH2:7][CH2:6][CH2:5][N:4]([C:8]4[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[C:10]([NH:17][C:18]5[CH:19]=[CH:20][C:21]([C:24]([N:26]6[CH2:31][CH2:30][O:29][CH2:28][CH2:27]6)=[O:25])=[CH:22][CH:23]=5)[N:9]=4)[CH2:3]3)=[N:37][N:36]=2)[CH2:34][CH2:33]1
Reactant: O=C(Nc1nnc(C2CC2)s1)Oc1ccccc1
Reactant: NC(=O)c1ccc(N2CCC[C@@H](N)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc(N2CCC[C@@H](NC(=O)Nc3nnc(C4CC4)s3)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
A suspension of (R)-6-(3-aminopiperidin-1-yl)-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (40 mg, 0.094 mmol), phenyl 5-cyclopropyl-1,3,4-thiadiazol-2-ylcarbamate (29.5 mg, 0.113 mmol), and Et3N (0.016 mL, 0.113 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The reaction mixture was diluted with CH2Cl2, washed with water, and concentrated. The residue was purified by prep-HPLC. The product containing fractions were collected, neutralized with saturated NaHCO3, extracted with CH2Cl2, separated, and concentrated to give 28 mg of (R)-6-(3-(3-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)ureido)piperidin-1-yl)-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide as a light pink solid. LCMS: (M+H)+=592.18. 1H NMR (400 MHz, CDCl3-MIX) δ ppm 11.09 (1H, s), 7.59 (2H, d, J=8.79 Hz), 7.55 (1H, d, J=9.23 Hz), 7.24-7.28 (2H, m), 6.04 (1H, d, J=8.79 Hz), 3.93 (1H, dd, J=13.18, 3.08 Hz), 3.73-3.86 (2H, m), 3.53 (7H, d, J=6.15 Hz), 3.31-3.41 (1H, m), 3.22-3.31 (2H, m), 2.11-2.21 (1H, m), 1.90-2.00 (1H, m), 1.67-1.79 (1H, m), 1.51-1.65 (2H, m), 1.03-1.12 (2H, m), 0.89-0.96 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])/[C:4](/[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)=[CH:5]/[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3](=[O:22])[CH:4]([C:12]1[CH:13]=[CH:14][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[CH:16][CH:17]=1)[CH2:5][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: COC(=O)/C(=C/C1CCCCC1)c1ccc(S(C)(=O)=O)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C(CC1CCCCC1)c1ccc(S(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.8 %

Procedure:
A solution of nickel(II) chloride hexahydrate (157 mg, 0.66 mmol) and (E)-3-cyclohexyl-2-(4-methanesulfonyl-phenyl)-acrylic acid methyl ester (1.07 g, 3.31 mmol) in methanol (30 mL) was cooled to 0° C. and then treated with sodium borohydride (380 mg, 10 mmol) in four portions. After the addition, the black reaction mixture was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 15 h. The black solid was filtered using filter paper and washed with methanol. The combined solvents were concentrated in vacuo, and the residue was diluted with water (50 mL) and ethyl acetate (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×25 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford racemic 3-cyclohexyl-2-(4-methanesulfonyl-phenyl)-propionic acid methyl ester (1.04 g, 97%) as an amorphous white solid: EI-HRMS m/e calcd for C17H24O4S (M+) 324.1395, found 324.1395.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][C@@:12]([OH:19])([C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:13][OH:14].C(N(CC)CC)C>C(Cl)Cl>[CH3:11][C@@:12]([OH:19])([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:13]=[O:14]
Reactant: CC(C)(C)[C@@](C)(O)CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[C@@](C)(O)C=O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of dimethylsulfoxide (2,578 ml. 36.3 mmol) in methylene chloride (3 ml) was added dropwise at -78° C. to a stirred solution of oxalyl chloride (1.585 ml, 18.2 mmol) over 5 minutes and stirred at -78° C. for 10 minutes. A solution of (R)-2,3,3-trimethyl-1,2-butanediol in methylene chloride (25 ml) was added dropwise and stirred for 15 minutes at -78° C. Triethylamine (11.51 ml, 82.6 mmol) was added and the reaction was allowed to come to room temperature. The mixture was diluted with additional methylene chloride, washed with 10% sulfuric acid, the combined aqueous phase was extracted with methylene chloride, and the combined organic layer was washed with saturated sodium bicarbonate, dried (magnesium sulfate), and concentrated by distillation at atmospheric pressure to afford 2.15 g of (R)-2,3,3-trimethyl-2-hydroxybutanal as a pale gummy solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[N:9][C:8]=2[C:18]([NH2:20])=O)=[CH:4][CH:3]=1.COC(OC)[N:26]([CH3:28])C.C(O)(=O)C.[NH2:35]N>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[N:9][C:8]=2[C:18]2[NH:26][CH:28]=[N:35][N:20]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: COC(OC)N(C)C
Reactant: NC(=O)c1nc(-c2ccncc2)oc1Cc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Clc1ccc(Cc2oc(-c3ccncc3)nc2-c2nnc[nH]2)cc1
Temperature: 40 °C
Yield: 5.1 %

Procedure:
A mixture of 5-(4-chlorobenzyl)-2-pyridin-4-yl-1,3-oxazole-4-carboxamide (0.130 g, 0.41 mmol) and 1,1-Dimethoxy-N,N-dimethylmethanamine (3.0 mL, 22 mmol) in Toluene (25 mL) was heated under argon at 40° C. overnight. The reaction mixture was then concentrated to an oily residue. Acetic acid (20 mL, 350 mmol) and Hydrazine (1.0 mL, 30 mmol) were added to the flask and the mixture was heated 60° C. for another 1 hour. The mixture was concentrated and the residue was purified by HPLC to afford 4-[5-(4-chlorobenzyl)-4-(4H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]pyridine (7 mg, 5. 2%). LCMS (FA) ES+338.0, 339.9. 1H NMR (400 MHz, MeOD) δ ppm 8.73-8.64 (m, 2H), 8.49-8.33 (m, 1H), 8.05-7.97 (m, 1H), 7.89-7.75 (m, 2H), 7.38 (d, J=7.16 Hz, 2H), 7.30 (d, J=6.64 Hz, 2H), 4.60 (s, 2H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][C:10]1[C:11]([Cl:28])=[N:12][C:13]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]2[CH3:27])=[N:14][C:15]=1[CH3:16]>CN(C)C=O>[ClH:28].[CH3:9][C:10]1[C:11]([N:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH3:1])=[N:12][C:13]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]2[CH3:27])=[N:14][C:15]=1[CH3:16]
Reactant: CNc1ccccc1
Reactant: Cc1nc(N2CCc3ccccc3C2C)nc(Cl)c1C
Solvent: CN(C)C=O
Product: Cc1nc(N2CCc3ccccc3C2C)nc(N(C)c2ccccc2)c1C
Product: Cl
Yield: 47.5 %

Procedure:
After N-methylaniline(0.6 ml, 5 mmol) was added to a mixture solution of 5,6-dimethyl-2-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-4-chloropyrimidine(0.7 g, 2.4 mmol) and dimethylformamide(10 ml), 0.45 g of the titled compound was obtained in accordance with the same procedure as in Step 4 of Example 57.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:36])=[C:11]([C:15]#[C:16][C:17]4[CH:22]=[C:21]([CH2:23][C:24]5[C:25]([NH2:31])=[N:26][C:27]([NH2:30])=[N:28][CH:29]=5)[CH:20]=[C:19]([O:32][CH3:33])[C:18]=4[O:34][CH3:35])[C:12]=3[F:14])[C:7](=[O:37])[C:6]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:5]2)[CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[NH2:30][C:27]1[N:26]=[C:25]([NH2:31])[C:24]([CH2:23][C:21]2[CH:20]=[C:19]([O:32][CH3:33])[C:18]([O:34][CH3:35])=[C:17](/[CH:16]=[CH:15]\[C:11]3[C:12]([F:14])=[C:13]4[C:8]([C:7](=[O:37])[C:6]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:5][N:4]4[CH:1]4[CH2:3][CH2:2]4)=[CH:9][C:10]=3[F:36])[CH:22]=2)=[CH:29][N:28]=1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(C#Cc3cc(Cc4cnc(N)nc4N)cc(OC)c3OC)c(F)cc2c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(/C=C\c3cc(Cc4cnc(N)nc4N)cc(OC)c3OC)c(F)cc2c1=O
Yield: 53 %

Procedure:
A suspension of 250 mg of ethyl 1-cyclopropyl-7-[5-(2,4-diamino-pyrimidin-5-ylmethyl)-2,3-dimethoxy-phenylethynyl]-6,8-difluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylate (Example 12a)) and 50 mg of 5% palladium-on-charcoal in 50 ml of methanol is hydrogenated at normal hydrogen pressure. The reaction mixture is filtered after 6 hrs. The filtrate is concentrated and the crude product is triturated in succession with 20 ml and 10 ml of ethyl acetate and filtered off under suction. 133 mg (53%) of ethyl (Z)-7-[2-[5-(2,4-diamino-pyrimidin-5-ylmethyl)-2,3-dimethoxy-phenyl]-vinyl]-1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylate are obtained as a colourless solid. M.p.>220°. Mass spectrum: peaks: inter alia at 577 (M+, 100%), 562 (35%), 530 (28%), 516 (68%), 474 (45%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([C:19]([F:37])([F:36])[C:20]1[N:24]3[CH:25]=[C:26]([C:30]4[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=4)[CH:27]=[C:28]([F:29])[C:23]3=[N:22][N:21]=1)=[CH:14][CH:13]=2)C1C=CC=CC=1.FC(F)(F)C(O)=O.C(Cl)Cl>CO>[F:37][C:19]([F:36])([C:20]1[N:24]2[CH:25]=[C:26]([C:30]3[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=3)[CH:27]=[C:28]([F:29])[C:23]2=[N:22][N:21]=1)[C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([OH:8])=[CH:18]2
Reactant: Cn1cc(-c2cc(F)c3nnc(C(F)(F)c4ccc5ncc(OCc6ccccc6)cc5c4)n3c2)cn1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(-c2cc(F)c3nnc(C(F)(F)c4ccc5ncc(O)cc5c4)n3c2)cn1
Temperature: 65 °C
Yield: 43.9 %

Procedure:
To a flask charged with 3-(benzyloxy)-6-(difluoro(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)quinoline (10 mg, 20 μmol) was added trifluoroacetic acid (1.5 mL, 20 mmol). The resulting solution was heated at 65° C. for 18 h. The solution was concentrated for purification by MPLC using 98:2 CH2Cl2: MeOH to 90:10 CH2Cl2: MeOH gradient to afford 6-(difluoro(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)quinolin-3-ol (3.6 mg, 44% yield) as a colorless solid. LRMS (ESI) m/z calcd for C20H14F3N6O (M+H) 411.1. found 411.3.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][C@@H:9]([F:12])[CH2:8]2)=[CH:4][CH:3]=1.[CH3:15][C:16]1([CH3:25])[CH2:21][CH:20]([CH3:22])[O:19][B:18]([CH:23]=[CH2:24])[O:17]1>>[F:12][C@@H:9]1[CH2:10][CH2:11][N:7]([CH2:6][C:5]2[CH:13]=[CH:14][C:2](/[CH:24]=[CH:23]/[B:18]3[O:17][C:16]([CH3:25])([CH3:15])[CH2:21][CH:20]([CH3:22])[O:19]3)=[CH:3][CH:4]=2)[CH2:8]1
Reactant: F[C@@H]1CCN(Cc2ccc(Br)cc2)C1
Reactant: C=CB1OC(C)CC(C)(C)O1
Product: CC1CC(C)(C)OB(/C=C/c2ccc(CN3CC[C@@H](F)C3)cc2)O1

Procedure:
The title compound was synthesized according to the method of Example A51A, except substituting (R)-1-(4-bromobenzyl)-3-fluoropyrrolidine (1.07 g, 4.15 mmol) and 4,4,6-trimethyl-2-vinyl-1,3,2-dioxaborinane (0.77 mL, 4.57 mmol) which gave 1.40 g, 91% of a pale orange solid; MS ESI [M+H]+ 332.3, calcd for [C19H27BFNO2+H]+ 332.22.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[CH2:15]O)=[CH:8][C:7]=1[O:21][CH3:22].N1C=CC=CC=1>O>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[CH2:15][Cl:3])=[CH:8][C:7]=1[O:21][CH3:22]
Reactant: COc1cc(Sc2ccccc2CO)ccc1Cl
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: COc1cc(Sc2ccccc2CCl)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
Thionyl chloride (6.5 g) is added dropwise to a stirred mixture of the alcohol from the preceding preparation (11.2 g) and pyridine (4.0 g) at 10°-20° C. The mixture is stirred at room temperature for 3 hours and, after standing overnight, for one additional hour at 30°-40° C. The cooled mixture is decomposed by dropwise addition of water (20 ml) and the product extracted with benzene. The work-up of the extract, followed by crystallization of the crude residue from a small volume of hexane, yields 10.2 g (85%) of 2-(4-chloro-3-methoxyphenylthio)benzyl chloride which in the pure state melts at 57°-59° C.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[C:27]([NH2:28])=[CH:26][C:9]2[CH2:10][C@@H:11]3[C:16]([CH3:18])([CH3:17])[C@:15]([CH3:19])([C:8]=2[CH:7]=1)[CH2:14][CH2:13][N:12]3[C:20](=[O:25])[C:21]([F:24])([F:23])[F:22].C(O)(=O)C>O>[F:23][C:21]([F:24])([F:22])[C:20]([N:12]1[CH2:13][CH2:14][C@:15]2([CH3:19])[C:16]([CH3:17])([CH3:18])[C@H:11]1[CH2:10][C:9]1[CH:26]=[C:27]3[N:28]=[N:1][NH:5][C:6]3=[CH:7][C:8]=12)=[O:25]
Reactant: O=N[O-]
Reactant: CC1(C)[C@H]2Cc3cc(N)c(N)cc3[C@]1(C)CCN2C(=O)C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)[C@H]2Cc3cc4nn[nH]c4cc3[C@]1(C)CCN2C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of NaNO2 (330 mg) in water (2 mL) is slowly added to a flask charged with a stir bar, 1-[(2R,6S)-8,9-diamino-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone (650 mg), and acetic acid (15 mL) and chilled in an ice bath. The resulting mixture is stirred in the cooling bath for 2 h and at ambient temperature for 1 h. Then, the solution is poured into ice-cold water and the precipitate formed is separated by filtration and dried to afford the title compound that is used without further purification.
Reaction SMILES: [O-]CC.[Na+].[C:5]1([CH3:16])[CH:10]=[CH:9][C:8]([C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[CH:7][CH:6]=1.Br[CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][CH2:18][N:13]1[N:14]=[N:15][C:11]([C:8]2[CH:7]=[CH:6][C:5]([CH3:16])=[CH:10][CH:9]=2)=[N:12]1)[CH3:24]
Reactant: Cc1ccc(-c2nnn[nH]2)cc1
Reactant: CCOC(=O)CCBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCn1nnc(-c2ccc(C)cc2)n1

Procedure:
Sodium ethoxide (21%, 173 μL, 0.536 mmol) was dissolved in 650 μL absolute ethanol along with 5-p-tolyl tetrazole (65.9 mmol) at reflux. Ethyl 3-bromo-propionate (69 μL, 0.536 mmol) was added at reflux and the mixture was maintained at reflux overnight. The crude mixtures were filtered, concentrated and extracted with diethyl ether and sat. NaHCO3. The organic layers were dried and evaporated. When necessary, further purification was performed by RP-HPLC to provide ethyl-3-(5-p-tolyl-2-tetrazolyl)propionate.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[CH3:11][Sn:12](Cl)([CH3:14])[CH3:13].O>CCOCC>[CH3:11][Sn:12]([CH3:14])([CH3:13])[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccoc1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: C[Sn](C)(C)c1ccco1
Temperature: -30 °C
Yield: 96.3 %

Procedure:
To a solution of 6.8 g furan in 100 ml dry ether at 0° C. under nitrogen was added 10.5 ml 9.5M n-butyllithium. The reaction mixture was heated at reflux for 15 min., then cooled to -30° C. and 19.9 g trimethyltin chloride was added. The reaction mixture was allowed to warm to room temperature and then poured into water. The ether layer was separated, washed with water and passed through an alumina column, eluting with hexane. Removal of the solvent provided 22.2 g (96%) 2-(trimethylstannyl)furan as a pale-yellow liquid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)[CH:2]1[O:4][CH2:3]1.[NH2:16][CH2:17][CH2:18][NH:19][C:20]1[N:21]([CH3:30])[C:22](=[O:29])[N:23]([CH3:28])[C:24](=[O:27])[C:25]=1[CH3:26].CN(C)C=O.O>C(Cl)Cl>[CH3:15][O:14][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[O:12][CH3:13])[O:5][CH2:1][CH:2]([OH:4])[CH2:3][NH:16][CH2:17][CH2:18][NH:19][C:20]1[N:21]([CH3:30])[C:22](=[O:29])[N:23]([CH3:28])[C:24](=[O:27])[C:25]=1[CH3:26]
Reactant: COc1ccc(OCC2CO2)cc1OC
Reactant: Cc1c(NCCN)n(C)c(=O)n(C)c1=O
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(OCC(O)CNCCNc2c(C)c(=O)n(C)c(=O)n2C)cc1OC
Reaction time: 48 h

Procedure:
4.2 g. 3,4-Dimethoxyphenyl glycidyl ether and 8.5 g. 4-(2-aminoethylamino)-1,3,5-trimethylpyrimidine-2,6(1H,3H)-dione in 5 ml. dimethylformamide are left to stand for 48 hours at ambient temperature. The reaction mixture is then dissolved in methylene chloride, shaken out five times with water and the organic phase is extracted with 1N acetic acid. The aqueous phase is rendered alkaline by the addition of dilute aqueous sodium hydroxide solution and then extracted with methylene chloride. After drying the extract, the solution is chromatographed over silica gel using, as elution agent, methylene chloride-methanol-ammoniacal methanol (saturated) (20:1:1 v/v/v). After evaporating the pure fractions, the residue obtained is recrystallized from ethyl acetate. There are obtained 2.0 g. (24% of theory) of the desired product in the form of colorless crystals; m.p. 103°-104° C.