Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:26])=[C:6]([C:22]([F:25])=[CH:23][CH:24]=1)[O:7][C:8]1[CH2:12][N:11]([C@@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14](O)=[O:15])[C:10](=[O:21])[CH:9]=1)[CH3:2].[CH3:27][C:28]1([CH3:40])[O:32][C@H:31]([CH2:33][N:34]2[CH:38]=[CH:37][C:36]([NH2:39])=[N:35]2)[CH2:30][O:29]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:27][C:28]1([CH3:40])[O:32][C@H:31]([CH2:33][N:34]2[CH:38]=[CH:37][C:36]([NH:39][C:14](=[O:15])[C@@H:13]([N:11]3[CH2:12][C:8]([O:7][C:6]4[C:22]([F:25])=[CH:23][CH:24]=[C:4]([O:3][CH2:1][CH3:2])[C:5]=4[F:26])=[CH:9][C:10]3=[O:21])[CH2:17][CH:18]([CH3:19])[CH3:20])=[N:35]2)[CH2:30][O:29]1
Reactant: CCOc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)O)C2)c1F
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)C2)c1F
Temperature: 0 °C
Yield: 94.8 %

Procedure:
To a solution of (S)-2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.837 g, 2.27 mmol) in N,N-dimethylformamide (50 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.559 g, 2.83 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (1.505 g, 3.40 mmol). The mixture was stirred at 0° C. and N,N-diisopropylethylamine (0.732 g, 5.66 mmol) was added. The mixture was stirred at room temperature overnight and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g, 50% to 90% ethyl acetate/hexanes) which afforded (S)-2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (1.180 g, 95%) as a pale yellow solid: HR-ES-MS m/z calculated for C27H34F2N4O6 [M+H]+ 549.2519, observed 549.2514, 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00 0.90 (d, J=6.4 Hz, 3H), 0.93 (d, J=6.4 Hz, 3H), 1.25 (s, 3H), 1.30 (s, 3H), 1.35 (t, J=6.9 Hz, 3H), 1.38-1.49 (m, 1H), 1.50-1.67 (m, 1H), 1.68-1.84 (m, 1H), 3.73 (dd, J=8.5, 6.0 Hz, 1H), 3.96-4.19 (m, 5H), 4.27 (d, J=18.7 Hz, 1H), 4.31-4.40 (m, 1H), 4.63 (d, J=18.7 Hz, 1H), 4.88 (dd, J=10.7, 4.7 Hz, 1H), 5.06 (s, 1H), 6.43 (d, J=2.1 Hz, 1H), 7.11-7.22 (m, 1H), 7.27 (dt, J=9.7, 1.5 Hz, 1H), 7.60 (d, J=2.1 Hz, 1H), 10.82 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=O)(C)(C)C.[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.[NH2:35][C@@H:36]([CH2:45][OH:46])[C@H:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[OH:38]>>[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:35][C@@H:36]([CH2:45][OH:46])[C@@H:37]([OH:38])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:18])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: N[C@@H](CO)[C@@H](O)c1ccccc1
Product: CON=C1C[C@@H](C(=O)N[C@@H](CO)[C@@H](O)c2ccccc2)N(S(=O)(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-sulfonyl chloride, and (1S,2S)-2-amino-1-phenyl-1,3-propanediol, the title compound was obtained in 82% purity by HPLC. MS(ESI+): m/z=524.
Reaction SMILES: [CH:1]12[CH2:14][CH2:13][CH:5]([CH:6]3[C:11](=[O:12])[O:10][C:8](=O)[CH:7]31)[CH:4]1[CH:2]2[CH2:3]1.C1CC=CC=CC=1.C1(=O)OC(=O)C=C1.[Cl:29][C:30]1[CH:31]=[C:32]([CH:34]=[C:35]([Cl:37])[CH:36]=1)[NH2:33]>C1(C)C=CC=CC=1>[Cl:29][C:30]1[CH:31]=[C:32]([N:33]2[C:8](=[O:10])[CH:7]3[CH:6]([CH:5]4[CH2:13][CH2:14][CH:1]3[CH:2]3[CH:4]4[CH2:3]3)[C:11]2=[O:12])[CH:34]=[C:35]([Cl:37])[CH:36]=1
Reactant: O=C1OC(=O)C2C3CCC(C4CC43)C12
Reactant: Nc1cc(Cl)cc(Cl)c1
Agent: O=C1C=CC(=O)O1
Solvent: C1=CC=CCC=C1
Solvent: Cc1ccccc1
Product: O=C1C2C3CCC(C4CC43)C2C(=O)N1c1cc(Cl)cc(Cl)c1

Procedure:
19.2 g of tricyclo-[3.2.2.02.4 ]-nonane-6,7-dicarboxylic acid anhydride (prepared from the cycloheptatriene/maleic acid anhydride adduct (see Ex. 1a) by catalytic hydrogenation, K. Alder, Ber. 86, 1528-39 (1953) and 19.4 g of 3,5-dichloroaniline are refluxed in 1000 ml of toluene for 16 hours, whereby thewater forming during the reaction is separated with a water separator. After cooling, the toluene is removed in vacuum, and the residue recrystallised from ethyl acetate, M.P. 145° - 153° C.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)CCC.I[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-:28])=[O:27]>CN(C)C=O.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>[N+:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccccc1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1-c1cccs1
Yield: 80 %

Procedure:
Bis(triphenylphosphine)palladium(II) chloride (350 mg) and 2-(tributylstannyl)thiophene (57 g, 0.15 mol) were added to a solution of 1-iodo-2-nitrobenzene (35 g, 0.14 mol) in 500 ml of N,N-dimethylformamide. This mixture was heated for 16 h to 100° C. After concentration in vacuo, the residue was taken up in diethyl ether, washed with water and brine, dried over magnesium sulfate and evaporated. The remaining oil was purified by silica gel chromatography using ethyl acetate and hexane as eluents, yielding 23 g of 2-(2-nitro-phenyl)-thiophene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[C:11]1[C:20]([CH3:21])=[CH:19][C:18]2[C:17]([CH3:23])([CH3:22])[CH2:16][CH:15]([CH3:24])[CH:14]([CH3:25])[C:13]=2[CH:12]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][C:4]=1[C:11]1[C:20]([CH3:21])=[CH:19][C:18]2[C:17]([CH3:23])([CH3:22])[CH2:16][CH:15]([CH3:24])[CH:14]([CH3:25])[C:13]=2[CH:12]=1
Reactant: COc1ccc(C=O)cc1-c1cc2c(cc1C)C(C)(C)CC(C)C2C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CO)cc1-c1cc2c(cc1C)C(C)(C)CC(C)C2C
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a solution of 4-methoxy-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) benzaldehyde (200 mg, 0.59 mmol) in methanol (5 mL) was added at 0° C. in small portions sodium borohydride (70 mg, 1.77 mmol). The solution was stirred 1 hour at 0° C. then quenched with 2N HCl. The reaction mixture was diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated to afford 195 mg (98%) of 4-methoxy-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) benzyl alcohol.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]([F:11])[F:10])=[CH:4][N:3]=1.ClC1N=CC(OC2CCN(C)CC2)=CN=1.[F:27][C:28]1([F:74])[CH2:33][CH2:32][CH:31]([C:34]2[C:43]3[CH:42]([O:44]CC4C=CC(OC)=CC=4)[CH2:41][C:40]([CH3:55])([CH3:54])[CH2:39][C:38]=3[N:37]=[C:36]([CH:56]3[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]3)[C:35]=2[CH:62]([F:73])[C:63]2[CH:68]=[CH:67][C:66]([C:69]([F:72])([F:71])[F:70])=[CH:65][CH:64]=2)[CH2:30][CH2:29]1>>[F:74][C:28]1([F:27])[CH2:33][CH2:32][CH:31]([C:34]2[C:43]3[CH:42]([OH:44])[CH2:41][C:40]([CH3:54])([CH3:55])[CH2:39][C:38]=3[N:37]=[C:36]([CH:56]3[CH2:61][CH2:60][N:59]([C:2]4[N:7]=[CH:6][C:5]([O:8][CH:9]([F:11])[F:10])=[CH:4][N:3]=4)[CH2:58][CH2:57]3)[C:35]=2[CH:62]([F:73])[C:63]2[CH:68]=[CH:67][C:66]([C:69]([F:71])([F:72])[F:70])=[CH:65][CH:64]=2)[CH2:30][CH2:29]1
Reactant: FC(F)Oc1cnc(Cl)nc1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCNCC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Agent: CN1CCC(Oc2cnc(Cl)nc2)CC1
Product: CC1(C)Cc2nc(C3CCN(c4ncc(OC(F)F)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1

Procedure:
Reactions similar to those of Reference Example 29 and Example 38 were performed except for using 2-chloro-5-(difluoromethoxy)pyrimidine, which was prepared by a method similar to that of Reference Example 32, instead of 2-chloro-5-[(1-methylpiperidin-4-yl)oxy]pyrimidine, and from 102 mg (151 μmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 10, 52 mg of the title compound was obtained as a white solid (yield: 49%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[N:18][C:19]=3[NH2:21])[N:14]([CH2:22][C@H:23]3[CH2:27][CH2:26][CH2:25][NH:24]3)[N:13]=2)=[CH:8][CH:7]=1.[C:31]([CH2:33][C:34](O)=[O:35])#[N:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O>[NH2:21][C:19]1[N:18]=[CH:17][N:16]=[C:15]2[N:14]([CH2:22][C@H:23]3[CH2:27][CH2:26][CH2:25][N:24]3[C:34](=[O:35])[CH2:33][C:31]#[N:32])[N:13]=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][C:4]4[CH:28]=[CH:29][CH:30]=[C:2]([F:1])[CH:3]=4)=[CH:7][CH:8]=3)[C:20]=12
Reactant: N#CCC(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3cccc(F)c3)cc1)nn2C[C@H]1CCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
Into a 100-mL round-bottom flask, was placed 3-[4-(3-fluorophenoxy)phenyl]-1-[(2R)-pyrrolidin-2-ylmethyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (216 mg, 0.53 mmol, 1.00 equiv), 2-cyanoacetic acid (36.8 mg, 0.43 mmol, 0.80 equiv), HATU (166 mg, 0.44 mmol, 0.80 equiv), triethylamine (109 mg, 1.08 mmol, 2.00 equiv), N,N-dimethylformamide (50 mL). The resulting solution was stirred for 3 h at 25° C. The resulting solution was extracted with ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was loaded on a silica gel column and eluted with dichloromethane methanol (50 1) to give 150 mg (60%) of 3-[(2R)-2-([4-amino-3-[4-(3-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidin-1-yl]-3-oxopropanenitrile as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=1)#[CH:13].N>>[F:20][C:18]1[CH:19]=[C:14]([C:12]2[O:9][N:8]=[C:7]([C:6]3[CH:5]=[N:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH:13]=2)[CH:15]=[C:16]([F:21])[CH:17]=1
Reactant: ON=C(Cl)c1cncc(F)c1
Reactant: C#Cc1cc(F)cc(F)c1
Agent: N
Product: Fc1cncc(-c2cc(-c3cc(F)cc(F)c3)on2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 28B (88 mg, 0.5 mmol) and 1-ethynyl-3,5-difluorobenzene (Apollo, 69 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) 87.16 (tt, J=9.1, 2.2 Hz, 1H), 7.53 (s, 1H), 7.54-7.63 (m, 2H), 8.17 (ddd, J=9.1, 2.8, 1.6 Hz, 1H), 8.62 (d, J=2.8 Hz, 1H), 8.97 (t, J=1.6 Hz, 1H) ppm; MS (DCI/NH3) m/z 277 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:33])[NH:23][S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:17]=1.[OH-].[Na+].C(OCC)(=O)C>CO>[CH3:1][C:2]1([CH3:34])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:33])[NH:23][S:24]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH:17]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)NS(=O)(=O)c3ccccc3)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(C(=O)NS(=O)(=O)c2ccccc2)c1
Yield: 48.9 %

Procedure:
A mixture of methyl 3,3-dimethyl-2-(3-(phenylsulfonylcarbamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (250 mg, 0.44 mmol, 1.0 eq.) in methanol (8 mL) and 1N sodium hydroxide aqueous solution (6.6 mL, 6.6 mmol, 15.0 eq.) was heated to reflux for 1 h, Thin layer chromatography (petroleum ether:ethyl acetate=1:1) and LC-MS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure and the residual was acidified with 1 M hydrochloric acid solution to pH=3. The white solid precipitated was collected by filtration and washed with acetone to give 100 mg of 3,3-dimethyl-2-(3-(phenylsulfonylcarbamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a off-white solid, yield: 50.4%. LC-MS (M+1)=465.1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[CH:13]([C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20])[C:14]([CH3:18])([CH2:16]Br)[S:15][C@H:11]12)=[O:8].N1C=CC=CC=1>C1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[C:13]([C:19]([O:21][CH2:22][C:23]([Cl:24])([Cl:25])[Cl:26])=[O:20])=[C:14]([CH3:16])[CH2:18][S:15][C@H:11]12)=[O:8]
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Yield: 56.5 %

Procedure:
2,2,2-trichloroethyl 6-[2-(thiophene-2-yl)acetamido]-2-methyl-2-bromomethylpenam-3-carboxylate (0.85 g.) was dissolved in benzene (12 cc), and thereto was added pyridine (0.24 g.). The mixture was refluxed for 2 hours, washed with water, dried and concentrated. Ether was added to the residue and the precipitate was collected by filtration to yield crystals (0.41 g.) of 2,2,2-trichloroethyl 7-[2-(thiophene-2-yl)-acetamido]-3-methyl-3-cephem-4-carboxylate, m.p. 151°-152° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]1[C:17](=[C:18]2[CH2:22][CH:21]([CH2:23]I)[O:20][C:19]2=[O:25])[O:16][C@H:15]2[N:12]1[C:13](=[O:26])[CH2:14]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.COC(C)(C)C>C(OCC)(=O)C.[Pd]>[CH2:1]([O:8][C:9]([CH:11]1[C:17](=[C:18]2[CH2:22][CH:21]([CH3:23])[O:20][C:19]2=[O:25])[O:16][C@H:15]2[N:12]1[C:13](=[O:26])[CH2:14]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OC(CI)CC1=C1O[C@@H]2CC(=O)N2C1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Solvent: CCOC(C)=O
Product: CC1CC(=C2O[C@@H]3CC(=O)N3C2C(=O)OCc2ccccc2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1800 mg of 10% Pd/C and 390 ml of ethyl acetate is stirred at room temperature under hydrogen atmosphere for 30 minutes. A solution of the compound of Example 41 (800 mg) in 10 ml of ethyl acetate is introduced with a syringe, and stirring is continued under hydrogen atmosphere. At time points of 1 hour 20 minutes, 2 hour 40 minutes, 4 hour and 5 hour 35 minutes further amounts of 1800 mg 10% Pd/C each are added. After a total reaction time of 6 hours 50 minutes, the mixture is filtered through celite and stripped of the solvents to obtain a residue which is subjected to chromatography thrice over SiO2 using toluene/t-butyl methyl ether (17/1). The title compound is obtained as a foam, having characterization data as indicated below.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:7][C:8]=1[CH3:9].[Br:14]Br.O>C(O)(=O)C>[Br:14][C:6]1[CH:7]=[C:8]([CH3:9])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:10][C:11]([OH:13])=[O:12]
Reactant: BrBr
Reactant: COc1cc(CC(=O)O)ccc1C
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(CC(=O)O)c(Br)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.4 %

Procedure:
To a solution of (3-methoxy-4-methyl-phenyl)-acetic acid (6.1 g, 33.9 mmol) in glacial acetic acid (30 mL) under argon was added bromine (1.96 mL, 37.2 mmol). The mixture was stirred at room temperature for three hours. Water (100 mL) was added, and solid was filtered off, washed with water and dried to obtain (2-bromo-5-methoxy-4-methyl-phenyl)-acetic acid (6.8 g, 77%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:13][CH:14]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)[CH3:15].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][CH:14]([C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=[N:4][CH:3]=2)=[CH:18][CH:17]=1)[CH3:15]
Reactant: CCOC(=O)c1cncc(Br)c1
Reactant: CC(C)c1ccc(B(O)O)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+]
Solvent: CN(C)C=O
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1cncc(-c2ccc(C(C)C)cc2)c1
Temperature: 85 °C
Reaction time: 18 h

Procedure:
4.68 g (20.32 mmol) of ethyl 5-bromonicotinate, 5.00 g (30.49 mmol) of 4-(1-methylethyl)-phenylboronic acid, 0.12 g (0.10 mmol) of tetrakis(triphenylphosphine)palladium(0) and 4.31 g (40.65 mmol) of sodium carbonate were dissolved in a mixture of 37 ml of 1,2-dimethoxyethane, 10.5 ml of water and 84 ml of dimethylformamide and stirred at 85° C. for 18 h. For work-up, some of the dimethylformamide was removed under reduced pressure, and the reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was dried over sodium sulphate and the crude product was purified by preparative HPLC. Yield: 2.42 g (44% of theory)
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[C:9]([I:10])[N:4]2[N:3]=1.[NH:11]1[C:19]2[C:14](=[CH:15][C:16](B(O)O)=[CH:17][CH:18]=2)[CH:13]=[CH:12]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[I:10][C:9]1[N:4]2[C:5]([S:6][C:2]([C:16]3[CH:15]=[C:14]4[C:19](=[CH:18][CH:17]=3)[NH:11][CH:12]=[CH:13]4)=[N:3]2)=[N:7][CH:8]=1
Reactant: Brc1nn2c(I)cnc2s1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Ic1cnc2sc(-c3ccc4[nH]ccc4c3)nn12
Temperature: 110 °C
Yield: 54.6 %

Procedure:
A mixture of 2-bromo-5-iodoimidazo[2,1-b][1,3,4]thiadiazole (0.150 g, 0.455 mmol, 1 eq) and 5-indolylboronic acid (0.088 g, 0.546 mmol, 1.2 eq), 2M aq Na2CO3 (1 mL) and PdCl2(PPh3)2 (0.064 g, 0.091 mmol, 0.2 eq) in dioxane (5 mL) was heated at 110° C. for 2 h. The solvent was removed in vacuo, redissolved in DCM/water (150 mL) and extracted with DCM (2×80 mL). The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (20-70% EtOAc in cyclohexane) to afford the desired product (91 mg, 54%) as a yellow solid. HPLC-MS (10-95% B in 4 min at 0.5 mL+2 min 100% B, flow 0.8 mL/min, 50° C.): tR=4.53 min, [M+H]+ m/z 367.0.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[OH:36].C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:32]1[CH:33]=[CH:34][C:35]([OH:36])=[C:30]([F:29])[CH:31]=1
Reactant: OB(O)c1ccc(O)c(F)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3ccc(O)c(F)c3)n(-c3ccccc3)c(=O)c12
Yield: 5.7 %

Procedure:
(S)-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.10 mol) was treated with (3-fluoro-4-hydroxyphenyl)boronic acid (24 mg, 0.15 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (14 mg, 0.02 mol) and sodium carbonate (2M, 231 μl, 0.46 mol) according to the method described in Example 3 to give 4 mg (9% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@H:11]2[C@H:12]3[C@H:21]([CH2:22][CH2:23][C@:9]2([CH3:10])[C@@H:8]([OH:26])[CH2:7]1)[C:20]1[CH:19]=[CH:18][C:17]([O:24][CH3:25])=[CH:16][C:15]=1[CH2:14][CH2:13]3)=[O:5])[CH3:2].[CH2:27](Cl)[O:28][CH3:29].O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C@@H:6]1[C@H:11]2[C@H:12]3[C@H:21]([CH2:22][CH2:23][C@:9]2([CH3:10])[C@@H:8]([O:26][CH2:27][O:28][CH3:29])[CH2:7]1)[C:20]1[CH:19]=[CH:18][C:17]([O:24][CH3:25])=[CH:16][C:15]=1[CH2:14][CH2:13]3)=[O:5])[CH3:2]
Reactant: COCCl
Reactant: CCOC(=O)[C@H]1C[C@H](O)[C@@]2(C)CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@H]12
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@H]1C[C@H](OCOC)[C@@]2(C)CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@H]12
Yield: 86.1 %

Procedure:
A solution of 59.9 mg (0.155 mmol) of 55, 269 μL (1.55 mmol) of iPrEt2N, 118 μL (1.55 mmol) of MOMCl in anhydrous toluene (2 mL) was stirred at rt for 22 h. The reaction mixture was poured into H2O (70 mL) and extracted with CH2Cl2 (3×, 50 mL). Combined organic extracts were dried over Na2SO4 and concentrated in vacuo giving a yellow oil. Purification by flash chromatography on a 2×17 cm column of silica gel using 3:1 hexanes/EtOAc as eluent gave 53.7 mg (80%) of 56. Data for 56: TLC, T-2, Rf 0.8; 1H NMR (500 MHz, CDCl3) δ 0.85 (s, 3H, H-18), 1.29 (t, 3H, J=7.2 Hz, CH2CH3), 3.37 (s, 3H, —CH2OCH3), 3.77 (t, 1H, J=8.7 Hz, H-17α), 3.78 (s, 3H, ArOCH3), 4.20–4.14 (m, 2H, —CH2CH3), 4.66 (s, 2H, OCH2O), 6.61 (d, 1H, J=2.8 Hz, H-4), 6.71 (dd, 1H, J=8.8, 2.8 Hz, H-2), 7.21 (d, 1H, J=8.8 Hz, H-1).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[N:16]([CH3:27])[N:17]=[N:18][C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:9][CH:8]=1>O.C1COCC1.CO>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]2[N:18]=[N:17][N:16]([CH3:27])[C:15]=2[C:14]#[C:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:28])=[O:5])=[CH:8][N:9]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccc(C#Cc2c(-c3ccc(F)cc3)nnn2C)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cn1nnc(-c2ccc(F)cc2)c1C#Cc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.7 %

Procedure:
A solution of lithium hydroxide monohydrate (30 mg, 0.72 mmol) in water (0.9 mL) was added dropwise to a suspension of 6-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylethynyl]-nicotinic acid methyl ester (121 mg, 0.36 mmol) in THF (0.9 mL) and methanol (0.2 mL). The reaction mixture was then stirred at room temperature for 18 h and was then evaporated and the residue dissolved in water, acidified with HCl (1N), and the resulting precipitate filtered off to afford the title product (89 mg, 77%) as a light yellow solid after trituration with ethyl acetate. MS: m/e=321.1 [M−H]−.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([CH3:7])=[N:3]1.Cl[S:9]([OH:12])(=O)=[O:10].[NH3:13].O>CCOCC>[CH3:1][N:2]1[CH:6]=[C:5]([S:9]([NH2:13])(=[O:12])=[O:10])[C:4]([CH3:7])=[N:3]1
Reactant: O=S(=O)(O)Cl
Reactant: N
Reactant: Cc1ccn(C)n1
Solvent: O
Solvent: CCOCC
Product: Cc1nn(C)cc1S(N)(=O)=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 19024.9 %

Procedure:
59 g (0.615 mmol) of 1,3-dimethylpyrazole is added slowly to 300 g (2.5 mmol) of chlorosulfonic acid at 0° C. The reaction is warmed to 90° C. for 3 hours, cooled and poured onto 500 g of ice. The aqueous solution is extracted with 3×100 ml of ether. The organic extract is dried over anhydrous sodium sulfate and filtered. The ether solution is added dropwise to a solution of 55 grams of anhydrous ammonia (2.5 mmol) in 250 ml of ether. After standing overnight, water is added and the layers separated. The aqueous solution is extracted with ethyl acetate, the organic solutions combined and dried over anhydrous sodium sulfate. After removal of the drying agent, the solvent is removed in vacuo giving 20.5 g of product, m.p. =97°-105° C.