Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[NH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([CH2:24][OH:25])[CH2:19]1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:8][C:6]1[NH:5][C:4]2[C:3]([N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=2)=[C:2]([N:18]2[CH2:23][CH2:22][CH2:21][CH:20]([CH2:24][OH:25])[CH2:19]2)[N:7]=1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: OCC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1nc(N2CCCC(CO)C2)c2nc(-c3ccccc3)cc-2[nH]1
Yield: 30.3 %

Procedure:
This compound was prepared according to the method described in Example 26 by employing 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (0.10 g, 0.41 mmol), 3-piperidinemethanol (Aldrich Chemical Company) (0.241 g, 2.09 mmol) and K2CO3 (0.34 g, 2.50 mmol) in H2O (2.5 mL) to obtain crude pink solids. Recrystallization from EtOH/MeOH gave 0.040 g (30%) of the title compound as an off-white solid. Mp: 255-256° C. 1H NMR (DMSO-d6; 500 MHz): δ 1.45 (m, 1), 1.59 (m, 1), 1.67 (m, 1), 1.83 (m, 2), 2.42 (s, 3), 3.47 (m, 2), 3.55 (m, 1), 3.68 (m, 2), 3.86 (m, 1), 5.44 (br s, 1), 6.77 (s, 1), 7.38 (m, 1), 7.47 (m, 2), 7.87 (d, 2, J=7.2), 11.24 (br s, 1). MS m/z: 321 (M−1).
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:11]([O:13][C:14]([N:16]1[CH2:22][C:21](=O)[C:20]2[CH:24]=[CH:25][S:26][C:19]=2[CH2:18][CH2:17]1)=[O:15])[CH3:12]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:11]([O:13][C:14]([N:16]1[CH2:22][C:21](=[CH2:1])[C:20]2[CH:24]=[CH:25][S:26][C:19]=2[CH2:18][CH2:17]1)=[O:15])[CH3:12]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)N1CCc2sccc2C(=O)C1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1CN(C(=O)OCC)CCc2sccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
Methyl triphenylphosphonium bromide (6.3 g, 17.6 mmol) was dissolved in 150 mL THF and cooled to 0° C. KHMDS (3.2 g, 16.2 mmol) was added portionwise and the reaction was stirred for ½ hour. The product of Example 1, step (c) (3.0 g, 12.5 mmol) was added as a solution in 25 mL THF. The reaction was warmed to room temperature and stirred for 1 hour. The mixture was concentrated and the title product was purified by silica gel chromatography (0% to 40% EtOAc in hexanes) to give 2.6 g of the sub-title compound.
Reaction SMILES: Br[CH:2]1[C:7](=[O:8])[CH2:6][CH:5]([CH3:9])[CH2:4][C:3]1=O.C([O-])(=O)C.[Na+].[NH2:16][C:17]([NH2:19])=[S:18]>C(O)(=O)C>[NH2:19][C:17]1[S:18][C:2]2[C:7](=[O:8])[CH2:6][CH:5]([CH3:9])[CH2:4][C:3]=2[N:16]=1
Reactant: CC1CC(=O)C(Br)C(=O)C1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1CC(=O)c2sc(N)nc2C1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 24 in acetic acid (540 mL) was added sodium acetate (44.3 g, 540 mmol) and thiourea (28.8 g, 378 mmol). The reaction mixture was stirred with a mechanical stirrer at 100° C. for 3 h. The reaction mixture was partially concentrated in vacuo. EtOAc was added (500 mL). The mixture was made basic with 1 M NaOH, and the layers were separated. The aqueous layer was extracted with EtOAc (2×300 mL). The combined organic layers were dried, filtered, and concentrated in vacuo to give 49.3 g of 25, which was taken on without further purification. LCMS-ESI+: calc'd for C8H11N2OS: 183.1 (M+H+); Found: 183.1 (M+H+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH2:26][NH:27][OH:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.C[Si]([N:33]=[C:34]=[O:35])(C)C>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2([CH2:26][N:27]([OH:28])[C:34]([NH2:33])=[O:35])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:17][CH:18]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: ONCC1(c2ccc(OCc3ccc4ccccc4n3)cc2)CCCCCC1
Product: NC(=O)N(O)CC1(c2ccc(OCc3ccc4ccccc4n3)cc2)CCCCCC1

Procedure:
In analogy to the procedure of Example 2, the title compound is prepared from 2.3 g (6.11 mmol) of the compound from Example XV and 0.77 g (6.68 mmol) of trimethylsilyl isocyanate.
Reaction SMILES: FC1C=C(C2CCC3C(=CC=C(O)C=3)O2)C=CC=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:35][CH:34](O)[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([OH:37])[CH:32]=3)[O:27]2)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([OH:37])[CH:32]=3)[O:27]2)=[CH:22][CH:21]=1
Reactant: Oc1ccc2c(c1)C(O)CC(c1ccc(F)cc1)O2
Agent: Oc1ccc2c(c1)CCC(c1cccc(F)c1)O2
Product: Oc1ccc2c(c1)CCC(c1ccc(F)cc1)O2

Procedure:
2-(4-Fluorophenyl)chroman-6-ol was prepared as described for 2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 480 mg of 2-(4-fluorophenyl)-chroman-4,6-diol. 1H NMR (400 MHz, CDCl3) δ: 7.38 (m, 2H), 7.06 (m, 2H), 6.77 (d, 1H, J 8.6 Hz), 6.61 (dd, 1H, J 8.6, 2.9 Hz), 6.57 (d, 1H, 8.6 Hz), 4.97 (dd, 1H, J 10.2, 2.4 Hz), 2.95 (ddd, 1H, J −16.8, 11.4, 6.2 Hz), 2.74 (ddd, 1H, J −16.8, 5.3, 3.1 Hz), 2.15 (m, 1H), 2.05 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=C)=[CH:6][N:5]2[CH:10]=[CH:11][N:12]=[C:4]2[CH:3]=1.I([O-])(=O)(=O)=[O:14].[Na+].N1C(C)=CC=CC=1C.C(O)(C)(C)C>O1CCOCC1.O.C([O-])(O)=O.[Na+].[Os]>[F:1][C:2]1[C:7]([CH:8]=[O:14])=[CH:6][N:5]2[CH:10]=[CH:11][N:12]=[C:4]2[CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cn2ccnc2cc1F
Agent: [Os]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1cccc(C)n1
Solvent: C1COCCO1
Product: O=Cc1cn2ccnc2cc1F
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To 7-fluoro-6-vinyl-imidazo[1,2-a]pyridine (xv) (94 mg, 0.58 mmol), sodium periodate (496 mg, 2.32 mmol) and 2,6-lutidine (0.135 mL, 1.16 mmol) in dioxane/water 3:1 (4.8 mL) was added in two portions a 2.5% solution of osmium tetroxyde in tert-butanol (2×0.728 mL, 2×0.058 mmol). The RM was stirred at rt for 19.5 h and at 50° C. for 24 h. The RM was diluted with aqueous saturated NaHCO3 and extracted twice with EtOAc. The organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by chromatography with DCM and MeOH to yield the title product as a brown solid (TLC RF (DCM/MeOH 9: 1)=0.40, MH+=165).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][CH:18]2O)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C@H:21]3[S:20][CH2:19][CH:18]=2)=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(O)CS[C@H]12
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Temperature: -10 °C
Yield: 75.4 %

Procedure:
To a suspension of 3-hydroxy-7beta-phenylacetylaminocepham-4-carboxylic acid diphenylmethyl ester (2) in dichloromethane (13 parts) cooling at -10° C. under nitrogen are added triethylamine (4 equivalents) and then methanesulfonyl chloride (2.0 equivalents) at -10° C. over 7 minutes. The produced methanesulfonate ester (3) solution is let react at -10° C. for 30 minutes, and diluted with dichloromethane, washed with water, 5% sulfuric acid, and water, dried over sodium sulfate, and concentrated. The residue is crystallized from methanol (4 parts) to give 7beta-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester (6). (Yield: 75.4%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N:11]1[C:15]2=[N:16][CH:17]=[CH:18][C:19]([I:20])=[C:14]2[C:13]([CH:21]([CH3:23])[CH3:22])=[N:12]1)[C:6]#[N:7])=O.[CH3:24][NH:25][CH3:26]>C(O)(=O)C.CO>[CH3:24][N:25]([CH2:1][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N:11]1[C:15]2=[N:16][CH:17]=[CH:18][C:19]([I:20])=[C:14]2[C:13]([CH:21]([CH3:23])[CH3:22])=[N:12]1)[C:6]#[N:7])[CH3:26]
Reactant: CC(C)c1nn(-c2ccc(C#N)cc2C=O)c2nccc(I)c12
Reactant: CNC
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)c1nn(-c2ccc(C#N)cc2CN(C)C)c2nccc(I)c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 40 %

Procedure:
Compound (125a) (0.500 g), 2-picoline-borane complex (0.166 g), and dimethylamine (0.216 mL) were dissolved in acetic acid (1.0 mL) and methanol (10 mL), followed by stirring at room temperature for 12 hr. The reaction solution was concentrated, and the residue was purified by basic silica gel column chromatography (hexane/ethyl acetate) to obtain 3-{(dimethylamino)methyl}-4-{4-iodo-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile (0.213 g, 40%). This 3-{(dimethylamino)methyl}-4-{4-iodo-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile was dissolved in DMSO (1.6 mL), and a hydrogen peroxide solution (30 wt %) (0.060 mL) and a 4 mol % aqueous sodium hydroxide solution (0.132 mL) were added to the resulting solution, followed by stirring at room temperature for 20 min. Water was added to the reaction solution, and the precipitate was collected by filtration and was dried under reduced pressure to obtain 3-{(dimethylamino)methyl}-4-{4-iodo-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide (0.144 g, 65%). According to Example 97(2), compound (126) (64%) was prepared as a white solid using 3-{(dimethylamino)methyl}-4-{4-iodo-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide instead of compound (97a) and using 4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazole hydrochloride instead of 4-phenyl-1H-imidazole.
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=C(OC)C=2)=[CH:10][C:11]#[N:12])=CC=1[N+]([O-])=O.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([C:37]([C:39]2[CH:44]=[C:43]([O:45][CH3:46])[C:42]([O:47][CH3:48])=[C:41]([O:49][CH3:50])[CH:40]=2)=O)[CH:31]=[CH:32][C:33]=1[N+:34]([O-:36])=[O:35].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([C:37]([C:39]2[CH:44]=[C:43]([O:45][CH3:46])[C:42]([O:47][CH3:48])=[C:41]([O:49][CH3:50])[CH:40]=2)=[CH:10][C:11]#[N:12])[CH:31]=[CH:32][C:33]=1[N+:34]([O-:36])=[O:35]
Reactant: COc1ccc(C(=CC#N)c2ccc(OC)c([N+](=O)[O-])c2)cc1OC
Reactant: COc1cc(C(=O)c2cc(OC)c(OC)c(OC)c2)ccc1[N+](=O)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COc1cc(C(=CC#N)c2cc(OC)c(OC)c(OC)c2)ccc1[N+](=O)[O-]
Yield: 70 %

Procedure:
3-(3-Methoxy-4-nitro-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrile (E and Z isomers) were prepared analogously to 3-(4-methoxy-3-nitro-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrile using (3-methoxy-4-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanone (1.2 g, 3.5 mmol), lithium bis(trimethylsilyl)amide (3.9 ml, 3.9 mmol) and diethyl cyanomethylphosphate (0.7 g, 3.9 mmol). The crude product was purified by flash chromatography (silica gel, CH2Cl2) to afford mixture isomers of 3-(3-methoxy-4-nitro-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrile (0.9 g, 70%): 1H NMR (CDCl3) δ 7.93 (dd, J=8.4 and 6 Hz, 1H), 7.06-6.96 (m, 2H), 6.65 (s, 1H), 6.46 (s, 2H), 5.80(5.71) (s, 1H), 4.00-3.81 (m, 12H).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([N:13]=[C:14]2[NH:18][CH2:17][C:16]3([CH2:22][CH2:21][CH2:20][CH2:19]3)[S:15]2)=[CH:5][CH:4]=1)#[N:2].[CH2:23](Br)[CH:24]([CH3:26])[CH3:25]>>[CH2:23]([N:18]1[CH2:17][C:16]2([CH2:19][CH2:20][CH2:21][CH2:22]2)[S:15][C:14]1=[N:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)CBr
Reactant: N#Cc1ccc(N=C2NCC3(CCCC3)S2)c2ccccc12
Product: CC(C)CN1CC2(CCCC2)SC1=Nc1ccc(C#N)c2ccccc12

Procedure:
1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. 1-Amino-4-cyanonaphthalene was converted into 4-cyano-1-naphthyl isothiocyanate according to Method A2a, Step 3. The 2-chloroethylamine was reacted with 4-cyano-1-naphthyl isothiocyanate to Method C1a to give 2-(4-cyano-1-naphthylimino)-1-thia-3-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2b to give 3-isobutyl-2-(4-cyano-1-naphthylimino)-1-thia-3-azaspiro[4.4]nonane.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[N:33][CH:34]=1>>[Cl:28][C:29]1[CH:30]=[C:31]([C:2]2[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@@:13]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]3=[O:27])[CH3:9])=[CH:6][CH:7]=2)[CH:32]=[N:33][CH:34]=1
Reactant: OB(O)c1cncc(Cl)c1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2cncc(Cl)c2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one and 5-chloropyridine-3-boronic acid following a procedure analogous to that described in Example 75 Step 1.
Reaction SMILES: C(=[N:14][C:15]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]2[C:17](=[CH:18][C:19]([S:31][C:32]3[CH:33]=[C:34]([C:38]4([C:44]#[N:45])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)[CH:35]=[CH:36][CH:37]=3)=[CH:20][CH:21]=2)[N:16]=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.NO.C([O-])(=O)C.[K+]>CO>[NH2:14][C:15]1[CH:24]=[C:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:22]2[C:17](=[CH:18][C:19]([S:31][C:32]3[CH:33]=[C:34]([C:38]4([C:44]#[N:45])[CH2:39][CH2:40][O:41][CH2:42][CH2:43]4)[CH:35]=[CH:36][CH:37]=3)=[CH:20][CH:21]=2)[N:16]=1
Reactant: N#CC1(c2cccc(Sc3ccc4c(-c5ccccc5)cc(N=C(c5ccccc5)c5ccccc5)nc4c3)c2)CCOCC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: CO
Product: N#CC1(c2cccc(Sc3ccc4c(-c5ccccc5)cc(N)nc4c3)c2)CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1s (110 mg, 0.18 mmol), hydroxylamine hydrochloride (25 mg, 0.36 mmol), and potassium acetate (44 mg, 0.45 mmol) were dissolved in MeOH (10 mL) and stirred at room temperature for 30 minutes. The reaction was concentrated and diluted with EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated to give 1t.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.O[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2nc(I)c3c(N)ncnc32)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 235.6 %

Procedure:
3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (17.3 g, 66.33 mmol) was suspended in tetrahydrofuran (800 mL) and a solution of tert-butyl 4-hydroxy-1-piperidinecarboxylate (20 g, 99.5 mmol) in tetrahydrofuran (300 mL) and triphenylphosphine (34.8 g, 132.66 mmol) were added The reaction mixture was cooled to 0° C. and diethyl azodicarboxylate (23.1 g, 132.66 mmol) was added dropwise. After 2 hours at room temperature, the reaction was concentrated under reduced pressure to yield crude tert-butyl 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate as an orange oil (69.44 g). HPLC-RT: 14.29 min., 19%, (flow rate: 1 mL/min λ=254 nm Gradient: 5% to 85% acetonitrile/0.1M aqueous ammonium acetate gradient over 20 min.; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[CH2:25][C:26]([N:28]1[C:36]2[C:31](=[CH:32][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:35]=2)[CH2:30][CH2:29]1)=[O:27].C([O-])(O)=O.[Na+].N#N>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.O1CCOCC1>[F:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[CH2:25][C:26]([N:28]1[C:36]2[C:31](=[CH:32][C:33]([C:2]3[C:10]4[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=4[N:4]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:3]=3)=[CH:34][CH:35]=2)[CH2:30][CH2:29]1)=[O:27]
Reactant: CC1(C)OB(c2ccc3c(c2)CCN3C(=O)Cc2cc(F)ccc2F)OC1(C)C
Reactant: CC(C)CCn1cc(Br)c2c(N)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)CCn1cc(-c2ccc3c(c2)CCN3C(=O)Cc2cc(F)ccc2F)c2c(N)ncnc21
Temperature: 100 °C
Yield: 30.6 %

Procedure:
To 5-bromo-7-(3-methylbutyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (113 mg, 0.399 mmol), 1-[(2,5-difluorophenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole (207 mg, 0.519 mmol) in a 5 ml sealable vial was added 1,4-Dioxane (2 mL) and saturated NaHCO3 (1 mL). The mixture was then bubbled with N2 gas for 10 min then Pd(Ph3P)4 (46.1 mg, 0.040 mmol) was added. The mixture was again bubbled N2 gas for 5 minutes then capped and the reaction was heated at 100° C. overnight. The reaction was diluted with water (3 ml) then extracted with EtOAc (3×mL). The organic swere combined and washed with brine, dried over Mg2SO4, filtered and concentrated. The resulting amber color oil was dissolved in 3 ml DMSO and purified by HPLC: (HPLC condition: Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 ml/min, 30% ACN/H2O, 0.1% TFA to 55% ACN/H2O, 0.1% TFA) with UV detection at 254 nm). Product fractions were combined and the volume was reduced to remove most of the MeCN. The water left behind was added to saturated NaHCO3 and then extracted with EtOAc (3×15 mL). The organic was combined wash with saturated NaCl solution, dried over MgSO4, filtered and concentrated. Then it was transferred into a 40 mL vial with MeCN then added water and freeze-dried to give 5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-(3-methylbutyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (58 mg, 30.6% yield) as a white solid. For 50-A1: LC/MS (ES) m/z=476.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 8.08 (d, J=8.34 Hz, 1H), 7.35 (s, 1H), 7.33 (s, 1H), 7.15-7.30 (m, 4H), 6.06 (br. s., 2H), 4.29 (t, J=8.34 Hz, 2H), 4.18 (t, J=7.20 Hz, 2H), 3.95 (s, 2H), 3.27 (t, J=8.46 Hz, 2H), 1.69 (q, J=7.07 Hz, 2H), 1.44-1.56 (m, 1H), 0.93 (d, J=6.57 Hz, 6H).
Reaction SMILES: [CH:1]1([CH2:7][C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]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.[CH3:38][C:39]([Si:42]([CH3:78])([CH3:77])[O:43][C@H:44]([C@@H:55]([CH3:76])[CH2:56]/[C:57](/[CH3:75])=[CH:58]\[C@H:59]([CH3:74])[C@@H:60]([O:66][Si:67]([C:70]([CH3:73])([CH3:72])[CH3:71])([CH3:69])[CH3:68])[C@@H:61]([CH3:65])[CH2:62][NH:63][CH3:64])[C@H:45]([CH3:54])[C@@H:46]([OH:53])[C@@H:47]([CH3:52])/[CH:48]=[CH:49]\[CH:50]=[CH2:51])([CH3:41])[CH3:40].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:71][C:70]([Si:67]([CH3:68])([CH3:69])[O:66][C@H:60]([C@@H:59]([CH3:74])/[CH:58]=[C:57](/[CH3:75])\[CH2:56][C@H:55]([CH3:76])[C@@H:44]([O:43][Si:42]([C:39]([CH3:41])([CH3:40])[CH3:38])([CH3:78])[CH3:77])[C@H:45]([CH3:54])[C@@H:46]([OH:53])[C@@H:47]([CH3:52])/[CH:48]=[CH:49]\[CH:50]=[CH2:51])[C@@H:61]([CH3:65])[CH2:62][N:63]([CH3:64])[C:8](=[O:10])[CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([CH3:73])[CH3:72]
Reactant: C=C/C=C\[C@H](C)[C@H](O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C/C(C)=C\[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CNC
Reactant: O=C(O)CC1CCCCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=C/C=C\[C@H](C)[C@H](O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C/C(C)=C\[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CN(C)C(=O)CC1CCCCC1
Temperature: 23 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
A DMF (2 mL) solution of cyclohexaneacetic acid (30.2 mg, 0.222 mmol) and BOP (131 mg, 0.296 mmol) is added to the stirred DMF (3 mL) solution of (3Z,5S,6S,7R,8R,9S,11Z,13S,14R,15S)-8,14-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-5,7,9,11,13,15-hexamethyl-16-(methylamino)-1,3,11-hexadecatrien-6-ol (90 mg, 0.148 mmol) and DIEA (77 μL, 0.444 mmol) dropwise at 0° C. The solution is warmed up to 23° C. and stirred for an additional 1 hour. DMF is removed in vacuo and the residue is dissolved in EtOAc (10 mL). The organic solution is washed with H2O (1×10 mL) and brine (1×10 mL). The aqueous layer is extracted with Et2O (3×20 mL) and the combined extracts are dried (Na2SO4) and concentrated. Chromatography (SiO2, 0–30% EtOAc-hexanes gradient elution) provided the desired compound (70 mg, 65%). HRMS: ESI m/z 734.5906 (M+H+), Calcd. 734.5939.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:30])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([C:16]2[C:17]([CH2:26][NH:27][CH2:28][CH3:29])=[N:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:9]=1)[CH3:4].[CH3:31][O:32][CH2:33][C:34](Cl)=[O:35]>>[CH2:3]([O:5][C:6](=[O:30])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([C:16]2[C:17]([CH2:26][N:27]([CH2:28][CH3:29])[C:34](=[O:35])[CH2:33][O:32][CH3:31])=[N:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:9]=1)[CH3:4]
Reactant: COCC(=O)Cl
Reactant: CCNCc1nc2ccccc2cc1-c1cc(CC(=O)OCC)ccc1OC
Agent: Cl
Product: CCOC(=O)Cc1ccc(OC)c(-c2cc3ccccc3nc2CN(CC)C(=O)COC)c1

Procedure:
Prepared according to the procedure described in Example 5, Step 5, using the following starting materials: [3-(2-ethylaminomethyl-quinolin-3-yl)-4-methoxy-phenyl]-acetic acid ethyl ester, dihydrochloride and methoxyacetyl chloride.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][N:12]=1)[N:9]([C@H:13]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24].Cl.Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][N:12]=1)[N:9]([C@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH2:14]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24]
Reactant: ClCCN1CCOCC1
Reactant: CCOC(=O)c1cn([C@H]2CCCNC2)c2cnc(Br)cc2c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1cn([C@H]2CCCN(CCN3CCOCC3)C2)c2cnc(Br)cc2c1=O
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
To a suspension of (S)-ethyl 6-bromo-4-oxo-1-(piperidin-3-yl)-1,4-dihydro-1,7-naphthyridine-3-carboxylate hydrochloride (Intermediate 62, 1 g, 2.4 mmol, 1 equiv.) in acetonitrile (6 mL) was added 4-(2-chloroethyl)morpholine hydrochloride (447 mg, 2.4 mmol, 1 equiv.) followed by sodium iodide (360 mg, 2.4 mmol, 1 equiv.) and potassium carbonate (1.66 g, 12 mmol, 5 equiv.). This was stirred in the microwave at 120° C. for 30 min. The reaction was cooled to room temperature and diluted with ethyl acetate. The precipitates were removed, and the filtrate was concentrated to provide (S)-ethyl 6-bromo-1-(1-(2-morpholinoethyl)piperidin-3-yl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylate as a solid (501.3 mg, 43%). Calcd for C22H29BrN4O4 [M+H]+: 495.07.