Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+:2].CO.[CH3:5][C:6]1[CH:7]=[N:8][C:9]([CH2:15][S+:16]([O-:28])[C:17]2[NH:18][C:19]3[CH:20]=[CH:21][C:22]([O:26][CH3:27])=[CH:23][C:24]=3[N:25]=2)=[C:10]([CH3:14])[C:11]=1[O:12][CH3:13]>C1(C)C=CC=CC=1>[CH3:5][C:6]1[CH:7]=[N:8][C:9]([CH2:15][S+:16]([O-:28])[C:17]2[N-:18][C:19]3[CH:20]=[CH:21][C:22]([O:26][CH3:27])=[CH:23][C:24]=3[N:25]=2)=[C:10]([CH3:14])[C:11]=1[O:12][CH3:13].[Na+:2]
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Yield: 80.9 %

Procedure:
3.47 g of sodium hydroxide and 105 ml of methanol were taken into a round bottom flask and stirred for dissolution. 30 g of esomeprazole was taken into a separate round bottom flask and dissolved in 150 ml of toluene and this solution was added to the above sodium hydroxide solution. The combined mixture was stirred for 1.5 hours, and distilled completely at 55° C. The residue was then co-distilled with 450 ml of toluene in three equal lots. The residue was dissolved in 60 ml of toluene and stirred at 29° C. for 1 hour, 20 minutes and filtered. The solid was dried at 34° C. for 9 hours to yield 25.8 g of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([C:24]([NH2:26])=[O:25])=[C:11]2[CH2:16][NH:15][CH2:14][CH2:13][N:12]2[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.[CH:34]1([CH2:40][CH2:41][C:42](Cl)=[O:43])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCl>[Cl:8][C:9]1[C:10]([C:24]([NH2:26])=[O:25])=[C:11]2[CH2:16][N:15]([C:42](=[O:43])[CH2:41][CH2:40][CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[CH2:14][CH2:13][N:12]2[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)CCC1CCCCC1
Reactant: NC(=O)c1c(Cl)c(-c2ccccc2)n2c1CNCC2
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1c(Cl)c(-c2ccccc2)n2c1CN(C(=O)CCC1CCCCC1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
A suspension of 7-chloro-6-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylic acid amide trifluoroacetic acid salt (100 mg, Reference Example 1) in dry dichloromethane (10 mL) was treated with dry triethylamine (0.11 mL), then with a solution of 3-cyclohexylpropionyl chloride (45 mg) in dry dichloromethane (5 mL). After stirring at room temperature overnight the reaction mixture was washed with water, then the organic phase was dried over magnesium sulfate and evaporated. The residue was subjected to column chromatography on silica eluting with a mixture of methanol and dichloromethane (1:19, v/v) to give 7-chloro-2-(3-cyclohexylpropionyl)-6-phenyl-1,2,3,4-tetrahydropyrrolo [1,2-a]pyrazine-8-carboxylic acid amide (80 mg) as a white solid, m.p. 181–182° C. MS: 416 [MH]+, 414 [MH]+.
Reaction SMILES: [F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@@H:14]([O:26][CH2:27][CH:28]4[CH2:30]O4)[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17][OH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:32])[CH2:4][CH2:5][C:6](=[O:31])[CH:7]=1.I(O)(=O)(=O)=O>O1CCCC1.O.ClCCl>[CH2:27]([O:26][C@@H:14]1[CH2:13][C@@H:12]2[C@:20]([CH3:24])([CH2:21][C@H:22]([OH:23])[C@@:2]3([F:1])[C@H:11]2[CH2:10][CH2:9][C:8]2[C@:3]3([CH3:32])[CH2:4][CH2:5][C:6](=[O:31])[CH:7]=2)[C@@:15]1([OH:25])[C:16](=[O:19])[CH2:17][OH:18])[CH:28]=[CH2:30]
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](OCC4CO4)[C@](O)(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Agent: [O-][I+3]([O-])([O-])O
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CCO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO
Yield: 22.7 %

Procedure:
A solution of 20.1 g of crude 9-fluoro-11β ,17,21-trihydroxy-16α-(oxiranyl-methoxy)pregn-4-ene-3,20 -dione, 21-acetate in 300 ml of tetrahydrofuran is stirred with a solution of 30 g of periodic acid in 75 ml of water for 6 3/4 hours. The solution is diluted with water and extracted with chloroform. The chloroform extract was washed with 5% sodium bicarbonate solution, dried, and evaporated in vacuo to give 18.2 g of crude product. This material is dissolved in 60 ml of dichloromethane and chromatographed on a 450 g-silica gel column. Fractions of 250 ml are collected as the column is eluted with 3 liters of dichloromethane, 3 liters of chloroform, and then 3 liters of 19:1 chloroform-ethyl acetate. Fractions 17-21 are combined and evaporated in vacuo to give 4.4 g of 16α-allyloxy-9-fluoro-11β ,17,21-trihydroxypregn-4-ene-3,20-dione, 21-acetate.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:13](=O)[CH2:14][CH2:15][CH:16]=[CH2:17].[BH4-].[Na+]>CO.Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][CH2:17][CH2:16][CH2:15][CH:14]=[CH2:13])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: C=CCCC=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C=CCCCNCc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 29 %

Procedure:
0.44 ml of 4-tert-butylbenzylamine (2.5 mmol) and 0.414 ml of pent-4-enal (3.75 mmol) were dissolved in 7.5 ml methanol at rt and then refluxed for 1.5 h. After cooling down to rt, 114 mg (3 mmol) of sodium borohydride were added and after stirring for 15 min at rt, the reaction mixture was then refluxed for 2¼ h. After cooling down to rt again 114 mg of sodium borohydride were added and the mixture was again refluxed for additional 1¼ h. After cooling down to rt, the reaction mixture was treated with 5 drops 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:1) to give 172 mg light yellow oil (29%). MS (ISP) 232.3 (M+H)+.
Reaction SMILES: O.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:5][CH2:4]1.[C:20]1([CH3:29])[CH:25]=[CH:24][CH:23]=[C:22]([N:26]=[C:27]=[O:28])[CH:21]=1.Cl.CCOCC>>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH2:10][CH2:9][N:6]2[CH2:7][CH2:8][CH:3]([NH:2][C:27]([NH:26][C:22]3[CH:21]=[C:20]([CH3:29])[CH:25]=[CH:24][CH:23]=3)=[O:28])[CH2:4][CH2:5]2)=[CH:12]1
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Reactant: Cc1cccc(N=C=O)c1
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: Cc1cccc(NC(=O)NC2CCN(CCc3c[nH]c4ccccc34)CC2)c1
Yield: 83.2 %

Procedure:
Condensation of 3-[2-(4-Aminopiperidyl)ethyl]indole, hydrate (1.31 g.) and 3-tolyl isocyanate (0.70 g., 5% excess) in the manner of Example 1 gave the crude title compound (1.70 g.) from which was obtained a pure hydrochloride (1.57 g., m.p. 228.9°, dec.) by treatment with ethanolic HCl/ether.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([S:20]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=2)[N:8]=1)=O.[Cl:29][C:30]1[CH:39]=[C:38]2[C:33]([C:34]([NH:40][NH2:41])=[CH:35][CH:36]=[N:37]2)=[CH:32][CH:31]=1>>[Cl:29][C:30]1[CH:39]=[C:38]2[C:33]([C:34]([N:40]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:15]=[C:16]([S:20]([N:23]([CH2:24][CH3:25])[CH2:26][CH3:27])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=5)[N:8]=4)=[CH:4][CH:3]=[N:41]3)=[CH:35][CH:36]=[N:37]2)=[CH:32][CH:31]=1
Reactant: NNc1ccnc2cc(Cl)ccc12
Reactant: CCN(CC)S(=O)(=O)c1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Product: CCN(CC)S(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccnc4cc(Cl)ccc34)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N,N-diethyl-benzenesulfonamide (A-21) and (7-chloro-quinolin-4-yl)-hydrazine according to the method described for example 91. MS: M=533.1 (M+H)+
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][O:31]C6CCCCO6)[CH2:25][CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl>CO>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][OH:31])[CH2:25][CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCN(CCOC4CCCCO4)CC3)ccc1-2
Agent: Cl
Solvent: CO
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCN(CCO)CC3)ccc1-2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 154.7 %

Procedure:
To a solution of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-piperidin-4-yl}-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (103 mg, 0.20 mmol) in MeOH (2 mL) was added HCl (1 mL, 4N in dioxan) and the reaction mixture stirred at RT for 30 min. The reaction mixture was concentrated in vacuo and the residue freeze dried from MeOH/H2O to give 512 as a solid (136 mg). LCMS: RT=3.16 min, [M+H]+=440 [ad823338] 1H NMR 400 MHz (d6-DMSO) δ: 8.27 (1H, d, J=8.19 Hz), 8.03 (1H, s), 7.04 (1H, dd, J=8.13, 1.84 Hz), 6.89 (1H, d, J=1.75 Hz), 5.79-5.71 (1H, m), 4.31 (2H, t, J=5.0 Hz), 3.74 (2H, t, J=5.0 Hz), 3.57 (2H, d, J=12.01 Hz), 3.37 (2H, t, J=4.96 Hz), 3.08-3.07 (4H, m), 2.79 (1H, t, J=7.80 Hz), 1.98-1.97 (4H, m), 1.49 (6H, d, J=6.59 Hz)
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20].C[O-].[Na+].Cl>O.CN(C)P(N(C)C)(N(C)C)=O>[O:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: Oc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: O=C(O)CCCCCCCCCCOc1ccccc1
Temperature: 100 °C

Procedure:
To a mixture of 9.4 g of phenol, 26.5 g of 11-bromoundecanoic acid and 250 ml of hexamethylphosphoramide chilled in an ice bath is added 10.5 g of sodium methoxide. A viscous mass developes and the mixture is stirred and heated at 100° C. for 20 hours. The mixture is diluted with cold water, acidified with concentrated hydrochloric acid, filtered and the solid washed with water to give gray crystals. Recrystallization from acetone gives pale gray crystals, mp 76°-78° C. A second crop of crystals is obtained from mother liquors, mp 75°-77° C.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[NH2:4].[C:13](B1OC(C)(C)C(C)(C)O1)([CH3:15])=[CH2:14].P(C1CCCCC1)(C1CCCCC1)C1CCCCC1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:9][C:7]1[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]([NH2:4])=[C:2]([C:13]([CH3:15])=[CH2:14])[CH:8]=1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: Nc1cc([N+](=O)[O-])c(F)cc1Br
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)c1cc(F)c([N+](=O)[O-])cc1N
Temperature: 100 °C
Yield: 66.8 %

Procedure:
A mixture of 2-bromo-4-fluoro-5-nitroaniline (2.85 g, 12.13 mmol, 1.0 eq), isopropenylboronic acid pinacol ester (5.09 g, 30.33 mmol, 2.5 eq), Pd(OAc)2 (0.82 g, 3.64 mmol, 0.3 eq), Cy3P (1.70 g, 6.07 mmol, 0.5 eq) and Cs2CO3 (39.51 g, 121.28 mmol, 10 eq) in toluene (100 mL) and H2O (25 mL) was de-gassed with N2 for 15 minutes. The mixture was then heated at 100° C. (oil bath temperature). After allowing to cool to room temperature, the mixture was diluted with EtOAc (100 mL) and H2O (50 mL) and the mixture filtered through celite. The filter cake was washed with EtOAc (2×50 mL) and the filtrate partitioned. The organic layer was dried (Na2SO4), filtered and the solvent removed under vacuum to leave a crude residue. The residue was purified by column chromatography on silica gel (residue dry-loaded on to silica gel) using EtOAc/hexanes (1:5 gradient) as eluent to give the product (1.59 g, 64%) as a dark brown solid.
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:12])[C:4](=[O:11])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[OH-].[Na+].CN(C=O)C.[Cl:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=2)=[O:26])=[CH:23][CH:22]=1>C(O)C.O>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31][S:1][C:2]3[N:3]([CH3:12])[C:4](=[O:11])[C:5]4[S:10][CH:9]=[CH:8][C:6]=4[N:7]=3)=[CH:29][CH:28]=2)=[O:26])=[CH:35][CH:36]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: Cn1c(S)nc2ccsc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(SCc2ccc(C(=O)c3ccc(Cl)cc3)cc2)nc2ccsc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
To a solution of 2-mercapto-3-methylthieno[3,2-d]pyrimidin-4-(3H)-one (1.0 g) and sodium hydroxide (205 mg) in 50% ethanol (12 ml)-DMF (20 ml) was added 4-(4-chlorobenzoyl)benzyl bromide (1.56 g) and the mixture was stirred at room temperature for 1 hour. This reaction mixture was poured in water and the resulting crystals were collected by filtration, rinsed with water and methanol, and recrystallized from methanol to provide the title compound as colorless solid (1.497 g) . 1H-NMR (CDCl3) δ: 3.61(3H,s), 4.58(2H,s), 7.23(1H,d,J=5.2Hz), 7.45(2H,d,J=8.6Hz), 7.59(2H,d,J=8.2Hz), 7.70-7.80(5H,m).
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[N:17]=2)[CH2:11][CH2:10]1)=[O:5].[C:37](OC(=O)C)(=[O:39])[CH3:38].[OH-].[NH4+]>O>[C:37]([NH:1][C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[N:17]=2)[CH2:11][CH2:10]1)=[O:5])(=[O:39])[CH3:38]
Reactant: Nc1ccccc1C(=O)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: CC(=O)OC(C)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1ccccc1C(=O)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 7.7 parts of 2-amino-N-[2-[4-[[1-[(4-fluorophenyl)-methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]benzamide, 20 parts of acetic acid anhydride and 80 parts of water was stirred for 4 hours at 100° C. Water was added and the whole was alkalized with ammonium hydroxide. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and recrystallized from acetonitrile, yielding 7.7 parts of 2-(acetylamino)-N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]benzamide; mp. 170.9° C. (compound 51).
Reaction SMILES: F.F.F.[CH2:4](N(CC)CC)C.C(N(CC)CC)C.[Si]([O:35][CH:36](C)[C@H:37]1[O:41][C@@H:40]([N:42]2[CH:49]=[CH:48][C:46](=[O:47])[NH:45][C:43]2=[O:44])[C@H:39]([O:50][CH2:51][CH2:52][O:53][N:54]([CH3:56])[CH3:55])[C@@H:38]1[OH:57])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CO>C1COCC1.C(Cl)Cl>[CH3:56][N:54]([CH3:55])[O:53][CH2:52][CH2:51][O:50][C@@H:39]1[C@H:38]([OH:57])[C@@H:37]([CH2:36][OH:35])[O:41][C@H:40]1[N:42]1[CH:49]=[C:48]([CH3:4])[C:46](=[O:47])[NH:45][C:43]1=[O:44]
Reactant: CCN(CC)CC
Reactant: CC(O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OCCON(C)C)[C@@H]1O
Agent: F
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCON(C)C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.4 %

Procedure:
Triethylamine trihydrof luoride (3.91 mL, 24.0 mmol) was dissolved in dry THF and triethylamine (1.67 mL, 12 mmol, dry, kept over KOH). This mixture of triethylamine-2HF was then added to 5′-O-tert-butyldiphenylsilyl-2′-O-[N,N-dimethylaminooxyethyl]-5′-methyluridine (1.40 g, 2.4 mmol) and stirred at room temperature for 24 hrs. Reaction was monitored by TLC (5% MeOH in CH2Cl2). Solvent was removed under vacuum and the residue placed on a flash column and eluted with 10% MeOH in CH2Cl2 to get 2′-O-(dimethylaminooxyethyl)-5-methyluridine (766 mg, 92.5%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>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>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:5]1[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1cnc(Br)cn1
Reactant: COc1ccccc1B(O)O
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: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1-c1cnc(N)cn1
Temperature: 110 °C
Yield: 15.6 %

Procedure:
A solution of 2-amino-5-bromopyrazine (1.16 g, 6.67 mmol) and 2-methoxyphenylboronic acid (1.17 g, 7.70 mmol) in N,N-dimethylformamide (15 mL) was treated with tetrakis(triphenylphosphine)palladium(0) (193 mg, 0.17 mmol) and potassium carbonate (1.87 g, 13.34 mmol). The mixture was heated at 110° C. overnight. The reaction mixture was extracted with chloroform and water. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 2/1 ethyl acetate/hexanes (2/1 ratio) afforded 5-(2-methoxy-phenyl)-pyrazin-2-ylamine (210 mg, 16%).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12](O)=[O:13])[CH2:8][C:7]1=[O:15].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1.O>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][OH:13])[CH2:8][C:7]1=[O:15]
Reactant: O=C(O)C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C(=O)C1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1CC(CO)CCN1Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]-2-oxopiperidine-4-carboxylic acid (16.8 g) and triethylamine (9.8 mL) in tetrahydrofuran (200 mL) was added ethyl chloroformate (8.0 mL) under cooling to 0° C. under a nitrogen atmosphere. The reaction mixture was stirred for 1 hr under cooling to 0° C., sodium borohydride (5.18 g) was added, and the mixture was further stirred at 30° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (10.9 g).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:3][CH2:2]1.Cl[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:21]([CH3:23])[N:22]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:15]=23)[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3cc(OC)ccc3OCC3CC3)ccnc12
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(OC)ccc3OCC3CC3)ccnc12

Procedure:
Starting from ethyl 7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylate (example D.a5) and commercially available (2-chloromethoxy-ethyl)-trimethyl-silane the title compound is prepared as pale yellow viscous oil.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[N:7]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2].[CH:25]1([N:28]2[CH:32]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:30]=[N:29]2)[CH2:27][CH2:26]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:31]3[CH:30]=[N:29][N:28]([CH:25]4[CH2:27][CH2:26]4)[CH:32]=3)=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[N:7]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2cc([N+](=O)[O-])c(Br)cc2N(C(=O)OC(C)C)C[C@@H]1C
Reactant: CC1(C)OB(c2cnn(C3CC3)c2)OC1(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N1c2cc([N+](=O)[O-])c(-c3cnn(C4CC4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Temperature: 90 °C

Procedure:
A mixture of isopropyl (S)-4-acetyl-7-bromo-3-methyl-6-nitro-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.131 g, 0.327 mmol), 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.092 g, 0.392 mmol), cesium carbonate (0.319 g, 0.980 mmol), XPhos (0.016 g, 0.033 mmol) and tris(dibenzylideneacetone)dipalladium (0.015 g, 0.016 mmol) in 1,4-dioxane (3 mL) and water (0.6 mL) was heated for 16 h at 90° C. The reaction was cooled to rt and concentrated. The residue was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic phase was concentrated and the residue was purified by mass triggered preparatory HPLC. The product-containing fractions were combined and concentrated in a Genevac to afford isopropyl (S)-4-acetyl-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-6-nitro-3,4-dihydroquinoxaline-1(2H)-carboxylate. MS (ESI, pos. ion) m/z 428 [M+H]+.
Reaction SMILES: [CH2:1]([C:4]1[CH:25]=[CH:24][C:7]([NH:8][C:9]2[C:21]([F:22])=[C:20]([F:23])[CH:19]=[CH:18][C:10]=2[C:11]([NH:13][O:14][CH2:15][CH2:16][OH:17])=[O:12])=[C:6]([F:26])[CH:5]=1)[CH:2]=[CH2:3]>CCO.[Pd]>[F:22][C:21]1[C:9]([NH:8][C:7]2[CH:24]=[CH:25][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][C:6]=2[F:26])=[C:10]([CH:18]=[CH:19][C:20]=1[F:23])[C:11]([NH:13][O:14][CH2:15][CH2:16][OH:17])=[O:12]
Reactant: C=CCc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: CCCc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Yield: 77 %

Procedure:
The product of Example 6, 2-(4-Allyl-2-fluoroanilino)-3,4-difluoro-N-(2-hydroxyethoxy)benzamide was dissolved in absolute EtOH and hydrogenated in the presence of 5% Pd/C by the procedure of Example 1, Step D. Purification of the resulting oil was carried out by filtration through a plug of silica gel (50% EtOAc/PE as eluant) to give 3,4-difluoro-2-(2-fluoro-4-propylanilino)-N-(2-hydroxyethoxy)benzamide as a white solid (77%); m.p. (EtOAc/hexane) 144-146° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.85 (br s, 1 H), 8.76 (br s, 1 H), 7.43-7.33 (m, 1 H), 7.14-7.06 (m, 1 H), 7.04 (dd, J=12.5, 1.5 Hz, 1 H), 6.88 (dd, J=8.3, 1.7 Hz, 1 H), 6.83 (ddd, J=8.6, 8.6, 4.2 Hz, 1 H), 4.70 (br s, 1 H), 3.86 (t, J=4.9 Hz, 2 H), 3.57 (t, J=4.9 Hz, 2 H), 2.49 (t, J=7.7 Hz, 2 H), 1.56 (sextet, J=7.4 Hz, 2 H), 0.87 (t, J=7.3 Hz, 3 H). Anal. calcd. for C18H19F3N2O3:C, 58.7; H, 5.2; N, 7.6. Found C, 58.8; H, 5.2; N, 7.7.