Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([C:14]2[O:22][C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[NH:23][C:24]([C@H:26]2[CH2:31][CH2:30][C@H:29]([NH:32][CH3:33])[CH2:28][CH2:27]2)=[O:25])=[O:13])=[N:9][CH:10]=1.[C:34]([O:38][C:39]([NH:41][CH2:42][CH2:43][CH:44]=O)=[O:40])([CH3:37])([CH3:36])[CH3:35].C(OC(OCC)CCN)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([C:14]2[O:22][C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[NH:23][C:24]([C@H:26]2[CH2:31][CH2:30][C@H:29]([N:32]([CH3:33])[CH2:44][CH2:43][CH2:42][NH:41][C:39](=[O:40])[O:38][C:34]([CH3:35])([CH3:36])[CH3:37])[CH2:28][CH2:27]2)=[O:25])=[O:13])=[N:9][CH:10]=1
Reactant: CN[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3cccnc23)CC1
Reactant: CC(C)(C)OC(=O)NCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CCOC(CCN)OCC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(CCCNC(=O)OC(C)(C)C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3cccnc23)CC1
Temperature: 25 °C

Procedure:
N-(5-Chloropyridin-2-yl)-3-({[trans-4-(methylamino)cyclohexyl]-carbonyl}amino)furo[3,2-b]pyridine-2-carboxamide trihydrochloride (300 mg) obtained in Example 119 is suspended in chloroform (7 ml). To the suspension are added 3-t-butoxycarbonylaminopropanal (208 mg), which can be prepared from 3-aminopropionaldehyde diethyl acetal in two steps according to the method described in a literature (Synthesis, 1994, 37) and triethylamine (334 μl) under ice-cooling, and the mixture is stirred for a few minutes. After addition of sodium triacetoxy borohydride (190 mg), the reaction solution is warmed to room temperature and stirred for 2 hours. To the reaction solution is poured saturated aqueous sodium hydrogen carbonate solution under ice-cooling, and the mixture is extracted with chloroform. The organic layer is washed successively with water and saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (eluent: ethyl acetate followed by ethyl acetate/methanol=20/1) to give the title compound (291 mg).
Reaction SMILES: [C:1]([CH2:6][NH:7][C:8]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11])([O:3][CH2:4][CH3:5])=[O:2].CC(C)([O-])C.[K+]>O1CCCC1.C(OCC)(=O)C>[NH2:11][C:10]1[C:9]2[C:8](=[CH:15][C:14]([F:16])=[CH:13][CH:12]=2)[NH:7][C:6]=1[C:1]([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CNc1cc(F)ccc1C#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c2cc(F)ccc2c1N
Reaction time: 1 h
Yield: 76.5 %

Procedure:
Dissolve 2-(Carbethoxy)methylamino-4-fluorobenzonitrile (220 mg, 1 mmol) in tetrahydrofuran (3 mL) and add dropwise with stirring to a solution of potassium tert-butoxide (1 mL of a 1M solution in 1 mL tetrahydrofuran) under a nitrogen atmosphere. After 1 hour, dilute with ethyl acetate, rinse with water, dry the organic phase and concentrate in vacuo to yield the title compound (170 mg, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:15]([CH3:17])[OH:16])[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:18]([O:21]C(=O)C)(=[O:20])[CH3:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:15]([CH3:17])[OH:16])[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1.[C:18]([O-:21])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Agent: CC(O)C1(c2cccc(Cl)c2)CCN(C)CC1
Product: CC(=O)[O-]

Procedure:
A mixture of 1.00 g of 4-(3'-chlorophenyl)-α,1-dimethyl-4-piperidinemethanol (Example 1) and 5 mL of acetic anhydride was heated under reflux for 90 minutes. Removal of the excess acetic anhydride and short-path distillation of the residue (170° bath temperature, 1 micron) gave 1.05 g of the title compound as an oil. NMR (CDCl3): δ7.1-7.4 (m,4H); 4.9 (quartet, J=7 Hz,1H); 2.8 (m,2H); 2.2 (s,3H); 2.0 (s,3H); 1.9-2.4 (m,6H); and 0.9 (d,J=7 Hz,3H).
Reaction SMILES: [CH2:1]([OH:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Na]>C1(C)C=CC=CC=1>[CH2:1]([O:6][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)CO
Agent: [Na]
Solvent: Cc1ccccc1
Product: CC(C)(C)COCC(C)(C)C

Procedure:
Unfluorinated bis-neopentyl ether was synthesized by a method described by V. Gosh, J. Org. Chem. 37 No. 13, p.(1972). A brief summary of that process follows. 0.23 mole (20 g) of neopentyl alcohol (Aldrich Chemical Co., Milwaukee, WI) was dissolved in 150 ml of reagent grade toluene. A stoichiometric amount (5.3 g) of elemental sodium was added. The mixture was stirred and refluxed at a temperature slightly above the boiling point of toluene (109° C.) until all of the metallic sodium had been dissolved, according to the following reaction: ##STR7##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([N:8]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C@H:9]([CH3:17])[CH2:10][CH2:11][CH2:12][S:13](O)(=[O:15])=[O:14])[CH:7]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([N:8]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C@H:9]([CH3:17])[CH2:10][CH2:11][CH2:12][S:13]([Cl:30])(=[O:15])=[O:14])[CH:7]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: C[C@H](CCCS(=O)(=O)O)N(c1cc(Cl)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Product: C[C@H](CCCS(=O)(=O)Cl)N(c1cc(Cl)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Yield: 81 %

Procedure:
(4R)-4-[N-[5-chloro-2-fluorophenyl][(4-chlorophenyl)sulfonyl]amino]pentylsulfonyl chloride was prepared analogous to (4R)-4-[N-[2,5-dichlororophenyl][(4-chlorophenyl)sulfonyl]amino]pentyl-sulfonyl chloride by reacting (4R)-4-[N-[5-chloro-2-fluorophenyl][(4-chlorophenyl)sulfonyl]amino]-pentylsulfonic acid with phosphorus pentachloride: Yield=81%; MS (ESI) 489 (+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:17]1[N:24]=[CH:23][CH:22]=[CH:21][C:18]=1[C:19]#[N:20]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][C:17]1[C:18]([C:19]#[N:20])=[CH:21][CH:22]=[CH:23][N:24]=1
Reactant: N#Cc1cccnc1Cl
Reactant: COc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(Oc2ncccc2C#N)c1
Reaction time: 0.75 h
Yield: 90.1 %

Procedure:
3-Methoxyphenol (124 g) and anhydrous potassium carbonate (69 g) were heated together with stirring in dry DMF (500 ml) at 80° C. under an atmosphere of nitrogen. After 45 minutes, the greyish solution was cooled and 2-chloronicotinonitrile (138.5 g) and cooper bronze (10 g) were added (washed in with 100 ml DMF). The resulting brown reaction mixture was heated to 125°-130° C. After 21/2 hours, the reaction mixture was cooled and filtered to remove excess copper bronze and undissolved solid material. The resulting solution was added to water (3 liters) and left to stand overnight. The resulting precipitate was filtered, washed with water then dissolved in ether. The ether solution was dried, filtered and evaporated to afford 2-(3-methoxyphenoxy)-3-cyanopyridine as an off-white solid (203.5 g, 90%).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][CH2:12][OH:13].[NH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24]2[N:28]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:27]3[CH:37]=[CH:38][CH:39]=[CH:40][C:26]=3[N:25]=2)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+]>O>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][N:28]2[C:27]3[CH:37]=[CH:38][CH:39]=[CH:40][C:26]=3[N:25]=[C:24]2[NH:23][CH:20]2[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][NH:14][C:2]3[N:10]=[CH:9][N:8]=[C:7]4[C:3]=3[N:4]=[CH:5][N:6]4[CH2:11][CH2:12][OH:13])[CH2:18][CH2:19]2)=[CH:31][CH:32]=1
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: OCCn1cnc2c(Cl)ncnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: OCCn1cnc2c(NCCN3CCC(Nc4nc5ccccc5n4Cc4ccc(F)cc4)CC3)ncnc21
Temperature: 130 °C
Yield: 53 %

Procedure:
A mixture of 2 parts of 6-chloro-9H-purine-9-ethanol, 3.7 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine, 1.06 parts of sodium carbonate and 45 parts of N;N-dimethylacetamide was stirred and heated for 3 hours at 130° C. The reaction mixture was poured into water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 2.8 parts (53%) of 6-[[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]amino]-9H-purine-9-ethanol; mp. 168.7° C. (compound 93).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]([O:15][CH3:16])[C:5]=2[N:6]=1.[CH:17]12[NH:24][CH:21]([CH2:22][CH2:23]1)[CH2:20][CH:19]([O:25][CH2:26][C:27]1[C:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][C:42]([F:45])([F:44])[F:43])=[N:29][O:30][C:31]=1[CH:32]1[CH2:34][CH2:33]1)[CH2:18]2.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH:32]1([C:31]2[O:30][N:29]=[C:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][C:42]([F:43])([F:44])[F:45])[C:27]=2[CH2:26][O:25][CH:19]2[CH2:18][CH:17]3[N:24]([C:2]4[S:3][C:4]5[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]([O:15][CH3:16])[C:5]=5[N:6]=4)[CH:21]([CH2:22][CH2:23]3)[CH2:20]2)[CH2:33][CH2:34]1
Reactant: FC(F)(F)Oc1ccccc1-c1noc(C2CC2)c1COC1CC2CCC(C1)N2
Reactant: COC(=O)c1cc(OC)c2nc(Cl)sc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OC)c2nc(N3C4CCC3CC(OCc3c(-c5ccccc5OC(F)(F)F)noc3C3CC3)C4)sc2c1
Temperature: 120 °C
Yield: 53.3 %

Procedure:
The ester, methyl 2-chloro-4-methoxybenzo[d]thiazole-6-carboxylate (124 mg, 0.48 mmol) and 4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole (200 mg, 0.48 mmol) and diisopropylethylamine (0.1 mL, 0.7 mmol) were sequentially dissolved in dimethylacetamide (1 mL) and heated to 120° C. overnight. The reaction mixture was allowed to cool to room temperature and then diluted with ethyl acetate and aqueous saturated sodium bicarbonate solution. The organics were separated, the aqueous layer was subjected to a further wash with ethyl acetate, and the organics were combined and dried (MgSO4) then evaporated in vacuo. The product was purified by silica gel chromatography with a gradient of 0-100% ethyl acetate/hexanes to furnish 161 mg of a clear oil that was used directly in the following transformation without further manipulation.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH3:33])=[CH:4][CH:3]=1.[CH3:34][C:35]1([CH3:38])[CH2:37][O:36]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[OH:36][C:35]([CH3:38])([CH3:37])[CH2:34][O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH3:33])=[CH:6][CH:7]=1
Reactant: CCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(OCC(C)(C)O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
To a solution of 4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) and 2,2-dimethyloxirane (0.70 mL) in N,N-dimethylformamide (10 mL) was added cesium carbonate (1.5 g), and the mixture was stirred at 70° C. for 12 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.91 g, 78%).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]=1/[CH:19]=[CH:20]/[CH:21]([OH:30])[CH2:22][C:23](=[O:29])[CH2:24][C:25]([O:27][CH3:28])=[O:26].Cl>C(O)C.O>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]=1/[CH:19]=[CH:20]/[CH:21]([OH:30])[CH2:22][CH:23]([OH:29])[CH2:24][C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)CC(=O)CC(O)/C=C/c1c(Cl)cc(Cl)cc1OCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)CC(O)CC(O)/C=C/c1c(Cl)cc(Cl)cc1OCc1ccccc1
Yield: 99.4 %

Procedure:
Sodium tetrahydridoborate (1.55 g, 41.1 mmole) was added with stirring to a cooled solution (5° C.) of methyl (E)-7-(2,4-dichloro-6-phenylmethoxyphenyl)-5-hydroxy-3-oxo-6-heptenoate (34.8 g, 82.3 mmole) in ethanol (200 ml) at a rate sufficient to maintain the internal temperature at 15°-20° C. The resulting solution was stirred with ice-bath cooling for 15 min. and then acidified with 6N hydrochloric acid. The resulting mixture was diluted with water (500 ml) and extracted with ether (3×250 ml). The organic extracts were combined, washed with brine (4×100 ml), dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo, leaving the title compound as a yellow oil (34.8 g, 99.5%): pmr CDCl3) δ2.45 (2H, d), 3.65 (3H, s), 4.18 (H, m), 4.45 (H, m), 4.98 (2H, s), 7.28 (5H, s).
Reaction SMILES: [C:1]1([C:7]([NH:20][CH2:21][CH:22]2[CH2:24][CH:23]2[CH2:25][OH:26])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[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.[H-].[Na+].[O:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Br)=[CH:40][CH:39]=1.[I-].[K+]>C1COCC1.CN(C=O)C>[C:1]1([C:7]([NH:20][CH2:21][C@@H:22]2[CH2:24][C@H:23]2[CH2:25][O:26][CH2:42][C:41]2[CH:44]=[CH:45][C:38]([C:30]3[O:29][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[N:31]=3)=[CH:39][CH:40]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCC1CC1CNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: BrCc1ccc(-c2nc3ccccc3o2)cc1
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: c1ccc(C(NC[C@@H]2C[C@H]2COCc2ccc(-c3nc4ccccc4o3)cc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 8 h

Procedure:
To a mixture of 2-triphenylmethylaminomethyl-1-hydroxymethylcyclopropane (0.338 g; 0.984 mmol) in 30 ml THF and 5 ml DMF is added sodium hydride (60%; 0.059 g; 1.48 mmol) followed by 4-(benzoxazol-2-yl)benzyl bromide (0.255 g; 0.886 mmol) and a pinch of potassium iodide. This is stirred overnight, quenched with water, concentrated in vacuo and flash chromatographed using hexane:ethyl-acetate; 7:1 to obtain trans-2-triphenylmethylaminomethyl-[4-(benzoxazol-2-yl)-benzyloxymethyl]cyclopropane as a pale yellow oil which is used directly in the next step.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])[N:8]=1)(=O)=O.CN(C=O)C.CC1(C)C(C)(C)OB([C:41]2[CH:42]=[C:43]([CH2:47][C:48]([O:50]C)=[O:49])[CH:44]=[CH:45][CH:46]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O>[F:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([F:25])[C:18]=1[N:9]1[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=2[C:7]([C:41]2[CH:42]=[C:43]([CH2:47][C:48]([OH:50])=[O:49])[CH:44]=[CH:45][CH:46]=2)=[N:8]1
Reactant: COC(=O)Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2-c1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nccc2c1c(-c1cccc(CC(=O)O)c1)nn2-c1c(F)cccc1F
Temperature: 90 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
To a solution of 1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (600 mg) obtained in Step C of Example 35 in a mixed solvent of DMF (5 mL)/water (0.5 mL) were added methyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (567 mg), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (60 mg) and potassium carbonate (405 mg). The reaction mixture was stirred overnight at 90° C. The reaction mixture was diluted with water, and the aqueous layer was washed with ethyl acetate. The aqueous layer was neutralized with 1M hydrochloric acid at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (205 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([N+:18]([O-])=O)=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:9]2=[O:21])[CH2:4][CH2:3]1.[H][H]>[Pd].C(O)C>[NH2:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:8]([CH:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)[C:9](=[O:21])[CH2:10][CH2:11]2
Reactant: [H][H]
Reactant: CN1CCC(N2C(=O)CCc3cc([N+](=O)[O-])ccc32)CC1
Agent: [Pd]
Solvent: CCO
Product: CN1CCC(N2C(=O)CCc3cc(N)ccc32)CC1

Procedure:
A suspension of 1-(1-methylpiperidin-4-yl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (300 mg, 1.04 mmol) and palladium on activated carbon (10% wt, 55 mg, 0.05 mmol) in 20 mL ethanol/4 mL THF was stirred under a balloon of hydrogen overnight. The suspension was filtered through a pad of celite. The filter pad was rinsed with 50 mL methanol, and the filtrate was concentrated to give a viscous oil. The crude product was used without further purification. (250 mg, 92.6%). 1H-NMR (CDCl3) δ 7.06 (d, J=9.3 Hz, 1H), 6.54-6.49 (m, 2H), 4.46-4.36 (m, 1H), 3.42 (brs, 2H), 2.97-2.94 (m, 2H), 2.73-2.49 (m, 6H), 2.31 (s, 3H), 2.27-2.05 (m, 2H), 1.27-1.21 (m, 2H). MS (ESI): 260.2 (M+1, 100%).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]1[O:34][C:33]2[C:12](=[CH:13][C:14]3[N:18]=[C:17]([S:19]([CH2:21][C:22]4[C:27]([CH3:28])=[C:26]([O:29][CH3:30])[C:25]([CH3:31])=[CH:24][N:23]=4)=[O:20])[NH:16][C:15]=3[CH:32]=2)[O:11]1.C(N(CC)CC)C>C(Cl)Cl>[C:1]1([NH:7][C:8]([N:16]2[C:15]3[CH:32]=[C:33]4[O:34][CH2:10][O:11][C:12]4=[CH:13][C:14]=3[N:18]=[C:17]2[S:19]([CH2:21][C:22]2[C:27]([CH3:28])=[C:26]([O:29][CH3:30])[C:25]([CH3:31])=[CH:24][N:23]=2)=[O:20])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1c(C)cnc(CS(=O)c2nc3cc4c(cc3[nH]2)OCO4)c1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C)cnc(CS(=O)c2nc3cc4c(cc3n2C(=O)Nc2ccccc2)OCO4)c1C
Temperature: 25 °C
Reaction time: 50 h
Yield: 4.5 %

Procedure:
Phenylisocyanate (0.20 g, 0.00167 mol) dissolved in CH2Cl2 (5 ml) was added dropwise under stirring to a solution of 5,6-methylenedioxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole (0.50 g, 0.00139 mol) and triethylamine (0.28 g, 0.00278 mol) in CH2CL2 (15 ml). The mixture was then stirred at room temperature for 50 hours. The CH2Cl2 -solution was washed with water, dried (MgSO4) and the solvent was evaporated giving the desired product as an oil (0.03 g, 5%). NMR data for the final product is given below.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=O)[CH3:2].Cl.[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][NH2:19])=[CH:14][CH:13]=1.Cl>C(O)C>[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18]/[N:19]=[C:1](\[C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)/[CH3:2])=[CH:14][CH:13]=1
Reactant: CC(=O)c1cccnc1
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: CCO
Product: C/C(=N/Nc1ccc(F)cc1)c1cccnc1
Reaction time: 1 h

Procedure:
3-Acetylpyridine (5.00 g, 40.45 mmol) and 4-fluorophenylhydrazine hydrochloride (6.44 g, 38.43 mmol) are suspended in ethanol (70 mL) and heated to reflux. After 1 h, HCl (4M in dioxane, 150 mL, 600 mmol) is added and the mixture is heated to reflux for 16 h. The mixture is concentrated in vacuo and taken up in a little ethanol. The solid is filtered off and washed with ethanol to give a yellow solid. The filtrate is concentrated to dryness. The resulting solid is washed with small amounts of ice-cold ethanol and filtered off. The two fractions are combined and used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9](Br)[CH:8]=[CH:7][N:6]=1)=[O:4].[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[Cl:19]>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([C:16]2[CH:15]=[CH:14][C:13]([Cl:12])=[C:18]([Cl:19])[CH:17]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(Br)ccn1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: COC(=O)c1cc(-c2ccc(Cl)c(Cl)c2)ccn1

Procedure:
The title compound, MS: m/e=281.0 (M+) was obtained as a light yellow solid (10% yield) by the reaction of 4-bromo-pyridine-2-carboxylic acid methyl ester with 3,4-dichlorophenyl boronic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][C:7]=1[CH2:19]Br)=[O:5])[CH3:2].[CH2:21]([O:23][C:24](=[O:34])[CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH3:22].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][C:7]=1[CH2:19][N:26]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:34])=[O:5])[CH3:2]
Reactant: CCOC(=O)CNC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1sc(N(C)c2ccccc2)nc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1nc(N(C)c2ccccc2)sc1C(=O)OCC)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 49.6 %

Procedure:
A mixture of 4-bromomethyl-2-(methyl-phenyl-amino)-thiazole-5-carboxylic acid ethyl ester (974 mg, 2.75 mmol), tert-butoxycarbonylamino-acetic acid ethyl ester (559 mg, 2.75 mmol) and sodium hydride (60% in mineral oil, 132 mg, 3.30 mmol) in anhydrous dimethylformamide (10 mL) was stirred at 0° C. for two hours and room temperature for 18 h before it was quenched with brine. It was partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (652 mg): MS: (+) m/z 500.0 (M+Na+).
Reaction SMILES: [NH2:1][C:2]1[C:7](C(OCC)=O)=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([Br:24])=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=3)[C:3]=12.[OH-].[Na+].C1(OC2C=CC=CC=2)C=CC=CC=1>C(O)C>[Br:24][C:15]1[S:14][C:4]2[N:5]=[C:6]([CH3:13])[CH:7]=[C:2]([NH2:1])[C:3]=2[C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=1
Reactant: CCOC(=O)c1c(C)nc2sc(Br)c(-c3cccc(C)c3)c2c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1cccc(-c2c(Br)sc3nc(C)cc(N)c23)c1
Temperature: 90 °C
Yield: 65.8 %

Procedure:
To a stirred solution of ethyl 4-amino-2-bromo-6-methyl-3-(3-methyl phenyl)thieno[2,3-b]pyridine-5-carboxylate (Description 58) (900 mg, 2.221 mmol) in ethanol (20 mL) at RT was added aqueous NaOH (5M) (1.0 mL, 5.0 mmol). The reaction mixture was heated to 90° C. for ca. 2 h. After cooling to RT the solvent was removed in vacuo. The residue was re-dissolved in water (ca. 80 mL) and neutralized to ca. pH 7 using aqueous HCl (5M). The solution was then extracted with 20% MeOH in DCM (ca. 50 mL×2). The combined organic layer was passed through a phase separator and the solvent removed in vacuo to give a residue which was subsequently re-dissolved in diphenyl ether (10 mL, 62.9 mmol) and heated to 200° C. for ca. 3 h. The reaction mixture was cooled to RT, passed through an SCX cartridge (eluting with MeOH/2M NH3 MeOH). The basic fractions were combined and the solvent removed in vacuo, to give the title compound (487 mg). LCMS (A) m/z: 333/335 [M+1]+, Rt 0.86 min (acidic).