Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[NH:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]#[N:31])[CH2:25][CH2:24]1.O.[OH-].[Na+]>O1CCCC1>[NH2:31][CH2:30][CH2:29][N:26]1[CH2:27][CH2:28][CH:23]([NH:22][C:14]2[N:13]([CH2:12][C:8]3[S:7][CH:11]=[CH:10][CH:9]=3)[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]=2)[CH2:24][CH2:25]1
Reactant: N#CCN1CCC(Nc2nc3ccccc3n2Cc2cccs2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCCN1CCC(Nc2nc3ccccc3n2Cc2cccs2)CC1
Reaction time: 3 h
Yield: 72 %

Procedure:
To a stirred mixture of 2.5 parts of lithium aluminum hydride and 225 parts of tetrahydrofuran was added dropwise a solution of 13 parts of 4-[[1-(2-thienylmethyl)-1H-benzimidazol-2-yl]amino]-1-piperidineacetonitrile in tetrahydrofuran under nitrogen atmosphere. Upon completion, stirring was continued for 3 hours at reflux. The reaction mixture was cooled in an ice bath and decomposed by the successive additions of 2.5 parts of water, 7.5 parts of sodium hydroxide solution 15% and 7.5 parts of water. The whole was filtered over Hyflo and the filtrate was evaporated. The residue was crystallized from acetonitrile, yielding 9.5 parts (72%) of N-[1-(2-aminoethyl)-4-piperidinyl]-1-(2-thienylmethyl)-1H-benzimidazol-2-amine; mp. 137.1° C. (131).
Reaction SMILES: C([O:3][C:4](=O)[NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O=P(Cl)(Cl)Cl>[CH3:15][O:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[C:4](=[O:3])[NH:5][CH2:6][CH2:7]2
Reactant: CCOC(=O)NCCc1cccc(OC)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)CCNC2=O
Temperature: 120 °C
Reaction time: 1 h
Yield: 7.6 %

Procedure:
Using an analogous procedure and workup as described in Example 1, step 4, [2-(3-methoxy-phenyl)-ethyl]-carbamic acid ethyl ester (I-11c: 6.2 g, 29.5238 mmol) in POCl3 (62 mL) was reacted with P2O5 (8.38 g, 59.047 mmol). The resulting mixture was stirred at 120° C. for 1 hour to afford the crude product. Purification by column chromatography on silica gel (2% methanol in DCM) afforded 0.400 g of the product (7.6% yield).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:29])[NH:5][C:6]1[CH:27]=[CH:26][C:9]([O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:24][CH3:25])=[C:18]([C:21]([OH:23])=O)[CH:19]=3)[N:14]=[CH:13][CH:12]=2)=[CH:8][C:7]=1[F:28])[CH3:2].[CH2:30]([O:32][CH2:33][CH2:34][NH2:35])[CH3:31].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)CC)C>[CH2:30]([O:32][CH2:33][CH2:34][NH:35][C:21]([C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][C:17]=1[O:24][CH3:25])[N:14]=[CH:13][CH:12]=[C:11]2[O:10][C:9]1[CH:26]=[CH:27][C:6]([NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:29])=[C:7]([F:28])[CH:8]=1)=[O:23])[CH3:31]
Reactant: CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(=O)O)cc23)cc1F
Reactant: CCOCCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(=O)NCCOCC)cc23)cc1F

Procedure:
4-(4-(3-Ethylureido)-3-fluorophenoxy)-7-methoxyquinoline-6-carboxylic acid (50 mg) was treated with ethoxyethylamine, triethylamine and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in the same manner as Example 634, to obtain the title compound (18 mg) as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][NH:9]1.F[C:20](F)(F)S(OC)(=O)=O>>[CH3:20][N:9]1[CH:10]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12](=[O:13])[N:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: CCOC(=O)c1c[nH]n(-c2ccccc2C)c1=O
Reactant: COS(=O)(=O)C(F)(F)F
Product: CCOC(=O)c1cn(C)n(-c2ccccc2C)c1=O
Yield: 66 %

Procedure:
In the same manner as in Reference Example 64 and using ethyl 2-(2-methylphenyl)-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (3.1 g, 12 mmol) and methyl trifluoromethanesulfonate (2.5 mL) as starting materials, the title compound (2.1 g, 66%) was obtained as a pale-yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[Cl:19].O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:19][C:13]1[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:12]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Oc1ccc(Br)c(Cl)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Oc1ccc(-c2ccc(F)cc2)c(Cl)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 93.7 %

Procedure:
4-Fluorobenzeneboronic acid (405 mg, 2.89 mmol) and 4-bromo-3-chlorophenol (500 mg, 2.41 mmol) were dissolved in dioxane (15 mL) and water (3 mL) under nitrogen. The solution was degassed before tetrakis(triphenylphosphine) palladium (0) (278 mg, 0.24 mmol) was added followed by caesium carbonate (2.36 g, 7.23 mmol) and the reaction was stirred at 80° C. for 18 hours. The cooled reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (20% ethyl acetate in heptane) to afford the title compound (503 mg, 94%) as a tan oil which solidified on standing.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=2)[CH:3]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][C:30]([OH:33])([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:8]=3)[CH:3]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Brc1ccc2cc(OCc3ccccc3)ccc2c1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc3cc(OCc4ccccc4)ccc3c2)CC1
Yield: 33.5 %

Procedure:
Beginning with 5.0 gm (15.9 mMol) 2-bromo-6-benzyloxynaphthalene and 3.34 gm (16.8 mMol) 1-tert-butyloxycarbonyl-4-piperidone, 2.31 gm (33%) of the title compound were recovered as a white solid by the procedure described in Preparation I.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:22][CH:23]([CH3:25])[CH3:24])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[CH2:20])=[C:15]([OH:21])[CH:14]=1)(=[O:12])=[O:11].ClC1C=C(C=CC=1)C(OO)=[O:31]>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:22][CH:23]([CH3:25])[CH3:24])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:20][O:31]2)=[C:15]([OH:21])[CH:14]=1)(=[O:11])=[O:12]
Reactant: C=Cc1ccc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)cc1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C3CO3)c(O)c2)c(C)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(2,4-dimethylphenyl)-3-hydroxy-N-isobutyl-4-vinylbenzenesulfonamide (100.8 mg, 0.280 mmol) in dichloromethane (DCM) (20 mL) stirred under nitrogen at 0° C. was added meta-chloroperoxybenzoic acid (mCPBA) (194 mg, 1.122 mmol) portionwise. The reaction mixture was stirred at 0° C. for 30 minutes, then for 72 hours at room temperature. DCM (20 mL) was added to the mixture and the organic phase washed with water (20 mL), dried using a hydrophobic frit and concentrated under a stream of nitrogen to give the crude product, 60 mg, which was used directly in the next step with no further purification. LCMS [LCMS2] Rt 1.42 min, m/z (ES−) 374 (M−H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C(#N)C>[CH:14]1([NH:20][CH2:2][C:3]([N:5]2[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]2[C:12]#[N:13])=[O:4])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NC1CCCCC1
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.035 g, 0.178 mmol, Example 8D) in acetonitrile (3 mL) at room temperature under nitrogen was added cyclohexylamine (0.041 ml, 0.356 mmol). The reaction mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was flash chromatographed with 2-3% MeOH/CH2Cl2 to provide the desired compound as a pale yellow oil. MS (DCI) m/z 260 (M+H)+; 1H NMR (300 MHz, DMSO) δ 1.5-2 (10H, m), 2.13-2.31 (2H, m), 2.41-2.48 (2H, m), 3.76 (1H, d), 3.8-4.5 (2H, m), 4.53-4.55 (1H, t), 4.9 (1H, m), 5.05 (1H, m).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:14][CH2:15][CH3:16])(=[O:13])[CH:10]([CH3:12])[CH3:11].[CH3:17][O:18][C:19]1[C:27]([CH3:28])=[C:26]2[C:22]([C:23](=[O:29])[O:24][CH2:25]2)=[C:21]([O:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[C:20]=1[CH2:37]/[CH:38]=[C:39](\[CH3:42])/[CH2:40]Br.[NH4+].[Cl-]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C.C(Cl)Cl.CCOC(C)=O>[CH3:36][O:35][CH2:34][CH2:33][O:32][CH2:31][O:30][C:21]1[C:20]([CH2:37]/[CH:38]=[C:39](\[CH3:42])/[CH2:40][C:10]([CH3:12])([CH3:11])[C:9]([O:14][CH2:15][CH3:16])=[O:13])=[C:19]([O:18][CH3:17])[C:27]([CH3:28])=[C:26]2[C:22]=1[C:23](=[O:29])[O:24][CH2:25]2
Reactant: CCOC(=O)C(C)C
Reactant: COCCOCOc1c(C/C=C(\C)CBr)c(OC)c(C)c2c1C(=O)OC2
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)C/C(C)=C/Cc1c(OC)c(C)c2c(c1OCOCCOC)C(=O)OC2
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 74 %

Procedure:
A freshly prepared solution of lithium diisopropylamide (2.8 mmol/10 ml THF) was cooled to -78° C. and ethyl isobutyrate (0.75 ml) was added slowly. The solution was stirred at -78° C. for 40 minutes and then a solution of (E)-4-(1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7-methyl -3-oxoisobenzofuran-5-yl)-2-methylbut-2-enyl bromide (0.6 g) in THF (2 ml) and HMPA (1.5 ml) was added via syringe at such rate that the temperature was maintained below -60° C. After stirring for 30 minutes at -78° C., the mixture was poured onto 100 ml of a concentrated solution of NH4Cl. The organic and aqueous phases were separated and the aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic layers were dried over Na2SO4 and evaporated to give a residue which was passed through a column (silica gel, CH2Cl2 -EtOAc 95:5) to afford 480 mg (74%) of ethyl (E)-6-(4-methoxyethoxymethoxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran -5-yl)-2,2,4-trimethyl-4-hexenoate as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([N+:23]([O-:25])=[O:24])=[C:10]([O:11]C(C3C(Cl)=CC=C(F)C=3Cl)C)[C:5]=2[O:4][CH:3]=1.Br>O>[Br:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([N+:23]([O-:25])=[O:24])=[C:10]([OH:11])[C:5]=2[O:4][CH:3]=1
Reactant: CC(Oc1c([N+](=O)[O-])ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Agent: Br
Solvent: O
Product: O=[N+]([O-])c1ncc2c(Br)coc2c1O
Temperature: 25 °C

Procedure:
A solution of 3-Bromo-7-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-6-nitrofuro[3,2-c]pyridine (Intermediate 9a) (1.90 g, 0.00422 mol) in 48% aq. hydrogen bromide (100 mL, 2.0 mol) was stirred at 60° C. overnight. The reaction mixture was cooled down to rt. The reaction solution was diluted with H2O (100 mL) and extracted with DCM (5×50 mL). The DCM solution was dried over Na2SO4 and concentrated under vacuum. The resulting solid was triturated with DCM/hexanes to give the title compound. MS (ES+): m/z 258.85/260.89 [MH+]. HPLC: tR=2.81 min (ZQ3, polar—5 min). 1H NMR (400 MHz, CD3OD): δ=8.28 (s, 1H) 8.32 (s, 1H).
Reaction SMILES: [OH-].[K+].[CH3:3][NH:4][CH:5]1[CH2:9][N:8]([CH3:10])[CH2:7][CH2:6]1.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1>CS(C)=O>[CH3:3][N:4]([CH:5]1[CH2:6][CH2:7][N:8]([CH3:10])[CH2:9]1)[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CNC1CCN(C)C1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CN1CCC(N(C)c2ccc([N+](=O)[O-])cc2)C1
Temperature: 62.5 °C

Procedure:
To a suspension of potassium hydroxide (1.4 g, 25 mmol) and N,N′-dimethyl-3-aminopyrrolidine (1.4 g, 12 mmol) in dimethylsulfoxide (13 mL) is added dropwise 4-fluoronitrobenzene (1.1 mL, 10 mmol). The mixture is heated in a 60-65° C. oil bath for 4 hours. After cooling to room temperature, ice is added to the reaction mixture. The resulting precipitate is collected, washed with water, and dried under vacuum to give methyl-(1-methyl-pyrrolidin-3-yl)-(4-nitro-phenyl)-amine.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10](=[O:46])[CH2:11][C@H:12]([O:38][Si](C(C)(C)C)(C)C)[CH2:13][C:14](=[O:37])/[CH:15]=[CH:16]/[C:17]2[C:18]([CH:34]3[CH2:36][CH2:35]3)=[N:19][C:20]3[C:25]([C:26]=2[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.Cl.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.CCCCCC>[C:1]1([C@@H:7]([NH:9][C:10](=[O:46])[CH2:11][C@H:12]([OH:38])[CH2:13][C:14](=[O:37])/[CH:15]=[CH:16]/[C:17]2[C:18]([CH:34]3[CH2:35][CH2:36]3)=[N:19][C:20]3[C:25]([C:26]=2[C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](NC(=O)C[C@@H](CC(=O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1)O[Si](C)(C)C(C)(C)C)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCO
Solvent: Cc1ccccc1
Product: C[C@H](NC(=O)C[C@H](O)CC(=O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1)c1ccccc1
Temperature: 2 °C
Reaction time: 4 h

Procedure:
Crude (E)-(R)-3-(tert-Butyl-dimethyl-silanyloxy)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-5-oxo-hept-6-enoic acid ((S)-1-phenyl-ethyl)-amide (655.1 g) from example c) is placed in a 4-necked, round bottomed flask, equipped with a mechanical stirrer, digital thermometer, nitrogen inlet-outlet and a condenser. Ethanol (2400 mL) is added to obtain a solution. The solution is cooled to 0-4° C. and hydrochloric acid (2M aqueous solution, 657.1 g, 1276 mmol) is added dropwise at this temperature. The reaction mixture is warmed up to 25° C. and stirred at this temperature for additional 4 hours for completion of the deprotection. The reaction mixture is then poured onto an aqueous solution of sodium bicarbonate (7400 mL of a 2% solution) and extracted with ethyl acetate (5000 mL). The organic layer is washed with brine (1800 mL), the water layers are combined and extracted with ethyl acetate (2000 mL). The organic layers are combined, dried over magnesium sulfate and the solvent is evaporated in vacuo to obtain 561.2 g of a braun, honey-like crude product. The crude product is dissolved in toluene (860 mL) and n-hexane (1075 mL) is added. The mixture is heated at 60° C. for 2 hours and at 50° C. for 1 hour. n-Hexane (1075 mL) is added at 50° C. and the suspension is allowed to cool down to room temperature. Stirring is continued over night at room temperature and for additional 3 hours at 0° C. The solid product is isolated by filtration, the filter cake is washed with ice-cold n-hexane (502 mL) and dried in vacuo to obtain (E)-(R)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3-hydroxy-5-oxo-hept-6-enoic acid ((S)-1-phenyl-ethyl)-amide as a yellow powder.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:26][CH2:25][C@@H:24]([O:27][Si](C(C)(C)C)(C)C)[CH2:23]5)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:35]=[CH:36][C:37](=[O:40])[N:38]([CH3:39])[C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(O)=O.[Na+].C(OCC)C>C1COCC1.CO>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]5)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:35]=[CH:36][C:37](=[O:40])[N:38]([CH3:39])[C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cn1c(=O)ccc2c3cnc(Nc4ccc(N5CC[C@@H](O[Si](C)(C)C(C)(C)C)C5)cn4)nc3n(C3CCCC3)c21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: CCOCC
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(=O)ccc2c3cnc(Nc4ccc(N5CC[C@@H](O)C5)cn4)nc3n(C3CCCC3)c21
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 49.8 %

Procedure:
Compound 276 (53.0 mg, 94.7 μmol) was dissolved in THF (2 mL).). Tetrabutylammonium fluoride, 1.0M in THF (0.500 mL, 500 μmol) was added and the reaction was stirred at room temperature for 4.5 hours. The solvent was evaporated to give an orange oil. Preparative reverse phase HPLC (gradient elution 0.1% TFA in water/10-70% acetonitrile) afforded a yellow solid. This residue was added to aqueous NaHCO3 (saturated, 10 mL) and extracted with dichloromethane+10% methanol (3×30 mL). The combined organics were dried (MgSO4) and evaporated to give a yellow solid. This product was taken up in methanol (2 mL) and 1 mL methanol (saturated at room temperature with HCl) was added. 20 mL diethyl ether was added to precipitate the product, which was washed with ether and dried in vacuo to give compound 275 as yellow solid (21 mg, 50%). 1H NMR (500 MHz, DMSO-d6) δ 9.21 (s, 2 H) 8.56 (d, J=8.56 Hz, 2 H) 7.63 (d, J=2.69 Hz, 4 H) 7.44-7.57 (m, 2 H) 6.87 (d, J=8.56 Hz, 2 H) 5.43 (quin, J=8.62 Hz, 1 H) 4.47 (br. s., 1 H) 4.00 (s, 3 H) 3.09-3.21 (m, 1H) 2.00-2.22 (m, 5 H) 1.90-2.04 (m, 1 H) 1.66-1.85 (m, 2 H) ppm.
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:13][CH:12]=2)=[C:6]([NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)[CH:5]=1.[Li+].[OH-]>C1COCC1.CO>[C:21]([O:20][C:18]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([S:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:40])=[O:2])=[CH:5][C:6]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:16][CH:15]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(Nc2ncnc3nc(C(C)(C)C)ccc23)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(Sc2ccc(C(=O)O)cc2Nc2ncnc3nc(C(C)(C)C)ccc23)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 971.3 %

Procedure:
To a solution of 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-tert-butyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid methyl ester (0.53 g, 0.1 mmol) in a mixture of THF (9 mL) and MeOH (3 mL) was added aqueous LiOH [prepared from LiOH monohydrate (0.21 g, 5.0 mmol) and H2O (3 mL)] dropwise at room temperature. The mixture was stirred at 50° C. for 4 hours, and then evaporated. The aqueous mixture was diluted with H2O, washed with AcOEt, and then carefully acidified to pH 4-5 with 10% HCl at 5° C. under stirring. The resulting solid was collected by filtration, washed with H2O, and dried at 60° C. overnight under reduced pressure to give the title compound as yellow powder (0.53 g, 99%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:8][C:9]=1[N:10]1[C:15](=[O:16])[CH2:14][CH:13]([NH2:17])[CH2:12][CH:11]1[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:4].[O:30]([CH2:37][C:38](Cl)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:8][C:9]=1[N:10]1[C:15](=[O:16])[CH2:14][CH:13]([NH:17][C:38](=[O:39])[CH2:37][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:12][CH:11]1[CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)=[O:4]
Reactant: O=C(Cl)COc1ccccc1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N1C(=O)CC(N)CC1C1CCCCC1
Solvent: ClCCl
Product: COC(=O)c1sc(-c2ccccc2)cc1N1C(=O)CC(NC(=O)COc2ccccc2)CC1C1CCCCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 50.1 %

Procedure:
To a solution of 3-(4-amino-2-cyclohexyl-6-oxo-piperidin-1-yl)-5-phenyl-thiophene-2-carboxylic acid methyl ester (30 mg, 0.073 mmol, 1.0 equiv) in DCM (1.0 mL) at 0° C. was added phenoxyacetyl chloride (0.02 ml, 0.145 mmol, 2.0 equiv) and TEA (0.02 mL). The resulting mixture was then stirred at 0° C. for 20 minutes after which the solvent was removed under vacuum. The residue was purified by silica gel column chromatography (EtOAc/hepatane 10%˜80%) to give product (20 mg). MS: 547 [M+H+].)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[OH:16])=O.P(Cl)(Cl)(Cl)(Cl)Cl.[NH3:26]>>[NH2:26]/[C:5](/[C:4]1[CH:17]=[CH:18][CH:19]=[C:2]([CH3:1])[CH:3]=1)=[C:7]1\[C:8](=[O:16])[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[S:11]\1
Reactant: N
Reactant: Cc1cccc(C(=O)c2sc3ccccc3c2O)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: Cc1cccc(/C(N)=C2\Sc3ccccc3C2=O)c1
Yield: 36 %

Procedure:
Prepared as in Example 1 from 2-(3-methylbenzoyl)-benzo[b]-thiophen-3-ol, phosphorus(V) chloride and concentrated ammonia with a yield of 36% of theory. M.p. 114°-115° C. (ethyl acetate/petroleum ether 1:1)
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].COCCOC.Br[C:14]1[CH:15]=[N:16][CH:17]=[N:18][CH:19]=1.[C:20]([O:24][C:25]([N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[CH:29]=[C:28]1B(O)O)=[O:26])([CH3:23])([CH3:22])[CH3:21]>O.[Cl-].[Na+].O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:37][O:36][C:33]1[CH:34]=[C:35]2[C:30]([CH:29]=[C:28]([C:14]3[CH:15]=[N:16][CH:17]=[N:18][CH:19]=3)[N:27]2[C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])=[CH:31][CH:32]=1
Reactant: COc1ccc2cc(B(O)O)n(C(=O)OC(C)(C)C)c2c1
Reactant: Brc1cncnc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Solvent: O
Product: COc1ccc2cc(-c3cncnc3)n(C(=O)OC(C)(C)C)c2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 54.6 %

Procedure:
Sodium carbonate (364 mg) was dissolved in water (3.44 mL). 1,2-Dimethoxyethane (13.7 mL), 5-bromopyrimidine (273 mg), [1-(tert-butoxycarbonyl)-6-methoxy-1H-indol-2-yl]boronic acid (500 mg) and tetrakis(triphenylphosphine)-palladium(0) (99.2 mg) were added thereto, and the mixture was stirred at 100° C. for 1 hour under microwave irradiation. The reaction mixture was left to be cooled. To the reaction mixture was added a mixed solution of water and saturated brine (each 10 mL), followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (305 mg). 1H-NMR (CDCl3) δ ppm: 1.41 (9H, s), 3.91 (3H, s), 6.60-6.64 (1H, m), 6.94 (1H, dd, J=2.3, 8.7 Hz), 7.47 (1H, d, J=8.7 Hz), 7.83 (1H, d, J=2.3 Hz), 8.78 (2H, s), 9.17 (1H, s).
Reaction SMILES: O[C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=O.C([O-])(=O)C.[Na+].Cl.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][NH2:34]>>[OH:18][C:16]1[CH:17]=[C:2]2[C:3]([C:4]([C:6]3[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=3[OH:13])=[N:34][N:33]2[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[O:26][CH3:25])=[CH:14][CH:15]=1
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Reactant: COc1ccccc1NN
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: COc1ccccc1-n1nc(-c2ccc(O)cc2O)c2ccc(O)cc21
Yield: 5.7 %

Procedure:
Prepared according to Method B from 2,2′,4,4′-tetrahydroxybenzophenone (0.123 g, 0.5 mmol), sodium acetate (0.041 g, 0.5 mmol) and 2-methoxyphenylhydrazine hydrochloride (0.087 g, 0.5 mmol) to give 0.010 g of product as a tan solid.