Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C)(C)[N:6]1[C:14]2[C:9](=[C:10]([Cl:16])[C:11]([OH:15])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:16][C:10]1[C:11]([OH:15])=[CH:12][CH:13]=[C:14]2[C:9]=1[CH:8]=[CH:7][NH:6]2
Reactant: CC(C)(C)[Si](C)(C)n1ccc2c(Cl)c(O)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Oc1ccc2[nH]ccc2c1Cl
Temperature: 0 °C

Procedure:
1-(tert-Butyl-dimethyl-silanyl)-4-chloro-1H-indol-5-ol (5.35 g, 18.98 mmol) is dissolved in THF (90 mL) and cooled to 0° C. TBAF (4.96 g, 18.98 mmol) is added over 5 minutes to the brown solution. After 1 hour the reaction is quenched with ammonium chloride. The reaction is diluted with ethyl acetate and washed with water and then brine. The organic phase is removed, dried (sodium sulfate) and concentrated. The mixture is absorbed onto silica and purified via FCC (0-40% ethyl acetate:heptanes) to obtain the title compound as a solid. MS (ESI) m/z 168.15 (M+1).
Reaction SMILES: [OH:1][C:2]1[O:9][C@H:8]([CH2:10][OH:11])[CH2:7][C@H:5]([OH:6])[C:3]=1[OH:4].[S:12](Cl)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13]>N1C=CC=CC=1>[S:12]([O:11][CH2:10][C@H:8]1[O:9][C:2]([OH:1])=[C:3]([OH:4])[C@@H:5]([OH:6])[CH2:7]1)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@@H]1C[C@H](O)C(O)=C(O)O1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@H](O)C(O)=C(O)O2)cc1

Procedure:
Dissolve 10 gm. of the alcohol and 15.4 gm. of tosyl chloride in 100 ml. of dry pyridine and let the solution stand at 25°C. for 17 hours. Add ethanol and evaporate the solution to a residue and then azeotrope with toluene. Chromatograph the residue on a silica gel column (110 × 2.5 cm) using 10% acetone in hexane as the eluant to obtain 4-deoxy-6O-tosyl-D-threo-hex-1-enopyranose.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]#[N:5].OO.CS(C)=[O:18].[OH-].[K+]>CO.O>[CH3:10][C:8]1[CH:9]=[C:2]([CH3:1])[C:3]([C:4]([NH2:5])=[O:18])=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=1
Reactant: CS(C)=O
Reactant: Cc1cc(C)c(C#N)c([N+](=O)[O-])c1
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C)c(C(N)=O)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 43 %

Procedure:
To a solution of 4,6-dimethyl-2-nitroaniline (3 g, 18.07 mmol) in acetic acid (20 mL) and 6 N HCl (60 mL) at 0° C. was added a solution of sodium nitrite (2.18 g, 31.62 mmol) in water (5 mL). The reaction mixture was stirred at 0° C. for 30 min after completion of addition and copper (I) cyanide (3.24 g, 3 mmol) was added pinch by pinch. The resulting mixture was stirred at 0° C. for 5 h and at room temperature for an additional 2 h. The mixture was passed through a Celite pad, extracted with EtOAc (3×100 mL), and concentrated using a rotary evaporator to afford a solid residue. The solid was further purified by column (SiO2, hexanes/EtOAc=7:1) to yield 2-chloro-1,5-dimethyl-3-nitro-benzene (2.6 g, 81%) as a light yellow solid. A solution of 2-chloro-1,5-dimethyl-3-nitro-benzene (2.6 g, 15.7 mmol) and copper (I) cyanide (7.05 g, 78.3 mmol) in DMAC (20 mL) was stirred at reflux for 14 h. The reaction mixture was cooled to room temperature, quenched by adding water (30 mL), filtered through a Celite pad, extracted with EtOAc (3×100 mL), and concentrated using a rotary evaporator to afford a solid residue. The solid was further purified by column (SiO2, hexanes/EtOAc=6:1) to yield 0.64 g of 2,4-dimethyl-6-nitro-benzonitrile (23%). A solution of 2,4-dimethyl-6-nitro-benzonitrile (1.1 g, 6.24 mmol) in MeOH (20 mL) and water (10 mL) was mixed with hydrogen peroxide (10 mL), DMSO (10 mL) and potassium hydroxide (0.636 g, 11.36 mmol). The reaction mixture was stirred at 60° C. for 3 h, diluted with water (100 mL), extracted with EtOAc (3×100 mL), and concentrated using a rotary evaporator to afford 4,6-dimethyl-2-nitrobenzamide (0.52 g, 43%). A solution of 4,6-dimethyl-2-nitrobenzamide (0.52 g, 2.68 mmol) in MeOH (30 mL) was mixed with palladium carbon (0.25 g). The resulting suspension was stirred at room temperature under hydrogen for 14 h. The mixture was passed through a Celite pad, concentrated using a rotary evaporator to afford 2-amino-4,6-dimethyl benzamide (0.42 g, 95%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])[CH:14]=2)[CH2:10][C:9]1=[O:29])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH:11]2[CH2:12][NH:8][C:9](=[O:29])[CH2:10]2)=[CH:14][C:15]=1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28]
Reactant: COc1ccc(C2CC(=O)N(C(=O)OC(C)(C)C)C2)cc1Oc1ccccc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C2CNC(=O)C2)cc1Oc1ccccc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The deprotection of 4-(4-methoxy-3-o-tolyloxyphenyl)-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester was performed in a 25% TFA/DCM solution. This solution was stirred for 30 min at r.t. After neutralization and extraction in EtOAc, the mixture was concentrated under reduced pressure to give the desired compound without purification.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:9]([O:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2.[C:24]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16]([O:18][CH3:24])=[O:17])=[C:9]([O:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2
Reactant: COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)CC/C(C)=C/Cc1c(O)c2c(c(C)c1OC)COC2=O
Reaction time: 72 h
Yield: 1243.2 %

Procedure:
A solution of 15.1 g (47.1 mmol) of (E)-6-(1,3-dihydro-4-hydroxy-6- methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid (mycophenolic acid) and 0.7 g (3.7 mmol) of p-toluenesulfonic acid in 400 ml of methanol was allowed to stand at room temperature for 3 days. The mixture was concentrated under reduced pressure to approximately 75 ml and then partitioned between aqueous sodium bicarbonate and ethyl acetate. The organic phase was further washed with brine and then dried over sodium sulfate. Concentration of the organic phase under reduced pressure gave 15.4 g (46.0 mmol, 98%) of methyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate as a white solid, mp 104°-105° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:29](=[O:30])[N:13]2[CH2:14][CH:15]3[CH2:20][CH2:19][C:18]([NH:21][C:22](=[O:28])[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])([C:12]2=[N:11][C:10]=1[C:31](=[O:44])[NH:32][CH2:33][C:34](=O)[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[CH2:17][CH2:16]3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[CH2:1]([O:8][C:9]1[C:29](=[O:30])[N:13]2[CH2:14][CH:15]3[CH2:20][CH2:19][C:18]([NH:21][C:22](=[O:28])[C:23]([N:25]([CH3:26])[CH3:27])=[O:24])([C:12]2=[N:11][C:10]=1[C:31]1[O:44][C:34]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=2)=[CH:33][N:32]=1)[CH2:17][CH2:16]3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)C(=O)NC12CCC(CC1)Cn1c2nc(C(=O)NCC(=O)Cc2ccc(F)cc2)c(OCc2ccccc2)c1=O
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: CN(C)C(=O)C(=O)NC12CCC(CC1)Cn1c2nc(-c2ncc(Cc3ccc(F)cc3)o2)c(OCc2ccccc2)c1=O
Yield: 53.6 %

Procedure:
To a mixture of N′-(3-(benzyloxy)-2-((3-(4-fluorophenyl)-2-oxopropyl)carbamoyl)-4-oxo-6,7,8,9-tetrahydro-7,10-ethanopyrimido[1,2-a]azepin-10(4H)-yl)-N,N-dimethylethanediamide, Intermediate 16 (125 mg, 0.207 mmol) in THF (8 mL) was added Burgess Reagent (345 mg, 1.450 mmol) and the mixture heated to reflux for 5 h. The mixture was then cooled, concentrated and purified by preparative HPLC to afford the title compound (65 mg, 0.111 mmol, 53.6% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 9.24 (1H, s), 7.38-7.42 (2H, m), 7.30-7.34 (3H, m), 7.18-7.23 (2H, m), 7.11 (1H, s), 6.99-7.04 (2H, m), 5.38 (2H, s), 4.18 (2H, d, J=3.66 Hz), 4.02 (2H, s), 3.30 (3H, s), 3.03 (3H, s), 2.88-2.96 (2H, m), 2.54 (1H, br. s.), 1.94-2.10 (4H, m), 1.71-1.80 (2H, m). LCMS (M+H)=586.31.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.CS[C:14](=[NH:19])[NH:15][N+:16]([O-:18])=[O:17]>CO>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:14]([NH:15][N+:16]([O-:18])=[O:17])=[NH:19]
Reactant: NCCCCc1ccccn1
Reactant: CSC(=N)N[N+](=O)[O-]
Solvent: CO
Product: N=C(NCCCCc1ccccn1)N[N+](=O)[O-]

Procedure:
A solution of 2-(4-aminobutyl)pyridine (2.9 g) and S-methyl-N-nitroisothiourea (2.9 g) in methanol (50 ml) was heated at 50-65° for 4-5 hours. Concentration, followed by recrystallisation of the residue yielded N-[4-(2-pyridyl)butyl]-N'-nitroguanidine.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1)=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]3[CH:38]=[CH:39][C:40]([OH:43])=[CH:41][CH:42]=3)=[O:36])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C(CCCCCBr)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccc(O)cc2)CC1
Yield: 28 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (0.57 g) as starting compound, potassium carbonate (0.82 g) and 6-bromo-1-(4-hydroxyphenyl)-1-hexanone (0.42 g) were reacted and treated in the same manner as in Example 172 to give 0.21 g of 4-amino-5-chloro-N-((1-(6-(4-hydroxyphenyl)-6-oxohexyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [CH2:1]([O:13][C:14]1[N:15]=[CH:16][S:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Li]CCCC.[CH:24]([Si:27]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])Cl)([CH3:26])[CH3:25]>C1COCC1>[CH2:1]([O:13][C:14]1[N:15]=[C:16]([Si:27]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:24]([CH3:26])[CH3:25])[S:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CCCCCCCCCCCCOc1cscn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOc1csc([Si](C(C)C)(C(C)C)C(C)C)n1
Temperature: -78 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
A solution of 4.38 g (16.3 mmol) of 4-dodecyloxythiazole (10) in 150 mL of THF was cooled to −78° C. The resulting suspension was treated dropwise with 6.50 mL (16.3 mmol) of n-BuLi (2.5 M in hexanes). The mixture was stirred for 2 hours then the dry ice bath was removed for several minutes to form a yellow solution. The mixture was cooled to −78° C. and treated with 3.76 g (19.5 mmol) of triisopropylchlorosilane. The dry ice bath was removed and the mixture was stirred at ambient temperature for 90 minutes. The mixture was concentrated in vacuo and separated by flash chromatography (silica gel, 5.5×33 cm, chloroform) to give 6.24 g (90% yield) of compound 11 as a pale yellow oil. 1H NMR (500 MHz) δ 6.24 (s, 1H), 4.10 (t, 2H, J=6.7 Hz), 1.83 (m, 2H), 1.49-1.23 (m, 21H), 1.13 (d, 18H), 0.90 (t, 3H, J=7.0).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CS(C)=O.C(OCC)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: Nc1ccc(CCC(=O)c2ccc(F)cc2)cc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Nc1ccc(CCC(=O)c2ccc(N3CCOCC3)cc2)cc1
Temperature: 105 °C

Procedure:
A mixture of 3-(4-aminophenyl)-1-(4-fluorophenyl)propan-1-one (0.56 g, 2.32 mmol) (prepared as described in Example 1b) and morpholine (1.01 g, 11.62 mmol) in dimethylsulfoxide (12 mL) was heated at 100-110° C. under nitrogen for about 12 hours. The reaction mixture was cooled, diluted with ethyl acetate (150 mL), washed with cold water and brine. The organic layer was separated, dried, and evaporated in vacuo to give the title compound as an oil which was used as such in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:9]=2[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[N:19]1([CH2:24][CH:25]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)O)[CH:23]=[CH:22][N:21]=[CH:20]1>>[N:19]1([CH2:24][CH:25]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:18][C:16]2[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:17]=2)[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: COC(=O)c1ccc(O)cc1-c1ccc(F)cc1
Reactant: OC(Cn1ccnc1)c1ccc(F)cc1
Product: COC(=O)c1ccc(OC(Cn2ccnc2)c2ccc(F)cc2)cc1-c1ccc(F)cc1

Procedure:
Methyl 4-[2-(imidazol-1-yl)-1-(4-fluorophenyl)ethoxy]-2-(4-fluorophenyl)benzoate was prepared from methyl 2-(4-fluorophenyl)-4-hydroxybenzoate and 2-(imidazol-1-yl)-1-(4-fluorophenyl)ethanol using the Mitsunobu reaction as described for the preparation of methyl 5-[2-(2-methylimidazol-1-yl 1-(4-fluorophenyl/ethoxy]-2-(4-fluorophenethyl)benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:28])=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=2)[CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][N:3]=1)[C:8]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:28])=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=2)[CH:17]=1)=[O:9]
Reactant: COC(=O)c1ccc(-c2cc(N)ccc2C)cc1
Reactant: O=C(Cl)c1ccnc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(-c2cc(NC(=O)c3ccnc(Cl)c3)ccc2C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 60.6 %

Procedure:
2-Chloropyridine-4-carbonyl chloride (1.58 g, 9.0 mmol) in DCM (10 ml) was added dropwise to a solution of methyl 5′-amino-2′-methyl-1,1′-biphenyl-4-carboxylate (1.81 g, 7.5 mmol) and triethylamine (3.13 ml, 22.5 mmol) in DCM (10 ml) at 0° C. The reaction was stirred at room temperature for 20 h, the solvent evaporated under vacuum and the residue partitioned between ethyl acetate (50 ml) and saturated aqueous sodium bicarbonate (50 ml). The aqueous was extracted with ethyl acetate (50 ml) and the combined organic phases washed with brine (50 ml), dried (magnesium sulphate) and the solvent evaporated under vacuum. The residue was purified by flash column chromatography on silica eluting with DCM/ethanol/ammonia (300:8:1). The solvents were evaporated under vacuum to give methyl 5′-[(2-chloroisonicotinoyl)amino]-2′-methyl-1,1′-biphenyl-4-carboxylate (1.73 g, 61%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[C:6](=[O:13])[NH:5][C:4]1=[O:14])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]1[N:33]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:26]2[N:27]=[C:28]([C:31]#[N:32])[N:29]=[CH:30][C:25]=2[CH:24]=1>CS(C)=O>[CH3:36][C:35]([CH3:38])([CH3:37])[CH2:34][N:33]1[C:26]2[N:27]=[C:28]([C:31]#[N:32])[N:29]=[CH:30][C:25]=2[CH:24]=[C:23]1[CH2:22][N:10]1[CH2:11][CH2:12][C:7]2([N:3]([CH2:1][CH3:2])[C:4](=[O:14])[NH:5][C:6]2=[O:13])[CH2:8][CH2:9]1
Reactant: CC(C)(C)Cn1c(CBr)cc2cnc(C#N)nc21
Reactant: CCN1C(=O)NC(=O)C12CCNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCN1C(=O)NC(=O)C12CCN(Cc1cc3cnc(C#N)nc3n1CC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.2 %

Procedure:
To a solution of 2,4-dioxo-1,3,8-triaza-spiro[4.5]decane-3,8-dicarboxylic acid di-tert-butyl ester (0.4 g, 1.1 mmol) in DMF (8 ml), NaH (80 mg, 2.2 mmol) and ethyl bromide (166 □1, 2.16 mmol) are added at room temperature. The reaction mixture is stirred at ambient temperature for 15 h, quenched with saturated ammonium clroride and extracted with AcOEt. The organic layer is washed with brine, dried over magnesium sulfate and filtrated. To a solution of 1-ethyl-2,4-dioxo-1,3,8-triaza-spiro[4.5]decane-3,8-dicarboxylic acid di-tert-butyl ester (1.1 mmol) in CH2Cl2 (10 ml), TFA (10 ml) are added at 0° C. The reaction mixture is stirred at room temperature for 1 h. After removal of the solvent, ethyl ether is added to the residue to give 34 mg of desired product in 10% yield. To a solution of 1-ethyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione (30 mg, 0.096 mmol) in DMSO (1 ml), potassium carbonate (13.8 mg, 0.1 mmol) and 6-bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (30.7 mg, 0.1 mmol) are added to the mixture at ambient temperature. The reaction mixture is stirred at ambient temperature for 3 h, quenched with saturated ammonium clroride and extracted with AcOEt. The combined extracts are washed with H2O, brine and dried over magnesium sulfate. The combined extracts are concentrated and the residue is purified by reverse phase preparative HPLC to give 20 mg of desired product in 3.6% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:26]([O:11][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:12])[CH:10]=[CH:9][CH:8]=1)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13]
Reactant: CCCCCCCCCCCCCCBr
Reactant: COC(=O)Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCOc1cccc(CC(=O)OC)c1
Reaction time: 24 h
Yield: 44.4 %

Procedure:
A mixture of 46.5 g of 3-hydroxybenzeneacetic acid methyl ester, 77.6 g n-tetradecyl bromide and 42.54 g of potassium carbonate in 500 ml of acetone is refluxed for 24 hours. Another 15.5 g of potassium carbonate is added and reflux continued for another 24 hours. An additional 15.5 g of potassium carbonate is added and reflux continued for another 24 hours. The mixture is filtered and the filtrate evaporated to a residue which is poured into water and extracted with ether. The organic layer is dried and evaporated to a residue which is crystallized from hexane to give 45 g of the desired product as a white solid, m.p. 31°-33° C.
Reaction SMILES: CO[C:3]([C:5]1[N:13]=[CH:12][C:11]2[NH:10][C:9]3[N:14]=[CH:15][C:16]([C:18]4[CH:23]=[CH:22][C:21]([CH2:24][N:25]5[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]5)=[CH:20][CH:19]=4)=[CH:17][C:8]=3[C:7]=2[CH:6]=1)=[O:4].[CH2:31]([NH2:33])[CH3:32]>C1COCC1>[CH2:31]([NH:33][C:3]([C:5]1[N:13]=[CH:12][C:11]2[NH:10][C:9]3[N:14]=[CH:15][C:16]([C:18]4[CH:19]=[CH:20][C:21]([CH2:24][N:25]5[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]5)=[CH:22][CH:23]=4)=[CH:17][C:8]=3[C:7]=2[CH:6]=1)=[O:4])[CH3:32]
Reactant: CCN
Reactant: COC(=O)c1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Solvent: C1CCOC1
Product: CCNC(=O)c1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Yield: 48 %

Procedure:
A solution of 3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid methyl ester (152 mg, 0.380 mmol) in 2M ethylamine in THF (8.0 mL) was heated to 80° C. for 4 days in a sealed tube. The mixture was allowed to cool and concentrated in vacuo. The residue was redissolved in DMSO and purified by preparative HPLC [2-60% MeCN/water modified with 0.1% ammonium hydroxide] to afford a dark brown solid (74.9 mg, 48%). 1H NMR (DMSO-D6, 500 MHz): 9.19 (d, J=2.2 Hz, 1H), 8.99 (s, 1H), 8.97 (d, J=2.2 Hz, 1H), 8.91 (s, 1H), 8.72 (m, 1H), 8.24 (s, 1H), 7.81 (d, J=8.1 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 3.47-3.33 (m, 2H), 2.38 (m, 4H), 1.53 (m, 4H), 1.42 (m, 2H), 1.18 (t, J=7.2 Hz, 3H). LCMS (Method E): RT=3.30 min, M+H+=414.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.[NH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([Cl:24])=[CH:19][CH:20]=2)[N:15]=1.C(#N)C>O>[Cl:24][C:18]1[N:17]=[C:16]2[C:21]([CH:22]=[CH:23][C:14]([NH:13][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][CH:11]=[C:3]([N:2]([CH3:1])[CH3:12])[CH:4]=3)=[N:15]2)=[CH:20][CH:19]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: CN(C)c1cccc(C(=O)O)c1
Solvent: O
Solvent: CC#N
Product: CN(C)c1cccc(C(=O)Nc2ccc3ccc(Cl)nc3n2)c1
Temperature: 4 °C
Yield: 63.1 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 3-dimethylaminobenzoic acid (6.6 g), N,N'-carbonyldiimidazole (6.5 g) and 2-amino-7-chloro-1,8-naphthyridine (5.4 g). The product produced by precipitation in water (9 g; m.p. 212° C.) is dissolved in boiling acetonitrile (400 cc). After 3 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (3×20 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)-3-dimethylaminobenzamide (6.2 g) is produced, m.p. 215° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([CH2:14][OH:15])=[CH:11][S:12][CH:13]=2)=[CH:5][CH:4]=1)[CH3:2].C(C1C=CC(C2C=C(C(F)(F)F)SC=2CO[C:35]2[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][C:43]([O:45]CC)=[O:44])=[C:37]([CH3:48])[C:36]=2[CH3:49])=CC=1)C>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10]([CH2:14][O:15][C:35]3[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][C:43]([OH:45])=[O:44])=[C:37]([CH3:48])[C:36]=3[CH3:49])=[CH:11][S:12][CH:13]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1ccc(OCc2sc(C(F)(F)F)cc2-c2ccc(CC)cc2)c(C)c1C
Reactant: CCc1ccc(-c2cscc2CO)cc1
Product: CCc1ccc(-c2cscc2COc2ccc(CCC(=O)O)c(C)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 208 step 6 and 7 by coupling of (4-(4-ethylphenyl)thiophen-3-yl)methanol and ethyl 3-(4-hydroxy-2,3-dimethyl phenyl) propanoate followed by hydrolysis of ethyl 3-(4-((3-(4-ethylphenyl)-5-(trifluoromethyl)thiophen-2-yl)methoxy)-2,3-dimethylphenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.48 (m, 1H), 7.36 (d, J=7.0 Hz, 2H), 7.28 (s, 1H), 7.22 (d, J=7.0 Hz, 2H), 6.95 (d, J=6.5 Hz, 1H), 6.67 (d, J=6.5 Hz, 1H), 4.98 (s, 2H0, 2.94 (t, J=7.0 Hz, 2H), 2.70 (m, 2H), 2.60 (t, J=7.0 Hz, 2H), 2.24 (s, 3H), 2.20 (s, 3H), 1.28 (t, J=6.5 Hz, 3H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH3:36])[C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21]([N:24]5[C@H:28]([CH2:29][OH:30])[CH2:27][CH2:26][C:25]5=[O:31])=[CH:20][C:19]=4[S:32]([CH3:35])(=[O:34])=[O:33])=[O:17])[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.S(C1C=CC(C)=CC=1)(O[CH3:41])(=O)=O>>[CH:1]1([C:4]2[CH:5]=[C:6]([CH3:36])[C:7]([N:10]3[CH2:11][CH2:12][N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21]([N:24]5[C@H:28]([CH2:29][O:30][CH3:41])[CH2:27][CH2:26][C:25]5=[O:31])=[CH:20][C:19]=4[S:32]([CH3:35])(=[O:33])=[O:34])=[O:17])[CH2:14][CH2:15]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)CC[C@H]3CO)cc2S(C)(=O)=O)CC1
Product: COC[C@@H]1CCC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)c(S(C)(=O)=O)c1

Procedure:
Using (S)-1-{4-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]-3-methanesulfonylphenyl}-5-hydroxymethylpyrrolidin-2-one (240 mg) described in Example 298 and methyl tosylate (71 μL) and by the reaction and treatment in the same manner as in Example 36, the title compound (28 mg) was obtained.