Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([Mg]Br)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](=[S:17])=[S:16].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:15]([S:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[S:16])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccc(-c2ccccc2)cc1
Reactant: BrCc1ccccc1
Reactant: S=C=S
Solvent: C1CCOC1
Product: S=C(SCc1ccccc1)c1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Yield: 87 %

Procedure:
In 50 mL of dry tetrahydrofuran, 204 mL of (4-phenyl)phenyl magnesium bromide (a 0.5M tetrahydrofuran solution) was added, and the resulting mixture was stirred and then cooled to 0° C. While keeping 0° C., 7.77 g of carbon disulfide was added over 15 minutes, and the resulting mixture was stirred at 0° C. for 1 hour. Subsequently, 15.86 g of benzyl bromide was added over 15 minutes, and the resulting mixture was stirred at room temperature for 1 hour. After adding 300 mL of ice water, the organic layer was extracted with 500 mL of ethyl acetate. Furthermore, the organic layer was washed with 300 mL of brine and dried over anhydrous magnesium sulfate. The anhydrous magnesium sulfate was removed by filtration, and the residual solvent was then removed. The residue was purified on silica gel (ethyl acetate/hexane solvent) to obtain benzyl (4-phenyl)dithiobenzoate (28.4 g, yield: 87%) (exchange-chain transfer type RAFT agent).
Reaction SMILES: N[C@@H]1CCN([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)C1.[CH3:25][C@@:26]1([OH:31])[CH2:30][CH2:29][NH:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[OH:31][C@:26]1([CH3:25])[CH2:30][CH2:29][N:28]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:27]1
Reactant: C[C@@]1(O)CCNC1
Reactant: N#Cc1ccc(-c2ccc(OCCCN3CC[C@@H](N)C3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@]1(O)CCN(CCCOc2ccc(-c3ccc(C#N)cc3)cc2)C1
Yield: 40 %

Procedure:
4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile (177 mg, 0.65 mmol), (3R)-3-methyl-3-pyrrolidinol (75 mg, 0.74 mmol), potassium carbonate (153 mg) and potassium iodide (184 mg) in 10 mL of DMF were heated at 110° C. for 10 hours. The mixture was evaporated under reduced pressure and the residue was purified by chromatography (CHCl3:MeOH:NH4OH, 9:1:0.1) to provide the title compound (40 % yield).
Reaction SMILES: C(OC(C1C=C(C2C=CC(C[S:19][CH2:20][CH2:21][OH:22])=CC=2)C=CC=1)=O)C.[CH2:23]([O:25][C:26]([C:28]1[CH:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40]Br)[CH:35]=2)[CH:31]=[CH:32][CH:33]=1)=[O:27])[CH3:24].SCCO.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:23]([O:25][C:26]([C:28]1[CH:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][S:19][CH2:20][CH2:21][OH:22])[CH:35]=2)[CH:31]=[CH:32][CH:33]=1)=[O:27])[CH3:24]
Reactant: CCOC(=O)c1cccc(-c2cccc(CBr)c2)c1
Reactant: CCOC(=O)c1cccc(-c2ccc(CSCCO)cc2)c1
Agent: O=C([O-])[O-]
Agent: OCCS
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(-c2cccc(CSCCO)c2)c1

Procedure:
3′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester was synthesized as described for 4′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester. 3′-Bromomethyl-biphenyl-3-carboxylic acid ethyl ester (3.4 g, 10.65 mmol, 1 eq.) in anhydrous DMF was treated with 2-mercaptoethanol (1.0g, 12.78 mmol, 1.2 eq.) and potassium carbonate (4.42 g, 31.95 mmol, 3 eq.). When complete, the reaction was worked up as described leaving a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(O)(=O)C.[N:21]([O-])=[O:22].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:16])[C:12](=[N:21][OH:22])[C:13](=[O:15])[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(=O)CC(C)=O)cc1OC
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C(=O)C(=NO)C(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5 g of 1-(3,4-dimethoxyphenyl)butane-1,3-dione (41) were initially introduced into 25 ml of acetic acid, and 1.71 g of sodium nitrite, dissolved in 5 ml of water, were then added dropwise at 15° C. The reaction solution was stirred at RT for 1 h and then remained standing for 2 h. 50 g of ice were added to the solution and the whole was then stored at 0° C. for 12 h, in connection with which the product precipitated out. The product was subsequently filtered off with suction and dried at 50° C. in a drying oven. The following was obtained: 42 C12H13NO5 (251.24); MS (ESI) 252 (M+H)
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl.[CH2:5]([O:7][CH:8]([O:10][CH:11]([CH:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:9])[CH3:6].[C-:26]#[N:27].[K+]>CO.O1CCCC1.O>[CH3:1][N:2]([CH3:3])[C:22]1([C:26]#[N:27])[CH2:23][CH2:24][CH:19]([CH:11]([O:10][CH:8]([O:7][CH2:5][CH3:6])[CH3:9])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:20][CH2:21]1
Reactant: CCOC(C)OC(Cc1ccccc1)C1CCC(=O)CC1
Reactant: CNC
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCOC(C)OC(Cc1ccccc1)C1CCC(C#N)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
40% aqueous dimethylamine solution (6.05 ml, 47.9 mmol) was added to a mixture of 4 M hydrochloric acid (2.61 ml) and methanol (1.56 ml), while cooling with ice. A solution of 4-[1-(1-ethoxy-ethoxy)-2-phenylethyl]cyclohexanone (2.91 g, 10.0 mmol) in methanol (6 ml) and tetrahydrofuran (3 ml) was added to this mixture. Thereafter, potassium cyanide (1.56 g, 24.1 mmol) was added to the mixture, the mixture was stirred at room temperature overnight, water (150 ml) was then added and the mixture was extracted with diethyl ether (4×50 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The residue was taken up in methylene chloride (50 ml) and the mixture was washed with water (30 ml). The organic phase was dried again with sodium sulfate and concentrated i. vac.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C@@H:4]1[C@@H:6]([C:7](Cl)=[O:8])[C:5]1([CH3:11])[CH3:10].[CH3:13][C:14]1[CH:15]([OH:25])[CH2:16][C:17](=[CH2:24])[C:18]=1[CH2:19][C:20]([F:23])([F:22])[F:21].N1C=CC=CC=1.N>CN(C)C1C=CN=CC=1.O1CCCC1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[CH3:1][C:2]([CH3:12])=[CH:3][C@@H:4]1[C@@H:6]([C:7]([O:25][CH:15]2[CH2:16][C:17](=[CH2:24])[C:18]([CH2:19][C:20]([F:21])([F:22])[F:23])=[C:14]2[CH3:13])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: C=C1CC(O)C(C)=C1CC(F)(F)F
Reactant: CC(C)=C[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Agent: CN(C)c1ccncc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: N
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=C1CC(OC(=O)[C@@H]2[C@@H](C=C(C)C)C2(C)C)C(C)=C1CC(F)(F)F
Reaction time: 2 h
Yield: 52.4 %

Procedure:
Under ice-water cooling, 350 mg of (1R)-trans-3-(2-methyl-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid chloride was added dropwise to the mixed solution of 300 mg of (RS)-2-methyl-4-methylidene-3-(2,2,2-trifluoroethyl)cyclopent-2-en-1-ol, 5 mg of 2,6-di-tert-butyl-4-methylphenol, 185 mg of pyridine and 5 mg of 4-dimethylaminopyridine in 10 ml of dry terahydrofuran and then the resultant reaction mixture was allowed to react further 6 hours at room temperature. Then 10 ml of 10% aqueous ammonia solution was added to the solution and vigorously stirred for 2 hours. The reaction mixture was extracted three times with diethyl ether and the ether layers were combined. The combined layer was washed with brine and dried over anhydrous magnesium sulfate. After removal of the drying agent, the solvent was evaporated. The obtained residue was subjected to silica gel column chromatography to afford 280 mg of the desired (RS)-2-methyl-4-methylidene-3-(2,2,2-trifluoroethyl)cyclopent-2-en-1-yl (1R)-trans-3-(2-methyl-1-propenyl)-2,2-dimethylcyclopropanecarboxylate (Compound No.15). Yield 52% (Eluent: n-hexane/ethyl acetate=30/1, 2,6-di-tert-butyl-4-methylphenol 0.1% ) nD21 1.4805
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][O:15][C:14]3[N:18]=[CH:19][C:20]([C:22]#[N:23])=[CH:21][C:13]2=3)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH2:27][OH:28].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[OH:28][NH:27][C:22]([C:20]1[CH:19]=[N:18][C:14]2[O:15][CH2:16][CH2:17][N:12]([S:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:25])([F:24])[F:1])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[C:13]=2[CH:21]=1)=[NH:23]
Reactant: N#Cc1cnc2c(c1)N(S(=O)(=O)c1ccc(C(F)(F)F)cc1)CCO2
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N=C(NO)c1cnc2c(c1)N(S(=O)(=O)c1ccc(C(F)(F)F)cc1)CCO2
Temperature: 80 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
To a suspension of 1-(4-(trifluoromethyl)phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carbonitrile (75 mg, 0.203 mmol) in ethanol (2 mL) and water (0.5 mL) was added hydroxylamine hydrochloride (42.3 mg, 0.609 mmol) and sodium carbonate (108 mg, 1.015 mmol). The reaction was heated to 80° C. and stirred at that temperature for 16 h. The reaction mixture was concentrated in vacuo. The resulting paste was suspended in water (10 mL) and extracted with EtOAc (2×20 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated in vacuo to provide N-hydroxy-1-(4-(trifluoromethyl)phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboximidamide (80 mg, 0.199 mmol, 98% yield) as a white solid, which was used without further purification. LCMS (+ESI) m/z=403.1 [M+H]+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CS(O[CH:15]1[CH2:18][N:17]([CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16]1)(=O)=O>CN(C=O)C>[C:20]1([CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:17]2[CH2:18][CH:15]([O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:16]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 66.6 %

Procedure:
To a cooled solution of phenol (149 mg, 1.58 mmol) in DMF (3.9 mL), NaH (60% in oil, 95 mg, 2.37 mmol) was added portionwise and the suspension was stirred at 0° C. for 15 min. 1-(Diphenylmethyl)azetidin-3-yl methanesulfonate (500 mg, 1.58 mmol; which may be prepared as described in Step 1) was then added and the reaction mixture stirred at 80° C. overnight and concentrated under reduced pressure. The residue was purified on column chromatography (eluent: pentane/EtOAc 98/2 to 95/5) to give the title compound (332 mg, 67%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([N:15]3[CH2:18][CH:17]([OH:19])[CH2:16]3)=[O:14])=[N:10][N:9]=2)=[CH:4][CH:3]=1.ClC1C=CC(C2OC(C(OC)=O)=NN=2)=CC=1.C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>ClCCl>[CH3:43][S:44]([O:19][CH:17]1[CH2:16][N:15]([C:13]([C:11]2[O:12][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:9][N:10]=2)=[O:14])[CH2:18]1)(=[O:46])=[O:45]
Reactant: O=C(c1nnc(-c2ccc(Cl)cc2)o1)N1CC(O)C1
Reactant: CS(=O)(=O)Cl
Agent: COC(=O)c1nnc(-c2ccc(Cl)cc2)o1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(C(=O)c2nnc(-c3ccc(Cl)cc3)o2)C1
Reaction time: 7 h
Yield: 75 %

Procedure:
A suspension of 2B —which contained approximately 50% of methyl 5-(4-chlorophenyl)-1,3,4-oxadiazole-2-carboxylate as an impurity—(1.38 g, 2.47 mmol) in dichloromethane (50 mL) was cooled in an ice-bath. Triethylamine (0.51 mL, 3.70 mmol) was added followed by methanesulfonyl chloride (0.27 mL, 3.45 mmol). After the addition, the cooling bath was removed. The mixture was stirred for 7 h. The reaction mixture was transferred to a reparatory funnel and was washed with water followed by aqueous NaHCO3. The organic solution was dried (phase separator) and evaporated. Dichloromethane (50 mL) and diethyl ether (200 mL) were added and the solid product was collected by filtration. The solid was washed twice with diethyl ether and then dried in vacuo. The product was purified using flash column chromatography first eluting with dichloromethane and then with a mixture of dichloromethane and methanol containing 2M NH3 (20:1). There was obtained 0.66 g (75%) of 2C as a solid. 1H NMR (500 MHz, CDCl3): δ 3.13 (s, 3H), 4.43 (dd, 1H), 4.65 (dd, 1H), 4.87 (dd, 1H), 5.12 (dd, 1H), 5.41 (m, 1H), 7.53 (d, 2H), 8.10 (d, 2H), MS (APCI+) m/z 358 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH:22]=O)=[C:12]2[CH3:24])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[Cl-].C[NH3+].[C:28]([BH3-])#[N:29].[Na+]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH2:22][NH:29][CH3:28])=[C:12]2[CH3:24])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: [BH3-]C#N
Reactant: Cc1c(C=O)cc(-c2ccccc2)n1S(=O)(=O)c1cccc(Cl)c1
Agent: C[NH3+]
Agent: [Cl-]
Agent: [Na+]
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(Cl)c2)c1C
Product: Cl
Yield: 65.5 %

Procedure:
Using 1-[(3-chlorophenyl)sulfonyl]-2-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (171 mg), methylammonium chloride (311 mg) and sodium cyanoborohydride (103 mg), a procedure as in Example 4 was performed to give the title compound as a colorless oil (yield 64 mg, 34%).
Reaction SMILES: [O:1]1[CH:6]([C:7]([OH:9])=[O:8])[CH:2]1[C:3]([OH:5])=O.[CH2:10]([K])[CH3:11].C(Cl)(=O)C(Cl)=O.[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([NH:25][C:3](=[O:5])[CH:2]2[O:1][CH:6]2[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(O)C1OC1C(=O)O
Reactant: NC1CCCCC1
Reactant: CC[K]
Agent: O=C(Cl)C(=O)Cl
Product: CCOC(=O)C1OC1C(=O)NC1CCCCC1
Yield: 58.1 %

Procedure:
Following the procedure of Example 1, monoethyl potassium epoxysuccinate (5 g) was successively treated with oxalyl chloride (3.72 g) and cyclohexylamine (5 g) to give 3.5 g of ethyl N-cyclohexyl-2,3-epoxysuccinamate (Compound No. 19) as colorless needles melting at 98°-100° C.
Reaction SMILES: CC(C)([O-])C.[K+].[Br-].[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:10])=[O:9].[C:35]([C:39]1[C:44]2[CH2:45][C:46](C=O)([CH3:48])[O:47][C:43]=2[CH:42]=[C:41]([C:51]([CH3:54])([CH3:53])[CH3:52])[C:40]=1[O:55][Si](C)(C)C)([CH3:38])([CH3:37])[CH3:36]>C1COCC1>[C:35]([C:39]1[C:44]2[CH2:45][C:46]([CH:15]=[CH:14][CH2:13][CH2:12][CH2:11][C:8]([OH:10])=[O:9])([CH3:48])[O:47][C:43]=2[CH:42]=[C:41]([C:51]([CH3:54])([CH3:53])[CH3:52])[C:40]=1[OH:55])([CH3:38])([CH3:37])[CH3:36]
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(C=O)Cc2c(cc(C(C)(C)C)c(O[Si](C)(C)C)c2C(C)(C)C)O1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C=CCCCC(=O)O)Cc2c(cc(C(C)(C)C)c(O)c2C(C)(C)C)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
Under a nitrogen atmosphere, a solution of 0.92 g of potassium t-butoxide in 10 ml of THF was added dropwise to a suspension of 0.46 g of 5-carboxypentyltriphenylphosphonium bromide in 5 ml of THF at 0° C., and the mixture was stirred for 30 minutes. To the reaction solution was added dropwise a solution of 4,6-di-t-butyl-2-formyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran synthesized in Example 72-2) in 10 ml of THF, and the mixture was stirred overnight while slowly warming to room temperature. The reaction solution was extracted with water and diethyl ether, and the combined aqueous layers were acidified with concentrated hydrochloric acid and extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography eluting with n-hexane containing 50% ethyl acetate to give 0.22 g of 6-(4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl)-5-hexenoic acid as a colorless viscous liquid (yield 43%).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6].O[C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]34[CH2:29][CH2:28][C:25]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([CH2:26][CH2:27]3)[CH2:24][CH2:23]4)=[CH:18][CH:17]=2)=[N:14][CH:15]=1>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:8][C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]34[CH2:29][CH2:28][C:25]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([CH2:26][CH2:27]3)[CH2:24][CH2:23]4)=[CH:20][CH:21]=2)=[N:14][CH:15]=1)(=[O:7])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6]
Reactant: CCC/C=C/C(=O)O
Reactant: CCCCCC12CCC(c3ccc(-c4ncc(O)cn4)cc3)(CC1)CC2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC/C=C/C(=O)Oc1cnc(-c2ccc(C34CCC(CCCCC)(CC3)CC4)cc2)nc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
A solution of N,N-dicyclohexylcarbodiimide (0.22 g, 1.1 mmol) in dichloromethane (10 cm3) is added to a solution of (E)-hex-2-enoic acid (0.10 g, 0.9 mmol), 1-[4-(5-hydroxypyrimidin-2-yl) phenyl]-4-pentylbicyclo[2.2.2]octane (0.25 g, 0.9 mmol), 4-(dimethylamino)pyridine (0.04 g) in dichloromethane (20 cm3), cooled in an ice bath (0° C.) under an atmosphere of nitrogen. The reaction mixture is stirred overnight, filtered to remove precipitated material and the filtrate is evaporated down under reduced pressure. The crude product is purified by column chromatography on silica gel using a 9:1 petroleum ether (40-60° C.)/ethyl acetate mixture as eluent, followed by recrystallisation from ethanol to yield the desired ester (0.15 g, 45%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:9]=[C:10]([CH:14]([OH:20])[C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[CH:11]=[N:12][CH:13]=2)=[CH:6][N:5]=[C:4]2[N:21](COCC[Si](C)(C)C)[CH:22]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])[C:3]=12.[CH3:40][NH:41][CH3:42].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.CNC.C(N(CC)C(C)C)(C)C>O1CCOCC1.CN(C=O)C>[CH3:40][N:41]([CH3:42])[C:2]1[C:7]([C:8]2[CH:9]=[C:10]([CH:14]([OH:20])[C:15]([N:17]([CH3:18])[CH3:19])=[O:16])[CH:11]=[N:12][CH:13]=2)=[CH:6][N:5]=[C:4]2[NH:21][CH:22]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])[C:3]=12
Reactant: CNC
Reactant: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncc(-c3cncc(C(O)C(=O)N(C)C)c3)c(Cl)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cncc(C(O)C(=O)N(C)C)c3)c(N(C)C)c12
Temperature: 150 °C
Reaction time: 1 h
Yield: 1.1 %

Procedure:
2-{5-[4-Chloro-3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridin-3-yl}-2-hydroxy-N,N-dimethyl-acetamide (18 mg, 0.317 mmol) was dissolved in a solution of dimethyl amine (2 mL, 17.7 mmol) and 1,4 dioxane (1 mL). The mixture was heated for at 150° C. for 15 hours in a sealed vessel and concentrated under in vacuo. To the residue were added O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (14.5 mg, 0.0381 mmol), dimethylamine hydrochloride salt (12 mg, 0.147 mmol), N,N-dimethylformaldehyde and N,N-Diisopropylethylamine (33 μL, 0.317 mmol). After stirring at 23° C. for 1 hour, the mixture was concentrated. The crude product was dissolved in 1 mL TFA and stirred at 23° C. for 1 hour. The solvent was evaporated and the resulting oil was dissolved in 1 mL DMSO and 50 μL ethylenediamine and purified by mass triggered reverse phase HPLC to afford 2-{5-[4-Dimethylamino-3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridin-3-yl}-2-hydroxy-N,N-dimethyl-acetamide (1.60 mg, 0.00359 mmol, 1.1% yield). 1H-NMR [500 MHz, d6-DMSO] δ: 8.56 (d, 2H), 7.99 (s, 1H), 7.63 (s, 1H), 7.32 (m, 1H), 7.24 (dd, 1H), 7.04 (d, 1H), 6.97 (t, 1H), 5.57 (s, 1H) 3.68 (s, 4H), 2.95 (s, 4H), 2.82 (s, 3H), 2.18 (s, 6H); MS [MH+] m/z: 446.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10]>C(Cl)Cl>[CH3:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:22][N:23]=2)=[CH:14][CH:13]=1)(=[O:10])=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
TFA (2 mL) was added to a solution of 1,1-dimethylethyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (705 mg, 1.58 mmol) in CH2Cl2 (50 mL) at ambient temperature. The mixture was stirred at ambient temperature overnight. The mixture was concentrated, and the crude product was purified by chromatography on a silica gel column using 0 to 10% MeOH/CH2Cl2 give 460 mg (84%) of 2-[4-(methylsulfonyl)phenyl]-5-[(4-piperidinylmethyl)oxy]pyridine as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.44 (d, 1H, J=2.9 Hz), 8.29 (d, 2H, J=8.6 Hz), 8.08 (d, 1H, J=8.8 Hz), 8.00 (d, 2H, J=8.6 Hz), 7.55 (dd, 1H, Ja=8.8 Hz, Jb=3.0 Hz), 4.04 (d, 2H, J=6.2 Hz), 3.40-3.25 (m, 2H), 3.25 (s, 3H), 3.01-2.83 (m, 2H), 2.22-2.02 (m, 1H), 2.00-1.90 (m, 2H), 1.60-1.37 (m, 2H); LRMS (ESI), m/z 347 (M+H).
Reaction SMILES: CC1C=CC(B2OC(C)(C)C(C)(C)O2)=C([NH:8]C(=O)OC(C)(C)C)C=1.Cl[C:26]1[C:27]([C:37]#[N:38])=[N:28][CH:29]=[C:30]([CH:36]=1)[C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[Na+].[Na+].[C:45]1([CH3:51])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(O)C>CO>[NH2:8][C:37]1[C:27]2[N:28]=[CH:29][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:36][C:26]=2[C:48]2[CH:47]=[CH:46][C:45]([CH3:51])=[CH:50][C:49]=2[N:38]=1
Reactant: Cc1ccccc1
Reactant: CCOC(=O)c1cnc(C#N)c(Cl)c1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(NC(=O)OC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CCOC(=O)c1cnc2c(N)nc3cc(C)ccc3c2c1
Temperature: 25 °C

Procedure:
A solution of tert-butyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (from Example 5/step 2) (1.0 eq.) and ethyl 5-chloro-6-cyanonicotinate (from the previous step) (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol %), and 2N aqueous sodium carbonate solution (2.0 eq.) in toluene/ethanol (2:1, 0.03 M) was stirred at 100° C. overnight. After cooling to ambient temperature, the reaction content was diluted with methanol. The insoluble solids were filtered off, and the filtrate was concentrated en vaccuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give ethyl 5-amino-8-methylbenzo[f][1,7]naphthyridine-2-carboxylate.
Reaction SMILES: C1(C[CH2:8][CH2:9][NH2:10])C=CC=CC=1.[CH2:11]([NH:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([N:26]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([C:35]([OH:37])=O)[CH:32]=3)[CH2:27]2)=[O:25])=[CH:19][CH:18]=1)=[O:16])[CH2:12][CH3:13].[CH2:38]1C2C(=CC=CC=2)[CH2:40][N:39]1C(NC1C=CC(C(O)=O)=CC=1)=O>>[CH3:38][N:39]([CH3:40])[CH2:8][CH2:9][NH:10][C:35]([C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[CH2:27][N:26]([C:24]([NH:23][C:20]1[CH:19]=[CH:18][C:17]([C:15](=[O:16])[NH:14][CH2:11][CH2:12][CH3:13])=[CH:22][CH:21]=1)=[O:25])[CH2:34]2)=[O:37]
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Reactant: NCCCc1ccccc1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(C(=O)O)cc3C2)cc1
Product: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(C(=O)NCCN(C)C)cc3C2)cc1

Procedure:
The title compound was prepared as described in Example 1C, substituting N1,N1-dimethylethane-1,2-diamine for 3-phenylpropan-1-amine and 2-{[4-(propylcarbamoyl)phenyl]carbamoyl}isoindoline-5-carboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.28 (s, 1H), 8.70 (t, J=5.6 Hz, 1H), 8.62 (s, 1H), 8.26 (t, J=5.6 Hz, 1H), 7.86-7.74 (m, 4H), 7.68-7.61 (m, 2H), 7.49 (d, J=7.8 Hz, 1H), 4.84 (bs, 4H), 3.66-3.55 (m, 2H), 3.29-3.12 (m, 4H), 2.90-2.80 (m, 6H), 2.28-1.46 (m, 2H), 0.89 (t, J=7.4 Hz, 3H); MS (ESI(+)) m/e 438 (M+H)+.