Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([N:9]([CH:52]([CH3:54])[CH3:53])[S:10]([C:13]2[CH:14]=[C:15]([CH:49]=[CH:50][CH:51]=2)[C:16]([NH:18][C:19]2[S:20][C:21]3[CH2:48][CH2:47][CH2:46][CH2:45][C:22]=3[C:23]=2[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]3[CH:44]=[CH:43][C:38]([C:39]([O:41]C)=[O:40])=[CH:37][CH:36]=3)=[CH:29][CH:28]=2)=[O:25])=[O:17])(=[O:12])=[O:11])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1([N:9]([CH:52]([CH3:53])[CH3:54])[S:10]([C:13]2[CH:14]=[C:15]([CH:49]=[CH:50][CH:51]=2)[C:16]([NH:18][C:19]2[S:20][C:21]3[CH2:48][CH2:47][CH2:46][CH2:45][C:22]=3[C:23]=2[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]3[CH:44]=[CH:43][C:38]([C:39]([OH:41])=[O:40])=[CH:37][CH:36]=3)=[CH:29][CH:28]=2)=[O:25])=[O:17])(=[O:12])=[O:11])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(N(C(C)C)S(=O)(=O)c2cccc(C(=O)Nc3sc4c(c3C(=O)Nc3ccc(CCc5ccc(C(=O)OC)cc5)cc3)CCCC4)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1(N(C(C)C)S(=O)(=O)c2cccc(C(=O)Nc3sc4c(c3C(=O)Nc3ccc(CCc5ccc(C(=O)O)cc5)cc3)CCCC4)c2)CC1
Yield: 59.4 %

Procedure:
A mixture of 290 mg of methyl 4-(2-{4-[({2-[(3-{[1-(ethoxycarbonyl)cyclopropyl](isopropyl)sulfamoyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate, 1.5 mL of a 1.0 M aqueous sodium hydroxide solution, and 2.9 mL of ethanol was heated and refluxed overnight. The reaction mixture was concentrated under reduced pressure, and to the residue were added water, citric acid, dichloromethane, and THF in this order. The organic layer was separated and then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol). The crude purified product thus obtained was washed with diethyl ether to obtain 169 mg of 4-(2-{4-[({2-[(3-{[1-(ethoxycarbonyl)cyclopropyl](isopropyl)sulfamoyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoic acid as a pale yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].C(=O)=O.[CH2:10]([N:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[CH:17][N+:18]([O-])=O)[CH3:11]>[Cu].[Pd].CO>[NH2:18][CH2:17][CH:13]1[CH2:14][CH2:15][CH2:16][N:12]1[CH2:10][CH3:11]
Reactant: CCN1CCCC1=C[N+](=O)[O-]
Agent: [Cu]
Agent: [Pd]
Agent: O=C([O-])[O-]
Solvent: CO
Product: CCN1CCCC1CN
Reaction time: 2.5 h
Yield: 95 %

Procedure:
A 200 ml. glass beaker having inserted therein a porous unglazed cylinder (40 mm. diameter × 140 mm. length) was used as the electrolytic apparatus and a copper plate (40 × 180 mm2) as the cathode and a palladium plate (30 × 40 mm2) as the anode were used. In the anode chamber (the porous unglazed cylinder) was added 50 ml. of a saturated aqueous sodium carbonate solution and in the cathode chamber (the glass beaker) were added 70 ml. of a 2 N aqueous sodium carbonate solution and 30 ml. of methanol. Then, after carrying out pre-electrolysis for several minutes while passing carbon dioxide through the catholyte solution, 1.56 g. of the powder of 1-ethyl-2-nitromethylenepyrrolidine was added to the cathode chamber and current of 1 ampere was electrified for 2.5 hours with stirring at 20°-23° C. while passing carbon dioxide through the catholyte solution to carry out the electrolysis. Then, by treating the product as in Example 1, 1.22 g. of oily 2-aminomethyl-1-ethylpyrrolidine was obtained with a yield of 95%.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]([CH3:46])([CH3:45])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[CH:21][C:20]=1[C:38]1[N:39]([CH3:44])[N:40]=[CH:41][C:42]=1[Cl:43].[CH:47](=O)[CH2:48][CH3:49].C(Cl)(=O)C>C1COCC1.CO>[Cl:43][C:42]1[CH:41]=[N:40][N:39]([CH3:44])[C:38]=1[C:20]1[CH:21]=[C:22]([NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=2)[CH:23]=[CH:24][C:19]=1[O:18][CH2:17][C:16]([CH3:46])([NH:15][CH2:47][CH2:48][CH3:49])[CH3:45]
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCC(C)(C)N
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)Cl
Product: CCCNC(C)(C)COc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.3 %

Procedure:
Sodium triacetoxyborohydride (34 mg, 161 μmol) was added to a solution of N-(4-(2-amino-2-methylpropoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)phenyl)-3-(trifluoromethyl)benzamide (53.8 mg, 115 μmol) and propionaldehyde (6.7 mg, 115 μmol) in THF (0.5 mL), and the mixture was stirred at room temperature. After 4 hours, the reaction was quenched with saturated sodium bicarbonate and extracted with dichloromethane. The extract was evaporated to dryness, the residue was redissolved in methanol, and the products were isolated by preparative HPLC. Product containing fractions were combined and concentrated in a vacuum centrifuge to one fourth of the original volume. The solution was made alkaline with saturated sodium bicarbonate, the product was extracted with dichloromethane, and the extract was evaporated to dryness. The residue was dissolved in a solution of acetyl chloride (16 μl, 230 μmol) in methanol (1 mL) and evaporated to dryness. The residue was dissolved in water and lyophilized to give the title compound (30 mg, 48%) as the hydrochloride salt. LCMS m/z (%)=511.4 (M+H, 37Cl 60.5), 509.3 (M+H, 35Cl 100.0%). 1H NMR (400 MHz, DMSO-d6) δ 0.87 (t, J=7.45 Hz, 3H) 1.26 (s, 6H) 1.46-1.58 (m, 2H) 2.53-2.64 (m, 2H) 3.65 (s, 3H) 4.06 (d, J=10.36 Hz, 1H) 4.16 (d, J=10.36 Hz, 1H) 7.33 (d, J=9.09 Hz, 1H) 7.69 (s, 1H) 7.73 (d, J=2.78 Hz, 1H) 7.80 (t, J=7.83 Hz, 1H) 7.94-8.02 (m, 2H) 8.28 (d, J=8.34 Hz, 1H) 8.31 (s, 1H) 8.65 (s, 2H) 10.59 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[CH2:9]1)[CH2:4][CH3:5])[CH3:2].[H-].[Na+].[Cl:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25][CH:24]=1.Cl.C(=O)(O)[O-].[Na+]>CN(C=O)C.O>[ClH:21].[C:26]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:25]=[CH:24][C:23]([CH2:22][O:18][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][CH:8]([CH2:7][CH2:6][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH2:17][CH2:16]3)=[CH:28][CH:27]=1
Reactant: CCN(CC)CCC1CCc2cc(O)ccc2C1
Reactant: ClCc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCC1CCc2cc(OCc3ccc(-c4ccccc4)cc3)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
To a solution of (+)-2-[2-(N,N-diethylamino)ethyl]-6-hydroxytetralin (4.5 g) in DMF (60 ml) was added sodium hydride (60% in oil, 1.46 g) at 0° C. The reaction mixture was stirred at room temperature for 30 min and a solution of 4-chloromethylbiphenyl (4.08 g) in DMF (40 ml) was added. After stirring at room temperature for 2 hr, the reaction mixture was poured into water, neutralized with 1 N aqueous hydrochloric acid. Saturated aqueous sodium bicarbonate (50 ml) was added and the reaction mixture was extracted with combined solvent of ethyl acetate and THF (1:1). The organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate to ethyl acetate:triethylamine=4:1) and converted into its hydrochloride, which was recrystallized from ethanol-dulsopropyl ether to obtain the titled compound (6 g).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][O:15][C:16]2[CH:27]=[CH:26][C:19]([CH:20]=[CH:21][C:22]([O:24]C)=[O:23])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].S(=O)(=O)(O)O>[OH-].[K+]>[CH2:1]([C@H:8]1[CH2:9][CH2:10][C@H:11]([CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([CH:20]=[CH:21][C:22]([OH:24])=[O:23])=[CH:26][CH:27]=2)[CH2:12][CH2:13]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC[C@H]1CC[C@H](COc2ccc(C=CC(=O)OC)cc2)CC1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: CCCCCCC[C@H]1CC[C@H](COc2ccc(C=CC(=O)O)cc2)CC1
Reaction time: 16 h

Procedure:
A mixture of 8 g of methyl 4-[(trans-4-heptylcyclohexyl)methoxy]cinnamate and 50 ml of 10 percent methanolic potassium hydroxide solution is allowed to stand for 16 hours at room temperature. Thereafter, acidification is effected with aqueous 1 N sulfuric acid with continuous stirring and with cooling, extraction is effected with methylene chloride and the organic phase is washed several times with water, dried over magnesium sulfate and evaporated down. Crystallization from hexane/ethyl acetate gives 4-[(trans-4-heptylcyclohexyl)methoxy]cinnamic acid.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:20])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1>N1C=CC=CC=1.C(OC(=O)CC)(=O)CC>[C:2]([O:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:20])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1)(=[O:1])[CH2:3][CH3:4]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: CCC(=O)OC(=O)CC
Solvent: c1ccncc1
Product: CCC(=O)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 0 °C
Reaction time: 1 h
Yield: 173.9 %

Procedure:
3-Hydroxy-oestra-1,3,5(10)-trien-17-one (2 g) in pyridine (20 ml.) and propionic anhydride (20 ml) was allowed to stand at room temperature for 1 hour. The solution was poured into ice-water (250 ml) and the precipitated steroid was extracted into ethyl acetate. The organic solution was washed with sodium carbonate solution, then water, dried and the solvent was evaporated. Crystallisation from ethyl acetate gave the title compound (2.10 g, 88%). m.p. 134°-6°, [α]D + 136° (c. 1.03).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=3)[CH:11]=2)[CH:6]=[CH:7][C:8]=1[OH:9].[N+:26]([O-])([OH:28])=[O:27]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[N:17]=3)[CH:11]=2)[CH:6]=[C:7]([N+:26]([O-:28])=[O:27])[C:8]=1[OH:9]
Reactant: COc1cc(-c2cccc(-c3cccc(C(F)(F)F)n3)c2)ccc1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1cc(-c2cccc(-c3cccc(C(F)(F)F)n3)c2)cc([N+](=O)[O-])c1O

Procedure:
To a solution of 3-methoxy-3′-(6-(trifluoromethyl)pyridin-2-yl)biphenyl-4-ol (0.476 g, 1.38 mmol) in acetic acid (10 mL) at room temperature was added 60% nitric acid (0.12 mL, 1.52 mmol) dropwise. The resulting mixture was allowed to stir for thirty minutes then poured onto ice-water (100 mL) and the resulting precipitate was filtered off, washed with water and dried. After chromatography over silica gel (petroleum ether/ethyl acetate, 2:1), 3-methoxy-5-nitro-3′-(6-(trifluoromethyl)pyridin-2-yl)biphenyl-4-ol was obtained as a yellow solid, 0.323 g (60%).
Reaction SMILES: COC1C=CC(C[N:8]2[C:13](=[O:14])[C:12]3[N:15]([CH3:25])[C:16](=[O:24])[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:18][C:11]=3[CH:10]=[N:9]2)=CC=1>C(O)(C(F)(F)F)=O>[CH3:25][N:15]1[C:12]2[C:13](=[O:14])[NH:8][N:9]=[CH:10][C:11]=2[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:16]1=[O:24]
Reactant: CCOC(=O)c1cc2cnn(Cc3ccc(OC)cc3)c(=O)c2n(C)c1=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc2cn[nH]c(=O)c2n(C)c1=O
Temperature: 25 °C

Procedure:
A solution of ethyl 7-(4-methoxybenzyl)-1-methyl-2,8-dioxo-1,2,7,8-tetrahydropyrido[2,3-d]pyridazine-3-carboxylate (5) (2.45 g, 6.63 mmol) in TFA (15 mL) was heated in a microwave at 125° C. for 150 min, then cooled to RT. The volatiles were removed in vacuo to give crude ethyl 1-methyl-2,8-dioxo-1,2,7,8-tetrahydropyrido[2,3-d]pyridazine-3-carboxylate which was used directly in the next step.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]6[CH:45]=[CH:46][CH:47]=[CH:48][C:43]6=[N:42][CH:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]6[CH:45]=[CH:46][CH:47]=[CH:48][C:43]6=[N:42][CH:41]=5)=[O:58])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cnc5ccccn45)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cnc5ccccn45)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(imidazo[1,2-a]pyridin-3-ylmethylthio)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (0.80 g) in dichloromethane (10 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.44 g) in dichloromethane (10 ml) at −78° C. The mixture was stirred for 1 hour at −78° C., sodium thiosulfate solution was added to the mixture at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethyl acetate:hexane 3:1→ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(imidazo[1,2-a]pyridin-3-ylmethylsulfinyl)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 167) (642 mg) as yellow amorphous.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:21].[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH:32](O)[CH3:33])=[N:30][CH:31]=1.CCCCC>C(Cl)Cl>[Cl:21][CH:32]([C:29]1[CH:28]=[CH:27][C:26]([F:25])=[CH:31][N:30]=1)[CH3:33]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(O)c1ccc(F)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCC
Solvent: ClCCl
Product: CC(Cl)c1ccc(F)cn1
Reaction time: 0.17 h
Yield: 3 %

Procedure:
A mixture of triphenylphospine (0.92 g, 3.5 mmol) and CCl4 (4 mL) was stirred for 10 min. and then a solution of 1-(5-fluoropyridin-2-yl)ethanol (0.25 g, 1.7 mmol) in DCM (2 mL) was added. After 18 h, pentane (20 mL) was added, the solid material was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (eluent heptane:ethyl acetate 3:1) affording the title compound (8 mg, 3% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([CH3:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O.CO>[C].[Pd].O1CCCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([CH3:13])=[O:12])=[CH:8][CH:9]=1
Reactant: CC(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)Cc1ccc(N)cc1
Yield: 67.6 %

Procedure:
A solution of 1-(4-nitrophenyl)acetone (2.00 g, 11.2 mmol), 10% palladium-carbon (200 mg), methanol (20 ml) and tetrahydrofuran (10 ml) was stirred under a hydrogen atmosphere for 12 hours. Insolubles were filtered off to obtain the desired product (1.13 g, 67.6%) as an oil.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:21]([NH2:23])=[N:20][CH:19]=[N:18][C:17]=3[N:16]([CH2:24][C@@H:25]3[CH2:29][CH2:28][CH2:27][NH:26]3)[CH:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([C:32](=[CH:36][CH:37]1[CH2:39][CH2:38]1)[C:33](O)=[O:34])#[N:31].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH2:23][C:21]1[C:22]2[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)=[CH:15][N:16]([CH2:24][C@@H:25]3[CH2:29][CH2:28][CH2:27][N:26]3[C:33]([C:32](=[CH:36][CH:37]3[CH2:39][CH2:38]3)[C:30]#[N:31])=[O:34])[C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: N#CC(=CC1CC1)C(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C[C@@H]1CCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@H]1Cn1cc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.1 %

Procedure:
To a mixture of (S)-5-(4-phenoxy-phenyl)-7-pyrrolidin-2-ylmethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (100 mg, 0.26 mmol, 1.0 eq), 2-cyano-3-cyclopropyl-acrylic acid (45 mg, 0.32 mmol, 1.2 eq) and DIEA (102 mg, 0.78 mmol, 3.0 eq) in 10 ml DCM was added HATU (150 mg, 0.40 mmol, 1.5 eq). The reaction mixture was stirred for 4 h at RT under N2. The mixture was purified by Pre-TLC to give the title compound (71 mg). LCMS: m/z 486.2 (M+H)+
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][N:7]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]2[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:16][N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=23)=[N:8]1)=[O:4].[OH-].[Na+]>CO>[C:3]([CH2:5][CH2:6][N:7]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]2[C:15]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[N:16][N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=23)=[N:8]1)([OH:4])=[O:2]
Reactant: COC(=O)CCn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Yield: 66.4 %

Procedure:
A mixture of 3-[2-(2-methoxycarbonylethyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (1.94 g) and 24% aqueous sodium hydroxide (2 ml) in methanol (8 ml) was refluxed for 30 minutes and then evaporated in vacuo. The residue was dissolved in water (30 ml) and the aqueous solution was acidified with hydrochloric acid, and extracted with chloroform (25 ml). The extract was dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of ethanol and n-hexane to give 3-[2-(2-carboxyethyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (1.24 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[C:5]([I:12])=[CH:4][N:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)([O-])O.[Na+]>CN1CCCC1=O>[F:13][C:14]1[CH:15]=[C:16]([NH:17][C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[C:5]([I:12])=[CH:4][N:3]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: Nc1cccc(F)c1
Reactant: CCCNc1nc(Cl)ncc1I
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1I
Temperature: 45 °C
Reaction time: 6 h
Yield: 91.9 %

Procedure:
To a solution of 2-chloro-5-iodo-N-propylpyrimidin-4-amine (F1, 596 mg) and 3-fluoroaniline (1.11 g) in N-methylpyrrolidone (10 mL), (1S)-(+)-10-camphorsulfonic acid (2.32 g) was added at room temperature, and the mixture was stirred at 40 to 50° C. for 6 hours. The reaction mixture was cooled to room temperature, and then saturated aqueous sodium hydrogencarbonate was added to the reaction mixture. The solid matter was taken by filtration, washed with water, and then dried under reduced pressure to obtain N2-(3-fluorophenyl)-5-iodo-N4-propylpyrimidine-2,4-diamine (F2, 685 mg) as white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[ClH:17].[N:18]12[CH2:25][CH2:24][CH:21]([CH2:22][CH2:23]1)[CH:20]([CH2:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32](Br)[CH:31]=1)=[O:28])[CH2:19]2.[OH-].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:17].[N:18]12[CH2:25][CH2:24][CH:21]([CH2:22][CH2:23]1)[CH:20]([CH2:26][C:27]([NH:29][C:30]1[CH:31]=[C:32]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:33]=[CH:34][CH:35]=1)=[O:28])[CH2:19]2
Reactant: O=C(CC1CN2CCC1CC2)Nc1cccc(Br)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(CC1CN2CCC1CC2)Nc1cccc(-c2ccc(F)cc2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
22.1 mg (0.16 mmol) of 4-fluorophenylboronic acid, 0.17 ml (0.34 mmol) of 2M aqueous sodium carbonate solution and 5.8 mg (0.01 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride are added to a solution of 75 mg (0.16 mmol) of 2-(1-azabicyclo[2.2.2]oct-3-yl)-N-(3-bromophenyl)acetamide hydrochloride in 1 ml of DMF. The reaction mixture is stirred at 80° C. overnight. A further 22.1 mg (0.16 mmol) of 4-fluorophenylboronic acid, 23.2 mg (0.03 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride and 0.48 ml (0.48 mmol) of 1M sodium hydroxide solution are added. The mixture is then heated at 80° C. for a further 12 h. After the reaction is complete, the mixture is cooled, filtered through silica gel and then purified by preparative HPLC. The product fractions are concentrated, taken up in methanol, mixed with 4M HCl in dioxane and again concentrated. Drying under high vacuum results in 49.6 mg (83.4% of theory) of the title compound.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([C:14]1[N:15]([CH2:27][CH2:28][CH2:29][NH2:30])[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[CH:18][C:17]=2[N:26]=1)[CH2:11][CH2:12][CH3:13]>ClCCl>[CH2:10]([C:14]1[N:15]([CH2:27][CH2:28][CH2:29][NH:30][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[CH:18][C:17]=2[N:26]=1)[CH2:11][CH2:12][CH3:13]
Reactant: O=C=Nc1ccccc1
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCCN
Solvent: ClCCl
Product: CCCCc1nc2cnc3ccccc3c2n1CCCNC(=O)Nc1ccccc1
Yield: 87.9 %

Procedure:
A solution of phenyl isocyanate (1.00 g, 7.79 mmol) in dichloromethane (10 mL) was added dropwise over 5 minutes with stirring to a solution of 3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propylamine (2.00 g, 7.08 mmol) in dichloromethane (50 mL). The resulting precipitate was isolated by filtration to provide 2.50 g of N-[3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-phenylurea.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:13])[CH:7]([C:11]#[N:12])[CH:8]1[CH2:10][CH2:9]1)C>C1COCC1>[C:11]([CH:7]([CH:8]1[CH2:10][CH2:9]1)[C:6]([OH:13])=[O:5])#[N:12]
Reactant: CCOC(=O)C(C#N)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#CC(C(=O)O)C1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
IN NaOH (3.26 ml, 3.26 mmol) was added to a solution of cyano-cyclopropyl-acetic acid ethyl ester (0.5 g, 3.26 mmol) in THF (15 ml). After 4 hours stirring at 25° C., the reaction mixture was evaporated in vacuo, re-dissolved in water (20 ml) and neutralized by the addition of 1N HCl solution (3.26 ml). This mixture was then extracted with EtOAc (3×20 ml) and the combined, dried (Na2SO4) organics evaporated in vacuo to give impure cyano-cyclopropyl-acetic acid as a clear oil. This material was used without any further purification in the preparation of Example 4B.