Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH2:10])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:10])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(Cl)nc1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc(Cl)nc1
Yield: 83.1 %

Procedure:
A mixture of 6-chloropyridine-3-carboxamide (14 g), phosphorous oxychloride (35 ml) and chloroform (120 ml) is refluxed for 2 hr, cooled, and concentrated. The residue is stirred with water and the resulting precipitate is collected and recrystallized from ethanol to provide 10.3 g (83 %) of 6-chloropyridine-3-carbonitrile. This nitrile (2.77 g) is added to a solution of sodium octanolate (prepared from 1-octanol (2.78 g) and sodium hydride (0.88g of 60% dispersion) in DMF (20 ml)). After 30 min at room temperature, the mixture is poured into water, and the product extracted with ether. The extracts are concentrated and chromatographed with 2:3 hexane-dichloromethane, to provide 6-(octyloxy)pyridine-3-carbonitrile as a colorless oil (3.7 g, 80%). This nitrile is dissolved in toluene (15 ml), cooled to -20°, and diisobutylaluminum hydride (12.5 ml of 1.5M solution in toluene) is added dropwise. After an hour, the mixture is poured into 1.0N hydrochloric acid and the product extracted with ether. The extracts are dried, filtered, and concentrated to leave 6-(octyloxy)pyridine-3-carboxaldehyde (2.36 g) as a yellow oil.
Reaction SMILES: N1(C([O-])=O)CCCCC1.Cl.[NH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=2)[CH:15]=[C:14]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([N:30]([CH3:32])[CH3:31])[N:25]=2)[CH:13]=1.C(N(CC)C(C)C)(C)C.O=[C:43]1[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>ClCCCl.C(OCC)(=O)C.C(O)(=O)C>[CH3:32][N:30]([CH3:31])[C:26]1[N:25]=[C:24]([C:14]2[CH:13]=[C:12]([NH:11][CH:43]3[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]3)[C:21]3[C:16]([CH:15]=2)=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[CH:29]=[CH:28][N:27]=1
Reactant: COc1ccc2cc(-c3ccnc(N(C)C)n3)cc(N)c2c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])N1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc2cc(-c3ccnc(N(C)C)n3)cc(NC3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
Synthesis of tert-butyl 4-(3-(2-(dimethylamino)pyrimidin-4-yl)-7-methoxynaphthalen-1-yl)amino)piperidine-1-carboxylate (142): To a slurry of 4-(4-amino-6-methoxynaphthalen-2-yl)-N,N-dimethylpyrimidin-2-amine (141) (203 mg) in 1,2-dichloroethane (12 ml) was added N,N-diisopropylethylamine (240 μl) and the mixture stirred at room temperature for 30 min until all of the material was in solution. Acetic acid (0.5 ml) was added followed by tert-butyl 4-oxopiperidine-1-carboxylate (165 mg) and sodium triacetoxyborohydride (219 mg). The mixture was stirred at room temperature for 24 hours. A further (100 mg) of both tert-butyl 4-oxopiperidine-1-carboxylate and triacetoxyborohydride was added and the mixture stirred for a further 8 hours. The mixture was poured into ethyl acetate (150 ml) washed with water (300 ml) and the organic layer dried over anhydrous magnesium sulfate. Evaporation to dryness gave a yellow oil that was purified by silica gel chromatography eluting with 20-30% ethyl acetate in hexanes to yield tert-butyl 4-((3-(2-(dimethylamino)pyrimidin-4-yl)-7-methoxynaphthalen-1-yl)amino)piperidine-1-carboxylate (142) as a yellow foam (215 mg). 1H NMR (CDCl3) 400 MHz δ 8.38 (d, J=5.2 Hz, 1H), 7.87 (s, 1H), 7.82 (d, J=9.2 Hz, 1H), 7.52 (m, 1H), 7.18 (dd, J=2.4 and 9.2 Hz 1H), 7.04 (m, 1H), 7.02 (d, J=5.6 Hz, 1H) 4.15-4.1 (m, 2H), 3.97 (s, 3H), 3.76 (m, 1H), 3.31 (s, 6H), 3.03 (m, 2H), 2.24 (m, 2H), 1.58-1.51 (m, 2H), 1.49 (s, 9H), LCMS m/e 478 (M+H)
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=2[O:2]1.[C:14](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=2[O:2]1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.6 %

Procedure:
A mixture of (3,4-methylenedioxyphenyl)acetic acid (4.64 g, 25.74 mMol) in dry DMF (40 mL), cesium carbonate (9.2 g, 25.74 mMol) and methyl iodide (3.7 g, 26.0 mMol) in dry DMF (40 mL) was stirred at room temperature for 3h. At the end of this period, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic phase was washed with saturated NaHCO3, water, brine and then dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to provide pure methyl (3 ,4-methylened ioxyphenyl)acetate as an oil (4.38 g).
Reaction SMILES: Br[CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.[CH:20]1([NH:26][CH3:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C1(C)C=CC=CC=1>[CH:20]1([N:26]([CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: CNC1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C(=O)OCC)N(C)C1CCCCC1
Yield: 28.5 %

Procedure:
Diethyl bromomalonate (17.0 g), triethylamine (9.1 g), and dry toluene (10 ml) were mixed, and with stirring, the mixture was heated under reflux. Then, N-cyclohexyl-N-methylamine (8.1 g) diluted with dry toluene (5 ml) was added dropwise, and the mixture was heated under reflux for 2.5 hours with stirring. The reaction mixture was washed with water three times, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was distilled under reduced pressure to give 5.5 g (29%) of diethyl (N-cyclohexyl-N-methylamino)malonate having the following properties.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:9]=[C:8]([C:19]([O:21]C(C)(C)C)=[O:20])[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[N:9]=[C:8]([C:19]([OH:21])=[O:20])[CH:7]=1
Reactant: COc1ccc(-n2nc(C(=O)OC(C)(C)C)cc2-c2ccco2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-n2nc(C(=O)O)cc2-c2ccco2)cc1
Temperature: 25 °C
Yield: 93.8 %

Procedure:
Part C. To tert-butyl 5-(2-furyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylate (1.0 g, 3.0 mmol) was added dichloromethane (7 mL) and Trifluoroacetic acid (7 mL). The resulting black solution was maintained at rt under nitrogen for 2 h and was then concentrated to dryness. The resulting mixture was triturated with chloroform, and the remaining solid was washed with 50% hexanes in chloroform to afford 5-(2-furyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylic acid (800 mg, 96%) as a light brown solid. 1H NMR (d6-DMSO) δ 7.75 (b m, 1H), 7.41 (d, 2H), 7.10 (d, 2H), 7.09 (s, 1H), 6.51 (br m, 1H), 6.09 (d, 1H), 3.84 (s, 3H).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C:11]2[C:6](=[C:7]([C:12]3[S:16][C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=4)[C:22]#[N:23])=[N:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.Br[CH2:30][CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].O>CN(C=O)C>[Si:33]([O:32][CH2:31][CH2:30][NH:2][C@H:3]1[C:11]2[C:6](=[C:7]([C:12]3[S:16][C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=4)[C:22]#[N:23])=[N:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@H]4N)s2)cc1C#N
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@H]4NCCO[Si](C)(C)C(C)(C)C)s2)cc1C#N
Temperature: 95 °C
Reaction time: 12 h
Yield: 15.6 %

Procedure:
Prepared using General Procedure 9. To a suspension of (R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 5 (50 mg, 0.12 mmol) in anhydrous DMF (5 mL) was added TEA (36.7 mg, 0.36 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (34.6 mg, 0.14 mmol). The solution was stirred at 95° C. After 16 h more (2-bromoethoxy)(tert-butyl)dimethylsilane (34.6 mg, 0.14 mmol) was added and heating continued for 12 h. Water (5 mL) was added and the reaction mixture was extracted with EA (2×5 mL). The organic layers were washed with brine, dried, and purified by column chromatography (EA/hexanes) to afford 10 mg (15%) of (R)-5-(5-(1-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile. LCMS-ESI (m/z) calculated for: C29H38N4O2SSi: 534.3; found 535.3 [M+H]+, tR=3.08 min.
Reaction SMILES: [Na].[CH:2]1([N:5]([CH:33]2[CH2:35][CH2:34]2)[C:6]([C:8]2[N:30]([CH2:31][CH3:32])[C:11]3=[N:12][C:13]([NH:20][C:21]4[CH:25]=[C:24]([CH:26]=[O:27])[N:23]([CH2:28][CH3:29])[N:22]=4)=[C:14]4[N:18]=[CH:17][N:16]([CH3:19])[C:15]4=[C:10]3[CH:9]=2)=[O:7])[CH2:4][CH2:3]1>CO>[CH:33]1([N:5]([CH:2]2[CH2:3][CH2:4]2)[C:6]([C:8]2[N:30]([CH2:31][CH3:32])[C:11]3=[N:12][C:13]([NH:20][C:21]4[CH:25]=[C:24]([CH2:26][OH:27])[N:23]([CH2:28][CH3:29])[N:22]=4)=[C:14]4[N:18]=[CH:17][N:16]([CH3:19])[C:15]4=[C:10]3[CH:9]=2)=[O:7])[CH2:34][CH2:35]1
Reactant: CCn1nc(Nc2nc3c(cc(C(=O)N(C4CC4)C4CC4)n3CC)c3c2ncn3C)cc1C=O
Agent: [Na]
Solvent: CO
Product: CCn1nc(Nc2nc3c(cc(C(=O)N(C4CC4)C4CC4)n3CC)c3c2ncn3C)cc1CO
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
Sodium boronhydride (10 wt % on alumina, 13.14 mg, 0.035 mmol) was added to N,N-dicyclopropyl-6-ethyl-4-(1-ethyl-5-formyl-1H-pyrazol-3-ylamino)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 101C, 16 mg, 0.035 mmol) in methanol (1 mL) at room temperature and the reaction mixture stirred for 0.5 h. The solid alumina was filtered off and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography on silica gel using an automated ISCO system (4 g column, eluting with 2-10% methanol/dichloromethane). N,N-dicyclopropyl-6-ethyl-4-(1-ethyl-5-(hydroxymethyl)-1H-pyrazol-3-ylamino)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (14 mg, 86% yield) was obtained as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[CH:12]=[CH:11][C:10]2[C:13]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH:18]3[CH3:30])=[CH:14][CH:15]=[CH:16][C:9]1=2.[Cl:31]CCl.[ClH:34]>CO>[ClH:31].[ClH:34].[S:8]1[CH:12]=[CH:11][C:10]2[C:13]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH:18]3[CH3:30])=[CH:14][CH:15]=[CH:16][C:9]1=2
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1c1cccc2sccc12
Reactant: ClCCl
Agent: Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC1CNCCN1c1cccc2sccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (6 ml) was added to a solution of 1.22 g (3.7 mmol) of tert-butyl 4-benzo[b]thiophen-4-yl-3-methylpiperazin-1-carboxylate in a dichloromethane solution (12 ml) and the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure, and a 5% aqueous potassium carbonate solution was added to the residue and the resulting mixture was extracted with dichloromethane. The extraction solution with dichloromethane was dried over magnesium sulfate and thereafter concentrated under reduced pressure. To the residue obtained, concentrated hydrochloric acid (0.6 ml) and methanol (10 ml) were added and the resulting mixture was concentrated under reduced pressure. The obtained residue was subjected to recrystallization from acetonitrile to obtain 1-benzo[b]thiophen-4-yl-2-methylpiperazine dihydrochloride (0.98 g) as light brown powder.
Reaction SMILES: Cl.Cl.[OH:3][C@H:4]1[CH2:8][NH:7][C@H:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=CN=2)[CH2:5]1.[F-].[C:18]([N+:22](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C)(C)C>C1COCC1>[OH:3][C@H:4]1[CH2:8][NH:7][C@H:6]([CH2:9][O:10][C:11]2[CH:18]=[N:22][CH:14]=[CH:15][CH:16]=2)[CH2:5]1
Reactant: O[C@H]1CN[C@H](COc2ccccn2)C1
Reactant: CC(C)(C)[N+](C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: O[C@H]1CN[C@H](COc2cccnc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 1.35 g sample of the compound from step 72d above was dissolved in 9 mL of THF and 9.3 mL of tetra-(t-butyl)ammonium fluoride was added. The reaction mixture was stirred at room temperature for 16 hours, and the volatiles were removed under vacuum. The residue was purified on silica gel, eluting with 3:1 ethyl acetate:hexane, to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][CH:6]=[C:5]2[CH:12]=[O:13].CC1(C)COB([C:21]2[CH:26]=[CH:25][C:24]([C:27]3([CH2:30][OH:31])[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)OC1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CCO.O.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]>[OH:31][CH2:30][C:27]1([C:24]2[CH:25]=[CH:26][C:21]([C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][C:10]=3[CH3:11])[NH:7][CH:6]=[C:5]4[CH:12]=[O:13])=[CH:22][CH:23]=2)[CH2:29][CH2:28]1
Reactant: CC1(C)COB(c2ccc(C3(CO)CC3)cc2)OC1
Reactant: Cc1cc2[nH]cc(C=O)c2cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1cc2[nH]cc(C=O)c2cc1-c1ccc(C2(CO)CC2)cc1
Temperature: 25 °C
Yield: 74.1 %

Procedure:
A solution of 5-bromo-6-methyl-1H-indole-3-carbaldehyde (200 mg, 0.84 mmol) and {1-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]cyclopropyl}methanol (242 mg, 0.93 mmol) in toluene (6 mL) and EtOH (2.0 mL) was added to a solution of potassium carbonate (350 mg, 2.52 mmol) in water (1.0 mL) and Pd(dppf)Cl2 (34 mg, 0.042 mmol) at room temperature under N2. TLC (petroleum ether/EtOAc=1:1) showed the reaction was complete. The reaction was cooled to room temperature, and extracted with ethyl acetate (20 mL×3). The organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated to give a crude ARRR!!!!, which was purified by column chromatography to give the title compound (190 mg, 74%) as a yellow solid.
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]4[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][CH:20]=4)=[CH:13][C:12]=3[OH:30])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH-].[Li+].C1COCC1.Cl>O>[C:1]12([C:11]3[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]4[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:28][CH:29]=4)=[CH:13][C:12]=3[OH:30])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CCOC(=O)c1ccc(/C=C/c2ccc(C34CC5CC(CC(C5)C3)C4)c(O)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(/C=C/c2ccc(C34CC5CC(CC(C5)C3)C4)c(O)c2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
258 mg (0.5 mmol) of ethyl (E)-4-[[2-[4-(1-adamantyl)-3-hydroxyphenyl]ethenyl]]benzoate, 105 mg (2.5 mmol) of lithium hydroxide and 10 ml of THF were introduced into a round-bottomed flask. The reaction medium was stirred at room temperature for 12 hours, poured into water, neutralized with hydrochloric acid and extracted with ethyl ether. The organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. The residue obtained was triturated from a mixture of dichloromethane and hexane, filtered and dried. 95 mg (51%) of the expected acid, having a melting point of 334°-5° C., were recovered.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:24](COCC[Si](C)(C)C)[C:18]4[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=4[C:16]=3[CH2:33][OH:34])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1>O>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:24][C:18]4[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=4[C:16]=3[CH2:33][OH:34])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:13])[F:14])[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CC3)c2)c(CO)c2c(=O)[nH]ncc21
Solvent: O
Product: O=c1[nH]ncc2[nH]c(-c3ccc(OC(F)F)c(OC4CC4)c3)c(CO)c12
Yield: 86 %

Procedure:
Reaction was carried out in the same manner as in Example 1-(b) except for using 80 mg (0.16 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-hydroxymethyl-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 10-(b) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one. After completion of the reaction, water was added to the reaction mixture and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried under reduced pressure to obtain 50 mg of the title compound as a white solid. (Yield: 85%)
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[C:22][C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[NH:29][CH:28]([CH2:33][N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH2:27][CH2:26]4)=[N:19][CH:20]=2)=[CH:11][CH:10]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[C:22][C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[N:29]([C:5](=[O:7])[CH3:6])[CH:28]([CH2:33][N:34]3[CH2:35][CH2:36][CH2:37][CH2:38]3)[CH2:27][CH2:26]4)=[N:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: Clc1ccc(-c2ccc(C#Cc3ccc4c(c3)CCC(CN3CCCC3)N4)nc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N1c2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc2CCC1CN1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
74 μL (0.77 mmol) acetic anhydride are added to a solution of 220 mg (0.51 mmol) 6-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-pyrrolidin-1-ylmethyl-1,2,3,4-tetrahydro-quinoline (see Example 3.46) in 5 mL DCM and the mixture is stirred for 2 h at RT. Another 0.37 mL (3.85 mmol) acetic anhydride are added and the reaction is stirred for a further 4 days at RT. The solvent is eliminated i.vac. The purification is carried out by column chromatography using HPLC-MS.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13](Cl)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[CH:4][CH:3]=1.[SH:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([S:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(S)cc1
Reactant: O=C(Nc1ccc(Br)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Br)cc1)c1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 74.6 %

Procedure:
A solution of the product of Example 10A (553 mg, 1.557 mmol) in anhydrous N,N-dimethylformamide (15 mL) was treated with 4-mercaptophenol (196 mg, 1.557 mmol) and cesium carbonate (1.015 g, 3.114 mmol) at room temperature, then heated at 100° under a nitrogen atmosphere for 3 hours. The reaction was cooled to room temperature and the solvent removed by rotary evaporation in vacuo. The residue was taken up in H2O (30 mL) and the pH adjusted to 3 with 1N aqueous HCl. The aqueous was extracted with ethyl acetate (2×50 mL), and the combined organic extracts washed with brine (25 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. The residue was purified by trituration with methylene chloride and silica gel flash chromatography with a gradient of 6% to 30% ethyl acetate/methylene chloride to give the product as a dark yellow solid (517 mg, 75%).
Reaction SMILES: [ClH:1].[O:2]1[C:7]2=[CH:8][N:9]=[C:10]([CH2:12][NH:13][CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][N:22]4[C:31]5[C:26](=[N:27][CH:28]=[C:29](F)[CH:30]=5)[CH:25]=[CH:24][C:23]4=[O:33])[CH2:16][CH2:15]3)[CH:11]=[C:6]2[CH2:5][CH2:4][CH2:3]1.C[O-].[Na+].CO.O.[C:40](OCC)(=[O:42])C>CO>[ClH:1].[O:2]1[C:7]2=[CH:8][N:9]=[C:10]([CH2:12][NH:13][CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][N:22]4[C:31]5[C:26](=[N:27][CH:28]=[C:29]([O:42][CH3:40])[CH:30]=5)[CH:25]=[CH:24][C:23]4=[O:33])[CH2:16][CH2:15]3)[CH:11]=[C:6]2[CH2:5][CH2:4][CH2:3]1
Reactant: CCOC(C)=O
Reactant: O=c1ccc2ncc(F)cc2n1CCN1CCC(NCc2cc3c(cn2)OCCC3)CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cnc2ccc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCC5)CC3)c2c1
Reaction time: 4 h

Procedure:
To a suspension of 60 mg of 1-(2-(4-((3,4-dihydro-2H-pyrano(2,3-c)pyridin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one hydrochloride in 2 mL of methanol, 60 mg of a 28% sodium methoxide/methanol solution, and the mixture was heated under reflux while stirring for 4 hours. Thereto were added water and ethyl acetate, the organic layer was separated, and the aqueous layer was saturated with sodium chloride, and then extracted with ethyl acetate twice. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the resultant residue, 1 mL of ethyl acetate was added, and 1 mL of a 4.0 mol/L hydrogen chloride/ethyl acetate solution was added at room temperature. The solvent was distilled off under reduced pressure, ethyl acetate was added to the resultant residue, and the solid was filtered off to obtain 31 mg of 1-(2-(4-((3,4-dihydro-2H-pyrano(2,3-c)pyridin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one hydrochloride as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH3:17])[C:8]2[NH:12][C:11]([CH2:13][CH2:14][CH3:15])=[N:10][C:9]=2[CH:16]=1)=[O:4].CC(C)([O-])C.[K+].Br[CH2:25][C:26]1[CH:43]=[CH:42][C:29]2/[C:30](=[CH:39]/[C:40]#[N:41])/[C:31]3[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=3[CH2:33][CH2:34][C:28]=2[CH:27]=1.C(OCC)(=O)C>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH3:17])[C:8]2[N:12]=[C:11]([CH2:13][CH2:14][CH3:15])[N:10]([CH2:25][C:26]3[CH:43]=[CH:42][C:29]4/[C:30](=[CH:39]/[C:40]#[N:41])/[C:31]5[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=5[CH2:33][CH2:34][C:28]=4[CH:27]=3)[C:9]=2[CH:16]=1)=[O:4]
Reactant: N#C/C=C1\c2ccccc2CCc2cc(CBr)ccc21
Reactant: CCCc1nc2cc(C(=O)OC)cc(C)c2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)cc(C(=O)OC)cc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Reaction time: 0.17 h
Yield: 73 %

Procedure:
[step 1] 6-Methoxycarbonyl-4-methyl-2-propylbenzimidazole (EP502314; 1.19 g, 5.13 mmol) was dissolved in DMF (15 mL), potassium tert-butoxide (0.60 g, 5.3 mmol) was added at 0° C., and the mixture was stirred for 10 min. To this mixture was added a solution of (E)-(2-bromomethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)acetonitrile obtained in Reference Example B1 in DMF (8 mL), and the mixture was stirred at room temperature for 2 hr. Ethyl acetate was added to the mixture, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 tot/3) to give (E)-[2-(6-methoxycarbonyl-4-methyl-2-propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (1.78 g, 73%).