Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]4[N:24]=[CH:25][CH:26]=[CH:27][C:15]=4[N:14]3[C:28]=2[C:29]2[CH:34]=[CH:33][C:32]([C:35]3([NH:39]C(=O)OC(C)(C)C)[CH2:38][CH2:37][CH2:36]3)=[CH:31][CH:30]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[ClH:47].O1CCOCC1>C(Cl)Cl>[ClH:47].[ClH:47].[ClH:47].[NH2:39][C:35]1([C:32]2[CH:33]=[CH:34][C:29]([C:28]3[N:14]4[C:15]5[CH:27]=[CH:26][CH:25]=[N:24][C:16]=5[NH:17][C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=5[C:13]4=[N:12][C:11]=3[C:8]3[CH:7]=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:10][CH:9]=3)=[CH:30][CH:31]=2)[CH2:38][CH2:37][CH2:36]1
Reactant: CC(=O)Nc1ccc(-c2nc3n(c2-c2ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(-c2nc3n(c2-c2ccc(C4(N)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 93.5 %

Procedure:
tert-Butyl (1-{4-[2-(4-acetamidophenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (22.6 mg, 0.0369 mmol) was dissolved in DCM (1 mL). 4M HCl/dioxane (1 mL) was added to the mixture and stirred at room temperature for 6 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (21.5 mg, 93.5%) as pale yellow solid. 1HNMR (DMSO-d6) 400 MHz δ: 10.08 (s, 1H), 8.70 (br s, 2H), 8.64 (s, 1H), 8.11 (dd, J=4.8, 1.6 Hz, 1H), 7.95 (dd, J=7.8, 1.8 Hz, 1H), 7.58-7.49 (m, 4H), 7.44-7.36 (m, 3H), 7.34-7.28 (m, 3H), 7.17-7.10 (m, 1H), 6.89 (dd, J=8.0, 1.6 Hz, 1H), 6.75 (dd, J=7.8, 4.6 Hz, 1H), 2.65-2.39 (m, 4H), 2.26-2.13 (m, 1H), 2.04 (s, 3H), 1.89-1.75 (m, 1H); LCMS: 513 [M+H].
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[N:16][C:8]=3[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:5]2=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(O)C.C(=O)(O)[O-].[Na+].[C:46]1(B(O)O)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C1(C)C=CC=CC=1>[C:46]1([C:2]2[N:6]3[C:7]4[CH:19]=[CH:18][CH:17]=[N:16][C:8]=4[NH:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:5]3=[N:4][C:3]=2[C:20]2[CH:21]=[CH:22][C:23]([C:26]3([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:35])[CH3:36])[CH2:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4n(c3Br)-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4n(c3-c3ccccc3)-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
To a suspension of tert-butyl (1-(4-(3-bromo-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-2-yl)phenyl)cyclobutyl)carbamate (0.213 g, 1 eq.) in a mixture of toluene (5 mL), ethanol (5 mL), and saturated sodium bicarbonate (1 mL) was added phenyl boronic acid (0.07 g, 1.5 eq.). The reaction was degassed (nitrogen) for 5 minutes and tetrakis(triphenylphosphine)palladium(0) added (0.025 g). The reaction was again degassed for 5 minutes and stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and poured onto water (50 mL). The aqueous phase was extracted with dichloromethane (2×50 mL) and the organic extracts were combined and washed with water (1×50 mL), brine (1×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (25-75% ethyl acetate in hexanes) gave the product which was triturated with ether to give tert-butyl (1-(4-(3-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-2-yl)phenyl)cyclobutyl)carbamate (0.084 g, 40%) as a yellow solid. 1H NMR (DMSO-d6) 400 MHz δ 8.55 (s, 1 H), 8.06 (dd, JA=4.8 Hz, JB=2.4 Hz, 1H), 7.95 (dd, JA=7.6 Hz, JB=1.2 Hz, 1H), 7.78 (dd, JA=7.6 Hz, JB=1.6 Hz, 1H), 7.58-7.50 (m, 1H), 7.44-7.36 (m, 4H), 7.35-7.31 (m, 2H), 7.30-7.18 (m, 4H), 7.14-7.09 (m, 1H), 6.89 (dd, JA=7.6 Hz, JB=1.2 Hz, 1H), 6.73 (dd, JA=7.6 Hz, JB=4.8 Hz, 1H), 2.45-2.28 (m, 4H), 2.04-1.92 (m, 1H), 1.83-1.70 (m, 1H), 1.33 (br. s, 9H); LCMS: 556 [M+H].
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9](=[O:41])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[S:25][C:24]3[C:23]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[N:22][C:21]([C:32]4[CH:40]=[CH:39][CH:38]=[C:37]5[C:33]=4[CH:34]=[N:35][NH:36]5)=[N:20][C:19]=3[CH:18]=2)[CH:12]=1)(C)(C)C.FC(F)(F)C(O)=O.ClCCl>>[NH:36]1[C:37]2[C:33](=[C:32]([C:21]3[N:22]=[C:23]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[C:24]4[S:25][C:17]([C:13]5[CH:12]=[C:11]([NH:10][C:9](=[O:41])[CH2:8][NH2:7])[CH:16]=[CH:15][CH:14]=5)=[CH:18][C:19]=4[N:20]=3)[CH:40]=[CH:39][CH:38]=2)[CH:34]=[N:35]1
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1cccc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC(=O)Nc1cccc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1
Yield: 20.4 %

Procedure:
Tert-butyl(3-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenylcarbamoyl)methylcarbamate (82 mg) was treated with 2 mL of trifluoroacetic acid/dichloromethane (1:1). Upon completion, the reaction mixture was evaporated. The product was purified by reverse phase HPLC to yield 13.9 mg of 137. MS (Q1) 486 (M)+.
Reaction SMILES: [C:1]([Li])(C)(C)C.CCCCC.Br[C:12]1[C:20]2[C:15](=[CH:16][C:17]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])=[CH:18][CH:19]=2)[N:14]([Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH:13]=1.CI>C1COCC1>[C:32]([Si:29]([CH3:31])([CH3:30])[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[C:17]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:16]=2)[C:12]([CH3:1])=[CH:13]1)([CH3:35])([CH3:34])[CH3:33]
Reactant: [Li]C(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(Br)cn([Si](C)(C)C(C)(C)C)c2c1
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: CI
Product: Cc1cn([Si](C)(C)C(C)(C)C)c2cc(O[Si](C)(C)C(C)(C)C)ccc12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 1.5 M solution of tert-butyllithium in pentane (3.3 ml, 4.99 mmol) was added dropwise to a solution of 3-bromo-1-(tert-butyl-dimethyl-silanyl)-6-(tert-butyl-dimethyl-silanyloxy)-1H-indole (1 g, 2.27 mmol) in THF (6 ml) at −78° C. under an argon atmosphere. After 15 min methyl iodide (0.28 ml, 4.54 mmol) was added at −78° C. The reaction mixture was stirred for another 30 min at −78° C. and then for 2 h at RT. After quenching with saturated aqueous NaHCO3 solution the reaction mixture was partitioned between ether and water. The ether phase was dried over sodium sulfate and concentrated in vacuo to give 863 mg (2.3 mmol, quant.) 1-(tert-butyl-dimethyl-silanyl)-6-(tert-butyl-dimethyl-silanyloxy)-3-methyl-1H-indole as red crystals.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8].C(Cl)Cl.C(O)(=O)C>CCOC(C)=O>[Br:1][C:12]1[CH:11]=[C:6]([CH:5]=[C:4]([F:3])[C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8]
Reactant: BrBr
Reactant: COC(=O)c1ccc(O)c(F)c1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(F)c(O)c(Br)c1
Temperature: 25 °C
Reaction time: 40 h
Yield: 95 %

Procedure:
Bromine (1.60 mL, 31.1 mmol) was added dropwise with stirring over 30 minutes to an ice-cooled solution of 66.49A (4.79 g, 28.1 mmol) in a 1:1 mixture of DCM (20 mL) and acetic acid (20 mL). Upon complete addition, the reaction mixture was allowed to warm to room temperature and monitored with TLC and LC-MS. After stirring at room temperature for 40 hours, the mixture was diluted with EtOAc, and then the resulting solution was washed twice with aqueous saturated Na2SO3, once with water, and once with brine. After drying over anhydrous magnesium sulfate, filtration, and concentration, the white solid 66.49B was obtained 6.69 g, 95% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.05 (1H, m), 7.75 (1H, dd, J=10.6, 2.0 Hz), 6.12 (1H, s), 3.94 (3H, s).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#[C:7][CH2:8][CH2:9][CH:10]=O.[Cl-].[CH2:13]([N:17]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:18](=[O:20])[CH3:19])[CH:14]([CH3:16])[CH3:15]>>[CH2:13]([NH:17][C:18](=[O:20])/[CH:19]=[CH:10]/[CH2:9][CH2:8][C:7]#[C:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: CC(=O)N(CC(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CCCC#Cc1cccs1
Agent: [Cl-]
Product: CC(C)CNC(=O)/C=C/CCC#Cc1cccs1

Procedure:
N-isobutyl 7-thienyl-(2E)-hepten-6-ynamide was prepared from 5-thienyl-4-pentyn-1-al and N-isobutyl acetamidotriphenyl-phosphonium chloride as in Example 9 and then converted to the title product by semi-hydrogenation as in Example 9.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=1B(O)O.C(=O)([O-])O.[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:28]2[C:29]([O:33][CH3:34])=[CH:30][CH:31]=[CH:32][C:27]=2[F:26])[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(F)c1B(O)O
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cccc(F)c1-c1cc(CN(C)C(=O)OC(C)(C)C)cn1S(=O)(=O)c1cccnc1
Temperature: 100 °C
Reaction time: 20 h
Yield: 21 %

Procedure:
tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (431 mg), (2-fluoro-6-methoxyphenyl)boronic acid (256 mg), sodium hydrogencarbonate (253 mg) and tetrakis(triphenylphosphine)palladium (176 mg) were added to a mixture of 1,2-dimethoxyethane (8 mL) and water (2 mL), and the mixture was stirred under a nitrogen atmosphere at 100° C. for 20 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=1:1) to give the title compound as a colorless oil (yield 100 mg, 21%).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][C:6]([S:9][CH2:10][CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[N:7][N:8]=1.[CH2:18]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)/[CH:19]=[C:20](/[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])\[CH3:21]>O1CCCC1>[CH2:18]([O:28][C:29]1[CH:30]=[CH:31][C:32]([C:33]([NH:3][C:4]2[S:5][C:6]([S:9][CH2:10][CH2:11][CH2:12][N:13]([CH2:14][CH3:15])[CH2:16][CH3:17])=[N:7][N:8]=2)=[O:34])=[CH:36][CH:37]=1)/[CH:19]=[C:20](/[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])\[CH3:21]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Reactant: CCN(CC)CCCSc1nnc(N)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)CCCSc1nnc(NC(=O)c2ccc(OC/C=C(\C)CCC=C(C)C)cc2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.3 %

Procedure:
Sodium hydride (0.4 g) and 2-amino-5-diethylaminopropylthio-1,3,4-thiadiazole (1.5 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes while being cooled with ice. 4-Geranyloxybenzoic acid (1.8 g) and carbonyldlimidazole (1.1 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes at room temperature and the mixture was added to the former reaction mixture. The mixture was stirred for 4 hours at room temperature, and then concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=15:1). The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 3.1 g of the aimed compound.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH2:4]([C:8]1[C:15]([CH3:16])=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=1)[CH:5]([CH3:7])[CH3:6]>CO>[OH:3][NH:2][C:12](=[NH:13])[C:11]1[CH:14]=[C:15]([CH3:16])[C:8]([CH2:4][CH:5]([CH3:6])[CH3:7])=[N:9][CH:10]=1
Reactant: NO
Reactant: Cc1cc(C#N)cnc1CC(C)C
Agent: Cl
Solvent: CO
Product: Cc1cc(C(=N)NO)cnc1CC(C)C
Temperature: 0 °C
Yield: 95.4 %

Procedure:
To an ice-cooled solution of potassium tert.-butylate (284 g, 2.53 mmol) in methanol (4 mL), hydroxylamine hydrochloride (151 mg, 2.17 mmol) is added. The suspension is stirred for 30 min before 6-isobutyl-5-methyl-nicotinonitrile (126 mg, 0.723 mmol) is added. The mixture is refluxed for 1 h before the solvent is evaporated. The residue is dissolved in sat. aq. NaHCO3-solution (10 mL) and extracted with EA (3×15 mL). The combined org. extracts are dried over MgSO4, filtered, concentrated and dried under HV to give N-hydroxy-6-isobutyl-5-methyl-nicotinamidine (143 mg) as a white solid; LC-MS: tR=0.56 min, [M+1]+=208.13; 1H NMR (CDCl3): δ 0.97 (d, J=6.8 Hz, 6H), 2.16 (hept, J=7.0 Hz, 1H), 2.36 (s, 3H), 2.72 (d, J=7.3 Hz, 2H), 4.91 (s, 2H), 7.70 (d, J=1.3 Hz, 1H), 8.66 (d, J=1.8 Hz, 1H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[O:10].[Cl:11][C:12]([O:15]C(Cl)=O)(Cl)Cl>O1CCCC1>[O:10]=[C:2]1[N:3]([C:12]([Cl:11])=[O:15])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:1]1
Reactant: O=c1[nH]c2ccccc2[nH]1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=C(Cl)n1c(=O)[nH]c2ccccc21

Procedure:
It was prepared by suspending 5 g of 2,3-dihydro-1H-benzimidazole-2-one in 200 ml of distilled tetrahydrofuran and by adding 13.5 ml of trichloromethylchloroformate. The reaction mixture was refluxed for 3 hrs until a clear solution was obtained. After cooling the separated solid was removed by filtration and after concentration to dryness of the mother liquors 6.5 g of the title compound were obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][C:6]1[C:7]2[C:8](=[C:13]([CH3:17])[NH:14][C:15]=2[CH3:16])[C:9](=[O:12])[NH:10][N:11]=1.C(N(C(C)C)C(C)C)C.CC[O:32][C:33](C)=[O:34]>CN(C)C1C=CN=CC=1.O1CCOCC1.O.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo].C(O[Pd]CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C)(=O)C>[CH3:16][C:15]1[NH:14][C:13]([CH3:17])=[C:8]2[C:7]=1[C:6]([CH2:5][C:4]1[CH:3]=[C:2]([CH:20]=[CH:19][CH:18]=1)[C:33]([OH:34])=[O:32])=[N:11][NH:10][C:9]2=[O:12]
Reactant: CCOC(C)=O
Reactant: Cc1[nH]c(C)c2c(=O)[nH]nc(Cc3cccc(Br)c3)c12
Agent: CC(=O)O[Pd]Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Mo]
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1[nH]c(C)c2c(=O)[nH]nc(Cc3cccc(C(=O)O)c3)c12
Temperature: 150 °C
Yield: 100 %

Procedure:
4-(3-Bromobenzyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (50) (0.188 g, 0.57 mmol), molybdenum hexacarbonyl (0.224 g, 0.85 mmol), N,N-dimethylpyridin-4-amine (0.138 g, 1.13 mmol), N-ethyl-N-isopropylpropan-2-amine (0.197 mL, 1.13 mmol) and acetoxy(2-(dio-tolylphosphino)benzyl)palladium (0.027 g, 0.03 mmol) were suspended in a mixture of dioxane (2.0 mL) and water (2.0 mL) and sealed into a microwave tube. The reaction was heated to 150° C. for 30 minutes in the microwave reactor and cooled to room temperature. The reaction mixture was diluted with water (50 mL) and EtOAc (50 mL). The mixture was filtered through celite. The layers were separated and the aqueous was adjusted to pH2 with 2M HCl. The resulting precipitate was collected by filtration, washed with water (50 mL), Et2O (50 mL) and dried under vacuum to afford the desired material as a brown solid (0.200 g, >100% yield), which was used without further purification. 1H NMR (400.132 MHz, DMSO) δ 2.26 (3H, s), 2.51 (3H, s), 4.13 (2H, s), 7.39-7.48 (2H, m), 7.78 (2H, m), 11.08 (1H, s), 11.93 (1H, s), 12.86 (1H, s); m/z (LC-MS, ESI+), RT=1.41 min (M+H=298.08).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.[CH2:19]([C@H:21]1[CH2:26][CH2:25][C@H:24](O)[CH2:23][CH2:22]1)[CH3:20].O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(OCC)(=O)C>[CH2:19]([C@@H:21]1[CH2:26][CH2:25][C@H:24]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([C@:12]2([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]2)[CH:6]=[CH:5]3)[CH2:23][CH2:22]1)[CH3:20]
Reactant: CC[C@H]1CC[C@H](O)CC1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC[C@H]1CC[C@@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Reaction time: 0.08 h
Yield: 88.2 %

Procedure:
(R)-4-(6-Hydroxynaphthalen-2-yl)-4-methyl-oxazolidin-2-one (0.3594 g, 0.001477 mol) was added to a capped 40 mL vial. trans-4-Ethylcyclohexanol (0.227 g, 0.00177 mol) was added, followed by tetrahydrofuran (6.00 mL, 0.0740 mol). Triphenylphosphine polymer-bound (1.28 g, 0.00236 mol) was added and the mixture was stirred for 5 minutes. Diisopropyl azodicarboxylate (0.465 mL, 0.00236 mol) was added and the mixture was stirred for 48 hours at room temperature. The mixture was diluted in ethyl acetate, filtered through CELITE™, concentrated under vacuum and purified by flash chromatography (0-20% EtOAc in methylene chloride) to give 0.4603 g of the title compound (88% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([O-:15])(=O)=[O:13])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[K+].O=P(Cl)(Cl)[Cl:19]>C(#N)C.S1(CCCC1)(=O)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([Cl:19])(=[O:15])=[O:13])=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1ccc(S(=O)(=O)[O-])cc1
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: CC#N
Product: CCOC(=O)c1ccc(S(=O)(=O)Cl)cc1
Temperature: 75 °C

Procedure:
A round bottom flask, fitted with a magnetic stir bar and a hose adapter connected to a source of nitrogen gas, was charged with a solution of potassium 4-ethoxycarbonylbenzenesulfonate (75.1 g) dissolved in a 3:1 (v/v) mixture of acetonitrile (300 mL) and sulfolane (100 mL). As the solution was stirred, POCl3 (55 mL) was added slowly and the stirring mixture was heated at 75° C. under a nitrogen atmosphere for 3 hours. The heterogeneous reaction mixture was allowed to cool to room temperature and was then concentrated using a rotary evaporator. The flask was then cooled in an ice bath and ice was added to the mixture in the flask. The product crystallized as a white solid and was filtered and washed with cold deionized water. The product was dried under vacuum at room temperature and 3 mmHg for 2 hours to afford 76 g of white solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12])=O.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20].CC(C)=O.C(N(CC)CC)C>C(#N)C>[N+:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]1[CH:20]=[C:15]2[N:14]([CH:2]=1)[CH:19]=[CH:18][CH:17]=[CH:16]2)([O-:13])=[O:12]
Reactant: O=C(CBr)c1ccccc1[N+](=O)[O-]
Reactant: Cc1ccccn1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccccc1-c1cc2ccccn2c1
Temperature: 25 °C

Procedure:
First, 4.1 mmol of 2-bromo-2′-nitroacetophenone and 5.33 mmol (1.3 eq.) of picoline are dissolved into 12 ml of acetone and the reaction mixture is allowed to react at 90° C. for 3 hours. After the completion of the reaction, the reaction mixture is cooled at room temperature and filtered, and then the filtered solid is washed with 5 ml of dichloromethane. To 20 ml of acetonitrile, 4.1 mmol of the obtained solid and 20.5 mmol (5 eq.) of triethylamine are added. Then, the reaction mixture is allowed to react at 60° C. for 16 hours. After the completion of the reaction, the reaction mixture is concentrated under reduced pressure, and then the concentrated reaction mixture is purified by silica gel column chromatography using hexane:ethyl acetate:dichloromethane=30:1:2 as a solvent to obtain the target compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][OH:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(N(CC)CC)C>[CH3:19][S:20]([O:18][CH2:17][CH2:16][CH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCc1cccc(OCc2ccccc2)c1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCc1cccc(OCc2ccccc2)c1

Procedure:
Using 3-(3-benzyloxyphenyl)propanol (13.5 g), triethylamine (8.16 ml) and methanesulfonyl chloride(4.53 ml), the same reaction as Reference Example 9-(iv) was carried out to yield the titled compound (19.7 g) as an oily substance.
Reaction SMILES: [F:1][C:2]1([F:56])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH:42]=[O:43])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:44]([F:55])[C:45]2[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=2)[CH2:4][CH2:3]1.[BH4-].[Na+].[Cl-].[NH4+]>C(O)C>[F:56][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:31][CH2:32][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH2:42][OH:43])=[CH:38][N:37]=4)[CH2:34][CH2:35]3)[C:9]=2[CH:44]([F:55])[C:45]2[CH:46]=[CH:47][C:48]([C:51]([F:52])([F:54])[F:53])=[CH:49][CH:50]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(C=O)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(CO)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
To a solution of 94 mg (0.12 mmol) of 4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-formylpyrimidin-2-yl)piperidin-4-yl]-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 16, in 0.6 ml of ethanol, 5.0 mg (0.13 mmol) of sodium borohydride was added, and the reaction solution was stirred at 0° C. for 2 hours. After completion of the reaction, saturated ammonium chloride aqueous solution was poured into the reaction solution and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=100/0-60/40 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 89 mg of 4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-[5-(hydroxymethyl)pyrimidin-2-yl]piperidin-4-yl]-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline.