Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH:7]([NH:9]CC1C=CC(OC)=CC=1)[CH3:8]>CO.[Pd]>[O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH:7]([NH2:9])[CH3:8]
Reactant: COc1ccc(CNC(C)C2COCCO2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(N)C1COCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a solution of 1-(1,4-dioxan-2-yl)ethanone (12 g, 92.2 mmol) in 1,2-dichloroethane (100 mL) was added (4-methoxyphenyl)methanamine (25 g, 184.4 mmol) at room temperature. The mixture was allowed to stir for 3 hours, and then sodium triacetoxyborohydride (39 g, 184.4 mmol) was added. The resulting mixture was allowed to stir for 48 hours at room temperature. The reaction mixture was quenched by adding water, extracted with dichloromethane (100 mL×3). The combined organic phase was dried by anhydrous sodium sulphate, and then filtered. The filtrate was concentrated and purified by column chromatograph on silica gel (elute: dichloromethane/methanol 100:1→50:1→20:1) to give 1-(1,4-dioxan-2-yl)-N-(4-methoxybenzyl)ethanamine (16.4 g, 71%) as a yellow solid. LCMS (M+H+) m z: calcd. 251.15. found 251.9. To a solution of 1-(1,4-dioxan-2-yl)-N-(4-methoxybenzyl)ethanamine (5 g, 19.9 mmol) in anhydrous methanol (100 mL) was added palladium 10% on carbon (240 mg, 2 mmol), then purged with hydrogen (30 psi), the mixture was allowed to stir overnight at room temperature. The reaction mixture was filtered, and the filtrate was concentrated to afford the title compound (2.5 g, 96%) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([C:21]#[CH:22])[CH:20]=1)[C:5]([NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[O:6].[C:23]([O:27][C:28](=[O:48])[NH:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([O:40][C:41]2[CH:46]=[CH:45][N:44]=[C:43](Cl)[N:42]=2)=[CH:32][CH:31]=1)([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C>[C:23]([O:27][C:28](=[O:48])[NH:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([O:40][C:41]2[CH:46]=[CH:45][N:44]=[C:43]([NH:1][C:2]3[CH:3]=[C:4]([C:5](=[O:6])[NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[CH:18]=[C:19]([C:21]#[CH:22])[CH:20]=3)[N:42]=2)=[CH:32][CH:31]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: C#Cc1cc(N)cc(C(=O)NCCOCCOCCOC)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(Cl)n2)c2ccccc12
Solvent: CN(C)C=O
Product: C#Cc1cc(Nc2nccc(Oc3ccc(NC(=O)OC(C)(C)C)c4ccccc34)n2)cc(C(=O)NCCOCCOCCOC)c1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
To a stirred solution of the product from step (iv) above (1 g, 3.13 mmol) and tert-butyl(4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate (see, for example, Ito, K. et al., WO 2010/067130, 17 Jun. 2010; 777 mg, 2.090 mmol) in DMF (60 mL) was added pTSA monohydrate (200 mg, 1.051 mmol). The resulting solution was stirred at 60° C. for 72 h. The reaction was cooled to rt, then partitioned between EtOAc (150 mL) and sat. aq. NaHCO3 (100 mL). The aqueous layer was further extracted with EtOAc (2×150 mL), then the combined organic extracts were washed with water (3×200 mL) and brine (200 mL), before being dried (MgSO4), filtered and concentrated to afford an orange oil (1.17 g). The crude product was purified by chromatography on silica gel (80 g column, 0-5% MeOH in EtOAc) to afford the sub-title compound (552 mg) as a light brown foam.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:30]=[C:29]([CH2:31][CH3:32])[CH:28]=[CH:27][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH:21]([CH2:23][OH:24])[O:20][C:19]2=[O:25])=[CH:14][C:13]=1[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl.O>[CH2:1]([O:8][C:9]1[CH:30]=[C:29]([CH2:31][CH3:32])[CH:28]=[CH:27][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH:21]([CH2:23][O:24][S:41]([CH3:40])(=[O:43])=[O:42])[O:20][C:19]2=[O:25])=[CH:14][C:13]=1[F:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ccc(Oc2ccc(N3CC(CO)OC3=O)cc2F)c(OCc2ccccc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(Oc2ccc(N3CC(COS(C)(=O)=O)OC3=O)cc2F)c(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 43.1 %

Procedure:
To a solution of 3-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluoro phenyl]-5-hydroxymethyloxazolidin-2-one (240 mg, 0.54 mmol) in 5 ml of dry dichloromethane and 0.16 ml (1.1 mmol) of triethylamine, cooled to 0° C., was added a solution of methanesulfonyl chloride (0.06 ml, 0.76 mmol) in 0.5 ml of dichloromethane dropwise. The reaction was allowed to warm to rt overnight. The reaction mixture was diluted with 20 ml water, 20 ml of dichloromethane were added and the layers separated. The aqueous layer was extracted with dichloromethane and the combined dichloromethane fraction was dried over anhydrous Na2SO4 and concentrated. The crude residue obtained was column purified over silica gel using 20% ethyl acetate in petroleum ether as eluant to get 120 mg, 42.8% of the title compound.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:37])[N:32]([C:38]1([CH3:46])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45])[C:31]2=[O:47].CCOC(C)=O>CN(C)C=O>[CH2:1]([S:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:26][CH2:27][C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[C:33](=[O:37])[N:32]([C:38]2([CH3:46])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]2=[O:45])[C:31]3=[O:47])=[O:10])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CC1(N2C(=O)c3ccc(CN)cc3C2=O)CCC(=O)NC1=O
Reactant: CCSc1ccc(C(=O)O)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCSc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2(C)CCC(=O)NC2=O)C3=O)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 39.7 %

Procedure:
A stirred mixture of 4-(ethylthio)benzoic acid (0.36 g, 2.00 mmol) and CDI (0.34 g, 2.10 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 2 h, 5-aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.670 g, 2.00 mmol) was added and the mixture was heated at 40° C. for 2 h. The mixture was cooled to rt and EtOAc (75 mL) was added. The organic layer was washed with sat. aq. NaHCO3 (3×100 mL) then concentrated in vacuo. The crude residue was purified by column chromatography (hexanes/EtOAc, gradient, product eluted at ˜95% EtOAc). The product fractions were combined and concentrated to give 4-ethylsulfanyl-N-[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-benzamide as a white solid (0.37 g, 61% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 50/50 CH3CN/0.1% H3PO4, 4.03 min (99.73%); mp: 135-137° C.; 1H NMR (DMSO-d6) δ 1.27 (t, J=7.3 Hz, 3H), 1.89 (s, 3H), 1.95-2.11 (m, 1H), 2.53-2.61 (m, 2H), 2.61-2.77 (m, 1H), 3.06 (q, J=7.3 Hz, 2H), 4.61 (d, J=5.7 Hz, 2H), 7.38 (d, J=8.3 Hz, 2H), 7.72-7.88 (m, 5H), 9.18 (t, J=5.9 Hz, 1H), 11.01 (s, 1H); 13C NMR (DMSO-d6) δ 13.92, 21.02, 25.19, 28.57, 29.11, 42.58, 58.76, 121.60, 123.18, 126.32, 127.83, 129.59, 130.38, 131.38, 133.38, 141.22, 147.51, 165.86, 167.73, 167.88, 172.13, 172.19; LCMS: MH=466; Anal Calcd for C21H23N3O5S+0.3H2O: C, 61.21; H, 5.05; N, 8.92. Found: C, 61.27; H, 5.13; N, 8.80.
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]([NH:16][C:17]([C:19]3([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[CH2:21][CH2:20]3)=[O:18])[N:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.Cl>O1CCOCC1>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([C:19]2([C:17]([NH:16][C:11]3[CH:12]=[CH:13][C:14]([CH3:15])=[C:9]([C:8]4[C:3](=[O:2])[NH:4][CH:5]=[CH:6][CH:7]=4)[N:10]=3)=[O:18])[CH2:20][CH2:21]2)=[CH:23][CH:24]=1
Reactant: COc1ccc(C2(C(=O)Nc3ccc(C)c(-c4cccnc4OC)n3)CC2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(C2(C(=O)Nc3ccc(C)c(-c4ccc[nH]c4=O)n3)CC2)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
N-(2′-Methoxy-3-methyl-2,3′-bipyridin-6-yl)-1-(4-methoxyphenyl)cyclopropane carboxamide (TFA salt) (˜39 mg, ˜0.10 mmol) was dissolved in 1,4-dioxane (0.6 mL) in a reaction tube. An aqueous 4M HCl (0.27 mL, 1.1 mmol) was added and the reaction mixture was stirred at 90° C. for 1 hour. The resulting material was cooled to room temperature, filtered, and purified by reverse phase preparative HPLC to yield 1-(4-methoxyphenyl)-N-(5-methyl-6-(2-oxo-1,2-dihydropyridin-3-yl)pyridin-2-yl)cyclo-propanecarboxamide. ESI-MS m/z calc. 375.2. found 376.7 (M+1)+. Retention time 1.26 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.47-7.42 (m, 3H), 7.38 (dd, J=6.8, 2.1 Hz, 1H), 6.98 (d, J=8.7 Hz, 2H), 6.25 (t, J=6.6 Hz, 1H), 3.77 (s, 3H), 2.08 (s, 3H), 1.52-1.49 (m, 2H), 1.13-1.11 (m, 2H).
Reaction SMILES: [H-].[Na+].[N:3]1([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[NH:15][C:16]([C:21]4[CH:26]=[C:25]([N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)[CH:24]=[CH:23][N:22]=4)=[CH:17][C:18](=[O:20])[CH:19]=3)[CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:32]I>CN(C)C=O>[CH3:32][O:20][C:18]1[CH:17]=[C:16]([C:21]2[CH:26]=[C:25]([N:27]3[CH2:28][CH2:29][CH2:30][CH2:31]3)[CH:24]=[CH:23][N:22]=2)[N:15]=[C:14]([C:10]2[CH:9]=[C:8]([N:3]3[CH2:4][CH2:5][CH2:6][CH2:7]3)[CH:13]=[CH:12][N:11]=2)[CH:19]=1
Reactant: CI
Reactant: O=c1cc(-c2cc(N3CCCC3)ccn2)[nH]c(-c2cc(N3CCCC3)ccn2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(-c2cc(N3CCCC3)ccn2)nc(-c2cc(N3CCCC3)ccn2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
26 mg of sodium hydride dispersion (60% strength, 0.65 mmol) are suspended under argon in 5 ml of abs. N,N-dimethylformamide and cooled to 0° C. Then 193 mg (0.5 mmol) of 4,4″-di-pyrrolidin-1-yl-1′H-[2,2′;6′,2″]terpyridin-4′-one (L18 from Example 24) are added. The yellow suspension is stirred for 30 minutes 0° C. and then heated at room temperature for 15 minutes. The mixture is cooled again and a solution of 40 μl (0.65 mmol) of methyl iodide is added. The mixture is stirred for a further 45 minutes and the precipitate that forms is filtered off and recrystallised from methanol. 4′-Methoxy-4,4″-di-pyrrolidin-1-yl-[2,2′;6′,2″]-terpyridine is obtained in the form of a white solid. 168.1 (quart.); 157.9 (quart.); 156.6 (quart.); 152.9 (quart.); 149.5 (tert.); 107.4 (tert.); 107.1 (tert.); 105.0 (tert.); 55.9 (prim.); 47.3 (sec.); 25.8 (sec.). MS (EI, 70 eV), m/z: 401 (50, [M+]); 373 (80); 372 (100); 332 (20); 28 (40).
Reaction SMILES: [CH2:1]([NH:18][C:19](=[O:36])[O:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][O:23][C@H:22]1[CH2:27][O:28]CC1C=CC=CC=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[H][H]>CO.[Pd]>[CH2:1]([NH:18][C:19](=[O:36])[O:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][O:23][C@H:22]1[CH2:27][OH:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCCCCNC(=O)O[C@@H]1CCCO[C@H]1COCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCNC(=O)O[C@@H]1CCCO[C@H]1CO

Procedure:
3.800 g of dl-trans-2-benzyloxymethyltetrahydropyran-3-yl N-heptadecylcarbamate (prepared as described in Preparation 3) were dissolved in 120 ml of methanol and allowed to react with hydrogen at room temperature for 8 hours in the presence of 10% w/w palladium on activated carbon in a Paal's apparatus at 4 atmospheres (about 4 bar). The catalyst was then filtered off, and the solvent was removed from the filtrate by distillation under reduced pressure, to give 2.729 g of the title compound as a white solid, melting at 84°-86° C. (after recrystallization from diethyl ether).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:25])[N:6]2[C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=[CH:15][CH:16]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.N1C=CC=CC=1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Cu+2]>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([C:30]1[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=1)[C:5](=[O:25])[N:6]2[C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH:14]=[CH:15][CH:16]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(-n2c(=O)[nH]c3c(N)ncnc32)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1cccc(-n2c(=O)n(-c3ccc(Cl)cc3)c3c(N)ncnc32)c1
Temperature: 35 °C
Yield: 58.7 %

Procedure:
To a mixture of tert-butyl 3-(6-amino-8-oxo-7H-purin-9(8H)-yl)phenylcarbamate (5) (300 mg, 0.88 mmol) and 4 A MS (300 mg) in dry DMF (10 mL) were added 4-chlorophenylboronic acid (413 mg, 2.64 mmol), Cu(OAc)2 (160 mg, 0.88 mmol) and pyridine (1 mL). The reaction mixture was heated to 35° C. overnight under an O2 atmosphere, and filtered through a Celite pad. The filtrate was diluted with water (50 mL), extracted with EtOAc (30 mL×3). The combined organic layer was washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (silica gel, 0 to 5% methanol in methylene chloride) to give tert-butyl 3-(6-amino-7-(4-chlorophenyl)-8-oxo-7H-purin-9(8H)-yl)phenylcarbamate (12) (234 mg, 59.1%). LC-MS (ESI): m/z (M/M+2) 453/455.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][N:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]([O:20]C)=[O:19])=[CH:17][C:12]=3[N:11]=[C:10]2[S:22]([CH3:25])(=[O:24])=[O:23])=[O:7])=[CH:4][C:3]=1[S:28](=[O:31])(=[O:30])[NH2:29]>[OH-].[Na+]>[C:18]([C:16]1[CH:15]=[CH:14][C:13]2[N:9]([NH:8][C:6](=[O:7])[C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[C:3]([S:28](=[O:30])(=[O:31])[NH2:29])[CH:4]=3)[C:10]([S:22]([CH3:25])(=[O:23])=[O:24])=[N:11][C:12]=2[CH:17]=1)([OH:20])=[O:19]
Reactant: COC(=O)c1ccc2c(c1)nc(S(C)(=O)=O)n2NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)c1nc2cc(C(=O)O)ccc2n1NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 84.5 %

Procedure:
A suspension containing 5.4 g of 1-(4'-chloro-3'-sulfamoylbenzoyl)amino-5-methoxycarbonyl-2-methylsulfonylbenzimidazole in 30 ml of 2N sodium hydroxide solution was stirred at 50° C. for 4 hours to give a clear violet solution which was clarified by activated carbon, filtered and the filtrate was acidified to pH 2 by adding 2N hydrochloric acid. The white precipitate was filtered by suction, washed with water and dried to give 4.43 g (85.7%) of 5-carboxy-1-(4'-chloro-3'-sulfamoylbenzoyl)amino-2-methylsulfonylbenzimidazole, as a white powdery solid, m.p.: 222°-225° C. (with decomposition) which is not changed after recrystallization from a mixture of dimethylformamide and water (3:2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][N:12]=1)=O.P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:23][NH2:24].O>C1(C)C=CC=CC=1>[NH2:23][NH:24][C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][N:12]=1)=[N:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: NN
Reactant: O=C(Nc1ccccc1Cl)c1ccncn1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: NNC(=Nc1ccccc1Cl)c1ccncn1

Procedure:
To a suspension of N-(2-chlorophenyl)pyrimidine-4-carboxamide 3 (0.2 g, 0.86 mmol) in 20 mL of PhMe was added 0.65 g of PCl5. The mixture was stirred at reflux for 3 h. To this solution was added 3 mL of NH2NH2.H2O. The mixture was stirred at ambient temperature for 2 h. After removal of all solvent, the residue was purified by column (2:1 of hexane/ethyl acetate) to give N-amino-N′-(2-chlorophenyl)pyrimidine-4-carboxamidine 5 as a solid. Yield: 0.15 g, 70%. 1HNMR (DMSO-d6) δ (ppm): 9.15 (s, 1H); 8.70 (d, 1H); 7.98 (d, 1H); 7.35 (m, 1H); 7.15 (m, 1H); 6.80 (m, 1H); 6.45 (d, 1H); 5.60 (s, 2H).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:21])([CH3:20])[C:8]1[N:9]=[CH:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:22]([Li])CCC.IC>C1COCC1>[C:1]([SiH2:5][O:6][C:7]([CH3:21])([CH3:20])[C:8]1[N:9]=[C:10]([CH3:22])[N:11]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cn(-c2ccc(F)cc2)cn1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1nc(C(C)(C)O[SiH2]C(C)(C)C)cn1-c1ccc(F)cc1
Temperature: -25 °C
Reaction time: 0.17 h

Procedure:
4-(tert-Butyl-dimethyl-silanyloxymethyl)-1-(4-fluoro-phenyl)-1H-imidazole (18.2 g, 59.2 mmol) was dissolved in 600 mL dry THF and cooled to −78° C. n-Butyl lithium (55.5 mL, 1.6M in hexane, 88.8 mmol) was added dropwise. The reaction mixture was warmed up to −25° C., kept at −25° C. for 10 min and then cooled again to −78° C. Iodomethane (7.4 mL, 11.8 mmol) was added dropwise. The reaction mixture was slowly warmed up to room temperature and stirred at room temperature overnight. The solvent was evaporated. The residue was taken up in 300 mL water and extracted three times with ethyl acetate (200 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by column chromatography on silica gel (cyclohexane/ethyl acetate 50:50->20:80 gradient) and the desired compound was obtained as an orange oil (14.7 g, 77%), MS: m/e=321.1 (M+H+).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[CH3:8].[C:10]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Cl:9][C:5]1[N:4]=[N:3][C:2]([CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([O:18][CH2:19][CH3:20])=[O:17])=[C:7]([CH3:8])[CH:6]=1
Reactant: Cc1cc(Cl)nnc1Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1nnc(Cl)cc1C
Temperature: 110 °C
Reaction time: 4 h
Yield: 25.8 %

Procedure:
A mixture of 4.29 g of 3,6-dichloro-4-methylpyridazine, 8.80 g of diethyl malonate, 25 ml of dimethyl sulfoxide and 17.9 g of cesium carbonate was stirred for 4 hours at 110° C. under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, then, to this was added ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine twice, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 7.08 g of the resultant residue was subjected to silica gel column chromatography, to obtain 1.95 g of diethyl (6-chloro-4-methyl-3-pyridazinyl)malonate.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:17](=O)[C:16](=O)[N:15]3[C@H:10]([CH2:11][O:12][CH2:13][CH2:14]3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>CCOCC.CCOC(C)=O.C1(CN2C(=O)C(=O)N3[C@H](COCC3)C2)C=CC=CC=1>[C:1]1([CH2:7][N:8]2[CH2:17][CH2:16][N:15]3[C@H:10]([CH2:11][O:12][CH2:13][CH2:14]3)[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C(=O)N2CCOC[C@@H]2CN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: c1ccc(CN2CCN3CCOC[C@@H]3C2)cc1
Temperature: 35 °C
Reaction time: 144 h
Yield: 102.2 %

Procedure:
To a 0° C. mixture of two combined batches of (9aS)-8-(phenylmethyl)hexahydropyrazino[2,1-c][1,4]oxazine-6,7-dione (combined total 42.29 g, 162.5 mmol) in Et2O (406 mL) was added 1 M LiAlH4 in Et2O (406 mL, 406 mmol) via dropping funnel over 40 min. The mixture was then warmed to 35° C. and stirred for 6 days. The mixture was then cooled to 0° C., and EtOAc (100 mL) was slowly added, followed by water (20 mL), 15% aqueous NaOH (20 mL), and water (60 mL). The mixture was vigorously stirred for 1 h, and then diluted with EtOAc (500 mL). The mixture was filtered, and the filter cake was diluted with 1 N aqueous NaOH (500 mL) and extracted with Et2O (2×200 mL). The combined organic phase (filtrate and Et2O extractions) was dried over anhydrous Na2SO4, filtered, concentrated in vacuo, azeotroped with MeOH (100 mL), and dried overnight under high vacuum. The resulting colorless oil was combined with a second batch of product prepared in the same fashion from (9aS)-8-(phenylmethyl)hexahydropyrazino[2,1-c][1,4]oxazine-6,7-dione (0.3047 g, 1.1 mmol) to give crude (9aS)-8-(phenylmethyl)octahydropyrazino[2,1-c][1,4]oxazine (combined total 38.59 g, >100% crude yield). LCMS: (M+H)+: 233.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][C:5]2([CH3:13])[CH3:12].[C:14]1([C@H:20]([CH2:22][OH:23])[NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(=O)C.[BH4-].[Na+]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@@H:7]([NH:21][C@H:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:22][OH:23])[CH2:6][C:5]2([CH3:13])[CH3:12]
Reactant: N[C@@H](CO)c1ccccc1
Reactant: CC1(C)CC(=O)c2ccc(Cl)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC1(C)C[C@H](N[C@@H](CO)c2ccccc2)c2ccc(Cl)cc21
Temperature: 140 °C
Yield: 89.1 %

Procedure:
To a mixture of 5-chloro-3,3-dimethylindan-1-one (4.33 g, 0.0222 mol) and (R)-(−)-2-phenylglycinol (3.2 g, 0.0234 mol) in toluene (200 mL) was added p-toluenesulfonic acid monohydrate (241 mg, 0.00127 mol). The reaction was stirred at reflux (140° C.) under an atmosphere of nitrogen overnight, cooled and diluted with toluene. The mixture was washed with saturated aqueous NaHCO3 and water and the organic phase was concentrated. The residue was dissolved in THF (200 mL) under an atmosphere of nitrogen and cooled at 0° C. To this was added acetic acid (3.79 mL, 0.0667 mol) and sodium borohydride (1.26 g, 0.0334 mol). The reaction was stirred under at atmosphere of nitrogen overnight. The reaction was partitioned between CH2Cl2 and saturated aqueous NaHCO3 solution, separated, and the organic phase was evaporated. The residue was purified by flash chromatography (20 to 100% EtOAc/hexanes) to afford the title compound (6.25 g, 90%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:32])[C:19]([C:22]2[CH:31]=[CH:30][C:29]3[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=3[CH:23]=2)=[CH:20][OH:21])=[CH:11][C:10]=1[O:33][CH3:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl[CH:38]([F:40])[F:39].Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.COCCOC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:32])[C:19]([C:22]2[CH:31]=[CH:30][C:29]3[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=3[CH:23]=2)=[CH:20][O:21][CH:38]([F:40])[F:39])=[CH:11][C:10]=1[O:33][CH3:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)Cl
Reactant: COc1cc(CCNC(=O)C(=CO)c2ccc3c(c2)CCCC3)ccc1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: COCCOC
Product: COc1cc(CCNC(=O)C(=COC(F)F)c2ccc3c(c2)CCCC3)ccc1OCc1ccccc1

Procedure:
4.20 g (9.19 mmol) of N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-3-hydroxy-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide, 14.3 g (23.0 mmol) of 10% aqueous potassium hydroxide solution, 0.60 g (1.84 mmol) of tetrabutylammonium bromide and 40 ml of ethylene glycol dimethyl ether were mixed and chlorodifluoromethane gas was blown thereto at room temperature. After a sample was taken out from the reaction mixture and the disappearance of the starting material was confirmed by thin layer chromatography, 5% hydrochloric acid was added to the reaction mixture. The reaction mixture was extracted with ethyl acetate, washed with 5% hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (eluent, hexane:ethyl acetate=2:1) and the obtained product was washed with hexane to give 2.4 g of N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-3-difluoromethoxy-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide (the present compound 1281).