Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C@@H:9]([OH:12])[CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].[C:21]1(=O)[O:26][C:24](=[O:25])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.CCN(CC)CC>CN(C=O)C>[C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C@H:9]([OH:12])[CH2:10][N:11]1[C:24](=[O:25])[C:23]2[C:22](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]1=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)CN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Reaction time: 24 h
Yield: 57.5 %

Procedure:
(1R,2S)-(3-amino-1-benzyl-2-hydroxy-propyl)-carbamic acid t-butyl ester (1.4 g, 5 mmol) prepared in Preparation 103 was dissolved in DMF (20 mL), to which was added phthalic anhydride (735 mg, 5 mmol). Et3N (1.4 mL, 10 mmol) was added thereto, and the mixture was stirred for 24 h at 80° C. The reaction was quenched by water, and the reaction mixture was extracted with EtOAc, and dried over MgSO4. The solvent was removed under reduced pressure, and the residue was dissolved in DCM. TFA was added thereto, and the mixture was stirred for 2 h at room temperature. After completion of the reaction, the solvent was removed under reduced pressure. The residue was recrystallized from DCM/Hex to give the title compound (1.18 g, Yield 71%).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[C:5]([O:9][C:10](=[O:28])[NH:11][C:12]1[CH:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][N:20]=2)[C:15]([Cl:26])=[CH:14][C:13]=1[F:27])([CH3:8])([CH3:7])[CH3:6].BrBr>C(O)(=O)C>[C:5]([O:9][C:10](=[O:28])[NH:11][C:12]1[CH:17]=[C:16]([O:18][C:19]2[N:20]=[C:21]3[S:1][C:2]([NH2:3])=[N:25][C:22]3=[CH:23][CH:24]=2)[C:15]([Cl:26])=[CH:14][C:13]=1[F:27])([CH3:8])([CH3:6])[CH3:7]
Reactant: N#C[S-]
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc(N)cn2)c(Cl)cc1F
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3nc(N)sc3n2)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
Potassium thiocyanate (2.70 g, 27.8 mmol) was dissolved in acetic acid (190 mL), tert-butyl{5-[(5-aminopyridin-2-yl)oxy]-4-chloro-2-fluorophenyl}carbamate (2.40 g, 6.78 mmol) was added, and the mixture was stirred at room temperature for 30 min. To the solution was added dropwise a solution (20 mL) of bromine (1.13 g, 7.07 mmol) in acetic acid, and the mixture was stirred at room temperature for 13 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL), and the solution was washed with saturated aqueous sodium hydrogen carbonate solution (100 mL×2) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. The dried organic layer was purified by basic silica gel chromatography (15 g, ethyl acetate), and the eluted fraction was concentrated under reduced pressure to give the title compound (2.69 g, 97%) as a white powder.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[C@H:11]1([NH2:18])[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[NH2:17].[BH4-].[Na+]>O>[CH2:1]([NH:17][C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@@H:11]1[NH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: N[C@H]1CCCC[C@@H]1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N[C@H]1CCCC[C@@H]1NCc1ccccc1
Temperature: 25 °C
Yield: 48 %

Procedure:
Benzaldehyde (3.05 mL, 30.0 mmol) was added to a methanol (300 mL) solution of (1S,2S)-cyclohexane-1,2-diamine (3.43 g, 30.0 mmol) with stirring at room temperature, and the mixture was stirred overnight at the same temperature. The reaction mixture was cooled to 0° C. Sodium borohydride (2.27 g, 60.0 mmol) was added thereto, and the mixture was stirred at 0° C. for 2 hours. To the reaction mixture, water (30 mL) was added, and the product was extracted twice with methylene chloride (50 mL). The organic layers were combined and dried over magnesium sulfate, and the solvent was then distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane) to obtain (1S,2S)-N-benzylcyclohexane-1,2-diamine (cas no. 207450-11-1) (2.95 g, yield: 48%) in a pale yellow oil form.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[C:12]([CH2:14][CH3:15])[C:11]([CH2:16][C:17]([N:19]([CH3:28])[N:20]=[C:21]([CH3:27])[C:22]([O:24]CC)=O)=[O:18])=[C:10]([CH2:29][CH3:30])[CH:9]=1>O1CCCC1.C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:9]=[C:10]([CH2:29][CH3:30])[C:11]([C:16]2[C:17](=[O:18])[N:19]([CH3:28])[N:20]=[C:21]([CH3:27])[C:22]=2[OH:24])=[C:12]([CH2:14][CH3:15])[CH:13]=1
Reactant: CCOC(=O)C(C)=NN(C)C(=O)Cc1c(CC)cc(Cl)cc1CC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCc1cc(Cl)cc(CC)c1-c1c(O)c(C)nn(C)c1=O
Reaction time: 0.17 h
Yield: 14.6 %

Procedure:
A solution of 0.55 g of potassium tert-butoxide in 20 mL of tetrahydrofuran was stirred at 36 to 38° C. under nitrogen atmosphere. To the solution was added dropwise a solution of 0.79 g of ethyl 2-[2-(4-chloro-2,6-diethylphenylacetyl)-2-methylhydrazono]propanoate (compound VI-2) in 15 mL of toluene over about 20 minutes. The mixture was further stirred at the same temperature for 10 minutes. Then, the reaction mixture was concentrated under reduced pressure. To the residue was added 20 mL of ice water, followed by extraction with tert-butyl methyl ether (20 mL×2). An aqueous layer was acidified by an addition of 0.6 g of 35% hydrochloric acid, followed by extraction with ethyl acetate (20 mL×2). The ethyl acetate extracts were combined, washed with an aqueous saturated sodium chloride solution (20 mL×2), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography (ethyl acetate:hexane=1:4) to give 0.1 g of a solid. The solid was washed with an ethyl acetate-hexane mixture solvent (1:10) and air dried to give 0.07 g of the title compound as a white powder.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].N1C=CN=C1.[Si:11](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O.O>[Si:11]([O:5][CH2:4][CH2:3][NH:2][CH3:1])([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CNCCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CNCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
To a solution of N-methylethanolamine (600 mg), in N,N-dimethylformamide were added imidazole (1.13 g) and tert-butyldiphenylsilyl chloride (2.20 g) at ambient temperature with stirring. After 8 hours, the mixture was diluted with water (60 ml) and was extracted with ethyl acetate (20 ml) twice. The organic layer was washed with water three times and brine, dried over magnesium sulfate. The solvent was removed in vacuo. The residue was purified by column chromatography eluting with dichloromethane-methanol to give N-(2-tert-butyldiphenylsilyloxyethyl)-N-methylamine (780 mg) as an oil.
Reaction SMILES: C(N[C:6](=O)[N:7]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])(C)(C)C.[CH:22]1[CH:23]=[CH:24][NH+]=[CH:26][CH:27]=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[CH:15]1([N:7]([CH:6]2[CH2:24][CH2:23][CH2:22][CH2:27][CH2:26]2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[O:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CC(C)(C)NC(=O)N(CCCCCCO)C1CCCCC1
Reactant: c1cc[nH+]cc1
Agent: O=[Cr](=O)([O-])Cl
Solvent: ClCCl
Product: O=CCCCCCN(C1CCCCC1)C1CCCCC1
Reaction time: 2 h
Yield: 50.7 %

Procedure:
To a stirred suspension of silica gel (432 mg) in methylene chloride (10 mL) at room temperature was added 3-(tert-butyl)-1-cyclohexyl-1-(6-hydroxyhexyl)urea (400 mg, 1.34 mmol) and PCC (432 mg, 2.0 mmol). The mixture was stirred at this temperature for 2 hours, and then filtered through a pad of celite. The filtrate was concentrated and purified on silica gel column with a gradient of ethyl acetate in hexanes from 0:1 to 2:8 provided the product as a clear oil (190 mg, 48%). 1H NMR (300 MHz, CDCl3): δ 9.78 (t, J=1.8 Hz, 1H), 4.16 (s, 1H), 3.86-3.50 (m, 1H), 3.00 (t, J=7.9 Hz, 2H), 2.46 (td, J=7.3, 1.8 Hz, 2H), 1.87-1.46 (m, 9H), 1.46-1.20 (m, 15H), 1.20-0.95 (s, 1H).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1.O>CN(C)C=O>[C:3]1([S:8][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[S:1][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1
Reactant: Sc1ccccc1S
Reactant: Clc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(Sc2ccccc2Sc2ccc(Cl)cn2)nc1

Procedure:
In 50 ml of stirred dimethylformamide, a mixture of 3.0 grams (0.02 mole) dimercaptobenzene, 7.0 grams potassium carbonate, and 7.0 grams of 2,5-dichloropyridine is heated at 80° for 5 hours. Thereafter pouring into excess H2O, the mixture is extracted with ethyl ether (200 ml) and washed with H2O, saturated NaHCO3, and brine, dried (MgSO4), and evaporated to yield the crude product which can be recrystallized from 1-chlorobutane.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]#[N:8].Br[CH2:10][CH2:11]Cl.[H-].[Na+]>CS(C)=O.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([C:7]#[N:8])[CH2:11][CH2:10]1
Reactant: ClCCBr
Reactant: N#CCc1ccco1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC1(c2ccco2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of furan-2-acetonitrile (28.4 g) and 1-bromo-2-chloroethane (33.1 ml) in dimethyl sulphoxide (50 ml) was added slowly to a stirred suspension of sodium hydride (60% dispersion in mineral oil ; 31.85 g) in dry dimethyl sulphoxide (300 ml) keeping the internal temperature just below 35° C. by occasional cooling. After stirring for 18 hours at ambient temperature the mixture was diluted with water (500 ml) and extracted with ether (1×200 then 2×100 ml). The combined extracts were dried over potassium carbonate and evaporated to an oil which was distilled at reduced pressure to give 1-(2-furyl)cyclopropanecarbonitrile (28.0 g) as a colourless oil, bp 54° C./0.55 mbar.
Reaction SMILES: [CH3:1][C:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([OH:15])=O)[C:11](=[O:12])[N:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH2:28]([NH2:31])[CH2:29][CH3:30]>C(Cl)(Cl)Cl>[CH2:28]([NH:31][C:13]([C:10]1[C:11](=[O:12])[N:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:7]2=[N:8][CH:9]=1)=[O:15])[CH2:29][CH3:30]
Reactant: Cc1cccn2c(=O)c(C(=O)O)cnc12
Reactant: CCCN
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCNC(=O)c1cnc2c(C)cccn2c1=O
Reaction time: 0.08 h
Yield: 70.7 %

Procedure:
A mixture containing 9.2 g (0.045 mol) of 9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 7.05 ml (0.05 mol) of triethylamine in 280 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 3.7 ml (0.045 mol) of methyl chloroformate dissolved in 25 ml of chloroform is dropped to the above mixture at -21° C. during 10 minutes. After stirring for 5 minutes, 2.95 g (0.05 mol) of propylamine dissolved in 50 ml of chloroform are dropped to the above solution at a temperature between -21° C. and -19° C. during 45 minutes. The reaction mixture is stirred below -10° C. for 1 hour, then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 70 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 70 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to give 7.8 g (70.7%) of the named compound as snow-white crystals after recrystallization from ethanol, m.p.: 138°-140° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17](=[O:25])[NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.[C:26]([O:30][C:31](=[O:36])[NH:32][CH2:33][CH2:34][NH2:35])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31](=[O:36])[NH:32][CH2:33][CH2:34][NH:35][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:8]([C:5]2[CH:6]=[N:7][C:2]([NH2:1])=[C:3]([C:17](=[O:25])[NH:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH:4]=2)=[CH:9][CH:10]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1C(=O)Nc1ccncc1
Reactant: CC(C)(C)OC(=O)NCCN
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)cc1

Procedure:
Reaction of 4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid with (2-amino-ethyl)-carbamic acid tert-butyl ester gives “A96”; method 1: HPLC/MS: 1.47 min, [M+H]=477;
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:18])([F:17])[C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1.CO.[CH2:21](Cl)Cl>CS(C)=O>[F:18][C:4]([F:17])([F:3])[C:5]1[N:10]=[CH:9][C:8]([C@@H:11]2[CH2:21][C@H:12]2[C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1
Reactant: ClCCl
Reactant: COC(=O)/C=C/c1ccc(C(F)(F)F)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: COC(=O)[C@@H]1C[C@H]1c1ccc(C(F)(F)F)nc1
Reaction time: 0.05 h
Yield: 10 %

Procedure:
To a vigorously stirring mixture of NaH (31.0 mg, 1. 16 mmol) in DMSO (5 mL) at ambient temperature under an argon (g) atmosphere was added (CH3)3S(I)O (248 mg, 1. 12 mmol) in small portions over ca. 1 min. Following complete addition, the reaction was stirred for 20 min. A DMSO (1 mL) solution of 26A (200 mg, 0.870 mmol) was added dropwise over ca. 1 min. The reaction was left to stir for 5 h then quenched with H2O (25 mL) and extracted into EtOAc (3×30 mL). The combined organics were washed with H2O (1×15 mL), brine (15 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was subjected to flash chromatography (SiO2—12 g; gradient elution: 0.25% MeOH/DCM for 3 min then 0.25-4% MeOH/DCM over 14 min at 25 mL/min) to afford 22.0 mg 26B (10% yield). m/z (ES+) M+1=246.1; HPLC tR=1.09 min. 1H NMR (500 MHz, CDCl3) δ 8.54 (d, J=1.8 Hz, 1H), 7.59 (d, J=8.2 Hz, 1H), 7.55-7.46 (m, 1H), 3.75 (s, 3H), 2.60 (ddd, J=9.6, 6.1, 4.1 Hz, 1H), 2.00 (ddd, J=8.6, 5.6, 4.1 Hz, 1H), 1.73 (dt, J=9.2, 5.1 Hz, 1H), 1.38 (ddd, J=8.6, 6.4, 5.1 Hz, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]([CH2:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:8](=[O:23])[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Br:22])=[CH:11][CH:10]=2)=[O:5].C(N(CC)CC)C.[CH3:38][N:39]=[C:40]=[O:41]>O1CCCC1>[CH3:2][O:3][C:4]([C:6]1[N:7]([CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([C:40](=[O:41])[NH:39][CH3:38])[CH2:27][CH2:26]2)[C:8](=[O:23])[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Br:22])=[CH:11][CH:10]=2)=[O:5]
Reactant: CN=C=O
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1CC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)N1CCC(Cn2c(C(=O)OC)c(-c3ccccc3)c3cc(Br)ccc3c2=O)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 33 %

Procedure:
To a solution of 6-bromo-1-oxo-4-phenyl-2-(piperidin-4-ylmethyl)-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester hydrochloride (100 mg) in tetrahydrofuran (5 ml) were added triethylamine (0.06 ml) and methylisocyanate (0.018 ml), and the mixture was stirred at room temperature for 24 hrs. The solvent was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by preparative HPLC to give the title compound (34 mg, 33%).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]#N)[CH:8]=[CH:9][CH:10]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([C:26]3[CH:31]=C[C:29]([N+:32]([O-])=[O:33])=[CH:28][CH:27]=3)[O:25][CH2:24][CH2:23][O:22]2)=[CH:17][CH:16]=1.O>CO>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2([C:26]3[CH:27]=[CH:28][C:29]4[C:12]([CH:31]=3)=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH3:3])[CH:6]=3)[O:33][N:32]=4)[O:22][CH2:23][CH2:24][O:25]2)=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(C2(c3ccc(Cl)cc3)OCCO2)cc1
Reactant: COc1cccc(CC#N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cccc(-c2onc3ccc(C4(c5ccc(Cl)cc5)OCCO4)cc23)c1
Yield: 90 %

Procedure:
Sodium hydroxide (16.4 g) and (3-methoxyphenyl)acetonitrile (20.6 ml) were added at room temperature to a solution of interm. (5-a) (25 g) in methanol (100 ml) and the mixture was stirred at room temperature overnight. Water was added, the precipitate was filtered off, washed with cold methanol and dried. The product was used without further purification, yielding 30 g (90%) of 5-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-3-(3-methoxyphenyl)-2,1-benzisoxazole (interm. 5-b).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)C>[Cl:13][CH2:12][CH2:11][CH2:10][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: ClCCCBr
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: ClCCCOc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.5 %

Procedure:
4-Iodophenol (10 g, 45.4 mmol), 1-bromo-3-chloropropane (7 g, 50.0 mmol) and potassium carbonate (7.54 g, 54.5 mmol) were mixed in DMF, and stirred at room temperature for 15 hours. The reaction liquid was diluted with diethyl ether, washed with water and saturated saline in that order, and the organic layer was dried with sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified through silica gel column chromatography (eluate: ethyl acetate/hexane=5/95) to obtain the entitled compound (11.1 g, 82.3%) as a pale yellow solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[N:7]([CH3:33])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH:30]([CH3:32])[CH3:31])[N:9]=3)[CH2:2]1.[CH3:34][C:35]1([O:38][CH2:37]1)[CH3:36].CN(C=O)C>O>[CH:30]([C:22]1[N:21]([C:10]2[N:9]=[C:8]3[C:13]([N:14]=[C:6]([O:5][CH:3]4[CH2:4][N:1]([CH2:34][C:35]([CH3:37])([OH:38])[CH3:36])[CH2:2]4)[N:7]3[CH3:33])=[C:12]([N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)[N:11]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)([CH3:31])[CH3:32]
Reactant: CC1(C)CO1
Reactant: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(OC3CNC3)n(C)c2n1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(OC3CN(CC(C)(C)O)C3)n(C)c2n1
Temperature: 60 °C

Procedure:
The mixture of 4-(8-(azetidin-3-yloxy)-2-(2-isopropyl-1H-benzo[d]imidazol-1-yl)-9-methyl-9H-purin-6-yl)morpholine (46.3 mg), isobutylene oxide (0.0183 mL), DMF (0.75 mL) and water (0.25 mL) was heated at 60° C. for 3 h. The contents were concentrated. Diluted aqueous Na2CO3 solution was added. The mixture was extracted with DCM (2×). The DCM extracts were dried with Na2SO4. The crude was purified with HPLC to give the product (17.2 mg). 1H NMR (400 MHz, CDCl3) δ 7.83 (dd, J=6.9, 2.0 Hz, 1H), 7.77 (dd, J=6.8, 1.9 Hz, 1H), 7.25-7.20 (m, 2H), 5.41 (p, J=5.8 Hz, 1H), 4.21 (s, 4H), 3.95 (ddd, J=20.5, 14.5, 7.9 Hz, 3H), 3.87-3.79 (m, 4H), 3.61 (s, 3H), 3.48-3.37 (m, 2H), 2.56 (s, 2H), 1.44 (d, J=6.8 Hz, 6H), 1.17 (s, 6H). LCMS: M+H+=521.3.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.[C:31](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO.ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:24][CH:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:22])([F:23])[F:21])=[CH:15][CH:14]=1)[CH2:7]2
Reactant: Cc1cc(CC2CCNCC2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(CC2CCN(C)CC2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2

Procedure:
7-Methyl-5-piperidin-4-ylmethyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (50.0 mg, 0.124 mmol) was dissolved in methanol (0.2 mL) and acetic acid (0.2 mL) and 37% formaldehyde (0.2 mL) was added at room temperature. The mixture was stirred for ten minutes and sodium cyanoborohydride (1M in THF, 0.2 mL, 0.20 mmol) was added and the mixture was allowed to stir overnight at room temperature. The reaction was diluted with dichloromethane, washed with sodium bicarbonate (sat) and brine dried over sodium sulphate, filtered and concentrated. Column chromatography provided the title compound as an off white foam (23.8 mg, 44%). 1H NMR (300 MHz, CDCl3): δ 7.37 (d, 2H), 7.21 (d, 2H), 6.99 (d, 2H), 4.77 (s, 2H), 4.22 (s, 2H), 2.91 (d, 1H), 2.77 (m, 4H), 2.58 (d, 2H), 2.30 (m, 3H), 1.99 (m, 1H), 1.67-1.27 (m, 6H).
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[NH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1>C1COCC1.O>[CH2:1]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[C:2]#[CH:3]
Reactant: C1CNCCN1
Reactant: C#CCBr
Solvent: O
Solvent: C1CCOC1
Product: C#CCN1CCNCC1
Yield: 22.9 %

Procedure:
Propargyl bromide (1.19 g, 10 mmol) and piperazine (8.61 g, 100 mmol) were dissolved in THF (90 ml). Stir under N2 and reflux for 4 h. Remove solvent and dissolve in 40 ml of H2O. Extracted with 4×40 ml of EtOAc, washed with 2×15 ml of brine, dried over MgSO4. After solvent was removed, brownish solid 29.83 (285 mg, 23% yield) was obtained. 1H NMR (CDCl3, 200 MHz): δ=2.28 (t, 1H, J=2.4 Hz), 2.56 (m, 4H), 2.92 (m, 4H), 3.30 (d, 2H, J=2.6 Hz).
Reaction SMILES: [F:1][CH:2]([F:21])[C@@H:3]1[C@@H:11]2[C@@:6]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=3[F:20])([N:7]=[C:8]([NH2:12])[S:9][CH2:10]2)[CH2:5][O:4]1.S(=O)(=O)(O)O.[N+:27]([O-])([OH:29])=[O:28].C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O>[F:20][C:14]1[C:15]([F:19])=[CH:16][C:17]([N+:27]([O-:29])=[O:28])=[CH:18][C:13]=1[C@:6]12[CH2:5][O:4][C@H:3]([CH:2]([F:1])[F:21])[C@H:11]1[CH2:10][S:9][C:8]([NH2:12])=[N:7]2
Reactant: NC1=N[C@@]2(c3cccc(F)c3F)CO[C@H](C(F)F)[C@H]2CS1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@]2(c3cc([N+](=O)[O-])cc(F)c3F)CO[C@H](C(F)F)[C@H]2CS1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
(4aS,5S,7aS)-5-(difluoromethyl)-7a-(2,3-difluorophenyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine, obtained in Preparation Example 1-(9), (565 mg) was dissolved in TFA (3 mL), and the solution was cooled to 0° C. Sulfuric acid (conc., 0.8 mL) was added, followed by fuming nitric acid (0.08 mL) dropwise over 20 mins. After stirring at 0° C. for 90 min, the reaction mixture carefully neutralized with NaHCO3 (sat., aq., 50 mL) and extracted with EtOAc (3×100 mL), and the combined organic portions dried over MgSO4 and evaporated. The residue was purified by silica gel column chromatography (0% to 80% EtOAc in hexanes) to afford the title compound (700 mg, purity approx. 80%) which was used in the subsequent step without purification. 1H NMR (400 MHz, CDCl3) δ ppm 3.04 (dd, J=14.0, 3.9 Hz, 1H), 3.23-3.31 (m, 1H), 3.59 (d, J=3.0 Hz, 1H), 4.23 (d, J=9.9 Hz, 1H), 4.44-4.60 (m, 2H), 6.02 (t, J=57.6 Hz, 1H), 8.02-8.26 (m, 2H)