Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[NH:11][CH2:10][CH2:9][CH2:8][N:7]([CH2:12][C:13]3[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[C:6]=2[N:22]=1.[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[CH2:12][N:7]1[CH2:8][CH2:9][CH2:10][NH:11][C:5]2[N:4]=[CH:3][C:2]([C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([N:26]4[CH2:25][CH2:24][O:23][CH2:28][CH2:27]4)[CH:34]=3)=[N:22][C:6]1=2
Reactant: CC1(C)OB(c2cccc(N3CCOCC3)c2)OC1(C)C
Reactant: Fc1ccc(F)c(CN2CCCNc3ncc(Br)nc32)c1Cl
Product: Fc1ccc(F)c(CN2CCCNc3ncc(-c4cccc(N5CCOCC5)c4)nc32)c1Cl

Procedure:
9-(2-chloro-3,6-difluorobenzyl)-2-[3-(morpholin-4-yl)phenyl]-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b][1,4]diazepine was prepared from 2-bromo-9-(2-chloro-3,6-difluorobenzyl)-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b][1,4]diazepine and 3-morpholinophenylboronic acid pinacol ester using standard Suzuki conditions as described in Example 1 or 2.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]([NH:15][C:16]1[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=[CH:18][N:17]=1)=O.CCN(C(C)C)C(C)C>CN(C=O)C>[O:23]=[C:22]1[C:21]2[C:16](=[N:17][CH:18]=[N:19][CH:20]=2)[N:15]=[C:13]([CH2:12][N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])[NH:24]1
Reactant: NC(=O)c1cncnc1NC(=O)CN1C(=O)c2ccccc2C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1nc2ncncc2c(=O)[nH]1
Yield: 76.6 %

Procedure:
4-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-acetylamino]-pyrimidine-5-carboxylic acid amide (100 mg, 0.31 mmol) in DMF (2 mL) was treated with DIPEA (0.39 mL, 2.29 mmol) for 2 hours at 90° C. The reaction mixture was evaporated, the residue was triturated with EtOAc and filtrated to yield 2-(4-oxo-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2-ylmethyl)-isoindole-1,3-dione as a light yellow solid (73 mg, 77%). MS (m/e): 308.4 [M+H+].
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:4]=2[NH:3]1.[Cl:19][S:20](Cl)(=[O:22])=[O:21]>>[Cl:19][S:20]([C:15]1[CH:16]=[CH:17][C:18]2[C:4]3[NH:3][C:2](=[O:1])[C:11]4[C:6]([C:5]=3[CH2:12][C:13]=2[CH:14]=1)=[CH:7][CH:8]=[CH:9][CH:10]=4)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=c1[nH]c2c(c3ccccc13)Cc1ccccc1-2
Product: O=c1[nH]c2c(c3ccccc13)Cc1cc(S(=O)(=O)Cl)ccc1-2
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
Compound 6 (40 g, 0.17 mol) was added in small portions to chlorosulfonyl chloride (112 mL, 1.71 mol) at 0°C. and the reaction mixture was allowed to warm to room temperature and stir for 2 h. The reaction mixture was slowly poured on ice and the resulting yellow solid was filtered, washed thoroughly with water and EtOAc and dried in vacuo to provide the above-titled product 7 (52 g, 92%). 1H NMR (DMSO-D6): δ 3.91 (s, 2H), 7.43-7.48 (m, 1H), 7.60 (d, J=7.2 Hz, 1H), 7.74-7.76 (m, 2H), 7.79 (s, 1H), 7.90 (d, J=7.5 Hz, 1H), 8.23 (d, J=7.8 Hz, 1H), Anal. Calcd for C16H12ClNO4S: C, 54.94; H, 3.46; N, 4.00. Found C, 55.28; H, 3.43, N, 3.68, Karl-Fisher, 2.95.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH:16][C:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][C:25]=5[O:27][C@H:28]([CH3:32])[C:29]([OH:31])=O)[N:20]=[CH:19][N:18]=4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)[N:3]=[CH:2]1.OC1C=CC=C[N+]=1[O-].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:32][C@@H:28]([O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:12]1[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:4]1[N:3]=[CH:2][S:1][CH:5]=1)[N:8]=[CH:9]3)=[N:18][CH:19]=[N:20]2)[C:29]([N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)=[O:31]
Reactant: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12)C(=O)O
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: [O-][n+]1ccccc1O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.3 %

Procedure:
A mixture of (2R)-2-[(4-{[1-(1,3-thiazol-4-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoic acid (250 mg, 0.56 mmol), 2-hydroxypyridine-N-oxide (124 mg, 1.1 mmol), morpholine (0.098 ml, 1.1 mmol), diisopropylethylamine (0.195 ml, 1.1 mmol) and EDCI (214 mg, 1.1 mmol) in DMF (2 ml) was stirred at room temperature for 18 hours. Additional coupling agents were added (1 equivalent) and the mixture was stirred for 2 hours more. The reaction mixture was directly injected on an HPLC column (C18, 5 microns, 20 mm diameter, 100 mm length) of a preparative HPLC-MS system eluting with a mixture of water and acetonitrile containing 2 g/l of ammonium carbonate (gradient) to give the title compound as a white solid (180 mg, 62%); NMR Spectrum 1.58 (d, 3H), 3.70-3.40 (m, 8H), 5.79 (s, 2H), 5.88 (q, 1H), 7.29 (d, 1H), 7.35 (s, 1H), 7.51 (s, 1H), 7.75 (m, 2H), 7.84 (m, 1H), 8.10 (s, 1H), 8.51 (s, 2H), 9.04 (s, 1H), 11.12 (br s, 1H); Mass spectrum: MH+ 516.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=4)[CH:18]=[C:13]3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:30]([O:32][C:33](=[O:42])[C:34]1[CH:39]=[CH:38][C:37]([C:40]#[CH:41])=[CH:36][CH:35]=1)[CH3:31].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:30]([O:32][C:33](=[O:42])[C:34]1[CH:39]=[CH:38][C:37]([C:40]#[C:41][C:12]2[C:13]3[C:14](=[N:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=4)[CH:18]=3)[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:11]=2)=[CH:36][CH:35]=1)[CH3:31]
Reactant: C#Cc1ccc(C(=O)OCC)cc1
Reactant: COc1ccc(-c2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccccc2)cc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(-c4ccc(OC)c(OC)c4)cc23)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
1-Benzenesulfonyl-5-(3,4-dimethoxy-phenyl)-3-iodo-1H-pyrrolo[2,3-b]pyridine (0.0800 g, 0.000151 mol), 4-Ethynyl-benzoic acid ethyl ester (0.0321 g, 0.000181 mol), Bis(triphenylphosphine)palladium(II) chloride (0.0048 g, 0.0000069 mol), and Copper(I) iodide (0.00024 g, 0.0000013 mol) were dissolved in Triethylamine (0.8 mL, 0.005 mol) under an atmosphere of Nitrogen. The resulting mixture was heated to 60° C. and stirred under an atmosphere of Nitrogen for 2 hours. The reaction mixture was was concentrated under reduced pressure and water (30 mL) was added to the residue. This slurry was extracted with ether. (20 mL 2×). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude was purified by chromatography (Silica gel, ethyl acetate/hexanes to give 85 mg of the titled product as a pale orange solid. MS(ESI) [M+H+]+=567.10
Reaction SMILES: [OH-:1].[Na+].ClCl.[Cl:5][C:6]1[CH:7]=[C:8]([C:12](=[O:14])C)[S:9][C:10]=1[Cl:11]>O.O1CCOCC1>[Cl:5][C:6]1[CH:7]=[C:8]([C:12]([OH:14])=[O:1])[S:9][C:10]=1[Cl:11]
Reactant: [OH-]
Reactant: CC(=O)c1cc(Cl)c(Cl)s1
Agent: ClCl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(Cl)c(Cl)s1
Temperature: 50 °C

Procedure:
Into a solution of sodium hydroxide (19.2 grams, 48.0 mmole) in water (30 ml) and ice (120 g) at −10° C. was bubbled Cl2 gas until 14.4 g was obtained. The solution was warmed to 50° C. and 1-(4,5-Dichloro-thiophen-2-yl)-ethanone (8.5 0 grams, 40.0 mmole) in dioxane (40 ml) was added dropwise as the temperature rose to 80-90° C. This temperature was maintained for 30 minutes. The mixture was poured into 500 ml water. This was extracted with diethyl ether, and the aqueous was treated with NaHSO3, then acidified to pH 1 with concentrated HCl. The resultant precipitate was filtered, and dried to give a white solid. (5.7 g). MW 197.04; 1H NMR (DMSO-d6) d 7.731 (1H, s).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC[CH:19]([CH2:36]C([O-])=O)[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:24][CH:23]=1>CS(C)=O.[Na+].[Cl-]>[C:1]([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:36][CH:19]([O:7][C:6](=[O:5])[CH3:8])[CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:26][CH:27]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCCCCc1ccc(OCC(CBr)CC(=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)c1c[nH]c2ccccc12
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCCCCc1ccc(OCC(Cn2cc(C(=O)OC(C)(C)C)c3ccccc32)OC(C)=O)cc1
Temperature: 110 °C
Reaction time: 0.25 h

Procedure:
0.50 g (2.30 mmol) tert-butylindole-3-carboxylate is dissolved in 15 ml absolute DMSO, mixed with 0.28 g (2.50 mmol) potassium-tert-butylate and stirred at 110° C. for 15 min. A solution of 0.89 g (2.31 mmol) [1-bromo-3-(4-octylphenoxy)propan-2-yl]acetate in 15 ml absolute DMSO is added drop-wise. Following heating at 110° C. for 30 minutes and subsequent cooling, hydrolysis is carried out in saturated NaCl solution. Four extractions with diethyl ether, combination of the organic phases, concentration to half the volume on the rotary evaporator, three wash steps with saturated NaCl solution, drying on sodium sulfate, filtration and reconcentration on the rotary evaporator leave as a crude product a yellow oil which is purified on silica gel by means of flash column chromatography (flow agent: petroleum ether/ethyl acetate 95:5) and yields the product as a yellowish oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]3[CH2:13][CH2:14][CH:9]2[CH2:10][CH2:11]3)=[CH:4][C:3]=1[O:15]COC.[ClH:19].O1CCOCC1>C1COCC1.CO>[ClH:19].[CH:12]12[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([OH:15])[CH:4]=3)[CH:9]([CH2:14][CH2:13]1)[CH2:10][CH2:11]2
Reactant: COCOc1cc(N2C3CCC2CC3)ccc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CO
Product: Oc1cc(N2C3CCC2CC3)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-(4-fluoro-3-(methoxymethoxy)phenyl)-7-azabicyclo[2.2.1]heptane (D81) (423 mg, 1.683 mmol) in THF (10 mL) and MeOH (1 mL) was added 4M solution of HCl in 1,4-dioxane (2.104 mL, 8.42 mmol). The mixture was stirred overnight at RT. The reaction mixture was evaporated in vacuo to give the title compound (427 mg), which was carried over to next step without purification. LCMS (A): m/z [(M−HCl)+H]+ 208, Cl2H14FNO.HCl requires 243 (acidic).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C@@H:8]([OH:9])[C@H:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([F:20])[CH:12]=2)[CH2:6][S:5](=[O:22])(=[O:21])[CH2:4]1.CC([O-])=O.[Na+].[C:28]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH:35]=O)([CH3:31])([CH3:30])[CH3:29].[BH3-]C#N.[Na+].Cl.C([O-])([O-])=O.[K+].[K+]>CO.C(Cl)Cl>[C:28]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH:2][C@@H:3]1[C@@H:8]([OH:9])[C@H:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([F:20])[CH:12]=2)[CH2:6][S:5](=[O:22])(=[O:21])[CH2:4]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)c1cccc(C=O)c1
Reactant: N[C@H]1CS(=O)(=O)C[C@@H](Cc2ccc([N+](=O)[O-])c(F)c2)[C@@H]1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)c1cccc(CN[C@H]2CS(=O)(=O)C[C@@H](Cc3ccc([N+](=O)[O-])c(F)c3)[C@@H]2O)c1
Reaction time: 16 h

Procedure:
To a solution of (3R*,4S*,5S*)-3-amino-5-(3-fluoro-4-nitro-benzyl)-1,1-dioxo-hexahydro-1lambda*6*-thiopyran-4-ol hydrochloride (0.14 g, 0.39 mmol) in MeOH-CH2Cl2 1:1 (3 mL) was added NaOAc (0.065 g, 0.78 mmol) and 3-tert-butyl-benzaldehyde (0.07 g, 0.43 mmol). The reaction mixture was stirred at 25° C. for 0.5 h before NaBH3CN (0.039 g, 0.59 mmol) was added followed by stirring for 16 h. The reaction mixture was acidified with 1N aq. HCl, stirred for 15 min, basified with K2CO3-solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and evaporated. The title compound was obtained after purification by flash-chromatography on silica gel (hexane-CH2Cl2-MeOH 20:20:1 to 1:20:5) as a light yellow foam: TLC (EtOAc) Rf=0.45; HPLC RtA=1.78 min; ESIMS [M+H]+=465; 1H NMR (400 MHz, CDCl3): δ 8.02 (t, 1H), 7.1-7.4 (m, 6H), 4.18 (s, 1H), 3.88 (d, 1H), 3.78 (d, 1H), 3.64 (m, 1H), 3.41 (ddd, 1H), 3.24 (ddd, 1H), 3.12 (dt, 1H), 3.00 (dd, 1H), 2.84, (m, 2H), 2.69 (m, 2H), 2.44 (m, 1H), 1.33 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][CH2:17]Cl)[CH2:10][C@H:9]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([CH3:27])[CH:21]=1)=[O:7].Cl.[CH2:38]([O:40][C:41]([C@@H:43]1[CH2:48][O:47][CH2:46][CH2:45][NH:44]1)=[O:42])[CH3:39].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][CH2:17][N:44]2[CH2:45][CH2:46][O:47][CH2:48][C@H:43]2[C:41]([O:40][CH2:38][CH3:39])=[O:42])[CH2:10][C@H:9]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([CH3:27])[CH:21]=1)=[O:7]
Reactant: Cc1ccc(C[C@@H]2CN(CC#CCCl)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reactant: CCOC(=O)[C@@H]1COCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1COCCN1CC#CCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc(C)c(C)c2)C1
Yield: 20.2 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-chloro-2-butynyl]piperazine (1.2 g) and (3S)-3-ethoxycarbonylmorpholine hydrochloride (0.43 g), potassium carbonate (1.09 g) and a trace of potassium iodide in N,N-dimethylformamide (50 ml) was stirred at 55° C. for 12 hours. After cooling, the solvent was removed by evaporation, and ethyl acetate and water were added thereto. The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane (2:3) as an eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-((3S)-3-ethoxycarbonylmorpholino)-2-butynyl]piperazine (0.29 g) as an oil.
Reaction SMILES: [C:1](O)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>O>[CH3:3][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2]
Reactant: CC(C)(O)c1ccccc1
Solvent: O
Product: C=C(C)c1ccccc1

Procedure:
The dehydration step is a step of supplying cumyl alcohol obtained in the epoxidation step to a dehydration catalyst to obtain α-methyl styrene and water. Examples of catalyst to be used include acids such as sulfuric acid, phosphoric acid, and p-toluenesulfonic acid; and metal oxides such as activated alumina, titania, zirconia, silica-alumina, and zeolite, of which activated alumina is preferable in view of separation from a reaction solution, catalyst life, and selectivity.
Reaction SMILES: C([O:8][C:9]([NH:11][C:12]12[CH2:19][C:16]([C:20]([O:22]C)=O)([CH2:17][CH2:18]1)[CH2:15][CH2:14][CH2:13]2)=O)C1C=CC=CC=1.[Li+].[BH4-].N#N.[CH2:28]1COCC1>>[OH:22][CH2:20][C:16]12[CH2:19][C:12]([NH:11][C:9](=[O:8])[CH3:28])([CH2:18][CH2:17]1)[CH2:13][CH2:14][CH2:15]2
Reactant: COC(=O)C12CCCC(NC(=O)OCc3ccccc3)(CC1)C2
Reactant: C1CCOC1
Agent: N#N
Agent: [BH4-]
Agent: [Li+]
Product: CC(=O)NC12CCCC(CO)(CC1)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a stirred solution of methyl 5-(benzyloxycarbonylamino)bicyclo[3.2.1]octane-1-carboxylate (1.0 g, 3.15 mmol) in THF (20 mL) at 0° C. was added LiBH4 (2M in THF, 3 mL, 6 mmol) dropwise under N2. After stirring at 0° C. for 30 min, the reaction was allowed to warm up to room temperature overnight. The reaction was quenched with Sat. NH4Cl and resulting mixture was extracted with ethyl acetate (3×20 mL). Combined organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford a residue, which was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3/1) to give 750 mg (81%) of the title compound, N-(5-(hydroxymethyl)bicyclo[3.2.1]octan-1-yl)acetamide as a colorless oil. ESI-MS m/z: 290 (M+H)+
Reaction SMILES: Cl.Br[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>COCCOC.O>[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][C:16]([C:3]2[CH:4]=[C:5]([CH2:6][NH2:7])[CH:8]=[CH:9][CH:10]=2)=[CH:15][CH:14]=1
Reactant: NCc1cccc(Br)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: NCc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
A suspension of 3-bromobenzylamine hydrochloride 22 (1 g, 4.49 mmol) in DME (50 mL) was added with 4-trifluoromethyl phenyl boronic acid (1.2 mol eq, 1.0 g) and NaHCO3 (3 mol eq, 1.13 g) suspended in water (30 mL). The mixture was degassed under vacuum, then Tetrakispalladium was added (catalytic amount) and the reaction was stirred at 100° C. under inert atmosphere for 12 h. The solvent was removed under reduced pressure and water was added to the residue (80 mL). The aqueous phase was extracted with EtOAc (3×40 mL) and the combined organic layer was washed with brine (50 mL) and dried over Na2SO4. The solvent was evaporated under vacuum to afford 23A as a pale brown oil (1.5 g, quantitative yield).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[F:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][C:44]=1[CH:45]=[O:46]>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:41]3[CH:42]=[CH:43][C:44]([CH:45]=[O:46])=[C:39]([F:38])[CH:40]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: O=Cc1ccc(B(O)O)cc1F
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4ccc(C=O)c(F)c4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-3-(5bromo-2-thienylmethyl)-4-chlorobenzene obtained in Example 128-(4) and 3-fluoro-4-formylphenylboronic acid were treated in a manner similar to Example 168-(1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro3-(5-(3-fluoro-4-formylphenyl)-2-thienylmethyl)benzene as colorless foam. APCI-Mass m/Z 678/680 (M+NH4).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:5][CH:6]1[C:20](=[O:21])[C:10]2[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:12][O:13][C:9]=2[CH2:8][CH2:7]1)[CH3:4].[BH4-].[Na+].Cl.C(=O)(O)[O-].[Na+]>CO.Cl.CCOCC.CCOCC>[ClH:1].[CH3:4][N:3]([CH2:5][C@H:6]1[C@H:20]([OH:21])[C:10]2[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:12][O:13][C:9]=2[CH2:8][CH2:7]1)[CH3:2]
Reactant: CN(C)CC1CCc2onc(-c3ccccc3)c2C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CCOCC
Solvent: CO
Product: CN(C)C[C@@H]1CCc2onc(-c3ccccc3)c2[C@H]1O
Reaction time: 1 h

Procedure:
6,7-Dihydro-5-dimethylaminomethyl-3-phenyl-1,2-benzisoxazol-4(5H)-one hydrochloride (7.5 g) was dissolved in 100 ml methanol and treated with 5.0 g sodium borohydride. After stirring for 1 hour the reaction mixture was distributed between 5% HCl and ether. The aqueous phase was then made basic with solid sodium bicarbonate and extracted with ether. Concentration under reduced pressure gave the product as a mixture of trans and cis isomers which was chromatographed by preparative HPLC (ethyl acetate/CH3CN/diethylamine; 90:10:1) to give 3.31 g of the pure trans isomer. The hydrochloride was formed in HCl/ether and then recrystallized from methanol/ether to give 2.90 g of trans-5-(dimethylaminomethyl)-4-hydroxy-3-phenyl-4,5,6,7-tetrahydro-1,2-benzisoxazole hydrochloride, m.p. 231°-232° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11]C(=O)OC(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH2:11]
Reactant: CC(C)(C)OC(=O)Nc1ccc2cnccc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc2cnccc2n1
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
A 50% TFA/DCM mixture (10 mL) was added to tert-butyl 1,6-naphthyridin-2-ylcarbamate (2.7 g, 11.0 mmol) from the above step. After 30 minutes, the reaction mixture was concentrated and diluted with 30 mL of water. A saturated NaHCO3 solution (15 mL) was added, and the reaction mixture was extracted twice with 50 mL of EtOAc. The organic layers were combined, concentrated, and purified by chromatography through a Redi-Sep® pre-packed silica gel column (120 g), eluting with a gradient 0-15% MeOH/DCM to give 1,6-naphthyridin-2-amine (1.6 g, 99% yield). MS m/z: 145 (M+1). 1H NMR (400 MHz, (CD3OD)): δ ppm 6.93 (d, J=9.00 Hz, 1H), 7.41 (d, J=6.06 Hz, 1H), 8.05 (d, J=9.00 Hz, 1H), 8.37 (d, J=5.87 Hz, 1H), 8.83 (s, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH2:26]([N:28]1[CH2:32][CH2:31][C@@H:30]([CH2:33][NH2:34])[CH2:29]1)[CH3:27]>CS(C)=O.CO>[CH2:26]([N:28]1[CH2:32][CH2:31][C@@H:30]([CH2:33][NH:34][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([NH:11][C:12]2[C:21]([C:22]([OH:24])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:25][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH2:29]1)[CH3:27]
Reactant: CCN1CC[C@@H](CN)C1
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Solvent: CO
Solvent: CS(C)=O
Product: CCN1CC[C@@H](CNc2ccccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)OCC2CC32)C1
Temperature: 120 °C

Procedure:
A solution of (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic (Intermediate 67, 0.08 g), and ((S)-1-ethylpyrrolidin-3-yl)methylamine (Intermediate 169, 0.8 g) in DMSO (0.2 mL) was stirred and heated at 120° C. for 24 hours. After cooling, the mixture was diluted with methanol and concentrated under vacuum. The residue was purified by HPLC (C18) to give (1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-3-ylmethyl)amino]benzene-sulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]-chromene-4-carboxylic acid (0.03 g) as a white solid.