Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:6][N:5]=1)[CH2:2][CH3:3].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Br)=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.C([O-])(O)=O.[Na+]>C(OCC)C>[CH2:12]([O:11][C:9]([C:7]1[CH:8]=[C:4]([CH2:1][CH2:2][CH3:3])[N:5]([CH2:21][C:18]2[CH:17]=[N:16][C:15]([Br:14])=[CH:20][CH:19]=2)[N:6]=1)=[O:10])[CH3:13]
Reactant: CCCc1cc(C(=O)OCC)[nH]n1
Reactant: BrCc1ccc(Br)nc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCc1cc(C(=O)OCC)nn1Cc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 3-n-propylpyrazole-5-carboxylate (1.7 g, 9.1 mmol), 2-bromo-5-bromomethylpyridine (4.6 g, 9.1 mmol) and potassium carbonate (1.8 g, 12.7 mmol) were dissolved in DMF (70.0 mL, 904 mmol). The resulting suspension was stirred at room temperature overnight. The material was diluted with aqueous. NaHCO3 and diethyl ether. The aqueous layer was further extracted with diethyl ether. The combined organics were dried over MgSO4, filtered and concentrated. The residue was purified using flash chromatography [1st 30:1 hexanes/EtOAc; 2nd 10:1 hexanes/EtOAc]. The two isomers were separated and analyzed by NMR and NOE: 1-(6-bromopyridin-3-ylmethyl)-5-propyl-1H-pyrazole-3-carboxylic acid ethyl ester (1.2 g) and 2-(6-bromopyridin-3-ylmethyl)-5-propyl-2H-pyrazole-3-carboxylic acid ethyl ester.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[N:18]([C:19]3[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=3)[C:17](=[O:26])[C@@H:16]2[CH2:27][CH2:28][C@@H:29]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[OH:30])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:38]([NH2:41])[C:39]#[CH:40].C(N(CC)CC)C>CN(C=O)C.[Cu]I>[NH2:41][CH2:38][C:39]#[C:40][C:22]1[CH:23]=[CH:24][C:19]([N:18]2[C@H:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:10][CH:11]=3)[C@@H:16]([CH2:27][CH2:28][C@@H:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[OH:30])[C:17]2=[O:26])=[CH:20][CH:21]=1
Reactant: C#CCN
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@@H]2[C@@H](CC[C@H](O)c3ccc(F)cc3)C(=O)N2c2ccc(I)cc2)cc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@@H]2[C@@H](CC[C@H](O)c3ccc(F)cc3)C(=O)N2c2ccc(C#CCN)cc2)cc1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a solution of 8 mg (0.013 mmol, 1 equiv.) (3R,4S)-4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-(4-iodophenyl)azetidin-2-one (intermediate step A) in 0.5 mL DMF was added 2.2 mg (0.002 mmol, 0.15 equiv.) tetrakistriphenylphosphine palladium(0) and 0.8 mg (0.004 mmol, 0.3 equiv) copper(I) iodide. The solution was deoxygenated by a slow stream of anhydrous nitrogen delivered by a needle through a rubber septum. To the resulting solution was added by syringe 0.012 mL (0.177 mmol, 14 equiv.) propargyl amine and 0.012 mL (0.09 mmol, 7 equiv.) triethylamine. The resulting solution was stirred at room temperature for 1.25 hr at which time the solvent was removed under vacuum. The residue was purified by prep. Tlc eluting with CH2Cl2/MeOH (9/1) to afford the title compound. m/z (ES) 559.3 (MH+), 542.3 (MH−NH3+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.C(O)C.[CH3:14][C@:15]1([CH2:18][O:19][C:20]2[CH:21]=[C:22]([C:26]3[C:30]4[S:31][CH:32]=[CH:33][C:29]=4[O:28][N:27]=3)[CH:23]=[CH:24][CH:25]=2)[CH2:17][O:16]1.C(OCC)(=O)C>CO.ClCCl>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][CH2:14][C@@:15]([CH3:17])([OH:16])[CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[C:30]4[S:31][CH:32]=[CH:33][C:29]=4[O:28][N:27]=3)[CH:21]=2)=[CH:5][CH:4]=1
Reactant: C[C@]1(COc2cccc(-c3noc4ccsc34)c2)CO1
Reactant: COc1ccc(CN)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(CNC[C@@](C)(O)COc2cccc(-c3noc4ccsc34)c2)cc1
Yield: 42.4 %

Procedure:
Add 1 mL of a solution of 4-methoxybenzylamine (0.048 g, 0.00035 mol, Aldrich Chemical Company) and ethanol to 3 mL of a solution of (R)-3-[3-(2-methyloxiranylmethoxy)phenyl]-thieno[2,3-d]isoxazole (example 6, 0.10 g, 0.00035 mol) and ethanol. Shake the reaction mixture under argon at reflux temperature for four hours in a Bohdan apparatus. Cool and concentrate in vacuo to remove the solvent. Purify the residue by flash chromatography (Waters SepPak, silica gel) eluting in step gradient fashion sequentially with 2:1 heptane:ethyl acetate and then with 10:1 dichloromethane:methanol to afford after concentration of the desired fractions the title compound (0.063 g, 42% yield).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:63]1[C:68]2[O:69][CH2:70][C:71](=[O:73])[NH:72][C:67]=2[C:66]([OH:74])=[CH:65][CH:64]=1)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14]CC1C=CC(C2C=CC(NC(C3C=C(S(C4C=C5C(=C(C)C=4)N=CC(C(N)=O)=C5NC4C=CC=C(OC)C=4)(=O)=O)C=CC=3)=O)=CC=2)=CC=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:75][O:76][C:77]1[CH:78]=[C:79]([NH:83][C:84]2[C:93]3[C:88](=[C:89]([CH3:114])[CH:90]=[C:91]([S:94]([C:97]4[CH:102]=[CH:101][CH:100]=[C:99]([C:103](=[O:113])[N:104]([CH3:112])[CH2:105][CH2:106][CH2:107]CCC=O)[CH:98]=4)(=[O:96])=[O:95])[CH:92]=3)[N:87]=[CH:86][C:85]=2[C:115]([NH2:117])=[O:116])[CH:80]=[CH:81][CH:82]=1>>[Si:1]([O:8][C@H:9]([C:63]1[C:68]2[O:69][CH2:70][C:71](=[O:73])[NH:72][C:67]=2[C:66]([OH:74])=[CH:65][CH:64]=1)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:107][CH2:106][CH2:105][N:104]([CH3:112])[C:103]([C:99]1[CH:98]=[C:97]([S:94]([C:91]2[CH:92]=[C:93]3[C:88](=[C:89]([CH3:114])[CH:90]=2)[N:87]=[CH:86][C:85]([C:115]([NH2:117])=[O:116])=[C:84]3[NH:83][C:79]2[CH:80]=[CH:81][CH:82]=[C:77]([O:76][CH3:75])[CH:78]=2)(=[O:96])=[O:95])[CH:102]=[CH:101][CH:100]=1)=[O:113])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N(C)CCCCCC=O)c4)cc23)c1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(-c6ccc(CCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c7ccc(O)c8c7OCC(=O)N8)cc6)cc5)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N(C)CCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c5ccc(O)c6c5OCC(=O)N6)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described in Intermediate 151, using Intermediate 114 in place of Intermediate 124. ES/MS calcd. C48H60N6O9SSi 942.4. Found m/z=925 (M+H)+.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[SH:20][C:21]1[N:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([S:20][C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[O:3][C:4]=2[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:9]=1
Reactant: COC(=O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: Sc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1oc(Sc2ncccn2)nc1-c1ccc(Cl)cc1
Temperature: 105 °C
Reaction time: 4 h

Procedure:
A mixture of methyl 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionate (2.00 g), 2-mercaptopyrimidine (819 mg), anhydrous potassium carbonate (1.10 g) and N,N-dimethylformamide (10 ml) was heated to 100-110° C. and stirred for 4 hours. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (100 ml×2). The organic layer was dried over anhydrous magnesium sulfate and then concentrated, the residue was subjected to silica gel column chromatography, and methyl 4-(4-chlorophenyl)-2-(2-pyrimidinylsulfanyl)-5-oxazolepropionate was obtained as a yellow oil (1.42 g, 57%) from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([N:17]2[CH2:21][CH2:20][S:19][C:18]2=[S:22])=[O:16])=[CH:13][C:12]([C:23]([N:25]2[CH2:29][CH2:28]SC2=S)=[O:24])=[CH:11][C:10]=1[C:31]([N:33]1[CH2:37][CH2:36][S:35][C:34]1=[S:38])=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:39][O:40]CCN.CO>ClCCl>[CH2:1]([O:8][C:9]1[C:14]([C:15]([N:17]2[CH2:21][CH2:20][S:19][C:18]2=[S:22])=[O:16])=[CH:13][C:12]([C:23]([NH:25][CH2:29][CH2:28][O:40][CH3:39])=[O:24])=[CH:11][C:10]=1[C:31]([N:33]1[CH2:37][CH2:36][S:35][C:34]1=[S:38])=[O:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1cc(C(=O)N2CCSC2=S)c(OCc2ccccc2)c(C(=O)N2CCSC2=S)c1)N1CCSC1=S
Reactant: COCCN
Solvent: ClCCl
Solvent: CO
Product: COCCNC(=O)c1cc(C(=O)N2CCSC2=S)c(OCc2ccccc2)c(C(=O)N2CCSC2=S)c1

Procedure:
To a slurry of the trithiazolide 17 (31.0 g, 0.05 mol) in dichloromethane (600 mL), a solution of 2-methoxyethylamine (0.38 g, 5 mmol) in dichloromethane (30 mL) was added dropwise over 48 h. The reaction mixture was applied directly onto a gradient flash silica column (1-5% methanol in methylene chloride). The desired product was obtained as yellow, thick oil; yield 2.1 g (73% based on the methoxyethylamine). 25.8 g of unreacted starting trithiazolide was also recovered during the separation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:16]1[N:21]=[C:20]([C:22]2[CH:34]=[CH:33][C:25]3[N:26]=[C:27]([NH:29][C:30](=[O:32])[CH3:31])[S:28][C:24]=3[CH:23]=2)[CH:19]=[CH:18][N:17]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C:16]2[N:21]=[C:20]([C:22]3[CH:34]=[CH:33][C:25]4[N:26]=[C:27]([NH:29][C:30](=[O:32])[CH3:31])[S:28][C:24]=4[CH:23]=3)[CH:19]=[CH:18][N:17]=2)[CH3:12])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CNS(=O)(=O)c1ccc(F)cc1
Reactant: CC(=O)Nc1nc2ccc(-c3ccnc(Cl)n3)cc2s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc2ccc(-c3ccnc(N(C)S(=O)(=O)c4ccc(F)cc4)n3)cc2s1
Reaction time: 0.5 h

Procedure:
To a microwave vial equipped with a stir bar, was added 4-fluoro-N-methylbenzenesulfonamide (0.23 g, 1.2 mmol) and DMF (3 ml). Then sodium hydride (0.120 g, 4.9 mmol) was added to the mixture and allowed to stir 30 minutes. Then palladium(II) acetate (0.011 g, 0.049 mmol), N-(6-(2-chloropyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide (0.150 g, 0.49 mmol) and Xantphos (0.010 g) was added to the mixture. The vial was capped and placed into a CEM Microwave for 10 minutes at 100° C., while 100 watts of energy was supplied via Powermax® (Simultaneous heating while cooling technology). The progress of the reaction was monitored by LC/MS, which showed desired product peaks. The mixture was added to a round-bottom flask and diluted with hot water (150 ml). The mixture was allowed to stir overnight. The precipitate was collected by filtration and washed with Hexanes (3×50 ml), then finally with ethyl ether (50 ml). The crude was diluted with DMSO (5 ml) and purified by reverse-phase HPLC. This gave N-(6-(2-(4-fluoro-N-methylphenylsulfonamido)pyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide (0.030 g, 13% yield) as a light-yellow solid. MS (ESI pos. ion) m/z: 458 (MH+). Calc'd exact mass for C20H16FN5O3S2: 457. 1H NMR (400 MHz, DMSO-d6): 1.97 (s, 3H), 3.69 (s, 3H), 7.36-7.47 (m, 3H), 7.64 (s, 1H), 7.82 (d, J=8.03 Hz, 1H), 8.11 (s, 2H), 8.19 (s, 1H), 8.51 (d, J=3.51 Hz, 1H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[NH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(N(CC)CC)C>C(Cl)Cl>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2](=[O:3])[NH:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NN1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NN1CCOCC1)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 56.1 %

Procedure:
To a solution of 4-nitrophenyl chloroformate (27.8 g, 0.14 mole) in CH2Cl2 (350 mL) at 0° C. was added a solution of 4-aminomorpholine (10.2 g, 0.1 mole) and triethylamine (10.2 g, 0.1 mole) in CH2Cl2 (40 mL) via addition funnel over 1 h. A white ppt formed during the addition. After the addition was complete, the ice bath was removed and the reaction was stirred an additional 1 h. The solid was collected by filtration, re-suspended in Et2O and filtered to give the desired product as a white solid (15 g, 62% yield).
Reaction SMILES: O=[C:2]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH:4]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:3]1[CH:25]1[CH2:27][CH2:26]1.C1([SiH2]C2C=CC=CC=2)C=CC=CC=1>C1COCC1.[C-]#[O+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Rh]>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([CH:4]2[C:5]3([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[CH2:7][CH2:6]3)[CH2:2][N:3]2[CH:25]2[CH2:27][CH2:26]2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(C1CC1)C2c1ccc(Cl)cc1
Agent: [Rh]
Agent: [C-]#[O+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(C1CC1)C2c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
Under a nitrogen atmosphere, treat 1,1-dimethylethyl 1-oxo-3-(4-chlorophenyl)-2-cyclopropyl-2,7-diazaspiro[3.5]nonane-7-carboxylate (9) (0.76 g) in anhydrous THF (2 mL) with RhH(CO)(PPH3)3 (18 mg) and then, diphenylsilane (9.1 mL). The resulting mixture was shaken at room temperature for 2 h. Place the reaction mixture on silica gel plates (12, 1000 u) and elute with hexane/EtOAc 85/15 to give a colorless residue (0.700 g). Place this material on silica gel plates (12, 1000 u) and elute with hexane/EtOAc 85/15 to give the title compound (10) as a colorless foam (0.58 g)
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:15])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3.[Cl:18][CH2:19][CH2:20][N:21]=[C:22]=[O:23]>ClCCl>[CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH:15][C:22]([NH:21][CH2:20][CH2:19][Cl:18])=[O:23])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3
Reactant: O=C=NCCCl
Reactant: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Solvent: ClCCl
Product: CC1(C)Oc2cc3nonc3cc2C(NC(=O)NCCCl)C1O
Reaction time: 6 h
Yield: 82.9 %

Procedure:
400 mg (1.70 mmol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazole and 40 ml of dichloromethane were stirred at room temperature, and 200 μl (1.87 mmol) of 2-chloroethyl isocyanate were added thereto and stirred for 6 hours. The crystals precipitated were filtered off to obtain 480 mg of the intended compound as colorless crystals. (yield: 83%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3](=O)[CH2:4][C:5]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)=O.[NH:15]([C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20])[NH2:16]>C(O)(=O)C.CCOC(C)=O>[O:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:5]1[N:15]([C:17]2[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=2[C:19]([OH:21])=[O:20])[N:16]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccco1
Reactant: NNc1ccccc1C(=O)O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccccc1-n1nc(C(F)(F)F)cc1-c1ccco1

Procedure:
4,4,4-Trifluoro-1-(2-furyl)-1,3-butanedione (2.4 mL, 16 mmol) was added to 2-hydrazinobenzoic acid (3.01 g, 16 mmol) in acetic acid (20 mL) and heated at reflux for 25 h. The reaction was cooled, diluted with EtOAc, and extracted twice with water. The organic layer was dried over Na2SO4, filtered, and evaporated to yield a thick red paste (5.71 g, >100%). 1H NMR (CDCl3) δ8.18 (dd, 1H, J=7.7, J′=1.8), 7.74 (td, 1H, J=7.7, J′=1.4), 7.65 (td, 1H, J=7.7, J′=1.5), 7.50 (dd, 1H, J=7.3, J′=1.1), 7.35 (m, 1H), 6.89 (s, 1H), 6.28 (m, 1H), 5.76 (d, 1H, J=3.3).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:29])[C:17]2[C:22]([NH2:23])=[CH:21][CH:20]=[C:19]([CH3:24])[C:18]=2[CH:25]=[C:26]([CH3:28])[CH3:27])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[NH2:23][C:22]1[C:17]([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14]2)=[O:29])=[C:18]([CH:25]=[C:26]([CH3:27])[CH3:28])[C:19]([CH3:24])=[CH:20][CH:21]=1
Reactant: CCOC(=O)C1(NC(=O)c2c(N)ccc(C)c2C=C(C)C)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)=Cc1c(C)ccc(N)c1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The mixture (224) and KOH (500 mg, 8.9 mmol) is dissolved in EtOH (8 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 4 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate formed. After the filtration, the crude solid is purified by HPLC to give 48 mg brown solid (225).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CC(C)=O>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[I:1])[CH3:21]
Reactant: Oc1ccccc1I
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccccc1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9.10 g (41.4 mmol) of o-iodophenol was dissolved in 102 ml of acetone and treated subsequently at 0° C. with 14.8 g (1.1 eq.) of cesium carbonate and 4.57 ml (1.0 eq.) of ethyl bromoacetate. After vigorous stirring for 1 h at ambient temperature and filtration, the bulk of solvent was evaporated and the residue redissolved in EtOAc. Washing with water, drying over magnesium sulfate, and evaporation of the solvents finally produced 12.66 g of pure title compound as colorless oil, MS: 306.0 (M)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:32])[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][N:21]4[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:14][CH:13]=3)=[C:9]([C:33]3[CH:38]=[CH:37][C:36]([O:39]C)=[CH:35][CH:34]=3)[S:8][C:7]=2[CH:41]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:32])[C:12]3[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][N:21]4[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:16][CH:17]=3)=[C:9]([C:33]3[CH:34]=[CH:35][C:36]([OH:39])=[CH:37][CH:38]=3)[S:8][C:7]=2[CH:41]=1
Reactant: CCCCCCN1CCCCC1COc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Product: CCCCCCN1CCCCC1COc1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Yield: 43.9 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)-3-(4-[(1-hexylpiperidin-2-yl)methoxy]benzoyl)benzo[b]thiophene (464 mg, 0.812 mmol), ethane thiol (4.06 mmol), and aluminum chloride (649 mg, 4.87 mmol) were converted to 194 mg (44%) of the title compound by the procedure of Example 16. MS(FD) 544(M+). IR (CHCl3) ν max 3380, 2930, 2858, 1598, 1467, 1256, 1166.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH2:9]([NH2:15])[C:10]1[O:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([NH:15][CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)[C:10]1[O:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCc1ccco1
Reactant: CN1CCC(=O)CC1
Product: CN1CCC(NCc2ccco2)CC1

Procedure:
Starting materials: 1-Methyl-4-piperidone (0.5 g, 4.4 mmol, 1.0 eq.), Furfurylamine (0.43 g, 1.0 eq.).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:18][CH2:19][CH:20]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:22][C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=1[N:30]1[CH2:31][CH2:32][N:33]([CH2:20][CH2:19][CH2:18][C:9]2[CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:34][CH2:35]1
Reactant: O=CCCc1cc(-c2ccccc2)n(-c2ccccc2)n1
Reactant: Cc1cccc(N2CCNCC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N2CCN(CCCc3cc(-c4ccccc4)n(-c4ccccc4)n3)CC2)c1C

Procedure:
77 mg (81%) of target compound was obtained by using a method same as in Example 1 by using 3-(1,5-diphenyl-1H-pyrazol-3-yl)propanal (64 mg, 0.231 mmol), 1-(2,3-dimethylphenyl)piperazine (40 mg, 0.210 mmol), DIPEA (0.037 mL, 0.210 mmol) and NaBH(OAc)3 (156 mg, 0.735 mmol).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@H:17]([C:19]4[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=4)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C@H:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:27][CH3:28])=[O:4].[CH:35]1([CH2:40]O)[CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH:35]1([CH2:40][O:25][C:22]2[CH:23]=[CH:24][C:19]([C@H:17]3[CH2:16][O:15][C:11]4=[CH:12][C:13]5[CH2:14][C@@H:5]([C:3]([OH:2])=[O:4])[N:6]([C@H:26]([C:29]6[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=6)[CH2:27][CH3:28])[CH2:7][C:8]=5[CH:9]=[C:10]4[O:18]3)=[CH:20][CH:21]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: OCC1CCCC1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)OC)OC[C@H](c1ccc(O)cc1)O3
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCC2CCCC2)cc1)O3

Procedure:
(3S,8S)-3-(4-Hydroxy-phenyl)-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid methyl ester (20 mg) was reacted with cyclopentylmethanol according to General Procedure K and the resulting ester was hydrolyzed according to General Procedure AB to provide (3S,8S)-3-(4-cyclopentylmethoxy-phenyl)-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (18 mg). The title compound (17 mg) was prepared from (3S,8S)-3-(4-cyclopentylmethoxy-phenyl)-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (18 mg) and (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride according to General Procedures L and B. LCMS (m/z): 781.
Reaction SMILES: [CH:1]1([CH:6]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[CH:25]=[CH:24][N:23]=[C:22]3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:16][CH:15]=2)[C:7]([O:9]C(C)(C)C)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>O1CCOCC1>[CH:1]1([CH:6]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[CH:25]=[CH:24][N:23]=[C:22]3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:16][CH:15]=2)[C:7]([OH:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)C(c1ccc(Cn2ccnc2-c2ccccc2)cc1)C1CCCC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)C(c1ccc(Cn2ccnc2-c2ccccc2)cc1)C1CCCC1
Yield: 103 %

Procedure:
3.0 g (7 mmol) of the compound from Example I are dissolved in 14 ml of dioxane, treated with 2 ml of conc. HCl and the solution is refluxed for 5 h. It is concentrated, the residue is taken up in CH2Cl2 and the solution is washed with water. 2.6 g (96%) of the title compound are obtained as an oil.
Reaction SMILES: II.[BH4-].[Na+].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]([NH:15][CH3:16])=O.CO>C1COCC1>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][NH:15][CH3:16]
Reactant: CNC(=O)Cc1ccccc1Cl
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CNCCc1ccccc1Cl
Temperature: 0 °C
Yield: 18.8 %

Procedure:
At 0° C., a solution of iodine (29.9 g, 0.12 mol) in THF (100 ml) was added dropwise to a suspension of sodium borohydride (11.1 g, 0.29 mol) and 2-(2-chlorophenyl)-N-methylacetamide (21.6 g, 0.12 mol) in THF (150 ml). After the addition was completed, the reaction mixture was heated to reflux for 16 hours. It was cooled to 0° C. Methanol (150 ml) was added dropwise. The solvent was removed in vacuo. The residue was dissolved in a mixture of tert-butyl methyl ether (200 ml) and a 20% aqueous solution of sodium hydroxide (200 ml). The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (2×100 ml). The combined organic layers were dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (300 g), using a mixture of DCM/methanol/25% aqueous ammonia (first: 100:10:1, then: 100:20:2, then 100:30:3) as eluent, to give 3.82 g of N-[2-(2-chlorophenyl)ethyl]-N-methylamine.