Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@:2]([C:14]1([CH2:17][OH:18])[CH2:16][CH2:15]1)([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[F:13])[CH3:3].[C:19](Br)#[N:20].C([O-])(=O)C.[Na+]>C1COCC1.Cl.O1CCOCC1>[F:13][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[C@:2]1([CH3:3])[C:14]2([CH2:15][CH2:16]2)[CH2:17][O:18][C:19]([NH2:20])=[N:1]1
Reactant: N#CBr
Reactant: C[C@@](N)(c1cc([N+](=O)[O-])ccc1F)C1(CO)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: C[C@]1(c2cc([N+](=O)[O-])ccc2F)N=C(N)OCC12CC2
Temperature: 80 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
Intermediate Ea3 (R1,2=cyclopropyl, R3=Me): To a solution of {1-[(S)-1-amino-1-(2-fluoro-5-nitro-phenyl)-ethyl]-cyclopropyl}-methanol (0.50 g) in dry THF (20 ml) was added bromocyanogen (0.24 g) and sodium acetate (0.19 g) and the mixture was stirred at 80° C. overnight. The mixture was cooled to 22° C., diluted with HCl in dioxane (4M, 2.4 ml) and stirring was continued for 1 h. The mixture was partitioned between aqueous saturated Na2CO3 and ethyl acetate, the organic layer was dried, evaporated and the residue purified by chromatography over silca-NH2 using ethyl acetate to give (S)-8-(2-fluoro-5-nitro-phenyl)-8-methyl-5-oxa-7-aza-spiro[2.5]oct-6-en-6-ylamine (0.30 g) as a pale yellow solid. MS (ESI): m/z=280.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[Cl:13])[C:7](Cl)=[O:8])([O-:3])=[O:2].N1C=CC=CC=1.[CH:20]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[Cl:13])[C:7]([O:26][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:8])([O-:3])=[O:2]
Reactant: OC1CCCCC1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(OC1CCCCC1)c1ccc(Cl)c([N+](=O)[O-])c1
Yield: 88 %

Procedure:
Twelve grams (0.055 mole) for crude 3-nitro-4-chlorobenzoyl chloride were dissolved in 200 ml. of benzene. Eight milliliters of pyridine were added to the reaction mixture. Six milliliters of cyclohexanol were dissolved in 50 ml. of benzene and the solution was added dropwise to the acid chloride-pyridine mixture. The reaction mixture was refluxed for 4 hours and filtered. The benzene filtrate was washed successively with dilute acid, dilute base and water. The washed benzene solution was dried and evaporated in vacuo to yield 12.5 g (88 percent) of cyclohexyl 3-nitro-4-chlorobenzoate, mp 57°-58° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@@:13]([C:16]#[CH:17])([CH2:14][OH:15])[O:12][C@@H:11]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:27][C:28](OC(C)=O)=[O:29]>N1C=CC=CC=1>[C:28]([O:15][CH2:14][C@@:13]1([C:16]#[CH:17])[O:12][C@@H:11]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:10][C@H:9]1[O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])(=[O:29])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: C#C[C@]1(CO)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1O[Si](C)(C)C(C)(C)C
Solvent: c1ccncc1
Product: C#C[C@]1(COC(C)=O)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 11 h
Yield: 94.9 %

Procedure:
To a pyridine (4 mL) solution of 10a (161 mg, 0.423 mmol) was added Ac2O (120 mL, 1.269 mmol) at 0° C., and the mixture was stirred at room temperature for 11 h. The reaction mixture was partitioned between CHCl3/saturated aqueous NaHCO3 (60 mL×3/20 mL). Silica gel column chromatography (hexane/EtOAc=3/1) of the organic layer gave 11 (169.7 mg, 95%) as a foam: UV (MeOH): λmax 266 nm (ε9200), λmin 234 nm (ε2000); 1H NMR (CDCl3) δ0.10 and 0.14 (6H, each as s, SiMe), 0.90 (9H, s, SiBu-t), 1.90-1.94 (4H, m, H-2′a and Me), 2.14 (3H, s, Ac), 2.58 (1H, s, ethynyl), 3.01 (1H, ddd, Jgem=14.8 Hz, J1′,2′b=8.3 Hz and J2′b,3′=5.0 Hz, H-2′b), 4.37 (1H, d, Jgem=11.1 Hz, H-5′a), 4.45 (1H, d, J2′b,3′=5.0 Hz, H-3′), 4.53 (1H, d, Jgem=11.1 Hz, H-5′b), 6.40 (1H, dd, J1′,2′a=2.8 Hz and J1′,2′b=8.3 Hz, H-1′), 7.53 (1H, d, J6,Me=1.3 Hz, H-6), 8.04 (1H, br, NH); FAB-MS m/z 461 (M++K). Anal. Calcd for C20H30N2O6Si: C, 56.85; H, 7.16; N, 6.63. Found: C, 56.84; H, 7.35; N, 6.26.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][C:4]1[S:8][CH:7]=[C:6]([C:9]([OH:11])=O)[CH:5]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH:45]1[CH:54]2[CH:49]([CH2:50][CH2:51][CH2:52][CH2:53]2)[CH2:48][CH2:47][CH2:46]1>CN(C=O)C.O.C(#N)C>[N:45]1([C:9]([C:6]2[CH:5]=[C:4]([CH2:3][C:2]([F:1])([F:13])[F:12])[S:8][CH:7]=2)=[O:11])[C@@H:54]2[C@@H:49]([CH2:50][CH2:51][CH2:52][CH2:53]2)[CH2:48][CH2:47][CH2:46]1
Reactant: O=C(O)c1csc(CC(F)(F)F)c1
Reactant: C1CCC2NCCCC2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(c1csc(CC(F)(F)F)c1)N1CCC[C@@H]2CCCC[C@@H]21
Reaction time: 8 h
Yield: 10 %

Procedure:
5-(2,2,2-Trifluoro-ethyl)-thiophene-3-carboxylic acid (0.05 g, 0.32 mol) was dissolved in DMF (2 mL). HATU (0.23 mmol), triethylamine (1.5 mmol) and decahydroquinoline (3:2 mixture of cis- and trans-isomers; 0.64 mmol) were added and the reaction stirred overnight. The reaction mixture was then diluted with water and acetonitrile and separated by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound (21.2 mg). LCMS m/z 332.12 [M+H]+ RT=11.62 min (Analytical Method 2). 1H NMR (400 MHz, CHCl3-d): δ 7.4 (s, 1H), 7.1 (s, 1H), 4.6 (m, 1H), 3.8-3.7 (m, 1H), 3.6 (q, 2H), 3.1-2.8 (m, 1H), 2.0-1.1 (m, 13H).
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:7]=[C:6]([OH:19])[CH:5]=1)([CH3:3])[CH3:2].Br[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=1>>[CH:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:7]=[C:6]([O:19][CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(O)nc(-c2cccc([N+](=O)[O-])c2)n1
Reactant: COC(=O)c1ccc(CBr)cc1
Product: CC(C)c1cc(OCc2ccc(C(=O)O)cc2)nc(-c2cccc([N+](=O)[O-])c2)n1

Procedure:
The title compound was prepared from 6-isopropyl-2-(3-nitro-phenyl)-pyrimidin-4-ol (which was obtained in Intermediate 8) and methyl 4-(bromomethyl)benzoate according to Method A and Method B; LC retention time 3.40 min; MS: m/z (ESI) 394 (M+H).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[N:14]=[CH:13][CH:12]=[N:11][C:5]=3[NH:6][C:7]=2[CH:8]=[CH:9][CH:10]=1.[CH2:15]([S:17]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)(=[O:19])=[O:18])[CH3:16].C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:15]([S:17]([C:20]1[CH:25]=[C:24]([C:2]2[C:3]3[C:4]4[N:14]=[CH:13][CH:12]=[N:11][C:5]=4[NH:6][C:7]=3[CH:8]=[CH:9][CH:10]=2)[CH:23]=[CH:22][CH:21]=1)(=[O:18])=[O:19])[CH3:16]
Reactant: Brc1cccc2[nH]c3nccnc3c12
Reactant: CCS(=O)(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1cccc(-c2cccc3[nH]c4nccnc4c23)c1
Temperature: 150 °C
Yield: 68.2 %

Procedure:
Compound 80 (50 mg, 0.2 mmol), 3-ethanesulfonyl-phenylboronic acid (65 mg, 0.3 mmol), tetrakis(triphenylphosphine)palladium (0) (116 mg, 0.1 mmol), and potassium carbonate (83 mg, 0.6 mmol), were combined in dioxane (2 mL) and H2O (0.2 mL) in a sealed tube under nitrogen. The reaction was heated at 150° C. in the microwave for 20 min and then concentrated in vacuo. Purification by silica gel chromatography (5% MeOH/CH2Cl2) gave 46 mg (68%) of the title compound as a light orange solid. 1H NMR (400 MHz, CH3OD) δ 8.42 (t, 1H, J=2.8 Hz), 8.31 (d, 1H, J=2.8 Hz), 8.24 (d, 1H, J=2.8 Hz), 8.06 (d, 1H, J=7.6 Hz), 7.96 (d, 1H, J=7.6 Hz), 7.60-7.75 (m, 3H), 7.31 (dd, 1H, J=7.2, 1.2 Hz), 3.33 (q, 2H, J=7.2 Hz), 1.37 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C18H15N3O2S, 338; found 338.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][NH:9][C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([OH:18])[CH:12]=2)=O)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C(#N)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]2[O:19][C:10]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([OH:18])[CH:12]=3)=[N:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)NNC(=O)c2ccc(Cl)cc2)cc1O
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2nnc(-c3ccc(Cl)cc3)o2)cc1O
Reaction time: 0.08 h

Procedure:
To a solution of 3-hydroxy-4-methyl-benzoic acid N′-(4-chloro-benzoyl)-hydrazide (1.28 g, 4.20 mmol) (from Example 44 supra) in acetonitrile (20 mL) was added diisopropylethylamine (4.4 mL, 25.2 mmol) and triphenylphosphine (2.21 g, 8.40 mmol). After stirring 5 minutes, hexachloroethane (1.49 g, 6.30 mmol) (Aldrich) was added and the mixture was allowed to stir for 1 day at room temperature. The solvent was evaporated. The residue was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (1×). The combined organic phase washed with water and brine, dried (magnesium sulfate) and concentrated. The residue was purified by flash chromatography eluting with 0-60% ethyl acetate in hexanes to give 5-[5-(4-chloro-phenyl)-[1,3,4]-oxadiazol-2-yl]-2-methyl-phenol. (Yield 0.34 g, 28%).
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[CH3:9][C:10]([CH2:12]O)=O>C(O)C.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH3:12][C:10]1[C:2]2[C:1](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]=2[O:7][CH:9]=1
Reactant: O=C1CCCC(=O)C1
Reactant: CC(=O)CO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1coc2c1C(=O)CCC2
Yield: 37.5 %

Procedure:
A mixture of 1,3-cyclohexanedione (3.36 g, 30 mmol), acetol (hydroxyacetone; 2.22 g, 30 mmol), and zinc chloride (4.09 g, 30 mmol) in ethanol (10 mL) was heated at reflux temperature for 3 hours. After cooling, the mixture was dissolved in ethyl acetate (100 mL). The whole was washed with water (100 mL), brine (100 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chlomatography eluting with ethyl acetate - hexane (1:10) to give the subtitle compound (1.69 g, 38% yield).
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][N:9]1[CH:13]([C:14]([OH:16])=O)[CH2:12][N:11]([C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[C:10]1=[O:24].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N1CCOCC1)C.[Cl:56][C:57]1[C:62]([C:63]([F:66])([F:65])[F:64])=[CH:61][CH:60]=[CH:59][C:58]=1[CH2:67][NH2:68]>ClCCl>[Cl:56][C:57]1[C:62]([C:63]([F:65])([F:66])[F:64])=[CH:61][CH:60]=[CH:59][C:58]=1[CH2:67][NH:68][C:14]([CH:13]1[CH2:12][N:11]([C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[C:10](=[O:24])[N:9]1[CH3:8])=[O:16]
Reactant: Cc1ccc(N2CC(C(=O)O)N(C)C2=O)cn1
Reactant: NCc1cccc(C(F)(F)F)c1Cl
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1ccc(N2CC(C(=O)NCc3cccc(C(F)(F)F)c3Cl)N(C)C2=O)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44.5 %

Procedure:
A mixture of 3-methyl-1-(6-methyl-3-pyridinyl)-2-oxo-4-imidazolidinecarboxylic acid TFA salt (175 mg, 0.5 mmol), 1-hydroxybenzotriazole hydrate (115 mg, 0.75 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (144 mg, 0.75 mmol) and N-ethyl morpholine (0.319 ml, 2.5 mmol) in dichloromethane (8 ml) was stirred at room temperature for 10 minutes. A solution of {[2-chloro-3-(trifluoromethyl)phenyl]methyl}amine (105 mg, 0.5 mmol) in dichloromethane (2 ml) was added and the reaction stirred at room temperature for 4 hours. The mixture was partitioned between dichloromethane and saturated sodium hydrogen carbonate solution. The organic phase was separated, washed with water and brine, dried and evaporated. The residue was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give N-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-3-methyl-1-(6-methyl-3-pyridinyl)-2-oxo-4-imidazolidinecarboxamide (95 mg, 44%). LC/MS [M+H]+=427, retention time=1.98 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:53]=[CH:52][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[C:15]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:16]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[C:11]3[C:10]([C:36]#[C:37][C:38]3[CH:39]=[N:40][N:41]([CH2:43][C:44]4[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=4)[CH:42]=3)=[N:9]2)=[CH:5][CH:4]=1.N1C2C(=CC=CC=2)C=CC=1>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[C:15]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:16]([N:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:21][CH2:22]4)=[C:11]3[C:10](/[CH:36]=[CH:37]\[C:38]3[CH:39]=[N:40][N:41]([CH2:43][C:44]4[CH:45]=[CH:46][C:47]([O:50][CH3:51])=[CH:48][CH:49]=4)[CH:42]=3)=[N:9]2)=[CH:52][CH:53]=1
Reactant: COc1ccc(Cn2cc(C#Cc3nn(Cc4ccc(OC)cc4)c4ncc(-c5ccccc5)c(N5CCN(C(=O)OC(C)(C)C)CC5)c34)cn2)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Solvent: c1ccc2ncccc2c1
Solvent: c1ccccc1
Product: COc1ccc(Cn2cc(/C=C\c3nn(Cc4ccc(OC)cc4)c4ncc(-c5ccccc5)c(N5CCN(C(=O)OC(C)(C)C)CC5)c34)cn2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74 %

Procedure:
A solution of tert-butyl 4-(1-(4-methoxybenzyl)-3-((1-(4-methoxybenzyl)-1H-pyrazol-4-yl)ethynyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.12 g, 0.169 mmol), quinoline (0.011 g, 0.085 mmol) and Lindlar's Catalyst (0.18 g, 0.085 mmol) in MeOH (3 mL) and benzene (3 mL) was charged with 1 atmosphere H2 and stirred at room temperature for 6 hours. The catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo, and the residue obtained was purified flash chromatography on silica gel (hexane:ethyl acetate=1:1) to give (Z)-tert-butyl 4-(1-(4-methoxybenzyl)-3-(2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)vinyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.089 g, 74%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[N:15]([CH2:16][C:17](=[O:24])[N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:14]=[CH:13][N:8]2[C:9](=[O:12])[C:10]=1[OH:11])=[O:4].C([O-])([O-])=O.[K+].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[N:15]([CH2:16][C:17](=[O:24])[N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:14]=[CH:13][N:8]2[C:9](=[O:12])[C:10]=1[O:11][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1nc2n(CC(=O)N3CCCCC3)ccn2c(=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1nc2n(CC(=O)N3CCCCC3)ccn2c(=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
The crude product of example 2 was dissolved in DMF (50 ml) and then K2CO3 (3.3 g, 0.024 mol) was added. After stirring at room temperature for about 0.5 hours, benzyl bromide (4.0 g, 0.0234 mol) was added drop-wise. Then the mixture was heated at 80° C. for another 5 hours. After cooling to room temperature, the solids were filtered off and washed with ethyl acetate. The filtrate was diluted with EA, washed with water and then brine, dried and concentrated. The residue was purified by column chromatography (CH2Cl2/MeOH=50/1) to give the titled compound (2.0 g, 2-step yield 49.3%).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:22][N:23]([CH3:32])[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.C([BH3-])#N.[Na+].C(O)C>C(OCC)(=O)C>[CH:12]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:28][C:27]4[CH:30]=[CH:31][C:24]([N:23]([CH3:32])[CH3:22])=[CH:25][CH:26]=4)[CH2:20][CH2:21]3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: C1=Cc2ccccc2C(C2CCNCC2)c2ccccc21
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C)c1ccc(CN2CCC(C3c4ccccc4C=Cc4ccccc43)CC2)cc1
Yield: 17.6 %

Procedure:
1.00 gram (3.47 millimoles) of 4-(5H-dibenzo[a,d]cyclohepten-5-yl)piperidine, 0.52 gram (3.47 millimoles) of p-dimethylaminobenzaldehyde, 0.63 gram (10.0 millimoles) of sodium cyanoborohydride and 10 milliliters of ethanol were stirred together at room temperature for 24 hours. At the end of this period, the mixture was diluted with 150 milliliters of ethyl acetate and the ethyl acetate solution washed successively with two 50 milliliter portions of 15 percent aqueous sodium bisulfite, one 50 milliliter portion of saturated sodium bicarbonate, and one 100 milliliter portion of brine and then dried over magnesium sulfate. The solvent was vaporized from the dried solution in vacuo to obtain a yellow oil. The oil was flash chromatographed on silica gel with 50/50 ethyl acetate/hexane as eluant to obtain 250 milligrams of a colorless oil which crystallized on standing overnight. The product after recrystallization from acetonitrile had a melting point of 163°-165° C. Elemental analyses of the product were as follows:
Reaction SMILES: C[O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16]C)=[C:8]2[C:4]=1[CH2:5][CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:29])[CH3:28])[CH2:7]2.N1C(C(O)=O)=CC=CC=1C(O)=O.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O.C(OCC)(=O)C>[CH3:13][O:12][C:11]1[C:3](=[O:2])[C:4]2[CH2:5][CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:29])[CH3:28])[CH2:7][C:8]=2[C:9](=[O:16])[C:10]=1[O:14][CH3:15]
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCNC(C)=O)C2
Agent: O=C(O)c1cccc(C(=O)O)n1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC1=C(OC)C(=O)C2=C(CC(CCCCCCCCNC(C)=O)C2)C1=O
Reaction time: 0.25 h
Yield: 76.3 %

Procedure:
To a mixture of N-[8-(4,5,6,7-tetramethoxyindan-2-yl)octyl]acetamide (700 mg), 2,6-pyridinedicarboxylic acid (857 mg), acetonitrile (7.0 ml), ethyl acetate (7.0 ml), and water (7.0 ml) was dropwise added a solution of CAN (3.75 g) in acetonitrile (3.5 ml) and water (3.5 ml) with cooling with ice. After being stirred for 15 min, the reaction mixture was diluted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate) and then with recrystallization from hexane-ethyl acetate) to yield the entitled compound (495 mg) as crystals.
Reaction SMILES: [F:1][C:2]1[C:3]([O:26][CH3:27])=[C:4]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.[ClH:28]>O1CCOCC1>[ClH:28].[F:1][C:2]1[C:3]([O:26][CH3:27])=[C:4]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][CH2:12][CH:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(F)cccc1[C@@H]1C[C@H]1NCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: COc1c(F)cccc1[C@@H]1C[C@H]1NCC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of trans-2-(3-fluoro-2-methoxyphenyl)cyclopropanamine hydrochloride (Biochemistry 2010, 49(30), 6494) (500 mg, 2.76 mmol) in a mixture of 1,2-dichloroethane (20 mL) and MeOH (5 mL) was added tert-butyl 4-formylpiperidine-1-carboxylate (588 mg, 2.76 mmol) and stirred for 3 min then Na(OAc)3BH (1.75 g, 8.28 mmol) was added and stirred for 10 min at RT. The reaction mixture was diluted with DCM (100 mL) and washed with water (2×50 mL), and brine (20 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated. The crude was purified by column chromatography using silica gel, eluting with 2% MeOH in DCM to afford tert-butyl 4-(((trans)-2-(3-fluoro-2-methoxyphenyl)cyclopropylamino)methyl)piperidine-1-carboxylate (250 mg, 25% yield) as yellow liquid. LCMS (ES) m/e 379.45 (M+H)+. To a solution of tert-butyl 4-(((trans)-2-(3-fluoro-2-methoxyphenyl)cyclopropylamino)methyl)piperidine-1-carboxylate (200 mg, 0.529 mmol) in 1,4-dioxane (5 mL) was added 4N HCl in 1,4-dioxane (30 mL) and stirred for 8 h at RT. The reaction mixture was concentrated and the residue was triturated with diethyl ether (50 mL), EtOAc (20 mL) and dried under high vacuum to afford (trans)-2-(3-fluoro-2-methoxyphenyl)-N-(piperidin-4-ylmethyl)cyclopropanamine hydrochloride (130 mg, 88%) as off white solid. LCMS (ES) m/e 279.45 (M+H)+, 95.34%, (DMSO-d6) δ ppm 9.53 (bs, 2H), 8.88 (bs, 1H), 8.69 (bs, 1H), 7.15 (t, J=8.4 Hz, 1H), 7.09-7.07 (m, 1H), 6.78 (d, J=8.0 Hz, 1H), 3.90 (s, 3H), 3.29 (d, 2H), 3.0 (bs, 3H), 2.79-2.89 (m, 3H), 2.05 (bs, 1H), 1.96 (d, J=13.6 Hz, 2H), 1.63 (m, 1H), 1.38-1.47 (m, 2H), 1.24-1.29 (m, 1H).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6](=[O:12])[CH2:5]2.[OH:13][C@:14]1([C:21]2[CH:26]=[CH:25][CH:24]=[C:23](I)[CH:22]=2)[CH2:19][CH2:18][O:17][C@@H:16]([CH3:20])[CH2:15]1>>[OH:13][C@:14]1([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([S:1][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([CH3:11])[C:6](=[O:12])[CH2:5]4)[CH:22]=2)[CH2:19][CH2:18][O:17][C@@H:16]([CH3:20])[CH2:15]1
Reactant: C[C@H]1C[C@@](O)(c2cccc(I)c2)CCO1
Reactant: CN1C(=O)Cc2cc(S)ccc21
Product: C[C@H]1C[C@@](O)(c2cccc(Sc3ccc4c(c3)CC(=O)N4C)c2)CCO1
Yield: 55 %

Procedure:
Using an analogous procedure to that described in Example 6, 5-mercapto-1-methylindolin-2-one was reacted with (2S,4R)-4-hydroxy-4(3-iodophenyl)-2-methyltetrahydropyran to give (2S,4R)-4-hydroxy-2-methyl-4-[3-(1-methyl-2-oxoindolin-5-ylthio)phenyl]tetrahydropyran in 55% yield, m.p. 110°-111° C. (recrystallised from a mixture of diethyl ether and ethyl acetate);
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][CH2:8][CH2:9][N:10]1[C:15]2[CH:16]=[C:17]([C:21]([O:23][CH3:24])=[O:22])[C:18]([CH3:20])=[CH:19][C:14]=2[O:13][C:12]([CH3:26])([CH3:25])[C:11]1=[O:27])(C)(C)C.C(O)(C(F)(F)F)=O.C(=O)([O-])O.[Na+]>>[CH3:24][O:23][C:21]([C:17]1[C:18]([CH3:20])=[CH:19][C:14]2[O:13][C:12]([CH3:25])([CH3:26])[C:11](=[O:27])[N:10]([CH2:9][CH2:8][CH2:7][C:6]([OH:28])=[O:5])[C:15]=2[CH:16]=1)=[O:22]
Reactant: COC(=O)c1cc2c(cc1C)OC(C)(C)C(=O)N2CCCC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc2c(cc1C)OC(C)(C)C(=O)N2CCCC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To methyl 4-(4-tert-butoxy-4-oxobutyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (2.7 g) was added TFA (5 ml), and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution, and the precipitated compound was extracted with ethyl acetate. The obtained ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue (950 mg) was used in the subsequent reaction without further treatment.