Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH2:9][CH:10]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[N+:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)([O-:27])=[O:26].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[N+:25]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH2:9][CH:10]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=2)=[CH:30][CH:29]=1)([O-:27])=[O:26]
Reactant: CCOC(=O)C(CCc1ccccc1)CC(=O)c1ccc(Br)cc1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CCc1ccccc1)CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 85 °C
Yield: 75.2 %

Procedure:
Ethyl 4-(4-bromophenyl)-4-oxo-2-(2-phenylethyl)butanoate (4.32 g, 11.1 mmol) and 4-nitrophenylboronic acid (2.22, 13.3 mmol) was added to a dry flask under argon. Toluene (100 mL), dioxane (25 mL), saturated aqueous sodium carbonate (30 mL), and [1,1′-bis(diphenyl-phosphino)-ferrocene]dichloro palladium(II) (1:1 complex with dichloromethane, 453 mg, 0.55 mmol) were added and the mixture was thoroughly degassed. The resulting mixture was then heated at 85° C. for 16 h before it was cooled to rt. Water was added and the mixture was extracted twice with ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage flash 75, 5:1 ethyl acetate/hexane) to afford ethyl 4-(4′-nitro-1,1′-biphenyl-4-yl)-4-oxo-2-(2-phenylethyl)butanoate (3.6 g, 75%). HPLC ret. time 3.99 min, 1H NMR (300 MHz, CDCl3) δ 1.29 (t, 3H), 1.85–2.08 (m, 2H), 2.71 (t, 2H), 3.05–3.20 (m, 2H), 3.45–3.52 (m, 1H), 4.20 (q, 2H), 7.18–7.31 (m, 5H), 7.72 (d, 2H), 7.78 (d, 2H), 8.05 (d, 2H), 8.33 (d, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH3:8].[C:9]([O:13][C:14]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>COCCOC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:8][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[C:20]1[CH:21]=[C:16]([CH:17]=[CH:18][CH:19]=1)[C:14]([O:13][C:9]([CH3:11])([CH3:12])[CH3:10])=[O:15]
Reactant: Cc1cnccc1Cl
Reactant: CC(C)(C)OC(=O)c1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1cnccc1-c1cccc(C(=O)OC(C)(C)C)c1
Temperature: 80 °C
Yield: 71.3 %

Procedure:
4-Chloro-3-methylpyridine (2.00 g, 15.7 mmol), 3-(tert-butoxycarbonyl)phenylboronic acid (5.42 g, 24.4 mmol), a 2M aqueous solution of potassium carbonate (31.4 mL, 62.8 mmol), and palladium tetrakis(triphenylphosphine) (Pd(PPh3)4, 0.906 g, 0.784 mmol) were suspended in 1,2-dimethoxyethane (DME, 150 mL). The resulting mixture was stirred and heated to 80° C. for 60 hours. The crude reaction mixture was cooled to room temperature and then the layers were separated. The organic layer was evaporated to dryness and then purified on 120 g of silica gel utilizing a gradient of 0-70% ethyl acetate in hexanes to yield the pure product as a pale yellow oil (3.02 g, 11.2 mmol, 71.4%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)=[CH:15][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Br-].[Zn+2].[Br-]>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[N:14]=[CH:15][C:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)=[CH:17][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cnc(OCCCOCc3ccccc3)nc2)C(OCc2ccc3ccccc3c2)C1
Agent: [Br-]
Agent: [Zn+2]
Product: c1ccc(COCCCOc2ncc(C3CCNCC3OCc3ccc4ccccc4c3)cn2)cc1

Procedure:
In an analogous manner to that described in Example 125(h), from tert-butyl (3RS,4RS)-4-[2-(3-benzyloxy-propoxy)-pyrimidin-5-yl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate by cleavage of the BOC group by means of anhydrous zinc bromide there was obtained 2-(3-benzyloxy-propoxy)-5-[(3RS,4RS)-3-(naphthalen-2-ylmethoxy)-piperidin-4-yl]-pyrimidine in the form of a yellowish gum; MS: 485 (M+H)+.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](OC)=[O:14])=[CH:11][CH:10]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.[NH2:20][NH2:21]>>[NH:20]([C:13]([C:12]1[CH:17]=[CH:18][C:9]([NH:8][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:10][CH:11]=1)=[O:14])[NH2:21]
Reactant: NN
Reactant: CCCCCC(=O)Nc1ccc(C(=O)OC)cc1
Solvent: O
Product: CCCCCC(=O)Nc1ccc(C(=O)NN)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55 %

Procedure:
To a suspension of methyl 4-(hexanoylamino)benzoate (583 mg, 2.34 mmol) in ETOH (8 mL) was added hydrazine hydrate (1.8 mL). After stirring for 15 h at reflux, the reaction mixture was cooled to rt and a white solid precipitated out. Filtration, washing with water (2×2 mL), and drying under vacuo at rt for 72 hrs gave 321 mg of the title compound (55%) as a white solid in 96.6% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH:1]1([N:7]2[C:12](=[O:13])[CH2:11][C:10](=[O:14])[N:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])[C:8]2=[O:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[N:35]([CH2:38][C:39]([O:41]CC)=[O:40])=[C:36]=[S:37]>C(Cl)(Cl)Cl>[C:39]([CH2:38][NH:35][C:36]([C:11]1[C:12](=[O:13])[N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8](=[O:25])[N:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:10]=1[OH:14])=[S:37])([OH:41])=[O:40]
Reactant: CCOC(=O)CCCCCN1C(=O)CC(=O)N(C2CCCCC2)C1=O
Reactant: CCOC(=O)CN=C=S
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CCCCCn1c(O)c(C(=S)NCC(=O)O)c(=O)n(C2CCCCC2)c1=O
Reaction time: 168 h
Yield: 60.2 %

Procedure:
A mixture of ethyl 6-(3-cyclohexyl-2,4,6-trioxotetrahydro-1(2H)-pyrimidinyl)hexanoate (330 mg, 0.94 mmoles), diisopropylethylamine (324 uL, 1.87 mmoles) and ethyl isothiocyanatoacetate (139 uL, 1.12 mmoles) in chloroform (20 mL) was stirred for 7 days. The mixture was washed with 1 molar hydrochloric acid (×2), dried and evaporated. The residue was purified by flash chromatography (hexane—20% ethyl acetate in hexane) to give the title compound as a clear oil (250 mg, 60%). The diester was dissolved in ethanol (3 mL) and treated with 1 molar sodium hydroxide (2 mL). The mixture was stirred overnight, taken up in ethyl acetate and washed with 1 molar hydrochloric acid (×2), dried and evaporated. Crystallization from acetic acid afforded the title compound (160 mg, 40%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.13 (br s, 1 H), 12.50 (s, 1 H), 12.03 (br s, 1 H), 4.71 (m, 1 H), 4.35 (d, J=5.05 Hz, 2 H), 3.84 (t, J=7.20 Hz, 2 H), 2.10-2.38 (m, 4 H), 1.80 (d, J=12.63 Hz, 2 H), 1.42-1.71 (m, 7 H), 1.21-1.42 (m, 4 H), 1.01-1.22 (m, 1 H).
Reaction SMILES: Cl.C([N:9]1[CH2:14][CH2:13][C:12]2([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([O:28][CH3:29])[C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:11][CH2:10]1)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:29][O:28][C:23]1[C:22]2[O:21][C:20]3[C:15]([C:12]4([CH2:13][CH2:14][NH:9][CH2:10][CH2:11]4)[C:27]=2[CH:26]=[CH:25][CH:24]=1)=[CH:16][CH:17]=[CH:18][CH:19]=3
Reactant: COc1cccc2c1Oc1ccccc1C21CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1cccc2c1Oc1ccccc1C21CCNCC1

Procedure:
A solution of 1'-benzyl-4-methoxyxanthene-9-spiro-4'-piperidine hydrochloride (3.0 g.) in absolute ethanol (100 ml.) is hydrogenatedusing 5% palladium on carbon catalyst, at 4 atmospheres pressure and 50° C. The catalyst is filtered off and the solvent evaporated to dryness. The residue is crystallised from ethanol-ether to give 4-methoxyxanthene-9-spiro-4'-piperidine, m.p. 214°-216° c.
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)CN)[CH2:25][CH2:24]1.C1(O)C=CC=CC=1>>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:7]2[S:6][C:5]3[C:3](=[O:4])[N:12]([CH2:14][C:32]4[CH:35]=[CH:36][CH:37]=[C:30]([CH2:29][N:26]5[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]5)[CH:31]=4)[CH:11]=[N:10][C:9]=3[CH:8]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N=CN(C)C
Reactant: CN1CCN(Cc2cccc(CN)c2)CC1
Solvent: Oc1ccccc1
Product: CN1CCN(Cc2cccc(Cn3cnc4cc(-c5ccc(Cl)cc5)sc4c3=O)c2)CC1
Temperature: 25 °C

Procedure:
5-(4-Chloro-phenyl)-3-(dimethylamino-methyleneamino)-thiophene-2-carboxylic acid methyl ester (0.177 g, 0.547 mmol), 3-(4-methyl-piperazin-1-ylmethyl)-benzylamine (0.100 g, 0.456 mmol) and phenol (1.00 g) were stirred at 130° C. for 1.5 hours. The reaction mixture was allowed to cool to r.t. The product was partly purified by flash chromatography using EtOAc, MeOH and TEA mixtures as eluent to give a yellow solid. The solid was washed with MeOH to give the product. Yield: 0.122 g (48%). 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.63 (d, 2H, J=8.52 Hz), 7.45 (s, 1H), 7.43 (d, 2H, J=8.52 Hz), 7.21-7.34 (m, 4H), 5.20 (s, 2H), 3.47 (s, 2H), 2.41 (bs, 8H), 2.25 (s, 3H). MS (ESI+) 464.93 (M+1H+).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[N:4]1.I[CH2:13][CH2:14][CH:15]1[CH2:21][CH2:20][C:19]2[C:22]([O:32][CH3:33])=[C:23]([O:30][CH3:31])[C:24]([O:28][CH3:29])=[C:25]([O:26][CH3:27])[C:18]=2[CH2:17][CH2:16]1>C1COCC1.O>[CH3:27][O:26][C:25]1[C:18]2[CH2:17][CH2:16][CH:15]([CH2:14][CH2:13][N:3]3[C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=4[N:5]=[N:4]3)[CH2:21][CH2:20][C:19]=2[C:22]([O:32][CH3:33])=[C:23]([O:30][CH3:31])[C:24]=1[O:28][CH3:29]
Reactant: c1ccc2[nH]nnc2c1
Reactant: COc1c2c(c(OC)c(OC)c1OC)CCC(CCI)CC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1c2c(c(OC)c(OC)c1OC)CCC(CCn1nnc3ccccc31)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
To a suspension of sodium hydride (60% oil dispersion, 230 mg) in THF (6 ml) was added a solution of 1,2,3-benzotriazole (680 mg) in THF(6 ml) with cooling with ice. The reaction mixture was warmed to room temperature and stirred at ambient temperature for 30 min. 7-(2-Iodoethyl)-1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene (1.20 g) was added and the stirring was continued for 12 hr. The reaction mixture was heated under reflux for 6 hr, diluted with water, and extracted 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 alumina column chromatography(hexane to hexane:ethyl acetate=4:1) and then with recrystallization from hexane-ethyl acetate to obtain the entitled compound (920 mg).
Reaction SMILES: [C:1](Cl)(=O)[CH2:2][CH2:3][CH2:4][CH3:5].[Si:8]([O:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[CH:22][C:21]=1[NH2:30])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]>CN1C(=O)CCC1>[CH2:2]([C:1]1[N:19]([CH2:18][CH2:17][CH2:16][O:15][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])[C:20]2[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:23]=[CH:22][C:21]=2[N:30]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCCCNc1c(N)cnc2ccccc12
Solvent: CN1CCCC1=O
Product: CCCCc1nc2cnc3ccccc3c2n1CCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Pentanoyl chloride (3.7 mL) was added dropwise to a stirred solution of the product from step (iii) (10 g) and TEA (5 mL) in NMP (110 mL) at rt under nitrogen. The mixture was stirred at rt for 2 h then heated to 100° C. for 6 h. After cooling, the reaction mixture was partitioned between diethyl ether/water, the organics were separated, washed with water, dried, and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 50-70% EtOAc/isohexane, yield 6.58 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9].Cl[Sn]Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9])[NH2:10]
Reactant: CCc1ccc([N+](=O)[O-])cc1Cl
Agent: Cl[Sn]Cl
Product: CCc1ccc(N)cc1Cl
Yield: 97.9 %

Procedure:
A solution of 8.9 g (48 mmol) of 31 and 54.6 g (241 mmol) of SnCl2, 2H2O in 100 mL of absolute alcohol was refluxed for 1 h. It was evaporated to remove most of the solvent and the residue was treated with 2N NaOH to pH =9. The mixture was filtered and the solid was washed with methanol (10 mL) and ethyl acetate (200 mL). The filtrate was separated and the aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic solution was dried (MgSO4) and evaporated to leave 7.31 g (98%) of liquid. 1H NMR (CDCl3), 1.178 (t, 3, J=7.5), 2.639 (q, 2, J=7.4), 6.532 (dd, 1, J=2.2, 8.1), 6.700 (d, 1, J=2.2), 6.996 (d, 1, J=8.2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Cl.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][Cl:19]>C(O)C>[ClH:19].[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=2)=[CH:4][CH:3]=1
Reactant: ClCc1ccccn1
Reactant: Fc1ccc(S)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Fc1ccc(SCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 70.2 %

Procedure:
4-Fluorobenzenethiol (5 g) was added to a solution of sodium hydroxide (3.14 g) in ethanol (50 ml) and the resulting solution was treated with 2-picolyl chloride, hydrochloride (6.4 g) in ethanol (25 ml) and the mixture was stirred for 6 hours at ambient temperature. The mixture was filtered, the solvent removed by evaporation and the residue was converted into the hydrochloride with ethereal HCl. Recrystallisation from ethanol-ether gave 2-(((4-fluorophenyl)thio)methyl)pyridine, hydrochloride (7 g) mp 190°-2° C. (Found: C,56.1; H, 4.4; N,5.2 C12H10FNS.HCl requires C,56.4; H,4.3; N,5.4%).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH3:16][S:17][CH2:18][C:19]([NH:21][CH3:22])=[O:20].C(OCl)(C)(C)C.C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:4](=[O:5])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:12][CH:13]=[CH:14][C:15]=1[CH:18]([S:17][CH3:16])[C:19]([NH:21][CH3:22])=[O:20]
Reactant: Nc1ccccc1C(=O)c1ccccc1
Reactant: CNC(=O)CSC
Agent: CC(C)(C)OCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)C(SC)c1cccc(C(=O)c2ccccc2)c1N
Temperature: 25 °C
Yield: 65.7 %

Procedure:
A solution of 29.6 g (0.15 mole) of 2-aminobenzophenone in 350 ml of methylene chloride was cooled to -70° C. and 17.9 g (0.15 mol) of 2-methylthio-N-methylacetamide in 20 ml of methylene chloride was added. To the (-70° C.) mixture was added dropwise a solution of 17.2 g (0.15 mole) of 95% t-butylhypochlorite in 30 ml of methylene chloride. The temperature was maintained at or below -65° C. for 1.5 hr, then 15.1 g (0.15 mole) of triethylamine was added rapidly. The solution was allowed to warm to room temperature and was washed with water. The organic solution was concentrated and the residue crystallized when mixed with isopropyl ether. The solid was recrystallized from isopropyl alcohol to give 31 g (65%) of yellow needles, m.p. 149.0°-150.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]([C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=3)([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[OH:19])[CH2:14][CH2:13]2)=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CO>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([C:31]3[CH:32]=[CH:33][C:34]([O:37][C:38]([F:41])([F:39])[F:40])=[CH:35][CH:36]=3)([C:20]3[CH:21]=[CH:22][C:23]([O:26][C:27]([F:28])([F:30])[F:29])=[CH:24][CH:25]=3)[OH:19])[CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(=O)N2CCC(C(O)(c3ccc(OC(F)(F)F)cc3)c3ccc(OC(F)(F)F)cc3)CC2)cc1Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CN2CCC(C(O)(c3ccc(OC(F)(F)F)cc3)c3ccc(OC(F)(F)F)cc3)CC2)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.5 %

Procedure:
To a stirred solution of 0.50 gram (0.0008 mole) of N-(3-chloro-4-methoxyphenylcarbonyl)-4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine in 5 mL of tetrahydrofuran was slowly added 0.42 mL (0.0040 mole) of borane-methyl sulfide complex (10M in BH3). Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 18 hours. The reaction mixture was then cooled in an ice-bath, and 20 mL of methanol was added slowly to quench the reaction. The reaction mixture was then concentrated under reduced pressure to a residue. Another 20 mL of methanol was stirred with the residue, and this was concentrated under reduced pressure to the residue. The process of adding 20 mL of methanol and concentrating the solution to the residue was repeated once more. The residue was partitioned between ethyl acetate and water, and the mixture was stirred for 15 minutes. The organic layer was separated, washed with an aqueous solution saturated with sodium chloride, and then dried with sodium sulfate. The mixture was filtered and concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel, with mixtures of ethyl acetate in hexane as eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.13 gram of N-(3-chloro-4-methoxyphenylmethyl)-4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][C:14]1([CH3:27])[CH3:26])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCOCC1>[CH2:2]([O:9][C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][C:14]1([CH3:27])[CH3:26])=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)C(C)(C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)CNCCC1NC(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
6 N HCl (200 ml) was added to a stirred solution of 4-benzyloxycarbonylamino-1-t-butyloxycarbonyl-3,3-dimethylpiperidine (350 g, 0.96 mol) in dioxane (200 ml). The resulting mixture was stirred for 1 hr and concentrated to dryness. The resultant residue was treated with water (3.0 L) water and was extracted with 1.0 L×2 ethyl acetate. The aqueous layer was basified with 2 M aqueous NaOH and extracted with 2.5 L×2 dichloromethane. Combined organic extract was washed with water, dried over Na2SO4 and concentrated to afford 4-benzyloxycarbonylamino-3,3-dimethylpiperidine in 89% (224 g) yield.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:12](Br)[C:13]#[CH:14].C([O-])([O-])=O.[K+].[K+]>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:14][C:13]#[CH:12])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C#CCOc1ccc(S(C)(=O)=O)cc1

Procedure:
A mixture of 4-methylsulfonyl-phenol, propargyl bromide and K2CO3 was refluxed overnight. After cooling, the mixture was filtered through a pad of celite. The filtrate was concentrated in vacuo. The crude solid product was purified on silica gel to give the desired product as a pale yellow solid. 1H NMR (CDCl3): δ 7.9 (2H, d), 7.12 (2H, d), 4.79 (2H, d), 3.05 (3H, s), 2.58 (1H, t).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.C([O:14][CH2:15][CH:16]1[CH2:24][CH:23]2[CH:19]([CH2:20][N:21]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:22]2)[C:18](=[O:32])[CH2:17]1)(=O)C.[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1>[CH2:25]([N:21]1[CH2:20][CH:19]2[CH:23]([CH2:24][CH:16]([CH2:15][OH:14])[CH2:17][C:18]2([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[OH:32])[CH2:22]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1ccccc1[Mg]Br
Reactant: CC(=O)OCC1CC(=O)C2CN(Cc3ccccc3)CC2C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccccc1C1(O)CC(CO)CC2CN(Cc3ccccc3)CC21
Temperature: 20 °C
Reaction time: 20 h
Yield: 37.9 %

Procedure:
To a suspension of 2-methoxyphenylmagnesium bromide (prepared from 24.9 cm3 of 2-bromoanisole and 4.86 g of magnesium) in 200 cm3 of anhydrous tetrahydrofuran is added a solution of 8.0 g of (3aRS,6SR,7aSR)-6-acetoxymethyl-2-benzyl-4-perhydroisoindolone in 60 cm3 of anhydrous tetrahydrofuran. The reaction mixture is stirred for 20 hours at 20° C. and then cooled to +5° C. and treated with 120 cm3 of saturated aqueous ammonium chloride solution and 100 cm3 of ethyl acetate. After filtration of the mixture, the organic phase is washed with brine and then dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.06-0.200 mm, height 40 cm) in a mixture of 1,2-dichloroethane and methanol (95/5 by volume). After recrystallization in ethyl ether, 3.2 g of (3aRS,4RS,6SR, 7aSR)-2-benzyl-6-hydroxymethyl-4-(2-methoxyphenyl)-4-perhydroisoindolol are obtained, in the form of a white solid melting at 110° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:20][CH2:19][C:18]4[CH:21]=[C:22]([NH2:25])[CH:23]=[CH:24][C:17]=4[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.Cl[C:27]1[N:32]=[C:31]([NH:33][C@@H:34]2[C@@H:39]3[CH2:40][C@@H:36]([CH:37]=[CH:38]3)[C@@H:35]2[C:41]([NH2:43])=[O:42])[C:30]([Cl:44])=[CH:29][N:28]=1>>[Cl:44][C:30]1[C:31]([NH:33][C@@H:34]2[C@@H:39]3[CH2:40][C@@H:36]([CH:37]=[CH:38]3)[C@@H:35]2[C:41]([NH2:43])=[O:42])=[N:32][C:27]([NH:25][C:22]2[CH:23]=[CH:24][C:17]3[CH2:16][CH2:15][CH:14]([N:11]4[CH2:12][CH2:13][CH:8]([N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)[CH2:9][CH2:10]4)[CH2:20][CH2:19][C:18]=3[CH:21]=2)=[N:28][CH:29]=1
Reactant: CN1CCN(C2CCN(C3CCc4ccc(N)cc4CC3)CC2)CC1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: CN1CCN(C2CCN(C3CCc4ccc(Nc5ncc(Cl)c(N[C@H]6[C@@H](C(N)=O)[C@@H]7C=C[C@H]6C7)n5)cc4CC3)CC2)CC1

Procedure:
The title compound was prepared from 7-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine and (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide in an analogous manner to Example 179 heating at 140° C. Product was isolated as a tan solid (33 mg, 40%). LCMS (m/e) 605 (M+1); 1H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.38 (dd, 1H, J=7.8 Hz), 7.30 (d, 1H, J=17 Hz), 7.04 (d, 1H, J=8.08 Hz), 6.87 (s, 1H), 6.79 (t, 1H, J=8.08 Hz), 6.33 (m, 1H), 6.30 (m, 1H), 5.59 (s, 1H), 5.43 (s, 1H), 4.37 (t, 1H, J=8.33 Hz), 3.06 (s, 1H), 3.00 (s, 1H), 2.90-2.60 (m, 12H), 2.49-2.38 (m, 5H), 2.27 (s, 4H), 2.19-2.26 (m, 2H), 2.06 (m, 2H), 1.79 (d, 2H, J=11 Hz), 1.63 (d, 1H, J=9.35 Hz), 1.51 (q, 2H, J=11 Hz), 1.38 (m, 2H).