Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])[N:5]1C(OCC1C=CC=CC=1)=O>CO.[Pd]>[CH3:1][O:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])[NH:5]1
Reactant: COCC1CCC(c2ccccc2OC)N1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COCC1CCC(c2ccccc2OC)N1
Yield: 54.2 %

Procedure:
To a solution of 2-methoxymethyl-5-(2-methoxyphenyl)-N-(carbobenzyloxy)-tetrahydropyrrole (1.3 g, 3.66 mmol) in methanol (40 mL) was added 10% Pd-C (1.3 g) and the resulting suspension was hydrogenated (50 psi) for 3 hours. Pd-C was then filtered off and the crude reaction mixture was concentrated in vacuo to give a yellowish residue, which was purified by silica gel flash chromatography (5% MeOH-0.5% NH3 .diamond-solid.H2O-94.5% CH2Cl2) to afford the title compound as a colorless oil (439.2 mg, 54%). MS m/z: 222 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:26])[C:3]=1[OH:27].[C:28]([O:38]C)(=[O:37])[C@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)O>>[Br:26][C:4]1[CH:5]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=[C:2]([Br:1])[C:3]=1[O:27][C@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:28]([OH:38])=[O:37]
Reactant: COC(=O)[C@@H](O)c1ccccc1
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Product: O=C(O)[C@H](Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br)c1ccccc1

Procedure:
Prepared from 2,6-dibromo-4-(6-bromo-benzo[b]naphtho [2,3-d]thiophen-11 -yl)-phenol (Example 21) and commercially avialable methly (s)-(+)-mandelate. White solid: mp 135-137° C.: MS (FAB-): [M-H]-, 693; Anal. Calc. for C3OH17Br3O3S: C, 51.68, H, 2.46, N, 0.00. Found: C 51.57, H, 2.89, N, 0.14.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][N:23]5[CH2:27][CH2:26][CH2:25][C:24]5=[O:28])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:31])[CH:3]=1.CCN(C(C)C)C(C)C.ClC(Cl)(O[C:45](=[O:51])OC(Cl)(Cl)Cl)Cl.[NH2:53][C:54]1[CH:55]=[C:56]([CH:60]=[CH:61][CH:62]=1)[C:57]([NH2:59])=[O:58]>C1COCC1>[F:31][C:4]1[CH:3]=[C:2]([NH:1][C:45](=[O:51])[NH:53][C:54]2[CH:55]=[C:56]([CH:60]=[CH:61][CH:62]=2)[C:57]([NH2:59])=[O:58])[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][N:23]4[CH2:27][CH2:26][CH2:25][C:24]4=[O:28])=[CH:20][N:21]=3)[S:15][C:8]=12
Reactant: NC(=O)c1cccc(N)c1
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCCC5=O)cn4)sc23)c(F)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NC(=O)c1cccc(NC(=O)Nc2ccc(Oc3ccnc4cc(-c5ccc(CN6CCCC6=O)cn5)sc34)c(F)c2)c1
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 7.9 %

Procedure:
To a solution of 104 (83 mg, 0.191 mmol, scheme 26) in THF (19 mL) at −10° C. was added DIPEA (334 μl, 1.910 mmol) and triphosgene (56.7 mg, 0.191 mmol). The reaction mixture was stirred for 90 min at −10° C. then 3-aminobenzamide (104 mg, 0.764 mmol) was added. The reaction mixture was allowed to warm to RT, stirred for 3 h, quenched with MeOH, and concentrated. The residue was suspended in 2 mL of MeOH and a saturated aqueous solution of ammonium chloride was added, stirred for 30 min, collected by filtration, and dried. The crude product was purified by Biotage (SNAP 25 g cartridge; MeOH/DCM: 0/100 to 30/70 over 20 CV) to produce a material that was further purified by Gilson (Phenomenex, Luna, 15μ, C18(2) 100A, 250×50.00 mm, 15 μm, 0.05% of formic acid in both MeOH/water (30 mL/min): 30/70 to 95/5 over 60 min), to afford the title compound 106 (8.7 mg, 0.015 mmol, 7% yield, formate salt) as an yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 11.34 (s, 1H), 11.06 (s, 1H), 8.55-8.50 (m, 2H), 8.41 (s, 4H), 8.35 (s, 1H), 8.26 (d, J=8.0 Hz, 1H), 8.05 (t, J=2.0 Hz, 1H), 7.90-7.77 (m, 3H), 7.71-7.67 (m, 1H), 7.44-7.38 (m, 3H), 7.34-7.27 (m, 2H), 6.68 (dd, J=5.2, 0.8 Hz, 1H), 4.46 (s, 2H), 3.31 (t, J=7.2 Hz, 2H), 2.31 (t, J=8.0 Hz, 2H), 1.95 (quint, J=8.0 Hz, 2H). MS (m/z): 597.5 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1B(O)O.Br[C:15]1[CH:16]=[C:17]([S:21]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])(=[O:23])=[O:22])[CH:18]=[N:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+].O>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.CN(C=O)C.O1CCOCC1>[CH2:27]([N:24]([CH2:25][CH3:26])[S:21]([C:17]1[CH:18]=[N:19][CH:20]=[C:15]([C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:16]=1)(=[O:22])=[O:23])[CH3:28]
Reactant: Cn1c(B(O)O)cc2ccccc21
Reactant: CCN(CC)S(=O)(=O)c1cncc(Br)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: CN(C)C=O
Solvent: C1COCCO1
Product: CCN(CC)S(=O)(=O)c1cncc(-c2cc3ccccc3n2C)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A flask is charged with 1-methyl-1H-indol-2-ylboronic acid (90 mg, 0.512 mmol), 5-bromo-N,N-diethylpyridine-3-sulfonamide (100 mg, 0.341 mmol) and polymer supported Pd(PPh3)4 (189 mg, 0.017 mmol), and the flask is flushed with N2 for 5 min. 1,4-Dioxane (10 mL) and 2M K2CO3 in water (0.512 mL, 1.023 mmol) are added under N2 and the mixture is stirred at 90° C. under N2 for 2 h. The mixture is then cooled to room temperature and DMF (4 mL) is added. The mixture is concentrated in vacuo and the residue is filtered and the filtrate is purified by Xterra RP18 eluting with a 1:9 to 9:1 acetonitrile-water gradient to give N,N-diethyl-5-(1-methyl-1H-indol-2-yl)pyridine-3-sulfonamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.1 Hz, 6H), 3.29 (d, J=7.1 Hz, 4H), 3.80 (s, 3H), 6.85 (s, 1H), 7.08-7.14 (m, 1H), 7.26 (td, J=7.71, 1.26 Hz, 1H), 7.56 (dd, J=8.3, 0.5 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H), 8.33 (t, J=2.1 Hz, 1H), 9.00 (d, J=2.0 Hz, 1H), 9.10 (d, J=2.2 Hz, 1H). HRMS: (ESI) m/z 344.1428 [(M+H)+ Calcd for C18H22N3O2S 344.1427].
Reaction SMILES: [Cl-:1].C(OC([NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][N+:12]([CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]([O:44][CH3:45])=[O:43])=[CH:36][CH:35]=2)([CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:21][CH:20]=2)[CH2:11]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[ClH:1].[Cl-:1].[NH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][N+:12]([CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]([O:44][CH3:45])=[O:43])=[CH:36][CH:35]=2)([CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:24]=2)[CH2:11]1
Reactant: COC(=O)COc1ccc(CCC[N+]2(CCCc3ccc(OCC(=O)OC)cc3)CCCC(NC(=O)OC(C)(C)C)C2)cc1
Agent: [Cl-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)COc1ccc(CCC[N+]2(CCCc3ccc(OCC(=O)OC)cc3)CCCC(N)C2)cc1
Product: Cl

Procedure:
3-tert-Butoxycarbonylamino-1,1-bis-[3-(4-methoxycarbonylmethoxy-phenyl)-propyl]-piperidinium chloride (707 mg, 1.09 mmol) is dissolved in dichloromethane (1 ml) and trifluoroacetic acid (1 ml) and stirred at room temperature overnight. The mixture is evaporated, dissolved in acetonitrile and 1 M HCl (5 ml) and evaporated again. LC (method L): tR=0.95 min; Mass spectrum (ESI+): m/z=513 [M]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[C:14]([O:18][C:19](=[O:34])[C@H:20]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH:21][C:22](=[O:26])[C@H:23]([CH3:25])[NH2:24])([CH3:17])([CH3:16])[CH3:15].C(N[C@H](C(O)=O)C)(OC(C)(C)C)=O.Cl.C(OC(=O)[C@H](CC1C=CC=CC=1)N)(C)(C)C>CO.C(Cl)(Cl)Cl>[C:14]([O:18][C:19](=[O:34])[C@H:20]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[NH:21][C:22](=[O:26])[C@H:23]([CH3:25])[NH:24][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)([CH3:15])([CH3:16])[CH3:17]
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: C[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C

Procedure:
Following General Procedure C and using 3,5-difluorophenylacetic acid (Oakwood) and N-(L-alaninyl)-L-phenylalanine tert-butyl ester hydrochloride (prepared from N-BOC-L-alanine (Sigma) and L-phenylalanine tert-butyl ester hydrochloride (Advanced Chemtech) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a gel. The reaction was monitored by tlc (Rf=0.5 in 4% MeOH/CHCl3) and the product was purified by silica gel chromatography using 4% MeOH/CHCl3 as the eluent.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][N:14]=[CH:15]3)=[CH:2]1.[H-].[Na+].I[CH3:23].CO>CN(C=O)C>[CH3:23][N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][N:14]=[CH:15]3)=[CH:2]1
Reactant: CI
Reactant: c1cc(-c2c[nH]c3ncccc23)c2ccncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1cc(-c2cccc3cnccc23)c2cccnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
53 mg (0.216 mmol) of 5-(1H-pyrrolo[2,3-b]pyridin-3-yl)isoquinoline are added to a suspension, kept under an argon atmosphere, of 26 mg (0.65 mmol) of sodium hydride, (60% suspension in paraffin oil) in 1 ml of DMF, and the reaction mixture is stirred at room temperature for 1 hour. 18 μl (0.65 mmol) of iodomethane are then added, and the reaction mixture is stirred at room temperature for a further 17 hours. 0.5 ml of methanol is then added, and the reaction mixture is subsequently evaporated in vacuo. The residue is chromatographed on a silica-gel column with dichloromethane/methanol as eluent, giving 5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)isoquinoline as colourless solid; MS (EI): 259 [M]+;
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:29]=[CH:28][N:14]3[C:15](=[O:27])[C:16]([CH:25]=O)=[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:18]=[C:13]3[C:12]=2[O:30][CH3:31])[S:7][CH:8]=1)([CH3:3])[CH3:2].[C:32]([O:36][C:37]([CH:39]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>O1CCCC1.CN(C)C=O>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:29]=[CH:28][N:14]3[C:15](=[O:27])[C:16](/[CH:25]=[CH:39]/[C:37]([O:36][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:38])=[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:18]=[C:13]3[C:12]=2[O:30][CH3:31])[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: COc1c(CCc2nc(C(C)C)cs2)ccn2c(=O)c(C=O)c(N3CCOCC3)nc12
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1c(CCc2nc(C(C)C)cs2)ccn2c(=O)c(/C=C/C(=O)OC(C)(C)C)c(N3CCOCC3)nc12
Temperature: 80 °C
Reaction time: 15 h
Yield: 57 %

Procedure:
The 8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-9-methoxy-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbaldehyde (300 mg) obtained in (H) was dissolved in tetrahydrofuran (4 ml) and dimethylformamide (1 ml), added with (tert-butoxy-carbonylmethylene)triphenylphosphorane (767 mg), and stirred at 80° C. for 15 hours. After the solvent was evaporated, the residue was purified by silica gel column chromatography to obtain the title compound (209 mg) as yellow powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[O:12]1[CH2:20][CH:13]1[CH2:14][O:15][CH2:16][CH:17]1[O:19][CH2:18]1>C(O)C>[OH:12][CH:13]([CH2:20][N:3]1[C:4]([CH3:9])([CH3:10])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1])[CH2:14][O:15][CH2:16][CH:17]([OH:19])[CH2:18][N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1]
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: C(OCC1CO1)C1CO1
Solvent: CCO
Product: CC1(C)CC(O)CC(C)(C)N1CC(O)COCC(O)CN1C(C)(C)CC(O)CC1(C)C

Procedure:
2,2,6,6-Tetramethyl-4-hydroxypiperidine 15.7 g and bis(2,3-epoxypropyl)ether was dissolved in 30 ml ethanol and refluxed for ten hours. Ethanol was distilled off, and 21.8 g of colorless liquid was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][Cl:7].[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C)C=O>[Cl-:7].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][P+:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1cccc(CCl)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [Cl-]
Temperature: 150 °C
Yield: 60.8 %

Procedure:
3-Methoxybenzyl chloride (1.05 g, 6.69 mmol), triphenylphosphine (1.75 g, 6.67 mmol) was dissolved in dimethylformamide (10 ml) and heated at 150° C. for 40 minutes. The reaction mixture was cooled to room temperature, and the solid precipitated was collected by filtration and washed and ethyl ether, and then dried under reduced pressure to obtain the title compound as colorless solid 1.70 g (yield: 61%).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[C:15]2[CH:16]=[C:17]([C:28]([NH2:30])=[O:29])[C:18]([O:20][CH2:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:19][C:14]=2[CH2:13][CH2:12][CH2:11][CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@@H:9]1[C:15]2[CH:16]=[C:17]([C:28]([NH2:30])=[O:29])[C:18]([O:20][CH2:21][CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)=[CH:19][C:14]=2[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCc2cc(OCC3CCCCC3)c(C(N)=O)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1cc2c(cc1OCC1CCCCC1)CCCC[C@@H]2N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a cooled (0° C.) solution of (S)-9-tert-butoxycarbonylamino-3-cyclohexylmethoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylic acid amide (198 mg, 0.475 mmol) in DCM (1 mL) was added TFA (1 mL). After 10 min, the reaction was allowed to warm to rt and after 1 h, the reaction was evaporated to dryness. The material was used without further purification for the next step.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[F:9][C:10]([F:20])([C:17](O)=O)[C:11]([F:16])([F:15])[C:12](O)=O>>[N:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][C:12]=1[C:11]([F:16])([F:15])[C:10]([C:17]1[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=1)([F:20])[F:9]
Reactant: Nc1ccccc1N
Reactant: O=C(O)C(F)(F)C(F)(F)C(=O)O
Product: FC(F)(c1nc2ccccc2[nH]1)C(F)(F)c1nc2ccccc2[nH]1
Temperature: 160 °C
Reaction time: 7 h

Procedure:
In a 250 mL 35/25 ball joint flask, 1,2-phenylenediamine (5.92 g, 54.7 mmol) was combined with tetrafluorosuccinic acid (5.2 g, 27.36 mmol). Polyphosphoric acid (83 g) was added directly to the solid mixture. The flask was fitted with an air-driven mechanical stirring shaft and heated to 160° C. under a nitrogen purge maintained with a septum and needle. The molten mixture was stirred for 7 hours and subsequently poured slowly into a large (1 L) excess of cold water. A Waring™ blender was used to grind the solid product/water slurry. The water was then neutralized to a pH of ˜8 with ammonium hydroxide. The brown particulate product, 1,2-bis(benzimidazol-2-yl)-1,1,2,2-tetrafluoroethane, was isolated by filtration, dried in a vacuum oven, ground to a fine powder with a mortar and pestle, and once again slurried in ca. 1 L water which was then neutralized to pH 8 with ammonium hydroxide. The solid was again collected by filtration and dried under diffusion pump vacuum at 110° C. for several days (7.96 g, 87%; C16H10F4N4, FW=334.27). A small amount of water was still present by 1H NMR (br s, 3.35 ppm). 1H NMR (d6-DMSO): δ 13.66 (br s, 2 H, NH), 7.67 and 7.34 (each br s, 4 H, aryl C—H. 13C{1H} NMR (solid state): δ 142.2, 135.5 (C—N), 124.2, 120.2, 114.4 (aryl) (C═N and CF2 not observed). 19F NMR (d6-DMSO, vs. CFCl3): δ −110.61. IR (KBr pellet, cm−1): 3063 (m), 3011 (m), 2947 (m), 2864 (s), 2749 (s), 2699 (sh), 2647 (s), 2546 (m), 2527 (m), 1942 (w), 1903 (w), 1778 (w), 1622 (w), 1591 (m), 1537 (w), 1492 (m), 1456 (s), 1441 (s), 1389 (w), 1317 (m), 1279 (m), 1231 (m), 1202 (w), 1161 (vs), 1140 (vs), 1030 (m), 1014 (m), 999 (m), 941 (m), 909 (m), 887 (m), 789 (w), 766 (w), 739 (s), 675 (w), 619 (w), 590 (m), 545 (w), 434 (m). Elemental analysis calculated for C16H10F4N4: C, 57.49; H, 3.02; F, 22.73; N, 16.76. Found: C, 56.74; H, 2.82; F, 21.95; N, 16.70. FD-MS m/z (%): 334 (M+, 100), 167 (C8H5F2N2, 6). Melting point (DSC, maximum): 383° C.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:13].[C:14](=O)([O-])[O-].[Cs+].[Cs+].BrCCl>CN(C=O)C>[CH2:14]1[O:12][C:11]2[C:2](=[C:3]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:13])[CH2:6][CH2:5][CH2:4]3)[O:1]1
Reactant: O=C([O-])[O-]
Reactant: O=C1CCCc2c1ccc(O)c2O
Agent: ClCBr
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1CCCc2c1ccc1c2OCO1
Temperature: 100 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a solution of the product of Example 177 (30 g) in DMF (390 ml) was added cesium carbonate (83 g) followed by bromochloromethane (33 g) and the resulting mixture heated to 100° C. and mechanically stirred for 2 hours. The reaction was cooled, filtered and the solids washed with ethyl acetate. The filtrate concentrated and the residue taken up into water and toluene. The layers were separate and the aqueous layer reextracted with toluene. The extracts were combined, dried (MgSO4), filtered, treated with charcoal, refiltered and concentrated to provide 29.9 g of the desired product, m.p. 132°-136° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](OC)=[O:6].[Li+].[B-](CC)(CC)CC>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[C:3]([Cl:12])=[C:4]([CH2:5][OH:6])[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1cccc(Br)c1Cl
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1cccc(Br)c1Cl
Reaction time: 16 h

Procedure:
To a solution of methyl 3-bromo-2-chlorobenzoate (1.9 g, 7.6 mmol) in THF (30 mL) was added Super Hydride (23 mL, 23 mmol) at 0° C. The reaction was allowed to stir for 16 hours. TLC showed clean reaction. The reaction was diluted with EtOAc, washed with brine, dried over sodium sulfate, and purified by MPLC to furnish (3-bromo-2-chlorophenyl)methariol. LC-MS (IE, m/z): 205 [M-17]+;
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:17][C:16]2[C:11](=[C:12]([OH:19])[CH:13]=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[C:27]1[CH:38]=[CH:37][CH:36]=[CH:35][C:28]=1[C:29]([O:31][CH2:32][CH:33]=[CH2:34])=[O:30].C(OCC)(=O)C.CCCCCC>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@:9]1([C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:17][C:16]2[C:11](=[C:12]([O:19][C:27]3[CH:38]=[CH:37][CH:36]=[CH:35][C:28]=3[C:29]([O:31][CH2:32][CH:33]=[CH2:34])=[O:30])[CH:13]=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@]1(NC(=O)OC(C)(C)C)CCc2cccc(O)c2C1
Reactant: C=CCOC(=O)c1ccccc1I
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=CCOC(=O)c1ccccc1Oc1cccc2c1C[C@](NC(=O)OC(C)(C)C)(C(=O)OC)CC2
Yield: 79.5 %

Procedure:
In analogy to Example 4.1.a, 2.5 g (7.78 mmol) of methyl (S)-2-(tert.butoxycarbonylamino)-8-hydroxy-1,2,3,4-tetrahydronaphthalene-2-carboxylate in 5 ml of pyridine were reacted at 130° for 2 hours with 370 mg of sodium hydride dispersion, 2.23 g (10.9 mmol) of copper bromide-dimethyl sulphide complex and 4.48 g (15.56 mmol) of prop-2-enyl 2-iodobenzoate. After chromatography on 500 g of silica gel with ethyl acetate/hexane (1:9→1:1) there were obtained 2.98 g (80%) of methyl (S)-2-(tert.butoxycarbonylamino)-8-[2-(prop-2-enyloxycarbonyl)phenoxy]-1,2,3,4-tetrahydronaphthalene-2-carboxylate as a viscous oil. [α]D ==57.0° (c=0.4, chloroform
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:11]=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[BH3-]C#N.[Na+].C(O)(=O)C>ClCCCl>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:11][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: O=CC1(c2ccc(I)cc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Ic1ccc(C2(CN3CCOCC3)CC2)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 1-(4-iodophenyl)cyclopropanecarbaldehyde (7 g, 0.025 mol) in 1,2-Dichloroethane (100 mL) is added morpholine (4.5 mL, 0.051 mol) in drops at 0° C. . After 10 min, NaBH3CN (3.2 g, 30 mmol) is added in a portion wise fashion at 0° C. followed by acetic acid (500 μL). The reaction mixture is stirred for another 1 h at same temperature and then at Rt for 10 h. After this time, the reaction mixture is quenched with 10% sodium bicarbonate and extracted with EtOAc. The combined organic layer is washed with water, brine, dried over sodium sulphate and evaporated. The crude product is purified by column chromatography (pet ether and EtOAc) to afford the title compound as colourless liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.60-7.56 (m, 2H), 7.13-7.08 (m, 2H), 3.47-3.43 (m, 4H), 2.50-2.46 (m, 2H), 2.34 (bs, 4H) 0.0.80-0.77 (m, 2H),0.72-00.69 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH2:8])=[O:7].[N-:14]=[N+:15]=[N-:16].[Na+].Cl.C([N:21]([CH2:24][CH3:25])CC)C.Cl>CN1CCCC1=O.O>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:3]1[CH:2]=[CH:12][CH:11]=[C:25]([C:24]2[NH:21][N:16]=[N:15][N:14]=2)[CH:9]=1)=[O:7]
Reactant: CCN(CC)CC
Reactant: [N-]=[N+]=[N-]
Reactant: NC(=O)COc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(-c2nnn[nH]2)c1
Temperature: 150 °C
Reaction time: 8 h
Yield: 142.8 %

Procedure:
A mixture of N-(3-cyano-phenyl)-2-(2,4-dichloro-phenoxyacetamide (70.0 mg, 0.22 mmol), sodium azide (42.9 mg, 0.66 mmol) and triethylamine hydrochloride (45.4 mg, 0.33 mmol) in N-methylpyrrolidone (6 ml) (NMP) was stirred at 150° C. under nitrogen overnight. After cooling, the reaction mixture was diluted with water, acidified to PH 1 with 10% v/v hydrochloric acid, and extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (CH2CH2:MeOH=3:1) to give 2-(2,4-dichloro-phenoxy)-N-[3-(1H-tetrazole-5-yl)-phenyl]-acetamide as a solid (57.2 mg, 71.6% yield).
Reaction SMILES: [ClH:1].[NH:2]1[CH2:7][CH2:6][CH:5]([CH:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:17])[CH2:4][CH2:3]1.[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[CH2:19].O.O.O.C([O-])(=O)C.[Na+].O>CO>[ClH:1].[ClH:1].[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:18][CH2:19][N:2]1[CH2:3][CH2:4][CH:5]([CH:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:17])[CH2:6][CH2:7]1
Reactant: C=Cc1ccccn1
Reactant: O=C1c2ccccc2CC1C1CCNCC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1c2ccccc2CC1C1CCN(CCc2ccccn2)CC1

Procedure:
A mixture of 0.251 g (0.001 mol) of 2-(4-piperidyl)-1-indanone hydrochloride, 0.21 g (0.002 mol) of 2-vinylpyridine, 0.272 g (0.002 mol) sodium acetate trihydrate, 2 mL of water, and 2 mL of methanol was stirred and refluxed for 20 hours. The solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate and dried over magnesium sulfate. The product was isolated in pure form by chromatography on silica gel using 5% methanol in chloroform. A hydrochloride salt was prepared and was recrystallized from ethanol to give 2-[1-(2-pyridylethyl)-4-piperidyl]-1-indanone dihydrochloride, mp 195°-196° C.