Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC[C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:11]=2)=[O:8])=[CH:5][CH:4]=1.CC(O)=O.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:45][N:46]([CH:48]=O)[CH3:47]>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([CH2:48][N:46]([CH3:45])[CH3:47])=[CH:24][CH:23]=2)=[CH:11][C:12]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: NCc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Reactant: CN(C)C=O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(C)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
4-(aminomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide (80 mg) was dissolved in DMF (5 mL) and treated with AcOH (10 □L), paraformaldehyde (48 mg), and sodium triacetoxyborohydride (125 mg) for 16 h. The reaction mixture was concentrated, and the crude residue was dissolved in ethyl acetate and washed with 1 N sodium hydroxide, dried (MgSO4) and concentrated. The crude product was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((dimethylamino)methyl)benzamide. MS (Q1) 365.0 (M)+.
Reaction SMILES: ClCC([O:5][C:6]1[CH:14]=[CH:13][C:12]2[N:11]([CH3:15])[C:10]3[C:16](=[O:19])[CH2:17][CH2:18][C:9]=3[C:8]=2[CH:7]=1)=O.[OH-].[Na+]>CCO>[OH:5][C:6]1[CH:14]=[CH:13][C:12]2[N:11]([CH3:15])[C:10]3[C:16](=[O:19])[CH2:17][CH2:18][C:9]=3[C:8]=2[CH:7]=1
Reactant: Cn1c2c(c3cc(OC(=O)CCl)ccc31)CCC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c2c(c3cc(O)ccc31)CCC2=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7-Chloroacetyloxy-1,4-dihydro-4-methylcyclopent[b]indol-3(2H)-one (5.0 g) was suspended in EtOH (100 ml), and thereafter 10% NaOH solution (50 ml) was added and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo, CH2Cl2 (100 ml) was added followed by 10% HCl until the aqueous layer was neutralized. The layers were separated and the aqueous phase extracted with CH2Cl2 (2×100 ml). The organic portion was dried (Na2SO4) and concentrated and the residue was recrystallized from 95% EtOH to provide 1,4-dihydro-7-hydroxy-4-methylcyclopent[b]indol-3(2H)-one as an off-white solid. The phenol was dissolved in CH2Cl2 (100 ml), and thereafter 1,8-diazabicyclo[5.4.0]undec-7-ene (0.4 g) was added followed by methyl isocyanate (1.4 g) and the mixture was stirred overnight. The mixture was concentrated in vacuo to afford an oily solid which was crystallized from EtOH to provide 1,4-dihydro-7-methylaminocarbonyloxy-4-methylcyclopent[b] indol-3(2H)-one (1.1 g).
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=O)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].[OH:17][CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)[CH2:19][NH2:20]>>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:20][CH2:19][CH:18]([OH:17])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:30])[F:28])[CH:22]=2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2]
Reactant: NCC(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)COc1ccc(CC(C)=O)cc1
Product: COC(=O)COc1ccc(CC(C)NCC(O)c2cccc(C(F)(F)F)c2)cc1

Procedure:
The compound was prepared as in Example 5 from 1-(4-carbomethoxymethoxyphenyl)propan-2-one (2.22 g) and 2-hydroxy-2-(3-trifluoromethylphenyl) ethanamine (2.05 g). The compound crystallised from hexane m.p. 70°-85° as a 1:1 mixture of diastereoisomers.
Reaction SMILES: Cl.[CH2:2]([NH:9][OH:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:11]([O-:14])(=O)[CH3:12].[Na+].C=O.C(O)/[CH:19]=[CH:20]\[CH2:21][OH:22]>C(O)C>[CH2:2]([N:9]1[CH2:19][CH:20]([CH2:21][OH:22])[CH:12]([CH2:11][OH:14])[O:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OC/C=C\CO
Reactant: CC(=O)[O-]
Reactant: ONCc1ccccc1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: OCC1CN(Cc2ccccc2)OC1CO
Reaction time: 0.5 h

Procedure:
A mixture of N-benzylhydroxylamine hydrochloride (13.59 g, 85.15 mmol) and sodium acetate (9.31 g, 114 mmol) were stirred together in ethanol (75 mL) at rt for 15 mins. Aqueous 37% formaldehyde solution (12.68 ml, 170 mmol) was added and stirring continued for 30 mins, then cis-2-butene-1,4-diol (4.67 ml, 56.8 mmol) added and the mixture heated under reflux for 16 h. The solvent was evaporated and the residue dissolved in CHCl3 and washed with aq. sat. NaHCO3, dried (MgSO4) and the solvent evaporated to give a brown syrup suitable for use without further purification (12.5 g, 98%). An aliquot was purified by chromatography on silica gel (EtOAc then EtOAc-MeOH, 95:5) to give ((4RS,5RS)-2-benzylisoxazolidine-4,5-diyl)dimethanol as a colourless syrup. 13C NMR (CDCl3, referenced to the centre line of CDCl3 at 77.0 ppm) δ 136.5, 129.0, 128.4, 127.6, 78.5, 62.4, 61.3, 60.4, 56.8, 45.8.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]=1[O:16]C)([CH3:3])[CH3:2].O.C(OCC)C>C(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]=1[OH:16])([CH3:3])[CH3:2]
Reactant: COc1c(-c2ccccc2)cccc1C(C)C
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)c1cccc(-c2ccccc2)c1O
Reaction time: 12 h
Yield: 94 %

Procedure:
A mixed solution of 8 mL of water and 32 mL of dimethoxyethane was added into a flask into which 2-bromo-6-isopropylanisole (1.98 g, 8.64 mmol), phenylboronic acid (2.10 g, 17.28 mmol), palladium acetate (96 mg, 0.43 mmol), triphenylphosphine (0.225 g, 0.86 mmol), and potassium phosphate (11 g, 51.84 mmol) were already added, and then refluxed at normal temperature for 12 hours. After cooling to normal temperature, an ammonium chloride aqueous solution (15 mL) and 30 mL of diethylether were added thereto to separate an organic layer and extract residues using diethylether. The separated organic layer was dried with magnesium sulfate and volatile materials were removed to produce 2 g of grey 2-isopropyl-6-phenylanisole solid. The anisole thus produced was dissolved in 15 mL of methylene chloride without separate purification, 12 mL of boron tribromide (1 M methylene chloride solution) were dropped thereonto at −78° C., and the reaction was carried out for 12 hours while the temperature was slowly increased to normal temperature. After the reaction, a mixed solution of water (15 mL) and diethylether (30 mL) was added to separate an organic layer and extract an aqueous solution layer using diethylether (15 mL×3), and the separated organic layer was dried. Residues from which volatile components were removed at reduced pressure were purified using a silica gel chromatography tube in a mixed solvent of hexane and methylene chloride to produce 1.72 g of white 2-isopropyl-6-phenylphenol solid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]3[CH:16]=[CH:17][C:18](=[O:21])[NH:19][N:20]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.CO.[C:24]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25]1.C([BH3-])#N.[Na+]>CN(C=O)C.C(O)(=O)C>[CH:24]1([N:2]2[CH2:3][CH2:4][CH:5]([O:8][C:9]3[N:14]=[CH:13][C:12]([C:15]4[CH:16]=[CH:17][C:18](=[O:21])[NH:19][N:20]=4)=[CH:11][CH:10]=3)[CH2:6][CH2:7]2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=c1ccc(-c2ccc(OC3CCNCC3)nc2)n[nH]1
Reactant: O=C1CCCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CC(=O)O
Product: O=c1ccc(-c2ccc(OC3CCN(C4CCCC4)CC3)nc2)n[nH]1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
6-[6-(piperidin-4-yloxy)-pyridin-3-yl]-2H-pyridazin-3-one hydrochloride (407 mg, 1.18 mmol) in a mixture of DMF (5 mL), methanol (15 mL), and acetic acid (250 μL) was added cyclopentanone (314 μL, 3.54 mmol), followed by sodium cyanoborohydride (371 mg, 5.9 mmol). After stirring at 60° C. for 2 h, the reaction was concentrated, partitioned between dichloromethane/1N sodium carbonate, washed with water/brine, dried over sodium sulfate, and concentrated. The product was purified using prep TLC plates (9:1 dichloromethane:methanol) (25%); Mp 233-237° C.; MS m/z 341 (M+H).
Reaction SMILES: CN1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][CH2:15][C:16]3[CH:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[O:25]1CCC(=O)CC1.CN1CCC(=O)CC1>>[CH3:13][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:14][CH2:15][C:16]3[CH:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=3)[C:5]3[CH2:23][CH2:24][O:25][CH2:3][C:4]=3[C:12]=2[CH:11]=1
Reactant: O=C1CCOCC1
Reactant: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(C)C1
Agent: CN1CCC(=O)CC1
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCOC1

Procedure:
8-Methyl-5-[2-(6-methyl-pyridin-3-yl)-ethyl]-1,3,4,5-tetrahydro-pyrano[4,3-b]indole is prepared in an analagous manner to Dimebon, except that tetrahydro-pyran-4-one is used in the final step in place of 1-methyl-piperidin-4-one.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]#[C:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[N+:19]([O-])([OH:21])=[O:20].O>C(O)(=O)C>[Cl:1][C:2]1[C:3]([C:13]#[C:14][Si:15]([CH3:16])([CH3:18])[CH3:17])=[C:4]([N+:19]([O-:21])=[O:20])[C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1cc(Cl)c(C#C[Si](C)(C)C)cc1O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)c(C#C[Si](C)(C)C)c([N+](=O)[O-])c1O
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
A solution of methyl 5-chloro-2-hydroxy-4-[(trimethylsilyl)ethynyl]benzoate (15 g, 53 mmol) in acetic acid (110 mL) at 55° C. was treated with a solution of nitric acid (7.8 mL, 190 mmol) in acetic acid (7.8 mL, 140 mmol) dropwise and stirred at 55° C. for 30 minutes. The reaction mixture contained only starting material and was treated with an additional solution of nitric acid (2.2 mL, 53 mmol) in acetic acid (2.2 mL, 39 mmol) dropwise and stirred at 55° C. for 1.5 hour. The reaction mixture was cooled to 0° C. and treated with ice followed by cold water. The reaction mixture was stirred until the ice melted, filtered, washed with cold water, and air dried to give the desired product (11.7 g, 67%) as a tan solid. This material was used without further purification. LCMS for C13H15ClNO5Si (M+H)+: m/z=328.0; Found: 327.8.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][OH:17])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][O:17][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: OCc1ccc(Cl)cc1
Product: O=[N+]([O-])c1cnccc1OCc1ccc(Cl)cc1
Yield: 78 %

Procedure:
In accordance with the same procedures as in Preparation 2, except for using 4-chloro-3-nitropyridine prepared in Step 1 of Preparation 1 and 4-chlorobenzyl alcohol, the titled compound was obtained as a white solid. (Yield: 78.0%)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].N1CCCC1.[C:16]([C:20]1[CH:34]=[CH:33][C:23]([C:24]([N:26]2[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]2)=[O:25])=[CH:22][C:21]=1[O:35][CH3:36])([CH3:19])([CH3:18])[CH3:17]>CO>[C:16]([C:20]1[CH:34]=[CH:33][C:23]([C:24]([N:26]2[CH2:31][CH2:30][C:29]3([CH2:9][C:8](=[O:10])[C:3]4[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=4)[O:1]3)[CH2:28][CH2:27]2)=[O:25])=[CH:22][C:21]=1[O:35][CH3:36])([CH3:19])([CH3:17])[CH3:18]
Reactant: COc1cc(C(=O)N2CCC(=O)CC2)ccc1C(C)(C)C
Reactant: CC(=O)c1ccccc1O
Solvent: CO
Solvent: C1CCNC1
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2ccccc2O3)ccc1C(C)(C)C
Temperature: 80 °C
Yield: 93.7 %

Procedure:
1-(2-Hydroxyphenyl)ethanone (260 μL, 2.2 mmol) was added portion-wise at room temperature to pyrrolidine (370 μL, 4.4 mmol) followed by portion-wise addition of 1-(4-tert-butyl-3-methoxy-benzoyl)piperidin-4-one (630 mg, 2.2 mmol). Anhydrous methanol (140 μL) was added and the slurry was heated at 80° C. for 3 h. The mixture was then partitioned between ethyl acetate and 1M aqueous HCl. The layers were separated and the aqueous layer was discarded. Saturated aqueous sodium bicarbonate was added and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (0-25% ethyl acetate/hexanes) to give 1′-(4-tert-butyl-3-methoxybenzoyl)spiro[chroman-2,4′-piperidin]-4-one (840 mg, 94%) as a light yellow solid. ESI-MS m/z calc. 407.2. found 408.2 (M+1)+; Retention time: 2.07 minutes (3 min run).
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH2:18][C:19]([CH3:22])(C)[CH3:20])[C:11]([CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:10]2OCCCC)(=O)=O.[C:37]1(=[O:47])[NH:41][C:40](=[O:42])[C:39]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:38]12.[K].O>CN(C)C=O>[C:28]([O:27][C:25](=[O:26])[NH:24][CH2:23][C:11]1[N:12]([CH2:18][CH:19]([CH3:20])[CH3:22])[C:13](=[O:17])[C:14]2[C:9]([C:10]=1[C:7]1[CH:8]=[CH:9][CH:14]=[CH:15][CH:16]=1)=[CH:8][C:7]([CH2:6][N:41]1[C:37](=[O:47])[C:38]3[C:39](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:40]1=[O:42])=[CH:16][CH:15]=2)([CH3:29])([CH3:31])[CH3:30]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)(C)C)c(=O)c2ccc(COS(C)(=O)=O)cc12
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CN3C(=O)c4ccccc4C3=O)ccc2c1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 165.9 %

Procedure:
To a solution of (3-{[(tert-butoxycarbonyl)amino]methyl}-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl)methyl methanesulfonate (1.1 g, 2.11 mmol) in N,N-dimethylformamide (20 mL) was added potassium phthalimide (0.47 g, 2.5 mmol), and the mixture was stirred at room temperature for 17 h. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (100 mL×2). The organic layers were combined, washed with 0.2N hydrochloric acid (100 mL), saturated aqueous sodium hydrogencarbonate (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:2 (v/v)) to give tert-butyl{6-[(1,3-dioxo-1,3-dihydro-2H -isoindol-2-yl)methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl}methylcarbamate (0.99 g, 84%) as colorless crystals.
Reaction SMILES: [NH:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH3:8].[CH3:9][N:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11](Cl)=[O:12]>C1C=CC=CC=1>[CH3:9][N:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([N:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH3:8])=[O:12]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CN1CCCCC1=N
Solvent: c1ccccc1
Product: CN1CCCCC1=NC(=O)N(C)c1ccccc1
Temperature: 25 °C

Procedure:
The hydrochloride salt of 2-imino-1-methylpiperidine (14.8 g.; 0.1 mole) is converted to free base by adding 10 ml. of 50% NaOH and extracting into benzene. After drying over K2CO3, the benzene layer is stirred at room temperature and 8.84 g. (0.05 mole) of N-methyl-phenylcarbamoyl chloride (prepared according to the method of J. A. Aeschlimann, U.S. Pat. No. 2,449,440), dissolved in anhydrous benzene, is added dropwise to this solution. The mixture is stirred at room temperature overnight (about 17 hours) and then filtered. The filtrate is taken to dryness in vacuo and the residue is dissolved in and recrystallized from hexane to give the product, 1-methyl-3-(1-methyl-2-piperidylidene)-1-phenylurea.
Reaction SMILES: C(SCCCC)CCC.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Li].[C:17]([O:21][C:22](=[O:36])[CH:23]=[CH:24][CH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[C:33]([CH3:35])[CH:34]=1)[NH:31][N:30]=[CH:29]2)([CH3:20])([CH3:19])[CH3:18]>CCOCC>[C:17]([O:21][C:22](=[O:36])[CH2:23][CH:24]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=1)[CH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[C:33]([CH3:35])[CH:34]=1)[NH:31][N:30]=[CH:29]2)([CH3:19])([CH3:20])[CH3:18]
Reactant: Cc1cc(CC=CC(=O)OC(C)(C)C)cc2cn[nH]c12
Reactant: [Li]c1ccccn1
Solvent: CCCCSCCCC
Solvent: CCOCC
Product: Cc1cc(CC(CC(=O)OC(C)(C)C)c2ccccn2)cc2cn[nH]c12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a 50-mL oven-dried flask was added di-n-butylsulfide (261 mg, 1.781 mmol, 6.4 equiv) and cuprous iodide (170 mg, 0.891 mmol, 3.2 equiv) under nitrogen. Anhydrous ether (1 mL) was added and the suspension was cooled to 0° C. before the solution of 2-pyridinyl lithium was added via canuula. A yellowish brown precipitate was formed. After stirring at 0° C. for 15 min, the cooling bath was removed and 4-(7-methyl-1H-indazol-5-yl)-but-2-enoic acid tert-butyl ester (75.8 mg, 0.278 mmol, 1.0 equiv) in anhydrous ether (1 mL) was added via syringe. The dark solution was stirred at room temperature for 40 min. LCMS indicated the formation of the desired product. The reaction mixture was then partitioned between an aqueous ammonium hydroxide/ammonium chloride solution and ethyl acetate (upon shaking, the solids gradually dissolved to a blue aqueous solution). The layers were separated and the organic layer was washed with water, brine, dried over sodium sulfate and concentrated in vacuo to an oil. Careful flash column chromatography (5% methanol in methylene chloride) afforded the desired product (10.4 mg, 11%) which was carried on without farther purification. MS (ESI) 352 (M H)+, 296 (M-tBu)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:9]=2)=[N:6][CH:7]=1.[CH2:22]([O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.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.O>[CH2:15]([O:14][C:10]1[CH:9]=[C:8]([C:5]2[N:4]=[CH:3][C:2]([C:34]3[CH:35]=[CH:36][C:31]([O:30][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:32][CH:33]=3)=[CH:7][N:6]=2)[CH:13]=[CH:12][CH:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Brc1cnc(-c2cccc(OCc3ccccc3)c2)nc1
Reactant: CCCCCCCCOc1ccc(B(O)O)cc1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCOc1ccc(-c2cnc(-c3cccc(OCc4ccccc4)c3)nc2)cc1
Yield: 97.6 %

Procedure:
8.00 g (23.40 mmol) of 5-bromo-2-(3-benzyloxyphenyl)pyrimidine, 7.03 g (28.10 mmol) of 4-octyloxybenzeneboronic acid (preparation analogous to 3-benzyloxybenzeneboronic acid), 7.00 g (65.52 mmol) of sodiumcarbonate and 0.27 g (0.23 mmol) of tetrakis(triphenylphosphine)palladium(0) are heated at 80° C. for 2 hours in 200 ml of toluene, 100 ml of ethanol and 50 ml of water. The reaction mixture is subsequently partitioned between water and ether, the organic phase is washed twice with sodium chloride solution, dried over sodium sulfate and evaporated, and the residue is purified by chromatography (silica gel/dichloromethane: ethyl acetate=98:2), giving 10.66 g of 2-(3-benzyloxyphenyl)-5-(4-octyloxyphenyl)pyrimidine. ##STR15## 10.66 g (22.84 mmol) of 2-(3-benzyloxyphenyl)-5-(4-octyloxyphenyl)pyrimidine are hydrogenated together with 2.00 g of Pd (10%)/C in 100 ml of tetrahydrofuran until the calculated volume of hydrogen has been consumed, the catalyst is subsequently filtered off, and the filtrate is evaporated and dried, giving 8.43 g of 2-(3-hydroxyphenyl)-5-(4-octyloxyphenyl)pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][S:14][CH2:13][CH:12]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)[NH:11]2)=[CH:4][C:3]=1[O:26][CH3:27].Br[CH:29](Br)[CH3:30].C(N(CC)CC)C>CC(N(C)C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:30][CH2:29][N:11]3[CH:10]([CH2:15][S:14][CH2:13][CH:12]3[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)[CH2:9]2)=[CH:4][C:3]=1[O:26][CH3:27]
Reactant: CC(Br)Br
Reactant: COc1cc(NCC2CSCC(c3ccc(OC)c(OC)c3)N2)ccc1Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COc1cc(N2CCN3C(CSCC3c3ccc(OC)c(OC)c3)C2)ccc1Cl
Temperature: 90 °C
Reaction time: 4 h
Yield: 31.9 %

Procedure:
A solution of (4-chloro-3-methoxy-phenyl)-[5-(3,4-dimethoxy-phenyl)-thiomorpholin-3-ylmethyl]-amine (100 mg, 0.245 mmol, 1.0 equivalents), dibromoethane (0.31 ml, 3.55 mmol, 14.5 equivalents) and triethylamine (0.15 ml, 1.09 mmol, 4.5 equivalents) in dimethylacetamide (2 ml) was heated at 90° C. for 4 hours. Additional dibromoethane (0.16 ml, 1.84 mmol, 7.5 equivalents) and triethylamine (0.25 ml, 1.76 mmol, 7.2 equivalents) was added and reaction was stirred for 4 hours at 90° C. Additional dibromoethane (0.14 ml, 1.62 mmol, 6.6 equivalents) and triethylamine (0.10 ml, 0.71 mmol, 2.9 equivalents) were added and reaction was stirred 18 hours at 90° C. Reaction was cooled and filtered to remove triethylammonium hydrobromide. Filtrate was concentrated. Residue was purified on a 1000 micron preparative TLC. 34 mg of 8-(4-chloro-3-methoxy-phenyl)-4-(3,4-dimethoxy-phenyl)-octahydro-pyrazino[2,1-c][1,4]thiazine (Compound 8) was obtained, along with 36 mg recovered starting material. Yield of product: 32%. H1 NMR (400 MHz, CDCl3): 7.19 (1H, d), 6.86 (3H, m), 6.42 (2H, m), 3.89 (3H, s), 3.88 (3H, s), 3.86 (3H, s), 3.50 (1H, m), 3.19 (2H, dd), 2.92 (1H, m), 2.75 (5H, m), 2.48 (2H, t), 2.15 (1H, dt). MS (LC-MS): Calculated for C22H27ClN2O3S 435.14, 435.24.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:21])=O)=[CH:17][C:18]=4[N:9]3[CH:8]=[CH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C1N=C[N:24](C(N2C=NC=C2)=O)C=1.CNC(N)=O.C(O)(C(F)(F)F)=O>>[CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH2:24])=[O:21])=[CH:17][C:18]=4[N:9]3[CH:8]=[CH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc2cc3n(c2c1)C=CCc1ccccc1-3
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC(N)=O
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ccc2cc3n(c2c1)C=CCc1ccccc1-3

Procedure:
(5H-indolo[2,1-a][2]benzazepine-10-carboxamide, 13-cyclohexyl-N-[(dimethylamino)sulfonyl]-6,7-dihydro-6-[[(3-methoxycyclohexyl)carbonyl]methylamino]-) was prepared from (5H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6,7-dihydro-6-[[(3-methoxycyclohexyl)carbonyl]methylamino]-) using CDI as a coupling reagent in a similar manner as described before; Analytical HPLC method: Solvent A=10% MeO{tilde over (H)}90% H2Õ0.1% TFA, Solvent B=90% MeO{tilde over (H)}10% H2Õ0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Flow Rate=5 ml/min, Column: Xterra MS C18 S7 3.0×50 mm; LC/MS: (ES+) m/z (M+H)+=635.32, HPLC Rt=2.042 min.