Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][C:17]=1[C:24]([F:27])([F:26])[F:25]>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:18][C:17]=1[C:24]([F:25])([F:26])[F:27]
Reactant: OCc1ccc(Cl)c(C(F)(F)F)c1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Cl)c(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-chloro-3-(trifluoromethyl)phenyl]methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.25 (2H, s), 5.76 (1H, d, J=1.6 Hz), 7.42 (1H, dd, J=1.6, 5.2 Hz), 7.54 (2H, s), 7.58 (1H, d, J=2.0 Hz), 7.89 (1H, s), 8.00 (1H, s), 8.06 (1H, s), 8.69 (1H, d, J=4.8 Hz). [M+H] Calc'd for C17H10ClF3N4O, 379. Found, 379.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.C(O)(=O)C.[Br:13][C:14]1[C:20]([CH3:21])=[CH:19][C:17]([NH2:18])=[C:16]([O:22][CH3:23])[C:15]=1[F:24]>[Cl-].[Na+].O>[Br:13][C:14]1[C:20]([CH3:21])=[C:19]([I:1])[C:17]([NH2:18])=[C:16]([O:22][CH3:23])[C:15]=1[F:24]
Reactant: COc1c(N)cc(C)c(Br)c1F
Reactant: O=C1CCC(=O)N1I
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1c(N)c(I)c(C)c(Br)c1F
Temperature: 25 °C
Reaction time: 67 h

Procedure:
N-iodosuccinimide (1.91 g, 8.5 mmol) was added to an acetic acid (40 ml) solution of 4-bromo-3-fluoro-2-methoxy-5-methylaniline (I-43) (1.90 g, 8.1 mmol), followed by stirring at room temperature for 67 hours. Saturated brine was added to the reaction liquid, followed by extraction twice with ethyl acetate, the organic layer was washed three times with saturated brine, dried over anhydrous magnesium sulfate.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:15]=[CH:14][C:11]([CH2:12][O-:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na+].[C:17]1([CH2:23][CH2:24][CH2:25]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[C:17]1([CH2:23][CH2:24][CH2:25][O:13][CH2:12][C:11]2[CH:10]=[CH:9][C:8]([CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:15][CH:14]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [O-]Cc1ccc(CN2CCCCC2)cc1
Reactant: BrCCCc1ccccc1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc(CCCOCc2ccc(CN3CCCCC3)cc2)cc1

Procedure:
4-(Piperidinomethyl)benzoic acid methyl ester (22 mmol) in dry tetrahydrofurane was added dropwise to a suspension of 44 mmol of lithium aluminium hydride in 30 ml of dry tetrahydrofurane at 0° C. After refluxing for 2 hours a saturated solution of ammonium chloride in water was added dropwise. After stirring for 12 hours at ambient temperature the organic layer was isolated and the aqueous layer extracted with methylene chloride. The organic extracts were combined and the solvent was evaporated under reduced pressure. The residue was crystallized with maleic acid from diethyl ether/2-propanol (Yield: 91%). Sodium 4-(piperidinomethyl)benzyl alcoholate (5 mmol) and 6 mmol of 3-phenylpropyl bromide in 10 ml of dry toluene were refluxed for 6 hours. The solvent was evaporated under reduced pressure. The residue was purified by rotatory chromatography on silica gel using methylene chloride/ammonia atmosphere as eluent. The product was crystallized with oxalic acid from diethyl ether/ethanol.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[CH3:27][C:28]1[NH:29][C:30]([NH:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[N:31][N:32]=1>>[CH3:27][C:28]1[N:29]=[C:30]2[N:33]([CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[C:17](=[O:18])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:22]([CH2:23][CH2:24][CH3:25])[N:31]2[N:32]=1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Reactant: Cc1nnc(NC2CCOCC2)[nH]1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOCC2)c2nc(C)nn12
Temperature: 250 °C
Reaction time: 0.25 h
Yield: 48.1 %

Procedure:
A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (0.87 g) and 5-methyl-N-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine (0.3 g) was stirred at 250° C. for 15 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.37 g, 48%).
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[O:19][C:18]([NH2:20])=[N:17][N:16]=3)=[CH:11][CH:10]=2)[CH:3]=1.[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>N1C=CC=CC=1.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[O:19][C:18]([NH:20][C:27](=[O:28])[C:26]4[CH:30]=[CH:31][CH:32]=[C:24]([O:23][C:22]([F:21])([F:33])[F:34])[CH:25]=4)=[N:17][N:16]=3)=[CH:13][CH:14]=2)[CH:3]=1
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Reactant: Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1
Agent: Br
Solvent: CO
Solvent: c1ccncc1
Product: O=C(Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1)c1cccc(OC(F)(F)F)c1
Reaction time: 3 h
Yield: 17.5 %

Procedure:
5-[4-(Pyridin-3-yloxy)phenyl]-1,3,4-oxadiazol-2-amine hydrobromide salt (167.5 mg, 0.5 mmol) was suspended in 2 mL of anhydrous pyridine. Neat 3-trifluoromethoxybenzoyl chloride (117 uL) was added directly into the solution. The reaction mixture formed an orange-red solution with a small amount of white precipitate. It was left to stir for 3 hours. Then it was diluted with ca. 1 mL of MeOH, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetonitrile/water mixture containing 0.01% of TFA. Fractions, containing the product, were combined and partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated aqueous NaHCO3. The EtOAc layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title product as a yellow solid (38.8 mg). Yield 17.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH2:17](O)[CH3:18]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([O:6][CH2:17][CH3:18])=[O:5]
Reactant: CCO
Reactant: Cc1ccc(Cl)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(C)ccc1Cl
Yield: 96 %

Procedure:
To a solution of 2-chloro-5-methylbenzoic acid (7.62 mmol, 1.30 g) in ethanol (16 ml), H2SO4 (35 mmol, 1.82 ml) was added and the mixture was refluxed for 20 hours. The solvent was evaporated and the crude residue was dissolved in water. The solution neutralised with 6N NaOH aqueous solution and extracted with CHCl3. The organic phase was evaporated affording 1.46 g (yield 96%) of the expected product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1[NH2:9].[CH:10]([N:13]=[C:14]=[S:15])([CH3:12])[CH3:11].[H-].[Na+]>CN(C=O)C>[Cl:8][C:6]1[N:5]=[CH:4][C:3]2[N:9]=[C:14]([NH:13][CH:10]([CH3:12])[CH3:11])[S:15][C:2]=2[CH:7]=1
Reactant: CC(C)N=C=S
Reactant: Nc1cnc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Nc1nc2cnc(Cl)cc2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.5 %

Procedure:
To a solution of 4,6-dichloropyridin-3-amine (0.50 g, 3.07 mmol, 1.0 eq.) and isopropyl isothiocyanate (0.33 mL, 3.10 mmol, 1.0 eq.) in DMF under nitrogen at 0° C. was added NaH (60% in mineral oil, 0.194 g, 4.85 mmol, 1.6 eq.). After 10 min., the cold bath was removed, and the reaction mixture was stirred to room temperature for 10 min. It was then heated at 65° C. for 1 hr and cooled to room temperature. At 0° C., aqueous HCl (1 N), water and EtOAc were added, and the reaction mixture was stirred. The layers were separated, and the organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo. Silica gel chromatography using CH2Cl2:MeOH (100:1) as eluent afforded 6-chloro-N-isopropylthiazolo[4,5-c]pyridin-2-amine as a white solid (0.43 g, 61% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[C:18]1([N:24]=[C:25]=[S:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([NH:24][C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[S:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: S=C=Nc1ccccc1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=S)Nc4ccccc4)cc3c2C1
Yield: 45.2 %

Procedure:
Beginning with 10.0 mg (0.0437 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 11.8 mg (0.0874 mMol) phenyl isothiocyanate, 7.2 mg (39%) of the title compound were recovered.
Reaction SMILES: Cl[C:2]1C=C(SC2C3C(=CC(C)=CC=3)NC=2CCC(N)=O)C=C(Cl)C=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][C:40]=3[CH3:42])[NH:35][C:34]=2[C:43]([OH:45])=[O:44])=[CH:28][CH:27]=1.C(Cl)(=O)C(Cl)=O.CO>C1COCC1>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][C:40]=3[CH3:42])[NH:35][C:34]=2[C:43]([O:45][CH3:2])=[O:44])=[CH:30][CH:31]=1
Reactant: Cc1cccc2[nH]c(C(=O)O)c(Sc3ccc(Cl)cc3)c12
Reactant: Cc1ccc2c(Sc3cc(Cl)cc(Cl)c3)c(CCC(N)=O)[nH]c2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1[nH]c2cccc(C)c2c1Sc1ccc(Cl)cc1
Yield: 81 %

Procedure:
Following the method used to prepare 24a, the use of 1a (0.19 mmol) and oxalyl chloride in THF followed by allowing the intermediate acid chloride to react with MeOH (3 mL) provided 52 mg (81%) of product 9 as a white solid, mp 192-193° C. 1H NMR (300 MHz, DMSO-d6) δ 2.57 (s, 3H), 3.84 (s, 3H), 6.88 (d, J=7 Hz, 1H), 6.95-6.98 (m, 2H), 7.24 (t, J=8 Hz, 1H), 7.26-7.29 (m, 2H), 7.41 (d, J=9 Hz, 1H), 12.52 (s, 1H). LC-MS (CI): m/z 332.1 [(M+H)+ C17H14ClNO2S requires 331.04]. Purity (100%). Calcd for C17H14ClNO2S: C, 61.53; H, 4.25; N, 4.22; S, 9.66; Cl, 10.68. Found: C, 61.25; H, 4.24; N, 4.14; S, 9.56; Cl, 10.64.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([C:23](=[O:25])[CH3:24])[C:5]([OH:22])=[C:6]([O:10][CH2:11][CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH3:14])[C:7]=1[O:8][CH3:9].[Br:27][CH2:28][CH2:29][CH2:30]Br>>[Br:27][CH2:28][CH2:29][CH2:30][O:22][C:5]1[C:6]([O:10][CH2:11][CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH3:14])=[C:7]([O:8][CH3:9])[C:2]([Cl:1])=[C:3]([CH3:26])[C:4]=1[C:23](=[O:25])[CH3:24]
Reactant: BrCCCBr
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(O)c1OCCC(C)c1ccc(F)cc1
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCCBr)c1OCCC(C)c1ccc(F)cc1

Procedure:
Example 7c (179 mg, 0.47 mmol) was reacted with 1,3-dibromopropane (10.0 eq.) as described under General Procedure F to afford the title compound (641 mg, quantitative yield) as a light yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.19-7.15 (m, 2H), 7.01-6.95 (m, 2H), 4.10 (t, J=5.9 Hz, 2H), 3.94 (t, J=6.7 Hz, 2H), 3.84 (s, 3H), 3.49 (t, J=6.5 Hz, 2H), 2.99 (m, 1H), 2.46 (s, 3H), 2.17 (m, 5H), 2.07-1.99 (m, 2H), 1.30 (d, J=6.9 Hz, 3H). MS (ES+) m/z 503.0 (M+H+)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.C([Li])CCC.C[Si]([N:21]=[C:22]=[S:23])(C)C.Cl>CCCCCC.O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:22](=[S:23])[NH2:21])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: C[Si](C)(C)N=C=S
Reactant: Cc1cnc2c(c1)CCCC2
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Product: Cc1cnc2c(c1)CCCC2C(N)=S
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
A solution of 3-methyl-5,6,7,8-tetrahydroquinoline (7.3 g., 0.05 mol.) in hexane (50 ml.) was cooled to 0° C and treated dropwise with stirring with a 15% w/w solution of butyl lithium in hexane (26 ml., 0.06 mol.) in an atmosphere of nitrogen. The reaction mixture was stirred at 0° C for an additional 1 hour and was added portionwise to a solution of trimethylsilylisothiocyanate (13.1 g., 0.1 mol.) in hexane (50 ml.) and under nitrogen keeping the internal temperature at -20° C. The reaction mixture was stirred for an additional 30 minutes at -20° C, allowed to warm to room temperature and diluted with water (50 ml.). The pH was adjusted to 2.0 with conc. HCl and the hexane layer separated and discarded. The aqueous solution was adjusted to pH 10.0 with sodium carbonate and extracted with ethyl acetate (3 × 50 ml.). The combined extracts were dried (MgSO4) and the solvent removed in vacuo. The residue was triturated with n-hexane and solid filtered and recrystallised from benzene to give the title compound as colourless needles (3.5 g., 39%) m.p. 153° identical in all respects to authentic material. (Found: C, 64.6; H, 7.0; N, 13.9%. C11H14N2S Requires: C, 64.1; H, 6.8; N, 13.6%). The hexane soluble material was distilled to give recovered 3-methyl-5,6,7,8-tetrahydroquinoline (3.5 g., 50%) b.p. 120°/15 mm.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22]([C:24](O)=[O:25])=[CH:21][C:20]=2[CH:27]=1>>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C@H:3]([CH2:2][NH:1][C:24]([C:22]2[O:23][C:19]3[CH:18]=[CH:17][C:16]([Cl:15])=[CH:27][C:20]=3[CH:21]=2)=[O:25])[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Reactant: O=C(O)c1cc2cc(Cl)ccc2o1
Product: CC(C)(C)OC(=O)N1CC[C@H](CNC(=O)c2cc3cc(Cl)ccc3o2)C1

Procedure:
67.1 Using general procedure E, (R)-3-aminomethyl-1-N-tert-butoxycarbonyl-pyrrolidine was coupled with 5-chloro-benzofuran-2-carboxylic acid to give (R)-3-{[(5-chloro-benzofuran-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester. White solid. MS377.3 ([M−H]−)
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH2:9][CH2:10][C:11]([F:14])([CH3:13])[CH3:12])C1C=CC=CC=1.[C:22]([OH:25])(=[O:24])[CH3:23]>CO.[Pd]>[C:22]([OH:25])(=[O:24])[CH3:23].[F:14][C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][NH2:8]
Reactant: CC(C)(F)CCN(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(F)CCN

Procedure:
Treat a solution of N,N-dibenzyl-3-fluoro-3-methylbutan-1-amine (18.03 g, 63.2 mmol) in MeOH (150 mL) and acetic acid (7.23 mL, 126 mmol) with 10% Pd/C (3.36 g, 3.16 mmol) and hydrogenate (345 kPa) for 2.5 days. Add additional palladium on carbon (1 g) and hydrogenate the mixture (345 kPa) overnight. Filter the mixture through diatomaceous earth, rinse well with MeOH and concentrate the filtrate to dryness to afford the title compound. MS (m/z): 106.1 (M-AcOH+1).
Reaction SMILES: [CH2:1]([C@@:8]1([OH:15])[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32]Cl)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([C@@:8]1([OH:15])[CH2:13][CH2:12][N:11]([CH2:32][CH2:31][O:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:25][CH:26]=2)[CH2:10][C@H:9]1[OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1CNCC[C@]1(O)Cc1ccccc1
Reactant: ClCCOc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O[C@@H]1CN(CCOc2ccc(OCc3ccccc3)cc2)CC[C@]1(O)Cc1ccccc1
Temperature: 90 °C
Yield: 100 %

Procedure:
To a solution of 5.0 g (24 mmol) (3R,4R)-4-benzyl-3,4-dihydroxy-piperidine in 150 ml DMF were added 7.4 g (24 mmol) 1-benzyloxy-4-(2-chloro-ethoxy)-benzene and 5.0 g (36 mmol) K2CO3 and the reaction mixture was heated to 90° C. for 72 hours. After the addition of water the aqueous phase was extracted three times with ethyl acetate and the combined organic layers were washed with water, dried over MgSO4 and the solvent was removed under reduced pressure to give 10.5 g (24 mmol, 100%) (3R,4R)-4-benzyl-1-[2-(4-benzyloxy-phenoxy)-ethyl]-piperidine-3,4-diol as a solid.
Reaction SMILES: FC1C=C(C=C(F)C=1)CNC(=O)C(C)C([NH:11][CH:12]([CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)[C:13]([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1)=[O:14])=O.[F:41][C:42]1[CH:43]=[C:44]([CH:56]=[C:57]([F:59])[CH:58]=1)[CH2:45][NH:46][C:47](=[O:55])[CH:48]([CH:52]([CH3:54])[CH3:53])[C:49]([OH:51])=O>>[F:59][C:57]1[CH:56]=[C:44]([CH:43]=[C:42]([F:41])[CH:58]=1)[CH2:45][NH:46][C:47](=[O:55])[CH:48]([CH:52]([CH3:54])[CH3:53])[C:49]([NH:11][CH:12]([CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)[C:13]([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1)=[O:14])=[O:51]
Reactant: CC(C)C(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Reactant: CC(C(=O)NCc1cc(F)cc(F)c1)C(=O)NC(Cc1c[nH]c2ccccc12)C(=O)N1CCc2ccccc2C1
Product: CC(C)C(C(=O)NCc1cc(F)cc(F)c1)C(=O)NC(Cc1c[nH]c2ccccc12)C(=O)N1CCc2ccccc2C1

Procedure:
N-(3,5-Difluoro-benzyl)-N′-[2-(3,4-dihydro-1H-isoguinolin-2-yl)-1-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-2-isopropyl-malonamide. MS: m/e=573.3 (M+H+), was prepared in analogy to N-(3,5-difluoro-benzyl)-N′-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-2-methyl-malonamide (example 16) from N-(3,5-difluoro-benzyl)-2-isopropyl-malonamic acid.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[S:16][CH:15]=1.[CH3:23][S:24]SC>C1COCC1>[Br:13][C:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[S:16][C:15]=1[S:24][CH3:23]
Reactant: Brc1csc2ncccc12
Reactant: CSSC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CSc1sc2ncccc2c1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (3.25 mL, 1.7M in hexanes, 5.2 mmol) was added to a cooled solution of diisopropylamine (0.74 mL, 5.2 mmol) in THF (15 mL) at −78° C. The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. The reaction was cooled to 0° C. and 3-bromothieno[2,3-b]pyridine (prepared by the method of Klemm L. H. et al., Journal of Heterocyclic Chemistry, 1974, 11(2), 205-209) (1 g, 4.7 mmol) added. After stirring for a further 20 minutes dimethyl disulphide (443 mg, 0.42 mL, 4.7 mmol) was added, and the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction was quenched with water, extracted into DCM, dried (sodium sulphate), filtered and concentrated in vacuo. Chromatography (silica; DCM) yielded the title compound as a pale yellow solid (850 mg). δH (DMSO-d6) 8.57 (1H, dd, J 4.7, 1.5 Hz), 8.00 (1H, m), 7.54 (1H, dd, J 8.1, 4.5 Hz), 2.70 (3H, m). LCMS (pH 3) RT 2.64 minutes, (ES+) 259/261 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH:22]=[O:23])=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CCO)cc2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CC=O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.2 %

Procedure:
A solution of 4-[4-(2-hydroxyethyl)-phenoxy]piperidine-1-carboxylic acid tert-butyl ester (8.10 g, 25.2 mmol) in 90 mL of CH2Cl2 was cooled to 0° C. as Dess-Martin periodinane (11.2 g, 26.5 mmol) was added in portions. After stirred at rt overnight, the reaction was diluted with 100 mL of CH2Cl2, and washed with saturated NaHCO3 (5×100 mL), water, and dried over Na2SO4. Flash chromatography with 60% Et2O in hexane gave 2.83 g (35%) of 4-[4-(2-oxo-ethyl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester: MS m/z 220 (M−Boc+H).
Reaction SMILES: [S:1]1[C:5]2[C:6](=O)[NH:7][CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=[CH:2]1.[BH4-].[Na+].O>O1CCCC1>[S:1]1[C:5]2[CH2:6][NH:7][CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C1NCCCc2ccsc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: c1cc2c(s1)CNCCC2
Yield: 66.8 %

Procedure:
To a mixture of 6.7 g of 4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one and 4.5 g of sodium borohydride in 70 ml of tetrahydrofuran was added boron trifluoride-ether complex dropwise under ice-cooling and the mixture was refluxed under heating for an hour. The mixture was poured into water, washed with chloroform, made alkaline with 10% potassium hydroxide solution and extracted with chloroform. The extract was washed with water, dried and concentrated to give 4.1 g of 5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>O1CCCC1.CO.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([N:10]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccc([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCN(c2cccc(N)c2)CC1
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To 10% palladium-carbon (10 mg), a solution of tert-butyl 4-(3-nitrophenyl)-1,4-diazepane-1-carboxylate (C27, 15 mg) in tetrahydrofuran (2 mL) and methanol (2 mL) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour under a hydrogen atmosphere. The insoluble matter was removed by filtration through Cerite, and then the solvent was evaporated under reduced pressure to obtain tert-butyl 4-(3-aminophenyl)-1,4-diazepane-1-carboxylate (C28, 12 mg).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[C:8](=[O:13])[CH2:7][CH2:6][CH2:5]2.[C:14]1([S-:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[K+]>CS(C)=O.Cl>[F:12][C:10]1[CH:11]=[C:2]([S:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=[C:4]2[C:9]=1[C:8](=[O:13])[CH2:7][CH2:6][CH2:5]2
Reactant: [S-]c1ccccc1
Reactant: O=C1CCCc2cc(F)cc(F)c21
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1CCCc2cc(Sc3ccccc3)cc(F)c21
Temperature: 50 °C

Procedure:
A mixture of 6,8-difluoro-3,4-dihydro-2H-naphthalen-1-one (1.0 gram, 5.5 moles) and potassium thiophenolate (0.81 gram, 5.5 mmole) in 4 mL DMSO was heated at 50° C. for 0.5 hour. The mixture was diluted with 30 mL 0.1N hydrochloric acid and then it was extracted with 50 mL diethyl ether. The organic phase was washed with water, dried (magnesium sulfate) and concentrated under reduced pressure. 8-Fluoro-6-phenylsulfanyl-3,4-dihydro-2H-naphthalen-1-one was obtained by recrystallization of the residue from ethyl acetate/hexane, 0.871 gram (58%), m.p. 112-113° C., M+H=273.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O>>[CH2:1]([N:8]([CH2:24][C:23]1[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=1[F:21])[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NCc2ccccc2)cccc1NS(C)(=O)=O
Reactant: O=Cc1ccccc1F
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccccc1F

Procedure:
The product from Example 8A and 2-fluorobenzaldehyde were processed as described in Example 1C to provide the title compound. 1H NMR (300 MHz, CDCl3) δ7.22 (m, 8H), 7.10 (t, J=8.0 Hz, 1H), 6.98 (m, 3H), 6.11 (s, 1H), 4.13 (s, 2H), 4.10 (s, 2H), 2.91 (s, 3H), 2.31 (s, 3H); MS (ESI+) m/z 399 (M+H)+; Analysis calculated for C22H23FN2O2S 0.20 TFA: C, 63.96; H, 5.55; N, 6.65. Found: C, 64.11; H, 5.69; N, 6.61.