Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[OH:5][C:6]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[S:20]([CH3:23])(=[O:22])=[O:21])[NH:9][C:8]=2[CH:7]=1>>[CH:2]([O:5][C:6]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[S:20]([CH3:23])(=[O:22])=[O:21])[NH:9][C:8]=2[CH:7]=1)([CH3:4])[CH3:3]
Reactant: CS(=O)(=O)c1cccc2c1Sc1ccc(O)cc1N2
Reactant: CC(C)I
Product: CC(C)Oc1ccc2c(c1)Nc1cccc(S(C)(=O)=O)c1S2
Yield: 99.9 %

Procedure:
2-Isopropoxy-6-methylsulphonylphenothiazine (21.7 g.) is prepared by reacting 2-iodopropane (17.0 g.) with 2-hydroxy-6-methylsulphonylphenothiazine (m.p. 218°-219°C.; 19.0 g.).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([N:8]([CH3:10])[CH3:9])[CH2:7][CH2:6][S:5][CH2:4]1.C1C=C(Cl)C=C(C(OO)=[O:19])C=1>C(Cl)Cl.CO>[NH2:1][CH2:2][C:3]1([N:8]([CH3:10])[CH3:9])[CH2:4][S:5](=[O:19])[CH2:6][CH2:7]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN(C)C1(CN)CCSC1
Solvent: ClCCl
Solvent: CO
Product: CN(C)C1(CN)CCS(=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-(aminomethyl)-N,N-dimethyltetrahydrothiophen-3-amine (160 mg, 0.998 mmol) in DCM: MeOH (4:1, 10 mL) was added MCPBA (246 mg, 1.098 mmol) at 0° C. The reaction was slowly warmed to room temperature and stirred overnight. The crude was purified by cation exchange resin to give the title compound without further purification.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[C:23]1([C@H:33]([N:35]([CH2:43][C@@H:44]2[C@@H:48]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH2:47][NH:46][CH2:45]2)[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH3:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.[C:55]([O:66][CH3:67])(=[O:65])[C:56]1[CH:64]=[CH:63][C:59]([C:60]([O-])=[O:61])=[CH:58][CH:57]=1>ClCCl.C(N(CC)CC)C>[C:38]([O:37][C:36]([N:35]([CH2:43][C@@H:44]1[C@@H:48]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH2:47][N:46]([C:60]([C:59]2[CH:63]=[CH:64][C:56]([C:55]([O:66][CH3:67])=[O:65])=[CH:57][CH:58]=2)=[O:61])[CH2:45]1)[C@@H:33]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:34])=[O:42])([CH3:40])([CH3:41])[CH3:39]
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CNC[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)N2C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)[C@@H](c3ccccc3)C2)cc1

Procedure:
At room temperature, WSC hydrochloride, HOBt, tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[(3R,4S)-4-phenylpyrrolidin-3-yl]methyl}carbamate and triethylamine were added in that order to a mixture of monomethyl terephthalate and dichloromethane and stirred for 7.5Hours. Monomethyl terephthalate was further added thereto and stirred for 16Hours, and then work-up and purification were carried out in the standard method to obtain methyl 4-{[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}benzoate. FP: 593.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[C:21]([F:24])([F:23])[F:22])[O:11][CH3:12])=[O:9])[C:4](=[O:25])O1.[CH2:27]=O.[NH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>CO>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:10]([O:11][CH3:12])[C:8]([C:7]2[CH2:27][N:29]([CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:4](=[O:25])[C:5]=2[OH:6])=[O:9])=[C:15]([C:21]([F:22])([F:23])[F:24])[CH:16]=1
Reactant: C=O
Reactant: CON(Cc1ccc(F)cc1C(F)(F)F)C(=O)C=C1OC(C)(C)OC1=O
Reactant: NCCN1CCOCC1
Solvent: CO
Product: CON(Cc1ccc(F)cc1C(F)(F)F)C(=O)C1=C(O)C(=O)N(CCN2CCOCC2)C1
Yield: 50 %

Procedure:
Reaction of 2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-(4-fluoro-2-trifluoromethyl-benzyl)-N-methoxy-acetamide (0.21 g, 0.55 mmol) with the paraformaldehyde-N-(2-aminoethyl)morpholine adduct in methanol using a procedure similar to the one described in the preparation of compound 13 gave 0.13 g (50% yield) of the title compound as a solid after chromatography on reversed phase silica gel. 1HNMR 400 MHz (CDCl3) δ (ppm); 2.51 (4H, m, 2×NCH2), 2.60 (2H, t, J=6.1 Hz, NCH2), 3.65 (6H, m, 2×OCH2 and NCH2), 3.71 (3H, s, OCH3), 4.32 (2H, s, NCH2), 5.09 (2H, s, NCH2), 7.23–7.27 (2H, m, aromatics), 7.39–7.48 (2H, m, aromatics). MS (ESI+) calculated for C20H24F4N3O5: [M+H]+: 462. found: 462.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=3)=[CH:19][C:18](=[O:31])[C:13]([C:14]([O:16]C)=[O:15])=[CH:12]2)=[CH:7][CH:6]=1)C(C)=O.C(O)(=O)C>C(O)C.[OH-].[Na+].O>[NH2:1][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=3)=[CH:19][C:18](=[O:31])[C:13]([C:14]([OH:16])=[O:15])=[CH:12]2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1cn(-c2ccc(NC(C)=O)cc2)c(-c2ccc3ccccc3c2)cc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Nc1ccc(-n2cc(C(=O)O)c(=O)cc2-c2ccc3ccccc3c2)cc1
Temperature: 25 °C
Yield: 88 %

Procedure:
In a mixed solvent of 10 ml of ethanol and 10 ml of a 10% by weight aqueous sodium hydroxide solution was dissolved 0.5 g of methyl 1-(4-acetaminophenyl)-6-(2-naphthyl)-4-oxo-1,4-dihydronicotinate, and the solution was refluxed for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and diluted with 20 ml of water. This solution was then adjusted to a pH of 5.5 with acetic acid, and the precipitated crystals were collected by filtration, washed with water, and dried to obtain 0.38 g of 1-(4-aminophenyl)-6-(2-naphthyl)-4-oxo-1,4-dihydronicotinic acid having a melting point of 148°-151° C.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:13][CH2:14]OC)[CH2:11][CH2:10][C:9](=[CH2:12])[CH2:8][CH2:7]1)=[O:5])C.[CH:17]1([C:20]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=2)[CH2:19][CH2:18]1.[Cl-].C[Al+]C.Cl>C1(C)C=CC=CC=1.O>[CH:17]1([C:20]2[CH:26]=[CH:25][C:23]([N:24]3[CH2:14][CH2:13][C:6]4([CH2:7][CH2:8][C:9](=[CH2:12])[CH2:10][CH2:11]4)[C:4]3=[O:5])=[CH:22][CH:21]=2)[CH2:19][CH2:18]1
Reactant: C=C1CCC(CCOC)(C(=O)OCC)CC1
Reactant: Nc1ccc(C2CC2)cc1
Agent: C[Al+]C
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: C=C1CCC2(CC1)CCN(c1ccc(C3CC3)cc1)C2=O
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 0.3 g (1.3 mmol) 1-(2-methoxy-ethyl)-4-methylene-cyclohexanecarboxylic acid ethyl ester and 0.264 g (1.98 mmol) 4-cyclopropylaniline in 6 mL toluene was treated with 2.65 mL (2.65 mmol) dimethylaluminium chloride (1M in toluol) and stirred for 4 h at 100° C. After cooling to room temperature water and 1N HCl aq. was carefully added and the mixture poured onto water and extracted with ethyl acetate. The combined organic layers were washed with water, dried with MgSO4, filtered and evaporated to dryness. The residue was purified by flash column chromatography over silica eluting with a gradient formed from hexane and ethyl acetate to yield after evaporation of the product containing fractions 0.264 g (71%) of the title compound as yellow crystals. MS (m/e): 282.4 [MH+].
Reaction SMILES: [CH3:1][C:2]1[CH2:6][C:5]([CH3:7])=[C:4]([CH3:8])[C:3]=1[CH3:9].C([Li])CCC.[Cl:15][Si:16](Cl)([CH3:18])[CH3:17]>O1CCCC1.CCCCCC>[CH3:1][C:2]1[C:3]([CH3:9])=[C:4]([CH3:8])[C:5]([Si:16]([CH3:18])([CH3:17])[Cl:15])([CH3:7])[CH:6]=1
Reactant: C[Si](C)(Cl)Cl
Reactant: CC1=C(C)C(C)=C(C)C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1=CC(C)([Si](C)(C)Cl)C(C)=C1C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Into a two-necked round-bottomed flask, the atmosphere in which was replaced with nitrogen, were charged 15 g of tetrahydrofuran, 12 g of n-hexane and 1.10 g of tetramethylcyclopentadiene. The mixture was cooled to 0° C. with stirring and 4.90 ml of n-butyl lithium (1.6M solution in n-hexane) (7.84 mmol as n-butyl lithium) was gradually added dropwise thereto over 20 minutes. The obtained reaction mixture in the form of a white slurry was stirred for at 0° C. for 3 hours, and a pre-cooled tetrahydrofuran (10 g) solution containing 1.01 g (7.84 mmol) of dichlorodimethylsilane was added in several divided portions. The mixture was then gradually heated to room temperature.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:26]=[CH:25][C:7]([CH2:8][CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([O:20]C)[CH:16]=3)[CH:11]2[CH3:24])=[CH:6][CH:5]=1.Cl.CCOCC>Br.CO.C(O)(C)C>[ClH:1].[ClH:1].[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([OH:20])[CH:16]=3)[CH:11]2[CH3:24])=[CH:25][CH:26]=1
Reactant: COc1cc2c(cc1OC)C(C)N(CCc1ccc(N)cc1)CC2
Agent: Br
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: CC(C)O
Product: COc1cc2c(cc1O)CCN(CCc1ccc(N)cc1)C2C
Temperature: 0 °C

Procedure:
N-(4-Aminophenethyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline dihydrochloride (20.0 g, 0.05 m) was suspended in 49% HBr (50 ml) maintained under nitrogen and heated to 120° for 1.5 hr. The mixture was cooled and then poured into 500 cc of ice/water and the solution basified to pH 11 and extracted with ether (3×250 ml). The aqueous phase was buffered to pH 8 by adding glacial acetic acid and dilute NaOH as needed, then extracted with chloroform (4×300 ml). The chloroform extracts were dried over MgSO4 and evaporated to an oil, 8.5 g. This crude product was purified by HPLC on silica gel eluting with ammonia saturated 5% CH3OH/CHCl3. Pure fractions were combined and evaporated to give a yellow oil, 5.5 g. This was dissolved in methanol (20 ml) and isopropanol (10 ml), acidified with HCl gas and the stirred solution treated with ether (100 ml). The solid precipitate was collected by filtration, washed with 10% isopropanol/ether and vacuum dried to give N-(4-aminophenethyl)-1,2,3,4-tetrahydro-6-hydroxy-7-methoxy-1-methylisoquinoline dihydrochloride as a white solid, m.p. 201°-205°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:16][CH2:17]C[CH2-].ICC>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([CH2:16][CH3:17])=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccn1
Reactant: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1cccnc1NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 42.8 %

Procedure:
2-t-Butoxycarbonylaminopyridine (10 g, 51.5 mmol) was dissolved in tetrahydrofuran (80 mL), and cooled to -78° C. N-butyllithium (80 mL of 1.49M in hexanes, 120 mmol) was added dropwise over a period of 1 h. After stirring for an additional 15 min at -78° C. and then for 2.5 hours at -10° C., the solution was then recooled back down to -78° C. and iodoethane (77.2 mmol, 6.18 mL) was added dropwise over a period of 15 min via syringe. The solution was allowed to warm to room temperature. The reaction was quenched with 100 mL of a saturated ammonium chloride and extracted with ethyl acetate (3×). The organic layers were collected, dried over magnesium sulfate, and concentrated. The resulting solid was purified by flash chromatography on silica gel (25% ethyl acetate/hexanes) to provide the 4.9 g (43%) of the titled product as a light brown solid:
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH3:10])[C:4]1=[O:11].C(N(CC)CC)C.O=C1CCC(=O)N1[C:26]1[C:34]2[C:29](=[CH:30][C:31]([C:44]([O-])=[O:45])=[C:32]([O:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=3[F:43])[CH:33]=2)[N:28]([CH2:47][CH:48]([CH3:50])[CH3:49])[N:27]=1>CN(C)C=O.C(OCC)(=O)C>[F:43][C:37]1[CH:38]=[C:39]([F:42])[CH:40]=[CH:41][C:36]=1[O:35][C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][C:31]=1[C:44]([NH:2][C@H:3]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH3:10])[C:4]1=[O:11])=[O:45])[N:28]([CH2:47][CH:48]([CH3:50])[CH3:49])[N:27]=[CH:26]2
Reactant: CN1CCCC[C@H](N)C1=O
Reactant: CC(C)Cn1nc(N2C(=O)CCC2=O)c2cc(Oc3ccc(F)cc3F)c(C(=O)[O-])cc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H]3CCCCN(C)C3=O)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.6 %

Procedure:
(S)-3-Amino-1-methylazepan-2-one hydrochloride (0.112 g, 0.627 mmol) was dissolved in triethylamine (0.238 mL, 1.71 mmol) and N,N-dimethylformamide (3 mL). To this was added 2,5-dioxopyrrolidin-1-yl-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylate (prepared according to Example 16, Step A; 253 mg, 0.570 mmol), and the reaction mixture was allowed to stir at ambient temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude reaction mixture was purified by flash chromatography on a silica gel column, eluting with 60% ethyl acetate/hexanes to yield pure (S)-5-(2,4-difluorophenoxy)-1-isobutyl-N-(1-methyl-2-oxoazepan-3-yl)-1H-indazole-6-carboxamide (If) (208 mg, 78%). Mass spec: 471 (M+1). 1H NMR (CDCl3) δ 9.15 (br, 1H), 8.32 (s, 1H), 7.85 (s, 1H), 7.21 (m, 1H), 6.99 (m, 2H), 6.92 (m, 1H), 4.91 (ddd, 1H), 4.21 (d, 2H), 3.67 (dd, 1H), 3.22 (dd, 1H), 3.04 (s, 3H), 2.35 (m, 1H), 2.21 (m, 1H), 2.05-1.81 (m, 3H), 1.54 (m, 1H), 1.45 (m, 1H), 0.92 (d, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8](Cl)=[C:7]([S:10]([CH3:13])(=[O:12])=[O:11])[S:6](=[O:14])[N:5]=1)[CH3:2].C[Si]([NH:19][Si](C)(C)C)(C)C.CO>C(#N)C>[CH2:1]([O:3][C:4]1[C:8]([NH2:19])=[C:7]([S:10]([CH3:13])(=[O:12])=[O:11])[S:6](=[O:14])[N:5]=1)[CH3:2]
Reactant: CCOC1=NS(=O)C(S(C)(=O)=O)=C1Cl
Reactant: C[Si](C)(C)N[Si](C)(C)C
Solvent: CO
Solvent: CC#N
Product: CCOC1=NS(=O)C(S(C)(=O)=O)=C1N
Temperature: 25 °C
Yield: 60.3 %

Procedure:
To a solution of crude 3-ethoxy-4-chloro-5- methylsulfonylisothiazole-1-oxide (0.90 g, 1.6 mmol) in acetonitrile (10 ml) under a nitrogen atmosphere was added hexamethyldisilizane (0.70 ml, 3.3 mmol). The reaction mixture was heated at 70° for 11/2 hours, cooled to room temperature and methanol (1.0 ml) was added. The reaction was filtered and evaporated. The residue was triturated with methanol/ethyl acetate to afford crude title compound (0.3 g). Recrystallization from methanol/ethyl acetate after treatment with charcoal gave 0.23 g of pure product, mp 191°-193°.
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:4]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[N:3]=1.O.Cl[C:27]([O:29][CH3:30])=[O:28].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:21]1([CH3:24])[CH:22]=[CH:23][C:18]([S:15]([O:14][C:4]2[N:3]=[C:2]([NH:1][C:27]([O:29][CH3:30])=[O:28])[N+:7]([O-:8])=[C:6]([NH:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=2)(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: COC(=O)Cl
Reactant: COC(=O)Nc1cc(OS(=O)(=O)c2ccc(C)cc2)nc(N)[n+]1[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)Nc1cc(OS(=O)(=O)c2ccc(C)cc2)nc(NC(=O)OC)[n+]1[O-]
Reaction time: 0.17 h

Procedure:
150 g of methyl 2-amino-6-[(p-tolylsulfonyl)oxy]-4-pyrimidinecarbamate-3-oxide are suspended in 2 l of methylene chloride and 2 l of water while stirring. After cooling to 0°-5°, 50 ml of methyl chloroformate are added thereto. After stirring vigorously for about 10 minutes, the mixture is adjusted to a pH of 7-7.5 with about 150 g of sodium bicarbonate. The mixture is subsequently stirred at 0°-5° for a further 3 hours. The organic phase is separated and the aqueous phase is extracted with 1 l of methylene chloride. The combined organic phases are washed twice with 1 l of water each time, dried over sodium sulphate and evaporated in vacuo. There is obtained crude dimethyl 6-[(p-tolylsulfonyl)oxy]-2,4-pyrimidinedicarbamate-3-oxide which is used in the next step (a pure product of melting point 178°-180° can be obtained by digestion with ethyl acetate).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]=[C:6]=[O:7].CCN(CC)CC.[NH:15]1[CH:24]2[CH:19]([CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:18][CH2:17][CH2:16]1.CCOC(C)=O>C1COCC1>[Cl:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([N:15]1[CH:24]2[CH:19]([CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:18][CH2:17][CH2:16]1)=[O:7]
Reactant: C1CCC2NCCCC2C1
Reactant: O=C=NCCCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(NCCCCl)N1CCCC2CCCCC21
Yield: 84.6 %

Procedure:
2.5 g (21 mmol) of 3-chloropropylisocyanate are dissolved in 150 mL of anhydrous THF and 6.4 mL (46 mmol) of Et3N. Once dissolved 3.4 mL (23 mmol) of decahydroquinoline are slowly added and it is refluxed for 18 h. AcOEt is then added and the resulting solution is sequentially washed with water, 1N HCl and brine. The organic phase is dried over anhydrous Na2SO4, it is filtered and the solvent is evaporated under reduced pressure yielding 4.6 g of intermediate IIIf.1. Method B: tr: 3.58 min; m/z: 259
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31].C(N(CC)CC)C>>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][CH:35]=[C:27]([C:26]([F:25])([F:36])[F:37])[CH:28]=4)=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1cccc(C(F)(F)F)c1
Yield: 28.8 %

Procedure:
As described for Example 9, 0.314 g (1 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine is reacted with 0.302 g (1.4 mmol) of 3-(trifluoromethyl)benzoyl chloride in 9 ml and 0.145 g (1.4 mmol) of triethylamine for 1.5 hour at room temperature. The product is recrystallized from ethyl acetate-hexane to give 0.14 g of crystals, m.p. 190°-191° C.
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[S:22]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23]1.C1(C)C=CC=CC=1.CCO>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>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C:5]2[CH:15]=[CH:16][C:2]([C:24]3[CH:25]=[CH:26][S:22][CH:23]=3)=[CH:3][CH:4]=2)=[CH:8][CH:9]=1
Reactant: COc1ccc(Cc2ccc(I)cc2)cc1
Reactant: OB(O)c1ccsc1
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: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(Cc2ccc(-c3ccsc3)cc2)cc1
Temperature: 25 °C
Yield: 48.2 %

Procedure:
To a mixture of 1-(4-iodobenzyl)-4-methoxybenzene (0.300 g, 0.925 mmol), 2N aqueous NaHCO3 solution (1.85 mL, 3.7 mmol), and 3-thiopheneboronic acid (0.237 g, 1.85 mmol) in a solution of toluene/EtOH (17.6/0.8 mL) at ambient temperature under an atmosphere of nitrogen was added tetrakis(triphenylphosphine)palladium(0) (0.107 g, 0.093 mmol). The mixture was refluxed for 18 h, cooled to ambient temperature, and diluted with H2O (30 mL). After extracting with EtOAc (3×25 mL) and filtering the EtOAc through a silica gel bed, the organic layer was washed with brine (25 mL), dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash column chromatography (70% hexane in dichloromethane) to afford the title product as a white solid (0.125 g, 48%): 1H NMR (400 MHz, CDCl3): δ 7.50 (d, 2H, J=8.4 Hz), 7.40 (t, 1H, J=2.0 Hz), 7.36 (d, 2H, J=2.4 Hz), 7.20 (d, 2H, J=8.4 Hz), 7.12 (d, 2H, J=8.8 Hz), 6.84 (d, 2H, J=8.8 Hz), 3.94 (s, 2H), 3.78 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:4]=1[CH2:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[C:15]([S:18][CH3:19])[CH:16]=[CH:17][C:10]=2[NH:9][C:8](=O)[CH2:7]1.CN(C)C1C=CC(C)=CC=1.P(Cl)(Cl)([Cl:39])=O>C1(C)C=CC=CC=1>[Cl:39][C:8]1[CH2:7][N:6]([CH2:5][C:4]2[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:3]=2[O:2][CH3:1])[C:12](=[O:13])[C:11]2[CH:14]=[C:15]([S:18][CH3:19])[CH:16]=[CH:17][C:10]=2[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(CN2CC(=O)Nc3ccc(SC)cc3C2=O)c(OC)c1
Solvent: Cc1ccccc1
Solvent: Cc1ccc(N(C)C)cc1
Product: COc1ccc(CN2CC(Cl)=Nc3ccc(SC)cc3C2=O)c(OC)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
4-(2,4-Dimethoxy-benzyl)-7-methylsulfanyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (630 mg, 1.7 mmol) and N,N-dimethyl-p-toluidine (489 μL, 3.4 mmol) were mixed in toluene (5 mL) and heated to 100° C. Then phosphorus oxychloride (170 μL, 1.9 mmol) was added dropwise and heating at 100° C. was continued for 1 h. The resulting dark red solution was used directly in the subsequent step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]([O:12][CH3:13])[O:10][CH3:11])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:34][CH2:35][N:36]([CH3:44])[C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:34][CH2:35][N:36]([CH3:44])[C:37](=[O:43])[O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[C:4]([CH:9]([O:12][CH3:13])[O:10][CH3:11])[CH:3]=1
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: COC(OC)c1cc(Br)ccc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: COC(OC)c1cc(Br)ccc1OCCN(C)C(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
To a solution of 4-bromo-2-dimethoxymethylphenol (6.00 g, 24.3 mmol) in benzene (100 ml) were added triphenylphosphine (7.63 g, 29.1 mmol) and t-butyl 2-hydroxyethylmethylcarbamate (5.10 g, 29.1 mmol) synthesized in step 1). The reaction solution was cooled to 0° C. in an ice bath, and diisopropyl azodicarboxylate (5.88 g. 5.73 ml, 29.1 mmol) was dropwise added thereto, after which it was allowed to react for 1 hour. Following extraction with brine and ethyl acetate, the organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated in a vacuum. The residue was purified through column chromatography (ethyl acetate/n-hexane=1/20) to afford the object compound (colorless oil, 11.30 g, 96.1%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([O:16]CC)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][N:20](C)[C:21]([C@H]1CCCNC1)=O.C(N(C(C)C)CC)(C)C.C(Br)C1C=CC=CC=1>>[CH3:19][N:20]([CH3:21])[C:14]([C@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1)=[O:16]
Reactant: CCOC(=O)C1CCCN(Cc2ccccc2)C1
Reactant: CN(C)C(=O)[C@H]1CCCNC1
Agent: BrCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)[C@H]1CCCN(Cc2ccccc2)C1

Procedure:
This reaction was run in the same manner as ethyl 1-benzyl-3-piperidinecarboxylate, starting with (S)-N,N-dimethyl-3-piperidinecarboxamide (275 mg; 1.76 mmol), diisopropylethylamine (310 μl; 1.78 mmol), and benzyl bromide (210 μl; 1.77 mmol). Crude product was purified by chromatography on silica eluting with 5% methanol/95% dichloromethane, giving (S)-N,N-dimethyl 1-benzyl-3-piperidinecarboxamide (322.2 mg) as a colorless oil. MS m/z (positive ion) 247 (MH+; 100).