Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[O:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)[CH2:9][CH2:8]1.[ClH:23].[C:24]([C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33]([CH2:37][C:38](=[O:40])[NH2:39])=[C:32](O)[CH:31]=[CH:30]2)(=[NH:26])[NH2:25].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.O>[ClH:23].[ClH:23].[O:7]1[CH2:8][CH2:9][N:10]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([O:20][C:32]3[CH:31]=[CH:30][C:29]4[C:34](=[CH:35][CH:36]=[C:27]([C:24](=[NH:25])[NH2:26])[CH:28]=4)[C:33]=3[CH2:37][C:38](=[O:40])[NH2:39])=[O:19])=[CH:16][CH:15]=2)[CH2:11][CH2:12]1
Reactant: O=C(O)c1ccc(CN2CCOCC2)cc1
Reactant: N=C(N)c1ccc2c(CC(N)=O)c(O)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: N=C(N)c1ccc2c(CC(N)=O)c(OC(=O)c3ccc(CN4CCOCC4)cc3)ccc2c1
Reaction time: 2 h
Yield: 67.4 %

Procedure:
15 Milliliters of anhydrous pyridine was added to 612.2 mg of 4-morpholinomethylbenzoic acid, 703.9 mg of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 622.6 mg of DCC and 30.7 mg of DMAP, followed by stirring for 2 hours under cooling with ice and then 3 days under cooling with water. Thereafter, the same procedure as in Example 1 was carried out to obtain 440.7 mg of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH2:4]Br.[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20]3[CH2:25][CH2:24][CH:23]([N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH2:22][CH:21]=3)=[CH:19][C:14]=2[O:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>>[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20]3[CH2:25][CH2:24][CH:23]([N:26]4[CH2:31][CH2:30][N:29]([CH2:4][C:3]5[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:2]=5[F:1])[CH2:28][CH2:27]4)[CH2:22][CH:21]=3)=[CH:19][C:14]=2[O:13][CH2:12]1
Reactant: Fc1ccc(F)c(CBr)c1
Reactant: C1=C(c2ccc3c(c2)OCO3)CCC(N2CCNCC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccc(F)c(CN2CCN(C3CC=C(c4ccc5c(c4)OCO5)CC3)CC2)c1

Procedure:
The title compound was prepared from 2,5-difluorobenzyl bromide (0.21 g, 1 mmole), and 1-[4-(1,3-benzodioxol-5-yl)-3-cyclohexen-1-yl]piperazine (0.29 g, 1 mmole), and excess powdered K2CO3 as described in example 45 to give the product (62%, mp: 108-109° C.). Calc'd for C24H26F2N2O2 : C, 69.88%; H, 6.35%; N, 6.79%. Found: C, 69.82; H, 6.35%; N, 6.69%.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C@@H:8]([OH:10])[CH3:9])[C:5]([F:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[H][H]>[Pd].C(Cl)Cl>[F:11][C:5]1[C:6]([C@@H:8]([OH:10])[CH3:9])=[N:7][CH:2]=[CH:3][CH:4]=1
Reactant: C[C@H](O)c1nc(Br)ccc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](O)c1ncccc1F
Yield: 64.8 %

Procedure:
(1S)-1-(6-Bromo-3-fluoro-pyridin-2-yl)ethanol (1.3 g, 5.9 mmol), triethylamine (1.6 mL, 11.5 mmol) and palladium on carbon (0.64 g, 0.34 mmol) were mixed in DCM (25 mL). The flask was evacuated/filled with hydrogen gas in 4 cycles and then left at 2.5 atm pressure hydrogen gas at room temperature for 24 h. The mixture was filtered and the solid washed with DCM. The filtrate was washed with water and Brine and dried over sodium sulphate and concentrated in vacuo. The crude product was purified by flash column chromatography (eluent DCM:methanol gradient) to yield 0.54 g (65% yield) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[O:6][CH2:7][CH:8]1[CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][N:12]2[C:11](=O)[CH2:10][O:9]1)[CH3:2].B>O1CCCC1.C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[O:6][CH2:7][CH:8]1[CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][N:12]2[CH2:11][CH2:10][O:9]1)[CH3:2]
Reactant: CCOc1ccccc1OCC1OCC(=O)N2CCCCC12
Agent: B
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCOc1ccccc1OCC1OCCN2CCCCC12
Temperature: 5 °C
Reaction time: 2 h
Yield: 65.8 %

Procedure:
In 300 ml of tetrahydrofuran (freshly distilled from lithium aluminum hydride) was dissolved 1-[(2-ethoxyphenoxy)methyl]-6,7,8,9-tetrahydro-1H-pyrido[2,1-c][1,4]oxazin-4(3H)-one (8.12 g, 0.0265 mole). The solution was cooled to 5° C. in an ice bath and 40 ml of 1M borane in tetrahydrofuran was added by syringe to the stirred solution under nitrogen. The solution was stirred at room temperature for 2 hr and then heated at reflux for 2 hr. The reaction mixture was cooled to room temperature and slowly quenched with glacial acetic acid. The solvent was removed in vacuo. The residue was partitioned between 10% sodium hydroxide and diethyl ether. Removal of the diethyl ether gave a yellow oil. This oil was then dissolved in a minimum amount of chloroform and chromatographed on a 500 g. Silica Gel column (gradient elution with chloroform methanol). Fractions from the column were combined which gave a single spot on TLC (methanol-chloroform) at similar Rf. A total of 5.08 g (65.8%) of a light yellow oil was obtained.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[CH3:23].CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][N:35](C(OC(C)(C)C)=O)[CH:36]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([CH3:23])=[C:2]([C:32]4[CH:33]=[N:34][NH:35][CH:36]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(C)sc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3cn[nH]c3)c(C)sc2n1
Temperature: 100 °C
Yield: 11 %

Procedure:
Under nitrogen, N-(3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 61) (100 mg, 0.232 mmol) was dissolved in 1,4-dioxane (2.5 mL) and water (1 mL). 1,1-Dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (102 mg, 0.347 mmol), bis(triphenylphosphine)palladium(II) chloride (16.26 mg, 0.023 mmol) and potassium carbonate (96 mg, 0.695 mmol) were added and the mixture heated in a microwave at 100° C. for 15 min (×3). The solution was concentrated, ethyl acetate (10 mL) added and the mixture washed with water (2×5 mL). The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by normal phase chromatography, eluting with a gradient of 0-60% ethyl acetate in cyclohexane, to give the title compound (10.7 mg). LCMS (A) m/z: 419 [M+1]+, Rt 1.20 min (acidic).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH:5]1[C:18]2[NH:17]C3C(=CC=CC=3)SC=2C=C[CH:6]=1.[C:19](O)([CH3:22])([CH3:21])[CH3:20].[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>>[C:1](#[N:4])[CH:2]=[CH2:3].[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[C:19]([NH:17][C:18](=[O:27])[CH:5]=[CH2:6])([CH3:22])([CH3:21])[CH3:20]
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Reactant: CC(C)(C)O
Solvent: C=CC#N
Solvent: O=C(O)C(F)(F)F
Product: C=CC(=O)NC(C)(C)C
Reaction time: 6 h

Procedure:
84 g of acrylonitrile are added dropwise to a solution of 1 g of phenothiazine in 90 g of trifluoroacetic acid at 20° C., whilst stirring. Thereafter, 43 g of tert.-butanol are added dropwise at 35° C. The reaction mixture is kept at 60° to 70° C. for 6 hours and then worked up by distillation. Acrylonitrile, trifluoroacetic acid and some of the N-tert.-butylacrylamide formed are distilled off under reduced pressure. 36 g of N-tert.-butylacrylamide (melting point 120° to 122° C.) remain as the distillation bottom product. The distillate can be re-used in the reaction with the same result.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:8]1[CH2:9][CH:10]=[C:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3ccccc3n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1=C(c2ccc3ccccc3n2)CCNC1
Reaction time: 0.75 h
Yield: 95.1 %

Procedure:
A solution of 4-quinolin-2-yl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.072 g, 0.23 mmol) in methylene chloride (5 mL) was added dropwise to a solution of trifluoroacetic acid at 0° C. under N2. After stirring for 45 minutes. at 0° C., the reaction was concentrated to a yellow oil which was slurried in 5% sodium carbonate (5 mL) and stirred for 30 minutes. at ambient temperature. The mixture was concentrated to a yellow solid; the solid was triturated with chloroform (20 mL) which was dried over sodium sulfate. Concentration yielded 2-(1,2,3,6-tetrahydro-pyridin-4-yl)-quinoline (46 mg, 96%) as a yellow oil which was used without further purification. 1H NMR CDC13 δ 8.06 (d, J=9 Hz, 1H), 8.03 (d, J=9 Hz, 1H), 7.75 (d, J=8 Hz, 1H), 7.68-7.63 (m, 1H), 7.55 (d, J=9 Hz, 1H), 7.46 (t, J=8 Hz, 1H), 6.75-6.40 (m, 1H), 3.70-3.65 (m, 2H), 3.42-3.29 (m, 1H), 3.20 (t, J=6 Hz, 2H), 2.85-2.78 (m, 2H).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH2:6][C:7]1[CH:11]=[CH:10][O:9][N:8]=1.C(N(CC)CC)C>C(OCC)C>[Br:1][CH2:2][C:3]([NH:6][C:7]1[CH:11]=[CH:10][O:9][N:8]=1)=[O:4]
Reactant: O=C(Br)CBr
Reactant: Nc1ccon1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(CBr)Nc1ccon1
Reaction time: 3 h

Procedure:
To a stirred solution of bromoacetylbromide (5.36 ml, 61.6 mmol) in diethylether (100 ml) at −40° C. is added, dropwise over 20 minutes, a solution of 3-aminoisoxazol (5.0 ml, 67.0 mmol) and triethylamine (8.5 ml, 61.4 mmol) in diethylether (20 ml). Additional diethylether (50 ml) is added and stirring continued for 3 hours. The reaction mixture is filtered and the solution then washed with 1 M sodium carbonate solution, 1 M hydrochloric acid and brine. Concentration followed by purification by flash silica column chromatography (ethyl acetate/iso-hexane 4:7) gives the title compound as a white solid.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].O1CCCC1.C([Li])CCC.C([O:20][C:21](=O)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])C>C(O)(=O)C>[O:20]=[C:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: CCCCCCCCCCCC(=O)OCC
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)CP(=O)(OC)OC
Reaction time: 0.5 h

Procedure:
84 g. of dimethyl methylphosphonate were dissolved in 400 ml. of tetrahydrofuran and cooled to -60°C. Under an atmosphere of nitrogen, n-butyllithium (prepared from 14 g. of lithium, 116 g. of n-butyl bromide and 510 ml. of diethyl ether) was added dropwise to the solution while maintaining the temperature below -50°C. and then stirred for 30 minutes. To the solution thus obtained, 38 g. of lauric acid ethyl ester in 140 ml. of tetrahydrofuran were added at below -55°C. and stirred for 16 hours. The reaction mixture was then neutralized with acetic acid, concentrated, dissolved in a small amount of water and extracted with diethyl ether. The extracts were washed with water, dried, concentrated and distilled to give 50 g. of the title compound having the following physical characteristic:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[N:21]=[C:20]([CH:22]4[CH2:27][CH2:26][N:25](S(CC5C=CC=CC=5)(=O)=O)[CH2:24][CH2:23]4)[NH:19][C:18]=3[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=3)=[CH:16][C:11]=2[O:10][CH2:9]1.C(N(C(C)C)CC)(C)C>C1COCC1>[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[N:21]=[C:20]([CH:22]4[CH2:27][CH2:26][N:25]([C:1](=[O:3])[CH3:2])[CH2:24][CH2:23]4)[NH:19][C:18]=3[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=3)=[CH:16][C:11]=2[O:10][CH2:9]1
Reactant: CC(=O)OC(C)=O
Reactant: O=S(=O)(Cc1ccccc1)N1CCC(c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.6 %

Procedure:
Acetic anhydride (0.011 mL, 0.12 mmol) was added to a solution of 2-(5-benzo[1,3]dioxol-5-yl-2-piperidin-4-yl-3H-imidazol-4-yl)-pyridine (0.035 g, 0.10 mmol; prepared as described in Example 11) and diisopropylethylamine (0.021 mL, 0.12 mmol) in anhydrous THF (3 mL). The mixture was stirred at room temperature for 18 hours and was partitioned between ethyl acetate and water. The organic solution was washed with brine, dried over sodium sulfate, filtered, and concentrated. HPLC purification eluting with acetonitrile:water gave 0.010 g (26%) of the title compound as a yellow solid. MS (ESP+) m/z 391.2 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 8.59 (m, 1H), 7.73 (m, 1H), 7.34 (m, 2H), 6.94 (m, 3H), 5.98 (s, 2H), 4.83 (s, 3H), 4.60 (m, 2H), 4.01 (m, 2H), 3.28 (m, 3H), 2.69 (m, 2H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:7]([C:8](O)=[O:9])[CH:6]=1)[CH:2]=[CH2:3].[NH2:18][C:19]1[NH:23][N:22]=[N:21][N:20]=1.O>CN(C)C=O>[CH2:1]([O:4][C:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:7]([C:8]([NH:18][C:19]2[NH:23][N:22]=[N:21][N:20]=2)=[O:9])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(C(=O)O)nc2ccccc12
Reactant: Nc1nnn[nH]1
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1cc(C(=O)Nc2nnn[nH]2)nc2ccccc12
Reaction time: 1 h

Procedure:
N,N'-Carbonyldiimidazole (1.27 g) and 4-allyloxyquinaldic acid (1.2 g) in dimethylformamide (30 ml) were heated at 100° for 4 hours. 5-Aminotetrazole (1.33 g) was added and the mixture was stirred at 100° for 1 hour and cooled. Water (30 ml) was added and the solid was collected and dissolved in hot aqueous dimethylaminoethanol (15 ml, 5%). The solution was filtered and the filtrate was acidified with glacial acetic acid. 4-Allyloxy-N(1H-tetrazol- 5-yl)quinaldamide was collected and dried, m.p. 260° (d).
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[C:14]2[CH2:13][CH2:12][N:11]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:10][CH:9]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:8]=2[S:7][CH:6]=1.CO>CN(C)C=O>[C:21]1([CH:9]2[C:8]3[S:7][CH:6]=[C:5]([C:2]#[N:3])[C:14]=3[CH2:13][CH2:12][N:11]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:10]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N#C[Cu]
Reactant: O=C(N1CCc2c(Br)csc2C(c2ccccc2)C1)C(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Product: N#Cc1csc2c1CCN(C(=O)C(F)(F)F)CC2c1ccccc1

Procedure:
A mixture of copper (I) cyanide (0.45 g) and 3-bromo-8-phenyl-5,6,7,8-tetrahydro-6-trifluoroacetyl-4H-thieno[2,3-d]azepine (1.0 g) in dry dimethylformamide (10 ml) was heated under reflux for 5 hours. After allowing to cool to room temperature methanol (35 ml) was added and the mixture stirred vigorously, filtered and the filtrate evaporated to a yellow oil. Chromatography on silica eluting with diethylether gave the nitrile product, m.p. 107°.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH3:21])[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:20]([C:16]1[N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=[CH:18][CH:17]=1)[CH3:21]
Reactant: CCc1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 22.4 %

Procedure:
A mixture of methyl thiosalicylate (1.3 g, 7.5 mmol), 2-cyano-6-ethylpyridine (0.99 g, 7.5 mmol), triethylamine (1.60 ml, 11.5 mmol) and toluene (6.0 ml) was refluxed for 16 hrs. After cooling, the precipitated crystals were collected by filtration and recrystallized from ethanol to give the titled compound (0.45 g, 22%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=3[CH:24]([OH:32])[CH2:23][CH2:22][CH2:21]2)=[O:19])=[C:15]([CH3:17])[CH:16]=1)=[O:9].[Cl:33][CH2:34][CH2:35][N:36]=[C:37]=[O:38]>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[Cl:33][CH2:34][CH2:35][NH:36][C:37](=[O:38])[O:32][CH:24]1[CH2:23][CH2:22][CH2:21][N:20]([C:18](=[O:19])[C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:8](=[O:9])[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[CH3:1])=[CH:16][C:15]=2[CH3:17])[C:26]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]1=2
Reactant: O=C=NCCCl
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3cc(Cl)ccc32)c(C)c1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OC(=O)NCCCl)c3cc(Cl)ccc32)c(C)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
Tolvaptan (1.0 g, 2.2 mmol) was suspended in toluene (7 ml). 2-Chloroethyl isocyanate (0.28 ml, 3.3 mmol) and 4-dimethylaminopyridine (DMAP) (27 mg, 0.22 mmol) were added thereto, and the mixture was stirred at 80° C. for 24 hours. After cooling to room temperature, the insoluble materials were filtered off and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (n-hexane:ethyl acetate=54:46→33:67). The purified product was concentrated under reduced pressure to obtain 1.0 g of {7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl} (2-chloroethyl)carbamate as white amorphous solid.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[N:16]2[CH2:19][CH:18]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH2:17]2)=[CH:11][CH:10]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)[N:16]2[CH2:19][CH:18]([N:20]([CH2:21][C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)[S:36]([CH3:35])(=[O:38])=[O:37])[CH2:17]2)=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: Clc1ccc(C(c2ccc(Cl)cc2)N2CC(NCc3ccncc3)C2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1ccncc1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 0 °C

Procedure:
346 mm3 of triethylamine are added, at room temperature under an argon atmosphere, to a solution of 398 mg of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(pyrid-4-ylmethyl)amine in 8 cm3 of dichloromethane. The mixture is cooled to around 0° C. before adding thereto 155 mm3 of methylsulfonyl choride, and then it is stirred at room temperature for 3 hours. The reaction mixture is diluted with 35 cm3 of dichloromethane and is then washed with twice 20 cm3 of distilled water. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography on silica gel [eluent:dichloromethane/methanol (97/3 by volume)]. 288 mg of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(pyrid-4-ylmethyl)methylsulfonamide are obtained in the form of a cream-colored foam [1H NMR spectrum (300 MHz, CDCl3, δ in ppm):2.83 (s:3H); 3.02 (broad t, J=7.5 Hz: 2H); 3.40 (broad t, J=7.5 Hz: 2H); 4.23 (s: 1H); 4.43 (mt: 1H); 4.57 (s: 2H); from 7.20 to 7.35 (mt: 8H); 7.32 (broad d, J=5.5 Hz: 2H); 8.60 (broad d, J=5.5 Hz: 2H)].
Reaction SMILES: [CH3:1][CH:2]([C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12]([CH2:13][C@@H:14]([O:29][C:30]([O:32][CH3:33])=[O:31])[CH2:15][C@@H:16]2[O:24][C:25]([O:27][CH3:28])=[O:26])=[CH:11][CH:10]=3)[CH2:7][CH2:6]1)[CH2:3]O.P(Br)(Br)[Br:35]>N1C=CC=CC=1>[Br:35][CH2:3][CH:2]([CH3:1])[C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12]([CH2:13][C@@H:14]([O:29][C:30]([O:32][CH3:33])=[O:31])[CH2:15][C@@H:16]2[O:24][C:25]([O:27][CH3:28])=[O:26])=[CH:11][CH:10]=3)[CH2:7][CH2:6]1
Reactant: BrP(Br)Br
Reactant: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CO)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Solvent: c1ccncc1
Product: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CBr)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
IN 1 ml of pyridine was dissolved 75 mg of 20-methyl-1α,3β-bis(methoxycarbonyloxy)pregna-5,7-dien-21 -ol and, then, under ice-cooling, 0.05 ml of phosphorus tribromide was added. The mixture was stirred at the same temperature for 15 minutes. The reaction mixture was then poured into ice water and extracted with diethyl ether. The extract was washed with aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give 53 mg of 21-bromo-20-methyl-1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[N:13]=1.[CH2:21]([O:23][C:24]1[CH:29]=[CH:28][C:27]([Sn](C)(C)C)=[CH:26][N:25]=1)[CH3:22].[Cl-].[Li+]>O1CCOCC1.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>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:27]3[CH:28]=[CH:29][C:24]([O:23][CH2:21][CH3:22])=[N:25][CH:26]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: CCOc1ccc([Sn](C)(C)C)cn1
Reactant: Fc1cccc(F)c1C1=NC(c2ccc(Br)cc2)CO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CCOc1ccc(-c2ccc(C3COC(c4c(F)cccc4F)=N3)cc2)cn1

Procedure:
2-(2,6-Difluorophenyl)-4-(4-bromophenyl)oxazoline (VP4) (5.00 g, 14.8 mmol) was mixed with 2-ethoxy-5-trimethylstannylpyridine (VP8) (5.06 g, 17.8 mmol), Pd(PPh3)4 (0.68 g, 0.59 mmol) and lithium chloride (0.12 g, 2.9 mmol) in dioxane (40 ml) and the mixture was refluxed under nitrogen (7 hours). After extraction and chromatography, 2-(2,6-difluorophenyl)-4-[4-(2-ethoxypyridin-5-yl)phenyl]oxazoline was obtained, 3.86 g, m.p. 119° C.; 1H NMR (CDCl3, ppm): 1.42, 4.35, OCH2CH3; 4.40, 4.84, 5.51, oxazoline; 6.79, 7.77, 8.36, pyridine; 7.00, 7.41, 7.54, phenyl.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([F:10])=[C:4](Cl)[N:3]=1.Cl.[CH3:13][NH:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([N:14]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:13])[C:5]([F:10])=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CNCC(C)(C)C
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(CC(C)(C)C)c1nc(Cl)c(C#N)cc1F
Yield: 83 %

Procedure:
A solution of 2,6-dichloro-3-cyano-5-fluoropyridine (1.0 g, 5.23 mmol), N-methyl-neopentylamine hydrochloride (830 mg, 6.0 mmol) and triethylamine (1.6 mL) in acetonitrile (20 mL) was stirred at room temp for 4 hours. Then volatiles were removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was dried (sodium sulfate) and concentrated in vacuo to afford the product (1.11 g, 83%). C12H15ClFN3 MS m/e=256 (M+H).