Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([Sn](CCCC)(CCCC)C=C)[CH2:19]CC>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6](=[O:17])[NH:7][C@@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:18]=[CH2:19])[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1cccc(Br)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cccc([C@@H](C)NC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Yield: 82.2 %

Procedure:
A solution of [(R)-1-(3-bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (10.26 g, 0.0342 mol.) and tributyl(vinyl)stannane (32.5 g, 30 mL, 0.103 mol.) in toluene (175 mL) was purged with nitrogen for 30 minutes before addition of bis(triphenylphosphine palladium II chloride (2.38 g, 0.0034 mol.). The stirred mixture was heated to 60° C. for 16 hours before cooling to room temperature. The reaction mixture was filtered through hyflo-supercel then evaporated to give a dark coloured oil. The oil was purified by silica gel chromatography using iso-hexanes/ethyl acetate 19:1 to yield the title compound (6.95 g, 82%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ1.39-1.51 (m, 12H), 4.80 (br s, 2H), 5.24-5.32 (m, 1H), 5.77 (d, J=17.6 Hz, 1H), 6.73 (dd, J=17.6, 10.9 Hz, 1H), 7.18-7.36 (m, 4H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[F:12][C:13]([F:25])([F:24])[C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:25][C:13]([F:12])([F:24])[C:14]1[CH:15]=[CH:16][C:17]([S:20]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([CH:10]=[O:11])=[CH:2]2)(=[O:22])=[O:21])=[CH:18][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: O=Cc1c[nH]c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=Cc1cn(S(=O)(=O)c2ccc(C(F)(F)F)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A solution of 1H-indole-3-carboxaldehyde (0.290 g, 2.00 mmol) in methylene chloride (4 mL) was added with 4-(trifluoromethyl)phenylsulfonyl chloride (0.587 g, 2.40 mmol) and diisopropylethylamine (0.310 g, 2.40 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate to terminate the reaction, and then extracted three times with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 1-[4′ (trifluoromethyl)phenylsulfonyl]-1H-indole-3-carboxaldehyde (0.650 g, 92%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]3([CH:29]=[CH:28][C:27](=[O:30])[CH:26]=[CH:25]3)[N:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]3[CH:29]=[CH:28][C:27](=[O:30])[CH:26]=[CH:25][C:16]3=[C:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C=CC2(C=C1)N=C(N1CCN(Cc3ccccc3)CC1)C=C2c1ccccc1
Solvent: ClCCl
Product: O=c1ccc2c(-c3ccccc3)cc(N3CCN(Cc4ccccc4)CC3)n2cc1
Temperature: 20 °C
Yield: 71.9 %

Procedure:
2-(4-Benzyl-1-piperazinyl)-4-phenyl-1-azaspiro[4.5]deca-1,3,6,9-tetraen-8-one (14.6 g) is heated for 10 minutes to a temperature of about 200° C. After being cooled to a temperature of about 20° C., the residue obtained in dissolved in methylene chloride (500 cc) and the solution is poured into silica (300 g) contained in a column 4.2 cm in diameter. Elution is performed first with pure methylene chloride (4 liters); the corresponding eluate is rejected. Elution is then performed with a mixture of methylene chloride and methanol (90:10 by volume) (3 liters) and the eluate is evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. After recrystallization of the residue in acetonitrile (200 cc), 3-(4-benzyl-1-piperazinyl)-1-phenyl-7H-pyrrolo[1,2-a]azepin-7-one (10.5 g), m.p. 157° C., is obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]([NH2:13])[C:8]2([CH3:12])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.C([O:16][C:17]1[C:18](=[O:33])[C:19](=O)[C:20]=1[NH:21][C:22]1[C:30]2[NH:29][C:28](=[O:31])[NH:27][C:26]=2[CH:25]=[CH:24][CH:23]=1)C>>[CH3:1][C:2]1[O:6][C:5]([CH:7]([NH:13][C:19]2[C:18](=[O:33])[C:17](=[O:16])[C:20]=2[NH:21][C:22]2[C:30]3[NH:29][C:28](=[O:31])[NH:27][C:26]=3[CH:25]=[CH:24][CH:23]=2)[C:8]2([CH3:12])[CH2:9][O:10][CH2:11]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(N)C2(C)COC2)o1
Reactant: CCOc1c(Nc2cccc3[nH]c(=O)[nH]c23)c(=O)c1=O
Product: Cc1ccc(C(Nc2c(Nc3cccc4[nH]c(=O)[nH]c34)c(=O)c2=O)C2(C)COC2)o1
Temperature: 65 °C
Yield: 18 %

Procedure:
0.33 g of C-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine (1.80 mmol, 1.2 eq) was added to a solution of 0.41 g of 3-ethoxy-4-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-ylamino)cyclobut-3-ene-1,2-dione (1.50 mmol, 1 eq). The reaction medium was heated at 65° C. for 18 hours. The methanol was evaporated off and the residue was chromatographed on silica gel, eluent 95/5 dichloromethane/methanol with 0.1% of triethylamine. The product remains stuck on the silica. The paste obtained was crystallized from diethyl ether, filtered and dried under vacuum at 40° C. 0.11 g of 3-{[(5-methylfuran-2-yl)-(3-methyloxetan-3-yl)methyl]amino}-4-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-ylamino)cyclobut-3-ene-1,2-dione was obtained. Yield=18%. HPLC 94.8%, ES− [407].
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH:23]([C:26]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]([CH3:35])[CH3:34])[C:27]=1[NH2:28])([CH3:25])[CH3:24].[Br:36][CH2:37][C:38](O)=[O:39]>CN(C)C=O>[Br:36][CH2:37][C:38]([NH:28][C:27]1[C:26]([CH:23]([CH3:25])[CH3:24])=[CH:32][CH:31]=[CH:30][C:29]=1[CH:33]([CH3:35])[CH3:34])=[O:39]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C(O)CBr
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CBr
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.3 %

Procedure:
1-(3′-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC) (2.1 g, 11 mmols) and 1-hydroxybenzotriazole (HOBt) (1.49 g, 11 mmols) were added to an N,N-dimethylformamide (DMF) (30 ml) solution of 2,6-diisopropylaniline (1.97 g, 10 mmols) and bromoacetic acid (2.08 g, 15 mmols), and stirred at room temperature for 12 hours. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, 1 N HCl, an aqueous saturated solution of sodium hydrogencarbonate and saturated saline in that order, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. Then, the residue was purified through silica gel column chromatography (developer: hexane/acetone=5/1), and the resulting crystals were recrystallized from ether-hexane to obtain 1.26 g (42%) of 2-bromo-N-(2,6-diisopropylphenyl)acetamide as colorless needle-like crystals.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>>[Cl:26][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:39][C:36]2[CH:35]=[CH:34][C:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=3)=[CH:38][CH:37]=2)=[N:3][CH:4]=1
Reactant: Oc1ccc(-c2ccccn2)cc1
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(-c2ccccn2)cc1)c1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from tert-butyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 45) and 4-pyridin-2-ylphenol (Tetrahedron, 1998, 54, 1289): 1H-NMR (CDCl3) δ 8.71 (1H, m), 8.56 (1H, d, J=2.8 Hz), 8.19–7.71 (8H, m), 7.41 (2H, d, J=1.8 Hz), 7.29–7.25 (3H, m), 5.36 (1H, m), 1.58 (3H, d, J=7.0 Hz), 1.57 (9H, s).
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([CH2:19][CH2:20][CH3:21])[C:7]([OH:22])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[I-].[K+].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][S:35][C:36]1[CH:41]=[CH:40][C:39]([C:42](=[O:44])[CH3:43])=[C:38]([OH:45])[C:37]=1[CH2:46][CH2:47][CH3:48]>CC(C)=O>[C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([CH2:19][CH2:20][CH3:21])[C:7]([O:22][CH2:32][CH2:33][CH2:34][S:35][C:36]2[CH:41]=[CH:40][C:39]([C:42](=[O:44])[CH3:43])=[C:38]([OH:45])[C:37]=2[CH2:46][CH2:47][CH3:48])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCCc1c(SCCCBr)ccc(C(C)=O)c1O
Reactant: CCCc1c(O)ccc(C(C)=O)c1OCCCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(SCCCOc2ccc(C(C)=O)c(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Temperature: 25 °C

Procedure:
To a stirred mixture of ethyl 4-(6-acetyl-3-hydroxy-2-propylphenoxy)butyrate (1.6 g), potassium iodide (0.5 g) and potassium carbonate (1.45 g) in acetone (30 ml) was added drop wise a solution of 4-(3-bromopropylthio)-2-hydroxy-3-propylphenyl-ethanone (1.9 g) in acetone (10 ml) with heating to reflux. After refluxing six hours the mixture was cooled to room temperature and inorganic materials were separated by filtration. The filtrate was concentrated and the residue was separated and purified by silica-gel column chromatography (eluting with benzene:ethyl acetate=9:1) to give the title compound as crude crystals (2.1 g, 72.4%) which were recrystallized from ethanol to give colorless crystals, mp 65-66° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].I[CH2:11][CH3:12].C([O-])([O-])=O.[K+].[K+].CCOCC>CN(C=O)C>[Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH2:11][CH3:12]
Reactant: Oc1cccc(F)c1Br
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOc1cccc(F)c1Br
Temperature: 80 °C

Procedure:
A mixture of commercially available 2-bromo-3-fluorophenol (5.000 g; 26.20 mmol), iodoethane (8.166 g; 52.40 mmol), and K2CO3 (4.342 g; 31.40 mmol) in anh. DMF (100 ml) was heated to 80° C., under nitrogen, for 1.5 h. Et2O was added and the organic layer was washed with water, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 2-bromo-1-ethoxy-3-fluorobenzene as a yellow oil. LC-MS (conditions A): tR=0.88 min.; no ionisation.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=O)[CH2:7]1)=[O:5])[CH3:2].S(Cl)([Cl:16])=O>ClCCl>[Cl:16][C:11]([CH:8]1[CH2:9][CH2:10][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7]1)=[O:13]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)N1CCC(C(=O)O)C1
Solvent: ClCCl
Product: CCOC(=O)N1CCC(C(=O)Cl)C1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred solution of 44 parts of 1-(ethoxycarbonyl)-3-pyrrolidinecarboxylic acid in 520 parts of dichloromethane were added dropwise 35.7 parts of thionyl chloride at 20° C. Upon complete addition, stirring was continued overnight and the reaction mixture was evaporated, yielding 49 parts (100%) of ethyl 3-(chlorocarbonyl)-1-pyrrolidinecarboxylate as an oily residue (int. 25).
Reaction SMILES: [CH3:1][N:2]([S:16]([C:19]1[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=1)(=[O:18])=[O:17])[CH2:3][CH2:4]OS(C1C=C(C)C=CC=1)(=O)=O.[CH3:26][C:27]1[NH:28][C:29]2[C:34]([C:35]=1[C:36]1[CH2:37][CH2:38][NH:39][CH2:40][CH:41]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2>>[CH3:25][C:21]1[CH:20]=[C:19]([S:16]([N:2]([CH3:1])[CH2:3][CH2:4][N:39]2[CH2:40][CH:41]=[C:36]([C:35]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[NH:28][C:27]=3[CH3:26])[CH2:37][CH2:38]2)(=[O:17])=[O:18])[CH:24]=[CH:23][CH:22]=1
Reactant: Cc1[nH]c2ccccc2c1C1=CCNCC1
Reactant: Cc1cccc(S(=O)(=O)OCCN(C)S(=O)(=O)c2cccc(C)c2)c1
Product: Cc1cccc(S(=O)(=O)N(C)CCN2CC=C(c3c(C)[nH]c4ccccc34)CC2)c1

Procedure:
The title compound was prepared using the procedure described in Example 1 using toluene-3-sulfonic acid 2-(methyl-(toluene-3-sulfonyl)-amino)-ethyl ester (D1) and 2-methyl-3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H indole. MH+ 424.
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.N12CCN(CC1)CC2.[CH3:20][N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:23][CH2:22]1>C(O)(C)C>[Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:35][C:32]2[CH:31]=[CH:30][C:29]([O:28][CH2:27][CH:24]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]3)=[CH:34][CH:33]=2)=[N:4][CH:3]=1
Reactant: Brc1ncc(Br)n2ccnc12
Reactant: CN1CCC(COc2ccc(N)cc2)CC1
Agent: C1CN2CCN1CC2
Solvent: CC(C)O
Product: CN1CCC(COc2ccc(Nc3ncc(Br)n4ccnc34)cc2)CC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 5,8-dibromo-imidazo[1,2-a]pyrazine (0.100 g, 0.36 mmol) in isopropanol (5 mL) are added 1,4-diazabicyclo[2,2,2]octane (DABCO) (0.036 mL, 0.36 mmol) and 4-(1-methyl-piperidin-4-ylmethoxy)-phenylamine (79.6 mg, 0.36 mmol). The reaction mixture is stirred at 90° C. overnight. The solvent is evaporated and the residue chromatographed on silica gel column eluting with 97:3 followed by 94:6 and 90:10 DCM:MeOH. The title compound is obtained as a solid (20 mg, 13%). LCMS: Rt 2.30min (94%), m/z (APCI) 417.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2Cl)=[CH:4][CH:3]=1.[CH2:13]([NH:16][CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[N:16]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1
Reactant: Clc1nccc2ccc(Br)cc12
Reactant: CCCNCCC
Product: CCCN(CCC)c1nccc2ccc(Br)cc12
Yield: 62 %

Procedure:
A solution of 7-bromo-1-chloroisoquinoline from step 1 (500 mg, 2.1 mmol) and dipropylamine (2.8 mL, 21 mmol) was heated at 150° C. in a sealed tube for 2 d. The reaction mixture was cooled, and the solvent was removed under reduced pressure to provide 7-bromo-N,N-dipropylisoquinolin-1-amine (400 mg): 1H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 1H), 7.90 (d, J=6 Hz, 1H), 7.75–7.64 (m, 2H), 6.87 (d, J=6 Hz, 1H), 3.42 (q, J=7 Hz, 4H), 1.65 (q, J=7 Hz, 4H), 0.94 (t, J=7 Hz, 6H).
Reaction SMILES: Cl[C:2]1[C:3]([OH:35])=[C:4]([CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:13]2=[O:34])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.F[C:37]1C=C(O)C(C2C3C(=CC=CC=3)N(CC3C=CC(OC)=CC=3)C2=O)=CC=1C#N>>[C:28]1([CH:21]([N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12]3([C:4]4[C:5]5[O:10][CH2:9][CH2:8][O:7][C:6]=5[CH:11]=[CH:2][C:3]=4[O:35][CH2:37]3)[C:13]2=[O:34])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C1C(c2c(O)c(Cl)cc3c2OCCO3)c2ccccc2N1C(c1ccccc1)c1ccccc1
Reactant: COc1ccc(CN2C(=O)C(c3cc(C#N)c(F)cc3O)c3ccccc32)cc1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1ccc3c(c12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 2.40 and making non-critical variations using 3-(7-chloro-6-hydroxy-2,3-dihydro-1,4-benzodioxin-5-yl)-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one to replace 2-fluoro-4-hydroxy-5-[1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile, (diphenylmethyl)-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one was obtained (65%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.42-7.26 (m, 10H), 7.20-7.15 (m, 1H), 7.11 (s, 1H), 7.03-6.95 (m, 2H), 6.78 (s, 1H), 6.50-6.45 (m, 1H), 5.02 (d, J=8.7 Hz, 1H), 4.76 (d, J=8.7 Hz, 1H), 4.12-3.84 (m, 4H); MS (ES+) m/z 496.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=2[F:19])=[CH:6][C:5]=1[CH3:20].C=O.[C:24](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=2[F:19])[CH3:24])=[CH:6][C:5]=1[CH3:20]
Reactant: COC(=O)c1ccc(CNc2ccc(O)cc2F)cc1C
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CN(C)c2ccc(O)cc2F)cc1C
Reaction time: 0.67 h
Yield: 50.5 %

Procedure:
A mixture of 4-[(2-fluoro-4-hydroxy-phenylamino)-methyl]-2-methyl-benzoic acid methyl ester (1.89 g, 6.53 mmol) and 2.0 mL of 37% formaldehyde in 20 mL of acetic acid is stirred for 40 minutes. Sodium triacetoxyborohydride (2.80 g, 13.2 mmol) is added. Upon completion, the mixture is concentrated and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer is extracted with ethyl acetate (3×). The combined ethyl acetate layers are dried (MgSO4) and concentrated. The residue is purified on 120 g silica with ethyl acetate in heptane gradient (10% to 60%) to provide 1.0 g (51%) of the titled compound as a white solid. LC-ES/MS m/e 304.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13](O)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:27][CH:26]=1.C(N(CC)CC)C.[I-].C[N+]1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:13]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:29][CH:30]=2)=[O:14])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: O=C(O)C(Cc1ccccc1)NS(=O)(=O)c1ccc(Cl)cc1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1ccc(NC(=O)C(Cc2ccccc2)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 33.3 %

Procedure:
The procedure described in Example 177 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-phenylpropanoic acid (1 g) and ethyl 4-aminophenylacetate hydrochloride (571 mg) were condensed in chloroform (35 ml) in the presence of triethylamine (1.64 ml) and 1-methyl-2-chloropyridinium iodide (902 mg) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl) phenyl)-3-phenylpropanamide (442.3 mg).
Reaction SMILES: [C:1]([CH:3]([CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])[C:4]([O:6][CH3:7])=[O:5])#[N:2].Br[CH:17]([CH2:22][CH2:23][Br:24])[C:18]([O:20][CH3:21])=[O:19].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[C:10]1([CH:8]([C:3]([C:1]#[N:2])([C:4]([O:6][CH3:7])=[O:5])[CH:17]([C:18]([O:20][CH3:21])=[O:19])[CH2:22][CH2:23][Br:24])[CH3:9])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)C(C#N)C(C)c1ccccc1
Reactant: COC(=O)C(Br)CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)C(CCBr)C(C#N)(C(=O)OC)C(C)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A mixture of methyl 2-cyano-3-phenylbutyrate (78 g, 0.37 mole), methyl 2,4-dibromobutyrate (122 g, 0.47 mole), potassium carbonate (65 g, 0.47 mole) and DMSO (50 ml) was stirred on a ball mill apparatus. The reaction was completed in four hours. Ice water was added and the mixture was neutralized by adding cold hydrochloric acid. The aqueous solution was extracted several times with ether. The combined organic solution was washed sequentially with cold aqueous sodium bicarbonate and brine, then dried over magnesium sulfate. After removal of the solvent, the residue was purified by Kugelrohr distillation (100° C., 30 microns) to remove low boiling materials. The remaining oily residue (118 g., 84%) was found to be mainly the title bromide condensation product (ν<95% GC purity). MS m/e (% relative intensity) 383(M+., 3) 381 (3), 202 (33), 182 (7), 180 (7), 105 (100).
Reaction SMILES: [C:1](Cl)(=O)[C:2](Cl)=O.[Na].O[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=[S:15]>C1C=CC=CC=1.CN(C=O)C.CN(C1C=CN=CC=1)C>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][C:2]1[CH:1]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: On1ccccc1=S
Reactant: O=C(Cl)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: [Na]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: c1ccc(Sc2ccccn2)nc1
Yield: 72 %

Procedure:
360 mg (1 mmol) of peracetoquinic acid (32) are taken into solution with stirring in 5 ml of benzene with the addition of 1 ml of oxalyl chloride and 1 drop of DMF for 3 hours. After evaporation to dryness, the residue is taken up in 5 ml of benzene and added with stirring to a suspension of 180 mg (1.1 mmol) of the sodium salt of N-hydroxypyridine-2-thione and 12 mg (0.1 mmol) of DMAP. The reaction mixture is kept refluxing in 10 ml of toluuene under an atmosphere of nitrogen. After 2 hours of heating under reflux, the cooled reaction mixture is filtered on Celite and evaporated to dryness. By flash chromatography on silica (90% of CH2Cl2 ; 10% EtOAc), 306 mg of pyridyl sulfide of formula (34) are obtained in the form of a yellowish oil. Yield 72%.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][C:5]1[S:9][C:8]([NH:10][C:11]([C:13]2([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:15][CH2:14]2)=[O:12])=[N:7][CH:6]=1.Br.Br[CH2:30][CH2:31][N:32]([CH2:35][CH3:36])[CH2:33][CH3:34].[H-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][C:5]1[S:9][C:8](=[N:10][C:11]([C:13]2([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:15][CH2:14]2)=[O:12])[N:7]([CH2:30][CH2:31][N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])[CH:6]=1
Reactant: COc1ccc(C2(C(=O)Nc3ncc(Cc4ccccc4Cl)s3)CC2)cc1
Reactant: CCN(CC)CCBr
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)CCn1cc(Cc2ccccc2Cl)sc1=NC(=O)C1(c2ccc(OC)cc2)CC1
Yield: 20 %

Procedure:
1-(4-Methoxy-phenyl)-cyclopropanecarboxylic acid [5-(2-chloro-benzyl)-thiazol-2-yl]-amide (39.9 mg, 0.100 mmol) and (2-bromo-ethyl)-diethyl-amine hydrobromide (26.1 mg, 0.100 mmol) were dissolved in 1 mL of tetrahydrofuran. Sodium hydride (60% dispersion in oil, 8.8 mg, 0.22 mmol) was added and the reaction was subjected to microwave irradiation for 10 minutes at 100° C. The solvent was evaporated to dryness and the crude mixture was purified by reverse-phase preparative liquid chromatography to yield 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid [5-(2-chloro-benzyl)-3-(2-diethylamino-ethyl)-3H-thiazol-2-ylidene]-amide (10 mg, 0.020 mmol, 20%) ESI-MS m/z calc. 497.2. found 498.3 (M+1)+. Retention time of 2.64 minutes. 1H NMR (400 MHz, CD3CN) δ 1.07-1.17 (m, 8H), 1.54-1.59 (m, 2H), 2.88-2.94 (m, 4H), 3.19-3.24 (m, 2H), 3.80 (s, 3H), 4.07 (s, 2H), 4.24 (t, J=6.4 Hz, 2H), 6.86-6.91 (m, 2H), 6.97 (s, 1H), 7.26-7.47 (m, 6H) and 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid [5-(2-chloro-benzyl)-thiazol-2-yl]-(2-diethylamino-ethyl)-amide (14 mg, 0.028 mmol, 28%) ESI-MS m/z calc. 497.2. found 498.3 (M+1)+. Retention time of 2.65 minutes. 1H NMR (400 MHz, CD3CN) δ 1.08-1.17 (m, 6H), 1.30-1.37 (m, 2H), 1.51-1.57 (m, 2H), 2.55-2.59 (m, 2H), 3.00-3.05 (m, 4H), 3.79 (s, 3H), 4.26 (s, 2H), 4.42 (t, J=3.0 Hz, 2H), 6.90-6.95 (m, 2H), 7.16-7.23 (m, 2H), 7.27-7.50 (m, 5H).