Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CO>[CH2:15]([NH:14][C:12]([NH:11][C:8]1[S:9][C:10]2[C:2]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[F:23])=[CH:3][C:4]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:5][C:6]=2[N:7]=1)=[O:13])[CH3:16]
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(Br)c2s1
Reactant: OB(O)c1ccccc1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3ccccc3F)c2s1
Temperature: 80 °C
Yield: 23 %

Procedure:
A stirred mixture of 1-(7-Bromo-5-pyridin-3-yl-benzothiazol-2-yl)-3-ethyl-urea (50 mg, 0.133 mmol), 2-fluorobenzeneboronic acid (19 mg, 0.139 mmol), powdered potassium phosphate tribasic (34 mg, 0.160 mmol) and 1,1′-bis(diphenylphosphino)ferrocene palladium(II)chloride complex (16 mg, 0.01995 mmol) in anhydrous 1,4-dioxane (1 ml) and anhydrous methanol (2 ml) was purged with nitrogen for 5 min and heated in a sealed vessel for 16 h at 80° C. After cooling to ambient temperature, the mixture was filtered through kieselguhr. The kieselguhr was thoroughly washed with methanol and the combined filtrates evaporated to dryness in vacuo to give the crude 1-Ethyl-3-[7-(2-fluoro-phenyl)-5-pyridin-3-yl-benzothiazol-2-yl]-urea which was purified by “flash” silica chromatography eluting with 0 to 30% methanol in ethyl acetate. 12 mg of a pale-brown solid was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH:5](N=C(C1C=CC=CC=1)C1C=C(Cl)C=CC=1O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(Cl)(=O)C1C=CC=CC=1>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(N=C(c1ccccc1)c1cc(Cl)ccc1O)C(=O)OCC
Solvent: c1ccncc1
Solvent: O=C(Cl)c1ccccc1
Product: CCOC(=O)CC(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 7.8 g. of [(5-chloro-2-hydroxy-α-phenylbenzyliden)amino] malonic acid diethyl ester in 15 ml. of pyridine is treated at 10°-15° C. with 3.5 ml. of benzoyl chloride. The mixture is stirred at room temperature for 1 hour and then poured on to 150 ml. of ice-water. The separated oily product is extracted with ether and the organic phase washed with water, then with 2-N sodium carbonate solution and finally with water. After drying over sodium sulfate and evaporation of the solvent, the oily residue is triturated with hexane, crystallization setting in. There is obtained [(2-benzoylloxy-5-chloro-α-phenylbenzyliden)amino] malonic acid diethyl ester in the form of colorless crystals, having a melting point of 108°-110° C. Recrystallization from ethanol increases the melting point to 109°-111° C.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5]S[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=O)C=1.[S:25]([O-:29])([O-])(=[O:27])=S.[Na+].[Na+].C(N(CC)CC)C.C(OC([O-])=O)(OC(OC(C)(C)C)=O)=O>ClCCl>[O:27]=[S:25]1(=[O:29])[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCSCC1
Reactant: O=S([O-])([O-])=S
Agent: CC(C)(C)OC(=O)OC(=O)OC(=O)[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCS(=O)(=O)CC1
Yield: 91.6 %

Procedure:
tert-Butyl thiomorpholine-4-carboxylate (1.91 g, 9.42 mmol) was dissolved in dichloromethane (50 ml); m-chloroperbenzoic acid (5.0 g, 19 mmol) was gradually added while cooled with ice bath, stirred, and under nitrogen atmosphere; and the reaction mixture was stirred at room temperature for 12 hours. After addition of a saturated aqueous solution of sodium thiosulfate, the reaction mixture was kept stirred for a while; and this was subjected to extraction with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Triethylamine (8.1 ml, 58 mmol) were added to the obtained crystals; and the reaction mixture was stirred at room temperature. tert-Butoxycarbonyl dicarbonate (13.3 ml, 58 mmol) was added thereto; and the reaction mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure; and the obtained crystals were suspended with a solvent mixture of diethyl ether:ethanol=10:1, filtered off, washed with diethyl ether and dried under aeration to yield the title compound as colorless crystals (2.03 g, 8.63 mmol, 91.6%).
Reaction SMILES: B.O1CCCC1.[CH3:7][C:8]1[S:12][C:11]([CH2:13][CH2:14][O:15][CH2:16][C:17]([NH2:19])=O)=[CH:10][CH:9]=1.CO>O1CCCC1>[CH3:7][C:8]1[S:12][C:11]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH2:19])=[CH:10][CH:9]=1
Reactant: Cc1ccc(CCOCC(N)=O)s1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(CCOCCN)s1

Procedure:
Borane-tetrahydrofuran solution (1.0 M in THF, 21.7 ml) was added dropwise to a stirred solution of the product from step b) (1.25 g) in dry tetrahydrofuran (100 ml). The reaction was heated at reflux under an inert atmosphere for 5 hours. The reaction was cooled and methanol (10ml) added cautiously. The solvents were removed in vacuo and the residue dissolved in methanol (100 ml) to which was added concentrated hydrochloric acid (sg. 1.18, 0.45 ml). This solution was heated at reflux for 15 min then the solvent removed in vacuo. The residue was purified by flash chromatography (dichloromethane: 5% methanol as eluant) to give the subtitle compound as a white solid (0.916 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:19])[CH2:15][C:16]([OH:18])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:21]1([CH2:27][CH2:28][CH2:29][CH:30]([NH2:40])[CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:34]1([CH2:33][CH2:32][CH2:31][CH:30]([NH:40][C:16](=[O:18])[CH2:15][C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:19])[CH2:29][CH2:28][CH2:27][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NC(CCCc1ccccc1)CCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CC(=O)O)CC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CC(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-3-oxopropionic acid (36) (1.20 g; 4.41 mmol) is dissolved in methylene chloride (40 mL) at ambient temperature. 1,7-Diphenyl-4-aminoheptane hydrochloride (1) (1.61 g; 5.29 mmol), N,N-diisopropylethylamine (1.82 g; 14.1 mmol) and PyBOP (2.75 g; 5.29 mmol) are added sequentially. The reaction is stirred for 14 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography (40%→70% ethyl acetate in hexanes) affording the desired product as a solid. ESMS: MH− 522.4
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:26]1([N:36]2[CH2:41][CH2:40][N:39]([CH2:42][CH2:43][CH2:44][CH2:45][NH2:46])[CH2:38][CH2:37]2)[C:35]2[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=2[CH:29]=[CH:28][CH:27]=1>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([NH:46][CH2:45][CH2:44][CH2:43][CH2:42][N:39]2[CH2:40][CH2:41][N:36]([C:26]3[C:35]4[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=4[CH:29]=[CH:28][CH:27]=3)[CH2:37][CH2:38]2)=[O:11])[CH:2]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCCCN1CCN(c2cccc3c2CCCC3)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(C=Cc1cccnc1)NCCCCN1CCN(c2cccc3c2CCCC3)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1.6 g (11.1 mmol) 3-(3-pyridyl)-acrylic acid and 6.2 ml (44.3 mmol) TEA are suspended in 80 ml absolute dichloromethane and cooled to ca. 0° C. under moisture exclusion. 2.0 g (12.1 mmol) 81% HOBT and 2.3 g (12.1 mmol) EDC are added and the mixture is stirred for 30 min under ice cooling. 4.0 g (10.1 mmol) 4-[4-(5,6,7,8-tetrahydro-naphthalin-1-yl)-piperazin-1-yl]-butylamine are added and the mixture is stirred without cooling overnight at RT. Subsequently, the batch is washed twice with 25 ml 2M sodium hydroxide solution and 25 ml water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically pre-purified over silica gel with CHCl3/CH3OH (95/5) and crystallized twice from acetonitrile (25 ml and 15 ml): Colorless crystals of MP. 108-109° C.; yield 2.7 g (64%).
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][CH:29]=1)[CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:30]([N:32]([CH2:46][CH3:47])[C:33]([N:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]([CH:44]=O)=[CH:36]1)=[O:34])[CH3:31]>O1CCCC1>[CH2:46]([N:32]([CH2:30][CH3:31])[C:33]([N:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]([CH:44]=[CH:7][C:6]2[CH:27]=[CH:28][CH:29]=[C:4]([O:3][CH3:2])[CH:5]=2)=[CH:36]1)=[O:34])[CH3:47]
Reactant: CCN(CC)C(=O)n1cc(C=O)c2ccccc21
Reactant: COc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCN(CC)C(=O)n1cc(C=Cc2cccc(OC)c2)c2ccccc21
Yield: 59.2 %

Procedure:
3-Methoxybenzyltriphenylphosphonium chloride (1.71 g) and 1-diethylcarbamoyl-3-formylindole (1.71 g), which had been synthesized according to the method of Tetrahedron Lett., 1869 (1986)., were reacted in tetrahydrofuran (5 ml) as in the above Production Example 41-1 to give the title compound (0.842 g) as a brown oil (yield: 59.1%). (59-2) 1-Diethylcarbamoyl-3-(3-methoxyphenethyl)indole
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6](/[CH:7]=[CH:8]/[S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:15][NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6](/[CH:7]=[CH:8]/[S:9]([N:16]([CH3:15])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(/C=C/S(=O)(=O)Cl)cc1
Reactant: CNc1ccccc1
Product: COc1ccc(/C=C/S(=O)(=O)N(C)c2ccccc2)cc1
Yield: 80.9 %

Procedure:
A solution of (E)-4-methoxystyrylsulfonyl chloride (10 mmol) and N-methyl aniline (10 mmol) was subjected to General Procedure 1, part B. The title compound, melting point 126-129° C., was obtained 80.9% yield.
Reaction SMILES: [CH3:1][N:2]1[C:16]2[C:17]3[C:4]([CH2:5][C@@H:6]4[C@@H:11]([C:12]=3[CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]([C:18]([OH:20])=O)[CH2:8][N:7]4[CH3:21])=[CH:3]1.P(Cl)(Cl)(Cl)=O.[NH2:27][CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1.[OH-].[NH4+]>CN(C)C=O>[N:31]1[CH:32]=[CH:33][CH:34]=[C:29]([CH2:28][NH:27][C:18]([C@@H:9]2[CH2:10][C@H:11]3[C@@H:6]([CH2:5][C:4]4[C:17]5[C:16](=[CH:15][CH:14]=[CH:13][C:12]3=5)[N:2]([CH3:1])[CH:3]=4)[N:7]([CH3:21])[CH2:8]2)=[O:20])[CH:30]=1
Reactant: NCc1cccnc1
Reactant: CN1CC(C(=O)O)C[C@@H]2c3cccc4c3c(cn4C)C[C@H]21
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CN1C[C@H](C(=O)NCc2cccnc2)C[C@@H]2c3cccc4c3c(cn4C)C[C@H]21
Reaction time: 0.5 h

Procedure:
One gram of 1,6-dimethylergoline-8-carboxylic acid was slurried with 40 ml of dimethylformamide under a nitrogen atmosphere. The mixture was cooled by means of an external ice/acetone bath. To the slurry were added 700 mcl of phosphorous oxychloride in dropwise fashion keeping the temperature below 0° C. After stirring for 30 minutes, 800 mcl of 3-(aminomethyl)pyridine were added. After stirring an additional two hours, the mixture was poured into approximately 200 ml of dilute ammonium hydroxide and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, dried over sodium sulfate, and concentrated in vacuo. The residue was crystallized from ethyl acetate/hexane to provide 700 mg of the desired title product, m.p. 185°-187° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].[Br-].[CH:24]1([Zn+])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C1COCC1>CN1CCCC1=O.CC(P(C(C)(C)C)C(C)(C)C)(C)C.CC(P(C(C)(C)C)C(C)(C)C)(C)C.[Pd]>[CH:24]1([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:4][C:3]=2[C:19]([F:22])([F:21])[F:20])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COc1ccc(COCc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: [Zn+]C1CCCCC1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: COc1ccc(COCc2ccc(C3CCCCC3)c(C(F)(F)F)c2)cc1
Temperature: 105 °C

Procedure:
1-Chloro-4-(4-methoxy-benzyloxymethyl)-2-trifluoromethyl-benzene (2 g, 6.51 mmol), Pd(t-Bu3P)2 (66.54 mg, 0.13 mmol) and cyclohexylzinc bromide/THF solution (0.5 M, 40 mL, 19.5 mmol) are mixed in 1-methyl-2-pyrrolidinone (NMP) (40 mL). The mixture is purged with N2 (g) and then heated at 105° C. for 16 hours. The reaction mixture is poured into saturated aqueous NH4Cl (250 mL) and extracted with EtOAc. The combined extracts are washed with brine and dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (8:1 hexanes/EtOAc) to give 1-Cyclohexyl-4-(4-methoxy-benzyloxymethyl)-2-trifluoromethyl-benzene. To a solution of this material in DCM (8 mL) is added TFA (8 mL). The reaction mixture is stirred at room temperature for 16 hours. After concentration, the residue is partitioned between saturated aqueous NH4Cl and EtOAc. The aqueous phase is extracted with EtOAc. The combined organic extracts are washed with brine and dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (4:1 hexanes/EtOAc) to give (4-Cyclohexyl-3-trifluoromethyl-phenyl)-methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH:12]([C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)=O.S(OS([O-])=O)([O-])=O.[Na+].[Na+]>CN(C)C(=O)C>[CH3:21][O:20][C:18](=[O:19])[C:17]1[CH:22]=[CH:23][C:14]([C:12]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][CH:9]=[C:8]([F:11])[CH:7]=3)[N:1]=2)=[CH:15][CH:16]=1
Reactant: NC(=O)c1cc(F)ccc1N
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: O=S([O-])OS(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(-c2nc3ccc(F)cc3c(=O)[nH]2)cc1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A suspension of 2-amino-5-fluorobenzamide (1.00 g, 6.49 mmol), methyl 4-formylbenzoate (1.06 g, 6.49 mmol) and sodium disulfite (1.26 g, 6.62 mmol) in N,N-dimethylacetamide (13 ml) is heated to 150° C. and stirred at this temperature for 3 hours. The reaction mixture is allowed to reach room temperature and poured into ice water. The resulting precipitate is collected by filtration, washed with water and dried under vacuum to afford 4-(6-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl)-benzoic acid methyl ester as yellow solid; HPLC/MS 2.08 min (C), [M+H] 299.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>ClCCl.C(O)C>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: BrCc1ccc(I)cc1
Solvent: CCO
Solvent: ClCCl
Product: Ic1ccc(CN2CCCCC2)cc1

Procedure:
Prepared analogously to Example 1.1 c. from 4-iodobenzyl bromide and piperidine. Yield: 0.85 g (67% of theory); C12H16IN (M=301.17); calc.: molecular ion peak (M+H)+: 322; found: molecular ion peak (M+H)+: 302; Rf value: 0.55 (silica gel, dichloromethane/ethanol (20:1)).
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][C@H:6]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]([F:26])[F:25])=[C:19]([O:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)[CH:18]=1)[CH2:7][C:8]1[C:13]([Cl:14])=[CH:12][N+:11]([O-:15])=[CH:10][C:9]=1[Cl:16])=[O:4].[N+:32]([C:35]1[CH:40]=[CH:39][C:38]([CH2:41][S:42](Cl)(=[O:44])=[O:43])=[CH:37][CH:36]=1)([O-:34])=[O:33]>N1C=CC=CC=1.CCOC(C)=O>[Cl:16][C:9]1[CH:10]=[N+:11]([O-:15])[CH:12]=[C:13]([Cl:14])[C:8]=1[CH2:7][C@@H:6]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]([F:26])[F:25])=[C:19]([O:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)[CH:18]=1)[O:5][C:3](=[O:4])[CH2:2][NH:1][S:42]([CH2:41][C:38]1[CH:37]=[CH:36][C:35]([N+:32]([O-:34])=[O:33])=[CH:40][CH:39]=1)(=[O:43])=[O:44]
Reactant: O=[N+]([O-])c1ccc(CS(=O)(=O)Cl)cc1
Reactant: NCC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(CNS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-4-(2-(2-aminoacetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (prepared in an analogous manner to that described in Scheme 1, Step 1-2) (243 mg, 0.509 mmol) dissolved in pyridine (1 mL), cooled at 0° C., (4-nitrophenyl)methanesulfonyl chloride (100 mg, 0.424 mmol) was added. The mixture was stirred at 0° C. for 2 hours. The mixture was then diluted with EtOAc and washed with HCl 0.1N, NaHCO3 sat. sol. and brine. The organic phase was dried over Na2SO4 and the solvent was evaporated. (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-((4-nitrophenyl)methyl-sulfonamido)acetoxy)ethyl)pyridine 1-oxide was obtained (287 mg, 0.42 mmol, quantitative yield).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13]>C(N(CC)CC)C>[CH2:12]([N:14]([CH2:15][CH3:16])[C:9](=[O:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)[CH3:13]
Reactant: O=C(Cl)Cc1ccc(I)cc1
Reactant: CCNCC
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
4-Iodobenzeneacetyl chloride (10.62 g) was added portionwise to diethylamine (3.0 g) in triethylamine (40 ml) and washed in with MC (5 ml) at 0° under nitrogen and the suspension was stirred at room temperature for 2 h. ER (150 ml) was added, the mixture was filtered and the filtrate was concentrated to give a residue (7.94 g) which was purified by FCC eluting with ER-H (2:1) to give the title compound as a yellow oil (4.72 g). T.l.c. (ER) Rf 0.31.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=S)[CH2:6][CH2:5][C:4]=2[C:3]=1[C:13]#[N:14].[C:15]([NH:18][NH2:19])(=O)[CH3:16]>C(O)CCC>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]3[C:15]([CH3:16])=[N:18][N:19]=[C:7]3[CH2:6][CH2:5][C:4]=2[C:3]=1[C:13]#[N:14]
Reactant: N#Cc1c(Br)ccc2c1CCC(=S)N2
Reactant: CC(=O)NN
Solvent: CCCCO
Product: Cc1nnc2n1-c1ccc(Br)c(C#N)c1CC2
Temperature: 120 °C

Procedure:
To a stirred solution of 6-bromo-2-thioxo-1,2,3,4-tetrahydroquinoline-5-carbonitrile (145-3; 0.5 g, 0.00188 mol) in n-butanol (10 mL) was added acetic hydrazide (0.35 g, 0.0047 mol). Reaction mass was heated at 120° C. for 16 h. The reaction mixture was concentrated and directly purified by silica gel column chromatography to obtain title compound. (MS (M+1): 289.
Reaction SMILES: [C:1]1([N:7]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:8][C@H:9]([NH:14][C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH3:33])[N:27]=2)=[CH:20]3)=[O:16])[C:10]([NH:12][NH2:13])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:40](Cl)(Cl)=[O:41].C1(C)C=CC=CC=1>C(Cl)Cl>[C:34]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][C@H:9]([NH:14][C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH3:33])[N:27]=2)=[CH:20]3)=[O:16])[C:10]2[O:11][C:40](=[O:41])[NH:13][N:12]=2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CNc1nccc(-c2cc3cc(C(=O)N[C@@H](CN(c4ccccc4)c4ccccc4)C(=O)NN)ccc3[nH]2)n1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CNc1nccc(-c2cc3cc(C(=O)N[C@@H](CN(c4ccccc4)c4ccccc4)c4n[nH]c(=O)o4)ccc3[nH]2)n1

Procedure:
200 mg (0.384 mmol) of N—((S)-2-diphenylamino-1-hydrazinocarbonylethyl)-2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxamide (27) were suspended in 20 ml of methylene chloride, and a 20% solution of phosgene in toluene (0.398 mmol) was added dropwise at 0° C. and while stirring. The mixture was stirred at room temperature for a further 15 h and the solvent was evaporated. The oxadiazolone 28 was then isolated by flash chromatography on silica gel (DCM:MeOH=9:1). Yield: 160 mg (76%)
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][C:10]2[NH:9][C:8](=O)[CH:7]=[CH:6][C:5]=2[C:4](=[O:13])[CH2:3]1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:8]1[CH:7]=[CH:6][C:5]2[C:4](=[O:13])[CH2:3][C:2]([CH3:14])([CH3:1])[CH2:11][C:10]=2[N:9]=1
Reactant: CC1(C)CC(=O)c2ccc(=O)[nH]c2C1
Reactant: O=P(Cl)(Cl)Cl
Product: CC1(C)CC(=O)c2ccc(Cl)nc2C1
Yield: 60 %

Procedure:
In analogy to (Shanazarov, A. K.; Kuzovkin, V. A.; Chistjakov, V. V.; Granik, V. G. Khim. Geterotsikl. Soedin. 1991, (1) 86-92.) 7,7-dimethyl-7,8-dihydro-1H,6H-quinoline-2,5-dione was treated with phosphoryl chloride (POCl3) to give the title compound as a gray solid in 60% yield.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:23](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:41][S:42]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)(=[O:44])=[O:43].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:23]([C:48]2[CH:49]=[CH:50][C:45]([S:42]([CH3:41])(=[O:44])=[O:43])=[CH:46][CH:47]=2)=[CH:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cc(C(F)(F)F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(C(F)(F)F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 50.5 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (500 mg, 0.93 mmol), 4-methylsulfonyl phenylboronic acid (560 mg, 2.78 mmol) and dichlorobis(triphenylphosphine)palladium (II) (65.3 mg, 0.09 mmol) in dioxane (4 mL) was added an aqueous sodium carbonate solution (2 M, 1.40 mL, 2.8 mmol). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash column chromatography (silica gel from QingDao, 200-300 mesh, 35% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine (270 mg, 93%) as a light yellow solid: LC/MS m/e calcd for C28H25F3N2O4S2 [M+H]+ 575.65, observed 574.7.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O1CCCC1.Cl[C:13]1[C:18]([N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)=[CH:17][C:16]([N+:24]([O-:26])=[O:25])=[CH:15][N:14]=1>O>[O:4]1[CH2:5][CH2:6][N:1]([C:13]2[C:18]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:17][C:16]([N+:24]([O-:26])=[O:25])=[CH:15][N:14]=2)[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1cnc(Cl)c(-n2cccn2)c1
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cnc(N2CCOCC2)c(-n2cccn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Morpholine (50 μl) was added to a tetrahydrofuran solution (1 ml) containing 2-chloro-5-nitro-3-(1H-pyrazol-1-yl)pyridine (30 mg), followed by stirring at room temperature for 2 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, and a yellow solid of 2-morpholino-5-nitro-3-(1H-pyrazol-1-yl)pyridine (37 mg) was thus obtained.