Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[S:11][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=3)=[N:9][N:5]2[C:6](=[O:8])[CH:7]=1.[N:21]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C>CC#N>[N+:18]([C:14]1[CH:13]=[C:12]([C:10]2[S:11][C:4]3=[N:3][C:2]([N:24]4[CH2:23][CH2:22][N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25]4)=[CH:7][C:6](=[O:8])[N:5]3[N:9]=2)[CH:17]=[CH:16][CH:15]=1)([O-:20])=[O:19]
Reactant: O=c1cc(Cl)nc2sc(-c3cccc([N+](=O)[O-])c3)nn12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2cc(=O)n3nc(-c4cccc([N+](=O)[O-])c4)sc3n2)CC1
Temperature: 150 °C
Yield: 96.9 %

Procedure:
To 7-chloro-2-(3-nitrophenyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (1.0 g, 3.24 mmol) in MeCN (30 ml) in a microwave vial is added tert-butyl 1-piperazinecarboxylate (0.724 g, 3.89 mmol) followed by DIPEA (1.697 ml, 9.72 mmol). The mixture is heated in the microwave to 150° C. for 25 min., cooled and concentrated in vacuo and purified via column chromatography on a 50 g snap column with 0-10% MeOH/DCM gradient elution to give tert-butyl 4-(2-(3-nitrophenyl)-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate (1.44 g, 3.14 mmol, 97% yield) as a tan solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][CH:11]2[N:12]([CH3:24])[C:13]3[C:14]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:16](Br)=[CH:17][C:18]=3[CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.CC([O-])(C)C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][CH:11]2[N:12]([CH3:24])[C:13]3[C:14]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:16]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[CH:17][C:18]=3[CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1c2c(cc(Br)cc2C(F)(F)F)C2CN(C(=O)OC(C)(C)C)CCC21
Reactant: Nc1ccccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN1c2c(cc(Nc3ccccn3)cc2C(F)(F)F)C2CN(C(=O)OC(C)(C)C)CCC21
Temperature: 80 °C

Procedure:
8-bromo-5-methyl-6-trifluoromethyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 44 or 45, 1.0 eq.), aminopyridine (3.0 eq.), and NaOt-Bu (3.0 eq.) were dissolved in anhydrous toluene (0.17 M). The mixture was degassed with argon for 30 min. Pd2(dba)3 (0.06 eq.) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.18 eq.) were added; the reaction was heated at 80° C. for 16 h. The reaction was cooled to room temperature, diluted with EtOAc, filtered through a bilayer pad of diatomaceous earth and silica gel, and concentrated. Purification of the residue by flash column chromatography (silica gel, 2–30% EtOAc/hexanes) provided 5-methyl-8-(pyridinylamino)-6-trifluoromethyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester derivatives. The intermediate was dissolved in CH2Cl2/TFA (5/1) at rt stirred for 1 h. Upon concentration in vacuo, the residue was partitioned between CH2Cl2/1 M NaOH. The aqueous phase was extracted with CH2Cl2. The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:48][Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])[CH2:21][N:22]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([N+:45]([O-])=O)=[CH:41][CH:40]=2)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C.O.NN>CO.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[NH2:45][C:42]1[CH:41]=[CH:40][C:39]([CH2:38][CH2:37][O:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][N:22]([CH2:21][C@@H:20]([C:12]2[CH:11]=[CH:10][C:9]([O:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[C:18]3[C:13]=2[CH:14]=[CH:15][C:16](=[O:19])[NH:17]3)[O:48][Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)Oc1ccc([C@H](CN(CCCCCCOCCc2ccc([N+](=O)[O-])cc2)C(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C)c2ccc(=O)[nH]c12
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)Oc1ccc([C@H](CN(CCCCCCOCCc2ccc(N)cc2)C(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C)c2ccc(=O)[nH]c12
Yield: 48.9 %

Procedure:
A solution of Intermediate 110 (0.38 mmol) in methanol (9 mL) was treated with iron (III) chloride hexahydrate (10 mg) and decolorizing charcoal (100 mg). While the mixture was being heated to reflux, hydrazine monohydrate (1.0 mL) was added dropwise via syringe. After two hours of heating at reflux, the mixture was allowed to cool and was filtered through a pad of Celite diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure and the residue was purified via automated flash silica gel chromatography, using a 12 g Silicycle SiliSep flash column (dichloromethane/methanol/ammonium hydroxide). Concentration of the desired fractions under reduced pressure provided the title compound (0.14 g, 56%) as a black foam. ES/MS calcd. for C36H56N3O6Si+ 654.4. Found m/z=654.5 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]([NH2:9])=[N:7][CH:8]=1.[C:10](Cl)(=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].NCC(O)=O>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]([NH:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[N:7][CH:8]=1
Reactant: CCCCCC(=O)Cl
Reactant: COc1cnc(N)nc1
Agent: NCC(=O)O
Solvent: c1ccncc1
Product: CCCCCC(=O)Nc1ncc(OC)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
5-Methoxypyrimidin-2-amine (12.3 g, 98.3 mmol) was dissolved in pyridine (123 mL), the solution was added with hexanoyl chloride (14.5 g, 108 mmol) on an ice bath, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was added with 1 M aqueous glycine (98.3 mL) at 0° C., and the mixture was stirred for 1 hour, and then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, and the resulting residue was azeotroped with toluene. The resulting residue was recrystallized from chloroform-hexane to obtain N-(5-methoxypyrimidin-2-yl)hexanamide (18.4 g, 84%) as colorless solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[CH:8][C:9]=1[F:10].F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](=[O:24])[C:20]([O:22][CH3:23])=[O:21]>CS(C)=O>[Br:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[F:10])[O:11][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](=[O:24])[C:20]([O:22][CH3:23])=[O:21]
Reactant: Oc1ccc(F)c(Br)c1
Reactant: COC(=O)C(=O)c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(=O)c1ccccc1Oc1ccc(F)c(Br)c1
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
A suspension of 3.75 g of 80% pure NaH in 50 ml of dimethyl sulfoxide (DMSO) was admixed with 21.7 g of 3-bromo-4-fluorophenol (cf. DE-A 192 80 27) and then stirred at 20-25° C. for 30 min, and a solution of 22.7 g of methyl 2-(2-fluorophenyl)oxoacetate in 100 ml of DMSO was added dropwise. The reaction mixture was stirred at 20-25° C. for approximately 12 hours, poured into ice-water and then extracted with ethyl acetate. The organic phases were washed with 1 N aqueous sodium hydroxide solution and water and dried, and the solvent was distilled off, giving 35 g of the title compound.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].CS[C:8]1[S:12][CH:11]=[CH:10][S+:9]=1.[CH2:13]([NH:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>O1CCCC1>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[S:9]1[CH:10]=[CH:11][S:12][C:8]1=[N+:17]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCNCCCC
Reactant: CSc1scc[s+]1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Product: CCCC[N+](CCCC)=c1sccs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 10 ml of tetrahydrofuran, 2.0 g of 2-methylthio-1,3-dithiolium perchlorate was suspended, and 0.75 ml of dibutylamine was dropwise added over a period of 5 minutes. The mixture was stirred at room temperature for 30 minutes, and the solvent was distilled off under reduced pressure. The residue was dissolved in a mixture of acetone-ethyl ether, and cooled to -70° C. in a cooling medium, whereupon crystals precipitated. The crystals were collected by decantation under cooled condition, and purified by liquid chromatography (column: Senshu pack, Senshu ODS-5301, mobile phase: methanol/water=50/50), whereby 0.20 g (yield: 75%) of N-(1,3-dithiol-2-ylidene)-N,N-di(n-butyl)ammonium perchlorate was obtained as oily substance. (Compound No. 23)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH:11]([NH2:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH:11]([NH:14][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])([CH3:13])[CH3:12]
Reactant: CC(C)N
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)Nc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To a cold solution of 2-fluoro-nitrobenzene (31.8 g, 0.225 mol) in ethanol (300 mL) cooled in an ice bath was added isopropylamine (54.0 mL, 0.634 mol), followed by the addition of a solution of potassium carbonate (31.1 g, 0.225 mol) in water (120 mL). The mixture was stirred at 0° C. for 1 h, then refluxed for 6 h. The reaction was terminated by cooling the mixture to ambient temperature, and evaporating it under reduced pressure yielding an orange residue. The residue was partitioned between ethyl ether (800 mL) and a brine solution (300 mL). The organic layer was dried and filtered, to provide the title intermediate (39 g) as an orange liquid. 1H-NMR (CDCl3, 300 MHz): δ (ppm) 8.06 (d, 1H), 7.30 (t, 1H), 6.74 (d, 1H), 6.48 (t, 1H), 3.73 (hept, 1H), 1.20(d, 6H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]3[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([S:27]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([CH:10]4[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]4)=[CH:7][CH:8]=3)[CH:3]=[N:2]2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc3[nH]ncc3c2)C1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CC(C)(C)OC(=O)N1CC(c2ccc3c(cnn3S(=O)(=O)c3ccccc3)c2)C1

Procedure:
This compound was prepared from tert-butyl 3-(1H-indazol-5-yl)azetidine-1-carboxylate and benzenesulfonylchloride by the method outlined under 44.c).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:14]=[C:15]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH:16]=[CH:17][CH:18]=2)[CH2:9][CH2:8]1.[C:25]1([CH:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1.C(Cl)Cl>[C:35]1([CH:31]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:32]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]2[CH2:8][CH2:9][CH:10]([C:13]3[CH:14]=[C:15]([NH:19][C:20](=[O:24])[CH:21]([CH3:22])[CH3:23])[CH:16]=[CH:17][CH:18]=3)[CH2:11][CH2:12]2)=[O:33])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCN)CC2)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q2 (THF/DCM, 1:3)) and Scheme AT using N-{3-[1-(5-aminopentyl)-4-piperidinyl]phenyl}-2-methylpropanamide and diphenylacetyl chloride: ESMS m/e: 526.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:20])[CH:12]=[C:13]([O:18][CH3:19])[C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][C:34]([O:36][CH3:37])=[O:35]>C(OCC)(=O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:13]([O:18][CH3:19])[C:14]=1[N+:15]([O-:17])=[O:16])[O:20][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: COc1cc(O)cc(OCc2ccccc2)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cc(OC)c([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
A mixture of 3-benzyloxy-5-methoxy-4-nitrophenol(3.85 g), N,N-dimethyl formamide (20 mL), potassium carbonate(2.8 g) and methyl bromoacetate(2.42 g) was stirred at ambient temperature for 3 h. The mixture was treated with water and ethyl acetate and the organic phase was separated, washed with brine, dried and evaporated to dryness. The residue was purified by flash chromatography eluting with increasingly polar mixtures of ethyl acetate and hexane to give the product (4.6 g), (m/e348, MH+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:19][S:20][C:21]2[NH:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[N:22]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl[CH2:31][C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][C:2]1[C:3]([CH2:19][S:20][C:21]2[NH:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][N:11]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:31][C:32]([O:34][CH3:35])=[O:33]
Reactant: Cc1c(SCCNCc2ccccc2)ccnc1CSc1nc2ccccc2[nH]1
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CN(CCSc1ccnc(CSc2nc3ccccc3[nH]2)c1C)Cc1ccccc1

Procedure:
2-((3-Methyl-4-(2-benzylaminoethylthio)pyridin-2-yl)methylthio)-1H-benzimidazole (2 g) was dissolved in dimethylformamide and reacted with methyl chloroacetate (0.45 ml) in the presence of potassium carbonate (0.71 g) at 50°-60° C. After the completion of the reaction, the dimethylformamide was distilled away and the residue was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled away to give an oily product. The oily product was purified by column chromatography to give 2-((3-methyl-4-(2-(N-benzyl-N-methoxycarbonylmethylamino)ethylthio)-2-pyridyl)methylthio)-1H-benzimidazole.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH3:27])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([CH2:19]S(C(F)(F)F)(=O)=O)[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH:30]([N:32]1[CH:36]=[N:35][CH:34]=[N:33]1)=C>>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH3:27])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([CH:19]=[CH:30][N:32]3[CH:36]=[N:35][CH:34]=[N:33]3)[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cn1cncn1
Reactant: CC(C)(Cc1c[nH]c2c(CS(=O)(=O)C(F)(F)F)cccc12)NC(=O)OC(C)(C)C
Product: CC(C)(Cc1c[nH]c2c(C=Cn3cncn3)cccc12)NC(=O)OC(C)(C)C

Procedure:
{1,1-Dimethyl-2-[7-(2-[1,2,4]triazol-1-yl-vinyl)-1H-indol-3-yl]-ethyl}-carbamic acid tert-butyl ester is prepared from [1,1-dimethyl-2-(7-trifluoromethanesulfonyhnethyl-1H-indol-3-yl)-ethyl]-carbamic acid tert-butyl ester and 1-vinyl-1,2,4-triazole as described for the preparation of Amine 23 (93%). FDMS m/e=381.2 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][N:10]([CH2:19][C:20]([OH:22])=[O:21])[C:9]2=[O:23])=[CH:4][CH:3]=1.S(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH2:6]([O:21][C:20](=[O:22])[CH2:19][N:10]1[CH:11]=[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]1=[O:23])[CH2:7][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C(O)Cn1cc(-c2ccccc2)n(-c2ccc(Cl)cc2)c1=O
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CCCCCCOC(=O)Cn1cc(-c2ccccc2)n(-c2ccc(Cl)cc2)c1=O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
1 g of [3-(4-chlorophenyl)-2-oxo-4-phenyl-4-imidazolin-1-yl] acetic acid are dissolved in a small amount of anhydrous chloroform. 0.7 g of thionylchloride are added thereto and the mixture is stirred at about 50° C. for 2 hours. The mixture is evaporated in a vacuum, the residue is mixed with a small amount of chloroform and 0.31 g of hexanol are added to the mixture. After stirring for one hour at room temperature, the CHCl3 -solution is first extracted with an NaHCO3 -solution and then with water. It finally is dried over Na2SO4. The CHCl3 -solution is evaporated, remaining hexanol is distilled off a high vacuum and the residue is further purified chromatographically on silicic acid gel using CHCl3 as eluant.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:12][C:13]([OH:15])=[O:14]>O>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)CCl
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: O
Product: O=C(O)CNc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
To a suspension of 4-nitroaniline (13.8 g, 100 mmol) in water (300 mL) was added chloroacetic acid (18.9 g, 200 mmol). The reaction mixture was refluxed overnight and cooled to rt. The title compound was collected by filtration, washed with water and a mixture of hexane and ether (1:1) and dried in vacuo to yield 14.6 g (74%). 1H NMR (400 MHz, DMSO-d6) δ: 12.83 (s, 1H), 8.00 (d, 2H), 7.45 (t, 1H), 6.65 (d, 2H), 4.00 (d, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].C1(O)C=CC=CC=1.[OH:22][C@@H:23]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([OH:40])[CH:35]=1)[CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30]>CC(C)=O.CCOC(C)=O.O>[OH:22][C@@H:23]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH2:2][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH:35]=1)[CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30]
Reactant: BrCc1ccncc1
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Oc1ccccc1
Product: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(OCc2ccncc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(Bromomethyl)pyridine (298 mg, 1.17 mmol) and K2CO3 (774 mg, 5.61 mmol) were added to a solution of phenol (7, Intermediate I) (300 mg, 1.12 mmol) in acetone (20 mL). The reaction mixture was stirred overnight at ambient temperature, diluted with EtOAc and water. The organic layer was washed with 5% aq. NaOH, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (50% EtOAc:hexane) gave (R)-tert-butyl (3-hydroxy-3-(3-(pyridin-4-ylmethoxy)phenyl)propyl)carbamate (15) as dark brown solid. Yield (0.183 g, 46%); 1H NMR (400 MHz, DMSO-d6): δ 8.61 (d, J=5.2 Hz, 2H), 7.36 (d, J=5.2 Hz, 2H), 7.28-7.24 (m, 1H), 7.03 (s, 1H), 6.96 (d, J=8.0 Hz, 1H), 6.85-6.83 (m, 1H), 5.10 (s, 2H), 4.86 (bs, 1H), 4.74-4.71 (m, 1H), 3.52-3.49 (m, 1H), 3.39 (bs, 1H), 3.19-3.12 (m, 1H), 1.86-1.77 (m, 2H), 1.45 (s, 9H); MS: m/z 359.19 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][C:5]=1[CH:6]=[O:7])([O-:3])=[O:2].[BH4-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CO>[N+:1]([C:4]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2]
Reactant: O=Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(Oc2ccccc2)cc1CO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-nitro-5-phenoxy-benzaldehyde (2.0 g, 8.22 mmol) was dissolved in methanol (20 mL) and cooled with an ice bath to 0° C. Sodium borohydride (0.9 g, 24.66 mmol) was added in 4 portions over 20 minutes and the reaction mixture was allowed to stir at 0° C. for one hour. A solution of sodium carbonate (10% w/v in water) was added to quench the reaction followed by pouring the crude reaction mixture into a separatory funnel with ethyl acetate. The organic layer was washed 3 times with 10% sodium carbonate solution followed by one wash with saturated brine. The phases were separated and the organic layer was dried with sodium sulfate and filtered, and the ethyl acetate was removed under reduced pressure to yield the a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:27][C:26]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[C:31]#[N:32])=[CH:25][C:24](=O)[O:23]1>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:15]=[CH:16][CH:17]=[CH:18]2)=[CH:10][C:9]=1[NH:19][C:24](=[O:23])[CH2:25][C:26]([C:28]1[CH:35]=[CH:34][CH:33]=[C:30]([C:31]#[N:32])[CH:29]=1)=[O:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1

Procedure:
The title compound was prepared from (2-amino-4-pyrrol-1-yl-phenyl)-carbamic acid tert.-butyl ester (Example J2) (137 mg, 0.5 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example L1) (115 mg, 0.5 mmol) according to the general procedure M. Obtained as a light red solid (139 mg).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][C:10]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:11]([CH2:14][CH3:15])[CH:12]=2)[O:7][C:6]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:4].[Br:28][CH2:29][CH2:30][CH2:31][CH2:32]Br.C(=O)([O-])[O-].[Cs+].[Cs+].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>CC(N(C)C)=O.O>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][C:10]([N:16]([CH2:32][CH2:31][CH2:30][CH2:29][Br:28])[S:17]([CH3:20])(=[O:19])=[O:18])=[C:11]([CH2:14][CH3:15])[CH:12]=2)[O:7][C:6]=1[C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)=[O:4]
Reactant: CCc1cc2c(C(=O)NC)c(-c3ccc(F)cc3)oc2nc1NS(C)(=O)=O
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCc1cc2c(C(=O)NC)c(-c3ccc(F)cc3)oc2nc1N(CCCCBr)S(C)(=O)=O
Reaction time: 0.08 h
Yield: 49.8 %

Procedure:
5-Ethyl-2-(4-fluoro-phenyl)-6-methanesulfonylamino-furo[2,3-b]pyridine-3-carboxylic acid methylamide (60 mg, 0.153 mmol), 1,4-dibromobutane (662 mg, 3.07 mmol) and cesium carbonate (52.4 mg, 0.161 mmol) in DMA (766 μL) are heated for 15 min at 120° C. by microwave. 1 mL CAN and 0.5 mL water are added and the mixture is filtered with a 0.45μ PTFE filter. Purification is achieved by reverse phase HPLC with a C8 column with 20-100% CAN//H2O (0.1% TFA) over 15 min with 5 min hold to give 6-[(4-Bromo-butyl)-methanesulfonyl-amino]-5-ethyl-2-(4-fluoro-phenyl)-furo[2,3-b]pyridine-3-carboxylic acid methylamide (40.1 mg, 50%) MS (ESI) m/z 527.8 (M+1). Retention time=1.78 min, Method A.