Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1.[C:15]([C:19]1[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[NH:21][N:20]=1)([CH3:18])([CH3:17])[CH3:16].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([N:21]2[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:23][C:19]([C:15]([CH3:16])([CH3:18])[CH3:17])=[N:20]2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1cc(C(C)(C)C)n[nH]1
Reactant: OB(O)c1ccc(-c2nnco2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(C)(C)C)nn1-c1ccc(-c2nnco2)cc1
Yield: 80.8 %

Procedure:
A mixture of 4-(1,3,4-oxadiazol-2-yl)phenylboronic acid (303 mg, 1.60 mmol) and powdered 4A molecular sieves (300 mg) in CH2Cl2 (6 mL) was heated to reflux for 2 h. Ethyl 3-tert-butyl-1H-pyrazole-5-carboxylate (310 mg, 1.6 mmol), pyridine (0.13 mL, 1.6 mmol) and copper (II) acetate (290 mg, 1.6 mmol) were added and the reaction mixture was refluxed for 24 h. The reaction was filtered and the solid was washed with EtOAc (40 mL) and MeOH (40 mL). The combined filtrate and washings were concentrated in vacuo and partitioned between EtOAc (40 mL) and water (20 mL). The organics were washed with water (20 mL), satd aq NaHCO3 (20 mL), water (20 mL), and brine (20 mL), dried (Na2SO4) and concentrated in vacuo. The oily residue was chromatographed to provide ethyl 1-(4-(1,3,4-oxadiazol-2-yl)phenyl)-3-tert-butyl-1H-pyrazole-5-carboxylate (440 mg, > 100% yield) as a visocus oil contaminated with the starting ester. The mixture was used without further purification.
Reaction SMILES: [C:1]1([N:7]([C:9]2[CH:14]=[C:13]([Cl:15])[N:12]=[C:11]([Cl:16])[N:10]=2)N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])=O.Cl>O>[Cl:16][C:11]1[N:10]=[C:9]([N:7]2[C:1]3[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:20]([CH2:21][C:22]([OH:24])=[O:23])=[C:18]2[CH3:17])[CH:14]=[C:13]([Cl:15])[N:12]=1
Reactant: CC(=O)CCC(=O)O
Reactant: NN(c1ccccc1)c1cc(Cl)nc(Cl)n1
Agent: Cl
Solvent: O
Product: Cc1c(CC(=O)O)c2ccccc2n1-c1cc(Cl)nc(Cl)n1

Procedure:
A mixture of N-phenyl-N-(2,6-dichloropyrimidin-4-yl)hydrazine (30g.) and laevulinic acid (50g.) was heated at 100° C. for 3 hours whilst a stream of hydrogen chloride gas was passed through it. The mixture was cooled and added to water (400ml.), and the resulting mixture filtered to give 1-(2,6-dichloropyrimidin-4-yl)-2-methylindol-3-ylacetic acid, m.p. 205°-207° C.
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]2[O:7][CH2:8][C@@H:9]([O:10][C:11](=[O:25])[CH2:12][CH2:13][CH2:14][C@H:15]([O:21][N+:22]([O-:24])=[O:23])[CH2:16][O:17][N+:18]([O-:20])=[O:19])[C@H:5]2[O:4][CH2:3]1.CCN(CC)CC.Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=1)=[O:35]>C1COCC1>[N+:43]([C:40]1[CH:41]=[CH:42][C:37]([O:36][C:34]([O:1][C@H:2]2[C@H:6]3[O:7][CH2:8][C@@H:9]([O:10][C:11](=[O:25])[CH2:12][CH2:13][CH2:14][C@H:15]([O:21][N+:22]([O-:24])=[O:23])[CH2:16][O:17][N+:18]([O-:20])=[O:19])[C@H:5]3[O:4][CH2:3]2)=[O:35])=[CH:38][CH:39]=1)([O-:45])=[O:44]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(CCC[C@@H](CO[N+](=O)[O-])O[N+](=O)[O-])O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCC[C@@H](CO[N+](=O)[O-])O[N+](=O)[O-])O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2OC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
To a solution of (S)-((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)5,6bis(nitrooxy)hexanoate (0.80 g, 2.18 mmol) and Et3N (0.66 g, 6.54 mmol) in THF (30 mL) was added 4-Nitrophenyl chloroformate (0.44 g, 2.18 mmol) as solid. After stirring at rt over night, the mixture was concentrated. The residue was diluted with EtOAc and washed with NaH2PO4 5%. The organic layer was dried over MgSO4 and concentrated. The residue was purified by flash chromatography (Biotage SP1; column SNAP 50; TLC method: n-hexane/ethyl acetate 1/1; Rf=0.38), affording the title product as a pale yellow oil. 1H-NMR (300 MHz, CDCl3); δ 8.32-8.29 (2H, m), 7.44-7.28 (2H, m), 5.33 (1H, m), 5.21-5.05 (2H, m), 4.89-4.65 (3H, m), 4.50 (1H, m), 4.20-3.95 (4H, m), 3.94-3.85 (1H, m), 2.50 (2H, m), 1.84 (4H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[N+:14]([O-:16])=[O:15])=[C:4]([F:19])[CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[NH2:13][C:9]1[C:8]([N+:14]([O-:16])=[O:15])=[C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([NH:1][C:28]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([C:30]([F:32])([F:31])[F:33])[CH:23]=3)=[O:29])=[CH:3][C:4]=2[F:19])[CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Oc2ccnc(N)c2[N+](=O)[O-])c(F)c1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: Nc1nccc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2F)c1[N+](=O)[O-]
Yield: 41.3 %

Procedure:
Method H3 was used with 4-(4-amino-2-fluorophenoxy)-3-nitropyridin-2-amine (0.25 g, 0.946 mmol) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate (0.21 g, 0.946 mmol) to afford the title compound (0.19 g, 42%). 1H NMR (250 MHz, 6, ppm, DMSO-d6): 5.98 (dd, 1H, Ja=5.7 Hz, Jb=1.0 Hz), 7.21 (s, 2H), 7.26 (dd, 1H, Ja=9.1 Hz, Jb=2.3 Hz), 7.34 (t, 1H, J=8.8 Hz), 7.60-7.73 (m, 3H), 8.01 (d, 1H, J=5.7 Hz), 8.10 (d, 1H, J=2.1 Hz), 9.19 (s, 1H), 9.27 (s, 1H). m/z 486.1 [(M+H)+ calcd. for C19H12ClF4N5O4 485.1].
Reaction SMILES: [Cl-].[Na+].[Cl-].[Al+3].[Cl-].[Cl-].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:19])[CH2:15][CH2:16][CH2:17]Cl)=[CH:10][CH:9]=1>Cl>[Br:7][C:8]1[CH:13]=[C:12]2[C:11](=[CH:10][CH:9]=1)[C:14](=[O:19])[CH2:15][CH:16]2[CH3:17]
Reactant: O=C(CCCCl)c1ccc(Br)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC1CC(=O)c2ccc(Br)cc21
Temperature: 180 °C
Yield: 89.6 %

Procedure:
To a mixture of sodium chloride (1.23 g, 21.0 mmol) and aluminum chloride (5.0 g, 38.2 mmol) at 130° C. was added 1-(4-bromophenyl)-4-chlorobutan-1-one (1.0 g, 3.82 mmol) and the resulting mixture was heated to 180° C. for 20 minutes. The mixture was allowed to cool to room temperature and poured to a cold 1N aqueous HCl solution (300 mL). The mixture was extracted several times with dichloromethane. The combined organic layers were separated, dried over magnesium sulfate, filtered and concentrated to give 5-bromo-3-methyl-indan-1-one (0.77 g, 89%). The title compound, 1-methyl-5-(3-methyl-1-oxo-2,3-dihydro-1H-inden-5-yl)-1H-pyrrole-2-carbonitrile as an orange solid (0.65 g, 76%), was prepared from 5-bromo-3-methyl-indan-1-one and 1-methyl-2-cyanopyrrole according to the same coupling procedure as described in example 1. MS (ES) m/z 251.2; Anal. Calcd for C16H14N2O: C, 76.78; H, 5.64; N, 11.19. Found: C, 76.49; H, 5.49; N, 11.10. HRMS: calcd for C16H14N2O+H+, 251.1179; found (ESI, [M+H]+), 251.1179.
Reaction SMILES: Cl.[CH:2](=[NH:6])[O:3][CH2:4][CH3:5].Cl.[F:8][C:9]([F:13])([F:12])[CH2:10]N.C(=O)([O-])[O-].[K+].[K+].O>C(Cl)Cl>[F:8][C:9]([F:13])([F:12])[CH2:10][N:6]=[CH:2][O:3][CH2:4][CH3:5]
Reactant: CCOC=N
Reactant: NCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCOC=NCC(F)(F)F
Reaction time: 0.05 h

Procedure:
Ethyl formimidate hydrochloride (0.555 g, 5 mmole), 2,2,2-trifluoroethylamine hydrochloride (0.677 g, 5 mmole) and potassium carbonate (0.345 g, 2.5 mmole) are suspended in 20 ml CH2Cl2 and treated with 1 ml H2O. The mixture is shaken vigorously for 3 minutes. The organic phase is separated and the aqueous extracted twice with 10 ml portions of CH2Cl2. The combined organic phase is dried and the CH2Cl2 distilled through a Vigreauxe column to give the Ethyl N-(2,2,2-trifluoroethyl)formimidate. n.m.r. δ1.333 t (CH3CH2); 3.8 q (j=10 c.p.s., CF3CH2) 4.23 q (j=7.5, CH3CH2O); 7.6 S (H--C=N).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][N:4]=[C:5]([NH2:24])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[N:21][C:22]#[N:23])SC)[N:8]=1.[CH2:27]([CH2:29][NH2:30])[OH:28]>CO>[F:1][C:2]([F:26])([F:25])[CH2:3][N:4]=[C:5]([NH2:24])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH:30][CH2:29][CH2:27][OH:28])=[N:21][C:22]#[N:23])[N:8]=1
Reactant: NCCO
Reactant: CSC(=NC#N)NCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Solvent: CO
Product: N#CN=C(NCCO)NCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[3-(3-cyano-2-methylisothioureido)propylthio]pyrimidine (0.2 g.), methanol (2 ml.) and ethanolamine (0.5 ml.) was stirred at room temperature for 3 days and then evaporated to dryness. Water was added to the residue, the mixture extracted with ethyl acetate and the ethyl acetate extract dried and evaporated to dryness. The residue was recrystallised from acetonitrile to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[3-(2-cyano-3-[2-hydroxyethyl]guanidino)propylthio]pyrimidine (0.1 g.), m.p. 114°-116°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccc(Br)cc2)cc1
Temperature: 170 °C

Procedure:
The mixture of 4-bromophenol (10 g, 57.8 mmol), 4-fluorobenzaldehyde (7.17 g, 57.9 mmol), and potassium carbonate (12 g, 86.7 mmol) in DMF was heated at 170° C. for 4 hours. After cooling to ambient temperature, the reaction mixture was poured into ice-water. The resulting solid, 4-(4-bromophenoxy)benzaldehyde, was isolated by filtration (15 g, 94%), 1H NMR (CDCl3) δ 9.95 (s, 1H), 7.85 (d, 2H), 6.62 (d, 2H), 7.17 (d, 2H), 6.96 (d, 2H) ppm.
Reaction SMILES: [CH3:1][Si:2]([CH3:14])([CH3:13])[C:3]#[C:4][CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1.Br[CH2:16]/[CH:17]=[CH:18]\[CH3:19]>>[CH3:14][Si:2]([CH3:13])([CH3:1])[C:3]#[C:4][CH:5]([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[CH2:16]/[CH:17]=[CH:18]\[CH3:19]
Reactant: C/C=C\CBr
Reactant: C[Si](C)(C)C#CCOC1CCCCO1
Product: C/C=C\CC(C#C[Si](C)(C)C)OC1CCCCO1

Procedure:
Reaction of trimethyl(3-(tetrahydro-2H-pyran-2-yloxy)prop-1-ynyl)silane (0.157 g, 0.74 mmol) and (Z)-1-bromobut-2-ene (0.12 g, 0.89 mmol) according to General Procedure 11.A provided (Z)-trimethyl(3-(tetrahydro-2H-pyran-2-yloxy)hept-5-en-1-ynyl)silane. The (Z)-1-bromobut-2-ene starting material was synthesized in two steps according to General Procedures 11.F and 11.G.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.[B:29](OC)([O:32]C)[O:30]C.Cl>C1COCC1>[F:16][C:17]1[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:19][CH:20]=[CH:21][C:22]=1[B:29]([OH:32])[OH:30]
Reactant: COB(OC)OC
Reactant: Fc1ccccc1-c1ccccn1
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cccc(-c2ccccn2)c1F
Temperature: -78 °C

Procedure:
2,2,6,6-Tetramethylpiperidine (8.61 mL, 7.23 g, 51.2 mmol) was added dropwise with stirring to a mixture of 2.5 M solution of n-butyllithium in hexanes (19.6 mL, 49 mmol) and THF (130 mL) at −78° C. 2-(2-Fluoro-phenyl)pyridine (8.06 g, 46.5 mmol) in THF (25 mL) was added dropwise with stirring to the resulting solution at −78° C., and the mixture was stirred at the same temperature for 2 h. Trimethyl borate (10.5 mL, 9.67 g, 93 mmol) was added at −78° C., and the mixture was stirred for a further 10 min before being allowed to warm to room temperature. 2 N Hydrochloric acid (12 mL) was added, then the mixture was stirred for 30 min at room temperature, and was concentrated in vacuo. The residual material was stirred with 2 N hydrochloric acid (130 mL) for 1 h. The mixture was adjusted to pH 14 by addition of 2 N sodium hydroxide solution, and was then washed with diethyl ether. Concentrated hydrochloric acid was added to the aqueous phase with ice-bath cooling, until the pH was ˜8, precipitating a white solid. The slurry was stirred at 0° C. for 1 h, and was then filtered, yielding the residual boronic acid as a sticky white solid. This was refluxed in diethyl ether overnight, and was then filtered, affording 2-fluoro-3-(pyridin-2-yl)benzeneboronic acid as a white powder (3.4 g, 34%). m/z (ES+) 218 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Cl.Cl[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reaction time: 8 h

Procedure:
A mixture of 39.5 g. (0.24 mole) ethyl 4-aminobenzoate (free base), 140 ml. n-butanol and 47.1 g. (0.265 mole) bis-(2-chloroethyl)-amine hydrochloride is heated at reflux temperature for 36 hours, then 16.8 g. (0.12 mole) powdered anhydrous potassium carbonate are added thereto followed by further heating for 80 hours. The hot reaction mixture is then suction filtered, the filter cake is washed with some hot butanol and the combined filtrates are cooled. After standing overnight, the solid product obtained is filtered off with suction, washed twice with 50 ml. amounts of diethyl ether and dried. Yield: 33.4 g. (64% of theory) of yellow crystals which are recrystallised from ethanol/diethyl ether (2:1 v/v) to give 28.45 g. (55% of theory) of the desired product in the form of an almost colourless hydrochloride; m.p. 176°-178° C. The product is hydroscopic.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]([C:10]1[S:11][C:12]([S:26][CH3:27])=[C:13]([S:15]([C:18]2[CH:19]=[N:20][C:21](Cl)=[C:22]([Br:24])[CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[NH2:29][CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>C1COCC1>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]([C:10]1[S:11][C:12]([S:26][CH3:27])=[C:13]([S:15]([C:18]2[CH:19]=[N:20][C:21]([NH:29][CH2:30][C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)=[C:22]([Br:24])[CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccncc1
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cnc(Cl)c(Br)c1
Solvent: C1CCOC1
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cnc(NCc2ccncc2)c(Br)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a vessel containing a stir bar was added {[4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.035 g, 0.066 mmol), 4-aminomethylpyridine (0.015 g, 0.133 mmol), THF [3 mL]. The reaction vessel was sealed and heated to 70° C. for 18 hours, cooled to room temperature and concentrated in vacuo. The crude residue was dissolved in a solution of chloroform/trifluoroacetic acid (1/1) [2 mL] and was allowed to stir at room temperature for 2 hours. The reaction was concentrated in vacuo followed by reverse-phase HPLC [acetonitrile/water (0.01% TFA)] to give the title compound. ESI-MS (m/z): Calcd. for C17H16BrN5O2S3: 499.44 (M+H); found 498.0, 500.0.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][N:6]([CH3:8])[CH2:5][C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:3]1.[H][H]>CO.[Pd]>[OH:1][C@H:2]1[CH2:3][C@@H:4]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:5][N:6]([CH3:8])[CH2:7]1
Reactant: [H][H]
Reactant: Cc1ccc(C2=CC(O)CN(C)C2)cc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc([C@@H]2C[C@H](O)CN(C)C2)cc1
Yield: 77.7 %

Procedure:
A solution of 5-hydroxy-1-methyl-3-(4-methylphenyl)-1,2,5,6-tetrahydropyridine (5.1 g, 25 mM) in methanol (200 ml) was hydrogenated in a Parr apparatus at 50 psi (about 3.51×104 kg/sq.m.) and room temperature over 10% palladium-on-charcoal (1 g). After the theoretical uptake of hydrogen had occurred (about 3 hours) the catalyst was removed by filtration and the solvent removed under vacuum. Recrystallisation from cyclohexane gave the title compound (4 g). A portion was converted to the hydrochloride and recrystallized from methanol/ether to give the title compound hydrochloride, m.p. 218°-9°.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9](=[O:37])[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([N:20]2[CH2:29][C:28]3[CH:27]=[N:26][N:25]([CH3:30])[C:24]=3[NH:23][C:22]3[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:21]2=3)=[O:19])=[CH:14][C:13]=1[F:36])(C)(C)C.Cl.O1CCOCC1>>[ClH:35].[NH2:7][CH2:8][C:9]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([N:20]2[CH2:29][C:28]3[CH:27]=[N:26][N:25]([CH3:30])[C:24]=3[NH:23][C:22]3[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:21]2=3)=[O:19])=[CH:14][C:13]=1[F:36])=[O:37]
Reactant: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)c1ccc(CNC(=O)CNC(=O)OC(C)(C)C)c(F)c1)C2
Agent: Cl
Solvent: C1COCCO1
Product: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)c1ccc(CNC(=O)CN)c(F)c1)C2
Yield: 83 %

Procedure:
{[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzylcarbamoyl]-methyl}-carbamic acid tert-butyl ester from Example E113 (120 mg, 0.22 mmol) was reacted with 4N HCl/dioxan using an analogous procedure to that de-scribed for Example E4.2 to yield the title compound (95 mg, 83%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4](Br)[CH:3]=1.[C:23]1([S:29]([O-:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Na+]>>[Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([S:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:31])=[O:30])[CH:3]=1
Reactant: O=S([O-])c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(Br)cc3c2C1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(S(=O)(=O)c4ccccc4)cc3c2C1
Yield: 43 %

Procedure:
The product of step B was coupled with sodium benzenesulfinate using the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 3:2 hexane/ethyl acetate) provided tert-butyl 6-chloro-8-phenylsulfonyl-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (750 mg, 43%) as an off-white solid: 1H NMR (CDCl3, 300 MHz) δ 7.98-7.94 (m, 3H), 7.84 (d, J=1.2 Hz, 1H), 7.58-7.49 (m, 3H), 4.56 (s, 2H), 3.83 (t, J=5.7 Hz, 2H), 2.90 (br s, 2H), 1.49 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:5][N:6]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=1)=[O:26]>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][S:13]([C:10]2[CH:11]=[CH:12][C:7]([C:4]3[O:3][C:2]([CH3:1])=[N:6][CH:5]=3)=[CH:8][CH:9]=2)(=[O:15])=[O:14])=[C:19]([C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)=[O:26])[CH:20]=1
Reactant: Cc1cccc(C(=O)c2cc(Cl)ccc2N)n1
Reactant: Cc1ncc(-c2ccc(S(=O)(=O)Cl)cc2)o1
Product: Cc1cccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(-c3cnc(C)o3)cc2)n1

Procedure:
The title compound was prepared according to the general procedure for the preparation of N-aryl-benzenesulfonamides using 4-(2-methyl-oxazol-5-yl)-benzenesulfonyl chloride and (2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-2-yl)-methanone and purified by HPLC. MS: m/z 468.0 (M++1).
Reaction SMILES: [NH2:1][C:2]1([C:15]([O:17][CH3:18])=[O:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.N1C=CC=CC=1.[Cl:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30]>C(Cl)Cl>[CH3:18][O:17][C:15]([C:2]1([NH:1][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][Cl:25])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:6][CH2:7]1)=[O:16]
Reactant: COC(=O)C1(N)CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)CCCCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C1(NC(=O)CCCCl)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 4-amino-1-BOC-piperidine-4-carboxylate (2.0 g, 6.78 mmol) in DCM (15 mL) and pyridine (2.10 mL, 20.35 mmol), 4-chlorobutyryl chloride (0.84 mL, 7.5 mmol) in DCM (5 mL) was added slowly at 0° C. The reaction mixture was gradually warmed to room temperature and stirred for 16 hours. The reaction mixture was diluted with DCM (40 mL), and quenched with saturated NaHCO3 (30 mL). The organic layer was separated and the aqueous layer was extracted twice with DCM. The combined organic layers were then washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered and concentrated to give 4-(4-chloro-butyrylamino)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester which was used further without purification.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][C:2]1=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:14]>N1C=CC=CC=1>[NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][C:2]1=[S:14]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1CCCc2ccccc2N1
Solvent: c1ccncc1
Product: S=C1CCCc2ccccc2N1
Temperature: 120 °C

Procedure:
To a solution of Example 182A (12.435 g, 77 mmol) in pyridine (309 mL) under nitrogen was added phosphorus pentasulfide (34.3 g, 154 mmol), and the mixture was heated at 120° C. (reflux) for 2 hours. The solvent was decanted and water was added. The product was extracted with dichloromethane, pre-absorbed onto silica gel and purified by silica gel chromatography (Analogix IntelliFlash™ 280, SF10-150) eluting with 30% ethyl acetate/hexanes to obtain the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 11.75 (s, 1H), 7.32-7.25 (m, 2H), 7.19 (td, J=7.5, 1.2, 1H), 7.10-7.00 (m, 1H), 2.63 (m, 4H), 2.20 (m, 2H); MS (ESI−) m/z 176.1 (M−H)−.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([NH2:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].CC([O-])(C)C.[Na+].O(CCCC)CCCC>>[CH2:8]([NH:14][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCN
Reactant: Clc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCCCOCCCC
Product: CCCCCCNc1ccccc1
Temperature: 85 °C
Yield: 90.6 %

Procedure:
Following general procedure D, a mixture of chlorobenzene (1.02 mL, 10 mmol), hexylamine (1.83 mL, 14 mmol), NaOt-Bu (1.15 g, 12 mmol), 10 (4 mg, 0.05 mol %), 1 (2.5 mg, 0.05 mol %), and Bu2O (3 mL) was heated to 85° C. for 1 h. The crude product was purified via the Biotage SP4 (silica-packed 50 g; 0-50% EtOAc/hexanes) to provide the title compound as a clear oil (1.607 g, 91%). 1H NMR (300 MHz, CDCl3) δ: 7.33 (t, J=7.5 Hz, 2H), 6.85 (t, J=7.5 Hz, 1H), 6.74 (d, J=7.5 Hz, 2H), 3.70 (s, 1H), 3.23 (t, J=7.0 Hz, 2H), 1.74 (pentet, J=7.0 Hz, 2H), 1.51 (m, 6H), 1.09 (t, J=7.0 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3) 6: ppm 148.9, 129.6, 117.4, 113.0, 44.4, 32.1, 29.9, 27.3, 23.1, 14.5. IR (neat, cm−1): 3412, 2956, 2928, 1603, 1507, 1321, 1259, 748, 692. Anal. Calcd. for C12H19N: C, 81.30; H, 10.80. Found: C, 81.37; H, 10.73.
Reaction SMILES: P(=O)(O)(O)O.Cl[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[N+:16]([O-:18])=[O:17])[NH:9][CH:8]=1.[OH2:19]>COCCO>[N+:16]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH2:7][C:8](=[O:19])[NH:9]2)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1cccc2[nH]cc(Cl)c12
Reactant: O
Agent: O=P(O)(O)O
Solvent: COCCO
Product: O=C1Cc2c(cccc2[N+](=O)[O-])N1
Temperature: 95 °C
Reaction time: 3.5 h

Procedure:
Phosphoric acid (35 mL of 86%) is added to a solution of 3-chloro-4-nitroindole (1.27 g, 6.46 mmol) in 2-methoxyethanol (50 mL) at 100° C. The resulting brown colored solution is stirred at 95° C. for 3.5 hours. The reaction is cooled to room temperature and then poured into 500 mL of water. The aqueous layer is extracted three times with ethyl acetate. The ethyl acetate layer is dried over magnesium sulfate, filtered and the solvents removed by rotary evaporation. The crude material is purified via silica gel column chromatography using 2% methanol/methylene chloride as the eluent. The product containing fractions are combined and the solvents removed by rotary evaporation to yield 0.90 g of slightly impure 4-nitrooxindole as an orange solid.