Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:22](OCCC(C)C)=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]2[C:3]=1[CH:9]=[N:22][NH:5]2
Reactant: CC(C)CCON=O
Reactant: Cc1c(N)cccc1Br
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: Brc1cccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
To a solution of 3-bromo-2-methylaniline (5 g, 27 mmol) in chloroform (1 mL) was added acetic anhydride (5 g, 27 mmol) at 0° C. and the mixture was stirred at room temperature for 1 h. Potassium acetate (0.75 g, 7.8 mmol) and isoamyl nitrite (0.78 g, 58 mmol) were added and the reaction mixture was refluxed for 18 h. The volatiles were removed under reduced pressure and water (0.65 mL) was added. The mixture was concentrated, diluted with concentrated hydrochloride acid (1 mL) and heated at 50° C. for 2 h. After being cooled to room temperature, aqueous sodium hydroxide solution (50%) was added until pH=10. The aqueous mixture was extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, evaporated and purified on silica gel column (3% ethyl acetate in petroleum ether) to give the desired product (2.69 g, 34% yield) as a solid. MS (ESI): m/z 197.0 [M+1]+.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:28][CH2:27][C:20]4=[N:21][NH:22][C:23](=[O:26])[CH:24]([CH3:25])[N:19]4[C:18]=3[CH:29]=2)[CH2:11][CH2:10][N:9]1C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C(Cl)Cl>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[CH2:1]([CH:8]1[CH2:13][CH:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:28][CH2:27][C:20]4=[N:21][NH:22][C:23](=[O:26])[CH:24]([CH3:25])[N:19]4[C:18]=3[CH:29]=2)[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1C(=O)NN=C2COc3ccc(C4CCN(C(=O)OC(C)(C)C)C(Cc5ccccc5)C4)cc3N21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1C(=O)NN=C2COc3ccc(C4CCNC(Cc5ccccc5)C4)cc3N21
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
To a solution of tert-butyl 2-benzyl-4-(1-methyl-2-oxo-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)piperidine-1-carboxylate (0.147 g, 0.3 mmol) in DCM (2.5 mL) was added TFA (0.5 mL) and the mixture was stirred at ambient temperature for 2 h. The solvent was removed in vacuo and EtOAc (2 mL) was added to the residue. The precipitate was collected by filtration and washed with EtOAc (1 mL) and petroleum ether (2 mL) to give 9-(2-benzylpiperidin-4-yl)-1-methyl-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one trifluoroacetic acid (0.030 g, 20% yield for three steps) as a solid. LC/MS (Table 1, Method 4) Rt=1.651 min; MS m/z: 391 [M+H]+.
Reaction SMILES: [N:1]1([CH2:10][C:11]([OH:13])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl[Si](C)(C)[CH3:16]>CCOCC>[O:13]=[C:11]([CH3:16])[CH2:10][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)Cn1ccc2ccccc21
Solvent: CCOCC
Product: CC(=O)Cn1ccc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of indole-N-acetic acid (KNK, 10 g, 57 mmol) in dry ether (150 mL) was added dropwise at 0° C. a solution of MeLi (75 mL, 1.4M in ether as LiBr complex). The reaction mixture was then stirred at r.t. for 2 hrs. Chlorotrimethylsilane (70 mL, 0.57 mol) was added dropwise at 0° C. Then the cooling bath was removed and 1N HCl (70 mL) was added at r.t. The aqueous portion was extracted with ethyl acetate and the combined organic phase was washed with brine, dried over MgSO4 and evaporated. Purification by flash chromatography usine 30% ethyl acetate in hexanes gave the title compound.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=O)([CH3:3])[CH3:2].[C:13](O)(=[O:18])[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH:1]([N:4]1[C:5]2[C:6](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:14]([C:15]([OH:17])=[O:16])[C:13]1=[O:18])([CH3:3])[CH3:2]
Reactant: CC(C)Nc1ccccc1C=O
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)n1c(=O)c(C(=O)O)cc2ccccc21
Yield: 55.1 %

Procedure:
A solution of 5.0 g of 2-isopropylaminobenzaldehyde, 4.8 g of malonic acid, 5 ml of piperidine, 5 ml of acetic acid and 50 ml of toluene was heated to reflux for 3.5 hours. The reaction solution was washed with water. The crude product partly precipitated was filtered. The filtrate was extracted with 2N sodium hydroxide aqueous solution and the precipitates above was dissolved in the extract. The resulting solution was washed with toluene and aqueous hydrochloric acid solution was then added thereto to render the system acidic. The precipitates were washed with water and dried to give 3.9 g of 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:39])[N:10]([C@H:19]([C:21]2[N:30](COCC[Si](C)(C)C)[C:24]3=[N:25][CH:26]=[C:27](Br)[CH:28]=[C:23]3[N:22]=2)[CH3:20])COCC[Si](C)(C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:40][C:41]1([CH3:65])[CH2:50][CH2:49][C:48]2[N:47]=[CH:46][N:45]=[C:44]([N:51]3[CH2:57][C:56]4[CH:58]=[C:59](B(O)O)[CH:60]=[CH:61][C:55]=4[O:54][CH2:53][CH2:52]3)[C:43]=2[CH2:42]1>>[C:1]1([CH2:7][O:8][C:9](=[O:39])[NH:10][C@H:19]([C:21]2[NH:22][C:23]3[C:24]([N:30]=2)=[N:25][CH:26]=[C:27]([C:59]2[CH:60]=[CH:61][C:55]4[O:54][CH2:53][CH2:52][N:51]([C:44]5[C:43]6[CH2:42][C:41]([CH3:40])([CH3:65])[CH2:50][CH2:49][C:48]=6[N:47]=[CH:46][N:45]=5)[CH2:57][C:56]=4[CH:58]=2)[CH:28]=3)[CH3:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Reactant: C[C@@H](c1nc2cc(Br)cnc2n1COCC[Si](C)(C)C)N(COCC[Si](C)(C)C)C(=O)OCc1ccccc1
Product: C[C@H](NC(=O)OCc1ccccc1)c1nc2ncc(-c3ccc4c(c3)CN(c3ncnc5c3CC(C)(C)CC5)CCO4)cc2[nH]1

Procedure:
Prepared according to the method of example 5 by using phenylmethyl{(1S)-1-[6-bromo-3-({[2-(trimethylsilyl)ethyl]oxy}methyl)-3H-imidazo[4,5-b]pyridin-2-yl]ethyl}({[2-(trimethylsilyl)ethyl]oxy}methyl)carbamate (reagent preparation 19) and [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, Methanol-d4): 8.56 (br, 1H), 8.36 (br, 1H), 8.09 (br, 1H), 7.60 (s, 1H), 7.51 (d, 1H), 7.42 to 7.25 (m, 5H), 7.10 (d, 1H), 5.17 to 5.03 (dd, 2H), 4.73 (s, 2H), 4.61 (m, 1H), 4.37 (m, 1H), 3.95 (m, 1H), 2.79 (t, 2H), 2.48 (s, 2H), 1.72 to 1.56 (m, 5H), 0.90 (s, 6H); MS (EI) for C35H37N7O3: 604 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][O:13][NH:14][C:15](=[O:17])[CH3:16].[C:18](Cl)(=O)/[CH:19]=C/C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][O:13][NH:14][C:15](=[O:17])/[CH:16]=[CH:18]/[CH3:19]
Reactant: COc1ccc2[nH]cc(CONC(C)=O)c2c1
Reactant: C/C=C/C(=O)Cl
Product: C/C=C/C(=O)NOCc1c[nH]c2ccc(OC)cc12

Procedure:
By carrying out the procedure in the same manner as for the synthesis of the compound of Example 13, but replacing the acetic acid chloride with crotonic acid chloride, the title compound is obtained.
Reaction SMILES: [NH2:1][NH2:2].Cl[C:4]([O:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])[CH3:9])=[O:5]>C(Cl)Cl>[N+:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH:8]([CH3:9])[CH2:7][O:6][C:4]([NH:1][NH:2][C:4]([O:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])[CH3:9])=[O:5])=[O:5])([O-:18])=[O:17]
Reactant: NN
Reactant: CC(COC(=O)Cl)c1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Product: CC(COC(=O)NNC(=O)OCC(C)c1ccccc1[N+](=O)[O-])c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.6 %

Procedure:
A solution of hydrazine (0.32 mL, 10.25 mmol) in DCM (20 mL) was added dropwise to a solution of 2-(2-nitrophenyl)propyl chloroformate (5.0 g, 20 mmol) in methylene chloride (25 mL) over a period of 30 min. The reaction mixture was stirred at room temperature for an additional 15 min. The solvent was evaporated and the residue was purified on a silica gel column. Elution of the column with 20% ethyl acetate in hexanes gave 1.46 g (3.26 mmol, 32% yield) of di-(2-(2-nitrophenyl)propoxycarbonyl)hydrazine. 1H-NMR (300 MHz, DMSO-d6): δ 9.06-8.73 (d, 1H, CONH), 7.84 (d, J=7.8 Hz, 1H, Ar—H), 7.63 (m, 2H, Ar—H), 7.48 (m, 1H, Ar—H), 4.20 (m, 2H, CH2), 3.39 (m, 1H, CH), 1.26 (d, J=6.9 Hz, 3H, CH3). 13C-NMR (75 MHz, DMSO-d6): δ 156.19 (OCOR), 149.85 (C ipso to NO2), 136.53 (C ipso to CH(CH3)CH2OCOR), 132.91 (C para to NO2), 128.52 (C para to CH(CH3)CH2OCOR), 127.76 (C ortho to CH(CH3)CH2OCOR), 123.77 (C ortho to NO2), 67.86 (CH2OCOR), 33.30 (CH), 17.99 (CH3). Mass analysis (MALDI-TOF): calculated for C20H22N4O8 446.42, found 446.24 (C20H22N4O8Na 469.38 is the major peak). TLC: 5% methanol in chloroform, Rf=0.7.
Reaction SMILES: P(O)(O)([O-])=O.[Na+].[O-2].[La+3:8].[O-2].[O-2].[La+3].[N+:12]([O-:15])([OH:14])=[O:13]>O.Cl.O(Cl)Cl.[Zr]>[N+:12]([O-:15])([O-:14])=[O:13].[La+3:8].[N+:12]([O-:15])([O-:14])=[O:13].[N+:12]([O-:15])([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Agent: [Zr]
Agent: Cl
Agent: ClOCl
Solvent: O
Product: O=[N+]([O-])[O-]
Temperature: 80 °C

Procedure:
Zirconium oxychloride (ZrOCl2.8H2O) (36.1 g, 0.112 mole) was dissolved in 50 ml of water. Separately, monosodium phosphate (NaH2PO4.2H2O) (156 g, 1 mole) was dissolved in 200 ml of 3 N hydrochloric acid followed by heating the resulting solution to 80° C. The former solution was then added to the latter solution with stirring to form a white precipitate. After continuing the stirring for a further one hour, the white precipitate was thoroughly water-washed by the decantation method, after which it was filtrably separated and washed in water. After drying the white precipitate at 120° C., it was calcined in air at 400° C., and thereafter molded into granules of 10-16-mesh size to prepare a Zr(HPO4)2 catalyst. Next, lanthanum oxide (La2O3) (0.065 mole) was completely dissolved in an aqueous nitric acid solution, after which the resulting solution was concentrated by heating to prepare lanthanum nitrate, to which 400 cc of water was added to form an aqueous lanthanum nitrate solution. When 100 cc of an aqueous solution containing 20.3 g (0.143 mole) of sodium hydrogenphosphate (Na2HPO4) was added to the aqueous lanthanum nitrate solution, a white precipitate formed. The precipitate thus obtained was stirred at 80° C. for one hour, after which it was thoroughly washed in water. The precipitate was separated by filtration, water-washed and dried at 120° C. The white precipitate was then calcined in a stream of air at 400° C. for 6 hours. The calcined product was then molded into granules of 10-16-mesh size to prepare a LaPO4 catalyst.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([CH3:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]([O:28][CH3:29])=[O:27].O>CN(C=O)C>[CH3:29][O:28][C:26](=[O:27])[CH2:25][NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17])=[CH:10][C:11]=1[CH3:16]
Reactant: COC(=O)CBr
Reactant: Cc1cc(OCC(=O)OC(C)(C)C)ccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CNc1ccc(OCC(=O)OC(C)(C)C)cc1C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a mixture of 2.1 g (8.9 mmol) of the title B compound, (4-amino-3-methylphenoxy)-acetic acid t-butyl ester and 2.44 g (17.7 mmol) of potassium carbonate in 8 mL of DMF are added 1.76 g (11.5 mmol) of methyl bromoacetate. The mixture is stirred at 60° C. for 1 h, then allowed to cool to RT. The mixture is poured into water and extracted with EtOAc. The organic phase is washed with water and brine, and dried over anhydrous Na2SO4. The solvent is removed under reduced pressure and the residue is chromatographed using CH2Cl2 as the eluant to afford (4-t-butoxycarbonylmethoxy-2-methylphenylamino)-acetic acid methyl ester as an oil (contaminated with approx 25% of dialkylated product): 1H-NMR (CDCl3) δ 6.76-6.64 (m, 2H), 6.40 (d, J=8.46, 1H), 4.43 (s, 2H), 3.91 (s, 2H), 3.78 (s, 3H), 2.19 (s, 3H), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][Li].[OH:3][C@@H:4]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C@@H:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:20]2[C:19](=[O:25])[CH2:18][C@@:17]2([CH3:26])[C@H:10]3[CH2:11][CH:12]=[C:13]2[C:14](=[O:16])[CH3:15])[CH2:5]1.[Cl-].[NH4+]>CCOCC.O1CCCC1>[OH:3][C@@H:4]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C@@H:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:20]2[C:19](=[O:25])[CH2:18][C@@:17]2([CH3:26])[C@H:10]3[CH2:11][C@@H:12]([CH3:1])[C@@H:13]2[C:14](=[O:16])[CH3:15])[CH2:5]1
Reactant: [Li]C
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@@]21C
Reaction time: 0.5 h

Procedure:
To a stirred slurry of cuprous iodide (950 mg) in dry ether (75 ml) under dry nitrogen at 0° was added a solution of methyl-lithium in ether (1.6M; 6 ml.) until the initially formed yellow precipitate just rediseolved to give a clear solution. To the stirred solution at 0° was added a solution of 3α-hydroxy-5α-pregn-16-ene-11,20-dione (600 mg) in dry tetrahydrofuran (50 ml.). During the addition a bright yellow precipitate formed. The mixture was stirred at 0° for 30 minutes, and then poured into cold, saturated ammonium chloride solution (200 ml.) More ether (200 ml) was added and the organic layer was separated, washed with saturated ammonium chloride solution (200 ml) and with water (200 ml.) dried over sodium sulphate and purified by preparative t.l.c. in ethyl acetate to give a product which was further purified by preparative t.l.c. in ethyl acetate/chloroform, 1/1 to give a white solid (380 mg) which was recrystallised from ether/petrol to give title compound (248 mg) as colourless plates, m.p. 138°-140°, [α]D + 99°, (c 0.95).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:19])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>N1C=CC=CC=1>[Br:1][C:2]1[C:3]([CH3:19])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=2)[C:5]([NH:8][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=2)(=[O:28])=[O:27])=[N:6][CH:7]=1
Reactant: Cc1c(Br)cnc(N)c1-c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ncc(Br)c(C)c2-c2cccc(C(F)(F)F)c2)cc1
Temperature: 80 °C
Yield: 86.1 %

Procedure:
To a solution of 5-bromo-4-methyl-3-(3-trifluoromethyl-phenyl)-pyridin-2-ylamine (Int. 1, 1.91 g, 5.77 mmol) in pyridine (25 mL) was added p-toluenesulfonyl chloride (1.75 g, 9.18 mmol) and then the reaction mixture was heated at 80° C. for 23 hrs. The solvent was removed by evaporation in vacuo and then the residue was purified by flash chromatography, eluting with a gradient of 0-30% EtOAc in cyclohexane, to give the title compound as an off-white solid (2.41 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=[CH:5]2.[B-](F)(F)(F)[F:17].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C.C(OCC)(=O)C>[F:17][C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]([O:14][CH3:15])=[O:13]
Reactant: F[B-](F)(F)F
Reactant: COC(=O)c1cccc2cc(O)ccc12
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1cccc2c(F)c(O)ccc12
Temperature: 85 °C

Procedure:
To a stirred solution of methyl 6-hydroxy-1-naphthoate (25 g, 123.8 mmol) in anhydrous acetonitrile (130 mL), SelectFluor (45 g, 127.5 mmol) was added and the reaction vessel sealed (sealed tube). The reaction mixture was heated to 85° C. for 3 d. The reaction mixture was allowed to cool to RT, diluted with ethyl acetate and washed with water, then brine, dried with Na2SO4, filtered and evaporated. The mixture was purified by column chromatography using methylene chloride as the eluent. The title compound was obtained as a tan solid.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:28]=[CH:29][CH:30]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[CH:9]=2)[N:4]([S:31]([C:34]2[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH:3]=1.[F:41][C:42]1[CH:43]=[C:44]([CH:60]=[CH:61][CH:62]=1)[CH2:45][N:46]1[CH:50]=[C:49](B2OC(C)(C)C(C)(C)O2)[CH:48]=[N:47]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[F:41][C:42]1[CH:43]=[C:44]([CH:60]=[CH:61][CH:62]=1)[CH2:45][N:46]1[CH:50]=[C:49]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([CH:28]=[CH:29][CH:30]=4)[CH2:14][CH:15]4[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]4)[CH:9]=3)[N:4]([S:31]([C:34]3[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=3)(=[O:33])=[O:32])[CH:3]=2)[CH:48]=[N:47]1
Reactant: CC1(C)OB(c2cnn(Cc3cccc(F)c3)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cccc(CC5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cccc(CC5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Yield: 63.1 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 4-(3-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzyl)piperidine-1-carboxylate (intermediate 66G) (300 mg, 0.44 mmol) was coupled with 1-(3-fluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 11) (170 mg, 0.58 mmol) using Pd(DPPF)Cl2 (15 mg, 0.02 mmol) and sodium carbonate (140 mg, 1.32 mmol) in toluene/ethanol/water (15/8/4 ml) to afford 200 mg (62.3% yield) of the titled compound after column purification using 30% ethyl acetate in hexane as eluent. MS: m/z=720.3 (M+1).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([S:7]([N-:10]Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Na+].II.[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[CH2:21])=[CH:18][CH:17]=1.ClCCl>C(#N)C.O>[C:4]1([S:7]([N:10]2[CH2:21][CH:20]2[C:19]2[CH:22]=[CH:23][C:16]([Br:15])=[CH:17][CH:18]=2)(=[O:9])=[O:8])[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: O=S(=O)([N-]Cl)c1ccccc1
Reactant: C=Cc1ccc(Br)cc1
Agent: II
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: O=S(=O)(c1ccccc1)N1CC1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 48.7 %

Procedure:
To a stirred suspension of chloramine B (CAS [127-52-6], 1.35 g) in acetonitrile (18 mL) under argon was added iodine (0.16 g). 4-Bromostyrene (2.41 g) was added and the mixture was stirred for 19 h at room temperature. Dichloromethane (240 mL) and water (120 mL) were added and the mixture was extracted with dichloromethane. The org. phase was washed with water and brine, dried over MgSO4 and K2CO3 and filtered. The filtrate was concentrated and the product was purified using column chromatography (SiO2, cyclohexane/ethyl acetate 95:5=>ethyl acetate) to give 1-benzenesulfonyl-2-(4-bromo-phenyl)-aziridine (1.04 g) as a colorless oil. MS: 340.0 ([M+H]+)
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[CH:12]([C:21]#[N:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]>C(O)C.[Ni]>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[CH2:4][C:3](=[O:2])[NH:22][CH2:21][CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[C:6]=2[CH:7]=1
Reactant: COC(=O)Cc1ccc(Cl)cc1C(C#N)c1ccccc1OC
Agent: [Ni]
Solvent: CCO
Product: COc1ccccc1C1CNC(=O)Cc2ccc(Cl)cc21
Reaction time: 2.5 h

Procedure:
201 mg of the compound from Example 20A (0.61 mol) are dissolved in 30 ml of ethanol, introduced into a hydrogenation apparatus and mixed with anhydrous Raney nickel. The catalyst has previously been obtained by washing 1.0 ml of a 50% strength aqueous Raney nickel suspension with ethanol several times. Hydrogenation is carried out under atmospheric pressure and at room temperature for 2.5 h. The catalyst is then filtered off under an argon atmosphere and washed three times with ethanol, and the combined filtrates are concentrated. The residue is dissolved in 30 ml of toluene and heated under reflux for 5 h. The solvent is removed in a rotary evaporator, and the residue is purified by preparative HPLC (eluent: acetonitrile/water, gradient 20:80→95:5). 55 mg (30% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:13][C:12]3=[O:25])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][CH2:29][C:3]1=2.[ClH:37]>CO.CCOCC>[ClH:37].[ClH:37].[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:13][C:12]3=[O:25])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:26][NH:27][CH2:28][CH2:29][C:3]1=2
Reactant: Cn1c2c(c3ccc(-n4ccc(CCc5ccccc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cn1c2c(c3ccc(-n4ccc(CCc5ccccc5)cc4=O)cc31)CNCC2
Reaction time: 3 h
Yield: 80 %

Procedure:
tert-Butyl 5-methyl-7-(2-oxo-4-phenethylpyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (120 mg, 0.248 mmol) was dissolved in MeOH (1.5 mL) and 2 N HCl in Et2O (5 mL) was added. The reaction was allowed to proceed for 3 h. The resulting precipitate was collected by filtration and washed with Et2O to provide the title compound (90 mg, 80%) as a yellow solid: mp 282-286° C.; 1H NMR (500 MHz, CD3OD) δ 7.70 (d, J=6.9 Hz, 1H), 7.62 (d, J=8.3 Hz, 1H), 7.52 (s, 1H), 7.33-7.26 (m, 4H), 7.22 (t, J=7.2 Hz, 1H), 7.09 (dd, J=8.3, 1.6 Hz, 1H), 6.59-6.56 (m, 2H), 4.50 (s, 2H), 3.76 (s, 3H), 3.70 (t, J=6.2 Hz, 2H), 3.24 (t, J=6.0 Hz, 2H), 3.04-3.01 (m, 2H), 2.98-2.95 (m, 2H); ESI MS m/z 384 [M+H]+; HPLC (Method B)>99% (AUC), tR=13.3 min.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].I[CH:15]([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:15]([CH3:17])[CH3:16])[C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: COC(=O)c1ccc(O)c(C#N)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(C)C)c(C#N)c1
Temperature: 50 °C
Yield: 98.5 %

Procedure:
To a solution of methyl 3-cyano-4-hydroxybenzoate (82 g, 463 mmol; J. Med Chem, 2002, 45, 5769) in dimethylformamide (800 mL) was added 2-iodopropane (93 mL, 926 mmol) and potassium carbonate (190 g, 1.4 mol). The resulting mixture was heated at 50° C. for 16 h, at which time it was allowed to cool to room temperature. The reaction was filtered and the mother liquor diluted with 0.5 N sodium hydroxide (1 L). The resulting mixture was extracted with ether (2×1 L) and the organics washed with 1 N HCl (1 L) and brine (700 mL), dried (MgSO4) and concentrated to give 100 g (1100%) of methyl 3-cyano-4-[(1-methylethyl)oxy]benzoate as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH:13]2[CH:9]1[CH2:10][NH:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[CH2:23][N:24]=[C:25]=[O:26]>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH:13]2[CH:9]1[CH2:10][N:11]([C:25](=[O:26])[NH:24][CH2:23][C:17]1[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=1[Cl:15])[CH2:12]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=NCc1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CC2CNCC21
Product: CC(C)(C)OC(=O)N1CC2CN(C(=O)NCc3ccc(Cl)cc3Cl)CC21
Yield: 88 %

Procedure:
In analogy to the experimental procedure of example 1a) rac-3,6-diaza-bicyclo[3.2.0]heptane-6-carboxylic acid tert-butyl ester instead of 6-(tert-butoxycarbonyl)-2,6-diaza-spiro[3.3]heptane oxalate was converted using 2,4-dichloro-1-(isocyanatomethyl)benzene into the title compound (691 mg, 88%) which was obtained as a colorless solid. MS (EI) m/e: 400.1 (M+H)+.