Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C@@H:8]([NH2:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[O-]S([O-])(=O)=O.[Mg+2]>C1C=CC=CC=1>[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[N:10][C@@H:8]([CH3:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:14][CH:13]=1
Reactant: C[C@H](N)Cc1ccccc1
Reactant: O=Cc1ccc(Br)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: c1ccccc1
Product: C[C@@H](Cc1ccccc1)N=Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-1-phenylpropan-2-amine (323 mg, 2389 μmol) in benzene (5 mL) was added 4-bromobenzaldehyde (442 mg, 2389 μmol and MgSO4 (500 mg, 4154 μmol) and the suspension was stirred at RT 4 h. The suspension was filtered and the solid washed with benzene (2×2 mL). The combined filtrates were concentrated to give (S)—N-(4-bromobenzylidene)-1-phenylpropan-2-amine which was used without purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[C:5]([N+:11]([O-:13])=[O:12])[C:4]=1[N+:14]([O-:16])=[O:15].[Br-].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:43]=[C:44]([O:48][CH3:49])[C:45]=1[O:46][CH3:47])[CH2:23][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+]>ClCCl>[N+:11]([C:5]1[C:4]([N+:14]([O-:16])=[O:15])=[C:3]([O:2][CH3:1])[CH:10]=[CH:9][C:6]=1/[CH:7]=[CH:23]\[C:22]1[CH:43]=[C:44]([O:48][CH3:49])[C:45]([O:46][CH3:47])=[C:20]([O:19][CH3:18])[CH:21]=1)([O-:13])=[O:12]
Reactant: COc1ccc(C=O)c([N+](=O)[O-])c1[N+](=O)[O-]
Reactant: COc1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc(OC)c1OC
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(/C=C\c2ccc(OC)c([N+](=O)[O-])c2[N+](=O)[O-])cc(OC)c1OC
Temperature: 25 °C
Reaction time: 7 h
Yield: 50.3 %

Procedure:
4-methoxy-2,3-dinitrobenzaldehyde (2.94 mmol) and 3,4,5-trimethoxybenzyltriphenyl phosphonium bromide (1.54 g, 2.94 mmol, 1.0 equiv) in anhydrous dichloromethane (25 mL) was added NaH (0.424 g, 17.67 mmol, 6.0 equiv). The reaction mixture was stirred at room temperature for about 7 hours and monitored by TLC. The reaction was quenched by adding water, the organic layer was separated and the aqueous layer was extracted with dichloromethane (3×25 mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to orange colored slush. To this was added about 15 mL of dichloromethane and refrigerated overnight. The crude mixture was subjected to flash chromatography to isolate 2′,3′-Dinitro-3,4,4′,5-tetramethoxy-(Z)-stilbene (0.581 g, 1.48 mmol, 51%, solid)
Reaction SMILES: [CH2:1]([Li])CCC.O=[C:7]([CH3:15])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].O.Cl>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O.C1COCC1>[CH3:1][C:7](=[CH2:15])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: [Li]CCCC
Reactant: CC(=O)CCCCC(=O)O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: C=C(C)CCCCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
n-Butyllithium (10.8 ml of 2.5 M in hexanes, 27 mmol, 1.3 equiv) was added to a solution of methyltriphenylphosphonium bromide (9.7 g, 27 mmol, 1.3 equiv) in dimethyl sulfoxide (50 ml) at 0° C., and the mixture was stirred at room temperature for 1 h. It was added to a solution of 6-oxo-heptanoic acid 6 (3 g, 20.82 mmol, 1 equiv) and n-butyllithium (8.33 ml of 2.5 M in hexanes, 20.82 mmol, 1 equiv) in THF (30 ml). The mixture was stirred at room temperature for 48 hr. Water was added and the mixture was acidified with 2 N HCl and extracted with methylene chloride (3×50 ml). The organic layer was washed with 10% sodium hydroxide solution. The aqueous layer was acidified with 2 N HCl and extracted with ethyl acetate (3×60 ml). The organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (10% EtOAc/hexanes) gave pure acid 7 (2.32 g, 78%) as a colorless oil: TLC Rf=0.47 (silica gel, 25% EtOAc/hexanes); 1H NMR (600 MHz, CDCl3) δ 4.69 (s, 1H), 4.65 (s, 1H), 2.34 (t, J=7.8 Hz, 2H), 2.01 (t, J=7.8 Hz, 2H), 1.69 (s, 3H), 1.64-1.58 (m, 2H), 1.50-1.44 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 180.7, 145.6, 110.4; 37.5, 34.2, 27.1, 24.4, 22.5.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.[Cl-].[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1cccc(Br)c1
Reactant: COc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cccc(-c2ccccc2OC)c1
Yield: 121.8 %

Procedure:
Methyl (3-bromophenyl)acetate (2.06 g, 9.0 mmol), tetrakis(triphenylphosphine)palladium (0)(115 mg), sodium carbonate (2.61 g, 25 mmol in 2 ml water) and toluene (10 ml) were degassed under nitrogen in a 25 ml flask fitted with a reflux condenser. 2-Methoxybenzene boronic acid (1.5 g, 9.87 mmol) in toluene (1 ml) was added and the mixture was heated at reflux overnight, then mixed with 1:1 saturated sodium chloride/ethyl acetate (15 ml). The organic materials were separated, dried (MgSO4), then concentrated under reduced pressure which gave 2.81 g of methyl (3-(2-methoxyphenyl)phenyl)acetate.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][NH:5][C:4]1=[O:8].Br[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.CO>C1COCC1.C1COCC1.CN(C=O)C.O>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:5]2[CH2:6][CH2:7][O:3][C:4]2=[O:8])=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: O=C1NCCO1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C1OCCN1Cc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of NaH (60% as a dispersion in oil, 0.34 mol) in anhydrous THF (60 ml) at 0° C. there is added, dropwise, a solution of oxazolidin-2-one (0.31 mol) under an inert atmosphere. The reaction mixture is brought to ambient temperature and stirred for one hour. A solution of 1-bromomethyl-4-nitro-benzene (0.35 mol) in a mixture of THF/DMF (10/1) (250 ml) is added dropwise at 0° C. The reaction mixture is then stirred overnight at ambient temperature. The solution is then cooled to 0° C. There are then added, in succession, 20 ml of MeOH and 20 ml of water. The suspension obtained is then concentrated and then poured into 500 ml of water. The solution is then extracted with DCM and the organic phases are combined. The organic phase obtained is washed with water and with saturated aqueous NaCl solution, is dried over sodium sulphate and is then filtered. The filtrate obtained is concentrated and the solid formed is filtered off, washed with ethyl ether and then dried in vacuo to yield the title product, which is used directly in the next Step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:30]1[CH2:29][CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=3)[CH2:32][CH2:31]1)=[O:19])=[N:5]2
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Product: COc1nc2ccc(Cl)cc2nc1NC(=O)N1CCN(c2ccc(F)cc2)CC1
Yield: 77 %

Procedure:
Ethyl N-(6-chloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(4-fluorophenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound (yield, 77%). 1H NMR (300 MHz, CDCl3): δ 3.13-3.20 (m, 4H), 3.77 (s, 3H), 4.14 (s, 4H), 6.88-7.02 (m, 4H), 7.20-7.24 (m, 1H), 7.36-7.44 (m, 1H), 7.50-7.67 (m, 1H), 7.80 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](I)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[NH:31]1CCC[C@H:32]1[C:33](O)=O.C(=O)([O-])[O-].[K+].[K+].Cl.C(N)C.[OH-].[NH4+]>CS(C)=O.[Cu]I>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([NH:31][CH2:32][CH3:33])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: Clc1cc2c(cn1)c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CCN
Agent: Cl
Solvent: CS(C)=O
Product: CCNc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12

Procedure:
6-Chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridine (Intermediate 1C; 5.53 g, 10.60 mmol), proline (0.42 g, 3.65 mmol), copper (I) iodide (0.21 g, 1.103 mmol), potassium carbonate (7.40 g, 53.5 mmol), and ethylamine hydrochloride (2.78 g, 34.1 mmol) were stirred in DMSO (30 mL) at 70° C. for 24 h. Room temperature was attained, ammonium hydroxide was added and the products extracted into DCM (×2). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (6-50% EtOAc-hexanes) gave 6-chloro-N-ethyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-amine. MS ESI calc'd. For C27H23ClN4 [M+1]+ 439. found 439.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([Cl:9])[CH:3]=1.[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12]>C(NCC)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.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([C:15]#[C:14][Si:11]([CH3:13])([CH3:12])[CH3:10])[CH:5]=[C:4]([Cl:9])[CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Clc1cc(Cl)cc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: C[Si](C)(C)C#Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1,3-dichloro-5-iodo-benzene (5.44 g, 20 mmol) in diethylamine (75 mL) was added PdCl2(PPh3)2 (280 mg, 0.4 mmol), trimethylsilylacetylene (2.36 g, 24.0 mmol) and copper(I)iodide (20 mg, 0.1 mmol). The reaction mixture was stirred at room temperature for 24 h, filtered and evaporated. The residue was purified by column chromatography using heptane:ethyl acetate (8:2) as eluent. The desired (3,5-dichlorophenylethynyl)-trimethyl-silane product was isolated in 4.85 g yield.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:10]=[N:11][C:12]([Cl:32])=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[C:22](=O)[C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[F:30])(C)(C)C.FC(F)(F)C(O)=O.O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Cl:32][C:12]1[N:11]=[CH:10][C:9]2[CH2:8][N:7]=[C:22]([C:23]3[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=3[F:30])[C:16]3[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=3[C:14]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)NCc1cnc(Cl)cc1-c1ccc(Cl)cc1C(=O)c1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Fc1cccc(F)c1C1=NCc2cnc(Cl)cc2-c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
Tert-butyl({6-chloro-4-[4-chloro-2-(2,6-difluorobenzoyl)phenyl]pyridin-3-yl}-methyl)carbamate (165.0 mg, 0.3345 mmol) was dissolved in methylene chloride (5 mL). Trifluoroacetic acid (5 mL, 0.06 mol) was added and the reaction was stirred at room temperature under an atmosphere of nitrogen overnight. Water (20 mL) and methylene chloride (15 mL) were added and the resulting mixture was stirred while solid sodium carbonate (4.50 g, 0.04 mol) was slowly added with stirring. The resulting basic mixture was stirred at room temperature for 30 minutes and then transferred to a separatory funnel. The organic layer was separated and the aqueous phase was extracted with additional methylene chloride (10 mL). The organic extracts were combined, washed with water (10 mL) and brine (10 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting white solid was purified by column chromatography on silica gel (elution gradient from dichloromethane to 7.5% ethyl acetate/dichloromethane) to yield 2,9-dichloro-7-(2,6-difluorophenyl)-5H-pyrido[3,4-d][2]-benzazepine (108 mg, 86%) as a white solid. The product structure was confirmed by NMR and MS.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:5][C:4]=1[CH2:17][NH:18][CH:19]1[CH2:24][CH2:23][CH:22]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]1.[Cl:34][C:35]1[C:36]2[CH:46]=[CH:45][CH:44]=[CH:43][C:37]=2[S:38][C:39]=1[C:40](Cl)=[O:41]>>[Cl:34][C:35]1[C:36]2[CH:46]=[CH:45][CH:44]=[CH:43][C:37]=2[S:38][C:39]=1[C:40]([N:18]([CH2:17][C:4]1[CH:5]=[C:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH:19]1[CH2:24][CH2:23][CH:22]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])[CH2:21][CH2:20]1)=[O:41]
Reactant: COc1ccc(-c2ccc(OC)c(CNC3CCC(N(C)C(=O)OC(C)(C)C)CC3)c2)cc1
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Product: COc1ccc(-c2ccc(OC)c(CN(C(=O)c3sc4ccccc4c3Cl)C3CCC(N(C)C(=O)OC(C)(C)C)CC3)c2)cc1

Procedure:
Biaryl amine 25 (212 mg, 0.46 mmol) is treated with 3-chloro-benzo[b]thiophene-2-carbonyl chloride (108 mg, 0.46 mmol) using Method D to give the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:6](SC2C=CC=CC=2C)[CH:5]=1)(=[O:3])[CH3:2].OO.[CH2:25]([OH:27])[CH3:26]>C(O)(=O)C>[C:1]([C:4]1[CH:14]=[CH:13][C:7]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[C:6]([O:27][C:25]2[CH:5]=[CH:4][CH:1]=[CH:2][C:26]=2[S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCO
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)c(Sc2ccccc2C)c1
Agent: OO
Solvent: CC(=O)O
Product: CC(=O)c1ccc(NS(C)(=O)=O)c(Oc2ccccc2S(C)(=O)=O)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4'-acetyl-2'-(2-methylthiophenoxy)methanesulfonanilide (1.2 g) in acetic acid (7 ml) was added dropwise 30% hydrogen peroxide (1 ml). The mixture was stirred for 2 hours at 70° C. and cooled to room temperature. Ethanol (10 ml) was added, and the precipitates were filtered and washed with ethanol to give colorless needles of 4'-acetyl-2'-(2-methylsulfonylphenoxy)methanesulfonanilide (1.1 g).
Reaction SMILES: [C:1]([C:3]([CH3:38])([CH3:37])[C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=4)[N:20]([CH3:28])[N:19]=3)[N:16]=2)[N:11](COCC[Si](C)(C)C)[CH:10]=1)=[O:8])[CH3:5])#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:3]([CH3:37])([CH3:38])[C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=4)[N:20]([CH3:28])[N:19]=3)[N:16]=2)[NH:11][CH:10]=1)=[O:8])[CH3:5])#[N:2]
Reactant: C[C@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C(C)(C)C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C(C)(C)C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-cyano-1,2,2-trimethyl-ethyl)-amide (120 mg, 0.22 mmol) in CH2Cl2 (2 mL) was added TFA (0.75 mL). The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was redissolved in 10:90:0.5 MeOH/CH2Cl2/NH4OH (3 mL) and stirred at room temperature for 3 h then concentrated. The residue was taken up in 10% MeOH/CH2Cl2 and water was added. The resultant precipitate was collected via filtration then triturated with EtOAc to afford 77 mg (84%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-cyano-1,2,2-trimethyl-ethyl)-amide as a light yellow powder. MS: (M+H)+=422; mp=322-328° C.; 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 12.78 (s, 1H), 8.99 (s, 1H), 8.38 (s, 1H), 8.34 (d, J=9.1 Hz, 1H), 8.01 (d, J=9.6 Hz, 1H), 7.86 (d, J=1.5 Hz, 1H), 7.19 (dd, J=8.6, 1.5 Hz, 1H), 4.20-4.34 (m, 1H), 4.04 (s, 3H), 1.31 (d, J=6.6 Hz, 3H), 1.28 (s, 3H), 1.25 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]([N:16]1[CH2:21][CH2:20][CH:19]([CH:22]=O)[CH2:18][CH2:17]1)(=[O:15])[CH3:14].Cl.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+]>CO.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:13]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[NH:1][C:2]3[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=[CH:10][C:11]=3[N:12]=2)[CH2:18][CH2:17]1)(=[O:15])[CH3:14]
Reactant: CC(=O)N1CCC(C=O)CC1
Reactant: COC(=O)c1cccc(N)c1N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CO
Product: COC(=O)c1cccc2nc(C3CCN(C(C)=O)CC3)[nH]c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
3.3 g (19.9 mmol) of methyl 2,3-diaminobenzoate were dissolved in 100 ml of methanol, and a solution of 4.0 g (25.8 mmol) of N-acetylpiperidine-4-carbaldehyde in 100 ml of methanol was added dropwise at room temperature. The whole was stirred for about 10 minutes at room temperature. Thereafter, 5.2 g (25.8 mmol) of copper(II) acetate, which was dissolved in 100 ml of water, were added dropwise and the whole was refluxed for 30 minutes. After cooling, 25 ml of concentrated hydrochloricacid were added carefully and the whole was again refluxed. 7.15 g (29.8 mmol) of sodium sulfide nonahydrate, dissolved in 100 ml of water, were then added dropwise and the whole was boiled for a further 10 minutes. After cooling, the reaction solution was evaporated down under reduced pressure. The residue obtained was dispersed in water and filtered. The filtrate was rendered alkaline with aqueous sodium bicarbonate solution and was extracted several times with ethyl acetate. The combined organic phases were washed with water, dried and evaporated down under reduced pressure. 4.5 g of the product were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[CH2:6][CH2:7][CH:8]3[CH:17]([C:4]=2[CH:3]=1)[C:16]1[CH:15]=[C:14]([Br:18])[CH:13]=[CH:12][C:11]=1[CH2:10][CH2:9]3.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[CH:6]=[CH:7][C:8]3[CH:9]=[CH:10][C:11]4[CH:12]=[CH:13][C:14]([Br:18])=[CH:15][C:16]=4[C:17]=3[C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)C1c3cc(Br)ccc3CCC1CC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: Brc1ccc2ccc3ccc4ccc(Br)cc4c3c2c1
Temperature: 25 °C

Procedure:
46 g (118 mmol) of 2,11-dibromo-5,6,6a,7,8,12b-hexahydrobenzo[c]phenanthrene and 80.6 g (355 mmol) of DDQ are heated under reflux for 30 h in 300 ml of toluene. After the reaction mixture has been cooled to room temperature, the precipitated hydroquinone is filtered off and washed twice with 50 ml of toluene each time. The solvent is stripped off from the combined organic phases, and the residue is dried in vacuo. The crude product is sublimed at 190° C. and 0.01 mbar, and the sublimate is recrystallised from isopropanol. Yield: 19.6 g (110 mmol), 43%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][C@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18](O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([NH:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14]2)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(N[C@H]2CCNC2)C1
Reactant: O=C(O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(N[C@H]2CCN(C(=O)c3ccccc3)C2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.1 %

Procedure:
To a solution of compound 5c (1 g, 4.14 mmol), compound 4a (0.557 g, 4.56 mmol), and Et3N (1.27 mL, 8.28 mmol) in CH2Cl2 (20 mL) was added HATU (2.05 g, 5.38 mmol). The reaction mixture was stirred at room temperature for 18 h. The resultant mixture was diluted with CH2Cl2 and washed with aq. NaHCO3. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 5% MeOH/EtOAc+0.5 TEA %) gave compound 5d (0.96 g). MS m/z (M+Na+) 368.0.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)(=[O:3])[CH3:2].C(O[CH:18](N(C)C)[N:19]([CH3:21])[CH3:20])(C)(C)C>>[CH3:18][N:19]([CH3:21])[CH:20]=[CH:2][C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)=[O:3]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(=O)c1c[nH]c2ccccc12
Product: CN(C)C=CC(=O)c1c[nH]c2ccccc12

Procedure:
A mixture of 3.18 g of 3-acetylindole and 5.17 ml. (4.36 g) of tert-butoxybis(dimethylamino)methane was heated on a steam bath for 4 hours. The cooled reaction mixture was triturated with n-hexanes and gave a semi-solid. The solvent was removed in vacuo and the material was triturated with dichloromethane giving 3.08 g of the desired compound as a tan crystalline solid, mp 239°-245° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH2:8].[F:9][C:10]([F:27])([F:26])[C:11]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([O:24][CH3:25])[C:12]=1[C:13](O)=[O:14]>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:13](=[O:14])[C:12]1[C:11]([C:10]([F:26])([F:27])[F:9])=[CH:19][C:18]([C:20]([F:21])([F:22])[F:23])=[CH:17][C:16]=1[O:24][CH3:25]
Reactant: N[C@@H]1CCCC[C@@H]1N
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)O
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N

Procedure:
The title compound, yellow foam, MS: m/e=385.1 [(M+H)+], was prepared in accordance with the general method of intermediate G from cis-1,2-diaminocyclohexane and 2,4-bis(trifluoromethyl)-6-methoxybenzoic acid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([N:11]([CH3:23])[C:12]2[CH:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:13]=2)[CH:8]=[C:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:6]=1[OH:28])([CH3:4])[CH3:3].C([Li])CCC.[C:34](Cl)(=[O:36])[CH3:35].O>O1CCCC1>[C:34]([O:28][C:6]1[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[CH:10][C:9]([N:11]([CH3:23])[C:12]2[CH:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:13]=2)=[CH:8][C:7]=1[C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: CN(c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)c1ccn(-c2ccccc2)n1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Oc1c(C(C)(C)C)cc(N(C)c2ccn(-c3ccccc3)n2)cc1C(C)(C)C
Reaction time: 16 h

Procedure:
To 2,6-bis (1,1-dimethylethyl)-4-(N-methyl-N-[1-phenyl-1H-pyrazol-3-yl]amino)phenol (0.6 g) in dry tetrahydrofuran (15 ml) at -78° under nitrogen was added butyl lithium (1.29 ml of 1.4M hexane solution). After 10 minutes acetyl chloride (0.2 ml) was added. The reaction was left for 16 hours, poured into water and extracted with ethyl acetate. Evaporation, and chromatography (silica, dichloromethane/hexane [1:1]) of the residue, followed by recrystallisation from hexane at -20° gave the title compound (0.35 g), mp 102°-103°.