Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][CH:11]([C:13]#[N:14])[CH2:12][CH:7]2[CH2:6]1)=[O:4].[CH2:16](I)[CH3:17].C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>O1CCCC1.O>[CH3:1][N:2]([CH3:15])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([C:13]#[N:14])([CH2:16][CH3:17])[CH2:12][CH:7]2[CH2:6]1)=[O:4]
Reactant: CN(C)C(=O)N1CC2CC(C#N)CC2C1
Reactant: CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCC1(C#N)CC2CN(C(=O)N(C)C)CC2C1
Yield: 48.1 %

Procedure:
5-Cyano-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 12a (3.0 g, 14.5 mmol) was dissolved in 60 mL of tetrahydrofuran with stirring followed by addition of ethyl iodide (4.52 g, 29 mmol) and lithium hexamethyldisilazide (29 mL, 29 mmol) under nitrogen atmosphere. The reaction mixture was reacted at room temperature for 2 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was diluted with 20 mL of water and extracted with ethyl acetate (200 mL×3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain an oil. TLC showed that there are two adjacent spots, and then the oil was purified by silica gel column chromatography to obtain the title compound 5-cyano-5-ethyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 19a (1.64 g) as a light yellow solid.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=[O:14])=[CH:5]1)[CH:2]=[CH2:3].B1C2CCCC1CCC2.[OH-:24].[Na+]>C1COCC1.C(OCC)C>[OH:24][CH2:3][CH2:2][CH2:1][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=[O:14])=[CH:5]1
Reactant: [OH-]
Reactant: C=CCn1cc(C=O)c2ccccc21
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=Cc1cn(CCCO)c2ccccc12

Procedure:
In a 10 mL round-bottom flask, 1-Allyl-1H-indole-3-carbaldehyde (169 mg, 0.91 mmol) is dissolved in 0.5 mL of anhydrous THF. To this solution is added 0.5 M of 9-BBN in THF (2 mL, 1.0 mmol). The reaction is allowed to stir at room temperature for 1 hr, whereupon a 1M solution of NaOH (2.5 mL) is added. The organic layer is diluted with 10 mL of diethyl ether and the aqueous layer is removed. The organic layer is washed 3×10 mL with 1M NaOH, followed by 2×10 mL water and 2×10 mL saturated NaCl solutions. The organic layer is then dried over Na2SO4 and the solvent is removed under reduced pressure to afford 1-(3-hydroxy-propyl)-1H-indole-3-carbaldehyde.
Reaction SMILES: Cl.C(O)(=O)C.[Br:6][C:7]1[C:8]([F:36])=[C:9]([F:35])[CH:10]=[C:11]2[C:16]=1[N:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([NH:24]C(C)(C)C)[N:18]=1)[CH:14]=[C:13]([C:29]([O:31]CC)=[O:30])[C:12]2=[O:34]>O>[NH2:24][C:19]1[N:18]=[C:17]([N:15]2[C:16]3[C:11](=[CH:10][C:9]([F:35])=[C:8]([F:36])[C:7]=3[Br:6])[C:12](=[O:34])[C:13]([C:29]([OH:31])=[O:30])=[CH:14]2)[CH:22]=[CH:21][C:20]=1[F:23]
Reactant: CCOC(=O)c1cn(-c2ccc(F)c(NC(C)(C)C)n2)c2c(Br)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Br)c32)ccc1F
Reaction time: 2 h
Yield: 86.5 %

Procedure:
To 4 ml of the mixed solution (1:1) of 4N hydrochloric acid and acetic acid was added 480 mg of ethyl 8-bromo-1-[6-(t-butylamino)-5-fluoropyridine-2-yl]-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux with stirring for 2 hours. After adding 4 ml of distilled water, the solution was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 345 mg of the title compound as a colorless powder.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1(=[O:14])[O:13][CH2:12][CH2:11][CH2:10]1.[Cl-].[NH4+].Cl>C1COCC1>[C:1]1([C:9]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([OH:14])[CH2:10][CH2:11][CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1CCCO1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OCCCC(O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
60 ml (120 mmol) of 2 M solution of phenyl magnesium bromide in THF was added dropwise to 4.33 g (50.3 mmol) of γ-butyrolactone in 60 ml of THF for the duration of 50 minutes. After stirring at room temperature overnight, a saturated aqueous ammonium chloride solution and then 2 N hydrochloric acid were added dropwise to the reaction mixture. After the extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[N:22]([C:24](Br)=[C:25]([CH3:27])[N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:36]([O:40][CH3:41])(=[O:39])[CH:37]=[CH2:38].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH3:41][O:40][C:36](=[O:39])/[CH:37]=[CH:38]/[C:24]1[N:22]2[N:23]=[C:18]([C:15]3[CH:16]=[CH:17][C:12]([C:8]4([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:35])[CH2:11][CH2:10][CH2:9]4)=[CH:13][CH:14]=3)[C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:20][C:21]2=[N:26][C:25]=1[CH3:27]
Reactant: Cc1nc2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nn2c1Br
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)/C=C/c1c(C)nc2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nn12
Temperature: 110 °C
Reaction time: 3 h

Procedure:
200 mg (0.375 mmol) {1-[4-(3-Bromo-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, intermediate example Int-2-3, 64.5 mg (0.75 mmol) methyl acrylate, 19.4 mg (0.064 mmol) tri-2-tolylphosphane, 16.8 mg (0.075 mmol) palladium(II) acetate and 0.06 mL (0.427 mmol) triethylamine in 2.6 mL degassed acetonitrile were heated in the microwave at 110° C. for three hours. Due to an incomplete reaction additional 32.2 mg (0.375 mmol) methyl acrylate and 8.5 mg (0.037 mmol) palladium(II) acetate were added, and heating in the microwave was continued for three hours. The reaction mixture was poured on water/saturated ammonium chloride/dichloromethane and vigorously stirred for 30 minutes. The organic phase was separated, washed twice with brine, dried, and the solvent was removed. The crude product (300 mg) was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6].O.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:12])([F:13])[F:14])[C:5]([OH:7])=[O:6])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc(C(F)(F)F)c(O)c1
Solvent: O
Product: CC(=O)Oc1cc(C(=O)O)ccc1C(F)(F)F
Reaction time: 0.17 h

Procedure:
3.5 g (17 mmol) of 3-hydroxy-4-trifluoromethyl-benzoic acid (prepared as described in WO 2006/128184) were dissolved in 35 ml of acetic acid anhydride and heated to reflux for 3 h. 60 ml of water were added and heating to reflux was continued for 10 min. After cooling and stirring overnight, the formed precipitate was collected by suction and dried to give 3.0 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:14](OC(=O)C1C=C(N2CCCCC2)C=CC=1N)[CH3:15].S(Cl)(Cl)=O>C(O)C>[CH2:14]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cc(N2CCCCC2)ccc1N
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 48 h

Procedure:
5-Chloro-2-nitro-benzoic acid (compound A′) (10.0 g) was dissolved in ethanol (100 ml). Thionyl chloride (20 ml) was added dropwise to the solution at 0° C., and the mixture was then heated under reflux with stirring for 48 hr. After the completion of the reaction, the reaction solution was concentrated under the reduced pressure. Distilled water was added to the residue, and the mixture was neutralized with a saturated aqueous sodium hydrogencarbonate solution under ice cooling, and was then subjected to separatory extraction with ethyl acetate. The organic layer was dried over sodium sulfate and was then concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a chloroform-methanol system to give 5-chloro-2-nitro-benzoic acid ethyl ester as a useful intermediate (11.0 g, yield 97%).
Reaction SMILES: [CH2:1]([P:18](=[O:33])([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[P:2](=[O:17])([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C=O.[CH2:36](NCC)C>CO>[C:1]([P:2](=[O:17])([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])([P:18](=[O:33])([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH2:36]
Reactant: CCCCCCOP(=O)(CP(=O)(OCCCCCC)OCCCCCC)OCCCCCC
Reactant: CCNCC
Agent: C=O
Solvent: CO
Product: C=C(P(=O)(OCCCCCC)OCCCCCC)P(=O)(OCCCCCC)OCCCCCC
Yield: 73.6 %

Procedure:
22.2 g (44.0 mmol) of tetra-n-hexyl methylenebisphosphonate, 6.61 g (220.0 mmol) of paraformaldehyde and 3.22 g (64.0 mmol) of diethylamine are combined with the same reactants and the same conditions as described above in Example I. This mixture is then refluxed for 48 hours. After the methanol is eliminated as described above in Example I, about 17 g of tetra-n-hexyl ethenylidenebisphosphonate is produced as a clear liquid.
Reaction SMILES: [OH:1][C:2]1([C:11]2[S:12][C:13]([C:16]3[CH:21]=[C:20]([NH:22][C:23]4[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=4)[CH:19]=[C:18]([CH3:33])[CH:17]=3)=[CH:14][N:15]=2)[CH2:7][CH2:6][CH2:5][C:4](=O)[C:3]1([CH3:10])[CH3:9].Cl.[NH2:35][OH:36]>N1C=CC=CC=1>[OH:36]/[N:35]=[C:4]1/[C:3]([CH3:9])([CH3:10])[C:2]([C:11]2[S:12][C:13]([C:16]3[CH:21]=[C:20]([NH:22][C:23]4[N:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[CH:25][N:24]=4)[CH:19]=[C:18]([CH3:33])[CH:17]=3)=[CH:14][N:15]=2)([OH:1])[CH2:7][CH2:6][CH2:5]/1
Reactant: NO
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCCC(=O)C3(C)C)s2)c1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCC/C(=N\O)C3(C)C)s2)c1
Temperature: 60 °C
Yield: 96.8 %

Procedure:
A mixture of the product of Step 2 (300 mg, 0.63 mmol) and hydroxylamine hydrochloride (87 mg, 1.26 mmol) in pyridine (3 mL) was heated to 60° C. for 1 h, concentrated, and purified by flash chromatography to afford the title compound (301 mg, 0.61 mmol). MS ESI: [M+H]+ m/z 492.2. 1H NMR (500 MHz, DMSO-d6) δ 10.36 (s, 1H), 10.26 (s, 1H), 8.84 (d, J=4.9, 1H), 7.98 (s, 1H), 7.96 (s, 1H), 7.48 (s, 1H), 7.29 (d, J=4.9, 1H), 7.16 (s, 1H), 5.97 (s, 1H), 2.82 (m, 1H), 2.33 (s, 3H), 2.24-2.38 (m, 2H), 1.65-1.85 (m, 3H), 1.08 (s, 3H), 1.07 (s, 3H). rhSYK activity=+++
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[CH:3][CH:2]=1.[CH:15]([Si:18]([C:25]#[CH:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16].C(N(CC)CC)C>[Cu](I)I.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>[C:4]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:26]#[C:25][Si:18]([CH:15]([CH3:17])[CH3:16])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[CH:9]=2)[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Reactant: Brc1cccc(Nc2ccccc2)c1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)[Si](C#Cc1cccc(Nc2ccccc2)c1)(C(C)C)C(C)C
Yield: 78 %

Procedure:
Into two Biotage microwave process vials (0.5-2.0 ml) were divided 3-Bromodiphenylamine (636 mg, 2.56 mmol), triisopropylsilylacetylene (0.46 g, 2.56 mmol), copper iodide (20 mg, 0.356 mmol), tetrakis(triphenylphosphine)palladium (60 mg, 0.176 mmol) and triethylamine (3.40 g, 3.36 mmol). The vials were quickly agitated then irradiated in a Biotage Initiator™ microwave instrument for 30 minutes at 80° C. The microwave reactions were recombined and purified by column chromatography (5% EtOAc/hexanes) to afford an oil 698 mg (78%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.05 (s, 21H) 6.82-6.86 (m, 2H) 7.00-7.12 (m, 4H) 7.15-7.28 (m, 3H) 8.23 (s, 1H); MS (ES) m/z 350.2 [M+H]+
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:17]=[C:16]([Cl:18])[N:15]=[C:14]2[C:10]=1[NH:11][CH:12]=[N:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:25](Br)([CH3:27])[CH3:26]>CS(C)=O>[CH2:1]([NH:8][C:9]1[N:17]=[C:16]([Cl:18])[N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH:25]([CH3:27])[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc(NCc2ccccc2)c2[nH]cnc2n1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)n1cnc2c(NCc3ccccc3)nc(Cl)nc21
Reaction time: 8 h
Yield: 85.1 %

Procedure:
A mixture of 6-benzylamino-2-chloropurine (Hocart C. H., Letham D. S., Parker C. W.: Phytochemistry 30,2477 (1991)) 1.32 g, 5.08 mmol), potassium carbonate (4.3 g, 31 mmol) and isopropylbromide (5.5 ml, 58 mmol) in 35 ml of dry dimethyl sulfoxide was vigorously shaken overnight. The reaction mixture was evaporated in vacuum and then partitioned between water and ethylacetate. The organic layer was dried (sodium sulfate) and evaporated. Crystallization from methanol afforded 1.305 g (85%) of product 2, m.p. 181-182° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[S:21][C:22]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)=[CH:23][N:24]=1.CCN=C=NCCCN(C)C.N1C=CC=CC=1.[CH3:47][O:48][C:49]1[CH:50]=[C:51]([CH:55]=[CH:56][C:57]=1[O:58][CH3:59])[C:52](O)=[O:53]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:47][O:48][C:49]1[CH:50]=[C:51]([CH:55]=[CH:56][C:57]=1[O:58][CH3:59])[C:52]([O:18][CH2:17][C@@H:10]1[C@@H:11]([OH:16])[C@H:12]([OH:15])[C@@H:13]([OH:14])[C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:19][C:20]3[S:21][C:22]([C:25]4[CH:29]=[CH:28][S:27][CH:26]=4)=[CH:23][N:24]=3)[CH:4]=2)[O:9]1)=[O:53]
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccsc4)s3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)OC[C@H]2O[C@@H](c3ccc(Cl)c(Cc4ncc(-c5ccsc5)s4)c3)[C@H](O)[C@@H](O)[C@@H]2O)cc1OC
Reaction time: 16 h
Yield: 27 %

Procedure:
To a solution of 48 (150 mg, 0.33 mmol), EDCI (130 mg, 0.66 mmol) and DMAP (20 mg, 0.16 mmol) and pyridine (0.13 ml, 1.65 mmol) in CH2Cl2 (4 ml) was added 3,4-dimethoxybenzoic acid (120 mg, 0.66 mmol) at room temperature and stirred for 16 hours. The reaction mixture was diluted with CH2Cl2 (8 ml), and washed with brine (8 ml). The organic phase was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was purified by prep HPLC (C18) to provide the titled compound (55 mg, 27%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O>C1C=CC=CC=1>[Cl:8][C:9]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:10]=1[C:11]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:13]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Reactant: Clc1ccccc1
Solvent: c1ccccc1
Product: O=C(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1Cl
Yield: 50 %

Procedure:
Repeating Example 21 in every detail except that a chlorobenzene solution of 2-chloro-4-nitrobenzoic acid was employed in lieu of the benzene solution of the same, there is obtained a 50% yield of 2,4'-dichloro-4-nitrobenzophenone in good yield and purity having a melting point of 117° C.-117.5° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[C:20]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:32](=[O:33])[C:31]3[CH:30]=[CH:29][C:28]([C:20](=[O:27])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:36][CH:35]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)c1ccc(C(=O)c2ccccc2)cc1
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1ccc(C(=O)c2ccccc2)cc1
Yield: 16.2 %

Procedure:
Using the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.51 g, 2.0 mmol) was reacted with 4-benzoylbenzoyl chloride (2.0 mmol) to provide 0.15 g of N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin1-yl)butyl]-4-benzoylbenzamide as a white solid, m.p. 159-161° C. 1H NMR (500 MHz, CDCl3) δ8.06 (s, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.85 (d, J=8.0 Hz, 2H), 7.81 (d, J=8.0 Hz, 2H), 7.76 (d, J=8.0 Hz, 2H), 7.60 (m, 2H), 7.49 (t, J=8.0 Hz, 2H), 7.48 (t, J=8.0 Hz, 1H), 7.24 (broad s, 1H), 6.86 (broad s, 1H), 6.60 (t, J=6 Hz, 1H), 4.69 (t, J=7.0 Hz, 2H), 3.62 (q, J=6.0 Hz, 2H), 2.14 (quintet, J=7.0 Hz, 2H), 1.82 (quintet, J=7.0 Hz, 2H); MS (EI) m/e 463.2002 (463.2008 calcd for C28H25N5O2).
Reaction SMILES: [Br:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([CH3:23])=[CH:4][N:3]=1.[CH3:24][O:25][CH2:26]Cl.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[Br:1][C:2]1[C:7]([N:8]([CH2:24][O:25][CH3:26])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:10])=[O:11])=[CH:6][C:5]([CH3:23])=[CH:4][N:3]=1
Reactant: Cc1cnc(Br)c(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCN(c1cc(C)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.9 %

Procedure:
A mixture of N-(2-bromo-5-methyl-pyridin-3-yl)-4-chloro-3-trifluoromethyl-benzenesulfonamide (1.4 g, 3.27 mmol), chloromethyl methyl ether (0.4 mL, 5.23 mmol) and K2CO3 (1.35 g, 9.81 mmol) in THF (20 mL) was stirred at room temperature for 3 h. The mixture was filtered and the filtrate was concentrated and purified by flash chromatography (SiO2, 20% EtOAc-hexanes) to afford N-(2-bromo-5-methyl-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benz-enesulfonamide (1.3 g) as a white solid in 84% yield. ESMS m/z (relative intensity): 473 (M+H)+ (100).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4](Cl)=[O:5].[CH:12]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]([CH3:19])[CH:13]=1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([O:18][C:17]1[CH:12]=[CH:13][C:14]([CH3:19])=[CH:15][CH:16]=1)=[O:5]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: Cc1ccc(O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(OC(=O)c2c(Cl)cccc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
2,6-Dichlorobenzoyl chloride (2.14 g) was added to a solution of p-cresol (1.08 g) and triethylamine (1.11 g) in dichloromethane (30 ml) dropwise at 4° C. The mixture was stirred at ambient temperature overnight. The reaction mixture was washed with aqueous saturated sodium bicarbonate and brine, dried over sodium sulfate and evaporated in vacuo to give 4-methylphenyl 2,6-dichlorobenzoate (2.73 g) as an oil. NMR (CDCl3, δ): 2.38 (3H, s), 7.17 (2H, d, J=8 Hz), 7.25 (2H, d, J=7 Hz), 7.30-7.45 (3H, m)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@H:5]23)[CH:10]=1.[CH3:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1B(O)O>>[CH3:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:16][C@H:5]23)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(Br)cc3c1N2CC3
Reactant: COc1ccc(B(O)O)c(OC)c1
Product: COc1ccc(-c2cc3c4c(c2)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@H]2N4CC3)c(OC)c1

Procedure:
The title compound was prepared by the method of Example 90 from tert-butyl(±)-cis-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (143 mg, 0.32 mmol) and corresponding 2,4-dimethoxyphenylboronic acid (115 mg, 0.63 mmol), to afford after chromatographic purification the title compound (92 mg, 66%) as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ 7.15–7.18 (m, 1H), 7.08 (s, 1H), 7.04 (s, 1H), 6.40–6.60 (m, 2H), 3.75–4.00 (m, 7H), 3.60–3.70 (m, 1H), 3.00–3.50 (m, 7H), 2.70–2.90 (m, 1H), 1.70–1.90 (m, 2H), 1.48 (s, 9H) ppm. MS (CI, NH3): 437 (base, M+H).
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:21]([CH3:22])[CH2:20][C@@:19]2([CH3:23])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:24])[CH2:16][C@@:15]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[Br:26]Br>CO>[Br:26][CH2:13][C:12](=[O:14])[C@@H:11]1[C@:15]2([CH3:25])[C@H:8]([C@H:7]3[C@H:18]([C:17](=[O:24])[CH2:16]2)[C@:19]2([CH3:23])[C@H:4]([CH2:3][C@H:2]([OH:1])[C@@H:21]([CH3:22])[CH2:20]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1
Reactant: BrBr
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](C)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Solvent: CO
Product: C[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(=O)CBr)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O

Procedure:
A solution of 3α-hydroxy-2β-methyl-5α-pregnane-11,20-dione (1.04g.) in dry methanol (150ml) was stirred at 0°-5° during the dropwise addition of a solution of bromine (0.16ml) in dry methanol (20ml) over a period of 2.5 hours. The reaction mixture was partitioned between ethyl acetate and water and the organic layer was separated, washed with water, dried (MgSO4) and evaporated to a white foam; purification by preparative t.l.c. (ethyl acetate: benzene 1:2.5) gave the title compound (510mg.), m.p. 140° dec.; [α]D + 133° (c 0.95).
Reaction SMILES: [O:1]1[CH2:28][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20]([CH3:25])=[CH:19]4)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:26][CH3:27].[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>CN(C=O)C>[OH:1][CH:2]([CH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20]([CH3:25])=[CH:19]4)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:26][CH3:27]
Reactant: C1CCNCC1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CO1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC(O)CN1CCCCC1
Temperature: 70 °C
Yield: 64.1 %

Procedure:
A mixture of 7-(2,3-epoxypropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (100 mg, 0.27 mmol) and piperidine (79ul, 0.8 mmol) in DMF (4 ml) was heated at 70° C. for 24 hours. The solvent was removed by evaporation and the residue was recrystallised from acetonitrile. The solid was filtered, washed with diethyl ether and dried to give 7-(2-hydroxy-3-piperidinopropoxy)-6-methoxy-4-(2-methylindol-5yloxy)quinazoline (80 mg, 65%).