Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1)[NH2:5].[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:12](=[O:14])[CH3:13])[CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(Br)cc([N+](=O)[O-])c1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(Br)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.3 %

Procedure:
28.40 g (0.131 mol) of 3-bromo-5-nitroaniline were dissolved in 250 ml of pyridine and treated with 30 ml (0.317 mol) of acetic anhydride. The mixture was stirred at room temperature for 18 hrs. and subsequently at 40° C. for 2 hrs. Then, the residue was digested in water and the precipitate was filtered off. The filter material was rinsed with a large amount of water and dried at 45° C. in a high vacuum. There were obtained 31.0 g (91.5%) of N-(3-bromo-5-nitrophenyl)-acetamide as orange-yellow crystals. MS (ISP): me/e=260, 258 (C8H8BrN2O3+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[CH3:8].C>[Pd].CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(C=CC(=O)O)cc1C
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(CCC(=O)O)cc1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 3-(3,4-dimethyl-phenyl)-acrylic acid (19.269 g; 109.355 mmol) and 10% palladium over activated charcoal (1.920 g) was placed under nitrogen before MeOH (300 ml) was carefully added. The resulting suspension was placed under vacuum, then under hydrogen (1 atm), and the reaction mixture was vigorously stirred at rt for 4 h. The reaction mixture was filtered over a pad of celite, and concentrated under reduced pressure to give the expected product 3-(3,4-dimethyl-phenyl)-propionic acid as a grey solid which was further dried under HV (19.070 g; 98%). LC-MS: tR=0.85 min; [M+H]+: no ionisation.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:26][C:27]([CH3:36])=[CH:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1>C1(C)C=CC=CC=1.O>[CH3:12][C:4]1[C:3]([CH3:13])=[C:2]([O:1][CH2:26][C:27]([CH3:36])=[CH:28][C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[NH:9][CH:10]=[O:11]
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Reactant: CC(=Cc1ccc(C)cc1)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=Cc1ccc(C)cc1)COc1cc(C)c(NC=O)c(C)c1C
Temperature: 50 °C
Reaction time: 14 h
Yield: 78.9 %

Procedure:
To a mixture of N-(4-hydroxy-2,3,6-trimethylphenyl)formamide (660.4 g), potassium carbonate (1019 g) and dimethylformamide (3302 ml) was added a solution of 1-(3-chloro-2-methyl-1-propenyl)-4-methylbenzene (755 g) in toluene (675 ml), and the mixture was stirred at 50° C. for 14 hr. Water (5944 ml) was then added thereto and the mixture was stirred at 30° C. for 1 hr. The precipitated crystals were collected by filtration and washed with water and isopropylether to give the title compound (940 g, yield 74.5%).
Reaction SMILES: Cl.[NH2:2]O.[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][C:12](=O)[CH2:11]2)[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].[Na+].[Cl-]>CO.O.C1COCC1>[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH2:2])[CH2:11]2)[CH:5]=1
Reactant: O=C1CCCC(c2cccnc2)C1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Al+3]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: NC1CCCC(c2cccnc2)C1
Temperature: 0 °C

Procedure:
Hydroxylamine hydrochloride (67.7 mg, 0.975 mmol) was added to a stirred mixture of 8c (122 mg, 0.696 mmol) and potassium carbonate (96.0 mg, 0.696 mmol) in MeOH (3.00 mL) and water (600 μl). After the reaction was deemed to be complete, the reaction mixture was partially concentrated in vacuo and partitioned between EtOAc and brine. The layers were separated, and the aq. layer was extracted with EtOAc. The combined organics were dried (Na2SO4), filtered and concentrated in vacuo to afford a crude residue (m/z (ES) 191 (MH)+), which was dissolved in THF (3.50 mL) and cooled to 0° C. Lithium aluminum hydride (106 mg, 2.78 mmol) was added in several portions, and after the reaction was deemed to be complete, 1N NaOH was added. The resulting mixture was saturated with NaCl(s) and extracted with EtOAc. The combined organics were dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound, 8d. m/z (ES) 177 (MH)+
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=O.[CH2:12]([N:19]1[C:31]2[C:30]3[CH:29]=[CH:28][C:27]([Br:32])=[CH:26][C:25]=3[N:24]=[CH:23][C:22]=2[N:21]=[C:20]1[NH2:33])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:46]>>[CH2:12]([N:19]1[C:31]2[C:30]3[CH:29]=[CH:28][C:27]([Br:32])=[CH:26][C:25]=3[N:24]=[C:23]([NH2:46])[C:22]=2[N:21]=[C:20]1[NH2:33])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [NH4+]
Reactant: Nc1nc2cnc3cc(Br)ccc3c2n1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: Nc1nc2cc(Br)ccc2c2c1nc(N)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Chloroperoxybenzoic acid (3.7 g of approximately 77% pure material) was added to a solution of 1-benzyl-7-bromo-1H-imidazo[4,5-c]quinolin-2-amine (2.91 g, 8.24 mmol), and the reaction was stirred for two hours at room temperature. Concentrated aqueous ammonium hydroxide (50 mL) and p-toluenesulfonyl chloride (3.1 g, 16 mmol) were added, and the mixture was stirred overnight at room temperature. The organic layer was separated and washed with water (3×200 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product (1.88 g) was purified by automated flash chromatography (silica cartridge, eluting with aqueous ammonium hydroxide:methanol:dichloromethane in a gradient from 0:0:100 to 0.55:10.45:89) to provide 123 g of 1-benzyl-7-bromo-1H-imidazo[4,5-c]quinolin-2,4-diamine as a reddish-brown solid.
Reaction SMILES: CCOCC.C1([Mg]Br)CC1.[CH3:11][O:12][C:13](=[O:33])[C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](I)=[CH:24]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1.[C:34]1(=[O:40])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>C1COCC1>[CH3:11][O:12][C:13](=[O:33])[C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([C:34]3([OH:40])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:24]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(I)c3ccccc32)cc1
Reactant: O=C1CCCCC1
Agent: Br[Mg]C1CC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccc(S(=O)(=O)n2cc(C3(O)CCCCC3)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 20.2 %

Procedure:
Via addition funnel slowly add over 0.5 hours the 2M EtOEt solution of cyclopropyl magnesium bromide (2.16 g, 6.23 ml, 12.46 mmol, 1.1 eq) to the −78° C. THF solution (30 ml) of 4-(3-Iodo-indole-1-sulfonyl)-benzoic acid methyl ester (5 g, 11.33 mmol, 1.00 eq). Stir for 2 hours and then warm to 0° C. Stir for 0.5 hours. Recool to −10° C. and then slowly add a THF solution (3 ml) of cyclohexanone (1.298 g, 13.03 mmol, 1.15 eq). Stir for 15 min and warm to room temperature. Stir for 1.5 days. Quench reaction with saturated aqueous ammonium chloride, remove organics on rotovap, and add EtOAc to crude mix. Extract product into organics, separate organics, dry over MgSO4, and concentrate on rotovap to give crude product as an oil. Purify by silica gel chromatography to give 4-[3-(1-Hydroxy-cyclohexyl)-indole-1-sulfonyl]-benzoic acid methyl ester (948 mg, 20% yield).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1)([O-:11])=[O:10].C(N(CC)CC)C>C(#N)C>[CH2:1]([N:21]1[CH2:22][CH2:23][N:18]([C:15]2[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:17][CH:16]=2)[CH2:19][CH2:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: BrCc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Yield: 63.8 %

Procedure:
Benzyl bromide (1.42 mL, 11.6 mmol) was added to a solution of 1-(4-nitrophenyl)piperazine (2.0 g, 11.6 mmol) in acetonitrile (30 mL) with triethylamine (2.68 mL, 19.32 mmol) and refluxed for 12 h. The mixture was concentrated in vacuo and the residue partitioned between water and ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 1-benzyl-4-(4-nitrophenyl)piperazine (2.2 g, 77%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[S:21][C:20]([NH2:23])=[N:19][C:18]=3[C:17]([O:24][CH3:25])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[F:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1.CO>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:40](=[O:41])[C:39]4[CH:43]=[CH:44][C:36]([F:35])=[CH:37][CH:38]=4)=[N:19][C:18]=3[C:17]([O:24][CH3:25])=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2sc(N)nc12
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2sc(NC(=O)c3ccc(F)cc3)nc12
Temperature: 40 °C
Yield: 82.4 %

Procedure:
To a solution of 0.25 g (0.69 mMol) 4-(2-amino-4-methoxy-benzothiazol-7-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester in 5 ml THF were added 0.37 ml ethyl diisopropyl amine and 1.0 ml (0.83 mMol) 4-fluoro-benzoyl chloride. The reaction mixture was heated to 40° C. for 3 h. Then 1 ml methanol was added. The solvent was evaporated to dryness, the residue taken up in dichloro methane and washed with water and brine. The organic phase was dried over sodium sulfate and evaporated to dryness in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane 1:1) to yield 0.275 g (82%) of 4-[2-(4-fluoro-benzoylamino)-4-methoxy-benzothiazol-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as an off-white solid; F.p.: 205-211° C.
Reaction SMILES: C([O:4][CH:5]1[C:13]2[C:8](=[C:9]([N:14]3[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)(=O)C.[OH-].[K+]>O.C(O)C>[N:14]1([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:8]=2[CH2:7][CH2:6][CH:5]3[OH:4])[CH:15]=[CH:16][CH:17]=[CH:18]1
Reactant: CC(=O)OC1CCc2c1cccc2-n1cccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OC1CCc2c1cccc2-n1cccc1
Yield: 27 %

Procedure:
In the manner of Example 1, step H, hydrolysis of 13.0 g (0.054 mole) of 4-(1-pyrrolyl)-1-indanyl acetate with 4.3 g of potassium hydroxide in 77 mL of water and 154 mL of ethanol gave 2.9 g of 4-(1-pyrrolyl)-1-indanol, m.p. 80°-81° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=1.[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>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(O)C>[F:15][C:16]1[CH:21]=[C:20]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cn1
Reactant: OB(O)c1cccc(F)c1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(-c2cccc(F)c2)cn1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
To a reaction flask was added tert-butyl 5-bromopicolinate 33-4 (516 mg, 2.00 mmol), 3-fluorophenylboronic acid 6-6 (280 mg, 2.00 mmol), Pd(PPh3)4 (140 mg, 0.20 mmol), toluene (10 mL), ethanol (2 mL) and 2M Na2CO3 (3 mL). The reaction mixture was bubbled with nitrogen for 2 minutes and stirred at 90° C. for 10 hours with the flask sealed. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated NaHCO3 aqueous solution, H2O and brine. The organic phase was dried over Na2SO4 and concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography, and eluted with 30% hexanes in ethyl acetate to give tert-butyl 5-(3-fluorophenyl)picolinate 33-5 as a white solid. MS m/z 274.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][N:16]=1.[Cl-].[NH4+]>CO.[Zn]>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc([N+](=O)[O-])cn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Cc1onc(-c2ccccc2)c1COc1ccc(N)cn1
Temperature: 70 °C
Yield: 8.5 %

Procedure:
To a suspension of 2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-5-nitro-pyridine (2.6 g, 83.5 mmol) in methanol (45 mL) was added ammonium chloride (2.23 g, 417.6 mmol) and Zinc (dust, 10.92 g, 167 mmol) and the resulting mixture heated at 70° C. for 1 h. After cooling to room temperature the mixture was filtered and the filtrate evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 4:1) afforded the title compound (2.0 g, 85%) which was obtained as a light yellow oil. MS: m/e=282.0 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]1[C:21](Cl)=[N:20][C:19]([N:23]2[CH2:27][CH2:26][CH2:25][CH:24]2[CH2:28][O:29][CH3:30])=[CH:18][N:17]=1)[CH2:9][C@@H:10]([OH:14])[CH2:11][O:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].O>CN(C=O)C>[CH2:1]([N:8]1[CH2:15][C:16]2[N:17]=[CH:18][C:19]([N:23]3[CH2:27][CH2:26][CH2:25][CH:24]3[CH2:28][O:29][CH3:30])=[N:20][C:21]=2[O:14][C@@H:10]([CH2:11][O:12][CH3:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCC1CCCN1c1cnc(CN(Cc2ccccc2)C[C@@H](O)COC)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC1CCCN1c1cnc2c(n1)O[C@@H](COC)CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
To a solution of (2R)-1-[benzyl({3-chloro-5-[2-(methoxymethyl)pyrrolidin-1-yl]pyrazin-2-yl}methyl)amino]-3-methoxypropan-2-ol (578 mg) in DMF (10 mL) was added potassium tert-butoxide (179 mg), and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 10→50% ethyl acetate/hexane) to give the title compound (467 mg, 88%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10]([C:12]1[CH:13]=[C:14]([S:19]([NH:22][C:23]2[S:27][N:26]=[CH:25][N:24]=2)(=[O:21])=[O:20])[CH:15]=[CH:16][C:17]=1F)#[N:11]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][C:17]1[CH:16]=[CH:15][C:14]([S:19]([NH:22][C:23]2[S:27][N:26]=[CH:25][N:24]=2)(=[O:21])=[O:20])=[CH:13][C:12]=1[C:10]#[N:11]
Reactant: Oc1ccc(F)cc1Br
Reactant: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1F
Product: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1Oc1ccc(F)cc1Br

Procedure:
Prepared according to the process of Preparation 51, using 2-bromo-4-fluorophenol and 3-cyano-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (Preparation 65). LCMS Rt=3.01 min MS m/z 284 [MH]+ 1HNMR (d6-DMSO): δ 6.8 (m, 1H), 7.4 (m, 1H), 7.6 (m, 1H), 7.8 (m, 1H), 8.0 (m, 1H), 8.3 (m, 1H), 8.5 (s, 1H).
Reaction SMILES: NN.[NH2:3][C:4]1[C:13]2[N:14]=[C:15]([CH2:23][N:24]3C(=O)C4C(=CC=CC=4)C3=O)[N:16]([CH2:17][C:18]3([OH:22])[CH2:21][CH2:20][CH2:19]3)[C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1>C(O)C>[NH2:3][C:4]1[C:13]2[N:14]=[C:15]([CH2:23][NH2:24])[N:16]([CH2:17][C:18]3([OH:22])[CH2:21][CH2:20][CH2:19]3)[C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1
Reactant: Nc1nc2ccccc2c2c1nc(CN1C(=O)c3ccccc3C1=O)n2CC1(O)CCC1
Agent: NN
Solvent: CCO
Product: NCc1nc2c(N)nc3ccccc3c2n1CC1(O)CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
Under a nitrogen atmosphere, hydrazine (0.89 mL, 28 mmol) was added to a suspension of 2-({4-amino-1-[(1-hydroxycyclobutyl)methyl]-1H-imidazo[4,5-c]quinolin-2-yl}methyl)-1H-isoindole-1,3(2H)-dione (2.42 g, 5.66 mmol) in ethanol (57 mL), and the reaction was stirred for two hours at room temperature. The ethanol was removed under reduced pressure, and the resulting white solid was triturated with 2 N hydrochloric acid. The resulting suspension was filtered to remove a solid, and the filter cake was washed with water. The filtrate was made basic with the addition of solid sodium bicarbonate. A precipitate formed and was isolated by filtration, washed with water, and dried at 50° C. for three days in a vacuum oven to provide 0.994 g of 1-{[4-amino-2-(aminomethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclobutanol as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]([NH:19][CH2:20][C:21]4[C:22]([O:28][CH3:29])=[N:23][CH:24]=[C:25]([F:27])[CH:26]=4)=[N:16][C:17]=3[F:18])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:36]([NH2:39])(=[O:38])[CH3:37].CNCCNC>O1CCOCC1.[Cl-].[Na+].O.[Cu]I.C(OCC)(=O)C>[F:18][C:17]1[C:12]([CH2:11][C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([NH:39][C:36](=[O:38])[CH3:37])[CH:3]=3)[NH:8][CH:9]=2)=[CH:13][CH:14]=[C:15]([NH:19][CH2:20][C:21]2[C:22]([O:28][CH3:29])=[N:23][CH:24]=[C:25]([F:27])[CH:26]=2)[N:16]=1
Reactant: CC(N)=O
Reactant: COc1ncc(F)cc1CNc1ccc(Cc2c[nH]c3ncc(Br)cc23)c(F)n1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ncc(F)cc1CNc1ccc(Cc2c[nH]c3ncc(NC(C)=O)cc23)c(F)n1
Temperature: 100 °C

Procedure:
[5-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(5-fluoro-2-methoxy-pyridin-3-ylmethyl)-amine (P-1497, 1 equivalent) is dissolved in 25 mL of dioxane in a sealable vial. Cesium carbonate (2.1 equivalents), copper(I) iodide (1.5 equivalents), acetamide (174, 22 equivalents) and N,N′-dimethylethylenediamine (17 equivalents) are added. The vial is sealed and heated at 100° C. overnight. The reaction is added to ethyl acetate and brine and extracted. The organic layer is concentrated under vacuum and the resulting material dissolved in dichloromethane and purified by silica gel column chromatography, eluting with 0-10% methanol in dichloromethane. Appropriate fractions are concentrated, and the material dissolved in tetrahydrofuran for further purification on a C18 reverse phase column, eluting with 0-100% methanol (with 10% tetrahydrofuran)/water. Appropriated fractions are combined and concentrated under vacuum. The resulting material is triturated with methyl tert-butyl ether and filtered, washing with methyl tert-butyl ether, then heptane. The solid is dried under vacuum to provide the desired compound.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([Cl:11])[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1.[NH2:18][C:19]1([CH3:31])[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CCOC(C)=O>[Cl:11][C:6]1[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=[C:2]([NH:18][C:19]2([CH3:31])[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]2)[C:7]=1[CH2:8][CH2:9][OH:10]
Reactant: CC1(N)CCN(C(=O)OC(C)(C)C)C1
Reactant: OCCc1c(Cl)nc(N2CCOCC2)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC1(Nc2nc(N3CCOCC3)nc(Cl)c2CCO)CCN(C(=O)OC(C)(C)C)C1
Temperature: 130 °C
Reaction time: 30 h
Yield: 80 %

Procedure:
To a solution of 2-[4,6-dichloro-2-(morpholin-4-yl)pyrimidin-5-yl]ethanol (Preparation 1)(3.47 g, 12.5 mmol) and tert-butyl 3-amino-3-methylpyrrolidine-1-carboxylate (racemic from a commercial source or Preparation 3 for a chirally pure enantiomer) (5.00 g, 24.97 mmol) in NMP (40 mL) was added DIPEA (8.07 g, 62.44 mmol) at 10° C. The resulting mixture was stirred at 130° C. for 30 h. The mixture was diluted with EtOAc (30 mL) and washed with brine (20 mL×3). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography, eluting with petroleum ether/EtOAc (1:1) to give the title compound (4.40 g, 80%) as a light yellow gum. 1H NMR (400 MHz, 80° C., DMSO-d6) δ 6.48 (s, 1 H), 4.76 (t, J=5.0 Hz, 1 H), 3.76 (d, J=11.1 Hz, 1 H), 3.68-3.53 (m, 10 H), 3.45-3.28 (m, 3 H), 2.69 (t, J=6.24 Hz, 2 H), 2.35-2.26 (m, 1 H), 2.01-1.92 (m, 1 H), 1.49 (s, 3 H), 1.40 (s, 9 H). m/z (APCI+) for C20H32ClN5O4 442.2 (M+H)+.
Reaction SMILES: C[O-].[Na+].[C:4]([O:13][CH3:14])(=[O:12])[C:5]1[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH2:7].[CH2:15](O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]C>CO>[C:4]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])(=[O:12])[C:5]1[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH2:7]
Reactant: CCCCCCCCO
Reactant: COC(=O)c1ccccc1N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCOC(=O)c1ccccc1N

Procedure:
To a methanolic solution of sodium methoxide (prepared from 30 ml of methanol and 0.2 g. of sodium) were added 91 g. of methyl anthranilate and 78 g. of 1-octanol. The reaction mixture was heated at 90° C. for 0.75 hour and at 125° C. for 0.75 hour while methanol was removed by distillation. The residue was washed with water, dried, and distilled. n-Octyl anthranilate was obtained as a clear liquid, b.p. 139°-144° C. at about 0.5 mm.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:6][CH:7]=1)=O.[CH3:13][NH:14][CH3:15].C([BH3-])#N.[Na+].O>CO>[CH3:13][N:14]([CH2:1][C:3]1[CH:4]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:6][CH:7]=1)[CH3:15]
Reactant: CNC
Reactant: CCOC(=O)c1cc(C=O)c[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)c1cc(CN(C)C)c[nH]1
Temperature: 20 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a mixture of ethyl 4-formylpyrrole-2-carboxylate (8.8 g, 52.7 mmol) and dimethylamine (2 M in THF, 40 mL, 1.5 equiv) in methanol (60 mL) was added sodium cyanoborohydride (3.3 g, 1 equiv) in portions and the mixture was stirred for 3 h at 20° C. Water was added and the mixture was extracted with EtOAc. The combined organic layer was washed with water and dried over Na2SO4. Evaporation of solvent afforded a crude, which was purified by column chromatography on silica gel, eluted with MeOH-DCM (1:9) to afford ethyl 4-dimethylaminomethyl-pyrrole-2-carboxylate as a solid (7.8 g, 76%). MS (ES): 392 (MH+) 197.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]=1)=[O:5]
Reactant: Cc1c(C(=O)Cl)cccc1[N+](=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: Cc1c(C(=O)c2ccccc2)cccc1[N+](=O)[O-]

Procedure:
reacting one mole of said 2-methyl-3-nitrobenzoyl chloride in refluxing benzene in the presence of two moles of aluminum chloride for a period of 2-3 hours to form 2-methyl-3-nitrobenzophenone,