Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:8][CH:7]2[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.C1(C)C=CC(S([CH2:26][N+:27]#[C-])(=O)=O)=CC=1.CC(C)([O-])C.[K+].C(O)C>COCCOC>[C:26]([CH:2]1[CH2:8][CH:7]2[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:4]([CH2:5][CH2:6]2)[CH2:3]1)#[N:27]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C2CCC1CC(C#N)C2

Procedure:
tert-Butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate was reacted in the presence of p-toluenesulfonylmethylisocyanide, potassium tert-butoxide and ethanol in 1,2-dimethoxyethane to produce tert-butyl 3-cyano-8-azabicyclo[3.2.1]octane-8-carboxylate.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([Br:11])[CH:5]=1.O.[NH2:14][NH2:15]>CO>[Br:11][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[CH3:10])[C:3]([NH:14][NH2:15])=[O:2]
Reactant: NN
Reactant: COC(=O)c1ccc(C)c(Br)c1
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=O)NN)cc1Br
Temperature: 80 °C
Yield: 50.1 %

Procedure:
A mixture of methyl-3-bromo-4-methylbenzoate (5.0 g, 21.8 mmol, 1.0 eq) and hydrazine hydrate (5 mL, 99 mmol, 4.5 eq) in methanol (50 mL) was heated to 80° C. overnight. The reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated under vacuum. The residue was taken in ethyl acetate (100 mL) and washed with water (2×50 mL), brine (50 mL), dried (Na2SO4) and filtered. The filtrate was evaporated under reduced pressure to afford 2.5 g (50%) of the desired product as a white solid. 1HNMR (400 MHz, DMSO-d6) δ 9.83 (s, 1H, D2O exchangeable), 8.01 (d, J=2.0 Hz, 1H), 7.74 (dd, J=8.0, 2.0 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 4.50 (s, 2H, D2O exchangeable), 2.37 (s, 3H); ESI-MS (m/z) 229, 231 [(MH)+, Br79,81].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[NH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C.Cl>CN(C=O)C>[CH:20]1([CH2:19][NH:18][C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][C:3]=2[N+:15]([O-:17])=[O:16])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=[N+]([O-])c1cc(Oc2ccccc2)ccc1Cl
Reactant: NCC1CCCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Oc2ccccc2)ccc1NCC1CCCCC1
Yield: 65.3 %

Procedure:
A solution of 1-chloro-2-nitro-4-phenoxy-benzene (0.60 g, 2.58 mmol), (aminomethyl)cyclohexane (1.0 mL, 7.76 mmol) and N,N′-diisopropylethylamine (1.36, 7.76 mmol) in DMF (20.00 mL) was stirred at 100° C. under an inert atmosphere for 18.5 h. The reaction mixture was transferred to a separatory funnel containing HCl (2.0 N). The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water, brine and dried over MgSO4. The solution was filtered through diatomaceous earth and the solvent was evaporated. The resulting dark red residue was flash chromatographed (10% EtOAc/hexane) to give cyclohexylmethyl-(2-nitro-4-phenoxy-phenyl)-amine as a dark red solid (0.55 g, 65.6% yield).
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].[F:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[CH:29]2.[CH2:35](Cl)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CCOCC.O>[CH2:35]([N:31]1[C:32]2[C:28](=[CH:27][C:26]([F:25])=[CH:34][CH:33]=2)[CH:29]=[CH:30]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: ClCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: Fc1ccc2c(ccn2Cc2ccccc2)c1
Reaction time: 0.5 h
Yield: 14.1 %

Procedure:
To a solution of 0.8 g (3.03 mmoles) of 18-crown-6 in 100 ml of dry ether was added 3.27 g (29.14 mmoles) of potassium tert-butoxide. The mixture was stirred while a solution of 3.75 g (27.75 mmoles) of 5-fluoroindole in 80 ml of ether was added. The stirring was continued for 0.5 hour. Solid was present. Then 3.69 g (29.15 mmoles) of benzyl chloride in 80 ml of ether was added. The mixture was stirred for 28 hours. Water (100 ml) was added. The layers were separated. The aqueous layer was extracted with 100 ml of ether. The combined ether layers were washed with 50 ml of brine and dried over MgSO4. Evaporation of the solvent left 6.95 g of orange oil. The oil was chromatographed on a 600 g column of silica gel. The column was eluted with 30% CH2Cl2 -Skellysolve B and 200 ml fractions were collected. The fractions were assayed by silica gel tlc (1×4") (30% CH2Cl1 -Skellysolve B). Fractions 11-15 were combined giving 0.88 g (14%) of 1-benzyl-5-fluoroindole as a pale yellow oil which contained a small amount of 1,3-dibenzyl-5-fluorindole.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])(=[O:4])=[O:3].O.[NH3:15]>CO>[CH:11]1[CH:10]=[C:6]2[C:7]([NH:15][S:2](=[O:4])(=[O:3])[C:5]2=[CH:13][CH:12]=1)=[O:8]
Reactant: O=C(Cl)c1ccccc1S(=O)(=O)Cl
Reactant: N
Solvent: CO
Solvent: O
Product: O=C1NS(=O)(=O)c2ccccc21
Yield: 93 %

Procedure:
A 20 g amount of the mixture of o-chlorosulfonylbenzoylchloride and dichlorotolylsultone was added dropwise to 40 ml of methanol with stirring at 15°-20° C. and the mixture was stirred and reacted for 1 hour. After the reaction, the reaction mixture was added dropwise to 35 g of 8% ammonia water with stirring at 20°-25° C., and the reaction mixture was kept for one night. Then, methanol was removed by distillation from the reaction mixture under a reduced pressure, and hydrochloric acid was added to the residual product to adjust pH to 1-2. The precipitated crystals were filtered and washed with water and dried, to obtain 14.3 g of white crystals of o-sulfobenzimide having a melting point of 227°-228° C. (yield of 93%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[C:13](Cl)(=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1.C(N(CC)CC)C>C1COCC1>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[C:13]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=1)=[O:22]
Reactant: Nc1ccc2c(c1)CCCC2=O
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Nc2ccc3c(c2)CCCC3=O)c1
Yield: 92 %

Procedure:
Reaction of 6-Amino-3,4-dihydro-2H-naphthalen-1-one (80 mg, 0.50 mmol) in THF (6 mL) with m-anisoyl chloride (90 μL, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave 3-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzamide (135 mg, 0.46 mmol, 92% yield) as a white powder after purification by flash chromatography on silica gel (eluent:EtOAc/DCM 0/10 to 2/8).
Reaction SMILES: [N:1]([C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][C:7]([O:13][CH3:14])=[C:6]([O:15][CH3:16])[N:5]=1)=[N+]=[N-].[CH3:17]O>[Pd]>[CH3:16][O:15][C:6]1[N:5]=[C:4]2[N:1]=[CH:17][NH:10][C:9]2=[CH:8][C:7]=1[O:13][CH3:14]
Reactant: COc1cc([N+](=O)[O-])c(N=[N+]=[N-])nc1OC
Reactant: CO
Agent: [Pd]
Product: COc1cc2[nH]cnc2nc1OC

Procedure:
A suspension of 11.6 g of 2-azido-5,6-dimethoxy-3-nitropyridine (example E5) in 600 ml methanol was treated with 1.7 g Pd/C (10% Pd) and hydrogenated for 16 h under atmospheric pressure. The reaction mixture was rapidly filtered through a plug of CELITE® (diatomaceous earth), the filtrate was concentrated under vacuum and the residue was refluxed in 100 ml of formic acid for 18 h. The formic acid was removed under vacuum and the resulting residue was dried under vacuum at 100-110° C. to yield crude 5,6-dimethoxy-1H-imidazo[4,5-b]pyridine (as formic acid salt and/or as free base) that was used for the following step without further purification (MS (MH+ found)=180.2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][CH:7]=1.C[CH2:10][N:11](CC)CC.[Si](C#N)(C)(C)C>CC#N.C(Cl)Cl>[F:1][C:2]1[C:3]([C:10]#[N:11])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: [O-][n+]1cccc(F)c1
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Solvent: ClCCl
Product: N#Cc1ncccc1F
Yield: 77.3 %

Procedure:
To a solution of 3-fluoropyridine 1-oxide (1.21 g, 10.7 mmol) in CH3CN (10 mL) was added Et3N (4.4 mL, 31.6 mmol) followed by TMSCN (4.3 mL, 32.2 mmol) and the reaction was stirred at reflux for 6.5 hours. The mixture was diluted with CH2Cl2 (100 mL) and washed with saturated aqueous NaHCO3 (50 mL). The aqueous layer was extracted with CH2Cl2 (3×40 mL) and the combined organic layers were dried (Na2SO4), filtered and concentrated to give a crude dark red oil. Purification of the crude material by column chromatography on silica gel (CH2Cl2/MeOH, 98:2) afforded the title compound as a yellow solid (1.01 g, 77%). 1H NMR (CDCl3): δ 7.58–7.67 (m, 2H), 8.54–8.57 (m, 1H).
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:16][CH:15]2[CH:11]([CH2:12][NH:13][CH2:14]2)[CH2:10]1)=[O:8].Cl[C:24]1[N:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=1>>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:10][CH:11]2[CH:15]([CH2:14][N:13]([C:24]3[N:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=3)[CH2:12]2)[CH2:16]1)=[O:8]
Reactant: Cc1ccnc(Cl)n1
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNCC2C1
Product: Cc1ccnc(N2CC3CN(C(=O)c4ccccc4-c4ccccc4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 17 and 2-chloro-4-methyl-pyrimidine. MS (ESI) mass calcd. for C24H24N4O, 384.49; m/z found, 385.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Cl:18])[C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:26]=[O:27]>>[Cl:1][C:2]1[CH:3]=[C:4]([Cl:18])[C:5]2[N:6]([C:8]([CH:26]=[O:27])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[N:10]=2)[CH:7]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc(-c2cn3cc(Cl)cc(Cl)c3n2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c(-c2ccc(F)cc2)nc2c(Cl)cc(Cl)cn12
Yield: 75 %

Procedure:
6,8-Dichloro-2-(4-fluorophenyl)imidazo[1,2-α]pyridine (6 g, 0.021 moles) was treated with phosphorous oxychloride (3.0 mL, 33 mmol) in N,N-dimethylformamide in a similar manner as described in Example 2 to give 6,8-dichloro-2-(4-fluorophenyl)imidazo[1,2-α]pyridine-3-carbaldehyde (4.9 g, 75%) as a white solid. 1H NMR (CDCl3): δ 10.05 (s, 1H), 9.69 (d, 1H), 7.86 (q, 2H), 7.65 (d, 1H), 7.25 (t, 2H); 19F NMR (CDCl3) δ −110.3; MS m/z 309 (M+1).
Reaction SMILES: [CH2:1]([N:5]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:15])[CH2:13]I)[CH:2]([CH3:4])[CH3:3].CCN(CCO)CC.[NH2:37][C:38]1[CH:39]=[N:40][C:41]2[C:46]([CH:47]=1)=[CH:45][CH:44]=[CH:43][CH:42]=2>>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([S:19]([N:5]([C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([CH2:13][NH:37][C:38]2[CH:39]=[N:40][C:41]3[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:47]=2)=[O:15])[CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:21])=[O:20])=[CH:23][CH:24]=1
Reactant: Nc1cnc2ccccc2c1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CI)C(=O)O)cc1
Agent: CCN(CC)CCO
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CNc2cnc3ccccc3c2)C(=O)O)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-iodoacetyl-L-lysine (200 mg, 0.38 mmol, example 105, step B) by following the indications of general procedure H using DEEA (0.19 mL, 1.09 mmol) and 3-aminoquinoline (260 mg, 1.80 mmol). The crude material was purified by preparative HPLC. The product was isolated as a solid (24 mg, 12% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Br:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][NH:21][CH:22]2[CH3:25])=[CH:17][CH:16]=1>>[Br:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][N:21]([C:11]([C:9]3[CH:10]=[C:5]4[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]4[N:8]=3)=[O:13])[CH:22]2[CH3:25])=[CH:17][CH:16]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2ccc(Br)cc21
Product: CC1c2cc(Br)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1.[H-].[Na+].O>CN(C)C=O>[CH3:10][N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:13][CH2:12]1
Reactant: N#Cc1cccnc1F
Reactant: CN1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(Oc2ncccc2C#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.3 %

Procedure:
To a mixture of 2-fluoro-nicotinonitrile (400 mg, 3.3 mmol) and 1-methyl-piperidin-4-ol (380 mg, 3.3 mmol) in N,N-dimethylformamide (30 mL) was added NaH (60%) (160 mg, 4.0 mmol) in portions. The reaction was stirred overnight at rt. The mixture was poured into water, and extracted with ethyl acetate (2×). The solvent was removed, and the resulting residue was chromatographed using ethyl acetate/methanol (8:1) to give the title compound (210 mg, 29%). MS (DCI/NH3) m/z 218 (M+1)+
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH3:9])[CH:3]=1.[Br:10]N1C(=O)CCC1=O>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][NH:5][C:4]([Br:10])([CH3:9])[CH:3]=1
Reactant: Cc1cc(Cl)c(F)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCCl
Solvent: ClCCl
Product: CC1(Br)C=C(Cl)C(F)=CN1
Temperature: 75 °C
Yield: 69 %

Procedure:
4-Chloro-5-fluoro-2-picoline (2.9 g, 20 mmol), the product of Example 66, was dissolved in 50 mL of 1,2-dichloroethane in a dry flask. The resultant solution was heated, with stirring, to 75° C. and 4.09 (23 mmol) of N-bromosuccinimide was added, followed by 100 mG (0.7 mmol) of 2,2-azobisisobutyronitrile (AIBN), a free radical initiator. After the reaction mixture was stirred at 75° C. for 24 hours, it was diluted with 450 mL of methylene chloride and washed with 3×400 mL of water. The organic layer was separated and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dried in vacuo to give 3.5 g (69% yield) of the title compound as an amber oil; 1H NMR (CDCl3) d 4.50 (s, 2H), 7.54 (d, 1H), 8.44 (s, 1H).
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[CH:24]1([CH2:30][NH2:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.CCN(CC)CC>CCO>[CH:24]1([CH2:30][NH:31][C:2]2[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:17])([F:16])[F:18])[CH2:9][C:10]([F:12])([F:13])[F:11])=[O:7])=[CH:4][C:3]=2[N+:21]([O-:23])=[O:22])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NCC1CCCCC1
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(c1ccc(NCC2CCCCC2)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F

Procedure:
Following the general procedure for Intermediate 2 using 4-fluoro-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (100 mg, 0.287 mmol) and cyclohexylmethyl amine (0.041 mL, 0.315 mmol) in 3 mL of EtOH containing Et3N (0.080 mL, 0.574 mmol). The product was purified by flash chromatography on silica gel using 4:1/hexanes:EtOAc as eluent. Yield: 107 mg (85%); 1H NMR (CDCl3) 1.05 (m, 2H), 1.24 (m, 4H), 1.69 (m, 2H), 1.75 (m, 2H), 1.83 (m, 1H), 3.17 (t, J=6.64 Hz, 2H), 4.23 (q, J=8.53 Hz, 4H), 6.91 (d, J=8.98 Hz, 1H), 7.51 (d, J=8.89 Hz, 1H), 8.28 (s, 1H), 8.39 (s, 1H); MS (ESI) 442.29 (MH+).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[N:28]=[C:27]([C:29](O)=[O:30])[CH:26]=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:34][C:35]1[CH:36]=[C:37]([CH2:41][NH2:42])[CH:38]=[CH:39][CH:40]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[Br:34][C:35]1[CH:36]=[C:37]([CH2:41][NH:42][C:29]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:32][CH3:33])=[O:22])[N:28]=2)=[O:30])[CH:38]=[CH:39][CH:40]=1
Reactant: NCc1cccc(Br)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(Br)c2)n1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
A mixture of 6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylic acid (600 mg, 1.326 mmol), 1-(3-bromophenyl)methanamine (247 mg, 1.326 mmol), HBTU (o-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (603 mg, 1.591 mmol) and Et3N (0.924 mL, 6.63 mmol) in DCM was stirred at room temperature over the weekend. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with brine and then concentrated under vacuum to give a crude residue. It was then purified with flash chromatography eluting with 0 to 100% ethyl acetate in hexane (product came out at 100% ethyl acetate in hexane). The product fractions were combined to give N-[(3-bromophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (632 mg, 49.9%). LC-MS m/z 620 (M+H)+, 0.89 min (ret time).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:32]=[CH:31][C:15]([O:16][CH2:17][C:18]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:19]=3[O:20][CH:21]([CH3:25])[C:22]([OH:24])=[O:23])=[CH:14][CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].[CH2:33](I)[CH3:34]>C(#N)C>[Cl:1][C:2]1[C:3]([C:12]2[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:19]=3[O:20][CH:21]([CH3:25])[C:22]([O:24][CH2:33][CH3:34])=[O:23])=[CH:31][CH:32]=2)=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:9])[F:10]
Reactant: Cc1ccc(COc2ccc(-c3nn(C)c(OC(F)F)c3Cl)cc2)c(OC(C)C(=O)O)c1
Reactant: CCI
Solvent: CC#N
Product: CCOC(=O)C(C)Oc1cc(C)ccc1COc1ccc(-c2nn(C)c(OC(F)F)c2Cl)cc1
Yield: 60.6 %

Procedure:
A stirred solution of 1.6 grams (0.003 mole) of 2-[2-[4-(4-chloro-5-difluoromethoxy-1-methylpyrazol-3-yl)phenoxymethyl]-5-methylphenoxy]-propanoic acid, 0.32 mL (0.004 mole) of ethyl iodide, and 0.49 mL (0.3 mole) of 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU) in 40 mL of acetonitrile was heated at reflux for two hours. The reaction mixture was then cooled and concentrated under reduced pressure to a residue. The residue was taken up in water and extracted with three 60 mL portions of ethyl acetate. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, using 3:7 diethyl ether in heptane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.9 gram of title compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>CO>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:18][CH2:17]1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1F
Reactant: CN1CCNCC1
Solvent: CO
Product: COC(=O)c1cc([N+](=O)[O-])ccc1N1CCN(C)CC1

Procedure:
A solution of methyl 2-fluoro-5-nitro-benzoate (3.487 g, 17.511 mmol) and N-methylpiperazine (3.855 mL, 3.508 g, 35.022 mmol) in 30 mL of anhydrous methanol was heated to reflux for 5 hours.
Reaction SMILES: [C:1]([NH:5][C:6]1[NH:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1)([O:3][CH3:4])=[O:2].[Cl:15][S:16](O)(=[O:18])=[O:17]>>[Cl:15][S:16]([C:13]1[CH:12]=[CH:11][C:9]2[N:10]=[C:6]([NH:5][C:1]([O:3][CH3:4])=[O:2])[NH:7][C:8]=2[CH:14]=1)(=[O:18])=[O:17]
Reactant: COC(=O)Nc1nc2ccccc2[nH]1
Reactant: O=S(=O)(O)Cl
Product: COC(=O)Nc1nc2ccc(S(=O)(=O)Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A solution of 2-carbomethoxyamino-benzimidazole (5.0 g, 0.026 mole) in chlorosulfonic acid (35.00 mL) was stirred at 0° C. for 30 minutes and at room temperature for 3 hours. The resulting dark colored reaction mixture was poured into an ice-water mixture (200 mL), and stirred at room temperature for 30 minutes. The resulting precipitate was filtered and washed with cold water (500 mL). The solid was dried overnight under high vacuum in a desiccator over NaOH pellets to give 5-chlorosulfonyl-2-carbomethoxyamino-benzimidazole (5.9 g, 78%) as a grey powder. 1H NMR (DMSO-d6) d: 3.89 (s, 3H), 7.55 (d, J=8.4 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.88 (s, 1H). (German Patent DE 3826036)
Reaction SMILES: C([CH2:3][NH:4][C:5]1[NH:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:7][C:6]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O.B.[ClH:24].[C:25](=O)([O-])O.[Na+]>O1CCCC1>[ClH:24].[CH3:25][N:4]([CH3:3])[C:5]1[NH:9][C:8]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[N:7][C:6]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=CCNc1[nH]c(-c2ccc(F)cc2)nc1-c1ccccc1
Reactant: O=C([O-])O
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)c1[nH]c(-c2ccc(F)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-formylmethylamino-2-(4-fluorophenyl)-4-phenylimidazole (200 mg) in tetrahydrofuran (5 ml) was added dropwise 10M borane.dimethylsulfide complex (0.34 ml), and the mixture was stirred under argon atmosphere at room temperature for overnight. To the reaction mixture was slowly added 10% hydrochloric acid, and the mixture was refluxed for one hour. After cooling, the mixture was neutralized by adding a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel flush column chromatography (solvent: hexane:ethyl acetate=5:1), and then, treated with hydrogen chloride-methanol solution to obtain 5-dimethylamino-2-(4-fluorophenyl)-4-phenylimidazole hydrochloride (174 mg) as colorless powder.
Reaction SMILES: C1(OC)C=CC=CC=1.[N+:9]([C:12]1[C:25]2[C:24](=[O:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:27])[C:16]=2[CH:15]=[CH:14][CH:13]=1)([O-])=O.[H][H].ONC1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C=CC=1>[Pd]>[NH2:9][C:12]1[C:25]2[C:24](=[O:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:27])[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: [H][H]
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: [Pd]
Agent: O=C1c2ccccc2C(=O)c2c(NO)cccc21
Solvent: COc1ccccc1
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Reaction time: 0.5 h
Yield: 97 %

Procedure:
300 Parts by weight of anisole are mixed with 27 parts of (97 percent) 1-nitroanthraquinone and 0.2 parts by weight of a palladium/charcoal catalyst (5 percent of Pd on active charcoal) and heated to 130° in an autoclave. At this temperature, hydrogen is blown through until the rate of up-take of the hydrogen has fallen to 10 percent of the original value. At this stage, about 2 percent of overhydrogenated product is present (ascertained by TLC). After interruption of the hydrogen supply, at 130°, 0.4 parts by weight of 1-hydroxylaminoanthraquinone are added and stirring is effected for 30 minutes. The catalyst is separated off at the upper temperature, the filtrate is concentrated and cooled and the 1-aminoanthraquinone is filtered off. No nuclear hydrogenated 1-aminoanthraquinone is present in the mother liquor. 23 Parts of 97 percent pure 1-aminoanthraquinone is obtained.