Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([N:10]=[C:11]=S)=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:13])[CH:3]=1.[NH2:14][C:15]1[C:16]([NH:39][CH3:40])=[CH:17][C:18]([O:34][CH2:35][CH:36]([F:38])[F:37])=[C:19]([CH:33]=1)[C:20]([NH:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([C:29]([F:32])([F:31])[F:30])[CH2:25][CH2:24]1)=[O:21].CC(C)N=C=NC(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([F:13])[C:5]([C:6]#[N:7])=[CH:8][C:9]=1[NH:10][C:11]1[N:39]([CH3:40])[C:16]2[CH:17]=[C:18]([O:34][CH2:35][CH:36]([F:37])[F:38])[C:19]([C:20]([NH:22][C@H:23]3[CH2:28][CH2:27][C@H:26]([C:29]([F:32])([F:31])[F:30])[CH2:25][CH2:24]3)=[O:21])=[CH:33][C:15]=2[N:14]=1
Reactant: N#Cc1cc(N=C=S)c(Cl)cc1F
Reactant: CNc1cc(OCC(F)F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2cc(C#N)c(F)cc2Cl)nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(OCC(F)F)cc21

Procedure:
The sub-title compound was prepared in accordance with the procedure in Example 72, step (a) using 4-chloro-2-fluoro-5-isothiocyanatobenzonitrile (270 mg; 1.27 mmol), 5-amino-2-(2,2-difluoroethoxy)-4-(methylamino)-N-((trans)-4-(trifluoromethyl)cyclohexyl)benzamide [502 mg; 1.27 mmol, prepared from 4-trans-trifluoromethyl-cyclohexylamine and 2-(2,2-difluoroethoxy)-4-(methylamino)-5-nitrobenzoic acid in analogy to Example 66, step (f+g)], DIC (160 mg; 1.27 mmol) and DMF (10 mL). Yield: 210 mg (29%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[CH:4][N:3]=1.CC(C)([O-])C.[Na+].Br[C:17]1[C:25]2[NH:24][C:23]3[CH2:26][CH2:27][N:28]([CH3:30])[CH2:29][C:22]=3[C:21]=2[CH:20]=[CH:19][CH:18]=1>C(P([Pd]P(C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C)(C)C.O1CCOCC1>[CH3:30][N:28]1[CH2:27][CH2:26][C:23]2[NH:24][C:25]3[C:17](/[CH:9]=[CH:8]/[C:5]4[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][CH:6]=4)=[CH:18][CH:19]=[CH:20][C:21]=3[C:22]=2[CH2:29]1
Reactant: C=Cc1ccc(C)nc1
Reactant: CN1CCc2[nH]c3c(Br)cccc3c2C1
Agent: CC(C)(C)[PH]([Pd][PH](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc(/C=C/c2cccc3c4c([nH]c23)CCN(C)C4)cn1
Temperature: 105 °C
Reaction time: 4 h

Procedure:
A mixture of bis(tri-t-butylphosphino)palladium (25.4 mg, 0.05 mmol; Aldrich), the product of Example 1B (142 mg, 1.19 mmol), sodium t-butoxide (159 mg, 1.66 mmol; Aldrich) and the product of Example 1A (200 mg, 0.66 mmol) was combined with 1,4-dioxane (6 mL). The reaction mixture was purged with nitrogen and stirred at 105° C. for 4 hours in a sealed tube. The mixture was then heated at 105° C. for another 60 hours. The reaction mixture was cooled to room temperature, filtered through a glass microfiber frit, rinsed with CH3OH (3 mL) and purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 50-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (500 MHz, methanol-d4) δ ppm 2.54 (s, 3H), 2.56 (s, 3H), 2.90 (t, J=5.8 Hz, 2H), 2.98 (t, J=5.6 Hz, 2H), 3.69 (br s, 2H), 7.02 (t, J=7.6 Hz, 1H), 7.23 (d, J=16.5 Hz, 1H), 7.29-7.33 (m, 2H), 7.40 (d, J=7.3 Hz, 1H), 7.67 (d, J=16.5 Hz, 1H), 8.02 (dd, J=8.2, 2.1 Hz, 1H), 8.61 (d, J=2.1 Hz, 1H); MS (APCI) m/z 304 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7][C:6]=2[C:5]([NH2:15])=[C:4]([Br:16])[CH:3]=1.N1C=CC=CC=1.[C:23](Cl)(=[O:25])[CH3:24]>ClCCl>[Br:1][C:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7][C:6]=2[C:5]([NH:15][C:23](=[O:25])[CH3:24])=[C:4]([Br:16])[CH:3]=1
Reactant: CC(=O)Cl
Reactant: Nc1c(Br)cc(Br)c2c1oc1ccccc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1c(Br)cc(Br)c2c1oc1ccccc12
Yield: 70.2 %

Procedure:
In a 2 L round-bottomed flask, 1,3-dibromodibenzo[b,d]furan-4-amine (76 g, 223 mmol) in dichloromethane (800 mL) and pyridine (180 mL, 2229 mmol) were cooled by ice bath. Acetyl chloride (31.7 mL, 446 mmol) was added dropwise while stirring. Then the ice bath was removed. The reaction was stirred at room temperature for 1 h. The residue was collected by filtration and washed by water and dichloromethane to give N-(1,3-dibromodibenzo[b,d]furan-4-yl)acetamide (60 g, 70.3% yield) as brown solid.
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)(=O)=O.[I-:17].[K+]>CN(C)C=O>[I:17][CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(I)C1
Temperature: 100 °C

Procedure:
A mixture of tert-butyl 3-[(methylsulfonyl)oxy]-1-azetidinecarboxylate (prepared as described in Synlett 1998, 379; 5.0 g, 19.9 mmol), and potassium iodide (16.5 g, 99.4 mmol) in N,N-dimethylformamide (25 mL), was heated at 100° C. for 42 h. The cooled mixture was partitioned between water and ethyl acetate, and the layers separated. The organic phase was dried over MgSO4, concentrated under reduced pressure and the residue azeotroped with xylene. The crude product was purified by flash column chromatography (dichloromethane as eluant) to give the title compound, 3.26 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.C(=O)([O-])[O-].[K+].[K+].[CH2:22]([NH2:25])[C:23]#[CH:24].O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10]([NH:25][CH2:22][C:23]#[CH:24])=[O:11])[CH2:7]1
Reactant: C#CCN
Reactant: O=C(Cl)N1CC(Oc2cccc(Br)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCNC(=O)N1CC(Oc2cccc(Br)c2)C1
Reaction time: 42 h
Yield: 64.7 %

Procedure:
A stirred mixture of 5.8 g (0.02 mole) of 3-(3-bromophenoxy)-1-azetidinecarbonyl chloride and 2.8 g (0.02 mole) of potassium carbonate in 20 ml of tetrahydrofuran was treated with 1.1 g (0.02 mole) of 2-propynylamine added dropwise from a needle and syringe. A piece of ice was added and stirring was continued for 42 hr. The solid residue which remained was stirred with 100 ml of water then filtered, yielding 5.3 g of crude product. Recrystallization from ethanol yielded 4.0 g of fine beige crystals, m.p. 145°-147° C. After drying at 100° C. in vacuo, m.p. was 146°-147° C. (64.7%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.COB(OC)OC.C(#N)C>O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([N:25]4[CH:24]=[CH:23][N:22]=[CH:27][CH2:26]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: COB(OC)OC
Solvent: O
Solvent: CC#N
Product: COc1c(N2C=CN=CC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Yield: 81.7 %

Procedure:
A mixture of 1.48 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (5 mmol), 0.86 g of anhydrous piperazine (10 mmol), 1.04 g of trimethoxyborane (10 mmol) and 7.5 ml of acetonitrile was refluxed with heating for 4 hours. The reaction solution was cooled to room temperature, 20 ml of water was added therein, a pH was adjusted to 8 with 6N--HCl, and separated crystals were filtered and dried to obtain 1.46 g of the objective compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[Cl:11][C:12]1[CH:13]=[C:14]([S:19](Cl)(=[O:21])=[O:20])[CH:15]=[CH:16][C:17]=1[Cl:18]>N1C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]([S:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[CH:5]3)(=[O:20])=[O:21])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc2[nH]ncc2c1)c1ccc(Cl)c(Cl)c1
Yield: 21.4 %

Procedure:
3,4-Dichloro-N-(1H-indazol-5-yl)benzenesulfonamide can be obtained as described in Example 2 from 1 g of 5-amino-1H-indazole, 20 ml of pyridine and 1.84 g of 3,4-dichlorobenzenesulfonyl chloride. 0.55 g of 3,4-dichloro-N-(1H-indazol-5-yl)benzenesulfonamide is thus obtained in the form of a green solid melting at 209° C. (analysis C13H9Cl2N3O2S % calculated C, 45.63; H, 2.65; Cl, 20.72; N, 12.28; O, 9.35; S, 9.37. % found C, 45.87; H, 2.72; Cl, 21.10; N, 12.27; S, 9.21).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[F-].[K+].C(=O)([O-])[O-].[K+].[K+].[CH:21]1([NH2:24])[CH2:23][CH2:22]1>ClCCl>[CH:21]1([NH:24][C:2]2[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH2:23][CH2:22]1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Reactant: NC1CC1
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(F)c(F)cc1NC1CC1
Temperature: 90 °C

Procedure:
2,4,5-Trifluoronitrobenzene (2.00 g, 11.3 mmol), potassium fluoride (0.656 g, 11.3 mmol), potassium carbonate (1.561 g, 11.29 mmol), and cyclopropylamine (0.93 ml, 13.55 mmol) were added to a vial and heated in a microwave at 90° C. for 10 min. The reaction was then diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. Purification by flash chromatography on silica gel (0-15% ethyl acetate in hexanes) provided the title compound: 1H NMR (500 MHz, CDCl3) δ 8.04 (dd, J=10.4, 8.5 Hz, 1 H), 7.09 (dd, J=12.6, 7.0 Hz, 1 H), 2.55-2.54 (m, 1 H), 0.97-0.93 (m, 2 H), 0.69-0.66 (m, 2 H).
Reaction SMILES: [OH:1][C:2]1[C:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[CH:16]=[CH:17][C:4]=2[CH:3]=1.[N+](=[CH2:23])=[N-]>CO.CCOCC>[CH3:23][O:19][C:18]([C:15]1[CH:16]=[CH:17][C:4]2[CH:3]=[C:2]([OH:1])[C:8]3[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=3[S:6][C:5]=2[CH:14]=1)=[O:20]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1ccc2c(c1)Sc1ccc(F)cc1C(O)=C2
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1ccc2c(c1)Sc1ccc(F)cc1C(O)=C2
Yield: 78 %

Procedure:
10-Hydroxy-8-fluoro-dibenzo[b,f]thiepin-3-carboxylic acid (4 g; 13.8 mmoles) dissolved in methanol (100 mL) and treated with excess diazomethane in ether. The volatiles removed under vacuum and the residue, taken up in chloroform, is purified by chromatography in Silica Gel. Elution with 20% ethyl acetate in toluene yielded 3.26 g (78%) of the title compound, m.p. 85°-88° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O)[CH3:2].S(=O)(=O)(O)[OH:16].[Al].C(O)(=O)C(C(C(O)=O)O)O>O.C(OCC)(=O)C>[CH2:1]([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([OH:16])[CH:9]=[CH:8][C:7]=1[NH2:12])[CH3:2]
Reactant: CCOCCc1ccccc1[N+](=O)[O-]
Reactant: O=S(=O)(O)O
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: [Al]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOCCc1cc(O)ccc1N
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
58.5 g (0.3 mole) of 1-(β-ethoxyethyl)2-nitrobenzene was added at a temperature of 90° C. to a solution of 100 ml of concentrated sulphuric acid diluted in 1 liter of distilled water. 17 g of aluminium powder was added using a spatula and with vigourous stirring. Stirring was maintained for 40 minutes and then 70 g of tartaric acid was added. Stirring was continued for a further 15 minutes with the temperature maintained at 90° C. and then the reaction medium was cooled and the suspension filtered through sintered glass. The filtrate was neutralised with 20% ammonium hydroxide at a temperature below 20° C. A pinkish beige precipitate was obtained. The precipitate was taken up in 0.5 l of refluxing ethyl acetate, hot filtered and dry concentrated. It was recrystallised again from ethyl acetate to obtain beige crystals of the expected product which had a melting point of 102° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([C:20](O)=[O:21])[CH2:16][CH2:15]3)[NH:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.ClCCl>[CH3:25][C:26]1[CH:27]=[CH:28][C:29]([S:32]([NH:35][C:20]([C@H:17]2[CH2:16][CH2:15][C@H:14]([C:11]3[NH:12][CH:13]=[C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:24])([F:23])[F:1])[CH:4]=4)[N:10]=3)[CH2:19][CH2:18]2)=[O:21])(=[O:34])=[O:33])=[CH:30][CH:31]=1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(O)[C@H]1CC[C@H](c2nc(-c3cccc(C(F)(F)F)c3)c[nH]2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)[C@H]2CC[C@H](c3nc(-c4cccc(C(F)(F)F)c4)c[nH]3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice-water cooled mixture of trans-4-{4-[3-(trifluoromethyl)phenyl]imidazol-2-yl}cyclohexanecarboxylic acid (1.48 mmol), 4-methylbenzenesulfonamide (1.48 mmol), and DMAP (1.48 mmol) in dichloromethane (10 mL) under nitrogen, EDC (1.48 mmol) was added. The mixture was stirred at room temperature overnight, concentrated and chromatographed on silica gel (19:1 EtOAc-MeOH eluent) to give trans-N-[(4-methylphenyl)sulfonyl](4-{4-[3-(trifluoromethyl)phenyl]-imidazol-2-yl}cyclohexyl)carboxamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[NH:11])[NH:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[C:14](OC)(=O)[CH3:15].O>O1CCCC1>[CH3:14][C:15]1[O:10][N:9]=[C:8]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[NH2:1])[N:11]=1
Reactant: N=C(NO)c1cccc(N)c1
Reactant: COC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2cccc(N)c2)no1
Temperature: 65 °C

Procedure:
To a stirred solution of Intermediate 18 (5.3 g) in dry tetrahydrofuran (50 ml) was added 4 Å molecular sieves, followed by sodium hydride (60% dispersion in mineral oil; 1.5 g) and the mixture heated at 65° C. for 30 min. After cooling to room temperature methyl acetate (2.8 ml) was added and the mixture heated under reflux for 16 h. After cooling to 20° C. the mixture was added to water (100 ml) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulphate and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with dichloromethane to give the title compound as a white solid (4.0 g).
Reaction SMILES: [Cl:1][C:2]1[O:25][C:5]2=[C:6]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1.[Li+].[CH3:27]C([N-]C(C)C)C.CI>C1COCC1>[Cl:1][C:2]1[O:25][C:5]2=[C:6]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:27]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(Cl)oc12
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(Cl)oc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 102.6 %

Procedure:
Di-tert-butyl (2-chlorofuro[2,3-c]pyridin-7-yl)imidodicarbonate (3.0 g, 8.15 mmol) in dry THF (100 mL) was cooled to −65° C. to −75° C. and LDA (1.8 M in THF/heptanes/ethylbenzene, 6.0 mL, 10.8 mmol), pre-cooled to the same temperature, was added slowly via syringe over a period of 10 min. The mixture was stirred for 1.5 h at −65° C. to −75° C. and then treated with methyl iodide (0.76 mL, 12.2 mmol) in dry THF added slowly via syringe. The mixture was allowed to warm to RT overnight and was quenched by the addition of water (50 mL) and diluted with EtOAc (100 mL). The phases were separated and the organic phase was dried over Na2SO4, and concentrated in vacuo leaving 3.2 g of a brown solid which was used without further purification. 1H NMR (400 MHz, CDCl3): δ 8.25 (d, J=5.5 Hz, 1H), 7.39 (d, J=5.5 Hz, 1H), 2.22 (s, 3H), 1.40 (s, 18H).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:12][C:13]1[CH:14]=[C:15]([NH2:22])[C:16](=[CH:20][CH:21]=1)[C:17]([OH:19])=[O:18]>CO.O>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[C:15]([NH:22][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH:14]=1
Reactant: Nc1cc(Br)ccc1C(=O)O
Reactant: COC(=O)c1ccccc1I
Solvent: CO
Solvent: O
Product: COC(=O)c1ccccc1Nc1cc(Br)ccc1C(=O)O
Yield: 70 %

Procedure:
Reaction of methyl 2-iodobenzoate and 4-bromoanthranilic acid by the reported method [Rewcastle and Denny, Synth. Comm, 1987, 17, 309] gave 4-bromo-2-[(2-methoxycarbonyl-phenyl)amino]benzoic acid (70%), mp (MeOH/H2O) 218-219.5° C. 1H NMR [(CD3)2SO] δ 3.85 (s, 3 H, COOCH3), 7.08-7.12 (m, 2 H, 2×ArH), 7.50 (d, J=1.9 Hz, 1 H, H-3), 7.57 (d, J=3.8 Hz, 3 H, 2×ArH), 7.84 (d, J=8.4 Hz, 1 H, ArH), 7.93 (d, J=7.7 Hz, 1 H, ArH), 10.80 (s, 1 H, NH), 13.33 (br s, 1 H, COOH). Anal. (C15H12BrNO4) C, H, N.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:17][C:18](O)=[O:19])[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[OH-].[Na+].[OH-].[NH4+:29]>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:17][C:18]([NH2:29])=[O:19])[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C(O)Cn1c(=O)n(Cc2ccccc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: NC(=O)Cn1c(=O)n(Cc2ccccc2)c2ccccc21
Temperature: 25 °C

Procedure:
A mixture of 1.55 g. (0.005 mole) of 3-benzyl-2-oxo-1-benzimidazolineacetic acid and 10 ml. of thionyl chloride dissolved in 300 ml. of chloroform is refluxed for a period of approximately 2.5-4 hours. After cooling to room temperature (~25° C.), the reaction mixture is slowly poured into a solution consisting of 4.5 g. of sodium hydroxide dissolved in 100 ml. of ammonium hydroxide. The resulting chloroform layer is then separated and subsequently evaporated to near dryness while under reduced pressure to give a residual solid. Recrystallization of the latter material from ethanol-water then yields pure 3-benzyl-2-oxo-1-benzimidazolineacetamide in fine crystalline form.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[N:8]=1)=O.[C:23]1([NH:29]N)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(-n2ccc(=O)c(C(=O)C=CN(C)C)n2)c1
Reactant: NNc1ccccc1
Solvent: CO
Product: COc1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3)n2)c1
Yield: 14 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-(3-methoxyphenyl)pyridazin-4(1H)-one (crude 640 mg, 2.14 mmol) in 20 mL of methanol was added phenylhydrazine (347 mg, 3.21 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-(3-methoxyphenyl)-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (106 mg, 14% for two steps) as a yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:13]2[C:21]([Br:26])=[C:22]([F:25])[CH:23]=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.Cl[C:29]1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[N:31]=[CH:32][N:33]2[CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][O:39]1.CCN(C(C)C)C(C)C>Cl.O1CCOCC1>[Br:26][C:21]1[C:13]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:10]([C@@H:8]([NH:7][C:29]3[N:37]=[CH:36][N:35]=[C:34]4[C:30]=3[N:31]=[CH:32][N:33]4[CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][O:39]3)[CH3:9])=[N:11][C:12]=2[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)c(Br)c2n1-c1ccccn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(Br)c2n1-c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
[(S)-1-(7-Bromo-6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester (220 mg, 0.66 mmol) was dissolved in hydrochloric acid in dioxane (15 mL, 4M) and the reaction stirred at RT for 1 h. The reaction mixture was concentrated in vacuo then the residue dissolved in IPA and 6-chloro-9-(tetrahydro-pyran-2-yl)-9H-purine (203 mg, 0.85 mmol) and DIPEA (168 μL, 0.99 mmol) added. The reaction mixture was heated at 90° C. for 16 h then concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% methanol in EtOAc) to yield the title compound as a white solid (267 mg, 76%). LCMS (Method C): RT=3.01 min, [M+H]+=537+538.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]2[CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[NH:18][C:17]3=[O:25])[CH2:12][CH2:11]2)[CH2:2]1.[H-].[Na+].CC1C=CC(S(O[CH2:39][C@@H:40]2[CH2:44][O:43][C:42]([CH3:46])([CH3:45])[O:41]2)(=O)=O)=CC=1.O>CN(C)C=O>[CH3:45][C:42]1([CH3:46])[O:41][C@H:40]([CH2:39][N:18]2[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:16]([CH:13]3[CH2:12][CH2:11][N:10]([CH2:9][C@H:4]4[CH2:5][CH2:6][CH2:7][CH2:8][C:3]54[CH2:2][CH2:1]5)[CH2:15][CH2:14]3)[C:17]2=[O:25])[CH2:44][O:43]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Reactant: O=c1[nH]c2ccccc2n1C1CCN(C[C@H]2CCCCC23CC3)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OC[C@@H](Cn2c(=O)n(C3CCN(C[C@H]4CCCCC45CC5)CC3)c3ccccc32)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
3-{1-[(4S)-spiro[2.5]oct-4-ylmethyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one (2.94 g) was dissolved in dimethylformamide (60 mL), and to which 60-72% sodium hydride (oil dispersion) (706.6 mg) was added at room temperature and stirred for 30 minutes. To the reaction mixture, [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl 4-methylbenzene-sulfonate (7.25 g) was added and stirred at 80° C. for 7 hours. After cooling the reaction mixture to room temperature, water was added, followed by extraction with ethyl acetate. The extract washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was removed by distillation and the resulting residue was purified on silica gel column chromatography (hexane/ethyl acetate=2/1−1/2) to provide 3.43 g of the title compound as a pale yellow, oily substance.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[N:11]([CH3:12])[N:10]=[CH:9][C:8]=1[C:13]1[N:14]=[CH:15][N:16]2[C:21]=1[C:20](=O)[NH:19][CH:18]=[N:17]2.C([N:26]([CH2:30][CH3:31])[CH:27](C)C)(C)C.N1CCC1>C1(C)C=CC=CC=1>[N:26]1([C:20]2[C:21]3=[C:13]([C:8]4[CH:9]=[N:10][N:11]([CH3:12])[C:7]=4[Br:6])[N:14]=[CH:15][N:16]3[N:17]=[CH:18][N:19]=2)[CH2:27][CH2:31][CH2:30]1
Reactant: Cn1ncc(-c2ncn3nc[nH]c(=O)c23)c1Br
Reactant: CCN(C(C)C)C(C)C
Agent: C1CNC1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1ncc(-c2ncn3ncnc(N4CCC4)c23)c1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Phosphorus oxychloride (0.046 mL, 0.503 mmol) was added to a mixture of 5-(5-bromo-1-methyl-1H-pyrazol-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.17 mmol) in toluene (1 mL). After addition of N,N-diisopropylethylamine (99.5%, 0.149 mL, 0.84 mmol), the reaction was allowed to stir at room temperature for 18 hours. After removal of solvent in vacuo, the residue was dissolved in dichloromethane and treated with azetidine (0.023 mL, 0.34 mmol). After 66 hours, the reaction was concentrated under reduced pressure and the residue was purified by silica gel chromatography (Gradient: 0% to 10% methanol in ethyl acetate) to provide C8. Yield: 25 mg, 0.075 mmol, 44%. LCMS m/z 336.1 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.26-2.34 (m, 2H), 3.5-4.4 (v br m, 4H), 3.97 (s, 3H), 7.70 (s, 1H), 7.84 (s, 1H), 8.47 (s, 1H).