Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[C:3]([CH:15]=O)[C:2]=1[CH:17]=O.[CH2:19]([C:23]#[N:24])[CH2:20][C:21]#[N:22].C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[C:21]([C:20]1[C:19]([C:23]#[N:24])=[CH:15][C:3]2[C:2](=[CH:1][C:14]3[C:5]([CH:4]=2)=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=3)[CH:17]=1)#[N:22]
Reactant: O=Cc1cc2cc3ccccc3cc2cc1C=O
Reactant: N#CCCC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc2cc3cc4ccccc4cc3cc2cc1C#N
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3.5 g of anthracene-2,3-dialdehyde (E. Mallonli et al., Synthesis 1980, page 689), 1.8 g of succinodinitrile, 3 g of K2CO3 and 250 ml of dimethyl sulfoxide is heated with stirring at 60°-70° C. for 30 minutes. It is then cooled to 15° C. and 50 ml of water are added. The precipitate which has been deposited is filtered off and is sublimed at 300° C. Yield 485 mg (12%), λmax : 772 nm.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:30])=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: O=C(Nc1ccc2[nH]cc(C3CCNCC3)c2n1)c1ccc(F)cc1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-tert-butoxycarbonylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.062 mMol) 4-fluorobenzoyl chloride, the title compound was prepared.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:13]([O:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH2:18])[CH3:14]>>[CH2:13]([O:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH:18][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)[CH3:14]
Reactant: CCOC(=O)[C@H](C)N
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: CCOC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure G' and using 3,5-difluorophenylacetic acid (Aldrich) and alanine ethyl ester (Aldrich), the title compound was prepared as a solid with a melting point of 93°-95° C. The reaction was monitored by tlc on silica gel (Rf=0.8 in EtOAC) and purification was by chromatography on silica gel using EtOAc as the eluant followed by recrystallization from 1-chlorobutane.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([OH:9])[C:5]([Cl:8])=[CH:6][CH:7]=1.Cl[C:12]([F:17])([F:16])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH:12]([F:17])[F:16])[C:3]=1[F:10]
Reactant: Oc1c(Cl)ccc(Br)c1F
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1c(Br)ccc(Cl)c1OC(F)F
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 3-bromo-6-chloro-2-fluorophenol (1.00 g, 4.44 mmol) and sodium chlorodifluoroacetate in dimethylformamide (DMF; 9 mL) was added potassium carbonate (1.22 g, 5.32 mmol) and water (1.77 mL) and the resulting mixture heated to 100° C. for 4 hours. The solution was cooled to ambient temperature and concentrated hyrdrochlroric acid (2.5 mL) and water (4 mL) were added and stirred at ambient temperature overnight. The solution was cooled in an ice bath and neutralized with 2N sodium hydroxide and then extracted with ethyl ether (2×25 mL). The combined extracts were washed with brine, dried (sodium sulfate), and concentrated to give 1-bromo-4-chloro-2-fluoro-3-difluoromethoxybenzene (1.20 g, 4.2 mmol). This material was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH:17]([CH2:22]O)[C:18]([O:20][CH3:21])=[O:19])[S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>N1C=CC=CC=1>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([S:6]([N:5]([CH2:4][C:3]2[CH:24]=[CH:25][CH:26]=[CH:27][C:2]=2[NH:1][S:29]([CH3:28])(=[O:31])=[O:30])[C:17](=[CH2:22])[C:18]([O:20][CH3:21])=[O:19])(=[O:8])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)C(CO)N(Cc1ccccc1N)S(=O)(=O)c1ccc(OC)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: C=C(C(=O)OC)N(Cc1ccccc1NS(C)(=O)=O)S(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 78 %

Procedure:
To a solution of 1.0 g (2.54 mmol) of methyl [(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate in 10 ml of pyridine cooled to −5° C. was added 0.432 ml (5.58 mmol) of methanesulfonyl chloride. The mixture was stirred at 0° C. for 48 hours. To the mixture was added ice and H2O and the mixture was extracted with ethyl acetate. The extract was washed with H2O, 2 N citric acid, brine and dried with Na2SO4. The solvent was removed under vacuum and the residue triturated with ethyl acetate-hexane to give 0.90 g of a solid, 128-142° C. Anal. for C19H22N2O7S2: Calc'd: C, 50.2; H, 4.9; N, 6.2; S, 14.1; Found: C, 49.6; H, 5.0; N, 6.9; S, 14.0.
Reaction SMILES: C([Li])CCC.[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[C:7]#[CH:8].[C:13]1([C@H:19]2[C:24](=[O:25])[CH2:23][CH2:22][CH2:21][NH:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[CH2:11]([O:10][C:6]([C:7]#[C:8][C@:24]1([OH:25])[CH2:23][CH2:22][CH2:21][NH:20][C@H:19]1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:9])[CH3:12]
Reactant: O=C1CCCN[C@H]1c1ccccc1
Reactant: C#CC(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C#C[C@]1(O)CCCN[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of n-butyllithium (55.4 ml, 1.4 M in hexanes, 77.6 mmol) was added dropwise to a stirred solution of ethyl propiolate (7.9 ml, 77.7 mmol) in tetrahydrofuran (200 ml), keeping the temperature of the reaction below −65° C. The mixture was stirred for 10 min and a solution of (2S)-2-phenyl-3-piperidone in tetrahydrofuran (50 ml) added dropwise at −72° C. over 15 min. The reaction mixture was stirred at this temperature for 40 min, quenched with acetic acid (10 ml) and warm up to room temperature. Solvent was removed in vacuo. The residue was treated with saturated aqueous NaHCO3 (200 ml) and extracted with ethyl acetate (3×100 ml). The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (210 g, hexane:diethyl ether 5-40%) to afford the product (11.9 g, 83%, 96% ee) as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1.[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12]C.OS([O-])(=O)=O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: COc1ccsc1
Reactant: CCCCCCO
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCOc1ccsc1
Temperature: 125 °C
Reaction time: 3 h

Procedure:
20 cm3 of 3-methoxythiophene (0.2 mol) and 50 cm3 of 1-hexanol were dissolved in 30 cm3 of toluene, and 1 g of NaHSO4 (0.01 mol) was added. The mixture was heated to 125° C. and stirred, and about 10 cm3 of a mixture of methanol and toluene were distilled off through a Vigreux column at a head temperature of 63° to 64° C., which took about 3 hours. The mixture was then washed three times with 50 cm3 of saturated NaHCO3 solution until neutral, dried over MgSO4 and fractionated in vacuo. After the toluene had been distilled off together with excess haxanol, 34 g of 3-n-hexyloxythiophene distilled over at 70° C. and 0.13 mbar, which corresponds to 92% of the theoretical yield. 97% pure by GC; 1H-NMR and mass spectrum confirm the structure.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]([CH:8]1[CH2:13][CH2:12][C:11]([C:15]([OH:17])=O)([CH3:14])[CH2:10][CH2:9]1)([CH3:7])[CH3:6]>>[CH:5]([CH:8]1[CH2:13][CH2:12][C:11]([CH3:14])([C:15]([Cl:3])=[O:17])[CH2:10][CH2:9]1)([CH3:7])[CH3:6]
Reactant: CC(C)C1CCC(C)(C(=O)O)CC1
Reactant: O=S(Cl)Cl
Product: CC(C)C1CCC(C)(C(=O)Cl)CC1
Reaction time: 3 h
Yield: 86.4 %

Procedure:
An excess of thionyl chloride was added to 10 g of 4-isopropyl-1-methylcyclohexylcarboxylic acid (cis:trans=1:1, b.p.=122° C./2 mm Hg), and the mixture was stirred for 3 hours. The remaining thionyl chloride was distilled off in a vacuum from the resulting reaction mixture, and the oily product obtained was distilled in a vacuum to obtain 9.5 g of 4-isopropyl-1-methylcyclohexylcarbonyl chloride having a boiling point of 150° to 152° C./60 mm Hg. (Yield: 86.4%.)
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:25]I.[CH2:27]([O:34][C:35]1[CH:40]=[C:39]([CH2:41]O)[CH:38]=[CH:37][C:36]=1[N:43]1[S:47](=[O:49])(=[O:48])[N:46]([CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[C:45](=[O:56])[CH2:44]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[CH2:27]([O:34][C:35]1[CH:40]=[C:39]([CH2:41][I:25])[CH:38]=[CH:37][C:36]=1[N:43]1[S:47](=[O:49])(=[O:48])[N:46]([CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[C:45](=[O:56])[CH2:44]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: II
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CO)cc2OCc2ccccc2)S1(=O)=O
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CI)cc2OCc2ccccc2)S1(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To slurry of resin-bound PPh3 (850 mg, 2.5 mmol) in DCM (10 mL) at 0° C., in a pressure vessel, is added imidazole (200 mg, 2.8 mmol) and iodine (650 mg, 2.5 mmol). The mixture is vigorously stirred at 0° C. for 30 min. To the mixture is added a solution of 5-(2-benzyloxy-4-hydroxymethylphenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (550 mg, 1.2 mmol) in DCM (10 mL) dropwise. The vessel is sealed and heated to 45° C., with stirring, for 2 h. The reaction is allowed to cool to ambient temperature and the mixture is filtered through a plug of cotton to remove the resin. The organic solution is washed with saturated Na2SO3 and saturated NaCl, then dried over MgSO4. The solvent is removed under reduced pressure to afford 5-(2-benzyloxy-4-iodomethylphenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one as a white solid, which is used in the next step without further purification: MS (M+H)+=576.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1.[CH3:25][O:26][CH2:27][CH2:28]Br.C(=O)([O-])[O-].[K+].[K+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:17]([C:20]3[CH:24]=[N:23][N:22]([CH2:28][CH2:27][O:26][CH3:25])[CH:21]=3)=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1
Reactant: COCCBr
Reactant: COC(=O)c1cc(-c2cn[nH]c2)ccc1OCc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COCCn1cc(-c2ccc(OCc3ccc(F)cc3)c(C(=O)OC)c2)cn1
Temperature: 25 °C

Procedure:
To a solution of methyl 2-{[(4-fluorophenyl)methyl]oxy}-5-(1H-pyrazol-4-yl)benzoate (may be prepared as described in Description 115; 200 mg, 0.61 mmol) was added 2-bromoethyl methyl ether (0.10 ml, 1.23 mmol), potassium carbonate (254 mg, 1.84 mmol) and the reaction mixture was stirred at room temperature. The reaction mixture was then warmed to 50° C. for 5 hours. The reaction was filtered to remove the potassium carbonate, and the organics were evaporated on a buchi under reduced pressure. The solid was taken up into ethyl acetate (50 ml) and this was washed with water (1×25 ml). The organics were dried (MgSO4) and evaporated under reduced pressure on a buchi to yield the title compound. The crude product was used directly without further purification. 240 mg.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[Cl:11].[CH3:12][C:13]1[N:18]=[C:17]([SH:19])[N:16]=[C:15]([OH:20])[CH:14]=1.C(N(CC)CC)C>C(O)C>[Cl:11][C:4]1[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=1[CH2:2][S:19][C:17]1[N:16]=[C:15]([OH:20])[CH:14]=[C:13]([CH3:12])[N:18]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: COc1ccc(CBr)c(Cl)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(CSc2nc(C)cc(O)n2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
A mixture of 1-(bromomethyl)-2-chloro-4-methoxybenzene (1.0 g, 4.2 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (550 mg, 3.9 mmol), and triethylamine (585 μL, 4.2 mmol) in absolute ethanol (20 mL) was stirred at room temperature overnight. The product was recovered by filtration, washed with water (2×20 mL) and diethyl ether (2×20 mL), and dried in vacuo, affording the title compound (929 mg, 81% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.07 (s, 3H), 3.76 (s, 3H), 4.41 (s, 2H), 6.00 (s (br), 1H), 6.89 (dd, 1H, J=2.5 Hz, 8.6 Hz), 7.07 (d, 1H, J=8.6 Hz), 7.52 (d, 1H, J=8.6 Hz); M+ 297.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:6]([NH:8][CH:9]1[CH2:11][CH2:10]1)=[O:7].CN1CCOCC1.[Cl:23][CH2:24][C:25](Cl)=[O:26]>CC(C)=O>[Cl:23][CH2:24][C:25]([NH:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:6]([NH:8][CH:9]1[CH2:10][CH2:11]1)=[O:7])=[O:26]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)CCl
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 94.9 %

Procedure:
To a suspension of 3-amino-N-cyclopropyl-4-methyl-benzamide hydrochloride (Compound 1D, 22.7 g, 0.1 mol) in acetone (200 mL) was added 4-methyl morpholine (42.4 mL, 0.3 mol). The solution was cooled to −20° C. and chloroacetyl chloride (12 mL, 0.15 mol) was added dropwise. The reaction mixture was stirred at −10° C. for 10 min before being quenched with H2O (200 mL). The precipitate formed was collected by vacuum filtration and dried to provide 3-(2-chloro-acetylamino)-N-cyclopropyl-4-methyl-benzamide (38C) (25.3 g, 95% yield). mp: decomp 150° C.; 1H NMR(500 MHz, DMSO-D6) δ 9.83 (s, 1H), 8.39 (d, J=3.8 Hz, 1H), 7.82 (s, 1H), 7.58 (d, J=6.6 Hz, 1H), 7.28 (d, J=8.3, 1H), 4.32 (s, 2H), 2.82 (m, 1H), 2.22 (s, 3H), 0.66 (m, 2H), 0.56 (m, 2H); 13C NMR (100 MHz, DMSO-D6) δ: 167.2, 165.4, 136.0, 135.8, 132.8, 130.5, 124.8, 124.7, 43.4, 23.4, 18.1, 6.0;
Reaction SMILES: [CH2:1]([C:4]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([NH:17][CH2:18][CH2:19][CH3:20])=[O:16])=[CH:11][CH:10]=2)[N:7]=[N:6][C:5]=1[C:21]([OH:23])=O)[CH2:2][CH3:3].C1C=C[C:27]2N(O)N=[N:30][C:28]=2[CH:29]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH:28]1([NH:30][C:21]([C:5]2[N:6]=[N:7][N:8]([C:9]3[CH:10]=[CH:11][C:12]([C:15]([NH:17][CH2:18][CH2:19][CH3:20])=[O:16])=[CH:13][CH:14]=3)[C:4]=2[CH2:1][CH2:2][CH3:3])=[O:23])[CH2:29][CH2:27]1
Reactant: On1nnc2ccccc21
Reactant: CCCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCC)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96.8 %

Procedure:
5-Propyl-1-{4-[(propylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxylic acid (498 mg, 1.57 mmol) obtained in Example 55b), HOBt (215 mg, 1.57 mmol, 1.0 eq.) and cyclopropylamine (0.146 ml, 2.05 mmol, 1.3 eq.) were dissolved in acetonitrile (4 ml) and DMF (4 ml), WSC (370 mg, 1.89 mmol, 1.2 eq.) was added and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (50 ml), and washed with 5% aqueous sodium hydrogen carbonate solution, 10% aqueous ammonium chloride solution and saturated brine. The aqueous layers were each extracted with ethyl acetate-hexane (2:1, 20 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated, and diethyl ether was added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (542 mg, 1.52 mmol, 97.1%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][C:8]=2[CH:9]=1)=[O:4].B(Br)(Br)Br>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:8]=2[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc2cc(OC)ccc2o1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1cc2cc(O)ccc2o1
Reaction time: 3 h
Yield: 43.4 %

Procedure:
A solution of 5-methoxy-benzofuran-2-carboxylic acid methyl ester (5.0 g, 24 mmol) in 50 mL DCM at 0° C. was treated portionwise with boron tribromide (4.4 mL of a 1 M solution in DCM). After 3 hours, the reaction mixture was carefully quenched with 50% NH4OH. The organic layer was separated and washed 1×50 mL brine, dried (Na2SO4), and concentrated in vacuo to give 2 g (43%) of the title compound pure enough for subsequent use. 400 MHz 1H NMR (DMSO-d6) δ 9.47 (s, 1H), 7.56 (s, 1H), 7.45 (d, 1H, J=8.8 Hz), 7.00 (s, 1H), 6.91 (d, 1H, J=8.8 Hz), 3.81 (s, 3H). Preparation of 5-Dimethylthiocarbamoyloxy-benzofuran-2-carboxylic acid methyl ester (Compound 6B)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]([O:14]C)=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[NH:16]1[CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:18]=[N:17]1>>[NH:16]1[CH:20]=[C:19]([C:2]2[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[CH:5]=[C:6]([CH:11]=2)[C:7]([OH:9])=[O:8])[CH:18]=[N:17]1
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: O=C(O)c1cc(C(=O)O)cc(-c2cn[nH]c2)c1

Procedure:
Following standard cross coupling procedure described herein, dimethy 5-bromoisophthalate (623 mg, 2.3 mmol) and 4-pyrazoleboronic acid pinacol ester (443 mg, 2.3 mmol) were reacted. The resulting aqueous layer was acidified to pH 5 and extracted with EtOAc to provide 5-(1H-pyrazol-4-yl)isophthalic acid as a yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]([O-:5])=[O:4].[Li+].[C:7]([O-:15])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Li+]>CN(C=O)C>[C:7]([O:15][CH2:2][C:3]([OH:5])=[O:4])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C([O-])CCl
Reactant: O=C([O-])c1ccccc1
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(O)COC(=O)c1ccccc1
Reaction time: 3 h

Procedure:
13 g lithium chloroacetate (0.10 m) and 17.6 g lithium benzoate (0.10 m) were combined in a 250 ml R.b. flask with 50 ml DMF. This was heated on an oil bath to 110°-120° C. with magnetic stirring for 3 hrs. (The solution at first was clear, but after 2-3 hrs. a white precipitate formed).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:6][CH:7]=1.Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCOCC1>[OH:21][C:19]1[N:17]=[C:15]([OH:16])[C:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=3)[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NC(=O)c1nc(-c2cccc(F)c2)ccc1N
Solvent: C1COCCO1
Product: Oc1nc(O)c2nc(-c3cccc(F)c3)ccc2n1
Temperature: 25 °C

Procedure:
A mixture of 3-amino-6-(3-fluorophenyl)-pyridine-2-carboxylic acid amide (0.46 g, 2.0 mmol) and triphosgene (0.30 g, 1.0 mmol) in dioxane (10 ml) was heated under reflux for 2 hours. After cooling to room temperature, the precipitate was collected by filtration and washed with diethyl ether. The title compound was obtained as a yellowish solid (410 mg, yield 80%) which was characterised as follows: MS (m/z): 258 ([M+H]+, 100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][CH:11]=[C:12]([C:18]([O:20]CC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C1CCCCC1>C1(OC2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([C:18]([OH:20])=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=[N:10]2)=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CCOC(=O)C(=CNc1ccc(OC)c(F)c1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: C1CCCCC1
Product: CCOC(=O)c1cnc2cc(F)c(OC)cc2c1O
Temperature: 25 °C
Yield: 74.9 %

Procedure:
A stirred solution of 37.75 g of diethyl 2-[(3-fluoro-4-methoxyphenylamino)methylene]malonate in 170 cm3 of diphenyl ether is brought to 245° C. for 3.5 hours. After cooling to ambient temperature, 220 cm3 of cyclohexane are added, and the precipitate thus obtained is filtered off and washed with cyclohexane and then with pentane and is spin-filtered to dryness. 24.10 g of ethyl 7-fluoro-4-hydroxy-6-methoxy-quinoline-3-carboxylate are obtained, in the form of a solid which melts at 280° C.
Reaction SMILES: [Li]CCCC.Br[C:7]1[N:8]=[C:9]([C:21]([CH3:24])([CH3:23])[CH3:22])[N:10](COCC[Si](C)(C)C)[C:11]=1[Br:12].[Cl:25][C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1>C1COCC1.O=[Mn]=O>[Br:12][C:11]1[N:10]=[C:9]([C:21]([CH3:22])([CH3:23])[CH3:24])[NH:8][C:7]=1[C:28]1[CH:29]=[CH:30][N:31]=[C:26]([Cl:25])[N:27]=1
Reactant: CC(C)(C)c1nc(Br)c(Br)n1COCC[Si](C)(C)C
Reactant: Clc1ncccn1
Agent: O=[Mn]=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1nc(Br)c(-c2ccnc(Cl)n2)[nH]1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
n-BuLi (1.5 M in hexane, 40 mL, 60 mmol) was added dropwise to a cooled solution of 4,5-dibromo-2-tert-butyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (23.6 g, 57.2 mmol) in anhydrous THF (250 mL) at −78° C. After 30 min at −78° C., a solution of 2-chloropyrimidine (7.21 g, 63.0 mmol) in anhydrous THF (2 mL) was added dropwise and the reaction was stirred at −78° C. for 1 h. The reaction was quenched by the addition of saturated aqueous NH4Cl solution and allowed to warm to rt. The mixture was partitioned with EtOAc and the layers separated. The aqueous portion was extracted with EtOAc (3×) and the combine organic layers were washed with water, brine, dried (MgSO4), and concentrated. The resulting residue was dissolved in dry EtOAc, treated with MnO2 (5.2 g, 60 mmol), and heated to reflux for 3 h. The reaction was allowed to cool to rt and filtered through Celite. The filter cake was washed thoroughly with EtOAc and the combine filtrates were concentrated. The remaining residue was purified by flash chromatography (SiO2, 100:0-90:10 hexanes-EtOAc) to give 10 g (37%) of 4-(4-bromo-2-tert-butyl-1H-imidazol-5-yl)-2-chloropyrimidine: LCMS (m/z): 447.10 (MH+), tR=1.30 min. 1H NMR (400 MHz, CDCl3) δ 8.64 (d, J=5.3 Hz, 1H), 7.83 (d, J=5.3 Hz, 1H), 5.85 (s, 2H), 3.45 (m, 2H), 0.76 (m, 2H), −0.08 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1[N:12]([CH2:25][C:26]([F:29])([CH3:28])[CH3:27])[C:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:16]([O-])=[CH:15][C:14]=2[N:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:30].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1[N:12]([CH2:25][C:26]([F:29])([CH3:28])[CH3:27])[C:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH2:30])[C:14]=2[N:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: CC(C)(F)Cn1c(CCOCc2ccccc2)nc2c[n+]([O-])c3cccnc3c21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(F)Cn1c(CCOCc2ccccc2)nc2c(N)nc3cccnc3c21
Reaction time: 1 h

Procedure:
2-[2-(Benzyloxy)ethyl]-1-(2-fluoro-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine 5-oxide (1.97 g, 5.00 mmol) was dissolved in 50 mL of CH2Cl2 and treated with 5 mL of concentrated aqueous NH4OH solution. The mixture was stirred rapidly and then p-toluenesulfonyl chloride (1.00 g, 5.33 mmol) was carefully added. Rapid stirring was continued for 1 hour. The reaction mixture was then treated with 20 mL of H2O. The layers were separated and the organic portion was washed successively with 5% Na2CO3 solution, H2O and brine. The organic portion was dried over Na2SO4, filtered, and concentrated under reduced pressure. Chromatography (SiO2, 10% CMA/CHCl3) gave 0.90 g of 2-[2-(benzyloxy)ethyl]-1-(2-fluoro-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine as a yellow solid.