Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=O)[CH:5]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[F:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([NH:36]O)=[NH:35])=[CH:32][CH:31]=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]2[O:9][N:36]=[C:34]([C:33]3[CH:38]=[CH:39][C:30]([F:29])=[CH:31][CH:32]=3)[N:35]=2)[CH:5]=1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: N=C(NO)c1ccc(F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2nc(-c3ccc(F)cc3)no2)c1
Temperature: 115 °C
Reaction time: 2 h

Procedure:
In a 50 ml flask, 1.17 g (6.5 mmol) of isophtalic acid monomethyl ester are dissolved in 10 ml of DMF. To this solution, 1.16 g (7.2 mmol, 1.1 eq.) of 1,1′-carbonyl-diimidazole is added at room temperature under nitrogen. The mixture is stirred until carbon dioxide formation stops. Then, 1.00 g (6.5 mmol) of 4-fluoro-N-hydroxy-benzamidine is added and the resulting yellow solution stirred for 2 h. Now, another 1.16 g (7.2 mmol, 1.1 eq.) of 1,1′-carbonyl-diimidazole are added and the mixture is heated to 115° C. After 2 h at this temperature, the reaction mixture is cooled to room temperature and the solvent removed in vacuo. After chromatographical purification (160 g SiO2;eluent: hexane/CH2Cl2 6:4 to 1:1) the title compound is obtained as a white solid. Mass spectrum: m/z (M+H)+: 299.0
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]([F:38])([F:37])[C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]2[O:14][CH:15]=[C:16]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][N:30]4[CH:34]=[CH:33][N:32]=[C:31]4[CH:35]=[O:36])=[CH:22][CH:21]=3)[N:17]=2)=[CH:7][CH:6]=1.O>CO>[F:37][C:4]([F:3])([F:38])[C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]2[O:14][CH:15]=[C:16]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][N:30]4[CH:34]=[CH:33][N:32]=[C:31]4[CH2:35][OH:36])=[CH:22][CH:21]=3)[N:17]=2)=[CH:7][CH:6]=1
Reactant: O=Cc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
Sodium borohydride (193 mg) was added to a solution of 1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazole-2-carbaldehyde (2.30 g) in methanol at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was combined with water and concentrated to give crystals, which were washed with water and recrystallized from ethyl acetate-hexane to give the titled compound (2.16 g) as a colorless crystal powder.
Reaction SMILES: C(O[C:4](=[O:6])C)=O.[CH3:7][C:8]([N:15]([CH3:17])[CH3:16])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][NH2:10].[OH-].[Na+].CO>CCOCC>[CH3:7][C:8]([N:15]([CH3:16])[CH3:17])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][NH:10][CH:4]=[O:6]
Reactant: CCCCC(C)(CN)N(C)C
Reactant: CC(=O)OC=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: CCCCC(C)(CNC=O)N(C)C
Reaction time: 8 h

Procedure:
To a solution of acetic formic anhydride (2.9 mls., 20 mmole) (prepared by stirring acetic anhydride [2.04 ml.] and formic acid [0.86 ml.] on a water bath at 50°-60° for two hrs. and cooling), was added dropwise, with stirring, 2-methyl-2-dimethylamino-hexylamine (2.37 g.,) at such a rate that the temperature never rose above 40°C. The solution was stirred for 30 mins. ether (6 ml) was added, and stirring continued at room temperature overnight. The mixture was diluted with ether (50 ml.), basified with 2N sodium hydroxide solution and extracted with ether (4 × 100 ml.). Evaporation of the washed (2 × 100 ml.), dried (Na2SO4) extracts gave a colourless oil (2.2 g.). T.L.C. (silica, methanol) showed two spots: RF 0.5 and RF 0.0. The oil was chromatographed on a column of silica (20 × 3.0 cm.) eluting with methanol and fractions (6 × 100 ml.) were collected. Fractions 2-5 were combined and evaporated affording N-[2-methyl-2-dimethylamino-hexyl]formamide as a colourless oil (1.427 g., 51%).
Reaction SMILES: [BH4-].[Li+].C([O:5][C:6]([C:8]1([C:23](O)=[O:24])[CH2:12][CH2:11][N:10]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])C>C(O)(C)C>[OH:24][CH2:23][C:8]1([C:6]([OH:7])=[O:5])[CH2:12][CH2:11][N:10]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:9]1
Reactant: CCOC(=O)C1(C(=O)O)CCN(C(=O)c2ccc(OC)cc2)C1
Agent: [BH4-]
Agent: [Li+]
Solvent: CC(C)O
Product: COc1ccc(C(=O)N2CCC(CO)(C(=O)O)C2)cc1
Temperature: 5 °C
Reaction time: 4 h
Yield: 36.1 %

Procedure:
Lithium borohydride (207 mL, 414.0 mmol, 2M in THF) was added to a stirred solution of 1-(4-methoxy-benzoyl)-pyrrolidine-3,3-dicarboxylic acid ethyl ester (88.63 g, 275.8 mmol) (see Preparation 8) in isopropyl alcohol (600 mL) at 5° C. The mixture was stirred for 4 hours at 5° C. then quenched with 2M HCl aqueous solution (300 mL) and stirred for 15 minutes. The solvent volume was reduced by concentration under reduced pressure and the aqueous residue was extracted with ethyl acetate (300 mL). The organic layer was separated, washed with water (300 mL) then concentrated under reduced pressure to afford a pale brown solid. This was triturated with acetonitrile to afford the title compound as a white solid (27.8 g, 36%). (99.3:0.7 ratio of isomers)
Reaction SMILES: Cl.[Br:2][C:3]1C(C#N)=[N:5][CH:6]=[CH:7][CH:8]=1.CCCCCCC.C[CH2:19][O:20][C:21]([CH3:23])=[O:22]>>[CH3:19][O:20][C:21]([C:23]1[C:3]([Br:2])=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:22]
Reactant: N#Cc1ncccc1Br
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CCCCCCC
Product: COC(=O)c1ncccc1Br
Temperature: 2.5 °C
Reaction time: 20 h

Procedure:
A 50 L three-neck round bottom flask is equipped with a mechanical stirrer, thermocouple, nitrogen inlet and reflux condenser. The flask is charged with HCl (20 L) and 3-bromopyridine-2-carbonitrile (6790 g, 37.1 mol) (prepared, for example, essentially as described in the Alternate Procedure for Intermediate 3). The reaction mixture is heated to reflux and the starting material dissolves and a pink suspension forms. The reaction mixture is stirred for 20 h at reflux. The reaction progress is monitored by TLC (heptane:EtOAc, 1:1). No starting material is present at Rf=0.5 or intermediate amide at Rf=0.15. Once the reaction is deemed complete, the reaction mixture is cooled to 0-5° C. and then stirred at this temperature for 3 h. After this time the solids are collected by filtration (do not wash and press on a filter). The solids (3-bromopyridine-2-carboxylic acid) are dried in a vacuum oven at 50° C. with use of appropriate trapping as HCl is present in the wet product. A 50 L three-neck round bottom flask is equipped with a mechanical stirrer, thermocouple and reflux condenser. The flask is charged with MeOH (25.5 L), and 3-bromoopyridine-2-carboxylic acid (5.098 kg) followed by HCl (15 mL). The reaction mixture is heated to reflux at about 64-65° C. and stirred at this temperature for 9 h. The reaction mixture is allowed to cool to 40-50° C. and then concentrated to a paste. A 50 L separatory funnel is charged with water (12 L) and solid NaHCO3 (2338 g) and the mixture is stirred for 10-15 min. The residue from the concentrated paste is added in portions to the stirred sodium bicarbonate solution at a rate to control foaming. After all of the residue is added, EtOAc (10 L) is charged to the to the funnel and stirred for 10-15 min. The aqueous layer is separated and the organic layer washed with saturated aqueous sodium bicarbonate solution (1 L), then dried over magnesium sulfate, filtered, and concentrated. The combined aqueous layers are extracted with EtOAc (2×2 L) and the combined organic layers are washed with saturated aqueous sodium bicarbonate solution (1 L), then dried over magnesium sulfate, filtered, and concentrated along with the first extract. A pale yellow oil is obtained which solidifies on cooling. The resulting material is dried in a vacuum oven overnight at room temperature.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[C:7]([CH3:9])[NH:6][N:5]=1.Cl[C:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:15]([CH3:24])[N:14]=[N:13][C:12]=1[CH3:25].C(OCC)(=O)C>CN(C=O)C>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]2[C:11]([N:5]3[C:4]([CH3:3])=[CH:8][C:7]([CH3:9])=[N:6]3)=[C:12]([CH3:25])[N:13]=[N:14][C:15]=2[CH3:24])=[CH:22][CH:21]=1
Reactant: Cc1nnc(C)c(-c2ccc(Cl)cc2)c1Cl
Reactant: Cc1cc(C)[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C)n(-c2c(C)nnc(C)c2-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.7 %

Procedure:
70 mg of sodium hydride (55% oil dispersion) was added to 1 ml of N,N-dimethylformamide (hereinafter, described as DMF) To this was added 0.17 g of 3,5-dimethylpyrazole, and the mixture was stirred for 1 hour at room temperature. To the resultant mixture was added a solution of 0.15 g of 4-chloro-5-(4-chlorophenyl)-3,6-dimethylpyridazine in 2 ml of DMF, and the mixture was stirred for 7 hours on an oil bath of 60° C. To the reaction mixture was added ethyl acetate and the mixture was washed with brine five times. The organic layer was dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. To 0.33 g of the resultant residue was added 50 ml of ethyl acetate, and washed with 50 ml of 1 mol/L hydrochloric acid and brine sequentially, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.21 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.12 g of 5-(4-chloro-phenyl)-4-(3,5-dimethyl-1-pyrazolyl)-3,6-dimethylpyridazine (hereinafter, described as compound (3) of the present invention).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[C:11]([O:15][C:16]([N:18]1[C:26]2[C:21](=[CH:22][C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[F:39])=[O:29])=[CH:24][CH:25]=2)[C:20]([NH2:40])=[N:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:40][C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[F:39])=[O:29])[CH:22]=2)[N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[N:19]=1)=[O:6]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)n1nc(N)c2cc(NC(=O)NCc3cc(F)ccc3F)ccc21
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)n1nc(NC(=O)c2cccc(Cl)c2)c2cc(NC(=O)NCc3cc(F)ccc3F)ccc21
Temperature: 90 °C
Reaction time: 24 h
Yield: 34 %

Procedure:
7.1 93 mg of 3-chlorobenzoyl chloride are added to a mixture of 200 mg of tert-butyl-3-amino-5-[3-(2,5-difluorobenzyl)ureido]indazole-1-carboxylate (0.48 mmol, preparation analogous to Example 1.1), 2.0 ml of pyridine, 8 mg of 4-(dimethylamino)pyridine and 100 μl of dioxane, and the mixture is stirred at 90° C. for 24 hours. After cooling, the batch is evaporated, and the residue is purified by column chromatography on silica gel (eluent:heptane/EA 3:2), giving 90 mg of tert-butyl 3-(3-chlorobenzoylamino)-5-[3-(2,5-difluorobenzyl)ureido]indazole-1-carboxylate (34%), MS-FAB (M+H+)=556.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[NH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1>>[C:10]1([CH:8]([OH:9])[CH:7]([NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NCC1CCCCO1
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Product: OC(c1ccccc1)C(NCC1CCCCO1)c1ccccc1
Temperature: 140 °C
Reaction time: 14 h
Yield: 83.2 %

Procedure:
A mixture of trans-stilbene oxide (1.96 g, 0.010 mol) and 2-aminomethyltetrahydropyran (3.45 g, 0.030 mol) was heated in an oil bath at 140° C. for 6 hours. After standing at ambient temperature for 14 hours, the solidified reaction mixture was triturated with isooctane, and the tan solid collected by filtration to obtain 2.59 g (83% yield) of the product. The material was recrystallized from toluene-isooctane; mp 159°-163° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([CH:11](Br)[CH3:12])=[CH:7][C:6]=12.[CH3:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([CH:11]([N:15]([CH3:14])[C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=3)[CH3:12])=[CH:7][C:6]=12
Reactant: CNc1ccc(C)cn1
Reactant: CC(Br)c1ccn2ncc(Br)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(N(C)C(C)c2ccn3ncc(Br)c3c2)nc1
Temperature: 90 °C
Yield: 46.1 %

Procedure:
A suspension of 3-bromo-5-(1-bromoethyl)pyrazolo[1,5-a]pyridine (I-18, 400 mg, 1.32 mmol), N,5-dimethylpyridin-2-amine (230 mg, 1.98 mmol) and K2CO3 (546 mg, 3.96 mmol) in acetonitrile was heated to 90° C. in a sealed tube for overnight. The reaction mixture was cooled to room temperature and water (10 mL) was added. The aqueous phase was extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over Na2SO4 and solvents were removed under reduced pressure. The resulting crude product was purified by column chromatography over silica gel (petroleum ether/EtOAc, 0-4% EtOAc) to afford 210 mg (46%) of N-(1-(3-bromopyrazolo[1,5-a]pyridin-5-yl)ethyl)-N,5-dimethylpyridin-2-amine (I-19) as a yellow solid. ESI-LC/MS (m/z): [M+H]+ 345.2, [(M+2)+H]+ 347, RT 3.31 min.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:10])[CH2:6][C:7]([CH3:9])=O)[CH:2]=[CH2:3].[NH3:11]>C(O)C>[CH2:1]([NH:4][C:5](=[O:10])/[CH:6]=[C:7](\[NH2:11])/[CH3:9])[CH:2]=[CH2:3]
Reactant: C=CCNC(=O)CC(C)=O
Reactant: N
Solvent: CCO
Product: C=CCNC(=O)/C=C(/C)N
Reaction time: 8 h
Yield: 82.7 %

Procedure:
Acetoacetic allylamide (111.4 g, 0.79 mole) is dissolved in ethanol (80 ml) and thereto is passed ammonia gas, while the temperature is controlled below 30° C. by cooling with a water bath. After passing ammonia gas for about 3 hours, colorless crystals precipitate. The reaction mixture is allowed to stand at 0° C. overnight. The precipitates are separated by filtration and washed with diethyl ether to give the title compound (91.5 g, yield 82.7%) as colorless prisms, m.p. 143°-144° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10](=[O:12])[CH3:11].[Br:13]Br>C(O)(=O)C>[Br:13][CH2:11][C:10]([C:3]1[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])=[O:12]
Reactant: BrBr
Reactant: CC(=O)c1c(C)cc(C)cc1C
Solvent: CC(=O)O
Product: Cc1cc(C)c(C(=O)CBr)c(C)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
0.3 mol of 1-(2,4,6-trimethylphenyl)-1-ethanone are dissolved in 200 ml of glacial acetic acid and 31.8 g of bromine are added dropwise, while maintaining the reaction medium at a temperature below 10° C. After the addition, the reaction medium is allowed to return to room temperature and is left at this temperature for 2 hours. The reaction medium is then poured into 500 ml of ice-water and the aqueous phase is extracted with ethyl ether. The organic extracts are washed with saturated aqueous sodium bicarbonate solution and then with salted water, and are dried over anhydrous magnesium sulphate.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][NH:12][C:13]([NH2:15])=[S:14].[O-]CC.[Na+].[C:20]([CH2:22][C:23](OCC)=[O:24])#[N:21].S(=O)(=O)(O)O>C(O)C.O>[NH2:21][C:20]1[N:12]([CH2:11][CH2:10][C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[C:13](=[S:14])[NH:15][C:23](=[O:24])[CH:22]=1
Reactant: CCOC(=O)CC#N
Reactant: NC(=S)NCCc1nc2ccccc2[nH]1
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cc(=O)[nH]c(=S)n1CCc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.7 %

Procedure:
To a suspension of 1-[2-(1H-benzimidazol-2-yl)ethyl]thiourea (0.44 g, 2.0 mmol, obtained from Example 12(a)) in absolute ethanol (5 mL) at 80° C. were added, over 2 h, a solution of sodium ethoxide (21% w/v, 2.2 mL, 6.0 mmol) and a solution of ethyl cyanoacetate (0.64 mL, 6.0 mmol) in absolute ethanol (1.3 mL). The reaction was kept at 80° C. for an additional 3 h. After cooling to r.t., water (75 mL) was added and the pH adjusted to ˜7 using concentrated sulfuric acid. The solid that formed was collected by filtration, washed with water and dried in vacuo to give the title compound (0.55 g, 96% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.Br[CH2:18][C:19]1[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:22]=[CH:21][C:20]=1[F:29]>>[F:29][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([F:26])([F:27])[F:28])[C:19]=1[CH2:18][NH:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3
Reactant: Nc1ccc2c(=O)[nH]c3ncccc3c2c1
Reactant: Fc1cccc(C(F)(F)F)c1CBr
Product: O=c1[nH]c2ncccc2c2cc(NCc3c(F)cccc3C(F)(F)F)ccc12
Yield: 5.3 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 458 using 70 (122 mg, 0.58 mmol) and 2-(bromomethyl)-1-fluoro-3-(trifluoromethyl)benzene (179 mg, 0.70 mmol) to provide 461 (12 mg, 5% yield) as a white powder. LC-MS (M+H=388, obsd.=388). 1H NMR (400 MHz, DMSO-D6) δ 8.53 (dd, J=1.7, 8.0, 1H), 8.43 (dd, J=1.6, 4.7, 1H), 8.00 (d, J=8.7, 1H), 7.95 (s, 1H), 7.63 (d, J=7.8, 1H), 7.46 (dd, J=8.1, 13.2, 1H), 7.40 (d, J=2.1, 1H), 7.32 (dd, J=4.7, 7.9, 2H), 6.88 (dd, J=2.0, 8.7, 1H), 6.20 (s, 2H), 5.90 (s, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:12]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][C:14]=2[CH3:22])=[C:11]([CH3:23])[O:10][N:9]=1.O[N:25]=[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35])[NH2:27].CCN(C(C)C)C(C)C>>[CH3:7][C:8]1[C:12]([C:13]2[CH:21]=[CH:20][C:16]([C:17]3[O:19][N:27]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH3:35])[N:25]=3)=[CH:15][C:14]=2[CH3:22])=[C:11]([CH3:23])[O:10][N:9]=1
Reactant: Cc1cc(C(=O)O)ccc1-c1c(C)noc1C
Reactant: COc1ccccc1C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1noc(-c2ccc(-c3c(C)noc3C)c(C)c2)n1

Procedure:
Oxalyl chloride (132 μL; 1.56 mmol; 3 eq.), Intermediate 30 (120 mg; 0.52 mmol; 1 eq.), Intermediate 1 (86 mg; 0.52 mmol, 1 eq.) and DIEA (268 μL; 1.56 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography c-hexane/ethyl acetate, 80/20) afforded the title compound as an orange foam.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:23])[NH:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]O)=[CH:17][CH:16]=1.CCCCCCC>ClCCl>[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:23])[NH:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][Cl:3])=[CH:17][CH:16]=1
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: CCCCCCC
Solvent: ClCCl
Product: Cc1ccccc1NC(=O)Nc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
5.66 ml (78.12 mmol) of thionyl chloride were added dropwise with ice cooling to a suspension of 10 g (39.06 mmol) of 4-(3-(2-methylphenyl)ureido)benzyl alcohol in 150 ml of dichloromethane. The reaction mixture was subsequently stirred at room temperature for 1.5 hours and poured onto 200 ml of n-heptane. The heptane was decanted off from the deposited oil and the oil was stirred with diisopropyl ether. The solid obtained was filtered off and washed with diisopropyl ether. Yield: 8.32 g (78%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH2:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:12][O:13][CH2:14][C:15](Cl)=[O:16]>N1C=CC=CC=1>[CH3:12][O:13][CH2:14][C:15]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH:11][C:15](=[O:16])[CH2:14][O:13][CH3:12])[CH:10]=1)[C:5]([OH:7])=[O:6])=[O:16]
Reactant: Nc1cc(N)cc(C(=O)O)c1
Reactant: COCC(=O)Cl
Solvent: c1ccncc1
Product: COCC(=O)Nc1cc(NC(=O)COC)cc(C(=O)O)c1
Reaction time: 2 h

Procedure:
To a solution of 3,5-diaminobenzoic acid (6.1 g) in pyridine (80 ml) is added dropwise methoxyacetyl chloride (8.0 ml) at room temperature, and the mixture is stirred for 2 hours as it stands. From the reaction mixture, pyridine is distilled off under reduced pressure. To the residue is added 1N hydrochloric acid, and the resulting solid substance is separated by filtration and washed with water. The resulting crude crystals are recrystallized from ethanol to give the title compound (8.0 g) having the following physical properties.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([O:12][CH3:13])=[O:11])[CH2:7][C:6]=2[CH:14]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[C:19]([F:31])=[CH:18][N:17]=1>>[Cl:30][C:25]1[CH:24]=[C:23]([NH:22][C:20]2[C:19]([F:31])=[CH:18][N:17]=[C:16]([NH:1][C:2]3[CH:3]=[CH:4][C:5]4[O:9][CH:8]([C:10]([O:12][CH3:13])=[O:11])[CH2:7][C:6]=4[CH:14]=3)[N:21]=2)[CH:28]=[CH:27][C:26]=1[Cl:29]
Reactant: COC(=O)C1Cc2cc(N)ccc2O1
Reactant: Fc1cnc(Cl)nc1Nc1ccc(Cl)c(Cl)c1
Product: COC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4ccc(Cl)c(Cl)c4)n3)ccc2O1

Procedure:
In like manner to the preparation of (±)-N4-(3,4-difluorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine, the reaction of (±)-5-amino-2,3-dihydro-2-methoxycarbonylbenzofuran with 2-chloro-N4-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidineamine gave (±)-N4-(3,4-dichlorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.13 (bs, 1H), 9.70 (bs, 1H), 8.21 (d, 1H, J=4.8 Hz), 8.04 (d, 1H, J=2.4 Hz), 7.68 (m, 1H), 7.54 (d, 1H, J=9.0 Hz), 7.37 (bs, 1H), 7.19 (m, 1H), 6.80 (d, 1H, J=8.7 Hz), 5.35 (dd, 1H, J=6.6 Hz), 3.69 (s, 3H), 3.53 (dd, 1H, J=10.5 and 11.1 Hz), 3.21 (dd, 1H, J=6.0 Hz); LCMS: purity: 100%; MS (m/e): 450 (MH+).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH3:12][S:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][N:21]=1)[C:17]#[N:18].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:12][S:13][C:14]1[CH:15]=[C:16]([C:17]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:18]=2)[CH:19]=[CH:20][N:21]=1
Reactant: COC(=O)c1ccccc1S
Reactant: CSc1cc(C#N)ccn1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CSc1cc(-c2nc(=O)c3ccccc3s2)ccn1
Temperature: 25 °C
Yield: 16.7 %

Procedure:
Methyl thiosalicylate (0.76 g, 4.5 mmol) and 2-methylthioisonicotinonitrile (0.34 g, 2.3 mmol) were dissolved in toluene (2.0 ml). Triethylamine (0.70 ml, 5.0 mmol) was added thereto and the mixture was refluxed for 6 hrs. The reaction mixture was cooled at room temperature and the precipitated crystals were collected and recrystallized from ethanol to give the titled compound (0.11 g, 17%) as white crystals.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>O>[N:11]1([C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][N:3]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: C1CNCCN1
Reactant: Clc1noc2ccccc12
Solvent: O
Product: c1ccc2c(N3CCNCC3)noc2c1
Yield: 82 %

Procedure:
A mixture of 3-chloro-1,2-benzisoxazole (19.6 g., 0.128 mole) and piperazine (110 g., 1.28 mole) is heated for a period of 20 hr. at 120° C. in a closed reactor. The reaction mixture is diluted with water and the aqueous mixture repeatedly extracted with methylene chloride. Extracts are combined, dried over magnesium sulfate and concentrated in vacuo to afford 21.2 g. (82% yield) of 3-(1-piperazinyl)-1,2-benzisoxazole free base.