Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:11])=[CH:3][CH:4]([CH:8]([CH3:10])[CH3:9])[C:5](O)=[O:6].S(Cl)([Cl:14])=O>C1C=CC=CC=1>[Cl:1][C:2]([Cl:11])=[CH:3][CH:4]([CH:8]([CH3:10])[CH3:9])[C:5]([Cl:14])=[O:6]
Reactant: CC(C)C(C=C(Cl)Cl)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)C(C=C(Cl)Cl)C(=O)Cl

Procedure:
In 15 ml of dry benzene were dissolved 1.8 g of α-(2,2-dichlorovinyl)isovaleric acid, followed by the addition of 3.5 g of thionyl chloride. The mixture was refluxed for 5 hours and, then, distilled to remove the low-boiling fraction. By the above procedure there was obtained α-(2,2-dichlorovinyl)isovaleroyl chloride. This chloride was dissolved in 20 ml of benzene, and 2.0 g of α-ethynyl-3-phenoxybenzyl alcohol were added. This was followed by the addition of 2.9 g of pyridine and the mixture was stirred at room temperature for 8 hours. The resultant reaction mixture was diluted with diethyl ether, washed with water and dilute aqueous hydrogen chloride and dried over anhydrous magnesium sulfate. The low-boiling fraction was then distilled off and the residue was chromatographed on a column of silica gel (benzene/n-hexane=1:1 v/v). By the above procedure there were obtained 2.6 g of α-ethynyl-3-phenoxybenzyl α-(2,2-dichlorovinyl)isovalerate (compound [2]) having the following properties [yield: 71% based on α-(2,2-dichlorovinyl)isovaleric acid].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([B:8]2[O:12][CH2:11][CH2:10]O2)[CH:5]=[CH:6][CH:7]=1.Br[C:14]1C=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1COCOC>>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]2[B:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[O:12][CH2:11][C:10]=2[CH:18]=1
Reactant: Fc1cccc(B2OCCO2)c1
Reactant: COCOCc1cc(Cl)ccc1Br
Product: Fc1cccc(B2OCc3cc(Cl)ccc32)c1

Procedure:
This was prepared as per the procedure in Example 11, from 2-(3-fluorophenyl)-[1,3,2]-dioxaborolane and 1-bromo-4-chloro-2-((methoxymethoxy)methyl)benzene to afford white crystalline product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[CH:12]=2)=[CH:7][CH:6]=1.C(O)(=O)C.[CH2:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][NH:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:25]3[CH2:26][C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:24]3)[CH:12]=2)=[CH:7][CH:6]=1
Reactant: c1ccc2c(c1)CNC2
Reactant: COC(=O)Cc1ccc(-c2cccc(C=O)c2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)Cc1ccc(-c2cccc(CN3Cc4ccccc4C3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.3 %

Procedure:
(3′-Formyl-biphenyl-4-yl)-acetic acid methyl ester (1.22 g), acetic acid (0.23 mL) and iso-indoline (0.48 g) were combined in methanol (10 mL). After 1 hour, sodium triacetoxyborohydride (1.27 g) was added and stirred for 18 hours, at room temperature, under nitrogen. The reaction was quenched with 0.880 ammonia solution and concentrated. The residue was dissolved in methanol and loaded onto a conditioned SCX cartridge (50 g Varian). The cartridge was washed with methanol (3×50 mL), then eluted with methanolic ammonia solution (2×50 mL) and the combined elution fractions evaporated. Purification on silica, eluting with triethylamine/ethyl acetate/iso-hexane [1:19:80], to give the subtitle compound as a dark brown oil (450 mg).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:31]1([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[NH2:11])[N:4]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:3]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1ncnc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncnc2c1c(-c1ccccc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 18.5 h
Yield: 45.1 %

Procedure:
A solution of 3-iodo-1-trityl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.0 g, 1.99 mmol) in dimethylformamide (20 mL) was treated with phenylboronic acid (0.485 g, 3.8 mmol), tetrakis(triphenylphosphine)palladium (0.138 g, 0.119 mmol), and a solution of sodium carbonate (0.506 g, 4.78 mmol) in water (10 mL). The reaction mixture was stirred at 80° C. for 18.5 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and water (15 mL) was added. The precipitate was filtered and was washed with water. The crude solid was triturated with diethyl ether (30 mL). The resulting solid was dried over night on the lyophilizer to give 0.407 g (45%) of 3-phenyl-1-trityl-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (DMSO-d6, 400 MHz) δ 7.9416 (s, 1H), 7.6190-7.6011 (m, 2H), 7.5369-7.4493 (m, 3H), 7.3995-7.2248 (m, 15H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rf=11.813 min (97%).
Reaction SMILES: ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[CH:16]=[C:17]([Cl:43])[C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@@H:32]([CH3:42])[CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH:30]=3)[C:25](O)=[O:26])=[N:19][CH:20]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.[NH2:44][C:45]1[CH:50]=[N:49][C:48]([CH3:51])=[CH:47][N:46]=1.N1C=CC=CC=1>C(Cl)Cl>[N:9]1([C:13]([C:15]2[CH:16]=[C:17]([Cl:43])[C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@@H:32]([CH3:42])[CH2:33][O:34][Si:35]([C:38]([CH3:40])([CH3:41])[CH3:39])([CH3:36])[CH3:37])[CH:30]=3)[C:25]([NH:44][C:45]3[CH:50]=[N:49][C:48]([CH3:51])=[CH:47][N:46]=3)=[O:26])=[N:19][CH:20]=2)=[O:14])[CH2:10][CH2:11][CH2:12]1
Reactant: Cc1cnc(N)cn1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(C(=O)O)c1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cnc(NC(=O)c2cc(Oc3ncc(C(=O)N4CCC4)cc3Cl)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)cn1
Reaction time: 1 h
Yield: 50.7 %

Procedure:
1-Chloro-N,N,2-trimethyl-1-propenylamine (0.1 mL, 0.75 mmol) was added to a solution of 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]benzoic acid (0.3 g, 0.58 mmol) in DCM (10 mL) and stirred for 1 hour. 2-Amino-5-methylpyrazine (126 mg, 1.15 mmol) then pyridine (0.094 mL, 1.15 mmol) were added and the mixture stirred for a further 30 mins before being reduced in vacuo and partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer was further extracted into ethyl acetate (50 mL) and the combined organics washed with water (50 mL), brine (50 mL), dried (MgSO4), and reduced in vacuo. The crude oil was chromatographed on silica, eluting with 40-100% ethyl acetate in isohexane, to give the title compound as an oil (180 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(=O)C=COC=1C)C1C=CC=CC=1.C(N1C=CC(=O)C(O)=C1C)(=O)C.[NH2:45][CH2:46][CH2:47][C:48]([OH:50])=[O:49].[OH-].[Na+]>O.C(O)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:45]([CH2:46][CH2:47][C:48]([OH:50])=[O:49])[C:10]=1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1occc(=O)c1OCc1ccccc1
Reactant: NCCC(=O)O
Agent: CC(=O)n1ccc(=O)c(O)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CCC(=O)O
Yield: 70 %

Procedure:
3-Benzyloxy-2-methyl-4-pyrone, prepared as described under (J), (20 g) and beta-alanine (9 g) are dissolved in 3:2 v/v water/ethanol (500 ml) containing NaOH (10 g) to provide a solution with a pH of at least 13. The solution is refluxed for 15 minutes whereupon it turns from a light orange to an intense red colour. The solution is acidified to pH 7.0 and the ethanol is removed by rotary evaporation. The resulting aqueous solution is washed twice with ethylacetate (100 ml). This solution is then subjected to rotary evaporation until the volume is reduced to 100 ml and this reduced volume of solution is acidified to pH 3.0 to give a white precipitate, which is filtered off to give 3-benzyloxy-1-(2'-carboxyethyl)-2-methylpyrid-4-one in 70% yield, m.p. 156°-157° C. 1-(2'-Carboxyethyl)-3-hydroxy-2-methylpyrid-4-one hydrochloride
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7][CH2:8][CH3:9])=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1.[CH3:16][N:17]([CH2:26][C:27]([OH:29])=O)[C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(OCC)C.C(Cl)Cl>[Cl:1][C:2]1[C:6]([N:7]([CH2:8][CH3:9])[C:27](=[O:29])[CH2:26][N:17]([CH3:16])[C:18](=[O:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1
Reactant: CCNc1cn(-c2cccnc2)nc1Cl
Reactant: CN(CC(=O)O)C(=O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCN(C(=O)CN(C)C(=O)c1ccccc1)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine (0.075 g, 0.34 mmol), 2-(N-methylbenzamido)acetic acid (0.098 g, 0.51 mmol), and DMAP (0.062 g, 0.51 mmol) in dry diethyl ether (1.0 mL) and dry CH2Cl2 (1.1 mL) was cooled to a temperature of about 0° C. under N2. DCC (0.17 g, 0.81 mmol) was added, and the reaction was slowly warmed up to room temperature under N2, then stirred at room temperature overnight. The reaction mixture was filtered using additional CH2Cl2 (0.5 mL) to remove solids and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0%-10% MeOH/CH2Cl2 to afford the title compound F83 as a white solid (0.12 g, 87%).
Reaction SMILES: CC1(C)[O:6][C:5](=[O:7])[CH:4]([CH:8]([CH2:12][CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=O)[O:3]1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>>[OH:3][C@@H:4]([C@H:8]([C:9]([N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:11])[CH2:12][CH2:13][CH2:14][CH3:15])[C:5]([OH:6])=[O:7]
Reactant: c1cncc(C2CCCN2)c1
Reactant: CCCCC(C(=O)O)C1OC(C)(C)OC1=O
Product: CCCC[C@@H](C(=O)N1CCCC1c1cccnc1)[C@H](O)C(=O)O

Procedure:
The title compound is prepared from 2-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)hexanoic acid B-5 and commercially available 3-pyrrolidin-2-yl-pyridine A-5 according to General Procedure B.
Reaction SMILES: [Cl-].[Li+].[CH2:3]([O:10][C:11]1[C:18]([CH3:19])=[CH:17][C:14]([CH:15]=O)=[CH:13][C:12]=1[CH3:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:21]=[C:22]1[O:26][C:25]2([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[O:24][CH:23]1P(=O)(OCC)OCC.CN(C)C(=N)N(C)C>O1CCCC1.C(OC)(C)(C)C>[CH3:20][C:12]1[CH:13]=[C:14](/[CH:15]=[C:23]2\[C:22](=[O:21])[O:26][C:25]3([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[O:24]\2)[CH:17]=[C:18]([CH3:19])[C:11]=1[O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cc(C=O)cc(C)c1OCc1ccccc1
Reactant: CCOP(=O)(OCC)C1OC2(CCCCC2)OC1=O
Agent: CN(C)C(=N)N(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: Cc1cc(/C=C2/OC3(CCCCC3)OC2=O)cc(C)c1OCc1ccccc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
4.2 g lithium chloride (0.1 Mol), 20.0 g (83.2 mmol) of 4-benzyloxy-3,5-dimethylbenzaldehyde (D) and 31.62 g (108.2 mmol) of diethyl (3-oxo-1,4-dioxaspiro[4.5]dec-2-yl)-phosphonate (C) are suspended in 130 mL tetrahydrofuran and cooled to −20° C. At this temperature 12.5 mL (0.1 Mol) tetramethylguanidine are added dropwise. After the addition has ended the suspension formed is heated to ambient temperature and stirred for 1 hour. After the addition of 190 mL tert.butyl-methylether the organic phase is washed with 150 mL water and 30 mL saturated saline solution, dried and evaporated down. The resulting yellow oil is taken up in 145 mL methanol and stirred intensively for 1 hour at −10° C., during which time a white solid is formed. The solid formed is suction filtered, washed twice with 20 mL methanol/water (1:1) and dried at 45° C.
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][CH:21]=[C:22]([C:28]([O:30]CC)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:15]=1>C(O)C>[OH:30][C:28]1[C:15]2[C:16](=[CH:17][CH:18]=[CH:19][N:14]=2)[N:20]=[CH:21][C:22]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C(=CNc1cccnc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)c1cnc2cccnc2c1O
Temperature: 25 °C
Yield: 75 %

Procedure:
A mixture of 265 g. of diphenyl and 735 g. of diphenyl ether is heated to 255° C., and then the above diethyl 2-([3-pyridylamino]methylene)-malonate is added all at once. The temperature of the mixture is maintained at 255° C. until ethanol is no longer evolved. The mixture is cooled to 25° C. and the precipitate is removed by filtration. It is washed liberally with hexane and dried. This affords 40.5 g. (75% yield) of ethyl 4-hydroxy-1,5-naphthyridine-3-carboxylate.
Reaction SMILES: [C:1]([C:5]1[CH:25]=[CH:24][CH:23]=[CH:22][C:6]=1[C:7]([NH:9][N:10]([CH3:21])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)=[S:12])=[O:8])(OC)=[O:2].[BH4-].[Na+].O.Cl>C(O)C>[OH:2][CH2:1][C:5]1[CH:25]=[CH:24][CH:23]=[CH:22][C:6]=1[C:7]([NH:9][N:10]([CH3:21])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)=[S:12])=[O:8]
Reactant: COC(=O)c1ccccc1C(=O)NN(C)C(=S)Nc1cccc(F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN(NC(=O)c1ccccc1CO)C(=S)Nc1cccc(F)c1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
1-(2-Carbomethoxybenzoyl)-2-methyl-4-(3-fluorophenyl)-3-thiosemicarbazide (7.2 g) was dissolved in ethanol (100 ml). The solution was cooled to below 10° and sodium borohydride (1.1 g) added. The mixture was then stirred at room temperature for 60 hours. Water was then added with production of an amorphous precipitate. Dilute hydrochloric acid was then added to the filtrate to bring it to pH 7 and further precipitate removed by filtration. The filtrate was thereupon acidified to yield the title product as a solid, m.p.136°-137°, yield 3.4 g.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[N+:13]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19]O)([O-:15])=[O:14].[O:25]=[C:26]1[NH:30][C:29](=[O:31])[CH2:28][N:27]1[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[N+:13]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19][N:30]1[C:29](=[O:31])[CH2:28][N:27]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:26]1=[O:25])([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1cc(CO)ccc1Cl
Reactant: CCOC(=O)CN1CC(=O)NC1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CN1CC(=O)N(Cc2ccc(Cl)c([N+](=O)[O-])c2)C1=O
Yield: 78.1 %

Procedure:
A solution of 5.2 mL of diethyl azodicarboxylate in 30 mL of tetrahydrofuran was added to a solution of 5.13 g of 3-nitro-4-chlorobenzyl alcohol, 4.70 g of ethyl 2,4-dioxoimidazolidine-1-acetate and 8.68 g of triphenylphosphine in 30 mL of tetrahydrofuran at 0° C. The reaction mixture was poured over water and the mixture was extracted with ethyl acetate several times. The extracts were combined, washed with a saturated saline solution, dried over sodium sulfate and concentrated. The concentrate was purified by a silica gel column and recrystallized from a mixed solvent of ethanol and water to give 7.01 g of ethyl 3-(3-nitro-4-chlorobenzyl)-2,4-dioxoimidazolidine-1-acetate.
Reaction SMILES: N1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])NC1=O.N1C=CC(=O)NC1=O.C[Si](C)(C)CCO[CH2:26][Cl:27]>>[CH2:4]([O:11][CH2:26][Cl:27])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=c1[nH]c(=O)c2ccccc2[nH]1
Agent: O=c1cc[nH]c(=O)[nH]1
Product: ClCOCc1ccccc1

Procedure:
In a similar manner to the procedures described in Reference Example 3, reactions were carried out using quinazoline-2,4-dione, instead of pyrimidine-2,4-dione, and using 2-(trimethylsilyl)ethoxymethyl chloride, instead of benzyloxymethyl chloride, to give the title compound (yield 87%) as a white powder.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH:8]1[CH2:12][CH:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[CH:10]12[CH2:11][CH:12]([CH:8]=[CH:9]1)[CH:2]1[C:1]([O:6][C:4](=[O:5])[CH:3]21)=[O:7]
Reactant: O=C1C=CC(=O)O1
Reactant: C1=CCC=C1
Solvent: Cc1ccccc1
Product: O=C1OC(=O)C2C3C=CC(C3)C12

Procedure:
A solution of bicyclo[2. 2. 1]hept-5-ene-2,3-dicarboxylic anhydride in toluene is prepared by reacting 1960 grams (20 moles) of maleic anhydride dissolved in 3000 grams of toluene with 1320 grams (20 moles) of cyclopentadiene at a reaction temperature in the range of from about 70° to 75°C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[C:21]([O:28][CH3:29])[CH:20]=1.ClC1C=C(C2C=CC(F)=CC=2OC)C=CN=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=3)[CH:3]=2)=[C:21]([O:28][CH3:29])[CH:20]=1
Reactant: O=[N+]([O-])c1cccc(Nc2cc(I)ccn2)c1
Reactant: COc1cc(F)ccc1B(O)O
Agent: COc1cc(F)ccc1-c1ccnc(Cl)c1
Product: COc1cc(F)ccc1-c1ccnc(Nc2cccc([N+](=O)[O-])c2)c1
Yield: 80.2 %

Procedure:
The title compound C2 was prepared from A5 (122 mg, 0.36 mmol) and (4-fluoro-2-methoxyphenyl)boronic acid (112 mg, 0.66 mmol) following the procedure reported for the intermediate A2. The residue was purified by flash chromatography on silica gel (cHex/EtOAc 100:0 to 50:50) to yield the desired product C2 as an orange solid (98 mg, 80%). MS (ES) C18H14FN3O3 requires: 339. found: 340 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH:9](O)([CH3:11])[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH:9]([O:8][C:4]1[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=1)([CH3:11])[CH3:10]
Reactant: CC(C)O
Reactant: Nc1cccc(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)Oc1cccc(N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.3 %

Procedure:
To a mixture of 3-aminophenol (1.50 g, 13.8 mmol), isopropanol (3.3 g, 55 mmol), and triphenylphosphine (14.4 g, 54.9 mmol) in THF (15 mL), was added dropwise diethylazodicarboxylate (9.60 g, 55.0 mmol) over a 30 min period. The mixture was stirred at room temperature for 3 h and concentrated. The residue was diluted with water, acidified with aqueous 2N HCl and extracted with ether. The aqueous phase was basified with aqueous 2N NaOH and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated. The resulting crude product was purified by silica gel column chromatograph (petroleum ether/EtOAc 10:1 to 5:1) to afford 3-isopropoxybenzenamine as yellow oil (1.3 g, 64%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:21][C:22]([CH3:27])([CH3:26])[C:23](Cl)=[O:24]>ClCCl>[CH3:21][C:22]([CH3:27])([CH3:26])[C:23]([NH:13][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][N:11]=1)=[O:24]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(-c2ccccc2)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc(-c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
5-phenylpyridin-2-amine (2.4 g, 14.10 mmol) was dissolved in 75 ml of dichloromethane. The solution was treated with triethylamine (1.57 g, 15.51 mmol) and trimethylacetylchloride (1.87 g, 15.51 mmol) and the mixture was stirred at room temperature for 1 hour. Silica gel (9 g) was added and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with hexanes/ethyl acetate (5:1) to afford 2,2-dimethyl-N-(5-phenylpyridin-2-yl)propanamide (2.58 g) as a white solid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](Cl)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:21])(=O)C.[CH3:22][NH:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1.[OH-].[Na+]>C1COCC1.CO>[C:28]([C:27]1[CH:30]=[CH:31][C:24]([N:23]([C:13](=[C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:4][C:5]2=[O:21])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:22])=[CH:25][CH:26]=1)#[N:29]
Reactant: CNc1ccc(C#N)cc1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccccc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C(=C1C(=O)Nc2ccccc21)c1ccccc1)c1ccc(C#N)cc1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone and 4-methylamino-benzonitrile in THF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [C:1]([C:3]1[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)=[CH:7][C:6]([NH:16][C@H:17]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)[C:18]([NH2:20])=[O:19])=[C:5]([F:34])[CH:4]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:41]>CCO.CS(C)=O>[NH2:20][C:18](=[O:19])[C@H:17]([NH:16][C:6]1[C:5]([F:34])=[CH:4][C:3]([C:1]([NH2:2])=[O:41])=[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)[CH:7]=1)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1
Reactant: CC(=O)O
Reactant: Cc1cc(Nc2cc(N[C@H](Cc3ccc(-c4ccncc4)cc3)C(N)=O)c(F)cc2C#N)sn1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: Cc1cc(Nc2cc(N[C@H](Cc3ccc(-c4ccncc4)cc3)C(N)=O)c(F)cc2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-2-(4-cyano-2-fluoro-5-(3-methylisothiazol-5-ylamino)phenylamino)-3-(4-(pyridin-4-yl)phenyl)propanamide (12 mg, 0.025 mmol) in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.5 mL, 0.50 mmol) and aq. H2O2 (50%, 0.5 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was purified by HPLC to give the titled compound (6 mg). MS 491.1 (M+H); UV 216.8, 278.0, 312.5 nm.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:9][CH:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[NH:17]1[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:18]1>>[CH3:1][O:2][C:3]1[C:4]([O:9][CH:10]2[CH2:15][CH2:14][CH:13]([N:17]3[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=4)=[O:23])[CH2:18]3)[CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: COc1cccnc1OC1CCC(=O)CC1
Product: COc1cccnc1OC1CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(3-methoxy-pyridin-2-yloxy)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.