Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]([F:18])([F:17])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[NH2:16])=[N:8][CH:9]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:50][C:51]1[CH:52]=[CH:53][C:54]([N:60]2[N:64]=[CH:63][CH:62]=[N:61]2)=[C:55]([CH:59]=1)[C:56](O)=[O:57]>CN(C=O)C>[CH3:50][C:51]1[CH:52]=[CH:53][C:54]([N:60]2[N:64]=[CH:63][CH:62]=[N:61]2)=[C:55]([CH:59]=1)[C:56]([NH:16][CH:12]1[CH2:13][CH2:14][CH2:15][CH:11]1[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([F:17])([F:2])[F:18])=[CH:9][N:8]=1)=[O:57]
Reactant: NC1CCCC1Cc1ccc(C(F)(F)F)cn1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nccn2)c(C(=O)NC2CCCC2Cc2ccc(C(F)(F)F)cn2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-{[5-(trifluoromethyl)pyridin-2-yl]methyl}cyclopentan-1-amine hydrochloride (Intermediate 36; 0.60 g, 2.44 mmol) in DMF (5 ml) was added DIPEA (0.63 g, 4.80 mmol), TBTU (0.94 g, 2.93 mmol) and added 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 6; 0.49 g, 2.44 mmol). The reaction was stirred at room temperature for 1 hour and then partitioned between ethyl acetate (50 ml) and water (10.0 ml). The aqueous layer was further extracted with ethyl acetate (50 ml) and the combined organics were concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-2% methanol/DCM) to afford the title compound.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][CH2:13][C:14]2=[O:17])=[CH:10][CH:9]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C1(C)C=CC=CC=1>C(OCC)(=O)C.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>[F:18][C:19]1[CH:24]=[C:23]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][CH2:13][C:14]3=[O:17])=[CH:10][CH:9]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: O=C1CCc2ccc(Br)cc21
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: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1CCc2ccc(-c3cccc(F)c3)cc21
Temperature: 80 °C
Yield: 81.1 %

Procedure:
Cesium carbonate (618 mg, 1.90 mmol) was added to a solution of 6-bromo-2,3-dihydro-1H-inden-1-one (200 mg, 0.948 mmol), (3-fluorophenyl)boronic acid (265 mg, 1.90 mmol) and toluene (20 mL) in a 50 mL Schlenk tube at room temperature. A nitrogen atmosphere was established by evacuating and refilling with nitrogen (3×), then tetrakis(triphenylphosphine)palladium (0) (11 mg, 0.001 mmol) was added to the reaction. The flask was sealed and heated in a 80° C. oil bath overnight. The resulting mixture was cooled to room temperature. The reaction was then diluted with ethyl acetate and filtered through celite. Ethyl acetate (30 mL) was used to wash the flask and the combined organic filtrate was concentrated in vacuo. The resulting crude residue was purified on a Teledyne-Isco combiflash machine (40 g column, hexanes→100% ethyl acetate/hexanes, gradient) to afford 174 mg (81%) of 6-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-one.
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:7][O:6][C:5]([NH2:8])=[N:4][C@@:3]21[C:17]1[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=1)[CH2:11][CH2:10][CH2:9]2.[C:20]([C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1)#[N:21]>>[NH2:8][C:5]1[O:6][CH2:7][C:2]([F:1])([F:19])[C@@:3]2([C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:28](=[O:29])[C:25]4[CH:24]=[CH:23][C:22]([C:20]#[N:21])=[CH:27][N:26]=4)[CH:16]=3)[CH2:11][CH2:10][CH2:9]2)[N:4]=1
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: NC1=N[C@@]2(CCCc3ccc(N)cc32)C(F)(F)CO1
Product: N#Cc1ccc(C(=O)Nc2ccc3c(c2)[C@@]2(CCC3)N=C(N)OCC2(F)F)nc1
Yield: 38 %

Procedure:
The condensation of (R)-5′,5′-difluoro-3,4,5′,6′-tetrahydro-2H-spiro[naphthalene-1,4′-[1,3]oxazine]-2′,7-diamine (intermediate A7.1) and 5-cyanopicolinic acid yielded the title compound (38% yield) as a white solid. MS (ISP): m/z=398.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[N:5]=[C:4]([S:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][C:27]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:28])[N:20]=2)[N:3]=1.C(N(CC)CC)C.[C:43](Cl)(=[O:46])[CH2:44][CH3:45]>C(#N)C>[NH2:1][C:2]1[N:3]=[C:4]([S:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][C:27]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:28])[N:20]=2)[N:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:43](=[O:46])[CH2:44][CH3:45])=[CH:12][CH:11]=2)[C:7]=1[C:8]#[N:9]
Reactant: CCC(=O)Cl
Reactant: CN1CCN(C(=O)CCc2cccc(CSc3nc(N)c(C#N)c(-c4ccc(N)cc4)n3)n2)CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCC(=O)Nc1ccc(-c2nc(SCc3cccc(CCC(=O)N4CCN(C)CC4)n3)nc(N)c2C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.9 %

Procedure:
The compound of Example 56 (150 mg) and triethylamine (0.5 mL) were dissolved in 10 mL of acetonitrile, and 0.1 g of propionyl chloride was added dropwise to the mixture and the mixture was stirred at room temperature for 30 minutes. After removing the solvent, the residue was dissolved in chloroform. Thereto water was added, the organic layer was washed with water (twice), then brine (once), and dried over magnesium sulfate. After the solvent was removed under reduced pressure, the resulting oil was purified by chromatography on silica gel (methylene chloride-methanol-aqueous ammonia=90:10:1) to give 50 mg of N-[4-(6-amino-5-cyano-2-{6-[3-(4-methylpiperazin-1-yl)-3-oxopropyl]pyridin-2-ylmethylsulfanyl}pyrimidin-4-yl)phenyl]propionamide as a light yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:19][C:20]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[C:21]=1[CH2:22]C1C=C(N)NN=1>O1CCCC1>[CH3:22][C:21]1[C:29]([CH3:34])=[CH:30][C:31]([CH3:33])=[CH:32][C:20]=1[CH2:19][C:5]1[CH:6]=[C:2]([NH:1][CH:8]=[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[NH:3][N:4]=1
Reactant: Nc1cc[nH]n1
Reactant: O=C1Nc2ccccc2/C1=C/O
Reactant: Cc1cc(C)c(Cc2cc(N)[nH]n2)c(C)c1
Solvent: C1CCOC1
Product: Cc1cc(C)c(C)c(Cc2cc(NC=C3C(=O)Nc4ccccc43)[nH]n2)c1

Procedure:
The named compound is prepared by substituting 5-(2,4,6-trimethyl-benzyl)-2H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.2758 gms. 5-(2,4,6-trimethyl-benzyl)-2H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (2.0 mL) overnight.
Reaction SMILES: [CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:3]([NH:4][C:5]3=[S:12])[CH2:2]1)[CH2:9]2.[CH3:13][I:14]>CO>[IH:14].[CH3:13][S:12][C:5]1[CH:6]2[CH2:11][CH:1]3[CH2:9][CH:8]([CH2:10][CH:3]([CH2:2]3)[N:4]=1)[CH2:7]2
Reactant: CI
Reactant: S=C1NC2CC3CC(C2)CC1C3
Solvent: CO
Product: CSC1=NC2CC3CC(C2)CC1C3
Product: I
Yield: 77.3 %

Procedure:
A mixture of the 5-thione derivative 5c (1.45 gram, 8 mmol) and methyl iodide (1.21 gram, 8.5 mmol) in 100 ml methanol was refluxed for 6 hours. The solvent was evaporated to dryness leaving the hydroiodide salt 6 (2 grams) as a white solid. Melting point 235°-238° C. (recrystallized from absolute ethanol).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[NH2:17])[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:19]([C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[CH2:20][CH2:21][CH3:22].[C:31](O)(=O)[CH3:32]>CO>[CH2:19]([C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[N:1][C:2]2[C:15]3[C:14](=[O:16])[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][C:12]=4[N:17]=[CH:12][C:13]4[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][CH2:31][CH3:32])=[CH:15][CH:14]=4)[C:7](=[O:18])[C:6]=3[CH:5]=[CH:4][CH:3]=2)=[CH:25][CH:24]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CC(=O)O
Reactant: Nc1cccc2c1C(=O)c1c(N)cccc1C2=O
Reactant: CCCCc1ccc(C=O)cc1
Solvent: CO
Product: CCCCc1ccc(C=Nc2cccc3c2C(=O)c2c(N=Cc4ccc(CCCC)cc4)cccc2C3=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution at 80° C. of 2.38g (0.1 mol) 1,8-diaminoanthraquinone in 3.16 g (0.2 mol) p-n-butylbenzaldehyde is added about 1 ml. glacial acetic acid. Heating is continued for one hour and 50 ml methanol is added to dissolve the reaction mixture. The solution is poured into 100 ml ice water and the product collected and recrystallized from 1:1 methanol-water as above to give 1,8-bis(p-n-butylbenzylidene amino)anthraquinone as fine purple needles, melting with decomposition at 288°-9° C.
Reaction SMILES: [C:1]([CH:4]([C:12](=O)[CH3:13])[CH:5]([C:9](=O)[CH3:10])[C:6](=O)[CH3:7])(=O)[CH3:2].C[C:16]1[CH:22]=[C:21]([O:23][C:24]([F:27])([F:26])[F:25])[CH:20]=[CH:19][C:17]=1[NH2:18].[NH2:28][NH2:29]>>[CH3:2][C:1]1[C:4]2=[C:12]([CH3:13])[N:18]([C:17]3[CH:19]=[CH:20][C:21]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:22][CH:16]=3)[C:9]([CH3:10])=[C:5]2[C:6]([CH3:7])=[N:29][N:28]=1
Reactant: Cc1cc(OC(F)(F)F)ccc1N
Reactant: NN
Reactant: CC(=O)C(C(C)=O)C(C(C)=O)C(C)=O
Product: Cc1nnc(C)c2c(C)n(-c3ccc(OC(F)(F)F)cc3)c(C)c12

Procedure:
Utilizing the general procedure outlined in Example 48, 1,1,2,2-tetraacetylethane (200 mg, 1.0 mol), 2-methyl-4-(trifluoromethoxy) aniline (191 mg, 1.0 mmol) and hydrazine (50 μL) reacted to give 1,4,5,7-Tetramethyl-6-(4-trifluoromethoxy-phenyl)-6H-pyrrolo[3,4-d]pyridazine as light yellow solid: 1H NMR (CDCl3, 500 MHz) δ 8.27 (s, 1H), 8.11 (s, 1H), 4.50 (q, 1H), 2.80 (s, 6H), 2.48 (s, 6H), 1.50 (t, 3H); MS (ESI) 298 (M+H)+; MS (ESI) 350 (M+H)+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[NH:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH3:20])=[CH:12]1.Cl[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].O>CN(C)C=O>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][N:10]([C:9]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[F:3])[N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH3:20])=[CH:12]1)[CH3:27]
Reactant: CCOC(=O)CCl
Reactant: Cc1cn(Nc2ccncc2F)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(c1ccncc1F)n1cc(C)c2ccccc21
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (60% in oil, 1.48 g) in 10 ml of dimethylformamide (DMF) at ice bath temperature was added dropwise a solution of N-(3-fluoro-4-pyridinyl)-3-methyl-1H-indol-1-amine (8.5 g) in 40 ml of DMF, when addition was complete, the mixture was stirred for 15 minutes at ice bath temperature, and then cooled to -20° C. Ethyl chloroacetate (3.95 ml) was added dropwise in 10 ml of DMF. The mixture was stirred at -20° C. for one hour. The mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried (sat. NaCl, anhy. MgSO4). After filtering, the solvent was evaporated to yield an oil (12.2 g) which was eluted with 10% ethyl acetate/DCM on a silica gel column via HPLC. The desired fractions were evaporated to yield 6.9 g of a solid, m.p. 105°-108° C.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]2[C:10]([CH:11]=1)=[C:9]([OH:12])[CH:8]=[CH:7][CH:6]=2)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].O>CN(C)C=O>[C:37]([O:36][C:34](=[O:35])[CH2:33][O:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[C:3]([CH2:1][CH3:2])[N:4]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCc1cc2c(O)cccc2n1Cc1ccccc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc2c(OCC(=O)OC(C)(C)C)cccc2n1Cc1ccccc1-c1ccccc1
Temperature: 25 °C

Procedure:
2-Ethyl-4-hydroxy-1-(2-phenyl-phenylmethyl)-1H-indole (0.8 g, 0.00245 mol) was added to a slurry of cesium carbonate (0.98 g, 0.003 mol) in 15 mL of dimethylformamide, stirred at room temperature for ten minutes and then the t-butyl bromoacetate was added all at once. After stirring at room temperature overnight, the solution was poured into water and extracted in ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated to an oil that crystallized on standing at room temperature. This material was slurried in hexane and filtered to give 0.93 g of subtitled compound as a tan solid.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[Cl:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10]([NH2:17])=[N:11][NH:12]2>N1C=CC=CC=1>[Cl:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10]([NH:17][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[N:11][NH:12]2
Reactant: CCCC(=O)Cl
Reactant: Nc1n[nH]c2cccc(Cl)c12
Solvent: c1ccncc1
Product: CCCC(=O)Nc1n[nH]c2cccc(Cl)c12
Temperature: 10 °C
Reaction time: 17 h

Procedure:
0.23 cm3 of butyryl chloride is added to 1 g of 4-chloro-1H-indazole-3-amine, prepared as described in patent EP 90 972, in 10 cm 3 of pyridine, cooled to about 10° C. The temperature is allowed to return to about 19° C. over 17 hours. The reaction medium is evaporated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 25 cm3 of ethyl acetate and 25 cm3 of distilled water. The organic phase is washed with 2×25 cm3 of distilled water and with 25 cm3 of saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered through a sinter funnel and then evaporated under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4 cm), eluting with a dichloromethane/methanol mixture (99/1 by volume) and collecting 30 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). 80 mg of N-[4-chloro-1H-indazol-3-yl]butanamide are thus obtained in the form of a white solid melting at 198° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[Cl:7][CH2:8][O:9][C:10](=[S:12])[CH3:11]>>[Cl-:7].[C:10]([O:9][CH2:8][N+:4]1[CH:5]=[CH:6][N:2]([CH3:1])[CH:3]=1)(=[S:12])[CH3:11]
Reactant: CC(=S)OCCl
Reactant: Cn1ccnc1
Product: CC(=S)OC[n+]1ccn(C)c1
Product: [Cl-]
Reaction time: 0.17 h

Procedure:
To 0.7 g (8.52 millimoles) of 1-methylimidazole was added slowly and with cooling, 1.5 g of (16.2 millimoles) chloromethylthioacetate. The solution solidified in 10 minutes and was left stoppered at room temperature overnight.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([OH:13])[C:10]([OH:12])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[C:14]1(C)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO>[O:11]=[C:10]1[O:12][C:14]2([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[O:13][CH:9]1[P:4](=[O:5])([O:3][CH2:1][CH3:2])[O:6][CH2:7][CH3:8]
Reactant: Cc1ccccc1
Reactant: CCOP(=O)(OCC)C(O)C(=O)O
Solvent: CO
Product: CCOP(=O)(OCC)C1OC2(CCCCC2)OC1=O
Temperature: 110 °C

Procedure:
In a reaction vessel with a descending condenser, 50 g (0.236 Mol) (diethoxyphosphinyl)-hydroxyacetic acid (A) and 240 mL toluene are mixed at ambient temperature and then heated to 110° C. When the boiling temperature of toluene is reached, a mixture of 71.7 mL (0.471 Mol) cyclohexane-dimethylketal (B) and 10 mL toluene are slowly added dropwise, while the azeotrope of toluene and methanol is distilled off. After the addition has ended the reaction mixture is refluxed for 90 minutes. Any solvent distilled off is replaced by the addition of 50 mL toluene. In order to achieve total conversion, a further 10 mL (0.066 Mol) of cyclohexane-dimethylketal (B) are added dropwise. The mixture is heated to a 110° C. for another hour and the solvent distilled off is replaced by the addition of another 100 mL toluene. After the addition of another 120 mL toluene the solvent is distilled off in vacuo. The residue is taken up in 200 mL tert.butyl-methylether and successively extracted twice with 200 mL of 10% potassium carbonate solution, once with 250 mL of 30% sodium bisulphite solution and once with 150 mL of 30% sodium bisulphite solution. After subsequent extraction with 40 mL saturated saline solution the organic phase is dried and evaporated down.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=O.N1CCCN[C:8]1=[O:13].[O:14]=[C:15]1[C:20](=[O:21])[NH:19][CH2:18][CH2:17][NH:16]1>>[C:15](=[C:20]1[NH:1][CH2:5][CH2:4][NH:3][C:2]1=[C:8]=[O:13])=[O:14].[NH:19]1[CH2:18][CH2:17][NH:16][C:20]1=[O:21]
Reactant: O=C1NCCNC1=O
Reactant: O=C1NCCCN1
Agent: O=C1NCCN1
Product: O=C=C1NCCNC1=C=O

Procedure:
An analogous product is obtained when, instead of imidazolidin-2-one there is used either hexahydropyrimidin-2-one or 2,3-diketopiperazine.
Reaction SMILES: [Na].[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][OH:6].Cl[C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([N:19]2[CH2:24][CH2:23][CH:22]([NH:25][C:26]([C:28]3[NH:29][C:30]([CH3:35])=[C:31]([Cl:34])[C:32]=3[Cl:33])=[O:27])[CH2:21][CH2:20]2)[N:18]=1)[C:12]([O:14]C)=[O:13].Cl>CN(C=O)C>[Cl:33][C:32]1[C:31]([Cl:34])=[C:30]([CH3:35])[NH:29][C:28]=1[C:26]([NH:25][CH:22]1[CH2:23][CH2:24][N:19]([C:17]2[CH:16]=[C:11]([CH:10]=[C:9]([O:6][CH2:5][CH2:4][N:3]([CH3:7])[CH3:2])[N:18]=2)[C:12]([OH:14])=[O:13])[CH2:20][CH2:21]1)=[O:27]
Reactant: COC(=O)c1cc(Cl)nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)c1
Reactant: CN(C)CCO
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)cc(OCCN(C)C)n3)CC2)c(Cl)c1Cl

Procedure:
Sodium (155 mg, 6.74 mmol) and 2-(dimethylamino)ethanol (0.677 ml, 6.74 mmol) were stirred together in DMF (1.5 ml). Methyl 2-chloro-6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)isonicotinate (Example 333; 200 mg, 0.449 mmol) was added. The reaction mixture was refluxed overnight, then brought to room temperature and acidified with 10% HCl. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with water, then with brine, dried over sodium sulfate and concentrated to give the desired product. The crude product was purified by reversed phase HPLC eluting with water/acetonitrile/TFA mixtures to afford the desired product (60 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26]O)[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1C=CC(OP(OC2C=CC=CC=2)([N:76]=[N+:77]=[N-:78])=O)=CC=1.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>O1CCCC1>[N:76]([CH2:26][C@@H:18]1[C@H:19]2[O:23][C:22]([CH3:24])([CH3:25])[O:21][C@H:20]2[C@H:16]([N:13]2[C:9]3[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]4[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:3]=4[O:2][CH3:1])[C:8]=3[CH:15]=[CH:14]2)[O:17]1)=[N+:77]=[N-:78]
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CO)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN=[N+]=[N-])[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
A solution of ((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (2.83 g, 6.20 mmol) and triphenylphosphine (2.28 g, 8.68 mmol) in dry tetrahydrofuran (32 mL) was cooled at 0° C. in an ice/water bath. Diisopropyl azodicarboxylate (1.71 mL, 8.68 mmol) was added dropwise, followed by a solution of diphenylphosphonic azide (1.87 mL, 8.68 mmol) in tetrahydrofuran (5.3 mL, 66 mmol). Upon addition of the DPPA solution, a white milky precipitate formed. After about 30 minutes, the reaction mixture was allowed to warm to room temperature and stir overnight. After 24 h, HPLC indicated that all the starting material had been consumed. The reaction mixture was concentrated to about ½ the original volume and purified by flash chromatography (175 g silica gel, 10-55% EA/hept) to yield the title compound (2.49 g, 83%) as a slightly yellow stiff foam: MS (ESI+) for C23H27N7O5 m/z 482.2 (M+H)+; (ESI−) for C23H27N7O5 m/z 480.1 (M+H) m/z 526.1 (M+CO2H)−; HPLC purity 97% (ret. time, 3.64 min).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH3:10].C(=O)([O-])[O-].[K+].[K+].[CH2:17]([N:19]([CH2:23][CH3:24])[C:20](Cl)=[O:21])[CH3:18].C1(C)C=CC=CC=1>C(#N)C.O>[CH2:17]([N:19]([CH2:23][CH3:24])[C:20]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH3:10])=[O:21])[CH3:18]
Reactant: CCN(CC)C(=O)Cl
Reactant: COc1cccc(O)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)Oc1cccc(OC)c1C
Temperature: 100 °C
Reaction time: 0.98 h
Yield: 103.1 %

Procedure:
A solution of 3.15 g (22.8 mmol) of 2-hydroxy-6-methoxytoluene in 16 mL acetonitrile was added with 3.50 g (25.1 mmol) of potassium carbonate and 3.4 g (25.1 mmol) of diethylcarbamoyl chloride and heated and stirred on a 100° C. oil bath for 59 minutes. After addition of 0.6 g (4.4 mmol) of diethylcarbamoyl chloride and heated for 38 minutes, while stirring on an ice-water bath, 30 mL of toluene and 30 mL of water, were added into the reaction mixture, and the mixture was stirred for 20 minutes, transferred to a separatory funnel and settled. The aqueous layer was separated and discarded and after the organic layer was washed with 10 mL of 2 N aqueous sodium hydroxide and 10 mL of water twice, and the solvent was evaporated to obtain 5.58 g of the crude title compound. Since the mixture solidified, a part thereof was obtained as seed crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[C:21]#[N:22])=[N:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:6][CH:7]=1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(#N)C>[C:21]([C:20]1[CH:19]=[C:18]([CH:25]=[CH:24][CH:23]=1)[O:17][C:3]1[C:2]([NH:1][C:33]([NH:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:34])=[CH:7][CH:6]=[C:5]([O:8][C:9]2[CH:16]=[CH:15][CH:14]=[C:11]([C:12]#[N:13])[CH:10]=2)[N:4]=1)#[N:22]
Reactant: O=C=Nc1ccccc1
Reactant: N#Cc1cccc(Oc2ccc(N)c(Oc3cccc(C#N)c3)n2)c1
Solvent: CC#N
Product: N#Cc1cccc(Oc2ccc(NC(=O)Nc3ccccc3)c(Oc3cccc(C#N)c3)n2)c1

Procedure:
To 3,3′-[3-amino-2,6-pyridinediylbis(oxy)]bis(benzonitrile) (3.0g, 8.7 mmol) dissolved in acetonitrile (100 mL) was added phenyl isocyanate (1.1 g, 9.5 mmol). After refluxing for 4 hours, the reaction was partitioned between ether and water. The organic layer was separated, washed with water, saturated aqueous sodium bicarbonate, and brine, dried (MgSO4), and the solvent was removed in vacuo. Chromatography on silica gel with ethyl acetate/hexane (1/4) as eluent gave material which was crystallized from ethyl acetate/hexane to give N-[2,6-bis(3-cyano-phenoxy) pyridin-3-yl]-N′-phenylurea; NMR (CDCl3) 8.65 (d,1), 7.4 (m,8), 7.1-7.3 (m,6), 6.8 (s,1), 6.7 (d,1) ppm.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16]Cl.CN1C(=O)N(C)CCC1>C1COCC1>[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][O:10][C:6]1[CH:5]=[C:4]([I:3])[CH:9]=[CH:8][CH:7]=1
Reactant: Oc1cccc(I)c1
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COCCOCOc1cccc(I)c1
Temperature: 0 °C

Procedure:
To a suspension of 60% sodium hydride (1.76 g, 44 mmol) in THF (10 mL), cooled to 0° C., is added 3-iodophenol (8.8 g, 40 mmol) and methoxyethoxymethyl chloride (5 mL, 44 mmol) in THF (50 mL). Then DMPU (10 mL) is added, the cooling bath is removed and the reaction is stirred for an hour. The reaction is diluted with ether, washed with water and brine and the organic layer dried over magnesium sulfate. The solvent is removed in vacuo to give the title compound.