Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.I[C:12]1[C:20]2[C:15](=[N:16][CH:17]=[N:18][C:19]=2[NH2:21])[N:14]([CH:22]([CH3:24])[CH3:23])[N:13]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:21][C:19]1[N:18]=[CH:17][N:16]=[C:15]2[N:14]([CH:22]([CH3:24])[CH3:23])[N:13]=[C:12]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)[C:20]=12
Reactant: OB(O)c1ccc(O)cc1
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
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: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2ccc(O)cc2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 34.3 %

Procedure:
A solution of 4-Hydroxyphenylboronic acid (30 mg, 0.14 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (40 mg, 0.13 mmol) in DME (12 mL). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA56 (12 mg, 32% yield). ESI-MS (M+H)+ m/z calcd 270.1, found 270.1.
Reaction SMILES: [C:1](/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[C:1](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:19][CH3:20])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)/C=C/C(=O)c1ccccc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)/C=C/C(=O)c1ccccc1
Temperature: 62 °C
Reaction time: 3 h

Procedure:
A mixture of 7.75 g of trans-β-benzoylacrylic acid, 25.8 ml of ethanol and 1.63 g of sulfuric acid was stirred at 62° C. for 3 hours. A pressure was gradually reduced with the aspirator and ethanol was distilled away for 20 minutes. After a pressure was finally reduced to 20 mmHg, the resultant was stirred at 62° C. for 1.5 hours and then cooled, followed by the procedure as in Example 1 to give 8.18 g of ethyl trans-β-benzoylacrylate.
Reaction SMILES: [CH:1](OCC#N)=[O:2].[CH:7]1([NH:10][C:11]([C:13]2[C:21]3[CH:20]=[C:19]([C:22]4[C:27]([Cl:28])=[CH:26][N:25]=[C:24]([NH:29][CH2:30][CH2:31][CH2:32][CH:33]5[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]5)[N:23]=4)[S:18][C:17]=3[CH:16]=[CH:15][CH:14]=2)=[O:12])[CH2:9][CH2:8]1>CN(C=O)C.C(OCC)(=O)C>[CH:7]1([NH:10][C:11]([C:13]2[C:21]3[CH:20]=[C:19]([C:22]4[C:27]([Cl:28])=[CH:26][N:25]=[C:24]([NH:29][CH2:30][CH2:31][CH2:32][CH:33]5[CH2:34][CH2:35][N:36]([CH:1]=[O:2])[CH2:37][CH2:38]5)[N:23]=4)[S:18][C:17]=3[CH:16]=[CH:15][CH:14]=2)=[O:12])[CH2:8][CH2:9]1
Reactant: N#CCOC=O
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCCC4CCNCC4)ncc3Cl)cc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=CN1CCC(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Reaction time: 18 h
Yield: 74.8 %

Procedure:
Cyanomethyl formate (10 mg, 0.11 mmol) is added to a stirred suspension of 2-[5-chloro-2-(3-piperidin-4-yl-propylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (50 mg, 0.11 mmol) in DMF (1 mL) and stirred for 18 hours to form a thick suspension. The mixture is diluted with ethyl acetate (1 mL) then filtered to give the title compound as a solid (41 mg). ES+(m/z) 498 (35Cl) and 500 (37Cl) [M+H].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1.[OH-].[Na+].Br[CH2:13][CH2:14][CH2:15][Cl:16]>CC(C)=O>[Cl:16][CH2:15][CH2:14][CH2:13][N:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1
Reactant: NC(=O)C1CCNCC1
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: NC(=O)C1CCN(CCCCl)CC1
Yield: 20 %

Procedure:
Piperidine-4-carboxylic acid amide (0.5 g, 3.90 mmol), acetone (1.5 ml, 3 vol), 5M NaOH solution (1.20 ml, 1.2 eq.) and 1-bromo-3-chloropropane (0.50 ml, 5.04 mmol, 1 eq.) were reacted together according to general procedure A to give the title compound (0.16 g, 20%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:17][C:16](=O)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.S(Cl)([Cl:21])=O>CN(C)C=O>[Cl:21][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:17]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]c(-c2ccccc2Cl)nc2ccccc12
Solvent: CN(C)C=O
Product: Clc1ccccc1-c1nc(Cl)c2ccccc2n1
Temperature: 0 °C

Procedure:
A mixture of 17.5 g of 2-(2-chlorophenyl)quinazolin-4(3H)-one and 130 ml of thionyl chloride was treated as described in Example I with 5 g of dimethylformamide. The mixture was poured into 1000 ml of ice water and stirred until the ice was melted. The solid was collected by filtration and allowed to air-dry overnight. The solid was triturated with 500 ml of boiling cyclohexane. The insoluble solid was removed by filtration and the cyclohexane solution allowed to cool slowly. The solid which separated was collected to give pale yellow needles, m.p. 127°-129°. Recrystallization of the yellow needles from cyclohexane gave 9.9 g of 4-chloro-2-(2-chlorophenyl)quinazoline, m.p. 129.5°-130.5°; ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(OC)(O[CH3:22])(=O)=O.[OH-].[K+]>CC(C)=O>[CH3:22][N:16]1[C:17]2[C:13](=[CH:12][CH:11]=[CH:10][C:9]=2[C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=[CH:15]1
Reactant: O=C(c1ccccc1)c1cccc2cc[nH]c12
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cn1ccc2cccc(C(=O)c3ccccc3)c21

Procedure:
A mixture of 8.57 g. (38.8 mmoles) of 7-benzoylindole, 5.38 g. (42.7 mmoles) of dimethyl sulfate and 5.12 g. of 85% potassium hydroxide in 40 ml. of acetone was heated to reflux for 75 minutes. The mixture was poured into 500 ml. of water and extracted with methylene chloride. The organic phase was separated, dried and concentrated. The residue was chromatographed on silica gel using methylene chloride-hexane as the eluant. The fractions containing the product were combined and concentrated to dryness, 6.5 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21]Br.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:21][C:16]3[C:15](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14]2=[O:13])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: NCCCc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2CN1CCCc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 80.2 %

Procedure:
A mixture of 3-(4-fluorophenyl)-propylamine (306 mg, 2 mmol), 2-bromomethyl-benzoic acid methyl ester (458 mg, 2 mmol), and K2CO3 (200 mg, 1.45 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 16 h. Workup and silica gel column chromatography using a gradient of hexanes to 50% ethyl acetate in hexanes afforded 2-[3-(4-fluorophenyl)-propyl]-2,3-dihydroisoindol-1-one (432 mg, 80%). GC/MS gave: m/z (rel.int.) 269 (M+, 32), 147 (100), 146 (76), 119 (43), 109 (30) and 91 (39).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:17]=[C:11]3[CH:12]([CH3:16])[NH:13][CH2:14][CH2:15][N:10]3[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.C=O.[BH3-][C:21]#N.[Na+].CC(O)=O>CO>[CH3:7][C:4]1[N:3]([C:8]2[CH:17]=[C:11]3[CH:12]([CH3:16])[N:13]([CH3:21])[CH2:14][CH2:15][N:10]3[N:9]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: Cc1ccc(C)n1-c1cc2n(n1)CCNC2C
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(C)n1-c1cc2n(n1)CCN(C)C2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 287g (1.54 g, 1.0 eq., 6.70 mmol), formaldehyde (37% in water) (1.09 g, 2.0 eq., 13.4 mmol), NaBH3CN (2.11 g, 5.0 eq., 33.5 mmol), HOAc (3 mL), and methanol (30 mL). The mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was partitioned between water (50 mL) and dichloromethane (50 mL). The water phase was extracted with dichloromethane (3×50 mL). The combined organic layer was concentrated under reduced pressure to afford crude 287h, which was used in the next step without further purification. MS-ESI: [M+H]+ 245.0
Reaction SMILES: [H-].[Na+].C(=N/[OH:11])\C1C=CC=CC=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:32]([O:34]CC)=O)[CH2:24][CH2:23][C:22]3([O:29][CH2:28][C:27]([CH3:31])([CH3:30])[CH2:26][O:25]3)[CH2:21][CH2:20]2)=[C:15]([C:37]#[C:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH:14]=1>O1CCOCC1.CN(C=O)C>[Cl:12][C:13]1[CH:14]=[C:15]2[C:16](=[CH:17][CH:18]=1)[C:19]1([CH2:20][CH2:21][C:22]3([O:29][CH2:28][C:27]([CH3:31])([CH3:30])[CH2:26][O:25]3)[CH2:23][CH2:24]1)[C:32](=[O:34])[C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:37]2[OH:11]
Reactant: O/N=C/c1ccccc1
Reactant: CCOC(=O)C#Cc1cc(Cl)ccc1C1(C(=O)OCC)CCC2(CC1)OCC(C)(C)CO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCC3(CC2)OCC(C)(C)CO3)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
A stirred mixture of NaH (60% dispersion in mineral oil (0.39 mL, 9.3 mmol)) in 40 mL dioxane at room temperature, was treated with a mixture of (E)-benzaldehyde oxime (1.0 g, 8.6 mmol) in 40 mL DMF. The resulting mixture was stirred for 30 minutes. The mixture was then cooled to 0° C. and treated with a mixture of ethyl 4′-(4-chloro-2-(3-ethoxy-3-oxoprop-1-ynyl)phenyl)-5,5-dimethyl-spiro[1,3-dioxane-2,1′-cyclohexane]-4′-carboxylate (3.6 g, 7.8 mmol) in 30 mL DMF. The resulting mixture was stirred for 1 hour. The mixture was then carefully quenched with 10 mL H2O and brought to a pH of 5 by addition of 10% HCl. The mixture was extracted with ethyl ether (3×50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, concentrated in vacuo, and purified by column chromatography eluting with 20-30% EtOAc to give 2.2 g of the product as a pale yellow solid. MS (m/z)=435 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][CH:10]1[CH2:14][CH2:13][N:12](C(OCC)=O)[CH2:11]1.[OH-].[K+]>CC(O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][CH:10]1[CH2:14][CH2:13][NH:12][CH2:11]1
Reactant: CCOC(=O)N1CCC(Nc2cccc(C)c2C)C1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1cccc(NC2CCNC2)c1C
Yield: 63 %

Procedure:
A mixture of 13.10 parts of ethyl 3-[(2,3-dimethylphenyl)amino]-1-pyrrolidinecarboxylate, 28 parts of potassium hydroxide and 240 parts of 2-propanol was stirred and refluxed for 6 hours. The reaction mixture was evaporated. The residue was taken up in water. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. Yielding 6 parts (63%) of N-(2,3-dimethylphenyl)-3-pyrrolidinamine as a residue (intermediate 68).
Reaction SMILES: [Na].[CH2:2]1[O:4][CH:3]1[CH2:5][OH:6].[CH:7]([OH:10])([CH3:9])[CH3:8]>>[CH:7]([O:10][CH2:2][CH:3]([OH:4])[CH2:5][OH:6])([CH3:9])[CH3:8]
Reactant: CC(C)O
Reactant: OCC1CO1
Agent: [Na]
Product: CC(C)OCC(O)CO
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Into a 3-L separable flask equipped with a stirrer and a condenser, 1200 g of isopropanol was introduced. Then 4.6 g of sodium was added and heated to 80° C. to dissolve. After complete dissolution of the sodium, 300 g of glycidol was dropped at 80° C. over 1 hour. After completion of the dropping, stirring was conducted for 3 hours. Then the stirring was stopped and the mixture was cooled to room temperature. At this time, the mixture separated into an upper layer and a lower layer. The upper layer was isolated and concentrated by an evaporator. Furthermore, 3-isopropoxy-1,2-propanediol (boiling point: 60° C./2 mmHg) was obtained through distillation under reduced pressure. 3-Isopropoxy-1,2-propanediol thus obtained is a model compound in the case where one molecule of glycidol reacted with a hydroxyl group of EVOH.
Reaction SMILES: [C:1](=[NH:25])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:20][C:21]([F:24])([F:23])[F:22])[CH:14]=2)=[CH:8][CH:7]=1)[NH2:2].[OH:26]/[CH:27]=[C:28](/[CH2:33][C:34]1[CH:35]=[N:36][CH:37]=[N:38][CH:39]=1)\[C:29](OC)=O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:29]=[C:28]([CH2:33][C:34]4[CH:39]=[N:38][CH:37]=[N:36][CH:35]=4)[C:27](=[O:26])[N:25]=3)=[CH:11][CH:10]=2)=[CH:14][C:15]=1[O:20][C:21]([F:24])([F:22])[F:23]
Reactant: N=C(N)OCCc1ccc(Oc2ccc(Cl)c(OC(F)(F)F)c2)cc1
Reactant: COC(=O)/C(=C\O)Cc1cncnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=c1nc(OCCc2ccc(Oc3ccc(Cl)c(OC(F)(F)F)c3)cc2)[nH]cc1Cc1cncnc1
Temperature: 110 °C
Yield: 43.7 %

Procedure:
A mixture of 4-(4-chloro-3-(trifluoromethoxy)phenoxy)phenethyl carbamimidate (80 mg, 0.213 mmol), (Z)-methyl 3-hydroxy-2-(pyrimidin-5-ylmethyl)acrylate (124 mg, 0.640 mmol) and Cs2CO3 (174 mg, 0.534 mmol) in 1,4-dioxane (2 mL) was heated with a microwave condition at 110° C. for 2 h. After cooling, the mixture was filtered through the celite. The filtrate was concentrated and purified via reverse phase flash chromatography to afford the title compound (48 mg, 0.093 mmol, 43.3% yield). LCMS: rt=3.48 min, [M+H+]=519
Reaction SMILES: [CH2:1]([O:4][C:5]1[N:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[N:7][C:6]=1[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:2][CH3:3].[CH3:19]OC(C1C=NC(Cl)=C(Br)N=1)=O.N1CCCC1.[OH-].[K+]>C(O)CCC>[CH2:1]([O:4][C:5]1[N:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[N:7][C:6]=1[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:2][CH2:3][CH3:19]
Reactant: COC(=O)c1cnc(Cl)c(Br)n1
Reactant: CCCOc1nc(C(=O)O)cnc1N1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Solvent: C1CCNC1
Product: CCCCOc1nc(C(=O)O)cnc1N1CCCC1
Yield: 8 %

Procedure:
In analogy to the procedure described for the synthesis of 6-propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid (example 10, step c), the title compound was synthesized from 6-Bromo-5-chloro-pyrazine-2-carboxylic acid methyl ester, butanol (commercially available), pyrrolidine (commercially available) and subsequent saponification with KOH in 8% yield. m/z (ES+): 266.0 (M+H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([N:6]([CH3:8])[CH3:7])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[C:26]([CH3:39])=[C:27]([CH3:38])[C:28]4[O:32][C:31]([CH3:34])([CH3:33])[C:30](=[O:35])[C:29]=4[C:36]=3[CH3:37])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1>C(OCC)(=O)C.CCCCCC>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[C:26]([CH3:39])=[C:27]([CH3:38])[C:28]4[O:32][C:31]([CH3:34])([CH3:33])[C:30]([C:2]5[CH:10]=[CH:9][C:5]([N:6]([CH3:8])[CH3:7])=[CH:4][CH:3]=5)([OH:35])[C:29]=4[C:36]=3[CH3:37])[CH2:23][CH2:24]2)=[CH:17][CH:18]=1
Reactant: CN(C)c1ccc(Br)cc1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(=O)C(C)(C)O4)CC2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3ccc(N(C)C)cc3)C(C)(C)O4)CC2)cc1
Yield: 73 %

Procedure:
Using 4-bromo-N,N-dimethylaniline and 4-(4-methoxyphenyl)-1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-on-5-yl)piperazine obtained in Reference Example 13, the title compound was synthesized in the same manner as in Example 33. Yield 73%. mp. 144–146° C. (ethyl acetate-hexane).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27]Br)=[CH:21][N:20]=1)[P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[C:29]([O-:32])(=[S:31])[CH3:30].[Na+]>CC(C)=O>[CH2:1]([O:3][P:4]([CH:9]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][S:31][C:29](=[O:32])[CH3:30])=[CH:21][N:20]=1)[P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CC([O-])=S
Reactant: CCOP(=O)(OCC)C(Nc1ccc(CCCBr)cn1)P(=O)(OCC)OCC
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOP(=O)(OCC)C(Nc1ccc(CCCSC(C)=O)cn1)P(=O)(OCC)OCC
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A solution of [(5-(3-bromopropyl)-2-pyridinyl)aminomethylene]bis[phosphonic acid] tetraethyl ester (5.0 mmol) is stirred in dry acetone (35 ml) and sodium thioacetate (5.2 mmol) is added. The mixture is stirred at 50° C. for 12 hours. After cooling to room temperature the solvent is removed under reduced pressure. The crude residue is dissolved in methylene chloride and washed with water. The organic layer is then dried and concentrated under reduced pressure. The desired product is purified by flash chromatography using a 5-10% isopropanol in methylene chloride gradient on silica gel.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](=[S:5])[NH2:4].Br[CH2:8][C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C(O)C>[CH:2]([C:3]1[S:5][CH:8]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:4]=1)([CH3:6])[CH3:1]
Reactant: CC(C)C(N)=S
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(C(C)C)n1
Temperature: 70 °C
Yield: 108.2 %

Procedure:
A solution containing the product from Example 56A (8.6 g, 83.5 mmol) in ethanol (250 mL) was treated with ethyl bromopyruvate (12.6 mL, 100 mmol), and the mixture was heated at 70° C. for 3 hours, cooled to 25° C., concentrated, and partitioned between dichloromethane and saturated NaHCO3. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound (18 g, 57% yield), which was used without further purification.
Reaction SMILES: [CH2:1]1COCC1.[C:6]([CH:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)([CH3:9])([CH3:8])[CH3:7]>C(Cl)Cl.CCCCCC>[C:6]([CH:10]1[CH2:15][CH2:14][C:13](=[CH2:1])[CH2:12][CH2:11]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: C1CCOC1
Reactant: CC(C)(C)C1CCC(=O)CC1
Solvent: CCCCCC
Solvent: ClCCl
Product: C=C1CCC(C(C)(C)C)CC1
Reaction time: 8 h
Yield: 70 %

Procedure:
BDAM (3.00 grams) was suspended in 40 milliliters of methylene chloride and 2 molar equivalents of THF were added at 0° C. After a homogeneous solution was formed, 1 molar equivalent of TEAL in 10 milliliters of hexane was added followed by 2.20 grams of 4-tert-butylcyclohexanone. After overnight stirring, reaction mixture was hydrolyzed and worked up as described in Example 1. A total of 1.50 grams of 4-tert-butyl-1-methylenecyclohexane was isolated (70% yield).
Reaction SMILES: [C:1]([CH2:3][C:4](O)=[O:5])#[N:2].[CH:7]1([CH2:13][NH:14][C:15]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>C(OC(=O)C)(=O)C>[NH2:2][C:1]1[N:14]([CH2:13][CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[C:15](=[O:16])[N:17]([CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:4](=[O:5])[CH:3]=1
Reactant: O=C(NCC1CCCCC1)NCC1CCCCC1
Reactant: N#CCC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Nc1cc(=O)n(CC2CCCCC2)c(=O)n1CC1CCCCC1
Temperature: 80 °C
Yield: 94.2 %

Procedure:
Cyanoacetic acid (Aldrich, 21.0 g) was dissolved in acetic anhydride (260 ml). This solution was added to 1,3-bis(cyclohexylmethyl)urea (from step (a), 54.5 g) and the solution maintained at 80° C. for 2 h under nitrogen. Volatiles were removed in vacuo and the residual oil dried by evaporation of portions of 10% water-ethanol (3×400 ml). The residual solids were dissolved in ethanol (600 ml)water(300 ml) at 80° C. with adjustment of the pH to 10 by addition of 10% aqueous sodium carbonate. The hot solution was diluted with water (75 ml) and cooled to ambient temperature. The colorless crystals which formed were filtered off, washed with water and dried at 0.5 Torr to give 6-amino-1,3-bis(cyclohexylmethyl)uracil (64.98 g, 94%), m.p. 138-141° C.; 1H-NMR (DMSO-d6) δ: 6.73 (br s, 2, NH2), 4.63 (s, 1, H-5), 3.67 (d, J=7.3 Hz, 2, NCH2), 3.57 (d, J=7.3 Hz, 2, NCH2), 1.55 and 1.09 (both m, 22, 2 cyclohexyl).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[C:12]([C:20](O)=[O:21])=[CH:11]2)[C:4]=1[CH3:23].[CH:24]1([CH2:27][NH2:28])[CH2:26][CH2:25]1>>[CH:24]1([CH2:27][NH:28][C:20]([C:12]2[C:13]3=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=[C:18]3[N:10]([CH2:9][C:5]3[C:4]([CH3:23])=[C:3]([O:2][CH3:1])[N:8]=[CH:7][N:6]=3)[CH:11]=2)=[O:21])[CH2:26][CH2:25]1
Reactant: NCC1CC1
Reactant: COc1ncnc(Cn2cc(C(=O)O)c3ncc(C)cc32)c1C
Product: COc1ncnc(Cn2cc(C(=O)NCC3CC3)c3ncc(C)cc32)c1C
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
See FIG. 18(b). 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (0.100 g, 0.32 mmol) and cyclopropylmethanamine (0.046 g, 0.64 mmol), TEA (0.134 mL, 0.96 mmol) was added. After 3 min1-Propanephosphonic acid cyclic anhydride (0.255 g, 0.80 mmol) was added. The resulting reaction mixture was stirred at rt for 50 min. LCMS analysis showed formation of required product. Reaction was diluted with DCM and water. DCM layer was extracted and washed with brine and dried over sodium sulphate and concentrated. Purification was done on Waters RP system to get product N-(cyclopropylmethyl)-1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-6-methyl-H-pyrrolo[3,2-b]pyridine-3-carboxamide (0.045 g, 38.5%). ES+MS m/z: 366.44. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.21-0.33 (m, 2H ) 0.41-0.56 (m, 2 H ) 1.08 (m, J=6.97 Hz, 1 H ) 2.24 (s, 3 H ) 2.40 (s, 3 H ) 3.26 (d., 2 H ) 3.94 (s, 3 H ) 5.63 (s, 2 H ) 7.75 (s, 1 H ) 8.11 (s, 1 H) 8.35 (s, 1 H ) 8.42 (s, 1H ) 8.74 (t, J=5.65 Hz, 1 H ).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH3:10])[CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1>O.C(O)(=O)C>[CH2:9]([NH:8][C:4]1[CH:3]=[C:2]([NH:22][C:21]2[CH:20]=[CH:19][C:18]([N:15]3[CH2:14][CH2:13][N:12]([CH3:11])[CH2:17][CH2:16]3)=[CH:24][CH:23]=2)[N:7]=[CH:6][N:5]=1)[CH3:10]
Reactant: CCNc1cc(Cl)ncn1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: O
Solvent: CC(=O)O
Product: CCNc1cc(Nc2ccc(N3CCN(C)CC3)cc2)ncn1
Temperature: 100 °C
Yield: 60.5 %

Procedure:
A mixture of (6-chloro-pyrimidin-4-yl)-ethyl-amine (363 mg, 2.30 mmol, 1.1 eq.) and 4-(4-methylpiperazin-1-yl)-aniline (400 mg, 2.09 mmol) in water (0.8 ml) and glacial acetic acid (3.2 ml) is heated to 100° C. 3 h. After solvent evaporation, the residue is taken up in methanol, made alkaline by addition of 25% NH3 in water and concentrated. The residue is purified by MPLC (silica gel) (DCM/MeOH) to afford 395 mg of the title compound as a white solid: ESI-MS: 313.2 [MH]+; tR=1.25 min (purity: ˜90%, gradient J); TLC: Rf=0.12 (DCM/MeOH, 9:1).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:11]=[C:10]([I:12])[CH:9]=[C:8]2[C:4]=1[C:5](=[O:14])[C:6](=[O:13])[NH:7]2.[H-].[Na+].[CH3:19][Si:20]([CH3:27])([CH3:26])[CH2:21][CH2:22][O:23][CH2:24]Cl.O>CN(C)C=O>[CH3:19][Si:20]([CH3:27])([CH3:26])[CH2:21][CH2:22][O:23][CH2:24][N:7]1[C:8]2[C:4](=[C:3]([C:2]([F:15])([F:1])[F:16])[CH:11]=[C:10]([I:12])[CH:9]=2)[C:5](=[O:14])[C:6]1=[O:13]
Reactant: O=C1Nc2cc(I)cc(C(F)(F)F)c2C1=O
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCN1C(=O)C(=O)c2c1cc(I)cc2C(F)(F)F
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
A solution of 4-trifluoromethyl-6-iodo-1H-indole-2,3-dione (12.0 g, 35.2 mmol) in N,N-dimethylformamide (120 mL) was cooled to 0° C. under nitrogen, and thereto was added 55% sodium hydride (1.70 g, 39.0 mmol) and the mixture was stirred for 30 minutes. Then, to the reaction solution was added dropwise 2-(trimethylsilyl)-ethoxymethyl chloride (7.00 mL, 39.6 mmol), and the mixture was stirred at room temperature for 5 minutes. To the reaction solution was added water, and the mixture was extracted with ethyl acetate-toluene (1:1) twice, washed with water twice, and then dried over magnesium sulfate, and filtered. The filtrate was evaporated and purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to give the titled compound (13.7 g, 83%).