Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]([O:15]CC)=[O:14])=[CH:10][C:9]=2[S:18][CH:19]([F:21])[F:20])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][C:9]=2[S:18][CH:19]([F:21])[F:20])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(SC(F)F)c(-c2ccc(Cl)cc2)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(SC(F)F)c(-c2ccc(Cl)cc2)[nH]1
Temperature: 0 °C
Yield: 104 %

Procedure:
A solution of ethyl 5-(p-chlorophenyl)-4-[(difluoromethyl)thio]pyrrole-2-carboxylate (166 mg, 0.5 mmol) in ethanol is treated under nitrogen with a solution of sodium hydroxide (100 mg, 2.5 mmol) in water. The reaction mixture is refluxed for three hours, poured into ice-water, treated with hydrochloric acid and extracted with ethyl acetate. The combined organic extracts are washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the title product as an orange solid (158 mg, mp 165° C. (dec)) which is identified by HNMR and CNMR spectral analyses.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1>C(O)C.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(N)c2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(N)c2)CC1
Yield: 84.2 %

Procedure:
A mixture of 3.10 g of tert-butyl 4-(3-aminophenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate (11.3 mmol) and 1.0 g of 10% Pd/C in 200 mL of ethanol was hydrogenated at room temperature using the balloon method for 2 days. The reaction mixture was filtered through Celite and washed with ethanol. The combined ethanol extracts were concentrated in vacuo and the residue was chromatographed on silica (dichloromethane:methanol:isopropylamine=95:5:1) to give 2.63 g of the desired product (84%): ESMS m/e: 277.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][C:14]([CH3:17])([NH2:16])[CH3:15].[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=O>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][C:14]([CH3:17])([NH:16][CH2:23][C:19]1[S:18][CH:22]=[CH:21][CH:20]=1)[CH3:15]
Reactant: O=Cc1cccs1
Reactant: CC(C)(N)COc1ccc2ccccc2c1Cl
Product: CC(C)(COc1ccc2ccccc2c1Cl)NCc1cccs1
Yield: 40 %

Procedure:
Prepared from 1-[(1-chloronaphthalen-2-yl)oxy]-2-methylpropan-2-amine and thiophen-2 carbaldehyde in 40% yield as a brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[CH2:13]([CH:15]1[O:17][CH2:16]1)Br.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[O:17]1[CH2:16][CH:15]1[CH2:13][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: BrCC1CO1
Reactant: O=c1ccc2ccc(O)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=c1ccc2ccc(OCC3CO3)cc2o1

Procedure:
Five grams of 7-(2,3-epoxypropoxy)cumarin obtained by the reaction of 7-hydroxycumarin with epibromohydrin in methyl ethyl ketone in the presence of anhydrous potassium carbonate is heated at reflux for seven hours with 3.1 g of N-carbamoylpiperazine in 100 ml of methanol. After the reaction, methanol is evaporated therefrom in vacuo and the residual crystals are washed with ethyl acetate to give 7.9 g of the product. Hydrochloride recrystallized from a mixture of ethanol and dimethyl formamide melts at 198°-200° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-:12].[Na+].[CH2:14]=O>>[OH:12][CH2:14][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=[CH:7][C:8]=1[OH:11]
Reactant: C=O
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: [OH-]
Agent: [Na+]
Product: CC(C)(C)c1ccc(O)c(CO)c1

Procedure:
The general procedure of Example 35 was repeated except that 50 grams (0.333 mole) of p-tert-butyl phenol was used, along with 14 grams (0.35 mole) of 98% sodium hydroxide and 33.73 grams (0.416 mole) of the formaldehyde solution to obtain the intermediate 2-hydroxymethyl-4-tert-butyl phenol. The desired product, 2-(2-hydroxyethyl)thiomethyl-4-tert-butyl phenol, was obtained from 17.2 grams (0.095 mole) of the intermediate and 7.4 grams of the 2-mercaptoethanol (0.095 mole) in 50 ml of toluene, along with 0.10 gram of the catalyst. Structural formula 26 for the product was confirmed by 1H and 13C NMR.
Reaction SMILES: Br[Si](C)(C)C.C(O[C:9](=[P:40]([OH:42])=[O:41])[C:10]1[N:14]2[C:15]3[C:20]([NH:21][C:22](=[O:23])[C:13]2=[N:12][N:11]=1)=[CH:19][C:18]([C:24]([F:27])([F:26])[F:25])=[C:17]([N:28]1[CH:32]=[C:31]([CH3:33])[N:30]=[C:29]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:16]=3)C.CN(C)C=[O:46]>>[CH3:33][C:31]1[N:30]=[C:29]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:28]([C:17]2[CH:16]=[C:15]3[C:20]([NH:21][C:22](=[O:23])[C:13]4[N:14]3[C:10]([CH2:9][P:40]([OH:41])([OH:42])=[O:46])=[N:11][N:12]=4)=[CH:19][C:18]=2[C:24]([F:25])([F:27])[F:26])[CH:32]=1
Reactant: CCOC(c1nnc2c(=O)[nH]c3cc(C(F)(F)F)c(-n4cc(C)nc4-c4ccccc4)cc3n12)=[P+]([O-])O
Reactant: CN(C)C=O
Agent: C[Si](C)(C)Br
Product: Cc1cn(-c2cc3c(cc2C(F)(F)F)[nH]c(=O)c2nnc(CP(=O)(O)O)n23)c(-c2ccccc2)n1

Procedure:
Bromotrimethylsilane (1 ml, 7 mmol) was added dropwise to a stirred solution of 1-(ethoxy-hydroxy-phosphorylmethyl)-8-(4-methyl-2-phenyl-1H-imidazol-1-yl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one (500 mg, 0.94 mmol) in 20 ml of dry N,N-dimethylformamide.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:30]([O-:32])=[O:31])=[C:15]([CH2:18][S:19][C:20]4[N:24]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[N:23]=[N:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[K+].[CH:36]1([C:42]([O:44][CH:45](I)[CH:46]([CH3:48])[CH3:47])=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.CCOCC.[ClH:55]>CC(N(C)C)=O>[ClH:55].[ClH:55].[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:30]([O:32][CH:45]([O:44][C:42]([CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]4)=[O:43])[CH:46]([CH3:48])[CH3:47])=[O:31])=[C:15]([CH2:18][S:19][C:20]4[N:24]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[N:23]=[N:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CN(C)CCn1nnnc1SCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3csc(N)n3)[C@H]2SC1
Reactant: CC(C)C(I)OC(=O)C1CCCCC1
Agent: Cl
Agent: [K+]
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: CC(C)C(OC(=O)C1=C(CSc2nnnn2CCN(C)C)CS[C@@H]2[C@H](NC(=O)Cc3csc(N)n3)C(=O)N12)OC(=O)C1CCCCC1
Temperature: 0 °C

Procedure:
In 120 ml of dimethylacetamide is dissolved 6.0 g of potassium 7β[2-(2-aminothiazol-4-yl) acetamido]-3-[[[1-(2-dimethylaminoethyl) -1H-tetrazol-5-yl]thio]-methyl]ceph-3-em-4-carboxylate and the solution is cooled to 0° C. With stirring, 9.0 g of 1-iodo-2-methylpropyl cyclohexanecarboxylate is added at one stroke to the solution, followed by stirring for further 10 minutes. To the reaction mixture is added 70 ml of 2 N HCl-ether, followed by addition of 300 ml of ether. The ether layer is discarded and the residue is dissolved in 50 ml of 1 N hydrochloric acid and subjected to column chromatography on XAD-II ®resin (Rohm & Haas Co. U.S.A.), elution being carried out with water-acetonitrile (3:1). The fractions containing the desired product are combined, evaporated under reduced pressure to remove the solvent and lyophilized to give 2.5 g of the title compound as a colorless powder.
Reaction SMILES: FC(F)(F)C(O)=O.ClC1C=CC([CH:15]2N[C:18]([C:20]3C=CC(OC)=[CH:22][C:21]=3OCC)=[N:17][CH:16]2[CH:31]2CCCC2)=CC=1.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]2[N:47]([C:48]([N:50]3[CH2:55]CN(C)C[CH2:51]3)=[O:49])[C:46]([C:57]3[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][C:58]=3[O:65][CH2:66][CH3:67])=[N:45][CH:44]2[CH2:68][CH:69]2[CH2:73][CH2:72][CH2:71]C2)=[CH:39][CH:38]=1>>[Cl:36][C:37]1[CH:38]=[CH:39][C:40]([CH:43]2[N:47]([C:48]([N:50]3[CH2:55][CH2:31][CH:16]([N:17]4[CH2:22][CH2:21][CH2:20][CH2:18]4)[CH2:15][CH2:51]3)=[O:49])[C:46]([C:57]3[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][C:58]=3[O:65][CH2:66][CH3:67])=[N:45][CH:44]2[CH:68]2[CH2:69][CH2:73][CH2:72][CH2:71]2)=[CH:41][CH:42]=1
Reactant: CCOc1cc(OC)ccc1C1=NC(C2CCCC2)C(c2ccc(Cl)cc2)N1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(OC)ccc1C1=NC(C2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
[5-(4-Chloro-phenyl)-4-cyclopentyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone was prepared from 5-(4-chloro-phenyl)-4-cyclopentyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole, trifluoroacetate salt (Example 19) in an analogous manner as described for the preparation of [5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone (Example 24). HR-MS (ES, m/z) observed 579.3104, calculated for C33H44N4O3Cl [(M+H)+]579.3097.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:17]1[NH:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:20][N:21]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15])(C)(C)C.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30].C(Cl)Cl>>[F:32][C:31]([F:34])([F:33])[C:29]([O-:35])=[O:30].[F:32][C:31]([F:34])([F:33])[C:29]([O-:35])=[O:30].[NH3+:7][C@H:8]([C:17]1[NH2+:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:20][N:21]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)CCCCC[C@H](NC(=O)OC(C)(C)C)c1ncc(-c2ccccc2)[nH]1
Solvent: ClCCl
Product: CC(=O)CCCCC[C@H]([NH3+])C1=NC=C(c2ccccc2)[NH2+]1
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A2 (1 eq.) was dissolved in TFA/DCM (1:1) at 0° C. The cooling bath was removed and the mixture was stirred for 60 min at RT. The solvents were removed under reduced pressure and the residue was left under high vacuum for a further 3 h. The crude amine salt A3 was used without further purification. MS (ES) C17H23N3O requires: 285, found: 286 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]=3[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8]2)[CH2:4]1.Cl[C:32]([O:34][CH3:35])=[O:33].C(N(CC)CC)C>ClCCl>[CH3:35][O:34][C:32](=[O:33])[NH:1][CH2:2][C@H:3]1[CH2:4][C@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]=3[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8]2)[CH2:6]1
Reactant: NC[C@H]1C[C@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NC[C@H]1C[C@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 50 mg (0.125 mmol) of trans-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine in 2 ml of dry dichloromethane are added at RT 12 μl (0.150 mmol) of methyl chloroformate (Fluka, Buchs, Switzerland) and 21 μl (0.150 mmol) of triethylamine. After stirring for 2 h at RT, working-up is effected by partitioning between water and ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated in vacuo to provide trans-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-carbamic acid methyl ester. Analytical HPLC: tR=7.08 min (Grad 2); ES-MS: m/eo=458.0.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[K+].[CH3:9][N:10]([CH3:16])[CH2:11][CH:12]([OH:15])[CH2:13]O.CS([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])(=O)=O>O>[CH2:22]([O:21][CH:11]([N:10]([CH3:16])[CH3:9])[CH:12]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH3:13])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOS(C)(=O)=O
Reactant: CN(C)CC(O)CO
Reactant: CCCCCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCC/C=C\C/C=C\CCCCCCCCOC(C)C(OCCCCCCCC/C=C\C/C=C\CCCCC)N(C)C
Reaction time: 19 h

Procedure:
In a nitrogen atmosphere, hexane (30 mL), potassium hydroxide (3.1 g, 54.4 mmol), and water (0.6 g: 3 parts by weight relative to 100 parts by weight of hexane) were added to a four-necked flask, and 3-(dimethylamino)-1,2-propanediol (0.72 g, 6.04 mmol: DAP) was dropped under agitation. Thereafter, linoleyl methane sulfonate (5.0 g, 14.5 mmol) was added, and agitation was performed at 40° C. for 19 hours. The reaction was terminated because remaining linoleyl methane sulfonate became 1.0% (degree of conversion: 64.0%, integrated value of isomer: 0.009).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[NH2:14].[Cl:15]N1C(=O)CCC1=O>C(#N)C>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([Cl:15])[CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[NH2:14]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1c(OCCCl)cccc1[N+](=O)[O-]
Solvent: CC#N
Product: Nc1c(OCCCl)cc(Cl)cc1[N+](=O)[O-]
Yield: 95.3 %

Procedure:
A solution of 2-(2-chloro-ethoxy)-6-nitro-phenylamine (30.0 g, 0.14 mol), N-chlorosuccinimide and acetonitrile (1.3 L) was refluxed for 4 hours. The mixture was concentrated under vacuum and the residue was diluted with ethyl acetate (500 ml). The organic layer was washed with water (2×250 ml) and brine (250 ml), dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum to give an orange solid residue. Crystallization from ethyl acetate-hexanes gave 33.5 g (95.3%) of product as an orange solid: mp 109-110° C.; MS (EI) 250/252/254 m/e (M+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:22]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccccc1Cl
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccccc4Cl)nc23)CC1
Yield: 92.4 %

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.067 mL (0.53 mMol) 2-chlorobenzoyl chloride, 0.015 gm (91%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:9]2[CH2:12][CH:11]([CH2:13][O:14][C:15]3[C:24]([CH:25]4[CH2:27][CH2:26]4)=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[C:17]([F:28])[CH:16]=3)[CH2:10]2)=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:9]2[CH2:12][CH:11]([CH2:13][O:14][C:15]3[C:24]([CH:25]4[CH2:27][CH2:26]4)=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[C:17]([F:28])[CH:16]=3)[CH2:10]2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(C2CC2)c(OCC2CN(C(c3ccccc3)c3ccc(Cl)cc3)C2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1cc(C2CC2)c(OCC2CN(C(c3ccccc3)c3ccc(Cl)cc3)C2)cc1F
Temperature: 50 °C
Reaction time: 3 h
Yield: 107.3 %

Procedure:
A mixture of methyl 4-((1-((4-chlorophenyl)(phenyl)methyl)azetidin 3-yl)-methoxy)-5-cyclopropyl-2-fluorobenzoate (50 mg, 0.10 mmol) and lithium hydroxide (13 mg, 0.31 mmol) in THF (10 mL) and H2O (10 mL) was stirred at 50° C. for 3 h. The mixture was diluted with EtOAc (100 mL), washed with HCl (2.0 M, 20 mL), brine (50×2 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the target product (50 mg) as oil which was used in the next step without further purification. LCMS (ESI) m/z: 466.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:6]([CH2:12]Cl)=[N:7]2.O.[SH:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:6]([CH2:12][S:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]3[C:25]=1[N:26]=[CH:27][NH:28]3)=[N:7]2
Reactant: Sc1ncnc2nc[nH]c12
Reactant: O=c1c2c(Cl)cccc2nc(CCl)n1-c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(Cl)cccc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1Cl
Yield: 84.8 %

Procedure:
Prepared according to Procedure C using Intermediate 2f (300 mg, 0.883 mmol), 6-mercaptopurine monohydrate (165 mg, 0.972 mmol), K2CO3 (134 mg, 0.972 mmol), and DMF (4 mL). The crude product was recrystallized from EtOH to provide 341 mg of a pale orange crystalline solid (85%), mp 233.7-234.4° C. (decomposes). 1H NMR (DMSO-d6) δ: 13.58 (br s, 1H); 8.50 (s, 1H); 8.47 (s, 1H); 7.77-7.85 (m, 2H); 7.68 (d, J=8.1 Hz, 2H); 7.65 (d, J=7.7 Hz, 1H); 7.41-7.56 (m, 2H); 4.45 (d, J=1.2 Hz, 2H). 13C NMR (DMSO-d6) ppm: 158.7, 156.8, 153.8, 151.5, 149.6, 149.5, 143.5, 135.4, 134.1, 133.3, 132.2, 131.6, 131.6, 130.5, 130.2, 128.8, 127.1, 117.6, 32.0. MS (ES): m/z 455.0 (M+). Anal. calcd. for C20H12Cl2N6OS.C2H6O.0.3H2: C, 52.14; H, 3.70; Cl, 13.99; N, 16.58; S, 6.33. Found: C, 52.07; H, 3.37; Cl, 13.40; N, 16.65; S, 6.42.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[O:2].[C:6](OCC)(=[O:9])[CH2:7][CH3:8].[H-].[Na+].[H][H]>C1COCC1.O>[CH:6]([CH:7]([CH3:8])[C:1]([O:3][CH2:4][CH3:5])=[O:2])=[O:9]
Reactant: CCOC(=O)CC
Reactant: CCOC=O
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)C=O
Reaction time: 2 h

Procedure:
A mixture of ethyl formate (55.2 g) and ethyl propionate (51.0 g) was added dropwise with stirring to a suspension of sodium hydride (20.9 g, 60% dispersion in mineral oil) in dry THF (260 ml) under nitrogen. On completion of the addition, the temperature of the reaction mixture rose gradually from ambient temperature to 45° C. accompanied by rapid evolution of hydrogen. The reaction mixture was stirred for 2 hours then cooled and water (400 ml) was added cautiously. The basic solution was washed with ether, then acidified with dilute hydrochloric acid and extracted with ether to give an oil. The oil was distilled and the fraction boiling in the range 100°-160° C. was collected to give ethyl 2-formylpropionate.
Reaction SMILES: [Zn:1].[CH3:2][O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][Br:19])=[CH:14][CH:13]=1)=[O:5]>O1CCCC1>[Br-:19].[CH3:2][O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][Zn+:1])=[CH:14][CH:13]=1)=[O:5]
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: [Zn]
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1-c1ccc(C[Zn+])cc1
Product: [Br-]

Procedure:
Using the procedure of Example 1,800 mg of electrolytic zinc, 2 ml of anhydrous tetrahydrofuran and 3.05 g of [(2'-(methoxycarbonyl)-(1,1'-biphenyl)-4-yl)-methyl]-bromide in 12 ml of anhydrous tetrahydrofuran were reacted.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1.[C:27](=[O:30])([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[OH-:5].[C:1]([O:5][C:6]([NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N+:10]([CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:30][CH3:27])[CH:20]=2)([CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH2:9]1)=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: COc1cccc(CCCBr)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: COc1cccc(CCC[N+]2(CCCc3cccc(OC)c3)CCC[C@H](NC(=O)OC(C)(C)C)C2)c1
Product: [OH-]

Procedure:
(S)-Piperidin-3-yl-carbamic acid tert-butyl ester (2.72 g, 13.6 mmol) and 1-(3-Bromo-propyl)-3-methoxy-benzene (6.6 g, 28.8 mmol), potassium carbonate (2.5 g, 18 mmol) and sodium iodide (4 g, 26.7 mmol) are dissolved in acetonitril (40 ml) and stirred at reflux for 1 day and the solvent is removed under vacuo. The residue is taken up in dichloromethane, filtered through a pad of silica, washed with a mixture of dichloromethane: methanol:conc.ammonia=4:1:0.1 and the filtrate is evaporated. LC (method L): tR=1.30 min; Mass spectrum (ESI+): m/z=497 [M]+.
Reaction SMILES: C[Al](C)C.[CH3:5][CH:6]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[N:19]=[CH:18][C:17]([C:20]([O:22]C)=O)=[CH:16][N:15]=2)[CH2:9]1)[CH3:7].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:34][CH2:35][C:36]2[CH:37]=[C:38]([NH2:41])[NH:39][N:40]=2)[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1>C1(C)C=CC=CC=1>[CH3:33][O:32][C:30]1[CH:29]=[C:28]([CH2:34][CH2:35][C:36]2[CH:37]=[C:38]([NH:41][C:20]([C:17]3[CH:18]=[N:19][C:14]([N:10]4[CH2:11][CH2:12][NH:13][C@@H:8]([CH:6]([CH3:5])[CH3:7])[CH2:9]4)=[N:15][CH:16]=3)=[O:22])[NH:39][N:40]=2)[CH:27]=[C:26]([O:25][CH3:24])[CH:31]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: COC(=O)c1cnc(N2CCN[C@@H](C(C)C)C2)nc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCN[C@@H](C(C)C)C4)nc3)[nH]n2)cc(OC)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 62.1 %

Procedure:
Trimethylaluminium (2M in toluene, 1.23 mL, 2.46 mmol) was added dropwise to a stirred suspension of (S)-methyl 2-(3-propan-2-ylpiperazin-1-yl)pyrimidine-5-carboxylate (260 mg, 0.98 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (243 mg, 0.98 mmol) in toluene (8.38 mL) at room temperature. The reaction was then stirred at 60° C. for 18 h under a nitrogen atmosphere. The reaction mixture was quenched into methanol (100 mL) and treated with HCl (2N aqueous solution, until the pH was 7 or lower). The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford impure product. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (292 mg, 62%) as a white solid.