Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH2:13]S)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:9]([O:8][C:6]([NH:5][C:4](=[CH2:13])[C:3]([O:2][CH3:1])=[O:15])=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: COC(=O)[C@H](CS)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(NC(=O)OC(C)(C)C)C(=O)OC
Temperature: 0 °C
Yield: 99.4 %

Procedure:
MSH 1 (439 mg, 2.0 mmol) was added to a 10 mL round bottom flask and dissolved in DMF (3 mL). In a separate vial, N-(tert-butoxycarbonyl)-L-cysteine methyl ester 2 (48 mg, 0.20 mmol) was added and dissolved in DMF (3 mL). The vial was cooled to 0° C. and a solution of potassium carbonate (138 mg, 1.0 mmol) in water (3.0 mL) was added. The resulting solution was added dropwise by pipette over a period of 3 min to the stirred MSH solution at room temperature. The vial was rinsed with DMF (2×1 mL) to ensure complete transfer. TLC (petrol:ethyl acetate, 4:1) analysis after completion of the addition revealed a single, UV active product (Rf 0.6). The reaction mixture was transferred to a separatory funnel and diluted with diethyl ether (150 mL) and water (100 mL). After separation, the organic layer was washed successively with water (80 mL) and brine (80 mL) before drying (MgSO4) and filtering. The solvent was removed under reduced pressure and the resulting residue purified by column chromatography to provide methyl 2-[(tert-butoxycarbonyl)amino]acrylate 3 as a clear oil (40 mg, 98%).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[CH3:25][N:26]([CH3:35])[C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([NH2:34])=[CH:29][N:28]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[Cl:19][C:18]1[C:4]2[N:3]=[C:2]([NH:34][C:30]3[CH:29]=[N:28][C:27]([N:26]([CH3:25])[CH3:35])=[CH:32][C:31]=3[CH3:33])[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=1
Reactant: Cc1cc(N(C)C)ncc1N
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)CCCn1c(Nc2cnc(N(C)C)cc2C)nc2c(Cl)ccc(C(CC)CC)c21
Yield: 43.1 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 472 mg, 1.27 mmol), N2,N2,4-trimethylpyridine-2,5-diamine (580 mg, 3.81 mmol) and p-toluenesulfonic acid monohydrate (241 mg, 1.27 mmol) in 1-methyl-2-pyrrolidinone (4 mL) was irradiated by microwave at 180° C. for 135 min. After cooling, aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. Organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 20-80% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give a solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound (266 mg, 0.547 mmol, 43%) as a colorless solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:24][C:25]#[CH:26])[C:5](=[O:23])[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[CH2:14][C:15]1[C:16]([O:21]C)=[N:17][CH:18]=[CH:19][CH:20]=1)[C:2]#[CH:3].S(Cl)(Cl)=O.[OH-].[Na+]>C(O)C>[CH2:1]([N:4]([CH2:24][C:25]#[CH:26])[C:5](=[O:23])[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[CH2:14][C:15]1[C:16](=[O:21])[NH:17][CH:18]=[CH:19][CH:20]=1)[C:2]#[CH:3]
Reactant: C#CCN(CC#C)C(=O)CCC1CCCCN1Cc1cccnc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: C#CCN(CC#C)C(=O)CCC1CCCCN1Cc1ccc[nH]c1=O
Reaction time: 8 h
Yield: 104.1 %

Procedure:
300 mg of N1,N1-di(2-propynyl)-3-[1-[(2-methoxy-3-pyridyl)methyl]-2-piperidyl]propanamide obtained in Example 176, 0.4 ml of thionyl chloride and 5 ml of ethanol were stirred under reflux for 1 hour, and then the mixture was left overnight. An aqueous dilute sodium hydroxide was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate. The sodium sulfate was removed, and the solvent was evaporated. The residue was purified by silica gel chromatography (hexane:ethyl acetate=3:1, subsequently ethyl acetate:methanol=9:1), to give 300 mg of a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([OH:33])=[O:32])=[CH:26][CH:25]=1.COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)N(CC3C=CC(C(O)=O)=CC=3)N=2)C=CC=1OC>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([CH2:30][C:31]([OH:33])=[O:32])=[CH:28][CH:29]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: O=C(O)Cc1ccc(CCl)cc1
Agent: COc1ccc(C2=NN(Cc3ccc(C(=O)O)cc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(Cc3ccc(CC(=O)O)cc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound 1 and 4-chloromethylphenylacetic acid as described for compound 83. Purified by chromatography (ethyl acetate). Crystallized from diethyl ether. M.p. 164°-166° C.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].O>C(OCC)C>[Cl:13][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[Cl:12])[C:4](=[O:5])[CH2:3][Br:1]
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: O
Product: O=C(CBr)c1ccc(Cl)c(Cl)c1

Procedure:
Bromine in a quantity of 10.2 ml (0.2 mol) is added dropwise to a mixture of 37.8 g 3.4-dichloroacetophenone and approx. 1.0 g anhydrous AlCl3 in 600 ml dry diethylether while stirring and cooling in ice. After stirring for 0.5 hr at 0° C. and 1.5 hr at room temperature, 30 ml water are added slowly. The organic phase is separated, washed twice with water, dried and evaporated to dryness. A small amount of petroleum ether (40-60) is added to the residue and the mixture is stirred at approx. 0° C. The desired 3.4-dichlorophenacylbromide is obtained as a crystalline material in a yield of 39.8 g (74%); melting point 55°-58° C.; TLC (CH2Cl2)=0.5.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:21]([OH:23])=O)=[CH:19][NH:20][C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:24][C:25]([CH3:29])([CH3:28])[C:26]#[N:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:26]([C:25]([NH:24][C:21]([C:18]1[C:16]2=[N:17][C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)=[CH:13][N:14]=[C:15]2[NH:20][CH:19]=1)=[O:23])([CH3:29])[CH3:28])#[N:27]
Reactant: CC(C)(N)C#N
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C#N)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.6 %

Procedure:
A mixture of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (60 mg, 0.193 mmol), 2-amino-2-methylpropanenitrile (25 mg, 0.29 mmol), HATU (217 mg, 0.57 mmol) and DIEA (74 mg, 0.57 mmol) in DMF (3 mL) was stirred at room temperature for 16 hours. Then the mixture was filtered and the cake was washed with DMSO and MeOH to give N-(2-cyanopropan-2-yl)-2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (15 mg, 20.5%) as light yellow solid. MS: (M+H)+=400; 1H NMR (300 MHz, DMSO): δ 13.03 (s, 1H), 9.13 (s, 1H), 8.58 (s, 1H), 8.54-8.50 (m, 1H), 8.35 (s, 1H), 7.32-7.69 (m, 1H), 7.23-7.22 (m, 1H), 4.17 (s, 3H), 1.88 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2([C:14]#[N:15])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:27][C:28]1[CH:29]=[C:30]([CH:49]=[CH:50][CH:51]=1)[O:31][C:32]1[CH:46]=[CH:45][C:35]2[N:36]=[C:37]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[S:38][C:34]=2[C:33]=1[C:47]#[N:48]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]([C:11]2([C:14]#[N:15])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:27][C:28]1[CH:51]=[CH:50][CH:49]=[C:30]([O:31][C:32]2[CH:46]=[CH:45][C:35]3[N:36]=[C:37]([NH:39][C:40]([CH:42]4[CH2:44][CH2:43]4)=[O:41])[S:38][C:34]=3[C:33]=2[C:47]#[N:48])[CH:29]=1)=[O:6]
Reactant: N#Cc1c(Oc2cccc(N)c2)ccc2nc(NC(=O)C3CC3)sc12
Reactant: N#CC1(c2cccc(C(=O)O)c2Cl)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1c(Oc2cccc(NC(=O)c3cccc(C4(C#N)CC4)c3Cl)c2)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
To a solution of 2-chloro-3-(1-cyanocyclopropyl)benzoic acid (75 mg, 0.339 mmol) in tetrahydrofuran (2 mL) were added oxalyl chloride (36 μL, 0.420 mmol) and N,N-dimethylformamide (20 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (2 mL). N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (100 mg, 0.29 mmol) produced in Example 3(vi) was added to the solution, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate (50 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (25 mL) and saturated brine (25 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=70/30→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (113 mg, 72%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[O:15][C:14]([NH:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)=[N:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[NH:30][CH:31]=O.CCOC(C)=O>C(O)(=O)C>[NH:30]1[C:3]2[CH:4]=[CH:5][C:6]([C:8]3[C:16]4[O:15][C:14]([NH:17][C:18]5[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=5)=[N:13][C:12]=4[CH:11]=[CH:10][CH:9]=3)=[CH:7][C:2]=2[N:1]=[CH:31]1
Reactant: COc1cc(Nc2nc3cccc(-c4ccc(NC=O)c(N)c4)c3o2)cc(OC)c1OC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc(Nc2nc3cccc(-c4ccc5[nH]cnc5c4)c3o2)cc(OC)c1OC

Procedure:
A solution of 0.182 g (0.243 mmol) N-{2-amino-4-[2-(3,4,5-trimethoxy-phenylamino)-benzooxazol-7-yl]-phenyl}-formamide in 3 ml acetic acid is stirred at 100° C. for 1 h. Then EtOAc is added to the reaction mixture and the organic layer is washed with 4N NaOH solution (2×) and with water (2×), dried over MgSO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography (silicagel, EtOAc=>EtOAc:MeOH=95:5) to afford the title compound as an orange solid. Rt=1.86 min (Waters Symmetry C8, 2.1×50 mm, detection 210-250 nM, 5% to 100% CH3CN in H2O in 2 min+0.05% TFA, flow rate 1.0 ml/min); MS: 417 (M+1)+; m.p. 150-156° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[N:6][CH:7]=1.[O:13]1[C:17]2[CH:18]=[C:19]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:29])[CH3:28])[CH3:25])[CH:20]=[CH:21][C:16]=2[N:15]=[CH:14]1>>[CH:10]1([CH2:9][O:8][C:5]2[N:4]=[CH:3][C:2]([C:14]3[O:13][C:17]4[CH:18]=[C:19]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:29])[CH3:28])[CH3:25])[CH:20]=[CH:21][C:16]=4[N:15]=3)=[CH:7][N:6]=2)[CH2:12][CH2:11]1
Reactant: Brc1cnc(OCC2CC2)nc1
Reactant: CC(=O)N[C@@H](C)COc1ccc2ncoc2c1
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3cnc(OCC4CC4)nc3)oc2c1

Procedure:
Using 5-bromo-2-(cyclopropylmethoxy)pyrimidine and N-((2S)-1-(1,3-benzoxazol-6-yloxy)propan-2-yl)acetamide, and in the same manner as in Step B of Example 22, the title compound was obtained.
Reaction SMILES: CN(C=O)C.[Cl:6][C:7]1[CH:37]=[CH:36][C:10]([CH2:11][N:12]2[C:20]3[C:15](=[CH:16][C:17]([CH:21]=[C:22]4[S:26][C:25]([N:27]([CH3:34])[CH:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)=[N:24][C:23]4=[O:35])=[CH:18][CH:19]=3)[CH:14]=[N:13]2)=[C:9]([C:38]([F:41])([F:40])[F:39])[CH:8]=1.Br[CH2:43][CH2:44][O:45][CH3:46].C([O-])([O-])=O.[K+].[K+]>O>[Cl:6][C:7]1[CH:37]=[CH:36][C:10]([CH2:11][N:12]2[C:20]3[C:15](=[CH:16][C:17]([CH:21]=[C:22]4[S:26][C:25]([N:27]([CH:28]5[CH2:33][CH2:32][N:31]([CH2:43][CH2:44][O:45][CH3:46])[CH2:30][CH2:29]5)[CH3:34])=[N:24][C:23]4=[O:35])=[CH:18][CH:19]=3)[CH:14]=[N:13]2)=[C:9]([C:38]([F:41])([F:40])[F:39])[CH:8]=1
Reactant: CN(C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1)C1CCNCC1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCN1CCC(N(C)C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1
Temperature: 70 °C
Reaction time: 4 h
Yield: 50.7 %

Procedure:
To a DMF solution (1 mL) containing 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(methyl-piperidin-4-yl-amino)-thiazol-4-one (Example 16, 54 mg, 0.1 mmol) was added 1-bromo-2-methoxyethane (27.8 mg, 0.2 mmol) and K2CO3 (28 mg, 0.2 mmol). The mixture was stirred at 70° C. for 4 h, diluted with water and extracted with EtOAc. The combined EtOAc extracts were washed with brine, dried (Na2SO4), and evaporated. The residue was purified by flash column chromatography on silica gel (EtOAc→10% MeOH/EtOAc) to afford the desired product (30 mg, 50%).
Reaction SMILES: [OH:1][C:2]1[C:26]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:25][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N+:22]([O-])=O)=[C:11]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:12]=2)=[CH:4][C:3]=1[C:31]([CH3:34])([CH3:33])[CH3:32]>[Pd].CO>[NH2:22][C:10]1[CH:9]=[CH:8][C:7]([O:6][C:5]2[CH:4]=[C:3]([C:31]([CH3:32])([CH3:33])[CH3:34])[C:2]([OH:1])=[C:26]([C:27]([CH3:29])([CH3:30])[CH3:28])[CH:25]=2)=[CH:12][C:11]=1[N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)ccc1N
Yield: 101.3 %

Procedure:
In a similar manner to that described in Reference Example 7, a reaction was carried out using t-butyl N-[5-(4-hydroxy-3,5-di-t-butylphenoxy)-2-nitrophenyl]-N-methylcarbamate (0.58 g), palladium on carbon (10%, 0.12 g) and methanol (20 ml) and the reaction mixture was purified to give the title compound (0.55 g).
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[O:5].[OH-].[Na+].[C:9](#[N:12])[CH:10]=[CH2:11]>O>[C:9]([CH:10]([NH:2][NH:3][C:4]([NH2:6])=[O:5])[CH3:11])#[N:12]
Reactant: NNC(N)=O
Reactant: C=CC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C#N)NNC(N)=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
1672 g of semicarbazide hydrochloride is dissolved in 2 liters of water, and neutralised, with cooling, with 600 g of sodium hydroxide in 1 liter of water. After the addition dropwise of 795 g of acrylonitrile, the mixture is heated for 7 hours at 80° C. and then allowed to stand for 4 hours at 0° C.; the precipitated crystalline product is subsequently filtered off, and dried under vacuum. There is obtained 1152 g of white product having a melting point of 125°-128° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:7]=1[CH2:8][N:9]([CH3:14])[C:10](=[O:13])[CH:11]=[CH2:12])[CH:2]([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.Br[C:31]1[CH:42]=[N:41][C:34]2[NH:35][C:36](=[O:40])[CH2:37][NH:38][CH2:39][C:33]=2[CH:32]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:5][C:6]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:7]=1[CH2:8][N:9]([CH3:14])[C:10](=[O:13])/[CH:11]=[CH:12]/[C:31]1[CH:42]=[N:41][C:34]2[NH:35][C:36](=[O:40])[CH2:37][NH:38][CH2:39][C:33]=2[CH:32]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: O=C1CNCc2cc(Br)cnc2N1
Reactant: C=CC(=O)N(C)Cc1cccc(OC)c1OCC(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: COc1cccc(CN(C)C(=O)/C=C/c2cnc3c(c2)CNCC(=O)N3)c1OCC(C)C
Yield: 21.3 %

Procedure:
A solution of N-(2-isobutoxy-3-methoxybenzyl)-N-methylacrylamide (0.387 g, 1.40 mmol) in propionitrile (5 mL) and DMF (1 mL) was deoxygenated with Ar for 20 min. Then treated with diisopropylethylamine (0.39 mL, 2.25 mmol) and 7-bromo-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one (0.300 g, 1.07 mmol). The solution was deoxygenated with Ar for 20 min. Then Pd(OAc)2 (0.024 g, 0.10 mmol) and P(o-tol)3 (0.065 g, 0.21 mmol) were added and the solution deoxygenated with Ar for 20 min. The solution was heated to reflux for 18 h, then allowed to cool. The solution was diluted with H2O (30 mL) and was washed with EtOAc (3×50 mL). The organics were washed with brine (2×100 mL), dried over Na2SO4, filtered and concentrated to an orange-brown semi-solid. Purification by column chromatography (silica gel, CH2Cl2 to CH2Cl2/MeOH, 100 to 95:5) gave the title compound (0.10 g, 23%) as an yellow-orange solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.08-10.06 (m, 1H), 8.44-8.39 (m, 1H), 8.02-7.95 (m, 1H), 7.53-7.48 (m, 1H), 7.30-7.25 (m, 1H), 7.04-6.93 (m, 2H), 6.66-6.41 (m, 1H), 4.79-4.64 (m, 2H), 3.91-3.87 (m, 2H), 3.79 (s, 3H), 3.71-3.61 (m, 4H), 3.11-2.87 (m, 4H), 2.03-1.99 (m, 1H), 1.00-0.97 (m, 6H); MS (ESI) m/e 439 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[O:34][CH:33]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=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>[O:34]1[C:33]2=[CH:32][CH:36]=[CH:37][C:38]2=[CH:39][C:40]([C:14]2[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:10]([N:16]3[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]3)[CH:11]=[CH:12][CH:13]=2)=[CH:35]1
Reactant: CC1(C)OB(c2coc3ccccc23)OC1(C)C
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
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: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1CN(c2cccc(-c3coc4cccc-4c3)c2OCc2ccccc2)S(=O)(=O)N1
Temperature: 80 °C
Reaction time: 7 h

Procedure:
A mixture of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (80 mg, 0.18 mmol), 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzofuran (44 mg, 0.18 mmol), Cs2CO3 (235 mg, 0.72 mmol) and Pd(PPh3)4 (8 mg) in DMF (5 mL) is stirred at 80° C. for 7 h. The mixture is cooled to RT and is diluted with EtOAc, washed with water and bride and dried over magnesium sulfate. The solvent is removed under reduced pressure to give the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([CH:14]1[NH:18][C:17](=[O:19])[N:16]([CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:22][CH2:21]2)[C:15]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[CH2:7]([CH:14]1[CH2:15][N:16]([CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:22][CH2:21]2)[C:17](=[O:19])[NH:18]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1NC(Cc2ccccc2)C(=O)N1C1CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1NC(Cc2ccccc2)CN1C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 26 %

Procedure:
Lithium aluminum hydride (3.96 mL, 3.96 mmol, 1 M) was added to a solution of 5-benzyl-3-(1-benzylpiperidin-4-yl)imidazolidine-2,4-dione (120 mg, 0.330 mmol) in tetrahydrofuran (15 mL) at 0° C. and then warmed to ambient temperature. After 16 h, the reaction was quenched with water (0.150 mL), a 15% sodium hydroxide solution (0.150 mL), and water (0.450 mL). The mixture was filtered, washed with tetrahydrofuran, and concentrated. Purification by column chromatography (silica gel, 1 to 12% {1% ammonium hydroxide/methanol} in methylene chloride gradient elution), gave the title compound (30 mg). MS 350.3 (M+1)
Reaction SMILES: I[CH2:2][C:3]1([CH2:6][C:7]#[C:8][Si:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][CH2:4]1.[CH2:13]([O:15][C:16](=[O:29])[C:17]([O:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[CH3:28])([CH3:19])[CH3:18])[CH3:14]>>[CH2:13]([O:15][C:16](=[O:29])[C:17]([CH3:19])([O:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:2][C:3]2([CH2:6][C:7]#[C:8][Si:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][CH2:4]2)=[CH:23][C:22]=1[CH3:28])[CH3:18])[CH3:14]
Reactant: C[Si](C)(C)C#CCC1(CI)CC1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Product: CCOC(=O)C(C)(C)Oc1ccc(OCC2(CC#C[Si](C)(C)C)CC2)cc1C

Procedure:
In analogy to the procedure described in example 20A], [3-(1-iodomethyl-cyclopropyl)-prop-1-ynyl]-trimethylsilane and 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) gave after 18 h at room temperature the title compound as light yellow oil.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:3]1.[C:20]([CH2:22][C:23](O)=[O:24])#[N:21].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[C:8]1([C@@H:4]2[CH2:5][CH2:6][CH2:7][N:2]([C:23](=[O:24])[CH2:22][C:20]#[N:21])[CH2:3]2)[N:12]2[C:13]3[CH:19]=[CH:18][NH:17][C:14]=3[N:15]=[CH:16][C:11]2=[N:10][N:9]=1
Reactant: c1cc2c(ncc3nnc([C@@H]4CCCNC4)n32)[nH]1
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CCC(=O)N1CCC[C@@H](c2nnc3cnc4[nH]ccc4n23)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.4 %

Procedure:
To a suspension of (R)-1-(piperidin-3-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine hydrochloride (0.074 g, 0.265 mmol; Example #I.1.1) and 2-cyanoacetic acid (0.034 g, 0.398 mmol) in DMF (3 mL) was added HOBt (0.041 g, 0.265 mmol), EDC.HCl (0.051 g, 0.265 mmol) and DIEA (0.093 mL, 0.531 mmol). The reaction mixture was stirred at ambient temperature for about 16 h. The crude reaction mixture was purified by RP-HPLC (Table 2, Method f). The appropriate fractions were concentrated in vacuo and lyophilized to afford (R)-3-(3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)piperidin-1-yl)-3-oxopropanenitrile as a white solid (0.052 g, 63%): LC/MS (Table 2, Method a) Rt=1.30 min; MS m/z: 310 (M+H)+.