Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:12]([C:15](=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=O)[CH3:13]>C(O)C>[CH2:19]([O:18][C:16]([C:15]1[CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[N:6]2[CH:5]=[N:4][C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]2[NH:1][C:12]=1[CH3:13])=[O:17])[CH3:20]
Reactant: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Reactant: CCOC(=O)c1nc[nH]c1N
Solvent: CCO
Product: CCOC(=O)C1=C(C)Nc2c(C(=O)OCC)ncn2C1c1cccc([N+](=O)[O-])c1
Yield: 48.4 %

Procedure:
A solution of 2 g of 5-amino-4-ethoxycarbonylimidazole and 3.4 g of ethyl α-acetyl-3-nitrocinnamate in 50 ml of ethanol is refluxed under heating for 7 hours under a nitrogen atmosphere. The ethanol is removed under reduced pressure, the resulting oil is purified by column chromatography on silica gel with a mixture of chloroform and methanol as eluent. Recrystallization from a mixture of isopropyl alcohol and isopropyl ether gives 2.5 g of 3,8-diethoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydroimidazo[1,5-a]pyrimidine, melting at 160°-162° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)#N.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:22]([NH:24][CH2:25][CH2:26][NH2:27])[CH3:23].[O-]CC.[Na+]>C(O)C>[CH2:22]([N:24]1[CH2:25][CH2:26][N:27]=[C:1]1[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[CH3:23]
Reactant: N#CCCc1ccncc1
Reactant: CCNCCN
Agent: CC[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CCO
Product: CCN1CCN=C1CCc1ccncc1
Temperature: 190 °C
Yield: 59.1 %

Procedure:
A mixture of 4-(2-cyanoethyl)pyridine (1.32 g, 0.01M) and N-ethyl-1,2-diaminoethane mono-p-toluenesulfonate (5.5 g, 0.02M) were heated at 190° C. for 4 hrs under nitrogen. The reaction mixture was dissolved in ethanol (30 ml) and sodium ethoxide (0.02M) in ethanol (50 ml) was added. The mixture was filtered and the filtrate was stripped to dryness and distilled at 130° C./0.2 mmHg to yield 4-[2-(1-ethyl-4,5-dihydro-imidazol-2-yl)ethyl]-pyridine (1.2 g, 60% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH3:18])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[SH:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([O:25][CH3:26])=[O:24]>>[CH3:18][C:13]1=[N:14][NH:15][C:16](=[O:17])/[C:12]/1=[C:4]1\[NH:5][C:6]2[C:11]([C:2]([S:19][C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([O:25][CH3:26])=[O:24])=[CH:3]\1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COC(=O)c1cccc(S)c1
Reactant: CC1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Product: COC(=O)c1cccc(SC2=C/C(=C3/C(=O)NN=C3C)Nc3ccccc32)c1

Procedure:
The title compound was prepared from (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one and methyl 3-mercaptobenzoate using a procedure analogous to the one described in Example 6. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.96 (s, 3H) 3.90 (s, 3 H) 6.77 (s, 1H) 7.65-7.69 (m, 3H) 7.86-7.96 (m, 3H) 7.99 (d, J=8.08 Hz, 1H) 8.16 (d, J=8.34 Hz, 1H) 10.35 (s, 1H) 13.04 (bs, 1H); ESI-MS: m/z calc'd for C21H17N3O3S 391.10. found 392.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>CO.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Cc1ccc([N+](=O)[O-])cc1N1CCCC1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(N)cc1N1CCCC1

Procedure:
The mixture containing (2-methyl-5-nitrophenyl)pyrrolidine in methanol with catalytic amount of 10% Pd/C was hydrogenated to yield 4-methyl-3-pyrrolidinylphenylamine.
Reaction SMILES: [Br:1][CH:2]1[C:7](=O)[C:6]([Br:9])=[CH:5][N:4]=[CH:3]1.P(Cl)(Cl)(Cl)(Cl)[Cl:11]>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1[Cl:11]
Reactant: O=C1C(Br)=CN=CC1Br
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: Clc1c(Br)cncc1Br
Temperature: 0 °C
Reaction time: 3 h
Yield: 87.3 %

Procedure:
A mixture of 3,5-dibromo-4-pyridone (VIII, W=Br) (79.0 g, 0.312 mol) and PCl5 (79 g, 0.38 mol) was kept at 160° C. for 3 h. The reaction mixture was cooled to 0° C. and quenched by slow addition of water (200 mL). The resulting precipitate was crushed, filtered off, washed with water, and transferred on top of a flash silica column which was subsequently eluted with CH2Cl2. The crude product thus obtained was crystallised from EtOH to give the title compound, 3,5-dibromo-4-chloropyridine (VII, W=Br) (73.9 g, 72%) as white needles: Rf =0.60 (CH2Cl2); mp 95.0-96.5° C. (EtOH); 1H NMR (250 MHz, CDCl3) δ8.65 (s); 13C NMR (63 MHz, CDCl3) δ121.8, 144.0, and 150.9; IR (CHCl3) νmax 1549, 1524, 1410, and 1394 cm−1; MS (EI+) m/z (rel intensity) 271 (100%, M+) and 192 (30); HRMS calcd for C5H2Br2ClN (M+) 268.8242, found 268.8231.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:36])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19]([CH:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)=[N:18][N:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.Br>CO>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:36])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[N:18][N:17]=[CH:16]4)[CH:12]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(C3CCN(C(=O)OC(C)(C)C)CC3)nncc2c1
Agent: Br
Solvent: CO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(C3CCNCC3)nncc2c1
Reaction time: 1 h

Procedure:
0.42 g of Tert-butyl 4-(6-(5-(cyclopropylcarbamoyl)-2-methylphenyl)phthalazin-1-yl)piperidine-1-carboxylate was dissolved in 2 mL methanol, treated with 1 mL 48% HBr at RT and stirred for 1 h. The mixture was quenched with 20 mL 10% Na2CO3 and extracted with dichloromethane (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with 10% -20% 2 M ammonia methanol/dichloromethane to give the title product as pale yellow solid. Found MS (ES+): 387(M+H)+.
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[C:15]1[C:16](Br)=[C:17]([CH:23]=[CH:24][C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].N#N>C1(C)C=CC=CC=1.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.CCO>[C:1]1([C:24]2[CH:23]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]([C:9]3[C:10]4[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=4)[CH:6]=[CH:7][CH:8]=3)=[CH:15][C:25]=2[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccc(C(=O)OCC)c(Br)c1Br
Reactant: OB(O)c1cccc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(-c2cccc3ccccc23)c(C(=O)OCC)cc1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
193.3 g (0.82 mol) of naphthylboronic acid, 180.4 g (474 mmol) of diethyl dibromoterephthalate and 315.9 g (2-29 mol) of potassium carbonate are initially introduced in a mixture of 850 ml of toluene and 850 ml of water and saturated with N2 for 30 min. After addition of 1.36 g (1.18 mmol) of Pd(PPh3)4, the mixture is heated at the boil for 4 h. After cooling to RT and addition of 400 ml of EtOH, the mixture is cooled to room temperature and stirred for 1 h, and the precipitate is filtered off with suction, washed with water, EtOH and heptane and dried at 80° C. in vacuo. The yield of colourless solid is 160.7 g (71%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:18]1[C:27]2[CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23][C:22]=2[CH:21]=[CH:20][CH:19]=1.[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:28][CH:25]2[CH2:26][C:27]3[N:18]=[CH:19][CH:20]=[CH:21][C:22]=3[CH2:23][CH2:24]2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CCc2cccnc2C1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(CNC2CCc3cccnc3C2)cc1
Reaction time: 0.03 h
Yield: 100.2 %

Procedure:
Using general procedure B: Reaction of (4-Formyl-benzyl)-carbamic acid tert-butyl ester (356 mg, 1.51 mmol), 5,6,7,8-Tetrahydro-quinolin-7-ylamine (224 mg, 1.51 mmol) in anhydrous MeOH (5 mL) at room temperature overnight under N2 and 2 min of stirring after addition of sodium borohydride (115 mg, 3.00 mmol), followed by purification of crude material using chromatography on silica gel (2:2:96 CH3OH—NH3 H2O—CH2Cl2) afforded the title compound (556 mg, 100%) as a white foam.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][C:6](=[O:28])[C:7]([C:26]#[N:27])=[N:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:24]#[N:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])=[CH:12][CH:11]=1)C.C([O-])(=O)C.[K+]>C(O)(=O)C>[C:24]([C:16]([C:13]1[CH:14]=[CH:15][C:10]([N:9]2[C:4](=[O:3])[NH:5][C:6](=[O:28])[C:7]([C:26]#[N:27])=[N:8]2)=[CH:11][CH:12]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17])#[N:25]
Reactant: CCOC(=O)NC(=O)C(C#N)=NNc1ccc(C(C)(C#N)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C#N)(c1ccccc1)c1ccc(-n2nc(C#N)c(=O)[nH]c2=O)cc1

Procedure:
A mixture of 7.8 parts of ethyl[2-cyano-2-[[4-(1-cyano-1-phenylethyl)phenyl]hydrazono]acetyl]carbamate, 1.98 parts of anhydrous potassium acetate and 120 parts of acetic acid was stirred and refluxed for 3 hours. The reaction mixture was concentrated to a volume of 30 parts. Water was added till the product was precipitated. It was sucked off, washed with water and dissolved in trichloromethane. The remaining water was separated and the organic phase was dried, filtered and evaporated, yielding 6.86 parts of 2-[4-(1-cyano-1-phenylethyl)phenyl]-2,3,4,5-tetrahydro-3,5-dioxo-1,2,4-triazine-6-carbonitrile as a residue (intermediate 65).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10]([CH2:13][C:14]#[N:15])(=[O:12])=[O:11])=[CH:5][CH:4]=1.[F:18][C:19]([S:22][CH2:23][CH2:24]OS(C(F)(F)F)(=O)=O)([F:21])[F:20]>>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][S:10]([CH:13]([CH2:24][CH2:23][S:22][C:19]([F:21])([F:20])[F:18])[C:14]#[N:15])(=[O:12])=[O:11])=[CH:7][CH:8]=1
Reactant: O=S(=O)(OCCSC(F)(F)F)C(F)(F)F
Reactant: N#CCS(=O)(=O)Cc1ccc(C(F)(F)F)cc1
Product: N#CC(CCSC(F)(F)F)S(=O)(=O)Cc1ccc(C(F)(F)F)cc1

Procedure:
Compound II-11 was prepared from (4-trifluoromethyl-phenylmethanesulfonyl)-acetonitrile and trifluoro-methanesulfonic acid 2-trifluoromethylsulfanyl-ethyl ester as described for compound II-1.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[CH:17]1([C:23](Cl)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(Cl)(=O)C>>[CH:17]1([C:23]([NH:1][C:2]2[N:3]=[CH:4][N:5]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[C:7]([NH2:9])=[O:8])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Solvent: CC(=O)Cl
Product: NC(=O)c1c(NC(=O)C2CCCCC2)ncn1Cc1ccccc1
Yield: 49 %

Procedure:
An amidation reaction and a post-treatment were carried out according to the conditions of Example 18, using 2.2 g (10 mmol) of 4-amino-1-benzyl-5-imidazolecarboxamide prepared in Reference Example 2 and cyclohexanecarbonyl chloride separately prepared according to a conventional method, instead of acetyl chloride, to obtain a crude crystals. The crude crystals were purified by suspension in hot methanol to obtain 1.62 g of 4-cyclohexylcarbonylamino-1-benzyl-5-imidazolecarboxamide (yield 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[CH:10]=[N:11][N:12]([CH:19]3[CH2:21][CH2:20]3)[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([CH3:32])[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=1>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:23][C:24]2[CH:25]=[C:26]([CH3:32])[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=2)[C:9]2[CH:10]=[N:11][N:12]([CH:19]3[CH2:21][CH2:20]3)[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(C(O)c2ccc(Cl)cc2)cnn1C1CC1
Reactant: Cc1cc(N)cn(C)c1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C(Nc2cc(C)c(=O)n(C)c2)c2ccc(Cl)cc2)cnn1C1CC1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-cyclopropyl-1H-pyrazole-5-carboxylate (Step 34.3) and 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2). tR: 4.78 min (HPLC 1); tR: 1.10 min (LC-MS 2); ESI-MS: 441 [M+H]+ (LC-MS 2); Rf=0.31 (EtOAc).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][O:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][C:47]=1B1OC(C)(C)C(C)(C)O1)[NH2:44].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[NH4+]>CN(C)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>[NH2:44][C:43]1[CH:45]=[CH:46][C:47]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)=[C:41]([O:40][CH3:39])[CH:42]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: COc1cc(N)ccc1B1OC(C)(C)C(C)(C)O1
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: [Cl-]
Solvent: CN(C)C=O
Product: COc1cc(N)ccc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Temperature: 90 °C
Reaction time: 5 h
Yield: 89.8 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (400 mg, 0.67 mmol) was dissolved in 6 mL N,N-dimethylformamide. 3-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (490 mg, 1.77 mmol, 90% purity), 2M sodium carbonate aqueous solution (0.81 mL, 1.62 mmols) and tetrakis(triphenylphosphine)palladium(0) (233 mg, 0.2 mmol) were added under argon atmosphere and the reaction mixture was stirred at 90° C. for 5 h. The reaction mixture was poured into a saturated ammonium chloride solution and extracted twice with water. The organics were washed with water, brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified using SP1® Purification System (0% to 100%, hexane-ethyl acetate) to give 383 mg (81% yield) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=O.C(O)(C(F)(F)F)=O>>[F:13][C:14]1[CH:15]=[C:16]([CH:17]2[C:5]3[NH:6][C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]=3[CH2:3][CH2:2][NH:1]2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(C=O)cc1F
Reactant: NCCc1c[nH]c2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2NCCc3c2[nH]c2ccccc32)cc1F
Yield: 58.5 %

Procedure:
This product was prepared using the same procedure as for Intermediate 1 with tryptamine (4.80 g, 30.0 mmol), 3-fluoro4-methoxybenzaldehyde (4.86 g, 1.05 equiv.) and TFA (4.6 mL, 2 equiv.) to give the title compound (5.2 g, 59%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=[S:11].Cl.C([O:15][C:16](=O)[CH2:17][NH:18][CH3:19])C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:16](=[O:15])[CH2:17][N:18]([CH3:19])[C:10]1=[S:11]
Reactant: CCOC(=O)CNC
Reactant: S=C=Nc1c(Cl)cccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN1CC(=O)N(c2c(Cl)cccc2Cl)C1=S
Yield: 87.8 %

Procedure:
The title compound was prepared by the procedure described in Example 1 using 14.28 g of 2,6-dichlorophenyl-isothiocyanate, 10.75 g of sarcosine ethyl ester hydrochloride, 14.5 g of triethyl amine, and 200 mL of chloroform. Crystallization from diethyl ether afforded the title compound (16.9 g) as a light peach solid, m.p. 207°-209° C. Anal. Calcd. for C10H8C12N2O S: C, 43.65; H, 2.93; N, 10.18. Found: C, 43.57; H, 2.61; N, 10.14. Mass spectrum (El, M.+) m/z 274.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12](OS(C(F)(F)F)(=O)=O)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[CH3:24][N:25]([CH3:29])[CH2:26][C:27]#[CH:28].C(N(CC)CC)C.CO.ClCCl>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([C:28]#[C:27][CH2:26][N:25]([CH3:29])[CH3:24])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: C#CCN(C)C
Reactant: CCOC(=O)c1oc2cccc(OS(=O)(=O)C(F)(F)F)c2c1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)c1oc2cccc(C#CCN(C)C)c2c1C
Yield: 65 %

Procedure:
To the product of Example 20, Step 1, 3-methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid ethyl ester (900 mg, 2.56 mmol, 1 eq), under nitrogen was added 1-dimethylamino-2-propyne (425 mg, 5.11 mmol, 2 eq), PdCl2(PPh3)2 (90 mg, 0.13 mmol, 0.05 eq), and triethylamine (1.4 mL, 10.23 mmol, 4 eq), in 25 mL of toluene. The reaction mixture was heated at reflux for 16 h until the reaction was complete by TLC. After work up and column chromatography (0-10% MeOH/dichloromethane), 4-(3-dimethylamino-prop-1-ynyl)-3-methyl-benzofuran-2-carboxylic acid ethyl ester was obtained in 65% yield (474 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.4 (t, J=7.1 Hz, 3 H) 2.3 (s, 6 H) 2.8 (s, 3 H) 3.6 (s, 2 H) 4.4 (q, J=7.1 Hz, 2 H) 7.4 (dd, J=7.3, 1.0 Hz, 1 H) 7.5 (m, 1 H) 7.7 (dd, J=8.2, 0.9 Hz, 1 H).
Reaction SMILES: Br[C:2]1[C:11]([NH2:12])=[CH:10][C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6]C)=O.O=C1CC(=O)CN(C(OCC2C=CC=CC=2)=O)C1.[CH3:32][N:33]1[CH2:45][C:44]2NC3C=CC=C4C(=O)[NH:47][N:48]=[C:35]([C:36]=2C=34)[CH2:34]1>>[F:13][C:9]1[CH:8]=[C:3]2[C:4](=[O:6])[NH:47][N:48]=[C:35]3[C:36]4[C:2]2=[C:11]([NH:12][C:44]=4[CH2:45][N:33]([CH3:32])[CH2:34]3)[CH:10]=1
Reactant: CN1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1
Reactant: COC(=O)c1cc(F)cc(N)c1Br
Agent: O=C1CC(=O)CN(C(=O)OCc2ccccc2)C1
Product: CN1CC2=NNC(=O)c3cc(F)cc4[nH]c(c2c34)C1

Procedure:
Compound 55 was prepared from methyl 2-bromo-5-fluoro-3-aminobenzoate and benzyl 3,5-dioxopiperidine-1-carboxylate according to the procedures similar to those for Compound 44. 1H NMR (DMSO-d6) δ 11.9 (s, 1H), 10.1 (s, 1H), 7.36 (dd, 1H, J=1.8, 9.6 Hz), 7.20 (dd, 1H, J=1.8, 10.2 Hz), 3.75 (s, 2H), 3.24 (s, 2H), 2.44 (s, 3H). MS (ESI) m/e [M+1]+ 259.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[O:18][C:19]2[C:25]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:24][CH:23]=[CH:22][C:20]=2[CH:21]=1)=[O:16])(C)(C)C.NC1C=CC=CC=1NC(C1SC2C=CC(OCC3C=CC=CN=3)=CC=2C=1)=O>>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[O:18][C:19]2[C:25]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:24][CH:23]=[CH:22][C:20]=2[CH:21]=1)=[O:16]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1cc2cccc(OCc3ccccn3)c2o1
Agent: Nc1ccccc1NC(=O)c1cc2cc(OCc3ccccn3)ccc2s1
Product: Nc1ccccc1NC(=O)c1cc2cccc(OCc3ccccn3)c2o1

Procedure:
was prepared from (2-{[7-(Pyridin-2-ylmethoxy)-benzofuran-2-carbonyl]-amino}-phenyl)-carbamic acid tert-butyl ester (54) in an analogous manner to that described for the preparation of (51) example 22, step 2; mp.: 105–135° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([OH:11])=[CH:6][C:3]=1[CH:4]=O.C([O:14][C:15](=O)[CH2:16][C:17]1[N:18]=[N:19][NH:20][N:21]=1)C.N1CCCCC1.C(O)(=O)C>CN(C=O)C>[OH:11][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][C:8]=1[OH:10])[O:1][C:15](=[O:14])[C:16]([C:17]1[N:18]=[N:19][NH:20][N:21]=1)=[CH:4]2
Reactant: CCOC(=O)Cc1nn[nH]n1
Reactant: O=Cc1cc(O)c(O)cc1O
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: O=c1oc2cc(O)c(O)cc2cc1-c1nn[nH]n1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 2,4,5-trihydroxybenzaldehyde (1.23 g), (2H-tetrazol-5-yl)-acetic acid ethyl ester (1.25 g), piperidine (1.36 g) and acetic acid (0.06 g) in DMF (10 ml) was stirred at 90° C. under nitrogen for two hours. After ice water treatment and acidification to pH 2 the product was filtered and triturated with hot ethanol. Yield: 0.55 g.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:41])[C@@H:6]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:7][C:8]1[CH:32]=[CH:31][C:11]([O:12][C:13]([NH:15][C@H:16]([C:28](O)=[O:29])[CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[C:42]([S:61][CH2:62][C@@H:63]([C:65]([NH2:67])=[O:66])[NH2:64])([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:4][C:5](=[O:41])[C@@H:6]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]([NH:15][C@H:16]([C:28]([NH:64][C@H:63]([C:65]([NH2:67])=[O:66])[CH2:62][S:61][C:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[O:29])[CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14])=[CH:31][CH:32]=1)[CH:2]=[CH2:3]
Reactant: NC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)N[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)N[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
1.50 g (2.59 mmol) of the compound from example 11A was dissolved in 60 ml dichloromethane. 0.940 g (2.59 mmol) S-Trityl-L-cysteinamide, 0.45 ml (2.60 mmol) N,N-diisopropylethylamine and 0.984 g (2.59 mmol) HATU were added. The reaction mixture was split into 3 portions. The portions were heated for 30 min in a sealed tube at 60° C. in a microwave synthesizer. From the combined reaction mixture the solvent was removed by rotary evaporation (approx. 40° C., approx. 200 mbar, approx. 30 min.). The raw product was dissolved in dichloromethane and chromatographed over approx. 400 ml silica gel. Solvents used were dichloromethane/ethyl acetate 2/1, dichloromethane/ethyl acetate 1/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 1.72 g (1.64 mmol, 63% of theory, 88% purity) of the desired product.