Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH:10]1[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]1=[O:12]>C(O)C>[O:12]=[C:11]1[N:13]2[CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:15]=[C:14]2[CH:16]=[CH:17][NH:10]1
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1cc[nH]c(=O)n1
Solvent: CCO
Product: CCOC(=O)c1cn2c(=O)[nH]ccc2n1
Yield: 14.1 %

Procedure:
Ethyl bromopyruvate (18.00 mmol, 3.51 g) was dissolved in ethanol (50 ml). Cytosine (18.00 mmol, 2 g) was added and the resulting mixture was refluxed for 5.5 h. The mixture was evaporated and DCM was added. The precipitate was filtered and washed with water. The filtrate was washed with NaHCO3, water and evaporated. The evaporation residue and the previously filtered precipitate were purified by flash chromatography and trituration from water, respectively. 0.526 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.31 (t, 3H), 4.29 (q, 2H), 6.60 (d, 1H), 7.30-7.38 (m, 1H), 8.22 (s, 1H), 11.77 (bs, 1H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:16][CH:13]([O:14][CH3:15])[CH2:12][C@@H:11]1[OH:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.C1(C)C=CC=CC=1.O.C(=O)([O-])[O-].[Ag+2]>[CH2:18]([O:17][C@@H:11]1[C@@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[O:16][CH:13]([O:14][CH3:15])[CH2:12]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC1C[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O1
Reactant: BrCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: COC1C[C@H](OCc2ccccc2)[C@@H](CO[Si](C)(C)C(C)(C)C)O1
Temperature: 65 °C

Procedure:
A mixture of 9.0 g. (0.034 mole) of methyl 5-O-(t-butyldimethylsilyl)-2-deoxyribofuranoside, 15 g (0.19 mole) of benzyl bromide, and 21 g (0.076 mole) silver carbonate in 50 ml dry dimethylformamide or other aprotic solvent is heated at 60° C. under a dry nitrogen atmosphere for five days. The mixture is cooled and the solids filtered. The filtrate is then concentrated at reduced pressure to 30 ml volume. To this are added 20 ml pyridine and the mixture heated at 65° C. for three hours. The solvents are again removed under reduced pressure affording a dark gummy residue which is taken up in a mixture of 150 ml toluene and 100 ml DI water. The organic phase is separated, washed with water (2×100 ml), dried (Na2SO4) and filtered. The solvent is removed at reduced pressure affording the methyl 3-O-benzyl-5-O-(t-butyldimethylsilyl)-2-deoxyribofuranoside compound as a red oil.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)[CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:14]=2)[NH:9][N:8]=1)=[O:5].C(N(CC)C(C)C)(C)C.[NH:45]1[CH:49]=[CH:48][CH:47]=[C:46]1[C:50](Cl)=[O:51]>ClCCl>[C:19]1([S:16]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[NH:9][N:8]=[C:7]3[NH:6][C:4]([C:3]2[CH:25]=[CH:26][C:27]([N:29]3[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]3)=[CH:28][C:2]=2[NH:1][C:50]([C:46]2[NH:45][CH:49]=[CH:48][CH:47]=2)=[O:51])=[O:5])(=[O:18])=[O:17])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(S(=O)(=O)c5ccccc5)cc34)c(N)c2)CC1
Reactant: O=C(Cl)c1ccc[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(S(=O)(=O)c5ccccc5)cc34)c(NC(=O)c3ccc[nH]3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.6 %

Procedure:
2-Amino-N-(5-benzenesulfonyl-1H-indazol-3-yl)-4-(4-methyl-piperazin-1-yl)-benzamide (245 mg, 0.5 mmol) was suspended in dichloromethane (10 mL), treated first with neat N,N-diisopropylethylamine (0.35 mL, 2 mmol) then with solid 1H-pyrrole-2-carbonyl chloride (258 mg, 2 mmol). The reaction was stirred at room temperature overnight then treated with additional acid chloride (258 mg) and N,N-diisopropylethylamine (0.35 mL). After two hours the solvent was removed under reduced pressure and the crude was taken up with tetrahydrofuran (30 mL) and treated with 2N NaOH (10 mL). After stirring overnight the solvent was removed and the solid was filtered and washed thoroughly with water. The crude was purified by flash chromatography over silica gel (eluent: ethyl acetate/methanol/aq.33% NH4OH in 9:1:0.1 ratio) to give 60 mg of title compound.
Reaction SMILES: [C:1]([NH:3][C:4](=[NH:12])OC1C=CC=CC=1)#[N:2].[CH:13]1([NH2:23])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1>CCOCC>[C:1]([NH:3][C:4](=[NH:12])[NH:23][CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1)#[N:2]
Reactant: N#CNC(=N)Oc1ccccc1
Reactant: NC1CCCc2ccccc21
Solvent: CCOCC
Product: N#CNC(=N)NC1CCCc2ccccc21
Temperature: 220 °C

Procedure:
A 25 ml round bottom flask containing a mixture of 4.8 g of N-cyano-O-phenylisourea and 6 g of 1,2,3,4-tetrahydro-1-naphthylamine was placed in an oil bath preheated to 190° C. The bath temperature was raised to 220° C. over 20 minutes and maintained at 220° C. for 8 minutes. Upon cooling, the reaction mixture had a glass-like appearance. The product was isolated from the reaction mixture by thorough shaking of the reaction mixture with ether to remove the remaining starting materials and phenol, and decanting the ether solution which left the crude product as a white gummy residue. The crude product was further purified by chromatography on a column packed with silica gel and eluting initially with toluene then with toluene-ethyl acetate mixtures with gradual increase in the ethyl acetate content. This gave 4.61 g of the desired compound that had satisfactory data in spectroscopic analysis.
Reaction SMILES: [I:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN=C=NCCCN(C)C.[NH2:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[OH:33]>N1C=CC=CC=1>[OH:33][C:24]1[CH:25]=[CH:26][C:27]([C:29]([F:30])([F:31])[F:32])=[CH:28][C:23]=1[NH:22][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][N:9]=[CH:10][C:2]=1[I:1]
Reactant: O=C(O)c1ccncc1I
Reactant: Nc1cc(C(F)(F)F)ccc1O
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Product: O=C(Nc1cc(C(F)(F)F)ccc1O)c1ccncc1I
Temperature: 50 °C
Yield: 68.3 %

Procedure:
A mixture of 1.78 g of 3-iodo-isonicotinic acid, 1.38 g of WSC and 12 ml of pyridine was stirred while heating at 50° C. for 15 minutes. Then, 1.15 g of 2-amino-4-(trifluoromethyl)phenol was added to the reaction mixture. The reaction mixture was stirred while heating at 80° C. for two hours. The reaction mixture was returned to room temperature, and concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give 1.81 g of N-[2-hydroxy-5-(trifluoromethyl)phenyl]-3iodo isonicotinamide.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].Cl[C:9]1[C:18]([CH3:19])=[C:17]([Cl:20])[C:16]2[C:11](=[CH:12][C:13]([F:22])=[CH:14][C:15]=2[F:21])[N:10]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>CC(O)(C)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:20][C:17]1[C:16]2[C:11](=[CH:12][C:13]([F:22])=[CH:14][C:15]=2[F:21])[N:10]=[C:9]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)[C:18]=1[CH3:19]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: O=C1CNCCN1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1c(N2CCNC(=O)C2)nc2cc(F)cc(F)c2c1Cl
Temperature: 100 °C
Reaction time: 4 h

Procedure:
The piperazin-2-one (161 mg, 1.613 mmol) and 2,4-dichloro-5,7-difluoro-3-methylquinoline (400.0 mg, 1.613 mmol) were dissolved in t-BuOH (7.00 mL) and heated in the microwave at 100° C. for 30 min. Only a trace amount of product present. Potassium carbonate (557 mg, 4.03 mmol) was added and the mixture heated in the microwave at 100° C. for 45 min. Again, only a trace amount of product was observed. The 2-(dicyclohexylphosphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (123 mg, 0.258 mmol) and Pd2(dba)3 (59.1 mg, 0.065 mmol) was then added and the mixture was stirred in the microwave at 120° C. for 4 h. The reaction was then diluted with water (˜50 mL) and the mixture was extracted with EtOAc (1×100 mL), DCM (1×100 mL) and 10% MeOH:DCM (1×100 mL). The combined organic layers were dried over magnesium sulfate and the crude product was purified by medium pressure chromatography (silica, 0 to 10% 2M ammonia in MeOH:DCM) to give 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)piperazin-2-one. Mass Spectrum (ESI) m/e=312.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[NH:40]N>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:40][C:35]3[C:36]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:37][CH:38]=[CH:39][C:34]=3[CH3:33])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1NN
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(Br)c3)CC2)c1
Agent: Cl
Product: Cc1cccc2c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3cccc(Br)c3)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(2-methylphenyl)hydrazine hydrochloride: ESMS m/e: 572 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([C@@H:17]2[CH2:19][C@H:18]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:16])=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([C@@H:17]4[CH2:19][C@H:18]4[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH3:16])=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)[C@@H]1C[C@H]1c1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)[C@@H]4C[C@H]4c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[trans-1-(2-phenyl-cyclopropyl)-ethyl]-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@@H:13]([CH3:14])[CH2:12][N:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=O)=[CH:18][CH:17]=2)[CH2:10][C@H:9]1[CH3:28])=[O:7])([CH3:4])[CH3:3].C1CCC(N=C=NC2CCCCC2)CC1.ON1C2C=CC=CC=2N=N1.[F:54][C:55]1[CH:60]=[CH:59][C:58]([NH:61][CH:62]2[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]2)=[CH:57][CH:56]=1.C(O)C(N)(CO)CO.[N-]=C=O>CN(C=O)C.C(Cl)Cl>[F:54][C:55]1[CH:60]=[CH:59][C:58]([NH:61][CH:62]2[CH2:67][CH2:66][N:65]([C:23](=[O:25])[C:22]([C:19]3[CH:18]=[CH:17][C:16]([CH2:15][N:11]4[CH2:12][C@H:13]([CH3:14])[N:8]([C:6]([O:5][C:2]([CH3:3])([CH3:1])[CH3:4])=[O:7])[C@H:9]([CH3:28])[CH2:10]4)=[CH:21][CH:20]=3)([CH3:26])[CH3:27])[CH2:64][CH2:63]2)=[CH:57][CH:56]=1
Reactant: C[C@@H]1CN(Cc2ccc(C(C)(C)C(=O)O)cc2)C[C@H](C)N1C(=O)OC(C)(C)C
Reactant: Fc1ccc(NC2CCNCC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC(CO)(CO)CO
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(C(C)(C)C(=O)N3CCC(Nc4ccc(F)cc4)CC3)cc2)C[C@H](C)N1C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
A mixture of D48 (100 mg, 0.256 mmol), polymer-supported DCC (296 mg, 1.3 mmol/g, 0.385 mmol) and 1-hydroxybenzotriazole (18 mg, 0.128 mmol) in 1:4 DMF/DCM (5 ml) was treated with D2 (50 mg, 0.256 mmol) and the mixture stirred overnight. Scavenger resins (PS-trisamine, PS-isocyanate and Si-carbonate) were added, the mixture was shaken for 2 h and then filtered and concentrated to give 1,1-dimethylethyl (2R,6S)-4-{[4-(2-{4-[(4-fluorophenyl)amino]-1-piperidinyl}-1,1-dimethyl-2-oxoethyl)phenyl]methyl}-2,6-dimethyl-1-piperazinecarboxylate, MS (ES): MH+ 567. This whole was treated with 4M HCl in 1,4-dioxane (2 ml) for 1 h. The solvents were removed in vacuo to give the dihydrochloride salt of the title compound (115 mg). MS (ES): MH+ 467.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14]([CH3:16])[CH3:15])/[C:10](=[C:17](\[C:21]3[CH:25]=[C:24]([CH3:26])[O:23][C:22]=3[CH3:27])/[CH:18]([CH3:20])[CH3:19])/[C:9]2=[O:28])=[CH:4][CH:3]=1.[C:29](Cl)(=[O:32])[CH:30]=[CH2:31]>ClCCl.C(N(CC)CC)C>[C:29]([O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14]([CH3:16])[CH3:15])/[C:10](=[C:17](\[C:21]3[CH:25]=[C:24]([CH3:26])[O:23][C:22]=3[CH3:27])/[CH:18]([CH3:20])[CH3:19])/[C:9]2=[O:28])=[CH:4][CH:3]=1)(=[O:32])[CH:30]=[CH2:31]
Reactant: CC(C)=C1C(=O)N(c2ccc(O)cc2)C(=O)/C1=C(/c1cc(C)oc1C)C(C)C
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)Oc1ccc(N2C(=O)C(=C(C)C)/C(=C(\c3cc(C)oc3C)C(C)C)C2=O)cc1
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a solution obtained by dissolving 1.13 g of n-(4-hydroxyphenyl)-2-[(E)-1-(2,5-dimethyl-3-furyl)isobutylidene]-3-isopropylidenesuccinimide obtained in Example 18 in 30 ml of dichloromethane, 0.62 ml of triethylamine, followed by dropwise addition of 0.36 ml of acryloyl chloride in 10 minutes. The reaction was carried out at room temperature for additional 30 minutes with stirring. After the reaction, the reaction solution was well washed with water, dried over anhydrous magnesium sulfate, and subjected to removal of the solvent by distillation. The resulting residue was purified by column chromatography (filler: Wakogel C-300, eluent: a mixed solvent of n-hexane and ethyl acetate) to give yellow crystals of N-(4-acryloyloxyphenyl)-2-[(E)-1-(2,5-dimethyl-3-furyl) isobutylidene]-3-isopropylidenesuccinimide in yield of 60%.
Reaction SMILES: [C:1]([C:3]1[S:11][C:6]2[S:7][CH2:8][CH2:9][NH:10][C:5]=2[CH:4]=1)#[N:2].C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20].C(OCC)(=O)C>ClCCl.O>[C:19]([N:10]1[CH2:9][CH2:8][S:7][C:6]2[S:11][C:3]([C:1]#[N:2])=[CH:4][C:5]1=2)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: N#Cc1cc2c(s1)SCCN2
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)N1CCSc2sc(C#N)cc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 6-cyano-2,3-dihydrothieno[2,3-b][1,4]thiazine (0.3 g) and triethylamine (0.46 ml) in dichloromethane (10 ml) was dropwise added acetyl chloride (0.23 ml). After stirring for 5 hours at room temperature, the reaction mixture was poured into a mixture of ethyl acetate and water. The organic layer was successively washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was pulverized from diisopropyl ether to give 1-acetyl-6-cyano-2,3-dihydrothieno [2,3-b][1,4] thiazine (0.33 g)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]2[CH:24]=[C:23](B3OC(C)(C)C(C)(C)O3)[C:22]([C:34]3[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=3)=[N:21]2)=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]2[CH:24]=[C:23]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[NH:8][CH:9]=[CH:10][C:3]=34)[C:22]([C:34]3[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=3)=[N:21]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(Cn2cc(B3OC(C)(C)C(C)(C)O3)c(-c3ccc([N+](=O)[O-])cc3)n2)cc1
Reactant: Brc1ccnc2[nH]ccc12
Product: COc1ccc(Cn2cc(-c3ccnc4[nH]ccc34)c(-c3ccc([N+](=O)[O-])cc3)n2)cc1

Procedure:
Following the procedure described for Intermediate 6 with 4-bromo-1H-pyrrolo[2,3-b]pyridine and 1-{[4-(methyloxy)phenyl]methyl}-3-(4-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole provided the title compound. ESMS [M+H]+: 426.2
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:10]([O-])=O)=[C:4]([OH:9])[CH:5]=[C:6]([OH:8])[CH:7]=1.[H][H]>CO.[Pd]>[NH2:10][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([OH:8])=[CH:5][C:4]=1[OH:9]
Reactant: [H][H]
Reactant: Cc1cc(O)cc(O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(O)cc(O)c1N

Procedure:
2.43 g (14.4 mmol) 5-methyl-4-nitrobenzene-1,3-diol were placed in 200 mL methanol and hydrogenated under a hydrogen atmosphere and with the addition of 0.20 g Pd/C (10%) at 50° C. and a hydrogen pressure of 5 bar until all the hydrogen had been taken up. The catalyst was filtered off and the filtrate was evaporated down i.vac.
Reaction SMILES: [CH2:1]([CH2:5][C:6](=O)[CH3:7])[C:2]([CH3:4])=O.[Cl:9][C:10]1[CH:21]=[C:20]([C:22]2[CH:23]([CH3:29])[NH:24][C:25](=[O:28])[NH:26][N:27]=2)[CH:19]=[CH:18][C:11]=1[O:12][CH2:13][C:14]([NH:16][NH2:17])=[O:15]>C(O)(=O)C>[Cl:9][C:10]1[CH:21]=[C:20]([C:22]2[CH:23]([CH3:29])[NH:24][C:25](=[O:28])[NH:26][N:27]=2)[CH:19]=[CH:18][C:11]=1[O:12][CH2:13][C:14]([NH:16][N:17]1[C:6]([CH3:7])=[CH:5][CH:1]=[C:2]1[CH3:4])=[O:15]
Reactant: CC(=O)CCC(C)=O
Reactant: CC1NC(=O)NN=C1c1ccc(OCC(=O)NN)c(Cl)c1
Solvent: CC(=O)O
Product: Cc1ccc(C)n1NC(=O)COc1ccc(C2=NNC(=O)NC2C)cc1Cl
Temperature: 70 °C
Yield: 64 %

Procedure:
0.27 g of acetonylacetone was added to a solution of 0.5 g of α-[2-chloro-4-(2,3,4,5-tetrahydro-5-methyl-3-oxo-1,2,4-triazin-6-yl)phenoxy]acetohydrazide (prepared as described in Example 13) dissolved in 5 ml of acetic acid, and the mixture was heated at 70° C. for 4 hours. The acetic acid used as the solvent was removed by evaporation under reduced pressure, and the residue was mixed with water to precipitate crystals. These crystals were collected by filtration, washed with water and dried. The product was purified by column chromatography through silica gel (eluent: a 98:2 by volume mixture of methylene chloride and ethanol), followed by recrystallization from ethanol to give 0.4 g of the title compound melting at 189°-190° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:25])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CCCCCC.CCOC(C)=O>[Br:25][C:8]1[NH:9][C:10]2[C:15]([C:7]=1[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ccc(Cc2c[nH]c3ccccc23)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(Cc2c(Br)[nH]c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2 g of 3-(4-chlorobenzyl)-1H-indole in 50 mL of CCl4 was added 1.8 g of NBS. The reaction mixture was stirred for 1 hour at room temperature and diluted with 50 mL of 5:1 hexane/EtOAc. The mixture was then filtered through a pad of silica gel and the filtrate was concentrated under reduced pressure to give the crude title compound, which was used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.N1C=CC=CC=1.[C:18](Cl)(=[O:22])[CH:19]([CH3:21])[CH3:20].C(=O)(O)O>ClCCl>[C:18]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1)(=[O:22])[CH:19]([CH3:21])[CH3:20]
Reactant: CCOC(=O)c1csc(N)n1
Reactant: CC(C)C(=O)Cl
Agent: O=C(O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1csc(NC(=O)C(C)C)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cold mixture of ethyl 2-amino-1,3-thiazole-4-carboxylate (2 g) prepared in a similar manner according to Step 1 of the following Production Example 7, pyridine (1.3 ml) and dichloromethane (20 ml) was added isobutyryl chloride (0.91 ml) and stirred for 30 minutes. To the mixture was added saturated aqueous hydrogen bicarbonate (30 ml), and the organic layer was separated, dried over sodium sulfate and concentrated in vacuo. The crystalline residue was collected and washed with ethyl acetate to give ethyl 2-(isobutyrylamino)-1,3-thiazole-4-carboxylate (1.34 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11])[CH3:2].[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([Cl:21])=[CH:16][N:15]=1>>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:16]1[C:17]([Cl:21])=[CH:18][N:19]=[C:14]([Cl:13])[N:15]=1)[CH3:2]
Reactant: CCOC(=O)c1ccccc1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Product: CCOC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl

Procedure:
2-(2,5-Dichloro-pyrimidin-4-ylamino)-benzoic acid ethyl ester was prepared from 2-amino-benzoic acid ethyl ester and 2,4,5-trichloro-pyrimidine in an analogous manner to Example 308b. Product isolated as a white solid (2.28 g, 27%). m.p.=156-157° C.; LCMS (m/e) 312 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 11.68 (bs, 1H), 8.91 (d, 1H, J=8.6 Hz), 8.28 (s, 1H), 8.14 (d, 1H, J=8.0 Hz), 7.70-7.62 (m, 1H), 7.22-7.13 (m, 1H), 4.45 (q, 2H, J=7.1 Hz), 1.46 (t, 3H, J=7.1 Hz).
Reaction SMILES: [CH:1]1([C:10]([OH:12])=[O:11])[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][NH:2]1.C([O-])([O-])=O.[Na+].[Na+].[Cl:19][C:20]1[CH:21]=[C:22]([S:27](Cl)(=[O:29])=[O:28])[CH:23]=[C:24]([Cl:26])[CH:25]=1.Cl>O>[Cl:26][C:24]1[CH:23]=[C:22]([S:27]([N:2]2[CH2:3][CH:4]3[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]3)[CH:1]2[C:10]([OH:12])=[O:11])(=[O:28])=[O:29])[CH:21]=[C:20]([Cl:19])[CH:25]=1
Reactant: O=C(O)C1NCC2CCCCC21
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C1C2CCCCC2CN1S(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Yield: 192.7 %

Procedure:
Octahydroisoindole-1-carboxylic acid (4.12 gm) was dissolved in a solution of water (125 mL) containing 5.32 g of Na2CO3. Upon complete dissolution, 4.93 g of 3,5-dichlorobenzenesulfonyl chloride was added. The reaction was stirred at rt over night. The reaction mixture was then washed with EtOAc (2×100 mL). The aqueous layer was isolated and acidified to pH=3 by the dropwise addition of a concentrated HCl solution. A solid precipitate formed in the aqueous layer and was filtered and dried in vacuo to afford N-(3,5-dichlorobenzenesulfonyl)-octahydro-isoindole-1-carboxylic acid (14.64 g) as a white solid.
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.[CH2:31]([O:33][CH2:34][C:35](O)=[O:36])[CH3:32]>>[NH2:16][C:15]1[C:10]2[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][N:7]([C@H:5]3[CH2:4][C@H:3]([CH2:2][NH:1][C:35](=[O:36])[CH2:34][O:33][CH2:31][CH3:32])[CH2:6]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: CCOCC(=O)O
Reactant: NC[C@H]1C[C@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Product: CCOCC(=O)NC[C@H]1C[C@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1

Procedure:
trans-N-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-2-ethoxy-acetamide is prepared starting from trans-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine and ethoxy-acetic acid (Fluka, Buchs, Switzerland) according to a procedure known in the art (M. Bodanszky in Principles of Peptide Synthesis, Akad.-Verlag, 1984). Analytical HPLC: tR=7.07 min (Grad 2); ES-MS: m/eo=486.2.