Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:10][CH:9]2[CH:5]([CH2:6][CH2:7][CH2:8]2)[CH:4]1[CH2:11][NH:12][C:13](=[O:27])[C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([NH:21]C(=O)C)=[CH:16][C:15]=1[O:25][CH3:26])[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([N:3]1[CH2:10][CH:9]2[CH:5]([CH2:6][CH2:7][CH2:8]2)[CH:4]1[CH2:11][NH:12][C:13](=[O:27])[C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([NH2:21])=[CH:16][C:15]=1[O:25][CH3:26])[CH3:2]
Reactant: CCN1CC2CCCC2C1CNC(=O)c1cc(Cl)c(NC(C)=O)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN1CC2CCCC2C1CNC(=O)c1cc(Cl)c(N)cc1OC

Procedure:
7 parts of N-ethyl-2-(2-methoxy-4-acetylamino-5-chloro benzamido methyl)-3-azabicyclo (3,3,0) octane were heated for 30 minutes in the presence of 17.7 parts of a 2N solution of sodium hydroxide and 15 parts of ethanol. After cooling, the precipitate was filtered and recrystallized in 40 parts of acetonitrile. There were obtained 5 parts of N-ethyl-2-(2-methoxy-4-amino-5-chloro benzamido methyl)-3-azabicyclo (3,3,0) octane, M.P. 128°-129° C.
Reaction SMILES: F[C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[O:22]1[CH2:23][CH2:24][N:19]([C:2]2[CH:18]=[CH:17][C:5]([C:6]([C:8]3[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=3)=[O:7])=[CH:4][CH:3]=2)[CH2:20][CH2:21]1
Reactant: O=C(c1ccc(F)cc1)c1ccc([N+](=O)[O-])cc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(c1ccc(N2CCOCC2)cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 105 °C
Yield: 91.3 %

Procedure:
A mixture containing 4-(4-fluorobenzoyl)-nitrobenzene (1.96 9, 8 mmol), morpholine (0.84 g, 9.6 mmol), and potassium carbonate (1.33 g, 9.6 mmol) in dimethyl sulfoxide (15 mL) was heated to 100-110° C. for 12 hours. The reaction mixture was cooled to room temperature and diluted with cold water, and filtered. The crude product was washed several times with water and dried to give 4-(4-morpholinobenzoyl)-nitrobenzene (2.28 g, 91%), m.p. 173-175° C., and was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12]([OH:15])(=O)=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.CN(C=O)C.S(Cl)([Cl:23])=O>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([S:12]([Cl:23])(=[O:15])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(O)c1cccc2c(Cl)nccc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1cccc2c(Cl)nccc12

Procedure:
A suspension of 1-chloro-5-isoquinolinesulphonic acid (1.14 g, 4.68 mmol) in thionyl chloride (13 mL) and DMF (0.3 mL, 3.9 mmol) was heated to reflux for 3 h. Concentration in vacuo and azeotroping with toluene gave 1-chloro-5-chlorosulphonylisoquinoline as an off-white solid which was used immediately.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=[C:25]([C:28]4[CH:29]=[N:30][N:31]([CH2:33][CH2:34][NH:35][CH2:36][CH2:37]O)[CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH:42]1(N)[CH2:46]C[CH2:44][CH2:43]1.NCCO>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:37]1([CH2:36][NH:35][CH2:34][CH2:33][N:31]2[CH:32]=[C:28]([C:25]3[CH:26]=[C:27]4[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=3)[NH:21][CH:20]=[C:19]4[CH:16]3[CH2:15][CH2:14][N:13]([S:10]([CH2:8][CH3:9])(=[O:11])=[O:12])[CH2:18][CH2:17]3)[CH:29]=[N:30]2)[CH2:44][CH2:43][CH2:42][CH2:46]1
Reactant: NC1CCCC1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cnn(CCNCCO)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: NCCO
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cnn(CCNCC5CCCC5)c4)cc23)CC1
Yield: 40 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)amino]ethyl}1H-pyrazol-4-yl)-1H-indole-7-carboxamide trifluoroacetate, substituting cyclopentanamine (37 mg, 0.43 mmol) for the 2-aminoethanol to afford 11 mg of the title compound (40%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].[C:20]1([CH3:31])[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29]Br)=[CH:22][CH:21]=1>O1CCCC1>[CH2:9]([O:8][C:6](=[O:7])[C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH2:29][CH2:28][CH2:27][CH2:26][C:23]1[CH:22]=[CH:21][C:20]([CH3:31])=[CH:25][CH:24]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:17])[CH3:10]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: Cc1ccc(CCCCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCCCc1ccc(C)cc1)(C(=O)OCC)c1ccccc1
Yield: 55 %

Procedure:
Phenylmalonic acid diethyl ester (8.8 mmol) dissolved in 5 ml absolute tetrahydrofuran is added dropwise to 20 ml absolute tetrahydrofuran and sodium hydride (9.7 mmol). Then 4-p-tolylbutyl bromide (8.8 mmol) dissolved in 10 ml absolute tetrahydrofuran is added after 15 minutes. It is heated for 3 days under reflux. The solvent is concentrated in a vacuum. The residue is taken up in 50 ml ethyl acetate and extracted with 2×50 ml water. The organic phase is dried over magnesium sulfate, filtered and concentrated by evaporation. It is purified by chromatography on silica gel (heptane/ethyl acetate 9:1). Yield 55% colourless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.Br[C:18]1[CH:19]=[C:20]([C:23]#[N:24])[O:21][CH:22]=1>>[CH3:1][C:2]1([CH3:16])[O:3][C:4](=[O:15])[NH:5][C:6]2[CH:11]=[CH:10][C:9]([C:18]3[CH:19]=[C:20]([C:23]#[N:24])[O:21][CH:22]=3)=[CH:8][C:7]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: N#Cc1cc(Br)co1
Product: CC1(C)OC(=O)Nc2ccc(-c3coc(C#N)c3)cc21

Procedure:
4-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-furan-2-carbonitrile was prepared from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 4-bromo-2-furancarbonitrile according to Procedure B. Off-white solid: mp 255-256° C. 1H-NMR (DMSO-d6) δ 10.32 (s, 1H, D2O exchangeable), 8.57 (s, 1H), 8.15 (s, 1H), 7.61 (s, 1H), 7.55 (dd, 1H, J=8.3, 1.5 Hz), 6.92 (d, 1H, J=8.2 Hz), 1.65 (s, 6H); MS (ESI) m/z 269 (M+H, 72%). Anal. Calcd. For C15H12N2O3: C, 67.16, H, 4.51, N, 10.44. Found: C, 67.14, H, 4.59, N, 10.07.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:4][C:5]2[O:9][C:8](I)=[C:7]([C:11]([NH:13][CH3:14])=[O:12])[C:6]=2[CH:15]=1.C([O-])([O-])=O.[K+].[K+].[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1>CN(C=O)C>[Br:1][C:2]1[C:3]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:4][C:5]2[O:9][C:8]([N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)=[C:7]([C:11]([NH:13][CH3:14])=[O:12])[C:6]=2[CH:15]=1
Reactant: c1c[nH]cn1
Reactant: CNC(=O)c1c(I)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-n2ccnc2)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 60 °C
Yield: 80.2 %

Procedure:
To a degassed solution of 5-bromo-2-iodo-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (100 mg, 0.21 mmol) and K2CO3 (43 mg, 0.31 mmol) in DMF (1 mL) was added 1H-imidazole (14 mg, 0.21 mmol) under N2 at 0° C. The mixture was heated at 60° C. for 10 hours. The reaction mixture was concentrated and it was extracted with EtOAc. The residue was washed with H2O, brine, dried over Na2SO4. After being concentrated, the crude product was purified by column (PE:EA=1:1) to give of 5-bromo-2-(1H-imidazol-1-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (72 mg, yield: 83%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.40 (d, J=4.4 Hz, 1H), 8.36 (s, 1H), 8.10 (s, 2H), 7.80 (s, 1H), 7.19 (s, 1H), 3.21 (s, 3H), 3.20 (s, 3H), 2.81 (d, J=4.4 Hz, 3H). MS (M+H)+: 427/429.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]#[N:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)=O.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>>[N:14]1([CH2:1][C:3]2[CH:8]=[CH:7][C:6]([C:9]3([C:12]#[N:13])[CH2:11][CH2:10]3)=[CH:5][CH:4]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNC1
Reactant: N#CC1(c2ccc(C=O)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: N#CC1(c2ccc(CN3CCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(4-formylphenyl)cyclopropanecarbonitrile (0.30 g, 0.0018 mol), pyrrolidine (0.18 mL, 0.0021 mol) and sodium triacetoxyborohydride (0.74 g, 0.0035 mol) in methanol (5.0 mL, 0.12 mol) was stirred ar rt for 1 h. The reaction mixture was adjusted to be basic (pH=12) and extracted with ethyl acetate. The combined organic extract was washed with brine, dried and concentrated to provide the desired product. LC-MS: 227.1 (M+H)+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([CH:16]=O)=[N:14][N:13]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][O:19]4)[C:10]3=[N:11][CH:12]=2)[CH:2]=1.[F:24][C:25]1[CH:26]=[C:27]([C:31]2[C:32]([NH2:38])=[C:33]([NH2:37])[CH:34]=[N:35][CH:36]=2)[CH:28]=[CH:29][CH:30]=1.[S]>C(O)CCC>[F:24][C:25]1[CH:26]=[C:27]([C:31]2[C:32]3[N:38]=[C:16]([C:15]4[C:9]5[C:10](=[N:11][CH:12]=[C:7]([C:3]6[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=6)[CH:8]=5)[N:13]([CH:18]5[CH2:23][CH2:22][CH2:21][CH2:20][O:19]5)[N:14]=4)[NH:37][C:33]=3[CH:34]=[N:35][CH:36]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: Nc1cncc(-c2cccc(F)c2)c1N
Reactant: O=Cc1nn(C2CCCCO2)c2ncc(-c3cccnc3)cc12
Agent: [S]
Solvent: CCCCO
Product: Fc1cccc(-c2cncc3[nH]c(-c4nn(C5CCCCO5)c5ncc(-c6cccnc6)cc45)nc23)c1
Temperature: 25 °C

Procedure:
A solution of 5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde (CXXXI) (65 mg, 0.21 mmol), 5-(3-fluorophenyl)pyridine-3,4-diamine (LXXV) (45 mg, 0.22 mmol) and sulfur (7 mg, 0.22 mmol) in n-butanol (10 mL) was heated at reflux overnight. The solution was cooled to room temperature, filtered and the solvent was evaporated under reduced pressure to give crude 3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine (CXXXII). CXXXII was dissolved in dry DCM (5 mL) before adding triethylsilane (84 μL, 0.52 mmol) and TFA (2.5 mL). The reaction was stirred at room temperature for 2 h under argon. The solvent was evaporated under reduced pressure; the residue was taken up water (10 mL), and basified with 5N NH4OH. The precipitates were filtered, washed by cold water and dried under vacuum at room temperature. The crude product was suspended in DCM (10 mL), sonicated briefly and then heated to boiling for 5 min. The solution was cooled to room temperature and the solids were filtered, washed with DCM and dried under vacuum at room temperature to produce 3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-5-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine (3) as a yellow solid (53 mg, 0.13 mmol, 62% yield). 1H NMR (DMSO-d6) δ ppm 7.25-7.34 (m, 1H), 7.54-7.65 (m, 2H), 8.11-8.21 (m, 1H), 8.23-8.30 (m, 1H), 8.37-8.50 (m, 1H), 8.63-8.70 (m, 1H), 8.70-8.80 (m, 1H), 9.02-9.09 (m, 2H), 9.09-9.15 (m, 1H), 13.94 (brs, 1H), 14.59 (s, 1H); ESIMS found for C23H14FN7 m/z 408.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH2:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)[CH2:14][CH3:15]>>[CH2:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1)[CH2:14][CH3:15]
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCCc1ccc(S(=O)(=O)Nc2nc(CC(=O)OCC)cs2)cc1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-n-propylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (16.0 mg) with purity >90%. LCMS (pos) m/z 369.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:16][C@H:17]2[O:21][C:20]([CH3:23])([CH3:22])[N:19]([C:24]([O:26][C@H:27]3[C@H:34]4[C@H:30]([O:31][CH2:32][CH2:33]4)[O:29][CH2:28]3)=[O:25])[C@H:18]2[CH2:35][C:36]2[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=2)[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:50][C:51]1[CH:52]=[C:53]([CH:56]=[CH:57][CH:58]=1)[C:54]#[N:55].CCOCC>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:16][C@H:17]2[O:21][C:20]([CH3:22])([CH3:23])[N:19]([C:24]([O:26][C@H:27]3[C@H:34]4[C@H:30]([O:31][CH2:32][CH2:33]4)[O:29][CH2:28]3)=[O:25])[C@H:18]2[CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:42][CH2:50][C:51]3[CH:58]=[CH:57][CH:56]=[C:53]([C:54]#[N:55])[CH:52]=3)=[CH:40][CH:41]=2)[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)CN(C[C@H]1OC(C)(C)N(C(=O)O[C@@H]2CO[C@H]3OCC[C@H]32)[C@H]1Cc1ccc(O)cc1)S(=O)(=O)c1ccc(N)cc1
Reactant: N#Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)CN(C[C@H]1OC(C)(C)N(C(=O)O[C@@H]2CO[C@H]3OCC[C@H]32)[C@H]1Cc1ccc(OCc2cccc(C#N)c2)cc1)S(=O)(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.5 %

Procedure:
To a stirred mixture of (3S,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (4S,5R)-5-{[[(4-aminophenyl)sulfonyl](isobutyl)amino]methyl}-4-(4-hydroxybenzyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (40 mg, 0.07 mmol) and cesium carbonate (22 mg, 0.07 mmol) in 1.5 mL of N,N-dimethylformamide was added 3-bromomethylbenzonitrile (13 mg, 0.07 mmol). The mixture was stirred at room temperature for 12 hours followed by dilution with 25 mL of ether. The ether was extracted with water (5×15 mL). The organic phase was dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on silica gel using ethyl acetate-hexanes (8.5:1.5) as eluent to provide 41 mg (85%) of the title compound. 1H-NMR (DMSO-d6): δ 0.80-0.86 (6H,dd), 1.37 (3H,s), 1.48,1.55 (3H,s)*, 1.75 (2H,m), 1.94 (1H,m), 2.58-2.78 (6H,m), 2.92-3.09 (2H,m), 3.15-3.21 (1H,m), 3.61 (2H,m), 3.81 (1H,m), 4.14 (1H,m), 4.74 (1H,q), 5.17 (2H,s), 5.53,5.57 (1H,d)*, 5.99 (2H,s,b), 6.58 (2H,d), 6.95 (2H,d), 7.11,7.14 (2H,d)*, 7.22,7.28 (2H,d)*, 7.60 (1H,t), 7.80 (2H,m,b), 7.91 (1H,s).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[OH-].[Na+].[CH3:17]I.Cl>C(O)C>[CH3:17][S:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: CI
Reactant: O=C(O)c1cc(S)cc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1cc(C(=O)O)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 10 g. (0.045 mole) of 3-mercapto-5-trifluoromethylbenzoic acid, and 100 ml. of 1N sodium hydroxide in 100 ml. of ethanol is added 3.8 ml. (0.06 mole) of methyl iodide. After the reaction has stirred at room temperature for one hour, it is acidified with 12N hydrochloric acid, and the precipitate of the final product is filtered and dried,8.6 g., m.p. 135°-140° C. A sample is sublimed at 175° C. and 0.03 mm pressure, m.p. 151°-152.5° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.C(O[CH:13]1[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:20][C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)(=O)C>C1C=CC=CC=1>[N:4]1([CH2:3][CH2:2][NH:1][CH:13]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[O:20][C:21]3[C:26]2=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:8]=[CH:7][N:6]=[CH:5]1
Reactant: NCCn1ccnc1
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Solvent: c1ccccc1
Product: c1ccc2c(c1)Oc1ccccc1C2NCCn1ccnc1

Procedure:
A solution of 1.86 g. of 1-(2-aminoethyl)imidazole and 4.0 g. of 9-acetoxyxanthene dissolved in 100 ml. of dry benzene was refluxed for 24 hours. After cooling the solution was washed with 5% aqueous sodium carbonate solution and water, then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was redissolved in ether and deposited white crystals which were filtered and recrystallized from benzene-hexane to give N-[2-(1-imidazolyl)ethyl]-9-xanthenylamine, m.p. 90°-92° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:17])[C:3]([NH:5][CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)=[O:4].[N+:18]([C:21]1[CH:51]=[CH:50][C:24]([CH2:25][O:26][C:27]([N:29]=[C:30]([NH:36][C:37](=[O:49])[O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=2)N2C=CC=N2)=[O:28])=[CH:23][CH:22]=1)([O-:20])=[O:19]>O1CCCC1>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([CH2:25][O:26][C:27]([N:29]=[C:30]([NH:36][C:37]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=2)=[O:49])[NH:1][C@@H:2]([CH3:17])[C:3]([NH:5][CH:6]2[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]2)=[O:4])=[O:28])=[CH:50][CH:51]=1)([O-:20])=[O:19]
Reactant: O=C(N=C(NC(=O)OCc1ccc([N+](=O)[O-])cc1)n1cccn1)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@H](N)C(=O)NC1CN(C(=O)OC(C)(C)C)C1
Solvent: C1CCOC1
Product: C[C@H](NC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)NC1CN(C(=O)OC(C)(C)C)C1
Yield: 98.6 %

Procedure:
To a solution of tert-butyl 3-[(2S)-2-amino-2-methylacetylamino]-1-azetidinecarboxylate (557 mg) in anhydrous tetrahydrofuran (10 ml), a solution of 4-nitrobenzyl [(4-nitrobenzyloxy)carbonylimino-pyrazol-1-ylmethyl]carbamate (974 mg) in tetrahydrofuran (20 ml) was added. The reaction mixture was then treated in a similar manner to that described in Referential Example 16-(1), whereby 1.32 g of the title compound were obtained as an amorphous substance.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([O:11][C:12]([Sn](CCCC)(CCCC)CCCC)=[CH2:13])[CH3:10]>CN(C=O)C.CCOC(C)=O.[F-].[K+].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>[Br:8][C:5]1[CH:4]=[N:3][C:2]([C:9]([O:11][CH2:12][CH3:13])=[CH2:10])=[CH:7][N:6]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1cnc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C(OCC)c1cnc(Br)cn1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 67.6 %

Procedure:
To a solution of 2,5-dibromopyrazine (1 g, 4.20 mmol) in DMF was added 1-ethoxyvinyltri-n-butyltin (1.420 mL, 4.20 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.148 g, 0.210 mmol). The reaction mixture was heated at 100° C. for 4 hrs. The reaction mixture was diluted with EtOAc and aq. KF. The two phase mixture was stirred for 20 min at rt before being filtered through diatomaceous earth (Celite®). The filtrate was washed with sat. NaHCO3, sat. NaCl, dried over anhydrous Na2SO4, concentrated. The crude product was purified by silica gel chromatography (0-100% EtOAc in hexane) to yield 2-bromo-5-(1-ethoxyvinyl)pyrazine (0.65 g). LC/MS (Cond. N-1): [M+H]+ 229.05, RT=3.799 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[CH:14]([NH:17][C:18](=[O:22])[CH2:19][C:20]#[N:21])([CH3:16])[CH3:15]>>[CH:14]([NH:17][C:18](=[O:22])[C:19]([C:20]#[N:21])=[CH:5][C:4]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]([OH:10])=[C:2]([OH:1])[CH:3]=1)([CH3:16])[CH3:15]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: CC(C)NC(=O)CC#N
Product: CC(C)NC(=O)C(C#N)=Cc1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
The procedure described in Example 99 was repeated using 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 1.3 g of N-isopropylcyanoacetamide. Yield 1.46 g (50%), m.p. 243-245° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[CH3:14][CH:15]([N:19]=[C:20]=S)[CH:16]([CH3:18])[CH3:17]>C(OCC)(=O)C>[Cl:8][C:6]1[C:5]([Cl:9])=[CH:4][C:3]2[S:10](=[O:12])(=[O:11])[N:13]=[C:20]([NH:19][CH:15]([CH3:14])[CH:16]([CH3:18])[CH3:17])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)c(Cl)cc1S(N)(=O)=O
Reactant: CC(C)C(C)N=C=S
Solvent: CCOC(C)=O
Product: CC(C)C(C)NC1=NS(=O)(=O)c2cc(Cl)c(Cl)cc2N1

Procedure:
The title compound was prepared from 2-amino-4,5-dichlorobenzenesulfonamide and 1,2-dimethylpropyl isothiocyanate by a method analogous to the one described in Example 4; m.p. 242-250° C. (ethyl acetate); 1H-NMR (DMSO-d6): δ 0.90 (d, 3H, CH3), 0.91 (d, 3H, CH3), 1.10 (d, 1H, CH3), 1.77 (m, 1H, CH(CH3)2), 3.71 (m, 1H, NHCH), 7.29 (br., 1H, NH), 7.49 (br.s, 1H, ArH), 7.89 (s, 1H, ArH), 10.41 (br.s, 1H, NH); MS: m/e 335/337/339 (M+); (C12H15N3Cl2O2S1) calc. C, 42.87; H, 4.50; N, 12.50; found C, 42.94; H, 4.68; N, 12.45.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH2:14][C:15](=[O:19])[NH:16][CH2:17][CH3:18])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:13]([CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH2:14][C:15]([NH:16][CH2:17][CH3:18])=[O:19])=[CH:22][CH:23]=1
Reactant: CCNC(=O)CN(Cc1ccc(Cl)cc1)C1CCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)CN(Cc1ccc(Cl)cc1)C1CCNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-[(4-chloro-benzyl)-ethylcarbamoylmethyl-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.12 g, 0.31 mmol) in dichloromethane cooled at 0° C. was treated with trifluoroacetic acid (20%) The resulting mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The combined organics were dried over sodium sulfate. The product was used without any further purification. ESI-MS m/z: 296 (M+1), UV retention time: 1.02 min.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[OH-].[K+].[OH:7][C:8]1[C:17]([CH:18]=[O:19])=[C:16]([O:20][CH3:21])[CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11].Cl>CS(C)=O>[CH2:1]([O:7][C:8]1[C:17]([CH:18]=[O:19])=[C:16]([O:20][CH3:21])[CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11])[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc(OC)c(C=O)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: C=CCOc1c(C(=O)OC)ccc(OC)c1C=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.1 %

Procedure:
At room temperature, 23.2 g (0.192 mol) of allyl bromide were added dropwise to a mixture of 21.0 g (0.375 mol) of potassium hydroxide and 20.2 g (0.096 mol) of methyl 2-hydroxy-3-formyl-4-methoxybenzoate in 500 ml of dimethyl sulfoxide, and the mixture was stirred at room temperature for 4 hours. The mixture was subsequently stirred into 1.5 l of 3% strength aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic phases were washed with water and dried, and the solvent was removed. Silica gel chromatography using cyclohexane/ethyl acetate=1:2 gave 7.7 g (36%) of methyl 2-allyloxy-3-formyl-4-methoxybenzoate in the form of a yellowish oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[SH:10].Cl[C:12]([CH2:14]Cl)=[CH2:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[C:3]2[S:10][C:12]([CH3:14])=[CH:13][C:4]=2[C:5]([F:9])=[C:6]([F:8])[CH:7]=1
Reactant: C=C(Cl)CCl
Reactant: Fc1cc(S)c(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc2c(F)c(F)cc(Br)c2s1
Temperature: 60 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
2-Bromo-4,5-difluorothiophenol (4.68 g, 20.8 mmol), 2,3-dichloro-1-propene (2.1 mL, 22.9 mmol), potassium carbonate (3.45 g, 24.9 mmol), and acetone (100 mL) were added, and stirred at 60° C. for 2 hours. The solvent was distilled away under reduced pressure, and after diluted with ethyl acetate, the resultant was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away, and to the resulting residue, dimethylaniline (50 mL) was added, and stirred at 220° C. overnight. After cooling, ethyl acetate and a 2 N hydrochloric acid aqueous solution were added to the reaction solution and stirred. After the insoluble material was filtered off, extraction was performed with ethyl acetate. The organic phase was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane) to thus obtain the title compound.