Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH2:30][CH:31]([F:33])[F:32])=[C:6]([C:8]2[C:9]3[N:10]([N:14]=[C:15]([NH:17][C:18]4[CH:28]=[CH:27][C:21]5[CH2:22][CH2:23][NH:24][CH2:25][CH2:26][C:20]=5[CH:19]=4)[N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH:7]=1.Cl[CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH2:30][CH:31]([F:33])[F:32])=[C:6]([C:8]2[C:9]3[N:10]([N:14]=[C:15]([NH:17][C:18]4[CH:28]=[CH:27][C:21]5[CH2:22][CH2:23][N:24]([CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37])[CH2:25][CH2:26][C:20]=5[CH:19]=4)[N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH:7]=1
Reactant: CN(C)C(=O)CCl
Reactant: FC(F)COc1ccc(Cl)cc1-c1cccn2nc(Nc3ccc4c(c3)CCNCC4)nc12
Product: CN(C)C(=O)CN1CCc2ccc(Nc3nc4c(-c5cc(Cl)ccc5OCC(F)F)cccn4n3)cc2CC1

Procedure:
2-(7-{8-[5-Chloro-2-(2,2-difluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-N,N-dimethyl-acetamide was prepared from {8-[5-chloro-(2,2-difluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-(2,3,4,5-tetrahydro-1H-3-benzazepin-7yl)-amine (0.075 g, 0.160 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.025 mL, 0.239 mmol) in a manner analogous to Example 313 to give product (0.030 g, 34%). MP=190-191° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.54 (s, 1H), 8.78 (d, 1H), 7.80 (s, 1H), 7.65 (d, 1H), 7.50 (m, 3H), 7.30 (d, 1H), 7.05 (m, 2H), 6.25 (br m, 1H), 4.35 (m, 2H), 3.22 (s, 2H), 3.05 (s, 3H), 3.75 (m, 7H), 2.55 (m, 4H). MS=556 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1.[NH2:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24]>>[ClH:1].[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24])=[CH:3][C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: NCC(O)CO
Reactant: COc1ccc2c(Cl)cc(-c3ccccc3)nc2c1
Product: COc1ccc2c(NCC(O)CO)cc(-c3ccccc3)nc2c1
Product: Cl

Procedure:
The title compound, m.p. 218-222° C., and MS: m/e=325.3 (M+H+), was prepared from 4-chloro-7-methoxy-2-phenyl-quinoline and (RS)-3-amino-1,2-propandiol.
Reaction SMILES: [O:1]=[C:2]([N:14]1[CH2:19][CH2:18][CH2:17][CH:16]([O:20][Si](C(C)(C)C)(C)C)[CH2:15]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(O)(=O)C.O1CCCC1.[OH-].[Na+]>O>[O:1]=[C:2]([N:14]1[CH2:19][CH2:18][CH2:17][CH:16]([OH:20])[CH2:15]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCC(=O)N1CCCC(O[Si](C)(C)C(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCCCCCCCCC(=O)N1CCCC(O)C1
Temperature: 75 °C

Procedure:
Mix 1-oxododecyl-3-(O-tert-butyldimethylsilyloxy)piperidine (3.5 mmol) with a solution of acetic acid (9 mL), tetrahydrofuran (6 mL) and water (6 mL). Heat at 75° C. overnight. Cool to room temperature and make basic with cold 10% sodium hydroxide and extract into methylene chloride. Wash with water, then with brine and dry (Na2SO4). Evaporate the solvent in vacuo and purify by flash chromatography (5% methanol/methylene chloride) to give the title compound.
Reaction SMILES: COC1C=CC=C(C=1)C([O:21][C:22]([C:37]1[CH:42]=[CH:41]C=[CH:39][CH:38]=1)([C:29]1[CH:34]=[C:33](OC)[CH:32]=[CH:31][CH:30]=1)C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl[CH:45](Cl)C(O)=O.[CH3:50][N:51](C)[CH:52]=[O:53]>>[N:51]([C:50]1[CH:39]=[CH:38][C:37]([C:22]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=2[CH3:45])=[O:21])=[CH:42][CH:41]=1)=[C:52]=[O:53]
Reactant: O=C(O)C(Cl)Cl
Reactant: COc1cccc(C(OC(c2ccccc2)(c2ccccc2)c2cccc(OC)c2)(c2ccccc2)c2ccccc2)c1
Reactant: CN(C)C=O
Product: Cc1ccccc1C(=O)c1ccc(N=C=O)cc1

Procedure:
Modification of 5′-amino DNA: DNA to serve as the 3′-probe, carrying a 5′-deoxy-5′-amino nucleoside, is prepared by standard solid phase synthesis according to standard protocols. Phosphoramidites, including the 5′-amino nucleoside analog where the 5′-amino group is protected as a 5′-monomethoxytrityl ether, are available from Glen Research. The final detritylation will be done with 2% dichloroacetic acid for 15 min. The product is then treated with the isocyanato derivative in dimethylformamide at 25° C. The products are then purified by standard oligonucleotide HPLC (reversed phase C-18, water-acetonitrile eluant).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.N1C=CC=CC=1.[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14]>ClCCCl>[N+:13]([C:16]1[CH:17]=[CH:18][C:19]([C:20]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[O:21])=[CH:23][CH:24]=1)([O-:15])=[O:14]
Reactant: Nc1nccs1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: O=C(Nc1nccs1)c1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Yield: 96 %

Procedure:
2-Aminothiazole (100 mmol) was suspended in 1,2-dichloroethane (200 mL) and pyridine (100 mmol) was added. The mixture was added portion wise to a suspension of 4-nitro benzoic acid chloride (150 mmol) in 1,2-dichloroethane (500 mL) and stirred at 60° C. over night. The reaction mixture was cooled and filtered. The filtrate was washed with 1,2-dichloroethane and dried in vacuo to give 4-nitro-N-thiazol-2-yl-benzamide.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([OH:12])=[CH:7][C:6]=1[CH3:13])=O.[NH2:14][C:15]([NH2:17])=[S:16]>CCO>[NH2:17][C:15]1[S:16][CH:2]=[C:3]([C:5]2[C:10]([CH3:11])=[CH:9][C:8]([OH:12])=[CH:7][C:6]=2[CH3:13])[N:14]=1
Reactant: NC(N)=S
Reactant: Cc1cc(O)cc(C)c1C(=O)CBr
Solvent: CCO
Product: Cc1cc(O)cc(C)c1-c1csc(N)n1
Yield: 79 %

Procedure:
A mixture of 2-bromo-1-(4-hydroxy-2,6-dimethylphenyl)ethanone (5-1, 2.43 g, 10.0 mmol) and thiourea (1.37 g, 18.0 mmol) in 95% EtOH (30 mL) was heated at reflux for 120 min. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and washed with a solution of 50% EtOAc in hexanes. The solids were dried under vacuum to give 4-(2-aminothiazol-4-yl)-3,5-dimethylphenol (5-2, 1.74 g) as pale yellow solids in 79% yield: 1H NMR (500 MHz, CDCl3) δ 8.7 (s, 2 H), 6.17 (s, 2 H), 5.97 (s, 1 H), 1.71 (s, 6 H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[CH2:20][CH2:19][C:18]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:11][C:10]=3[CH2:9]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(Cl)(Cl)Cl>[CH2:9]1[C:10]2[NH:11][C:12]3[C:17]([C:18]=2[CH2:19][CH2:20][N:8]1[CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:2][CH2:3]1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: c1ccc2c3c([nH]c2c1)CN(CC1CCNCC1)CC3
Reactant: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(CN2CCc3c([nH]c4ccccc34)C2)CC1

Procedure:
7.06 g (26.2 mmol) of 2-[(4-piperidyl)methyl]-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole, 70 ml of chloroform and 4 ml (26.2 mmol) of triethylamine are introduced under an argon atmosphere into a Keller flask, and 2.8 ml (26.2 mmol) of ethyl chloroformate are added.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11](Cl)=[C:12]([F:17])[CH:13]=2)[N:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:7]=1)=[O:5])[CH3:2].Cl.[F:24][C:25]([F:37])([F:36])[C:26]([N:28]1[CH:33]2[CH2:34][CH2:35][CH:29]1[CH2:30][NH:31][CH2:32]2)=[O:27].N12CCCN=C1CCCCC2>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([N:31]3[CH2:32][CH:33]4[N:28]([C:26](=[O:27])[C:25]([F:36])([F:37])[F:24])[CH:29]([CH2:35][CH2:34]4)[CH2:30]3)=[C:12]([F:17])[CH:13]=2)[N:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:7]=1)=[O:5])[CH3:2]
Reactant: O=C(N1C2CCC1CNC2)C(F)(F)F
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc(Cl)c(F)cc2c1=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cn(C(C)(C)C)c2nc(N3CC4CCC(C3)N4C(=O)C(F)(F)F)c(F)cc2c1=O
Temperature: 60 °C
Yield: 22.1 %

Procedure:
A mixture of 653 mg (2 mmoles) 1-(1,1-dimethylethyl)-1,4-dihydro-6-fluoro-7-chloro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester and 732 mg (3 mmoles) 8-trifluoroacetyl-3,8-diazabicyclo[3.2.1]octan, hydrochloride and 985 mg (6.48 mmoles) 1,8-diazabicyclo[5.4.0] undec-7-ene in 30 mL acetonitrile was heated at 60° C. for 72 hours. The solution was cooled and evaporated to dryness. The residue was worked up with dichloromethane and water. The organic layer was dried over magnesium sulfate and evaporated to give an oil. Purification was achieved by silicagel column chromatography to obtain 220 mg of 7-(8-trifluoroacetyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-1-(1,1-dimethylethyl)-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester. MP 205° C.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:36])[N:10]([CH2:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1[C:24]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[C:26]([CH2:32][C:33]([OH:35])=[O:34])[CH:25]=1)[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:37]([O:44][C:45]([C@@H:47]1[C@@H:52]([OH:53])[C@H:51]([OH:54])[C@@H:50]([OH:55])[C@H:49](O)[O:48]1)=[O:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C[N+]1([O-])CCOCC1>CC#N>[CH2:37]([O:44][C:45]([C@@H:47]1[C@@H:52]([OH:53])[C@H:51]([OH:54])[C@@H:50]([OH:55])[C@H:49]([O:34][C:33](=[O:35])[CH2:32][C:26]2[CH:25]=[C:24]([C:15]3[CH:16]=[CH:17][C:18]([C:20]([F:22])([F:23])[F:21])=[CH:19][C:14]=3[CH2:13][N:10]([CH2:11][CH3:12])[C:9]([NH:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:36])[C:29]([O:30][CH3:31])=[CH:28][CH:27]=2)[O:48]1)=[O:46])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: O=C(OCc1ccccc1)[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)NCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[N+]1([O-])CCOCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O[C@@H]2O[C@H](C(=O)OCc3ccccc3)[C@@H](O)[C@H](O)[C@H]2O)ccc1OC)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
[2′-(3-Benzyl-1-ethyl-ureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid (0.110 g, 0.2 mmol), (2S,3S,4S,5R,6R)-3,4,5,6-tetrahydroxy-tetrahydro-pyran-2-carboxylic acid benzyl ester (0.060 g, 0.2 mmol), HATU (0.026 g, 0.2 mmol), and N-methylmorpholine-N-oxide (0.05 mL, 0.4 mmol) were combined in MeCN (2 mL) and stirred for 2 days at room temperature. The mixture was concentrated, and the residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: [ClH:1].[CH2:2]([C:9]1[N:10]=[C:11]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:12]2[CH2:18][CH2:17][N:16](CC3C=CC=CC=3)[CH2:15][C:13]=2[N:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1CC=CCC=1>CCO.[Pd]>[ClH:1].[CH2:2]([C:9]1[N:10]=[C:11]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[C:12]2[CH2:18][CH2:17][NH:16][CH2:15][C:13]=2[N:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Fc1ccc(-c2nc(Cc3ccccc3)nc3c2CCN(Cc2ccccc2)C3)cc1
Agent: [Pd]
Agent: Cl
Solvent: C1=CCC=CC1
Solvent: CCO
Product: Fc1ccc(-c2nc(Cc3ccccc3)nc3c2CCNC3)cc1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
To a solution of 2,7-dibenzyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride in EtOH was added 10% Pd/C (1 equiv) followed by 1,4-cyclohexadiene (5 equiv). The mixture was heated at 85° C. for 5 h, filtered and concentrated. The residue was dissolved in CH2Cl2 and treated with Dowex 550A resin. After 1 h, the resin was removed by filtration and the filtrate was concentrated. Chromatography on SiO2 (2 M NH3 in MeOH/CH2Cl2) afforded the title compound. MS (ESI): exact mass calcd. for C20H18FN3, 319.15; m/z found, 320.4 [M+H]+. 1H NMR (MeOH-d4): 7.70-7.67 (m, 2H), 7.36-7.35 (m, 2H), 7.31-7.25 (m, 4H), 7.20-7.17 (m, 1H), 4.42 (s, 2H), 4.26 (s, 2H), 3.48 (t, J=6.1, 2H), 3.09 (t, J=6.1, 2H). The compounds in Examples 77-81 were prepared using methods similar to those described in Example 76.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:6]=1[C:21]1[NH:22][C:23](=[O:38])[C:24]2[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:28][N:27]([CH2:36][CH3:37])[C:25]=2[N:26]=1)[CH3:3].[CH2:39](O)CC>>[NH3:14].[CH2:36]([N:27]1[C:25]2[N:26]=[C:21]([C:6]3[CH:7]=[C:8]([S:11]([N:14]4[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]4)(=[O:12])=[O:13])[CH:9]=[CH:10][C:5]=3[O:4][CH2:2][CH2:3][CH3:39])[NH:22][C:23](=[O:38])[C:24]=2[C:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:28]1)[CH3:37]
Reactant: CCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nc2c(c(-c3ccccc3)nn2CC)c(=O)[nH]1
Reactant: CCCO
Agent: [Na]
Product: CCCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nc2c(c(-c3ccccc3)nn2CC)c(=O)[nH]1
Product: N

Procedure:
A suspension of sodium (25 mg, 1.1 mmol) in n-propanol (1 ml) was added to the title compound of example 6 (80 mg, 0.15 mmol) in n-propanol (1 ml), and the reaction mixture heated under reflux for 72 hours. Further sodium (100 mg, 4.34 mmol) and n-propanol (5 ml) were added portionwise over a further 48 hours, then the mixture cooled and evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel, using dichloromethane:methanol:0.88 ammonia (95:5:0.5) as eluant, to afford the title compound, (8 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[CH3:10][O-:11].[Na+]>CO>[CH3:10][O:11][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9]
Reactant: C[O-]
Reactant: OCCCCCCCBr
Agent: [Na+]
Solvent: CO
Product: COCCCCCCCO
Temperature: 90 °C
Reaction time: 7 h

Procedure:
A mixture of 7-bromo-1-heptanol (25 g) and sodiummethoxide, 28% solution in methanol (37 ml) in methanol (250 ml) was stirred for 7 hours at 90° C. After being cooled to room temperature, the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of dichloromethane and methanol (100:1→25:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give 7-methoxy-1-heptanol (18.2 g).
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]([N:9]1[CH2:16][C:15]([OH:26])([CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C.N>>[OH:26][C:15]1([CH2:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:16][N:9]([C:7](=[O:8])[CH2:6][CH2:5][SH:4])[C@H:10]([C:11]([OH:13])=[O:12])[CH2:14]1
Reactant: CC(=O)SCCC(=O)N1CC(O)(CCCc2ccccc2)C[C@H]1C(=O)O
Agent: N
Product: O=C(O)[C@@H]1CC(O)(CCCc2ccccc2)CN1C(=O)CCS

Procedure:
The product from part (b) is treated with concentrated ammonia according to the procedure of Example 2 to yield 4-hydroxy-1-(3-mercapto-1-oxopropyl)-4-(phenylpropyl)-L-proline.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([OH:11])=[CH:9][C:8](=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[N:6]=1)=O.C(O)(=O)C.[NH3:27]>CO>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([N:7]2[C:8](=[O:12])[CH:9]=[C:10]([OH:11])[C:5]([C:3]([NH2:27])=[O:2])=[N:6]2)[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: N
Reactant: COC(=O)c1nn(-c2ccc(OC)c(OC)c2)c(=O)cc1O
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(-n2nc(C(N)=O)c(O)cc2=O)cc1OC

Procedure:
The pyridazine (29) (295 mg) was dissolved in 3 ml of 7N NH3 in methanol and heated to reflux in a sealed tube for 4 hours. The reaction was allowed to cool, neutralized with acetic acid, and concentrated to dryness to give 266 mg of desired amide (30) as a solid. MS+: m/e=292.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:11])=[O:10])=[CH:4][CH:3]=1.[S:12](=[O:15])(=[O:14])=[O:13]>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([S:12]([OH:15])(=[O:14])=[O:13])[C:9]([Cl:11])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)=O
Reactant: Cc1ccc(CC(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(C(C(=O)Cl)S(=O)(=O)O)cc1
Temperature: 25 °C

Procedure:
A solution of 4-methylphenylacetyl chloride (1.69 g, 10 mmole) in dichloromethane (20 ml) was treated with a suspension of sulphur trioxide--dioxane complex (15 mmole) in dichloromethane. The mixture was stirred at room temperature for eighteen hours and evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[OH:21][CH:22]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([N:24]2[CH2:25][CH2:26][CH2:27][CH:22]([OH:21])[CH2:23]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: OC1CCCNC1
Product: O=C(c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1)N1CCCC(O)C1

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (150 mg, 0.43 mmol) and 3-hydroxyl piperidine (52 mg, 0.52 mmol). The title compound was obtained as a solid (22 mg, 12% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.97 (2H, m), 7.99 (1H, m), 4.96 (1H, m), 3.61 (3H, m), 1.72 (2H, m), 1.49 (2H, m). MS m/z: 434.08, 436.03 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:25])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([O:8][C:16](=[O:25])[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: Oc1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1ccccc1)Oc1cccc(Cl)c1
Reaction time: 0.5 h

Procedure:
To a solution of 3-chlorophenol (1, 50.1 g, 0.3 mol), triethylamine (TEA, 85 mL), and CH2Cl2 (500 mL) at 23° C. was added hydrocinnamoyl chloride (2, 31 mL, 0.3 mol) over 5 minutes. After 30 minutes, the reaction mixture was concentrated in vacuo. The crude slurry was then dissolved in 10:1 hexanes:EtOAc (300 mL) and washed with 1 N NaOH (100 mL) and brine (100 mL). The organic layer was dried (MgSO4) and filtered through a plug of silica gel (10:1 hexanes:EtOAc rinse). The eluent was concentrated to afford 78 g of a slightly yellow oil, which was used without any further purification.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([O:26][C@@H:27]1[C@@:31]2([CH2:51][O:52][C@H:28]1[C@H:29]([N:53]1[C:68]3[N:67]=[C:60]([NH:61][C:62](=[O:66])[CH:63]([CH3:65])[CH3:64])[NH:59][C:57](=[O:58])[C:56]=3[N:55]=[CH:54]1)[O:30]2)[CH2:32][O:33][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH2:19]([O:26][C@@H:27]1[C@@:31]2([CH2:51][O:52][C@H:28]1[C@H:29]([N:53]1[C:68]3[N:67]=[C:60]([NH:61][C:62](=[O:66])[CH:63]([CH3:64])[CH3:65])[NH:59][C:57](=[O:58])[C:56]=3[N:55]=[CH:54]1)[O:30]2)[CH2:32][OH:33])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@@H]2O[C@@]3(CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)CO[C@@H]2[C@@H]3OCc2ccccc2)c(=O)[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1nc2c(ncn2[C@@H]2O[C@@]3(CO)CO[C@@H]2[C@@H]3OCc2ccccc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
Tetrabutylammonium fluoride (1.0 M in THF, 0.90 ml, 0.90 mmol) was added, at room temperature, to a tetrahydrofuran solution (3.0 ml) of Compound 46 (41.3 mg, 0.060 mol), and the mixture was stirred for 1 hour at room temperature. The reaction mixture was distilled under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (AcOH-EtOH, 20:1) to obtain a white powder, Compound 47 (27.1 mg, 0.060 mmol, quant.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.N1C=CC=CC=1.[CH2:16]([O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](Cl)=[O:39])=[CH:33][CH:32]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(Cl)Cl.C(Cl)(Cl)Cl>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][CH2:2][NH:1][C:38](=[O:39])[CH2:37][C:34]1[CH:35]=[CH:36][C:31]([O:30][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:32][CH:33]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)Cl)cc1
Reactant: NCCc1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)NCCc2ccccn2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 44.9 %

Procedure:
To a 0° C. solution of 5.24 g of 2-(2-aminoethyl)pyridine, 13.22 ml of pyridine and 50 ml of methylene chloride is added, dropwise, 15 g of product from Example 53 in 150 ml of methylene chloride. The reaction is stirred at 0° C. for 4 hours followed by 68 hours at room temperature. The reaction is diluted with chloroform, washed with saturated sodium bicarbonate, water and saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel:75-100% ethyl acetate/hexane) to give 8.3 g of the desired product as colorless prisms.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][NH:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:37][C:38](O)=[O:39])[CH:23]=[CH:24][C:25]=1[NH:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH3:36])=[O:28].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:37][C:38]([N:1]2[CH2:5][CH2:4][CH2:3][CH:2]2[CH2:6][NH:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[O:39])[CH:23]=[CH:24][C:25]=1[NH:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH3:36])=[O:28]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: COC(=O)c1ccc(NCC2CCCN2)cc1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NCC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
The mixture of the above methyl 4-(2-pyrrolidinylmethylamino)benzoate (397.8 mg, 1.69 mmol), 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (587.1 mg, 1.87 mmol), EDC (HCl) (486 mg, 2.54 mmol), HOBt (23 mg, 0.17 mmol), and DMAP (21 mg, 0.17 mmol) in DMF (4 mL) was stirred overnight at room temp. The mixture was diluted with EtOAc, washed with brine, and dried over Na2SO4. The solvent was removed under a reduced pressure. The residue was chromatographed on-silica-gel with CHCl3-MeOH (50:1, v/v) as eluent to afford 882 mg (98%) methyl 4-[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl methylamino]benzoate as a brown amorphous solid, which is used to the subsequent reaction without further purification.