Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:31])[C@@H:5]([CH3:30])[CH2:6][C@H:7]([NH:22][C:23](=[O:29])[CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:11][CH:10]=1)C.[OH-].[Na+].Cl>CCO>[C:26]([CH2:25][CH2:24][C:23]([NH:22][C@H:7]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:11][CH:10]=1)[CH2:6][C@H:5]([CH3:30])[C:4]([OH:31])=[O:3])=[O:29])([OH:28])=[O:27]
Reactant: CCOC(=O)[C@@H](C)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)CCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@@H](C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)CCC(=O)O)C(=O)O
Yield: 59.8 %

Procedure:
To a stirred solution of (2S,4S)-4-(3-carboxy-propionylamino)-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester (25 mg, 0.056 mmol) in 2 ml EtOH was added 1 ml of aqueous 1M NaOH and the solution was stirred for an hour. The reaction mixture was acidified to pH=2 to 3 with aqueous 1M HCl. Solvent was removed under reduced pressure and the residue was purified by RP-HPLC to give 14 mg (2S,4S)-4-(3-carboxy-propionylamino)-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid. MS m/z 418.2 (M+H), 416.2 (M−H). LC/MS (Condition A): 1.18 min 1H NMR (400 MHz, DMSO-d6): 0.98-1.00 (d, J=6.82 Hz, 3H), 1.39-1.45 (m, 1H), 1.71-1.78 (m, 1H), 2.18-2.38 (m, 5H), 2.67-2.76 (m, 2H), 3.97-4.07 (m, 1H), 7.26-7.28 (d, J=8.34 Hz, 2H), 7.38-7.41 (m, 1H), 7.45-7.49 (t, J=7.83 Hz, 1H), 7.60-7.64 (m, 3H), 7.70-7.71 (t, J=1.77 Hz, 1H), 7.75-7.77 (d, J=8.84 Hz, 1H), 12.08 (br s, 2H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[N:20]=[C:21]([CH3:24])[O:22][C:23]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.[F:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:36]=1[NH:35][CH:34]=[C:33]2[C:37]1[CH2:38][CH2:39][NH:40][CH2:41][CH:42]=1>CS(C)=O.C(OCC)(=O)C>[F:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:36]=1[NH:35][CH:34]=[C:33]2[C:37]1[CH2:38][CH2:39][N:40]([CH2:12][CH:13]2[O:14][C:15]3[C:16](=[CH:17][CH:18]=[C:19]4[N:20]=[C:21]([CH3:24])[O:22][C:23]4=3)[O:25][CH2:26]2)[CH2:41][CH:42]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)oc4c3O2)cc1
Reactant: Fc1cccc2c(C3=CCNCC3)c[nH]c12
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1nc2ccc3c(c2o1)OC(CN1CC=C(c2c[nH]c4c(F)cccc24)CC1)CO3
Temperature: 80 °C

Procedure:
[(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-yl]methyl 4-methylbenzenesulfonate (0.50 g, 1.31 mmole) and 7-fluoro-3-(1,2,3,6-tetrahydro4-pyridinyl)-1H-indole (1.0 g, 4.6 mmole) were combined in 10 mL of DMSO under nitrogen. This solution was heated at 80° C. under nitrogen for six hours. After completion, the reaction was cooled to room temperature and diluted to 400 mL with ethyl acetate. The organic phase was washed with 400 mL portions of saturated aqueous sodium bicarbonate, water and saturated brine and concentrated in vacuum. The crude residue was column chromatographed on silica gel using 1% methanol/chloroform to give 0.50 g of the (S)-enantiomer of the title compound, which was a yellow solid (m.p. 208-210° C.) after evaporation of the solvent.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([OH:27])=O)[CH:4]=[N:3]1.[CH3:28][NH:29][CH2:30][C:31]1[CH:32]=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=1.C(N(C(C)C)CC)(C)C.CCCP(=O)=O>O1CCCC1>[CH3:28][N:29]([CH2:30][C:31]1[CH:32]=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=1)[C:25]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]([NH:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:17]=[C:11]2[CH:10]=1)=[O:24])=[O:27]
Reactant: CNCc1ccc(C)nc1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(CN(C)C(=O)c2cnn(C)c2C(=O)Nc2ccn3nc(-c4ccccc4)nc3c2)cn1
Temperature: 70 °C
Reaction time: 20 h
Yield: 93.5 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 μmol), N-methyl-1-(6-methylpyridin-3-yl)methanamine (50 mg, 367 μmol), diisopropylethylamine (145 μl, 828 μmol) and propylphosphonic anhydride (50% in ethyl acetate, 407 μl, 690 μmol) in tetrahydrofurane (7.00 ml) is stirred for 20 hours at 70° C. under nitrogen atmosphere. The solvent is evaporated and to the residue is added sat. aqueous sodium hydrogencarbonate solution. The mixture is stirred for 20 minutes while a white solid precipitates. The solid is collected by filtration, washed with diethylether and dried affording N4,1-dimethyl-N4-((6-methylpyridin-3-yl)methyl)-N5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-4,5-dicarboxamide (124 mg, 93.5%) as a white solid. mp.: 110-150° C. MS: m/z=481.4 (M+H+).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:23][C:22]([C:24]([O:26]C)=[O:25])=[CH:21][C:9]=3[N:10]([CH2:18][O:19][CH3:20])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CO>[CH:1]1([C:7]2[C:8]3[S:23][C:22]([C:24]([OH:26])=[O:25])=[CH:21][C:9]=3[N:10]([CH2:18][O:19][CH3:20])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COCn1c(-c2ccccc2)c(C2CCCCC2)c2sc(C(=O)OC)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COCn1c(-c2ccccc2)c(C2CCCCC2)c2sc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 21 h
Yield: 93 %

Procedure:
A solution (0.1 M) of methyl 6-cyclohexyl-4-(methoxymethyl)-5-phenyl-4H-thieno[3,2-b]pyrrole-2-carboxylate in THF/MeOH (1:1) was treated with aqueous NaOH (1 N solution, 5 eq.). The mixture was stirred at RT for 21 h then concentrated and acidified to pH 4-5 with aqueous HCl (1 N) and extracted with AcOEt. The combined organic phase was dried and concentrated to give a residue that was triturated with MeCN/Et2O (20:1) and filtered to afford the title compound (93%) as a solid.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]#[C:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[Br:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:9]2[CH2:10][CH2:11][C:6]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]#[C:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:27][CH:28]=3)(=[O:22])=[O:21])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[CH:18][CH:17]=1
Reactant: CCCCCC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(Br)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(Br)cc3)CC2)cc1

Procedure:
1-(4-Bromobenzyl)-4-(4-oct-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid was prepared starting from 1-(4-bromobenzyl)-4-(4-oct-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid ethyl ester (1.36 g, 2.3 mmol) dissolved in THF:methanol (50:50 ml) and 10 N NaOH (10 ml). The resulting reaction mixture was worked up as outlined in Example 1 (Step 7). Yield 660 mg (51%); off white solid; mp 199° C.; MS: 562 (M+H)+.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Br:16])=[N:7][N:8]([CH:13]([CH3:15])[CH3:14])[C:9]2=[O:12])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:20][CH2:21][S:22][CH3:23]>CN(C=O)C>[Br:16][C:6]1[C:5]2[C:10](=[CH:11][C:2]([S:1][CH2:20][CH2:21][S:22][CH3:23])=[CH:3][CH:4]=2)[C:9](=[O:12])[N:8]([CH:13]([CH3:14])[CH3:15])[N:7]=1
Reactant: CSCCCl
Reactant: CC(C)n1nc(Br)c2ccc(S)cc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCCSc1ccc2c(Br)nn(C(C)C)c(=O)c2c1
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 90.7 %

Procedure:
To a solution of crude 7-mercapto-2-isopropyl-4-bromo-2H-phthalazin-1-one (0.40 g, 1.3 mmol) in DMF (8 ml), was added NaH (60%, 0.064 g, 1.6 mmol) portion-wise. After stirring for 5 min, chloroethyl methylsulfide (0.17 g, 1.6 mmol) was added dropwise. The mixture was heated to 60° C. for two hours, after which time the mixture was concentrated under vacuum and the residue was subjected to flash column chromatography (elution: 90% heptane, 10% EtOAc) to give the title compound (0.44 g, 54% yield) as a white solid. δH (400 MHz, DMSO), 8.03 (1H, d), 7.92 (1H, d), 7.81 (1 H, d), 5.26-5.15 (1H, m), 3.41 (2H, t), 2.78 (2H, t), 2.15 (3H, s), 1.36 (6H, d).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][N:6]=[C:5]([SH:8])[N:4]=1.[H-].[Na+].Cl[C:12]1[C:13]([C:18]#[N:19])=[N:14][CH:15]=[CH:16][N:17]=1>CN(C=O)C.C1C=CC=CC=1>[CH3:1][S:2][C:3]1[S:7][N:6]=[C:5]([S:8][C:12]2[C:13]([C:18]#[N:19])=[N:14][CH:15]=[CH:16][N:17]=2)[N:4]=1
Reactant: CSc1nc(S)ns1
Reactant: N#Cc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CSc1nc(Sc2nccnc2C#N)ns1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound was prepared according to Example 1 by using 5-(methylthio)-1,2,4-thiadiazole-3-thiol (328 mg, 2.00 mmol), NaH (60% dispersion in mineral oil, 88 mg, 2.20 mmol), and 3-chloropyrazine-2-carbonitrile (280 mg, 2.00 mmol) in DMF and benzene (6 ml, 1/1) by stirring at room temperature under nitrogen atmosphere for 2 hr.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=O.[C:14]1([C:20]2[N:21]=[C:22]([CH:31]([NH2:33])[CH3:32])[O:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:14]1([C:20]2[N:21]=[C:22]([CH:31]([NH:33][CH:8]3[C:9]4[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=4)[CH2:5][CH2:6][CH2:7]3)[CH3:32])[O:23][C:24]=2[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(N)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: COc1cccc2c1CCCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cccc2c1CCCC2NC(C)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.4 %

Procedure:
A solution of 5-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene (0.67 g), 1-(4,5-diphenyloxazol-2-yl)ethylamine (0.98 g) and p-toluenesulfonic acid (catalytic amount) in toluene (30 ml) was refluxed for 7 hours with Dean-stark equipment. The solution was evaporated in vacuo and methanol (MeOH) (10 ml) was added to the residue. To the MeOH solution, NaBH4 (0.21 g) was added at 0° C. After being stirred for 2 hours at room temperature, the solution was evaporated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine. The dried solvent was evaporated in vacuo, and the residue was purified by chromatography on silica gel to give 1-[1-(4,5-diphenyloxazol-2-yl)ethylamino]-1,2,3,4-tetrahydro-5-methoxynaphthalene (0.73 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:17])[CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[C:18]([O:26][CH2:27][CH3:28])(=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:17])[CH2:9][CH:10]([CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:18]([O:26][CH2:27][CH3:28])=[O:25])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(C=Cc1ccccc1)c1cccc(Cl)c1
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)C(C(=O)OCC)C(CC(=O)c1cccc(Cl)c1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 1-(3-chlorophenyl)-3-phenylprop-2-en-1-one and diethyl malonate, diethyl 2-[3-(3-chlorophenyl)-3-oxo-1-phenylpropyl]malonate was obtained as colourless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]([N:9]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[NH:10][C:11]([NH2:13])=[O:12])=O)=[CH:5][CH:4]=1.C(O)C>[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]2[N:9]([C:14]3[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[N:10]=[C:11]([OH:12])[N:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)N(NC(N)=O)c2ccc(OC)nc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2nc(O)nn2-c2ccc(OC)nc2)cc1
Temperature: 60 °C
Yield: 72.7 %

Procedure:
A mixture of 2-(4-methoxybenzoyl)-2-(6-methoxypyridin-3-yl)hydrazinecarboxamide (1.0 g, 3.16 mmol) in 10% sodium hydroxide solution (2 mL)-ethanol (3mL) was heated at 60° C. for 1.5 hours. After cooling, the solvent was removed under reduced pressure. Water was added to the residue and the mixture was adjusted pH to ca. 4 to 5. A generated precipitate was isolated by filtration, washed with water and small amount of ethyl acetate, dried in vacuo to give 5-(4-methoxyphenyl)-1-(6-methoxypyridin-3-yl)-1H-1,2,4-triazol-3-ol (685 mg, 72.6% yield).
Reaction SMILES: [CH3:1][C:2]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:12][CH:11]=1)[CH2:3][C:4]([O:6]CC)=[O:5].FC(F)(F)C(O)=O>CO.[OH-].[Na+]>[CH3:1][C:2]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:14][CH:15]=1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)CC(C)(Cc1ccc(OCCCNc2ccccn2)cc1)c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(CC(=O)O)(Cc1ccc(OCCCNc2ccccn2)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product of STEP 9 (148 mg, 0.35 mmol) was dissolved in 5 ml methanol and 5 ml 1N sodium hydroxide solution. The reaction was stirred at room temperature for 18 h, acidified with 2 ml trifluoroacetic acid, and concentrated. The residue was purified on HPLC using acetonitrile gradient 10-50% in 30 min to yield 90.6 mg. FAB-MS:(MH+)=406.5. H NMR (DMSO-d6) δ1.43 (s, 3H), 2.03 (p, 2H), 2.61 (d, 1H), 2.92 (d,1IH), 2.96 (d, 1H), 3.07 (d, 1H), 3.48 (t, 2H), 4.01 (t, 2H), 6.76 (s, 4H), 6.85 (t,1H), 7.06 (d, 1H), 7.88 (m, 2H), 7.93 (d, 1H), 8.40 (d, 1H), 8.72 (d,1H), 8.76 (s, 1H), 8.90 (br, 1H); Anal Calcd. for C24H27N3O3 plus 2.75 CF3COOH: C, 48.67; H, 4.26; N, 5.77. Found: 48.56; H, 4.29; N, 6.05.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][Cl:13])=[C:6]([NH2:14])[CH:5]=1.[C:16]([O-])(O)=O.[Na+]>C(O)=O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH2:11][CH2:12][Cl:13])[CH:16]=[N:14][C:6]=2[CH:5]=1)=[O:15]
Reactant: O=C([O-])O
Reactant: COC(=O)c1ccc(NCCCl)c(N)c1
Agent: [Na+]
Solvent: O=CO
Product: COC(=O)c1ccc2c(c1)ncn2CCCl
Temperature: 100 °C
Yield: 86 %

Procedure:
To 3-amino-4-(2-chloroethylamino)-benzoic acid methyl ester (11.0 g, 0.0482 mol) was added HCO2H (30 mL) and heated at 100° C. for 1 h. The reaction was cooled to ambient temperature and diluted with ice water (100 mL). The pH of the reaction mixture was adjusted to 7 with NaHCO3 and the solid precipitated was filtered, washed with water and dried under vacuum to get a pale green solid (9.9 g, 86%) of 1-(2-chloroethyl)-1H-benzimidazole-5-carboxylic acid methyl ester. MS-ESI m/z 239 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13]Br)=[CH:6][C:5]=1[NH:15][C:16](=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([F:26])([F:25])[F:24].[C:29]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:34]=[CH:33][C:32]([CH:35]=[N:36][OH:37])=[CH:31][CH:30]=1>>[C:29]1([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:30]=[CH:31][C:32](/[CH:35]=[N:36]/[O:37][CH2:13][CH2:12][CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:28])=[C:5]([NH:15][C:16](=[O:27])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]([F:25])([F:26])[F:24])[CH:6]=2)=[CH:33][CH:34]=1
Reactant: ON=Cc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1ccc(OCCCBr)cc1NC(=O)c1ccccc1C(F)(F)F
Product: O=C(O)c1ccc(OCCCO/N=C/c2ccc(-c3ccccc3)cc2)cc1NC(=O)c1ccccc1C(F)(F)F
Yield: 92 %

Procedure:
The title compound (0.193 g, 92%) was prepared as a white solid from 4-(3-bromo-propoxy)-2-(2-trifluoromethyl-benzoylamino)-benzoic acid methyl ester and Biphenyl-4-carbaldehyde oxime using a procedure similar to step 1 of example 6. mp=170.5-172.5° C.; mass spectrum API-ES, (M−H) m/z 561. 1H NMR (400 MHz, DMSO-d6); δ 13.40 (bs, 1H), 12.00 (bs, 1H), 8.32 (s, 1H), 8.27 (d, 1H), 7.98 (d, 1H), 7.88 (d, 1H), 7.81 (m, 2H), 7.76 (m, 1H), 7.68 (m, 6H), 7.46 (m, 2H), 7.38 (m, 1H), 6.82 (dd, 1H), 4.32 (t, 2H), 4.20 (t, 2H), 2.20 (m, 2H). Elemental analysis: Calcd. for C31H25F3N2O5: C, 66.19; H, 4.48; N, 4.98, Found: C, 65.26; H, 4.49; N, 4.77.
Reaction SMILES: [NH2:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].O.[OH-].[Na+].[CH3:11][O:12][C:13]1[CH:18]=[C:17]([CH2:19][O:20][C:21](Cl)=[O:22])[C:16]([N+:24]([O-:26])=[O:25])=[CH:15][C:14]=1[O:27][CH3:28]>O1CCOCC1>[CH3:28][O:27][C:14]1[C:13]([O:12][CH3:11])=[CH:18][C:17]([CH2:19][O:20][C:21]([NH:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5])=[O:22])=[C:16]([N+:24]([O-:26])=[O:25])[CH:15]=1
Reactant: COc1cc(COC(=O)Cl)c([N+](=O)[O-])cc1OC
Reactant: CC(N)CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(COC(=O)NC(C)CC(=O)O)c([N+](=O)[O-])cc1OC
Temperature: 0 °C
Yield: 36 %

Procedure:
3-Amino-butyric acid (147 mg, 1.43 mmol) was mixed with water (10 mL), dioxane (10 mL) and 2 M NaOH (10 mL). The mixture was cooled to 0° C. and treated with Nvoc-Cl (1.58 mmol). 2 M NaOH was added in small portions (8×1.25 mL) during 75 minutes. The cooling bath was removed and the reaction mixture was left at room temperature o/n. Water (30 mL) was added and the mixture was filtered. The aqueous phase was adjusted to pH=4 with 2 M HCl (aq.) and extracted with diethyl ether (3×50 mL). The solid was dissolved in water (50 mL) and diethyl ether (50 mL). The combined organic phases were dried over MgSO4 and evaporated in vacuo affording 176 mg (36%) pure 3-(4,5-dimethoxy-2-nitro-benzyloxycarbonylamino)-butyric acid. 1H-NMR (CDCl3): 7.72 (s, 1H), 7.02 (s, 1H), 5.51 (s, 2H), 5.40-5.30 (br s, 1H), 4.15 (m, 1H), 3.96 (s, 3H), 3.92 (s, 3H), 2.60 (d, 2H), 1.31 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:12][C:13]1[C:14]([NH2:28])=[N:15][C:16]2([C:26]3[C:21](=[CH:22][CH:23]=[C:24]([NH2:27])[CH:25]=3)[O:20][CH2:19][CH2:18]2)[N:17]=1>>[NH2:28][C:14]1[C:13]([CH3:12])=[N:17][C:16]2([C:26]3[C:21](=[CH:22][CH:23]=[C:24]([NH:27][C:9](=[O:11])[C:3]4[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=4)[CH:25]=3)[O:20][CH2:19][CH2:18]2)[N:15]=1
Reactant: CC1=NC2(CCOc3ccc(N)cc32)N=C1N
Reactant: O=C(O)c1ncc(Cl)cc1Cl
Product: CC1=NC2(CCOc3ccc(NC(=O)c4ncc(Cl)cc4Cl)cc32)N=C1N
Yield: 63.5 %

Procedure:
The title compound (59 mg, 62% yield) was prepared as described for Example 13a starting from 3,5-dichloropicolinic acid (45 mg, 0.23 mmol) and 5′-methylspiro[chroman-4,2′-imidazole]-4′,6-diamine (Intermediate 30, 54 mg, 0.23 mmol): 1H NMR (400 MHz, DMSO-d6) δ ppm 1.82-2.01 (m, 2H), 2.22 (s, 3H), 4.29-4.49 (m, 2H), 6.57 (s, 2H), 6.75-6.85 (m, 2H), 7.48-7.57 (m, 1H), 8.41 (d, 1H), 8.68 (d, 1H), 10.39 (s, 1H); MS (APCI+) m/z 404 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]([CH2:20][CH3:21])[CH:4]([NH2:19])[C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:8]=[CH:7][CH:6]=1)[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.S(Cl)(Cl)(=O)=O>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:19][CH:4]([C:5]2[N:9]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[N:8]=[CH:7][CH:6]=2)[CH:3]([CH2:1][CH3:2])[CH2:20][CH3:21])(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCC(CC)C(N)c1ccnn1Cc1ccc(OC)cc1
Solvent: O=S(=O)(Cl)Cl
Product: CCC(CC)C(NS(=O)(=O)c1ccc(Cl)cc1)c1ccnn1Cc1ccc(OC)cc1
Yield: 52 %

Procedure:
The compound of example 2 was synthesized from {2-ethyl-1-[1-(4-methoxybenzyl)-1H-pyrazol-5-yl]butyl}amine in a manner similar to that of example 1 but using 4-chlorobenzenesulfonyl chloride as the sulfonyl chloride in step 1 D. The product was isolated as white foam in 52% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][O:14][CH3:15])[C:8](=O)[CH2:7][CH2:6]2.CC1C=CC(N=[CH:25][C:26]2[C:27]([NH2:35])=[CH:28][C:29]3[O:33][CH2:32][O:31][C:30]=3[CH:34]=2)=CC=1>>[CH3:15][O:14][CH2:13][O:12][C:11]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[CH2:6][C:7]3[C:8]([C:9]=2[CH:10]=1)=[N:35][C:27]1[CH:28]=[C:29]2[O:33][CH2:32][O:31][C:30]2=[CH:34][C:26]=1[CH:25]=3
Reactant: COCOc1cc2c(cc1OC)CCC2=O
Reactant: Cc1ccc(N=Cc2cc3c(cc2N)OCO3)cc1
Product: COCOc1cc2c(cc1OC)Cc1cc3cc4c(cc3nc1-2)OCO4

Procedure:
Using the procedure of Example 1, 5-methoxy-6-methoxymethoxyindan-1-one (452 mg, 2.03 mmol) is reacted with 6[[(4-methylphenyl)imino]methyl]-1,3-benzodioxol-5-amine (517 mg, 2.03 mmol) to yields 7-methoxymethoxy-8-methoxy-10H-1,3-dioxolo[4,5-g]indeno[1,2-b]quinoline. This material is used directly in part (B) without further isolation or purification except for the few milligrams need for NMR and mass spectral studies.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].CO>>[OH:18][C:17]1[C:16]2[C:11](=[CH:12][C:13]([S:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9][C:8]=1[C:6]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:7]
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1ncc2cc(Sc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2cc(Sc3ccccc3)ccc2c1O
Yield: 90.8 %

Procedure:
A mixture of 113 mg of 4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (0.32 mmol), 244 mg of glycine (3.2 mmol), and 6.4 ml of a 0.5 N solution of sodium methoxide in methanol (3.2 mmol) was refluxed for 24 h with stirring. Then the solvent was evaporated in vacuo, the residue dissolved in 25 ml of water and the resulting solution was washed twice with 50 ml of ethyl acetate. The pH of the solution was subsequently adjusted to about 3 by addition of concentrated hydrochloric acid and the resulting slurry was extracted twice with 25 ml of ethyl acetate. The combined extracts were dried over MgSO4 and evaporated in vacuo. 103 mg of the title compound were obtained; 1H NMR (DMSO-d6): δ=9.32 (t, 1H), 8.74 (s, 1H), 8.19 (d, 1H), 7.94 (d, 1H), 7.45 to 7.65 (m, 6H), 4.02 (d, 2H).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH3:7][P:8](OC)(=[O:11])[O:9][CH3:10]>C(O)C>[CH3:10][O:9][P:8]([CH3:7])([CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])=[O:11]
Reactant: C=CC(=O)OC
Reactant: COP(C)(=O)OC
Solvent: CCO
Product: COC(=O)CCP(C)(=O)OC
Temperature: 60 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
A mixture of 86 g of methyl acrylate and 80 g of ethanol is added dropwise in the course of 30 minutes at 60° C. under nitrogen to a solution of 108 g of dimethyl methanephosphonate. The reaction mixture is then stirred at 60° C. for one hour. A total of 55 g of methyl ethyl ether are collected in the cooling trap. Excess ethanol is then removed by vacuum distillation. The crude product is obtained in a yield of 184 g with a 95.4% purity, which corresponds to a theoretical yield of 97.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([NH:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][C:10]([CH2:18][OH:19])([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:6].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([NH:7][C:8]12[CH2:15][CH:14]3[CH2:13][CH:12]([CH2:11][C:10]([CH:18]=[O:19])([CH2:16]3)[CH2:9]1)[CH2:17]2)=[O:6]
Reactant: O=C(NC12CC3CC(CC(CO)(C3)C1)C2)c1cccc(Cl)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CC12CC3CC(C1)CC(NC(=O)c1cccc(Cl)c1)(C3)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a solution of 3-chloro-N-[3-(hydroxymethyl)-1-adamantyl]benzamide (200 mg, 0.63 mmol) in DCM (15 mL) was added PCC (200 mg, 0.93 mmol) in one portion and the reaction mixture was stirred at room temperature for two hours. The reaction mixture was then filtered through a pad of silica gel and the filtrate was concentrated under reduced pressure to give 200 mg (100%) of crude title compound, 3-chloro-N-(3-formyl-1-adamantyl)benzamide, as a brown oil. ESI-MS m/z: 318 (M+H)+.