Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H][H].[C:3]([OH:24])(=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][C@@H:10]1[C@@H:14]([C:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][CH2:12][CH2:11]1>[Pd].C(OCC)(=O)C>[C:3]([OH:24])(=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][C@@H:10]1[C@@H:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][CH2:12][CH2:11]1
Reactant: CCCCCCC#C[C@H]1CCC[C@@H]1SCCCCCC(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCC[C@H]1CCC[C@@H]1SCCCCCC(=O)O
Yield: 85.6 %

Procedure:
To a suspension of 50 mg of 10% palladium on charcoal in 1 ml of ethyl acetate, which had been pre-reduced with hydrogen gas was added 7-thia-13-prostynoic acid (15 mg) in 1.5 ml of ethyl acetate. After 5 hrs the catalyst was removed by filtration washed with ethyl acetate and the combined filtrates evaporated to yield 13 mg of a semisolid. Analysis by nmr indicated that there still remained starting material plus some 7-thia-13-cis-prostenoic acid. The material was therefore reduced again with 50 mg of fresh palladium catalyst for 1/2 hour and the reduced material isolated by filtration and removal of the solvent. 8 Milligrams of the saturated acid was obtained, which after recrystallization from hexane melted at 40°-41°.
Reaction SMILES: [I-].[Na+].[CH2:3]([NH2:5])[CH3:4].[Br:6][C:7]1[CH:8]=[C:9]([N:14]2[CH2:18][CH2:17][CH:16](OS(C)(=O)=O)[C:15]2=[O:24])[CH:10]=[CH:11][C:12]=1[F:13].O>O1CCCC1>[Br:6][C:7]1[CH:8]=[C:9]([N:14]2[CH2:18][CH2:17][CH:16]([NH:5][CH2:3][CH3:4])[C:15]2=[O:24])[CH:10]=[CH:11][C:12]=1[F:13]
Reactant: CS(=O)(=O)OC1CCN(c2ccc(F)c(Br)c2)C1=O
Reactant: CCN
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCNC1CCN(c2ccc(F)c(Br)c2)C1=O
Reaction time: 2 h

Procedure:
Sodium iodide (1.1 g), followed by ethylamine (1.92 ml) was added to a solution in tetrahydrofuran (60 ml) of the ethylamino compound prepared in Step 2 (2.6 g). The solution was stirred for two hours and then left to stand overnight. The reaction mixture was then poured into water and extracted with ethyl acetate three times. The extracts were combined, washed twice with water and once with brine, dried (magnesium sulphate), and concentrated to yield a dark brown oil. This was chromatographed on a silica column using a mixture of triethylamine and ethyl acetate (1:9) as the eluent. The title compound was obtained as a yellow solid. The NMR spectrum was consistent with the expected structure.
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][NH:7][C:8](=[O:31])[CH:9]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:10][S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)(=[O:13])=[O:12].FC(F)(F)C(O)=O>ClCCl>[OH:6][NH:7][C:8](=[O:31])[CH:9]([CH2:27][CH:28]([CH3:29])[CH3:30])[CH2:10][S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)(=[O:12])=[O:13]
Reactant: COc1ccc(CONC(=O)C(CC(C)C)CS(=O)(=O)N2CCN(c3ccc(F)cc3)CC2)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CC(CS(=O)(=O)N1CCN(c2ccc(F)cc2)CC1)C(=O)NO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.5 %

Procedure:
To a solution of N-(2,4-dimethoxybenzyloxy)-3-[4-(4-fluorophenyl)piperazine-1-sulfonyl]-2-isobutylpropionamide (220 mg) in dichioromethane (4 ml) was added trifluoroacetic acid (200 μl) andtriethylsilane (145 μl). The mixture was stirred at room temperature for 15 minutes, evaporated in vacuo and the residue was purified on silica gel (eluant: dichloromethane-ether-methanol (80:20:0.5) to dichloromethane-methanol (80:20) to give the title compound (88 mg, 56%).
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].O[CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[C:28]3[CH2:27][C:26]4[C:21](=[CH:22][C:23](=[O:29])[CH2:24][CH:25]=4)[S:20][C:19]=3[CH:18]=[CH:17][C:16]=2[N:30]=1>CN(C=O)C.C(Cl)Cl>[Cl:3][CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[C:28]3[CH2:27][C:26]4[C:21](=[CH:22][C:23](=[O:29])[CH2:24][CH:25]=4)[S:20][C:19]=3[CH:18]=[CH:17][C:16]=2[N:30]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: O=C1C=C2Sc3ccc4nc(CO)ccc4c3CC2=CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1C=C2Sc3ccc4nc(CCl)ccc4c3CC2=CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 438.2 %

Procedure:
A solution of cyanuric chloride (0.29 g, 0.16 mmol) in DMF (1 mL) was stirred for 0.5 hrs, resulting in a white precipitate. Dichloromethane (30 mL) was added, followed by a solution of 3-hydroxymethylpyridothioxanthone (0.25 g, 1.0 mmol) in DCM (20 mL). The solution was stirred at r.t. overnight, then washed with hydrochloric acid (0.5 M, 30 mL) and water, and then dried over sodium sulfate. The mixture was purified by column chromatography on silica gel with DCM/hexane (2:3) as the eluant, yielding 3-chloromethylpyridothioxanthone (0.22 g, 82%). 1H-NMR (CDCl3): 8.88 (1H, d, J 8.4, H1), 8.61 (1H, d, J 8.1, H8), 7.73-7.64 (3H, m, H2+H5+H6), 7.57-7.52 (1H, m, H7), 4.76 (2H, s)). m/z (ES+): 262 [M+H]+, 284 [M+Na]+, 545 [2M+Na]+.
Reaction SMILES: C(=O)([S:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[N:13]=[CH:12]2)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CO>[F:24][C:21]1[CH:20]=[CH:19][C:18]([N:14]2[C:15]3[C:11](=[CH:10][C:9]([SH:8])=[CH:17][CH:16]=3)[CH:12]=[N:13]2)=[CH:23][CH:22]=1
Reactant: O=C(Sc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Fc1ccc(-n2ncc3cc(S)ccc32)cc1

Procedure:
To S-1-(4-fluorophenyl)-1H-indazol-5-yl benzothioate (0.046 g, 0.13 mmol) in methanol (3 mL), potassium carbonate (0.011 mL, 0.20 mmol) was added and the mixture was stirred at r.t. for 2 h. water was than added, 1N HCl (2 ml) and extracted with EtOAc (2*20 ml), dried, evaporated and then purified on HPLC. The relevant fractions were collected freeze dried and analysed by LC/MS.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:3]=12.[O:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31]O)[CH2:26][CH2:25]1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:31][CH2:30][N:27]3[CH2:28][CH2:29][O:24][CH2:25][CH2:26]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:3]=12
Reactant: OCCN1CCOCC1
Reactant: Fc1cccc(-c2n[nH]c3nnc(-c4ccccc4)c(Cl)c23)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Fc1cccc(-c2nn(CCN3CCOCC3)c3nnc(-c4ccccc4)c(Cl)c23)c1

Procedure:
A mixture of 4-chloro-3-(3-fluorophenyl)-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (0.33 mmol), 2-morpholinoethanol (0.65 mmol), diethyl azodicarboxylate (114 mg, 0.65 mmol) and triphenyl phosphine (171 mg, 0.65 mmol) in 1,4-dioxane (2 mL) was heated using microwave irradiation to a temperature between 85 and 120° C. for a 30 to 90 min period. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC to provide Compound 9.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[C:14]2[N:13]=[C:12]([CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]3[C:22]([C:24]3[N:25]=[C:26]([CH3:36])[S:27][C:28]=3[C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[O:23])[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4].O>CO>[F:35][C:32]1[CH:31]=[CH:30][C:29]([C:28]2[S:27][C:26]([CH3:36])=[N:25][C:24]=2[C:22]([N:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]2[CH2:15][C:12]2[NH:11][C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([CH:3]([OH:5])[CH3:4])[C:14]=3[N:13]=2)=[O:23])=[CH:34][CH:33]=1
Reactant: CC(=O)c1cccc2[nH]c(CC3CCCCN3C(=O)c3nc(C)sc3-c3ccc(F)cc3)nc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1nc(C(=O)N2CCCCC2Cc2nc3c(C(C)O)cccc3[nH]2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Sodium borohydride (145 mg) was added portionwise over 2 min. to a cooled (0-10° C.) solution of (RS)-1-[2-(4-acetyl-1H-benzimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluorophenyl)-2-methylthiazol-4-yl]methanone, E68 (365 mg) in methanol (10 ml). After stirring for a further 2.5 h at room temperature, water (100 ml) was added and the mixture was extracted with dichloromethane (2×). The combined organics were dried (Na2SO4), evaporated and the residue chromatographed (silica gel, 0-100% ethyl acetate-hexane then 2-10% methanol-ethyl acetate) to afford the title compound as a solid (320 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][O:9][C:10]1[C:15](B(O)O)=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[N:11]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:8][O:9][C:10]1[C:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[N:11]=1
Reactant: Brc1ccccn1
Reactant: COc1ccc(B(O)O)c(OC)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccccn2)c(OC)n1
Temperature: 90 °C
Reaction time: 20 h

Procedure:
2-Bromopyridine (0.475 mL, 0.78 g, 4.9 mmol) and 2,6-dimethoxy-3-pyridineboronic acid (1.09 g, 6.0 mmol, excess) were dissolved in THF (25 mL) at RT. Aqueous solution of K2CO3 (1.65 g in 10 mL of water, 12 mmol, excess) was added, followed by Pd(PPh3)4 (295 mg, 0.25 mmol). The mixture was stirred at 90° C. for 20 h under argon to give yellow solution. Organic solvent was removed under reduced pressure and the residue was extracted with dichloromethane and water. Evaporation of organic phase provided red oil that was purified by chromatography on silica gel eluting with CH2Cl2/MeOH 0 to 0.2%. The fractions containing pure product were collected, while those containing impurities were again purified by chromatography using the same conditions. After three chromatographic purifications the total yield was 965 mg (4.39 mmol; 90%) of yellow oil that crystallized as yellow solid on standing. Anal. Calcd for C12H12N2O2.0.2H2O (MW 219.84): C, 65.56; H, 5.69; N, 12.74. Found: C, 65.74; H, 5.63; N, 12.53. 1H NMR (400 MHz, CD2Cl2): 8.64 (d, J 4.0, 1H), 8.32 (d, J 8.0, 1H), 8.03 (d, J 8.0, 1H), 7.74 (t, J 8.0, 1H), 7.19 (m, 1H), 6.47 (d, J 8.0, 1H), 4.06 (s, 3H), 4.00 (s, 3H). 13C NMR (100 MHz, CD2Cl2): 163.24, 160.16, 154.36, 149.44, 142.44, 136.01, 123.97, 121.38, 114.30, 102.02, 53.75, 53.52.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26]O)[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:26][CH:23]2[CH2:22][CH2:21][N:20]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:25][CH2:24]2)=[O:11])=[CH:2]1
Reactant: OCC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1c[nH]c2ccccc12
Product: O=C(OCC1CCN(Cc2ccccc2)CC1)c1c[nH]c2ccccc12
Yield: 88 %

Procedure:
Indole-3-carboxylic acid was converted to its acid chloride and then reacted with 1-benzyl-4-piperidinemethanol (D7) using the method given in Example 1a. The resulting orange oil was chromatographed on silica gel eluting with chloroform/ethanol (9:1) to afford (1-benzyl-4-piperidyl)methyl indole-3-carboxylate as a yellow oil (88%).
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].C(N(CC)CC)C.[Br:27][C:28]1[S:32][C:31]([S:33](Cl)(=[O:35])=[O:34])=[CH:30][CH:29]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:27][C:28]1[S:32][C:31]([S:33]([NH:3][C@@H:4]([CH2:16][N:17]([CH3:18])[CH3:19])[CH2:5][C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])(=[O:35])=[O:34])=[CH:30][CH:29]=1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NS(=O)(=O)c1ccc(Br)s1
Yield: 44 %

Procedure:
To a solution of (R)-benzyl 3-amino-4-(dimethylamino)butanoate dihydrochloride (1 g, 3.2 mmol), triethylamine (1.3 mL, 9.6 mmol) and DMAP (20 mg, 0.16 mmol) in anhydrous CH2Cl2 (25 mL) was added 5-bromothiophene-2-sulfonyl chloride (2.5 g, 9.6 mmol). Methylene chloride (200 mL) was added and the solution was washed with dilute NaOH (10 mL), water (10 mL), dried over MgSO4 and concentrated to dryness. The residue was purified by silica gel chromatography (95:5 CH2Cl2/MeOH) to give the title compound as a yellow solid (650 mg, 44%). 1H NMR (400 MHz, CDCl3) δ 7.44 (d, 1H, J=3.8 Hz), 7.41-7.27 (m, 5H), 7.04 (d, 1H, J=3.8 Hz), 5.14-5.07 (m, 2H), 3.87-8.83 (m, 1H), 2.92-2.89 (m, 1H), 2.83-2.78 (m, 1H), 2.69-2.64 (m, 1H), 2.60-2.54 (m, 1H), 2.43 (s, 6H); MS ESI 461.3 [M+H]+, calcd for [C17H21BrN2O4S2]+ 461.00.
Reaction SMILES: [CH3:1][N:2]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:24][CH:23]=1)[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.[OH-].[Li+].C(O)(C(F)(F)F)=O>C1COCC1>[CH3:1][N:2]([CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:26][CH:27]=1)[CH:3]1[CH2:4][CH2:5][N:6]([CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)[CH2:7][CH2:8]1
Reactant: COC(=O)c1ccc(CN2CCC(N(C)CCc3ccc(Oc4ccccc4)cc3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CN(CCc1ccc(Oc2ccccc2)cc1)C1CCN(Cc2ccc(C(=O)O)cc2)CC1
Yield: 12.7 %

Procedure:
A solution of methyl 4-[[4-[methyl[2-(4-phenoxyphenyl)ethyl]amino]-1-piperidinyl]methyl]benzoate (about 0.71 mmol) in aqueous THF was treated with an aqueous solution of lithium hydroxide. The reaction was acidified with TFA. Purification by preparatory HPLC gave 40 mg of 4-[[4-[methyl[2-(4-phenoxyphenyl)ethyl]amino]-1-piperidinyl]methyl]benzoic acid; 1H NMR (400 MHz, DMSO-d6) δ 7.95 (d, 2H), 7.56 (dbr, 2H), 7.32 (ddd, 2H), 7.26 (d, 2H), 7.07 (tt, 1H), 6.88-6.96 (m, 4H), 4.27 (br, 2H), 3.25 (br, 3H), 2.86 (br, 4H), 2.72 (s, 3H), 2.14 (br, 2H) 1.85 (br, 2H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:38]([OH:40])=[O:39])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:37])[NH:19]S(C1C(C)C2CC(C)(C)OC2=C(C)C=1C)(=O)=O)=[O:11].FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:38]([OH:40])=[O:39])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:19])[NH2:37])=[O:11]
Reactant: CC1=C2OC(C)(C)CC2C(C)C(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)C=Cc2ccccc2F)C(=O)O)=C1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N=C(N)NCCC[C@H](NC(=O)C=Cc1ccccc1F)C(=O)O
Reaction time: 24 h
Yield: 89.5 %

Procedure:
To methylene chloride solution of the compound obtained in Example 115 (2.8 g) was added dropwise trifluoroacetic acid (50 mL) at room temperature, and the mixture was allowed to stir for 24 hours. To the residue obtained by distilling off the solvent under a reduced pressure was added diethylether, and the mixture was stirred for 24 hours at room temperature. The crystals precipitated were filtered, to give the captioned compound (1.4 g, 68%).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:16])[O:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][CH3:15])[CH:8]=2)(=[O:3])[CH3:2].[CH2:17]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)[CH3:18]>N1CCCCC1.C(#N)C>[CH2:17]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[CH:2][C:1]([C:4]2[C:5](=[O:16])[O:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[C:9]([O:14][CH3:15])[CH:8]=3)=[O:3])=[CH:22][CH:21]=1)[CH3:18]
Reactant: COc1ccc2cc(C(C)=O)c(=O)oc2c1
Reactant: CCOc1ccc(C=O)cc1
Solvent: CC#N
Solvent: C1CCNCC1
Product: CCOc1ccc(C=CC(=O)c2cc3ccc(OC)cc3oc2=O)cc1

Procedure:
A suspension of 2.18 g 3-acetyl-7-methoxycoumarin and 1.65 g p-ethoxybenzaldehyde in 100 ml alcohol was heated under reflux on a steam bath. Acetonitrile was added until solution was attained. Fifty drops of piperidine were added and the reaction mixture heated under reflux for 90 minutes. An additional fifty drops of piperidine were added and the solution was heated under reflux another hour. The product separated upon cooling and was washed with alcohol before being recrystallized from a mixture of alcohol and acetonitrile.
Reaction SMILES: C([C:5]1[N:10]=[C:9]([NH2:11])[C:8]([C:12]2[NH:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)=[CH:7][N:6]=1)(C)(C)C.N[C:22]1C(C2NC3C=CC=CC=3N=2)=CC=CN=1>>[CH:7]1[C:8]2[C:12]3[N:16]([CH:22]=[N:11][C:9]=2[N:10]=[CH:5][N:6]=1)[C:15]1[C:14](=[CH:20][CH:19]=[CH:18][CH:17]=1)[N:13]=3
Reactant: Nc1ncccc1-c1nc2ccccc2[nH]1
Reactant: CC(C)(C)c1ncc(-c2nc3ccccc3[nH]2)c(N)n1
Product: c1ccc2c(c1)nc1c3cncnc3ncn21

Procedure:
Preparation analogous to 7), using 26.7 g (100 mmol) of 2-(2-tert-butyl-4-aminopyrimidin-5-yl)benzimidazole (S55) (employed as equimolar mixture with 2-tert-butylbenzimidazole as obtained from synthesis 26)) instead of 100 mmol of the 2-(2-aminopyridin-3-yl)benzimidazole derivative. After crystallisation from methanol, the crude products are passed through a silica-gel column (heptane:ethyl acetate, 3:1 vv). The solids obtained in this way are freed from low-boiling components and non-volatile secondary components by sublimation (p about 1×10−5 mbar, T about 200-240° C.). Purity according to 1H-NMR typically >99.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[CH3:25][O:26][CH:27]([O:30][CH3:31])[CH2:28][NH2:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:25][O:26][CH:27]([O:30][CH3:31])[CH2:28][NH:29][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:21]
Reactant: COC(CN)OC
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2C)OC
Yield: 78.7 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (2,2-dimethoxy-ethyl)-amide (700 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (716 mg), 2,2-dimethoxy-ethylamine (265 mg), HBTU (952 mg), and DIEA (700 uL) in DMF (5 mL).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][CH2:2]1.[CH2:11]([OH:13])[CH3:12]>C(OC(=O)C)(=O)C.[OH-].[Na+]>[C:11]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][CH2:2]1)(=[O:13])[CH3:12]
Reactant: c1ccc2c(c1)NCCN2
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCNc2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1,2,3,4-tetrahydroquinoxaline obtained in Reference Example 26 (360 mg) in ethanol (10 ml), acetic anhydride (254 μl) was added dropwise under ice cooling and stirred at room temperature for 10 minutes. The reaction mixture was diluted with 1M aqueous sodium hydroxide (10 ml) and extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The desiccant was filtered off and the solvent was distilled off under reduced pressure to give the titled compound, i.e., 1-acetyl-1,2,3,4-tetrahydroquinoxaline (494 mg) as a brown oil.
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:12]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N12CCCN=C1CCCCC2.[CH3:28][O:29][C:30]1[N:35]=[C:34]([CH3:36])[N:33]=[C:32]([N:37](C2C=CC=CC=2)[C:38](=O)[O-:39])[N:31]=1>O1CCOCC1>[CH:1]1([O:6][C:7]2[C:12]([S:13]([NH:16][C:38]([NH:37][C:32]3[N:31]=[C:30]([O:29][CH3:28])[N:35]=[C:34]([CH3:36])[N:33]=3)=[O:39])(=[O:15])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NS(=O)(=O)c1cccnc1OC1CCCC1
Reactant: COc1nc(C)nc(N(C(=O)[O-])c2ccccc2)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2cccnc2OC2CCCC2)n1
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
To a mixture of 4.84 g of 2-cyclopentyloxypyridin-3-ylsulfonamide and 3.13 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene in 50 ml of absolute dioxan are added 5.46 g of N-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)phenylcarbamate at 20° to 25° C. The mixture is stirred for 1/2 hour, the precipitate is isolated and the filtrate is concentrated by evaporation. The residue is triturated with 10 ml of 2N hydrochloric acid and the crystals so obtained are isolated, washed with ether and water and dried, affording 7.79 g of N-(2-cyclopentyloxypyridin-3-ylsulfonyl)-N'-(4-methoxy-6methyl-1,3,5-triazin-2-yl)urea with a melting point of 170°-172° C.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[F:28])[C:22](O)=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].ClC(OCC(C)C)=O.[CH3:38][N:39]1CCOC[CH2:40]1.CN>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[F:28])[C:22]([N:39]([CH3:40])[CH3:38])=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cc(C(=O)O)ccc1F
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: CN
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cc(C(=O)N(C)C)ccc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 29.8 %

Procedure:
A solution of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzoic acid (1 g, 2.1 mmol) in N,N-dimethylformamide (20 mL) was cooled to −10 C. Isobutyl chloroformate (0.27 mL, 2.1 mmol) and N-methyl morpholine (0.23 mL, 2.1 mmol) were added to the reaction vessel. After stirring at −10 C for 20 minutes, a solution of N-methyl amine (2.1 mL, 4.2 mmol, 2 M in THF) was added and the reaction mixture was warmed to room temperature as it stirred for 18 hours. The reaction mixture was concentrated in vacuo and partitioned between water and ethyl acetate. The organic layer was washed with brine and concentrated in vacuo. The solid was chromatographed on silica (95:5 methylene chloride:isopropyl alcohol) to give the desired product as a white powder (0.31 g, 30%). 1H NMR (400 MHz, CD3OD) δ 7.64 (m, 1H), 7.50 (dd, J=2.4 and 7.2 Hz, 1H), 7.45 (t, J=9.6 Hz, 1H), 7.04 (t, J=9.2 Hz, 2H), 6.65 (s, 1H), 5.36 (s, 2H), 3.09 (s, 3H), 3.05 (s, 3H), 2.10 (s, 3H) ppm. 19F NMR (400 MHz, CD3OD) δ −111.51 (1F), −115.88 (1F), −121.90 (1F) ppm. ES-HRMS m/z 495.0508 (M+H calcd for C22H19BrF3N2O3 requires 495.0526).
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([CH2:13][C@H:14]([NH:25][C:26]([O:28][CH3:29])=[O:27])[C:15]([O:17]CC2C=CC=CC=2)=[O:16])[N:10]=[N:9]1)C1C=CC=CC=1>CO.[Pd]>[CH3:29][O:28][C:26]([NH:25][C@@H:14]([CH2:13][C:11]1[N:10]=[N:9][NH:8][CH:12]=1)[C:15]([OH:17])=[O:16])=[O:27]
Reactant: COC(=O)N[C@@H](Cc1cn(Cc2ccccc2)nn1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)N[C@@H](Cc1c[nH]nn1)C(=O)O

Procedure:
(S)-Benzyl 3-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-(methoxycarbonylamino)propanoate (502 mg, 1.11 mmol) was hydrogenated in the presence of Pd—C (82 mg) in MeOH (5 mL) at atmospheric pressure for 12 h. The mixture was filtered through diatomaceous earth (CELITE®) and concentrated in vacuo. (S)-2-(methoxycarbonylamino)-3-(1H-1,2,3-triazol-4-yl)propanoic acid was obtained as a colorless gum (266 mg, 111%) which was contaminated with ca. 10% of the methyl ester. The material was used as is without further purification. 1H NMR (400 MHz, DMSO-d6) δ 12.78 (s, br, 1H), 7.59 (s, 1H), 7.50 (d, J=8.0 Hz, 1H), 4.19-4.24 (m, 1H), 3.49 (s, 3H), 3.12 (dd, J=4.8 Hz, 14.9 Hz, 1H), 2.96 (dd, J=9.9, 15.0 Hz, 1H). LC-MS: Anal. Calcd. for C7H10N4O4: 214. found: 215 (M+H)+.