Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([N:5]2[CH2:10][C:9]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[O:8][CH2:7][C:6]2=[O:16])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:24]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:42]=[C:41]3[C:36]([CH:37]=[CH:38][CH:39]=[N:40]3)=[CH:35][CH:34]=2)=[CH:29][CH:28]=1)[C:25]#[N:26]>CN(C)C=O.O>[CH:2]1([N:5]2[CH2:10][C:9]3([CH2:11][CH2:12][N:13]([CH:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]5[CH:42]=[C:41]6[C:36]([CH:37]=[CH:38][CH:39]=[N:40]6)=[CH:35][CH:34]=5)=[CH:29][CH:28]=4)[C:25]#[N:26])[CH2:14][CH2:15]3)[O:8][CH2:7][C:6]2=[O:16])[CH2:4][CH2:3]1
Reactant: N#CC(Br)c1ccc(-c2ccc3cccnc3c2)cc1
Reactant: O=C1COC2(CCNCC2)CN1C1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(c1ccc(-c2ccc3cccnc3c2)cc1)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride (0.101 mmol) in N,N-dimethylformamide (0.5 mL) was treated with potassium carbonate (0.209 mmol) and 2-bromo-2-(4-(quinolin-7-yl)phenyl)acetonitrile (0.070 mmol). The reaction was stirred overnight at room temperature, at which point it was diluted with water (50 mL) and was extracted with three times with dichloromethane. The aqueous layer was further diluted with brine (25 mL) and was extracted twice with tetrahydrofuran. The organic layers were combined and dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude material was purified by silica gel chromatography (0-9% methanol/dichloromethane). The fractions containing the desired product were combined, concentrated in vacuo, and lyophilized from water to afford the title compound a pale yellow solid (15%). MS(ES)+ m/e 453.2 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)#[N:2].CO.[ClH:17].CO[CH:20](OC)[CH2:21][NH2:22]>CCOCC>[ClH:17].[NH:2]1[CH:20]=[CH:21][N:22]=[C:1]1[CH2:3][CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1
Reactant: COC(CN)OC
Reactant: COC(=O)c1ccc(CCC#N)cc1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1ccc(CCc2ncc[nH]2)cc1

Procedure:
Nitrile 23-3 (400 mg, 2.11 mmol) was dissolved in 10 mL Et2O at 0° MeOH (289 μL, 4.2 mmol) was added, the mixture was saturated with anhydrous HCl. Once the white ppt. formed, the solvent was evaporated and replaced with MeOH (5 mL), cooled to 0°, and aminoacetaldehyde dimethylacetal (250 μL, 2.3 mmol) was added. The reaction was heated to reflux for 3 days then concentrated, diluted in 10 mL 6 N HCl and concentrated again providing 23-4 as a solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[S-:9][C:10]#[N:11].[K+].NC1C(N)=CC=CN=1>CC(C)=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:11]=[C:10]=[S:9])=[O:7]
Reactant: O=C(Cl)c1ccco1
Reactant: N#C[S-]
Agent: Nc1cccnc1N
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(N=C=S)c1ccco1
Temperature: 10 °C

Procedure:
2-Furoylisothiocyanate is prepared from 2-furoyl chloride (13 g., 0.1 moles) and potassium thiocyanate (9.7 g., 0.1 moles) in acetone (35 ml.). The mixture is stirred at 10° C. for fifteen minutes. 2,3-Diaminopyridine (2.8 g., 0.0257 moles) is added as a solid, the mixture stirred at 10° C. and allowed to warm to room temperature for three hours. The yellow solid is filtered, washed with acetone, slurried in 500 ml. water, filtered, washed with water and air dried. The product, 8.45 g. (80%) is purified by recrystallization from acetone giving 6.1 g. (57%) of desired product, as yellow crystals, m.p. 174° C. dec., of 2,3-bis[3-(2-furoyl)-2-thioureido]pyridine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:20][NH:21][NH2:22]>FC(F)(F)C(O)C(F)(F)F>[CH3:20][N:21]1[C:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:22]1
Reactant: CNN
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: CCOC(=O)c1cc(-c2ccc([N+](=O)[O-])cc2)n(C)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl 4-(4-nitrophenyl)-2,4-dioxobutanoate (500 mg, 1.885 mmol) was dissolved in hexafluoroisopropanol (4 ml) and methylhydrazine (87 mg, 1.885 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours, concentrated to dryness, triturated with ether; and filtered to provide the title compound.
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:44])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH:36](Cl)[C:37](OCC)=[O:38])=[CH:31][CH:30]=1)([CH2:17][CH2:18][CH:19]([CH3:26])[CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:9][C:8]2=[O:43])(=O)C.[NH2:45][C:46](N)=[S:47].S1(CCCC1)(=O)=[O:50].Cl>COCCO>[CH3:26][CH:19]([CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:18][CH2:17][C:10]1([CH2:27][O:28][C:29]2[CH:30]=[CH:31][C:32]([CH2:35][CH:36]3[S:47][C:46](=[O:50])[NH:45][C:37]3=[O:38])=[CH:33][CH:34]=2)[CH2:9][C:8](=[O:43])[C:7]2[C:12](=[C:13]([CH3:16])[C:14]([CH3:15])=[C:5]([OH:4])[C:6]=2[CH3:44])[O:11]1
Reactant: O=S1(=O)CCCC1
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC2(CCC(C)CCCC(C)C)CC(=O)c3c(C)c(OC(C)=O)c(C)c(C)c3O2)cc1
Reactant: NC(N)=S
Agent: Cl
Solvent: COCCO
Product: Cc1c(C)c2c(c(C)c1O)C(=O)CC(CCC(C)CCCC(C)C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2

Procedure:
The procedure described in Example 3 was repeated, but using 1.1 g of ethyl 3-{4-[6-acetoxy-2-(3,7-dimethyloctyl)-5,7,8-trimethyl-4-oxochroman-2-ylmethoxy]phenyl}-2-chloropropionate (prepared as described in Preparation 33), 0.2 g of thiourea, 1.5 ml of sulfolane, 5 ml of 2N aqueous hydrochloric acid and 10 ml of ethylene glycol monomethyl ether, to give the title compound, as a slightly yellow powder, softening at 41°-45° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[C:14](=O)[NH:13][N:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[C:11]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=2)=[N:12][N:13]=1
Reactant: COc1cc(OC)cc(-c2n[nH]c(=O)c3cc(OC)ccc23)c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc(OC)cc(-c2nnc(Cl)c3cc(OC)ccc23)c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-(3,5-dimethoxyphenyl)-7-methoxy-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Br:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1>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>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[C:2]([F:1])[CH:3]=2)=[CH:23][CH:22]=1
Reactant: CCCCCCCCOc1ccc(B(O)O)cc1F
Reactant: Brc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1F

Procedure:
This was prepared using a similar method to that described for compound 8. Quantities: 3-fluoro-4-octoxyphenyl boronic acid (7.0 g, 0.026 mol), 4-bromoiodobenzene (5.88 g, 0.021 mol), tetrakis(triphenylphosphine)palladium (0) (0.8 g, 0.7 mol).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O.ClCCl>[CH3:28][O:20][C:19](=[O:21])[CH2:18][CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]2[N:9]=[C:8]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]=2[CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)CCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CI
Product: COC(=O)CCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Reaction time: 48 h

Procedure:
45 mg of 3-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]propanoic acid was dissolved in 0.5 ml of N,N-dimethylformamide and mixed with 41 mg of cesium carbonate and 10 μl of methyl iodide. It was allowed to stir for 2 days, diluted with dichloromethane, filtered, the filtrate was concentrated by evaporation in a vacuum, and the residue was chromatographed on silica gel.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH:11][S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])[CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ccc([N+](=O)[O-])cc1NS(=O)(=O)c1ccccc1

Procedure:
A solution of 4-nitro 1,2-phenylene diamine (1.53 g, 10.0 mmol) in DMF was treated with phenyl sulfonyl chloride (1.76 g, 10.0 mmol) and triethyl amine (1.01 g) in DMF for 12 h at 23° C. The reaction mixture was partitioned between saturated NH4Cl and methylene chloride. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting solid was recrystallized (EtOH) to afford desired (0.275 g, 9%). 1H NMR(DMSO) 9.5 (s, 1H, br), 7.83 (dd, 1H, J=10 Hz, 2 Hz), 7.74 (d, 2H, J=8 Hz), 7.76 (t, 1H, J=8 Hz), 7.56 (t, 2H, J=8 Hz), 7.55 (d,1H, J=2 Hz), 6.79 (d, 1H, J=8 Hz), 6.5 (s, 2H, br)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.N12CCCN=C1CCCCC2.[C:23]1([CH2:29][SH:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O>[CH2:29]([S:30][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: SCc1ccccc1
Reactant: FC(F)(F)c1cc(Cl)ccn1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: FC(F)(F)c1cc(SCc2ccccc2)ccn1
Temperature: 100 °C
Yield: 75.5 %

Procedure:
4-Chloro-2-(trifluoromethyl)pyridine (141 μl, 1.102 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (199 μl, 1.322 mmol), and phenylmethanethiol (129 μl, 1.102 mmol) were dissolved in dry dimethylformamide (2 mL). The reaction mixture was heated at 100° C. in a microwave for 30 minutes, then partitioned between ether (25 mL) and water (25 mL). The aqueous layer was extracted with ether (2×25 mL) and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give a pale yellow oil. The crude product was purified by chromatography on silica gel (gradient: 0-30% ethyl acetate in isohexane) to afford 4-(benzylthio)-2-(trifluoromethyl)pyridine (224 mg) as a colourless oil. LCMS (Method F, ES-API): RT 2.79 min, m+H=270.1.
Reaction SMILES: [C:1]([C:4]1[N:12]=[C:11]2[C:7]([NH:8][C:9](=[O:39])[N:10]2[C:13]2[CH:18]=[C:17]([O:19][CH2:20][C:21]3[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[C:23]([F:29])[C:22]=3[F:30])[C:16]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:15][C:14]=2[Cl:38])=[C:6]([O:40][CH3:41])[N:5]=1)(=[O:3])[CH3:2].O.[C:43]1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:54](OC)(OC)[O:55]C>CO>[Cl:38][C:14]1[CH:15]=[C:16]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:17]([O:19][CH2:20][C:21]2[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[C:23]([F:29])[C:22]=2[F:30])=[CH:18][C:13]=1[N:10]1[C:9](=[O:39])[NH:8][C:7]2[C:11]1=[N:12][C:4]([C:1]([O:55][CH3:54])([O:3][CH3:43])[CH3:2])=[N:5][C:6]=2[O:40][CH3:41]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(OC)OC
Reactant: CCOC(=O)COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(C(C)=O)nc32)cc1OCc1c(OC)ccc(F)c1F
Solvent: CO
Solvent: O
Product: CCOC(=O)COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(C(C)(OC)OC)nc32)cc1OCc1c(OC)ccc(F)c1F

Procedure:
A mixture of 2-acetyl-9-[2-chloro-4-ethoxycarbonylmethoxy-5-(2,3-difluoro-6-methoxybenzyloxy)phenyl]-6-methoxy-7,9-dihydro-8H-purin-8-one (0.18 g), p-toluene-sulfonic acid monohydrate (12 mg), trimethyl orthoformate (1 mL) and methanol (1 mL) was heated at reflux overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−ethyl acetate) to give 9-[2-chloro-4-ethoxycarbonylmethoxy-5-(2,3-difluoro-6-methoxybenzyloxy)phenyl]-6-methoxy-2-(1,1-dimethoxyethyl)-7,9-dihydro-8H-purin-8-one (74 mg). This material was dissolved in ethanol (1 mL)-tetrahydrofuran (1 mL). To the solution was added sodium borohydride (45 mg), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (2 mL). To the solution were added concentrated hydrochloric acid (0.1 mL) and water (0.1 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate) to give the title compound (25 mg).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([C:32]1[N:33]=[C:34](Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.CN(C)C1CCNC1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][CH:24]([N:33]([CH3:34])[CH3:32])[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CN(C)C1CCNC1
Product: CN(C)C1CCN(c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and N,N-dimethylpyrrolidin-3-amine. MS(m/e): 414.3 (MH+).
Reaction SMILES: CSC.[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C@@H:19]([NH:23][C:24]([C:26]3[CH:27]=[C:28]([C:34]4[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=4)[CH:29]=[CH:30][C:31]=3[O:32]C)=[O:25])[CH2:20][O:21][CH3:22])=[CH:14][CH:13]=2)[CH:8]=[CH:9][C:10]=1[F:11].CO>C(Cl)Cl>[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C@@H:19]([NH:23][C:24]([C:26]3[CH:27]=[C:28]([C:34]4[CH:35]=[CH:36][C:37]([C:40]([F:43])([F:41])[F:42])=[CH:38][CH:39]=4)[CH:29]=[CH:30][C:31]=3[OH:32])=[O:25])[CH2:20][O:21][CH3:22])=[CH:14][CH:13]=2)[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: COC[C@@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)NC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1OC
Solvent: ClCCl
Solvent: CSC
Solvent: CO
Product: COC[C@@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)NC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1O
Temperature: -78 °C
Reaction time: 2 h
Yield: 62.7 %

Procedure:
DMS (13 mg, 0.04 mmol) was added to a solution of 4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid [2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-methoxymethyl-ethyl]-amide (24 mg, 0.04 mmol) in 3 mL of anhydrous CH2Cl2, at −78° C. and slowly allowed to come to room temperature and stirred for 2 h. After completion of the reaction, reaction was cooled to −78° C. and 0.5 mL of MeOH was added, solvent was removed under vacuum and the residue was taken in ethyl acetate (4 mL) and washed with aq NaHCO3 solution, water, brine and dried over Na2SO4. Solvent was removed under vacuum and silica gel column chromatography (Ethyl acetate: Hexanes) gave pure 4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid [2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-methoxymethyl-ethyl]-amide (14 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]([OH:10])=O)[C:4](=[O:11])[CH2:3]1.[NH2:12][CH2:13][C:14]([N:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1([CH3:23])[CH3:22])=[O:15].C1CCC(N=C=NC2CCCCC2)CC1>CS(C)=O.O1CCCC1.O>[CH3:22][C:17]1([CH3:23])[NH:18][C:19](=[O:21])[CH2:20][N:16]1[C:14](=[O:15])[CH2:13][NH:12][C:8](=[O:10])[CH2:7][N:5]1[CH2:6][CH:2]([OH:1])[CH2:3][C:4]1=[O:11]
Reactant: CC1(C)NC(=O)CN1C(=O)CN
Reactant: O=C(O)CN1CC(O)CC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC1(C)NC(=O)CN1C(=O)CNC(=O)CN1CC(O)CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.9 %

Procedure:
Into an ice cold solution of 4-hydroxy-2-oxo-1-pyrrolidineacetic acid (0.95 g) and 1-(2-aminoacetyl)-2,2-dimethyl-4-imidazolidinone (1 g) in dimethylsulfoxide (30 ml) a solution of DCC (1,22 g) in tetrahydrofuran (10 ml) was added dropwise. The solution was stirred at room temperature overnight and then heated at 50° for 4 hours. After cooling the solution was diluted with water and the resulting precipitate was filtered off. The filtrate was evaporated to dryness under vacuum. The residue was dissolved in water and eluted on a column of Amberlite IR 120H (20 ml). The eluate was treated with Amberlite IRA 68 (10 ml), filtered and evaporated under vacuum. The residue was triturated with isopropanol to yield 0.4 g of the title compound, m.p. 227°-229° .
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][CH:6]1[OH:7])(=[O:3])[CH3:2].C1CCN2C(=NCCC2)CC1.C([O:43][C:44](=[O:47])[CH2:45]Br)C1C=CC=CC=1.COC(C)(C)C>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][CH:6]1[O:7][CH2:45][C:44]([OH:47])=[O:43])(=[O:3])[CH3:2]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CC(=O)OC[C@H]1OC(O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: COC(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1OC(OCC(=O)O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C

Procedure:
A mixture that consists of 34.83 g (100 mmol) of 2,3,4,6-tetra-O-acetyl-glucopyranose, 1.39 g (5 mmol) of tetrabutylammonium chloride and 15.22 g (100 mmol) of DBU in 300 ml of tetrahydrofuran is cooled to 0° C. At 0° C., 34.36 g (150 mmol) of 2-bromoacetic acid benzyl ester, dissolved in 40 ml of tetrahydrofuran, is added in drops over 30 minutes while being stirred vigorously. It is stirred for three hours at 0° C. 300 ml of MTB (methyl-tert-butyl ether) is added, solid is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is taken up in 500 ml of tetrahydrofuran. 5 g of palladium (10%) on activated carbon is added thereto and hydrogenated until hydrogen absorption is completed. Then, catalyst is filtered out, it is rewashed with a little tetrahydrofuran and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/n=hexane/ethanol/acetic acid=20:5:3:0.5). The product-containing fractions are concentrated by evaporation, dissolved in 400 ml of ethyl acetate and shaken out three times with 200 ml of water. Then, the organic phase is separated and evaporated to the dry state in a vacuum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[CH3:15][C:16]1([CH3:22])[CH2:20][CH2:19][CH2:18][C@H:17]1[NH2:21].C(C1C=NN2C=C(C(OCC)=O)C=C2C=1N[C@@H]1CCCC1(C)C)(=O)N.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:21][C@@H:17]3[CH2:18][CH2:19][CH2:20][C:16]3([CH3:22])[CH3:15])=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: CC1(C)CCC[C@H]1N
Agent: CCOC(=O)c1cc2c(N[C@@H]3CCCC3(C)C)c(C(N)=O)cnn2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CCC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 120 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
A mixture of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 300 mg, 1.093 mmol) and (R)-2,2-dimethylcyclopentanamine (from Step 3 of Intermediate 5, 164 mg, 1.093 mmol) in DMF (4 mL) was added DIPEA (0.573 mL, 3.28 mmol). The mixture was heated at 120° C. for 60 min in a microwave reactor. Water (4 volumes) was added and the resulting suspension was stirred for 1 h. The solids were filtered, rinsed with water (2×), and then dried to afford the title compound (324 mg, 84% yield) as a pale yellow solid. HPLC (conditions 0): retention time=4.07 min; LCMS: 351.01 (M+), 353.00 (M+2); 1H NMR (methanol-d4, 400 MHz) δ 8.14 (s, 1H), 7.62 (d, J=1.8 Hz, 1H), 7.02 (d, J=1.8 Hz, 1H), 4.15 (t, J=7.3 Hz, 1H), 2.32 (m, 1H), 1.61-1.86 (m, 5H), 1.13 (s, 3H), 1.10 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[S:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C([C:26]1[C:27]([N:32]=[CH:33][N:34]([CH3:36])C)=[N:28][CH:29]=[CH:30][CH:31]=1)#N.NC1C=C(OCC2C=CC=C(F)C=2)C=CC=1SC1C=CC(O)=CC=1>>[CH2:9]([O:8][C:6]1[CH:5]=[CH:4][C:3]([S:16][C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)=[C:2]([NH:1][C:36]2[C:26]3[CH:31]=[CH:30][CH:29]=[N:28][C:27]=3[N:32]=[CH:33][N:34]=2)[CH:7]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1cc(OCc2ccccc2)ccc1Sc1ccc(O)cc1
Reactant: CN(C)C=Nc1ncccc1C#N
Agent: Nc1cc(OCc2cccc(F)c2)ccc1Sc1ccc(O)cc1
Product: Oc1ccc(Sc2ccc(OCc3ccccc3)cc2Nc2ncnc3ncccc23)cc1

Procedure:
The product from Example 27A and the product from Example 57A were reacted according to the procedure in Example 57E substituting the product of Example 27A for the product of Example 57D to provide the title compound which was isolated as the acetic acid salt (79 mg, 48%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 5.10 (s, 3H), 6.61-6.72 (m, 2H), 6.93 (d, J=9.56 Hz, 1H), 7.11 (d, J=8.46 Hz, 4H), 7.24 (s, 1H), 7.32-7.47 (m, 5H), 7.59-7.68 (m, 1H), 8.54 (s, 1H), 8.83 (d, J=9.56 Hz, 1H), 9.04 (s, 1H); ESI+ m/z 453 (M+H)+, ESI− m/z 451 (M−H)−.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=O)=O.O[C@H]1[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[C@H:16]([C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][O:42][C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=3)=[O:44])[CH2:36][CH2:35]2)=[O:33])[CH2:15]1>O1CCCC1>[SH:9][C@@H:8]1[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[C@H:16]([C:32]([N:34]2[CH2:35][CH2:36][N:37]([CH2:40][CH2:41][O:42][C:43]([O:45][CH2:46][C:47]3[CH:48]=[CH:49][C:50]([N+:53]([O-:55])=[O:54])=[CH:51][CH:52]=3)=[O:44])[CH2:38][CH2:39]2)=[O:33])[CH2:15]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCCN1CCN(C(=O)[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(OCCN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
89 μl of triethylamine and 50 μl of methanesulfonyl chloride were added, whilst ice-cooling, to a solution of 321 mg of (2S,4R)-4-hydroxy-2-{4-[2-(4-nitrobenzyloxycarbonyl)oxyethyl]-1-piperazinylcarbonyl}-1-(4-nitrobenzyloxycarbonyl)pyrrolidine in 3.2 ml of dry tetrahydrofuran, and the resulting mixture was stirred at between 0° C. and 5° C. for 30 minutes and then at room temperature for a further 1 hour. At the end of tis time, the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting residue was mixed with an aqueous solution of sodium hydrogencarbonate; the mixture was then extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, to give 345 mg of the title compound as a powder.