Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7]O)C.[CH2:10]1[CH2:15]O[CH:13]=[CH:12][CH2:11]1.CC1(C)C2([CH2:25][S:26]([OH:29])(=[O:28])=[O:27])C(CC1CC2)=O>N1C=CC=CC=1>[CH2:5]1[CH2:4][O:3][CH:1]=[CH:7][CH2:6]1.[CH3:1][C:11]1[CH:12]=[CH:13][C:25]([S:26]([OH:29])(=[O:28])=[O:27])=[CH:15][CH:10]=1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: CCOC(=O)CCCO
Agent: C1=COCCC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O)cc1

Procedure:
Scheme 7 depicts the synthesis of intermediate 11e wherein R3 and Y2 are the same and X═Br. Thus, commercially-available 4-hydroxy-butanoic acid ethyl ester 37 is treated with DHP and CSA, or with DHP, TsOH, and pyridine to provide ester 38. Reduction with LiAlD4 affords deuterated alcohol 39, which is treated with either triphenyl phosphine in CCl4 (Sabitha, G et al., Tetrahedron Letters, 2006, (volume date 2007), 48(2): 313-315) or with methanesulfonyl chloride, lithium chloride, and 2,6-lutidine in DMF (Blaszykowski, C et al., Organic Letters, 2004, 6(21): 3771-3774) to afford chloride 40. Following the same methods as in Scheme 6, chloride 40 may be converted to 11e.
Reaction SMILES: C(O)(=O)C1C(=CC=CC=1)C(O)=O.ClCl.[OH-].[Na+].[Cl:17][C:18]1[CH:19]=[C:20]([C:28]([OH:30])=[O:29])[C:21](=[CH:25][C:26]=1Cl)[C:22]([OH:24])=[O:23].ClC1C(Cl)=CC=C(C(O)=O)C=1C(O)=O.ClC1C=CC(Cl)=C(C(O)=O)C=1C(O)=O.ClC1C=C(C(O)=O)C(C(O)=O)=C(Cl)C=1Cl>O>[Cl:17][C:18]1[CH:19]=[C:20]([C:28]([OH:30])=[O:29])[C:21](=[CH:25][CH:26]=1)[C:22]([OH:24])=[O:23]
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1C(=O)O
Agent: ClCl
Agent: O=C(O)c1c(Cl)ccc(Cl)c1C(=O)O
Agent: O=C(O)c1cc(Cl)c(Cl)c(Cl)c1C(=O)O
Solvent: O
Product: O=C(O)c1ccc(Cl)cc1C(=O)O
Reaction time: 10 h
Yield: 4 %

Procedure:
The chlorination of the phthalic acid is effected in analogy with known methods in water at 45° to 50° by admitting chlorine gas with the pH value being kept at approximately 5 by the addition of aqueous sodium hydroxide. After approximately 10 hours reacting, a mixture containing approximately 63% 4,5-dichlorophthalic acid, 17% 3,4-dichlorophthalic acid, 9% 3,6-dichlorophthalic acid, 6% trichlorophthalic acid and 4% 4-chlorophthalic acid (chromatographic analysis) is obtained. The mixture is heated under low vacuum to approximately 200° to yield the corresponding chlorophthalic acid anhydride. The product is employed as such for the reaction with the 1,8-diaminonaphthalene.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)[CH:7]=1.[CH3:13][O:14][C:15]1[N:20]=[C:19]([O:21][CH3:22])[C:18](B(O)O)=[CH:17][N:16]=1.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>C(OCC)(=O)C>[CH3:13][O:14][C:15]1[N:20]=[C:19]([O:21][CH3:22])[C:18]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=3)[CH:7]=2)=[CH:17][N:16]=1
Reactant: O=Cc1cnc2ccc(Br)cn12
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ncc(-c2ccc3ncc(C=O)n3c2)c(OC)n1
Yield: 47.43 %

Procedure:
6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde (Compound of step 1 of Intermediate 1, 200 mg, 0.89 mmol), 2,4-dimethoxypyrimidin-5-ylboronic acid (212.57 mg, 1.15 mmol), dichlorobis(triphenylphosphine) palladium (II) (20 mg, 10% mmol) and 2M aqueous Na2CO3 (1 mL) were added to DMF (8 mL) and refluxed for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with H2O and brine. The solvent was evaporated to obtain crude product, which was purified by column chromatography (silica gel, 1% methanol in chloroform) to obtain the title compound. Yield: 47.43%; 1H NMR (DMSO-d6; 300 MHz): δ 9.97 (s, 1H), 9.59 (s, 1H), 8.56-8.58 (d, 2H, J=4.5 Hz), 7.88-7.98 (m, 2H), 3.96 (s, 3H), 3.98 (s, 3H); MS: m/z 285.1 (M+1)+
Reaction SMILES: ClCC([NH:5][C:6]1[S:7][CH:8]=[C:9](/[C:11](=[N:42]/[O:43][CH3:44])/[C:12]([NH:14][C@H:15]2[C@@H:18]([CH2:19][O:20][C:21](=[O:36])/[C:22](/[C:26]3[N:27]=[C:28]([NH:31]C(=O)CCl)[S:29][CH:30]=3)=[N:23]\[O:24][CH3:25])[N:17]([S:37]([O-:40])(=[O:39])=[O:38])[C:16]2=[O:41])=[O:13])[N:10]=1)=O.[Na+:45].CSC(=S)N.[Na]>O>[NH2:5][C:6]1[S:7][CH:8]=[C:9](/[C:11](=[N:42]/[O:43][CH3:44])/[C:12]([NH:14][C@H:15]2[C@@H:18]([CH2:19][O:20][C:21](=[O:36])/[C:22](/[C:26]3[N:27]=[C:28]([NH2:31])[S:29][CH:30]=3)=[N:23]\[O:24][CH3:25])[N:17]([S:37]([O-:40])(=[O:39])=[O:38])[C:16]2=[O:41])=[O:13])[N:10]=1.[Na+:45]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1COC(=O)/C(=N\OC)c1csc(NC(=O)CCl)n1)c1csc(NC(=O)CCl)n1
Agent: CSC(N)=S
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1COC(=O)/C(=N\OC)c1csc(N)n1)c1csc(N)n1

Procedure:
To a solution of 221 mg of sodium cis-3-[2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-methoxyiminoacetamido]-4-[2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-methoxyiminoacetoxymethyl]-2-oxoazetidine-1-sulfonate in 10 ml of water is added under ice-cooling 85 mg of sodium monomethyldithiocarbamate with stirring. The mixture is stirred at room temperature for one hour, followed by addition of 40 mg of sodium monomethyldithiocarbamate. The mixture is stirred at room temperature for further one hour. The reaction mixture is washed with ethyl acetate and ether in this order, followed by concentration under reduced pressure. The concentrate is purified by a column chromatography on Amberlite XAD-II, followed by lyophilization to give sodium cis-3-[2-(2-amino-4-thiazolyl)-(Z)-2-methoxyiminoacetamido]-4-[2-(2-amino-4-thiazolyl)-(Z)-2-methoxyiminoacetoxymethyl]-2-oxoazetidine-1-sulfonate.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:12]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].[OH-].[K+].C(O)(=O)C>CO.O>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([CH:20]=[C:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:1]2=[O:11])=[CH:22][CH:23]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: O=C1CCCc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(C=C2CCc3ccccc3C2=O)cc1

Procedure:
A mixture of 3,4-dihydro-1(2H)-naphthalenone (4.5 g) and 4-tert-butylbenzaldehyde (5.0 g) was stirred with a solution of 4% potassium hydroxide in methanol (100 ml) for 64 hours at room temperature. The mixture was neutralised with glacial acetic acid, followed by dilution with water (100 ml). The resulting copious white precipitate was filtered off, washed with water and dried in vacuo to give 2-(4-tert-butylbenzylidene)-3,4-dihydro-1(2H)-naphthalenone.
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:20]=[CH:19][C:14]2[C:15](=[O:18])[O:16][CH2:17][C:13]=2[C:12]=1[CH3:21])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][C:5]1=[O:10].[CH3:22][C:23]1[C:31]2[CH2:30][O:29][C:28](=[O:32])[C:27]=2[CH:26]=[CH:25][C:24]=1[C@@H:33]1[CH2:35][O:34]1>CCO>[OH:34][C@H:33]([C:24]1[CH:25]=[CH:26][C:27]2[C:28](=[O:32])[O:29][CH2:30][C:31]=2[C:23]=1[CH3:22])[CH2:35][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[C:11]2[CH:20]=[CH:19][C:14]3[C:15](=[O:18])[O:16][CH2:17][C:13]=3[C:12]=2[CH3:21])[C:5](=[O:10])[CH2:6]1
Reactant: Cc1c(C(O)CN2CCNCC2=O)ccc2c1COC2=O
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Solvent: CCO
Product: Cc1c(C(O)CN2CCN(C[C@H](O)c3ccc4c(c3C)COC4=O)CC2=O)ccc2c1COC2=O
Temperature: 150 °C

Procedure:
A mixture of 1-[2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-2-one (49 mg, 0.17 mmol) and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one (64 mg, 0.34 mmol) in EtOH (2 mL) in a 5 mL microwave tube was heated to 150° C. for 2 hours. LC showed formation of the product, which was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 481 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:40])=[C:4]([NH:18][C:19]([NH:21][C:22]2[C:27]([I:28])=[C:26]([C:29]([NH:31][CH2:32][CH:33]([OH:36])[CH2:34][OH:35])=[O:30])[C:25]([I:37])=[C:24]([NH2:38])[C:23]=2[I:39])=[O:20])[C:5]([I:17])=[C:6]([C:9]([NH:11][CH2:12][CH:13]([OH:16])[CH2:14][OH:15])=[O:10])[C:7]=1[I:8]>C(OC(=O)C)(=O)C.N1C=CC=CC=1.CN(C=O)C>[NH2:38][C:24]1[C:23]([I:39])=[C:22]([NH:21][C:19]([NH:18][C:4]2[C:5]([I:17])=[C:6]([C:9]([NH:11][CH2:12][CH:13]([O:16][C:9](=[O:10])[CH3:6])[CH2:14][O:15][C:14](=[O:15])[CH3:13])=[O:10])[C:7]([I:8])=[C:2]([NH2:1])[C:3]=2[I:40])=[O:20])[C:27]([I:28])=[C:26]([C:29]([NH:31][CH2:32][CH:33]([O:36][C:34](=[O:35])[CH3:33])[CH2:34][O:35][C:29](=[O:30])[CH3:26])=[O:30])[C:25]=1[I:37]
Reactant: Nc1c(I)c(NC(=O)Nc2c(I)c(N)c(I)c(C(=O)NCC(O)CO)c2I)c(I)c(C(=O)NCC(O)CO)c1I
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)OCC(CNC(=O)c1c(I)c(N)c(I)c(NC(=O)Nc2c(I)c(N)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c2I)c1I)OC(C)=O
Temperature: 25 °C
Reaction time: 65 h

Procedure:
N,N'-bis[3-amino-2,4,6-triiodo-5-(2,3-dihydroxypropylaminocarbonyl)phenyl]urea (1.23 g, 1.0 mmol) was dissolved in a mixture of acetic anhydride (5 ml), pyridine (5.5 ml) and DMF (5 ml). The solution was stirred at room temperature for 65 h, and the solvents were evaporated. The residue was dissolved in CH2Cl2 (250 ml) and the solution was washed with water (2×50 ml) 0.1M aqueous HCl (50 ml), water (100 ml) and a saturated aqueous solution of NaHCO3. After drying (Na2SO4) and evaporation, NMR and HPLC analysis of the residue showed an essentially pure product. Yield: 1.0 g (71%).
Reaction SMILES: NC([O:4][C@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[N:12]=[C:13]3[CH:26]=[C:25]([C:27]([NH:29][C:30]4[S:31][CH:32]=[C:33]([C:35]([CH3:38])([CH3:37])[CH3:36])[N:34]=4)=[O:28])[CH:24]=[CH:23][N:14]3[C:15](=[O:22])[C:16]=2/C=C/C(O)=O)[CH2:6]1)=O.C(C1N=C(NC(C2C=CN3C(=O)CC(=O)N=C3C=2)=O)SC=1)(C)(C)C.Cl.O[C@H]1CCCNC1>>[C:35]([C:33]1[N:34]=[C:30]([NH:29][C:27]([C:25]2[CH:24]=[CH:23][N:14]3[C:15](=[O:22])[CH:16]=[C:11]([N:7]4[CH2:8][CH2:9][CH2:10][C@H:5]([OH:4])[CH2:6]4)[N:12]=[C:13]3[CH:26]=2)=[O:28])[S:31][CH:32]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)c1csc(NC(=O)c2ccn3c(=O)c(/C=C/C(=O)O)c(N4CCC[C@H](OC(N)=O)C4)nc3c2)n1
Agent: CC(C)(C)c1csc(NC(=O)C2=CC3=NC(=O)CC(=O)N3C=C2)n1
Agent: Cl
Agent: O[C@H]1CCCNC1
Product: CC(C)(C)c1csc(NC(=O)c2ccn3c(=O)cc(N4CCC[C@H](O)C4)nc3c2)n1
Yield: 62 %

Procedure:
Reactions were performed in the same manner as in Example 8, (E) by using N8-[4-(tert-butyl)-1,3-thiazol-2-yl]-2,4-dioxo-3,4-dihydro-2H-pyrido[1,2-a]pyrimidine-8-carboxamide (600 mg, 1.74 mmol) and (S)-(−)-3-hydroxypiperidine hydrochloride (360 mg, 2.61 mmol) to obtain 463 mg (62%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[NH:8][C:7]2=[O:17].C([O-])([O-])=O.[K+].[K+].[CH3:24][C@@H:25]1[C:29]2[NH:30][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:32][C:28]=2[C:27](=[O:42])[NH:26]1.O1CCOCC1>C(Cl)Cl.O>[C:13]([NH:12][C:9]1[NH:8][C:7](=[O:17])[C:6]2[C:11](=[C:2]([C:31]3[NH:30][C:29]4[C@@H:25]([CH3:24])[NH:26][C:27](=[O:42])[C:28]=4[CH:32]=3)[CH:3]=[CH:4][CH:5]=2)[N:10]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)Nc1nc2c(Br)cccc2c(=O)[nH]1
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: C[C@H]1NC(=O)c2cc(-c3cccc4c(=O)[nH]c(NC(C)(C)C)nc34)[nH]c21
Yield: 8.1 %

Procedure:
Argon was bubbled into a mixture of 8-bromo-2-(tert-butylamino)quinazolin-4(3H)-one (408a, 62 mg, 0.21 mmol), K2CO3 (0.116 g, 0.84 mmol), dichlorobis(p-dimethylamino-phenylditbutylphosphine)palladium (ii) (Aldrich; 0.030 g, 0.042 mmol), (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (706; 0.110 g, 0.419 mmol) and 2 mL dioxane and 0.4 mL water for 1 min. The reaction was sealed and placed in a 100° C. oil bath for 30 min. The reaction was cooled and partitioned between sat'd aq. NH4Cl and DCM. The aqueous layer was extracted with 5% IPA/CHCl3 three times and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. This material was dissolved in DMSO, filtered, and purified by RPHPLC, Phenomenex Gemini 150×30 mm C18 column, 10-70% ACN/H2O with 0.1% TFA; product-containing fractions were treated with saturated aqueous NaHCO3 and DCM. The aqueous layer was extracted 3×DCM and combined organics dried over Na2SO4, filtered, and concentrated in vacuo to give 21 mg as a tan solid. The material was sonicated in 0.5 mL DCM for 2 min, then filtered, rinsing 2×DCM. The solid was collected and dried in vacuo to give (R)-2-(tert-butylamino)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinazolin-4(3H)-one (6 mg, 0.017 mmol, 8% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.21 (1H, br. s.), 10.63 (1H, s), 7.95 (1H, dd, J=7.6, 1.6 Hz), 7.82 (1H, dd, J=7.8, 1.6 Hz), 7.62 (1H, s), 7.16 (1H, t, J=7.7 Hz), 6.79 (1H, d, J=1.4 Hz), 6.30 (1H, s), 4.54 (1H, d, J=6.7 Hz), 1.47 (9H, s), 1.36 (3H, d, J=6.7 Hz). m/z (ESI, +ve ion) 352.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[F:35])[CH2:16][CH2:15][CH:14]([O:17][S:18]([NH:21][CH2:22][CH2:23][O:24]C(=O)C)(=[O:20])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Li+].C(OCC)(=O)C>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[F:35])[CH2:12][CH2:13][CH:14]([O:17][S:18](=[O:19])(=[O:20])[NH:21][CH2:22][CH2:23][OH:24])[CH2:15][CH2:16]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(=O)OCCNS(=O)(=O)OC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=S(=O)(NCCO)OC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Reaction time: 2 h

Procedure:
To a stirred solution of the product from Example 116 (54 mg, 0.1 mmol) in tetrahydrofuran (2 mL) was added lithium hydroxide (35 mg, 1.5 mmol) in water (2 mL) and the mixture stirred for 2 hours. Ethyl acetate (20 mL) was added, the solution washed with saturated aqueous ammonium chloride (10 mL), saturated aqueous sodium bicarbonate (10 mL) and brine (20 mL), dried (MgSO4) and evaporated to leave a residue which was purified by column chromatography on silica eluting with ethyl acetate:iso-hexane 1:1, to afford the title compound. (33 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[F:20][C:21]([F:33])([F:32])[C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:20])([F:32])[F:33])[CH:23]=2)(=[O:30])=[O:29])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: O=S(=O)(Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1)c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 3-(trifluoromethyl)benzene-1-sulfonyl chloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([NH2:15])([CH2:13][OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC1C([O:23][C:24]([C:26]2[N:27]=[N:28][C:29]([CH2:45][CH2:46][CH2:47][CH3:48])=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)=[CH:34][CH:33]=3)[CH:31]=2)=O)=C(F)C(F)=C(F)C=1F>ClCCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([NH:15][C:24]([C:26]2[N:27]=[N:28][C:29]([CH2:45][CH2:46][CH2:47][CH3:48])=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH:39]4[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]4)=[CH:34][CH:33]=3)[CH:31]=2)=[O:23])([CH2:13][OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCc1nnc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)(CO)C1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCCCc1nnc(C(=O)NC2(CO)CCN(C(=O)OC(C)(C)C)C2)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 3-amino-3-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 mmol, 0.21 g) in anhydrous DCE (2 mL), 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid pentafluorophenyl ester (Example 93, 0.5 mmol, 0.26 g) and TEA (0.5 mL) was stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with NaOH (0.5 M) solution, water, and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography using ethyl acetate:hexanes (7:3) to provide 3-{[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carbonyl]-amino}-3-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:20]=[CH:21][N:22]=2)[C:15]([O:17]CC)=[O:16])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C(O)C.Cl>O1CCCC1>[C:1]1([CH2:7][CH2:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:20]=[CH:21][N:22]=2)[C:15]([OH:17])=[O:16])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccnc(NC(=O)CCc2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(CCc1ccccc1)Nc1cc(C(=O)O)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of ethyl 2-[(3-phenylpropanoyl)amino]isonicotinate (3.41 g, 11.43 mmol), 1 M aqueous sodium hydroxide solution (15 mL), ethanol (20 mL) and tetrahydrofuran (20 mL) was stirred at room temperature for 1 hr. The reaction mixture was neutralized with hydrochloric acid, and the precipitate was collected by filtration and washed with water to give the title compound (3.09 g, yield 100%) as colorless crystals.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:22]=[CH:21][C:20]3[N:19]=[CH:18][C:17]4[N:23]([CH3:34])[C:24](=[O:33])[N:25]([C:26]5[C:27]([CH3:32])=[N:28][N:29]([CH3:31])[CH:30]=5)[C:16]=4[C:15]=3[CH:14]=2)[CH:12]=1)([CH3:6])[CH3:5].CO.[BH4-].[Na+]>C1COCC1>[CH3:31][N:29]1[CH:30]=[C:26]([N:25]2[C:16]3[C:15]4[CH:14]=[C:13]([C:11]5[CH:10]=[N:9][CH:8]=[C:7]([C:4]([CH3:6])([CH3:5])[CH2:3][OH:2])[CH:12]=5)[CH:22]=[CH:21][C:20]=4[N:19]=[CH:18][C:17]=3[N:23]([CH3:34])[C:24]2=[O:33])[C:27]([CH3:32])=[N:28]1
Reactant: COC(=O)C(C)(C)c1cncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncc(C(C)(C)CO)c4)cc3c21

Procedure:
To a solution of 2-{5-[1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridin-3-yl}-2-methyl-propionic acid methyl ester (Stage 229.1.1, 0.134 mmol) in THF (1.2 ml) were added MeOH (0.009 ml) and NaBH4 (0.185 mmol) four times during the course of the heating at 40° C. for 39 h. After that, the RM was quenched with saturated aqueous NaHCO3 and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was taken in DMF and purified by preparative HPLC. The fractions containing product were basified with NaHCO3, concentrated and extracted with dichloromethane (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, evaporated and dried under vacuum to give the title compound as a white foam. (HPLC: tR 2.06 min (Method A); M+H=442 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.62-8.58 (m, 2H), 8.15-8.11 (m, 2H), 8.01-7.96 (m, 1H), 7.74-7.71 (m, 1H), 7.62-7.59 (m, 1H), 4.79 (t, 1H), 3.88 (s, 3H), 3.58 (s, 3H), 3.50 (d, 2H), 1.96 (s, 3H), 1.30 (s, 6H))
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([OH:20])[CH:18]=2)[N:13]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:12]=12.[CH2:26]([O:28][C:29](=[O:34])[C:30](Br)([CH3:32])[CH3:31])[CH3:27]>>[CH2:26]([O:28][C:29](=[O:34])[C:30]([O:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:12]1=[C:11]2[C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)([CH3:32])[CH3:31])[CH3:27]
Reactant: Oc1ccc2c(c1)c(-c1ccc3ccccc3n1)c1n2CCCCC1
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccc3ccccc3n1)c1n2CCCCC1

Procedure:
This compound was prepared from 11-(2-quinolyl)-7,8,9,10-tetrahydro-6H-azepino[1,2-a]indole-2-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:14]1(Br)[CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:14]1([O:1][C:2]2[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1ccc(C#N)c(O)c1OC
Reactant: BrC1CCCC1
Product: COc1ccc(C#N)c(OC2CCCC2)c1OC
Yield: 95 %

Procedure:
The subtitle compound was prepared from 2-hydroxy-3,4-dimethoxybenzonitrile and freshly distilled cyclopentyl bromide following the procedure described in Example 10(d). The crude product was purified on silica gel eluting with dichloromethane to give the subtitle compound as a colourless oil (95%). Rf 0.50 (dichloromethane). MS m/z 265 (MNH4)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1C2C=CC(O[CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]([C:33]4([C:37]5[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=5)[CH2:36][CH2:35][CH2:34]4)=[O:32])[CH2:26]3)=CC=2OC1>>[Cl:43][C:40]1[CH:41]=[CH:42][C:37]([C:33]2([C:31]([N:27]3[CH2:28][CH2:29][CH2:30][CH:25]([CH2:24][O:1][C:2]4[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=4)[CH2:26]3)=[O:32])[CH2:36][CH2:35][CH2:34]2)=[CH:38][CH:39]=1
Reactant: O=C(N1CCCC(COc2ccc3c(c2)OCO3)C1)C1(c2ccc(Cl)cc2)CCC1
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C(N1CCCC(COc2cccnc2)C1)C1(c2ccc(Cl)cc2)CCC1

Procedure:
Compound 85 was synthesized from 3-hydroxypyridine (0.25 g, 2.60 mmol), cesium carbonate (1.27 g, 3.89 mmol) and compound 43 (1.0 g, 2.60 mmol), using the method described for the synthesis of compound 44 to give 0.52 g of the desired product 85. C22H25ClN2O2, LRMS (m/z)=385 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Br[CH:11]([Cl:14])[CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:14][CH2:11][CH2:12][CH2:13][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: CCC(Cl)Br
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(OCCCCl)cc1

Procedure:
A mixture of 4-cyanophenol, 125.0 g (1.05 mole), bromochloropropane, 189.0 g (1.2 mole) and potassium carbonate, 145.0 g (1.05 mole) was heated overnight at reflux in 750 ml of acetone. The reaction mixture was filtered and stripped to dryness. The resulting residue was dissolved in chloroform and extracted with 5% sodium hydroxide. Removal of chloroform gave an oil which crystallized to a white solid. A 5 g sample was recrystallized from isopropyl ether. This furnished 1.22 g (24.4%) of white solid, m.p. 40°-44° C. which contained a dimer impurity.
Reaction SMILES: [H-].[Na+].C(O[C:6](=O)[CH:7](C)[C:8]([CH3:10])=[O:9])C.[CH2:13]1[CH2:19][S:16](=[O:18])(=[O:17])[O:15][CH2:14]1>C1COCC1>[CH3:6][CH:7]([C:8](=[O:9])[CH3:10])[CH2:14][CH2:13][CH2:19][S:16]([OH:15])(=[O:18])=[O:17]
Reactant: O=S1(=O)CCCO1
Reactant: CCOC(=O)C(C)C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)C(C)CCCS(=O)(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium hydride (2.1 g, 80 wt %=69 mmol) was slurried in 10 ml dry THF. The suspension was cooled to 0° C. and a solution of ethyl-2-methylacetoacetate (10 g, 69 mmol) in 10 ml dry THF was added dropwise. The solution was stirred at room temperature for one h. A solution of 1,3-propanesultone (8.42 g, 69 mmol) in 10 ml dry THF was added dropwise. Once the addition was complete, the solution was stirred for two h at 40° C. The solution was evaporated to dryness. The residue was dissolved in 100 ml water. The aqueous solution was extracted twice with ethylacetate, then 100 ml concentrated HCl was added and the solution was refluxed for two hours. The solvent was evaporated in vacuum. The residue was purified by column chromatography (silica, methanol/dichloromethane) to give 4-methyl-5-oxohexane sulfonic acid. Yield 10 g; MS (ESI−): 193.2 [M]−