Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1N(C2C=CC=CC=2OC)[N:5]=[CH:4][C:3]=1[C:15]#N.[F:17][C:18]1([F:26])[CH2:23][CH2:22][CH:21]([NH:24][NH2:25])[CH2:20][CH2:19]1>>[NH2:5][C:4]1[N:24]([CH:21]2[CH2:22][CH2:23][C:18]([F:26])([F:17])[CH2:19][CH2:20]2)[N:25]=[CH:15][C:3]=1[C:2]#[N:1]
Reactant: NNC1CCC(F)(F)CC1
Reactant: COc1ccccc1-n1ncc(C#N)c1N
Product: N#Cc1cnn(C2CCC(F)(F)CC2)c1N

Procedure:
Following the procedure for the preparation of 5-amino-1-(2-methoxyphenyl)-1H-pyrazole-4-carbonitrile but substituting 1-(4,4-difluorocyclohexyl)hydrazine provided the title compound. 400 MHz 1H NMR (CDCl3) δ 7.5 (m, 1H), 3.90 (m, 1H), 2.40-1.00 (m, 8H).
Reaction SMILES: [C:1](=O)([O:47]C1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C@H:14]([NH:35][C:36]([O:38][C@@H:39]2[C@H:46]3[C@H:42]([O:43][CH2:44][CH2:45]3)[O:41][CH2:40]2)=[O:37])[C@H:15]([OH:34])[CH2:16][N:17]([S:22]([C:25]2[CH:33]=[CH:32][C:28]3[O:29][CH2:30][O:31][C:27]=3[CH:26]=2)(=[O:24])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:9][CH:8]=1.[CH3:58][NH2:59].O1CCCC1>>[O:29]1[C:28]2[CH:32]=[CH:33][C:25]([S:22]([N:17]([CH2:18][CH:19]([CH3:20])[CH3:21])[CH2:16][C@@H:15]([OH:34])[C@@H:14]([NH:35][C:36](=[O:37])[O:38][C@@H:39]3[C@H:46]4[C@H:42]([O:43][CH2:44][CH2:45]4)[O:41][CH2:40]3)[CH2:13][C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][O:2][C:1]([NH:59][CH3:58])=[O:47])=[CH:12][CH:11]=3)(=[O:24])=[O:23])=[CH:26][C:27]=2[O:31][CH2:30]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCOC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)OCCCOc1ccc(C[C@H](NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)[C@H](O)CN(CC(C)C)S(=O)(=O)c2ccc3c(c2)OCO3)cc1

Procedure:
3-(4-{(2S,3R)-2-({[(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl}amino)-4-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-3-hydroxybutyl}phenoxy)propyl 4-nitrophenyl carbonate was treated with 2M methylamine/tetrahydrofuran as described above to provide the title compound as a white solid. 1H NMR (DMSO-d6): δ 0.78 (3H, d), 0.84 (3H, d), 1.1-1.2 (1H, m), 1.2 (1H, br quintuplet), 1.9-2.0 (3H, m), 2.17 (1H, t), 2.45 (3H, d), 2.6-2.8 (3H, m), 2.83-3.00 (2H, m), 3.4-3.6 (5H, m), 3.7 (1H, br s), 3.8 (1H, br s), 3.9 (2H, br s), 4.0 (2H, br s), 4.8-4.9 (1H, m), 5.0 (1H, d), 5.5 (1H, d), 6.17 (2H, s), 6.7-6.8 (2H, m), 6.9 (1H, br s), 7.0-7.1 (3H, m), 7.2-7.4 (3H, m); MS: 708 (MH+);
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH2:7][C:8]([OH:10])=O)[O:4][N:3]=1.[NH2:11][CH:12]1[C:30](=[O:31])[N:14]2[C:15]([C:27]([OH:29])=[O:28])=[C:16]([CH:19]([C:21]3[S:22][C:23]([CH3:26])=[N:24][N:25]=3)[SH:20])[CH2:17][S:18][C@H:13]12>C(#N)C>[CH3:1][C:2]1[N:6]=[C:5]([CH2:7][C:8]([NH:11][CH:12]2[C:30](=[O:31])[N:14]3[C:15]([C:27]([OH:29])=[O:28])=[C:16]([CH:19]([C:21]4[S:22][C:23]([CH3:26])=[N:24][N:25]=4)[SH:20])[CH2:17][S:18][C@H:13]23)=[O:10])[O:4][N:3]=1
Reactant: Cc1nnc(C(S)C2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Reactant: Cc1noc(CC(=O)O)n1
Solvent: CC#N
Product: Cc1noc(CC(=O)NC2C(=O)N3C(C(=O)O)=C(C(S)c4nnc(C)s4)CS[C@H]23)n1
Yield: 58 %

Procedure:
Using the same procedure, 21.65 mmol of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid and 21.65 mmol of 7-amino-3-(5-methyl-1,3,4-thiadiazol-2-yl-mercaptomethyl)-3-cephem-4-carboxylic acid in 220 ml of dry acetonitrile were reacted for 3 hours at room temperature and 3 hours at 50° C.±5° C. to obtain a 58% yield of pure 7-[3-methyl-1,2,4-oxadiazol-5-yl-acetamido]-3-[5-methyl-1,3,4-thiadiazol-2-yl-mercaptomethyl]-3-cephem-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[C:30]4[C@H:37]([CH3:38])[CH2:36][C@@H:35]([OH:39])[C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:25][CH2:24]2)=[O:22])[CH2:9][N:10]([CH:18]([CH3:20])[CH3:19])C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.Cl.N1CCNCC1>C(O)CC>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH2:9][NH:10][CH:18]([CH3:20])[CH3:19])[C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[C:30]4[C@H:37]([CH3:38])[CH2:36][C@@H:35]([OH:39])[C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:27][CH2:28]2)=[O:22])=[CH:4][CH:3]=1
Reactant: CC(C)N(C[C@@H](C(=O)N1CCN(c2ncnc3c2[C@H](C)C[C@H]3O)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: C1CNCCN1
Agent: Cl
Solvent: CCCO
Product: CC(C)NC[C@@H](C(=O)N1CCN(c2ncnc3c2[C@H](C)C[C@H]3O)CC1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl ((S)-2-(4-chlorophenyl)-3-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl)(isopropyl)carbamate (50 g) in 1-propanol (128 g) was added HCl in 1-propanol (45.2 g, 5.5N). The solution was heated until complete deprotection. The solution was cooled to room temperature and then a solution of piperazine (7.3 g) in 1-propanol (36.5 g) was added dropwise. The resulting solid piperazine.HCl was filtered off and the filtrate was carbon treated, concentrated and solvent-switched to ethyl acetate. The resulting solid (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one monohydrochloride was filtered and washed with ethyl acetate and dried under vacuum (Yield 22.9 g, 99.8% purity by LC).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=CN=1.[CH2:8]([O:10][C:11](=[O:14])[CH2:12]Br)C.C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[CH3:8][O:10][C:11](=[O:14])[CH2:12][C@@H:2]1[CH2:7][CH2:6][CH2:5][O:1]1
Reactant: Oc1ccccn1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)C[C@@H]1CCCO1
Temperature: 25 °C

Procedure:
A mixture of crude hydroxy-pyridine 22b (30.0 g, 0.151 mol), bromo-acetic acid ethyl ester (16.9 ml, 0.151 mol) and K2CO3 (41.7 g, 0.301 mol) in acetone (1000 mL) is heated to reflux for 5 h. The mixture is cooled to RT, poured into water (800 mL) and extracted with EtOAc (500 mL×2). The combined organic layers are washed with brine, dried (Na2SO4). The solvent is evaporated and the residue is purified by column to afford ester 22c.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15].[OH:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[I:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([CH3:13])[C:3]([S:14]([CH3:17])(=[O:16])=[O:15])=[C:2]2[N:21]1[CH2:22][CH2:23][CH2:24][C@@H:19]([OH:18])[CH2:20]1
Reactant: O[C@@H]1CCCNC1
Reactant: Cc1nc2ccc(I)cc2c(Cl)c1S(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc2ccc(I)cc2c(N2CCC[C@@H](O)C2)c1S(C)(=O)=O
Yield: 59.6 %

Procedure:
4-Chloro-6-iodo-3-methanesulfonyl-2-methyl-quinoline (compound of example D.2) (300 mg, 0.786 mmol), (R)-(+)-3-hydroxypiperidine (119 mg, 0.865 mmol) and N,N-diisopropyl ethyl amine (0.148 mL, 0.865 mmol) were heated in dry N,N-dimethylformamide (3 mL) for 0.5 h at 100° C. N,N-Dimethylformamide was evaporated at 40° C./0.1 mbar, the residue was extracted with dichloromethane and 10% Na2CO3, and then purified by chromatography on silica gel in dichloromethane/methanol 20:1. One obtained a yellow oil which was triturated with ethyl acetate and the resulting white crystals were filtered off. One obtained 209 mg (60%) of white crystals. MS: m/z=447 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14]Br)=[CH:10][CH:9]=2)[CH:4]=[N:3]1.[F:16][C:17]([F:45])([F:44])[O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([C:33]2[CH:38]=[CH:37][C:36]([O:39][C:40]([F:43])([F:42])[F:41])=[CH:35][CH:34]=2)([OH:32])[CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:21][CH:20]=1.C(N(CC)C(C)C)(C)C.CCCCCCC>CS(C)=O.C(OCC)(=O)C>[CH3:1][N:2]1[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:29]3[CH2:30][CH2:31][CH:26]([C:25]([C:22]4[CH:21]=[CH:20][C:19]([O:18][C:17]([F:16])([F:44])[F:45])=[CH:24][CH:23]=4)([C:33]4[CH:38]=[CH:37][C:36]([O:39][C:40]([F:43])([F:42])[F:41])=[CH:35][CH:34]=4)[OH:32])[CH2:27][CH2:28]3)=[CH:10][CH:9]=2)[CH:4]=[N:3]1
Reactant: OC(c1ccc(OC(F)(F)F)cc1)(c1ccc(OC(F)(F)F)cc1)C1CCNCC1
Reactant: Cn1ncn(-c2ccc(CBr)cc2)c1=O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncn(-c2ccc(CN3CCC(C(O)(c4ccc(OC(F)(F)F)cc4)c4ccc(OC(F)(F)F)cc4)CC3)cc2)c1=O
Yield: 51.4 %

Procedure:
This compound was prepared in a manner analogous to that of Step D of Example 12, with 2.0 grams (0.007 mole) of 4,5-dihydro-1-methyl-5-oxo-4-(4-bromomethylphenyl)-1H-1,2,4-triazole, 2.0 grams (0.005 mole) of 4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine (prepared as in Step C of Example 12), and 3.2 grams (0.025 mole) of N,N-diisopropylethylamine in about 15 mL of dimethyl sulfoxide as reagents. The crude reaction product was subjected to column chromatography on silica gel, with 2:8 heptane:ethyl acetate, and then pure ethyl acetate as eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding 1.6 grams of N-[4-(4,5-dihydro-1-methyl-5-oxo-1H-1,2,4-triazol-4-yl)phenylmethyl]-4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH3:9].[NH2:11][OH:12].O>C(O)(=O)C.O1CCOCC1.C(Cl)(Cl)Cl.C(O)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:11][OH:12])[CH3:9]
Reactant: NO
Reactant: CC(=O)c1ccccc1Br
Solvent: O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CC(=NO)c1ccccc1Br
Temperature: 150 °C
Yield: 83 %

Procedure:
Combine 1-(2-bromo-phenyl)-ethanone (4.5 g, 22.6 mmol), 50% hydroxylamine in water (2.3 g, 69.6 mmol) and 1 mL of acetic acid in 15 mL of dioxane in a pressure vessel. Seal the vessel and heat the mixture in an oil bath for 3 h at 150° C. Cool the mixture to room temperature (RT). Dilute with chloroform/IPA (3/1), wash with water and aqueous saturated sodium chloride. Separate the layers and dry the organic layer over sodium sulfate. Concentrate in vacuo to give the crude product. Purify by column chromatography (20% THF in dichloromethane (DCM) to give the title compound (4.0 g, 83%). MS (ES) m/z 214/216 [M+1]+.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CI.[H-].[Na+].[C:21](OCC)(=O)C>O1CCCC1.C(Cl)(Cl)Cl.CO.O>[C:4]([O:3][C:1]([N:8]([CH3:21])[C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13])=[O:2])([CH3:5])([CH3:7])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
This was prepared by the method of Cheung and Benoitin (1977). In brief, Boc-L-leucine (5 g, 21.6 mmol) and methyl iodide (24.6 g, 172.8 mmol) were dissolved in anhydrous tetrahydrofuran (30 ml) and chilled to 0° C. Sodium hydride (0.26 g, 32.4 mmol) was added slowly with vigorous stirring to the solution over a period of 10 minutes. The reaction was allowed to proceed for a further 24 hours at room temperature. Ethyl acetate (50 ml) followed by water (20 ml) was added and the solution was reduced to dryness in vacuo. The residue was partitioned between diethyl (50 ml) and water (50 ml). The aqueous layer was removed and the organic layer was washed with 5% NaHCO3 (50 ml). The aqueous extracts were combined and acidified by the addition of 5% NaHSO4. The product was extracted into ethyl acetate (100 ml) and washed successively with water (2×50 ml), 10% Na2S2O3 (2×50 ml) and water (100 ml). The organic layer was dried over magnesium sulphate and reduced to dryness. The product was obtained as a pale yellow oil which solidified at -20° C. Yield 4.69 g (88%), m.p. 53°-55° C. (lit. 56°-57° C., Cheung and Benoiton, 1977). The product was homogeneous as judged by tlc in chloroform/methanol (4:1) (Rf 0.375) or chloroform/methanol (1:1) (Rf 0.683). (Found: C, 58.47; H, 9.19; N, 5.71. C12H23O4N1 requires C, 59.77; H, 9.38; N, 5.71%). 1H n.m.r. (p.p.m) CDCl3 δ 0.98 (6H, α, (CH3)2), 1.5 (9H, s, C(CH3)3), 1.82 (3H, m, CH2CH), 2.84 (3H, s, N--CH3), 9.94 (1H, s, COOH).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[NH:21][N:20]=[N:19][N:18]=2)[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH:21]1[C:17]([CH:13]2[CH2:14][CH2:15][CH2:16][NH:11][CH2:12]2)=[N:18][N:19]=[N:20]1
Reactant: O=C(OCc1ccccc1)N1CCCC(c2nnn[nH]2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C1CNCC(c2nnn[nH]2)C1
Reaction time: 30 h

Procedure:
To a solution of 3-(1H-tetrazol-5-yl)-piperidine-1-carboxylic acid benzyl ester (1 g, 3.5 mmol) in MeOH (20 mL) is added Pd on carbon (10%, 150 mg) at room temperature. The mixture is charged with Ar gas a few times before attaching a hydrogen gas balloon. After 30 h at 20° C., the mixture is filtered, and concentrated to afford 3-(1H-tetrazol-5-yl)-piperidine. LCMS: RT=0.54 minutes, MS: 154 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:10]1[C:16]2[CH:17]=[C:18](B3OC(C)(C)C(C)(C)O3)[S:19][C:15]=2[C:14](=[O:29])[NH:13][CH2:12][CH2:11]1)[CH3:9].I[C:31]1[N:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]2=[N:33][CH:32]=1.C([O-])([O-])=O.[K+].[K+].O>C1(C)C=CC=CC=1.CCO.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.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:10]1[C:16]2[CH:17]=[C:18]([C:31]3[N:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]4=[N:33][CH:32]=3)[S:19][C:15]=2[C:14](=[O:29])[NH:13][CH2:12][CH2:11]1)[CH3:9]
Reactant: CC(c1ccccc1Cl)N1CCNC(=O)c2sc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: Ic1cnc2ccccn12
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: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(c1ccccc1Cl)N1CCNC(=O)c2sc(-c3cnc4ccccn34)cc21
Temperature: 140 °C
Yield: 35.6 %

Procedure:
1-[1-(2-Chloro-phenyl)-ethyl]-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,4-tetrahydro-thieno[3,2-e][1,4]diazepin-5-one (251 mg, 0.58 mmol, 1.3 Eq), 3-iodo-imidazo[1,2-a]pyridine (109 mg, 0.45 mmol, 1.0 Eq) and Pd(PPh3)4 (52 mg, 0.045 mmol, 0.1 Eq) were dissolved in toluene (1.6 mL) and EtOH (0.4 mL). 2M K2CO3 (0.45 mL, 0.89 mmol, 2.0 Eq) was added and the reaction heated at 140° C. for 15 minutes under microwave conditions. Water (10 mL) and EtOAc (15 mL) was added and the layers separated. The aqueous layer was extracted with EtOAc (3×10 mL) and the combined organic layers washed with brine (15 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography to give the title compound as a pale yellow solid (66 mg, 0.16 mmol, 35%); 1H NMR (DMSO D6) 1.57 (3H, d), 2.92-3.00 (1H, m), 3.10-3.18 (1H, m), 3.29-3.33 (2H, m), 5.51 (1H, q), 7.12 (1H, t), 7.36-7.46 (4H, m), 7.52 (1H, d), 7.59 (1H, d), 7.69-7.75 (2H, m), 7.95 (1H, s), 8.62 (1H, d); LC/MS M+1 (obs.) 423.1, LC/MS M−1 (obs.) 421.3.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=O)=[CH:14][CH:13]=2)[N:4]=1.[CH3:24][NH:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:24][N:25]([CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:19](=[O:21])[CH2:18][C:15]1[CH:14]=[CH:13][C:12]([N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:23])([F:22])[F:1])=[N:4]2)=[CH:17][CH:16]=1
Reactant: CNCCc1ccccc1
Reactant: O=C(O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Product: CN(CCc1ccccc1)C(=O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
The title compound was prepared from {4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetic acid and N-methylphenethylamine using a similar procedure to that described for Example 13, but purified by flash column chromatography eluting from 0-88% ethyl acetate in hexane, followed by mass directed auto-prep.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:21])[NH:17][C:18](=[S:20])[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:22]#[N:23])[CH3:2].IC.[CH:26](N(C(C)C)CC)(C)C.CCCCCC>C(O)C>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:21])[N:17]=[C:18]([S:20][CH3:26])[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:22]#[N:23])[CH3:2]
Reactant: CCOc1c(C#N)cnc2ccc(/C=C3\SC(=S)NC3=O)cc12
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: CCO
Solvent: CCCCCC
Product: CCOc1c(C#N)cnc2ccc(/C=C3\SC(SC)=NC3=O)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.3 %

Procedure:
To the suspension of 4-ethoxy-6-[4-oxo-2-thioxo-thiazolidin-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile (example 14f) (1.7 g, 5 mmol), iodomethane (0.62 mL, 10 mmol) and DIEA (diisopropylethylamine) (1.7 mL, 10 mmol) in anhydrous ethanol (25 mL) was stirred at room temperature for 24 h. After adding hexane (50 mL), the solid was collected by filtration, washed with hexane and dried. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 0%-5% methanol in methylene chloride in 30 min) afforded to obtain 4-ethoxy-6-[2-methylsulfanyl-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile(1.25 g, 75%) as a yellow solid. LC-MS m/e 356 (MH+)
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][N:12]([C:23](=[O:37])[CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[CH2:13][CH2:14][CH2:15][C:16]([O:18][C:19](C)(C)C)=[O:17])[CH:6]=[C:5]([CH2:38][OH:39])[N:4]=1.C(O)(C(F)(F)F)=O.C[Si](C=[N+]=[N-])(C)C.C(O)(=O)C>C(Cl)Cl.CO.CCCCCC>[OH:39][CH2:38][C:5]1[CH:6]=[C:7]([O:9][CH2:10][CH2:11][N:12]([C:23](=[O:37])[CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=[C:3]([CH2:2][OH:1])[N:4]=1
Reactant: COCCOCCOCCOCCC(=O)N(CCCC(=O)OC(C)(C)C)CCOc1cc(CO)nc(CO)c1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: COCCOCCOCCOCCC(=O)N(CCCC(=O)OC)CCOc1cc(CO)nc(CO)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 62.3 %

Procedure:
To a solution of 460 mg of tert-butyl 4-[[2-(2,6-bis-hydroxymethyl-pyridin-4-yloxy)-ethyl]-(3-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-propionyl)-amino]-butanoate in 7 ml of DCM were added 1.14 ml of TFA. The mixture was stirred for 15 hours at room temperature and then concentrated under reduced pressure. To the residue obtained, dissolved in 3.8 ml of MeOH, was added, at 50° C., 3.1 ml of a 2M solution of (trimethylsilyl)diazomethane in hexane. The mixture was stirred for 1 hour at 5° C. and 100 μl of acetic acid were then added. After concentration under reduced pressure, the residue obtained was purified by flash chromatography on silica (Analogix Super Flash SiO2 SF25-40g), using a gradient of 2 to 10% MeOH in DCM. The fractions containing the desired product were combined and concentrated under reduced pressure. 265 mg of methyl 4-[[2-(2,6-bis-hydroxymethyl-pyridin-4-yloxy)-ethyl]-(3-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-propionyl)-amino]-butanoate were obtained. 1H NMR (400 MHz, DMSO-d6): 50%-50% mixture of conformers with: 1.67 to 1.86 (m, 2H); 2.27 (t, J=7.3 Hz, 1H); 2.36 (t, J=7.3 Hz, 1H); 2.57 (t, J=6.7 Hz, 1H); 2.66 (t, J=6.7 Hz, 1H); 3.23 (s, 3H); 3.31 to 3.75 (m, 21H); 4.14 (t, J=5.6 Hz, 1H); 4.19 (t, J=5.6 Hz, 1H); 4.45 (m, 4H); 5.30 (m, 2H); 6.84 (s, 1H); 6.86 (s, 1H). LC/MS (G): tr=0.62 min; [M+H]+: m/z 517; [M−H+HCO2H]−: m/z 561
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8](O)=[O:9].C(Cl)[Cl:15].C(Cl)(=O)C(Cl)=O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([Cl:15])=[O:9]
Reactant: COc1cccc(OCC(=O)O)c1
Reactant: ClCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COc1cccc(OCC(=O)Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A 500 mL flask fitted with a stir-bar, addition funnel, and an Ar inlet was charged with 3-methoxyphenoxyacetic acid (20.0 g, 110 mmol), CH2Cl2 (120 mL), and DMF (0.2 mL). Oxalyl chloride (2M in CH2Cl2, 69 mL, 137 mmol) was added to the resultant solution over 45 min forming an orange solution. The mixture stirred overnight at rt. The solution was concentrated in vacuo to give 22.7 g of 47b as an orange oil (100%). HPLC analysis (15:10:75 H2O:A1:MeOH) showed a purity of 93% with a retention time of 3.9 min.
Reaction SMILES: [ClH:1].O1CCOCC1.[CH3:8][O:9][C:10]1[CH:30]=[CH:29][C:13]([C:14]([O:16][CH2:17][C:18]([NH:21]C(OC(C)(C)C)=O)([CH3:20])[CH3:19])=[O:15])=[CH:12][CH:11]=1>C(Cl)Cl>[ClH:1].[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][CH2:17][C:18]([NH2:21])([CH3:20])[CH3:19])=[O:15])=[CH:29][CH:30]=1
Reactant: COc1ccc(C(=O)OCC(C)(C)NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(C(=O)OCC(C)(C)N)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
A solution of hydrochloric acid in dioxane (5.0 mL, 20.0 mmol) was added to a solution of 2-[(tert-butoxycarbonyl)amino]-2-methylpropyl 4-methoxybenzoate (0.32 g, 1.0 mmol) in DCM (10 mL) and the mixture was stirred for 1.5 h at room temperature. The reaction mixture was concentrated to give the title compound (0.26 g, 100%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.32 (br s, 3 H), 8.11 (m, J=8.9 Hz, 2 H), 7.06 (m, J=8.9 Hz, 2 H), 4.24 (s, 2 H), 3.85 (s, 3 H), 1.35 (s, 6 H). m/z (APCI+) for C12H17NO3 224.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:25][C:24]4=[N:26][CH:27]=[C:28](I)[N:23]4[N:22]=3)=[CH:17][C:16]=2[O:30][CH3:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][N:35]=1.CCN(CC)CC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:25][C:24]4=[N:26][CH:27]=[C:28]([C:37]5[CH:36]=[N:35][C:34]([O:33][CH3:32])=[CH:39][CH:38]=5)[N:23]4[N:22]=3)=[CH:17][C:16]=2[O:30][CH3:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(-c2nn3c(I)cnc3s2)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1ccc(B(O)O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(-c2cnc3sc(-c4ccc(OC5CCN(C(=O)OC(C)(C)C)CC5)c(OC)c4)nn23)cn1
Temperature: 120 °C
Yield: 13.2 %

Procedure:
A mixture of 4-[4-(5-iodo-imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-methoxy-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (94 mg, 0.169 mmol, 1 eq), 2-methoxy-5-pyridineboronic acid (39 mg, 0.253 mmol, 1.5 eq), EtOH (5 ml), Et3N (0.070 ml, 0.507 mmol, 3 eq) and Pd(PPh3)2Cl2 (12 mg, 0.0169 mmol, 0.1 eq) was heated under microwave irradiation (120° C., 30 min). The solvents were removed under reduced pressure and the residue was treated with Et2O. The filtrate was evaporated and the residue was purified by HPLC to give the desired product (12 mg; 13%) as a colourless oil. HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=3.30 min, [M+H]+ m/z 538.3; 1H NMR (300 MHz, CD3COCD3) δ 8.87 (m, 1H), 8.28 (dd, J=8.7, 2.5 Hz, 1H), 7.64 (s, 1H), 7.59 (d, J=2.1 Hz, 1H), 7.54 (dd, J=8.4, 2.2 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 6.89 (dd, J=8.7, 0.7 Hz, 1H), 4.71 (m, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.75 (m, 2H), 3.32 (m, 2H), 1.98 (m, 2H), 1.70 (m, 2H), 1.45 (s, 9H).