Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl[CH2:11][C:12]1[CH2:13][S:14][C@@H:15]2[C@H:35]([NH:36][C:37](=[O:45])[CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:34](=[O:46])[N:16]2[C:17]=1[C:18]([O:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].[SH:47][C:48]1[CH2:52][O:51][C:50](=[O:53])[CH:49]=1>ClCCl>[O:53]=[C:50]1[CH:49]=[C:48]([S:47][CH2:11][C:12]2[CH2:13][S:14][C@@H:15]3[C@H:35]([NH:36][C:37](=[O:45])[CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:34](=[O:46])[N:16]3[C:17]=2[C:18]([O:20][CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:52][O:51]1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: O=C1C=C(S)CO1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSC3=CC(=O)OC3)CS[C@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
N,N-Diisopropylethylamine (0.52 ml) was added to a stirred solution of diphenylmethyl 3-chloromethyl-7β-phenylacetamidoceph-3-em-4-carboxylate (1.59 g) and 4-mercapto-2(5H)-furanone (400 mg) in dichloromethane (30 ml). The mixture was stirred at room temperature for 2 hours and then washed successively with aqueous citric acid solution, water, sodium bicarbonate solution, water and brine. The solution was dried over magnesium sulphate and evaporated. The title compound (1.64 g) was isolated by column chromatography of the residue using gradient elution (Kieselgel, 1:1 going to 3:7 hexane:ethyl acetate), m.p. 178°-180° C. from ethyl acetate/hexane (Found: C, 64.89; H, 4.61; N, 4.57; S, 10.30: C33H28N2O6S2 requires; C, 64.69; H, 4.61; N, 4.57; S, 10.47). υmax (CHCl3) 3400, 1780, 1745, and 1680 cm-1. δH (CDCl3) 3.36 (1H, d, J 18.3Hz), 3.57 (1H, d, J 18.3Hz), 3.62 (1H, d, J 16.2Hz), 3.70 (1H, d, J 16.2Hz), 3.86 (1H, d, J 12.5Hz), 4.01 (1H, d, J 12.5Hz), 4.71 (2H, s), 4.98 (1H, d, J 4.8Hz), 5.64 (1H, s), 5.88 (1H, dd, J 4.8 and 9.0Hz), 6.06 (1H, d, J 9.0Hz), 6.95 (1H, s), 7.2-7.4 (15H, m).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[N:4][CH:3]=1.Cl.Cl[CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([CH:24]=1)[C:20]([O:22][CH3:23])=[O:21].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH:8]([C:7]1[CH:6]=[C:5]([O:10][CH3:11])[N:4]=[CH:3][C:2]=1[O:1][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([CH:24]=1)[C:20]([O:22][CH3:23])=[O:21])=[O:9]
Reactant: COC(=O)c1cncc(CCl)c1
Reactant: COc1cc(C=O)c(O)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cncc(COc2cnc(OC)cc2C=O)c1
Temperature: 60 °C
Yield: 50.6 %

Procedure:
A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (352 mg, 2.29 mmol, 1 eq.), methyl 5-(chloromethyl)nicotinate hydrochloride (506 mg, 2.29 mmol, 1 eq.), and K2CO3 (1.26 g, 9.16 mmol, 4 eq.) in DMF (8.0 mL) was heated at 60° C. for 3 h. The mixture was cooled and added into water (50 mL) dropwise. The precipitate was filtered, washed with water, and dried to give methyl 5-((4-formyl-6-methoxypyridin-3-yloxy)methyl)nicotinate (350 mg, 85%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.47 (s, 1H), 9.26 (d, J=2.0 Hz, 1H), 8.90 (d, J=2.2 Hz, 1H), 8.42 (t, J=2.1 Hz, 1H), 8.09 (s, 1H), 7.15 (s, 1H), 5.29 (s, 2H), 4.01 (s, 3H), 3.95 (s, 3H). LRMS (M+H+) m/z 303.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:22][C:23]([C:25]1[C:34]([OH:35])=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1)=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](C2C=CC3C(=CC=CC=3)C=2)=[CH:8][CH:7]=1.[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][OH:46])=[CH:40][CH:39]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:22][C:23]([C:25]1[C:34]([OH:35])=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1)=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:46][CH2:45][CH2:44][C:41]2[CH:42]=[CH:43][C:38]([Cl:37])=[CH:39][CH:40]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc3ccccc3c2)cc1)NC(=O)c1cc2ccccc2cc1O
Reactant: OCCc1ccc(Cl)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(OCCc2ccc(Cl)cc2)cc1)NC(=O)c1cc2ccccc2cc1O
Yield: 39.7 %

Procedure:
0.05 g (0.1 mmol) of resin-bound 2-(S)-(3-Hydroxy-naphthalene-2-carbonyl)-amino-3-(4-hydroxy-phenyl)-propionic acid methyl ester obtained in Example 105 was reacted with 2-(4-chloro-phenyl)-ethanol (156 mg, 1.0 mmol), DIAD (1.0 mmol), Ph3P (1.0 mmol) in THF at rt overnight. The resulting resin was hydrolyzed according to general procedure C. The resin was then washed and cleaved as described in Example 28 to give the title compound (20 mg). LC/MS (m/z) 490 (M+1)+.
Reaction SMILES: [NH2:1][C:2]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][N:4]1[C:11](=[O:29])[C:12]([OH:28])=[C:13]([C:15]3[NH:16][CH:17]=[C:18]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[N:19]=3)[N:14]=[C:3]21.[CH3:30][N:31]([CH3:37])[C:32](=[O:36])[C:33](O)=[O:34].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:18]2[N:19]=[C:15]([C:13]3[N:14]=[C:3]4[C:2]5([NH:1][C:33](=[O:34])[C:32]([N:31]([CH3:37])[CH3:30])=[O:36])[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]5)[CH2:5][N:4]4[C:11](=[O:29])[C:12]=3[OH:28])[NH:16][CH:17]=2)=[CH:22][CH:23]=1
Reactant: NC12CCC(CC1)Cn1c2nc(-c2nc(Cc3ccc(F)cc3)c[nH]2)c(O)c1=O
Reactant: CN(C)C(=O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)C(=O)NC12CCC(CC1)Cn1c2nc(-c2nc(Cc3ccc(F)cc3)c[nH]2)c(O)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 8 %

Procedure:
To a stirred solution of 10-amino-2-(4-(4-fluorobenzyl)-1H-imidazol-2-yl)-3-hydroxy-7,8,9,10-tetrahydro-7,10-ethanopyrimido[1,2-a]azepin-4(6H)-one, Example 1 (27 mg, 0.068 mmol) and 2-(dimethylamino)-2-oxoacetic acid (11.99 mg, 0.102 mmol) in DMF (3 mL) was added N,N-diisopropylethylamine (0.061 mL, 0.35 mmol), DMAP (1.668 mg, 0.014 mmol) and HATU (38.9 mg, 0.102 mmol) and the resulting mixture stirred at room temp for 3 h. The mixture was then concentrated and purified by preparative HPLC to afford the title compound (6 mg, 8% yield) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ ppm 1.63-1.77 (m, 2H), 1.93-1.98 (m, 2H), 2.29-2.38 (m, 4H), 2.50 (br. s., 1H), 3.00 (s, 3H), 3.17 (s, 3H), 4.03 (s, 2H), 4.14 (s, 2H), 6.82 (br. s., 1H), 7.00 (t, J=8.39 Hz, 1H), 7.21-7.27 (m, 3H), 7.70 (s, 1H). LCMS (M+H)=495.20.
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1.[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[C:21]([F:26])[CH:20]=1>C(O)(C)C>[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:10][CH:11]=3)[N:6]=[CH:5][N:4]=2)=[C:21]([F:26])[CH:20]=1
Reactant: COCCOc1ccc2c(Cl)ncnc2c1
Reactant: Nc1ccc(Cl)cc1F
Agent: Cl
Solvent: CC(C)O
Product: COCCOc1ccc2c(Nc3ccc(Cl)cc3F)ncnc2c1
Yield: 83.9 %

Procedure:
A solution of 4-chloro-7-(2-methoxyethoxy)quinazoline hydrochloride (624 mg, 2.27 mmol) and 4-chloro-2-fluoroaniline (305 μl, 2.6 mmol) in isopropanol (20 ml) was heated at reflux for 30 minutes. The solvent was removed by evaporation and the residue partitioned between ethyl acetate and water. The organic layer was separated, washed with aqueous sodium hydrogen carbonate solution, then with water, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with ether to give 4-(4-chloro-2-fluoroanilino)-7-(2-methoxyethoxy)quinazoline (662 mg, 84%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]4[NH:28][CH:29]=[CH:30][C:23]=34)=[C:17]([F:31])[CH:16]=2)[N:3]=1.S(=O)(=O)(O)O.[CH2:37](O)[CH3:38]>>[NH2:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:37][CH3:38])=[O:12])[CH:5]=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]4[NH:28][CH:29]=[CH:30][C:23]=34)=[C:17]([F:31])[CH:16]=2)[N:3]=1
Reactant: CCO
Reactant: Nc1nc(CCCC(=O)O)cc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)n1
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCCc1cc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)nc(N)n1

Procedure:
396 mg (0.86 mmol) of 4-(2-amino-6-{[3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]amino}pyrimidin-4-yl)butyric acid (from example 130) in 20 ml of ethanol are, after addition of 0.10 ml of sulfuric acid, heated under RF for 20 hours. The mixture is concentrated under reduced pressure, dichloromethane and a little methanol are added and the mixture is extracted with sodium bicarbonate solution. The organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. This gives the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10])[CH:5]=O.C(C1C=C(C=C(C)C=1O)C#[N:19])C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10])[C:5]#[N:19]
Reactant: COc1cc(C=O)cc(Cl)c1O
Reactant: CCc1cc(C#N)cc(C)c1O
Product: COc1cc(C#N)cc(Cl)c1O

Procedure:
The title compound is prepared from commercially available 3-chloro-4-hydroxy-5-methoxy-benzaldehyde in analogy to literature procedures (see 3-ethyl-4-hydroxy-5-methyl-benzonitrile); LC-MS: tR=0.82 min; 1H NMR (CDCl3): δ3.98 (s, 3H), 6.36 (s, 1H), 7.04 (s, 1H), 7.34 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[OH:9].[Br:10][CH2:11][CH2:12]Br>[OH-].[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[O:9][CH2:12][CH2:11][Br:10]
Reactant: Oc1cc(Br)ccc1Br
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Product: BrCCOc1cc(Br)ccc1Br
Temperature: 80 °C
Reaction time: 40 h
Yield: 51.4 %

Procedure:
A mixture of 2,5-dibromophenol (134) (1.26 g, 5 mmol) and 1,2-dibromoethane (135) (431 μl, 5 mmol) in 5 ml 1N NaOH was stirred at 80° C. for 40 h. After cooling down, the reaction mixture was extracted with diethyl ether. Org. phase was washed with 1 N NaOH and brine subsequently. Org. phase was dried over sodium sulfate concentrated to give 922 mg (yield 51%, purity ca 90%) 1,4-dibromo-2-(2-bromoethoxy)benzene (136) as orange-red oil which was used directly for further reaction without purification.
Reaction SMILES: O.NN.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:14]2[C@H:23]3[C@H:18]([CH2:19][CH2:20][CH2:21][CH2:22]3)[C:17](=[O:24])[NH:16][N:15]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]>>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:14]2[C@H:23]3[C@H:18]([CH2:19][CH:20]=[CH:21][CH2:22]3)[C:17](=[O:24])[NH:16][N:15]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: NN
Solvent: O
Product: COc1ccc(C2=NNC(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from hydrazine hydrate and compound C (see starting compounds) as described for compound 1. M.p. 173-174° C.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13]([CH3:15])=[O:14].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>>[CH3:18][N:19]([CH3:21])[CH:20]=[CH:15][C:13]([C:3]1[N:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:6][C:2]=1[CH3:1])=[O:14]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1nc(-c2ccccc2)[nH]c1C
Product: Cc1[nH]c(-c2ccccc2)nc1C(=O)C=CN(C)C
Temperature: -10 °C

Procedure:
A mixture of 10.0 g (0.05 moles) of methyl 5-methyl-2-phenyl-4-imidazolyl ketone [A. C. Verones, et al., J. Het. Chem., 17, 1723 (1980)] and 45.0 ml of N,N-dimethylformamide dimethyl acetal was refluxed for 16 hours in an oil bath. The reaction mixture was cooled at -10° C., then filtered. The product was washed with 50 ml of cold ethanol, air dried and gave 4.6 g of 3-(dimethylamino)-1-(5-methyl-2-phenyl-1H-imidazol-4-yl)-2-propen-1-one as a yellow solid, mp 218°-222° C.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[S:3]([C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([NH2:13])[C:7]=1[OH:14])(=[O:5])=[O:4].[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]=[C:24]=[S:25]>C(O)C>[Cl:12][C:11]1[CH:10]=[CH:9][C:8]([NH:13][C:24]([NH:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[Br:16])=[S:25])=[C:7]([OH:14])[C:6]=1[S:3]([N:2]([CH3:15])[CH3:1])(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(N)c1O
Reactant: S=C=Nc1ccccc1Br
Solvent: CCO
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2ccccc2Br)c1O
Yield: 22.1 %

Procedure:
A solution of N,N-dimethyl-3-amino-6-chloro-2-hydroxybenzene sulfonamide (480 mg, 3.58 mmol) and 2-bromophenylisothiocyanate (0.53 μL, 3.94 mmol) in 10 mL of ethanol was stirred at room temperature for overnight. Purification by column chromatography on silica gel, eluting with ethyl acetate/hexane (gradient elution) gave the desired product (368 mg, 22%). EI-MS (m/z) 463.67, 465.66, 467.65, 468.64 (M+).
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[C:9]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)[N:8]3[CH2:21][CH2:22][N:23]=[C:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[CH2:25][CH2:26][CH2:27][S:28]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)(=[O:30])=[O:29]>>[N:31]1([S:28]([CH2:27][CH2:26][CH2:25][O:1][C:2]2[C:11]3[N:10]=[C:9]([NH:12][C:13](=[O:20])[C:14]4[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=4)[N:8]4[CH2:21][CH2:22][N:23]=[C:7]4[C:6]=3[CH:5]=[CH:4][CH:3]=2)(=[O:30])=[O:29])[CH2:32][CH2:33][O:34][CH2:35][CH2:36]1
Reactant: O=C(NC1=Nc2c(O)cccc2C2=NCCN12)c1cccnc1
Reactant: O=S(=O)(CCCCl)N1CCOCC1
Product: O=C(NC1=Nc2c(OCCCS(=O)(=O)N3CCOCC3)cccc2C2=NCCN12)c1cccnc1

Procedure:
The procedure used for the preparation of Example 1 was used to prepare the title compound from N-(7-hydroxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide (Intermediate C) and 4-[(3-chloropropyl)sulfonyl]morpholine (Intermediate E). High vacuum drying at 60° C. gave the title compound (42 mg, 34%): HPLC MS RT=1.82 min, MH+=499.2; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.26-2.31 (2H, m), 3.13-3.24 (4H, m), 3.37-3.43 (2H, m), 3.60-3.63 (4H, m), 4.27-4.34 (2H, m), 4.43 (2H, t), 4.58-4.65 (2H, m), 7.58 (1H, t), 7.73 (1H, d), 7.84 (1H, d), 7.94 (1H, dd), 8.86 (1H, d), 8.98 (1H, dd), 9.46 (1H, d).
Reaction SMILES: [C:1](C1C(=O)N(CC(C)C)N=C(C2C=CC(F)=C(F)C=2)C=1)(O)=O.[C:23]([C:26]1[C:27](=[O:40])[NH:28][N:29]=[C:30]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[F:39])[CH:31]=1)([OH:25])=[O:24]>>[F:39][C:33]1[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:32]=1[C:30]1[CH:31]=[C:26]([C:23]([O:25][CH3:1])=[O:24])[C:27](=[O:40])[NH:28][N:29]=1
Reactant: CC(C)Cn1nc(-c2ccc(F)c(F)c2)cc(C(=O)O)c1=O
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)n[nH]c1=O
Product: COC(=O)c1cc(-c2ccc(F)cc2F)n[nH]c1=O
Yield: 81.2 %

Procedure:
Following the procedure of Example 1 (5), 4-carboxy-6-(2,4-difluorophenyl)-2H-pyridazin-3-one was reacted to yield the title compound as a pale yellow crystalline powder (yield: 81.2%).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([O:21][CH2:22][C:23](=O)[NH:24][NH:25][C:26]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[O:27])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>C(Cl)Cl>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([O:21][CH2:22][C:23]2[O:27][C:26]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[N:25][N:24]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:9])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(OCC(=O)NNC(=O)c2ccncc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OCc2nnc(-c3ccncc3)o2)CC1
Reaction time: 18 h

Procedure:
Triethylamine (149 μl, 1.06 mmol was added to stirred solution of 4-{2-oxo-2-[N′-(pyridine-4-carbonyl)hydrazino]ethoxy}piperidine-1-carboxylic acid tert-butyl ester (Preparation 16, 200 mg, 0.53 mmol) and 2-chloro-1,3-dimethyl-2-imidazolinium hexafluorophosphate (147 mg, 0.53 mmol) in CH2Cl2 (10 ml). After 18 h at rt, the solvent was reduced to a small volume and this mixture purified by flash chromatography (EtOAc), affording the title compound: RT=3.42 min; m/z (ES+)=361.1 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][OH:7].[CH3:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([CH2:14][CH2:15]Br)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.[I-].[Na+]>[OH:7][CH2:6][C@@H:2]1[CH2:3][CH2:4][CH2:5][N:1]1[CH2:15][CH2:14][C:13]1[CH:17]=[CH:18][C:10]([O:9][CH3:8])=[CH:11][CH:12]=1
Reactant: COc1ccc(CCBr)cc1
Reactant: OC[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(CCN2CCC[C@H]2CO)cc1
Yield: 57.3 %

Procedure:
A mixture of (S)-2-pyrrolidinemethanol (3.0 g), 4-methoxyphenethyl bromide (7.0 g), sodium carbonate (3.5 g) and sodium iodide (100 mg) in acetonitrile (40 ml) was heated under reflux for 16 hours and evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water and the organic layer washed with water and extracted with 2M hydrochloric acid. The acidic extract was washed with ethyl acetate, basified with solid sodium carbonate and extracted with ethyl acetate. The organic extract was dried over sodium sulphate and evaporated under reduced pressure to give the title compound as a colourless oil, (4.0 g, 57%).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:28])[C:13]([C:25]([OH:27])=[O:26])=[CH:14][N:15]2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:10][C:9]=1[F:29].C[C:31](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:32]>C(O)=O>[CH:31]([N:5]1[CH2:6][CH:1]2[CH2:7][CH:4]1[CH2:3][N:2]2[C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:28])[C:13]([C:25]([OH:27])=[O:26])=[CH:14][N:15]2[C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)=[CH:10][C:9]=1[F:29])=[O:32]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2cc(N3CC4CC3CN4)c(F)cc2c1=O
Solvent: O=CO
Product: O=CN1CC2CC1CN2c1cc2c(cc1F)c(=O)c(C(=O)O)cn2-c1ccc(F)cc1
Reaction time: 6 h
Yield: 31 %

Procedure:
To 1.2 g (3 m Mol) 7-(2,5-diazabicyclo(2.2.1)hept-2-yl)-6-fluoro-1-(4-fluorophenyl)1,4-dihydro-4-oxoquinoline-3-carboxylic acid in 10 ml of formic acid was added 2.64 g (30 m Mol) of the mixed anhydride of acetic and formic acids and the mixture was stirred for 6 hrs. The volatiles were removed in vacuo and the residue recrystallized to give 0.4 g (31%) of the product, mp 274° C.-276° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH:11]=[O:12].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][O:13]1)[N:6]=[C:5]2[CH:11]=[O:12]
Reactant: O=Cc1n[nH]c2ccc(Br)cc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=Cc1nn(C2CCCCO2)c2ccc(Br)cc12
Yield: 62.5 %

Procedure:
A solution of 5-bromo-1H-indazole-3-carbaldehyde (1.00 g, 4.44 mmol), dihydropyran (912 uL, 10.0 mmol), and p-toluenesulfonic acid monohydrate (16.9 mg, 0.0889 mmol) in DCM (8.8 mL) was stirred at room temperature for 24 h. The reaction was poured into saturated aqueous sodium bicarbonate (10 mL) and extracted with dichloromethane (3×5 mL). The combined organic fractions were washed with saturated aqueous sodium chloride (1×10 mL), dried over sodium sulfate, filtered, and concentrated. Purification by ISCO chromatography (10 to 40% ethyl acetate:heptane) afforded 858 mg (56%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.17 (s, 1 H), 8.28 (d, J=1.8 Hz, 1 H), 7.92 (d, J=8.3 Hz, 1 H), 7.80-7.61 (m, 1 H), 6.08 (dd, J=2.5, 9.3 Hz, 1 H), 3.99-3.69 (m, 2 H), 2.46-2.26 (m, 1 H), 2.17-1.92 (m, 2 H), 1.87-1.67 (m, 1 H), 1.68-1.53 (m, 2 H); MS (ESI): 309.03, 311.05 [M+H]+; HPLC tR=3.38 min (ZQ3, nonpolar—4 min).
Reaction SMILES: [C:1]([Si:5]([CH3:14])([CH3:13])[O:6][C@@H:7]1[CH2:11][CH2:10][C@H:9]([NH2:12])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.Cl[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][N:22]=1.C([O-])([O-])=O.[K+].[K+]>[Pd].CO>[C:1]([Si:5]([CH3:14])([CH3:13])[O:6][C@@H:7]1[CH2:11][CH2:10][C@H:9]([NH:12][C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][N:22]=2)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](N)C1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](Nc2ccc(N)cn2)C1
Temperature: 75 °C
Reaction time: 60 h

Procedure:
To a 20 mL vial containing cis-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamine, prepared according to literature reference (see Chen, et al US 2004/0204427 A1), (580 mg, 2.69 mmol) was added DMF (10 mL), 2-chloro-5-nitro-pyridine (428 mg, 2.69 mmol), and TEA (1.5 mL). The vessel was purged with Ar, sealed, heated to 75° C. for 4.5 hr, cooled to room temperature and allowed to stir over the weekend (60 hr). The reaction mixture was heated again at 75° C. for an additional 6 hr and then allowed to cool to RT overnight (18 hr). The reaction mixture was concentrated and redissolved in DMF (10 mL). 2 eq of K2CO3 was added (744 mg) and heated to 70° C. for 1 hr. The reaction mixture was concentrated, supported on silica gel, and purified by flash chromatography using an Analogix with a 80 g Redisep silica gel column at 60 mL/min with increasing concentrations of Et2O in hexane (0-5 min: 0%, 5-25 min: 0-20%, 25-40 min: 30%, 40-65 min: 30-100%). The appropriate fractions were collected and dried producing a clear oil, 490.8, 54.0% (LCMS 4.23 min, 338 (M+H), calcd. C16H27N3O3Si (m/e) 337, 50-100% ACN in H2O/HCOOH, C18, APCI). The nitropyridyl compound was transferred to a PARR vessel with MeOH (10 mL), Pd/C (10%) was added and the vessel was pressurized with H2 at 54 psi. After 3 hr the reaction mixture was filtered through a bed of celite and concentrated to dryness twice from DCM. The purple black material was used immediately for amide coupling (LCMS 2.94 min, 308 (M+H), calcd. C16H27N3O3Si (m/e) 307, 10-100% ACN in H2O/HCOOH 0.3%, C18, APCI).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[N:4]=1.[CH3:15][C:16]1[S:17][C:18]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C@H:27]([OH:35])[CH2:28][N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:21][C:19]=2[N:20]=1.C(N(C(C)C)CC)(C)C>CCO>[F:14][C:10]1[CH:9]=[C:8]([C:5]2[N:4]=[C:3]([CH2:2][N:32]3[CH2:33][CH2:34][N:29]([CH2:28][C@@H:27]([OH:35])[CH2:26][O:25][C:22]4[CH:23]=[CH:24][C:18]5[S:17][C:16]([CH3:15])=[N:20][C:19]=5[CH:21]=4)[CH2:30][CH2:31]3)[O:7][N:6]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1nc2cc(OC[C@H](O)CN3CCNCC3)ccc2s1
Reactant: Fc1cccc(-c2noc(CCl)n2)c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(Cc4nc(-c5cccc(F)c5)no4)CC3)ccc2s1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To 5-(chloromethyl)-3-(3-fluorophenyl)-1,2,4-oxadiazole (300 mg, 1.41 mmol) and (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazine-1-yl-propan-2-ol, a compound of formula (6) (291 mg, 0.94 mmol) in EtOH (20 mL, anhydrous) was added diisopropylethylamine (0.329 m, 1.89 mmol), and the reaction was shaken on a J-Kem™ block overnight at 90° C. Upon cooling to room temperature, the solution was concentrated to an oil and purified on an Isco™ Combi Flash Si 10X, using Redi Sep columns (10 g), eluting with ethyl acetate, then gradient to 4:1 ethyl acetate/methanol, to yield (2R)-3-(4-{[3-(3-fluorophenyl)(1,2,4-oxadiazol-5-yl)]methyl}piperazinyl)-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol, a compound of Formula I.