Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:19]([Mg]Br)[CH2:20][CH3:21]>C1COCC1.CCOCC>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]=[CH:4][N:3]=[C:2]3[CH2:19][CH2:20][CH3:21])=[CH:13][CH:14]=1
Reactant: CCC[Mg]Br
Reactant: Fc1ccc(-c2ccc3ncnc(Cl)c3c2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCc1ncnc2ccc(-c3ccc(F)cc3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of 4-chloro-6-(4-fluorophenyl)-quinazoline (258 mg, 1 mmol) and Fe(acac)3 (17 mg, 0.05 mmol) in THF (5 ml) was added n-propyl magnesium bromide (600 ul of 2M THF solution). The reaction was stirred at RT for 1 hour at RT then diluted with ether (5 ml) and quenched with 3 drops 2N HCl. The mixture was further diluted with ether and extracted with H2O. The aqueous layer was neutralized with a saturated aqueous NaHCO3 solution and extracted 3× with ether. The combined organics were washed once with NaHCO3 and once with a saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by column chromatography on SiO2 using EtOAc/hex (10-30% EtOAc) to give the title compound (115 mg, 43% yield) which was characterized by mass spectrum as follows: (m/z): 267 ([M+H]) 100).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:24]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26][CH2:25]1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([NH:15][CH:10]([C:11]([O:13][CH3:14])=[O:12])[C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([NH:1][C:24]([CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:31])[CH:3]=2)=[CH:21][CH:20]=1)#[N:23]
Reactant: COC(=O)C(Nc1ccc(C#N)cc1)c1ccc(OC)c(N)c1
Reactant: O=C1CCCC(=O)O1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(Nc1ccc(C#N)cc1)c1ccc(OC)c(NC(=O)CCCC(=O)O)c1

Procedure:
In analogy to Example 70.4-6, from the methyl (RS)-(3-amino-4-methoxy-phenyl)-(4-cyano-phenylamino)-acetate described in Example 70.3, glutaric anhydride and Hünig's base in DMF there was obtained (RS)-4-{5-[(4-cyano-phenylamino)-methoxycarbonyl-methyl]-2-methoxy-phenylcarbamoyl}-butyric acid, which was subsequently converted via (RS)-4-{5-[carboxy-(4-cyano-phenylamino)-methyl]-2-methoxy-phenylcarbamoyl}-butyric acid into (RS)-(E)- and/or -(Z)-4-(5-{carboxy-[4-(N-hydroxycarbamimidoyl)-phenylamino]-methyl}-2-methoxy-phenylcarbamoyl)-butyric acid.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/[C:8]([O-:10])=[O:9])=[C:4]([NH:13]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.[N+:23]([C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28](=[O:31])[CH2:29]Br)([O-:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6]([CH2:7][C:8]([OH:10])=[O:9])=[C:29]([C:28](=[O:31])[C:27]3[CH:32]=[CH:33][CH:34]=[CH:35][C:26]=3[N+:23]([O-:25])=[O:24])[NH:13]2)=[CH:11][CH:12]=1
Reactant: O=C(CBr)c1ccccc1[N+](=O)[O-]
Reactant: O=C([O-])/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)Cc1c(C(=O)c2ccccc2[N+](=O)[O-])[nH]c2cc(Cl)ccc12
Reaction time: 18 h
Yield: 16.8 %

Procedure:
To a mixture of polymer-bound trans 4-chloro-2-(phenylsulfonylamino)cinnamate (step 1, 100 mg, 53 μmol) and 2-nitrophenacyl bromide (39 mg, 0.16 mmol) in acetone (3 ml) was added potassium carbonate (37 mg, 0.27 mmol). The mixture was agitated for 18 h. and filtrated. The residual resin was washed with water (20 ml×3), acetone (20 ml×3), dichloromethane (20 ml×3) and THF (20 ml×2) and dried. The resin was diluted with THF (4 ml) and then DBU was added (40 μl, 0.27 mmol). After agitating for 6 h, the resin was filtered off and washed with THF (20 ml×3), acetone (20 ml×3) and dichloromethane (20 ml×3). To the resin was added 95% trifluoroacetic acid in dichloromethane (5 ml) and the mixture was agitated for 3 h. The mixture was filtered and the residue was washed with dichloromethane (20 ml×5). The filtrate was concentrated and the residue was purified by HPLC (MeOH/AcONH4 aquous solution=60/40-90/10) to give 3.2 mg (17%) of the title compound.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=1.CC([O-])(C)C.[K+]>C1COCC1>[Cl:8][C:6]1[CH:7]=[C:2]([NH:21][C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH3:12])=[CH:20][CH:19]=2)[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=1
Reactant: Clc1cc(Br)c2nccn2n1
Reactant: CCOc1ccc(N)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOc1ccc(Nc2cc(Cl)nn3ccnc23)cc1
Temperature: 50 °C

Procedure:
(1c variation 1) To a mixture of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (257 mg, 0.956 mmol) from 1b in THF (2.0 ml) was added p-phenetidine (131 mg, 0.956 mmol) and a 1.0 M solution of KOt-Bu in THF (2.5 eq, 2.4 ml, 2.39 mmol). The mixture was allowed to heat at 50° C. for 1 hour. The solution was then concentrated in vacuo to provide crude 6-chloro-N-(4-ethoxyphenyl)imidazo[1,2-b]pyridazin-8-amine as a solid. The solid was then used as is in the following step.
Reaction SMILES: C(O)(=O)C.Br[C:6]1[C:7]([NH:12][C:13]([NH:15][CH2:16][C:17]2[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:18]=2[O:25][CH3:26])=[NH:14])=[N:8][CH:9]=[CH:10][CH:11]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31](OB(O)O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].C([O-])(=O)C>>[CH3:26][O:25][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=1[CH2:16][NH:15][C:13]([NH:12][C:7]1[C:6]([C:31]2[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)=[NH:14]
Reactant: OB(O)Oc1ccc(F)cc1
Reactant: COc1cccc(OC)c1CNC(=N)Nc1ncccc1Br
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cccc(OC)c1CNC(=N)Nc1ncccc1-c1ccc(F)cc1
Temperature: 110 °C
Yield: 31.3 %

Procedure:
The preparation was carried out analogously to Example 56, using 0.200 g (0.470 mmol) N-(3-bromopyridin-2-yl)-N′-(2,6-dimethoxybenzyl)guanidine acetate, 0.099 g (0.705 mmol) (4-fluorophenyl)boric acid, 0.149 g (1.411 mmol) sodium carbonate, and 0.038 g (0.033 mmol) tetrakis-(triphenylphosphine)palladium(0). The mixture was likewise heated in a reaction block for 24 hr at 110° C. under a nitrogen atmosphere. After appropriate workup and purification via preparative HPLC, 65 mg (0.147 mmol, 31%) pure N-(2,6-dimethoxybenzyl)-N′-[3-(4-fluorophenyl)pyridin-2-yl]guanidine was obtained in the form of the acetate salt (base/acetate in a ratio of 1:1).
Reaction SMILES: C([O:8][N:9]1[C:13](=[O:14])[CH2:12][C@H:11]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:10]1=[O:30])C1C=CC=CC=1>C(OCC)(=O)C.CO.[Pd]>[CH2:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([NH:15][C@H:11]2[CH2:12][C:13](=[O:14])[N:9]([OH:8])[C:10]2=[O:30])(=[O:17])=[O:18])=[CH:20][CH:21]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCOc1ccc(S(=O)(=O)N[C@H]2CC(=O)N(OCc3ccccc3)C2=O)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCOc1ccc(S(=O)(=O)N[C@H]2CC(=O)N(O)C2=O)cc1
Yield: 74.9 %

Procedure:
N-(1-Benzyloxy-2,5-dioxo-pyrrolidin-3(S)-yl)-4-butoxy-benzenesulfonamide (100 mg, 0,23 mmol) was hydrogenated at atmospheric pressure for 1 h in ethyl acetate/methanol (1:1, 4 mL) with palladium on activated charcoal (50 mg, 10%). The mixure was filtered through Celite® and concentrated. The residue was purified by silica gel chromatography (ethyl acetate-acetic acid, 100:2) to give 59 mg (75%) of the title compound.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:11][C:10](=[O:12])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>C(Cl)Cl>[CH2:1]([C@@H:8]1[N:11]([Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C:10](=[O:12])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1C[C@H](Cc2ccccc2)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)N1C(=O)C[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.7 %

Procedure:
To a solution of 4(S)-benzylazetidin-2-one (400 mg, 2.48 mmol) in CH2Cl2 (8 mL) was added DIEA (648 μL, 3.72 mmol), followed by tert-butyldimethylsilyl chloride (411 mg, 2.73 mmol). The reaction mixture was stirred for 16 h at room temperature. The CH2Cl2 was evaporated and the residue was purified by flash chromatography (SiO2, 12% EtOAc in hexane) to give 4(S)-benzyl-1-(tert-butyldimethylsilyl)azetidin-2-one (647 mg, 95% yield) as a white solid. 1H-NMR (400 MHz, CDCl3) δ7.34-7.15 (m, 5H), 3.77-3.70 (m, 1H), 3.25 (dd, J=13.5, 3.5 Hz, 1H), 2.99 (dd, J=15.5 Hz, 5 Hz, 1H), 2.70 (dd, J=15.5, 2.5 Hz, 1H), 2.59 (dd, J=13.5, 11 Hz, 1H), 1.01 (s, 9H), 0.31 (s, 3H), 0.29 (s, 3H).
Reaction SMILES: [CH:1]([N:4]([C:6]1[CH:7]=[C:8]([OH:14])[C:9](=[CH:12][CH:13]=1)[CH:10]=O)[CH3:5])([CH3:3])[CH3:2].[C@@H:15]1([NH2:22])[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1[NH2:21]>>[CH:1]([N:4]([C:6]1[CH:7]=[C:8]([OH:14])[C:9](=[CH:12][CH:13]=1)[CH:10]=[N:21][C@@H:16]1[CH2:17][CH2:18][CH2:19][CH2:20][C@H:15]1[N:22]=[CH:10][C:9]1[C:8](=[CH:7][C:6]([N:4]([CH3:5])[CH:1]([CH3:2])[CH3:3])=[CH:13][CH:12]=1)[OH:14])[CH3:5])([CH3:3])[CH3:2]
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: CC(C)N(C)c1ccc(C=O)c(O)c1
Product: CC(C)N(C)c1ccc(C=N[C@@H]2CCCC[C@H]2N=Cc2ccc(N(C)C(C)C)cc2O)c(O)c1

Procedure:
Synthesis and working up are carried out as in Example 9, starting from 500 mg (2.59 mmol) of 4-(N-isopropyl-N-methylamino)salicylaldehyde and 141 mg (1.23 mmol) of trans-1,2-cyclohexanediamine. Yield: 504 mg (88%), yellow solid.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].C[O-].[Na+].[Cl:10][C:11]1[CH:29]=[CH:28][C:14]([C:15]([C:17]2[CH:26]=[CH:25][C:20]([CH2:21][N:22]=[N+:23]=[N-:24])=[CH:19][C:18]=2[Cl:27])=[O:16])=[CH:13][CH:12]=1>C(O)C>[NH2:2][C:1]1[N:22]([CH2:21][C:20]2[CH:25]=[CH:26][C:17]([C:15](=[O:16])[C:14]3[CH:28]=[CH:29][C:11]([Cl:10])=[CH:12][CH:13]=3)=[C:18]([Cl:27])[CH:19]=2)[N:23]=[N:24][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: N#CCC(N)=O
Reactant: [N-]=[N+]=NCc1ccc(C(=O)c2ccc(Cl)cc2)c(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1nnn(Cc2ccc(C(=O)c3ccc(Cl)cc3)c(Cl)c2)c1N
Temperature: 25 °C
Yield: 30.7 %

Procedure:
A stirred suspension of 2-cyanoacetamide (378 mg, 4.50 mmol) in ethanol (15 ml) was treated with sodium methoxide (236 mg, 4.37 mmol), refluxed 10 minutes, cooled slightly, and treated with 4-(4-chlorobenzoyl)-3-chlorobenzyl azide (1.03 g, 3.36 mmol) dissolved in ethanol (4 ml). The mixture was refluxed 2 hours, cooled to ambient temperature, and filtered. The solids were washed with ethanol, and the combined filtrate and wash were evaporated to dryness under vacuum. The residue was dissolved in 19:1 (v/v) dichloromethane-methanol (40 ml) and chromatographed on a column of silica gel (60 g) eluted in 20 ml fractions with 97:3 (v/v) dichloromethane-methanol. Fractions 15-42 were combined and evaporated under vacuum to provide 402 mg (32%) of 5-amino-1-(4-[4-chlorobenzoyl]-3-chlorobenzyl)-1,2,3-triazole-4-carboxamide, m.p. 203°-205° C.
Reaction SMILES: [Br-].[CH:2]1([Zn+])[CH2:5][CH2:4][CH2:3]1.Br[C:8]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]>>[CH:2]1([C:8]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:9]=2[C:10]([O:12][CH3:13])=[O:11])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(C)cc1Br
Reactant: [Zn+]C1CCC1
Agent: [Br-]
Product: COC(=O)c1ccc(C)cc1C1CCC1
Temperature: 65 °C
Yield: 80.8 %

Procedure:
Cyclobutylzinc(II) bromide (50 mL, 0.5 M in THF, 25.0 mmol) was added to a mixture of methyl 2-bromo-4-methylbenzoate (compound 89.1, 5.0 g, 21.8 mmol) and PdCl2(dppf)CH2Cl2 (1.78 g, 2.20 mmol). The mixture was degassed with argon, then heated at 65° C. under argon for 24 hours. The mixture was cooled to 0° C., then carefully quenched with water (10 mL). The mixture was diluted with EtOAc (200 mL) and washed with water then brine. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes:EtOAc 30:1 to 20:1) to yield 3.6 g (81%) of the title compound. 1H NMR (400 MHz, Chloroform-d) δ 7.68 (d, 1H), 7.23-7.17 (s, 1H), 7.03 (d, 1H), 4.16 (m, 1H), 3.86 (s, 3H), 2.39 (s, 3H), 2.34 (m, 2H), 2.16-1.96 (m, 3H), 1.80 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.S(Cl)(Cl)=O.[CH3:19]O>C(=O)(O)[O-].[Na+]>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][C:12]([O:14][CH3:19])=[O:13])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(CC(=O)O)cc(OC)c1
Reactant: CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cc(OC)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(3,5-dimethoxyphenyl)acetic acid (5) (600 mg, 3.06 mmol) in MeOH (30 mL) was added dropwise thionyl chloride (3 mL) at 0° C., and the reaction mixture was stirred at room temperature overnight. The reaction was monitored by liquid chromatography-mass spectrometry (LCMS). The mixture was diluted with saturated sodium bicarbonate (aq., 20 mL) and extracted by EtOAc (3×20 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated to give methyl 2-(3,5-dimethoxyphenyl)acetate (crude, 700 mg) as a yellow oil. MS (ES+) C11H14O4 requires: 210. Found: 211 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34](O)=[O:35])[N:21]([C@@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)=[CH:9][CH:8]=1.[CH3:43][O:44][C:45](=[O:63])[C@@H:46]([NH2:62])[CH2:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[CH:58][C:57]([C:60]#[N:61])=[CH:56][CH:55]=2)=[CH:50][CH:49]=1>>[CH3:43][O:44][C:45](=[O:63])[C@@H:46]([NH:62][C:34]([C@@H:20]1[CH2:19][C:18]2[CH:17]=[C:16]3[O:37][CH2:38][C@H:13]([C:10]4[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]5[CH:39]=[CH:40][C:41]([Cl:42])=[C:2]([Cl:1])[CH:3]=5)=[CH:12][CH:11]=4)[O:14][C:15]3=[CH:24][C:23]=2[CH2:22][N:21]1[C@@H:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:26][CH3:27])=[O:35])[CH2:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[CH:58][C:57]([C:60]#[N:61])=[CH:56][CH:55]=2)=[CH:50][CH:49]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: CC[C@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Product: CC[C@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)OC)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-((R)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (75 mg) was coupled with (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester according to General Procedure L to give (S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((R)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-propionic acid methyl ester (30 mg). LCMS (m/z): 866.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13]N(C3C=CC(N4C=CC=CC4=O)=CC=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[I:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[C:32]([F:37])[CH:31]=1>>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:34]([C:33]3[CH:35]=[CH:36][C:30]([I:29])=[CH:31][C:32]=3[F:37])[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccc(-n3ccccc3=O)cc2)nn1)c1ccc(Cl)s1
Reactant: Nc1ccc(I)cc1F
Product: O=C(NCc1cn(-c2ccc(I)cc2F)nn1)c1ccc(Cl)s1

Procedure:
The title compound was prepared by the same procedure for compound 35 described in Example 290 in Scheme 5, using 4-iodo-2-fluoroaniline in place of 4-iodoaniline. MS found for C14H9ClFIN4OS as (M+H)+ 462.0, 464.0
Reaction SMILES: C(O[C:6](=[O:21])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)(C)(C)C.[CH2:22]([O:24][C:25](=[O:37])[CH:26](C(OCC)=O)[C:27](OCC)=[O:28])[CH3:23]>>[CH2:22]([O:24][C:25]([C:26]1[C:6](=[O:21])[N:7]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]2[C:27]=1[OH:28])=[O:37])[CH3:23]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Cl)cc1)n1cccc1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1c(O)c2cccn2n(Cc2ccc(Cl)cc2)c1=O

Procedure:
Prepared according to the thermal cyclization condition used in Example 1 step c) from (4-chloro-benzyl)-pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.) and 2-ethoxycarbonyl-malonic acid diethyl ester (3.0 eq.). ESI (m/z): 347 (M+H)+.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][CH:10]=[C:9]3[CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([CH:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25]O)[CH2:20][CH2:19]2)[CH:5]=1.C([N:35](CC)CC)C.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.N>CO.C1COCC1>[N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][CH:10]=[C:9]3[CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([CH:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][NH2:35])[CH2:20][CH2:19]2)[CH:5]=1
Reactant: CCN(CC)CC
Reactant: OCC(c1ccccc1)N1CCN(CCCc2c[nH]c3ccc(-n4cnnc4)cc23)CC1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: NCC(c1ccccc1)N1CCN(CCCc2c[nH]c3ccc(-n4cnnc4)cc23)CC1
Yield: 55.9 %

Procedure:
In the same way as that described in Example 7, Step 1 using 1-[3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]-4-[2-hydroxy-1-phenylethyl]piperazine (330 mg, 0.77 mmol), triethylamine (214 μL, 1.53 mmol), methanesulphonyl chloride (118 μL, 1.53 mmol) and THF (15 mL). The crude mesylate was then reacted with ammonia (7.7 mL of a 2.0M solution in MeOH, 15.3 mmol) in the same way as that described in Example 7, Step 1. The amine (185 mg, 56%) was isolated as a pale yellow foam. 1H NMR (250 MHz, CDCl3) δ1.88-2.00 (2H, m), 2.38-2.76 (12H, m), 2.79 (2H, t, J=7.5 Hz), 4.11 (1H, dd, J=10.4 and 3.6 Hz), 7.13-7.18 (2H, m), 7.22-7.39 (5H, m), 7.47 (1H, d, J=8.6 Hz), 7.59 (1H, s), 8.34 (1H, br s), 8.46 (2H, s). MS (430, M+1).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[NH:9]1[CH2:13][CH2:12][C@@H:11]([O:14]/[N:15]=[C:16]2\[CH2:17][CH:18]3[C@:31]([CH3:35])([CH2:32][C@H:33]\2[F:34])[C@@H:30]2[C@H:21]([C@H:22]4[C@@:26]([CH2:28][CH2:29]2)([CH3:27])[C@@H:25]([OH:36])[CH2:24][CH2:23]4)[CH2:20][C:19]3=O)[CH2:10]1.Cl.[CH3:39][O:40][NH2:41]>>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[NH:9]1[CH2:13][CH2:12][C@@H:11]([O:14]/[N:15]=[C:16]2\[CH2:17][CH:18]3[C@:31]([CH3:35])([CH2:32][C@H:33]\2[F:34])[C@@H:30]2[C@H:21]([C@H:22]4[C@@:26]([CH2:28][CH2:29]2)([CH3:27])[C@@H:25]([OH:36])[CH2:24][CH2:23]4)[CH2:20]/[C:19]/3=[N:41]\[O:40][CH3:39])[CH2:10]1
Reactant: C[C@]12CC[C@H]3[C@@H](CC(=O)C4C/C(=N\O[C@@H]5CCNC5)[C@H](F)C[C@@]43C)[C@@H]1CC[C@@H]2O
Reactant: CON
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Product: CO/N=C1\C[C@H]2[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]2[C@@]2(C)C[C@@H](F)/C(=N/O[C@@H]3CCNC3)CC12

Procedure:
The title compound was obtained in 56% yield following the procedure described in Example 34 starting from (E)-3-[3-(R)-pyrrolidinyl]oxyimino-2α-fluoro-17β-hydroxyandrostan-6-one fumarate (Example 35, 72 mg) and methoxyamine hydrochloride (14 mg). After evaporation of the solvent the crude reaction mixture was purified by flash chromatography (SiO2, CHCl3/MeOH/26% NH4OH 90/10/1). To the concentrated fractions, a stoichiometric amount of fumaric acid in MeOH was added. The resulting precipitate was rinsed with heptane and filtered to give the title compound I-bk.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[S:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>O1CCCC1>[OH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[S:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CSC(CCCCOC1CCCCO1)CCCc1cccnc1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CSC(CCCCO)CCCc1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.241 g (0.59 mmol) ethyl 8-(2-tetrahydropyranyloxy)-4-[3-(3-pyridyl)propyl]-3-thia-octanoate in 1 ml tetrahydrofuran is added 1 ml of 1N hydrochloric acid. After stirring for 1 h at room temperature, thin layer chromatography indicates incomplete conversion. Another 0.35 ml of 6N hydrochloric acid is added and the mixture is stirred for 1 h. The pH of the reaction mixture is then adjusted to 8.0 and the resulting solution is extracted with methylene chloride. The organic layer is washed with brine, dried, filtered and evaporated to give a yellow oil which is purified by preparative thin layer chromatography over silica gel using ether/ethyl acetate 4:1 as eluent to give ethyl 8-hydroxy-4-[3-(3-pyridyl)propyl]-3-thia-octanoate; IR (CH2Cl2): 3679, 1730 cm-1.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([CH3:25])=[C:22]([CH3:24])[N:23]=3)[CH:20]=2)[C:11](=[O:26])[CH:10]=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[CH3:24][C:22]1[N:23]=[C:18]2[CH:17]=[CH:16][C:15]([N:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]3=[O:26])=[CH:20][N:19]2[C:21]=1[CH3:25]
Reactant: Cc1nc2ccc(-n3ccc(OCc4ccccc4)cc3=O)cn2c1C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2ccc(-n3ccc(O)cc3=O)cn2c1C
Temperature: 130 °C
Yield: 83.9 %

Procedure:
To a stirred solution of 4-(benzyloxy)-1-(2,3-dimethylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (500 mg) in TFA (21 ml) was added anisole (7 ml), and the reaction mixture was heated at 130° C. for 4 h. The mixture was concentrated in vacuo to afford the title compound (310 mg) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].I[CH3:16]>>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH3:16])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CI
Product: CN1CCC(NC(=O)OC(C)(C)C)CC1
Yield: 79.4 %

Procedure:
The procedure of Preparation Example (1-iii-1) was repeated except for using t-butyl-piperidin-4-ylcarbamate (1.67 g, 8.4 mmol) obtained in Preparation Example 1-ii and iodomethane as the starting materials, to obtain 1.43 g of the title compound as pale yellow oil (yield 79.4%).
Reaction SMILES: [CH3:1][N:2]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]CC)=[O:22])=[CH:16][CH:15]=1)[C:3]1[S:4][C:5]2[N:13]=[CH:12][CH:11]=[CH:10][C:6]=2[C:7](=[O:9])[N:8]=1.C(O)C.[OH-].[Na+].Cl>O>[CH3:1][N:2]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1)[C:3]1[S:4][C:5]2[N:13]=[CH:12][CH:11]=[CH:10][C:6]=2[C:7](=[O:9])[N:8]=1
Reactant: CCOC(=O)Cc1ccc(N(C)c2nc(=O)c3cccnc3s2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(c1ccc(CC(=O)O)cc1)c1nc(=O)c2cccnc2s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
To a mixture of 250 mg of ethyl [4-[N-methyl-N-(4-oxo-4H-pyrido[3,2-e]-1,3-thiazin-2-yl)amino)phenyl]acetate and 1.55 ml of ethanol was added 1.55 ml of a 0.5 N aqueous solution of sodium hydroxide under cooling with ice. The mixture was then stirred at room temperature for 4 hours. The reaction mixture was diluted with 5 ml of water, and then adjusted with a 0.5 N hydrochloric acid to pH 1. The resulting crystal was collected by filtration, washed with water and then with diethyl ether, and then dried under reduced pressure to obtain 227 mg of [4-[N-methyl-N-(4-oxo-4H-pyrido[3,2-e]-1,3-thiazin-2-yl)amino]phenyl]acetic acid. Nuclear magnetic resonance spectrum (CDCl3, TMS internal standard) δ: 3.64 (3H, s), 3.77 (2H, s), 7.33 (2H, d, J=7.6 Hz), 7.38 (1H, dd, J=8.0, 4.8 Hz), 7.49 (2H, d, J=7.6 Hz), 8.54-8.60 (1H, m), 8.67 (1H, d, J=8.0 Hz)