Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[Br:20]N1C(=O)CCC1=O>CN(C=O)C>[C:1]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([Br:20])=[CH:10][CH:9]=2)=[CH:5][CH:6]=1
Reactant: c1ccc(Nc2ccc(-c3ccccc3)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Brc1ccc(Nc2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 25.5 h
Yield: 284.8 %

Procedure:
(Biphenyl-4-yl)-phenylamine (35.0 g) and DMF (700 ml) were added and dissolved in a nitrogen-substituted reaction vessel, and N-bromosuccinimide (8.5 g) was added under ice-cooled conditions. The reaction temperature was raised to room temperature while adding N-bromosuccinimide (17.0 g) in two separate portions. After being stirred for 25.5 hours, the reaction solution was dropped to water (3,500 ml), and the precipitated solid was collected by filtration. Toluene (2,500 ml) was added to dissolve the solid, and the solid was dried over magnesium sulfate. After filtration, the filtrate was concentrated. The resulting concentrate was dispersed and washed by addition of n-hexane (500 ml), and dried overnight under reduced pressure to obtain a reddish solid of (biphenyl-4-yl)-(4-bromophenyl)amine (44.1 g; yield 95.4%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C@@H:5]([NH:9][C:10](=[O:24])[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)[CH:6]([CH3:8])[CH3:7])[CH3:2].[NH2:26][CH2:27][C@@H:28]([C:30]1[CH:31]=[CH:32][C:33]([OH:41])=[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=1)[OH:29]>>[CH2:1]([O:3][C:4](=[O:25])[C@@H:5]([NH:9][C:10](=[O:24])[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([NH:26][CH2:27][C@H:28]([OH:29])[C:30]3[CH:31]=[CH:32][C:33]([OH:41])=[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)[CH:6]([CH3:8])[CH3:7])[CH3:2]
Reactant: CCOC(=O)[C@@H](NC(=O)c1ccc(N2CCC(=O)CC2)cc1)C(C)C
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CCOC(=O)[C@@H](NC(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1)C(C)C

Procedure:
The title compound was prepared from 3-methyl-(2S)-2-[4-(4-oxo-piperidin-1-yl)-benzoylamino]-butyric acid ethyl ester (which was obtained in Example 163) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 180 as an off-white solid; mp>85° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 0.92 (d, J=6.8 Hz, 3 H), 0.97 (d, J=6.8 Hz, 3 H), 1.17 (t, J=7.1 Hz, 3 H), 1.20–1.40 (m, 2 H), 1.75–1.95 (m, 2 H), 2.05–2.20 (m, 1 H), 2.55–2.90 (m, 5 H), 2.90 (s, 3 H), 3.70–3.85 (m, 2 H), 4.00–4.20 (m, 2 H), 4.22 (t, J=7.7 Hz, 1 H), 4.48 (dd, J=8.0, 4.4 Hz, 1 H), 6.80 (d, J=8.2 Hz, 1 H), 6.95 (d, J=8.9 Hz, 2 H), 6.98 (dd, J=8.2, 2.0 Hz, 1 H), 7.17 (d, J=2.0 Hz, 1 H), 7.76 (d, J=8.9 Hz, 2 H), 8.17 (d, J=7.9 Hz, 1 H); MS (ES) m/z: 577.2 (MH+); HRMS Calcd. for C29H43N4O7S (MH+): 577.2690. Found: 577.2682.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][N:18]([C:21]4[C:26]5[CH:27]=[CH:28][S:29][C:25]=5[CH:24]=[CH:23][N:22]=4)[CH2:17][CH2:16]3)=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.Cl[CH2:31][C:32]([NH2:34])=[O:33].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][N:18]([C:21]4[C:26]5[CH:27]=[CH:28][S:29][C:25]=5[CH:24]=[CH:23][N:22]=4)[CH2:17][CH2:16]3)=[CH:7][C:8](=[O:12])[N:9]2[CH2:31][C:32]([NH2:34])=[O:33])=[CH:4][CH:3]=1
Reactant: NC(=O)CCl
Reactant: O=c1cc(CCN2CCN(c3nccc4sccc34)CC2)c2ccc(F)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)Cn1c(=O)cc(CCN2CCN(c3nccc4sccc34)CC2)c2ccc(F)cc21
Temperature: 50 °C

Procedure:
66.9 kg of 7-fluoro-4-[2-[4-[thieno[3,2-c]pyridin-4-yl]piperazin-1-yl]ethyl]-quinolin-2(1H)-one (V), 18.4 kg of 2-chloroacetamide (1.2 eq.), 51.5 kg of potassium carbonate (2 eq.) and 335 l of DMF are introduced into a reactor. The mixture is stirred at 50° C. for twenty hours and then cooled to 25° C. and 1000 l of water are added. The suspension obtained is filtered and washed with water and a paste is re-formed in 307 l of ethanol. The solid is filtered off. 60.7 kg, estimated on a dry basis, of a white solid (II) are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26]O.C(C=P(CCCC)(CCCC)CCCC)#N.CCCCCC>C1(C)C=CC=CC=1.C(OCC)(=O)C.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH2:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: OCc1ccccn1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(Cl)cc1)C(Cc1ccccn1)c1cc(F)ccc1F
Yield: 49.5 %

Procedure:
Under an argon atmosphere, the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (150 mg, 0.495 mmol) obtained in Example 5 and 2-pyridylmethanol (95.5 μl, 0.990 mmol) were dissolved in toluene (5 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (239 mg, 0.990 mmol). The resulting mixture was heated under reflux for 18 hours under an argon atmosphere. The reaction mixture was then concentrated. The residue thus obtained was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate=1:1 eluate was concentrated. The solid thus obtained was recrystallized from ethyl acetate-hexane, whereby the title compound (96.6 mg, 0.245 mmol, 49%) was obtained as colorless needle crystals.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](=[S:27])[NH2:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:29][C:30](=O)[CH2:31][CH:32]([CH3:34])[CH3:33]>>[CH3:33][CH:32]([CH3:34])[CH2:31][C:30]1[N:26]=[C:25]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[S:27][CH:29]=1
Reactant: NC(=S)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: CC(C)CC(=O)CBr
Product: CC(C)Cc1csc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
150 mg (about 0.315 mmol) of the compound from Example 53A and 76 mg (0.426 mmol) of 1-bromo-4-methylpentan-2-one (J. Org. Chem., 19, 2005, 4141-4153) were reacted according to the General Method 3. Yield: 68 mg (40% of theory).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[C:11]1[C:16]([O:17][CH2:18][CH3:19])=[CH:15][C:14]([C:20]2[C:25]([CH2:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:28][CH3:29])=[N:13][C:12]=1[CH3:30])C>C1COCC1.CCOCC>[CH2:28]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([CH2:26][CH3:27])[C:20]=1[C:14]1[N:13]=[C:12]([CH3:30])[C:11]([CH2:10][OH:9])=[C:16]([O:17][CH2:18][CH3:19])[CH:15]=1)[CH3:29]
Reactant: CCOC(=O)c1c(OCC)cc(-c2c(CC)cccc2CC)nc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOc1cc(-c2c(CC)cccc2CC)nc(C)c1CO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of LiAlH4 (1 M in THF, 20 mL) is added dropwise to a solution of 6-(2,6-diethyl-phenyl)-4-ethoxy-2-methyl-nicotinic acid ethyl ester (2.3 g, 6.7 mmol) in THF (20 mL). The reaction mixture is stirred at room temperature for 4 hours, diluted with ether (10 mL), and quenched with Na2SO4.10H2O (10 g). The resulting mixture is stirred for one hour, filtered through Celite, and concentrated in vacuo to give [6-(2,6-diethyl-phenyl)-4-ethoxy-2-methyl-pyridin-3-yl]-methanol.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:16])[C:5]([Cl:17])=[CH:4][N:3]=1.[CH2:18]([O:25][CH2:26][CH2:27][CH2:28]O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][CH2:26][CH2:27][CH2:28][O:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([F:15])[C:9]=1[NH:8][C:6]1[C:5]([Cl:17])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCCCOCc1ccccc1
Reactant: Oc1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: Fc1cccc(OCCCOCc2ccccc2)c1Nc1nc(Cl)ncc1Cl

Procedure:
[2-(3-Benzyloxy-propoxy)-6-fluoro-phenyl]-(2,5-dichloro-pyrimidin-4-yl)-amine was prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-phenol and 3-Benzyloxy-propan-1-ol in an analogous manner to Example 1283c. Title compound was isolated as a white foam (247 mg, 46%). HPLC purity=95%. LCMS 424.13 (M+H), HNMR 8.15 (s, 1H), 7.25-7.21 (m, 1H), 6.82-6.77 (m, 2H), 6.71 (s, 1H), 6.36-6.32 (m, 5H), 4.48 (s, 2H), 4.16-4.13 (m, 2H), 3.57-3.53 (m, 2H), 2.07-2.02 (m, 2H).
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([O:14][CH2:15][CH3:16])=[C:7]([O:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])[CH:6]=1)C.O.[OH-].[Na+].Cl>O1CCOCC1>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[CH2:19][CH2:18][O:17][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]=1[O:14][CH2:15][CH3:16])[C:4]([OH:28])=[O:3]
Reactant: CCOC(=O)c1cc(OCC)c(OCC)c(OCCc2ccc(Cl)cc2Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCOc1cc(C(=O)O)cc(OCCc2ccc(Cl)cc2Cl)c1OCC
Temperature: 60 °C
Reaction time: 16 h

Procedure:
0.66 g (1.54 mmol) of 3-[2-(2,4-Dichlorophenyl)-ethoxy]-4,5-diethoxy-benzoic acid ethyl ester was dissolved in 6 ml of dioxan. 5 ml of water and 2N aqueous NaOH was added to the solution to give a pH of 13. The reaction solution was heated at 60° C. for 4 h and stirred at room temperature for 16 h. The reaction solution was cooled to 0° C. and concentrated hydrochloric acid was added to give a pH of 1–2, whereupon the product precipitated from solution. The suspension was stirred for 30 min, then the product was filtered off and dried under reduced pressure.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[O-]S([O-])(=O)=O.[Mg+2].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:17]=1[CH:18]=O>C(Cl)(Cl)Cl>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:17]=1[CH:18]=[N:5][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1]
Reactant: COc1ccc(OC)c(C=O)c1
Reactant: COC(CN)OC
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClC(Cl)Cl
Product: COc1ccc(OC)c(C=NCC(OC)OC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
Aminoacetaldehyde dimethylacetal (20.0 mL, 19.5 g, 0.185 mol) was dissolved in chloroform (100 mL) and MgSO4 (10 g) was added. Then 2,5-dimethoxybenzaldehyde (10d, 7.00 g, 0.042 mol) was also added and the mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with chloroform (100 mL), washed with water (2×200 mL), brine (200 mL), dried (Na2SO4), and concentrated to provide the pure imine as a yellow oil (10.64 g, 100%). 1H NMR (300 MHz CDCl3) 8.66 (s, 1H), 7.47 (d, J=3.0 Hz, 1H), 6.91 (dd, J1=9.0 Hz, J2=3.0 Hz, 1H), 6.81 (d, J=9.0 Hz, 1H), 4.65 (t, J=5.1 Hz, 1H), 3.78 (s, 3H), 3.77 (s, 3H), 3.76 (dd, J1=5.4 Hz, J2=1.2 Hz, 2H), 3.38 (s, 6H).
Reaction SMILES: [CH2:1]([CH2:3][C:4]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N:16]=[N+]=[N-])=[CH:10][CH:9]=1)([CH3:6])[CH3:5])[CH3:2]>CO.[Pd]>[CH2:1]([CH2:3][C:4]([O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][NH2:16])=[CH:12][CH:13]=1)([CH3:5])[CH3:6])[CH3:2]
Reactant: CCCC(C)(C)Oc1ccc(CCN=[N+]=[N-])cc1
Agent: [Pd]
Solvent: CO
Product: CCCC(C)(C)Oc1ccc(CCN)cc1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
Pd/C at 10% (16 mg) is added to a solution of ethyl 2-[4-(2-azidoethyl)phenoxy]-2-methylpropane (784 mg, 2.89 mM) in methanol (42 ml) and the suspension is maintained in agitation for the whole night at a pressure of 5 atmospheres of H2 at room temperature until the substrate disappears [TLC (silica gel; mobile phase: ethyl acetate/petroleum ether=2:8)]. The mixture is filtered to remove the catalyst and the solvent is removed at reduced pressure. 539 mg of ethyl 2-[4-(2-aminoethyl)phenoxy]-2-methylpropane is obtained as a colorless oil (74% of yield).
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[NH:9][C:10]1[N:14]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[N:13]=[C:12]([CH3:25])[CH:11]=1)(=O)C.Cl>CO>[C:15]1([N:14]2[C:10]([NH:9][C:5]3[NH:6][CH2:7][CH2:8][N:4]=3)=[CH:11][C:12]([CH3:25])=[N:13]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)N1CCN=C1Nc1cc(C)nn1-c1cccc2ccccc12
Agent: Cl
Solvent: CO
Product: Cc1cc(NC2=NCCN2)n(-c2cccc3ccccc23)n1

Procedure:
1-Acetyl-2[1-(1-naphthyl)-3-methyl-5-pyrazolyl] amino-2-imidazoline (15.27 g.) was treated with HCl in methanol as described in Example II to give 11.82 g. product, mp 221°-224°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([CH2:12][CH2:13][CH2:14]OS(C)(=O)=O)[C:8]1=[O:28].[CH2:36]([O:38][CH2:39][CH2:40][N:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N:43]=[C:42]1[N:50]1[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)[CH3:37]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][CH2:14][N:53]2[CH2:54][CH2:55][CH2:56][N:50]([C:42]3[N:41]([CH2:40][CH2:39][O:38][CH2:36][CH3:37])[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:51][CH2:52]2)([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[C:8]1=[O:28]
Reactant: COc1cc(CN2CCC(CCCOS(C)(=O)=O)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Product: CCOCCn1c(N2CCCN(CCCC3(Cc4ccc(F)cc4)CCN(Cc4cc(OC)c(OC)c(OC)c4)C3=O)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(3-methanesulfonyloxypropyl)-2-oxopyrrolidine and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to give the title compound: Rf=0.39 (silica gel, 2%triethylamine/20% methanol/ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:23][C:8]2=[N:9][CH:10]=[CH:11][C:12]([O:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=3)=[C:7]2[CH:6]=1)=[O:4]>[Fe]>[CH3:1][O:2][C:3]([C:5]1[O:23][C:8]2=[N:9][CH:10]=[CH:11][C:12]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)=[C:7]2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2o1
Agent: [Fe]
Product: COC(=O)c1cc2c(Oc3ccc(N)cc3)ccnc2o1
Yield: 86.9 %

Procedure:
4-(4-Nitrophenoxy)-furo[2.3-b]pyridine-2-carboxylic acid methyl ester (70 mg) was subjected to iron reduction by the same method as in Production Example 10 to obtain the title compound (55 mg).
Reaction SMILES: [Na+].[Br:2][C:3]1[C:4]([F:17])=[CH:5][C:6]([N+:14]([O-])=O)=[C:7]([NH:9][CH2:10][C:11]([O-])=[O:12])[CH:8]=1.O.O.[Sn](Cl)Cl>C(O)C>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][C:4]=1[F:17])[NH:14][C:11](=[O:12])[CH2:10][NH:9]2
Reactant: O=C([O-])CNc1cc(Br)c(F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1CNc2cc(Br)c(F)cc2N1
Temperature: 25 °C

Procedure:
A solution of N-(5'-bromo-4'-fluoro-2'-nitrophenyl)glycine sodium salt (0.450 g, 1.54 mmol, as prepared above) and tin (II) chloride dihydrate (1.039 g, 4.605 mmol, Aldrich, used as received) in ethanol (7.0 mL) was refluxed for 30 min. It was then cooled to room temperature and solvent was removed under vacuum. The residue was diluted with water (15.0 mL) and basified with 10% Na2CO3 to pH~8. The resulting suspension was extracted with ethyl acetate (100 mL). The ethyl acetate was dried over anhydrous Na2SO4 and removed under vacuum to yield 0.241 g (64%).of the title compound as a yellow powder, m.p. 214-216° C.; 1H NMR (DMSO-d6): δ 3.684 (s, 2H), 6.062 (s, 1H), 6.631 (d, 1H, J=9.3 Hz), 6.825 (d, 1H, J=6.6 Hz), 10.303 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([CH3:23])([CH3:22])[S:20](=[O:25])(=[O:24])[CH2:19][C@:18]([C:27]2[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[CH:29][C:28]=2[F:36])([CH3:26])[N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:47][C:48]1([CH3:51])[CH2:50][O:49]1.B(F)(F)F.CCOCC.[Cl-].[NH4+]>C1COCC1>[C:11]([O:10][C:9]([N:8]([C:16]1[C:21]([CH3:23])([CH3:22])[S:20](=[O:25])(=[O:24])[CH:19]([CH2:47][C:48]([OH:49])([CH3:51])[CH3:50])[C@:18]([C:27]2[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[CH:29][C:28]=2[F:36])([CH3:26])[N:17]=1)[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:15])([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@](C)(c2cc([N+](=O)[O-])ccc2F)CS(=O)(=O)C1(C)C
Reactant: CC1(C)CO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: FB(F)F
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(O)CC1[C@@](C)(c2cc([N+](=O)[O-])ccc2F)N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(C)(C)S1(=O)=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
A solution of tert-butyl N-tert-butoxycarbonyl-N-[(3R)-3-(2-fluoro-5-nitro-phenyl)-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-5-yl]carbamate (0.4 g, 0.756 mmol) in THF (3.8 mL) was cooled to −78° C. and to this was added LHMDS (1.0M in THF; 1.51 ml, 1.51 mmol) dropwise via syringe. The reaction was stirred at −78° C. for 1 hr. 2,2-dimethyloxirane (0.134 ml, 1.51 mmol) was then added followed by BF3.OEt2 (1.44 ml, 1.44 mmol) as a solution in 2 mL of THF. The reaction was stirred at −78° C. for 1 hr. The reaction was treated with aqueous ammonium chloride solution and extracted with ethyl acetate. The organic portion was dried over Na2SO4, filtered, concentrated and purified by column chromatography, eluting with 0-40% EtOAc/Heptanes to give the title compound (376 mg, 0.624 mmol, 83% yield) as a white solid. MS m/z=624.2 (M+Na).
Reaction SMILES: NC1C(C=[N:11][NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=NC(Cl)=C(Cl)N=1.ClC1C=CC(S(Cl)(=O)=O)=CC=1.NN>>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([S:13]([NH:12][NH2:11])(=[O:14])=[O:15])=[CH:21][CH:20]=1
Reactant: Nc1nc(Cl)c(Cl)nc1C=NNS(=O)(=O)c1ccc(Cl)cc1
Agent: NN
Agent: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: NNS(=O)(=O)c1ccc(Cl)cc1

Procedure:
p-Chlorobenzenesulfonic acid 2-[(3-amino-5,6-dichloropyrazinyl)methylene]hydrazide by the reaction of p-chlorobenzenesulfonyl chloride with hydrazine to form p-chlorobenzenesulfonylhydrazine, followed by the reaction of the latter with 3-amino-5,6-dichloropyrazinaldehyde.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH2:28]>C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])[N:3]=1
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Reactant: NCCCCCCCCN
Solvent: CCO
Product: NCCCCCCCCNc1nc(N)nc2c1ncn2[C@H]1C=C[C@@H](CO)C1
Yield: 42.8 %

Procedure:
A solution of (±)-(cis)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol (272 mg, 1.00 mmol) and 1,8-diaminooctane (1.44 g, 10 mmol) in absolute ethanol (15 mL) was refluxed under nitrogen for 1.5 hours. The solution was concentrated, cooled, and the resulting precipitate filtered and crystallised from i-propanol to give title compound as white solid (160 mg, 42%), m.p. 125-127° C.
Reaction SMILES: NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4N(CCC#N)C(=O)COC=4N=3)=CC=2)CCC1.C(OC(=O)[NH:39][C:40]1([C:44]2[CH:49]=[CH:48][C:47]([C:50]3[C:51]([C:63]4[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=4)=[CH:52][C:53]4[N:58]([CH3:59])[C:57](=[O:60])[C@@H:56]([CH3:61])[O:55][C:54]=4[N:62]=3)=[CH:46][CH:45]=2)[CH2:43][CH2:42][CH2:41]1)(C)(C)C>>[NH2:39][C:40]1([C:44]2[CH:45]=[CH:46][C:47]([C:50]3[C:51]([C:63]4[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=4)=[CH:52][C:53]4[N:58]([CH3:59])[C:57](=[O:60])[C@@H:56]([CH3:61])[O:55][C:54]=4[N:62]=3)=[CH:48][CH:49]=2)[CH2:41][CH2:42][CH2:43]1
Reactant: C[C@H]1Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2N(C)C1=O
Agent: N#CCCN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Product: C[C@H]1Oc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc2N(C)C1=O
Yield: 50.8 %

Procedure:
Following the procedure for 3-(6-(4-(1-aminocyclobutyl)phenyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)propanenitrile, (R)-tert-butyl(1-(4-(1,3-dimethyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (16 mg, 0.032 mmol) was reacted to afford the title compound (6.5 mg). 1H NMR (500 MHz, CH3OD) 7.56 (s, 1H), 7.42 (d, 2H), 7.38 (d, 2H), 7.31 (m, 3H), 7.24 (m, 2H), 5.06 (q, 1H), 3.44 (s, 3H), 2.73-2.77 (m, 2H), 2.53-2.59 (m, 2H), 2.20-2.26 (m, 1H), 1.95-1.97 (m, 1H), 1.67 (d, 3H). LCMS (Method D): RT=0.85 min, M+H+=400.2.
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][NH:4][C:5](=[O:7])[CH3:6].[C:14]([O-])(O)=[O:15].[Na+].C=O.[Na+].[Cl-]>CCO>[OH:15][CH2:14][CH:3]([NH:4][C:5](=[O:7])[CH3:6])[C:2](=[O:1])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)NCC(=O)c1ccccc1
Reactant: O=C([O-])O
Agent: C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)NC(CO)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 144.8 %

Procedure:
N-(1-oxo-1-phenylethan-2-yl)acetamide (10) (1.1 g, 6.0 mmol, 1.0 equiv.) was added to a 100 mL RBF followed by EtOH (25 mL, 200 proof). Next, a 0.5 M solution of NaHCO3 (250 mg, 3.0 mmol, 0.5 equiv.) was added followed by a 37% solution of formaldehyde (730 μL, 9.0 mmol, 1.5 equiv.). The solution was stirred at rt. for 24 h and transferred to a separatory funnel with a 1.0 M solution of NaCl (2.9 g, 50.0 mmol). The solution was extracted with CH2Cl2 (5×60 mL). The organic layer was dried over Na2SO4, concentrated on a rotary evaporator, and dried under vacuum to give a crude off-white solid. The solid was washed with EtOAc (10 mL) to remove all impurities. The remaining solid was dried under vacuum to give 900 mg (72%) of 11 as a white solid. Rf=0.11 (5% MeOH/CH2Cl2); mp=115-117° C.; IR (KBr) 3312, 3262, 2915, 1696, 1639, 1537, 1228, 1101 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.00 (d, J=7.0 Hz, 2H, Ph-H), 7.61 (t, J=7.0 Hz, 1H, Ph-H), 7.48 (t, J=7.0 Hz, 2H, Ph-H), 7.17 (d, J=7.0 Hz, 1H, Ac—NH), 5.63 (m, 1H, Ac—NH—CH), 4.01 (m, 1H, CH—CH2), 3.88 (m, 1H, CH—CH2), 2.06 (s, 3H, NH—COCH3); 13C NMR (125 MHz, CDCl3) δ 197.0, 171.2, 134.3, 129.1, 128.9, 64.4, 57.3, 23.2; LRMS (ESI-MS m/z): Mass calcd for C11H13NNaO3 [M+Na]+, 230.22. Found 208. Anal. calcd for C11H13NO3: C, 63.76; H, 6.32; N, 6.76. Found: C, 63.92; H, 6.34; N, 6.74. Spectroscopic data were consistent with the literature data for this compound.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:7](=[O:11])[N:8]([CH2:9][CH3:10])[C:4]=2[CH:3]=1.[O:20]=[S:21]1(=[O:37])[C:25]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=2[C:23](=[O:31])[N:22]1[CH2:32][CH2:33][CH2:34][CH2:35]Br>>[O:37]=[S:21]1(=[O:20])[C:25]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=2[C:23](=[O:31])[N:22]1[CH2:32][CH2:33][CH2:34][CH2:35][N:15]1[CH2:14][CH2:13][CH:12]([N:6]2[C:5]3[CH:18]=[CH:19][C:2]([CH3:1])=[CH:3][C:4]=3[N:8]([CH2:9][CH3:10])[C:7]2=[O:11])[CH2:17][CH2:16]1
Reactant: CCn1c(=O)n(C2CCNCC2)c2ccc(C)cc21
Reactant: O=C1c2cc(Cl)ccc2S(=O)(=O)N1CCCCBr
Product: CCn1c(=O)n(C2CCN(CCCCN3C(=O)c4cc(Cl)ccc4S3(=O)=O)CC2)c2ccc(C)cc21

Procedure:
From 4-(5-methyl-3-ethyl-2-oxo-1-benzimidazolinyl)piperidine and 1,1-dioxido-2-(4-bromobutyl)-5-chloro-1,2-benzisothiazol-3(2H)-one (prepared as shown in Example 22) using the procedures described in Example 1 there was obtained a white solid upon formation of the HCl salt (from methanol), melting point 229-231° C. Analysis calculated for C26H31N4O4S.HCl.0.75 H2O: C, 53.82; H, 5.80; N, 9.66; found: C, 53.79; H, 5.52; N, 9.53. The NMR was consistent with the structure.