Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)=[CH:4][C:3]=1[Cl:18].[CH3:19][N:20]1[C:24]([CH3:25])=[C:23]([C:26](O)=[O:27])[C:22](=[O:29])[N:21]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl.O>[Cl:18][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:2]=1[NH:1][C:26]([C:23]1[C:22](=[O:29])[N:21]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:20]([CH3:19])[C:24]=1[CH3:25])=[O:27])[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Reactant: NC(=O)c1cc(Oc2ccc(N)c(Cl)c2)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)cc2Cl)c(=O)n(-c2ccccc2)n1C
Temperature: 46 °C
Reaction time: 6 h
Yield: 46.5 %

Procedure:
To a suspension of 4-(4-amino-3-chlorophenoxy)picolinamide (191 mg, 0.72 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (168 mg, 0.72 mmol) in DCM (10 mL) was added EDCI (166 mg, 0.86 mmol) and HOAT (20 mg, 0.14 mmol). The reaction was stirred at 46° C. for 6 hours, followed by the addition of 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (32 mg, 0.14 mmol) and EDCI (27 mg, 0.14 mmol). The mixture was continued to stir at 46° C. for 13 hours, then cooled to rt and diluted with water (10 mL). The resulted mixture was extracted with ethyl acetate (10 mL×3), and the combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v)=50/1) to give the title compound as a pale yellow solid (160 mg, 46.5%).
Reaction SMILES: C([O:5][C:6](=[O:54])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:46])[NH:16][CH2:17][C@H:18]([CH:43]([CH3:45])[CH3:44])[CH2:19][C@H:20]([NH:35]C(OC(C)(C)C)=O)[C@@H:21]([OH:34])[CH2:22][C@H:23]([C:27](=[O:33])[NH:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:24]([CH3:26])[CH3:25])=[C:11]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][O:52][CH3:53])[CH:10]=1)(C)(C)C.Cl>O1CCOCC1>[NH2:35][C@H:20]([C@@H:21]([OH:34])[CH2:22][C@H:23]([C:27](=[O:33])[NH:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:24]([CH3:26])[CH3:25])[CH2:19][C@@H:18]([CH:43]([CH3:44])[CH3:45])[CH2:17][NH:16][C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:54])=[O:5])=[CH:10][C:11]=1[O:47][CH2:48][CH2:49][CH2:50][CH2:51][O:52][CH3:53])=[O:46]
Reactant: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](C[C@H](CNC(=O)c1ccc(OCC(=O)OC(C)(C)C)cc1OCCCCOC)C(C)C)NC(=O)OC(C)(C)C)C(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCCCNC(=O)[C@@H](C[C@H](O)[C@@H](N)C[C@H](CNC(=O)c1ccc(OCC(=O)O)cc1OCCCCOC)C(C)C)C(C)C
Reaction time: 13 h

Procedure:
After reaction of (2S,4S,5S,7S)-{4-[4-(tert-butoxycarbonyl)amino-7-butylcarbamoyl-5-hydroxy-2-isopropyl-8-methyl-nonylcarbamoyl]-3-(4-methoxybutoxy)-phenoxy}-acetic acid (tert-butyl) ester (93 mg) in a 4N hydrochloric acid solution in dioxane (2 ml) at 0° C. for 45 minutes and then at room temperature for 13 hours, the solvent is rapidly concentrated under a high vacuum with vigorous stirring until frozen and is subsequently removed by lyophilisation. (2S,4S,5S,7S)-[4-(4-Amino-7-butylcarbamoyl-5-hydroxy-2-isopropyl-8-methyl-nonylcarbamoyl)-3-(4-methoxybutoxy)-phenoxy]-acetic acid is obtained: HPLC Rt =11.7 min. MS(FAB) m/e 610 (M+ +1).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Br-:12].[Br:13][CH2:14][CH2:15][CH2:16][N+:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:18][CH3:19]>C(#N)C>[Br-:13].[Br-:12].[CH2:18]([N+:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:16][CH2:15][CH2:14][N+:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH3:1])=[CH:3][CH:4]=1)[CH3:19]
Reactant: CC[N+](CC)(CC)CCCBr
Reactant: Cc1ccnc2ccccc12
Agent: [Br-]
Solvent: CC#N
Product: CC[N+](CC)(CC)CCC[n+]1ccc(C)c2ccccc21
Yield: 87.6 %

Procedure:
4-Methylquinoline (470 mg, 3.3 mmol), (3-bromopropyl)triethylammonium bromide (1.0 g, 3.3 mmol), and 10 mL acetonitrile were stirred at 90° C. in a pressure vessel for 64 h. After cooling down, the solvent was removed under vacuum and the residue was purified by column chromatography (SiO2, gradient from CH2Cl2 to MeOH) to furnish 1-(3-triethylammoniopropyl)-4-methylquinolinium dibromide as a white solid (1.29 g, 88%). 1H NMR (400 MHz, CD3OD): δ 1.35 (t, J=7.4 Hz, 9 H), 2.54 (m, 2 H), 3.10 (s, 3 H), 3.39 (q, J=7.2 Hz, 6 H), 3.60 (t, J=8.0 Hz, 2 H), 5.18 (t, J=8.0 Hz, 2 H), 8.04 (d, J=6.0 Hz, 1 H), 8.09 (t, 1 H), 8.33 (t, 1 H), 8.61 (d, 1 H), 8.65 (d, 1 H), 9.43 (d, J=6.0 Hz, 1 H); HRMS (FAB+): m/z=365.1581 [M-Br]+ (calcd for C19H30BrN2: 365.1587).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].C1C2CCCCC=2C=CC=1O.[N:34]1([CH2:41][CH2:42][O:43][C:44]2[CH:51]=[CH:50][C:47]([CH:48]=O)=[CH:46][CH:45]=2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[N:34]1([CH2:41][CH2:42][O:43][C:44]2[CH:51]=[CH:50][C:47]([CH2:48][CH2:2][CH2:1][NH:3][C:4]3[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=3[CH:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:46][CH:45]=2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: O=Cc1ccc(OCCN2CCCCCC2)cc1
Reactant: CCNc1ccc(OC)cc1C1CCc2cc(O)ccc2C1
Agent: Oc1ccc2c(c1)CCCC2
Product: COc1ccc(NCCCc2ccc(OCCN3CCCCCC3)cc2)c(C2CCc3cc(O)ccc3C2)c1

Procedure:
Synthesized from 6-(2-ethylamino-5-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol according to an analogous synthetic method to Example 36, 642-ethylamino-5-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (40 mg) and 4-(2-azepan-1-ylethoxy)benzaldehyde (202 mg) were used according to an analogous synthetic method to Example 38 to provide the title compound (32 mg).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[C:10]([O:21]C)[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br>>[C:1]1([N:7]2[C:12](=[O:13])[C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[C:10]([OH:21])[CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cnn(-c2ccccc2)c(=O)c1-c1ccc(F)cc1
Agent: Br
Product: O=c1c(-c2ccc(F)cc2)c(O)cnn1-c1ccccc1
Yield: 92 %

Procedure:
The 2-phenyl-4-(4-fluorophenyl)-5-methoxy-3(2H)-pyridazinone product was treated with 48% HBr according to the method of Example 7 to furnish 2-phenyl-4-(4-fluorophenyl)-5-hydroxy-3(2H)-pyridazinone (yield: 957 mg, 92%). MS (DCI/NH3) m/z 283 (M+H)+, 300 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]=[S:9])[CH:5]=[CH:4][N:3]=1.[C:10]([O:14][C:15]([N:17]1CCC(N)CC1)=O)([CH3:13])([CH3:12])[CH3:11].[O-]S([O-])(=O)=O.[Mg+2].ClCl>>[C:10]([O:14][C:15](=[NH:17])[N:3]1[CH2:2][CH2:8][CH:6]([NH2:7])[CH2:5][CH2:4]1)([CH3:13])([CH3:12])[CH3:11].[CH3:1][C:2]1[N:7]=[C:6]([CH:8]=[S:9])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: Cc1nccc(C=S)n1
Agent: ClCl
Agent: O=S(=O)([O-])[O-]
Product: CC(C)(C)OC(=N)N1CCC(N)CC1
Temperature: 23 °C
Reaction time: 16 h

Procedure:
2-Methylthiopyrimidine-4-carboxaldehyde (1.51 g, 9.8 mmol), 1-t-butoxycarbonyl-4-aminopiperidine (Mach R. H., et al., J. Med. Chem. 1993 36, 3707) (2.1 g, 10.5 mmol), MgSO4 (ca 2 g) and CH2 Cl2 (75 mL) were combined and stirred at 23° C. for 16 h. Filtration and concentration of the filtrate afforded the title compound as a yellow oil: 1H NMR (CDCl3) δ 8.57 (d, 1), 8.27 (s, 1), 7.58 (d, 1), 4.05 (m, 2), 3.55 (m, 1), 3.00 (m, 2), 2.60 (s, 3), 1.75 (m, 4), 1.48 (s, 9).
Reaction SMILES: C(O[CH:6](N(C)C)[N:7]([CH3:9])[CH3:8])(C)(C)C.[C:13]([O:17][C:18]([NH:20][C@@:21]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:26][C:25](=[O:27])[C@@H:24]2[C@H:22]1[C@H:23]2[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:19])([CH3:16])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1.C(OC)(C)(C)C.CCCCCC>[C:13]([O:17][C:18]([NH:20][C@@:21]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:26](=[CH:6][N:7]([CH3:9])[CH3:8])[C:25](=[O:27])[C@@H:24]2[C@H:22]1[C@H:23]2[C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)CC(=O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Solvent: CCCCCC
Product: CN(C)C=C1C(=O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]2[C@]1(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
Tert-butoxybis(dimethylamino)methane (481.1 ml, 2.33 mol) is added to a suspension of di-tert-butyl(1S,2S,5R,6R)-2-[(tert-butoxycarbonyl)amino]-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylate (600 g, 1.46 mol) in dry toluene (3.6 L) at room temperature under nitrogen. The mixture is heated at 80° C. for 3 hour and 45 minutes, then cooled to room temperature and stirred overnight. The reaction volume is reduced in vacuo, diluted with methyl tert-butyl ether (1.8 L) and hexane (1.8 L), and stirred for 3 hours at 15° C. After 3 hours, the resulting solid is collected by filtration, washed with cold hexane (2×1.8 L), and dried under vacuum to obtain the title compound (620.4 g, yield 91%). HPLC-MS: 98%.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[C:16]1([C:3]2[C:2]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([O:24][C:23]([F:22])([F:34])[F:35])[CH:26]=3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=3)[N:4]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(-c3cccc(OC(F)(F)F)c3)nc2c1
Yield: 56.3 %

Procedure:
The product was obtained via a Suzuki coupling reaction using the method previously shown in Example 20, Step 3, using methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (100 mg, 0.29 mmol, 1.00 equiv) and 3-(trifluoromethoxy)phenylboronic acid (89.6 mg, 0.43 mmol, 1.50 equiv) as reactants. Purification via silica gel column (dichloromethane/methanol (10:1)) afforded 67 mg (55%) of 2-phenyl-3-(3-(trifluoromethoxy)phenyl)quinoxaline-6-carboxylic acid as a white solid.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Br:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][C:9]=1[OH:17].I[CH:19]([CH3:21])[CH3:20].CCOC(C)=O>CN(C=O)C>[Br:7][C:8]1[C:9]([O:17][CH:19]([CH3:21])[CH3:20])=[CH:10][CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1cccc(O)c1Br
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1cccc([N+](=O)[O-])c1Br
Temperature: 0 °C
Reaction time: 17 h
Yield: 97.2 %

Procedure:
Cs2CO3 was added in 3 portions over 15 min to a stirred solution of 2-bromo-3 nitrophenol (3.00 g, 13.8 mmol) and 2-iodopropane (4.79 g, 27.6 mmol) in 50 ml anhydrous DMF cooled to 0° C. under N2. The reaction was allowed to warm to ambient temperature (2 h) and stirred overnight (17 h). EtOAc (250 ml) was added, the reaction mixture washed with water (2×250 ml) and brine (250 ml), dried (Na2SO4) and concentrated in vacuo to an orange oil (3.78 g). Purification by column chromatography (EtOAc/hexane, 5:95) afforded 3.49 g (97%) of 2-bromo-3-isopropoxynitrobenzene as a yellow oil. TLC (EtOAc/hexane 20:80)Rf =0.12; HPLC (Tr =16.1); 1H-NMR (CDCl3) d 1.35 (d, J=6 Hz, 6H), δ 4.56 (m, J=6 Hz, 1H), δ 6.95 (dd, J=8 Hz, J=3 Hz, 1H), δ 7.34 (d, J=3 Hz, 1H), δ 7.57 (d, J=8 Hz, 1H): MS m/z (relative intensity) 260 (MH+, 100), 262 (MH+ +2, 72).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[F:24][C:25]([F:31])([F:30])[C:26]([CH3:29])([NH2:28])[CH3:27].CCN=C=NCCCN(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:28][C:26]([CH3:29])([CH3:27])[C:25]([F:31])([F:30])[F:24])=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)(N)C(F)(F)F
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C(F)(F)F)c3n2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.4 %

Procedure:
A mixture of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.07 g, 0.3 mmol), 1,1,1-trifluoro-2-methylpropan-2-amine (0.05 g, 0.39 mmol), EDCI (0.057 g, 0.3 mmol), DMAP (0.037 g, 0.3 mmol), HATU (0.114 g, 0.3 mmol) and DIPEA (0.163 g, 1.26 mmol) in 10 mL of DMF were stirred at room temperature overnight. The solvent was removed under reduced pressure at 70° C. The residue was triturated with water and then purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 55% acetonitrile/45% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 80% acetonitrile/20% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give 2-(6-chloro-1-methyl-1H-indazol-3-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.015 g, 16%) as a white solid. MS: (M+H)+=437; 1H NMR (300 MHz, DMSO): δ 13.03 (s, 1H), 9.10 (s, 1H), 8.53-8.82 (m, 1H), 8.42 (d, 1H, J=8.4 Hz), 8.14 (s, 1H), 8.39 (s, 1H), 7.28 (d, 1H, J=8.7 Hz), 4.20 (s, 3H), 1.77 (s, 6H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[NH:10][C:11]3[C:17]([C:18](=[O:22])[CH2:19][C:20]#[N:21])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C>[C:1]1([CH2:7][CH2:8][C:9]2[NH:10][C:11]3[C:17]([CH:18]([OH:22])[CH2:19][C:20]#[N:21])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCC(=O)c1cccc2nc(CCc3ccccc3)[nH]c12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#CCC(O)c1cccc2nc(CCc3ccccc3)[nH]c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
To a suspension of 3-(2-(2-Phenylethyl)benzimidazol-4-yl)3-oxopropionitrile (400 mg) obtained in Inventive Example 25 in ethanol (4.8 mL), while cooling in an ice bath, was added sodium borohydride (26 mg), and the mixture was stirred at the same temperature for 1 hour. The reaction solution was poured into ice water (20 mL) and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was crystallized from ether and collected by filtration to obtain the title compound as crystal (297 mg)
Reaction SMILES: [C:1]([NH:4][C:5]1[C:12]([Cl:13])=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[Cl:14])(=[O:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[C:1]([NH:4][C:5]1[C:6]([Cl:14])=[CH:7][C:8]([CH2:9][NH2:10])=[CH:11][C:12]=1[Cl:13])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(Cl)cc(C#N)cc1Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1c(Cl)cc(CN)cc1Cl
Reaction time: 3 h
Yield: 30 %

Procedure:
Step B (2): To a solution of 4-acetamido-3,5-dichloro-benzonitrile (114 mg, 0.5 mmol) in 5 mL of THF was added lithium aluminum hydride (120 mg, 3.2 mmol) in one portion and the resulting mixture was stirred for 3 h. Sodium sulfate decahydrate (1 g, 3.2 mmol) was added in one portion and the mixture was stirred for 30 min. The solid was filtered off and the filtrate was concentrated. The residue was purified by HPLC to give 4-acetamido-3,5-dichloro-benzylamine (35 mg, 30%). 1H NMR (500 MHz, CD3OD): δ 7.46 (s, 2 H), 3.78 (s, 2H), 2.18 (s, 3 H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].Cl.Cl.Cl.[NH2:10][C:11]1[S:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH2:23])[N:17]=2)[N:15]=1.C(N(CC)CC)C>CN(C)C=O.O1CCCC1>[NH2:10][C:11]1[S:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH:23][C:2]([O:4][CH2:5][CH3:6])=[O:3])[N:17]=2)[N:15]=1
Reactant: NCc1cccc(-c2csc(N)n2)n1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)NCc1cccc(-c2csc(N)n2)n1
Reaction time: 1 h
Yield: 133.9 %

Procedure:
Ethyl chloroformate (3.7 g) was added slowly to a suspension of 2-amino-4-(6-aminomethylpyridin-2-yl)thiazole trihydrochloride (8.9 g) and triethylamine (11.4 g) in N,N-dimethylformamide (80 ml) and tetrahydrofuran (80 ml) with cooling on an ice bath. The mixture was stirred with cooling for 1.5 hours and then at room temperature for 1 hours. The solvent was removed under reduced pressure. The residue was dissolved in water (300 ml). The mixture was alkalized with a saturated aqueous potassium carbonate solution and then was extracted with a mixture of ethyl acetate (500 ml) and tetrahydrofuran (100 ml). The extract was dried over magnesium sulfate and then was evaporated to afford 2-amino-4-(6-ethoxycarbonylaminomethylpyridin-2-yl)thiazole (10.51 g).
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@@H:10]([N:11]2[CH2:15][CH2:14][C@H:13]([NH:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[C:12]2=[O:27])[CH2:9][CH2:8][C@@H:7]([NH:28]C(=O)OC(C)(C)C)[CH2:6]1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:4][C@@H:5]1[CH2:6][C@H:7]([NH2:28])[CH2:8][CH2:9][C@@H:10]1[N:11]1[CH2:15][CH2:14][C@H:13]([NH:16][C:17](=[O:18])[O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:12]1=[O:27])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N[C@@H]1C[C@H](N)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirring solution of tert-butyl (1R,3R,4S)-3-acetamido-4-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)cyclohexylcarbamate (66 g, 0.135 mol) in dichloromethane (216 mL) was charged with trifluoroacetic acid (216 mL). The reaction was stirred for 2 h at room temperature and concentrated in vacuo. The residue was dissolved in methanol and the resultant solution was concentrated in vacuo; this was repeated once. Benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-aminocyclohexyl)-2-oxopyrrolidin-3-ylcarbamate was obtained as an oil and used directly in Step 8 below. LC/MS found [M+H]+=389.4. 1H-NMR (400 MHz, d4-MeOH): δ 7.3-7.4 (m, 5H), 5.12 (s, 2H), 4.41 (br. s, 1H), 4.15 (m, 1H), 4.00 (t, J=9.3 Hz, 1H), 3.81 (t, J=9.1 Hz, 1H), 3.65 (q, J=8.4 Hz, 1H), 3.3-3.4 (m, 1H), 2.45 (m, 1H), 1.95-2.24 (m, 5H), 2.00 (s, 3H), 1.6-1.8 (m, 2H).
Reaction SMILES: C([O:5][C:6](=[O:38])[CH:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=3)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:9][CH:8]([CH3:10])[CH:7]([NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:35])[F:37])=[CH:30][N:29]=3)=[CH:23][CH:22]=2)=[CH:19][CH:20]=1)(=[O:14])=[O:13])[C:6]([OH:38])=[O:5]
Reactant: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)cc1)C(=O)O
Reaction time: 6 h
Yield: 66 %

Procedure:
3-Methyl-2-[4′-(5-trifluoromethyl-pyridin-2-yloxy)-biphenyl-4-sulfonylamino]-butyric acid tert-butyl ester (97 mg) was dissolved in CH2Cl2 (6 mL) and added with TFA (2 mL). Reaction was complete in 6 hrs as determined by TLC. After removing solvent, residue was purified by column chromatography (10% MeOH/CH2Cl2) to afford 3-Methyl-2-[4′-(5-trifluoromethyl-pyridin-2-yloxy)-biphenyl-4-sulfonylamino]-butyric acid in 66% yield (54.5 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2].[OH-].[K+].Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[CH2:16]([N:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[N:7]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cccc2c1cnn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33 %

Procedure:
To a solution of 4-nitro-1H-indazole (0.500 g, 3.06 mmol) in acetone (0.4M, 7.5 mL) cooled to 0° C. was added KOH (0.258 g, 4.60 mmol). After 15 minutes at 0° C., (bromomethyl)benzene (0.400 mL, 3.37 mmol) was added. The reaction mixture was allowed to stir at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (50% EtOAc/hexanes) providing 256 mg (33%) of the title compound.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:30]3[C:25](=[CH:26][C:27]([F:32])=[C:28](F)[CH:29]=3)[C:24](=[O:33])[N:23]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:22]2=[O:42])=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[C:30]3[C:25](=[CH:26][C:27]([F:32])=[C:28]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:29]=3)[C:24](=[O:33])[N:23]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:22]2=[O:42])=[CH:19][CH:20]=1
Reactant: C1CCNC1
Reactant: COc1ccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(F)cc32)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(N4CCCC4)cc32)cc1
Yield: 91 %

Procedure:
Using General Method 4, the reaction of pyrrolidine (0.125 mL, 1.5 mmol), triethylamine (0.2 mL, 1.5 mmol), and 1-(4-methoxyphenyl)-3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example C-1, 0.20 g, 0.5 mmol) provided 0.21 g of the title compound as a solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=1.C(O)C.[OH-].[K+].Cl>O>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1ccc(NCCCCCCCCCCCO)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(NCCCCCCCCCCCO)cc1

Procedure:
A solution of 5 g. of ethyl 4-(11-hydroxyundecylamino)benzoate in 75 ml. 95% ethanol is saponified with 2.5 g. of 85% potassium hydroxide by refluxing for 5 hours. The warm solution is diluted with 150 ml. water and adjusted to pH 5 with 37% hydrochloric acid. The precipitate is filtered, washed with water, dried in vacuo and crystallized from acetic acid to yield 4-(11-hydroxyundecylamino)benzoic acid as a white solid.
Reaction SMILES: C[O-].[Na+].[C:4]1([OH:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=1>CO.COCCOCCOC>[Br:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:10][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:13]=1
Reactant: Oc1ccccc1
Reactant: Brc1cccc(Br)c1
Agent: C[O-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: CO
Product: Brc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 38.4 %

Procedure:
To a stirred mixture of 23 g sodium methylate in 69 g methanol and 200 ml of 2-methoxyethyl ether (diglyme) at room temperature was added dropwise 40.0 g of phenol in a period of 1/2 hour. The reaction mixture was then heated to 165°, and 5.0 g cuprous bromide was added. The reaction mixture was cooled to 150° and 100.0 g of 1,3-dibromobenzene was added rapidly. Upon complete addition, the reaction mixture was warmed to 165° and stirred for 24 hours. The reaction mixture was then allowed to cool to room temperature and filtered. The filter cake was washed with two 75 ml portions of chloroform. The filtrate was dried with sodium sulfate and filtered. Chloroform was evaporated from the filtrate under reduced pressure, leaving a residue. The residue was distilled under reduced pressure to give 40.5 g of 1-bromo-3-phenoxybenzene; bp, 98°-100°/0.5 mm. The nmr and the ir spectra were consistent with the assigned structure.