Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11](=[O:13])[CH:12]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].BrC[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[N:39]([C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)[N:38]=[N:37][N:36]=2)=[CH:25][CH:24]=1.O>CN1C(=O)CCC1>[CH2:1]([C:3]1[CH:12]=[C:11]([O:13][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[N:39]([C:40]4[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=4)[N:38]=[N:37][N:36]=3)=[CH:27][CH:28]=2)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1cc(=O)c2c([nH]1)CCCC2
Reactant: O=[N+]([O-])c1ccc(-n2nnnc2-c2ccccc2-c2ccc(CCBr)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCc1cc(OCc2ccc(-c3ccccc3-c3nnnn3-c3ccc([N+](=O)[O-])cc3)cc2)c2c(n1)CCCC2
Temperature: 60 °C
Yield: 60 %

Procedure:
A mixture of 2-ethyl-5,6,7,8-tetrahydro-4(1H)-quinolone (1.95 g), and potassium carbonate (2.28 g) in NMP (75 ml) was heated at 60° C. for 20 minutes with stirring. Compound E (5.2 g) was added and the reaction mixture was heated at 80° C. for 90 minutes. The mixture was allowed to cool to ambient temperature and water (150 ml) was added. The resultant precipitate was collected by filtration, dried at 60° C., then recrystallised from toluene to give 2-ethyl-4-[(2'-(1-(4-nitrophenyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methoxy]-5,6,7,8-tetrahydroquinoline, as a solid in 60% yield; m.p. 205°-207° C.; NMR (CDCl3):1.30(3H,t), 1.90(4H,m), 2.60-3.00(6H,m), 5.04(2H,m), 6.52(2H,d), 6.60(1H,s), 6.80(2H,d), 7.11(2H,d), 7.40(1H,d), 7.67(2 H,d), 7.92(3H,m).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[O:8][C:4]=2[CH:3]=1.[C:12](=O)(O)[O-].[Na+].S(OC)(OC)(=O)=O>O>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([S:9][CH3:12])[O:8][C:4]=2[CH:3]=1
Reactant: Oc1ccc2nc(S)oc2c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CSc1nc2ccc(O)cc2o1
Yield: 25.2 %

Procedure:
A mixture of 6-hydroxy-2-mercaptobenzoxazole (165 mg), sodium bicarbonate (84 mg) and dimethyl sulfate (94 μl) was dissolved in water (2 ml) with stirring and under an argon atmosphere. The reaction mixture was stirred at RT overnight and HPLC showed that all starting material was gone. The reaction mixture was evaporated to dryness to give a dark brown solid (one can also extract the reaction mixture with chloroform to give the crude product). Chromatography on silica gel using 10% ethyl acetate/hexane gave the pure product as a near-white crystalline solid (45 mg, 25%).
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:6]([C:7]([O:9][CH3:10])=[O:8])[C@@H:5]([CH3:11])[N:4]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C@H:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH:28]([C:31]1[CH:32]=[CH:33][C:34]([O:39][CH3:40])=[C:35]([CH:38]=1)[CH:36]=O)([CH3:30])[CH3:29].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>C(Cl)Cl>[CH2:15]([O:14][C:12]([N:4]1[C@H:5]([CH3:11])[C@H:6]([C:7]([O:9][CH3:10])=[O:8])[C@H:2]([NH:1][CH2:36][C:35]2[CH:38]=[C:31]([CH:28]([CH3:30])[CH3:29])[CH:32]=[CH:33][C:34]=2[O:39][CH3:40])[C@@H:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:13])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc(C(C)C)cc1C=O
Reactant: COC(=O)[C@@H]1[C@H](N)[C@H](c2ccccc2)N(C(=O)OCc2ccccc2)[C@@H]1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)[C@@H]1[C@H](NCc2cc(C(C)C)ccc2OC)[C@H](c2ccccc2)N(C(=O)OCc2ccccc2)[C@@H]1C
Temperature: 25 °C
Yield: 126.4 %

Procedure:
To a stirred solution of (2S*,3S*,4R*,5R*)-3-amino-1-benzyloxycarbonyl-4-methoxycarbonyl-5-methyl-2-phenylpyrrolidine (0.93 g, 2.52 mmol) in dry CH2Cl2 (20 ml) was added a solution of 5-isopropyl-2-methoxybenzaldehyde (0.56 g, 3.15 mmol) in dry CH2Cl2 (5 ml) at room temperature. To this was added NaBH(OAc)3 (0.80 g, 3.78 mmol) portionwise at room temperature. The added NaBH(OAc)3 dissolved gradually with stirring at room temperature. After stirring for 1.5 hours at room temperature, the reaction mixture was basified to pH 10-11 by adding 10% NaOH aq. solution with ice-cooling. The layers were separated, and the aqueous layer was extracted with CHCl3 (×3). The combined CH2Cl2 layer and CHCl3 extracts were washed with sat. NaCl aq. solution (×1), dried (Na2SO4 --K2CO3), and concentrated in vacuo to give a yellow viscous oil (1.69 g). This was chromatographed over SiO2 (Merck Kieselgel 60, 20 g). Elution with n-hexane-AcOEt (30: 1) followed by CH2Cl2 --MeOH (200:1) gave title compound (1.36 g, quant.) as a pale yellow viscous oil: IRmax (film): 3350(w), 1735(s), 1700(vs), 1487(s), 1290(s), 1250(s), 1030(s), 810(s), 735(s), 700(s) cm-1 ; 1H-NMR δ: 7.50-7.15(m, 10H), 7.03(dd, J=8.4, 2.2 Hz, 1H), 6.96(d, J=2.2 Hz, 1H), 6.70(d, J=8.4 Hz, 1H), 5.15(br.d, J=7.7 Hz, 1H), 5.03(br.s, 2H), 4.22-4.06(m, 1H), 3.84-3.58(m, 3H), 3.71(s, 3H), 3.64(s, 3H), 2.90-2.58 (m, 2H), 1.61(br.d, J=5.5 Hz, 3H), 1.19(d, J=7.0 Hz, 6H) ppm.
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]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH:35]([OH:39])[CH2:34]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:39][CH:35]1[CH2:36][CH2:37][CH2:38][CH:33]([NH:32][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[CH:19]=2)=[O:23])[CH2:34]1
Reactant: NC1CCCC(O)C1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC2CCCC(O)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.10 g, 0.22 mmol), 3-aminocyclohexanol (mixture of cis and trans) (45 mg, 0.39 mmol), HBTU (0.10 g, 0.26 mmol), and HOBT (0.03 g, 0.26 mmol). Then added DMF (1.0 mL) followed by N,N-diisopropylethylamine (0.07 ml, 0.26 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (30 mL). The organic layer was washed once with saturated NaHCO3 and water. The combined aqueous layers were back extracted with EtOAc (25 mL). The combined organic layers was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/hexanes (gradient: 0-100% EtOAc) to afford 106 mg of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-hydroxy-cyclohexyl)amide as an off-white foam. MS: [M+H]+=556.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])[CH:8]=O.Cl.[NH2:27][C@@H:28]([C:30]([NH2:32])=[O:31])[CH3:29]>>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])[CH2:8][NH:27][C@H:28]([CH3:29])[C:30]([NH2:32])=[O:31]
Reactant: C[C@@H](N)C(N)=O
Reactant: O=Cc1ccc(OCc2ccccc2F)c(Cc2ccccc2F)c1
Agent: Cl
Product: C[C@@H](NCc1ccc(OCc2ccccc2F)c(Cc2ccccc2F)c1)C(N)=O

Procedure:
The compound of the title is prepared by reacting 3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)benzaldehyde (VIb) prepared as in Example 9a) with D-alaninamide hydrochloride according to the procedure of the Example 8b).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=1)=O>>[Cl:34][C:29]1[CH:28]=[C:27]([C:25]2[N:12]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=3)[S:13][CH:24]=2)[CH:32]=[CH:31][C:30]=1[Cl:33]
Reactant: O=C(CBr)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 37 %

Procedure:
4-[4-(3,4-Dichloro-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (109 mg, 37%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-bromo-3′,4′-dichloroacetophenone (available from Oakwood Products, Inc.) using the procedure described for the preparation of Example 1. The compound of Example 15 has the same formula as the compound of Example 16. 1H NMR (300 MHz, DMSO-d6) δ 13.18 (s, 1H), 8.56 (s, 1H), 8.47 (s, 1H), 8.26-8.32 (m, 2H), 8.15 (d, J=8.2 Hz, 1H), 8.07 (d, J=8.4 Hz, 1H), 8.03 (d, J=8.6 Hz, 1H), 7.41-7.81 (m, 5H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([F:17])=[CH:8][C:9]2[S:14][CH2:13][C:12](=[O:15])[NH:11][C:10]=2[CH:16]=1)=O)C.C(OC(=O)C1C=C([N+]([O-])=O)C(SCC(OCC)=O)=CC=1F)C>C(O)(=O)C.[Fe]>[F:17][C:7]1[C:6]([CH:4]=[O:3])=[CH:16][C:10]2[NH:11][C:12](=[O:15])[CH2:13][S:14][C:9]=2[CH:8]=1
Reactant: CCOC(=O)c1cc2c(cc1F)SCC(=O)N2
Agent: [Fe]
Agent: CCOC(=O)CSc1cc(F)c(C(=O)OCC)cc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: O=Cc1cc2c(cc1F)SCC(=O)N2
Temperature: 80 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid ethyl ester. To a solution of 4-ethoxycarbonylmethylsulfanyl-2-fluoro-5-nitro-benzoic acid ethyl ester (2.7 g, 8.2 mmol) in acetic acid (50 mL) was added iron (4.8 g, 86 mmol) and the suspension was heated to 80° C. and stirred for 2 h. The reaction mixture was filtered and the filtrate was partitioned between H2O and EtOAc (1×200 mL; 2×100 mL). The combined organic layers were washed with brine (300 mL), dried (MgSO4), filtered and concentrated to provide 1.7 g (82%) of the title compound as a tan solid. MS (ESI): exact mass calculated for C11H10FNO3S, 255.04; m/z found, 256.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.75 (br s, 1H), 7.46 (d, J=6.1, 1H), 7.12 (d, J=10.4, 1H), 4.40 (q, J=7.1, 2H), 3.48 (s, 2H), 1.38 (t, J=7.1, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[CH:18]=[N:17][CH:16]=[CH:15][N:14]=2)=[CH:7][C:4]=1[CH:5]=O.[C:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)(=[O:21])[CH3:20]>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[CH:18]=[N:17][CH:16]=[CH:15][N:14]=2)=[CH:7][C:4]=1/[CH:5]=[CH:20]/[C:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)=[O:21]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1cc(OC)c(-c2cnccn2)cc1C=O
Product: COc1cc(OC)c(-c2cnccn2)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Yield: 4 %

Procedure:
The title compound was prepared by condensing 2,4-dimethoxy-5-pyrazin-2-yl-benzaldehyde (Ex-46D) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 238° C. (dec.), 4% yield. 1H-NMR (DMSO-D6) δ 9.04 (d, J=2 Hz, 1H), 8.75–8.76 (m, 1H), 8.56 (d, J=2 Hz, 1H), 8.32 (s, 1H), 8.19 (d, J=9 Hz, 2H), 8.05–8.11 (m, 3H), 7.83 (d, J=16 Hz, 1H), 6.90 (s, 1H), 4.05 (s, 3H), 4.00 (s, 3H). HRMS m/z=calc. 391.1294. found 391.1313.
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9][C:10](=[O:13])[O:11][CH3:12])[CH2:7][CH2:6][C:5](=[O:14])[N:4]2[CH2:15][CH2:16][CH2:17][C@@H:18]([C:19]3[NH:20][C:21]([C:24]4[CH:29]=[CH:28][C:27](B5OC(C)(C)C(C)(C)O5)=[CH:26][CH:25]=4)=[CH:22][N:23]=3)[N:3]12.[Br:39][C:40]1[CH:41]=[C:42]2[C:47](=[CH:48][CH:49]=1)[N:46]=[C:45](Cl)[CH:44]=[N:43]2.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Br:39][C:40]1[CH:41]=[C:42]2[C:47](=[CH:48][CH:49]=1)[N:46]=[C:45]([C:27]1[CH:26]=[CH:25][C:24]([C:21]3[NH:20][C:19]([C@H:18]4[N:3]5[C:2](=[O:1])[C@@H:8]([NH:9][C:10](=[O:13])[O:11][CH3:12])[CH2:7][CH2:6][C:5](=[O:14])[N:4]5[CH2:15][CH2:16][CH2:17]4)=[N:23][CH:22]=3)=[CH:29][CH:28]=1)[CH:44]=[N:43]2
Reactant: Clc1cnc2cc(Br)ccc2n1
Reactant: COC(=O)N[C@H]1CCC(=O)N2CCC[C@@H](c3ncc(-c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)[nH]3)N2C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)N[C@H]1CCC(=O)N2CCC[C@@H](c3ncc(-c4ccc(-c5cnc6cc(Br)ccc6n5)cc4)[nH]3)N2C1=O
Temperature: 80 °C
Yield: 86.5 %

Procedure:
In a 10 ml seal tube, methyl (4S,7S)-6,10-dioxo-4-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)octahydro-1H-pyridazino[1,2-a][1,2]diazepin-7-ylcarbamate (240 mg, 459 μmol) (Intermediate 3), 6-bromo-2-chloroquinoxaline (112 mg, 459 μmol) and Cs2CO3 (299 mg, 917 μmol) were combined with 1,4-dioxane (3.00 ml) and water (0.5 ml) to give a light brown solution. It was degassed for 10 min and tetrakis(triphenylphosphine)palladium (0) (53.0 mg, 45.9 μmol) was added. The reaction mixture was heated at 80° C. for 16 h. It was diluted with EtOAc (6 ml) and concentrated in vacuo. The residue was purified on a silica gel column (CH2Cl2, 2%, 3%, 5%, 8% and 10% MeOH/CH2Cl2) to afford methyl (4S,7S)-4-(5-(4-(6-bromoquinoxalin-2-yl)phenyl)-1H-imidazol-2-yl)-6,10-dioxooctahydro-1H-pyridazino[1,2-a][1,2]diazepin-7-ylcarbamate as a red solid (240 mg, 86.6%). ESI-LRMS m/e calcd for C28H26BrN7O4 [M+] 604. found 605 [M+H+].
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:12])[NH:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCCCCC.C(=O)([O-])[O-].[Ag+2]>[CH2:13]([O:12][C:3]1[C:2]([Br:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]cc(C(F)(F)F)cc1Br
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CCCCCC
Product: FC(F)(F)c1cnc(OCc2ccccc2)c(Br)c1
Reaction time: 18 h
Yield: 91.3 %

Procedure:
3-Bromo-5-trifluoromethyl-2(1H)-pyridone (6.09 g, 25.2 mmol) and silver carbonate (7.18 g, 26.0 mmol) were suspended in hexane (200 mL) and treated with benzyl bromide (6 mL, 50.3 mmol). The mixture was stirred for 18 hrs, then filtered. The filtrate was concentrated and the residue purified by silica chromatography to give the product as a white solid (7.65 g, 23 mmol, 91% yield).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[NH:6][C:5]1=[O:24])[CH:2]=[CH2:3].Cl[C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([N+]([O-])=O)=[CH:29][N:28]=1>>[CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C:27]2[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][N:28]=2)[C:5]1=[O:24])[CH:2]=[CH2:3]
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(c2cc(C)ccn2)C1=O

Procedure:
The title compound was prepared from (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one (Example 71, Step D) and 2-chloro-4-methyl-5-nitropyridine as described in Example 113 Steps A-C to provide a white solid.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]([C:27]#[N:28])=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)C.[OH-].[Li+].CO>O>[C:27]([C:5](=[CH:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:17]=2)=[CH:11][CH:12]=1)[C:4]([OH:29])=[O:3])#[N:28].[C:27]([C:5](=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)[C:4]([OH:29])=[O:3])#[N:28]
Reactant: CCOC(=O)C(C#N)=Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)Oc1ccc(CCOc2ccc(C=C(C#N)C(=O)O)cc2)cc1
Product: N#CC(=Cc1ccc(OCCc2ccc(O)cc2)cc1)C(=O)O

Procedure:
2-Cyano-3-{4-[2-(4-methanesulfonyloxyphenyl)ethoxy]phenyl}acrylic acid ethyl ester (described in Example 6) (0.201 g; 0.483 mmole), lithium hydroxide (0.04 g; 1.67 mmole), methanol (2.3 ml) and water (2.3 ml) was stirred at 40° C. for 23 hours. More water was added, methanol was removed by evaporation in vacuo and the mixture was acidified using potassium hydrogen sulfate. The mixture was extracted with ethyl acetate and the organic phase was dried (sodium sulfate), filtered and evaporated in vacuo. The crude products were purified on preparative HPLC using acetonitrile (gradient 30-60%): ammonium acetate (0.1 M). The fractions were acidified with potassium hydrogen sulfate and then extracted with ethyl acetate. The organic phases were combined and evaporated in vacuo to give 7 mg of 2-cyano-3-{4-[2-(4-methanesulfonyloxyphenyl)ethoxy]-phenyl}acrylic acid and 21,8 mg of 2-cyano-3-{4-[2-(4-hydroxyphenyl)ethoxy]phenyl}-acrylic acid.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=S.[CH:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[CH:5]1([N:1]=[C:2]=[N:4][CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: NC(N)=S
Reactant: c1ccccc1
Product: C(=NC1CCCCC1)=NC1CCCCC1

Procedure:
They are heated to reflux into 200 ml benzene, 33 g of the thiourea obtained in the step G, together with 16 g dicyclohexyl carbodiimide for 5 hours. After achievement of the reaction, it is cooled, washed with water than with an aqueous solution of sodium carbonate and further with water. It is dried and concentrated to dryness under vacuum, the residue is taken up with 100 ml methanol and 20 ml water, then the pH value is adjusted to 1 with concentrated hydrochloric acid. The end of the reaction is followed by TLC on silica plates with chloroform 7--ethanol 3 (revelation UV and Iodoplatinate). It is neutralized after dilution with water using sodium carbonate then sodium hydroxide to obtain a pH value of 12. It is extracted with methylene chloride, the organic solution is washed with water, dried, filtered and concentrated to dryness. 37 g of raw product are produced which are washed with isopropyl ether and 24 g of the pure compound are obtained. The product is recrystallized from ethyl acetate containing a little methanol. MP=164.8°165.2° C.
Reaction SMILES: [N:1]1C2C(=CC=CC=2)C=CC=1COC1C=CC(C(C2C=CC(OCC3C=CC4C(=CC=CC=4)N=3)=CC=2)(C)CCO)=CC=1.[N:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44][C:43]=1[CH2:52][O:53][C:54]1[CH:59]=[CH:58][C:57]([C:60]([C:66]2[CH:71]=[CH:70][C:69]([O:72][CH2:73][C:74]3[CH:83]=[CH:82][C:81]4[C:76](=[CH:77][CH:78]=[CH:79][CH:80]=4)[N:75]=3)=[CH:68][CH:67]=2)(C)[CH2:61][CH2:62][CH2:63][OH:64])=[CH:56][CH:55]=1>>[N:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44][C:43]=1[CH2:52][O:53][C:54]1[CH:59]=[CH:58][C:57]([CH:60]([C:66]2[CH:71]=[CH:70][C:69]([O:72][CH2:73][C:74]3[CH:83]=[CH:82][C:81]4[C:76](=[CH:77][CH:78]=[CH:79][CH:80]=4)[N:75]=3)=[CH:68][CH:67]=2)[CH2:61][CH2:62][CH2:63][O:64][NH2:1])=[CH:56][CH:55]=1
Reactant: CC(CCCO)(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: CC(CCO)(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Product: NOCCCC(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
The desired compound was prepared according to the method of Example 5, steps 1 and 2, except substituting 3,3-bis(4-(2-quinolylmethoxy)phenyl)butan-1-ol, prepared as in step 1, for 4,4-bis(4-(2-quinolylmethoxy)phenyl)pentan-1-ol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]([S:14][CH3:15])=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1.C(=O)(O)[O-].[Na+].O1CCOCC1>CC(=O)OCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:15][S:14][C:5]1[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:7][C:2]([C:20]2[CH:21]=[CH:22][C:17]([NH2:16])=[CH:18][CH:19]=2)=[N:3][CH:4]=1
Reactant: CSc1cnc(Cl)nc1N1CCOCC1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CSc1cnc(-c2ccc(N)cc2)nc1N1CCOCC1
Reaction time: 12 h
Yield: 48.8 %

Procedure:
A mixture of 4-(2-chloro-5-(methylthio)pyrimidin-4-yl)morpholine (0.3 g, 1.22 mmole), 4-aminophenylboronic acid pinacol ester (0.58 g, 2.68 mmole), sodium bicarbonate (0.28 g, 2.68 mmole), Pd(PPh3)4 (0.14 g, 0.122 mmole), dioxane (15 ml) and H2O (3.5 ml) was heated to reflux. After 12 hrs, the reaction mixture was cooled, diluted with EA, washed with brine, and dried (MgSO4), and the solvent was removed in vacuo. Purification on silica gel (EA/Hex=1/2) yielded the desired compound (180 mg, 49%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][C:10](=O)[NH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.P(Cl)(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[Cl:21][C:10]1[N:11]=[N:12][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ncc(-c2ccccc2)n[nH]1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Clc1ncc(-c2ccccc2)nn1
Yield: 81.4 %

Procedure:
A mixture of 6-phenyl-1,2,4-triazin-3(2H)-one (2.45 g, 0.0141 mol) and DMF (0.5 mL) in phosphoryl chloride (20.0 mL, 0.214 mol) and chloroform (20.0 mL) was heated under reflux overnight. After cooling, the volatiles were removed under reduced pressure. The residue was dissolved in DCM (60 mL) and was poured into ice with stirring. The mixture was neutralized with NaOH (1N), and filtered through a pad of celite to remove a small amount of insoluble residue. The organic layer was separated. The aqueous layer was extracted with DCM (3×20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was flash chromatographed on a silica gel column to give the desired product (2.20 g, 81.1%). Analytical LCMS: (M+H)+=192.1/194.1.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[C:31]2[O:30][C:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:28][C:27](=[O:37])[C:26]=2[CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OC(=O)C)C>[C:32]([C:29]1[O:30][C:31]2[C:22]([CH2:21][O:1][C:2]3[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]4[CH:17]=[CH:16][C:15]5[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=5)[N:9]=4)=[CH:18][CH:19]=3)=[CH:23][CH:24]=[CH:25][C:26]=2[C:27](=[O:37])[CH:28]=1)([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(=O)c1cc(=O)c2cccc(CBr)c2o1
Reactant: Oc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(=O)c2cccc(COc3ccc(OCc4ccc5ccccc5n4)cc3)c2o1
Yield: 28.2 %

Procedure:
1.8 g of 2-(4-hydroxyphenoxy)methylquinoline, 2.2 g of 8-bromomethyl-2-carboethoxy-4-oxo-4H-1-benzopyran and 1.0 g of potassium carbonate are combined in 100 ml of acetone and refluxed for 18 hours. The mixture is cooled, diluted with ethylacetate and filtered. The filtrate is concentrated and the crude product purified by flash chromatography on silica gel in 5% ethanol in chloroform/hexane (1:1) to give 0.96 g 2-carboethoxy-8-(4- (quinolin-2-yl-methoxy)phenoxymethyl)-4-oxo-4H-1-benzopyran: m.p. 124°-27° C.