Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)[C@@H](NC([C@@H]1CC2C=C3C(O[C@H](C4C=CC(O)=CC=4)C(=O)N3C)=CC=2CN1[C@H](C1C=CC=CC=1)CC)=O)CC1C=CC(C2C=CC(F)=CC=2)=CC=1.C[O:56][C:57](=[O:117])[C@@H:58]([NH:73][C:74]([C@@H:76]1[CH2:89][C:88]2[CH:87]=[C:86]3[C:81]([O:82][C@H:83]([C:92]4[CH:97]=[CH:96][C:95]([O:98][CH2:99][C:100]5[CH:105]=[CH:104][C:103]([Cl:106])=[C:102]([Cl:107])[CH:101]=5)=[CH:94][CH:93]=4)[C:84](=[O:91])[N:85]3[CH3:90])=[CH:80][C:79]=2[CH2:78][N:77]1[C@H:108]([C:111]1[CH:116]=[CH:115][CH:114]=[CH:113][CH:112]=1)[CH2:109][CH3:110])=[O:75])[CH2:59][C:60]1[CH:65]=[CH:64][C:63]([C:66]2[CH:71]=[CH:70][C:69]([F:72])=[CH:68][CH:67]=2)=[CH:62][CH:61]=1>>[Cl:107][C:102]1[CH:101]=[C:100]([CH:105]=[CH:104][C:103]=1[Cl:106])[CH2:99][O:98][C:95]1[CH:96]=[CH:97][C:92]([C@H:83]2[O:82][C:81]3[C:86](=[CH:87][C:88]4[CH2:89][C@@H:76]([C:74]([NH:73][C@@H:58]([CH2:59][C:60]5[CH:65]=[CH:64][C:63]([C:66]6[CH:67]=[CH:68][C:69]([F:72])=[CH:70][CH:71]=6)=[CH:62][CH:61]=5)[C:57]([OH:117])=[O:56])=[O:75])[N:77]([C@H:108]([C:111]5[CH:112]=[CH:113][CH:114]=[CH:115][CH:116]=5)[CH2:109][CH3:110])[CH2:78][C:79]=4[CH:80]=3)[N:85]([CH3:90])[C:84]2=[O:91])=[CH:93][CH:94]=1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(F)cc2)cc1)C(=O)OC)N(C)C(=O)[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(F)cc2)cc1)C(=O)OC)N(C)C(=O)[C@@H](c1ccc(O)cc1)O3
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(F)cc2)cc1)C(=O)O)N(C)C(=O)[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Yield: 92.9 %

Procedure:
(S)-3-(4′-Fluoro-biphenyl-4-yl)-2-{[(3R,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester was converted to (S)-2-{[(3R,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-3-(4′-fluoro-biphenyl-4-yl)-propionic acid methyl ester (70 mg) using general procedure K. This ester upon hydrolysis furnished title compound (64 mg) LCMS (m/z): 872.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:24])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[C:13]([CH3:22])[C:12]=2Cl)[CH2:5][CH2:4]1.[CH:27]12[CH2:32][CH:31]1[CH2:30][NH:29][CH2:28]2.CCN(C(C)C)C(C)C>O1CCOCC1>[F:1][C:2]([F:26])([F:25])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:24])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[C:13]([CH3:22])[C:12]=2[N:29]2[CH2:30][CH:31]3[CH:27]([CH2:32]3)[CH2:28]2)[CH2:5][CH2:4]1
Reactant: CNc1c([N+](=O)[O-])cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(Cl)c1C
Reactant: C1NCC2CC12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CNc1c([N+](=O)[O-])cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(N2CC3CC3C2)c1C

Procedure:
The sub-title compound is prepared in analogy to 6a from N-(trans-4-trifluoromethyl-cyclohexyl)-2-chloro-3-methyl-4-methylamino-5-nitro-benzoic acid amide (250 mg, 0.64 mmol), 3-aza-bicyclo[3.1.0]hexane (151 mg, 1.27 mmol), DIPEA (0.44 mL, 2.5 mmol) and dioxane (8 mL). Yield: 130 mg. HPLC Rt=1.62 min (method H). MS m/z: 441 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][CH:10]=[CH:11][N:12]=1.[Cl:13]N1C(=O)CCC1=O>>[Cl:13][C:10]1[S:9][C:8]([NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: c1ccc(Nc2nccs2)nc1
Product: Clc1cnc(Nc2ccccn2)s1
Reaction time: 8 h

Procedure:
Pyridin-2-yl-thiazol-2-yl-amine (5-2) and 1.2 equivalents of N-chlorosuccinimide were combined in a flame dried flask and allowed to stir together overnight under argon in anhydrous dioxane (0.25 M). The dioxane solution was then diluted with water and the resulting product filtered off. 1H-NMR (DMSO-d6) δ 11.463 (1H, s) 8.30 (dd, 1H, J=4.9, 0.9 Hz) 7.73 (t, 1H, J=8.42 Hz) 7.38 (s, 1H) 7.03 (d, 1H, J=8.4 Hz) 6.96 (t, 1H, J=5.9 Hz). MS [M+H]+=211.9.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[NH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]2[N:16]([C@H:36]3[CH2:41][CH2:40][C@@H:39]([N:42]4[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]4)[CH2:38][CH2:37]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=O)[CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:21][CH:20]=3)[C:11]=12.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[CH3:48][N:45]1[CH2:44][CH2:43][N:42]([C@@H:39]2[CH2:40][CH2:41][C@H:36]([N:16]3[C:12]4=[N:13][CH:14]=[N:15][C:10]([NH2:9])=[C:11]4[C:18]([C:19]4[CH:20]=[CH:21][C:22]([NH:25][CH2:26][CH2:27][CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:23][CH:24]=4)=[N:17]3)[CH2:37][CH2:38]2)[CH2:47][CH2:46]1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(NC(=O)CCc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(NCCCc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 34.1 %

Procedure:
Cis-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-3-phenylpropanamide diacetate (0.090 g, 0.000167 mol) was suspended in anhydrous tetrahydrofuran (5 mL), the suspension was cooled to 0° C. and lithium aluminum hydride (0.01 g, 0.00025 mol) was added at once. The resulting mixture was warmed up to ambient temperature and stirred under an atmosphere of nitrogen for 18 hours. It was quenched by dropwise addition of water, the solvents were removed under reduced pressure and the residue purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-{4-[(3-phenylpropyl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate (0.037 g, 0.000057 mol) as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:4][CH2:5][CH2:6][CH2:7][OH:8])[CH3:2].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1>>[CH2:1]([N:3]([CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCCCCCCN(CC)CCCCO
Product: CCCCCCCN(CC)CCCCOc1ccc([N+](=O)[O-])cc1

Procedure:
In a manner similar to Preparation 2, react 4-[ethyl(heptyl)amino]butanol with 4-fluoronitrobenzene to obtain the title compound.
Reaction SMILES: C(C1C=CC(C[NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=CC=1)(=O)C>C(OCC)(=O)C>[CH3:21][C:18]1[CH:17]=[CH:16][C:15]([S:12]([NH2:11])(=[O:14])=[O:13])=[CH:20][CH:19]=1
Reactant: CC(=O)c1ccc(CNS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(N)(=O)=O)cc1
Reaction time: 8 h

Procedure:
A mixture of the product of step i) (1.0 g) and cupric bromide (1.47 g) in ethyl acetate (3.0 ml) was heated at reflux temperature for 16 hours. Additional cupric bromide (1.0 g) was added and heating continued for a further 8 hours. The mixture was filtered and the filtrate concentrated to dryness in vacuo. This residue was purified by flash chromatography on silica, eluting with hexane/ethyl acetate (2:1 v/v). Evaporation of the fractions gave N-(14-bromoacetylphenyl]methyl)-4-methylphenylsulphonamide, 1.13 g, as a white solid: m.p. 116°-117° C., NMR (CDl3) δ 7.9(2H,d), 7.75(2H,d), 7.34(4H,m), 4.77(1H,t), 4.40(2H,s), 4.22(2H,d), 2.44(3H,s): m/e 382/384 (M+H)+, 1 Br pattern.
Reaction SMILES: [C:1](O)(=O)[C:2]#C.[N:6]([C@H:9]([CH3:26])[C@:10]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25])([OH:17])[CH2:11][N:12]1[CH:16]=[N:15][CH:14]=[N:13]1)=[N+:7]=[N-:8]>C1(C)C=C(C)C=C(C)C=1>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[C@:10]([OH:17])([C@H:9]([N:6]1[CH:2]=[CH:1][N:8]=[N:7]1)[CH3:26])[CH2:11][N:12]1[CH:16]=[N:15][CH:14]=[N:13]1
Reactant: C#CC(=O)O
Reactant: C[C@@H](N=[N+]=[N-])[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: Cc1cc(C)cc(C)c1
Product: C[C@@H](n1ccnn1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 120 °C

Procedure:
A mixture of propiolic acid (0.84 ml), mesitylene (20 ml) and (2R,3R)-3-azido-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (1 g) was heated for 3 hours at 120° C. After cooling, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (silica gel 30 g, eluent: ethyl acetate/methanol=10:1) to give the Compound 6 (0.11 g) as a colorless powder.
Reaction SMILES: [N:1]([CH2:4][C:5]1[O:6][C:7]([CH:10]([F:12])[F:11])=[CH:8][CH:9]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[F:11][CH:10]([F:12])[C:7]1[O:6][C:5]([CH2:4][NH2:1])=[CH:9][CH:8]=1
Reactant: [N-]=[N+]=NCc1ccc(C(F)F)o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(C(F)F)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
To a solution of 2-(azidomethyl)-5-(difluoromethyl)furan (0.50 g, 2.92 mmol) in a mixture of tetrahydrofuran (10 mL) and water (1 mL) was added triphenylphosphine (1.15 g, 4.39 mmol). The reaction mixture was stirred at ambient temperature for 18 hours. The solvent was removed in vacuo and the residue was purified on strong cation exchange column to afford (5-(difluoromethyl)furan-2-yl)methanamine as a yellow oil in 70% yield (0.30 g): MS (ES+) m/z 3148.2 (M+1).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([C:25]3[C:17](=[CH:18][C:19]4[O:20][CH2:21][O:22][C:23]=4[CH:24]=3)[C:16](=O)[CH2:15]2)[C:7]1=[O:27])[CH2:2][CH2:3][CH2:4][CH3:5].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[CH2:1]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([C:25]3[C:17](=[CH:18][C:19]4[O:20][CH2:21][O:22][C:23]=4[CH:24]=3)[CH2:16][CH2:15]2)[C:7]1=[O:27])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCN1C(=O)C2(CC(=O)c3cc4c(cc32)OCO4)c2ccccc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCCCCN1C(=O)C2(CCc3cc4c(cc32)OCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
A mixture of 1′-pentylspiro[indeno[5,6-d][1,3]dioxole-5,3′-indole]-2′,7(1′H,6H)-dione (0.04 g, 0.11 mmol), triethylsilane (1.50 mL) and trifluroacetic acid (2.00 mL, excess) was stirred at ambient temperature overnight. The mixture was concentrated in vacuo to dryness. The residue was subjected to flash column chromatography to afford the title compound (0.02 g, 47%) as an oil: 1H NMR (300 MHz, CDCl3) δ 7.25 (td, 1H), 7.06-6.95 (m, 2H), 6.88 (d, 1H), 6.77 (s, 1H), 6.05 (s, 1H), 5.88-5.82 (m, 2H), 3.81-3.60 (m, 2H), 3.37-3.24 (m, 1H), 3.13-3.01 (m, 1H), 2.70-2.59 (m, 1H), 2.44-2.32 (m, 1H), 1.76-1.64 (m, 2H), 1.39-1.28 (m, 4H), 0.88 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 179.5, 147.9, 147.0, 142.9, 138.2, 136.7, 134.7, 128.1, 123.5, 122.6, 108.3, 105.3, 103.6, 101.2, 59.9, 40.0, 38.3, 31.6, 29.0, 27.1, 22.6, 14.0; MS (ES+) m/z 372.1 (M+23), 350.1 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:16]=[C:15](B(O)O)[CH:14]=[CH:13][N:12]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].CC(O)CC>[F:10][C:11]1[CH:16]=[C:15]([C:2]2[CH:3]=[CH:4][C:5]([CH2:8][NH2:9])=[CH:6][N:7]=2)[CH:14]=[CH:13][N:12]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: OB(O)c1ccnc(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCC(C)O
Product: NCc1ccc(-c2ccnc(F)c2)nc1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
To a flask containing (6-chloropyridin-3-yl)methanamine 33-2 (642 mg, 4.50 mmol), 2-fluoropyridin-4-ylboronic acid 38-1 (634 mg, 4.50 mmol), Pd(OAc)2 (51 mg, 0.23 mmol), S-Phos (186 mg, 0.45 mmol) and potassium phosphate (2.85 g, 13.50 mmol) under argon was added 2-butanol (5 mL). The mixture was stirred at 100° C. for 10 hours. After cooling to room temperature, the mixture was filtered through celite cake. The filtrate was diluted with ethyl acetate, washed with H2O and brine, dried over Na2SO4, and concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography, eluted with 5% methanol containing ˜7N ammonia in dichloromethane to give (2′-fluoro-2,4′-bipyridin-5-yl)methanamine 38-2 as yellow solid. MS m/z 204.1 (M+1)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:13](=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:21]2[CH:22]=[N:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=2)[CH3:10])[C:5]([I:36])=[CH:4][N:3]=1.[OH-].[NH4+:38]>O1CCOCC1>[NH2:38][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:13](=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:21]2[CH:22]=[N:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=2)[CH3:10])[C:5]([I:36])=[CH:4][N:3]=1
Reactant: COc1ncc(-c2cccc3cc([C@H](C)Nc4nc(Cl)ncc4I)n(-c4ccccc4)c(=O)c23)cn1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ncc(-c2cccc3cc([C@H](C)Nc4nc(N)ncc4I)n(-c4ccccc4)c(=O)c23)cn1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
To a solution of (S)-3-(1-((2-chloro-5-iodopyrimidin-4-yl)amino)ethyl)-8-(2-methoxypyrimidin-5-yl)-2-phenylisoquinolin-1 (2H)-one 3 (800 mg, 1.31 mmol) in anhydrous 1,4-dioxane (4 mL) in a sealed tube, ammonium hydroxide (7 mL) was added and the resulting mixture was stirred at 110° C. for 20 h. The mixture was allowed to cool to RT, quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by ISCO column chromatography using a silica gel cartridge and eluting with 0-8% MeOH-DCM to afford the product, (S)-3-(1-((2-amino-5-iodopyrimidin-4-yl)amino)ethyl)-8-(2-methoxypyrimidin-5-yl)-2-phenylisoquinolin-1(2H)-one 4.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[N+]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]([CH3:24])=[CH:18]2)([O-])=O>C(Cl)CCl>[C:24]1([C:19]2[NH:20][C:21]3[C:17]([C:18]=2[C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])=[CH:16][CH:15]=[CH:23][CH:22]=3)[CH:4]=[CH:3][CH:2]=[CH:10][CH:9]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2[nH]1
Solvent: ClCCCl
Product: O=C(O)c1ccccc1C(=O)c1c(-c2ccccc2)[nH]c2ccccc12

Procedure:
Proceeding in a manner similar to that described in part A of Example 10, 29.6 g (0.20 mole) of phthalic anhydride and 35.2 g (0.20 mole) of 5-nitro-2-methylindole were interacted in 100 ml of ethylene dichloride to obtain 2-[(2-methyl-5-nitro-3-indolyl)carbonyl]benzoic acid (Formula VIII: Ro =R1 =R2 =R3 =R6 =H; R5 =CH3 ; Y1 =5-NO2), a red brown solid melting at 144°-148° C. and showing a strong carbonyl absorption maximum at 1700 cm-1 in the infrared spectrum.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[O:13][CH2:12][CH2:11][CH2:10][O:9]1.[Mg].[CH2:15]1[O:27][C:26]2[CH:25]=[C:24]3[C:19]([CH:20]=[C:21]([N+:28]([O-:30])=[O:29])[CH2:22][O:23]3)=[CH:18][C:17]=2[O:16]1.O>C1COCC1.BrCCBr>[CH2:15]1[O:27][C:26]2[CH:25]=[C:24]3[C:19]([CH:20]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=4[CH:8]4[O:13][CH2:12][CH2:11][CH2:10][O:9]4)[CH:21]([N+:28]([O-:30])=[O:29])[CH2:22][O:23]3)=[CH:18][C:17]=2[O:16]1
Reactant: O=[N+]([O-])C1=Cc2cc3c(cc2OC1)OCO3
Reactant: Brc1ccccc1C1OCCCO1
Agent: [Mg]
Solvent: BrCCBr
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])C1COc2cc3c(cc2C1c1ccccc1C1OCCCO1)OCO3
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 61.4 %

Procedure:
Acetal (5a) (9.04 g, 37.22 mmol) was dissolved in 50 ml of dry THF under an inert atmosphere in a two necked flask equipped with a condenser. Magnesium (1.8 g, 74.44 mmol) and one drop of 1,2 dibromoethane were added. This mixture was stirred at 80° C. for 45 min, and cooled to room temperature. A 50 ml solution of 2.74 g of nitrochromene (3a) (12.41 mmol) in THF was cannulated into this flask. This mixture was stirred for 30 min, and water was added to quench the reaction. The mixture was extracted with CH2Cl2 (100 ml×3), the extracts washed with brine (100 ml), dried over MgSO4 filtered, and the solvent evaporated to a brown oil from which (6a) precipitated spontaneously. The precipitate was filtered, rinsed with 30 ml of EtOAc and dried to give 2.91 g (61.4% yield). The remaining liquor was purified by flash column chromatography to give an additional 550 mg (72% combined yield): mp 207° C.; 1H-NMR (CDCl3) δ 7.50 (m, 1, ArH); 7.29 (m, 2, ArH); 6.99 (m, 1, ArH); 6.47 (s, 1, ArH); 6.38 (s, 1, ArH); 5.90 (d, 2, ArOCH2); 5.70 (s, 2, OCH2O); 4.97 (s, 1, O2CHAr); 4.71 (dq, 1, Ar2CH, J=10 Hz); 4.23 (m, 2+1, CH2(CH2O)2, CHNO2); 3.98 (m, 2, CH2(CH2O)2); 2.22 (m, 1, CH2); 1.43 (d, 1, CH2); Low resolution CIMS: m/z (rel. intensity) 386 (MH+, 100). Anal. Calcd. for C20H19NO7: C, 62.33; H, 4.97; N, 3.63. Found: C, 62.18; H, 5.37; N, 3.38.
Reaction SMILES: [ClH:1].[C:2]1([C:8]#[C:9][CH2:10][O:11][CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20](Br)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[ClH:1].[CH2:20]([N:17]1[CH2:18][CH2:19][CH:14]([CH2:13][CH2:12][O:11][CH2:10][C:9]#[C:8][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:15][CH2:16]1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C(#Cc1ccccc1)COCCC1CCNCC1
Reactant: BrCCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C(#Cc1ccccc1)COCCC1CCN(CCc2ccccc2)CC1
Yield: 46.5 %

Procedure:
The amine salt (0.34 g, 1.4 mmol), phenethyl bromide (0.26 g, 1.4 mmol), and potassium carbonate (0.50 g) were heated at reflux in absolute ethanol (50 mL) for 48 hours. After cooling, the mixture was filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with 10% methanol in chloroform, and concentrated in vacuo to yield a colorless oil (0.25 g, 51%). 1H NMR(300 MHz, CDCl3 /TMS, δ): 7.45-7.10(m,10H), 4.36(s,2H), 3.6(t,2H,J=6Hz), 3.04-1.20(m,15H).
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].C[O-].[Na+].[C:15](Cl)(=[O:18])[CH2:16][CH3:17].[Na+].[Cl-].CSCCC[Si](OC)(OC)OC.C(SCCC[Si](OC)(OC)OC)(=O)C>C1(C)C=CC=CC=1>[C:15]([S:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:6][CH3:7])[O:8][CH3:9])(=[O:18])[CH2:16][CH3:17]
Reactant: CO[Si](CCCS)(OC)OC
Reactant: CCC(=O)Cl
Agent: CO[Si](CCCSC(C)=O)(OC)OC
Agent: CO[Si](CCCSC)(OC)OC
Agent: C[O-]
Solvent: Cc1ccccc1
Product: CCC(=O)SCCC[Si](OC)(OC)OC

Procedure:
1,035 grams of 3-mercapto-1-propyltrimethoxysilane, 1,096 grams of a 25 weight percent methanolic solution of sodium methoxide, and 1,764 grams of toluene were charged to a 5-liter flask under an atmosphere of nitrogen. The stirred mixture developed a pinkish color. The flask was placed into a water bath at 64° C. Methanol was removed from the flask by distilling off a methanol-toluene azeotrope under a partial vacuum. The vacuum was kept such that the temperature in the distillation head was maintained at 30° to 35° C. during which time 1,500 ml of distillate, consisting of a toluene-methanol azeotrope, was collected. During this time the contents of the flask turned colorless. An additional 429 grams of toluene were added, and the distillation resumed. The appearance of a strong density current in the distillate, which coincided with an increase in distillation head temperature from 35° to 55° C., and the appearance of a changing liquid surface tension in the condenser signaled the point at which methanol removal from the flask was complete. The contents of the flask had become a viscous fluid. With continued stirring, the contents of the flask were allowed to cool. The flask was placed in an ice-water bath, resulting in what appeared to be a thick paste. 427 grams of propionyl chloride was added to the flask dropwise and/or in small portions with continued stirring in an ice-water bath until the reaction was complete. Aliquots of the stirred mixture were taken periodically. An alkaline reading indicated the completion of the reaction. The final mixture was a white suspension of NaCl in a toluene solution of the product. This mixture was filtered, and the solvent was removed from the filtrate to yield a nearly colorless product. Gas chromatography indicated (by weight) 3 percent of 3-mercapto-1-propyltrimethoxysilane, 1 percent of 3-(methylthio)-1-propyltrimethoxysilane, and 96 percent of 3-(acetylthio)-1-propyltrimethoxysilane (product). Flash distillation from one to two grams of powdered sodium methoxide yielded a colorless product. The sodium methoxide was added to ensure that any remaining acidity was neutralized. Further optional fractional distillation yielded a product in excess of 98 percent purity by GC.
Reaction SMILES: C([O:3][C:4](=O)/[CH:5]=[C:6](/[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)\[CH3:7])C.CC(C[AlH]CC(C)C)C>>[Br:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH:12]=[CH:13][C:8](/[C:6](/[CH3:7])=[CH:5]/[CH2:4][OH:3])=[CH:9][CH:10]=2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(-c2ccc(Br)cc2)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: C/C(=C\CO)c1ccc(-c2ccc(Br)cc2)cc1

Procedure:
(E)-3-(4′-bromo-biphenyl-4-yl)-but-2-en-1-ol was prepared from (E)-3-(4′-bromo-biphenyl-4-yl)-but-2-enoic acid ethyl ester (3.45 g, 10.0 mmol) and DIBAL-H (1M in toluene, 40 ml, 40 mmol) by a procedure analogous to that described in example 1b, yielding 1.68 g (55%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH:39]([CH3:41])[CH3:40])\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:38][CH:39]([CH3:40])[CH3:41])=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)/C=C(\CBr)Oc1ccccc1OC(C)C
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2ccccc2OC(C)C)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 29.9 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (1.20 g, 0.006 mol) in N,N-dimethylformamide (8 mL) was added N,N-diisopropylethylamine (3.76 g, 0.029 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(2-isopropoxy-phenoxy)-but-2-enoic acid ethyl ester (2.00 g, 0.006 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[4-(2-isopropoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (0.720 g, 28%) as a yellow oil.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:15](=[NH:16])[N:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]3=[N:12][C:11]=2[S:21][CH3:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:29](Cl)(=[O:31])[CH3:30]>C(Cl)Cl>[C:1]1([S:7]([C:10]2[C:15](=[N:16][C:29](=[O:31])[CH3:30])[N:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]3=[N:12][C:11]=2[S:21][CH3:22])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CSc1nc2ccccn2c(=N)c1S(=O)(=O)c1ccccc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CSc1nc2ccccn2c(=NC(C)=O)c1S(=O)(=O)c1ccccc1
Reaction time: 8 h

Procedure:
3-Benzenesulfonyl-2-methylsulfanyl-pyrido[1,2-a]pyrimidin-4-ylideneamine (100 mg, 0.30 mmol) was dissolved in anhydrous methylenechloride (2 ml) to which pyridine (48 mg, 0.6 mmol) was added. Acetylchloride was then added at room temperature and the reaction mixture was stirred overnight. The reaction was quenched with saturated aqueous NaHCO3, extracted with methylene chloride, and purified by flash chromatography to yield 79 mg of a yellow solid product.