Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:14][C:15]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:16]=1[C:17](Cl)=O>ClCCl>[Cl:14][C:15]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:16]=1[CH2:17][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1cc(I)ccc1Cl
Reactant: CCOc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOc1ccc(Cc2cc(I)ccc2Cl)cc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To a 250 mL of 4-necked flask equipped with an internal thermometer and a condenser was added ethoxybenzene (6.4 g, 52.5 mmol) and dichloromethane (19.2 mL) and the mixture was cooled to −5° C. Aluminum (III) chloride (7.4 g, 55 mmol) was added over 1 h while maintaining the internal temperature below 0° C. After the addition was completed, the mixture was stirred for 30 min at 0˜5° C., and a solution of 2-chloro-5-iodobenzoyl chloride (15.0 g, 50 mmol) in dichloromethane (21 mL) was added dropwise over 1 hour while maintaining the internal temperature below 5° C. The mixture was stirred for another 1 hour at 0˜5° C. and warmed to 10˜15° C. Polymethylhydrosiloxane (PMHS) (15.0 g, 0.25 mol) was added dropwise while maintaining the internal temperature below 25° C. After stirring for 10 hours at 25° C., additional PMHS (9.0 g, 0.15 mol) was added to the above mixture. After stirring for another 16 hours at 30° C., the mixture was cooled to 5˜10° C. and ice water (50 mL) was added slowly dropwise over 1 hour with stirring. The mixture was filtered and the filter cake was slurried with dichloromethane (100 mL) containing diatomite (20 g). The mixture was filtered and the filter cake was washed with dichloromethane (2×50 mL). The combined organic layers were washed with brine (100 mL). After removal of the volatiles, the residue was dissolved in absolute ethanol (45 mL) and refluxed with mechanical stirring (100 RPM) and cooled to 0° C. After stirring for another 16 h at 0˜5° C., the mixture was filtered and the filter cake was washed with pre-cooled (0˜5° C.) ethanol (2×5 mL), dried under vacuum at 40° C. for 12 h to give 14.2 g of 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene as a white solid. This solid was recrystallized from ethanol (42.6 mL) to give 12.5 g of 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene as a white solid. Yield, 67%, HPLC purity, HPLC-0002: 99.5%. 1H NMR (CDCl3, 400 MHz): δ 7.21˜7.29 (m, 3H), 7.11 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 3.99˜4.07 (m, 4H), 1.43 (t, J=7.2 Hz, 3H).
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].Br[CH2:35][CH2:36][CH2:37][CH:38]=[CH2:39]>>[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][N:25]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:39][CH2:38][CH2:37][CH:36]=[CH2:35])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:10]
Reactant: C=CCCCBr
Reactant: CC(C)C[C@@H](C(=O)NNS(C)(=O)=O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Product: C=CCCCN(NC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NO)S(C)(=O)=O

Procedure:
The starting material was prepared in an analogous manner to that described in Example 15, part (iii), starting from (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-(methanesulphonyl)-4-methylvalerohydrazide and 5-bromo-1-pentene.
Reaction SMILES: [Si]([O:18][C:19]1[CH:57]=[CH:56][C:22]([O:23][CH2:24][C@@H:25]([OH:55])[CH2:26][NH:27][CH2:28][CH2:29][O:30][C:31]2[CH:54]=[CH:53][C:34]([NH:35][CH:36]3[CH2:41][CH2:40][N:39]([C:42]([NH:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[O:43])[CH2:38][CH2:37]3)=[CH:33][CH:32]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH2:45]([NH:44][C:42]([N:39]1[CH2:40][CH2:41][CH:36]([NH:35][C:34]2[CH:53]=[CH:54][C:31]([O:30][CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:55])[CH2:24][O:23][C:22]3[CH:21]=[CH:20][C:19]([OH:18])=[CH:57][CH:56]=3)=[CH:32][CH:33]=2)[CH2:37][CH2:38]1)=[O:43])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(OCCNC[C@H](O)COc3ccc(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)cc3)cc2)CC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(OCCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 54.6 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino]ethoxy)anilino]-N-octyl-1-piperidinecarboxamide (0.30 g, 0.377 mmol) was reacted according to Procedure H (eluant: 10:1 chloroform-methanol) to give the title compound (0.115 g, 0.206 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:5]([CH:9]=[C:10]2[NH:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])[CH:6]=[CH:7][CH:8]=1.Cl.C(=C1NC(=O)NC1=O)C1C=CC=CC=1>CO.[Zn]>[CH3:1][O:2][C:3]1[C:4]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:5]([CH2:9][CH:10]2[NH:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C=C2NC(=O)NC2=O)c1OCc1ccccc1
Agent: Cl
Agent: O=C1NC(=O)C(=Cc2ccccc2)N1
Agent: [Zn]
Solvent: CO
Product: COc1cccc(CC2NC(=O)NC2=O)c1OCc1ccccc1
Temperature: 50 °C
Yield: 47.1 %

Procedure:
Zinc powder (40.00 g; 0.61 mole) is added to a stirred suspension of 48.00 g (0.16 mole) of the benzylidine hydantoin from Example 3 in 1,200 mL of methanol under nitrogen. Concentrated hydrochloric acid (30 mL) is added and the mixture is heated on the steam bath for 20 minutes (after 10 minutes the starting benzylidene hydantoin dissolves). Another 30 mL of concentrated hydrochloric acid is added and the mixture is heated at reflux for another 20 minutes. The cooled (50° C.) mixture is cautiously filtered and the cake washed with 100 mL of methanol. Water (500 mL) is added to the filtrate to yield 24.60 g of crystalline product; mp 202°-204° C. Recrystallization from methanol gives pure product; mp 205°-207° C.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:17][CH:16]=2)=[CH:10][N:9]=1)=O)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:25]([O:24][C:22](=[O:23])[NH:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][C:11]2[CH:10]=[N:9][C:8]([CH2:6][OH:5])=[CH:13][CH:12]=2)=[CH:20][CH:19]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(C(=O)OC(C)(C)C)nc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(CO)nc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
A solution of 5-(4-t-butoxycarbonylamino-phenoxy)-pyridine-2-carboxylic acid t-butyl ester (0.5 g, 1.3 mmol) in THF (2.0 ml) was added dropwise to a 0° C. suspension of LiAlH4 (0.1 g, 2.6 mmol) in dry THF (5.0 ml). The reaction was stirred at 0° C. for 2 h and was quenched with 10% aqueous NaOH (1.0 mL). The mixture was filtered and the filtrate was concentrated in vacuo to give [4-(6-hydroxymethyl-pyridin-3-yloxy)-phenyl]-carbamic acid t-butyl ester (0.38 g, 92% yield). MS (ESI) m/z: (M+H+) 317.2.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].N1C=CN=C1.C([Si](C)(C)Cl)(C)(C)C.C(N(CC)CC)C.[N:30]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>ClCCl.C(Cl)(Cl)Cl>[OH:8][CH2:7][CH:5]([NH:6][C:36]([N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:37])[C:4]([O:3][CH3:2])=[O:9]
Reactant: O=C(Cl)N1CCCCC1
Reactant: COC(=O)[C@@H](N)CO
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)C(CO)NC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.00 g (6.43 mmol) of serine methyl ester hydrochloride and 960 mg (14.1 mmol) of imidazole were dissolved in 10 ml of dichloromethane. 10 ml of a solution of 1.07 g (7.07 mmol) of t-butyldimethylchlorosilane in dichloromethane was added dropwise to the obtained solution under cooling with ice, and they were stirred at room temperature for 1 hour. After concentrating under reduced pressure, ethyl acetate was added to the residue. The reaction mixture was washed with saturated aqueous ammonium chloride solution, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in 10 ml of dichloromethane. 1.35 ml (9.65 mmol) of triethylamine and 0.97 ml (7.72 mmol) of 1-piperidinecarbonyl chloride were added dropwise to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. 20 ml of chloroform was added to the reaction mixture, and they were stirred at 50° C. for 3 hours and then concentrated under reduced pressure. The residue was dissolved in 15 ml of methanol. 10 ml of 2 N hydrochloric acid was added dropwise to the obtained solution under cooling with ice, and they were stirred at room temperature for 2 hours. After the concentration under reduced pressure, ethyl acetate was added to the residue. The product was washed with 1 N aqueous hydrochloric acid solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by the silica gel chromatography (dichloromethane:methanol=1:0 to 9:1) to obtain the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.CC(O)C.[NH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1.C([O-])(O)=O.[Na+]>O>[CH3:17][C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[C:14]([CH3:15])[C:9]=1[NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=2)[N:7]=1
Reactant: Cc1cc(C)c(Nc2ccnc(Cl)n2)c(C)c1
Reactant: N#Cc1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Cc1cc(C)c(Nc2ccnc(Nc3ccc(C#N)cc3)n2)c(C)c1
Temperature: 42.5 °C
Yield: 85.5 %

Procedure:
A mixture of intermediate 49 (0.082 mol) and 5.4 N HCl in 2-propanol (0.086 mol) in water (300 ml) was stirred and warmed to 40-45° C. over 30 minutes. 4-Amino-benzonitrile (0.242 mol) was added at 40-45° C. The reaction mixture was stirred and refluxed for 4.5 hours, then cooled to room temperature. The mixture was alkalized by portionwise addition of NaHCO3. This mixture was extracted with ethylacetate. The organic layer was separated, washed with brine, dried, filtered, and the solvent was evaporated. This fraction was stirred in ethanol p.a. (100 ml), filtered off, washed with ethanol (50 ml), then dried, yielding 23.1 g (86%) 4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile (compound 52).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[CH2:7][C:8]([S:10][C:5]=2[CH:4]=1)=[O:9].[CH:13](=O)[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:16]>C(O)C.C(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[CH:7]3[CH:13]([S:10][C:5]=2[CH:4]=1)[C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[O:16][C:8]3=[O:9]
Reactant: COc1ccc2c(c1)SC(=O)C2
Reactant: O=Cc1ccccc1O
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)SC1c3ccccc3OC(=O)C21
Reaction time: 1 h
Yield: 82.8 %

Procedure:
To a stirred solution of 6-methoxythianaphthen-2-one (52.6 g, 290 mmol) in a mixture of ethanol (260 mL) and methylene chloride (130 mL) was added triethylamine (2.0 mL, 14.8 mmol) followed by salicylaldehyde (32 mL, 300 mmol) at room temperature. After 1 h, a solid began to precipitate and stirring was continued for 3.5 h. The mixture was then diluted with cold hexane and filtered to yield 68.3 g (83%) of the title product as a powdery white solid, pure by 1H-NMR analysis: 1H NMR (300 MHz, CDCl3) δ7.45 (d, J=7.5 Hz, 1H), 7.33 (m, 2H), 7.17 (m, 1H), 7.07 (d, J=8.1 Hz, 1H), 6.77 (d, J=2.4 Hz, 1H), 6.69 (dd, J=2.4, 8.5 Hz, 1H), 5.25 (d, J=7.4 Hz, 1H), 4.37 (d, J=7.3 Hz, 1H), 3.77 (s, 3H); 13C NMR (75 MHz, CDCl3) δ166.4, 160.7, 150.8, 141.4, 130.1, 129.0, 127.7, 127.0, 124.9, 119.5, 117.2, 111.2, 108.3, 55.5, 50.6, 49.6; IR (CHCl3) 1766 cm-1 ; MS (FD) m/e 284 (M+); Anal. calc'd. for C16H12O3S: C, 67.59; H, 4.26. Found: C, 67.77; H, 4.24.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14].Br[CH2:16][C:17]([O:19][CH3:20])=[O:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:20][O:19][C:17](=[O:18])[CH2:16][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1]
Reactant: COC(=O)CBr
Reactant: Oc1ccccc1OCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)COc1ccccc1OCCCCCBr
Yield: 66.4 %

Procedure:
A mixture of 2.6 g (10 mmol) of 2-[(5-bromopentyl)oxy]phenol, 1.8 g (12 mmol) of methyl bromoacetate, 4.4 g (32 mmol) of anhydrous granular potassium carbonate, and 60 mL of dry acetonitrile was stirred and refluxed for 20 hr. The mixture was cooled and filtered with suction. The solids were washed with ether and the filtrate and washes were combined and concentrated in vacuo. The oily residue was purified by flash chromatography on silica gel, eluting with 3:1 hexane-ether. There was obtained 2.2 g (66.5%) of [2-[(5-bromopentyl)oxy]phenoxy]acetic acid methyl ester as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=[O:21])=[CH:16][CH:15]=2)=[CH:12][CH:11]=[N:10]1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]C#N)=[CH:27][CH:26]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]3=[N:20][O:21][C:31]([C:28]4[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=4)=[C:16]3[CH:15]=2)=[CH:12][CH:11]=[N:10]1
Reactant: COc1ccc(CC#N)cc1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccc(F)cc2F)cc1
Product: COc1ccc(-c2onc3ccc(-c4ccnn4-c4ccc(F)cc4F)cc23)cc1

Procedure:
The title compound, yellow solid (21 mg, 16%), MS (ISP) m/z=404.3 [(M+H)+], mp 165° C., was prepared in accordance with the general method of example 1 from 1-(2,4-difluoro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate I) (100 mg, 353 μmol) and commercially available 2-(4-methoxy-phenyl)-acetonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[NH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[CH:3]=1.[CH2:16]([C:18]([O-:20])=[O:19])[CH3:17].[Cl:21][C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1>>[Cl:21][C:22]1[CH:23]=[C:24]([S:28]([NH:1][C:2]2[CH:11]=[CH:10][C:9]3[NH:8][C:7](=[O:12])[C:6]4[NH:13][CH:14]=[CH:15][C:5]=4[C:4]=3[CH:3]=2)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1.[CH2:16]([C:18]([O-:20])=[O:19])[CH3:17]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: Nc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Agent: CCC(=O)[O-]
Product: O=c1[nH]c2ccc(NS(=O)(=O)c3cccc(Cl)c3)cc2c2cc[nH]c12
Yield: 27.5 %

Procedure:
This compound is prepared according to synthesis 37, from 60 mg (0.22 mmol) of 8-amino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate (synthesis 64) and 34 μL (0.24 mmol) of 3-chloro-benzenesulfonyl chloride. After recrystallization from methanol then trituration in hot methanol, 27 mg (27%) of 8-(3-chloro-benzenesulfonylamino)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[C:17]([C:23]4[CH:28]=[C:27]([C:29](=[O:40])[NH:30][C:31]5([C:34]6[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=6)[CH2:33][CH2:32]5)[CH:26]=[CH:25][C:24]=4[CH3:41])=[CH:16][C:11]=3[C:12]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.Cl.[CH3:43][NH2:44]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[C:17]([C:23]4[CH:28]=[C:27]([C:29](=[O:40])[NH:30][C:31]5([C:34]6[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=6)[CH2:33][CH2:32]5)[CH:26]=[CH:25][C:24]=4[CH3:41])=[CH:16][C:11]=3[C:12]=2[C:13]([NH:44][CH3:43])=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)NC2(c3ccccc3)CC2)cc1-c1cc2c(C(=O)O)c(-c3ccc(F)cc3)oc2cc1[N+](=O)[O-]
Reactant: CN
Agent: Cl
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(-c3cc(C(=O)NC4(c5ccccc5)CC4)ccc3C)cc12

Procedure:
Prepared by the coupling of 2-(4-fluorophenyl)-5-(2-methyl-5-(1-phenylcyclopropylcarbamoyl)phenyl)-6-nitrobenzofuran-3-carboxylic acid with methylamine hydrochloride under the conditions as described. LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters MICROMASS®. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column: XTERRA® MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)+=564.36, HPLC Rt=1.768 min.
Reaction SMILES: Br[C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:12][O:13][C:14](=[O:31])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=1>>[CH3:12][O:13][C:14](=[O:31])[CH2:15][C:16]1[CH:21]=[C:20]([C:2]2[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(C=O)c1Br
Reactant: COC(=O)Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Product: COC(=O)Cc1cccc(-c2c(C=O)cccc2OC)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 2-bromo-3-methoxy-benzaldehyde and [3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester.
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH:30]=[CH:29][CH:28]=[CH:27]4)=[CH:22][CH:21]=3)[N:18]=[C:17]([C:31]([F:34])([F:33])[F:32])[CH:16]=2)=[CH:11][CH:10]=1)(=O)C.Cl>C1COCC1.CO>[N:26]1([C:23]2[CH:24]=[CH:25][C:20]([N:19]3[C:15]([C:12]4[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][OH:6])=[CH:10][CH:11]=4)=[CH:16][C:17]([C:31]([F:33])([F:32])[F:34])=[N:18]3)=[CH:21][CH:22]=2)[CH:30]=[CH:29][CH:28]=[CH:27]1
Reactant: CC(=O)OCCc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(-n3cccc3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: OCCc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(-n3cccc3)cc2)cc1
Reaction time: 2 h
Yield: 83.4 %

Procedure:
1M NaOH (436 μl) was added to a solution of 2-{4-[1-[4-(1H-pyrrol-1-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethyl acetate (128 mg) in THF (1.5 ml) and MeOH (0.3 ml) under ice bath cooling. The mixture was stirred at 0° C.˜ambient temperature for 2 hours. The mixture was neutralized with 1M HCl (436 μl), and was partitioned between AcOEt and H2O. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography developed by AcOEt/n-hexane=50%. The separated silica gel was extracted with 10% MeOH/CHCl3 and the solvent was evaporated in vacuo to give 2-{4-[1-[4-(1H-pyrrol-1-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethanol (96.5 mg) as an amorphous powder.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:15]([OH:17])=[O:16])[CH2:13][OH:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[C:25]([CH3:28])([CH3:27])[CH3:26]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.CC#N>[C:25]([O:16][C:15](=[O:17])[CH:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2])[CH2:13][OH:14])([CH3:28])([CH3:27])[CH3:26]
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)Br
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Product: CC(C)(C)OC(=O)C(CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
A mixture of Cbz-L-serine (10.0 g, 42 mmol), benzyltriethylammonium chloride (9.5 g, 42 mmol) and potassium carbonate (38.0 g, 275 mmol) in CH3CN (80 mL) was stirred vigorously for 5 h at RT. 2-Bromo-2-methyl propane was added and the reaction mixture was warmed to 45-50° C. and stirred rapidly. The reaction mixture became very thick after 2-3 h. Additional CH3CN was added (50 mL) to facilitate stirring and the resulting reaction mixture was stirred for 24 h. The reaction mixture was then cooled to RT and most of the CH3CN was removed by rotary evaporation. The reaction mixture was then partitioned between ethyl acetate (200 mL) and water (100 mL). The aqueous layer was extracted with ethyl acetate (3×100 mL). The ethyl acetate layers were combined and washed with water (100 mL), then with sat. aq. NaCl solution (2×100 mL), and then dried over Na2SO4, filtered and concentrated. If the product did not crystallize upon concentration, it was triturated with hexanes and filtered to give 2-benzyloxycarbonylamino-3-hydroxy-propionic acid tert-butyl ester as a white solid (10.0 g, 81% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:12]=[CH:11][NH:10][C:9]2=O.O=P(Cl)(Cl)[Cl:24]>C1(C)C=CC=CC=1>[Cl:24][C:9]1[C:8]2[C:13](=[CH:14][C:15]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=2)[N:12]=[CH:11][N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCCOc1cc2nc[nH]c(=O)c2cc1OCCOC
Solvent: Cc1ccccc1
Product: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Temperature: 125 °C
Yield: 91 %

Procedure:
According to the procedure described in Example 6A Step 5, a mixture of 6,7-bis(2-methoxyethoxy)quinazolin-4(3H)-one (2.28 g, 7.7 mmol) and POCl3 (10 mL) in toluene (30 mL) was heated at 125° C. for 5 hours, to afford 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline as a solid (2.212 g, 91%). 1H NMR (300 MHz, CDCl3) δ 8.86 (s, 1H), 7.44 (s, 1H), 7.34 (s, 1H), 4.34 (t, 4H), 3.89 (t, 4H), 3.50 (s, 3H), 3.49 (s, 3H); LC-MS (ESI) m/z 313 (M+H)+.
Reaction SMILES: [C:1]([OH:9])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].ClCC(OC(=O)CCl)=O.[C:19]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)(=[O:21])[CH3:20]>ClCC(Cl)(Cl)Cl>[C:19]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Oc1ccc(-c2ccccc2)cc1
Reactant: CCCCCCC(=O)O
Agent: ClCC(Cl)(Cl)Cl
Agent: O=C(CCl)OC(=O)CCl
Product: CCCCCCC(=O)c1ccc(-c2ccc(OC(C)=O)cc2)cc1
Temperature: 100 °C
Reaction time: 10 h
Yield: 74 %

Procedure:
In 50 ml of tetrachloroethane were dissolved 6.51 g (0.05 mole) of heptanoic acid and 9.83 g (0.0575 mole) of monochloroacetic anhydride. To the resulting solution were added 12.74 g (0.06 mole) of 4-acetoxybiphenyl and 0.8 g of boron trifluoride-diethyl ether complex and the resulting mixture was then stirred at 100° C. for 10 hours. After completion of the reaction, the reaction solution was cooled and washed with 5% aqueous sodium carbonate solution and water in this order. The organic layer was concentrated under reduced pressure to obtain 12.0 g of 4-acetoxy-4'-heptanoylbiphenyl.
Reaction SMILES: [N:1]1([C:10]2[CH:23]=[CH:22][C:13]([C:14]([N:16]3[CH2:20][CH2:19][C@@H:18]([OH:21])[CH2:17]3)=[O:15])=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C(N(C(C)C)CC)(C)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[CH3:33][S:34]([O:21][C@@H:18]1[CH2:19][CH2:20][N:16]([C:14](=[O:15])[C:13]2[CH:22]=[CH:23][C:10]([N:1]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=[CH:2]3)=[CH:11][CH:12]=2)[CH2:17]1)(=[O:36])=[O:35]
Reactant: O=C(c1ccc(-n2cnc3ccccc32)cc1)N1CC[C@@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)O[C@@H]1CCN(C(=O)c2ccc(-n3cnc4ccccc43)cc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
A solution of (3R)-1-[4-(1H-benzimidazol-1-yl)benzoyl]pyrrolidin-3-ol (2.30 g, 7.48 mmol) in anhydrous dichloromethane at 0° C. is treated with diisopropylethyl amine (2.13 g, 16.46 mmol) and methanesulfonyl chloride (1.29 g, 11.22 mmol), stirred at 0° C. for 2 hours and concentrated to give a crude oil. Purification of this oil by flash column chromatography (silica, methanol:dichloromethane 5:95) provides the title product as a yellow solid, 2.3 g (81% yield), identified by NMR and mass spectral analyses. MS [386.5 m/e (M+H)].