Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29]C(=O)C)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].C(O)C>O>[OH:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCCCCCCCOC(C)=O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(-c2ccc(OCCCCCCCCCCO)cc2)cc1
Yield: 97.3 %

Procedure:
30 m moles(13.2 g) of the above 4'-(10-acetyloxydecyloxy)biphenyl-4-carboxylic acid ethyl ester and 10 g of sodium hydroxide were stirred for 10 min. at 70° C. in a mixed solvent of 40 ml of ethanol and 80 ml of water. After the reaction, the reaction solution was concentrated to obtain 10.8 g of 4'-(10-hydroxydecyloxy)biphenyl-4-carboxylic acid. (yield: 97%)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13](Cl)=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[C:9]2[C:8]([CH2:11][CH2:12][C:13]2=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(CCC(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)c1ccc2c(c1)C(=O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 131 %

Procedure:
A 3 neck round bottom flask fit with a thermometer, nitrogen inlet, condenser, overhead stirrer, and solids addition funnel was charged with 3-(4-t-butylphenyl)propionyl chloride (99.0 g, 0.442 mol) and methylene chloride (2.0 L). The reaction mixture was cooled to 10 C. and aluminum chloride (62.1 g, 0.466 mol) was added slowly to the reaction mixture. After allowing the reaction to warm to room temperature and stir overnight the reaction was quenched into 5% HCl/ice (1 L). The organics were washed with water (10×200 mL), filtered through celite, and dried over anhydrous sodium sulfate. The solvents were removed by rotary evaporation to yield the crude 6-t-butyl-1-indanone (109 g). 1HNMR (CDCl3, 500 MHz) δ7.79 (d, J=1.5 Hz, 1H); 7.66 (dd, JAB=2.8 Hz, 1H); 7.42 (d, J=8 Hz, 1H); 3.10 (t, J=6 Hz, 2H); 2.70 (t, J=6 Hz, 2H); 1.34 (s, 9H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>O1CCOCC1>[ClH:23].[F:21][C:17]1[CH:16]=[C:15]([C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:22])[CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(F)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(c1cccc(F)c1)N1CCNCC1
Yield: 89 %

Procedure:
A cold solution of 4-(3-fluoro-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester (400 mg, 1.29 mmol) in 1,4-dioxane.HCl (1 mL) was stirred at 0° C. for 1 hour. The reaction mixture was then concentrated under reduced pressure and the resulting crude residue was washed with ether and dried to afford 280 mg (89%) of (3-fluoro-phenyl)-piperazin-1-yl-methanone.hydrochloride.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:47][CH:48]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:49]1[CH:54]=[CH:53][C:52]([P:55]([CH2:60][CH2:61][CH3:62])(=[O:59])[O:56][CH2:57][CH3:58])=[CH:51][CH:50]=1>CC#N>[OH:1][C:2]1[C:7]([C:8]([NH:47][CH:48]([C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)[C:49]2[CH:50]=[CH:51][C:52]([P:55]([CH2:60][CH2:61][CH3:62])(=[O:59])[O:56][CH2:57][CH3:58])=[CH:53][CH:54]=2)=[O:10])=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1
Reactant: CCCP(=O)(OCC)c1ccc(C(N)c2ccccc2)cc1
Reactant: O=C(O)c1cnc(-n2cccn2)nc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCP(=O)(OCC)c1ccc(C(NC(=O)c2cnc(-n3cccn3)nc2O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid (8-b, 526 mg, 2.56 mmol) in MeCN (10 ml) was added Et3N (645 mg, 6.39 mmol), then added HATU (1068 mg, 2.81 mmol). After 5 mins, ethyl 4-(amino(phenyl)methyl)phenyl(propyl)phosphinate, 16-e, (810 mg, 2.56 mmol) was added and the resulting mixture was stirred at rt for 2 hours. The mixture was then evaporated and the residue was diluted with ethyl acetate followed by washing with brine. The organic layer was dried and concentrated under vacuo to give the title compound, 16-f, (crude product, 2.1 g).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>CCO>[N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCN1CCOCC1
Solvent: CCO
Product: NCCCCN1CCOCC1
Temperature: 0 °C

Procedure:
A solution of phthalimide 307 (9.42 g, 32.7 mmol) and N2H4—H2O (3.2 mL, 65.3 mmol) in EtOH (140 mL) was stirred at reflux temperature for 2 h. The mixture was cooled to 0° C., filtered, the filtrate cooled at 0° C. for 3 h, and filtered. The filtrate was evaporated and the residue dissolved in 1 M HCl. The solution was washed with ether (2×50 mL) and the pH adjusted to 10 with aqueous NH3 solution. The resulting mixture was extracted with CHCl3 (4×50 mL), the combined organic fraction dried and the solvent evaporated to give diamine 308 (Thompson, A. M.; et. al., J. Med. Chem., 1997, 40, 3915-3925) (2.0 g, 39%) as a colourless oil: 1H NMR δ 3.72 (br t, J=4.7 Hz, 4H, 2×CH2O), 2.71 (br dd, J=6.9, 6.7 Hz, 2H, CH2N), 2.44 (br t, J=4.6 Hz, 4H, 2×CH2N), 2.34 (br dd, J=7.8, 7.0 Hz, 2H, CH2N), 1.62 (br s, 2H, NH2), 1.42-1.59 (m, 4H, 2×CH2)—
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[C:20]([CH3:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[N:31]1[CH:36]=C[CH:34]=[C:33](B(O)O)[CH:32]=1>>[C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[C:20]([C:23]2[CH:36]=[N:31][CH:32]=[CH:33][CH:34]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: OB(O)c1cccnc1
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)c(C)c2ccccc2c1-c1ccc(Cl)cc1
Product: Cc1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1-c1cccnc1

Procedure:
2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-4-(pyridin-3-yl)naphthalen-2-yl)acetic acid (138) was prepared in a manner similar to 2-tert-butoxy-2-(1-(4-chlorophenyl)-3,4-dimethylnaphthalen-2-yl)acetic acid of Example 125, except using pyridin-3-yl-boronic acid in the Suzuki reaction, giving the title compound (mono trifluoroacetic acid salt). 1H-NMR: (400 MHz, DMSO-d6): δ 12.8 (s, broad, 1H), 8.80 (d, J=5.1 Hz, 1H), 8.62 (d, J=12.9 Hz, 1H), 7.97-7.92 (m, 1H), 7.76-7.69 (m, 3H), 7.60-7.54 (m, 1H), 7.47-7.40 (m, 3H), 7.28 (d, J=9.2 Hz, 1H), 7.18 (d, J=9.4 Hz, 1H), 5.15 (s, 1H), 2.25 (s, 3H), 0.96 (s, 9H). 19F-NMR: (377 MHz, DMSO-d6): δ−74.7 (s) LCMS-ESI+ (m/z): [M+H]+ calcd for C28H27ClNO3: 460.2; Found: 460.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[Br:10]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:10][C:6]1[C:5]([F:8])=[CH:4][C:3]([OH:9])=[C:2]([F:1])[CH:7]=1
Reactant: BrBr
Reactant: Oc1cc(F)ccc1F
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Oc1cc(F)c(Br)cc1F
Reaction time: 3 h

Procedure:
To 2,5-difluorophenol (594, 5.50 g, 0.0423 mol) in chloroform (110.0 mL), bromine (2.18 mL, 0.0423 mol) was added slowly. After 3 hours, the reaction was poured into a solution of sodium thiosulfate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and purified with silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a colorless oil (595, 6.20 g, 70.2%).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:5](=[C:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@:25]([OH:30])([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:18]([CH2:19][C:20]4([O:34][CH2:33][CH2:32][O:31]4)[CH2:21][CH2:22]2)=[CH:17][CH2:16]3)[CH2:13][CH2:12]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].P([O-])(O)(O)=O.[K+]>O1CCCC1>[C:3]([CH:5]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@:25]([OH:30])([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:18]([CH2:19][C:20]4([O:31][CH2:32][CH2:33][O:34]4)[CH2:21][CH2:22]2)=[CH:17][CH2:16]3)[CH2:13][CH2:12]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4]
Reactant: CCOC(=O)C(C#N)=C1CC[C@H]2[C@@H]3CC=C4CC5(CC[C@]4(C)[C@@]3(O)CC[C@]12C)OCCO5
Agent: O=P([O-])(O)O
Agent: [Al+3]
Agent: [BH4-]
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)[C@H]1CC[C@H]2[C@@H]3CC=C4CC5(CC[C@]4(C)[C@@]3(O)CC[C@]12C)OCCO5
Temperature: 25 °C
Reaction time: 5 h
Yield: 46.4 %

Procedure:
Sodium borohydride (0.70 g) was added in small portions to a stirred solution of ethyl 20-cyano-3,3-ethylenedioxy-9α-hydroxypregna-5,17(20)-dien-21-oate (1.76 g) in dry tetrahydrofuran (15 ml). After stirring at room temperature for 5 hours, lithium aluminium hydride (0.12 g) was added in 3 portions and stirring was continued for 3 hours. Aqueous saturated potassium dihydrogen phosphate (15 ml) was added and the mixture was extracted with ethyl acetate. The organic extract was washed with aqueous sodium bicarbonate, then washed twice with water, dried and concentrated under reduced pressure to afford 0.82 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH:12][C@H:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:19]2[NH:27][C:26]3[CH2:25][CH2:24][NH:23][C:22](=[O:28])[C:21]=3[CH:20]=2)[N:3]=1.[CH3:29][C:30](OC(C)=O)=[O:31]>C(Cl)Cl>[C:30]([N:15]1[CH2:16][CH2:17][CH2:18][C@H:13]([NH:12][C:11]2[C:2]([CH3:1])=[N:3][C:4]3[C:9]([N:10]=2)=[C:8]([C:19]2[NH:27][C:26]4[CH2:25][CH2:24][NH:23][C:22](=[O:28])[C:21]=4[CH:20]=2)[CH:7]=[CH:6][CH:5]=3)[CH2:14]1)(=[O:31])[CH3:29]
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@H]1CCCNC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CCC[C@H](Nc2nc3c(-c4cc5c([nH]4)CCNC5=O)cccc3nc2C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.6 %

Procedure:
Prepared according to Example 50, using TEA (37.7 μl, 0.271 mmol, Sigma Aldrich), (S)-2-(2-methyl-3-(piperidin-3-ylamino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Ex. 76, 85 mg, 0.226 mmol), Ac2O (42.6 μl, 0.452 mmol), and DCM (2.3 mL) and stirring at 25° C. for 1 h. Purification by concentration of the reaction solution, solubilization in MeOH, and filtration through a pre-washed column of Si-carbonate (SiliaPrep, Silicyle) provided 2-(3-(((3S)-1-acetyl-3-piperidinyl)amino)-2-methyl-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (28 mg, 30%). 1H NMR (DMSO-d6) δ: 7.85-7.91 (m, 1H), 7.77-7.83 (m, 1H), 7.54-7.63 (m, 2H), 7.30-7.40 (m, 2H), 7.05-7.11 (m, 1H), 4.45-4.55 (m, 1H), 4.27-4.39 (m, 1H), 4.13-4.27 (m, 1H), 3.96-4.10 (m, 1H), 3.86-3.95 (m, 1H), 3.76-3.86 (m, 1H), 3.39-3.46 (m, 3H), 2.87-2.97 (m, 1H), 2.01-2.07 (m, 3H), 1.59 (s, 3H), 1.10-1.22 (m, 3H). m/z (ESI, +ve) 419.1 (M+H)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:49][CH:50]1[C@H:54]2[C@H:55](OC3CCCCO3)[N:56](C(OC(C)(C)C)=O)[C:57]3[CH:64]=[CH:63][C:62]([O:65][CH3:66])=[CH:61][C:58]=3[C:59](=[O:60])[N:53]2[CH2:52][C:51]1=[CH2:81])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH:17]1[C@H:21]2[C@H:22](OC3CCCCO3)[N:23](C(OC(C)(C)C)=O)[C:24]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:25]=3[C:26](=[O:27])[N:20]2[CH2:19][C:18]1=[CH2:48].C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:15]([O:16][CH:17]1[C@@H:21]2[CH:22]=[N:23][C:24]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:25]=3[C:26](=[O:27])[N:20]2[CH2:19][C:18]1=[CH2:48])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:49][CH:50]1[C@@H:54]2[CH:55]=[N:56][C:57]3[CH:64]=[CH:63][C:62]([O:65][CH3:66])=[CH:61][C:58]=3[C:59](=[O:60])[N:53]2[CH2:52][C:51]1=[CH2:81]
Reactant: C=C1CN2C(=O)c3cc(OC)ccc3N(C(=O)OC(C)(C)C)[C@@H](OC3CCCCO3)[C@@H]2C1OCCCCCCCCOC1C(=C)CN2C(=O)c3cc(OC)ccc3N(C(=O)OC(C)(C)C)[C@@H](OC3CCCCO3)[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C=C1CN2C(=O)c3cc(OC)ccc3N=C[C@H]2C1OCCCCCCCCOC1C(=C)CN2C(=O)c3cc(OC)ccc3N=C[C@@H]12
Reaction time: 1 h
Yield: 83.8 %

Procedure:
95% TFA (2 mL) was added dropwise to dimer compound 28a (77 mg, 0.074 mmol) at 0° C. which was stirred for 1 h and then poured into saturated aqueous NaHCO3 (30 mL). The mixture was extracted with chloroform (3×20 mL) and the organic layer was then washed with water (20 mL), brine (20 mL), dried (MgSO4) and filtered. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 29a (39 mg, 0.062 mmol, 84%) as a solid: [α]29D=+428° (c=0.07, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.33-1.54 (m, 8H, 14-H, 15-H), 1.78-1.93 (m, 4H, 13-H), 2.86-2.97 (m, 2H, 1-H), 3.04-3.17 (m, 2H, 1-H), 3.83-3.89 (m, 2H, 11a-H), 3.93 (s, 6H, 7-OMe), 3.99-4.12 (m, 4H, 12-H), 4.28 (s, 4H, 3-H), 5.16-5.19 (m, 4H, 2a-H), 6.79 (s, 2H, 9-H), 7.49 (s, 2H, 6-H), 7.66 (d, 2H, J=4.42 Hz, 11-H); 13C NMR (CDCl3, 100 MHz): δ 25.2, 25.8, 28.8, 29.2, 35.5, 51.3, 53.8, 56.1, 58.4, 69.0, 109.3, 110.4, 111.4, 119.6, 140.7, 141.7, 147.9, 151.0, 162.4, 164.8; IR (neat): 3310, 2932, 2855, 1598, 1503, 1463, 1451, 1429, 1381, 1260, 1216, 1096, 1013, 911, 786, 729 cm−1; MS (ES+) m/z (relative intensity) 627 ([M+H]+., 100), 628 ([M+2H]+., 53), 332 (92), 323 (61).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[CH:10]=[CH:9][C:8]=2[CH:15]=1)([O-])=O.Cl[Sn]Cl.[OH-].[Na+]>C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:13])([CH3:14])[CH:10]=[CH:9][C:8]=2[CH:15]=1
Reactant: CC1(C)C=Cc2cc([N+](=O)[O-])ccc2O1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)C=Cc2cc(N)ccc2O1

Procedure:
A solution of 6-nitro-2,2-dimethyl-2H-benzopyran (prepared as described in Evans et al., J. Med. Chem.) (4.65 g, 22.66 mmoles) and SnCl2. 2H2O (25.57 g, 0.11 mole) in ethanol (46.5 ml) was heated at reflux for 45 minutes. The reaction mixture was poured onto ice/H2O (180 g), made basic (pH 10-11) with 50% sodium hydroxide solution, and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate, and evaporated in vacuo to obtain 3.88 g of the title A compound as a brown oil.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)[C:4]=1[CH3:18])=[O:2].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:18][C:4]1[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:11]([C:12]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)=[O:14])[CH:10]=2)=[C:6]([CH3:8])[NH:7][C:3]=1[CH:1]=[O:2]
Reactant: Cc1[nH]c(C=O)c(C)c1-c1cccc(C(=O)O)c1
Reactant: CN1CCNCC1
Product: Cc1[nH]c(C=O)c(C)c1-c1cccc(C(=O)N2CCN(C)CC2)c1

Procedure:
3-(5-Formyl-2,4-dimethyl-1H-pyrrol-3-yl)-benzoic acid was reacted with 1-methylpiperazine using General Amidation Procedure 1 to give 3,5-dimethyl-4-[3-(4-methyl-piperazine-1-carbonyl)-phenyl]-1H-pyrrole-2-carbaldehyde. MS m/z 326 [M+1].
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[C:16]1([CH3:25])[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>>[CH3:25][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(I)cc1
Reactant: Cc1ccccc1B(O)O
Product: CCOC(=O)/C=C(\C)c1ccc(-c2ccccc2C)cc1

Procedure:
The colourless solid, (E)-ethyl 3-(2′-methyl-biphenyl-4-yl)-but-2-enoate was prepared from (E)-ethyl 3-(4-iodophenyl)-but-2-enoate (example 91a) and ortho-tolyl boronic acid by a procedure analogous to that described in example 91b.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[C:19](=O)[CH2:18][O:17][CH:16]([CH2:21][O:22][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]3[C:31]=2[CH2:30][CH:29]=[CH:28]3)[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[CH2:7]([N:14]1[CH2:19][CH2:18][O:17][CH:16]([CH2:21][O:22][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]3[C:31]=2[CH2:30][CH:29]=[CH:28]3)[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1COC(COc2cccc3c2CC=C3)CN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C1=Cc2cccc(OCC3CN(Cc4ccccc4)CCO3)c2C1
Yield: 89 %

Procedure:
In 300 ml. of anhydrous tetrahydrofuran was suspended 20 g. of lithium aluminum hydride and after adding slowly to the suspension a solution prepared by dissolving 8.0 g. of 4-benzyl-2-(7-indenyloxymethyl)morpholin-5-one in 50 ml. of tetrahydrofuran, the mixture was treated in a similar manner as in Example 1 to provide 6.8 g. (yield 89%) of oily 4-benzyl-2-(7-indenyloxymethyl)morpholine.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C@H:14]([C:16]([O:18]CCCC)=O)[O:13][C:12]3=[O:23])=[CH:10][C:5]=2[S:4][C:3]1=[O:24].Cl.[F:26][CH2:27][CH2:28][NH2:29]>N1C=CC=CC=1.C(Cl)Cl>[F:26][CH2:27][CH2:28][NH:29][C:16]([C@@H:14]1[O:13][C:12](=[O:23])[N:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3](=[O:24])[S:4][C:5]=3[CH:10]=2)[CH2:15]1)=[O:18]
Reactant: CCCCOC(=O)[C@H]1CN(c2ccc3c(c2)sc(=O)n3C)C(=O)O1
Reactant: NCCF
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1c(=O)sc2cc(N3C[C@H](C(=O)NCCF)OC3=O)ccc21
Temperature: 90 °C

Procedure:
A solution of butyl(5R)-3-(2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate (EXAMPLE 29, Step 2, 985 mg, 2.81 mmol) in pyridine (5.5 mL) in a thick-walled, screw-cap vial is treated with fluoroethylamine hydrochloride (2.20 g, 22.1 mmol), and the stirred reaction mixture is placed in an oil bath maintained at 90° C. for 24 h. The mixture is then cooled to ambient temperature, diluted with CH2Cl2 (50 mL), washed with 0.2 M hydrochloric acid (25 mL portions, until the washings are at pH<2) and saline (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is chromatographed on a Flash 40M 90 g silica gel cartridge with MeOH/CH2Cl2 (1/99-2.5/97.5). Those fractions with an Rf=0.32 by TLC (MeOH/CHCl3, 5/95) are pooled and concentrated and the residue triturated and filtered from MeOH to give the title compound, mp 201-203° C.; MS (ESI−) for C14H14N3O4FS m/z 338 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][N:25]([CH3:42])[C:26]1[C:27]([CH3:41])=[N:28][CH:29]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:31]=1>>[CH3:24][N:25]([CH3:42])[C:26]1[CH:31]=[C:30]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:29]=[N:28][C:27]=1[CH3:41]
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N(C)C
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1N(C)C

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and dimethyl-[2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine (Stage 164.1.1) to give the title compound as an off-white foam. (HPLC: tR 2.15 min (Method A); M+H=428 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.30-8.27 (m, 1H), 8.13-8.08 (m, 2H), 7.99-7.94 (m, 1H), 7.59-7.56 (m, 1H), 7.33-7.30 (m, 1H), 3.88 (s, 3H), 3.58 (s, 3H), 2.72 (s, 6H), 2.50 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](OCC)=[C:8]2[C:14]([CH3:15])=[N:13][O:12][C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22]>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:23][CH2:19][CH2:20][CH2:21][CH3:22])=[C:8]2[C:14]([CH3:15])=[N:13][O:12][C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2onc(C)c2c1OCC
Reactant: CCCCN
Solvent: c1ccccc1
Product: CCCCNc1c(C(=O)OCC)cnc2onc(C)c12

Procedure:
25 g. of 4-ethoxy-3-methylisoxazolo[5,4-b]pyridine-5-carboxylic acid ethyl ester (0.113 mol.) are dissolved in 100 ml. of benzene and after adding 8 g. of butylamine (0.23 mol.), the solution is refluxed for 12 hours. The solvent is distilled off and the residual 4-butylamino-3-methylisoxazolo[5,4-b]pyridine-5-carboxylic acid ethyl ester is recrystallized from ligroin, m.p. 60°, yield 23.5 g. (85%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([Br:13])[C:8]([I:14])=[C:7]([CH3:15])[C:3]=1[C:4]([OH:6])=[O:5].[O:16]1CCC[CH2:17]1>>[Br:13][C:9]1[C:8]([I:14])=[C:7]([CH3:15])[C:3]2[C:4](=[O:6])[O:5][C:17](=[O:16])[NH:1][C:2]=2[C:10]=1[O:11][CH3:12]
Reactant: C1CCOC1
Reactant: COc1c(N)c(C(=O)O)c(C)c(I)c1Br
Product: COc1c(Br)c(I)c(C)c2c(=O)oc(=O)[nH]c12
Temperature: 40 °C
Reaction time: 1 h

Procedure:
According to the same method as in Reference Example 31, 2-amino-4-bromo-5-iodo-3-methoxy-6-methylbenzoic acid (I-4) (3.42 g, 8.86 mmol) and bis(trichloromethyl) carbamate (893 mg, 3.01 mmol) were dissolved in dewatered tetrahydrofuran (70 ml) under nitrogen atmosphere, followed by stirring at 40° C. for 1 hour. The reaction liquid was concentrated under reduced pressure to obtain the entitled compound (3.89 g, quant.) as a pale brown solid. Not further purified, this was used in the next reaction.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Br:9])[N:3]=1.[OH:10][C:11]([C@@H:18]1[CH2:23][CH2:22][C@H:21]([C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])[CH2:20][CH2:19]1)([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)[CH3:12].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C(C)(C)C>C(OCC)(=O)C.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.CN(C)C(=O)C>[Br:9][C:4]1[N:3]=[C:2]([C:15]2[S:14][C:13]([C:11]([C@@H:18]3[CH2:23][CH2:22][C@H:21]([C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])[CH2:20][CH2:19]3)([OH:10])[CH3:12])=[N:17][CH:16]=2)[CH:7]=[C:6]([CH3:8])[CH:5]=1
Reactant: Cc1cc(Br)nc(Br)c1
Reactant: CCCCOC(=O)[C@H]1CC[C@@H](C(C)(O)c2nccs2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCCOC(=O)[C@H]1CC[C@@H](C(C)(O)c2ncc(-c3cc(C)cc(Br)n3)s2)CC1

Procedure:
To a vial were added 2,6-dibromo-4-methylpyridine (121 mg, 0.482 mmol), cis-butyl 4-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]cyclohexanecarboxylate (75 mg, 0.241 mmol), potassium carbonate (100 mg, 0.722 mmol), pivalic acid (5.59 μl, 0.048 mmol), tetrakis(triphenylphosphine)palladium(0) (11.1 mg, 9.63 μmol) and N,N-dimethylacetamide (760 μl). The vial was sealed and placed under argon through 3 cycles of evacuation and argon flushing then reacted at 80° C. overnight. The resulting mixture was cooled, diluted with ethyl acetate, filtered through a plug of CELITE and concentrated. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate/hexanes) to afford racemic-cis-butyl 4-{1-[5-(6-bromo-4-methylpyridin-2-yl)-1,3-thiazol-2-yl]-1-hydroxyethyl}-cyclohexanecarboxylate.