Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].[N+:13]([CH:16](C(OC)=O)[C:17]([O:19][CH3:20])=[O:18])([O-])=[O:14].F[P-](F)(F)(F)(F)F.C([N+]1C=CN(C)C=1)CCC>C1(C)C=CC=CC=1>[CH2:3]([C:2]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[N:13][O:14][C:1]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCC#Cc1ccccc1
Reactant: COC(=O)C(C(=O)OC)[N+](=O)[O-]
Agent: CCCC[n+]1ccn(C)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1ccccc1
Product: CCCCc1c(C(=O)OC)noc1-c1ccccc1
Yield: 34 %

Procedure:
A solution of hex-1-ynylbenzene (0.274 mL, 1.56 mmol), dimethyl 2-nitromalonate (0.421 mL, 3.12 mmol), 1-butyl-3-methylimidazoliumhexafluorophosphate (0.032 mL, 0.156 mmol) in toluene (6 mL) was subjected to the microwave at 170° C. for 150 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography using 5% ethyl acetate in hexane to give methyl 4-butyl-5-phenylisoxazole-3-carboxylate (0.142 g, 0.531 mmol, 34.1% yield) as a clear, colorless oil. The product was 97% pure by HPLC with a ret. time=3.11 min.−Column. CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=260.2.
Reaction SMILES: [C:1]([NH:20][C@H:21]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:48](Br)[CH:49]=[CH2:50]>C1COCC1>[CH2:50]([CH:23]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH2:22][C@@H:21]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[NH:20][C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:49]=[CH2:48]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(C[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 2 h
Yield: 100.8 %

Procedure:
A solution of di-tert-butyl N-trityl-L-glutamate (1.99 g, 1.85 mmol) in THF (50 mL) was cooled to −70° C. and a 1.0 M solution of lithium bis(trimethylsilyl)amide 47 mL, 47 mmol) in THF was added slowly (over a period of 20 min). The solution was stirred for 2 h at −70° C., and allyl bromide (1.44 g g, 11.9 mmol) was added drop wise at −70° C. After stirring for 1.5 h, the reaction mixture was quenched with saturated aqueous solution of NH4Cl, and warmed up to room temperature, and concentrated under vacuum. The resulting aqueous solution was extracted with dichloromethane, the combined organic phase was washed with water and was dried over sodium sulfate. After filtration, the solution was evaporated and the crude product was purified by flash chromatography (silica, ethyl acetate/n-hexane) to give the di-tert-butyl 4-allyl-N-trityl-L-glutamate (1.01 g, 46%) as a mixture of (4S,4S)/(2S,4R) diastereoisomers.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:10][C@H:11]([C:13]([OH:15])=[O:14])[CH3:12].C1(NN=CC2C=CC=CC=2O)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>O.[Cu]I.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][CH:11]([CH3:12])[C:13]([OH:15])=[O:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[C@H](N)C(=O)O
Reactant: Clc1ccc(I)cc1Cl
Agent: [Cu]I
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Temperature: 80 °C
Reaction time: 40 h
Yield: 83.9 %

Procedure:
A mixture of 3,4-dichloroiodobenzene (1.50 g, 5.50 mmol), L-alanine (734 mg, 8.25 mmol), copper(I) iodide, 2-hydroxybenzaldehyde phenylhydrazone (233 mg, 1.10 mmol), tri-potassium phosphate (3.50 g, 16.5 mmol), and N,N-dimethylformamide (8 mL) was stirred at 80° C. for 40 h, then after cooling diluted with water and acidified to pH 3 by addition of 37% aq. HCl solution. The mixture was extracted with EtOAc, the organic phase was washed with brine, dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; EtOAc) afforded the title compound (1.08 g, 67%) as a 71:29 mixture of the (S) and (R) stereoisomers (accordingly, when D-alanine was used instead of L-alanine as starting material, the title compound was obtained as a 29:71 mixture of the (S) and (R) stereoisomers). Brown solid, MS: 232.1 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:18])=[N:6][C:5]=2[N:19]=1.Cl[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:22][CH3:23]>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:12][OH:13])=[N:8][C:7]([S:18][CH:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:22][CH3:23])=[N:6][C:5]=2[N:19]=1
Reactant: CCC(Cl)c1ccccc1
Reactant: CC(C)C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Product: CCC(Sc1nc(N[C@@H](CO)CC(C)C)c2sc(N)nc2n1)c1ccccc1
Yield: 31 %

Procedure:
The title compound was synthesized as a mixture of two diastereomers by general method A from the reaction of (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol (30 mg, 100 μmol) with (1-chloropropyl)benzene (15.5 μL, 100 μmol) to give 13 mg (31% yield) as an oil.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:23][C@@H:24]1[S:30][C@@H:29]([C:31]([OH:33])=O)[CH2:28][C:27]2[CH:34]=[C:35]3[O:40][CH2:39][O:38][C:36]3=[CH:37][C:26]=2[C:25]1=[O:41].[NH2:42][C:43]1[CH:55]=[CH:54][C:46]([CH2:47][P:48](=[O:53])([O:51][CH3:52])[O:49][CH3:50])=[CH:45][CH:44]=1>CN(C)C=O.O>[CH3:50][O:49][P:48]([CH2:47][C:46]1[CH:54]=[CH:55][C:43]([NH:42][C:31]([C@H:29]2[CH2:28][C:27]3[CH:34]=[C:35]4[O:40][CH2:39][O:38][C:36]4=[CH:37][C:26]=3[C:25](=[O:41])[C@H:24]([CH3:23])[S:30]2)=[O:33])=[CH:44][CH:45]=1)([O:51][CH3:52])=[O:53]
Reactant: COP(=O)(Cc1ccc(N)cc1)OC
Reactant: C[C@@H]1S[C@@H](C(=O)O)Cc2cc3c(cc2C1=O)OCO3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COP(=O)(Cc1ccc(NC(=O)[C@H]2Cc3cc4c(cc3C(=O)[C@H](C)S2)OCO4)cc1)OC
Temperature: 0 °C
Reaction time: 15 h
Yield: 64.3 %

Procedure:
1-Hydroxybenzotriazole (HOBt) (0.51 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.69 g) were added to a solution of (2R,4S)-(−)-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxylic acid (0.84 g) and dimethyl 4-aminobenzylphosphonate (0.65 g) in N,N-dimethylformamide (DMF) (10 ml) at 0° C. This mixture was stirred at 0° C. for 1 hour and at room temperature for 15 hours, after which it was poured into water and extracted with ethyl acetate-tetrahydrofuran (3:1). The ethyl acetate layer was washed successively with 1N HCl , water, a saturated sodium hydrogencarbonate solution, water and brine, and dried (MgSO4), after which the solvent was distilled off. The residual solid was collected by filtration, followed by recrystallization from ethanol-hexane to yield (2R,4S)-(−)-N-[4-(dimethoxyphosphorylmethyl)phenyl]-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxamide (0.92 g, 64%). Colorless needles. Melting point 198-199° C. Optical rotation [α]D (23° C.) −198.8° (c=0.50, CHCl3).
Reaction SMILES: [Br:1][CH2:2][CH:3]1[O:9][CH2:8][CH:7]([OH:10])[CH:6]([OH:11])[CH2:5][O:4]1.[CH3:12][C:13]([CH3:15])=O>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(Cl)Cl>[Br:1][CH2:2][CH:3]1[O:4][CH2:5][CH:6]2[CH:7]([O:10][C:13]([CH3:15])([CH3:12])[O:11]2)[CH2:8][O:9]1
Reactant: OC1COC(CBr)OCC1O
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC1(C)OC2COC(CBr)OCC2O1
Reaction time: 9 h
Yield: 93 %

Procedure:
A mixture of 0.93 mol (211 g) of 2-bromomethyl-5,6-dihydroxy-1,3-dioxepane, 5.75 mol (422 ml) of acetone, 1.8 g of p-toluenesulphonic acid and 750 ml of methylene chloride was heated under reflux and the water formed was separated by means of a water separator. After about 9 h, the methylene chloride was drawn off in the rotary evaporator (filter pump), and the residue underwent fractional distillation under a medium high vacuum. At 89°-92° C. (0.5 mbar), 231 g of 4-bromomethyl-9,9-dimethyl-3,5,8,10-tetraoxabicyclo[5,3,0]decane (93% yield) were obtained as a colourless liquid which exhibited crystalline deposits in some cases at room temperature and was a mixture of isomers.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.C([Li])(C)(C)C.CCCCC.[CH2:20]([C:27]1([N:34]([CH3:36])[CH3:35])[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[S:1]1[C:5]([C:30]2([OH:33])[CH2:31][CH2:32][C:27]([CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([N:34]([CH3:36])[CH3:35])[CH2:28][CH2:29]2)=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: c1ccc2sccc2c1
Reactant: CN(C)C1(Cc2ccccc2)CCC(=O)CC1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CN(C)C1(Cc2ccccc2)CCC(O)(c2cc3ccccc3s2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 37.9 %

Procedure:
A solution of benzo[b]thiophene (1.50 mg, 3.73 mmol) in 20 ml dry THF was cooled to −5° C. under a stream of argon. tert-Butyllithium (4.47 mmol, 2.63 ml of a 1.7 molar pentane solution) was then added dropwise such that a reaction temperature of 0° C. was not exceeded during the addition. When the addition had ended the reaction mixture was stirred for two hours at 0° C. Thereafter, a solution of 4-benzyl-4-dimethylaminocyclohexanone (3.86 mg, 3.73 mmol) in dry THF (8 ml) was added dropwise at 0° C. The mixture was stirred for 15 minutes at 0° C. and then for five hours at room temperature. The reaction mixture was quenched with saturated ammonium chloride solution (30 ml), the organic phase was separated and the aqueous phase was extracted four times with methylene chloride (25 ml). The combined organic phases were dried over sodium sulfate and filtered and the solvent was removed in vacuo. Purification was carried out by means of flash chromatography over silica gel with cyclohexane/ethyl acetate (v/v=9:1). 517 mg 1-benzo[b]thiophen-2-yl-4-benzyl-4-dimethylaminocyclohexanol with a melting point of 128-131° C. were obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[C:3]=1[CH3:19].[CH3:20][C:21]1([CH3:36])[C:29]2[C:24](=[CH:25][C:26]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:27][CH:28]=2)[NH:23][CH2:22]1.[H-].[Na+]>CN(C=O)C>[CH3:20][C:21]1([CH3:36])[C:29]2[C:24](=[CH:25][C:26]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:27][CH:28]=2)[N:23]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[C:3]=2[CH3:19])[CH2:22]1
Reactant: CC1(C)CNc2cc(N3CCOCC3)ccc21
Reactant: Cc1c(-c2cccnc2)nc2cc(F)ccc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2cccnc2)nc2cc(F)ccc2c1N1CC(C)(C)c2ccc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure M using 4-chloro-7-fluoro-3-methyl-2-(pyridin-3-yl)quinoline (250 mg, 0.92 mmol), 4-(3,3-dimethylindolin-6-yl)morpholine (213 mg, 0.92 mmol) and sodium hydride (44 mg, 1.833 mmol) in DMF (2.0 mL) and heating the reaction at 120° C. for 3 h. After purification 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-indol-1-yl)-7-fluoro-3-methyl-2-(3-pyridinyl)-quinoline was obtained as a yellow film. 1H NMR (400 MHz, chloroform-d) δ ppm 8.90 (1H, br. s.), 8.66-8.81 (1H, m), 8.00 (1H, dt, J=7.8, 2.0 Hz), 7.89 (1H, dd, J=9.4, 5.9 Hz), 7.81 (1H, dd, J=10.0, 2.5 Hz), 7.48 (1H, dd, J=7.8, 4.7 Hz), 7.23-7.30 (1H, m), 7.09 (1H, d, J=8.2 Hz), 6.34 (1H, dd, J=8.2, 2.3 Hz), 5.61 (1H, d, J=2.3 Hz), 3.68-3.81 (6H, m), 2.90-3.02 (4H, m), 2.30 (3H, s), 1.52 (3H, s), 1.47 (3H, s). Mass Spectrum (ESI) m/e=469 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[C:8](=[O:20])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4].[CH3:21][Mg+].[Br-]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[C:8]([OH:20])([CH3:21])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4]
Reactant: COC(=O)c1nc2c(s1)C(=O)COc1ccc(Br)cc1-2
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)c1nc2c(s1)C(C)(O)COc1ccc(Br)cc1-2
Temperature: -70 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
To a stirred solution of 9-Bromo-4-oxo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (500 mg, 1.41 mmol) in THF (20 mL) at −70° C., was added MeMgBr (1.8 M in THF, 1.57 mL, 2.82 mmol) dropwise. The reaction was stirred at −70° C. for 3 h, and then warmed to −30° C. for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution at −30° C. and extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by flash column chromatography (silica gel, EtOAc in hexane from 0 to 30%) to give 9-Bromo-4-hydroxy-4-methyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester as a yellow solid (387 mg, 74%) LC-MS (ESI & APCI): 372.2 (M+2).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:28])[C:5]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[CH:6][N:7]2[CH2:16][C:17]([OH:19])=O.[NH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(N(CC)CC)C.C(OP(C#N)(=O)OCC)C>O.CN(C=O)C>[F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:28])[C:5]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[CH:6][N:7]2[CH2:16][C:17]([NH:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:19]
Reactant: NCCN1CCOCC1
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CC(=O)O)c12
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CC(=O)NCCN3CCOCC3)c12
Temperature: 25 °C
Reaction time: 23 h
Yield: 76.6 %

Procedure:
To a DMF solution (2 ml) of [5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]acetic acid (800 mg, 2.07 mmol) were sequentially added a DMF solution (1 ml) of 4-(2-aminoethyl)morpholine (273 mg), triethylamine (506 mg, 5.0 mmol), diethylphosphorocyanidate (DEPC, 405 mg, 2.48 mmol) and DMF (1 ml) while ice-cooling, followed by stirring at room temperature for 23 hours. Water was added to the reaction mixture and then subjected to extraction using ethyl acetate. The thus-obtained organic layer was washed with an aqueous saturated sodium chloride solution twice, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane:methanol=30:1→15:1). The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate, giving a white powder of 2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-N-(2-morpholin-4-ylethyl)acetamide (789 mg, yield: 77%).
Reaction SMILES: [CH2:1]1[C:14]2[C:15]3[C:16]4[C:11](=[CH:12][CH:13]=2)[CH2:10][CH2:9][CH2:8][C:7]=4[CH:6]=[C:5]([CH:17]=[O:18])[C:4]=3[CH2:3][CH2:2]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[CH:1]1[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[C:5]([CH:17]=[O:18])[C:4]3=[CH:3][CH:2]=1
Reactant: O=Cc1cc2c3c(ccc4c3c1CCC4)CCC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: O=Cc1cc2cccc3ccc4cccc1c4c32
Yield: 77.4 %

Procedure:
1,2,3,6,7,8-Hexahydro-4-pyrenecarbaldehyde (19A, 11.81 g, 50 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (Aldrich, 39.75 g, 0.175 mol) were refluxed for 4 h in 1 L of PhCH3. The reaction mixture was cooled and then filtered. The filtrate was washed with 2N NaOH (3×500 mL), satd. NaCl solution (2×500 mL), dried (Na2SO4), and passed through a plug of SiO2 (200 g). The solvent was then removed to give a bright yellow solid that was dried at 50° to give 8.91 g (77%) of 4-pyrenecarbaldehyde which was used without further purification. An analytical sample had mp 172°-174°, (CH2Cl2 /hexane), (C, H), (lit. mp 177°-179°, Y. E. Gerasimenko and I. N. Shevcbuk, Zh. Org. Khim. 4 2198 (1968)).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[CH2:14][CH2:15][OH:16])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[CH2:14][CH2:15][OH:16]
Reactant: CC(C)(C)OC(=O)Nc1ccncc1CCO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccncc1CCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
A solution of [3-(2-hydroxy-ethyl)-pyridin-4-yl]-carbamic acid tert-butyl ester (91 mg, 0.38 mmol) in CH2Cl2 (3 mL) was treated with TFA (2 mL) and stirred at room temperature for 3 hours. Concentrated under vacuum to provide 21 mg (23%) of desired product. MS (DCI) m/e 139 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[S:15][CH2:16][C:17]1[CH:22]=[C:21]([C:23](=[O:25])[CH3:24])[CH:20]=[CH:19][C:18]=1[O:26][CH3:27].[OH-].[Li+]>C1COCC1>[C:23]([C:21]1[CH:20]=[CH:19][C:18]([O:26][CH3:27])=[C:17]([CH:22]=1)[CH2:16][S:15][C:6]1[N:5]([CH2:4][C:3]([OH:28])=[O:2])[C:9]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=2[N:7]=1)(=[O:25])[CH3:24]
Reactant: COC(=O)Cn1c(SCc2cc(C(C)=O)ccc2OC)nc2ccc(F)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(C(C)=O)cc1CSc1nc2ccc(F)cc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.3 %

Procedure:
To a solution of methyl[2-(5-acetyl-2-methoxy-benzylsulfanyl)-6-fluoro-benzoimidazol-1-yl]-acetate (Precursor 6-F-H-11b, 11.3 mg, 0.029 mmol) in dry THF (0.3 ml) is added some 1 N aqueous lithium hydroxide solution (0.140 ml, 5 eq.). The resulting biphasic solution is allowed to stir 1 h at rt. The solvents are removed in vacuo, water is added as well as 1N HCl in water so as to set the pH of the aqueous solution to pH=1. The resulting acidic aqueous phase is extracted three times with AcOEt. The organic phase is dried over Na2SO4 and the solvent removed in vacuo and the product was dried under high vacuum. This yields the title compound (6 mg) in 55% as a greyish solid: tR=0.95 min (LC-3), ESI-MS (pos.): m/z 388.89 [M+H]+, ESI-MS (neg.): m/z 387.10 [M−H]+; 1H-NMR (DMSO-d6): δ (ppm) 2.40 (s, 3H, COCH3), 3.87 (s, 3H, OCH3), 4.49 (s, 2H, SCH2), 4.82 (s, 2H, CH2CO2), 7.01 (t, 1Harom), 7.09 (d, 1Harom), 7.42 (d, 1Harom), 7.53 (dd, 1Harom), 7.86 (d, 1Harom), 7.98 (s, 1Harom).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].Cl[C:10]1[C:15]2[O:16][CH2:17][CH2:18][N:19]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[C:14]=2[N:13]=[CH:12][N:11]=1>>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:10]1[C:15]2[O:16][CH2:17][CH2:18][N:19]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[C:14]=2[N:13]=[CH:12][N:11]=1
Reactant: Nc1ccncc1F
Reactant: CC(C)OC(=O)N1CCC(N2CCOc3c(Cl)ncnc32)CC1
Product: CC(C)OC(=O)N1CCC(N2CCOc3c(Nc4ccncc4F)ncnc32)CC1

Procedure:
By the procedure described in Example 3, with the exception that 3-fluoro-4-aminopyridine was used instead of 2-fluoro-4-(methylsulfonyl)aniline, isopropyl 4-(4-chloro-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate from Example 20A was converted into Example 121. 1H NMR (500 MHz, CDCl3) δ ppm 1.23 (d, J=6.60 Hz, 6H) 1.62 (s, 2H) 1.66-1.73 (m, 2H) 2.84-2.93 (m, 2H) 3.43-3.46 (m, 2H) 4.23-4.31 (m, 4H) 4.79-4.87 (m, 1H) 4.87-4.94 (m, 1H) 7.19 (d, J=3.30 Hz, 1H) 8.08 (s, 1H) 8.25 (d, J=6.05 Hz, 1H) 8.33 (d, J=2.20 Hz, 1H) 8.65-8.70 (m, 1H). LRMS (ESI): 417.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]([C:16]3[C:24]([Cl:25])=[CH:23][C:19]4[O:20][CH2:21][O:22][C:18]=4[CH:17]=3)[C:12]([O:14][CH3:15])=[O:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH:26](OC(C)C)(C)C>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]([C:16]3[C:24]([Cl:25])=[CH:23][C:19]4[O:20][CH2:21][O:22][C:18]=4[CH:17]=3)[C:12]([O:14][CH3:15])=[O:13])=[CH:7][N:8]2[CH3:26])=[CH:4][CH:3]=1
Reactant: CC(C)OC(C)C
Reactant: COC(=O)C(c1cc2c(cc1Cl)OCO2)c1c[nH]c2cc(Br)ccc12
Product: COC(=O)C(c1cc2c(cc1Cl)OCO2)c1cn(C)c2cc(Br)ccc12

Procedure:
The subtitle compound was prepared following the procedure of Example 92(d), using methyl 2-(6-bromo-1H-3-indolyl)-2-(6-chloro-1,3-benzodioxol-5-yl)acetate from step (c). m.p. 183-185° C., from diisopropyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH2:14][C:15]2[CH:25]=[CH:24][C:18]3[CH:19]=[C:20]([C:22]#[N:23])[O:21][C:17]=3[CH:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[N-:26]=[N+:27]=[N-:28].[Na+].[Cl-].[NH4+]>CN(C=O)C.O>[N:23]1[NH:26][N:27]=[N:28][C:22]=1[C:20]1[O:21][C:17]2[CH:16]=[C:15]([CH2:14][NH:13][C:4]3[CH:5]=[CH:6][C:7]([O:8][C:9]([F:10])([F:11])[F:12])=[C:2]([Br:1])[CH:3]=3)[CH:25]=[CH:24][C:18]=2[CH:19]=1
Reactant: N#Cc1cc2ccc(CNc3ccc(OC(F)(F)F)c(Br)c3)cc2o1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc(NCc2ccc3cc(-c4nn[nH]n4)oc3c2)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.5 %

Procedure:
6-(((3-bromo-4-(trifluoromethoxy)phenyl)amino)methyl)benzofuran-2-carbonitrile (651 mg, 1.58 mmol), sodium azide (0.12 g, 1.90 mmol) and ammonium chloride (0.10 g, 1.90 mmol) were dissolved in DMF (15.84 ml). The mixture was stirred at RT for 18 hr. After 18 hr the r×n was not complete and the reaction was heated to 50° C. for 2 hr. The reaction was cooled to RT and diluted with water (pH˜1). The crude material was extracted from the diluted aqueous pH=1 layer three times with a 10% MeOH/90% EtOAc mixture. The combined organic layers were washed 5× with pH=1 water to remove DMF and sodium azide, they were then washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude mixture was purified on basic HPLC (ammonium hydroxide modifier) 15-40% MeCN/Water to give N-((2-(2H-tetrazol-5-yl)benzofuran-6-yl)methyl)-3-bromo-4-(trifluoromethoxy)aniline (413 mg). LCMS retention time=1.35 minutes (LC method 1); MS (m+1)=454.2. 1H NMR (400 MHz, DMSO-d6) δ 4.39 (d, J=5.8 Hz, 2H), 6.66 (dd, J=9.0, 2.8 Hz, 1H), 6.83 (t, J=5.9 Hz, 1H), 6.93 (d, J=2.7 Hz, 1H), 7.08 (d, J=0.9 Hz, 1H), 7.17 (dd, J=9.2, 1.1 Hz, 1H), 7.25 (dd, J=8.0, 1.3 Hz, 1H), 7.54-7.64 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C:12]([CH2:15][OH:16])([CH3:14])[C:11](=[O:17])[NH:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH:18]1[CH:23]=[C:22]2[C:24]([O:26][S:27](=[O:29])(=[O:28])[C:21]2=[CH:20][CH:19]=1)=[O:25]>C(#N)C>[S:27]([C:21]1[CH:20]=[CH:19][CH:18]=[CH:23][C:22]=1[C:24]([O:16][CH2:15][C:12]1([CH3:14])[CH2:13][N:9]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)[NH:10][C:11]1=[O:17])=[O:25])([OH:29])(=[O:28])=[O:26]
Reactant: Cc1ccc(N2CC(C)(CO)C(=O)N2)cc1C
Reactant: O=C1OS(=O)(=O)c2ccccc21
Solvent: CC#N
Product: Cc1ccc(N2CC(C)(COC(=O)c3ccccc3S(=O)(=O)O)C(=O)N2)cc1C
Temperature: 25 °C
Yield: 76.6 %

Procedure:
To a suspension of {1-(3,4-dimethylphenyl)-4-hydroxymethyl-4-methyl-3-pyrazolidinone (10.0 g, 42.74 mmol) in dry acetonitrile (200 ml), was added 2-sulfobenzoic acid cyclic anhydride (7.86 g, 42.74 mmol) in a single portion at room temperature with stirring. The reaction mixture was heated to reflux under nitrogen for 22 hours until complete dissolution was observed. After cooling the mixture to room temperature, a heavy precipitate formed, which was recovered by filtration with suction. After washing with acetonitrile and drying under vacuum, 13.7 g (77%) of {1-(3,4-dimethylphenyl)-4-methyl-3-oxo-pyrazolidin-4-yl}methyl 2-sulfobenzoate (Compound III) were isolated in the form of a pale pink solid.