Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:22][C:23]1[N:28]=[CH:27][C:26]2[C:29](=O)[O:30][CH:31]([CH2:32][CH3:33])[C:25]=2[C:24]=1[Cl:35].Cl>C1COCC1>[Cl:22][C:23]1[N:28]=[CH:27][C:26]2[C:29](=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[O:30][CH:31]([CH2:32][CH3:33])[C:25]=2[C:24]=1[Cl:35]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CCC1OC(=O)c2cnc(Cl)c(Cl)c21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1OC(=C2C(=O)Nc3ccc(F)cc32)c2cnc(Cl)c(Cl)c21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 35 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (1.44 g, 9.52 mmol.) in THF (10 mL) is cooled to 0° C. under an Argon atmosphere and treated with a solution of lithium bis(trimethylsilyl)amide (19 mL of a 1 M solution in THF, 19.0 mmol) dropwise. The resulting solution is stirred at 0° C. for 10 min and then warmed room temperature. A solution of 6,7-dichloro-1-ethyl-1H-furo[3,4-c]pyridin-3-one (1.47 g, 6.33 mmol) in THF (9 mL) is added dropwise to the reaction mixture and the reaction mixture is stirred for 4 h. The reaction mixture is poured into aqueous 10% HCl solution (200 mL). The resulting mixture is heated to 100° C. for 2 h and then stirred at room temperature for 36 h. The precipitate which formed is collected by filtration, washed with small volumes of ethyl acetate (10×3 mL) and dried under vacuum to give the title compound as a yellow solid (810 mg, 35%).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([NH:15][C@H:16]([CH2:20][CH3:21])[C@H:17]([OH:19])[CH3:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:22][CH2:23][C:24](Cl)=[O:25]>ClCCl>[CH2:8]([N:15]([C@H:16]([CH2:20][CH3:21])[C@H:17]([OH:19])[CH3:18])[C:24](=[O:25])[CH2:23][Cl:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC[C@@H](NCc1ccccc1)[C@@H](C)O
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H]([C@@H](C)O)N(Cc1ccccc1)C(=O)CCl
Temperature: -40 °C
Reaction time: 1 h

Procedure:
Triethylamine (0.43 mL, 3.4 mmol) was added to a −40° C. solution of (2R,3R)-3-(benzylamino)pentan-2-ol (220 mg, 1.1 mmol) in dichloromethane (100 mL), followed by the addition of 2-chloroacetyl chloride (0.10 mL, 1.1 mmol) dropwise. The reaction mixture was stirred at −40° C. for 1 hour and then quenched with saturated NaHCO3 solution. The layers were separated, and the aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification of the residue on a silica gel column (0 to 50% EtOAc/hexanes) afforded N-benzyl-2-chloro-N-((2R,3R)-2-hydroxypentan-3-yl)acetamide. MS APCI calc'd for C14H20ClNO2 [M+H]+ 270. found 270.
Reaction SMILES: C([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([CH2:13][O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[OH:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([CH2:13][O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: [H][H]
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc2n(c(=O)c1O)CCOC2
Yield: 93.3 %

Procedure:
A solution of intermediate 6, ethyl 3-benzyloxy-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate, (0.236 g, 0.714 mmol) in a mixture of ethyl acetate (60 ml) and ethanol (20 ml) was treated with 1 atm of hydrogen at 25° C. over 10% palladium on activated carbon (0.10 g) for 2.5 h to give 0.160 g (94% yield) of the title compound as white needles; mp 172–174° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ ppm: 1.47 (3H, t, J=7.3 Hz, CH3), 4.08 (4H, m, 2×CH2), 4.54 (2H, q, J=7.3 Hz, OCH2), 4.72 (2H, s, OCH2), 10.75 (1H, s, OH). Anal. Calcd for C10H12N2O5: C, 50.00; H, 5.03; N, 11.66. Found: C, 50.01; H, 4.95; N, 11.54.
Reaction SMILES: C(O[C:6]1([F:38])[C:33](CC=O)=[CH:32][C:31]([F:37])=[CH:30][CH:7]1[O:8][CH2:9][CH2:10][C@@H:11]1[CH2:13][C@@H:12]1[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:16][CH2:15]1)(C)(C)C.[C:39]([OH:45])([C:41](F)(F)F)=[O:40]>ClCCl>[CH2:23]([O:22][C:20]([N:17]1[CH2:16][CH2:15][CH:14]([C@H:12]2[CH2:13][C@H:11]2[CH2:10][CH2:9][O:8][C:7]2[C:6]([F:38])=[CH:33][C:32]([CH2:41][C:39]([OH:45])=[O:40])=[C:31]([F:37])[CH:30]=2)[CH2:19][CH2:18]1)=[O:21])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC1(F)C(CC=O)=CC(F)=CC1OCC[C@@H]1C[C@@H]1C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: ClCCl
Product: O=C(O)Cc1cc(F)c(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OCc3ccccc3)CC2)cc1F
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Benzyl 4-{(1R,2S)-2-[2-(2-tert-butoxy-2-oxoethyl-2,5-difluorophenoxy)ethyl]cyclopropyl}piperidine-1-carboxylate (0.350 g, 0.661 ml) was dissolved in dichloromethane (1.5 ml) and TFA (1.5 ml) added. The mixture was stirred at RT for 3.5 h and the volatiles removed under vacuum to afford the title compound. LC/MS (m/z): 474.3 (M+H)+.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:14]=[C:15]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][C:22]=2[CH3:31])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].C(Br)(Br)(Br)[Br:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:33][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:14]=[C:15]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][C:22]=2[CH3:31])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CO)c2)c(C)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CBr)c2)c(C)c1
Temperature: 25 °C

Procedure:
To a 0° C. solution of methyl 2″-(hydroxymethyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (1.500 g, 3.49 mmol) in CH2Cl2 (14 mL) was added CBr4 (2.429 g, 7.33 mmol), and then a solution of triphenyl phosphine (1.830 g, 6.98 mmol) in CH2Cl2 (15 mL). The solution was warmed to room temperature and stirred for twelve hours. The reaction was concentrated, and the residue was purified by flash chromatography on silica gel (0 to 25% EtOAc/hexanes) to afford methyl 2″-(bromomethyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate. Rf=0.59 (50% EtOAc/hexanes). LCMS=494.8 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.95 (s, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.80 (s, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.40-7.33 (m, 3H), 7.21 (d, J=2.3 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 4.44-4.39 (m, 2H), 3.93 (s, 3H), 3.82 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[CH2:16][C@H:17]([N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29])[CH3:18]>>[O:29]=[C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27](=[O:28])[N:19]1[C@H:17]([CH3:18])[CH2:16][N:12]1[CH:13]=[CH:14][C:10]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([CH3:1])[CH:9]=2)=[N:11]1
Reactant: Cc1cc(-c2cc[nH]n2)ccc1C#N
Reactant: C[C@H](CBr)N1C(=O)c2ccccc2C1=O
Product: Cc1cc(-c2ccn(C[C@@H](C)N3C(=O)c4ccccc4C3=O)n2)ccc1C#N
Yield: 16.7 %

Procedure:
2-Methyl-4-(1H-pyrazol-3-yl)benzonitrile (2.23 g, 12.2 mmol) was reacted with (R)-2-(1-bromopropan-2-yl)isoindoline-1,3-dione (3.92 g, 14.6 mmol) using the method of Example 27(a). Crude product was purified by chromatography (CombiFlash, silica column, eluent: 0-100% EtOAc/heptane) to yield 0.753 g (17%) of the title compound. Product was used in the next step without analysis.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15]S(C3C=CC(C)=CC=3)(=O)=O)=[C:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:36][C:37]([CH3:42])=[CH:38][CH2:39][CH2:40]O.N>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:40][CH2:39][CH:38]=[C:37]([CH3:42])[CH3:36])=[C:11]([C:26]3[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)=CCCO
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)cc3)c2=O)cc1
Agent: N
Product: CC(C)=CCCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared according to the method of Example 335, substituting 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 4-methyl-3-penten-1-ol in place of isobutanol (yield: 0.1165 g, 77%). mp 111-114° C. 1H NMR (300 MHz, DMSO d6) δ 1.46 (s, 3H), 1.56 (s 3H), 2.26 (m, 2H), 3.30 (s, 1H), 4.43 (t, J=7 Hz, 2H), 4.96 (m, 1H), 7.37 (m, 2H), 7.65 (m, 2H), 7.91 (m, 2H), 8.06 (m, 2H), 8.18 (s, 1H). MS (DCI/NH3) m/z 443 (M+H)+, 460 (M+NH4)+. Anal. calc. for C23H23FN2O4S: C, 62.43; H, 5.24; N, 6.33. Found: C, 62.32; H, 5.30; N, 6.25.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:3].[S:17]1[CH:21]=[C:20]([C:22]2[NH:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)[N:19]=[CH:18]1>N1C=CC=CC=1>[CH:6]1([CH2:5][O:4][C:2]([N:26]2[C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[N:23]=[C:22]2[C:20]2[N:19]=[CH:18][S:17][CH:21]=2)=[O:3])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: c1ccc2[nH]c(-c3cscn3)nc2c1
Reactant: O=C(Cl)OCC1CCCCCCCCCC1
Solvent: c1ccncc1
Product: O=C(OCC1CCCCCCCCCC1)n1c(-c2cscn2)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
20.3 G. (0.082 moles) of cycloundecylmethyl chloroformate is added dropwise at room temperature to 16.4 g. (0.082 moles) of 2-(4-thiazolyl)-benzimidazole suspended in 200 ml. of pyridine. The temperature rises spontaneously to 35° C and the reaction mixture is then stirred overnight at room temperature, filtered and the filtrate evaporated to dryness in vacuo. The residue is treated with methylene chloride and washed 3 times with 2.5N hydrochloric acid and twice with water. The methylene chloride is treated with charcoal, filtered and evaporated to dryness in vacuo affording 25 g. of an oil which solidifies on standing and is recrystallized from hexane affording 20 g. of 1-cycloundecylmethoxycarbonyl-2-(4-thiazolyl)-benzimidazole, melting point 86° to 87° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C@H:6]([CH2:13][CH3:14])[N:5]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:4]=2[N:3]=1.[C:20]1(C)C=CC(S(OC)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:20])[C:7](=[O:12])[C@H:6]([CH2:13][CH3:14])[N:5]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:4]=2[N:3]=1
Reactant: CC[C@H]1C(=O)Nc2cnc(Cl)nc2N1C1CCCC1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC[C@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Reaction time: 12 h
Yield: 84.8 %

Procedure:
(7S)-2-Chloro-8-cyclopentyl-7-ethyl-5,7-dihydropteridin-6-one 41e (2.80 g, 10 mmol) was dissolved in 50 mL of acetone followed by the addition of methyl p-toluenesulfonate (2.80 g, 15 mmol) and potassium carbonate (2.76 g, 20 mmol) successively, stirred for 12 hours. The resulting solution was added with 50 mL of water and extracted with ethyl acetate (100 mL×3). The combined organic phase was washed with water (20 mL) and saturated sodium chloride solution (20 mL) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure, The resulting residue was purified by silica gel column chromatography with elution system B to obtain the title compound (7S)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-7H-pteridin-6-one 41f (2.50 g, yield: 85.0%) as a white solid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=[O:11].OS(O)(=O)=O.[CH3:18]O>>[CH3:18][O:11][C:10]([CH:2]1[CH2:1][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)=[O:12]
Reactant: CO
Reactant: O=C(O)C1Cc2ccccc2C1
Agent: O=S(=O)(O)O
Product: COC(=O)C1Cc2ccccc2C1
Yield: 95 %

Procedure:
Indan-2-carboxylic acid (2.0 g, 12.34 mmol) was dissolved in MeOH (50 mL) and was then treated with H2SO4 (1 mL). The reaction mixture was refluxed overnight. MeOH was evaporated and the residue was diluted with water and ether. Layers were separated and the aqueous layer was extracted with ether (2×30 mL). The combined organics were dried with MgSO4 and condensed to afford the product (2.01 g, 95%) as white crystals.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[S:17]([C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23])(=[O:19])=[O:18]>C(Cl)Cl>[CH2:1]([NH:8][S:17]([C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23])(=[O:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Reactant: NCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1S(=O)(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 12.6 %

Procedure:
To a solution of benzylamine 42 (0.140 mL, 1.278 mmol) in DCM (2.557 mL) was added triethylamine (0.535 mL, 3.84 mmol) and methyl 2-(chlorosulfonyl)benzoate 41 (300 mg, 1.278 mmol) and the resulting colorless solution was stirred at rt for 20 h. The reaction mixture was partitioned between DCM and H2O. The organic layer was washed with 1M HCl, saturated NaHCO3, and brine, dried over MgSO4, filtered and concentrated. The crude mixture was purified by Biotage using EtOAc/Hex ((20:80 to 40:60); 25+S column) to afford compound 43 (49 mgs, 13% yield) as a colorless oil. LRMS (ESI): (calc.) 305.07 (found) 306.2 (MH)+
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][N:7]([CH3:11])[C:8]([NH2:10])=[NH:9].[F:12][C:13]([F:18])([F:17])[C:14](O)=O>>[CH3:11][N:7]1[C:8]([NH2:10])=[N:9][C:14]([C:13]([F:18])([F:17])[F:12])=[N:6]1
Reactant: CN(N)C(=N)N
Reactant: O=C(O)C(F)(F)F
Agent: O=S(=O)(O)O
Product: Cn1nc(C(F)(F)F)nc1N

Procedure:
1-Amino-1-methyl guanidine sulphate (12.3 g) and trifluoroacetic acid (16 ml) were heated at reflux for 96 h. Excess trifluoroacetic acid was removed by distillation and the residue was basified with sodium bicarbonate and extracted with ethyl acetate. The extract was dried and evaporated to give a white solid (7.2 g) which was recrystallised from a mixture of methyl acetate (8 ml) and petroleum ether (b.p. 60°-80°) (20 ml) to give the title compound as a white powder (5.1 g) m.p. 165°-166°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[Br:22]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([CH2:10][Br:22])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(C)ccc1NC(=O)c1ccc(Cl)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COC(=O)c1cc(CBr)ccc1NC(=O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of compound 11.1 (1.0 mmol) in benzene (2.0 mL) is added N-bromosuccinimide (1 equivalent) and benzoyl peroxide (0.33 equivalent). The reaction mixture is refluxed overnight under N2. After cooling to room temperature, the solution is diluted with EtOAc, washed with H2O, brine, dried, filtered and concentrated under reduced pressure. The crude product is purified by flash column chromatography on silica gel to provide 5-bromomethyl-2-(4-chloro-benzoylamino)-benzoic acid methyl ester (compound 11.2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.CCOC(C)=O.O=[Pt]=O>[C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)[CH2:12]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=Cc1ccc(Cl)c(Cl)c1)C2
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C2CCC1CC(Cc1ccc(Cl)c(Cl)c1)C2
Yield: 84 %

Procedure:
3-(3,4-Dichloro-benzylidene)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.0 g, 2.7 mmol) in 10 mL of EtOH and 10 mL of EtOAc was stirred with 25 mg of PtO2 under 1 atm of H2 at rt for 3 h. It was then filtered through a celite bed and the filtrate was concentrated. The residue was purified on a silica gel column to give 0.84 g of 3-(3,4-dichloro-benzyl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (M++1: 370).
Reaction SMILES: [Br:1][C:2]1[C:6]([CH:7]=O)=[C:5](Br)[N:4]([CH:10]([O:12][CH2:13][CH3:14])[CH3:11])[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[SH:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(O)C>[Br:1][C:2]1[C:6]2[CH:7]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[S:21][C:5]=2[N:4]([CH:10]([O:12][CH2:13][CH3:14])[CH3:11])[N:3]=1
Reactant: CCOC(=O)CS
Reactant: CCOC(C)n1nc(Br)c(C=O)c1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc2c(Br)nn(C(C)OCC)c2s1
Yield: 88.4 %

Procedure:
1.19 g (3.81 mmol) of 3,5-dibromo-1-(1-ethoxyethyl)-1H-pyrazole-4-carboxaldehyde are introduced with stirring into 50 cm3 of ethanol under an argon atmosphere, at a temperature in the region of 20° C., followed by addition of 0.4 g (3.81 mmol) of sodium carbonate and 0.42 cm3 (3.81 mmol) of ethyl 2-mercaptoacetate. The reaction mixture is then refluxed for 2 hours, and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 60 cm3 of water and 60 cm3 of dichloromethane, and the phases are separated by settling. The organic phase is dried over magnesium sulfate and then concentrated to dryness under reduced pressure (2.7 kPa). 1.17 g of ethyl 3-bromo-1-(1-ethoxyethyl)-1H-thieno[2,3-c]pyrazole-5-carboxylate are thus obtained in the form of a clear yellow oil that crystallizes to give cream-colored crystals melting at 69° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[C:8]1[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=1.[CH2:18]([O:25][C:26](=[O:36])[NH:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH:31]([NH2:35])[CH2:30]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:18]([O:25][C:26](=[O:36])[NH:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH:31]([NH:35][C:13]([C:12]2[C:8]([C:7]3[C:6]([Cl:17])=[CH:5][N:4]=[CH:3][C:2]=3[Cl:1])=[N:9][O:10][C:11]=2[CH3:16])=[O:15])[CH2:30]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1onc(-c2c(Cl)cncc2Cl)c1C(=O)O
Reactant: NC1CCCC(CNC(=O)OCc2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2c(Cl)cncc2Cl)c1C(=O)NC1CCCC(CNC(=O)OCc2ccccc2)C1
Yield: 82.5 %

Procedure:
Combine 3-(3,5-dichloro-pyridin-4-yl)-5-methyl-isoxazole-4-carboxylic acid (0.41 g, 0.0015 mol) with (3-amino-cyclohexylmethyl)-carbamic acid benzyl ester (0.45 g, 0.0015 mol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.29, 0.0015 mol), 1-hydroxy-7-azabenzo-triazole (0.20 g, 0.0015 mol), and N,N-diisopropylethyl amine (0.78 mL, 0.0045 mol), in N,N-dimethylformamide (10 mL) and stir over a weekend at ambient temperature. Concentrate the mixture in vacuo and take up in water and extracte with ethyl acetate. Dry over sodium sulfate. Concentrate and elute over silica gel using methanol/dichloromethane to give 0.64 g (82%) of the desired amide as a white foam. MS(ES): (M+1)+ 516.9, 518.9 m/z.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:11]2[S:12][C:13]3[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:5][CH:4]=1)#[N:2].[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[S:31](Cl)(=[O:33])=[O:32])[CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][S:10][C:11]2[S:12][C:13]3[CH:19]=[C:18]([NH:20][S:31]([C:29]4[CH:28]=[CH:27][CH:26]=[C:25]5[C:30]=4[N:21]=[CH:22][CH:23]=[CH:24]5)(=[O:32])=[O:33])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: N#Cc1ccc(CSc2nc3ccc(N)cc3s2)cc1
Solvent: c1ccncc1
Product: N#Cc1ccc(CSc2nc3ccc(NS(=O)(=O)c4cccc5cccnc45)cc3s2)cc1

Procedure:
A mixture of 2.3 g (7.74 mmol) of 2-[(4-cyanophenyl)methylthio]-6-amino-benzothiazole and 1.85 g (8.1 mmol) of quinoline-8-sulphonic acid chloride is stirred in 30 ml of pyridine for 2 hours at ambient temperature. Then the solvent is distilled off in vacuo and the crude product is purified by flash chromatography (silica gel, methylene chloride/ethanol=99:1).
Reaction SMILES: [C:1]([C:3]1[C:4]([N:18]([CH3:20])[CH3:19])=[N:5][S:6][C:7]=1[NH:8][C:9](=[O:17])OC1C=CC=CC=1)#[N:2].[CH3:21][N:22](C)[CH:23]=O>>[CH3:21][N:22]([CH3:23])[C:9]([NH:8][C:7]1[S:6][N:5]=[C:4]([N:18]([CH3:20])[CH3:19])[C:3]=1[C:1]#[N:2])=[O:17]
Reactant: CN(C)C=O
Reactant: CN(C)c1nsc(NC(=O)Oc2ccccc2)c1C#N
Product: CN(C)C(=O)Nc1snc(N(C)C)c1C#N

Procedure:
In a pressure bottle were placed 6.1 g of phenyl (4-cyano-3-(dimethylamino)-5-isothiazolyl)carbamate and 25 ml of dimethylformamide. This solution was cooled to 0°, and 2.8 ml (1.9 g) of dimethylamine (previously collected in a graduated dropping funnel using a dry-ice trap) were added. The reaction mixture was heated at 80° for 4 hours, cooled to -10° and the bottle was opened. The reaction mixture was concentrated to dryness under vacuum to give a tan solid. Recrystallization of the tan solid from ethanol gave 4.0 g of 1,1-dimethyl-3-(4-cyano-3-(dimethylamino)-5-isothiazolyl)urea, m.p. 203°-204°. A second crop was collected and was recrystallized from ethanol to give 0.2 g of needles; m.p. 201°-202°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:27])[C:9]1[CH:26]=[CH:25][C:12]([CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:38])[CH:36]=[CH2:37]>>[C:35]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:27])[C:9]1[CH:26]=[CH:25][C:12]([CH:13]=[CH:14][C:15]2[CH:16]=[CH:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)(=[O:38])[CH:36]=[CH2:37]
Reactant: CN(CCCCCCO)c1ccc(C=Cc2ccc(S(C)(=O)=O)cc2)cc1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCCCCCN(C)c1ccc(C=Cc2ccc(S(C)(=O)=O)cc2)cc1
Yield: 36.9 %

Procedure:
A mixture of 4'-[(6-hydroxyhexyl)methylamino]-4-methylsulfonylstilbene (5.00 g, 12.9 mmol) was treated with triethylamine (1.63 g, 16.2 mmol) and acryloyl chloride (1.46 g, 16.2 mmol) as above. The product was purified by chromatography on silica gel (CH2CL2 eluent) and recrystallization from acetone/hexanes to yield 2.10 g (37%) of a yellow solid, mp 88°-90° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:25](=[O:36])[NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=3)=[C:11]([CH:22]([CH3:24])[CH3:23])[N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].O>CCO>[F:35][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][C:31]=1[F:34])[CH2:27][NH:26][C:25]([C:10]1[C:9]2[C:13](=[CH:14][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=2)[N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:11]=1[CH:22]([CH3:24])[CH3:23])=[O:36]
Reactant: CCOC(=O)c1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccn3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C(=O)O)cc2n1Cc1ccccn1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
Following General Procedure F, ethyl3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1 H-indole-6-carboxylate (Compound 45, 117 mg, 0.238 mmol) in EtOH (10 ml) was added NaOH (47 mg, 1.20 mmol) and H2O (1 ml). The reaction was stirred at 50° C. for 12 h, concentrated in vacuo to an oil then acidified to PH=5 with 10% HCl, diluted with EtOAc, washed organic with H2O, brine, dried over Na2SO4 and concentrated in vacuo to yield the title compound as a light yellow solid.