Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H][H].[OH:3][C:4]1[C:25]([CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])=[C:24]([O:31][CH3:32])[CH:23]=[C:22]([O:33][CH3:34])[C:5]=1[C:6](=[O:21])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][O:19][CH3:20])[CH:10]=1>[Pd].C(OCC)(=O)C>[OH:3][C:4]1[C:25]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[C:24]([O:31][CH3:32])[CH:23]=[C:22]([O:33][CH3:34])[C:5]=1[C:6](=[O:21])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][O:19][CH3:20])[CH:10]=1
Reactant: [H][H]
Reactant: COCOc1cc(C=CC(=O)c2c(OC)cc(OC)c(CC=C(C)C)c2O)ccc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCOc1cc(CCC(=O)c2c(OC)cc(OC)c(CCC(C)C)c2O)ccc1OC
Reaction time: 8 h
Yield: 87.2 %

Procedure:
To 40 ml of an ethyl acetate solution of 0.7 g of 5% palladium/carbon, in which hydrogen had been adsorbed in advance, was added 160 ml of an ethyl acetate solution of 5.0 g of the so-obtained 2'-hydroxy-4,4',6'-trimethoxy-3-methoxymethoxy-3'-(3-methyl-2-butenyl)chalcone, and hydrogen was further adsorbed with strong stirring. Then the mixture was stirred overnight, and the palladium/carbon was removed by using Celite and the solvent was removed by distillation. The residue was dissolved in diethyl ether and crystallized by addition of hexane to obtain 4.4 g (yield=91%) of 1-(2-hydroxy-4,6-dimethoxy-3-isopentylphenyl)-3-(4-methoxy-3-methoxymethoxyphenyl)-1-propanone in the form of a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:19]=[C:18]([NH:20][C:21]([NH:23][C:24]3[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=3)=[O:22])[CH:17]=[C:16]([F:31])[CH:15]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:31][C:16]1[CH:17]=[C:18]([NH:20][C:21]([NH:23][C:24]2[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[O:22])[CH:19]=[C:14]([O:13][CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:15]=1
Reactant: Cc1ccc(NC(=O)Nc2cc(F)cc(OC3CCN(C(=O)OC(C)(C)C)C3)c2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(NC(=O)Nc2cc(F)cc(OC3CCNC3)c2)cn1
Reaction time: 2 h

Procedure:
To 6.5 g of 3-{3-fluoro-5-[3-(6-methyl-pyridin-3-yl)-ureido]-phenoxy}-pyrrolidine-1-carboxylic acid tert-butyl ester was added 20 mL of a 1:1 mixture of trifluoroacetic acid and dichloromethane at room temperature and the resultant reaction mixture was stirred for 2 hours. The reaction mixture was concentrated. To the residue was added 5 mL of saturated brine solution and 1 N NaOH was added until a pH of 10 was observed. The mixture was extracted with ethyl acetate. The organics were dried with sodium sulfate, filtered, and concentrated to 1-[3-fluoro-5-(pyrrolidin-3-yloxy)-phenyl]-3-(6-methyl-pyridin-3-yl)-urea, a compound of Formula I, as an oil that was used directly in the subsequent reaction.
Reaction SMILES: [N:1]1([C:6]2[CH:20]=[CH:19][C:9]([O:10][CH2:11][C:12]([NH:15]C(=O)C)([CH3:14])[CH3:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[ClH:21]>>[ClH:21].[ClH:21].[N:1]1([C:6]2[CH:20]=[CH:19][C:9]([O:10][CH2:11][C:12]([CH3:14])([CH3:13])[NH2:15])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(=O)NC(C)(C)COc1ccc(-n2ccnc2)cc1
Agent: Cl
Product: CC(C)(N)COc1ccc(-n2ccnc2)cc1

Procedure:
Dissolve 27.0 g (0.106 mol) of N-[-2-[4-(1H-imidazol-1-yl)phenoxy]-1,1-dimethylethyl]acetamide in 270 mL of 2 N of hydrochloric acid and heat to reflux for 18 h. After this time, remove the water on the rotary evaporator and redissolve the residue in 50mL of isopropanol. Remove the isopropanol on a rotary evaporator and suspend the resulting solid in diethyl ether. Filter off the solid to provide the title compound.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:22])[CH2:4][CH2:5][CH2:6][CH:7]1[C:11]2([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[O:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2.[Br:23]N1C(=O)CCC1=O.O.C(=O)(O)[O-].[Na+]>CO>[ClH:1].[Br:23][C:20]1[CH:19]=[CH:18][C:9]2[O:10][C:11]3([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[CH:7]([CH2:6][CH2:5][CH2:4][N:3]([CH3:2])[CH3:22])[C:8]=2[CH:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CN(C)CCCC1c2ccccc2OC12CCCCCC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN(C)CCCC1c2cc(Br)ccc2OC12CCCCCC2
Reaction time: 0.33 h
Yield: 93.4 %

Procedure:
To a stirred solution of 3.89 g of 3-(3-dimethylaminopropyl)-spiro[benzofuran-2(3H),1'-cycloheptane] hydrochloride in 35 ml of methanol at room temperature under nitrogen was added 2.24 g of N-bromosuccinimide. All solid dissolved rapidly as the pot temperature rose to 33° C. A TLC analysis after 20 minutes showed a complete reaction. The mixture was poured into water (175 ml), and 250 ml of saturated sodium bicarbonate solution was added with stirring. The mixture was then extracted with ether (2×250 ml). The combined organic extracts were washed with water (100 ml) and saturated sodium chloride solution (100 ml), dried briefly over anhydrous sodium sulfate, filtered and concentrated in vacuo to an oil. This material was dissolved in 100 ml of ether and the solution was stirred and treated with hydrogen chloride-saturated ether solution until the liquid phase was acidic to a pH paper. After a few minutes, the salt was filtered off, washed with ether and dried to afford 4.52 g of a solid, m.p. 169°-172° C. This crude salt was combined with two other batches of previously prepared crude salt and recrystallized by dissolving the solids in 20 ml of absolute ethanol, filtering by gravity, and treating the stirred filtrate dropwise with ether (140 ml). After stirring for 30 minutes the recrystallized salt was filtered, triturated and washed with ethanol/ether (1:7) solution, then ether and finally hexane. Drying in vacuo afforded 5.08 g of crystalline solid, m.p. 174°-176° C.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:44])[NH:6][C:7]2[CH:42]=[CH:41][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][CH2:28][N:29]([CH2:37][CH2:38][O:39][CH3:40])C(=O)OC(C)(C)C)=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:43])[CH:8]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:42]=[CH:41][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][NH:29][CH2:37][CH2:38][O:39][CH3:40])=[CH:25][N:26]=5)[S:20][C:13]=34)=[C:9]([F:43])[CH:8]=2)=[O:44])[CH2:3][CH2:2]1
Reactant: COCCN(CCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCNCCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Reaction time: 18 h
Yield: 48.1 %

Procedure:
To a solution of 287 (840 mg, 1.35 mmol) in DCM (25 mL) was added TFA (10 mL) and the reaction mixture was stirred for 18 h. The reaction mixture was concentrated, diluted with water and 4N NaOH to pH 13 to form a precipitate which was collected by filtration, washed with water, and dried and purified twice by Biotage (SNAP 50 g; MeOH/DCM: 1/99 to 15/85 over 20 CV) to produce a material that upon trituration with MeOH afforded the title compound 288 (338 mg, 0.65 mmol, 48% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.72 (s, 1H), 8.54-8.49 (m, 2H), 8.30 (s, 1H), 8.19 (d, J=8.2 Hz, 1H), 7.81 (dd, J=8.0, 2.2 Hz, 1H), 7.73 (dd, J=13.5, 2.5 Hz, 1H), 7.38 (t, J=9.1 Hz, 1H), 7.20 (bd, J=8.6 Hz, 1H), 6.63 (d, J=5.5 Hz, 1H), 6.58 (bd, J=2.5 Hz, 1H), 3.37 (t, J=5.7 Hz, 2H), 3.23 (s, 3H), 2.84-2.73 (m, 4H), 2.68 (t, J=5.7 Hz, 2H), 2.59-2.51 (m, 1H), 2.00-1.50 (m, 1H), 0.72-0.58 (m, 2H), 0.50-0.36 (m, 2H).). MS (m/z): 522.6 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[CH:6]=[CH:7][N:8]3[CH:14]=[CH:13][CH:12]=[C:9]3[C:10](=[O:11])[C:4]=2[CH:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([NH:1][C:2]1[CH:16]=[CH:15][C:5]2[CH:6]=[CH:7][N:8]3[CH:14]=[CH:13][CH:12]=[C:9]3[C:10](=[O:11])[C:4]=2[CH:3]=1)(=[O:19])[CH3:18]
Reactant: Nc1ccc2ccn3cccc3c(=O)c2c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2ccn3cccc3c(=O)c2c1

Procedure:
9-Amino-11H-pyrrolo[2,1-b][3]benzazepin-11-one (2.1 g., 11.4 mmoles) dissolved in 15 ml. pyridine is treated with acetic anhydride (2 ml.) at room temperature for 19 hours. The volatiles are removed under vacuum and the residue is dissolved in chloroform, and chromatographed on silica gel. Elution with chloroform yields 9-acetamido-11H-pyrrolo[2,1-b][3]benzazepin-11-one.
Reaction SMILES: [CH:1]([C@:4]1([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=3)[CH2:21][CH2:20]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5]1)([CH3:3])[CH3:2].[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>C(Cl)Cl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[CH:1]([C@:4]1([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:34])[F:32])[CH:26]=3)[CH2:21][CH2:20]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@]1(C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)CC[C@@H](N)C1

Procedure:
tert-Butyl [(1R,3S)-3-isopropyl-3-({4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)cyclopentyl]carbamate (82 mg, 0.18 mmol) was treated with trifluoroacetic acid (3 mL) in methylene chloride (3 mL) for 1 h at room temperature. The mixture was concentrated and used for next step without purification. MS calculated for C20H28F3N3O: (M+H) 383; found 383.2.
Reaction SMILES: [O:1]=[C:2]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)[CH2:3][C:4]([O:6]C)=[O:5].C[O-].[Na+].CO.CO/[CH:26]=[CH:27]/[C:28](=O)[CH3:29].[OH-].[Na+].Cl>C(O)C.O>[CH3:26][C:27]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:2](=[O:1])[C:3]([C:4]([OH:6])=[O:5])=[CH:29][CH:28]=1
Reactant: COC(=O)CC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: CO/C=C/C(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 65 °C
Yield: 63 %

Procedure:
Methyl 3-oxo-3-(3-(trifluoromethyl)phenylamino)propanoate (39.5 kg, 1 mol eq, limiting reagent) was dissolved in ethanol (197.5 L, 5.0 rel vol). Sodium methoxide solution in methanol (74.6 kg, 25% w/w, 2.3 mol eq) was charged followed by an ethanol line wash (11.9 L, 0.3 rel vol). trans-4-Methoxy-3-buten-2-one (19.2 kg, 1.2 mol eq) in ethanol (26.5 L, 0.67 rel vol) was charged. The reaction was heated to 65° C. and stirred at this temperature until the reaction was deemed complete as judged by HPLC analysis. Water (67.2 L, 1.7 rel vol) and 2 M aqueous sodium hydroxide (29.6 L, 0.75 rel vol) were then added and the reaction mixture was stirred for 1 hour. To the solution was added 8 M aqueous hydrochloric acid (237.0 L, 6 rel vol) and the mixture stirred for a further 1 hour. The solution was cooled, stirred and isolated by filtration. The solid was washed with water (79.2 L, 2 rel vol) and iso-hexane (59.2 L, 1.5 rel vol) and dried to constant weight to yield the title compound (28.6 kg, 96.2 mol, 63% (uncorrected for assay)); 1H NMR (CDCl3): δ 2.14 (s, 3H); 6.57 (d, 1H, J=7.4 Hz); 7.46 (d, 1H, J=8.2 Hz); 7.52 (s, 1H); 7.77 (t, 1H, J=7.8 Hz); 7.85 (d, 1H, J=7.9 Hz); 8.53 (d, 1H, J 7.4 Hz); 13.66 (s, 1H) ppm; LCMS: m/z 298.3 (MH+).
Reaction SMILES: [CH2:1](Cl)/[CH:2]=[CH:3]/[CH2:4]Cl.[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:8].[Cl-].C(C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC)(=O)CCCCCCC.[OH-].[K+]>C1C=CC=CC=1>[CH:2]([CH:3]1[CH2:4][C:9]1([C:7]#[N:8])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH2:1]
Reactant: CCOC(=O)CC#N
Reactant: ClC/C=C/CCl
Agent: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: [Cl-]
Agent: [K+]
Solvent: c1ccccc1
Product: C=CC1CC1(C#N)C(=O)OCC

Procedure:
Ethyl 2-vinyl-1-cyanocyclopropane-1-carboxylate was prepared in accordance with the procedure of U.S. Pat. No. 4,252,739. For the reaction 750 ml benzene, 250 gms (2 moles) 1,4-dichlorobutene-2, 113 gms (1 mole) ethyl cyanoacetate and 3 gms tricaprylylmethylammonium chloride were charged to a reactor and heated to reflux with agitation. Potassium hydroxide (85%) pellets (132 gms; 2 moles) were then added to the stirred solution in small portions. A mild exotherm was observed with the addition of caustic and external cooling was provided as necessary to maintain mild reflux. When the KOH addition was complete the reaction was stirred at reflux for 5 hours while removing water by azeotropic distillation. The reaction mixture was then filtered and the benzene evaporated. Distillation under reduced pressure yielded ethyl 2-vinyl-1-cyanocyclopropane-1-carboxylate (B.p. 55° C. at 0.02 mm Hg, lit. 112° C. at 11 mm Hg.; nD25° 1.4661, lit. nD24° 1.4650).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:32])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:17][C:16]=1[CH3:31])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:30][S:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:13]([CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[O:32])=[C:16]([CH3:31])[CH:17]=1)(=[O:29])=[O:28]
Reactant: Cc1cc(-c2ccccc2S(C)(=O)=O)ccc1NC(=O)C1CCCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccccc2S(C)(=O)=O)ccc1NC(=O)C1CCCN1
Yield: 93 %

Procedure:
2-(2′-Methanesulfonyl-3-methyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.4 g, 0.87 mmol) was dissolved in 15 mL DCM and 5 mL trifluoroacetic acid and stirred at ambient temperature for 2 hour and concentrated. Redissolved in 100 mL EtOAc and 100 mL sat. NaHCO3, separated layers, washed organics with brine, dried with MgSO4, filtered and concentrated to yield title compound as an oil (0.29 g, 93%) APCI (AP−): 357.1 (M−H)−.
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:10])[C:4](C)(C)[CH2:5][CH:6]=[CH2:7].[C:11](O)(=O)CCCC=C>>[Br:1][CH2:2][C:3](=[O:10])[CH2:4][CH2:5][CH2:6][CH:7]=[CH2:11]
Reactant: C=CCC(C)(C)C(=O)CBr
Reactant: C=CCCCC(=O)O
Product: C=CCCCC(=O)CBr

Procedure:
The title compound was prepared according to the procedure described for Intermediate 4, using 5-hexenoic acid in place of 2,2-dimethylpent-4-enoic acid. 1H NMR (300 MHz, CDCl3) δ 5.77 (m, 1H), 5.05-4.98 (m, 2H), 3.87 (s, 2H), 2.66 (t, J 7.3, 2H), 2.89 (m, 2H), 2.09 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:2].Cl[C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([CH2:23][N:24]3[CH2:27][CH:26]([OH:28])[CH2:25]3)[N:19]2[CH3:22])=[C:15]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[N:14]=1>>[CH2:1]([C:3]1[N:4]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[C:18]([CH2:23][N:24]4[CH2:25][CH:26]([OH:28])[CH2:27]4)[N:19]3[CH3:22])=[C:15]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[N:14]=2)[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:2]
Reactant: Cn1c(CN2CC(O)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CCc1nc2ccccc2[nH]1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(O)C3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-ethylbenzimidazole and 1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)azetidin-3-ol were reacted to give 524. LCMS m/z: 449.2 (MH+)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[CH:3][C:4]=1[OH:11]
Reactant: CO
Reactant: Nc1ccc(C(=O)O)c(O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(N)cc1O
Temperature: 25 °C

Procedure:
To a stirred solution of 4-amino salicylic acid (110.0 g; 718 mmol) in dry MeOH (3025 mL) was slowly added concentrated sulfuric acid (187 mL; 3.5 mmol) via pipette at room temperature under nitrogen atmosphere. The resulting solution was heated to reflux for 20 hours then allowed to cool to room temperature. The reaction was concentrated at reduced pressure to about ¼ the original volume, then neutralized by the careful addition of saturated aqueous sodium bicarbonate to pH 7–8. The resulting precipitate was collected on a Buchner funnel with suction, washed with water, and allowed to air dry. The resulting gray solid was dissolved in EtOAc (1.5 L) and treated with decolorizing charcoal. Filtration and recrystallization (EtOAc/hexanes or MeOH/water (1:3)) provided the ester as an off white crystal (94.5 g; 79%).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[N:21]=3)[CH:19]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:22]2[CH:23]=[C:24]([CH3:26])[N:25]=[C:20]([N:18]3[CH:19]=[C:15]([C:12]4[CH:13]=[CH:14][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:10][CH:11]=4)[N:16]=[CH:17]3)[N:21]=2)=[CH:32][CH:31]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3ccc(S(=O)(=O)NC(C)(C)C)cc3)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3ccc(S(N)(=O)=O)cc3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 9 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-4-{1-[6-(4-chloro-phenyl)-4-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.64 g) in dichloromethane (7 mL) was added TFA (7 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as an off-white solid (0.051 g, 12%). MS (ISP) 426.1 [(M+H)+]; mp 312° C.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C@@H:13]2[O:30][C@H:29]([CH2:31][O:32]C(=O)C)[C@@H:24]([O:25]C(=O)C)[C@H:19]([O:20]C(=O)C)[C@H:14]2[O:15]C(=O)C)=[C:8]([O:36][CH3:37])[CH:7]=1)(=O)C.C[O-].[Na+]>CO>[C@@H:13]1([O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][OH:4])=[CH:7][C:8]=2[O:36][CH3:37])[O:30][C@H:29]([CH2:31][OH:32])[C@@H:24]([OH:25])[C@H:19]([OH:20])[C@H:14]1[OH:15]
Reactant: COc1cc(COC(C)=O)ccc1O[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CO)ccc1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-methoxybenzyl acetate (7) (333 mg, 0.632 mmol) was suspended in methanol (2 ml), and sodium methoxide 5 M methanol solution (20 μl, 0.10 mmol) was added while cooling in an ice bath. The ice bath was removed and the mixture was warmed to room temperature and stirred for 2 hours. Sodium methoxide 0.5 M methanol solution (0.12 ml, 0.06 mmol) was further added and the mixture was stirred for 1 hour. The reaction solution was neutralized with a strong acidic cation exchange resin (Amberlite IR120B H AG). The resin was filtered off, and the filtrate was concentrated under reduced pressure to give 4-(β-D-glucopyranosyloxy)-3-methoxybenzyl alcohol (8) (147 mg, 0.465 mmol, yield 74%) as a colorless solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)=[CH:16][CH:15]=2)[N:12]=1)(=O)=O.[O:34]1[CH2:38][CH2:37][CH2:36][C@H:35]1[CH2:39][NH2:40]>CS(C)=O>[O:24]1[C:20]([C:17]2[CH:18]=[CH:19][C:14]([NH:13][C:11]3[N:12]=[C:7]([NH:40][CH2:39][C@@H:35]4[CH2:36][CH2:37][CH2:38][O:34]4)[C:8]4[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=4[N:10]=3)=[CH:15][CH:16]=2)=[CH:21][N:22]=[CH:23]1
Reactant: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Reactant: NC[C@@H]1CCCO1
Solvent: CS(C)=O
Product: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(NC[C@@H]3CCCO3)c2C1
Reaction time: 8 h
Yield: 41.8 %

Procedure:
6-Acetyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (35 mg, 0.07 mmol, Example 26a) in DMSO (1 mL) was dispensed in a library plate. (S)-(tetrahydrofuran-2-yl)methanamine (7.08 mg, 0.07 mmol) was added to the plate and it was left to shake overnight at 80° C., filtered and purified by preparative HPLC to give (S)-1-(2-(4-(oxazol-5-yl)phenylamino)-4-((tetrahydrofuran-2-yl)methylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (12.7 mg, 40.4%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]2[C:15]=1[S:16]([OH:19])(=O)=[O:17].C(N(CCC)CCC)CC.P(Cl)(Cl)([Cl:32])=O>C(#N)C>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]2[C:15]=1[S:16]([Cl:32])(=[O:19])=[O:17]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cccn2c(S(=O)(=O)O)c(C)nc12
Agent: CCCN(CCC)CCC
Solvent: CC#N
Product: CCOC(=O)c1cccn2c(S(=O)(=O)Cl)c(C)nc12
Yield: 66.3 %

Procedure:
Ethyl 2-methyl-3-sulfo-imidazo[1,2-a]pyridine-8-carboxylate (1.7 g) and tri-n-propylamine (2.6 g) were added to acetonitrile (17 ml). Phosphorus oxychloride (1.1 ml) was added to the mixture, keeping the inner temperature to 50°-60° C. Then, the mixture was allowed to react at the same temperature for an hour. After completion of the reaction, the mixture was concentrated under reduced pressure, and water was added to the residue. The precipitated crystals were collected by filtration, washed with water and dried to obtain ethyl 2-methyl-3-chlorosulfonyl-imidazo[1,2-a]-pyridine-8-carboxylate (1.2 g, yield 66.3%) as crystals of m.p. 182°-183° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:30]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH:39]([C:42](O)=[O:43])[CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:42]([CH:39]4[CH2:40][CH2:41][N:37]([C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:36])[CH2:38]4)=[O:43])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)C2CCN(C(=O)OC(C)(C)C)C2)c1

Procedure:
Prepared as described in Example 83 using (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (37 mg, 0.17 mmol). Yield 38 mg (50%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:7][CH2:8][CH2:9][C:10]([O:12]CC)=[O:11])=[CH:2]1.C(=O)(O)[O-].[Na+].Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22].[OH-].[K+]>C(O)C>[CH2:24]([O:23][C:21]([N:7]([CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:22])[CH3:25]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)CCNCc1ccsc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)N(CCC(=O)O)Cc1ccsc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Compound 1046 (3.36 g, 15.75 mmol) in ethanol (100 mL) was added saturated sodium bicarbonate (25 mL) and ethyl chloroformate (1.801 mL, 18.9 mmol). The reaction mixture was stirred at room temperature overnight, at which point 1.0 M aqueous potassium hydroxide (63.0 mL, 63.0 mmol) was added. The mixture was stirred at room temperature overnight, concentrated under reduced pressure, made acidic with 6N HCl, and extracted with 10% nBuOH in chloroform. The organics were concentrated to give 3-(ethoxycarbonyl(thiophen-3-ylmethyl)amino)propanoic acid as a tan oil (Compound 1048, 2.04 g, 50%); 1H NMR (300 MHz, CDCl3): δ 7.56-7.48 (m, 1H), 7.44-7.38 (m, 2H), 4.75 (s, 2H), 4.49-4.39 (m, 4H), 3.92-3.77 (m, 2H), 2.62-2.58 (m, 2H) and 1.68-1.48 (m, 3H).