Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:10]([O:28][CH3:29])=[CH:11][C:12]([O:26][CH3:27])=[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:14]=2)[CH2:3]1.[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1B(O)O>>[CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:10]([O:28][CH3:29])=[CH:11][C:12]([O:26][CH3:27])=[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:31]4[S:30][CH:34]=[CH:33][CH:32]=4)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:14]=2)[CH2:3]1
Reactant: OB(O)c1cccs1
Reactant: COc1cc(OC)c(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(I)cc1
Product: COc1cc(OC)c(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2cccs2)cc1

Procedure:
The title compound (E244) was prepared from the product of Step 1 and 2-thienylboronic acid using a similar method to that described for Examples 237-243. MS (ES+) m/e 488 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N+:13]=1[O-].P(Br)(Br)([Br:22])=O.C([O-])([O-])=O.[Na+].[Na+]>ClC(Cl)C>[Br:22][C:14]1[N:13]=[C:12]([N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])[CH:17]=[CH:16][C:15]=1[CH3:18]
Reactant: O=P(Br)(Br)Br
Reactant: Cc1ccc(N2C(=O)c3ccccc3C2=O)[n+]([O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: Cc1ccc(N2C(=O)c3ccccc3C2=O)nc1Br
Temperature: 40 °C

Procedure:
To a solution of 2-(1,3-dioxoisoindolin-2-yl)-5-methylpyridine 1-oxide (501 mg, 1.97 mmol) in 1,1-dichloroethane (5 ml) is added POBr3 (679 mg, 2.36 mmol) in small portions at 0° C., and the solution is then heated at 40° C. for 2 hours. The solution is cooled to room temperature, poured into crushed ice, neutralized with Na2CO3 and extracted with dichloromethane. The separated organic layer is further washed with water, brine and dried over Na2SO4. After concentration, the crude product is purified by silica gel flash chromatography, eluted with 3% ethyl acetate in dichloromethane to afford 2-(6-bromo-5-methylpyridin-2-yl)isoindoline-1,3-dione as an off-white solid. LC-MS m/z: 317.2 (M+1).
Reaction SMILES: N1CCC(C2C=CC3N(C=NN=3)C=2)CC1.[N:16]1[N:17]=[CH:18][N:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[CH:21][C:20]=12.N1N=CN2C=C(C3CCN(C(OC(C)(C)C)=O)CC3)C=CC=12>>[NH:28]1[CH2:27][CH2:26][CH:25]([C:22]2[CH:23]=[CH:24][N:19]3[CH:18]=[N:17][N:16]=[C:20]3[CH:21]=2)[CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccn3cnnc3c2)CC1
Agent: CC(C)(C)OC(=O)N1CCC(c2ccc3nncn3c2)CC1
Agent: c1cc2nncn2cc1C1CCNCC1
Product: c1cn2cnnc2cc1C1CCNCC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 36.2, except tert-butyl 4-([1,2,4]triazolo[4,3-a]pyridin-7-yl)piperidine-1-carboxylate (compound 41.3) was used in place of tert-butyl 4-([1,2,4]thazolo[4,3-a]pyridin-6-yl)piperidine-1-carboxylate (compound 36.1) m/z (ES+) 203 (M+H)+.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.O[C:17]([C:20]1[N:21]=[C:22]([CH2:28][CH2:29][CH3:30])[NH:23][C:24]=1[C:25](O)=[O:26])([CH3:19])[CH3:18]>CC(C)=O>[CH3:18][C:17]1([CH3:19])[C:20]2[NH:21][C:22]([CH2:28][CH2:29][CH3:30])=[N:23][C:24]=2[CH2:25][O:26]1
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)O)[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(C)=O
Product: CCCc1nc2c([nH]1)C(C)(C)OC2
Reaction time: 48 h
Yield: 138.6 %

Procedure:
33.0 grams of dicyclohexylcarbodiimide (DCC) was added into a suspension of 30.0 grams of 4-(1-hydroxy-1-methylethyl)-2-propyl-imidazole-5-carboxylic acid (formula III) in 300 ml of acetone. The reaction was performed at ambient temperature for 48 hours. The mixture was suction filtered and washed. The filtrate was concentrated and acetone was recovered. 120 ml of ethyl acetate and 120 ml of water were added into the residual liquid, and pH was adjusted to 2-3 with concentrated hydrochloric acid. The aqueous layer was separated and the organic layer was further extracted with 20 ml×2 of water. 150 ml of ethyl acetate was added into the combined aqueous portion and pH was adjusted to 10 with 30% sodium hydroxide solution. Salt was added to be saturated and the organic layer was separated. The aqueous layer was further extracted with 30 ml×2 of ethyl acetate. Combined organic portion was dried over anhydrous magnesium sulfate and filtered, the solvent was evaporated to give 35.3 grams of 4,4-dimethyl-2-propyl-4,6-dihydrofuro[3,4-d]imidazole (formula II), resulting in a yield of 97%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](=O)[CH3:11])=[CH:4][CH:3]=1.[NH2:19]/[C:20](/[CH3:26])=[CH:21]\[C:22]([O:24][CH3:25])=[O:23].C(O)C>C(O)(=O)C>[CH3:26][C:20]1[NH:19][C:10]([CH3:11])=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:21]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: CC(=O)C(=Cc1ccc(F)cc1)c1ccccc1
Reactant: COC(=O)/C=C(/C)N
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(c2ccccc2)C1c1ccc(F)cc1
Yield: 111.1 %

Procedure:
24.0 g (0.1 mol) of 1-(4-fluorophenyl)-2-phenylbuten-3-one, 23 g (0.2 mol) of methyl 3-amino-crotonate and 6 ml (0.1 mol) of glacial acetic acid are heated under reflux overnight in 150 m of ethanol, heated under reflux for 18 h after addition of 11.5 g (0.1 mol) of methyl 3-aminocrotonate and 3 ml of glacial acetic acid and heated under reflux for 18 h once more after repeated addition of 11.5 g (0.1 mol) of methyl 3-aminocrotonate and 3 ml of glacial acetic acid. The solvent is removed in vacuo, 80 ml of methanol are added to the residue, undissolved material is filtered off with suction, the methanolic solution is concentrated in vacuo and excess aminocrotonate is distilled off from the residue at 73° C.-90° C./18 mbar and subsequently at 60° C.-70° C. 0.2 mbar. 37.5 g of crude product are obtained as a brittle fused mass.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([S:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:25])=[O:24])[CH:9]=2)[CH2:6][CH2:7]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN1CCC(c2c[nH]c3ccccc23)CC1
Product: CN1CCC(c2cn(S(=O)(=O)c3ccccc3)c3ccccc23)CC1

Procedure:
(23.9 mg, 67%) from 3-(1-methyl-4-piperidinyl)-1H-indole (Example 5d, 21.5 mg, 0.1 mmol) and phenylsulfonyl chloride (26.4 mg, 0.15 mmol), HRMS-FAB+ for C20H22N2O2S, calculated MH+ : 355.14807; found: 355.15074.
Reaction SMILES: ClC1C=CN(C2C=NC=CC=2)N=1.Cl.Cl.[NH:15]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[NH2:16].[C:23]([NH:26][C:27](=[CH2:32])[C:28](OC)=[O:29])(=[O:25])[CH3:24]>>[O:29]=[C:28]1[CH:27]([NH:26][C:23](=[O:25])[CH3:24])[CH2:32][N:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[NH:16]1
Reactant: NNc1cccnc1
Reactant: C=C(NC(C)=O)C(=O)OC
Agent: Cl
Agent: Clc1ccn(-c2cccnc2)n1
Product: CC(=O)NC1CN(c2cccnc2)NC1=O

Procedure:
3-(3-Chloro-1H-pyrazol-1-yl)pyridine (5b) in Scheme 1 may alternatively be prepared by reacting 3-hydrazinopyridine dihydrochloride with methyl 2-acetamidoacrylate to yield N-(3-oxo-1-(pyridin-3-yl)pyrazolidin-4-yl)acetamide and subsequent chlorination/elimination as shown in Scheme 2, step a1.
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=1.[OH-].[Na+]>C(O)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:12][CH:11]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CCOC(=O)C(C)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)Sc1ccc(Br)cc1
Yield: 85.5 %

Procedure:
A solution of 30 g (0.165 mol) of ethyl 2-bromopropionate in 30 ml of anhydrous ethanol is run over the course of 30 minutes into a solution of 29 g (0.150 mol) of p-bromothiophenol, taken as 98% strength, and of 6 g (0.150 mol) of sodium hydroxide pellets in 100 ml of anhydrous ethanol, and the mixture is then stirred for 1 hour at ambient temperature. The inorganic salts formed are removed by filtration and the alcohol is evaporated. The residue is taken up in diethyl ether and the organic phase obtained is washed successively with N sodium hydroxide solution and with water. After drying, and evaporating the solvent, 44.6 g of a limpid pale yellow oil are obtained. The purification of this oil by distillation under reduced pressure gives 37.1 g of a limpid colourless oil.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20]([CH2:22][NH:23][CH2:24][C:25]1[CH:26]=[C:27]([C:31]3[CH:36]=[CH:35][C:34]([NH:37][C:38]4[CH:47]=[CH:46][CH:45]=[CH:44][C:39]=4[C:40]([O:42]C)=[O:41])=[CH:33][CH:32]=3)[CH:28]=[CH:29][CH:30]=1)=[O:21])[CH:14]=[CH:13]2>O1CCCC1.CO.O.C(OCC)(=O)C>[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20]([CH2:22][NH:23][CH2:24][C:25]1[CH:26]=[C:27]([C:31]3[CH:36]=[CH:35][C:34]([NH:37][C:38]4[CH:47]=[CH:46][CH:45]=[CH:44][C:39]=4[C:40]([OH:42])=[O:41])=[CH:33][CH:32]=3)[CH:28]=[CH:29][CH:30]=1)=[O:21])[CH:14]=[CH:13]2
Reactant: COCCOCOc1ccc2cc(C(=O)CNCc3cccc(-c4ccc(Nc5ccccc5C(=O)OC)cc4)c3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COCCOCOc1ccc2cc(C(=O)CNCc3cccc(-c4ccc(Nc5ccccc5C(=O)O)cc4)c3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
80 mg (2 mmol) of sodium hydroxide are added to a solution of 0.8 g (1.3 mmol) of methyl 2-[3′-({[6-(2-methoxyethoxymethoxy)naphthalene-2-carbonyl]methylamino}methyl)biphenyl-4-ylamino]benzoate in 8 ml of tetrahydrofuran, 0.8 ml of methanol and a few drops of water. After stirring at room temperature for 8 hours, the reaction medium is diluted with ethyl acetate, washed with aqueous 1N hydrochloric acid solution, extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated under vacuum. The residue obtained is purified by chromatography on a column of silica eluted with a 70/30 heptane/ethyl acetate mixture and then triturated from heptane. 390 mg (50%) of 2-[3′-({[6-(2-methoxyethoxymethoxy)-naphthalene-2-carbonyl]methylamino}methyl)biphenyl-4-ylamino]benzoic acid are obtained in the form of a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=[O:13])[CH:6]=[C:5]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:4]=1.[BH4-].[Na+]>C(Cl)Cl.CO>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH2:12][OH:13])[CH:14]=[CH:15][CH:16]=2)[CH:6]=[C:5]([NH:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[N:4]=1
Reactant: COc1ccc(CCNc2cc(-c3cccc(C=O)c3)nc(OC)n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(CCNc2cc(-c3cccc(CO)c3)nc(OC)n2)cc1
Reaction time: 0.17 h
Yield: 109.5 %

Procedure:
A solution of 3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzaldehyde [33 mg, 0.08 mmol, Example 35(u)] in a mixture of DCM (3 mL) and MeOH (1 mL) is treated with sodium borohydride (100 mg). After 10 minutes at 20° C., the mixture is concentrated, and extracted twice with EtOAc (10 mL). The combined extracts are dried over magnesium sulfate and filtered through a plug of silica gel to afford (3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-methanol [32 mg, 100%, Example 9(c)]. LCMS: RT=2.18 minutes, MS: 366 (M+H).
Reaction SMILES: C(OC([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]1[CH2:17][C:18]#[N:19])=O)C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[C:18]([CH2:17][C@@H:12]1[CH2:13][C@@H:14]([OH:16])[CH2:15][NH:11]1)#[N:19]
Reactant: N#CC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: N#CC[C@@H]1C[C@@H](O)CN1

Procedure:
To a solution of (2R,4R)-1-benzyloxycarbonyl-2-cyanomethyl-4-hydroxypyrrolidine (5.94 g) in ethanol (60 ml), 10% palladium-carbon (600 mg) was added, and the resultant mixture was stirred at room temperature for 1.5 hours under an atmospheric pressure of hydrogen, followed by filtration. The filtrate was combined with 10% palladiumcarbon (600 mg) and stirred under the same condition as above. This operation was repeated three times. After removal of the catalyst by filtration, the solvent was removed by distillation to give (2R,4R)-2-cyanomethyl-4-hydroxypyrrolidine.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:30]2[C:31]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH2:44]O)=[CH:38][CH:37]=3)=[CH:32][O:33][C:29]=2[CH:28]=[CH:27][CH:26]=1)(=O)C.[NH2:46][CH:47]([CH2:50][OH:51])[CH2:48][OH:49].NCCO>>[C@@H:6]1([O:24][C:25]2[C:30]3[C:31]([CH2:34][CH2:35][C:36]4[CH:37]=[CH:38][C:39]([O:42][CH2:43][CH2:44][NH:46][CH:47]([CH2:50][OH:51])[CH2:48][OH:49])=[CH:40][CH:41]=4)=[CH:32][O:33][C:29]=3[CH:28]=[CH:27][CH:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: NC(CO)CO
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3occ(CCc4ccc(OCCO)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: NCCO
Product: OCC(CO)NCCOc1ccc(CCc2coc3cccc(O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)c23)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 21 using 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-{2-[4-(2-hydroxyethoxy)phenyl]ethyl}benzofuran and 2-amino-1,3-propanediol instead of 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-{2-[4-(3-hydroxypropoxy)phenyl]ethyl}benzofuran and 2-aminoethanol, respectively.
Reaction SMILES: BrC1C=CC=CC=1CO.[Br:10][C:11]1[CH:16]=[CH:15][C:14](F)=[CH:13][C:12]=1[CH2:18][O:19][CH2:20][O:21][CH3:22]>>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:18][O:19][CH2:20][O:21][CH3:22]
Reactant: COCOCc1cc(F)ccc1Br
Agent: OCc1ccccc1Br
Product: COCOCc1ccccc1Br

Procedure:
This compound was made from 2-bromobenzylalcohol in the same manner as compound 5b and used for the next step without purification.
Reaction SMILES: [CH2:1]([C:3]([CH2:24][CH3:25])=[CH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:23])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:21][CH3:22])[CH:15]=2)[CH2:7][CH2:6]1)[CH3:2]>C(O)C.[Pd]>[CH2:24]([CH:3]([CH2:1][CH3:2])[CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:23])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:21][CH3:22])[CH:15]=2)[CH2:7][CH2:6]1)[CH3:25]
Reactant: CCC(=C[C@H]1CC[C@H](NC(=O)Cc2ccc(O)c(OC)c2)CC1)CC
Agent: [Pd]
Solvent: CCO
Product: CCC(CC)C[C@H]1CC[C@H](NC(=O)Cc2ccc(O)c(OC)c2)CC1
Reaction time: 3 h

Procedure:
The compound (0.07 g) of Example 90 was dissolved in ethanol (10 ml), 10% palladium/carbon (10 mg) was added to the solution, and the mixture was hydrogenated at room temperature. After 3 hours, the catalyst was removed by filtration from the reaction mixture, and the solvent was evaporated under reduced pressure from the filtrate. The residue was crystallized from diisopropyl ether to give 46 mg of the desired compound as a crystal.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:23][C:24]1[S:25][C:26]([C:30]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[C:27]([CH3:29])[N:28]=1>O1CCCC1>[CH2:33]([NH:32][C:30]([C:26]1[S:25][C:24]([NH:23][C:5](=[O:7])[CH2:4][CH2:3][CH2:2][Br:1])=[N:28][C:27]=1[CH3:29])=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(O)CCCBr
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cc1nc(NC(=O)CCCBr)sc1C(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a solution of 4-bromobutyric acid (0.94 g, 5.50 mmol) and 4-methylmorpholine (0.70 mL, 6.20 mmol) in tetrahydrofuran (40 mL) was added isobutyl chloroformate (0.75 mL, 5.60 mmol) at 0° C. The resulting reaction mixture was stirred at 0° C. for 2 hours and then 2-amino-N-benzyl-4-methylthiazole-5-carboxamide (1.24 g, 5.00 mmol) was added. After 14 hours at ambient temperature, the solvent was removed in vacuo, and the residue was dissolved in ethyl acetate (200 mL), washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the residue was purified by column chromatography to yield the title compound (1.80 g, 90%): 1H NMR (300 MHz, CDCl3) δ 7.30-7.23 (m, 5H), 5.99 (s, 1H), 4.57-4.55 (m, 2H), 4.34-4.27 (m, 2H), 3.38-3.44 (m, 2H), 2.64-2.18 (m, 5H); MS (ES+) m/z 396.3 (M+1) and 398.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:10]([O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1ccc(F)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(OCc2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.9 %

Procedure:
To 2,4-difluoro-phenol (35, 7.60 g, 0.0584 mol) in N,N-dimethylformamide (50.0 mL) were added benzyl bromide (8.0 mL, 0.067 mol) and potassium carbonate (9.00 g, 0.0651 mol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give the compound as white solid (525, 3.20 g, 25%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]3[CH:15]=[C:14]([C:16]4[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=4)[CH:13]=[N:12][C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(CC)=C.[OH:29]P([O-])(O)=O.[Na+].Cl([O-])=O.[Na+]>CC(O)(C)C.C1COCC1>[C:1]1([C:7]2[CH:8]=[N:9][N:10]3[CH:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([C:20]([OH:29])=[O:21])=[CH:22][CH:23]=4)[CH:13]=[N:12][C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2cnc3c(-c4ccccc4)cnn3c2)cc1
Reactant: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: C=C(C)CC
Product: O=C(O)c1ccc(-c2cnc3c(-c4ccccc4)cnn3c2)cc1
Reaction time: 1 h

Procedure:
A solution of 4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)benzaldehyde (1-5, 250 mg, 0.835 mmol, 1 equiv) in a 4:1 mixture of THF and t-BuOH (20 mL) was treated with 2-methyl butene (5 mL), an aqueous solution of sodium phosphate monobasic (0.14 M, 230 mg, 1.67 mmol, 2 equiv) and sodium chlorite (194 mg, 2.15 mmol, 2.57 equiv). After 1 hour at 23° C., additional solid sodium phosphate monobasic (230 mg, 1.67 mmol, 2 equiv) and sodium chlorite (194 mg, 2.15 mmol, 2.57 equiv) were added. The reaction mixture was stirred for an additional 4 hours, concentrated, and the residue dissolved in EtOAc (100 mL) then washed with a 25:1 mixture of aqueous 10% sodium bisulfite solution and 10% potassium hydrogen sulfate solution (2×100 mL). The organic layer was dried over sodium sulfate and concentrated to afford 4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)benzoic acid (3-1) as a yellow solid. LRMS m/z: Calc'd for C19H14N3O2 (M+H) 316.35, found 316.1.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][OH:7].[OH-].[Na+].[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=O)[CH3:11].OS(O)(=O)=O>CO>[C:10](=[N:6][OH:7])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:11]
Reactant: NO
Reactant: CC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=NO)c1ccccc1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
In a 500 mL 3-neck flask was placed solid hydroxylamine sulfate (28 g; 0.17 mol) and absolute methanol (100 mL) was added to it. The slurry was stirred vigorously using a magnetic bar over a stir plate and a solution of sodium hydroxide pellets (14 g; 0.35 mol) in absolute methanol (175 mL) was then added slowing with cooling in ice bath (<5° C.). At the completion of addition of the solution, acetophenone (40 g; 0.33 mol) was added and stirring in the cold was continued for 5 hours. Concentrated H2SO4 (1.8 g) was added to adjust the pH of the solution to 6.5. Methanol (50 mL) was added to the slurry and the mixture heated (40° C.) for 2 hours and then filtered hot. The clear filtrate (colorless) was concentrated under reduced pressure and crystalline acetophenone oxime was collected after cooling and filtration. Yield, 40.5 g (90.8%). Purity >98% of isomeric mixture.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=O)[CH3:2].[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][C:21]([CH3:24])([OH:23])[CH3:22])=[CH:16][C:15]([Br:25])=[CH:14][CH:13]=2.ClCCl.C(N(CC)CC)C>O>[Br:25][C:15]1[CH:14]=[CH:13][C:12]2[N:11]=[CH:10][C:9]3[N:8]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:19]([CH2:20][C:21]([CH3:24])([OH:23])[CH3:22])[C:18]=3[C:17]=2[CH:16]=1
Reactant: CCOCC(=O)Cl
Reactant: CC(C)(O)CNc1c(N)cnc2ccc(Br)cc12
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOCc1nc2cnc3ccc(Br)cc3c2n1CC(C)(C)O
Reaction time: 16 h

Procedure:
Ethoxyacetyl chloride (6.2 g, 50.5 mmol) was added dropwise to a solution of crude 1-[(3-amino-6-bromoquinolin-4-yl)amino]-2-methylpropan-2-ol, dichloromethane (500 mL), and triethylamine (7 mL, 50.5 mmol). After stirring for 16 hours, water was added and the mixture was stirred for an additional 2 hours. The fractions were separated. The organic fraction was washed with water, concentrated under reduced pressure and redissolved in ethanol (500 mL). Water (150 mL) and potassium carbonate (10.5 g) were added and the mixture was heated at reflux temperature for 3 hours. The ethanol was removed under reduced pressure. The remaining aqueous fraction was extracted with ethyl acetate (2×500 mL). The organic fractions were combined, washed with water followed by saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Recrystallization from acetonitrile provided 10.4 g of 1-[8-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a tan powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:19][CH2:20][CH3:21])[C:10]([O:17][CH3:18])([O:15][CH3:16])[C:11]([O:13]C)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:19][CH2:20][CH3:21])[C:10]([O:15][CH3:16])([O:17][CH3:18])[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(OC)(OC)C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCC[C@H](NC(=O)OC(C)(C)C)C(OC)(OC)C(=O)O
Reaction time: 20 h

Procedure:
To ((S)-methyl 3-((tert-butoxycarbonyl)amino)-2,2-dimethoxyhexanoate) of Example 16 (0.8 mmol) in methanol (8 mL) was added an aqueous KOH solution (0.13 mL, 2.4 mmol, 50 w/w %) and the reaction was stirred for 20 h. pH was adjusted to pH=3 with 1N HCl and extraction with CH2Cl2 provided 260 mg of the crude acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[C:25]([C:27]1[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=1)#[N:26]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:33][C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([C:25]#[N:26])[CH:28]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: N#Cc1cccc(O)c1
Product: CC(NC(=O)c1coc(Oc2cccc(C#N)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 73.2 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 3-cyanophenol (31 mg, 0.26 mmol) to give the title compound (44 mg, 73%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).