Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=O.[CH2:24]([OH:27])[CH2:25][OH:26]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:24]1[O:27][C:5]([O:7][CH2:8][CH3:9])([CH2:4][CH2:3][C:2](=[O:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[O:26][CH2:25]1
Reactant: CCCCCCCCCCCCCCC(=O)CCC(=O)OCC
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCC(=O)CCC1(OCC)OCCO1
Yield: 71.5 %

Procedure:
A mixture of 9.25 g (28 mmol) of ethyl γ-ketooctadecanoate and 9.00 g of ethylene glycol (145 mmol) was refluxed for 5 hours in 300 ml of toluene in the presence of a small amount of p-toluenesulfonic acid catalyst while removing water by means of Dean-Stark apparatus. The resulting mixture was washed with an aqueous saturated sodium bicarbonate solution and then with an aqueous saturated solution of sodium chloride. An oily product obtained by removing the solvent under reduced pressure was subjected to column chromatography over silica gel (eluent: ethyl acetate/hexane=1/10) to give 7.42 g (71% yield) of ethyl γ-ketooctadecanoate ethylene ketal.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2].[N+:17]([O-])([OH:19])=[O:18]>O>[C:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([N+:17]([O-:19])=[O:18])=[C:10]([O:15][CH3:16])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)CCC(NC(C)=O)C2
Reactant: O=[N+]([O-])O
Solvent: O
Product: COc1cc2c(cc1[N+](=O)[O-])CC(NC(C)=O)CC2

Procedure:
30 g of 2-acetylamino-6-methoxy-1,2,3,4-tetrahydronaphthalene are introduced in small amounts into 600 ml of nitric acid (d=1.38), the temperature being kept between -5° and -10° C. The reaction has ended when total dissolution has taken place. The solution is then poured into 2 liters of water and ice and the solid is filtered off, washed and dried. This gives a mixture of the two mononitro isomers, the one being nitrated in the 5-position and the other in the 7-position, and of the dinitro compound. They are separated on a silica column with a 99/1 methyl ethyl ketone/methanol mixture. The compound nitrated in the 7-position melts at 175° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].CN1CCOCC1.[N:13]1([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[C:17](=[O:18])[CH2:16][CH2:15][C@H:14]1[C:19]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23](O)=[O:24])=[O:20]>C(Cl)Cl>[N:13]1([C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:30])[C:17](=[O:18])[CH2:16][CH2:15][C@H:14]1[C:19]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:24])=[O:20]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Reactant: NCC(=O)O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(O)CNC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
Two solutions were prepared before the peptide coupling. Solution A: H-Gly-OH (1.2 eq.) was dissolved in MSA (3.0 eq.) at maximum 60° C. The suspension was cooled down to 25° C., diluted with DCM and stirred for at least 8 hours before being cooled to −15° C. In solution B, the carboxylic function of the Z-Glp-Pro-OH was dissolved with DCM and NMM (1.05 eq.). The solution was cooled to −15° C. The carboxylic acid was activated with IBCF (1.05 eq.) and the silylated solution A was then added to the slurry. The slurry was stirred for at least 0.5 h and left to warm to 25° C. The mixture was quenched with water and the addition of a solution of KHSO4 under stirring precipitated the peptide. The solid was filtered and washed with water. After drying under vacuum, 80% of Z-Glp-Pro-Gly-OH was recovered.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([OH:27])=O)[CH:4]=[N:3]1.Cl.[C@H:29]12[CH2:35][C@H:32]([NH:33][CH2:34]1)[CH2:31][O:30]2.CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]2[N:17]=[C:11]3[CH:10]=[C:9]([NH:8][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[CH:4][C:5]=4[C:25]([N:33]4[CH2:34][C@H:29]5[CH2:35][C@@H:32]4[CH2:31][O:30]5)=[O:27])=[O:24])[CH:14]=[CH:13][N:12]3[N:15]=2)[CH:19]=1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3cccnc3)nc2c1
Reactant: C1O[C@@H]2CN[C@H]1C2
Agent: CCCP(=O)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(C(=O)N2C[C@H]3C[C@@H]2CO3)c1C(=O)Nc1ccn2nc(-c3cccnc3)nc2c1
Yield: 53.1 %

Procedure:
A mixture of 1-methyl-5-(2-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (150 mg, 335 μmol), (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (136 mg, 1.00 mmol), propylphosphonic anhydride (50% in ethyl acetate, 493 μl, 837 μmol) and N,N-diisopropylethylamine (398 μl, 2.34 mmol) in tetrahydrofuran (7.00 ml) was refluxed for 2.5 days (weekend). The solvent was evaporated, the residue was triturated with sodium hydrogencarbonate solution. The precipitated solid was filtered off, washed with water and dried affording 2-methyl-4-((1R,4R)-2-oxa-5-aza-bicyclo[2.2.1]heptane-5-carbonyl)-2H-pyrazole-3-carboxylic acid (2-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (79 mg, 53.1%) as a white solid. mp: 272-273° C., MS: m/z=445.1 (M+H+)
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]1[S:22][CH:23]([CH2:26][C:27]([OH:29])=O)[CH2:24][N:25]=1)[NH:6]2.C[N:31](C)C=O.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:13])=[O:14])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]1[S:22][CH:23]([CH2:26][C:27]([NH2:31])=[O:29])[CH2:24][N:25]=1)[NH:6]2
Reactant: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C3=NCC(CC(=O)O)S3)cc12
Reactant: CN(C)C=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C3=NCC(CC(N)=O)S3)cc12
Temperature: 25 °C
Yield: 92 %

Procedure:
To a mixture of (2-{4-methyl-7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (0.25 g), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (0.11 g) and N,N-dimethylformamide (15 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.14 g) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 2 days. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=9:1-10:0), and the obtained colorless oil was crystallized from ethyl acetate-hexane to give the title compound (228 mg, yield: 92%) as colorless crystals. MS:449(MH+), melting point 120-121° C.
Reaction SMILES: [Br:1]/[CH:2]=[CH:3]/[C:4]1[C:5](=[O:35])[NH:6][C:7](=[O:34])[N:8]([C@@H:10]2[O:14][C@H:13]([CH2:15][O:16][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[O:12][CH2:11]2)[CH:9]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CC#N>[Br:1]/[CH:2]=[CH:3]/[C:4]1[C:5](=[O:35])[NH:6][C:7](=[O:34])[N:8]([C@@H:10]2[O:14][C@H:13]([CH2:15][OH:16])[O:12][CH2:11]2)[CH:9]=1
Reactant: CC(C)(C)[Si](OC[C@@H]1OC[C@H](n2cc(/C=C/Br)c(=O)[nH]c2=O)O1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Product: O=c1[nH]c(=O)n([C@H]2CO[C@@H](CO)O2)cc1/C=C/Br

Procedure:
A solution of 25 (278 mg, 0.499 mmol) in CH3CN (15 mL) was treated with tetra-n-butylammoniumfluorid (I M solution in THF) (0.6 mL, 0.6 mmol) at rt for 1 h. After concentration of the mixture, the residue was purified by silica gel column chromatography (CHCl3:MeOH, 20:1) to give 27 (151 mg, 95 as a white solid: mp 176-177° C.; [α]D+6.5 (c 0.47, MeOH); UV (MeOH) λmax 249.5 (ε 15600), 291.0 nm 11700) (pH 7), 248.5 (ε 16300), 291.5 nm (ε 11800) (pH 2), 253.5 (ε 16500), 284.5 nm (sh) (pH 11).
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1B(O)O>>[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)s1
Reactant: COc1ccc(B(O)O)c(OC)c1
Product: COc1ccc(-c2ccc(S(=O)(=O)Nc3cccc(-c4nnn[nH]4)c3)s2)c(OC)c1
Yield: 15.8 %

Procedure:
The product was prepared according to General Procedure 3, described in Example 22, starting from 5-bromo-N-[3-(1H-tetrazol-5-yl)phenyl]thiophene-2-sulfonamide (Intermediate 17) (19 mg, 0.05 mmol) and 2,4-dimethoxyphenylboronic acid (11 mg, 0.06 mmol) giving 3.5 mg (16%) of the title compound. MS (ESI+) calcd for C19H17N5O4S2 443.072195, found 443.071935.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:11]2[O:10][N:9]=[C:8]([NH2:12])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:17]=1[C:18](Cl)=[O:19]>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:17]=1[C:18]([NH:12][C:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:13])[F:14])[C:11]=2[O:10][N:9]=1)=[O:19]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: Nc1noc2c(C(F)(F)F)cccc12
Solvent: Cc1ccccc1
Product: O=C(Nc1noc2c(C(F)(F)F)cccc12)c1c(Cl)cccc1Cl

Procedure:
7-(Trifluoromethyl)-3-aminobenzisoxazole (2 gram), 2,6-dichlorobenzoylchloride (2 gram), and 50 ml. of toluene are heated at reflux for 16 hours. After evaporation of the solvent at reduced pressure, the resultant oily semi-solid is triturated with ether. The solid so formed is then washed with ether and water and constitutes the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:5]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:29])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])=[CH:9][CH:8]=1)[CH3:5]
Reactant: COC(=O)C(C)Oc1ccc(NC(=O)CCCCCOCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(C)Oc1ccc(NC(=O)CCCCCO)cc1
Reaction time: 16 h
Yield: 51.6 %

Procedure:
2-[4-(6-Benzyloxyhexanoylamino)-phenoxy]-propionic acid methyl ester 59 (15 g, 37.59 mmol) was dissolved in methanol (150 ml) in a pressure vessel. Palladium on carbon (50% wet, 5%, 15 g) was added and the mixture stirred under hydrogen atmos-phere (4 kg) for 16 hrs. Catalyst was removed by filtration and methanol distilled off. Crude 60 was purified by column chromatography on silica gel using chloroform as eluant to get pure 60 (6 g, 51.6%) as a white powder with an m.p between 62-64.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH2:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22](OCC)=[O:23])[N:21]=2)[CH:18]=1>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22]([NH:11][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)([CH3:9])[CH3:10])=[O:23])[N:21]=2)[CH:18]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: CC(C)(N)c1ccc(F)cc1
Product: CC(C)(NC(=O)c1cn2cc(Br)ccc2n1)c1ccc(F)cc1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using 2-(4-fluorophenyl)propan-2-amine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[CH2:6][CH2:7][NH2:8].C(O[CH:16](OCC)[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]=[CH2:28])=[CH:21][CH:20]=1)C.O>C(O)CCC.Cl>[ClH:1].[CH2:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH:16]2[C:9]3[C:5](=[CH:4][C:3]([OH:2])=[C:11]([OH:12])[CH:10]=3)[CH2:6][CH2:7][NH:8]2)=[CH:20][CH:21]=1)[CH:27]=[CH2:28]
Reactant: C=CCOc1ccc(OCC(OCC)OCC)cc1
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: C=CCOc1ccc(OCC2NCCc3cc(O)c(O)cc32)cc1
Yield: 94.8 %

Procedure:
A solution of 3,4-dihydroxyphenethylamine hydrochloride (3.3 g) and (4-allyloxyphenoxy)acetaldehyde diethyl acetal (5.2 g) in a mixture of n-butanol (45 ml), water (12 ml) and concentrated hydrochloric acid (2 drops) was refluxed for 4 hours. After the reaction, the reaction mixture was concentrated to dryness. The residue was crystallized by adding acetone, and the crystals were recrystallized from a mixed solvent of 99% ethanol and ether to give 1-(4-allyloxyphenoxy)methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (6.0 g), mp 114° to 116° C.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])([NH:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[O:20])[C:15]([NH2:17])=[O:16])[CH2:10][CH2:9]2)[CH2:3][CH2:2]1.C=O.[BH3-][C:40]#N.[Na+]>CO>[CH3:40][N:1]1[CH2:7][CH2:6][CH2:5][CH:4]([N:8]2[CH2:9][CH2:10][N:11]([C:14]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])([NH:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[O:20])[C:15]([NH2:17])=[O:16])[CH2:12][CH2:13]2)[CH2:3][CH2:2]1
Reactant: COc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)(C(N)=O)N1CCN(C2CCCNCC2)CC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)(C(N)=O)N1CCN(C2CCCN(C)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.2 %

Procedure:
To a solution of 4-(homopiperidin-4-yl)piperazin-1-yl-2-(2-methoxyphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide (150 mg, 0.30 mmol) and HCHO (37% aq., 0.067 mL, 0.90 mmol) in MeOH (5.0 mL), NaBH3CN (57 mg, 0.90 mmol) was added. After being stirred at room temperature overnight, the mixture was purified by HPLC to give the titled compound (40 mg). MS 514.5 qnd 516.5 (M+H, Cl pattern).
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10](Cl)(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.Cl.O.[NH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([N:16]3[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]3)(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: O=S(=O)(Cl)c1cccc2nsnc12
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Product: O=C1CCN(S(=O)(=O)c2cccc3nsnc23)CC1

Procedure:
The title compound was prepared from benzo[1,2,5]thiadiazole-4-sulfonyl chloride and 4-piperidone monohydrate hydrochloride according to the procedure of Intermediate 22 as an off-white solid; 1H NMR (CDCl3) δ 2.57 (t, J=6.21 Hz, 2H), 3.77 (t, J=6.21 Hz, 2H), 7.60-7.84 (m, 1H), 8.25-8.32 (m, 1H), 8.40-8.46 (m, 1H); MS (ES) m/z 297.9 (MH+). C11H11 N3O3S2
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].OC1C=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1>S(=O)(=O)(O)O>[C:5]([O:4][C:1]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:16][CH:2]=1)(=[O:7])[CH3:6]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)Oc1ccc(C(=O)O)cc1
Temperature: 15 °C

Procedure:
For example, 500 grams of acetic anhydride and 2 drops of sulfuric acid are placed in a vessel and 274 grams of p-hydroxy benzoic acid are added with stirring. The contents of the vessel are stirred at 100°C. for 1 hour, and are cooled to about 15°C. The p-acetoxy benzoic acid formed is recovered by pouring the hot acetic anhydride solution over an ice/water mixture, removing the product by filtration, washing the same with deionized water in a high shear mixer, and drying in a forced air oven. A like quantity of m-acetoxy benzoic acid is formed in an identical manner utilizing m-hydroxy benzoic acid as one of the reactants.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([OH:5])[CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:20]=[C:19](C(Cl)(Cl)Cl)[N:18]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH2:31])[N:26]=3)[C:17]=2[CH:32]=1.O>CN(C=O)C>[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:20]=[C:19]([O:5][CH:3]3[CH2:4][O:1][CH2:2]3)[N:18]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH2:31])[N:26]=3)[C:17]=2[CH:32]=1
Reactant: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(Br)cc32)n1
Reactant: OC1COC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nccc(-n2c(OC3COC3)nc3ccc(Br)cc32)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of oxetan-3-ol (0.04 ml, 0.61 mmol) in DMF (5 ml) at 0° C. was added cesium carbonate (499.75 mg, 1.53 mmol) followed by 4-[6-bromo-2-(trichloromethyl)-1,3-benzodiazol-1-yl]pyrimidin-2-amine (250 mg, 0.61 mmol). The reaction was stirred at RT overnight, then re-charged with oxetan-3-ol (3 eq) and stirred for a total of 5 days at RT. Water was added (15 ml) to the combined reaction mixtures and the product extracted into DCM (2×30 ml). The combined organic extracts were washed with water and brine (10 ml each), dried (Na2SO4), filtered and concentrated in vacuo to give the title compound; 1H NMR (500 MHz, DMSO) delta 4.83-4.70 (2H, m), 5.03-4.89 (2H, m), 5.85-5.75 (1H, m), 7.19-7.05 (3H, m), 7.51-7.34 (2H, m), 8.40 (1H, d, J=5.5 Hz), 8.45 (1H, d, J=1.7 Hz); LC-MS: m/z=+362/364 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[NH:29]1[CH2:32][CH:31]([N:33]2[CH2:38][CH2:37][O:36][C:35]([CH3:40])([CH3:39])[CH2:34]2)[CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:39][C:35]1([CH3:40])[O:36][CH2:37][CH2:38][N:33]([CH:31]2[CH2:30][N:29]([CH2:11][C:10]3[N:2]([CH3:1])[C:3]4[C:8]([N:9]=3)=[C:7]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:6]=[C:5]([N:19]3[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]=[C:20]3[CH3:28])[N:4]=4)[CH2:32]2)[CH2:34]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: CC1(C)CN(C2CNC2)CCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCOC(C)(C)C4)C3)n(C)c2n1
Reaction time: 16 h

Procedure:
A mixture of 9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde (100 mg, 0.26 mmol), 4-azetidin-3-yl-2,2-dimethylmorpholine (54 mg, 0.32 mmol) and 4 Å powdered molecular sieves (200 mg) in DCE (5 mL) was stirred at room temperature for 4 h before the addition of sodium triacetoxyborohydride (112 mg, 0.53 mmol). The reaction mixture was stirred for 16 h then filtered through celite, washing with DCM. The organic phase was washed with brine (×1) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-15%). The resulting oil was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 353 as a white solid (113 mg, 82%). LCMS (Method G): RT 6.47 min [M+H]+ 532.3. 1H NMR (CDCl3, 400 MHz): δ 8.10-8.05 (m, 1 H); 7.73-7.69 (m, 1 H); 7.29-7.24 (m, 2 H); 4.35 (m, 4 H); 3.89-3.83 (m, 9 H); 3.73 (m, 2 H); 3.55 (t, J=6.5 Hz, 2 H); 3.08 (t, J=6.8 Hz, 2 H); 3.01-2.90 (m, 4 H); 2.24 (m, 2 H); 2.07 (s, 2 H) and 1.25 (s, 6 H)
Reaction SMILES: C(OCC)C.[CH3:6][C:7]([CH:14]=[CH:15][CH:16]=[C:17]([CH3:29])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:28])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])=[CH:8][C:9](OCC)=[O:10].C(Cl)(=O)OCC.[NH3:36]>C(N(CC)CC)C>[CH3:6][C:7]([CH:14]=[CH:15][CH:16]=[C:17]([CH3:29])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:28])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])=[CH:8][C:9]([NH2:36])=[O:10]
Reactant: N
Reactant: CCOC(=O)C=C(C)C=CC=C(C)CCC=C(C)CCC=C(C)C
Agent: CCOC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)=CCCC(C)=CCCC(C)=CC=CC(C)=CC(N)=O
Reaction time: 0.17 h

Procedure:
In 20 ml. of diethyl ether was dissolved 3.0 g. of the above-obtained 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid. To this solution was added 1 g. of triethylamine, and further added 1.1 g. of ethyl chlorocarbonate under stirring at room temperature. After 10 minutes, gaseous ammonia was introduced into the solution. The reaction liquid was washed with three 10 ml. portions of water, dried over magnesium sulfate, and evaporated to remove the solvent. The residue was purified by alumina column chromatography and crystallized from a mixture of acetone and n-hexane (1:2). There was obtained 1.7 g. of the desired product as pale yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[NH:12]1[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13]1>CN(C=O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([N:12]1[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13]1)=[O:11]
Reactant: O=C(O)Cc1ccccc1O
Reactant: O[C@H]1CCNC1
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1O)N1CC[C@H](O)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 46.3 %

Procedure:
A mixture of (2-hydroxyphenyl)acetic acid (304 mg, 2.0 mmol) and N,N′-carbonyldiimidazole (405 mg, 2.5 mmol) in DMF (5 nL) was stirred at room temperature for 45 min. A solution of (3S)-pyrrolidin-3-ol (435 mg, 5.0 mmol) in DMF (1.5 mL) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (0-3% methanol in dichloromethane) to give the subtitled compound (205 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:25])/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27]>CO.CCOC(C)=O.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:25])[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)=[CH:16][CH:17]=2)=[CH:4][C:3]=1[C:26]([F:29])([F:27])[F:28]
Reactant: O=C(/C=C/c1ccc(Cc2ccncc2)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(CCc1ccc(Cc2ccncc2)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 18 h

Procedure:
To a solution of (2E)-N-[4-chloro-3-(trifluoromethyl)phenyl]-3-[4-(pyridin-4-ylmethyl)phenyl]acrylamide (70 mg, 0.17 mmol) in MeOH (2 mL) and EtOAc (2 mL) was added Pd/C (10 wt %, 20 mg). The mixture was stirred under hydrogen (60 psi) for 18 h and then filtrated through Celite. The filtrate was concentrated and purified by column chromatography to give A-84 (28 mg, 41%). 1H NMR (300 MHz, CD3OD) δ: 8.35 (d, 2H), 8.03 (d, 1H), 7.70 (dd, 1H), 7.48 (d, 1H), 7.10-7.24 (m, 6H), 3.96 (s, 2H), 2.97 (dd, 2H), and 2.65 (dd, 2H). LCMS: (FA) ES+ 419.2 (M+1), ES− 417.2 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@@H:4]([OH:8])[CH:5]([CH3:7])[CH3:6].C(N(C(C)C)CC)(C)C.[CH3:19][Si:20]([CH3:27])([CH3:26])[CH2:21][CH2:22][O:23][CH2:24]Cl>ClCCl>[CH3:1][O:2][C:3](=[O:9])[C@@H:4]([O:8][CH2:24][O:23][CH2:22][CH2:21][Si:20]([CH3:27])([CH3:26])[CH3:19])[CH:5]([CH3:7])[CH3:6]
Reactant: COC(=O)[C@@H](O)C(C)C
Reactant: C[Si](C)(C)CCOCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](OCOCC[Si](C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of methyl-2-(S)-hydroxy-3-methylbutanoate (1.0 eq; J. Org. Chem. (1997), 62(7), 2292-2297, incorporated herein by reference) in dichloromethane was stirred with diisopropylethylamine (2.0 eq) under nitrogen. 2-Trimethylsilylethoxymethyl chloride (3 eq; Aldrich) was added dropwise via syringe. The solution was stirred at room temperature for 17 hours. The solution was washed with 1.0N HCl, and the water layer was back extracted with dichloromethane. The organics were combined, dried over Na2SO4, and the solvents removed in vacuo. The residue was purified via radial chromatography using 20% ethyl acetate in hexanes affording the title intermediate as a clear oil.