Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=O)[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[C:3](=O)[NH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH2:1]1[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][NH:2]1
Reactant: O=C1NC(=O)C2CCCCC12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C1CCC2CNCC2C1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
A solution of hexahydro-1H-isoindole-1,3(2H)-dione (1.0 g, 6.5 mmol) in dry THF (14 mL) was added dropwise to a stirred slurry of LiAlH4 in dry THF (6 mL) at such a rate that the solvent gentle refluxed. The resulting reaction mixture was heated to reflux for 20 h and then allowed to cool to RT. The reaction mixture was cooled with an ice-bath, and H2O (1 mL), a 20% aqueous solution of NaOH (2.5 mL) and H2O (2 mL) were sequentially added. The mixture was filtered and THF removed under reduced pressure. The aqueous phase was extracted with Et2O, and the separated organics were dried over Na2SO4, filtered and concentrated to dryness, affording the title compound (690 mg, 5.52 mmol) as a white powder that was used in the next step without any further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([OH:8])=[CH:6][CH:7]=1.[CH:10]1([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23](O)=[O:24])[CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(N(CC)CC)C.C(Cl)Cl>CN(C=O)C>[CH:10]1([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=3[CH3:9])=[O:24])[CH:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Reactant: Cc1cc(O)ccc1N
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(O)ccc1NC(=O)c1cc(NC2CCCCC2)ncn1
Reaction time: 16 h

Procedure:
A mixture of 4-amino-m-cresol (Fluka, 40.00 mg; 0.32 mmol), 6-(cyclohexylamino)pyrimidine-4-carboxylic acid, Intermediate 4 (86.2 mg; 0.39 mmol) and triethylamine (136 μl; 0.97 mmol) in dry DMF (5.00 mL) was treated with polymer-supported Mukaiyama reagent (520 mg; 0.65 mmol) and stirred for 16 hours. DCM was added to the reaction mixture and the solution was filtered through a SPE-NH2 column (2 g). The DCM was evaporated in vacuo, the resulting solution was diluted with EtOAc, washed three times with brine, then the organic phase was dried over magnesium sulfate, filtered and evaporated in vacuo. The solid obtained was triturated in acetonitrile to afford the title compound as a yellow solid.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4].[CH:8]12[CH2:14][CH:11]([CH:12]=[CH:13]1)[CH2:10][CH:9]2[CH:15]=[O:16].O1CCCC1.Cl>[Zn].CCCCCC>[OH:16][CH:15]([CH:9]1[CH2:10][CH:11]2[CH2:14][CH:8]1[CH:13]=[CH:12]2)[CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4]
Reactant: O=C1OCCC1Br
Reactant: O=CC1CC2C=CC1C2
Agent: Cl
Agent: [Zn]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1OCCC1C(O)C1CC2C=CC1C2
Yield: 71.2 %

Procedure:
Addition reaction was carried out by mixing 98 g of zinc powder, 247 g of α-bromo-γ-butyrolactone, 122 g of 5-norbornene-2-carbaldehyde, and 2 kg of dry tetrahydrofuran and heating the mixture under reflux for 10 hours in a nitrogen atmosphere. The reaction mixture was cooled, to which dilute hydrochloric acid was added for neutralization and hexane was added for extraction. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum. Purification by silica gel column chromatography yielded 148 g (yield 71%) of α-[hydroxy(5-norbornen-2-yl)methyl]-γ-butyrolactone.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]2[S:25][C:26]([CH:29]=O)=[CH:27][N:28]=2)[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1.C(O)(=O)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:29][C:26]2[S:25][C:24]([NH:23][C:13]3[CH:14]=[CH:15][C:16]([N:17]4[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]4)=[C:11]([O:10][CH3:9])[CH:12]=3)=[N:28][CH:27]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: COc1cc(Nc2ncc(C=O)s2)ccc1-n1cnc(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc(Nc2ncc(CNc3ccc(F)cc3)s2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
21 mg (0.19 mmol) 4-Fluoroaniline was dissolved in tetrahydrofurane (1 ml). 65 mg (0.21 mmol) 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazole-5-carbaldehyde was added. The suspension was stirred at room temperature for 10 minutes. 133 mg (0.56 mmol) sodium triacetoxyborohydride and 23 mg (0.38 mmol) acetic acid were added and the reaction was stirred at room temperature over night. Since the reaction was not complete the same amount of 4-fluoroaniline, sodium triacetoxyborohydride and acetic acid were added and the reaction stirred at room temperature over night. 2N aqueous NaOH solution was added and the reaction was extracted once with methylene chloride. The organic layer was washed with brine, dried over sodium sulphate, filtered and the solvent was evaporated under reduced pressure. The crude product was purified on silica gel with ethyl acetate yielding 22 mg (26%) [5-(4-fluoro-benzyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a light yellow solid. MS ISP (m/e): 410.1 (100) (M+H)+. 1H NMR (CDCl3, 250 MHz): δ (ppm)=7.63 (s, 1H), 7.28-7.16 (m, 4H), 6.95-6.87 (m, 4H), 6.66-6.60 (m, 2H), 4.39 (s, 2H), 3.85 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:27]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:4]2[N:3]=1.[C:28](Cl)(=[O:31])[CH2:29][CH3:30]>CN(C)C(=O)C.C(=O)([O-])O.[Na+]>[CH3:26][C:25]1[C:20]([C:18]([NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([O:10][C:8]3[CH:7]=[CH:6][C:5]4[N:4]([N:3]=[C:2]([NH:1][C:28](=[O:31])[CH2:29][CH3:30])[N:27]=4)[CH:9]=3)[CH:12]=2)=[O:19])=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCC(=O)Cl
Reactant: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(N)nn3c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)c4ncccc4C)c3)cn2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a solution of N-{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]phenyl}-3-methylpyridine-2-carboxamide (120 mg, 0.333 mmol) in N,N-dimethylacetamide (5 mL) was added propionylchloride (29.2 μL, 0.336 mmol), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0%→100% ethyl acetate-hexane) to give the title compound (101 mg, 73%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:33]([NH:36][CH2:37][CH2:38][CH3:39])[CH2:34][CH3:35].C(N(CC)CC)C>ClCCl>[CH2:33]([N:36]([CH2:37][CH2:38][CH3:39])[C:8]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=1)=[O:10])[CH2:34][CH3:35]
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: CCCNCCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)c1cc(Cl)ccn1
Yield: 67.3 %

Procedure:
Stir a solution of 4-chloro-2-pyridine carboxylic acid (1.0 g, 6.3 mmol), 1-hydroxybenzotriazole (850 mg, 6.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.21 g, 6.3 mmol), dipropyl amine (862 μL, 6.3 mmol), and triethylamine (1.75 mL, 12.6 mmol) in dichloromethane (63 mL) at room temperature over the weekend. Wash the solution with 0.1 N citric acid (2×50 mL), saturated aqueous sodium bicarbonate (50 mL), saturated aqueous sodium chloride (50 mL), dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with 10:90 to 20:80 ethyl acetate:hexanes)to give the title compound (1.02 g, 67%).
Reaction SMILES: [C:1]([C:5]1[C:10]2[CH2:11][C:12]([CH3:17])([C:14]([OH:16])=[O:15])[O:13][C:9]=2[CH:8]=[C:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[O:22][Si](C)(C)C)([CH3:4])([CH3:3])[CH3:2].[CH3:27]O>Cl>[C:1]([C:5]1[C:10]2[CH2:11][C:12]([C:14]([O:16][CH3:27])=[O:15])([CH3:17])[O:13][C:9]=2[CH:8]=[C:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[OH:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C(=O)O)Cc2c(cc(C(C)(C)C)c(O[Si](C)(C)C)c2C(C)(C)C)O1
Reactant: CO
Agent: Cl
Product: COC(=O)C1(C)Cc2c(cc(C(C)(C)C)c(O)c2C(C)(C)C)O1
Reaction time: 3 h

Procedure:
In 5 ml of a saturated solution of hydrogen chloride in methanol was dissolved 0.20 g of 4,6-di-t-butyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran-2-carboxylic acid at room temperature and the mixture was stirred for 3 hours, then the reaction solution was concentrated. The residue was purified on a short column of silica gel eluting with n-hexane containing 16% ethyl acetate to give 0.15 g of 4,6-di-t-butyl-5-hydroxy-2-methoxycarbonyl-2-methyl-2,3-dihydrobenzofuran as a colorless powder.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[NH:14][C:15]([NH2:24])=[C:16]2[C:20]([N:21]=1)=[N:19][C:18]([O:22][CH3:23])=[N:17]2)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][CH2:28][CH:29]1[CH2:33][CH2:32][O:31][CH2:30]1>>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][CH:29]2[CH2:33][CH2:32][O:31][CH2:30]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: BrCCCC1CCOC1
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCOC3)c2n1

Procedure:
Prepared similarly to Intermediate 216 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 3-(3-bromopropyl)tetrahydrofuran.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=O)[C:3]=1[C:10]#[N:11].P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:4]1[N:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[C:10]#[N:11]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(C)c(C#N)c(=O)[nH]1
Product: Cc1cc(C)c(C#N)c(Cl)n1
Yield: 90 %

Procedure:
4,6-Dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (5 g, 34 mmol) was added to phosphorus oxychloride (20 ml). The reaction was stirred at reflux for 2 h, after which it was seen complete. Volatiles were removed and the residue triturated with petrol. The resultant solid was filtered off and washed with hexane, and dried to give a pure white solid (5.1 g, 90%). δH (250 MHz, CDCl3) 2.55 (3 H, s, CH3), 2.57 (3 H, s, CH3), 7.09 (1 H, s, ArH); δC (250 MHz, CDCl3) 162.64 (C), 154.39 (C), 152.26 (C), 123.22 (CH), 114.28 (C), 108.31 (C), 24.5 (CH3), 20.54 (CH3); m/z 189 (M+Na)
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:26][O:27][CH2:28][CH3:29])[N:14]([CH2:15][C:16]([NH:19][C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37]C(=O)OC(C)(C)C)=[CH:5][C:4]=2[N:3]=1.C(O)C>Cl>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:26][O:27][CH2:28][CH3:29])[N:14]([CH2:15][C:16]([NH:19][C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])([CH3:17])[CH3:18])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(OCCCCCCNC(=O)OC(C)(C)C)ccc3c2n1CC(C)(C)NC(=O)NC(C)C
Agent: Cl
Solvent: CCO
Product: CCOCc1nc2c(N)nc3cc(OCCCCCCN)ccc3c2n1CC(C)(C)NC(=O)NC(C)C
Temperature: 25 °C
Yield: 84.8 %

Procedure:
A solution of tert-butyl 6-{[4-amino-2-(ethoxymethyl)-1-(2-{[(isopropylamino)carbonyl]amino}-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}hexylcarbamate (4.20 g, 6.84 mmol) in 3 M HCl in ethanol (50 mL, 150 mmol) was heated at reflux for five minutes, then was allowed to cool to room temperature and was concentrated under reduced pressure. The resulting orange solid was dissolved water and the solution was washed with dichloromethane (2×). The aqueous layer was treated with ammonium hydroxide until a basic pH was reached, then was extracted with dichloromethane (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to yield 2.98 g of N-{2-[4-amino-7-[(6-aminohexyl)oxy]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-N′-isopropylurea as a dark orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:20]([O:21][CH3:22])=[CH:19][C:6]2[NH:7][C:8]([S:10][CH2:11][C:12]3[N:17]=[C:16]([NH2:18])[CH:15]=[CH:14][CH:13]=3)=[N:9][C:5]=2[CH:4]=1.[OH2:23]>>[CH3:1][O:2][C:3]1[C:20]([O:21][CH3:22])=[CH:19][C:6]2[NH:7][C:8]([S:10]([CH2:11][C:12]3[N:17]=[C:16]([NH2:18])[CH:15]=[CH:14][CH:13]=3)=[O:23])=[N:9][C:5]=2[CH:4]=1
Reactant: O
Reactant: COc1cc2nc(SCc3cccc(N)n3)[nH]c2cc1OC
Product: COc1cc2nc(S(=O)Cc3cccc(N)n3)[nH]c2cc1OC

Procedure:
The title compound (600 mg) was prepared by the method of Example 85 using 1.6 g (5.0 mmole) of 6-[[(5,6-dimethoxy-1H-benzimidazol-2-yl)thio]methyl]-2-pyridinamine (see Example 98) instead of 6-[(1H-benzimidazol-2-ylthio)-methyl]-2-pyridinamine. Structure assignment was supported by the nmr spectrum and by elemental analysis. Analysis. Calc'd. for C15H16N4SO3*¼ H2O: C, 53.48; H, 4.90; N, 16.63; S, 9.52. Found: C, 53.54; H, 4.57; N, 16.45; S, 9.79.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([O-:24])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Na+].[CH2:28](Br)[CH:29]=[CH2:30]>CN(C)P(N(C)C)(N(C)C)=O>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:30][CH:29]=[CH2:28])=[O:23])=[CH:25][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=CCBr
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)[O-])cc1
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCOC(=O)c1ccc(NCCCCCCCCCCCCCCCC)cc1

Procedure:
A solution of 7.66 g. of sodium 4-(n-hexadecylamino)benzoate and 12.1 g. of allyl bromide in 100 ml. of dry hexamethylphosphoramide is added to a reaction flask. After 6 hours the solution is poured into 100 ml. of water and the solid collected and recrystallized from 50 ml. of acetonitrile. This material is recrystallized from hexanol to yield the title compound, m.p. 81°-83° C.
Reaction SMILES: [Cl:1][C:2]([Cl:11])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].C(OC(=O)C)(=O)C.[N+:19]([O-])([OH:21])=[O:20].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[N+:19]([C:7]1[NH:6][C:5]([C:3](=[O:4])[C:2]([Cl:1])([Cl:10])[Cl:11])=[CH:9][CH:8]=1)([O-:21])=[O:20]
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(c1ccc([N+](=O)[O-])[nH]1)C(Cl)(Cl)Cl
Temperature: 25 °C

Procedure:
21.3 g (0.1 mol) of 2-trichloroacetylpyrrole and 100 ml of acetic anhydride were introduced into a round-bottomed flask. At 0° C., a solution of 4.2 ml of fuming nitric acid, 8 ml of acetic acid and 8 ml of acetic anhydride was added dropwise and the temperature was permitted to increase to room temperature. The reaction medium was poured into ice, the pH adjusted to 8 with sodium bicarbonate, extracted with dichloromethane, the organic phase decanted off, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with a mixture of dichloromethane and hexane (60-40). There were recovered 5.5 g (21%) of 5-nitro-2-trichloroacetylpyrrole in the form of a dark green oil and 11.2 g of 4-nitro-2-trichloroacetylpyrrole of melting point 160°-163° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:16]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:15]([CH3:22])[N:14]=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.I[CH2:40][CH2:41][CH3:42]>CN(C=O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:16]([CH:17]([CH2:40][CH2:41][CH3:42])[C:18]([O:20][CH3:21])=[O:19])=[C:15]([CH3:22])[N:14]=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCCI
Reactant: COCOc1cccc(-c2nc(-c3ccccc3)nc(C)c2CC(=O)OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1cccc(OCOC)c1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
A solution of methyl 2-(4-(3-(methoxymethoxy)phenyl)-6-methyl-2-phenylpyrimidin-5-yl)acetate (79 mg; 0.209 mmol) in dry DMF (1 mL) was cooled to −15° C. (acetone/ice). LHMDS (0.230 mL; 0.230 mmol; 1M in THF) was added dropwise and the mixture was stirred at −15° C. for 15 min followed by the dropwise addition of iodopropane (0.031 mL; 0.313 mmol), after stirring for 2 h at −15° C. the mixture was allowed to warm to room temperature. After 1 h the reaction was quenched by adding a saturated solution of ammonium chloride. The mixture was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (2-10%) in heptane to give 65 mg (73%) of the title compound as a colorless oil. ESI/APCI(+): 421 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[Cl:15][CH2:16][C:17]([CH3:19])=[CH2:18]>>[Cl:15][CH2:16][C:17]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9])([CH3:19])[CH3:18]
Reactant: COc1ccc(C)cc1
Reactant: C=C(C)CCl
Agent: O=S(=O)(O)O
Product: COc1ccc(C)cc1C(C)(C)CCl
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a yellow solution of 4-methylanisole (20 g, 183.5 mmol) and 1.7 mL of concentrated sulfuric acid was added 19.17 mL of 3-chloro-2-methylpropene by addition funnel. The reaction became warm and turned dark purple. After 20 minutes, solids began to precipitate. TLC of an aliquot showed some starting anisole left and a new, slightly less polar spot forming. The reaction mixture was stirred overnight and TLC then showed that the reaction was complete. The reaction mixture was poured onto ice and extracted with diethyl ether. The organics were combined, dried over magnesium sulfate, and concentrated in vacuo to leave an oil. The residue was taken up in hexanes, cooled to −78° C., and the solids collected by filtration to give 14 g of 2-(2-chloro-1,1-dimethylethyl)-1-methoxy-4-methylbenzene as an oil upon warming. The filtrate was concentrated in vacuo to give 15.5 g of a 4:1 mixture of product and starting anisole.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.Cl[C:26]1[O:27][C:28]2[C:29](=[C:31]([C:35]#[N:36])[CH:32]=[CH:33][CH:34]=2)[N:30]=1>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4][C@H:3]2[CH2:2][NH:1][C:26]2[O:27][C:28]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[N:36])[C:29]=3[N:30]=2)=[CH:11][C:12]=1[F:17]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Reactant: N#Cc1cccc2oc(Cl)nc12
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CNc2nc3c(C#N)cccc3o2)C1

Procedure:
Using tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate and 2-chloro-1,3-benzoxazole-4-carbonitrile, and in the same manner as in Example 391, step A, the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=1)[C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[F:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][C:35]=1[C:43]([F:46])([F:45])[F:44].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.C(#N)C.CCOC(C)=O>[F:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([NH:1][C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:20])([F:21])[F:19])[CH:12]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:30])([F:31])[F:32])[CH:23]=2)[C@@H:3]([OH:4])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:39])=[CH:36][C:35]=1[C:43]([F:44])([F:45])[F:46]
Reactant: NC(c1cccc(OC(F)(F)F)c1)(c1cccc(OC(F)(F)F)c1)[C@@H](O)c1ccccc1
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(NC(c1cccc(OC(F)(F)F)c1)(c1cccc(OC(F)(F)F)c1)[C@@H](O)c1ccccc1)c1ccc(F)c(C(F)(F)F)c1
Yield: 15 %

Procedure:
A solution of (S)-2-amino-1-phenyl-2,2-bis(3-(trifluoromethoxy)phenyl)ethanol (44 mg, 0.096 mmol), 4-fluoro-3-(trifluoromethyl)benzoic acid (20 mg, 0.096 mmol), EDCI (28 mg, 0.14 mmol), HOBT (14 mg, 0.096 mmol) and a catalytic amount of DMAP in acetonitrile (3 mL) was stirred for 24 h at rt. The reaction mixture was diluted with EtOAc and washed successively with 1 N HCl, 1 N NaOH, sat. NaCl, dried over MgSO4, filtered and concentrated. The residue was purified by preparative HPLC Shimadzu-YMC Sunfire 5μ column, 30×100 mm eluting with 50-100% MeOH (90% in H2O, 0.1% TFA) gradient over 10 min with flow rate 40 mL/min and UV detection at 220 nm. (S)-4-Fluoro-N-(2-hydroxy-2-phenyl-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-3-(trifluoromethyl)benzamide (Example 311) was isolated as a colorless film (10 mg, 15% yield). HPLC: RT=4.143 minutes (Phenomenex Luna C18 5 u column eluting with 10-90% aqueous methanol containing 0.1% phosphoric acid over a 4 minute gradient monitoring at 220 nm). LCMS: [M+H] 648.0 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 8.23 (m, 1H), 7.37-6.9 (m, 15H), 5.41 (s, 1H).
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[S:3][C:2]=1[C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([NH:20][C:21](=[O:34])[C:22]2[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=2)[CH:19]=1)[C:13]([O:15]C)=[O:14].O.[OH-].[Na+].Cl>C1COCC1>[N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[S:3][C:2]=1[C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([NH:20][C:21](=[O:34])[C:22]2[CH:23]=[C:24]([O:32][CH3:33])[C:25]([O:30][CH3:31])=[C:26]([O:28][CH3:29])[CH:27]=2)[CH:19]=1)[C:13]([OH:15])=[O:14]
Reactant: COC(=O)c1cc(NC(=O)c2cc(OC)c(OC)c(OC)c2)cc(-c2nc3ccncc3s2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)Nc2cc(C(=O)O)cc(-c3nc4ccncc4s3)c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
Methyl 3-(thiazolo[5,4-c]pyridin-2-yl)-5-(3,4,5-trimethoxybenzamido)benzoate (80 mg, 0.167 mmol) was dissolved in 5 mL of THF and 2 mL of water containing 30 mg of sodium hydroxide. The reaction mixture was stirred at room temperature for 1 hour. It was then acidified to pH 4 with 6 N HCl and concentrated. The solids were collected by filtration and dried to afford 60 mg of 3-(thiazolo[5,4-c]pyridin-2-yl)-5-(3,4,5-trimethoxybenzamido)benzoic acid (78% yield) (MS, M++H=466).