Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22]CC)=[O:21])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[C:25]1[CH:34]=[CH:33][C:32]2[C:31]([CH3:36])([CH3:35])[CH2:30][CH2:29][C:28]([CH3:38])([CH3:37])[C:27]=2[CH:26]=1.Cl>O1CCCC1>[OH:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([OH:22])=[O:21])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[C:25]1[CH:34]=[CH:33][C:32]2[C:31]([CH3:36])([CH3:35])[CH2:30][CH2:29][C:28]([CH3:38])([CH3:37])[C:27]=2[CH:26]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCO)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(-c3cc(-c4ccc(C(=O)O)cc4)ccc3OCCCO)ccc21
Temperature: 40 °C
Reaction time: 48 h
Yield: 90.4 %

Procedure:
2.05 ml (2.05 mmol) of an aqueous solution of sodium hydroxide (1M) are added to a solution of 0.20 g (0.41 mmol) of ethyl 4′-(3-hydroxypropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate in 5 ml of tetrahydrofuran. The reaction mixture is stirred for 48 h while heating at 40° C. The reaction mixture is placed under a stream of nitrogen in order to eliminate the tetrahydrofuran and then 2.5 ml (2.5 mmol) of a solution of hydrochloric acid (1M) are added. The product precipitates in the form of a white solid. After filtration, the product is washed twice with 5 ml of diethyl ether and then placed in an oven under vacuum overnight. 0.17 g of 4′-(3-hydroxypropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylic acid is obtained (white solid, Mp=317° C., yield=90%).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]([CH:8]1[CH2:13][CH2:12][C:11]([C:15]([OH:17])=O)([CH3:14])[CH2:10][CH2:9]1)([CH3:7])[CH3:6]>>[CH:5]([CH:8]1[CH2:13][CH2:12][C:11]([CH3:14])([C:15]([Cl:3])=[O:17])[CH2:10][CH2:9]1)([CH3:7])[CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CC(C)C1CCC(C)(C(=O)O)CC1
Product: CC(C)C1CCC(C)(C(=O)Cl)CC1
Reaction time: 3 h
Yield: 86.4 %

Procedure:
An excess of thionyl chloride was added to 10 g of 4-isopropyl-1-methylcyclohexylcarboxylic acid (cis:trans=1:1, b.p.=122° C./2 mm Hg), and the mixture was stirred for 3 hours. The remaining thionyl chloride was distilled off in a vacuum from the resulting reaction mixture, and the oily product obtained was distilled in a vacuum to obtain 9.5 g of 4-isopropyl-1-methylcyclohexylcarbonyl chloride having a boiling point of 150° to 152° C./60 mm Hg. (Yield: 86.4%.)
Reaction SMILES: [C:1](=[O:30])([O:8][CH2:9]/[C:10](/[C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1)=[C:11](/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)\[CH2:12][OH:13])[O:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7].C[C:32](OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:33].CC(=CC)C.P(=O)(O)(O)O.[O-]Cl=O.[Na+]>ClCCl.C1COCC1.CC(O)(C)C.O>[Br:7][CH2:6][CH2:5][CH2:4][CH2:3][O:2][C:1]([O:8][CH2:9]/[C:10](/[C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:22][CH:21]=1)=[C:11](/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)\[C:12]([O:33][CH3:32])=[O:13])=[O:30]
Reactant: CS(=O)(=O)c1ccc(/C(COC(=O)OCCCCBr)=C(/CO)c2ccccc2)cc1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC=C(C)C
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: O
Product: COC(=O)/C(=C(\COC(=O)OCCCCBr)c1ccc(S(C)(=O)=O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
To a solution of 4.2 g of 4-bromobutyl (2Z)-4-hydroxy-2-[4-(methylsulfonyl)phenyl]-3-phenylbut-2-enyl carbonate in 50 mL of dichloromethane, 4.2 g of Dess-Martin reagent was added and the mixture was stirred at rt for 1 hr. Then 0.5 mL of water was added and the mixture was stirred at rt for 0.5 hr. The resulting mixture was filtered and evaporated. The crude thus obtained was dissolved in a solvent mixture of 30 mL of THF with 30 mL of t-BuOH. To this mixture, 5 mL of 2-methyl-2-butene was added followed by the addition of 50 mL of 1 M phosphoric acid and 25 mL of 1 M of NaClO2. The resulting mixture was stirred at rt for 15 min. The organic phase was separated and the aqueous phase was extracted with EtOAc. The organic phase was combined, dried over Na2SO4, filtered, treated with CH2N2, and then evaporated. The crude was purified by flash chromatography over silica gel (5–50% EtOAc/hexane) to afford 3.89 g of the titled compound as a clear oil. The solvent was evaporated and the residue was purified by flash chromatograph over silica gel to afford 4.3 g of the titled compound. 1H NMR (acetone-d6, 500 M Hz): δ 7.80 (d, 2 H), 7.47 (d, 2 H), 7.22–7.15 (m, 3 H), 7.12–7.05 (m, 2 H), 5.30 (s, 2 H), 4.14 (t, 2 H), 3.82 (s, 3 H), 3.53 (t, 2 H), 3.09 (s, 3 H), 1.91–1.86 (m, 2H), 1.81–1.70 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[CH:6]([S:8]([CH:10]=[CH2:11])=[O:9])=[CH2:7]>O>[OH:5][CH2:4][CH2:3][CH2:2][N:1]1[CH2:11][CH2:10][S:8](=[O:9])[CH2:6][CH2:7]1
Reactant: NCCCO
Reactant: C=CS(=O)C=C
Solvent: O
Product: O=S1CCN(CCCO)CC1
Yield: 95.9 %

Procedure:
Step 1. To a solution of 3-amino-1-propanol (1.33 g, 17.64 mmol) in water (30 ml) was added divinylsulfoxide (2.0 g, 19.6 mmol). After the reaction mixture was refluxed for 0.5 h, it was concentrated and dried in vacuo at 50° C. to afford 4-(3-hydroxypropyl)thiomorpholine 1-oxide (3.0 g, 96%) as a colorless liquid. 1H NMR (500 MHz, CDCl3) δ 1.71-1.85 (m, 2H), 2.65 (t, J=6.4 Hz, 2H), 2.75-2.99 (m, 6H), 3.01-3.27 (m, 2H), 3.73 (t, J=5.9 Hz, 2H), 4.22 (brs, 1H). Step 2. To a solution of OZ288 (0.50 g, 1.4 mmol), 4-(3-hydroxypropyl)thiomorpholine 1-oxide (0.50 g, 2.8 mmol), triphenylphosphine (0.74 g, 2.8 mmol), and triethylamine (0.4 ml, 2.8 mmol) in dry THF (50 ml) at 0° C. was added dropwise a solution of DIAD (0.57 g, 2.8 mmol) in THF (10 ml). After stirring at rt overnight, the solvent was removed in vacuo. The residue was dissolved in EtOAc (50 ml) and washed with water (3×50 ml), dried over MgSO4, and concentrated. The residue was purified by chromatography (silica gel, 50% EtOH in EtOAc) to afford OZ466 free base (0.47 g, 65%) as a colorless solid. To a solution of OZ466 free base (0.47 g, 0.91 mmol) in EtOAc (10 ml) at 0° C. was added dropwise a solution of methanesulfonic acid (0.09 g, 0.91 mmol) in ether (10 ml). The resulting precipitate was filtered, washed with ether (25 ml), and dried in vacuo at 40° C. to afford trioxolane OZ466 (0.50 g, 90%) as a colorless solid. mp 156-158° C.; 1H NMR (500 MHz, DMSO-d6) δ 1.45-1.98 (m, 22H), 2.12-2.21 (m, 2H), 2.39 (s, 3H), 2.51-2.61 (m, 1H), 3.04-3.85 (m, 10H), 4.02 (t, J=6.1 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 7.13 (d, J=8.8 Hz, 2H), 9.78 (brs, 1H); 13C NMR (125.7 MHz, DMSO-d6) δ 23.50, 26.01, 26.42, 31.49, 34.29, 34.45, 35.98, 36.28, 40.89, 42.13, 54.50, 64.91, 108.32, 110.73, 114.63, 127.65, 138.48, 156.68. Anal. Calcd for C30H45NO8S2: C, 58.89; H, 7.41; N, 2.29. Found: C, 57.47; H, 6.94; N, 2.23.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[CH:14]1([CH2:19][NH2:20])[CH2:18][CH2:17][CH2:16][CH2:15]1.Cl.CN(C)CCCN=C=NCC.C(Cl)Cl>CN(C)C1C=CN=CC=1.C(OCC)(=O)C.CN(C)C=O>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11](=[O:13])[NH:20][CH2:19][CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1
Reactant: NCC1CCCC1
Reactant: O=C(O)c1ccc2c(Br)n[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(NCC1CCCC1)c1ccc2c(Br)n[nH]c2c1
Reaction time: 48 h
Yield: 72 %

Procedure:
To a mixture of 3-bromo-6-carboxyindazole (5.84 g), cyclopentylmethylamine (3.48 ml), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.25 g), methylene chloride (120 ml) and dimethylformamide (40 ml) was added 4-dimethylaminopyridine (5.10 g). After stirring for 48 hours, the reaction mixture was added to 450 ml ethyl acetate; washed with 1N hydrochloric acid, 0.5M sodium carbonate and brine: dried (MgSO4); and evaporated. The residue was flash chromatographed over 175 g silica gel, eluting sequentially with methylene chloride (350 ml), 15:85 ethyl acetate:methylene chloride (350 ml), and 1:3 ethyl acetate:methylene chloride to afford 3-bromo-6-(N-cyclopentylmethylcarbamoyl)indazole as a light red solid (5.6 g, 72%), mp 119°-125°.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:17])[CH:9]2[O:16][CH:10]2[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:18](O)(C)C.S(=O)(=O)(O)O>C1C=CC=CC=1>[C:1]1([NH:7][C:8](=[O:17])[CH:9]2[O:16][CH:10]2[C:11]([O:13][CH:14]([CH3:18])[CH3:15])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1OC1C(=O)Nc1ccccc1
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CC(C)OC(=O)C1OC1C(=O)Nc1ccccc1
Yield: 77.4 %

Procedure:
To a solution of ethyl N-phenyl-2,3-epoxysuccinamate (Compound No. 1) (0.5 g) and isopropanol (1.0 g) in benzene (30 ml), a catalystic amount of a concentrated sulfuric acid was added, the mixture was refluxed for 5 hours. The reaction mixture was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated to dryness. The residue thus obtained was treated by silica gel column chromatography using benzene as a developer and the resulting crude crystals were recrystallized from a mixture of n-hexane-acetone to give 0.41 g of isopropyl N-phenyl-2,3-epoxysuccinamate (Compound No. 93) as colorless needles melting at 113°-114.5° C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:66][CH2:67][CH2:68][CH2:69][CH2:70][OH:71]>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:66][CH2:67][CH2:68][CH2:69][CH2:70][OH:71])=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: NCCCCO
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NCCCCO)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.08 h
Yield: 73.3 %

Procedure:
A mixture of 0.045 g (0.1 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.042 g (0.110 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 ml (0.30 mmole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.013 g (0.15 mmole) 4-Amino-butan-1-ol was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient, 100:0-20:80) to give 0.038 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(4-hydroxy-butyl)-3-methoxy-benzamide (I-39) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[S:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:41])[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[S:18][CH:19]2[CH2:20][CH2:21][N:22]([C:32]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:41])[CH2:23][CH2:24]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(Cn2c(SC3CCNCC3)nc3ccccc32)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(Sc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 1 h

Procedure:
To a stirred mixture of 10.2 parts of 1-[(4-fluorophenyl)methyl]-2-[(4-piperidinyl)thio]-1H-benzimidazole, 3.1 parts of N,N-diethylethanamine and 130 parts of dichloromethane was added dropwise a solution of 5.12 parts of (phenylmethyl) carbonochloridate in 65 parts of dichloromethane. Upon completion, stirring was continued for 1 hour at room temperature. The reaction mixture was washed with water. The organic layer was dried, filtered and evaporated, yielding 14.3 parts of (phenylmethyl) 4-[[1-[(4-fluorophenyl)-methyl]-1H-benzimidazol-2-yl]thio]-1-piperidinecarboxylate as a residue (75).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([NH2:22])=[C:12](Br)[CH:11]=1)[CH2:5][CH:6]1[CH2:9][CH2:8][CH2:7]1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.[F-].[Cs+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:24])[CH:4]([C:10]1[CH:11]=[C:12]([C:30]2[CH:31]=[CH:32][C:27]([C:26]([F:37])([F:36])[F:25])=[CH:28][CH:29]=2)[C:13]([NH2:22])=[C:14]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[CH:15]=1)[CH2:5][CH:6]1[CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCC1)c1cc(Br)c(N)c(OCC(F)(F)F)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COC(=O)C(CC1CCC1)c1cc(OCC(F)(F)F)c(N)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 100 °C
Yield: 104.5 %

Procedure:
To a solution of 2-[4-amino-3-bromo-5-(2,2,2-trifluoro-ethoxy)-phenyl]-3-cyclobutyl-propionic acid methyl ester (13.8 g, 29.6 mmol) in DME (anhydrous, 100 mL) under argon atmosphere were added 4-trifluoromethylphenylboronic acid (6.8 g, 35.8 mmol), CsF (11 g, 72.3 mmol), and Pd(PPh3)4 (3.4 g, 2.94 mmol). The reaction mixture was refluxed for 18 h (oil bath, 100° C.). On the next day, a mixture water and EtOAc (100 mL/100 mL) was added and the layers were separated. The organic phase was dried over MgSO4 and evaporated to give a crude yellow oil, which was purified by a short silica gel column chromatography by use of Heptane-EtOAc (4:1) to give the product (14.7 g, 94%) as a yellowish oil. 1H NMR (300 MHz, CDCl3/TMS): δ 7.70 (d, J=8.2 Hz, 2H), 7.59 (d, J=8.0 Hz, 2H), 6.78 (dd, J=9.6, 1.4 Hz, 2H), 4.43 (q, J=8.0 Hz, 2H), 3.95 (br s, 2H), 3.66 (s, 3H), 3.39 (t, J=7.7 Hz, 1H), 2.25-2.07 (m, 2H), 2.03-1.91 (m, 2H), 1.88-1.75 (m, 3H), 1.69-1.52 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 174.6, 144.8, 133.1, 129.2, 128.6, 126.3, 125.7 (q, 3JCF=3.6 Hz), 123.8, 123.3 (q, 1JCF=277.6 Hz), 111.4, 66.5 (q, 1JCF=35.4 Hz), 52.0, 49.0, 40.9, 34.1, 28.3, 28.1, 18.5.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][Si](C(C)(C)C)(C)C)=[CH:7][CH:8]=2)[C:3]=1[N:20]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:43])[CH2:27][C:28]2[N:32]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[C:36]([F:42])[CH:35]=3)[CH:31]=[N:30][CH:29]=2)[C:21]1=[O:44].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C([O-])(O)=O.[Na+]>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[C:3]=1[N:20]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:43])[CH2:27][C:28]2[N:32]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[C:36]([F:42])[CH:35]=3)[CH:31]=[N:30][CH:29]=2)[C:21]1=[O:44]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2ccc(Br)c(N3CC[C@H](NC(=O)Cc4cncn4Cc4ccc(C#N)c(F)c4)C3=O)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1ccc(Cn2cncc2CC(=O)N[C@H]2CCN(c3c(Br)ccc4ccc(O)cc34)C2=O)cc1F
Reaction time: 0.75 h

Procedure:
(S)-N-{1-[2-Bromo-7-(tert-butyldimethylsilyloxy)naphthalen-1-yl]-2-oxopyrrolidin-3-yl}-2-[1-(4-cyano-3-fluorobenzyl)-1H-imidazol-5-yl]acetamide, as described above in Step K, (171 mg, 0.264 mmol) was dissolved in THF (5 mL) and TBAF (1.0 M in THF, 0.26 mL, 0.26 mmol) was added. After 45 min, the mixture was poured into saturated aqueous NaHCO3 and extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with a gradient of CH2Cl2—1% to 10% MeOH—0.1% to 1% NH4OH, to yield the above-titled compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:20]I.O[CH2:23][C:24]#[C:25][CH2:26][O:27][CH2:28][C:29]#[N:30].N1C=CN=C1>C(Cl)Cl>[I:20][CH2:23][C:24]#[C:25][CH2:26][O:27][CH2:28][C:29]#[N:30]
Reactant: II
Reactant: N#CCOCC#CCO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#CCOCC#CCI
Reaction time: 0.08 h
Yield: 92 %

Procedure:
Triphenylphosphine (10.94 g, 41.7 mmol) and iodine (10.55 g, 41.6 mmol were added sequentially to a solution of (4-hydroxy-but-2-ynyloxy)-acetonitrile (4.35 g, 34.8 mmol) in CH2Cl2 (100 mL). The reaction mixture became homogeneous after 5 min at rt and imidazole (2.76 g, 40.5 mmol) was added slowly in small portions. After 1.5 h at rt, the reaction was filtered through activity I basic alumina, washing with 20% EtOAc/Hexane. The filtrate was concentrated in vacuo then purified by flash column chromatography on silica gel (hexane→10% EtOAc/hexane, gradient) to afford 7.51 g (92%) of (4-iodo-but-2-ynyloxy)-acetonitrile.
Reaction SMILES: C(N(CC)CC)C.C(OC([N:15]([C:23]1[C:28]([C:29]#[CH:30])=[N:27][C:26]([N:31]2[CH2:36][CH2:35][N:34]([S:37]([CH2:40][CH3:41])(=[O:39])=[O:38])[CH2:33][CH2:32]2)=[CH:25][N:24]=1)C(=O)OC(C)(C)C)=O)(C)(C)C.[OH:42][N:43]=[C:44](Cl)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.Cl.O1CCOCC1>C1COCC1>[CH2:40]([S:37]([N:34]1[CH2:35][CH2:36][N:31]([C:26]2[N:27]=[C:28]([C:29]3[O:42][N:43]=[C:44]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH:30]=3)[C:23]([NH2:15])=[N:24][CH:25]=2)[CH2:32][CH2:33]1)(=[O:38])=[O:39])[CH3:41]
Reactant: ON=C(Cl)c1ccccc1
Reactant: C#Cc1nc(N2CCN(S(=O)(=O)CC)CC2)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(-c3cc(-c4ccccc4)no3)n2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.7 %

Procedure:
Triethylamine (10.21 mg, 14.06 μL, 0.1009 mmol) was added to a solution of tert-butyl N-tert-butoxycarbonyl-N-[5-(4-ethylsulfonylpiperazin-1-yl)-3-ethynyl-pyrazin-2-yl]carbamate (50 mg, 0.1009 mmol) and N-hydroxybenzimidoyl chloride (15.70 mg, 0.1009 mmol) in THF (4 mL) and the reaction mixture allowed to stir at ambient temperature for 1 hour. After this time the reaction mixture was heated under reflux for 3 hours and allowed to cool to RT. The reaction was treated with HCl in dioxane (126.1 μL of 4 M, 0.5045 mmol), allowed to stir overnight at ambient temperature, concentrated in vacuo and the resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound as an orange solid (9.9 mg, 18% Yield). 1H NMR (DMSO) d 1.03 (3H, t), 2.90 (2H, q), 3.11 (4H, m), 3.33 (4H, m), 5.88 (2H, br s), 7.34-7.36 (4H, m), 7.77 (2H, m), 7.92 (1H, s) ppm; MS (ES+) 414.98
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.[H-].[Na+].[Si:31]([O:38][CH2:39][C:40]1([CH:46]=O)[CH2:44][O:43][C:42]([CH3:45])=[N:41]1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>C1COCC1>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[CH:46][C:40]2([CH2:39][O:38][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33])[CH2:44][O:43][C:42]([CH3:45])=[N:41]2)=[CH:27][CH:28]=1
Reactant: CC1=NC(C=O)(CO[Si](C)(C)C(C)(C)C)CO1
Reactant: Brc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=NC(C=Cc2ccc(Br)cc2)(CO[Si](C)(C)C(C)(C)C)CO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of (4-bromobenzyl)triphenyl-phosphonium bromide (6 mmol) in dry THF (25 mL) is added NaH (6 mmol) in portions. After stirring at room temperature for 30 min, a solution of 4-(t-butyidimethylsilanyloxymethyl)-2-methyl-4,5-dihydrooxazole-4-carbaldehyde (prepared according to Scheme 3 using well-known chemistry in the art) (5 mmol) in THF (10 mL) is added in one portion. The mixture is stirred at room temperature for 12 h. After concentration, the residue is treated with EtOAc/hexane (1/5) (100 mL) and the solid is filtrated. The filtrate is washed with brine and dried over Na2SO4. After concentration, the crude product is purified by column chromatography by EtOAc/hexane (1/5) to give the desired product as a colorless oil. MS: (ES+): 410.1 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11]O)[CH:10]=1)[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]2.[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][N:25]=[CH:24]2)=[O:20]>>[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH2:11][C:9]1[CH:10]=[C:2]([F:1])[CH:3]=[C:4]3[C:8]=1[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]3)[N:25]=[CH:24]2)=[O:20]
Reactant: COC(=O)c1ccc2[nH]ncc2c1
Reactant: CC(C)Cn1ncc2cc(F)cc(CO)c21
Product: COC(=O)c1ccc2c(cnn2Cc2cc(F)cc3cnn(CC(C)C)c23)c1
Yield: 53 %

Procedure:
Compound 27 was prepared following general method 3A, using compound 19 as a starting material and 1H-indazole-5-carboxylic acid methyl ester as the heterocycle. Yield: 53%.
Reaction SMILES: [CH:1](=O)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.S([O-])([O-])(=O)=O.[Mg+2].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[O:6]1[CH:5]=[CH:4][CH:3]=[C:2]1/[CH:1]=[N:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccccc1
Reactant: O=Cc1ccco1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: C(=N/c1ccccc1)\c1ccco1
Temperature: 25 °C
Reaction time: 15 h
Yield: 86 %

Procedure:
Furfural (A, 580.0 mg, 6.04 mmol) was placed in a round-bottom flask and dissolved in 7.50 mL dichloromethane. Magnesium sulfate (750 mg, 6.23 mmol, 1.03 equiv) was added to it followed by aniline (B, 660 uL, d 1.02 g/mL, 1.23 mmol, 1.20 equiv) and the reaction mixture was stirred at room temperature for 15 hrs. Upon completion, the drying reagent was filtered off and the residual solvent was removed on the rotary evaporator. The product imine C (883.0 mg, 86% yield) was recovered as volatile red-brown oil that was used without further purification. 1H NMR (500 MHz, CDCl3) δ 8.30 (s, 1H), 7.63 (br s, 1H), 7.44-7.36 (m, 2H), 7.30-7.22 (m, 3H), 7.02 (s, 1H), 6.57 (dd, J=3.4, 1.7 Hz, 1H). (1H-NMR: Purity>95%).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13](OCC)=[O:14])[CH:10]=[CH:9][C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN[CH2:30][CH2:31]NC.C([Al](CC)CC)C>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:12]=[C:11]([C:13](=[O:14])[CH2:30][CH3:31])[CH:10]=[CH:9][C:8]=2[C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNCCNC
Reactant: CCOC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(-c2ccccc2)n1
Agent: CC[Al](CC)CC
Solvent: Cc1ccccc1
Product: CCC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(-c2ccccc2)n1

Procedure:
Following General Procedure O, 6-phenyl-5-(4-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid ethyl ester (Compound 25, 94 mg, 0.25 mmol) in toluene (3 ml), N,N′-dimethylethylenediamine (DMEDA, 25 mg, 0.28 mmol) and triethylaluminum (0.7 ml, 0.76 mmol, 1 M in hexane) were reacted to produce the title compound as a oil.
Reaction SMILES: [N+:1](C)([O-:3])=[O:2].[C:5]([OH:8])(=[O:7])[CH3:6]>>[N+:1]([O-:3])([OH:7])=[O:2].[C:5]([OH:8])(=[O:7])[CH3:6].[N+:1]([O-:3])([OH:7])=[O:2]
Reactant: C[N+](=O)[O-]
Solvent: CC(=O)O
Product: O=[N+]([O-])O

Procedure:
Nitromethane was formed from acetic acid and nitric acid in an acetic acid/nitric acid molar ratio of 1.2. The reaction was conducted at 410° C. under a pressure of 6 bar for 10.5 seconds.