Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:3](=[O:19])[C:4]2[CH:9]=[CH:8][NH:7][C:6](=[O:10])[C:5]=2[O:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:20](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[I:1][C:2]1[C:3](=[O:19])[C:4]2[CH:9]=[CH:8][N:7]([CH3:20])[C:6](=[O:10])[C:5]=2[O:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=c1c(I)c(-c2ccccc2)oc2c(=O)[nH]ccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ccc2c(=O)c(I)c(-c3ccccc3)oc2c1=O
Reaction time: 72 h
Yield: 61.2 %

Procedure:
To a mixture of 3-iodo-2-phenyl-7H-pyrano[2,3-c]pyridine-4,8-dione (50 mg, 0.137 mmol) and potassium carbonate (76 mg, 0.548 mmol) in DMF (2 mL) was added iodomethane (26 μL, 0.411 mmol) at RT. After 3 days, the reaction mixture was partitioned between ethyl acetate and water. The resultant biphasic mixture was separated, the aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was crystallised from ethyl acetate to give the title compound (31.8 mg, 61%) as a cream solid. The mother liquors were evaporated, the residue was dissolved in DCM and subjected to flash chromatography (SiO2, gradient 70 to 100% ethyl acetate in cyclohexane) to afford a further quantity of the title compound (17.6 mg, 34%). LCMS (Method A): RT=3.78 min, [M+H]+=380.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:8]([CH2:11][C:12]([CH3:17])([N+:14]([O-:16])=[O:15])[CH3:13])=[CH:9][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O>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.O1CCOCC1>[CH3:13][C:12]([N+:14]([O-:16])=[O:15])([CH3:17])[CH2:11][C:8]1[N:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)[C:3]2=[N:10][CH:9]=1
Reactant: CC(C)(Cc1cnc2c(Br)cccn12)[N+](=O)[O-]
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(Cc1cnc2c(-c3cccs3)cccn12)[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
A mixture of 8-bromo-3-(2-methyl-2-nitropropyl)imidazo[1,2-a]pyridine (1.5 g, 5.0 mmol), Pd(PPh3)4 (0.68 g), 2M aqueous sodium carbonate solution (8 ml), and dioxane (68 ml) is stirred for 30 minutes under an atmosphere of argon. After addition of thiophene-2-boronic acid (0.96 g, 7.5 mmol), the mixture is stirred overnight at 80° C. The solids are removed by filtration, and the residue is chromatographed (silica gel, dichloromethane/ethanol 95:5) to give 1.52 g of 3-(2-methyl-2-nitropropyl)-8-(2-thienyl)imidazo[1,2-a]pyridine (100%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9][CH2:8][CH:7]([CH3:10])[C:6]1=[O:11])=[O:4].[CH2:20]([O:22][C:23]([C:25]1([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[CH2:29][CH2:28][CH:27]([CH3:30])[C:26]1=[O:31])=[O:24])[CH3:21].[H-].[Na+]>>[CH3:1][O:2][C:3]([C:5]1([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH2:9][CH2:8][C:7]([CH3:20])([CH3:10])[C:6]1=[O:11])=[O:4].[CH2:20]([O:22][C:23]([C:25]1([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[CH2:29][CH2:28][C:27]([CH3:1])([CH3:30])[C:26]1=[O:31])=[O:24])[CH3:21]
Reactant: COC(=O)C1(Cc2ccc(Cl)cc2)CCC(C)C1=O
Reactant: CCOC(=O)C1(Cc2ccc(Cl)cc2)CCC(C)C1=O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C1(Cc2ccc(Cl)cc2)CCC(C)(C)C1=O
Product: COC(=O)C1(Cc2ccc(Cl)cc2)CCC(C)(C)C1=O

Procedure:
reacting 1-[(4-chlorophenyl)methyl]-3-methyl-2-oxocyclopentanecarboxylic acid methyl ester or 1-[(4-chlorophenyl)methyl]-3-methyl-2-oxocyclopentanecarboxylic acid ethyl ester with sodium hydride and methyl halide to obtain 1-[(4-chlorophenyl)methyl]-3,3-dimethyl-2-oxocyclopentanecarboxylic acid methyl ester or 1-[(4-chlorophenyl)methyl]-3,3-dimethyl-2-oxocyclopentanecarboxylic acid ethyl ester; and
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][NH2:12])[CH2:6][CH2:5]1.[CH2:13]1[NH:15][CH2:14]1.[Cl-].[NH4+]>>[NH2:15][CH2:14][CH2:13][NH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][NH2:12])[CH2:6][CH2:5]1
Reactant: C1CN1
Reactant: NCCC1CCC(CCN)CC1
Agent: [Cl-]
Agent: [NH4+]
Product: NCCNCCC1CCC(CCN)CC1

Procedure:
1,4-Bis-(2-aminoethyl)cyclohexane (68 gm., 0.4 mole) and ethyleneimine (4.3 gm., 0.1 mole) with 0.4 g. ammonium chloride is mixed in a glasslined pressure reactor and filled with nitrogen to 100 psi. The mixture is shaken and heated to 85°-95° C. for 48 hours. After cooling, it is distilled rapidly free of the salt and then fractionated under high vacuum. The starting diamine is readily distinguished from the triamine product by thin layer chromatography and silica gel using a mixture of 1 volume concentrated aqueous ammonium hydroxide with 4 volume methyl alcohol, the diamine having a much higher Rf.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[NH:12][C:13]([C:16](=O)[C:17]3[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=3F)=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.O.[NH2:30][NH2:31].CN1CCCC1=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[NH:12][C:13]([C:16]3[C:17]4[C:18](=[CH:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=4)[NH:31][N:30]=3)=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1cccc(F)c1)c1ccc(C(=O)c2cc(C(F)(F)F)ccc2F)[nH]1
Reactant: NN
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(Nc1cccc(F)c1)c1ccc(-c2n[nH]c3ccc(C(F)(F)F)cc23)[nH]1
Temperature: 120 °C

Procedure:
A mixture of 5-(2-fluoro-5-trifluoromethyl-benzoyl)-1H-pyrrole-2-carboxylic acid (3-fluoro-phenyl)-amide, hydrazine hydrate, 1-methyl-pyrrolin-2-one and toluene was heated at 120° C. for 2 hours. The reaction was concentrated, mixed with water and filtered. The solid was washed to give the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([N:12]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:13][C@H:14]([OH:23])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][OH:11])=[CH:4][CH:3]=1.[NH:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[C:36](O)=[O:37].Cl.CN(C)CCCN=C=NCC>ClCCl>[CH2:24]([N:12]([C@H:9]([CH2:10][OH:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:36]([C:32]2[NH:31][CH:35]=[CH:34][CH:33]=2)=[O:37])=[CH:3][CH:4]=1)[CH2:13][C@H:14]([OH:23])[CH2:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Nc1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)COc2ccccc2)cc1
Reactant: O=C(O)c1ccc[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)COc2ccccc2)cc1)c1ccc[nH]1
Temperature: 25 °C
Reaction time: 47 h
Yield: 49.4 %

Procedure:
To a mixture of (2S)-3-(4-aminophenyl)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-1-propanol (79 mg) and pyrrole-2-carboxylic acid (26 mg) in dichloromethane (0.8 ml) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (59 mg), and the mixture was stirred at room temperature for 47 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate) to give N-[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropyl]-phenyl]-1H-pyrrole-2-carboxamide (48 mg) as a white amorphous powder.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][CH:8]=1.CCN(C(C)C)C(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C1COCC1>[CH3:26][S:27]([O:1][CH2:2][C:3]1[CH:8]=[N:7][C:6]([NH:9][C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])=[CH:5][CH:4]=1)(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CO)cn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(COS(C)(=O)=O)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 49.1 %

Procedure:
To a mixture containing tert-butyl 5-(hydroxymethyl)pyridin-2-ylcarbamate (101; 4.5 g, 20.2 mmol) and DIPEA (16.0 g, 121 mmol) in THF (45 mL) was added MsCl (6.93 g, 60.5 mmol) over a period of 30 min at 0° C. The resulting reaction mixture was stirred at room temperature for 12 h. The mixture was then washed with water (2×5 mL), dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (10:1 petroleum ether/ethyl acetate) to afford (6-(tert-butoxycarbonylamino)pyridin-3-yl)methyl methanesulfonate 102 (3.0 g, 61%).
Reaction SMILES: C(O)=O.C(OC(=O)[NH:10][CH:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[O:18][C:19]3[CH:25]=[C:24]([O:26][C:27]4[S:28][C:29]5[C:30]([N:35]=4)=[N:31][CH:32]=[CH:33][CH:34]=5)[CH:23]=[CH:22][C:20]=3[CH:21]=2)[CH2:12]1)(C)(C)C.[ClH:37].O1CCOCC1>C(Cl)Cl>[ClH:37].[S:28]1[C:29]2[C:30](=[N:31][CH:32]=[CH:33][CH:34]=2)[N:35]=[C:27]1[O:26][C:24]1[CH:23]=[CH:22][C:20]2[CH:21]=[C:17]([CH2:16][N:13]3[CH2:14][CH2:15][CH:11]([NH2:10])[CH2:12]3)[O:18][C:19]=2[CH:25]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2cc3ccc(Oc4nc5ncccc5s4)cc3o2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O=CO
Product: NC1CCN(Cc2cc3ccc(Oc4nc5ncccc5s4)cc3o2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 95 %

Procedure:
To a suspension of {1-[6-(thiazolo[4,5-b]pyridin-2-yloxy)-benzofuran-2-ylmethyl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester formate (435 mg, 0.849 mmol) in DCM (10 mL) was added 4 M HCl in dioxane (1.06 mL, 4.25 mmol) and the reaction mixture was stirred (rt, 14 h). The reaction mixture was concentrated in vacuo to afford the title compound as a yellow solid (320 mg, 95%). MS (ESI): mass calcd. for C19H18N4O2S, 366.1; m/z found, 367.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C@@H:11]1[NH:16][CH2:15][CH2:14][N:13]([C:17]2[C:26]3[CH:25]=[C:24]([CH3:27])[S:23][C:22]=3[NH:21][C:20]3[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=3[N:18]=2)[CH2:12]1.C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C@@H:11]1[N:16]([CH3:34])[CH2:15][CH2:14][N:13]([C:17]2[C:26]3[CH:25]=[C:24]([CH3:27])[S:23][C:22]=3[NH:21][C:20]3[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=3[N:18]=2)[CH2:12]1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccc(F)cc2F)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CCc2ccc(F)cc2F)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60.1 %

Procedure:
Combine 10-((S)-3-[2-(2,4-difluoro-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (57.3 mg, 0.61 mmol), formaldehyde (11.7 μL, 0.14 mmol, 37% in water), and 1,2-dichloroethane (5.0 ml). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (41.5 mg, 0.20 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion, extract the aqueous with dichloromethane and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue to give 54.4 mg (92%) of the title compound: mass spectrum (ion spray): m/z=452.9 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[CH2:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C.[C:20](OC(=O)C)(=O)C>>[CH3:20][C:6]([C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])=[CH:12][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: CCc1ccccn1
Reactant: CC(=O)OC(C)=O
Product: CC(=Cc1ccccn1)c1ccccc1[N+](=O)[O-]

Procedure:
A mixture of o-nitrobenzaldehyde (127 g., 0.84 mole), 2-ethylpyridine (90 g., 0.84 mole) and acetic anhydride (171 g., 1.68 mole) is heated at reflux for 24 hr. Excess acetic anhydride is evaporated in vacuo and the residue poured into 500 ml. of water. The mixture is adjusted to pH 11 with 50% NaOH providing a precipitate which is collected and dried. Crystallization from isopropyl ether yields 136.7 g. (67%) of 2-β-methyl-2-nitrostyryl)pyridine, m.p. 62°-64° C. which, after a second crystallization, is analytically pure.
Reaction SMILES: N1CCCCC1.[CH2:7]([O:10][CH2:11][C:12](=O)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]#[CH:9].[Cl:20][C:21]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=O.[NH2:30]/[C:31](/[CH3:37])=[CH:32]\[C:33]([O:35][CH3:36])=[O:34]>>[Cl:20][C:21]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]1[C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]([CH3:37])[NH:30][C:12]([CH2:11][O:10][CH2:7][C:8]#[CH:9])=[C:13]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: COC(=O)/C=C(/C)N
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: C#CCOCC(=O)CC(=O)OCC
Solvent: C1CCNCC1
Product: C#CCOCC1=C(C(=O)OCC)C(c2cccc(Cl)c2Cl)C(C(=O)OC)=C(C)N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 19.9 %

Procedure:
Piperidine (2.4 g) was added dropwise over 10 minutes to a stirred mixture of ethyl 4-(prop-2-ynoxy)acetoacetate (63 g) (see Preparation 9) and 2,3-dichlorobenzaldehyde (60 g) in isopropnol (600 ml) and the mixture was stirred at room temperature for 24 hours. The mixture was then treated with methyl 3-aminocrotonate (39 g), stirred at room temperature for four days and evaporated. The residual oil was dissolved in methanol (300 ml) and the solution kept at -20° for two days. The resulting solid was collected, washed with cold methanol and dried to give the title compound (29.5 g), m.p. 104°-105°, which was used directly.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][C:8](=[O:10])[O:7][C:5]1=[O:6])[CH:2]=[CH2:3].[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[NH2:15].C(N(CC)CC)C.C1(C)C(C)=CC=CC=1>O>[Cl:11][C:12]1[CH:13]=[C:14]([N:15]=[C:5]([OH:6])[CH:4]([CH2:1][CH:2]=[CH2:3])[CH2:9][C:8]([OH:7])=[O:10])[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: C=CCC1CC(=O)OC1=O
Reactant: Nc1cc(Cl)cc(Cl)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Solvent: O
Product: C=CCC(CC(=O)O)C(O)=Nc1cc(Cl)cc(Cl)c1
Reaction time: 4 h
Yield: 89.4 %

Procedure:
28 g (0.2 moles) of allylsuccinic acid anhydride, 32.4 g (0.2 moles) of 3,5-dichloroaniline, 0.6 g of triethylamine and 150 ml of xylene are reacted at 125° C., with stirring. The water produced during the reaction is removed azeotropically by way of a water separator. The duration of the reaction is 4 hours. The solvent is subsequently drawn off and the residue is recrystallized from ethyl acetate with the addition of active carbon. The product has a melting point of 121° C. The yield is 89.4% of the theoretical yield.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH3:14])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:15][C:16]1[CH:17]=[C:18](B(O)O)[S:19][CH:20]=1>>[CH3:15][C:16]1[CH:17]=[C:18]([C:2]2[N:6]3[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH3:14])[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)[S:19][CH:20]=1
Reactant: Cc1csc(B(O)O)c1
Reactant: CCCNc1ccc2ncc(Br)n2n1
Product: CCCNc1ccc2ncc(-c3cc(C)cs3)n2n1
Yield: 16 %

Procedure:
Prepared from the product of step A and 4-methylthiophene-2-boronic acid according to general procedure 2 providing the title compound (30 mg, 16%) as a brown solid: 1H NMR (500 MHz, CD3OD) δ 7.61 (s, 1H), 7.45 (m, 2H), 6.90 (t, J=1.1 Hz, 1H), 6.55 (d, J=9.6 Hz, 1H), 3.31 (t, J=7.1 Hz, 2H), 2.20 (s, 3H), 1.66 (sext, J=7.2 Hz, 2H), 0.95 (t, J=7.4 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 155.5, 138.5, 137.6, 130.9, 127.7, 126.8, 125.7, 125.4, 121.4, 113.6, 44.8, 22.9, 15.6, 12.0; HPLC tR=13.5 min (Luna), 98.7%; ES-MS: (M+H)=273 m/z.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]([OH:9])[C:6]([OH:8])=[O:7].[C:13](Cl)(=[O:15])[CH3:14]>>[C:13]([O:9][CH:5]([C:4]1[CH:10]=[CH:11][CH:12]=[C:2]([Cl:1])[CH:3]=1)[C:6]([OH:8])=[O:7])(=[O:15])[CH3:14]
Reactant: CC(=O)Cl
Reactant: O=C(O)C(O)c1cccc(Cl)c1
Product: CC(=O)OC(C(=O)O)c1cccc(Cl)c1

Procedure:
1 g of racemic 3-chloromandelic acid is mixed with 2 ml of acetyl chloride.
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][C:4]([P:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[CH2:23]([Br:25])[CH3:24]>C1(C)C(C)=CC=CC=1>[Br-:25].[CH2:23]([P+:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:22])=[CH:2][CH:3]=1)([C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[CH3:24]
Reactant: CCBr
Reactant: Cc1ccc(P(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Solvent: Cc1ccccc1C
Product: CC[P+](c1ccc(C)cc1)(c1ccc(C)cc1)c1ccc(C)cc1
Product: [Br-]
Temperature: 32 °C

Procedure:
Into a 1 liter glass reactor equipped with a thermometer connected to a temperature controller, a heating mantle, a condenser and a magnetic stirring bar, are charged 250 gms (0.822 mole) of tri-p-tolylphosphine and 600 gms of xylene. The slurry is heated to 32° C., then 117 gms (1.073 mole) of ethyl bromide is added. This reaction mass is maintained at 32° C. for 1.5 hours, then heated to 45° C. and maintained at that temperature for 21 hrs, then heated to 65° C. and maintained at that temperature for 2 hours, then heated to 90° C. and maintained at that temperature for 2 hours. This mixture is cooled to 32° C., then 43.9 gms of ethyl bromide is added and mixed for 1 hour, then heated to 45° C. and maintained at that temperature for 18 hours, then cooled to 33° C. and an additional 15.7 gms of ethyl bromide is added and the temperature is maintained for 1 hour. The reaction mass is then heated to 45° C. and maintained at that temperature for 2 hours. The reaction material is then cooled to 50° C. and filtered. The solid phosphonium salt is washed with 200 gms of xylene resulting in 220 gms of clean phosphonium salt. The phosphonium salt has a melting point of 222°-224° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@@H:10]2[CH2:19][CH2:18][C:17]3[N+:16]([O-])=[CH:15][C:14]([CH3:21])=[CH:13][C:12]=3[CH2:11]2)=[CH:5][CH:4]=1.C(OC(=O)C)(=[O:24])C>C1(C)C=CC=CC=1>[OH:24][C@@H:18]1[C:17]2[N:16]=[CH:15][C:14]([CH3:21])=[CH:13][C:12]=2[CH2:11][C@H:10]([CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:19]1
Reactant: COc1ccc(C[C@@H]2CCc3c(cc(C)c[n+]3[O-])C2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(C[C@H]2Cc3cc(C)cnc3[C@@H](O)C2)cc1
Reaction time: 3 h

Procedure:
(+)-(6S)-5,6,7,8-Tetrahydro-6-((4-methoxyphenyl)methyl)-3-methylquinoline-N-oxide (3,48g 0.012 mol) in toluene (40 ml) was added slowly to refluxing acetic anhydride (18 ml) and the mixture stirred for a further 3 hours. After cooling overnight, the reaction mixture was concentrated under reduced pressure and dissolved in methanol. The resulting solution was treated with 5M KOH until it was basic and again concentrated under reduced pressure. The residue was dissolved in water (40 ml) and washed with chloroform (3×40 ml). The combined organic phases were washed with brine (1×40 rml), dried (MgSO4) and concentrated under reduced pressure to give an oil (3.98 g) which solidified on standing. The product (1.9 g) was chromatographed on silica gel eluting with ethyl acetate to give the title compound (0.21 g), [α]D25 =+115% (1% CHCl3) mp 105°-7° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([F:25])[CH:17]=2)=[N:4][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([OH:14])[C@@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1.[P:26]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])([O:28][CH2:29][C@@H:30]([NH2:39])[C:31]1[CH:36]=[C:35]([I:37])[CH:34]=[C:33]([F:38])[CH:32]=1)=[O:27].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1.C(OCC)(=O)C>[P:26]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])([O:28][CH2:29][C@@H:30]([NH:39][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([C:3]2[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C@H:8]3[CH2:13][CH2:12][C@H:11]([OH:14])[C@@H:10]([F:15])[CH2:9]3)[N:4]=2)=[CH:17][C:18]=1[F:25])[C:31]1[CH:36]=[C:35]([I:37])[CH:34]=[C:33]([F:38])[CH:32]=1)=[O:27]
Reactant: CC(C)(C)OP(=O)(OC[C@@H](N)c1cc(F)cc(I)c1)OC(C)(C)C
Reactant: Nc1ncc([C@H]2CC[C@H](O)[C@@H](F)C2)nc1-c1ccc(C(=O)O)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OP(=O)(OC[C@@H](NC(=O)c1ccc(-c2nc([C@H]3CC[C@H](O)[C@@H](F)C3)cnc2N)cc1F)c1cc(F)cc(I)c1)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
To a solution of 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzoic acid (3927 mg, 9.3 mmol) in NMP (Volume: 60 mL) was added (S)-2-amino-2-(3-fluoro-5-iodophenyl)ethyl di-tert-butyl phosphate (4740 mg, 9.30 mmol), DIEA (9.75 mL, 55.8 mmol), and then HATU (5304 mg, 13.95 mmol). The reaction mixture was stirred at room temperature for 2 hours followed by LCMS. To the crude reaction was added 850 ml of ethyl acetate washed with saturated bicarbonate (2×), water (3×), saturated salt solution, dried sodium sulfate, filtered and dried to residue. The crude product was purified by silica gel chromatograph 330 g column eluting with 0-70% (EtOAc with 10% MeOH)/heptane. The desired peak was concentrated to constant mass to give 5.75 grams of crude product. The material was re-purified by silica gel chromatograph 330 g column eluting with 0-60% (EtOAc with 10% MeOH)/heptane to give 5.03 grams of crude product. The material was further purified by adding 1200 ml of ethyl acetate to dissolve and 200 ml of heptane, washed with 200 ml of 0.5 N HCl (5×), water, saturated sodium bicarbonate, water (3×), saturated salt solution, dried sodium sulfate, filtered and concentrated to constant mass to give 4.70 grams of desired product, yield used as is. (61% yield over two steps). LCMS (m/z): 805.4 (MH+), 0.99 min. 1H NMR (<cd3od>) d: 7.90 (s, 1H), 7.77-7.86 (m, 1H), 7.68-7.73 (m, 2H), 7.63 (dd, J=11.8, 1.2 Hz, 1H), 7.42-7.52 (m, 1H), 7.26 (d, J=9.5 Hz, 1H), 5.43 (t, J=5.7 Hz, 1H), 4.30-4.49 (m, 1H), 4.28 (t, J=6.3 Hz, 2H), 3.58-3.72 (m, 1H), 2.83 (t, J=11.6 Hz, 1H), 2.27 (dt, J=6.2, 3.1 Hz, 1H), 2.02-2.13 (m, 1H), 1.77-1.94 (m, 2H), 1.58-1.74 (m, 1H), 1.48-1.55 (m, 1H), 1.45 (d, J=5.8 Hz, 18H).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:14])[C:4]([CH3:13])([CH2:8][CH:9]=C(C)C)[CH2:5][CH2:6][CH:7]=1.C([Al](Cl)Cl)C.[NH4+].[Cl-].[C:22]1(C)[CH:27]=CC=C[CH:23]=1>>[CH:22]([C:6]12[CH2:5][C:4]([CH3:13])([CH2:8][CH2:9]1)[C:3](=[O:14])[C:2]([CH3:1])=[CH:7]2)([CH3:27])[CH3:23]
Reactant: CC(C)=CCC1(C)CCC=C(C)C1=O
Reactant: Cc1ccccc1
Agent: CC[Al](Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Product: CC1=CC2(C(C)C)CCC(C)(C2)C1=O
Yield: 90 %

Procedure:
To a solution of 2,6-dimethyl-6-(3-methyl-but-2-enyl)-cyclohex-2-enone (5.00 g, 26.04 mmol) in toluene (40 ml) was added dropwise neat EtAlCl2 (97%, 1.5 eq., 4.96 g, 39.06 mmol). During the addition, the temperature was kept below 10° C. The brown mixture was kept at room temperature over night and was then poured on icecold saturated NH4Cl. The mixture was extracted with MTBE, washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was distilled bulb to bulb to yield 4.50 g (90%) of an colorless oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[CH:17]1([OH:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH:17]1([O:23][C:10]2[C:11]([I:12])=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[N:7]=[C:8]([NH2:16])[N:9]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: OC1CCCCC1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Nc1nc(OC2CCCCC2)c(I)c(-c2ccco2)n1

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine, cyclohexanol and DBU in THF. ES-MS m/e (%): 386 (M+H+, 100).