Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.Br[CH2:6][CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)#[N:23].C(=O)([O-])[O-].[K+].[K+]>O.C1(C)C=CC=CC=1>[C:22]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:6][CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:26][CH:25]=1)#[N:23]
Reactant: N#Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(CCCOc2ccc(C#N)cc2)CC1
Reaction time: 26 h
Yield: 97.7 %

Procedure:
To a dimethylsulfoxide (130 mL) solution of 13.2 g of tert-butyl 4-(3-bromopropyl)-1-piperidinecarboxylate were added 5.13 g of 4-cyanophenol and 11.9 g of potassium carbonate at room temperature, which was then stirred at the same temperature for 26 hours. The reaction mixture was added to a mixture of toluene and water. The organic layer was separated, washed with a saturated sodium chloride aqueous solution, and dried with anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure to provide 14.5 g of tert-butyl 4-[3-(4-cyanophenoxy)propyl]-1-piperidinecarboxylate as white solid form.
Reaction SMILES: [NH3:1].[C:2]([NH:5][C:6]1[C:7](=[O:20])[C:8]2[C:13]([C:14](=[O:17])[C:15]=1Br)=[CH:12][C:11]([CH3:18])=[C:10]([CH3:19])[CH:9]=2)(=[O:4])[CH3:3]>[N+](C1C=CC=CC=1)([O-])=O>[C:2]([NH:5][C:6]1[C:7](=[O:20])[C:8]2[C:13]([C:14](=[O:17])[C:15]=1[NH2:1])=[CH:12][C:11]([CH3:18])=[C:10]([CH3:19])[CH:9]=2)(=[O:4])[CH3:3]
Reactant: N
Reactant: CC(=O)NC1=C(Br)C(=O)c2cc(C)c(C)cc2C1=O
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)NC1=C(N)C(=O)c2cc(C)c(C)cc2C1=O
Temperature: 216 °C

Procedure:
Dry ammonia was passed through a stirred refluxing solution of 2-acetamido-3-bromo-6,7-dimethyl-1,4-naphthoquinone (7.5 g) in nitrobenzene (50 ml) for 1 hr. and the mixture cooled. The red solid which separated was filtered off, washed well with ether-petrol and then water to give 4.46 g. (77%) of material of mp 212°-216° C. Recrystallisation from ethanol raised the melting point to 216° C., ν max(mull), 3400, 3270, 1675, 1665, 1630 cm-1. δ (DMSO) 2.05 (3H,s); 2.35 (6H,s); 6.64 (2H, exchangeable s); 7.71(2H,s); 9.00 (1H, exchangeable s.) (Found; C, 65.07; H, 5.43; N, 10.66; C14H14N2O3 requires; C, 65.10; H, 5.46; N, 10.85%).
Reaction SMILES: [CH2:1]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:8]Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[I-:18].[Na+]>CC(C)=O>[CH2:1]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:8][I:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCC(CCl)CCCCCC
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCCCCC(CI)CCCCCC
Temperature: 60 °C
Yield: 84.8 %

Procedure:
To a reaction vessel, 2.682 g (10.3 mmol) of 2-hexyl-1-chlorodecane, 7.483 g (49.9 mmol, 4.8 eq) of sodium iodide, and 100 mL of acetone were added. The whole was refluxed at 60° C. overnight. The reaction mixture was allowed to reach room temperature, and acetone was removed by evaporation. The residue was extracted with ethyl acetate, and then the organic phase was washed with a saturated brine three times. The organic phase was dried over magnesium sulfate and filtered. The filtrate was concentrated, and the concentrate was dried under vacuum to give 3.075 g (8.73 mmol) of 2-hexyl-1-iododecane as a dark red liquid (crude yield: 85%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:18]=[C:17]([C@H:19]4[O:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]4)[CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1)[CH3:2].[ClH:32]>O1CCOCC1>[ClH:32].[CH2:1]([O:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:18]=[C:17]([C@H:19]4[O:24][CH2:23][CH2:22][NH:21][CH2:20]4)[CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(-c2nc3ccc([C@@H]4CN(C(=O)OC(C)(C)C)CCO4)cc3o2)cn1
Agent: Cl
Solvent: C1COCCO1
Product: CCOc1ccc(-c2nc3ccc([C@@H]4CNCCO4)cc3o2)cn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
(R)-tert-Butyl 2-(2-(6-ethoxypyridin-3-yl)benzo[d]oxazol-6-yl)morpholine-4-carboxylate (31 mg, 0.073 mmol) was dissolved in dioxane (0.3 ml). Then a solution of HCl in dioxane (4M, 0.27 ml, 1.09 mmol) was added and the reaction mixture was stirred at 60° C. for 2 hours. After cooling, the solid was filtered off and washed with diethylether and dried in vacuo to afford (R)-2-(6-ethoxypyridin-3-yl)-6-(morpholin-2-yl)benzo[d]oxazole hydrochloride (15 mg, 58%) as a light yellow solid. MS (ISP): 326.6 ([M+H]+).
Reaction SMILES: C(OC([N:11]1[CH:16]([CH3:17])[CH2:15][N:14]([CH2:18][C:19]2[CH:28]=[C:27]3[C:22]([C:23]([NH2:29])=[N:24][CH:25]=[N:26]3)=[CH:21][CH:20]=2)[C:13](=[O:30])[C@@H:12]1[CH3:31])=O)C1C=CC=CC=1.[H][H]>[Pd].CO.C(O)(=O)C>[NH2:29][C:23]1[C:22]2[C:27](=[CH:28][C:19]([CH2:18][N:14]3[CH2:15][CH:16]([CH3:17])[NH:11][C@@H:12]([CH3:31])[C:13]3=[O:30])=[CH:20][CH:21]=2)[N:26]=[CH:25][N:24]=1
Reactant: CC1CN(Cc2ccc3c(N)ncnc3c2)C(=O)[C@H](C)N1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC1CN(Cc2ccc3c(N)ncnc3c2)C(=O)[C@H](C)N1
Yield: 153.9 %

Procedure:
Palladium on carbon (10%, 700 mg) is added to a solution of (2S,6RS)-4-(4-amino-quinazolin-7-ylmethyl)-2,6-dimethyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (1.62 g, 3.87 mmol) in 20 mL of methanol and 2 mL of acetic acid. The reaction mixture is left to stir in an atmosphere of hydrogen for eight hours. The palladium is filtered off, and the volitale solvents are removed on the rotovap. The crude product (1.7 g, 95%) is isolated as a white solid. The two epimers are separated on silica gel (1% triethylamine/15% methanol/methylene chloride). The minor epimer is assigned as (3S,5R)-1-(4-amino-quinazolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one and the major epimer is assigned as (3S,5S)-1-(4-amino-quinazolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[CH:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[C:13]([As:18]([OH:21])([OH:20])=[O:19])[CH:12]=1.[Br:22][CH2:23][C:24](Br)=[O:25].C(=O)=O.S(=O)(=O)(O)O>ClCCl.O>[Br:22][CH2:23][C:24]([NH:17][C:16]1[CH:11]=[CH:12][C:13]([As:18](=[O:20])([OH:21])[OH:19])=[CH:14][CH:15]=1)=[O:25]
Reactant: Nc1ccc([As](=O)(O)O)cc1
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: O=C(CBr)Nc1ccc([As](=O)(O)O)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Sodium carbonate (40.14 g, 378.7 mmol) was added to water (200 mL) and stirred at room temperature until all solids had dissolved. To the stirred carbonate solution was added p-arsanilic acid (29.99 g, 138.2 mmol), portionwise, and the volume of the solution made up to 300 mL with addition of more water. The solution (pH 10 to 11) was allowed to stir for 30 mins, and if necessary, was filtered to remove any undissolved solid before being refridgerated for 2 to 3 hours. The solution was transferred to a separating funnel and ice chips were added. Bromoacetyl bromide (15 mL, 34.76 g, 172.1 mmol) was diluted in dichloromethane (50 mL) and approximately half of the dichloromethane solution was added carefully to the cold aqueous solution. The mixture was cautiously shaken, with frequent venting to avoid excessive build up of pressure. After 1 to 2 mins, the evolution of carbon dioxide had subsided, and more vigorous shaking was undertaken. The remaining portion of bromoacetyl bromide was carefully added and the procedure repeated. When the reaction was over, the solution was found to be pH 7. The lower dichloromethane layer was discarded, and the aqueous layer transferred to a 1 L flask and carefully acidified by dropwise addition of 98% sulfuric acid. Complete precipitation of the white product required addition of acid until the solution was approximately pH 1. The crude product was collected and dried at the pump, typically in yields of 50% to 75%. 1H-NMR (d6-DMSO): δ 4.09 (s, 2H), 7.73 (d, J=9 Hz, 2H), 7.83 (d, J=9 Hz, 2H), 10.87 (s, 1H). 13C-NMR (d6-DMSO): δ 30.53, 119.97, 127.34, 131.56, 143.08, 166.00 ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](OS(C(F)(F)F)(=O)=O)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[SH:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1.O.C(O)(=O)C>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1
Reactant: O=C(O)c1ccc(S)cc1
Reactant: Cc1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Cc1ccc(Sc2ccc(C(=O)O)cc2)c([N+](=O)[O-])c1
Yield: 91.6 %

Procedure:
The product from Example 4a (0.94 g, 3.31 mmol) was reacted with 4-mercapto-benzoic acid (0.51 g, 3.31 mmol) in aqueous ethanol at 80° C. under nitrogen. The reaction mixture was poured into water and acidified with glacial acetic acid. The solid product was collected by filtration, water washed and dried in vacuo to give the title compound (0.877 g, 91%) sufficiently pure for use as isolated.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[C:14]([CH:15]([OH:24])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][C:9]2[O:10][CH2:11][O:12][C:8]=2[CH:7]=1.CCN(CC)CC.[C:32](OC(=O)C)(=[O:34])[CH3:33].CN(C1C=CC=CN=1)C>C(Cl)Cl.CCOC(C)=O>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[C:14]([CH:15]([O:24][C:32](=[O:34])[CH3:33])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][C:9]2[O:10][CH2:11][O:12][C:8]=2[CH:7]=1
Reactant: OC(CCc1ccccc1)c1cc2c(cc1C1OCCO1)OCO2
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)OC(CCc1ccccc1)c1cc2c(cc1C1OCCO1)OCO2
Yield: 81.4 %

Procedure:
A solution of (±)-5-(1,3-dioxolanyl)-[6-(1-hydroxy-3-phenylpropyl)]-1,3-benzodioxole (Compound 12, 182 mg, 0.554 mmol), Et3N ) (0.23 mL, 1.66 mmol), acetic anhydride (78 μl, 0.832 mmol) and dimethylaminopyridine (DMAP, 33.8 mg, 0.277 mmol) in CH2Cl2 (1.0 mL) was stirred at 23° C. for 16 hours. The reaction was diluted with EtOAc and washed with 1N HCl saturated ag. Na HCO3, brine. The organic portion was dried (MgSo4), filtered and concentrated in vacuo. Flash column chromatography (silica gel, 6:1 hex(EtOAc) gave 167 mg (82%) of the title compound.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])O[C:2]2=O.C(OC(=O)C)(=O)C.[CH3:20][C:21]1OC(=O)[C:24]2[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=2[N:22]=1.NC1C(C)=CC=CC=1>CC1C=CC=CC=1C>[CH3:20][C:21]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=2[CH3:2])[C:5](=[O:12])[C:31]2[C:23](=[CH:24][CH:28]=[CH:29][CH:30]=2)[N:22]=1
Reactant: Cc1nc2ccccc2c(=O)o1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1N
Solvent: CC(=O)OC(C)=O
Product: Cc1ccccc1-n1c(C)nc2ccccc2c1=O
Yield: 64 %

Procedure:
The isatoic anhydride and acetic anhydride were reacted under the condition described for the preparation of 2-methyl-4H-3,1-benzoxazine-4-one. The pyridine was distilled from the reaction mixture under reduced pressure. The crude reaction product was taken up in 100 ml of o-xylene and placed in a 200 ml one-necked flask equipped with a Dean-Stark trap and a reflux condenser. The o-toluidine was added to the xylene solution. The reaction mixture was heated to reflux for 4 hours. 1.8 ml of water was collected in the Dean-Stark trap. The xylene was removed from the reaction product by distillation under reduced pressure. The resulting residue was crystallized twice from methanol to give 16 parts (64% yield) of 2-methyl-3-(o-tolyl)-quinazoline-4 (3H)-one with m.p. 113°-115° C. The reaction product was characterized by melting point, IR and NMR.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:11]([CH:12]=[O:13])=[C:10](Br)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:15]#[N:16])[CH:8]=2)[O:3]1.P(Br)(Br)Br.[NH:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]1=[O:28].C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl.C(OCC)(=O)C.CN(C=O)C>[CH3:1][C:2]1([CH3:17])[C:11]([CH:12]=[O:13])=[C:10]([N:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]2=[O:28])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:15]#[N:16])[CH:8]=2)[O:3]1
Reactant: CC1(C)Oc2ccc(C#N)cc2C(Br)=C1C=O
Reactant: O=c1cccc[nH]1
Agent: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC1(C)Oc2ccc(C#N)cc2C(n2ccccc2=O)=C1C=O
Reaction time: 1 h

Procedure:
A mixture of 1.4 g of 2,2-dimethyl-3-formyl-4-bromo-6-cyano-3-chromene (m.p. 124°-125°; obtainable by dropwise addition of a solution of 2,2-dimethyl-5-cyano-5-chromanone in chloroform to a mixture of equal volume parts of DMF and PBr3 in chloroform and subsequent boiling for 11 hours), 0.9 g of 1H-2-pyridone, 3 g of K2CO3 and 20 ml of DMF is stirred at 60° for 1 hour. The mixture is diluted with ethyl acetate and filtered, and customary working up of the filtrate gives 2,2-dimethyl-3-formyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-cyano-3-chromene ("A") m.p. 190°-192° C.
Reaction SMILES: CN(C)[C:3](=O)[S:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:6]=1[C:13]([O:15][CH3:16])=[O:14].C[O-].[Na+].BrC[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CO>[CH2:3]([S:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:6]=1[C:13]([O:15][CH3:16])=[O:14])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1c(OC)cccc1SC(=O)N(C)C
Reactant: BrCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(OC)cccc1SCc1ccccc1

Procedure:
A solution of S-2-carbomethoxy-3-methoxyphenyl dimethylthiocarbamate (1.2 g, 4.5 mmol) and sodium methoxide (0.24 g, 4.5 mmol) in methanol (10 ml) was stirred at reflux temperature under a nitrogen atmosphere for 4 hours. α-Bromotoluene (0.60 ml, 4.9 mmol) was then added, and heating was maintained for an additional hour. The cooled mixture was evaporated, and the residue partitioned between diethyl ether and water. The organic layer was separated and washed with 1% aqueous sodium hydroxide solution, water, saturated aqueous sodium chloride solution, dried (sodium sulfate), and evaporated. The residue was vacuum filtered through a pad of silica gel (Merck No. 7734), eluting successively with 10:1 and 5:1 hexane-ether. Evaporation of the appropriate fractions gave methyl 2-benzylthio-6-methoxybenzoate as a colorless syrup; yield (0.70 g, 54%); NMR (CDCl3, 60 MHz): δ4.06 (s, SCH2Ph) p.p.m.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]#[C:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[S:17][C:10]=12.[CH2:29]([N:36]1[CH:41]=[C:40]([Cl:42])[CH:39]=[C:38]([C:43](O)=[O:44])[C:37]1=[O:46])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([N:36]1[CH:41]=[C:40]([Cl:42])[CH:39]=[C:38]([C:43]([NH:28][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]3[CH:14]=[CH:13][N:12]=[C:11]4[CH:15]=[C:16]([C:18]#[C:19][CH2:20][N:21]5[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]5)[S:17][C:10]=34)=[C:2]([F:1])[CH:3]=2)=[O:44])[C:37]1=[O:46])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(O)c1cc(Cl)cn(Cc2ccccc2)c1=O
Reactant: CN1CCN(CC#Cc2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Product: CN1CCN(CC#Cc2cc3nccc(Oc4ccc(NC(=O)c5cc(Cl)cn(Cc6ccccc6)c5=O)cc4F)c3s2)CC1
Yield: 52 %

Procedure:
Prepared from 3-fluoro-4-(2-(3-(4-methylpiperazin-1-yl)prop-1-ynyl)thieno[3,2-b]pyridin-7-yloxy)aniline (Example 17, Step B) and 1-benzyl-5-chloro 2-oxo-1,2-dihydropyridine-3-carboxylic acid according to the procedure of Example 89. The crude was purified by silica gel flash column chromatography (5% MeOH in CH2Cl2) to afford 16.7 mg (52%) of the desired product. LRMS (APCI pos) m/e 642.1, 644.1 (M+1, Cl pattern). 1H-NMR (400 MHz, CD3OD) δ 8.50 (t, 2H), 8.29 (d, 1H), 8.02 (dd, 1H), 7.59 (s, 1H), 7.33-7.48 (m, 7H), 6.71 (d, 1H), 5.32 (s, 2H), 3.67 (s, 2H), 2.56-2.74 (m, 8H), 2.30 (s, 3H); 19F NMR (376 MHz, CD3OD) δ −129.7.
Reaction SMILES: O.[C:2]([N:5]([CH2:10][C:11]([OH:13])=[O:12])[CH2:6][C:7]([OH:9])=[O:8])(=O)C.[P:14]([OH:17])([OH:16])[OH:15].O.C1(C)C(S(O)(=O)=O)=CC=CC=1.C=O>O>[P:14]([CH2:2][N:5]([CH2:10][C:11]([OH:13])=[O:12])[CH2:6][C:7]([OH:9])=[O:8])([OH:17])([OH:16])=[O:15]
Reactant: OP(O)O
Reactant: CC(=O)N(CC(=O)O)CC(=O)O
Agent: C=O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Product: O=C(O)CN(CC(=O)O)CP(=O)(O)O
Temperature: 120 °C
Yield: 72.7 %

Procedure:
A pressure reactor was charged with N-acetyliminodiacetic acid monohydrate (19.3 g), water (16.6 g), phosphorous acid (9.8 g) and toluenesulfonic acid monohydrate (35.2 g). The mixture was heated to 120° C. and 47% formaldehyde (5.8 mL) was added drop wise over a 3/4 hour period. After another 3/4 hour at 120° C. the mixture was cooled. The mixture was filtered and the solid was washed with water to give 16.5 g of N-(phosphonomethyl)iminodiacetic acid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[BH4-].[Na+]>C(O)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][OH:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1ccc2c(c1)OCCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
2,3-Dihydro-benzo[1,4]dioxine-6-carbaldehyde [RN 29668-44-8] (3.04 g, 18.54 mmol) was dissolved in ethanol (100 mL) and cooled to 0° C. To the resulting solution was added sodium borohydride (1.41 g, 37.07 mmol). The resulting slurry was stirred at room temperature for 1 hour and then quenched with water (10 mL) before being concentrated to dryness under reduced pressure. The residue was partitioned between a 5% aqueous solution of sodium hydrogen carbonate (20 mL) and dichloromethane (2×50 mL). The organic phases were combined and dried over magnesium sulfate then evaporated under reduced pressure to provide and oil which was purified on silica gel using a dichloromethane and methanol solvent gradient. This provided the desired product as a colourless oil (3.00 g, 97%).
Reaction SMILES: C(OC([N:8]1[CH2:22][CH2:21][C:12]2=[C:13](Cl)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=O)(C)(C)C.[NH:23]1[CH2:26][CH:25]([C:27]2[O:28][C:29]3[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=3[N:31]=2)[CH2:24]1>>[O:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[CH:25]1[CH2:24][N:23]([C:13]2[N:14]3[C:18]([N:19]=[C:11]4[CH2:10][CH2:9][NH:8][CH2:22][CH2:21][C:12]=24)=[CH:17][CH:16]=[N:15]3)[CH2:26]1
Reactant: c1ccc2oc(C3CNC3)nc2c1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(Cl)c2CC1
Product: c1ccc2oc(C3CN(c4c5c(nc6ccnn46)CCNCC5)C3)nc2c1

Procedure:
The product was prepared using 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in route 1 (step e and f), in step e (route 1) 2-azetidin-3-yl-benzooxazole was used as the amine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH:29][CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: CC(C)(C)OC(=O)N1CCC(NCc2cccc(-c3ccnc(Cl)n3)c2)CC1

Procedure:
Intermediate 1 was coupled with 4-Amino-piperidine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 403.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:23]([OH:25])=O)[CH2:6][S:7][CH2:8][CH:9]=[C:10]([CH2:12][CH2:13][CH:14]=[C:15]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[CH3:16])[CH3:11])(=[O:3])[CH3:2].[NH2:26][NH2:27]>ClCCl.C1COCC1>[NH:26]([C:23](=[O:25])[C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6][S:7][CH2:8]/[CH:9]=[C:10](\[CH3:11])/[CH2:12][CH2:13]/[CH:14]=[C:15](\[CH3:16])/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[NH2:27]
Reactant: CC(=O)N[C@@H](CSCC=C(C)CCC=C(C)CCC=C(C)C)C(=O)O
Reactant: NN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)N[C@@H](CSC/C=C(\C)CC/C=C(\C)CCC=C(C)C)C(=O)NN
Reaction time: 0.5 h
Yield: 80 %

Procedure:
In 50 mL round bottom flask, N-acetyl-S-farnesyl-L-cysteine (368 mg, 1.0 mmole) was dissolved in dichloromethane (10 mL). N-Cyclohexylcarbodiimide,N′-methyl polystyrene HL (1.7 g, 3.3 mole, from NovabioChem) was added followed by sufficient dichloromethane to swell the resin and keep the reaction mobile and the mixture gently magnetically stirred in 30 minutes. 5 mL of hydrazine in THF (1M) was added to the reaction solution and the reaction mixture was stirred in 3 hours at room temperature. The used resin was removed by filtration and washed with dichloromethane. Evaporation of the filtrate provided crude reaction mixture. The desired product was purified by preparative HPLC (305 mg, 80% yield) to yield Compound I: 1H-NMR (500 MHz, CDCl3): δ 1.60 (s, 6H), 1.67 (s, 6H), 1.70 (S, 3H), 1.92-2.09 (m, 8H), 2.75 (dd, J=7.9, 13.9 Hz, 1H), 2.88 (dd, J=5.7, 13.6 Hz, 1H), 3.20 (d, J=7.9 Hz, 2H), 4.51 (dd, J=7.6, 13.6 Hz, 1H), 5.10 (m, 2H), 5.24 (t, J=7.6 Hz, 1H). 13C-NMR (125 MHz, CDCl3): δ 16.0, 16.1, 16.2, 17.6, 17.7, 23.2, 23.4, 23.5, 25.7, 25.8, 26.2, 26.3, 26.5, 26.7, 30.0, 31.8, 31.9, 32.9, 33.2, 39.6, 39.7, 39.9, 51.3, 51.4, 119.6, 120.3, 123.6, 124.2, 131.4, 131.6, 135.5, 135.6, 135.8, 140.2, 140.3, 170.2, 171.1; ES-MS: mass calcd for Chemical Formula: C20H35N3O2S 381.2 (M+). Found (M+Na) m/z 404.3.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][C:8](=[O:10])[CH3:9])(=[O:6])[O:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].C(C1C=CC(S([N:38]=[N+:39]=[N-])(=O)=O)=CC=1)CCCCCCCCCCC.[NH4+].[Cl-]>CC#N>[CH3:1][O:2][P:3]([C:7](=[N+:38]=[N-:39])[C:8](=[O:10])[CH3:9])(=[O:6])[O:4][CH3:5]
Reactant: COP(=O)(CC(C)=O)OC
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Product: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A suspension of dimethyl(2-oxopropyl)phosphonate (2.1 g, 12.9 mmol) and potassium carbonate (2.2 g, 15.9 mmol) in dry MeCN (40 mL) was treated with slow addition of a solution of 4-dodecylbenzenesulfonyl azide (5.7 g, 16.2 mmol) in dry MeCN (90 mL) for over 30 min. After being stirred for 2.5 h under N2 atmosphere at room temperature, the mixture was treated with saturated NH4Cl (100 mL), poured into a separatory funnel and extracted with EtOAc (3×100 mL), dried over Na2SO4, filtered, solvent evaporated and the residue chromatographed in a cartridge of silicagel (40 g) eluted with 15% to 100% EtOAc in hexane (UV detection at 254 nm), to afford reagent 29 as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1F.[ClH:18].Cl.[NH:20]1[C:24]2=[N:25][CH:26]=[CH:27][C:28]([O:29][C:30]3[CH:35]=[CH:34][C:33]([NH:36]C4N=CC=CC=4C(NC4C=CC=CC=4C)=O)=[CH:32][C:31]=3[F:53])=[C:23]2[CH:22]=[CH:21]1>>[ClH:1].[ClH:18].[NH:20]1[C:24]2=[N:25][CH:26]=[CH:27][C:28]([O:29][C:30]3[CH:35]=[CH:34][C:33]([NH:36][C:11]4[N:12]=[CH:13][CH:14]=[CH:15][C:10]=4[C:9]([NH:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[O:17])=[CH:32][C:31]=3[F:53])=[C:23]2[CH:22]=[CH:21]1
Reactant: Cc1ccccc1NC(=O)c1cccnc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Reactant: O=C(Nc1ccccc1Cl)c1cccnc1F
Agent: Cl
Product: O=C(Nc1ccccc1Cl)c1cccnc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Yield: 36 %

Procedure:
N-(2-Chlorophenyl)-2-fluoronicotinamide (0.050 g, 0.20 mmol) was converted to the title compound (0.037 g, 36%) in a manner similar to the preparation of 2-(4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenylamino)-N-o-tolylnicotinamide (Step B of Example 8). 1H NMR (DMSO-d6) δ 12.75 (s, 1H), 10.80 (s, 1H), 10.49 (s, 1H), 8.10-8.44 (m, 4H), 7.24-7.60 (m, 7H), 6.96-7.10 (m, 1H), 6.70 (m, 1H), 6.45-6.50 (m, 1H); HRMS(ESI+), 474.1133 (M+H)+ calc, 474.1129 (M+H)+ found.