Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[CH:7][C:8]#[N:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:10]([CH3:13])([O-:12])=[O:11].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[N+:10]([CH2:13][C:1]1([CH2:7][C:8]#[N:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([O-:12])=[O:11]
Reactant: C[N+](=O)[O-]
Reactant: N#CC=C1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#CCC1(C[N+](=O)[O-])CCCCC1
Yield: 70.7 %

Procedure:
The nitrile (compound 2, 0.78 g, 6.44 mmol), nitromethane (0.80 g, 13.11 mmol) and tetrabutyl ammonium fluoride (1.0 M in tetrahydrofuran, 10 mL, 10 mmol) were heated in 20 mL tetrahydrofuran to 70° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with dilute hydrochloric acid and water, dried over magnesium sulphate, filtered, and evaporated to dryness. The residue was purified by chromatography on silica eluting with heptane/ethyl acetate 3:1 to give the required product as a yellow oil (0.83 g, 71%).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[CH2:10][CH2:11][CH2:12][CH:3]([C:4]=23)[C:2]1=[O:13].[H-].[Na+].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20]Br>CN(C)C=O>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][C:3]12[CH2:12][CH2:11][CH2:10][C:5]3[C:4]1=[C:9]([CH:8]=[CH:7][CH:6]=3)[NH:1][C:2]2=[O:13]
Reactant: BrCCCCBr
Reactant: O=C1Nc2cccc3c2C1CCC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2cccc3c2C1(CCCCBr)CCC3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2a,3,4,5-Tetrahydro-1H-benz[cd]indol-2-one (3.0 g, 17 mmol) was dissolved in anhydrous N,N-dimethylformamide (120 ml), and the solution was mixed with sodium hydride (60%, 760 mg, 190 mmol) and stirred at room temperature for 1 hour. The reaction solution was mixed with 1,4-dibromobutane (6.3 ml, 52 mmol) and again stirred for 17 hours. The solvent was removed by evaporation under a reduced pressure, and ethyl acetate, water and hydrochloric acid (1 N) were added to the resulting residue. The reaction product was extracted with ethyl acetate, washed with saturated brine and dried with anhydrous sodium sulfate, the solvent was removed by evaporation under a reduced pressure, and then the thus obtained material was separated and purified by a silica gel column chromatography to obtain 1.8 g (5.8 mmol, 33% in yield) of the title compound.
Reaction SMILES: [I-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[CH3:9].[OH-].[K+].[C:12]1([CH:22]=O)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.O>CO>[I-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[CH:9]=[CH:22][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: CC1N(C)C=C[NH+]1C
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN1C=C[NH+](C)C1C=Cc1cccc2ccccc12

Procedure:
A mixture of 6.0 g of 1,2,3-trimethyl-1H-imidazolium iodide, 1 g of potassium hydroxide and 6 ml of 1-naphthaldehyde in 25 ml of methanol is refluxed for 15 minutes during which time a precipitate is formed. The reaction mixture is cooled and 5 ml of water is added. The solid is filtered off, dried, and crystallized from absolute ethanol to yield 3.7 g of the title compound, melting point 251°-253° C.
Reaction SMILES: ClC(OCC(C)C)=O.C[N:10]1[CH2:15][CH2:14]O[CH2:12][CH2:11]1.[C:16]([O:20][C:21]([NH:23][CH2:24][C:25]([C:27]1[CH:37]=[CH:36][C:30]([O:31][CH2:32][C:33]([OH:35])=O)=[CH:29][CH:28]=1)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C(NCC)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:16]([O:20][C:21](=[O:22])[NH:23][CH2:24][C:25]([C:27]1[CH:28]=[CH:29][C:30]([O:31][CH2:32][C:33](=[O:35])[N:10]([CH2:15][CH3:14])[CH2:11][CH3:12])=[CH:36][CH:37]=1)=[O:26])([CH3:17])([CH3:18])[CH3:19]
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)NCC(=O)c1ccc(OCC(=O)O)cc1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)COc1ccc(C(=O)CNC(=O)OC(C)(C)C)cc1
Reaction time: 0.25 h

Procedure:
Isobutyl chloroformate (0.84 ml; 6.5 mmol) was added to a stirred solution of 4-methylmorpholine (0.72 ml; 6.5 mmol) and the compound of example 1f (2.0 g; 6.5 mmol) in DMF (10 ml) at −25° C., followed by the addition of diethyl amine (0.88 ml; 8.45 mmol). The reaction mixture was stirred for 15 min., poured into a 10% aqueous NaHCO3 solution and extracted with EtOAc. The EtOAc layer was washed with brine, concentrated and crystallized using EtOAc-PE60-80° C. to obtain the title compound. Yield, 1.95 g (82%); mp, 100-01° C.; MS (EI): 364 (M+), 291, 234 (100%); analysis: C19H28N2O5 requires C, 62.62; H, 7.74; N, 7.69; found: C, 62.43; H, 7.60; N, 7.25%.
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:3]1=[O:21].N1C(C)=CC=CC=1C>C1(C)C=CC=CC=1>[CH2:9]([N:4]1[CH2:5][CH2:6][CH:7]=[CH:8][CH2:2][C:3]1=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCN1CCCCC(Br)C1=O
Solvent: Cc1ccccc1
Solvent: Cc1cccc(C)n1
Product: CCCCCCCCCCCCN1CCC=CCC1=O
Temperature: 25 °C

Procedure:
A solution of 10.0 g (28 mmol) of 3-bromo-1-dodecylazacycloheptan-2-one (Example 1-A) and 5.1 g 47 mmol) of 2,6-lutidine was refluxed for 3 hours. The reaction was cooled to room temperature, 100 ml of toluene was added, and the mixture was filtered. The filtrate was concentrated in vacuo and the residue subjected to flash chromatography (silica gel, 7:3 petroleum ether/EtOAc V/V) to yield the product as a white solid, Rf =0.5; Kuglerohr distilled at 155°-160° C./0.2 mm Hg.
Reaction SMILES: Cl[C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])[NH:10][C:11]1[S:12][C:13]([S:16]CC(C)(C)C(O)=O)=[CH:14][N:15]=1.C(Br)C1C=CC=CC=1.C([O:46][C:47](=[O:58])[C:48](SC1SC(N)=NC=1)([CH3:50])[CH3:49])C>>[CH2:4]([O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])[NH:10][C:11]1[S:12][C:13]([S:16][C:48]([CH3:50])([CH3:49])[C:47]([OH:58])=[O:46])=[CH:14][N:15]=1)[C:3]1[CH:2]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(CSc1cnc(NC(=O)N(CCOCc2ccccc2Cl)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Agent: BrCc1ccccc1
Product: CC(C)(Sc1cnc(NC(=O)N(CCOCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 3-{2-[3-[2-(2-chloro-benzyloxy)-ethyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid using benzyl bromide and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]([CH2:20][OH:21])=[CH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)[CH2:10][CH2:9]1.C1C=CC=CC=1>N1C=CC=CC=1>[C:1]([O:21][CH2:20][C:6]([F:5])=[CH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)[CH2:9][CH2:10]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: OCC(F)=CC1(c2ccc3c(c2)OCO3)CC1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OCC(F)=CC1(c2ccc3c(c2)OCO3)CC1
Yield: 93 %

Procedure:
The method of Example 17 was repeated using acetyl chloride (1.4 ml), 1-(2-fluoro-3-hydroxyprop-1-enyl)-1-(3,4-methylenedioxyphenyl)cyclopropane (Example 14) (0.68 g), benzene (40 ml) and pyridine (0.26 ml) to yield the title compound (0.73 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([O:24][CH3:25])=[C:19]([CH:23]=2)[C:20]([OH:22])=O)[N:10]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:57][C:58]([F:70])([F:69])[C:59]1[CH:64]=[CH:63][C:62]([C:65]2([NH2:68])[CH2:67][CH2:66]2)=[CH:61][CH:60]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([O:24][CH3:25])=[C:19]([CH:23]=2)[C:20]([NH:68][C:65]2([C:62]3[CH:63]=[CH:64][C:59]([C:58]([F:57])([F:69])[F:70])=[CH:60][CH:61]=3)[CH2:67][CH2:66]2)=[O:22])[N:10]=1
Reactant: NC1(c2ccc(C(F)(F)F)cc2)CC1
Reactant: COc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1C(=O)NC1(c2ccc(C(F)(F)F)cc2)CC1
Yield: 16.9 %

Procedure:
The title compound was prepared according to the procedure described in Example-17 by using 5-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-methoxybenzoic acid (Intermediate-11, 0.100 g, 0.270 mmol), THF (10 mL), di-isopropyl ethyl amine (10.0 mL), TBTU (0.177 g, 0.540 mmol) and 1-[4-(trifluoromethyl)phenyl]cyclopropanamine (intermediate-13, 0.066 g, 0.320 mmol) to afford 0.025 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 1.23 (s, 4H), 3.94 (s, 3H), 7.26 (d, J=9.0 Hz, 1H), 7.42 (d, J=8.4 Hz, 3H), 7.30-7.48 (m, 4H), 7.99 (d, J=9.3 Hz, 1H), 8.05 (s, 1H), 8.96 (s, 1H), 12.51 (br s, 1H); MS (m/z): 547.15 (M+).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.[H-].[Na+].[CH2:37](Cl)[C:38]([OH:40])=[O:39].Cl>CN(C)C=O>[C:38]([CH2:37][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1)([OH:40])=[O:39]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: O=C(O)CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC(=O)O)cc1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
A solution of 0.953 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 10 ml of N,N-dimethylformamide is admixed with stirring at room temperature with 0.16 g of sodium hydride dispersions (60%). The reaction mixture is stirred at 60° C. over 10 minutes, admixed with 0.191 g of chloroacetic add and then stirred at 60° C. over 24 hours. The reaction mixture is admixed with 0.5N HCl and extracted with ethyl acetate (2×). The combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (95:5 dichloromethane-methanol); Rt=5.18.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:24])=[N:19][CH:20]=[CH:21][C:22]=3[F:23])[CH:12]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1>>[F:24][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[C:22]([F:23])[CH:21]=[CH:20][N:19]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1
Reactant: Fc1ccc(Br)cc1
Product: O=C(c1ccc(F)cc1)c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1

Procedure:
This compound is prepared by method C using compound 12j and 1-bromo-4-fluorobenzene
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]2[O:6][CH:7]([CH2:9][N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])[CH2:8][C:4]=2[CH:3]=1.[C:17]([O-])(=O)[C:18]([O-])=O>>[OH:1][C:2]1[CH:16]=[CH:15][C:5]2[O:6][CH:7]([CH2:9][N:10]([CH2:14][CH2:17][CH3:18])[CH2:11][CH2:12][CH3:13])[CH2:8][C:4]=2[CH:3]=1
Reactant: O=C([O-])C(=O)[O-]
Reactant: CCCN(C)CC1Cc2cc(O)ccc2O1
Product: CCCN(CCC)CC1Cc2cc(O)ccc2O1

Procedure:
(+) and (-)-5-hydroxy-2,3-dihydro-N-methyl-N-propyl-3-benzofuranmethylamine, oxalate. M.P. 170°-171° C. (Lu 25-020) and (Lu 25-021)
Reaction SMILES: [Na].[NH:2]1[CH:6]=[N:5][CH:4]=[N:3]1.Cl[CH2:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][N:23]3[CH:31]=[CH:32][CH:33]=[C:22]3[CH2:21]2)=[O:19])=[CH:14][CH:13]=1)=[O:10]>CN1CCCN(C)C1=O>[CH:33]1[CH:32]=[CH:31][N:23]2[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:20]([C:18]([C:15]3[CH:14]=[CH:13][C:12]([NH:11][C:9](=[O:10])[CH2:8][N:2]4[CH:6]=[N:5][CH:4]=[N:3]4)=[CH:17][CH:16]=3)=[O:19])[CH2:21][C:22]=12
Reactant: c1nc[nH]n1
Reactant: O=C(CCl)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Agent: [Na]
Solvent: CN1CCCN(C)C1=O
Product: O=C(Cn1cncn1)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.5 %

Procedure:
To a suspension of 0.20 g of 1,2,4-triazole sodium in 1 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone is added 0.10 g of 2-chloro-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]acetamide in 1 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone followed by stirring at room temperature for 3 hours. The reaction mixture is quenched with 15 ml of water and the resulting solid is collected, washed with water and hexanes to give 70 mg of the desired product as a tan solid. MS(CI): 413 (M+H).
Reaction SMILES: CS(O)(=O)=O.C(N[C:9](=[O:13])[NH:10][CH2:11][CH3:12])C.C(N[C:17](=[O:21])[NH:18][CH2:19][CH3:20])C.[C:22]1(C)[CH:27]=CC=C[CH:23]=1>CC1C=CC=CC=1C>[CH3:27][C:22]1[C:19](=[CH:20][C:11](=[CH:12][CH:23]=1)[N:10]=[C:9]=[O:13])[N:18]=[C:17]=[O:21]
Reactant: Cc1ccccc1
Reactant: CCNC(=O)NCC
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1C
Product: Cc1ccc(N=C=O)cc1N=C=O
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
A mixture of 12.7 g 2,4-toluene bis (diethylurea) in 248 g o-xylene was charged to a 500 ml fluted flask equipped with a bottom take-off, a mechanical stirrer using a 1.5 inch "Teflon" crescent-shaped paddle, a condenser, and a thermocouple to monitor reaction temperature. The mixture was heated to 120° C. and then 8.75 g methane sulfonic acid was added in one portion. The mixture was stirred for 15 min at 120° C. and then the phases were allowed to settle at 50° C. The bottom salt phase was drawn off through the bottom take-off. Analysis of the xylene phase by HPLC and infrared analysis showed 100% conversion of the toluene bis (diethylurea) with a 98% yield of toluene diisocyanate. The xylene phase was then transferred to a round bottom flask equipped with a 12" Vigreux column and a distillation head for vacuum distillation. Octadecane, 65 g, was added to the flask and then the xylene was distilled overhead at 40 mm Hg. TDI was then distilled over 10 mm Hg. A heart cut of TDI containing 6.1 g TDI was obtained for an isolated yield of 88% for toluene diisocyanate.
Reaction SMILES: [CH2:1]([NH:6][CH2:7][C:8]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][NH:10]C(=O)OC(C)(C)C)[C:2]([CH3:5])([CH3:4])[CH3:3].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([NH:6][CH2:7][C:8]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:9][NH2:10])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)CNCC(CNC(=O)OC(C)(C)C)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CNCC(CN)(c1ccccc1)c1ccccc1

Procedure:
The title material was prepared by treating a solution of the crude tert-butyl 3-(neopentylamino)-2,2-diphenylpropylcarbamate (0.055 g) in dichloromethane (5 mL) with trifluoroacetic acid (1 mL) at 23° C. for 30 minutes. The reaction was concentrated to dryness and the residue was used as such in the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=2[F:25])=[C:7]([F:16])[C:8]2[N:9]([C:11]([C:14]#[CH:15])=[CH:12][N:13]=2)[CH:10]=1)=[O:4]>[Pd]>[CH3:1][O:2][C:3]([C:5]1[C:6]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=2[F:25])=[C:7]([F:16])[C:8]2[N:9]([C:11]([CH2:14][CH3:15])=[CH:12][N:13]=2)[CH:10]=1)=[O:4]
Reactant: C#Cc1cnc2c(F)c(Nc3ccc(C)cc3F)c(C(=O)OC)cn12
Agent: [Pd]
Product: CCc1cnc2c(F)c(Nc3ccc(C)cc3F)c(C(=O)OC)cn12
Reaction time: 1 h
Yield: 86.3 %

Procedure:
A mixture of 3-ethynyl-8-fluoro-7-(2-fluoro-4-methyl-phenylamino)-imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (16 mg, 0.047 mmol) and 10% Pd/C (5 mg) under an atmosphere of hydrogen (balloon) was stirred vigorously for one hour. The mixture was filtered through a plug of rinsing with dichloromethane and concentrated to provide the desired product (14 mg, 86%) as a yellow foam. MS APCI (+) m/z 346 (M+1) detected. 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 8.31 (s, 1H), 7.38 (s, 1H), 6.91 (d, 1H), 6.84 (s, 2H), 3.97 (s, 3H), 2.86 (q, 2H), 2.30 (s, 3H), 1.43 (t, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([N+:13]([O-:15])=[O:14])=[CH:5][CH:4]=1.[CH3:16][O:17][P:18]([O:21]C)[O:19][CH3:20]>>[N+:13]([C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([CH2:2][P:18](=[O:21])([O:19][CH3:20])[O:17][CH3:16])=[CH:4][CH:5]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(CBr)c2ccccc12
Reactant: COP(OC)OC
Product: COP(=O)(Cc1ccc([N+](=O)[O-])c2ccccc12)OC

Procedure:
1-Bromomethyl-4-nitronaphthalene and trimethylphosphite ((CH3O)3P) were treated in the same manner as in Reference Example 43 to yield dimethyl (4-nitro-1-naphthyl)methylphosphonate, which was then recrystallized from ethanol-hexane to yield yellow prisms having a melting point of 128°-129° C.
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[NH2:7][C:8]([CH3:29])([CH3:28])[CH2:9][N:10]1[C:22]2[C:21]3[N:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[C:11]1[CH2:24][O:25][CH2:26][CH3:27]>ClCCl>[NH2:23][C:14]1[C:13]2[N:12]=[C:11]([CH2:24][O:25][CH2:26][CH3:27])[N:10]([CH2:9][C:8]([NH:7][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])([CH3:28])[CH3:29])[C:22]=2[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: CC(C)N=C=O
Reactant: CCOCc1nc2c(N)nc3cccnc3c2n1CC(C)(C)N
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cccnc3c2n1CC(C)(C)NC(=O)NC(C)C
Temperature: 25 °C
Yield: 83.7 %

Procedure:
Under a nitrogen atmosphere, isopropyl isocyanate (206 μL, 2.10 mmol) was added to a chilled (0° C.) solution of 1-(2-amino-2-methylpropyl)-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (628 mg, 2.00 mmol) in dichloromethane (20 mL). The reaction mixture was allowed to warm slowly to ambient temperature overnight. The resulting precipitate was isolated by filtration and then dried under vacuum at 70° C. to provide 669 mg of 1-[2-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)-1,1-dimethylethyl]-3-(1-methylethyl)urea as white powder, mp 172.5-173.5° C. Anal. calcd for C20H29N7O2: % C, 60.13; % H, 7.32; % N, 24.54. Found: % C, 59.88; % H, 7.55; % N, 24.51.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:13]([OH:15])=O)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[NH2:21][C:22]1[C:23]([CH3:37])=[C:24]([CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:25]=[CH:26][CH:27]=1>CN(C=O)C.N1C=CC=CC=1>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:13]([NH:21][C:22]2[C:23]([CH3:37])=[C:24]([CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH:25]=[CH:26][CH:27]=2)=[O:15])=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: Cc1c(N)cccc1CCC(=O)OC(C)(C)C
Reactant: CC(=O)OCc1ccc(C(C(=O)O)C2CCCC2)cc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)OCc1ccc(C(C(=O)Nc2cccc(CCC(=O)OC(C)(C)C)c2C)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
11.41 g (90% pure, 37.16 mmol) of (+/−)-{4-[(acetyloxy)methyl]phenyl}(cyclopentyl)acetic acid were dissolved in a mixture of 71.8 ml of DMF and 22.5 ml of pyridine, and 15.54 g (40.88 mmol) of 1-[bis(dimethylamino)methylene]-5-chloro-3-oxy-1H-benzotriazol-1-ium tetrafluoroborate and 8.75 g (37.16 mmol) of tert-butyl 3-(3-amino-2-methylphenyl)propanoate were added. The reaction mixture was stirred at RT overnight and then concentrated under high vacuum. The residue was taken up in 100 ml of ethyl acetate and washed successively with 10% strength aqueous citric acid, saturated sodium bisulfate solution and saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1→3:1). This gave 16.36 g (89.2% of theory) of the title compound.
Reaction SMILES: Cl[S:2]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:4])=[O:3].[CH:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([CH3:22])[CH3:21])[C:15]=1[OH:23])([CH3:13])[CH3:12]>>[CH:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH:11]([CH3:13])[CH3:12])[C:15]=1[O:23][S:2]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:4])=[O:3])([CH3:22])[CH3:21]
Reactant: CC(C)c1cccc(C(C)C)c1O
Reactant: CCOC(=O)CS(=O)(=O)Cl
Product: CCOC(=O)CS(=O)(=O)Oc1c(C(C)C)cccc1C(C)C

Procedure:
The general procedure of Example I(A) was followed to react ethyl chlorosulfonylacetate with 2,6-diisopropylphenol to give ethyl (2,6-diisopropylphenoxysulfonyl)acetate. The ethyl acetate derivative was hydrolyzed to 2,6-diisopropylphenoxysulfonyl acetic acid. The acetic acid derivative was reacted with dodecylamine and DCC according to Example I(B) to provide 2,6-diisopropylphenyl N-dodecylcarbamoylmethylsulfonate, mp 75°-78° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].Cl.[NH2:14][CH:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=2)[O:17][C:16]1([CH3:29])[CH3:28]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH:14][CH:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=2)[O:17][C:16]1([CH3:29])[CH3:28])=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: COc1ccc2c(c1)OC(C)(C)C(N)C2=O
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc2c(c1)OC(C)(C)C(NC(=O)c1cc(Cl)ccc1OC)C2=O
Temperature: 27 °C
Reaction time: 3 h

Procedure:
28.7 g (0.14 mol) of 5-chloro-2-methoxybenzoyl chloride were introduced into a solution of 33.5 g (0.13 mol) of 3-amino-2,2-dimethyl-7-methoxy-4-chromanone hydrochloride in 150 ml of pyridine at 10° C. After the mixture had been stirred at about 27° C. for three hours, it was introduced into ice/water and extracted twice with methylene chloride. The combined methylene chloride extracts were washed twice with 2N hydrochloric acid and with water and then dried and evaporated, and the residue was recrystallized from ethanol/DMF. The 3-(5-chloro-2-methoxybenzamido)-2,2-dimethyl-7-methoxy-4-chromanone had a melting point of 174° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].CC(C)([O-])C.[K+].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=1[CH3:36]>CS(C)=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=1[CH3:36])[CH3:2]
Reactant: Cc1cc(Cl)ccc1CBr
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1ccc(Cl)cc1C)N=C(c1ccccc1)c1ccccc1
Reaction time: 0.33 h
Yield: 50.1 %

Procedure:
To a solution containing (Benzhydrylidene-amino)-acetic acid ethyl ester (2.3 g, 8.6 mmol) in 50 mL of DMSO under a nitrogen atmosphere was added potassium t-butoxide (1.2 g, 11 mmol) After stirring for 20 minutes, 1-Bromomethyl-4-chloro-2-methyl-benzene (1.89 g, 8.6 mmol) was added and the reaction allowed to stir at room temperature overnight. The reaction was diluted with ethyl acetate and washed with brine. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via biotage eluting with 20% ethyl acetate/hexanes gave 2-(Benzhydrylidene-amino)-3-(4-chloro-2-methyl-phenyl)-propionic acid ethyl ester (1.75 g, 50%) as a yellow oil. LCMS (APCI+) m/z 406 [M+H]+; Rt: 4.16 min.