Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].[Cl:8][C:9]1[C:17](F)=[C:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]>CN(C)C=O>[Cl:8][C:9]1[C:17]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[C:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: c1cn[nH]c1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1-n1cccn1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Pyrazole (210 mg, 3.09 mmol) was added to 190 mg (4.75 mmol) of 60 percent oil dispersed sodium hydride suspended in 7 mL of dry dimethylformamide. After the gas evolution had subsided, 500 mg (1.98 mmol) of 2-chloro-3-fluoro-4-methylsulfonylbenzoic acid was added and the mixture was stirred at 50° C. overnight. The mixture was then concentrated by evaporation under reduced pressure and the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid. The aqueous phase was extracted with ethyl acetate. The organic phases were combined and extracted with dilute aqueous sodium bicarbonate solution. The aqueous extract was acidified with 1N aqueous hydrochloric acid and extracted with dichloromethane. The organic extract was concentrated by evaporation under reduced pressure. The crystalline residue obtained was purified by rinsing with ethyl acetate to obtain 540 mg (91 percent of theory) of the title compound as a white powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:46]=[CH:45][CH:44]=[CH:43][C:5]=1[O:6][CH2:7][CH2:8][O:9][CH:10]1[CH:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[CH:18][CH:17]=2)[CH2:14][CH2:13][N:12]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:11]1.Cl[C:48]([O:50][CH3:51])=[O:49]>ClCCl.C(N(CC)CC)C>[CH3:35][O:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][O:26][CH2:25][CH2:24][CH2:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([CH:15]2[CH2:14][CH2:13][N:12]([C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])[CH2:11][CH:10]2[O:9][CH2:8][CH2:7][O:6][C:5]2[CH:43]=[CH:44][CH:45]=[CH:46][C:4]=2[CH2:3][CH2:2][NH:1][C:48]([O:50][CH3:51])=[O:49])=[CH:21][CH:20]=1
Reactant: COC(=O)Cl
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCN)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NCCc1ccccc1OCCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.25 g of tert-butyl 3-{2-[2-(2-aminoethyl)phenoxy]ethoxy}-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 56b) in 13 ml of dichloromethane and 0.12 ml of triethylamine is admixed at room temperature with a solution of 0.034 ml of methyl chloroformate in 1 ml of dichloromethane and stirred at room temperature over 2 hours. The reaction mixture is diluted with dichloromethane, washed with 1M potassium bisulphate solution (2×), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.15 (1:2 EtOAc-heptane); Rt=5.95.
Reaction SMILES: CC(P(C(C)(C)C)[C:6]1[C:11]([C:12]2C=CC=C[CH:13]=2)=[CH:10][CH:9]=[CH:8][CH:7]=1)(C)C.[C:22]1([C:28]#[C:29][P:30](=[O:35])([OH:34])[O:31][CH2:32][CH3:33])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(C1CCCCC=1)#C>[Au].ClC(Cl)C>[CH2:32]([O:31][P:30]1(=[O:34])[CH:29]=[C:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:13]=[C:12]([C:11]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=2)[O:35]1)[CH3:33]
Reactant: CCOP(=O)(O)C#Cc1ccccc1
Reactant: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: [Au]
Agent: C#CC1=CCCCC1
Solvent: CC(Cl)Cl
Product: CCOP1(=O)C=C(c2ccccc2)C=C(C2=CCCCC2)O1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62 %

Procedure:
A gold (Ag(I)) catalyst {[Au(JohnPhos)NCCH3]+SbF6—} [JohnPhos:(2-biphenyl)di-tert-butylphosphine] (11.3 mg, 0.015 mmol) was put into a reaction container, and dichloroethane (0.4 mL) was added thereto. After stirring at room temperature for 5 minutes, ethyl hydrogen phenylethynylphosphonate (63.0 mg, 0.3 mmol) diluted with 0.5 mL of dichloroethane was added thereto. Then 1-ethynylcyclohex-1-ene (63.6 mg, 0.6 mmol) was put thereinto, followed by stirring at 30° C. for 18 hours, and when all of the starting materials disappeared in the TLC, the reaction was allowed to be completed. After the solvent was removed under low atmospheric pressure, the product was separated by chromatography to obtain 2-ethoxy-4-phenyl-6-1-cyclohexenyl-1,2-oxaphosphorin 2-oxide (58.8 mg, 62%) which is a title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)=[CH:6][CH:5]=1)([O-])=O>CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=2)=[CH:8][CH:9]=1
Reactant: COc1cc(/C=C/c2ccc([N+](=O)[O-])cc2)cc(OC)c1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(CCc2ccc(N)cc2)cc(OC)c1OC
Yield: 78.3 %

Procedure:
A solution of nitrostilbene 6l (250 mg, 0.8 mmol) in EtOAc (20 mL) was hydrogenated at 30 psi in the presence of 10% Pd-C (25 mg) at room temperature for 4 h, and the catalyst was filtered off. Evaporation of the solvent and crystallization of the residue from hexanes gave the amine 8z (180 mg, 80%); mp 84°-5° C; IR (KBr) 3450, 3400, 3020, 2920, 2840, 1600, 1580, 1520, 1330, 1240, 1120, 980 cm-1 ; 1H NMR (CDCl3, 300 MHz) d 6.98 (d, J=8.2 Hz, 2H), 6.63 (d, J=8.2 Hz, 2H), 6.63 (d, J=8.2 Hz, 2H), 6.37 (s, 2H), 3.83 (s, 9H), 3.57 (bs, 2H), 2.80 (s, 4H); CIMS (isobutane) m/e 288 (MH+, 100). Anal. (C17H21NO3) C, H.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][O:6][NH2:7])[CH3:2].[C:9](O)(=[O:14])[CH2:10][CH2:11][C:12]#[CH:13].C1(N=C=NC2CCCCC2)CCCCC1>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:8])[CH2:5][O:6][NH:7][C:9](=[O:14])[CH2:10][CH2:11][C:12]#[CH:13])[CH3:2]
Reactant: CCOC(=O)CON
Reactant: C#CCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: C#CCCC(=O)NOCC(=O)OCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-Aminoxy-acetic acid ethyl ester (573 mg, 4.8 mmol) and 4-Pentynoic acid (441 mg, 4.5 mmol) in 15 mL EtOAc were added dicyclohexylcarbodiimide (928 mg, 4.5 mmol) and the resulting mixture was stirred at room temperature for 16 h.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([C:21](=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[N:14][CH:13]=[C:12]2[CH:31]=[O:32])(=[O:3])[CH3:2].O.P([O-])(O)(O)=[O:35].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C(O)(C)(C)C.O.CCCCCC>[C:1]([O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([C:21](=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[N:14][CH:13]=[C:12]2[C:31]([OH:35])=[O:32])(=[O:3])[CH3:2]
Reactant: O=P([O-])(O)O
Reactant: COc1cccc(C(=O)c2ncc(C=O)c3cc(OCCCOC(C)=O)c(OC)cc23)c1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CCCCCC
Solvent: CC(C)(C)O
Product: COc1cccc(C(=O)c2ncc(C(=O)O)c3cc(OCCCOC(C)=O)c(OC)cc23)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 39.2 %

Procedure:
To a stirred solution of afforded 6-(3-acetoxy-propoxy)-7-methoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carbaldehyde (20 mg, 0.045 mmol) in t-butanol (1 mL) and water (1 mL) solution was added sodium dihydrogenphosphate monohydrate (25.3 mg, 0.18 mmol), 2-methyl-2-butene (0.030 mL, 0.27 mmol) and sodium chlorite (24.8 mg, 0.27 mmol) at room temperature. The reaction suspension was then stirred at room temperature for 14 hrs. The resulting two-phase mixture was partitioned between dichloromethane and water and acidified to pH=3 by addition of acetic acid. The aqueous phase was then extracted with dichloromethane (3×20 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a brown semi-solid oil. The crude product was recrystallized in ethyl acetate and hexane to afford 6-(3-acetoxy-propoxy)-7-methoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carboxylic acid (8.0 mg, 39% yield) as a white solid: HR-MS m/e calcd for C24H23N1O8 (M−H+) 454.1496, found 454.1502; 1H NMR (300 MHz) compatible.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10](Cl)(=[O:14])[CH2:11][CH2:12][CH3:13].[C:16]([O:20][C:21]([NH:23][C:24]1[CH:25]=[CH:26][C:27]([OH:33])=[C:28]([CH:32]=1)[C:29]([OH:31])=[O:30])=[O:22])([CH3:19])([CH3:18])[CH3:17].Cl.Cl.CCOCC>ClCCl.C(OCC)C>[C:16]([O:20][C:21]([NH:23][C:24]1[CH:25]=[CH:26][C:27]([O:33][C:10](=[O:14])[CH2:11][CH2:12][CH3:13])=[C:28]([CH:32]=1)[C:29]([OH:31])=[O:30])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CCCC(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c(C(=O)O)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CCCC(=O)Oc1ccc(NC(=O)OC(C)(C)C)cc1C(=O)O
Temperature: 0 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
Diisopropylethylamine (3 eq) (complete dissolution) followed by butyryl chloride (2 eq) is added to a suspension of about 0.4 M of the compound (II) in dichloromethane, cooled to 0° C. and in inert atmosphere. It is stirred at ambient temperature for 16 hours. HCl 1N (cooled in an ice bath) up to acid pH is added. The organic phase is washed with water, anhydrified and evaporated. At this stage a mixture of the desired product (III) and deacylated product (probably the corresponding anhydride) is obtained as a whitish solid. The mixture is dissolved in ethyl ether (concentration of about 0.1 M), a 2N solution of HCl in ethyl ether (0.2 eq) is added and it is stirred at ambient temperature for 25 days, during which 2N hydrochloride ether is added other 2 times (0.4 eq HCl totally) up to obtaining complete conversion in the product (III). The solvent is evaporated, the resulting solid is triturated with hexane (2 times), it is filtered and it is dried, obtaining the product (III) as white solid. 88% yield, LC-MS 99% purity.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.C1(C)C=CC=CC=1.[OH-].[Na+].S([NH:34][N:35]=[CH:36][CH:37](Cl)Cl)(C1C=CC(C)=CC=1)(=O)=O>O.CO>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][CH2:4][CH2:3][N:2]2[CH:37]=[CH:36][N:35]=[N:34]2)=[CH:12][CH:11]=1
Reactant: COc1ccc(CCCCN)cc1
Reactant: Cc1ccc(S(=O)(=O)NN=CC(Cl)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: COc1ccc(CCCCn2ccnn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.5 %

Procedure:
1-(4-Aminobutyl)-4-methoxybenzene hydrochloride (1.0 g, 4.64 mmol) was dissolved in water. Toluene (10 ml) and 2N-sodium hydroxide (10 ml) were added and the mixture was partitioned. The organic layer was washed with 20% brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in methanol (8 ml), and a suspension of 2,2-dichloroacetaldehyde tosylhydrazone (2.61 g, 9.28 mmol) in methanol (12 ml) was added dropwise at 15-20° C. The mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. To the residue was added ethyl acetate (50 ml) and then was added saturated aqueous sodium hydrogen carbonate (50 ml). The mixture was stirred for 10 min and partitioned, which was followed by washing with saturated brine and concentration under reduced pressure. Purification by silica gel column gave 1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole (1.1 g, yield 100%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]1[C:14]2[C:9](=[C:10]([F:16])[C:11]([F:15])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)C.[Li+].[BH4-]>CCOC(C)=O.C1COCC1.CO.[Pd]>[F:16][C:10]1[C:11]([F:15])=[CH:12][CH:13]=[C:14]2[C:9]=1[CH2:8][CH2:7][CH:6]2[CH2:5][CH2:4][OH:3]
Reactant: CCOC(=O)CC1CCc2c1ccc(F)c2F
Agent: [Pd]
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: OCCC1CCc2c1ccc(F)c2F

Procedure:
A mixture of E- and Z-(4,5-difluoro-indan-1-ylidene)-acetic acid ethyl ester (Intermediate TWENTY-3) (1.1 g) in EtOAc (25 mL) was hydrogenated with 10% Pd/C (0.16 g) under H2 (balloon) at rt for 16 h. The mixture was filtered through a bed of Celite® and the filtrate was evaporated under vacuum. The ester, (4,5-difluoro-indan-1-yl)-acetic acid ethyl ester (1.1 g, 4.58 mmol) in THF (60 mL) and MeOH (1 mL) was treated with LiBH4 (0.21 g, 8.5 mmol) at 65° C. for 5 h. The mixture was cooled and THF was removed under vacuum. The solution was diluted with EtOAc and sat. NH4Cl. The layers were separated and the organic layer was dried over MgSO4 and filtered. After evaporation, the alcohol, 2-(4,5-difluoro-indan-1-yl)-ethanol (Intermediate TWENTY-4) was isolated as a clear, colorless oil, 1.7 g, (88%). Use, 2-(4,5-difluoro-indan-1-yl)-ethanol (Intermediate TWENTY-4) in Method SEVENTEEN produced 4-(4,5-difluoro-indan-1-ylmethyl)-1,3-dihydro-imidazole-2-thione (Compound 156).
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>O1CCCC1.C(OCC)C>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][C:7]([C:8]#[N:9])([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:26]
Reactant: CCOC(=O)CBr
Reactant: N#CCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccccc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
Combine phenylacetonitrile (5.85 g, 50.0 mmol) and tetrahydrofuran (140 mL). Cool to about 5° C. Add dropwise, a solution of sodium bis(trimethylsilyl)amide (800 mL, 1 M in tetrahydrofuran, 800 mmol). When the addition is complete, warm the reaction mixture to ambient temperature and allow to stir for 1 hour. Transfer the above solution via cannula into a cooled (−8° C.) solution of ethyl bromoacetate (84.5 mL, 762 mmol) in tetrahydrofuran (500 mL) at such a rate that the temperature of the reaction mixture does not rise above about 20° C. Allow to stir at ambient temperature. After 18 hours, dilute with diethyl ether (1.5 L) and extract with saturated aqueous solution of ammonium chloride, then water, and then saturated aqueous solution of sodium chloride. Dry the organic layer over MgSO4, filter, and concentrate in vacuo to obtain a residue. Distill the residue by bulb-to-bulb distillation to give the title compound: bp; 140-150° C. at 0.2 mm Hg.
Reaction SMILES: [Li+].[F:2][C:3]([F:23])([F:22])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]([O-])=[O:20])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[N+:58]([C:61]1[CH:73]=[CH:72][C:64]([O:65][CH:66]2[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]2)=[CH:63][C:62]=1[C:74]([F:77])([F:76])[F:75])([O-:60])=[O:59]>CN(C)C=O.ClCCl.O1CCCC1>[N+:58]([C:61]1[CH:73]=[CH:72][C:64]([O:65][CH:66]2[CH2:71][CH2:70][N:69]([C:19](=[O:20])[CH2:18][CH2:17][CH2:16][N:13]3[CH2:14][CH2:15][N:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([F:23])([F:2])[F:22])=[CH:5][CH:6]=4)[CH2:11][CH2:12]3)[CH2:68][CH2:67]2)=[CH:63][C:62]=1[C:74]([F:77])([F:75])[F:76])([O-:60])=[O:59]
Reactant: O=C([O-])CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: O=[N+]([O-])c1ccc(OC2CCNCC2)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1)N1CCC(Oc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reaction time: 0.08 h

Procedure:
4-[4-(4-Trifluoromethyl-phenyl)-piperazin-1-yl]-butyric acid lithium salt (18 mg; 0.05 mmol, prepared in accordance with Example 3), diisopropylethyl amine (19 μL; 0.11 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (21 mg; 0.05 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (1.5 mL) and the resulting solution is stirred for 5 minutes. A solution of 4-(4-nitro-3-trifluoromethyl-phenoxy)-piperidine hydrochloride (18 mg; 0.05 mmol, prepared in accordance with Example 44) in dimethylformamide (0.5 mL) is added and the reaction is then stirred for 3 hours at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (3×5 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is finally purified by preparative HPLC to deliver the desired product in pure form (20 mg; 0.03 mmol). The structure was confirmed using Protocol I-C. Calculated mass=589; observed mass=589; HPLC retention time=3.08 min.
Reaction SMILES: [Br:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH3:18])[N:11]2[C:16]=1[C:15](Cl)=[N:14][CH:13]=[N:12]2.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][CH3:29])=[CH:23][CH:22]=1>ClCCl.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH3:18])[N:11]2[C:16]=1[C:15]([N:28]([CH2:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=1)[CH3:29])=[N:14][CH:13]=[N:12]2
Reactant: CNCc1ccc(OC)cc1
Reactant: Cc1nc(-c2cnn(C)c2Br)c2c(Cl)ncnn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CN(C)c2ncnn3c(C)nc(-c4cnn(C)c4Br)c23)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-(5-bromo-1-methyl-1H-pyrazol-4-yl)-4-chloro-7-methylimidazo[5,1-f][1,2,4]triazine (9.80 g, 29.9 mmol) in dichloromethane (100 mL) was treated with 1-(4-methoxyphenyl)-N-methylmethanamine (4.52 g, 29.9 mmol). After stirring at room temperature for 10 minutes, the reaction was diluted with saturated aqueous sodium bicarbonate solution (100 mL) and stirred for an additional hour. The organic layer was then washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the product as a solid. Yield: 12.9 g, 29.2 mmol, 98%. LCMS m/z 443.9 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.71 (s, 3H), 2.79 (s, 3H), 3.78 (s, 3H), 3.89 (s, 3H), 4.67 (br s, 2H), 6.82 (br d, J=8.7 Hz, 2H), 7.10 (br d, J=8.6 Hz, 2H), 7.64 (s, 1H), 7.92 (s, 1H).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]2=[O:20])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([O-:4])=[O:3].[N:21]1([CH2:30][C:31](O)=[O:32])[CH:29]=[C:27]([CH3:28])[C:25](=[O:26])[NH:24][C:22]1=[O:23]>>[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][N:17]([C:31](=[O:32])[CH2:30][N:21]3[CH:29]=[C:27]([CH3:28])[C:25](=[O:26])[NH:24][C:22]3=[O:23])[CH2:16][C:15]2=[O:20])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Reactant: O=C1CNCCN1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: Cc1cn(CC(=O)N2CCN(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)C(=O)C2)c(=O)[nH]c1=O
Yield: 95.6 %

Procedure:
The title compound (151 mg, 95%) was synthesized by reaction of 1-(4-nitro-benzenesulfonyl)-piperazin-2-one HCl salt (113 mg, 0.35 mmol) with (thymin-1-yl)-acetic acid (64 mg, 0.35 mmol) as per the procedure of example 64. 1H-NMR (500 MHz; DMSO-d6) δ 11.31 (s, 0.6H), 11.29 (s, 0.4H), 8.44 (d, 2H), 8.29 (d, 2H), 7.34 (s, 0.6H), 7.27 (s, 0.4H), 4.64 (s, 1.2H), 4.55 (s, 0.8H), 4.33 (s, 0.8H), 4.18 (s, 1.2H), 4.14 (t, 1.2H), 4.00 (t, 0.8H), 3.90 (t, 1.2H), 3.80 (t, 0.8H), 1.74 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=2[F:19])=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.N1C2=C(OC3C=CC(N[C:37]([NH:39][C:40](=[O:48])[CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[S:38])=CC=3F)N=CC=C2C=C1>>[Br:1][C:2]1[C:3]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:37]([NH:39][C:40](=[O:48])[CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[S:38])=[CH:14][C:13]=2[F:19])=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2nccc3cc[nH]c23)c(F)c1
Reactant: Nc1ccc(Oc2c(Br)cnc3ccsc23)c(F)c1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2c(Br)cnc3ccsc23)c(F)c1
Yield: 99 %

Procedure:
Starting from the compound 273 and following the procedure described above for the synthesis of compound 262a (scheme 59, example 218, step 4), title compound 274 was obtained in 99% yield as a white solid. 1H NMR (DMSO-d6) δ (ppm):12.44(s, 1H), 11.79(s, 1H), 8.82(s, 1H), 8.03(d, 1H), 7.99(dd, 1H), 7.54(d, 1H), 7.41(dd, 1H), 7.32-7.24(m, 6H), 3.80(s, 2H). MS (m/z):517.0 (M+H) (found).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C@@H:5]([NH:12]C(=O)OC(C)(C)C)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][C@H:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH2:12]
Reactant: COCC[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCC[C@@H](N)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-tert-Butyl 3-methoxy-1-phenylpropylcarbamate (Intermediate 61, 78 mg, 0.294 mmol) was dissolved in DCM (4.5 ml) and TFA (0.5 ml) was added. The reaction mixture was stirred for 1 h at room temperature when LCMS indicated that the reaction was complete. The reaction mixture was concentrated in vacuo, and the crude product was taken onto next step without further purification (0.294 mmol). LCMS [M+H]=166
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[C@H:6]([CH:7]=[O:8])[C@:5]1([CH3:21])[C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:12]=[C:11]([CH:18]([CH3:20])[CH3:19])[CH:10]=1.CC12C(C)(C)C(C(OC[C@H]3[C@H](COC)[C@@]3(C)C3C=C(C(C)C)C=C(C(C)C)C=3)=O)(CC1)OC2=O>>[CH3:1][O:2][CH2:3][C@H:4]1[C@H:6]([CH:7]=[O:8])[C@:5]1([CH3:21])[C:9]1[CH:10]=[C:11]([CH:18]([CH3:19])[CH3:20])[CH:12]=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=1
Reactant: COC[C@@H]1[C@H](C=O)[C@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Agent: COC[C@H]1[C@H](COC(=O)C23CCC(C)(C(=O)O2)C3(C)C)[C@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Product: COC[C@H]1[C@H](C=O)[C@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Yield: 95 %

Procedure:
Following a procedure similar to that for the preparation of Intermediate 45 but using Intermediate 43a as the starting material afforded the title compound (16 mg, 95% yield) as a colorless oil:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:22][C:23](=[O:36])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][CH2:32][N:33]=[N+]=[N-])[CH:26]=1)[CH3:21].O>O1CCCC1>[CH2:20]([O:22][C:23](=[O:36])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][CH2:32][NH2:33])[CH:26]=1)[CH3:21]
Reactant: CCOC(=O)Cc1cccc(CCN=[N+]=[N-])c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)Cc1cccc(CCN)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 90.4 %

Procedure:
Triphenylphosphine (3.88 g, 23.3 mmol) was added in one portion to a stirred solution of ethyl[3-(2-azidoethyl)phenyl]acetate (Preparation 57) (3.88 g, 16.6 mmol) in tetrahydrofuran (100 ml) at room temperature under nitrogen. The reaction was stirred for 18 hours and water (5 ml) added and the reaction heated at 50° C. for 4 hours, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was dissolved in saturated aqueous sodium hydrogen carbonate (40 ml) and the aqueous extracted with dichloromethane (3×50 ml). The combined organics were dried (sodium sulfate), the solvent removed in vacuo and the residue purified by flash column chromatography on silica gel eluting with dichlromethane:methanol (95:5, by volume) to give the title compound as a colourless oil (3.11 g). 1H NMR (400 MHz, CDCl3): δ 7.26-7.22 (1H, t), 7.13-7.08 (3H, t), 4.16-4.11 (2H, m), 3.58 (2H, s), 2.96-2.93 (2H, t), 2.74-2.71 (2H, t), 1.25-1.22 (3H, t) ppm. LRMS (electrospray): M/Z [M+H]+ 208, [M+NA]+ 230, [M−H]− 206.