Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]([O:17][C@H:18]1[O:23][CH2:22][CH2:21][N:20]([CH2:24][C:25]2[NH:30][C:28](=[O:29])[N:27]([P:31]([OH:34])([OH:33])=[O:32])[N:26]=2)[C@H:19]1[C:35]1[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=1)[C:3]1[CH:4]=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.O>CO>[CH3:1][C@@H:2]([O:17][C@H:18]1[O:23][CH2:22][CH2:21][N:20]([CH2:24][C:25]2[N:30]=[C:28]([OH:29])[N:27]([P:31]([OH:33])([OH:34])=[O:32])[N:26]=2)[C@H:19]1[C:35]1[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=1)[C:3]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]=1
Reactant: C[C@@H](O[C@H]1OCCN(Cc2nn(P(=O)(O)O)c(=O)[nH]2)[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: O
Solvent: CO
Product: C[C@@H](O[C@H]1OCCN(Cc2nc(O)n(P(=O)(O)O)n2)[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 79 %

Procedure:
6.0 gm of fosaprepitant dimeglumine salt, prepared as in Part B, 120 ml of water and 120 ml of methanol were charged in a clean and dry round bottom flask followed by cooling to about 0° C. The pH of the reaction mixture was adjusted to about 1 by the addition of 1N hydrochloric acid solution at about 0° C.-5° C. The resultant reaction mixture was stirred for about 5 minutes. The separated solid was filtered and the solid was washed with copious amount of water to neutral pH. Finally, the solid was washed with 12 ml of methanol followed by drying the solid obtained at about 35° C.-40° C. under vacuum to afford 2.9 gm of fosaprepitant, neutral form, having the XRPD pattern, which is substantially in accordance with FIG. 3; and a DSC thermogram, which is substantially in accordance with FIG. 4.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:8][C:7]([C:17]([NH2:19])=O)=[N:6]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N(CC)CC)C>>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:8][C:7]([C:17]#[N:19])=[N:6]1
Reactant: COCCn1nc(C(N)=O)cc1CC1CCOCC1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COCCn1nc(C#N)cc1CC1CCOCC1
Yield: 99.8 %

Procedure:
The method described in Part F of Example 3 was used to treat 1-(2-methoxyethyl)-5-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazole-3-carboxamide (3.41 g, 12.7 mmol) with trifluoroacetic anhydride (1.98 mL, 14.0 mmol) in the presence of triethylamine (3.86 g, 38.1 mmol) with the following modifications. Extractions were carried out four times with chloroform, and the automated flash chromatography column was eluted with ethyl acetate. 1-(2-Methoxyethyl)-5-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazole-3-carbonitrile (3.16 g) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:16][CH2:17][OH:18])[CH2:13][CH2:14][OH:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClCCl.C(N(CC)CC)C>[C:6]1([C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:13][CH2:14][O:15][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:16][CH2:17][O:18][S:2]([CH3:1])(=[O:4])=[O:3])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCC(CCO)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCC(CCOS(C)(=O)=O)(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A solution of 62 cm3 of methanesulphonyl chloride in 100 cm3 of dichloromethane is added over 10 minutes to a solution, cooled to -20° C., of 95 g of 3,3-diphenyl-l,5-pentanediol (prepared according to P. EILBRACHT et al., Chem. Ber. 118, 825-839 (1985)) in 950 cm3 of dichloromethane and 113 cm3 of triethylamine. After stirring for 2 hours at 20° C., the reaction mixture is washed with twice 500 cm3 of water, the organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The oily residue is crystallized from ethyl ether, the crystals are washed with ethyl ether, drained and dried. 140 g of 3,3-diphenyl-l,5-bis(methanesulphonyloxy)pentane are obtained in the form of white crystals; melting point 99° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:10]OC)[C:5]([NH2:8])=[N:6][CH:7]=1.Cl(O)(=O)(=O)=O>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:10][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COC=C(c1cc(Br)cnc1N)C1CCCC1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: C1COCCO1
Product: Brc1cnc2[nH]cc(C3CCCC3)c2c1
Temperature: 80 °C
Yield: 67.5 %

Procedure:
A mixture of 5-bromo-3-(1-cyclopentyl-2-methoxy-vinyl)-pyridin-2-ylamine (116.9 mg, 0.39 mmol) and perchloric acid (0.1 mL) in dioxane (1 mL) was heated at 80° C. for 2 hrs. Solvents were evaporated and the residue was washed with a solution of 2M sodium carbonate (5 mL). A precipitate was formed and filtered off. It was washed with water and dried to afford the product 5-bromo-3-cyclopentyl-1H-pyrrolo[2,3-b]pyridine (69.8 mg, 67% yield) as a brown solid. MS: m/z 265/266 [MH+].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH2:13]1[C:21]2[C:16](=[CH:17][C:18]([CH:22]=O)=[CH:19][CH:20]=2)[CH2:15][CH2:14]1.C(O)(C(F)(F)F)=O>>[CH2:13]1[C:21]2[C:16](=[CH:17][C:18]([CH:22]3[C:5]4[NH:6][C:7]5[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=5)[C:4]=4[CH2:3][CH2:2][NH:1]3)=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=Cc1ccc2c(c1)CCC2
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)CCC2)NCC3
Yield: 15.6 %

Procedure:
This product was prepared using the same procedure as for Intermediate 1 with tryptamine (1.28 g, 8.0 mmol), indan-5-carboxaldehyde (1.3 g, 1.1 equiv.) and TFA (1.2 mL, 2 equiv.) to give the title compound (0.36 g, 14%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:5]2[C:22]([F:25])([F:24])[F:23].CNCCNC.CC(O)(C)C.[Na+].[I-:38]>C(Cl)Cl.[Cu]I>[I:38][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:5]2[C:22]([F:25])([F:24])[F:23]
Reactant: [I-]
Reactant: FC(F)(F)c1nc2ccc(Br)cc2c(C(F)(F)F)c1-c1ccccc1
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: FC(F)(F)c1nc2ccc(I)cc2c(C(F)(F)F)c1-c1ccccc1

Procedure:
A mixture of 6-bromo-3-phenyl-2,4-bis(trifluoromethyl)quinoline (273 mg, 0.650 mmol, Intermediate 8, step c), CuI (14 mg, 0.074 mmol), N,N′-dimethylethylenediamine (0.0158 mL, 0.147 mmol), t-BuOH (0.65 mL), and NaI (200 mg, 1.33 mmol) was microwaved at 150° C. for 30 min (Biotage). The reaction was diluted with DCM (10 mL), filtered through Celite® and a 0.45 um filter, and concentrated. The residue was flash chromatographed with a heptane to 20% EtOAc/heptane gradient to afford the title compound as a light yellow oil that crystallized upon standing.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH:5]([CH3:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:17]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:18]>C(Cl)(Cl)Cl>[CH3:8][CH:5]1[CH2:6][CH2:7][N:2]([NH:1][C:17](=[O:18])[O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:3][CH2:4]1
Reactant: CC1CCN(N)CC1
Reactant: CCCCCCCCCCCCCCCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCOC(=O)NN1CCC(C)CC1
Temperature: 25 °C

Procedure:
6.3 Grams of N-amino-4-methylpiperadine, 6.0 g of triethylamine and 120 ml of chloroform were charged in a flask equipped with a stirrer, a condenser and a calcium chloride drying tube and stirred with ice cooling. To the solution was slowly added dropwise 15.2 g of hexadecyl chloroformate. After completion of the addition, the temperature of the solution was returned to room temperature, followed by refluxing with heating for 0.5 hour. The reaction mixture was cooled to room temperature, washed with water, dried over anhydrous magnesium sulfate and, then, concentrated under reduced pressure. The residue was recrystallized from acetonitrile to obtain 16.8 g of the desired product. m.p. 92° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[NH2:14].[CH2:16]([Sn](CCCC)(CCCC)C=CC)[CH2:17][CH2:18]C.[F-].[K+]>O1CCOCC1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([CH:16]=[CH:17][CH3:18])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[NH2:14]
Reactant: CC=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1N
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC=Cc1cc(C(=O)OC)c(N)c([N+](=O)[O-])c1
Reaction time: 0.33 h
Yield: 77 %

Procedure:
A solution of 0.5 g (1.8 mmol) of the above ester 0.9 g (2.7 mmol) of tributyl-propenyl-stannane, 0.18 g (0.18 mmol) of (tetrakistriphenyl phosphine) palladium (0) in 25 mL of dioxane was degassed with nitrogen for 20 min then refluxed under nitrogen for 12 h. The reaction mixture was cooled, 20 mL of 2 M KF solution was added. The mixture was stirred for 20 min, extracted with ethyl acetate washed with water and brine. The residue was purified by column chromatography using 8:2 hexane and ethyl acetate to afford 0.35 g (77%) of the 2-amino-3-nitro-5-propenyl-benzoic acid methyl ester as a solid LCMS: 239 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:6]=[CH:5]2.C([Li])CCC.CN([CH:25]=[O:26])C>C1COCC1>[C:13]([O:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:25]=[O:26])[CH:3]=2)[CH:8]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)Oc1ccc2cc(Br)ccc2c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)Oc1ccc2cc(C=O)ccc2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a −78° C. solution of 6-bromo-2-t-butyloxynaphthalene (2.00 g, 7.16 mmol) in dry THF (30 mL) under nitrogen was added 2.5 m n-butyl lithium in hexanes (3.16 mL, 7.88 mmol). The resulting solution was stirred 0.5 hours at −78° C. and dry DMF (1.66 mL, 21.56 mL) was added neat. The cooling bath was removed, the reaction was allowed to stir for 1 h, and quenched with excess saturated ammonium chloride. The reaction was partitioned between ethyl acetate and brine. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated under vacuum. Purification on silica gel with 10% ethyl acetate/hexanes gave the title compound (1.47 g, 90%) as a colorless oil. mp 51-52° C.;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:12](Cl)(=O)C(Cl)=O.CO>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:12])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(Br)ccc1Cl
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)ccc1Cl
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a suspension of 5-bromo-2-chloro-benzoic acid (2.5 g, 10.6 mmol) in dichloromethane (50 ml) was added a solution of oxalyl chloride in dichloromethane (2 M, 6 ml, 12 mmol) followed by N,N-dimethylformamide (5 drops). After stirring for 30 minutes, methanol (10 ml) was added and the mixture was stirred for 20 hours. The mixture was concentrated under reduced pressure and partitioned between ethyl acetate (150 ml) and saturated aqueous potassium carbonate solution (100 ml). The organic layer was concentrated under reduced pressure to provide methyl 5-bromo-2-chloro-benzoate (2.4 g, 91% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([O:9]CC)=[O:8])[C:2]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.[ClH:18]>>[ClH:18].[ClH:18].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:9])=[O:8])[C:2]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1cccnc1-c1ccncc1
Agent: Cl
Product: O=C(O)c1cccnc1-c1ccncc1

Procedure:
A solution of ethyl 2,4′-bipyridine-3-carboxylate (14.1 g) in 6 N hydrochloric acid (200 mL) was heated under reflux overnight. The solvent was evaporated under reduced pressure, to the obtained residue was added toluene, and the solvent was again evaporated under reduced pressure to give the title compound (16.4 g).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](Cl)=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[NH:4][N:3]=1.[CH3:24][O-:25].[Na+].Cl>CO>[NH2:1][C:2]1[C:6]2[C:7]([O:25][CH3:24])=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[NH:4][N:3]=1
Reactant: C[O-]
Reactant: C[C@@H](NC(=O)Nc1cc2[nH]nc(N)c2c(Cl)n1)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1nc(NC(=O)N[C@H](C)c2ccccc2)cc2[nH]nc(N)c12
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (R)-1-(3-amino-4-chloro-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (0.12 g, 0.36 mmol) in methanol (3.0 mL) was added sodium methoxide (0.78 mL, 3.62 mmol, 25% solution in MeOH) and stirred at 120° C. for 1 h in a microwave reactor. After confirming the completion of reaction by TLC, the reaction mixture was acidified with 1.5N HCl and concentrated under reduced pressure and crude product which was purified by preparative HPLC to afford (R)-1-(3-amino-4-methoxy-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. 1H NMR (ppm, 400 MHz, DMSO-d6): δ 11.48 (s, 1H), 8.76 (s, 1H), 7.94 (s, 1H), 7.35-7.33 (m, 4H), 7.26-7.21 (m, 1H), 6.86 (d, J=8.00 Hz, 1H), 5.12 (s, 2H), 4.88-4.85 (m, 1H), 3.87 (s, 3H), 1.41 (d, J=8.00 Hz, 3H), MS ES calc'd. for C16H18N6O2 [M+H]+ 327. Found 327.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].C([CH2:17][S:18]([CH2:21][S:22]([CH2:25][C:26](O)=O)(=[O:24])=[O:23])(=[O:20])=[O:19])(O)=O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6](/[CH:7]=[CH:17]/[S:18]([CH2:21][S:22](/[CH:25]=[CH:26]/[C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=2)(=[O:23])=[O:24])(=[O:19])=[O:20])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)CS(=O)(=O)CS(=O)(=O)CC(=O)O
Reactant: COc1ccc(C=O)cc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: COc1ccc(/C=C/S(=O)(=O)CS(=O)(=O)/C=C/c2ccc(OC)c([N+](=O)[O-])c2)cc1[N+](=O)[O-]
Yield: 85 %

Procedure:
A solution of 4-methoxy-3-nitrobenzaldehyde (2 mmol) and carboxymethane-sulfonylmethanesulfonyl-acetic acid (1 mmol) in acetic acid (10 mL) was subjected to General Procedure 1, to yield the title compound in 85% yield. m.p. 263-265° C.
Reaction SMILES: [CH2:1]([N:5]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)(=[O:34])=[O:33])[C@H:6]([C:29]([OH:31])=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](OCC1C2C=CC=CC=2C2C1=CC=CC=2)=[O:13])[CH:2]([CH3:4])[CH3:3].[C:44]([NH:47][C:48]1[CH:53]=[CH:52][C:51]([S:54]([NH:57][C@H:58](C(O)=O)[CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)(=[O:56])=[O:55])=[CH:50][CH:49]=1)(=[O:46])[CH3:45]>>[CH3:3][CH:2]([CH2:1][N:5]([S:32]([C:35]1[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=1)(=[O:33])=[O:34])[C@H:6]([C:29]([OH:31])=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C@@H:58]([NH:57][S:54]([C:51]1[CH:50]=[CH:49][C:48]([NH:47][C:44]([CH3:45])=[O:46])=[CH:53][CH:52]=1)(=[O:56])=[O:55])[CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)=[O:13])[CH3:4]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Reactant: CC(C)CN([C@@H](CCCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)N[C@@H](Cc2ccccc2)C(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1

Procedure:
The title compound was prepared from solid phase bound Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-Nε-(9-fluorenylmethoxycarbonyl)-L-lysine (step A) as described in general procedure Bb using Nα-(4-acetamidobenzenesulfonyl)-L-phenylalanine (400 mg, 1.2 mmol) which was prepared in step A of example 3. The final product was purified by preparative HPLC to yield 55 mg (60%) of the desired material.
Reaction SMILES: Cl.[CH:2]([NH:5][CH:6]([CH3:26])[CH2:7][C:8]1[C:9](=[O:25])[NH:10][CH2:11][CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=3)[C:14]=12)([CH3:4])[CH3:3].[CH:27](=O)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C([BH3-])#N.[Na+].Cl>C(#N)C.C(O)(=O)C>[CH:2]([N:5]([CH:6]([CH3:26])[CH2:7][C:8]1[C:9](=[O:25])[NH:10][CH2:11][CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=3)[C:14]=12)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([CH3:3])[CH3:4]
Reactant: COc1ccc2c(c1)CCC1CCNC(=O)C(CC(C)NC(C)C)=C21
Reactant: CCCCCCC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCCCCCCN(C(C)C)C(C)CC1=C2c3ccc(OC)cc3CCC2CCNC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.66 ml of glacial acetic acid are added dropwise to the ice-cooled mixture of 5.0 g of slow moving 1-(2-isopropylaminopropyl)-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2one hydrochloride, 15.2 g of heptaldehyde, 2.52 g of sodium cyanoborohydride and 53 ml of acetonitrile. The mixture is stirred at room temperature for 2 hours, cooled, acidified to pH=1 with concentrated hydrochloric acid and evaporated to remove the acetonitrile. The residue is diluted with water, the solution washed with diethyl ether, basified to pH=10-11 with 3 N aqueous sodium hydroxide and extracted with chloroform. The extract is dried, evaporated and the residue crystallized from ethanol-water (5:2) to give the 1-[2-(N-isopropyl-N-heptylamino)propyl]-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one, RR racemate melting at 102°-104°.
Reaction SMILES: [F:1][C:2]1[C:3]([C:33]2[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=2)=[N:4][C:5]([NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][C@H:11]1[CH2:14][CH2:13][N:12]1[C:15](OC(C)(C)C)=[O:16])=[O:8].FC(F)(F)[C:41](O)=[O:42].C(O)(=O)CO.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[C:3]([C:33]2[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=2)=[N:4][C:5]([NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][C@H:11]1[CH2:14][CH2:13][N:12]1[C:15](=[O:16])[CH2:41][OH:42])=[O:8]
Reactant: Cn1cc(-c2nc(NCCc3cccc(F)c3)c(C(=O)NC[C@H]3CCN3C(=O)OC(C)(C)C)cc2F)cn1
Reactant: O=C(O)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1cc(-c2nc(NCCc3cccc(F)c3)c(C(=O)NC[C@H]3CCN3C(=O)CO)cc2F)cn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a mixture of (R)-tert-butyl 2-((5-fluoro-2-(3-fluorophenethylamino)-6-(1-methyl-1H-pyrazol-4-yl)nicotinamido)methyl)azetidine-1-carboxylate (16.5 g, 31.4 mmol) in 100 mL DCM at 0° C. was added trifluoroacetic acid (24 mL, 314 mmol) slowly. The mixture was stirred at r.t for 2 hours until the Boc protection group was completely removed. The mixture was then concentrated. The residue was dissolved in 100 mL DMF and cooled down to 0° C. To the mixture was added a mixture of glycolic acid (2.86 g, 38 mmol), HBTU (14.3 g, 38 mmol), HOBT (5.1 g, 38 mmol) and DIEA (16.4 ml, 94 mmol). The mixture was warmed up to r.t and stirred at r.t. for 2 hours. The mixture was extracted with EtOAc. The organic layer was further washed with 1N NaOH (300 ml) and brine, dried and concentrated. The residue was subjected to a Biotage silica gel chromatography using gradient 0-40% B as eluant (A=dichloromethane, B=10% MeOH in dichloromethane) to give the crude product. The yellow solid was further tritirated with 100 mL EtOAc. (R)-5-fluoro-2-(3-fluorophenethylamino)-N-((1-(2-hydroxyacetyl)azetidin-2-yl)methyl)-6-(1-methyl-1H-pyrazol-4-yl)nicotinamide was obtained as a pale yellow solid (12.7 g, 83% yield). LRMS (M+H+) m/z 485.1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]#[C:9][CH3:10].CN(C)C=O.[Cl:17][C:18]1[NH:28][C:21]2[CH:22]=[N:23][N:24]([CH3:27])[C:25](=[O:26])[C:20]=2[N:19]=1>C(OCC)(=O)C>[CH2:7]([N:19]1[C:20]2[C:25](=[O:26])[N:24]([CH3:27])[N:23]=[CH:22][C:21]=2[N:28]=[C:18]1[Cl:17])[C:8]#[C:9][CH3:10]
Reactant: Cn1ncc2[nH]c(Cl)nc2c1=O
Reactant: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCn1c(Cl)nc2cnn(C)c(=O)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.166 g of potassium carbonate and 0.106 μl of 2-butynyl bromide were added to a 10 ml N,N-dimethylformamide solution of 0.184 g of 2-chloro-5-methyl-1,5-dihydroimidazo[4,5-d]pyridazin-4-one, and the mixture was stirred at room temperature for 18 hours. 50 ml of ethyl acetate was added to the solution, and the mixture was washed three times with 20 ml of water and then with 20 ml of a saturated sodium chloride solution. The organic liquid was dried over magnesium sulfate, and concentrated under reduced pressure. Then, the residue was purified by silica gel column chromatography. Thus, 0.175 g of 3-(2-butynyl)-2-chloro-5-methyl-3,5-dihydroimidazo[4,5-d]pyridazin-4-one was obtained from the fraction eluted with hexane-ethyl acetate (4:1), and 0.033 g of 1-(2-butynyl)-2-chloro-5-methyl-1,5-dihydroimidazo[4,5-d]pyridazin-4-one was obtained from the fraction eluted with hexane-ethyl acetate (2:3).
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:2]=1[I:1]
Reactant: CO
Reactant: COc1ccc(C(=O)O)c(I)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(OC)cc1I

Procedure:
411 G. of 2-iodo-4-methoxy-benzoic acid, 4 liters of methanol and 400 ml. of concentrated sulfuric acid are heated under reflux for 4 hours. The solution is evaporated under reduced pressure, treated with water and extracted with ether. The organic phase is washed successively with aqueous sodium sulfate and aqueous sodium bicarbonate and then dried over sodium sulfate. The sodium is filtered, evaporated under reduced pressure, distilled, and there is obtained 2-iodo-4-methoxy-benzoic acid methyl ester having a boiling point of 95°-98° C/0.04 mm.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[N:10]=[C:9]([C:29]([F:32])([F:31])[F:30])[N:8]=1>>[Cl:6][C:7]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:15][CH:14]=2)=[C:11]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=2)[N:10]=[C:9]([C:29]([F:32])([F:30])[F:31])[N:8]=1
Reactant: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)nc(Cl)c2-c2ccccc2)cc1
Reactant: O=S(=O)(O)Cl
Product: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)nc(Cl)c2-c2ccc(S(=O)(=O)Cl)cc2)cc1
Temperature: 0 °C
Yield: 65.59 %

Procedure:
To a solution of chlorosulphonic acid (605 mmol, 40.4 ml) was added 4-chloro-6-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidine (5.0 g, 12.1 mmol, prepared according to the procedure described in PCT/IB03/02879) slowly under continuous stirring at 0° C. until the completion of the addition. The reaction mixture was further stirred at 32° C. until TLC confirmed the completion. Subsequently the resulting reaction mass was poured slowly under vigorous stirring onto crushed ice and the solid obtained was filtered, washed thoroughly with water (100 ml) and extracted with ethyl acetate (3×200 ml). The combined organic layer was washed with brine (150 ml), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 4-{4-chloro-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonyl chloride (2.75 g, yield 65.59%, purity by HPLC 98.17%); m.p: 207-210° C. 1H-NMR (400 MHz, CDCl3) δ: 3.01 (s, 3H), 7.511-7.515 (d, 2H), 7.53-7.67 (m, 1H), 7.72-7.76 (t, 1H), 7.86-7.89 (m, 3H), 8.11-8.13 (d, 1H). IR (KBr) cm−1: 1557, 1524; MS m/z: 511.6 (M+).