Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:13][CH:14]([CH:22]([CH3:24])[CH3:23])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.N1C=CC=CC=1.[S:31](Cl)(Cl)=[O:32]>C(Cl)Cl>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH:3]2[CH2:2][O:1][S:31](=[O:32])[N:13]2[CH:14]([CH:22]([CH3:24])[CH3:23])[C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])=[CH:6][CH:7]=1
Reactant: COc1ccc(CC(CO)NC(C(=O)OC(C)(C)C)C(C)C)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(CC2COS(=O)N2C(C(=O)OC(C)(C)C)C(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 8.2 %

Procedure:
t-Butyl 2-(1-hydroxymethyl-2-(4-methoxyphenyl)ethylamino)-3-methylbutyrate (2.49 g; 7.4 mmol) was dissolved in CH2Cl2 (180 ml). The reaction solution was cooled to −78° C. Then pyridine (3 ml; 37 mmol) was added and subsequently thionyl chloride (0.64 ml; 8.88 mmol) was added dropwise. The reaction mixture was stirred for 1 h, during which the temperature was allowed to reach 0° C. It was taken up in CH2Cl2 and washed with aqueous HCl (1%; 2×) and NaHCO3 solution. The organic phase was dried over Na2SO4 and concentrated in a rotary evaporator. The crude product was purified by filtration through silica gel (100 g). t-Butyl 2-(4-(4-methoxybenzyl)-2-oxo-(1,2,3)oxathiazolidin-3-yl)-3-methylbutyrate (2.35 g; 0.61 mmol) was obtained as a dark yellow oil. MS: 384.20 (M+H); Rt: 1.76 min (method: gradient 0 min 96% H2O (0.05% TFA) 2.0 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 μL (YMC J'sphere ODS H80 20X2 1.4μ); 30° C.)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[CH:9][C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[OH:17])=[C:4](F)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O.C1OCCOCCOCCOCCOCCOC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[CH:9][C:10]3[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=3[O:17][C:4]=2[CH:3]=1
Reactant: Cc1cccc(O)c1C=Nc1ccc(Br)cc1F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cccc2c1C=Nc1ccc(Br)cc1O2
Temperature: 140 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
To a solution of 2-[(4-bromo-2-fluorophenyl)iminomethyl]-3-methylphenol (31.7 g, 102.9 mmol) in DMSO (0.27 L), K2CO3 (28.6 g, 206.9 mmol) and 18-Crown-6 (477 mg, 1.8 mmol) were added. The resulting mixture was stirred at 140° C. for 1 h and then allowed to cool to ambient temperature. Water was added and the mixture was extracted with toluene/ethyl acetate (8:2). The combined organic layers were washed with water and with brine, dried (Na2SO4) and evaporated to afford the crude compound which was purified by flash chromatography (SiO2, CH2Cl2) to give 7-bromo-1-methyldibenz[b,f][1,4]oxazepine (25.05 g, 84%). 1H-NMR (400 MHz, CDCl3) δ 2.47 (s, 3H), 7.01 (m, 2H), 7.18-7.37 (m, 4H), 8.77 (s, 1H). (m/z)=288+290 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([N+:24]([O-])=O)=[CH:16][CH:15]=2)[CH:10]=[CH:9][N:8]=1)=[O:5].C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C.[Fe]>[NH2:24][C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([O:13][C:11]2[CH:10]=[CH:9][N:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH:12]=2)=[CH:15][CH:16]=1
Reactant: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COCC(=O)Nc1cc(Oc2ccc(N)c3ccccc23)ccn1
Temperature: 45 °C
Yield: 86.6 %

Procedure:
A stirred suspension of 2-methoxy-N-(4-(4-nitronaphthalen-1-yloxy)pyridin-2-yl)acetamide (11) (44.0 g, 125 mmol) and iron powder (41.7 g, 747 mmol) in acetic acid (300 mL) was heated at 45° C. After 3 hr the mixture was cooled to RT and poured slowly and cautiously onto solid Na2CO3 (200 g). The mixture effervesced vigorously. The mixture was partitioned between water (500 mL) and EtOAc (500 mL). The aqueous layer was basified with solid Na2CO3 to pH 11 and filtered through a pad of celite. The aqueous layer and celite pad were extracted with EtOAc (3×500 mL) and the combined extracts were washed with saturated aqueous NaHCO3 solution (500 mL), dried (MgSO4) and evaporated in vacuo to afford N-(4-(4-aminonaphthalen-1-yloxy)pyridin-2-yl)-2-methoxyacetamide (12) (35.0 g, 78%) as a purple foam: m/z 324 (M+H)+ (ES+).
Reaction SMILES: [CH3:1][CH:2]([C:5]#[N:6])[C:3]#[N:4].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[CH2:12]([O:11][C:9]([CH2:8][C:2]([CH3:1])([C:5]#[N:6])[C:3]#[N:4])=[O:10])[CH3:13]
Reactant: CC(C#N)C#N
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)CC(C)(C#N)C#N
Temperature: 25 °C
Reaction time: 4 h
Yield: 24.1 %

Procedure:
2.0 g of 2-methylmalononitrile and 4.2 g of ethyl bromoacetate were dissolved in 10 ml of dimethyl sulfoxide. 3.4 g of potassium carbonate was added thereto and stirred for 4 hours at room temperature. Then, to the reaction mixture was added dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography to give 1.0 g of 2-(ethoxycarbonylmethyl)-2-methylmalononitrile (hereinafter referred to as the present invention compound (74)).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7](S(C1C=CC=CC=1)(=O)=O)[CH:6]=[C:5]2[CH2:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1.[OH-].[Na+]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[CH2:22][N:23]1[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cn(S(=O)(=O)c3ccccc3)c(=O)c3ccc(Br)cc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2c[nH]c(=O)c3ccc(Br)cc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
To a solution of tert-butyl 4-{[6-bromo-1-oxo-2-(phenylsulfonyl)-1,2-dihydroisoquinolin-4-yl]methyl}piperazine-1-carboxylate (Example 27a, 1.35 g) in THF (10 mL) was added sodium hydroxide (0.29 g) in water (5 mL). The reaction was stirred at room temperature for 2 h. The reaction was then heated to 50° C. for 2 h. The volatiles were removed under reduced pressure, and the residue partitioned between ethyl acetate (100 mL) and water (100 mL). The aqueous was extracted further with ethyl acetate (2×100 mL), and the combined organics dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was triturated with ethyl acetate to afford the subtitle compound as a white solid (0.29 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:17]3[O:21][C:20]([P:22]([OH:25])([OH:24])=[O:23])=[C:19]([CH2:26][CH3:27])[C:18]=3[CH2:28][CH3:29])[CH:14]=[C:13]([C:30]([OH:32])=[O:31])[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:33][CH2:34]N=C=NCCCN(C)C.C(O)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:17]3[O:21][C:20]([P:22]([OH:25])([OH:24])=[O:23])=[C:19]([CH2:26][CH3:27])[C:18]=3[CH2:28][CH3:29])[CH:14]=[C:13]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1c(-c2cc(C(=O)O)cc(C(=O)Nc3cccc(Br)c3)c2)oc(P(=O)(O)O)c1CC
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(=O)Nc2cccc(Br)c2)cc(-c2oc(P(=O)(O)O)c(CC)c2CC)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 1-(3-bromophenylcarbamoyl)-3-carboxy-5-(diethyl 2-phosphonofuran-5-yl)benzene (1 mmol), EDCI (2 mmol), DMAP (0.1 mmol) and ethanol (1.5 mmol) in 70 mL of CH2Cl2 were stirred at rt for 14 h. After evaporation the mixture was redissolved in MeOH and slurried with 5 g of DOWEX 50WX8-400 free acid and 5 g of DOWEX 1X8-400 bicarbonate resin for 4 h and then filtered. The filtrate was evaporated to provide 1-(3-bromophenylcarbamoyl)-3-carboethoxy-5-(diethyl 2-phosphonofuran-5-yl)benzene.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][NH:10][CH2:9]2)[CH:5]=C[CH:7]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=1)[C:19]([NH:21][CH2:22][C:23](O)=[O:24])=[O:20].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:15][C:16]1[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=1)[C:19]([NH:21][CH2:22][C:23]([N:10]1[CH2:11][C:12](=[O:13])[N:8]([C:4](=[CH2:5])[C:3]([CH3:14])=[C:2]([Cl:1])[CH3:7])[CH2:9]1)=[O:24])=[O:20]
Reactant: O=C(O)CNC(=O)c1cccc(Cl)c1
Reactant: Cc1c(Cl)cccc1N1CNCC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: C=C(C(C)=C(C)Cl)N1CN(C(=O)CNC(=O)c2cccc(Cl)c2)CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(3-Chloro-2-methyl-phenyl)-imidazolidin-4-one (360 mg, 1.7 mmol, 1 eq), (3-Chloro-benzoylamino)-acetic acid (365 mg, 1.7 mmol, 1 eq), BOP (909 mg, 2.05 mmol, 1.2 eq), and TEA (0.88 ml) in DMF (5 ml) was stirred at room temperature overnight. It was purified with HPLC to give the desired product. LCMS observed for (M+H)+: 406.1
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([N:7]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.I[C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][N:27]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:32][C:29]1[CH:30]=[CH:31][C:26]([C:11]2[CH:12]=[CH:13][C:8]([N:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:24])=[CH:6][CH:5]=3)[C:17]3[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[CH:9][CH:10]=2)=[N:27][CH:28]=1
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2ccc(B(O)O)cc2)cc1
Reactant: Brc1ccc(I)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(-c3ccc(Br)cn3)cc2)cc1
Temperature: 95 °C
Yield: 82 %

Procedure:
A mixture of (4-(di-p-tolylamino)phenyl)boronic acid (Compound 26) (3.17 g, 10 mmol), 2-iodo-5-bromo-pyridine (5.68 g, 20 mmol), Pd(PPh3)4 (0.58 g, 0.5 mmol) and K2CO3 (2.76 g, 20 mmol) in dioxane/water (80 mL/15 mL) was degassed and heated at about 95° C. overnight. The resulting solution was diluted with ethyl acetate (200 mL), loaded on silica gel, and purified by flash column (hexanes to hexanes/dichloromethane 9:1 to 4:1 to 3:2). The desired fraction was collected and concentrated to give a light yellow solid (Compound 27) (3.5 g, in 82% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]([OH:13])[C:10]([NH2:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].Cl[C:15](OCC)=[O:16].O>[OH-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:10](=[O:11])[NH:12][C:15](=[O:16])[O:13]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)Cl
Reactant: NC(=O)N(O)c1ccc(F)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c(=O)n(-c2ccc(F)c(F)c2)o1
Reaction time: 1 h

Procedure:
1-(3,4-Difluorophenyl)-1-hydroxyurea (0.2 mole) dissolved in aqueous sodium hydroxide (200 ml; 2N) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The solution is cooled to a temperature of about 10°C and ethyl chloroformate (0.21 mole) is slowly added with stirring. After the addition is completed stirring is continued for a period of about one hour. The reaction mixture is then poured into 2 liters of water. The resulting aqueous solution is then filtered and the filtrate is cooled and acidified with concentrated hydrochloric acid to form a precipitate. The precipitate is recovered by filtration and is dried. The dried product is then dissolved in a methylene chloride-tetrahydrofuran mixture and the resulting solution is dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product 2-(3,4-difluorophenyl)-1,2,4-oxadiazolidin-3,5-dione as the residue.
Reaction SMILES: I[C:2]([F:6])=[C:3]([F:5])[F:4].C([Li])(CC)C.Cl[Si:13]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>C(OCC)C>[F:6][C:2]([Si:13]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])=[C:3]([F:5])[F:4]
Reactant: FC(F)=C(F)I
Reactant: CCO[Si](Cl)(OCC)OCC
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: CCO[Si](OCC)(OCC)C(F)=C(F)F
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A dry 3-neck round bottom flask with nitrogen and stir-bar is charged with approximately (9.5 mL, 14.5 g at −78° C., 0.12 mol) iodotrifluoroethylene and 200 mL diethylether pre-cooled to −78° C. Sec-butyl lithium (89 mL, 1.4 M solution, 0.12 mol) is added dropwise over 1 hour. Solution is allowed to stir for 5 minutes at −78° C. Chlorotriethoxysilane (24.35 mL, 0.12 mol) is added over 5 minutes at −78° C. The solution is allowed to warm slowly and allowed to stir overnight. A clear yellow solution remains. Fractional distillation is used to purify the product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][CH:23]=[N:22][C:21]=3[C:25]([O:27]CC)=[O:26])=[CH:16][CH:15]=2)[CH2:10][C:9]1([CH3:31])[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[O:24][CH:23]=[N:22][C:21]=3[C:25]([OH:27])=[O:26])=[CH:18][CH:19]=2)[CH2:10][C:9]1([CH3:31])[CH3:30])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ncoc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)C(C)(C)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ocnc3C(=O)O)cc2)CC1(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 133.4 %

Procedure:
To a solution of 4-[4-(4-ethoxycarbonyl-oxazol-5-yl)-phenyl]-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (2.4 g, 5.6 mmol) in 20 mL THF and 20 mL methanol was added 2N aqueous sodium hydroxide solution (11.2 mL, 22.4 mmol). The mixture was stirred at room temperature for 16 hrs and organic solvent was then removed in vacuo. The remaining aqueous mixture was adjusted to pH 4˜5 by the addition of 1N aqueous hydrogen chloride. The mixture was freeze-dried to yield 3 g of 4-[4-(4-carboxy-oxazol-5-yl)-phenyl]-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester as an off-yellow powder, which was used in the next step directly.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[CH2:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl.O1CCOCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([NH:44][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: NCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
A solution of 3-tert-butoxycarbonylaminopropanoic acid (2 g, 10.6 mmol.) and HOSu (1.22 g, 10.6 mmol.) in 40 mL DCM/Dioxane (2:1) was cooled in an ice bath. To this solution was added DCC (2.4 g, 11.6 mmol.), and the mixture was stirred at room temperature for 1 h. To the resulting mixture was added benzylamine (1.7 g, 15.8 mmol.), the mixture was stirred for 4 h at room temperature. The solid that formed in the mixture was removed by filtration and washed with EtOAc. The filtrate and washings were combined and washed with 1N HCl and saturated aqueous NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated to afford 3-tert-butoxycarbonylamino-N-benzylpropionamide (2.4 g, 82%). 3-tert-Butoxycarbonylamino-N-benzylpropionamide was dissolved in cooled HCl/MeOH (20 mL) and the resulting mixture was stirred at room temperature for 1.5 h. The solvent was removed to afford 3-amino-N-benzylpropionamide hydrochloride (1.8 g, 100%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:31][S:28]([C:24]1[CH:23]=[C:22]([NH:20][C:18]2[N:19]=[C:12]3[C:11]([C:8]4[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=4)=[CH:16][CH:15]=[CH:14][N:13]3[N:17]=2)[CH:27]=[CH:26][CH:25]=1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)c1cccc(Br)c1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4cccc(S(C)(=O)=O)c4)nc23)cc1

Procedure:
(3-Methanesulfonyl-phenyl)-[8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 1-bromo-3-methanesulfonyl-benzene (75.0 mg, 0.319 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (30.0 mg, 0.0549 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow solid (0.089 g, 77%). MP=230-234° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.55 (d, J=6.9 Hz, 1H), 8.47 (s, 1H), 8.26 (d, J=7.9 Hz, 2H), 8.12 (d, J=7.5 Hz, 2H), 7.74-7.69 (m, 2H), 7.58-7.50 (m, 2H), 7.17 (s, 1H), 7.12-7.07 (m, 1H), 3.11 (s, 6H). MS=443 (MH)+.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH2:14][CH2:13][C:12]4([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[C:11]3=[O:20])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.Br[CH2:22][C:23]([OH:25])=[O:24].CCN(CC)CC>C(Cl)Cl>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH2:14][CH2:13][C:12]4([CH2:19][CH2:18][N:17]([CH2:22][C:23]([OH:25])=[O:24])[CH2:16][CH2:15]4)[C:11]3=[O:20])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)CBr
Reactant: O=C1N(c2ccc(C3CC3)cc2)CCC12CCNCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)CN1CCC2(CC1)CCN(c1ccc(C3CC3)cc1)C2=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 0.4 g (1.47 mmol) 2-(4-Cyclopropyl-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, 0.226 g (1.63 mmol) bromoacetic acid and 0.299 g (2.96 mmol) NEt3 in 50 mL DCM was stirred at room temperature for 16 h. The mixture was concentrated and used without further purification in the consecutive step. MS m/e: 329.3 [M+H]+.
Reaction SMILES: [C:1]([NH:9][CH:10]([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[C:2]1([C:1]2[O:21][C:17]([CH:18]([CH3:19])[CH3:20])=[C:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccccc1)C(=O)C(C)C
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)Cc1nc(-c2ccccc2)oc1C(C)C
Yield: 82 %

Procedure:
6.5 g of ethyl 3-benzoylamino-3-isobutyrylpropionate, 30 ml of dimethylformamide and 4.8 g of phosphorus oxychloride are treated in the same manner as described in Example 1. 5.0 g of ethyl 2-(2-phenyl-5-isopropyl-4-oxazoly)acetate are thereby obtained. Yield: 81.4%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([OH:16])=O)[CH2:11][C@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[F:29][CH2:30][C:31]1([S:34]([NH2:37])(=[O:36])=[O:35])[CH2:33][CH2:32]1.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[F:29][CH2:30][C:31]1([S:34]([NH:37][C:14]([C@@:9]2([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:11][C@H:10]2[CH:12]=[CH2:13])=[O:16])(=[O:36])=[O:35])[CH2:33][CH2:32]1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)O
Reactant: NS(=O)(=O)C1(CF)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1(CF)CC1
Temperature: 55 °C
Reaction time: 18 h
Yield: 96.2 %

Procedure:
To a solution of (1R,2S)-1-(tert-butoxycarbonylamino)-2-vinylcyclopropanecarboxylic acid (7.5 g, 33 mmol) in DMF (50 mL) was added CDI (10.69 g, 66 mmol) and the reaction mass was heated at 55° C. for 4 h. To this reaction mass was added 1-fluoromethylcyclopropane-1-sulfonamide (6.5 g, 42.9 mmol) followed by DBU (6 mL, 42.9 mmol). The reaction mixture was stirred at 55° C. for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and acidified to pH ˜2 by using 1.5 N HCl solution. The precipitated solid was filtered and washed with water to get desired compound (11.5 g, 96%) as off-white solid. MS: MS m/z 361.4 (M+−1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH2:7].Cl[CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:20][C:21]1[C:22]([I:36])=[C:23]([CH2:29][CH:30]([CH2:34][CH3:35])[C:31]([OH:33])=[O:32])[C:24]([I:28])=[CH:25][C:26]=1[I:27])=[O:19])=[O:11]>>[NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:20][C:21]1[C:22]([I:36])=[C:23]([CH2:29][CH:30]([CH2:34][CH3:35])[C:31]([OH:33])=[O:32])[C:24]([I:28])=[CH:25][C:26]=1[I:27])=[O:19])=[O:11]
Reactant: NCCNCCN
Reactant: CCC(Cc1c(I)cc(I)c(NC(=O)CCCCCNC(=O)CCl)c1I)C(=O)O
Product: CCC(Cc1c(I)cc(I)c(NC(=O)CCCCCNC(=O)CNCCNCCN)c1I)C(=O)O
Yield: 48 %

Procedure:
According to the procedure described in Example 1, 123 g of diethylenetriamine (0.16 mol) are reacted with 121.7 g of compound (A) 3-[[6-[(chloroacetyl)amino]-1-oxohexyl]amino]-α-ethyl-2,4,6-triiodobenzene propanoic acid. 64 g of 3-[6-[[[2-[(2-aminoethyl)amino]ethyl]amino]acetyl amino]-1-oxohexyl]amino-α-ethyl-2,4,6-triiodobenzenepropanoic acid (0.077 mol) are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([CH:21]=1)[O:7][CH2:8][CH2:9][N:10]1C(=O)C2=CC=CC=C2C1=O.O.NN>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([CH:21]=1)[O:7][CH2:8][CH2:9][NH2:10]
Reactant: COc1ccc(F)cc1OCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(F)cc1OCCN
Yield: 64.9 %

Procedure:
A suspension of 10.0 g of N-[2-(5-fluoro-2-methoxyphenoxy)ethyl]phthalimide and 5.14 ml 5.14 ml of hydrazine hydrate in 100 ml of ethanol was heated for 1 hour at 50°-60° C. After cooling, the precipitate was filtered off and the filtrate was evaporated. The residue was diluted with water and extracted with chloroform. The extract was washed with water, dried and evaporated. The residue was distilled to give 3.81 g of the desired compound as a colorless oil, b.p. 126°-127° C. (9 mmHg).
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([CH:27]([CH2:31][CH2:32][CH2:33][CH3:34])[C:28]([O-])=O)C.[Na+]>C1C=CC=CC=1.C(OCC)(=O)C>[CH2:28]([NH:4][S:1]([NH2:5])(=[O:3])=[O:2])[C:27]1[CH:25]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCCCC(CC)C(=O)[O-]
Reactant: NS(N)(=O)=O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: NS(=O)(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
The condensed sulfamide having an allyloxycarbonyl protecting group obtained as Sample No. 3 of Example 1 is dissolved in benzene (10 vol.), and triphenylphosphine (0.3 Eq.), sodium 2-ethylhexanoate (1.5 Eq.) in ethyl acetate, and palladium tetrakistriphenylphosphine (0.02 Eq.) are added thereto successively. The mixture is stirred at room temperature for 30 minutes. The reaction mixture is diluted with ethyl acetate, washed with water, dried, and concentrated in vacuo. The residue is recrystallized from toluene to give benzylsulfamide having the same physical constants as that obtained in Reference Example 1. Pale yellow crystals. Yield: 64%.