Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:83]([O:85][C:86]([CH3:89])([CH3:88])[CH3:87])=[O:84])[C@H:2]([C:20]([NH:22][C@H:23]([C:41]([N:43]1[CH2:82][CH2:81][CH2:80][C@H:44]1[C:45]([NH:47][C@H:48]([C:50]([NH:52][C@H:53]([C:70]([O:72]CC1C=CC=CC=1)=[O:71])[CH2:54][CH2:55][CH2:56][CH2:57][NH:58][C:59]([O:61][CH2:62][C:63]1[CH:69]=[CH:68][CH:67]=[CH:66][C:64]=1[Cl:65])=[O:60])=[O:51])[CH3:49])=[O:46])=[O:42])[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:40])[NH:29][S:30]([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:32])=[O:31])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[OH-].[Na+].C(Cl)(Cl)Cl.CO>CO>[NH:1]([C:83]([O:85][C:86]([CH3:87])([CH3:89])[CH3:88])=[O:84])[C@H:2]([C:20]([NH:22][C@H:23]([C:41]([N:43]1[CH2:82][CH2:81][CH2:80][C@H:44]1[C:45]([NH:47][C@H:48]([C:50]([NH:52][C@H:53]([C:70]([OH:72])=[O:71])[CH2:54][CH2:55][CH2:56][CH2:57][NH:58][C:59]([O:61][CH2:62][C:63]1[CH:69]=[CH:68][CH:67]=[CH:66][C:64]=1[Cl:65])=[O:60])=[O:51])[CH3:49])=[O:46])=[O:42])[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:40])[NH:29][S:30]([C:33]1[CH:34]=[CH:35][C:36]([CH3:37])=[CH:38][CH:39]=1)(=[O:32])=[O:31])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:16])=[CH:17][CH:18]=1)(=[O:10])=[O:11]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCNC(=N)NS(=O)(=O)c2ccc(C)cc2)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCNC(=N)NS(=O)(=O)c2ccc(C)cc2)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
At 0° C. to the solution of 600 mg (0.464 mmol) of Boc-Arg(Tos)-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 18) in 10 ml of methanol 5 ml of the solution of NaOH in methanol (2 mol/L) were added. The reaction mixture was stirred at 0° C. for 2 h and TLC (chloroform/methanol, 15:1) indicated complete disappearance of Boc-Arg(Tos)-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 18). The reaction mixture was neutralized to pH 7 and evaporated at room temperature to remove methanol. The residue was acidified to pH 1–2 with hydrochloric acid (2 mol/L) to provide 420 mg (76%) of the title compound as a colorless powder.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[C:4]([C:9]([N:11]2[CH2:14][CH:13]([OH:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OCC)(=O)C>ClCCl>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[C:4]([C:9]([N:11]2[CH2:12][C:13](=[O:15])[CH2:14]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC(O)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol (132 mg, 0.295 mmol)ures similar to those in Example 1, was dissolved in dichloromethane (8 mL) and cooled to 0° C. Dess-Martin periodinane (187 mg, 0.441 mmol) was added and the mixture was stirred at ambient for 2 h. The mixture was quenched with saturated sodium bicarbonate solution: 10% sodium thiosulfate solution (1:1; 6 mL) and diluted with ethyl acetate. The organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 40-50% ethyl acetate in hexanes) gave 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-one (122 mg, 0.273 mmol, 93% yield): 1H NMR (400 MHz, CDCl3): 8.43 (br s, 1H), 7.44-7.38 (m, 1H), 7.36-7.32 (m, 1H), 7.27-7.20 (m, 1H), 6.86 (ddd, 1H), 6.64 (ddd, 1H), 4.94-4.93 (m, 4H); MS (EI) for C16H10F3IN2O2: 447 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][C:11]([O:13]CC)=[O:12])[CH:7]=[N:8][C:4]=2[CH:3]=1.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:27]=1[C:28]([OH:30])=O>>[CH3:36][O:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:26]([O:25][CH3:24])[C:27]=1[C:28]([NH:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH:9]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[N:8][C:4]=2[CH:3]=1)=[O:30]
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2cc(N)ccc21
Reactant: COc1cccc(OC)c1C(=O)O
Product: COc1cccc(OC)c1C(=O)Nc1ccc2c(c1)ncn2C(CC(=O)O)c1ccccc1

Procedure:
Using the procedure of Preparation 21, the title compound (31 mg) was prepared from ethyl 3-(5-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate and 2,6-dimethoxybenzoic acid. [LCMS (Method C, Mobile Phase I) RT=2.25 min, MH+ 446].
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:16][CH2:17][CH:18]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][C:21]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:16][CH2:17][CH2:18][N:31]2[CH2:32][CH2:33][N:28]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]([CH3:27])[C:21]=3[CH3:20])[CH2:29][CH2:30]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(N2CCNCC2)c1C
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N2CCN(CCCc3cc(-c4ccccc4)n(C(C)(C)C)n3)CC2)c1C

Procedure:
39 mg (45%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propanal (50 mg, 0.195 mmol), 1-(2,3-dimethylphenyl)piperazine (35.4 mg, 0.186 mmol), DIPEA (49 mL, 0.279 mmol) and NaBH(OAc)3 (118 mg, 0.558 mmol).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][NH:9][CH3:10]>C1COCC1>[CH3:8][N:9]([CH3:10])[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ncccn1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)c1ncccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-chloropyrimidine (5 g, 43.65 mmol) in dry THF (50 ml) is saturated with gaseous dimethylamine. The mixture is stirred at ambient temperature for 1 hour followed by evaporation of solvent. The residue is partitioned between water and ethyl acetate. The aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and evaporated to leave the product as a brownish oil. Yield 5.07 g (94%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[NH2:22][C:23]1([CH3:28])[CH2:27][CH2:26][NH:25][CH2:24]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:25]2[CH2:26][CH2:27][C:23]([NH2:22])([CH3:28])[CH2:24]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: CC1(N)CCNC1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC1(N)CCN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Yield: 60.4 %

Procedure:
A mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.5 g), 3-amino-3-methylpyrrolidine (0.76 g), DBU (0.77 g), and acetonitrile (30 ml) was refluxed for 7 hours. The precipitated crystals were collected by filtration after cooling, and washed with acetonitrile. The crystals were suspended in water (50 ml) and dissolved by addition of a 10% aqueous solution of acetic acid. The solution was treated with activated carbon, and adjusted to pH 7-8 with 10% aqueous ammonia. The precipitated crystals were collected by filtration, washed with water and then with ethanol, and dried to give 5-amino-7-(3-amino-3-methyl1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro4-oxoquinoline-3-carboxylic acid (1.15 g), m.p. 271°-273° C. (decomp.).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([O:8][C@@H:9]2[CH2:13][CH2:12][NH:11][C:10]2=[O:14])=[CH:4][CH:3]=1.[CH2:15]([S-:17])[CH3:16].[Li+]>>[CH2:15]([S:17][C:2]1[N:7]=[CH:6][C:5]([O:8][C@@H:9]2[CH2:13][CH2:12][NH:11][C:10]2=[O:14])=[CH:4][CH:3]=1)[CH3:16]
Reactant: O=C1NCC[C@H]1Oc1ccc(Br)nc1
Reactant: CC[S-]
Agent: [Li+]
Product: CCSc1ccc(O[C@@H]2CCNC2=O)cn1

Procedure:
Typical Procedure 8 was followed. Reaction of (R)-3-(6-bromo-pyridin-3-yloxy)-pyrrolidin-2-one with lithium ethanethiolate provided the title compound. MS ESI+: m/z=239 [M+H]+.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[OH:5][C@H:6]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:21]([CH2:22][CH2:23][C@:7]12[CH3:8])[C@@H:20]1[C:15]([CH2:16][C:17](=[O:24])[CH2:18][CH2:19]1)=[CH:14][C@H:13]3[CH3:25]>O1CCCC1>[C:1]([OH:4])(=[O:3])[CH3:2].[CH3:25][C@@H:13]1[CH:14]=[C:15]2[C@H:20]([CH2:19][CH2:18][C@H:17]([OH:24])[CH2:16]2)[C@@H:21]2[C@@H:12]1[C@H:9]1[C@@:7]([CH2:23][CH2:22]2)([CH3:8])[C@@H:6]([OH:5])[CH2:11][CH2:10]1
Reactant: C[C@@H]1C=C2CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]21
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@@H]1C=C2C[C@@H](O)CC[C@@H]2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 17β-hydroxy-7α-methyl-estr-5-en-3-one acetate dissolved in tetrahydrofuran is purged with nitrogen and slowly added to a suspension of lithium tertiarybutoxyaluminum hydride also purged with nitrogen. The mixture is stirred at room temperature for about 16 hours and excess hydride is destroyed by cautiously adding a solution of sodium potassium tartrate. The solid which forms is removed by filtration and the filtrate is extracted with methylene chloride. The combined methylene chloride extracts are washed with water, dried and concentrated under vacuum. Recrystalization of the residue from acetone-hexane yields the desired 7α-methyl-estr-5-ene-3β,17β-diol acetate.
Reaction SMILES: [C:1](OC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11]([NH2:14])[CH2:12][NH2:13]>>[C:2]1([C:1]2[NH:13][CH2:12][CH2:11][N:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCN
Reactant: COC(=O)c1ccccc1
Product: c1ccc(C2=NCCN2)cc1
Yield: 95 %

Procedure:
The procedure described in Example 5 is followed except that 272 parts of methyl benzoate and 132 parts of ethylenediamine are employed. 277 parts of 2-phenylimidazoline (95% of theory, based on methyl benzoate employed) of boiling point 295° C./1,013 mbar are obtained.
Reaction SMILES: Cl[CH2:2][C:3]([NH2:5])=[O:4].[CH:6]1([NH2:11])[CH2:10][CH2:9][CH2:8][CH2:7]1>CC(CC(C)=O)C>[CH:6]1([NH:11][CH2:2][C:3]([NH2:5])=[O:4])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: NC(=O)CCl
Reactant: NC1CCCC1
Solvent: CC(=O)CC(C)C
Product: NC(=O)CNC1CCCC1

Procedure:
To a solution of spiro[isobenzofuran-1(3H),4'-piperidine] (14 g) in dichloromethane (160 ml) triethylamine (11 ml) was added. After cooling to 10° C. a solution of chloroacetylchloride (8 ml) in dichloromethane (10 ml) was added dropwise during 20 minutes. The reaction mixture was finally allowed to reach room temperature. The mixture was subsequently filtered through silica gel (eluted with ethyl acetate/n-heptane 60:40) affording 12 g of the α-chloroacetamide derivative. A mixture of the thus obtained α-chloroacetamide derivative (1.4 g) and cyclopentylamine in MIBK (25 ml) was refluxed for 2 h. The solvent was evaporated in vacuo and the cyclopentylamino derivative was extracted from an alkaline (pH>9) aqueous solution with ethyl acetate. The organic phase was worked up as above yielding 2.0 g of the α-(cyclopentylamino)acetamide derivative as a visceous oil. To a solution of the α-(cyclopentylamino)acetamide derivative (2 g) in MIBK 1-chloracetylspiro[isobenzofuran-1(3H),4'-piperidine] (1.4 g) and potassium carbonate (1 g) were added. The mixture was refluxed for 3 h. After cooling to room-temperature the mixture was filtered through silica gel (eluted with 4% triethylamine in ethyl acetate. Evaporation of the solvents afforded 2.4 g of the diamide which was reduced with LiAlH4 as described in example 1. The title compound 3a crystallized from a mixture of ethanol and acetone (1:4). Yield 1.3 g, mp 258°-260° C. 1H NMR (DMSO-d6) δ 1.50-2.45 (m, 16 H), 3.25-3.80 (m, 17 H), 5.05 (s, 4 H), 7.10-7.40 (m, 8 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13](=[CH:21]O)[C:14](=O)[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:23][C:24]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:27][NH:26][N:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13]2[CH:21]=[N:23][C:24]4[N:25]([C:14]=2[CH2:15]3)[N:26]=[CH:27][C:28]=4[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1n[nH]cc1-c1ccccc1
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Product: O=S(=O)(c1ccc(Cl)cc1)N1C2CCCC1c1cnc3c(-c4ccccc4)cnn3c1C2

Procedure:
Prepared as described in Example 5 using 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one which was prepared as described in Example 34 and 3-amino-4-phenylpyrazole
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([C:16]1[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:25][O:26][C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:28].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:25][O:26][C:27](=[O:28])[C:29]1[CH:34]=[CH:33][C:32]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:24])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=3)[C:11]([F:13])([F:14])[F:12])=[C:2]([Cl:1])[CH:7]=2)=[CH:31][CH:30]=1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc(=O)n(C)c3)C(F)(F)F)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 103.7 %

Procedure:
To a solution of 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (64 mg) in CH2Cl2 (1.5 ml) were added 4-methoxycarbonylphenyl-boronic acid (96 mg), copper-(II)-acetate (96 mg), molecular sieve and pyridine (70 mg). The mixture was stirred at room temperature under an air atmosphere with exclusion of moisture for 18 hours. The mixture was filtered, diluted with CH2Cl2 and washed with 1 M HCl. The organic phase was dried (MgSO4), filtered and concentrated to dryness. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 4:1=>0:1) to give the title compound (91 mg) as a colorless foam. MS (m/e, ISP neg. ion)=494.1 [M−H+].
Reaction SMILES: C(OC(=O)[NH:7][S:8](=[O:31])(=[O:30])[NH:9][CH2:10][CH2:11][O:12][NH:13][C:14]([C@@H:16]1[CH2:22][CH2:21][C@@H:20]2[CH2:23][N:17]1[C:18](=[O:29])[N:19]2[O:24][S:25]([OH:28])(=[O:27])=[O:26])=[O:15])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[O:29]=[C:18]1[N:17]2[CH2:23][C@@H:20]([CH2:21][CH2:22][C@H:16]2[C:14]([NH:13][O:12][CH2:11][CH2:10][NH:9][S:8](=[O:30])(=[O:31])[NH2:7])=[O:15])[N:19]1[O:24][S:25]([OH:28])(=[O:26])=[O:27]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)NCCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl({2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}sulfamoyl)carbamate 81 (0.20 g, 0.40 mmol) in DCM (5.0 mL) was added trifluoroacetic acid (1.0 mL) at 0° C. The mixture was stirred at 0° C. for 0.5 h and at room temperature for 2 h, concentrated and washed with ether. The white solid was collected by centrifugation. The crude product was purified by preparative HPLC to provide
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:27])[CH2:13][CH:12]([C:14](OCC)=[O:15])[S:11][C:10]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Li+]>O1CCCC1.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C@:8]2([CH3:27])[CH2:13][C@@H:12]([CH2:14][OH:15])[S:11][C:10]([NH:19][C:20](=[O:21])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CC(C)(c2cccc(Br)c2)N=C(NC(=O)OC(C)(C)C)S1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cccc(Br)c2)C[C@@H](CO)S1
Temperature: 25 °C
Reaction time: 4 h
Yield: 29 %

Procedure:
To a 0° C. solution of ethyl 4-(3-bromophenyl)-2-(tert-butoxycarbonylamino)-4-methyl-5,6-dihydro-4H-1,3-thiazine-6-carboxylate (2.0 g, 4.4 mmol) in tetrahydrofuran (87 mL) and ethanol (25 mL) is added lithium borohydride (289 mg, 13.1 mmol, 3 equiv). The reaction is warmed to room temperature and stirred for 4 h. The reaction mixture is quenched with saturated NH4Cl. The layers are separated and the aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with saturated aqueous NaCl and dried over Na2SO4. The mixture is filtered and concentrated to give a light yellow oil. The oil is purified by column chromatography on silica gel (120 g) using a gradient of 0 to 100% ethyl acetate/hexane to give the title compound (29% yield): MS (m/z): 415, 417 (M+1).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.[NH2:18][C:19]1[N:24]2[O:25][C:26](=[O:28])[N:27]=[C:23]2[N:22]=[C:21]([N:29]([CH2:33][CH:34]=[CH2:35])[CH2:30][CH:31]=[CH2:32])[N:20]=1>CN(C)C1C=CN=CC=1.C(N(CC)CC)C.C(Cl)Cl>[CH2:33]([N:29]([CH2:30][CH:31]=[CH2:32])[C:21]1[N:20]=[C:19]([NH:18][C:1](=[O:9])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:24]2[O:25][C:26](=[O:28])[N:27]=[C:23]2[N:22]=1)[CH:34]=[CH2:35]
Reactant: O=C(O)c1ccccc1
Reactant: C=CCN(CC=C)c1nc(N)n2oc(=O)nc2n1
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)c1nc(NC(=O)c2ccccc2)n2oc(=O)nc2n1

Procedure:
3.3 g. of benzoic acid are dissolved in 70 ml. of methylene chloride and 2.7 g. of triethylamine. The solution is stirred and treted at 0° C. with 3.5 g. of isobutyl chloroformate in 25 ml. of methylene chloride. The mixture is then stirred at 0° C. for 30 minutes and subsequently at room temperature for 1 hour. The solution is treated with a suspension of 5 g. of 7-amino-5-diallylamino-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-2-one in 200 ml. of methylene chloride, 12.5 ml. of triethylamine and 0.6 g. of 4-dimethylaminopyridine. The mixture obtained is stirred at room temperature for 18 hours and then washed with 100 ml. of water. The organic phase is dried over magnesium sulfate and evaporated under reduced pressure. The residue obtained is purified by column chromatography, there being obtained N-{5-diallylamino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-7-yl}benzamide having a melting point of 182°-183° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]#[N:13].CCN(CC)CC.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>CCO>[C:12]([CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:23]([N:22]([CH3:26])[CH3:21])=[O:24])[CH:3]=2)[NH:7][CH:6]=1)#[N:13]
Reactant: N#CCc1c[nH]c2ccc(N)cc12
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)C(=O)Nc1ccc2[nH]cc(CC#N)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.2 %

Procedure:
To a solution of 7.0 g (0.041 mole) of 5-aminoindole-3-acetonitrile and 5.7 ml (0.041 mole) of Et3N in 100 ml of abs EtOH, under N2, was added 3.78 ml of dimethylcarbamyl chloride (0.041 mole). The reaction was stirred at room temperature for 24 hours. The solvent was removed in vacuo to yield a black goo (7.5 g). It was purified by dry column chromatography. Eluting it with ethylacetate first and then with 5% MeOH in EtOAc to give 3.5 g of brown solid. It was charcoaled to remove the color (MeOH as solvent). Removal of solvent gave 1.4 g of white product.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[C:10]([N+:20]([O-:22])=[O:21])[CH:9]=2)=[N:6][NH:5][C:4](=[O:23])[CH2:3]1.Br[CH2:25][CH2:26][CH2:27][N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][N:17]([CH2:25][CH2:26][CH2:27][N:28]4[C:32](=[O:33])[C:31]5=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]5[C:29]4=[O:38])[CH2:16][CH2:15]3)=[C:10]([N+:20]([O-:22])=[O:21])[CH:9]=2)=[N:6][NH:5][C:4](=[O:23])[CH2:3]1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CC1CC(=O)NN=C1c1ccc(N2CCNCC2)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CC(=O)NN=C1c1ccc(N2CCN(CCCN3C(=O)c4ccccc4C3=O)CC2)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture of 3.16 g (10 mmol) of 5-methyl-6-[3-nitro-4-(1-piperazinyl)-phenyl]-4,5-dihydro-3(2H)-pyridazinone, 2.68 g (10 mmol) of N-(3-bromopropyl)-phthalimide, 1.38 g (10 mmol) of potassium carbonate and 50 ml of dimethyl formamide is stirred at 100° C. for 24 hours.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[C:7]([I:12])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:15])=O>>[I:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[C:7]([I:12])[C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(O)c1c(I)cc(I)cc1I
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1c(I)cc(I)cc1I
Temperature: 25 °C

Procedure:
2,4,6-Triiodobenzoic acid (15 g) was suspended in thionyl chloride (75 ml) was refluxed. Thirty minutes after the starting material was dissolved, the reaction solution was cooled and evaporated in vacuo. The residue was dissolved in hot benzene (40 ml), cooled to room temperature, filtered and the filtrate evaporated in vacuo. Yield: 13.6 g. I.R. (KBr): 1785 cm -1 (--COCl).
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16]([OH:18])=O)(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([CH3:35])([CH3:34])[CH2:32][NH2:33])=[CH:27][CH:26]=1>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16]([NH:33][CH2:32][C:31]([C:28]3[CH:27]=[CH:26][C:25]([Cl:24])=[CH:30][CH:29]=3)([CH3:35])[CH3:34])=[O:18])(=[O:11])=[O:12])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: CC(C)(CN)c1ccc(Cl)cc1
Product: CC(C)(CNC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12)c1ccc(Cl)cc1

Procedure:
2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chlorobenzoic acid was coupled with 2-(4-chloro-phenyl)-2-methyl-propylamine as in EXAMPLE 1, Part C. HPLC: RT=11.08 min. MS (ESI−): mass calcd. for C23H20Cl2N4O3S2, 534.04; m/z found, 533/535 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.53 (s, 1H), 8.35 (dd, J=7.0, 1.0, 1H), 8.22 (dd, J=8.8, 1.0, 1H), 7.71 (dd, J=8.8, 7.0, 1H), 7.70 (d, J=1.8, 1H), 7.35-7.31 (m, 2H), 7.30-7.26 (m, 2H), 6.89 (d, J=8.3, 1H), 6.86 (dd, J=8.4, 1.8, 1H), 5.58-5.52 (m, 1H), 3.56 (d, J=6.1, 2H), 1.36 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][N:8]=1)=O.S(O)(O)(=O)=O.[CH3:23][S:24][C:25](=[NH:27])[NH2:26].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[CH3:23][S:24][C:25]1[N:27]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][N:8]=2)[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[N:26]=1
Reactant: CSc1ccc(C(=O)CC(=O)C(F)(F)F)nc1
Reactant: CSC(=N)N
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CSc1ccc(-c2cc(C(F)(F)F)nc(SC)n2)nc1
Temperature: 120 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4,4,4-trifluoro-1-(5-methylsulfanyl-pyridin-2-yl)-butane-1,3-dione (0.600 g, 2.28 mmol) in glacial acetic acid (6 mL) was added 2-methyl 2-thiopseudourea sulphate (0.761 g, 2.74 mmol) and sodium acetate (0.224 g, 2.74 mmol). The reaction was heated to 120° C. under nitrogen for 21 hours. The reaction was allowed to cool before the addition of water (10 mL), leading to precipitation of a solid. The reaction mixture was poured onto water (10 mL) and stirred for 15 minutes at 22° C. The precipitate was filtered from the aqueous solution, washed with water, and dried in vacuo to yield the title compound as a grey solid: MS m/z 317 (M+1).