Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH2:32][C:33]2[CH:34]=[C:35]([CH:44]=[C:45]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[CH:46]=2)[O:36][CH2:37][C@@H:38]2[CH2:40][C@H:39]2[C:41]([OH:43])=[O:42])[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][NH:9][CH2:8]2)=[O:6])[CH2:3][CH2:2]1.[N+](=[CH2:54])=[N-]>CCOCC>[CH:1]1([N:4]([CH2:32][C:33]2[CH:34]=[C:35]([CH:44]=[C:45]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[CH:46]=2)[O:36][CH2:37][C@@H:38]2[CH2:40][C@H:39]2[C:41]([O:43][CH3:54])=[O:42])[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:17][CH:18]=3)[CH2:11][CH2:10][NH:9][CH2:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: C=[N+]=[N-]
Reactant: COCCCc1cc(CN(C(=O)[C@H]2CNCC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OC[C@@H]2C[C@H]2C(=O)O)c1
Solvent: CCOCC
Product: COCCCc1cc(CN(C(=O)[C@H]2CNCC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OC[C@@H]2C[C@H]2C(=O)OC)c1

Procedure:
To a solution of (1R,2R)-2-{[3-({cyclopropyl[((3R,4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidin-3-yl)carbonyl]amino}methyl)-5-(3-methoxypropyl)phenoxy]methyl}cyclopropanecarboxylic acid (1 eq., neutral form) from Example 2 was added a solution of diazomethane in ether until a faint yellow color persisted. The solvent was evaporated by a stream of nitrogen gas. The residue was purified by flash column chromatography (SiO2, 10% MeOH in DCM plus 1% aqueous NH4OH) afford the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:11][C:12]([OH:14])=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:20][CH2:21]O>>[CH2:20]([O:13][C:12](=[O:14])[CH2:11][C:8]1([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1)[CH3:21]
Reactant: O=C(O)CC1(c2ccc(Br)cc2)CC1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CC1(c2ccc(Br)cc2)CC1
Temperature: 80 °C

Procedure:
[1-(4-Bromo-phenyl)-cyclopropyl]-acetic acid (from the previous step) was dissolved in EtOH (80 mL) and conc. H2SO4 (2 mL) was added. The reaction was heated to 80° C. overnight then concentrated and submitted to standard aqueous workup to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:35])=[C:14]([C:30](OCC)=[O:31])[C:15](=[O:29])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:28])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:36]([CH2:38][NH2:39])[OH:37]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:35])=[C:14]([C:30]([NH:39][CH2:38][CH2:36][OH:37])=[O:31])[C:15](=[O:29])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:28])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCC2=O)c1=O
Product: O=C(NCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxo-1-piperidinyl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and ethanolamine using methods similar to Example 563 to provide an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.64-1.79 (m, 6 H), 2.19 (t, J=6.42 Hz, 2 H), 3.21 (t, J=5.58 Hz, 2 H), 3.33-3.48 (m, 4 H), 3.50-3.61 (m, 2 H), 4.15-4.25 (m, 4 H), 4.93 (t, J=5.05 Hz, 1 H), 7.10-7.18 (m, 2 H), 7.37-7.44 (m, 2 H), 8.00 (d, J=1.26 Hz, 1 H), 8.55 (d, J=1.26 Hz, 1 H), 10.41 (t, J=5.90 Hz, 1 H); ES+ MS: 497 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([NH2:12])[CH:8]=[C:9]([F:11])[CH:10]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[Br:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:7]([NH:12][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([Br:20])=[CH:22][CH:23]=2)[CH:8]=[C:9]([F:11])[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CCOC(=O)c1cc(F)cn1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(F)cn1NC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-amino-4-fluoro-1H-pyrrole-2-carboxylic acid ethyl ester (1.18 g, 6.88 mmol) in dichloromethane (14 ml) is added triethylamine (3.34 ml, 24.1 mmol). Then 4-bromobenzoyl chloride (3.02 g, 13.8 mmol) is added in portions. The reaction mixture is stirred for 18 hours at room temperature. The reaction mixture is partitioned between water and dichloromethane. The organic layer is washed with 1 N HCl, dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 1-(4-bromo-benzoylamino)-4-fluoro-1H-pyrrole-2-carboxylic acid ethyl ester as white solid; HPLC/MS 2.78 min (B), [M+H] 355/357.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][NH:7][CH2:6][CH:5]([C:9]([O:11][CH3:12])=[O:10])[CH2:4]1.[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:15]=1[CH:16]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:15]=1[CH2:16][N:7]1[CH2:8][CH:3]([O:2][CH3:1])[CH2:4][CH:5]([C:9]([O:11][CH3:12])=[O:10])[CH2:6]1
Reactant: COC(=O)C1CNCC(OC)C1
Reactant: COc1cccc(F)c1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)C1CC(OC)CN(Cc2c(F)cccc2OC)C1
Reaction time: 0.25 h

Procedure:
To Methyl 5-methoxypiperidine-3-carboxylate (500 mg, 2.9 mmol) in DCM (10 mL) was added 2-fluoro-6-methoxybenzaldehyde (890 mg, 5.8 mmol) and 10 drops of acetic acid. After stirring for 15 min, sodium triacetoxyborohydride (2.4 g, 11.6 mmol) was added. The reaction mixture was stirred at room temperature overnight. After quench with saturated Na2CO3, the mixture was extracted with DCM. Dried and concentrated to give crude product.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+](=[CH2:17])=[N-]>C1COCC1.CCOCC>[NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: Nc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccc(C(F)(F)F)cc1N

Procedure:
To a solution of 2-amino-4-(trifluoromethyl)benzoic acid (5 g) in THF (85 ml) was added diazomethane (48.7 ml) in ether until completion of the reaction. Nitrogen was bubbled into the reaction mixture for 15 minutes to remove the excess of diazomethane and the solvent was removed under reduced pressure to provide a light brown solid (5.34 g). The compound was used in the next without purification. LRMS (ES+) m/z 220.1 (M+H)+.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[C:13]1[C:14]2[N:15]([C:19]([N:26]([CH2:30][CH:31]3[CH2:33][CH2:32]3)[CH2:27][CH2:28][CH3:29])=[C:20](S(C)(=O)=O)[N:21]=2)[CH:16]=[CH:17][N:18]=1>O>[Cl:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[C:13]1[C:14]2[N:15]([C:19]([N:26]([CH2:30][CH:31]3[CH2:33][CH2:32]3)[CH2:27][CH2:28][CH3:29])=[C:20]([O:2][CH3:1])[N:21]=2)[CH:16]=[CH:17][N:18]=1
Reactant: C[O-]
Reactant: CCCN(CC1CC1)c1c(S(C)(=O)=O)nc2c(-c3ccc(OC)cc3Cl)nccn12
Agent: [Na+]
Solvent: O
Product: CCCN(CC1CC1)c1c(OC)nc2c(-c3ccc(OC)cc3Cl)nccn12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 28% sodium methoxide solution (5 mL) was added to N-[8-(2-chloro-4-methoxyphenyl)-2-(methylsulfonyl)imidazo[1,2-a]pyrazin-3-yl]-N-cyclopropylmethyl-N-propylamine (80 mg), and the mixture was stirred for 6 hours by heating under reflux. After cooled to room temperature, water was added thereto, which was extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:5) to give the title compound (23 mg) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][CH:6]=[CH:5]2.C([O-])(=[O:15])C.[NH4+]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:15])[NH:7][CH:6]=[CH:5]2
Reactant: Clc1nccc2cc(Br)ccc12
Reactant: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=c1[nH]ccc2cc(Br)ccc12
Temperature: 100 °C
Reaction time: 3 h
Yield: 72.5 %

Procedure:
To a solution of 42.8 g (173.5 mmol) of 6-Bromo-1-chloro-isoquinoline (5) in 700 ml of acetic acid were added 133.6 g (1.74 mol) ammonium acetate. After stirring at 100° C. for 3 h, the solution was cooled to room temperature and the solvent was removed i. vac. to a small volume. The residue was poured on water and the suspension was stirred for some minutes. The precipitate was isolated by filtration and dried, to yield 28.2 g of the title compound. Rt=1.30 min (Method B). Detected mass: 224.0 (M+H+).
Reaction SMILES: [ClH:1].CC(C)=O.[OH:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[NH:14][C:15](=[O:26])[CH2:16][CH2:17][NH:18]C(OC(C)(C)C)=O>CCOCC>[ClH:1].[OH:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[NH:14][C:15](=[O:26])[CH2:16][CH2:17][NH2:18]
Reactant: Cc1ccc(NC(=O)CCNC(=O)OC(C)(C)C)c(O)c1
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)=O
Product: Cc1ccc(NC(=O)CCN)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
To 15 ml of a saturated solution of hydrogen chloride in ether, there were added 10 ml of acetone and 1.30 g (4.4 mmol) of N-(2-hydroxy-4-methylphenyl)-3-(tert-butoxycarbonyl)aminopropionamide and stirred at room temperature for 30 minutes. After the completion of the reaction, the crystals thus precipitated were filtered, washed with ether and dried. Thus 0.76 g (2.6 mmol) of N-(2-hydroxy-4-methylphenyl)-3-aminopropionamide hydrochloride was obtained. The yield was 59%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1>>[CH3:12][C:4]1[N:3]=[C:2]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1nc(Cl)c2ccccc2n1
Reactant: COc1ccc(N)cc1
Product: COc1ccc(Nc2nc(C)nc3ccccc23)cc1

Procedure:
The title compound was prepared from 4-chloro-2-methyl-quinazoline (108 mg, 0.605 mmol) and 4-methoxy-phenylamine (89.4 mg, 0.73 mmol) by a procedure similar to Example 72b. 1H NMR (DMSO-d6): 11.28 (brs, 1H), 8.73 (d, J=8.4 Hz, 1H), 8.06 (t, J=7.5 Hz, 1H), 7.85-7.78 (m, 2H), 7.66 (d, J=9 Hz, 2H), 7.06 (d, J=8.7 Hz, 2H), 3.81 (s, 3H), 2.60 (s, 3H).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][C:19]([C:24]([N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)=[O:25])=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].CS(O[CH2:41][C:42]([F:45])([F:44])[F:43])(=O)=O>CN(C)C=O>[N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:41][C:42]([F:45])([F:44])[F:43])[C:19]([C:24]([N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)=[O:25])=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCCCC2)CC1
Reactant: CS(=O)(=O)OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2CC(F)(F)F)N1CCC(N2CCCCC2)CC1
Yield: 89 %

Procedure:
The title compound was synthesized in analogy to example 51, from [5-([1,4′]bipiperidinyl-1′-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 168), sodium hydride and 2,2,2-trifluoroethyl methanesulfonate in N,N-dimethylformamide, to give the desired product as a colorless solid (89%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][N:3]1[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C@H:22]2[N:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:26]3[CH:35]=[CH:36][CH:37]=[CH:38][C:25]=3[N:24]([CH2:39][C:40]([F:43])([F:42])[F:41])[C:23]2=[O:44])=[O:20])[CH2:15][CH2:14]1.Cl.[CH3:46][O:47]C1C=C(C2NC(=O)N(C3CCNCC3)C=2)C=CC=1>>[O:1]=[C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:47][CH3:46])[CH:8]=2)=[CH:4][N:3]1[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C@H:22]2[N:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:26]3[CH:35]=[CH:36][CH:37]=[CH:38][C:25]=3[N:24]([CH2:39][C:40]([F:43])([F:42])[F:41])[C:23]2=[O:44])=[O:20])[CH2:15][CH2:14]1
Reactant: O=C(O[C@H]1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O)N1CCC(n2cc(-c3ccccc3)[nH]c2=O)CC1
Reactant: COc1cccc(-c2cn(C3CCNCC3)c(=O)[nH]2)c1
Agent: Cl
Product: COc1cccc(-c2cn(C3CCN(C(=O)O[C@H]4N=C(c5ccccc5)c5ccccc5N(CC(F)(F)F)C4=O)CC3)c(=O)[nH]2)c1

Procedure:
The title compound was prepared in the same way as (3R)-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-1,4-benzodiazepin-3-yl 4-(2-oxo-4-phenyl-2,3-dihydro-1H-imidazol-1-yl)piperidine-1-carboxylate, except using 4-(3-methoxyphenyl)-1-piperidin-4-yl-1,3-dihydro-2H-imidazol-2-one hydrochloride in place of 4-phenyl-1-piperidin-4-yl-1,3-dihydro-2H-imidazol-2-one hydrochloride. MS 634.2266 (M+1)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[CH:4][C:3]=1[Cl:9].[CH3:10][S-:11].[Na+].O>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:11][CH3:10])=[CH:4][C:3]=1[Cl:9]
Reactant: C[S-]
Reactant: Fc1ccc(Br)c(Cl)c1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CSc1ccc(Br)c(Cl)c1
Yield: 109.2 %

Procedure:
A solution of 1-bromo-2-chloro-4-fluorobenzene (7, 0.50 g, 2.39 mmol) and sodium thiomethoxide (0.17 g, 2.42 mmol) in DMSO (2.5 mL) was stirred at 100° C. for 1 h. The reaction mixture was added to 20 mL water with stirring, the aqueous mixture was extracted with ethyl acetate (2×20 mL) and the combined organic layers were dried over sodium sulfate, filtered and evaporated in vacuo. The title compound (0.62 g) was obtained as a colorless oil and was used in the next step without further purification.
Reaction SMILES: [C:1](/[N:3]=[C:4](\SC)/[NH:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[CH:7]=1)#[N:2].[NH2:16][NH2:17]>C(O)C>[NH2:2][C:1]1[N:3]=[C:4]([NH:5][C:6]2[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[CH:7]=2)[NH:17][N:16]=1
Reactant: CS/C(=N\C#N)Nc1cc(Cl)cc(Cl)c1
Reactant: NN
Solvent: CCO
Product: Nc1n[nH]c(Nc2cc(Cl)cc(Cl)c2)n1
Yield: 99 %

Procedure:
A solution of (Z)-methyl N′-cyano-N-(3,5-dichlorophenyl)carbamimidothioate (8 g, 30.8 mmol) and hydrazine (9.85 g, 9.65 ml, 308 mmol) in Ethanol (120 ml) was stirred at 70° C. for 3 h. It was concentrated to a small volume and water was added to give a suspension. The suspension was filtered, washed with water to give a white solid as desired product (7.44 g, 99% yield). MS +m/z: 244.0 (M+H)+
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18]2[C:13](=[CH:14][C:15]([C:21]([F:24])([F:23])[F:22])=[C:16]([C:19]#[N:20])[CH:17]=2)[N:12]=[C:11](Cl)[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:28][NH2:29].O>ClCCl>[CH2:1]([O:8][N:9]1[C:18]2[C:13](=[CH:14][C:15]([C:21]([F:24])([F:23])[F:22])=[C:16]([C:19]#[N:20])[CH:17]=2)[N:12]=[C:11]([NH:28][NH2:29])[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: N#Cc1cc2c(cc1C(F)(F)F)nc(Cl)c(=O)n2OCc1ccccc1
Solvent: O
Solvent: ClCCl
Product: N#Cc1cc2c(cc1C(F)(F)F)nc(NN)c(=O)n2OCc1ccccc1
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a solution of 5.2 g (13.7 mmol) of 1-benzyloxy-3-chloro-7-cyano-6-trifluoromethylquinoxalin-2(1H)-one in 150 ml of dichloromethane was added 2.7 ml of hydrazine monohydrate (~55.7 mmol) at 0° C. Stirring was continued at 0° C. for 1 h. The evaporated reaction mixture was stirred with water to give the title compound (5.0 g; 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:27]=[CH:26][C:18]3[C:19]([CH3:25])([CH3:24])[O:20][C:21](=[O:23])[NH:22][C:17]=3[CH:16]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:28]O>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:27]=[CH:26][C:18]3[C:19]([CH3:24])([CH3:25])[O:20][C:21](=[O:23])[NH:22][C:17]=3[CH:16]=2)=[O:28])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1(C)OC(=O)Nc2cc(OCCCCSc3ccc(Cl)c(Cl)c3)ccc21
Reactant: OO
Product: CC1(C)OC(=O)Nc2cc(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)ccc21

Procedure:
Prepared analogously to Example 2 from 7-[4-(3,4-dichloro-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:14]([C@@H:15]([OH:25])/[CH:16]=[CH:17]/[C:18]([CH3:24])([CH3:23])[CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([CH3:26])[CH2:12][C:11]1=[O:27].N1C=CC=CC=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:14]([C@@H:15]([O:25][C:35](=[O:37])[CH3:36])/[CH:16]=[CH:17]/[C:18]([CH3:23])([CH3:24])[CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([CH3:26])[CH2:12][C:11]1=[O:27]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCC(C)(C)/C=C/[C@H](O)[C@H]1[C@H](C)CC(=O)[C@@H]1C/C=C\CCCC(=O)OC
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCC(C)(C)/C=C/[C@H](OC(C)=O)[C@H]1[C@H](C)CC(=O)[C@@H]1C/C=C\CCCC(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the crude optically active (5Z,11alpha,13S,14E)-13-(hydroxy)-11,16,16-trimethyl-9-oxoprosta-5.14-dien-1-oic acid methyl ester (9.2 g) in methylene chloride (100 mL) was treated with pyridine (5.5 mL) and 4-dimethylaminopyridine (0.5 g), cooled to 0°, and treated with acetic anhydride (3.4 mL). The resulting mixture was stirred overnight at room temperature and then washed with 2 N HCL, water. NaHCO3 solution, and brine (75 mL of each). After drying over sodium sulfate, the solvent was stripped off leaving 9.7 g (~100%) of crude optically active (5Z,11alpha,13S,14E)-13-(acetyloxy)-11,16,16-trimethyl-9-oxoprosta-5,14-dien-1-oic acid methyl ester is a yellow oil. This material was used as is in Example XXII.
Reaction SMILES: [NH:1]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:2][C:3]([NH:5][C@H:6]([C:16]([NH:18][C@H:19]([C:24]([NH:26][C@H:27]([C:32]([O:34]CC)=O)[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:25])[CH2:20][C:21](=[O:23])[NH2:22])=[O:17])[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4].[NH2:44][NH2:45].O>CO>[NH:1]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH2:2][C:3]([NH:5][C@H:6]([C:16]([NH:18][C@H:19]([C:24]([NH:26][C@H:27]([C:32]([NH:44][NH2:45])=[O:34])[CH2:28][CH:29]([CH3:30])[CH3:31])=[O:25])[CH2:20][C:21](=[O:23])[NH2:22])=[O:17])[CH2:7][O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:4]
Reactant: NN
Reactant: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](COCc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C
Solvent: O
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](COCc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C)C(=O)NN
Reaction time: 48 h
Yield: 79 %

Procedure:
2.80 Grams of Boc-Gly-Ser(Bzl)-Asn-Leu-OEt was dissolved in 30 ml of methanol. Thereto was added 2.25 ml of NH2NH2.H2O. The mixture was allowed to stand for 2 days at room temperature. The resulting precipitate was collected by filtration and washed with methanol to obtain 2.16 g (yield: 79.0%) of the above objective compound. Melting point: 221°-224° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23]>C1(C)C=CC=CC=1>[CH2:20]([N:21]([CH2:24][CH3:25])[CH2:22][CH2:23][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:19]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1
Temperature: 100 °C

Procedure:
To a solution of 4-nitro-phenol 1 (36.0 mmol) in toluene (40 mL) is added cesium carbonate (53.8 mmol) and (2-chloro-ethyl)-diethyl-amine hydrochloride (28.7 mmol). The reaction mixture is heated at 100° C. for 2 h then cooled to rt. The solid is filtered under vacuum and washed with warm toluene. The filtrate is concentrated to afford diethyl-[2-(4-nitro-phenoxy)-ethyl]-amine 2 and used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 8.10-8.08 (m, 2H), 6.86-6.84 (m, 2H), 4.05 (t, J=4.0 Hz, 2H), 2.81 (t, J=4.0 Hz), 2.55 (q, J=8.0 Hz, 4H), 0.98 (t, J=8.0 Hz, 6H). MS (m/z) (M+1)+: 239.3.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:10])[C:6]=1[C:7]([NH2:9])=[O:8].[I:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](O)=[O:20])=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[I:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH3:10])[C:6]=2[C:7]([NH2:9])=[O:8])=[O:20])=[CH:14][CH:13]=1
Reactant: O=C(O)Cc1ccc(I)cc1
Reactant: Cc1csc(N)c1C(N)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1csc(NC(=O)Cc2ccc(I)cc2)c1C(N)=O
Reaction time: 18 h

Procedure:
To a solution of 2-amino-4-methylthiophene-3-carboxamide (1 g, 6.4 mmol) and 2-(4-iodophenyl)acetic acid (1.83 g, 7.0 mmol) in methylene chloride (10 mL) was added Hunig's base (i.e., N,N-diisopropylethylamine) (30.1 mL, 18 mmol) and HATU (2.66 g, 7.0 mmol). The heterogeneous mixture was stirred for 18 h. The reaction was quenched by addition of saturated aqueous ammonium chloride solution and the biphasic mixture was extracted with additional methylene chloride. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to provide a pale brown solid. LCMS method [2]: rt=2.02 min; M+Na 423.0. Material was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]([C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][C:25]=3[CH3:31])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:41]([O:43][P:44]([CH2:49]OS(C(F)(F)F)(=O)=O)([O:46][CH2:47][CH3:48])=[O:45])[CH3:42]>CN(C)C(=O)C>[CH2:41]([O:43][P:44]([CH2:49][NH:30][C:27]1[CH:28]=[CH:29][C:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([S:15]([C:13]3[CH:14]=[C:10]([C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:34])=[NH:9])[S:11][C:12]=3[S:32][CH3:33])(=[O:17])=[O:16])[CH:19]=2)=[C:25]([CH3:31])[CH:26]=1)(=[O:45])[O:46][CH2:47][CH3:48])[CH3:42]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2ccc(N)cc2C)c1
Reactant: CCOP(=O)(COS(=O)(=O)C(F)(F)F)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCOP(=O)(CNc1ccc(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)c(C)c1)OCC
Temperature: 50 °C
Yield: 98.1 %

Procedure:
To a mixture of {[4-(4′-amino-2′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (30 mg, 58.0 μmol), as prepared according to the procedure of step b of Example 120, cesium carbonate (19 mg, 58 μmol), and N,N-dimethylacetamide (0.4 mL) was added a solution of trifluoro-methanesulfonic acid diethoxy-phosphorylmethyl ester (18 mg, 58 μmol) (Xu, Y. et al, J. Org. Chem. 61, 7697 (1996); Phillion, D. et al, Tetrahedron Lett. 27, 1477 (1986)), and heated at 50° C. for 48 h. Additional trifluoro-methanesulfonic acid diethoxy-phosphorylmethyl ester (18 mg, 58 μmol) was added. The mixture was heated at 50° C. for additional 24 h. Solvent was evaporated. The resulting mixture was partitioned between DCM and H2O. Aqueous layer was separated and extracted with DCM. All the DCM layers were combined, washed with H2O and brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel column, eluting with EtOAc/DCM (20 and 30%) to give the title compound (38 mg, 98% yield) as an orange oil. 1H NMR (CDCl3): δ 8.23 (s, 1H), 7.92–7.88 (m, 2H), 7.53–7.46 (m, 2H), 6.98 (d, 1H, J=8.0 Hz), 6.56–6.53 (m, 2H), 4.23–4.15 (m, 4H), 3.56 (d, 2H, J=12.5 Hz), 2.43 (S, 3H), 2.16 (S, 3H), 1.52 (S, 9H), 1.35 (t, 6H, J=7.0 Hz). ESI-MS (m/z): Cald. For C29H39N3O7PS3: 668.2 (M+H); found: 667.8.