Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:50]([C:52]([C:74]1[CH:79]=[CH:78][C:77](B2OC(C)(C)C(C)(C)O2)=[C:76]([CH3:89])[CH:75]=1)([C:55]1[CH:60]=[CH:59][C:58]([C:61]#[C:62][C:63]([CH2:71][CH3:72])([O:66][Si:67]([CH3:70])([CH3:69])[CH3:68])[CH2:64][CH3:65])=[C:57]([CH3:73])[CH:56]=1)[CH2:53][CH3:54])[CH3:51].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:77]2[CH:78]=[CH:79][C:74]([C:52]([CH2:53][CH3:54])([C:55]3[CH:60]=[CH:59][C:58]([C:61]#[C:62][C:63]([CH2:71][CH3:72])([O:66][Si:67]([CH3:68])([CH3:69])[CH3:70])[CH2:64][CH3:65])=[C:57]([CH3:73])[CH:56]=3)[CH2:50][CH3:51])=[CH:75][C:76]=2[CH3:89])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: CCC(C#Cc1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)c(C)c2)cc1C)(CC)O[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(C#Cc1ccc(C(CC)(CC)c2ccc(-c3ccc(CC(=O)OC)cc3)c(C)c2)cc1C)(CC)O[Si](C)(C)C
Temperature: 100 °C
Reaction time: 1 h
Yield: 42.5 %

Procedure:
(4-Bromo-phenyl)acetic acid methyl ester (Tetrahedron Letters 44 (2003) 331-334; 27 mg, 0.118 mmol), palladium acetate (1.8 mg, 0.008 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (6.6 mg, 0.016 mmol), potassium phosphate (50 mg, 0.234 mmol) and water (0.2 mL) were added to a solution of 2-(4-{1-ethyl-1-[4-(3-ethyl-3-trimethylsilanyloxy-1-pentynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Example 125-(3); 44 mg, 0.078 mmol) in toluene (2 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for one hour. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to give the target compound as a colorless oil (19.3 mg, 42%).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)(=[O:16])=[O:15])[CH2:11][NH:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].Cl.[N:28]1([C:34]2([C:37](O)=[O:38])[CH2:36][CH2:35]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=3)(=[O:16])=[O:15])[CH2:11][N:10]2[C:37]([C:34]2([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:35][CH2:36]2)=[O:38])=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3cccc(C(F)(F)F)c3)CN2)CC1
Reactant: O=C(O)C1(N2CCCCC2)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3cccc(C(F)(F)F)c3)CN2C(=O)C2(N3CCCCC3)CC2)CC1
Yield: 56 %

Procedure:
The reaction of (2S,4R)-N-(1-cyanocyclopropyl)-4-(3-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxamide 7E with 1-(piperidin-1-yl)cyclopropanecarboxylic acid hydrochloride 16A carried out according to the general procedure L yielded (2S,4R)-N-(1-cyanocyclopropyl)-1-(1-(piperidin-1-yl)cyclopropanecarbonyl)-4-(3-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxamide as a light yellow solid (56%). MS ISP (m/e): 539.3 (100) [(M+H)]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([Cl:10])[C:3]=1[CH:11]([O:13][C:14]1[C:15]2[O:25][CH:24]=[C:23]([C:26]3[CH:27]=[N:28][N:29]([CH:31]4[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]4)[CH:30]=3)[C:16]=2[CH:17]=[N:18][C:19]=1[N+:20]([O-])=O)[CH3:12].Cl>Cl.[Fe].CCO>[NH2:20][C:19]1[N:18]=[CH:17][C:16]2[C:23]([C:26]3[CH:27]=[N:28][N:29]([CH:31]4[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:41])[CH3:42])=[O:38])[CH2:33][CH2:32]4)[CH:30]=3)=[CH:24][O:25][C:15]=2[C:14]=1[O:13][CH:11]([C:3]1[C:2]([Cl:1])=[C:7]([F:8])[CH:6]=[C:5]([F:9])[C:4]=1[Cl:10])[CH3:12]
Reactant: CC(Oc1c([N+](=O)[O-])ncc2c(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)coc12)c1c(Cl)c(F)cc(F)c1Cl
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: CC(Oc1c(N)ncc2c(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)coc12)c1c(Cl)c(F)cc(F)c1Cl

Procedure:
Into a round bottom flask were added tert-Butyl 4-(4-{7-[1-(2,6-dichloro-3,5-difluorophenyl)ethoxy]-6-nitrofuro[3,2-c]pyridin-3-yl}-1H-pyrazol-1-yl)piperidine-1-carboxylate (220 mg, 0.34 mmol), iron (192 mg, 3.44 mmol), 2 drops of 0.1 M HCl and EtOH (7 mL), and the reaction mixture was refluxed for 30 min. 0.1 M HCl was added dropwise and reaction refluxed until consumption of SM was observed. Reaction was stopped and filtered through silica gel washing with 5% MeOH in DCM. Reaction mixture was concentrated in vacuo to obtain the title compound. MS (ES+): m/z 608.06/610.07 (100/70) [MH+]. HPLC: tR=3.74 min (ZQ3, polar—5 min).
Reaction SMILES: [CH3:1][C:2]1[N+:11]([O-:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]2)=[N+:4]([O-:13])[C:3]=1[C:14]([O:16][CH3:17])=[O:15].[Br:18]Br.CO>CN(C)C=O>[Br:18][CH2:1][C:2]1[N+:11]([O-:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]2)=[N+:4]([O-:13])[C:3]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: BrBr
Reactant: COC(=O)c1c(C)[n+]([O-])c2ccccc2[n+]1[O-]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1c(CBr)[n+]([O-])c2ccccc2[n+]1[O-]
Reaction time: 1.5 h

Procedure:
Methyl 3-methyl-2-quinoxalinecarboxylate-1,4-dioxide (1.2 moles) were suspended in 475 ml of dimethylformamide and 64 ml of bromine was added dropwise with stirring over 1.5 hours while the temperature rose to 42° C. After additional stirring for 48 hours 1.5 liters of methanol were added and stirred for about 1/2 hour. The precipitated product was removed by filtration, washed with water and dried. Yield, 251 grams (68%); m.p. 113°-16° C.
Reaction SMILES: [NH2:1][CH:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[N+:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:1][CH:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCOC(=O)CC(C)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)Nc1ccccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 36 h
Yield: 45.2 %

Procedure:
A round bottomed flask was charged with ethyl 3-aminobutanoate (1 ml, 6.82 mmol), 1-fluoro-2-nitrobenzene (0.720 ml, 6.82 mmol), potassium carbonate (1884 mg, 13.63 mmol), and a stirbar. THF (35 mL, 0.2 M) was added, and the mixture was stirred at 100° C. for 36 h. The mixture was concentrated with celite and purified by silica gel chromatography to yield ethyl 3-(2-nitrophenylamino)butanoate as a yellow amorphous solid (0.776 mg, 3.08 mmol, 45%).
Reaction SMILES: C([O:8][C:9]([C:11]1[N:12]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[C:13]2[C:18]([CH:19]=1)=[C:17]([Br:20])[CH:16]=[CH:15][CH:14]=2)=O)C1C=CC=CC=1.[OH-].[Na+].C(Cl)(=O)C(Cl)=O.[NH3:37]>>[Br:20][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[CH:19]=[C:11]([C:9]([NH2:37])=[O:8])[N:12]2[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1
Reactant: N
Reactant: O=C(OCc1ccccc1)c1cc2c(Br)cccc2n1Cc1cccc(F)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)c1cc2c(Br)cccc2n1Cc1cccc(F)c1

Procedure:
4-Bromo-1-(3-fluoro-benzyl)-1H-indole-2-carboxylic acid amide was prepared from 4-bromo-1-(3-fluoro-benzyl)-1H-indole-2-carboxylic acid benzyl ester by hydrolysis with ethanolic NaOH, followed by treatment with oxalyl chloride and then ammonia, as described in steps 3 and 4 of Example 1 MS: 348 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C@@H:11]([NH:14][C:15]([C:17]2[C:18]3[CH:25]=[N:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:19]=3[CH:20]=[N:21][CH:22]=2)=[O:16])[CH2:12][CH3:13])[CH:8]=[C:7]([O:33]C)[N:6]=1)(=[O:4])=[O:3].Br>O>[CH3:1][S:2]([C:5]1[NH:6][C:7](=[O:33])[CH:8]=[C:9]([C@@H:11]([NH:14][C:15]([C:17]2[C:18]3[CH:25]=[N:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:19]=3[CH:20]=[N:21][CH:22]=2)=[O:16])[CH2:12][CH3:13])[CH:10]=1)(=[O:3])=[O:4]
Reactant: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1cc(OC)nc(S(C)(=O)=O)c1
Agent: Br
Solvent: O
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1cc(S(C)(=O)=O)[nH]c(=O)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-1-(2-methanesulfonyl-6-methoxy-pyridin-4-yl)-propyl]-amide (0.150 g, 310 mmol) in 48% aqueous hydrobromic acid (7.0 mL, 42 mmol) was warmed at 60° C. After 5 hours, the mixture was cooled to room temperature, diluted with water (25 mL) and extracted with ethyl acetate (4×20 mL). The combined organic layers were washed with saturated sodium bicarbonate (4×20 mL), brine (20 mL), dried over sodium sulfate and concentrated in vacuo. The crude material was triturated with ethyl acetate-ether to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[Br:15][C:16]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:17]=1[NH2:18]>>[Br:15][C:16]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:17]=1[NH:18][C:9](=[O:11])[C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[C:12]([NH2:14])=[O:13]
Reactant: Nc1ccc(Cl)cc1Br
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(Cl)cc1Br

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-bromo-4-chloroaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: C(Cl)(=O)C.OC=[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]4N(CC)N=C(C)C=4)=[O:26])=[CH:20][CH:19]=3)=[O:17])[CH:14]=2)[NH:9][C:8]1=[O:35]>C1COCC1>[O:35]=[C:8]1[CH2:7][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:26])[CH3:27])=[CH:20][CH:19]=3)=[O:17])[CH:14]=2)[NH:9]1
Reactant: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)C(=CO)C(=O)N3)cc1
Solvent: C1CCOC1
Solvent: CC(=O)Cl
Product: CC(=O)Nc1ccc(C(=O)c2ccc3c(c2)CC(=O)N3)cc1
Temperature: 25 °C
Yield: 75.7 %

Procedure:
A dry 25 mL flask was charged with acetyl chloride (0.209 g, 2.67 mmol) and THF (10 mL). 5-(4-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 7, 0.512 g, 2.06 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 3 h. The reaction mixture was then allowed to cool to room temperature. The precipitate that formed was filtered and washed with THF affording N-[4-(2-Oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-acetamide (0.503 g, 1.56 mmol, 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:4]=1[C:5](=[O:15])C(=O)[NH:7]2.[OH:16]O.[ClH:18]>[OH-].[Na+]>[ClH:18].[NH2:7][C:8]1[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:3]([O:2][CH3:1])[C:4]=1[C:5]([OH:15])=[O:16]
Reactant: OO
Reactant: COc1cc2c(c(OC)c1)C(=O)C(=O)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(N)c(C(=O)O)c(OC)c1
Temperature: 75 °C
Yield: 59 %

Procedure:
4,6-Dimethoxyisatin (5.00 g, 24.0 mmol) was dissolved in 33% (w/v) aqueous sodium hydroxide solution (42 ml) at 75° C. To this solution was added hydrogen peroxide (30%, 8 ml) dropwise over 30 minutes. The reaction was stirred for an hour at 75° C. and then cooled to room temperature. Ice was added, and the reaction mixture acidified to pH 1 with concentrated hydrochloric acid. The resulting precipitate was filtered, washed with water and dried in vacuo to yield 2-amino-4,6-dimethoxybenzoic acid hydrochloride salt (3.3 g, 59% yield) acid as a pale yellow solid:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH:24]([C:28]1[CH:32]=[C:31]([NH:33][C:34]([N:36]2[CH2:42][CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[O:35])[O:30][N:29]=1)([CH2:26][CH3:27])[CH3:25]>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[CH:24]([C:28]1[CH:32]=[C:31]([NH:33][C:34]([N:36]2[CH2:42][CH2:41][CH2:40][N:39]([C:7]([CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[O:9])[CH2:38][CH2:37]2)=[O:35])[O:30][N:29]=1)([CH2:26][CH3:27])[CH3:25]
Reactant: O=C(O)C1CCOCC1
Reactant: CCC(C)c1cc(NC(=O)N2CCCNCC2)on1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCC(C)c1cc(NC(=O)N2CCCN(C(=O)C3CCOCC3)CC2)on1
Reaction time: 8 h
Yield: 36 %

Procedure:
4-Tetrahydropyran-carboxylic acid (66 mg; 0.50 mmol; 1.1 equiv.), HOBt (81 mg; 0.6 mmol; 1.4 equiv.) and EDC (115 mg; 0.6 mmol; 1.4 equiv.) were combined in 2 mL anhydrous DMF. After 15 minutes [1,4]Diazepane-1-carboxylic acid (3-sec-butyl-isoxazol-5-yl)-amide from above (117 mg; 0.44 mmol; 1.0 equiv.) was added, followed by 2 mg of DMAP (catalytic). The mixture was left stirring overnight. Water was added to the reaction mixture and it was extracted with EtOAc. The organic layer was washed with water once then saturated aqueous NaHCO3 solution, saturated aqueous NH4Cl solution, then brine. The organics were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using 2.5% MeOH/DCM mixtures as eluent, then switched to 10% MeOH/DCM. Solvents were removed from the enriched fractions and 61 mg of 4-(Tetrahydro-pyran-4-carbonyl)-[1,4]diazepane-1-carboxylic acid (3-sec-butyl-isoxazol-5-yl)-amide was obtained (36% yield) as a light yellow solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:3])[CH3:2].C(Cl)(Cl)[Cl:15].N1C=CC=CC=1.ClCl>C(Cl)(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[S:6][C:7]([Cl:15])=[CH:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccsc1NC(C)=O
Reactant: ClC(Cl)Cl
Agent: ClCl
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Cl)sc1NC(C)=O
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4 parts of methyl 2-acetamidothiophene-3 -carboxylate in a mixture of 80 parts by volume of chloroform and 12 parts by volume of pyridine, 20 parts by volume of a 10 % (W/V) solution of chlorine in carbon tetrachloride is added dropwise. After stirring for further 30 minutes, the mixture is washed with an aqueous sodium bicarbonate solution and, then, with water. Evaporation of the solvent, and recrystallization of the residue from methanol gives methyl 2-acetamido-5-chlorothiophene-3-carboxylate as crystals. Colorless needles, melting point: 110°-110.5°C.
Reaction SMILES: CN.[S:3]([C:7]1[S:11][C:10]([CH2:12][CH2:13][N:14]2C(=O)C3=CC=CC=C3C2=O)=[CH:9][CH:8]=1)(=[O:6])(=[O:5])[NH2:4].[ClH:25]>C(O)C>[ClH:25].[NH2:14][CH2:13][CH2:12][C:10]1[S:11][C:7]([S:3]([NH2:4])(=[O:6])=[O:5])=[CH:8][CH:9]=1
Reactant: NS(=O)(=O)c1ccc(CCN2C(=O)c3ccccc3C2=O)s1
Agent: CN
Agent: Cl
Solvent: CCO
Product: NCCc1ccc(S(N)(=O)=O)s1
Reaction time: 22.5 h

Procedure:
To a solution of methylamine (9 g, 0.33 mol) in ethanol (40 ml), cooled in an ice bath, was added N-(2-(5-sulfamoyl-2-thienyl)ethyl)phthalimide (3.2 g, 9.5 mmol). After stirring for 20-25 hours, the precipitated by-product was removed by filtration. The filtrate was concentrated and diethyl ether was added to precipitate remaining by-product. This was collected on a filter. The filtrate was concentrated to dryness to give the product free base as an oil. This oil was dissolved in ethanol and 6N ethanolic HCl was slowly added as the product precipitated. The salt was twice recrystallized by dissolution in methanol and careful dilution with diethyl ether to give 1.3 g, m.p. 222°-224° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([C:17]2[CH:22]=[C:21]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:20]=[C:19]([F:30])[CH:18]=2)([NH2:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[C:31](Cl)(=[O:42])[O:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:16][C:31](=[O:42])[O:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)([C:17]2[CH:22]=[C:21]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:20]=[C:19]([F:30])[CH:18]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1
Reactant: N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamine (200 mg, 0.45 mmol) in DCM (2 mL) was added 4-nitrophenyl carbonochloridate (226.9 mg, 1.13 mmol) followed by the addition of K2CO3 (620.6 mg, 4.5 mmol). The reaction mixture was stirred at room temperature for 18 h and filtered through a small silica pad. The filtrate was diluted with DCM (20 mL), washed with saturated NaHCO3 (8×15 mL) till the aqueous layer only showed light yellow color. The organic layer was dried over MgSO4, filtered and concentrated to give (S)-4-nitrophenyl 1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethylcarbamate as a yellow oil (273 mg, crude 100%). This yellow oil was used directly to the next step without further purification. LCMS RT=2.213 min [M+H] 607.94 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].Br[C:10]1[N:11]=[CH:12][C:13]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[Cl:28])(=[O:20])=[O:19])=[N:14][C:15]=1[Cl:16]>>[Cl:28][C:22]1[C:23]([Cl:27])=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([NH:17][C:13]1[C:12]([O:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:11][CH:10]=[C:15]([Cl:16])[N:14]=1)(=[O:20])=[O:19]
Reactant: OCc1ccccn1
Reactant: O=S(=O)(Nc1cnc(Br)c(Cl)n1)c1cccc(Cl)c1Cl
Product: O=S(=O)(Nc1nc(Cl)cnc1OCc1ccccn1)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 31 using pyridine-2-methanol (0.22 g) and N-(3-bromo-6-chloro-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide (Example 98) (0.2 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6](=S)[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)[CH3:2].CNC(=N)S.[OH:21]S(O)(=O)=O>>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CC(=S)c1ccc(C)cc1
Reactant: O=S(=O)(O)O
Agent: CNC(=N)S
Product: CCOC(=O)CC(=O)c1ccc(C)cc1

Procedure:
The title compound was prepared from ethyl(4-methylthiobenzoyl)acetate (16.447 g, 69 mmol) (obtained in preparation 3) and methylthiopseudourea.H2SO4 (10.56 g, 38 mmol) according to the procedure described in preparation 4, (1.82 g, 11.5%, mp 266–267° C.). 1H-NMR (DMSO-d6): δ 2.53 (s, 3H), 6.48 (s, 1H), 7.37–7.39 (d, 2H), 7.79–7.81 (d, 2H), 7.92 (bs, 2H). MS m/z: 235 (M+). Preparation 7 Synthesis of 6-(4-methylphenyl)-2H-3,4-dihydro-1,3-oxazin-2,4-dione
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][N:13]([CH3:28])[CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH:26]=O)=[CH:20]2.N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:26][C:21]1[NH:22][C:23]2[C:19]([CH:20]=1)=[CH:18][C:17]([O:16][CH2:15][CH2:14][N:13]([CH3:12])[CH3:28])=[CH:25][CH:24]=2
Reactant: CN(C)CCOc1ccc2[nH]c(C=O)cc2c1
Reactant: O=C1Cc2cc(Br)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CN(C)CCOc1ccc2[nH]c(C=C3C(=O)Nc4ccc(Br)cc43)cc2c1
Temperature: 100 °C
Yield: 80.4 %

Procedure:
A mixture of 5-bromo-2-oxindole (46 mg, 0.215 mmol), 5-(2-dimethylamino-ethoxy)-1H-indole-2-carbaldehyde (50 mg, 0.21 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 72 mg (78%) of the title compound as a red solid.
Reaction SMILES: C1C(C(O)=[O:8])=CC2C(OC3(C4C=CC(O)=CC=4OC4C=C(O)C=CC3=4)C=2C=1)=O.ON1C(=O)CCC1=O.[CH:37]1([N:43]=[C:44]=[N:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>CN(C)C=O>[C:44]([NH:43][CH:37]1[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]1)([NH:45][CH:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1)=[O:8]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC21c2ccc(O)cc2Oc2cc(O)ccc21
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.08 h

Procedure:
A synthetic aldehyde, Pro4-de novo CHO, was prepared as follows. To a stirred solution of 5-carboxyfluorescein (5-FAM) (190 mg, 0.51 mmol) in anhydrous N,N-dimethylformamide (DMF (5 mL) were added N-hydroxysuccinimide (NHS) (77 mg, 0.67 mmol) and 1,3-dicyclohexylcarbodiimide (DCC) (126 mg, 0.61 mmol). After approximately 5 minutes, a white solid (dicyclohexylurea) started forming. The reaction mixture was stirred overnight under nitrogen. Thin layer chromatography (TLC) (40:9:1 CH2Cl2—CH3OH-water) indicated complete disappearance of the starting material. The mixture was then filtered, and the filtrate was added dropwise to a stirred solution of ethylene diamine (46 mg, 0.77 mmol) in DMF (3 mL). A solid was obtained. As evident from TLC, the reaction was complete instantaneously. This reaction mixture was subsequently treated with glyoxylic acid NHS ester prepared below.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)(=[O:35])[CH3:34]
Reactant: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)N[C@H]3CC[C@H](N)CC3)c[nH]c12
Reactant: CC(=O)Cl
Product: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)N[C@H]3CC[C@H](NC(C)=O)CC3)c[nH]c12

Procedure:
Starting from trans-4-[4-methoxy-2-(2-methoxy-ethoxy)-phenyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A182) and acetyl chloride the title compound was obtained as colorless solid.