Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:25]=[CH:24][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[C:9]([Cl:26])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C=O.[C:29]([BH3-])#N.[Na+].C(O)(=O)C>CO.C(OCC)(=O)C>[CH3:29][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:25]=[CH:24][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[C:9]([Cl:26])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: [BH3-]C#N
Reactant: O=C(c1ccc(N2CCNCC2)cc1Cl)N1CCCCc2ccccc21
Agent: C=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCN(c2ccc(C(=O)N3CCCCc4ccccc43)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
To a mixture of 1-[4-(1-piperazinyl)-2-chlorobenzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.25 g), 37% formaldehyde (0.45 g) and sodium cyanoborohydride (0.12 g) in methanol (5 ml) is added with stirring acetic acid (0.12 g) under ice-cooling, and the mixture is stirred at room temperature for one hour. To the reaction solution is added ethyl acetate, and the mixture is washed with a 2 N aqueous sodium hydroxide solution and distilled water. The organic layer is dried over magnesium sulfate, filtered, and concentrated, and the resulting residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol=10:1) to give 1-[4-(4-methyl-1-piperazinyl)-2-chlorobenzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.10 g) as white powder.
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[C:10](O)(=O)[C:11]1[C:12](=CC=[CH:16][CH:17]=1)[OH:13].[Se](=O)=O.[C:23](OO)(C)([CH3:25])[CH3:24]>ClCCl.C1C=CC=CC=1>[OH:13][CH2:12][C:11]([CH3:10])=[CH:17][CH2:16][C:7]1([CH2:25][CH:23]=[CH2:24])[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][C:8]1=[O:9]
Reactant: O=C(O)c1ccccc1O
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: CC(C)(C)OO
Agent: O=[Se]=O
Solvent: c1ccccc1
Solvent: ClCCl
Product: C=CCC1(CC=C(C)CO)C(=O)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of the barbituric acid derivative prepared in the preceding experiment (100 mg, 0.42 mmol) in 1.0 mL dichloromethane was added 6 mg (42 umol) salicylic acid and 9 mg (84 umol) selenium dioxide. The suspension was placed in a water bath, and 0.29 mL (3.8M, 1.09 mmol) of a anhydrous solution of tert-butyl hydroperoxide in benzene was added. The suspension was then vigorously stirred for 12 hours at ambient temperature. The reaction mixture was concentrated, and chromatographed directly on a silica gel column, eluting with 40%, 50%, 60%, and 70% ethyl acetate/hexane. In addition to some starting material as well as other products, 21 mg of a colorless oil was isolated.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[N:10]2)[N:3]=1.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.Cl>O.C(O)C>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[N:10]2)[N:3]=[C:2]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([Cl:16])=[CH:18][CH:19]=2)[CH:7]=1
Reactant: Cc1cc(C)n(-c2nc(Cl)cc(Cl)n2)n1
Reactant: Nc1ccc(Cl)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(C)n(-c2nc(Cl)cc(Nc3ccc(Cl)cc3)n2)n1
Temperature: 88 °C
Reaction time: 6 h
Yield: 99.7 %

Procedure:
4,6-Dichloro-2-(3,5-dimethyl-pyrazol-1-yl)-pyrimidine (3.5 g, 14.4 mmol) and 4-chloroaniline (3.7 g, 28.8 mmol) were suspended in water (120 mL) and ethanol (17 mL). Concentrated hydrochloric acid (0.6 mL, 7.2 mmol) was added and the mixture was heated to 88° C. over-night. Additional 4-chloroaniline (918 mg) was added and stirring was continued for six hours. The mixture was cooled to room temperature and diluted with water. The resulting solid was collected by filtration to give [6-chloro-2-(3,5-dimethylpyrazol-1-yl)-pyrimidin-4-yl]-(4-chloro-phenyl)-amine (4.8 g, 99%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C1(SC)C=CC=CC=1.[OH:16][C:17]1[CH:18]=[C:19]([CH:24]=[N:25][NH:26][S:27]([NH:30][C:31]([N:33]2[CH2:36][C@H:35]([NH:37]C(=O)OCC3C=CC=CC=3)[C:34]2=[O:48])=[O:32])(=[O:29])=[O:28])[CH:20]=[CH:21][C:22]=1[OH:23]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:37][C@H:35]1[CH2:36][N:33]([C:31]([NH:30][S:27]([NH:26][N:25]=[CH:24][C:19]2[CH:20]=[CH:21][C:22]([OH:23])=[C:17]([OH:16])[CH:18]=2)(=[O:28])=[O:29])=[O:32])[C:34]1=[O:48]
Reactant: O=C(N[C@H]1CN(C(=O)NS(=O)(=O)NN=Cc2ccc(O)c(O)c2)C1=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: N[C@H]1CN(C(=O)NS(=O)(=O)NN=Cc2ccc(O)c(O)c2)C1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 22 ml of trifluoroacetic acid and 5.8 ml of thioanisole was cooled to 0° C., and 5.5 g (11.5 mmol) of (S)-[1-[[[[2-[(3,4-dihydroxyphenyl)methylene]hydrazino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester were added. After stirring overnight at room temperature, the excess trifluoroacetic acid was evaporated in vacuo and the residue triturated with ether. The trifluoroacetic acid salt was filtered off by suction and dried in vacuo; yield: 2.64 g.
Reaction SMILES: Cl[C:2]1[C:18]([Cl:19])=[C:17]([OH:20])[CH:16]=[CH:15][C:3]=1[C:4](=[N:13][OH:14])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[CH3:12].[H-].[Na+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].O>CN(C=O)C>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][O:20][C:17]1[CH:16]=[CH:15][C:3]2[C:4]([C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=3[CH3:12])=[N:13][O:14][C:2]=2[C:18]=1[Cl:19])[CH3:29]
Reactant: CCOC(=O)CBr
Reactant: Cc1cccc(C(=NO)c2ccc(O)c(Cl)c2Cl)c1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(-c3cccc(C)c3C)noc2c1Cl
Temperature: 130 °C
Reaction time: 7 h

Procedure:
To a solution of 5 g of 2,3-dichloro-4-hydroxy-2',3'-dimethylbenzophenone oxime in 70 ml of DMF, 0.96 g of NaH is added. The internal temperature is held between 95°-120° C. for seven hours, then the mixture is heated at 130° C. for 1.5 hours. The reaction mixture is cooled and 2.94 g of ethyl bromoacetate is added dropwise. The mixture is stirred one hour and water is added dropwise. The product which forms is filtered off and recrystallized from 95% ethanol to yield ethyl-{[7-chloro-3-(2,3-dimethylphenyl)-1,2-benzisoxazol-6-yl]oxy}acetate, mp 89°-91° C.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][C:24]([C:35]1[C:43]2[NH:42][C:41](=[O:44])[NH:40][C:39]=2[CH:38]=[C:37]([C:45]2[C:46]([CH3:51])=[N:47][O:48][C:49]=2[CH3:50])[CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[CH:25]([OH:28])[CH2:26][CH3:27]>ClCCl.C1COCC1>[CH3:51][C:46]1[C:45]([C:37]2[CH:36]=[C:35]([C:24]([OH:23])([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:25](=[O:28])[CH2:26][CH3:27])[C:43]3[NH:42][C:41](=[O:44])[NH:40][C:39]=3[CH:38]=2)=[C:49]([CH3:50])[O:48][N:47]=1
Reactant: CCC(O)C(O)(c1ccccn1)c1cc(-c2c(C)noc2C)cc2[nH]c(=O)[nH]c12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCC(=O)C(O)(c1ccccn1)c1cc(-c2c(C)noc2C)cc2[nH]c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Dess-Martin Periodinane (90 mg, 0.24 mmol) was added to a solution of 4-(1,2-dihydroxy-1-(pyridin-2-yl)butyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one (50 mg, 0.12 mmol) in a mixture of dichlormethane and THF. The reaction was stirred for 72 h at room temperature, concentrated and purified by reverse-phase HPLC. A portion of this product was dissolved in concentrated HCl (0.1 mL) and ethanol (1 mL), heated at 80° C. for 3 h and concentrated to give 6-(3,5-dimethylisoxazol-4-yl)-4-(1-hydroxy-2-oxo-1-(pyridin-2-yl)butyl)-1H-benzo[d]imidazol-2(3H)-one.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:12]2[S:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[C:10]=1[Cl:11])=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)=[O:27].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:25][C:26]([N:28]2[CH2:29][CH2:30][N:31]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH2:32][CH2:33]2)=[O:27])[N:8]=[C:9]([C:12]2[S:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[C:10]=1[Cl:11])=[O:5])[CH3:2]
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: CCOC(=O)c1[nH]nc(-c2ccc(Cl)s2)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Cl)c(-c2ccc(Cl)s2)nn1CC(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 4-Chloro-5-(5-chloro-thiophen-2-yl)-2H-pyrazole-3-carboxylic acid ethyl ester, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3) afforded the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): 7.46-7.48 (m, 1H), 6.94-7.1 (m, 2H), 6.84-6.92 (m, 3H), 5.4 (s, 2H), 4.34-4.4 (q, 2H), 3.62-3.81 (m, 4H), 3.04-3.24 (m, 4H), 1.36-1.44 (m, 3H). MS (ES) M+H) expected=511.41, found 511.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][OH:12])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.O>CS(C)=O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1CO
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)c1ccccc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
To a solution of (2-tert-butylphenyl)methanol (935 mg) in DMSO (20 mL) were added triethylamine (4.81 mL) and sulfur trioxide pyridine complex (3.02 g). The reaction mixture was stirred at room temperature for 1 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (780 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:29])=[C:13]([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH:25]3[O:27][CH2:26]3)[CH:18]=2)[CH:14]=1)=[O:7].[CH3:34][N:35]([CH3:41])[CH2:36][CH2:37][CH2:38][NH:39][CH3:40]>>[CH3:1][N:2]([CH3:33])[C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:29])=[C:13]([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH:25]([OH:27])[CH2:26][N:39]([CH2:38][CH2:37][CH2:36][N:35]([CH3:41])[CH3:34])[CH3:40])[CH:18]=2)[CH:14]=1)=[O:7]
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(OCC2CO2)c1
Reactant: CNCCCN(C)C
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(OCC(O)CN(C)CCCN(C)C)c1
Yield: 45 %

Procedure:
Using an analogous procedure to that described in Example 31, N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-3-(2,3-epoxypropoxy)benzamide was reacted with N-(3-dimethylaminopropyl)-N-methylamine to give the title compound in 45% yield; NMR Spectrum: (DMSOd6) 1.8 (m, 2H), 2.18 (s, 3H), 2.33 (s, 3H), 2.58 (s, 6H), 2.6 (m, 2H), 2.92 (t, 2H), 2.96 (s, 6H), 4.03 (m, 5H), 6.9 (m, 1H), 7.15 (m, 1H), 7.2 (m, 3H), 7.28 (t, 1H), 7.48 (t, 1H), 7.56 (m, 2H), 7.8 (d, 1H), 9.95 (s, 1H), 10.13 (s, 1H); Mass Spectrum: M+H+ 562.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9](B(O)O)[S:8][C:7]=2[CH:14]=1.Cl[C:16]1[N:21]=[C:20](Cl)[C:19]([CH3:23])=[CH:18][N:17]=1.[NH2:24][CH:25]1[CH2:30][C:29]([CH3:32])([CH3:31])[NH:28][C:27]([CH3:34])([CH3:33])[CH2:26]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:18]3[C:19]([CH3:23])=[CH:20][N:21]=[C:16]([NH:24][CH:25]4[CH2:26][C:27]([CH3:34])([CH3:33])[NH:28][C:29]([CH3:32])([CH3:31])[CH2:30]4)[N:17]=3)[S:8][C:7]=2[CH:14]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: COc1ccc2cc(B(O)O)sc2c1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Product: COc1ccc2cc(-c3nc(NC4CC(C)(C)NC(C)(C)C4)ncc3C)sc2c1

Procedure:
The title compound was prepared analogous to Method A, starting 6-methoxy-benzo[b]thiophene-2-boronic acid, 2,4-dichloro-5-methyl-pyrimidine and 4-amino-2,2,6,6-tetramethylpiperidine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[N:17]1([C:23](Cl)=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:23]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:24])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Reactant: O=C(Cl)N1CCOCC1
Product: O=C(Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1)N1CCOCC1

Procedure:
The title compound was prepared from 4-(3,5-dichloro-pyridin-2-yloxy)-phenol and morpholine-4-carbonyl chloride. The crude product was purified by preparative HPLC (45%, crystals. HPLC-MS m/z=369.1 (M+1), Rt: 4.3 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:24][CH2:25][CH2:26]Br>>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]([CH2:24][CH2:25][CH3:26])[S:9]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CCCBr
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc(OC)cc2)cc1
Product: CCCN(Cc1ccc(OC)cc1)S(=O)(=O)c1ccc(C(=O)O)cc1

Procedure:
Prepared as in example 5-10 from Methyl 4-(N-(4-methoxybenzyl)sulfamoyl)benzoate (Example 5-10b) and n-propyl bromide. MS (M−H, 362.1); 1H NMR (400 MHz, CDCl3): δ, ppm: 0.70 (m, 3H), 1.35 (m, 3H), 3.08 (m, 2H), 3.73 (s, 3H), 4.31 (s, 2H), 6.83 (m, 2H), 7.17 (m, 2H), 7.93 (m, 2H), 8.23 (m, 2H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][CH:8]1[C:15]2[S:14][CH:13]=[CH:12][C:11]=2[CH:10]2[CH2:16][N:17](C(C3C=CC=CC=3)C)[CH2:18][CH:9]12.[Cl:27]CCOC(Cl)=O>CO>[CH3:7][CH:8]1[C:15]2[S:14][CH:13]=[CH:12][C:11]=2[CH:10]2[CH2:16][NH:17][CH2:18][CH:9]12.[ClH:27]
Reactant: O=C(Cl)OCCCl
Reactant: CC1c2sccc2C2CN(C(C)c3ccccc3)CC12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC1c2sccc2C2CNCC12
Product: Cl
Temperature: 25 °C

Procedure:
K2CO3 (320 mg, 2.32 mmol) was added to a solution of the product from step g) (165 mg, 0.58 mmol) in 6 mL followed by the addition of 2-chloroethylchloroformate (332 mg, 2.32 mmol) under vigorous stirring at room temperature. Next, the reaction was stirred for two hours at 75° C. after which the reaction mixture was cooled, filtered and the solvent was evaporated to leave an oily residue that was then dissolved in dry methanol (10 mL) and was stirred at room temperature for one hour. The solvent was evaporated and the residue was triturated in diethyl ether (5 mL) to give the subtitle compound as its HCl salt. MS calculated for C10H13NS +H: 180, observed: 180. 1H NMR (CDCl3300 MHz) δ 1.32 (d, 3H), 1.93 (s, 1H), 3.04 (m, 1H), 3.18 (m, 2H), 3.47 (m, 3H), 3.78 (m, 1H), 6.83 (d, 1H), 7.21 (d, 1H) ppm.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][C:6]=2[CH:5]=1)(O)=[O:2].S(Cl)(Cl)=O.[NH:22]1[CH2:27][CH2:26][NH:25][CH:24]([C:28]([OH:30])=[O:29])[CH:23]1[C:31]([OH:33])=[O:32].[OH-].[Na+].Cl>C1C=CC=CC=1.O1CCOCC1>[CH:5]1[C:6]2[CH:7]=[CH:8][C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15]=2[CH:16]=[CH:17][C:4]=1[C:1]([N:22]1[CH2:27][CH2:26][NH:25][C@H:24]([C:28]([OH:30])=[O:29])[C@@H:23]1[C:31]([OH:33])=[O:32])=[O:2]
Reactant: O=C(O)c1ccc2c(ccc3ccccc32)c1
Reactant: O=C(O)C1NCCNC1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: O=C(O)[C@H]1NCCN(C(=O)c2ccc3c(ccc4ccccc43)c2)[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 11.3 %

Procedure:
2-Carboxyphenanthrene (2 g, 0.009 mol) was suspended in dry benzene (50 ml) and heated under reflux in the presence of thionyl chloride (5 ml) for 5 hr. The solvent was removed and the corresponding acid chloride was used without further purification. Piperazine-2,3-dicarboxylic acid (0.508 g, 0.003 mol) was dissolved in a 0.991 M aqueous sodium hydroxide solution (9.4 ml, 0.009 mol), dioxane (10 ml) was added and the solution was cooled to 0° C. A solution of the acid chloride (0.84 g, 0.0035 mol) in dioxane (10 ml) was added to the reaction mixture. The reaction was warmed to room temperature and stirred for 2-3 hr. The reaction mixture was acidified to pH 2-3 with aqueous HCl. The solid was filtered, dissolved in dioxane/ H2O (50:50) and bound to an ion exchange resin (Dowex-AG50 H+ form) chromatography column. It was eluted with dioxane/H2O (50:50) until organic impurities are removed. The column was eluted with 10% aqueous pyridine and the ninhydrin fractions were combined. The solvent was removed and the solid was crystallised from H2O to give a white solid (0.128 g, 12%). m.p.=218.1-221.7 ° C. (dec.); 1H NMR (300 MHz, NaOD/ D2O) 7.7-8.8 (m, 9H, Ar), 5.6 (d, 0.5H, CH—CO2H, JAB=2.6Hz), 4.8 (d, 0.5H, CH—CO2H, JAB=2.6Hz), 4.4 (d, 0.4H, CH—CO2H, JAB=12.0Hz), 3.6 (d, 0.4H, CH—CO2H, JAB=12.0Hz), 2.5-3.8 (m, 4H, N—CH2CH2—NH); Elemental analysis calculated for C21,H18N2O5. 2.3H2O C:60.07, H:5.44, N:6.67. Found C:60.06, H:5.38, N: 6.85. The cis-isomerism was confirmed by COSEY 1H NMR.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:28][C:13]3=[N:14][CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH3:27])[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH3:32][S:33](Cl)(=[O:35])=[O:34]>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:28]([S:33]([CH3:32])(=[O:35])=[O:34])[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH3:27])[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: C[C@@H]1CCCN1CCCOc1cnc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Product: C[C@@H]1CCCN1CCCOc1cnc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2S(C)(=O)=O
Yield: 53 %

Procedure:
The title compound was synthesized in analogy to example 18 from (4,4-difluoro-piperidin-1-yl)-{5-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-1H-pyrrolo[2,3-b]pyridin-2-yl}-methanone (example 10)), sodium hydride and methanesulfonyl chloride, to give the desired product as a light yellow oil (53%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]([OH:8])=[O:7].CCOCC.C(=O)(O)[O-].[Na+].[N+:19]([C:22]1[CH:32]=[CH:31][C:25]([CH2:26][O:27][C:28](Cl)=[O:29])=[CH:24][CH:23]=1)([O-:21])=[O:20]>O>[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([CH2:26][O:27][C:28]([NH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]([OH:8])=[O:7])=[O:29])=[CH:31][CH:32]=1)([O-:21])=[O:20]
Reactant: NCCOCC(=O)O
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O=C(O)COCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 99.2 %

Procedure:
With cooling on an ice bath, to 596 mg of 2-(2-aminoethoxy)acetic acid dissolved in 10 ml of water was added an ether solution of 883 mg sodium bicarbonate and 1.29 g p-nitrobenzyloxycarbonyl chloride in dropwise manner. After stirring the reaction solution for 17 hours at room temperature, the resulting aqueous layer was collected, adjusted to acidic with concentrated hydrochloric acid and extracted with ethyl acetate, and the resulting organic layer was washed with water and dried over sodium sulfate, followed by evaporation of the solvent under a reduced pressure to yield 1.48 g of 2-(2-(p-nitrobenzyloxycarbonylamino)ethoxy)acetic acid.
Reaction SMILES: [I-].[Li+].[C:3]([C:5]1[CH:14]=[CH:13][C:12]2[CH2:11][CH:10]([C:15]([O:17]C)=[O:16])[CH2:9][CH2:8][C:7]=2[N:6]=1)#[N:4].N1C=CC=CC=1>>[C:3]([C:5]1[CH:14]=[CH:13][C:12]2[CH2:11][CH:10]([C:15]([OH:17])=[O:16])[CH2:9][CH2:8][C:7]=2[N:6]=1)#[N:4]
Reactant: COC(=O)C1CCc2nc(C#N)ccc2C1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: N#Cc1ccc2c(n1)CCC(C(=O)O)C2
Yield: 81.6 %

Procedure:
A mixture of lithium iodide (10.3 g, 77.0 mmol), methyl 2-cyano-5,6,7,8-tetrahydroquinoline-6-carboxylate (3.32 g, 15.4 mmol) and pyridine (39 mL, 480 mmol) was divided evenly between two 35 mL vials and the mixtures submitted to microwave irradiation for 4 hr at 130° C. The reactions were combined and concentrated to ˜15 mL. The residue was diluted with water (50 mL) and DCM (200 mL) and 1M citric acid (150 mL) was added until a pH of 4 was attained. The aqueous was extracted with additional DCM (200 mL) and the combined organics was washed with 0.25 M citric acid (150 mL). The citric acid wash was back extracted with DCM (50 mL) and the combined organics were dried ((Na2SO4), filtered and evaporated. The residue was dissolved in DCM (200 mL) and washed with 0.5 M citric acid (50 mL×2). Each citric acid wash was back extracted with DCM (25 mL) and the combined organics dried (Na2SO4), filtered and evaporated to obtain a yellow solid (2.54 g, 82%). m/z=201.2 (M−H)−. 1H NMR (400 MHz, DMSO-d6) δ 12.47 (br s, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.77 (d, J=8.1 Hz, 1H), 3.12-2.84 (m, 4H), 2.83-2.74 (m, 1H), 2.22-2.13 (m, 1H), 1.94-1.83 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH3:9].[CH3:10][S:11](Cl)(=[O:13])=[O:12].[Cl-].[Cl-].[Cl-].[Al+3].[C:19](Cl)(=[O:21])[CH3:20].Cl>N1C=CC=CC=1.C(Cl)Cl.C1(C)C=CC=CC=1>[C:19]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:11]([CH3:10])(=[O:13])=[O:12])=[C:3]([CH2:8][CH3:9])[CH:4]=1)(=[O:21])[CH3:20]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1ccccc1N
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCc1cc(C(C)=O)ccc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a solution of 2-amino-1-ethylbenzene (purchased from TCl, 12.1 g, 100 mmol) in pyridine (8.5 mL) and DCM (20 ml), methanesulfonyl chloride (7.74 ml, 11.4 g, 105 mmol) was added dropwise over 10 minutes at 0° C. The reaction mixture was stirred at room temperature for 1 hour. After cooling to 0° C., aluminum trichloride (33.3 g, 250 mmol) was added to the reaction mixture carefully. Then acetyl chloride (11 ml, 12 g, 150 mmol) was added dropwise over 15 minutes. The reaction mixture was diluted with toluene (50 ml) and poured into 2 M HCl aqueous solution (100 ml) with stirring at 0° C. The precipitates were filtered, washed with water and dried in vacuo to give the title compound (18 g, 75%) as yellow solids.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:20](Br)[CH:21]=[CH2:22]>C1COCC1>[CH2:22]([NH:9][C:3]1[C:2]([Br:1])=[N:7][C:6]([Br:8])=[CH:5][N:4]=1)[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: Nc1ncc(Br)nc1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCNc1ncc(Br)nc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
To a solution of 3,5-dibromo-pyrazin-2-ylamine (5.06 g, 20.00 mmol) in 100 mL of THF was added a solution of LiHMDS in THF (1M, 24 mL) at RT. The reaction mixture was stirred at RT for 2 hr, then allyl bromide (3.5 mL, 40 mmol) was added. The reaction mixture was stirred at RT overnight and quenched with saturated NH4Cl solution and extracted with EtOAc. The organic layer was washed with H2O and brine, dried (MgSO4) concentrated, and purified by SiO2 chromatography (200 g SiO2, hexanes/EtOAc 0-35% EtOAc) to give 3.51 g of allyl-(3,5-dibromo-pyrazin-2-yl)-amine as a yellow oil (60% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2=[N:6][O:7][N:8]=[C:4]2[CH:3]=1.[CH2:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](Cl)(=[O:21])=[O:20])[CH3:12]>>[CH2:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([NH:1][C:2]1[CH:10]=[CH:9][C:5]2=[N:6][O:7][N:8]=[C:4]2[CH:3]=1)(=[O:21])=[O:20])[CH3:12]
Reactant: Nc1ccc2nonc2c1
Reactant: CCc1ccccc1S(=O)(=O)Cl
Product: CCc1ccccc1S(=O)(=O)Nc1ccc2nonc2c1

Procedure:
Analogously to Example 1, by reaction of 5-amino-2,1,3-benzoxadiazole (obtainable by reduction of 5-nitro-2,1,3-benzoxadiazole-1- or 3-N-oxide with triethyl phosphite) with 2-ethylbenzenesulfonyl chloride, 2-ethyl-N-(2,1,3-benzoxadiazol-5-yl)-1-benzenesulfonamide is obtained.