Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[C:21]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:22]([CH:30]=[CH:31][CH:32]=2)[O:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:5]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:7]=1.O.[C:39]1(B(O)O)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:35]([CH2:34][CH2:33][C:21]1[C:20]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]#[C:13][C:4]2[CH:3]=[C:2]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:5]=2)=[CH:32][CH:31]=[CH:30][C:22]=1[O:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])([OH:37])=[O:36]
Reactant: OB(O)c1ccccc1
Reactant: CN(C)C(=O)c1cc(Br)cc(C#CCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CN(C)C(=O)c1cc(C#CCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccccc2)c1
Temperature: 78 °C

Procedure:
To a solution of 4-[3-[7-(3-bromo-5-dimethylcarbamoyl-phenyl)-hept-6-ynyl]-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (100 mg, 0.17 mmol) in EtOH (4 mL)/H2O (1 mL) were added phenylboronic acid (50 mg, 0.35 mmol), potassium carbonate (100 mg, 0.7 mmol) and Pd(PPh3)4 (5 mg, 0.004 mmol). The mixture was heated at 78° C. for 5 h and then cooled to room temperature. The reaction mixture was filtered using a syringe filter 0.45 μm and the filtrate was concentrated under reduced pressure. The crude oil was then purified by preparative HPLC using acetonitrile/water gradient.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:37][NH:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:47]=[N:48][CH:49]=[N:50][CH:51]=2)=[CH:42][CH:41]=1>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([N:38]([CH3:37])[CH2:39][C:40]3[CH:41]=[CH:42][C:43]([C:46]4[CH:51]=[N:50][CH:49]=[N:48][CH:47]=4)=[CH:44][CH:45]=3)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: CNCc1ccc(-c2cncnc2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(-c4cncnc4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AA using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (75 mg, 0.21 mmol), CDI (41 mg, 0.25 mmol) and N-methyl-1-[4-(pyrimidin-5-yl)phenyl]methanamine (42 mg, 0.21 mmol) in THF (4.5 mL) and DMF (0.6 mL). The crude product was purified using prep method A.
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH2:21].[I:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>ClCCl>[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH:21][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][C:23]([I:22])=[CH:24][CH:25]=1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.2 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide was prepared according to method C with triethylamine (2.23 mL; 15.90 mmol), 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (1.5 g; 6.36 mmol) and 4-iodobenzoyl chloride (1.82 g; 6.68 mmol) in dichloromethane (75 mL). The mixture was stirred for 20 minutes at room temperature and was evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) to provide 1.22 g (45%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@@H:4]([NH:23]C(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:21])=[CH:8][CH:7]=1.Cl>O1CCOCC1.C1COCC1.CO>[ClH:20].[CH3:1][O:2][C:3](=[O:31])[C@@H:4]([NH2:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=2[Cl:20])=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Reaction time: 0.08 h
Yield: 232.9 %

Procedure:
The solid (S)-2-tert-butoxycarbonylamino-3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid methyl ester (43.45 g, 92.97 mmol) in dioxane (90 mL) was treated with 166 mL of 4.0N hydrochloric acid in dioxane at room temperature. After 5 minutes, the solids went into solution and the mixture was stirred for 2 h. Then, some of the dioxane was removed under vacuum to afford a yellow syrup and 250 mL of ethyl ether was added. A gum was formed which was dissolved in THF (100 mL) and methanol (100 mL). The solvent was removed under vacuum to obtain 43.7 g (100% yield) of (S)-2-amino-3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid methyl ester hydrochloride salt as a white solid: mp 180-195° C. This was stored in the refrigerator under argon atmosphere. ES(+)-HRMS m/e calcd. for C17H16Cl2N2O3 (M+H)+ 367.0616, obsd. 367.0611.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[C@@H:10]([NH2:26])[CH2:11][CH2:12][CH2:13][CH2:14][NH:15]C(OCC1C=CC=CC=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N([CH:34]([CH3:36])[CH3:35])CC)(C)C.Br[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[C:51]2[N:55]([C:56]([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)([C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[N:54]=[N:53][N:52]=2)=[CH:41][CH:40]=1>CN(C)C=O>[CH2:1]([O:8][C:9]([C@@H:14]([NH:15][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[C:51]2[N:55]([C:56]([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)([C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[N:54]=[N:53][N:52]=2)=[CH:41][CH:40]=1)[CH2:13][CH2:12][CH2:11][CH:10]([NH2:26])[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:27])=[O:27])[C:35]1[CH:34]=[CH:36][CH:7]=[CH:2][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: NC(CCC[C@H](NCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
5.0 g of (S)-2-amino-6-benzyloxycarbonylamino-hexanoic acid benzyl ester are dissolved in 250 ml of N,N-dimethylformamide. The solution is treated with 4.33 ml of N,N-diisopropyl-N-ethyl-amine, and the mixture is warmed to 80°, stirred for 30 minutes, treated with 4.44 g of 4-bromomethyl-2'-(1-triphenylmethyl-1H-tetrazol-5-yl)-biphenyl, stirred for 16 hours at 80° and then evaporated. The residue is worked up using water and ethyl acetate. The organic phase is dried and purified by means of flash-chromatography (200 g of silica gel; system N4). The (S)-N-(1-benzyloxycarbonyl-5-benzyloxycarbonyl-amino-pent-1-yl)-N-[2'-(1-triphenylmethyl-1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine is obtained in the form of a brown oil [Rf : 0.18 (system N3)].
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.OS(O)(=O)=O.[CH3:19]O>>[NH2:2][CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH3:19])=[O:10])=[CH:7][CH:6]=1
Reactant: CO
Reactant: NCCc1ccc(C(=O)O)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(CCN)cc1
Temperature: 22 °C

Procedure:
To a solution of 2.02 g (10.0 mmol) of 4-(2-aminoethyl)benzoic acid hydrochloride in 25 mL of methanol was added 1.5 mL of H2SO4. The mixture was heated to reflux and became a homogeneous solution after 1 h. The solution was refluxed for about 16 h, cooled to 22° C. and concentrated to about 10 mL by evaporation. The solution was diluted with 100 mL of water, made basic with 1 N NaOH and extracted with 100 mL of dichloromethane (DCM). The aqueous layer was back-extracted with DCM (4×100 mL). The combined extracts were dried (Na2SO4) and evaporated to give methyl 4-(2-aminoethyl)benzoate as a colorless oil. The material was used directly in the subsequent transformation.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[O:5][C:6]1[C:7]2[CH:25]=[CH:24][NH:23][C:8]=2[N:9]=[C:10]([NH:12][C:13]2[CH:14]=[N:15][N:16]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[CH:17]=2)[N:11]=1.[C:29](Cl)(=[O:32])[CH:30]=[CH2:31]>C1COCC1>[CH3:21][N:20]([CH3:22])[CH2:19][CH2:18][N:16]1[CH:17]=[C:13]([NH:12][C:10]2[N:11]=[C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:29](=[O:32])[CH:30]=[CH2:31])[CH:28]=[CH:27][CH:26]=3)[C:7]3[CH:25]=[CH:24][NH:23][C:8]=3[N:9]=2)[CH:14]=[N:15]1
Reactant: CN(C)CCn1cc(Nc2nc(Oc3cccc(N)c3)c3cc[nH]c3n2)cn1
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Product: C=CC(=O)Nc1cccc(Oc2nc(Nc3cnn(CCN(C)C)c3)nc3[nH]ccc23)c1
Temperature: 10 °C
Reaction time: 3 h
Yield: 11 %

Procedure:
To a solution of 4-(3-aminophenoxy)-N-{1-[2-(dimethylamino)ethyl]-1H-pyrazol-4-yl}-7H-pyrrolo[2,3-d]pyrimidin-2-amine in THF (5 mL) which was cooled to 10° C. was added prop-2-enoyl chloride (47.8 mg, 0.528 mmol) and stirred at 10° C. for 3 hrs. The volatiles were removed in vacuo and the residue purified by HPLC (Phenominex Gemini C18, 21.2×100 mm, 5 μm column using the water/acetonitrile with 10 mM ammonium acetate, with the flow rate 40 mL/min with gradient 55%-67% acetonitrile in 6 min) which was then lyophilized to afford the title compound (28.5 mg, 11% yield) as a tan solid. 1H NMR (600 MHz, DMSO-D6) δ ppm 11.06-11.23 (m, 1H) 9.96-10.08 (m, 1H) 8.56-8.64 (m, 1H) 7.56-7.66 (m, 2H) 7.39-7.47 (m, 2H) 7.30-7.36 (m, 1H) 6.94-7.02 (m, 2H) 6.37-6.47 (m, 1H) 6.18-6.30 (m, 2H) 5.68-5.80 (m, 1H) 3.89-4.04 (m, 2H) 2.57-2.64 (m, 2H) 2.18 (s, 6H). m/z (ESI+) for C22H24N8O2 433.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[OH-].[K+].[CH2:14]([OH:17])[CH2:15]Br.O>CN(C)C=O>[N+:9]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:2]=1[Cl:1])[O:8][CH:14]([OH:17])[CH3:15])([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: OCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(O)Oc1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
2.5 mols (434 g) of 4-chloro-3-nitrophenol are dissolved in 1,300 ml of dimethylformamide heated to 70° C. beforehand. 3 mols of powdered potassium hydroxide (210 g of 80% pure potassium hydroxide) are added to this solution, and 3 mols (534 g) of glycol bromohydrin are then introduced in the course of 30 minutes, with stirring and whilst keeping the temperature at 70° C. When the addition has ended, the reaction medium is kept at 70° C. for 1 hour. 1 mol of powdered potassium hydroxide (70 g of 80% pure potassium hydroxide) and 1 mol of glycol bromohydrin (178 g) are then added. After heating for 1 hour, a further 1 mol of potassium hydroxide and 1 mol of glycol bromohydrin are added. The heating is continued for a further 1 hour and the cooled reaction medium is then poured into 7.5 liters of iced water. The expected product precipitates. It is filtered off and washed carefully with a 3N solution of sodium hydroxide and then with water. After drying in vacuo, it melts at 96° C.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:27])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[O:25][CH3:26])[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[CH3:28][O:29][CH2:30][CH2:31][NH2:32].CC(O)=O.O>CCO>[CH3:28][O:29][CH2:30][CH2:31][NH:32][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:27])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[O:25][CH3:26])[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4]
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccc(OC)cc3OC)ccc2c1O
Reactant: COCCN
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: COCCNC(=O)c1ncc2c(=O)n(Cc3ccc(OC)cc3OC)ccc2c1O
Temperature: 25 °C
Yield: 53.1 %

Procedure:
A mixture of 7-(2,4-dimethoxy-benzyl)-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (15 mg, 0.041 mmol) and 2-methoxyethylamine (0.012 mL, 0.14 mmol) in EtOH (2 mL) was refluxed for 16 h. After cooling the mixture to r.t., AcOH (0.1 mL) and water (2 mL) were added. The resulting precipitate was isolated by filtration, washed with cold MeOH/H2O (5 mL, 1:1), and dried under vacuum to give 9 mg of the title compound. MS: (+) m/z 414.36 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:19])=[N:10][NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([NH:19][S:21]([CH3:20])(=[O:23])=[O:22])=[N:10][NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: Nc1n[nH]c(-c2ccncc2)c1-c1ccc(F)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1n[nH]c(-c2ccncc2)c1-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A solution of 4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-amine prepared as set forth in Example 2 (200 mg, 0.77 mmol) and methanesulfonyl chloride (90 mg) in pyridine (5 ml) was stirred at room temperature overnignt. The pyridine was removed in vacuo and the residue was treated with methylene chloride and water. The resultant precipitate was filtered to give N-[4(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]methanesulfonamide. Additional N-[4(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]methanesulfonamide was contained in the methylene chloride layer. The methylene chloride was stripped in vacuo and the residue purified by chromatography on silica gel using mixtures of ethyl acetate and methanol as eluents. The purified N-[4(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]methanesulfonamide had m.p. 168–170° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5](=[C:7]1[CH2:12][C@@H:11]2[C@@H:9]([CH2:10]2)[C:8]1=O)[O-])[CH3:2].[K+].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[CH:19][N:18]=1>>[CH2:1]([O:3][C:4]([C:5]1[C:7]2[CH2:12][C@H:11]3[CH2:10][C@H:9]3[C:8]=2[N:23]([C:20]2[CH:19]=[N:18][C:17]([Br:16])=[CH:22][CH:21]=2)[N:24]=1)=[O:14])[CH3:2]
Reactant: NNc1ccc(Br)nc1
Reactant: CCOC(=O)C([O-])=C1C[C@H]2C[C@H]2C1=O
Agent: [K+]
Product: CCOC(=O)c1nn(-c2ccc(Br)nc2)c2c1C[C@H]1C[C@@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method C using potassium 2-ethoxy-2-oxo-1-((1R,5R)-2-oxobicyclo[3.1.0]hexan-3-ylidene)ethanolate and 2-bromo-5-hydrazinylpyridine. LCMS m/z=348.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.58 (td, J=4.8, 3.4 Hz, 1H), 1.30 (td, J=7.8, 5.1 Hz, 1H), 1.39 (t, J=7.2 Hz, 3H), 2.29-2.39 (m, 2H), 2.90 (d, J=16.6 Hz, 1H), 3.02 (dd, J=16.6, 6.2 Hz, 1H), 4.39 (q, J=7.1 Hz, 2H), 7.59 (d, J=8.2 Hz, 1H), 8.09 (dd, J=8.5, 2.9 Hz, 1H), 8.87 (d, J=2.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:23](O)=[O:24])=[CH:21][N:22]=3)[CH2:14][C@H:13]2[O:26][CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.[CH3:29][NH:30][CH3:31].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O.ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:23]([N:30]([CH3:31])[CH3:29])=[O:24])=[CH:21][N:22]=3)[CH2:14][C@H:13]2[O:26][CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(c3ncc(C(=O)O)s3)C[C@H]2OC)nc1Cl
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3ncc(C(=O)N(C)C)s3)C[C@H]2OC)nc1Cl
Yield: 93.2 %

Procedure:
The same operation as in Example (1g) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxylic acid obtained in Example (11b) (40 mg, 0.09 mmol), dimethylamine hydrochloride (9 mg, 0.11 mmol), WSC hydrochloride (61 mg, 0.32 mmol), HOBT (22 mg, 0.16 mmol), diisopropylethylamine (0.020 mL, 0.12 mmol), dichloromethane (0.75 mL) and DMA (0.75 mL), to obtain 37 mg of the title compound as a white solid (87%).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:26]=1[C:27](Cl)=[O:28].Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:26]=1[C:27]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=3)=[O:7])=[CH:22][CH:23]=1)=[O:28]
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3-c3ccccc32)cc1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3-c3ccccc32)cc1)c1c(Cl)cccc1Cl
Temperature: 100 °C
Reaction time: 144 h
Yield: 240.8 %

Procedure:
A mixture of 300 mg (0.5 mmol) of 5-(4-amino-benzoyl)-5,6-dihydrophenanthridine and 230 mg of (0.55 mmol) of 2,6-dichlorobenzoyl chloride in 1.2 ml of pyridine is heated (100° C.) for 3 hr and then stirred at room temperature for 6 days. To the mixture is added 10 mg of 4-(dimethylamino)pyridine and the mixture stirred for 22 days. To the mixture is added 6 ml of 2N HCl and the solid filtered and washed with 2N HCl, 1N NaOH, H2O to give 0.57 g of solid. The solid is chromatographed on thick layer silica gel plates with hexane ethyl-acetate (1:1) to give 110 mg of solid. Recrystallization from CH2Cl2 -diisopropyl ether to give 73 mg of white crystals, m.p. 230°-235° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[NH:7][S:8][C:4]=2[CH:3]=1.[CH:12]1([N:18]=[C:19]=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([NH:18][C:19]([N:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][C:4]=3[S:8]2)=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C=NC1CCCCC1
Reactant: O=c1[nH]sc2cc(Cl)ccc12
Product: O=C(NC1CCCCC1)n1sc2cc(Cl)ccc2c1=O

Procedure:
Following the synthetic procedure of 6a as described in Example 1, compound 6y (84% yield) was synthesized from 6-chloro-benzo[d]isothiazol-3-one and cyclohexyl isocyanate as a white solid. IR(CHCl3) 3289, 1711, 1533 cm−1; 1H-NMR (CDCl3) δ1.20-1.48 (m, 5H), 1.58-1.68 (m, 1H), 1.70-1.80 (m, 2H), 1.92-2.05 (m, 2H), 3.80-3.92 (m, 1H), 7.38 (d, J=8.3 Hz, 1H), 7.58 (s, 1H), 7.92 (d, J=8.3 Hz, 1H), 8.75 (d, J=7.8 Hz, 1H); ESIMS m/e 311 and 313 (M++1, 35Cl and 37Cl).
Reaction SMILES: C([Cl:4])(=[O:3])C.O.[O:6]=[C:7]([CH2:9][N:10]([C:12](=[NH:14])[NH2:13])[CH3:11])[OH:8]>C(O)C>[OH2:3].[O:6]=[C:7]([CH2:9][N:10]([C:12](=[NH:13])[NH2:14])[CH3:11])[OH:8].[ClH:4]
Reactant: CC(=O)Cl
Agent: CN(CC(=O)O)C(=N)N
Solvent: O
Solvent: CCO
Product: Cl
Temperature: 30 °C

Procedure:
Optimization experiments were performed by varying certain parameters of the reaction scheme in Example 1, as described below. A 1.5 mole equivalent of acetyl chloride was added dropwise to anhydrous ethanol to generate the acidified ethanol. Creatine monohydrate was added to the acidified ethanol at a ratio of 1 g:6 ml of ethanol and the reaction medium was heated to 37° C. for 20 hours. The reaction medium was then allowed to cool to 30° C. prior to filtration and the product (filter cake) was washed with ethanol chilled to 0° C. The amount of ethanol used in the wash was on a 1:1 w/v (g/ml) basis with the quantity of creatine monohydrate employed as the starting material. This reaction scheme yielded an 83 to 86% conversion of creatine monohydrate to CEE HCl.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH3:29])[N:17]=2)[CH2:9]1.[CH2:31]([O:33][CH2:34][CH:35]1[CH2:40][CH2:39][C:38](=O)[CH2:37][CH2:36]1)[CH3:32]>>[CH2:31]([O:33][CH2:34][CH:35]1[CH2:40][CH2:39][CH:38]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=4)[N:18]([CH3:29])[N:17]=3)[CH2:11]2)[CH2:37][CH2:36]1)[CH3:32]
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Reactant: CCOCC1CCC(=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCOCC1CCC(N2CC(NC(=O)CNc3nn(C)c4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 18, Step D) and 4-ethoxymethyl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [I-].[K+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17]Cl)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:8]=2[CH:27]=1.C[NH:29]C1CC1.O1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][NH:29][CH2:34][CH:35]4[CH2:37][CH2:36]4)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:8]=2[CH:27]=1
Reactant: Fc1cccc(F)c1C1=NCc2nnc(CCl)n2-c2ccc(Cl)cc21
Reactant: CNC1CC1
Reactant: C1CCOC1
Agent: [I-]
Agent: [K+]
Product: Fc1cccc(F)c1C1=NCc2nnc(CNCC3CC3)n2-c2ccc(Cl)cc21

Procedure:
In the manner given in Example 2, potassium iodide and 8-chloro-1-(chloromethyl)-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in tetrahydrofuran is treated with methylcyclopropylamine to give 8-chloro-1-[(cyclopropylmethylamino)methyl]-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:3]=1[C:4]([NH:6][CH:7]([CH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29])[CH:16]=[CH:15]2)[C:8]([OH:10])=[O:9])=[O:5].C(N(CC)CC)C.[C:42]([O:48][CH2:49]Cl)(=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44]>CCOC(C)=O>[C:42]([O:48][CH2:49][O:9][C:8](=[O:10])[CH:7]([NH:6][C:4](=[O:5])[C:3]1[C:30]([Cl:34])=[CH:31][CH:32]=[CH:33][C:2]=1[Cl:1])[CH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29])[CH:16]=[CH:15]2)(=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=C(NC(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)C(=O)O)c1c(Cl)cccc1Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OCOC(=O)C(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
To 2-[(2,6-dichlorobenzoyl)amino]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoic acid 38 (534 mg) are added 195 μl of triethylamine and, after 15 minutes, 290 μl of chloromethyl pivalate. The solution is stirred at RT overnight and then poured in AcOEt. The organic phases are washed with water and brine, dried over MgSO4 and concentrated. The resulting residue is purified over silica gel using CH2Cl2/C2H5OH 99/1 as eluent to give ({2-[(2,6-dichlorobenzoyl)amino]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoyl}oxy)methyl pivalate 129.