Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:20]2[S:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1.[NH2:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>>[NH2:26][C:27]1[CH:32]=[C:31]([C:2]2[C:3]([C:20]3[S:21][C:22]([Cl:25])=[CH:23][CH:24]=3)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]3[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]3=[O:19])=[N:6][CH:7]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2ccc(Cl)s2)n1
Reactant: Nc1cccc(B(O)O)c1
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(-c2cccc(N)c2)c(-c2ccc(Cl)s2)n1

Procedure:
The title compound was prepared from 1-{2-[5-bromo-4-(5-chlorothiophen-2-yl)pyrimidin-2-ylamino]ethyl}-5,5-dimethylimidazolidine-2,4-dione and 3-aminophenylboronic acid, hemihydrosulfate in a manner analogous to Example 269. MS (M+H)+ 457.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[C:31]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[Cl:25][C:26]1[C:31]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:29]=[CH:28][C:27]=1[C:5]1[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: OB(O)c1cccc(C(F)(F)F)c1Cl
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1cccc(C(F)(F)F)c1Cl
Yield: 2.3 %

Procedure:
Using the conditions of General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 2-chloro-3-(trifluoromethyl)phenylboronic acid (available from Combi-Blocks Inc.; 112 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-3′-trifluoromethyl-biphenyl-2-carboxylic acid (3 mg, 2%). 1H NMR (300 MHz, DMSO-d6) δ 13.22 (br s, 1H), 8.58 (br. s., 1H), 8.50 (s, 1H), 8.27-8.36 (m, 2H), 8.10 (d, J=7.3 Hz, 1H), 7.87-7.93 (m, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.61-7.70 (m, 2H), 7.47-7.53 (m, 1H).
Reaction SMILES: [NH2:1][C@H:2]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[C:20]([CH2:26][CH3:27])[CH:19]=1)[C:3](N([C@@H](C)[C@@H](O)C1C=CC=CC=1)C)=[O:4].[OH2:28]>O1CCOCC1>[NH2:1][C@H:2]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[C:20]([CH2:26][CH3:27])[CH:19]=1)[C:3]([OH:4])=[O:28]
Reactant: CCc1ccc(C[C@@H](N)C(=O)N(C)[C@@H](C)[C@@H](O)c2ccccc2)cc1CC
Reactant: O
Solvent: C1COCCO1
Product: CCc1ccc(C[C@@H](N)C(=O)O)cc1CC

Procedure:
A mixture of 7.8 g (21.2 mmol) of (R)-2-amino-3-(3,4-diethyl-phenyl)-N-((1S,2S)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-propionamide, 50 mL of water and 50 mL of 1,4-dioxane was refluxed for 7 days. The reaction mixture was evaporated down under reduced pressure, the residue remaining was stirred with EtOH and suction filtered. The desired product was obtained in the form of a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][C@:13]12[CH2:30][CH2:29][C@H:28]3[C@@H:18]([CH2:19][CH2:20][C@@H:21]4[C@:26]3([CH3:27])[CH2:25][CH2:24][C@H:23]([OH:31])[CH2:22]4)[C@@H:17]1[CH2:16][CH:15]=[CH:14]2.C[C@]12CC[C@H]3[C@@H](CC[C@@H]4[C@]3(C)CC[C@H]([OH:51])C4)[C@@H]1CCC2=O.O>N1C=CC=CC=1>[CH3:12][C@:13]12[CH2:30][CH2:29][C@H:28]3[C@@H:18]([CH2:19][CH2:20][C@@H:21]4[C@:26]3([CH3:27])[CH2:25][CH2:24][C@H:23]([OH:31])[CH2:22]4)[C@@H:17]1[CH2:16][CH:15]=[CH:14]2.[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:10])(=[O:51])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@]12CC[C@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: C[C@]12CC[C@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C=CC[C@@H]12
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Reaction time: 1 h

Procedure:
4-Methylbenzenesulphonyl chloride (20 g) was added to a stirred solution of (3β, 5α)-androst-16-en-3-ol (20 g), which was prepared from (3β, 5α)-androstan-3-ol- 17-one in a similar way as described in Examples 1 and 2, in pyridine (100 ml) at °C. The mixture was stirred at 0°-5° C. for 1 h., then set aside in a refrigerator for 3 d. Water was added to precipitate the product as off-white prisms. Recrystallisation from diethyl ether-methanol gave colourless prisms of (3β, 5α)-androst-16-en-3-ol 4-methylbenzenesulphonate, Which Was treated as described in Example 3.
Reaction SMILES: O.O.[Sn](Cl)Cl.[N:6]([CH:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[S:34])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]([C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)=[O:28])=[CH:22][CH:21]=2)=[CH:13][C:12]=1[Cl:35])[CH3:10])=[N+]=[N-]>CO.C(OCC)(=O)C>[NH2:6][CH:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[S:34])[NH:19][C:20]2[CH:21]=[CH:22][C:23]([NH:26][C:27]([C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)=[O:28])=[CH:24][CH:25]=2)=[CH:13][C:12]=1[Cl:35])[CH3:10]
Reactant: CC(N=[N+]=[N-])c1ccc(NC(=S)Nc2ccc(NC(=O)c3ccco3)cc2)cc1Cl
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC(N)c1ccc(NC(=S)Nc2ccc(NC(=O)c3ccco3)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of tin (II) chloride dihydrate (0.25 g) in methanol (2.5 mL) is added furan-2-carboxylic acid (4-{3-[4-(1-azido-ethyl)-3-chloro-phenyl]-thioureido}-phenyl)-amide (0.22 g) and the solution is stirred for approximately 15 hours at room temperature. The solution is then diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate then saturated aqueous sodium chloride, then dried over anhydrous sodium sulfate. After removal of the solvent by evaporation under reduced pressure the residue is chromatographed over silica gel (8% methanol in dichloromethane containing 1% triethylamine is used as the eluant) to provide the desired product as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[O:13][C:5]2=[C:6]([NH:11][CH3:12])[N:7]=[CH:8][C:9](I)=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:22]2[CH:23]=[N:24][N:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]3)[CH:26]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[Cl:1][C:2]1[O:13][C:5]2=[C:6]([NH:11][CH3:12])[N:7]=[CH:8][C:9]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:28][CH2:29][N:30]([C:33](=[O:35])[CH3:34])[CH2:31][CH2:32]4)[CH:26]=3)=[C:4]2[CH:3]=1
Reactant: CC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: CNc1ncc(I)c2cc(Cl)oc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CNc1ncc(-c2cnn(C3CCN(C(C)=O)CC3)c2)c2cc(Cl)oc12
Temperature: 95 °C
Yield: 99.1 %

Procedure:
A mixture of 2-chloro-4-iodo-N-methylfuro[2,3-c]pyridin-7-amine (125 mg, 0.405 mmol), 1-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidin-1-yl}ethanone (142 mg, 0.446 mmol), (1,1′-bis-(diphenylphosphine)-ferrocene)palladium dichloride (29.6 mg, 0.0405 mmol) and potassium carbonate (140 mg, 1.01 mmol) in 1,4-dioxane (1.35 mL) and water (0.58 mL) was heated to 95° C. for 20 h. The mixture was adsorbed directly onto a dry 5 g silica gel cartridge and purified by ISCO chromatography (0 to 10% methanol:ethyl acetate) to afford 150 mg (99%) of the title compound as a tan solid. 1H NMR (400 MHz, CD3OD): δ 8.06 (s, 1 H), 7.92 (s, 1 H), 7.82 (s, 1 H), 7.05 (s, 1 H), 4.74-4.60 (m, 1 H), 4.51 (tt, J=4.4, 11.5 Hz, 1 H), 4.14-4.00 (m, 1 H), 3.39-3.34 (m, 1 H), 3.05 (s, 3 H), 2.85 (td, J=3.0, 13.0 Hz, 1 H), 2.28-2.11 (m, 5 H), 2.11-1.89 (m, 2 H); MS (ESI): 374.11, 376.08 [M+H]+; HPLC tR=2.29 min (ZQ3, polar—4 min).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[Cl:26][C:27]1[N:32]=[C:31](Cl)[CH:30]=[CH:29][N:28]=1>>[Cl:26][C:27]1[N:32]=[C:31]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:30]=[CH:29][N:28]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Clc1ccnc(Cl)n1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(C#Cc4ccnc(Cl)n4)c3n2)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and commercially available 2,4-dichloropyrimidine (194 mg, 1.3 mmol) according to general procedure II. Obtained as an orange solid (220 mg, 47%). MS (ISP) 468.1 [(M+H)+]; mp 192-195° C.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[N:5]=[C:6]([S:16][CH3:17])[N:7]=[N:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OCC)(=O)C>O1CCCC1>[CH3:3][CH:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][NH:7][C:6]([S:16][CH3:17])=[N:5]1
Reactant: CSc1nnc(-c2ccccc2)c(C)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSC1=NC(C)C(c2ccccc2)=NN1
Yield: 34.3 %

Procedure:
Sodium borohydride (3.4 g) was added portionwise to a stirred solution of 5-methyl-3-methylthio-6-phenyl-1,2,4-triazine (10 g) in tetrahydrofuran (25 ml). To the reaction mixture was added ethyl acetate, and the mixture was washed successively with 1N-hydrochloric acid, water and brine, dried over sodium sulfate, and concentrated to dryness. The residual solid was recrystallized from a mixture of ethanol and water to give 5-methyl-3-methylthio-6-phenyl-2,5-dihydro-1,2,4-triazine (3.46 g), m.p. 159°~160° C.
Reaction SMILES: Cl[C:2]1[C:6]2[C:7]([Cl:11])=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[NH3:14]>>[NH2:14][C:2]1[C:6]2[C:7]([Cl:11])=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1
Reactant: O=S1(=O)N=C(Cl)c2c(Cl)cccc21
Reactant: N
Product: NC1=NS(=O)(=O)c2cccc(Cl)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.72 g of 3,4-dichlorobenzo[d]isothiazole-1,1-dioxide were added to 15 ml of 25% ammonia in 15 ml of ice water. After stirring at room temperature for two hours, the desired product was sucked off and dried; yield 4.20 g; melting-point 260° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:6]1[NH:7][C:8]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[C:16](=O)[CH2:15][CH2:14]3)[N:10]=1)([CH3:5])[CH3:4].[NH2:27][OH:28]>C(O)C>[NH2:1][CH2:2][C:3]([C:6]1[NH:7][C:8]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[C:16](=[N:27][OH:28])[CH2:15][CH2:14]3)[N:10]=1)([CH3:5])[CH3:4]
Reactant: NO
Reactant: CC(C)(CN)c1nc(-c2ccc3c(c2)CCC3=O)c(-c2ccncc2)[nH]1
Solvent: CCO
Product: CC(C)(CN)c1nc(-c2ccc3c(c2)CCC3=NO)c(-c2ccncc2)[nH]1
Temperature: 25 °C
Yield: 98 %

Procedure:
To a solution of the product of Step 6 (0.12 g, 0.350 mmol) in ethanol (5 ml) at 80° C. was added aqueous hydroxylamine (0.07 g, 1.04 mmol, 50% in water). After 30 min the mixture was cooled to room temperature and concentrated in vacuo to give the title compound, (0.124 g, 100%) as a yellow solid; MS(AP+) m/e 362 [M+H]+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([O:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:17]([OH:18])[CH:16]=1)(=[O:13])[CH3:12].[CH:22]([Si:25](Cl)([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23]>C1COCC1>[C:11]([O:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:17]([O:18][Si:25]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:22]([CH3:24])[CH3:23])[CH:16]=1)(=[O:13])[CH3:12]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CC(=O)Oc1cccc(O)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)Oc1cccc(O[Si](C(C)C)(C(C)C)C(C)C)c1
Reaction time: 0.17 h
Yield: 64.1 %

Procedure:
Lithium bis(trimethylsilyl)amide (73 ml, 73 ml, 1M solution in THF) was added dropwise to a solution of resorcinol monoacetate (10 g, 65.7 mmol) in THF (100 ml) at 78° C. under argon. The solution was stirred for 10 minutes and then triisopropylsilyl chloride (15.5 ml, 73 mmol) was added via syringe. After stirring at room temperature overnight, the mixture was partitioned between water and ethyl acetate. The organic layer was dried, filtered and evaporated under vacuum to yield 13 g of crude 3-[1,1-bis(Methylethyl)-2-methyl-1-silapropoxy]phenyl acetate which was used in the next step without further purification. NMR 1H Cl3CD δ: 7.19 (t, 1H, J=8 Hz), 6.75 (m, 1H), 6.68 (m, 1H), 6.63 (t, 1H, J=4 Hz), 2.29 (s, 3H), 1.25 (m, 3H), 1.11 (d, 18H, J=7.0 Hz).
Reaction SMILES: [CH2:1]([OH:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:7][N:8]([CH:10]=[O:11])C.[H-].[Na+].[Br:14][C:15]1[CH:16]=[C:17]2[C@:28]3([N:33]=C(N)[CH2:31][O:30][CH2:29]3)[C:27]3[CH:26]=[C:25](Cl)[N:24]=[CH:23][C:22]=3[O:21][C:18]2=[CH:19][CH:20]=1>C(OCC)(=O)C.O.[Cl-].[Na+].O>[Br:14][C:15]1[CH:16]=[C:17]2[C@:28]3([N:33]=[C:7]([NH:8][CH:10]=[O:11])[CH2:31][O:30][CH2:29]3)[C:27]3[CH:26]=[C:25]([O:6][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])[N:24]=[CH:23][C:22]=3[O:21][C:18]2=[CH:19][CH:20]=1
Reactant: CN(C)C=O
Reactant: NC1=N[C@@]2(COC1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Reactant: CC(C)(C)CO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)COc1cc2c(cn1)Oc1ccc(Br)cc1[C@@]21COCC(NC=O)=N1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A vial was charged with neopentyl alcohol (0.579 g, 6.57 mmol) and DMF (6.57 mL). Sodium hydride (60% in mineral oil; 0.263 g, 6.57 mmol) was added and the reaction was stirred for 10 minutes at room temperature. The vial was heated to 100° C. for 5 min. The vial was cooled to rt. (S)-7-bromo-3-chloro-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.500 g, 1.314 mmol) was added in one portion. The vial was sealed and heated to 100° C. three hours. The mixture was diluted with ethyl acetate and water. A small amount of brine was added and the layers were separated. The aq. layer was extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (0-100% EtOAc/Hexanes) to give 175 mg of (S)—N-(7-bromo-3-(neopentyloxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazine]-5′-yl)formamide as a light yellow solid.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][N:11]1[C:15]([Cl:16])=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=2)[C:13]([C:25]([O:27][CH3:28])=[O:26])=[CH:12]1)=O)(C)(C)C.Cl.O.N>CO>[NH2:8][CH2:9][CH2:10][N:11]1[C:15]([Cl:16])=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=2)[C:13]([C:25]([O:27][CH3:28])=[O:26])=[CH:12]1
Reactant: COC(=O)c1cn(CCNC(=O)OC(C)(C)C)c(Cl)c1-c1cccc(C#N)c1
Agent: Cl
Agent: N
Solvent: O
Solvent: CO
Product: COC(=O)c1cn(CCN)c(Cl)c1-c1cccc(C#N)c1
Temperature: 60 °C
Yield: 82.8 %

Procedure:
To a solution of 13.5 g (33.4 mmol) of methyl 1-(2-tert-butyloxycarbonylaminoethyl)-5-chloro-4-(3-cyanophenyl)-1H-pyrrole-3-carboxylate in 50 ml of methanol are added 80 ml (320 mmol) of 4N hydrochloric acid and the mixture is heated vigorously at 60° C. for 2 hours. 150 ml of water are then added and the solution is basified by adding aqueous ammonia. The product is extracted with dichloromethane, the organic phase is then dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give a yellow oil, which is purified by chromatography on a column of 80 g of silica gel, eluting with a mixture of 0.3% aqueous ammonia and 3% methanol in dichloromethane, to give 8.4 g of methyl 1-(2-aminoethyl)-5-chloro-4-(3-cyanophenyl)-1H-pyrrole-3-carboxylate in the form of a white powder after crystallizing, triturating in diisopropyl ether, filtering off and drying.
Reaction SMILES: [CH3:1][N:2]1[CH2:10][CH2:9][CH:5]([C:6](O)=[O:7])[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1.Cl.[CH3:31][NH:32][O:33][CH3:34].Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH3:34][O:33][N:32]([CH3:31])[C:6](=[O:7])[CH:5]1[CH2:9][CH2:10][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CNOC
Reactant: CN1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CCN(C)CC1
Reaction time: 0.08 h
Yield: 132.8 %

Procedure:
1-Methylisonipecotic acid (5.5 g, 38.4 mmol) was dissolved in dimethylformamide (100 ml) with heating. Diisopropylethylamine (8.0 ml, 46.1 mmol), 1-hydroxybenzotriazole (5.2 g, 38.4 mmol), and N,O-dimethylhydroxylamine hydrochloride (4.1 g, 42.2 mmol) were added and the reaction mixture was stirred 5 min. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.4 g, 38.4 mmol) was added and the resulting homogeneous solution was stirred for 63 hours at ambient temperature. The solvent was removed under reduced pressure. The residue was dissolved in water and the solution was basified to pH 9 with 5N sodium hydroxide solution. This aqueous solution was extracted with methylene chloride then saturated with sodium chloride and extracted with chloroform/isopropanol (3/1). The combined organic extracts were dried over sodium sulfate and the solvent was removed under reduced pressure to give 9.5 g of a yellow liquid. Purification by flash chromatography (silica gel, methylene chloride:methanol:ammonium hydroxide, 100:10:1) gave 5.7 g (80%) of product as a light yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9](Cl)=[N:10][OH:11].[Cl:13][CH:14]([Cl:26])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[CH:25])[CH:19]=1)=[O:16]>C1COCC1.C(N(CC)CC)C>[Cl:13][CH:14]([Cl:26])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[O:11][N:10]=[C:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[CH:25]=2)[CH:19]=1)=[O:16]
Reactant: ON=C(Cl)c1c(Cl)cccc1Cl
Reactant: C#Cc1cccc(NC(=O)C(Cl)Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cccc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1)C(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,6-Dichloro-N-hydroxybenzenecarboximidoyl chloride (2.72 g, 95.6 mmol) and 2,2-dichloro-N-(3-ethynylphenyl) acetamide (2.5 g, 110 mmol) were dissolved in anhydrous THF (40 mL) and triethylamine (1.8 mL). The mixture was stirred at room temperature for 1 h then heated at reflux for 5 h to generate the 2,6-dichlorophenyl nitrile oxide intermediate, which reacted by a 1,3-dipolar cycloaddition reaction with 2,2-dichloro-N-(3-ethynylphenyl) acetamide. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with water and brine. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was purified by column chromatography on silica gel, eluting with 8:2 hexanes-ethyl acetate. The appropriate fractions were combined and then crystallized from hexanes-ethyl acetate to give 2,2-dichloro-N-[3-[3-(2,6-dichlorophenyl)-5-isoxazolyl]phenyl] acetamide as a white crystalline solid, 1.80 g (m.p. 167° C.). NMR (300 MHz, CDCl3): 8.21 (broad s, 1H, NH), 8.08 (m, 1H), 7.71 (m, 2H), 7.52 (t, 1H), 7.42–7.46 (m, 2H), 7.32–7.38 (m, 1H), 6.69 (s, 1H), 6.07 ppm (s, 1H). MW=416 confirmed by LC-MS, tr=36.9 min (Method W) MH+=415–419.
Reaction SMILES: [CH2:1]([C:3]([CH2:11][CH3:12])([CH2:7][C:8]([OH:10])=O)[C:4]([OH:6])=[O:5])[CH3:2].C(Cl)(=O)C.[CH:17]1([C:23]2[N:24]=[C:25](/[CH:28]=[CH:29]/[C:30]3[CH:31]=[C:32]([NH2:36])[CH:33]=[CH:34][CH:35]=3)[S:26][CH:27]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C([O-])(=O)C.[Na+]>COCCOC>[CH:17]1([C:23]2[N:24]=[C:25](/[CH:28]=[CH:29]/[C:30]3[CH:31]=[C:32]([NH:36][C:8](=[O:10])[CH2:7][C:3]([CH2:1][CH3:2])([CH2:11][CH3:12])[C:4]([OH:6])=[O:5])[CH:33]=[CH:34][CH:35]=3)[S:26][CH:27]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCC(CC)(CC(=O)O)C(=O)O
Reactant: Nc1cccc(/C=C/c2nc(C3CCCCC3)cs2)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: COCCOC
Product: CCC(CC)(CC(=O)Nc1cccc(/C=C/c2nc(C3CCCCC3)cs2)c1)C(=O)O
Reaction time: 0.33 h
Yield: 30.1 %

Procedure:
A mixture of 9.26 g (53 mmol) of 2,2-diethylsuccinic acid and 30 ml of acetyl chloride was heated under reflux for 1.5 hr, cooled, and concentrated in vacuo. The residue was reconcentrated twice with toluene and then dissolved in 150 ml of 1,2-dimethoxyethane. To this solution was added 7.56 g (26.4 mmol) of the (E)-3-[2-[4-(cyclohexyl)-2-thiazolyl]-ethenyl]benzeneamine and 10.9 g of sodium acetate dissolved in 150 ml of 1,2-dimethoxyethane. This reaction mixture was heated on the steam bath for 3.5 hr and then concentrated in vacuo. The residue was digested with 600 ml of water on the steam bath for 20 min. The solid was collected to give 10 g of crude product. Recrystallization from ethanol gave 3.5 g of product, mp 180°-185°. Further recrystallization from methanol gave (E)-4-[[3-[2-(4-cyclohexyl-2-thiazolyl)-ethenyl]phenyl]amino]-2-methylene-4-oxobutanoic acid as off-white needles, mp 187°-189°.
Reaction SMILES: [CH:1]([N:4]([CH:27]([CH3:29])[CH3:28])[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=1)=[C:10]2[CH2:24][CH2:25][NH2:26])=[O:6])([CH3:3])[CH3:2].S([O-])([O-])(=O)=O.[Mg+2].[N:36]1[CH:41]=[CH:40][CH:39]=[C:38]([C:42]2[S:46][C:45]([CH:47]=O)=[CH:44][CH:43]=2)[CH:37]=1.[C:49]([BH3-])#[N:50].[Na+]>C(O)(=O)C.CO.C(Cl)(Cl)Cl>[CH:27]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]1[CH:17]=[C:18]([CH3:23])[CH:19]=[C:20]([CH3:22])[CH:21]=1)=[C:10]2[CH2:24][CH2:25][N:26]([CH2:47][C:45]1[S:46][C:42]([C:38]2[CH:37]=[N:50][CH:49]=[CH:40][CH:39]=2)=[CH:43][CH:44]=1)[CH2:47][C:45]1[S:46][C:42]([C:38]2[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=2)=[CH:43][CH:44]=1)=[O:6])([CH3:29])[CH3:28]
Reactant: O=Cc1ccc(-c2cccnc2)s1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)N(C(C)C)C(C)C)cc3c2CCN)c1
Reactant: [BH3-]C#N
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)N(C(C)C)C(C)C)cc3c2CCN(Cc2ccc(-c3cccnc3)s2)Cc2ccc(-c3cccnc3)s2)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indole-5-carboxylic acid diisopropylamide in a mixture of dry chloroform and methanol at 0° C. is added magnesium sulfate followed by 2.5 equivalents of 5-pyridin-3-yl-thiophene-2-carbaldehyde and the mixture stirred at low temperature. After 40 minutes, acetic acid is added followed by a solution of sodium cyanoborohydride and the mixture allowed to warm to room temperature. After completion, the reaction is quenched by the addition of saturated aqueous sodium bicarbonate, extracted with methylene chloride and the combined organics washed sequentially with water and brine. Purification of the concentrate by preparative tlc on silica gel gives the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[N:8]([CH2:16][O:17][CH3:18])[C:7]=2[CH:19]=1.[Cl-].[NH4+].[C:22](OCC)(=[O:24])C>C(OCC)=O>[CH3:18][O:17][CH2:16][N:8]1[C:7]2[CH:19]=[C:3]([CH2:2][NH:1][CH:22]=[O:24])[CH:4]=[CH:5][C:6]=2[S:11][C:10]2[N:12]=[CH:13][CH:14]=[N:15][C:9]1=2
Reactant: CCOC(C)=O
Reactant: COCN1c2cc(CN)ccc2Sc2nccnc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC=O
Product: COCN1c2cc(CNC=O)ccc2Sc2nccnc21

Procedure:
250 mg of 8-aminomethyl-10-methoxymethyl-10H-pyrazino-[2,3-b][1,4]benzothiazine was heated under reflux in 10 ml of ethyl formate for 3 hours. Then the reaction mixture was brought back to room temperature and distributed into an aqueous solution of ammonium chloride and ethyl acetate. The organic layer was extracted, washed with water and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the crystals thus precipitated were filtered after adding diisopropyl ether. Thus 230 mg of the title compound was obtained as yellow crystals.