Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:34])[N:24]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:25][CH2:26][CH2:27][OH:28])[CH:20]=[C:19]([Cl:35])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[Cl:35][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=1)[C:23]([N:24]([CH:29]1[CH2:30][CH2:31][CH2:32][CH2:33]1)[CH2:25][CH2:26][CH2:27][OH:28])=[O:34]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCO)C2CCCC2)c1)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1cc(Cl)cc(OCCNc2ccncc2)c1)N(CCCO)C1CCCC1
Reaction time: 1 h

Procedure:
A solution of (2-{3-chloro-5-[cyclopentyl-(3-hydroxy-propyl)-carbamoyl]-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tertbutyl ester (0.07 g) in a mixture of dichloromethane (2 ml) and trifluoroacetic acid (2 ml) was stored at room temperature for 1 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.011 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:45][CH3:46])[CH2:4][NH:5][C@:6]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:38])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34]C)=[O:33])=[CH:30][CH:29]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1.[OH-].[Na+]>O1CCOCC1.CO>[CH3:1][O:2][CH:3]([O:45][CH3:46])[CH2:4][NH:5][C@:6]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:38])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:36][CH:37]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCC(OC)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(NCC(OC)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 85 °C
Yield: 65 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2,2-dimethoxyethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.025 g, 0.040 mmol) in 1,4-dioxane (1 mL) was added NaOH (1N) (0.198 mL, 0.198 mmol). The mixture was heated to 85° C. After 6 h of heating, the mixture was cooled to rt, the reaction mixture was diluted with MeOH and was purified by prep HPLC. The fractions containing the expected product were combined and were concentrated under reduced pressure to give the title compound (17 mg, 0.026 mmol, 66.1% yield) as a clear film. LCMS: m/e 618.8 (M+H)+, 2.28 min (method 11). 1H NMR (500 MHz, CHLOROFORM-d) d ppm 7.99 (d, J=7.93 Hz, 2H), 7.20 (d, J=7.93 Hz, 2H), 5.28 (d, J=4.88 Hz, 1H), 5.12 (br. s., 1H), 4.72 (s, 1H), 4.58 (s, 1H), 4.53 (t, J=5.49 Hz, 1H), 3.44 (s, 3H), 3.41 (s, 3H), 2.64-2.74 (m, 2H), 2.60 (dd, J=11.44, 6.56 Hz, 1H), 1.97-2.13 (m, 2H), 1.86-1.95 (m, 2H), 1.81 (dd, J=12.51, 8.24 Hz, 1H), 1.68 (s, 3H), 1.11 (s, 3H), 0.98 (s, 3H), 0.97 (br. s., 3H), 0.95-1.72 (m, 17H), 0.93 (br. s., 6H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8](Br)Br)[N:5]=[C:4]([CH:11](Br)Br)[N:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[CH3:1][C:2]1[N:7]=[C:6]([CH:8]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:5]=[C:4]([CH:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1
Reactant: Cc1nc(C(Br)Br)nc(C(Br)Br)n1
Reactant: C1COCCN1
Product: Cc1nc(C(N2CCOCC2)N2CCOCC2)nc(C(N2CCOCC2)N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 2-methyl-4,6-Bis-(dibromomethyl)-s-triazine (0.4 g, 0.91 mmol) and morpholine (8 mL) was stirred at room temperature for 2 days and then heated to 70-80° C. and stirred for an additional 2 hours. The precipitate was filtered and the filtrate was evaporated under reduced pressure to remove the excess morpholine. The solid residue was recrystallized from ethyl acetate giving 0.40 g (95%) of the title compound as big cubic colorless crystals.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:17][C:18]1[CH:19]=[C:20]([CH:30]=[CH:31][CH:32]=1)[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]([C:14](=[O:16])[NH:29][C:26]1[CH:25]=[CH:24][C:23]([O:22][CH2:21][C:20]2[CH:30]=[CH:31][CH:32]=[C:18]([F:17])[CH:19]=2)=[CH:28][CH:27]=1)[CH2:10][CH2:11][S:12][CH3:13])([CH3:5])([CH3:6])[CH3:7]
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(OCc2cccc(F)c2)cc1

Procedure:
Condensation of (S)-BOC-methionine and 4-(3-fluorobenzyloxy)-phenylamine [Example 3b)] by HBTU yields the (S)-{1-[4-(3-fluoro-benzyloxy)-phenylcarbamoyl]-3-methylsulfanyl-propyl}-carbamic acid tert-butyl ester as a light yellow solid; MS: m/e=449 (M+H)+. The following methylation and cyclisation yields the (S)-{1-[4-(3-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-carbamic acid tert-butyl ester as a white solid; MS: m/e=401 (M+H)+. The cleavage of the BOC-group yields the (S)-3-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one hydrochloride as a white solid; MS: m/e=301 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[C:5]([C:11]([F:14])([F:13])[F:12])[NH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1.CC(C)([O-])C.[K+].[CH2:29]([O:31][CH2:32]Cl)[CH3:30]>O1CCCC1>[Br:1][C:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[C:5]([C:11]([F:14])([F:12])[F:13])[N:4]([CH2:32][O:31][CH2:29][CH3:30])[C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1
Reactant: CCOCCl
Reactant: FC(F)(F)c1[nH]c(-c2ccc(Cl)c(Cl)c2)c(Br)c1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOCn1c(-c2ccc(Cl)c(Cl)c2)c(Br)c(C(F)(F)F)c1C(F)(F)F
Yield: 93.8 %

Procedure:
To a chilled solution of 3-bromo-2-(3,4-dichlorophenyl)-4,5-bis(trifluoromethyl)pyrrole (0.854 g, 2 mmol) and tetrahydrofuran is added potassium tert-butoxide (0.247 g, 2.2 mmol). After stirring at ice bath temperature for 15 minutes chloromethyl ethyl ether (0.208 g, 2.2 mmol) is added to the reaction mixture and the ice bath is removed. Stirring is continued for 11/2 hours then the reaction mixture is diluted with water and extracted with ether. The combined organic extracts are washed sequentially with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow liquid (0.91 g, 94%). Identified by IR and NMR spectral analyses.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][CH:18]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]#[N:25])[CH2:19]1.N.[H][H]>[Ni].CO>[NH2:25][CH2:24][CH2:23][N:20]1[CH2:21][CH2:22][CH:18]([NH:17][C:9]2[N:8]([CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)[CH2:19]1
Reactant: N#CCN1CCC(Nc2nc3ccccc3n2Cc2ccccn2)C1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccccn2)C1
Yield: 91 %

Procedure:
A mixture of 11 parts of 3-[[1-(2-pyridinylmethyl)-1H-benzimidazol-2-yl]amino]-1-pyrrolidineacetonitrile and 320 parts of methanol, saturated with ammonia was hydrogenated at normal pressure and at room temperature with 3 parts of Raney-nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was solidified in 2,2'-oxybispropane while stirring. The product was filtered off and dried, yielding 10 parts (91%) of N-[1-(2-aminoethyl)-3-pyrrolidinyl]-1-(2-pyridinylmethyl)-1H-benzimidazol-2-amine; mp. 130° C. (compound 138).
Reaction SMILES: [C:1]1([CH:11]([CH2:16][C:17]([OH:19])=[O:18])[CH2:12][C:13]([OH:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:20](O)CC(C)C.CC(C)=O.O>>[CH3:20][O:14][C:13](=[O:15])[CH2:12][C@H:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH2:16][C:17]([OH:19])=[O:18]
Reactant: CC(C)CCO
Reactant: O=C(O)CC(CC(=O)O)c1cccc2ccccc12
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)C[C@@H](CC(=O)O)c1cccc2ccccc12

Procedure:
Formula C16H16O4. Yield 62%; TLC (isoamyl alcohol-acetone-H2O 5:2:2) Rf. 0.65 (N.B.: 3-(1-naphthyl) glutaric acid has Rf. 0.52 in the same eluent).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16]([CH2:18][C:19]([OH:21])=[O:20])=[O:17])[CH3:15])=[CH:10][CH:9]=1.[CH2:22](N(CC)CC)C.COC(Cl)=O>C(Cl)(Cl)Cl>[CH3:22][O:20][C:19](=[O:21])[CH2:18][S:16]([CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:9][CH:10]=1)[CH3:15])=[O:17]
Reactant: CC(c1ccc(-c2ccccc2F)cc1)S(=O)CC(=O)O
Reactant: CCN(CC)CC
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)CS(=O)C(C)c1ccc(-c2ccccc2F)cc1
Reaction time: 0.5 h

Procedure:
306 mgm (1 millimol) of [1-(2'-fluoro-4-biphenylyl)-ethylsulfinyl]-acetic acid and 0.15 ml of triethylamine were dissolved in 2 ml of chloroform, and 0.15 ml of chloroformic acid methyl ester was added to the solution at room temperature. After 30 minutes of standing, the mixture was washed with water, dried and evaporated, and the residue was recrystallized from 1 ml of isopropanol. Yield: 200 mgm (62.5% of theory); m.p. 75°-78° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[C:13]([C:15]([OH:17])=O)[N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[NH2:30][C:31]1[S:32][CH2:33][CH2:34][N:35]=1>>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[NH:11][C:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)=[N:14][C:13]=2[C:15]([NH:30][C:31]2[S:32][CH2:33][CH2:34][N:35]=2)=[O:17])=[CH:23][CH:22]=1
Reactant: NC1=NCCS1
Reactant: COc1ccc(-c2[nH]c(-c3ccc([N+](=O)[O-])cc3)nc2C(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: COc1ccc(-c2[nH]c(-c3ccc([N+](=O)[O-])cc3)nc2C(=O)NC2=NCCS2)cc1

Procedure:
2-(4-Nitrophenyl)-5-(4-methoxyphenyl)imidazole-4-carboxylic acid, 1 M hydrochloric acid—ether solution, thionyl chloride and 2-aminothiazoline were reacted and treated in the same manner as in Example 1 to give 5-(4-methoxyphenyl)-2-(4-nitrophenyl)-N-(2-thiazolinyl)imidazole-4-carboxamide.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.ClCC1[O:46][C:47]([CH3:50])=[N:48][N:49]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[O:46][C:47]([CH3:50])=[N:48][N:49]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: Cc1nnc(CCl)o1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: Cc1nnc(Cn2nnc3c(N4CCC(F)(F)C4)nc(C(C)(C)C)nc32)o1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(chloromethyl)-5-methyl-1,3,4-oxadiazole and isolated as colorless gum. MS(m/e): 379.3 (MH+).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=3)=[C:7]([CH:14]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:15]([O:17]C)=[O:16])[N:8]([CH3:13])[C:9]2=[O:12])=[CH:4][CH:3]=1.[CH3:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1.FC(F)(F)C([O-])=O>>[CH3:22][C:20]([O:19][CH:14]([C:7]1[N:8]([CH3:13])[C:9](=[O:12])[C:10]2[C:5]([C:6]=1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=1)=[CH:4][CH:3]=[C:2]([C:36]1[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=1)[CH:11]=2)[C:15]([OH:17])=[O:16])([CH3:21])[CH3:23]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(Br)cc2c(=O)n1C
Agent: O=C([O-])C(F)(F)F
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3cc(-c4cnn(C)c4)ccc23)cc1C

Procedure:
The title compound was prepared in two steps in a manner similar to that described in Example 191 from methyl [7-bromo-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl][(1,1-dimethylethyl)oxy]acetate and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and was isolated as a pale yellow solid (20 mg, 57%) after reverse phase chromatography as the trifluoroacetate salt: 1H NMR (400 MHz, CHLOROFORM-d) δ=8.59 (s, 1 H), 7.91 (s, 1 H), 7.82 (s, 1 H), 7.70-7.53 (m, 1 H), 7.45-7.31 (m, 1 H), 7.32-7.22 (m, 1 H), 7.17 (dd, J=8.5, 12.4 Hz, 1 H), 7.12-7.03 (m, 1 H), 5.36 (d, J=1.0 Hz, 1 H), 4.00 (s, 3 H), 3.73 (s, 3 H), 2.38 (s, 3 H), 2.33 (d, J=2.5 Hz, 3 H), 1.07 (d, 9 H); LC/MS (m/z) ES+=474 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16]C)=[O:15])=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:4]([F:18])[CH:3]=1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:4]([F:18])[CH:3]=1
Reactant: COC(=O)c1cnccc1-c1ccc(Cl)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cnccc1-c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.7 %

Procedure:
To a solution of methyl 4-(4-chloro-2-fluorophenyl)nicotinate (1 g, 3.76 mmol) in MeOH (10 mL) and water (10 mL) was added NaOH (0.602 g, 15.06 mmol) and the solution stirred at room temperature for 2 h. The volatile organic solvent was evaporated under reduced pressure. The reaction mixture was cooled to 0° C. and acidified with 50% aqueous HCl. The precipitated so formed was collected by vacuum filtration to yield 4-(4-chloro-2-fluorophenyl)nicotinic acid (0.3 g, 1.192 mmol, 30% crude yield) as an off-white solid which was carried directly into the next step. 1H NMR (400 MHz, CD3OD) δ 9.12 (s, 1H), 8.78 (d, J=5.20 Hz, 1H), 7.29-7.48 (m, 4H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH:18]=[CH2:19])[CH:16]=3)[O:11][C:10](=[O:20])[CH:9]=2)[CH2:3][CH2:2]1.[CH3:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[CH3:30])[CH:25]=O>>[CH3:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[CH3:30])[CH2:25][N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH:18]=[CH2:19])[CH:16]=3)[O:11][C:10](=[O:20])[CH:9]=2)[CH2:3][CH2:2]1
Reactant: C=Cc1ccc2oc(=O)cc(NC3CCNCC3)c2c1
Reactant: Cc1ccc(C=O)cc1C
Product: C=Cc1ccc2oc(=O)cc(NC3CCN(Cc4ccc(C)c(C)c4)CC3)c2c1

Procedure:
4-(Piperidin-4-ylamino)-6-vinyl-chromen-2-one and 3,4-dimethylbenzaldehyde were allowed to react in a manner analogous to that previously described to give the title compound. 1H NMR (500 MHz, DMSO-D6) δ ppm 1.65 (m, 2H) 1.92 (m, 2H) 2.08 (m, 2H) 2.20 (m, 6H) 2.84 (m, 2H) 3.42 (m, 2H) 3.50 (m, 1H) 5.23 (s, 1H) 5.34 (m, 1H) 5.94 (m, 1H) 6.76 (m, 1H) 7.01 (m, 1H) 7.07 (m, 2H) 7.24 (m, 2H) 7.69 (m, 1H) 8.20 (m, 1H); MS (DCI/NH3) m/z 389 [M+H]+.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:7][C:6]2[C:17]3[C:22]([CH:23]=[CH:24][C:5]=2[N:4]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[C:3]1=[O:30])=[CH:21][CH:20]=[CH:19][CH:18]=3.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>N1C=CC=CC=1>[CH2:35]([O:34][C:32]([O:1][C@@H:2]1[C@H:8]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[S:7][C:6]2[C:17]3[C:22]([CH:23]=[CH:24][C:5]=2[N:4]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[C:3]1=[O:30])=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:33])[CH3:36]
Reactant: CCOC(=O)Cl
Reactant: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)N(CCN(C)C)C(=O)[C@@H]2O)cc1
Solvent: c1ccncc1
Product: CCOC(=O)O[C@H]1C(=O)N(CCN(C)C)c2ccc3ccccc3c2S[C@H]1c1ccc(OC)cc1
Yield: 96.1 %

Procedure:
To a solution of 0.8 g of (±)-cis-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-5-[2-(dimethylamino)ethyl]naphtho[1,2-b]-1,4-thiazepin-4(5H)-one in 10 mL of pyridine (dried over potassiuwm hydroxide) in an ice-bath, 0.4 g of ethyl chloroformate was added dropwise then stored in the freezer overnight. The mixture was concentrated under reduced pressure and the residue was partitioned between ether and dilute sodium hydroxide. The ether solution was washed with brine then dried (magnesium sulfate) and removal of the solvent gave 0.9 g (97%) of (±)-cis-3-[(ethoxycarbonyl)oxy]-2,3-dihydro-2-(4-methoxyphenyl)-5-[2-(dimethylamino)ethyl]naphtho[1,2-b]-1,4-thiazepin-4(5H)-one. A sample was crystallized from ether--pet. ether, mp 168°-169°.
Reaction SMILES: Cl[C:2]([S:4]Cl)=[O:3].[CH3:6][O:7][CH2:8][C:9]([NH2:11])=[O:10]>C1(C)C=CC=CC=1>[CH3:6][O:7][CH2:8][C:9]1[O:10][C:2](=[O:3])[S:4][N:11]=1
Reactant: COCC(N)=O
Reactant: O=C(Cl)SCl
Solvent: Cc1ccccc1
Product: COCc1nsc(=O)o1
Temperature: 95 °C
Yield: 79.9 %

Procedure:
Chlorocarbonylsulfenyl chloride (7.35 g) was added to a suspension of methoxyacetamide (5 g) in toluene (30 cm3). The reaction mixture was stirred and heated at 90-100° C. for 5 hours, then cooled. The solvent was removed by evaporation under reduced pressure to give a brown gum (6.6 g). M+ =147; 1H NMR (DMSO-d6): δ3.30(3H,s); 4.30(2H,s) which was used in the next step without further purification.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]=[N:12][N:13]2[CH:17]=[N:16][NH:15][C:14]2=[O:18])[CH:6]=1>N1C=CC=CC=1>[C:1]([N:15]1[C:14](=[O:18])[N:13]([N:12]=[CH:11][C:7]2[CH:6]=[N:5][CH:10]=[CH:9][CH:8]=2)[CH:17]=[N:16]1)(=[O:3])[CH3:2]
Reactant: O=c1[nH]ncn1N=Cc1cccnc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)n1ncn(N=Cc2cccnc2)c1=O
Reaction time: 14 h

Procedure:
2.4 g of acetyl chloride are added to a suspension of 3.8 g of 4-(pyridin-3-ylmethyleneamino)-1,2,4-triazol-3-one in 50 ml of pyridine. The resulting solution is stirred for 14 hours at 20° and then concentrated by evaporation. Water is added to the residue and extraction is carried out with chloroform. The organic phase is concentrated by evaporation and the residue is stirred with ether. The crystals are filtered off with suction and then dried under a high vacuum. 4 g of the title compound having a melting point of 164-166° are thus obtained.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[CH:17]=[C:18]([C:25]([OH:27])=[O:26])[CH:19]=[C:20]([CH:24]=1)[C:21]([OH:23])=[O:22].O>CO.[N+]([O-])([O-])=O.[Ag+]>[C:21]([C:20]1[CH:24]=[C:16]([N:15]=[C:3]2[CH:4]=[C:5]3[C:14](=[N:13][C:12]4[C:7]([S:6]3)=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH:1]=[CH:2]2)[CH:17]=[C:18]([C:25]([OH:27])=[O:26])[CH:19]=1)([OH:23])=[O:22]
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Reactant: Nc1cc(C(=O)O)cc(C(=O)O)c1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(N=c2ccc3nc4ccccc4sc-3c2)cc(C(=O)O)c1
Temperature: 10 °C
Reaction time: 0.08 h
Yield: 82.4 %

Procedure:
Phenothiazine (1.0 g, 5.0 mmol) and 5-aminoisophthalic acid (0.9 g, 5.0 mmol) were dissolved in MeOH (200 mL), cooled to 10° C. and treated with 1 M aqueous AgNO3 (30 mL, 30 mmol). After stirring at 10° C. for 30 minutes H2O (40 mL) was added and stirring continued for an additional 5 minutes. The solid product was then collected by filtration and washed with H2O (50 mL). The solid was dissolved in MeOH (500 mL) containing concentrated aqueous NH4OH (10 mL), stirred for 20 minutes then filtered to remove Ag. The filtrate was concentrated to ca. half its original volume under reduced pressure and refrigerated overnight at 5° C. The mixture was then filtered through Celite (Celite Corp.) and concentrated in vacuo until solid began to separate. The resulting solution (ca. 100 mL) was again filtered through Celite, diluted with ethyl acetate (900 mL) and allowed to stand for 15 minutes. The red solid that separated was collected by filtration, washed with ethyl acetate and dried to give 18(1.55 g, 82.5%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH2:21]([N:23]([CH2:38][CH3:39])[CH2:24][CH2:25][NH:26][C:27]([C:29]1[C:33]([CH3:34])=[C:32]([CH:35]=O)[NH:31][C:30]=1[CH3:37])=[O:28])[CH3:22]>C(O)C.N1CCCCC1>[CH2:38]([N:23]([CH2:21][CH3:22])[CH2:24][CH2:25][NH:26][C:27]([C:29]1[C:33]([CH3:34])=[C:32]([CH:35]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=3)[NH:13][C:12]2=[O:18])[NH:31][C:30]=1[CH3:37])=[O:28])[CH3:39]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(C(F)(F)F)c4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 51.9 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (69.0 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 2,4-dimethyl-5-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (68 mg, 52%).
Reaction SMILES: N1([CH:7]=[C:8]([C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[S:12])[C:9]#[N:10])CCOCC1.I[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].CCN(C(C)C)C(C)C>C(#N)C>[C:9]([C:8]1[CH:7]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[S:12][C:11]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)#[N:10]
Reactant: CCOC(=O)CI
Reactant: N#CC(=CN1CCOCC1)C(=S)N1CCOCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(C#N)c(N2CCOCC2)s1
Reaction time: 0.17 h
Yield: 86.7 %

Procedure:
A mixture of 3-morpholin-4-yl-2-(morpholin-4-ylcarbonothioyl)acrylonitrile (0.07 g, 0.26 mmol), ethyl iodoacetate (0.034 mL, 0.29 mmol) and DIPEA (0.091 mL, 0.52 mmol) in ACN (0.55 mL) was subjected to MWI at 120° C. for 10 min. The crystals formed upon cooling were filtered, washed with cold MeOH and diethyl ether to give ethyl 4-cyano-5-morpholin-4-ylthiophene-2-carboxylate (0.06 g, 87%). LCMS: (AA) ES+ 267.1. 1H NMR (400 MHz, CDCl3) δ: 7.62 s, 1H), 4.30 (q, 2H), 3.85-3.87 (m, 4H), 3.58-3.60 (m, 4H) and 1.34 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9](=[O:11])[CH3:10].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:27]1([CH2:33][S:34][CH:35]([C:39](O)=[O:40])[C:36](O)=[O:37])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[O:11][C:36](=[O:37])[C:35]([S:34][CH2:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:39]([OH:40])[CH:10]=1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Reactant: CC(=O)c1c(C)cccc1C
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccc(C)c1-c1cc(O)c(SCc2ccccc2)c(=O)o1

Procedure:
The title compound was prepared by Method A using 2',6'-dimethyl acetophenone (0.785 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (0.977 g, 5.84 mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol), THF (58 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). m.p. 140°-143° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.15 (s, 6 H), 3.99 (s, 2 H), 6.12 (s, 1 H), 7.22 (m, 8H).