Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15][O:16]C(=O)C)=[CH:14][C:9]=2[O:8][CH:7]=1)C.[NH3:21]>>[OH:16][CH2:15][C:13]1[CH:12]=[CH:11][C:10]2[C:6]([CH2:5][C:4]([NH2:21])=[O:3])=[CH:7][O:8][C:9]=2[CH:14]=1
Reactant: N
Reactant: CCOC(=O)Cc1coc2cc(COC(C)=O)ccc12
Product: NC(=O)Cc1coc2cc(CO)ccc12
Temperature: 60 °C

Procedure:
(6-Acetoxymethyl-benzofuran-3-yl)-acetic acid ethyl ester (0.80 g, 2.90 mmol) was added to liquid ammonia at −78° C., the reaction flask was sealed and heated at 60° C. for 6 days. The reaction mixture was cooled, the excess of ammonia was allowed to evaporate and the residue was washed with in hexane and precipitated to give the 2-(6-hydroxymethyl-benzofuran-3-yl)-acetamide as an off white solid (0.54 g, 90%). 1H NMR (DMSO-d6, 400 MHz) 3.46 (s, 2H), 4.60 (d, J=5.6 Hz, 1H), 5.25 (t, J=5.6 Hz, 1H), 6.98 (brs, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.47 (s, 1H), 7.53 (brs, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.77 (s, 1H), 13C NMR (DMSO-d6, 400 MHz) 30.8, 63.4, 109.4, 115.4, 120.0, 121.6, 127.0, 139.9, 143.4, 155.2, 171.7.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([O:34][C:35](=[O:42])[NH:36][C:37]([CH3:41])([CH3:40])[CH:38]=[CH2:39])([CH3:33])([CH3:32])[CH3:31].C(N(CC)CC)C>CN(C=O)C>[C:30]([O:34][C:35](=[O:42])[NH:36][C:37]([CH3:41])([CH3:40])/[CH:38]=[CH:39]/[C:13]1[CH:12]=[CH:11][C:10]([N:16]2[CH2:17][C:18](=[O:29])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[S:20]2(=[O:22])=[O:21])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: C=CC(C)(C)NC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(/C=C/c1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (1.4 g, 3 mmol) in DMF (20 mL) is added (1,1-dimethylallyl)-carbamic acid tert-butyl ester (560 mg, 3 mmol), triethylamine (0.7 mL, 5 mmol) and tert-di(mu-acetato) bis[o-(di-o-tolylphosphino)benzyl]dipalladium (II) (25 mg). The mixture is stirred at 80° C. for 18 h. The solvent is removed under reduced pressure and the residue is purified by flash chromatography to give the title compound
Reaction SMILES: [C:1]1([S:7][CH:8]2[N:11]([CH2:12][C:13](=[O:22])[CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10](=[O:23])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:32])C=1.S([O-])([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>ClCCl>[C:1]1([S:7]([CH:8]2[N:11]([CH2:12][C:13](=[O:22])[CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10](=[O:23])[CH2:9]2)=[O:32])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(CCc1ccccc1)CN1C(=O)CC1Sc1ccccc1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CCc1ccccc1)CN1C(=O)CC1S(=O)c1ccccc1
Reaction time: 0.67 h
Yield: 27 %

Procedure:
A solution of 4-phenylthio-N-(4-phenyl-2-oxobutyl)azetidin-2-one (2.3 g, 7 mmol) in dichloromethane (80 ml) was cooled to -50 to -60° C. and a solution of m-chloroperbenzoic acid (1.5 g, 9 mmol) in dichloromethane (60 ml) was added dropwise with stirring over 40 min. After a further 2 hr. at -50 to -60° C. another portion of m-chloroperbenzoic acid (61 mg, 0.35 mmol) was added and stirring continued for 30 min. The reaction mixture was then shaken with a mixture of saturated aqueous sodium sulphite and saturated sodium hydrogen carbonate and the organic layer collected, dried (MgSO4) and evaporated. Crystallisation from ether then dichloromethane/ether gave the product as a white crystalline solid, mp 125-6° C., 27% yield 1H NMR δ (CDCl3), 2.78 (2H, m, CH2CO), 2.87 (1H, dd, J=4.7, 15.0 Hz, H3a), 2.94 (2H, m, CH2Ph), 3.42 (1H, dd, J=2.0, 15.0 Hz, H3b), 3.85, 4.46 (each 1H, d, J=18.9 Hz, CH2N), 4.73 (1H, dd, J=2.1, 4.7 Hz, H4), 7.17-7.35 (5H, m, Ph--H), 7.55 (5H, s, SOPh--H). Found: C, 66.7; H, 5.7; N, 4.2%; C19H19NO3S requires: C, 66.8; H, 5.6; N, 4.1%
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:16][CH2:15][C@H:14]([CH2:17][OH:18])[CH2:13]2)[C:9]2[C:8](=[O:19])[N:7]([CH3:20])[CH:6]=[N:5][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:31][CH:30]=2)O1.C([O-])([O-])=O.[K+].[K+].CC(O)C>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.O>[OH:18][CH2:17][C@H:14]1[CH2:15][CH2:16][N:12]([C:10]2[C:9]3[C:8](=[O:19])[N:7]([CH3:20])[CH:6]=[N:5][C:4]=3[CH:3]=[C:2]([C:29]3[CH:30]=[CH:31][C:32]([N:35]4[CH2:36][CH2:37][O:38][CH2:39][CH2:40]4)=[CH:33][CH:34]=3)[N:11]=2)[CH2:13]1
Reactant: Cn1cnc2cc(Cl)nc(N3CC[C@H](CO)C3)c2c1=O
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)cc2)OC1(C)C
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: CC(C)O
Solvent: O
Product: Cn1cnc2cc(-c3ccc(N4CCOCC4)cc3)nc(N3CC[C@H](CO)C3)c2c1=O
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-7-chloro-5-(3-(hydroxymethyl)pyrrolidin-1-yl)-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (26 mg, 0.088 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine (28 mg, 0.097 mmol), Pd(PPh3)4 (10.2 mg, 0.0088 mmol), K2CO3 (36 mg, 0.26 mmol), 2-propanol (3 mL) and H2O (1 mL) was stirred at 90° C. overnight. The reaction mixture was cooled to room temperature and worked-up. The residue was purified on slilica gel flash column chromatography (eluent: 0-10% methanol in dichloromethane) to afford (S)-5-(3-(hydroxymethyl)pyrrolidin-1-yl)-3-methyl-7-(4-morpholinophenyl)pyrido[4,3-d]pyrimidin-4(3H)-one as a slightly yellow solid. 1H NMR (CDCl3) δ (ppm) 8.06 (d, 2H), 8.01 (s, 1H), 7.19 (s, 1H), 6.96 (d, 2H), 3.91-3.81 (m, 5H), 3.78-3.65 (m, 4H), 3.65-3.58 (m, 1H), 3.50 (s, 3H), 3.27-3.24 (m, 4H), 2.57-2.47 (m, 1H), 2.15-2.07 (m, 1H), 1.90 (s, br, 1H), 1.82-1.72 (m, 1H); HPLC-MS calculated C23H27N5O3 (M+H+): 422.22, found: 422.20.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:9]=[C:8]([Cl:10])[C:7]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:6][C:4]=1[NH2:5].[C:15]1([CH2:21][CH2:22][CH2:23][CH2:24][C:25](O)=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Cl:10][C:8]1[C:7]([S:11](=[O:13])(=[O:14])[NH2:12])=[CH:6][C:4]2[NH:5][C:25]([CH2:24][CH2:23][CH2:22][CH2:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:2][C:3]=2[CH:9]=1
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1N
Reactant: O=C(O)CCCCc1ccccc1
Agent: Cl
Product: NS(=O)(=O)c1cc2[nH]c(CCCCc3ccccc3)nc2cc1Cl
Yield: 11.1 %

Procedure:
To 25 ml of 6 N hydrochloric acid was added 5.5 g of 2-amino-4-chloro-5-sulfamylaniline and 6.6 g of 5-phenylvaleric acid and the mixture refluxed for twenty-four hours. The gummy solid was collected by concentration in vacuo and then added to concentrated ammonium hydroxide. The suspension was stirred for twenty minutes, collected by filtration, and suspended in water at 50° C. The solid was collected by filtration, dissolved in methanol, brought to a boil, and charcoal added. The suspension was then filtered through two sheets of filter paper, cooled, and filtered through Celite. Recrystallization from acetonitrile provided 1.0 g of colorless crystals, m.p. 176°-180°.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][CH2:14][C:13](=[O:16])[C:12]=2[CH3:17])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC.C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH2:15][CH2:14][CH:13]([OH:16])[C:12]=2[CH3:17])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1=C(c2ccc(C(C)(C)C)cc2)CCC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1=C(c2ccc(C(C)(C)C)cc2)CCC1O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 97 %

Procedure:
A solution of 25.7 g (0.12 mol) of 3-(4-t-butylphenyl)-2-methyl-2-cyclopenten-1-one (EP 0259977) dissolved in 40 mL of ether was cooled to 0° C. Added dropwise was 43.7 mL (43.7 mmol) of a solution of 1M lithium aluminum hydride in THF. After stirring 20 min, the mixture was quenched by dropwise addition of saturated aqueous NaHSO3. The mixture was dried (MgSO4), solids were filtered and the filtrate was stripped to afford 26.8 g of 1-(4-t-butylphenyl)-2-methyl-cyclopenten-3-ol as an oil which slowly solidified.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:13][CH3:14])[C:11]=1F)[N:8]([CH2:15][CH2:16][F:17])[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[ClH:29]>CS(C)=O.C(O)C>[ClH:29].[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:13][CH3:14])[C:11]=1[N:26]1[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]1)[N:8]([CH2:15][CH2:16][F:17])[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21]
Reactant: CN1CCNCC1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(CCF)c12
Agent: Cl
Solvent: CS(C)=O
Solvent: CCO
Product: COc1c(N2CCN(C)CC2)c(F)cc2c(=O)c(C(=O)O)cn(CCF)c12
Temperature: 70 °C
Reaction time: 6 h

Procedure:
0.11 g (0.0004 mole) of 6,7-difluoro-1-(2-fluoroethyl)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (prepared as described in Preparation 15) and 0.20 g (0.002 mole) of N-methylpiperazine were dissolved in 3 ml of dimethyl sulfoxide, and the mixture was stirred at 70° C. for 6 hours. At the end of this time, the solvent and excess N-methylpiperazine were distilled off at the same temperature and under reduced pressure, and the residue was washed with ethyl acetate to give a pale-yellow powder. This powder was suspended in a mixture of 20 ml of ethanol and 1 ml of concentrated hydrochloric acid, and the suspension was concentrated by evaporation under reduced pressure. 20 ml of water were added to the residue, and the mixture was filtered to remove insoluble materials. The filtrate was concentrated by evaporation under reduced pressure to give 30 mg of 6-fluoro-1-(2-fluoroethyl)-8-methoxy-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride as a colorless powder melting at 270°-272° C. (with decomposition).
Reaction SMILES: Br[CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1.[O:17]1CCCC1>O.CCOCC.[B-](F)(F)(F)F.[Ag+]>[OH:17][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1
Reactant: O=C(O)CCCCCCC1=CC(Br)CC1=O
Reactant: C1CCOC1
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCOCC
Product: O=C(O)CCCCCCC1=CC(O)CC1=O
Reaction time: 1 h

Procedure:
To a stirred solution of 56.0 g. of crude 4-bromo-2-(6-carboxyhexyl)cyclopent-2-en-1-one (Example 93) in 400 ml. of tetrahydrofuran and 133 ml. of water at 3° C. is added 44.1 g. (0.226 moles) of silver fluoborate during 25 minutes. The mixture is stirred at 0°-5° C. for 60 minutes, diluted with water and ether, and filtered. The aqueous portion of the filtrate is saturated with solid sodium chloride and extracted with additional ether. The combined organic phases and washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. Column chromatography of the residue gives the subject compound as a mixture with 4-hydroxy-2-(6-carboxyhexyl)cyclopent-2-en-1-one. NMR (CDCl3) 3.60 (multiplet, O-methylene hydrogens) and 4.60 f (multiplet, O-methine hydrogen).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:18][C@H:19]([CH3:22])[CH2:20][OH:21])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([S:14](F)(=[O:16])=[O:15])[S:12][CH:13]=2)=[N:6][CH:7]=1.[NH2:23][CH2:24][CH:25]1[CH2:27][CH2:26]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.CC(O)CC>[CH:25]1([CH2:24][NH:23][S:14]([C:11]2[S:12][CH:13]=[C:9]([NH:8][C:5]3[N:4]=[C:3]([NH:18][CH:19]([CH3:22])[CH2:20][OH:21])[C:2]([Br:1])=[CH:7][N:6]=3)[CH:10]=2)(=[O:16])=[O:15])[CH2:27][CH2:26]1
Reactant: C[C@H](CO)Nc1nc(Nc2csc(S(=O)(=O)F)c2)ncc1Br
Reactant: NCC1CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCC(C)O
Product: CC(CO)Nc1nc(Nc2csc(S(=O)(=O)NCC3CC3)c2)ncc1Br

Procedure:
A reaction mixture of 130 mg (0.31 mmol) of (R)-4-[5-bromo-4-(2-hydroxy-1-methyl-ethylamino)-pyrimidin-2-ylamino]-thiophene-2-sulfonyl fluoride, 22 mg (0.31 mg) of aminomethylcyclopropane, 43 μl (0.31 mmol) of triethylamine as well as 38 mg (0.31 mmol) of DMAP in 2-butanol is stirred under reflux for 43 hours. It is mixed again with 22 mg (0.31 mg) of aminomethylcyclopropane, 43 μl (0.31 mmol) of triethylamine as well as 38 mg (0.31 mmol) of DMAP and stirred for another 24 hours under reflux. After cooling, the batch is purified by chromatography (Flashmaster II, DCM/ethanol 95:5), and the crude product that is obtained is recrystallized (ethanol/diisopropyl ether). 35 mg (0.08 mmol, 26% of theory) of the product 4-[5-bromo-4-(2-hydroxy-1-methyl-ethylamino)-pyrimidin-2-ylamino]-thiophene-2-sulfonic acid cyclopropylmethyl-amide is obtained.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:24]=[CH:23][C:11]2[CH2:12][CH2:13][N:14]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:16][C:10]=2[C:9]=1O.CI>CC(C)=O>[Br:7][C:8]1[CH:24]=[CH:23][C:11]2[CH2:12][CH2:13][N:14]([C:17](=[O:22])[C:18]([F:19])([F:21])[F:20])[CH2:15][CH2:16][C:10]=2[C:9]=1[O:4][CH3:1]
Reactant: O=C([O-])[O-]
Reactant: O=C(N1CCc2ccc(Br)c(O)c2CC1)C(F)(F)F
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(Br)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Reaction time: 0.17 h
Yield: 98.8 %

Procedure:
Add potassium carbonate (10.214 g, 73.9 mmol) to a solution of 7-bromo-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (5.0 g, 14.8 mmol) in acetone (50 mL) and stir for 10 min. Add methyl iodide (4.2 g, 1.5 mL, 29.6 mmol) and stir the mixture overnight at room temperature. Remove the solvent in vacuo and partition the residue between water and DCM. Extract the aqueous phase twice with DCM. Combine the organic extracts, dry over Na2SO4, filter and concentrate in vacuo to obtain the desired intermediate as a solid (5.15 g, 99%). MS (ES+) m/z: 352 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[CH:13][CH:14]=2)[C:9]1=[O:31].[F:32][C:33]([F:56])([F:55])[CH2:34][NH:35][C:36]([C:38]1([CH2:51][CH2:52][CH2:53]Br)[C:50]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[C:44]2[C:39]1=[CH:40][CH:41]=[CH:42][CH:43]=2)=[O:37]>>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[CH2:23][CH2:22][N:21]([CH2:53][CH2:52][CH2:51][C:38]4([C:36](=[O:37])[NH:35][CH2:34][C:33]([F:32])([F:55])[F:56])[C:50]5[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=5[C:44]5[C:39]4=[CH:40][CH:41]=[CH:42][CH:43]=5)[CH2:20][CH2:19]3)=[CH:13][CH:14]=2)[C:9]1=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)C(=O)N(CC2CCCCO2)CC3)CC1
Reactant: O=C(NCC(F)(F)F)C1(CCCBr)c2ccccc2-c2ccccc21
Product: O=C1c2cc(N3CCN(CCCC4(C(=O)NCC(F)(F)F)c5ccccc5-c5ccccc54)CC3)ccc2CCN1CC1CCCCO1

Procedure:
Step (b) of Example 97 was repeated, except that the compound prepared in step (a) of Example 99 and the compound prepared in step (a) of Example 93 were used as the starting compounds. Thus, the title compound was prepared.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=2)[CH2:32][CH2:31]1>>[CH3:29][N:30]1[CH2:31][CH2:32][N:33]([C:36]2[CH:42]=[CH:41][C:39]([NH:40]/[C:18](=[C:6]3\[C:5](=[O:28])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=4)/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:38][CH:37]=2)[CH2:34][CH2:35]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N2CCN(C)CC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and 4-(4-methyl-piperazin-1-yl)-aniline Rf value: 0.3 (aluminium oxide, ethyl acetate) C29H30N4O3
Reaction SMILES: C[Si](C)(C)[O:3][CH2:4][CH2:5][O:6][CH2:7]I.[CH:11]([N+:18]([O-:20])=[O:19])([N+:15]([O-:17])=[O:16])[N+:12]([O-:14])=[O:13]>>[OH:3][CH2:4][CH2:5][O:6][CH2:7][C:11]([N+:18]([O-:20])=[O:19])([N+:15]([O-:17])=[O:16])[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])C([N+](=O)[O-])[N+](=O)[O-]
Reactant: C[Si](C)(C)OCCOCI
Product: O=[N+]([O-])C(COCCO)([N+](=O)[O-])[N+](=O)[O-]

Procedure:
In the next step, the iodomethyl 2-(trimethylsilyloxy)ethyl ether is reacted with nitroform to produce 2,2,2-trinitroethyl 2-hydroxyethyl ether:
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:13][C:14]([NH:16]C(OCC)=O)=S)=[N:4][C:5]([C:8]([O:10][CH2:11]C)=[O:9])=[CH:6][CH:7]=1.Cl.NO.C([N:28](C(C)C)CC)(C)C>CO>[CH3:11][O:10][C:8]([C:5]1[N:4]2[N:28]=[C:14]([NH2:16])[N:13]=[C:3]2[C:2]([Br:1])=[CH:7][CH:6]=1)=[O:9]
Reactant: CCOC(=O)NC(=S)Nc1nc(C(=O)OCC)ccc1Br
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: NO
Solvent: CO
Product: COC(=O)c1ccc(Br)c2nc(N)nn12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of N-(3-bromo-6-ethoxycarbonyl-pyridin-2-yl)-N′-ethoxycarbonyl-thiourea (2 g, 5.52 mmol) in dry methanol (10 mL) were added hydroxylamine hydrochloride (1.92 g, 27.62 mmol) and diisopropyl ethylamine (2.98 mL, 16.57 mmol) under an argon atmosphere and stirred at room temperature for 4 hours. The solid was filtered and methanol (40 mL) was added to residue. The reaction mixture was heated to reflux for 12 hours. The solvent was evaporated and the title compound was obtained as off white solid (800 mg, 53%).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.[C:9](O)(=[O:18])[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.S(=O)(=O)(O)O>C(O)(=O)C>[Br:8][C:3]1[CH:4]=[C:5]2[C:6](=[CH:1][CH:2]=1)[O:7][C:9](=[O:18])[CH2:10][CH:11]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1ccc(Br)cc1
Reactant: O=C(O)C=Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C1CC(c2ccccc2)c2cc(Br)ccc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
A solution of p-bromophenol (138 g, 0.8 mole), cinnamic acid (148 g, 1.0 mole), acetic acid (200 g) and conc. sulfuric acid was refluxed for 2 h. Volatile material was distilled at reduced pressure. The residual syrup was cooled and triturated with cold water, giving a semi-crystalline mass. This was washed extensively with water, saturated sodium carbonate and finally with water again. The material was filtered through a sintered glass funnel, and then mixed with an equal weight of ethanol. The slurry was stirred at room temperature for 1 h and then filtered. The resulting product was washed briefly with ethanol and then diisopropyl ether. After drying, 135 g (55.7%) of the title compound was isolated as white crystals, melting at 117° C.
Reaction SMILES: [CH3:1][N:2](C)[C:3]([C:5]1[S:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25](=[O:33])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[S:23])=[CH:17][C:16]=2[F:34])[CH:6]=1)=[O:4].NC[CH2:38][N:39]([CH3:47])[C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43]>>[F:34][C:16]1[CH:17]=[C:18]([NH:21][C:22]([NH:24][C:25](=[O:33])[CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[S:23])[CH:19]=[CH:20][C:15]=1[O:14][C:11]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:6]=[C:5]([C:3]([NH:2][CH2:1][CH2:38][N:39]([CH3:47])[C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:4])[S:13][C:12]=12
Reactant: CN(C)C(=O)c1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Reactant: CN(CCN)C(=O)OC(C)(C)C
Product: CN(CCNC(=O)c1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1)C(=O)OC(C)(C)C

Procedure:
Following the procedures described above for the synthesis of compound 8a (Example 1, scheme 1) but replacing dimethyl amine with tert-butyl 2-aminoethyl(methyl)carbamate, title compound 138 was obtained (13%). LRMS (M+1) 638.2 (100%).
Reaction SMILES: [C:1]([C:5]1[CH:22]=[CH:21][C:8]([C:9]([NH:11][C:12]2[CH:16]=[CH:15][S:14][C:13]=2[C:17]([O:19]C)=[O:18])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O1CCOCC1.[OH-].[Na+].Cl>C(OCC)(=O)C>[C:1]([C:5]1[CH:22]=[CH:21][C:8]([C:9]([NH:11][C:12]2[CH:16]=[CH:15][S:14][C:13]=2[C:17]([OH:19])=[O:18])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sccc1NC(=O)c1ccc(C(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccsc2C(=O)O)cc1
Reaction time: 16 h
Yield: 88.9 %

Procedure:
A mixture of methyl 3-(4-t-butylbenzoylamino)thiophene-2-carboxylate (9.67 g, 30 mmol), dioxane (75 mL) and 2 M sodium hydroxide (75 mL) was stirred for 16 h. The reaction was acidified to pH 2 with 5 M hydrochloric acid. The mixture was diluted with ethyl acetate and the aqueous layer was extracted with ethyl acetate (3 times). The combined organic layers was magnesium sulfate dried, filtered, and concentrated to afford the title compound as a solid (8.09 g, 89%); NMR(CDCl3) d 1.36(s, 9H), 7.54(d, 2H, J=8.4 Hz), 7.61(d, 1H, J=5.1 Hz), 7.92(d, 2H, J=8.4 Hz), 8.34(d, 1H, J=5.1 Hz), 11.04(s, 1H); MS(FD): 303.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[CH3:14])=[N:6][CH:7]=1.C([Li])CCC.[Cl:20][CH2:21][C:22](N(OC)C)=[O:23].Cl>CC(OC)(C)C.O>[Cl:20][CH2:21][C:22]([C:2]1[CH:7]=[N:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[CH3:14])=[CH:4][CH:3]=1)=[O:23]
Reactant: CON(C)C(=O)CCl
Reactant: Cc1ccc(C)n1-c1ccc(Br)cn1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: COC(C)(C)C
Product: Cc1ccc(C)n1-c1ccc(C(=O)CCl)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.8 %

Procedure:
A solution of 5-bromo-2-(2,5-dimethylpyrrol-1-yl)pyridine (1.00 Kg 3.98 mol) in TBME (7.5 L) was cooled to −70° C. n-Butyl lithium (2.5N in hexane; 1.73 L, 4.32 mol) was added drop-wise over 1 hour maintaining the temperature between −74° C. and −69° C. The mixture was then stirred at a temperature between −74° C. and −69° C. for a further 15 minutes. A solution of 2-chloro-N-methoxy-N-methylacetamide (0.65 Kg, 4.72 mol) in TBME (3.0 L) was then added drop-wise over 100 minutes maintaining the temperature between −73° C. and −67° C. The resulting mixture was then stirred at temperature between −73 and −67° C. for a further 100 minutes. 2N HCl (5.0 L) was then added drop-wise over 45 minutes, allowing the temperature to rise from −70° C. to 17° C. during the addition. TBME (4.0 L) and water (2.0 L) was added to the resulting suspension and the mixture was stirred before allowing the phases to separate. The organic layer was washed with water (2.0 L), and aqueous NaHCO3 (0.13 Kg in 2.0 L of water) and water (2.0 L) before concentrating in vacuo. IPA (1.50 L) was added to the residue and the mixture was heated to reflux. The mixture was then allowed to cool to room temperature and stirred overnight, before cooling to 8-12° C. for 1 hour. The product was collected by filtration, washed with IPA (2×0.1 L) and dried at 45° C. under vacuum overnight. Yield 78.8% (0.78 Kg), δH (CDCl3, 300 MHz) 2.20 (6H, s), 4.70 (2H, s), 5.95 (2H, s), 7.35 (1H, d), 8.40 (1H, dd), 9.15 (1H, d) ppm. MS m/z 249 (MH+).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[C:19][CH2:20][CH2:21][CH2:22][OH:23])=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[C:19][CH2:20][CH2:21][CH2:22][O:23][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: OCCCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)OCCCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 15.1, 5-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-yn-1-ol and methane sulfonyl chloride were converted to yield Methanesulfonic acid 5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester light brown oil, MS: 369(M).