Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Li]CCCC.[CH3:19][Se:20][Se]C.C(OCC)(=O)C>C1COCC1>[CH3:19][Se:20][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: C[Se][Se]C
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Br
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Se]c1c(C(=O)O)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.3 %

Procedure:
To a solution of 500 mg (2.0 mmol) of 2-bromo-3-nitrobenzoic acid in anhydrous THF (15 mL) was added 2.80 mL (4.47 mmol) of n-BuLi (1.6 M soln. in Hex.) slowly at −78° C. After 10 minutes, a solution of 383 mg (2.03 mmol) of dimethyl diselenide in THF (5 mL) was added. After 30 minutes, the reaction mixture was warmed to room temperature. After additional stirring for 2 hours, ethyl acetate was added. The organic layer was washed with 1 N HCl solution, dried over MgSO4, and concentrated under reduced pressure. 470 mg of crude product was obtained and used for the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@@H:4]([CH3:13])[NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.Cl>C(Cl)Cl>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([N:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C@H:4]([CH3:13])[C:3]([O:2][CH3:1])=[O:14])(=[O:32])=[O:31])=[CH:28][CH:29]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@@H](C)NCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](C)N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-benzyl-D-alanine methyl ester (~2 g) in methylene chloride (40 mL) containing triethylamine (2.47 mL, 17.7 mmol) is added 4-methoxybenzenesulfonyl chloride (2.44 g, 11.8 mmol). The reaction mixture is stirred overnight at room temperature. The mixture is acidified with 1N HCl and extracted with methylene chloride. The combined organic extracts are washed with brine, dried (Na2SO4), and the solvent is evaporated. The crude product is purified by silica gel chromatography (10%-→20% ethyl acetate/hexanes) to provide methyl 2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]propionate.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[CH3:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][C:18]=1[CH:26]=O.N1CCCCC1>C(O)C>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:26][C:18]1[NH:19][C:20]2[C:25]([C:17]=1[CH3:16])=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2ccccc12
Solvent: CCO
Solvent: C1CCNCC1
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]c3ccccc3c1C)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
A mixture of 5-methylaminosulfonyl-2-oxindole (90 mg), 3-methylindole-2-carbaldehyde (56 mg) (prepared according to Synthetic Communications, 1986, 16, 1799) and piperidine (30 mg) in ethanol (1 mL) was held in a sealed tube at 90° C. overnight. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in a vacuum oven to give 90 mg (70% yield) of 3-(3-methyl-1H-indol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide (mixture of isomers).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][C@H:16]2[OH:28])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:28][C@H:16]1[C@H:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(OCc3ccccc3)cc2)[C@H](O)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(O)cc2)[C@H](O)C1
Reaction time: 16 h

Procedure:
A solution of (3S,4S)-tert-butyl 4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate (26 g, 67.8 mmol, intermediate C) in 260 mL of methanol was treated with 1.6 grams of 10% palladium on carbon (13.6 mmol) in a pressure bottle. Hydrogen at 50 psi was introduced, and the reaction mixture was stirred for 16 h.
Reaction SMILES: C([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[CH:16][C:11]=2[N:10]=[CH:9]1)(OC(C)(C)C)=O.C([O-])([O-])=O.[K+].[K+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C.O>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:17]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:15]2[CH:14]=[CH:13][C:12]3[N:8]=[CH:9][NH:10][C:11]=3[CH:16]=2)=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(CNc2ccc3c(c2)ncn3C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(Cc2ccccc2)c2ccc3nc[nH]c3c2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
N1-Boc-N-(4-methoxybenzyl)benzimidazol-5-amine (353 mg; 1 mmol; 1 eq.) was dissolved in DMF (5 ml), treated with K2CO3 (166 mg; 1.2 mmol; 1.2 eq.) and benzylbromide (0.143 ml; 1.2 mmol; 1.2 eq.) and stirred at room temperature for 24 h. The mixture was diluted with water and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The remains were taken up with THF (5 ml), treated with 5 N NaOCH3 and stirred for 2 h at room temperature. The mixture was diluted with water and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The residue was purified by flash chromatography on silica using a CHCl3/MeOH gradient. Yield: 0.049 g (14.3%); MS m/z: 344.1 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 3.70 (s, 3H); 4.60 (s, 2H), 4.64 (s, 2H); 6.71 (d, 1H, 4J=2.1 Hz); 6.77 (dd, 1H, 4J=2.1 Hz, 3J=8.9 Hz); 6.85-6.88 (m, 2H); 7.19-7.22 (m, 3H); 7.26-7.32 (m, 4H); 7.34 (d, 1H, 3J=8.9 Hz); 7.99 (s, 1H); HPLC (METHOD [A]): rt 15.26 min (99.8%)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[CH3:12][C:13](=[CH2:17])[CH2:14][CH2:15]O.CCOC(/N=N/C(OCC)=O)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1C=CC=CC=1.O>[CH3:17][C:13](=[CH2:12])[CH2:14][CH2:15][O:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: C=C(C)CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: c1ccccc1
Product: C=C(C)CCOc1cccc(NC(C)=O)c1
Temperature: 25 °C
Yield: 52 %

Procedure:
A suspension of the mixture of N-(3-hydroxy-phenyl)-acetamide and acetic acid 3-fonnylamino-phenyl ester (18.12 g, 0.12 mol), 3-methyl-but-3-en-1-ol (8.6 g, 0.1 mol), DEAD (87 g, 0.2 mol) and Ph3P (31.44 g, 0.12 mol) in benzene (250 mL) was heated at reflux overnight and then cooled to room temperature. The reaction mixture was poured into water and the organic layer was separated. The aqueous phase was extracted with EtOAc (300×3 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to give N-[3-(3-methyl-but-3-enyloxy)-phenyl]-acetamide (11 g, 52%).
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[Sn](CCCC)(CCCC)CCCC.Br[C:28]1[N:33]=[C:32]2[C:34]([C:56]([NH:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])=[CH:35][N:36]([C:37]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:31]2=[N:30][CH:29]=1>CN(C=O)C.O.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.[Cu](I)I>[C:59]([NH:58][C:56]([C:34]1[C:32]2=[N:33][C:28]([C:7]3[C:6]4[C:10](=[CH:11][CH:12]=[C:4]([O:3][CH:2]([F:1])[F:26])[CH:5]=4)[NH:9][N:8]=3)=[CH:29][N:30]=[C:31]2[N:36]([C:37]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:35]=1)=[O:57])([CH3:62])([CH3:60])[CH3:61]
Reactant: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2ccc(OC(F)F)cc12
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Temperature: 90 °C
Yield: 56.8 %

Procedure:
A mixture of 5-(difluoromethoxy)-3-(tributylstannyl)-1H-indazole (250 mg, 0.57 mmol), 2-bromo-N-tert-butyl-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (280 mg, 0.58 mmol), tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), copper iodide (26 mg, 1.36 mmol) in 10 mL of dry DMF was heated to 90° C. for 3 hours under N2. The reaction mixture was cooled to room temperature, diluted with 50 mL of water, product extracted with ethyl acetate (3×20 mL), organics combined dried with sodium sulfate, filtered and concentrated to give N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (208 mg, crude). LCMS: (M+H)+=643.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:32][CH2:33][C@@H:34]([OH:36])[CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[C:21]([C:22]([F:25])([F:23])[F:24])=[C:20]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:32][CH2:33][C@@H:34]([OH:36])[CH3:35])=[O:5]
Reactant: C[C@H](O)CN
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[C@H](O)CNC(=O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 47.1 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-IX, 30 mg, 0.070 mmol), (S)-1-aminopropan-2-ol (7.84 mg, 0.104 mmol), HATU (34.4 mg, 0.090 mmol), and 4-methylmorpholine (28.1 mg, 0.278 mmol) were added to DMF (1 mL). The reaction mixture was stirred for 1 h and it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=11.9 min) to provide (R/S)-2-hydroxy-N—((S)-2-hydroxypropyl)-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (18 mg, 0.033 mmol, 47.1% yield) as a mixture of diastereomers. LCMS=489.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.09-8.20 (2 H, m), 7.55-7.86 (7 H, m), 5.15 (1 H, s), 3.80-3.94(1 H, m, J=9.11, 6.67, 6.67, 4.62 Hz), 3.09-3.37 (2 H, m), 1.14 (3 H, dd, J=6.27, 1.21 Hz); HPLC peak RT=8.4 min (Method A).
Reaction SMILES: [O-]CC.[Na+].[Na].[C:6]([CH2:9][C:10](=[O:12])[CH3:11])(=[O:8])[CH3:7].[OH:13][C@@H:14]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:16]([CH2:17][CH2:18][C@@H:19]3[C@@H:31]2[C:30](=[O:36])[CH2:29][C@@:28]2([CH3:37])[C@H:20]3[CH2:21][CH2:22][C@@H:23]2[C:24](=[O:27])[CH:25]=[CH2:26])[CH2:15]1>C(O)C.O>[C:6]([CH:9]([C:10](=[O:12])[CH3:11])[CH2:26][CH2:25][C:24](=[O:27])[C@@H:23]1[C@:28]2([CH3:37])[C@H:20]([C@H:19]3[C@H:31]([C:30](=[O:36])[CH2:29]2)[C@:32]2([CH3:35])[C@H:16]([CH2:15][C@H:14]([OH:13])[CH2:34][CH2:33]2)[CH2:17][CH2:18]3)[CH2:21][CH2:22]1)(=[O:8])[CH3:7]
Reactant: CC(=O)CC(C)=O
Reactant: C=CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CC(=O)C(CCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C)C(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of sodium ethoxide, prepared from 120 mg of sodium in ethanol (20 ml), was treated with acetylacetone (1 ml) and the resulting solution added to a solution of 3α-hydroxy-21-methylene-5α-pregnane-11,20-dione (500 mg) in ethanol (20 ml). The mixture was stirred at room temperature for 1 hour, poured into water, and extracted into ether. The extract was washed with water, dried (Na2SO4) and evaporated to a white foam which was purified by preparative t.l.c. (ethyl acetate/petrol) to give title compound (480 mg) as a white foam [α]D + 79.5 °(c, 0.59).
Reaction SMILES: COC.[N:4]1([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([C:20]3[C:21]4[CH:36]=[CH:35][CH:34]=[CH:33][C:22]=4[S:23][C:24]=3[C:25]3[CH:30]=[CH:29][C:28]([O:31]C)=[CH:27][CH:26]=3)=[O:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7][CH2:6][CH2:5]1.[Al+3].[Cl-].[Cl-].[Cl-].CCS>ClC(Cl)C>[N:4]1([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([C:20]3[C:21]4[CH:36]=[CH:35][CH:34]=[CH:33][C:22]=4[S:23][C:24]=3[C:25]3[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=3)=[O:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: COc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(OCCN3CCCC3)cc2)cc1
Agent: COC
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: CCS
Product: O=C(c1ccc(OCCN2CCCC2)cc1)c1c(-c2ccc(O)cc2)sc2ccccc12
Yield: 33 %

Procedure:
By cleaving the methyl ether of 2-(4-methoxyphenyl)-benzo[b]thiophen-3-yl 4-[2-(1-pyrrolidinyl)ethoxy]phenyl ketone using AlCl3 (about 8 eq) and EtSH (about 10 eq) in dichloroethane at 0° C., the title compound was obtained in 33% yield as an oil following radial chromatography (SiO2; gradient of 2-10% MeOH in CH2Cl2).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[N+:23]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])#[C-:24].CC(C)([O-])C.[K+].Cl>O.O1CCOCC1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[N+:23]#[C-:24])[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: [C-]#[N+]CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: [C-]#[N+]C(C(=O)OCC)c1c(F)cc2c(=O)c(C(=O)OCC)cn(C3CC3)c2c1F
Reaction time: 2 h
Yield: 28.5 %

Procedure:
2.7 g of ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylate and 1.92 g of ethyl isocyanoacetate are initially introduced into 30 ml of dioxane. 1.91 g of potassium tert-butoxide are added and the mixture is heated to reflux for 3 hours. 0.39 g of potassium tert-butoxide is then added once more and the mixture is once more boiled for 2 hours. It is then diluted using water, acidified using HCl and the solid is isolated. After separation on silica gel (eluant CH2Cl2 /MeOH 95/5), 1.0 g of the title compound is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9](=[O:20])[N:8]([CH3:21])[C:6]=2[N:7]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[Cl:18][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:19])[C:12]=1[C:10]1[C:9](=[O:20])[N:8]([CH3:21])[C:6]2[N:7]=[C:2]([NH:1][C:22](=[O:24])[CH3:23])[N:3]=[CH:4][C:5]=2[CH:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(N)nc21
Product: CC(=O)Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Temperature: 25 °C

Procedure:
A mixture of 64.2 mg (0.20 mmol) of 2-amino-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7(8H)-one (from Example 12) and 1 mL of acetic anhydride was heated to reflux. The resulting solution was maintained at reflux for 20 minutes and concentrated at atmospheric pressure to about 0.25 mL volume. The solution was cooled to 25° C. and diluted with diethyl ether (1 mL). The separated crystals were filtered and washed with diethyl ether to provide N-[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl]acetamide, wt 44.0 mg; mp 258°-260° C.; MS (CI) 363 (M+ +1).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:22])[CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[C:13]([I:14])=[C:12]([NH2:15])[C:11]([I:16])=[C:10]([C:17]([OH:19])=[O:18])[C:9]=1[I:20].O.[C:24](Cl)(=[O:26])[CH3:25]>CC(N(C)C)=O>[CH3:1][NH:2][C:3](=[O:22])[CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[C:13]([I:14])=[C:12]([NH:15][C:24](=[O:26])[CH3:25])[C:11]([I:16])=[C:10]([C:17]([OH:19])=[O:18])[C:9]=1[I:20]
Reactant: CC(=O)Cl
Reactant: CNC(=O)CCNC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Solvent: O
Solvent: CC(=O)N(C)C
Product: CNC(=O)CCNC(=O)c1c(I)c(NC(C)=O)c(I)c(C(=O)O)c1I
Yield: 58.8 %

Procedure:
99.5 g. (0.15 mole) of N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-β -alanine methylamide . 1.1 H2O (IVf), m.p. 250°-252° C. (decomposition) in 190 ml. of dimethylacetamide yield, after reaction with 40.0 ml. of acetyl chloride analogously to Example 1, 60.4 g. (58.8%) of the desired compound. A sample for analysis is purified in alcohol by way of the dimethylammonium salt; m.p. 288°-289° C. (under decomposition).
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:37]([NH:39][CH3:40])[CH3:38]>C1COCC1>[CH2:37]([N:39]([CH3:40])[CH2:25][CH2:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[C:14]2[S: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)(=[O:12])=[O:13])[CH3:38]
Reactant: CCNC
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)cc1
Solvent: C1CCOC1
Product: CCN(C)CCOc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Temperature: 80 °C

Procedure:
A solution of toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (1.18 g, 2.26 mmol) and ethylmethylamine (2.0 mL, 23 mmol) in THF (20 mL) was stirred for 16 hours at 70° C. in a sealed tube. More ethylmethylamine (2.0 mL, 23 mmol) was added, and the reaction mixture was heated to 80° C. for 20 hours in a sealed tube. After cooling to ambient temperature, the reaction mixture was concentrated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 0.75% ammonium hydroxide/7.5% methanol in chloroform. Drying in vacuo at 69° C. for 20 minutes yielded ethyl-methyl-{2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-amine as a buff foam (0.409 g, 44.2%). Methanol, chloroform and ethereal hydrochloride were added. The resulting solution was concentrated and dried for 16 hours at 84° C. in vacuo. The hydrochloride was obtained as a buff semi-solid (0.424 g). Mass Spectrum (+EI, [M+H]+) m/z 410. 1HNMR (500 MHz, DMSO-d6): δ14.21 (s, 1H), 10.00-10.01 (s, 1H), 8.74-8.77 (m, 1H), 8.52 (dd, 1H, J=7.44 Hz and 1.22 Hz), 8.27 (d, 1H, J=8.29 Hz), 8.03-8.05 (m, 1H), 7.73 (dd, 1H, J=8.06 Hz and 7.57 Hz), 7.56-7.65 (m, 3H), 7.37 (d, 1H, J=2.20 Hz), 7.15-7.18 (m, 1H), 4.40 (t, 2H, J=5.00 Hz), 3.53-3.59 (m, 1H), 3.39-3.49 (m, 1H), 3.21-3.25 (m, 1H), 3.10-3.20 (m, 1H), 2.81 (d, 3H, J=4.88 Hz), 1.21-1.25 ppm (m, 3H). Elemental Analysis for C22H23N3O3S.1.00 mol HCl.0.30 mol H2O:
Reaction SMILES: [CH3:1][C:2]([CH3:14])=[CH:3][C:4]([NH:6][C:7]([N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)=[S:8])=[O:5].[C:15](=O)([O-])[O-].[Na+].[Na+].IC>O1CCCC1>[CH3:15][S:8]/[C:7](=[N:6]\[C:4](=[O:5])[CH:3]=[C:2]([CH3:14])[CH3:1])/[N:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)=CC(=O)NC(=S)N1CCCC1
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CS/C(=N\C(=O)C=C(C)C)N1CCCC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 48.7 %

Procedure:
A mixture of 3-methyl-N-(pyrrolidine-1-carbonothioyl)but-2-enamide (230 mg, 1.08 mmol, Eq: 1.00), sodium carbonate (121 mg, 1.14 mmol, Eq: 1.05) and iodomethane (769 mg, 339 μl, 5.42 mmol, Eq: 5) in tetrahydrofuran (7 ml) was stirred for 18 hours at 70° C. The crude material was applied on silicagel and purified by flash chromatography over a 20 g silicagel column using heptane/ethyl acetate 50-100% as eluent affording 3-methyl-but-2-enoic acid 1-methylsulfanyl-1-pyrrolidin-1-yl-meth-(Z)-ylideneamide (119 mg/48.5%) as a light yellow liquid. MS: m/e=227.1 (M+H+)
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:28][CH2:29][CH:30]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][C:33]=1[OH:39])[OH:31]>>[OH:39][C:33]1[CH:34]=[C:35]([OH:38])[CH:36]=[CH:37][C:32]=1[CH:30]([OH:31])[CH2:29][NH:28][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:16])=[O:17])=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: NCC(O)c1ccc(O)cc1O
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NCC(O)c4ccc(O)cc4O)CC3)cc2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidine-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and 2-amino-1-(2,4-dihydroxy-phenyl)-ethanol according to the procedure of Example 255 as a pale yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 1.55-1.75 (m, 2H), 1.95-2.15 (m, 2H), 2.08 (s, 3H), 2.50-3.20 (m, 5H), 3.60-3.70 (m, 2H), 5.04-5.10 (m, 1H), 6.65-6.75 (m, 1H), 6.24 (dd, J=8.1, 2.1 Hz, 1H), 6.32 (d, J=2.1 Hz, 1H), 6.80 (d, J=9.0 Hz, 2H), 6.88 (d, J=9.0 Hz, 2H), 7.12 (d, J=8.1 Hz, 1H), 7.59 (d, J=9.0 Hz, 2H), 7.70 (d, J=9.0 Hz, 2H), 9.26 (s, 1H), 9.71 (brs, 1H), 10.44 (s, 1H); MS (ES) m/z: 541.4 (MH+); HRMS Calcd. for C27H33N4O6S(MH+): 541.2121. Found: 541.2084.
Reaction SMILES: Cl.Br[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[CH2:11][C:10]([CH3:17])([CH2:14][CH2:15][CH3:16])[CH2:9][C:8]1=[O:18].[N:19]1([C:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[S:27][N:26]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[S:27]1[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:25]([N:19]2[CH2:20][CH2:21][N:22]([CH2:3][CH2:4][CH2:5][CH2:6][N:7]3[C:12](=[O:13])[CH2:11][C:10]([CH3:17])([CH2:14][CH2:15][CH3:16])[CH2:9][C:8]3=[O:18])[CH2:23][CH2:24]2)=[N:26]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: CCCC1(C)CC(=O)N(CCCCBr)C(=O)C1
Agent: Cl
Product: CCCC1(C)CC(=O)N(CCCCN2CCN(c3nsc4ccccc34)CC2)C(=O)C1

Procedure:
Title product hydrochloride--Reaction of N-(4-bromobutyl)-3-methyl-3-n-propylglutarimide with 3-(1-piperazinyl)-1,2-benzisothiazole and conversion of the free base to the hydrochloride salt according to the procedure of Example 3 affords 1-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-4-methyl-4-propyl-2,6-piperidinedione hydrochloride, m.p. 163°-165° C.