Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)O.[NH:5]([C:7](=[NH:9])[NH2:8])[NH2:6].[CH3:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14]>N1C=CC=CC=1>[CH3:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH:6][NH:5][C:7](=[NH:8])[NH2:9])=[O:14]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: N=C(N)NN
Agent: O=C(O)O
Solvent: c1ccncc1
Product: Cc1ccccc1C(=O)NNC(=N)N
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
To a solution of hydrazinecarboximidamide carbonic acid salt (12.0 g, 1.2 eq) in pyridine (100 mL) was added 2-methylbenzoyl chloride (crude afforded in step 1, 1.0 eq) dropwise at 0° C. The mixture was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum, diluted with water (30 mL), adjusted to pH 12 with NaOH (aq), and the solid was collected by filtration and washed with water (20 mL) to afford 2-(2-methylbenzoyl)hydrazinecarboximidamide (5.0 g, 35% of two steps) as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1.O=[C:13]([CH3:20])[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]>CC(O)=O>[CH3:2][O:3][C:4]1[CH:9]=[C:8]2[C:7](=[CH:6][CH:5]=1)[NH:10][C:13]([CH3:20])=[C:14]2[CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)CCC(C)=O
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)Cc1c(C)[nH]c2ccc(OC)cc12
Reaction time: 16 h

Procedure:
A suspension of 4-methoxyphenyl hydrazine hydrochloride (50 g, 0.286M) and methyl 4-oxo-pentanoate (40 mL, 0.315M) in HOAc (500 mL) was stirred for 16 h at reflux. The solvent was removed under vacuum, and the brown residue was partitioned between EtOAc and saturated NaHCO3 solution. The organic layer was washed with H2O and brine, and was then dried (MgSO4) and filtered. Following removal of the solvent, the crude product was purified by flash chromatography (1:20 EtOAc/toluene), to give 48 g of the title compound as a pale brown syrup.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].N1C=C[C:24]([C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH2:29][C:30](=[O:36])[NH:31]3)=CC=1>>[CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=[C:29]3[C:28]4[C:32](=[CH:33][CH:34]=[CH:35][C:27]=4[CH3:24])[NH:31][C:30]3=[O:36])=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2]
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4cccc(C)c43)c(C)c2C1=O
Yield: 64.9 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-pyridin-4-yl-1,3-dihydro-indol-2-one (prepared according to WO2002055517) as starting materials to give 5-(2-diethylamino-ethyl)-3-methyl-2-(4-methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (48 mg, 64.9%) as an orange solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].C(#N)C.[N+:8]([C:11]1[CH:12]=[C:13]([N:20]=[C:21]=[O:22])[CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=1)([O-:10])=[O:9]>O>[N+:8]([C:11]1[CH:12]=[C:13]([NH:20][C:21]([NH:1][CH2:2][CH2:3][OH:4])=[O:22])[CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=1)([O-:10])=[O:9]
Reactant: O=C=Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: NCCO
Solvent: O
Solvent: CC#N
Product: O=C(NCCO)Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
11.0 g (0.180 mol) of 2-aminoethanol was placed, in a nitrogen current, in a 0.3-l four-necked flask equipped with a nitrogen inlet tube, a dropping funnel, a reflux condenser, a thermometer and a mixing blade. Thereto was added 50 ml of acetonitrile, followed by stirring for dissolution. While the flask was being cooled with ice water, the flask contents were stirred. Thereto was dropwise added 50 ml of the above-obtained acetonitrile solution containing 3,5-dinitrophenyl isocyanate (compound 7). The mixture was stirred at room temperature for 1 hour and then poured into 0.7 l of water. The separated crystals were collected by suction filtration, washed with water and vacuum-dried at 35° C. for 12 hours to obtain N-(3,5-dinitrophenyl)-N-(2-hydroxyethyl)urea (compound 11) as a yellow powder. Yield: 16.7 g (74%) Melting point: 192-194° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].[H-].[Na+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C)C=O.O>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:1][C:2]1[C:3]2[CH2:4][CH2:5][CH2:6][C:7](=[O:12])[C:8]=2[CH:9]=[CH:10][CH:11]=1)[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: O=C1CCCc2c(O)cccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cccc2c1CCCC2=O
Reaction time: 0.17 h
Yield: 66.9 %

Procedure:
To a solution of 3,4-dihydro-5-hydroxy-1(2H)-naphthalenone (8.20 g, 50.6 mmol) in N,N-dimethylformamide (80 mL) was added sodium hydride (60% dispersion in liquid paraffin, 2.22 g, 55.6 mmol) at 0° C. and the mixture was stirred at that temperature for 10 minutes. Then, ethyl bromoacetate (9.29 g, 55.6 mmol) was added and the mixture was further stirred at room temperature for 30 minutes. This reaction mixture was poured in water (80 mL) and extracted with 2 portions of ethyl acetate. The organic layers were pooled, washed with water, dried over anhydrous magnesium sulfate (MgSO4), and filtered, and the filtrate was concentrated under reduced pressure. The residue was crystallized from hexane-diisopropyl ether to provide 8.40 g of the title compound. Yield 67%.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH2:17][CH:16]2[N:18]([CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C)[CH:13]([CH2:14][CH2:15]2)[CH:12]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH2:12][CH:13]2[N:18]([CH2:19][CH2:20][NH2:21])[CH:16]([CH2:15][CH2:14]2)[CH:17]=1
Reactant: CC(C)(C)OC(=O)NCCN1C2C=C(c3ccc4ccccc4c3)CC1CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCN1C2C=C(c3ccc4ccccc4c3)CC1CC2
Yield: 60 %

Procedure:
tert-Butyl 2-[3-(2-naphthyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]ethylcarbamate (0.50 g, 1.30 mmol) and 1 mL trifluoroacetic acid are stirred at 23 C in 20 mL CH2Cl2 for 2 h. The volatiles are evaporated, and the residue is partitioned between 50 mL of saturated aqueous NaHCO3 and 50 mL EtOAc. The aqueous layer is extracted with 2×25 mL EtOAc, and the combined organics are washed with 3×50 mL H2O, 1×50 mL brine, dried over MgSO4, filtered, and evaporated to give 0.22g (0.79 mmol, a 60% yield) of the title compound as an orange solid. mp: 62-65 C; MS (ES) m/z 279 (MH)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][CH2:12][C:13]([OH:15])=[O:14].C(=O)(O)[O-].[Na+]>O1CCOCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: NCC(=O)O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)CNc1ccc([N+](=O)[O-])cc1

Procedure:
From 1-fluoro-4-nitrobenzene by heating with glycine at reflux in a mixture of aqueous sodium bicarbonate and dioxane to give (4-nitro-phenylamino)-acetic acid, followed by treatment with formaldehyde and formic acid at reflux to give [methyl-(4-nitro-phenyl)-amino]-acetic acid. Treatment with thionyl chloride and catalytic DMF to give the acid chloride followed by amide formation with 2-amino-4,6-dimethylpyridine in triethylamine and chloroform gives N-(4,6-dimethyl-pyridin-2-yl)-2-(4-nitro-phenylamino)-acetamide. The amide is the reduced with borane-dimethylsulfide in THF at reflux then catalytic hydrogenation over Raney nickel in methanol gives the required aniline.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CCO.C1COCC1.[Pd]>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[CH:16]=1
Reactant: c1ccc(COc2ccc(-c3cccnc3)cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Oc1ccc(-c2cccnc2)cc1
Yield: 92.9 %

Procedure:
3-(4-Benzyloxy-phenyl)-pyridine 1.15 g, 4.4 mmol) in EtOH/THF (10 mL/25 mL) was treated with 10% Pd on carbon (1.5 g) over period of 48 h at rt under H 2 balloon, Reaction mixture was filtered through Celite and concentrated to obtain the product (700 mg, 93%).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[C:3]=1[C:14]([N:39]1[CH2:38][CH2:37][N:36]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[F:29])[CH2:41][CH2:40]1)=[O:16]
Reactant: Fc1ccccc1N1CCNCC1
Reactant: Nc1onc(-c2cccc(F)c2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1onc(-c2cccc(F)c2)c1C(=O)N1CCN(c2ccccc2F)CC1
Yield: 71.7 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(3-fluorophenyl)isoxazol-4-carboxylic acid (409 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(2-fluorophenyl)piperazine (332 mg, 1.84 mmol), a white solid required compound (508 mg, 1.32 mmol, 72%) was obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C@H:14]([O:18][CH3:19])[C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1.[O:20]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:19][O:18][C@@H:14]([CH2:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]#[C:5][CH2:4][CH2:3][CH2:2][O:1][C:30]2[CH:31]=[CH:32][C:27]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:28][CH:29]=2)=[CH:12][CH:11]=1)[C:15]([OH:17])=[O:16]
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: CO[C@@H](Cc1ccc(C#CCCCO)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(C#CCCCOc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(5-hydroxy-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid (Example 21, Step A) and 4-phenoxyphenol via the standard Mitsunobu coupling-hydrolysis procedure (Standard Procedure A) to produce a white oily solid. 1H-NMR (200.15 MHz, CDCl3): δ 7.26–7.19 (m, 4H), 7.07 (d, 2H, J=8.3), 6.98–6.78 (m, 7H), 4.01 (t, 2H, J=5.9), 3.91 (dd, 1H, J=7.3, 4.3), 3.30 (s, 3H), 3.05 (dd, 1H, J=14.2, 4.3), 2.90 (dd, 1H, J=14.2, 7.5), 2.54 (t, 2H, J=6.7), 1.98 (qn, 2H, J=6.4). MS (ES) for C27H26O5[M+NH4]+: 448, [M+Na]+: 453.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:17]2[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:18]=2)[C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1.[CH3:43][C:44]1[N:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1>>[NH2:24][C:19]1[N:20]=[C:21]([CH3:23])[N:22]=[C:17]([C:4]2[CH:3]=[C:2]([C:47]3[CH:48]=[N:49][C:44]([CH3:43])=[CH:45][CH:46]=3)[CH:7]=[N:6][C:5]=2[NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[N:18]=1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(OC)nc3)n2)cc1
Product: COc1ccc(Nc2ncc(-c3ccc(C)nc3)cc2-c2nc(C)nc(N)n2)cn1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 247 using 4-(5-chloro-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine and 6-methylpyridin-3-ylboronic acid (40.5 mg, 0.296 mmol) (Frontier Scientific), and was isolated as a yellow crystalline solid (56%). m/z (ESI, +ve ion) 401.0 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.85 (1H, s); 9.03 (1H, d, J=2.7 Hz); 8.77 (1H, d, J=2.2 Hz); 8.67 (1H, d, J=2.5 Hz); 8.56 (1H, d, J=2.7 Hz); 8.20 (1H, dd, J=8.8, 2.7 Hz); 7.99 (1H, dd, J=8.1, 2.2 Hz); 7.91 (1H, br. s.); 7.77 (1H, br. s.); 7.38 (1H, d, J=8.2 Hz); 6.85 (1H, d, J=8.8 Hz); 3.86 (3H, s); 2.52 (3H, s); 2.46 (3H, s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:13][C:14]([OH:16])=[O:15])[CH:5]=[C:6]([O:11][CH3:12])[C:7]=1[N+:8]([O-:10])=[O:9].[CH3:17]O>Cl>[OH:1][C:2]1[CH:3]=[C:4]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:5]=[C:6]([O:11][CH3:12])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CO
Reactant: COc1cc(CC(=O)O)cc(O)c1[N+](=O)[O-]
Agent: Cl
Product: COC(=O)Cc1cc(O)c([N+](=O)[O-])c(OC)c1

Procedure:
A solution of 3-hydroxy-5-methoxy-4-nitrophenylacetic acid (0.76 g, Reference Example 12) in methanol (100 mL) and concentrated hydrochloric acid (5 drops) was heated at reflux through 3A molecular sieve for 4 hours, then evaporated. The residue was partitioned between ethyl acetate and water. The organic phase was washed with water, then with brine, then dried and then evaporated. The residue was subjected to flash chromatography on silica eluting with dichloromethane, then with a mixture of methanol and dichloromethane (1:49, v/v) to give the title compound (0.34 g).
Reaction SMILES: [CH2:1]([CH:8]([O:25][C:26](=[O:28])[CH3:27])[CH:9]([NH:11][C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH3:24])[C:12]=4[NH:11][CH:9]([CH3:10])[CH:8]([O:25][C:26](=[O:28])[CH3:27])[CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:18][CH:19]=3)=[CH:39][CH:38]=2)[CH2:35][CH2:36]1)=[O:33])[CH3:30]
Reactant: CC(=O)OC(Cc1ccccc1)C(C)Nc1c(C)noc1-c1ccc(Br)cc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)C(Cc4ccccc4)OC(C)=O)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using acetic acid 1-benzyl-2-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamino]-propyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[CH:10]=[O:11].[CH:12]#[C:13][CH3:14]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1[CH:10]([OH:11])[C:12]#[C:13][CH3:14]
Reactant: C#CC
Reactant: CC1=C(C=O)C(C)(C)CC=C1
Product: CC#CC(O)C1=C(C)C=CCC1(C)C

Procedure:
Safranal, prepared according to Compt. rend. 262, 1725 (1966), was reacted with propyne to give 2,6,6-trimethyl-1-[1-hydroxy-2-butynyl]-1,3-cyclohexadiene, following the procedure outlined in Example 18, paragraph (b), for the reaction of citral with propyne. The above carbinol was oxidised with MnO2 to 2,6,6-trimethyl-1-tetrolyl-1,3-cyclohexadiene, following the procedure described in Example 18, paragraph (c), for the oxidation of the dihydro analogue. The above acetylenic ketone was then partially reduced to the title compound folowing the method described in Example 18, paragraph (a). Cis-2,6,6-trimethyl-1-crotonoyl-1,3-cyclohexadiene gave the following NMR data (CCl4): 1.06 (6 H, s) 1.69 (3 H, s), 2.09 (2 H, d, J=2.3 cps.), 2.14 (3 H, d, J=5.5 cps), 5.81 (2 H, t+s, J=2.3 cps), 6.2 (2 H, complex band) ppm (δ).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]3[S:19][C:20]([C:30]([OH:32])=[O:31])=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C:13]=23)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[CH3:38]O>>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]3[S:19][C:20]([C:30]([O:32][CH3:38])=[O:31])=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C:13]=23)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(-c2c(C(=O)O)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1sc2nc(C)cc(NS(=O)(=O)c3cccc(Cl)c3)c2c1-c1cccc(OC)c1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
A mixture of 4-{[(3-chlorophenyl)sulfonyl]amino}-6-methyl-3-[3-(methyloxy)phenyl]-thieno[2,3-b]pyridine-2-carboxylic acid (90 mg, 0.184 mmol) (Example 35) and concentrated sulfuric acid (0.069 mL, 1.288 mmol) in MeOH (5 mL) was heated at 70° C. under nitrogen for 20 h and then left stand at RT for 2 days. The reaction mixture was then concentrated and purified by chromatography on silica gel, eluting with a gradient of 30-50% ethyl acetate in cyclohexane, to give the title compound (46 mg). LCMS (A) m/z: 503 [M+1]+, Rt 1.41 min (acidic), Rt 0.96 min (basic).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[C:8]2[C:13](=[O:14])OC(C)(C)OC2=O)[NH:6][CH:7]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[CH2:18]([NH:25][C:13](=[O:14])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: CC1(C)OC(=O)C(=C2C=CC(Br)=CN2)C(=O)O1
Solvent: Cc1ccccc1
Product: O=C(Cc1ccc(Br)cn1)NCc1ccccc1
Yield: 96.4 %

Procedure:
A flask was charged with 5-(5-bromopyridin-2(1H)-ylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.039 g, 3.46 mmol), benzylamine (0.50 mL, 4.58 mmol), and toluene (20 mL). The reaction was brought to reflux under nitrogen for 18 hours, then cooled and placed in a freezer until cold. The product was collected by filtration and washed with hexanes to yield a mass of bright white crystals (1.018 g, 96%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:29][CH2:30][O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>>[C:35]([Si:32]([CH3:34])([CH3:33])[O:31][CH2:30][CH2:29][N:22]1[CH2:21][C@@H:20]([CH3:25])[N:16]2[C:17]3[CH:18]=[CH:19][C:11]([O:10][CH:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:12][C:13]=3[CH:14]=[C:15]2[C:23]1=[O:24])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CN(CCO[Si](C)(C)C(C)(C)C)C2=O)CC1
Yield: 50 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), sodium hydride and (2-bromoethoxy)-tert-butyldimethylsilane, to give the desired product as a colorless oil (50%).
Reaction SMILES: C(OC1C=CC([C@@H](O)CBr)=CC=1CO[Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])C1C=CC=CC=1.[N:28]([CH2:31][C@@H:32]([C:34]1[CH:35]=[CH:36][C:37]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[C:38]([NH:40][CH:41]=[O:42])[CH:39]=1)[OH:33])=[N+:29]=[N-:30]>>[N:28]([CH2:31][C@@H:32]([C:34]1[CH:35]=[CH:36][C:37]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[C:38]([NH:40][CH:41]=[O:42])[CH:39]=1)[O:33][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=NC[C@H](O)c1ccc(OCc2ccccc2)c(NC=O)c1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN=[N+]=[N-])c1ccc(OCc2ccccc2)c(NC=O)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 5, using Intermediate 10 in place of (R)-4-(2-bromo-1-hydroxyethyl)-2-(hydroxymethyl)phenol. ES/MS calcd. C22H31N4O3Si+ 427.2. found m/z=427 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]([O-:17])=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[K+].[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[OH:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][NH:19][C:15]([C:12]1[CH:13]=[N:14][C:9]([N:6]2[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:8][CH2:7]2)=[CH:10][CH:11]=1)=[O:17]
Reactant: CCN1CCN(c2ccc(C(=O)[O-])cn2)CC1
Reactant: NCCCCCCCCCCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CCN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCO)cn2)CC1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
To 4.07 g of potassium 6-(4-ethyl-1-piperazinyl)-pyridine-3-carboxylate and 3.00 g of 12-aminododecanol was added 50 ml of chloroform and then 2.01 g of 1-hydroxybenzotriazole (HOBt) and 3.07 g of 1,3-dicyclohexylcarbodiimide (DCC) were added thereto while stirring at room temperature and then the mixture was stirred at room temperature for 17 hours. A further 50 ml of chloroform was added, the mixture was stirred and then insolubles were filtered off. After the residue on a filter paper was washed with chloroform, the washing and the chloroform solution were combined and washed with a 10% aqueous solution of sodium hydroxide and dried over anhydrous magnesium sulfate. After the chloroform solution was concentrated, diisopropyl ether was added and the crystal thus separated out was recovered by filtration and dried under reduced pressure to afford 5.10 g of the title compound as a crystal.
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[CH:32][C:31]=1[O:39][CH3:40].CN(C)C=O>O>[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]4[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[CH:32][C:31]=4[O:39][CH3:40])[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)=O)ccc1OCCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 75 °C
Yield: 87.4 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (5.1 g, 0.02 mol), K2CO3 (5.2 g, 0.04 mol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (6.6 g, 22 mmol), and dimethylformamide (60 ml) was heated at 75° C. for 5 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO4), and the solvent was concentrated to yield initially an oil, which solidified upon standing. The solid was triturated with hexane and collected to afford 7.7 g of the product as a waxy solid. The compound was chromatographed on a Waters Prep 500 utilizing silica gel columns and eluting with dichloromethane/methanol (5%). Concentration of the appropriate fractions yielded 5.1 g of off-white solid 1-[4-[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-butoxy]-3-methoxyphenyl]ethanone, which when recrystallized from ethyl alcohol yielded 3.2 g (36%) of feathery-white needles, m.p.=88°-90° C.
Reaction SMILES: [OH-].[Na+].C([N:6]1[C:11]2[CH:12]=[C:13]([C:20](=[O:22])[CH3:21])[CH:14]=[C:15]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:10]=2[O:9][CH2:8][CH2:7]1)(=O)C>CO>[C:16]([C:15]1[C:10]2[O:9][CH2:8][CH2:7][NH:6][C:11]=2[CH:12]=[C:13]([C:20](=[O:22])[CH3:21])[CH:14]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(=O)c1cc2c(c(C(C)(C)C)c1)OCCN2C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)c1cc2c(c(C(C)(C)C)c1)OCCN2
Temperature: 70 °C
Reaction time: 0.67 h
Yield: 97.9 %

Procedure:
After adding 6 N aqueous sodium hydroxide (180 ml, 900 mmol) to a solution of the 1-[4-acetyl-8-(tert-butyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-1-ethanone (36.8 g, 134 mmol) in methanol (360 ml) under a nitrogen atmosphere, the mixture was stirred at 70° C. for 40 minutes. The methanol was distilled off under reduced pressure, and the precipitated crystals were filtered out and dried under reduced pressure to yield the title compound (30.6 g, 98.1% yield) as bright golden yellow crystals.