Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:11][CH:10]=[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:8]=2)([O-])=O>CO.[Pt]>[O:17]([CH2:16][CH2:15][NH:14][C:13]1[C:12]2[C:7](=[CH:8][C:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[NH2:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1cnc2cc(-c3ccccc3)ccc2c1NCCOc1ccccc1
Agent: [Pt]
Solvent: CO
Product: Nc1cnc2cc(-c3ccccc3)ccc2c1NCCOc1ccccc1

Procedure:
A solution of (3-nitro-7-phenylquinolin-4-yl)-(2-phenoxyethyl)amine (7.25 g, 18.8 mmol) in methanol (150 mL) was added to a Parr vessel charged with 5% platinum on carbon (0.84 g), and the reaction was placed under hydrogen pressure (50 psi, 3.4×105 Pa) for three hours. The reaction mixture was filtered through a layer of CELITE filter aid, and the filtrate was concentrated under reduced pressure, dissolved in toluene (2×25 mL), and concentrated under reduced pressure to provide N4-(2-phenoxyethyl)-7-phenylquinoline-3,4-diamine as a yellow semi-solid.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[S:11][C:12]([C:19]([O:21]CC)=O)=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH3:24]>CO>[C:1]([NH:8][CH2:9][C:10]1[S:11][C:12]([C:19]([NH2:24])=[O:21])=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: N
Reactant: CCOC(=O)c1sc(CNC(=O)OC(C)(C)C)nc1C(F)(F)F
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1nc(C(F)(F)F)c(C(N)=O)s1

Procedure:
Ethyl 2-(N-BOC-aminomethyl)-4-trifluoromethylthiazole-5-carboxylate [sic] (15 g, 42.33 mol) was dissolved in methanol. Ammonia was passed into the solution at room temperature until all of the ester had been converted into the carboxamide. The solvent was removed on a rotary evaporator and the crude product was purified by flash chromatography. Yield: 4.6 g (14.14 mmol, 33%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:3]=12.C([N-]C(C)C)(C)C.[Li+].CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C.[I:49]I>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]([I:49])=[CH:10][C:3]=12
Reactant: II
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Br)ccnc32)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2c(I)cc3c(Br)ccnc32)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of Example 369A (25 g, 71.2 mmol) in tetrahydrofuran (600 mL) at −78° C. was slowly added 2M lithium diisopropylamide in heptane/tetrahydrofuran/ethylbenzene (39.1 mL, 78 mmol) and the mixture was stirred at −78° C. for 1 hour. A solution of iodine (19.87 g, 78 mmol) in tetrahydrofuran (100 mL) was added slowly and the reaction was allowed to warm to room temperature gradually. The reaction mixture was stirred at room temperature for 3 hours and was quenched with saturated aqueous sodium thiosulfate, water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organics were dried over sodium sulfate, filtered and concentrated to give the title compound. MS (CI) m/z 477 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][S:8]([C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([N+:18]([O-])=O)[C:12]=2[OH:21])(=[O:10])=[O:9])=[CH:3][CH:2]=1.[H][H]>[Pd]>[N:1]1[CH:6]=[CH:5][C:4]([NH:7][S:8]([C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([NH2:18])[C:12]=2[OH:21])(=[O:10])=[O:9])=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Nc2ccncc2)c1O
Reactant: [H][H]
Agent: [Pd]
Product: Nc1ccc(Cl)c(S(=O)(=O)Nc2ccncc2)c1O
Yield: 91 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, N-(4-pyridinyl)-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (22.0 mg, 0.066 mmol) was reduced with hydrogen and Pd/C (10.3 mg) to form the desired product (18.0 mg, 90%). EI-MS m/z 298(M-H)−.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:3]=1[C:4]([NH:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>FC(F)(F)C1C=CC=CC=1>[F:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:3]=1[C:4]1[O:9][C:8]([O:10][CH2:11][CH3:12])=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:6]=1
Reactant: CCOC(=O)C(NC(=O)c1c(F)cccc1F)C(=O)OCC
Solvent: FC(F)(F)c1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCOC(=O)c1nc(-c2c(F)cccc2F)oc1OCC
Yield: 44.7 %

Procedure:
A solution of diethyl 2-(2,6-difluorobenzamido)malonate (5.00 g, 15.9 mmol) in trifluorotoluene (16 mL) and trifluoroacetic anhydride (8.33 mL, 129.7 mmol) was heated in the microwave at 160° C. for 5 minutes. The solvent was removed in vacuo and the residue purified by silica gel column chromatography using a gradient of 0-90% EtOAc in hexanes to afford ethyl 2-(2,6-difluorophenyl)-5-ethoxyoxazole-4-carboxylate (2.11 g, 7.1 mmol, 45%) as a white solid which was used without further purification. 1H NMR (CDCl3) δ 1.39 (3H, t), 1.53 (3H, t), 4.39 (2H, q), 4.58 (2H, q), 7.02 (2H, t), 7.41 (1H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH3:12].O1CCOCC1.[C:19](=O)([O-:21])[O-:20].[Na+].[Na+]>O>[Cl:11][C:9]1[CH:10]=[C:2]([C:19]([OH:21])=[O:20])[CH:3]=[C:4]2[C:8]=1[NH:7][N:6]=[C:5]2[CH3:12]
Reactant: O=C([O-])[O-]
Reactant: Cc1n[nH]c2c(Cl)cc(Br)cc12
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1n[nH]c2c(Cl)cc(C(=O)O)cc12
Temperature: 165 °C
Reaction time: 0.01 h
Yield: 80.4 %

Procedure:
A microwave tube was charged with 5-bromo-7-chloro-3-methyl-1H-indazole (610 mg, 2.48 mmol), dioxane (5 mL), Hermann's catalyst (119 mg, 0.12 mmol) and a solution of sodium carbonate (790 mg, 7.46 mmol) in water (10 mL). The mixture was stirred for 20 sec, heated at 165° C. for 30 minutes in a microwave reactor at very high absorption setting. The reaction was vented before handling. The mixture was filtered through diatomaceous earth and washed with EtOAc. The filtrate was concentrated, the residue was dissolved in water and acidified to pH ˜3 with conc HCl. The solids were collected by filtration and dried to afford the title compound (420 mg, 82%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:22])[CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=[C:7]1[CH2:19][CH2:20][CH3:21].C1C=C(Cl)C=C(C(OO)=O)C=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:46]>>[NH2:46][C:10]1[C:9]2[N:8]=[C:7]([CH2:19][CH2:20][CH3:21])[N:6]([CH2:5][CH2:4][C:3]([NH:2][CH3:1])=[O:22])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCC(=O)NC
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCC(=O)NC

Procedure:
N-Methyl-3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propanamide (4.7 g, 13 mmol) was treated with mCPBA (6.58 g, 38.2 mmol) followed by ammonium hydroxide (40 mL) and p-toluenesulfonyl chloride (3.27 g, 17.2 mmol) according to the method described in Part D of Example 8. The crude product was purified as described in Part D of Example 8 to provide 0.674 g of 3-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-N-methylpropanamide as a tan powder, mp 177-178° C.
Reaction SMILES: CN.ClC(Cl)C.[Cl:7][C:8]1[C:13]2[C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])=[N:15][CH2:16][C:17](=[O:20])[N:18]([CH3:19])[C:12]=2[CH:11]=[CH:10][C:9]=1[N:28]=[C:29]=[O:30].[NH2:31][C:32]1C=CC2N(C)C(=O)CN=C(C3C=CC=CC=3F)C=2C=1Cl>>[Cl:7][C:8]1[C:13]2[C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])=[N:15][CH2:16][C:17](=[O:20])[N:18]([CH3:19])[C:12]=2[CH:11]=[CH:10][C:9]=1[NH:28][C:29]([NH:31][CH3:32])=[O:30]
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2c1ccc(N=C=O)c2Cl
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2c1ccc(N)c2Cl
Agent: CN
Solvent: CC(Cl)Cl
Product: CNC(=O)Nc1ccc2c(c1Cl)C(c1ccccc1F)=NCC(=O)N2C

Procedure:
Excess gaseous methylamine is conducted into a dichloroethane solution of [6-chloro-5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]isocyanate, obtained in analogy to the procedure described in paragraph (a) of Example 1 from 10 g (0.031 M) of 7-amino-6-chloro-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one, and the mixture is concentrated. The residue is dissolved in methylene chloride/water and extracted with methylene chloride. The organic phase is separated, dried with sodium sulphate, filtered and concentrated. After purification on a 500 g silica gel column using ethyl acetate as the eluting agent, the product is crystallised from ethyl acetate/ether. There is obtained 1-[6-chloro-5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-3-methylurea which melts at 145°-160° C. with decomposition.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[CH:22]=[C:21]([OH:25])[CH:20]=[CH:19][C:18]=2[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][C@@H:16]2[F:26])([CH3:14])[C@@H:12]([OH:27])[CH2:11][CH2:10]1.[CH3:28][NH2:29].O>CN(C)C=O>[F:26][C@H:16]1[CH2:15][C@@:13]2([CH3:14])[C@@H:9]([CH2:10][CH2:11][C@@H:12]2[OH:27])[C@H:8]2[C@H:17]1[C:18]1[CH:19]=[CH:20][C:21]([OH:25])=[CH:22][C:23]=1[CH2:24][C@H:7]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:29][CH3:28]
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCBr)[C@H]3[C@@H]1CC[C@@H]2O
Reactant: CN
Solvent: CN(C)C=O
Solvent: O
Product: CNCCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F

Procedure:
A solution of 2 g of 7α-(5-bromopentyl)-11β-fluoro-estra-1,3,5(10)-triene-3,17β-diol in 20 ml of dimethylformamide is stirred with 8 ml of a 40% aqueous methylamine solution for 3.5 hours at 80° C. Then, it is added to water, extracted three times with ethyl acetate, washed with water and common salt solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. 1.77 g of 11β-fluoro-7α-[5-(methylamino)-pentyl]-estra-1,3,5(10)-triene-3,17β-diol is obtained.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C@@:5]1([OH:13])[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:20][C:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[C:26]([N:31]=[C:32]=S)[N:27]=[CH:28]2)=[CH:23][CH:22]=1.C(N=C=NC(C)C)(C)C>CN(C)C=O>[Br:20][C:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[C:26]([NH:31][C:32]3[O:13][C@:5]4([CH2:4][N:3]=3)[CH:10]3[CH2:9][CH2:8][N:7]([CH2:12][CH2:11]3)[CH2:6]4)[N:27]=[CH:28]2)=[CH:23][CH:22]=1
Reactant: S=C=Nc1cc2ccc(Br)cc2cn1
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Brc1ccc2cc(NC3=NC[C@@]4(CN5CCC4CC5)O3)ncc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.2 %

Procedure:
To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.207 g, 0.905 mmol) in N,N-dimethylformamide (20 mL) was added Cs2CO3 (0.737 g, 2.263 mmol) and 7-bromo-3-isothiocyanatoisoquinoline (0.24 g, 0.905 mmol). The suspension was stirred at room temperature for 30 minutes. N,N′-Diisopropylcarbodiimide (0.423 mL, 2.72 mmol) was then added and the mixture was stirred at room temperature for 18 hours. The mixture was concentrated and purified by silica gel chromatography using 5-15% [9:1 methanol:ammonium hydroxide] in ethyl acetate. The desired fractions were concentrated and further purified using 5-15% [9.5:0.5 methanol:ammonium hydroxide] in ethyl acetate to afford ((R)—N-(7-bromoisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.061 g, 0.156 mmol, 17% yield) as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 8.96 (1H, s), 8.12 (1H, s), 7.66 (2H, s), 7.32 (1 H, s), 4.01 (1H, d), 3.73 (1H, d), 3.35-3.42 (1H, m), 3.22-3.29 (1H, m), 2.84-3.17 (4H, m), 2.13-2.35 (2H, m), 1.62-1.96 (3H, m). LCMS: R.T.=1.76; [M+]+=387.21.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH3:24])=[CH:6][CH:7]=1
Reactant: Cc1ccccc1O
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCCO)o1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccccc1OCCCCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
To a mixture of 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolebutanol (1.32 g), 2-methylphenol (865 mg), tributylphosphine (1.21 g) and tetrahydrofuran (30 ml) was added 1,1′-(azodicarbonyl)dipiperidine (1.51 g) at room temperature, and the resulting mixture was stirred for 1 hour. After the reaction mixture was concentrated, the residue was subjected to silica gel column chromatography, and 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[4-(2-methylphenoxy)butyl]oxazole was obtained as crystals (1.61 g, 96%) from an ethyl acetate-hexane (1:1, v/v)-eluted fraction. Recrystallization from acetone-isopropyl ether gave colorless prisms. Melting point 71-72° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[O:27]1[CH2:32][CH2:31][CH:30](O)[CH2:29][CH2:28]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>O1CCCC1>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][C:4]2[CH:5]=[C:6]3[C:10](=[C:2]([O:1][CH:30]4[CH2:31][CH2:32][O:27][CH2:28][CH2:29]4)[CH:3]=2)[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]3)=[CH:18][CH:19]=1)(=[O:25])=[O:24]
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(O)c2[nH]1
Reactant: OC1CCOCC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OC3CCOCC3)c2[nH]1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
A mixture of ethyl 7-hydroxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (2.0 g), tetrahydro-2H-pyran-4-ol (2.02 mL), 1,1′-(azodicarbonyl)dipiperidine (5.3 g), tributylphosphine (5.3 mL), and tetrahydrofuran(60 mL) was stirred at 70° C. for 6 hr. To the reaction solution were added tetrahydro-2H-pyran-4-ol (1.02 mL), 1,1′-(azodicarbonyl)dipiperidine (2.5 g) and tributylphosphine (2.5 mL) and the mixture was stirred at 70° C. for 14 hr. The reaction solution was concentrated under reduced pressure to a half volume and the precipitated solid was filtered off. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (volume ratio, ethyl acetate:hexane=5:95 to 50:50), and then basic silica gel column chromatography (volume ratio, methanol:ethyl acetate:hexane=0:2:98 to 20:80:0) to give the title compound (5.33 g) as a yellow oily crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[NH:21][N:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=3.[CH3:30][N:31]([CH3:36])[S:32](Cl)(=[O:34])=[O:33]>>[CH3:30][N:31]([CH3:36])[S:32]([N:22]1[CH:23]=[CH:24][C:20]([C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:25])[C:12]2[N:26]([CH3:29])[C:27](=[O:28])[C:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])=[CH:10][C:11]3=2)=[N:21]1)(=[O:34])=[O:33]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn[nH]4)ccc3n(C)c21
Product: CN(C)S(=O)(=O)n1ccc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)n1

Procedure:
The process is carried out as indicated in Example 99 above, with the compound from Example 39, 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(2H-pyrazol-3-yl)-1,9-dihydropyrido[2,3-b]indol-2-one, and dimethyl sulphamoyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].NC1C=CC=CC=1.C([O:20][CH:21]=[C:22]([C:28](OCC)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])C>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]2[C:3]=1[NH:4][CH:28]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:21]2=[O:20]
Reactant: COc1ccc(N)c(F)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: Nc1ccccc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2c(F)cc(OC)cc2c1=O
Yield: 77 %

Procedure:
A mixture of aniline 2-fluoro-4-(methoxy)aniline (22.8 g, 162 mmol) and diethyl [(ethyloxy)methylidene]propanedioate (32.6 mL) were heated to reflux in Dowtherm A under a flow of argon. After 15 minutes (when all ethanol was removed), the mixture was allowed to cool down and was diluted with pentane. A precipitate was formed which was triturated with pentane, filtered and dried under vacuum to afford the product as an oil (33.06 g, 77%); MS (+ve ion electrospray) m/z 265 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29]Cl>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CC=CC[C@@H]23)cc1OC
Reactant: ClCc1ccccn1
Agent: Cl
Product: COc1ccc(C2=NN(Cc3ccccn3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound 3 and 2-picolylchloride hydrochloride as described for compound 105. Crystallized from diethyl ether. M.p. 146°-147° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[CH:25]=[CH2:26]>CN(C)C=O>[CH2:26]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[CH:25]=[CH2:24]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(-c2ccc(C(=O)OC)cc2)cc1
Temperature: 60 °C

Procedure:
A solution of methyl 4-(4′-hydroxyphenyl)benzoate (5 g) in N,N-dimethylformamide (50 ml) was treated with potassium carbonate (6.06 g) and allyl bromide (2.46 ml), then heated at 60° C. for 3 hours. After cooling, the reaction mixture was poured into ice-water (˜200 ml) and the resulting precipitate was collected by filtration, washed with water, then isopropyl ether, then dried to give methyl 4-[4′-(allyloxy) phenyl]benzoate (5.55 g) as a solid.
Reaction SMILES: [CH2:1](I)[CH3:2].[OH:4][CH:5]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=1)[CH2:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[OH:4][CH:5]([C:19]1[CH:20]=[CH:21][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:23][CH:24]=1)[CH2:6][CH2:7][CH2:8][N:9]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=1)[CH2:1][CH3:2]
Reactant: Cc1cccc(CCNCCCC(O)c2ccc(NS(C)(=O)=O)cc2)n1
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CCCC(O)c1ccc(NS(C)(=O)=O)cc1)CCc1cccc(C)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
0.24 ml 3.04 mmol) of ethyl iodide was added to a suspension of 1.0 g (2.77 mmol) of N-[4-[1-hydroxy- 4-[2-(6-methyl-2-pyridyl)ethylamino]butyl]phenyl]methanesulfonamide prepared in Example 3-(4) and 0.70 g (8.31 mmol) of sodium hydrogencarbonate in 15 ml of dimethylformamide. The mixture was stirred at 50° C. for 2 h and then filtered. The filtrate was concentrated to give a residue, which was purified by silica gel column chromatography (chloroform/methanol/aqueous ammonia=97:3:0.3). 0.96 g (yield: 89%) of the intended compound was obtained in the form of a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:12](=[O:15])(=[O:14])[NH2:13].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.Cl>O>[ClH:1].[CH3:11][C:9]1[C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]([S:12](=[O:15])(=[O:14])[NH2:13])=[C:2]([N:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)[CH:10]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc(Cl)c(S(N)(=O)=O)cc1C(=O)O
Agent: Cl
Solvent: O
Product: Cc1cc(N2CCN(C)CC2)c(S(N)(=O)=O)cc1C(=O)O
Reaction time: 1 h

Procedure:
125 g of 4-chloro-6-methyl-3-sulfamoylbenzoic acid (0.5 mole) were heated under reflux with 0.5 l of N-methylpiperazine for 6 hours. Subsequently the excess base was eliminated in vacuo, and the residue was dissolved in 1 l of water. After the solution had been acidified with concentrated hydrochloric acid, the final product precipitated in a crystalline form. After having stood at room temperature for 1 hour, it was suction-filtered and was dissolved and recrystallized from 50% ethanol, while activated charcoal was added.
Reaction SMILES: [Na+].[Cl:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:6][C:7]1[NH:8][C:9](=[O:20])[C:10]2[C:15]([CH3:16])=[C:14]([C:17]([O-:19])=[O:18])[S:13][C:11]=2[N:12]=1.[OH-].[Na+].Cl>O.C(O)C>[Cl:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:6][C:7]1[NH:8][C:9](=[O:20])[C:10]2[C:15]([CH3:16])=[C:14]([C:17]([OH:19])=[O:18])[S:13][C:11]=2[N:12]=1
Reactant: Cc1c(C(=O)[O-])sc2nc(Cc3ccc(Cl)c(Cl)c3)[nH]c(=O)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(C(=O)O)sc2nc(Cc3ccc(Cl)c(Cl)c3)[nH]c(=O)c12
Reaction time: 0.01 h

Procedure:
A mixture of 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid mono sodium salt (2.501 g), 1 mol/L aqueous sodium hydroxide solution (9.6 mL) and water (39.4 mL) was dissolved by stirring. The reaction mixture was ice-cooled, ethanol (10 mL) was added, the inside temperature was set to about 2° C., neutralized with 1 mol/L hydrochloric acid (16.0 mL), water (25.0 mL) was added (solvent amount was set to 100 mL), and the mixture was stirred under ice-cooling to confirm that the inside temperature was about 1° C. The suspension was poured into a G2 glass filter (diameter 3 cm), and the pressure reduction was started at 50 hpa. The time necessary to the increase of pressure by the completion of filtration was 42 minutes 52 seconds. The height of the solid at that time was 4.3 cm (bulk 30.4 cm3). Washing with water was not possible due to clogging.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:13][CH:14]([C:20](=[O:22])[CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:13][CH:14]([C:20](=[O:22])[CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(N)C(C)=O
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(NC(=O)CNC(=O)OC(C)(C)C)C(C)=O
Reaction time: 4 h

Procedure:
N-(tert-butoxycarbonyl)glycine (22.4 g, 128 mmol), ethyl 2-amino-3-oxobutanoate (21.1 g, 116 mmol), ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (28.9 g, 151 mmol), 1-hydroxybenzotriazole (23.1 g, 151 mmol), triethylamine (16.2 mL, 116 mmol), in chloroform (350 mL) was stirred for 13 h at room temperature, and then triethylamine (20.0 mL, 143 mmol) was added. After being stirred for 4 h at same temperature, the reaction mixture was poured into saturated aqueous sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer was combined, washed with saturated brine, dried over sodium sulfate, filtrated and concentrated in vacuo. The crude was purified by silica gel column chromatography (hexane:ethyl acetate=2:1 to 1:1) to give ethyl 2-{[N-(tert-butoxycarbonyl)glycyl]amino}-3-oxobutanoate. MS (APCI): m/z 320 (M+NH4), 303 (M+H).