Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[NH:7][CH:8]=1.[CH3:23][N:24]([CH3:29])[S:25](Cl)(=[O:27])=[O:26].O>CN(C)C=O.C(Cl)Cl.CC(C)=O>[I:3][C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:15][CH:16]=2)[N:7]([S:25]([N:24]([CH3:29])[CH3:23])(=[O:27])=[O:26])[CH:8]=1
Reactant: Ic1c[nH]c(CCc2ccc(-c3ccccn3)cc2)n1
Reactant: CN(C)S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: O
Product: CN(C)S(=O)(=O)n1cc(I)nc1CCc1ccc(-c2ccccn2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium hydride (384 mg, 16 mmol) was added to a solution of 2-{4-[2-(4-iodo-1H-imidazol-2-yl)ethyl]phenyl}pyridine (5 g, 13.3 mmol) in dimethylformamide (100 mL) at 0° C. After stirring at 0° C. for 1 hr, dimethylsulfamoyl chloride (2.15 mL, 20 mmol) was added. After stirring at rt overnight, the reaction mixture was poured into water and extracted with ethyl acetate. The extracts were washed with brine, dried (sodium sulfate) and concentrated to give a residue. Chromatography of the residue over silica gel eluting with 0-20% acetone methylene chloride afforded 4-iodo-N,N-dimethyl-2-[2-(4-pyridin-2-ylphenyl)ethyl]-1H-imidazole-1-sulfonamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].Br[CH2:13][C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:8]([C:6]1[CH:5]=[CH:4][C:3]([O:11][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:2]([CH3:1])[CH:7]=1)(=[O:9])[CH3:10]
Reactant: COC(=O)CBr
Reactant: CC(=O)c1ccc(O)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(C(C)=O)cc1C
Reaction time: 66 h

Procedure:
A mixture of 4-hydroxy-3-methylacetophenone (5 g), methyl bromoacetate (3.70 ml) and anhydrous potassium carbonate (5.52 g) in acetone (100 ml) was stirred for 66 hours. The mixture was filtered and the liltrate evaporated to give an oil which crystallised on standing giving methyl 4-acetyl-2-methylphenoxyacetate, 7.2 g: m.p. 51°-53° C.; NMR (d6DMSO) δ7.79 (1H, s), 7.77 (1H, d), 6.94(1H,d), 4.93 (2H, s), 3.71 (3H, s), 2.50 (3H, s+DMSO), 2.24 (3H, s).
Reaction SMILES: [Br-].[CH2:2]([N+:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+]>CO>[CH2:2]([N:9]1[CH2:14][CH2:13][CH:12]=[C:11]([CH3:15])[CH:10]1[CH2:16][NH:17][C:18](=[O:19])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccc[n+](Cc2ccccc2)c1CNC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Product: CC1=CCCN(Cc2ccccc2)C1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
To a solution of 1-benzyl-2-(((tert-butoxycarbonyl)amino)methyl)-3-methylpyridin-1-ium bromide (10.9 g, 35 mmol) in MeOH (500 ml) was added NaBH4 (3.95 g, 104 mmol) in three portions at 0° C. The solution was then stirred for 3 h at rt and then concentrated in vacuo. The crude residue was taken up in EtOAc and washed with sat aq. NaHCO3, dried (MgSO4), and concentrated. The crude residue was purified by chromatography on silica gel (EtOAc/hexanes) to give the title compound as a pale yellow oil (6.67, 61%). MS (ESI) 317 (M+H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:17])=[CH:16][N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7]([O:18][CH2:19][CH2:20][O:21][CH3:22])[C@H:6]([O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C@H:5]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:3])[CH3:2].C1C(=O)N([Cl:43])C(=O)C1>C(O)C>[C:1]([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:17])=[C:16]([Cl:43])[N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7]([O:18][CH2:19][CH2:20][O:21][CH3:22])[C@H:6]([O:23][C:24](=[O:29])[C:25]([CH3:26])([CH3:27])[CH3:28])[C@H:5]1[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COCCO[C@@H]1c2ccn3cc(C)nc3c2N(C(C)=O)[C@H](c2ccccc2)[C@H]1OC(=O)C(C)(C)C
Solvent: CCO
Product: COCCO[C@@H]1c2ccn3c(Cl)c(C)nc3c2N(C(C)=O)[C@H](c2ccccc2)[C@H]1OC(=O)C(C)(C)C
Reaction time: 2 h

Procedure:
To a of 0° C. cooled solution of 1.00 g (2.10 mmol) (7R,8R,9R)-10-acetyl-7-(2-methoxyethoxy)-2-methyl-9-phenyl-8-pivaloyloxy-7.8.9.10-tetrahydroimidazo[1.2-h][1.7]naphthyridine in ethanol (20 ml) is added 0.28 g (2.10 mmol) NCS and the mixture is stirred for 2 h. Afterwards the reaction is quenched by adding of saturated aqueous sodium hydrogen carbonate solution and is extracted twice with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulphate and evaporated in vacuo. The crude product is purified by column chromatography (ethyl acetate/cylohexane: 1/1) to provide 0.89 g (1.73 mmol/82%) of the title compound as a colourless solid with a melting point of 167–170° C. (cyclohexane).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH:4]([NH2:33])[CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([NH2:32])=[N:20][C:21]([C:23]2[C:28]([NH2:29])=[N:27][C:26]([NH2:30])=[C:25]([Cl:31])[N:24]=2)=[O:22])=[CH:10][CH:9]=1.O.[OH-].[Li+]>CO.C1COCC1.O>[NH2:33][CH:4]([CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([NH2:32])=[N:20][C:21]([C:23]2[C:28]([NH2:29])=[N:27][C:26]([NH2:30])=[C:25]([Cl:31])[N:24]=2)=[O:22])=[CH:12][CH:13]=1)[C:3]([OH:34])=[O:2]
Reactant: COC(=O)C(N)CCOc1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: NC(=NC(=O)c1nc(Cl)c(N)nc1N)NCCCCc1ccc(OCCC(N)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Amino-4-(4-{4-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]butyl}-phenoxy)butyric acid methyl ester (140) (110 mg, 0.223 mmol) was dissolved in a mixture of methanol (1 mL)/THF (1 mL)/water (1 mL). Lithium hydroxide monohydrate (14 mg, 0.334 mmol) was added and the reaction mixture was stirred at room temperature for 16 h before it was concentrated in vacuo. The resulting residue was diluted with water (1 mL), acidified to pH 2 with 1N aqueous HCl, and purified through a DOWEX 50WX 8-200 ion exchange resin eluting with 10% aqueous ammonium hydroxide. The desired product was obtained as a yellow solid (75 mg, 70% yield). 1H NMR (300 MHz, CD3OD) δ 1.55-1.78 (m, 4H), 2.10-2.45 (m, 2H), 2.52-2.65 (m, 2H), 3.30-3.35 (m, 2H), 3.65-3.75 (m, 1H), 4.05-4.15 (m, 2H), 6.85 (d, J=8.5 Hz, 2H), 7.10 (d, J=8.5 Hz, 2H). m/z (ESI) 479 [C20H27ClN8O4+H]+. mp 178-180° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:13]=[O:14])=[CH:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38](Cl)(=[O:40])=[O:39]>>[CH3:1][C:2]1[C:3]([CH:13]=[O:14])=[CH:4][N:5]([S:38]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=2)(=[O:40])=[O:39])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: Cc1c(C=O)c[nH]c1-c1ccccc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: Cc1c(C=O)cn(S(=O)(=O)c2ccccn2)c1-c1ccccc1

Procedure:
By a reaction under similar conditions as in Reference Example 65 and using 4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (185 mg), sodium hydride (60% in oil, 60 mg), 15-crown-5 (0.30 mL) and 2-pyridinesulfonyl chloride (231 mg) instead of 3-pyridinesulfonyl chloride hydrochloride, the title compound was obtained as an amorphous form (yield 262 mg, 80%).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][C:6](=[O:9])[CH2:7][Cl:8])=O.CN(C1C=CC=CN=1)C.[CH2:19]([O:21][CH:22]([O:24][CH:25]1[CH2:37][CH2:36][C:35]([O:39][CH:40]([O:42][CH2:43][CH3:44])[CH3:41])(C)[CH:34](O)C=[CH:32][CH:31]([CH3:46])[CH:30](/[C:47](/[CH3:68])=[CH:48]/[CH:49]=[CH:50]/[CH:51]([CH3:67])[CH2:52][CH:53]2[O:66][CH:54]2[CH:55]([CH3:65])[CH:56]([O:59][CH:60]([O:62][CH2:63][CH3:64])[CH3:61])[CH2:57][CH3:58])[O:29][C:27](=[O:28])[CH2:26]1)[CH3:23])[CH3:20].C(N(CC)CC)C>ClCCl.O.C(OCC)(=O)C>[Cl:8][CH2:7][C:6]([O:5][CH:3]1[C:35]([O:39][CH:40]([O:42][CH2:43][CH3:44])[CH3:41])([CH3:34])[CH2:36][CH2:37][CH:25]([O:24][CH:22]([O:21][CH2:19][CH3:20])[CH3:23])[CH2:26][C:27]([O:29][CH:30](/[C:47](/[CH3:68])=[CH:48]/[CH:49]=[CH:50]/[CH:51]([CH3:67])[CH2:52][CH:53]2[O:66][CH:54]2[CH:55]([CH3:65])[CH:56]([O:59][CH:60]([O:62][CH2:63][CH3:64])[CH3:61])[CH2:57][CH3:58])[CH:31]([CH3:46])[CH:32]=[CH:2]1)=[O:28])=[O:9]
Reactant: CCOC(C)OC1CCC(C)(OC(C)OCC)C(O)C=CC(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Reactant: O=C(CCl)OC(=O)CCl
Agent: CCOC(C)OC1CCC(C)(OC(C)OCC)C(O)/C=C/C(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Agent: CCOC(C)OC1CCC(C)(OC(C)OCC)C(OC(=O)CCl)/C=C/C(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCOC(C)OC1CCC(C)(OC(C)OCC)C(OC(=O)CCl)C=CC(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Reaction time: 1 h

Procedure:
A solution of chloroacetic anhydride (21.5 mmol, 0.122 mmol) and dimethylaminopyridine (1.2 mg, 10 μmol) in dichloromethane (0.5 mL) were added to a solution of (8E,12E,14E)-3,6,21-tri(1-ethoxyethoxy)-7-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (17.4 mg, 24.4 μmol) and triethylamine (25 mg, 0.244 mmol) in dichloromethane (2 mL) at room temperature, followed by stirring at the same temperature for one hour. Ethyl Acetate and water were added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and then evaporated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40 to 50 μm, ethyl acetate-hexane=1:4) to obtain the declared compound (18.1 mg, 94%) as a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:4].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(#N)C>[Cl:15][C:11]1[CH:10]=[C:9]2[C:14]([C:6]([NH:5][C:3](=[O:4])[CH2:2][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[N:7][NH:8]2)=[CH:13][CH:12]=1
Reactant: C1COCCN1
Reactant: O=C(CCl)Nc1n[nH]c2cc(Cl)ccc12
Solvent: CC#N
Product: O=C(CN1CCOCC1)Nc1n[nH]c2cc(Cl)ccc12

Procedure:
Working as in Example 75, starting with 500 mg of 2-chloro-N-(6-chloro-1H-indazol-3-yl)acetamide, 15 cm3 of acetonitrile and 0.54 cm3 of morpholine. The reaction medium is refluxed for 2 hours and then concentrated to dryness under reduced pressure (2.7 kPa; 50° C.) and the crude product obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with ethyl acetate. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.), then dried (90 Pa; 45° C.) to give 470 mg of N-(6-chloro-1H-indazol-3-yl)-4-morpholineacetamide in the form of a white powder melting at about 82-90° C.
Reaction SMILES: [Si:1]([O:8][CH:9]([CH:23]([CH3:25])[CH3:24])[C:10](=[O:22])[CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CO[CH:28](OC)[N:29]([CH3:31])[CH3:30]>C1(C)C=CC=CC=1>[Si:1]([O:8][CH:9]([CH:23]([CH3:25])[CH3:24])[C:10](=[O:22])/[C:11](=[CH:28]/[N:29]([CH3:31])[CH3:30])/[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)C(O[Si](C)(C)C(C)(C)C)C(=O)CC(=O)OCc1ccccc1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CC(C)C(O[Si](C)(C)C(C)(C)C)C(=O)/C(=C/N(C)C)C(=O)OCc1ccccc1
Temperature: 110 °C
Reaction time: 18 h
Yield: 29.9 %

Procedure:
To a solution of benzyl 4-{[tert-butyl(dimethyl)silyl]oxy}-5-methyl-3-oxohexanoate (0.39 g, 1.06 mmol) in toluene (5.3 mL) were added 1,1-dimethoxy-N,N-dimethylmethanamine (0.21 mL, 1.59 mmol). The mixture was heated to 110° C. After 18 h, excess amount of 1,1-dimethoxy-N,N-dimethylmethanamine was added and the mixture was concentrated. Purification by silica gel chromatography (75% hexanes/ethyl acetate 25% hexanes/ethyl acetate) gave the title compound (0.133 g).
Reaction SMILES: [F:1][C:2]1([F:21])[O:6][C:5]2[C:7]([Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:4]=2[O:3]1.[CH2:22](OCC)C.C[Si](C=[N+]=[N-])(C)C>CO>[CH3:22][O:12][C:11]([C:9]1[CH:8]=[C:7]([Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[C:5]2[O:6][C:2]([F:1])([F:21])[O:3][C:4]=2[CH:10]=1)=[O:13]
Reactant: CCOCC
Reactant: CC[Si](CC)(CC)c1cc(C(=O)O)cc2c1OC(F)(F)O2
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: CC[Si](CC)(CC)c1cc(C(=O)OC)cc2c1OC(F)(F)O2
Reaction time: 1 h

Procedure:
22.0 g of 2,2-difluoro-7-triethylsilanyl-benzo[1,3]dioxole-5-carboxylic acid were dissolved using 200 ml of diethyl ether and 100 ml of methanol. Then, 35.0 ml of a 2M solution of trimethylsilyldiazomethane was added at 10° C.-20° C. Stirring was continued for 1 h at room temperature and the mixture then evaporated. Chromatography on silica gel using EA/HEP 1:10 yielded 17.0 g of the title compound, colorless oil. Rf (EA/HEP 1:20)=0.39
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:11][C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH3:10].[CH2:19]([O:21]C=O)C>>[CH2:9]([O:11][C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][CH:19]=[O:21])[CH3:10]
Reactant: CCOC=O
Reactant: CCOC(=O)CCCCN
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCNC=O

Procedure:
1.4 ml of triethylamine are added to 1.8 g of 5-aminovaleric acid ethyl ester hydrochloride in 40 ml of formic acid ethyl ester and the whole is then heated under reflux for 2 hours. The precipitate is filtered off, washed with a small quantity of formic acid ethyl ester and concentrated by evaporation under reduced pressure in a rotary evaporator. The residue is partitioned between methylene chloride and sodium bicarbonate solution, and the organic phase is then washed with brine, dried and concentrated by evaporation. The title compound is obtained in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22](O)=[O:23])=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([NH:32]O)=[NH:31])=[CH:28][N:27]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:16])([F:18])[F:17])[N:12]3[N:19]=[CH:20][C:21]([C:22]4[O:23][N:32]=[C:30]([C:29]5[CH:34]=[CH:35][C:26]([NH2:25])=[N:27][CH:28]=5)[N:31]=4)=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Reactant: N=C(NO)c1ccc(N)nc1
Product: Nc1ccc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(Cl)c(Cl)c5)nc34)n2)cn1

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.9) (188 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate/heptane) and further purification by crystallization (dichloromethane/hexane) as a yellow solid (35 mg, 14%). MS (ISP) 492.0 [(M+H)+]; mp 289° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[N:7]3[CH2:15][CH2:14][NH:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.Br[CH:18]([CH2:20][CH3:21])[CH3:19]>CN(C=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[N:7]3[CH2:15][CH2:14][N:13]([CH:18]([CH2:20][CH3:21])[CH3:19])[CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCC(C)Br
Reactant: O=c1c2ccc(Br)cc2nc2n1CCNC2
Solvent: CN(C)C=O
Product: CCC(C)N1CCn2c(nc3cc(Br)ccc3c2=O)C1

Procedure:
A solution of 9-bromo-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one (30 mg, 0.11 mmol) and excess 2-bromobutane in DMF (5 mL) was stirred at 140° C. for 6 h. Then the reaction mixture was concentrated and purified by column chromatography to give the desired product. MS (ESI): 336, 338 (MH+).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[N:8][C:7]=1[NH2:13])[CH2:4][CH3:5])[CH3:2].Cl[CH2:15][C:16](=O)[CH3:17].C(=O)(O)[O-].[Na+]>C(O)C.C(OCC)(=O)C>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([CH:15]=[C:16]([CH3:17])[N:13]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nnc1N
Reactant: CC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2cc(C)nc12
Temperature: 100 °C

Procedure:
Heat 850 mg (4.74 mmol) of 4-(1-ethyl-propyl)-6-methyl-pyridazin-3-ylamine and 0.415 ml (5.22 ml) of chloroacetone in 20 ml of ethanol in microwave at 110° C. for 35 minutes. Add 1.2 g (14.2 mmol) of sodium bicarbonate and heat in oil bath with reflux condensor at 100° C. overnight. Evaporate solvents, take up in ethyl acetate and wash 3 X's with brine. Dry over sodium sulfate, filter, and evaporate to a brown oil. Chromatograph using hexanes to 6:1 hex:ethyl acetate to ethyl acetate gradient. Collect title compound as oil weighing 3.69 g (17.0 mmol, 84.4%). 1H-NMR (DMSO-d6): δ 7.34 (s, 1H); 6.84 (s, 1H); 2.85-3.10 (m, 1H); 2.43 (s, 3H); 2.32 (s, 3H); 1.70-1.80 (m, 4H); 0.712 (t, J=7.49 Hz, 6H) ppm. MS/ES+=219 (100%, M+2).
Reaction SMILES: O1CCCC1.[CH3:6][N:7]1[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]1.[C:14](=S)=[S:15]>>[N:13]([CH:10]1[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]1)=[C:14]=[S:15]
Reactant: CN1CCC(N)CC1
Reactant: S=C=S
Solvent: C1CCOC1
Product: CN1CCC(N=C=S)CC1
Temperature: -10 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred mixture of 412 parts of N,N'-methanetetraylbis[cyclohexanamine] and 2225 parts of tetrahydrofuran there were added dropwise 1092 parts of carbon disulfide and, after cooling to -10° C., portionwise 228 parts of 1-methyl-4-piperidinamine. The whole was stirred for 1 hour at room temperature and was then evaporated. The residue was recrystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 416.6 parts (100%) of 4-isothiocyanato-1-methylpiperidine (interm. 16).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]([OH:18])=O)=[CH:10]2)=[CH:5][CH:4]=1.Cl.Cl.[NH2:22][CH:23]1[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1.C(CC(CC)([NH-])C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1.CN(C=O)C>[N:25]12[CH2:30][CH2:29][CH:28]([CH2:27][CH2:26]1)[CH:23]([NH:22][C:16]([C:11]1[CH:12]=[CH:13][C:14](=[O:15])[N:9]([C:6]3[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:19])=[CH:8][CH:7]=3)[CH:10]=1)=[O:18])[CH2:24]2
Reactant: CN(C)c1ccc(-n2cc(C(=O)O)ccc2=O)cc1
Reactant: NC1CN2CCC1CC2
Agent: CCCC(C)([NH-])CC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)c1ccc(-n2cc(C(=O)NC3CN4CCC3CC4)ccc2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
After 300 mg (1.18 mmol) of 1-(4-dimethylaminophenyl)-1,6-dihydro-6-oxo-3-pyridinecarboxylic acid was dissolved in 20 mL of tetrahydrofuran and 2 mL of DMF, 391 mg (1.96 mmol) of 3-aminoquinuclidine dihydrochloride and 460 mg (3.54 mmol) of diethyliso-propylamide were added to the solution. After the reaction solution was stirred at room temperature for about 30 minutes, 600 g (1.57 mmol) of 0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) was added to the reaction solution. This reaction solution was stirred at room temperature for about 20 hours. After termination of the reaction was determined by liquid chromatography, the solvent was removed in vacuo, followed by extraction three times with chloroform and an aqueous NaOH solution (pH 12) and purification using liquid chromatography (chloroform:methanol:ammonia water=10:1:0.1) to obtain a target compound (Actual yield: 158 mg, Percent yield: 31%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13](Br)[CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH3:27][S:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29]>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:12]=[C:13]([C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([S:28]([CH3:27])(=[O:30])=[O:29])[CH:36]=2)[CH:14]=[CH:15][CH:16]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1cccc(Br)c1)c1ccc(Cl)c(Cl)c1
Product: CC(C)(C)OC(=O)NC(C(=O)c1cccc(-c2cccc(S(C)(=O)=O)c2)c1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[2-(3-Bromo-phenyl)-1-(3,4-dichloro-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and 3-methylsulfonylphenylboronic acid in analogy to Example 1b): MS (ISP): 551.5 ((M+NH4)+, MS (ISN): 532.2 (M−H)−
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].C1COCC1.[C:10]([C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([Cl:25])[C:21]=1[N:22]([CH3:24])[CH3:23])[CH:17]=[O:18])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C:14]1[CH:15]=[C:16]([CH:17]([OH:18])[C:1]#[CH:2])[CH:19]=[C:20]([Cl:25])[C:21]=1[N:22]([CH3:23])[CH3:24])([CH3:13])([CH3:11])[CH3:12]
Reactant: CN(C)c1c(Cl)cc(C=O)cc1C(C)(C)C
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC(O)c1cc(Cl)c(N(C)C)c(C(C)(C)C)c1
Yield: 48.9 %

Procedure:
In a manner analogous to example 1 e, the process is carried out by a reaction of 13 ml (6.5 mmol) of 0.5M ethynylmagnesium bromide/THF with 1.2 g (5 mmol) of 3-tert-butyl-5-chloro-4-dimethylaminobenzaldehyde. 650 mg of 1-(3-tert-butyl-5-chloro-4-dimethylamino-phenyl)prop-2-yn-1-ol are obtained in the form of a yellow solid (yield=49%).
Reaction SMILES: [N:1]1([C:7]2[C:16]3[CH2:17][CH:18]([CH3:19])[N:14]4[C:15]=3[C:10]([C:11](=[O:23])[C:12]([C:20]([OH:22])=[O:21])=[CH:13]4)=[C:9]([NH2:24])[C:8]=2[F:25])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:27](I)(F)F.CI>CN(C)C=O>[CH3:27][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[C:16]3[CH2:17][CH:18]([CH3:19])[N:14]4[C:15]=3[C:10]([C:11](=[O:23])[C:12]([C:20]([OH:22])=[O:21])=[CH:13]4)=[C:9]([NH2:24])[C:8]=2[F:25])[CH2:2][CH2:3]1
Reactant: FC(F)(F)I
Reactant: CC1Cc2c(N3CCNCC3)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Solvent: CN(C)C=O
Solvent: CI
Product: CC1Cc2c(N3CCN(C)CC3)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23

Procedure:
To a mixture of 9-(1-piperazinyl)-8-fluoro-7-amino-2-methyl-1,2-dihydro-6-oxo-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid (3.45 g) and dimethylformamide (20 ml) is added a dimethylformamide solution (20 ml) of trifluoromethyl iodide containing methyl iodide (7.7 g), and the mixture is reacted in a stainless steel autoclave on an oil bath at 110°-120° C. for 5 hours. After completion of reaction, dimethylformamide is distilled off under reduced pressure, and to the residue is added a 10% aqueous sodium hydroxide solution. Insoluble materials are removed by filtration. The filtrate is regulated to pH 8 with acetic acid, and the precipitated crystal is separated by filtration, washed with water, and dried to give 9-(4-methyl-1-piperazinyl)-8-fluoro-7-amino-2-methyl-1,2-dihydro-6-oxo-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid (1.82 g) as yellow cubic crystals. m.p. 240°-243° C.