Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[C:4]#[N:5].[CH2:11]1[O:21][C:15]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[O:14][CH:12]1[CH3:13]>CN(C=O)C.CCOCC.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:11]1[O:21][C:15]2([CH2:20][CH2:19][N:18]([C:2]3[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=3[C:4]#[N:5])[CH2:17][CH2:16]2)[O:14][CH:12]1[CH3:13]
Reactant: Cc1ccc(F)c(C#N)c1
Reactant: CC1COC2(CCNCC2)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1ccc(N2CCC3(CC2)OCC(C)O3)c(C#N)c1

Procedure:
A solution of 2-fluoro-5-methylbenzonitrile (2.76 g, 20.4 mmol) and 4-piperidone propylene ketal (3.39 g, 21.5 mmol) in DMF (50 mL) was heated in an oil bath (90° C., 20 h). The mixture was diluted with ether and sodium carbonate solution. The aqueous layer was extracted with two additional portions of ether and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. PCTLC (SiO2, 6 mm, 50-0% hexane/CHCl3) afforded the title compound (29).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.N1(O)C2C=CC=CC=2N=N1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=1>>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]2[N:8]([C:4]([CH2:3][O:37][C:33]3[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=3)=[C:5]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[N:6]=2)[CH:9]=1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CCl)cc1
Reactant: Oc1cccnc1
Agent: Cl
Agent: On1nnc2ccccc21
Product: Cc1ccc(-c2nc3ccc(C)cn3c2COc2cccnc2)cc1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochloride and 1H-benzo[d][1,2,3]triazol-1-ol. and pyridin-3-ol. m/e+ 350 for C21H20N3O [M+H]+; 1H-NMR (400 MHz, CDCl3) δ 8.38 (d, J=1.8 Hz, 1H), 8.27 (dd, J=1.8, 4.4 Hz, 1H), 8.21 (d, J=2.5 Hz, 1H), 8.02 (d, J=4.4 Hz, 1H), 7.91 (s, 1H), 7.59 (dd, J=1.4, 8.0 Hz, 2H), 7.23 (d, J=1.4, 8.0 Hz, 2H), 7.15 (m, 2H), 5.42 (s, 2H), 2.36 (s, 3H), 2.35 (s, 3H) ppm.
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[S:4][C:3]=1[CH3:17].C([Li])CCC.CN(C)[CH:25]=[O:26].Cl>O1CCCC1>[CH3:17][C:3]1[S:4][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)=[CH:6][C:2]=1[CH:25]=[O:26]
Reactant: Cc1sc(-c2cccc(C(F)(F)F)c2)cc1Br
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1sc(-c2cccc(C(F)(F)F)c2)cc1C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
The compound (0.83 g) obtained in Example 129a was dissolved in tetrahydrofuran (15 mL), cooled to −78° C., and n-butyllithium (2.5M hexane solution, 1.24 mL) was added. The mixture was stirred at the same temperature for 1 hr, N,N-dimethylformamide (1.0 mL) was added, the reaction mixture was warmed to room temperature and stirred for 1 hr. 1N Hydrochloric acid (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane/ethyl acetate) to give the title compound (0.45 g) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:4][C:3]=1[N+:19]([O-])=O.CO.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:19][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1cc(OCCOCc2ccccc2)ccc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1ccc(OCCOCc2ccccc2)cc1N

Procedure:
1.6 G. of 2-amino-4-(2-benzyloxyethoxy)-1-nitrobenzene is treated in 100 ml. of methanol and 50 ml. of water with 10 g. of sodium hydrosulfite (Na2S2O4) on the steam bath for 15 minutes. The reaction mixture is concentrated under vacuum and extracted with chloroform. Evaporation of the extract affords 1,2-diamino-4-(2-benzyloxyethoxy)benzene.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24]([C:26]1[N:27]=[C:28]([N:31]2[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]2)[S:29][CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:26]3[N:27]=[C:28]([N:31]4[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]4)[S:29][CH:30]=3)[CH2:23][C:22](=[O:37])[NH:21][C:9]=2[CH:10]=1
Reactant: Cc1cn(-c2nc(C(=O)CC(=O)Nc3cc(-c4ccccc4F)ccc3NC(=O)OC(C)(C)C)cs2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cn(-c2nc(C3=Nc4ccc(-c5ccccc5F)cc4NC(=O)C3)cs2)cn1

Procedure:
Prepared from (2′-fluoro-3-{3-[2-(4-methyl-imidazol-1-yl)-thiazol-4-yl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example K75) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (75 mg).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].CN(C)[CH:16]=[CH:17][C:18]([C:20]1[C:21]([O:32][CH3:33])=[C:22]([N:27]([CH3:31])[C:28](=[O:30])[CH3:29])[CH:23]=[C:24]([F:26])[CH:25]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[F:26][C:24]1[CH:25]=[C:20]([C:18]2[N:6]3[N:5]=[CH:4][C:3]([C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])=[C:2]3[N:1]=[CH:16][CH:17]=2)[C:21]([O:32][CH3:33])=[C:22]([N:27]([CH3:31])[C:28](=[O:30])[CH3:29])[CH:23]=1
Reactant: COc1c(C(=O)C=CN(C)C)cc(F)cc1N(C)C(C)=O
Reactant: Nc1[nH]ncc1C(=O)c1cccs1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1c(-c2ccnc3c(C(=O)c4cccs4)cnn23)cc(F)cc1N(C)C(C)=O
Yield: 40.5 %

Procedure:
A mixture of 0.180 g (0.93 mmol) of (5-amino-1H-pyrazol-4-yl)-thiophene-2-yl-methanone and 0.275 g (0.93 mmol) of N-[3-(3-dimethylamino-acryloyl)-5-fluoro-2-methoxy-phenyl]-N-methyl-acetamide in 10 mL of glacial acetic acid was refluxed for 2.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 mL of dichloromethane. The organic layers were washed with 10 mL of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 160 mg of N-{5-fluoro-2-methoxy-3-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-acetamide as a solid (yield 40%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([N:15]([CH3:17])[CH3:16])=[N:11][N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.O1CCC[CH2:19]1.[H-].[Na+].IC>C(O)(=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:19])[C:10]([N:15]([CH3:17])[CH3:16])=[N:11][N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: CN(C)C(=N[N+](=O)[O-])NCc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CI
Product: CN(C)C(=N[N+](=O)[O-])N(C)Cc1ccc(Cl)nc1
Reaction time: 0.5 h

Procedure:
To a mixture of 0.24g of 1-(6-chloro-3-pyridylmethyl)-3,3-dimethyl-2-nitroguanidine (Compound No. 6) and 6ml of dry tetrahydrofuran (THF) was added 0.045g of 60% sodium hydride (in mineral oil) at room temperature, followed by stirring for 30 minutes. A solution of 0.16g of iodomethane in lml of THF was added to the reaction mixture and allowed to react for 3 days. After adding 0.lml of acetic acid, the mixture was filtered to remove insoluble materials and the filtrate was concentrated. The residue was purified by a column chromatography [developing solvent: dichloromethanemethanol (20:1)] to obtain 0.17g of 1-(6-chloro-3-pyridylmethyl)-1,3,3-trimethyl-2-nitroguanidine (Compound No. 14) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:15]([C:16]([O:18]CC)=[O:17])=[C:5]2[CH:6]=[C:7]([C:10]([O:12]CC)=[O:11])[CH:8]=[CH:9][N:4]2[N:3]=1.[OH-].[Na+].O>C(O)C>[CH3:1][C:2]1[C:15]([C:16]([OH:18])=[O:17])=[C:5]2[CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: CCOC(=O)c1ccn2nc(C)c(C(=O)OCC)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nn2ccc(C(=O)O)cc2c1C(=O)O
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
A mixture of diethyl 2-methylpyrazolo[1,5-a]pyridine-3,5-dicarboxylate (100 mg), a 50% aqueous sodium hydroxide solution (160 mg), water (0.5 ml) and ethanol (1.0 ml) was refluxed under heating for 30 min. Then, the reaction mixture was adjusted to pH 4 under ice-cooling and stirred at the same temperature for 30 min. The precipitate was collected by filtration and washed with water to give the objective compound (50 mg) as a pale-brown powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:17]([NH2:19])=[C:16]([O:20][CH3:21])[C:15]([O:22][CH3:23])=[CH:14][C:13]=3[N:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[C:24](N1C=CN=C1)(N1C=CN=C1)=[S:25]>ClCCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:9]3[C:18]4[C:13]([N:12]=[CH:11][N:10]=3)=[CH:14][C:15]([O:22][CH3:23])=[C:16]([O:20][CH3:21])[C:17]=4[NH:19][C:24]2=[S:25])=[CH:6][CH:7]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COc1cc2ncnc(Nc3ccc(Cl)cc3)c2c(N)c1OC
Solvent: ClCCCl
Product: COc1cc2ncnc3c2c(c1OC)NC(=S)N3c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a solution of N4-(4-chloro-phenyl)-6,7-dimethoxy-quinazoline-4,5-diamine (120 mg, 0.36 mmol) (from Example 13, Step B, supra) in 1,2-dichloroethane (30 mL) was added 1,1′-thiocarbonyldiimidazole (0.65 g, 3.63 mmol) (Aldrich). The reaction mixture was heated with stirring at 90° C. for 4 hours. The solvents were evaporated and the residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:3:0.05) as eluent to give the desired 3-(4-chloro-phenyl)-8,9-dimethoxy-1H,3H-1,3,4,6-tetraaza-phenalene-2-thione as a yellow solid. (Yield 110 mg, 82%).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH2:5].Cl[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P(=O)(O)(O)O.O.S(=O)(=O)(O)O.C=CC1C=CC=CC=1>>[CH3:11][CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:2]=2)[CH2:5]1
Reactant: C=Cc1ccccc1Cl
Reactant: ClCCc1ccccc1
Agent: O=P(O)(O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C=Cc1ccccc1
Product: CC1CC(c2ccccc2)c2ccccc21

Procedure:
A mixture of 115 parts of o-chlorostyrene and 35 parts of o-chloroethylbenzene is added to a mixture of 652 parts of 78 per cent strength by weight phosphoric acid and 20 parts of sulfuric acid monohydrate at 30° to 35° C, whilst stirring vigorously. A mixture of 90 parts of styrene, 115 parts of o-chlorostyrene and 35 parts of o-chloroethylbenzene is then added at 30° to 35° C over 5 hours. After completion of the addition, the mixture is stirred for a further 2 hours and the organic phase is separated off and washed with 200 parts of 3 per cent strength by weight sodium hydroxide solution. Fractional distillation at 10 mm Hg gives 25 parts of 1-methyl-3-phenylindan, 30 parts of 1-methyl-3-(o-chloro)-phenylindan (b.p. 165° to 168° C (10 mm), nD25 : 1.5890) and 28 parts of 1-methyl-3-(o-chloro)-phenyl-7-chloroindan (b.p. 195° to 200° C (10 mm)).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18]O)[CH2:13][CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:39]1[CH2:43][C:42](=[O:44])[NH:41][C:40]1=[O:45].N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][CH2:18][N:41]2[C:42](=[O:44])[CH2:43][O:39][C:40]2=[O:45])[CH2:15][CH2:16]1
Reactant: O=C1COC(=O)N1
Reactant: OCCC1CCN(c2ccc3ccccc3n2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1COC(=O)N1CCC1CCN(c2ccc3ccccc3n2)CC1

Procedure:
The process is performed according to the procedure described in Example 5 (step 5.2). Starting with 2.22 g (8.65 mmol) of 2-[1-(2-quinolyl)-4-piperidyl]-ethanol, prepared in step 8.1, 2.50 g (9.52 mmol) of triphenylphosphine, 1.05 g (10.38 mmol) of 1,3-oxazolidine-2,4-dione and 1.75 g (8.65 mmol) of diisopropyl azodicarboxylate (DIAD), and after chromatography on silica gel, eluting with a 30/70 and then 40/60 mixture of ethyl acetate and cyclohexane, 2.63 g of product are obtained in the form of an amorphous white solid.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)=[CH:5][CH:4]=1.[C:24]([C:32](O)=[O:33])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(Cl)CCl>C(Cl)Cl>[O:31]=[C:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:32]([N:11]([CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:22])[F:23])=[CH:8][CH:7]=1)[C:12]1[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=1)=[O:33]
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: FC(F)(F)c1ccc(CCNc2ccc(C(F)(F)F)nc2)cc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(C(=O)N(CCc1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)nc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66 %

Procedure:
To a solution of [2-(4-trifluoromethyl-phenyl)-ethyl]-(6-trifluoromethyl-pyridin-3-yl)-amine (50 mg) in CH2Cl2 (3 mL) was added under a nitrogen atmosphere at 0° C. benzoyl formic acid (1.1 eq., commercially available) and EDC (1.1 eq). After stirring for 12 h a ambient temperature, the mixture was washed with aqueous Na2CO3 (saturated, 2.5 mL) and water (2.5 mL), the combined aqueous layers were extracted with CH2Cl2 (3×2.5 mL) and the combined organic layers dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 60:40) afforded the title compound (46 mg, 66%) as a light yellow solid. MS m/e: 467.2 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][C:5]2[S:8][C:9]([C:11]([O-:13])=O)=[N:10][C:4]=2[CH2:3]1.[Li+].Cl.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH:32]([C:36](=[O:47])[NH:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[O:45][CH3:46])[CH2:31]1)(=[O:29])=[O:28])[CH:21]=[CH:20]2>>[ClH:16].[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][N:33]([C:11]([C:9]3[S:8][C:5]4[CH2:6][NH:7][CH:2]([CH3:1])[CH2:3][C:4]=4[N:10]=3)=[O:13])[CH:32]([C:36](=[O:47])[NH:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[O:45][CH3:46])[CH2:31]1)(=[O:28])=[O:29])[CH:21]=[CH:20]2
Reactant: CC1Cc2nc(C(=O)[O-])sc2CN1
Reactant: COc1ccccc1CNC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1
Agent: Cl
Agent: [Li+]
Product: COc1ccccc1CNC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1nc2c(s1)CNC(C)C2

Procedure:
Starting materials: lithium 6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate, 1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-[[N-(2-methoxybenzyl)]carbamoyl]piperazine hydrochloride
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][NH2:10].[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=O>>[CH2:17]([O:16][C:11](=[O:15])[C:12](=[N:10][NH:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[Br:1])[CH3:14])[CH3:18]
Reactant: Cc1cccc(NN)c1Br
Reactant: CCOC(=O)C(C)=O
Product: CCOC(=O)C(C)=NNc1cccc(C)c1Br

Procedure:
The title compound, ISP-MS: m/e=299.3 and 301.3 (M+H+), was prepared in accordance with the general method of example 25b) from (2-bromo-3-methyl-phenyl)-hydrazine and ethyl pyruvate.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]3[N:14]([C:6]=2[C:5]([CH3:15])=[N:4][N:3]=1)[CH:13]=[CH:12][CH:11]=[CH:10]3.[CH3:16][N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[CH2:22][CH2:23][NH2:24].[Cl-].[NH4+]>>[CH3:15][C:5]1[N:4]=[N:3][C:2]([NH:24][CH2:23][CH2:22][CH:18]2[CH2:19][CH2:20][CH2:21][N:17]2[CH3:16])=[C:7]2[C:6]=1[N:14]1[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]1)=[CH:8]2
Reactant: Cc1nnc(Cl)c2cc3ccccn3c12
Reactant: CN1CCCC1CCN
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1nnc(NCCC2CCCN2C)c2cc3ccccn3c12

Procedure:
Following the procedure of Example 1, reaction of one equivalent of 1-chloro-4-methylpyridazino[4,5-b]indolizine, ten equivalents of 2-(1-methyl-2-pyrrolidinyl)ethylamine and one equivalent of ammonium chloride under reflux in a nitrogen atmosphere for 3 to 4 hours gave the title compound as the free base after removal of excess amine in vacuo and treatment of the residue with boiling ethyl acetate. The solid collected upon filtration was converted to the hydrochloride salt (methanol/ethereal HCl/ether), mp 169° C.
Reaction SMILES: [O:1]=[C:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]1[C:14]([OH:16])=[O:15])[CH:3]=[CH2:4].[C:17]([OH:25])(=[S:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[C:17]([S:24][CH2:4][CH2:3][C:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]1[C:14]([OH:16])=[O:15])=[O:1])(=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C=CC(=O)N1c2ccccc2CC1C(=O)O
Reactant: OC(=S)c1ccccc1
Solvent: ClCCl
Product: O=C(SCCC(=O)N1c2ccccc2CC1C(=O)O)c1ccccc1
Reaction time: 1 h

Procedure:
To a stirring mixture of 2,3-dihydro-1-(1-oxo-2-propenyl)-1H-indole-2-carboxylic acid (6.52 g.) and methylene chloride (160 ml.) was added dropwise thiobenzoic acid (95%, 4.36 g.) dissolved in a small amount of methylene chloride. During the addition, the reaction mixture was chilled in ice. The ice bath was removed in 10 minutes after the completion of the addition, but the stirring was continued for 1 hour. The reaction mixture was then immersed in an oil bath maintained at 80° for 2.5 hours. The reaction mixture was concentrated on a rotary evaporator under reduced pressure to ca. 30 ml., and kept in a refrigerator for 1 day. A precipitate was collected on a filter and washed with methylene chloride to give the titled compound which melted at 173°-175°, and weighed 11.0 g.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:12][C:13]1[N:14]=[C:15]([CH2:18][CH3:19])[S:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:18]([C:15]1[S:16][CH:17]=[C:13]([CH2:12][O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:14]=1)[CH3:19]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCc1nc(CCl)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc(COc2ccc([N+](=O)[O-])cc2)cs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 34.6 %

Procedure:
A mixture of 4-nitrophenol (5.48 g), 4-chloromethyl-2-ethyl-1,3-thiazole (7.40 g), potassium carbonate (5.45 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-ethyl-4-[(4-nitrophenoxy)methyl]-1,3-thiazole as colorless crystals (3.60 g, yield 35%) from a fraction eluted with hexane-ethyl acetate (4:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 79-80° C.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.P(Br)(Br)([Br:16])=O.C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O>[Br:16][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: O=P(Br)(Br)Br
Reactant: COc1ccc2c(O)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1ccc2c(Br)ccnc2c1
Temperature: 0 °C

Procedure:
22.74 g of 4-hydroxy-7-methoxyquinoline are added to 200 g of phosphorus oxybromide preheated to a temperature in the region of 110° C. The reaction medium is heated at this same temperature for 3 hours. The reaction medium is poured, while hot, into a mixture of 500 ml of EtOAc and 500 ml of ice-cold water. The medium is neutralized with potassium carbonate to pH 7. After separation of the phases by settling, the organic phase is dried over magnesium sulfate, evaporated under reduced pressure and then purified by column chromatography (SiO2, EtOAc/cyclohexane 50/50 by volume as eluents, Ar), and 14.6 g of the expected product are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:26]([O:27][CH2:28][CH3:29])=[CH:25][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:24])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([OH:23])[CH:16]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:30][CH2:31][CH3:32].[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([O:30][CH2:31][CH3:32])=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:15]3[CH:16]=[C:17]([O:23][S:34]([CH3:33])(=[O:36])=[O:35])[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=3)=[O:24])[CH2:9][CH2:8]2)=[CH:25][C:26]=1[O:27][CH2:28][CH3:29]
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cc(O)cc(OC)c3)CC2)cc(OCC)c1Cl
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(OS(C)(=O)=O)c3)CC2)cc(OCC)c1Cl

Procedure:
In analogy to the procedure described in example 72a), N-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-3-hydroxy-5-methoxy-benzamide (example 258) was reacted with methanesulfonyl chloride, N-ethyl-diisopropylamine in CH2Cl2 at rt to yield the title compound as colorless solid. MS: 541.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH:13]3[CH2:14][CH2:15][CH:9]2[CH2:10][O:11][CH2:12]3)[CH:5]=[C:4]([CH2:16]Cl)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][NH:25][CH3:26]>CN(C=O)C>[CH:13]12[N:8]([C:6]3[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([CH2:16][N:25]([CH3:26])[CH3:24])[CH:5]=3)[CH:9]([CH2:15][CH2:14]1)[CH2:10][O:11][CH2:12]2
Reactant: CNC
Reactant: ClCc1cc(N2C3CCC2COC3)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)Cc1cc(N2C3CCC2COC3)nc(Cl)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.7 %

Procedure:
A flask was charged with 8-(2-chloro-6-(chloromethyl)pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane (2.30 g, 8.39 mmol) and DMF (40 ml) was added to give a yellow solution. Potassium carbonate (2.90 g, 20.97 mmol) and dimethylamine (2.0M in THF, 4.6 ml, 9.23 mmol) were added and the reaction was allowed to stir at room temperature for 16 hours. The reaction mixture was filtered through a Buchner funnel and washed with methylene chloride and ethyl acetate. The filtrate was concentrated to provide crude product as a brown oil, which solidified upon standing (2.61 g). The crude product was added to a silica gel column and was eluted with 0-10% methanol in methylene chloride to provide 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-chloropyrimidin-4-yl)-N,N-dimethylmethanamine (2.01 g, 85%) as an off-white solid. HRMS; [M+H]+ Obs'd=283.1320, [M+H]+ Calc'd=283.1319.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21]OS(C)(=O)=O)[CH2:10]1.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+]>CS(C)=O>[C:1]([CH2:21][C@@H:11]1[CH2:10][C@@H:9]([CH2:8][C:7]2[CH:27]=[CH:28][C:29]([Cl:30])=[C:5]([Cl:4])[CH:6]=2)[CH2:13][N:12]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])#[N:2]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1C[C@H](Cc2ccc(Cl)c(Cl)c2)C[C@H]1COS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](Cc2ccc(Cl)c(Cl)c2)C[C@H]1CC#N
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 98.3 %

Procedure:
Sodium cyanide (4.3 g, 87.4 mmol) was added to a solution of crude (2S,4R)-4-(3,4-dichlorobenzyl)-1-tert-butoxycarbonyl-2-(methanesulfonyloxymethyl)pyrrolidine (7.7 g, 17.5 mmol) in dry DMSO (120 mL) and the mixture was heated at 80° C. with stirring for 3.5 hrs. The reaction mixture was cooled and worked up between EtOAc and aqueous Na2CO3. Vacuum drying of the product afforded 6.34 g (17.2 mmol) of (2S,4R)-2-(cyanomethyl)-4-(3,4-dichloro-benzyl)-1-tert-butoxycarbonylpyrrolidine as an amber oil.