Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:6](=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[S:5][C:4]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:3]1.[NH2:27][CH2:28][C@H:29]([OH:44])[CH2:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([OH:43])=[C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:37]=1>>[OH:43][C:35]1[CH:34]=[CH:33][C:32]([O:31][CH2:30][C@@H:29]([OH:44])[CH2:28][NH:27][CH:17]2[CH2:16][CH2:15][N:14]([C:11]3[CH:12]=[CH:13][C:8]([CH:7]=[C:6]4[S:5][C:4]([N:21]5[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]5)=[N:3][C:2]4=[O:1])=[CH:9][CH:10]=3)[CH2:19][CH2:18]2)=[CH:37][C:36]=1[NH:38][S:39]([CH3:42])(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Nc1cc(OC[C@@H](O)CN)ccc1O
Reactant: O=C1CCN(c2ccc(C=C3SC(N4CCCCC4)=NC3=O)cc2)CC1
Product: CS(=O)(=O)Nc1cc(OC[C@@H](O)CNC2CCN(c3ccc(C=C4SC(N5CCCCC5)=NC4=O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 1-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one (which was obtained in Intermediate 25) and N-[5-((2S)-3-amino-2-hydroxy-propoxy)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Intermediate 14) according to the procedure of Example 1 as a yellowish solid; mp>95° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2 H), 1.55-1.70 (m, 6 H), 1.85-2.00 (m, 2 H), 2.55-2.90 (m, 6 H), 2.92 (s, 3 H), 3.60 (br s, 2 H), 3.70-3.95 (m, 6 H), 6.61 (dd, J=8.8, 2.9 Hz, 1 H), 6.75-6.80 (m, 2 H), 7.02 (d, J=9.0 Hz, 2 H), 7.45 (d, J=9.0 Hz, 2 H), 7.50 (s, 1 H); MS (ES) m/z: 315.6 ((M+2H)2+, 100%); 630.1 (MH+, 100%); HRMS Calcd. for C30H40N5O6S2 (MH+): 630.2420. Found: 630.2397.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C@H:10]([NH:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=1[CH:20]=[N:21][NH:22]3)=[O:16])[CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C:36](Cl)=[O:37])[CH2:32][CH2:31]1.O>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C@H:10]([NH:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=1[CH:20]=[N:21][N:22]3[C:36]([N:33]1[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]1)=[O:37])=[O:16])[CH2:9][CH2:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: CC(C)(C)c1ccc2c(c1)CC[C@H]2NC(=O)Nc1cccc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(C(=O)n2ncc3c(NC(=O)N[C@@H]4CCc5cc(C(C)(C)C)ccc54)cccc32)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of the product from Example 56J (240 mg, 0.69 mmol) in N,N-dimethylformamide (5 mL) was treated with 60% NaH (45 mg, 1.13 mmol) and stirred at room temperature for 15 min. 4-methylpiperazine carbonyl chloride (1.64 mmol) was then added, and the reaction mixture was stirred overnight at 80° C. It was then cooled to room temperature and poured into H2O, and the resulting precipitate was collected by filtration. Chromatography on silica gel (eluted with 97:3 CH2Cl2-methanol) afforded the desired product. 1H NMR (d6-DMSO) 67 8.59 (s, 1H), 8.07 (s, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.28 (m, 3H), 7.17 (d, J=7.5 Hz, 1H), 6.66 (d, J=7.5 Hz, 1H), 5.17 (m, 1H), 4.44 (m, 2H), 3.48 (m, 2H), 3.02 (m, 1H), 2.90 (m, 1H), 2.81 (m, 1H), 2.53 (s, 3H), 2.42 (m, 1H), 1.80 (m, 1H), 1.27 (s, 9H). MS (DCI) m/z 475 (M+H). C27H34N6O2.0.5H2O: C, 67.06; H, 7.29; N, 17.38. Found: C, 66.87; H, 7.22; N, 17.04.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1>C(Cl)Cl>[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:2][CH3:1])=[O:9])=[CH:6][CH:5]=1
Reactant: CN
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Product: CNC(=O)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
The starting material is prepared as follows: To a mixture of 1250 ml of a 40% aqueous solution of methylamine and 1250 ml of methylene chloride, cooled in an ice bath, is added with stirring a solution of 500 g of 4-chlorobenzoyl chloride in 625 ml of methylene chloride. After the addition (50 minutes), the mixture is stirred for an additional 2 hours. The white precipitate is filtered off and air dried and the methylene chloride layer of the filtrate is dried and evaporated to give the crude 4-chloro-N-methyl-benzamide, which, after crystallization from 1200 ml of methanol, melts at 158°-161°; an additional amount of the product is recovered from the mother liquor, m.p. 158°-160°.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C([CH2:15][S:16]([CH2:19][S:20]([CH2:23][C:24](O)=O)(=[O:22])=[O:21])(=[O:18])=[O:17])(O)=O>C(O)(=O)C>[F:1][C:2]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:15]/[S:16]([CH2:19][S:20](/[CH:23]=[CH:24]/[C:3]1[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:2]=1[F:1])(=[O:22])=[O:21])(=[O:18])=[O:17]
Reactant: N#Cc1ccc(C=O)c(F)c1
Reactant: O=C(O)CS(=O)(=O)CS(=O)(=O)CC(=O)O
Solvent: CC(=O)O
Product: N#Cc1ccc(/C=C/S(=O)(=O)CS(=O)(=O)/C=C/c2ccc(C#N)cc2F)c(F)c1
Yield: 72 %

Procedure:
A solution of 2-fluoro-4-cyanobenzaldehyde (2 mmol) and carboxymethane-sulfonylmethanesulfonyl-acetic acid (1 mmol) in acetic acid (10 mL) was subjected to General Procedure 1, to yield the title compound in 72% yield. m.p. 268-270° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[O:12])[N:10]=2)[CH2:3]1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[CH3:20][S:21]([O:1][CH:2]1[CH2:3][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[O:12])[N:10]=2)[CH2:5]1)(=[O:23])=[O:22]
Reactant: CN1CCN(C(=O)c2csc(N3CC(O)C3)n2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(C(=O)c2csc(N3CC(OS(C)(=O)=O)C3)n2)CC1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 3-hydroxy-1-[4-(4-methylpiperazine-1-carbonyl)-1,3-thiazol-2-yl]azetidine (422 mg, 1.49 mmol) (obtained as described in Reference Example 30(2)) in methylene chloride (21 ml) were added methanesulfonyl chloride (0.14 ml, 1.79 mmol) and triethylamine (0.25 ml, 1.79 mmol) in an ice bath, and then the mixture was stirred for 1 hour. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:methanol (3:1) as the eluant to afford 3-methanesulfonyloxy-1-[4-(4-methylpiperazine-1-carbonyl)-1,3-thiazol-2-yl]azetidine (537 mg, yield 100%) as a pale yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])[CH:4]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:27]([CH2:32][C@H:33]([OH:38])[C:34]([F:37])([F:36])[F:35])[C:28](=[O:31])[NH:29][N:30]=2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:27]([CH2:32][C@H:33]([OH:38])[C:34]([F:36])([F:37])[F:35])[C:28](=[O:31])[N:29]([CH2:2][C:3]3[CH:8]=[CH:7][N:6]=[C:5]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[C:15]([F:18])([F:17])[F:16])[CH:4]=3)[N:30]=2)=[CH:22][CH:21]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: FC(F)(F)c1ccccc1-c1cc(CBr)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=c1n(Cc2ccnc(-c3ccccc3C(F)(F)F)c2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 60 °C
Reaction time: 16 h

Procedure:
145 mg (0.46 mmol) of the compound from Example 64A were dissolved in 3 ml of acetonitrile, and 141 mg (0.46 mmol) of the compound from Example 5A and 224 mg (0.69 mmol) of cesium carbonate were added. The mixture was stirred at 60° C. for 16 h. After cooling to RT, the solid was filtered off and rinsed with a little acetonitrile. Under reduced pressure, the filtrate was reduced to a volume of about 2 ml, 0.1 ml of 1 N hydrochloric acid was added and the product was directly purified chromatographically [Method 19]. This gave 49 mg (20% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([O:17][CH3:18])(=[O:16])[CH2:12][C:13]([CH3:15])=[O:14]>N1C=CC=CC=1.C(O)(=O)CCCCC.C1C=CC=CC=1>[CH3:18][O:17][C:11](=[O:16])[C:12](=[CH:4][C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:10])[C:2]=1[Cl:1])[C:13](=[O:14])[CH3:15]
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1cccc(Cl)c1Cl
Solvent: c1ccccc1
Solvent: CCCCCC(=O)O
Solvent: c1ccncc1
Product: COC(=O)C(=Cc1cccc(Cl)c1Cl)C(C)=O
Reaction time: 4 h

Procedure:
A mixture containing 8.7 g of 2,3-dichlorobenzaldehyde, 5.8 g of methyl acetoacetate, 28 drops of pyridine and 38 drops of hexanoic acid in 280 ml of benzene is brought to reflux with stirring for 4 hours. It is transferred to a separating funnel and washed with 10% strength sodium bicarbonate solution, then with N hydrochloric acid solution and then with water. The mixture is dried and evaporated. The crystals obtained are washed with isopropyl ether.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:13]=[CH:12][C:11]=2[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:9]=1)=[CH2:7])CCC.O.[Br:35]N1C(=O)CCC1=O>O1CCCC1>[Br:35][CH2:5][C:6]([C:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:13]=[CH:12][C:11]=2[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:9]=1)=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(OCCCC)c1cn(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ncc2c(c(C(=O)CBr)cn2COCC[Si](C)(C)C)c1=O
Reaction time: 2 h
Yield: 72.2 %

Procedure:
To 8.80 g (17.8 mmol) of 3-(1-butoxyvinyl)-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 57-(a) were added 21.1 ml of water and 341 ml of tetrahydrofuran, and 100 ml of tetrahydrofuran solution containing 4.70 g (26.4 mmol) of N-bromosuccinimide was added dropwise to the mixture under cooling in ice-bath. After the dropwise addition, the mixture was stirred at the same temperature 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=1:3 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 6.64 g of the title compound as a white solid. (Yield: 72%)
Reaction SMILES: [Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[C:9]([F:16])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:18].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].CN(C)C=O>O>[Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[C:9]([F:16])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:18][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: O=c1c2ccc(O)c(Cl)c2oc2cccc(F)c12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(=O)c3c(F)cccc3oc2c1Cl
Reaction time: 4 h
Yield: 98.7 %

Procedure:
A mixture of 2.6 g of 4-chloro-8-fluoro-3-hydroxy-9-oxo-9H-xanthene, 2.8 g of potassium carbonate, 3.3 g of ethyl bromoacetate and 40 ml of N,N-dimethylformamide (DMF) was stirred at 60°-70° C. for 4 hours. After cooling the mixture, water was added thereto and the resulting crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 3.4 g of ethyl 4-chloro-8-fluoro-9-oxo-9H-xanthene-3-yloxyacetate. A mixture of this ester (3.3 g), sodium hydroxide (1.9 g) and water (100 ml) was refluxed for 30 minutes. After cooling, the mixture was rendered acidic with concentrated hydrochloric acid and the resulting crystal was recovered by filtration and dried. Recrystallization from DMF gave 2.5 g of 4-chloro-8-fluoro-9-oxo-9H-xanthene-3-yloxyacetic acid. m.p. 300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][N:22](C)[CH3:23])[CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.ClC(OC(Cl)C)=O>ClCCCl>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][NH:22][CH3:23])[CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCn1cc(S(=O)(=O)c2cccc(Cl)c2)c2cccnc21
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: CNCCn1cc(S(=O)(=O)c2cccc(Cl)c2)c2cccnc21
Product: Cl
Yield: 108.1 %

Procedure:
A stirred solution under nitrogen of N-(2-{3-[(3-chlorophenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-1-yl}ethyl)-N,N-dimethylamine (0.540 g, 1.49 mmol) in 1,2-dichloroethane is treated with 1-chloroethyl chloroformate (0.40 mL, 3.7 mmol), heated at reflux temperature for 2 h cooled, and concentrated in vacuo. The resultant residue is treated with ethanol, heated at reflux temperature for 2 h and concentrated in vacuo. This resultant residue is chromatographed using 2:98 concentrated NH4OH:ethanol as eluent to afford the free amine of the title product as a semi-solid (311 mg, 60%). The free amine is dissolved in ethanol, treated with 4 M HCl in dioxane and filtered. The filtercake is dried to give the title product as a pale yellow solid, 274 mg (48% yield), mp 263–265° C. (dec.), identified by mass spectral and HNMR analyses.
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=O)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[C:34]1([NH:44]N)[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1>>[CH3:1][CH:2]([CH3:32])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[C:35]4[C:34](=[C:43]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]5=[CH:37][CH:36]=4)[NH:44][C:24]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: NNc1cccc2ccccc12
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCC(=O)c3ccccc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCc3c(-c4ccccc4)[nH]c4c3ccc3ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(7-oxo-7-phenylheptyl)-4-piperidinyl]phenyl)propanamide and 1-(1-naphthyl)hydrazine hydrochloride: ESMS m/e: 558.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3([C:14]([O:16]CC)=[O:15])[CH2:13][CH2:12]3)[N:10]=[C:6]2[C:5]([O:19][CH3:20])=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.CCOC(C)=O.O>[Br:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3([C:14]([OH:16])=[O:15])[CH2:13][CH2:12]3)[N:10]=[C:6]2[C:5]([O:19][CH3:20])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(c2nc3c(OC)ccc(Br)n3n2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Br)n2nc(C3(C(=O)O)CC3)nc12
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To a solution of ethyl 1-(5-bromo-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxylate (3.00 g, 8.82 mmol) in THF (25 mL) was added an aqueous 1 M solution of LiOH (25 mL). The mixture was stirred at 80° C. for 30 minutes, cooled to room temperature and diluted with EtOAc (50 mL) and water (50 mL). The organic phase was extracted with an aqueous 0.1 M solution of NaOH (25 mL) and the combined aqueous phases were acidified with conc. HCl to pH 0-1, and extracted four times with DCM (30 mL). Evaporation to dryness of the combined organic phases yielded the title compound (2.54 g, 94%). 1H NMR (DMSO, 400 MHz): δ=12.61 (s, 1H), 7.42 (d, 1H, J=8.3 Hz), 7.06 (d, 1H, 3=8.3 Hz), 3.97 (s, 3H), 1.53 (q, 2H, 3=3.9 Hz), 1.40 (q, 2H, J=3.9 Hz) ppm.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]([N+:18]([O-])=O)=[C:11]([CH:17]=2)[O:12][CH2:13][CH2:14][C:15]#[N:16])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:28][C:29]1[N:34]=[C:33](Cl)[C:32]([Cl:36])=[CH:31][N:30]=1.O>[Pd].C(O)C>[Cl:28][C:29]1[N:34]=[C:33]([NH:18][C:10]2[CH:9]=[CH:8][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:17][C:11]=2[O:12][CH2:13][CH2:14][C:15]#[N:16])[C:32]([Cl:36])=[CH:31][N:30]=1
Reactant: N#CCCOc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: N#CCCOc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reaction time: 8 h
Yield: 65.6 %

Procedure:
3-(5-Morpholin-4-yl-2-nitro-phenoxy)-propionitrile (209 mg, 0.754 mmol) and 10% Palladium on Carbon (50% Wet) (120 mg) in Ethanol (45 mL) was shaken under an atmosphere of Hydrogen (45 psi) for 1 h. The mixture was filtered, washing with ethanol, and Triethylamine (0.21 mL, 1.5 mmol) and 2,4,5-Trichloro-pyrimidine (0.13 mL, 1.1 mmol) were added to the filtrate. The mixture was stirred overnight, then poured into 100 mL water, then cooled. The solids were collected by filtration, to give 3-[2-(2,5-Dichloro-pyrimidin-4-ylamino)-5-morpholin-4-yl-phenoxy]-propionitrile as a purple solid (195 mg, 66%). 1H-NMR (CDCl3): 8.28 (d, 1H, J=8.0 Hz), 8.16 (s, 1H), 6.65 (d, 1H, J=8.0 Hz), 6.49 (s, 1H), 4.31 (t, 2H, J=5.2 Hz), 3.88 (t, 4H, J=4.1 Hz), 3.15 (t, 4H, J=4.1 Hz), 2.89 (t, 2H, J=5.2 Hz).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](O)(=[O:13])=[O:12])=[C:7]([F:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(C1C=C(F)C=CC=1S(O)(=O)=O)(C)(C)C.P(Cl)(Cl)(Cl)(Cl)[Cl:32]>ClC(Cl)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([Cl:32])(=[O:13])=[O:12])=[C:7]([F:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(C)(C)c1ccc(S(=O)(=O)O)c(F)c1
Agent: CC(C)(C)c1cc(F)ccc1S(=O)(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)(C)c1ccc(S(=O)(=O)Cl)c(F)c1

Procedure:
Synthesized as described for 2 using a 3:1 regioisomeric mixture of 107 (23.68 g; 0.10 mol) and 2-tert-butyl-4-fluorobenzenesulfonic acid, phosphorus pentachloride (23.13 g; 0.11 mol) and dichloroethane (700 mL). The title compound was obtained as a white solid which was a 1:1 regioisomeric ratio of itself and 2-tert-butyl-4-fluorobenzene-1-sulfonyl chloride (10.0 g).
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][C:3](=[O:9])[CH2:2]2.Cl.[CH3:11][NH:12][CH3:13].Cl.[CH3:15]C#N>>[CH3:11][N:12]([CH2:15][CH:4]1[C:3](=[O:9])[CH2:2][CH:1]2[CH2:8][CH:5]1[CH2:6][CH2:7]2)[CH3:13]
Reactant: O=C1CC2CCC(C1)C2
Reactant: CC#N
Reactant: CNC
Agent: Cl
Product: CN(C)CC1C(=O)CC2CCC1C2
Yield: 78.7 %

Procedure:
Stir a mixture of bicyclo[3.2.1]octan-3-one (5.2 g, 41.9 mmol), (HCHO)n (1.51 g, 50.3 mmol), dimethylamine hydrochloride (3.42 g, 41.9 mmol) and 0.5 mL of conc. HCl in MeCN (50 mL) at 80° C. for 2 hours. After removal of the solvent under vacuum, dissolve the residue in H2O (20 mL) and wash with EtOAc (20 mL×3). Basify the aqueous solution with NaOH to pH=10. Extract the resultant aqueous mixture with EtOAc (60 mL×3). The combined organic layers are washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give crude 2-dimethylaminomethyl-bicyclo[3.2.1]octan-3-one as brown oil (5.9 g, yield: 78.7%). MS (m/z): 182 (M+1).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1.[CH2:14]([O:16][C:17]([CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)=[O:18])[CH3:15].O>C(OCC)C>[CH2:14]([O:16][C:17]([CH:19]1[CH2:24][CH2:23][C:22]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=2)([OH:25])[CH2:21][CH2:20]1)=[O:18])[CH3:15]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: Clc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C1CCC(O)(c2ccc(Cl)cn2)CC1
Reaction time: 0.5 h

Procedure:
Butyllithium (15% in hexane; 15 ml) was added dropwise to a solution of 2-bromo-5-chloropyridine (3.8 g) in diethyl ether (80 ml) at −78° C. and, after one hour, a solution of 4-oxocyclohexanecarboxylic acid ethyl ester (3.7 g) in diethyl ether (10 ml) was added dropwise. After 30 minutes, water was cautiously added and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 283.76 (C14H18ClNO3); MS (ESI): 284 (M+H+) was obtained in this way.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[N:6][C:5]([Cl:10])=[C:4]([Cl:11])[N:3]=1.[CH2:12]([Mg]Cl)[CH:13]=[CH2:14].[Cl-].[NH4+]>O1CCCC1.CCOCC>[NH2:1][C:2]1[C:7]([CH:8]([OH:9])[CH2:14][CH:13]=[CH2:12])=[N:6][C:5]([Cl:10])=[C:4]([Cl:11])[N:3]=1
Reactant: Nc1nc(Cl)c(Cl)nc1C=O
Reactant: C=CC[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC(O)c1nc(Cl)c(Cl)nc1N
Reaction time: 0.25 h

Procedure:
In 4 ml of tetrahydrofuran and 4 ml of ether there was dissolved 288 mg (1.5 mMol) of 2-amino-5,6-dichloro-3-formylpyrazine prepared as in Example 1, Step B, after which the reaction mixture was cooled in a dry-ice/acetone bath, followed by addition of 2-propenyl magnesium chloride (1.5 ml). The reaction mixture was stirred for 15 minutes, an ammonium chloride solution was then added, followed by stirring for 15 minutes at room temperature, after which ether was added. The resulting aqueous layer was extracted twice with ether, and the combined extracts and ether layer were washed well with water, dried, and the solvent evaporated. The remaining material was passed through a silica gel column and eluted with dichloromethane to obtain the product (120 mg).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:13][CH2:14][CH:15]1[O:19][C:18]([CH3:21])([CH3:20])[O:17][CH2:16]1)[CH:10]1[O:12][CH2:11]1>C(O)C>[CH2:1]([NH:8][CH2:11][CH:10]([OH:12])[CH2:9][O:13][CH2:14][CH:15]1[O:19][C:18]([CH3:21])([CH3:20])[O:17][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CC1(C)OCC(COCC2CO2)O1
Solvent: CCO
Product: CC1(C)OCC(COCC(O)CNCc2ccccc2)O1
Temperature: 80 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
A 500-ml three-necked flask equipped with a dropping funnel, thermometer and reflux condenser was charged with 174 ml (1.59 mol) of benzylamine and48.0 ml of ethanol. While heating and stirring the mixture at 80° C.in a nitrogen atmosphere, 20.3 g (0.11 mol) of 2,3-(dimethylmethylenedioxy)propyl glycidyl ether were added dropwise over2 hours. After completion of the addition, the heating and stirring were continued for an additional 1 hour under the same conditions. After the reaction mixture was concentrated under reduced pressure, the resulting residue was purified by flash chromatography on silica gel, thereby obtaining 20.4 g (yield: 64%) of the title compound (3a) as a pale yellow oil.
Reaction SMILES: CN1CCN([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[C:11]([C:17]([OH:19])=[O:18])[NH:12]3)CC1.C(N1C=CN=C1)([N:22]1C=CN=C1)=O.[H-].[Na+]>CN(C)C=O>[NH:12]1[C:13]2[C:9](=[CH:8][CH:16]=[CH:15][CH:14]=2)[CH:10]=[C:11]1[C:17]([NH2:22])=[O:19].[NH:12]1[C:13]2[C:9](=[CH:8][CH:16]=[CH:15][CH:14]=2)[CH:10]=[C:11]1[C:17]([O-:19])=[O:18]
Reactant: CN1CCN(c2cccc3[nH]c(C(=O)O)cc23)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc2ccccc2[nH]1
Product: O=C([O-])c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-(4-methylpiperazin-1 yl)indole-2-carboxylic acid (0.259 g, 1.00 mmol) in anhydrous N,N-dimethylformamide (6 mL) at room temperature was added carbonyldiimidazole (0.574 g, 2.00 mmol, 2.0 equivalents). The resulting reaction solution was stirred at room temperature under nitrogen for 2 hours. Then, the appropriate amine (4.00 mmol, 4.0 equivalents) or alcohol (4.00 mmol, 4.0 equivalents) was added directly, and the resulting reaction solution was stirred at room temperature under nitrogen overnight. In the case of alcohols, sodium hydride (60% in oil, 0.160 g, 4.00 mmol, 4.0 equivalents) was added, and the resulting reaction was heated an additional 2 hours at 50° C. The reaction solution was then evaporated under reduced pressure, and redissolved in chloroform (5 mL). Undissolved solid was removed via filtration through Celite®, and the filtrate was evaporated under reduced pressure. The residue was column chromatographed using silica gel (approximately 50 g) and elution with an appropriate solvent system to afford the corresponding indole-2-carboxamide or indole-2-carboxylate.