Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])[CH:8]=1)[CH3:2].[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:24])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:15]2[CH:20]=[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:18]=[CH:17][C:16]=2[F:22])=[O:23])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cccc(NC(=O)c2cc(Br)ccc2F)c1
Reactant: OB(O)c1ccccc1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2cc(-c3ccccc3)ccc2F)c1

Procedure:
The phenyl bromide (106) (100 mg, 0.25 mmol) was coupled to phenylboronic acid (34 mg, x 0.28 mmol) using Method E. The residue was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][N:11]([CH3:18])[C:12]1[NH:16][N:15]=[C:14]([NH2:17])[CH:13]=1.CCN(C(C)C)C(C)C>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][C:14]2[CH:13]=[C:12]([N:11]([CH3:18])[CH3:10])[NH:16][N:15]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CN(C)c1cc(N)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CN(C)c1cc(Nc2nc(Cl)ncc2F)n[nH]1
Yield: 39 %

Procedure:
2,4-dichloro-5-fluoropyrimidine (166 mg, 1 mmol), N5,N5-dimethyl-1H-pyrazole-3,5-diamine (Method 34, 150 mg, 1.2 mmol), and DIEA (0.35 ml, 2 mmol) in ethanol (3 ml) was heated at 55° C. overnight. Solvent was removed, and the residue was purified by silica gel chromatography (by ISCO Combiflash with a gradient of 0-5% methanol in methylene chloride with 1% NH4OH). 100 mg product was obtained as a white solid (40%). MS: 257 (M+1); NMR (DMSO-d6, 400 MHz, 80° C.) δ11.60 (br, 1H), 10.26 (br, 1H), 8.23 (s, 1H), 5.73 (s, 1H), 2.76 (s, 6H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][C:22]([NH2:26])=[CH:23][C:24]=3[CH2:25][C@H:14]12>>[NH2:26][C:22]1[CH:21]=[CH:20][C:19]2[C@@H:15]3[C@@H:14]([N:13]([C:10]([C:8]4[CH:7]=[CH:6][C:5]5[NH:1][CH:2]=[N:3][C:4]=5[CH:9]=4)=[O:12])[CH2:18][CH2:17][CH2:16]3)[CH2:25][C:24]=2[CH:23]=1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: Nc1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Product: Nc1ccc2c(c1)C[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Yield: 30 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-7-ylamine following a procedure analogous to that described in Example 1. Yield: 30% of theory; LC (method 1): tR=0.79 min; Mass spectrum (ESI+): m/z=333 [M+H]+.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:4])[CH:2]=[CH2:3].[CH:10]([NH2:13])([CH3:12])[CH3:11]>>[CH:10]([NH:13][CH2:3][CH2:2][C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4])([CH3:12])[CH3:11]
Reactant: C=CC(=O)OCCCC
Reactant: CC(C)N
Product: CCCCOC(=O)CCNC(C)C
Yield: 81.2 %

Procedure:
27.8 g of n-butyl acrylate are added dropwise to 15.6 g of isopropylamine under ice-cooling and stirring. The mixture is further stirred at room temperature for 5 hours. Then, the reaction mixture is distilled under reduced pressure. 33 g of n-butyl 3-isopropylaminopropionate are thereby obtained as a colorless oil.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:16]=[CH:15][C:11]([CH2:12][C:13]#[N:14])=[CH:10][CH:9]=1.Cl[C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21]>CN(C)C=O>[C:20]([C:19]1[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=1[CH:12]([C:13]#[N:14])[C:11]1[CH:15]=[CH:16][C:8]([F:7])=[CH:9][CH:10]=1)#[N:21]
Reactant: N#CCc1ccc(F)cc1
Reactant: N#Cc1ccccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1C(C#N)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 700 gr potassium tert-butoxide in 3.6 ltr N,N-dimethylformamide (DMF) is added gradually a solution of 401.4 gr 4-fluorobenzylcyanide and 429.2 gr 2-chlorobenzonitrile in 1.2 ltr DMF, maintaining an internal temperature between 25° C. and 30° C. (ice bath). The reaction mixture is subsequently stirred for one hour at ambient temperature and quenched with dilute hydrochloric acid. Extractive work-up with diethylether gives the product 2-cyano-4'-fluorobenzhydrylcyanide.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH:13]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1>>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:18]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:19])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: O=C(Cl)C1CCCC1
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)C1CCCC1
Yield: 74.1 %

Procedure:
5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H) and cyclopentanecarbonyl chloride (173 mg, 1.30 mmol) were processed as described in Example 29, Step A to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopentanecarboxamide (210 mg, 74% yield). 1H NMR (400 MHz, (CD3)2SO) δ 12.04 (br s, 1H), 8.34 (d, 1H), 7.56 (s, 1H), 2.88-2.80 (m, 1H), 1.89-1.81 (m, 2H), 1.77-1.64 (m, 4H), 1.57-1.53 (m, 2H); LCMS (APCI+) m/z 326, 327.9 (M+H)+, Retention time=3.18 minutes (Method 2).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[CH:33]=[CH:32][C:14]2[N:15]=[C:16]([CH2:21][CH2:22][CH2:23][CH2:24][N:25]([CH2:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28])[N:17]([CH2:18][CH2:19][CH3:20])[C:13]=2[CH:12]=1)=O.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH2:29]([N:25]([CH2:26][CH2:27][CH3:28])[CH2:24][CH2:23][CH2:22][CH2:21][C:16]1[N:17]([CH2:18][CH2:19][CH3:20])[C:13]2[CH:12]=[C:11]([CH2:9][OH:8])[CH:33]=[CH:32][C:14]=2[N:15]=1)[CH2:30][CH3:31]
Reactant: CCCN(CCC)CCCCc1nc2ccc(C(=O)OC)cc2n1CCC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCCN(CCC)CCCCc1nc2ccc(CO)cc2n1CCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
Lithium aluminum hydride (138 mg) was suspended in THF (7.0 ml) and then the whole was cooled to 0° C. After that, a THF solution (7.0 ml) containing the compound (361 mg) obtained in Example 3-3 was dropped in the suspension, followed by stirring at 0° C. for 1 hour. After completion of the reaction, sodium sulfate decahydrate was added to the solution until bubbling was stopped, and a 1 mol/l sodium hydroxide aqueous solution was then added to the mixture until a white precipitate was generated. The solid component was separated through filtration and the solvent was then distilled off from the filtrate under reduced pressure. The residue was dried under vacuum, thereby obtaining the subject compound (302 mg) as a pale-yellow oily substance.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=3)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:24]1([C:27](Cl)=[O:28])[CH2:26][CH2:25]1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[C:1]1([C:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:27]([CH:24]4[CH2:26][CH2:25]4)=[O:28])[CH:18]=3)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cc(-c2nc(-c3ccccc3)c(-c3nnc[nH]3)s2)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: O=C(Nc1cc(-c2nc(-c3ccccc3)c(-c3nnc[nH]3)s2)ccn1)C1CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.4 %

Procedure:
A mixture of 4-[4-phenyl-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]pyridin-2-amine (150 mg, 0.47 mmol) produced in Example 2-B, cyclopropanecarbonyl chloride (0.13 mL, 1.40 mmol) and pyridine (5 mL) was stirred at room temperature for 6 hr. To the reaction mixture was added cyclopropanecarbonyl chloride (0.085 mL, 0.94 mmol) and the mixture was stirred at room temperature for 1 day. To the reaction mixture was added aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→100/0), and 1N aqueous sodium hydroxide solution (0.5 mL), methanol (5 mL) and tetrahydrofuran (10 mL) were added to the crude product. The mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and water was added to the obtained residue. After neutralization with 1N hydrochloric acid, the resulting precipitate was collected by filtration, washed with water and diethyl ether and dried to give the title compound (145 mg, 80%) as a pale-yellow solid.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[Br:9][CH:10]([CH3:14])[C:11]([OH:13])=[O:12].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:5]1[C:6](=[O:7])[N:2]([OH:1])[C:3](=[O:8])[CH2:4]1.[Br:9][CH:10]([CH3:14])[C:11]([O-:13])=[O:12]
Reactant: CC(Br)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: CC(Br)C(=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
N-hydroxysuccinimide (4.51 g, 39.22 mmol) and 2-bromopropionic acid (2.9 mL, 32.68 mmol) were dissolved in anhydrous DCM (1000 ml) in a 2000 mL round-bottomed flask under nitrogen equipped with a magnetic stirrer. The flask was then cooled to 0° C. with an ice bath before the dropwise addition of a solution of N,N′-Dicyclohexylcarbodiimide (6.70 g, 32.68 mmol) in 50 mL of anhydrous DCM. After addition, the mixture was stirred at room temperature overnight. The reaction mixture was then filtered and the solvent evaporated to give a yellow solid that was purified by flash chromatography (CC, SiO2, Et2OO, Rf(ester)=0.31). Obtained 7.2 g (28.91 mmol, 74%) of product as a white solid. Melting point: 69-70° C. 1H NMR (CDCl3) δ (ppm) 1.96 (d, 3H, CH(CH)Br, J=6.78 Hz), 2.86 (s, 4H, Hcycl), 4.61 (q, 1H, CH(CH3)Br, J=7.03 Hz). 13C NMR (CDCl3) δ (ppm) 21.67 (1C, CH(CH3)Br) 25.74 (2C, Ccycl), 34.97 (1C, CH(CH3)Br), 166.17 (1C, C═O), 168.69 (2C, Ccycl═O). IR (solid, ATR cell) ν (cm−1) 1808, 1781 (Ccycl═O), 1729 (C═O). Mass spectroscopy (+EI, m/z) 248.964. Elem. Anal. Theoretical for C7H8NO4Br: C, 33.62; H, 3.22; N, 5.60. Found: C, 33.47; H, 3.16; N, 5.46.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1.[OH:13][C:14]1[N:19]=[C:18]([C:20](Cl)=[O:21])[CH:17]=[CH:16][CH:15]=1>>[CH3:12][O:11][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:20]([C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:13])[N:19]=3)=[O:21])[S:3][C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: COc1cccc2sc(N)nc12
Reactant: O=C(Cl)c1cccc(O)n1
Product: COc1cccc2sc(NC(=O)c3cccc(O)n3)nc12
Yield: 5 %

Procedure:
Using 2-Amino-4-methoxybenzothiazole (450 mg, 2.5 mmol) and 6-hydroxypicolinic acid chloride (1.5 g, 10 mmol) the title compound was obtained as a beige powder in 5% yield. MS: m/e=301 (M+).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[CH2:20]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:21]1[O:23][CH2:22]1>O1CCCC1.O>[C:25]1([O:24][CH2:20][CH:21]([OH:23])[CH2:22][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: Cc1cccnc1
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OC(CCc1cccnc1)COc1ccccc1
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
Under argon gas, a solution of diisopropylamine (1.67 g, 16.5 mmol) in tetrahydrofuran (5 mL) was added dropwise to n-butyllithium (1.53 M in hexane, 9.8 mL, 15 mmol) at 5° C. and the mixture was stirred for 30 minutes. To this was further added a solution of 3-methylpyridine (2.794 g, 30 mmol) in tetrahydrofuran (5 mL) dropwise at 5° C., and the mixture was stirred for 30 minutes. Then, a solution of phenyl glycidyl ether (1.50 g, 10 mmol) in tetrahydrofuran (5 mL) was added at 5° C. and the reaction was carried out for 2 hours. This reaction mixture was diluted with 20 mL of water for hydrolysis, and extracted with 30 mL of ethyl acetate. The organic layer was washed with 20 mL of water twice and the solvent was distilled off under reduced pressure to give a deep-red oil. This oil was purified by silica gel column chromatography (Merck's Kieselgel 60, hexane/ethyl acetate=1/2) to give 1.911 g (isolation yield: 79%) of 1-O-phenyl-4-(3-pyridyl)-1,2-butanediol (yellow oil).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH3:12][O:13][CH2:14][CH2:15]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:12][O:13][CH2:14][CH2:15][O:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: COCCO
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COCCOc1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 89.8 %

Procedure:
To a mixture of 4-hydroxy-2-nitroaniline (25.0 g), 2-methoxyethanol (21.0 g), tributylphosphine (49.2 g) and tetrahydrofuran (700 mL) was added 1,1′-(azodicarbonyl)dipiperidine (61.3 g) at room temperature, and the mixture was stirred at room temperature for 2.5 days. The precipitate was filtered off, and the filtrate was concentrated. Diisopropyl ether was added to the residue, and the insoluble substance was filtered off. The filtrate was concentrated, and the residue was subjected to basic silica gel column chromatography, and eluted with hexane-ethyl acetate (2:1, volume ratio). The obtained crude product was further subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-2:1, volume ratio) to give the title compound (30.9 g, yield 90%) as orange crystals. The crystals were recrystallized from hexane-ethyl acetate to give orange prism crystals. melting point 89-90° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:23](O)=[O:24].[CH2:26]([S:33][CH:34]([CH:37]([O:40][CH3:41])[O:38][CH3:39])[CH2:35][NH2:36])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[CH2:26]([S:33][CH:34]([CH:37]([O:38][CH3:39])[O:40][CH3:41])[CH2:35][NH:36][C:23]([C:5]1[N:4]([CH2:3][O:2][CH3:1])[C:12]2[C:7]([CH:6]=1)=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)(=[O:16])=[O:15])=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COCn1c(C(=O)O)cc2cccc(NS(=O)(=O)c3ccccn3)c21
Reactant: COC(OC)C(CN)SCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCn1c(C(=O)NCC(SCc2ccccc2)C(OC)OC)cc2cccc(NS(=O)(=O)c3ccccn3)c21
Yield: 105.2 %

Procedure:
A solution of 1-(methoxymethyl)-7-[(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.94 g), 2-(benzylthio)-3,3-dimethoxypropan-1-amine (0.70 g), N-ethyldiisopropylamine (1.0 mL) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.2 g) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 20 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=4:6-6:4) to give the title compound (1.6 g, yield: 100%) as a pale-yellow oil. MS: 553 (MH+).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][C:17]3([C:23]([OH:25])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)(=[O:15])=[O:14])=[CH:10][CH:11]=2)[C:6]([NH:26][C:27]([NH2:29])=[NH:28])=[N:5][CH:4]=1.Cl.N[C:32](N)=N.ClC1C2C(=CC=C(S(NC3(C(OC)=O)CCCCC3)(=O)=O)C=2)C(Cl)=CN=1.O>CS(C)=O>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][C:17]3([C:23]([O:25][CH3:32])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)(=[O:14])=[O:15])=[CH:10][CH:11]=2)[C:6]([NH:26][C:27]([NH2:29])=[NH:28])=[N:5][CH:4]=1
Reactant: N=C(N)N
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)NC3(C(=O)O)CCCCC3)cc12
Agent: COC(=O)C1(NS(=O)(=O)c2ccc3c(Cl)cnc(Cl)c3c2)CCCCC1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C1(NS(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)CCCCC1
Temperature: 60 °C
Yield: 5.8 %

Procedure:
1-{[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}cyclohexanecarboxylic acid hydrochloride ##STR54## NaH (22.3 mg, 80% dispersion by wt in mineral oil, 0.743 mmol) was added in one portion to a stirred solution of guanidine hydrochloride (117 mg, 1.98 mmol) in DMSO (5 mL) and the mixture was heated at 50-70° C. under N2 for 25 min. Methyl 1-{[(1,4-dichloro-7-isoquinolinyl)sulphonyl]amino}-cyclohexanecarboxylate (124 mg, 0.30 mmol) was added in one portion and the mixture heated at 80° C. for 8 h. The cooled mixture was poured into water (50 mL), extracted with EtOAc (2×50 mL) and the combined organic extracts were washed with water, brine, dried (MgSO4) and evaporated in vacuo. The residue was crystallised from a minimum of hot EtOAc to give methyl 1-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}cyclohexanecarboxylate (12 mg, 0.043 mmol) as yellow solid. Evaporation of the mother liquors and trituration of the residue with Et2O gave a second crop (7 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[CH:11]=1.[I-].[Na+].[OH:14][CH2:15][C:16]([O:18]CC)=[O:17].[H-].[Na+].ICC1N=C2C=CC=CN2C=1>O1CCCC1>[N:4]1[C:3]([CH2:2][O:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:11][N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=12
Reactant: CCOC(=O)CO
Reactant: ClCc1cn2ccccc2n1
Agent: ICc1cn2ccccc2n1
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: O=C(O)COCc1cn2ccccc2n1
Temperature: 0 °C
Yield: 69.1 %

Procedure:
4.24 g (25.4 mmol) of 2-(chloromethyl)imidazo[1,2-a]pyridine were dissolved in 150 ml of tetrahydrofurane with magnetic stirring and then 4.2 g (28 mmol) of sodium iodide were added. The mixture was stirred at r.t. for 3 h. In another flask, 9.84 ml (101.8 mmol) of ethyl 2-hydroxyacetate were solubilized in 100 ml of tetrahydrofurane with magnetic stirring, and then the mixture was cooled to 0° C. and 4.072 g (101.8 mmol) of sodium hydride were added portionwise. The mixture was stirred 15 min at 0° C. and then the freshly prepared solution of 2-(iodomethyl)imidazo[1,2-a]pyridine in tetrahydrofurane was added drop wise within 15 min. The mixture was stirred at r.t. for 24 h before being filtered on silica (eluent: tetrahydrofurane 100%). The filtrate was concentrated in vacuo and directly purified by flash chromatography on a silica gel cartridge (eluent: dichloromethane/methanol gradient, from 100% to 70% of dichloromethane, v/v; and then washing the cartridge with 100% methanol). 3.62 g (yield=69%) of 2-(imidazo[1,2-a]pyridin-2-ylmethoxy)acetic acid were obtained as a beige solid. LC-MS: m/z=207 (MH+); UV purity at 254 nm=98%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([I:11])=[CH:8][C:6]=2[N:7]=1.[C:18]([NH:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)(=[O:20])[CH3:19]>C([O-])([O-])=O.[Na+].[Na+].C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([C:26]3[CH:27]=[C:22]([NH:21][C:18](=[O:20])[CH3:19])[CH:23]=[CH:24][CH:25]=3)([I:11])[CH2:8][C:6]=2[N:7]=1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)Nc1cccc(C2(I)Cc3nc(Cl)nc(N4CCOCC4)c3S2)c1
Yield: 53 %

Procedure:
2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19, 129 mg of 3-acetamidophenylboronic acid (250 mg) and 23 mg of bis(triphenylphosphine)palladium(II) dichloride in 1.5 mL of 1M Na2CO3 aqueous solution and 1.5 mL of acetonitrile was heated to 100° C. in a sealed microwave reactor for 15 min. Upon completion, the reaction mixture was evaporated. The crude product was purified by flash chromatography eluting with 20˜100% EtOAc/hexane to yield N-(3-(2-chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine-6-yl)phenyl)acetamide (530 mg, 53%).
Reaction SMILES: [CH:1]1([N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8](Cl)=[S:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28]>>[O:28]=[C:19]1[C:20]2[C:21](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:23])[N:18]1[O:17][C:8](=[S:9])[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: S=C(Cl)N(C1CCCCC1)C1CCCCC1
Product: O=C1c2ccccc2C(=O)N1OC(=S)N(C1CCCCC1)C1CCCCC1

Procedure:
This compound was prepared in analogy to example 8 starting from 24.94 g (0.096 mol) of dicyclohexyl-thiocarbamoyl chloride (prepared as described in (Chem. Ber., 101, (1968), 113) and N-hydroxyphthalimide. Yield 9.65 g of white crystals after recrystallization from hexane, mp. 148-150° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:11]C(=O)N(C)C)[CH:8]=2)[CH2:3]1.[OH-].[K+].Br[C:20]([CH3:29])([CH3:28])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CO>[C:24]([O:23][C:21](=[O:22])[C:20]([S:11][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH2:3][CH:2]([NH2:1])[CH2:10]2)([CH3:29])[CH3:28])([CH3:27])([CH3:26])[CH3:25]
Reactant: CN(C)C(=O)Sc1ccc2c(c1)CC(N)C2
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)C(C)(C)Sc1ccc2c(c1)CC(N)C2
Temperature: 25 °C
Yield: 76.3 %

Procedure:
To dimethylthiocarbamic acid S-(2-aminoindan-5-yl) ester (4.9 g; 20.9 mmol), dissolved in MeOH (60 mL) is added a solution of KOH (11.8 g; 10 0.210 mol) in MeOH (110 mL) at RT. The solution is stirred at reflux for 5 h and cooled to RT. tert-Butyl 2-bromoisobutyrate (7.0 g; 31.3 mmol) is added to the solution and stirred for 18 h at RT. The solvent is evaporated under reduced pressure and the crude residue partitioned between H2O and EtOAc. The aqueous phase is extracted with EtOAc and the combined organic extracts were washed with H2O, brine, dried over Na2SO4, filtered and evaporated under reduced pressure to afford 4.9 g (76%) of 2-(2-aminoindan-5-ylsulfanyl)-2-methylpropionic acid tert-butyl ester as a brown oil.