Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4]1)[CH3:2].[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:8][CH:5]1[CH2:6][CH2:7][N:3]([CH2:1][CH3:2])[CH2:4]1
Reactant: Oc1ccccc1Br
Reactant: CCN1CCC(O)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN1CCC(Oc2ccccc2Br)C1
Temperature: 25 °C

Procedure:
1-Ethyl-3-pyrrolidinol (0.5 ml), 2-bromophenol (0.37 ml) and triphenylphosphine (1.02 g) were dissolved in tetrahydrofuran (10 ml) and the mixture cooled in an ice bath before dropwise addition of diisopropyl azodicarboxylate (0.77 ml). The mixture was allowed to warm to room temperature over 3 h. The mixture was concentrated in vacuo and partitioned between ether (50 ml) and water (50 ml) and the aqueous phase was extracted further with ether (50 ml). The combined organic phases were washed with water (2×25 ml), brine (2×25 ml), dried (MgSO4) and concentrated in vacuo. The product was dissolved in ethyl acetate (50 ml) and extracted with 2M aqueous hydrochloric acid (3×20 ml). The aqueous washings were combined and basified by the addition of solid sodium hydroxide and extracted with ethyl acetate (3×20 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by cation exchange chromatography eluting with ammonia/methanol/dichloromethane mixtures. This gave the title compound as a pale orange oil (529 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:31])[N:5]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:6]([CH:12]([NH:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]3[C:17]=1[N:18]=[CH:19][NH:20]3)[CH2:13]C)=[N:7]2.[Cl:32]C1C=C(C=CC=1)N.NC1C=CC=CC=1.O=C1CCC(=O)N1OC(=O)C(NC(OC(C)(C)C)=O)C.O=C1CCC(=O)N1OC(=O)C(NC(OCC1C=CC=CC=1)=O)CC.C(O)(C(F)(F)F)=O.NC1N=C2C(N=CN2)=C(NC(C2N(C3C=CC=C(C)C=3)C(=O)C3C(=CC=CC=3C)N=2)C)N=1>>[Cl:32][C:29]1[CH:30]=[C:25]([N:5]2[C:4](=[O:31])[C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[CH3:1])[N:7]=[C:6]2[CH:12]([NH:15][C:16]2[N:24]=[CH:23][N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][NH:20]3)[CH3:13])[CH:26]=[CH:27][CH:28]=1
Reactant: CCC(Nc1ncnc2[nH]cnc12)c1nc2cccc(C)c2c(=O)n1-c1ccccc1
Reactant: Nc1cccc(Cl)c1
Agent: CC(NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Agent: CCC(NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: Cc1cccc(-n2c(C(C)Nc3nc(N)nc4[nH]cnc34)nc3cccc(C)c3c2=O)c1
Solvent: Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc2nc(C(C)Nc3ncnc4[nH]cnc34)n(-c3cccc(Cl)c3)c(=O)c12

Procedure:
Compound 66 was prepared using the general procedure described above with respect to compound 14, but 3-chloroaniline was substituted for aniline in step A, 2-tert-butoxycarbonylamino-propionic acid 2,5-dioxopyrrolidin-1-yl ester was substituted for 2-benzyloxycarbonylaminobutyric acid 2,5-dioxo-pyrrolidin-1-yl ester in step B, and the alternate procedure (TFA deprotection) was used in step C. 1H NMR (dmso-d6): 8.40-8.31 (m, 2H); 7.73-7.66 (m, 1H); 7.55-7.32 (m, 6H); 5.04-4.86 (m, 1H); 2.72 (s, 3H); 1.52-1.50 (m, 3H). Compound 65 is shown below.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:19])[CH:16]=[CH:17][N:18]=3)[S:13][C:6]=12.[BH4-].[Na+]>CO.C1COCC1>[F:1][C:2]1[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:19])[CH:16]=[CH:17][N:18]=3)[S:13][C:6]=12
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To a solution of the nitro compound 8 (1.50 g, 4.05 mmol) and NiCl2.6H2O (2.02 g, 8.52 mmol) in MeOH/THF (45 mL/68 mL) at 0° C. was added NaBH4 (0.618 g, 16.3 mmol) portion wise with vigorous stirring. The reaction mixture was stirred for 30 minutes at 0° C. and concentrated under reduced pressure. The resultant black residue was suspended in 1M HCl (10 mL) and the mixture was basified (pH˜11) with cone. NH4OH. The cloudy suspension was filtered; the solid residue was separated, washed with water and dried under reduced pressure to afford the title compound 9 as a brown solid (0.73 g, 52% yield), which was used in the next step without further purification. MS (m/z): 341.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.C(N(CC)CC)C.Cl.[NH:27]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[NH2:28]>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[OH:9])[N:27]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:28]=1
Reactant: CCOC(=O)CNN
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1nc(-c2ccccc2O)nc1-c1ccccc1O

Procedure:
51.5 g of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one, 30.5 ml of triethylamine and 33.4 g of ethyl hydrazinoacetate hydrochloride are boiled under reflux for 0.5 h in 450 ml of ethanol. On cooling, the product precipitates in crystalline form. It is filtered off and washed with ethanol. After drying, ethyl [3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate remains as colorless crystals of m.p. 172-174° C.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]#[C:8][CH2:9][NH:10][C:11](=[O:26])[C:12]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O.C(Cl)(Cl)Cl>[Cl:3][CH2:6][C:7]#[C:8][CH2:9][NH:10][C:11](=[O:26])[C:12]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(NCC#CCO)C(O)(c1ccccc1)C1CCCCC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(NCC#CCCl)C(O)(c1ccccc1)C1CCCCC1

Procedure:
Thionyl chloride (4.8 ml) was added dropwise to a mixture of N-(4-hydroxy-2-butynyl)-2-cyclohexyl-2-hydroxy-2-phenylacetamide (6.56 g) and N,N-dimethylformamide (5 drops) in dry chloroform (145 ml) at 0° C. and the reaction mixture was refluxed for 1 hour. The mixture was washed successively with water, 1N aqueous sodium hydroxide solution, and sodium chloride, aqueous solution, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of n-hexane and ethyl acetate (5:1) as an eluent to give N-(4-chloro-2-butynyl)-2-cyclohexyl-2-hydroxy-2-phenylacetamide as white powder (6.7 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=2[N+:25]([O-])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO>[NH2:25][C:18]1[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:17]=1[CH2:16][CH2:15][NH:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1
Reactant: COc1ccc([N+](=O)[O-])c(CCNC2CCN(Cc3ccccc3)CC2)c1
Reactant: [H][H]
Solvent: CO
Product: COc1ccc(N)c(CCNC2CCN(Cc3ccccc3)CC2)c1

Procedure:
26.0 g (70.3 mmol) (1-benzylpiperidin-4-yl)-[2-(5-methoxy-2-nitrophenyl)-ethyl]-amine were hydrogenated with 5.00 g (2.45 mmol) rhodium charcoal (5%, moistened with water) in 350 mL methanol in a 3 bar hydrogen atmosphere for 3 h at RT. The catalyst was removed by suction filtering and the solution was concentrated by rotary evaporation. The residue was immediately further reacted without any further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][O:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][O:3]1.C(Cl)(=O)C(Cl)=O.[CH2:18](O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.ClCCl>[CH2:18]([O:9][C:8]([CH:5]1[CH2:4][O:3][C:2]([CH3:11])([CH3:1])[CH2:7][O:6]1)=[O:10])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC1(C)COC(C(=O)O)CO1
Reactant: OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)COC(C(=O)OCc2ccccc2)CO1
Temperature: 25 °C
Reaction time: 20 h
Yield: 74 %

Procedure:
A solution of (5,5-dimethyl-[1,4]dioxan-2-yl)-methanol (657 mg, 4.5 mmol) in 1 M potassium hydroxide solution (6.7 mL, 6.7 mmol) was stirred at 5° C. A solution of potassium permanganate (1.42 g, 9 mmol) in water (10 mL) was added dropwise maintaining the internal temperature below 10° C. The reaction mixture was stirred at 5° C. for 1 h and then at room temperature for 18 h. The reaction mixture was filtered through Celite and the filter pad was washed with water and methanol and the filtrate was evaporated. The residue was acidified to pH 2 with hydrochloric acid (2 M) and the mixture was extracted with ethyl acetate and chloroform. The organic extracts were combined and washed with a small volume of brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated to afford crude 5,5-dimethyl-[1,4]dioxane-2-carboxylic acid (694 mg, 4.5 mmol) as a waxy solid. LCMS (m/z) 159.1 [M−H], Tr=0.88 min. A solution of 5,5-dimethyl-[1,4]dioxane-2-carboxylic acid (750 mg, 4.7 mmol), oxalyl chloride (600 mg, 0.4 mL, 4.7 mmol) and N,N-dimethylformamide (2 drops) in dichloromethane (15 mL) was stirred at room temperature under nitrogen for 2 h. A solution of benzyl alcohol (508 mg, 0.5 mL, 4.7 mmol) in dichloromethane (2 mL) was added and the reaction mixture was stirred at room temperature for 20 h. Additional benzyl alcohol (0.5 mL, 4.7 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The solvent was evaporated and the residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 9:1 to 1:1 to afford the title compound (870 mg, 74%) as an oil. 1H NMR (300 MHz, CDCl3) δ 1.19 (s, 3H), 1.32 (s, 3H), 3.43 (d, J=11.4 Hz, 1H), 3.72 (d, J=11.4 Hz, 1H), 3.88-3.92 (m, 2H), 4.21 (dd, J=8.2, 4.7 Hz, 1H), 5.24 (s, 2H), 7.34-7.39 (m, 5H). LCMS (m/z) 273.1 [M+Na], Tr=2.41 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:40])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[CH:39]=[N:38][N:37]=[N:36]2)[CH:30]=1)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:21][C:26](=[O:25])[CH2:27][C:28](=[O:40])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[CH:39]=[N:38][N:37]=[N:36]2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)c1cccc(-n2cnnn2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(-n2cnnn2)c1

Procedure:
Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G39) and 3-oxo-3-(3-tetrazol-1-yl-phenyl)-propionic acid ethyl ester (Example H15) according to the general procedure K. Obtained as a light yellow solid (159 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[N:9][C:10]=2I)[CH:7]=1.C([Mg]Cl)(C)C.[CH2:17]([Sn:21]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])Cl)[CH2:18][CH2:19][CH3:20]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[N:9][C:10]=2[Sn:21]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:17][CH2:18][CH2:19][CH3:20])[CH:7]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Fc1ccc2c(I)ncn2c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ncn2cc(F)ccc12
Temperature: 25 °C

Procedure:
To a −16° C. solution of 6-fluoro-1-iodoimidazo[1,5-a]pyridine (158 mg, 603 μmol) in THF (4.64 mL) was added isopropylmagnesium chloride (368 μL, 736 μmol) dropwise. After 20 min tributylchlorostannane (232 mg, 193 μL, 712 μmol) was added dropwise at −16° C. and allowed to warm to room temperature. After 2 h the reaction was quenched with saturated ammonium chloride and diluted with ethyl acetate. The phases were separated and the organic phase washed with brine. The organic layer was collected, concentrated in vacuo, and used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH:15]([OH:16])[CH:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]([C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:28][SiH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH:25]=[CH2:26])[O:12]1.CN(C1C=CC=CN=1)C.[C:55]1([O:61][C:62](Cl)=[S:63])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>C(#N)C>[C:55]1([O:61][C:62](=[S:63])[O:16][CH:15]2[CH:14]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:13]([C:27]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[O:28][SiH2:29][C:30]([CH3:31])([CH3:32])[CH3:33])([CH:25]=[CH2:26])[O:12][CH:11]2[N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[NH2:1])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: S=C(Cl)Oc1ccccc1
Reactant: C=CC1(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)OC(n2cnc3c(N)ncnc32)C(O)C1OCc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: CC#N
Product: C=CC1(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)OC(n2cnc3c(N)ncnc32)C(OC(=S)Oc2ccccc2)C1OCc1ccccc1
Yield: 82 %

Procedure:
A flask was charged with 2-(6-Amino-purin-9-yl)-4-benzyloxy-5-(tert-butyl-diphenyl-silanyloxymethyl)-5-vinyl-tetrahydro-furan-3-ol, acetonitrile, dimethylamino pyridine (DMAP), and PhOCSCl. The reaction was stirred, extracted, and the solvent was evaporated to provide the titled compound in 82% yield.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:18]([OH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:25][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Reactant: OCc1ccccc1
Product: N=C(OCc1ccccc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and benzyl alcohol, there is obtained benzyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as an oil, mas spectrum m/e: M+ 328 (4), 237 (44), 194 (100), 179 (21), 165 (30), 91 (62);
Reaction SMILES: C(OC([NH:8][C@H:9]([C:24]([O:26][CH3:27])=[O:25])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][CH2:21][CH2:22][CH3:23])[CH:12]=1)=O)(C)(C)C.[ClH:28].O1CCOCC1>C(Cl)Cl>[ClH:28].[CH2:20]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH2:10][C@@H:9]([C:24]([O:26][CH3:27])=[O:25])[NH2:8])=[CH:12]1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCn1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)c2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCCn1cc(C[C@H](N)C(=O)OC)c2ccccc21
Yield: 63 %

Procedure:
The same procedures as in Example 143 were carried out from the compound obtained in Example 142 (4.2 g), 4 mol/L of hydrogen chloride-dioxane solution (14.0 mL), and methylene chloride (140 mL), to give the captioned compound (2.2 g, 63%) as crystals.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([S:20]([CH3:23])(=[O:22])=[O:21])=[C:6]([NH:8][CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH:10]2[CH3:19])[CH:7]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C.O>CN(C)C=O>[CH3:19][CH:10]1[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]1[NH:8][C:6]1[CH:7]=[C:2]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:3]=[CH:4][C:5]=1[S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: CC1CCc2ccccc2C1Nc1cc(F)ccc1S(C)(=O)=O
Reactant: C1CNCCN1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCc2ccccc2C1Nc1cc(N2CCNCC2)ccc1S(C)(=O)=O
Yield: 92.2 %

Procedure:
A solution of N-(5-fluoro-2-(methylsulfonyl)phenyl)-1,2,3,4-tetrahydro-2-methylnaphthalen-1-amine (63.3 mg, 0.19 mmol), piperazine (328 mg, 3.79 mmol) and N,N-diisopropylethylamine (0.34 mL, 1.99 mmol) in N,N-dimethylformamide (3 mL) was stirred at 110° C. for 16 h. The reaction mixture was cooled down, poured over 10 mL of water and extracted with diethyl ether. After evaporation of solvent the crude product was purified by silica chromatography (10% methanol in dichloromethane) to yield 70 mg (92%) of desired product. 1H NMR (400 MHz, CDCl3): δ 7.61 (d, 1H), 7.29 (m, 1H), 7.14 (m, 3H), 6.46 (d, 1H), 6.27 (dd, 1H), 12.2 (d, 1H), 4.28 (t, 1H), 3.29 (m, 1H), 3.20 (m, 4H), 3.01 (m, 1H), 2.96 (m, 4H), 2.88 (s, 3H), 2.30-1.70 (m, 4H), 1.12 (d, 3H); MS (ESI) m/z: 400.1 (M++1).
Reaction SMILES: [CH:1]1([NH:5][C:6]2[N:7]=[N:8][C:9]([C:12]#[C:13][Si](C)(C)C)=[CH:10][CH:11]=2)[CH2:4][CH2:3][CH2:2]1>C(Cl)Cl.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[CH:1]1([NH:5][C:6]2[N:7]=[N:8][C:9]([C:12]#[CH:13])=[CH:10][CH:11]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)C#Cc1ccc(NC2CCC2)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: C#Cc1ccc(NC2CCC2)nn1
Yield: 75.1 %

Procedure:
Into a solution of N-cyclobutyl-6-(2-(trimethylsilyl)ethynyl)pyridazin-3-amine (0.49 g, 2 mmol) in CH2Cl2, TBAF was added. The reaction was monitored by TLC. The reaction mixture was concentrated and the residue obtained was purified by silica gel chromatography (eluent: 30% ethyl acetate in n-hexane, ethyl acetate was added 0.5% Et3N) to give an off-white solid (0.26 g, 75.1%). 1H NMR (300 MHz, CDCl3) δ: 7.26-7.29 (1H, d, J=9.0 Hz), 6.51-6.54 (1H, d, J=9.0 Hz), 5.57 (1H, s), 4.17-4.24 (1H, m), 3.21 (1H, s), 2.40-2.46 (2H, m), 1.89-1.98 (2H, m), 1.77-1.85 (2H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].II.[I:14]([O-])(=O)(=O)=O.[Na+].S(=O)(=O)(O)O>O.C(O)(=O)C>[I:14][C:8]1[C:9]([CH3:11])=[CH:10][C:2]([CH3:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc(C(=O)O)c(C)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: II
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(C)c(C(=O)O)cc1I
Temperature: 105 °C
Reaction time: 6 h
Yield: 149.2 %

Procedure:
Commercially available 2,4-dimethylbenzoic acid (6.6 g, 44.0 mmol), iodine (12.1 g, 47.8 mmol), and sodium periodate (4.38 g, 22.1 mmol) were placed in a reaction vessel, and acetic acid (60 ml), anhydrous acetic acid (3 ml), and sulfuric acid (0.75 g) were added thereto. The resulting mixture was stirred at 105° C. for 6 hours. The reaction solution was poured into water (300 ml). The resulting insoluble material was isolated by filtration, washed with water (500 ml), and then dissolved in ethyl acetate (400 ml). The obtained solution was washed sequentially with 5% aqueous sodium thiosulfate solution (100 ml) and saturated sodium chloride solution (200 ml). Then, the solution was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting solid material was recrystallized with a 2:1 mixture of ethanol and water (450 ml) to yield 5-iodo-2,4-dimethylbenzoic acid (9.1 g, 75%) as needle crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]3[N:13]=[C:14]([NH:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[Cl:31][CH2:32][C:33](Cl)=[O:34].C([O-])(O)=O.[Na+]>C(Cl)Cl.CO>[Cl:31][CH2:32][C:33]([NH:24][C@H:21]1[CH2:22][CH2:23][C@H:18]([NH:17][C:14]2[CH:15]=[CH:16][C:11]3[N:12]([C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)=[CH:9][N:10]=3)[N:13]=2)[CH2:19][CH2:20]1)=[O:34]
Reactant: N[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CCl)N[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of trans-N1-(3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl)cyclohexane-1,4-diamine (90 mg, 0.26 mmol) and pyridine (0.08 mL, 1.04 mmol) in CH2Cl2 (2.6 mL) was added dropwise chloroacetyl chloride (0.03 mL, 0.39 mmol). The resulting mixture was stirred at room temperature overnight. TLC (CH2Cl2:MeOH=10:1) showed the reaction was complete. The mixture was poured into sat. aq. NaHCO3 (100 mL) and extracted with EtOAc (50 mL*3). The extracts were dried over Na2SO4, filtered and concentrated in vacuo to give crude 2-chloro-N-(trans-4-((3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)acetamide (110 mg, 101%) as a yellow solid.
Reaction SMILES: C1(S([NH2:10])(=O)=O)C=CC=CC=1.[OH-].[Na+].[CH:13]1([N:19]=[C:20]=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O>CC(C)=O>[CH:13]1([NH:19][C:20](=[O:21])[NH2:10])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C=NC1CCCCC1
Reactant: NS(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: NC(=O)NC1CCCCC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
6.0 g of 4-(β-<1-ethyl-1,2-dihydro-2-oxo-nicotinamido>-ethyl)-benzenesulfonamide (melting point 215 - 216° C, prepared from 4-(β-aminoethyl)-benzenesulfonamide and 1-ethyl-1,2-dihydro-2-oxo-nicotinic acid chloride) were suspended in 60 ml acetone. After the addition of 8.55 ml 2N sodium hydroxide solution, the reaction mixture was cooled to 0° C, 2.35 g of cyclohexyl isocyanate in 5 ml acetone were added dropwise while stirring and stirring was continued for 1 hour at 0° C and for 4 hours at room temperature. The volume of the reaction mixture was then doubled by adding water, the mixture was filtered and the filtrate acidified with 2N hydrochloric acid. The precipitate was dissolved in dilute ammonia solution and precipitated again with dilute hydrochloric acid, stirred with sodium bicarbonate solution and recrystallized from methanol. The N-[4-(β-<1-ethyl-1,2-dihydro-2-oxo-nicotinamido>-ethyl)-benzenesulfonyl]-N'-cyclohexyl urea obtained in this manner melted at 189 - 190° C.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[F:7][C:8]1[CH:9]=[C:10]([B:15]([CH:17]([O:24][CH:25]([B:32]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[C:36]([F:41])[CH:35]=2)[OH:33])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)O)[CH:11]=[CH:12][C:13]=1[F:14]>C(O)C>[F:7][C:8]1[CH:9]=[C:10]([B:15]([CH:17]([O:24][CH:25]([B:32]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[C:36]([F:41])[CH:35]=2)[O:33][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[CH:11]=[CH:12][C:13]=1[F:14]
Reactant: CN(C)CCO
Reactant: OB(c1ccc(F)c(F)c1)C(OC(B(O)c1ccc(F)c(F)c1)c1ccccc1)c1ccccc1
Solvent: CCO
Product: CN(C)CCOB(c1ccc(F)c(F)c1)C(OC(B(OCCN(C)C)c1ccc(F)c(F)c1)c1ccccc1)c1ccccc1

Procedure:
The entitled compound (15 mg) was obtained by allowing 20 mg of dimethylethanolamine to act on 49 mg of bis(4,4′-(3,4-difluorophenyl-hydroxyboryl)benzyl) ether in 0.6 mL of ethanol.
Reaction SMILES: [C:1]1([C:7]2[S:15][C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:16])[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Br:24])C(=O)C1.O>CN(C=O)C>[Br:24][C:13]1[C:14]2[S:15][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][C:9]=2[C:10](=[O:16])[NH:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1[nH]ccc2sc(-c3ccccc3)cc12
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]cc(Br)c2sc(-c3ccccc3)cc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To compound 2 (3.92 g, 17.24 mmol) in DMF (133 mL) was added NBS (3.37 g, 19.0 mmol). The solution was heated to 60° C. After 1 h, the solution volume was reduced to approximately one half the volume, and the solution was poured into H2O (700 mL). The precipitate was filtered, washed with water, and dried to yield 5.08 g of 3. 1H NMR (400 MHz, d6-DMSO) δ: 11.84 (s, 1H), 8.05 (s, 1H), 7.82 (d, J=7 Hz, 2H), 7.61 (s, 1H), 7.48 (t, J=7 Hz 2H), 7.4 (t, J=7 Hz, 1H).