Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[CH2:4][CH:3]1[CH2:5][CH2:6][OH:7].[C:17]([N:21]=[C:22]=[S:23])([CH3:20])([CH3:19])[CH3:18]>C(#N)C>[C:17]([NH:21][C:22]([NH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[CH2:4][CH:3]1[CH2:5][CH2:6][OH:7])=[S:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)N=C=S
Reactant: NC1(c2cccc([N+](=O)[O-])c2)CC1CCO
Solvent: CC#N
Product: CC(C)(C)NC(=S)NC1(c2cccc([N+](=O)[O-])c2)CC1CCO
Temperature: 80 °C
Reaction time: 36 h
Yield: 67.3 %

Procedure:
To a solution of 2-((1SR,2SR)-2-amino-2-(3-nitrophenyl)cyclopropyl)ethanol (intermediate A2c) (1.44 g, 6.48 mmol, Eq: 1.00) in dry acetonitrile (30 ml) was added at 23° C. tert-butyl isothiocyanate (1.12 g, 1.23 ml, 9.72 mmol, Eq: 1.5) and the mixture was stirred at 80° C. for 36 h. Evaporated to dryness and chromatography. The residue was chromatographed on 50 g SiO2 with 0-50% ethyl acetate in dichloromethane to give the 1-tert-butyl-3-((1SR,2SR)-2-(2-hydroxyethyl)-1-(3-nitrophenyl)cyclopropyl)thiourea (1.47 g, 4.36 mmol, 67.2% yield) as a light brown solid. MS (ISP): m/z=338.4 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:9][CH:10]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1

Procedure:
1.44 parts of 4-(2-chloro-4-trifluoromethylphenoxy)phenol, 0.84 part of ethyl bromoacetate, and 1.38 parts of anhydrous potassium carbonate were refluxed for 3 hours in 20 parts by volume of methyl ethyl ketone in an atmosphere of nitrogen. After the reaction, the reaction mixture was filtered. The filtrate was concentrated, and water was added. The mixture was then extracted with ethyl acetate. The extract was washed with a 1N aqueous solution of sodium hydroxide and then with water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 1.5 parts of ethyl 4-(2-chloro-4-trifluoromethylphenoxy)phenoxyacetate.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[C:21]#[N:22].C(N(CC)CC)C.[C:30](Cl)(=[O:34])[C:31]([CH3:33])=[CH2:32]>O1CCOCC1>[C:30]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[C:21]#[N:22])(=[O:34])[C:31]([CH3:33])=[CH2:32]
Reactant: N#Cc1ccc(N=Nc2ccc(OCCO)c(C#N)c2)cc1
Reactant: C=C(C)C(=O)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCOc1ccc(N=Nc2ccc(C#N)cc2)cc1C#N
Temperature: 65 °C
Reaction time: 2 h

Procedure:
5.8 g (4-(2-hydroxyethyloxy)-3,4′-dicyanoazobenzene are dissolved in 15 ml dioxane at 65° C.; 2.4 g triethylamine are added. A solution of 3.1 g methacrylic acid chloride in 3 ml dioxane is added and the reaction mixture is stirred at 65° C. for 2 h and then introduced into 350 ml ice-water. The precipitate is filtered off with suction and dried. Purification is carried out by chromatography on silica gel in toluene/THF (½). The yield of 4-(2-methacryloyloxyethyloxy)-3,4′-dicyanoazobenzene is 5.9 g. M.p.=110° C.; max=352 nm (DMF).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:9][C:10]([NH:12][NH2:13])=O)([CH3:4])([CH3:3])[CH3:2].Cl[C:26]1[C:27]2[N:28]([N:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=2)[CH:29]=[CH:30][N:31]=1>>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:9][C:10]1[N:31]2[C:26]([C:27]3[N:28]([N:32]=[C:33]([C:35]([F:38])([F:36])[F:37])[CH:34]=3)[CH:29]=[CH:30]2)=[N:13][N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1cc2c(Cl)nccn2n1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)NN)Cc1cc(F)c(F)cc1F
Product: CC(C)(C)OC(=O)N[C@H](Cc1cc(F)c(F)cc1F)Cc1nnc2c3cc(C(F)(F)F)nn3ccn12

Procedure:
A mixture of 7.7 mg (0.22 mmol) of tert-butyl[(1R)-3-hydrazino-3-oxo-1-(2,4,5-trifluorobenzyl)propyl]carbamate (Intermediate 4), 4.9 mg (0.22 mmol) of 4-chloro-2-(trifluoromethyl)pyrazolo[1,5-a]pyrazine (Intermediate 39), and 0.5 mL of xylenes was stirred at reflux for 19 h. The cooled solution was concentrated to yield the title compound, sufficiently pure for use in the next step. LC-MS 515 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:18]=[C:17]([NH2:19])[CH:16]=[C:6]([C:7]([N:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26](Cl)=[O:27]>>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:18]=[C:17]([NH:19][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][Cl:21])[CH:16]=[C:6]([C:7]([N:9]([CH2:10][CH2:11][CH3:12])[CH2:13][CH2:14][CH3:15])=[O:8])[CH:5]=1
Reactant: O=C(Cl)CCCCCl
Reactant: CCCN(CCC)C(=O)c1cc(N)cc(C(=O)OC)c1
Product: CCCN(CCC)C(=O)c1cc(NC(=O)CCCCCl)cc(C(=O)OC)c1

Procedure:
Description 90 was prepared in an analogous manner to Description 89 from 5-amino-N,N-dipropyl-isophthalamic acid methyl ester (D88) and 5-chlorovaleryl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:24][CH2:25][CH3:26]>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:7][N:8]2[CH2:24][CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)C(F)(F)F
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 118.1 %

Procedure:
A mixture of 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (200 mg, 0.81 mmol) and potassium carbonate (214 mg, 2.02 mmol) in N,N-dimethylformamide (4 mL) was stirred at 25° C. for 30 min. At this time, the reaction was treated with 1-iodopropane (0.12 mL, 1.21 mmol) and heated at 60° C. for 5 h. The reaction mixture was cooled to 25° C. and then concentrated in vacuo. The residue was diluted with ethyl acetate (50 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×50 mL), water (2×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 1-(6-chloro-1-propyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (277.1 mg) as an orange solid which was used without further purification or characterization.
Reaction SMILES: [F:1][C:2]1[C:3]([C:13]([F:16])([F:15])[F:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2.Br[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[C:24]([F:27])([F:26])[F:25].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:1][C:2]1[C:3]([C:13]([F:16])([F:14])[F:15])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[C:24]([F:27])([F:26])[F:25])[CH2:8][CH2:7]2
Reactant: FC(F)(F)c1ccncc1Br
Reactant: O=C1NCCc2ccc(C(F)(F)F)c(F)c21
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1c2c(ccc(C(F)(F)F)c2F)CCN1c1cnccc1C(F)(F)F
Yield: 15.4 %

Procedure:
8-Fluoro-7-(trifluoromethyl)-3,4-dihydroisoquinolin-1(2H)-one (I-77d: 100 mg, 0.4288 mmol) was reacted with 3-bromo-4-(trifluoromethyl)-pyridine (120 mg, 0.5575 mmol), 1,4-dioxane (5 mL), copper iodide (8.1 mg, 0.0428 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (6.1 mg, 0.0428 mmol) and potassium phosphate (273 mg, 1.2866 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3), followed by preparative HPLC afforded 25 mg of the product (15.4% yield).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23]([O:25]C)=O)[CH:5]=[CH:6][CH:7]=1.Cl.[OH-].[NH4+:29]>C1COCC1.C(OCC)(=O)C>[I:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:29])[CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(I)c1
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(I)c1
Yield: 37 %

Procedure:
A solution of the 9-[(3-iodophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (170 mg, 0.37 mM) in 10 mL THF and 30 mL concentrated aqueous ammonium hydroxide was stirred vigorously at room temperature for 120 hours. The mixture was diluted with ethyl acetate and acidified to pH 2 with 5 N HCl. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 61 mg (37%) of the 9-[(3-iodophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (dd, 1H, J=1 and 8 Hz), 7.6-7.4 (m, 4H), 7.3 (t, 1H, J=8 Hz), 7.1-6.9 (m, 3H), 6.6 (d, 1H, J=8 Hz), and 5.7 (s, 2H). IR (CHCl3, cm−1) 3423, 3201 (br), 1630, 1600, 1579, 1564, 1445, 1330, 1261, and 775. MS (ES) m/e 441, 443.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]#[CH:22])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>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>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]#[C:22][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Ic1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.9 %

Procedure:
Iodobenzene (135 μl, 1.2 mmols), 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (209 mg, 1 mmols) and triethylamine (167 μl, 1.2 mmols) were dissolved in acetonitrile (6 ml). Dichlorobis(triphenylphosphine)palladium(II) (35 mg, 0.05 mmols) and Cul (10 mg, 0.05 mmols) were added, and reaction mixture was stirred at room temperature overnight and continued to stir at 50 C. for two more hours before partitioning between ethyl acetate and water. Organic layer was isolated, washed with 1 N HCl, brine and dried (MgSO4). Solvents were removed and residue was purified by column chromatography on silica gel using solutions of ethyl acetate in hexanes (1:4; 1:2) to yield the title compound (74 mg). LCMS m/e (230, M−t-Bu+2H)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:14][N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])=[N:8][NH:9][C:10]=1[CH:11]1[CH2:13][CH2:12]1)=[O:5])[CH3:2].[F:26][C:27]([F:39])([F:38])[O:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:14][N:15]2[C:16](=[O:25])[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]2=[O:24])=[N:8][N:9]([C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([O:28][C:27]([F:26])([F:38])[F:39])[CH:30]=2)[C:10]=1[CH:11]1[CH2:13][CH2:12]1)=[O:5])[CH3:2]
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: CCOC(=O)c1c(CN2C(=O)c3ccccc3C2=O)n[nH]c1C1CC1
Product: CCOC(=O)c1c(CN2C(=O)c3ccccc3C2=O)nn(-c2cccc(OC(F)(F)F)c2)c1C1CC1
Yield: 54 %

Procedure:
In analogy to the procedure described in Example 160C], 5-cyclopropyl-3-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-1H-pyrazole-4-carboxylic acid ethyl ester and 3-(trifluoromethoxy)benzeneboronic acid gave the title compound as a white solid (54%). MS: 500.0 (MH+).
Reaction SMILES: [CH2:1]([N:5]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)[C:6]([C:8]1[C:12]([Cl:13])=[C:11]([CH3:14])[NH:10][N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].F[C:25]1[CH:40]=[CH:39][C:28]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])=[CH:27][C:26]=1[C:41]([N:43]1[CH2:52][CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1)=[O:42]>>[CH2:1]([N:5]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)[C:6]([C:8]1[C:12]([Cl:13])=[C:11]([CH3:14])[N:10]([C:25]2[CH:40]=[CH:39][C:28]([C:29]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:30])=[CH:27][C:26]=2[C:41]([N:43]2[CH2:52][CH2:51][C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH2:44]2)=[O:42])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OCc1ccccc1)c1ccc(F)c(C(=O)N2CCc3ccccc3C2)c1
Reactant: CCCCN(Cc1ccc(Cl)c(Cl)c1)C(=O)c1n[nH]c(C)c1Cl
Product: CCCCN(Cc1ccc(Cl)c(Cl)c1)C(=O)c1nn(-c2ccc(C(=O)OCc3ccccc3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Yield: 64 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 1E, N-butyl-4-chloro-N-(3,4-dichlorobenzyl)-5-methyl-1H-pyrazole-3-carboxamide (1.73 g, 4.62 mmol) and benzyl 4-fluoro-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (Intermediate 122B, 1.80 g, 4.62 mmol) were converted to the title compound (2.20 g, 64%). 1H NMR (CDCl3, mixture of amide rotamers) δ 8.24 (d, J=8.4 Hz, 1H), 8.16-8.09 (m, 1H), 7.53-7.03 (m, 12H), 6.98-6.76 (m, 1H), 5.41 (br s, 2H), 4.86-4.20 (m, 4H), 3.64-3.03 (m, 4H), 2.78 (br s, 2H), 2.37-2.17 (m, 3H), 1.61-1.38 (m, 1H), 1.36-1.21 (m, 2H), 1.18-1.01 (m, 1H), 0.97-0.83 (m, 2H), 0.80-0.67 (m, 1H); MS(ESI+) m/z 745.2 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.Br[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[O:11]([CH2:10][CH2:9][CH2:8][N:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O[C@@H]1CCNC1
Reactant: BrCCCOc1ccccc1
Product: O[C@@H]1CCN(CCCOc2ccccc2)C1
Yield: 71.3 %

Procedure:
Prepared as in Intermediate I-15 from (3R)pyrrolidin-3-ol (commercially available) and (3-bromopropoxy)benzene. The yield was 2.26 g (71.3%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([OH:12])=O)=[CH:4][C:3]=1[Cl:13].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1.O>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([NH:26][CH2:27][CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)=[O:12])=[CH:4][C:3]=1[Cl:13]
Reactant: COc1nc(N)c(Cl)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(N)c(Cl)cc1C(=O)NCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 71.4 %

Procedure:
A mixture of 6-amino-5-chloro-2-(methyloxy)-3-pyridinecarboxylic acid (Y. Hirokawa et al., Bioorg. Med. Chem. Lett., 1998, 12, 1551–1554, 500 mg, 2.47 mmol) and 1,1′-carbonyldiimidazole (440 mg, 2.71 mmol) in N,N-dimethylformamide (15 ml) was stirred at room temperature for 45 min. A solution of 1,1-dimethylethyl 4-(aminomethyl)-1-piperidinecarboxylate (529 mg, 2.47 mmol) in N,N-dimethylformamide (5 ml) was added and the resulting mixture was stirred at room temperature for 5 h. The mixture was poured into water (200 ml) and extracted with ethyl acetate/toluene (2:1, 200 ml×3). The combined organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo. The obtained residue was chromatographed on a column of silica gel eluting with methanol/dichloromethane (1:25) to give 703 mg (71%) of the title compound as a pale yellow amorphous solid.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:25])([F:24])[F:23])[CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([NH2:36])[CH2:32][CH2:33][O:34][CH3:35]>>[CH3:35][O:34][CH2:33][CH2:32][C:31]1[N:36]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:25])([F:23])[F:24])[CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[O:8])[CH2:10]2)[O:27][N:30]=1
Reactant: O=C(O)C1CC(c2cccc(OC(F)(F)F)c2)CN(C(=O)N2CCOCC2)C1
Reactant: COCCC(N)=NO
Product: COCCc1noc(C2CC(c3cccc(OC(F)(F)F)c3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
200 mg (0.50 mmol) of the compound from Example 201A and 117 mg (0.75 mmol) of N′-hydroxy-3-methoxypropanimidamide were reacted according to the General Method 2. Yield: 106 mg (44% of theory)
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][N:7]1[CH2:11][C@H:10]2[CH:12]([NH2:15])[CH2:13][CH2:14][C@H:9]2[CH2:8]1.C(N(CC)CC)C.[F:28][C:29]([F:41])([F:40])[C:30]1[CH:31]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>ClCCl>[F:41][C:29]([F:28])([F:40])[C:30]1[CH:31]=[C:32]([S:36]([NH:15][C@@H:12]2[C@H:10]3[C@H:9]([CH2:8][N:7]([CH2:6][C:5]4[CH:16]=[CH:17][CH:18]=[C:3]([C:2]([F:19])([F:1])[F:20])[CH:4]=4)[CH2:11]3)[CH2:14][CH2:13]2)(=[O:37])=[O:38])[CH:33]=[CH:34][CH:35]=1
Reactant: NC1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@@H]12
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (3aS*,6aR*)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 122 Step E (200 mg, 0.703 mmol) in dichloromethane (2 mL) was added triethylamine (0.147 mL, 1.055 mmol) followed by 3-(trifluoromethyl)benzene-1-sulfonyl chloride (0.124 mL, 0.774 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with dichloromethane. The organics were reduced in volume and loaded onto a silica gel cartridge (Analogix®, Burlington, Wis., RS-24). The title compounds were eluted with a gradient of 0% to 10% methanol (2 N ammonia)/dichloromethane over 20 minutes.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C@H:12]([C:14]2[N:15]=[C:16]([CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][C:18]=3Cl)[CH3:13])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.C(N(CC)CC)C>[Pd].CO>[O:30]1[CH2:29][CH2:28][N:27]([CH2:26][CH2:25][C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:23]=[C:14]([C@@H:12]([NH:11][C:4]3[C:5]4[N:6]([CH:8]=[CH:9][N:10]=4)[N:7]=[CH:2][CH:3]=3)[CH3:13])[N:15]=2)[CH2:32][CH2:31]1
Reactant: C[C@H](Nc1cc(Cl)nn2ccnc12)c1cc2cccc(Cl)c2c(CCN2CCOCC2)n1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@H](Nc1ccnn2ccnc12)c1cc2ccccc2c(CCN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Palladium on carbon (10%, 10 mg) was added to a mixture of (S)-6-chloro-N-(1-(8-chloro-1-(2-morpholinoethyl)isoquinolin-3-yl)ethyl)imidazo[1,2-b]pyridazin-8-amine 76 (40 mg, 0.085 mmol, 1.0 eq) and triethylamine (0.2 mL, 1.5 mmol, 17.6 eq) in MeOH (10 mL). The resulting mixture was degassed and back-filled with hydrogen three times and then stirred at RT under hydrogen for 5 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (1-4% MeOH-DCM) to afford the product (S)—N-(1-(1-(2-morpholinoethyl)isoquinolin-3-yl)ethyl)imidazo[1,2-b]pyridazin-8-amine 77. ESI-MS m/z: 403.2 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C@H:5]([CH2:9][O:10][CH3:11])[C:6]([OH:8])=O)(=[O:3])[CH3:2].ClC(OCC(C)C)=O.CN1CCOCC1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[C:1]([NH:4][C@H:5]([CH2:9][O:10][CH3:11])[C:6]([NH:34][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: COC[C@@H](NC(C)=O)C(=O)O
Reactant: NCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC[C@@H](NC(C)=O)C(=O)NCc1ccccc1
Temperature: -10 °C
Reaction time: 0.67 h
Yield: 56.7 %

Procedure:
(R)-2-Acetylamino-3-methoxypropionic acid (8.06 g, 0.05 mol) was dissolved in tetrahydrofuran (80 mL). Isobutyl chloroformate (7.8 mL, 0.06 mol) was added at −10° C. within 10 minutes, followed by 4-methylmorpholine (6.6 mL, 0.06 mol), and the mixture was stirred at −10° C. for 40 minutes. A solution of benzylamine (6.55 mL, 0.06 mol) in tetrahydrofuran (10 mL) was then added at −10° C. The mixture was allowed to warm to room temperature, the solvent evaporated and the residue dissolved in dichloromethane. The solution was successively washed with water (30 mL), 1M HCl (30 mL), 5% sodium hydrogencarbonate solution (30 mL) and again with water (30 mL). The solvent was evaporated and the residue crystallized in ethyl acetate to afford the title compound (7.09 g, 57%). LCMS analysis: 98.0%.
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)[CH2:26][C:25]1=[O:45]>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:33]3[CH:32]=[CH:31][C:30]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[C:25](=[O:45])[CH2:26]4)=[CH:35][CH:34]=3)[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1=O
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Product: COc1cc(CCc2cnc3[nH]c(-c4ccc(N5CCN(C)C(=O)C5)cc4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-2-one. LCMS calculated for C27H30N5O3 (M+H)+: m/z=472.2. Found 472.1.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].Cl.[CH3:12]O>>[O:1]([CH3:12])[C@@H:2]1[O:8][C@H:7]([CH2:9][OH:10])[C@@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: CO
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Agent: Cl
Product: CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
D-ribose (2.0 g) was dissolved in methanol (40 ml), to which was added 1N methanolic HCl solution (4 ml) and the mixture was allowed to stand at 5° C to produce methyl β-D-ribofuranoside. The compound formed was dissolved in pyridine (50 ml) and the solution was subjected to action of nitrobenzoyl chloride 8.2 g at room temperature. The solvent was distilled off and the residue was dissolved in chloroform. The solution was washed with saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate and distilled to remove the solvent therefrom. Methyl 2,3,5-tri-O-(p-nitrobenzoyl)-β-D-ribofuranoside (4.2 g) thus obtained was dissolved in anhydrous dichloromethane (20 ml). To the solution was added acetic acid (20 ml) which had been saturated with hydrogen bromide under ice-cooling and the mixture was allowed to stand in the dark for 1 hour. The reaction solution was concentrated under a reduced pressure and the resulting sprupy concentrate was dissolved in dichloromethane. The solution was washed with a sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate and distilled to remove the solvent therefrom. The residue was recrystallized from anhydrous benzene to obtain the titled compound. Yield 3.4 g.