Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2=C3C(C4C5C(=CC=CC2=5)C=CC=4)=CC=C2C(OC(=O)C(=C23)C=1)=O.C1(N)CCCCCCCCCCC1.N1C=CN=C1.[CH2:44]([CH:50]([N:57]1[C:79](=[O:80])[C:76]2[C:77]3[C:78]4[C:73](=[CH:74][CH:75]=2)[C:72]2[C:81]5[C:68]([CH:69]=[CH:70][CH:71]=2)=[CH:67][CH:66]=[CH:65][C:64]=5[C:63]=4[CH:62]=[CH:61][C:60]=3[C:58]1=[O:59])[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55]C)[CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]>C(Cl)(Cl)Cl>[CH:50]1([N:57]2[C:58](=[O:59])[C:60]3[C:77]4[C:78]5[C:63](=[CH:62][CH:61]=3)[C:64]3[C:81]6[C:68]([CH:67]=[CH:66][CH:65]=3)=[CH:69][CH:70]=[CH:71][C:72]=6[C:73]=5[CH:74]=[CH:75][C:76]=4[C:79]2=[O:80])[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: CCCCCCC(CCCCCC)N1C(=O)c2ccc3c4cccc5cccc(c6ccc(c2c36)C1=O)c54
Agent: NC1CCCCCCCCCCC1
Agent: O=C1OC(=O)c2ccc3c4cccc5cccc(c6ccc1c2c63)c54
Agent: c1c[nH]cn1
Solvent: ClC(Cl)Cl
Product: O=C1c2ccc3c4cccc5cccc(c6ccc(c2c36)C(=O)N1C1CCCCCCCCCCC1)c54

Procedure:
190 mg (0.56 mmol) of perylene-3,4-dicarboxylic anhydride are reacted with 140 mg (1.28 mmol) of cyclododecylamine and 2.0 g of imidazole under an argon inert atmosphere as in 2c, and the reaction product is worked up. After chromatography on silica gel using chloroform, it is recrystallized by extraction with toluene. Yield 190 mg (66%), m.p. 285° C., Rf (CHCl3 /silica gel)=0.58. UV (CHCl3): λmax (ε): 454 (shoulder, 19085), 484 (32630), 507 (32015). Fluorescence (CHCl3, exc. 584 nm) λmax (Irel)=538 (1), 572 (sh, 0.44).
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]4.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1/[CH:26]=[CH:27]/B1OC(C)(C)C(C)(C)O1>>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1/[CH:26]=[CH:27]/[C:2]1[C:10]2[NH:9][C:8]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]4
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Reactant: CC1(C)OB(/C=C/c2ccc(F)cc2F)OC1(C)C
Product: Fc1ccc(/C=C/c2cccc3c4c([nH]c23)C2CCN(CC2)C4)c(F)c1

Procedure:
A suspension of the product of Example 1B (100 mg, 0.34 mmol) and trans-2-(2,4-difluorophenyl)vinylboronic acid pinacol ester (101 mg, 0.38 mmol; Aldrich) was processed as described in Example 4 to provide the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 1.98-2.19 (m, 4 H), 3.03-3.17 (m, 3 H), 3.21-3.28 (m, 2 H), 4.24 (s, 2 H), 6.93-7.05 (m, 3 H), 7.25 (d, J=7.6 Hz, 1 H), 7.30 (d, J=16.2 Hz, 1 H), 7.37 (d, J=7.3 Hz, 1 H), 7.63 (d, J=16.5 Hz, 1 H), 7.79-7.88 (m, 1 H); MS (DCI) m/z 351 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:30]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:29][C:5]2[N:6]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[C:37]1([CH2:43][C:44](Cl)=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[F:1][C:2]1[C:30]([N:31]2[CH2:36][CH2:35][N:34]([C:44](=[O:45])[CH2:43][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:33][CH2:32]2)=[CH:29][C:5]2[N:6]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:22][CH:23]=3)[C:7]([CH2:9][O:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(OC(F)(F)F)cc3)c2cc1N1CCNCC1
Solvent: ClCCl
Product: O=C(Cc1ccccc1)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
80 mg of 5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole (0.16 mmol) and 0.033 ml TEA (0.24 mmol) were dissolved in 1.5 ml dichloromethane and treated with 0.027 ml phenyl-acetyl chloride (0.2 mmol). After 5 h stirring at rt, the reaction mixture was diluted with dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 89 mg light yellow solid (86%). MS (ISP) 619.4 (M+H)+.
Reaction SMILES: N(C1SC=C(CSCCN)N=1)C(N)=N.COC1C(OC)=NS(=O)(=O)N=1.CO[C:28]1[C:32]([NH:33][CH2:34][CH2:35][S:36][CH2:37][C:38]2[N:39]=[C:40]([NH:43][C:44]([NH2:46])=[NH:45])[S:41][CH:42]=2)=[N:31][S:30](=[O:48])(=[O:47])[N:29]=1.[NH2:49][CH2:50][CH:51]([OH:54])[CH2:52][OH:53]>>[OH:54][CH:51]([CH2:52][OH:53])[CH2:50][NH:49][C:28]1[C:32]([NH:33][CH2:34][CH2:35][S:36][CH2:37][C:38]2[N:39]=[C:40]([NH:43][C:44]([NH2:46])=[NH:45])[S:41][CH:42]=2)=[N:31][S:30](=[O:47])(=[O:48])[N:29]=1
Reactant: COC1=NS(=O)(=O)N=C1NCCSCc1csc(NC(=N)N)n1
Reactant: NCC(O)CO
Agent: COC1=NS(=O)(=O)N=C1OC
Agent: N=C(N)Nc1nc(CSCCN)cs1
Product: N=C(N)Nc1nc(CSCCNC2=NS(=O)(=O)N=C2NCC(O)CO)cs1

Procedure:
When a methanolic solution of 2-[(2-guanidinothiazol-4-yl)methylthio]ethylamine is reacted with 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide by the procedure of Example 31 and the resultant 3-methoxy-4-{2-[(2-guanidinothiazol-4-yl)methylthio]ethylamino}-1,2,5-thiadiazole 1,1-dioxide is treated with 3-amino-1,2-propanediol, the title compound is thereby produced.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>CCOC(C)=O>[I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]
Reactant: CCOP(OCC)OCC
Reactant: BrCc1ccccc1I
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1ccccc1I)OCC
Temperature: 160 °C
Reaction time: 4 h
Yield: 38.6 %

Procedure:
A mixture of 2-iodobenzyl bromide 10 (5 g, 16.84 mmol) and triethyl phosphite (3.3 g, 20 mmol) was stirred at 160° C. After 4 h, the mixture was cooled to room temperature. The residue was subjected to flash chromatography (EtOAc: Hex, 1:4), and gave 2.3 g of 11 (39%). 1H NMR (200 MHz, CDCl3): δ 1.24 (t, J=7.04 Hz, 6H), 3.40 (d, J=22.00 Hz, 2H), 4.03 (m, 4H), 6.91 (m, 1H), 7.32 (m, 1H), 7.44 (m, 1H), 7.82 (m, 1H); 13C NMR (50 MHz, CDCl3): δ 16.27 (J=6.00 Hz), 38.31 (J=137.50 Hz), 62.16 (J=6.70 Hz), 101.16 (J=9.45 Hz), 128.23 (J=3.35 Hz), 128.45 (J=3.55 Hz), 130.60 (J=5.10 Hz), 135.36 (J=8.80 Hz), 139.60 (J=2.85 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[Cl:19][C:20]1[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[C:21]=1[C:22](Cl)=[O:23]>C(Cl)(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:19][C:20]1[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[C:21]=1[C:22]([NH:1][C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3)=[O:23]
Reactant: COc1ccc2c(c1)CCn1c-2cc(N)nc1=O
Reactant: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)CCn1c-2cc(NC(=O)c2c(Cl)cc(Cl)cc2Cl)nc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.7 %

Procedure:
To a suspension of 2-amino-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (7) (40 mg, 0.16 mmol) in CHCl3 (3 mL), DMAP (30.1 mg, 0.24 mmol) and 2,4,6-trichlorobenzoyl chloride (37.5 uL, 0.24 mmol) was added and stirred at 25° C. overnight. After cooling, the mixture was purified on BondElut® SCX (Varian Incorporated) then column chromatography on silica gel (CHCl3/MeOH=50/1 as eluant) to give the title compound (17.1 mg, 24%). 1H-NMR (400 MHz, CDCl3) δ 7.90 (d, 1H), 7.42 (s, 2H), 6.95 (dd, 1H), 6.82 (d, 1H), 4.27 (t, 2H), 3.90 (s, 3.17) and 3.03 (t, 2H); MS (ESI) (M+H)+ 449.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][CH2:18][OH:19].C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.C(P(CCCC)CCCC)CCC.[CH3:51][O:52][C:53](=[O:65])[CH2:54][C:55]1[C:59]2[CH:60]=[CH:61][C:62](O)=[CH:63][C:58]=2[O:57][CH:56]=1>C1(C)C=CC=CC=1.O>[CH3:51][O:52][C:53](=[O:65])[CH2:54][C:55]1[C:59]2[CH:60]=[CH:61][C:62]([O:19][CH2:18][CH2:17][C:3]3[N:4]=[C:5]([C:7]4[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=4)[S:6][C:2]=3[CH3:1])=[CH:63][C:58]=2[O:57][CH:56]=1
Reactant: COC(=O)Cc1coc2cc(O)ccc12
Reactant: Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1CCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)Cc1coc2cc(OCCc3nc(-c4ccc(C(F)(F)F)cc4)sc3C)ccc12
Temperature: 25 °C
Yield: 32.3 %

Procedure:
To a solution of 2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethanol (0.12 g, 0.43 mmol) in toluene (3 mL) at 0° C. is added ADDP (0.14 g, 0.57 mmol) followed by tri-n-butylphosphine (0.14 mL, 0.56 mmol). A toluene solution of (6-Hydroxy-benzofuran-3-yl)-acetic acid methyl ester (0.52 g, 1.22 mmol) is added, and the mixture is allowed to warm to RT overnight. Water is added, and the aqueous phase is extracted with EtOAc. The organics are dried with MgSO4 and purified by flash chromatography to yield the title compound (0.066 g, 33%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([C:10]2([F:25])[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.C(N(C(C)C)CC)(C)C.[CH3:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([Cl:45])(=[O:44])=[O:43])=[CH:38][CH:37]=1>C(Cl)Cl>[ClH:45].[F:25][C:10]1([C:6]2[CH:5]=[C:4]([NH:3][S:42]([C:39]3[CH:40]=[CH:41][C:36]([CH3:35])=[CH:37][CH:38]=3)(=[O:44])=[O:43])[CH:9]=[CH:8][CH:7]=2)[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:14][CH2:15]1
Reactant: Nc1cccc(C2(F)CCN(CCOc3ccccc3)CC2)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)Nc2cccc(C3(F)CCN(CCOc4ccccc4)CC3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
To a suspension of 4-(3-aminophenyl)-1-(2-phenoxyethyl) 4-fluoropiperidine dihydrochloride (100 mg, 0.26 mmol) in methylene chloride (5 mL) was added diisopropylethylamine (118 mg, 0.91 mmol) and the mixture stirred at room temperature until a clear solution resulted. This solution was then cooled to 0° C. and 4-methyl-benzenesulfonyl chloride (58 mg, 0.28 mmol) was then added and the reaction stirred at 0° C. for 1 hour then room temperature for 3 hours. After this time the mixture was quenched by the addition of 25% ammonium chloride solution (10 mL). The organic layer was separated and the aqueous extracted with ethyl acetate (2×10 mL). The combined extracts were dried over magnesium sulfate and filtered and concentrated. The residue was re-dissolved in ethyl acetate (20 mL), washed with water (2×10 mL) and brine (10 mL), dried over magnesium sulfate and filtered. The filtrate was concentrated to a viscous yellow oil which was treated with 10% methanolic hydrogen chloride (10 mL) and re-concentrated. The residue was triturated with ethyl acetate (5 mL) and then dried under high vacuum to afford a 49% yield of the title compound as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][NH2:13]>C(O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:13][CH3:12])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: CN
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Solvent: CCO
Product: CNc1ccc(Br)cc1[N+](=O)[O-]

Procedure:
Prepared analogously to Example 7a from 2,5-dibromo-nitrobenzene and methylamine solution in ethanol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH:18]2[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]2)[CH:14]=1)([O-])=O.[H][H]>CO.[Pd]>[N:15]12[CH2:16][CH2:17][CH:18]([CH2:19][CH2:20]1)[CH:13]([C:7]1[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([NH2:1])[CH:5]=3)[NH:9][CH:8]=1)[CH2:14]2
Reactant: O=[N+]([O-])c1ccc2[nH]cc(C3=CN4CCC3CC4)c2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2[nH]cc(C3CN4CCC3CC4)c2c1

Procedure:
0.2 g of Pd/C (10%) is added to a suspension of 7.4 mmol of 3-(5-nitro-1H-indol-3-yl)-1-azabicyclo[2.2.2]oct-2-ene in 50 ml of methanol, and the mixture is stirred at room temperature for 12 hours in a hydrogen atmosphere at atmospheric pressure. The mixture is filtered, and the filter residue is subjected to conventional work-up, giving 3-(1-azabicyclo[2.2.2]-oct-3-yl)-1H-indol-5-ylamine.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:10]=[C:9]([C:11]([OH:13])=O)[N:8]([CH3:14])[N:7]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:26][C:27]1[CH:28]=[C:29]([CH:46]=[CH:47][C:48]=1[F:49])[O:30][C:31]1[CH:32]=[CH:33][C:34]2[N:35]([CH:37]=[C:38]([NH:40][C:41]([CH:43]3[CH2:45][CH2:44]3)=[O:42])[N:39]=2)[N:36]=1>CN(C)C=O.CN1CCCC1=O>[CH:43]1([C:41]([NH:40][C:38]2[N:39]=[C:34]3[CH:33]=[CH:32][C:31]([O:30][C:29]4[CH:46]=[CH:47][C:48]([F:49])=[C:27]([NH:26][C:11]([C:9]5[N:8]([CH3:14])[N:7]=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:10]=5)=[O:13])[CH:28]=4)=[N:36][N:35]3[CH:37]=2)=[O:42])[CH2:44][CH2:45]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: COCCOc1cc(C(=O)O)n(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: COCCOc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)n(C)n1
Yield: 50.2 %

Procedure:
Using 3-(2-methoxyethoxy)-1-methyl-1H-pyrazole-5-carboxylic acid (200 mg, 1.0 mmol), N,N-dimethylformamide (2 drops), tetrahydrofuran (15 mL), oxalyl chloride (0.172 mL, 2.0 mmol), N-methylpyrrolidone (5 mL) and N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (164 mg, 0.50 mmol), and in the same manner as in Example 173, the title compound (128 mg, yield 50%) was obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][CH:5]=[C:6]([CH:11]([CH2:13]C)C)[C:7]=1[N+:8]([O-:10])=[O:9].[OH:15]O.[C:17](O)(=O)[CH3:18]>>[CH3:1][S:2]([C:3]1[NH:4][CH:5]=[C:6]([CH2:11][CH2:13][CH2:17][CH3:18])[C:7]=1[N+:8]([O-:10])=[O:9])=[O:15]
Reactant: OO
Reactant: CCC(C)c1c[nH]c(SC)c1[N+](=O)[O-]
Reactant: CC(=O)O
Product: CCCCc1c[nH]c(S(C)=O)c1[N+](=O)[O-]

Procedure:
2-Methylthio-3-nitro-4-b-butylpyrrole (3.7 g) was suspended in glacial acetic acid (50 ml) and 30% hydrogen peroxide (1.62 g) was added. The mixture was heated to 80° for 7 hours, and it was then evaporated to a brown oil. The crude product was purified by column chromatography using silica gel, eluted with benzene and chloroform, to give an oil which crystallized on standing. This was recrystallised from 2-propanol to give 2-methylsulphinyl-3-nitro-4-n-butylpyrrole (1.6 g), m.p 133°-4°.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9]1[CH:47]=[CH:46][C:12]([C:13]([O:28][CH2:29][C@H:30]2[O:34][C@@H:33]([N:35]3[CH:42]=[C:41]([CH3:43])[C:39](=[O:40])[NH:38][C:36]3=[O:37])[C@H:32]([OH:44])[C@@H:31]2[OH:45])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1.[Si:48](Cl)([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49]>C1COCC1.[N+]([O-])([O-])=O.[Ag+]>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([O:28][CH2:29][C@H:30]2[O:34][C@@H:33]([N:35]3[CH:42]=[C:41]([CH3:43])[C:39](=[O:40])[NH:38][C:36]3=[O:37])[C@H:32]([O:44][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[C@@H:31]2[OH:45])([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:12]2[CH:46]=[CH:47][C:9]([O:8][CH3:7])=[CH:10][CH:11]=2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84.8 %

Procedure:
Anhydrous pyridine (9.9 mL) was added to a solution of 5′-O-(4,4′-dimethoxitrityl)-5-methyluridine (6.9 g) and AgNO3 (2.51 g) in dry THF (123 mL) and stirred at room temperature for 20 min under an argon atmosphere. Followed by addition of tert-butyldimethylsilyl chloride (2.51 g) in dry THF (6 mL) and stirred at the same temperature for 2-3 h. The solids were filtered off and the filtrate was concentrated to a crude residue which was applied to a column of silica gel eluted with hexane-ethyl acetate (3:1) to give a pure title compound (7.04 g) as an amorphous solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([CH2:18][CH3:19])[CH:17]=3)[N:12]=[C:6]2[C:5]=1[NH:20][C@H:21]1[C@@H:25]([CH2:26][F:27])[CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]1)(=[O:3])[NH2:2].[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[CH2:18]([N:16]1[CH:17]=[C:13]([C:11]2[N:12]=[C:6]3[C:5]([NH:20][C@H:21]4[C@@H:25]([CH2:26][F:27])[CH2:24][NH:23][CH2:22]4)=[C:4]([C:1]([NH2:2])=[O:3])[CH:9]=[N:8][N:7]3[CH:10]=2)[CH:14]=[N:15]1)[CH3:19].[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]
Reactant: CCn1cc(-c2cn3ncc(C(N)=O)c(N[C@@H]4CN(C(=O)OC(C)(C)C)C[C@@H]4CF)c3n2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1cc(-c2cn3ncc(C(N)=O)c(N[C@@H]4CNC[C@@H]4CF)c3n2)cn1

Procedure:
A solution of (3S,4S)-tert-butyl 3-((7-carbamoyl-2-(1-ethyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-8-yl)amino)-4-(fluoromethyl)pyrrolidine-1-carboxylate (15 mg, 0.032 mmol) in DCM (0.5 ml) was treated with TFA (0.024 ml, 0.317 mmol) at room temperature for 2 h. The reaction mixture was concentrated to give 2-(1-ethyl-1H-pyrazol-4-yl)-8-(((3S,4S)-4-(fluoromethyl)pyrrolidin-3-yl)amino)imidazo[1,2-b]pyridazine-7-carboxamide, 2 TFA (15.1 mg, 0.025 mmol, 79% yield) as a white solid. ESI-MS (Method A): m/z 373.3 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1)=[O:4].[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([CH2:17]Cl)[CH:16]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:17][C:15]1[CH:14]=[N:13][CH:12]=[C:11]([Br:10])[CH:16]=1)=[O:4]
Reactant: ClCc1cncc(Br)c1
Reactant: COC(=O)[C@@H]1CCCN1
Product: COC(=O)[C@@H]1CCCN1Cc1cncc(Br)c1

Procedure:
In analogy to the procedure described for the preparation of intermediates B-1 [B], (S)-pyrrolidine-2-carboxylic acid methyl ester has been coupled to 3-bromo-5-chloromethyl-pyridine (intermediate B-1 [A]) to yield the title compound as light yellow oil. MS: 299.2, 301.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:11]=2[C:12](O)=[O:13])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[F:19][C:16]1[CH:17]=[CH:18][C:10]2[CH2:9][CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=3[C:12](=[O:13])[C:11]=2[CH:15]=1
Reactant: O=C(O)c1cc(F)ccc1CCc1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1c2cc(F)ccc2CCc2ccc(F)cc21
Yield: 85 %

Procedure:
A mixture of 2-[2-(4-fluorophenyl)ethyl]-5-fluorobenzoic acid (2.02 g, 7.71 mmol, 1 equiv) and oxalyl chloride (1.37 g, 10.8 mmol, 1.4 equiv) in CH2Cl2 (20 mL) was refluxed for 30 min. The resulting solution was then added to a stirring suspension of aluminum chloride (1.44 g, 10.8 mmol, 1.4 equiv) in CH2Cl2 (50 mL). This mixture was refluxed for 1 h. The reaction mixture was then washed with 1N HCL (3×20 mL), aq. satd. NaCl (1×50 mL), and H2O (1×50 mL) The organic layer was dried (anhyd. Na2SO4) and rotary evaporated to provide 1.6 g of a light-orange-colored semisolid. This material was chromatographed (3:1 hexane/CHCl3) through silica gel (150 mm×25-mm dia.). Evaporation of the combined fractions containing product provided 0.93 g (49%) of the desired product as a light-yellow shiny solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:18]1([NH2:21])[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:15]([NH:21][CH:18]3[CH2:20][CH2:19]3)=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Reactant: NC1CC1
Product: O=C(NC1CC1)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Yield: 25 %

Procedure:
The tile compound was synthesized from 1-(3,4-dichlorophenyl)-cyclohexanecarboxylic acid (372 mg, 1.37 mmol) and cyclopropylamine using General Procedure G and was isolated in 25% yield as a white solid. HPLC Rt=10.6 min; 1H NMR (400 mHz, CDCl3) 7.45 (d, J=2.2 Hz, 1H), 7.39 (d, J=8.43 Hz, 1H), 7.23-7.21 (m, 1H), 5.49 (bs, 1H), 2.62-2.59 (m, 1H), 2.25-2.20 (m, 2H), 1.84-1.78 (m, 2H), 1.59-1.55 (m, 5H), 1.38-1.33 (m, 1H), 0.73-0.68 (m, 2H), 0.37-0.33 (m, 2H); 13C NMR (100 mHz, CDCl3) 176.0, 144.8, 133.0, 131.0, 130.8, 128.6, 126.2, 50.4, 34.9, 25.7, 23.1, 6.91; GC-MS (SCOUT) 13.5 min, M+ 311.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Na].F[C:7]1[C:8]([CH:14]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])[CH3:15])=[N:9][CH:10]=[CH:11][C:12]=1[I:13]>C(O)C.O>[I:13][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([CH:14]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])[CH3:15])[C:7]=1[O:1][CH2:2][CH3:3]
Reactant: CC[O-]
Reactant: Cc1ccc(C)n1C(C)c1nccc(I)c1F
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOc1c(I)ccnc1C(C)n1c(C)ccc1C
Yield: 8.5 %

Procedure:
A solution of sodium ethoxide was initially prepared by dissolving 2.0 g (87 mmole) of sodium metal in 300 ml of anhydrous absolute ethanol. To the stirring solution thus prepared was added 3.5 g (10.2 mmole) of N-[(3-Fluoro-4-iodopyrid-2-yl)eth-2-yl]-2,5-dimethylpyrrole and the mixture was refluxed under nitrogen for 4 days. The solution was cooled, diluted to 1 liter with water, and extracted with ethyl acetate (2×). The organic layer was dried over sodium sulfate, filtered, and concentrated to a resin. Chromatography over flash silica gel (30% ethyl acetate in hexanes) gave initially 320 mg (8.5%) of N-[(4-Iodo-3-ethoxypyrid-2-yl)-eth-2-yl]-2,5-dimethylpyrrole: 1H NMR (300 MHz, DMSO-d6) δ 7.95 (d, 1H), 7.62 (d, 1H), 5.80 (s, 2H), 4.10 (t, 2H), 4.00 (q, 2H), 3.15 (t, 2H), 2.20 (s, 6H), 1.45 (t, 3H); MS (FD) m/e 370 (Mt). Further elution provided the titled compound, 1.7 g (64%): IR (KBr, cm-1) 2991, 1608, 1495, 1309, 1075; 1H NMR (300 MHz, DMSO-d6) δ 8.22 (d, 1H), 7.15 (t, 1H), 5.60 (s, 2H), 4.20 (q, 2H), 4.10 (t, 2H), 2.98 (dt, 2H), 2.10 (s, 6H), 1.38 (t, 3H): MS (FD) m/e 262 (Mt). Anal. Calc'd. for C15H19FN2O 0.25 H2 O: C, 67.55; H, 7.31; N, 10.50. Found: C, 67.56; H, 7.35; N, 10.46.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:21])=[C:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[C:6]=1[C:7](O)=[O:8].[NH2:22][C:23]1([C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=2)[CH2:25][CH2:24]1>>[C:30]([C:29]1[CH:28]=[CH:27][C:26]([C:23]2([NH:22][C:7]([C:6]3[C:5]([CH2:10][C:11]4[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=4)=[C:4]([CH3:21])[S:3][C:2]=3[CH3:1])=[O:8])[CH2:25][CH2:24]2)=[CH:33][CH:32]=1)#[N:31]
Reactant: N#Cc1ccc(C2(N)CC2)cc1
Reactant: Cc1sc(C)c(C(=O)O)c1Cc1ccc(C(F)(F)F)cc1
Product: Cc1sc(C)c(C(=O)NC2(c3ccc(C#N)cc3)CC2)c1Cc1ccc(C(F)(F)F)cc1

Procedure:
2,5-Dimethyl-4-[4-(trifluoromethyl)benzyl]thiophene-3-carboxylic acid from Example 11, Step 4 (286 mg, 0.910 mmol) was reacted with 4-(1-aminocyclopropyl)benzonitrile from Example 14, Step 1 (144 mg, 0.910 mmol) under conditions similar to Example 1, Step 10. The crude product was purified by Combi Flash chromatography system (2-5% EtOAc/CHCl3 in 20 min.) to afford the desired product as a pale yellow solid.