Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([CH3:24])([CH3:23])[C:14]([N:16]3[CH:20]4[CH2:21][CH2:22][CH:17]3[CH2:18][CH2:19]4)=[O:15])[CH:11]=2)[NH:6][C:5]=1[C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[CH:26]=1.[CH3:33][C:34]([CH3:45])=[CH:35][CH:36]1[O:38][CH:37]1[C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:17]12[N:16]([C:14](=[O:15])[C:13]([C:10]3[CH:11]=[C:12]4[C:7](=[CH:8][CH:9]=3)[NH:6][C:5]([C:25]3[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[CH:26]=3)=[C:4]4[CH2:3][CH2:2][NH:1][C:34]([CH3:45])([CH3:33])[CH:35]=[CH:36][CH:37]([OH:38])[C:39]3[CH:40]=[CH:41][N:42]=[CH:43][CH:44]=3)([CH3:24])[CH3:23])[CH:20]([CH2:19][CH2:18]1)[CH2:21][CH2:22]2
Reactant: CC(C)=CC1OC1c1ccncc1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2CCN)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2CCNC(C)(C)C=CC(O)c2ccncc2)c1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
To a solution of 2-[3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-1-(7-azabicyclo[2.2. 1 ]hept-7-yl)-2-methylpropan-1-one (prepared essentially as described in EXAMPLE 2, 70 mg in 6 mL dry tetrahydrofuran) was added 2 mL of a solution of 86 mg 4-[3-(2-methylpropenyl)oxiranyl]pyridine in tetrahydrofuran followed by 24 mg tetrakis(triphenylphosphine)palladium and the mixture heated to 65 ° C. on an oil bath. After 2 hours, the mixture was cooled to room temperature, concentrated in vacuo. The residue was purified by flash chromatography on silica gel (methylene chloride:methanol, 92:8; then 88:12) to give the title compound (91 mg).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[C:10](Cl)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Cl:26])[C:24]=1[CH3:25].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[C:32](Cl)=[O:33]>>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[C:32]([O:11]/[C:10](/[C:9]1[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:7]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:8]=1)=[CH:25]\[C:24]1[C:23]([Cl:26])=[CH:22][N:21]=[CH:20][C:19]=1[Cl:18])=[O:33]
Reactant: COc1ccc(C(=O)Cl)cc1OC1CCCC1
Reactant: Cc1c(Cl)cncc1Cl
Reactant: COc1ccc(C(=O)Cl)cc1OC
Product: COc1ccc(C(=O)O/C(=C\c2c(Cl)cncc2Cl)c2ccc(OC)c(OC3CCCC3)c2)cc1OC

Procedure:
The compound was obtained starting from 3-cyclopentyloxy-4-methoxy-benzoyl chloride, 3,5-dichloro-4-methylpyridine and 3,4-dimethoxy-benzoyl chloride, following the procedure of Example 24.
Reaction SMILES: [F:1][C:2]1[C:3]([C:33]2[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=2[O:40][CH3:41])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH:12]=3)[N:8](S(C3C=CC=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[OH-].[Na+].FC(F)(F)C(O)=O>O1CCOCC1.ClCCl>[F:1][C:2]1[C:3]([C:33]2[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=2[O:40][CH3:41])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(F)cc1-c1c(F)cnc2c1cc(C1=CCN(C(=O)OC(C)(C)C)CC1)n2S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: COc1ccc(F)cc1-c1c(F)cnc2[nH]c(C3=CCNCC3)cc12
Reaction time: 3 h

Procedure:
A mixture of Example 231D (2.00 g, 3.44 mmol) and 5M sodium hydroxide (2.407 mL, 12.04 mmol) in dioxane (20 mL) was heated at 90° C. for 8 hours. After concentration, the residue was treated with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate, filtered, concentrated, and purified on silica gel using an ISCO Companion eluting with heptanes/ethyl acetate (6:4 to 4:6) to give the protected intermediate. A solution of the intermediate in dichloromethane (25 mL) was treated with trifluoroacetic acid (2.27 mL, 29.4 mmol) and the mixture was stirred for 3 hours and concentrated. The residue was dissolved in 6 mL methanol and treated slowly with 5 mL 2M hydrogen chloride in ether. The suspension was sonicated, diluted with ether and stirred for 10 minutes. The solid was filtered, washed with ether and vacuum oven-dried to give the title compound as a hydrochloride salt. MS (ESI+) m/z 342.1 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[CH:11](=[O:16])[CH2:12][CH:13]([CH3:15])[CH3:14]>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:11]([OH:16])[CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CC=O
Reactant: c1ccoc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)CC(O)c1ccco1
Temperature: 25 °C
Yield: 49 %

Procedure:
Furan was added dropwise to a stirred solution of n-butyllithium (2.5M in hexanes, 58.8 ml, 147 mmol) in dry THF (200 ml) at -20° C. under argon. The mixture was allowed to warm to room temperature and was then heated at reflux for 4 h. The mixture was cooled to -30° C. and isovaleraldehyde (12.8 g, 147 mmol) was added dropwise. The mixture was allowed to warm to room temperature and was then heated at reflux for 16 h. The reaction mixture was allowed to cool to room temperature, poured onto crushed ice, extracted with ether and the combined organic extracts dried over anhydrous potassium carbonate, filtered and concentrated to give a dark yellow oil. Distillation under reduced pressure gave 1-(2-furyl)-3-methylbutanol (11.0 g, 49%) as a colourless oil.
Reaction SMILES: O[C:2]([C:4](F)(F)F)=[O:3].COC(=O)[CH:11]([NH:18][C:19]([NH:21][C:22]1[N:27]=[CH:26][C:25]2[C:28]([NH:31][CH2:32][CH3:33])=[N:29][NH:30][C:24]=2[CH:23]=1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:35][Mg]Br>C1COCC1>[CH2:32]([NH:31][C:28]1[C:25]2[CH:26]=[N:27][C:22]([NH:21][C:19]([NH:18][CH:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:2]([OH:3])([CH3:4])[CH3:35])=[O:20])=[CH:23][C:24]=2[NH:30][N:29]=1)[CH3:33]
Reactant: C[Mg]Br
Reactant: O=C(O)C(F)(F)F
Reactant: CCNc1n[nH]c2cc(NC(=O)NC(C(=O)OC)c3ccccc3)ncc12
Solvent: C1CCOC1
Product: CCNc1n[nH]c2cc(NC(=O)NC(c3ccccc3)C(C)(C)O)ncc12
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To the solution of (S)-methyl 2-(3-(3-((tert-butoxycarbonyl)(ethyl)amino)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)ureido)-2-phenylacetate (0.078 g, 0.109 mmol) in anhydrous CH2Cl2 (1 mL) was added TFA (imp followed by Et3SiH (2 drops). The resultant mixture was stirred at ambient temperature. After 2 h of stirring, solvent was removed under reduced pressure, the residue (TFA salt) thus obtained was triturated in diethyl ether to afford the compound which was taken as such for next step. At 0° C., to the solution of [3-(3-Ethylamino-1H-pyrazolo[4,3-c]pyridin-6-yl)-ureido]-phenyl-acetic acid methyl ester TFA salt (0.06 g, 0.163 mmol) in anhydrous THF was added methyl magnesium bromide (1 M solution in toluene, 1.63 mL, 1.63 mmol) and resultant mixture was allowed to warm and stirred at ambient temperature. After 10 h, the reaction was quenched with saturated aqueous NH4Cl solution (5 mL), and the organic contents were extracted with CH2Cl2 (3×10 mL). The volatiles were removed under reduced pressure and the residue thus obtained was further purified by prep HPLC to afford the title compound. 1H NMR (ppm, 400 MHz, CD3OD): δ 8.69 (s, 1H), 7.44-7.39 (m, 2H), 7.33-7.29 (m, 2H), 7.26-7.23 (m, 1H), 6.99 (s, 1H), 4.78 (s, 1H), 3.36 (q, J=7.2 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H), 1.30 (s, 3H), 1.16 (s, 3H). MS ESI calc'd. for C19H24N6O2 [M+H]+ 369. Found 369.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:16]1([N+:22]#[C-:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([O:34][CH3:35])[CH:33]=1)[CH:29]=O>Cl(O)(=O)(=O)=O>[CH2:9]([O:8][C:7]1[C:2]2[N:3]([C:23]([NH:22][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[C:29]([C:28]3[CH:31]=[C:32]([O:34][CH3:35])[CH:33]=[C:26]([O:25][CH3:24])[CH:27]=3)[N:1]=2)[CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: [C-]#[N+]C1CCCCC1
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: COc1cc(C=O)cc(OC)c1
Agent: [O-][Cl+3]([O-])([O-])O
Product: COc1cc(OC)cc(-c2nc3c(OCc4ccccc4)cccn3c2NC2CCCCC2)c1

Procedure:
Compound (10) was prepared according to the general synthesis instructions from 1.0 ml of 2-amino-3-benzyloxypyridine solution (0.1 M, DCM), 0.575 ml of cyclohexyl isocyanide solution (0.2 M, DCM), 0.500 ml of 3,5-dimethoxybenzaldehyde solution (0.3 M, DCM), and 10 μl of perchloric acid (w=20%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:31]=[CH:30][C:12]([CH2:13][C:14]3[C:15]4[CH:29]=[CH:28][CH:27]=[CH:26][C:16]=4[S:17][C:18]=3[C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:32]([Si]([O:42][Si](C(C)C)(C(C)C)C(C)C)(C(C)C)C(C)C)([CH3:34])[CH3:33].[C:53]([O-:56])([O-:55])=[O:54].[Cs+].[Cs+].O>CN(C=O)C>[C:22]([OH:25])(=[O:42])[C:53]([OH:56])=[O:55].[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:31]=[CH:30][C:12]([CH2:13][C:14]3[C:15]4[CH:29]=[CH:28][CH:27]=[CH:26][C:16]=4[S:17][C:18]=3[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:33][CH2:32][CH2:34][OH:54])=[CH:21][CH:20]=3)=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Oc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Reactant: O=C([O-])[O-]
Reactant: CC(C)[Si](O[Si](C(C)C)(C(C)C)C(C)C)(C(C)C)C(C)C
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)C(=O)O
Product: OCCCOc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
4-[3-[4-[2-(1-Pyrrolidinyl)ethoxy]benzyl]benzo[b]thiophen-2-yl]phenol (0.25 g; 0.58 mmol), 0.21 g (0.70 mmol) of the triisopropylsilyl ether prepared above and Cs2CO3 (1.33 g; 4.07 mmol) were combined in 5 mL of DMF in a flame-dried, argon-filled flask and heated in an oil bath maintained at 70° C. for 2 h. After cooling to room temperature, water was added (25 mL) and extraction was carried out with EtOAc (4×25 mL). The combined organics were dried by passage through Na2SO4. The triisopropylsilyl protecting group was removed by stirring with an excess of tetrabutylammonium fluoride in THF at room temperature for 0.5 h. The product was isolated as a colorless oil (165 mg; 58%) by flash chromatography on silica gel, eluting with EtOAc(10-90%)/Et3N(0-5%)/MeOH(0-5%). Conversion to the oxalate was effected in the usual way.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[N:4]=1)=[CH2:2].CO[CH2:13][N:14](C[Si](C)(C)C)[CH2:15][CH:16]=[CH2:17].[CH2:23]=CC1C=CC=CC=1>FC(F)(F)C(O)=O.ClCCl>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH:1]2[CH2:23][CH2:13][N:14]([CH2:15][CH:16]=[CH2:17])[CH2:2]2)[N:4]=1
Reactant: C=Cc1cccc(OC)n1
Reactant: C=Cc1ccccc1
Reactant: C=CCN(COC)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCN1CCC(c2cccc(OC)n2)C1
Yield: 30 %

Procedure:
To a solution of 2-ethenyl-6-methoxypyridine a1-51 (400 mg, 3 mmol, 1 eq) in trifluoroacetic acid/dichloromethane (200 μl/2 ml) is added N-(methoxymethyl)-N-[(trimethylsilyl)methyl]prop-2-en-1-amine until all styrene a1-51 is consumed. The solvent is removed under vacuum and the crude residue is purified by basic reverse phase chromatography over silicagel (gradient: CH3CN/H2O/NH4OH from 50/50/0.1 to 80/20/0.1) to afford 210 mg of pure 2-methoxy-6-[1-(prop-2-en-1-yl)pyrrolidin-3-yl]pyridine a1-55.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[N:12]=[CH:13][N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=1.[Li]CCCC.CON(C)[C:32](=[O:45])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]1([CH3:44])[O:43][CH2:42][CH2:41][O:40]1.O>C1COCC1.CCCCCC>[CH3:44][C:39]1([CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][C:32]([C:13]2[N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=[C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)[N:12]=2)=[O:45])[O:40][CH2:41][CH2:42][O:43]1
Reactant: CON(C)C(=O)CCCCCCC1(C)OCCO1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc3ccccc3c2)c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(CCCCCCC(=O)c2nc(-c3ccc4ccccc4c3)cn2COCC[Si](C)(C)C)OCCO1
Reaction time: 0.5 h

Procedure:
To a solution of E2 (1.0 eq.) in THF (0.1 M solution) at −78° C. was added a solution of n-BuLi (1.3 eq.) in hexane. The solution was stirred for 30 min and then a solution of N-methoxy-N-methyl-7-(2-methyl-1,3-dioxolan-2-yl)heptanamide (1.5 eq.) in THF was slowly added. The reaction mixture was stirred for 1 hr at −78° C. and then 1 hr at RT. Then water was added and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (MgSO4) and the solvent was removed under reduced pressure. The crude was purified by column chromatography on silica gel eluting with 20-50% EtOAc/petroleum ether to obtain E3 as yellow solid. 1H NMR (300 MHz, CDCl3) δ: 8.32 (1H, s), 7.96-7.81 (4H, m), 7.68 (1H, s) 7.53-7.42 (2H, m), 5.85 (2H, s), 3.92 (4H, s), 3.64 (2H, t, J=8.2 Hz), 3.26 (2H, t, J=8.2 Hz), 1.77 (2H, m), 1.69-1.36 (8H, m), 1.31 (3H, s), 0.97 (2H, t, J=8.2 Hz), 0.19 (9H, s). MS (ES) C30H42N2O4Si requires: 522, found: 523 (M+H)+.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[CH2:6]([O:9][C:10]([N:12]1[C@H:16]([CH2:17][C:18]2[N:19]3[CH:25]=[N:24][CH:23]=[C:20]3[S:21][CH:22]=2)[CH2:15][C@@H:14](OS(C)(=O)=O)[CH2:13]1)=[O:11])[CH:7]=[CH2:8].O>CN(C=O)C>[C:1]([S:3][C@H:14]1[CH2:15][C@@H:16]([CH2:17][C:18]2[N:19]3[CH:25]=[N:24][CH:23]=[C:20]3[S:21][CH:22]=2)[N:12]([C:10]([O:9][CH2:6][CH:7]=[CH2:8])=[O:11])[CH2:13]1)(=[O:4])[CH3:2]
Reactant: CC([O-])=S
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1Cc1csc2cncn12
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1Cc1csc2cncn12
Temperature: 70 °C
Reaction time: 8.5 h
Yield: 92.4 %

Procedure:
Potassium thioacetate (365 mg) is added to a solution of 427.7 mg of (3R,5R)-1-allyloxycarbonyl-5-(imidazo[5,1-b]thiazol-3-yl)methyl-3-methanesulfonyloxypyrrolidine in 4.5 ml of DMF, and the mixture is stirred under an argon stream at 70° C. for 8.5 hr. The reaction solution is cooled, water is added thereto, and the mixture is extracted four times with ethyl acetate. The organic layer is washed once with saturated saline, dried over anhydrous magnesium sulfate, and filtered. The solvent is removed by evaporation under reduced pressure to give a crude product which is then purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give 374.7 mg of the title compound as a brown viscous material.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([F:14])[C:11](Cl)=[N:12][C:5]=2[N:4]([CH:15]2[CH2:17][CH2:16]2)[C:3]1=[O:18].[C:19]([O:23][C:24](=[O:31])[NH:25][C@H:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)([CH3:22])([CH3:21])[CH3:20].C(N(CC)C(C)C)(C)C.C(#N)C>O>[C:19]([O:23][C:24](=[O:31])[NH:25][CH:26]1[CH2:30][CH2:29][N:28]([C:11]2[C:10]([F:14])=[CH:9][C:6]3[C:7](=[O:8])[N:2]([NH2:1])[C:3](=[O:18])[N:4]([CH:15]4[CH2:17][CH2:16]4)[C:5]=3[N:12]=2)[CH2:27]1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: Nn1c(=O)c2cc(F)c(Cl)nc2n(C2CC2)c1=O
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCN(c2nc3c(cc2F)c(=O)n(N)c(=O)n3C2CC2)C1
Temperature: 0 °C
Yield: 83.2 %

Procedure:
A solution of 0.11 g (0.4 mmol) of 3-amino-7-chloro-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example 24b), 0.105 g (0.56 mmol) of (S)-3-pyrrolidinylcarbamic acid tert-butyl ester (J. Med. Chem., 1992; 35:1764), 1.2 mL of N,N-diisopropylethylamine and 3 mL of acetonitrile is heated at 50° C. for 18 hours. The reaction mixture is diluted with 9 mL of water, cooled to 0° C. and the solid is removed by filtration, washed with 50% aqueous acetonitrile and dried in vacuo to give 0.14 g of the title compound, mp 108–110° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.O>C1(C)C=CC=CC=1>[O:1]1[CH2:6][CH:5]=[C:4]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=C1CCOCC1
Solvent: O
Solvent: Cc1ccccc1
Product: C1=C(N2CCOCC2)CCOC1
Reaction time: 5 h

Procedure:
650 mg of tetrahydro-4H-pyran-4-one together with 950 mg of morpholine were dissolved in 10 ml of toluene and the mixture was heated under reflux in a light water separator for 5 hours. Subsequently, the mixture was concentrated under reduced pressure, and residue (1.3 g) was used further without further workup.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.CCN(CC)CC.Cl[C:23]([O:25][CH3:26])=[O:24].OS([O-])(=O)=O.[K+]>C(Cl)Cl>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:23]([O:25][CH3:26])=[O:24])[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 638.8 %

Procedure:
A solution of 4.00 g (2.00 mmol) of 4-amino-1-BOC-piperidine and 4.18 ml (3.00 mmol) of Et3N in 50 ml of CH2Cl2 was treated at 0° C. with 1.62 ml (2.10 mmol) of methyl chloroformate. The reaction was stirred for 16 h at RT, neutralized with aqueous 10% KHSO4 and extracted with CH2Cl2 (3×). The organic phases were washed with aqueous 10% NaCl, dried over Na2SO4 evaporated and purified by flash silica gel column (n- heptane/EtOAc 1:1 to 1:2) to yield 3.30 g (64%) of the title compound as white solid. MS: 259.2 (MH+).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([NH:12][CH2:13][CH2:14]O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CCOCC>C(Cl)(Cl)Cl>[CH2:5]([NH:12][CH2:13][CH2:14][Cl:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCCNCc1ccccc1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: ClCCNCc1ccccc1

Procedure:
100 ml. of thionyl chloride are added to a stirred solution of 100 g. of 2-benzylaminoethanol in 500 ml. of chloroform over a period of 20 minutes. The mixture is refluxed for 6 hours. 1350 ml. of ether is added to the cooled chloroform solution and the mixture is stored in the refrigerator overnight. The product, N-benzyl-2-chlorethylamine hydrochloride, is filtered off and crystallized from ethanol-ether; yield 130.9 g., m.p. 192°-194°.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:14]#[CH:15]>>[CH3:9][N:8]([CH3:10])[C:6](=[O:7])[C:5]1[CH:11]=[CH:12][C:2]([C:15]#[C:14][CH2:13][O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:3][CH:4]=1
Reactant: CN(C)C(=O)c1ccc(I)cc1
Reactant: C#CCOCCCCCCNCc1ccccc1
Product: CN(C)C(=O)c1ccc(C#CCOCCCCCCNCc2ccccc2)cc1
Yield: 83 %

Procedure:
From 4-iodo-N,N-dimethylbenzamide (2.5 g) and N-[6-[(2-propynyl)oxy]- hexyl]benzenemethanamine (2.23 g). FCC purification eluting with ethyl acetate-triethylamine (100:1) gave the title compound as an orange oil (2.96 g), t.l.c. (Ethyl acetate+few drops triethylamine) Rf 0.15.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][C@H:9]1[C:19]([OH:21])=O)=[O:7])(C)(C)C.[C:22]1([CH:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)C(Cl)=O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH2:38]([N:40]([CH2:44][CH3:45])[CH2:41][CH2:42][NH2:43])[CH3:39]>>[C:15]([O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6](=[O:7])[CH:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C@H:9]([C:19]([NH:43][CH2:42][CH2:41][N:40]([CH2:44][CH3:45])[CH2:38][CH3:39])=[O:21])[CH2:10]1)([CH3:16])([CH3:17])[CH3:18]
Reactant: CCN(CC)CCN
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)ON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CCN(CC)CCNC(=O)[C@@H]1CC(=NOC(C)(C)C)CN1C(=O)C(c1ccccc1)c1ccccc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinecarboxylic acid, diphenylacetyl chloride, and N1,N1-diethyl-1,2-ethanediamine the title compound was obtained in 80% purity by LC/MS. MS(ESI+): m/z=493.4.
Reaction SMILES: [Br:1][C:2]1[N:7]=[N:6][C:5]([O:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>C1COCC1>[Br:1][C:2]1[N:7]=[N:6][C:5]([O:8][CH2:9][C:10]([N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(O)COc1ccc(Br)nn1
Reactant: C1CCNCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: O=C(COc1ccc(Br)nn1)N1CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
146 mg (0.626 mmol) of (6-bromo-pyridazin-3-yloxy)-acetic acid, 216.5 mg (1.88 mmol) of NEM and 226 mg (0.689 mmol) of TOTU in 10 ml of THF were stirred at room temperature for 15 min, 80 mg (0.94 mmol) of piperidine added, and the reaction mixture stirred at room temperature for 3 h. After evaporation, a sodium hydrogencarbonate solution and ethyl acetate were added to the residue, and the organic phase was separated, washed, dried and evaporated. Yield: 190 mg.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]2[N:9]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)=[CH:11][C:3]=12.[CH3:28][O:29][C:30]1[CH:59]=[CH:58][C:33]([CH2:34][NH:35][C:36]2([C:40]3[S:41][C:42]([Sn](CCCC)(CCCC)CCCC)=[CH:43][N:44]=3)[CH2:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>CN(C)C=O.C(OCC)(=O)C.O.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:8][C:7]1[C:2]([C:42]2[S:41][C:40]([C:36]3([NH:35][CH2:34][C:33]4[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:59][CH:58]=4)[CH2:39][CH2:38][CH2:37]3)=[N:44][CH:43]=2)=[C:3]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[N:9]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:4]2=[N:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(Cl)c(Cl)cnc32)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(C2(NCc3ccc(OC)cc3)CCC2)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CNC2(c3ncc(-c4c(Cl)cnc5c4cc(-c4cnn(C)c4)n5S(=O)(=O)c4ccc(C)cc4)s3)CCC2)cc1
Temperature: 100 °C

Procedure:
A solution of 4,5-dichloro-2-(1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Example 113C) (1.3 g, 3.09 mmol) and N-(4-methoxybenzyl)-1-(5-(tributylstannyl)thiazol-2-yl)cyclobutanamine (Example 112C) (2.45 g, 4.35 mmol) in anhydrous N,N-dimethylformamide (10 mL) was degassed for about 15 minutes under nitrogen. Bis(triphenylphosphine)palladium(II) dichloride (0.108 g, 0.154 mmol) was added to the degassed solution, and reaction was put under nitrogen, sealed, and heated to 100° C. for 16 hours. The reaction was cooled and diluted with ethyl acetate and water. The layers were separated, and organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 40% to 50% ethyl acetate in hexanes, to provide the title compound. MS ESI(+) m/z 659.1 [M+H]+.
Reaction SMILES: [I:1][CH2:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[F:12][C:13]1[C:21]2[CH2:20][CH2:19][S:18][C:17]=2[C:16](O)=[CH:15][CH:14]=1>>[F:12][C:13]1[C:21]2[CH2:20][CH2:19][S:18][C:17]=2[C:16]([O:5][C@@H:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:3][CH2:2][I:1])=[CH:15][CH:14]=1
Reactant: O[C@@H](CCI)c1ccccc1
Reactant: Oc1ccc(F)c2c1SCC2
Product: Fc1ccc(O[C@H](CCI)c2ccccc2)c2c1CCS2

Procedure:
using (S)-1-iodo-3-phenyl-3-propanol with 4-fluoro-2,3-dihydrobenzo[b]thiophen-7-ol, to give 243 mg of the title compound as a colourless solid: δH (300 MHz, CDCl3) 7.32-7.12 (5H, m, 3-ArH), 6.46-6.27 (3H, m, ArH), 5.15-5.06 (1H, m, CHO), 3.43-3.11 (6H, m CH2CH2HI and SCH2CH2), 2.50-2.31 (1H, m, CHHCH2I) and 2.27-2.09 (1H, m, CHHCH2I).