Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][N:33]1[CH:37]=[C:36]([C:38](O)=[O:39])[CH:35]=[N:34]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:27]1([CH2:26][N:10]2[C:9]3[N:8]=[C:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:38]([C:36]5[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=5)=[O:39])=[CH:31][CH:30]=4)[NH:15][C:14]=3[C:13](=[O:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:11]2=[O:25])[CH2:28][CH2:29]1
Reactant: Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reactant: Cn1cc(C(=O)O)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)Nc2ccc(Cc3nc4c([nH]3)c(=O)n(Cc3ccccc3F)c(=O)n4CC3CC3)cc2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.3 %

Procedure:
A solution of 8-(4-amino-benzyl)-3-cyclopropylmethyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione (50 mg, 0.12 mmol) in N,N-dimethylformamide at 25° C. was treated with a solution of 1-methyl-1H-pyrazole-4-carboxylic acid (15 mg, 0.12 mmol), O-benzotriazol-1-yl-N,N.N′N′-tetramethyluronium hexafluorophosphate (49.7 mg, 0.13 mmol), and N,N-diisopropylethylamine (62 μL, 0.36 mmol). The resulting solution was stirred at 25° C. for 18 h. At this time, the reaction was concentrated in vacuo. The residue was dissolved in chloroform and then was washed with a 1N aqueous hydrochloric acid solution (1×10 mL) and a saturated aqueous sodium chloride solution (1×10 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 760mesh, 5:95 methanol/dichloromethane) afforded 1-methyl-1H-pyrazole-4-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-amide (13.5 mg, 21.5%) as a tan solid: EI-HRMS m/e calcd for C28H26N7O3 (M+) 527.2081, found 527.2083.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH2:7][CH2:8][C:9]1[N:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([O:17][CH3:18])[N:10]=1)(=[O:4])=[O:3].[CH2:19](OC1C=C(OC)N=C(CCCO)N=1)C>>[CH3:1][S:2]([O:5][CH2:6][CH2:7][CH2:8][C:9]1[N:14]=[C:13]([O:15][CH2:16][CH3:19])[CH:12]=[C:11]([O:17][CH3:18])[N:10]=1)(=[O:3])=[O:4]
Reactant: CCOc1cc(OC)nc(CCCO)n1
Reactant: COc1cc(OC)nc(CCCOS(C)(=O)=O)n1
Product: CCOc1cc(OC)nc(CCCOS(C)(=O)=O)n1

Procedure:
The title compound was synthesized according to the procedure described for 3-(4,6-dimethoxypyrimidin-2-yl)propyl methanesulfonate (step 4), starting from 3-(4-ethoxy-6-methoxypyrimidin-2-yl)propan-1-ol. LC-MS conditions B: tR=0.68 min, [M+H]+=291.08.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([CH:14]2[CH2:16][CH2:15]2)=[C:7]([F:13])[C:8](OCC)=[O:9])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:14]2[CH2:16][CH2:15]2)=[C:7]([F:13])[CH2:8][OH:9])=[CH:17][CH:18]=1
Reactant: CCOC(=O)C(F)=C(c1ccc(Cl)cc1)C1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC(F)=C(c1ccc(Cl)cc1)C1CC1
Temperature: -55 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
A solution of ethyl p-chloro-β-cyclopropyl-α-fluorocinnamate, (L)- and (Z)- (32.25 g, 0.12 mol) in ether is added dropwise to a mixture of lithium aluminum hydride (5.46 g, 0.144 mol) in ether while maintaining the temperature at -55° C. After the addition is complete, the reaction mixture is warmed to and stirred at -20° C. for 90 minutes, quenched sequentially with ethyl acetate, methanol and 2N hydrochloric acid, and extracted with ether. The organic extracts are combined, washed sequentially with water, saturated sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product as a colorless oil (26.4 g, 97%).
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)=[C:13]([C@:22]([C@@H:30]2[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]2)([OH:29])[CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.[N+](C1C=CC([O:50][C:51]([NH:53][C@H:54]2[CH2:59][CH2:58][CH2:57][N:56]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:55]2)=O)=CC=1)([O-])=O>C(Cl)Cl>[F:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)=[C:13]([C@:22]([C@@H:30]2[CH2:35][CH2:34][CH2:33][N:32]([C:51]([NH:53][C@H:54]3[CH2:59][CH2:58][CH2:57][N:56]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:55]3)=[O:50])[CH2:31]2)([OH:29])[CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Reactant: COCCCC[C@@](O)(c1cccc(F)c1-c1cccc(C)c1)[C@@H]1CCCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCCC[C@@](O)(c1cccc(F)c1-c1cccc(C)c1)[C@@H]1CCCN(C(=O)N[C@H]2CCCN(C(=O)OC(C)(C)C)C2)C1
Reaction time: 0.5 h

Procedure:
A solution of (S)-1-(6-fluoro-3′-methylbiphenyl-2-yl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol TFA salt (62.7 mg, 0.13 mmol) in anhydrous CH2Cl2 (0.5 mL) containing triethyl amine (0.1 mL) was added to above solution of (S)-tert-butyl 3-((4-nitrophenoxy)carbonylamino)piperidine-1-carboxylate within 1 min. The mixture was stirred for 30 min. The reaction mixture was evaporated and the residue was purified by preparative HPLC to afford (S)-tert-Butyl 3-((R)-3-((S)-1-(6-fluoro-3′-methylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamido)piperidine-1-carboxylate (35 mg). MS m/z 612 (M+H)+.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[C:6]([O:14][C@H:15]1[C@H:20](O)[C@@H:19]([CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:18][CH2:17][CH2:16]1)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>N1C=CC=CC=1>[C:6]([O:14][C@@H:15]1[CH2:16][CH2:17][O:18][C@H:19]([CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:20]1[Cl:4])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C(O[C@@H]1CCO[C@H](COCc2ccccc2)[C@H]1O)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(O[C@@H]1CCO[C@H](COCc2ccccc2)[C@@H]1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sulfonyl chloride (29 μl) was added to a solution of 1,5-anhydro-3-O-benzoyl-6-O-benzyl-2-deoxy-D-arabino-hexitol obtained by the method described in J. Org. Chem. 67. 3346-3354 (2002) (94 mg) in pyridine (27 mg) under ice-cooling, and the mixture was stirred at room temperature for 4 hours. Water was added, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developed with ethyl acetate-hexane) to give the title compound (27 mg).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:23])=[O:11].F[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[C:17]([N:18]3[N:22]=[CH:21][CH:20]=[N:19]3)=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:23])=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1
Reactant: Cc1cccc(-n2nccn2)c1C(=O)N1CCC[C@@H](C)[C@H]1CN
Reactant: Fc1ccc(C(F)(F)F)cn1
Product: Cc1cccc(-n2nccn2)c1C(=O)N1CCC[C@@H](C)[C@H]1CNc1ccc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A264 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(2-methyl-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 459 [M+1]+. 1H NMR (500 MHz, CD3OD) δ 8.35-6.55 (m, 8H), 5.10-2.85 (m, 5H), 2.43-0.75 (m, 11H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([NH:21][S:22]([CH:25]2[CH2:28][CH:27]([O:29]CC3C=CC=CC=3)[CH2:26]2)(=[O:24])=[O:23])=[C:12]2[NH:20][CH2:19][CH2:18][N:13]2[C:14](=[O:17])[C:15]=1[CH3:16].B(Cl)(Cl)Cl>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([NH:21][S:22]([CH:25]2[CH2:28][CH:27]([OH:29])[CH2:26]2)(=[O:23])=[O:24])=[C:12]2[NH:20][CH2:19][CH2:18][N:13]2[C:14](=[O:17])[C:15]=1[CH3:16]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC(OCc3ccccc3)C2)c2n(c1=O)CCN2
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC(O)C2)c2n(c1=O)CCN2
Temperature: 25 °C
Reaction time: 6 h
Yield: 29.5 %

Procedure:
3-Benzyloxy-cyclobutanesulfonic acid [7-(2-fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-1,2,3,5-tetrahydro-imidazo[1,2-a]pyridin-8-yl]-amide (120 mg, 0.19 mmol) in DCM (3 mL) was reacted with 1M BCl3 (67 mg, 0.57 mmol) at 0° C. The resulting mixture was stirred at room temperature for 6 hours. Purification by column chromatography on silica gel (5% MeOH in CHCl3), followed by preparative HPLC afforded 30 mg of the product (29.4% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH3:12][CH:13]([OH:17])[CH2:14][CH:15]=[CH2:16].O>C(N(CC)CC)C.C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:8][C:5]1[CH:6]=[CH:7][C:2](/[CH:16]=[CH:15]/[CH2:14][CH:13]([OH:17])[CH3:12])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Reactant: C=CCC(C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: Cc1ccc(/C=C/CC(C)O)cc1[N+](=O)[O-]
Yield: 77.3 %

Procedure:
A mixture of 4-bromo-2-nitrotoluene (2.16 g, 10.0 mmol), 4-penten-2-ol (904 mg, 10.5 mmol), palladium(II) acetate (22 mg, 0. 10 mmol) and tri-o-tolylphosphine (122 mg, 0.400 mmol) was diluted with triethylamine (3 mL) and acetonitrile (6 mL) and refluxed under nitrogen for 28 h. The mixture was poured into water (30 mL) and extracted with chloroform (2×30 mL). The chloroform extracts were dried (Na2SO4) and evaporated, and the residue was column chromatographed on 100 g of Merck silica gel 60 (70-230 mesh) with 20-40% (v/v) ethyl acetate, 20% (v/v) chloroform in hexane. This gave 1.71 g (77.4% yield) of yellow oil.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]2)=[CH:16][CH:15]=1.Cl.C(N(CC)CC)C>C(#N)C>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:22]1[CH2:23][CH2:24][CH2:25][CH:20]([C:17]2[CH:16]=[CH:15][C:14]([CH3:13])=[CH:19][CH:18]=2)[CH2:21]1
Reactant: Cc1ccc(C2CCCNC2)cc1
Reactant: BrCC1COc2ccccc2O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(C2CCCN(CC3COc4ccccc4O3)C2)cc1

Procedure:
A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (36 mg, 0.16 mmol), 3-(4-methylphenyl)piperidine.HCl (35 mg, 0.16 mmol) and triethylamine (38 mg, 0.38 mmol) in acetonitrile (2 mL) was heated in a microwave reactor at 140-150° C. for 9 h. The mixture was absorbed on silica and purified by flash chromatography using a gradient of heptane and EtOAc as eluent to give 20 mg of the title compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[I:16])=[O:4].C([O-])([O-])=O.[K+].[K+].[OH-].[K+].Br[CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31]>C1(C)C=CC=CC=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].CCOCC>[CH3:31][C:30]([CH3:32])=[CH:29][CH2:28][N:5]([CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[I:16])[C:3](=[O:4])[C:2]([F:1])([F:17])[F:18]
Reactant: COc1ccc(I)c(CCNC(=O)C(F)(F)F)c1
Reactant: CC(C)=CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1ccc(I)c(CCN(CC=C(C)C)C(=O)C(F)(F)F)c1
Reaction time: 3 h
Yield: 32.8 %

Procedure:
A solution of N-trifluoroacetyl-2-iodo-5-methoxyphenethylamine (0.700 g, 1.88 mmol) in toluene (25 mL) was treated with K2CO3 (0.340 g, 2.4 mmol), KOH (0.210 g, 3.76 mmol), n-Bu4NBr (0.060 g, 0.19 mmol) and 4-bromo-2-methyl-2-butene (0.364 g, 2.44 mmol). The mixture was stirred at 80 C for 3 hours, cooled to 20 C, diluted with ether (100 mL), washed with 10% HCl (50 mL) and concentrated. Flash chromatography (10% EtOAc in hexane, silica) resulted in 0.272 g of a clear oil. 1H NMR (400 MHz, CDCl3, mixture of rotamers) d 7.65 (m, 1H), 6.75 (m, 1H), 6.54 (m, 1H), 5.20 (m, 0.4H), 5.0 (m, 0.6H), 4.10 (m, 1H), 3.82 (m, 1H), 3.76 (d, 2H), 3.50 (m, 2H), 3.02 (m, 2H), 1.75 (m, 3H), 1.66(m, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([CH3:12])=[CH:7]2.[C:14](OCC)(OCC)(OCC)[CH3:15]>>[CH3:14][C:15]1[O:13][C:3]2[CH:4]=[CH:5][C:6]3[CH:7]=[C:8]([CH3:12])[CH:9]=[N:10][C:11]=3[C:2]=2[N:1]=1
Reactant: Cc1cnc2c(N)c(O)ccc2c1
Reactant: CCOC(C)(OCC)OCC
Product: Cc1cnc2c(ccc3oc(C)nc32)c1
Temperature: 25 °C

Procedure:
3.48 g (20 mmol) of 8-amino-7-hydroxy-3-methylquinoline and 16.2 g (100 mmol) of triethyl orthoacetate are heated at 100° C. for 1 hour. The reaction mixture is then allowed to cool to room temperature, 50 ml of petroleum ether are added while stirring vigorously, and the precipitate is filtered off with suction.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].[N+:12]([O-])([OH:14])=[O:13].O>S(=O)(=O)(O)O>[CH3:1][C:2]([C:4]1[C:5]([OH:11])=[C:6]([N+:12]([O-:14])=[O:13])[CH:7]=[C:8]([F:10])[CH:9]=1)=[O:3]
Reactant: CC(=O)c1cc(F)ccc1O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)c1cc(F)cc([N+](=O)[O-])c1O
Temperature: -20 °C

Procedure:
5-Fluoro-2-hydroxyacetophenone (20.0 g) was dissolved in concentrated sulphuric acid (150 ml), and the mixture was cooled to -20° C. A mixture of concentrated nitric acid (17.0 ml; s.g. 1.42) in concentrated sulphuric acid (18.0 ml) was then added to it, dropwise with stirring, keeping the temperature of the reaction mixture between -15° and -5° C. The reaction mixture was then allowed to warm up to -5° C. and was poured into iced water (2 liters). The yellow precipitated product was filtered off and recrystallised from ethanol to give 5-fluoro-2-hydroxy-3-nitroacetophenone (11.9 g), m.p. 87°-90° C.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>CCO.[Pd].[C]>[CH2:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC#Cc1ccc2[nH]ccc2c1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 46.5 %

Procedure:
A mixture of the product of Step A (0.17 g; 0.75 mmol) and 10% Pd/carbon (0.2 g) in EtOH (15 ml) was stirred at room temperature for 40 min under H2 (balloon). The catalyst was removed by filtration through the Celite pad, washed with CH2Cl2 (2×10 ml) and combined filtrates were evaporated to dryness under reduced pressure. The residue was purified by FCC (SiO2; hexane/EtOAc; 9:1) to give the title compound (0.08 g; 46%) as a colourless syrup. 1H-NMR (CDCl3) 0.86 (tr, 3H, J=6.7 Hz); 1.28 (m, 10H); 1.65 (m, 2H); 2.68 (tr, 2H, J=7.9 Hz); 6.47 (m, 1H); 7.02 (dd, 1H, J=1.5, 8.3 Hz); 7.16 (m, 1H); 7.29 (d, 1H, J=8.3 Hz); 7.42 (s, 1H); 8.04 (broad s, 1H).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1([Li])C=CC=CC=1.[Cl:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]([CH:40]2[CH2:42][CH2:41]2)=O)[C:33]=1[O:43][CH:44](F)F>CCOCC>[Cl:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]([CH:40]2[CH2:42][CH2:41]2)=[CH:2][O:3][CH3:4])[C:33]=1[O:43][CH3:44]
Reactant: O=C(c1nccc(Cl)c1OC(F)F)C1CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]c1ccccc1
Solvent: CCOCC
Product: COC=C(c1nccc(Cl)c1OC)C1CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 13.6 %

Procedure:
18.27 g of (methoxymethyl) triphenyl phosphonium chloride is suspended in 200 ml of anhydrous ether, 51.3 ml of phenyllithium (1.04 M) was dropped and the resulting mixture was stirred at a room temperature for 15 minutes. 145 ml of ether solution of 12.57 g of (4-chloro-3-difluoromethoxy-2-pyridyl)cyclopropylketone (X) was dropped to the mixture, which was stirred at a room temperature for 12 hours. The resulting residue was separated by filtering and washed with ether, and thereafter, the ether filtrate and ether used for washing were collected together and the collected solution was washed with water, and thereafter, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=4:1) to obtain 1.66 g of 2-(4-chloro-3-difluomethoxy-2-pyridyl)-2-cyclopropyl-1-methoxyethene (XI).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([NH2:15])=[O:14])=[N:10][C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:4][CH:3]=1.[H-].[Na+].[F:26][C:27]([F:33])([F:32])[CH2:28][CH2:29][CH2:30]Br>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13]([NH:15][CH2:30][CH2:29][CH2:28][C:27]([F:33])([F:32])[F:26])=[O:14])=[N:10][C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:6][CH:7]=1
Reactant: NC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)s1
Reactant: FC(F)(F)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NCCCC(F)(F)F)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Part B: To a cooled (0° C.) stirred solution of 5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxamide (1.16 gram, 3.02 mmol) in anhydrous DMF (20 mL) is added NaH (0.13 gram of a 60% dispersion) in a nitrogen atmosphere. The resulting mixture is stirred for 1 hour and excess 4,4,4-trifluoro-1-bromobutane (0.7 mL) is added. The resulting solution is stirred at room temperature for 1 hour, poured onto ice/water and extracted twice with diethyl ether. The collected diethyl ether layers are twice washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The residue is further purified by column chromatography (silica gel: eluant: dichloromethane) to give 5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)-N-(4,4,4-trifluorobutyl)thiazole-2-carboxamide. Melting point: 99-101° C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:66][CH2:67][CH:68]([OH:76])[CH2:69][N:70]1[CH2:75][CH2:74][NH:73][CH2:72][CH2:71]1>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:66][CH2:67][CH:68]([OH:76])[CH2:69][N:70]5[CH2:71][CH2:72][NH:73][CH2:74][CH2:75]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: NCC(O)CN1CCNCC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NCC(O)CN2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.08 h
Yield: 68 %

Procedure:
A mixture of 0.045 g (0.1 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (I-22), 0.042 g (0.110 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 ml (0.300 mmole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.019 g (0.12 mmole) 1-amino-3-piperazin-1-yl-propan-2-ol was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 0:100-80:20) to give 0.04 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(2-hydroxy-3-piperazin-1-yl-propyl)-3-methoxy-benzamide (I-121) as a white solid.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])[N:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=[O:6].[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:3][CH2:4][C:5]([N:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])[N:16]=[CH:15][N:14]=3)[CH2:9][CH2:8]2)=[O:6])=[O:30])=[CH:27][CH:26]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: CC(C)COc1cc(N2CCN(C(=O)CN)CC2)ncn1
Agent: Cl
Product: CC(C)COc1cc(N2CCN(C(=O)CNC(=O)c3ccc(F)cc3)CC2)ncn1

Procedure:
The title compound was prepared according to the procedure described in Example 3 using 2-amino-1-(4-(6-isobutoxypyrimidin-4-yl)piperazin-1-yl)ethanone dihydrochloride and 4-fluorobenzoic acid.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:20]=3[CH:21]=[CH:22][CH:23]=[N:24]4)[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[N:31]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:20]=3[CH:21]=[CH:22][CH:23]=[N:24]4)[CH:13]=[N:12]2)[C:8]([NH:29][C:30]2[CH:34]=[CH:33][N:32]([CH2:35][C:36]([OH:38])([CH3:37])[CH3:39])[N:31]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc3ncccc23)cc1=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3cccc4ncccc34)cc2=O)n1
Yield: 59 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[6-oxo-4-(quinolin-5-yloxy)-6H-pyridazin-1-yl]-propionic acid (Intermediate 57) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[6-oxo-4-(quinolin-5-yloxy)-6H-pyridazin-1-yl]-propionamide as a white solid (0.69 g, 59%); ES+-HRMS m/e calcd for C28H32N6O4 [M+H+] 517.2558 found 517.2557. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.04 (s, 3H), 1.05 (s, 3H), 1.10 (m, 1H), 1.21-1.77 (m, 8H), 1.92 (m, 1H), 2.28 (m, 1H), 3.89 (s, 2H), 4.67 (s, 1H), 5.46 (dd, J=4.4, J=10.7 Hz, 1H), 5.78 (d, J=2.7 Hz, 1H), 6.40 (d, J=2.1 Hz, 1H), 7.52 (d, J=2.1 Hz, 1H), 7.57 (d, Jo=7.8 Hz, 1H), 7.62 (dd, Jo=8.5, 4.0 Hz, 1H), 7.86 (t, Jo=8.2 Hz, 1H), 8.04 (d, Jo=8.5 Hz, 1H), 8.29 (d, J=2.7 Hz, 1H), 8.39 (d, Jo=8.5 Hz, 1H), 9.01 (dd, Jo=4.0, Jm=1.5 Hz, 1H), 10.81 (s, 1H).