Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:3]=12.[N:24]1([CH2:29][CH2:30]O)[CH:28]=[CH:27][N:26]=[CH:25]1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:30][CH2:29][N:24]3[CH:28]=[CH:27][N:26]=[CH:25]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:3]=12
Reactant: OCCn1ccnc1
Reactant: Fc1cccc(-c2n[nH]c3nnc(-c4ccccc4)c(Cl)c23)c1
Product: Fc1cccc(-c2nn(CCn3ccnc3)c3nnc(-c4ccccc4)c(Cl)c23)c1

Procedure:
Compound IIs was synthesized from 4-chloro-3-(3-fluorophenyl)-5-phenyl-1H-pyrazolo[3,4-c]pyridazine and 2-(1H-imidazol-1-yl)ethanol following the general procedure for the Mitsunobu reaction as described above.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([O:10][CH2:11][CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH:7]([N:20]=[N+]=[N-])[CH2:6]1)=[O:4].[Cl:23][C:24]1[S:28][C:27]([C:29](O)=[O:30])=[CH:26][CH:25]=1>O=[Pt]=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][C@H:8]([O:10][CH2:11][CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C@@H:7]([NH:20][C:29]([C:27]2[S:28][C:24]([Cl:23])=[CH:25][CH:26]=2)=[O:30])[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1CC(N=[N+]=[N-])[C@@H](OCCOC2CCCCO2)C1
Reactant: O=C(O)c1ccc(Cl)s1
Agent: O=[Pt]=O
Product: COC(=O)C1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](OCCOC2CCCCO2)C1

Procedure:
In analogy to example 10A and example 1B, (S,4S)-3-azido-4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-cyclopentanecarboxylic acid methyl ester was hydrogenated in the presence of PtO2 and coupled with 5-chloro-2-thiophenecarboxylic acid to give (3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-cyclopentanecarboxylic acid methyl ester. Brown gum. MS 432.2 ([M+H]+).
Reaction SMILES: [CH2:1]([C:3]([OH:35])([CH2:33][CH3:34])[CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[C:9](\[C:11]1[CH:12]=[C:13]([CH:30]=[CH:31][CH:32]=1)[O:14][CH2:15][C:16]1[CH:17]=[C:18]([C:26](OC)=[O:27])[C:19](=[CH:24][CH:25]=1)[C:20](OC)=[O:21])/[CH3:10])[CH3:2].[BH4-].[Li+]>>[OH:27][CH2:26][C:18]1[CH:17]=[C:16]([CH:25]=[CH:24][C:19]=1[CH2:20][OH:21])[CH2:15][O:14][C:13]1[CH:12]=[C:11](/[C:9](/[CH3:10])=[CH:8]\[CH2:7][CH2:6][CH2:5][CH2:4][C:3]([CH2:1][CH3:2])([OH:35])[CH2:33][CH3:34])[CH:32]=[CH:31][CH:30]=1
Reactant: CCC(O)(CC)CCCC/C=C(/C)c1cccc(OCc2ccc(C(=O)OC)c(C(=O)OC)c2)c1
Agent: [BH4-]
Agent: [Li+]
Product: CCC(O)(CC)CCCC/C=C(/C)c1cccc(OCc2ccc(CO)c(CO)c2)c1

Procedure:
In a manner similar to Example 53(e), by reacting 1.21 g (2.58 mmol) of dimethyl 4-(3-((Z)-7-ethyl-7-hydroxy-1-methylnon-1-enyl)phenoxymethyl]-phthalate (prepared in a manner similar to Example 73(a)) with 170 mg (7.76 mmol) of lithium borohydride, a colourless oil is obtained (m=865 mg; Y=81%).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]3[C:24]4[C:18]5([CH2:26][CH:21]([C:22](=[O:25])[CH:23]=4)[CH2:20][CH2:19]5)[CH2:17][C:14]=32)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:27]N1C(=O)CCC1=O>CN(C)C=O>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]3[C:24]4[C:18]5([CH2:26][CH:21]([C:22](=[O:25])[C:23]=4[Cl:27])[CH2:20][CH2:19]5)[CH2:17][C:14]=32)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=C2c3ccc4nn(Cc5ccccc5)cc4c3CC23CCC1C3
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: O=C1C(Cl)=C2c3ccc4nn(Cc5ccccc5)cc4c3CC23CCC1C3
Temperature: 25 °C

Procedure:
A solution of 2-benzyl-2,9,10,11-tetrahydro-8,10a-methanoazuleno[2,1-e]indazol-7(8H)-one (0.737 g, 2.17 mmol) in 15 mL of dimethylformamide was heated to 60° C. and N-chlorosuccinimide (0.290 g, 2.17 mmol) was added. After heating for 45 minutes, additional N -chlorosuccinimide (0.074 g, 0.55 mmol) was added. After heating for 55 minutes more, the reaction mixture was cooled to room temperature and partitioned between EtOAc and water. The organic phase was washed with water and brine, dried over MgSO4 and concentrated under vacuum. The residue was purified by chromatography on silica gel (elution with 15:85 to 80:20 EtOAc/hexanes) to yield 2-benzyl-6-chloro-2,9,10,11-tetrahydro-8,10a-methanoazuleno[2,1-e]indazol-7(8H)-one as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]2[CH3:21])[C:5]2[CH2:10][N:9]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[CH2:8][C:6]=2[N:7]=1.[CH3:22][NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=1)=[O:25].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.O>[CH:12]1([CH2:11][N:9]2[CH2:10][C:5]3[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]4[CH3:21])=[N:3][C:2]([C:30]4[CH:29]=[CH:28][C:27]([NH:26][C:24]([NH:23][CH3:22])=[O:25])=[CH:32][CH:31]=4)=[N:7][C:6]=3[CH2:8]2)[CH2:14][CH2:13]1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(CC1CC1)C2
Reactant: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: CNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(CC2CC2)C3)cc1
Temperature: 130 °C
Yield: 51.5 %

Procedure:
To a solution of (S)-4-(2-chloro-6-(cyclopropylmethyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (intermediate 8) (50 mg, 0.16 mmol) and 1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (407 mg, 0.39 mmol) in DME/EtOH/H2O (7:3:2) (5 mL) was added Pd(PPh3)2(Cl)2 (7 mg, 0.008 mmol) and Na2CO3 (26 mg, 0.24 mmol). The reaction mixture was then heated by microwave at 130° C. for 30 minutes. The crude reaction mixture was then partitioned between water and EtOAc, the organic layer recovered, dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by prep. LCMS (low pH). The solvent was removed in vacuo. The residue was then re-purified by Flash SCX2 column chromatography, affording the title compound as a white solid (34.8 mg, 51% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[CH2:6]([O:8][C:9](=[O:29])[N:10]([C:18]1[CH:23]=[C:22](Br)[N:21]=[C:20]([NH2:25])[C:19]=1[N+:26]([O-:28])=[O:27])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:7]>>[CH2:6]([O:8][C:9](=[O:29])[N:10]([C:18]1[CH:23]=[C:22]([NH:5][CH2:4][CH2:3][O:2][CH3:1])[N:21]=[C:20]([NH2:25])[C:19]=1[N+:26]([O-:28])=[O:27])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:7]
Reactant: COCCN
Reactant: CCOC(=O)N(Cc1ccccc1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Product: CCOC(=O)N(Cc1ccccc1)c1cc(NCCOC)nc(N)c1[N+](=O)[O-]

Procedure:
The title compound was prepared following the example in preparation 102 using 2-methoxyethylamine (1.0 ml) and (2-amino-6-bromo-3-nitro-pyridin-4-yl)-benzyl-carbamic acid ethyl ester (150 mg), giving the product (121 mg) as a yellow gum.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([F:33])=[C:12]([C:16]2[CH:17]=[N:18][C:19]([N:22]3[CH2:27][CH2:26][N:25]([S:28]([CH:31]=[CH2:32])(=[O:30])=[O:29])[CH2:24][CH2:23]3)=[N:20][CH:21]=2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C[O:37][CH2:36]C1.CO.[OH-].[Na+]>C(Cl)(Cl)Cl>[Si:1]([O:8][CH2:9][C:10]1[C:11]([F:33])=[C:12]([C:16]2[CH:17]=[N:18][C:19]([N:22]3[CH2:23][CH2:24][N:25]([S:28]([CH2:31][CH2:32][O:37][CH3:36])(=[O:30])=[O:29])[CH2:26][CH2:27]3)=[N:20][CH:21]=2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: C=CS(=O)(=O)N1CCN(c2ncc(-c3cccc(CO[Si](C)(C)C(C)(C)C)c3F)cn2)CC1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COCCS(=O)(=O)N1CCN(c2ncc(-c3cccc(CO[Si](C)(C)C(C)(C)C)c3F)cn2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-2-[4-(vinylsulfonyl)piperazin-1-yl]pyrimidine (360 mg) was mixed with THF (3 ml) and MeOH (4 ml), and a 1 M aqueous NaOH solution (1.46 ml) was added thereto, followed by stirring at room temperature for 3 hours. CHCl3 was added to the reaction mixture, which was washed with water and saturated brine, and dried over Na2SO4. Then, the organic layer was concentrated under reduced pressure to obtain 5-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-2-{4-[(2-methoxyethyl)sulfonyl]piperazin-1-yl}pyrimidine (353 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pt]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccc(Cl)cc2)cc1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Nc1ccc(CCc2ccc(Cl)cc2)cc1

Procedure:
A solution of 5.0 g (19.2 mmol) 4-[2-(4-chloro-phenyl)-vinyl]-1-nitro-benzene in 100 ml ethyl acetate is treated with 200 mg of platinum 5% on charcoal. Hydrogenation is performed at room temperature and normal pressure overnight. The catalyst is filtered off and the filtrate evaporated to yield 3.17 g (71%) of a slightly yellow solid. MS: m/e=231.9 (M++H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][C@H:8]([CH2:12][C@H:13]([CH3:17])[CH2:14][CH2:15][CH3:16])[C:9](O)=[O:10])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.[Cl-].[Na+].O>[C:1]([O:5][C:6](=[O:18])[CH2:7][C@@H:8]([CH2:9][OH:10])[CH2:12][C@H:13]([CH3:17])[CH2:14][CH2:15][CH3:16])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCC[C@@H](C)C[C@@H](CC(=O)OC(C)(C)C)C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCC[C@@H](C)C[C@H](CO)CC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 58.5 %

Procedure:
To acid 102 (3.68 g, 0.014 mol) in THF (100 mL) at 0° C. was added BH3.Me2 (36 mL of a 2 M solution in THF, Aldrich) upon which the solution was warmed to room temperature. After 15 hours ice was carefully added (in order to control the effervescence) to the solution followed by brine. The solution was extracted with ether and the combined organic phases dried (MgSO4) and concentrated under reduced pressure. Flash chromatography (4:1 hexane/EtOAc) gave alcohol 103 as an oil (2.0 g, 59%). 13C NMR (100 MHz; CDCl3) 173.56, 80.85, 65.91, 39.74, 39.20, 38.90, 35.65, 29.99, 28.31, 20.18, 19.99, 14.56.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[CH2:13]([OH:16])[C:14]#[CH:15]>C(O)(C)(C)C.O.O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][N:1]2[CH:15]=[C:14]([CH2:13][OH:16])[N:3]=[N:2]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CN=[N+]=[N-])cc1
Reactant: C#CCO
Solvent: CC(C)(C)O
Solvent: O
Product: COc1ccc(Cn2cc(CO)nn2)cc1
Reaction time: 48 h
Yield: 59.1 %

Procedure:
93 mmol 1-(azidomethyl)-4-methoxybenzene, 110 mmol propargyl alcohol were mixed in 230 ml tert-butyl alcohol/H2O (1:1) solution. 1 mmol CuSO4.5H2O and 10 mmol Ascorbic acid sodium salts dissolved in 2 ml water were added into the solution. The mixture was stirred for 2 days. After evaporation, the mixture was purified by flash column to give 55 mmol (1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-yl) methanol. 1H NMR (CDCl3): 7.42 (1H, s), 7.22 (2H, d, JH-H=8.70), 6.88 (2H, d, JH-H=8.70), 5.43 (2H, s), 4.73 (2H, s), 3.79 (3H, s).
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH3:8])=[O:6])=[N+]=[N-].[CH2:9]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][C:18]=1[F:25])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:8][O:7][C:5]([C:4]1[NH:1][C:23]2[C:20]([CH:21]=1)=[CH:19][C:18]([F:25])=[C:17]([O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:24]=2)=[O:6]
Reactant: O=Cc1ccc(OCc2ccccc2)c(F)c1
Reactant: COC(=O)CN=[N+]=[N-]
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2cc(F)c(OCc3ccccc3)cc2[nH]1

Procedure:
A mixture of methyl 2-azidoacetate, 4-benzyloxy-3-fluoro-benzaldehyde and sodium methanolate (in methanol) in toluene was reacted for 3 h at 0° C. The residue after filtration of the suspension was washed with methanol, partitioned between ethyl acetate and ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were dried with Na2SO4, evaporated to dryness and the residue taken up in p-xylene and brought to reflux temperature for 2 h. After concentration the mixture was left to crystallize and the formed crystals were filtered off and washed with toluene. The title compound was after drying at 40° C. under vacuum obtained as yellow crystals. MS (m/e): 300.3 (MH+, 100%).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[C:5]([C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[S:14](Cl)(=[O:16])=[O:15])#[N:6]>C(OCC)C>[C:5]([C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[S:14]([NH:4][CH:1]([CH3:3])[CH3:2])(=[O:16])=[O:15])#[N:6]
Reactant: CC(C)N
Reactant: N#Cc1c(F)cccc1S(=O)(=O)Cl
Solvent: CCOCC
Product: CC(C)NS(=O)(=O)c1cccc(F)c1C#N
Reaction time: 1 h

Procedure:
To a solution of 5.2 ml of isopropylamine in 50 ml of diethyl ether cooled in an ice bath, a solution of 4.4 g of 2-cyano-3-fluorobenzenesulphonylchloride in 50 ml of diethylether was added dropwise while stirring; reaction temperature approx. 5° C. After leaving to stand at room temperature for one hour, the reaction mixture was washed twice with ice water, dried on anhydrous Na2SO4, filtered and evaporated to dryness. The desired product was obtained in a yield of 4.16 g; melting-point 97°-105° C.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.II.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].S(=O)(=O)(O)O>C1COCC1.[Zn]>[OH:7][C:1]1([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CBr
Reactant: O=C1CCCCC1
Agent: II
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)CCCCC1
Yield: 95.2 %

Procedure:
To a solution of cyclohexanone (9.52 g, 97.0 mmol), a zinc powder (7.6 g, 116.4 mmol) and a small amount of iodine in THF (100 ml) was added dropwise ethyl bromoacetate (11.8 ml, 106.7 mmol) under a nitrogen atmosphere, and the mixture was heated under reflux for 5 hrs. 10% Sulfuric acid (100 ml) was carefully added under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous MgSO4, and concentrated under reduced pressure to give the title compound (17.2 g, 94%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[NH:7][C:6]=2[CH:15]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C@@H:24]2[C@@H:29]3[CH2:30][C@@H:26]([CH:27]=[CH:28]3)[C@@H:25]2[C:31]([NH2:33])=[O:32])[C:20]([Cl:34])=[CH:19][N:18]=1>>[Cl:34][C:20]1[C:21]([NH:23][C@@H:24]2[C@@H:29]3[CH2:30][C@@H:26]([CH:27]=[CH:28]3)[C@@H:25]2[C:31]([NH2:33])=[O:32])=[N:22][C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[NH:7][C:6]=3[CH:15]=2)=[N:18][CH:19]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: CC1(C)CCC(=O)Nc2cc(N)ccc21
Product: CC1(C)CCC(=O)Nc2cc(Nc3ncc(Cl)c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)n3)ccc21

Procedure:
Title compound was prepared from 8-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide in a manner analogous to Example 1221d. (120° C., 30 min). Product was isolated as a white foam (82 mg, 49%), HPLC purity 90%, LCMS 467.24 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.52 (bs, 1H), 9.08 (bs, 1H), 7.88 (bs, 1H), 7.80 (s, 1H), 7.72 (s, 1H), 7.32 (s, 1H), 6.95 bs, 1H), 6.67 (bs, 1H), 6.31-6.28 (m, 1H), 6.18-6.16 (m, 1H), 4.26 (t, J=7.6 Hz, 1H), 3.05 (s, 1H), 2.94 (s, 1H), 2.65 (d, J=8.0 Hz, 1H), 2.56-2.50 (m, 1H), 2.47-2.36 (m, 1H), 2.17-2.10 (m, 3H), 1.54 (d, J=8.8 Hz, 1H), 1.42 (s, 6H).
Reaction SMILES: Br/[CH:2]=[CH:3]/[C@H:4]([OH:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.C(NCC)C.[CH:20](/[C@H:26]1[O:30][C:29]([CH3:32])([CH3:31])[O:28][C@H:27]1[CH2:33][O:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[CH:21]\[CH:22]=[CH:23]\[C:24]#[CH:25]>C1COCC1.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.[Cu]I>[OH:14][C@H:4]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)/[CH:3]=[CH:2]/[C:25]#[C:24]/[CH:23]=[CH:22]/[CH:21]=[CH:20]/[C@H:26]1[O:30][C:29]([CH3:32])([CH3:31])[O:28][C@H:27]1[CH2:33][O:34][CH2:35][C:36]([O:38][CH3:39])=[O:37]
Reactant: C#C/C=C/C=C/[C@H]1OC(C)(C)O[C@H]1COCC(=O)OC
Reactant: O[C@@H](/C=C/Br)COc1ccc(F)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: C1CCOC1
Product: COC(=O)COC[C@@H]1OC(C)(C)O[C@@H]1/C=C/C=C/C#C/C=C/[C@H](O)COc1ccc(F)cc1
Reaction time: 4 h
Yield: 79.6 %

Procedure:
In a flame dried flask, a solution of (1E,3S)-1-bromo-4-(4-fluorophenoxy)-3-hydroxy-1-butene (0.84 g, 3 mmol), tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.2 mmol) and copper(I) iodide (60 mg, 0.3 mmol) in THF (50 mL) and diethylamine (5 mL, 48 mmol) was carefully deoxygenated by bubbling in argon gas for 45 minutes. The reaction was stirred as a solution of 2-[[(4S,5R)-5-[(1E,3E)-1,3-hexadien-5-ynyl]-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]ethanoic acid, methyl ester, (0.9 g, 3.2 mmol) in THF (50 mL), which had been deoxygenated by bubbling in argon for 45 minutes, was added. After about 4 hours, the reaction was complete. The reaction mixture was diluted with hexane and filtered through a pad of silica gel and the silica gel was eluted with ether. The combined filtrates were concentrated to give an oil. Purification by chromatography using a 20–75% gradient of ether in hexane gave 1.1 g of 2-[[(4S,5R)-5-[(1E,3E,7E,9S)-9-hydroxy-10-(4-fluorophenoxy)-1,3,7-decatrien-5-ynyl]-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]ethanoic acid, methyl ester, a compound of formula (EE), as an oil; 1H NMR (CDCl3) δ 1.37 (s, 3H), 1.5 (s, 3H), 3.52 (m, 2H), 3.75 (s, 3H), 3.83 (m, 2H), 4.13 (m, 2H), 4.44 (m, 1H), 5.74 (m, 1H), 5.76 (m, 2H), 6.05 (m, 1H), 6.17 (m, 1H), 6.29 (m, 1H), 6.58 (dd, 1H), 6.88 (m, 4 H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][NH:10][C:6]=2[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][N:3]=1.[H-].[Na+].[CH2:18](I)[CH3:19]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH2:18][CH3:19])[C:6]=2[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(Cl)c2cc[nH]c12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(Cl)c2ccn(CC)c12
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Ethyl 4-chloro-1H-pyrrolo[3,2-c]pyridine-7-carboxylate (0.10 g) was dissolved in dimethylformamide (2 ml), cooled to 0° C. and sodium hydride (60% dispersion in oil) (0.027 g) added. The reaction mixture was stirred for 45 minutes at 0° C., allowed to warm to room temperature and stirred for a further 45 minutes. The reaction mixture was cooled to 0° C., ethyl iodide (0.039 ml) added, the reaction mixture allowed to warm to room temperature, and stirred for 1 hour. The reaction mixture was partitioned between ethyl acetate and water, the aqueous was separated and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated to afford the title compound as a yellow oil (0.095 g).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:17]([NH:19][C:20](=[O:22])[CH3:21])[CH:18]=1)[CH2:4][CH2:5][CH3:6].Br[CH2:39][CH2:40]CC([Cl:44])=O.CCN(C(C)C)C(C)C.[H-].[Na+].Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C.O.CCOC(C)=O.CCOCC>[ClH:44].[ClH:1].[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:17]([N:19]2[CH2:40][CH2:39][CH2:21][C:20]2=[O:22])[CH:18]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(NC(C)=O)c1
Reactant: O=C(Cl)CCCBr
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.6 %

Procedure:
To a solution of 5-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-phenylamine (Example 62, 0.2 mmol, 88 mg) in dry DCM (1.0 mL) was added 4-bromobutyryl chloride (0.4 mmol, 47 μL), DIEA (0.4 mmol, 70 μL), and DMAP (10 mg). And the mixture was stirred at room temperature for 1 hour then condensed. It was then diluted with water/EtOAc. The solvent was removed in vacuo and dried under vacuum over night. The residue was dissolved in dry THF (1.0 mL) at 0° C., NaH (60% dispersion in mineral oil, 0.8 mmol, 32 mg) was added and the mixture was heated at 50° C. for 1 hour. It was then poured into ice-water and extracted with ethyl acetate. The organic layers were combined, condensed and the residue was purified by silica gel chromatography (DCM to DCM+10% 2N NH3 in MeOH) to give a colorless sticky solid, which was dissolved in DCM (1.0 mL), 2N HCl in ether (1.0 mL) was added, kept at room temperature for 10 min, condensed, triturated with hexanes to provide the title compound (25 mg). LCMS: m/z 508 [M+1]. 1H NMR (400 MHz, CD3OD): δ 7.56 and 7.67 (1H, s), 7.41-7.48 (1H, m), 7.33-7.37 (1H, m), 7.25-7.31 (1H, m), 5.36-5.55 (1H, m), 4.52-4.58 (1H, m), 3.20-3.70 (8H, m), 3.07-3.13 (2H, m), 2.93 (3H, s), 1.92-2.59 (8H, m), 1.27-1.82 (12H, m), 0.80 (3H, t).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[O:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:15]=[C:14]([N:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)[N:13]=2)[CH2:8][CH2:7]1.[OH-].[Na+].[C:38](OCC)(=[O:40])C>CN(C)C=O>[O:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([CH:38]=[O:40])=[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:15]=[C:14]([N:24]3[CH2:25][CH2:26][N:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:28][CH2:29]3)[N:13]=2)[CH2:8][CH2:7]1
Reactant: CCOC(C)=O
Reactant: c1ccc(N2CCN(c3nc(N4CCOCC4)cc(N4CCOCC4)n3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c(N2CCOCC2)nc(N2CCN(c3ccccc3)CC2)nc1N1CCOCC1
Reaction time: 0.08 h
Yield: 80 %

Procedure:
The synthesis method shall be explained concretely, and in order, below. Phosphorus oxychloride (0.12 ml, 1.3 mmol) was added to dimethylformamide (0.3 ml, 4.0 mmol) at 0 degrees Celsius, and this was agitated for 5 minutes at 0 degrees Celsius. To this solution, 4,6-dimorpholino-2-(4-phenylpiperazin-1-yl)pyrimidine was dissolved in dimethylformamide (6 ml) and added, and this was agitated under heating for 1 hour at 100 degrees Celsius. After 2N NaOH solution was added to make the reaction liquid basic, extraction was carried out 2 times with ethyl acetate. After washing the organic layer with saturated saline, drying was done with MgSO4, and the solvent was distilled away under reduced pressure. Purification was done by silica gel chromatography (hexane:ethyl acetate=2:3), and 350 mg of 4,6-dimorpholino-5-formyl-2-(4-phenylpiperazin-1-yl)pyrimidine (yield 80%) was obtained. The melting point measurement result, the MS measurement result, and the NMR data for the obtained Compound 142 are shown below.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12](Cl)[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=3)=[C:10]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([Cl:28])[CH:23]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.FC1C=CC(C2C3N([CH:58]=[N:59][N:60]=3)C(NC(C3C=CC=CC=3)(C)C)=NC=2C2C=CN=CC=2)=CC=1>>[CH3:21][C:17]1[CH:16]=[C:15]([C:11]2[C:12]3[N:13]([CH:58]=[N:59][N:60]=3)[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=3)=[N:9][C:10]=2[C:22]2[CH:27]=[CH:26][N:25]=[C:24]([Cl:28])[CH:23]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cccc(-c2c(Cl)nc(-c3ccnc(Cl)c3)nc2-c2ccnc(Cl)c2)c1
Reactant: CC(C)(Nc1nc(-c2ccncc2)c(-c2ccc(F)cc2)c2nncn12)c1ccccc1
Product: Cc1cccc(-c2c(-c3ccnc(Cl)c3)nc(-c3ccnc(Cl)c3)n3cnnc23)c1

Procedure:
The title compound was synthesized from 2,6-bis(2-chloro(4-pyridyl))-4-chloro-5-(3-methylphenyl)pyrimidine in the same manner as 2-(8-(4-fluorophenyl)-7-(4-pyridyl)-1,2,4-triazolo[4,3-c]pyrimidin-5-yl)amino-2-phenylpropane; MS (m/z) 434.9 (M+H)+; C22H14Cl2N6 requir. 433.29.