Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[O:8][CH2:7]1.[O:14]([CH2:18][CH2:19][CH2:20][NH:21][C:22]([NH:24][CH2:25][CH2:26][NH2:27])=[O:23])[N+:15]([O-:17])=[O:16]>C(O)CCC>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=1[O:4][CH2:5][CH:6]([OH:8])[CH2:7][NH:27][CH2:26][CH2:25][NH:24][C:22]([NH:21][CH2:20][CH2:19][CH2:18][O:14][N+:15]([O-:17])=[O:16])=[O:23]
Reactant: NCCNC(=O)NCCCO[N+](=O)[O-]
Reactant: Cc1ccc(Cl)c(OCC2CO2)c1
Solvent: CCCCO
Product: Cc1ccc(Cl)c(OCC(O)CNCCNC(=O)NCCCO[N+](=O)[O-])c1

Procedure:
3.1 g. 1-(2-Chloro-5-methylphenoxy)-2,3-epoxypropane and 8.5 g. 2-[(3-nitroxypropylamino)-carbonylamino]-ethylamine in 100 ml. n-butanol are stirred at ambient temperature for 18 hours. The solvent is distilled off at 30° C. bath temperature under oil pump vacuum, the residue is dissolved in 150 ml. ethyl acetate and this solution is washed 4 times with 60 ml. amounts of water. The organic phase is dried and evaporated and the residue is chromatographed on silica gel with methylene chloride/methanol (6:4 v/v). The appropriate fractions are evaporated and the residue is triturated with diethyl ether, filtered off with suction and dried. There are obtained 2.2 g. (35% of theory) of the desired product in the form of crystals; m.p. 109°-111° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:10](=[O:21])[N:11]([S:13]([C:16]3[NH:20][N:19]=[CH:18][N:17]=3)(=[O:15])=[O:14])[N:12]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[F:40][C:41]([F:51])([F:50])[C:42]1[CH:49]=[CH:48][CH:47]=[CH:46][C:43]=1[CH2:44]Br>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:10](=[O:21])[N:11]([S:13]([C:16]3[N:20]([CH2:44][C:43]4[CH:46]=[CH:47][CH:48]=[CH:49][C:42]=4[C:41]([F:40])([F:50])[F:51])[N:19]=[CH:18][N:17]=3)(=[O:15])=[O:14])[N:12]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: COc1ccc(Cn2c(-c3ccc(Cl)cc3)nn(S(=O)(=O)c3ncn[nH]3)c2=O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(Cn2c(-c3ccc(Cl)cc3)nn(S(=O)(=O)c3ncnn3Cc3ccccc3C(F)(F)F)c2=O)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
334 mg (0.75 mmol) of the compound from Example 94A were dissolved in 5 ml of dichloromethane, and 154 μl (0.93 mmol) of N,N-diisopropylethylamine were added. 223 mg (0.93 mmol) of 2-(trifluoromethyl)benzyl bromide dissolved in 0.5 ml of dichloromethane were then added, and the mixture was stirred at RT for 20 h. For work-up, the mixture was concentrated under reduced pressure and the crude product was purified chromatographically [Method 19]. This gave 245 mg (54% of theory) of the target compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:36]([NH2:38])=[O:37])[CH:24]=[C:25]([C:28]4[S:29][CH:30]=[C:31]([CH2:33][NH:34][CH3:35])[CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH3:39]N>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:36]([NH2:38])=[O:37])[CH:24]=[C:25]([C:28]4[S:29][CH:30]=[C:31]([CH2:33][NH:34][CH2:35][CH:2]([CH3:3])[CH3:39])[CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:17][CH2:18]1)(=[O:11])=[O:12])[CH3:9]
Reactant: CN
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CNC)cs4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CNCC(C)C)cs4)cc23)CC1
Yield: 25 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-[(methylamino)methyl]-2-thienyl}-1H-indole-7-carboxamide trifluoroacetate, substituting 2-methyl-1-propanamine (0.1 mL) for 2 M methylamine to afford 15.4 mg of the title compound (25%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]([CH3:12])[CH3:11])=[N:6][C:7]=1[O:8][CH3:9].C([Li])CCC.CC1CCCO1.[CH3:24][O:25][C:26]([C:28]1[C:36]2[C:31](=[CH:32][C:33]([Cl:38])=[C:34](Br)[CH:35]=2)[N:30]([S:39]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)(=[O:41])=[O:40])[CH:29]=1)=[O:27]>C1COCC1.CC(C)=O.[Cl-].[Cl-].[Zn+2]>[CH3:24][O:25][C:26]([C:28]1[C:36]2[C:31](=[CH:32][C:33]([Cl:38])=[C:34]([C:2]3[C:7]([O:8][CH3:9])=[N:6][C:5]([N:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=3)[CH:35]=2)[N:30]([S:39]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)(=[O:41])=[O:40])[CH:29]=1)=[O:27]
Reactant: COC(=O)c1cn(S(=O)(=O)c2ccc(C)cc2)c2cc(Cl)c(Br)cc12
Reactant: COc1nc(N(C)C)ccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CC1CCCO1
Product: COC(=O)c1cn(S(=O)(=O)c2ccc(C)cc2)c2cc(Cl)c(-c3ccc(N(C)C)nc3OC)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87 %

Procedure:
To a solution of Intermediate (5-bromo-6-methoxy-pyridin-2-yl)dimethyl-amine (78.8 g, 341 mmol) in THF (400 mL) at −70° C. was added a solution of n-butyllithium (2.5 M in hexanes, 127 mL, 317 mmol) dropwise, keeping the internal temperature below −60° C. The purple solution was stirred between −65° C. and −70° C. for 20 min. A solution of ZnCl2 in 2-methyltetrahydrofuran (1.9 M, 167 mL, 317 mmol) was added dropwise to the aryl lithium solution, keeping the internal temperature below −60° C. The resulting mixture was stirred between −65° C. and −70° C. for 20 min and then warmed to room temperature and stirred for 2 h, resulting in a clear pale yellow solution. The aryl zinc solution was then cannulated into a flask containing Intermediate 5-bromo-6-chloro-1-(toluene-4-sulfonyl)-1H-indole-3-carboxylic acid methyl ester (107.8 g, 244 mmol) and dichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(II) (8.72 g, 12.2 mmol) in THF (200 mL). The resulting mixture was stirred at room temperature for 2.5 h before quenching with sat. aq. NH4Cl (800 mL) and extracting with ethyl acetate (1500 mL). The aqueous layer was back extracted with ethyl acetate (750 mL) and the combined organics washed with brine (1000 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was triturated with methanol (˜600 mL) and stirred overnight. The suspension was filtered to give a tan solid. This was dissolved in hot acetone (2 L) which was partially concentrated to ˜500 mL, then slowly cooled and stirred overnight. The resulting solid was filtered to yield one crop of desired product (109.1 g). The filtrate was also concentrated to a dark solid which was slurried in acetone, filtered, and the solid dissolved in hot acetone, which was then cooled to yield a second crop (3.3 g) of desired product as an off white solid. (90% total yield). 1H NMR (DMSO-d6, 400 MHz) δ=8.51 (s, 1H), 8.11 (d, J=8.6 Hz, 2H), 8.00 (s, 1H), 7.88 (s, 1H), 7.49 (d, J=8.2 Hz, 2H), 7.31 (d, J=8.2 Hz, 1H), 6.22 (d, J=8.2 Hz, 1H), 3.84 (s, 3H), 3.74 (s, 3H), 3.06 (s, 6H), 2.37 (s, 3H); MS (ES+) 514.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([CH2:10][C:11]([F:14])([F:13])[F:12])[N:3]=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]([N:37]=[C:38]([NH:40][C:41]([CH:43]3[CH2:45][CH2:44]3)=[O:42])[N:39]=2)[CH:36]=1>CN(C)C=O.CN(C)C(=O)C>[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:7]([C:5]5[N:4]([CH2:10][C:11]([F:14])([F:13])[F:12])[N:3]=[C:2]([CH3:1])[CH:6]=5)=[O:9])[CH:28]=4)=[CH:36][N:35]3[N:37]=2)=[O:42])[CH2:44][CH2:45]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1F
Reactant: Cc1cc(C(=O)O)n(CC(F)(F)F)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)ccc2F)n(CC(F)(F)F)n1
Yield: 83.5 %

Procedure:
In the same manner as in Example 18-4 and using 3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboxylic acid (254 mg, 1.22 mmol), tetrahydrofuran (7 mL), oxalyl chloride (160 μL, 1.83 mmol), N-[6-(3-amino-4-fluorophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.611 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (264 mg, 84%) was obtained as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH2:10][CH:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[O:8][N:7]=1)=O)C.[BH4-].[Na+].O>C1COCC1>[F:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH:9]2[O:8][N:7]=[C:6]([CH2:4][OH:3])[CH2:10]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)C1=NOC(Cc2ccc(F)cc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCC1=NOC(Cc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
To a solution of 5-(4-Fluoro-benzyl)-4,5-dihydro-isoxazole-3-carboxylic acid ethyl ester (0.17 g, 0.677 mmol) in THF (10 ml), NaBH4 (0.051 g, 0.81 mmol) was added slowly at 0° C. The reaction mixture was stirred for 2 h at room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue obtained was purified by column chromatography to obtain [5-(4-Fluoro-benzyl)-4,5-dihydro-isoxazol-3-yl]-methanol (140 mg, 100%) as an yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[C:5](/[CH:10]=[CH:11]/[C:12]([CH2:14][C:15](/[CH:17]=[CH:18]/[C:19]2[CH:27]=[C:24]([O:25][CH3:26])[C:22]([OH:23])=[CH:21][CH:20]=2)=[O:16])=[O:13])[CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:34](Br)[C:35]#[CH:36].O>CN(C=O)C>[CH2:36]([CH:14]([C:12](/[CH:11]=[CH:10]/[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([OH:9])=[CH:7][CH:6]=1)=[O:13])[C:15](=[O:16])/[CH:17]=[CH:18]/[C:19]1[CH:27]=[C:24]([C:22]([OH:23])=[CH:21][CH:20]=1)[O:25][CH3:26])[C:35]#[CH:34]
Reactant: C#CCBr
Reactant: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)c(OC)c2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCC(C(=O)/C=C/c1ccc(O)c(OC)c1)C(=O)/C=C/c1ccc(O)c(OC)c1
Temperature: 25 °C
Reaction time: 49 h
Yield: 47 %

Procedure:
Curcumin (5 g, 13.57 mmol) and K2CO3 (1.88 g, 13.62 mmol) were dissolved in 60 mL DMF, and 1.62 g (13.61 mmol) of propargyl bromide was added. The mixture was stirred at room temperature under Ar for 49 h. H2O was added to the mixture and solvent was removed under vacuum. The product was purified on column chromatography, eluting with CH2Cl2: hexane 50:50- CH2Cl2. Yield 47%. NMR NMR 1H (CDCl3), δ (ppm): 2.54 (s, 1H); 3.94 (d, 6H); 4.81 (d, 2H); 5.82 (s, 1H); 5.93 (s, 1H); 6.47-6.52 (t, 2H); 6.93-7.15 (m, 6H); 7.59-7.61 (dd, 2H). MS (ESI) calcd. for C24H22O6: 406.43. Found: 407.2 [M+H]+, 445.2 [M++K].
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Sn+2:5].[C:6]([O-:9])(=[O:8])[CH3:7]>C(O)(=O)C>[C:1]([O-:4])(=[O:3])[CH3:2].[Sn+4:5].[C:6]([O-:9])(=[O:8])[CH3:7].[C:1]([O-:4])(=[O:3])[CH3:2].[C:1]([O-:4])(=[O:3])[CH3:2]
Reactant: [Sn+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: [Sn+4]
Temperature: 25 °C

Procedure:
Catalyst preparation was conducted as follows. That is, 1.5 g of commercial tin (II) acetate (a product of Kanto Chemical Company, Inc.) was dissolved in 150 ml of acetic acid with heating. The solution was cooled to room temperature to obtain a solution of tin acetate in acetic acid. 5 g of a commercial silicon dioxide powder having an average particle diameter of 25 μm (a product of Mizusawa Industrial Chemicals, Ltd.) was weighed in a 500-ml beaker, after which 200 ml of water was added to suspend the silicon dioxide powder therein. To the suspension being stirred were slowly added dropwise the above-prepared solution of tin acetate in acetic acid and 25 ml of an aqueous palladium nitrate solution containing 1 g/l of palladium, simultaneously. After the completion of the dropwise addition, the mixture was heated to 80° C. with stirring, to evaporate and remove the acetic acid and water in the mixture. The residue was dried to obtain a powder. The powder was calcined in an air stream at 500° C. for 1 hours and then reduced in a hydrogen stream at 250° C. for 1 hour to obtain a catalyst in which palladium and tin were supported in amounts of 0.5% by weight and 15% by weight, respectively, based on the weight of the silicon dioxide used.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:30])=[C:4]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][NH:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[C:22]([C:23](O)=[O:24])[C:16]=3[N:15]=2)[CH2:8][CH2:7]1.O.O[N:33]1[C:37]2[CH:38]=CC=C[C:36]=2N=N1.C(N)(C)C.C(N=C=NC(C)C)(C)C>CN(C)C=O.CO>[CH:37]([NH:33][C:23]([C:22]1[C:16]2[N:15]=[C:14]([NH:13][CH2:12][CH:9]3[CH2:8][CH2:7][N:6]([CH2:5][C:4]4[CH:26]=[C:27]([Cl:29])[CH:28]=[C:2]([Cl:1])[C:3]=4[OH:30])[CH2:11][CH2:10]3)[NH:18][C:17]=2[CH:19]=[CH:20][CH:21]=1)=[O:24])([CH3:38])[CH3:36]
Reactant: O=C(O)c1cccc2[nH]c(NCC3CCN(Cc4cc(Cl)cc(Cl)c4O)CC3)nc12
Reactant: On1nnc2ccccc21
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Solvent: CC(C)N
Solvent: CO
Product: CC(C)NC(=O)c1cccc2[nH]c(NCC3CCN(Cc4cc(Cl)cc(Cl)c4O)CC3)nc12
Temperature: 40 °C
Reaction time: 8 h

Procedure:
2-{[1-(3,5-Dichloro-2-hydroxy-benzyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazole-4-carboxylic acid (30.0 mg, 0.0668 mmol) was suspended in dimethylformamide (0.50 ml). After adding 1-hydroxybenzotriazole monohydrate (30.6 mg, 0.200 mmol), isopropylamine (11.8 mg, 0.200 mmol) and diisopropylcarbodiimide (30.8 μl, 0.200 mmol) thereto, the mixture was stirred at 40° C. overnight. Methanol (2 ml) was added to the reaction mixture, and after stirring for 10 minutes, the reaction mixture was passed through SCX (Bond Elute SCX500MG) and the SCX was washed with methanol. After elution with a 2N ammonia-methanol solution, the solvent was distilled off under reduced pressure to obtain a residue. The residue was purified by preparative HPLC to obtain 2-{[1-(3,5-dichloro-2-hydroxy-benzyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazole-4-carboxylic acid isopropylamide. The compound was identified by LC-MS.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.C(OC([NH:51][C@H:52]([CH3:56])[C:53](O)=[O:54])=O)(C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[NH2:51][C@@H:52]([C:53]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1)=[O:54])[CH3:56]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@H]1CC[C@H](Nc2cc(Nc3ccccn3)c3ncc(C(=O)Nc4ccncc4F)n3n2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](N)C(=O)N[C@H]1CC[C@H](Nc2cc(Nc3ccccn3)c3ncc(C(=O)Nc4ccncc4F)n3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-((trans)-4-aminocyclohexylamino)-N-(3-fluoropyridin-4-yl)-8-(pyridin-2-ylamino)imidazo[1,2-b]pyridazine-3-carboxamide (0.020 g, 0.043 mmol) in DMF (1 mL) at room temperature was added DIEA (0.038 mL, 0.217 mmol), (R)-2-(tert-butoxycarbonylamino)propanoic acid (0.016 g, 0.087 mmol), and BOP (0.058 g, 0.130 mmol). The resulting clear, colorless solution was stirred at room temperature for 30 minutes. Volatiles were removed in vacuo and the crude material was suspended in dichloromethane (0.5 mL) and TFA (0.5 mL). The resulting suspension was stirred vigorously at room temperature for 1.5 h. Volatiles were removed via a stream of nitrogen, and the crude material was diluted with 1 mL MeOH and purified via preparatory HPLC using a YMC ODS C-18 column (30×250 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 60 min, flow rate 25 mL/min. Rt=49.547 min. 6-((trans-4-(D-alanylamino)cyclohexyl)amino)-N-(3-fluoro-4-pyridinyl)-8-(2-pyridinylamino)imidazo[1,2-b]pyridazine-3-carboxamide (0.006 g, 18.20% yield) was obtained as a white solid. LC/MS, m/z 533.2 (M+1). HPLC Rt=3.616 min. YMC S5 ODS-A column (4.6×50 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.2% H3PO4). Solvent A: (10% MeOH, 90% H2O, 0.2% H3PO4). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% 1 min, flow rate 4 mL/min. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.27 (1H, d, J=1.76 Hz), 9.85 (1H, s), 8.67 (1H, d, J=2.77 Hz), 8.48-8.55 (1H, m), 8.44 (1H, d, J=5.54 Hz), 8.34 (1H, dd, J=4.91, 1.38 Hz), 8.28 (1H, d, J=7.55 Hz), 8.13 (1H, s), 8.04 (2H, d, J=4.53 Hz), 7.98 (1H, s), 7.71-7.78 (1H, m), 7.51 (1H, d, J=8.31 Hz), 7.28 (1H, d, J=8.31 Hz), 7.02 (1H, dd, J=7.05, 5.79 Hz), 3.87 (1H, s), 3.73-3.81 (1H, m), 3.58 (1H, s), 2.07 (2H, d, J=3.78 Hz), 1.86 (2H, s), 1.34 (3H, d, J=6.80 Hz), 1.28-1.44 (4H, m).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([OH:14])=[O:13])[CH:3]=1.[NH2:15][C@@H:16]1[C@@H:21]([OH:22])[CH2:20][CH2:19][O:18][CH2:17]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([OH:14])=[O:13])[CH:3]=1.[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:15][C@@H:16]2[C@@H:21]([OH:22])[CH2:20][CH2:19][O:18][CH2:17]2)=[O:14])[CH:3]=1
Reactant: N[C@H]1COCC[C@@H]1O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)c1cc(Br)c2ccccc2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H]1COCC[C@@H]1O)c1cc(Br)c2ccccc2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Bromoquinoline-2-carboxylic acid (A3) was prepared as described in Example 1. To a solution of A3 (0.35 g, 1.4 mmol) in 6.0 mL CH2Cl2 was added (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol (0.20 g, 1.7 mmol), BOP reagent (0.74 g, 1.7 mmol), and triethylamine (0.58 mL, 4.2 mmol). The reaction mixture was stirred at room temperature for 16 h, diluted with CH2Cl2, washed with water, dried over sodium sulfate, filtered, and concentrated. The resultant residue was subjected to silica gel chromatography eluting with 25-100% ethyl acetate in hexanes to afford 4-bromo-N-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]quinoline-2-carboxamide that gave a mass ion (ES+) of 353.1 (81Br) for M+H+.
Reaction SMILES: Cl.O[CH2:3][C:4]1[CH:8]=[C:7](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:6][N:5]=1.S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl>[Cl:19][CH2:3][C:4]1[CH:8]=[C:7](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:6][N:5]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(/C=C/c2ccccc2)[nH]n1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: ClCc1cc(/C=C/c2ccccc2)[nH]n1
Temperature: 50 °C
Yield: 82 %

Procedure:
90 mg of the hydrochloride was dissolved in 3 ml of chloroform, and 0.5 ml of thionyl chloride was added. The mixture was heated at 50° C. for 20 hours. The reaction mixture was evaporated under reduced pressure. The residue was washed with ethyl acetate and filtered to give 60 mg (yield 82%) of the captioned compound as a colorless crystalline powder.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([CH3:29])([CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=1)=[N+]=[N-]>[Pd]>[NH2:1][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C:14]([CH3:29])([CH2:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:12]=1
Reactant: CCOC(=O)C(C)(CCCc1ccccc1)Cc1ccc(OCCN=[N+]=[N-])cc1
Agent: [Pd]
Product: CCOC(=O)C(C)(CCCc1ccccc1)Cc1ccc(OCCN)cc1
Yield: 99.6 %

Procedure:
In a similar manner to that described in Reference example 1(d), a reaction was carried out using ethyl 3-[4-(2-azidoethoxy)phenyl]-2-methyl-2-(3-phenylpropyl)propionate (0.86 g), which is the product of Reference example 7(h), and palladium on carbon (5%, 129 mg) and the reaction mixture was treated to afford the title compound (0.80 g) as a syrup.
Reaction SMILES: [CH2:1]([C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[C:18]=1[N:26]=[C:27]=[O:28])([CH3:16])[CH3:15]>CCCCCC>[CH2:1]([C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH:9][C:27]([NH:26][C:18]1[C:17]([CH:14]([CH3:15])[CH3:16])=[CH:22][CH:21]=[CH:20][C:19]=1[CH:23]([CH3:25])[CH3:24])=[O:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccccc1N
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: CCCCCC
Product: CCCCCCc1ccccc1NC(=O)Nc1c(C(C)C)cccc1C(C)C
Reaction time: 16 h
Yield: 61 %

Procedure:
To a 5 ml n-hexane solution of 0.42 g (2.35 mmol) of 2-hexylaniline was added 5 ml (2.35 mmol) of a hexane solution of 0.47M 2,6-diisopropylphenyl isocyanate at room temperature and the whole was stirred for 16 hours. The precipitated crystals were collected by filtration to give 0.55 g (61% yield) of 1-(2-hexylphenyl)-3-(2,6-diisopropylphenyl)urea, the physical properties of which being shown in the following Table 3. The compound No. 25 listed in Table 3 was similarly prepared as above.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[O:3]1.[C:17]1([N:23]=[C:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[C:17]1([NH:23][C:24]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)=[CH:14][N:13]=2)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(NC(=O)Nc3ccccc3)nc2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ambient solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.350 g, 1.59 mmol) in tetrahydrofuran (4 mL) was added phenyl isocyanate (0.174 mL, 1.59 mmol). The solution was stirred at room temperature for 1 h and was then concentrated under reduced pressure. The solid was washed with diethyl ether (2 mL) and air-dried to give the title compound. MS (ESI) m/z 221 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([O:7][CH2:8][C:9]#[N:10])=[CH:5][CH:4]=1.[Na].[CH:14]([O:17]C(C)C)(C)C>CO>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([O:7][CH2:8][C:9](=[NH:10])[O:17][CH3:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(OCC#N)cc1
Reactant: CC(C)OC(C)C
Agent: [Na]
Solvent: CO
Product: COC(=N)COc1ccc(OC)cc1

Procedure:
Obtained using the procedure described in section a of Example 16, starting with 27.3 g (0.167 mole) of (4-methoxyphenoxy)acetonitrile [prepared according to K. J. S. Arora et al., J. Chem. Soc. C 1971, 2865] and 0.38 g (0.0167 gram-atom) of sodium in 275 ml of methanol. Reaction time: 24 hours. Yld: 23.9 g (73%), m.p. 95°-96° C. (isopropyl ether).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[C:8]([F:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=1[O:14]S(C)(=O)=O.CS(C)=O.[OH-].[K+].Cl>CS(C)=O.O>[F:10][C:8]1[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]([OH:14])=[C:4]([CH:9]=1)[CH:3]=[O:2]
Reactant: COC(OC)c1cc(F)c([N+](=O)[O-])cc1OS(C)(=O)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1cc(F)c([N+](=O)[O-])cc1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.2 %

Procedure:
To a mixture of 0.348 g (1.13 mmole) of methanesulfonic acid 2-dimethoxymethyl-4-fluoro-5-nitro-phenyl ester (IV.46a) and 4 mL of dimethylsulfoxide, cooled briefly in an ice bath, was added dropwise a cold solution of 0.10 g of potassium hydroxide in 1 mL of dimethylsulfoxide-water (1:1). The resulting dark red mixture was stirred at room temperature for 15 minutes and then was made acidic by addition of 1 M hydrochloric acid to give a yellow mixture. The mixture was partitioned between 50 mL of ethyl acetate and 50 mL of water. The aqueous layer was extracted three times with 25 mL of ethyl acetate. The combined organic layers were washed three times with 30 mL of water, once with 30 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 0.195 g of 5-fluoro-2-hydroxy-4-nitro-benzaldehyde (IV.46b) as a yellow solid.