Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([NH:10][CH2:11][C@H:12]1[C@H:18]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([F:26])[CH:20]=2)[O:17][CH2:16][CH2:15][N:14]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:13]1)=[O:9].C(N(CC)CC)C.[C:41](=O)(OC(Cl)(Cl)Cl)[O:42]C(Cl)(Cl)Cl.O>C1COCC1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C@@H:18]2[O:17][CH2:16][CH2:15][N:14]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:13][C@H:12]2[CH2:11][N:10]2[C:8](=[O:9])[C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=3)[NH:1][C:41]2=[O:42])=[CH:20][C:21]=1[F:26]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CNC(=O)c2ccccc2N)C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](Cn2c(=O)[nH]c3ccccc3c2=O)C1
Temperature: 50 °C
Reaction time: 3 h
Yield: 96.2 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-({[(2-aminophenyl)carbonyl]amino}methyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate (191.1 mg) and triethylamine (167 μL) in THF (5 mL) was added bis(trichloromethyl) carbonate (142 mg) at 0° C., and the mixture was stirred at 50° C. for 3 hr. The reaction mixture was allowed to cool to room temperature, and poured into water, and the mixture was partitioned twice with ethyl acetate. The organic layers were combined, and the mixture was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (193.8 mg).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:9]=2)[NH:4][CH:3]=1.Cl[C:21]1[N:26]=[N:25][C:24]([O:27][C@@H:28]2[CH:33]3[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]3)[CH2:29]2)=[CH:23][CH:22]=1.N>>[N:30]12[CH2:31][CH2:32][CH:33]([CH2:34][CH2:35]1)[C@@H:28]([O:27][C:24]1[N:25]=[N:26][C:21]([C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][CH:7]=3)[NH:4][CH:3]=[C:2]4[CH3:1])=[CH:22][CH:23]=1)[CH2:29]2
Reactant: Clc1ccc(O[C@H]2CN3CCC2CC3)nn1
Reactant: Cc1c[nH]c2ccc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: N
Product: Cc1c[nH]c2ccc(-c3ccc(O[C@H]4CN5CCC4CC5)nn3)cc12

Procedure:
The product of Example 10A (240 mg, 1 mmol) coupled with the product of Example 9A (250 mg, 1 mmol) according to the procedure in Example 8A, The title product was purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 μm, 40×100 mm. Eluting Solvent, MeCN/H2O (with 0.2% v. TFA) (v. 90/10 to 10/90 over 20 min. flow rate, 75 mL/min., uv, 250 nm) as solid (40 mg, yield, 12%). 1H NMR (300 MHz, CD3OD) δ 1.50–1.64 (m, 1H), 1.69–1.92 (m, 2H), 2.01–2.14 (m, 1H), 2.29–2.35 (m, 1H), 2.37 (s, 3H), 2.81–3.04 (m, 5H), 3.43–3.55 (m, 1H), 5.27–5.34 (m, 1H), 7.06 (d, J=1.4 Hz, 1H), 7.24 (d, J=9.2 Hz, 1H), 7.44 (dd, J=8.5, 0.7 Hz, 1H), 7.71 (dd, J=8.8, 2.0, Hz, 1H), 8.07–8.12 (m, 2H) ppm. MS (DCl/NH3): m/z 335 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:11]([CH3:12])=[C:10]([C:13]([O:15]C(C)(C)C)=[O:14])[S:9][C:4]=2[NH:5][C:6](=[O:8])[N:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:1][C:2]1[C:3]2[C:11]([CH3:12])=[C:10]([C:13]([OH:15])=[O:14])[S:9][C:4]=2[NH:5][C:6](=[O:8])[N:7]=1
Reactant: Cc1c(C(=O)OC(C)(C)C)sc2[nH]c(=O)nc(N)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(C(=O)O)sc2[nH]c(=O)nc(N)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To a solution of tert-butyl 4-amino-5-methyl-2-oxo-1,2-dihydrothieno[2,3-d]pyrimidine-6-carboxylate (example 64a) (10.7 g, 38.03 mmol) in CH2Cl2 (25 mL), was added trifluoroacetic acid (25 mL, 324.5 mmol). The reaction mixture was stirred at rt overnight. The precipitated solid was collected by filtration, and washed with CH2Cl2 to yield 4-Amino-5-methyl-2-oxo-1,2-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid (6.98 g, 82%) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ2.78 (s, 3H). MS 226.0 (MH+).
Reaction SMILES: [OH:1][N:2]1[CH:5]([CH2:6][OH:7])[CH:4]([N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:3]1=[O:26].[CH3:27][O:28][C:29]1[CH:50]=[CH:49][C:32]([C:33](Cl)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)=[CH:31][CH:30]=1>N1C=CC=CC=1>[OH:1][N:2]1[CH:5]([CH2:6][O:7][C:33]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:32]2[CH:31]=[CH:30][C:29]([O:28][CH3:27])=[CH:50][CH:49]=2)[CH:4]([N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:3]1=[O:26]
Reactant: O=C(Nc1ncnc2c1ncn2C1C(=O)N(O)C1CO)c1ccccc1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(OCC2C(n3cnc4c(NC(=O)c5ccccc5)ncnc43)C(=O)N2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 8 h

Procedure:
1-N-Hydroxy-3-(N-benzoyladenin-9-yl)-4-hydroxymethyl-2-azetidinone (10 mmole) is dissolved in pyridine (20 ml) and 4,4'-dimethoxytrityl chloride (12 mmole) is added and stirred under argon for 8 hours. The reaction mixture is concentrated under reduced pressure. The crude product is purified by flash chromatorgraphy using silica gel and ethyl acetate/di-chloromethane/1% triethylamine as eluants to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][CH2:29][CH2:30][CH2:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[C:36](O)=[O:37].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:15]([CH3:16])[CH3:17])[C:36](=[O:37])[C:35]2[CH:39]=[CH:40][C:41]([O:42][CH3:43])=[C:33]([O:32][CH2:31][CH2:30][CH2:29][O:28][CH3:27])[CH:34]=2)[C@H:10]([C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)NC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(C)(C)O[SiH2]C(C)(C)C
Reactant: COCCCOc1cc(C(=O)O)ccc1OC
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C(C)(C)O[SiH2]C(C)(C)C)C(C)C)ccc1OC

Procedure:
A mixture of ((3S,4R)-3-(tert-butyl-dimethyl-silanyloxymethyl)-4-(isopropylamino-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (8.9 g, 23.02 mmol), 3-(3-methoxy-propoxy)-4-methoxy-benzoic acid (6.08 g, 25.32 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (6.45 g, 25.32 mmol) and triethylamine (7.62 mL, 92.07 mmol) in CH2Cl2 (230 mL) is refluxed for 3 h. The reaction is quenched by the addition of an aqueous saturated solution of NaHCO3. The organic layer is separated, and the aqueous phase is extracted 3 times with AcOEt. The combined organic extracts are dried (Na2SO4), and the solvent is removed in vacuo. The crude product is purified by flash chromatography on silica gel (eluent: CH2Cl2/acetone 95:5 to CH2Cl2/MeOH 95:5) to give the title product. TLC, Rf (CH2Cl2/MeOH 95:5)=0.47. MS (LC-MS): 609.4 [M+H]+; tR (HPLC, C18 column, 5-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 7.05 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[N-:12]([C:15]#[N:16])[C:13]#[N:14].[Na+]>>[C:13]([N:12]=[C:15]([NH2:16])[NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:4][CH:3]=1)#[N:14]
Reactant: N#C[N-]C#N
Reactant: Nc1ccc(C(F)(F)F)nc1
Agent: [Na+]
Product: N#CN=C(N)Nc1ccc(C(F)(F)F)nc1

Procedure:
A solution of 5-amino-2-(trifluoromethyl)pyridine and sodium dicyanamide was processed as described in Example 71A to provide the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27]C)=[O:26])[CH:16]=4)[N:11]=3)=[CH:7][C:6]=2[CH:29]=1.[OH-].[Na+].O>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([OH:27])=[O:26])[CH:16]=4)[N:11]=3)=[CH:7][C:6]=2[CH:29]=1
Reactant: COC(=O)c1ccc2nc(-c3cc4cc(F)ccc4o3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1cc2cc(F)ccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
To a solution of methyl 2-(5-fluorobenzofuran-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (560 mg, 1.42 mmol) in methanol (30 ml) was added sodium hydroxide (227.9 mg, 5.69 mmol) and water (2 ml) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo and dissolved in water (30 ml), adjusted to pH 5 with HCl (3N). The product was precipitated from water and collected by filtration to afford 2-(5-fluorobenzofuran-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a light yellow solid (486 mg, 90%).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[C:20]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])=[N:25][NH:24][C:21]3=[N:22][CH:23]=2)=[CH:14][C:8]=1[C:9]([N:11]([CH3:13])[CH3:12])=[O:10]>ClCCl>[CH3:5][O:4][C:2](=[O:3])[NH:6][C:7]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[C:20]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])=[N:25][NH:24][C:21]3=[N:22][CH:23]=2)=[CH:14][C:8]=1[C:9](=[O:10])[N:11]([CH3:13])[CH3:12]
Reactant: COc1ccccc1-c1n[nH]c2ncc(-c3ccc(N)c(C(=O)N(C)C)c3)cc12
Reactant: COC(=O)Cl
Solvent: ClCCl
Product: COC(=O)Nc1ccc(-c2cnc3[nH]nc(-c4ccccc4OC)c3c2)cc1C(=O)N(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 22 %

Procedure:
Methyl chloroformate (42 ul, 0.53 mmol) was added dropwise to a solution of 2-amino-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4,b]pyridin-5-yl]-N,N-dimethyl-benzamide (21 mg, 0.05 mmol) in dichloromethane/saturated aqueous sodium bicarbonate (1:1) at 0° C. The mixture was stirred for another 3 hours, allowing to slowly warm to room temperature. The reaction was washed three times with water (5 ml), dried over sodium sulfate and concentrated to dryness. The crude was purified by flash chromatography on silica gel using a gradient of ethyl acetate and hexane to afford {2-dimethylcarbamoyl-4[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-carbamic acid methyl ester (4.9 mg, 21% yield). 1H NMR (500 MHz, DMSO-d6) δ 2.88 (d, 6H), 3.58 (s, 3H), 3.77 (s, 3H), 7.03 (m, 1H), 7.15 (d, 1H), 7.40 (m, 1H), 7.58 (s, 1H), 7.64 (d, 1H), 7.73 (d, 1H), 8.27 (s, 1H), 8.78 (s, 1H), 9.03 (s, 1H), 13.75 (s, 1H); MS: m/z 446.1 (M+H+).
Reaction SMILES: [CH2:1]([C@@H:8]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][NH:10]CC1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[OH-].[OH-].[Pd+2]>[NH2:10][CH2:9][C@H:8]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CNCc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CN)Cc1ccccc1
Reaction time: 3.25 h
Yield: 99.3 %

Procedure:
The product from Example 70B (3.36 g, 9.9 mmol) in methanol (10 mL) was treated with 20% Pd(OH)2/C (wet) (335 mg) under a hydrogen atmosphere (4 atmospheres) at 50° C. After 3.25 hours, the solution was filtered and the filtrate was concentrated. The residue was dried under reduced pressure to provide the title compound as a white solid (2.46 g). 1H NMR (DMSO-d6) δ 7.32-7.12 (m, 5H), 6.54 (d, 1H), 3.53 (m, 1H), 2.79-2.69 (dd, 2H), 2.66-2.50 (m, 4H), 1.31 (s, 9H); MS (ESI+) m/z 251 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH:10]=1.N1(C2C=CC(N[C:40]([C:42]3[CH:43]=[C:44]([CH:52]=[CH:53][CH:54]=3)[CH2:45][S:46][CH2:47][CH2:48][C:49]([OH:51])=[O:50])=[O:41])=C(C3C=C(NCC4C=CC=C(C)C=4)N=CN=3)C=2)CCCCC1.NC1C=CC(N2CCCCC2)=CC=1C1N=CN=C(NCC2C=CC=C(C)C=2)C=1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:40]([C:42]2[CH:43]=[C:44]([CH:52]=[CH:53][CH:54]=2)[CH2:45][S:46][CH2:47][CH2:48][C:49]([OH:51])=[O:50])=[O:41])=[C:3]([C:9]2[CH:10]=[C:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:24])[F:26])[CH:18]=3)[N:12]=[CH:13][N:14]=2)[CH:4]=1
Reactant: Cc1cccc(CNc2cc(-c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)O)c3)ncn2)c1
Reactant: Nc1ccc(Cl)cc1-c1cc(NCc2cccc(C(F)(F)F)c2)ncn1
Agent: Cc1cccc(CNc2cc(-c3cc(N4CCCCC4)ccc3N)ncn2)c1
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(Cl)cc2-c2cc(NCc3cccc(C(F)(F)F)c3)ncn2)c1

Procedure:
This compound was prepared from 6-(2-amino-5-chlorophenyl)-N-(3-(trifluoromethyl)benzyl)pyrimidin-4-amine 65b using the procedure described for the preparation of 3-((3-((4-(piperidin-1-yl)-2-(6-((3-methylbenzyl)amino)pyrimidin-4-yl)phenyl)carbamoyl)benzyl)thio)propanoic acid 3.2 from 6-(2-amino-5-(piperidin-1-yl)phenyl)-N-(3-methylbenzyl) pyrimidin-4-amine 3.2b. 1H-NMR (400 MHz, DMSO-d6, ppm): δ 8.79 (s, 1H), 8.48 (s, 1H), 7.91 (s, 1H), 7.81 (d, J=5.7 Hz, 2H), 7.63 (s, 1H), 7.56 (m, 6H), 7.09 (s, 1H), 4.74 (s, 2H), 3.88 (s, 2H), 2.57 (d, J=4.8 Hz, 2H). MS (ES, m/z): 601 [M+H]+.
Reaction SMILES: I[C:2]1[C:10]2[CH2:9][CH2:8][C:7]([CH3:12])([CH3:11])[CH2:6][C:5]=2[N:4]([CH3:13])[N:3]=1.C([Mg]Cl)(C)C.[CH2:19]([Sn:23]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])Cl)[CH2:20][CH2:21][CH3:22]>C1COCC1>[CH3:13][N:4]1[C:5]2[CH2:6][C:7]([CH3:12])([CH3:11])[CH2:8][CH2:9][C:10]=2[C:2]([Sn:23]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:19][CH2:20][CH2:21][CH3:22])=[N:3]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cn1nc(I)c2c1CC(C)(C)CC2
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2c1CCC(C)(C)C2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 52.2 %

Procedure:
To a solution of 3-iodo-1,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indazole (0.150 g, 0.49 mmol) in THF (3 mL) at 0° C. was slowly added isopropylmagnesium chloride (2.0 M in THF) (0.30 mL, 0.59 mmol). The reaction mixture was stirred at 0° C. for 20 min then tributylchlorostannane (0.16 mL, 0.59 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min then warmed to room temperature and stirred for 1 h. The reaction was quenched with water and extracted with EtOAc (2×). The combined organics were dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 0% to 10% EtOAc/hexanes (0.5% Et3N) to afford 116 mg (52%) of 1,6,6-trimethyl-3-tributylstannanyl-4,5,6,7-tetrahydro-1H-indazole as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ (ppm) 3.74 (s, 3H), 2.49 (t, J=6.4 Hz, 2H), 2.30 (s, 2H), 1.45-1.61 (m, 8H), 1.25-1.41 (m, 6H), 1.04-1.13 (m, 6H), 1.01 (s, 6H), 0.89 (t, J=7.2 Hz, 9H).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[C:10]([Cl:12])[N:9]=[CH:8][C:7]=1[CH2:13][OH:14])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[C:1]([NH:5][C:6]1[C:7]([CH:13]=[O:14])=[CH:8][N:9]=[C:10]([Cl:12])[CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Nc1cc(Cl)ncc1CO
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)(C)Nc1cc(Cl)ncc1C=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 80.4 %

Procedure:
A mixture of (4-tert-butylamino-6-chloro-pyridin-3-yl)-methanol (5.0 g, 23.4 mmol) and MnO2 (14.3 g, 163.6 mmol) in anhydrous CH2Cl2 (100 mL) was stirred at RT for 10 h. The reaction was filtered and the filtrate was concentrated to give 4-(tert-butylamino)-6-chloronicotinaldehyde (4.0 g, 87.0% yield), which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ 9.83 (s, 1 H), 8.90 (s, 1 H), 8.44 (s, 1 H), 6.86 (s, 1 H), 1.40 (s, 9 H).
Reaction SMILES: [CH3:1][C:2]1O[C:5]([C:7]2[CH:12]=[CH:11][N:10]3[C:13]([C:16]4[CH:17]=[C:18]([NH:22][C:23]([NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[O:24])[CH:19]=[CH:20][CH:21]=4)=[CH:14][N:15]=[C:9]3[CH:8]=2)=[N:4][N:3]=1.[CH3:31][NH2:32]>>[CH3:31][N:32]1[C:2]([CH3:1])=[N:3][N:4]=[C:5]1[C:7]1[CH:12]=[CH:11][N:10]2[C:13]([C:16]3[CH:17]=[C:18]([NH:22][C:23]([NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[O:24])[CH:19]=[CH:20][CH:21]=3)=[CH:14][N:15]=[C:9]2[CH:8]=1
Reactant: Cc1nnc(-c2ccn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)o1
Reactant: CN
Product: Cc1nnc(-c2ccn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)n1C

Procedure:
Alternatively the title compound could be prepared through reaction of 1-{3-[7-(5-methyl-[1,3,4]oxadiazol-2-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea with methylamine.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:16][C:17]1[N:18]=[C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:27]=[C:28]([NH:32][C:33](=[O:45])[C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([C:40]5([C:43]#[N:44])[CH2:42][CH2:41]5)[CH:35]=4)[CH:29]=[CH:30][CH:31]=3)=[N:21][N:20]2[CH:46]=1.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C=O.CN1CCCC1=O>[C:43]([C:40]1([C:36]2[CH:35]=[C:34]([CH:39]=[CH:38][CH:37]=2)[C:33]([NH:32][C:28]2[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=2)[O:25][C:22]2[CH:23]=[CH:24][C:19]3[N:20]([CH:46]=[C:17]([NH:16][C:1](=[O:9])[C:2]4[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=4)[N:18]=3)[N:21]=2)=[O:45])[CH2:41][CH2:42]1)#[N:44]
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(N)cn5n4)c3)c2)CC1
Reactant: O=C(O)c1cccnc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)c6cccnc6)cn5n4)c3)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
To a solution of nicotinic acid (54 mg, 0.438 mmol) in tetrahydrofuran (3 mL) were added N,N-dimethylformamide (1 drop) and oxalyl chloride (64 μL, 0.734 mmol), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and the residue and N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide (150 mg, 0.365 mmol) were dissolved in N-methylpyrrolidone (3 mL), and the mixture was stirred at room temperature for 14 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→100/0) to give the title compound (100 mg, 53%) as a pale-green powder.
Reaction SMILES: [CH3:1][CH:2]([C:4](Br)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH3:3].[Cl-].[Li+].O>CN(C=O)C>[CH3:1][C:2](=[C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH3:3]
Reactant: CCCCC(=O)C(Br)(c1ccccc1)C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(=O)C(=C(C)C)c1ccccc1
Temperature: 130 °C
Yield: 46 %

Procedure:
The crude 2-methyl-3-bromo-3-phenyloctan-4-one (intermediate IIb-1) was dissolved in magnetically stirred anhydrous DMF (35 ml) under a nitrogen atmosphere. Lithium chloride (3.2 gram, 0.075 mol) was added and the resulting mixture was heated at 130° C. for 90 minutes. The resulting mixture was allowed to attain room temperature and was subsequently poured into water and extracted with diethyl ether. The organic layer was separated and washed with water (4 portions). The organic layer was dried over Na2SO4, filtered and concentrated. The obtained residue was purified using Sepacore equipment: (petroleum ether/diethyl ether=98/2 (v/v)) to give 2-methyl-3-phenyloct-2-en-4-one (Intermediate III-1) (1.96 gram, 46% yield) as a pale yellow oil; 1H-NMR (400 MHz, CDCl3) δ 0.81 (d, J=7, 3H), 1.13-1.24 (m, 2H), 1.43-1.52 (m, 2H), 1.66 (s, 3H), 2.00 (s, 3H), 2.25 (t, J=7, 2H), 7.15 (br d, J=8, 2H), 7.20-7.39 (m, 3H).
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(F)=CC=1)C.C=O.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][NH2:31].[F:32][C:33]1[CH:51]=[CH:50][C:36]([CH2:37][N:38]([CH3:49])[C:39]([C:41]2[CH2:42]N(C)[C:44](=[O:47])[C:45]=2[OH:46])=[O:40])=[CH:35][CH:34]=1>>[F:32][C:33]1[CH:51]=[CH:50][C:36]([CH2:37][N:38]([CH3:49])[C:39]([C:41]2[CH2:42][N:31]([CH2:30][CH2:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[F:22])[C:44](=[O:47])[C:45]=2[OH:46])=[O:40])=[CH:35][CH:34]=1
Reactant: NCCc1ccccc1F
Reactant: CN1CC(C(=O)N(C)Cc2ccc(F)cc2)=C(O)C1=O
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(F)cc1
Product: CN(Cc1ccc(F)cc1)C(=O)C1=C(O)C(=O)N(CCc2ccccc2F)C1

Procedure:
3-[(4-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 1-D) was treated with paraformaldehyde and 2-(2-fluoro-phenyl)-ethylamine as described in the preparation of Compound 1. HRMS (M+H) calcd for C21H21N2F2O3: 387.1520. found: 387.1525. 1H NMR (500 MHz, CDCl3) δ: 2.96 (overlapping m, 5), 3.75 (t, 2, J=7), 4.02 (s, 2), 4.58 (s, 2), 6.98–7.22 (overlapping m, 8). 13C NMR (125 MHz, CDCl3) δ: 28.13, 28.14, 34.55, 43.38, 49.34, 51.52, 109.53, 115.31, 115.48, 115.68, 115.85, 124.38, 124.41, 124.87, 124.99, 128.68, 128.75, 129.29, 129.35, 130.96, 130.99, 131.98, 132.01, 152.46, 160.26, 161.40, 162.21, 163.36, 165.04, 166.09.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][O:14][C:15]([C:17]1[S:21][C:20]2[CH2:22][CH2:23][CH2:24][CH2:25][C:19]=2[CH:18]=1)=[O:16].[I:26]I>O1CCCC1.CCOC(C)=O>[CH3:13][O:14][C:15]([C:17]1[S:21][C:20]2[CH2:22][CH2:23][CH2:24][CH2:25][C:19]=2[C:18]=1[I:26])=[O:16]
Reactant: COC(=O)c1cc2c(s1)CCCC2
Reactant: II
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1sc2c(c1I)CCCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
A −78° C. solution of diisopropylamine (23.2 g, 230 mmol) in Tetrahydrofuran (THF) (100 mL) was treated with added n-BuLi (92 mL, 230 mmol) dropwise. The pale yellow solution was stirred at 0° C. for 30 min and recooled to −78° C. To above solution was added the solution of 4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid methyl ester (25 g, 127 mmol) in 20 mL THF dropwise over a period of 5 min. The deep-red solution was stirred at −78° C. for 45 min, the solution of Iodine (48.5 g, 191 mmol) in 20 mL THF was added. The mixture was stirred at −78° C. for 30 min and then warm to room temperature, quenched with saturated aqueous NH4Cl (100 mL) and saturated aqueous Na2S2O3(100 mL). The aqueous layer was extracted with ethyl acetate (150 mL×2). The combined ethyl acetate solution was dried over Na2SO4 and concentrated, which was purified by silica gel chromatography eluted with PE:EtOAc=10:1 to afford title product (15 g, 36% yield). LCMS (m/z) ES+=323 (M+1)
Reaction SMILES: [F:1][C:2]1[C:11]([OH:12])=[C:10]([F:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].Cl[CH:21]([F:23])[F:22].Cl>CN(C)C=O.O.C(OCC)(=O)C>[F:1][C:2]1[C:11]([O:12][CH:21]([F:23])[F:22])=[C:10]([F:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: FC(F)Cl
Reactant: COC(=O)c1ccc(F)c(O)c1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(F)c(OC(F)F)c1F

Procedure:
In 20 ml of N,N-dimethylformamide was dissolved 1.00 g of methyl 2,4-difluoro-3-hydroxy-benzoate, followed by adding thereto 0.88 g of potassium carbonate and then 12 ml of a 6 M solution of chlorodifluoromethane in N,N-dimethylformamide, and the resulting mixture was stirred in a sealed tube at 120-130° C. for 2.5 hours. The reaction mixture was added to a mixed solvent of 100 ml of ethyl acetate and 200 ml of water and the pH was adjusted to 2 with 6N hydrochloric acid, after which the organic layer was separated. The organic layer obtained was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The resulting residue was purified by a column chromatography (eluent; n-hexane:ethyl acetate=4:1) to obtain 1.02 g of methyl 2,4-difluoro-3-difluoromethoxybenzoate as colorless crystals.