Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1([O:8][CH3:9])[CH2:7][CH2:6][NH:5][CH2:4]1.[F:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1F)[N:17]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29])[CH:16]=[C:15]([C:30]([OH:32])=[O:31])[C:14]2=[O:33].C(N(CC)CC)C>>[CH3:1][O:2][C:3]1([O:8][CH3:9])[CH2:7][CH2:6][N:5]([C:20]2[CH:19]=[C:18]3[C:13]([C:14](=[O:33])[C:15]([C:30]([OH:32])=[O:31])=[CH:16][N:17]3[C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])=[CH:12][C:11]=2[F:10])[CH2:4]1
Reactant: COC1(OC)CCNC1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2cc(F)c(F)cc2c1=O
Solvent: CCN(CC)CC
Product: COC1(OC)CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccc(F)cc2F)C1
Temperature: 45 °C

Procedure:
Into an oven-dried glass flask flushed with dry N2, and containing 6 mL of dry pyridine were placed 0.116 g (0.88 mmol) of 3,3-dimethoxypyrrolidine, from Step 4, then 0.150 g (0.44 mmol) of 6,7-difluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-3-quinoline carboxylic acid (preparation described by H. Tone et al., Eur. Pat. Appl. EP 181521, May, 1986), and 180 mL (1.3 mmol) of triethylamine. This reaction solution was maintained under N2 and heated to 45° C. for 41 hours. The pyridine was then removed by azeotropic distillation with toluene, the residue triturated with water, the pH adjusted to pH 5 to 6 with acetic acid, and the solution filtered. The solid was washed with hot ethanol:water (3:1), which was refiltered and dried to afford the title compound, mp 228°-230° C.; MS(DCl) M/Z: 449 (M+H), 404 (M-COOH); NMR d 2.13 (dd, 2H, J=7.5 Hz), 3.41 (dd, 2H, J=1.5 Hz, J=7.5 Hz), 3.62 (d, 2H, J=3.6 Hz), 3.27 (s, 6H), 5.87 (d, 1H, J=7.5 Hz), 7.30 (m, 2H), 7.65 (m, 1H), 7.95 (d, 1H, J=13.5 Hz), 8.60 (s, 1H). Analysis calculated for C22H19F3N2O5 ·0.5 H2O: C, 59.77; H, 4.41; N, 6.12. Found: C, 58.28; H, 4.34; N, 6.21.
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1)#[N:2].[CH3:15][NH:16][CH3:17]>CO>[C:1]([CH2:3][C:4]1([N:16]([CH3:17])[CH3:15])[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1)#[N:2]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Solvent: CO
Product: CN(C)C1(CC#N)CN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
1.20 g (6,18 mmol) of tert-butyl 3-cyanomethyleneazetidine-1-carboxylate (WO 2009/064 835) are dissolved in 15 mL of methanol in a sealed tube. 6.18 mL (12.36 mmol) of a solution of dimethylamine in methanol are added and the reaction medium is stirred at 80° C. for 3 hours.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([F:21])[CH:18]=[C:19]([F:20])[C:14]=3[O:13][CH2:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C([BH3-])#N.[Na+]>>[F:21][C:17]1[CH:18]=[C:19]([F:20])[C:14]2[O:13][CH2:12][C:11](=[O:22])[N:10]([CH2:9][CH2:8][N:5]3[CH2:4][CH2:3][CH:2]([NH:1][CH2:34][C:32]4[CH:31]=[CH:30][C:27]5[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=5[N:33]=4)[CH2:7][CH2:6]3)[C:15]=2[CH:16]=1
Reactant: NC1CCN(CCN2C(=O)COc3c(F)cc(F)cc32)CC1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C1COc2ccc(CNC3CCN(CCN4C(=O)COc5c(F)cc(F)cc54)CC3)nc2N1
Yield: 8.7 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6,8-difluoro-2H-1,4-benzoxazin-3(4H)-one (Intermediate 71) (1 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (220 mg, 1.24 mmol) and sodium cyanoborohydride (130 mg, 2.1 mmol) were reacted as described for Example 21 to give 41 mg (8%) product as a dry film.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[C:13]#[C:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1>C(O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1/[CH:13]=[CH:14]\[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1
Reactant: COc1ccc2c(c1C#CCCN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Product: COc1ccc2c(c1/C=C\CCN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.8 %

Procedure:
A solution of tert-butyl 4-[4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)but-3-ynyl]piperazine-1-carboxylate (0.0801 g, 0.200 mmol) synthesized in Example B49, Step 2 in ethanol (5 mL) was added with Lindlar's catalyst (0.0800 g), and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and then the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl (Z)-4-[4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)but-3-enyl]piperazine-1-carboxylate (0.0562 g, 69%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH2:12]O)[CH:11]=1)[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:7]=[CH:6]2.C(Br)(Br)(Br)[Br:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.CCCCC>[Br:25][CH2:12][C:10]1[CH:11]=[C:3]([C:2]([F:23])([F:22])[F:1])[CH:4]=[C:5]2[C:9]=1[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:7]=[CH:6]2
Reactant: BrC(Br)(Br)Br
Reactant: C[Si](C)(C)CCOCn1ncc2cc(C(F)(F)F)cc(CO)c21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCC
Product: C[Si](C)(C)CCOCn1ncc2cc(C(F)(F)F)cc(CBr)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)methanol (980 mg, 2.83 mmol) and carbon tetrabromide (1.41 g, 4.24 mmol) in tetrahydrofuran (10 mL) at 0° C. was added triphenylphosphine (1.11 g, 4.24 mmol). The resulting solution was stirred at room temperature for 30 min. The reaction was diluted with several volumes of pentane and filtered to remove undissolved solids. The organics were concentrated and purified by column chromatography (4%→8% EtOAc/Hex) to give 1.155 g (100%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 8.12 (s, 1H), 8.03 (s, 1H), 7.61 (d, J=1.2 Hz, 1H), 6.05 (s, 2H), 5.01 (s, 2H), 3.52 (m, 2H), 0.87 (m, 2H), −0.08 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 138.4, 135.1, 126.4, 125.7, 124.4 (q, J=33 Hz), 124.3 (q, J=273 Hz), 122.5, 120.1, 80.5, 66.6, 29.7, 17.9, −1.4.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[CH:4][CH:3]=1.N1C=CN=C1.[C:25]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])([CH3:27])[CH3:26]>ClCCl.O>[Si:29]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])=[CH:6][CH:7]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(CCc1ccc(O)cc1)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CCC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 92.3 %

Procedure:
A solution of benzyl 3-(4-hydroxyphenyl)propanoate (1.0 g, 11.70 mmol) in dichloromethane (60 ml) was cooled to 0° C., and imidazole (1.30 g, 18.73 mmol) and tert-butylchlorodimethylsilane (1.94 g, 12.87 mmol) were added thereto, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and was extracted with ethyl acetate. The organic layer was washed with saturated brine and was dried over anhydrous sodium sulfate, and the filtrate was removed by distillation under reduced pressure. The residue was chromatographed on silica gel column (hexane:ethyl acetate=95:5) to give the title compound as an oil (4.0 g, yield 95%).
Reaction SMILES: [Br:1][C:2]1[C:3](I)=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.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>[Br:1][C:2]1[C:3]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Clc1cc(I)c(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Clc1ccc(-c2cc(Cl)ncc2Br)cc1
Temperature: 20 °C
Yield: 70.7 %

Procedure:
To a degassed solution of 5-bromo-2-chloro-4-iodopyridine (Ref. Cottet, F. and Schlosser, M. Tetrahedron 60, 11896-11874 (2004)) (2.0 g, 6.3 mmol), 4-chlorophenylboronic acid (1.1 g, 6.9 mmol) and K2CO3 (1.7 g, 12.6 mmol) in 1,2-dimethoxyethane (24 mL) and H2O (8.0 mL) was added Pd(PPh3)4 (0.727 g, 0.63 mmol) under argon at 20° C. The reaction mixture was refluxed for 15 h under argon, then allowed to cool to 20° C. The reaction was quenched by addition of H2O (30 mL) and extracted with EtOAc (50 mL×3). The combined organic was washed with saturated aqueous NaHCO3 (50 mL) and saturated aqueous NaCl (50 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was crystallized in EtOH to afford 1.35 g of the title compound as a light beige solid as the first crop. The second crop of the title product (0.44 g) was also isolated by concentrating the mother liquid followed by recrystallization in EtOH. LC/MS (method B): retention time=2.03 min, [M+H]+=301.9.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([O:12][CH:13]([CH3:17])[C:14]#[C:15][CH3:16])[CH:3]=1.[C:18](Cl)(=[O:25])[O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>ClCCl>[Cl:11][C:10]1[C:2]([NH:1][C:18]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:25])=[CH:3][C:4]([O:12][CH:13]([CH3:17])[C:14]#[C:15][CH3:16])=[C:5]([CH:9]=1)[C:6]([NH2:8])=[O:7]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC#CC(C)Oc1cc(N)c(Cl)cc1C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC#CC(C)Oc1cc(NC(=O)OCC(Cl)(Cl)Cl)c(Cl)cc1C(N)=O

Procedure:
0.75 g of (S)-N-(8-methyl-8-azabicyclo 3.2.1!oct-3α-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzamide, 0.51 g of 2,2,2-trichloroethyl chlorocarbonate and 0.41 g of potassium carbonate were added to toluene. The obtained mixture was refluxed for 3 hours and cooled, followed by the addition thereto of dichloromethane. The resulting mixture was washed with 1N hydrochloric acid, dried over magnesium sulfate, and freed from the solvent. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane (1:4) mixture) to give 0.50 g of (S)-N-(8-(2,2,2-trichloroethoxycarbonyl)-8-azabicyclo 3.2.1!oct-3α-yl)-5-chloro-2-(1-methyl-2-butynyl)oxy-4-(2,2,2-trichloroethoxycarbonylamino)benzamide.
Reaction SMILES: [C:1]([OH:8])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:9][C:10]([CH3:14])([CH3:13])[CH2:11]O>>[CH3:11][C:10]1([CH3:14])[CH2:13][O:8][C:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[N:9]1
Reactant: CC(C)(N)CO
Reactant: CCCCCC(=O)O
Product: CCCCCC1=NC(C)(C)CO1
Temperature: 185 °C
Yield: 81.2 %

Procedure:
Following the procedure under Example 8, 6.085 g (52.4 mmoles) of hexanoic acid and 10 ml (9.34 g, 104.8 mmoles) of 2-amino-2-methylpropanol were heated to 185° C. Work up and fractional distillation gave 7.2 g (81%) of product, b.p. 90°-92° C./25 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=3)[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[C:6]([NH:24]C(=O)C(F)(F)F)[C:5]2=1.[C:31]([O-])([O-])=O.[K+].[K+].O>CO>[NH2:24][C:6]1[C:5]2[C:4]3[C:12](=[C:13]([NH:15][C:16](=[O:23])[C:17]4[CH:22]=[CH:21][CH:20]=[N:19][C:18]=4[CH3:31])[CH:14]=[C:2]([Cl:1])[CH:3]=3)[NH:11][C:10]=2[CH:9]=[N:8][CH:7]=1
Reactant: O=C(Nc1cc(Cl)cc2c1[nH]c1cncc(NC(=O)C(F)(F)F)c12)c1cccnc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ncccc1C(=O)Nc1cc(Cl)cc2c1[nH]c1cncc(N)c12
Temperature: 60 °C
Yield: 55.6 %

Procedure:
N-[6-chloro-4-(2,2,2-trifluoro-acetylamino)-9H-β-carbolin-8-yl]-nicotinamide (41 mg, 0.092 mmol, 1 equiv.) was suspended in 5 ml of MeOH and a 2 ml aqueous solution of K2CO3 (127 mg, 0.92 mmol, 10 equiv.) was added thereto. The resulting clear solution was heated at 60° C. for 16 hr and then allowed to cool to RT. Additional water was added producing fine solids that were captured by filtration, washed once with 10 ml of 5% MeOH in Et2O, and dried under high vacuum to give 18 mg of N-(4-amino-6-chloro-9H-β-carbolin-8-yl)-2-methyl-nicotinamide as powdery yellow solids (56% yield). 1H-NMR (300 MHz, DMSO-d6): δ 11.18 (s, 1H), 10.41 (s, 1H), 8.62 (d, J=3.6, 1H),), 8.32 (s, 1H), 8.20 (s, 1H), 8.11 (d, J=7.5, 1H), 7.91 (s, 1H), 7.79 (s, 1H), 7.43 (m, 1H), 5.91 (br, 2H), 2.66 (s, 3H). Formic acid standard conditions. DAD RT=1.63 min. M+H=352.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.C(NC(C)C)(C)C.Cl[C:22]1[C:23]2[N:24]([N:28]=[CH:29][CH:30]=2)[CH:25]=[CH:26][N:27]=1>CN1C(=O)CCC1>[N:28]1[N:24]2[CH:25]=[CH:26][N:27]=[C:22]([N:1]3[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]3)[C:23]2=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: Clc1nccn2nccc12
Solvent: CC(C)NC(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2nccn3nccc23)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To a solution of (S)-tert-butyl pyrrolidin-3-ylcarbamate (0.50 g, 2.7 mmol, 1 eq) and diisopropylamine (0.66 mL, 3.8 mmol, 1.4 eq) in 0.2 mL of NMP was added 4-chloropyrazolo[1,5-a]pyrazine (0.47 mL, 3.1 mmol, 1.1 eq). After stirring for 1 h at room temperature, the mixture was concentrated and purified by silica gel column chromatography (100% EtOAc) to afford (S)-tert-butyl (1-(pyrazolo[1,5-a]pyrazin-4-yl)pyrrolidin-3-yl)carbamate (0.740 g, 2.4 mmol, 91%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Cl.C(N(CC)CC)C>CN(C)C=O>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C1CCCCN1
Reactant: COc1cccc(CCl)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCCCN1Cc1cccc(OC)c1

Procedure:
A solution of ethyl 2-piperidinecarboxylate (10.0 ml), 3-methoxybenzyl chloride (9.2 ml), and triethylamine (26.6 ml) in N,N-dimethylformamide (64.0 ml) was stirred at room temperature overnight and partitioned between ethyl acetate and water. The organic layer was separated, washed with water (four times) and brine, dried over MgSO4, and evaporated in vacuo. The residue was chromatographed over silica gel to afford ethyl 1-(3-methoxybenzyl)-2-piperidinecarboxylate (12.06 g) as a colorless oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:4]=1[CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][CH2:17][C@@H:18]([C:20]1[CH:21]=[CH:22][C:23]2[O:28]C(C)(C)[O:26][CH2:25][C:24]=2[CH:31]=1)[OH:19].C(=O)(O)[O-].[Na+].ClCCl>C(O)C>[Cl:2][C:3]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:4]=1[CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][CH2:17][C@@H:18]([C:20]1[CH:21]=[CH:22][C:23]([OH:28])=[C:24]([CH2:25][OH:26])[CH:31]=1)[OH:19]
Reactant: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCOCc3c(Cl)cccc3Cl)ccc2O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: OCc1cc([C@@H](O)CNCCCCCCOCCOCc2c(Cl)cccc2Cl)ccc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.1 %

Procedure:
1N HCl (295 mL) was added to a solution of (R)-2-{6-[2-(2,6-dichlorobenzyloxy)-ethoxy]-hexylamino}-1-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)-ethanol (52 g, 0.099 mol) in ethanol (312 mL), and the reaction stirred at ambient temperature for 1.5 h. Saturated sodium bicarbonate solution (500 mL) was added followed by dichloromethane (500 mL). The aqueous layer was separated and extracted with further dichloromethane (500 mL). The combined organic solutions were washed with water/brine mixture (500 mL/100 mL), then evaporated. The residue (50 g) was chromatographed on silica (800 g, Biotage) eluting with a dichloromethane/ethanol/ammonia mixture (50/8/1), to afford the title compound as an oil (35.2 g)-LC RT=4.1 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24](O)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:30]([O:34][C:35](=[O:43])[C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=1)([CH3:33])([CH3:32])[CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:42][C:39]4[CH:38]=[CH:37][C:36]([C:35]([O:34][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:43])=[CH:41][CH:40]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(N3CCCC(C(=O)O)C3)nc3scnc23)cc1OC
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(Nc2nc(N3CCCC(C(=O)Nc4ccc(C(=O)OC(C)(C)C)cc4)C3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.7 %

Procedure:
A mixture of 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxylic acid (57 mg, 0.137 mmol), tert-butyl-4-aminobenzoate (34.4 mg, 0.178 mmol), HATU (67.6 mg, 0.178 mmol) and DIEA (53 mg, 0.411 mmol) in 10 mL of DMF was stirred at room temperature for 72 hours. The solvent was evaporated and the residue was purified by silica gel chromatography (silica gel 200-300 mesh, ethyl acetate:petroleum ether=1:1) to give tert-butyl 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxamido)benzoate (75 mg, 92%) as a solid. LC-MS: 591.2 [M+H]+, tR=1.77 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[Na+].[CH:23]1([CH2:26]Br)[CH2:25][CH2:24]1.[I-].[Na+]>CO>[CH:23]1([CH2:26][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][C:10]3[CH:9]=[C:8]([C:7]4[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=4)[O:12][N:11]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: BrCC1CC1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ncccc1-c1cc(Cc2ccc(OCC3CC3)cc2)no1
Temperature: 60 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
To a mixture of 4-(5-(2-amino-pyridin-3-yl)isoxazol-3-ylmethyl)-phenol (4.2 mg, 0.016 mmol) described in Manufacturing Example 5-1-1 and methanol (0.4 mL) was added 1 N aqueous sodium hydroxide solution (16 μL, 0.016 mmol), which was then concentrated under a reduced pressure. To a mixture of the residue and N,N-dimethylformamide (0.5 mL) were added cyclopropylmethyl bromide (2.3 μL, 0.019 mmol) and sodium iodide (1 mg, 7 μmol) at room temperature, which was stirred for 2 hours at 60° C. The reaction mixture was cooled to room temperature and then purified as is by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid). The eluate was neutralized by triethylamine while being concentrated. The solvent was evaporated under a reduced pressure. The residue was washed with water to obtain the title compound (1.6 mg, 30%).
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH2:5].[Br:8][C:9]1[CH:10]=[C:11]([C:16](Cl)=[N:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=2[Cl:25])[C:12]([Cl:15])=[N:13][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[Br:8][C:9]1[CH:10]=[C:11]([C:16]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=3[Cl:25])[CH:3]=[CH:4][N:5]=2)[C:12]([Cl:15])=[N:13][CH:14]=1
Reactant: ClC(=Nc1cccc(Cl)c1Cl)c1cc(Br)cnc1Cl
Reactant: COC(CN)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: Clc1cccc(-n2ccnc2-c2cc(Br)cnc2Cl)c1Cl
Reaction time: 8 h
Yield: 90.3 %

Procedure:
To a solution of 2,2-dimethoxyethanamine (0.053 g, 0.505 mmol) in anhydrous tetrahydrofuran (5 mL) at 0-5° C. was added the N-((5-bromo-2-chloropyridin-3-yl)chloromethylene)-2,3-dichlorobenzenamine (0.1 g, 0.2526 mmol) as a solution in anhydrous tetrahydrofuran (5 mL). After stirring overnight, p-toluene sulfonic acid (0.05 g, 0.51 mmol) was added and the reaction mixture was stirred an additional 2 hours. After concentration to dryness the resulting solid purified by flash chromatography (0 to 30% ethyl acetate/methylene chloride) to provide 0.092 g of 5-bromo-2-chloro-3-(1-(2,3-dichlorophenyl)-1H-imidazol-2-yl)pyridine. Using the same procedure, 5-bromo-2-chloro-3-(1-(2,3-difluorophenyl)-1H-imidazol-2-yl)pyridine and 5-bromo-2-chloro-3-(1-(3-chloro-2-fluorophenyl)-1H-imidazol-2-yl)pyridine can be produced from 5-bromo-2-chloro-N-(2,3-difluorophenyl)pyridine-3-carboxamide and 5-bromo-2-chloro-N-(3-chloro-2-fluorophenyl)pyridine-3-carboxamide, respectively.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[C:4]([O:6]C)=O.[C:13]([C:18]#[N:19])(=[O:17])[O:14][CH2:15][CH3:16].Cl>CC(O)=O>[F:12][C:9]1[CH:8]=[C:3]2[C:2](=[CH:11][CH:10]=1)[N:1]=[C:18]([C:13]([O:14][CH2:15][CH3:16])=[O:17])[NH:19][C:4]2=[O:6]
Reactant: COC(=O)c1cc(F)ccc1N
Reactant: CCOC(=O)C#N
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1nc2ccc(F)cc2c(=O)[nH]1
Temperature: 70 °C
Yield: 85.8 %

Procedure:
A stirred mixture of methyl 2-amino-5-fluorobenzoate (1 g, 5.92 mmol) and ethyl carbonocyanidate (1.17 g, 11.8 mmol) in HOAc (8 mL) was treated with a 12 N aq solution of hydrochloric acid (0.8 mL). The resulting mixture was heated at 70° C. for 3 h. After cooling to rt, the solvent was removed under reduced pressure. The residue was suspended in water and treated with a saturated aq solution of NaHCO3 until pH=7. The solid was filtered, washed with water/diethyl ether and dried under reduced pressure to afford ethyl 6-fluoro-4-oxo-3,4-dihydroquinazoline-2-carboxylate (1.2 g, 86%). 1H NMR (300 MHz, DMSO-d6) δ 12.79 (s, 1H), 7.76-7.95 (m, 3H), 4.39 (q, J=7.0 Hz, 2H), 1.36 (t, J=7.0 Hz, 3H); LC-MS (ESI) m/z 237 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](O)[CH:5]=[C:4]([CH3:9])[N:3]=1.P(Br)(Br)([Br:12])=O.[OH-].[K+]>C(Cl)(Cl)Cl>[Br:12][C:6]1[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([CH3:9])[CH:5]=1
Reactant: Cc1cc(O)cc(C)n1
Reactant: O=P(Br)(Br)Br
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1cc(Br)cc(C)n1
Temperature: 100 °C
Yield: 220.7 %

Procedure:
2,6-Dimethyl-pyridin-4-ol 10I (6.16 g, 50 mmol), PBr5 (11.9 g, 27.65 mmol) and POBr3 (2.5 mL, 24.6 mmol) was combined and CHCl3 (2.5 mL) was added. The reaction was heated at 100° C. for 5 hrs and then cooled in an ice bath. Solid KOH was added till PH reached 7-8 followed by extraction with Et2O (3×75 mL). The combined ether layer was dried and evaporated in vacuo to give a thick clear crude oil (10.1 g) as the title compound.