Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][N:12]2[C:18](=[O:19])[C@H:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][S:15][C@@H:14]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:13]2)[CH2:10][CH2:9]1>ClCCl>[NH2:20][C@@H:17]1[CH2:16][S:15][C@@H:14]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:13][N:12]([CH2:11][CH:8]2[CH2:10][CH2:9]2)[C:18]1=[O:19]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CS[C@@H](c2ccccc2)CN(CC2CC2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CS[C@@H](c2ccccc2)CN(CC2CC2)C1=O
Reaction time: 1 h
Yield: 86.3 %

Procedure:
Trifluoroacetic acid (2.0 mL) was added to a solution of tert-butyl (2S,6S)-4-(cyclopropylmethyl)-5-oxo-2-phenyl-1,4-thiazepan-6-ylcarbamate (90 mg, 0.239 mmol) in dichloromethane (5 mL). After 1 h, the mixture was concentrated and aqueous saturated sodium bicarbonate was added. The mixture was extracted with dichloromethane (2×), and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated to give the crude product (57 mg). 1H NMR (500 MHz, CDCl3) □ 7.38-7.30 (m, 5H), 4.36-4.28 (m, 2H), 4.06 (d, J=9.3 Hz, 1H), 3.74 (dd, J=14.4, 1.5 Hz, 1H), 3.67 (dd, J=13.9, 7.3 Hz, 1H), 3.08 (dd, J=13.9, 6.6 Hz, 1H), 3.00 (dd, J=14.4, 9.8 Hz, 1H), 2.66 (dd, J=14.4, 1.9 Hz, 1H), 1.02-0.99 (m, 1H), 0.57-0.53 (m, 2H), 0.27-0.23 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5](I)[S:4][C:3]=1[C:8]1[N:12]=[CH:11][N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:9]=1.[N:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCOC(C)=O.O>[Br:1][C:2]1[CH:6]=[C:5]([C:24]2[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=2)[S:4][C:3]=1[C:8]1[N:12]=[CH:11][N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:9]=1
Reactant: OB(O)c1ccncc1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2sc(I)cc2Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: C[Si](C)(C)CCOCn1cnc(-c2sc(-c3ccncc3)cc2Br)n1
Temperature: 110 °C
Yield: 74.7 %

Procedure:
A mixture of 3-(3-bromo-5-iodo-2-thienyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazole (653.0 mg, 1.34 mmol), pyridine-4-boronic acid (248 mg, 2.02 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride (55.2 mg, 0.067 mmol) and cesium carbonate (1.80 g, 5.37 mmol) in 1,4-dioxane (8.40 mL, 107 mmol) and water (1.2 mL, 67.1 mmol) was heated at 110° C. under an atmosphere of argon overnight. Water (3 mL) and EtOAc (3 mL) were added, the organic layer was separated, washed with brine, dried over MgSO4, filtered, concentrated and the obtained residue was purified by column chromatography (SiO2, elution with 0-10% MeOH in DCM) to give the title compound as a white solid (438 mg, 74.6%). LCMS: (FA) ES+ , 438, 440. 1H NMR (400 MHz, d6-DMSO) δ: 8.87 (s, 1H), 8.62-8.64 (dd, J=1.5 Hz, 2H), 7.98 (s, 1H), 7.30-7.75 (dd, J=1.5, 2H), 5.58-5.59 (s, br, 2H), 3.40-3.69 (m, 2H), 0.840-0.890 (m, 2H), −0.04 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[CH3:14][NH2:15]>>[CH3:14][NH:15][C:11]([C:8]1([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=2)[CH2:10][CH2:9]1)=[O:13]
Reactant: CN
Reactant: O=C(O)C1(c2cccc(Br)n2)CC1
Product: CNC(=O)C1(c2cccc(Br)n2)CC1
Yield: 70 %

Procedure:
The title compound was prepared from 1-(6-bromo-pyridin-2-yl)-cyclopropanecarboxylic acid and methylamine (2 mol/L in tetrahydrofuran) following a procedure analogous to that described in Step 2 for Intermediate 5. Yield: 70% of theory; LC (method 3): tR=2.27 min; Mass spectrum (ESI+): m/z=255/257 (Br) [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:16]O>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:16])=[O:8]
Reactant: CO
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(N)ccc1Cl
Yield: 95 %

Procedure:
To a solution of 5-amino-2-chlorobenzoic acid (6.0 g, 35 mmol) in anhydrous methanol (100 ml) was added dropwise thionyl chloride (15 ml) with stirring under a nitrogen atmosphere. After stirring for 3 hours the volatiles were removed by spin evaporation in vacuo and the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate and then water. The organic layer was concentrated by spin evaporation in vacuo with the addition of dichloromethane (3 times) to give methyl 5-amino-2-chlorobenzoate as a white solid (6.2 g, 95%). 1H-NMR (400 MHz, DMSO-d6): δ 7.20-7.14 (m, 1H), 7.13-7.02 (m, 1H), 6.73-6.67 (m. 1H), 3.89 (s, 3H). ES-LCMS m/z 186 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:15]([NH:17][CH:18]3[CH2:20][CH2:19]3)=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[C:25]1([CH3:34])[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.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>[CH:18]1([NH:17][C:15](=[O:16])[C:14]2[CH:21]=[CH:22][C:23]([CH3:24])=[C:12]([C:8]3[CH:7]=[C:6]4[C:11](=[CH:10][CH:9]=3)[C:2]([C:28]3[CH:29]=[CH:30][C:25]([CH3:34])=[CH:26][CH:27]=3)=[N:3][N:4]=[CH:5]4)[CH:13]=2)[CH2:20][CH2:19]1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(Cl)nncc2c1
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: CCO
Solvent: COCCOC
Product: Cc1ccc(-c2nncc3cc(-c4cc(C(=O)NC5CC5)ccc4C)ccc23)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(1-chlorophthalazin-6-yl)-N-cyclopropyl-4-methylbenzamide (0.1 g, 296 μmol), p-tolyl boronic acid (40 mg, 296 μmol) and tetrakis(triphenylphosphine)palladium (17 mg, 15 μmol) in 5 mL DME/EtOH (4:1) was treated with 2 M potassium carbonate (444 μl, 888 μmol). The mixture was stirred at 90° C. for 2 h. The mixture was cooled to room temperature and purified via flash chromatography (silica gel) eluting with a gradient of 2% 2 M ammonia in MeOH/DCM to 6% 2 M ammonia in MeOH/DCM to give title compound in (95 mg) as a pale yellow solid. Found MS (ES+): 394(M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:3]=1.P(Br)(Br)[Br:19].N>O>[Br:19][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:3]=1
Reactant: BrP(Br)Br
Reactant: FC(F)(F)c1ccc(-c2cncc(Cl)n2)cc1
Agent: N
Solvent: O
Product: FC(F)(F)c1ccc(-c2cncc(Br)n2)cc1
Temperature: 25 °C

Procedure:
To a flask containing 2-chloro-6-[4-(trifluoromethyl)phenyl]pyrazine (0.8 g, 3.1 mmol), was added phosphorus tribromide (20 mL) and the mixture heated at reflux for 6 h under nitrogen. The reaction mixture was cooled to room temperature prior to pouring carefully into iced water (400 mL), the resulting mixture was adjusted to pH 6–7 using aqueous ammonia and extracted with diethylether (3×250 mL). The organic solution was dried (MgSO4) and the solvent removed in vacuo to afford the title compound as a pale yellow crystalline solid (0.97 g).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([NH2:8])[CH2:5][CH2:6][CH3:7].C([O:11][C:12](=O)[C:13]([C:15]1[CH:23]=[CH:22][C:18]2[O:19][CH2:20][O:21][C:17]=2[CH:16]=1)=[O:14])C>C(O)C>[O:19]1[C:18]2[CH:22]=[CH:23][C:15]([C:13](=[O:14])[C:12]([NH:8][CH:4]([CH2:5][CH2:6][CH3:7])[CH2:3][CH2:2][CH3:1])=[O:11])=[CH:16][C:17]=2[O:21][CH2:20]1
Reactant: CCOC(=O)C(=O)c1ccc2c(c1)OCO2
Reactant: CCCC(N)CCC
Solvent: CCO
Product: CCCC(CCC)NC(=O)C(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.1 %

Procedure:
4-Heptylamine (2.5 g, 22 mmol) was added to a stirred solution of benzo[1,3]dioxol-5-yl-oxo-acetic acid ethyl ester (2 g, 9 mmol)) in ethanol (40 ml)) at room temperature. The resulting reaction mixture was heated to reflux for 4 hours. Then ethanol was distilled off and stirring was continued at 110° C. for 2 hours. The reaction mixture was cooled to room temperature and then 50 ml of THF and 100 ml of aqueous HCl solution were added and stirred for 30 minutes. The mixture was extracted twice with DCM (50 ml). The organic layer was washed twice with water (50 ml) and concentrated in vacuum. The crude product was chromatographed on a silica gel column using ethylacetate/heptane (2:3) as eluent to provide the title compound (0.5 g, 29% yield) as red crystals.
Reaction SMILES: C(C1C=CC(N2CC[C@H](N[C@@H](C3C4C(=CC=CC=4)C=CC=3)C)C2)=CC=1)(=O)C.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([C@H:36]([NH:38][CH:39]2[CH2:43][CH2:42][N:41](C(OC(C)(C)C)=O)[CH2:40]2)[CH3:37])[CH:33]=[CH:34][CH:35]=1.[ClH:51]>C(Cl)(Cl)Cl.O1CCOCC1>[ClH:51].[ClH:51].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([C@H:36]([NH:38][C@@H:39]2[CH2:43][CH2:42][NH:41][CH2:40]2)[CH3:37])[CH:33]=[CH:34][CH:35]=1
Reactant: COc1cccc([C@@H](C)NC2CCN(C(=O)OC(C)(C)C)C2)c1
Agent: CC(=O)c1ccc(N2CC[C@H](N[C@H](C)c3cccc4ccccc34)C2)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: COc1cccc([C@@H](C)N[C@@H]2CCNC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 25 g of tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate and 25.9 g of diisopropylethylamine dissolved in 500 ml of methylene chloride was added dropwise 100 ml of a solution of 49 g of anhydrous trifluoromethanesulfonic acid in methylene chloride at −20° C. or lower. The reaction mixture was stirred for 15 minutes while maintaining it to −20° C., and then, to the mixture was added dropwise 100 ml of a solution of 24.2 g of (R)-1-(3-methoxyphenyl)ethylamine in methylene chloride at −20° C. or lower, and the reaction mixture was stirred at room temperature for 16 hours. To the reaction mixture were added a saturated aqueous sodium bicarbonate solution and chloroform, the mixture was stirred and the liquids were separated. The organic layer was dried and the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:2) to obtain 19.32 g of tert-butyl 3-[(R)-1-(3-methoxyphenyl)ethylamino]pyrrolidine-1-carboxylate. (2) To a solution of 19.32 g of tert-butyl 3-[(R)-1-(3-methoxyphenyl)ethylamino]pyrrolidine-1-carboxylate dissolved in 30 ml of chloroform was added 300 ml of a solution of 4M hydrochloric acid in dioxane, and the mixture was stirred at room temperature for 16 hours. The resulting precipitates were collected by filtration, washed with ethyl acetate, and recrystallized from methanol and tetrahydrofuran twice to obtain 8.54 g of (R)-3-[(R)-1-(3-methoxyphenyl)ethylamino]pyrrolidine dihydrochloride (the following Reference example Table, Reference example 1.003).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH2:15][CH2:16][C:17]([O:19]C)=O)[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.[Pd]>[C:17]1(=[O:19])[N:5]2[C:6]3[C:7]([NH:12][C:3](=[O:2])[CH:4]2[CH2:15][CH2:16]1)=[CH:8][CH:9]=[CH:10][CH:11]=3
Reactant: COC(=O)CCC(Nc1ccccc1[N+](=O)[O-])C(=O)OC
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: O=C1Nc2ccccc2N2C(=O)CCC12
Reaction time: 2 h

Procedure:
To N-(2-nitrophenyl)-DL-glutamic acid dimethyl ester (XI, EXAMPLE 279, 5.09 g) in methanol (150 ml) is added p-toluenesulfonic acid (0.158 g) and palladium on carbon (10%, 0.495 g). The mixture is shaken under hydrogen at 37 psi for 2 hr; the mixture is then filtered and the tiltrate is concentrated to about 70 ml. Additional p-toluenesulfonic acid (0.15 g) is added, and the solution is heated at 60° for 1 hr. After cooling, the solid is collected, washed with methanol, and dried to give the title compound, mp 231°-232°; NMR (CDCl3) 2.65, 4.41, 6.93, 7.14, 8.10 and 8.55 δ.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:16]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH4-].[Na+]>>[CH2:17]([N:13]1[CH2:12][CH:11]=[C:10]([C:8]2[S:9][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:16][C:6]=3[N:7]=2)[CH2:15][CH2:14]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Clc1ccc2sc(-c3ccncc3)nc2c1
Reactant: BrCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: Clc1ccc2sc(C3=CCN(Cc4ccccc4)CC3)nc2c1
Yield: 65.5 %

Procedure:
4-(5-Chlorobenzothiazol-2-yl)pyridine (1.8 g, 7.3 mmol) was reacted with benzyl bromide (1.3 ml, 10.95 mmol), followed by sodium borohydride (361 mg, 9.5 mmol) as exemplified in Example 7 step 2. The crude product was purified by flash chromatography eluting with 15% ethyl acetate in petroleum ether to give a solid. Recrystallisation from ethyl acetate afforded the title compound as a pale yellow solid (1.63 g, 66%); (Found: C, 66.83; H, 5.00; N, 8.20. C19H17ClN2S requires C, 66.95; H, 5.03; N, 8.22%). δH (CDCl3), 2.76 (4H, m, CH2), 3.24 (2H, m, CH2), 3.67 (2H, s, NCH2Ar), 6.70 (1H, m, NCH2CH), 7.32 (5H, m, ArH), 7.71 (1H, d, J 8.5Hz, ArH), 7.95 (1H, d, J 1.9Hz, ArH). m/z (ES+) 341 (M+1)+.
Reaction SMILES: [C:1]1([CH2:11][CH2:12][OH:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[C:26]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:29])[CH:27]=[CH2:28]>CO>[C:1]1([CH2:11][CH2:12][O:13][CH2:28][CH2:27][C:26]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: OCCc1cccc2ccccc12
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)CCOCCc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
1-Naphthalene ethanol (10 g) was treated with benzyltrimethylammonium hydroxide (Triton B®; 0.9 mL of a 40% solution in methanol) and the resulting mixture stirred in vacuo for 30 minutes. The mixture was then cooled to 0° C. and treated with tert-butyl acrylate (8.19 g). The resulting mixture was slowly warmed to room temperature and stirred overnight. The crude mixture was subsequently absorbed onto aluminium oxide (30 g) and eluted with diethylether (200 mL). The organics were concentrated to give a crude material (16.6 g) which was purified by flash silica chromatography eluting with 1:8, diethylether:hexane to give the subtitled compound (12.83 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:8](=[O:19])[C:7]2([CH3:21])[CH3:20].C([Li])CCC.Br[CH2:28][CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>O1CCCC1>[Si:31]([O:30][CH2:29][CH2:28][CH:11]([N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[F:1])[C:7]([CH3:21])([CH3:20])[C:8]1=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC1(C)C(=O)N(Cc2cccc(F)c2)c2c(F)cccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)C(=O)N(C(CCO[Si](C)(C)C(C)(C)C)c2cccc(F)c2)c2c(F)cccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.3 %

Procedure:
7-fluoro-1-(3-fluorobenzyl)-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (1.01 g, 3.5 mmol) was dissolved in tetrahydrofuran and cooled to −78° C. n-Butyl lithium (2.5 M in hexane, 1.55 mL, 3.97 mmol) was added dropwise and the mixture was warmed to 0° C. (2-Bromoethoxy)-tert-butyldimethylsilane (1.14 mL, 5.25 mmol) was added and the mixture was allowed to warm to 25° C. The mixture was stirred for 16 hours then quenched with saturated aqueous ammonium chloride, diluted with ether, washed with water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Isco chromatography (Redisep, silica, gradient 0-10% ethyl acetate in hexane) to afford 0.8 g (55%) 1-[3-{[tert-butyl(dimethyl)silyl]oxy}-1-(3-fluorophenyl)propyl]-7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]1[N:13]([CH3:14])[C:12]2[C:15]3[CH2:16][C:17]([CH3:26])([CH3:25])[O:18][C:19]=3[C:20]([C:22]([OH:24])=O)=[CH:21][C:11]=2[N:10]=1.[CH:28]1([CH2:31][NH2:32])[CH2:30][CH2:29]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN(C=O)C>C1COCC1>[CH:28]1([CH2:31][NH:32][C:22]([C:20]2[C:19]3[O:18][C:17]([CH3:26])([CH3:25])[CH2:16][C:15]=3[C:12]3[N:13]([CH3:14])[C:9]([NH:8][C:7]4[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=4[Cl:27])=[N:10][C:11]=3[CH:21]=2)=[O:24])[CH2:30][CH2:29]1
Reactant: Cn1c(Nc2c(Cl)cncc2Cl)nc2cc(C(=O)O)c3c(c21)CC(C)(C)O3
Reactant: NCC1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1c(Nc2c(Cl)cncc2Cl)nc2cc(C(=O)NCC3CC3)c3c(c21)CC(C)(C)O3
Yield: 18.6 %

Procedure:
The title compound was prepared following the procedure described for Example-1 by using 2-((3,5-dichloropyridin-4-yl)amino)-1,7,7-trimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylic acid (Intermediate-61, 0.100 g, 0.245 mmol), cyclopropylmethanamine (0.025 g, 0.363 mmol), TBTU (0.157 g, 0.49 mmol), DMF (5 mL), THF (3 mL) to afford 0.021 g of the desired product. 1HNMR (DMSO-d6): δ 0.22 (d, J=4.2 Hz, 2H), 0.44 (d, J=6.6 Hz, 2H), 1.02 (m, 1H), 1.54 (s, 6H), 3.19 (m, 2H), 3.44 (s, 2H), 3.56 (s, 3H), 7.22 (s, 1H), 7.80 (m, 1H), 8.45 (s, 2H), 10.79 (s, 1H); MS [M+]+: 459.03.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@H:11]([C:13]3[C:14]([F:24])=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][C:28]1=[O:33]>CN1C(=O)CCC1.CCOC(C)=O>[F:24][C:14]1[C:13]([C@@H:11]([C:8]2[N:6]3[N:7]=[C:2]([N:30]4[CH2:31][CH2:32][NH:27][C:28](=[O:33])[CH2:29]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:21]([F:22])[CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[CH3:23]
Reactant: C[C@@H](c1c(F)cc2c(cnn2C)c1F)c1cnc2ccc(Cl)nn12
Reactant: O=C1CNCCN1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: C[C@@H](c1c(F)cc2c(cnn2C)c1F)c1cnc2ccc(N3CCNC(=O)C3)nn12
Temperature: 170 °C
Reaction time: 3 h

Procedure:
6-Chloro-3-[(S)-1-(4,6-difluoro-1-methyl-1H-indazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine (Intermediate Q, 50 mg, 0.144 mmol), KF, 42.6 mg, 0.719 mmol) and piperazin-2-one (44.5 mg, 0.431 mmol) were suspended in NMP (0.3 mL). The RM was stirred at 170° C. for 3 h. The mixture was diluted with EtOAc and washed with NaHCO3 10% (2×) and water (4×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography and then crystallized in EtOAc/Pentane to afford the title compound as a light brown solid (tR 3.63 min (conditions 5), (tR 10.82 min (conditions 2), MH+=412.2, 1H-NMR in DMSO-d6: 8.07 (s, 1H); 8.03 (s, 1H); 7.79 (d, 1H); 7.52 (s, 1H); 7.36 (d, 1H); 7.02 (d, 1H); 4.85 (m, 1H); 3.95 (d, 1H); 3.95 (s, 3H); 3.73 (d, 1H); 3.54 (m, 2H); 3.17 (m, 2H); 1.79 (d, 3H)).
Reaction SMILES: Cl[CH2:2][P:3]([OH:6])(=[O:5])[OH:4].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17]>O>[OH2:4].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:2][P:3]([OH:6])(=[O:5])[OH:4]
Reactant: NCCCCCCCCCN
Reactant: O=P(O)(O)CCl
Solvent: O
Product: NCCCCCCCCCNCP(=O)(O)O
Yield: 157.2 %

Procedure:
Chloromethanephosphonic acid (4.0 g, 30.6 mmoles) and 1.9-diaminononane (20.1 g, 127.2 mmoles) were dissolved in water (100 cm3) and the resultant solution heated under reflux for 20 hours. The water was then distilled off and methanol (80 cm3) added to the residue. The solid was filtered off, washed with methanol (2×50 cm3) and dried in a vacuum oven at 60° C. for three hours to yield the crude N-(9-aminononyl)aminomethanephosphonic acid monohydrate (6.5 g, 78.5%), having a melting point of 240°-241° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([CH:20]=[O:21])=[CH:18][N:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[C:4]([F:30])[CH:3]=1.[H-].[Na+].I[CH3:34].O>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([CH:20]=[O:21])=[CH:18][N:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:29])[CH3:28])[C:14]4=[N:15][CH:16]=3)=[N:7][N:8]2[CH3:34])=[C:4]([F:30])[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(-c3n[nH]c4cc(Cl)cc(F)c34)cnc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1nc(-c2cnc3c(n2)c(C=O)cn3COCC[Si](C)(C)C)c2c(F)cc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.9 %

Procedure:
2-(6-Chloro-4-fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (0.5 g, 1.12 mmol) was dissolved in DMF (5.6 ml) and cooled in an ice bath. Sodium hydride (60% dispersion, 67 mg, 1.68 mmol) was carefully added. The mixture was stirred for 10 min then iodomethane (84 ul, 1.35 mmol) was added and the reaction was warmed to room temperature and stirred for 18 h. Water and ethyl acetate were added to the reaction. The layers were separated and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed water and sodium chloride solution and dried over sodium sulfate. After evaporation the remaining residue was purified by silica gel chromatography (ethyl acetate/dichloromethane) to give 257 mg (50%) of 2-(6-chloro-4-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde. (M+H)+=460.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:34]C(=O)C)=[C:18]([O:21][CH:22]4[CH2:27][CH2:26][N:25]([C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])[CH2:24][CH2:23]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[F:9].C(=O)([O-])O.[Na+]>CO>[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:34])=[C:18]([O:21][CH:22]4[CH2:27][CH2:26][N:25]([C:28](=[O:33])[C:29]([F:30])([F:31])[F:32])[CH2:24][CH2:23]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: CC(=O)Oc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OC1CCN(C(=O)C(F)(F)F)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C(N1CCC(Oc2cc3c(Nc4ccc(F)c(Cl)c4)ncnc3cc2O)CC1)C(F)(F)F

Procedure:
Prepared by treating 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-acetoxy-quinazoline-hydrochloride with saturated sodium hydrogen carbonate solution in methanol at ambient temperature. In addition to the desired product, some 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-hydroxy-quinazoline is also isolated as a by-product.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[CH:24][CH:23]=3)=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:33])=O>>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([Cl:33])=[O:30])=[CH:24][CH:23]=3)=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCOc1ccc(-c2ccccc2-c2ccc(C(=O)O)cc2)cc1
Product: CCCCCCCCOc1ccc(-c2ccccc2-c2ccc(C(=O)Cl)cc2)cc1

Procedure:
After 1.6 g of 4-n-octyloxyterphenyl-4"-carboxylic acid was heated with an excess amount of thionyl chloride under reflux condition for 6 hours, unreacted thionyl chloride was distilled off to obtain 4-n-octyloxyterphenyl-4"-carboxylic acid chloride.