Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:35])[CH:4]([O:32][CH2:33][CH3:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][N:14]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:15]([N:17]([CH3:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:16])=[CH:8][CH:7]=1.[Li+].[OH-]>O1CCCC1>[CH2:33]([O:32][CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][N:14]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:15]([N:17]([CH3:24])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:16])=[CH:8][CH:7]=1)[C:3]([OH:35])=[O:2])[CH3:34]
Reactant: CCCCCCCN(CCc1ccc(CC(OCC)C(=O)OC)cc1)C(=O)N(C)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCN(CCc1ccc(CC(OCC)C(=O)O)cc1)C(=O)N(C)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.9 %

Procedure:
A solution of 2-ethoxy-3-{4-[2-(1-heptyl-3-methyl-3-phenyl-ureido)-ethyl]-phenyl}-propionic acid methyl ester (98 mg, 0.20 mmol) and 1 M LiOH (0.60 mmol, 0.60 mL) in tetrahydrofuran (1 mL) was allowed to stir at room temperature for 16 hours. 2 N HCL was then added until the solution had a pH<2. After dilution with twice its volume in water, the aqueous layer was extracted with diethyl ether (2×). The organic layers were combined, washed with 2 M HCl (2×), dried over anhydrous sodium sulfate, and concentrated to give 2-ethoxy-3-{4-[2-(1-heptyl-3-methyl-3-phenyl-ureido)-ethyl]-phenyl}-propionic acid as a clear oil (73 mg, 78%).
Reaction SMILES: [CH3:1][C:2]([C:4]1([CH3:19])[CH2:9][O:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[O:6][CH2:5]1)=[O:3].[BH4-].[Na+]>CO.O>[CH3:1][CH:2]([C:4]1([CH3:19])[CH2:9][O:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[O:6][CH2:5]1)[OH:3]
Reactant: CC(=O)C1(C)COC(c2cccc([N+](=O)[O-])c2)OC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(O)C1(C)COC(c2cccc([N+](=O)[O-])c2)OC1

Procedure:
To a solution of 5-methyl-2-(m-nitrophenyl)1,3-dioxan-5-yl methyl ketone (9.0 g) in methanol (100 ml) was added a solution of sodium borohydride (4.5 g) in water (20 ml). The mixture was heated under reflux for 1 hour, methanol was removed in vacuo and the residue was extracted with ether (3 × 100 ml). The extracts were dried (Na2SO4) and concentrated and the residue was crystallised from diethyl ether as pale yellow crystals m.p. 97°, cis isomer.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:26])[CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:12][CH:11]1[C:27]([O:29]C)=[O:28])=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:26])[CH2:17][NH:18][C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:12][CH:11]1[C:27]([OH:29])=[O:28])=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: COC(=O)C1CN(C(=O)CNC(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC(=O)N1CCN(C(=O)OC(C)(C)C)C(C(=O)O)C1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A solution of 1 N sodium hydroxide (728 mL) was added to a stirred solution of Methyl 1-tert-butoxycarbonyl-4-(N-tert-butoxycarbonylglycyl)piperazine-2-carboxylate (A, 195 mg) in methanol (3 mL). The mixture was stirred at room temperature for 23 hr and evaporated in vacuo. The residue was diluted with water and washed with ether. The aqueous layer was acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to give the title compound (186 mg) as a colorless solid: 1H NMR (400 MHz, CD3OD) δ 1.44 (br s, 18H) and 2.70-4.80 (m, 9H).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][N:10]2[C:15](=[O:16])[C:14](Br)=[C:13]([Br:18])[CH:12]=[N:11]2)=[CH:7][CH:6]=1>C1(C)C=CC=CC=1>[CH3:3][O:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][N:10]2[C:15](=[O:16])[C:14]([NH:2][CH3:1])=[C:13]([Br:18])[CH:12]=[N:11]2)=[CH:7][CH:6]=1
Reactant: CN
Reactant: COc1ccc(Cn2ncc(Br)c(Br)c2=O)cc1
Solvent: Cc1ccccc1
Product: CNc1c(Br)cnn(Cc2ccc(OC)cc2)c1=O
Temperature: 90 °C

Procedure:
In a glass pressure reactor vessel equipped with a magnetic stir bar, toluene (100 mL) was saturated with anhydrous methylamine at 0° C. then 2-(4-methoxybenzyl)-4,5-dibromopyridazin-3(2H)-one (1) (22 g, 59 mmol) was added. The vessel was sealed and the suspension was stirred and heated at 90° C. for 18 h. The resulting suspension was allowed to cool to RT. Anhydrous methylamine was bubbled through the mixture for 15 min, the reactor was sealed again, and the mixture was stirred and heated at 90° C. for an additional 18 h. After cooling to RT, the mixture was concentrated in vacuo to dryness. The resulting brown solid was suspended in MeOH and sonicated. The solid was collected by suction filtration, washed with MeOH, and dried in vacuo to give 2-(4-methoxybenzyl)-5-bromo-4-(methylamino)pyridazin-3(2H)-one as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([N+:13]([O-])=O)[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.C(O)(=O)C.[OH-].[Na+]>CO.O=[Pt]=O>[NH2:13][C:11]1[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[C:10]=1[NH:9][CH2:8][CH2:7][CH2:6]2
Reactant: COc1cc([N+](=O)[O-])c2ncccc2c1
Agent: O=[Pt]=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(N)c2c(c1)CCCN2
Reaction time: 2.5 h

Procedure:
A suspension of 6-methoxy-8-nitroquinoline (20 g, 98 mmol) in methanol (200 ml) was hydrogenated over PtO2 (0.5 g) at 50 p.s.i. for 2.5 hours. The solution was treated with acetic acid (11.5 ml, 200 mmol) and PtO2 (0.5 g) and hydrogenated at 50 p.s.i. for 18 hours. The catalyst was removed by filtration and the solution evaporated in vacuo to give an oil. The residue was basified with 1 N-sodium hydroxide (200 ml) and the aqueous mixture extracted with diethyl ether (2×200 ml). The extracts were dried (MgSO4) and evaporated in vacuo to give crude 8-amino-1,2,3,4-tetrahydro-6-methoxyquinoline as a red oil.
Reaction SMILES: C(OC(=O)[NH:5][C:6](=S)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=3)=[O:23])[CH:16]=2)=[CH:10][N:9]=1)C.[Cl-].O[NH3+].C([N:39](CC)C(C)C)(C)C.C(O)C>CO>[NH2:39][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:16]=[C:17]([NH:21][C:22]([C:24]4[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=4)=[O:23])[CH:18]=[CH:19][CH:20]=3)=[CH:10][N:9]2[N:5]=1
Reactant: CCOC(=O)NC(=S)Nc1ccc(Oc2cccc(NC(=O)c3ncccc3C)c2)cn1
Reactant: CCN(C(C)C)C(C)C
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CO
Solvent: CCO
Product: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(N)nn3c2)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 84.6 %

Procedure:
A mixture of ethyl{[5-(3-{[(3-methylpyridin-2-yl)carbonyl]amino}phenoxy)pyridin-2-yl]carbamothioyl}carbamate (2.00 g, 4.43 mmol), hydroxylammonium chloride (3.13 g, 45.0 mmol), N,N-diisopropylethylamine (4.70 mL, 26.9 mmol), ethanol (50 mL) and methanol (50 mL) was stirred at 80° C. for 5 hr. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the residue. The mixture was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate to give the title compound (1.35 g, 84%) as a white solid.
Reaction SMILES: [C:1]1([CH3:38])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[NH:14][CH2:13][CH:12]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=3)=[O:24])[C:11]2=[O:37])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH2:39]([CH:41]([CH2:45][CH3:46])[C:42](Cl)=[O:43])[CH3:40].N1C=CC=CC=1.O>ClCCCl.C(OCC)(=O)C>[C:1]1([CH3:38])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:42](=[O:43])[CH:41]([CH2:45][CH3:46])[CH2:39][CH3:40])[CH2:13][CH:12]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=3)=[O:24])[C:11]2=[O:37])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CNc3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Reactant: CCC(CC)C(=O)Cl
Solvent: O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)C(CC)CC)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Yield: 111.9 %

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (500 mg) obtained from Step 1 of Example 93 was suspended in 1,2-dichloroethane (10 ml), 2-ethyl-n-butanoyl chloride (144 mg) and pyridine (87 μl) were added thereto, the mixture was refluxed for 2 hours. Water (100 ml) and ethyl acetate (100 ml) were added to the reaction mixture, and separated. The organic layer was washed with 1N hydrochloric acid, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 666 mg of the titled compound (Yield: 100%).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[CH3:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][C:9]=1[CH3:16].C(=O)=O>O>[CH3:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[N:2][OH:3])=[CH:10][C:9]=1[CH3:16]
Reactant: COc1ccc(C=O)cc1C
Reactant: NO
Agent: Cl
Agent: O=C=O
Agent: [Na+]
Solvent: O
Product: COc1ccc(C=NO)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
A cold solution of hydroxylamine.hydrochloride (15 g, 0.22 mol) in H2O (50 ml) was mixed with a cold solution of NaOH (20 g, 0.5 mol) in H2O (150 ml) and then 4-methoxy-3-methylbenzaldehyde (30 g, 0.2 mol) was added in a steady stream. After stirring at room temperature for 30 minutes, the solution was saturated with CO2. The separated solid was collected, washed with H2O, and dried to yield 30.9 g (94%) of 20; m.p. 70°-2° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[C:8]([CH3:13])=[N:7]2.P(Cl)(Cl)([Cl:16])=O>O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:16])[C:8]([CH3:13])=[N:7]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2cccc(Br)c2[nH]c1=O
Solvent: O
Product: Cc1nc2cccc(Br)c2nc1Cl
Temperature: 0 °C
Yield: 74.9 %

Procedure:
A slurry of 8-bromo-3-methylquinoxalin-2(1H)-one (6.33 g, 26.5 mmol) in phosphorus oxychloride (20 mL, 219 mmol) was heated at reflux for 1.5 h in a round-bottomed flask fitted with a water-cooled reflux condenser and drying tube. Excess POCl3 was removed in vacuo (16 Torr, 36° C.), and the residue was taken up in DCM (50 mL), transferred to an Erlenmeyer flask, cooled to 0° C., and saturated aq. NaHCO3 (ca. 80 mL) was added (cautiously, with rapid stirring). The resulting biphasic mixture was stirred rapidly for 5 min. Upon cessation of gas evolution, the mixture was extracted with DCM (3×200 mL), and the combined extracts were dried over Na2SO4, filtered, and concentrated onto silica gel. Chromatographic purification of the residue (silica gel, 0-30% EtOAc/hexanes) furnished 5-bromo-3-chloro-2-methylquinoxaline (126e; 5.12 g, 19.85 mmol, 75% yield) as a light-yellow solid: 1H NMR (400 MHz, CDCl3) δ ppm 8.02 (1H, d, J=7.6 Hz), 8.00 (1H, dd, J=8.4, 1.2 Hz), 7.60 (1H, t, J=7.9 Hz), 2.87 (3H, s). m/z (ESI, +ve) 256.9 (M+H)+.
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:5]1)#[N:2]>C(O)C.[Pd]>[C:1]([CH2:3][C@H:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[C@@H:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:5]1)#[N:2]
Reactant: CCOC(=O)C1CC(=CC#N)CCN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@H]1C[C@@H](CC#N)CCN1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
Ethyl 4-cyanomethylidene-N-t-butoxycarbonyl-2-piperidinecarboxylate (9.00 g, 0.031 mol) was hydrogenated in 140 ml of ethanol with 0.90 g of 5% by weight palladium-on-carbon at room temperature and 60 p.s.i. for 60 minutes. The mixture was filtered through Celite and concentrated under vacuum. High pressure liquid chromatography of the residue provided 8.20 g of ethyl cis-4-cyanomethyl-N-t-butoxycarbonyl-2-piperidinecarboxylate.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]1[NH:21][C:22]([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[CH:31]=[C:30]([C:35]2[CH:36]=[C:37]4[C:57](=[CH:58][CH:59]=2)[C:41]2[NH:42][C:43]([C@@H:45]5[CH2:49][CH2:48][CH2:47][N:46]5C(OC(C)(C)C)=O)=[N:44][C:40]=2[CH:39]=[CH:38]4)[CH:29]=[CH:28]3)=[CH:23][N:24]=1)=O)(C)(C)C>C(Cl)Cl>[NH:46]1[CH2:47][CH2:48][CH2:49][C@H:45]1[C:43]1[NH:42][C:41]2[C:57]3[C:37]([CH:38]=[CH:39][C:40]=2[N:44]=1)=[CH:36][C:35]([C:30]1[CH:29]=[CH:28][C:27]2[C:32](=[CH:33][CH:34]=[C:25]([C:22]4[NH:21][C:20]([C@@H:16]5[CH2:17][CH2:18][CH2:19][NH:15]5)=[N:24][CH:23]=4)[CH:26]=2)[CH:31]=1)=[CH:59][CH:58]=3
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc5c(ccc6nc([C@@H]7CCCN7C(=O)OC(C)(C)C)[nH]c65)c4)ccc3c2)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc2cc(-c3cnc([C@@H]4CCCN4)[nH]3)ccc2cc1-c1ccc2c(ccc3nc([C@@H]4CCCN4)[nH]c32)c1
Reaction time: 2 h
Yield: 102 %

Procedure:
TFA (2 mL, 26.0 mmol) was added in one portion to a stirred solution of (5)-tert-butyl 2-(7-(6-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (137 mg) in CH2Cl2 (10 mL) at room temperature. The mixture was stirred for 2 h at room temp. and then the solvents were removed in vacuo. The residue was taken up in 50% methanol/CH2Cl2 and filtered through an MCX cartridge (Strata XC). The cartridge was washed with methanol and the compound was eluted with a solution of NH3 in methanol (2M). The appropriate fractions were concentrated in vacuo to afford 2-((S)-pyrrolidin-2-yl)-7-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-naphtho[1,2-d]imidazole (98 mg, 0.20 mmol) as orange solid. LC-MS retention time 1.245 min; m/z 499.30 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 10% MeOH/90% H2O/0.1% TFA and Solvent B was 10% H2O/90% MeOH/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (TFA salt, 500 MHz, MeOD) δ ppm 8.59 (d, J=8.5 Hz, 1H), 8.43 (d, J=1.5 Hz, 1H), 8.36 (s, 1H), 8.31 (s, 1H), 8.13 (dd, J=8.6, 1.8 Hz, 1H), 8.01-8.10 (m, 3H), 7.90-7.98 (m, 2H), 7.87 (s, 1H), 7.80 (d, J=8.6 Hz, 1H), 5.18 (t, J=7.9 Hz, 1H), 5.05 (t, J=8.1 Hz, 1H), 3.63-3.72 (m, 1H), 3.52-3.63 (m, 3H), 2.61-2.77 (m, 2H), 2.45-2.58 (m, 2H), 2.33-2.43 (m, 2H), 2.20-2.33 (m, 2H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:14]([NH:15][C:16]2[N:21]=[C:20]([N:22]([CH:32]3[CH2:34][CH2:33]3)CC3C=CC(OC)=CC=3)[C:19]3=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:18]3[N:17]=2)=[CH:13][C:12]([C:40]#[N:41])=[CH:11][C:10]=1[N:42]1[CH2:47][CH2:46][C@@H:45]([NH:48]C(=O)OC(C)(C)C)[C@H:44]([O:56][Si:57]([CH:64]([CH3:66])[CH3:65])([CH:61]([CH3:63])[CH3:62])[CH:58]([CH3:60])[CH3:59])[CH2:43]1.C1(OC)C=CC=CC=1>ClCCl>[NH2:48][C@@H:45]1[CH2:46][CH2:47][N:42]([C:10]2[C:9]([Cl:8])=[C:14]([NH:15][C:16]3[N:21]=[C:20]([NH:22][CH:32]4[CH2:33][CH2:34]4)[C:19]4=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:18]4[N:17]=3)[CH:13]=[C:12]([C:40]#[N:41])[CH:11]=2)[CH2:43][C@H:44]1[O:56][Si:57]([CH:61]([CH3:63])[CH3:62])([CH:64]([CH3:66])[CH3:65])[CH:58]([CH3:59])[CH3:60]
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CC[C@@H](NC(=O)OC(C)(C)C)[C@H](O[Si](C(C)C)(C(C)C)C(C)C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[Si](O[C@@H]1CN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CC[C@H]1N)(C(C)C)C(C)C
Temperature: 30 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
TFA (1 mL, 3.24 mmol) was added to a solution of tert-butyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-((triisopropylsilyl)oxy)piperidin-4-yl)carbamate (184 mg, 0.219 mmol) and anisole (20 μl, 0.183 mmol) in dichloromethane (1 mL) and the reaction solution was stirred at 30° C. overnight. LCMS showed completion of reaction. The reaction mixture was diluted with dichloromethane and washed with cold saturated sodium bicarbonate/1N aqueous sodium hydroxide (pH 10), the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g column, eluting with 1-4% methanol/dichloromethane). 2-((3-((3R,4R)-4-amino-3-((triisopropylsilyl)oxy)piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (126 mg) was obtained as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].I[CH:11]([CH3:13])[CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH:11]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6])([CH3:13])[CH3:12]
Reactant: CC(C)I
Reactant: OCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1cccc(CO)c1
Temperature: 85 °C
Yield: 123.4 %

Procedure:
A mixture of 3-hydroxybenzyl alcohol (2.00 g, 0.014 mol), 2-iodopropane (2.4 ml, 8.29 mmol), cesium carbonate (8.00 g, 0.0246 mol) in DMF (10 ml) was heated at 85° C. for 8 h. The reaction was diluted with water (100 ml) and extracted with DCM (30 ml) and this was washed with water (2×30 ml). The product was chromatographed on silica using DCM:methanol (19:1) to afford 3-isopropoxybenzyl alcohol (1.70 g, 73%) as an orange liquid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:22]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[S:14][C:13]=3[C:12]([O:23]C(=O)OC(C)(C)C)=[CH:11][CH:10]=2)O1.Cl[C:33]1[O:34][C:35]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[CH:36][C:37](=[O:39])[CH:38]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[OH:23][C:12]1[C:13]2[S:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:21][C:22]=2[C:9]([C:33]2[O:34][C:35]([N:40]3[CH2:41][CH2:42][O:43][CH2:44][CH2:45]3)=[CH:36][C:37](=[O:39])[CH:38]=2)=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)Oc1ccc(B2OC(C)(C)C(C)(C)O2)c2c1Sc1ccccc1C2
Reactant: O=c1cc(Cl)oc(N2CCOCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=c1cc(-c2ccc(O)c3c2Cc2ccccc2S3)oc(N2CCOCC2)c1
Temperature: 90 °C
Yield: 18.9 %

Procedure:
Carbonic acid tert-butyl ester 1-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-9H-thioxanthen-4-yl ester (3.00 g, 6.81 mmol), 2-chloro-6-morpholin-4-yl-pyran-4-one (1.22 g, 5.67 mmol) and potassium carbonate (2.07 g, 14.98 mmol) were suspended in anhydrous dioxane (6 ml) under nitrogen atmosphere. The solution was degassed for 15 minutes. To the solution tetrakis(triphenylphosphino) palladium (291 mg, 5% eq.) was added. The mixture was degassed for a further 5 minutes. The reaction was heated at 90° C. under nitrogen atmosphere for 24 hours. The solvent was evaporated in vacuo and the crude mixture was purified by column chromatography (9:1, ethyl acetate/ethanol), to yield the title compound (421 mg, 16%) as a light yellow amorphous solid. 1H NMR (300 MHz, DMSO-d6): δH=3.33 (4H, t), 3.67 (4H, t), 3.88 (2H, s), 5.45 (1H, d), 6.05 (1H, d), 6.87 (1H, d), 7.24–7.65 (5H, m), 10.62 (1H, bs); m/z (LC-MS, ESP), RT=3.96 min, (M++1)=394.
Reaction SMILES: CO[C:3]([C:5]1[S:28][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][C@H:22]3[CH2:27][CH2:26][CH2:25][O:24][CH2:23]3)[C:7]=2[C:6]=1[CH3:29])=[O:4].[CH3:30][N:31]([CH3:36])[CH2:32][CH2:33][CH2:34][NH2:35]>>[CH3:30][N:31]([CH3:36])[CH2:32][CH2:33][CH2:34][NH:35][C:3]([C:5]1[S:28][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][C@H:22]3[CH2:27][CH2:26][CH2:25][O:24][CH2:23]3)[C:7]=2[C:6]=1[CH3:29])=[O:4]
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCOC3)c2c1C
Reactant: CN(C)CCCN
Product: Cc1c(C(=O)NCCCN(C)C)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCOC3)c12

Procedure:
Prepared analogously to example 10.4 from 4-{4-fluoro-2-[(S)-(tetrahydro-pyran-3-yl)oxy]-phenylamino}-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester and N,N-dimethyl-1,3-propanediamine.
Reaction SMILES: [Mg].BrCCBr.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[CH3:17][C:18]([CH3:20])=[O:19]>C1COCC1>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([C:18]([OH:19])([CH3:20])[CH3:17])=[CH:8][CH:9]=1
Reactant: CC(C)=O
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(C(F)(F)F)cc1
Reaction time: 0.75 h

Procedure:
To magnesium turnings (30.2 g, 1.24 mol) in THF (30 mL) is added 1,2-dibromoethane (0.7 mL) followed by dropwise addition, over 1 h, of 4-bromotrifluoromethylbenzene (200 g, 0.89 mol) dissolved in THF (700 mL). The reaction is heated occasionally to maintain a gentle reflux and is stirred 45 min after the addition is complete. The dark reaction mixture is then cooled in an ice bath and acetone (103 g, 1.78 mol) added dropwise. After stirring an additional 1.5 h the reaction is carefully quenched with aqueous saturated NaHSO4, ethyl acetate added, the organics dried over MgSO4, concentrated and purified by silica gel chromatography (9:1 to 3:2, hexane to ethyl acetate) to give 4-trifluoromethyl-α,α-dimethylbenzyl alcohol of sufficient purity to carry to the next step; yield: 114 g (63%).
Reaction SMILES: [N:1]([C@H:4]([C@H:14]1[O:18][C:17](=[O:19])[C@H:16]([CH:20]([CH3:22])[CH3:21])[CH2:15]1)[CH2:5][O:6]CC1C=CC=CC=1)=[N+]=[N-].[ClH:23].O1CCOCC1.[H][H]>C(O)C.[C].[Pd]>[ClH:23].[NH2:1][C@H:4]([C@H:14]1[O:18][C:17](=[O:19])[C@H:16]([CH:20]([CH3:22])[CH3:21])[CH2:15]1)[CH2:5][OH:6]
Reactant: [H][H]
Reactant: CC(C)[C@@H]1C[C@@H]([C@H](COCc2ccccc2)N=[N+]=[N-])OC1=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)[C@@H]1C[C@@H]([C@@H](N)CO)OC1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A suspension of 10.12 g of (3S,5S)-5-[(S)-1-azido-2-benzyloxyethyl]-3-isopropyldihydrofuran-2-one obtained in Example (1e) (33.5 mmol), 16.7 ml of a solution of 4 N hydrochloric acid in dioxane (66.8 mmol) and 3.57 g of 10% palladium-carbon (50% wet) in ethanol (170 ml) was stirred under a hydrogen atmosphere at room temperature for six hours. Hydrogen in the reaction vessel was replaced by nitrogen, and then the reaction mixture was diluted with 170 ml of ethanol. Palladium-carbon was separated by filtration and washed with ethanol. The solvent was evaporated from the filtrate under reduced pressure to obtain 8.50 g of crude (3S,5S)-5-[(S)-1-amino-2-hydroxyethyl]-3-isopropyldihydrofuran-2-one hydrochloride.