Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:8][N:9]1[CH2:20][CH2:19][N:18]2[CH2:21][CH:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=3)[CH2:23][N:12]([CH2:13][CH2:14][N:15]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:16][CH2:17]2)[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>C(O)C.[Pd]>[C:35]([CH2:34][N:15]1[CH2:14][CH2:13][N:12]2[CH2:23][CH:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=3)[CH2:21][N:18]([CH2:19][CH2:20][N:9]([CH2:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:10][CH2:11]2)[CH2:17][CH2:16]1)([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36]
Reactant: CC(C)(C)OC(=O)CN1CCN2CCN(CC(=O)OC(C)(C)C)CCN(CC1)CC(Cc1ccc([N+](=O)[O-])cc1)C2
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CN1CCN2CCN(CC(=O)OC(C)(C)C)CCN(CC1)CC(Cc1ccc(N)cc1)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.9 %

Procedure:
To a solution of compound 31 (4.18 g, 7.26 mmol) in ethanol (100 mL) was added 10% Pd/C (1.25 g). The resulting mixture was stirred under H2 (g) atmosphere at room temperature for 12 hours. The reaction mixture was filtered through a celite pad and washed with ethanol (2×20 mL). The combined filtrate was evaporated in vacuo to give an oily residue which was triturated with Et2O to provide an off-white solid 32 (3.88 g, 98% yield).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=O.[NH2:8][C:9]1[CH:10]=[C:11]([C:26]2[CH:31]=[CH:30][C:29]([C@@H:32]([OH:36])[CH:33]([F:35])[F:34])=[CH:28][CH:27]=2)[CH:12]=[C:13]([NH:15][C:16]2[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=2)[CH:14]=1.C([BH3-])#N.[Na+].FC(F)(F)C=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[F:34][CH:33]([F:35])[C@@H:32]([C:29]1[CH:28]=[CH:27][C:26]([C:11]2[CH:12]=[C:13]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[CH:18][N:17]=3)[CH:14]=[C:9]([NH:8][CH2:3][C:2]([F:7])([F:6])[F:1])[CH:10]=2)=[CH:31][CH:30]=1)[OH:36]
Reactant: Nc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc([C@@H](O)C(F)F)cc2)c1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: O=CC(F)(F)F
Agent: [BH3-]C#N
Solvent: ClCCl
Product: O[C@H](c1ccc(-c2cc(NCC(F)(F)F)cc(Nc3nccc(C(F)(F)F)n3)c2)cc1)C(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a cooled (0° C.) mixture of (1R)-1-(3′-amino-5′-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-4-yl)-2,2-difluoroethanol (100 mg, 0.244 mmol) and sodium cyanoborohydride (30.6 mg, 0.487 mmol) in dichloromethane (0.5 mL) at 0° C. Trifluoroacetaldehyde (85 mg, 0.731 mmol) was added to the reaction mixture, and then stirred at room temperature for 3 hours. Aqueous sodium carbonate was added to the reaction mixture, extracted with ethyl acetate and the combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes) to give (1R)-2,2-difluoro-1-(3′-[(2,2,2-trifluoroethyl)amino]-5′-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-4-yl)ethanol as a yellow solid. MS ESI calc'd. for C21H17F8N4O [M+H] 493. found 493. 1H NMR (400 MHz, CDCl3): δ 8.66 (d, J=5.0 Hz, 1H); 7.70 (s, 1H); 7.63 (d, J=8.0 Hz, 2H); 7.52 (d, J=8.0 Hz, 2H); 7.39 (s, 1H); 7.13 (s, 1H); 7.08 (d, J=5.0 Hz, 1H); 6.65 (s, 1H); 5.83 (td, J=56.0, 4.8 Hz, 1H); 4.91 (td, J=10.1, 4.8 Hz, 1H); 3.87 (q, J=8.9 Hz, 2H).
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[F:6][C:7]1[CH:13]=[C:12](I)[CH:11]=[CH:10][C:8]=1[NH2:9]>C1COCC1.[Cl-].[Cl-].[Zn+2].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>[CH2:2]([C:12]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([F:6])[CH:13]=1)[CH2:3][CH2:4][CH3:5]
Reactant: [Li]CCCC
Reactant: Nc1ccc(I)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCCCc1ccc(N)c(F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 29.1 %

Procedure:
ZnCl2 (5.17 g, 38.0 mmol) was weighed into a flask, which was then flame dried and flushed with N2. Anhydrous THF (20 ml) was then added at 0° C., followed by 2.5 M nBuLi (15.2 ml, 38.0 mmol). The reaction mixture was stirred at 0° C. for 15 min, after which 2-fluoro-4-iodoaniline (3.00 g, 12.7 mmol) in anhydrous THF (10 ml) and Pd(PPh3)4 (0.74 g, 0.64 mmol) were added sequentially. The mixture was allowed to warm to RT and stirred for a further 6 h. The mixture was poured into ice/Et2O, the organic layer separated and the aqueous layer further extracted with Et2O. The combined organic fractions were washed with sat. NaHCO3, dried (Na2SO4) and concentrated under reduced pressure. The resulting solid was removed from the mixture by filtration and the filtrate purified by flash chromatography on silica (12.5% EtOAc/Hexane as eluant) to give the desired product (30%, 3.7 mmol). 1H NMR [400 MHz, CDCl3] δ 6.80 (dd, J=12.1, 1.8 Hz, 1 H), 6.76–6.65 (m, 2 H), 3.65 (br s, 2 H), 2.49 (t, J=7.7 Hz, 2 H), 1.57–1.49 (m, 2 H), 1.32 (sextet, J=7.3 Hz, 2 H), 0.91 (t, J=7.3 Hz, 3 H). LCMS (ACPI+) 168 (100%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[CH:9]([CH:16]3[CH2:18][CH2:17]3)[O:8][C:6]=2[CH:7]=1.[C:19]([O:23][C:24](=[O:33])[NH:25][C@@H:26]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:27][OH:28])([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:19]([O:23][C:24](=[O:33])[NH:25][C@@H:26]([CH2:29][CH:30]([CH3:31])[CH3:32])[CH2:27][O:28][C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[CH:9]([CH:16]3[CH2:18][CH2:17]3)[O:8][C:6]=2[CH:7]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Clc1ccc2c(c1)OC(C1CC1)c1cnccc1-2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CC(C)C[C@@H](COc1ccc2c(c1)OC(C1CC1)c1cnccc1-2)NC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 53.4 %

Procedure:
To a stirred solution of 8-chloro-5-cyclopropyl-5H-chromeno[3,4-c]pyridine (275 mg, 1.067 mmol) in toluene (3 mL) was added (S)-tert-butyl(1-hydroxy-4-methylpentan-2-yl)carbamate (696 mg, 3.20 mmol), cesium carbonate (427 mg, 1.310 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (272 mg, 0.640 mmol) and palladium (II) acetate (71.9 mg, 0.320 mmol). Nitrogen was bubbled through the reaction mixture for 10 min then the mixture was heated at 80° C. for 12 h. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with brine (1×15 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified via silica gel chromatography (ethyl acetate/pet ether) to give tert-butyl-(2S)-1-(5-cyclopropyl-5H-chromeno[3,4-c]pyridin-8-yloxy)-4-methylpentan-2-ylcarbamate (250 mg, 0.57 mmol, 50% yield). LCMS (ESI) m/e 439.2 [(M+H)+, calcd for C26H35N2O4 439.3]; LC/MS retention time (Method C): tR=2.16 min.
Reaction SMILES: C([N:4]1[CH2:9][C:8](=[O:10])[N:7]([C:11](=[O:13])[CH3:12])[CH2:6][C:5]1=[O:14])(=O)C.[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:17]=1[CH:18]=O.C(N(CC)CC)C>CN(C=O)C>[C:11]([N:7]1[CH2:6][C:5](=[O:14])[NH:4]/[C:9](=[CH:18]\[C:17]2[C:16]([Cl:15])=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:24])/[C:8]1=[O:10])(=[O:13])[CH3:12]
Reactant: CC(=O)N1CC(=O)N(C(C)=O)CC1=O
Reactant: O=Cc1c(Cl)cccc1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CC(=O)N/C(=C\c2c(Cl)cccc2Cl)C1=O
Yield: 40 %

Procedure:
1,4-Diacetyl-2,5-piperazinedione prepared by the published procedure mentioned in Reference Example 3, was stirred in DMF with 2,6-dichlorobenzaldehyde and triethylamine and heated to 120°-130° C. for 1-3 h. The title compound was obtained with a yield of 40%.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[C@H:6]([C:15](=[O:23])[N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])[O:5][C:4]([C:24]([O:26]C)=[O:25])=[CH:3]1.C(N(CC)CC)C>O>[NH2:1][C@@H:2]1[C@@H:7]([NH:8][C:9](=[O:14])[C:10]([F:12])([F:11])[F:13])[C@H:6]([C:15](=[O:23])[N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])[O:5][C:4]([C:24]([OH:26])=[O:25])=[CH:3]1
Reactant: CCCN(CCC)C(=O)[C@@H]1OC(C(=O)OC)=C[C@H](N)[C@H]1NC(=O)C(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)[C@@H]1OC(C(=O)O)=C[C@H](N)[C@H]1NC(=O)C(F)(F)F
Temperature: 50 °C
Yield: 100.6 %

Procedure:
A mixture of (4S,5R,6R)-4-amino-6-(dipropylcarbamoyl)-5-(2,2,2-trifluoroacetylamino)-5,6-dihydro-4H-pyran-2-carboxylic acid, methyl ester (0.34 g), triethylamine (1 ml) and water (2 ml) was heated at 50° C. for 2 hours. The solvent was removed in vacuo and the residue was co-evaporated with dioxane (×3) to afford the title compound as a white solid (330 mg). 1H NMR (250 MHz, D6 -DMSO) 9.40 (1H, s), 5.56 (1H, d, J=3 Hz), 4.70 (1H, d, J=9 Hz), 4.15 (1H, m), 3.85 (2H, m), 3.38 (2H, m), 3.15 (2H, m), 2.84 (2H, m), 1.47 (2H, m), 1.30 (2H, m), 0.72 (6H, m). Mass analysis: C15H22F3N3O5. 1.25 H2O. Required: C, 44.61; H, 6.11; N, 10.40. Found: C, 44.61; H, 6.10; N, 10.13.
Reaction SMILES: [S:1](S([O-])=O)([O-:4])(=[O:3])=[O:2].[Na+:8].[Na+].[S:10]([O-:13])([O-:12])=[O:11].[Na+].[Na+].[H][H]>O>[S:1]([O-:4])([O-:3])=[O:2].[Na+:8].[Na+:8].[S:10](=[O:11])([OH:13])[O-:12]
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: [H][H]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=S([O-])O

Procedure:
An aqueous solution of sodium sulfite and bisulfite was prepared by mixing 38.8 lbs of sodium metabisulfite and 17.0 lbs of sodium sulfite with 88.2 lbs of water. The salt solution was metered into the recycle loop at a rate of 7.6 lbs per hour. Simultaneously a glyceryl epoxide wherein R is normal alkyl of 12 to 15 carbon atoms, R' is hydrogen and n is average value of 1 according to Formula 1 was metered into the recycle loop at a rate of 10.0 lbs/hour. The recycle loops residence time was thirty minutes. At steady state, the temperature maintained in the recycle loop was 160° C. and the pressure was 100 psig. The residence times were varied in sequential runs by increasing the metering rates of the reactants proportionately to achieve residence times of 15, 10 and 5 minutes.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12](B(O)O)=[CH:11][C:10]=3[CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)S(O[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH2:30][N:29]([CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:28][CH2:27]2)(=O)=O.C(N(CC)CC)C>C(O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:1]1([C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([C:24]4[CH:25]=[C:26]5[C:31](=[CH:32][CH:33]=4)[CH2:30][N:29]([CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:28][CH2:27]5)=[CH:11][C:10]=3[CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CCN1CCc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Reactant: OB(O)c1cc2cc(C3CCCC3)ccc2o1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCN1CCc2cc(-c3cc4cc(C5CCCC5)ccc4o3)ccc2C1
Yield: 33.2 %

Procedure:
A mixture of 5-cyclopentylbenzofuran-2-ylboronic acid (78 mg, 0.34 mmol), tert-butyl 3-(6-(trifluoromethylsulfonyloxy)-3,4-dihydroisoquinolin-2(1H)-yl)propanoate (93 mg, 0.23 mmol), triethylamine (0.95 mL, 6.8 mmol) and bis(triphenylphosphine) palladium(II) chloride (16 mg, 0.02 mmol) in ethanol (5 mL) was irradiated in a microwave instrument at 100° C. for 20 min. The reaction mixture was cooled, and the solvent was removed. The residue was purification by silica gel chromatography on ISCO system yielding the title compound (34 mg, 34% yield). 1H NMR (400 MHz, CDCl3) δ 7.59 (m, 2H), 7.40 (d, 2H), 7.15 (dd, 1H), 7.07 (d, 1H), 6.91 (s, 1H), 3.70 (s, 2H), 3.08 (m, 1H), 2.96 (dd, 2H), 2.85 (dd, 2H), 2.78 (dd, 2H), 2.54 (dd, 2H), 2.11 (m, 2H), 1.84 (m, 2H), 1.68 (m, 4H), 1.46 (s, 9H). MS (ESI) m/z: Calculated: 445.26; Observed: 446.00 (M++1).
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.Cl[C:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:11].C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>ClCCl>[O:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:10](=[O:11])[O:12][C:13]2[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)[CH2:4][CH2:3]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NC1CCOCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCOCC1)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 85.5 %

Procedure:
To a solution of 5.00 g (36.3 mmol) of tetrahydro-2H-pyran-4-yl-amine hydrochloride (CAS 38041-19-9) in 300 ml of dichloromethane, cooled to −15° C. are added portionwise 13.2 g (65.4 mmol) of 4-nitrophenyl chloroformate (CAS 7693-46-1) and then 12.7 ml (72.7 mmol) of diisopropylethylamine. Stirring is continued at −0° C. for 2 hours, and 20 ml of saturated aqueous sodium hydrogen carbonate solution are then added. The organic phase is separated out by settling and dried over sodium sulfate and the solvent is evaporated off under reduced pressure. The residue is purified by chromatography on a column 80 g of silica gel, eluting with a mixture of 20% acetone in dichloromethane, to give 8.26 g of 4-nitrophenyl tetrahydro-2H-pyran-4-ylcarbamate in the form of a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12](N)=[O:13])=[N:9][C:8]([O:15][CH3:16])=[CH:7][CH:6]=2>O1CCCC1.Cl.C1([Zr]C2C=CC=C2)C=CC=C1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]=[O:13])=[N:9][C:8]([O:15][CH3:16])=[CH:7][CH:6]=2
Reactant: COc1ccc2ncc(Cl)c(C(N)=O)c2n1
Agent: C1=CC([Zr]C2C=CC=C2)C=C1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc2ncc(Cl)c(C=O)c2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.6 %

Procedure:
Bis(cyclopentadienyl)zirconium hydrochloride (814 mg, 3.2 mmol, 1.5 eq) is added at room temperature to a stirred solution of 3-chloro-6-methoxy-[1,5]naphthyridine-4-carboxylic acid amide (500 mg, 2.1 mmol, 1.0 eq) in tetrahydrofuran (35 mL). After 10 minutes stirring at room temperature, the reaction mixture is filtered through decalite, concentrated and purified by column chromatography (silica gel, eluent: ethyl acetate:petroleum ether, 1:8, v/v) to afford 3-chloro-6-methoxy-[1,5]naphthyridine-4-carbaldehyde as an off-white solid (185 mg, 28% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[N:38]1([CH2:44][CH2:45][OH:46])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:37])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:41]3[CH2:42][CH2:43][N:38]([CH2:44][CH2:45][OH:46])[CH2:39][CH2:40]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:31])[CH3:32])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: OCCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)O)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)O)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCO)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazin-1-yl-ethanol (Chemical Dynamics) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 30% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C35H43N4O4Cl2 [(M+H)+] 653.2656, observed 653.2657.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH2:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:16]#[C:17][NH2:18].Cl.[OH-].[Na+]>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:15][C:17]([NH2:18])=[NH:16])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(OCc2ccccc2)c1
Reactant: N#CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: N=C(N)Nc1cccc(OCc2ccccc2)c1
Temperature: 80 °C
Yield: 98.4 %

Procedure:
To a suspension of 3-benzyloxyphenylamine (20.0 g, 100.35 mmol) in 1,4-dioxane (150 mL) was added cyanamide (7.39 g, 175.95 mmol followed by 4M HCl in 1,4-dioxane (44 ml, 176.00 mmol). The resulting suspension was heated at 80° C. overnight then cooled to ambient temperature and 6N NaOH (35 ml, 210.00 mmol) was added. The volume of solution was reduced to 50 ml in vacuo and the resulting precipitate was collected by filtration. The solid product was dried under vacuum overnight to afford 23.8 g in 98.4% yield. 1H NMR (MeOH-d4) δ 6.4–7.5 (m, 9H), 5.1 (s, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([CH2:13][O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:20]([OH:22])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:26]=1[C:27]([NH:29][CH3:30])=[O:28]>>[F:35][C:32]1[CH:33]=[CH:34][C:25]([CH2:24][NH:23][C:20]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:16][CH2:15][O:14][CH2:13]3)=[O:22])=[C:26]([C:27](=[O:28])[NH:29][CH3:30])[CH:31]=1
Reactant: O=C(O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2
Reactant: CNC(=O)c1cc(F)ccc1CN
Product: CNC(=O)c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2

Procedure:
The title compound can be prepared from intermediate 7, 3-(benzyloxy)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylic acid and intermediate 39, 2-(aminomethyl)-5-fluoro-N-methylbenzamide. White crystals; mp 189–190° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.01 (3H, d, J=4.5 Hz, NCH3), 4.00 (2H, m, CH2), 4.08 (1H, m, CH), 4.50 (2H, d, J=6.6 Hz, NCH2), 4.71 (2H, s, OCH2), 5.38 (2H, s, OCH2), 6.88 (1H, broad q, NH), 7.07 (1H, m, aromatic), 7.16 (1H, dd, J=2.5 Hz and J=8.6 Hz, aromatic), 7.30–7.44 (6H, m, aromatics), 8.55 (1H, broad t, NH). Anal. Calcd for C24H23FN4O5: C, 61.80; H, 4.97; N, 12.01. Found: C, 61.84; H, 4.82; N, 12.00.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[C:10]1[N:15]=[CH:14][C:13]2[O:16][C:17]3[C:22]([C@@:23]4([CH2:28][CH2:27][O:26][C:25]([NH2:29])=[N:24]4)[C:12]=2[CH:11]=1)=[CH:21][C:20]([NH2:30])=[CH:19][CH:18]=3.[O:31]1[CH2:36][CH2:35][CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH2:32]1>O1CCOCC1.O>[O:31]1[CH2:36][CH2:35][CH:34]=[C:33]([C:10]2[N:15]=[CH:14][C:13]3[O:16][C:17]4[C:22]([C@@:23]5([CH2:28][CH2:27][O:26][C:25]([NH2:29])=[N:24]5)[C:12]=3[CH:11]=2)=[CH:21][C:20]([NH2:30])=[CH:19][CH:18]=4)[CH2:32]1
Reactant: CC1(C)OB(C2=CCCOC2)OC1(C)C
Reactant: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1cnc(Cl)cc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1cnc(C3=CCCOC3)cc12
Temperature: 120 °C
Yield: 74.8 %

Procedure:
A microwave reaction vessel was charged with potassium phosphate (tribasic) (0.670 g, 3.16 mmol), (S)-3-chloro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (0.2 g, 0.631 mmol), and 2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.398 g, 1.894 mmol) in dioxane (4 ml) and water (2 ml). The vessel was capped and the solution was purged with nitrogen for 10 minutes. Next, bis[di-tert-butyl(4 dimethylaminophenyl)phosphine]dichloropalladium(II) (0.022 g, 0.032 mmol) was added and the vessel was sealed. The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 120° C. for 35 minutes. The reaction was poured into water and the mixture was extracted with EtOAc. The combined organic extracts were washed with saturated aqueous sodium chloride and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel chromatography by eluting with 20:1 solution of DCM to a 2M solution of NH3 in MeOH, to provide (S)-3-(5,6-dihydro-2H-pyran-3-yl)-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (0.172 g, 0.472 mmol, 74.8% yield) as an off-white solid.
Reaction SMILES: [FH:1].[O:2]1[C:4]2([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:3]1[C:9]#[N:10].C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1.ClCCl>[F:1][C:4]1([CH:3]([OH:2])[C:9]#[N:10])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: N#CC1OC12CCCC2
Reactant: F
Agent: *CC*
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#CC(O)C1(F)CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.1 %

Procedure:
Anhydrous dichloromethane (3 mL) and a 70% w/w solution of hydrogen fluoride (2.68 mL, 20.44 mmol) in pyridine are mixed in a polyethylene bottle at 0° C. under a nitrogen atmosphere. A solution of 1-oxa-spiro[2.4]heptane-2-carbonitrile (3.30 g, 26.76 mmol) in anhydrous dichloromethane (3.2 mL) is added slowly. The reaction is stirred at 0° C. for 1 h and at room temperature for 1 h. The mixture is cooled at 0° C. and a saturated solution of sodium carbonate is added carefully. The aqueous layer is extracted with diethyl ether. The organic layers are combined, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent is removed. The residue is purified by chromatography in a 20 g silica gel cartridge eluting with hexane:diethyl ether (100:0 to 80:20) to obtain 1.7 g of desired compound as a colourless oil. 1H NMR (CDCl3) δ (ppm): 4.47 (d, 1H), 3.50 (bs, 1H), 2.12-1.67 (m, 8H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH:3]=1.FC(F)(F)C(O)=O.[Cl:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[CH:31]=[C:30]([S:35]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)(=[O:37])=[O:36])[CH:29]=[CH:28]2>>[ClH:24].[Cl:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[CH:31]=[C:30]([S:35]([N:38]1[CH2:39][CH2:40][N:41]([C:12](=[O:14])[C:11]3[CH:10]=[CH:9][C:8]([C:4]4[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=4)=[CH:16][CH:15]=3)[CH2:42][CH2:43]1)(=[O:36])=[O:37])[CH:29]=[CH:28]2
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: O=C(O)c1ccc(-c2cccnc2)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(-c2cccnc2)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1

Procedure:
In a similar manner to Example 4 except for the use of 4-(3-pyridyl)benzoic acid hydrochloride and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine trifluoroacetate as the raw materials, the reaction was conducted, whereby the title compound was obtained as a colorless solid.