Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN1CCOCC1>CO>[CH2:21]([NH:28][S:17]([C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:3]3[C:4]([CH3:7])=[N:5][NH:6][C:2]=3[NH2:1])[S:9][C:10]=2[CH:16]=1)(=[O:19])=[O:18])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Solvent: CN1CCOCC1
Solvent: CO
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCc3ccccc3)cc2s1
Yield: 13.4 %

Procedure:
the title compound (16 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), benzylamine (66 μL, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 400.5 (M+1, 100%). Yield=13%.
Reaction SMILES: [CH:1]1([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[C:19](=[O:34])[CH2:20][NH:21][CH2:22][CH2:23][O:24][C@@H:25]2[CH2:29][CH2:28][CH2:27][C@@H:26]2[O:30]COC)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CCOC(C)=O>CO>[CH:1]1([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[C:19](=[O:34])[CH2:20][NH:21][CH2:22][CH2:23][O:24][C@H:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[OH:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCO[C@H]1CCC[C@H]1OCCNCC(=O)N1CCc2ccc(OC)cc2C1C1CCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc2c(c1)C(C1CCCCC1)N(C(=O)CNCCO[C@H]1CCC[C@H]1O)CC2
Temperature: 60 °C
Reaction time: 5 h
Yield: 83.8 %

Procedure:
2-(1-cyclohexyl-7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-N-(2-{[cis-2-(methoxymethoxy)cyclopentyl]oxy}ethyl)-2-oxoethanamine (500 mg) was dissolved in MeOH (8 mL). To the reaction liquid was added 4 M HCl/EtOAc (0.8 mL) under ice-cooling, followed by stirring at 60° C. for 5 hours. The solvent was evaporated and saturated aqueous sodium bicarbonate was added to the resulting residue, followed by extraction with chloroform. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform-MeOH) to obtain cis-2-(2-{[2-(1-cyclohexyl-7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]amino}ethoxy)cyclopentanol (380 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:12])[N:8]=[C:7]2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[OH:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:12][C:9]1[N:8]=[C:7]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:6]2[C:11](=[C:2]([C:24]3[CH:25]=[C:20]([OH:19])[CH:21]=[CH:22][CH:23]=3)[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: Clc1nc(N2CCOCC2)c2cccc(Br)c2n1
Reactant: OB(O)c1cccc(O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1cccc(-c2cccc3c(N4CCOCC4)nc(Cl)nc23)c1
Temperature: 95 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
To a 50 mL round bottom flask, 8-bromo-2-chloro-4-morpholin-4-yl-quinazoline (150 mg, 0.00046 mol), 3-hydroxyphenylboronic acid (57 mg, 0.00041 mol), sodium carbonate (97 mg, 0.00091 mol), DMF (10 mL) and water (5 mL) were added. The reaction mixture was degassed with nitrogen for 5-10 min. To the same flask Pd(PPh3)2Cl2 (16 mg, 0.000022 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude residue. The crude product was purified using column chromatography (60-120 silica gel, 1% MeOH in chloroform) to yield the desired title product (85 mg, 46%). 1H NMR: (300 MHz, CDCl3): δ 7.70-7.78 (m, 2H), 7.40-7.44 (m, 1H), 7.20-7.26 (m, 1H), 7.03-7.05 (m, 2H), 6.78-6.83 (m, 1H), 3.81-3.83 (m, 8H); LC-MS (ESI): Calculated mass: 341.1; Observed mass: 342.1 [M+H]+ (RT: 1.53 min).
Reaction SMILES: ClC1C=C(C(OO)=[O:9])C=CC=1.[C:12]([Si:16]([CH3:26])([CH3:25])[O:17][C@:18]1([CH3:24])[CH2:23][CH2:22][CH2:21][CH:20]=[CH:19]1)([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[C:12]([Si:16]([CH3:26])([CH3:25])[O:17][C@:18]1([CH3:24])[CH2:23][CH2:22][CH2:21][C@@H:20]2[C@H:19]1[O:9]2)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)O[C@@]1(C)C=CCCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@]1(C)CCC[C@H]2O[C@H]21
Reaction time: 20 h

Procedure:
3-chlorobenzenecarboperoxoic acid (2.47 g, 11.00 mmol) was added in one portion to a stirred solution of (R)-tert-butyldimethyl(1-methylcyclohex-2-enyloxy)silane, 50b, (1.98 g, 8.87 mmol) and sodium hydrogen carbonate in 30 mL of dry dichloromethane at room temperature under nitrogen. The resulting mixture was stirred for 20 hours. Then, 25% sodium sulfite solution (30 mL) was added and the resulting biphasic mixture was stirred for 15 minutes. The 2 layers were separated and the aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic phases were washed with aqueous saturated NaHCO3, dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0-10% EtOAc-hexanes gradient) to provide 647 mg of compound 50c.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([OH:13])[C:7]=1[CH2:14][CH2:15][CH:16]1[O:21][C:20](=[O:22])[CH2:19][CH:18]([OH:23])[CH2:17]1.N1C=CC=CC=1>CCOCC>[C:1]([O:13][C:8]1[CH:9]=[C:10]([Cl:12])[CH:11]=[C:6]([Cl:5])[C:7]=1[CH2:14][CH2:15][CH:16]1[O:21][C:20](=[O:22])[CH2:19][CH:18]([OH:23])[CH2:17]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: O=C1CC(O)CC(CCc2c(O)cc(Cl)cc2Cl)O1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)Oc1cc(Cl)cc(Cl)c1CCC1CC(O)CC(=O)O1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Acetyl chloride (0.08 ml, 1.05 mmole) was added dropwise to a stirred solution of 6-[2-(2,4-dichloro-6-hydroxyphenyl)ethyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (300 mg, 1 mmole) and pyridine (0.09 ml, 1.05 mmole) in ether (10 ml) at 0° C. The ice bath was removed and the reaction mixture was stirred at 20° C. for 1 hour and then diluted with H2O (10 ml). The organic layer was separated and washed with 1 N HCl (10 ml), H2O (2×10 ml) and brine, dried over MgSO4, filtered and evaporated to provide the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([C:8]1[CH:9]=[N:10][C:11]([N+:17]([O-])=O)=[C:12]([O:14][CH2:15][CH3:16])[CH:13]=1)([OH:7])[CH3:6])[CH3:2].C([O-])=O.[NH4+].C1COCC1.CO>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4](=[O:20])[C:5]([C:8]1[CH:9]=[N:10][C:11]([NH2:17])=[C:12]([O:14][CH2:15][CH3:16])[CH:13]=1)([OH:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(O)c1cnc([N+](=O)[O-])c(OCC)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(O)c1cnc(N)c(OCC)c1
Yield: 74.2 %

Procedure:
A mixture of 2-(6-nitro-5-ethoxy-pyridin-3-yl)-2-hydroxy-propionic acid ethyl ester (1.3 g), ammonium formate (1.5 g), and 10% Pd/C (100 mg) was stirred in a 1:1 mixture of THF/methanol overnight. The reaction mixture was filtered through diatomaceous earth, and the filtrate evaporated to yield an oil. The oil was dissolved in EtOAc, washed with water and brine, and the organic layer separated and dried over magnesium sulfate. Evaporation furnished 863 mg of the title compound. LC/MS+=255.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH2:27][CH2:28][CH3:29])[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[CH:9]=C)[CH3:2].I([O-])(=O)(=O)=[O:31].[Na+].C(#N)C.O>CC(C)=O.[Os](=O)(=O)(=O)=O>[CH2:1]([C:3]1[N:4]=[C:5]([CH2:27][CH2:28][CH3:29])[N:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[CH:9]=[O:31])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1c(CC)nc(CCC)n(Cc2ccc(-c3ccccc3C#N)cc2)c1=O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(C)=O
Solvent: O
Product: CCCc1nc(CC)c(C=O)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 4 h
Yield: 64.1 %

Procedure:
To a solution of 4′-[(4-ethyl-6-oxo-2-propyl-5-vinylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (5.9 g) and sodium periodate (16 g) in acetone (100 mL)-acetonitrile (100 mL)-water (100 mL) was added osmium tetroxide (5 g, 7% polymer-bound catalyst), and the mixture was stirred for 4 hr. The insoluble material was filtered off through celite, and the filtrate was diluted with ethyl acetate, washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (3.8 g, 64%).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH:4]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[CH2:5][C:6](=[O:19])[N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH2:9][CH2:8]1.[OH-].[Na+].C(O)(=O)C>CO>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][CH:4]([CH2:5][C:6](=[O:19])[N:7]2[CH2:8][CH2:9][N:10]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)[CH2:11][CH2:12]2)[C:3]([OH:29])=[O:2])=[CH:26][CH:25]=1
Reactant: COC(=O)C(CC(=O)N1CCN(c2ccncc2)CC1)Cc1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(CC(CC(=O)N2CCN(c3ccncc3)CC2)C(=O)O)cc1
Reaction time: 6 h
Yield: 91.8 %

Procedure:
To a solution of 2-(4-methoxybenzyl)-4-oxo-4-(4-pyridin-4-ylpiperazin-1-yl)butanoic acid methyl ester (3.94 g) in methanol (30 ml) was added 2N sodium hydroxide (12 ml) and the solution was stirred for 6 hours. To the solution was added acetic acid (1.5 ml) and the reaction solution was concentrated. The concentrate was purified by CHP-20 column chromatography (H2O→30% acetonitrile aqueous solution) and recrystallized with acetone to give the titled compound (3.49 g) as a colorless crystal.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][CH2:10][C:11](O)=[O:12])[N:5]=[CH:4][C:3]=1[NH:14][C@@H:15]1[CH2:20][C@@H:19]2[CH2:21][C@@H:17]([C:18]2([CH3:23])[CH3:22])[C@H:16]1[CH3:24].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[C:44]1([CH:50]([NH2:52])[CH3:51])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][CH2:10][C:11]([NH:52][CH:50]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH3:51])=[O:12])[N:5]=[CH:4][C:3]=1[NH:14][C@@H:15]1[CH2:20][C@@H:19]2[CH2:21][C@@H:17]([C:18]2([CH3:23])[CH3:22])[C@H:16]1[CH3:24]
Reactant: CC(N)c1ccccc1
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CCC(=O)O)c(=O)c1Br)C2(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(NC(=O)CCn1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Br)c1=O)c1ccccc1
Yield: 94.7 %

Procedure:
3-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}propanoic acid (32 mg, 0.080 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31 mg, 0.160 mmol), 1-hydroxybenzotriazole anhydride (11 mg, 0.080 mmol) and triethylamine (22 μL, 0.160 mmol) in N,N-dimethylformamide (1 mL) were stirred with 1-phenylethylamine (20 μL, 0.160 mmol) at room temperature for 24 hours. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform/methanol=15/1) to give the desired product (38 mg, 95% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH:9]1[NH:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10]1.[H][H]>[Pt]=O.C(O)(=O)C>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][CH:9]1[NH:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C1CCCCC(CCc2ccccn2)N1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: O=C1CCCCC(CCC2CCCCN2)N1
Yield: 93.2 %

Procedure:
Example 296 A) A sample of the Hexahydro-7-[2-(2-pyridyl) ethyl]-1H-azepin-2-one product of Example 290b (2.4 g, 11 mmol), platinum oxide (500 mg) and glacial acetic acid (30 mL) were shaken on a Parr hydrogenator at 55 psi of hydrogen overnight. The contents were filtered and the filtrate was concentrated in vacuo. The residue was dissolved in water and adjusted to pH 9 with 2.5N NaOH. The aqueous solution was extracted with CH2Cl2 and the organic layer was dried over MgSO4 and concentrated in vacuo leaving hexahydro-7-[2-(2-piperidyl)ethyl]-1H-azepin-2-one as a white solid (2.3 g).
Reaction SMILES: Br[C:2]1[S:6][N:5]=[CH:4][CH:3]=1.Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:46])([CH3:45])[CH2:15][C:16]2[N:17]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:18]=[C:19]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[N:20]=2)=[CH:10][CH:9]=1.C[Sn](C)C.C[Sn](C)C>O1CCOCC1.O.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.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.[Pd]>[CH3:23][C:22]([CH3:25])([CH3:24])[CH2:21][C:19]1[N:20]=[C:16]([CH2:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:2]3[S:6][N:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)([OH:46])[CH3:45])[N:17]([C:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:18]=1
Reactant: CC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(C)(O)c2ccc(Br)cc2)n1
Reactant: Brc1ccns1
Agent: [Pd]
Agent: C[Sn](C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(C)(O)c2ccc(-c3ccns3)cc2)n1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
Palladium tetrakis(triphenylphosphine) (39 mg, 0.03 mmol) was added to a degassed, ambient temperature solution of 5-bromoisothiazole (55 mg, 0.34 mmol), 2-(4-bromophenyl)-1-[4-(2,2-dimethylpropyl)-1-trityl-1H-imidazol-2-yl]propan-2-ol (200 mg, 0.34 mmol) and hexamethylditin (110 mg, 0.34 mmol) in 1,4-dioxane (15 mL). After stirring at 90° C. for 16 h, the reaction mixture was diluted with water and extracted with ethyl acetate and methylene chloride. The combined organic extracts were concentrated in vacuo. Chromatography over silica eluting with 0-50% ethyl acetate/hexane afforded 1-[4-(2,2-dimethylpropyl)-1-trityl-1H-imidazol-2-yl]-2-(4-isothiazol-5-ylphenyl)propan-2-ol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:16](=[O:17])[C:15]([C:18]([OH:20])=[O:19])=[CH:14][N:6]3[CH2:7][CH2:8][N:9]([CH3:13])[C:10]([C:11]=1F)=[C:5]23.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:16](=[O:17])[C:15]([C:18]([OH:20])=[O:19])=[CH:14][N:6]3[CH2:7][CH2:8][N:9]([CH3:13])[C:10]([C:11]=1[N:25]1[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]1)=[C:5]23
Reactant: CN1CCn2cc(C(=O)O)c(=O)c3cc(F)c(F)c1c32
Reactant: CN1CCNCC1
Product: CN1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2N(C)CC4)CC1

Procedure:
Using 9,10-difluoro-1-methyl-7-oxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxylic acid and 4-methylpiperazine, the same procedure as in Production Example 1 was followed to yield the title compound.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C:22]([F:25])([F:24])[F:23])[C@@H:10]([NH:14]C(OC(C)(C)C)=O)[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:26]>CCOC(C)=O>[ClH:26].[NH2:14][C@H:10]([C@H:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:22]([F:24])([F:25])[F:23])[C:11]([OH:13])=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)[C@H](OCc1ccccc1)C(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H](C(=O)O)[C@H](OCc1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
To a solution of (2R,3S)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)-4,4,4-trifluorobutanoic acid (1.56 g, 4.2 mmol) in EtOAc (30 mL) was added EtOAc saturated with hydrogen chloride (30 mL) at 0° C. Then, the mixture was stirred at room temperature for 1.5 h. After concentration of the reaction mixture to about 15 mL, the white solid was collected by filtration and washed with EtOAc, dried in vacuum to give the title compound (2R,3S)-2-amino-3-(benzyloxy)-4,4,4-trifluorobutanoic acid hydrochloride salt (1.06 g, 84% for two steps). 1H NMR (400 MHz, CD3OD, δ in ppm) 7.32˜7.44 (m, 5H), 4.86 (d, J=2.0 Hz, 2H), 4.70 (dq, J=3.6, 6.6 Hz, 1H), 4.50 (d, J=3.6 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].II>C(OCC)C.C1(C)C=CC=CC=1.[Zn]>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[OH:12]
Reactant: CCOC(=O)CBr
Reactant: O=C1CCc2c(F)cc(F)cc21
Agent: II
Agent: [Zn]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1(O)CCc2c(F)cc(F)cc21
Reaction time: 24 h
Yield: 110.7 %

Procedure:
A mixture of 4,6-difluoro-1-indanone (12.6 g, 0.08 mol), ethyl bromoacetate (19.0 g, 0.11 mol, Aldrich), activated zinc powder (7.5 g, 0.11 mol, Aldrich; Org. Syn., Coll. Vol. 6, 290, 1988) and a few crystals of iodine in diethyl ether:toluene (1:1, 300 mL) was heated at 30-35° C. under a nitrogen atmosphere for 24 h. A few more crystals of iodine were added, the temperature was adjusted to 40-45° C., and the mixture was kept at that temperature for an additional 24 h. The reaction mixture was filtered and concentrated in vacuo. The residue was treated with a mixture of diethyl ether (450 mL), concentrated ammonium hydroxide (135 mL) and water (135 mL). The aqueous phase was separated and extracted with diethyl ether. The combined organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo to give 22.7 g of crude Ethyl 2-(4,6-difluoro-1-hydroxy-1-indanyl)acetate which was Chromatographed on silica gel with dichloromethane:hexanes (9:1) as eluent gave 12.7 g (66%) of a yellow oil; NMR (CDCl3): d 6.67-6.88 (m, 2H), 4.22 (q, 2H), 3.02 (m, 1H), 2.75 (2m's, 3H), 2.31 (m, 2H), 1.28 (t, 3H).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=[C:10](S(C)(=O)=O)[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.Cl.O1CCOCC1.C(=O)(O)[O-].[Na+]>O.CN1C(=O)CCC1>[CH:1]1([NH:7][C:8]2[C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=[C:10]([NH:31][C:30]3[CH:29]=[CH:28][C:27]([N:24]4[CH2:25][CH2:26][O:21][CH2:22][CH2:23]4)=[CH:33][CH:32]=3)[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CS(=O)(=O)c1ncc(C(N)=O)c(NC2CCCCC2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Solvent: O
Product: NC(=O)c1cnc(Nc2ccc(N3CCOCC3)cc2)nc1NC1CCCCC1
Temperature: 90 °C
Reaction time: 1 h
Yield: 13.4 %

Procedure:
A 6 ml portion of NMP solution containing 303 mg of 4-cyclohexylamino-2-(methylsulfonyl)pyrimidine-5-carboxamide was mixed with 1.05 ml of 1 M n-tetrabutylammonium fluoride/THF solution, followed by stirring at 90° C. for 1 hour. Next, this was mixed with 200 mg of 4-morpholinoaniline and 2.77 ml of 4 M hydrogen chloride/1,4-dioxane solution, followed by stirring at 90° C. for 3 hours. The reaction mixture was cooled down to room temperature, diluted with water, mixed with saturated sodium bicarbonate aqueous solution and then extracted with ethyl acetate-THF mixed solution. The organic layer was washed with saturated brine, and then the solvent was evaporated and the resulting residue was purified by a silica gel column chromatography (chloroform:methanol) to obtain 54 mg of 4-cyclohexylamino-2-[(4-morpholinophenyl)amino]pyrimidine-5-carboxamide as a pale brown solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:9][OH:10])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].[O:11]1CCC[CH2:12]1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(N(CC)CC)C>[C:4]([C:3]1([CH3:8])[CH2:9][O:10][C:12](=[O:11])[O:1][CH2:2]1)([O:6][CH3:7])=[O:5]
Reactant: C1CCOC1
Reactant: COC(=O)C(C)(CO)CO
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)C1(C)COC(=O)OC1
Temperature: -78 °C

Procedure:
In a 500 mL three neck RB flask were added methyl 2,2-bis(hydroxymethyl)propionate (12.45 g) and tetrahydrofuran (THF) (100 mL). The resulting mixture was stirred under nitrogen via a mechanical stirrer until a homogeneous solution results. Triphosgene (8.78 g) was added and the solution cooled to -78° C. Triethylamine (18.3 g) was slowly added to the cooled solution. The resulting mixture was stirred at this temperature for one hour and then allowed to warm to room temperature. The triethylamine/HCl salt was filtered off and the resulting filtrate pass through a shallow bed of silica gel. The filtrate was concentrated at reduced pressure and then dried under vacuum affording 13.4 g of product which had a small amount of contamination. This contamination was removed via washing with warm diethyl ether. 1H NMR (CDCl3) ppm: 4.67 (ab doublet, 2H), 4.20 (ab doublet, 2H), 3.77 (S, 3H), 1.30 (S, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:6]1[O:10][C:9]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:8]=2[O:7]1>>[CH2:2]([O:15][C:12]1[CH:13]=[CH:14][C:8]2[O:7][CH2:6][O:10][C:9]=2[CH:11]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCBr
Reactant: Oc1ccc2c(c1)OCO2
Product: CCCCOc1ccc2c(c1)OCO2

Procedure:
Starting from commercially available bromobutane and sesamol the title compound is obtained as colorless oil.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.BrC1C=CC2OCCN3C(CO)=C(I)N=C3C=2C=1.CC1NC=CN=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:61]1[CH:62]=[CH:63][C:64]2[O:70][CH2:69][CH2:68][N:67]3[C:71]([CH2:77][N:78]4[CH:82]=[CH:81][N:80]=[C:79]4[CH3:83])=[C:72]([C:74]([NH2:76])=[O:75])[N:73]=[C:66]3[C:65]=2[CH:84]=1.[CH3:85][C:86]([OH:90])([C:88]#[CH:89])[CH3:87]>O1CCCC1>[OH:90][C:86]([CH3:87])([CH3:85])[C:88]#[C:89][C:61]1[CH:62]=[CH:63][C:64]2[O:70][CH2:69][CH2:68][N:67]3[C:71]([CH2:77][N:78]4[CH:82]=[CH:81][N:80]=[C:79]4[CH3:83])=[C:72]([C:74]([NH2:76])=[O:75])[N:73]=[C:66]3[C:65]=2[CH:84]=1
Reactant: Cc1nccn1Cc1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Reactant: C#CC(C)(C)O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: Cc1ncc[nH]1
Agent: OCc1c(I)nc2n1CCOc1ccc(Br)cc1-2
Solvent: C1CCOC1
Product: Cc1nccn1Cc1c(C(N)=O)nc2n1CCOc1ccc(C#CC(C)(C)O)cc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 2 %

Procedure:
Di-tert-butyl azodicarboxylate (470 mg, 1.79 mmol, 1.50 equiv) in tetrahydrofuran (2 mL) was added dropwise to a stirred solution of (10-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-3-yl)methanol (500 mg, 1.19 mmol, 1.00 equiv)), 2-methyl-1H-imidazole (200 mg, 2.44 mmol, 2.00 equiv), and triphenylphosphine (400 mg, 1.74 mmol, 1.50 equiv) in tetrahydrofuran (3 mL) at 0° C. under nitrogen. The resulting solution was stirred for 3 h at room temperature and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1). This resulted in 260 mg (45%) of 10-bromo-2-iodo-3-((2-methyl-1H-imidazol-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepineas as a colorless solid. This intermediate was converted to 10-bromo-3-((2-methyl-1H-imidazol-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide similar to as described in Example 10 (carbonylative amidation). Similar to as described in General Procedure G, 10-bromo-3((2-methyl-1H-imidazol-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-methylbut-3-yn-2-ol to give the titled compound as a colorless solid (2 mg, 2%).