Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([N:9]3[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[N+:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27])([O-:19])=[O:18].C(N(CC)CC)C.CN(C)C=O>O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([N:9]3[CH2:13][CH2:12][CH:11]([NH:14][S:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N+:17]([O-:19])=[O:18])(=[O:27])=[O:28])[CH2:10]3)[S:8][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: NC1CCN(c2nc3ccc(Cl)cc3s2)C1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CCN(c2nc3ccc(Cl)cc3s2)C1
Temperature: 60 °C
Reaction time: 3 h
Yield: 46.7 %

Procedure:
A mixture of 1-(6-chlorobenzothiazole-2-yl)pyrrolidine-3-ylamine (2.49 g), 2-nitrobenzenesulphonyl chloride (2.40 g), triethylamine (3.02 mL) and dimethylformamide (15 mL) was stirred at 60° C. for 3 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (2.01 g). Yield: 47
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:6][N:7]([CH2:15][C:16]1[C:17]([N:27]([CH2:32][CH:33]2[CH2:35][CH2:34]2)[CH2:28][CH:29]2[CH2:31][CH2:30]2)=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26])[C:8]1[N:13]=[C:12](Cl)[N:11]=[CH:10][N:9]=1.C(N(C(C)C)CC)(C)C.[NH:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1>CN(C=O)C.CCOC(C)=O>[F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:6][N:7]([CH2:15][C:16]1[C:17]([N:27]([CH2:32][CH:33]2[CH2:35][CH2:34]2)[CH2:28][CH:29]2[CH2:31][CH2:30]2)=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26])[C:8]1[N:13]=[C:12]([N:54]2[CH2:59][CH2:58][O:57][CH2:56][CH2:55]2)[N:11]=[CH:10][N:9]=1
Reactant: C1COCCN1
Reactant: Cc1cccc2cc(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3ncnc(Cl)n3)c(N(CC3CC3)CC3CC3)nc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc2cc(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3ncnc(N4CCOCC4)n3)c(N(CC3CC3)CC3CC3)nc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 78 %

Procedure:
A mixture of (3-{[(3,5-bis-trifluoromethyl-benzyl)-(4-chloro-[1,3,5]triazin-2-yl)-amino]methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine (Example 117) (60 mg, 0.09 mmol), diisopropyl ethylamine (13 μL, 0.1 mmol) was taken in DMF (10 mL). The flask was cooled to 0° C. and the contents were stirred for 5 min. To this, morpholine (12 μL, 0.13 mmol) was added and the stirring was continued for 30 min at 0° C. and then warming up to room temperature. Contents of the flask were taken in 100 mL EtOAc and washed with water (100 mL×3). The organic layer was separated, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography; (silica gel 230-400 mesh). Elution with 2% EtOAc in hexane afforded 58 mg of colorless mass (yield: 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:17][CH2:16][CH2:15][C@H:14]3[N:9]2[C:10](=[O:19])[CH:11](I)[CH2:12][CH2:13]3)=[CH:4][CH:3]=1.[P:20]([O:27]CC)([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23]>>[CH2:22]([O:21][P:20]([CH:11]1[C:10](=[O:19])[N:9]2[C@H:14]([CH2:15][CH2:16][CH2:17][C@H:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12]1)(=[O:27])[O:24][CH2:25][CH3:26])[CH3:23]
Reactant: O=C1C(I)CC[C@H]2CCC[C@@H](c3ccc(Cl)cc3)N12
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(OCC)C1CC[C@H]2CCC[C@@H](c3ccc(Cl)cc3)N2C1=O
Temperature: 120 °C
Reaction time: 2 h

Procedure:
In nitrogen atmosphere, trimethylsilyl iodide (0.74 mL) was added to a methylene chloride solution (25 mL) of (6S,9aR)-6-(4-chlorophenyl)-octahydroquinolizin-4-one (877 mg) and N,N,N′,N′-tetramethylethylenediamine (1.76 mL) at 0° C. The resulting reaction solution was stirred at 0° C. for 30 min, and then iodine (1.26 g) was added thereto at 0° C. The resulting reaction solution was stirred at 0° C. for 1 hr, and a sodium thiosulfate aqueous solution and ethyl acetate were added thereto. The organic layer was separated, washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure to give (6S,9aR)-6-(4-chlorophenyl)-3-iodooctahydroquinolizin-4-one. A mixture of the (6S,9aR)-6-(4-chlorophenyl)-3-iodooctahydroquinolizin-4-one and triethyl phosphite (10 mL) was stirred at 120° C. for 2 hr. This reaction solution was allowed to cool to room temperature and then concentrated under reduced pressure to give [(6S,9aR)-6-(4-chlorophenyl)-4-oxooctahydroquinolizin-3-yl]phosphonic acid diethyl ester. To a solution mixture of tetrahydrofuran (21 mL) and ethanol (7 mL) of the [(6S,9aR)-6-(4-chlorophenyl)-4-oxooctahydroquinolizin-3-yl]phosphonic acid diethyl ester and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (869 mg), lithium hydroxide monohydrate (422 mg) was added. The resulting reaction solution was stirred at room temperature for 2 hr, and then ethyl acetate and a saturated sodium hydrogencarbonate aqueous solution were added thereto. The organic layer was separated, washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH, eluting solvent: heptane-ethyl acetate system) and then by silica gel column chromatography (eluting solvent: heptane-ethyl acetate system and then ethyl acetate-methanol system) to give 1.07 g of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([CH3:16])[CH2:10][O:11][CH2:12][C:13](Cl)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+]>C(O)(C)(C)C>[CH2:1]([N:8]1[C@H:9]([CH3:16])[CH2:10][O:11][CH2:12][C:13]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](COCC(=O)Cl)NCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: C[C@@H]1COCC(=O)N1Cc1ccccc1
Yield: 63 %

Procedure:
(R)-2-(2-(benzylamino)propoxy)acetyl chloride was dissolved in tert-butanol (500 mL). Sodium tert-butoxide (14.0 g, 125 mmol) was then added in one portion and the reaction mixture heated at reflux for 18 h. The reaction was cooled and concentrated under reduced pressure to remove the solvent. The residue was dissolved in diethyl ether (300 mL) and then washed with 2 N HCl (150 mL), H2O (150 mL) and saturated brine (100 mL). The organic phase was then dried (Na2SO4), filtered, and concentrated under reduced pressure to afford a light yellow oil. Purification by column chromatography (silica gel, 10-50% EtOAc in heptanes) afforded (R)-4-benzyl-5-methylmorpholine-3-one (17.2 g, 63%) as a light yellow oil. 1H NMR and MS consistent.
Reaction SMILES: C[O:2][CH:3](OC)[CH:4]([CH3:27])[N:5]1[C:9]2[CH:10]=[C:11]([O:14][C:15]3[CH:20]=[C:19]([F:21])[C:18]([C:22]([F:25])([F:24])[F:23])=[C:17]([Cl:26])[CH:16]=3)[CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1.OS(O)(=O)=O>C(O)(=O)C.O.C(Cl)Cl>[Cl:26][C:17]1[CH:16]=[C:15]([O:14][C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[N:6][N:5]([CH:4]([CH3:27])[CH:3]=[O:2])[C:9]=3[CH:10]=2)[CH:20]=[C:19]([F:21])[C:18]=1[C:22]([F:25])([F:24])[F:23]
Reactant: COC(OC)C(C)n1nnc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc21
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C=O)n1nnc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc21
Temperature: 70 °C

Procedure:
A solution of 6-[(2-chloro-α,α,α,6-tetrafluoro-p-tolyl) oxy]-α-methyl-1H-benzotriazole-1-acetaldehyde dimethyl acetal (20 g, 0.046 mole) in acetic acid is treated with 47 ml of 2.5N H2SO4, heated for 12 hours at 70° C., cooled and diluted with water and methylene chloride. The phases are separated and the aqueous phase is extracted with methylene chloride. The combined organic phases are dried (MgSO4), filtered through a pad of Al2O3, and concentrated in vacuo to afford the title compound as a solid, mp 107°-108° C., characterized by elemental and NMR analyses.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH:6]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](Cl)[N:10]=2)[CH2:5][C:4]([CH3:19])([CH3:18])[NH:3]1.[CH:21]1([C:24]2[C:29]([N:30]3[CH:34]=[N:33][N:32]=[N:31]3)=[CH:28][C:27]([NH2:35])=[C:26]([F:36])[CH:25]=2)[CH2:23][CH2:22]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.FC1C(NC2CC(C)(C)NC(C)(C)C2)=NC(OC(C)C)=NC=1>CC(O)C>[CH3:1][C:2]1([CH3:20])[CH2:7][CH:6]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11]([NH:35][C:27]3[CH:28]=[C:29]([N:30]4[CH:34]=[N:33][N:32]=[N:31]4)[C:24]([CH:21]4[CH2:22][CH2:23]4)=[CH:25][C:26]=3[F:36])[N:10]=2)[CH2:5][C:4]([CH3:19])([CH3:18])[NH:3]1
Reactant: Nc1cc(-n2cnnn2)c(C2CC2)cc1F
Reactant: CC1(C)CC(Nc2nc(Cl)ncc2C#N)CC(C)(C)N1
Agent: CC(C)Oc1ncc(F)c(NC2CC(C)(C)NC(C)(C)C2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: CC1(C)CC(Nc2nc(Nc3cc(-n4cnnn4)c(C4CC4)cc3F)ncc2C#N)CC(C)(C)N1
Temperature: 80 °C

Procedure:
A mixture of 4-(2,2,6,6-tetramethylpiperidin-4-ylamino)-2-chloropyrimidine-5-carbonitrile (112 mg, 0.380 mmol, 1 equiv), 4-cyclopropyl-2-fluoro-5-(1H-tetrazol-1-yl)benzenamine (100 mg, 0.456 mmol, 1.2 equiv), and para-toluenesulfonic acid monohydrate (58 mg, 0.304 mmol, 0.8 equiv) in IPA (4 mL) were heated to 80° C. overnight. LCMS indicated desired product plus approximately 18% of 5-fluoro-2-isopropoxy-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidin-4-amine byproduct. After cooling to ambient temperature, the crude mixture was quenched with 2M NH3/MeOH followed by concentrating to dryness and repeating once. The crude product was purified by flash chromatography and eluted with DCM:2M NH3/MeOH (100:0 to 95:5 using 1% 2M NH3/MeOH increments) to provide the desired product which was recrystallized with DCM/IPA to give the title compound (88 mg, 49%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.C([Mg]Br)CC.C1COCC1.[N+:19]([C:22]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:23]=1[CH:24]=[O:25])([O-:21])=[O:20]>C1COCC1>[Cl:30][C:27]1[CH:28]=[CH:29][C:22]([N+:19]([O-:21])=[O:20])=[C:23]([CH:24]([C:5]2[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[OH:25])[CH:26]=1
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Clc1ccc(I)cn1
Agent: CCC[Mg]Br
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Cl)cc1C(O)c1ccc(Cl)nc1
Temperature: -45 °C
Reaction time: 0.08 h

Procedure:
A solution of 1.0 g 2-chloro-5-iodopyridine (4.1 mmol, 1.0 eq.) in 10 mL anhyd. THF was stirred at −40° C. to −50° C. After five minutes, 2.2 mL of 2.1 M PrMgBr/THF (4.6 mmol, 1.1 eq.) were added drop wise over 1 minute and the reaction mixture is maintained at −40 to −50° C. for 30 minutes. 1.3 g 2-nitro-5-chlorobenzaldehyde (7.0 mmol, 1.7 eq.) was then added and the reaction was maintained at −50° C. After 1 hour, the reaction was allowed to warm to −10° C., and quenched with 50 mL saturated brine after a further fifteen minutes. The crude product was extracted with EtOAc, dried on Na2SO4 and concentrated by rotary evaporation to yield desired product. MS: (M+H)/z=298.9
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C:12]1[C:17]([C:18](OC)=[O:19])=[C:16]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:15]=[C:14]([CH3:29])[N:13]=1.[OH-].[K+]>O1CCCC1>[CH3:11][C:12]1[C:17]([CH2:18][OH:19])=[C:16]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:15]=[C:14]([CH3:29])[N:13]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)cc(C)nc1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(F)cc2)c(CO)c(C)n1
Temperature: 25 °C

Procedure:
5.3 ml (5.3 mmol) of diisobutylaluminum hydride (1M in toluene) are added under nitrogen at -78° C. to 1.35 g (5.2 mmol) of the compound from Example 28 in 25 ml of absolute tetrahydrofuran and, after warming to 25° C., the mixture is hydrolyzed using 20% strength potassium hydroxide solution. The aqueous phase is washed with ethyl acetate and the combined organic phases are dried. After evaporating in vacuo, 1.12 g of crude product are obtained.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][C:5]=1[CH3:11])=[O:2]>CO>[CH:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:11])=[O:2]
Reactant: Cc1cc(Cl)ccc1NC=O
Solvent: CO
Product: Cc1ccccc1NC=O

Procedure:
Splitting of the 2-formylamino-5-chlorotoluene, formed on chlorination of 2-formylaminotoluene, with methanol is performed at a temperature of between 20° and 60° C., preferably at between 25° and 30° C. The reaction duration is about 1 to 2 hours.
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6]1[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]([F:14])[C:7]=1[F:15])=[O:4].[C:18]([N:21]1[C:32]2[C:24](=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28]C(C(O)=O)=[CH:26]3)[CH2:23][CH2:22]1)(=[O:20])[NH2:19].C(N(CC)CC)C>CN(C=O)C>[C:18]([N:21]1[C:32]2[C:24](=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][C:2]([C:3]([O:5][C:6]2[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]([F:14])[C:7]=2[F:15])=[O:4])=[CH:26]3)[CH2:23][CH2:22]1)(=[O:20])[NH2:19]
Reactant: NC(=O)N1CCc2c1ccc1[nH]c(C(=O)O)cc21
Reactant: O=C(Oc1c(F)c(F)cc(F)c1F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)N1CCc2c1ccc1[nH]c(C(=O)Oc3c(F)c(F)cc(F)c3F)cc21
Reaction time: 1 h
Yield: 75 %

Procedure:
2,3,5,6-Tetrafluorophenyl trifluoroacetate (2.6 g, 10 mmol, H. B. Gamper, M. W. Reed, T. Cox, J. S. Virosco, A. D. Adams, A. A. Gall, J. K. Scholler and R. B. Meyer, Jr. Nucleic Acids Res., 1993, Vol. 21, No.1, 145-150) was added dropwise to a solution of 3-carbamoyl-1,2-dihydro-3H-pyrrolo[3,2-e]indole-7-carboxylic acid (1.4 g, 6.1 mmol, D. L. Boger, R. S. Coleman, and B. J. Invergo. J. Org. Chem., 1987, Vol.52, 1521-1530) and triethylamine (1.4 ml, 10 mmol) in 15 ml of anhydrous DMF. After 1 hr, the reaction mixture was concentrated under vacuum (0.2 mm). The residue was triturated with 2 ml of dry dichloromethane. Ethyl ether (50 ml) was added and the mixture was left at 0° C. overnight. The precipitate was collected by filtration on sintered glass funnel, washed first with 50% ether/CH2Cl2 (10 ml), then with ether (50 ml) and dried in vacuo. The product was obtained as a yellow solid (1.8 g, 75%): 1H NMR (Me2SO-d6, 200 MHz, ppm) 12.32 (s, 1H, NH), 8.13 (d, 1H, J=9 Hz, C4-H), 8.01 (m, 1H, C6F4H), 7.41 (s, 1H, C8-H), 7.26 (d, 1H, J=9 Hz, C5-H), 6.17 (s, 2H, CONH2), 3.99 (t, 2H, J=9 Hz, NCH2CH2), 3.30 (t, 2H, J=9 Hz, NCH2CH2). Anal. Calcd. for C18H11 N3O3F4 ×2H2O: C, 50.3; H, 3.52; N, 9.7. Found; C, 50.81; H, 3.60; N, 9.95.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[C:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[C:14]([OH:23])[C:13]([C:24]([F:27])([F:26])[F:25])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH3:28][C:29]1[CH:30]=[C:31]([CH2:44][C:45]([O:47][CH3:48])=[O:46])[CH:32]=[CH:33][C:34]=1B1OC(C)(C)C(C)(C)O1>>[OH:23][C:14]1[C:13]([C:24]([F:27])([F:26])[F:25])=[CH:12][CH:11]=[C:10]([CH2:9][O:8][C:5]2[CH:6]=[N:7][C:2]([C:34]3[CH:33]=[CH:32][C:31]([CH2:44][C:45]([O:47][CH3:48])=[O:46])=[CH:30][C:29]=3[CH3:28])=[CH:3][CH:4]=2)[C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: CC(C)(C)OC(=O)c1c(COc2ccc(Cl)nc2)ccc(C(F)(F)F)c1O
Reactant: COC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Product: COC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C(=O)OC(C)(C)C)cn2)c(C)c1
Yield: 50 %

Procedure:
According to a method similar to Example (76-1), from tert-butyl 6-{[(6-chloro-3-pyridinyl)oxy]methyl}-2-hydroxy-3-(trifluoromethyl)benzoate (240 mg, 0.59 mmol) obtained in Example (84-1) and methyl [3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (224 mg, 0.77 mmol) obtained in Example (84-3), tert-butyl 2-hydroxy-6-{[(6-{4-[(methoxycarbonyl)methyl]-2-methylphenyl}-3-pyridinyl)oxy]methyl}-3-(trifluoromethyl)benzoate was obtained (157 mg, yield: 50%).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[CH:12]1([C:16]#[N:17])[CH2:15][CH2:14][CH2:13]1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].Cl>C1(C)C=CC=CC=1>[CH3:7][N:6]1[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=[C:2]1[C:12]1([C:16]#[N:17])[CH2:15][CH2:14][CH2:13]1
Reactant: N#CC1CCC1
Reactant: Cn1c(Cl)nc2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cn1c(C2(C#N)CCC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
To a solution of Example 275A (1.90 g, 11.4 mmol) in toluene (30 mL) was added cyclobutanecarbonitrile (1.01 g, 12.5 mmol) and potassium hexamethyldisilazide (34.2 mL, 17.1 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was poured into 1N HCl solution (50 mL) and the aqueous layer was extracted with EtOAc (3×20 mL). The combined layers were washed with brine (100 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by prep. TLC on silicagel (eluted with EtOAc:petroleum ether=1:10) to give the title compound (1.0 g, 4.69 mmol, 41.1% yield) as a white solid. MS: MS (M+H)+; 1H NMR (400 MHz, CDCl3): δ 7.80-7.78 (m, 1H), 7.36-7.30 (m, 3H), 3.83 (s, 3H), 3.13-3.05 (m, 2H), 2.99-2.92 (m, 2H), 2.48-2.41 (m, 1H), 2.24-2.18 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[O:10][C@H:11]([CH2:14]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2].[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[C:36]1([OH:44])[CH2:42][CH:41]2[NH:43][CH:38]([CH2:39][CH2:40]2)[CH2:37]1.C([O-])([O-])=O.[K+].[K+].C(#N)C>C(Cl)(Cl)Cl.CO.O>[CH2:1]([O:3][C:4]1[C:9]2[O:10][CH:11]([CH2:14][N:43]3[CH:38]4[CH2:39][CH2:40][C@H:41]3[CH2:42][C:36]([C:27]3[CH:28]=[CH:29][C:30]5[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH:26]=3)([OH:44])[CH2:37]4)[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: OC1(c2ccc3ccccc3c2)CC2CCC(C1)N2
Reactant: CCOc1cccc2c1O[C@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CCOc1cccc2c1OC(CN1C3CC[C@H]1CC(O)(c1ccc4ccccc4c1)C3)CO2
Reaction time: 18 h
Yield: 48 %

Procedure:
To 117 mg (0.32 mmol) (S)-toluene-4-sulfonic acid 8-ethoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester was added 84 mg (0.33 mmol) 3-naphthalen-2-yl-8-aza-bicyclo[3.2.1]octan-3-ol, 95.0 mg K2CO3, and 7 mL acetonitrile. The reaction was refluxed and was monitored by TLC on a silica gel plate using CHCl3:MeOH (10:1) as eluent. After 18 h, the mixture was transferred to a separatory funnel containing 50 mL water. The aqueous layer was extracted with CH2Cl2 (2×25 mL), washed with brine, dried over Na2SO4, filtered and evaporated to an oil. The crude material was purified by flash chromatography on silica gel, using a gradient elution of CHCl3:MeOH (40:1 to 20:1). The appropriate fractions were combined and evaporated to afford 68.1 mg (0.15 mmol, a 48% yield) of the title compound as a tan solid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=3[O:19][CH2:18][C:17]2=[O:27])[CH2:10][CH2:9]1)(C)(C)C.NC1CCN(CCN2C3C(=CC=C(C#N)C=3)C=CC2=O)CC1>>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=3[O:19][CH2:18][C:17]2=[O:27])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCN2C(=O)COc3ccc(Cl)cc32)CC1
Agent: N#Cc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Product: NC1CCN(CCN2C(=O)COc3ccc(Cl)cc32)CC1

Procedure:
tert-Butyl{1-[2-(6-chloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 57) (640 mg, 1.56 mmol) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative yield).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]21[C:47]1[C:42](=[CH:43][C:44]([Cl:57])=[C:45]([CH2:48][C:49]3[CH:54]=[CH:53][C:52]([CH2:55][CH3:56])=[CH:51][CH:50]=3)[CH:46]=1)[CH:41]([OH:58])[CH2:40]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]21[C:47]1[C:42](=[CH:43][C:44]([Cl:57])=[C:45]([CH2:48][C:49]3[CH:50]=[CH:51][C:52]([CH2:55][CH3:56])=[CH:53][CH:54]=3)[CH:46]=1)[C:41](=[O:58])[CH2:40]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)C(O)C[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCc1ccc(Cc2cc3c(cc2Cl)C(=O)C[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 90.8 %

Procedure:
To a 0° C. solution of (1S,3′R,4′S,5′R,6′R)-3′,4′,5′-tris(benzyloxy)-6′-(benzyloxymethyl)-5-chloro-6-(4-ethylbenzyl)-2,3,3′,4′,5′,6′-hexahydrospiro[indene-1,2′-pyran]-3-ol (40 mg, 0.05 mmol) in dry dichloromethane (1.0 mL) was added dropwise a solution of Dess-Martin reagent (43 mg, 0.1 mmol) in 0.5 mL of dry dichloromethane. The reaction mixture was stirred for 3.5 h at room temperature and quenched by addition of 2 mL of 1 M aqueous NaOH solution when TLC showed the reaction was complete. The organic layer was separated and the aqueous layer was extracted 2× with CH2Cl2 (10 mL). The combined organic layers were washed 1× with NaHSO3 (10 mL), 2× with NaHCO3 (10 mL), 3× with brine (10 mL) prior to drying over anhydrous Na2SO4. Concentration under reduced pressure and purification of the crude product by preparative TLC provided 36 mg of the pure product.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[CH:11][N:10]=[C:9]2[NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)=[C:21]([Cl:34])[CH:20]=1)=[O:4].[C:35](O)(=[O:38])[CH:36]=[CH2:37].N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC>C1COCC1>[Cl:34][C:21]1[CH:20]=[C:19]([NH:18][C:9]2[C:8]3[C:13](=[CH:14][C:15]([O:16][CH3:17])=[C:6]([NH:5][C:3]([CH2:2][NH:1][C:35](=[O:38])[CH:36]=[CH2:37])=[O:4])[CH:7]=3)[N:12]=[CH:11][N:10]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1
Reactant: C=CC(=O)O
Reactant: COc1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2cc1NC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=CC(=O)NCC(=O)Nc1cc2c(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)ncnc2cc1OC
Temperature: 0 °C
Yield: 27 %

Procedure:
170 mg of 2-amino-N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-7-methoxy-quinazolin-6-yl}-acetamide as a starting material was dissolved in 5 ml of THF, and cooled to 0° C. The solution was reacted with 0.04 ml of acrylic acid, 0.06 ml of pyridine and 134 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride at 0° C. for 1 hour and at room temperature for 5 hours. The reacted solution was extracted with chloroform after adding saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent-ethylacetate methanol=10:1) to obtain the title compound (51 mg, 27%).