Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]3[N:42](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:41]=[N:40][N:39]=3)=[CH:28][CH:27]=2)[C:7](=[O:24])[N:8]([CH2:10][CH2:11][CH2:12][O:13][C:14](=[O:23])[N:15]([CH3:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]>C(O)(=O)C>[CH2:1]([C:5]1[N:6]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]3[NH:42][N:41]=[N:40][N:39]=3)=[CH:30][CH:31]=2)[C:7](=[O:24])[N:8]([CH2:10][CH2:11][CH2:12][O:13][C:14](=[O:23])[N:15]([CH3:22])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(CCCOC(=O)N(C)c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCCCc1nn(CCCOC(=O)N(C)c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 68 %

Procedure:
Deprotection of 5-n-butyl-2,4-dihydro-2-[3-(N-methyl-N-phenylcarbamoyloxy)propyl]-4-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]-3H-1,2,4-triazol-3-one in 50% aqueous acetic acid was accomplished by the procedure of Example 3, Step B. After work-up, the residue was flash chromatographed over silica gel (35 mL for 0.13 mmole, gradient elution using 2-10% MeOH/CH2Cl2) to give the desired material as a foam in 68% yield, homogeneous by TLC in 10% MeOH/CH2Cl2, mass spectrum (FAB) m/e 567 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:12][S:13][CH2:14][S:15]([CH3:17])=[O:16]>C1COCC1>[Cl:1][C:2]1[C:3]([CH:4]=[C:14]([S:13][CH3:12])[S:15]([CH3:17])=[O:16])=[CH:6][CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CSCS(C)=O
Reactant: COc1cccc(C=O)c1Cl
Solvent: C1CCOC1
Product: COc1cccc(C=C(SC)S(C)=O)c1Cl
Yield: 47.8 %

Procedure:
To a solution of 2-chloro-3-methoxybenzaldehyde 7a (4.65 g, 27.3 mmol) and methyl (methylthio)methyl sulfoxide (4.3 mL, 43.9 mmol) in THF (25 mL) was added a 40% methanolic solution of Triton B (6.2 mL, 13.6 mmol) and the resulting solution was refluxed for 16 hours. After THF was removed, the residue was taken up in ethyl acetate, washed with 1 N HCl, H2O, and brine, then was dried over Na2SO4, and concentrated. Purification by column chromatography on silica gel with dichloromethane afforded 2-chloro-1-methoxy-3-[2-(methylsulfanyl)-2-(methylsulfinyl)vinyl]benzene 7b (3.61 g, 48% ) as a yellow oil. GCMS (El) m/z 225 (M+-Cl-16), 210 (M+-Cl—OMe).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH3:8][C:9]1C(C)=[N+:13]([O-])[C:12]([C:17]#[N:18])=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+]>>[C:5]([O:4][CH2:1][C:2]1[C:9]([CH3:8])=[CH:10][CH:11]=[C:12]([C:17]#[N:18])[N:13]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(C#N)[n+]([O-])c1C
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)OCc1nc(C#N)ccc1C
Temperature: 120 °C
Yield: 67 %

Procedure:
To acetic anhydride (12 ml) at 120° C. was added 5,6-dimethyl-2-pyridine-carbonitrile 1-oxide (3.02 g) and the solution heated at 120° C. for 5 minutes then under reflux for 2.5 hours. After cooling the solution was added to ice (ca. 80 g) and the mixture neutralized with sodium bicarbonate. It was extracted with ether (80 ml then 2×40 ml) and the combined extracts washed with brine (40 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by Biotage chromatography eluting with 2:1 hexane:ethyl acetate to afford the title compound (2.60 g, 67%) as a pale yellow solid. LC/MS [MH+]=191, RT=2.05 min.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH:21]#[C:22][CH3:23].C=C=C.CCC>C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[C:1]([O:20][C:22]([CH3:23])=[CH2:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: C#CC
Agent: C=C=C
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: CCC
Product: C=C(C)OC(=O)CCCCCCCCCCCCCCCCC
Temperature: 120 °C

Procedure:
The zeolite was prepared in a conventional way using a 1N aqueous zinc acetate solution and drying the partially exchanged zeolite for about 16 hours at about 150° C. The dried zeolite contained about 4.0% zinc. Fifteen grams of the loaded zeolite plus 100 g (0.36 moles) of melted stearic acid were sealed in a 1-liter pressure vessel equipped with a magnetic stirrer, a gas inlet tube and a thermocouple, and the air within replaced by nitrogen. Approximately 80 ml of a liquified gas, the composition of which is about 60% of a 50--50 mixture of propyne and allene and about 40% propane, containing approximately 0.5 mole methyl acetylene in a pressure burette was pushed into the pressure vessel using pressurized nitrogen gas. An electric heater was used to heat the vigorously stirred mixture for 10 minutes at 120° C. at a pressure of about 400 pounds per square inch at which time the pressure vessel and its contents were rapidly cooled and the pressure in the vessel discharged to atmospheric pressure. Infrared analysis of the pale ivory colored solid gave the same spectra as that of a reference sample of isopropenyl stearate.
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[CH2:14]([C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][CH:24]=O)[CH2:19][CH2:18]1)[CH2:15][CH3:16]>>[CH2:14]([C@H:17]1[CH2:18][CH2:19][C@H:20]([CH:23]=[CH:24][N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:21][CH2:22]1)[CH2:15][CH3:16]
Reactant: CCC[C@H]1CC[C@H](CC=O)CC1
Reactant: C1CCNCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: CCC[C@H]1CC[C@H](C=CN2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.078 mol of anhydrous sodium sulfate and 0.086 mol of piperidine were mixed and treated dropwise at -5° C. under nitrogen with 0.039 mol of trans-4-propylcyclohexylacetaldehyde. The reaction mixture was stirred at room temperature for 24 hours. Subsequently the precipitate was filtered off and washed with hexane. Distillation of the combined filtrates under a vacuum gave 1-[2-(trans-4-propylcyclohexyl)vinyl]piperidine of b.p. 118°-120° C./1 Torr in 75% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([S:13]([OH:16])(=[O:15])=O)=[CH:11][C:10]([C:17]([F:20])([F:19])[F:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:21][C:22]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:23]=1[C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[O:25].C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([S:13]([NH:21][C:22]3[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:23]=3[C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[O:25])(=[O:16])=[O:15])=[CH:11][C:10]([C:17]([F:19])([F:20])[F:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C(=O)NC(C)C)c1N
Reactant: O=S(=O)(O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C(=O)NC(C)C)c1NS(=O)(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 9 h
Yield: 9.8 %

Procedure:
To 2.84 g (10.2 mmol) of 1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-sulfonic acid (i.e. the title material from Step C) in 70 mL of dichloromethane was added 1.96 g (10.2 mmol) of 2-amino-3-methyl-N-(1-methylethyl)benzamide (i.e. the title compound of Step E) 1.78 mL (10.2 mmol) of diisopropylethylamine and approximately 5 mg of 4-(dimethylamino)pyridine. The reaction mixture was stirred for 9 hours, then washed with water and dried (sodium sulfate). The solvent was removed with a rotary evaporator. The residue was purified by MPLC (20–40% ethyl acetate in hexanes as eluant) to afford 0.50 g of the title compound as a foamy white solid melting at 69–72° C. 1H NMR (CDCl3) δ 0.1.12 (d, 6H), 2.32 (s, 1H), 3.85 (m, 1H), 5.96 (brd, 1H), 7.07 (s, 1H), 7.35 (m, 3H), 7.39 (dd, 1H), 7.89 (dd, 1H), 8.20 (dd, 1H), 9.26 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8](Br)Br)[N:5]=[C:4]([CH:11](Br)Br)[N:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[CH3:1][C:2]1[N:7]=[C:6]([CH:8]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:5]=[C:4]([CH:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1
Reactant: C1COCCN1
Reactant: Cc1nc(C(Br)Br)nc(C(Br)Br)n1
Product: Cc1nc(C(N2CCOCC2)N2CCOCC2)nc(C(N2CCOCC2)N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 2-methyl-4,6-Bis-(dibromomethyl)-s-triazine (0.4 g, 0.91 mmol) and morpholine (8 mL) was stirred at room temperature for 2 days and then heated to 70-80° C. and stirred for an additional 2 hours. The precipitate was filtered and the filtrate was evaporated under reduced pressure to remove the excess morpholine. The solid residue was recrystallized from ethyl acetate giving 0.40 g (95%) of the title compound as big cubic colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:22]([CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:21]([CH2:30]Cl)=[N:20][C:14]=3[C:15]([NH2:19])=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[O:40]([NH2:42])[CH3:41]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:22]([CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:21]([CH2:30][NH:42][O:40][CH3:41])=[N:20][C:14]=3[C:15]([NH2:19])=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON
Reactant: Nc1nc2cc(OCc3ccccc3)ccc2c2c1nc(CCl)n2CC1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CONCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC1CCOCC1
Temperature: 50 °C
Reaction time: 40 h
Yield: 36.1 %

Procedure:
7-(Benzyloxy)-2-(chloromethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine (2.3 g, 5.26 mmol) and triethylamine (1.6 g, 15.78 mmol) were added to a solution of methoxylamine hydrochloride (0.88 g, 10.52 mmol) in N,N-dimethylformamide (DMF) (11 mL). The reaction was heated with stirring for 40 hours at 50° C., allowed to cool to ambient temperature, and partitioned between dichloromethane (50 mL) and water (50 mL). The aqueous layer was extracted with another portion of dichloromethane (50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography using a HORIZON HPFC system equipped with a FLASH 40+M silica cartridge eluting with dichloromethane:methanol in a gradient from 100:0 to 90:10. The resulting product (1.0 g) was recrystallized from acetonitrile, and the crystals were isolated by filtration, washed with acetonitrile, and dried overnight in a vacuum oven at 65° C. to provide 0.85 g of 7-(benzyloxy)-2-[(methoxyamino)methyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a yellow, crystalline solid, mp 190-193° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH2:12][CH3:13])[C:9]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:8]=2[CH2:7][CH2:6]1)=[O:4].[Cl:22]N1C(=O)CCC1=O>C(#N)C>[F:21][C:2]([F:1])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH2:12][CH3:13])[C:9]2[CH:14]=[C:15]([Cl:22])[C:16]([O:18][CH3:19])=[CH:17][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCC1CN(C(=O)C(F)(F)F)CCc2cc(OC)ccc21
Solvent: CC#N
Product: CCC1CN(C(=O)C(F)(F)F)CCc2cc(OC)c(Cl)cc21
Reaction time: 8 h
Yield: 391.8 %

Procedure:
A solution of N-trifluoroacetyl-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.600 g, 1.99 mmol) in acetonitrile (20 mL) was treated with N-chlorosuccinimide (0.057 g, 0.32 mmol), and stirred overnight at 60 C. The product mixture was concentrated, diluted with EtOAc (100 mL), washed with water (50 mL) and brine (50 mL), dried with Na2SO4 and concentrated. Flash chromatography (10% EtOAc in hexanes, silica) resulted in 0.421 g of a clear oil. MS calculated for C15H17ClF3NO2+H: 336, observed: 336.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([C:17]2[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=2)([C:13]([F:16])([F:15])[F:14])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.O>ClCCCl.CO>[Cl:25][C:19]1[CH:18]=[C:17]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:22]=[C:21]([Cl:23])[C:20]=1[Cl:24]
Reactant: FC(F)(F)C1(c2cc(Cl)c(Cl)c(Cl)c2)CCN(Cc2ccccc2)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Solvent: CO
Solvent: O
Product: FC(F)(F)C1(c2cc(Cl)c(Cl)c(Cl)c2)CCNC1
Yield: 92.6 %

Procedure:
To a stirred solution of 1-benzyl-3-(3,4,5-trichloro-phenyl)-3-trifluoromethyl-pyrrolidine (Preparation 38, 4 g, 9.828 mmol) in 1,2-dichloroethane (40 mL) was added 1-chloroethyl chloroformate (1.91 mL, 17.69 mmol) and the resulting reaction mixture was refluxed for 3 hours. After complete consumption of starting material, reaction mixture was concentrated under reduced pressure to afford yellow oily residue, which was dissolved in MeOH (40 mL) and the mixture was refluxed at 2 hours. After complete consumption of starting material, reaction mixture was concentrated in vacuo to afford yellow oil, to which water (50 mL) was added and extracted with hexane (3×50 mL). Aqueous layer was basified using saturated sodium bicarbonate solution and extracted with ethyl acetate (3×50 mL). Combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford brown thick oil (5.5 g, crude). Crude compound was purified by column chromatography using 100-200 mesh silica gel. Desired compound was eluted in 4% methanol in dichloromethane to afford product as yellow thick oil (2.9 g, impure). Impure compound was as such for next reaction. (m/z): 317.9 (M+H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])[CH2:2]1.C1(C)C=CC(S(O[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)(=O)=O)=CC=1>>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH2:29][N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]34[CH2:18][CH:13]5[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]5)[CH2:10]3)[CH2:16]4)=[O:8])[CH2:2]2)=[CH:32][CH:33]=1
Reactant: O=C(N[C@H]1CCNC1)C12CC3CC(CC(C3)C1)C2
Reactant: COc1ccc(CCOS(=O)(=O)c2ccc(C)cc2)cc1
Product: COc1ccc(CCN2CC[C@H](NC(=O)C34CC5CC(CC(C5)C3)C4)C2)cc1
Yield: 18.8 %

Procedure:
(S)-N-(Pyrrolidin-3-yl)-1-adamantanecarboxamide (0.38 g) and 2-(4-methoxyphenyl)ethyl p-toluenesulfonate (0.56 g) were reacted under the same conditions as in Example 1 to give (S)-N-(1-(2-(4-methoxyphenyl)ethyl)pyrrolidin-3-yl)-1-adamantanecarboxamide (0.11 g), melting point 81-83° C.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.[C:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)#[N:18]>O1CCCC1>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([NH:8][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([C:17]#[N:18])=[CH:20][CH:21]=2)=[CH:10][CH:11]=1)#[N:14]
Reactant: N#Cc1ccc(N)cc1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1ccc(NC(=O)c2ccc(C#N)cc2)cc1

Procedure:
13.1 g (0.13 moles) of triethylamine were added to a solution of 14.2 g (0.12 moles) of 4-aminobenzonitrile in 100 ml of tetrahydrofuran and the temperature was then kept at about 5° C. and 20 g (0.12 moles) of 4-cyanobenzoyl chloride were added dropwise. The mixture was left to react for 12 h under agitation. The solvent was evaporated, the residue was taken up with H2O and the precipitate formed was filtered. The precipitate was washed with dilute HC1, a 10% solution of bicarbonate and again with H2O.
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([O:27][C:28]2[CH:37]=[C:36]([CH3:38])[C:31]3[NH:32][C:33](=[O:35])[O:34][C:30]=3[CH:29]=2)[CH:20]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[CH3:26][O:25][C:23]1[N:24]=[C:19]([N:14]2[CH2:13][CH2:12][C:5]3([O:4][C:3](=[O:17])[NH:2][C:7]4[N:8]=[CH:9][CH:10]=[CH:11][C:6]3=4)[CH2:16][CH2:15]2)[CH:20]=[C:21]([O:27][C:28]2[CH:37]=[C:36]([CH3:38])[C:31]3[NH:32][C:33](=[O:35])[O:34][C:30]=3[CH:29]=2)[N:22]=1
Reactant: COc1nc(Cl)cc(Oc2cc(C)c3[nH]c(=O)oc3c2)n1
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(Oc2cc(C)c3[nH]c(=O)oc3c2)cc(N2CCC3(CC2)OC(=O)Nc2ncccc23)n1

Procedure:
58 mg (0.23 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 70 mg (0.20 mmol) 6-(6-chloro-2-methoxypyrimidin-4-yloxy)-4-methylbenzo[d]oxazol-2(3H)-one and 0.10 mL DIPEA (0.57 mmol) in 1.0 mL DMF were stirred for 3 h at 90° C. The reaction mixture was mixed with water, the precipitate w suction filtered, washed and dried. The residue was purified by preparative HPLC-MS. The fractions containing product were combined and freeze-dried.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN([C:29]([O:33][N:34]1N=NC2C=CC=C[C:35]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.Cl>CN(C=O)C.O>[CH3:29][O:33][N:34]([CH3:35])[C:14]([C@@H:10]1[O:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:16]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](C(=O)O)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)[C@H]1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Yield: 112.4 %

Procedure:
To a solution of (R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (1.05 g, 4.54 mmol) in DMF (10 mL) at 0° C. C, was added DIEA (3.9 mL, 22.7 mmol), followed by HBTU (1.89 g, 4.99 mmol) and HOBt (0.67 g, 4.99 mmol). MeONMHMe.HCl (0.48 g, 4.92 mmol) was added and the resulting solution was warmed to rt and stirred until no starting material remained (˜2 h). The mixture was diluted with H2O (10 mL) and extracted with EtOAc (4×10 mL). The combined organic layers were washed with 1 N aq HCl (10 mL), 1 N aq NaOH (3×10 mL), water (2×10 mL) and brine (10 mL), and dried over Na2SO4. The solvent was removed under vacuum to give (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate (1.40 g, quant.), which was used without further purification. 1H NMR (400 MHz, CDCl3): 4.36 (br, 1 H), 4.08 (m, 1 H), 4.00 (d, 1 H), 3.84 (m, 1 H), 3.76 (s, 3 H), 3.58 (m, 1 H), 3.20 (s, 3 H), 3.04 (m, 2 H), 1.44 (s, 9 H); MS m/z 297 (M+Na+).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11](O)[C:10]2[C:5](=[C:6]([O:14][CH3:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:11]1[C:10]2[C:5](=[C:6]([O:14][CH3:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([CH2:1][CH3:2])[CH:12]=1
Reactant: CCc1cc(O)c2cccc(OC)c2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CCc1cc(Cl)c2cccc(OC)c2n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-ethyl-4-hydroxy-8-methoxyquinoline (9.96 g) in phosphoryl chloride (30 ml) was added N,N-dimethylaniline (12.44 ml) below 8° C. in an ice bath. After 10 minutes the mixture was stirred at ambient temperature for 1.5 hours. The solvent was removed in vacuo. The residue was partitioned into dichloromethane and saturated sodium bicarbonate solution. The organic layer was washed with brine and dried over magnesium sulfate. The organic layer was evaporated in vacuo. The residue was purified by column chromatography (hexane--ethyl acetate) and recrystallized from hexane to give 4-chloro-2-ethyl-8-methoxyquinoline (8.90 g) as crystals. mp: 80-81° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][CH2:13][C:14]2=[O:17])=[CH:9][CH:8]=1)(=O)=O.[C:20]1(OB(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>O>[C:20]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][C:14]3=[O:17])=[CH:9][CH:8]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CCCc2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: OB(O)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CCCc2ccc(-c3ccccc3)cc21
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
While stirring a mixture comprising 15.32 g (52.06 mmol) of 7-trifluoromethanesulfonyloxy-3,4-dihydro-1(2H)-naphthalenone obtained in the Synthesis Example A-1, 12.7 g (104.12 mmol) of phenylboric acid, 10.8 g (78.09 mmol) of potassium carbonate and 450 ml of toluene at room temperature, nitrogen gas was bubbled thereinto for 30 minutes. Next, 1.81 g (1.57 mmol) of tetrakistriphenylphosphine palladium was added thereto. The mixture was slowly heated to thereby maintain the bulk temperature at about 90° C. After stirring at this temperature for 90 minutes, the reaction mixture was cooled and water was added thereto. The insoluble matters were filtered through celite and thoroughly washed with ethyl acetate. The organic phase was collected, washed successively with a saturated aqueous solution of sodium hydrogencarbonate, water, 1N hydrochloric acid, water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography. After successively eluting with hexane:ethyl acetate in a ratio ranging from 20:1 (v/v) to 12:1 (v/v), 9.53 g of the title compound was obtained as white crystals. Yield 82%.
Reaction SMILES: [ClH:1].[Si]([O:9][CH2:10][CH:11]1[N:16]([CH2:17][CH:18]([N:22]2[CH:26]=[C:25]([C:27]3[C:28]4[CH:35]=[CH:34][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:29]=4[N:30]=[CH:31][N:32]=3)[CH:24]=[N:23]2)[CH2:19][C:20]#[N:21])[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]1)(C(C)(C)C)(C)C>O1CCOCC1>[ClH:1].[OH:9][CH2:10][CH:11]1[CH2:12][NH:13][CH2:14][CH2:15][N:16]1[CH2:17][CH:18]([N:22]1[CH:26]=[C:25]([C:27]2[C:28]3[CH:35]=[CH:34][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:41])([CH3:43])[CH3:42])[C:29]=3[N:30]=[CH:31][N:32]=2)[CH:24]=[N:23]1)[CH2:19][C:20]#[N:21]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(CC#N)n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C(CO[Si](C)(C)C(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCNCC4CO)c3)ncnc21
Reaction time: 1.33 h

Procedure:
4.0 M of hydrogen chloride in p-dioxane (1.6 mL, 6.4 mmol) was added to a solution of tert-butyl 3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-{3-cyano-2-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}piperazine-1-carboxylate (0.32 g, 0.45 mmol, a mixture of diastereomers from Step 3) in 1,4-dioxane (2 mL). After stirring for 80 min, solvent was removed from the mixture in vacuo to afford the product as a light yellow solid, which was used without further purification (270 mg). LCMS (M+H)+: 497.2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.[H][H]>C1COCC1.C(O)C.[Rh]>[OH:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:13][CH2:12][CH:8]([C:9]([OH:11])=[O:10])[CH2:7][CH2:6]1
Reactant: [H][H]
Reactant: O=C(O)c1ccc(OCCO)cc1
Agent: [Rh]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C1CCC(OCCO)CC1

Procedure:
1.00 g (5.49 mmol) of 4-(2-hydroxyethoxy)benzoic acid is dissolved in 30 ml of dry THF and 30 ml of dry ethanol, and 1.13 mg (0.55 mmol) of rhodium on alumina are added. The reaction mixture is hydrogenated at +50° C. at a hydrogen pressure of 50 bar for 12 h. The mixture is then hydrogenated at +60° C. at a hydrogen pressure of 80 bar for a further 48 h. After filtration, the filtrate is concentrated on a rotary evaporator. The residue is directly used in the next reaction without further purification.