Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25](O)=[O:26]>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=3)=[O:26])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1ccccn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3ccccn3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and pyridine-2-carboxylic acid following procedure I yielded the title compound as a colorless solid. MS (ISP): m/z=365.2 [M+H]+.
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[NH:10][N:9]2[CH:13]=[CH:14][CH:15]=[C:8]2[C:7]=1[OH:16])=[O:5])C.[NH2:17][CH2:18][C:19]([O-:21])=[O:20].[Na+]>COCCO>[OH:16][C:7]1[C:8]2[N:9]([CH:13]=[CH:14][CH:15]=2)[NH:10][C:11](=[O:12])[C:6]=1[C:4]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:5]
Reactant: CCOC(=O)c1c(O)c2cccn2[nH]c1=O
Reactant: NCC(=O)[O-]
Agent: [Na+]
Solvent: COCCO
Product: O=C(O)CNC(=O)c1c(O)c2cccn2[nH]c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (1.0 eq.) and sodium glycinate (15 eq.) in 2-methoxyethanol. ESI (m/z): 252 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@@H:12]([CH2:22][O:23][CH3:24])[O:11][C@H:10]1[N:25]1[CH:33]=[N:32][C:31]2[C:26]1=[N:27][C:28]([CH2:49][C:50]#[N:51])=[N:29][C:30]=2[NH:34][CH2:35][CH:36]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N.[H][H]>C(O)C.[Ni]>[NH2:51][CH2:50][CH2:49][C:28]1[N:27]=[C:26]2[C:31]([N:32]=[CH:33][N:25]2[C@H:10]2[C@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[C@H:13]([O:14][Si:15]([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16])[C@@H:12]([CH2:22][O:23][CH3:24])[O:11]2)=[C:30]([NH:34][CH2:35][CH:36]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:29]=1
Reactant: [H][H]
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CC#N)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [Ni]
Agent: N
Solvent: CCO
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCN)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 96 h
Yield: 56.7 %

Procedure:
A solution of 2-{9-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}acetonitrile (1.9 g, 2.6 mmol) (preparation 17) in ethanol (40 ml) saturated with ammonia gas was treated with Raney Nickel (400 mg), pressurised to 414 kPa (60 psi) with hydrogen in a sealed vessel and stirred at room temperature for 4 days. The mixture was then filtered through Arbocel (trade mark) and the residue washed with ethanol. The solvent was removed under reduced pressure from the filtrate, the residue dissolved in pentane and the solvent again removed under reduced pressure to give the title compound as a powder (1.08 g). MS: 733 (MH+).
Reaction SMILES: [CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[NH:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Br>>[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][N:10]1[C:11]([CH3:15])([CH3:14])[C:12](=[O:13])[N:9]1[CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Clc1ccccc1CBr
Reactant: CC1(C)NN(C2CCCCCCC2)C1=O
Product: CC1(C)C(=O)N(C2CCCCCCC2)N1Cc1ccccc1Cl

Procedure:
2-Cyclooctyl-4,4-dimethyl-1,2-diazetidin-3-one and 2-chlorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([Cl:13])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:16][CH2:17][C@@H:18]([OH:20])[CH3:19]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:16]([CH2:17][C@@H:18]([OH:20])[CH3:19])[C:5]=32)=[CH:10][CH:9]=1
Reactant: O=CCC1Cc2ccc(Cl)cc2C1=O
Reactant: C[C@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@H](O)Cn1ccc2c1-c1cc(Cl)ccc1C2
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
A solution of 2.5 g of (RS)-2-(2-oxoethyl)-6-chloro-1-indanone and 100 mg of p-toluenesulfonic acid in 120 ml in anhydrous toluene was heated on a water separator. A solution of 3.6 g of (S)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for 30 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1.56 g (53%) of (S)-1-(7-chloro-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil which was used directly in the next reaction.
Reaction SMILES: [CH3:1][C:2]1([OH:26])[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:10]=2)[NH:5][CH2:4][CH2:3]1.O=[CH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[OH:26][C:2]1([CH3:1])[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=3)[N:10]=2)[N:5]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:4][CH2:3]1
Reactant: CCOC(=O)CCCCCC=O
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)C(C)(O)CCN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)CCCCCCN1CCC(C)(O)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 8-methyl-2,3-di-p-tolyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazin-8-ol (Intermediate G) (290 mg, 0.840 mmol) in DCE (10 ml) was added ethyl 7-oxoheptanoate (434 mg, 2.52 mmol) followed by sodium triacetoxyborohydride (534 mg, 2.52 mmol). The reaction mixture was left to stir overnight at room temperature under an atmosphere of nitrogen and then water was added (20 ml). The product was extracted with EtOAc (2×20 ml) and the combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give a crude brown oil. Purification of the crude product by C18 reverse phase chromatography eluting with water/acetonitrile afforded the title compound;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11]COC)=[CH:7][C:4]=1[CH:5]=[O:6].Cl>C1COCC1.O>[OH:11][C:8]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[C:4]([CH:7]=1)[CH:5]=[O:6]
Reactant: COCOc1ccc(OC)c(C=O)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(O)cc1C=O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-methoxy-5-(methoxymethoxy)benzaldehyde (10 g, 0.05 mol) in THF (100 mL) was added 3 N HCl (150 mL). The reaction was stirred at 50° C. for 30 min, cooled to rt, and diluted with water (100 mL). The mixture was neutralized to pH 7-8 and extracted with EtOAc (200 mL) three times. The organic layer was dried over Na2SO4 and concentrated to give 5-hydroxy-2-methoxybenzaldehyde.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([OH:22])=O)[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][OH:29].ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[C:20]([NH:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][OH:29])=[O:22])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: NCCOCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCCOCCO
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
To a solution of N-t-butoxycarbonyl-L-tryptophan, (128 g, 0.42 mol), 2-(2-aminoethoxy)ethanol (46.42 g, 0.44 mol), 1-hydroxybenzotriazole (60.0 g, 0.44 mol) in 700 mL of DMF at 0° C. was added DCC (100 g, 0.48 mol). After stirring at 0° C. for 15 minutes, the mixture was stirred at room temperature overnight. The white solids were filtered and washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was taken up in ether and a small amount of EtOAc, washed with it HCl (3×500 mL), saturated NaHCO3 (3×500 mL), and brine (3×500 mL). The organic layer was dried (MgSO4), filtered and concentrated to give 2-(S)-t-butoxycarbonylamino-N-[2-(2-hydroxy-ethoxy)ethyl]-3-(1H-indol-3-yl)-propionamide, 150 g (yield 91%), MS: 392.2 (M+H)+.
Reaction SMILES: C1(C[O:8][CH2:9][CH:10]2[S:14][CH2:13][CH:12]([S:15][C:16](=[O:18])[CH3:17])[CH2:11]2)C=CC=CC=1.B(F)(F)F.CCOCC>C(Cl)(Cl)Cl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:8][CH2:9][CH:10]1[S:14][CH2:13][CH:12]([S:15][C:16](=[O:18])[CH3:17])[CH2:11]1
Reactant: CC(=O)SC1CSC(COCc2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: FB(F)F
Agent: [I-]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CC(=O)SC1CSC(CO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
A 0° C. solution, under argon, of 0.123 g of product from Example 139 in 1.0 ml of dry chloroform is treated with 51.1 microliter of boron trifluoride etherate and 0.193 g of tetra n-butylammonium iodide. The reaction mixture is stirred at room temperature overnight and concentrated in vacuo. The residue is purified by chromatography (silica gel: 0-100% ethyl acetate/hexane) to give 0.079 g of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=O)[CH3:11])=[CH:4][CH:3]=1.[CH3:13][NH:14][CH3:15]>C(O)C.Cl.[Pd]>[CH3:13][N:14]([CH3:15])[CH:10]([CH3:11])[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: CC(=O)CCc1ccc(O)cc1
Reactant: CNC
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(CCc1ccc(O)cc1)N(C)C
Reaction time: 8 h
Yield: 47 %

Procedure:
A solution of 4-(4-hydroxyphenyl)-2-butanone (100 g) in 500 ml of ethanol with anhydrous dimethylamine (300 ml) and 5% palladium on sulfide carbon (100 g) was placed in a high pressure reaction vessel and kept under 1000 psi of H2 at 175° C. for 8 hours. The resultant solution was then filtered and the solvent removed in vacuo to give an oil which was dissolved in 1N hydrochloric acid (100 ml) and extracted with two 100 ml portions of ether. The aqueous layer was adjusted to pH7 with 2N sodium hydroxide and extracted with an additional two 100 ml volumes of ether. The organic extract was retained and dried and reduced in volume to give 55 g (47% yield) of the desired subtitled intermediate.
Reaction SMILES: Br[C:2]1(Br)[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])=[CH:8][CH:9]=2)[O:4][CH2:3]1.[OH:25][C:26]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)CC)C>CC#N>[OH:25][C:26]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:31][CH2:30][N:29]([C:2]2[C:11](=[O:12])[C:10]3[C:5](=[CH:6][C:7]([O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])=[CH:8][CH:9]=3)[O:4][CH:3]=2)[CH2:28][CH2:27]1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: CC(C)[Si](Oc1ccc2c(c1)OCC(Br)(Br)C2=O)(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)[Si](Oc1ccc2c(=O)c(N3CCC(O)(c4ccccc4)CC3)coc2c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
3,3-Dibromo-7-(triisopropylsilyloxy)-4-chromanone (5.0 g, 10.5 mmol) was dissolved in CH3CN (150 ml) and 4-hydroxy-4-phenylpiperidine (2.2 g, 12.5 mmol) and triethylamine (2.9 ml, 20.8 mmol) were added. The mixture was stirred overnight at ambient temperature, then concentrated and the residue partitioned between ethyl acetate and water. The organic layer was washed with water (2×50 ml) and brine, dried over CaSO4, concentrated, and the residue chromatographed on silica gel, using gradient elution with ethyl acetate/hexane to yield title product as a white solid (2.3 g, 54%). A portion was recrystallized from ethanol/ether; mp 163°-163.5° C.; IR (KBr) 3437, 2950, 2870, 1635, 1615, 1600, 1447, 1285, 1247, 1200, 1185, 703, 690. Anal. Calcd. for C29H39NO4Si: C, 70.55; H, 7.96; N, 2.84. Found: C., 70.44; H, 7.76; N, 2.84.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:5]([NH2:7])=[O:6])[CH3:4].CO.[F:10][C:11]1[CH:12]=[C:13]([CH:24]=[CH:25][CH:26]=1)[CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1>C(N(CC)CC)C>[F:10][C:11]1[CH:12]=[C:13]([CH:24]=[CH:25][CH:26]=1)[CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[N:2][C@H:3]([CH3:4])[C:5]([NH2:7])=[O:6])=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(OCc2cccc(F)c2)cc1
Reactant: C[C@@H](N)C(N)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@@H](N=Cc1ccc(OCc2cccc(F)c2)cc1)C(N)=O
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 49.1 %

Procedure:
In a 250 mL, 4 necked round bottom flask, equipped with mechanical stirrer, thermometer, reflux condenser and under a flow of nitrogen, D-alaninamide hydrochloride (6.1 g) and methanol (80 mL) are charged and stirred for 15 min at 20° C. Triethylamine (5 g) is added at such a rate that the temperature remains below 30° C. The mixture is stirred for 10 min, whereupon solid 4-(3-fluorobenzyloxy)benzaldehyde (10 g, Example 10 b) is added portion wise in about 30 min. After stirring for 3 hours at 20° C., the mixture is cooled to 5° C. After stirring for 3 hours at this temperature, the solid is filtered and washed with small amount of pre-cooled methanol. The wet solid is dried under vacuum for 12 hours a 25° C., yielding 6.4 g of title compound as white solid, with 46.4% yield; m.p 111.9.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]([C:28]1[S:32][CH:31]=[C:30]([C:33]([OH:35])=O)[CH:29]=1)([CH3:27])[CH3:26].[O:36]1[C:41]2([CH2:46][CH2:45][N:44]([CH2:47][C:48]3[C:49]([F:57])=[C:50]([CH2:54][CH2:55][OH:56])[CH:51]=[CH:52][CH:53]=3)[CH2:43][CH2:42]2)[CH2:40][NH:39][CH2:38][CH2:37]1.C(N(CC)CC)C>CN(C=O)C>[F:57][C:49]1[C:50]([CH2:54][CH2:55][OH:56])=[CH:51][CH:52]=[CH:53][C:48]=1[CH2:47][N:44]1[CH2:45][CH2:46][C:41]2([O:36][CH2:37][CH2:38][N:39]([C:33]([C:30]3[CH:29]=[C:28]([CH:25]([CH3:26])[CH3:27])[S:32][CH:31]=3)=[O:35])[CH2:40]2)[CH2:42][CH2:43]1
Reactant: CC(C)c1cc(C(=O)O)cs1
Reactant: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1cc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4F)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HATU (0.183 g) was added in one portion to a stirred solution at 0° C. of 5-isopropylthiophene-3-carboxylic acid (0.063 g) and 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-2-fluorophenyl)ethanol (example 67, step f) (0.114 g) and triethylamine (0.155 mL) in DMF (5 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 2.5% methanol in dichloromethane with 1% triethylamine as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.100 g.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:23])[CH:8]=2)[N:3]=1.[NH:24]1[CH2:34][CH2:33][CH:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:26][CH2:25]1.CN1CCCC1=O>O>[CH2:31]([O:30][C:28]([CH:27]1[CH2:33][CH2:34][N:24]([C:2]2[CH:11]=[C:10]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:23])[CH:8]=3)[N:3]=2)[CH2:25][CH2:26]1)=[O:29])[CH3:32]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Clc1ccc2nc(Cl)cc(NCc3ccc4c(c3)OCO4)c2c1
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)C1CCN(c2cc(NCc3ccc4c(c3)OCO4)c3cc(Cl)ccc3n2)CC1
Reaction time: 3 h

Procedure:
A reaction of a mixture comprising 130 mg of 2,6-dichloro-4-(3,4-methylenedioxybenzyl)aminoquinoline, 500 μl of ethyl isonipecotate and 1 ml of N-methyl-2-pyrrolidone was conducted on an oil bath at 150° C. for 3 hours. The reaction mixture was cooled, followed by the addition of water. The resulting mixture was extracted with ethyl acetate and the ethyl acetate layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography with 20 to 50% ethyl acetate/hexane to give 150 mg of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=[O:5].Cl[CH2:18][C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:19]([CH2:18][O:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=[O:5])#[N:20]
Reactant: N#CCCl
Reactant: Cc1ccc(C(=O)c2ccccc2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2ccccc2OCC#N)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.3 %

Procedure:
A mixture of 2-hydroxy-4'-methylbenzophenone (18.3 g), chloroacetonitrile (7.87 g) and potassium carbonate (14.2 g) in N,N'-dimethylformamide (183 ml) was stirred at ambient temperature for 5 hours and then poured into ice water. The separated oil was extracted with dichloromethane (×2). The organic layer were washed with water (×3), dried and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluted with dichloromethane to give 2-cyanomethoxy-4'-methylbenzophenone (21.3 g) as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23]([OH:25])=O)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][NH:33][CH2:34][CH2:35][OH:36]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:22][C:23]([N:33]([CH2:34][CH2:35][OH:36])[CH2:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=2)=[O:25])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: OCCNCc1ccccn1
Product: Cc1ccc(N(CC(=O)N(CCO)Cc2ccccn2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with 2-[(pyridin-2-ylmethyl)-amino]-ethanol
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:11])=[C:4]([OH:10])[CH:5]=[C:6]([CH:9]=1)[CH:7]=O.[S:12]([CH2:18][C:19]#[N:20])([CH2:15][C:16]#[N:17])(=[O:14])=[O:13].N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[C:15]([C:16]#[N:17])[S:12]([CH2:18][C:19]#[N:20])(=[O:14])=[O:13])[CH:5]=[C:4]([OH:10])[C:3]=1[OH:11]
Reactant: O=Cc1cc(O)c(O)c(Br)c1
Reactant: N#CCS(=O)(=O)CC#N
Solvent: CCO
Solvent: C1CCNCC1
Product: N#CCS(=O)(=O)C(C#N)=Cc1cc(O)c(O)c(Br)c1
Yield: 6.3 %

Procedure:
A mixture of 500 mg of 5-bromo-3,4-dihydroxybenzaldehyde and 700 mg of sulfonly diacetonitrile in 6 ml of ethanol was refluxed with few drops of piperidine for 4 hours. Ethanol was removed in rotavap and the mixture worked up with ethyl acetate, diluted acid and brine. A portion of the crude was then purified by HPLC on a C-18 column to provide about 50 mg of 2-(3-bromo-4,5-dihydroxyphenyl)-1-cyano-1-cyanomethylsulfonly ethene.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH2:13]([N:15]1[C:21]2[N:22]=[CH:23][C:24]([CH2:26][CH2:27][OH:28])=[CH:25][C:20]=2[C:19](=[O:29])[N:18]([CH3:30])[C:17]2[CH:31]=[CH:32][CH:33]=[N:34][C:16]1=2)[CH3:14].O[C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:46]=[C:45]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[O:44][N:43]=2)=[CH:38][C:37]=1[CH3:52].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH2:13]([N:15]1[C:21]2[N:22]=[CH:23][C:24]([CH2:26][CH2:27][O:28][C:36]3[CH:41]=[CH:40][C:39]([C:42]4[CH:46]=[C:45]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[O:44][N:43]=4)=[CH:38][C:37]=3[CH3:52])=[CH:25][C:20]=2[C:19](=[O:29])[N:18]([CH3:30])[C:17]2[CH:31]=[CH:32][CH:33]=[N:34][C:16]1=2)[CH3:14]
Reactant: CCN1c2ncc(CCO)cc2C(=O)N(C)c2cccnc21
Reactant: CCOC(=O)c1cc(-c2ccc(O)c(C)c2)no1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccc(OCCc3cnc4c(c3)C(=O)N(C)c3cccnc3N4CC)c(C)c2)no1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.3 %

Procedure:
DEAD (55 μL, 0.35 mmol) was added over 30 min to a solution of 11-ethyl-5,11-dihydro-8-(2-hydroxyethyl)-5-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (70.0 mg, 0.23 mmol), ethyl 3-(4-hydroxy-3-methylphenyl)-5-isoxazolecarboxylate (86.5 mg, 0.35 mmol) and PPh3 (91.8 mg, 0.35 mmol) in THF (2 mL) at 25° C. The reaction mixture was stirred at 25° C. for 18 h. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (CH2Cl2:EtOAc, 10:1) to give the title compound (55 mg, 45% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10]([NH:14][CH2:15][CH2:16][CH3:17])[CH2:11]2)=[CH:6][CH:5]=1)[CH3:2].[CH3:18][S:19]([N:22]1[CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]1)(=[O:21])=[O:20].CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10]([N:14]([CH2:28][CH:25]3[CH2:26][CH2:27][N:22]([S:19]([CH3:18])(=[O:21])=[O:20])[CH2:23][CH2:24]3)[CH2:15][CH2:16][CH3:17])[CH2:11]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCCNC1CCc2ccc(OCC)cc2C1
Reactant: CS(=O)(=O)N1CCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCCN(CC1CCN(S(C)(=O)=O)CC1)C1CCc2ccc(OCC)cc2C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of afford (7-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine (200 μL of a 0.25M solution in 1,2-dichloroethane, 50 μmole) was added 220 μL of a solution of 1-(methylsulfonyl)-4-piperidinecarboxaldehyde (0.25 M in 1,2-dichloroethane) followed by 30 μL DIEA and 300 μL of a 0.25 M slurry of sodium triacetoxyborohydride in 1,2-dichloroethane. The solution was shaken at 25° C. for 48 h under N2. The reaction was quenched with 1 mL 2% NaOH and the mixture was transferred along with 0.5 mL H2O and EtOAc to workup flasks. The flask was shaken, allowed to settle and the aqueous phase was removed and discarded. The organic phase was washed with water, transferred into a tube and concentrated in vacuo. The final product was isolated by preparative RPHPLC (YMC Combiprep ODS-A column, 10-90% acetonitrile: water (0.1% TFA)) to afford (7-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-(1-methanesulfonyl-piperidin-4-ylmethyl)-propyl-amine (8 mg) 104[M+H]+=409.