Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[ClH:1].[ClH:1].[N:13]1([CH:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=3)[CH2:8]2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: O=C1CCc2cc(Cl)ccc2C1
Reactant: C1CNCCN1
Solvent: Cc1ccccc1
Product: Cl
Product: Clc1ccc2c(c1)CCC(N1CCNCC1)C2
Yield: 81.7 %

Procedure:
A mixture consisting of 6-chloro-2-tetralone (5.41 g), piperazine (5.16 g), and 4A molecular sieves (8 g) in 100 ml of dry toluene was heated at reflux with stirring for a short period of time under nitrogen. The toluene was evaporated, and 100 ml of THF and 10 ml of methanol were added to the residue. Sodium cyanoborohydride (1.86 g) was added, the solution was stirred in the cold under nitrogen, and gaseous HCl was added portionwise periodically above the surface until the reaction solution remained acidic. After stirring at room temperature overnight, the sieves were filtered off, and the filtrate was evaporated to dryness. The residue was partitioned between 1N HCl and ether; the aqueous phase was separated and extracted twice with ether. The solution was made basic with sodium hydroxide. The oil which formed was extracted into ether, and the ether solution was dried over Na2SO4. Evaporation of the ether left of a solid (5.1 g). A solution of the solid in ethanol was treated with excess gaseous HCl. After chilling for a period of time, the crystals which had separated were filtered and washed with ethanol. After recrystallization from methanol there was obtained 2.64 g of the title compound. m.p. 264-265° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24](=O)[C:23](=[C:35](SC)[S:36][CH3:37])[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:42][NH2:43]>C(O)C>[C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][C:25]4[C:24]5=[N:42][NH:43][C:35]([S:36][CH3:37])=[C:23]5[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CSC(SC)=C1CCc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2C1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CSc1[nH]nc2c1CCc1nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc1-2
Temperature: 80 °C
Yield: 28.1 %

Procedure:
To a solution of tert-butyl(1-(4-(6-(bis(methylthio)methylene)-5-oxo-3-phenyl-5,6,7,8-tetrahydroquinolin-2-yl)phenyl)cyclobutyl)carbamate (200 mg, 0.35 mmol) in anhydrous ethanol (1.7 mL) was added hydrazine monohydrate (25 μL, 0.52 mmol). The reaction mixture was heated to 80° C. under a nitrogen atmosphere for 2 hours. After cooling to room temperature the reaction mixture was concentrated to dryness under reduced pressure, purified by Biotage chromatography (silica, hexane:ethyl acetate, gradient elution from 90:10 to 80:20) to give the desired product as a yellow solid (53 mg, 28% yield). 1H-NMR (500 MHz, CDCl3) δ 7.94 (1H, s), 7.16-7.24 (4H, m), 7.11-7.16 (3H, m), 7.06-7.10 (2H, m), 3.16 (2H, t), 2.83 (2H, t), 2.35 (3H, s), 2.15-2.45 (4H, br m), 1.88-2.01 (1H, m), 1.64-1.77 (1H, m), 1.00-1.35 (9H, br m). LCMS (Method A) RT=6.94 min, M+H+=539.15.
Reaction SMILES: [Li].C([N-]C(C)C)(C)C.[CH2:9]([O:11][C:12](=[O:18])[CH2:13][O:14][CH2:15][CH2:16][CH3:17])[CH3:10].[CH3:19][Si:20]([CH3:37])([CH3:36])[CH2:21][CH2:22][O:23][CH2:24][N:25]1[C:33]2[C:28](=[CH:29][C:30]([CH:34]=[O:35])=[CH:31][CH:32]=2)[CH:27]=[CH:26]1>O1CCCC1>[CH2:9]([O:11][C:12](=[O:18])[CH:13]([O:14][CH2:15][CH2:16][CH3:17])[CH:34]([OH:35])[C:30]1[CH:29]=[C:28]2[C:33](=[CH:32][CH:31]=1)[N:25]([CH2:24][O:23][CH2:22][CH2:21][Si:20]([CH3:36])([CH3:19])[CH3:37])[CH:26]=[CH:27]2)[CH3:10]
Reactant: C[Si](C)(C)CCOCn1ccc2cc(C=O)ccc21
Reactant: CCCOCC(=O)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CCCOC(C(=O)OCC)C(O)c1ccc2c(ccn2COCC[Si](C)(C)C)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
To a solution of 30 mmol lithium-diisopropylamide in 50 ml tetrahydrofuran were added at −78° C. 4.39 g propoxy-acetic acid ethyl ester [Journal of the American Chemical Society (1996), 118(41), 9901-9907] dissolved in 25 ml of tetrahydrofuran; after 30 min. stirring at −78° C., a solution of 3.31 g 1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole-5-carbaldehyde in 30 ml tetrahydrofuran was added and after another 30 min., the reaction mixture was quenched with 25 ml H2O and then warmed up to ambient temperature. It was then extracted with ethyl acetate and the combined organic phases were washed with water, dried over magnesium sulfate and evaporated to give a light brown oil which was purified by chromatography (silicagel, eluent: gradient of n-heptane/EtOAc) to yield 4.65 g 3-hydroxy-2-propoxy-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-5-yl]-propionic acid ethyl ester (mixture of diasteromers) as a yellow oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([C:15]2[C:16]([C:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH:22]=3)=[N:17][CH:18]=[CH:19][N:20]=2)[CH2:12]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:24]1[CH2:23][CH:22]=[C:21]([C:16]2[C:15]([CH:13]3[CH2:12][N:11]([C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:1]=4)[CH2:14]3)=[N:20][CH:19]=[CH:18][N:17]=2)[CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2nccnc2C2CN(c3ccc4ccccc4n3)C2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1=C(c2nccnc2C2CN(c3ccc4ccccc4n3)C2)CCNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
A mixture of tert-butyl 4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.100 g, 0.225 mmol, SCHEME 5) CH2Cl2 (1 mL) and TFA (0.174 mL, 2.255 mmol) was stirred at RT for 1 h. LCMS showed the product and no more starting material was present. The mixture was concentrated in vacuo and neutralized with Na2CO3. The mixture was extracted with a mixture of CHCl3:i-PrOH (3:1) three times. The organic layer was dried over Na2SO4 and concentrated in vacuo. The product was obtained as a white solid (77 mg, 99%).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:21]=[CH:20][CH:19]=[CH:18][C:7]=1[CH2:8][N:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]=[C:10]1[CH2:16]O>>[Cl:5][C:6]1[CH:21]=[CH:20][CH:19]=[CH:18][C:7]=1[CH2:8][N:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]=[C:10]1[CH2:16][Cl:3]
Reactant: Cc1nc(CO)n(Cc2ccccc2Cl)c1C
Reactant: O=S(Cl)Cl
Product: Cc1nc(CCl)n(Cc2ccccc2Cl)c1C
Temperature: 50 °C

Procedure:
To 3 ml of thionyl chloride is added 2.39 g (9.5 mmol) of 1- (2-chlorobenzyl)-4,5 dimethyl-2-hydroxymethylimidazole. The mixture is heated at 50° C. for about 5 min., and the thionyl choride is evaporated in vacuo. The residue is then dissolved in 10 ml of dichloromethane, and subsequently evaporated in vacuo. This is repeated twice to give 1-(2-chlorobenzyl)-4,5-dimethyl-2-chloromethylimidazole (4) as a cream colored foam which is used without further purification.
Reaction SMILES: [ClH:1].[CH:2]([O:5][C:6]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:7]=1[C:8]#[N:9])([CH3:4])[CH3:3].[CH2:16]([OH:18])[CH3:17]>>[ClH:1].[CH:2]([O:5][C:6]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:7]=1[C:8](=[NH:9])[O:18][CH2:16][CH3:17])([CH3:4])[CH3:3]
Reactant: COc1ccc(C#N)c(OC(C)C)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1ccc(OC)cc1OC(C)C
Temperature: 25 °C
Reaction time: 168 h
Yield: 99 %

Procedure:
Hydrogen chloride gas was passed through a solution of 2-isopropoxy-4-methoxybenzonitrile (13.2 g, 69 mmol) in absolute ethanol (200 mL) in a pressure tube for 1 h at −10° C. The tube was sealed and stirred at room temperature for 7 d. The tube was cooled to −10° C. and more ethanol (100 mL) was added. Hydrogen chloride gas was passed through it for additional 30 min at −10° C. The tube was resealed and stirred at room temperature for 7 d. Evaporation of the solvents and trituration of the residue in diethyl ether gave ethyl 2-isopropoxy-4-methoxy-benzimidate hydrochloride as a white solid (17.5 g, 99%). It was used without further purification.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:30][C:31]1[CH:35]=[CH:34][O:33][C:32]=1[CH3:36]>O>[CH3:36][C:32]1[O:33][CH:34]=[CH:35][C:31]=1[CH2:30][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Reactant: Cc1occc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2Cc2ccoc2C)CC1
Reaction time: 0.5 h
Yield: 19 %

Procedure:
To a stirred mixture of 4.6 parts of a sodium hydride dispersion 50% and 450 parts of N,N-dimethylformamide were added portionwise 57.6 parts of ethyl 4-(1H-benzimidazol-2-ylamino)-1-piperidinecarboxylate under nitrogen atmosphere. Upon complete addition, stirring was continued for 30 minutes at room temperature. 27.0 Parts of 3-(chloromethyl)-2-methylfuran were added dropwise while cooling. Upon completion, stirring was continued for 1 hour. Water was added dropwise to the mixture and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was stirred in 1,1'-oxybisethane. The solid product was filtered off and purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was stirred in 1,1'-oxybisethane. The product was filtered off and dried, yielding 37.5 parts (19.0%) of ethyl 4-[[1-[(2-methyl-3-furanyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate; mp. 150.4° C. (int. 23).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:4][C:3]=1[C:22](=O)[CH3:23].Cl.O>[Pd].C(O)(=O)C>[CH2:22]([C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:6]=[CH:7][C:2]=1[OH:1])[CH3:23]
Reactant: CCCCCCCCCCCCCCc1ccc(O)c(C(C)=O)c1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCc1ccc(O)c(CC)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 72.6 %

Procedure:
A mixture of 23 g of 1-(2-hydroxy-5-tetradecylphenyl)ethanone, 5 g of 5% palladium on carbon catalyst, 10 ml of concentrated hydrochloric acid, 100 ml of water and 100 ml of glacial acetic acid was warmed to 50° C. and then hydrogenated in a Parr apparatus for 24 hours. This mixture was filtered, the solvent removed and the residue dissolved in ether. The ether solution was washed with water, then a small amount of dilute aqueous sodium bicarbonate and dried. The residue was purified by HPLC, giving 16 g of the desired compound, mp 45.5°-46.5° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.Cl[C:25]([O:27][CH2:28][CH:29]1[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:26]>ClCCl.C(OCC)C>[CH:40]1[C:41]2[CH:29]([CH2:28][O:27][C:25]([N:7]3[C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[CH2:10][N:4]4[CH:3]=[CH:2][CH:1]=[C:5]4[CH2:6]3)=[O:26])[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:36]=2[CH:37]=[CH:38][CH:39]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.9 %

Procedure:
To a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (19.23 g, 0.104 mol) and N,N-diisopropylethylamine (27.3 mL, 0.157 mol) in dichloromethane (500 mL) was added 9-fluorenylmethyl chloroformate (27 g, 0.104 mol). The reaction mixture was stirred at room temperature under nitrogen for 4 hours, and then washed with 1 M hydrochloric acid (3×300 mL), water (300 mL) and brine (300 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a pale yellow solid. The solid was slurried in dichloromethane (75 mL), the slurry was diluted with diethyl ether (300 mL) and the resulting white suspension stirred overnight. Filtration afforded the title compound (34.64 g, 82%) as a white solid, m.p. 141-142° C.
Reaction SMILES: [C:1]([Mg]Br)([CH3:3])=[CH2:2].[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]([N+:22]([O-:24])=[O:23])=[C:18]([CH:21]=1)[CH:19]=[O:20])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.Cl>C1COCC1>[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]([N+:22]([O-:24])=[O:23])=[C:18]([CH:19]([OH:20])[C:1]([CH3:3])=[CH2:2])[CH:21]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C=C(C)[Mg]Br
Reactant: O=Cc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)C(O)c1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
35.9 ml (16.33 mmol) of a 0.5 M isopropenylmagnesium bromide solution in THF are slowly added at −78° C. to a solution of 3.0 g (11.66 mmol) of 5-benzyloxy-2-nitrobenzaldehyde in 50 ml of THF. After addition is complete, the mixture is stirred at −78° C. for 2 h, then treated with 40 ml of water and warmed to room temperature. The mixture is treated with 10 ml of 1 N hydrochloric acid, the aqueous phase is extracted 2× with ethyl acetate, and the combined organic extracts are dried over sodium sulphate and freed from the solvent in vacuo. Purification of the crude product on silica gel (CH2Cl2) affords 1.7 g (48.7%) of 1-[5-(benzyloxy)-2-nitrophenyl]-2-methyl-2-propen-1-ol as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:24][C:25]1[CH:31]=[CH:30][C:28]([OH:29])=[CH:27][C:26]=1[OH:32].Cl>C1(C)C(C)=CC=CC=1>[Cl:24][C:25]1[C:26]([OH:32])=[CH:27][C:28]([OH:29])=[C:30]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]=[C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:3]=2)[CH:31]=1
Reactant: Oc1ccc(Cl)c(O)c1
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1C
Product: Oc1cc(O)c(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)cc1Cl
Temperature: 80 °C
Yield: 78.5 %

Procedure:
To a 350 mL sulfonation flask equipped with a mechanical stirrer, condenser and a nitrogen atmosphere are charged 26.8 g (100 mmol) of 2-chloro4,6-diphenyl-s-triazine, and 100 mL, of xylene (mixture of isomers). To the beige suspension are added 14.9 g (112 mmol) of aluminum chloride in one portion. The mixture is warmed to ca. 80° C. for 2 hours. 17.4 g (120 mmol) of 4-chlororesorcinol are then added in five portions over 40 minutes to the now homogeneous solution. The reaction mixture is heated at 90° C. for 42 hours and refluxed for another 24 hours. After cooling to room temperature, the contents of the flask are poured into 100 mL of 12% aqueous hydrochloric acid. The precipitate formed is removed by filtration, washed to pH 7 with water, rinsed with methanol and dried at 70° C. under vacuum. The rifle compound is obtained as a crude ocher-red product (29.5 g) and melts at 255°-265° C. It can be used without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C@H:9]1[CH2:37][C@@:36]2([CH3:38])[C@@H:20]([CH2:21][C@H:22]([CH3:46])[C@:23]2([O:39][C:40](=[O:45])[CH2:41][CH2:42][CH2:43][CH3:44])[C:24](=[O:35])[CH:25]([O:27][C:28](=[O:34])[C@@H:29]([NH2:33])[CH:30]([CH3:32])[CH3:31])[OH:26])[C@H:19]2[C@@:10]1([F:49])[C@:11]1([CH3:48])[C:16]([CH2:17][CH2:18]2)=[CH:15][C:14](=[O:47])[CH:13]=[CH:12]1.[NH:50]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[C@H:51]([C:53]([NH:55][C@H:56]([C:58]([N:60]1[CH2:67][CH2:66][CH2:65][C@H:61]1[C:62](O)=[O:63])=[O:59])[CH3:57])=[O:54])[CH3:52].CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[F:49][C@:10]12[C@@H:9]([OH:8])[CH2:37][C@@:36]3([CH3:38])[C@@H:20]([CH2:21][C@H:22]([CH3:46])[C@:23]3([O:39][C:40](=[O:45])[CH2:41][CH2:42][CH2:43][CH3:44])[C:24](=[O:35])[CH:25]([O:27][C:28](=[O:34])[C@H:29]([CH:30]([CH3:32])[CH3:31])[NH:33][C:62](=[O:63])[C@@H:61]3[CH2:65][CH2:66][CH2:67][N:60]3[C:58](=[O:59])[C@H:56]([CH3:57])[NH:55][C:53](=[O:54])[C@H:51]([CH3:52])[NH:50][C:68]([O:70][C:71]([CH3:72])([CH3:73])[CH3:74])=[O:69])[OH:26])[C@@H:19]1[CH2:18][CH2:17][C:16]1[C@:11]2([CH3:48])[CH:12]=[CH:13][C:14](=[O:47])[CH:15]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CCCCC(=O)O[C@]1(C(=O)C(O)OC(=O)[C@@H](N)C(C)C)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: CCCCC(=O)O[C@]1(C(=O)C(O)OC(=O)[C@@H](NC(=O)[C@@H]2CCCN2C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(C)C)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Temperature: 25 °C
Reaction time: 20 h
Yield: 63 %

Procedure:
1.04 g (1.50 mmol) of H-Val-O-BMV x TFA (Example 37), 500 mg (1.40 mmol) of Boc-Ala-Ala-Pro-OH and 168 mg (1.40 mmol) of Nhydroxybenzotriazole are dissolved in this sequence in 50 ml of dichloromethane, and 330 μl (3.00 mmol) of N-methylmorpholine is added. Then, a solution of 289 mg (1.40 mmol) of dicyclohexylcarbodiimide in 2 ml of dichloromethane is added and stirred for 20 hours at room temperature. Then, it is suctioned off from precipitated urea, the filtrate is concentrated by evaporation and filtered again. Chromatography of this amount of raw material (300 g of silica gel, hexane/acetone 1:1) yields 806 mg(63% ) of N-(N-(N-(N-((1,1-dimethyl)ethoxycarbonyl)-L-alanyl) -L-alanyl)-L-prolyl)-L-valine [9α-fluoro-11β,21-dihydroxy-16β-methyl-3,20-dioxo-17-valeroyloxy-pregna-1,4-dien-21-yl ] ester. Crystallization from dichloromethane/diisopropyl ether 542 mg (42%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.FC(F)(F)S(O[C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[Si](C)(C)C)(=O)=O.[F-].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1>[C:15]1([CH:16]2[O:17][CH:2]3[CH:3]=[CH:4][C:5]4[C:10]([N:1]3[C:33]3[CH:32]=[CH:31][C:30]5[C:35]([C:34]2=3)=[CH:26][CH:27]=[CH:28][CH:29]=5)=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:18]=[CH:19][CH:12]=[CH:13][CH:14]=1
Reactant: C[Si](C)(C)c1ccc2ccccc2c1OS(=O)(=O)C(F)(F)F
Reactant: O=Cc1ccc(Cl)cc1
Reactant: c1ccc2ncccc2c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: C1=CC2OC(c3ccccc3)c3c(ccc4ccccc34)N2c2ccccc21
Yield: 67 %

Procedure:
Following the general procedure, treatment of quinoline (0.064 g, 59 μL, 0.50 mmol) and 4-chlorobenzaldehyde (0.105 g, 0.75 mmol) with 2-(trimethylsilyl)naphthalen-1-yl trifluoromethanesulfonate (0.209 g, 0.60 mmol) in the presence of KF (0.070 g, 1.2 mmol) and 18-crown-6 (0.317 g, 1.2 mmol) in THF (2.0 mL) at −10° C. to room temperature for 12 hrs followed by flash column chromatography (Pet. Ether/EtOAc=75/25) of the crude reaction mixture afforded 5-phenyl-5H,6aHnaphtho[2′,1′:4,5][1,3]oxazino[3,2-a]quinoline as a yellow solid (0.133 g, 67% yield, dr determined by 1H NMR analysis of crude reaction mixture is >20:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].[F:27][C:28]1[CH:29]=[C:30]([N:35]2[CH:39]=[CH:38][C:37]([NH2:40])=[N:36]2)[CH:31]=[CH:32][C:33]=1[F:34].N1C2C(=NC=CC=2)N(O)N=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17](=[O:19])[NH:40][C:37]3[CH:38]=[CH:39][N:35]([C:30]4[CH:31]=[CH:32][C:33]([F:34])=[C:28]([F:27])[CH:29]=4)[N:36]=3)=[CH:20][CH:21]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: Nc1ccn(-c2ccc(F)c(F)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccn(-c5ccc(F)c(F)c5)n4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 60 h
Yield: 92.3 %

Procedure:
To a solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (0.050 g, 0.13 mmol), 1-(3,4-difluorophenyl)-1H-pyrazol-3-amine (0.028 g, 0.15 mmol), and 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (0.018 g, 0.13 mmol) in DMF (0.7 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.028 g, 0.15 mmol), and the reaction was allowed to stir at ambient temperature for 60 hours. The reaction was diluted with EtOAc and washed with 10% citric acid, saturated sodium bicarbonate, and saturated sodium chloride. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a linear gradient of 5-70% EtOAc/hexanes to yield the desired product (0.067 g, 0.12 mmol, 91% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH:9]([CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:10](O)=[O:11])[N:5]=[CH:4][C:3]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27].[NH2:28][C:29]1[CH:33]=[CH:32][N:31]([CH2:34][C:35]([CH3:38])([OH:37])[CH3:36])[N:30]=1>>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH:9]([CH2:13][CH:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:10]([NH:28][C:29]2[CH:33]=[CH:32][N:31]([CH2:34][C:35]([OH:37])([CH3:36])[CH3:38])[N:30]=2)=[O:11])[N:5]=[CH:4][C:3]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27]
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCOCC1)n1ncc(Oc2ccccc2Cl)c(Cl)c1=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCOCC2)n2ncc(Oc3ccccc3Cl)c(Cl)c2=O)n1

Procedure:
Using the method described in Example 49 from 2-[5-chloro-4-(2-chloro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(tetrahydro-pyran-4-yl)-propionic acid (Intermediate 96) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 2-[5-chloro-4-(2-chloro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide (354 mg); ES+-HRMS m/e calcd for C25H29N5O5Cl2 [M+H+] 550.1619 found 550.1622. 1H NMR (300 MHz, CDCl3) δ ppm 1.17 (s, 6H), 1.22-1.55 (m, 4H), 1.55-1.77 (m, 2H), 2.10-2.25 (m, 2H), 3.24-3.41 (m, 2H), 3.86-3.96 (m, 2H), 3.98 (s, 2H), 5.75 (t, J=7.5 Hz, 1H), 6.65 (d, J=1.8 Hz, 1H), 7.23-7.26 (m, 1H), 7.29-7.35 (m, 2H), 7.35-7.43 (m, 1H), 7.49 (s, 1H), 7.54 (d, J=7.8 Hz, 1H), 8.74 (br. s., 1H).