Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([O-])([O-])=O.[NH4+].[Ce+4].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=[O:20].[CH2:23]([O:25][C:26]([C:28]1[O:29][C:30]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)=[C:31]2[C:36]=1[CH:35]=[CH:34][CH:33]=[CH:32]2)=[O:27])[CH3:24]>O>[CH2:23]([O:25][C:26](=[O:27])[C:28]([C:36]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:30](=[O:29])[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)=[O:20])[CH3:24]
Reactant: CCOC(=O)c1oc(-c2ccc(Cl)cc2)c2ccccc12
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Product: CCOC(=O)C(=O)c1ccccc1C(=O)c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
11.5 G. of cerium (IV) ammonium nitrate are dissolved in 20 ml. of water and 20 ml. of glacial acid. Thereafter, there are added 3.0 g. of 3-(p-chlorophenyl)-isobenzofuran-1-carboxylic acid ethyl ester and the mixture is boiled for 2-3 minutes until the color of the solution obtained changes from orange to light-yellow. After cooling, there are added 150 ml. of ice-water and the mixture is stirred for 1 hour in an ice-bath. The product which first separates as an oil solidifies. The solid is separated by decantation of the aqueous solution and is dissolved in ether. The ethereal solution is washed with 2-N sodium carbonate and water, dried over sodium sulfate and evaporated. After crystallization of the residue from ethanol, there is obtained [o-(p-chlorobenzoyl)-phenyl]glyoxylic acid ethyl ester in the form of colorless crystals having a melting point of 79°-81° C.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][N:11]=2)[CH2:6][CH2:5]1.F[C:20]1[CH:21]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:24][CH:25]=1.O>CN(C)C=O>[CH3:3][N:4]1[CH2:5][CH2:6][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[N:11]=2)[CH2:8][CH2:9]1
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Reactant: Fc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCC(c2nn(-c3cccc(C(F)(F)F)c3)c3ccccc23)CC1
Temperature: 90 °C
Reaction time: 1 h
Yield: 17.7 %

Procedure:
To a stirred suspension of 4.9 g of a 50% oil dispersion of sodium hydride in 60 ml of dimethylformamide was added dropwise a solution a 10.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole in 80 ml of hot dimethylformamide. The reaction mixture was stirred for 1 hr and then 15.2 g of 3-fluorobenzotrifluoride was added. The reaction was heated at 90° C. for 22 hrs, cooled and poured into water. The aqueous mixture was extracted with ether. The ethereal extracts were dried over anhydrous magnesium sulfate and concentrated to give an oil. The oil was flash chromatographed (silica gel, diethylamine-ethyl acetate (1:9)). Evaporation of the appropriate fractions followed by recrystallization twice from hexane yielded 2.96 g (18%) of product, mp 103°-105° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[CH:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)([CH3:21])[CH3:20]>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([CH:19]([CH3:20])[CH3:21])=[CH:23][CH:24]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Reactant: CC(C)c1ccc(C(=O)O)cc1
Product: CCOc1cc(CN2CCC(NC(=O)c3ccc(C(C)C)cc3)CC2)ccc1Cl
Yield: 17 %

Procedure:
The title compound (7 mg, 17%) was prepared analogously to example 8 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with 4-isopropylbenzoic acid. MS: 415.5 (MH+)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH:17]1(Br)[CH2:21][CH2:20][CH2:19][CH2:18]1>CN(C)C=O>[CH:17]1([O:8][C:6]2[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[O:9][CH3:10])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: BrC1CCCC1
Reactant: COc1ccc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Br)cc1OC1CCCC1
Temperature: 60 °C
Yield: 96.6 %

Procedure:
A stirred solution of 5-bromo-2-methoxyphenol (74 g) and anhydrous potassium carbonate (73.6 g) in dry dimethylformamide (500 mL) is treated with cyclopentyl bromide (80.5 g) and the solution is heated at 60° C. for 16 hours. It is then concentrated, and the resulting residue is triturated with water (250 mL), and extracted with dichloromethane (3×250 mL). The combined extracts are dried and evaporated, to give 3-cyclopentyloxy-4-methoxyphenyl bromide (95.5 g), in the form of a light brown oil.
Reaction SMILES: [OH:1][C@@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[Br:24][C:25]1[CH:26]=[C:27]([F:35])[CH:28]=[C:29]2[C:33]=1[NH:32][C:31](=[O:34])[CH2:30]2.N1CCCCC1>C(O)C>[Br:24][C:25]1[CH:26]=[C:27]([F:35])[CH:28]=[C:29]2[C:33]=1[NH:32][C:31](=[O:34])/[C:30]/2=[CH:14]\[C:11]1[NH:10][C:7]2[CH2:8][CH2:9][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:5](=[O:16])[C:6]=2[C:12]=1[CH3:13]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Reactant: O=C1Cc2cc(F)cc(Br)c2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(/C=C2\C(=O)Nc3c(Br)cc(F)cc32)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Temperature: 25 °C
Yield: 75.3 %

Procedure:
(S)-5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 5f (40 mg, 0.125 mmol) was dissolved in 2 mL of ethanol under stirring at room temperature, and 7-bromo-5-fluoro-1,3-dihydro-indol-2-one 12b (25.8 mg, 0.112 mmol) was then added to the solution. Upon completion of the addition, the reaction mixture was stirred until all dissolved, and piperidine (0.05 mL, 0.5 mmol) was then added to the solution. Upon completion of the addition, the reaction mixture was heated to reflux in an oil bath for 2 hours. The reaction was completed until TLC showed the disappearance of starting materials, and the reaction mixture was naturally cooled down to room temperature, and filtered under reduced pressure to give the title compound (S,Z)-2-(7-bromo-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 12 (45 mg, 75.4%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[C:4]([NH:11][CH:12]([CH3:14])[CH3:13])[C:5]([N+:8]([O-])=O)=[CH:6][CH:7]=1>CCOC(C)=O>[F:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[C:4]([NH:11][CH:12]([CH3:13])[CH3:14])[C:5]([NH2:8])=[CH:6][CH:7]=1
Reactant: CC(C)Nc1c([N+](=O)[O-])ccc(F)c1-c1ccccn1
Solvent: CCOC(C)=O
Product: CC(C)Nc1c(N)ccc(F)c1-c1ccccn1
Reaction time: 8 h
Yield: 107 %

Procedure:
(3-Fluoro-6-nitro-2-pyridin-2-yl-phenyl)isopropylamine (0.49 g, 1.79 mmol) was dissolved in EtOAc (10 mL). The flask was evacuated and purged with N2. Pd/C (10%) was added and the mixture was hydrogenated at atmospheric pressure under a H2 atmosphere. The mixture was stirred overnight. The flask was evacuated and purged with N2. The catalyst was removed by filtration and the filtrate was concentrated in vacuo and the resulting residue was purified by chromatography (Si—PPC, gradient 0-50% EtOAc/cyclohexane) to afford the title compound as a yellow oil (0.47 g, 99%). 1H NMR (CDCl3, 400 MHz): δ 8.71 (1H, ddd, J=6.6, 2.4, 1.3 Hz), 7.78 (1H, ddd, J=10.6, 10.2, 2.5 Hz), 7.57 (1H, ddt, J=10.6, 5.2, 1.4 Hz), 7.26 (1H, ddd, J=10.0, 6.6, 1.6 Hz), 6.76-6.66 (2H, m), 5.34 (1H, br s), 3.80 (2H, br s), 3.19 (1H, sept, J=8.5 Hz), 7.63 (6H, d, J=8.5 Hz)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.N#N.[F:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:3]=1
Reactant: CC(=O)Nc1cc(Br)cc([N+](=O)[O-])c1
Reactant: OB(O)c1cc(F)ccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: COCCOC
Product: CC(=O)Nc1cc(-c2cc(F)ccc2F)cc([N+](=O)[O-])c1
Yield: 67 %

Procedure:
A solution of N-(3-bromo-5-nitrophenyl)acetamide of Example 1(c) (0.8 g, 3.07 mmol) in 1,2-dimethoxyethane (15 ml) was degassed by N2 bubbling for 5 min. 2,5-Difluorophenylboronic acid (0.58 g, 3.69 mmol, 1.2 eq.) was added and the mixture was degassed for another 5 min. Pd(dppf)Cl2 (0.5 g, 0.615 mmol, 0.2 eq.) and aqueous sodium carbonate (0.98 g, 9.23 mmol, 3.0 eq.) were added and the procedure of Example 1(d) was followed. The crude residue of the product was purified by column chromatography (60-120 silica gel, 25% ethyl acetate in hexane) to give the product in 67% yield (0.6 g). 1H NMR (300 MHz, DMSO-d6): δ 10.56 (s, 1H), 8.65 (t, 1H), 8.14 (s, 1H), 8.06 (s, 1H), 7.56-7.52 (m, 1H), 7.47-7.37 (m, 2H), 2.12 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C:8](=[NH:32])[C:9]1[S:10][C:11]([S:30][CH3:31])=[C:12]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[C:24]([CH3:29])=[N:25][CH:26]=[N:27][CH:28]=3)[CH:18]=2)(=[O:16])=[O:15])[CH:13]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.O>[CH3:29][C:24]1[C:23]([C:19]2[CH:18]=[C:17]([S:14]([C:12]3[CH:13]=[C:9]([C:8]([NH2:32])=[NH:7])[S:10][C:11]=3[S:30][CH3:31])(=[O:15])=[O:16])[CH:22]=[CH:21][CH:20]=2)=[CH:28][N:27]=[CH:26][N:25]=1
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2cncnc2C)c1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2cncnc2C)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 32 %

Procedure:
The (imino-{4-[3-(4-methyl-pyrimidin-5-yl)-benzenesulfonyl]-5-methylsulfanyl-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester ((Example 293: step a) 15 mg, 0.03 mmol) was dissolved in dichloromethane (1 mL), water (1 drop) was added, followed by trifluoroacetic acid (1 mL). The solution was stirred for 1 h 40 min at rt. The solvents were removed in vacuo, the residue was co-evaporated with dichloromethane and methanol, then purified by preparative TLC (10% methanol in dichloromethane) which yielded the title compound as a pale yellow glass (4 mg, 32%). 1H-NMR (CD3OD): δ 9.05 (s, 1H), 8.61 (s, 1H), 8.13–8.08 (m, 2H), 8.04 (s, 1H), 7.78–7.76 (m, 2H), 2.66 (s, 3H), 2.49 (s, 3H). ESI-MS (m/z): Calcd. for C17H16N4O2S3: 404.5 (M+H); found: 405.1.
Reaction SMILES: [Cl:1][C:2]1[N:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:17](OCC)(OCC)[O:18][CH2:19][CH3:20]>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[N:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[C:4]([C:6](=[CH:17][O:18][CH2:19][CH3:20])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)nc1Cl
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1ccc(Cl)nc1Cl
Temperature: 140 °C
Reaction time: 2 h

Procedure:
Ethyl 2-(2,6-dichloronicotinoyl)acetate (7.03 g, 26.8 mmol) was dissolved in acetic anhydride (30 ml), and after adding triethyl orthoformate (60 ml) thereto, it was stirred in an oil bath of 140° C. for 2 hours. After letting the reaction solution cool, it was concentrated under a reduced pressure, and after adding toluene (50 ml) to the residue obtained, a concentration operation under a reduced pressure was performed. This operation was repeated 3 times, and the residue obtained was dried under a reduced pressure. 8.42 g of ethyl 2-(2,6-dichloronicotinoyl)-3-ethoxyacrylate was thereby obtained in the form of a yellow oily substance.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[N:20]=[C:21]([CH3:24])[O:22][C:23]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.[C:27]1([C:33]2([OH:41])[CH2:39][CH:38]3[NH:40][CH:35]([CH2:36][CH2:37]3)[CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CS(C)=O.C(OCC)(=O)C>[CH3:24][C:21]1[O:22][C:23]2[C:15]3[O:14][CH:13]([CH2:12][N:40]4[CH:38]5[CH2:37][CH2:36][CH:35]4[CH2:34][C:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([OH:41])[CH2:39]5)[CH2:26][O:25][C:16]=3[CH:17]=[CH:18][C:19]=2[N:20]=1
Reactant: OC1(c2ccccc2)CC2CCC(C1)N2
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)oc4c3O2)cc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1nc2ccc3c(c2o1)OC(CN1C2CCC1CC(O)(c1ccccc1)C2)CO3
Temperature: 77.5 °C

Procedure:
(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl 4-methylbenzenesulfonate (0.375 g, 1.00 mmole) and 3-phenyl-8-aza-bicyclo[3.2.1]-octan-3-ol (0.25 g, 1.2 mmole) were combined in 8 mL of DMSO. This solution was heated to 75-80° C. under nitrogen for 8 hours. After completion, the reaction was cooled to room temperature and diluted to 500 mL with ethyl acetate. The mixture was washed twice with 400 mL portions of saturated aqueous sodium bicarbonate, with 300 mL of water and twice with 400 mL of saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum. The crude oil was column chromatographed on silica gel using first methylene chloride to remove impurities and then 0.5% methanol/methylene chloride to give, after concentration of the product fractions in vacuum, 0.12 g of the (S)-enantiomer of the title compound as an off-white solid, m.p. 203-205° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH:9]1([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1.Br[CH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].Cl>O1CCCC1.C(OCC)C>[C:23]([O:22][C:20](=[O:21])[CH2:19][CH2:18][C:9]1([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)CCBr
Reactant: O=C(O)C1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCC1(C(=O)O)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.5 %

Procedure:
To a stirred solution of lithium diisopropylamide (0.43 mole) in dry tetrahydrofuran (300 ml) at -20° C. under nitrogen atmosphere was added cyclopentane carboxylic acid (22.7 g; 0.20 mole). The solution was allowed to warm to room temperature and after 2 hours was cooled to -10° C. and added by cannula to a stirred solution of t-butyl 3-bromopropionate (44.4 g, 0.21 mole) in tetrahydrofuran (100 ml). The resulting solution was allowed to warm to room temperature and kept overnight. Hydrochloric acid (3N, 250 ml) was cautiously added, followed by diethyl ether (500 ml) and the layers allowed to separate. The aqueous layer was washed with diethyl ether (300 ml) and the ether layers were combined, washed with water (300 ml), dried over magnesium sulphate and evaporated to give an oil. The oil was taken up in diethyl ether (300 ml) and washed with saturated sodium hydrogen carbonate solution (3×100 ml) until no further cyclopentane carboxylic acid remained. The diethyl ether solution was then extracted with 10% sodium carbonate solution, (4×150 ml), the aqueous phase separated, acidified with 2N hydrochloric acid, and extracted with diethyl ether (3×200 ml). The diethyl ether layer was separated, washed with water (300 ml), dried over magnesium sulphate and evaporated to give an oil that readily crystallised. Recrystallisation from pentane gave a colourless solid (10.4 g, 21%) m.p. 78°-81° C. (from pentane). Found: C,64.70;; H,9.18. C13H22O4 requires: C,64.44; H,9.15%.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C@@H:10]([OH:23])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:33]([Si:37]([CH3:40])([CH3:39])Cl)([CH3:36])([CH3:35])[CH3:34].N1C=CN=C1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCCCCC.C(OCC)(=O)C.O.C1COCC1>[C:1]([NH:8][C@@H:9]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C@@H:10]([O:23][Si:37]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:40])[CH3:39])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](Cc2ccccc2)C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)[C@H](C[C@@H](Cc2ccccc2)C(=O)O)O[Si](C)(C)C(C)(C)C)cc1
Temperature: 0 °C

Procedure:
2.9 g (6.54 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-methoxyphenyl)-2(R)-(phenylmethyl)hexanoic acid in 7 ml of DMF are silylated, at RT for 20 h and under an N2 atmosphere, with 4.5 g (30 mmol) of tert-butyldimethylchlorosilane and 3.65 g (53.6 mmol) of imidazole. The reaction mixture is poured onto 500 ml of ice-water, and this mixture is extracted 3× with ethyl acetate. The organic phases are washed with 10% citric acid solution, 2× water and saline, dried with Na2SO4 and evaporated. Hydrolysis of the residue in 80 ml of methanol and 30 ml of THF with 5.4 g of potassium carbonate and 30 ml of water, working up after 3 h in analogy with Example 7c), and column chromatography (SiO2, hexane/ethyl acetate, 2:1), affords the title compound: TLC Rf (D)=0.13; tRet (II)=20.3 min.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][NH:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:30]1[CH2:31][C@@H:32]([OH:33])[C@H:28]([NH:27][C:25]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:8]4[CH:9]=[C:10]([CH2:13][CH3:14])[CH:11]=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:16]=3[NH:23][C:22]=2[CH3:24])=[O:26])[CH2:29]1)(=[O:36])[CH3:35]
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CNC[C@H]4O)c(C)[nH]c23)c1
Reactant: CC(=O)Cl
Agent: Cl
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CN(C(C)=O)C[C@H]4O)c(C)[nH]c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f51) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]1([C:7]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH2:10])=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1(=[O:23])[CH2:22][CH2:21][CH2:20][CH:19]=[CH:18]1>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH2:8][CH:21]3[CH:22]([CH2:10][C:9]=2[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:17](=[O:23])[CH2:18][CH2:19][CH2:20]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C=CCCC1
Reactant: C=C(C(=C)c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C1CCCC2CC(c3ccccc3)=C(c3ccccc3)CC12

Procedure:
A mixture of 2,3-diphenyl-1,3-butadiene (2.772 g, 13.44 mmol) and cyclohex-2-enone (1 eq.) was refluxed in toluene (26 mL) for 48 h. The reaction mixture was then concentrated and purified on SiO2 (20% ethyl acetate/hexane) to yield 6,7-diphenyl-3,4,4a,5,8,8a-hexahydro-2H-naphthalen-1-one.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]([NH:15][C:16]([C@H:18]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:21][CH2:20][S:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)=O.[CH2:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:38]([NH:45][CH2:6][CH2:7][CH:8]([NH:15][C:16]([CH:18]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)(=[O:24])=[O:25])[CH2:21][CH2:20][S:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: NCc1ccccc1
Reactant: CS(=O)(=O)OCC[C@H](NC(=O)[C@@H]1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Product: O=C(NC(CCNCc1ccccc1)c1ccccc1)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general method B as outlined in Example 16, starting from 3-({[3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidin-2-yl]carbonyl}amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and benzylamine, the title compound was obtained in 99% purity by HPLC.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow solid (358 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:13])[CH:9]=[C:8]2[NH:14][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:16][NH2:17].[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[BH4-].[Na+]>>[CH2:24]([NH:17][CH2:16][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:14][C:8]1[C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=2)[N:11]=[C:10]([CH3:13])[CH:9]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=Cc1ccccc1
Reactant: COc1cccc2c(NC(CN)c3ccccc3)cc(C)nc12
Agent: [BH4-]
Agent: [Na+]
Product: COc1cccc2c(NC(CNCc3ccccc3)c3ccccc3)cc(C)nc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
N*1*-(8-Methoxy-2-methylquinolin-4-yl)-1-phenylethane-1,2-diamine (Example 75, 150 mg, 0.488 mmole) and benzaldehyde were stirred at RT for 20 hrs. Molecular sieve (4A) was added and the mixture was heated to 60° C. within 2 hrs. NaBH4 was added and the mixture was stirred for 1 h at RT. The resulting mixture was filtered and extracted with dichloromethane. The organic phases were dried and concentrated. The residue was purified using preparative HPLC (RP-18, water/acetonitrile) to obtain the product (21 mg, 11%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[C:9]([CH3:15])=[N:10][CH:11]=[C:12]([Br:14])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:20]>CN(C=O)C>[C:1]([O:5][C:6](=[O:16])[N:7]([C:8]1[C:9]([CH3:15])=[N:10][CH:11]=[C:12]([Br:14])[CH:13]=1)[CH3:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ncc(Br)cc1NC(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ncc(Br)cc1N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
A solution of (5-bromo-2-methyl-pyridin-3-yl)-carbamic acid tert-butyl ester (Stage 158.1.2, 4.53 mmol) in DMF (20 ml) was cooled with an ice-bath and 55% NaH in oil (5.89 mmol) was added. The RM was stirred for 25 min at 0° C. then was added iodomethane (5.22 mmol). The RM was stirred for 2 h at it then was quenched with aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with water (3×), with brine (3×), dried over Na2SO4, filtered, evaporated and dried under vacuum to give the title compound as a brown solid (HPLC: tR 3.20 min (Method A); M+H=301, 303 MS-ES).