Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13][NH:14][C:15]([C:17]2[C:18]3[CH:19]=[N:20][N:21]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:22]=3[CH:23]=[CH:24][CH:25]=2)=[O:16])=[CH:9][CH:8]=1)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)C>[C:6]([C:7]1[N:12]=[CH:11][C:10]([CH2:13][NH:14][C:15]([C:17]2[C:18]3[CH:19]=[N:20][N:21]([C:26]4[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=4)[C:22]=3[CH:23]=[CH:24][CH:25]=2)=[O:16])=[CH:9][CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#Cc1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)cn1
Reaction time: 2 h

Procedure:
To a mixture of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid (6-bromo-pyridin-3-ylmethyl)-amide (105 mg, 0.247 mmol), trimethylsilyl acetylene (0.105 mL, 0.741 mmol), copper(I) iodide (4.7 mg, 0.025 mmol) and Pd(PPh3)2Cl2 (8.7 mg, 0.012 mmol) was added triethylamine (1.0 mL) and anhydrous DMF (0.25 mL). After 16 hours, the mixture was diluted with diethyl ether (50 mL) and quenched with saturated aqueous ammonium chloride (50 mL). The organic layer was washed with saturated aqueous ammonium chloride (50 mL) and brine (50 mL), dried over MgSO4 and concentrated. The crude solid was purified by silica gel chromatography eluting with a gradient of 0-50% ethyl acetate in hexanes to afford 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid (6-trimethylsilanylethynyl-pyridin-3-ylmethyl)-amide as a tan solid. 1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid (6-trimethylsilanylethynyl-pyridin-3-ylmethyl)-amide (70.0 mg, 0.158 mmol) was dissolved in THF (1.0 mL) and treated with a 1 M solution of TBAF in THF (0.16 mL, 0.16 mmol) at room temperature. The solution was stirred for 2 hours and then diluted with diethyl ether (10 mL) and quenched with water (10 mL). The aqueous layers were extracted with diethyl ether (3×5 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography eluting with a gradient of 0-70% ethyl acetate in hexanes to afford the title compound as a white solid.
Reaction SMILES: [CH2:1]1OCCOCCOCCOCCOCCOC1.CC([O-])(C)C.[K+].[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[C:34]([N:36]2[CH2:40][C@@H:39]([CH:41]3[CH2:43][CH2:42]3)[C@H:38]([CH2:44][N:45]3[CH2:50][CH2:49][CH:48]([C:51]4[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=4)[CH2:47][CH2:46]3)[CH2:37]2)=[O:35])[CH:27]=[CH:26]1.CI>C1COCC1>[CH3:1][N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[C:34]([N:36]2[CH2:40][C@@H:39]([CH:41]3[CH2:42][CH2:43]3)[C@H:38]([CH2:44][N:45]3[CH2:50][CH2:49][CH:48]([C:51]4[CH:52]=[CH:53][C:54]([F:57])=[CH:55][CH:56]=4)[CH2:47][CH2:46]3)[CH2:37]2)=[O:35])[CH:27]=[CH:26]1
Reactant: O=C(c1cccc2cc[nH]c12)N1C[C@@H](CN2CCC(c3ccc(F)cc3)CC2)[C@H](C2CC2)C1
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1ccc2cccc(C(=O)N3C[C@@H](CN4CCC(c5ccc(F)cc5)CC4)[C@H](C4CC4)C3)c21
Reaction time: 1 h

Procedure:
To a solution of 0.015 g (0.06 mmol) of 18-crown-6 and 0.060 mL (0.06 mmol) of KOtBu (1M in THF) in 2 mL of THF was added 0.15 g (0.34 mmol) of 1-(7-indolecarbonyl)-3-(R)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(S)-(cyclopropyl)pyrrolidine and the mixture was stirred for 15 min after which 0.0062 mL (0.1 mmol) methyl iodide was added. After 2 h another 0.005 mL of methyl iodide was added and the reaction mixture was stirred for 1 h. The reaction mixture was partitioned between ethyl acetate and sat'd NaHCO3 solution. The organic fraction was dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chomatography (silica, Waters RCM 8×10 Novapak) (acetone:hexanes, 1:5) to give the title compound. 1H NMR (CD3OD) d (key peaks) 7.58 (m, 2H), 7.15-6.92 (m, 5H), 7.39 (m, 1H), 6.53 (m, 1H), 3.80 (s, 3H), 0.06 (m, 5H); Mass Spectrum (CI) m/e=460 (M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[N:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11].CO>O1CCCC1>[Cl:7][C:8]1[C:9]([CH2:10][OH:11])=[CH:13][CH:14]=[C:15]([Cl:17])[N:16]=1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1ccc(Cl)nc1Cl

Procedure:
Lithium aluminum hydride (1.78 g) was suspended in dry tetrahydrofuran (10 ml), and 2,6-dichloronicotinic acid was added under ice-cooling at an inside temperature of not more than 10° C. The mixture was stirred under ice-cooling for 1 hr and 28% aqueous amonia was added dropwise to the reaction mixture until foams disappeared. Methanol was added and the mixture was stirred at room temperature for 3 hr, and filtered through celite. The mother liquor was concentrated and the residue was applied to flash silica gel column chromatography (silica gel, 200 ml) and eluted with chloroform:ethyl acetate=8:1 to give 2,6-dichloro-3-hydroxymethylpyridine as colorless crystals (2.89 g).
Reaction SMILES: O.O.[Na+:3].[OH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([O-:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1>[OH-].[Na+].C(O)C>[Na+:3].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][O:4][C:5]2[CH:10]=[CH:9][C:8]([S:11]([O-:14])(=[O:12])=[O:13])=[CH:7][CH:6]=2)=[CH:18][CH:17]=1
Reactant: O=S(=O)([O-])c1ccc(O)cc1
Reactant: Fc1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=S(=O)([O-])c1ccc(OCc2ccc(F)cc2)cc1
Temperature: 22 °C
Yield: 73.6 %

Procedure:
To a stirred solution of 4-hydroxybenzenesulfonic acid sodium salt dihydrate (5.13 g, 22.1 mmol) in 23 mL of 1 N sodium hydroxide was added a solution of 4-fluorobenzyl bromide (3.3 mL, 26.5 mmol) in 20 mL of ethanol. The mixture was heated at reflux for two days, then cooled to ambient temperature (22° C.), whereupon a white precipitate formed. The flaky white solids were collected by filtration, rinsed with ethyl acetate and diethyl ether, and dried to give 4.95 g of 4-(4-fluoro-benzyloxy)-benzenesulfonic acid sodium salt. A stirred solution of 4-(4-fluoro-benzyloxy)-benzenesulfonic acid sodium salt (13.0 g, 42.7 mmol) in 50 mL of thionyl chloride and two drops of dimethylformamide was heated at a gentle reflux for 8 hours. The mixture was concentrated to a yellow solid which was suspended in ethyl acetate and filtered. The filtrate was concentrated to 11.2 g of 4-(4-fluorobenzyloxy)benzenesulfonyl chloride as a light yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.95-7.98 (m, 2 H), 7.38-7.41 (m, 2 H), 7.06-7.12 (m, 4 H), 5.12 (s, 2 H).
Reaction SMILES: CN1CCCC1=O.F[C:9]1[C:14]([F:15])=[C:13]([CH3:16])[C:12]([F:17])=[C:11]([F:18])[N:10]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)(Cl)Cl>[CH2:19]([NH:26][C:9]1[C:14]([F:15])=[C:13]([CH3:16])[C:12]([F:17])=[C:11]([F:18])[N:10]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: Cc1c(F)c(F)nc(F)c1F
Solvent: ClC(Cl)Cl
Solvent: CN1CCCC1=O
Product: Cc1c(F)c(F)nc(NCc2ccccc2)c1F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To 2 ml of N-methylpyrrolidone were added 1.65 g of 2,3,5,6-tetrafluoro-4-methylpyridine and 2.30 g of benzylamine, and the mixture was stirred at 80° C. for 2 hours and allowed to cool. After adding 25 ml of chloroform, the mixture was washed three times with 300 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound in crude form.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][C:7]1[N:15]=[CH:14][C:13]([F:16])=[CH:12][C:8]=1[C:9]([OH:11])=O.C(N(CC)CC)C.[NH2:27][C@@H:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]([OH:34])[CH2:29]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:16][C:13]1[CH:14]=[N:15][C:7]([O:6][C:5]2[CH:17]=[CH:18][CH:19]=[C:3]([S:2][CH3:1])[CH:4]=2)=[C:8]([CH:12]=1)[C:9]([NH:27][C@@H:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]([OH:34])[CH2:29]1)=[O:11]
Reactant: N[C@@H]1CCC[C@@H](O)C1
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@@H]2CCC[C@@H](O)C2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.6 %

Procedure:
2-[3-(Methylsulfanyl)phenoxy]-5-fluoronicotinic acid (345 mg, 1.26 mmol) was dissolved in dimethylformamide (10 ml) and triethylamine (865 μl, 11.8 mmol) was added followed by (1R,3R)-3-aminocyclohexanol hydroformate (200 mg, 1.24 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (715 mg, 3.73 mmol) and 1-hydroxybenzotriazole (185 mg, 1.37 mmol). The reaction was stirred under nitrogen at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between 10% aq. citric acid solution (50 ml) and diethyl ether (50 ml). The organic was washed with sat. sodium bicarbonate solution (50 ml), water (25 ml) and brine (10 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate:cyclohexane (10:90 to 70:30) as eluant to give 5-fluoro-N-[(1R,3R)-3-hydroxycyclohexyl]-2-[3-(methylsulfanyl)phenoxy]nicotinamide (171 mg) as a colourless gum.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]([NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(O)(=O)C.[H][H]>[Pt].C(O)(C)C>[Cl:1][C:2]1[C:11]([NH2:12])=[C:10]([NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: [H][H]
Reactant: CC(C)CNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Agent: [Pt]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC(C)CNc1c(N)c(Cl)nc2ccccc12
Yield: 73 %

Procedure:
A solution of 2-chloro-N-(2-methylpropyl)-3-nitro-4-quinolinamine (120 g), acetic acid (300 mL), isopropyl alcohol (300 mL), and 5% platinum on carbon (7.2 g) was allowed to stand at room temperature for 30 h under 2 bars of hydrogen pressure. The resulting solution was filtered, and the solvent was removed from the filtrate at reduced pressure. The residue was dissolved in aqueous hydrochloric acid (1 L, 4N). The product was precipitated by adding this solution to a solution of sodium hydroxide. The precipitate was filtered and washed with water to afford the product 2-chloro-N4 -(2-methylpropyl)-3,4-quinolinediamine in 73% yield.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]2[OH:32])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.Br[CH2:35][C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[CH:42]=[N:41][CH:40]=[CH:39]2>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:21][CH:20]2[O:32][CH2:35][C:36]2[CH:37]=[C:38]3[C:43](=[CH:44][CH:45]=2)[CH:42]=[N:41][CH:40]=[CH:39]3)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccc2cnccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccc3)cc2)C(O)C1
Agent: Br
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3cnccc3c2)C1

Procedure:
By alkylating tert-butyl (3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-hydroxy-piperidine-1-carboxylate [Example 86 (n)] with 6-bromomethyl-isoquinoline hydrobromide (Example 4) analogously to Example 1 (g) there was obtained tert-butyl (3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-(isoquinolin-6-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 583 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([CH:18]1[CH2:22][CH:21]([CH2:23][NH:24][C:25]([C:27]2[S:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[O:26])[CH:20]([NH:33][CH3:34])[CH2:19]1)=[O:17].[CH3:35][S:36](Cl)(=[O:38])=[O:37]>>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([CH:18]1[CH2:22][CH:21]([CH2:23][NH:24][C:25]([C:27]2[S:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[O:26])[CH:20]([N:33]([S:36]([CH3:35])(=[O:38])=[O:37])[CH3:34])[CH2:19]1)=[O:17]
Reactant: CNC1CC(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)CC1CNC(=O)c1ccc(Cl)s1
Reactant: CS(=O)(=O)Cl
Product: CN(C1CC(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)CC1CNC(=O)c1ccc(Cl)s1)S(C)(=O)=O

Procedure:
In analogy to example 26 5-chloro-thiophene-2-carboxylic acid {4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-methylamino-cyclopentylmethyl}-amide (example 33) was reacted with methane sulfonylchloride to give 5-chloro-thiophene-2-carboxylic acid [4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-(methanesulfonyl-methyl-amino)-cyclopentylmethyl]-amide. Light yellow solid. 581.2 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][C:11](=[CH2:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:24])C=1>>[C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:9][CH2:10][C:11]2([O:24][CH2:14]2)[CH2:12][CH2:13]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C1CCC(NC(=O)OC(C)(C)C)CC1
Product: CC(C)(C)OC(=O)NC1CCC2(CC1)CO2
Yield: 93 %

Procedure:
(4-Methylene-cyclohexyl)-carbamic acid tert-butyl ester (Raju, B. et al, Bioorganic and Medicinal Chemistry Letters 2004, 14(12), 3103-3107) (2.3 g, 10.9 mmol) was treated with 3-chloroperbenzoic acid (70% purity, 3.76 g, 21.8 mmol, uncorrected) according to the method of Example 7 Step B. After work up the title compound was obtained (2.3 g, 93% yield) as a yellow solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:17][N:5]2[CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][C@@H:4]2[CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].[F:24][C:25]([F:37])([F:36])[C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>CN(C)C=O.ClCCl>[F:37][C:25]([F:24])([F:36])[C:26]1[CH:27]=[C:28]([S:32]([NH:1][C@@H:2]2[CH2:17][N:5]3[CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:9][C@@H:4]3[CH2:3]2)(=[O:33])=[O:34])[CH:29]=[CH:30][CH:31]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@@H](N)C[C@H]2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN2C[C@@H](NS(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (7S,8aS)-tert-butyl 7-aminohexahydropyrrolo[1,2-a]-pyrazine-2(1H)-carboxylate (0.22 g, 0.92 mmol) in dimethylformamide/dichloromethane (1:5, 5 mL) was added sodium carbonate (0.166 g, 1.56 mmol) and 3-(trifluoromethyl)-benzene-1-sulfonyl chloride (0.315 g, 1.29 mmol). The mixture was stirred at room temperature for 18 hours and then concentrated. The residue was purified by chromatography on silica gel (dichloromethane/methanol=15:1) to give the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.19 (m, 1H), 1.38 (s, 9H), 1.40 (m, 2H), 1.70 (m, 1H), 1.84 (m, 1H), 2.00 (m, 1H), 2.18 (m, 1H), 2.64 (m, 1H), 2.79 (m, 1H), 3.70 (m, 1H), 3.80-3.95 (m, 2H), 7.83 (m, 1H), 8.05 (m, 1H), 8.11 (m, 2H), 8.15 (m, 1H); MS (ESI) m/z 450 (M+H)+.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:15]([Si:19]([CH3:25])([CH3:24])[O:20][CH2:21][CH2:22][OH:23])([CH3:18])([CH3:17])[CH3:16].[CH2:26]([O:28][C:29](=[O:60])[C@@H:30]([O:58][CH3:59])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][O:42][C:43]2[CH:48]=[CH:47][C:46]([C:49](=[O:57])[C:50]3[CH:55]=[CH:54][C:53](O)=[CH:52][CH:51]=3)=[CH:45][CH:44]=2)=[CH:34][CH:33]=1)[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:26]([O:28][C:29](=[O:60])[C@@H:30]([O:58][CH3:59])[CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:39][CH2:40][CH2:41][O:42][C:43]2[CH:44]=[CH:45][C:46]([C:49](=[O:57])[C:50]3[CH:51]=[CH:52][C:53]([O:23][CH2:22][CH2:21][O:20][Si:19]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:25])[CH3:24])=[CH:54][CH:55]=3)=[CH:47][CH:48]=2)=[CH:36][CH:37]=1)[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)OCCO
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(C(=O)c3ccc(O)cc3)cc2)cc1)OC
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(C(=O)c3ccc(OCCO[Si](C)(C)C(C)(C)C)cc3)cc2)cc1)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diisopropyl azodicarboxilate (0.2 mmol, 0.04 mL) was added dropwise to a solution of 2-(tert-butyl-dimethyl-silanyloxy)-ethanol (0.26 mmol, 46 mg) (Example 122, Step A), (2S)-3-(4-{3-[4-(4-hydroxy-benzoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionic acid ethyl ester (0.13 mmol, 65 mg) and triphenylphosphine (0.2 mmol, 38 mg) in anhydrous toluene (2 mL) at 0° C. under nitrogen. The mixture was stirred overnight at room temperature, quenched with water and extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under vacuum. The crude mixture was chromatographed on silica gel using a 4/1 hexane/EtOAc mixture as eluent to afford the title product 1H-NMR (200.15 MHz, CDCl3): δ 7.76 (d, 4H, J=8.9), 7.13 (d, 2H, J=8.6), 6.96 (d, 4H, J=8.6), 6.83 (d, 2H, J=8.6), 4.26–4.09 (m, 8H), 4.02–3.87 (m, 3H), 3.35 (s, 3H), 2.97 (m, 2H), 2.28 (qn, 2H, J=5.9), 1.23 (t, 3H, J=7.1), 0.91 (s, 9H), 0.11 (s, 6H).
Reaction SMILES: COC(=O)C.C[O:7][C:8](=O)[CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[C@@H:16]([CH3:30])[CH2:15][C@H:14]2[N:31]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[C:32](=[O:35])[CH2:33][CH3:34].[NH3:44]>CO>[C:8]([CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21](=[O:29])[C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)[C@@H:16]([CH3:30])[CH2:15][C@H:14]2[N:31]([C:36]1[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=1)[C:32](=[O:35])[CH2:33][CH3:34])(=[O:7])[NH2:44]
Reactant: N
Reactant: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(OCC(=O)OC)cc21
Solvent: CO
Solvent: COC(C)=O
Product: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(OCC(N)=O)cc21
Temperature: 25 °C

Procedure:
(±)-Cis-N-[6-carbamoylmethoxy-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-(4-chloro-phenyl)-propionamide was prepared from (±)-cis-4-[(4-chloro-phenyl)-propionyl-amino]-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-6-yloxy]-acetic acid methyl ester. To solid (±)-cis-[4-[(4-chloro-phenyl)-propionyl-amino]-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-6-yloxy]-acetic acid methyl ester (76 mg, 0.14 mmol) was added a solution of ammonia in methanol (2 M, 10 mL). The resulting solution was stirred over night at room temperature and concentrated. The resulting crude amide was purified by silica gel chromatography (100% hexanes—100% ethyl acetate gradient) to afford pure product (59 mg, 76%).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4][C:3]1=[N:10][OH:11].[CH3:12][N:13]([S:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)[C:14](F)=[O:15].C(N(CC)CC)C>O1CCOCC1>[CH3:12][N:13]([S:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)[C:14]([O:11][N:10]=[C:3]1[N:2]([CH3:1])[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4]1)=[O:15]
Reactant: CN1C(=O)C(C)(C)SC1=NO
Reactant: Cc1ccc(SSN(C)C(=O)F)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1ccc(SSN(C)C(=O)ON=C2SC(C)(C)C(=O)N2C)cc1

Procedure:
2-[[O-[N-Methyl-N-(4-methylphenylthiosulfenyl)carbamoyl]oximino]]-3,5,5-trimethylthiazolidin-4-one was prepared according to the procedure described in Example I, by reacting 5.0 g (0.0287 m) of 3,5,5-trimethyl-2-oximino thiazolidin-4-one, 6.64 g (0.028 m) of N-methyl-N-(4-methylphenylthiosulfenyl)carbamoyl fluoride and 2.9 g (0.0287 m) of triethylamine in 50 ml of dioxane. 2-[[O-[N-Methyl-N-(4-methylphenylthiosulfenyl)carbamoyl]oximino]]-3,5,5-trimethylthiazolidin-4-one was crystallized from ethylacetate-hexane to yield 8.0 g of solid, m.p. 116°-118° C. It was then recrystallized from ethyl acetate isopropyl ether, to yield a solid, m.p. 123°-125° C.
Reaction SMILES: [N+:1](=[CH:3][CH3:4])=[N-:2].[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=[O:16]>CCOCC>[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:13]=[C:14]([C:15](=[O:16])[C:3](=[N+:1]=[N-:2])[CH3:4])[CH:18]=[CH:19][CH:20]=1
Reactant: CC=[N+]=[N-]
Reactant: O=C(Cl)c1cccc(Oc2ccccn2)c1
Solvent: CCOCC
Product: CC(=[N+]=[N-])C(=O)c1cccc(Oc2ccccn2)c1

Procedure:
To a solution of diazoethane (2.5 mol equivalent) in ether (150 ml), a solution of 3-(2-pyridyloxy)benzoyl chloride in anhydrous ether (90 ml) is added dropwise at -20°C for 40 minutes. The resultant mixture is stirred at -20°C for 20 minutes. The diazoethane is evaporated at -20°C under reduced pressure, and the ether is evaporated at -10°C to 0°C under reduced pressure. The residue is chromatographed on a column of silica gel, which is eluted with 20% ether/benzene and 30% ether/benzene to give 3-(2-pyridyloxy)-1-(2-diazopropionyl)benzene (2.87 g) as an oily substance. IR (CCl4): 2060, 1630 cm-1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH2:15][CH:16]([CH3:27])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:37]=[CH:38][C:39]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH2:15][CH:16]([CH3:27])[CH2:17][C:18]4[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=4)=[CH:6][CH:7]=3)=[CH:40][CH:41]=2)[CH2:34][CH2:35]1)=[O:32])[CH3:29]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NCC(C)Cc1ccc(C(C)C)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NCC(C)Cc4ccc(C(C)C)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[3-(4-isopropyl-phenyl)-2-methyl-propyl]-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][N:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:12]([O-])=O)[C:3]1=[O:15].[H][H]>[Pd].C(OCC)(=O)C>[NH2:12][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[N:11][N:2]([CH3:1])[C:3]2=[O:15]
Reactant: Cn1ncc2c([N+](=O)[O-])cccc2c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cn1ncc2c(N)cccc2c1=O
Yield: 94 %

Procedure:
1.57 g of 2-methyl-5-nitro-phthalazin-1-one and 130 mg of palladium on activated carbon are suspended in 45 ml of ethyl acetate and hydrogenated with hydrogen under normal pressure. It is filtered through diatomaceous earth, and the solvent is removed in a vacuum. 1.26 g of 5-amino-2-methyl-phthalazin-1-one is obtained as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]=[N:15][CH:16]=[C:11]2[C:10](Br)=[C:9]1[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:34]=[O:35]>CCCCCC.O1CCCC1>[CH2:1]([N:8]1[C:12]2=[C:13]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]=[N:15][CH:16]=[C:11]2[C:10]([CH:34]=[O:35])=[C:9]1[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(Br)c2cnnc(NCc3ccccc3)c2n1Cc1ccccc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1c(C=O)c2cnnc(NCc3ccccc3)c2n1Cc1ccccc1
Yield: 44 %

Procedure:
0.58 g (1.4 mmol) of 1-benzyl-7-benzylamino-3-bromo-2-methylpyrrolo[2,3-d]pyridazine, 3.5 ml (5.7 mmol) of 15% strength solution of n-butyllithium in hexane and 0.55 ml (7 mmol) of dimethylformamide are reacted in 40 ml of anhydrous tetrahydrofuran as described for Example 2a. Yield: 44%, m.p.: 171°-172° C.