Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH:4]([OH:9])[CH2:5][C:6]([OH:8])=[O:7])#[N:2].[CH2:10](N(CC)CC)[CH3:11].S(OCC)(OCC)(=O)=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[C:1]([CH2:3][CH:4]([OH:9])[CH2:5][C:6]([O:8][CH2:10][CH3:11])=[O:7])#[N:2]
Reactant: N#CCC(O)CC(=O)O
Reactant: CCN(CC)CC
Agent: CCOS(=O)(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(O)CC#N
Temperature: 57.5 °C
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
35 g of 4-cyano-3-hydroxybutanoic acid was dissolved in 250 g of ethyl acetate, and 41 g of triethylamine and 54 g of diethyl sulfate were added thereto at room temperature. Then, the mixture was stirred at an internal temperature of 55 to 60° C. for 30 minutes. After the reaction solution was left cooled down to room temperature, it was added to a saturated sodium bicarbonate solution, and ethyl acetate was used for extraction. The organic layer was washed with saturated saline solution, and the residue obtained by concentrating under reduced pressure was subjected to distillation under reduced pressure, whereby 24.5 g of ethyl 4-cyano-3-hydroxybutanoate was obtained. The purity of the obtained ethyl 4-cyano-3-hydroxybutanoate was 99% (gas chromatography in area percentage).
Reaction SMILES: [CH2:1]([O:6][CH2:7][CH:8]([OH:25])[C@@H:9]([NH:14]C(OCC1C=CC=CC=1)=O)[CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:2][CH:3]([CH3:5])[CH3:4].[ClH:26]>CO.[Pd]>[ClH:26].[CH2:1]([O:6][CH2:7][CH:8]([OH:25])[C@@H:9]([NH2:14])[CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CCOCC(O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)CCOCC(O)[C@@H](N)CC(C)C

Procedure:
To a solution of 95 mg of the ether obtained in 2 ml of methanol was added 0.27 ml of a 1N-hydrochloric acid, and the mixture was hydrogenated over 10 mg of a 10% palladium charcoal under hydrogen atmosphere. After filtration of the catalyst, the filtrate was evaporated under reduced pressure to obtain 65 mg of (2RS, 3S)-3-amino-2-hydroxy-5-methylhexyl isoamyl ether hydrochloride as a colorless viscous oil.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]2[C:22]3[C:17](=[C:18]([NH:23][C:24]([C:26]4[N:30]5[CH:31]=[CH:32][CH:33]=[CH:34][C:29]5=[N:28][CH:27]=4)=[O:25])[CH:19]=[CH:20][CH:21]=3)[C:16]([CH2:35][CH3:36])=[N:15]2)[N:8]=1)(=O)=O.[N:39]1([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH2:35]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24]([C:26]2[N:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]3=[N:28][CH:27]=2)=[O:25])[N:14]([CH2:13][C:9]2[N:8]=[C:7]([N:42]3[CH2:41][CH2:40][N:39]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:44][CH2:43]3)[CH:12]=[CH:11][CH:10]=2)[N:15]=1)[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCc1nn(Cc2cccc(OS(=O)(=O)C(F)(F)F)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCc1nn(Cc2cccc(N3CCN(C(=O)OC(C)(C)C)CC3)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Temperature: 90 °C
Yield: 37.5 %

Procedure:
To a reaction vial was added 6-((3-ethyl-4-(imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)pyridin-2-yl trifluoromethanesulfonate (30 mg, 0.0551 mmol; prepared according to Example 24, Step A), tert-butyl piperazine-1-carboxylate (20.5 mg, 0.110 mmol) and cesium carbonate (53.9 mg, 0.165 mmol). Toluene (2 mL) was added and argon was bubbled through the mixture for 10 minutes. To this solution was added rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (6.86 mg, 0.0110 mmol) and tris(dibenzylideneacetonyl)bis-palladium (5.05 mg; 0.00551 mmol). The reaction vial was sealed and the mixture was heated at 90° C. for 3 hours. The mixture was allowed to cool, filtered through Celite®, rinsing with toluene and concentrated under a stream of nitrogen. The material was purified using preparative thin layer chromatography on silica, eluting with 10% methanol in dichloromethane containing 0.5% ammonium hydroxide solution to provide tert-butyl 4-(6-((3-ethyl-4-(imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)pyridin-2-yl)piperazine-1-carboxylate (12 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[O:11][CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30]>CC(C)=O>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10]2[O:11][CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=2)=[CH:3][C:2]=1[O:1][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30]
Reactant: CC(C)=CCBr
Reactant: CCOC(=O)c1coc(Nc2ccc(C)c(O)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1coc(Nc2ccc(C)c(OCC=C(C)C)c2)n1
Yield: 30 %

Procedure:
Following the general procedure for O-alkylation, Method A, a mixture of ethyl 2-(3-hydroxy-4-methylphenylamino)oxazole-4-carboxylate (118 mg, 0.45 mmol) and K2CO3 (68 mg, 0.50 mmol) in acetone (4.5 mL) was treated with 4-bromo-2-methyl-2-butene (0.063 mL, 0.54 mmol) at 60° C. Reaction control by TLC showed full conversion after 4 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 7/3) in 30% yield (45 mg).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1.Cl.C[Si](C)(C)N[Si](C)(C)C.[CH:23]1[C:28]([O:29][C:30](Cl)=[O:31])=[CH:27][CH:26]=[C:25]([Cl:33])[CH:24]=1.[OH-].[Na+].Cl>O>[Cl:33][C:25]1[CH:26]=[CH:27][C:28]([O:29][C:30]([N:2]([CH2:3][C@H:4]2[CH2:9][CH2:8][C@H:7]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]2)[CH3:1])=[O:31])=[CH:23][CH:24]=1
Reactant: CNC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CN(C[C@H]1CC[C@H](C(=O)O)CC1)C(=O)Oc1ccc(Cl)cc1
Temperature: 140 °C
Reaction time: 8 h

Procedure:
0.60 g (2.89 mmol) of trans-4-methylaminomethyl-cyclohexanecarboxylic acid·HCl were mixed with 7.57 mL (36.28 mmol, 12.5 eq) of hexamethyldisilazane and heated under reflux to 140° C. for 2.5 h. The solution was evaporated, dissolved in 6 mL of THF and treated with 0.45 mL (3.18 mmol, 1.1 eq) of 4-chlorophenylchloroformate at 0° C. and stirred at RT overnight. Then 3 mL of water were added at RT followed by 10 mL of 1M NaOH. After stirring for 1 h at RT 15 mL of 1M HCl were added. The solution was then partitioned between EtOAc (×3)/H2O, dried over Na2SO4 and evaporated to yield 0.92 g (98%) of trans-4-{[(4-chloro-phenoxycarbonyl)-methyl-amino]-methyl}-cyclohexane carboxylic acid, MS: 324 (M−H−, 1Cl).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:17][C@H:18]([OH:30])[C:19]2[C:27]3[S:26][C:25](=[O:28])[NH:24][C:23]=3[C:22]([OH:29])=[CH:21][CH:20]=2)=[CH:11][CH:10]=1)(=O)=O.[C:38]1([C:44]2[S:45][CH:46]=[C:47]([C:49]([N:51]3[CH2:56][C:55]4([CH2:61][CH2:60][NH:59][CH2:58][CH2:57]4)[O:54][CH2:53][CH2:52]3)=[O:50])[N:48]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(CC)CC)C>CC#N>[OH:30][C@H:18]([C:19]1[C:27]2[S:26][C:25](=[O:28])[NH:24][C:23]=2[C:22]([OH:29])=[CH:21][CH:20]=1)[CH2:17][N:16]([CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:59]2[CH2:60][CH2:61][C:55]3([O:54][CH2:53][CH2:52][N:51]([C:49]([C:47]4[N:48]=[C:44]([C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)[S:45][CH:46]=4)=[O:50])[CH2:56]3)[CH2:57][CH2:58]2)=[CH:10][CH:11]=1)[C:31](=[O:32])[O:33][C:34]([CH3:35])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(OCCOS(C)(=O)=O)cc1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Reactant: O=C(c1csc(-c2ccccc2)n1)N1CCOC2(CCNCC2)C1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(Cc1ccc(OCCN2CCC3(CC2)CN(C(=O)c2csc(-c4ccccc4)n2)CCO3)cc1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution of (R)-2-(4-((tert-butoxycarbonyl(2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl)amino)methyl)phenoxy)ethyl methanesulfonate (example 108, step c) (0.619 g) in MeCN (3 mL) was added dropwise to a solution of (2-phenylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (example 112, step b) (0.274 g) and triethylamine (0.22 mL) in MeCN (7.3 mL) at RT under argon. The resulting mixture was stirred at 80° C. under argon for 16 h. After cooling to RT the solvent was removed in vacuo. The residue was taken up in DCM, washed with brine and water, dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-70% EtOAc in petroleum ether (40-60° C.) to give the subtitled compound as a yellow solid. Yield 0.42 g.
Reaction SMILES: Br[C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[CH2:8][O:7][C:6]=2[N:13]=1.[C:20]([O:24][C:25](=[O:45])[NH:26][C:27]1([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)[CH2:29][CH2:28]1)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.[Cl-].[Na+].O>[C:20]([O:24][C:25](=[O:45])[NH:26][C:27]1([C:30]2[CH:31]=[CH:32][C:33]([C:2]3[C:3]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:4][C:5]4[N:10]([CH3:11])[C:9](=[O:12])[CH2:8][O:7][C:6]=4[N:13]=3)=[CH:34][CH:35]=2)[CH2:28][CH2:29]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: CN1C(=O)COc2nc(Br)c(-c3ccccc3)cc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CC4)cc3)c(-c3ccccc3)cc21
Temperature: 80 °C
Yield: 101.8 %

Procedure:
In a 15 mL reaction tube was added 6-bromo-1-methyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (40 mg, 0.125 mmol) and tert-butyl(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropyl)carbamate (54 mg, 0.150 mmol) in 1,4-dioxane (1 ml), followed by a solution of sodium carbonate (40 mg, 0.3 mmol) in water (0.25 ml) to give a white suspension. This was degassed by bubbling nitrogen for 10 minutes, followed by the addition of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (9 mg, 0.013 mmol). The reaction mixture was heated to 80° C. overnight. The reaction mixture was allowed to cool to room temperature, diluted with brine (4 ml) and extracted into ethyl acetate (3×4 ml). The combined organic phases were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by Biotage chromatography (cyclohexane:ethyl acetate, gradient elution from 90:10 to 20:80) to give the desired product as a white solid (60 mg, quantitative yield). 1H-NMR (500 MHz, CDCl3) δ 7.14-7.26 (6H, m), 7.08-7.14 (2H, m), 6.93 (2H, d), 4.99-5.27 (1H, br m), 4.80 (2H, s), 3.31 (3H, s), 1.35 (9H, br s), 1.25 (2H, br s), 1.03 (2H, br s). LCMS (Method D): RT=1.44 min, M+H+=472.20.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].ClCCCl.[CH3:9][NH2:10].ClC(Cl)C.[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[O:20][CH2:19]2>>[Br:15][C:16]1[CH:24]=[CH:23][C:22]([C:21]([NH:10][CH3:9])=[O:25])=[C:18]([CH2:19][OH:20])[CH:17]=1
Reactant: O=C1OCc2cc(Br)ccc21
Reactant: CN
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: CNC(=O)c1ccc(Br)cc1CO
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 59.5 %

Procedure:
A 500 mL RB flask was charged with aluminum(III) chloride (4.1 g, 31 mmol) and 10 mL of 1,2-dichloroethane (90 ml, 1142 mmol), then cooled to 0° C. A separate 250 mL flask was charged with 90 mL of 1,2-dichloroethane (90 ml, 1142 mmol) and cooled to 0° C.; methylamine (gas) (1.8 g, 59 mmol) was bubbled through the solution for 10 minutes. The dichloroethane solution was slowly poured into the aluminum chloride solution, resulting in the formation of a thick white slush. This was warmed to room temperature. 5-bromoisobenzofuran-1(3H)-one (5.00 g, 23 mmol) was added in one portion and the reaction mixture was stirred for 2.5 hours and quenched with water. The mixture was filtered to remove the solid impurities, then the filtrate was washed with 0.5N aqueous HCl (100 mL) and brine (200 mL). The organic layer was dried with MgSO4, filtered, and concentrated to give a white solid. This was triturated with EtOAc and filtered to give 4-bromo-2-(hydroxymethyl)-N-methylbenzamide (3.34 g, 58% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH2:6])[CH3:5].C[O:8][C:9]([C:11]1[C:15]([NH:16][C:17]([C:19]2[C:24]([NH:25][C:26]3[CH:27]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:23][CH:22]=[C:21]([CH:32]3[CH2:34][CH2:33]3)[N:20]=2)=[O:18])=[CH:14][N:13]([CH3:35])[N:12]=1)=O>>[CH3:1][O:2][CH2:3][CH:4]([NH:6][C:9]([C:11]1[C:15]([NH:16][C:17]([C:19]2[C:24]([NH:25][C:26]3[CH:27]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:23][CH:22]=[C:21]([CH:32]3[CH2:34][CH2:33]3)[N:20]=2)=[O:18])=[CH:14][N:13]([CH3:35])[N:12]=1)=[O:8])[CH3:5]
Reactant: COCC(C)N
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: COCC(C)NC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 16 %

Procedure:
According to the general method described in step 5 of example 27, reaction of 2-methoxy-1-methyl-ethylamine with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (16%) as amorphous yellow solid.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]([N+:21]([O-])=O)=[C:8]([C:10]([N:12]2[CH2:17][CH2:16][NH:15][C:14](=[O:18])[C:13]2([CH3:20])[CH3:19])=[O:11])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:21][C:7]1[NH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:9][C:8]=1[C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=[O:18])[C:13]1([CH3:19])[CH3:20])=[O:11]
Reactant: CC(C)(C)c1cc(C(=O)N2CCNC(=O)C2(C)C)c([N+](=O)[O-])[nH]1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)c1cc(C(=O)N2CCNC(=O)C2(C)C)c(N)[nH]1
Reaction time: 8 h

Procedure:
To 4-(2-tert-butyl-5-nitro-1H-pyrrole-4-carbonyl)-3,3-dimethylpiperazin-2-one (120 mg) in methanol (10 mL) was added Pd catalyst (10% on carbon, 60 mg) and the resulting reaction mixture was stirred under H2 at 60 psi for overnight. After the solids were removed by filtration over Celite, the solvent was removed in vacuo to afford 4-(2-amino-5-tert-butyl-1H-pyrrole-3-carbonyl)-3,3-dimethylpiperazin-2-one 7 as a yellow film (100 mg, 92%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2[CH:22]=[CH:23][CH:24]=[N:25]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1(N)CC1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:25][CH:24]1[CH2:22][CH2:23]1)=[O:7]
Reactant: O=C(O)c1cccc(Br)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-Bromo-benzoic acid (2.5518 g, 12.7 mmol) and HATU (5.2230 g, 13.7 mmol) were dissolved in DMF (40 mL). DIEA (4.644 mL, 26.7 mmol) was added, and the mixture was allowed to stir at room temperature for 15 minutes. Then cyclopropylamine (0.88 mL, 12.7 mmol) was added, and the reaction was stirred at ambient temperature overnight. The solvent was removed, and the crude was purified via silica gel chromatography to yield the desired product.
Reaction SMILES: [C:1]([NH:10][NH2:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].N1C=CC=CC=1.[CH2:18]([O:20][C:21](Cl)=[O:22])[CH3:19].O>CC(N(C)C)=O>[CH2:18]([O:20][C:21]([N:10]([C:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[NH2:11])=[O:22])[CH3:19]
Reactant: NNC(=O)c1ccccc1O
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)N(N)C(=O)c1ccccc1O
Temperature: 25 °C

Procedure:
30.4 g. of salicylic acid hydrazide are dissolved in 200 ml of dimethylacetamide and 16 g of pyridine and 22 g of chloroformic acid ethyl ester are then added simultaneously over the course of 30 minutes. Thereafter the reaction mixture is heated to 80°-90° C for 5 hours whilst stirring and is then cooled to room temperature, and about 500 ml of water are added carefully. Hereupon the N-salicyloyl-hydrazine-carboxylic acid ethyl ester produced (Stabiliser No. 1) separates out as a micro-crystalline precipitate. The compound is isolated and is purified by washing with water and recrystallised from ethanol. Melting point 126° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:38]1([CH2:44][C:45]([NH:47][CH2:48][CH:49]2[CH2:53][CH2:52][CH2:51][O:50]2)=[O:46])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:41]3[CH2:40][CH2:39][N:38]([CH2:44][C:45]([NH:47][CH2:48][CH:49]4[CH2:53][CH2:52][CH2:51][O:50]4)=[O:46])[CH2:43][CH2:42]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C(CN1CCNCC1)NCC1CCCO1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NCC2CCCO2)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 2-piperazin-1-yl-N-(tetrahydro-furan-2-ylmethyl)-acetamide (Enamine) to give the title compound as a mixture of diastereomers. HR-MS (ES, m/z) calculated for C40H51Cl2N6O4 [(M+H)+] 749.3344, observed 749.3341.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Br)=[CH:9][CH:8]=1)#[N:6]>CN(C=O)C.O>[N:1]([CH2:11][C:10]1[CH:13]=[CH:14][C:7]([C:5]#[N:6])=[CH:8][CH:9]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(CBr)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.2 %

Procedure:
Sodium azide (Aldrich, 3.5 g, 54 mmol) was added to a solution of p-cyanobenzyl bromide (Aldrich, 10 g, 51 mmol) in DMF (100 mL), and the resulting mixture was stirred at ambient temperature for 5 hours. The reaction mixture was then diluted with water (350 mL) and extracted with ether (2×100 mL). Combined organic layers were washed with brine and dried (MgSO4). Removal of solvent gave the title compound (8 g, 96%). 1HNMR (CDCl3) δ4.42 (s, 2H), 7.41 (d, 2H, J=8.1 Hz), 7.65 (d, 2H, J=8.1 Hz).
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:36]COC)=[CH:6][C:7]([O:32]COC)=[C:8]([C:10]2[N:11]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:12]([S:15]([CH2:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])(=[O:17])=[O:16])=[N:13][N:14]=2)[CH:9]=1)([CH3:3])[CH3:2].Cl.C(=O)([O-])O.[Na+]>C(O)C>[CH3:23][N:21]([CH3:22])[CH2:20][CH2:19][CH2:18][S:15]([C:12]1[N:11]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[C:10]([C:8]2[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]([OH:36])=[CH:6][C:7]=2[OH:32])=[N:14][N:13]=1)(=[O:17])=[O:16]
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1-c1nnc(S(=O)(=O)CCCN(C)C)n1-c1ccc(OC)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-n2c(-c3cc(C(C)C)c(O)cc3O)nnc2S(=O)(=O)CCCN(C)C)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 35.7 %

Procedure:
{3-[5-(5-isopropyl-2,4-bis-methoxymethoxy-phenyl)-4-(4-methoxy-phenyl)-4H-[1,2,4]triazole-3-sulfonyl]-propyl}-dimethylamine (6.8 g, crude F68-02 in the previous step), ethanol (50 mL) and 3 N hydrochloric acid (50 mL) were placed in a 200 mL eggplant shaped flask and the mixture was stirred at 50° C. for 5 hours. After completing the reaction, the reaction mixture was neutralized with saturated sodium hydrogencarbonate, extracted twice with ethyl acetate. The organic layer was washed 4 times with saturated sodium chloride, dried with sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol), followed by basic silica gel column chromatography (methylene chloride/methanol) to obtain the title compound (F68-03: 1.5 g, 35.7% in 2 steps)
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2([CH2:14][C:13](=[O:15])[C:12]3[C:16]([OH:23])=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:11]=3[O:10]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:24](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[C:1]([N:4]1[CH2:5][CH2:6][C:7]2([CH2:14][C:13](=[O:15])[C:12]3[C:16]([O:23][CH3:24])=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:11]=3[O:10]2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)N1CCC2(CC1)CC(=O)c1c(ccc([N+](=O)[O-])c1O)O2
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c([N+](=O)[O-])ccc2c1C(=O)CC1(CCN(C(C)=O)CC1)O2
Temperature: 25 °C
Reaction time: 72 h
Yield: 101.7 %

Procedure:
A mixture of 1'-acetyl-3,4-dihydro-5-hydroxy-6-nitro-spiro[2H-1-benzopyran-2,4'-piperidine]-4-one (3.84 g, 12 mmol), potassium carbonate (1.66 g, 12 mmol) and methyl iodide (3.74 ml, 8.51 g, 60 mmol) in DMF (30 ml) was stirred in a sealed vessel at room temperature for 3 days, adding further portions of methyl iodide (1 ml) after 24 and 48 h. The solvent was evaporated under reduced pressure, water (60 ml) was added, the pH was adjusted to 6.5 with HCl-H2O (2M) and the mixture was extracted with methylene chloride (3×60 ml). The combined organic fractions were dried (Na2SO4) and evaporated under reduced pressure. The crude product was re-subjected to the above procedure, the solvent was evaporated under reduced pressure, water (60 ml) was added and the mixture was extracted with methylene chloride (3×60 ml). The combined organic fractions were dried (Na2SO4) and evaporated under reduced pressure to give the ketone (4.08 g) as a yellow solid, m.p. 160°-165° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.I[CH:13]([CH3:15])[CH3:14]>C(=O)([O-])[O-].[Ag+2].CCCCCCC>[Cl:1][C:2]1[N:7]=[C:6]([O:8][CH:13]([CH3:15])[CH3:14])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1O
Reactant: CC(C)I
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CCCCCCC
Product: CC(C)Oc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 130 °C
Yield: 88.5 %

Procedure:
1.63 g of 6-chloro-3-nitropyridin-2-ol, 66 ml of heptane, 3.175 g of 2-iodopropane and 3.09 g of silver carbonate are introduced. The reaction medium is microwave-heated at 130° C. for 10 minutes and is then evaporated to dryness, bound to silica and purified by flash chromatography on silica gel (40-63 μm), elution being carried out with a mixture of heptane and ethyl acetate (90/10). 1.79 g of 6-chloro-3-nitro-2-(propan-2-yloxy)pyridine are obtained in the form of a beige solid.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([F:14])=[CH:8][C:5]=1[CH:6]=[O:7]>C(O)C>[F:3][C:4]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([F:14])=[CH:8][C:5]=1[CH2:6][OH:7]
Reactant: COc1cc(F)cc(C=O)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(F)cc(CO)c1F
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
Sodium borohydride (2.83 g, 74.7 mmol) was added to a stirred solution of 2,5-difluoro-3-methoxybenzaldehyde (8.57 g, 49.8 mmol) in ethanol (100 ml) at room temperature. After 30 min, the mixture was concentrated, the residue was diluted with ether (300 ml) and successively washed with water (200 ml), 10% citric acid (200 ml), water (200 ml), brine (200 ml), and dried over magnesiun sulfate. Removal of solvent gave 8.26 g (95%) of the titled compound as a white solid.