Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][CH:10]=[C:9]3[CH2:15][CH:16]2[CH2:23][CH:22]3[CH:18]([CH2:19][N:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:21]3)[NH:17]2)[CH:5]=1.[C:29](O)(=O)C.C=O.O.C([BH3-])#N.[Na+]>CO>[CH3:29][N:17]1[CH:16]([CH2:15][C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[C:6]([N:4]4[CH:3]=[N:2][N:1]=[CH:5]4)[CH:7]=3)[NH:11][CH:10]=2)[CH2:23][CH:22]2[CH:18]1[CH2:19][N:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:21]2
Reactant: CCOC(=O)N1CC2CC(Cc3c[nH]c4ccc(-n5cnnc5)cc34)NC2C1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)N1CC2CC(Cc3c[nH]c4ccc(-n5cnnc5)cc34)N(C)C2C1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 86 %

Procedure:
To a stirred solution of (1RS,3RS,5RS)-3-[{5-(1,2,4-triazol-4-yl)-1H-indol-3-yl}methyl]-2,7-diazabicyclo[3.3.0]octane-7-carboxylic acid, ethyl ester (1.6514 g, 4.34 mmol) in methanol (70 mL) was added glacial acetic acid (0.99 mL, 17.3 mmol), 37% solution of formaldehyde in water (0.423 mL, 5.64 mmol) and sodium cyanoborohydride (0.3309 g, 5.27 mmol). The mixture was stirred at room temperature under argon for 3.5 h before quenching with saturated K2CO3 solution (200 mL) and extracting with EtOAc (3×50 mL). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, CH2Cl2 --MeOH--NH3 (aq); 95:5:0.5 then 94:6:0.6) to give 1.4723 g (86.0%) of the title compound as a cream solid. δH (250 MHz, CDCl3) 1.23 (3H, t), 1.63 (1H, m), 1.84-1.96 (1H, m), 2.52 (3H, s), 2.59 (1H, m), 3.78 (1H, m), 4.10 (2H, q, J=7.0 Hz), 7.14-7.20 (2H, m), 7.50 (1H, d, J=12.6 Hz), 7.52 (1H, s), 8.48 (2H, s), 8.63 (1H, br s). m/e (ES+) 395 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=1[C:22]1[O:23][CH2:24][C:25]([CH3:28])([CH3:27])[N:26]=1.[Cl:29]C(Cl)(Cl)C(C(Cl)(Cl)Cl)=O>C1COCC1.O>[Cl:29][C:19]1[C:14]([F:13])=[C:15]([C:22]2[O:23][CH2:24][C:25]([CH3:28])([CH3:27])[N:26]=2)[CH:16]=[C:17]([F:21])[C:18]=1[F:20]
Reactant: CC1(C)COC(c2cc(F)c(F)cc2F)=N1
Reactant: O=C(C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC1(C)COC(c2cc(F)c(F)c(Cl)c2F)=N1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.4 %

Procedure:
A solution of 7.6 ml (54.2 mmol) of diisopropylamine in 100 ml of dry THF was cooled to -78° C. under argon, treated with 20.5 ml (47.2 mmol) of 2.3M n-butyllithium, and stirred for 15 minutes. To this solution was added a solution of 10.3 g (45.0 mmol) of 2-(2,4,5-trifluorophenyl)-4,4-dimethyl-2-oxazoline in 100 ml of dry THF. The reaction mixture was stirred at -78° C. for 45 minutes. To this mixture was added 26.5 g (100 mmol) of hexachloroacetone, and the solution was warmed to room temperature. Water was added; the organic phase was washed with water, 1N hydrochloric acid, and 5% sodium bicarbonate, and was dried over magnesium sulfate. Concentration gave a dark oil which was chromatographed on silica gel to give 7.05 g of the title compound as a yellow oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12].[OH-].[K+].Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>C1C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:20]([O:19][C:17](=[O:18])[CH2:16][O:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: OCCCCOC1CCCCO1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)COCCCCOC1CCCCO1

Procedure:
35.98 g of 4-(2-tetrahydropyranyloxy)-1-butanol was dissolved in 300 ml of benzene and then 33.95 g of tetra-n-butylammonium hydrogen sulfate and 300 ml of an aqueous 40% potassium hydroxide solution were added. While stirring vigorously under ice cooling, 10.5 ml of tert-butyl bromoacetate was added dropwise so as to control the inner temperature to 5 to 10° C. or lower. After stirring for 45 minutes, an ice bath was removed and the mixture was stirred at room temperature for one hour. The reaction solution was diluted with water and then extracted with diethyl ether. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 36.21 g of the desired compound as a colorless oily substance.
Reaction SMILES: O.NN.[N+:4]([C:7]1[CH:8]=[C:9]([C:13]2[CH:14]3[CH:16]([C:17](=[O:20])[NH:18][N:19]=2)[CH2:15]3)[CH:10]=[CH:11][CH:12]=1)([O-])=O>C(O)C.[Ni]>[NH2:4][C:7]1[CH:8]=[C:9]([C:13]2[CH:14]3[CH:16]([C:17](=[O:20])[NH:18][N:19]=2)[CH2:15]3)[CH:10]=[CH:11][CH:12]=1
Reactant: O=C1NN=C(c2cccc([N+](=O)[O-])c2)C2CC12
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1cccc(C2=NNC(=O)C3CC23)c1
Reaction time: 1 h
Yield: 76.5 %

Procedure:
A solution of 0.65 g (13.0 millimoles) of hydrazine hydrate in 10 ml of ethanol is added, whilst stirring, to a mixture of 1.5 g (6.5 millimoles) of 2-(m-nitrophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one (see Example 32b), 20 ml of ethanol and a small amount of an aqueous Raney nickel suspension in the course of 5 minutes, during which the temperature rises from 25° to 35° C. Stirring is continued for 1 hour and the reaction mixture is then slowly raised to the boil. It is refluxed for 5 minutes and filtered hot, and the filtrate is concentrated. After recrystallization from ethyl acetate/methanol, 1.0 g (76% of theory) of 2-(m-aminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one is obtained as colorless crystals, identical with the compound from Example 33.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C@@H]1(N)CCCC[C@H]1N.[O:15]=[C:16]1[NH:21][CH2:20][CH:19]2[CH2:22][CH2:23][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH:18]2[O:17]1.I[C:34]1[CH:43]=[CH:42][C:37]2[O:38][CH2:39][CH2:40][O:41][C:36]=2[CH:35]=1>O1CCOCC1.[Cu]I>[O:38]1[CH2:39][CH2:40][O:41][C:36]2[CH:35]=[C:34]([N:21]3[CH2:20][CH:19]4[CH2:22][CH2:23][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH:18]4[O:17][C:16]3=[O:15])[CH:43]=[CH:42][C:37]1=2
Reactant: Ic1ccc2c(c1)OCCO2
Reactant: CC(C)(C)OC(=O)N1CCC2CNC(=O)OC2C1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC2CN(c3ccc4c(c3)OCCO4)C(=O)OC2C1
Temperature: 25 °C
Reaction time: 40 h
Yield: 62.4 %

Procedure:
A vial was charged with K2CO3 (0.22 g, 1.56 mmol, 2 eq.), CuI (0.01 g, 0.08 mmol, 0.1 eq.) and trans-1,2-cyclohexane diamine (0.01 g, 0.08 mmol, 0.1 eq.), rac-(4aR*,8aR*)-tert-butyl 2-oxohexahydro-2H-pyrido[4,3-e][1,3]oxazine-7(3H)-carboxylate (Preparation A, 0.2 g, 0.78 mmol) and flushed with nitrogen for 5 min. A solution of 6-iodo-2,3-dihydrobenzo[b][1,4]dioxine (0.21 g, 0.78 mmol, 1.01 eq.) in dry dioxane (0.78 mL) was added and the resulting suspension was at 110° C. for 40 h. The reaction mixture was cooled to rt and filtered over Celite. The solid was washed by EA (2×10 mL). The filtrate was concentrated to dryness and the residue was purified by CC (DCM/MeOH 49:1 to 19:1) to give the title compound as a beige foam (0.19 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][N:32]4[C:36]([CH3:37])=[CH:35][CH:34]=[N:33]4)=[CH:27][CH:26]=3)[CH:23]=2)=[O:18])=[C:10]([CH3:38])[N:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[N:9]=[C:10]([CH3:38])[C:11]([CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][N:32]4[C:36]([CH3:37])=[CH:35][CH:34]=[N:33]4)=[CH:27][CH:26]=3)[CH:23]=2)=[O:18])=[C:12]([CH3:14])[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cn(Cc2ccc(Cn3nccc3C)cc2)nn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(N)nc(C)c1CNC(=O)c1cn(Cc2ccc(Cn3nccc3C)cc2)nn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of {4,6-Dimethyl-5-[({1-[4-(5-methyl-pyrazol-1-ylmethyl)-benzyl]-1H-[1,2,3]triazole-4-carbonyl}-amino)-methyl]-pyridin-2-yl}-carbamic acid tert-butyl ester (132 mg, 0.249 mmol) and 5 mL of TFA in 10 mL of DCM was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters SunFire Prep C18 OBD 5 μm 30×100 mm, Flow 40 mL/min, ACN/water (0.1% TFA) 5/95 over 2 min, then ACN/water (0.1% TFA) 5/95-100/0 over 15 min) to yield the title compound. 1H-NMR (DMSO-d6, 600 MHz) 8.59 (s, 1H), 8.29 (t, 1H), 7.33 (s, 1H), 7.28 (d, 2H), 7.09 (d, 2H), 6.09 (s, 1H), 6.05 (s, 1H), 5.63 (s, 2H), 5.59 (s, 2H), 5.26 (s, 2H), 4.32 (d, 2H), 2.29 (s, 3H), 2.17 (s, 3H), 2.16 (s, 3H); [M+H]+=431.0.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[OH:32])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15](/[CH:18]=[CH:19]\[C:20]4[CH:21]=[N:22][CH:23]=[N:24][CH:25]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[CH2:34]([CH:36]([CH2:42][CH3:43])[C:37]([O:39][CH2:40]I)=[O:38])[CH3:35].C(OCC)(=O)C>CN(C)C(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[OH:32])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O:28][CH2:40][O:39][C:37](=[O:38])[CH:36]([CH2:42][CH3:43])[CH2:34][CH3:35])=[O:27])=[C:15](/[CH:18]=[CH:19]\[C:20]4[CH:25]=[N:24][CH:23]=[N:22][CH:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CCC(CC)C(=O)OCI
Reactant: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(/C=C\c4cncnc4)CS[C@H]23)cs1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCC(CC)C(=O)OCOC(=O)C1=C(/C=C\c2cncnc2)CS[C@@H]2[C@H](NC(=O)/C(=N\O)c3csc(N)n3)C(=O)N12

Procedure:
The compound (100 mg) of Example 16 was dissolved in N,N-dimethylacetamide (2 ml), followed by the addition of 2-ethylbutanoyloxymethyl iodide (50 mg). They were reacted for 1 hour. Ethyl acetate (50 ml) was added. The resulting mixture was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. Ether was added to the residue and the resulting solid was collected by filtration, whereby the title compound (55 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][NH2:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:13](=O)C1C=CC=CC=1.CI>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][NH:12][CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(CN)cc1OC
Solvent: CI
Solvent: CCO
Product: CNCc1ccc(OC)c(OC)c1
Yield: 63.7 %

Procedure:
3,4-Dimethoxybenzenemethanamine (100 g) was mixed with benzaldehyde (64 g), and rotoevaporated to give an oil. Methyl iodide (75 ml) was then added and the mixture was heated for 48 h at 40° and then boiled with 80% ethanol (800 ml) for 3 h. After half of the ethanol had evaporated, the solution was treated with ether (1 liter) to give a solid that was filtered, washed with ether, treated with dilute sodium hydroxide and extracted with ether to give the title compound (69 g) as an oil that was distilled under reduced pressure, b.p. 0.03 mm; 91°.
Reaction SMILES: N#N.[F:3][C:4]([C:7]1[O:8][CH:9]=[C:10]([C:12](OCC)=[O:13])[N:11]=1)([F:6])[CH3:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C1COCC1.O>[F:3][C:4]([C:7]1[O:8][CH:9]=[C:10]([CH2:12][OH:13])[N:11]=1)([F:6])[CH3:5]
Reactant: CCOC(=O)c1coc(C(C)(F)F)n1
Agent: N#N
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CC(F)(F)c1nc(CO)co1
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of ethyl 2-(1,1-difluoroethyl)oxazole-4-carboxylate (1.23 g, 6.00 mmol) in THF (15.0 mL) was added dropwise at 0° C. to a solution of lithim aluminium hydride (6.7 mL of a 1M sol in THF, 6.70 mmol) in THF (5.0 mL) and the reaction mixture was stirred for 1 h at 0° C. Water (2.0 mL) was added followed by 1M NaOH (2.0 mL) and water (2.0 mL) and the reaction mixture was allowed to warm to rt. The solvents were removed under reduced pressure to give the title compound as a colorless oil. TLC: rf (EA)=0.18. LC-MS-conditions 01: tR=0.57 min; [M+H]+=164.04.
Reaction SMILES: [Cl-].[Li+].C(OP([CH:11]([CH2:17][CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.C1CCN2C(=NCCC2)CC1.[CH2:30]([O:37][C:38]([N:40]1[C@@H:44]([CH2:45][CH:46]([CH3:48])[CH3:47])[C@H:43]([CH:49]=O)[O:42][C:41]1([CH3:52])[CH3:51])=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>C1COCC1>[CH2:30]([O:37][C:38]([N:40]1[C@@H:44]([CH2:45][CH:46]([CH3:47])[CH3:48])[C@H:43]([CH:49]=[C:11]([CH2:17][CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:42][C:41]1([CH3:51])[CH3:52])=[O:39])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)C[C@H]1[C@H](C=O)OC(C)(C)N1C(=O)OCc1ccccc1
Reactant: CCOC(=O)C(CC)P(=O)(OCC)OCC
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(=C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC(C)C)CC
Yield: 88.1 %

Procedure:
71.6 mg of lithium chloride was suspended in 5 ml of dry THF under an argon atmosphere, and 426 mg of ethyl 2-diethylphosphonobutanoate dissolved in 0.6 ml of dry THF was added thereto under stirring. The mixture was stirred at room temperature for 5 minutes, and then 323 mg of 1,8-diazabicyclo[5,4,0]-7-undecene (hereinafter referred to simply as DBU) was added thereto in the form of a 50% dry THF solution, and the mixture was stirred at room temperature for 10 minutes. Then, 450 mg of (4S,5R)-3-benzyloxycarbonyl-2,2-dimethyl-5-formyl-4-isobutyloxazolidine dissolved in 1.0 ml of dry THF was added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was cooled to 0° C. and neutralized with 1N hydrochloric acid. Then, the solution was extracted three times with ethyl acetate. The organic layer was washed with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=10/1) to obtain 518 mg of ethyl 3-[(4S,5S)-3-benzyloxycarbonyl-2,2-dimethyl-4-isobutyloxazolidin-5-yl]-2-ethyl-2-propenoate as colorless oily substance.
Reaction SMILES: [CH:1]1(OC(=O)[C@@H](NC(OCC2C=CC=CC=2)=O)COC(C)(C)C)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:27]([O:31][C:32]([NH:34][C@@H:35]([CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)[C:36]([OH:38])=[O:37])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[CH:1]1([O:37][C:36](=[O:38])[C@@H:35]([NH:34][C:32]([O:31][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:33])[CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Reactant: CC(C)(C)OC[C@H](NC(=O)OCc1ccccc1)C(=O)OC1CCCC1
Product: CC(C)(C)OC(=O)N[C@H](C(=O)OC1CCCC1)C1CCCCC1

Procedure:
This was prepared in the same manner as (S)-2-benzyloxycarbonylamino-3-tert-butoxy-propionic acid cyclopentyl ester (Method A, Stage 1) but from (S)-tert-butoxycarbonylamino-cyclohexyl acetic acid. 1H NMR (300 MHz, CDCl3), δ: 1.00-1.40 (10H, m, CH×10), 1.45 (9H, s, C(CH3)3), 1.60-2.00 (8H, m, 4×CH2), 4.15 (1H, m, CH), 5.05 (1H, d, NH, J=7.6 Hz), 5.25 (1H, m, CH).
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:6](=[O:25])[N:5]([CH2:26][C:27]3[O:31][N:30]=[C:29]([CH2:32][CH3:33])[N:28]=3)[C:4]=2[CH:3]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.Cl[Pd]Cl>[CH2:32]([C:29]1[N:28]=[C:27]([CH2:26][N:5]2[C:4]3[CH:3]=[C:2]([C:38]4[CH:39]=[CH:40][C:35]([F:34])=[CH:36][CH:37]=4)[S:10][C:9]=3[C:8](=[O:11])[N:7]([CH:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:16][CH2:17]3)[C:6]2=[O:25])[O:31][N:30]=1)[CH3:33]
Reactant: CCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(Br)cc32)n1
Reactant: CC1(C)OB(c2ccc(F)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccc(F)cc4)cc32)n1

Procedure:
Tert-butyl 4-{6-bromo-1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (500 mg, compound B99), 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (246 mg), dichlorobis(tricyclohexylphosphine)palladium (68 mg) and aqueous cesium carbonate solution (0.694 ml, 2.0 M) in dioxane (18 ml) are reacted according to the procedure described in example B55 to afford the title compound after purification by flash column chromatography [silica gel, elution gradient: DCM/EtOH, 100/0 to 70/30 (v/v)] as a solid.
Reaction SMILES: CO[C:3](=[O:18])[C:4]([C:9]1[S:10][C:11]([C:14]([F:17])([F:16])[F:15])=[N:12][N:13]=1)=[CH:5][N:6](C)C.[NH:19]([C:21]1[N:26]=[CH:25][N:24]=[C:23]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:22]=1)N.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CO>[N:27]1([C:23]2[N:24]=[CH:25][N:26]=[C:21]([N:19]3[C:3](=[O:18])[C:4]([C:9]4[S:10][C:11]([C:14]([F:15])([F:16])[F:17])=[N:12][N:13]=4)=[CH:5][NH:6]3)[CH:22]=2)[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1
Reactant: COC(=O)C(=CN(C)C)c1nnc(C(F)(F)F)s1
Reactant: NNc1cc(N2CCOCC2)ncn1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CO
Product: O=c1c(-c2nnc(C(F)(F)F)s2)c[nH]n1-c1cc(N2CCOCC2)ncn1

Procedure:
2.43 g (8.62 mmol) of the compound from Example 2A, 1.53 g of the compound from Example 16A and 182 mg (784 μmol) camphor-10-sulfonic acid are dissolved in 35 ml anhydrous methanol and the mixture is heated under reflux overnight. After cooling, the mixture is concentrated, the residue is taken up again in 325 ml methanol, 0.5 ml (8.62 mmol) of a 25% strength methanolic sodium methylate solution is added and the mixture is heated again under reflux overnight. After cooling, the precipitate formed is filtered off with suction, washed with diethyl ether and suspended in a little water, an excess of 1 M hydrochloric acid is added and the suspension is concentrated again. The residue is washed with water and diethyl ether and dried. 1.34 g (43% of th.) of the title compound are obtained.
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[C:4]([CH2:8][CH3:9])([CH3:7])[CH2:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[OH:25]>CN(C)C=O>[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[O:25][CH2:2][C:3](=[O:10])[C:4]([CH2:8][CH3:9])([CH3:7])[CH2:5][CH3:6]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: CCC(C)(CC)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(C)(CC)C(=O)COc1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 93.5 %

Procedure:
50 g (0.28 mole) of 1-chloro-3-ethyl-3-methyl-pentan-2-one, dissolved in 30 ml of N,N-dimethylformamide, are added to a mixture of 38.6 g (0.28 mole) of potassium carbonate and 45.6 g (0.28 mole) of 2,4-dichlorophenol in 200 ml of N,N-dimethylformamide at the boiling point. The mixture is heated at the boiling point for 10 hours, cooled to room temperature and filtered and the solvent is distilled off under reduced pressure. Distillation of the residue gives 75.7 g (93.5% of theory) of 1-(2,4-dichlorophenoxy)-3-ethyl-3-methyl-pentan-2-one as a color less liquid of boiling point 141°-144° C./0.15 mm. ##STR64##
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=1)=[O:30]>>[ClH:20].[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=3)=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C(CCCCCBr)c1cccc(Cl)c1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2cccc(Cl)c2)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(3-chlorophenyl)-1-hexanone were reacted and treated in the same manner as in Example 172 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(3-chlorophenyl)-6-oxohexyl)piperidin-4-yl)methyl)benzamide hydrochloride.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH:9]2[CH2:11][CH2:10]2)=[O:8])[CH:2]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH:9]1([C:7]([C:3]2[CH:2]=[C:1]([CH2:12][Br:13])[CH:6]=[CH:5][CH:4]=2)=[O:8])[CH2:10][CH2:11]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(C(=O)C2CC2)c1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1cccc(CBr)c1)C1CC1

Procedure:
A stirred suspension of cyclopropyl m-tolyl ketone (16 g) and N-bromosuccinimide (17.8 g) in carbon tetrachloride (100 ml) was irradiated and heated under reflux by means of a tungsten lamp for 2 hours and cooled. The solid was filtered off and the filtrate evaporated. The residual oil was distilled under reduced pressure and the fraction distilling at 115°-130°/0.1 mm was collected.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2/[CH:14]=[CH:15]/[C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=2)=[CH:4][CH:3]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2/[CH:14]=[CH:15]/[C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:25][CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:22])=[CH:18][N:17]=2)=[CH:6][CH:7]=1
Reactant: NC1CCOCC1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1/C=C/c1ccc(C(=O)O)cn1
Product: Cn1nnc(-c2ccc(F)cc2)c1/C=C/c1ccc(C(=O)NC2CCOCC2)cn1
Yield: 82 %

Procedure:
As described for example 56b, 6-{(E)-2-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-vinyl}-nicotinic acid (49 mg, 0.15 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (45 mg, 82%) which was obtained as a light yellow solid. MS: m/e=366.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([OH:12])=[CH:7]2.[H-].[Na+].I[C:16]1[CH:21]=[CH:20][N:19]=[C:18]2[NH:22][N:23]=[CH:24][C:17]=12>CN(C=O)C>[NH:22]1[C:18]2=[N:19][CH:20]=[CH:21][C:16]([O:12][C:6]3[CH:7]=[C:8]4[C:3](=[CH:4][CH:5]=3)[C:2]([NH2:1])=[CH:11][CH:10]=[CH:9]4)=[C:17]2[CH:24]=[N:23]1
Reactant: Ic1ccnc2[nH]ncc12
Reactant: Nc1cccc2cc(O)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1cccc2cc(Oc3ccnc4[nH]ncc34)ccc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
5-Aminonaphthalen-2-ol (356 mg, 2.24 mmol) was dissolved in DMF (2.5 mL) then cooled to 0° C. Sodium hydride (94 mg) was added slowly and the stirring was continued for 15 min at 0° C. 4-Iodo-1H-pyrazolo[3,4-b]pyridine (274 mg, 1.12 mmol) was then added slowly and the reaction was heated at 100° C. for 16 h, followed by 4.5 h at 120° C. The mixture was partitioned between water and EtOAc then washed with water, 1N aqueous NaOH, and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to give 6-(1H-pyrazolo[3,4-b]pyridin-4-yloxy)naphthalen-1-amine as a brown solid MS (ESI, pos. ion) m/z: 277.1 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:8][C@@H:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(C(C)C)C(C)C)C>C1(C)C=CC=CC=1>[C:10]1([C@H:9]([NH:16][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:8])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)CBr
Reactant: C[C@@H](N)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)CN[C@H](C)c1ccccc1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
Ethyl bromoacetate (4.14 g; 24.8 mmol) was treated with (R)α-methylbenzylamine (3 g, 24.8 mmol) and ethyldiisopropylamine (3.2 g; 24.8 mmol) in toluene (100 mL). After heating at reflux for 18 hours, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 20% ethyl acetate/pentane) to provide the title compound (3.2 g, 63% yield). MS (DCI/NH3) m/z 208 (M+H)+.