Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.[CH2:15]([O:17][C:18](=[O:23])[CH:19]=[C:20](Cl)[CH3:21])[CH3:16]>O1CCCC1>[CH2:15]([O:17][C:18](=[O:23])/[CH:19]=[C:20](/[O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([Cl:7])[CH:9]=1)\[CH3:21])[CH3:16]
Reactant: Oc1cccc(Cl)c1
Reactant: CCOC(=O)C=C(C)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1cccc(Cl)c1
Temperature: 23 °C
Yield: 40.3 %

Procedure:
Potassium t-butoxide (7.40 g, 0.066 mol) was added to a stirred solution of 3-chloro-phenol (4.22 g, 0.033 mol) in tetrahydrofuran (35 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191, 5.00 g, 0.034 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-(3-chloro-phenoxy)-but-2-enoic acid ethyl ester (3.20 g, 40%) as a yellow oil.
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[C:6]([C:11]1[N:12]([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([Cl:20])=[CH:15][CH:14]=2)([O:8][CH2:9][CH3:10])=[O:7]>C(OC(=O)C)(=O)C.ClCCl>[C:6]([C:11]1[N:12]([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:22])=[O:23])[C:13]2[C:18]([C:19]=1[S:1]([OH:3])(=[O:5])=[O:2])=[CH:17][C:16]([Cl:20])=[CH:15][CH:14]=2)([O:8][CH2:9][CH3:10])=[O:7]
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1c(S(=O)(=O)O)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C

Procedure:
Concentrated sulfuric acid (2.50 ml, 90 mmol) was added dropwise over 5 min at 0° C. to a stirred solution of 2-carboethoxy-5-chloro-1-phenylsulfonylindole (7.28 g, 20.0 mmol) in acetic anhydride (10 ml) and dry dichloromethane (50 ml). The resulting tan solution was warmed to RT (room temperature) and after 3 hours was poured onto ice and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried (Na2SO4) and evaporated in vacuo to a syrup. Residual acetic anhydride was removed by azeotroping with toluene (3×50 ml), and the residue was crystallized from dichloromethane. The dichloromethane was evaporated in vacuo to give the title compound as a tan powder:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]([CH2:13][CH3:14])=[C:11](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:10]=[N:9]2)[CH:5]=[C:4](Cl)[N:3]=1.Cl.[OH:24][CH:25]1[CH2:28][NH:27][CH2:26]1.C(N(CC)CC)C>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]([CH2:13][CH3:14])=[C:11](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:10]=[N:9]2)[CH:5]=[C:4]([N:27]2[CH2:28][CH:25]([OH:24])[CH2:26]2)[N:3]=1
Reactant: CCOC(=O)/C=C/c1cnn(-c2cc(Cl)nc(N)n2)c1CC
Reactant: OC1CNC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cnn(-c2cc(N3CC(O)C3)nc(N)n2)c1CC

Procedure:
A 4.14 g portion of ethyl 3-[1-[2-amino-6-chloro-4-pyrimidinyl]-5-ethyl-4-pyrazolyl]-2-trans-propenoate was suspended in 150 ml of ethanol, mixed with 3.07 g of 3-hydroxyazetidine hydrochloride and 7.8 ml of triethylamine and then heated under reflux for 2 days. The reaction solution was allowed to stand at room temperature, and then the resulting precipitate was collected by filtration to obtain 4.10 g of the title compound as colorless crystals.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)=O.[P:9]([OH:12])([OH:11])[OH:10].P(Cl)(Cl)Cl>O>[O:6]1[CH2:7][CH2:8][N:3]([CH:1]([P:9]([OH:12])(=[O:10])[OH:11])[P:9]([OH:12])(=[O:11])[OH:10])[CH2:4][CH2:5]1
Reactant: OP(O)O
Reactant: O=CN1CCOCC1
Solvent: O
Solvent: ClP(Cl)Cl
Product: O=P(O)(O)C(N1CCOCC1)P(=O)(O)O
Yield: 35 %

Procedure:
115 parts of N-formylmorpholine and 82 parts of phosphorous acid were mixed and reacted with 137 parts of phosphorus trichloride. The reaction mixture was then treated with about 5000 parts of water, and the solution was filtered and concentrated. The precipitate obtained was isolated and recrystallized from water/acetone. After drying, a yield of 35% of morpholinomethanediphosphonic acid was obtained.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[C:27]2[C:33]1[CH2:34][CH2:35][NH:36][CH2:37][CH:38]=1.C(N(CC)CC)C>C(OCC)(=O)C>[O:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:21][CH2:22][CH:13]1[CH2:12][N:36]1[CH2:37][CH:38]=[C:33]([C:27]2[C:26]3[C:30](=[CH:31][CH:32]=[C:24]([F:23])[CH:25]=3)[NH:29][CH:28]=2)[CH2:34][CH2:35]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccccc3O2)cc1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Fc1ccc2[nH]cc(C3=CCN(CC4CCc5ccccc5O4)CC3)c2c1
Temperature: 80 °C
Yield: 41.1 %

Procedure:
To a solution of 3,4-dihydro-2H-chromen-2-ylmethyl 4-methylbenzenesulfonate (0.500 g, 1.57 mmol) was added 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.590 g, 2.73 mmol) and triethylamine (0.314 g, 3.10 mmol) and the reaction mixture was heated to 80° C. for 8 h. The reaction mixture was allowed to cool to room temperature and was diluted with ethyl acetate (200 mL), washed with water (3×100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, methanol:dichloromethane 1:9) provided 0.234 g (40%) of 3-[1-(3,4-dihydro-2H-chromen-2-ylmethyl)-1,2,3,6-tetrahydro-4-pyridinyl]-5-fluoro-1H-indole as a yellow solid. mp 172-175° C.; Anal. Calcd. for C23H23FN2O: C, 76.22; H, 6.40; N, 7.73. Found: C, 75.82; H, 6.37; N, 7.63.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:16][C:17]([C:19]2([NH:34]C(=O)OC(C)(C)C)[CH2:24][CH2:23][N:22]([C:25]3[C:26]4[CH:33]=[CH:32][NH:31][C:27]=4[N:28]=[CH:29][N:30]=3)[CH2:21][CH2:20]2)=[O:18])[CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:34][C:19]1([C:17]([NH:16][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[O:18])[CH2:20][CH2:21][N:22]([C:25]2[C:26]3[CH:33]=[CH:32][NH:31][C:27]=3[N:28]=[CH:29][N:30]=2)[CH2:23][CH2:24]1
Reactant: CCN(CC)CC[C@H](NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)CC[C@H](NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.8 %

Procedure:
(S)-1-(4-Chlorophenyl)-N3,N3-diethylpropane-1,3-diamine (Intermediate 60) (119 mg, 0.49 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (179 mg, 0.49 mmol) and DIPEA (0.259 mL, 1.48 mmol) in DMA (5 mL). O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (207 mg, 0.54 mmol) was added and the resulting solution was stirred at 50° C. for 2 hours. The reaction mixture was diluted with EtOAc (25 mL), and washed sequentially with water (20 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 5 to 10% MeOH with ammonia in DCM. Pure fractions were evaporated to dryness to afford (S)-tert-butyl 4-(1-(4-chlorophenyl)-3-(diethylamino)propylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (189 mg, 65.5%) as a colourless gum. (S)-tert-butyl 4-(1-(4-chlorophenyl)-3-(diethylamino)propylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (189 mg, 0.33 mmol) was dissolved in DCM (5.00 mL) and TFA (1 mL) added. The reaction was stirred at ambient temperature for 2 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7N ammonia/MeOH and pure fractions were evaporated to dryness to afford crude product which was triturated with diethyl ether to afford (S)-4-amino-N-(1-(4-chlorophenyl)-3-(diethylamino)propyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (70.0 mg, 29.3%) as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=4)=[CH:18][C:17]=3[C:28]3[CH:29]=[CH:30][C:31]([C:34]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:35])=[N:32][CH:33]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH:22]1([C:19]2[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[CH:13][CH:12]=3)=[C:17]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:35])=[N:32][CH:33]=3)[CH:18]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(O)CCNC(=O)c1ccc(-c2cc(C3=CCCCC3)ccc2CNc2ccc(-c3ccc(F)cc3)cc2)cn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O=C(O)CCNC(=O)c1ccc(-c2cc(C3CCCCC3)ccc2CNc2ccc(-c3ccc(F)cc3)cc2)cn1

Procedure:
A mixture of 3-(5-(4-(((4′-fluoro-[1,1′-biphenyl]-4-yl)amino)methyl)-2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-3-yl)picolinamido)propanoic acid (47.6 mg, 0.087 mmol), ammonium formate (54.6 mg, 0.87 mmol) and 10% Pd—C (9.2 mg, 0.0087 mmol) in MeOH (5 mL) was refluxed for 1 h, then filtered through CELITE, washed with DCM-MeOH. The filtrate was concentrated and purified via column chromatography to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][O:15][C:16]3[CH:23]=[CH:22][C:19]([CH2:20][OH:21])=[C:18]([F:24])[CH:17]=3)[CH:9]=2)=[C:4]([CH3:25])[CH:3]=1>[O-2].[O-2].[Mn+4].C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][O:15][C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[C:18]([F:24])[CH:17]=3)[CH:9]=2)=[C:4]([CH3:25])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1-c1cccc(COc2ccc(CO)c(F)c2)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1-c1cccc(COc2ccc(C=O)c(F)c2)c1
Temperature: 40 °C
Reaction time: 17 h

Procedure:
In an atmosphere of nitrogen, a THF solution of methyl 4-[(4′-chloro-2′-methylbiphenyl-3-yl)methoxy]-2-fluorobenzoate was dropwise added to a THF suspension of lithium aluminum hydride under cooling on an ice-methanol bath, followed by stirring at room temperature for 1 hour to obtain 4-[(4′-chloro-2′-methylbiphenyl-3-yl)methoxy]-2-fluorobenzyl alcohol. By adding manganese dioxide to a THF solution of the resulting 4-[(4′-chloro-2′-methylbiphenyl-3-yl)methoxy]-2-fluorobenzyl alcohol and stirring at 40° C. for 17 hours, 4-[(4′-chloro-2′-methylbiphenyl-3-yl)methoxy]-2-fluorobenzaldehyde was obtained.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].[C:6]([C:8]1[C:9]([C:22]2[N:23]([CH3:30])[C:24]([N+:27]([O-:29])=[O:28])=[CH:25][N:26]=2)=[N:10][N:11]([CH3:21])[C:12]=1[NH:13][C:14](=[O:20])[C:15](OCC)=[O:16])#[N:7]>CO>[C:6]([C:8]1[C:9]([C:22]2[N:23]([CH3:30])[C:24]([N+:27]([O-:29])=[O:28])=[CH:25][N:26]=2)=[N:10][N:11]([CH3:21])[C:12]=1[NH:13][C:14]([C:15]([NH:2][OH:3])=[O:16])=[O:20])#[N:7]
Reactant: CCOC(=O)C(=O)Nc1c(C#N)c(-c2ncc([N+](=O)[O-])n2C)nn1C
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cn1nc(-c2ncc([N+](=O)[O-])n2C)c(C#N)c1NC(=O)C(=O)NO

Procedure:
Separate solutions were prepared of 0.94 g. of hydroxylamine hydrochloride in 10 ml. of methanol, and 0.728 g. of potassium hydroxide in 5 ml. of methanol at the boiling point of methanol. Both solutions were then cooled to about 30°-40° C., and the potassium hydroxide solution was added with shaking to the hydroxylamine hydrochloride solution. After the addition, the flask containing the mixture was flushed with nitrogen so that the mixture was maintained in a nitrogen atmosphere while being cooled in an ice bath for about 5 minutes to insure complete precipitation of the potassium chloride. The potassium chloride was filtered off and the filtrate diluted with about 50 ml. of methanol. To this methanolic solution, there was then added 2.3 g. (0.0067 mole) of N-[4-cyano-1-methyl-3-(1-methyl-5-nitroimidazol-2-yl)pyrazol-5-yl]oxamic acid, ethyl ester, and the mixture was stirred for about 3 hours at ambient room temperature. A precipitate formed which was filtered off. The solid so collected was refluxed in methanol and the solid which did not dissolve was collected on a filter. The solid weighed about 0.3 g. and had a melting point of about 179°-180° C. The solid was identified by NMR spectrum and elemental analyses as N-[4-cyano-1-methyl-3-(1-methyl-5-nitroimidazol-2-yl)pyrazol-5-yl]-N'-hydroxyoxamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[N+:20]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(OCC(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CC(C)(C)OC(=O)Nc1ccc(OCC(F)(F)F)cc1N

Procedure:
The title compound was prepared from [2-nitro-4-(2,2,2-trifluoro-ethoxy)-phenyl]-carbamic acid tert-butyl ester (Example A24) (3.65 g, 11 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a light brown solid (3.16 g, 94%).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([O:22][C:23]1[CH:27]=[CH:26][S:25][C:24]=1[C:28]([O:30][CH3:31])=[O:29])[CH3:21].C(O[B:36]1[O:40][C:39]([CH3:42])([CH3:41])[C:38]([CH3:44])([CH3:43])[O:37]1)(C)C.Cl>C1COCC1>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([O:22][C:23]1[CH:27]=[C:26]([B:36]2[O:40][C:39]([CH3:42])([CH3:41])[C:38]([CH3:44])([CH3:43])[O:37]2)[S:25][C:24]=1[C:28]([O:30][CH3:31])=[O:29])[CH3:21]
Reactant: COC(=O)c1sccc1OC(C)c1ccccc1Cl
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)c1sc(B2OC(C)(C)C(C)(C)O2)cc1OC(C)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51.6 %

Procedure:
2.5 M n-BuLi in hexanes (2.3 mL, 5.77 mmol, 1.5 Eq.) was added dropwise to a stirred solution of diisopropylamine (815 μL, 5.77 mmol, 1.5 Eq.) in anhydrous THF (20 mL) at −78° C. under nitrogen. The reaction was stirred at this temperature for 15 minutes then warmed to 0° C. for 30 minutes. The reaction was cooled to −78° C. and a solution of methyl 3-(1-(2-chlorophenyl)ethoxy)thiophene-2-carboxylate (1.14 g, 3.84 mmol, 1.0 Eq.) in anhydrous THF (10 mL) was added dropwise. After stirring at this temperature for 10 minutes, a solution of 2-isopropoxy-4,4,5,5-tetramethyl[1,3,2]-dioxaborolane (1.78 mL, 5.77 mmol, 1.0 Eq.) in anhydrous THF (10 mL) was added dropwise and stirred at −78° C. for 15 minutes then warmed to ambient temperature for 45 minutes. 1M HCl (30 mL) was added and the mixture extracted with EtOAc (3×40 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO4) and the solvent removed in vacuo. The residue was recrystalised from cyclohexane to give the sub-title compound as a white solid (837 mg, 1.98 mmol, 51%); 1H NMR (400 MHz, CDCl3) δ 1.38 (12H, s), 1.67 (3H, d), 3.90 (3H, s), 5.80 (1H, quint), 7.18 (1H, s), 7.21-7.7.34 (2H, m), 7.38 (1H, dd), 7.77 (1H, dd).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15]#[C:16][C:17]3[CH:44]=[CH:43][C:20]([O:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][CH:27]([CH:30]5[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]5)[CH2:26][CH2:25]4)=[CH:19][CH:18]=3)=[N:13][CH:14]=2)=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].O>C(O)(C)C.C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15]#[C:16][C:17]3[CH:44]=[CH:43][C:20]([O:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][CH:27]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH2:26][CH2:25]4)=[CH:19][CH:18]=3)=[N:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCN(CCOc3ccc(C#Cc4ccc(-c5ccc(Cl)cc5)cn4)cc3)CC2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Solvent: O
Product: Clc1ccc(-c2ccc(C#Cc3ccc(OCCN4CCC(C5CCNCC5)CC4)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3 mL of a 5 N HCl solution in isopropanol are added to a solution of 200 mg (0.33 mmol) tert-butyl 1′-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-[4,4′]bipiperidinyl-1-carboxylate (Example 4.29) in 5 mL DCM and the reaction mixture is stirred for 4 h at RT. It is diluted with 30 mL DCM, neutralised with saturated NaHCO3 solution, combined with 30 mL water, the aqueous phase is extracted exhaustively with DCM and the combined organic phases are dried over MgSO4. After the desiccant and solvent have been eliminated the desired product is obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH3:17])[N:14]=[C:15]([CH3:16])[C:3]=12.C(=O)([O-])[O-].[K+].[K+].[NH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>C(#N)C>[C:30]([O:29][C:28]([NH:27][CH2:26][CH2:25][NH:24][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH3:17])[N:14]=[C:15]([CH3:16])[C:3]=12)=[O:34])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CCOC(=O)c1cnc2c(c(C)nn2C)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cnc2c(c(C)nn2C)c1NCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.4 %

Procedure:
To a mixture of ethyl 4-chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (500 mg, 1.971 mmol) and potassium carbonate (817 mg, 5.91 mmol) in acetonitrile (15 ml) was slowly added tert-butyl N-(2-aminoethyl)carbamate (1.248 ml, 7.88 mmol) via a syringe. The reaction mixture was stirred at room temperature for 3 hours. The solids were filtered off over a glass filter and washed with a 1:1 mixture of EtOH and DCM. The combined filtrates were concentrated under reduced pressure to give a white semisolid, which was purified by column chromatography (silica gel using a gradient of ethanol (0-5%) in DCM) to yield 658 mg of a white solid (1.743 mmol, 88%). MS (ESI) m/z=378.2 [M+1]+.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:6]=1[N+:15]([O-])=O>CO.[Pd]>[F:14][C:11]([F:12])([F:13])[C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:5]=1[CH:4]=[CH:3][NH:15]2
Reactant: CN(C)/C=C/c1c([N+](=O)[O-])cccc1C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: FC(F)(F)c1cccc2[nH]ccc12
Yield: 58 %

Procedure:
7.7 mmol Dimethyl-[(E)-2-(2-nitro-6-trifluoromethyl-phenyl)-vinyl]-amine was dissolved in 20 ml methanol. 200 mg of palladium 5% on charcoal was added and the reaction mixture hydrogenated at room temperature and atmospheric pressure. When no further hydrogen is absorbed (ca. 3 hours), the reaction mixture is filtered, concentrated and dissolved in diethyl ether. The organic phase is washed with 2 M hydrochloric acid and brine and concentrated to yield the title compound as a yellowish solid. Yield=58%. MS (m/e): 184.9 ([M+H]+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]#[C:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=[C:22]3[CH3:32])=[C:17]([CH3:33])[CH:16]=1)[CH:7]=[CH:6]2.[CH3:34][O:35][C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([O:46][CH3:47])[C:43]=1[O:44][CH3:45])[CH:39]=O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]#[C:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=[C:22]3/[CH:32]=[CH:39]/[C:38]3[CH:41]=[C:42]([O:46][CH3:47])[C:43]([O:44][CH3:45])=[C:36]([O:35][CH3:34])[CH:37]=3)=[C:17]([CH3:33])[CH:16]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(C#Cc3ccc(-n4c(C)nc5ccccc5c4=O)c(C)c3)ccc2c1
Reactant: COc1cc(C=O)cc(OC)c1OC
Solvent: CC(=O)O
Product: COc1ccc2cc(C#Cc3ccc(-n4c(/C=C/c5cc(OC)c(OC)c(OC)c5)nc5ccccc5c4=O)c(C)c3)ccc2c1
Reaction time: 8 h

Procedure:
4-iodo-2-methylbenzenamine 24 (233 mg, 1 mmol) on reaction with 2-ethynyl-6-methoxynaphthalene (25c, 182 mg, 1 mmol) by employing Sonagashira coupling conditions using Pd(PPh3)4 (69.3 mg, 0.06 equiv) as catalyst, CuI (22.8 mg, 0.12 equiv) as cocatalyst, butyl amine (261 mg, 3 equiv) as base and ether as solvent and kept the reaction for 6 h. After completion of the reaction as indicated by TLC and the reaction mixture is extracted into ether (4×25 mL) from the aqueous layer and concentrated in vacuo. The compound was further purified by column chromatography using 60-120 silica gel (ethyl acetate/hexane, 1:9) to obtain 4-((6-methoxynaphthalen-2-yl) ethynyl)-2-methyl benzenamine (26c) as pure product. Anthranilic acid (27, 137 mg, 1 mmol) on reaction with acetic anhydride at 150° C. and reflux for 30 min, after completion of reaction aqueous sodium bicarbonate solution is added and extracted in ethyl acetate (4×25 mL) from the aqueous layer and concentrated in vacuo afforded 2-methyl-4H-benzo[d][1,3]oxazin-4-one compound (28) as pure product. To a stirred solution of 4-((6-methoxynaphthalen-2-yl)ethynyl)-2-methylbenzenamine (26c) with 2-methyl-4H-benzo[d][1,3]oxazin-4-one (28, 161 mg, 1 mmol) in acetic acid and reflux for 8 h After completion of the reaction as indicated by TLC. then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4 afforded 3-(4-((6-methoxynaphthalen-2-yl)ethynyl)-2-methylphenyl)-2-methylquinazolin-4(3H)-one (29c). Reaction of 3-(4-((6-methoxynaphthalen-2-yl)ethynyl)-2-methylphenyl)-2-methylquinazolin-4(3H)-one (29c, 430 mg, 1 mmol) with 3,4,5-trimethoxybenzaldehyde (30l, 196 mg, 1 mmol) was taken in acetic acid Then the resulting mixture was stirred under reflux conditions for 8 h and then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4. The resulting product (61) was purified by column chromatography employing EtOAc/Hexane as an eluent.