Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[N:8]2[C:17]3[CH:18]=[CH:19][C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:21][C:16]=3[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9]2=[O:27])=CC=1.C1(OC)C=CC=CC=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>CO.ClCCl.[Pd]>[O:27]=[C:9]1[NH:8][C:17]2[CH:18]=[CH:19][C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:21][C:16]=2[C:15]2[NH:14][CH2:13][CH2:12][CH2:11][C:10]1=2
Reactant: CCOC(=O)c1ccc2c(c1)c1ncccc1c(=O)n2Cc1ccc(OC)cc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CCOC(=O)c1ccc2[nH]c(=O)c3c(c2c1)NCCC3
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.9 %

Procedure:
The compound (27 mg, 0.069 mmol) prepared in step 3 was dissolved in methanol (5 ml) and dichloromethane (5 ml), and added with 10%-palladium. The mixture was stirred for 18 hours at room temperature under hydrogen gas. Once the reaction was completed, 10%-palladium (Pd) was removed by celite filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in trifluoroacetic acid (TFA, 2 ml), and the resultant mixture was added with anisol (0.64 ml, 0.58 mmol) and 12 N sulfuric acid aqueous solution (0.097 ml, 1.17 mmol). The reaction mixture was stirred for 18 hours at 100° C. The mixture was stirred for one hour at 140° C. The mixture was poured into a cold sodium bicarbonate aqueous solution and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (dichloromethane:methanol=7:1) to obtain the title compound (7.5 mg, yield: 47%, yellow solid).
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH2:7][C:6]1=[O:15].[CH:17](=[C:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]>CC#N>[CH:17](=[C:21]1[CH2:26][CH2:25][N:24]([CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:8][CH2:7][C:6]2=[O:15])[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCC=C1CCNCC1
Reactant: C[C@H](CI)CN1C(=O)CSc2ccccc21
Solvent: CC#N
Product: CCCC=C1CCN(C[C@@H](C)CN2C(=O)CSc3ccccc32)CC1
Temperature: 60 °C
Reaction time: 96 h
Yield: 59.6 %

Procedure:
The compound (S)-4-(3-Iodo-2-methyl-propyl]-4H-benzo[1,4]thiazin-3-one (108LM37-34) (0.432 g, 1.25 mmol) and 4-butylidenepiperidine (111MF05) (0.208 g, 1,49 mmol) in MeCN (½ mL) were reacted according to GP10 shaking at 60° C. for 4 days. Purified by cation exchange CC and flash CC (SiO2; MeOH/DCM 1:20) to give the title compound (108LM50-47) (0.267 g, 60%). 1H NMR (CDCl3) δ 7.35 (d, J=7.5 Hz, 1H), 7.26-7.18 (m, 2H), 6.98 (t, J=7.5 Hz, 1H), 5.10 (t, J=7.4 Hz, CH), 4.17-4.03 (m, 2H), 3.36 (s, CH2), 2.43-2.33 (m, 2H), 2.30-2.08 (m, 8H), 2.00-1.90 (m, 3H), 1.28-1.38 (m, 2H), 0.90-0.80 (m, 6H); 13C NMR (CDCl3) δ 166.0, 139.2, 136.4, 128.8, 127.1, 124.8, 123.5, 122.7, 118.8, 63.4, 56.4, 55.6, 47.7, 36.4, 32.1, 29.5, 29.4, 28.6, 23.4, 16.7, 14.0; HPLC-MS (ammonium acetate) [M+H]+=359.3.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([CH:14]=O)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:17][OH:18].N1C=CC=CC=1>CCO>[NH:1]([C:8]1[N:13]=[C:12]([CH:14]=[N:17][OH:18])[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccnc(Nc2ccccc2)n1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=Cc1ccnc(Nc2ccccc2)n1
Yield: 92.1 %

Procedure:
A suspension of 2-anilinopyrimidin-4-carbaldehyde (Method 3; 10 g, 50 mmol) and hydroxylamine hydrochloride (17.4 g, 250 mmol) in EtOH (360 ml) and pyridine (17.4 g, 215 mmol) was stirred and heated at reflux for 1 hour. The reaction mixture was allowed to cool and concentrated to about 150 ml total volume by evaporation. Distilled water (600 ml) was added and the precipitated solid collected by filtration, washed thoroughly with distilled water and dried to give the title compound (9.86 g, 92%) as a white solid. NMR: 6.92 (t, 1H), 7.08 (d, 1H), 7.23 (t, 2H), 7.75 (d, 2H), 7.93 (s, 1H), 8.45 (d, 1H), 9.67 (s, 1H), 12.1 (s, 1H); m/z 215.
Reaction SMILES: C1(O)C=CC=CC=1.[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[NH2:19])[CH:12]=[CH:11][CH:10]=1.[CH:20]1[CH:25]=[C:24]2[C:26](O[C:29]([C:31]3=[CH:32][CH:33]=[CH:34][C:22](=[C:23]23)[CH:21]=1)=O)=[O:27]>CO>[CH:16]1[C:17]2=[C:18]3[C:13]([CH:12]=[CH:11][CH:10]=[C:9]3[N:8]=[C:29]3[C:31]4[CH:32]=[CH:33][CH:34]=[C:22]5[CH:21]=[CH:20][CH:25]=[C:24]([C:23]=45)[C:26](=[O:27])[N:19]32)=[CH:14][CH:15]=1
Reactant: Nc1cccc2cccc(N)c12
Reactant: O=C1OC(=O)c2cccc3cccc1c23
Solvent: Oc1ccccc1
Solvent: CO
Product: O=c1c2cccc3cccc(c32)c2nc3cccc4cccc(c43)n12
Temperature: 150 °C
Reaction time: 2 h

Procedure:
250 g of phenol are melted at about 60° C. 47.4 g of 1,8-diaminonaphthalene and 59.4 g of 1,8-naphthalic acid anhydride are introduced, while passing over nitrogen, and the mixture is heated to 150° C. in the course of 1 hour and kept at this temperature for 2 hours. The reaction mixture is cooled to 80° C., 120 ml of methanol are added at a temperature of 80° to 65° C. in the course of 30 minutes, and the mixture is cooled to room temperature and filtered with suction. After the residue has been washed with 240 ml of methanol and dried at 150° C., 88.8 g of the stated dyestuff are obtained in a very good quality.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C:6](=[O:27])[C:7](=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]=[N+:14]=[N-:15])#[N:2].[NH2:28][C:29]([CH3:34])=[CH:30][C:31](=[O:33])[CH3:32]>CCO>[C:31]([C:30]1[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[C:7]([C:6]([O:5][CH2:4][CH2:3][C:1]#[N:2])=[O:27])=[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]=[N+:14]=[N-:15])[NH:28][C:29]=1[CH3:34])(=[O:33])[CH3:32]
Reactant: N#CCCOC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)C(=O)CCCCN=[N+]=[N-]
Reactant: CC(=O)C=C(C)N
Solvent: CCO
Product: CC(=O)C1=C(C)NC(CCCCN=[N+]=[N-])=C(C(=O)OCCC#N)C1c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 7-azido-2-[(4-nitrophenyl)methylene]-3-oxoheptanoic acid 2-cyanoethyl ester (1.12 g, 3.00 mmol) and 4-amino-3-penten-2-one (330 mg, 3.30 mmol) in 20 ml of EtOH was refluxed for 48 hrs. After the EtOH was removed in vacuo, the residue was dissolved in 150 ml of CHCl3, washed with water (2×100 ml) and dried over Na2SO4. After filtration and evaporation of solvent, the product was purified by chromatography (SiO2, CHCl3:MeOH=5:95). 5-Acetyl-2-(4-azidobutyl)-3-(2-cyanoethoxy) carbonyl-1,4-dihydro-6-methyl-4-(4-nitrophenyl) pyridine was obtain as a yellow oil (1.05 g, 77% yield).
Reaction SMILES: C[C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].CI.[C:16](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:13][O:12][C:3]1[CH:2]=[C:10]([CH3:11])[CH:9]=[CH:8][C:4]=1[C:5]([O:7][CH3:16])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: COc1c(C(=O)O)ccc(C)c1C
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)cc1OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Methyl 2-methoxy-4-methylbenzoic acid (1.5 g, 9.0 mmol, 1 eq) was dissolved in DMF, methyl iodide (0.86 ml, 13.5 mmol, 1.5 eq) was added to it followed by the addition of potassium carbonate (3.11 g, 22.5 mmol, 2.5 eq). The above mixture was stirred at room temperature for 12 h. Finally, the reaction mixture was passed through celite. The filtrate was evaporated and water was added and the product was extracted with ethyl acetate. The organic layer was washed with water and concentrated. Yield: 1.6 g (98%). 1HNMR (400 MHz, CDCl3): δ 2.31 (s, 3H), 3.86 (s, 3H), 3.89 (s, 3H), 6.77 (s, 1H), 6.79 (d, 1H), 7.14 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[H-].[Na+].[CH3:26]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:26])[C:7](=[O:12])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2[nH]c1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 162.7 %

Procedure:
To a mixture of ethyl 6-chloro-1,2-dihydro-2-oxo-4-phenyl-3-quinolinecarboxylate (2.62 g) and DMF (24 ml) was added portionwise 60% sodium hydride in oil (0.35 g), followed by stirring for 30 minutes at room temperature. The mixture was ice-cooled, to which methyl iodide (0.6 g) was dropwise added under stirring. The mixture was stirred for 3 hours at room temperature, diluted with and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and concentrated to remove the solvent. The residue was crystallized from isopropyl ether to give crystals of ethyl 6-chloro-1,2-dihydro -1-methyl-2-oxo-4-phenyl-3-quinolinecarboxylate (2.35 g, 92.7%). Recrystallization from ethanol gave colorless needles. mp 124°-125° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7]O.P(Br)(Br)[Br:13]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][Br:13]
Reactant: COc1cccc(CCO)c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: COc1cccc(CCBr)c1
Temperature: 25 °C
Yield: 130.5 %

Procedure:
To a cold solution of 3-methoxyphenethyl alcohol (7.55 g, 50 mmol) in 20 ml of dry (sieves) methylene chloride, a solution of phosphorus tribromide (7 g, 26 mmol) in 20 ml of methylene chloride was slowly added under nitrogen. The reaction mixture was permitted to warm to ambient temperature overnight. The reaction was then quenched in ice/water slowly and the resulting solution neutralized with 5N NaOH and then extracted with methylene chloride. The combined extracts were washed with water and brine, dried with anhydrous magnesium sulfate and concentrated to give 7.3 g of 3-methoxyphenethyl bromide. A solution of this bromide (7.3 g) in 10 ml of dry tetrahydrofuran (THF) was slowly added to a flask containing magnesium chips (1.03 g) and a small crystal of iodine in 30 ml of THF. The reaction mixture was then heated to reflux for 1 hour. To this mixture which was cooled with ice, a solution of dry acetone (2.2 g) in 10 ml of dry THF was added and the reaction mixture stirred at ambient temperature overnight. The mixture was quenched (0° C.) with a cold solution of NH4Cl followed by 1N HCl. The mixture was extracted with ethyl acetate and dried with anhydrous magnesium sulfate. Concentration and chromatography on silica gel (10-30% ethyl acetate in hexanes) afforded 2.31 g of carbinol. This carbinol (2.3 g) in 4 ml of glacial acetic acid was slowly added to a solution of KCN (2.36 g) and H2SO4 (3.63 g) in 15 ml of acetic acid. The reaction mixture was then stirred at 90° C. (bath temperature) overnight under nitrogen. Additional KCN (3.28 g), H2SO4 (8 ml in 24 ml of acetic acid) and acetic acid (18 ml) were added and the reaction mixture heated overnight. The reaction was quenched by pouring the reaction mixture into ice/water and adjusting the pH of the solution to neutrality with 5N NaOH. The solution was repeatedly extracted with ethyl acetate and the combined extracts backwashed with water and brine and then dried with anhydrous sodium sulfate. Concentration afforded 1.64 g of formamide which was hydrolyzed to the amine in 6N HCl (40 ml) at reflux for 3 hours. The reaction mixture was partially concentrated, diluted with water and the pH of the solution adjusted with 5N NaOH to 12. The solution was extracted with ethyl acetate and the combined extracts backwashed with brine and dried with anhydrous sodium sulfate. Concentration gave 1.2 g of the titled amine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[C:14]([I:17])=[CH:15][NH:16][C:11]2=[CH:10][CH:9]=1.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19].[OH-].[Na+]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[C:14]([I:17])=[CH:15][N:16]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:11]2=[CH:10][CH:9]=1
Reactant: Fc1ccccc1-c1ccc2[nH]cc(I)c2n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(-c4ccccc4F)ccc32)cc1
Temperature: 23 °C
Reaction time: 0.75 h
Yield: 72 %

Procedure:
A solution of 5-(2-fluorophenyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine (227 mg, 0.671 mmol) in THF (7 mL) was treated with TsCl (141 mg, 0.738 mmol, Fluka) and solid NaOH (32.2 mg, 0.806 mmol, VWR). The reaction was stirred at 23° C. under N2. After 45 min, the solution was diluted with EtOAc (100 ml) and washed with brine (75 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluent: 10-25% EtOAc/hexane), affording 5-(2-fluorophenyl)-3-iodo-1-tosyl-1H-pyrrolo[3,2-b]pyridine (238 mg, 72%). MS (ESI, pos. ion) m/z: 493.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([N:20]=O)[CH2:16][CH2:15]3)=[O:13])[C:6]=2[CH:22]=1.C(Cl)(Cl)Cl.CO.Cl>O.C(O)(=O)C.CCOCC.[Zn]>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:15][CH2:16][N:17]([NH2:20])[CH2:18][CH2:19]3)=[O:13])[C:6]=2[CH:22]=1
Reactant: O=NN1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Agent: Cl
Agent: [Zn]
Solvent: CCOCC
Solvent: O
Solvent: ClC(Cl)Cl
Product: NN1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
5-Chloro-3-[(4-nitroso-1-piperazinyl)carbonylmethyl]-2-benzothiazolinone (9.2 g) was dissolved in a mixture of water (120 ml) and acetic acid (400 ml). To the solution stirred at room temperature zinc dust (12.0 g) was added over 3 hours. The mixture was stirred for additional 2 hours at room temperature. The zinc dust unused in the reaction was filtered and washed once with acetic acid. The filtrate and the washing were combined and evaporated to dryness. Chloroform (200 ml) was added to the residue and insoluble material was then filtered. The chloroform solution was concentrated to give a syrup which was subjected to a silica gel column chromatography using a mixture of chloroform and methanol (10:1). The desired fractions were combined and evaporated to give a pale yellow oil which was converted into hydrochloride using hydrogen chloride in absolute ether. The crude crystals obtained were recrystallized from aqueous ethanol to give 5-chloro-3-[(4-amino-1-piperazinyl)carbonylmethyl]-2-benzothiazolinone hydrochloride (4.03 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[OH-].[K+].C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1F>CO.CS(C)=O.O>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][C:25]=1[O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cccc(O)c1
Reactant: Fc1cc(C(F)(F)F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: CO
Product: O=C(O)c1cccc(Oc2cc(C(F)(F)F)ccc2Cl)c1
Yield: 56.9 %

Procedure:
3-Hydroxybenzoic acid (3.45 g) was added to a solution of potassium hydroxide (2.8 g) in methanol. The solution was evaporated under reduced pressure to give a white solid. This was taken up in dry dimethylsulphoxide (25 ml). The resulting solution was stirred and heated at 170° with anhydrous potassium carbonate (1.25 g) and 4-chloro-3-fluorobenzotrifluoride (5 g) for 12 hours. The mixture was then cooled and poured into water, (500 ml). The mixture was extracted with ether and then acidified (HCl). The precipitate which formed was recrystallised from petroleum (b.p. 60°-80°) to give the required acid (4.5 g) with a melting point of 142°-143°.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]#[C:12][CH2:13]O.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.[C:36]([O:40][C:41](=[O:48])[NH:42][CH2:43][CH:44]1[CH2:47][NH:46][CH2:45]1)([CH3:39])([CH3:38])[CH3:37]>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]#[C:12][CH2:13][N:46]1[CH2:47][CH:44]([CH2:43][NH:42][C:41](=[O:48])[O:40][C:36]([CH3:38])([CH3:37])[CH3:39])[CH2:45]1
Reactant: O=[N+]([O-])c1ccc(Oc2ccncc2C#CCO)c(F)c1
Reactant: CC(C)(C)OC(=O)NCC1CNC1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC1CN(CC#Cc2cnccc2Oc2ccc([N+](=O)[O-])cc2F)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
A solution of 3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-yn-1-ol (43 mg, 0.15 mmol) and DIPEA (45 μL, 0.26 mmol) in anhydrous THF (1.5 mL) was cooled to 0° C. and treated with methanesulfonyl chloride (15 mg, 0.11 mmol) in portions. After stirring at 0° C. for 1 h, the mixture was concentrated under reduced pressure. The residue was treated with DMF (1.0 mL), DIPEA (45 μL, 0.26 mmol) and azetidin-3-ylmethyl-carbamic acid tert-butyl ester (Beta Pharma Inc., 145 mg, 0.78 mmol) and stirred at rt for 2 h. The reaction mixture was partitioned between EtOAc and saturated aq. NaHCO3 solution and the EtOAc phase separated, washed with brine dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography on SiO2 eluting with 1-5% MeOH/CH2Cl2 to afford the title compound (33 mg, 48%) as a colorless oil. 1H NMR (DMSO-d6) δ 8.74 (s, 1H), 8.51 (d, 1H, J=5.6 Hz), 8.41 (dd, 1H, J=10.7, 2.5 Hz), 8.15 (d, 1H, J=9.2 Hz), 7.53 (t, 1H, J=8.6 Hz), 7.09 (d, 1H, J=6.1 Hz), 6.86 (t, 1H, J=5.6 Hz), 3.39 (s, 2H), 3.24-3.14 (m, 2H), 3.07-2.98 (m, 2H), 2.94-2.87 (m, 2H), 2.37-2.26 (m, 1H), 1.33 (s, 9H); MS(ESI+): m/z 401.20 (100), [(M-C4H9)]+; m/z 457.20 (25), (M+H)+.
Reaction SMILES: [CH:1](=O)[CH3:2].[NH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[C:21]([CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[CH2:31][C:32]([NH2:34])=[O:33])[C:20]([C:35]([F:38])([F:37])[F:36])=[CH:19][N:18]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)Cl>[CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]3[N:22]=[C:21]([CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[CH2:31][C:32]([NH2:34])=[O:33])[C:20]([C:35]([F:38])([F:37])[F:36])=[CH:19][N:18]=3)=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)[CH3:2]
Reactant: CC=O
Reactant: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)cc2)ncc1C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.3 %

Procedure:
Acetaldehyde (84.5 μL, 1.51 mmol) was added to a suspension of 2-(2-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (11) (91.0 mg, 0.188 mmol) in anhydrous methanol (10 mL) under an atmosphere of nitrogen. Sodium triacetoxyborohydride (0.638 g, 3.01 mmol) was then added in one portion and the reaction was stirred at room temperature for 24 hours. The volatiles were removed in vacuo and the residue was diluted with EtOAc (35 mL) and sat. aq. NaHCO3 (40 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×35 mL), the combined organic layers were washed with water (30 mL), brine (30 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the residue dissolved in DCM (5 mL) and MeOH (2 mL). Cyclohexane (20 mL) was added and the solvent removed in vacuo to afford a tan solid which was purified by column chromatography on silica gel (0-100% EtOAc in petroleum benzine 40-60° C.; then 0-75% MeOH in EtOAc) to yield a white solid. The solid was suspended in DCM (5 mL) and cyclohexane (20 mL) and filtered to afford the title compound (31) (40.7 mg, 42%) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.13 (s, 1H), 8.65 (s, 1H), 7.66 (d, J=8.6 Hz, 2H), 7.43 (s, 1H), 7.26-7.12 (m, 6H), 6.92 (s, 1H), 3.50 (s, 2H), 3.14-3.06 (m, 2H), 3.05-2.92 (m, 4H), 2.43 (tt, J=11.7, 3.7 Hz, 1H), 2.33 (q, J=7.2 Hz, 2H), 1.93 (td, J=11.5, 2.1 Hz, 2H), 1.73 (dd, J=11.8, 2.0 Hz, 2H), 1.62 (ddd, J=24.8, 12.4, 3.6 Hz, 2H), 1.01 (t, J=7.2 Hz, 3H);
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1[O:21][N:20]=[C:19]([C:22](Cl)=[O:23])[CH:18]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(=S)=S>[CH3:12][C:11]([C:7]1[CH:8]=[C:9]([C:22]([C:19]2[CH:18]=[C:17]([CH3:16])[O:21][N:20]=2)=[O:23])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: Cc1cc(C(=O)Cl)no1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: Cc1cc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)no1
Reaction time: 1 h
Yield: 14 %

Procedure:
To a solution of 20.6 g (0.1 mole) of 2,6-di-tert-butylphenol and 15.6 g (0.107 mole) of 5-methylisoxazole-3-carboxylic acid chloride in 100 mL of CS2 is added 14.3 g (0.107 mole) of AlCl3 at +5° C. Vigorous stirring is maintained at that temperature for 1 hour and then at room temperature for 1 hour. The CS2 is decanted off and the residue treated with 350 mL of ice cold 1N HCl and extracted with Et2O. The extracts are washed with saturated NaHCO3 solution and brine, dried with Na2SO4 and evaporated to give a mixture of products. The desired product is separated by flash chromatography (0% to 50% CH2Cl2 /n-hexane) on silica gel to give 4.4 g of the crude ketone which is recrystallized from n-pentane to give 2.3 g (14%) of pale yellow crystals, [3,5-bis(1,1-dimethylethyl)-4 -hydroxyphenyl(5-methyl-3-isoxazolyl)methanone, mp 120° C.; 1H NMR (CDCl3) δ 1.48 (s, 18H, tert-butyl), 2.52 (s, 3H, CH3), 5.85 (s, 1H, OH), 6.48 (s, 1H, isoxazole aromatic), 8.23 (s, 2H, phenyl aromatics); IR (KBr) 1590, 1600, 1650, 3600 cm-1 ; MS (DEI) m/e 315 (M+), 300 (M-CH3).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[C:11]([NH2:32])=[N:12][CH:13]=[C:14]([C:16]3[N:17]=[N:18][N:19]([CH2:21][CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[N:20]=3)[CH:15]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]=[C:41]=[O:42])=[CH:36][C:35]=1[C:43]([F:46])([F:45])[F:44]>O1CCCC1.C(OCC)(=O)C>[NH2:32][C:11]1[C:10]([C:9]#[C:8][C:4]2[CH:3]=[C:2]([NH:1][C:41]([NH:40][C:37]3[CH:38]=[CH:39][C:34]([Cl:33])=[C:35]([C:43]([F:45])([F:44])[F:46])[CH:36]=3)=[O:42])[CH:7]=[CH:6][CH:5]=2)=[CH:15][C:14]([C:16]2[N:17]=[N:18][N:19]([CH2:21][CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:29])([CH3:31])[CH3:30])([CH3:26])[CH3:27])[N:20]=2)=[CH:13][N:12]=1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)(C)[Si](C)(C)OCCCn1nnc(-c2cnc(N)c(C#Cc3cccc(N)c3)c2)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCn1nnc(-c2cnc(N)c(C#Cc3cccc(NC(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)c3)c2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-((3-aminophenyl)ethynyl)-5-(2-(3-((tert-butyldimethylsilyl)oxy)propyl)-2H-tetrazol-5-yl)pyridin-2-amine (135 mg, 0.3 mmol, 1 eq) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate (67 mg, 1 eq) in anhydrous tetrahydrofuran (3 mL) was stirred at room temperature and under nitrogen atmosphere for 3 hours. The mixture was then diluted with ethyl acetate, washed sequentially with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, and brine, and dried with anhydrous sodium sulfate. The clear solution was decanted, concentrated under reduced pressure, and the resulting clear oil was dried in vacuo for 5 minutes. It was then treated with a small amount of EtoAc-Hex (1:9), followed by stirring at room temperature for 30 minutes. The white solid that appeared during the process was filtered giving 1-(3-((2-amino-5-(2-(3-((tert-butyldimethylsilyl)oxy)propyl)-2H-tetrazol-5-yl)pyridin-3-yl)ethynyl)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea in the amount of 201 mg.