Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:25]1[O:29][C:28](=[O:30])[C@H:27]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:26]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:38].[Li+]>C(COC)OC.O>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:13][CH:12]=1)[C@@H:25]([OH:29])[CH2:26][C@@H:27]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:28]([OH:38])=[O:30])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)C(=O)O1
Reactant: [OH-]
Agent: [Li+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H](O)C[C@@H](Cc1ccccc1)C(=O)O

Procedure:
Analogously to Example 1i), 0.502 g (1.00 mmol) of 5(S)-[1(S)-(Boc-amino)-2-(p-benzyloxyphenyl)-ethyl]-3(R)-(phenylmethyl)-dihydrofuran-2-(3H)-one in 16 ml of dimethoxyethane and 8.6 ml of water are hydrolysed with 4 ml of 1M lithium hydroxide solution. The reaction mixture, partially concentrated by evaporation, is poured onto a mixture of ice, 49 ml of sat. NH4Cl solution, 4.1 ml of 10% citric acid solution and methylene chloride, and ethanol is added until the precipitated solid has dissolved. The aqueous phase is extracted with 2 portions of methylene chloride/ethanol approximately 9:1, and the organic phases are washed with brine, dried with Na2SO4 and concentrated by evaporation: TLC Rf (A)=0.22.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[CH:4]=1.[Br:13]Br.O>ClCCl>[Br:13][C:4]1[C:5]([O:11][CH3:12])=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: BrBr
Reactant: COc1cc(OC)cc(OC)c1
Solvent: O
Solvent: ClCCl
Product: COc1cc(OC)c(Br)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
KM03 Dissolve 1,3,5-trimethoxybenzene (10.0 g, 59.46 mmol) in anhydrous dichloromethane (100 mL), cool the reaction mixture to −78° C., add dropwise bromine (3.0 mL, 59.44 mmol) stir the mixture for 1 h between −70° C. and −40° C. Warm up the solution to 0° C. and add water. Separate layers and extract the aqu. layer with EtAOc (3 times). Wash combined organic layer with water and brine and dry it with Na2SO4. Remove solvent and purify the crude product by recrystallization from hot EtOAc and cyclohexane to obtain 2-Bromo-1,3,5-trimethoxy-benzene (48) as a white solid (8.84 g, 60%). 1H NMR (400 MHz, CDCl3): 3.80 (s, 3H); 3.86 (s, 6H); 6.15 (s, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2F)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][NH:28][NH2:29].C([O-])(O)=O.[Na+]>C(O)CCC>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:16]3[C:17](=[CH:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=3)[N:28]([CH3:27])[N:29]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNN
Reactant: O=C(c1ccc(C(F)(F)F)cc1F)C1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: Cn1nc(C2CCN(Cc3ccccc3)CC2)c2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Yield: 82.4 %

Procedure:
A solution of (1-benzyl-piperidin-4-yl)-(2-fluoro-4-trifluoromethyl-phenyl)-methanone (2.0 g, 5.46 mmol), methylhydrazine (327 mg, 7.10 mmol), and n-butanol (22 mL) was heated at 120° C. in a seal vessel for 18 hours. The reaction was cooled to room temperature and basified with NaHCO3 and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, filtered, and evaporated. The product was chromatographed on silica, eluting with 1:1 ethyl acetate/heptane, to afford 1.68 g (82%) of the desired product as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][NH:9][CH2:10][CH2:11][OH:12].O>O1CCCC1>[CH3:8][N:9]([CH2:10][CH2:11][OH:12])[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CNCCO
Reactant: Clc1ncccn1
Solvent: C1CCOC1
Solvent: O
Product: CN(CCO)c1ncccn1

Procedure:
A mixture of 2-chloropyrimidine (10 g) and 2-methylaminoethanol in dry tetrahydrofuran (100 ml) was boiled under reflux for 3 hours. The solution was cooled, water (200 ml) was added, the mixture extracted with dichloromethane, the organic extracts were dried (MgSO4), filtered and evaporated to dryness. The residual oil was used in Preparation 5 without further purification.
Reaction SMILES: S(O[CH2:6][CH:7]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8]OS(=O)(=O)C)(=O)(=O)C.[S-2:22].[Na+].[Na+]>C(O)C>[C:18]([O:17][C:15]([NH:14][CH:7]1[CH2:8][S:22][CH2:6]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: [S-2]
Reactant: CC(C)(C)OC(=O)NC(COS(C)(=O)=O)COS(C)(=O)=O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CSC1
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
A solution of N-(tert-butyloxycarbonyl)-2-amino-1,3-propanediol dimesylate [prepared according to E. Benoist et al., Synthesis 1998, (8), 1113-1118] (25 g, 72.0 mmol) in ethanol (375 ml) is treated with sodium sulfide (Na2S.xH2O 32-38%, 16.82 g, ˜75.4 mmol) and the mixture is stirred at a temperature of 50° C. (bath 60° C.) for 45 minutes. The cooled reaction mixture is concentrated under reduced pressure and the solid residue poured into water, extracted with Et2O, the combined organic layers washed with brine, dried (Na2SO4), filtered, and concentrated. The crude solid product (12.6 g, 92%) is used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]=1.[O:12]1CCOCC1>>[N:3]1[C:4]2[C:9](=[N:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[CH:1]=[O:12]
Reactant: C1COCCO1
Reactant: Cc1ccc2ncccc2n1
Product: O=Cc1ccc2ncccc2n1
Temperature: 25 °C

Procedure:
To a solution of 2-methyl-1,5-naphthyridine (216.0 mg, 1.5 mmol) in 1,4-dioxane (5 mL) was added SeO2 (183.0 mg, 1.65 mmol) and the reaction mixture was refluxed for 0.5 hr, when the TLC showed no starting material left, then cooled to room temperature and filtered through celite. The solvent was removed under reduced pressure and the residue was purified by Biotage column (AcOEt: nHex=3:1) to give [1,5]naphthyridine-2-carbaldehyde as a white solid (142.3 mg, 60.0). LR-ES m/e 159 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:25](=[O:36])[NH:26][CH2:27][C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=3)=[C:11]([CH:22]([CH3:24])[CH3:23])[N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].O>CCO>[F:35][C:30]1[CH:29]=[C:28]([CH:33]=[C:32]([F:34])[CH:31]=1)[CH2:27][NH:26][C:25]([C:10]1[C:9]2[C:13](=[CH:14][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=2)[N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:11]=1[CH:22]([CH3:24])[CH3:23])=[O:36]
Reactant: CCOC(=O)c1ccc2c(C(=O)NCc3cc(F)cc(F)c3)c(C(C)C)n(Cc3ccccn3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)c1c(C(=O)NCc2cc(F)cc(F)c2)c2ccc(C(=O)O)cc2n1Cc1ccccn1
Temperature: 55 °C
Reaction time: 4 h

Procedure:
Following General Procedure F, ethyl3-(3,5-difluorobenzylcarbamoyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-6-carboxylate (Compound 48, 92 mg, 0.187 mmol) in EtOH (10 ml) was added NaOH (40 mg, 0.94 mmol) and H2O (1 ml). The reaction was stirred at 55° C. for 4 h, concentrated in vacuo to an oil then acidified to PH=5 with 10% HCl, diluted with EtOAc, washed organic with H2O, brine, dried over Na2SO4 and concentrated in vacuo to yield the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(B(O)O)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.[F-].[K+]>C1COCC1>[C:2]1([C:16]2[C:17]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: OB(O)c1cccc2ccccc12
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: c1ccc(-c2cccc3ccccc23)cc1
Yield: 99.8 %

Procedure:
Bromobenzene (82 mg, 0.52 mmol) reacted with 1-naphtylboronic acid (110 mg, 0.64 mmol) using 1 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (90 mg, 1.55 mmol) in THF (2 ml) at room temperature to give the title compound (106 mg, 99%) as a colorless oil: 1H-NMR (400 MHz, CDCl3): δ 7.99-7.91 (m, 3H), 7.60-7.47 (m, 9H). 13C{1H}-NMR (100 MHz, CDCl3): δ 140.71, 140.21, 133.75, 131.57, 130.05, 128.23, 127.60, 127.21, 126.90, 125.99, 125.74, 125.36. GC/MS(EI): m/z 204 (M+). Anal. Calcd for C16H12: C, 94.08; H, 5.92. Found: C, 93.96; H, 6.11.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[N:7]1([CH:12]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[CH2:13][CH2:14][CH2:15]Cl)[CH:11]=[CH:10][N:9]=[CH:8]1>O1CCCC1>[C:21]([C:20]1[CH:23]=[CH:24][C:17]([C:12]2([N:7]3[CH:11]=[CH:10][N:9]=[CH:8]3)[CH2:1][CH2:15][CH2:14][CH2:13]2)=[CH:18][CH:19]=1)#[N:22]
Reactant: N#Cc1ccc(C(CCCCl)n2ccnc2)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc(C2(n3ccnc3)CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of potassium tert-butoxide (1.10 g) in tetrahydrofuran (50 mL) is added dropwise to a solution of 4-[1-(1-imidazolyl)-4-chlorobutyl]benzonitrile (2.50 g) in tetrahydrofuran at 0° (ice-bath). The reaction is allowed to proceed at 0° for 30 minutes and is then allowed to warm to room temperature during 3 hours. The reaction is then quenched with water (100 mL) and the mixture is subsequently extracted with ethyl acetate (100 mL). The organic extract is extracted with 3N hydrochloric acid (3×30 mL) and the combined acid extracts are made basic with 6N sodium hydroxide. The crude product is extracted into ethyl acetate (3×30 mL) and the combined extracts are dried (MgSO4) and evaporated to afford 1-(4-cyanophenyl)-1-(1-imidazolyl)cyclopentane as an oil. The compound is dissolved in acetone and treated with ethereal HCl to afford the hydrochloride salt, m.p. 217°-219°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:42]=[CH:41][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([N:26]3[CH2:30][CH:29]4[CH2:31][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH:28]4[CH2:27]3)=[N:9]2)=[CH:5][CH:4]=1.[F:43][C:44]1[CH:49]=[CH:48][C:47]([N:50]2[C:55](=[O:56])[C:54]([C:57](O)=[O:58])=[CH:53][CH:52]=[N:51]2)=[CH:46][CH:45]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[F:25][C:19]1[CH:20]=[C:21]([NH:24][C:57]([C:54]2[C:55](=[O:56])[N:50]([C:47]3[CH:48]=[CH:49][C:44]([F:43])=[CH:45][CH:46]=3)[N:51]=[CH:52][CH:53]=2)=[O:58])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:42][CH:41]=3)[N:9]=[C:10]([N:26]3[CH2:30][CH:29]4[CH2:31][N:32]([C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[CH2:33][CH:28]4[CH2:27]3)[C:11]=12
Reactant: COc1ccc(Cn2nc(N3CC4CN(C(=O)OC(C)(C)C)CC4C3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2nc(N3CC4CN(C(=O)OC(C)(C)C)CC4C3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
A round-bottomed flask was charged with tert-butyl 5-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (44.8 mg, 0.0780 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (54.8 mg, 0.234 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (74.7 mg, 0.390 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (52.7 mg, 0.390 mmol), N-ethyl-N-isopropylpropan-2-amine (101 mg, 0.780 mmol) and DMF (10 mL). The reaction mixture was stirred at ambient temperature overnight. The reaction was partitioned between EtOAc and H2O. The phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude material was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to afford product (42.5 mg, 68.9%). LRMS (APCI pos): m/e 691 (M−99).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[CH:10][N:9]2[CH:12]=[CH:13][N:14]=[C:8]2[CH:7]=1)=[O:5].[C:16]([Mg]Br)#[C:17][CH3:18]>C1COCC1>[N:14]1[CH:13]=[CH:12][N:9]2[CH:10]=[CH:11][C:6]([C:4](=[O:5])[C:16]#[C:17][CH3:18])=[CH:7][C:8]=12
Reactant: CON(C)C(=O)c1ccn2ccnc2c1
Reactant: CC#C[Mg]Br
Solvent: C1CCOC1
Product: CC#CC(=O)c1ccn2ccnc2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of Imidazo[1,2-a]pyridine-7-carboxylic acid methoxy-methyl-amide (187 mg, 0.91 mmol) in THF (10 ml) at −78° C. was added 1-propynylmagnesium bromide (0.5M in THF, 2.74 ml). The reaction was allowed to warm to room temperature and stirred for 1.5 h before being quenched with 2M HCl (2 ml) and washed with CH2Cl2. The aqueous fraction was basified using Na2CO3 and extracted with CH2Cl2. The organic fraction was dried (MgSO4), filtered and the solvent removed in vacuo to afford the product (168 mg). MS: [M+H]+=185.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cu][C:16]#[N:17].C(Cl)Cl>CN(C)C=O>[C:16]([C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)#[N:17]
Reactant: O=[N+]([O-])c1ccc(Br)c2ncccc12
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1ccc([N+](=O)[O-])c2cccnc12

Procedure:
5.80 g of 8-bromo-5-nitroquinoline and 2.00 g of copper(I) cyanide in 15 ml of dimethylformamide were heated to 150° C. for 5 hours. After cooling, methylene chloride was added, insoluble particles were filtered off and the filtrate was concentrated.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:18])[C:4]([O:16]C)(OC)[C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([Mg]Br)=[CH:23][CH:22]=1>>[OH:18][C:3]1([C:24]2[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[C:4](=[O:16])[C:5]([C:6]2[CH:7]=[CH:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=2)=[C:2]1[CH3:1]
Reactant: COc1ccc([Mg]Br)cc1
Reactant: COc1ccc(C2=C(C)C(=O)C2(OC)OC)cc1
Product: COc1ccc(C2=C(C)C(O)(c3ccc(OC)cc3)C2=O)cc1

Procedure:
Synthesized according to the procedure utilized for Example 46 (Step 2) using 2-methyl-4,4-bis(methyloxy)-3-[4-(methyloxy)phenyl]-2-cyclobuten-1-one (260) and 4-methoxyphenylmagnesium bromide. 1H NMR (CDCl3, 300 MHz) δ 7.39-7.29 (m, 4H), 7.10-6.88 (m, 4H), 3.88 (s, 3H), 3.85 (s, 3H), 2.47 (s, 3H). TLC (60:40; hexanes/EtOAc): Rf=0.23.
Reaction SMILES: [C:1]([C:9]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)=[CH:29][C:10]=1[O:11][CH:12]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])[CH2:13][CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O1CCCC1>[C:1]([C:9]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)=[CH:29][C:10]=1[O:11][CH:12]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C(CCC(=O)OC(C)(C)C)Oc1cc(OCc2cccnc2)ccc1C(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccccc1C(CCC(=O)O)Oc1cc(OCc2cccnc2)ccc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of tert-butyl 4-[2-benzoyl-5-(pyridin-3-ylmethoxy)phenoxy]-4-(2-methylphenyl)butanoate, thought to be the (R)-enantiomer, (1 g) in a mixture of methanol (10 mL) and tetrahydrofuran (10 mL) is treated with 5 M aqueous sodium hydroxide solution (7.5 mL) and the reaction stirred at ambient temperature for 24 hours. The reaction is concentrated to low volume, acidified to pH 5 with dilute hydrochloric acid, and extracted into dichloromethane (2×30 mL). The combined organic layers are washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure to leave a yellow gum. Trituration with diethyl ether and recrystallization of the resultant solid from acetonitrile containing a little decolourizing charcoal gives 4-[2-benzoyl-5-(pyridin-3-ylmethoxy)phenoxy]-4-(2-methylphenyl)butanoic acid, thought to be the (R)-enantiomer, (0.2 g) as a pale yellow solid, m.p. 185-186° C. [Elemental analysis:- C, 74.83; H, 5.65; N, 2.91%; Calculated:- C, 75.01; H, 5.72; N,2.87%].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].Cl[CH2:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([S:20]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)(=[O:22])=[O:21])[CH2:16][CH2:15]1)=[O:13].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:11][C:12]([N:14]1[CH2:15][CH2:16][N:17]([S:20]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)(=[O:21])=[O:22])[CH2:18][CH2:19]1)=[O:13]
Reactant: O=C(CCl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(COc1ccc(F)cc1F)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Yield: 73.8 %

Procedure:
2,4-difluoro phenol (110 mg, 0.85 mmol), 2-chloro-1-(4-(naphthalen-2-ylsulfonyl)piperazin-1-yl)ethanone (compound 5, 0.3 g, 0.85 mmol) and anhydrous potassium carbonate (0.352 g, 2.55 mmol) were stirred for over night in dry acetonitrile (20 mL). The mixture was poured into a large volume of water and the solution extracted with ether. Un-reacted phenol was removed with cold 1N NaOH solution. The ether extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by re-crystallization to yield the title compound (280 mg, 73.87% yield) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[N:18]=3)=[CH:15][C:14]([CH:43]([N:45]3[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:47][CH2:46]3)[CH3:44])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:15][C:14]([CH:43]([N:45]3[CH2:46][CH2:47][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:49][CH2:50]3)[CH3:44])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)N4CCN(S(C)(=O)=O)CC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncc(C(C)N3CCN(S(C)(=O)=O)CC3)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 76 °C
Reaction time: 16 h
Yield: 62.4 %

Procedure:
4-(2-(5-Fluoro-6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (456.7 mg, 0.6026 mmol) was dissolved in trifluoroacetic acid (9.5 mL) and the reaction flask was fitted with a reflux condenser and put in a preheated oil bath (75-77° C.) and stirred for 16 h. The reaction was cooled to room temperature and concentrated. The reaction was diluted with DCM (40 mL) and treated with saturated sodium bicarbonate and 5N NaOH to raise the pH of the aqueous phase to about 8. Then, the layers were separated and the aqueous phase was extracted with DCM and 10:1 DCM/MeOH. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, treated with MeOH, and filtered. The solid was washed with MeOH. The solid was not >95% pure by HPLC, so the filtrate and solid were combined, concentrated, and purified on a silica gel column according to the procedure described by Still et al. (Journal of Organic Chemistry, 1978, 43, 2923-2925) using this eluent system: 30:1 DCM/2N ammonia in MeOH to 20:1 DCM/2N ammonia in MeOH to 15:1 DCM/2N ammonia in MeOH to 5:1 DCM/2N ammonia in MeOH. The fractions with product were collected, concentrated, treated with MeOH, and filtered. The solid was washed with MeOH, collected, and dried under high vacuum to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (194.7 mg, 62% yield) as a yellow powder. 1H NMR (CDCl3, 400 MHz) δ 11.93 (s, 1H), 8.71 (d, J=2.54 Hz, 1H), 8.31 (t, J=2.25 Hz, 1H), 8.27 (d, J=2.35 Hz, 1H), 8.05 (d, J=2.15 Hz, 1H), 5.42 (br s, 2H), 4.04 (s, 3H), 3.56 (quartet, J=6.65 Hz, 1H), 3.24 (t, J=4.69 Hz, 4H), 2.78 (s, 3H), 2.68-2.54 (m, 7H), 1.44 (t, J=6.85 Hz, 3H). m/z (ESI, pos. ion) 518 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[N:18]=[N:17]2)=[N:13][C:12]=1[CH3:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Li+].Cl>O>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[N:18]=[N:17]2)=[N:13][C:12]=1[CH3:26])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(-c2nc(C)c(C(=O)NCc3ccccc3)s2)nn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-n2cc(C(=O)O)nn2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53 %

Procedure:
To a solution of ethyl 1-(5-(benzylcarbamoyl)-4-methylthiazol-2-yl)-1H-1,2,3-triazole-4-carboxylate (0.20 g, 0.54 mmol) in a 1:1 mixture of tetrahydrofuran:water (20 mL) was added lithium hydroxide (0.11 g, 2.69 mmol). The reaction mixture was stirred at ambient temperature for 18 hours, acidified with 10% HCl solution and extracted with dichloromethane (2×50 mL). The organic layer was separated, dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to afford the title compound as a white solid in 53% yield (0.27 g): 1H NMR (300 MHz, DMSO-d6) δ 9.15 (s, 1H), 9.03 (t, J=6.0 Hz, 1H), 7.35-7.22 (m, 5H), 4.46 (d, J=6.0 Hz, 2H), 2.63 (s, 3H); MS (ES+) m/z 344.3 (M+1).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[C:7]([NH:14][CH2:15][CH3:16])[CH:6]=1)[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:29]([N:36]1[C:40](=[O:41])[C:39](=[C:42]2[N:46]([CH3:47])[C:45]3[CH:48]=[CH:49][CH:50]=[CH:51][C:44]=3[S:43]2)[S:38][CH2+:37]1SC)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([N:36]1[C:40](=[O:41])[C:39](=[C:42]2[N:46]([CH3:47])[C:45]3[CH:48]=[CH:49][CH:50]=[CH:51][C:44]=3[S:43]2)[S:38][C:37]1=[N:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([NH:3][CH2:1][CH3:2])=[O:17])=[CH:6][C:7]=1[NH:14][CH2:15][CH3:16])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Reactant: CCNC(=O)c1ccc([N+](=O)[O-])c(NCC)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNC(=O)c1ccc(N=C2SC(=C3Sc4ccccc4N3C)C(=O)N2Cc2ccccc2)c(NCC)c1

Procedure:
In a manner similar to Example 30, intermediate N-ethyl-3-ethylamino-4-nitrobenzamide was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. 1H-NMR (CDCl3): δ 7.46-7.54 (3H, m), 7.27-7.38 (4H, m), 7.19 (1H, m), 6.96-7.08 (4H, m), 6.04 (1H, br t), 5.19 (2H, s), 3.76 (3H, s), 3.49 (2H, m), 3.06 (2H, q), 1.25 (3H, t), 1.05 (3H, t); MS(ESI): 544 (MH+).