Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]#[N:14])=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].FC(F)(F)C(O)=O.[CH3:22][C:23]([CH3:25])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:13]([C:3]1[C:2]([NH:1][CH:23]([CH3:25])[CH3:22])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:12])[CH:4]=1)#[N:14]
Reactant: COC(=O)c1cc(N)c(C#N)cc1C
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(NC(C)C)c(C#N)cc1C
Temperature: 25 °C
Yield: 76.2 %

Procedure:
Methyl 5-amino-4-cyano-2-methylbenzoate (synthesized in reagent preparation 41, step 4) (240 mg, 1.26 mmol) was dissolved in 1,2-dichloroethane (7 mL) and was treated with trifluoroacetic acid (0.6 mL, 7.57 mmol), acetone (0.28 mL, 3.79 mmol), and sodium triacetoxyborohydride (802 mg, 3.78 mmol) at 45° C. for 20 min. The reaction mixture was cooled to ambient temperature and quenched with saturated aqueous sodium bicarbonate and was partitioned with dichloromethane. The aqueous portion was extracted with dichloromethane. The combined organic portion was washed with brine, dried over sodium sulfate, then filtered and concentrated to afford a yellow oil which was purified by column chromatography (silica gel, 10% dichloromethane in hexanes) to afford methyl 4-cyano-5-(isopropylamino)-2-methylbenzoate (224 mg, 0.96 mmol, 76% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.25 (s, 1H), 7.16 (s, 1H), 4.28 (d, 1H), 3.91 (s, 3H), 3.77-3.74 (m, 1H), 2.40 (s, 3H), 1.27 (s, 3H), 1.26 (s, 3H); MS (EI) for C14H16N2O2: 233 (MH+).
Reaction SMILES: [ClH:1].C[C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[C:5]([Br:15])[CH:4]=1.Cl.Br[C:18]1C(C)=CC=CC=1NN>>[ClH:1].[CH3:18][C:4]1[C:5]([Br:15])=[C:6]2[C:13](=[CH:14][CH:3]=1)[C:9]([CH2:10][CH2:11][NH2:12])=[CH:8][NH:7]2
Reactant: Cc1cccc(NN)c1Br
Reactant: Cc1cc(Br)c2[nH]cc(CCN)c2c1
Agent: Cl
Product: Cc1ccc2c(CCN)c[nH]c2c1Br

Procedure:
6-Methyl-7-bromotryptamine hydrochloride was prepared (2.42 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 4, except using 2-bromo-3-methylphenylhydrazine hydrochloride as starting material. ##STR52##
Reaction SMILES: [Cl:1][C:2]1([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32](OC)=[O:33])[CH:27]=2)[CH:7]=[CH:6][C:5]([N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[C:9](=[O:11])[NH2:10])=[C:4]([NH:22][C:23]([OH:25])=[O:24])[CH2:3]1.[CH3:36][NH2:37]>>[Cl:1][C:2]1([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32](=[O:33])[NH:37][CH3:36])[CH:27]=2)[CH:7]=[CH:6][C:5]([N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:19])([F:21])[F:20])[C:9](=[O:11])[NH2:10])=[C:4]([NH:22][C:23]([OH:25])=[O:24])[CH2:3]1
Reactant: CN
Reactant: COC(=O)c1cccc(C2(Cl)C=CC(N(C(N)=O)c3ccccc3C(F)(F)F)=C(NC(=O)O)C2)c1
Product: CNC(=O)c1cccc(C2(Cl)C=CC(N(C(N)=O)c3ccccc3C(F)(F)F)=C(NC(=O)O)C2)c1
Reaction time: 8 h

Procedure:
To a sample of N-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-(3-carbomethoxyphenyl) carboxyaminophenyl) urea (0.17 g, 0.34 mmol) was added methylamine (2 M in THF; 1 mL, 1.7 mmol) and the resulting mixture was stirred at room temp. overnight, then concentrated under reduced pressure to give N-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-(3-methylcarbamoylphenyl)carboxyaminophenyl) urea as a white solid: mp 247; TLC (100% EtOAc) Rf 0.35.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][C:30]([CH3:45])([CH3:44])[C:31]([NH:33][C:34]4[CH:43]=[CH:42][C:37]([C:38]([O:40]C)=[O:39])=[CH:36][CH:35]=4)=[O:32])=[O:28])=[CH:23][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCCC1.CO>[CH:1]1([C:7]2[C:8]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][C:30]([CH3:45])([CH3:44])[C:31]([NH:33][C:34]4[CH:43]=[CH:42][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=4)=[O:32])=[O:28])=[CH:23][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(=O)C(C)(C)NC(=O)c2ccc3c(C4CCCCC4)c4n(c3c2)CCOc2cc(OC)ccc2-4)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)OCCn1c-2c(C2CCCCC2)c2ccc(C(=O)NC(C)(C)C(=O)Nc3ccc(C(=O)O)cc3)cc21
Temperature: 25 °C
Reaction time: 64 h
Yield: 94.3 %

Procedure:
To a solution of methyl 4-{2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]-2-methylpropionylamino}benzoate (81 mg, 0.13 mmol) in tetrahydrofuran (8.0 ml) and methanol (2.0 ml) was added 2N aqueous sodium hydroxide solution (1.0 ml, 2.0 mmol), and the mixture was stirred at room temperature for 64 hr. The solvent was evaporated under reduced pressure, 1N aqueous HCl solution (3.0 ml, 3.0 mmol) and methanol (1.0 ml) were added, and the mixture was stirred. The precipitate was collected by filtration to give 4-{2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]-2-methylpropionylamino}benzoic acid (73 mg, yield 92%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:26])[N:20]([CH2:22][C:23](O)=[O:24])[N:21]=[C:8]2[N:7]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[C:6]=1[CH3:37])=[O:4].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:71][NH:72][CH2:73][CH2:74][N:75]([CH3:77])[CH3:76]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:26])[N:20]([CH2:22][C:23](=[O:24])[N:72]([CH2:73][CH2:74][N:75]([CH3:77])[CH3:76])[CH3:71])[N:21]=[C:8]2[N:7]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:35])([F:34])[F:36])[CH:28]=2)[C:6]=1[CH3:37])=[O:4]
Reactant: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(CC(=O)O)c(=O)n2C1c1ccc(C#N)cc1
Reactant: CNCCN(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(CC(=O)N(C)CCN(C)C)c(=O)n2C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
Intermediate 17 (48 mg, 0.09 mmol) was dissolved in DMF (1 mL), and then diisopropylethylamine (48 μL, 0.28 mmol) and HATU (39 mg, 0.10 mmol) were added. The reaction mixture was stirred at RT for 30 minutes and then N,N,N-trimethylethylenediamine (36 μL, 0.28 mmol) was added. After 3 hours of stirring at RT, another portion of HATU was added (10 mg, 0.03 mmol), and stirring was continued for 1 hour. The reaction mixture was partitioned between EtOAc and water. The organic layer was separated, and the aqueous layer further extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated in vacuo. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-10% (2M NH3 in MeOH) in DCM to give the title compound as a white solid (40 mg).
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8][C:7]=2[CH3:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:27])C(=O)C1>>[Br:27][C:11]1[CH:10]=[C:9]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:8]=[C:7]([CH3:19])[C:6]=1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)CCc1ccc(C2CCCC2)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)CCc1cc(C)c(C2CCCC2)c(Br)c1
Yield: 95.7 %

Procedure:
According to the procedure described in the synthesis method of Compound No. A-1, Intermediate 15 (437 mg) and NBS (320 mg) were reacted and treated to obtain the title compound (Compound No. A-24, 545 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:20]=[C:21](\[CH3:27])/[C:22]([O:24]CC)=[O:23])[C:6]2[C:11]([C:12]=1[O:13]COC)=[C:10]([CH2:17][CH2:18][CH3:19])[CH:9]=[CH:8][CH:7]=2.[OH-].[Na+].Cl>C(O)C>[OH:13][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:17][CH2:18][CH3:19])[C:5](/[CH:20]=[C:21](\[CH3:27])/[C:22]([OH:24])=[O:23])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CCCc1cccc2c(/C=C(\C)C(=O)OCC)cc(OC)c(OCOC)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1cccc2c(/C=C(\C)C(=O)O)cc(OC)c(O)c12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 107.1 %

Procedure:
2.2 g of ethyl (E)-3-(3-methoxy-4-methoxymethoxy-5-propyl-1-naphthyl)-2-methylpropenoate was dissolved in 50 ml of ethanol. A sodium hydroxide aqueous solution (sodium hydroxide 1.4 g/water 50 ml) was added, followed by stirring at 60° C. for 30 minutes. After cooling to room temperature, dilute hydrochloric acid was added to make the reaction mixture acidic, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant crystals were filtered to obtain 1.9 g of the titled compound as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH2:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[Br:16]Br>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]([Br:16])[C:8](=[O:13])[C:9]([CH3:10])([CH3:11])[CH3:12])=[CH:14][CH:15]=1
Reactant: CC(C)(C)C(=O)CCc1ccc(Cl)cc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)C(Br)Cc1ccc(Cl)cc1

Procedure:
4-Chlorobenzylpinacolone (11.2 g) in carbon tetrachloride (80 ml) was cooled to about 5° and bromine (8 g) in carbon tetrachloride (20 ml) added dropwise at that temperature over 2 hours. Care was taken to keep free bromine to a minimum in the reaction mixture in order to avoid byproduct formation. The solution was washed with saturated aqueous sodium bicarbonate and with water, dried (magnesium sulphate), and concentrated in vacuo to afford, as a white crystalline solid, crude 1-(4'-chlorophenyl)-2-bromo-4,4-dimethylpentan-3-one, m.p. 48°-50°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](O)=[N:6][CH:7]=1.P(Cl)(Cl)([Cl:14])=O>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.C(#N)C>[Cl:14][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cnc(O)c([N+](=O)[O-])c1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: CC#N
Product: Cc1cnc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 96.4 %

Procedure:
5-methyl-3-nitro-pyridin-2-ol (5 g, 32.4 mmol) and benzyltrimethyl ammonium chloride (3.01 g, 16.2 mmol) were dissolved in acetonitrile, and phosphorus oxychloride (9.0 ml, 97.2 mmol) was added thereto and stirred at 800 for 6 hours. The reaction mixture was cooled and poured into ice water to quench the reaction, and extracted with dichloromethane. The combined organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of dichloromethane. The fractions containing the product were collected and evaporated to obtain 2-chloro-5-methyl-3-nitro-pyridine as yellow solid (5.39 g, 97%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[CH:7]=1.[H-].[Na+].[CH3:11][OH:12]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([O:12][CH3:11])[CH:5]=[N:4][CH:3]=1
Reactant: Brc1cncc(Br)c1
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cncc(Br)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a suspension of 12 g of 3,5-dibromopyridine and 40 g of 60% NaH in DMF was added 4.05 mL of methanol, and the reaction mixture was stirred for 4 hours at room temperature and 1 hour at 60° C. The DMF was removed under reduced pressure, and the residue was taken directly to the next step. MS (DCI/NH3) m/e 188/190 (M+H)+, 205/207 (M+NH4)+. 1H NMR (CDCl3, 300 MHz) δ: 8.32 (d, J=1.8 Hz, 1H, 8.27 (d, J=2.6 Hz, 1H), 7.42 (dd, J=1.8, 2.6 Hz, 1H), 3.88 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=2)[CH2:3]1.N1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:14]=[C:15]([NH:19][S:28]([CH3:27])(=[O:30])=[O:29])[CH:16]=[CH:17][CH:18]=2)[CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(N)c1)N2
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(NS(C)(=O)=O)c1)N2
Yield: 32.7 %

Procedure:
To a stirred mixture of 3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (150 mg, 0.56 mmol) in dichloromethane (3 mL) was added pyridine (79 mg, 1.01 mmol) in dichloromethane (2 mL) and methanesulfonyl chloride (96 mg, 0.84 mmol) under nitrogen. The resultant mixture was stirred for 16 h. The reaction mixture was diluted with dichloromethane, washed with water (twice), saturated brine, and dried over magnesium sulfate. Magnesium sulfate was removed by filtration, and after evaporation, the residue was purified on chromatography column (silica gel, petroleum ether: ethyl acetate=10:1) to afford 63 mg of N-[3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-methanesulfonamide as yellow solid (Yield: 33%). MS (ESI+APCI) M+1=345.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]([N:8]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:9][CH2:10][C:11]([O:13]C)=O)=[O:7])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.CN(C=O)C>[O:7]=[C:6]1[CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:21])[C:11](=[O:13])[CH2:10][CH2:9][N:8]1[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)CC(=O)N(CCC(=O)OC)N1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)C1C(=O)CCN(N2CCCCC2)C1=O
Temperature: 77 °C

Procedure:
To a solution of methyl N-(3-ethoxy-3-oxopropanoyl)-N-(1-piperidinyl)-β-alaninate (43 g, 143 mmol) in a mixture of THF (2.26 L) and DMF (1.00 L) was added Cs2CO3 (140 g, 430 mmol). The resulting mixture was heated at reflux (77° C.) for 48 h. The cooled reaction was filtered, and the filtrate was evaporated. The filtrate residue and filtered solid were combined and purified by flash chromatography using 7:3 CH2Cl2/MeOH as eluant, to give 11.36 g of partially pure title material. LC-MS m/z 269.19 (MH+), retention time 2.20 min (method 2).
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([F:21])[C:7]([NH2:20])=[C:8]2[C:13]=1[O:12][CH2:11][C:10]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=[N:9]2>C(O)C.O>[Br:3][C:4]1[CH:5]=[C:6]([F:21])[C:7]([NH2:20])=[C:8]2[C:13]=1[O:12][CH2:11][CH:10]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[NH:9]2
Reactant: Nc1c(F)cc(Br)c2c1N=C(c1cccnc1)CO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1c(F)cc(Br)c2c1NC(c1cccnc1)CO2
Temperature: 90 °C

Procedure:
Sodium tetrahydroborate (44 mg, 1.2 mmol) was added to a solution of 8-bromo-6-fluoro-3-pyridin-3-yl-2H-1,4-benzoxazin-5-amine (190 mg, 0.58 mmol) in ethanol (4 mL) and water (1 mL), and heated at 90° C. for 15 minutes. The mixture was concentrated, diluted with water, and extracted with ethyl acetate. The organic solvents were evaporated to afford the product. LCMS calc. for C13H12BrFN3O (M+H)+: m/z=324.0. found: 324.0.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[F:19][C:20]1[C:28]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:22](=[O:23])[C:21]4[CH:25]=[CH:26][CH:27]=[C:28]([O:29][C:30]([F:31])([F:32])[F:33])[C:20]=4[F:19])[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1F
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)c1cccc(OC(F)(F)F)c1F
Yield: 11.7 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 2-fluoro-3-trifluoromethoxy-benzoyl chloride to afford the title compound (11 mg, 11.7%). 1H-NMR (δ, ppm, DMSO-d6): 6.50 (d, 1H, HPy,5, J=5.9 Hz), 6.91-6.94 (m, 1H, Harom), 7.43-7.46 (m, 3H, Harom), 7.53-7.55 (m, 2H, Harom), 7.70-7.74 (m, 1H, Harom), 7.81 (d, 1H, HPy,6, J=5.9 Hz), 10.70 (s, 1H, NHamide), 11.18 (s, 1H, NHPy7), 11.39 (s, 1H, NHPy9). LC-MS, tR=4.62 minutes, m/z: 449.08 (M+H)+, calculated for C20H13N4O4F4. HRMS (EI): m/z [M+H] calculated for C20H13N4O4F4: 449.0873; found: 449.0879.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]2[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=2)=[O:28])=[C:22]([C:39]([F:42])([F:41])[F:40])[CH:21]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[C:34](=[O:35])[C:33]2[CH:37]=[CH:38][C:30]([NH:29][C:27](=[O:28])[CH2:26][C:23]3[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][C:22]=3[C:39]([F:42])([F:40])[F:41])=[CH:31][CH:32]=2)=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)CNCc1ccc(Br)cc1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)O)cc2)c(C(F)(F)F)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(Br)cc3)cc2)c(C(F)(F)F)c1
Yield: 91 %

Procedure:
Prepared from INT-60 and INT-18. To a stirring solution of tert-butyl 2-((4-bromobenzyl)amino)acetate INT-60 (2.7 g, 8.99 mmol), 4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzoic acid INT-18 (3.18 g, 8.99 mmol) and TEA (2.507 mL, 17.99 mmol) in DMF was added PyBOP (4.91 g, 9.44 mmol) at room temperature. After 2 h the reaction mixture was diluted with EA (200 mL) and washed with 1 M HCl (100 mL), NaHCO3 (200 mL) and brine (200 mL). The organics were dried over MgSO4, pre-absorbed onto silica gel and purified by chromatography (EA/hexanes) to afford 5.2 g (91%) of tert-butyl 2-(N-(4-bromobenzyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetate INT-81 as a white foamy solid. LCMS-ESI (m/z) calculated for C30H30BrF3N2O5: 635; found 579/581 [M-tBu+H]+, tR=2.83 min (Method 10).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([NH:13][C:14](=O)[CH2:15][CH3:16])[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:33]2)=CC=1.C1(C)C=CC=CC=1.Cl>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([NH:13][C:14](=[S:33])[CH2:15][CH3:16])[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: CCC(=O)Nc1n[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCC(=S)Nc1n[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Yield: 61.4 %

Procedure:
175 mg of 5-(4-fluorophenyl)-3-propionylamino-4-(4-pyridyl)pyrazole and 450 mg of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide were added to 30 ml of toluene, followed by heating under reflux for 2 hours. After the reaction mixture was cooled, 10% hydrochloric acid and ethyl acetate were added thereto. The aqueous layer was separated, neutralized with a saturation solution of sodium hydrogen carbonate, and extracted with chloroform-methanol (5:1). After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (using chloroform-methanol (10:1) as the developing solvent). Thus, 113 mg (61% yield) of the title compound was obtained as pale-yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][C:10]2[C:15]([CH:16]([CH3:18])[CH3:17])=[CH:14][C:13]([OH:19])=[C:12]([I:20])[CH:11]=2)=[CH:4][N:3]=1.Br[CH2:22][CH2:23][O:24][Si:25]([C:28](C)(C)C)([CH3:27])[CH3:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[I:20][C:12]1[C:13]([O:19][CH2:22][CH2:23][O:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[CH:14][C:15]([CH:16]([CH3:18])[CH3:17])=[C:10]([CH:11]=1)[O:9][C:5]1[C:6]([NH2:8])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC(C)c1cc(O)c(I)cc1Oc1cnc(N)nc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1cc(OCCO[Si](C)(C)C)c(I)cc1Oc1cnc(N)nc1N
Temperature: 50 °C
Yield: 97 %

Procedure:
A mixture of 4-(2,4-Diamino-pyrimidin-5-yloxy)-2-iodo-5-isopropyl-phenol (0.3 g, 0.78 mmol), (2-bromoethoxy)-tert-butyl-dimethyl silane (0.28 g, 1.17 mmol), and K2CO3 (0.22 g, 1.56 mmol) in anhydrous DMF (5 ml) was heated at 50° C. for 16 hrs. Solvent was removed in vacuo. The residue was partitioned between methylene chloride and water. The combined organic extracts was washed with water, dried over Na2SO4, filtered and concentrated. Flash chromatography on silica (3% MeOH in methylene chloride with 0.1% NH4OH) gave 5-[5-Iodo-2-isopropyl-4-(2-trimethylsilanyloxy-ethoxy)-phenoxy]-pyrimidine-2,4-diamine (0.38 g, 90%) as a solid.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8](Cl)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:11][C:12]1([CH3:20])[O:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[O:13]1.N1C=CC=CC=1.Cl>C(Cl)Cl>[CH:1]1([CH2:6][CH2:7][C:8]([CH:15]2[C:16](=[O:18])[O:17][C:12]([CH3:20])([CH3:11])[O:13][C:14]2=[O:19])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)OC(=O)C(C(=O)CCC2CCCC2)C(=O)O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
3-Cyclopentylpropionyl chloride (0.64 ml, 4.16 mmol) was added to a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (500 mg, 3.47 mmol) in anhydrous methylene chloride (10 ml). After cooling to 0° C., pyridine (0.56 ml, 6.94 mmol) was added in portions. After stirring for 1 hour at 0° C. and 2 hours at ambient temperature the mixture was poured onto water (20 ml) containing concentrated hydrochloric acid (0.5 ml). The organic layer was separated, washed with water, brine, dried (MgSO4) and the volatiles were removed by evaporation to give 5-(3-cyclopentylpropionyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (900 mg, 96%).
Reaction SMILES: [C:1]([CH:3]1[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1)#[CH:2].Br[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.C(N(CC)CC)C>C(OCC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]Br>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:2]#[C:1][CH:3]3[CH2:12][CH2:11][C:6]4([O:7][CH2:8][CH2:9][O:10]4)[CH2:5][CH2:4]3)=[CH:15][CH:16]=2)=[CH:25][CH:24]=1
Reactant: Fc1ccc(-c2ccc(Br)cc2)cc1
Reactant: C#CC1CCC2(CC1)OCCO2
Agent: [Cu]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Fc1ccc(-c2ccc(C#CC3CCC4(CC3)OCCO4)cc2)cc1
Reaction time: 4.5 h

Procedure:
A mixture of 1.03 g of 8-ethynyl-1,4-dioxaspiro[4.5]decane, 1.197 g 4-bromo-4'-fluorobiphenyl, 0.11 g of tetrakis(triphenylphosphine)palladium, 0.041 g of copper(I) bromide and 45 ml of triethylamine was heated to boiling for 4.5 hours. After cooling the mixture was diluted with diethyl ether, washed twice with water, dried over sodium sulphate, filtered and concentrated. The crude 8-[(4'-fluoro-4-biphenylyl)ethynyl]-1,4-dioxaspiro[4.5]decane (1.82. g) obtained was purified by chromatography on 35 g of silica gel with hexane/ethyl acetate (vol. 9:1). Yield 1.30 g.