Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[CH:9])[CH:3]=1.C(Br)C.[Mg].[CH3:14][Si:15](Cl)([CH3:17])[CH3:16].[NH4+].[Cl-]>O1CCCC1>[CH3:14][Si:15]([C:9]#[C:8][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1)([CH3:17])[CH3:16]
Reactant: C[Si](C)(C)Cl
Reactant: C#Cc1cccc(Br)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCBr
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under an inert atmosphere, 9.5 g of the compound of Step A were introduced into 100 g of tetrahydrofuran, and at 25° C.±3° C., over 15 minutes, 69 ml of a 0.8M solution of magnesium ethyl bromide were added, with stirring for 15 minutes at 25° C. Then, over 2 minutes and without cooling, 8 ml of trimethylsilyl chloride were added with stirring for 30 minutes at 25° C. The reaction mixture was poured into a 2M aqueous solution of NH4Cl and was extracted with ether, dried, filtered, and the filtrate was concentrated to dryness by distilling under reduced pressure then rectified to obtain 12.1 g of 3-(trimethylsilylethynyl)bromobenzene with a boiling point at 0.05 mm/Hg=78° to 84° C.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([O:9]CC)=[O:8].[OH-].[Na+].C(O)(=O)C.[Br:18][CH:19]([CH:22]=O)[CH:20]=O>C(O)C>[Br:18][C:19]1[CH:20]=[N:1][C:2]2[N:6]([N:5]=[CH:4][C:3]=2[C:7]([OH:9])=[O:8])[CH:22]=1
Reactant: O=CC(Br)C=O
Reactant: CCOC(=O)c1cn[nH]c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)c1cnn2cc(Br)cnc12
Temperature: 70 °C
Yield: 50.9 %

Procedure:
A solution of ethyl 5-amino-1H-pyrazole-4-carboxylate (2 g, 12.89 mmol) and sodium hydroxide (19.34 mL, 38.7 mmol) (aqueous, 2M) in ethanol (30 mL) was heated at 80° C. overnight. The reaction mixture was concentrated in vacuo to give a crude mixture of carboxylate and sodium hydroxide. The crude mixture was dissolved in ethanol (4 mL) and acetic acid (14 mL, 245 mmol). Whilst stirring the mixture, bromomalonaldehyde (1.947 g, 12.90 mmol) was added and then the mixture heated to 70° C. for 1 h. The reaction mixture was allowed to cool and the precipitate was filtered and washed with ethanol. The solid product was dried in a vacuum oven to give the title compound (1.589 g).
Reaction SMILES: [N:1](C(OCC1C=CC=CC=1)=O)([CH2:3][C:4]([NH:6][C@H:7]([C:16]([NH:18][C@H:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[CH2:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:5])[CH3:2].O.O.C(O)(=O)C(O)=O>CO.[Pd]>[NH:1]([CH2:3][C:4]([NH:6][C@H:7]([C:16]([NH:18][C@H:19]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[CH2:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:5])[CH3:2]
Reactant: CC(C)[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CN(C)C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CO
Product: CNCC(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)OC(C)(C)C)C(C)C

Procedure:
The oily Z-Sar-Asp(OtBu)-Val-OtBu protected tripeptide obtained in a yield of 4.2 g (7.6 mmol) (Rf1 =0.75) is dissolved in 40 ml of methanol and, after adding 0.8 g of palladium-on-carbon catalyst, the mixture is hydrogenated in the usual manner. After filtering off the catalyst, 1.0 g (8.0 mmol) of oxalic acid dihydrate is added to the filtrate, the solution is evaporated and the residue is solidified by adding ether to obtain 2.24 g of H-Sar-Asp(OtBu)-Val-OtBu.oxalate (free tripeptide oxalate), m.p.: 190°-192° C., Rf3 =0.30.
Reaction SMILES: CC(C)([O-:4])C.[K+].[C:7]([O:11][C:12](=[O:36])[NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([CH:20]2[CH2:33][C:32]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([O:34][CH3:35])[CH:30]=4)[N:25]=[CH:24][C:23]=3[O:22][CH2:21]2)[CH2:16][CH2:15]1)([CH3:10])([CH3:9])[CH3:8]>CS(C)=O.C(O)(C)(C)C>[C:7]([O:11][C:12](=[O:36])[NH:13][C@H:14]1[CH2:15][CH2:16][C@H:17]([CH:20]2[CH:33]([OH:4])[C:32]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([O:34][CH3:35])[CH:30]=4)[N:25]=[CH:24][C:23]=3[O:22][CH2:21]2)[CH2:18][CH2:19]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc2ncc3c(c2c1)CC([C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)CO3
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(C)(C)O
Product: COc1ccc2ncc3c(c2c1)C(O)C([C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)CO3
Reaction time: 1 h

Procedure:
Potassium tert-butoxide (354 mg, 3.15 mmol, 2.5 eq) is added at room temperature to a stirred solution of [trans-4-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-yl)-cyclohexyl]-carbamic acid tert-butyl ester (2.6 g, 1.26 mmol, 1.0 eq) in dimethyl sulfoxide (45 mL) and tert-butanol (13 mL) under oxygen atmosphere. After 1 hour stirring under oxygen atmosphere, the reaction mixture is purged with nitrogen, and extracted with dichloromethane (3×200 mL) and water (200 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: dichloromethane:methanol, 250:1 to 100:1, v/v) to afford [trans-4-(4-hydroxy-6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-yl)-cyclohexyl]-carbamic acid tert-butyl ester as a white solid that is further purified by preparative HPLC to obtain a white solid (70 mg, 42% yield).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([F:7])([F:6])[F:5].[Cl:8][SiH:9]([Cl:11])[Cl:10]>C(P(CCCC)CCCC)CCC>[F:5][C:4]([F:7])([F:6])[CH2:3][CH2:2][Si:9]([Cl:11])([Cl:10])[Cl:8]
Reactant: FC(F)(F)CCCl
Reactant: Cl[SiH](Cl)Cl
Agent: CCCCP(CCCC)CCCC
Product: FC(F)(F)CC[Si](Cl)(Cl)Cl
Yield: 90.7 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.15 g (0.75 mmol) of tri-n-butylphosphine, 1.33 g (10.0 mmol) of 1-chloro-3,3,3-trifluoropropane, and 6.77 g (50.0 mmol) of trichlorosilane were reacted at 150° C. for 15 hrs. The resulting mixture was distilled to give 2.1 g of (3,3,3-trifluoropropyl)trichlorosilane (bp; 114° C., yield; 90%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1>>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][C:7]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CC(C)c1ccc(Br)cc1
Product: CC(C)c1ccc(Br)c([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 84 %

Procedure:
To fuming nitric acid (5 mL) cooled to 5° was added neat 4-bromoisopropylbenzene (1.0 g, 5.023 mmol) dropwise at such a rate that the reaction temperature remained below 10°. The reaction was stirred for 2 hours at 5-10°, quenched with ice (50 g), extracted with ethyl acetate (50 mL), and the organic extract was washed with water (2×25 mL) and brine (25 mL), then dried over magnesium sulfate.filtered and concentrated by rotary evaporation. The residue was purified by silica gel flash chromatography eluting with 5:95 ethyl acetate/hexanes to afford the title compound as a light yellow solid (1.03 g, 4.22 mmol, 84%). 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.27 (d, J=6.99 Hz, 6 H) 2.75-3.23 (m, 1 H) 7.29 (dd, J=8.82, 2.21 Hz, 1 H) 7.63 (d, J=8.09 Hz, 1 H) 7.69 (d, J=2.21 Hz, 1 H); MS (DCI) m/z 261/263 (M+NH4)+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH2:16][NH:17][C:18]([C:20]2[C:21]3[C:22]([CH3:33])=[CH:23][N:24]([CH:30]([CH3:32])[CH3:31])[C:25]=3[CH:26]=[C:27]([Br:29])[CH:28]=2)=[O:19])=[C:11]([O:34]C)[N:10]=1)(C)(C)C.Cl>O1CCCC1>[NH2:7][CH2:8][C:9]1[NH:10][C:11](=[O:34])[C:12]([CH2:16][NH:17][C:18]([C:20]2[C:21]3[C:22]([CH3:33])=[CH:23][N:24]([CH:30]([CH3:31])[CH3:32])[C:25]=3[CH:26]=[C:27]([Br:29])[CH:28]=2)=[O:19])=[C:13]([CH3:15])[CH:14]=1
Reactant: COc1nc(CNC(=O)OC(C)(C)C)cc(C)c1CNC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(CN)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Temperature: 80 °C
Yield: 82.3 %

Procedure:
To a stirred solution of tert-butyl((5-((6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxamido)methyl)-6-methoxy-4-methylpyridin-2-yl)methyl)carbamate (500 mg, 0.894 mmol) in Tetrahydrofuran (THF) (5 mL) was added 6N HCl (15 mL, 15.00 mmol). The reaction was stirred under N2 with heating at 80° C. for 18 hr. The reaction was cooled to RT and evaporated to dryness under vacuum. The remaining was purified by silica gel chromatography (Analogix, SF25-40 g, 0 to 10% (5% NH4OH in MeOH) in CH2C12). The pure fractions were combined and evaporated to dryness under vacuum. Dissolved with a small volume of CH2C12, scratched out by slowly adding hexanes, filtered, washed with hexanes and dried under vacuum to give the product N-((6-(aminomethyl)-4-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxamide (328 mg, 0.736 mmol, 82% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.26 (t, J=5.1 Hz, 1H), 7.76 (d, J=1.8 Hz, 1H), 7.33 (d, J=1.0 Hz, 1H), 7.01 (d, J=1.5 Hz, 1H), 6.01 (s, 1H), 5.77 (s, 0H), 4.74 (quin, J=6.6 Hz, 1H), 4.32 (d, J=5.1 Hz, 2H), 3.46 (s, 2H), 2.25 (s, 3H), 2.14 (s, 3H), 1.39 (d, J=6.8 Hz, 6H). MS(ES)+m/e 445.2 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].[S-:11][C:12]#[N:13].[K+]>C(O)C>[S:11]([CH2:2][CH2:3][C:4]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[C:12]#[N:13]
Reactant: N#C[S-]
Reactant: O=C(CCCl)N1CCCC1
Agent: [K+]
Solvent: CCO
Product: N#CSCCC(=O)N1CCCC1

Procedure:
1-(β-Chloropropionyl) pyrrolidine (16 grams; 0.1 mol), potassium thiocyanate (18 grams; 0.2 mol) and ethanol (100 ml) are charged into a glass reaction flask equipped with a mechanical stirrer and reflux condenser. The reaction mixture is then heated at reflux for a period of about 6 hours. After this time the reaction mixture is cooled and filtered. The filtrate is stripped of solvent and the residue is extracted with benzene. The benzene extract is evaporated under reduced pressure to yield 1-(β-thiocyanopropionyl) pyrrolidine as a residue.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:18])([CH3:17])[CH3:16])[O:11][C:10]([CH3:30])([CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=1)[CH:9]=[CH:8]2)(=[O:3])[CH3:2].[H][H]>C1C=CC=CC=1.C(O)(=O)C.[Pd]>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:18])([CH3:16])[CH3:17])[O:11][C:10]([CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([NH2:27])=[CH:25][CH:26]=1)([CH3:30])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)Oc1cc2c(cc1C(C)(C)C)OC(C)(COc1ccc([N+](=O)[O-])cc1)C=C2
Agent: [Pd]
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CC(=O)Oc1cc2c(cc1C(C)(C)C)OC(C)(COc1ccc(N)cc1)CC2

Procedure:
2.1 g of 6-acetoxy-7-t-butyl-2-methyl-2-(4-nitrophenoxymethyl)-2H-chromene (prepared as described in Preparation 57) were dissolved in a mixture of 20 ml of benzene and 2 ml of acetic acid, and the compound was reduced for 10 hours at room temperature, in the presence of 0.1 g of 10% w/w palladium-on-carbon, and under about 1 atmosphere (about 1 bar) pressure of hydrogen. The catalyst was filtered off, and the reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and then with water, after which it was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography, eluted with benzene, to give the title compound as a slightly brown oil.
Reaction SMILES: S=[C:2]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[N:6]2[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:5]2[CH2:4][NH:3]1.[CH3:20][O:21][CH:22]([O:25][CH3:26])[CH2:23][NH2:24]>>[CH3:20][O:21][CH:22]([O:25][CH3:26])[CH2:23][NH:24][C:2]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[N:6]2[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:5]2[CH2:4][N:3]=1
Reactant: CCOC(=O)c1ncn2c1CNC(=S)c1sccc1-2
Reactant: COC(CN)OC
Product: CCOC(=O)c1ncn2c1CN=C(NCC(OC)OC)c1sccc1-2

Procedure:
5. By reacting ethyl 5,6-dihydro-6-thioxo4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3-carboxylate with aminoacetaldehyde dimethyl acetal in an analogous manner to that described in Example 5 there is obtained ethyl 6-[(2,2-dimethoxyethyl)amino]-4H-imidazo[1,5-a]thieno[2,3-f][1,4]-diazepine-3-carboxylate of m.p. 134° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:8][OH:9].O=[C:11]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[CH:19][CH:18]=1)[CH2:12][CH2:13][C:14]([OH:16])=[O:15]>O.C(O)C>[OH:9]/[N:8]=[C:11](\[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[CH:19][CH:18]=1)/[CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: NO
Reactant: O=C(O)CCC(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)CC/C(=N/O)c1ccc(N2CCC(c3ccccc3)CC2)cc1
Reaction time: 0.25 h
Yield: 37.5 %

Procedure:
Sodium carbonate (0.80 g, 5.76 mmol) was added to hydroxylamine hydrochloride (0.80 g, 11.5 mmol) in water (3 mL), and the mixture stirred for 15 minutes with ice cooling. The resulting mixture was added to 4-oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid (2.99 g, 8.86 mmol) (Example 1) in ethanol (50 mL) and the resulting mixture refluxed for 6 hours, concentrated to one-third volume, and allowed to cool. The resulting precipitate was dissolved in hot sodium bicarbonate solution, filtered, and the filtrate acidified with 1M HCl to yield a slurry which was filtered, washed with water, and dried in vacuo to give the title compound as a white solid (1.17 g, %C,H,N found: 71.77, 6.79, 7.88).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][C@H:25]([NH2:29])[CH2:24]1.C(N(CC)CC)C>C(#N)C>[NH2:29][C@H:25]1[CH2:26][CH2:27][CH2:28][N:23]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=3[NH:12][C:13](=[O:21])[CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[N:3]=2)[CH2:24]1
Reactant: N[C@H]1CCCNC1
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N[C@H]1CCCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Temperature: 120 °C
Yield: 23.1 %

Procedure:
N-(2,6-Dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1(a)) (0.2 g), (3S)-3-piperidinamine (0.089 g) and triethylamine (0.25 mL) were placed into a 10 mL microwave vial followed by the addition of acetonitrile (5 mL). The vial was sealed and heated at 120° C. in a single mode microwave for 30 minutes, and a further 60 minutes at 150° C. The product crystallised from the reaction on cooling and was subsequently filtered and washed with acetonitrile (10 mL). Purification (SiO2, 7M ammonia in methanol:methanol:dichloromethane 1:4:95) gave the title compound (0.055 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16](F)[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][C:13]=2[F:22])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].[CH3:23][O-:24].[Na+]>CCOCC.CO>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([O:24][CH3:23])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][C:13]=2[F:22])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8]
Reactant: C[O-]
Reactant: Cn1nc(-c2cc(F)c([N+](=O)[O-])cc2F)c(Cl)c1C(F)(F)F
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: COc1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.04 g of 4-chloro-3-(2,5-difluoro-4-nitrophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole was dissolved in anhydrous ether and the solution cooled with an ice bath, then 3.7 ml of a 25 wt. % sodium methoxide in methanol was added. After addition, the ice bath was removed and the mixture stirred for 30 minutes at room temperature. The solution was then extracted 4 times with water, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was chromatographed to give 4.63g of 4-chloro-3-(2-fluoro-5-methoxy-4-nitrophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole, mp 115°-116°C..
Reaction SMILES: C[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12](O)=[O:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([S:22](=[O:25])(=[O:24])[NH2:23])=[CH:18][CH:17]=2)[N:3]=1.CN.C[CH2:29][N:30](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:29][NH:30][C:12]([C:8]1[CH:7]=[C:6]2[C:11]([CH:2]=[N:3][C:4]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([S:22](=[O:25])(=[O:24])[NH2:23])=[CH:20][CH:21]=3)=[N:5]2)=[CH:10][CH:9]=1)=[O:13]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nc(Nc2ccc(S(N)(=O)=O)cc2)nc2cc(C(=O)O)ccc12
Agent: CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CNC(=O)c1ccc2cnc(Nc3ccc(S(N)(=O)=O)cc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To methyl 2-(4-sulfamoylphenylamino)quinazolin-7-carboxylic acid (1 eq) was added methylamine (2 eq) and DIEA (4 eq) and HBTU (2 eq) and the mixture was stirred at RT overnight. The coupling went to completion and the mixture was concentrated and partitioned between ethyl acetate and water. The organic layers were concentrated and purified on the prep HPLC to give N-methyl-2-(4-sulfamoylphenylamino)quinazoline-7-carboxamide in 50% yield. ES/MS m/z 358 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:17])=[C:6]([CH:16]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:24](OC=C)(=O)[CH3:25]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:17])=[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][O:15][CH:24]=[CH2:25])=[CH:10][CH:9]=2)[CH:16]=1
Reactant: C=COC(C)=O
Reactant: OCc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=COCc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 67.1 %

Procedure:
To a solution of (4-(5-bromo-2-chlorobenzyl)phenyl)methanol (intermediate AK) (1.5 g, 4.81 mmol), [IrCl(cod)]2 (31 mg, 0.046 mmol) and sodium carbonate (0.29 g, 2.73 mmol) in toluene (6 mL) was added vinyl acetate (0.84 mL, 9.10 mmol) under argon. The reaction mixture was heated to 100° C. and stirred for 4 h. The solution was allowed to cool to room temperature, and then diluted with 50 mL of ethyl acetate. The mixture was washed with water (20 mL) and then with brine (20 mL), and dried over sodium sulfate. The residue was concentrated and purified by column chromatography (eluent EA:PE:Et3N=1:30:0.01) to provide 1.09 g of white solid. 1H NMR (CDCl3, 400 MHz): δ 7.36˜7.28 (m, 5H), 7.22 (d, 2H), 6.61 (dd, J=14.4 and 6.8 Hz, 1H), 4.78 (s, 2H), 4.37˜4.33 (dd, J=14.4 and 2.4 Hz, 1H), 4.14˜4.12 (dd, J=6.8 and 2.4 Hz, 1H), 4.09 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH2:10])[CH:3]=1.[C:18]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:23]=CC=C[CH:19]=1.C(O)(C)C.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:18]([CH3:23])[CH3:19])=[C:4]([C:9]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[CH2:10])[CH:3]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: C=C(c1ccc(C)cc1)c1cc(Br)ccc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: C=C(c1ccc(C)cc1)c1cc(Br)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 22.5 h

Procedure:
To a cold solution (0° C.) of 125 mg (0.4 mmol) of 4-bromo-2-[(1-p-tolyl)vinyl]phenol (Compound R) in 5 mL of tetrahydrofuran was added 125 mg (0.5 mmol) of triphenylphosphine and 0.04 mL (31 mg, 0.5 mmol) of isopropanol followed by 0.07 mL (82 mg, 0.5 mmol) of diethylazodicarboxylate. The dark yellow solution was removed from the ice bath, allowed to warm to ambient temperature on its own and stirred overnight (22.5 hours). The reaction mixture was concentrated in vacuo to a gummy yellow solid. Purification by flash chromatography (silica, 1% ethyl acetate in hexane) gave the title compound as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[O:29][C:30]3[CH:36]=[CH:35][C:34]([C:37]([O:39]C)=[O:38])=[CH:33][C:31]=3[N:32]=2)[CH2:24][CH:23]1[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[O:29][C:30]3[CH:36]=[CH:35][C:34]([C:37]([OH:39])=[O:38])=[CH:33][C:31]=3[N:32]=2)[CH2:24][CH:23]1[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc2oc(N3CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c4cccc5ccccc45)C(c4cccc(F)c4)C3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](c1cccc2ccccc12)N(CC1CCN(c2nc3cc(C(=O)O)ccc3o2)CC1c1cccc(F)c1)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 108.4 %

Procedure:
To a solution of 33 mg of methyl 2-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]-1,3-benzoxazole-5-carboxylate in 2.0 mL of THF and 1.0 mL of methanol was added 1.00 mL of a 1 M aqueous sodium hydroxide solution at room temperature, followed by stirring overnight. It was neutralized by addition of 1.00 mL of 1 M hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 35 mg of 2-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]-1,3-benzoxazole-5-carboxylic acid as a colorless resinous compound. ESI+: 624
Reaction SMILES: C(OC([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([Cl:22])=[C:14]([CH3:23])[CH:13]=3)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:22][C:15]1[N:16]=[C:17]2[C:12](=[CH:13][C:14]=1[CH3:23])[CH2:11][C@H:10]1[N:18]2[C@H:19]([CH3:21])[CH2:20][NH:8][CH2:9]1
Reactant: Cc1cc2c(nc1Cl)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(nc1Cl)N1[C@@H](CNC[C@H]1C)C2
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
To a solution of 0.20 g (0.59 mmol) (4R,9aR)-6-chloro-4,7-dimethyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 2 mL dichloromethane was added 0.91 mL (1.35 g, 11.8 mmol) trifluoroacetic acid. After 30 min., all volatile components were removed at a rotary evaporator and the residue was purified by column chromatography on silica gel with dichloromethane:methanol:ammonia (19:1:0.1) as eluant to give the desired compound as a colourless oil (95.9%).