Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]#[N:14])[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:21][CH2:20][S:19][CH2:18]1)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[BH4-].[Na+]>CO.[Co]>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH2:14])[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:21][CH2:20][S:19][CH2:18]1)=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C#N)C[C@H]1C(=O)N1CCSC1
Agent: [Co]
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](CN)C[C@H]1C(=O)N1CCSC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.6 %

Procedure:
To a mixture of Example 17C (31.1 g, 0.1 mol) and cobalt (TI) chloride (11.9 g, 0.05 mol) in methanol (300 mL) at 0° C. was added in portions sodium borohydride (15.2 g, 0.4 mol). The mixture was stirred for 1 hour at room temperature, the solvent was azeotroped off with chloroform (5×300 mL). The residue was purified by silica gel chromatography with 10% methanol/90% dichloromethane/0.2% ammonium hydroxide to provide the title compound (15 g). MS (ESI) m/e 316 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 1.39 (m, 9 H) 2.35 (m, 1 H) 2.50 (m, 1 H) 2.72 (m, 2 H) 3.00 (m, 1 H) 3.13 (m, 2 H) 3.75 (m, 2 H) 3.94 (m, 1 H) 4.57 (m, 2 H).
Reaction SMILES: [Br:1]/[C:2](=[CH:5]\N(C)C)/[CH:3]=O.C(=O)([O-])[O-].[K+].[K+].Cl.[OH:16][C:17]([CH3:22])(C)[C:18]([NH2:20])=[NH:19]>C(O)C>[Br:1][C:2]1[CH:3]=[N:19][C:18]([C@@H:17]([OH:16])[CH3:22])=[N:20][CH:5]=1
Reactant: CN(C)/C=C(\Br)C=O
Reactant: CC(C)(O)C(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C[C@H](O)c1ncc(Br)cn1
Temperature: 85 °C
Yield: 16 %

Procedure:
(Z)-2-bromo-3-(dimethylamino)prop-2-enal (11.5 g), potassium carbonate (13.4 g), ethanol (200 mL) and 2-hydroxy-2-methyl-propanamidine hydrochloride (12.1 g) were placed in a flask and the mixture heated at 85° C. overnight. The reaction mixture was cooled and the mixture filtered, washed with ethanol and the combined filtrates concentrated in vacuo with silica gel. This residue was purified by chromatography on silica, eluting with 0-50% ethyl acetate in heptane to give (1S)-1-(5-bromopyrimidin-2-yl)ethanol as a white solid (2.1 g, 16%). 1H NMR (CDCl3) δ 8.83 (s, 2H), 4.98 (m, 1H), 3.8 (m, 1H), 1.6 (d, J=6.6 Hz, 3H). Chiral HPLC: Column. Chirapak IC, 0.46 cm×25 cm; 20 min isocratic gradent; 5:95 EtOH:n-hexane+0.1% diethylamine) retention time=14.08 min. (racemic mixture: ˜14.5 min: S isomer; ˜17.5 min: R isomer).
Reaction SMILES: Cl.[CH2:2]([C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(OC(=O)C(=COCC)C(OCC)=O)C.CC[O-].[Na+].C(O[C:39]([C:41]1[C:42](O)=[N:43]C(C2C=CC(CCCCCCC)=CC=2)=[N:45][CH:46]=1)=O)C.P(Cl)(Cl)(Cl)=O.C(OC(C1C(Cl)=NC(C2C=CC(CCCCCCC)=CC=2)=NC=1)=O)C>C(O)C>[C:46]([C:41]1[CH:39]=[N:14][C:13]([C:12]2[CH:11]=[CH:10][C:9]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:16][CH:15]=2)=[N:43][CH:42]=1)#[N:45]
Reactant: CCCCCCCc1ccc(-c2ncc(C(=O)OCC)c(O)n2)cc1
Reactant: CCCCCCCc1ccc(C#N)cc1
Agent: CCCCCCCc1ccc(-c2ncc(C(=O)OCC)c(Cl)n2)cc1
Agent: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCc1ccc(-c2ncc(C#N)cn2)cc1

Procedure:
The starting material can be obtained according to the procedure of A. B. Todd and F. Bergel, J. Chem. Soc. 1937, 366 from p-n-heptylbenzamie hydrochloride [prepared according to H. Schubert and H. Zaschke, J. prakt. Chem. 312, 494 (1970) from p-n-heptylbenzonitrile; melting point 126.0°-127.3° C[ and ethoxymethylenemalonic acid diethyl ester with sodium ethylate in ethanol and subsequent treatment of the obtained 2-(p-n-heptylphenyl)-4-hydroxy-5-primidinecarboxylic acid ethyl ester (melting point 184.7°-185.3° C) with phosphorus oxychloride. The melting point of 2(-p-n-heptylphenyl)-4-chloro-5-pyrimidinecarboxylic acid ethyl ester is 49.2°-49.8° C.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=[CH:11]2.[CH:21]1[C:25]2[C:26](Cl)=[N:27][CH:28]=[N:29][C:24]=2[NH:23][CH:22]=1.Cl>CS(C)=O>[N:29]1[C:24]2[NH:23][CH:22]=[CH:21][C:25]=2[C:26]([O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=[CH:11]3)=[N:27][CH:28]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: O=C(O)c1cccc2cc(O)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=C(O)c1cccc2cc(Oc3ncnc4[nH]ccc34)ccc12
Temperature: 100 °C
Reaction time: 14 h

Procedure:
Cs2CO3 (23.4 g, 71.9 mmol) was added in one portion to a solution of 6-hydroxy-1-naphthoic acid (5.41 g, 28.7 mmol) and 6-chloro-7-deazapurine (3.68 g, 24.0 mmol) in DMSO (47.9 ml) at RT. The resulting mixture was heated to 100° C. and stirred for 14 hours. The mixture was cooled to RT and neutralized to a pH of 7 with 6N HCl. Solid material proceeded to crash out of solution. The entire mixture was centrifuged and the liquid was decanted. To the solid was added saturated aqueous NaHCO3 and the resulting mixture was agitated over night on a rotating plate. The mixture was centrifuged again and decanted into a 1 L flask. The solution was acidified to neutral pH, centrifuged again and decanted. EtOAc was added to the solid material, the mixture centrifuged and the liquid was decanted to reveal the desired compound. MS (ESI, pos. ion) m/z: 306.1 (M+1). Mass Calc'd for C18H15NO3: 305.08.
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[CH:20][C:19](F)=[CH:18][CH:17]=1)(=[O:15])=[O:14])[C:8]1[S:9][CH:10]=[CH:11][N:12]=1)(C)(C)C.C([Li])CCC.[O:29]1[CH:33]=[CH:32][C:31]([C:34]2[N:41]=[CH:40][CH:39]=[CH:38][C:35]=2[CH:36]=[O:37])=[CH:30]1.Cl>O1CCCC1.O.C(OCC)(=O)C>[O:29]1[CH:33]=[CH:32][C:31]([C:34]2[C:35]([CH:36]([OH:37])[C:19]3[CH:18]=[CH:17][C:16]([S:13]([NH:7][C:8]4[S:9][CH:10]=[CH:11][N:12]=4)(=[O:14])=[O:15])=[CH:21][CH:20]=3)=[CH:38][CH:39]=[CH:40][N:41]=2)=[CH:30]1
Reactant: O=Cc1cccnc1-c1ccoc1
Reactant: CC(C)(C)OC(=O)N(c1nccs1)S(=O)(=O)c1ccc(F)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=S(=O)(Nc1nccs1)c1ccc(C(O)c2cccnc2-c2ccoc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 11.2 %

Procedure:
100 mg (0.28 mmol) of tert-butyl((4-fluorophenyl)sulfonyl)(thiazol-2-yl)carbamate was dissolved in 5 mL of tetrahydrofuran under nitrogen gas, and cooled to −78° C. After adding 0.26 mL (0.42 mmol) of n-butyllithium (1.6 M in tetrahydrofuran) slowly, the mixture was stirred for 30 minutes as maintaining −78° C. 23 mg (0.13 mmol) of 2-(furan-3-yl)nicotinaldehyde was dissolved in 0.5 mL of tetrahydrofuran, and added to the above reacting solution. As warming from −78° C. to room temperature, the reacting solution was stirred for 24 hours. Ethyl acetate and water/1 N-hydrochloride were added to the reacting solution, and it was stirred. After separating layers, the organic layer only was collected and concentrated under reduced pressure. The obtained residue was separated by column chromatography (developing solvent, hexane:ethyl acetate=1:1) to obtain 6 mg (5.2% yield) of the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:18]([C:20]1[N:21]([CH2:34][C:35]#[CH:36])[C:22]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:25]=[C:24](N)[C:23]=2[N:33]=1)[CH3:19]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].[Cu]I>[CH2:18]([C:20]1[N:21]([CH2:34][C:35]#[C:36][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[C:22]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:25]=[CH:24][C:23]=2[N:33]=1)[CH3:19]
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: C#CCn1c(CC)nc2c(N)nc3ccccc3c21
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCc1nc2cnc3ccccc3c2n1CC#Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.4 %

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (95 mg, 0.03 eq.), 4-iodonitrobenzene (0.84 g, 1.1 eq.), triethylamine (0.92 g, 3 eq.), and copper (I) iodide (35 mg, 0.06, eq.) were added sequentially to a solution of 2-ethyl-1-(2-propynyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.72 g, 3.0 mmol, 1.0 eq.) in DMF. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane (30 mL) and water (50 mL). The organic layer was separated, washed twice with water, and then concentrated under reduced pressure to a solid. This material was purified by column chromatography (silica gel eluting with 3/97 methanol/dichloromethane) to provide 0.4 g of 2-ethyl-1-[3-(4-nitrophenyl)-2-propynyl]-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [I:1]Cl.[N+:3]([C:6]1[C:7]([Cl:13])=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9])([O-:5])=[O:4].S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[I:1][C:12]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([Cl:13])[C:6]=1[N+:3]([O-:5])=[O:4]
Reactant: ClI
Reactant: Nc1cccc([N+](=O)[O-])c1Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1ccc(I)c([N+](=O)[O-])c1Cl
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Iodine monochloride (1.25 ml) was added to a solution of 3-nitro-2-chloroaniline (4265 mg) in glacial acetic acid (40 ml). The mixture was stirred for four hours at 70° C. After the mixture was allowed to cool to ambient temperature, saturated sodium sulphite solution (100 ml) was added. The solution was extracted with EtOAc (200 ml), volatile material was removed by evaporation and the residue was redissolved in EtOAc (150 ml), washed with saturated sodium bicarbonate solution (75 ml), brine (75 ml) and dried. The volatile material was removed by evaporation and the residue was purified by chromatography eluting with 5-15% EtOAc in hexane to give a mixture of the title compound and the starting material (1.933 g) (ratio 1:1.75). Iodine monochloride (0.28 ml) was added to a solution of the mixture (1919 mg) in glacial acetic acid (10 ml). The mixture was stirred for four hours at 70° C. After the mixture was allowed to cool to ambient temperature, saturated sodium sulphite solution (50 ml) added. The solution was extracted with EtOAc (100 ml), volatile material was removed by evaporation and the residue was partitioned between EtOAc (100 ml) and saturated sodium bicarbonate solution (50 ml). The organic phase was separated, washed with brine (50 ml) and dried. The volatile material was removed by evaporation and the residue was purified by chromatography eluting with 5-15% EtOAc in hexane to give the title compound (1286 mg) as a solid. NMR: 6.19 (s, 2H), 6.73 (d, 1H), 7.50 (d, 1H); m/z 297.
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].C(Cl)Cl.[C:20]([O:24][C:25](=[O:53])[NH:26][C:27]([C:29]1[S:30][C:31]([S:51][CH3:52])=[C:32]([S:34]([C:37]2[CH:38]=[C:39]([C:43]3[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][C:44]=3[CH3:50])[CH:40]=[CH:41][CH:42]=2)(=[O:36])=[O:35])[CH:33]=1)=[NH:28])([CH3:23])([CH3:22])[CH3:21].NC(N)=S>>[C:20]([O:24][C:25](=[O:53])[NH:26][C:27](=[NH:28])[C:29]1[S:30][C:31]([S:51][CH3:52])=[C:32]([S:34]([C:37]2[CH:38]=[C:39]([C:43]3[CH:48]=[CH:47][C:46]([N:49]=[C:1]=[S:2])=[CH:45][C:44]=3[CH3:50])[CH:40]=[CH:41][CH:42]=2)(=[O:36])=[O:35])[CH:33]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2ccc(N)cc2C)c1
Agent: NC(N)=S
Solvent: ClCCl
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2ccc(N=C=S)cc2C)c1

Procedure:
A solution of 1,1′-thiocarbonyldi-2(1H)-pyridone in DCM (0.25 M, 300 μL, 0.075 mmol) was added to {[4-(4′-amino-2′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester ((Example 220: step b) 26 mg, 0.05 mmol) at rt. The orange color of the thiourea dissipated as the reagent was added, and a new higher spot appeared on TLC. The solvent was removed in vacuo and the residue was purified by preparative TLC to yield 23 mg of product. 1H-NMR (CDCl3): δ 8.01 (br s, 1H), 7.96 (d, 1H, J=7.4 Hz), 7.87 (s, 1H), 7.53 (m, 2H), 7.10 (d, 1H, J=7.9 Hz), 6.93 (br s, 1H), 6.87 (d, 1H, J=7.9 Hz), 2.51 (s, 3H), 2.17 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[F:21][C:22]([F:29])([F:28])[C:23]1[N:24]=[CH:25][NH:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:21][C:22]([F:29])([F:28])[C:23]1[N:24]=[CH:25][N:26]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=3[N:12]=2)[CH:27]=1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: FC(F)(F)c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3-n3cnc(C(F)(F)F)c3)nc2c1
Temperature: 50 °C
Yield: 101.2 %

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.18 g of 4-(trifluoromethyl)-1H-imidazole, 0.55 g of potassium carbonate and 2 ml of DMF was stirred while heating at 50° C. for 1.5 hours. Then, the reaction mixture was cooled to room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.40 g of 2-{3-[4-(trifluoromethyl)imidazole-1-yl]pyridin-4-yl}-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 57”).
Reaction SMILES: I(O)(=O)(=O)=[O:2].[OH:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:16][CH2:17][C@H:18]3[CH2:22][CH2:21][CH2:20][O:19]3)[CH:13]=2)[C:8]1=[O:23]>O.O.C1COCC1>[OH:2][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:16][CH2:17][C@H:18]3[CH2:22][CH2:21][CH2:20][O:19]3)[CH:13]=2)[C:8](=[O:23])[O:6]1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: O=C1c2ccc(OC[C@H]3CCCO3)cc2CC1O
Solvent: O
Solvent: C1CCOC1
Product: O=C1OC(O)Cc2cc(OC[C@H]3CCCO3)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of periodic acid in water (0.5 M; 5.2 mL) was added at 0° C. to a solution of 2-hydroxy-5-[(R)-1-(tetrahydrofuran-2-yl)methoxy]-indan-1-one (581 mg) in water/THF 1:1 (12 mL) and the solution was stirred at 0° C. for 1 h. After adding water it was extracted with ether, dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC. In this way the product was obtained with molecular weight 264.28 (C14H16O5); MS (ESI): 265 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].C(O)(=[O:13])C>>[CH3:9][C:5]1[C:6](=[O:13])[C:7]([CH3:8])=[C:2]([CH3:1])[C:3](=[O:10])[CH:4]=1
Reactant: CC(=O)O
Reactant: Cc1cc(C)c(C)c(O)c1
Product: CC1=CC(=O)C(C)=C(C)C1=O
Yield: 51 %

Procedure:
500 mg of 2,3,5-trimethylphenol and 10 mg of RuCl3.3H2O was reacted in 5 ml of acetic acid in the same manner as in Example 1, followed by the same treatment as in Example 1, whereby 100 mg of unreacted starting material and 230 mg (51% yield) of trimethylbenzoquinone was obtained.
Reaction SMILES: C1N(COCCO)[C:4]2NC(N)=[N:13][C:14](=O)[C:3]=2N=1.[CH:17]1[C:30]2C=CC3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[C:19](C(=NO)C)[CH:18]=1>>[CH:25]1[C:24]2[CH:23]=[CH:22][C:21]3[C:30](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:4]=2[CH:3]=[C:14]([NH2:13])[CH:26]=1
Reactant: CC(=NO)c1ccc2ccc3ccccc3c2c1
Reactant: Nc1nc(=O)c2ncn(COCCO)c2[nH]1
Product: Nc1ccc2ccc3ccccc3c2c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To 385 g of polyphosphoric acic at 100° C. was added 32 g (0.14 mol) of 1-(3-phenanthryl)ethanone oxime from Step 1 over 30 minutes. The mixture was stirred at 100° C. for 2 hrs, cooled down to room temperature followed by the addition of water/ice. Stirred 30 minutes, filtered and washed with water. This white solid was then placed in 500 mL of methanol and 40 mL of concentrated HCl. The reaction was refluxed overnight, cooled down to room temperature and concentrated down. A mixture of ethyl acetate/water was added to the residue and the resulting solution was made basic with 10 N KOH. The aqueous layer was extracted with ethyl acetate and combined organic layers were washed with water, brine, dried over sodium sulphate and volatiles were removed under reduced pressure to afford 25 g of 3-phenanthrylamine as a beige solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].CN1CCOCC1.[C:22]([N:30]1[C@@H:34]([CH3:35])[C:33](=O)[O:32]C1=O)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N[C@H](C(O)=O)C)(=O)C1C=CC=CC=1.Cl>O1CCCC1>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:33](=[O:32])[C@H:34]([CH3:35])[NH:30][C:22](=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C[C@H]1C(=O)OC(=O)N1C(=O)c1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: C[C@H](NC(=O)c1ccccc1)C(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)c1ccccc1
Reaction time: 0.33 h
Yield: 65 %

Procedure:
L-Phenylalanine methyl ester hydrochloride (518 mg, 2.4 mmol) was suspended in tetrahydrofuran (12 mL), and at 0° C., N-methylmorpholine (242 mg, 2.4 mmol) was added, followed by stirring for 20 minutes. (S)-3-Benzoyl-4-methyl-2,5-oxazolidinedione (N-benzoyl-L-alanine-NCA (438 mg, 2 mmol) was added as crystals at 0° C. After the resulting mixture was stirred for 15 minutes, the mixture was allowed to rise in temperature to room temperature, at which the mixture was stirred for 15 minutes. The reaction mixture was poured into 1 N hydrochloric acid (25 mL), followed by extraction with ethyl acetate (25 mL). The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate (25 mL) and a saturated aqueous solution of sodium chloride (25 mL), and was then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The resulting white solid was washed with hexane-ethyl acetate to afford the title compound (462 mg, 65%) as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][C:22]4[CH:30]=[CH:29][C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=4)[C:16]3=[O:31])=[CH:11][C:10]=2[CH3:32])=[N:6][CH:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[F:75][C:76]([F:87])([F:86])[C:77]1[CH:82]=[CH:81][C:80]([C:83](=[O:85])[CH3:84])=[CH:79][CH:78]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[BrH:1].[CH3:32][C:10]1[CH:11]=[C:12]([N:15]2[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][C:22]3[CH:30]=[CH:29][C:28]4[O:27][CH2:26][O:25][C:24]=4[CH:23]=3)[C:16]2=[O:31])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[CH:4]=[CH:3][C:2]([CH2:84][C:83](=[O:85])[C:80]2[CH:79]=[CH:78][C:77]([C:76]([F:75])([F:86])[F:87])=[CH:82][CH:81]=2)=[CH:7][N:6]=1
Reactant: Cc1cc(N2CCCN(Cc3ccc4c(c3)OCO4)C2=O)ccc1Oc1ccc(Br)cn1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: Br
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(N2CCCN(Cc3ccc4c(c3)OCO4)C2=O)ccc1Oc1ccc(CC(=O)c2ccc(C(F)(F)F)cc2)cn1
Reaction time: 0.08 h
Yield: 33.2 %

Procedure:
To a solution of 3-[4-(5-bromopyridin-2-yloxy)-3-methylphenyl]-1-piperonyltetrahydropyrimidin-2-one (0.11 g, 0.22 mmol) in toluene (10 mL) were added Pd2(dba)3 (10 mg, 0.01 mmol) and Xantphos (15 mg, 0.03 mmol) under a nitrogen atmosphere. The resulting solution was stirred for 5 minutes, and then 4′-(trifluoromethyl)acetophenone (63 mg, 0.33 mmol) and potassium bis(trimethylsilyl)amide (66 mg, 0.33 mmol) were added to the reaction solution. The resulting solution was stirred at 70 to 80° C. for 30 minutes, and left to cool. Water was added to the reaction solution, and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→1:1), to yield 50 mg of a free form. To this free form was added an equivalent amount of hydrobromic acid, to thereby yield 50 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([C:15]3([C:19]([NH:21]O)=O)[CH2:18][CH2:17][CH2:16]3)[NH:8][CH2:7][CH2:6][C:5]2=1.O1CCOCC1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([C:15]3([C:19]#[N:21])[CH2:18][CH2:17][CH2:16]3)[NH:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C(NO)C1(C2NCCc3c2[nH]c2ccc(Cl)cc32)CCC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: N#CC1(C2NCCc3c2[nH]c2ccc(Cl)cc32)CCC1

Procedure:
0.9 g of the compound obtained in Step B is stirred for 2 hours at ambient temperature in a solution of 10 ml of dioxane, 0.8 ml of pyridine and 0.42 ml of trifluoroacetic anhydride. After evaporating off the solvent, chromatography of the residue on silica gel (dichloromethane/ethyl acetate: 96/4) enables isolation of the expected product, which crystallises in heptane.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]([CH3:32])[C:11]2[N:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]3)=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:39][C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=1>CN(C=O)C>[F:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][C:2]2[N:7]=[CH:6][C:5]([C:8]([N:10]([CH3:32])[C:11]3[N:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]4)=[CH:13][CH:12]=3)=[O:9])=[CH:4][CH:3]=2)=[CH:42][CH:41]=1
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Cl)nc3)nc2)CCN1C(=O)OC(C)(C)C
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Oc4ccc(F)cc4)nc3)nc2)CCN1C(=O)OC(C)(C)C
Temperature: 130 °C
Yield: 33.3 %

Procedure:
To 1,1-dimethylethyl (2S)-4-({6-[[(6-chloro-3-pyridinyl)carbonyl](methyl)amino]-3-pyridinyl}methyl)-2-methyl-1-piperazinecarboxylate (D106) (0.139 g, 0.303 mmol) in DMF (4 mL) under an argon atmosphere was added potassium carbonate (0.293 g, 0.212 mmol) and 4-fluorophenol (0.169 g, 1.51 mmol). The reaction mixture was stirred and heated at 130° C. for 5 h then concentrated in vacuo. The residue was re-dissolved in DCM/water. The organic layer was washed with 2M NaOH solution and brine then dried (Na2SO4) and concentrated to give the crude product which was purified by column chromatography. Elution with EtOAc/DCM gave the title compound as a colourless oil (0.054 g). MS (ES): MH+ 536.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].[CH:13]1([CH2:16][NH2:17])[CH2:15][CH2:14]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:17][CH2:16][CH:13]2[CH2:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12]
Reactant: NCC1CC1
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Solvent: ClCCl
Product: O=S(=O)(NCC1CC1)c1ccc(Br)c(F)c1
Yield: 55.6 %

Procedure:
According to general procedure C, 4-Bromo-3-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and cyclopropylmethylamine (0.32 mL, 3.65 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-(cyclopropylmethyl)-3-fluorobenzenesulfonamide (0.25 g, 55%) was provided after purification. HRMS: calcd for C10H11BrFNO2S−H+, 305.96051; found (ESI, [M−H]−), 305.9603. HPLC purity 100.0% at 210-370 nm, 10.5 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.