Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[C:14]([C:19](Cl)=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:22][O:23][C:24](=[O:38])[CH2:25][C:26]1[S:27][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[NH2:37])=[CH:29][CH:30]=1>C(Cl)Cl.N1C=CC=CC=1>[CH3:22][O:23][C:24](=[O:38])[CH2:25][C:26]1[S:27][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[NH:37][C:19]([C:14]2[C:13]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:20])=[CH:29][CH:30]=1
Reactant: COc1cc(-c2ccccc2C(=O)Cl)cc(OC)c1OC
Reactant: COC(=O)Cc1ccc(-c2ccccc2N)s1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Cc1ccc(-c2ccccc2NC(=O)c2ccccc2-c2cc(OC)c(OC)c(OC)c2)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
Add a solution of 3′,4′,5′-Trimethoxy-biphenyl-2-carbonyl chloride (57) (0.18 mmol) in DCM (1.0 mL) to an ice cooled solution of [5-(2-Amino-phenyl)-thiophen-2-yl]-acetic acid methyl ester (36) (46 mg, 0.18 mmol) in anhydrous DCM (2.0 mL) and anhydrous pyridine (0.5 mL). Stir the reaction mixture for 1 h at 0° C. and additional 20 h at rt. Pour the reaction mixture into ice cooled 1M aqu. HCl, extract with EtOAc (2×) and DCM (2×), wash the combined organic layer with brine and dry with Na2SO4. Purify the crude product by preparative radial chromatography (silica gel, EtOAc/CyH 1+2) to obtain (5-{2-[(3′,4′,5′-Trimethoxy-biphenyl-2-carbonyl)-amino]-phenyl}-thiophen-2-yl)-acetic acid methyl ester (58) as a light brown solid (58 mg, 59%). 1H NMR (400 MHz, CDCl3): 3.70 (s, 3H); 3.76 (s, 6H); 3.78 (s, 2H); 3.80 (s, 3H); 6.29 (d, 1H, J=3.4 Hz); 6.60 (s, 2H); 6.75 (d, 1H, J=3.4 Hz); 7.07 (t, 1H, J=7.6 Hz); 7.23 (d, 1H, J=7.6 Hz); 7.31 (t, 1H, J=8.0 Hz); 7.37-7.43 (m, 2H); 7.48 (t, 1H, J=7.6 Hz); 7.52 (s, 1H); 7.69 (d, 1H, J=8.0 Hz); 8.45 (d, 1H, J=8.0 Hz).
Reaction SMILES: [Cl-].[Li+].[BH4-].[Na+].[C:5]([O:9][C:10]([NH:12][CH:13]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([F:27])[F:26])[CH:20]=1)[C:14](OCC)=[O:15])=[O:11])([CH3:8])([CH3:7])[CH3:6].Cl>C(O)C.O1CCCC1>[F:26][CH:25]([F:27])[C:21]1[CH:20]=[C:19]([CH:13]([NH:12][C:10](=[O:11])[O:9][C:5]([CH3:6])([CH3:8])[CH3:7])[CH2:14][OH:15])[CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)c1cccc(C(F)F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(CO)c1cccc(C(F)F)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
At RT, 11.97 mg (0.28 mmol) of lithium chloride and 10.68 mg (0.28 mmol) of sodium borohydride were stirred in 0.25 ml of ethanol for 15 min. Then the mixture was cooled to 0° C. and a solution of 62 mg (about 0.09 mmol, purity 49%) of the compound from Example 131A in 0.25 ml of tetrahydrofuran was added dropwise. The mixture was stirred overnight at RT. For work-up, it was cooled with ice-water and adjusted to a pH of 2 using 1M hydrochloric acid. The reaction mixture was purified by preparative HPLC [Method 20]. The product fraction was freed from the solvent on a rotary evaporator and dried in an HV. This gave 56 mg (about 45% purity, 93% of theory) of the title compound.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.C[O:14][C:15](=O)[C@H:16]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC(O)=O>C1COCC1>[C:18]([NH:17][C@@H:16]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:15](=[O:14])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COP(=O)(CC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1)OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
A solution of dimethyl methylphosphonate (3.06 mL, 28.27 mmol, 8.0 eq) in anhydrous THF (30 mL) was cooled to −78° C. and 2.5 N n-BuLi (2.66 mL, 28.60 mmol, 8.0 eq) was added dropwise. After addition, the solution was stirred at −78° C. for 30 min and then a solution of compound 1 (1.00 g, 3.53 mmol, 1.0 eq) in anhydrous THF (20 mL) was added slowly. The resulting mixture was stirred at −78° C. for 1 h and then at ambient temperature for 1 h. The solution was acidified with 10% AcOH (20 mL), extracted with EtOAc (3×50 mL). The extract was washed with 10% NaHCO3, brine, dried over anhydrous MgSO4 and evaporation of the solvent gave a crude residue, which was subjected to column chromatography on silica gel elution with 100% EtOAc afforded dimethyl [(3S)-3-[(N-benzoyl)amino]-2-oxo-4-phenyl-butyl]phosphonate 2 as a pale yellow oil (0.876 g, 66%): Rf 0.34 (EtOAc); 1H NMR (300 MHz, CDCl3) δH 3.10 (2H, m, —CH2Ph), 3.34 (2H, m, —CH2—), 3.69 and 3.73 (6H, 2xs, 2xOMe), 5.10 (1H, m, —CH—) and 7.18-7.82 (10H, m, Ar—H).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][S:8]([C:11]1[CH:19]=[CH:18]C(C(O)=O)=[CH:13][CH:12]=1)(=[O:10])=[O:9].CN(C)C=O>ClCCl>[Cl:7][S:8]([C:11]1[CH:19]=[CH:18][C:1]([C:2]([Cl:4])=[O:3])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Oxalyl chloride (2.2 mL) was added to a mixture of 4-(chlorosulfonyl)benzoic acid (0.662 g, 3.0 mmol) in anhydrous dichloromethane (25 mL) followed by one small drop of N,N-dimethylformamide. The mixture was stirred at room temperature overnight. Then the mixture was then concentrated to provide 4-(chlorosulfonyl)benzoyl chloride which was used without additional purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH3:12])[CH:6]=[C:5]2[CH:13]([CH3:17])[C:14](O)=[O:15].C[N:21](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH4+].[Cl-].CCN(C(C)C)C(C)C>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH3:12])[CH:6]=[C:5]2[CH:13]([CH3:17])[C:14]([NH2:21])=[O:15]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1c(Br)cc(F)c2c1c(C(C)C(=O)O)cn2C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1c(Br)cc(F)c2c1c(C(C)C(N)=O)cn2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
To the solution of 9-3 (150 mg, 0.45 mmol), HATU (260 mg, 0.68 mmol) and NH4Cl (26 mg, 0.49 mmol) in THF (10 mL) was added DIPEA (147 mg, 0.57 mmol) at 0° C. The mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate (30 mL) and washed with brine twice. The combined organic layers were dried over anhydrous sodium sulfate. After filtration and concentration, the obtained residue was purified by flash chromatography (Silica gel, DCM:MeOH) to afford 9-4 (90 mg, 84%) as yellow oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([OH:18])[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[C:19]1([N:25]=[C:26]=[S:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[CH3:1][N:2]([CH2:3][CH:4]([OH:18])[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2)[C:26]([NH:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[S:27]
Reactant: CNCC(O)COc1ccc2[nH]c(=O)ccc2c1
Reactant: S=C=Nc1ccccc1
Solvent: CCO
Product: CN(CC(O)COc1ccc2[nH]c(=O)ccc2c1)C(=S)Nc1ccccc1
Reaction time: 1 h

Procedure:
To a suspension of 6-(3-methylamino-2-hydroxypropoxy)carbostyril (0.7 g) in ethanol (10 ml) is added phenylisothiocyanate (0.35 ml) at room temperature, and the mixture is stirred at the same temperature for 1 hour. The insoluble product is collected by filtration and recrystallized from chloroform-methanol to give 6-[3-(1-methyl-3-phenylthioureido)-2-hydroxypropoxy]carbostyril (0.83 g), as white powder, m.p. 185.0°-186.5° C. (decomp.).
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[CH3:13])[CH2:3][CH2:4][CH3:5].[CH:14]1([C:19](Cl)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15]1>CN(C1C=CN=CC=1)C>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[CH:13]\[C:19]([CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:20])[CH2:3][CH2:4][CH3:5]
Reactant: O=C(Cl)C1CCCC1
Reactant: CCCC[n+]1c(C)sc(C)c1C
Agent: CN(C)c1ccncc1
Agent: [I-]
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by cyclopentanecarbonyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.88-0.97 (m, 3 H) 1.30-1.39 (m, 2 H) 1.51-1.62 (m, 4 H) 1.62-1.70 (m, 3 H) 1.77-1.87 (m, 2 H) 2.16-2.26 (m, 5 H) 2.73-2.86 (m, 1 H) 3.71-3.83 (m, 4 H) 5.84-5.94 (m, 1 H); MS (ESI) m/z 280 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Br[CH2:22][C:23]1[O:24][CH:25]=[CH:26][C:27]=1[C:28]([O:30][CH3:31])=[O:29]>>[CH3:31][O:30][C:28]([C:27]1[CH:26]=[CH:25][O:24][C:23]=1[CH2:22][N:8]1[C:9]([S:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19])=[O:29]
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: COC(=O)c1ccoc1CBr
Product: COC(=O)c1ccoc1Cn1c(Sc2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O
Yield: 33.7 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 2-bromomethyl-3-methoxycarbonylfurane were reacted by the same way with the example 1 to obtain the titled compound (139 mg, yield: 33.7%).
Reaction SMILES: C([Li])CCC.[Br-].[C:7]1([CH2:13][CH2:14][CH2:15][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(OC([N:42]1[CH2:47][CH2:46][C:45](=O)[CH2:44][CH2:43]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C1COCC1.ClCCl.O>[C:7]1([CH2:13][CH2:14][CH:15]=[C:45]2[CH2:46][CH2:47][NH:42][CH2:43][CH2:44]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: c1ccc(CCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: C(CCc1ccccc1)=C1CCNCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
n-Butyl lithium (2.5M in hexanes, 14 ml, 35 mmol) was carefully added to a cold (<0° C.) suspension of 3-phenylpropyltriphenylphosphonium bromide (18.7 g, 40.5 mmol) in THF (100 ml) under a nitrogen atmosphere at such a rate that the temperature did not exceed 0° C. The orange solution was stirred at <0° C. for 30 minutes before a solution of 1-(tert-butyloxycarbonyl)-4-piperidone (5.0 g, 27 mmol) was added as a solution in THF (20 ml) at such a rate that the temperature did not exceed 0° C. The mixture was stirred at 0° C. for 1 hour and then allowed to warm to room temperature before adding water (20 ml). The mixture was concentrated in vacuo and the residue extracted into dichloromethane (3×100 ml). The combined organics were washed with water (20 ml) and brine (20 ml), dried (MgSO4) and evaporated in vacuo to give a yellow oil. The oil was purified by column chromatography on silica eluting with 10% EtOAc/petrol 60/80 to give a clear oil. The oil was dissolved in dichloromethane (30 ml) and treated with trifluoroacetic acid (20 ml) and the mixture stirred at room temperature for 1.5 h. The solution was evaporated in vacuo and azeotroped with toluene (2×10 ml). The residue was dissolved in EtOAc (20 ml) and washed with sodium carbonate (saturated, 2×10 ml), water (10 ml) and brine (10 ml), dried (MgSO4) and evaporated in vacuo to give 4-(3-phenylpropylidene) piperidine as a pale oily solid (4.92 g, 90%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:26])([CH3:25])[CH2:9][NH:10][C:11]2[N:16]=[N:15][C:14]([C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[N:13][CH:12]=2)=[CH:4][CH:3]=1.C([O-])([O-])=[O:28].[K+].[K+].OO>CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:26])([CH3:25])[CH2:9][NH:10][C:11]2[N:16]=[N:15][C:14]([C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]([NH2:21])=[O:28])=[N:13][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(CNc1cnc(-c2cccc(C#N)c2)nn1)c1ccc(F)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(CNc1cnc(-c2cccc(C(N)=O)c2)nn1)c1ccc(F)cc1
Reaction time: 24 h
Yield: 7.8 %

Procedure:
To a solution of 3-(6-(2-(4-fluorophenyl)-2-methylpropylamino)-1,2,4-triazin-3-yl)benzonitrile (220 mg, 0.60 mmol) in DMSO (3.0 mL) was added K2CO3 (300 mg, 2.2 mmol) and 30% hydrogen peroxide (0.60 mL, 7.5 mmol). The mixture was stirred 24 h and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2×) and the combined organics were dried over Na2SO4 and evaporated to dryness in vacuo. Purification using silica gel chromatography (0-100% EtOAc/hexanes) gave the desired product (17 mg), m/z=366.1 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:9][CH2:10][O:11][CH2:12][CH2:13]O)=[CH:4][CH:3]=1.C([Li])CCC.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[NH:38]1[CH2:43][CH2:42][CH2:41][C@@H:40]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:39]1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH2:47]([O:46][C:44]([C@@H:40]1[CH2:41][CH2:42][CH2:43][N:38]([CH2:13][CH2:12][O:11][CH2:10][CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:39]1)=[O:45])[CH3:48]
Reactant: OCCOCC=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CCOC(=O)[C@@H]1CCCNC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CCCN(CCOCC=C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 10.7 %

Procedure:
A solution of 2-(3,3-bis(4-chlorophenyl)-2-propen-1-yloxy)ethanol (4.0 g, 12.4 mmol) in dry THF (25 ml) kept under a nitrogen atmosphere was cooled to 10° C. and a solution of n-butyllithium in hexanes (5.4 ml, 2.5 M) was added dropwise. The reaction mixture was stirred for 15 minutes at room temperature and p-toluenesulphonyl chloride (2.6 g, 13.8 mmol) was added. The mixture was stirred at room temperature for 1 h. Ethyl (R)-3-piperidinecarboxylate (1.9 g, 12.1 mmol) and potassium carbonate (3.4 g, 24.6 mmol) were added and the mixture was heated at reflux temperature for 18 h. To the cooled reaction mixture THF (50 ml) was added. The mixture was filtered and the solvent evaporated in vacuo. Flash chromatography of the residue on silica gel (100 g) using a mixture of n-heptane and ethyl acetate (3:2) as eluent provided 0.6 g (11%) of the title compound as an oil. 1H NMR (CDCl3)δ 4.02 (d, 2H); 6.20 (t, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][OH:15])=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]([C:20]1[N:21]([CH3:26])[N:22]=[C:23](O)[CH:24]=1)=[O:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:23]2[CH:24]=[C:20]([C:18]([O:17][CH3:16])=[O:19])[N:21]([CH3:26])[N:22]=2)=[CH:6][CH:7]=1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1CO
Reactant: COC(=O)c1cc(O)nn1C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)nnn2C)nn1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a solution of [5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-methanol (290 mg, 1.4 mmol) in THF (30 mL) was added 5-hydroxy-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (218 mg, 1.4 mmol) and triphenylphosphine (477 mg, 1.82 mmol) at ambient temperature under an argon atmosphere. Then diethyl azodicarboxylate (641 μL, 3.5 mmol) was added and the reaction mixture was stirred for 16 h at room temperature. Concentration and purification by chromatography (silica, 20 to 50% ethyl acetate in heptane) afforded the title compound (483 mg, 100%) as a white solid. MS: m/e=346.2 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1>>[N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH:23][C:35]([NH:34][C:31]4[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=4)=[O:36])=[CH:21][CH:20]=3)[N:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: COc1ccc(N=C=O)cc1
Product: COc1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)nc(N4CCOCC4)n3)cc2)cc1

Procedure:
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140 g 0.40 mmoles) and 4-methoxyphenyl isocyanate (91 mg, 0.63 mmoles) the title compound was isolated as a white solid. Yield; 48 mg (24%); (M+H)=492.3
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([O:12][CH2:13][CH2:14][C:15]2([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:20][CH2:19][N:18]([C:21]3[S:22][C:23]([Br:26])=[CH:24][N:25]=3)[CH2:17][CH2:16]2)[CH:6]=1.[OH-].[Na+].O1CCCC1.CO>O>[Br:26][C:23]1[S:22][C:21]([N:18]2[CH2:19][CH2:20][C:15]([CH2:14][CH2:13][O:12][C:7]3[CH:6]=[C:5]([CH2:4][C:3]([OH:32])=[O:2])[CH:10]=[C:9]([Cl:11])[CH:8]=3)([N:27]3[CH2:28][CH2:29][CH2:30][CH2:31]3)[CH2:16][CH2:17]2)=[N:25][CH:24]=1
Reactant: COC(=O)Cc1cc(Cl)cc(OCCC2(N3CCCC3)CCN(c3ncc(Br)s3)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)Cc1cc(Cl)cc(OCCC2(N3CCCC3)CCN(c3ncc(Br)s3)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.8 %

Procedure:
A mixture of [3-[2-[1-(5-bromothiazole-2-yl)-4-pyrrolidine-1-ylpiperidine-4-yl]ethoxy]-5-chlorophenyl]acetic acid methyl ester (1.45 g), 2N sodium hydroxide (3.3 mL), tetrahydrofuran (15 mL) and methanol (15 mL) was stirred at room temperature for 3 hours. To the reaction solution was added water and washed with chloroform. The water layer was neutralized with 2N hydrochloric acid and extracted with chloroform. The organic layer was washed with water and brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (916 mg). Yield: 65%.
Reaction SMILES: C([Li])CCC.[CH2:6]([S:8]([O:11][CH2:12][CH3:13])(=[O:10])=[O:9])[CH3:7].P(Cl)(OCC)(OCC)=O.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>C1COCC1.O>[Cl:23][C:24]1[CH:31]=[CH:30][C:27](/[CH:28]=[C:6](/[S:8]([O:11][CH2:12][CH3:13])(=[O:10])=[O:9])\[CH3:7])=[CH:26][CH:25]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCOS(=O)(=O)CC
Agent: CCOP(=O)(Cl)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOS(=O)(=O)/C(C)=C/c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57.5 %

Procedure:
n-Butyllithium (35.0 mL, 1.6M solution in hexanes) was added dropwise during 25 min to a solution of ethyl ethanesulfonate (6.9 g, 50 mmol) (Synth. Comm. 1985, 15, 1057) in THF (100 mL) at −78° C. The reaction mixture was stirred for 15 min then diethyl chlorophosphate (4.35 ml, 30 mmol) was added dropwise. The solution was stirred at −78° C. for 30 min, allowed to warm to 0° C. and then cooled to −78° C. again. 4-Chlorobenzaldehyde (4.2 g, 30 mmol) in THF (30 mL) was then added dropwise during 15 minutes and the resulting mixture was stirred for 1 h at −78° C. and then allowed to slowly reach RT. Water (10 mL) was added to the mixture and the mixture was concentrated in vacuo. The residue was extracted with diethyl ether and the combined organic extracts were washed with aqueous saturated sodium chloride, dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo. Purification by column chromatography, using a gradient of 10% ethyl acetate/hexanes to 15% ethyl acetate/hexanes as eluent, afforded the title compound (4.5 g, 58%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]Cl)([CH3:4])([CH3:3])[CH3:2].NC(N)=[S:15].[OH-].[Na+]>O>[C:1]([O:5][CH:6]([SH:15])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC(N)=S
Reactant: CC(C)(C)OCCCCCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCC(S)OC(C)(C)C
Temperature: 120 °C
Yield: 76.9 %

Procedure:
After 73.2 g of 1-tert-butoxy-6-chlorohexane (0.38 mol), 38 g of thiourea (0.5 mol), and 30 ml of distilled water were put into a 500 ml two-necked flask equipped with a condenser and refluxed at 120° C. for 5 hours, a temperature was cooled to room temperature, and 300 ml of a previously prepared aqueous solution of NaOH (30 g) was added thereto and refluxed at 110° C. for 14 hours. The reactant was cooled to room temperature, the formed organic layer was extracted with ether and dried over MgSO4, and then the solvent was removed under reduced pressure, thereby obtaining 55.6 g of an oily product (6-tert-butoxyhexane-1-thiol, yield 76.9 mol %). Purity of the product confirmed through gas chromatography (GC) analysis was 97%, and results of proton nuclear magnetic resonance (1H-NMR) spectroscopy were as follows.
Reaction SMILES: [CH2:1]([O:8][C:9]1([C:22](=[O:36])[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31](=[O:35])[N:32]([CH3:34])[CH3:33])[CH:25]=2)[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO>[CH3:33][N:32]([CH3:34])[C:31](=[O:35])[O:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([NH:23][C:22]([C:9]2([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:36])[CH:25]=1
Reactant: CN(C)C(=O)Oc1cccc(NC(=O)C2(OCc3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: CO
Product: CN(C)C(=O)Oc1cccc(NC(=O)C2(OCc3ccccc3)CCNCC2)c1
Temperature: 50 °C

Procedure:
To a solution of tert-butyl 4-(benzyloxy)-4-(3-(dimethylcarbamoyloxy)-phenylcarbamoyl)piperidine-1-carboxylate from step D (400 mg, 0.804 mmol) in methanol (4 mL) was added HCl (4 M solution in dioxane, 0.8 mL). The reaction was heated at 50° C. for 1 hour, and then concentrated under vacuum to provide the title compound as the hydrochloride salt. MS (ES+) [M+H]+=398.4.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[N:6][CH:7]=1.[Cl:14][CH:15]([Cl:34])[C:16]([NH:18][C@H:19]([CH2:32][F:33])[C@H:20]([OH:31])[C:21]1[CH:26]=[CH:25][C:24]([Sn](C)(C)C)=[CH:23][CH:22]=1)=[O:17].[Cl-].[Li+]>>[Cl:14][CH:15]([Cl:34])[C:16]([NH:18][C@H:19]([CH2:32][F:33])[C@H:20]([OH:31])[C:21]1[CH:22]=[CH:23][C:24]([C:2]2[CH:7]=[N:6][C:5]([CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:4][CH:3]=2)=[CH:25][CH:26]=1)=[O:17]
Reactant: CS(=O)(=O)NCc1ccc(Br)cn1
Reactant: C[Sn](C)(C)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Agent: [Cl-]
Agent: [Li+]
Product: CS(=O)(=O)NCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cn1
Temperature: 100 °C

Procedure:
N-((5-bromopyridin-2-yl)methyl)methanesulfonamide (previously described in WO9528400) (240 mg, 0.90 mmol) and 2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(trimethylstannyl)phenyl)propan-2-yl)acetamide (400 mg, 0.90 mmol) in 2-methylpyrrolidinone (5 mL) are treated with lithium chloride (115 mg, 2.7 mmol) and degassed and purged with nitrogen. Bis(triphenylphosphine)-palladium(ii) chloride is added and the mixture heated at 100° C. for 3 hours. The mixture is cooled, diluted with water and extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated and purified by reverse phase chromatography to give the title compound (324 mg): 1H NMR (400 MHz, CDCl3) δ: 2.96 (s, 3H), 4.2-4.3 (m, 3H), 4.4 (m, 0.5H), 4.57 (m, 0.5H), 4.58 (m, 0.5H), 4.70 (m, 0.5H), 4.90 (bs, 1H), 6.00 (s, 1H), 6.52 (s, 1H), 7.47 (d, 2H), 7.52, (d, 1H), 7.69 (d, 3H), 8.1 (m, 1H), 8.85 (m, 1H), 8.82 (bs, 1H). m/z (CI) 464.