Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:22]([O:25][CH2:26][C:27](Cl)=[O:28])(=[O:24])[CH3:23].O>C(Cl)Cl>[C:22]([O:25][CH2:26][C:27]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:3]=1[C:4]#[N:5])=[O:28])(=[O:24])[CH3:23]
Reactant: N#Cc1c(N)cccc1N1CCCCC1
Reactant: CC(=O)OCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCC(=O)Nc1cccc(N2CCCCC2)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-6-piperidinobenzonitrile (8.8 g) in methylene chloride (100 ml) is added pyridine (3.3 ml), and thereto is added dropwise acetoxyacetyl chloride (4.3 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 1 hour, and thereafter, water is added thereto, and the mixture is extracted with methylene chloride. The organic layer is dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The resulting crude crystals are recrystallized from ethyl acetate-hexane to give the title compound (3.2 g) having the following physical properties.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[C:7]([OH:11])([CH3:10])([CH3:9])[CH3:8].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:27][C:26]3[C:25](=[O:28])[N:24]([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]([OH:40])([CH3:39])[CH3:38])=[C:31]([O:41][CH3:42])[CH:30]=4)[CH:23]=[N:22][C:21]=3[CH:20]=2)=[CH:15][CH:14]=1.COC1C=C([N+]([O-])=O)C=CC=1OCC(C)(O)C.N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])(=[O:5])[C:2]([O:40][C:37]([CH3:39])([CH3:38])[CH2:36][O:35][C:32]1[CH:33]=[CH:34][C:29]([N:24]2[C:25](=[O:28])[C:26]3[S:27][C:19]([C:16]4[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=4)=[CH:20][C:21]=3[N:22]=[CH:23]2)=[CH:30][C:31]=1[O:41][CH3:42])=[O:3]
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC(C)(C)O
Reactant: CC(C)(C)O
Reactant: O=C(Cl)C(=O)Cl
Agent: COc1cc([N+](=O)[O-])ccc1OCC(C)(C)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC(C)(C)OC(=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.7 %

Procedure:
To oxalyl chloride (0.50 mL; 5.91 mmol) cooled to 0° C. was added t-butanol (0.28 mL; 2.95 mmol) over 30 min. After warming the solution to rt and concentration under reduced pressure, the residue was dissolved in 1 mL of CH2Cl2 whereupon 6-(4-chlorophenyl)-3-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)thieno[3,2-d]-pyrimidin-4(3H)-one (100 mg; 0.219 mmol) (the product of Example 82) and pyridine (42 uL; 0.522 mmol) were added. After the suspension was stirred at rt for 1.5 h, the solution was diluted with CH2Cl2, washed with 1N HCl and brine, dried over anhydrous MgSO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, Hexanes/EtOAc; 100:0 to 1:1 gradient) to afford 120 mg (94%) of the title compound as a white foam. 1H NMR (CDCl3) δ 1.55 (s, 9H), 1.70 (s, 6H), 3.87 (s, 3H), 4.24 (s, 2H), 6.92 (dd, J=8.25 Hz, 2.20 Hz, 1H), 6.96 (d, J=2.20 Hz, 1H), 7.04 (d, J=8.24 Hz, 1H), 7.44 (d, J=8.79 Hz, 2H), 7.53 (s, 1H), 7.65 (d, J=8.79 Hz, 2H), 8.13 (s, 1H); 13C NMR (CDCl3) δ 23.14, 27.74, 56.36, 74.39, 84.26, 84.51, 111.76, 115.30, 119.27, 120.84, 123.22, 127.65, 129.47, 130.78, 131.54, 135.67, 148.19, 149.25, 150.64, 151.63, 156.77, 157.22, 157.35, 157.60; HPLC (Method #1) 4.40 min retention time, (100%); MS (ES): m/z 585 [M+H]+.
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([OH:10])[CH2:5]1)[CH:2]=[CH2:3].[H-].[Na+].I[CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=2)[O:18][C:19]=1[CH3:20].CCOCC>CN(C)C=O>[CH2:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([O:10][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=3)[O:18][C:19]=2[CH3:20])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: Cc1cccc(-c2nc(CI)c(C)o2)c1
Reactant: C=CC[C@@H]1CCC[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CC[C@@H]1CCC[C@H](OCc2nc(-c3cccc(C)c3)oc2C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2 g of cis-3-allylcyclohexanol are dissolved in 30 ml of dimethylformamide, and 750 mg of sodium hydride (60% strength suspension in paraffin oil) are added. After 30 minutes, 6.7 g of 4-iodomethyl-5-methyl-2-(3-methylphenyl)oxazole, dissolved in 20 ml of dimethylformamide, are added dropwise. The mixture is stirred at room temperature for 1 hour. 200 ml of methy tert-buthyl ether are then added to the reaction mixture, and the mixture is washed three times with water. The organic phase is dried over magnesium sulfate and the solvent is then removed under reduced pressure. The residue is purified by RP-HPLC. This gives 1.56 g of 4-(cis-3-allylcyclohexyloxymethyl)-2-(3-methylphenyl)-5-methyloxazole as an oil. C21H27NO2 (325.45), MS (ESI): 326 (M+H+), Rf(n-heptane:ethylacetate=2:1)=0.28.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[N:3]1.N(C[CH2:34][N:35]([CH3:37])[CH3:36])N>>[CH3:34][N:35]([CH3:37])[CH2:36][CH2:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[N:3]1
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Reactant: CN(C)CCNN
Product: CN(C)CCn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Methyl-4-pyridin4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting (2-hydrazino-ethyl)-dimethyl-amine provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.44 (dd, J=4.6, 1.7, Hz, 2 H), 8.18 (d, J=8.3 Hz, 1 H), 8.06 (d, J=8.3 Hz, 1H), 7.82 (d, J=8.7 Hz, 1 H), 7.71 (m 2H), 7.55 (t, J=7.1 Hz, 1H), 7.38 (d, J=8.7 Hz, 2H), 7.15 (d, J=6.2 Hz, 2H) 7.00 (d, J=8.7 Hz, 2H), 5.38 (s, 2H), 4.25 (t, J=6.6 Hz, 2H), 2.82 (t, J=6.6 Hz, 2H), 2.28 (s, 6H); MS: (M+H m/z=450.4).
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][OH:7].Cl[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10].[OH-].[Na+]>>[OH:7][NH:6][C:9](=[O:10])[O:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: NO
Reactant: CCCCOC(=O)Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCCOC(=O)NO

Procedure:
DE3245503 discloses a process for producing methoxymethylamine via butyl N,O-dimethylcarbamate as an intermediate. According to this prior art process, the starting material hydroxylamine sulfate is allowed to react with butyl chloroformate in the presence of sodium hydroxide to form butyl hydroxycarbamate which is then subjected to the steps of extraction with dichloromethane and of drying, and after the solvent is distilled off, said butyl hydroxycarbamate is dimethylated with dimethyl sulfate in an aqueous solution of sodium hydroxide, followed by hydrolysis with hydrochloric acid, whereby methoxymethylamine hydrochloride is obtained in 65% yield.
Reaction SMILES: C[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:12]=[C:13]([C:17]([O:19][CH3:20])=[S:18])[S:14][C:15]=2[CH3:16])=[CH:6][CH:5]=1)C.N[C:22]1C=C(C(OC)=S)S[C:26]=1C.C(C1C=CC(B(O)O)=CC=1)(C)C>>[CH3:2][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[CH:12]=[C:13]([C:17]([O:19][CH3:20])=[S:18])[S:14][C:15]=2[CH3:16])=[C:8]([CH2:22][CH3:26])[CH:9]=1
Reactant: COC(=S)c1cc(N)c(C)s1
Reactant: COC(=S)c1cc(Nc2ccc(C(C)C)cc2)c(C)s1
Agent: CC(C)c1ccc(B(O)O)cc1
Product: CCc1cc(C)ccc1Nc1cc(C(=S)OC)sc1C
Yield: 12.5 %

Procedure:
Methyl 4-{[4-(methylethyl)phenyl]amino}-5-methylthiothiophene-2-carboxylate: Using a procedure similar to Example 208, step (a), 74.4 mg (0.36 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate was allowed to react with 118 mg (2 equiv, 0.72 mmol) of 4-isopropylphenyl boronic acid to give 14.5 mg (12.5%) of methyl 4-[(4-methylethylphenyl)amino]-5-methylthiothiophene-2-carboxylate. 1H NMR (CDCl3, 400 MHz) δ 1.26 (d, 6H, J=6.2 Hz), 2.39 (s, 3H), 2.89 (m, 1H), 3.89 (s, 3H), 6.98-7.01 (m, 2H), 7.17-7.19 (m, 2H), 7.73 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:22]=[CH:21][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[O:12])=[CH:9][C:8]=2[N+:23]([O-:25])=[O:24])=[CH:4][CH:3]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:11](=[O:12])[C:10]2[CH:21]=[CH:22][C:7]([O:6][C:5]3[CH:26]=[CH:27][C:2]([NH:1][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:3][CH:4]=3)=[C:8]([N+:23]([O-:25])=[O:24])[CH:9]=2)=[CH:15][CH:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(Oc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(Oc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 97.6 %

Procedure:
The product of Example 91A (195 mg, 0.4554 mmol) was dissolved in anhydrous pyridine (5 mL) under a nitrogen atmosphere, treated with methanesulfonyl chloride (0.106 mL, 1.366 mmol), and stirred at room temperature for 19 hours. The solvent was removed by rotary evaporation under vacuum, and the residue dissolved in ethyl acetate (100 mL) and washed with 1N aqueous hydrochloric acid (2×50 mL), water (50 mL), and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford the title compound as a light orange solid (225 mg, 98%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]([OH:11])=[O:10])[C:3]=1[Cl:12].[B-](F)(F)(F)[F:14].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>O>[NH2:1][C:2]1[C:7]([F:14])=[C:6]([Cl:8])[N:5]=[C:4]([C:9]([OH:11])=[O:10])[C:3]=1[Cl:12]
Reactant: Nc1cc(Cl)nc(C(=O)O)c1Cl
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: O
Product: Nc1c(F)c(Cl)nc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.5 %

Procedure:
A solution of 4-amino-3,6-dichloropyridine-2-carboxylic acid (1100 g, 5.31 mol), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (2100 g, 5.93 mol) in water (6000 mL) was warmed to 65° C. for six hours. After cooling to ambient temperature, the reaction mixture was stirred an additional 18 hours. The solution was concentrated and the resulting solid washed with 6 N hydrochloric acid (5×1000 mL) and dried to give 4-amino-3,6-dichloro-5-fluoropyridine-2-carboxylic acid (757 g, 3.53 mol. 58% purity). This crude material was added to methanol (3000 mL) which had been saturated with anhydrous hydrogen chloride and the reaction mixture was warmed to 45° C. for 2 hours. The solution was added with vigorous stirring to ice water (4000 mL) and the resulting solid collected. The crude ester was dissolved in ethyl acetate (1000 mL) and washed with saturated sodium bicarbonate solution (2×1000 mL), dried, and concentrated. The resulting solid was recrystallized from ethyl acetate/hexanes to give methyl 4-amino-3,6-dichloro-5-fluoropyridine-2-carboxylate (402.5 g, 1.67 mol), mp 128-131° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].[F:11][C:12]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:13]=1[CH2:14]Br>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:14][C:13]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:12]=2[F:11])=[CH:4][CH:3]=1
Reactant: Fc1ccc(F)c(CBr)c1
Reactant: Sc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1ccc(F)c(CSc2ccc(Cl)cc2)c1
Yield: 99.3 %

Procedure:
4-Chlorothiophenol (253 g, 1.75 mol) was dissolved in industrial methylated spirits (1265 mL) and 2M sodium hydroxide solution (901 mL) was added, maintaining the temperature below 20° C. A solution of 2,5-difluorobenzyl bromide (355 g, 1.72 mol) in industrial methylated spirits (250 mL) was added dropwise to the thiolate solution, maintaining the temperature below 15° C. Upon completion of the reaction, water (1000 mL) was added. The resulting slurry was aged at 5° C. and then filtered. The cake was washed sequentially with cold industrial methylated spirits: water (40:60) and then water (500 mL). Drying in vacuo at ambient temperature furnished 2-[[(4-chlorophenyl)thio]methyl]-1,4-difluorobenzene (462.3 g, 99.6%). 1H NMR (CDCl3)—as obtained for the corresponding intermediate of Method (a).
Reaction SMILES: Cl.C(OC(=O)[C:6]1[CH:11]=[CH:10][C:9]([NH:12]N)=[CH:8][CH:7]=1)C.CO[CH:17](OC)[CH2:18]CCCl>C(O)C.O>[NH:12]1[C:9]2[C:10](=[CH:11][CH:6]=[CH:7][CH:8]=2)[CH:18]=[CH:17]1
Reactant: COC(CCCCl)OC
Reactant: CCOC(=O)c1ccc(NN)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: c1ccc2[nH]ccc2c1
Yield: 68.5 %

Procedure:
A solution of ethyl-p-hydrazinobenzoate hydrochloride (10 g, 46 mmol) and 4-chlorobutanal dimethyl acetal (7.8 g, 46 mmol) in ethanol/water (5:1, 500 ml) was heated at reflux for 2 h. The solvent was removed under vacuum and the residue chromatographed through silica-gel eluting with dichloromethane/ethanol/ammonia (40:8:1) to give the title-indole as an oil (3.69 g). The hydrogen maleate salt was prepared, mp 127° C.; (Found: C, 59.46; H, 5.96; N, 8.47. C13H16N2O2.C4H4O4 requires C, 59.68; H, 5.93; N, 8.54%), m/e 232 (M+), δ(360 MHz, D2O) 1.43 (3H, t, J=7.1 Hz, Me); 3.21 (2H, t, J=7.0 Hz, CH2); 3.37 (2H, t, J=7.0 Hz, CH2); 4.42 (2H, q, J=7.1 Hz, CH2); 6.23 (2H, s, maleate-H); 7.40 (1H, s, indole-H); 7.56 (1H, d, J=8.8 Hz, aromatic-H); 7.88 (1H, dd, J=1.6 and 8.8 Hz, aromatic-H); 8.38 (1H, d, J=1.6 Hz, aromatic-H).
Reaction SMILES: C1([O:7][C:8](=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.Cl.Cl.Cl.[CH3:53][N:54]1[CH2:57][CH:56]([N:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)[CH2:55]1.C(N(CC)CC)C>CN(C)C=O>[F:48][C:27]1[CH:28]=[C:29]([NH:32][C:33]([C:35]2([C:38]([NH:39][C:40]3[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=3)=[O:47])[CH2:36][CH2:37]2)=[O:34])[CH:30]=[CH:31][C:26]=1[O:25][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([NH:9][C:8]([N:61]2[CH2:62][CH2:63][N:58]([CH:56]3[CH2:57][N:54]([CH3:53])[CH2:55]3)[CH2:59][CH2:60]2)=[O:7])[CH:24]=1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Reactant: CN1CC(N2CCNCC2)C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CC(N2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)Nc6ccc(F)cc6)CC5)cc4F)ccn3)CC2)C1
Reaction time: 25 h
Yield: 33.6 %

Procedure:
To a solution of [4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (66 mg) in N,N-dimethylformamide (1.0 ml) were added 1-(1-methylazetidin-3-yl)piperazine trihydrochloride (106 mg) and triethylamine (0.167 ml) at room temperature, followed by stirring for 25 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (20.2 mg, 33%).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:13]=[N:14][C:15]([NH:18][CH3:19])=[CH:16][CH:17]=2)=[O:11])=[CH:6][CH:5]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[Br:1][C:16]1[CH:17]=[C:12]([C:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)=[O:11])[CH:13]=[N:14][C:15]=1[NH:18][CH3:19]
Reactant: BrBr
Reactant: CNc1ccc(C(=O)c2ccc(Cl)cc2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CNc1ncc(C(=O)c2ccc(Cl)cc2)cc1Br
Reaction time: 1 h
Yield: 61.8 %

Procedure:
A solution of bromine (2.29 mL, 44.70 mmol) in acetic acid (30 mL) was added to a solution of compound C (11.0 g, 44.7 mmol) in acetic acid (80 mL) at RT. The mixture was stirred for 1 h, neutralized by the addition of saturated NaHCO3 solution and extracted with ethyl acetate (200 mL). The organic layer was washed with 10% sodium thiosulfate solution, water and brine. The organic layer was dried (Na2SO4), filtered and evaporated. The crude product was purified using column chromatography to obtain 9.0 g (62%) of compound D as viscous light yellow colored oil.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[NH:18][C:6]2[N:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]=[C:10](O)[C:5]=2[CH:4]=1.P(Cl)(Cl)([Cl:21])=O>O>[ClH:21].[Cl:1][C:10]1[C:5]2[CH:4]=[C:3]([CH3:2])[NH:18][C:6]=2[N:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc2c(O)nc(-c3ccccc3)nc2[nH]1
Agent: Cl
Solvent: O
Product: Cc1cc2c(Cl)nc(-c3ccccc3)nc2[nH]1
Temperature: 25 °C
Yield: 97 %

Procedure:
A heterogeneous mixture of 4 (4.0 g, 17.76 mmol) and phosphorus oxychloride (125 mL) was heated to reflux. After 14 h the homogeneous solution was cooled to room temperature and concentrated in vacuo yielding a black oil. Water was added to the oil and the mixture was warmed. The resulting solid was filtered, washed with water and dried at room temperature to yield 4.22 g of a brown solid (97%). 1H NMR (200 MHz, DMSO-d6): δ 2.43 (s, 3H), 6.31 (s, 1H), 7.49 (m, 3H), 8.34 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:44])[N:5]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]#[C:39][Si](C)(C)C)[CH:33]=1)[C:6]([CH:12]([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][N:19]3COCC[Si](C)(C)C)[CH3:13])=[N:7]2.Cl.[OH:46]C1C=C(N2C(=O)C3C(=CC=CC=3C)N=C2C(NC2N=CN=C3C=2N=CN3)C)C=CC=1>CO>[C:38]([C:34]1[CH:33]=[C:32]([N:5]2[C:4](=[O:44])[C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[CH3:1])[N:7]=[C:6]2[CH:12]([NH:14][C:15]2[N:23]=[CH:22][N:21]=[C:20]3[C:16]=2[N:17]=[CH:18][NH:19]3)[CH3:13])[CH:37]=[CH:36][CH:35]=1)(=[O:46])[CH3:39]
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4[nH]cnc34)n(-c3cccc(O)c3)c(=O)c12
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(C#C[Si](C)(C)C)c3)c(=O)c12
Agent: Cl
Solvent: CO
Product: CC(=O)c1cccc(-n2c(C(C)Nc3ncnc4[nH]cnc34)nc3cccc(C)c3c2=O)c1

Procedure:
Compound 139 was treated with 4N HCl in MeOH at 70° C. for 16 hours in accordance with the procedure described for compound 121 (step D). This reaction afforded compound 144, the structure of which is shown below. m/z=440 (M+H)
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:6]=1[CH:7]=O)([CH3:3])[CH3:2].C1(P(=[CH:36][C:37]([O:39][CH3:40])=[O:38])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:40][O:39][C:37](=[O:38])[CH:36]=[CH:7][C:6]1[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:5]=1[O:4][CH:1]([CH3:3])[CH3:2]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)Oc1cc(C(F)(F)F)ccc1C=O
Solvent: Cc1ccccc1
Product: COC(=O)C=Cc1ccc(C(F)(F)F)cc1OC(C)C
Temperature: 80 °C
Yield: 72 %

Procedure:
To a suspension of 2-isopropoxy-N-methoxy-N-methyl-4-trifluoromethyl-benzamide (28 mg, 0.096 mmol) in THF (1.5 mL) was added dropwise 1.0M LiAlH4 (0.048 ml, 0.5 eq) at −60° C. The mixture was slowly warmed up to −20° C. until the reaction was completed. The reaction was slowly quenched with sat'd KHSO4 (1 mL) and then diluted with water (1 mL). The reaction mixture was extracted with ether and the combined organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The resulting compound was vacuum dried to yield the 2-isopropoxy-4-trifluoromethyl-benzaldehyde. To the aldehyde prepared above was added toluene (1 mL) followed by portionwise addition of methyl (triphenylphosphoranylidene)acetate (32 mg, 0.105 mmol) (exothermic). Toluene (1 mL) was added to the reaction mixture, and the resulting mixture was heated at 80° C. for 3 hours. The reaction mixture was cooled to room temperature, and then was directly loaded to a short silica-gel column and eluted with the solvent (Hex/EtOAc=20/1) to give the title compound (20 mg, 72%).
Reaction SMILES: CN1CCOCC1.[O:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH:17][C@@H:18]([CH3:22])[C:19]([OH:21])=O)=[O:16])[CH2:10][CH2:9]1.[NH2:23][C@@H:24]([CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.O>[O:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]([NH:17][C@@H:18]([CH3:22])[C:19]([NH:23][C@@H:24]([CH2:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])=[O:21])=[O:16])[CH2:12][CH2:13]1
Reactant: C[C@H](NC(=O)CN1CCOCC1)C(=O)O
Reactant: N[C@@H](CCc1ccccc1)C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: C[C@H](NC(=O)CN1CCOCC1)C(=O)N[C@@H](CCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
N-Methylmorpholine (1.09 g, 10.8 mmol) was added to a mixture of (S)-2-(2-morpholinoacetamido)propanoic acid (0.58 g, 2.7 mmol), (S)-benzyl 2-amino-4-phenylbutanoate (TFA salt, 1.03 g, 2.7 mmol) and HATU (1.13 g, 2.97 mmol) in dichloromethane (50 mL) at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. Water (50 mL) was added and the resulting mixture was extracted with dichloromethane (50 mL×3). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=100:1 to 10:1) to afford (S)-benzyl 2-((S)-2-(2-morpholinoacetamido)propanamido)-4-phenylbutanoate (0.9 g, 71% yield).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.[CH3:11][N:12]([CH3:17])[C:13](=[O:16])[CH2:14]Cl.C(=O)(O)[O-].[Na+].O1CCCC1>CO>[CH3:11][N:12]([CH3:17])[C:13](=[O:16])[CH2:14][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1
Reactant: CN(C)C(=O)CCl
Reactant: CNCCc1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN(CCc1ccncc1)CC(=O)N(C)C

Procedure:
4-[2-(methylamino)ethyl]pyridine (34.4 g) and 29.18 g of chloroacetic acid-dimethylamide are dissolved in 200 ml of methanol. After the addition of 20 g of sodium bicarbonate the mixture is refluxed for 5 hours with stirring. For working up the mixture is combined with 1000 ml of tetrahydrofuran, decanted off from the precipitated salts and the solution is filtered through active charcoal. After the limination of the solvent, N,N-dimethyl-2-[methyl-(2-pyridine-4-yl-ethyl)-amino]-acetamide is obtained as a crude product.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1OCCCO.[H-].[Na+].Br[C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1.[C:22](O)(=O)[CH2:23][C:24](CC(O)=O)(C(O)=O)[OH:25]>CN(C=O)C>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([O:25][CH2:24][CH2:23][CH2:22][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[N:16][CH:17]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OCCCOC1CCCCO1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc(OCCCC2CCCCO2)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-tetrahydropyranyloxy-1-propanol (1.0 g, 6.25 mmol) in DMF (10.0 mL) was added NaH (0.17 g, 95%) and stirred at 0° C. After 30 minutes, 2,5 dibromopyridine (1.0 g, 4.22 mmol) was added and the mixture was stirred at room temperature for 2 hours. The mixture was then poured into 5% cold citric acid (10.0 mL) and extracted with EtOAc (3×15 mL). The combined organic extracts were washed with water (3×15 mL), dried (Na2SO4), and concentrated to dryness. The resulting material was purified by silica gel flash chromatography using 20% EtOAc in hexane containing 0.5% triethyl amine. The appropriate fractions (monitored by TLC in 30% EtOAc in hexane) were combined and concentrated to give the desired product (1.1 g) as a colorless syrup. 1H-NMR and mass spectral data were consistent with the structure.