Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](Br)=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH2:10]([O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Br:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:20][CH:21]=2)=[N:4][CH:5]=1
Reactant: Clc1cc(Br)cnc1Br
Reactant: CCCCCCCCOc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc(-c2ncc(Br)cc2Cl)cc1
Yield: 67.6 %

Procedure:
10.0 g (37.0 mmol) of 3-chloro-2,5-dibromopyridine, 11.11 g (44.4 mmol) of 4-octyloxybenzeneboronic acid, 7.85 g (74.0 mmol) of sodium carbonate and 0.46 g (0.4 mmol) of tetrakis(triphenylphosphine)palladium(0) are heated at 80° C. for 18 hours in 125 ml of toluene, 60 ml of ethanol and 60 ml of water. The mixture is subsequently partitioned between aqueous sodium chloride solution and ether, the organic phase is washed with aqueous sodium chloride solution, dried over sodium sulfate and evaporated, and the product is purified by chromatography (silica gel, dichloromethane:hexane =4:1), giving 9.93 g of 5-bromo-3-chloro-2-(4-octyloxyphenyl)pyridine. ##STR16##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=O)[NH:12][N:13]=2)=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:16]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[S:16])[NH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: O=c1ccc(-c2ccc(Cl)cc2)n[nH]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: S=c1ccc(-c2ccc(Cl)cc2)n[nH]1
Yield: 187.1 %

Procedure:
A mixture of 3.0 g of 6-(4-chlorophenyl)-pyridazinone, 50 ml of dry pyridine and 3.2 g of phosphorus pentasulfide was refluxed for 1 hour, evaporated to dryness and extracted with 200 ml of ether. The ether extract was washed with water (3×100 ml), brine (100 ml), dried over magnesium sulfate and evaporated to yield 3.0 g of 6-(4-chlorophenyl)-pyridazinthione as a yellow solid.
Reaction SMILES: Cl.C(N=C=N[CH2:7][CH2:8][CH2:9]N(C)C)C.[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)C#C>C(Cl)(Cl)Cl>[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:9][C:8]#[CH:7])=[O:25])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)CCCCCc1ccccc1
Agent: C#CCO
Agent: Cl
Solvent: ClC(Cl)Cl
Product: C#CCOC(=O)CCCCCc1ccccc1
Temperature: 0 °C
Yield: 25.9 %

Procedure:
Five hundred milligrams of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a mixture of 500 mg of 6-phenylhexanoic acid and 20 ml of dry chloroform at room temperature with stirring. After the resultant mixture had been stirred for 30 minutes at room temperature, 146 mg of propargyl alcohol was added thereto at room temperature. Thereafter, the resulting mixture was stirred for 12 hours at room temperature, poured into ice water and extracted with chloroform. The chloroform extract was washed with an aqueous saturated ammonium chloride solution and then with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was subjected to chromatography on silica gel to obtain 155 mg of propargyl 6-phenylhexanoate.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][C:4]([CH:7]([NH:14][CH3:15])[CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:3][CH:2]=1.[CH3:22][O:23][C:24]1[C:38]([C:39]([F:42])([F:41])[F:40])=[CH:37][C:27]2[N:28]([CH2:33][C:34]([OH:36])=O)[C:29](=[O:32])[CH2:30][O:31][C:26]=2[CH:25]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.FC(F)(F)C(O)=O>CN(C)C=O.CC#N.O>[C:1]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=[CH:5][C:4]([CH:7]([N:14]([CH3:15])[C:34](=[O:36])[CH2:33][N:28]2[C:27]3[CH:37]=[C:38]([C:39]([F:42])([F:41])[F:40])[C:24]([O:23][CH3:22])=[CH:25][C:26]=3[O:31][CH2:30][C:29]2=[O:32])[CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:3][CH:2]=1
Reactant: COc1cc2c(cc1C(F)(F)F)N(CC(=O)O)C(=O)CO2
Reactant: CNC(CN1CCCC1)c1ccc(-c2ccccc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc2c(cc1C(F)(F)F)N(CC(=O)N(C)C(CN1CCCC1)c1ccc(-c3ccccc3)cc1)C(=O)CO2
Reaction time: 0.25 h
Yield: 40 %

Procedure:
[1-(4-biphenylyl)-2-(1-pyrrolidinyl)ethyl]methylamine (0.084 g, 0.30 mmol) and [7-(methyloxy)-3-oxo-6-(trifluoromethyl)-2,3-dihydro-4H-1,4-benzoxazin-4-yl]acetic acid (0.1 g, 0.33 mmol) were dissolved in 1 mL of dimethylformamide. Triethylamine (0.13 mL, 0.9 mmol) was delivered to the room temperature mixture, and the solution was allowed to stir for several minutes before a separate solution of 1H-1,2,3-benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent, 0.146 g, 0.33 mmol) dissolved in 1 mL of dimethylformamide was added to the mixture at room temperature. The reaction was maintained at that temperature for 18 hours, before it was determined to be complete by LCMS (two Aquasil C18, 20×1 mm columns were run in sequence, 4 minutes at 0.1 mL/min, 1-99% CH3CN/H2O with 0.018% trifluoroacetic acid, ES) Rt=2.1 min and m/e 568 [M+1]+. The reaction mixture was filtered through a 0.45 μm PTFE Acrodisk and the crude residue was purified by prep HPLC (Waters, 50×100 mm, 84 mL/min, A: acetonitrile B: water (pH=10, NH4OH), A: 10 to 99% over 15 min, UV detection at 214 nm) to give the title compound (0.070 g. 0.12 mmol, 41%) as an off-white amorphous solid. MS (ES) m/e 568 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[S:13][C:14]([CH:16]=[CH2:17])=[CH:15][C:5]=2[N:4]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:16]([C:14]1[S:13][C:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[CH:3]([CH2:1][CH3:2])[N:4]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)(=[O:20])=[O:19])[C:5]=2[CH:15]=1)[CH3:17]
Reactant: C=Cc1cc2c(s1)-c1ccccc1C(CC)N2S(=O)(=O)c1ccc(OC)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1cc2c(s1)-c1ccccc1C(CC)N2S(=O)(=O)c1ccc(OC)cc1
Yield: 87.1 %

Procedure:
A solution of 5-ethyl-4-[(4-methoxyphenyl)sulfonyl]-2-vinyl4,5-dihydrothieno[3,2-c]isoquinoline (1.44 g, 3.50 mmol) in ethyl acetate (35 mL) was hydrogenated over 10% palladium-on-carbon (0.29 g) at 23° C. and 1 atm. After 1 h the catalyst was filtered (Celite), washed with ethyl acetate (35 mL), and the filtrate was concentrated in vacuo to give the crude product (1.37 g) as a pale yellow solid. Recrystallization from boiling hexane provided the title compound (1.26 g, 87%, m.p. 105.0-105.5° C.) as shiny pale yellow needles.
Reaction SMILES: C([O:4][C:5](=[O:52])[C@H:6]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][P:33]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:34])=[C:28]([N+:49]([O-:51])=[O:50])[CH:27]=1)[NH:7][C:8]([O:10][CH2:11][CH:12]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])C=C.CNC1C=CC=CC=1.CCOC(C)=O.OS([O-])(=O)=O.[K+]>C1COCC1>[C:8]([NH:7][C@H:6]([C:5]([OH:52])=[O:4])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][P:33]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[O:34])=[C:28]([N+:49]([O-:51])=[O:50])[CH:27]=1)([O:10][CH2:11][CH:12]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9]
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OP(=O)(Cc2ccccc2)Cc2ccccc2)c([N+](=O)[O-])c1)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CNc1ccccc1
Product: O=C(N[C@@H](Cc1ccc(OP(=O)(Cc2ccccc2)Cc2ccccc2)c([N+](=O)[O-])c1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 95.7 %

Procedure:
Synthesis Fmoc-3-nitro-O-(dibenzylphosphoryl)tyrosine allyl ester 3 (3.15 g, 4.2 mmol) was dissolved in dry THF (20 mL), after which N-methylaniline (1.40 mL, 12.9 mmol) and tetrakis triphenylphosphine palladium (254 mg, 0.22 mmol) were added. After stirring for 2 h at room temperature under a N2-atmosphere in the dark, EtOAc (50 mL) and 1M KHSO4 (50 mL) were added. After drying on Na2SO4 and column chromatography (5% MeOH in DCM), the product (2.72 g, 91%) was obtained as a light yellow foam.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[NH+:10]([O-:20])[N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)([O-])=O>C(O)C.[Pt]=O>[NH2:1][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[NH+:10]([O-:20])[N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1
Reactant: O=[N+]([O-])c1ccncc1[NH+]([O-])n1ccc2ccccc21
Agent: O=[Pt]
Solvent: CCO
Product: Nc1ccncc1[NH+]([O-])n1ccc2ccccc21
Reaction time: 4 h
Yield: 56.2 %

Procedure:
A mixture of N-(4-nitro-3-pyridinyl)-1H-indol-1-amine N1 -oxide (5 g) and 0.5 g of platinum oxide in 250 ml of ethanol was hydrogenated at 50 psi (pounds per square inch) for four hours. The mixture was filtered and the filtered liquid was concentrated to a dark residue which was purified by flash chromatography (silica, 10% methanol in dichloromethane) to give 2.5 g of solid, d 235°. This material was recrystallized from methanol/ether to give 2.1 g of crystals, d 235°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1)[O:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)([O-])=O>CO.[Pd]>[O:13]1[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][O:7][C:6]2[CH:5]=[C:4]([CH:18]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:16]=2)[NH2:1])[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1cc(OCCN2CCOCC2)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(OCCN2CCOCC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.6 %

Procedure:
To a mixture of 4-(2-(3-nitro-5-(trifluoromethyl)phenoxy)ethyl)morpholine (600 mg, 1.873 mmol) in MeOH (50 mL) was added Pd/C (19.94 mg, 0.187 mmol) under N2. The mixture was stirred under H2 at 25° C. for 5 h. The mixture was filtered, and the filtrate was concentrated to give a yellow oil of 3-(2-morpholinoethoxy)-5-(trifluoromethyl)aniline (500 mg, 1.490 mmol, 80% yield): 1H NMR (400 MHz, CDCl3): δ 6.52 (d, J=9.2 Hz, 2H), 6.35 (s, 1H), 4.12-4.02 (m, 2H), 3.82 (s, 2H), 3.76-3.66 (m, 4H), 2.78 (t, J=5.6 Hz, 2H), 2.57 (d, J=4.0 Hz, 4H). ES-LCMS m/z: 291 (M+H).
Reaction SMILES: C([O:5][C:6](=O)[C@@H:7]([O:9][C:10]1[CH:31]=[CH:30][C:13]2[C:14]3[N:18]([CH2:19][CH2:20][O:21][C:12]=2[CH:11]=1)[CH:17]=[C:16]([C:22]1[N:23]([CH:27]([CH3:29])[CH3:28])[N:24]=[CH:25][N:26]=1)[N:15]=3)[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O.C[N:41](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(CC)CC)C>C(Cl)Cl>[CH:27]([N:23]1[C:22]([C:16]2[N:15]=[C:14]3[C:13]4[CH:30]=[CH:31][C:10]([O:9][C@@H:7]([CH3:8])[C:6]([NH2:41])=[O:5])=[CH:11][C:12]=4[O:21][CH2:20][CH2:19][N:18]3[CH:17]=2)=[N:26][CH:25]=[N:24]1)([CH3:29])[CH3:28]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(O[C@@H](C)C(=O)OC(C)(C)C)cc1OCC2
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(O[C@@H](C)C(N)=O)cc1OCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.2 %

Procedure:
To a solution of (S)-2-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy]-propionic acid tert-butyl ester (64 mg, 0.15 mmol) in DCM (10 mL) was added TFA (0.5 mL) and the reaction mixture stirred at RT for 16 h. The reaction mixture was concentrated in vacuo and the crude carboxylic acid 512 dissolved in DMF (2 mL). HATU (130 mg, 0.34 mmol), ammonium chloride (27 mg, 0.51 mmol) and triethylamine (71 μL, 0.51 mmol) were added and the reaction mixture stirred at RT for 1 hour. The reaction mixture was concentrated in vacuo, the residue dissolved in ethyl acetate (10 mL) and the mixture washed with water extracting with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2 gradient 0-10% methanol in ethyl acetate) to yield 436 as a white solid (50 mg, 90%). LCMS: RT=3.07 min; [M+H]+=383, 1H NMR (400 MHz, d6-DMSO) 8.26 (1H, d, J=8.6 Hz), 7.81 (1H,S), 7.85 (1H, s), 7.51 (1H, s), 7.21 (1H, s), 6.72 (1H, dd, J=8.6, 2.6 Hz), 6.49 (1H, d, J=2.6 Hz), 5.85 (1H, sept, J=6.6 Hz), 4.62 (1H, q, J=6.6 Hz), 4.55-4.36 (4H, m), 1.47-1.36 (9H, m)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:14][CH3:15])[CH:3]=1.[B-](F)(F)(F)[F:17].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.O>C(#N)C>[NH2:1][C:2]1[CH:3]=[C:4]([O:14][CH3:15])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:10]([O:12][CH3:13])[C:11]=1[F:17]
Reactant: COC(=O)c1c(OC)cc(N)cc1OC
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: O
Product: COC(=O)c1c(OC)cc(N)c(F)c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
To a solution of methyl 4-amino-2,6-dimethoxybenzoate (510 mg, 2.42 mmol) in acetonitrile (10 mL) at 0° C. was added Selectfluor® (940 mg, 2.66 mmol). The mixture was stirred 30 minutes at 0° C. then water (10 mL) was added. The reaction was extracted twice with ethyl acetate (30 mL). The organic phases were combined, passed through a hydrophobic frit and the solvent was removed in vacuo. Purification of the residue via silica gel column chromatography (0-100% EtOAc in iso-hexane) gave methyl 4-amino-3-fluoro-2,6-dimethoxybenzoate (114 mg, 20%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 6.05 (d, J=6.4 Hz, 1H), 3.93 (s, 3H), 3.88 (s, 3H), 3.75 (s, 3H).
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][C:13]([C:16](=O)[CH:17]([CH3:22])[CH2:18][C:19]([OH:21])=O)=[CH:12][CH:11]=2)[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[CH:2]1.O.[NH2:25][NH2:26]>C(O)C>[N:1]1([C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:17]([CH3:22])[CH2:18][C:19](=[O:21])[NH:25][N:26]=3)=[CH:14][CH:15]=2)[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(CC(=O)O)C(=O)c1ccc(-n2cnc3c2CCCC3)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC1CC(=O)NN=C1c1ccc(-n2cnc3c2CCCC3)cc1
Yield: 43.7 %

Procedure:
A mixture of 4-(4,5,6,7-tetrahydro-1H-benzimidazol-1-yl)-β-methyl-γ-oxobenzenebutanoic acid (7.3 g, 0.023 mol), 80% hydrazine hydrate (1.75 g, 0.028 mol) in ethanol (75 ml) is heated under reflux for six hours. The solution is concentrated to a small volume and filtered. The residue is washed with 2-propanol, followed by ether to give 3.1 g of 4,5-dihydro-6-[4-(4,5,6,7-tetrahydro-1H-benzimidazol-1-yl)phenyl]-5-methyl-3(2H)-pyridazinone, mp 199°-200° C.
Reaction SMILES: CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.[CH3:25][NH:26][CH2:27][C:28]1([N:34]([CH3:36])[CH3:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[CH:37]([OH:39])=O>>[CH:37]([N:26]([CH3:25])[CH2:27][C:28]1([N:34]([CH3:36])[CH3:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:39]
Reactant: CNCC1(N(C)C)CCCCC1
Reactant: O=CO
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Product: CN(C=O)CC1(N(C)C)CCCCC1
Reaction time: 1 h
Yield: 77.7 %

Procedure:
Formic acid (6.9 g, 0.15 mole) and acetic anhyride (15.3 g, 0.15 mole) were mixed without cooling and kept at room temperature for 1 hr. 1-methylaminomethylcyclohexyldimethylamine (5.9 g, 0.034 mole) was dissolved in formic acid (12 ml) and the formylating mixture (16 ml) added slowly. This produced vigorous effervescence and a temperature rise to 75°. The mixture was then left at room temperature for 2 hr. and then heated on a water bath at 55° for 0.75 hr. The solvents were removed under reduced pressure to give an amber oil (5.32 g, 77.7%) which crystallised as colourless prisms of 1-(N-formyl-1-methylaminomethyl) cyclohexyldimethylamine from light petroleum (b.p. 60°-80°), m.p. 59°-60°.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH3:13][C:14]([CH3:16])=[O:15].[OH-].[Na+].O>C(O)C>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[CH:13][C:14](=[O:15])[CH:16]=[CH:5][C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[C:2]([F:1])([F:11])[F:12]
Reactant: CC(C)=O
Reactant: O=Cc1ccccc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(C=Cc1ccccc1C(F)(F)F)C=Cc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.7 %

Procedure:
2-(Trifluoromethyl)-benzaldehyde (1w, 0.75 ml, 5.7 mmol) and acetone (19, 0.21 ml, 2.8 mmol) were combined in ethanol (20 ml) and stirred for 10 min at room temperature. A solution of sodium hydroxide (0.34 g, 8.5 mmol) and water (15 ml) was added and the mixture stirred for 18 hr at room temperature. The resulting precipitate was filtered and recrystallized from ethanol to afford 0.92 g (87%) of a yellow solid: mp 131-133° C. [expected mp 131° C.]; 1H NMR: δ 6.99 (d, 2H, J=15.9 Hz), 7.48 (t, 2H, J=7.6 Hz), 7.56 (t, 2H, J=7.0 Hz), 7.70 (d, 2H, J=7.7 Hz), 7.77 (d, 2H, J=7.6 Hz), 8.07 (d, 2H, J=15.7 Hz); 13C NMR: δ 123.9, 126.2, 127.9, 128.8, 129.4, 129.7, 132.1, 133.7, 139.1, 188.0.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.Cl.[C:23]1([CH2:29][CH2:30][NH2:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:30]([NH:31][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)[CH2:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCCc1ccccc1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(NCCc3ccccc3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), 2-phenylethanamine hydrochloride (207.8 mg, 1.32 mmol, 3.00 equiv), potassium carbonate (304.4 mg, 2.21 mmol, 5.00 equiv), N,N-dimethylformamide (2 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50). This resulted in 120 mg (71%) of methyl 3-(phenethylamino)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([CH3:13])[CH2:8][N:7]([CH2:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.I[CH3:22].[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:22])[C:10](=[O:12])[CH:9]([CH3:13])[CH2:8][N:7]([CH2:14][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19]3)[C:6]=2[N:20]=1
Reactant: CI
Reactant: CC1CN(CC2CCCC2)c2nc(Cl)ncc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CN(CC2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Reaction time: 2 h
Yield: 95.5 %

Procedure:
To a mixture of 1.10 g (0.00373 mole) of (rac)-2-chloro-9-cyclopentylmethyl-7-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-55), 0.35 mL (0.0056 mole) of iodomethane and 15 mL of N,N-dimethyl-formamide at 0 degrees, was added 0.22 g (0.0056 mole) of 60% oil dispersion of sodium hydride. The mixture was stirred at 0 degrees for 2 hours, then partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with hexanes-ethyl acetate (100:0-60:60) to give 1.10 g of (rac)-2-chloro-9-cyclopentylmethyl-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-55) as white powder. HRMS (ES+) m/z Calcd for C15H21ClN4O+H [(M+H)+]: 309.1477. Found: 309.1476.
Reaction SMILES: [Sn].[CH3:2][C:3]([N:6]([CH2:11][C:12]1[C:17]([N+:18]([O-])=O)=[CH:16][CH:15]=[C:14]([Cl:21])[C:13]=1[Cl:22])[CH2:7][C:8]([OH:10])=[O:9])([CH3:5])[CH3:4]>[Pd].[Pt].[Pt]=O.[Rh]>[CH3:5][C:3]([N:6]([CH2:11][C:12]1[C:17]([NH2:18])=[CH:16][CH:15]=[C:14]([Cl:21])[C:13]=1[Cl:22])[CH2:7][C:8]([OH:10])=[O:9])([CH3:2])[CH3:4]
Reactant: CC(C)(C)N(CC(=O)O)Cc1c([N+](=O)[O-])ccc(Cl)c1Cl
Agent: O=[Pt]
Agent: [Pd]
Agent: [Pt]
Product: CC(C)(C)N(CC(=O)O)Cc1c(N)ccc(Cl)c1Cl

Procedure:
Where possible, the invention seeks to avoid the use of a tin-reagent to effect the reduction. Thus in another procedure according to the invention, 1,1-dimethyl-ethyl N-(2,3-dichloro-6-nitrobenzyl)glycine (compound XXII) may also be catalytically hydrogenated using a metal or metal-based catalyst such as platinum, platinum oxide, rhodium, and palladium on carbon under hydrogen pressure. The catalyst is then removed by filtration and the filtrate concentrated, diluted with water and an organic solvent and basified using an alkali to a pH of about 9-10. The organic phase is separated and concentrated and the crude material purified by low temperature recrystallization to give 1,1-dimethyl-ethyl-(6-amino-2,3-dichlorobenzyl)glycine.
Reaction SMILES: [C:1](O)(=[O:5])[CH:2]([CH3:4])[OH:3].[OH:7][CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[NH2:10].Cl.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[C:1]([NH:10][C@@H:9]1[C@@H:11]([OH:12])[C@H:13]([OH:14])[C@@H:15]([CH2:17][OH:18])[O:16][CH:8]1[OH:7])(=[O:5])[CH:2]([CH3:4])[OH:3]
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CC(O)C(=O)O
Agent: Cl
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CC(O)C(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O

Procedure:
75 g of lactic acid (90% pure) was mixed with 22.5 g of glucosamine.HCl and 2.5 g of Dextrose. The mixture was reacted at 120 C for 4 hours. The reacted mixture was cooled down and stored at 4 C.