Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=O)C(C)(C)C)=[CH:6][CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=1.C1COCC1.[H-].[Na+].CI>O>[Cl:1][C:2]1[C:7]([NH:8][CH3:9])=[CH:6][CH:5]=[C:4]([C:15]([F:16])([F:17])[F:18])[N:3]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(C(F)(F)F)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: CNc1ccc(C(F)(F)F)nc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
To a mixture of N-(2-chloro-6-trifluoromethylpyridin-3-yl)-2,2-dimethylpropionamide (6.59 g) and THF (30 ml), sodium hydride (60% in oily, 1 g) was added under ice-cooling, and stirred at room temperature for 30 minutes. The reaction mixture was ice-cooled, and then methyl iodide (10 g) was added, and stirred at room temperature for 4 hours. Into the reaction mixture, water was poured, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. To the resulting residue, acetonitrile (40 ml), concentrated hydrochloric acid (40 ml), and isopropanol (40 ml) were added, and stirred at room temperature for 2 hours, at 60° C. for 2 hours, then at 80° C. for 2 hours. Into the reaction mixture cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was poured, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 2.60 g of (2-chloro-6-trifluoromethylpyridin-3-yl)-methylamine.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([CH:7]=[N:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=3)=[N:13][CH:14]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>CO>[F:28][C:2]([F:1])([F:29])[C:3]1[CH:27]=[CH:26][C:6]([CH2:7][NH:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=3)=[N:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(Oc2ccc(N=Cc3ccc(C(F)(F)F)cc3)cn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(Oc2ccc(NCc3ccc(C(F)(F)F)cc3)cn2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Methyl 4-{5-[(4-trifluoromethylbenzylidene)-amino]pyridin-2-yloxy}benzoate (2.64 g, 6.59 mmol) was suspended in methanol (25 mL), and to the resulting suspension was slowly added sodium borohydride (1.25 g, 33.0 mmol). The resulting solution was stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate, and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was washed with diethyl ether, to thereby yield 2.65 g of the title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6][NH2:7])[CH3:2].[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][CH2:22][NH:23][C:24](=[O:38])[C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][N:34]=[C:33](Cl)[N:32]=4)=[CH:27][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)#[N:11]>>[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][CH2:22][NH:23][C:24](=[O:38])[C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][N:34]=[C:33]([NH:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:8][CH3:9])[CH2:1][CH3:2])[N:32]=4)=[CH:27][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)#[N:11]
Reactant: CCN(CC)CCCN
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: CCN(CC)CCCNc1nccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)n1

Procedure:
Using 3-(diethylamino)-propylamine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C([Zn]CC)C.CCCCCC.Br[C:35]1[CH:44]=[CH:43][CH:42]=[C:41]2[C:36]=1[CH:37]=[CH:38][C:39]([C:45]([OH:47])=[O:46])=[CH:40]2.[CH3:48][N:49]1CCCC1=O>CC([O-])=O.CC([O-])=O.[Pd+2].[C-]#N.[C-]#N.[Zn+2]>[C:48]([C:35]1[CH:44]=[CH:43][CH:42]=[C:41]2[C:36]=1[CH:37]=[CH:38][C:39]([C:45]([OH:47])=[O:46])=[CH:40]2)#[N:49]
Reactant: CN1CCCC1=O
Reactant: O=C(O)c1ccc2c(Br)cccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[Zn]CC
Solvent: CCCCCC
Product: N#Cc1cccc2cc(C(=O)O)ccc12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A solution of Pd(OAc)2 (0.012 g, 0.054 mmol) and tri-o-tolylphosphine (0.073 g, 0.240 mmol) in degassed N-methylpyrrolidone (2 mL) is heated at 60° C. for 30 minutes. A solution of 1.0 M diethylzinc in hexane (0.11 mL, 0.11 mmol) is then added and stirring is continued for additional 30 minutes. To this mixture is added a mixture of 5-bromo-naphthalene-2-carboxylic acid, 1, (0.135 g, 0.536 mmol) and Zn(CN)2 (0.063 g, 0.536 mmol) in degassed N-methylpyrrolidone (2 mL). The resulting mixture is heated at 60° C. for 18 hrs. The reaction mixture is cooled and directly loaded to a prep-HPLC column eluting with CH3CN—H2O (0.1% TFA) to afford 0.085 g (80% yield) of the desired product as a white solid. m.p. 250° C. (dec.). 1H NMR (300 MHz, CDCl3): δ 8.61 (s, 1H), 8.18 (m, 2H), 8.14 (d, J=8.7 Hz, 1H), 7.94 (d, J=7.2 Hz, 1H), 7.54 (t, J=8.4 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 168.4, 134.9, 134.8, 134.5, 132.4, 131.9, 129.9, 128.5, 125.9, 125.5, 117.5, 110.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[O:9][CH2:10][CH:11]([CH2:13][OH:14])[O:12][C:7]=2[C:6]=1[CH3:17])=[O:4].C(N(CC)CC)C.[CH3:25][O:26][C@:27]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:31]([F:34])([F:33])[F:32])[C:28](Cl)=[O:29]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[O:9][CH2:10][CH:11]([CH2:13][O:14][C:28](=[O:29])[C:27]([O:26][CH3:25])([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:31]([F:33])([F:34])[F:32])[O:12][C:7]=2[C:6]=1[CH3:17])=[O:4]
Reactant: CO[C@](C(=O)Cl)(c1ccccc1)C(F)(F)F
Reactant: COC(=O)c1ccc2c(c1C)OC(CO)CO2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1C)OC(COC(=O)C(OC)(c1ccccc1)C(F)(F)F)CO2

Procedure:
To a round bottom flask equipped with magnetic stirring and a nitrogen inlet was added 3-hydroxymethyl-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid methyl ester (0.10 g, 0.44 mmol) and dry methylene chloride (1.5 mL). The mixture was cooled in an ice bath and triethylamine (0.12 mL, 0.87 mmol) was added followed by (R)-(−)-α-methoxy-α-trifluoromethylphenylacetyl chloride (0.09 mL, 0.48 mmol). The mixture was stirred for 2 hours at which point TLC showed the reaction to be incomplete. More (R)-(−)-α-methoxy-α-trifluoromethylphenylacetyl chloride (0.09 mL, 0.48 mmol) was added and the reaction was allowed to stir 1 hour at room temperature. The mixture was diluted with methylene chloride, washed once with 1N HCl, once with saturated sodium bicarbonate, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel eluting with methylene chloride to give a clear oil, 5-methyl 3-(3,3,3-trifluoro-2-methoxy-2-phenyl-propionyloxymethyl)-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid methyl ester, for which a yield was not determined. 1H-NMR (300 MHz, CD3COCD3) δ (ppm): 2.38 (s, 3H), 3.58 (s, 3H), 3.81 (s, 3H), 4.10 (m, 1H), 4.48 (dd, 1H), 4.65 (m, 2H), 4.86 (m, 1H) 6.78 (d, 1H) 7.47 (m, 5H), 7.60 (d, 1H); 19F-NMR (300 MHz, CD3COCD3) δ (ppm): −72.89 (s); both 1H- and 19F-NMR indicate the presence of only one stereo- and regioisomer; TLC: Rf=0.62 (1:1 ethyl acetate/hexane).
Reaction SMILES: [NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C@H:2]([C:19](O)=[O:20])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:6][CH:5]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:57][C@H:58]([C:63]([O:65][CH3:66])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61].CCN(C(C)C)C(C)C>C(Cl)Cl.C(OCC)(=O)C>[NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C@H:2]([C:19]([NH:57][C@H:58]([C:63]([O:65][CH3:66])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:20])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccc(CNC(=O)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 101.6 %

Procedure:
Cbz-Phe(4-CH2NHBoc)-OH (214 mg, 0.5 mmol, 1 equiv.) was dissolved in DCM. HBTU (228 mg, 0.6 mmol, 1.2 equiv.), HCl.H-Leu-OMe (100 mg, 0.55 mmol, 1.1 equiv.) and DiPEA (0.29 ml, 1.75 mmol, 3.5 equiv.) were added and the mixture was stirred for 2 hours before being concentrated. The residue was dissolved in ethyl acetate (EA) and washed with 1M HCl (2×), sat. aq. NaHCO3 (4×), brine and dried over MgSO4. Column chromatography (tol->30% EA:tol) yielded the title compound (282 mg, 508 μmol, quant.). 1H NMR (400 MHz, CDCl3): δ ppm 7.35-7.22 (m, 5H), 7.19-7.04 (m, 4H), 6.81 (d, J=6.7 Hz, 1H), 5.76 (d, J=8.4 Hz, 1H), 5.16-4.94 (m, 2H), 4.69-4.45 (m, 2H), 4.26-4.11 (m, 2H), 3.67 (s, 3H), 3.13-2.88 (m, 2H), 1.64-1.47 (m, 3H), 1.44 (s, 9H), 0.94-0.81 (m, 6H). 13C NMR (101 MHz, CDCl3): δ ppm 172.83, 170.76, 155.81, 137.23, 136.04, 135.30, 129.37, 128.28, 127.92, 127.70, 127.57, 79.13, 66.70, 55.73, 52.06, 50.51, 44.19, 41.08, 37.94, 28.23, 24.51, 22.52, 21.69.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:21]2=[CH:22][CH:23]=[N:24][CH:25]=[C:20]2[C:5]2[C:6]([OH:19])=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([O:19][C:6]1[C:5]2[C:20]3[C:21]([C:2]([CH3:1])([CH3:26])[O:3][C:4]=2[CH:9]=[C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])[CH:7]=1)=[CH:22][CH:23]=[N:24][CH:25]=3)(=[O:29])[CH3:28]
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCCCC(C)C(C)c1cc(OC(C)=O)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
A mixture of 3.53 g. (0.01 mole) of 5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-5H-[1]benzopyrano[3,4-d]pyridine, 1.22 g. (0.012 mole) of acetic anhydride, and 5 ml. of pyridine was stirred at room temperature for 24 hours. The reaction mixture was evaporated in vacuo, and the residue was taken up in ether. The ether solution was washed with water, dried with anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by chromatography on a Florosil® activated aluminum magnesium silicate 22 mm×30 inch column with chloroform to give the pure product.
Reaction SMILES: [CH:1]1(/[CH:7]=[CH:8]/[CH:9]=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C1C=C(C(C2C=C(C(F)(F)F)C=C(C(F)(F)F)C=2)(O[Si](C)(C)C)C2CCCN2)C=C(C(F)(F)F)C=1.[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O.[NH:62]1[CH:66]=[CH:65][CH:64]=[N:63]1>C1(C)C=CC=CC=1>[CH:1]1([CH:7]([N:62]2[CH:66]=[CH:65][CH:64]=[N:63]2)[CH2:8][CH:9]=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C/C=C/C1CCCCC1
Reactant: c1cn[nH]c1
Agent: C[Si](C)(C)OC(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN1
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Product: O=CCC(C1CCCCC1)n1cccn1
Reaction time: 72 h

Procedure:
A solution of (E)-3-cyclohexylacrylaldehyde (4.94 g) (made according to Organic Letters (2011), 13(1), 70-73), 2-(bis(3,5-bis(trifluoromethyl)phenyl)-(trimethylsilyloxy)methyl)pyrrolidine (0.712 g) and 4-nitrobenzoic acid (0.124 mL) in toluene (60 mL) was stirred at room temperature for 10 minutes and 1H-pyrazole (1.622 g) was added. The reaction mixture was stirred for 3 days, and purified by flash chromotography (silica gel, 0-50% ethyl acetate/hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>CO.CC#N>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([NH:30][C:29]2[C:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[CH:10][C:11]3[CH:16]=[N:15][C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[N:13][C:12]=3[N:28]=2)=[O:40])=[CH:34][CH:33]=1
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CC#N
Solvent: CO
Product: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(NC(=O)Nc4ccc(Cl)cc4)nc3n2)CC1
Yield: 62.7 %

Procedure:
6-(2,6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine (1.0 g) from Example 36 was reacted with 0.344 g of 4-chlorophenyl isocyanate according to the general procedure of Example 37 to give 0.8424 g of 1-(4-Chloro-phenyl)-3-{6-(2,6-dichlorophenyl)-2-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrido[2,3-d]pyrimidin-7-yl}-urea, ESMS (20/80 MeOH/CH3CN+0.1% AcOH+DMSO): M+ +H=601; mp 175.5°-181° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][NH:9][C:10]([NH2:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.Br[CH2:14][C:15]([O:17][CH3:18])=[O:16]>C1(C)C=CC=CC=1>[NH2:12][C:10]([NH:9][N:8]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)=[O:11]
Reactant: COC(=O)CBr
Reactant: Cc1cccc(NNC(N)=O)c1
Solvent: Cc1ccccc1
Product: COC(=O)CN(NC(N)=O)c1cccc(C)c1

Procedure:
A mixture of 2-(3-methylphenyl)hydrazinecarboxamide (5 g), DEA (10.5 ml) and methyl bromoacetate (4.5 ml) in toluene (100 ml) was heated under reflux for 20 h, and was then partitioned between ethyl acetate (200 ml) and water (200 ml). The organic layer was washed with water (2×100 ml) and saturated brine (100 ml) before being dried and evaporated in vacuo to leave an oil (6.1 g). This was purified by FCC eluting with ethyl acetate to give the title compound (4.4 g) as a solid, m.p. 68°-70° after recrystallisation from ethyl acetate and trituration with ether.
Reaction SMILES: ON1C2N=CC=CC=2N=N1.ClCCl.[Br:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17].[CH2:22]([N:24]([CH2:32][CH2:33][CH2:34][C:35](O)=[O:36])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=1)[CH3:23]>C(OCC)(=O)C.C(N(CC)CC)C>[Br:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH:17][C:35](=[O:36])[CH2:34][CH2:33][CH2:32][N:24]([CH2:22][CH3:23])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=1
Reactant: CCN(CCCC(=O)O)c1cccc(C)c1
Reactant: Nc1ccccc1Br
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCN(CCCC(=O)Nc1ccccc1Br)c1cccc(C)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
1-Ethyl-3-(3-dimethylamindpropyl)carbodiimide hydrochloride (150 mg), 1-hydroxy-7-azabenzotriazole (106 mg), dichloromethane (2 ml), 2-bromoaniline (134 μl), and triethylamine (162 μl) were added to the compound (100 mg) obtained in Step 2, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel chromatography (hexane-ethyl acetate) to give the title compound (56 mg).
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[S:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:19]([C:24](O)=[O:25])#[C:20][C:21]([OH:23])=[O:22]>>[CH2:12]([N:11]1[C:24](=[O:25])[C:19](=[CH:20][C:21]([OH:23])=[O:22])[S:10][C:9]1=[N:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCNC(=S)NCCCCCCC
Reactant: O=C(O)C#CC(=O)O
Product: CCCCCCCN=C1SC(=CC(=O)O)C(=O)N1CCCCCCC
Yield: 88.4 %

Procedure:
Prepared by the method described in Example 16 from N,N'-diheptylthiourea (18.0 g, 66 mmoles) and acetylenedicarboxylic acid (8.0 g, 66 mmoles). Recrystallization from acetonitrile gave the product (21.5 g), mp 80°-81° C.
Reaction SMILES: Cl.[OH:2][CH2:3][CH:4]1[CH:7]2[C:8]3[C:13]([CH2:14][CH2:15][N:6]2[CH2:5]1)=[CH:12][C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=3.[C:20]([Cl:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[ClH:28].[C:20]([O:2][CH2:3][CH:4]1[CH:7]2[C:8]3[C:13]([CH2:14][CH2:15][N:6]2[CH2:5]1)=[CH:12][C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=3)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc2c(cc1OC)C1C(CO)CN1CC2
Agent: Cl
Product: COc1cc2c(cc1OC)C1C(COC(=O)c3ccccc3)CN1CC2

Procedure:
0.01 mole (1,85 g) of 1-(hydroxymethyl)-7,8-dimethoxy-1,4,5,9b-tetrahydro-2H-azeto[2,1-a]isoquinoline hydrochloride is acylated with benzoyl chloride following the conventional Schotten-Baumann acylation method.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:18][O:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1Br.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.[Pd].C1(C)C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2)C2C=CC(C)=CC=2)=CC=1>[CH3:18][O:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[NH:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Reactant: Cc1ccc(CCc2ccc(N)cc2)cc1C
Agent: [Pd]
Agent: Cc1ccc(P(c2ccc(C)cc2)c2ccc3ccccc3c2-c2cccc3ccccc23)cc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc([N+](=O)[O-])ccc1Nc1ccc(CCc2ccc(C)c(C)c2)cc1
Yield: 87.8 %

Procedure:
The title compound was prepared from 4-[2-(3,4-dimethylphenyl)ethyl]-benzenamine (1.0 g, 4.43 mmol), 2-bromo-5-nitrobenzoic acid methyl ester (0.96 g, 3.69 mmol), cesium carbonate (1.68 g, 5.17 mmol), tris(dibenzylideneacetone-dipaladium(0) (101 mg, 0.11 mmol) and (S)-(2,2′-bis(di-p-tolylphosphino-1,1′-binaphthyl (98%, (S)-tol-BINAP) (113 mg, 0.17 mmol) (Ligand/Pd=1.5) in anhydrous toluene (32 mL) using the procedure described in Example 2, step C. This procedure yielded an yellow solid, 1.31 g (3.24 mmol, 73%) of the desired product. mp 115-117° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:10](=[O:11])[CH2:9][S:8][C:7]2[CH:12]=[CH:13][N:14]=[CH:15][C:6]1=2.C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[CH2:24]([CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH2:25][CH2:26][CH3:27]>CCCCCCC.CCOC(C)=O>[CH2:24]([CH:28]1[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][N:5]2[C:10](=[O:11])[CH2:9][S:8][C:7]3[CH:12]=[CH:13][N:14]=[CH:15][C:6]2=3)[CH2:30][CH2:29]1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCC1CCNCC1
Reactant: O=C1CSc2ccncc2N1CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCCC1CCN(CCCN2C(=O)CSc3ccncc32)CC1
Yield: 306.9 %

Procedure:
4-(3-Chloropropyl)-4H-pyrido[4,3-b][1,4]thiazin-3-one (81MF939b) (0.14 g, 0.57 mmol), K2CO3 (0.16 g, 11.4 mmol), NaI (0.18 g, 11.4 mmol) and 4-butylpiperidine (0.09 g, 0.06 mmol) were mixed according to GP12. CC (SiO2; Heptane/EtOAc 10:1-4) gave the title compound (81MF939) (0.064 g, 32%). 1H NMR (CDCl3) δ 8.48 (s, 1H), 8.17 (d, J=5.2 Hz, 1H), 7.25 (d, J=4.8 Hz, 1H), 4.06-4.12 (m, 2H), 3.41 (s, 2H), 2.82 (d, J=11.2, 2H), 2.33 (t, J=6.8 Hz, 2H), 1.83-1.89 (m, 4H), 1.64 (d, J=9.2 Hz, 2H), 1.16-1.29 (m, 9H), 0.87 (t, J=6.8 Hz, 3H); 13C NMR (CDCl3) δ 163.91, 143.84, 138.92, 136.20, 134.04, 122.31, 55.80, 54.32, 43.29, 36.43, 35.99, 32.68, 30.78, 29.19, 25.20, 23.05, 14.24.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=O)=[CH:4][CH:3]=1.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]2[O:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]2)=[CH:16][CH:15]=1)#[N:13].C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[NH:8][N:9]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([C@@H:20]4[O:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]4)=[CH:18][CH:19]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(C#N)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(-c3n[nH]c(-c4ccc(F)cc4)n3)cc2)C1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
4-Fluorobenzhydrazide (50 mg, 0.324) an (S)-tert-butyl 2-(4-cyanophenyl)morpholine-4-carboxylate (112 mg, 0.389 mmol) and potassium carbonate (22.5 mg, 0.162 mmol) was dissolved in butan-1-ol (1 ml) and stirred in a closed vial for 3 h at 150° C. The vial was opened and heating was continued for another 15 min to evaporate most of the solvent.
Reaction SMILES: [Cu]C#N.[CH2:4]([O:11][CH2:12][C@H:13]1[CH2:15][O:14]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:16]([Mg]Br)=[CH2:17].[NH4+].[Cl-].[NH4+].[OH-]>C1COCC1>[CH2:4]([O:11][CH2:12][C@@H:13]([OH:14])[CH2:15][CH:16]=[CH2:17])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C=C[Mg]Br
Reactant: c1ccc(COC[C@H]2CO2)cc1
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC[C@H](O)COCc1ccccc1
Temperature: -78 °C
Reaction time: 5 h

Procedure:
Copper(I)cyanide (120 mg, 1.34 mmol) was added to a solution of (R)-(-)-2-(benzyloxymethyl)oxirane (2.4 g, 14.6 mmol) in dry THF (200 ml). This mixture was cooled to -78° C. under argon atmosphere. A solution of vinylmagnesium bromide in THF (26 ml, 1M, 26 mmol) was added slowly to the epoxide solution at -78° C. The reaction mixture was stirred for 5 hours while the reaction temperature was allowed to warm to 0° C. Saturated aqueous NH4Cl and NH4OH were added to the reaction mixture till the reaction mixture became clear. Organic layer was separated and the aqueous layer was extracted with EtOAc (3×50 ml). Combined organic layers were dried over MgSO4 and concentrated. The residue was purified by chromatography (EtOAc/Hexane=1:9) to give 1-benzyloxy-2(S)-hydroxy-4-pentent (2.6 g, 13.5 mmol) NMR (CDCl3): 7.35 (bs, 5H), 5.84 (m, 1H), 5.14 (d, J=11, 1H), 5.11 (d, J=9, 1H), 4.57 (s, 2H), 3.90 (m, 1H), 3.53 (dd, J=3.4, 9.5, 1H), 3.39 (dd, J=7.4, 9.5, 1H) 2.29 (t, J=1.23, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([NH2:24])=[O:23]>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22](=[O:23])[NH2:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Reactant: NC(=O)[C@@H]1CCCN1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)CN1CCC[C@H]1C(N)=O

Procedure:
Using general procedure 1 and purification method D with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.10 g, 0.38 mmol) and (S)-proline amide (0.114 g, 0.57 mmol) gives the title compound.