Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:4])([O-:3])[NH2:2].[N-]=C=O.[C:8](Cl)(=O)N.[Cl:12][C:13]1[CH:14]=[C:15](N=C=O)[CH:16]=[C:17]([Cl:19])[CH:18]=1>CO>[Cl:12][C:13]1[CH:14]=[C:15]([NH:2][C:1](=[O:3])[O:4][CH3:8])[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: NC(=O)Cl
Reactant: NC(=O)[O-]
Agent: [N-]=C=O
Solvent: CO
Product: COC(=O)Nc1cc(Cl)cc(Cl)c1

Procedure:
The carbamate used as the starting material is obtained by reacting an isocyanate with an alcohol or a carbamic acid chloride with an alcohol in the presence of an alkali, in the conventional manner. For example, reaction of 3,5-dichlorophenyl isocyanate with methyl alcohol gives methyl N-(3,5-dichlorophenyl)-carbamate (melting point 121° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:12]=[C:11]([C:20]([OH:22])=O)[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=C(C2N(C3C=NC=CC=3)N=C(C([N:44]3[CH2:49][CH2:48][NH:47][C:46](=[O:50])[CH2:45]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:12]=[C:11]([C:20]([N:44]3[CH2:49][CH2:48][NH:47][C:46](=[O:50])[CH2:45]3)=[O:22])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3cccnc3)n2)CCN1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Br)c2)n(-c2cccnc2)n1
Agent: O=C1CNCCN1
Product: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Br)c3)n(-c3cccnc3)n2)CCN1

Procedure:
50 mg (0.14 mmol) of the compound of Example 32A is reacted analogously to the synthesis of the compound of Example 4 with 15 mg (0.15 mmol) of 2-oxopiperazine. 59 mg (96% of theory) of the title compound is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.Cl[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1.C(N(CC)C(C)C)(C)C>C(OCCO)C>[C:19]([O:18][C:16]([NH:15][C@@H:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][N:25]=2)=[CH:7][CH:6]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:17])([CH3:21])([CH3:20])[CH3:22]
Reactant: CCOC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Reactant: Clc1nccc2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCCO
Product: CCOC(=O)[C@H](Cc1ccc(Nc2nccc3ccccc23)cc1)NC(=O)OC(C)(C)C

Procedure:
A stirred solution of ethyl (S)-3-(4-aminophenyl)-2-(N-t-butyloxycarbonylamino)propanoate (3.08 g, 10.0 mmol), 1-chloroisoquinoline (1.80 g, 11.0 mmol) and N,N-diisopropylethylamine (1.42 g, 1.91 ml, 11.0 mmol) in 2-ethoxyethanol (1.0 ml) was heated at 130° for 4 h. The volatiles were removed in vacuo and the residue partitioned between EtOAc (120 ml) and saturated aqueous NaHCO3 (50 ml). The phases were separated and the aqueous layer was re-extracted with EtOAc (80 ml). The combined organic extracts were washed with brine (30 ml), dried (MgSO4) and evaporated in vacuo. The obtained dark oil was chromatographed (silica; 20-30% EtOAc/hexane) to afford the title compound as a pink oil which crystallised on standing (2.78 g, 64%). δH (CDCl3) 8.07 (1H, d, J 5.8 Hz), 7.93 (1H, d, J 8.4 Hz), 7.72 (1H, d, J 7.5 Hz), 7.63 (1H, d), 7.61 (2H, d, J 8.5 Hz), 7.51 (1H, t, J 6.8 Hz), 7.23 (1H, br s), 7.10 (1H, br s), 7.10 (2H, d, J 6.8 Hz), 5.02 (1H, br d, J 8.0 Hz), 4.54 (1H, br m), 4.16 (2H, t, J 7.1 Hz), 3.05 (2H, br m), 1.43 (9H, s), 1.25 (3H, t, J 7.1 Hz); m/z (ES+, 60V) 436 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[O:6][C@H:5]([C:7](=[O:29])[CH2:8][O:9][C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:4]([CH:30]=[CH2:31])[O:3]1.[CH:33]([Mg]Br)=[CH2:34]>O1CCCC1>[CH3:1][C:2]1([CH3:32])[O:6][C@H:5]([C@@:7]([OH:29])([CH:33]=[CH2:34])[CH2:8][O:9][C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:4]([CH:30]=[CH2:31])[O:3]1
Reactant: C=C[Mg]Br
Reactant: C=C[C@@H]1OC(C)(C)O[C@@H]1C(=O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: C=C[C@@H]1OC(C)(C)O[C@@H]1[C@@](O)(C=C)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred solution of 4 (14.66 g, 34.22 mmol) in tetrahydrofuran (150 ml) was added dropwise vinylmagnesium bromide (68.44 ml, 68.44 mmol, 1.0 M solution in tetrahydrofuran) at −78° C., and the reaction mixture was stirred for 1 hour at the same temperature. The reaction mixture was quenched by saturated ammonium chloride solution and brine, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated. The resulting oil was purified by column chromatography (hexane:ethyl acetate=9:1) to give 5 (15.62 g, 100%) as a white semi-solid; 1H NMR (400 MHz, CDCl3) δ 7.43-7.22 (m, 15H), 6.16 (dd, J=17.2, 10.8 Hz, 1H), 6.01-5.93 (m, 1H), 5.42 (dd, J=17.2, 1.2 Hz, 1H), 5.27 (dd, J=10.8, 1.2 Hz, 1H), 4.99 (d, J=16.0 Hz, 1H), 4.98 (d, J=11.2 Hz, 1H), 4.54-4.47 (m, 2H), 3.33 (d, J=8.8 Hz, 1H), 3.05 (d, J=8.4 Hz, 1H), 2.54 (bs, 1H), 1.46 (s, 3H), 1.40 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1.CN1CCCN(C)C1=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([O:16][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: O=C(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: Clc1ccc(C(=Cn2cncn2)OCc2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 7.2 %

Procedure:
670 mg (2.62 mmol) of 1-(2,4-dichlorophenyl)-2-[1,2,4]triazol-1-yl-ethanone in 12 ml of tetrahydrofuran and 4 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone were added to a suspension of 171 mg (3.92 mmol) of sodium hydride (55% in mineral oil) in 15 ml of tetrahydrofuran and 5 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) and stirred at room temperature for 3 hours. Thereafter, 396 mg (5.24 mmol) of benzyl bromide were added and the mixture was stirred at room temperature for a further 16 hours. The tetrahydrofuran was removed under a vacuum, the residue was added to 50 ml of water and extracted three times with 50 ml of diethyl ether each time. The combined organic phases were dried over magnesium sulphate and the diethyl ether was removed in a vacuum. The crude product was purified by column chromatography on silica gel (diethyl ether/pentane 1:4). In addition to mixed fractions with the C-alkylation product there were obtained 65 mg (7%) of pure 1-[2-(2,4-dichloro-phenyl)-2-benzyloxy-vinyl]-1H-[1,2,4]triazole as a colourless oil. [M+H]+ =345, 347.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:10])[C:5](=[CH:8][CH:9]=1)[CH:6]=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20]>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH:3]=1)[O:10][CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)C(C)Br
Reactant: O=Cc1ccc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cc(Cl)ccc1C=O
Temperature: 80 °C
Yield: 18.2 %

Procedure:
A mixture of 22.0 g (0.141 mole) of 4-chlorosalicylaldehyde, 30 g (0.22 mole) of anhydrous potassium carbonate, and 30.0 g (0.184 mole) of methyl 2-bromopropionate in 120 mL of N,N-dimethylformamide was heated at 80° C. for approximately 17 hours. At the end of that period, the reaction mixture was poured over ice and extracted successively with diethyl ether and ethyl acetate. The combined extracts were washed with water, dried over anhydrous magnesium sulfate, and filtered. The solvents were then evaporated under reduced pressure, leaving a residue weighing 20 g. This residue was purified by placing it on a silica gel column and eluting with diethyl ether/petroleum ether (25/75). After the product-containing fractions were combined and the solvents evaporated under reduced pressure, 6.23 g of methyl 2-(5-chloro-2-formylphenoxy)propionate was isolated as a yellow liquid. Similarly, other fractions were combined and evaporated, yielding 1.69 g of methyl 2-(3-chloro-2-formylphenoxy)propionate as a yellow liquid. The NMR spectra of both compounds were consistent with proposed structure of each. This reaction was repeated several times.
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[CH3:15][O:16][C:17](=[O:30])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=2)[CH:21]=[C:20]1[CH3:29].[F:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([C:41]2[CH:45]=[CH:44][S:43][C:42]=2[CH:46]=O)(=[O:40])=[O:39])=[CH:34][CH:33]=1>ClCCl.ClCCCl>[CH3:15][O:16][C:17](=[O:30])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=2)[C:21]([CH2:46][C:42]2[S:43][CH:44]=[CH:45][C:41]=2[S:38]([C:35]2[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=2)(=[O:39])=[O:40])=[C:20]1[CH3:29]
Reactant: O=Cc1sccc1S(=O)(=O)c1ccc(F)cc1
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cn1c(C)c(Cc2sccc2S(=O)(=O)c2ccc(F)cc2)c2cc(F)ccc21
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 79.1 %

Procedure:
A mixture of triethylsilane (0.79 g), trifluoroacetic acid (0.47 g) and 1,2-dichloroethane (2.0 mL) at −10° C. was treated dropwise with a mixture of (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester (0.1 g), 3-(4-fluorobenzenesulfonyl)thiophene-2-carbaldehyde (0.15 g) and 1,2-dichloroethane (3.0 mL), and the resulting mixture was stirred at −10° C. for 15 minutes and then at room temperature overnight. The mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and dichloromethane (1:1 to 0:1 by volume) to afford the title compound as a colourless gum (0.17 g).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:8]([C:9](O)=[O:10])=[CH:7][N:6]=[CH:5][CH:4]=1.Cl.[CH3:15][NH:16][O:17][CH3:18].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[CH3:18][O:17][N:16]([CH3:15])[C:9](=[O:10])[C:8]1[C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=[N:6][CH:7]=1
Reactant: CNOC
Reactant: O=C(O)c1cnccc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)c1cnccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-(trifluoromethyl)nicotinic acid (2.11 g, 11.04 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.077 g, 11.04 mmol) in DCM (20 mL) was added N-ethyl-N-isopropylpropan-2-amine (3.78 mL, 22.08 mmol), and HATU (4.20 g, 11.04 mmol). The reaction was stirred at rt under N2 for 5 h. The reaction was then diluted with H2O (50 mL) and extracted with DCM (2×50 mL). The organic layers were combined, dried (MgSO4), and concentrated to give the amide. Purification by ISCO (80 g SiO2, 10-50% EtOAc/hexanes) gives N-methoxy-N-methyl-4-(trifluoromethyl)nicotinamide as a yellow oil.
Reaction SMILES: [N+:1]([NH:4][C:5](=[NH:8])SC)([O-:3])=[O:2].[F:9][C:10]([F:28])([F:27])[CH2:11][N:12]=[C:13]([NH2:26])[NH:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([CH2:21][S:22][CH2:23][CH2:24][NH2:25])[N:16]=1.[C:29](#N)C>>[F:28][C:10]([F:9])([F:27])[CH2:11][N:12]=[C:13]([NH2:26])[NH:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([CH2:21][S:22][CH2:23][CH2:24][NH:25][C:5]([NH:8][CH3:29])=[N:4][N+:1]([O-:3])=[O:2])[N:16]=1
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: NCCSCc1nccc(NC(N)=NCC(F)(F)F)n1
Reactant: CC#N
Product: CNC(=N[N+](=O)[O-])NCCSCc1nccc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-Nitro-2-methylisothiourea (0.135 g.) was added to a stirred solution of 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[(2-aminoethyl)thiomethyl]pyrimidine (0.31 g.) in acetonitrile (5 ml.) and the suspension stirred at room temperature for 2 hours. The insoluble material was collected to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[2-(2-nitro-3-methylguanidino)ethyl thiomethyl]pyrimidine (0.35 g.) m.p. 199°-200° (decomp.)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]#[C:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:5]2.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][N:33]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[CH:34]=2)O1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.Cl[Pd]Cl>[NH3:6].[Cl:11][C:9]1[CH:10]=[C:2]([C:30]2[CH:31]=[N:32][N:33]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[CH:34]=2)[CH:3]=[C:4]2[C:8]=1[C:7](=[O:12])[N:6]([CH2:13][C:14]#[C:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:5]2
Reactant: CC1(C)OB(c2cnn(Cc3ccccn3)c2)OC1(C)C
Reactant: O=C1c2c(Cl)cc(Br)cc2CN1CC#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N
Product: O=C1c2c(Cl)cc(-c3cnn(Cc4ccccn4)c3)cc2CN1CC#Cc1ccccc1
Temperature: 110 °C
Yield: 128 %

Procedure:
To a solution of 5-bromo-7-chloro-2-(3-phenylprop-2-ynyl)-2,3-dihydroisoindol-1-one (60 mg, 0.167 mmol) in DMF (4 mL) was added 2-[4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)pyrazol-1-ylmethyl]pyridine (61.71 mg, 0.216 mmol), PdCl2 (13.57 mg, 0.017 mmol), and K2CO3 (70 mg, 0.5 mmol). The mixture was heated at 110° C. overnight, then poured into water and extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated. Column chromatography (4% (2M NH3 in MeOH)/CH2Cl2) provided the title compound (46.9 mg, 64%). 1H NMR (300 MHz, CDCl3): δ (ppm) 8.61 (d, 1H), 7.90 (dd, 1H), 7.45 (m, 4H), 7.32 (m, 5H), 7.18 (d, 1H), 5.49 (s, 2H), 4.66 (s, 2H), 4.53 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[O:15][C:14]([NH:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)=[N:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[NH:30][CH:31]=O.CCOC(C)=O>C(O)(=O)C>[NH:30]1[C:3]2[CH:4]=[CH:5][C:6]([C:8]3[C:16]4[O:15][C:14]([NH:17][C:18]5[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=5)=[N:13][C:12]=4[CH:11]=[CH:10][CH:9]=3)=[CH:7][C:2]=2[N:1]=[CH:31]1
Reactant: COc1cc(Nc2nc3cccc(-c4ccc(NC=O)c(N)c4)c3o2)cc(OC)c1OC
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1cc(Nc2nc3cccc(-c4ccc5[nH]cnc5c4)c3o2)cc(OC)c1OC

Procedure:
A solution of 0.182 g (0.243 mmol) N-{2-amino-4-[2-(3,4,5-trimethoxy-phenylamino)-benzooxazol-7-yl]-phenyl}-formamide in 3 ml acetic acid is stirred at 100° C. for 1 h. Then EtOAc is added to the reaction mixture and the organic layer is washed with 4N NaOH solution (2×) and with water (2×), dried over MgSO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography (silicagel, EtOAc=>EtOAc:MeOH=95:5) to afford the title compound as an orange solid. Rt=1.86 min (Waters Symmetry C8, 2.1×50 mm, detection 210-250 nM, 5% to 100% CH3CN in H2O in 2 min+0.05% TFA, flow rate 1.0 ml/min); MS: 417 (M+1)+; m.p. 150-156° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9](O)=[O:10])=[CH:4][CH:3]=1.S(Cl)([Cl:16])=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([Cl:16])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C(=O)Cl)c1ccc(Cl)cc1
Temperature: 40 °C

Procedure:
2-(4-chlorophenyl)-2-methyl propionyl chloride was prepared as follows: To a flask containing 2-(4-chlorophenyl)-2-methyl propionic acid (15.0 g, 75.6 mmol) was added thionyl chloride (approx. 6 mL). Dichloromethane (20 mL) was then added before adding an additional portion of thionyl chloride (approx. 12 mL). The reaction was allowed to heat to 40° C. for two hours before cooling to room temperature and concentrating in vacuo (azeotroping with tetrahydrofuran). The resulting acid chloride was used in the following acylation step without further purification or characterization.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1[C:19]1[O:20][CH2:21][CH:22]([OH:31])[CH:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:24]=1>ClCCCl>[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1[C:19]1[O:20][CH2:21][CH:22]([O:31][C:8](=[O:9])[NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:24]=1
Reactant: O=C=Nc1ccccc1
Reactant: OC1COC(c2cc3ccccc3[nH]2)=NC1c1ccccc1
Solvent: ClCCCl
Product: O=C(Nc1ccccc1)OC1COC(c2cc3ccccc3[nH]2)=NC1c1ccccc1
Reaction time: 7 h
Yield: 55.2 %

Procedure:
Phenyl isocyanate (2.3 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (4RS, 5RS)-2-(2-indolyl)-4-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (5.15 g) in 1,2-dichloroethane (50 cc). The solution obtained is stirred for 7 hours under reflux and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After two successive recrystallizations in diisopropyl ether, (4RS, 5RS)-2-(2-indolyl)-4-phenyl-5-phenylcarbamoyloxy-5,6-dihydro-4H-1,3-oxazine (4 g), m.p. 166° C., is obtained.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[CH:5][N:6](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:7]=1)=[O:2].BrC[C:29]1[CH:30]=[C:31]([C:40]([CH3:44])([CH3:43])[C:41]#[N:42])[CH:32]=[C:33]([C:35]([CH3:39])([CH3:38])[C:36]#[N:37])[CH:34]=1.C(#N)C.C(O)(=O)C>O>[CH:1]([C:3]1[N:4]([C:29]2[CH:34]=[C:33]([C:35]([CH3:38])([CH3:39])[C:36]#[N:37])[CH:32]=[C:31]([C:40]([CH3:43])([CH3:44])[C:41]#[N:42])[CH:30]=2)[CH:5]=[N:6][CH:7]=1)=[O:2]
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(C)(C#N)c1cc(CBr)cc(C(C)(C)C#N)c1
Solvent: CC(=O)O
Solvent: CC#N
Solvent: O
Product: CC(C)(C#N)c1cc(-n2cncc2C=O)cc(C(C)(C)C#N)c1

Procedure:
A mixture of 4-formyl-1-tritylimidazole (0.5 g), 2,2'-(5-bromomethyl-1,3-phenylene)di(2-methylpropiononitrile) and acetonitrile (2 ml) was heated under reflux for 30 h. The reaction mixture was treated with acetic acid (8 ml) and water (2 ml) and the mixture was then heated at 90° for 1 h. The mixture was diluted with water (20 ml) and washed with ether, the aqueous phase was basified with sodium carbonate, and the mixture was extracted three times with ethyl acetate. The combined extracts were dried and evaporated to dryness, and the residue was purified by flash chromatography using methanol (2% by volume) in chloroform as eluant, to give 2,2'-[5-(5-formylimidazol-1-yl)-1,3-phenylene]di(2-methylpropiononitrile), mp 108°-111°.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[CH2:2][C:3]([NH:5][C@H:6]([C:8]([N:10]1[CH2:21][CH2:20][CH2:19][C@H:11]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:9])[CH3:7])=[O:4].[H][H]>CO.[Pd]>[NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:8]([N:10]1[CH2:21][CH2:20][CH2:19][C@H:11]1[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[O:9])[CH3:7])=[O:4]
Reactant: [H][H]
Reactant: C[C@H](NC(=O)CNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: C[C@H](NC(=O)CN)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C

Procedure:
2.06 g of Z-Gly-Ala-Pro-OtBu are hydrogenated in 30 ml of methanol in the presence of 300 mg of Pd on charcoal (10%) at room temperature. The hydrogen uptake has ended after 90 minutes. The catalyst is filtered off and the filtrate is concentrated to about 5 ml. 10 ml of ether are added. The product crystallises out overnight. Melting point 132°-134° C.; Rf = 0.3 in the system chloroform-methanol (1:1) on silica gel.
Reaction SMILES: CCOC(C)=O.[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18](CNC(=O)OC(C)(C)C)=[CH:17][CH:16]=2)=[N:12][CH:13]=1.[CH2:30]([N:32](CC)CC)C.[F:37][C:38]1[C:46]([F:47])=[C:45]([F:48])[CH:44]=[CH:43][C:39]=1[C:40](Cl)=[O:41]>O>[F:37][C:38]1[C:46]([F:47])=[C:45]([F:48])[CH:44]=[CH:43][C:39]=1[C:40]([NH:7][C:8]1[CH:13]=[N:12][C:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([NH:32][CH3:30])=[CH:19][CH:20]=2)=[CH:10][CH:9]=1)=[O:41]
Reactant: O=C(Cl)c1ccc(F)c(F)c1F
Reactant: CC(C)(C)OC(=O)NCc1ccc(Oc2ccc(N)cn2)cc1
Reactant: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: CNc1ccc(Oc2ccc(NC(=O)c3ccc(F)c(F)c3F)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To an AcOEt (10 mL) solution of tert-butyl {4-[(5-aminopyridin-2-yl)oxy]phenyl}methylcarbamate (0.50 g) and triethylamine (0.32 g) was added 2,3,4-trifluorobenzoyl chloride (0.37 g) at 0° C. The mixture was stirred at room temperature for 1 hour. The mixture was poured into water and extracted with AcOEt. The organic layer was washed with water, saturated aqueous NaCl, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (10 mL), then added TFA (3 mL). After stirring at room temperature for 2 hours, the mixture was poured into saturated aqueous NaHCO3 and extracted with AcOEt. The organic layer was washed with water, saturated aqueous NaCl, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=2/1) to afford the title compound (0.55 g) as a white solid.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[N+:10]([O-])[CH:11]=[C:12]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21]CCl.[H][H]>C(O)C.[Pd]>[ClH:21].[O:1]([C:8]1[CH:9]=[N:10][CH:11]=[C:12]([N:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCl
Reactant: [O-][n+]1cc(Oc2ccccc2)cc(N2CCNCC2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cl
Product: c1ccc(Oc2cncc(N3CCNCC3)c2)cc1

Procedure:
To a solution of 12 g of 3-phenoxy-5-piperazinylpyridine N-oxide and 0.5 g of dichloromethane in 100 ml of ethanol is added 1 g of 20% Palladium on charcoal. The suspension is shaken under a pressure of 50 pounds per square inch of hydrogen atmosphere until no further drop in pressure occurs. The solution is filtered and concentrated in vacuo to give 3-phenoxy-5-piperazinylpyridine monohydrochloride; mp 191°-192.5° C. dec.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].O.[C:17](OCC)(=[O:19])[CH3:18]>C(OC(=O)C)(=O)C.S(=O)(=O)(O)O>[C:17]([O:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14])(=[O:19])[CH3:18]
Reactant: CCOC(C)=O
Reactant: O=C(O)C=Cc1ccc(O)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Oc1ccc(C=CC(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 g of 4-hydroxy-3-nitrocinnamic acid (prepared as described in Preparation 1) were dissolved in 30 ml of acetic anhydride. One drop of sulfuric acid was added to the solution, which was then stirred for 2 hours at room temperature. 50 ml of water were added the solution, and it was then stirred for a further 2 hours. At the end of this time, ethyl acetate was added, and the mixture was washed with water and with a saturated aqueous solution of sodium chloride, in that order, and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was mixed with toluene; the remaining acetic acid was removed by azeotropic distillation to obtain 10.2 g of the title compound as crystals.