Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([C:7]([SH:10])([CH3:9])[CH3:8])[NH2:6].[CH2:12]1CCN2C(=NCCC2)CC1.CI>CN(C=O)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([C:7]([S:10][CH3:12])([CH3:9])[CH3:8])[NH2:6]
Reactant: C1CCC2=NCCCN2CC1
Reactant: COC(=O)[C@H](N)C(C)(C)S
Agent: Cl
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@H](N)C(C)(C)SC
Reaction time: 1 h
Yield: 81 %

Procedure:
To a 0° C. solution of D-penicillamine methyl ester hydrochloride (0.250 g., 1.25 mmoles) in DMF (4 mL) was added DBU (0.382 ml., 2.56 mmoles), followed by methyl iodide (0.081 ml., 1.31 mmoles). After 1 hour, the solution was partitioned between brine and ethyl acetate, and the organic layer was dried over sodium sulfate and concentrated. The residue was purified on silica, eluting with 6% methanol in dichloromethane to give S-methyl-D-penicillamine methyl ester as a colorless oil in 81% yield: 1H--NMR (CDCl3) δ 1.25 (s, 3H) 1.35 (s, 3H), 2.02 (s, 3H), 3.44 (s,1H), 3.72 (s, 3H); FAB HRMS:expected (M+H)=178.0902, found (M+H)=178.0905.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:16]=[N:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=4[CH3:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH2:24][OH:25])=[CH:4][CH:3]=1.C(N(CC)CC)C>CS(C)=O.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:24]=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:16]=[N:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[CH3:21])[CH2:12][CH2:13][CH2:14][N:7]21
Reactant: COc1cc(C)c(N2CCCn3c2nc2c(Cl)ccc(CO)c23)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(C)c(N2CCCn3c2nc2c(Cl)ccc(C=O)c23)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 18.6 %

Procedure:
Sulfur trioxide-pyridine complex (3.42 g, 21.5 mmol) was added to a stirred solution of [9-chloro-1-(6-methoxy-4-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]methanol (1.19 g, 3.31 mmol), triethylamine (3.7 mL) in dimethyl sulfoxide (10 mL) at room temperature, and the mixture was stirred at room temperature for 5 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a pale yellow solid (220 mg, 0.617 mmol, 19%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Cl:11])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].Cl[Sn]Cl>C(O)C>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:11])=[CH:4][C:3]=1[C:12]([F:15])([F:13])[F:14]
Reactant: Nc1c([N+](=O)[O-])cc(Cl)cc1C(F)(F)F
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1cc(Cl)cc(C(F)(F)F)c1N
Temperature: 90 °C
Yield: 82.4 %

Procedure:
To a stirred mixture of 2-amino-5-chloro-3-nitrobenzotrifluoride (250 mg, 1.043 mmol) in ethanol (4 mL) was added SnCl2 ·2H2O (1.174 g, 5.217 mmol) in one portion. The mixture was refluxed at 80° C. (oil bath 90° C.) for 1 h. The solution was cooled to room temperature and ice water (20 g) was added. It was adjusted to pH=7 and extracted with ethyl acetate. The extract was dried (Mg2SO4) and evaporated to give 181 mg (83%) of 2,3-diamino-5-chlorobenzotrifluoride as a brown solid. 1H NMR (CDCl3): δ3.515 (s, 2H); 3.878 (s, 2H); 6.845 (s, 1H); 6.988 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH3:29][NH:30][CH2:31][CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:29][NH:30][CH2:31][CH2:32][NH:33][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:26])([F:28])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: CNCCN
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CNCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 60 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-methylamino-ethyl)-amide (28 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (41 mg), N-methyl-ethylendiamine (25 mg), HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 466. 1H NMR (DMSO-d6, 400 MHz): δ 8.43 (br, 1H), 8.20 (br, 1H), 7.95 (s, 1H), 7.88 (m, 1H), 7.69 (m, 2H), 7.56 (d, 1H), 7.38 (d, 1H), 7.23 (d, 1H), 3.59 (s, 3H), 3.44 (m, 2H), 2.98 (m, 2H), and 2.70 (d, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([C:11](=[O:13])[CH3:12])=[C:6]([CH3:14])[CH:5]=1)[CH3:2].[Br-:15].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[Br:15][CH2:12][C:11]([C:7]1[C:8]([CH3:10])=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=1[CH3:14])=[O:13]
Reactant: CCOc1cc(C)c(C(C)=O)c(C)c1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: CCOc1cc(C)c(C(=O)CBr)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.5 %

Procedure:
To a solution of 1-(4-ethoxy-2,6-dimethylphenyl)ethanone (4.00 g, 20.8 mmol) in acetonitrile (41.6 mL) was added tetrabutylammoniumtribromide (TBABr3, 10.0 g, 20.8 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-bromo-1-(4-ethoxy-2,6-dimethylphenyl)ethanone (6.40 g), which was used directly for the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14]CC2C=CC=CC=2)[C:9]=1[C:22]([NH2:24])=[O:23])=[O:6])[CH3:2].[H][H]>[Pd]>[CH2:1]([O:3][C:4](=[O:25])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[C:9]=1[C:22]([NH2:24])=[O:23])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)Nc1cccc(OCc2ccccc2)c1C(N)=O
Reactant: [H][H]
Agent: [Pd]
Product: CCOC(=O)C(=O)Nc1cccc(O)c1C(N)=O

Procedure:
A mixture of 3.4 g. of [2-(aminocarbonyl)-3-benzyloxyphenylamino]oxoacetic acid ethyl ester and 0.3 g. of 5% Pd on charcoal is hydrogenated until hydrogen uptake ceases. The mixture is filtered through celite; the filtrate is evaporated and the residue is recrystallized to give pure product, m.p. 200°-202° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[O:11][C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]([C:24]#[C:25][CH3:26])[CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=1.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.[F-].[Cs+]>COCCOC.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>[F:27][C:28]([F:39])([F:38])[C:29]1[CH:30]=[C:31]([C:10]2[CH:2]=[C:3]3[C:7](=[CH:8][CH:9]=2)[CH:6]([O:11][C:12]2[CH:13]=[CH:14][C:15]([C@@H:18]([C:24]#[C:25][CH3:26])[CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:17]=2)[CH2:5][CH2:4]3)[CH:32]=[CH:33][CH:34]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC#C[C@@H](CC(=O)OC)c1ccc(OC2CCc3c(Br)cccc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: CC#C[C@@H](CC(=O)OC)c1ccc(OC2CCc3cc(-c4cccc(C(F)(F)F)c4)ccc32)cc1
Temperature: 95 °C

Procedure:
A mixture of 1.3 (74 mg, 0.18 mmol), 4-(trifluoromethyl)phenylboronic acid (45.8 mg, 0.22 mmol) and CsF (56 mg, 0.37 mmol) in 1,2-dimethoxyethane (2 mL), was degassed with N2 for 3 minutes. Pd(PPh3)4 (21 mg, 0.018 mmol) was added, and the resulting mixture was heated at 95° C. for 8 hours. After cooling, the reaction mixture was quenched with water and extracted with EtOAc providing 1.4 (20 mg), which was directly hydrolyzed in the next step.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:4]=1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[CH:9][CH:8]=1.CCN(CC)CC.Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CC#N>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][N:15]1[CH2:16][CH2:17][O:18][CH:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]3[C:3]([Cl:2])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:23])=[CH:12][CH:11]=2)[CH2:14]1)[CH3:37]
Reactant: CCOC(=O)CBr
Reactant: Clc1cccc(Cl)c1COc1ccc(C2CNCCO2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CN1CCOC(c2ccc(OCc3c(Cl)cccc3Cl)cc2)C1
Temperature: 85 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A mixture of 2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine hydrochloride (0.65 g; 1.68 mmol), Et3N (0.58 mL; 4.2 mmol), and ethyl bromoacetate (0.24 ml; 2.19 mmol) in CH3CN (65 mL) was stirred at 85° C., overnight. After cooling to RT the mixture was concentrated in vacuo and the residue partitioned between water and CH2Cl2. The layers were separated and aqueous layer was extracted once more with CH2Cl2. The combined organic layers were concentrated in vacuo and the residue was purified by column chromatography (SiO2, Et2O:hexanes 2:1) to afford {2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-acetic acid ethyl ester (0.62 g).
Reaction SMILES: C1C=C[NH+]=CC=1.Br[Br-]Br.[CH3:10][C:11]1[NH:12][C:13](C)=[C:14]([C:29]([O:31][CH3:32])=[O:30])[CH:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])[C:16]=1[C:17]([O:19][CH3:20])=[O:18].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:10][C:11]1[NH:12][C:13]2[CH2:32][O:31][C:29](=[O:30])[C:14]=2[CH:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])[C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1OC
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1ccccc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
In a manner similar to that described in the preceding examples, 1.45 grams of 80 percent pyridinium bromide perbromide was added to a cooled to 0° C. solution of 1.00 gram (3.02 millimoles) of dimethyl 2,6-dimethyl-4(2-methoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylate and 0.40 milliliter of pyridine in 20 milliliters of chloroform. The mixture was then stirred at 0° C. for about 30 minutes and at reflux temperature for about 90 minutes. Thereafter the mixture was allowed to cool, diluted with chloroform, washed with 2N hydrochloric acid and brine, dried and the solvent evaporated to obtain a crude product residue. The latter was flash chromatographed on 35 grams of silica gel to obtain 510 milligrams (54 percent yield) of purified methyl 2-methyl-4-(2-methoxyphenyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate product. A portion of the product was recrystallized from ethyl acetate-hexane for elemental analyses which were as follows:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CC(C)([O-])C.[K+].[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[C:27]1([CH3:30])[CH2:29][O:28]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[C:27]([OH:28])([CH3:29])[CH2:30][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1c[nH]cn1
Reactant: CC1(c2cc(Cl)ccc2OCc2ccccc2)CO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(O)(Cn1ccnc1)c1cc(Cl)ccc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 91.1 %

Procedure:
Imidazole (4.0 g, 58.8 mmol) and potassium t-butoxide (6.5 g, 57.9 mmol) were added to a solution of 2-(2-(benzyloxy)-5-chlorophenyl)-2-methyloxirane [compound (10-1), obtained in Referential Example 8] (4.4 g) in dimethylformamide (60 mL), and the mixture was stirred for 12 hours at 80° C. After the mixture was cooled to room temperature, ice-water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography and dried under reduced pressure, to thereby yield 2-(2-(benzyloxy)-5-chlorophenyl)-1-(1H-1-imidazolyl)-2-propanol as colorless crystals (5.0 g, yield: 75.8%).
Reaction SMILES: Cl.[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH2:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:12][C:13]([F:23])([F:22])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.O>[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH:11][CH2:18][C:17]2[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:22])[F:23])=[CH:21][CH:20]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: FC(F)(F)c1ccc(CN[C@@H]2C[C@H]2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.9 %

Procedure:
A mixture of (trans)-2-phenylcyclopropanamine hydrochloride (0.23 g, 1.36 mmol) and 4-(trifluoromethyl)benzaldehyde (0.20 mL, 1.49 mmol) in CH2Cl2 (8 mL) and water (0.5 mL) was vigorously stirred at room temperature for 10 min. Then, NaBH(OAc)3 (0.37 g, 1.76 mmol) was slowly added and stirring continued for 30 min. The reaction mixture was washed with an aqueous saturated solution of NaHCO3 (8 mL), the organic layer was dried over anhydrous Na2SO4, filtered and, after removal of the solvent, the residual oil was purified by column chromatography on silica gel (1% MeOH/CH2Cl2) affording 0.15 g of N-[(trans)-2-phenylcyclopropyl]-N-[4-(trifluoromethyl)benzyl]amine [Rf=0.6 (5% MeOH/CH2Cl2), colorless oil, 38% yield].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][C:6]([C:10](=O)[CH3:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.CN.[BH3-][C:17]#[N:18].[Na+]>CCO>[CH3:17][NH:18][CH:10]([C:6]1[N:5]=[C:4]2[CH:3]=[CH:2][NH:1][C:9]2=[CH:8][CH:7]=1)[CH3:11]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1ccc2[nH]ccc2n1
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CNC(C)c1ccc2[nH]ccc2n1

Procedure:
A microwave vial was charged with 1-(1H-pyrrolo[3,2-b]pyridin-5-yl)ethanone (1.50 g, 9.36 mmol), methanamine hydrochloride (8.85 g, 131.1 mol), NaBH3CN (765.0 mg, 12.18 mmol), and anhydrous EtOH (31 mL) and stirred while irradiated in a microwave (300 Watts) at 130° C. for 2 min. The resulting solid was filtered and rinsed well with EtOH. The filtrate was concentrated in vacuo. The crude product was redissolved in EtOAc and twice washed with 10% aq. NaOH, water and brine. The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was triturated with DCM, and the insoluble solid was filtered through a pad of Celite®. The filtrate was concentrated in vacuo and dried under high vacuum to afford N-methyl-1-(1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine as a solid: 1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.45 (d, J=3.3 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 6.72 (d, J=3.3 Hz, 1H), 3.95 (q, J=6.7 Hz, 1H), 2.37 (s, 3H), 1.47 (d, J=6.7 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([CH2:26][CH3:27])=[N:12][CH:13]=[CH:14][C:15]=2[C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[C:18]([F:25])[CH:17]=2)=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([CH2:26][CH3:27])=[N:12][CH:13]=[CH:14][C:15]=2[C:16]2[CH:24]=[CH:23][C:19]([C:20]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:22])=[C:18]([F:25])[CH:17]=2)=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: CCc1nccc(-c2ccc(C(=O)O)c(F)c2)c1C#Cc1ccc(N)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1nccc(-c2ccc(C(=O)N3CCOCC3)c(F)c2)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP5 starting from 120 mg (0.33 mmol) 4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-benzoic acid (A-38) using 43 mg (0.50 mmoL) morpholine, 139 mg (0.37 mmol) HATU and 96 μL DIEA in 1.2 mL DMF. After completion of the reaction, DMF is removed under reduced pressure and the product is purified by chromatography on silica gel using a DCM/MeOH-gradient. Yield: 66 mg (46%).
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:30]([OH:32])[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:41]1([P:47](Cl)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O1CCCC1>[C:41]1([P:47]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)(=[O:48])[O:32][C:30]([CH3:31])=[C:16]([N:13]2[C:12](=[O:33])[CH:11]3[CH:14]2[S:15][C:9]([CH2:8][O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:10]3)[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Reactant: CC(O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(OP(=O)(c1ccccc1)c1ccccc1)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Temperature: 20 °C
Reaction time: 3 h

Procedure:
To a stirred solution of p-nitrobenzyl α-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-yl)-α-(1-hydroxyethylidene)acetate (4.69 g) in tetrahydrofuran (60 ml) under a nitrogen atmosphere at 0°-5° C. was added triethylamine (1.6 ml.) followed by diphenylphosphinyl chloride (2.73 g.) dropwise over 5 minutes. After stirring for 3 hours at 20° C., the tetrahydrofuran was evaporated and the residue dissolved in dichloromethane. The resulting solution was washed with 1% hydrochloric acid and then water, dried with magnesium sulphate and evaporated to give the title compound as a pale yellow friable foam in essentially quantitative yield. TLC (silica) RF 0.54 (ethyl acetate). NMRδCDCl3 2.5 (s, 3H), 3.63 and 4.40 (ABq, 2H, J=14 Hz), 5.13 (s, 2H), 5.68 (d, 1H, J=4 Hz), 5.85 (d, 1H, J=4 Hz) and 6.5-8.03 (m, 20H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[C:4]([F:11])[CH:3]=1.[O:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=2)[CH2:14][CH2:13]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:23]2[CH2:22][CH2:21][CH2:20][CH:19]=[C:18]2[N:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)=[S:10])=[C:4]([F:11])[CH:3]=1
Reactant: C1=C(N2CCOCC2)CCCC1
Reactant: Fc1cc(Cl)ccc1N=C=S
Solvent: ClC(Cl)Cl
Product: Fc1cc(Cl)ccc1NC(=S)C1CCCC=C1N1CCOCC1
Reaction time: 10 h
Yield: 87.9 %

Procedure:
In 400 ml of chloroform was dissolved 78.9 g of 4-chloro-2-fluorophenyl isothiocyanate, and 68.6 g of 1-morpholino-1-cyclohexene was added dropwise to the solution with stirring over a 10-minute period. After stirring was continued at room temperature for 10 hours, the reaction mixture was concentrated under reduced pressure, and the residue was treated with a small amount of cold ethanol. The resulting crystals were collected by filtration, and there was obtained 127.9 g (yield of 86%) of the subject compound, m.p. 86°-88° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]=1[CH:12]=O.[S:14]1[CH2:20][C:18](=[O:19])[NH:17][C:15]1=[S:16].C(O)(=O)C.C([O-])(=O)C.[Na+]>O>[C:6]([C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[C:4]=1[CH:12]=[C:20]1[S:14][C:15](=[S:16])[NH:17][C:18]1=[O:19])([OH:8])=[O:7]
Reactant: COc1cccc(C(=O)O)c1C=O
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc(C(=O)O)c1C=C1SC(=S)NC1=O

Procedure:
To a stirred hot solution of 0.45 g. (2.50 mM) of 3-methoxyphthalaldehydic acid and 0.34 g. (2.50 mM) rhodanine in 3ml. of acetic acid is added 0.68 g. (8.2 mM) of anhydrous sodium acetate. The resulting solution is refluxed 1.5 hours, cooled, and poured into 40 ml. of water to give a yellow gum which slowly solidifies to a yellow solid. The solid is collected, washed with water, and air-dried to give 5-(2-carboxy-6-methoxybenzylidene)rhodanine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[C:10](=[O:12])[CH:11]=2)=[CH:3][CH:2]=1.C1C(=O)N([Br:24])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:24][C:11]1[C:10](=[O:12])[C:9]2([CH2:16][CH2:15][CH2:14][CH2:13]2)[O:8][C:7]=1[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1C=C(c2ccncc2)OC12CCCC2
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C1C(Br)=C(c2ccncc2)OC12CCCC2
Reaction time: 1 h
Yield: 72.9 %

Procedure:
To a stirred solution of afford 2-(pyridin-4-yl)-1-oxaspiro[4.4]non-2-en-4-one (0.18 g, 0.84 mmol) in CHCl3 (10 mL) was added NBS (0.22 g, 1.25 mmol) portionwise at RT and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with DCM (30 mL), washed with water (10 mL), brine (10 mL), dried over Na2SO4, filtered and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 3-bromo-2-(pyridin-4-yl)-1-oxaspiro[4.4]non-2-en-4-one (0.18 g, 40%) as an oil.
Reaction SMILES: [CH2:1]([N:5]=[C:6]([OH:20])[C:7]1[C:8](=[C:12](Cl)[C:13](Cl)=[C:14](Cl)[C:15]=1Cl)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4].[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH2:1]([N:5]=[C:6]([OH:20])[C:7]1[C:8](=[C:12]([S:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]([S:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:14]([S:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]=1[S:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: Sc1ccccc1
Reactant: CCCCN=C(O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCCCN=C(O)c1c(Sc2ccccc2)c(Sc2ccccc2)c(Sc2ccccc2)c(Sc2ccccc2)c1C(=O)O

Procedure:
20 g (58.65 millimols) of tetrachlorophthalic acid N-n-butylimide, 26.49 g (240.5 millimols) of thiophenol, 49.04 g (355 millimols) of potassium carbonate and 200 ml of ethyl acetate are stirred at 25° C. for 18 hours and worked up as described in the preceding examples. After recrystallisation from toluene/cyclohexane, 35.99 g (97% of theory) of tetrakis-(phenylthio)-phthalic acid N-n-butylimide are obtained: melting point 159°-60° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=[O:13])[CH:6]=[C:5]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:4]=1.[BH4-].[Na+]>C(Cl)Cl.CO>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH2:12][OH:13])[CH:14]=[CH:15][CH:16]=2)[CH:6]=[C:5]([NH:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[N:4]=1
Reactant: COc1ccc(CCNc2cc(-c3cccc(C=O)c3)nc(OC)n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(CCNc2cc(-c3cccc(CO)c3)nc(OC)n2)cc1
Reaction time: 0.17 h
Yield: 109.5 %

Procedure:
A solution of 3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzaldehyde [33 mg, 0.08 mmol, Example 35(u)] in a mixture of DCM (3 mL) and MeOH (1 mL) is treated with sodium borohydride (100 mg). After 10 minutes at 20° C., the mixture is concentrated, and extracted twice with EtOAc (10 mL). The combined extracts are dried over magnesium sulfate and filtered through a plug of silica gel to afford (3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-methanol [32 mg, 100%, Example 9(c)]. LCMS: RT=2.18 minutes, MS: 366 (M+H).