Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:25]2[C:26](=[O:31])[NH:27][CH:28]=[CH:29][CH:30]=2)[CH:8]=[C:9](/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2C(F)(F)F)[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[F:32]C1C=CC=CC=1Br.FC(F)(F)C1C=CC=CC=1Br>>[C:1]([C:5]1[CH:6]=[C:7]([C:25]2[C:26](=[O:31])[NH:27][CH:28]=[CH:29][CH:30]=2)[CH:8]=[C:9](/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:32])[C:10]=1[O:11][CH3:12])([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1c(/C=C/c2ccccc2C(F)(F)F)cc(-c2ccc[nH]c2=O)cc1C(C)(C)C
Reactant: Fc1ccccc1Br
Agent: FC(F)(F)c1ccccc1Br
Product: COc1c(/C=C/c2ccccc2F)cc(-c2ccc[nH]c2=O)cc1C(C)(C)C

Procedure:
3-{3-tert-Butyl-4-methoxy-5-[(E)-2-(2-trifluoromethyl-phenyl)-vinyl]-phenyl}-1H-pyridin-2-one (I-239)) was prepared analogously except in step 2, o-fluoro-bromobenzene was replaced with o-trifluoromethyl-bromobenzene: MS (CI) mz/=429 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24].[CH3:27][C:28]1[C:32]([S:33]([Cl:36])(=[O:35])=[O:34])=[C:31]([CH3:37])[O:30][N:29]=1>>[ClH:36].[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:33]([C:32]3[C:28]([CH3:27])=[N:29][O:30][C:31]=3[CH3:37])(=[O:35])=[O:34])=[C:3]([NH:22][S:23]([CH3:26])(=[O:24])=[O:25])[CH:4]=2)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)c(NS(C)(=O)=O)c2)CC1
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Product: Cc1noc(C)c1S(=O)(=O)Nc1ccc(N2CCCNCC2)cc1NS(C)(=O)=O
Product: Cl

Procedure:
The compound was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}methanesulfonamide and 3,5-dimethylisoxazole-4-sulfonylchloride (89 mg, 0.455 mmol) 3 to give 120 mg of as purple solid. M+ 1 444.2 Calcd 444.13.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][O:11]C(=O)C)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].Cl.C(OCC(C)C)(=O)C>C(O)C(C)C>[CH2:6]([O:5][P:4]([CH2:9][CH2:10][OH:11])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(CCOC(C)=O)OCC
Agent: Cl
Solvent: CC(=O)OCC(C)C
Solvent: CC(C)CO
Product: CCOP(=O)(CCO)OCC
Yield: 62.8 %

Procedure:
100 g of 2-acetoxyethane phosphonic acid diethyl ester are blended with 200 ml of isobutyl alcohol containing 2 g of HCl and heated to 120°-150°C for 5 hours. A mixture of isobutyl acetate and isobutanol is removed continuously by distillation in the course of the reaction. By gas chromatography of the mixture of isobutyl acetate/isobutanol, no ethyl acetate and only traces of ethanol were found. 51 g of 2-hydroxyethane-phosphonic acid diethyl ester are obtained after distillation under reduced pressure, corresponding to a yield of 62% of the theoretical.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:13]([OH:21])[CH2:14]CCCCCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:13]([O:11][C:10](=[O:12])[C@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:1])(=[O:21])[CH3:14]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)OC(=O)[C@@H](N)Cc1ccccc1
Yield: 93.3 %

Procedure:
L-Phenylalanine (5.0 g, 0.03 mol), 1-octanol (3.9 g, 0.03 mol) and p-toluenesulfonic acid monohydrate (6.3 g, 0.038 mol) were suspended in toluene (200 ml) in a flask equipped with a Dean-Stark trap and refluxed for 20 h., resulting in a clear solution. Subsequently, the solvent was removed in vacuo and the remaining white solid was dissolved in CHCl3 (150 ml). This solution was extracted with 10% sodium carbonate, water and brine and dried over MgSO4. Evaporation of the solvent in vacuo yielded a colourless oil (7.7 g, 0.028 mol, 92%). 1H NMR (CDCl3): δ=7.19 (m, 5H), 4.04 (t, 2H, 3J=6.59 Hz), 3.67 (dd, 1H, 3JAB=5.5 Hz, 3JAB=7.7 Hz), 3.03 (dd, 1H, 2JAB=13.6 Hz, 3JAB=5.5 Hz), 2.81 (dd, 1H, 2JAB=13.6 Hz, 3JAB=7.7 Hz), 1.54 (m, 2H), 1.47 (s, 2H), 1.22 (a, 10H), 0.83 (t, 3H, 3J=6.8 Hz); 13C NMR (CDCl3): δ=175.1, 137.15, 129.15, 128.40, 126.65, 65.02, 55.75, 41.06, 31.65, 29.06, 28.41, 25.74, 22.51, 13.97.
Reaction SMILES: C([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH2:35])CCCCCCCCCCCCCCC.[N:36]#[C:37][NH2:38].[CH2:39](O)[CH2:40][CH2:41][CH3:42]>C(Cl)Cl>[CH2:42]([N:35]([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]/[CH:26]=[CH:25]\[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])[C:37](=[NH:38])[NH2:36])[CH2:41][CH2:40][CH2:39][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17]
Reactant: N#CN
Reactant: CCCCO
Reactant: CCCCCCCCCCCCCCCCCCCCCCCC/C=C\CCCCCCCCN
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCCN(CCCCCCCCCCCCCCCC)C(=N)N
Temperature: 120 °C
Reaction time: 2 h

Procedure:
The mixture of a hydrochloride salt of 1 (285 mg, 0.54 mmol), cyanamide (50 mg, 1.19 mmol) and 1-butanol (2 ml) was stirred at 120° C. for 2 hours. The cooled mixture was diluted with CH2Cl2(50 ml) and washed with saturated aqueous NaCl(Brine)/methanol 1:1 (50 ml). The organic layer was then dried (Na2SO4), evaporated to an oil and chromatographed on a column of silica gel using CH2Cl2/methanol/conc. NH4OH 40:10:2 giving 80 mg of the desired material (yield, 28%). 1H NMR (CDCl3) d 7.08 (br s, 1H, NH), 5.34 (m, 2H, CH═CH), 3.29 (m, 4H), 2.00 (m, 4H), 1.62 (m, 4H), 1.25 (m, 48H), 0.88 (m, 6H). FAB-MS: 535 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][C:15]=2[Cl:24])[CH:3]=1.[CH2:25](S(C1C=CC(F)=C(Cl)C=1)(=O)=O)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH2:23][CH3:25])(=[O:21])=[O:22])=[CH:16][C:15]=2[Cl:24])[CH:3]=1
Reactant: CS(=O)(=O)c1ccc(Nc2cc(Cl)ccc2CCC(=O)O)c(Cl)c1
Reactant: CCS(=O)(=O)c1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCS(=O)(=O)c1ccc(Nc2cc(Cl)ccc2CCC(=O)O)c(Cl)c1

Procedure:
A solution of the product from example 49 step (iii) (0.163 g) and the product of example 4 step (i) (0.200 g) and caesium carbonate (0.239 g) in NMP (10 ml) was refluxed at 100° C. for 3 hours. The mixture was partitioned between 2M sodium hydroxide and diethyl ether. The aqueous layer was acidified with 2M hydrochloric acid, extracted with ethyl acetate and the organic layer dried and concentrated under reduced pressure to give an oil. The residue was purified using RP prep HPLC. Yield 0.044 g.
Reaction SMILES: [O:1]=[C:2]1[C:14]2[C:13](OS(C3C=CC(C)=CC=3)(=O)=O)=[N:12][C:11]3[CH:26]=[CH:27][CH:28]=[CH:29][C:10]=3[C:9]=2[C:8]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]1=2.[NH2:30][CH2:31][CH2:32][CH2:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37][NH2:38].[C:40](=[O:43])([O-])[O-].[K+].[K+]>ClCCl>[CH3:39][N:34]([CH2:35][CH2:36][CH2:37][NH:38][C:13]1[C:14]2[C:40](=[O:43])[C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:8]=3[C:9]=2[C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[N:12]=1)[CH2:33][CH2:32][CH2:31][NH:30][C:13]1[C:14]2[C:2](=[O:1])[C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:8]=3[C:9]=2[C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[N:12]=1
Reactant: CN(CCCN)CCCN
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)Oc2nc3ccccc3c3c2C(=O)c2cnccc2-3)cc1
Agent: [K+]
Solvent: ClCCl
Product: CN(CCCNc1nc2ccccc2c2c1C(=O)c1cnccc1-2)CCCNc1nc2ccccc2c2c1C(=O)c1cnccc1-2

Procedure:
A mixture of toluene-4-sulfonic acid 7-oxo-7H-5,9-diaza-benzo[c]fluoren-6-yl ester (Reference Example 6c-2) (90 mg) and N1-(3-amino-propyl)-N1-methyl-propane-1,3-diamine (WAKO PURE CHEMICAL: 15 mg) and potassium carbonate (37 mg) was suspended in dichloromethane (10 ml) and heated at reflux temperature for five days under nitrogen. The mixture was roughly purified by short silica gel column chromatography developed by dichloromethane-methanol=100:1 and dichloromethane-methanol=1:1. The fractions that contained the desired product were combined and evaporated to dryness and purified again by silica gel thin layer chromatography developed by dichloromethane-methanol-ammonia water=90:10:1. The desired compound was obtained as a dark reddish powder.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[P:4]([OH:7])([OH:6])[OH:5]>O>[NH2:3][C:1]([P:4]([OH:7])([OH:6])=[O:5])([P:4]([OH:7])([OH:6])=[O:5])[CH3:2]
Reactant: OP(O)O
Reactant: CC#N
Solvent: O
Product: CC(N)(P(=O)(O)O)P(=O)(O)O
Temperature: 150 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
A 1 liter autoclave was charged with a mixture of acetonitrile (61.5 g, 1.5 moles), ISOPAR-M (300 g), and the wetting agents (7.5 g each). The mixture was pressurized with nitrogen and heated to 150° C. Melted phosphorous acid (246 g, 3.0 moles) was pumped into the reactor through 15 minutes. The reaction was continued for 3 hours, maintaining the temperature at 150° C. Water (300 g) was pumped in and the product was collected after cooling. Colorless crystals of 1-amino-1,1-diphosphono ethane was obtained as fine grains, 76% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][C:6](=[O:12])[C:5]2([CH3:14])[CH3:13].[C:15]([O:19][C:20]([N:22]1[CH:26]=[CH:25][CH:24]=[C:23]1B(O)O)=[O:21])([CH3:18])([CH3:17])[CH3:16].[F-].[K+].C1COCC1>CCOC(C)=O.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>[F:11][C:9]1[CH:10]=[C:2]([C:23]2[N:22]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH:26]=[CH:25][CH:24]=2)[CH:3]=[C:4]2[C:8]=1[NH:7][C:6](=[O:12])[C:5]2([CH3:14])[CH3:13]
Reactant: CC1(C)C(=O)Nc2c(F)cc(Br)cc21
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1cccc1-c1cc(F)c2c(c1)C(C)(C)C(=O)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.9 %

Procedure:
A vial was charged with 5-bromo-7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (1.0 g, 3.5 mmol), 1-tert-butoxycarbonyl-2-pyrroleboronic acid (1.12 g, 5.3 mmol), KF (0.67 g, 11.5 mmol), and Pd2(dba)3 monochloroform adduct (54 mg, 0.053 mmol) and placed under a nitrogen atmosphere. THF (8 mL) was added and the mixture was purged with nitrogen for 5 min. P(t-Bu)3 (10% wt. solution in hexane 0.370 mL, 0.126 mmol) was added via syringe and the mixture was stirred at 25° C. for 16 h. The mixture was diluted with EtOAc and filtered through a plug of silica gel and concentrated. Purification by flash chromatography (500 mL 25% hexane/CH2Cl2 then 500 mL 100% CH2Cl2 then 500 mL 5% ethyl acetate/CH2Cl2) afforded the title compound (1.06 g, 88%) as colorless crystals.
Reaction SMILES: [OH2:1].[CH3:2][P:3]([OH:5])[OH:4].[CH2:6]([OH:10])[CH2:7][CH2:8]C>>[C:6]([CH2:7][CH2:8][P:3]([CH3:2])(=[O:5])[OH:4])([OH:10])=[O:1]
Reactant: CCCCO
Reactant: O
Reactant: CP(O)O
Product: CP(=O)(O)CCC(=O)O

Procedure:
Hydrolysis of Dibutyl Carboxyethylmethylphosphinate 528 g (2 mol) of the dibutyl carboxyethylmethylphosphinate obtained according to Example 4 are charged to a 1 l five-neck flask fitted with thermometer, reflux condenser, high-speed stirrer and dropping funnel. At 160° C., 500 ml of water are metered in over 4 h and a butanol-water mixture is distilled off. 281 g of butanol are obtained, which corresponds to 95% of theory. The distillatively removed butanol is re-used to esterify the methylphosphonous acid. 300 g of carboxyethylmethylphosphinic acid are obtained as a white solid having a melting point of about 95° C. and a 31P NMR purity of >97%.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N:14]=[C:15]=[S:16])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CCOCC>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([NH:14][C:15]([N:21]3[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]3)=[S:16])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc2ccc(N=C=S)cc2s1
Reactant: CN1CCNCC1
Solvent: CCOCC
Product: CN1CCN(C(=S)Nc2ccc3nc(C(C)(C)C)sc3c2)CC1

Procedure:
70 g (0.28 mole) of 2-tert.-butyl-6-isothiocyanobenzthiazole are dissolved in 1200 ml of ether and 33 g (0.33 mole) of 4-methylpiperazine are added dropwise, while stirring. The mixture is stirred for 1 hour, filtered and washed first with ether, then with petroleum ether. 2-tert.-butyl-6-[(4-methylpiperazin-1-yl)-thiocarbonylamino]-benzthiazole having a melting point of 176-177° is obtained: ##STR13##
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[NH2:8].[Br:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH:17]=[CH:18][C:19](O)=O>>[Br:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[CH:17]=[CH:18]/[C:19]1[NH:1][C:2]2[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=2[N:8]=1
Reactant: COc1ccc(C=CC(=O)O)cc1Br
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Product: COc1ccc(/C=C/c2nc3c([nH]2)c(=O)n(C)c(=O)n3C)cc1Br
Yield: 43.3 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 2.00 g (11.8 mmol) of 5,6-diamino-1,3-dimethyluracil and 3.32 g (12.9 mmol) of 3-bromo-4-methoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dimethylformamide to give 2.00 g (yield 43%) of Compound 115 as a pale yellow powder.
Reaction SMILES: Br[CH:2]1[C:14]2([CH2:15][CH2:16][CH3:17])[C:9](=[CH:10][C:11](=[O:18])[CH2:12][CH2:13]2)[C:8]2[C:3]1=[CH:4][C:5]([O:21][CH3:22])=[C:6]([Cl:20])[C:7]=2[Cl:19].C[O:24]CCO>O.[N+]([O-])([O-])=O.[Ag+]>[Cl:19][C:7]1[C:6]([Cl:20])=[C:5]([O:21][CH3:22])[CH:4]=[C:3]2[C:8]=1[C:9]1[C:14]([CH2:15][CH2:16][CH3:17])([CH:2]2[OH:24])[CH2:13][CH2:12][C:11](=[O:18])[CH:10]=1
Reactant: CCCC12CCC(=O)C=C1c1c(cc(OC)c(Cl)c1Cl)C2Br
Reactant: COCCO
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: CCCC12CCC(=O)C=C1c1c(cc(OC)c(Cl)c1Cl)C2O

Procedure:
A mixture of 9-bromo-5,6-dichloro-7-methoxy-9a-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (6.29 g, 0.0157 mole) and silver nitrate (7.89 g, 0.047 mol) in 2-methoxyethanol (200 ml) and H2O (100 ml) was heated at reflux for 2 hours, filtered and evaporated to dryness. Chromatography of the residue on silica gel eluted with ethyl acetate-hexane (1:1) gave 1.2 g of 5,6-dichloro-9-hydroxy-7-methoxy-9a-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one which melted at 173°-5° C. and was used in Step C without further purification.
Reaction SMILES: [H-].[Na+].Cl.[C:4]([NH2:10])(=[NH:9])[CH2:5][CH2:6][CH2:7][CH3:8].[CH:11]([CH:13]=[CH:14][C:15]([O:17][CH3:18])=[O:16])=O.[CH2:19](O)C>C1C=CC=CC=1>[CH2:5]([C:4]1[NH:9][CH:11]=[C:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:10]=1)[CH2:6][CH2:7][CH3:8]
Reactant: COC(=O)C=CC=O
Reactant: CCO
Reactant: CCCCC(=N)N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCCCc1nc(CC(=O)OCC)c[nH]1

Procedure:
Sodium hydride (2.82 g, 0,117 mol) was dissolved in 30 ml of absolute ethanol at 0° C. Valeramidine hydrochloride (16.71 g, 0.123 mol) was added to this solution, and after 15 minutes the solution was filtered and the collected solid was washed with 20 ml of ethanol and 50 ml of benzene. The combined filtrates were diluted with 750 ml of benzene, 15 g (0.117 mol) of methyl 3-formylacrylate was added, and the mixture was refluxed for 18.5 h using a trap to remove water. The solvents were removed under vacuum and the residue slurried in ether. Evaporation of the ether solution gave the title compound as an oil.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([N:24]([CH3:26])[CH3:25])[CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C.[H][H].[Pd]>[CH3:25][N:24]([CH3:26])[C:21]1[CH:22]=[C:23]2[C:18]([CH:17]=[CH:16][N:15]=[C:14]2[N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:19][CH:20]=1
Reactant: CN(C)c1ccc2ccnc(N3CCN(Cc4ccccc4)CC3)c2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN(C)c1ccc2ccnc(N3CCNCC3)c2c1
Yield: 24.9 %

Procedure:
After dissolving 250 mg of 1-(4-benzylpiperazin-1-yl)-7-dimethylaminoisoquinoline as synthesized in above Step 2 in 20 ml of ethanol, 50 mg of 10% palladium-on carbon was added to the solution. This mixture was stirred for 16 hours at room temperature in hydrogen atmosphere. The insoluble matter was removed by filtration and the solvent was distilled off under reduced pressure. The residue was purified on silica gel column chromatography (methanol:chloroform=1:9) to provide 46 mg (25%) of 7-dimethylamino-1-piperazin-1-ylisoquinoline.
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[O:27])[CH:21]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C(O)C.Cl>O1CCCC1>[C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[O:27])[CH:21]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCc1cn(Cc2cccc(C(=O)Nc3ccccn3)c2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1cn(Cc2cccc(C(=O)Nc3ccccn3)c2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
A mixture of ethyl 3-[3-phenyl-1-[3-(2-pyridylaminocarbonyl)benzyl]-1H-pyrazol-4-yl]propionate (200 mg), 1 N aqueous sodium hydroxide solution (0.88 ml), ethanol (1 ml), and tetrahydrofuran (1 ml) was stirred at room temperature for one hour. 1 N hydrochloric acid (0.88 ml) was added to the reaction mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained crystals were collected by filtration, and 3-[3-phenyl-1-[3-(2-pyridylaminocarbonyl)benzyl]-1H-pyrazol-4-yl]propionic acid (110 mg, yield: 58%) was obtained. This was recrystallized from tetrahydrofuran-hexane. Melting point: 187–188° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]2[CH3:20])=[N:4][C:5]([Cl:9])=[N:6][C:7]=1[CH3:8].[F:21][C:22]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:23]=1[NH2:24]>CS(C)=O.C(OCC)(=O)C>[ClH:9].[CH3:1][C:2]1[C:3]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]2[CH3:20])=[N:4][C:5]([NH:24][C:23]2[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:22]=2[F:21])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3C2C)c1C
Reactant: Nc1ccc(F)cc1F
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1nc(Nc2ccc(F)cc2F)nc(N2CCc3ccccc3C2C)c1C
Product: Cl
Temperature: 120 °C
Reaction time: 2 h
Yield: 17.3 %

Procedure:
To the solution of 5,6-dimethyl-2-chloro4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine (0.8 g, 2.78 mmol) in dimethyl sulfoxide (1.5 ml), was added 2,4-difluoroaniline (0.5 ml, 4.9 mmol). The reaction mixture was heated to 120° C., stirred for 2 hours, and cooled to room temperature. The resulting solution was diluted with ethyl acetate, washed with water and sodium hydroxide solution, and dried over anhydrous magnesium sulfate. The organic layer was concentrated in vacuo. The resulting residue was subjected to silica gel column chromatography (eluent: ethyl acetate/dichloromethane =⅕), and then treated with ethyl ether solution saturated with hydrochloric acid to afford 0.2 g (17%) of the titled compound.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][C:11]([F:14])=[CH:12][N:13]=2)=[N:6][CH:5]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH:30]1[C:35]([OH:37])=[O:36]>>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][C:11]([F:14])=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH:30]2[C:35]([OH:37])=[O:36])=[C:4]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: O=C(O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncc(F)s2)=NC1c1ccc(Cl)cc1Cl
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2ncc(F)s2)=NC1c1ccc(Cl)cc1Cl
Yield: 60.8 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(5-fluorothiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.52 g, 1.06 mmol) was reacted with morpholine-3-carboxylic acid hydrochloride (0.21 g, 1.28 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellowish solid (0.35 g, 60%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:22][CH3:23])[CH:17]=3)[S:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH3:2].[C:26](O)(=[O:28])C.[OH-].[Na+].C(Cl)(Cl)Cl.CO>C=O.C(Cl)(Cl)Cl>[CH2:24]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:22][CH3:23])[CH:17]=3)[S:12][C:11]=2[C:10]([CH2:26][OH:28])=[CH:9][CH:8]=1)[CH3:25]
Reactant: CCN(CC)CCNc1cccc2sc3ccc(OC)cc3c(=O)c12
Reactant: CC(=O)O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCNc1ccc(CO)c2sc3ccc(OC)cc3c(=O)c12
Yield: 44.5 %

Procedure:
A solution of 2.70 g (7.5 mmol) of 1-[[2-(Diethylamino)ethyl]amino]-7-methoxy-9H-thioxanthen-9-one in 135 ml of 37% formalin containing 2.7 ml of N acetic acid was heated on the steam bath for 4 hr, cooled and made alkaline with 10N NaOH solution. The suspension was taken up in CHCl3. The extract was evaporated to dryness and covered with CHCl3. The extract was evaporated to dryness and covered with C2H5OH. The "dimer" separated: yield 400 mg. It was recrystallized from 2-methoxy-ethanol. The filtrate was evaporated to dryness to leave an oil, which, after chromatography on silica gel with CHCl3 -CH3OH as the eluant, furnished 1.30 g (44.5%) of the desired product, mp 103°-105° C. after crystallization from ethyl acetate-petroleum ether.
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([CH3:16])[CH:9]=2)=[O:4].[NH2:18][CH2:19][C:20]([O-:22])=[O:21].[Na+]>COCCO>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][C:10]([CH3:16])=[CH:11][CH:12]=2)[S:7][C:6](=[O:17])[C:5]=1[C:3]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:4]
Reactant: NCC(=O)[O-]
Reactant: COC(=O)c1c(O)c2ccc(C)cc2sc1=O
Agent: [Na+]
Solvent: COCCO
Product: Cc1ccc2c(O)c(C(=O)NCC(=O)O)c(=O)sc2c1
Yield: 94.8 %

Procedure:
A mixture of 4-hydroxy-7-methyl-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (80 mg, 0.32 mmol) and sodium glycinate (310 mg, 3.2 mmol) in 2-methoxyethanol (10 mL) was refluxed for 3 h. The reaction mixture was concentrated and the crude residue dissolved in water (50 mL), acidified to pH 3-4 using 1 N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to provide [(4-hydroxy-7-methyl-2-oxo-2H-thiochromene-3-carbonyl)-amino]-acetic acid (89 mg). MS ESI(−) m/e: 292.12 (M−1).
Reaction SMILES: C([N:3](CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=1)[O:12][CH2:13][CH:14]([OH:17])[CH2:15]N.[Cl:21][CH2:22][C:23](Cl)=[O:24]>O1CCCC1>[Cl:21][CH2:22][C:23]([NH:3][C:14]([CH2:13][O:12][C:11]1[CH:18]=[CH:19][CH:20]=[C:9]([Cl:8])[CH:10]=1)([OH:17])[CH3:15])=[O:24]
Reactant: O=C(Cl)CCl
Reactant: CCN(CC)CC
Reactant: NCC(O)COc1cccc(Cl)c1
Solvent: C1CCOC1
Product: CC(O)(COc1cccc(Cl)c1)NC(=O)CCl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 0.24 ml of triethylamine in 1 ml of anhydrous tetrahydrofuran was added to a solution of 300 mg of 3-(3-chlorophenoxy)-2-hydroxypropylamine in 4 ml of anhydrous tetrahydrofuran, whilst ice-cooling, and then 1 ml of a solution of 192 mg of chloroacetyl chloride in anhydrous tetrahydrofuran was added dropwise to the resulting mixture. The reaction mixture was then stirred at room temperature for 3 hours. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extract by evaporation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using a 3:2 by volume mixture of ethyl acetate and hexane as the eluent, to give 310 mg of the title compound, melting at 74° C. to 77° C.