Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH:23]=[C:22](OS(C(F)(F)F)(=O)=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH:21]=[C:22]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(C#N)c2)CC1
Yield: 77.9 %

Procedure:
3-Cyanophenyl boronic acid (1.8 g, 12.2 mmol) and 4-(trifluoromethanesulfonyloxy)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (5.0 g, 15.2 mmol;) are dissolved in acetonitrile (60 ml) and 0.4 M aqueous sodium carbonate (60 ml). The solution is degassed and treated with palladium tetrakistriphenyl phosphine (0.81 g, 0.7 mmol) at 90° C. for 1 hour. The reaction is cooled, filtered warmed and the filtrate is concentrated to an oil. The oil is extracted with methylene chloride (3×) and the solvent is removed under vacuum. The residue is chromatographed (15% ethyl acetate/hexane) to give the title compound as a white solid (2.7 g, 9.5 mmol). 1H NMR (CDCl3, 300 MHz) δ 7.63 (s, 1H), 7.55 (m, 2H), 7.44 (t, 1H), 6.10 (br, 1H), 4.09 (m, 2H), 3.63 (t, 2H), 2.50 (br, 2H). EI MS M++1: 285.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([NH:11]C(OC(C)(C)C)=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[C:5]1([CH:4]([NH2:11])[CH2:3][CH2:2][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)NC(CCBr)c1ccccc1
Product: NC(CCN1CCCCC1)c1ccccc1

Procedure:
The procedure given in Example 2 except for the formation of salts was followed using 3-bromo-1-(tert-butoxycarbonyl)amino-1-phenyl propane and piperidine as reactants, instead of d-1-bromo-2-(tert-butoxycarbonyl)amino-3-phenyl propane and hexamethyleneimine to give 1-Phenyl-3-(1-piperidinyl)-n-propylamine.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5]C[CH2:3][CH2:2]1.[CH:8]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C>C(OCC)(=O)C>[CH2:16]([O:15][C:8]1([O:12][CH2:13][CH3:14])[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]1)[CH3:17]
Reactant: O=C1CCCCC1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC1(OCC)CCCCC1
Reaction time: 1 h

Procedure:
In a 200-ml three-neck flask, 4.45 g (45.2 mmol) of cyclohexanone, 7.05 g (47.5 mmol) of triethyl orthoformate, 0.04 g of p-toluenesulfonic acid (monohydrate), 4.15 g (90 mmol) ethanol and 95 ml of ethyl acetate were heated to 100° C. and kept at this temperature for 1 hour (reflux). Thus, 1,1-diethoxycyclohexane was formed. Then 4.0 g (22.7 mmol) of D-isoascorbic acid was added and the first heterogeneous mixture was refluxed for 5 hours, and a clear solution was formed. Then 2 g of aluminum oxide was added, the suspension was stirred for 1 more hour at room temperature and filtered over Celite®, which was rewashed three times with ethyl acetate. The filtrate was concentrated by evaporation at 35° C./30 mbars to 20.5 g, and a viscous pulp was formed. The product was completely precipitated by addition of 20 ml of hexane, filtered off and dried. The yield was 5.05 g (86.8 percent). The product had a melting point: 177° to 178.5° C. The product had the following properties:
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:25]#[C:26][C:27]4[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:37]1(C)C=CC=CC=1.[OH-].[Na+].S(OC)(OC)(=O)=O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:1]12([C:11]3[CH:12]=[C:13]([C:25]#[C:26][C:27]4[CH:28]=[CH:29][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:35][CH:36]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH3:37])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COC(=O)c1ccc(C#Cc2ccc(OCCCCCCO)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Reactant: Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COCCCCCCOc1ccc(C#Cc2ccc(C(=O)OC)cc2)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 4 h

Procedure:
390 mg (0.8 mmol) of methyl 4-[3-(1-adamantyl)-4-(6-hydroxyhexyloxy)phenylethynyl]benzoate, 10 ml of toluene and 200 μl of a 50% sodium hydroxide solution were introduced into a round-bottomed flask. 20 mg (5.4 mmol) of tetrabutylammonium iodide and 100 μl (0.9 mmol) of dimethyl sulfate were added and stirring was carried out at room temperature for four hours. The reaction mixture was poured into water and extracted with ethyl acetate and the organic phase was separated by settling, dried over magnesium sulphate and evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)[CH2:9][C:10]([C:12]1[CH:13]=[N:14][C:15]([O:18]C)=[CH:16][CH:17]=1)=[O:11].Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[NH:14][CH:13]=1)=[O:11]
Reactant: COc1ccc(C(=O)CC(c2ccccc2Cl)C2CCN(C)CC2)cn1
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCC(C(CC(=O)c2ccc(=O)[nH]c2)c2ccccc2Cl)CC1

Procedure:
In analogy to example 162, step 2, 3-(2-chloro-phenyl)-1-(6-methoxy-pyridin-3-yl)-3-(1-methyl-piperidin-4-yl)-propan-1-one was reacted with concentrated aqueous HCl in 1,4-dioxane to give the title compound as a colorless foam, MS (ESI+): m/z=359.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:12][CH2:13][CH2:14][C@@H:15]([OH:19])[C:16]([OH:18])=[O:17].[OH-].[Na+].Cl>O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:12][CH2:13][CH2:14][C@@H:15]([OH:19])[C:16]([OH:18])=[O:17])=[O:8])=[CH:5][CH:4]=1
Reactant: NCC[C@@H](O)C(=O)O
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(C(=O)NCC[C@@H](O)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
17.2 g of p-methoxybenzoyl chloride are added while stirring well to 6.0 g of (R)-4-amino-2-hydroxy-butyric acid and 150 ml of ion-free water. The mixture is then adjusted to pH 10.5 with 2 N sodium hydroxide and stirred at room temperature for 70 minutes. The clear solution is treated with ice and adjusted to pH 1.4 with 25% hydrochloric acid. The separated solid is filtered off and washed with water. The filtrate is adjusted to pH 5.5 with sodium hydroxide and concentrated in a water-jet vacuum. The clear colourless solution is adjusted to pH 1.4 with 25% hydrochloric acid and extracted firstly with ether and then with ethyl acetate. The aqueous phases are adjusted to pH 5.5, concentrated, acidified with 25% hydrochloric acid and extracted with ethyl acetate. The combined ethyl acetate extracts are evaporated and the residue is recrystallised from ethyl acetate. There is obtained (R)-4-(p-methoxybenzoylamino)-2-hydroxy-butyric acid of melting point 105°-106° C.; [α]D20 = -12.4°; [α]36520 =-60.5° (c=1.0 in water). A further amount of (R)-4-(p-methoxybenzoylamino)-2-hydroxy-butyric acid of melting point 103.5°-104.5° C. can be isolated from the mother liquors.
Reaction SMILES: [CH2:1]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:18]1(=[O:25])[O:24][C:22](=[O:23])[CH2:21][O:20][CH2:19]1>>[CH3:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][N:9]([C:22]([CH2:21][O:20][CH2:19][C:18]([OH:25])=[O:24])=[O:23])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C1COCC(=O)O1
Reactant: CCCCCCCCNCCCCCCCC
Product: CCCCCCCCN(CCCCCCCC)C(=O)COCC(=O)O

Procedure:
In Examples 2, 3 and 4 wherein a ratio of the amount (B mmol) of dioctylamine to the amount (A mmol) of diglycolic anhydride is 1.0≦B/A≦1.2, the DODGAA's were obtained in high yields while their Nd/Pr separation factor indicative of the separation ability of a metal extractant and the phase separation were satisfactory.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].Cl.[NH2:26][C@@H:27]([CH3:32])[CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+]>COCCO>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:26][C@@H:27]([CH3:32])[CH2:28][C:29]([OH:31])=[O:30])=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: C[C@H](N)CC(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCO
Product: C[C@@H](CC(=O)O)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Yield: 38.2 %

Procedure:
To a mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (110 mg, 0.34 mmol) and 3-(S)-amino-butyric acid HCl salt (475 mg, 3.4 mmol) (Oakwood Products) in 2-methoxyethanol (10 mL) was added NaOMe solid (330 mg, 6.12 mmol). The resultant mixture was refluxed for 7 h. Reaction mixture was concentrated and the residue was dissolved in water (100 mL). It was acidified by 1 N HCl to pH=3-4 and then extracted with EtOAc. Organic layer was washed with water, brine and dried over MgSO4. It was filtered and concentrated. The crude product was triturated with (1/1) EtOAc/hexanes. Solid was collected and dried in vacuo to provide the title compound 52 mg (0.13 mmol) in 39% yield. LC-MS ESI−: 390.02 (M−1)−.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:26][O:27][C:28]([CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=[O:29]>ClCCCl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:32]3[CH2:33][CH2:34][CH:30]([C:28]([O:27][CH3:26])=[O:29])[CH2:31]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: COC(=O)C1CCNC1
Agent: Cl
Solvent: ClCCCl
Product: COC(=O)C1CCN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)C1
Reaction time: 3 h

Procedure:
A suspension of 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (1.21 g, 3.26 mmol) in DCL (25 mL) was slowly added to a solution of 3-(methoxycarbonyl)pyrrolidine hydrochloride (0.46 g, 3.58 mmol) and DIPLA (5.6 mL, 32.6 mmol) in DCE (80 mL). The reaction mixture was stirred for 3 h and the solvent was concentrated. The product was purified by MPLC on silica gel using EtOAc as eluent to provide the title compound as white solid. Yield: 0.60 g (39%); 1H NMR (400 MHz, CDCl3) δ 1.49-1.56 (m, 3 H), 1.55-1.58 (m, 1 H), 1.59 (s, 9 H), 1.93-2.13 (m, 2 H), 2.20-2.36 (m, 1 H), 2.89-3.01 (m, 1 H), 3.28-3.41 (m, 5 H), 3.60 (s, 3 H), 3.61-3.66 (m, 1 H), 3.94-4.06 (m, 2 H), 4.25 (d, J=7.42 Hz, 2 H), 7.44 (dd, J=8.50, 0.49 Hz, 1 H), 7.72 (dd, J=8.59, 1.76 Hz, 1 H), 8.24 (dd, J=1.76, 0.59 Hz, 1 H); MS (ESI) (M+H)+=464.0.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[N:7][NH:8][C:9]2=O)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2)[C:6]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[N:7][N:8]=1
Reactant: COc1ccc(-c2n[nH]c(=O)c3cc(Cl)ccc23)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2nnc(Cl)c3cc(Cl)ccc23)cc1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 7-chloro-4-(4-methoxyphenyl)-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: C1(NN[C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)[Cl:19].C1(O)C=CC=CC=1.O>C(OCC)C.CO>[Cl:19][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16]
Reactant: O=C(NNc1ccccc1)c1ccccc1F
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Solvent: Oc1ccccc1
Solvent: CCOCC
Product: O=C(Cl)c1ccccc1F
Reaction time: 20 h
Yield: 39.6 %

Procedure:
A mixture of 5.5 g of 2-fluorobenzoic acid, 2-phenylhydrazide, 6.0 g of PCl5 and 20 ml of diethyl ether was refluxed for 1 hour, under nitrogen, and then permitted to stand at ambient temperature for about 20 hours. In the following order, a solution of 5 g of phenol in 5 ml of diethyl ether, 30 ml of methanol, and sufficient water to reach the solution cloud point, were added, dropwise, to the reaction mixture. The mixture was extracted with diethyl ether and the extract washed with water, dried over anhydrous magnesium sulfate, and concentrated in vacuo to an oil. Purification of the oil by means of flash chromatography on silica gel utilizing hexane-ethyl acetate (5%) as the eluent, followed by recrystallization from hexane yielded 1.5 g of α-chloro-2-fluorobenzaldehyde, phenylhydrazone.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[H][H]>[Rh].O>[CH3:1][NH:2][CH:3]1[CH2:11][CH2:10][CH:6]([C:7]([OH:9])=[O:8])[CH2:5][CH2:4]1
Reactant: CNc1ccc(C(=O)O)cc1
Reactant: [H][H]
Agent: [Rh]
Solvent: O
Product: CNC1CCC(C(=O)O)CC1
Yield: 67 %

Procedure:
A slurry of 33.0 g (0.218 m) of 4-(methylamino)benzoic acid and 4.0 g of 5% rhodium on alumina catalyst in 350 ml of water was shaken under 1500 psig of hydrogen for 24 hours. The insolubles were removed by filtration. The slurry from partial removal of water under reduced pressure was diluted with 300 ml of N,N-dimethylformamide and chilled. The precipitated solid was filtered, washed with several portions of cold acetone, and dried to yield 23 g (75%) of 4-(methylamino)cyclohexanecarboxylic acid.
Reaction SMILES: FC1C=C(C=CC=1SC#N)N.[C:12]([NH:15][CH2:16][C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([S:29][C:30](C3C=CC=CC=3)(C3C=CC=CC=3)[C:31]3C=CC=CC=3)=[C:25]([F:49])[CH:24]=2)[CH2:18]1)(=[O:14])[CH3:13].BrCC[Cl:53]>CN1CCCC1=O>[C:12]([NH:15][CH2:16][C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([S:29][CH2:30][CH2:31][Cl:53])=[C:25]([F:49])[CH:24]=2)[CH2:18]1)(=[O:14])[CH3:13]
Reactant: ClCCBr
Reactant: CC(=O)NC[C@H]1CN(c2ccc(SC(c3ccccc3)(c3ccccc3)c3ccccc3)c(F)c2)C(=O)O1
Agent: N#CSc1ccc(N)cc1F
Solvent: CN1CCCC1=O
Product: CC(=O)NC[C@H]1CN(c2ccc(SCCCl)c(F)c2)C(=O)O1
Reaction time: 2 h

Procedure:
Prepared according to the General Procedure for Preparation of 5-(S)-(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazolidine-2-ones (Example 6) from 5-(S)-acetamidomethyl-3-[4′-(triphenylmethyl)thio-3′-fluorophenyl]-oxazolidine-2-one with 1-bromo-2-chloroethane (0.055 g, 0.38 mmol) in N-methylpyrrolidine-2-one (1 mL). The synthesis was performed at r.t. for 2 h. The crude product was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 0.047 g (72%). MS (m/z): 347 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]2[O:25][N:24]=[C:23]([CH2:26][O:27]C3CCCCO3)[CH:22]=2)[CH:20]=1)=O)(C)(C)C.[ClH:34]>CO.CCOCC>[ClH:34].[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([C:21]2[O:25][N:24]=[C:23]([CH2:26][OH:27])[CH:22]=2)[CH:18]=[N:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(-c2cc(COC3CCCCO3)no2)c1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: OCc1cc(-c2cncc(OC[C@@H]3CCCN3)c2)on1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]-5-[3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-5-isoxazolyl]pyridine (145 mg, 0.31 mmol) in MeOH (10 mL) was added at 0° C. 2M anhydrous HCl in ether (10 mL). The reaction mixture was stirred at room temperature for 12 h, then concentrated in vacuo. The residue was purified by HPLC to give the hydrochloride (90 mg). The 1H NMR spectrum (CD3OD, 400 MHz) of this material exhibits signals compatible with the postulated structure, but in addition a second set of signals of somewhat lower intensity for the heteroaromatic protons in close proximity to those of the title compound: δ 9.02 (s, 1H of minor component), 9.01 (s, 1H of major component), 8.74 (narrow m, 1H of minor component), 8.73 (narrow m, 1H of major component), 8.58 (narrow m, 1H of minor component), 8.55 (narrow m, 1H of major component), 7.30 (s, 1H of minor component), 7.28 (s, 1H of major component), 4.74 (s, 2H), 4.71-4.64 (m, 1H), 4.56-4.48 (m, 1H), 4.21-4.32 (m, 1H), 3.49-3.37 (m, 2H), 2.38-2.28 (m, 1H), 2.26-2.06 (m, 2H), 2.04-1.93 (m, 1H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:38])[C:6]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:24])=[CH:19][CH:18]=1)[CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:7])[CH3:3].COC1C(CCN)=CC(OC)=C([125I])C=1.[CH3:53][O:54][C:55]1[CH:60]=[CH:59][C:58]([S:61](Cl)(=[O:63])=[O:62])=[CH:57][CH:56]=1>CN(C1C=CN=CC=1)C.C1COCC1>[CH2:2]([O:4][C:5](=[O:38])[C:6]([N:8]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:24])=[CH:21][CH:22]=1)[CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([S:61]([C:58]2[CH:57]=[CH:56][C:55]([O:54][CH3:53])=[CH:60][CH:59]=2)(=[O:63])=[O:62])[CH2:14][CH2:15]1)=[O:7])[CH3:3]
Reactant: CCCCCCCCCCCCNC(=O)c1ccc(CN(CC2CCNCC2)C(=O)C(=O)OCC)cc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: COc1cc(CCN)c(OC)cc1[125I]
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCNC(=O)c1ccc(CN(CC2CCN(S(=O)(=O)c3ccc(OC)cc3)CC2)C(=O)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 88.7 %

Procedure:
To a solution of ethyl[{4-[(dodecylamino)carbonyl]benzyl}(piperidin-4-ylmethyl)amino](oxo)acetate hydrochloride (900 mg, 1.63 mmol), DIAE (527 mg, 4.07 mmol) and DMAP (20 mg, 0.16 mmol) in anhydrous THF (50 mL) was added 4-methoxybenzene-sulfonyl chloride (404 mg, 1.96 mmol) dissolved in THF (2.0 mL). The reaction mixture was stirred 14 h at rt. The solvent was evaporated and the resulting residue was dissolved in DCM (100 mL), washed with water (20 mL) and the aqueous layer was extracted with DCM (3×50 mL). The combined organic layers were dried over MgSO4, filtered and evaporated under vacuum. The crude product was purified by column chromatography over silica gel (AcOEt/c-Hex 1/4 to 1/1 in about 1 h) to give the title compound as a white foam (992 mg, 89%). 1H NMR (CDCl3, 300 MHz) δ 7.76 (d, 2H, J=8.3 Hz), 7.69 (d, 2H, J=9.2 Hz), 7.27 (t, 2H, J=7.9 Hz), 7.07 (m, 2H), 6.12 (m, 1H), 4.60 (s, 1H), 4.48 (s, 1H), 3.89 (s, 3H), 3.76 (m, 2H), 3.13 (d, 1H, J=6.8 Hz), 3.07 (d, 1H, J=7.0 Hz), 2.32-2.12 (m, 2H), 1.80-1.55 (m, 6H), 1.45-1.20 (m, 24H), 0.89 (t, 3H, J=7.9 Hz). M−(APCI): 684.4. HPLC (Condition A), Rt: 6.84 min (HPLC purity: 99.7%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH2:10][C:11]([NH2:13])=[NH:12].[C:14]([O:18][C:19](=[O:34])/[C:20](/O)=[C:21](\[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)/[C:22](O)=[O:23])([CH3:17])([CH3:16])[CH3:15].C[O-].[Na+].C(OCC)(=O)C>CO.CCCCCC.O>[C:14]([O:18][C:19]([C:20]1[C:21]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:22]([OH:23])[N:13]=[C:11]([CH2:10][C:4]2[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:3]=2[Br:2])[N:12]=1)=[O:34])([CH3:17])([CH3:15])[CH3:16]
Reactant: N=C(N)Cc1ccc(Cl)cc1Br
Reactant: CC(C)(C)OC(=O)/C(O)=C(\OCc1ccccc1)C(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)c1nc(Cc2ccc(Cl)cc2Br)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.9 %

Procedure:
To a stirred solution of 2-(2-bromo-4-chlorophenyl)-acetamidine hydrochloride (375) (7 g, 24.823 mmol) and 2-benzyloxy-3-hydroxy-but-2-enedioic acid 4-tert-butyl ester 1-methyl ester (4) (11.47 g, 37.23 mmol) in methanol (100 mL) was dropwise added sodium methoxide (16.1 mL) (25% in methanol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 16 h while silica thin layer chromatography was performed (50% ethyl acetate in hexane; Rf=0.5). The reaction mixture was quenched with 1N HCl (5 mL) and the methanol was removed under reduced pressure to yield a residue which was diluted with water (200 mL) and extracted with ethyl acetate (2×250 mL). The combined organic parts were dried and concentrated. The obtained crude product was purified by normal silica (100-200 mesh) column to get 5-benzyloxy-2-(2-bromo-4-chlorobenzyl)-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (376) (6.02 g, 47.95%) as a white solid.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:19]([O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)([CH3:21])[CH3:20]>>[CH:19]([O:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)=[CH:25][CH:24]=1)([CH3:21])[CH3:20]
Reactant: CC(C)Oc1ccc(N)cc1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Product: CC(C)Oc1ccc(NC(=O)c2cccc(S(=O)(=O)N3CCCCC3)c2)cc1

Procedure:
The entitled compound was produced according to the method of Example 73 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 4-isopropoxyaniline as the starting materials.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[CH:9]2)=[C:2]=[S:3].[OH:14][CH2:15][C@@H:16]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][NH:17]1>C(O)C>[OH:14][CH2:15][C@@H:16]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][N:17]1[C:2](=[S:3])[NH:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[CH:9]2
Reactant: S=C=Nc1cccc2cnccc12
Reactant: OC[C@@H]1Cc2ccccc2CN1
Solvent: CCO
Product: OC[C@@H]1Cc2ccccc2CN1C(=S)Nc1cccc2cnccc12
Reaction time: 15 h
Yield: 74.5 %

Procedure:
5-Isothiocyanatoisoquinoline (0.93 g.) is added to a solution of (S)-3-hydroxymethyl-1,2,3,4-tetrahydro isoquinoline (0.82 g.) in ethanol (10 cc.). After 15 hours at a temperature of about 20° C., the crystals formed are filtered off, washed with ethanol and then dried at 60° C. under reduced pressure (0.1 mm. Hg). (S)-3-Hydroxymethyl-N-(isoquinol-5-yl)-1,2,3,4-tetrahydroisoquinoline-2-carbothioamide (1.3 g. ), melting at 190° C., is thus obtained.
Reaction SMILES: [F:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([CH2:9][C:10]([O-:12])=O)=[N:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[Na+].[CH3:20][CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][C:25]([F:31])=[C:26]([F:30])[CH:27]=2)[NH:22]1>>[F:30][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[F:31])[N:22]([C:10](=[O:12])[CH2:9][C:5]1[NH:6][C:7](=[O:8])[C:2]([F:1])=[C:3]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:4]=1)[CH:21]([CH3:20])[CH2:29]2
Reactant: O=C([O-])Cc1nc(N2CCOCC2)c(F)c(=O)[nH]1
Reactant: CC1Cc2cc(F)c(F)cc2N1
Agent: [Na+]
Product: CC1Cc2cc(F)c(F)cc2N1C(=O)Cc1nc(N2CCOCC2)c(F)c(=O)[nH]1
Yield: 33.4 %

Procedure:
The product is prepared by following the procedure described in example 1a (step 5a) using 131 mg of sodium (5-fluoro-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate obtained in step 2a of example 6a and 93 mg of (+)-2-methyl-5,6-difluoro-2,3-dihydro-1H-indole (reference example 3a). After silica column purification: eluent 98/02 dichloromethane/methanol, 64 mg of 2-[2-((−)-5,6-difluoro-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-5-fluoro-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a solid, the characteristics of which are the following: