Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([CH2:15][CH2:16][CH3:17])=[C:13]([C:18]([OH:20])=O)[N:12]=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:21]1([NH2:24])[CH2:23][CH2:22]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(#N)C>[CH:21]1([NH:24][C:18]([C:13]2[N:12]=[N:11][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[C:14]=2[CH2:15][CH2:16][CH3:17])=[O:20])[CH2:23][CH2:22]1
Reactant: CCCc1c(C(=O)O)nnn1-c1ccc([N+](=O)[O-])cc1
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of 1-(4-nitrophenyl)-5-propyl-1H-1,2,3-triazole-4-carboxylic acid (1.38 g) obtained in Example 1b) in acetonitrile (50 ml) were successively added cyclopropylamine (0.38 ml), HOBt (0.84 g) and WSC (1.05 g), and the reaction mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/1) to give the title compound as a pale-yellow solid (1.29 g, 82%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[N:4]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=1)[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1B1OC(C)(C)C(C)(C)O1.[Cl:41][C:42]1[CH:47]=[C:46]([C:48]([O:50][CH3:51])=[O:49])[CH:45]=[CH:44][C:43]=1[C:52]1[CH:57]=[C:56](I)[C:55]([O:59][CH3:60])=[CH:54][C:53]=1[F:61].C(=O)([O-])[O-].[K+].[K+]>ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[F:39][C:36]([F:38])([F:37])[C:28]1[CH:27]=[C:26]([CH:31]=[C:30]([C:32]([F:34])([F:35])[F:33])[CH:29]=1)[CH2:25][N:4]([CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:14])([F:13])[F:15])[CH:9]=[CH:8][C:7]=1[C:56]1[CH:57]=[C:52]([C:43]2[CH:44]=[CH:45][C:46]([C:48]([O:50][CH3:51])=[O:49])=[CH:47][C:42]=2[Cl:41])[C:53]([F:61])=[CH:54][C:55]=1[O:59][CH3:60])[C:3]([O:2][CH3:1])=[O:40]
Reactant: COC(=O)c1ccc(-c2cc(I)c(OC)cc2F)c(Cl)c1
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2cc(-c3ccc(C(F)(F)F)cc3CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)C(=O)OC)c(OC)cc2F)c(Cl)c1

Procedure:
Methyl[3,5-bis(trifluoromethyl)benzyl][2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]carbamate (100 mg, 0.171 mmol), methyl 2-chloro-2′-fluoro-5′-iodo-4′-methoxybiphenyl-4-carboxylate (71.9 mg, 0.171 mmol), 1,1′-bis(diphenylphosphino) ferrocene-palladium dichloride dichloromethane adduct (13.95 mg, 0.017 mmol), potassium carbonate (0.256 ml, 0.513 mmol) and 1,4-dioxane (1 ml) were sealed and subjected to microwave irradiation for 30 min at 140° C. An aliquot indicated formation of the desired product. The crude reaction mixture was dried over Na2SO4. The resulting dark mixture was purified by preparative TLC (silica gel) developed by EtOAc/hexanes (20%, v/v) mixture to give a green glass as the title compound. LCMS calc.=751.12; found=752.36 (M+1)+.
Reaction SMILES: [CH2:1]([N:4]([CH2:16][C:17]([O:19]CC)=[O:18])[NH:5][C:6](=[O:15])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C=C.O.[OH-].[Li+]>>[CH2:8]([NH:7][C:6]([NH:5][N:4]([CH2:16][C:17]([OH:19])=[O:18])[CH3:1])=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C=CCN(CC(=O)OCC)NC(=O)NCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CN(CC(=O)O)NC(=O)NCc1ccccc1
Reaction time: 8 h
Yield: 88.5 %

Procedure:
According to the procedure described in the synthesis method of Compound VI-2 with the modification that the reaction was carried out overnight, ethyl 2-(1-allyl-2-(benzylcarbamoyl)hydrazinyl)acetate (Compound V-2) 1.33 g (5.0 mmol) was reacted with lithium hydroxide monohydrate 420 mg (10.0 mmol) to obtain the title compound 1.05 g (88%).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C@H:3]2[CH:7]=[CH:8][CH2:9][CH2:10][C@@H:2]12.Cl.[NH2:13][CH:14]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)[CH2:15][C:16]([O:18][CH3:19])=[O:17].C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:1]1(=[O:11])[N:13]([CH:14]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:4](=[O:6])[C@H:3]2[CH:7]=[CH:8][CH2:9][CH2:10][C@@H:2]12
Reactant: O=C1OC(=O)[C@@H]2CCC=C[C@H]12
Reactant: COC(=O)CC(N)c1ccc(OC)c(OC)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)CC(c1ccc(OC)c(OC)c1)N1C(=O)[C@H]2C=CCC[C@H]2C1=O
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
A stirred mixture of cis-1,2,5,6-tetrahydrophthalic anhydride (0.76 grams, 5.0 mmol), methyl 3-amino-3-(3,4-dimethoxyphenyl)propionate hydrochloride (1.38 grams, 5.0 mmol), and sodium acetate (0.41 grams, 5.0 mmol) in 20 mL of acetic acid under N2 was heated to reflux for 20 hours. The cooled reaction mixture was concentrated in vacuo and the residue diluted with 25 mL of methylene chloride and then 25 mL of saturated sodium bicarbonate was added in portions and the resulting mixture stirred for 30 minutes. The organic phase was separated, dried (sodium sulfate), and concentrated in vacuo to afford the crude product as an oil. The crude product was purified by flash chromatography (silica gel, 1/9 ethyl acetate/hexanes) to afford 0.85 grams (46%) of methyl 3-(cis-1,2,5,6-tetrahydrophthalimido)-3-(3,4-dimethoxyphenyl)-propionate as a solid: mp 100°-101.5° C.; 1H NMR (CDCl3 /TMS) δ 7.00 (m, 2H), 5.83 (m, 2H), 5.77 (dd, J=10.0, 5.9 Hz, 1H, CH), 3.85 (s, 6H, 2 OCH3), 3.62 (dd, J=10.0, 16.4 Hz, 1H), 3.64 (s, 3H, OCH3), 3.10 (dd, J=16.4, 5.9 Hz, 1H), 3.00 (m, 2H), 2.62-2.45 (m, 2H), 2.30-2.22 (m, 2H); 13C NMR (CDCl3 /TMS) δ 180.0, 179.7, 170.3, 148.8, 130.6, 127.6, 127.5, 120.1, 111.0, 110.8, 55.8, 55.8, 51.8, 51.4, 38.8, 35.3, 23.5, 23.4; TLC (1/9 EtOAc/hexanes, UV) Rf =0.34. Anal. Calcd for C20H23NO6. Theory C, 64.33; H, 6.21; N, 3.75. Found C, 64.29; H, 6.19; N, 3.68.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[CH3:10][C@H:11]1[CH2:16][NH:15][C@H:14]([CH3:17])[CH2:13][N:12]1[C:18](=[O:26])[C@:19]([OH:25])([CH3:24])[C:20]([F:23])([F:22])[F:21].C(N(CC)CC)C>CCOC(C)=O>[CH3:10][C@H:11]1[CH2:16][N:15]([S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:8])=[O:7])[C@H:14]([CH3:17])[CH2:13][N:12]1[C:18](=[O:26])[C@:19]([OH:25])([CH3:24])[C:20]([F:23])([F:21])[F:22]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: C[C@@H]1CN(C(=O)[C@@](C)(O)C(F)(F)F)[C@@H](C)CN1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(C(=O)[C@@](C)(O)C(F)(F)F)[C@@H](C)CN1S(=O)(=O)c1cccs1
Yield: 30.5 %

Procedure:
A solution of 2-thiophene sulphonyl chloride (129 mg, 0.707 mmol) in EtOAc (10 ml) was added to a stirred mixture of (R)-[(2S,5R)-2-methyl-5-methyl-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)piperazine] (J. Med. Chem., 1999, 42, 2741-2746) (150 mg, 0.59 mmol) and triethylamine (0.125 ml, 0.886 mmol) in EtOAc (15 ml). The resultant mixture was stirred at ambient temperature for 4 hours, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbon solution and brine, dried and evaporated. The residue was recrystallized from EtOAc/hexane to give the title compound as a solid (71 mg, 0.18 mmol). Mp: 116-117° C.; NMR: 0.95 (d, 3H), 1.25 (dd, 3H), 1.65 (s, 3H), 3.2 (s, 3H), 3.3 (s, 1H), 3.5 (dd, 1H), 4.05 (s, 1H), 4.15 (s, 1H), 4.3 (s, 1H), 4.75 (s, 1H), 7.0 (dd, 1H), 7.5 (dd, 2H); m/z 399.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[CH2:11][CH2:12][NH2:13].C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C>[CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]1[CH2:11][CH2:12][NH2:13]
Reactant: Cc1c(CCN)[nH]c2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC1c2ccccc2NC1CCN
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.2 %

Procedure:
To a solution of 2-(3-methylindol-2-yl)ethylamine (2.5 g) in acetic acid (25 ml) at 15° C. was added sodium cyanoborohydride (1.62 g) in one portion. The solution was stirred at room temperature. After 3 hours, sodium cyanoborohydride [1.0 g) was added and the mixture was stirred at room temperature for 12 hours. After dilution with ice-water, the reaction mixture was made basic with sodium hydroxide pellets and extracted three times with ether. The ether layer was washed with water and brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to give 2-(2,3-dihydro-3-methylindol-2-yl)ethylamine (1.80 g) as an oil. The oil was used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5](I)=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[CH3:20].[F:21][C:22]([F:61])([F:60])[C:23]1[CH:24]=[C:25]([C@H:33]2[O:37][C:36](=[O:38])[N:35]([CH2:39][C:40]3[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[CH:42][C:41]=3B3OC(C)(C)C(C)(C)O3)[C@H:34]2[CH3:59])[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1.C.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:61][C:22]([F:21])([F:60])[C:23]1[CH:24]=[C:25]([C@H:33]2[O:37][C:36](=[O:38])[N:35]([CH2:39][C:40]3[CH:45]=[C:44]([C:46]([F:47])([F:48])[F:49])[CH:43]=[CH:42][C:41]=3[C:5]3[CH:4]=[C:3]([C:10]4[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=4[CH3:20])[C:2]([F:1])=[CH:7][C:6]=3[F:8])[C@H:34]2[CH3:59])[CH:26]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:28]=1
Reactant: COC(=O)c1ccc(-c2cc(I)c(F)cc2F)c(C)c1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2cc(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c(F)cc2F)c(C)c1

Procedure:
methyl 2′,4′-difluoro-5′-iodo-2-methylbiphenyl-4-carboxylate (100 mg, 0.26 mmol, dissolved in 1 mL ethanol), (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one (INTERMEDIATE 9, 185 mg, 0.31 mmol, dissolved in 2.2 mL 1,4-dioxane), sodium carbonate (258 μL, aq., 2M, 0.516 mmol) and 1,1′-bis(diphenylphosphino) ferrocene-palladium dichloride dichloromethane adduct (42 mg, 0.05 mmol) were heated in an 80° C. oil bath for 2 hours. LCMS trace of reaction aliquot indicated completion of reaction. Reaction crude was dried/Na2SO4 and then deposited on 2 prep-TLC plates (SiO2). The plates were developed by a 20% EtOAc/hexanes mixture to afford a clear glass. The glass was further purified by reverse-phase prep-HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting w/a MeCN (0.1% TFA, v/v)/H2O (0.1% TFA, v/v) gradient mixture. Corresponding fractions were pooled & evaporated in vacuo to afford a colorless glass. This glass was dissolved in DCM and washed with water. Organic extracts were combined, dried/Na2SO4, filtered and evaporated to afford the title compound. LCMS (ESI) calc.=731.15; found=732.06 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:14]1([S:24](Cl)(=[O:26])=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.S(Cl)(Cl)(=O)=O.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[C:3]([N:8]2[CH2:9][CH2:10][N:11]([S:24]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=[CH:16][CH:15]=3)(=[O:26])=[O:25])[CH2:12][CH2:13]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccnc1N1CCNCC1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1cccc2ccccc12)N1CCN(c2ncccc2Cl)CC1
Yield: 70 %

Procedure:
Sulfonylation of 1-(3-chloropyridin-2-yl)piperazine (316 mg, 1.6 mmol) with naphthalene-1-sulfonyl chloride (362.7 mg, 1.6 mmol) was carried out according to a similar procedure described for example 2A (Except sulfonyl chloride was added before diisopropylethylamine) using anhydrous dichloromethane (3 mL) as solvent and diisopropylethylamine (1.4 mL, 8.0 mmol) as base. 1-(3-chloropyridin-2-yl)-4-(1-naphthylsulfonyl)piperazine was obtained in 70.0% yield (434.0 mg) as white solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[C:11](=[O:29])[CH2:10]1>C(Cl)Cl>[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:11](=[O:29])[CH2:10]1
Reactant: CN1CCN(CC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(CC2CCNCC2)C(=O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.7 %

Procedure:
TFA (1 mL, 12.98 mmol) was added to a stirred solution of tert-butyl 4-[(4-methyl-2-oxo-piperazin-1-yl)methyl]piperidine-1-carboxylate (98 mg, 0.3147 mmol) in DCM (2 mL) and the reaction stirred at ambient temperature for 16 hours. The solvent was removed in vacuo and the residue azeotroped with DCM (×2) and ether (×2). The residue was passed through a 5 g SCX-2 cartridge and washed with MeOH/DCM mixtures. The product was eluted by washing the cartridge with 2M NH3 in MeOH/DCM mixtures. The solvent was removed in vacuo to give 4-methyl-1-(piperidin-4-ylmethyl)piperazin-2-one as a colourless oil (65 mg, 98% Yield). MS (ES+) 212.0.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]2[C:13]([OH:14])=[CH:12][CH:11]=[C:10]([C:15]#[N:16])[CH:9]=2)=[CH:6][C:5]([C:17]#[N:18])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:26][CH2:27]Br.O>CN(C)C=O>[CH:6]1[C:7]2[C:8]3[CH:9]=[C:10]([C:15]#[N:16])[CH:11]=[CH:12][C:13]=3[O:14][CH2:27][CH2:26][O:1][C:2]=2[CH:3]=[CH:4][C:5]=1[C:17]#[N:18]
Reactant: N#Cc1ccc(O)c(-c2cc(C#N)ccc2O)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)-c1cc(C#N)ccc1OCCO2
Temperature: 150 °C
Yield: 29.8 %

Procedure:
A mixture of 6,6'-dihydroxy[1,1'-biphenyl]-3,3'-dicarbonitrile (11.8 g), sodium carbonate (10.6 g), and 1,2-dibromoethane (8.4 g) in 250 ml of anhydrous dimethylformamide is heated at 150° C for 18 hours under nitrogen. The reaction mixture is poured into water and extracted with three 200 ml portions of dichloromethane. The dichloromethane extracts are combined and washed with 10% sodium hydroxide, water, and brine. The solution is filtered through 100 ml of silica gel and concentrated. The resultant solid is recrystallized from benzene to yield 3.5 g of the title compound, melting point 195°-196° C.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:33])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][CH2:22]NC(OC(C)(C)C)=O)[C:16](Br)=[N:15][C:14]=2[N:13]([CH3:32])[C:11]1=[O:12])(=[O:3])[CH3:2].FC(F)(F)C(O)=O.ClCCl.C(=O)([O-])[O-].[K+].[K+].[C:50](#[N:52])C>>[C:1]([O:4][C@H:5]([CH3:33])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]3[CH2:21][CH2:22][CH2:50][NH:52][C:16]3=[N:15][C:14]=2[N:13]([CH3:32])[C:11]1=[O:12])(=[O:3])[CH3:2]
Reactant: CC#N
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(Br)n2CCNC(=O)OC(C)(C)C)n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc3n2CCCN3)n(C)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
(R)-1-(5-acetoxyhexyl)-8-bromo-7-(2-(N-tert-butoxycarbonylamino)ethyl)-3-methylxanthine (6.10 g, 11.2 mmol) was added to a solution of trifluoroacetic acid (50 ml) and dichloromethane (50 ml) and stirred at room temperature for 3 hours. Concentration under reduced pressure provided an oil to which was added acetonitrile (30 ml) followed by potassium carbonate (13.8 g, 100 mmol). The mixture was stirred at 65° C. for 3 hours and filtered to remove solids. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with ethyl acetate-methanol (4:1) to provide (R)-3-(5-acetoxyhexyl)-1-methyl-6,7,8,9-tetrahydro-pyrimido[2,1-f]purine-2,4(1H,3H)-dione (3.58 g, 88% yield) as a white powder.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:1][CH:2]([CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)[C:13]([OH:15])=[O:14])=[O:22])=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Product: O=C(NC(Cc1c[nH]c2ccccc12)C(=O)O)c1ccc(Cl)cc1
Yield: 79.2 %

Procedure:
By using 10 g of L-tryptophane and 9 g of 4-chlorobenzoyl chloride, and a method similar to that described in reference example 6, recrystallized from methanol-water there was obtained 13.3 g of 2-(4-chlorobenzoylamino)-3-(indol-3-yl)propionic acid in the form of colorless needle-like crystals. Melting point: 100°-102° C. [α]D25 -49.3° (C=1, methanol)
Reaction SMILES: [OH:1][C:2]([C:43]1[S:44][CH:45]=[CH:46][CH:47]=1)([C:38]1[S:39][CH:40]=[CH:41][CH:42]=1)[C:3]([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:14][CH2:15][CH2:16][C:17]([NH:19][C:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([CH2:28][O:29][Si](C(C)(C)C)(C)C)=[CH:22][C:21]=2[Cl:37])=[O:18])[CH3:13])[CH2:8][CH2:7]1)=[O:4].F.F.F.C(N(CC)CC)C>O1CCCC1>[OH:1][C:2]([C:38]1[S:39][CH:40]=[CH:41][CH:42]=1)([C:43]1[S:44][CH:45]=[CH:46][CH:47]=1)[C:3]([O:5][C@H:6]1[CH2:7][CH2:8][C@H:9]([N:12]([CH2:14][CH2:15][CH2:16][C:17]([NH:19][C:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([CH2:28][OH:29])=[CH:22][C:21]=2[Cl:37])=[O:18])[CH3:13])[CH2:10][CH2:11]1)=[O:4]
Reactant: COc1cc(NC(=O)CCCN(C)[C@H]2CC[C@H](OC(=O)C(O)(c3cccs3)c3cccs3)CC2)c(Cl)cc1CO[Si](C)(C)C(C)(C)C
Agent: F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(NC(=O)CCCN(C)[C@H]2CC[C@H](OC(=O)C(O)(c3cccs3)c3cccs3)CC2)c(Cl)cc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of trans-4-[(4-{[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-chloro-5-methoxyphenyl]amino}-4-oxobutyl)(methyl)amino]cyclohexyl hydroxy(di-2-thienyl)-acetate (intermediate 84; 90 mg, 0.12 mmol) in tetrahydrofuran (3.5 mL) was added triethylamine trihydrofluoride (0.55 mL, 5.46 mmol). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the crude obtained was purified by preparative reversed-phase HPLC (System 2), to give the title compound (23%).
Reaction SMILES: [CH2:1]([S:10][CH2:11][C:12]([O:14]C)=[O:13])[CH2:2][CH2:3][S:4][CH2:5][C:6]([O:8]C)=[O:7]>Cl>[CH2:3]([S:4][CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:1][S:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: COC(=O)CSCCCSCC(=O)OC
Agent: Cl
Product: O=C(O)CSCCCSCC(=O)O
Temperature: 25 °C
Yield: 72.4 %

Procedure:
Dimethyl 2,2′-(propane-1,3-diylbis(sulfanediyl))diacetate (11.3 g, 44.9 mmol) was heated to reflux for two hours in 2 N HCl (50 mL). Upon completion, the reaction mixture was cooled to room temperature. The reaction mixture was concentrated to dryness under reduced pressure to give 7.29 g of Compound 10 as an off-white solid (32.5 mmol, 72.4%). 1H NMR (400 MHz, CD2Cl2) δ 11.45 (s, 2H), 3.28 (s, 4H), 2.82-2.69 (m, 4H), 1.92 (p, J=7.2 Hz, 2H). 13C NMR (101 MHz, CD2Cl2) δ 177.36, 33.93, 31.90, 28.63.
Reaction SMILES: Cl.[CH2:2]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=O)=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH2:5][CH3:6].C(OC(=O)C(=COCC)C(OCC)=O)C.CC[O-].[Na+].C(O[C:38]([C:40]1[C:41](O)=[N:42]C(C2C=CC(CCCCC)=CC=2)=[N:44][CH:45]=1)=O)C.P(Cl)(Cl)(Cl)=O.C(OC(C1C(Cl)=NC(C2C=CC(CCCCC)=CC=2)=NC=1)=O)C>C(O)C>[C:45]([C:40]1[CH:38]=[N:13][C:11]([C:10]2[CH:14]=[CH:15][C:7]([CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:8][CH:9]=2)=[N:42][CH:41]=1)#[N:44]
Reactant: CCCCCc1ccc(C(N)=O)cc1
Reactant: CCCCCc1ccc(-c2ncc(C(=O)OCC)c(O)n2)cc1
Agent: CCCCCc1ccc(-c2ncc(C(=O)OCC)c(Cl)n2)cc1
Agent: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCc1ccc(-c2ncc(C#N)cn2)cc1

Procedure:
The starting material can be obtained according to the procedure of A. R. Todd and F. Bergel, J. Chem. Soc. 1937, 366 from p-n-pentylbenzamide hydrochloride and ethoxymethylenemalonic acid diethyl ester with sodium ethylate in ethanol and subsequent treatment of the obtained 2-(p-n-pentylphenyl)-4-hydroxy-5-pyrimidinecarboxylic acid ethyl ester (melting point 193.9°-194.4° C) with phosphorus oxychloride. The melting point of 2-(p-n-pentylphenyl)-4-chloro-5-pyrimidinecarboxylic acid ethyl ester is 58.5°-59.2° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:11]2[CH:20]=[CH:19][S:18][C:12]=2[NH:13][C:14](=O)[CH2:15][N:16]=1)([O-:3])=[O:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22].O>N1C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:11]2[CH:20]=[CH:19][S:18][C:12]=2[NH:13][C:14](=[S:22])[CH2:15][N:16]=1)([O-:3])=[O:2]
Reactant: O=C1CN=C(c2ccccc2[N+](=O)[O-])c2ccsc2N1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: O
Product: O=[N+]([O-])c1ccccc1C1=NCC(=S)Nc2sccc21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
15.7 g (0.055 mol) of 1,3-dihydro-5-(o-nitrophenyl)-2H-thieno[2,3-e]-1,4-diazepin-2-one are warmed to 60° C. in 40 ml of absolute pyridine and there are added with vigorous stirring 15.7 g of finely powdered phosphorus pentasulphide. The mixture is stirred for a further 1.5 hours at this temperature, subsequently poured on to 500 g of ice and 500 ml of water with vigorous stirring and stirred for 2 hours. The resulting precipitate is filtered under a vacuum and washed with a large amount of water. The precipitate is suspended in water and shaken out thoroughly with 500 ml of methylene chloride each time. After drying, the organic phase is evaporated under reduced pressure and the residue refluxed with a small amount of chloroform. After completion of the crystallization in a refrigerator, there is obtained 1,3-dihydro-5-(o-nitrophenyl)-2H-thieno[2,3-e]-1,4-diazepine-2-thione which, after recrystallization from absolute methanol, melts at 207°-209° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:14]([C:23]([NH2:25])=O)[O:13][C:12]=2[CH:26]=1.CCOC(C)=O>N1C=CC=CC=1>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:14]([C:23]#[N:25])[O:13][C:12]=2[CH:26]=1
Reactant: COc1ccc2c(c1)OC(C(N)=O)=C(c1ccccc1)O2
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)OC(C#N)=C(c1ccccc1)O2

Procedure:
0.9 ml (7.5 mmol) of phosphorus oxychloride are slowly added to a solution of 0.24 g (1.5 mmol) of the amide obtained in Step A in 5 ml of anhydrous pyridine. The reaction medium is heated at reflux for 1 hour under an inert atmosphere and then allowed to cool. After evaporation of the solvent in vacuo, the residue is taken up in dichloromethane and then hydrolysed with a saturated solution of sodium hydrogen carbonate. The aqueous phase is then extracted with dichloromethane. The organic phase, dried over magnesium sulphate and then filtered, is concentrated in vacuo. The residue obtained is passed over a silica column (eluant: AcOEt/PE: 25/75) to yield the title nitrile in the form of a white solid.