Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C@H:2]([C:10]([O:12]C1C(F)=C(F)C(F)=C(F)C=1F)=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:34][C@@H:35]([C:37]([OH:39])=[O:38])[CH3:36]>C1COCC1.O>[NH:1]([C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[C@H:2]([C:10]([NH:34][C@@H:35]([C:37]([OH:39])=[O:38])[CH3:36])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[C@@H](N)C(=O)O
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)Oc1c(F)c(F)c(F)c(F)c1F)OCc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
9.68 g (20.0 mmol) of Z-Phe-OPfp was dissolved in 20 ml of THF and to this was added 2.3 g (25.6 mmol) of H-D-Ala-OH dissolved in 5 ml water, pH 8.5. The reaction mixture was stirred for one day and one night at room temperature. The solvents were removed by evaporation under vacuum, 70 ml ethyl acetate was added, and the mixture was acidified to pH 2-3 by the addition of 70 ml of 2% sulfuric acid. The peptide was extracted twice with 70 ml ethyl acetate, washed with saturated sodium chloride solution to neutral pH, then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under vacuum, leaving a thick oil. The product was crystallized from ether/hexane. The yield was 7.6 g (97.7%), melting point was 153-154° C. Rf=0.40 in chloroform:ethyl acetate:methanol:acetic acid=6:3:1:0.1. Rf=0.53 in acetic acid:chloroform:methanol=0.5:16:1. Rf=0.58 in acetic acid:chloroform:methanol=0.5:9:1. [α]20D=+3.2(C=1, CH3OH).
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([OH:49])=O)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].ON1C2C=CC=CC=2N=N1.[OH:60][CH2:61][C@@H:62]([C@@H:64]([C@@H:66]([CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH3:81])[OH:67])[OH:65])[NH2:63].C(N=C=NC(C)C)(C)C.Cl>C(Cl)(Cl)Cl>[C:1]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([NH:63][C@H:62]([C@@H:64]([C@@H:66]([CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH3:81])[OH:67])[OH:65])[CH2:61][OH:60])=[O:49])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCC[C@@H](O)[C@@H](O)[C@@H](N)CO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)[C@H](O)CCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.1 %

Procedure:
A mixture of 27-oleoyloxyheptacosanoic acid (2 g, 2.9 mmoles), chloroform (76 ml), dried 1-hydroxybenzotriazole (1.28 g, 10.9 mmoles), phytosphingosine (1.23 g, 3.9 mmoles) and N,N'-diisopropylcarbodiimide (0.88 ml, 5.64 mmoles) was stirred under nitrogen for 24 hours at room temperature. After adding 50 ml of a 1N hydrochloric acid solution and stirring the organic layer was filtrated, washed with brine and concentrated. The title product (2.07 g) was obtained by crystallization from hot isopropanol (50 ml).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:11])[CH:8]=2)[NH:3]1.[CH2:12]([CH2:16][C:17](=O)[CH3:18])[C:13]([CH3:15])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[CH3:18][C:17]1[N:11]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C@H:2]([CH3:1])[CH2:10]3)[C:13]([CH3:15])=[CH:12][CH:16]=1
Reactant: C[C@@H]1Cc2cc(N)ccc2N1
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1ccc2c(c1)C[C@@H](C)N2
Temperature: 68 °C
Reaction time: 6 h

Procedure:
To a stirred solution of (2R)-2,3-dihydro-2-methyl-1H-indol-5-amine (Step 1, 0.896 g, 6.05 mmol) in THF (180 mL) is added acetonylacetone (0.732 mL, 6.05 mmol) and p-toluenesulfonic acid (0.008 g). The reaction mixture is stirred at 68° C. for 6 h and then concentrated under reduced pressure, and the residue is purified by chromatography on a Biotage Flash 40M 90 g silica gel cartridge (10% EtOAc/Hexanes eluent) to give the title compound, MS (ESI+) for C15H18N2 m/z 227 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[O:9]=[C:10]1[C:23]2[CH:22]=[C:21]([S:24](Cl)(=[O:26])=[O:25])[CH:20]=[CH:19][C:18]=2[C:17](=[O:28])[C:16]2[C:11]1=[CH:12][C:13]([S:29](Cl)(=[O:31])=[O:30])=[CH:14][CH:15]=2>N1C=CC=CC=1.C(Cl)Cl>[OH:8][C:4]1[CH:3]=[C:2]([NH:1][S:29]([C:13]2[CH:14]=[CH:15][C:16]3[C:17](=[O:28])[C:18]4[C:23](=[CH:22][C:21]([S:24]([NH:1][C:2]5[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=5)(=[O:26])=[O:25])=[CH:20][CH:19]=4)[C:10](=[O:9])[C:11]=3[CH:12]=2)(=[O:31])=[O:30])[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccc(S(=O)(=O)Cl)cc2C(=O)c2cc(S(=O)(=O)Cl)ccc21
Reactant: Nc1cccc(O)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1c2ccc(S(=O)(=O)Nc3cccc(O)c3)cc2C(=O)c2cc(S(=O)(=O)Nc3cccc(O)c3)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 28 %

Procedure:
3-aminophenol (0.76 g, 7 mmol) in pyridine (10 ml) was treated with the product from Example 10A in methylene chloride. The mixture was stirred at room temperature for 18 hours and the solvents removed under reduced pressure. The residue was taken up in ethyl acetate, washed three times with 1N hydrochloric acid, dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was filtered through a pad of silica gel with 5% methanol in methylene chloride. The filtrate was concentrated under reduced pressure and the residue was taken up in a mixture of ethyl acetate:hexanes (1:1). The mixture was washed three times with water, dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was titurated with methylene chloride and the orange solid collected by filtration to provide the title compound (0.47 g, 28% yield for 2 steps). 1H NMR (CD3OD) δ 7.16 (d, 2H, J=1.5 Hz), 6.86 (d, 2H, J=6 Hz), 6.69 (dd, 2H, J1=6 Hz, J2=1.5 Hz), 5.55-5.47 (m, 2H), 5.20-4.95 (m, 6H); MS (ESI−) 549 (M−H)−.
Reaction SMILES: [CH:1]([C:4]1[C:5]([OH:14])=[N:6][C:7]([O:12][CH3:13])=[N:8][C:9]=1[O:10][CH3:11])([CH3:3])[CH3:2].C1(N[S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23])C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl>[CH:1]([C:4]1[C:5]([O:14][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23])=[N:6][C:7]([O:12][CH3:13])=[N:8][C:9]=1[O:10][CH3:11])([CH3:3])[CH3:2]
Reactant: COc1nc(O)c(C(C)C)c(OC)n1
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: COc1nc(OC)c(C(C)C)c(OS(=O)(=O)C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.6 %

Procedure:
To a mixture of 5-isopropyl-2,6-dimethoxy-pyrimidin-4-ol (64 mg, 0.322 mmol) and N-phenyltrifluoromethane sulfonamide (127 mg, 1.1 eq.) in 3 mL of DCM, Cs2CO3 (116 mg, 1.1 eq.) was added. The reaction mixture was stirred at room temperature for 90 minutes. The reaction mixture was concentrated down and purified (silica gel, 0-80% EtOAC/hexane) to give white solid (74 mg, 69%). LC-MS shows 330.9 (M+1).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([C:15]2[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:3][CH2:2]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ncccc2C(F)(F)F)CC1
Yield: 33.9 %

Procedure:
tert-butyl piperazine-1-carboxylate (3.0 g, 16.11 mmol) and 2-chloro-3-trifluoromethyl pyridine (2.93 g, 16.11 mmol) charged to a microwave vial was added with diisopropylethylamine (7.05 mL, 40.28 mmol) and DMF (1.0 mL). The reaction mixture was subject to microwave irradiation at 160° C. for 30 minutes. The reaction mixture was partitioned between EtOAc and water, organic layer washed with brine and dried over Na2SO4. The crude product obtained by solvent evaporation was purified via flash column chromatography. 4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester was obtained in 33.9% yield (1.81 g) as light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][Br:9])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: BrCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: BrCCCCCCOc1ccc(Br)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 80.4 %

Procedure:
A mixture of 4-bromophenol (10 g), 1,6-dibromohexane (49.4 g) and potassium carbonate (9.59 g) in N,N-dimethylformamide (50 ml) was stirred for 4 hours at 60° C. (bath temp.), and then cooled to ambient temperature. To the reaction mixture was added ethyl acetate (200 ml), and the mixture was washed with water (200 ml×2) and brine. The organic layer was dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (1:0-1:1 hexane-ethyl acetate) to give 1-bromo-4-(6-bromohexyloxy)benzene (15.61 g).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][CH2:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:11])=[O:7].[OH:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH:29]=O.[BH3-]C#N.[Na+]>C(O)(=O)C.CO>[OH:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:29][N:17]1[CH2:18][CH2:19][CH:14]([CH2:13][NH:12][C:10](=[O:11])[CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:20]=[CH:21][CH:22]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:4]=2)[CH2:15][CH2:16]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCNCC1
Reactant: COc1ccc(C=O)cc1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(CN2CCC(CNC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)CC2)cc1O
Temperature: 60 °C
Reaction time: 15 h

Procedure:
A 5% acetic acid/methanol (1.0 mL) solution of 4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine (20.0 mg, 0.058 mm ol) and 3-hydroxy-4-methoxybenzaldehyde (33 mg) was added to a 5% acetic acid/methanol (1.0 mL) solution of NaBH3CN (16.5 mg), and the mixture was stirred at 60° C. for 15 hours. The resulting reaction mixture wa's then loaded onto a Varian™ SCX column and washed with methanol (15 mL). The obtained crude product was eluted with a 2 M NH3-methanol (5 mL) and concentrated to thereby afford 1-[3-hydroxy-4-methoxybenzyl]4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine (Comp d. No. 1452) (25.8 mg, 92%). The purity was determined by RPLC/MS (91%). ESI/MS m/e 480 (M++H, C24H28F3N3O4).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:11][C:12]1[CH:13]=[CH:14][C:15]2[N:21]([CH3:22])[C:20](=[O:23])[CH2:19][N:18]=[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:16]=2[CH:30]=1.CC(C1C=C(C(C)C)C(S([N:46]=[N+:47]=[N-:48])(=O)=O)=C(C(C)C)C=1)C.C(O)(=O)C>>[N:46]([CH:19]1[N:18]=[C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]2[CH:30]=[C:12]([F:11])[CH:13]=[CH:14][C:15]=2[N:21]([CH3:22])[C:20]1=[O:23])=[N+:47]=[N-:48]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Reactant: CN1C(=O)CN=C(c2ccccc2)c2cc(F)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CC(=O)O
Product: CN1C(=O)C(N=[N+]=[N-])N=C(c2ccccc2)c2cc(F)ccc21
Yield: 82.7 %

Procedure:
As illustrated in the scheme above and following General Procedure 6, KHMDS (1.34 mL of 0.5 M in toluene, 0.670 mmol), 7-fluoro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (0.171 g, 0.637 mmol), trisyl azide (0.493 g, 1.59 mmol) and acetic acid (0.16 mL, 2.8 mmol) were combined. After workup, purification of the crude product by silica gel column chromatography (100% CH2Cl2 to 9:1 CH2Cl2:EtOAc) provided the title compound as a pale yellow solid (0.163 g, 83%). 1H-NMR (CDCl3): δ 7.72-7.67 (m, 2H), 7.54-7.49 (m, 1H), 7.47-7.42 (m, 2H), 7.39 (dd, J=4.8 Hz, J=9.2 Hz, 1H), 7.36-7.30 (m, 1H), 7.08 (dd, J=2.8 Hz, J=8.4 Hz, 1H), 4.55 (s, 1H), 3.45 (s, 3H). MS (ESI) (M+H)+=310.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:9][CH2:10][CH2:11][C:12]([O:14][CH2:15]C)=[O:13].Cl.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[CH:26]([OH:31])[C:27](=N)OC.O>C(O)C>[NH2:8][C:4]1[C:3]2[N:9]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:27]([CH:26]([C:20]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=3[Cl:18])[OH:31])=[N:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)CCNc1c(N)cccc1N
Reactant: COC(=N)C(O)c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CCO
Solvent: O
Product: COC(=O)CCn1c(C(O)c2ccc(Cl)cc2Cl)nc2cccc(N)c21
Reaction time: 12 h
Yield: 90.2 %

Procedure:
To a stirred solution of ethyl N-(2,6-diaminophenyl)-beta-alaninate (4.11 g, 18.4 mmol) in ethanol (36.8 mL) was added methyl 2-(2,4-dichlorophenyl)-2-hydroxyethanimidoate hydrochloride (5.59 g, 20.7 mmol) at room temperature. After 12 h, the reaction mixture was poured into water (120 mL). The resulting solid was collected by filtration and washed with ethyl acetate to afford the desired product as colorless solid (6.77 g, 16.6 mmol, 90%).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][C:6]=2[C:7](=[O:9])[CH:8]=1)[CH3:2].[OH2:17]>CC(C)=O>[CH2:1]([C:3]1[O:4][C:5]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][C:6]=2[C:7](=[O:9])[CH:8]=1)[CH3:2]
Reactant: O
Reactant: CCc1cc(=O)c2cc(CCO)ccc2o1
Solvent: CC(C)=O
Product: CCc1cc(=O)c2cc(CC(=O)O)ccc2o1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
This red solution was added dropwise to a stirred solution of 2-(2-ethyl-4-oxo-4H-1-benzopyran-6-yl)ethan-1-ol (3.5g) in acetone (30 mls) maintained at 20° C until a permanent red colouration was obtained. The reaction was stirred at room temperature for a further 11/2 hours. Water was added and the product was extracted with ether (3x). The separated ethereal solution was extracted with sodium bicarbonate which was washed with water, acidified with dilute hydrochloric acid and extracted with chloroform. The chloroform solution was washed with a small volume of saturated brine solution and dried over anhydrous magnesium sulphate. Evaporation of the solvent yielded the product as an off-white solid (2.2g). Recrystallisation from benzene yielded pale yellow needle crystals mp 171°-172° C (1.1g). The mother liquors were concentrated and a second crop was obtained as a pale yellow solid (0.6g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:10]2[CH:15]=[C:14]([Cl:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[C:10]3[CH:15]=[C:14]([Cl:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(Cl)cc23)cc1OC
Product: COc1ccc(CNc2nc(-n3cccn3)nc3sc(Cl)cc23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2,6-dichloro-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-chloro-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([C:8]12[CH2:15][O:14][C:11]([CH:16]3[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]3)([O:12][CH2:13]1)[O:10][CH2:9]2)[CH2:6][CH3:7].N1C=CC=CC=1>ClCCl>[C:1]([N:18]1[CH2:19][CH2:20][CH2:21][CH:16]([C:11]23[O:10][CH2:9][C:8]([CH2:5][CH2:6][CH3:7])([CH2:13][O:12]2)[CH2:15][O:14]3)[CH2:17]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCCC12COC(C3CCCNC3)(OC1)OC2
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC12COC(C3CCCN(C(C)=O)C3)(OC1)OC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Acetyl chloride (81 μl) was added to a stirred solution of 3-(4-n-propyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)piperidine (0.25 g.) and pyridine (92 μl) in dichloromethane (15 ml) at 0°. The mixture was stirred at room temperature for 3 hours. The mixture was washed with water, saturated aqueous sodium hydrogen carbonate solution and finally brine. The dichloromethane extracts were dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was purified by chromatography on alumina (Alumina Woelm TSC) eluting with 1:3 dichlormethane:hexane, saturated with ammonia. N-Acetyl- 3-(4-n-propyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)piperidine (0.15 g.) was obtained as a colourless oil.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Agent: Cl
Product: CC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-1,3-benzodioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A138) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:17][CH2:16][CH:15]([O:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.ON1C2C=CC=CC=2N=N1.[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH:19][O:18][CH:15]2[CH2:14][CH2:13][N:12]([S:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:20])[F:21])[CH:4]=3)(=[O:11])=[O:10])[CH2:17][CH2:16]2)=[O:38])=[CH:35][CH:34]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: NOC1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NOC1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 61.9 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (138 mg, 0.72 mmol) was added to a solution of O-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yl)hydroxylamine (195 mg, 0.60 mmol), 1-hydroxybenzotriazole (97.0 mg, 0.72 mmol), 4-chlorobenzoic acid (94.0 mg, 0.60 mmol) and N,N-diisopropylethylamine (233 mg, 1.80 mmol) in N,N-dimethylformamide (6 ml). The reaction mixture was stirred at room temperature for 17 hours and quenched with H2O (8 ml) and aqueous 1 N HCl solution (pH=3). The aqueous phase was extracted with CH2Cl2 (20 ml×3) and the combined organic phase was washed with aqueous NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexane: 67/33) to give 4-chloro-N-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yloxy)benzamide (172 mg, 62%) as a white solid: LCMS: 463 [M+1]+. 1H NMR (DMSO-d6) δ: 1.70 (m, 2H), 1.90 (m, 2H), 3.01 (m, 2H), 3.13 (m, 2H), 3.98 (d, 1H), 7.51 (d, 2H), 7.68 (m, 2H), 7.95 (m, 2H), 8.11 (m, 2H), 11.6 (s, 1H).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([NH:7][C@H:8]([C:13]([O:15][CH2:16][C@H:17]1[O:21][C@@H:20]([N:22]2[CH:29]=[C:28]([F:30])[C:26](=[O:27])[NH:25][C:23]2=[O:24])[C@H:19]([OH:31])[C@@H:18]1[OH:32])=[O:14])[C@H:9]([CH2:11][CH3:12])[CH3:10])=[O:6])[CH3:4].[CH2:33]([O:40][C:41]([NH:43][C@H:44]([C:60](O)=[O:61])[CH2:45][CH2:46][CH2:47][CH2:48][NH:49][C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(P(C#N)(CC)=O)C.C(N(CC)CC)C>CN(C)C=O>[CH2:33]([O:40][C:41]([NH:43][C@H:44]([C:60]([NH:2][C@H:3]([C:5]([NH:7][C@H:8]([C:13]([O:15][CH2:16][C@H:17]1[O:21][C@@H:20]([N:22]2[CH:29]=[C:28]([F:30])[C:26](=[O:27])[NH:25][C:23]2=[O:24])[C@H:19]([OH:31])[C@@H:18]1[OH:32])=[O:14])[C@H:9]([CH2:11][CH3:12])[CH3:10])=[O:6])[CH3:4])=[O:61])[CH2:45][CH2:46][CH2:47][CH2:48][NH:49][C:50]([O:52][CH2:53][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)=[O:51])=[O:42])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](C)N)C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Reactant: O=C(NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Agent: CCP(=O)(C#N)CC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
0.46 Gram of 5'-O-(N-alanylisoleucyl)-5-fluorouridine hydrochloride obtained in Example 4 was dissolved in dimethylformamide (30 ml), and 1.42 g (3.42 mmol) of Nα,Nε -di-benzyloxycarbonyllysine and 0.90 g (5.52 mmol) of diethylphosphoryl cyanide were then added. To this solution was added under ice-cooling a solution of 1.30 g (12.9 mmol) of triethylamine in dimethylformamide, and the mixture was stirred for 1 hour at room temperature, allowed to stand overnight at room temperature and concentrated under reduced pressure. The residue was subjected to separation/purification by way of silica gel column chromatography (5×20 cm; a linear gradient of chloroform containing 3%→6% methanol) whereby 1.20 g (45.9%) of 5'-O-[N-{N-(Nα,Nε -di benzyloxycarbonyllysyl)alanyl}isoleucyl]-5-fluorouridine was obtained as a colorless powdery solid.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([CH3:17])[CH:16]=1)CBr>CN.CO.C(Cl)(Cl)Cl.CO>[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([CH3:17])[CH:16]=1)[CH2:7][CH2:6][NH2:3]
Reactant: CCN(CC)CC
Reactant: Cc1cc(Br)cc(CBr)c1
Agent: CN
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1cc(Br)cc(CCN)c1
Yield: 72.8 %

Procedure:
Triethylamine (3.62 g; 35.8 mmol) was dissolved in 40% solution of methylamine in methanol (100 ml). While the solution was stirred in an ice bath, 3-bromo-5-methylbenzyl bromide (9.44 g; 35.8 mmol) in chloroform/methanol (25 ml/25 ml) was added dropwise. After completion of the addition, the mixture was stirred for 72 hours at room temperature. Subsequently, the solvent was evaporated under reduced pressure, and the residue was taken up in 2N hydrochloric acid (100 ml), followed by washing with ether (100 ml). The aqueous layer was alkalinized with aqueous sodium hydroxide solution, and the mixture was extracted with chloroform (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=1:08→10:1), to thereby yield 5.58 g of the target compound as pale yellow oily matter (yield: 72.8%).