Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:12]([CH:13]=O)=[CH:11][CH:10]=[C:9]([Si:15]([CH3:18])([CH3:17])[CH3:16])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].Cl.[NH2:20]O.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[Cl:1][C:2]1[C:12]([C:13]#[N:20])=[CH:11][CH:10]=[C:9]([Si:15]([CH3:18])([CH3:17])[CH3:16])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5]
Reactant: NO
Reactant: CCNC(=O)c1c([Si](C)(C)C)ccc(C=O)c1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CCNC(=O)c1c([Si](C)(C)C)ccc(C#N)c1Cl
Temperature: 100 °C

Procedure:
A solution of the compound of Example 223 (0.28 g, 1.0 mmol) and hydroxylamine hydrochloride (0.12 g, 1.7 mmol) in pyridine (10 mL) was stirred at RT for 2 h. Acetic anhydride (0.75 mL, 8.0 mmol) was added and the solution was heated at 100° C. for 1.5 h. The mixture was concentrated, water added and the mixture extracted with ether. The organic layers were washed with 0.5 N HCl, sat NaHCO3, brine, dried (MgSO4) and concentrated to afford the title compound. The crude product was purified by recrystallization from ethyl acetate/hexanes to afford 0.21 g of white needles (74%). m.p. 111-112° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[CH:5][CH:4]=1.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[S:19](Cl)(=[O:21])=[O:20]>C(N(CC)CC)C>[OH:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([NH:2][S:19]([C:15]2[S:14][CH:18]=[CH:17][CH:16]=2)(=[O:21])=[O:20])=[CH:4][CH:5]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: Nc1ccc(O)c2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1ccc(O)c2ccccc12)c1cccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.957 g 4-aminonaphth-1-ol hydrochloride salt was suspended in 80 ml dichloromethylene, to which at 0° C. was added 3.0 ml triethylamine. The suspension became a dark brown solution. To the solution was added 1.827 g thiophene-2-sulfonyl chloride. The mixture was stirred at r.t. overnight. The reaction mixture was diluted with dichloromethylene to 200 ml and washed with 1N HCl solution (30 ml×3), water (30 ml×3) and brine (30 ml). Dried over MgSO4, the organic phase was filtered and the filtrate was concentrated to dryness. The crude product was suspended in 50% methanol/H2O and filtered. The solid was washed with 50% methanol/H2O affording 2.7 g (90%) brown solid, m.p.: 146-148° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH:21]1([CH2:24][C@H:25]([NH2:32])[CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])[CH2:23][CH2:22]1>>[CH:21]1([CH2:24][C@H:25]([NH:32][C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])[CH2:23][CH2:22]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: COCCOC[C@@H](N)CC1CC1
Product: COCCOC[C@H](CC1CC1)NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and (S)-2-cyclopropyl-1-(2-methoxy-ethoxymethyl)-ethylamine as starting materials, MS (EI): m/e=440.1 [M+H]+.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C@H:12]2[CH2:17][CH2:16][C@H:15](/[CH:18]=[CH:19]/[C:20]3[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3]CC.[F:29][C:30]1[CH:31]=[C:32]([OH:42])[CH:33]=[C:34]([F:41])[C:35]=1[O:36][C:37]([F:40])([F:39])[F:38].C1CCC(N=C=NC2CCCCC2)CC1.C1(C)C=CC=CC=1>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([C@H:6]1[CH2:7][CH2:8][C@H:9]([C@H:12]2[CH2:17][CH2:16][C@H:15](/[CH:18]=[CH:19]/[C:20]3[CH:28]=[CH:27][C:23]([C:24]([O:42][C:32]4[CH:31]=[C:30]([F:29])[C:35]([O:36][C:37]([F:39])([F:40])[F:38])=[C:34]([F:41])[CH:33]=4)=[O:25])=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)[CH2:10][CH2:11]1)[CH2:2][CH3:3]
Reactant: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](/C=C/c3ccc(C(=O)O)cc3)CC2)CC1
Reactant: Oc1cc(F)c(OC(F)(F)F)c(F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](/C=C/c3ccc(C(=O)Oc4cc(F)c(OC(F)(F)F)c(F)c4)cc3)CC2)CC1
Reaction time: 12 h

Procedure:
(E)-4-(2-(trans-4-(trans-4-pentylcyclohexyl)cyclohexyl)vinyl)benzoic acid in an amount of 1,3 g (3.7 mmol), 0.8 g (3.7 mmol) of 3,5-difluoro-4-trifluoromethoxyphenol, 0.1 g (1.1 mmol) of DMAP, and 30 ml of dichloromethane were mixed. To this mixture was added dropwise 5 ml of solution of 1.0 g (4.8 mmol) of DCC in dichloromethane while being cooled with ice in 5 min, and stirred as it was for 12 hours. Separated crystals were filtered off, and 80 ml of toluene was added to the filtrate, washed with 2N-NaOH five times and with water thrice, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure. The residue thus obtained was subjected to silica gel column chromatography (eluent: toluene) to obtain 1.7 g of a crude (E)-3,5-difluoro-4-trifluoromethoxyphenyl 4-(2-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)vinyl)benzoate.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N+:2]=[N-:3].N([CH2:25][CH2:26]N)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:25][CH3:26])=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Reactant: [N-]=[N+]=NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Yield: 84.2 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, (0.338 g, 1.23 mmol) was reacted with 2-azidoethanamine (0.106 g, 1.23 mmol) and triethylamine (0.249 g, 2.46 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)palmitamide (0.336 g, 84%). 1H NMR (300 MHz, CDCl3) δ 6.11 (s, 1H), δ 3.41 (s, 4H), δ 2.17 (t, 2H), δ 1.60 (m, 2H), δ 1.23 (m, 24H), δ 0.85 (t, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 173.9, 51.1, 39.1, 36.9, 32.1, 29.9, 29.8, 29.8, 29.7, 29.6, 29.5, 25.9, 22.9, 14.3 ppm; HRMS (ESI) calcd for C18H36N4O (M+) 324.2889. found 324.2879.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[CH3:11][S-:12].[Na+].C(OCC)(=O)C>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:12][CH3:11])[CH:5]=[O:6]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CSc1ccc(C=O)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.1 %

Procedure:
The 3,4-diflourobenzaldehyde (52.1 g, 0.36 mol) was dissolved in acetonitrile (500 mL). Sodium thiomethoxide (25.6 g, 0.36 mol) was added in four equal portions at 15 minute intervals. The slightly exothermic reaction was stirred at room temperature for 4 hours. The reaction mixture was poured into ethyl acetate (500 mL) and extracted with saturated sodium bicarbonate (2×200 mL) followed by saturated ammounium chloride (2×100 mL). The solution was dried over sodium sulfate and solvent removed at reduced pressure. The 3-flouro-4-(methylthio)-benzaldehyde (38.5 g, 0.22 mol) was isolated by vacuum distillation (135-145° C. at 25 mm Hg) as clear liquid. (61% yield) ESHRMS m/z 171.0302 (calcd for M+H, 171.0280).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28]Cl)[C:26]=2[Cl:27])=[O:21])=[N:6][CH:7]=1.[CH2:31]([NH2:34])[CH2:32][NH2:33].O.[CH:36](OCC)(OCC)OCC>CN(C=O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28][N:33]3[CH2:32][CH2:31][N:34]=[CH:36]3)[C:26]=2[Cl:27])=[O:21])=[N:6][CH:7]=1
Reactant: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(CCl)c1Cl
Reactant: CCOC(OCC)OCC
Reactant: NCCN
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(CN2C=NCC2)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
To N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide (1.5 g, 3.0 mmol) in DMF (15 mL), was added ethylene diamine (0.09 g, 15 mmol) at ambient temperature. After 2 hours, the reaction was poured into water and extracted with ethyl acetate. The ethyl acetate solution was dried (NaSO4) and concentrated in vacuo to afford the crude amine adduct. To the adduct was added triethyl orthoformate (1.33 g, 9 mmol) in acetic acid (20 mL). After stirring at ambient temperature for 1 hour, the reaction was poured into water and extracted with ethyl acetate. The ethyl acetate layer was dried (NaSO4), concentrated in vacuo, and purified by HPLC on a C18 Dynamax column with acetonitrile in water gradient with 0.1 % trifluoroacetic acid to afford 0.87 g of N-(5-chloropyridin-2-yl)-2-[((4-((imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide (870 mg), trifluoroacetic acid salt; NMR (DMSO-d6 /TFA) 10.9 (s, 1), 10.3 (s., 1 ), 9.4 (s, 1), 8.6 (d, 2), 8.3 (d, 1), 8.1 (d, 1), 7.8 (dd, 1), 7.3 (d, 1), 7.2 (d, 1), 4.6 (s, 2), 3.7~3.9 (m, 7) ppm.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C(N(CC)CC)C>C(OCC)C>[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([C:1](=[O:4])[CH:2]=[CH2:3])[CH2:9][CH2:8]1
Reactant: C=CC(=O)Cl
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=CC(=O)N1CCN(C)CC1
Reaction time: 72 h
Yield: 61.6 %

Procedure:
A solution of acryloyl chloride (9 g, 0.10 mole) in ethyl ether (20 ml) was added dropwise to a stirring, cold solution of N-methylpiperazine (10 g, 0.10 mole) and triethylamine (30.6 ml, 0.22 mole) in ethyl ether (150 ml) over a thirty minute period. An additional 75 ml of ethyl ether was added and the reaction stirred for 72 hours. The resulting white solid was filtered and washed well with ethyl ether. The ethyl ether was collected, combined with the filtrate and the solvent evaporated on a rotary evaporator to yield 9.5 g of product as an orange oil. NMR confirmed the structure of the product.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]=[C:11]=[O:12].[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][OH:19]>>[Cl:1][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:10][C:11](=[O:12])[O:19][CH2:18][C:14]1[S:13][CH:17]=[CH:16][CH:15]=1
Reactant: OCc1cccs1
Reactant: Cc1cccc(N=C=O)c1CCl
Product: Cc1cccc(NC(=O)OCc2cccs2)c1CCl
Temperature: 25 °C

Procedure:
2-Chloromethyl-1-isocyanato-3-methylbenzene (2.5 g) and thiophenemethanol (1.57 g) are combined and stirred at RT. When crystallization commences, petroleum ether 50/70 (20 ml) is added and the suspension is stirred for 16 h at RT. After filtration and washing with diethyl ether, 2.57 g (63%) of the title compound are obtained as a solid of m.p. 111-114° C.
Reaction SMILES: BrC[C:3](Cl)=[O:4].[C:6]([NH:10][C:11]([C:13]1[S:33][C:16]2[N:17]=[C:18]([C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)[N:19]=[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=3)[C:15]=2[C:14]=1[NH2:34])=[O:12])([CH3:9])([CH3:8])[CH3:7].CCN(C(C)C)C(C)C.[CH2:44]([Cl:46])Cl>>[C:6]([NH:10][C:11]([C:13]1[S:33][C:16]2[N:17]=[C:18]([C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)[N:19]=[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:3](=[O:4])[CH2:44][Cl:46])[CH:22]=3)[C:15]=2[C:14]=1[NH2:34])=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: O=C(Cl)CBr
Reactant: CC(C)(C)NC(=O)c1sc2nc(-c3cccs3)nc(-c3cccc(N)c3)c2c1N
Reactant: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NC(=O)c1sc2nc(-c3cccs3)nc(-c3cccc(NC(=O)CCl)c3)c2c1N
Reaction time: 3 h

Procedure:
Bromoacetyl chloride (2.40 ml) was added to a solution of tert-butyl 5-amino-4-(3-aminophenyl)-2-(2-thienyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 14(g), 5.0 g) and DIPEA (10.5 ml) in DCM (50 ml). After 3 h at room temperature, the mixture was diluted with DCM, washed with sat. aq. NaHCO3, dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel using heptane/EtOAc=3/2 (v/v) as eluent. A mixture of tert-butyl 5-amino-4-(3-(2-bromoacetamido)-phenyl)-2-(2-thienyl)-thieno[2,3-d]pyrimidine-6-carboxamide and tert-butyl 5-amino-4-(3-(2-chloroacetamido)-phenyl)-2-(2-thienyl)-thieno[2,3-d]pyrimidine-6-carboxamide was obtained.
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[N:10]([CH:18]2[CH2:20][CH2:19]2)[C:9]=1[CH3:21])=[O:7])[CH3:4]>C(O)(=O)C.O>[CH2:3]([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([Br:1])=[C:14]([OH:17])[CH:15]=2)[N:10]([CH:18]2[CH2:19][CH2:20]2)[C:9]=1[CH3:21])=[O:7])[CH3:4]
Reactant: CCOC(=O)c1c(C)n(C2CC2)c2ccc(O)cc12
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1c(C)n(C2CC2)c2cc(Br)c(O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
Bromine (277 μL, 5.40 mmol) is added to a suspension of 1-cyclopropyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (1.40 g, 5.40 mmol) in acetic acid (50 mL). The mixture is stirred for one hour at room temperature. The mixture is diluted with water and the resultant solids are filtered and washed with water. The solids are adsorbed onto silica gel and purified via flash chromatography eluting with 30% THF-heptane. The fractions are combined to yield the title compound (763 mg, 42%). ES/MS m/e 339.8 (M+1).
Reaction SMILES: [C:1]([CH2:3][C:4](O)=[O:5])#[N:2].[CH2:7]([NH:11][C:12]([NH2:14])=[O:13])[CH2:8][CH2:9][CH3:10]>C(OC(=O)C)(=O)C>[NH2:2][C:1]1[N:11]([CH2:7][CH2:8][CH2:9][CH3:10])[C:12](=[O:13])[NH:14][C:4](=[O:5])[CH:3]=1
Reactant: CCCCNC(N)=O
Reactant: N#CCC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCCCn1c(N)cc(=O)[nH]c1=O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 46 g (0.55 mol) cyanoacetic acid and 100 ml of acetic anhydride was added 58 g (0.5 mol) of n-butylurea. The solution was stirred at 70° C. for 2 hours. After cooling white crystals were filtered off and washed with ethanol. Yield 68 g (74% (VII). This was stirred in 500 ml of water and 20 ml of 5 N NaOH was added in portions so the solution the whole time was basic. The reaction mixture was refluxed for 20 minutes and then neutralized with 5 N HCl. After cooling, white crystals were filtered off. Yield 50.6 g (75%) (VIII), NMR.
Reaction SMILES: P(=O)(O)(O)O.C1C2NC3C(=CC=CC=3)SC=2C=CC=1.[CH2:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=[CH2:34])=[CH:31][CH:30]=1.Cl[CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH3:34][CH:33]1[C:32]2[C:31](=[CH:30][CH:29]=[CH:36][CH:35]=2)[CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20]1.[CH3:38][CH:39]1[C:40]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:33]([C:32]2[CH:35]=[CH:36][C:29]([Cl:28])=[CH:30][CH:31]=2)[CH2:34]1
Reactant: C=Cc1ccc(Cl)cc1
Reactant: ClCCc1ccccc1
Reactant: C=Cc1ccccc1
Agent: O=P(O)(O)O
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: CC1CC(c2ccc(Cl)cc2)c2ccccc21
Product: CC1CC(c2ccccc2)c2ccccc21
Temperature: 40 °C

Procedure:
A mixture of 375 parts of phosphoric cid (95% strength by weight) and 1 part of phenothiazine is irradiated for 10 minutes analogously to Example 11. A mixture of 52 parts of styrene, 69 parts of p-chlorostyrene and 61 parts of p-chloroethylbenzene is added to the irradiated solution over 3 hours at 35° to 40° C. After completion of the addition, the mixture is stirred for a further hour at 40° C. The organic phase is separated off and washed with 200 parts of 5 per cent strength by weight sodium hydroxide solution, and fractional distillation gives 18 parts of 1-methyl-3-phenylindan and 72 parts of 1-methyl-3-(p-chlorophenyl)-indan (b.p. 151° to 155° C (4 mm), nD25 : 1.5869).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13]OS(=O)(=O)[N:10]2[CH:16]([CH:24]([CH3:26])[CH3:25])[C:17]([O:19]C(C)(C)C)=[O:18])=[CH:5][CH:4]=1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[C:35]([O-])([O-])=[O:36].[Cs+].[Cs+].C(Cl)(Cl)=O.Cl>CCOC(C)=O.C(#N)C>[CH2:27]([N:34]1[CH2:13][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:10]([CH:16]([CH:24]([CH3:25])[CH3:26])[C:17]([OH:19])=[O:18])[C:35]1=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C([O-])[O-]
Reactant: NCc1ccccc1
Reactant: COc1ccc(C2COS(=O)(=O)N2C(C(=O)OC(C)(C)C)C(C)C)cc1
Agent: Cl
Agent: O=C(Cl)Cl
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc(C2CN(Cc3ccccc3)C(=O)N2C(C(=O)O)C(C)C)cc1
Temperature: 55 °C
Reaction time: 5 h
Yield: 50.1 %

Procedure:
t-Butyl 2-(4-(4-methoxyphenyl)-2,2-dioxo-(1,2,3) oxathiazolidin-3-yl)-3-methylbutyrate (0.30 g; 0.778 mmol) was introduced into acetonitrile (5 ml). Benzylamine (0.10 g; 0.93 mmol) and Cs2CO3 (0.50 g; 1.55 mmol) were added thereto, and the reaction mixture was stirred at 55° C. for 5 h. It was then filtered through kieselguhr, and the residue was washed with a solution of methanol (3%) in acetonitrile. The filtrate was concentrated in a rotary evaporator, and the residue was taken up in dioxane (10 ml) and concentrated aqueous H2SO4 (10 ml). The mixture was stirred at 70° C. for 2 h and then evaporated to dryness in a rotary evaporator. The residue was taken up in toluene, and 1N NaOH (10 ml) was added. After the reaction mixture had been cooled to 0° C., phosgene (20% in toluene; 0.58 ml; 1.16 mmol) was slowly added dropwise. The mixture was then stirred at 0° C. for 2 h. The reaction mixture was adjusted to pH 1-2 with dilute aqueous HCl, mixed with EtOAc and extracted with EtOAc (2×). The combined organic phases were dried over MgSO4, and the solvent was removed in a rotary evaporator. Purification by column chromatography (CH2Cl2/MeOH, gradient) resulted in 2-(3-benzyl-5-(4-methoxyphenyl)-2-oxoimidazolidin-1-yl)-3-methylbutyric acid (0.15 g; 0.39 mmol). MS: 383.15 (M+H); Rt: 1.52 min (method: gradient 0 min 96% H2O (0.05% TFA) 2.0 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 μL (YMC J'sphere ODS H80 20X2 1.4μ); 30° C.)
Reaction SMILES: [CH:1]1([C:6]2[NH:14][C:13]3[C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH3:18])[C:10]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=4)=[N:9][C:8]=3[N:7]=2)[CH2:5][CH:4]=[CH:3][CH2:2]1.C[N+]1([O-])CC[O:32]CC1.C(O)(C)(C)C.[OH2:41]>CC(C)=O.[Os](=O)(=O)(=O)=O>[OH:41][CH:3]1[CH:4]([OH:32])[CH2:5][CH:1]([C:6]2[NH:14][C:13]3[C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH3:18])[C:10]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=4)=[N:9][C:8]=3[N:7]=2)[CH2:2]1
Reactant: C[N+]1([O-])CCOCC1
Reactant: O
Reactant: CCCn1c(Oc2cccc(OC)c2)nc2nc(C3CC=CC3)[nH]c2c1=O
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)(C)O
Solvent: CC(C)=O
Product: CCCn1c(Oc2cccc(OC)c2)nc2nc(C3CC(O)C(O)C3)[nH]c2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 13 %

Procedure:
To a solution of 8-cyclopent-3-enyl-2-(3-methoxy-phenoxy)-1-propyl-1,7-dihydro-purin-6-one (0.075 g, 0.20 mmol) and N-methyl morpholine N-oxide (0.036 g, 0.30 mmol) in a mixture of acetone, t-butanol, and water in the ratio 60:1:1, catalytic amount of osmium tetroxide (2 mg) was added. Reaction mixture was allowed to stir for 2 hours at room temperature. The reaction mixture was quenched with saturated sodium sulphite solution and was diluted with ethyl acetate and water. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulphate and concentrated under vacuum. The crude product was purified by preparative TLC using 3% methanol in DCM to give the product (0.014 g, 13%) as light green solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][C:8]([NH:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]([CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH2:22])=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1)=[O:9].[F:30][C:31]([F:43])([F:42])[C:32]1[CH:33]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1.CCN(CC)CC>C(Cl)Cl>[N:24]1([CH2:23][C:21]([C:17]2[CH:16]=[C:15]3[C:20](=[CH:19][CH:18]=2)[CH:11]([NH:10][C:8](=[O:9])[CH2:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][N:1]2[S:38]([C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:30])([F:42])[F:43])[CH:33]=2)(=[O:40])=[O:39])[CH2:12][CH2:13][CH2:14]3)=[CH2:22])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: C=C(CN1CCCCC1)c1ccc2c(c1)CCCC2NC(=O)CC1CCCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(CN1CCCCC1)c1ccc2c(c1)CCCC2NC(=O)CC1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-piperidin-2-yl-N-[6-(1-piperidin-1-ylmethyl-vinyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide (155.8 mg, 0.39 mmol) in CH2Cl2(2 mL) was added 3-(trifluoromethyl)benzenesulfonyl chloride (Fluka, 0.1 mL, 0.59 mmol) and Et3N (Aldrich, 0.1 mL, 0.79 mmol). The mixture was stirred at rt overnight, diluted with CH2Cl2 (30 mL), washed with 10% Na2CO3 (twice) and brine. The organic solution was dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by silica gel chromatography (3%–10% MeOH—CH2Cl2) to provide the title compound. MS (ESI): 604 (M+H)+. Calc'd for C32H40F3N3O3S—603.27.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[CH:8][C:9]=1[F:10].[C:12]1(=[O:17])[O:16][CH:14]([CH3:15])[CH2:13]1.Cl>O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[F:10])[O:11][CH:14]([CH3:15])[CH2:13][C:12]([OH:17])=[O:16]
Reactant: Oc1ccc(F)c(Cl)c1
Reactant: CC1CC(=O)O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(CC(=O)O)Oc1ccc(F)c(Cl)c1
Temperature: 23 °C
Yield: 10.2 %

Procedure:
To a solution of 27.2 g (0.68 mol) sodium hydroxide in 272 ml water was added 100 g (0.68 mol) 3-chloro-4-fluorophenol. The solution was warmed to reflux and 55.4 ml (0.68 mol) of beta-butyrolactone was added dropwise over a 1 hour period. The reaction was cooled to 23° C. and the pH brought to 7 with concentrated hydrochloric acid. The neutral solution was washed with 3×150 ml diethyl ether to remove unreacted phenol and then acidified to pH 2 with concentrated hydrochloric acid, extracted with 150 ml 1,2-dichloroethane, dried over magnesium sulfate and concentrated in vacuo to 4.3 g of an oil which by nuclear magnetic resonance examination was composed of 44 mol percent product and 56% 3-hydroxybutyric acid. The original diethyl ether washes were extracted with 3×150 ml saturated sodium bicarbonate. The combined bicarbonate solutions were extracted with 150 ml diethyl ether and then the pH was brought to 2 with concentrated hydrochloric acid. Extraction with diethyl ether, washing with brine and drying over magnesium sulfate and concentration in vacuo gave 16.2 g (10.2%) of title product as an oil.
Reaction SMILES: FC(F)(F)C([O-])=O.[NH2:8][C@H:9]([C:20]([NH:22][C@H:23]([C:28]([NH2:30])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:21])[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[NH:19])[NH:15][N+:16]([O-:18])=[O:17].[NH:31](C(OC(C)(C)C)=O)[C@H:32]([C:34](O)=[O:35])[CH3:33].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[NH2:31][C@H:32]([C:34]([NH:8][C@H:9]([C:20]([NH:22][C@H:23]([C:28]([NH2:30])=[O:29])[CH2:24][CH:25]([CH3:26])[CH3:27])=[O:21])[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[NH:19])[NH:15][N+:16]([O-:18])=[O:17])=[O:35])[CH3:33]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)CCCNC(=N)N[N+](=O)[O-])C(N)=O
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@H](CCCNC(=N)N[N+](=O)[O-])NC(=O)[C@H](C)N)C(N)=O

Procedure:
443 g of trifluoroacetate of H-Arg(NO2)Leu-NH2 are dissolved in 2 l of DMF. 200 g of Boc-Ala-OH, then 500 g of BOP are added. The pH is adjusted to 7 with pH paper (on small samples of the reaction medium) with the aid of NEM. The medium is stirred and the development of the reaction is followed by TLC. The reaction is terminated after 4 hrs. The medium is evaporated to dryness in vacuo at 25° C. The residue is taken up in 2 l of water and 2 l of ethyl acetate. The organic phase is washed with a 5% aqueous solution of NaHCO3, with water, dried and evaporated. The tripeptide is recrystallized in ethyl acetate/ether, and finally dried in vacuo. It is monitored by TLC and NMR.