Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.O[CH2:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1.C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=1
Reactant: OCc1cccs1
Reactant: O=c1ncc(Br)c[nH]1
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: CN(C)C=O
Product: O=c1ncc(Br)cn1Cc1cccs1
Yield: 48 %

Procedure:
5-Bromopyrimidin-2-one (10 mmol), 2-hydroxymethylthiophene (36 mmol) and N,N-dimethylformamide dineopentyl acetal (15 mmol) in DMF (40 ml) were heated together at 80° C. for 150 min. The coloured solution was evaporated to dryness at reduced pressure (1 mmHg), the residual viscous material triturated with pet, ether (2×25 ml) and with ether (50 ml) when it solidified. This material was dissolved in chloroform and chromatographed on alumina (20 g, activity III). The title compound was eluted with chloroform; yield 48%, m.p. 188°-190° C. (EtOAc). 1H NMR (TFA) δ 5.68 (CH2); 7.18, 7.41, 7.58 (H3', H4', H5'), 8.95 (H4, H6).
Reaction SMILES: [C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[H][H]>N1C=CC=CC=1.[Pd]>[CH:1](/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:2]/[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: [H][H]
Reactant: CCCCCCCCCCCC#Cc1ccccc1CCC(=O)OC
Agent: [Pd]
Solvent: c1ccncc1
Product: CCCCCCCCCCC/C=C\c1ccccc1CCC(=O)OC
Yield: 77.5 %

Procedure:
A solution of methyl 3-[2-(1-tridecynyl)phenyl]propanoate (500 mg) in pyridine (20 ml) was hydrogenated at atmospheric pressure over 5% palladium on barium sulphate (20 mg) until 1 equivalent of hydrogen was absorbed. The catalyst was then removed by filtration and the filtrate evaporated to a pale yellow oil. Chromatograpy on silica eluting with 1:1 dichloromethane-petrol (bp 60°-80° C.) gave 390 mg (78%) of the title ester, νmax (film) 2930, 2850, 1740 cm-1, δ(CDCl3), 0.87 (3H, distorted t, terminal CH3), 1.28 (18H, m, alkylene chain), 2.09 (2H, m, allylic CH2), 2.50 (2H, m, ArCH2), 2.90 (2H, m, CH2CO2), 3.65 (3H, s, ester CH3), 5.70 (1H, d.t, Jd 11.5 Hz, Jt 7.5 Hz, C=CH--R), 6.42 (1H, distorted d, Ar CH=C), 7.17 (4H, m, arom).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[Cl-].[CH3:6][N:7]([CH3:13])[CH:8]1[CH2:12][CH2:11][NH:10][CH2:9]1>CC(C)=O>[CH3:6][N:7]([CH3:13])[CH:8]1[CH2:12][CH2:11][N:10]([C:2](=[S:1])[NH2:3])[CH2:9]1
Reactant: CN(C)C1CCNC1
Reactant: N#C[S-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C)C1CCN(C(N)=S)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 23.9 %

Procedure:
To a suspension of potassium thiocyanate (2.02 g, 20.8 mmol) in acetone (10.7 mL) at 0° C. was slowly added pivolyl chloride (2.6 mL, 21.1 mmol). The mixture was stirred at 0° C. for 3 h. Dimethylpyrrolidin-3-yl-amine (2.44 g, 21.3 mmol) was added slowly at 0° C., and the reaction was allowed to warm to room temperature. After stirring at room temperature overnight, the reaction was concentrated, and concentrated hydrochloric acid (10 mL) was added. The reaction was heated to 95° C. with stirring for 1 h. The mixture was allowed to cool to room temperature, and was extracted with dichloromethane. The aqueous layer was made basic with 20% aqueous sodium hydroxide. The basic solution was extracted with dichloromethane. The organics were combined, washed with brine, dried with anhydrous sodium sulfate, filtered, and concentrated. The mixture was diluted with diethyl ether and filtered to provide pure 3-dimethylamino-pyrrolidine-1-carbothioic acid amide (135) (0.863 g, 23.3%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][C@@H:8]1[C@@H:13]([OH:14])[C@H:12]([CH2:15][C:16]2[CH:21]=[C:20]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:19]([N+:28]([O-:30])=[O:29])=[C:18]([F:31])[CH:17]=2)[CH2:11]S[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].O[O:34][S:35]([O-:37])=O.[K+].C1CCCCC1.CCOC(C)=O>C1COCC1.O>[C:1]([O:5][C:6](=[O:32])[NH:7][C@@H:8]1[C@@H:13]([OH:14])[C@H:12]([CH2:15][C:16]2[CH:21]=[C:20]([O:22][CH2:23][C:24]([F:27])([F:25])[F:26])[C:19]([N+:28]([O-:30])=[O:29])=[C:18]([F:31])[CH:17]=2)[CH2:11][S:35](=[O:37])(=[O:34])[CH2:9]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CSC[C@@H](Cc2cc(F)c([N+](=O)[O-])c(OCC(F)(F)F)c2)[C@@H]1O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CS(=O)(=O)C[C@@H](Cc2cc(F)c([N+](=O)[O-])c(OCC(F)(F)F)c2)[C@@H]1O

Procedure:
To a solution of {(3R,4S,5S)-5-[4-Nitro-3-fluoro-5-(2,2,2-trifluoro-ethoxy)-benzyl]-4-hydroxy-tetrahydro-thiopyran-3-yl}-carbamic acid tert-butyl ester (1.5 g, 3.1 mmol) in THF (20 mL) and water (12 mL) at 0° C. was added oxone (5.71 g, 9.3 mmol) in portions. After 2 h excess oxone was destroyed with sodiummetabisulfite. The reaction mixture was diluted with EtOAc (200 mL) and washed with aqueous saturated bicarbonate solution and brine. The organic phase was dried with Na2SO4, filtered and evaporated to provide a beige powder: TLC (cyclohexane-EtOAc 1:1) Rf=0.12; ESIMS [M+NH4]+=534; 1H NMR (600 MHz, DMSO-d6): δ 7.10 (m, 2H), 6.89 (d, 1H), 5.25 (d, 1H), 5.01-4.94 (m, 2H), 3.70 (m, 1H), 3.20-3.00 (m, 5H), 2.93 (m, 1H), 2.68 (m, 1H), 2.17 (m, 1H), 1.38 (s, 9H).
Reaction SMILES: [CH2:1]([N:8]([CH2:20][CH2:21][C:22]1[CH:33]=[CH:32][C:25]([O:26][CH2:27][C:28](OC)=[O:29])=[CH:24][CH:23]=1)[CH2:9][CH:10]([OH:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CO>[CH2:1]([N:8]([CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][CH2:27][C:28]([N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:29])=[CH:32][CH:33]=1)[CH2:9][CH:10]([OH:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCNCC1
Reactant: COC(=O)COc1ccc(CCN(Cc2ccccc2)CC(O)COc2ccccc2)cc1
Solvent: CO
Product: O=C(COc1ccc(CCN(Cc2ccccc2)CC(O)COc2ccccc2)cc1)N1CCCCC1

Procedure:
A solution of methyl 4-[2-(N-benzyl-N-(2-hydroxy-3-phenoxypropyl)amino)ethyl]phenoxyacetate (6.0 g) and piperidine (16 ml) in methanol (60 ml) was stored at room temperature for 4 days. The solvent and excess reagent were evaporated under reduced pressure. Toluene was added to the residue and volatile material was evaporated. This procedure was repeated twice more. The crude intermediate (8.0 g) was purified by chromatography on K60 silica (210 g) using a mixture of methanol and dichloromethane of increasing polarity (1% to 2% methanol) to give N-(4-[2-(N-benzyl-N-(2-hydroxy-3-phenoxypropyl)amino)ethyl]phenoxyacetyl)piperidine (6.2 g) as a gum. The purified intermediate (6.2 g) was debenzylated in an analogous manner to that of Example 23, to give a colourless solid (5.1 g) which was recrystallised from propan 2-ol to yield N-(4-[2-(2-hydroxy-3-phenoxypropylamino)ethyl]phenoxyacetyl)piperidine hydrochloride (3.7 g) m.p. 139°-41°; NMR: 1.40-1.70 [m,6H, CH2 (CH2)3CH2 ]; 2.90-3.10[m,2H, CH2C6H4 ]; 3.10-3.35[m,4H, CH2NHCH2 ]; 3.35-3.55[m,4H, CH2NCH2 ]; 4.03[m,2H,PhOCH2 ]; 4.30[m,1H,CHOH]; 4.75[s,2H, OCH2CO]; 6.85-7.05[m,5H, aromatic H]; 7.15-7.38[m,4H, aromatic H]: microanalysis: found: C, 64.2; H, 7.4; N, 5.8; Cl, 7.7%; C24H32N2O4.HC1 requires: C, 64.2; H, 7.4; N, 6.2; Cl 7.9%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[C:6]([NH2:8])[CH:7]=1.C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.C1OCCOCCOCCOCCOCCOC1.C(O[N:55]=O)(C)(C)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([C:9]([S:10]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)(=[O:11])=[O:12])=[N:55][NH:8]2)=[CH:4][CH:3]=1
Reactant: Nc1cc(Br)ccc1CS(=O)(=O)c1ccc(F)cc1
Reactant: CC(C)(C)ON=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: O=S(=O)(c1ccc(F)cc1)c1n[nH]c2cc(Br)ccc12

Procedure:
To a suspension of (5-bromo-2-{[(4-fluorophenyl)sulfonyl]methyl}phenyl)amine (Intermediate 68) (0.42 g) in chloroform (10 ml) was added potassium acetate (0.135 g) and acetic anhydride (0.24 ml). The mixture was heated under nitrogen at reflux for 18 h. 18-Crown-6 (0.64 g) and tert-butylnitrite (0.435 ml) were added and the mixture was stirred at reflux for a further 42 h. The mixture was concentrated under vacuum and the residue was purified by column chromatography on silica eluting with cyclohexane:ethylacetate (4:1) to give the title compound (0.16 g).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][N:5]=1)[NH2:3].C(O)(C(F)(F)F)=O.[F:21][CH:22]([F:34])[C:23](=O)[CH2:24][C:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=O>C(O)C(F)(F)F>[CH:27]1([C:25]2[N:2]([C:4]3[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:11])=[O:12])=[CH:6][N:5]=3)[N:3]=[C:23]([CH:22]([F:21])[F:34])[CH:24]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CS(=O)(=O)c1ccc(NN)nc1
Reactant: O=C(CC(=O)C1CCCCC1)C(F)F
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: OCC(F)(F)F
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)F)cc2C2CCCCC2)nc1
Yield: 48.7 %

Procedure:
2-Hydrazino-5-(methylsulfonyl)pyridine hydrochloride (448 mg, 2 mmol) and TFA (1.38 mL, 18 mmol) were mixed in trifluoroethanol (10 mL) and stirred for 5 minutes 4,4-Difluoro-1-cyclohexyl-1,3-butanedione (408 mg, 2 mmol) was added. The resulting reaction mixture was heated at reflux temperature for 60 hours. The solvent was then removed in vacuo, and the residue was partitioned between EtOAc and water. The organic layer was washed with brine and concentrated in vacuo. The product was purified by recrystallization from 3:1 of isooctane:methylene chloride to give the title compound (346 mg, 49%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:47]([NH:50][CH:51]([CH3:53])[CH3:52])([CH3:49])[CH3:48]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:50]([CH:51]([CH3:53])[CH3:52])[CH:47]([CH3:49])[CH3:48])=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CC(C)NC(C)C
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(C(C)C)C(C)C)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with diisopropylamine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C42H55Cl2N5O3 [(M+H)+] 748.3755, observed 748.3758.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:17]1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C.N>C(Cl)Cl.CO>[C:14]([CH:11]1[CH:12]2[CH:10]1[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13]2)(=[O:16])[NH2:17]
Reactant: CC(C)(C)OC(=O)N1CC2C(C1)C2C(=O)O
Reactant: c1ccc2[nH]nnc2c1
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2C(C1)C2C(N)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.5 %

Procedure:
The 3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (252 mg, 1.11 mmol) prepared in Example 3, benzotriazole (180 mg, 1.33 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (255 mg, 1.33 mmol) were dissolved in 3.0 mL of methylene chloride and diisopropylethylamine (232 μL, 1.33 mmol) was added dropwise. After adding 2 M ammonia solution (2.49 mL, 4.98 mmol) dissolved in methanol dropwise at 0° C., the mixture was stirred at room temperature for 4 hours. The completion of the reaction was confirmed by TLC (CH2Cl2:MeOH=15:1). After the reaction was completed, the reaction mixture was diluted with methylene chloride and washed with saturated sodium chloride. The organic layer was dried with anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and separated by column chromatography (CH2Cl2:MeOH=15:1) to obtain 177 mg (70.6%) of the target compound.
Reaction SMILES: C[O:2][C:3]1[C:12]([C:13]2[O:17][C:16]([C@@H:18]([NH:28][C:29]([CH:31]3[CH2:34][N:33]([CH3:35])[CH2:32]3)=[O:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=[O:27])[CH2:25][CH3:26])=[N:15][CH:14]=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.Cl>C(Cl)Cl.O1CCOCC1>[CH3:35][N:33]1[CH2:34][CH:31]([C:29]([NH:28][C@H:18]([C:16]2[O:17][C:13]([C:12]3[C:3](=[O:2])[NH:4][C:5]4[C:10]([CH:11]=3)=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:14][N:15]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=[O:27])[CH2:25][CH3:26])=[O:30])[CH2:32]1
Reactant: CCC(=O)CCCCC[C@H](NC(=O)C1CN(C)C1)c1ncc(-c2cc3ccccc3nc2OC)o1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCC(=O)CCCCC[C@H](NC(=O)C1CN(C)C1)c1ncc(-c2cc3ccccc3[nH]c2=O)o1
Reaction time: 1 h

Procedure:
A solution of (S)-N-(1-(5-(2-methoxyquinolin-3-yl)oxazol-2-yl)-7-oxononyl)-1-methylazetidine-3-carboxamide (0.05 mmol, 1 eq), prepared as described above, in DCM (1 mL) was treated with 0.2 mL of HCl 4N in dioxane. The mixture was stirred 1 h at room temperatures, then concentrated and purified by RP-HPLC using water (+0.01% TFA) and MeCN (+0.01% TFA) as eluents (column C18). The pooled product fractions were lyophilized and the product was obtained as a white solid. MS (ES) C26H32N4O4 requires: 464.58, found: 465. 1H-NMR (400 MHz, DMSO-d6) δ: 12.21 (1 H, s), 9.83 (1 H, bs), 8.89-8.82 (1 H, m), 8.26 (1 H, s), 7.83 (1 H, d, J=7.6 Hz), 7.78 (1 H, s), 7.55 (1 H, t, J=7.2 Hz), 7.38 (1 H, d, J=8.4 Hz), 7.25 (1 H, t, J=7.6 Hz), 5.09 (1 H, bs), 4.36 (1 H, bs), 4.22-4.20 (1 H, m), 4.11 (1 H, bs), 3.98-3.92 (1 H, m), 3.57-3.55 (1 H, m, partially overlaps with water), 2.82 (3 H, s), 2.42-2.37 (4 H, m), 1.96-1.92 (1 H, m), 1.83-1.80 (1 H, m), 1.48-1.44 (2 H, m), 1.35-1.33 (4 H, m), 0.89 (3 H, t, J=7.2 Hz).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:6][CH:5]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.N1C=CC=CC=1>ClCCl>[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25]([O:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:6][CH:5]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CCCCCCCC(=O)c1ccc(CCO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCC(=O)c1ccc(CCOS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.6 %

Procedure:
4′-(2-Hydroxy ethyl)octanophenone (1.0 g) prepared in the step B was dissolved in dichloromethane (10 ml) to obtain a solution. p-Toluene sulfonyl chloride (923 mg) and pyridine (383 mg) were added to the solution with cooling, and the mixture was stirred at room temperature for 2 hours. After the reaction, ice water was added to the solution, the solution was stirred at room temperature for 20 minutes. Dichloromethane layer was washed with 2% hydrochloric acid, sodium bicarbonate solution, and water. The dichloromethane layer was dried over anhydrous sodium sulfate, and concentrated. The residue was recrystallized from hexane-ethyl acetate (10:1) to obtain 2-(4-octanoyl phenyl)ethyl p-toluene sulfonate (950 mg) in the form of colorless crystal.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[C:19]([NH2:21])[CH:20]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>N1C=CC=CC=1>[Si:1]([O:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[C:19]([NH:21][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)[CH:20]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)OCc1sccc1-c1ccc([N+](=O)[O-])c(N)c1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2cc(-c3ccsc3CO[Si](C)(C)C(C)(C)C)ccc2[N+](=O)[O-])cc1
Yield: 92.7 %

Procedure:
A solution of 91 (636 mg, 1.74 mmol) and 4-methoxybenzoyl chloride (446 mg, 2.62 mmol) in pyridine (10 ml) was stirred at room temperature during 16 h. The solvent was evaporated, ethyl acetate was added and washed with a saturated solution of NH4Cl and then with a saturated solution NaCl. The organic layer was dried over MgSO4, filtered and concentrated. After purification by flash chromatography on silica gel (eluent 5-10% EtOAc in Hexanes), 804 mg (93%) of compound 92 was obtained as a yellow oil. 1H NMR: (400 MHz, DMSO) δ (ppm): 10.64 (s, 1H), 8.05 (d, J=8.6 Hz, 1H), 7.95-7.93 (m, 3H), 7.59 (d, J=5.3 Hz, 1H), 7.46 (dd, J=8.6, 2.0 Hz, 1H), 7.28 (d, J=5.3 Hz, 1H), 7.10 (dt, J=9.0, 2.2 Hz, 2H), 4.95 (s, 2H), 3.85 (s, 3H), 0.88 (s, 9H), 0.09 (s, 6H).
Reaction SMILES: [H-].[Na+].[C:3]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:23][CH2:22][NH:21][C:20]2=[O:24])[CH2:15][CH2:14]1)([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][CH2:32][CH2:33]Br>CN(C)C=O>[C:3]([N:13]1[CH2:14][CH2:15][CH:16]([N:19]2[CH2:23][CH2:22][N:21]([CH2:33][CH2:32][O:31][CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][O:25]3)[C:20]2=[O:24])[CH2:17][CH2:18]1)([O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4]
Reactant: BrCCOC1CCCCO1
Reactant: O=C(OCc1ccccc1)N1CCC(N2CCNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCC(N2CCN(CCOC3CCCCO3)C2=O)CC1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 1.35 g of sodium hydride in 70 ml of dimethylformamide and 14.2 g of 1-(1-carbobenzoxy-4-piperidyl)-imidazolidin-2-one is stirred at 80° C. for 4 hours. A solution of 11.7 g of 2-bromoethyl 2-tetrahydro-pyranyl ether in 30 ml of absolute dimethylformamide is then added dropwise in the course of 15 minutes. The mixture is stirred for a further 4 hours at 80° C. and is then evaporated under reduced pressure. The residue is freed from dimethylformamide which is still adhering, by treatment with toluene. The reaction product is dissolved in ethyl acetate, the solution is washed twice with, in each case, 50 ml of water and the ethyl acetate phase is dried over sodium sulphate and evaporated. The residual oil is chromatographed on 1.5 g of silica gel using a mixture of chloroform/methyl alcohol (95:5) as the eluant mixture. In this way, 1-(1-carbobenzoxy-4-piperidyl)-3-[2-(2-tetrahydropyranyloxy)-ethyl]-imidazolidin-2-one is obtained in the form of a slightly yellowish oil.
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:24][O:25][C:26]([CH:28]1[CH2:32][C:31]2([S:37][CH2:36][CH2:35][CH2:34][S:33]2)[CH2:30][N:29]1C(=O)C(N)C(C)(C)C)=[O:27]>C(Cl)Cl>[CH3:24][O:25][C:26]([CH:28]1[CH2:32][C:31]2([S:33][CH2:34][CH2:35][CH2:36][S:37]2)[CH2:30][NH:29]1)=[O:27]
Reactant: COC(=O)C1CC2(CN1C(=O)C(N)C(C)(C)C)SCCCS2
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)C1CC2(CN1)SCCCS2
Reaction time: 2 h

Procedure:
L-Boc-cyclohexyl glycine (154 mg, Bachem), EDC (115 mg), HOBt (81 mg), and DIEA (284 mg) in CH2Cl2 (1 mL) was treated with amine salt 29 (189 mg) in CH2Cl2 (2 mL) and the mixture stirred for 2 hours. The mixture was partitioned between ethyl acetate and 1.0 N HCl, the organics washed with sodium bicarbonate, 1.0 N glycine sodium salt solution, 10% potassium carbonate solution and brine then dried over sodium sulfate, filtered, and concentrated in vacuo. Purification on a plug of silica gel eluting with 30% EtOAc/hexanes afforded 221 mg (70%) of 2-[2-tert-butoxycarbonylamino-2-cyclohexyl-acetylamino)-3,3-dimethyl-butyryl]-6,10-dithia-2-aza-spiro[4.5]decane-3-carboxylic acid methyl ester 30 as a white solid.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([C:19]([F:30])([F:29])[F:18])=[CH:21][CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(C(F)(F)F)cc4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, light yellow solid (83 mg, 88%), MS (ISP) m/z=378.4 [(M+H)+], mp 260.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 4-trifluoromethyl-phenylboronic acid (61.7 mg, 0.325 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]#[N:14])=[CH:11][NH:10][CH:9]=1.[CH2:15]=[O:16]>C(N(CC)CC)C>[OH:16][CH2:15][N:10]1[CH:11]=[C:12]([C:13]#[N:14])[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:9]1
Reactant: C=O
Reactant: N#Cc1c[nH]cc1-c1ccccc1Cl
Solvent: CCN(CC)CC
Product: N#Cc1cn(CO)cc1-c1ccccc1Cl
Temperature: 90 °C

Procedure:
60.8 g of 3-(2-chlorophenyl)-4-cyanopyrrole, 9.9 g of paraformaldehyde and 0.8 g of triethylamine are thoroughly mixed and and the mixture is then heated, with stirring, at a bath temperature of 90° C. The resultant melt is cooled to room temperature after 11/4 hours, when it congeals to a glass-like solid. Recrystallisation from toluene yields the title compound in the form of brownish crystals of m.p. 94°-97° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CI.NC1[CH:11]=[C:12]([C:22](=[O:24])[CH3:23])[CH:13]=[C:14]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:15]=1[O:16][CH3:17].C(OCC)(=O)C.[CH3:31][N:32]([CH3:35])[CH:33]=O>>[C:18]([C:14]1[CH:13]=[C:12]([C:22](=[O:24])[CH3:23])[CH:11]=[C:33]([N:32]([CH3:35])[CH3:31])[C:15]=1[O:16][CH3:17])([CH3:21])([CH3:19])[CH3:20]
Reactant: CN(C)C=O
Reactant: COc1c(N)cc(C(C)=O)cc1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: COc1c(N(C)C)cc(C(C)=O)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 13 h

Procedure:
Potassium carbonate (8.5 g, 62 mmol) and methyl iodide (8.8 g, 62 mmol) were added to a solution of 1-[3-amino-5-(tert-butyl)-4-methoxyphenyl]-1-ethanone (6 g, 21 mmol) in dimethylformamide (50 ml) and the mixture was stirred at room temperature for 13 hours. Ethyl acetate was added, the reaction mixture was washed with water and brine in that order and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and then the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (1.9 g) as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[O:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7](C)[C:6]=1[C:15](O)=[O:16].[CH3:22]COC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1>C(#N)C>[CH3:22][N:1]1[C:2]2[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=2[O:4][C:5]2[C:13]3[C:8]([NH:7][C:6]=2[C:15]1=[O:16])=[CH:9][CH:10]=[CH:11][CH:12]=3
Reactant: Cn1c(C(=O)O)c(Oc2ccccc2N)c2ccccc21
Reactant: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CC#N
Product: CN1C(=O)c2[nH]c3ccccc3c2Oc2ccccc21

Procedure:
In the same way as described in example 4, 3-[o-aminophenoxy]-1-methyl-indole-2-carboxylic acid was cyclized with EEDQ. Analytical material was obtained by recrystallization from acetonitrile, mp. 247°-8°.