Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:8][C:9]=1[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13]1)=[O:4].[CH3:25][C@H:26]1[CH2:31][CH2:30][C@H:29]([C:32](Cl)=[O:33])[CH2:28][CH2:27]1>ClCCCl.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:8][C:9]=1[N:10]([C:32]([CH:29]1[CH2:30][CH2:31][CH:26]([CH3:25])[CH2:27][CH2:28]1)=[O:33])[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13]1)=[O:4]
Reactant: C[C@H]1CC[C@H](C(=O)Cl)CC1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NCC1CCCN(C)C1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(-c2ccccc2)cc1N(CC1CCCN(C)C1)C(=O)C1CCC(C)CC1
Yield: 95 %

Procedure:
3-[(1-Methyl-piperidin-3-ylmethyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (162 mg, 0.348 mmol) was dissolved in 1,2-dichloroethane (3.0 mL) and treated with trans-4-Methyl-cyclohexanecarbonyl chloride in 1,2-dichloroethane (1.0 mL, 0.43 mol). The solution was heated at reflux for 1 day. The solvent was then evaporated and the residue purified by silica gel column chromatography using hexanes:EtOAc as eluent to provide 3-[(4-Methyl-cyclohexanecarbonyl)-(1-methyl-piperidin-3-ylmethyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester as an oil (0.194 g, 95% yield). 1H NMR (CDCl3, 400 MHz) Rotamer 65/35: 7.90 (s, 0.35H), 7.70 (d, 0.65 H), 7.62-7.10 (m, 10H), 5.20-5.00 (m, 2H), 4.70(m, 0.35H), 4.60-4.40 (m, 0.65H), 4.12 (m, 1H), 3.82 (s, 3H), 3.52 (t, 0.65H), 3.20 (t, 0.35H), 2.70 (d, 0.65H), 2.52 (t, 0.35H), 1.90 (m, 1H), 1.80-1.20 (m, 13H), 1.00-0.85 (m, 1H), 0.76 (d, 3H), 0.64 (m, 2H).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH3:8].CC(O)(C)C.N.[Li]>C1COCC1>[CH2:1]([OH:9])[CH2:2]/[CH:3]=[CH:4]/[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCC#CCCO
Agent: N
Agent: [Li]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CCCC/C=C/CCO
Reaction time: 2 h
Yield: 95.2 %

Procedure:
A solution of oct-3-yn-1-ol (2.52 g, 20.0 mmol), t-BuOH (5 g), THF (10 mL) and liquid NH3 was cooled to −36° C. Pieces of Lithium (0.34 g, 50 mmol) were introduced with vigorous stirrng and maintaining the temperature. After 2 h, NH3 was allowed to evaporate overnight. Saturated NH4Cl solution was added and the reaction mixture was extracted with hexane. The combined organic layers were washed with 1 M HCl, aqueous NaHCO3 and brine successively and dried. Evaporation of the solvent gave trans-oct-3-en-1-ol (2.44 g, 95%) as a pale yellow oil, which was used in the next step without further purification: 1H NMR (300 MHz, CDCl3) δ 5.54 (1H, m), 5.36 (1H, m), 3.66 (2H, t, J=6.3 Hz), 2.25 (2H, m), 2.02 (2H, m), 1.74 (1H, br s), 1.31 (4H, m), 0.88 (3H, t, J=7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 134.27, 125.78, 62.22, 36.22, 32.59, 31.86, 22.47, 14.20.
Reaction SMILES: C([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7](C)[C:6]=1[CH3:12])C.[OH:16][CH2:17][C@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23][CH2:24]CC#N>>[OH:16][CH2:17][C@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23][CH2:24][CH2:15][C:14]1[NH:3][C:4](=[O:13])[C:5]2[C:6]([CH:12]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: N#CCCCN1CCC[C@@H]1CO
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Product: O=c1[nH]c(CCCN2CCC[C@@H]2CO)cc2ccccc12
Yield: 16.8 %

Procedure:
By the reaction in the same manner as in Example 1a, using N,N-diethyl-2,3-dimethylbenzamide (5.0136 g) and (R)-4-(2-hydroxymethylpyrrolidin-1-yl)butyronitrile (2.2 g), (R)-3-[3-(2-hydroxymethylpyrrolidin-1-yl)propyl]-2H-isoquinolin-1-one (627.3 mg) was obtained. 1N aqueous HCl solution (2.4 ml) was added thereto in an acetone solvent, and the precipitated crystals were collected by filtration to give (R)-3-[3-(2-hydroxymethylpyrrolidin-1-yl)propyl]-2H-isoquinolin-1-one hydrochloride (555.3 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30](=[O:37])[NH:31][CH2:32][C:33]([O:35]C)=[O:34])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].[OH-].[Na+]>CO.O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30](=[O:37])[NH:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)CNC(=O)c1ccc(Cn2c(C(=O)OC)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(C(=O)NCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 15.4 %

Procedure:
To a mixed solution of 6-bromo-2-[4-(methoxycarbonylmethylcarbamoyl)benzyl]-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (100 mg) in methanol (3 ml) and tetrahydrofuran (3 ml) was added 8N aqueous sodium hydroxide solution (0.05 ml), and the mixture was stirred at room temperature for 12 hrs. The solvent was evaporated under reduced pressure, water was added and the mixture was acidified with 1N hydrochloric acid and extracted with dichloromethane. The extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure, and methanol was added to the obtained residue. The mixture was crystallized to give the title compound (15 mg, 15%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:23])[C:9]([CH2:21]Cl)=[C:10]([CH3:20])[C:11]=2[NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl.C([O-])([O-])=O.[K+].[K+].[NH:31]([CH3:33])[CH3:32]>C(Cl)(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:23])[C:9]([CH2:21][N:31]([CH3:33])[CH3:32])=[C:10]([CH3:20])[C:11]=2[NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CNC
Reactant: CC(=O)N1CCc2c(C)c(CCl)c(C)c(NC(=O)C(C)(C)C)c21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCc2c(C)c(CN(C)C)c(C)c(NC(=O)C(C)(C)C)c21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-(1-Acetyl-5-chloromethyl-4,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide (2.0 g) was dissolved in CHCl3 (40 ml) and (CH3)2NH. HCl (3.5 g) and K2CO3 (11.8 g) were added, which was followed by stirring at room temperature for 4 hr. CHCl3 (300 ml) was added, and the mixture was washed successively with 2N-hydrochloric acid, 2N aqueous NaOH and saturated brine, and dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3/MeOH=10/1−1/1) to give 700 mg of N-(1-acetyl-5-dimethylaminomethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide.
Reaction SMILES: Cl[C:2]1[C:11]2[N:10]=[CH:9][N:8]=[CH:7][C:6]=2[CH:5]=[C:4]2[O:12][CH:13]=[N:14][C:3]=12.[Br:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].Cl>C1COCC1.CC(O)C>[Br:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH:19][C:2]1[C:11]2[N:10]=[CH:9][N:8]=[CH:7][C:6]=2[CH:5]=[C:4]2[O:12][CH:13]=[N:14][C:3]=12
Reactant: Clc1c2ncncc2cc2ocnc12
Reactant: Nc1cccc(Br)c1
Agent: Cl
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Brc1cccc(Nc2c3ncncc3cc3ocnc23)c1
Yield: 45.5 %

Procedure:
A mixture of 4-chlorooxazolo[5,4-g]quinazoline (0.24 g, 1.16 mmol) and 3-bromoaniline (0.25 mL, 2.33 mmol) in a THF/propan-2-ol mixture (1:1, 40 mL) containing a trace of concentrated HCl is heated under reflux for 15 min, then concentration to dryness under reduced pressure. The residue is triturated with EtOAc, and then partitioned between saturated aqueous NaHCO3 and EtOAc. Workup of the organic portion gives 4-(3-bromoanilino)oxazolo[5,4-g]quinazoline (0.18 g, 33%) as a yellow powder, mp (MeOH) 232° C. (dec.).
Reaction SMILES: Cl([O-])(=O)(=O)=O.[Li+].[O:7]1[C:9]([CH3:11])([CH3:10])[CH2:8]1.[Br:12][C:13]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15].O>C(OCC)C>[Br:12][C:13]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][CH2:8][C:9]([CH3:11])([OH:7])[CH3:10]
Reactant: Cc1cccc(N)c1Br
Reactant: CC1(C)CO1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCOCC
Product: Cc1cccc(NCC(C)(C)O)c1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of lithium perchlorate (2.13 g, 20 mmol) in diethyl ether (4 mL) was added 1,2-epoxy-2-methylpropane (0.195 mL, 2.2 mmol), followed by 2-bromo-3-methylaniline (0.250 mL, 2 mmol) under an atmosphere of nitrogen gas. The reaction mixture was stirred overnight at RT. Water was added dropwise, and the product was extracted from the reaction mixture with DCM. The organic phase was dried over MgSO4. The solvent was removed under reduced pressure and the remaining residue was purified by flash chromatography (10-40% hexanes/EtOAc). 1-(2-bromo-3-methylphenylamino)-2-methylpropan-2-ol was obtained as a clear colorless oil.
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(C(C)C)C(C)C)C.[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>C1C=CC=CC=1>[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:39])=[CH:36][CH:35]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)CCCCCNc1ccccc1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccccc1
Product: CCOC(=O)CCCCCN(C(=O)c1ccc(Cl)cc1)c1ccccc1-c1ccccc1
Yield: 44.3 %

Procedure:
20.0 g of 2-aminobiphenyl, 15.3 g of ethyldiisopropylamine and 26.3 g of ethyl 6-bromocaproate are reacted, analogously to Example 47a), to obtain 36.0 g of ethyl 6-(biphenyl-2-yl)aminocaproate as a non-crystallizing oil. 18.0 g of this ester are reacted, analogously to Example 47b), with 7.5 g of ethyldiisopropylamine and 10.1 g of p-chlorobenzoyl chloride in 70 ml of benzene. The resulting reaction product is purified chromatographically over a silica gel column (eluent: methylene chloride) to obtain 11.5 g (44.2% of theory) of ethyl 6-[p-chloro-N-(biphenyl-2-yl)benzamido]caproate as a viscous non-distillable oil. Saponification of this ester yields 8.1 g (75.1% of theory) of 6-[p-chloro-N-(biphenyl-2-yl)benzamido]caproic acid, MP 93° to 95°.
Reaction SMILES: [F-:1].[K+].C1OCCOCCOCCOCCOCCOC1.Cl[C:22]1[N:31]2[CH:32]=[C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[N:34]=[C:30]2[C:29]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=2[N:23]=1.O>CN(C=O)C>[F:1][C:22]1[N:31]2[CH:32]=[C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[N:34]=[C:30]2[C:29]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=2[N:23]=1
Reactant: [F-]
Reactant: Fc1ccccc1-c1cn2c(Cl)nc3c(c2n1)CCCC3
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccccc1-c1cn2c(F)nc3c(c2n1)CCCC3
Temperature: 25 °C

Procedure:
To a solution of 700 mg of potassium fluoride and 200 mg 18-crown-6 in 10 mL of DMF was added 5-Chloro-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (200 mg). This mixture was refluxed for 1.5 h, cooled to room temperature and poured into water. The aqueous solution was extracted with ethyl acetate, the organic layer was separated and dried, and the solvent removed m vacuo to yield 5-Fluoro-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (Compound 41), m.p. 154°-155° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][OH:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[PH:11](=[O:14])([OH:13])[OH:12].[CH2:15]([C:17]([CH2:45][CH3:46])([CH:19](Br)[C:20]1[N:24]=[CH:23][N:22]([C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:21]=1)[CH3:18])[CH3:16].C(O)(=O)C>C(O)C>[PH:11](=[O:12])([OH:14])[OH:13].[CH2:45]([C:17]([CH2:15][CH3:16])([CH:19]([O:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9])[C:20]1[N:24]=[CH:23][N:22]([C:25]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:21]=1)[CH3:18])[CH3:46]
Reactant: CC(C)(C)OC(=O)NO
Reactant: CCC(C)(CC)C(Br)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=[PH](O)O
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CCC(C)(CC)C(ONC(=O)OC(C)(C)C)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Yield: 104.4 %

Procedure:
A stirred solution of t-butyl-N-hydroxycarbamate (0.25 g) in ethanol (10 ml) was treated with postassium hydroxide (0.10 g), then diethyl 3-bromo-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.0 g, prepared as described in Example 29) added. The mixture was allowed to stand for twenty hours, poured into ice-water, neutralized with a little acetic acid and extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulphate, and evaporated under reduced pressure to give crude diethyl 3-t-butoxycarbonylaminoxy-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.14 g) as a colourless gum. NMR (CDCl3): δ 1.3(6H,t), 1.4(9H,s), 1.5-1.8(2H,m), 2.2-2.3(2H,m), 4.1(4H,m), 5.0(1H,t), 7.1(6H,m), 7.3(9H,m), 7.95(1H,s). M/S: M+ 620.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]O)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][Cl:1])=[CH:23][CH:22]=1
Reactant: OCc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ClCc1ccc(OCc2ccc3ccccc3n2)cc1
Reaction time: 1.5 h

Procedure:
Solid N-chlorosuccinimide (16.69 g) was added in portions to a stirred solution of 4-(quinolin-2-ylmethoxy)benzyl alcohol (26.58 g) and triphenylphosphine (32.89 g) in dichloromethane (600 ml) at 0°-5° C. The mixture was stirred for a further 1.5 hours at 0°-5° C. and then purified rapidly by pouring the mixture onto flash silica and eluting with petroleum spirit 40°-60° C.-diethyl ether (2:1) under vacuum.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][CH3:14])[CH:6]=[CH:5]2.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:19]3[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCn1ccc2cc(Br)ccc21
Reactant: OB(O)c1ccc(Cl)cc1
Product: CCCCn1ccc2cc(-c3ccc(Cl)cc3)ccc21

Procedure:
The title compound was prepared from 5-bromo-1-butyl-1H-indole and 4-chlorophenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an oil. Mass spectrum (ESI, [M+H]+) m/z 284. 1HNMR (400 MHz, DMSO-d6): δ 7.81 (s, 1H), 7.67 (d, 2H, J=8.56 Hz), 7.54 (d, 1H, J=8.55 Hz), 7.46 (d, 2H, J=8.55 Hz), 7.42-7.40 (m, 2H), 6.47 (d, 1H, J=3.0 Hz), 4.18 (t, 2H, J=7.02 Hz), 1.73 (p, 2H, J=7.18, Hz), 1.24 (h, 2H, J=7.47 Hz), and 0.88 ppm (t, 3H, J=7.33 Hz). Elemental Analysis for C18H18ClN: Calculated: C, 76.18; H, 6.39; N, 4.94. Found: C, 75.71; H, 6.16; N, 4.74.
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7]C(C)([O-])C.[K+].O1CCCC1.[CH:18]([CH:20]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:21][CH:22]([CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[C:30]([O:37][CH2:38][CH2:39][O:40][CH3:41])[CH:31]=[CH:32][CH:33]=2)[CH:28]=1)[CH:23]([CH3:25])[CH3:24])=[O:19]>CS(C)=O>[CH3:41][O:40][CH2:39][CH2:38][O:37][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:29]=1[CH:28]=[C:27]([CH2:26][CH:22]([CH:23]([CH3:25])[CH3:24])[CH2:21][CH:20]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:47])([CH3:46])[CH3:48])[CH:18]1[CH2:7][O:19]1)[CH:36]=[CH:35]2
Reactant: COCCOc1cccc2ccc(CC(CC(C=O)NC(=O)OC(C)(C)C)C(C)C)cc12
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COCCOc1cccc2ccc(CC(CC(NC(=O)OC(C)(C)C)C3CO3)C(C)C)cc12
Temperature: 0 °C

Procedure:
3.87 g of trimethylsulphoxonium iodide and 1.98 g of potassium tert-butoxide are stirred under high vacuum overnight, admixed with 24 ml of tetrahydrofuran and subsequently cooled to 0° C. A solution of 3.03 g of tert-butyl {1-formyl-3-[8-(2-methoxyethoxy)naphthalen-2-ylmethyl]-4-methylpentyl}carbamate in 24 ml of dimethyl sulphoxide is added dropwise. On completion of reaction (TLC monitoring), the reaction mixture is partitioned between water and tert-butyl methyl ether, and the aqueous phase is extracted once again with tert-butyl methyl ether (2×). The combined organic phases are washed successively with water (3×) and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is identified on the basis of the Rf value from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([OH:12])=[CH:7][CH:6]=2.[CH2:13]([O:15][C:16](=[O:21])[CH:17](Cl)[S:18][CH3:19])[CH3:14]>>[CH2:13]([O:15][C:16](=[O:21])[CH:17]([O:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]=[CH:3][C:2]([I:1])=[CH:11]2)[S:18][CH3:19])[CH3:14]
Reactant: CCOC(=O)C(Cl)SC
Reactant: Oc1ccc2ncc(I)cc2c1
Product: CCOC(=O)C(Oc1ccc2ncc(I)cc2c1)SC

Procedure:
In a similar procedure to Stage 2, Step 1 of Example 5, 3-iodo-6-hydroxy-quinoline was reacted with chloro-methylsulfanyl-acetic acid ethyl ester to give (3-iodo-quinolin-6-yloxy)-methylsulfanyl-acetic acid ethyl ester as a yellow coloured solid.
Reaction SMILES: C(O)(=[S:3])C.[H-].[Na+].CS(O[C@H:12]1[CH2:16][N:15]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[C@H:14]([C:30]([N:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][O:40][C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][C:48]([N+:51]([O-:53])=[O:52])=[CH:47][CH:46]=3)=[O:42])[CH2:34][CH2:33]2)=[O:31])[CH2:13]1)(=O)=O.[Cl-].[Na+]>CN(C)C=O>[SH:3][C@@H:12]1[CH2:16][N:15]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[C@H:14]([C:30]([N:32]2[CH2:33][CH2:34][N:35]([CH2:38][CH2:39][O:40][C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][C:48]([N+:51]([O-:53])=[O:52])=[CH:47][CH:46]=3)=[O:42])[CH2:36][CH2:37]2)=[O:31])[CH2:13]1
Reactant: CC(O)=S
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)N2CCN(CCOC(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCCN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
51 μl of thioacetic acid were added, whilst ice-cooling, to a suspension of 26 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) in 1.4 ml of dry N,N-dimethylformamide, and the resulting mixture was stirred at room temperature for 30 minutes. A solution of 340 mg of (2S,4R)-4-methanesulfonyloxy-2-{4-[2-(4-nitrobenzyloxycarbonyl)oxyethyl]-1-piperazinylcarbonyl}-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step 90(c)(i) above] in 2 ml of dry N,N-dimethylformamide was then added to the mixture, and the mixture was stirred at between 80° C. and 90° C. for 4 hours. At the end of this time, the temperature of the reaction mixture was allowed to reduce to room temperature, after which the mixture was poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was worked up and purified according to the procedure described in step 90(b)(i) above, to give 166 mg of the title compound, as a powder. The infrared absorption spectrum and nuclear magnetic resonance spectrum of the compound thus obtained were identical with those of the compound prepared as described in step 90(b)(ii) above.
Reaction SMILES: Cl[C:2]1[N:37]=[CH:36][CH:35]=[CH:34][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[C:9]([O:20][CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][N:23]2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:8]=1)=[O:5].[F:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][NH2:44])=[CH:41][CH:40]=1>CCOC(C)=O.O>[F:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][NH:44][C:2]2[N:37]=[CH:36][CH:35]=[CH:34][C:3]=2[C:4]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[C:9]([O:20][CH2:21][CH:22]3[CH2:26][CH2:25][CH2:24][N:23]3[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:8]=2)=[O:5])=[CH:41][CH:40]=1
Reactant: NCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC1COc1cc(NC(=O)c2cccnc2Cl)ccc1C(F)(F)C(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1COc1cc(NC(=O)c2cccnc2NCc2ccc(F)cc2)ccc1C(F)(F)C(F)(F)F
Temperature: 130 °C

Procedure:
2-Chloro-N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenyl]-nicotinamide (442.8 mg) DIEA (351 μL) and 4-fluorobenzylamine (322 μL) were combined in a sealed tube and heated to 130° C. for 3 h. The mixture was diluted with EtOAc and H2O, the layers were separated and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified with silica gel chromatography (1% MeOH/CH2Cl2) to obtain an off-white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([NH2:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][CH2:25][C:26](=O)[CH2:27][CH3:28].C(O)(=O)C>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[C:22]([NH:23][CH:26]([CH2:27][CH3:28])[CH2:25][CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)CC
Reactant: Nc1cccnc1N1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CO
Solvent: CC(=O)O
Product: CCC(CC)Nc1cccnc1N1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
Following the general procedure of PREPARATION 3 and making non-critical variations but starting with 1-[benzyloxycarbonyl]-4-[(3-amino)-2-pyridinyl]piperazine (PREPARATION 33, 10.5 g), 3-pentanone (0.15 g) sodium cyanoborohydride (0.11 g), acetic acid (52.3 ml) and methanol (3.2), the title compound is obtained, NMR (300 MHz, CDCl3) 7.66, 7.38-7.33, 6.90, 6.79, 5.17, 4.21, 3.65, 3.15, 3.04, 1.66-1.46 and 0.93 δ.
Reaction SMILES: [Cl:1][CH:2]1[C:6]([OH:11])([C:7]([F:10])([F:9])[F:8])[O:5][N:4]=[C:3]1[C:12]1[CH:17]=[C:16]([F:18])[C:15]([Cl:19])=[CH:14][C:13]=1[F:20].[C:21](OC(=O)C)(=[O:23])[CH3:22]>S(=O)(=O)(O)O>[Cl:1][CH:2]1[C:6]([O:11][C:21]([CH3:22])=[O:23])([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=[C:3]1[C:12]1[CH:17]=[C:16]([F:18])[C:15]([Cl:19])=[CH:14][C:13]=1[F:20]
Reactant: OC1(C(F)(F)F)ON=C(c2cc(F)c(Cl)cc2F)C1Cl
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)OC1(C(F)(F)F)ON=C(c2cc(F)c(Cl)cc2F)C1Cl
Temperature: 160 °C

Procedure:
One drop of concentrated sulfuric acid was added to 3.2 g of 4-chloro-3-(4'-chloro-2',5'-difluorophenyl)-5-hydroxy-5-trifluoromethylisoxazoline in 45 ml of acetic anhydride. The mixture was subsequently briefly heated to 160° C. After cooling, the reaction mixture was then concentrated under reduced pressure. The oily crude product was purified by silica gel chromatography (eluent: methylene chloride). Yield: 2.5 g; oil.