Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[C:13]([O-])([O-])=O.[K+].[K+].C.[I].CCOC(C)=O>CN(C=O)C>[CH3:13][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(OC(F)(F)F)c1
Agent: C
Agent: [I]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 13 h
Yield: 128.4 %

Procedure:
To a suspension of 20.0 g of 3-(trifluoromethoxy)phenol and 23.3 g of K2CO3 (anhydrous) in DMF (100 ml) was added 23.9 g of iodine methane under ice cooling, then the reaction mixture was warmed to room temperature, and was stirred at room temperature for 13 hours. To the reaction solution was added EtOAc (100 ml) and purified water (150 ml), and the resulting mixture was stirred for 30 minutes. After liquid separation, the aqueous layer was extracted with EtOAc (50 ml×2), the combined organic layer was washed with purified water (100 ml×3) and with saturated brine (50 ml) and dried overover MgSO4, then, the drying agent was separated by filtration, and the solvent was removed under reduced pressure to obtain 27.7 g of the title compound (crude form, yellow oil). The present compound was used in the next reaction without purification.
Reaction SMILES: CC[O-].[Na+].[F:5][C:6]([F:23])([F:22])[C:7]([CH:9]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:10]([O:12]CC)=O)=O.Cl.[C:25]([NH2:28])(=[NH:27])[CH3:26].CCCCCC>CCO>[CH3:26][C:25]1[NH:28][C:10](=[O:12])[C:9]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:7]([C:6]([F:5])([F:22])[F:23])[N:27]=1
Reactant: CCOC(=O)CCC(C(=O)OCC)C(=O)C(F)(F)F
Reactant: CC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)CCc1c(C(F)(F)F)nc(C)[nH]c1=O
Yield: 24.1 %

Procedure:
To a solution of NaOEt (0.026 mol) in EtOH (prepared from 0.60 g of Na and 30 mL of EtOH) was added diethyl trifluoroacetylglutarate (3.70 g, 0.013 mol) and acetamidine hydrochloride (1.23 g, 0.013 mol). The reaction mixture was heated under reflux for 18 h , concentrated, and taken up in water. The mixture was acidified to pH 4 with 2N HCl and extracted with CH2Cl2. The extracts were dried (MgSO4) and concentrated to give a yellow solid. Trituration with hexane gave 0.87 g of product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:16])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[CH:23]1([C:29](O)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:16][C:29]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:30])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)N)c2c1N
Reactant: O=C(O)C1CCCCC1
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)NC(=O)C3CCCCC3)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminopropoxy)-2-methylquinoline-3-carboxylate (Example 26b) and cyclohexanecarboxylic acid as brown solid (28%). MS 414 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.BrC1C=C(O)C=CC=1.[C:21]1([CH:27]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30](=[O:37])[C:29]2=[O:38])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.FC(F)(F)C1OC(CN2C3C(=CC=CC=3)C(=O)C2=O)=CC=1>>[Cl:1][C:2]1[C:3]([OH:12])=[C:4]([C:30]2([OH:37])[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:28]([CH:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:29]2=[O:38])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: Oc1cc2c(cc1Cl)OCCO2
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Agent: Oc1cccc(Br)c1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1c(O)c(Cl)cc2c1OCCO2

Procedure:
Following the procedure as described in PREPARATION 2A and making non-critical variations using 7-chloro-2,3-dihydrobenzo[b][1,4]dioxin-6-ol to replace 3-bromophenol, and 1-(diphenylmethyl)-1H-indole-2,3-dione to replace 1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione, 3-(7-chloro-6-hydroxy-2,3-dihydro-1,4-benzodioxin-5-yl)-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one was obtained (18%) as a colorless solid: MS (ES+) m/z 522.1 (M+23), 524.1 (M+23).
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([C:7]1[S:11][C:10]([C:12]([O:14]C)=O)=[CH:9][CH:8]=1)=[O:6])[CH3:3].O.[NH2:17][NH2:18]>C(O)C>[CH3:1][CH:2]([NH:4][C:5]([C:7]1[S:11][C:10]([C:12]([NH:17][NH2:18])=[O:14])=[CH:9][CH:8]=1)=[O:6])[CH3:3]
Reactant: NN
Reactant: COC(=O)c1ccc(C(=O)NC(C)C)s1
Solvent: CCO
Solvent: O
Product: CC(C)NC(=O)c1ccc(C(=O)NN)s1
Yield: 45 %

Procedure:
Methyl 5-(2-propylcarbamoyl)thiophene-2-carboxylate (1.22 g, 5.37 mmol) in ethanol (40 mL) was heated with hydrazine monohydrate (2.7 g) at 85° C. for 16 hours with reflux. After cooling, the solvent was evaporated, the resulting solid was recrystallized from chloroform to give 549.2 mg of the desired product (yield 45%).
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[C:28]([CH3:36])=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(O[N:47]1N=[N:54][C:49]2C=CC=C[C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.NCC#N>CN(C=O)C>[C:48]([CH2:49][NH:54][C:30](=[O:32])[C:29]1[CH:33]=[CH:34][CH:35]=[C:27]([C:10]2[C:11]3[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]4[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=4[F:25])[C:12]=3[N:13]=[C:8]([NH:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:37][CH3:38])[CH2:1][CH3:2])[N:9]=2)[C:28]=1[CH3:36])#[N:47]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cccc(C(=O)NCC#N)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.5 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-2-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and aminoacetonitrile (9.3 mg, 0.1 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (9.1 mg, 33%). LC-MS m/z 560 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][CH2:8][CH:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:10][C:11]([NH:13][C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1)=[O:12].[S:31](Cl)([C:34]1[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=1)(=[O:33])=[O:32]>O1CCOCC1.O>[CH3:38][C:37]1[CH:39]=[CH:40][C:34]([S:31]([NH:7][CH2:8][CH:9]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:10][C:11]([NH:13][C:14]2[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=2)=[O:12])(=[O:33])=[O:32])=[CH:35][CH:36]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)c1ccc(NC(=O)CC(CN)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1ccc(NC(=O)CC(CNS(=O)(=O)c2ccc(C)cc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
Potassium carbonate (0.325 g, 2.35 mmol) was added to a solution of 51 (0.128 g, 0.392 mmol) in 1,4-dioxane/H2O 1:1 (5 mL) and followed by tosyl chloride (0.074 g, 0.392 mmol) at room temperature. After stirring for 2 h at room temperature, the resulting mixture was evaporated in vacuo to dryness. Water (10 ml) was added and the resulting white solid was separated by filtration and dried in vacuo. Pure 55 was obtained as an off-white solid (0.122 g, 0.254 mmol, 65%) without further purification, mp 135-137° C. 1H NMR (400 MHz, CD3OD) 1.36 (3H, t, J 7.2 Hz), 2.39 (3H, s), 2.63 (1H, dd, J 8.6, 14.6 Hz), 2.85 (1H, dd, J 6.2, 15.0 Hz), 3.05 (1H, dd, J 7.4, 13.0 Hz), 3.12 (1H, dd, J 6.8, 11.8 Hz), 4.32 (2H, q, J 7.2 Hz), 7.17-7.19 (3H, m), 7.23-7.27 (2H, m), 7.31 (2H, d, J 8.0 Hz), 7.54 (2H, d, J 8.4 Hz), 7.65 (2H, d, J 8.4 Hz), 7.90 (2H, d, J 8.8 Hz). 13C NMR (100 MHz, CDCl3) 14.57, 21.73, 40.65, 42.04, 47.77, 61.07, 119.15, 127.14, 127.75, 127.77, 129.29, 130.07, 130.94, 136.79, 140.74, 142.12, 143.97, 166.36, 170.24. νmax (solid)/(cm−1) 3324, 3191, 1707, 1675, 1597, 1534, 1270, 1157, 1105. MS (API-ES): m/z 481 [M+H]+ (100%), HRMS (API-ES) m/z found 481.1801 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[Br:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13]Br>CN(C)C=O>[Br:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][O:9][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: BrCc1ccccc1Br
Reactant: OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccccc1COC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
1.2 g of sodium hydride at 50% in suspension in oil are added at 5° C., in portions, to 5 g of cyclohexanol in solution in 150 ml of dimethylformamide. The mixture is stirred for 1 hour at room temperature and 12.5 g of 2-bromobenzyl bromide in solution in 15 ml of dimethylformamide are introduced at 5° C. After 2 hours at room temperature, the reaction medium is poured over ice-cold water and extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and evaporated to give 13.3 g of oil.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:11]3[CH:12]=[CH:13][CH:14]=[C:10]3[O:9][C:8]=2[CH2:16][C:17]([O:19]CC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:23][OH:24].C[O-].[Na+].Cl>O.CO>[C:1]1([C:7]2[CH:15]=[C:11]3[CH:12]=[CH:13][CH:14]=[C:10]3[O:9][C:8]=2[CH2:16][C:17]([NH:23][OH:24])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: CCOC(=O)Cc1oc2cccc-2cc1-c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(Cc1oc2cccc-2cc1-c1ccccc1)NO

Procedure:
A mixture of 5.0 g. of ethyl 3-phenyl-7-benzofuranacetate, 2.6 g. of hydroxylamine hydrochloride and 6.3 g. of sodium methoxide in 55 ml. of methanol is heated overnight at reflux. Water and dilute hydrochloric acid are added. The precipitate which forms is collected and recrystallized from ethanol to give 3-phenyl-7-benzofuranacethydroxamic acid, m.p. 163° (dec).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2].[CH2:22]([O:24][C:25](=[O:28])[CH2:26]Br)[CH3:23]>CS(C)=O>[CH2:22]([O:24][C:25](=[O:28])[CH2:26][N:7]1[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]([CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[C:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH3:23]
Reactant: CCOC(=O)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12
Reactant: CCOC(=O)CBr
Solvent: CS(C)=O
Product: CCOC(=O)Cn1c(C(=O)OCC)c2ccc(Cl)cc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 30.0 g. of 5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester in 300 ml. of dimethylsulfoxide is treated with 66.8 g. of bromoacetic acid ethyl ester and 27.6 g. of finely triturated, dry potassium carbonate and intensively stirred at room temperature for 17 hours. The mixture is poured into 750 ml. of ice-water and the separated product, after the addition of 50 g. of sodium chloride, is removed by filtration under suction, washed with water and then dissolved in methylene chloride. The aqueous layer is separated, the organic phase dried over sodium sulfate, filtered and concentrated to dryness. The resulting oil crystallizes on trituration with ether and pentane, and there is obtained 1-ethoxycarbonyl-5-chloro-3-phenylisoindole-2-acetic acid ethyl ester; melting point 100°-101° C. Recrystallization from ethanol increases the melting point to 103°-104° C.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][O:7][C:6]1=[O:10].[CH3:19][O:20][C:21](=[O:40])[CH2:22][C:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][C:24]=1[O:38][CH3:39].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][O:20][C:21](=[O:40])[CH2:22][C:23]1[CH:28]=[C:27]([C:2]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:3]=2[CH2:4][N:5]2[CH2:9][CH2:8][O:7][C:6]2=[O:10])[CH:26]=[CH:25][C:24]=1[O:38][CH3:39]
Reactant: O=C1OCCN1Cc1cc(C(F)(F)F)ccc1Br
Reactant: COC(=O)Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1cc(-c2ccc(C(F)(F)F)cc2CN2CCOC2=O)ccc1OC
Temperature: 90 °C
Reaction time: 3 h

Procedure:
3-(2-Bromo-5-trifluoromethyl-benzyl)-oxazolidin-2-one (0.085 g, 0.26 mmol), [2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester (0.120 g, 0.39 mmol), potassium carbonate (0.091 g, 0.66 mmol), and tetrakis(triphenylphosphine)palladium (0) (0.030 g, 0.03 mmol) were combined in DME:H2O (2:1; 10 mL), and the mixture was purged with N2. The reaction was stirred at 90° C. for 3 hours, until no starting material was seen by analytical LCMS. After cooling to room temperature, the mixture was worked-up with EtOAc and brine and purified by silica gel chromatography to give the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][CH:17]=[N:18]3)=[CH:4][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.Cl[CH2:24][C:25](=O)[CH3:26].C(N(CC)CC)C>C(O)C>[Br:1][C:2]1[C:3]([O:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][CH:17]=[N:18]3)=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:24]=[C:25]([CH3:26])[N:11]=2)=[N:6][CH:7]=1
Reactant: NC(=S)Nc1cc(Oc2cccc3ncccc23)c(Br)cn1
Reactant: CC(=O)CCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1csc(Nc2cc(Oc3cccc4ncccc34)c(Br)cn2)n1
Yield: 77.2 %

Procedure:
A mixture of 1-(5-bromo-4-(quinolin-5-yloxy)pyridin-2-yl)thiourea (2.00 g, 5.330 mmol), 1-chloropropan-2-one (0.6366 ml, 7.995 mmol), triethylamine (1.486 ml, 10.66 mmol), and ethanol (25 ml) was heated at reflux for two days. The organic solvents were concentrated, and hexanes:ethyl acetate (9:1) were added and the reaction was filtered. The residue was washed with water and ethyl acetate, and dried over high vacuum overnight to give the desired compound (1.70 g, 76.40% yield) as very light yellow solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([N:7]1[C:13](=[O:14])[CH:12]([CH3:15])[C:11]2[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=2[C:9]2[C:20]([NH2:24])=[CH:21][CH:22]=[CH:23][C:8]1=2)=[O:6])[CH3:4].N1C=CC=CC=1.[F:31][C:32]1[CH:33]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1>C1COCC1>[F:31][C:32]1[CH:33]=[C:34]([S:38]([NH:2][C@H:3]([C:5]([N:7]2[C:13](=[O:14])[CH:12]([CH3:15])[C:11]3[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=3[C:9]3[C:20]([NH2:24])=[CH:21][CH:22]=[CH:23][C:8]2=3)=[O:6])[CH3:4])(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC1C(=O)N(C(=O)[C@H](C)NS(=O)(=O)c2cccc(F)c2)c2cccc(N)c2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
To 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7B) (0.1500 g, 0.434 mmol) in THF (4 ml) was added pyridine (0.088ml, 1.09 mmol) and 3-fluorobenzenesulfonyl chloride (Fluorochem Limited) (0.0928 ml, 0.477 mmol), stirred at RT overnight. The reaction mixture was evaporated to dryness. Water was added, filtered. The solid was purified with flash chromatography (silica, 6% MeOH/CH2Cl2, crystallized with CH2Cl2/hexane and washed with Et2O/hexane (1:1, v/v) to give the title compound (0.0580 g, 29%) as a white solid.
Reaction SMILES: [CH3:1][C:2]12[O:9][C:6]([CH3:10])([CH:7]=[CH:8]1)[C:5](=[O:11])[CH2:4][C:3]2=[O:12].[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18][C:19]1[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22].C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C.CC(C)(O)C#N>C(#N)C>[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18][C:19]1[C:20]([C:21]([CH:4]2[C:3](=[O:12])[C:2]3([CH3:1])[O:9][C:6]([CH3:10])([CH:7]=[CH:8]3)[C:5]2=[O:11])=[O:22])=[CH:24][CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[N:27]=1
Reactant: COCCOCc1nc(C(F)(F)F)ccc1C(=O)O
Reactant: CC12C=CC(C)(O1)C(=O)CC2=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(O)C#N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COCCOCc1nc(C(F)(F)F)ccc1C(=O)C1C(=O)C2(C)C=CC(C)(O2)C1=O
Reaction time: 2 h

Procedure:
146 mg (0.879 mmol) of 1,5-dimethyl-8-oxa-bicyclo[3.2.1]oct-6-ene-2,4-dione and 245 mg (0.879 mmol) of 2-(2-methoxy-ethoxymethyl)-6-trifluoromethyl-nicotinic acid (preparation as described in WO 01/94339) are dissolved in 29 ml of acetonitrile and treated at ambient temperature with 199 mg (0.966 mmol) of dicyclohexylcarbodiimide. The reaction mixture is stirred for 2 hours and then 0.184 ml (1.318 mmol) of triethylamine and 0.08 ml (0.879 mmol) of acetone cyanohydrin are added. Stirring is carried out for a further 16 hours at ambient temperature, followed by concentration under reduced pressure. The residue that remains behind is chromatographed over silica gel (eluant: toluene/ethanol/dioxane/triethylamine/water 20:8:4:4:1). The product-containing fraction is concentrated. The oily residue is again dissolved in fresh ethyl acetate and washed with 10 ml of dilute hydrochloric acid (pH 1), and then with water (2×) and sodium chloride solution (2×). After the solution has been dried over sodium sulfate and concentrated by evaporation under reduced pressure, 128 mg (34%) of 3-[2-(2-methoxy-ethoxymethyl)-6-trifluoromethyl-pyridine-3-carbonyl]-1,5-dimethyl-8-oxa-bicyclo[3.2.1]oct-6-ene-2,4-dione are obtained in the form of a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[C:31]2[CH:32]=[CH:33][S:34][C:30]=2[CH:29]=[CH:28][N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[C:31]5[CH:32]=[CH:33][S:34][C:30]=5[CH:29]=[CH:28][N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Clc1nccc2sccc12
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nccc5sccc45)cc3CC[C@@H]12
Yield: 24.7 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 4-chlorothieno[3,2-c]pyridine (78 mg, 0.46 mmol) and 1 mL of anhydrous dimethyl formamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 37 mg (25%) of the title compound as a white solid. mp 196°-197°. FDMS: m/e=394. α[D]589 =+75.17 (c=0.57, chloroform).
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[N:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[I:39]I>O1CCCC1.C(O)(=O)C>[C:16]([O:20][C:21]([N:23]1[CH2:24][CH2:25][N:26]([C:29]2[N:30]=[N:31][C:32]([C:35]([F:36])([F:37])[F:38])=[C:33]([I:39])[CH:34]=2)[CH2:27][CH2:28]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)nn2)CC1
Reactant: II
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(I)c(C(F)(F)F)nn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a mixture of butyllithium (2.5 M in hexanes) (6.31 ml, 15.79 mmol) in tetrahydrofuran (125 ml) at 0° C., was added 2,2,6,6-tetramethylpiperidine (3.808 ml, 22.56 mmol). The reaction mixture was then stirred at room temperature for 1 h. The mixture was cooled to −78° C. and then a solution of 4-(6-trifluoromethyl-pyridazin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (D9) (2.5 g, 7.52 mmol) in tetrahydrofuran (20 ml) was added. The mixture was stirred for 1 h. at −78° C. before adding a solution of iodine (2.29 g, 9.024 mmol) in tetrahydrofuran (10 ml). The mixture was stirred at −78° C. for 1 h. and then diluted with a 10% solution of acetic acid in tetrahydrofuran. The mixture was then allowed to reach room temperature and then the solvent was evaporated in vacuo. The residue was diluted with dichloromethane and extracted with water. The organic layer was separated, dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was precipitated from diethyl ether to yield D10 (2.81 g, 82%) as a light yellow solid. C14H18F3IN4O2 requires 458; Found 459 (MH+).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([C:12]2[CH:17]=[C:16]([N+:18]([O-])=O)[C:15](=[O:21])[N:14]([CH3:22])[CH:13]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:23]1[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:29]=2)[C:24]1=[O:36])(=[O:3])[CH3:2].C(O)(=O)C>[Zn].C1COCC1>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:23]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:29]=3)[C:24]2=[O:36])=[CH:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH2:18])[C:15](=[O:21])[N:14]([CH3:22])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(-c2cc([N+](=O)[O-])c(=O)n(C)c2)cccc1N1Cc2cc(C(C)(C)C)ccc2C1=O
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)OCc1c(-c2cc(N)c(=O)n(C)c2)cccc1N1Cc2cc(C(C)(C)C)ccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 122c (600 mg, 1.23 mmol), acetic acid (10 mL) and THF (5 ml). Zinc dust (1.56 g, 20.5 mmol) was added in portions. The reaction mixture was stirred at room temperature for 1 h. After this time, the reaction mixture was filtered, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by flash chromatography to afford a 81% (460 mg) yield of 122d as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 7.85 (d, 1H, J=8.0 Hz), 7.58 (d, 1H, J=8.0 Hz), 7.52 (s, 1H), 7.45 (t, 1H, J=8.0 Hz), 7.28 (d, 2H, J=8.0 Hz), 6.74 (d, 1H, J=2.0 Hz), 6.57 (d, 1H, J=2.0 Hz), 5.08 (s, 2H), 4.78 (s, 2H), 4.37 (s, 2H), 3.60 (s, 3H), 1.85 (s, 3H), 1.40 (s, 9H); MS (ESI+) m/z 460.3 (M+H).
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([CH2:27][CH2:28][CH3:29])=[N:5][C:4]=1[C:30](=[O:33])[CH2:31][CH3:32])#[N:2].[CH3:34][Mg]Br>O1CCCC1>[C:1]([C:3]1[N:7]([C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:6]([CH2:27][CH2:28][CH3:29])=[N:5][C:4]=1[C:30]([OH:33])([CH3:34])[CH2:31][CH3:32])#[N:2]
Reactant: C[Mg]Br
Reactant: CCCc1nc(C(=O)CC)c(C#N)n1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCCc1nc(C(C)(O)CC)c(C#N)n1C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Following the procedure described in Preparation 17, but using 5.00 g of 5-cyano-4-propionyl-2-propyl-1-tritylimidazole (prepared as described in Preparation 16) and 12.5 ml of a 1M solution of methylmagnesium bromide in tetrahydrofuran, 3.32 g of the title compound were obtained as a crystalline powder, melting at above 120° C. (softening at 110° C.).