Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Br[CH:12]([CH3:20])[C:13](=O)[CH2:14][C:15]([O:17][CH3:18])=[O:16]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:18][O:17][C:15](=[O:16])[CH2:14][C:13]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[O:7][C:12]=1[CH3:20]
Reactant: COC(=O)CC(=O)C(C)Br
Reactant: NC(=O)c1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)Cc1nc(-c2ccc(F)cc2)oc1C
Temperature: 25 °C
Yield: 25.7 %

Procedure:
A solution of 667 mg (4.80 mmol) of 4-fluorobenzamide and 1.0 g (4.80 mmol) of methyl 4-bromo-3-oxo-pentanoate in 6 mL of dry toluene was heated at 120° C. for 16 h. The resulting dark slurry was cooled to rt, diluted with 10 mL of EtOAc, and washed with NaHCO3 (1×10 mL). The organic layer was separated, dried (MgSO4), and the solvents removed under reduced pressure. Purification of the material by silica gel flash column chromatography using hexane/EtOAc 4/1 as eluent to afford 308 mg of the title compound as a clear oil: 1H NMR (CDCl3, 400 MHz) δ7.97 (m, 2H), 7.11 (m, 2H), 3.73 (s, 3H), 3.56 (s, 2H), 2.36(s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].CC(C)=[O:20]>>[C:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]([OH:20])=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)=O
Reactant: N#Cc1ccc(Oc2ccc(C=O)cc2)cc1
Product: N#Cc1ccc(Oc2ccc(C(=O)O)cc2)cc1
Temperature: 0 °C
Yield: 70 %

Procedure:
To an ice cold solution of 4-(4-cyano-phenoxy)-benzaldehyde (2.0 g, 8.9 mmol) in acetone (10 mL), the Jone's reagent (7 mL) was added slowly drop wise until reaction completes. Acetone was removed completely and diluted with water. The mixture was extracted with ethyl acetate. the combined organic layers were dried over anhydrous sodium sulphate and concentrated to get the title compound (1.5 g, 70%)
Reaction SMILES: [CH:1]([OH:6])=[CH:2][CH2:3][CH2:4][OH:5].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1>O1CCCC1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:6][CH2:1]/[CH:2]=[CH:3]\[CH2:4][OH:5]
Reactant: C1=COCCC1
Reactant: OC=CCCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: OC/C=C\COC1CCCCO1
Reaction time: 21 h
Yield: 33.5 %

Procedure:
50 g of 1,4-butenediol was dissolved in 200 ml of tetrahydrofuran and 280 mg of pyridinium p-toluenesulfonate was added and a solution prepared by dissolving 10.27 g of 3,4-dihydro-2H-pyrane in 50 ml of tetrahydrofuran was added dropwise under ice cooling. After the temperature was returned to room temperature, the reaction solution was stirred for 21 hours. The solvent was evaporated under reduced pressure and the residue was extracted with diethyl ether after adding water. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain 7.05 g of a desired crude product as a colorless oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]2[C:5]([CH:6]3[CH2:14][CH:8]([N:9]=[C:10]2Cl)[CH2:7]3)=[CH:4][C:3]=1[F:15].[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH2:19][NH2:20]>CCCCO.O>[Br:1][C:2]1[CH:12]=[C:11]2[C:5]([CH:6]3[CH2:14][CH:8]([N:9]=[C:10]2[NH:20][CH2:19][CH:18]([O:21][CH3:22])[O:17][CH3:16])[CH2:7]3)=[CH:4][C:3]=1[F:15]
Reactant: COC(CN)OC
Reactant: Fc1cc2c(cc1Br)C(Cl)=NC1CC2C1
Solvent: CCCCO
Solvent: O
Product: COC(CNC1=NC2CC(C2)c2cc(F)c(Br)cc21)OC
Temperature: 100 °C
Yield: 107.7 %

Procedure:
Into a 100-mL 3-necked round-bottom flask was placed a solution of 5-bromo-8-chloro-4-fluoro-9-azatricyclo[8.1.1.0[2,7]]dodeca-2,4,6,8-tetraene (3.75 g, 13.00 mmol, 1.00 equiv) in n-BuOH (50 mL) and 2,2-dimethoxyethan-1-amine (1.5 g, 14.27 mmol, 1.10 equiv). The resulting solution was stirred at 100° C. for 1.5, diluted with 50 mL of water and extracted with 1×50 mL of ethyl acetate. The organic layers were combined and concentrated under vacuum to afford 5.0 g (crude) of 5-bromo-N-(2,2-dimethoxyethyl)-4-fluoro-9-azatricyclo[8.1.1.0[2,7]]dodeca-2,4,6,8-tetraen-8-amine as a yellow oil.
Reaction SMILES: [OH:1][NH:2][CH2:3][C:4]1[CH:26]=[CH:25][C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][NH:23][OH:24])=[CH:18][CH:17]=3)[CH:10]=2)=[CH:6][CH:5]=1.Cl[C:28]([N:30]=[C:31]=[O:32])=[O:29]>O1CCCC1>[O:29]=[C:28]1[NH:30][C:31](=[O:32])[O:24][N:23]1[CH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][C:7]3[CH:25]=[CH:26][C:4]([CH2:3][N:2]4[C:31](=[O:32])[NH:30][C:28](=[O:29])[O:1]4)=[CH:5][CH:6]=3)[CH:10]=2)=[CH:17][CH:18]=1
Reactant: ONCc1ccc(Oc2cccc(Oc3ccc(CNO)cc3)c2)cc1
Reactant: O=C=NC(=O)Cl
Solvent: C1CCOC1
Product: O=c1[nH]c(=O)n(Cc2ccc(Oc3cccc(Oc4ccc(Cn5oc(=O)[nH]c5=O)cc4)c3)cc2)o1
Reaction time: 0.17 h

Procedure:
1,3-Bis[4-(N-hydroxyaminomethyl)phenoxy]benzene (0.704 g) was dissolved in 21 ml of tetrahydrofuran to which, with ice-cooling and in an atmosphere of argon, was subsequently added dropwise 0.354 ml of chlorocarbonyl isocyanate. After 10 minutes of stirring at the same temperature, the stirring was continued for 2 hours at room temperature. The solvent was evaporated under a reduced pressure, and the resulting residue was subjected to silica gel column chromatography to obtain 0.44 g of 1,3-bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]benzene from fractions of chloroform-methanol (30:1) elution.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C@H:15]2[C@:10]([CH3:22])([CH2:11][CH2:12][C:13]3[C:20](Br)=[CH:19][CH:18]=[CH:17][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:30]=[O:31]>C1COCC1>[CH2:1]([N:8]1[CH2:16][C@H:15]2[C@:10]([CH3:22])([CH2:11][CH2:12][C:13]3[C:20]([CH:30]=[O:31])=[CH:19][CH:18]=[CH:17][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: C[C@]12CCc3c(Br)cccc3[C@H]1CN(Cc1ccccc1)C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@]12CCc3c(C=O)cccc3[C@H]1CN(Cc1ccccc1)C2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
cis-2-Benzyl-6-bromo-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (0.561 mmol, 200 mg) was dissolved in THF (5 ml) and the resulting solution was cooled to −78° C. Butyllithium (2.5 M in hexanes)(2.81 mmol, 1.123 ml) was added dropwise and the reaction mixture was stirred at −78° C. for 30 minutes. N,N-Dimethylformamide (8.42 mmol, 0.777 ml, 734 mg) was added and the reaction mixture was stirred at −78° C. for a further 2 h and then quenched by the addition of saturated aqueous ammonium chloride solution and allowed to warm to room temperature. The resulting biphasic solution was separated and the aqueous phase was further extracted with ether (2×). The combined organic extracts were dried over magnesium sulphate, filtered and the solvent removed in vacuo. The crude product was purified by silica column chromatography (eluting with heptane—50:50 EtOAc:Heptane) to afford cis-2-benzyl-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole-6-carbaldehyde (95 mg), 1H NMR (400 MHz, CDCl3) ppm 10.29 (1H, s, CHO), 7.67-7.61 (1H, m, Ar—H), 3.62-3.55 (2H, m, NCH2Ph), 3.32-3.04 (4H, m, 4×CH), 2.73 (1H, d, CH), 2.49 (1H, d, CH), 2.30 (1H, t, CH), 1.88-1.78 (1H, m, CH), 1.53-1.45 (1H, m, CH), 1.20 (3H, s, CH3).
Reaction SMILES: [C:1]([NH:7][C@H:8]([C:13]([OH:15])=O)[C@H:9]([CH2:11][CH3:12])[CH3:10])(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].Cl.[CH2:17]([O:21][C:22](=[O:26])[C@H:23]([CH3:25])[NH2:24])[CH:18]([CH3:20])[CH3:19].C(N[C@H](C(O)=O)C)(OC(C)(C)C)=O>CN(C1C=CN=CC=1)C.CC(C)CO>[CH2:17]([O:21][C:22](=[O:26])[C@H:23]([CH3:25])[NH:24][C:13](=[O:15])[C@H:8]([C@H:9]([CH2:11][CH3:12])[CH3:10])[NH:7][C:1](=[O:6])[CH2:2][CH:3]([CH3:4])[CH3:5])[CH:18]([CH3:20])[CH3:19]
Reactant: CC[C@H](C)[C@H](NC(=O)CC(C)C)C(=O)O
Reactant: CC(C)COC(=O)[C@H](C)N
Agent: CN(C)c1ccncc1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: CC(C)CO
Product: CC[C@H](C)[C@H](NC(=O)CC(C)C)C(=O)N[C@@H](C)C(=O)OCC(C)C

Procedure:
Following General Procedure C and using N-(isovaleryl)-L-isoleucine (prepared from isovaleric acid (Aldrich) and L-isoleucine methyl ester hydrochloride (Aldrich) using General Procedure C, followed by hydrolysis using General Procedure AF) and L-alanine iso-butyl ester hydrochloride (prepared from N-BOC-L-alanine (Sigma) and 2-methyl-1-propanol (Aldrich) using General Procedure C (with catalystic DMAP), followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp=142-146° C.). The reaction was monitored by tlc (Rf=0.4 in 1:1 EtOAc/hexanes) and the product was purified by silica gel chromatography using 1:1 EtOAc/hexanes as the eluent.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[CH:11][CH:10]=1)\[CH3:7])[CH3:2].[Br:21]N1C(=O)CCC1=O.N(C(C)(CC(C)C)C#N)=NC(C)(CC(C)C)C#N>ClCCl>[CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[C:6](/[O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[CH:13][CH:14]=1)\[CH2:7][Br:21])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)/C=C(\C)Oc1ccc(CC(C)(C)O)cc1
Agent: CC(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)C
Solvent: ClCCl
Product: CCOC(=O)/C=C(\CBr)Oc1ccc(CC(C)(C)O)cc1

Procedure:
A solution of (E)-3-[4-(2-hydroxy-2-methyl-propyl)-phenoxy]-but-2-enoic acid ethyl ester (prepared as in Example 239, 0.500 g, 1.80 mmol) in dichloromethane (50 mL) was treated with N-bromosuccinimide (0.350 g, 1.97 mmol) and 2,2′-azobis(2,4′-dimethylvaleronitrile) (0.045 g, 0.18 mmol) and heated to reflux for 5.5 h under a nitrogen atmosphere. The mixture was cooled and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0% to 30% ethyl acetate/hexanes) to afford (E)-4-bromo-3-[4-(2-hydroxy-2-methyl-propyl)-phenoxy]-but-2-enoic acid ethyl ester which was immediately dissolved in acetonitrile (30 mL) and treated with (S)-2-amino-4-methyl-pentanoic acid pyrazin-2-ylamide (0.341 g, 1.64 mmol) and N,N-diisopropylethylamine (0.230 g, 17.9 mmol). The resulting mixture was sealed in a tube and heated at 90° C. for 14 h. The mixture was cooled to room temperature and partition between water and ethyl acetate. The layers were separated and the ethyl acetate layer was concentrated in vacuo. The residue was purified by consecutive flash column chromatography (silica gel, 0% to 50% ethyl acetate/hexanes; silica gel, 0% to 30% ethyl acetate/dichloromethane) and the material obtained dissolved in tetrahydrofuran. The mixture was sealed in a tube and heated at 160° C. for 19 h. At this time, the reaction was cooled to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0% to 100% ethyl acetate/hexanes) to afford (S)-2-{4-[4-(2-hydroxy-2-methyl-propyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid pyrazin-2-ylamide (67 mg, 9%) as a white solid: HR-ES-MS m/z calculated for C24H30N4O4 [M+H]+ 439.234, observed 439.2341; 1H NMR (300 MHz, CDCl3) δ ppm 1.01 (d, J=6.3 Hz, 3H), 1.03 (m, J=6.3 Hz, 3H), 1.24 (s, 6H), 1.55-1.72 (m, 1H), 1.68-2.06 (m, 3H), 2.79 (s, 2H), 4.12 (d, J=18.1 Hz, 1H), 4.25 (d, J=18.1 Hz, 1H), 4.93 (dd, J=8.8, 6.6 Hz, 1H), 5.01 (s, 1H), 7.09 (d, J=8.5 Hz, 2H), 7.27 (d, J=8.5 Hz, 2H), 8.27 (s, 1H), 8.34 (d, J=2.4 Hz, 1H), 9.09 (s, 1H), 9.49 (s, 1H).
Reaction SMILES: Cl.C(OCC)(=O)C.C([O:12][C:13]1[C:14]([CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([C:26](=[O:35])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:22][CH2:21]2)=[N:15][CH:16]=[CH:17][N:18]=1)(C)(C)C.[OH-].[Na+]>ClCCl>[CH3:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][C:26]([CH:23]1[CH2:24][CH2:25][N:20]([CH2:19][C:14]2[C:13](=[O:12])[NH:18][CH:17]=[CH:16][N:15]=2)[CH2:21][CH2:22]1)=[O:35]
Reactant: Cc1ccccc1CC(=O)C1CCN(Cc2nccnc2OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccccc1CC(=O)C1CCN(Cc2ncc[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 50.6 %

Procedure:
After adding 3 ml of 4N hydrogen chloride/ethyl acetate to 153 mg of 1-[1-(3-tert-butoxy-2-pyrazinylmethyl)-piperidin-4-yl]-2-(2-methylphenyl)ethanone, the mixture was stirred for 5 hours at room temperature. Aqueous 1N sodium hydroxide was added to the reaction solution and extraction was performed with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Diethyl ether was added and the insoluble portion was filtered out to obtain the title compound (66 mg, 51% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH2:11])=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.[CH3:30][O:31][CH:32]([O:43][CH3:44])[C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[C:35](F)[CH:34]=1>O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:35]2[CH:34]=[C:33]([CH:32]([O:43][CH3:44])[O:31][CH3:30])[CH:38]=[CH:37][C:36]=2[N+:39]([O-:41])=[O:40])=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)=[O:5])[CH3:2]
Reactant: COC(OC)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CCOC(=O)c1sc(N)nc1-c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1sc(Nc2cc(C(OC)OC)ccc2[N+](=O)[O-])nc1-c1cccc(Cl)c1
Yield: 71.1 %

Procedure:
A mixture of 2.82 g (10 mmole) of 2-amino-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid ethyl ester, 9.75 g (30 mmole) of cesium carbonate, 20 mL of dimethylformamide, and 2.15 g (10 mmole) of 4-dimethoxymethyl-2-fluoro-1-nitro-benzene was heated at 80 degrees for 1 hour. The cooled mixture was diluted with 200 mL of water and extracted three times with 100 mL of dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified with silica gel chromatography, eluting with ethyl acetate-hexanes (gradient 0:100-10:90) to give 3.4 g of 4-(3-chloro-phenyl)-2-(5-dimethoxymethyl-2-nitro-phenylamino)-thiazole-5-carboxylic acid ethyl ester (VI.41a) as a yellow solid.
Reaction SMILES: [CH3:1]N(C)C(=O)C.[CH:7]1([C:13]2[CH:44]=[CH:43][C:16]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[N:26]=[C:27]([N:30]([CH2:32][C:33]5[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=5)[CH3:31])[S:28][CH:29]=4)=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CCCCCC>[CH:7]1([C:13]2[CH:44]=[CH:43][C:16]([CH2:17][N:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[N:26]=[C:27]([N:30]([CH2:32][C:33]5[CH:34]=[CH:35][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:41][CH:42]=5)[CH3:31])[S:28][CH:29]=4)=[CH:21][CH:20]=3)[CH3:1])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC(=O)N(C)C
Reactant: COC(=O)c1ccc(CN(C)c2nc(-c3ccc(NCc4ccc(C5CCCCC5)cc4)cc3)cs2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CCCCCC
Product: COC(=O)c1ccc(CN(C)c2nc(-c3ccc(N(C)Cc4ccc(C5CCCCC5)cc4)cc3)cs2)cc1
Temperature: 25 °C
Yield: 58.3 %

Procedure:
Under an argon stream, N,N-dimethylacetamide (351 ml, 5.0 v/w) was added to methyl 4-(N-(4-(4-(4-cyclohexylbenzylamino)phenyl)-2-thiazolyl)-N-methylaminomethyl)benzoate (70.3 g, 0.134 mol) obtained in Example 1(5) and potassium carbonate (73.9 g, 0.535 mol) was carefully added with stirring. After stirring the mixture at room temperature for 20 min., dimethyl sulfate (50.6 ml, 0.535 mol) was added. After stirring at 50° C. for 1 hr., potassium carbonate (18.4 g, 0.134 mol) and dimethyl sulfate (12.7 ml, 0.134 mol) were added and the mixture was stirred at 60° C. for 2 hr. After cooling to room temperature, n-hexane (422 ml, 6.0 v/w) was added, and the mixture was stirred for 1 hr. After ice-cooling, distilled water (562 ml, 8.0 v/w) was added. After stirring at room temperature for 1 hr., the resulting crystals were collected by filtration and washed with methanol (352 ml, 5.0 v/w) in a slurry form. Tetrahydrofuran (180 ml) was added to the obtained orange solid and insoluble materials were filtered off. The filtrate was concentrated to give the title compound (42.1 g, yield 58.3%) as a pale-yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[CH:18]([CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10]1>ClCCl>[NH:22]1[CH2:21][CH2:20][CH:19]([CH:18]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:8])[CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3ccccc3NC2=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2ccccc2CC1C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (3 mL) was added to a solution of tert-Butyl 4-(2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)piperidine-1-carboxylate (260 mg, 0.79 mmol) in dichloromethane (3 mL). Reaction stirred at room temperature for 1 hour. Reaction mixture was concentrated in vacuo. Residue was dissolved in methanol. Dowex 1×4-200 ion exchange resin was added to the mixture to create a slurry. Mixture stirred at room temperature for 30 minutes. Resin was filtered off and washed with methanol. Filtrate was concentrated. Title compound was obtained as dark foam in quantitative yield. MS m/e (M+H)+=231.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([NH:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=4)[CH2:16][CH2:15][N:14]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CCNC(=O)C2(c3ccc(Cl)cc3)CCC2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Temperature: 25 °C

Procedure:
1-(4-Chlorophenyl)-N-[2-(4-methoxyphenyl)ethyl]cyclobutanecarboxamide (10.58 g, 30.8 mmol) was treated with toluene (100 mL). Phosphoryl trichloride (4.72 g, 30.8 mmol) was added and the reaction mixture was heated under reflux for 8 h. After cooling to room temperature the reaction mixture was concentrated in vacuo and then slowly poured in ice water. Ethyl acetate was added and the organic layer was washed with water (2×), dried (MgSO4) and concentrated in vacuo to give an orange oil. Yield: 10.25 g.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:10])[CH2:7][C:8]#[N:9].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[CH3:21][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O:10][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:7][C:8]#[N:9])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: N#CCC(=O)c1ccco1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC(=CC#N)c2ccco2)cc1
Yield: 92.5 %

Procedure:
To a mixture of 3-(2-furyl)-3-oxopropanenitrile (5.29 g), p-toluenesulfonyl chloride (9.00 g) and dichloromethane (60 mL) was added dropwise triethylamine (5.99 g) under ice-cooling. After stirring under ice-cooling for 1.5 hrs, the mixture was diluted with dichloromethane (100 mL). The mixture was washed with water (150 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:methyl acetate=9:1→3:1) to give the title compound (10.48 g) as a mixture of (E)-form and (Z)-form (3:1).
Reaction SMILES: C1(C2C=CC(CNCCC3C=CC(F)=C(C(F)(F)F)C=3)=CC=2)CC1.[C:25]12([CH2:37][CH2:36]1)[C:33]1[C:28](=[CH:29][C:30]([CH:34]=O)=[CH:31][CH:32]=1)[CH2:27][CH2:26]2.[Cl:38][C:39]1[CH:40]=[C:41]([CH2:46][CH2:47][NH2:48])[CH:42]=[CH:43][C:44]=1[Cl:45].[BH4-].[Na+]>>[Cl:38][C:39]1[CH:40]=[C:41]([CH2:46][CH2:47][NH:48][CH2:34][C:30]2[CH:29]=[C:28]3[C:33](=[CH:32][CH:31]=2)[C:25]2([CH2:37][CH2:36]2)[CH2:26][CH2:27]3)[CH:42]=[CH:43][C:44]=1[Cl:45]
Reactant: NCCc1ccc(Cl)c(Cl)c1
Reactant: O=Cc1ccc2c(c1)CCC21CC1
Agent: Fc1ccc(CCNCc2ccc(C3CC3)cc2)cc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Product: Clc1ccc(CCNCc2ccc3c(c2)CCC32CC2)cc1Cl
Yield: 92.2 %

Procedure:
The title compound was synthesized in analogy to (4-cyclopropylbenzyl)-[2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-amine (described in example S53) using 2′,3′-dihydro-spiro-[cyclopropane-1,1′-[1H]indene]-5′-carboxaldehyde (62 mg, 0.36 mmol), 2-(3,4-dichloro-phenyl)-ethylamine (68 mg, 0.36 mmol) and sodium borohydride (20 mg, 0.54 mmol). The desired product (115 mg, 92%) was isolated without further purification as a colorless oil. MS (ISP) 346.2 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([S:8][CH2:9][CH:10]([CH3:14])[C:11](Cl)=[O:12])=[O:7].C(SCC(C)C(Cl)=O)(=O)C.C(SCC(C)C([N:38]1[CH2:42][CH2:41][CH:40]=[C:39]1[C:43]([OH:45])=[O:44])=O)(=O)C1C=CC=CC=1>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([S:8][CH2:9][CH:10]([CH3:14])[C:11]([N:38]1[CH2:42][CH2:41][CH:40]=[C:39]1[C:43]([OH:45])=[O:44])=[O:12])=[O:7]
Reactant: CC(CSC(=O)c1ccccc1)C(=O)N1CCC=C1C(=O)O
Reactant: CC(CSC(=O)c1ccco1)C(=O)Cl
Agent: CC(=O)SCC(C)C(=O)Cl
Product: CC(CSC(=O)c1ccco1)C(=O)N1CCC=C1C(=O)O

Procedure:
Following the procedure of Example 1 but substituting an equivalent amount of 3-[(2-furanylcarbonyl)thio]-2-methylpropanoyl chloride for the 3-acetylthio-2-methylpropanoyl chloride in part (b) and subjecting the product to the procedure of Example 1(c), one obtains (±)-4,5-dihydro-1-[3-[(2-furanylcarbonyl)thio]-2-methyl-1-oxopropyl]-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][C:3](=[O:9])[CH2:2]2.Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].CCN(C(C)C)C(C)C>C(Cl)Cl>[O:9]=[C:3]1[CH2:2][CH:1]2[N:8]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH:5]([CH2:6][CH2:7]2)[CH2:4]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1CC2CCC(C1)N2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CC2CCC(C1)N2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
8-azabicyclo[3.2.1]octan-3-one (5.10 g; 31.55 mmol) was dissolved in CH2Cl2 (50 mL) and treated with benzyl chloroformate (4.29 mL; 5.11 g; 29.98 mmol) DIPEA (16.48 mL; 12.23 g; 94.66 mmol) was added drop-wise (exothermic reaction). The resulting clear solution was allowed to stir at room temperature for 30 min and was subsequently diluted with 100 mL CH2Cl2. The organic phase was washed with 1 N HCl (2×100 mL), dried on Na2SO4 and concentrated to provide the crude product (7.2 g). 1H-NMR (400 MHz, CDCl3) δ 7.38 (m, 5H), 5.22 (s, 2H), 4.62 (s, 2H), 2.67 (m, 2H), 2.38 (d, J=15.9 Hz, 2H), 2.12 (m, 2H), 1.71 (dd, J=15.0, 7.2 Hz, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[S:13][C:14]#[N:15])([O-])=O.NC(N)=S.O>CN(C)C=O>[NH2:15][C:14]1[S:13][C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N:1]=1
Reactant: N#CSc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: NC(N)=S
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc2cc([N+](=O)[O-])ccc2s1
Temperature: 150 °C
Reaction time: 2 h
Yield: 108.4 %

Procedure:
11.71 g of 2,4-dinitrophenyl thiocyanate are added, over the course of 15 minutes, to a solution of 7.6 g of thiourea in 50 ml of dimethylformamide at 150° C. The mixture is stirred at 150° C. for a further 2 hours, and the product is discharged into 500 ml of water, and the solid is filtered off with suction and washed with water. 11 g of crude 2-amino-5-nitrobenzothiazole are obtained, its identity being confirmed by TLC comparison with authentic material.