Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:17]=[C:16]3[C:12]([C:13]([CH:18]=[CH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:14][NH:15]3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>ClCCl.O>[C:32]([NH:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:17]=[C:16]3[C:12]([C:13]([CH:18]=[CH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:14][NH:15]3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(Sc2ccc3c(C=Cc4ccccc4)n[nH]c3c2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1cccc(Sc2ccc3c(C=Cc4ccccc4)n[nH]c3c2)c1
Temperature: 23 °C
Reaction time: 0.17 h
Yield: 129.7 %

Procedure:
To a solution of 6-(3-aminophenylsulfanyl)-3-styryl-1H-indazole (43.7 mg, 0.10 mmol) in dichloromethane (0.5 mL) was added pyridine (81 μL, 1.0 mmol, 10 equiv), and acetic anhydride (47 μL, 0.5 mmol, 5 equiv). The mixture was allowed to stir for 10 min at 23° C. The mixture was diluted with water and the product was extracted with 30% hexane in ethyl acetate. The organic material was washed with 5% citric acid and saturated sodium bicarbonate. The organic material was dried over sodium sulfate, decanted and concentrated. Purification by silica gel chromatography (3:7 ethyl acetate-hexane) gave 6-(3-acetamido-phenylsulfanyl)-3-styryl-1H-indazole as an oil (50 mg, 97%): Rfsm 0.33, Rfp 0.18 (ethyl acetate-hexane 3:7); 1H NMR (300 MHz, CDCl3) δ 7.94 (d, 1H), 7.65-7.1 (m, 13H), 5.70 (s, 2H), 3.62 (t, 2H, J=8.2 Hz, 2.18 (s, 3H), 0.93 (t, 2H, J=8.2 Hz), −0.05 (s, 9H). HRMS (FAB) [M+Cs]/z Calc'd 648.1117, found 648.1098.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2.[CH3:17][NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH2:19]([N:18]([CH3:17])[C:1](=[O:5])[C:2]([C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([Br:7])[CH:9]=2)[NH:13][CH:12]=1)=[O:3])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CNCc1ccccc1
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)C(=O)C(=O)c1c[nH]c2ccc(Br)cc12
Reaction time: 2 h
Yield: 75.6 %

Procedure:
Oxalyl chloride (2.24 ml, 25 mmol) was added dropwise to a stirred solution of 5-bromoindole (5.0 g, 25 mmol) in anhydrous tetrahydrofuran (60 ml) under nitrogen at room temperature. After 2 hours the reaction mixture was ice-cooled and a solution of N-methylbenzylamine (10.8 g, 89 mmol) in anhydrous tetrahydrofuran (15 ml) added dropwise, then the resulting mixture was stirred for a further 2 hours at 0°-5° C. and partitioned between ethyl acetate and 2M hydrochloric acid. The organic phase was washed with 2M hydrochloric acid and then water, dried (Na2SO4) and evaporated under reduced pressure to give a solid which was triturated with a 1:2 mixture of hexane:ether, washed with ether (×3) and dried in vacuo, to afford the required product (7.02 g) as a solid. Rf 0.60 (SS 7). Found: C,57.65; H,4.02; N,7.50. C18H15BrN2O2 ; 0.33 H2O requires C,57.30; H,4.16; N,7.42%.
Reaction SMILES: Cl.[CH3:2][CH:3]([O:5][C:6]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]4[O:28][CH2:27][CH2:26][NH:25][CH2:24][C:23]=4[CH:29]=3)[N:15]=2)=[CH:10][C:7]=1[C:8]#[N:9])[CH3:4].CCN(C(C)C)C(C)C.Br[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]>C(#N)C.CCOC(C)=O>[C:8]([C:7]1[CH:10]=[C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]4[O:28][CH2:27][CH2:26][N:25]([CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:24][C:23]=4[CH:29]=3)[N:15]=2)[CH:12]=[CH:13][C:6]=1[O:5][CH:3]([CH3:2])[CH3:4])#[N:9]
Reactant: CCOC(=O)CCBr
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CNCCO4)no2)cc1C#N
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCN1CCOc2ccc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cc2C1
Temperature: 80 °C
Yield: 72 %

Procedure:
To a solution of 2-[(1-methylethyl)oxy]-5-[3-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1,2,4-oxadiazol-5-yl]benzonitrile hydrochloride (Example 35) (0.101 g, 0.268 mmol) in acetonitrile (2 ml) was added DIPEA (0.094 ml, 0.537 mmol) and ethyl 3-bromopropanoate (0.051 ml, 0.402 mmol). The reaction mixture was stirred and heated at 80° C. under Argon for 6 hours. DIPEA (0.094 ml, 0.537 mmol) and ethyl 3-bromopropanoate (0.051 ml, 0.402 mmol) were added and the reaction stirred and heated at 80° C. under Argon overnight. Additional quantities of DIPEA (0.094 ml, 0.537 mmol) and ethyl 3-bromopropanoate (0.051 ml, 0.402 mmol) were added and the reaction heated again. The reaction mixture was dissolved in EtOAc, washed with saturated NaHCO3 solution (3×15 ml) and water (15 ml), dried (MgSO4) and evaporated. The resulting crude was purified by flash chromatography, eluting with EtOAc/iso-Hexane 10-20% (Biotage Column) to give the title compound (92 mg). MS (ES): C26H28N4O5 requires 476; found 477 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].N1C=CC=CC=1.[P:11](Cl)([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12].Cl>ClCCl.C(OCC)C>[CH2:14]([O:13][P:11](=[O:12])([O:16][CH2:17][CH3:18])[O:4][CH2:3][CH2:2][Br:1])[CH3:15]
Reactant: OCCBr
Reactant: CCOP(=O)(Cl)OCC
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOP(=O)(OCC)OCCBr
Temperature: 25 °C
Reaction time: 24 h
Yield: 93 %

Procedure:
A solution of 2-bromo ethanol (1.42 mL, 20 mmol) and dry pyridine (3.23 mL, 40 mmol) in dry dichloromethane (25 mL) was cooled to 0° C. Diethyl chlorophosphate (3.36 mL, 23 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 24 h. Diethyl ether (40 mL) and 1 N HCl (40 mL) were added and the organic layer was separated and washed consecutively with 1 N HCl and saturated NaHCO3 and dried over MgSO4. After evaporation of the solvents the residue was purified by column chromatography (silica gel, ethyl acetate/pentane 1:1) to give the product (4.85 g, 18.6 mmol, 93%) as light yellowish oil. 1H NMR (CDCl3, 400 MHz) δ=1.34 (dt, 6H, 2×CH3, 3J(H,H)=7.2 Hz, 4J(H,P)=1.2 Hz); 3.52 (t, 2H, CH2Br, 3J=6 Hz); 4.13 (dq, 4H, 2×CH2CH3, 3J(H,H)=7.2 Hz, 3J(H,P)=7.2 Hz); 4.28 (dt, 4H, 2×OCH2CH2Br, 3J(H,H)=6.4 Hz, 3J(H,P)=8.4 Hz). 13C NMR (CDCl3, 100.5 MHz) δ=16.0 (d, 2×CH3, 3J=6.8 Hz); 29.4 (d, CH2Br, 2J=7.6 Hz); 64.0 (d, OCH2, 2J=5.3 Hz); 66.5 (d, OCH2, 2J=5.3 Hz).
Reaction SMILES: [K].C[Si]([N-][Si](C)(C)C)(C)C.[Cl-].[CH3:12][O:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:34][C:35]1[N:39](CC#CC)[C:38]([C:44]([O:46][CH3:47])=[O:45])=[C:37]([CH:48]=O)[N:36]=1.O>C1(C)C=CC=CC=1.O1CCCC1>[Br:34][C:35]1[NH:39][C:38]([C:44]([O:46][CH3:47])=[O:45])=[C:37](/[CH:48]=[CH:12]/[O:13][CH3:14])[N:36]=1
Reactant: CC#CCn1c(Br)nc(C=O)c1C(=O)OC
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CO/C=C/c1nc(Br)[nH]c1C(=O)OC
Temperature: -70 °C
Reaction time: 0.75 h

Procedure:
Under an argon atmosphere 38 ml of a 0.5 M solution of potassium-bis(trimethylsilyl)amide in toluene are added dropwise to an ice-cooled solution of 6.64 g methoxymethyltriphenyl phosphonium chloride in 140 ml of tetrahydrofuran over 10 min. The reaction mixture is stirred for a further 15 min in the ice bath and then cooled to −70° C. Then a solution of 4.41 g methyl 2-bromo-3-(2-butyn-1-yl)-5-formyl-3H-imidazole-4-carboxylate in 40 ml of tetrahydrofuran is added dropwise over 30 min. After a further 45 min stirring at −70° C. the solution is heated to ambient temperature and stirred for another 1 h at this temperature. Then water is added to the reaction solution and this is extracted with ethyl acetate. The organic extracts are dried over sodium sulphate, the solvent is removed and the residue is chromatographed through silica gel (cyclohexane/ethyl acetate 9:1->7:3).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[C:25]3[C:26]4=[C:27]5[C:22](=[CH:23][CH:24]=3)[CH:21]=[CH:20][CH:19]=[C:18]5[CH:17]=[CH:16][C:15]4=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.[CH3:28][C:29]1([CH3:63])[C:53]2[C:33]([CH:34]=[C:35]3[CH:52]=[C:51]4[C:38]([C:39]5[C:44]([C:45]6[C:50]4=[CH:49][CH:48]=[CH:47][CH:46]=6)=[CH:43][CH:42]=[CH:41][CH:40]=5)=[CH:37][C:36]3=2)=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30]1.C([O-])([O-])=O.[Na+].[Na+].CCO>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.C1(C)C=CC=CC=1>[CH3:63][C:29]1([CH3:28])[C:53]2[C:33]([CH:34]=[C:35]3[CH:52]=[C:51]4[C:38]([C:39]5[C:44]([C:45]6[C:50]4=[CH:49][CH:48]=[CH:47][CH:46]=6)=[CH:43][CH:42]=[CH:41][CH:40]=5)=[CH:37][C:36]3=2)=[CH:32][C:31]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:12]4[C:25]5[C:26]6=[C:27]7[C:22](=[CH:23][CH:24]=5)[CH:21]=[CH:20][CH:19]=[C:18]7[CH:17]=[CH:16][C:15]6=[CH:14][CH:13]=4)[CH:8]=3)[CH:3]=2)=[CH:30]1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Reactant: Brc1ccc2cc(-c3ccc4ccc5cccc6ccc3c4c56)ccc2c1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)C=C(c2ccc3cc(-c4ccc5ccc6cccc7ccc4c5c67)ccc3c2)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Temperature: 90 °C
Yield: 46.3 %

Procedure:
A mixture of 8.3 g (20.3 mmol) of 1-(6-bromonaphthalen-2-yl)pyrene, 9.5 g (20.3 mmol) of 2-(10,10-dimethyl-10H-indeno[1,2-b]triphenylen-12-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 0.29 g (0.25 mmol) of Tetrakis(triphenylphosphine)palladium, 17 ml of 2M Na2CO3, 40 ml of EtOH and 100 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 12 h. After the reaction finish, the mixture was allowed to cool to room temperature. Than 500 ml MeOH was added, while stirring and the precipitated product was filtered off with suction. To give 6.3 g (yield 46%) of yellow product which was recrystallized from toluene. MS(m/z,FAB+); 671.5; 1H NMR (CDCl3, 400 MHz): chemical shift(ppm) 9.01 (s, 1H), 8.52˜8.45 (m, 3H), 8.25 (s, 1H), 8.10˜7.89 (m, 9H), 7.78 (d, J=8.00 Hz, 1H), 7.66˜7.49 (m, 10H), 7.44 (d, J=8.00 Hz, 1H), 7.28 (d, J=8.00 Hz, 1H), 1.84 (s, 6H).
Reaction SMILES: [OH:1][C:2]1([C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:9](O)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)[N:38]([CH3:40])[CH3:39])C2C=CC=CC=2N=N1.CNC>C(Cl)Cl>[OH:1][C:2]1([C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:9]([N:38]([CH3:40])[CH3:39])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: COc1ccc([C@@H](C(=O)O)C2(O)CCCCC2)cc1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: COc1ccc([C@@H](C(=O)N(C)C)C2(O)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.1 %

Procedure:
A solution of (2R)-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)acetic acid (156 mg, 0.59 mmol) in methylene chloride (1 mL) was treated with benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (313 mg, 0.71 mmol) and dimethylamine (2.0 M in tetrahydrofuran, 1.5 mL, 2.95 mmol). The reaction was stirred at 25° C. for 1.5 h after which time the solvent was evaporated and the product was purified via Biotage™ Horizon chromatography (FLASH 25 M, silica, gradient from 5% ethyl acetate/hexane to 36% ethyl acetate/hexane over 650 mL) to yield 160 mg (93%) (2R)-2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)-N,N-dimethylacetamide as a white solid. MS (ESI) m/z 292; [α]D25=+81° (c=0.010 g/mL, EtOH).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:4]([OH:6])=[O:5].[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]Cl)([O-:14])=[O:13].O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21][NH:2][CH:3]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:4]([OH:6])=[O:5])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccccc1SCl
Reactant: COC(=O)CC(N)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CC(NSc1ccccc1[N+](=O)[O-])C(=O)O

Procedure:
9.2 g (50 millimoles) of DL-2-amino-3-methoxycarbonyl-propionic acid hydrochloride (i.e., DL-aspartic acid O62 -methyl ester HCl), 10.5 g of o-nitrophenylsulfenyl chloride, 50 ml of water, 70 ml of tetrahydrofuran and 24.3 g of potassium carbonate are treated in the same manner as described in Example 1-(1). 9.8 g of DL-2-(o-nitrophenylsulfenylamino)-3-methoxycarbonyl-propionic acid are obtained. M.p. 108°- 109° C.
Reaction SMILES: [CH3:1][C:2]([N+:14]([O-:16])=[O:15])([CH3:13])[CH2:3][CH2:4][CH:5]=[C:6]1[NH:10][C:9](=[O:11])[NH:8][C:7]1=[O:12].[H][H].CO>[C].[Pd].O.C(O)C>[CH3:13][C:2]([N+:14]([O-:16])=[O:15])([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]1[NH:10][C:9](=[O:11])[NH:8][C:7]1=[O:12]
Reactant: [H][H]
Reactant: CC(C)(CCC=C1NC(=O)NC1=O)[N+](=O)[O-]
Agent: [Pd]
Solvent: O
Solvent: CCO
Solvent: CO
Product: CC(C)(CCCC1NC(=O)NC1=O)[N+](=O)[O-]

Procedure:
(viv) 5-(4-Methyl-4-nitropentylidene)hydantoin is reduced with a transition metal catalyst (such as palladium) and the like to give 5-(4-methyl-4-nitropentyl)hydantoin. For example, 5-(4-methyl-4-nitropentylidene)hydantoin is reacted with hydrogen gas upon addition of palladium-carbon (generally 0.1–5 mol %, preferably 0.5–2 mol %) in a mixed solvent of a water soluble solvent, such as methanol, ethanol and the like, and water for 1–12 h, preferably 2–5 h. The reaction solvent is concentrated to dryness to give 5-(4-methyl-4-nitropentyl)hydantoin. The obtained 5-(4-methyl-4-nitropentyl)hydantoin can be isolated and/or purified by a conventional method, such as chromatography and the like, but generally, can be used in the next step without isolation and/or purification.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([C:4]2[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=2)=[O:14])=[CH:11][CH:10]=1
Reactant: Oc1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1

Procedure:
Phenol is reacted with p-chlorobenzoyl chloride in a Friedel-Crafts reaction in the presence of aluminium chloride to give 4-chloro-4'-hydroxybenzophenone, m.p. 179°-181° C. (A). To a solution of this (5 g.) in pyridine (6 ml.) was added methanesulphonyl chloride (2.5 g.), at room temperature. The reactants were heated on a steam bath for 11/2 hours and the liquid reaction product poured into dilute hydrochloric acid to give a solid which was filtered and air-dried. This solid was recrystallised from industrial methylated spirits to give 4-chloro-4'-methylsulphonyloxybenzophenone, m.p. 120°-121° C. (B). To a solution of this (9.35 g.) in ethanol (200 ml.) was added hydrazine hydrate (8 ml.) followed by glacial acetic acid (1.5 ml.). The mixture was heated under reflux with stirring for 17 hours. The solvent was evaporated under reduced pressure to give an oil which was extracted with chloroform. The extract was washed with water, aqueous sodium hydroxide and water and then dried over magnesium sulphate. The solvent was evaporated under reduced pressure to give an oil. On standing this crystallised to give 4-chloro-4'-methylsulphonyloxybenzophenone hydrazone, m.p. 70°-110° C. (C). This product (5 g.) was heated under reflux with acetone (25 ml.) for 24 hours. The mixture was then evaporated under reduced pressure to give 4-chloro-4'-methylsulphonyloxybenzophenone isopropylidenehydrazone m.p. 148°-9° C.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([SH:10])[CH2:8][CH3:9].Br[C:12]1[C:16]([Br:17])=[CH:15][S:14][C:13]=1[C:18]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=O>CN(C)C=O>[Br:17][C:16]1[C:12]([S:10][CH2:7][CH2:8][CH3:9])=[C:13]([CH2:18][C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[S:14][CH:15]=1
Reactant: O=C(c1cccs1)c1scc(Br)c1Br
Reactant: CCCS
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCSc1c(Br)csc1Cc1cccs1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a cloudy solution of 80 mL of dimethylformamide containing 3.7 g of potassium-t-butoxide, under a nitrogen blanket and cooled to 0°, was added 3.0 mL of n-propanethiol. This mixture was stirred for 5 minutes and then 12 g of the product of Example 8 was added in one portion. After stirring for 3 hours at room temperature, the mixture was poured into 400 mL of ice-water and extracted with methylene chloride. The organic layer was washed with 1N NaOH (aq), water and dried (MgSO4). Filtration and concentration of the filtrate in vacuo afforded 7.5 g of the subject compound as a dark oil.
Reaction SMILES: [OH-].[OH:2][C:3]1[N+:7]2[CH2:8][CH2:9][C:10]3[CH:14]=[CH:13][S:12][C:11]=3[C:6]=2S[C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1.[CH3:22][C:23](=[O:26])[C:24]#[CH:25]>C1(C)C=CC=CC=1>[C:23]([C:24]1[CH:25]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C:3](=[O:2])[N:7]2[C:6]=1[C:11]1[S:12][CH:13]=[CH:14][C:10]=1[CH2:9][CH2:8]2)(=[O:26])[CH3:22]
Reactant: C#CC(C)=O
Reactant: Oc1c(-c2cccc(F)c2)sc2[n+]1CCc1ccsc1-2
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(-c2cccc(F)c2)c(=O)n2c1-c1sccc1CC2

Procedure:
A solution of 0.303 g of 5,6-dihydro-3-hydroxy-2-(m-fluorophenyl)-thiazolo-[3,2-a]thieno[2,3-c]pyridinium hydroxide (internal salt) and 0.145 ml of 3-butyn-2-one in 5 ml of toluene was heated under reflux for 1 hour. The solvent is evaporated in vacuo and the residue is chromatographed over silica gel with toluene/ethyl acetate (1:1). After recrystallization from ethanol, there was obtained 10-acetyl-4,5-dihydro-8-(m-fluorophenyl)-7H-thieno[2,3-a]quinolizin-7-one of m.p. 109°-110°.
Reaction SMILES: [OH:1][C:2]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[C:3]([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][CH3:13])[CH2:8][CH2:7]1)=[O:4].Br[CH2:25][CH2:26][OH:27].C(N(CC)CC)C.BrC(O)C>C(#N)C.C1COCC1>[OH:1][C:2]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[C:3]([O:5][C@H:6]1[CH2:7][CH2:8][C@H:9]([N:12]([CH2:25][CH2:26][OH:27])[CH3:13])[CH2:10][CH2:11]1)=[O:4]
Reactant: OCCBr
Reactant: CN[C@H]1CC[C@H](OC(=O)C(O)(c2cccs2)c2cccs2)CC1
Agent: CC(O)Br
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1CCOC1
Product: CN(CCO)[C@H]1CC[C@H](OC(=O)C(O)(c2cccs2)c2cccs2)CC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of trans-4-(methylamino)cyclohexyl hydroxy(di-2-thienyl)acetate (intermediate 5; 300 mg; 0.85 mmol), 2-bromoethanol (0.145 ml; 2.05 mmol) and triethylamine (0.36 ml; 2.58 mmol) in 4.5 ml of acetonitrile and 3.5 ml of THF was stirred at 80° C. in a sealed vessel for 16 hr. Additional amounts of bromoethanol (0.145 ml; 2.05 mmol), triethylamine (0.36 ml; 2.58 mmol), acetonitrile (3.5 ml) and THF (3.5 ml) were added and the stirring and heating prosecuted for 24 additional hours. The solution was evaporated to dryness, dissolved in dichloromethane, washed with brine, dried and concentrated. Purification by preparative reversed-phase HPLC (Cl3CH/MeOH from 1:0 to 9:1) gave 76% of the title product as a colourless oil.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[C:15]([CH:16]=O)=[CH:14][NH:13][C:12]1=[S:18].Cl.[NH2:20][OH:21].[OH-].[Na+]>C(O)C.O>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[C:15]([CH:16]=[N:20][OH:21])=[CH:14][NH:13][C:12]1=[S:18]
Reactant: O=Cc1c[nH]c(=S)n1C1CCc2ccccc2C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=Cc1c[nH]c(=S)n1C1CCc2ccccc2C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
A mixture of 3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazole-4-carbaldehyde (0.25 g, 1.0 mmol), hydroxylamine hydrochloride (0.09 g, 1.3 mmol) and sodium hydroxide (0.064 g, 1.6 mmol) in 2 mL of ethanol and 2 mL of water was stirred at 60° C. for 1 hour. The mixture was cooled giving a crystalline material. The material was isolated by filtration and dried. The filtrate was stirred with ethyl acetate giving more crystalline material. The material was isolated by filtration and dried. Combining the crystalline material gave 1-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazole-5-carbaldehyde oxime (0.186 g, 0.68 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[O:21]=[C:22]([CH3:26])[C:23](O)=[O:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:23](=[O:24])[C:22](=[O:21])[CH3:26])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: CC(=O)C(=O)O
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: CC(=O)C(=O)Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and 2-oxo-propanoic acid (127-17-3) as starting materials; MS (EI) 373.0(M+H) +.
Reaction SMILES: CC1(C)[C@H]2CC[C@]1(CS(O)(=O)=O)C(=O)C2.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][C@H:21]([NH2:26])[CH2:20]2.C(=O)([O-])[O-].[K+].[K+].Cl[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]>CCOC(C)=O.O>[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][C@H:21]([NH:26][C:34](=[O:35])[O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:20]2
Reactant: N[C@H]1Cc2ccc(Br)cc2C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CC1(C)[C@H]2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1Cc2ccc(Br)cc2C1)OCc1ccccc1
Reaction time: 8 h
Yield: 107.7 %

Procedure:
(S)-5-bromo-2,3-dihydro-1H-inden-2-amine((1R,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (18.47 mmol, 8.21 g) was dissolved in EtOAc (30 mL)/water (30 mL) and potassium carbonate (55.4 mmol, 7.66 g) added. The mixture was cooled in an ice bath and benzyl chloroformate (20.32 mmol, 2.89 mL, 3.47 g) added dropwise. Stirring was continued overnight during which time the reaction came to room temperature. The crude reaction mixture was diluted with water and ethylacetate and the phases mixed and separated. The aqueous layer was further extracted with EtOAc (×2). Combined organics were dried and concentrated to give (S)-benzyl 5-bromo-2,3-dihydro-1H-inden-2-ylcarbamate as a colourless solid (6.89 g, 108%). 1H NMR (400 MHz, CDCl3) δ 2.79 (m, 2H) 3.26 (m, 2H) 4.53 (bm, 1H) 4.93 (bm, 1H) 5.10 (bs, 2H) 7.07 (m, 1H) 7.26-7.37 (m, 7H)
Reaction SMILES: [O:1]=[C:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[C@H:4]([C:17]([OH:19])=[O:18])[CH2:3]1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:20]([O:18][C:17](=[O:19])[C@@H:4]1[CH2:3][C:2](=[O:1])[CH2:6][N:5]1[C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1C[C@@H](C(=O)OCc2ccccc2)N(C(=O)OCc2ccccc2)C1
Reaction time: 1 h
Yield: 49 %

Procedure:
5 g (0.02 mmol) of 4-keto-1-[(phenylmethoxy)carbonyl]-L-proline was dissolved in 50 ml dimethylformamide, 2.62 ml (0.022 mmol) of benzyl bromide and 3.59 g (0.026 mmol) of potassium carbonate were added. The reaction mixture was stirred for 1 hour followed by normal extractive work to give the title compound, 3.5 gm (49% yield), m.p. 55°-56° C.