Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:38])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[CH3:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][CH:16]2[C:35]([OH:37])=O)[CH:12]=[CH:13][CH:14]=1.CC1(C)[O:44][C@@H:43]([CH2:45][CH2:46][NH2:47])[CH2:42][O:41]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:44][C@H:43]([CH2:42][OH:41])[CH2:45][CH2:46][NH:47][C:35]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:38])[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[CH3:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:32])([CH3:33])[CH3:34])[NH:17]1)=[O:37]
Reactant: CC1(C)OC[C@H](CCN)O1
Reactant: Cc1cc(Cl)ccc1C1(C#N)C(CC(C)(C)C)NC(C(=O)O)C1c1cccc(Cl)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Cl)ccc1C1(C#N)C(CC(C)(C)C)NC(C(=O)NCC[C@H](O)CO)C1c1cccc(Cl)c1F
Yield: 76.3 %

Procedure:
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 57c (0.4 g, 0.69 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.2 g, 1.4 mmol), HATU (0.4 g, 1.1 mmol) and iPr2NEt (0.8 g, 6.2 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.29 g, 76%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>CN(C1C=CN=CC=1)C>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)(=[O:22])=[O:21])=[CH:18][CH:19]=1
Reactant: Nc1cccc2cccnc12
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2cccc3cccnc23)cc1
Yield: 61.2 %

Procedure:
In the similar fashion using route 14 general procedure 27, 8-aminoquinoline (200 mg, 1.38 mmol), 4-methoxybenzenesulfonyl chloride (300 mg, 1.3 mmol) and DMAP (cat.) gave the title compound (250 mg, 58%) after purification by column chromatography with DCM/MeOH/NH3 (100-100:1:1 drop).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH: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:5]([NH2:27])[CH:4]=[N:3]1.O=C1CCC(=O)N1[O:35][C:36]([CH:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]1)=O>ClCCl>[CH3:1][N:2]1[C:6]([NH: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:5]([NH:27][C:36]([CH:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]2)=[O:35])[CH:4]=[N:3]1
Reactant: Cn1ncc(N)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)ON2C(=O)CCC2=O)CC1
Solvent: ClCCl
Product: Cn1ncc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 28.3 %

Procedure:
To a solution of 1-methyl-N5-trityl-1H-pyrazole-4,5-diamine (4 g) in dichloromethane (100 ml) was added tert-butyl 4-{[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl}-1-piperidinecarboxylate (4.05 g), and the mixture was refluxed for 72 hours. The reaction mixture was washed successively with water 10% aqueous citric acid solution, water and brine. The extract was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give tert-butyl 4-({[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}carbonyl)-1-piperidinecarboxylate (1.806 g).
Reaction SMILES: C([O:8][C:9]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:10]=1[CH2:11][N:12]([C:15]1[N:20]=[N:19][C:18]([C:21]([NH2:23])=[O:22])=[CH:17][CH:16]=1)[CH2:13][CH3:14])C1C=CC=CC=1.CSC.B(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+].C(OCC)C>ClCCl.CO>[Br:28][C:25]1[CH:26]=[CH:27][C:9]([OH:8])=[C:10]([CH:24]=1)[CH2:11][N:12]([C:15]1[N:20]=[N:19][C:18]([C:21]([NH2:23])=[O:22])=[CH:17][CH:16]=1)[CH2:13][CH3:14]
Reactant: CCN(Cc1cc(Br)ccc1OCc1ccccc1)c1ccc(C(N)=O)nn1
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: CCN(Cc1cc(Br)ccc1O)c1ccc(C(N)=O)nn1
Temperature: 25 °C
Reaction time: 144 h
Yield: 52.3 %

Procedure:
6-[N-(2-Benzyloxy-5-bromobenzyl)-N-ethylamino]pyridazine-3-carboxamide (3.24 g, 7.3 mmol) in dichloromethane (50 ml) was treated with boron trichloride dimethyl sulphide reagent (18.5 ml, 2M solution) in dichloromethane (37 mmol) and the solution stirred at ambient temperature for 6 days. The mixture was carefully treated with excess aqueous sodium bicarbonate solution to give a pH of around 9. Dichloromethane was added, the organic and aqueous layers separated and the aqueous layer washed with dichloromethane. The combined organic extracts were then washed with brine, dried and evaporated to give a sticky solid. This was treated with diethylether (30 ml) and methanol (3 ml) and left at ambient temperature overnight. The resultant solid was filtered, washed with diethylether and sucked dry to give 6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]-pyridazine-3-carboxamide (1.34 g, 52%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=O)=[O:5])[CH3:2].[C:16]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1>>[CH2:1]([O:3][C:4](=[O:5])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]([C:10](=[O:12])[NH:22][C:18]2[CH:17]=[C:16]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:21]=[CH:20][CH:19]=2)[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(C(=O)O)c1
Reactant: Nc1cccc(-c2ccccc2)c1
Product: CCOC(=O)Cc1cccc(C(=O)Nc2cccc(-c3ccccc3)c2)c1

Procedure:
3-Ethoxycarbonylmethyl-benzoic acid (126 mg, 0.61 mmol) was coupled to biphenyl-3-ylamine (105 mg, 0.62 mmol) using Method C. The residue was purified by column chromatography eluting with 100% DCM to give the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][N:10]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:11]2=[O:14])=[CH:6][C:5]=1F.O.[C:26]([O:30][C:31]([N:33]1[CH:38]2[CH2:39][CH2:40][CH:34]1[CH2:35][CH:36]([OH:41])[CH2:37]2)=[O:32])([CH3:29])([CH3:28])[CH3:27]>CC(N(C)C)=O>[C:26]([O:30][C:31]([N:33]1[CH:38]2[CH2:39][CH2:40][CH:34]1[CH2:35][CH:36]([O:41][C:5]1[CH:6]=[C:7]3[C:12](=[CH:13][C:4]=1[Cl:3])[C:11](=[O:14])[N:10]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH:9]=[CH:8]3)[CH2:37]2)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: COc1ccc(Cn2ccc3cc(F)c(Cl)cc3c2=O)cc1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(O)C2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc(Cn2ccc3cc(OC4CC5CCC(C4)N5C(=O)OC(C)(C)C)c(Cl)cc3c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
528 mg of sodium hydride (60%) were suspended in 8 mL of dimethyl acetamide and 1.00 g of 3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (70), dissolved in 4 mL of dimethyl acetamide, were added dropwise. After 1 h, 1.40 g of 7-Chloro-6-fluoro-2-(4-methoxy-benzyl)-2H-isoquinolin-1-one (62), dissolved in another 8 mL of dimethyl acetamide, were added. The reaction mixture was stirred at room temperature until the reaction was complete. 30 mL of water were added, the resulting suspension extracted three times with a mixture of dichloromethane and 2-propanol (3:1) and the combined organic layers were evaporated. Water was added and the crude product was subjected to lyophilization to remove remainders of dimethyl acetamide. The obtained crude product was purified by silica gel chromatography to yield 1.85 g of the title compound as a mixture of diastereoisomers (71). Rt=1.95 min, 2.03 min (Method C). Detected mass: 525.0 (M+H+).
Reaction SMILES: [C:1]([C:5]1[C:6]([N+:17]([O-])=O)=[C:7]([OH:16])[C:8]([OH:15])=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([C:5]1[C:6]([NH2:17])=[C:7]([OH:16])[C:8]([OH:15])=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C(C)(C)C)c([N+](=O)[O-])c(O)c1O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)c1cc(C(C)(C)C)c(O)c(O)c1N
Reaction time: 2 h
Yield: 32.8 %

Procedure:
To a solution of 4,6-di-tert-butyl-3-nitrobenzene-1,2-diol (1.92 g, 7.2 mmol) in EtOH (70 mL) was added Pd-5% wt. on carbon (200 mg). The mixture was stirred under H2 (1 atm) for 2 h. The reaction was recharged with Pd-5% wt. on carbon (200 mg) and stirred under H2 (1 atm) for another 2 h. The mixture was filtered through Celite and the filtrate was concentrated and purified by column chromatography (10-40% ethyl acetate-hexanes) to give 4,6-di-tert-butyl-3-aminobenzene-1,2-diol (C-26) (560 mg, 33%). 1H NMR (400 MHz, CDCl3) δ 7.28 (s, 1H), 1.42 (s, 9H), 1.38 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]2[N+:7]([O-])=[N+:8]([O-])[C:9]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:10]=3[CH2:11][CH2:12][C:5]=2[CH:4]=1.COC1C=CC(N=O)=C(CCC2C=C(OC)C=CC=2N=O)C=1>>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:9]([NH2:8])=[C:10]([CH2:11][CH2:12][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:22]=[CH:21][C:6]=2[NH2:7])[CH:13]=1
Reactant: COc1ccc2c(c1)CCc1cc(OC)ccc1[N+]([O-])=[N+]2[O-]
Agent: COc1ccc(N=O)c(CCc2cc(OC)ccc2N=O)c1
Product: COc1ccc(N)c(CCc2cc(OC)ccc2N)c1

Procedure:
A solution of compound 42 (2.46 g, 9.04 mmol) and sodium tunsgtate dihydrate (0.42 g, 1.26 mmol) in 95% ethanol (27.13 ml) and water (9.04 ml) was cooled to 5° C. and treated dropwise with 30% H2O2 (4.61 ml). The reaction mixture was stirred for 5 h at 5° C., then 10 ml of a saturated aqueous solution of NH4Cl was added, and extracted with CH2Cl2 (3×30 ml). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the crude product. Recrystallization in CH2Cl2/hexanes afforded 1.22 g (4.06 mmol, 45%) of green crystals. The mother solution was concentrated under reduced pressure, and the residue purified by flash chromatography on silica gel with hexanes/ethyl acetate: 3/1 as eluant to give an additional 0.431 g (1.47 mmol, 16%) of compounds 6a and 6b as green crystals. mp: 136-138° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]([C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=1)[CH2:7][CH2:8][CH2:9][NH:10]C(OC(C)(C)C)=O)[CH3:2].[ClH:26]>C(OCC)(=O)C>[ClH:26].[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]([C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=1)[CH2:7][CH2:8][CH2:9][NH2:10])[CH3:2]
Reactant: CCOC(=O)CC(CCCNC(=O)OC(C)(C)C)c1ccc(Br)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(CCCN)c1ccc(Br)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 3-(4-Bromo-phenyl)-6-tert-butoxycarbonylamino-hexanoic acid ethyl ester (2.43 g, 6.32 mmol) in ethyl acetate (3 mL) was added 4 N hydrogen chloride in ethyl acetate (6 mL) at room temperature. Removal of the solvent in vacuo after stirring for 30 min afforded 6-Amino-3-(4-bromo-phenyl)-hexanoic acid ethyl ester hydrochloride that was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:12][C@H:11]2[C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1)([O-])=O.O.O.[Sn](Cl)(Cl)(Cl)Cl>CN1CCCC1=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]2[CH2:12][C@H:11]2[C:13]([OH:15])=[O:14])=[CH:8][CH:9]=1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: Nc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Reaction time: 67 h

Procedure:
To a suspension of the Wang resin-supported racemic-(trans)-2-(4-nitrophenyl)cyclopropanecarboxylic acid (XIIc) in N-methylpyrrolidin-2-one (NMP, ˜15 ml/mmol) was added tin chloride dihydrate (15 equiv.). The mixture was shaken for 67 h and then filtered. The product resin was washed with NMP (×2), DCM, dioxane, dioxane-water (1:1×2), water (×2), dioxane-water (1:1×2) dioxane (×3), DCM (×3), methanol and ether, then dried in a vacuum oven at 40° C.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:10]=[C:9]([NH:11][C:12](=[O:17])[C:13](OC)=[O:14])[CH:8]=[CH:7][C:6]=1[CH:18]1[CH2:23][CH2:22][CH:21]([CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:20][CH2:19]1>C(O)C>[Cl:4][C:5]1[CH:10]=[C:9]([NH:11][C:12](=[O:17])[C:13]([NH:2][NH2:3])=[O:14])[CH:8]=[CH:7][C:6]=1[C@H:18]1[CH2:23][CH2:22][C@H:21]([CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:20][CH2:19]1
Reactant: NN
Reactant: CCOC(=O)C(C)C1CCC(c2ccc(NC(=O)C(=O)OC)cc2Cl)CC1
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C)[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of hydrazine hydrate (86 mg, 1.73 mmol) in ethanol (1 mL) was added dropwise to a stirred solution of ethyl 2-[4-(2-chloro-4-{[methoxy(oxo)acetyl]amino}phenyl)cyclo-hexyl]propanoate (0.58 g, 1.44 mmol) in ethanol (14 mL) and the reaction mixture was stirred at room temperature for 18 h. The mixture was filtered to leave a solid, which was washed with ethanol to give the title compound (Intermediate 106) (0.45 g, 81%) as a white solid; 1H NMR δ 1.14 (3H, d), 1.16-1.28 (2H, m), 1.27 (3H, t), 1.4-1.58 (2H, m), 1.6-1.7 (1H, m), 1.71-1.93 (4H, m), 2.29-2.39 (1H, m), 2.82-2.94 (1H, m), 4.15 (2H, dq), 4.7 (2H, s), 7.4 (1H, d), 7.8 (1H, dd), 8.01 (1H, d), 10.4 (1H, s), 10.8 (1H, s); MS m/e MH+ 396.
Reaction SMILES: C(O[C:4](=[N:6][C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH3:5])C.Cl.[NH:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1)[NH2:18].C(N(CC)CC)C.O>ClCCl.CO>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]2[N:17]([C:19]3[CH:20]=[CH:21][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:23][CH:24]=3)[N:18]=[C:4]([CH3:5])[N:6]=2)=[CH:13][CH:12]=1
Reactant: CCOC(C)=NC(=O)c1ccc(Cl)cc1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1nc(-c2ccc(Cl)cc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Reaction time: 8 h
Yield: 58 %

Procedure:
N-(1-ethoxy-ethylidene)-4-chloro-benzamide 472 mg (2.09 mmol) was dissolved in a mixed solvent of dichloromethane 20 ml and methanol 10 ml, and 4-hydrazinobenzenesulfonamide hydrochloride 515 mg (2.23 mmol) was added to the solution. Then, triethylamine 0.35 ml (2.51 mmol) was slowly added dropwise at room temperature for 10 minutes and stirred for 8 hours. After completing the reaction, water 20 ml was added to the reacting solution and extracted two times with dichloromethane and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 4-[5-(4-chloro-phenyl)-3-methyl-[1,2,4]triazole-1-yl]-benzenesulfonamide (423 mg, yield: 58%) was obtained as a solid phase.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: N#Cc1ccccc1CBr
Reactant: Oc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1COc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
A solution of 3-chlorophenol (9.26 g) in DMF (25 ml) was added dropwise to a stirred suspension of sodium hydride (1.44 g) in DMF (50 ml) (effervescence) and the resulting mixture was stirred at room temperature for 1 hour. A solution of 2-(bromomethyl)benzonitrile (11.76 g) in DMF (25 ml) was then added to the stirred reaction mixture and after a further hour at room temperature the mixture was poured into water and extracted with ether. The extracts were washed successively with water, dilute aqueous sodium hydroxide and brine, then dried and concentrated to give crude 2-(3-chlorophenoxymethyl)-benzonitrile (13.95 g) as an orange-brown oil which crystallised on standing. An analytical sample, recrystallised from petrol, had m.p. 56° C.
Reaction SMILES: [F:1][C:2]1[C:10]([I:11])=[C:9]([CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([CH3:12])=[C:10]([I:11])[C:2]=1[F:1]
Reactant: Cc1ccc(C(=O)O)c(F)c1I
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C)c(I)c1F
Temperature: 90 °C

Procedure:
In a 500 ml one-neck flask equipped with a magnetic stir-bar and condenser was added 2-fluoro-3-Iodo-4-methyl-benzoic acid (31.5 g, 112.5 mmol), 250 ml of methanol and 10 ml of sulfuric acid. The reaction was heated at 90° C. overnight.
Reaction SMILES: [C:1]1([C:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([OH:23])=[CH:15][CH:14]=2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>CC(C)=O>[C:1]1([C:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:15][CH:14]=2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCBr
Reactant: O=C(c1cccc2ccccc12)c1ccc(O)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCOc1ccc(C(=O)c2cccc3ccccc23)c2ccccc12
Reaction time: 0.03 h

Procedure:
11.0 g of naphthalen-1-yl-(4-hydroxy-naphthalen-1-yl)-methanone and 6.1 g of potassium carbonate in 130 ml of acetone are stirred for 15 min at reflux. Then, within 2 min, a solution of 6.8 ml 1-bromopentane in 20 ml of acetone is added and the suspension is stirred for additional 22 h at reflux. Conventional workup and subsequent chromatography affords naphthalen-1-yl-(4-pentyloxy-naphthalen-1-yl)-methanone.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[S:19]1[CH2:25][C:23](=[O:24])[NH:22][C:20]1=[S:21].NCCC(O)=O>C(O)(=O)C>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=[C:25]4[S:19][C:20](=[S:21])[NH:22][C:23]4=[O:24])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: NCCC(=O)O
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Yield: 66.2 %

Procedure:
A mixture of 4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzaldehyde(Taylor, E. C., Skotnicki, J. S. Synthesis, 1981, 606) (4.96 g, 20 mol), rhodanine (2.66 g, 20 mmol), and β-alanine (2.0 g, 22.5 mmol) in 50 mL of acetic acid (AcOH) was refluxed for 2 hours. The solid which was formed on cooling the solution was collected to give the title compound as a red solid (4.8 g, 66%); 1H NMR (300 MHz, CDCl3) δ 1.81 (t, J=5.5 Hz, 4H), 3.55 (t, J=5.5 Hz, 4H), 4.00 (s, 4H), 6.92 (d, J=8.9 Hz, 2H), 7.58 (d, J=8.9 Hz, 2H), 7.38 (s, 1H); MS (ES) m/z: 362.8 (MH+); HRMS Calcd. for C17H19N2O3S2 (MH+): 363.0837. Found: 363.0852. Anal. Calcd. for C17H18N2O3S2: C, 56.33; H, 5.01; N, 7.73. Found: C, 56.28; H, 4.89; N, 7.73.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]CC)=O)=[N:4][C:5]([Br:8])=[CH:6][CH:7]=1.[CH2:14]([NH2:16])[CH3:15].C1COCC1>C(O)C>[NH2:1][C:2]1[C:3]([C:9]([NH:16][CH2:14][CH3:15])=[O:11])=[N:4][C:5]([Br:8])=[CH:6][CH:7]=1
Reactant: CCN
Reactant: CCOC(=O)c1nc(Br)ccc1N
Solvent: CCO
Solvent: C1CCOC1
Product: CCNC(=O)c1nc(Br)ccc1N
Temperature: 120 °C
Yield: 70 %

Procedure:
A stirred suspension of ethyl 3-amino-6-bromopyridine-2-carboxylate (5 g, 20.3 mmol) in ethanol (40 mL) in a steel bomb was treated with a 2M solution of ethylamine in THF (220 mL, 440 mmol) and heated to 120° C. for 2 days. The reaction mixture was cooled to RT, the solvents were evaporated under reduced pressure and the residue was purified by column chromatography (SiO2, 0.5% methanol in dichloromethane) to give 3.5 g (70%) of the required material as white solid 1H NMR (400 MHz, CDCl3) δ 7.77 (brs, 1H), 7.21 (d, J=8.8 Hz, 1H), 6.85 (d, J=8.8 Hz, 1H), 5.99 (brs, 2H), 3.4 (q, J=7.2 Hz, 2H), 1.24 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][C@H:11]([C:13](=[O:18])N(OC)C)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1.C([Mg]Cl)(C)C.Cl>C1COCC1>[CH2:1]([O:8][C:9](=[O:19])[NH:10][C@@H:11]([CH3:12])[C:13]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccc(Br)cc1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OCc1ccccc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
[(S)-1-(Methoxy-methyl-carbamoyl)-ethyl]-carbamic acid benzyl ester (1 g, 3.8 mmol) and 4-bromochlorobenzene (0.9 g, 4.7 mmol) were dissolved in THF (10 mL). The solution was degassed with N2 for 5 minutes, and then cooled to 0° C. Isopropylmagnesium chloride (2M in THF; 4.7 mL, 9.4 mmol) was added slowly, and the reaction was stirred at room temperature for 2 hours. Once no starting material was seen by analytical tlc, the mixture was cooled to 0° C. 1N Aqueous HCl was added, and the organic layer was separated and washed with brine. After concentrating, the crude material was purified by silica gel chromatography to give the desired product as a colorless oil (1 g).
Reaction SMILES: [S:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.[CH3:12][CH:13](O)[CH:14]=[CH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>COC(OC)(C)C.C1(C)C=CC=CC=1>[CH2:12]([CH:2]1[CH2:3][C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[S:1]1)[CH:13]=[CH:14][CH3:15]
Reactant: C=CC(C)O
Reactant: O=C1CCSc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: COC(C)(C)OC
Product: CC=CCC1CC(=O)c2ccccc2S1
Yield: 48 %

Procedure:
A solution of 23.9 g of 4-thiochromanone, 30 ml of 3-buten-2-ol and 240 mg of p-toluenesulfonic acid in 30 ml of 2,2-dimethoxy-propane and 240 ml of anhydrous toluene was boiled under reflux for 20 hours. The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 5:1). 15.3 g (48%) of (RS)-2-(2-buten-1-yl)-4-thiochromanone were obtained as a yellow oil.