Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[CH3:16][C:17]1[C:18](B(O)O)=[CH:19][S:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH3:16][C:17]1[C:18]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[C:12]([F:15])([F:14])[F:13])=[CH:19][S:20][CH:21]=1
Reactant: Cc1cscc1B(O)O
Reactant: COC(=O)c1ccc(Br)c(C(F)(F)F)c1
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: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2cscc2C)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
A mixture of methyl 4-bromo-3-(trifluoromethyl)benzoate (3.5 g; 12.4 mmol; 1 eq.), 4-methyl-3-thiopheneboronic acid (1.93 g; 13.6 mmol; 1.1 eq.), potassium carbonate (8.54 g; 61.8 mmol; 5 eq.) and Pd(PPh3)4 (1.43 g; 1.24 mmol; 0.1 eq.) in toluene (17.5 mL) and water (17.5 mL) was refluxed for 24 h whereupon 4-methyl-3-thiopheneboronic acid (0.88 g; 6.2 mmol; 0.5 eq.) was added. The reaction mixture was stirred for a further 3 hours then cooled down to room temperature and filtered through a pad of CELITE which was washed with toluene (200 mL). The filtrate was concentrated in vacuo and the residue taken up in ethyl acetate (300 mL). The organic layer was washed with sat. aq. NaHCO3 (100 mL), water (100 mL) and brine (100 mL), dried over magnesium sulphate and concentrated in vacuo to afford the title compound (3 g, 81%) as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(N(CC)CC)C.O1CCCC1.[Br:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>O>[Br:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[OH:8])=[O:27])=[CH:24][CH:23]=1
Reactant: Nc1ccccc1O
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1ccccc1O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
4.5 g (20 mmol) of 2-aminophenol, 3.0 mL (22 mmol) of triethylamine, and 50 mL of tetrahydrofuran (THF) were put in a 200 mL three-neck flask, and cooled to 0° C. After the cooling, 50 mL of THF solution containing 4.5 g (20 mmol) of 4-bromobenzoyl chloride was dropped under a nitrogen atmosphere. This solution was stirred at 0° C. for four hours under a nitrogen atmosphere. Then, water was added to the solution, and an organic layer and an aqueous layer were separated. An organic substance was extracted with ethyl acetate from the aqueous layer. The resulting extracted solution was combined with the organic layer, and the organic layer was washed with 0.2 M hydrochloric acid and a saturated aqueous solution of sodium bicarbonate, and then dried with magnesium sulfate. This mixture was subjected to suction filtration through Celite (manufactured by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), and the filtrate was concentrated to give a solid. The obtained solid was recrystallized with ethyl acetate/hexane, whereby 5.3 g of the target white powder was obtained in a yield of 88%.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl-].C([O:15][CH2:16][CH3:17])(=O)C([O-])=O.[C:18]1([NH:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.ClCC(Cl)=O>O1CCCC1.O.C(N(CC)CC)C>[CH2:6]([O:5][C:3]([C:2]1[O:8][CH2:17][C:16](=[O:15])[N:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:25]=1)=[O:4])[CH3:7]
Reactant: CCOC(=O)C(=O)Cl
Reactant: NNc1ccccc1
Reactant: CCOC(=O)C(=O)[O-]
Agent: O=C(Cl)CCl
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=NN(c2ccccc2)C(=O)CO1
Reaction time: 1 h
Yield: 33 %

Procedure:
50 g (0.366 mole) ethyl chloro-oxoacetate (ethyl oxalate chloride, (4755-77-5) was added dropwise over 30 minutes into a solution of 39.5 g (0.365 mole) phenyl hydrazine and 50 ml triethylamine in 1000 ml tetrahydrofuran, under ice-cooling. After the dropwise addition, the mixture was stirred for 1 hour. Then the reaction mixture was poured into water and extracted with ethyl acetate, and the organic layer was successively washed with 10% aqueous citric acid, an aqueous sodium bicarbonate solution and a saline water, and then dried over anhydrous magnesium sulfate. The solvent was removed, and the resulting residue was crystallized from ether/hexane (1:1), collected by filtration and vacuum-dried. The resulting solid, 36 g, was dissolved in 600 ml 2-butanone, then 20.3 g (0.179 mole) chloroacetyl chloride was added thereto, followed by reacting at room temperature for 2 hours. Thereafter, the solution was heated under refluxed for further 8 hours. The reaction solution was cooled, poured into water and extracted wit ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was removed, to give an oil. It was crystallized from ethanol, to give the title compound (30 g, 0.12 mole, 33%).
Reaction SMILES: C([Li])CCC.C(OP([CH2:14][C:15]([OH:17])=[O:16])(OCC)=O)C.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1/[CH:23]=[CH:24]/[CH:25]=O.Cl>O1CCCC1.CO.O>[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=[CH:24][CH:25]=[CH:14][C:15]([OH:17])=[O:16]
Reactant: CCOP(=O)(CC(=O)O)OCC
Reactant: O=C/C=C/c1ccco1
Agent: Cl
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C=CC=Cc1ccco1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
Butyllithium (70 mL of 2.5 N solution) was added to 350 mL of anhydrous tetrahydrofuran (THF) at −65° C. A solution of diethylphosphonoacetic acid (15.9 g) in 130 mL of anhydrous THF was added dropwise to the stirred solution at −65° C. over a period of 75 minutes. The resulting solution was stirred at −65° C. for an additional 30 minutes and then a solution of trans-3-(2-furyl)acrolein (10.0 g) in 85 mL of anhydrous THF was added to the reaction at −65° C. over a period of 2 hours. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was then acidified with 5% hydrochloric acid (85 mL) to a pH of 3.5 followed by addition of 30 mL of water. The aqueous layer was extracted with 50 mL of ether twice and with 50 mL of ethyl acetate once. The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give an oil. The crude oil was dissolved in 45 mL of hot methanol and then refrigerated overnight. The crystals formed were filtered and dried under vacuum to afford 9.2 g of the desired 5-(2-furyl)-2,4-pentadienoic acid. 1H NMR (acetone-d6, 300 MHz), (ppm) 7.64 (broad s, 1H), 7.42 (m, 1H), 6.86 (m, 2H), 6.58 (m, 2H), 6.05 (d, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:11][CH2:12]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:42]N1C(=O)CCC1=O.CCOCC>ClCCl>[CH2:1]([O:8][CH2:9][CH:10]([CH2:11][CH2:12][Br:42])[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCC(COCc1ccccc1)COCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: BrCCC(COCc1ccccc1)COCc1ccccc1
Temperature: 0 °C

Procedure:
A solution of 4-benzyloxy-3-benzyloxymethylbutan-1-ol (41.75 g, 139 mmol) in 150 ml of dry dichloromethane was cooled in ice-water bath. Triphenylphosphine (42.0 g, 160 mmol) was added with stirring and then N-bromosuccinimide (26.0 g, 146 mmol) in portions during 15 min. After 1 h at room temperature ether (400 ml) was added and the precipitated triphenylphosphine oxide filtered off. The solution was concentrated in vacuum to a small volume, and more ether was added to extract the product from precipitated triphenylphosphine oxide. Finally, this extraction-precipitation step was repeated with light petroleum to give, after evaporation, 33.55 g (66%) of crude title compound.
Reaction SMILES: [C:1]([OH:12])(=[O:11])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[CH3:13][S:14][CH2:15]Cl.C(N(CC)CC)C>>[C:1]([O:12][CH2:13][S:14][CH3:15])(=[O:11])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4]
Reactant: CC(C)=CCC/C(C)=C/C(=O)O
Reactant: CSCCl
Solvent: CCN(CC)CC
Product: CSCOC(=O)/C=C(\C)CCC=C(C)C

Procedure:
This product was prepared according to the procedure described in Example 1, by reacting geranic acid with chloromethyl methyl sulfide in the presence of one equivalent of triethylamine; b.p. 111°-112° C./2 mm Hg, n20 1.4912.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl[CH2:11][O:12][CH3:13].[Si:14]([O:21][CH2:22][CH:23]([OH:38])[CH2:24][N:25]1[C:30](=[O:31])[CH:29]=[N:28][C:27]2[CH:32]=[CH:33][C:34]([O:36][CH3:37])=[N:35][C:26]1=2)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>ClCCl>[Si:14]([O:21][CH2:22][CH:23]([O:38][CH2:11][O:12][CH3:13])[CH2:24][N:25]1[C:30](=[O:31])[CH:29]=[N:28][C:27]2[CH:32]=[CH:33][C:34]([O:36][CH3:37])=[N:35][C:26]1=2)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16]
Reactant: COc1ccc2ncc(=O)n(CC(O)CO[Si](C)(C)C(C)(C)C)c2n1
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOC(CO[Si](C)(C)C(C)(C)C)Cn1c(=O)cnc2ccc(OC)nc21
Reaction time: 24 h
Yield: 67.3 %

Procedure:
N,N-Diisopropylethylamine (1.93 ml, 11.10 mmol) and chloromethylmethyl ether (0.56 ml, 7.40 mmol) were added under cooling on ice to a solution of 4-(3-{[tert-butyl(dimethyl)silyl]oxy}-2-hydroxypropyl)-6-methoxypyrido[2,3-b]pyrazin-3(4H)-one (1.35 g, 3.70 mmol) in dichloromethane (20 ml) and the mixture was stirred for 24 hours. The reaction solution was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield 1.02 g (67%) of the title compound in the form of a yellow oily product.
Reaction SMILES: C(N(CC)CC)C.C(O[C@@H:12]1[C@H:18]2[C@H:19]3[C@H:28]([CH2:29][CH2:30][C@:15]2([CH2:16][CH3:17])[C:14](=[O:33])[CH2:13]1)[C@@H:27]1[C:22](=[CH:23][C:24](=[O:31])[CH2:25][CH2:26]1)[CH:21]([OH:32])[CH2:20]3)(=O)C.O>CCO>[OH:32][CH:21]1[C:22]2[C@H:27]([CH2:26][CH2:25][C:24](=[O:31])[CH:23]=2)[C@@H:28]2[C@H:19]([C@H:18]3[C@@:15]([CH2:30][CH2:29]2)([CH2:16][CH3:17])[C:14](=[O:33])[CH:13]=[CH:12]3)[CH2:20]1
Reactant: CC[C@]12CC[C@H]3[C@@H](CC(O)C4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(C)=O)CC2=O
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: CC[C@]12CC[C@H]3[C@@H](CC(O)C4=CC(=O)CC[C@@H]43)[C@@H]1C=CC2=O
Temperature: 25 °C
Yield: 33.3 %

Procedure:
Triethylamine (0.5 ml, 3.6 mmol) was added to a suspension of 15α-acetoxy-6-hydroxy-18-methyl-estr-4-en-3,17-dione (0.5 g, 1.4 mmol) in EtOH (3 ml). The mixture was heated under reflux for 2 h, cooled to room temperature and then water (30 ml) was added. The mixture was extracted with ethyl acetate (30 ml), the organic layer was washed with water (50 ml), dried and the solvent removed. The crude product was purified by flash chromatography on silica gel eluting with diisopropyl ether/ethyl acetate (7/3) to afford pure 6-hydroxy-18-methyl-estra-4,15-dien-3,17-dione (0.14 g, yield: 34%) as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][N:8]([CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=1)[CH2:9][C:10]1[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[CH2:51]([N:54]([CH2:60][CH2:61][CH3:62])[CH2:55][CH2:56][CH2:57][CH2:58][NH2:59])[CH2:52][CH3:53]>CN(C=O)C>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][N:8]([CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:59][CH2:58][CH2:57][CH2:56][CH2:55][N:54]([CH2:60][CH2:61][CH3:62])[CH2:51][CH2:52][CH3:53])=[O:23])=[CH:19][CH:18]=1)[CH2:9][C:10]1[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=1
Reactant: Cn1ccnc1CN(Cc1ccc(C(=O)O)cc1)Cc1nccn1C
Reactant: CCCN(CCC)CCCCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCN(CCC)CCCCNC(=O)c1ccc(CN(Cc2nccn2C)Cc2nccn2C)cc1
Reaction time: 6 h

Procedure:
The compound (75.0 mg) obtained in Example 40-1 was dissolved in DMF (2.0 ml) and then added with DCC (46.0 mg) and HOBt (36.0 mg), followed by stirring for 6 hours. A solution of the compound (76.0 mg) obtained in Example 1-2 in DMF was added to the reaction system and then the whole was stirred for 15 hours. After completion of the reaction, DMF was distilled off and the residue was then dissolved in chloroform, followed by extraction with 1 mol/l hydrochloric acid. The aqueous layer was added with a 1 mol/l sodium hydroxide aqueous solution and then extracted with chloroform. The extract was dried with anhydrous magnesium sulfate and the solvent was then distilled off, followed by treating with hydrochloric acid. Subsequently, the treated product was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (23.9 mg) of the subject compound as a white solid.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[S:6][C:7]([S:10]([CH2:13][N+:14]([O-:16])=[O:15])(=[O:12])=[O:11])=[CH:8][CH:9]=1>C(O)(=O)C>[Br:1][C:9]1[CH:8]=[C:7]([S:10]([CH2:13][N+:14]([O-:16])=[O:15])(=[O:11])=[O:12])[S:6][C:5]=1[O:4][CH3:3]
Reactant: COc1ccc(S(=O)(=O)C[N+](=O)[O-])s1
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1sc(S(=O)(=O)C[N+](=O)[O-])cc1Br
Yield: 23.9 %

Procedure:
A solution of bromine (0.254 g) in acetic acid (2 ml) was added to a stirred solution of 2-methoxy-5-(nitromethylsulphonyl)thiophene (0.39 g) in acetic acid (8 ml). After 1hour the mixture was quenched with water (10 ml). The yellow precipitate was collected by filtration and recrystallised from ethanol to give 3-bromo-2-methoxy-5-(nitromethylsulphonyl)thiophene as a white solid (0.12 g) m.p. 120°-121° C.; m/e (electron impact): 315, 317 [mean M+ for Br=80 is 316]; NMR (90 MHz): 4.1 (s,3H), 5.60 (s,2H), 7.22 (s,1H); microanalysis, found: C,23.1; H,1.8; N,4.1%; C6H6BrNO5S2 requires C,22.8; H,1.9; N,4.4%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[N:14][N:13]=[N:12]2)=[CH:7][C:4]=1[CH:5]=[O:6].[C:16]1([CH3:26])C=CC(S(O)(=O)=O)=CC=1.[OH2:27]>C1(C)C=CC=CC=1.C(O)CO>[O:6]1[CH2:26][CH2:16][O:27][CH:5]1[C:4]1[CH:7]=[C:8]([N:11]2[CH:15]=[N:14][N:13]=[N:12]2)[CH:9]=[CH:10][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(-n2cnnn2)cc1C=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O
Solvent: Cc1ccccc1
Solvent: OCCO
Product: COc1ccc(-n2cnnn2)cc1C1OCCO1

Procedure:
To a suspension of 2-methoxy-5-tetrazol-1-yl-benzaldehyde (8 g) in toluene (400 ml), ethylene glycol (8 ml) and para-toluene sulphonic acid (50 mg) were added. The mixture was heated to reflux under Dean-Stark conditions and under a nitrogen atmosphere for 12 h whereupon evolution of water had ceased. The mixture was allowed to cool and the liquor decanted and extracted with 8% aqueous sodium bicarbonate solution (100 ml). The precipitated solid was dissolved in dichloromethane (200 ml) and then extracted with the aqueous layer. The aqueous layer was then extracted with dichloromethane (100 ml). The organic layers were then combined, dried (Na2SO4) and evaporated in vacuo to yield the title compound as a yellow solid (9.12 g).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:23]([N:25]([CH3:49])[C@@H:26]([C@@H:45]([CH3:48])[CH2:46][CH3:47])[C@H:27]([O:43][CH3:44])[CH2:28][C:29](OC3C(F)=C(F)C(F)=C(F)C=3F)=[O:30])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH:51]1([CH2:58][CH2:59][NH:60][C:61](=[O:72])[C@H:62]([CH3:71])[C@@H:63]([O:69][CH3:70])[C@@H:64]2[CH2:68][CH2:67][CH2:66][NH:65]2)[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=[CH:52]1.C(N(CC)C(C)C)(C)C>ClCCl>[CH:51]1([CH2:58][CH2:59][NH:60][C:61](=[O:72])[C@H:62]([CH3:71])[C@H:63]([C@@H:64]2[CH2:68][CH2:67][CH2:66][N:65]2[C:29](=[O:30])[CH2:28][C@@H:27]([O:43][CH3:44])[C@@H:26]([N:25]([CH3:49])[C:23](=[O:24])[C@H:19]([CH:20]([CH3:22])[CH3:21])[NH:18][C:16]([O:15][CH2:14][CH:12]2[C:13]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:17])[C@@H:45]([CH3:48])[CH2:46][CH3:47])[O:69][CH3:70])[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=[CH:57]1
Reactant: CO[C@@H]([C@@H]1CCCN1)[C@@H](C)C(=O)NCCC1C=CC=CC=C1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)Oc1c(F)c(F)c(F)c(F)c1F)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCC1C=CC=CC=C1)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.7 %

Procedure:
To a solution of #174 (706 mg, 1.02 mmol, 1 eq.) and #64 (311 mg, 1.02 mmol, 1 eq.) in dichloromethane (3 mL) was added N,N-diisopropylethylamine (400 mg, 3.07 mmol, 3 eq.). After 18 hours of stirring at room temperature, the reaction was concentrated in vacuo and purified by silica gel chromatography (Gradient: 0 to 100% ethyl acetate in heptane) to afford #175 (560 mg, 68%) as a white solid. LC-MS (Protocol Q1): m/z 611.8 [M+H+], retention time=1.15 minutes.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]=O)=[N:18][CH:19]=1.C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[CH2:11]([O:10][C:8]([C@@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[NH:2][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([F:13])=[CH:19][N:18]=1)=[O:9])[CH3:12]
Reactant: O=Cc1ccc(F)cn1
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1N
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)[C@@H]1CCC[C@@H]1NCc1ccc(F)cn1
Temperature: 50 °C
Reaction time: 72 h
Yield: 52.5 %

Procedure:
A solution of ethyl cis-2-amino-1-cyclopentane carboxylate hydrochloride (0.250 g, 1.29 mmol) in ethanol (10 mL) was treated with 5-fluoro-pyridine-2-carbaldehyde, glacial acetic acid (10 drops), sodium cyanoborohydride (0.162 g, 2.58 mmol) and stirred for 72 h at 50° C. The reaction was extracted with ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate solution (100 mL). The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0-10% methanol in dichloromethane) to afford the desired product, cis-2-[(5-fluoro-pyridin-2-ylmethyl)-amino]-cyclopentanecarboxylic acid ethyl ester (0.179 g, 0.678 mmol, 52.5%), as a light yellow oil. LC-MS (ESI) calcd for C14H19FN2O2 266.14, found 267.2 [M+H+].
Reaction SMILES: C[S:2][C:3]([S:13]C)=[CH:4][C:5]([C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1)=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:16]>C1(C)C(C)=CC=CC=1.ClCCCl.C(=S)=S>[N:8]1[CH:9]=[CH:10][N:11]=[CH:12][C:7]=1[C:5]1[S:16][S:2][C:3](=[S:13])[CH:4]=1
Reactant: CSC(=CC(=O)c1cnccn1)SC
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: S=C=S
Solvent: Cc1ccccc1C
Solvent: ClCCCl
Product: S=c1cc(-c2cnccn2)ss1
Temperature: 20 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
3,3-bis-Methylthio-1-(pyrazin-2-yl)-prop-2-en-1-one (2.26 g.) is added in the course of about one minute to a boiling suspension of phosphorus pentasulphide (7.1 g.) in anhydrous xylene (140 cc.). Heating under reflux is continued for one hour after the end of the addition, and the reaction mixture is then cooled to a temperature of about 20° C. An insoluble product is filtered off and washed with 1,2-dichloroethane (200 cc.). The filtrate is concentrated to dryness under reduced pressure and the residue obtained is taken up in 1,2-dichloroethane (100 cc.). An insoluble product is filtered off and washed with 1,2-dichloroethane (4 × 50 cc.). The filtrate is extracted successively with a 10% aqueous sodium carbonate solution (100 cc.) and with water (2 × 100 cc.) and is then dried over magnesium sulphate. After filtration of the dried solution, and concentration to dryness under reduced pressure (30 mm Hg), the residue obtained is suspended in carbon disulphide (50 cc.). The insoluble product is filtered off and taken up in boiling 1,2 -dichloroethane (25 cc.). The boiling suspension is filtered and then cooled. A product precipitates and is filtered off and then washed with 1,2-dichloroethane (2 × 2 cc.). After drying, 5-(pyrazin-2-yl)-1,2-dithiole-3-thione (0.36 g.) melting at 196° C. is obtained.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[CH3:11][CH:12]([NH2:16])[CH2:13][O:14][CH3:15].[Cl:17][CH2:18][CH2:19][N:20]=[C:21]=[O:22]>>[Cl:17][CH2:18][CH2:19][NH:20][C:21]([N:16]([CH:12]([CH3:11])[CH2:13][O:14][CH3:15])[CH:9]1[O:10][CH2:2][C@H:3]([OH:4])[C@H:5]([OH:6])[C@H:7]1[OH:8])=[O:22]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)CO
Reactant: O=C=NCCCl
Reactant: COCC(C)N
Product: COCC(C)N(C(=O)NCCCl)C1OC[C@H](O)[C@H](O)[C@H]1O
Yield: 47.5 %

Procedure:
3.0 g of L-arabinose, 3.6 g of (1-methyl-2-methoxy-ethyl)amine and 3.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 13-(1). 3.1 g of 1-(2-chloroethyl)-3-(1-methyl-2-methoxy-ethyl)-3-(L-arabinopyranosyl)urea are thereby obtained as colorless caramel.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3](SC)=[CH:4][C:5]#[N:6].O.[NH2:11][NH2:12]>C(O)C>[CH3:1][N:2]([CH3:9])[C:3]1[NH:12][N:11]=[C:5]([NH2:6])[CH:4]=1
Reactant: CSC(=CC#N)N(C)C
Reactant: NN
Solvent: CCO
Solvent: O
Product: CN(C)c1cc(N)n[nH]1
Temperature: 85 °C
Yield: 68.6 %

Procedure:
A mixture of (2E or Z)-3-(dimethylamino)-3-(methylthio)acrylonitrile (Method 33, 9.525 g, 67 mmol) and hydrazine hydrate (10.06 g, 201 mmol) in ethanol (70 ml) was heated at 85° C. overnight. Solvent was removed. The residue was purified by silica gel column chromatography (by ISCO Combiflash with a gradient of 0-10% methanol in methylenechloride with 1% NH4OH). 5.8 g (69%) product as obtained brownish thick oil. LC-MS, 127 (M+1). NMR (DMSO, 400 MHz) δ9.51 (br, 1H), 4.67 (s, 1H), 2.62 (s, 6H).
Reaction SMILES: Cl[CH:2]([C:7](=O)[CH2:8][CH3:9])[C:3]([O:5][CH3:6])=[O:4].[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:24]=[CH:23][N:22]=[N:21][C:20]=1[NH2:25]>O>[CH3:6][O:5][C:3]([C:2]1[N:21]2[N:22]=[CH:23][CH:24]=[C:19]([C:13]3[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=3[CH3:11])[C:20]2=[N:25][C:7]=1[CH2:8][CH3:9])=[O:4]
Reactant: Cc1ccc(-c2ccnnc2N)c(C)c1
Reactant: CCC(=O)C(Cl)C(=O)OC
Solvent: O
Product: CCc1nc2c(-c3ccc(C)cc3C)ccnn2c1C(=O)OC
Temperature: 155 °C
Yield: 37 %

Procedure:
Methyl 2-chloro-3-oxopentanoate (5 mL) was added to 4-(2,4-dimethylphenyl)-3-pyridazineamine (640 mg, 3.2 mmol), and the mixture was heated at 155° C. for 30 minutes. Water was added to the resulting reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a 5N aqueous sodium hydroxide solution and brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:N-hexane=1:3) to give the title compound (373 mg, 37%) as a brown oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([CH2:17][C:18](NC1N=NN(CCCCCCCCCCCC)N=1)=[O:19])(=[O:16])=[O:15])([CH3:3])[CH3:2].[CH2:38]([SH:48])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>>[CH2:38]([S:48][C:18](=[O:19])[CH2:17][S:14](=[O:15])(=[O:16])[NH:13][C:5]1[C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:10]([CH3:12])[CH3:11])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: CCCCCCCCCCCCn1nnc(NC(=O)CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Reactant: CCCCCCCCCCS
Product: CCCCCCCCCCSC(=O)CS(=O)(=O)Nc1c(C(C)C)cccc1C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 2, except that 2-DAT was replaced with decanthiol, mp 57°-59° C.