Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:9][CH:8]=1.CN(C)[CH:29]=[O:30].Cl>CCCCCC.O1CCCC1>[CH3:20][C:19]1[O:18][C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:16][C:15]=1/[CH:14]=[CH:13]/[C:10]1[CH:11]=[CH:12][C:7]([CH:29]=[O:30])=[CH:8][CH:9]=1
Reactant: Cc1oc(-c2ccccc2)nc1/C=C/c1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1oc(-c2ccccc2)nc1/C=C/c1ccc(C=O)cc1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 53.4 %

Procedure:
A solution of n-butyllithium in hexane (1.6M, 28.7 ml) was added dropwise to a solution of (E)-4-[2-(4-bromophenyl)vinyl]-5-methyl-2-phenyloxazole (13.0 g) in tetrahydrofuran (140 ml) at -70° C. The mixture was stirred at -70° C. for 15 minutes, and then a solution of N,N-dimethylformamide (4.2 g) in tetrahydrofuran (10 ml) was added dropwise at the same temperature. The reaction mixture was stirred at -70° C. for 30 minutes, and then warmed to room temperature. 1N hydrochloric acid (150 ml) was added dropwise, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate-hexane (1:2, v/v) gave (E)-4-[2-(5-methyl-2-phenyl-4-oxazolyl)vinyl]-benzaldehyde (5.9 g, 54%). The product was recrystallized from ethyl acetate-hexane. Pale brown prisms, mp: 158-159° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:21][C:22](=[O:34])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([CH3:32])[CH3:31])=[C:25]([Cl:33])[CH:24]=1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]3[CH:20]=2)=[CH:7][CH:6]=1.CC(OC([NH:42][C:43]([CH3:48])([C:45](O)=[O:46])[CH3:44])=O)(C)C>>[Cl:33][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[O:29][CH:30]([CH3:32])[CH3:31])[C:22]([NH:21][C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]3[CH:20]=2)=[CH:7][CH:6]=1)[CH2:2][NH:1][C:45](=[O:46])[C:43]([CH3:48])([CH3:44])[NH2:42])=[O:34]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: Cc1cccn2cc(-c3ccc(C[C@@H](CN)NC(=O)c4ccc(OC(C)C)c(Cl)c4)cc3)nc12
Product: Cc1cccn2cc(-c3ccc(C[C@@H](CNC(=O)C(C)(C)N)NC(=O)c4ccc(OC(C)C)c(Cl)c4)cc3)nc12

Procedure:
Following the procedure described above with N-((1S)-2-amino-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide and N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-methylalanine provided the title product as a white solid. ESMS [M+H]+: 563.2.
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:12])[CH:4]([CH3:13])[CH2:3]1>C(O)C.[Pd]>[OH:1][CH:2]1[CH2:11][CH2:10][CH:9]2[CH:5]([CH2:6][CH2:7][CH:8]2[CH3:12])[CH:4]([CH3:13])[CH2:3]1
Reactant: CC1=C2CCC(O)CC(C)C2CC1
Agent: [Pd]
Solvent: CCO
Product: CC1CCC2C(C)CC(O)CCC12
Yield: 68.7 %

Procedure:
3.6 g of 6-hydroxy-1,4-dimethyl-2,3,3a,4,5,6,7,8-octahydroazulene were hydrogenated in 25 ml of ethanol with 500 mg of palladium-on-carbon (10%). The reaction mixture was filtered, the filtrate evaporated and distilled under reduced pressure in a bulb-tube. There were obtained 2.5 g of 6-hydroxy-1,4-dimethyl-perhydroazulene; b.p.0.005 ca 82°; IR(film):νmax = 3360, 1460, 1375, 1030, 975 cm-1. The compound has a fresh, woody, earthy odour somewhat reminiscent of vetiver.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([CH3:11])[C:3]=1[C:12]#[N:13].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1>[C:12]([C:3]1[C:4]([CH3:11])=[C:5]([C:7]([O:9][CH3:10])=[O:8])[S:6][C:2]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)#[N:13]
Reactant: C1COCCN1
Reactant: COC(=O)c1sc(Br)c(C#N)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)c1sc(N2CCOCC2)c(C#N)c1C
Temperature: 25 °C
Yield: 72.9 %

Procedure:
A mixture of methyl 5-bromo-4-cyano-3-methylthiophene-2-carboxylate (6.29 g, 24.2 mmol), morpholine (2.53 g, 29.0 mmol) and cesium carbonate (15.8 g, 48.4 mmol) in anhydrous Tetrahydrofuran (110 mL) was heated to reflux for 19 hours, and then cooled to room temperature. The mixture was filtered and washed with DCM. The filtrate was rotavaped with Celite. The coated Celite was dry loaded in a silica gel cartridge and chromatographed using MeOH/DCM (1/99) to give a white solid product (4.70 g, yield 73%). LC/MS: (FA) ES+ 267. 1H NMR (400 MHz, d-chloroform) δ 3.85 (m, 4H), 3.82 (s, 3H), 3.58 (m, 4H), 2.56 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:12](=[O:13])[NH:11][CH:10]1[C:14]([O:16]C)=O)=[O:7])([CH3:4])(C)C.[BH4-].[Na+].[C:20](O)(=O)[CH3:21].[BH4-]>O1CCCC1.O>[CH2:1]([O:5][C:6]([NH:8][C@H:9]1[C:12](=[O:13])[NH:11][C@H:10]1[CH2:14][OH:16])=[O:7])[CH2:4][CH2:20][CH3:21]
Reactant: CC(=O)O
Reactant: COC(=O)C1NC(=O)C1NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCOC(=O)N[C@H]1C(=O)N[C@H]1CO
Reaction time: 0.33 h
Yield: 50 %

Procedure:
A solution of 2.0 g (8.2 mmole) of methyl 3-t-butoxycarbonylamino-4-oxoazetidine-2-carboxylate in 20 ml of tetrahydrofuran is cooled in ice and a solution of 0.75 g (20 mmole) of sodium borohydride in 10 ml of water is added. The mixture is stirred 20 min at 0° and then 1.5 hr at room temperature. Acetic acid is added dropwise to decompose the excess borohydride and the mixture is concentrated in vacuum. The residue is diluted with brine and extracted with ethyl acetate. The organic phase is washed with brine and 5% NaHCO3 ; dried over magnesium sulfate and evaporated to dryness to give 0.9 g (50%) of the title product as white crystals, mp 128°-131°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19][CH3:20])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:4][C:3]=1[F:28].ClC1C=CC(C(C2C=CC(Cl)=CC=2)C2C3C(=C(CS(C)=[O:48])C=CC=3)NC=2)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19]([CH3:20])=[O:48])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:4][C:3]=1[F:28]
Reactant: CS(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c[nH]c12
Reactant: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(Cl)c(F)c3)c[nH]c12
Product: CS(=O)Cc1cccc2c(C(c3ccc(F)cc3)c3ccc(Cl)c(F)c3)c[nH]c12

Procedure:
The title compound was prepared starting from 75 mg (0.18 mmol) of the compound from Example 283 in analogy to the synthesis of the compound from Example 296. 76 mg (98% of theory) of the target compound were obtained as mixture of diastereomers.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH3:5].C([Li])CCC.Br[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1>[Cl-].[Zn+2].[Cl-]>[C:1]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)#[C:2][CH2:3][CH2:4][CH3:5]
Reactant: Brc1cccs1
Reactant: C#CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Product: CCCC#Cc1cccs1

Procedure:
Quantities: pent-1-yne (6.80 g, 0.10 mol), n-butyllithium (10.0 ml, 10.0M in hexane, 0.044 mol), zinc chloride (13.60 g, 0.10 mol), 2-bromothiophene (16.00 g, 0.098 mol), tetrakis (triphenylphosphine)palladium(O) (3.40 g 2.94 mol).
Reaction SMILES: [C:1]([C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH2:14][C:15](=[O:17])[CH3:16])[CH2:7][CH2:8]C(OCC)=O)([O:3][CH2:4][CH3:5])=[O:2].[H-].[Na+].C([OH:28])(C)C>CN(C)C=O>[C:18]([C:6]1([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH2:7][C:8](=[O:28])[CH2:16][C:15](=[O:17])[CH2:14]1)([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)CCC(CC(C)=O)(C(=O)OCC)C(=O)OCC
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)OCC)CC(=O)CC(=O)C1
Reaction time: 15 h

Procedure:
A solution of 14.3 g (0.047 mol) of ethyl 3,3-biscarbethoxy-5-oxo-hexanecarboxylate in 40 ml of dimethylformamide was added dropwise to a suspension of 3.6 g (0.118 mol) of 80 % strength by weight sodium hydride in 200 ml of dimethylformamide. After stirring at 20°-25° C. for about 15 hours, the reaction was stopped by adding 5 ml of isopropanol. The reaction products were partitioned between ethyl acetate and 1 molar hydrochloric acid. The organic phase was then separated, dried and evaporated down. Yield: 2.2 g of a crude product oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].[P:19]([O:26]CC)([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>>[CH2:21]([O:20][P:19]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])([O:23][CH2:24][CH3:25])=[O:26])[CH3:22]
Reactant: CCOP(OCC)OCC
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCBr
Product: CCOP(=O)(CCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)OCC
Temperature: 150 °C
Reaction time: 18 h
Yield: 90.3 %

Procedure:
A mixture of 12.40 g of 1-bromo-4-(nonafluorobutyl)butane and 21.00 g of triethyl phosphite was heated at 150° C. After 18 hr, diethyl ethylphosphonate and other volatiles were removed from the mixture by distillation, b.p. 30-50° C. at 0.05 torr (7 Pa). Bulb-to-bulb distillation of the remaining concentrated mixture provided 13.0 g of 1-(diethylphosphono)-4-(nonafluorobutyl)butane as a clear, colorless liquid, b.p. 105-110° C. at 0.05 torr (7 Pa).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([C:15]([O:17]C)=[O:16])[C:5]2[O:6][C@@H:7]3[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]3[C:4]=2[CH:3]=1>[OH-].[Na+].O1CCOCC1.O>[Cl:1][C:2]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:5]2[O:6][C@@H:7]3[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]3[C:4]=2[CH:3]=1
Reactant: COC(=O)c1cc(Cl)cc2c1O[C@@H]1CCCC[C@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(Cl)cc2c1O[C@@H]1CCCC[C@H]21
Temperature: 60 °C
Reaction time: 5 h

Procedure:
A mixture of 2 g methyl 2-chloro-cis-5a,6,7,8, 9,9a-hexahydrodibenzofuran-4-carboxylate in 30 ml 1N sodium hydroxide and 5 ml dioxane is stirred at 60° C. for 5 hours. This is then diluted with water, filtered, acidified with acetic acid, extracted with ethyl acetate, dried over magnesium sulfate and evaporated to dryness to obtain an oily product which crystallizes on standing. This is recrystallyzed to obtain 2-chloro-cis-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylic acid. (M.P. 132°-4° C.)
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].C(O)(=O)C(C(C(O)=O)O)O>>[CH3:1][CH2:2][O:3][C:4]([C@H:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: CCOC(=O)C(N)c1ccccc1
Agent: O=C(O)C(O)C(O)C(=O)O
Product: CCOC(=O)[C@H](N)c1ccccc1

Procedure:
Similarly to Example 18 but using ethyl DL-phenylglycinate (5.070 g., -- contains 0.05 mole methylene chloride i.e. 27.6 mmole) and (+)-tartaric acid (4.275 g., 28.5 mmole, 1.03 equiv.) in the filtrate from a previous resolution (Example 18, 50 ml. -- made up to volume with the first and then second washes), and giving ethyl D-phenylglycinate (+)-hemitartrate solvated with 1.0 mole methanol (8.049 g., 81%), [α]D23 - 46.7° (c 2.520, H2O).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](Cl)=[O:11].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.O>CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: Nc1ccccc1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOCC
Product: O=C(Cc1ccc(Cl)cc1Cl)Nc1ccccc1
Temperature: 25 °C

Procedure:
2,4-Dichlorophenylacetyl chloride (0.075 mol) was added dropwise over 1 h to a stirred solution of aniline (6.8 g) and triethylamine (7.6 g) in dry ether (200 ml) at 0°-5° C. The reaction mixture was allowed to warm up to room temperature overnight. It was then poured into iced water. An oily layer separated out and gradually solidified. This was recrystallised from diisopropyl ether to give 2-(2,4-dichlorophenyl)acetanilide, m.p. 145.6°-146.5° C.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[S:14][C@@H:13]2[C@@H:5]([C@@H:6]3[C@@H:10]([C@@H:11]([CH2:15][OH:16])[O:12]2)[O:9][C:8]([CH3:18])([CH3:17])[O:7]3)[N:4]=1.C(=O)(O)[O-].[K+].BrN1C(=O)CCC1=O>ClCCl.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][N:2]([CH3:19])[C:3]1[S:14][C@@H:13]2[C@@H:5]([C@@H:6]3[C@@H:10]([C@@H:11]([CH:15]=[O:16])[O:12]2)[O:9][C:8]([CH3:17])([CH3:18])[O:7]3)[N:4]=1
Reactant: CN(C)C1=N[C@@H]2[C@H]3OC(C)(C)O[C@@H]3[C@@H](CO)O[C@@H]2S1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClCCl
Product: CN(C)C1=N[C@@H]2[C@H]3OC(C)(C)O[C@@H]3[C@@H](C=O)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
To a solution of 156 (500 mg, 1.7 mmol) in dichloromethane (20 mL) and water (5 mL) was added 2,2,6,6-tetramethylpiperidinooxy (13 mg, 0.08 mmol), tetrabutylammonium bromide (27 mg, 0.08 mmol), potassium bicarbonate (788 mg, 7.9 mmol) and N-bromosuccinimide (342 mg, 1.9 mmol). The resulting solution was stirred for 30 minutes at room temperature, before the reaction was quenched by the addition of saturated aqueous sodium sulfite solution (10 mL), which was then extracted with dichloromethane (2×10 mL). The combined organic layer was washed with brine (2×10 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The crude residue was purified by flash column chromatography with 10% ethyl acetate in dichloromethane to afford 157 as an off-white solid (300 mg, 54%). (ES, m/z): [M+H]+ 287.0; 1H NMR (300 MHz, CDCl3) δ 9.82 (s, 1H), 6.34 (d, J=6.0 Hz, 1H), 4.37-4.32 (m, 1H), 4.11-4.05 (m, 1H), 3.94-3.82 (m, 1H), 3.61-3.54 (m, 1H), 3.36-3.23 (m, 1H), 3.08 (s, 6H), 1.46 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[C:11](Cl)(Cl)=[S:12].O>C(OCC)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][N:6]=[C:11]=[S:12]
Reactant: S=C(Cl)Cl
Reactant: COc1ccccc1CN
Solvent: O
Solvent: CCOCC
Product: COc1ccccc1CN=C=S
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of 2-methoxybenzylamine (1.80 g) in diethylether (20 ml) was added dropwise under ice-cooling for 10 minutes thiophosgene (1.54 g). The mixture was stirred at room temperature for 1 hour. To the reaction solution was added water (30 ml), extracted with diethylether (60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give (2-methoxybenzyl)isothiocyanate (2.35 g, yield: 99%) as brown oil.
Reaction SMILES: [OH:1][CH2:2][C:3]([F:9])([F:8])[S:4](Cl)(=[O:6])=[O:5].C(=O)([O-])O.[Na+].[OH:15][N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22].O>C(#N)C>[F:8][C:3]([F:9])([S:4]([O:15][N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22])(=[O:6])=[O:5])[CH2:2][OH:1]
Reactant: O=S(=O)(Cl)C(F)(F)CO
Reactant: O=C1CCC(=O)N1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C1CCC(=O)N1OS(=O)(=O)C(F)(F)CO
Temperature: 0 °C
Yield: 57.9 %

Procedure:
In 100 mL of acetonitrile, 25.5 g of a liquid of 2-hydroxy-1,1-difluoroethanesulfonyl chloride (purity: 98%, equivalent to 0.138 mol) was dissolved by stirring. The resulting solution was cooled to 0° C., admixed with 14.0 g (0.166 mol) of sodium hydrogencarbonate and 17.5 g (0.152 mol) of N-hydroxysuccinimide, and then, reacted at 0° C. for 24 hours. To the thus-obtained reaction solution, 125 mL of water was added. The reaction solution was subsequently extracted twice with 100 mL of ethyl acetate. The resulting organic layer was washed twice with 100 mL of water. The organic layer was further subjected to concentration and purified by distillation. With this, 20.7 g of the target compound was obtained as a colorless oily substance (yield: 52%, purity: 90%, pure content: 18.7 g).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:10]=[S:11].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[C:27]2[C:28]3[CH2:34][CH2:33][NH:32][CH2:31][C:29]=3[S:30][C:26]=2[N:25]2[C:35]([CH3:38])=[N:36][N:37]=[C:24]2[CH2:23][N:22]=1>ClCCCl>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[C:27]2[C:28]3[CH2:34][CH2:33][N:32]([C:10](=[S:11])[NH:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:2]([F:12])([F:1])[F:13])[CH2:31][C:29]=3[S:30][C:26]=2[N:25]2[C:35]([CH3:38])=[N:36][N:37]=[C:24]2[CH2:23][N:22]=1
Reactant: FC(F)(F)c1ccccc1N=C=S
Reactant: Cc1nnc2n1-c1sc3c(c1C(c1ccccc1Cl)=NC2)CCNC3
Solvent: ClCCCl
Product: Cc1nnc2n1-c1sc3c(c1C(c1ccccc1Cl)=NC2)CCN(C(=S)Nc1ccccc1C(F)(F)F)C3
Reaction time: 4 h

Procedure:
A mixture containing 2-trifluoromethylphenyl isothiocyanate (0.82 g, 0.004 mol) and 6-(2-chlorophenyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4′,3′;4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (1 g, 0.0027 mol) in 30 ml of 1,2-dichloroethane is agitated for 4 hours and at a temperature close to 20° C. Half the solvent is evaporated off with the rotary evaporator then 10 ml of ether is added. Agitation is carried out for 20 minutes at a temperature close to 20° C. followed by filtering on frit then washing with 20 ml of ether, with 20 ml of isopropyl ether and with 20 ml of isopentane. After drying under vacuum a cream coloured solid is obtained (1.21 g, 78%). Melting point: 190–192° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7](=[CH:13][CH:14]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])([O-])=O.Cl.O.[OH-].[Na+]>C1C=CC=CC=1.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7](=[CH:13][CH:14]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])cc1C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)c1ccc(N)cc1C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.8 %

Procedure:
Compound 401 (1.5 g, 5.6 mmol) was dissolved in 280 ml of benzene, and 3.4 g of purified zinc dust was added. Then 10 ml of concentrated hydrochloric acid was added in portions. After 15 min. of stirring at room temperature, another 3.4 g of zinc dust was added and the mixture was stirred at room temperature for 12 hours. 340 ml of cold water was added to the reaction mixture and the mixture was neutralized with 1N NaOH solution. The mixture was transferred to a separatory funnel and the benzene layer was removed. The aqueous layer was extracted with benzene. The combined benzene extracts were washed with water and dried over anhydrous sodium sulfate. After evaporation of the solvent, the pale yellow crude solid was obtained and purified by silica gel column chromatography (n-hexane: acetic acid =8:1) to give 1.1 g (80.6%) of diethyl 4-aminophthalate (compound 402).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=4)[N:21]=3)[CH:19]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:34][C:29]1[CH:28]=[C:27]([C:22]2[CH:23]=[C:24]([CH3:26])[N:25]=[C:20]([N:18]3[CH:19]=[C:15]([C:12]4[CH:11]=[CH:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:14][CH:13]=4)[N:16]=[CH:17]3)[N:21]=2)[CH:32]=[CH:31][C:30]=1[Cl:33]
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(-c3ccc(S(=O)(=O)NC(C)(C)C)cc3)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(-c3ccc(S(N)(=O)=O)cc3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.9 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-4-{1-[6-(3,4-dichloro-phenyl)-4-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.2 g) in dichloromethane (3 mL) was added TFA (3 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (3 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as a white solid (0.13 g, 33%). MS (ISP) 460.1 [(M+H)+]; mp 282.5° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=O)=[C:9]([CH3:17])[N:8]=1.[CH:19]1([C:22]2[CH:23]=[C:24]([CH3:34])[C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][CH:27]=2)[CH2:21][CH2:20]1>>[CH:19]1([C:22]2[CH:23]=[C:24]([CH3:34])[C:25]([N:28]3[CH2:29][CH2:30][N:31]([C:11]([C:10]4[C:9]([CH3:17])=[N:8][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:18])=[CH:16][CH:15]=4)=[O:13])[CH2:32][CH2:33]3)=[N:26][CH:27]=2)[CH2:21][CH2:20]1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: COC(=O)c1ccc(N2CCCS2(=O)=O)nc1C
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)nc2C)CC1
Yield: 58.3 %

Procedure:
Using methyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methylnicotinate (300 mg) described in Preparation Example 37 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (265 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 109, the title compound (295 mg) was obtained.
Reaction SMILES: [CH2:1]([C@H:8]([NH2:11])[CH2:9]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].ClC[C@@H]([NH3+])CC1C=CC=CC=1.[CH3:24][C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[N:34]=[C:35]=[S:36]>>[CH3:24][C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[N:34]=[C:35]1[NH:11][C@@H:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][S:36]1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Agent: [Cl-]
Agent: [NH3+][C@H](CCl)Cc1ccccc1
Product: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@@H](Cc2ccccc2)CS1

Procedure:
(1S)-1-Benzyl-2-hydroxyethylamine was converted to (1S)-2-chloro-1-benzylethylammonium chloride according to Method B7b. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-2-chloro-1-benzylethylammonium chloride according to Method C1a to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-benzyl -1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-4-benzyl-3-isobutyl-1,3-thiazolidine HCl salt.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([N:25]([CH3:27])[CH3:26])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]([OH:24])([CH3:23])[CH3:22])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=O.CO.[NH3:30]>>[CH3:27][N:25]([CH3:26])[CH:8]1[C:7]2[S:6][C:5]([C:3]([NH2:30])=[O:2])=[N:14][C:13]=2[C:12]2[CH:15]=[C:16]([C:19]#[C:20][C:21]([OH:24])([CH3:23])[CH3:22])[CH:17]=[CH:18][C:11]=2[O:10][CH2:9]1
Reactant: N
Reactant: COC(=O)c1nc2c(s1)C(N(C)C)COc1ccc(C#CC(C)(C)O)cc1-2
Solvent: CO
Product: CN(C)C1COc2ccc(C#CC(C)(C)O)cc2-c2nc(C(N)=O)sc21
Yield: 87 %

Procedure:
A solution of 4-Dimethylamino-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (50 mg, 0.130 mmol), in methanol-ammonia (5 mL) was stirred at room temperature for 0.5 h. Then the mixture was filtered to afford compound 4-Dimethylamino-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide (42 mg, 87%) as a white solid. LC-MS (ESI & APCI): 372.4 (M+1). 1H NMR (400 MHz, DMSO-d6): δ 8.54 (d, J=1.9 Hz, 1H), 8.43 (s, 1H), 7.88 (s, 1H), 7.30 (dd, H1=8.4 Hz, J2=1.9 Hz, 1H), 7.05 (d, J=8.3 Hz, 1H), 5.46 (s, 1H), 4.40 (m, 3H), 2.36 (s, 6H), 1.49 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[S:24][CH3:23])[CH2:36][CH2:35]2)=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CSc1ccccc1N1CCNCC1
Reactant: COc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Product: COc1nc2ccccc2cc1NC(=O)N1CCN(c2ccccc2SC)CC1
Yield: 78 %

Procedure:
Phenyl N-(2-methoxyquinolin-3-yl)carbamate and 1-(2-methylthiophenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound.