Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])/[C:8]([O:10]CC)=[O:9])[N:6]=1.N1C=CC=CC=1.[Cl:32][CH2:33][C:34](Cl)=[O:35]>CC(N(C)C)=O.ClCCl>[Cl:32][CH2:33][C:34]([NH:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])/[C:8]([OH:10])=[O:9])[N:6]=1)=[O:35]
Reactant: CCOC(=O)/C(=N\OCCCNC(=O)OC(C)(C)C)c1csc(N)n1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCCCO/N=C(\C(=O)O)c1csc(NC(=O)CCl)n1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
In a mixture of 15 ml of dimethylacetamide and 15 ml of dichloromethane are dissolved 5.17 g of ethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(3-tert-butoxycarbonylaminopropoxyimino)acetate and 1.1 ml of pyridine and, under ice-cooling and stirring, 2.21 ml of chloroacetyl chloride is added dropwise. With ice-cooling, the mixture is stirred for 30 minutes and the reaction mixture is poured into 150 ml of ice-water and extracted with dichloromethane. The extract is washed with water, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution in that order and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the residue is subjected to silica gel (200 g) column chromatography, elution being carried out with chloroform-ethyl acetate (9:1 and 5:1). Fractions containing the desired compound are collected and concentrated under reduced pressure. The residue is dissolved in a mixture of 8.8 ml of dioxane and 62 ml of ethanol, followed by addition of 8.8 ml of 2 N aqueous sodium hydroxide solution. The mixture is stirred at room temperature for 48 hours and, then, 1.2 ml of 2 N aqueous sodium hydroxide solution is added and stirring is continued for 6 hours. The reaction mixture is concentrated under reduced pressure and the residue is dilluted with water and washed with ethyl acetate. The solution is adjusted to pH 2.0 with diluted hydrochloric acid and extracted with ethyl acetate. The extract is washed with aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and a mixture of hexane and ethyl acetate (4:1) is added to the residue. The resulting light yellow powder is collected by filtration to give 2.47 g of 2-(2-chloroacetamidothiazol-4-yl)-(Z)-2-(3-tert-butoxycarbonylaminopropoxyimino)acetic acid.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:38])([CH3:37])[O:6][C@@H:7]1[C@H:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[O:9][C@H:8]1[N:29]1[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]1=[O:31])([CH3:4])[CH3:3].[CH3:39][O:40][C:41]1[CH:56]=[CH:55][C:44]([C:45]([C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=2)=[O:46])=[CH:43][CH:42]=1>>[OH:46][C:45]([C:35]1[C:33](=[O:34])[NH:32][C:30](=[O:31])[N:29]([CH:36]=1)[C@@H:8]1[O:9][C@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24])[C@@H:11]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[C@H:7]1[O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:38])[CH3:37])([C:44]1[CH:55]=[CH:56][C:41]([O:40][CH3:39])=[CH:42][CH:43]=1)[C:47]1[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(O)(c2ccc(OC)cc2)c2cn([C@@H]3O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c(=O)[nH]c2=O)cc1

Procedure:
5-(Hydroxy-1,1-bis(4-methoxyphenyl)methyl)-2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine was prepared from 2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine according to the method of Example 1 step (i) (but using 4,4'-dimethoxybenzophenone instead of benzophenone).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][CH:8]([CH2:11][OH:12])[CH2:7][C:6]=2[CH:5]=[C:4]([CH3:13])[CH:3]=1.C1C(=O)N([Br:21])C(=O)C1>CN(C=O)C>[NH2:1][C:2]1[C:10]2[O:9][CH:8]([CH2:11][OH:12])[CH2:7][C:6]=2[C:5]([Br:21])=[C:4]([CH3:13])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(N)c2c(c1)CC(CO)O2
Solvent: CN(C)C=O
Product: Cc1cc(N)c2c(c1Br)CC(CO)O2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a mixture of (7-amino-5-methyl-2,3-dihydrobenzofuran-2-yl)methanol (7d) (0.80 g, 4.5 mmol) in DMF (13 mL) at 0° C. was added NBS (0.08 g, 4.5 mmol), it was stirred at 0° C. for 15 min. The mixture was extracted with EtOAc (150 mL), washed with NaHSO3 (50 mL), water, brine, dried and concentrated to give the title compound (7e) as a yellow solid. MS-ESI (m/z): 258 (M+1)+.
Reaction SMILES: CN(C)[CH:3]=[C:4]1[C:9](=O)[C:8]([CH3:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5]1.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([NH:41][C:42]([NH2:44])=[NH:43])[CH:32]=[CH:33][C:34]=1[N:35]1[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]1.C(N(CC)CC)C>C(O)C.C(OCC)(=O)C>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([NH:41][C:42]2[N:44]=[CH:3][C:4]3[CH2:5][CH2:6][CH2:7][C:8]([CH3:17])([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:9]=3[N:43]=2)[CH:32]=[CH:33][C:34]=1[N:35]1[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CN(C)C=C1CCCC(C)(c2ccccc2)C1=O
Solvent: CCN(CC)CC
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: COc1cc(Nc2ncc3c(n2)C(C)(c2ccccc2)CCC3)ccc1-n1cnc(C)c1
Yield: 19 %

Procedure:
A mixture of 6-[1-dimethylamino-methylidene]-2-methyl-2-phenylcyclohexanone (103 mg, 0.42 mmol), N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (157 mg, 0.42 mmol), and triethylamine (0.29 mL, 2.1 mmol) in ethanol (1 mL) was heated at reflux for 18 h. The mixture was cooled, diluted with ethyl acetate (30 mL) and then washed with saturated aqueous sodium carbonate solution (10 mL) and with brine (10 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residual material was purified by column chromatography on silica gel using dichloromethane/methanol (20:1 v/v) as eluent to give the title compound (34 mg, 19%). MS ISP (m/e): 426.1 [(M+H)+]. mp 207-209° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:8]=2)[CH:3]=[CH:2]1.[CH3:20]N1C2C(=CC=C(SC)C=2)C=C1.CSC1C=C2C(C=CN2)=CC=1>>[CH3:20][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:12])=[O:13])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=S(=O)(Oc1ccc2cc[nH]c2c1)c1ccccc1
Reactant: CSc1ccc2ccn(C)c2c1
Agent: CSc1ccc2cc[nH]c2c1
Product: Cn1ccc2ccc(OS(=O)(=O)c3ccccc3)cc21

Procedure:
Benzenesulfonic acid 1-methyl-1H-indol-6-yl ester was prepared from the known benzenesulfonic acid 1-H-indol-6-yl ester according to the procedure described above for the preparation of 1-methyl-6-methylsulfanyl-1H-indole from 6-methylsulfanyl-1H-indole.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:13])([O-:3])=[O:2].[CH2:14](Br)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[Na+].[Na+].Cl>O.CN(C)C=O>[CH2:31]([O:13][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 79.1 %

Procedure:
A mixture of 2,4-dinitrophenol (85 wt %, 6.72 g, 31 mmol), octadecyl bromide (20.7 g, 62 mmol), sodium carbonate (6.57 g, 62 mmol) and dimethylformamide (31 mL) was heated to 100° C. under a nitrogen atmosphere for 22 h. The cooled mixture was diluted with water (200 mL), acidified with 10N hydrochloric acid (50 mL) and extracted with ether. The extracts were washed with water and brine, and dried over magnesium sulfate. The solvent was removed and the solid recrystallized to give 1-octadecyloxy-2,4-dinitrobenzene (10.7 g, 79%): mp 63.5°-64.0° C.
Reaction SMILES: [CH3:1][C:2]1([CH2:8][OH:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[H-].[Na+].Cl[C:13]1[C:21]2[C:20]3[CH:22]=[C:23]([C:26]#[N:27])[N:24]=[CH:25][C:19]=3[N:18]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:17]=2[N:16]=[CH:15][CH:14]=1>O1CCOCC1.CN(C)C=O.O.C(OCC)(=O)C>[CH3:1][C:2]1([CH2:8][O:9][C:13]2[C:21]3[C:20]4[CH:22]=[C:23]([C:26]#[N:27])[N:24]=[CH:25][C:19]=4[N:18]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:17]=3[N:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(Cl)ccnc21
Reactant: CC1(CO)CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC1(COc2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)CCNCC1
Temperature: 40 °C

Procedure:
To a solution of (4-methylpiperidin-4-yl)methanol (989 mg, 7.7 mmol) in 1,4-dioxane (18 mL) and N,N-dimethylformamide (12 mL) was added sodium hydride as 60% dispersion in mineral oil (670 mg, 28 mmol). The reaction mixture was stirred at ambient temperature for 5 minutes before 4-chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (428 mg, 1.2 mmol) was added in one portion and the reaction mixture was heated at 40° C. for 18 hours. The cooled reaction mixture was diluted with water (20 mL) and ethyl acetate (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified flash chromatography (silica, 40 g, ISCO, 1-20% methanol in methylene chloride) to afford the title compound as an off-white solid, which was used in the next step without any further purification (300 mg, 56%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:22]1[N:27]=[C:26]([C:28]2[CH:29]=[N:30][N:31]3[CH:36]=[CH:35][N:34]=[CH:33][C:32]=23)[CH:25]=[N:24][CH:23]=1>CN(C=O)C.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[N:30]1[N:31]2[CH:36]=[CH:35][N:34]=[CH:33][C:32]2=[C:28]([C:26]2[N:27]=[C:22]([NH:1][C@@H:2]3[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]3)[CH:23]=[N:24][CH:25]=2)[CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: Clc1cncc(-c2cnn3ccncc23)n1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2cncc(-c3cnn4ccncc34)n2)C1
Temperature: 100 °C
Yield: 43.5 %

Procedure:
Tert-butyl (3R)-3-aminopiperidine-1-carboxylate (0.41 g, 2.05 mmol), tris(dibencylidenoacetone)dipalladium(0) (0.034 g, 0.037 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino) xanthene (0.043 g, 0.074 mmol) and cesium carbonate (0.848 g, 2.6 mmol) were added to a suspension of 3-(6-chloropyrazin-2-yl)pyrazolo[1,5-a]pyrazine (Preparation 29b, 0.43 g, 1.86 mmol)) in N,N′-dimethylformamide (10 mL) and the resulting mixture was purged with argon before being heated to 100° C. for 7 h. After cooling to ambient temperature, the reaction mixture was filtered though Celite®, eluting with methanol. The filtrate was evaporated and the residue was purified by flash chromatography (7:3 ethyl acetate/hexane to 100% ethyl acetate) to yield the title compound (0.320 g, 44%) as a greenish solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[N:15]([CH3:16])[CH:14]=[N:13][C:12]=2[CH3:17])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].O.Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[N:15]([CH3:16])[CH:14]=[N:13][C:12]=2[CH3:17])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: Cc1ncn(C)c1-c1ccc([N+](=O)[O-])c(Cl)c1
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ncn(C)c1-c1ccc(N)c(Cl)c1
Temperature: 40 °C
Yield: 71.7 %

Procedure:
5-(3-Chloro-4-nitrophenyl)-1,4-dimethyl-1H-imidazole (Preparation 160, 99 mg 0.39 mmole) was stirred in ethanol (3.6 mL) and 1M sodium dithionite in water (1.2 mL, 1.2 mmole) was added. The reaction was heated at 40° C. for 1 hour. 2M Hydrochloric acid (5 mL) was added and the reaction was heated at 50° C. for 1 hour. The solution was cooled and quenched with anhydrous sodium carbonate and the ethanol was evaporated. The solution was saturated with sodium chloride and extracted with ethyl acetate (4×6 mL). The organic layers were dried and evaporated to afford the title compound (62 mg, 71%). 1H-NMR (CD3OD, 500 MHz): δ 2.12 (s, 3H), 3.52 (s, 3H), 6.92 (d, J=8.20, 1H), 7.01 (d, J=1.89, 8.20 Hz, 1H), 7.18 (d, J=1.89 Hz, 1H), 7.53 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([C:12]([CH3:14])=O)[CH:9]([CH3:11])[CH3:10]>>[CH:9]([C:8]1[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:1][C:12]=1[CH3:14])([CH3:11])[CH3:10]
Reactant: Nc1ccccc1
Reactant: CC(=O)CC(C)C
Product: Cc1[nH]c2ccccc2c1C(C)C
Yield: 86 %

Procedure:
Aniline was reacted with methyl isobutyl ketone in the same way as in Example 3. 3-Isopropyl-2-methylindole was formed in a yield of 86% of the theoretical yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C[OH:16]>>[Cl:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[O:16])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ncccc2Cl)cc1
Reactant: CO
Product: O=Cc1ccc(-c2ncccc2Cl)cc1
Temperature: 25 °C
Yield: 60 %

Procedure:
{circle around (2)} 100 g (0.49 mol) of 3-chloro-2-para-tolylpyridine was dissolved in 0.5 L of methanol in a reactor. A solution of 537 g (0.98 mol) of ceric ammonium nitrate in 1 L of methanol was added dropwise, and the mixture was refluxed for 4˜6 hours. The reaction solution was cooled to 25° C. and concentrated under reduced pressure. A 10% sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, and concentrated under reduced pressure, yielding 4-(3-chloropyridin-2-yl)benzaldehyde as represented below in a 60% yield.
Reaction SMILES: [CH3:1][C:2]([NH:4][CH2:5][CH2:6][C:7]1[C:11]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=2[NH:9][CH:8]=1)=[O:3].[I:18]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[C:2]([NH:4][CH2:5][CH2:6][C:7]1[C:11]2[C:10](=[CH:15][CH:14]=[C:13]([O:16][CH3:17])[CH:12]=2)[NH:9][C:8]=1[I:18])(=[O:3])[CH3:1]
Reactant: COc1ccc2[nH]cc(CCNC(C)=O)c2c1
Reactant: O=C1CCC(=O)N1I
Solvent: ClC(Cl)Cl
Product: COc1ccc2[nH]c(I)c(CCNC(C)=O)c2c1
Temperature: -20 °C
Reaction time: 4.5 h

Procedure:
To a solution of melatonin (2.32 g: 10 mM) in chloroform (70 ml) cooled at -20° C. there is added N-iodosuccinimide (NIS:2.25 g; 10 nM); the reaction mixture is stirred at -20° C. for 4.5 hours.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:8][CH:7]([O:9][C:10]2[C:15]([CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:14][C:13]([F:22])=[CH:12][N:11]=2)[CH2:6]1)=[O:4].[OH-].[Li+].Cl>CO.O>[F:22][C:13]1[CH:14]=[C:15]([CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:10]([O:9][CH:7]2[CH2:8][CH:5]([C:3]([OH:4])=[O:2])[CH2:6]2)=[N:11][CH:12]=1
Reactant: COC(=O)C1CC(Oc2ncc(F)cc2C2CCOCC2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1CC(Oc2ncc(F)cc2C2CCOCC2)C1
Temperature: 50 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
To a solution of 3-[5-fluoro-3-(tetrahydro-pyran-4-yl)-pyridin-2-yloxy]-cyclobutanecarboxylic acid methyl ester (3.2 g) in MeOH (60 mL) and water (15 mL) at RT was added lithium hydroxide (1.0 g, 41.6 mmol). The reaction mixture was heated to 50° C. for 2 h and then additional LiOH (400 mg) was added. Stirring was continued at 50° C. for 1 h. The reaction was neutralized with 5 M HCl and concentrated. The concentrated solution was extracted with EtOAc (50 mL) and the organic layer was washed with water (10 mL), brine (10 mL), dried over MgSO4 and concentrated to give the product (1.5 g), which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:25])[CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][CH:16]2[S:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])=[CH:13][CH:12]=1.CS(C)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C(N(CC)CC)C>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:25])[CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][CH:16]2[S:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])=[CH:13][CH:12]=1
Reactant: O=C1NC(=O)C(Cc2ccc(OCC(O)c3ccccc3F)cc2)S1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1NC(=O)C(Cc2ccc(OCC(=O)c3ccccc3F)cc2)S1
Temperature: 0 °C
Reaction time: 3 h
Yield: 66.1 %

Procedure:
To a stirring solution of 5-{4-[2-(2-fluorophenyl)-2-hydroxyethoxy]benzyl}-1,3-thiazolidine-2,4-dione (0.29 g, 0.80 mmol) in DCM (15 ml) was added DMSO (0.5 ml) and the solution was cooled to 0° C. Phosphorus pentoxide (0.23 g, 0.80 mmol) was added, followed by triethylamine (0.50 mL, 3.6 mmol). The reaction was allowed to slowly warm to RT. After 3 hours, water was added and the phases were separated. The pH of the aqueous phase was adjusted to ca. 7 and the aqueous phase was extracted with DCM. The combined organic phases were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting white solid was chromatographed on a small silica gel column eluting with 10% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 0.19 g (66%) of the title compound as a white solid. MS (ESI−) for C18H14FNO4S m/z 358.0 (M−H)−.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[C:6]1([C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[C:12]([S:5][CH2:4][CH2:3][NH2:2])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCCS
Agent: Cl
Product: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
2-Aminoethanethiol hydrochloride (1.0 g, 8.6 mmol) was dissolved in acetic trifluoride (10 ml) and added with triphenylmethanol (2.32 g, 8.6 mmol). The resulting solution was stirred at room temperature for 1 hr and concentrated by distilling under reduced pressure. The filtrate was diluted with ethyl acetate (50 ml) and washed with 3 M sodium hydroxide aqueous solution, water, saturated sodium bicarbonate aqueous solution, saturated sodium chloride aqueous solution in sequence. The organic phase was dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain a white solid of 2-(tritylsulfanyl)-1-ethaneamine (2.32 g, 7.3 mmol, 85.2%).
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C@@H:10]([C@@H:21]([O:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=2)[CH3:22])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[F:20][C:15]1[CH:14]=[C:13]([C@H:11]2[CH2:12][NH:8][CH2:9][C@@H:10]2[C@@H:21]([O:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=2)[CH3:22])[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: C[C@H](Oc1ccc(C#N)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Oc1ccc(C#N)cn1)[C@H]1CNC[C@@H]1c1ccc(F)c(F)c1
Temperature: 100 °C
Yield: 85.4 %

Procedure:
To a solution of 6-{(S)-1-[(3R,4S)-1-benzyl-4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethoxy}-nicotinonitrile—66 mg (0.16 mmol) dissolved in toluene (2 mL) were added 67 mg (0.47 mmol) of 1-chloroethyl chloroformate and 61 mg (0.47 mmol) of Hunig's base. The reaction mixture was heated at 100° C. for one hour. After cooling down to RT, volatiles were removed under vacuo and the crude was dissolved in MeOH (10 mL). The reaction mixture was heated at 85° C. for 30 minutes and after cooling down to RT, volatiles were removed under vacuo and the residue was directly purified on column chromatography (SiO2, CH2Cl2/MeOH 9:1) yielded 45 mg (85%) of the title compound as a light yellow oil. ES-MS m/e: 330.3 (M+H+).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([C:8]2[CH:9]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]=[CH:12][C:13]=2[O:14][CH3:15])=[O:7])[N:3]=[CH:2]1.[CH:22]([Mg]Cl)([CH3:24])[CH3:23].[Cl-].[NH4+]>C1COCC1.O>[NH:1]1[CH:5]=[C:4]([C:6]([C:8]2[CH:9]=[C:10]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:11]=[CH:12][C:13]=2[O:14][CH3:15])([OH:7])[CH:22]([CH3:24])[CH3:23])[N:3]=[CH:2]1
Reactant: COc1ccc(-c2ccccc2)cc1C(=O)c1c[nH]cn1
Reactant: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2ccccc2)cc1C(O)(c1c[nH]cn1)C(C)C
Temperature: -40 °C
Reaction time: 1 h

Procedure:
1H-Imidazol-4-yl(4-methoxy[1,1′-biphenyl]-3-yl)methanone (0.62 g) was dissolved in THF (15 ml) and the mixture was cooled to −40° C. A solution (0.6 M; 15 ml) of isopropyl magnesium chloride in THF was slowly added dropwise and the mixture was warmed to room temperature. The mixture was stirred for 1 h and thereto was added saturated aqueous ammonium chloride solution. The mixture was diluted with water and extracted with ethyl acetate. The extract was dried and concentrated. The obtained residue was purified by silica gel column chomatography (eluent, dichloromethane:methanol=40:1) to give the colorless amorphous title compound (0.16 g).
Reaction SMILES: C(N(CC)CC)C.[I-].[Cl:9][C:10]1[C:25]([Cl:26])=[CH:24][C:13]2[N+:14]([CH2:22][CH3:23])=[C:15]([CH:19]=NO)[N:16]([CH2:17][CH3:18])[C:12]=2[CH:11]=1.[Cl:27]([O-:31])(=[O:30])(=[O:29])=[O:28].Cl[C:33](C)=[CH:34][C:35]1[S:36][C:37]2[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=2[N+:39]=1[CH2:40][CH3:41].C(OC(=O)C)(=O)C>C(#N)C.CCOCC>[Cl:27]([O-:31])(=[O:30])(=[O:29])=[O:28].[Cl:26][C:25]1[C:10]([Cl:9])=[CH:11][C:12]2[N+:16]([CH2:17][CH3:18])=[C:15]([C:19]#[C:33][CH:34]=[C:35]3[N:39]([CH2:40][CH3:41])[C:38]4[CH:42]=[CH:43][CH:44]=[CH:45][C:37]=4[S:36]3)[N:14]([CH2:22][CH3:23])[C:13]=2[CH:24]=1
Reactant: CC[n+]1c(C=C(C)Cl)sc2ccccc21
Reactant: CCn1c(C=NO)[n+](CC)c2cc(Cl)c(Cl)cc21
Agent: [I-]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(=O)OC(C)=O
Solvent: CC#N
Solvent: CCOCC
Product: CCN1C(=CC#Cc2n(CC)c3cc(Cl)c(Cl)cc3[n+]2CC)Sc2ccccc21
Reaction time: 0.08 h

Procedure:
Triethylamine (2.8 ml; 0.02 mol) is added to a stirred suspension of 5,6-Dichloro-1,3-diethyl-2-hydroxyiminomethyl benzimidazolium iodide (1.83 g, 0.005 mol), 2-(2-chloropropenyl)-3-ethyl benzothiazolium perchlorate and acetic anhydride (0.64 g, 0.006 mol) in acetonitrile (25 ml). The mixture is stirred for 5 minutes, then diluted to 200 ml with ether. The ether is decanted and the residue treated with methanol (25 ml) and chilled. After recrystallization from methanol, the yield of purified dye is 0.37 g (14%) mp indistinct.
Reaction SMILES: [BH4-].[Na+].Br.[Br:4][C:5]1[S:13][C:8]2[CH2:9][NH:10][CH2:11][CH2:12][C:7]=2[CH:6]=1.[C:14](O)(=O)[CH3:15]>O1CCCC1>[Br:4][C:5]1[S:13][C:8]2[CH2:9][N:10]([CH2:14][CH3:15])[CH2:11][CH2:12][C:7]=2[CH:6]=1
Reactant: Brc1cc2c(s1)CNCC2
Reactant: CC(=O)O
Agent: Br
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CCc2cc(Br)sc2C1
Temperature: 0 °C
Yield: 96 %

Procedure:
Sodium borohydride (146 mg, 3.85 mmol) was added to cooled (0° C.) a suspension of 2-bromo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine hydrobromide (230 mg, 0.77 mmol) in acetic acid (1.5 mL) and tetrahydrofuran (2.8 mL). On complete addition the mixture was heated to 60° C. for 3 h. The mixture was allowed to cool to ambient temperature then partitioned between ethyl acetate and water. The pH of the aqueous phase was adjusted to 10 by the addition of 3N sodium hydroxide solution and the layers separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated to give the title compound as a yellow oil (181 mg, 96%). 1H NMR (DMSO-D6, 300 MHz): 6.93 (s, 1H), 3.50-3.47 (m, 2H), 3.66-2.46 (m, 6H), 1.05 (t, J=7.2 Hz, 3H). LCMS (Method B): RT=1.79 min, M+H+=246/248.