Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].CO[CH:4]([O:12]C)[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1.Br[C:15]1[S:16][CH:17]=[CH:18][N:19]=1.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[S:16]1[CH:17]=[CH:18][N:19]=[C:15]1[C:8]1[CH:7]=[CH:6][C:5]([CH:4]=[O:12])=[CH:10][CH:9]=1
Reactant: Brc1nccs1
Reactant: COC(OC)c1ccc(Br)cc1
Agent: [Mg]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(-c2nccs2)cc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Under argon, 9.2 g (379 mmol) of magnesium are placed in 84 ml of THF and heated to 60° C. A solution of 82.6 g (357 mmol) of 4-bromobenzaldehyde dimethyl acetal (for preparation see J. Org. Chem. 56, 4280 (1991)) in 677 ml of THF is added dropwise thereto within a period of 30 min and the mixture is stirred at boiling temperature for a further 40 min. The Grignard solution is cooled, decanted into a dropping funnel and added dropwise within a period of 30 min to a reddish suspension of 31.7 ml (338 mmol) of 2-bromothiazole (Fluka, Buchs, Switzerland) and 5.39 g (9.95 mmol) of DPPP in 1.68 liters of THF. The mixture is stirred at room temperature for 12 hours; a further 5.39 g of DPPP are added and the mixture is stirred for a further 7 hours. 840 ml of water are added and the mixture is stirred for 10 min; the THF is evaporated off using a rotary evaporator and the residue is stirred for 1.5 hours in 1.0 liter of ether and 340 ml of 2N HCl. The aqueous phase is separated off and extracted 2× with ethyl acetate. The organic phases are washed 2× with 0.5N HCl, water, sat. NaHCO3 solution, water and brine, dried (Na2SO4) and concentrated by evaporation. Chromatography (SiO2 ; hexane/ethyl acetate 4:1) and digestion in hexane yield the title compound: TLC: Rf =0.21 (hexane/ethyl acetate 3:1); m.p: 91-92° C.; Anal. (C10H7NOS) calc. C 63.47, H 3.73, N 7.40, S 16.94: found C 63.14, H 3.79, N 7.27, S 17.08; 1H-NMR (CDCl3) δ 10.05(S, HCO), 8.15 (d, J=8, 2H), 7.95 (m, 3H), 7.45 (d, J=3, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][C@@H:12]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:13]([CH3:17])[C:14](O)=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[O:36][NH2:37]>C(Cl)Cl>[OH:36][NH:37][C:14](=[O:15])[C@@H:13]([CH3:17])[C@@H:12]([S:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(S[C@@H](CCCCc2ccccc2)[C@H](C)C(=O)O)cc1OC
Reactant: C[Si](C)(C)ON
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc(S[C@@H](CCCCc2ccccc2)[C@H](C)C(=O)NO)cc1OC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
(2R,3S)-3-(3,4-Dimethoxyphenylsulfanyl)-2-methyl-7-phenylheptanoic acid (0.46 g, 1.2 mmol) is dissolved in CH2Cl2 (4.5 mL) and cooled to 0° C. and to this is added 2 M oxalyl chloride in CH2Cl2 (1.9 mL, 3.8 mmol) over 5 minutes. The ice bath is removed and the reaction allowed to warm to room temperature. After 1.5 hours, the reaction is concentrated in vacuo and azeotroped with chloroform several times. The crude residue is dissolved in CH2Cl2 (4 mL) and O-trimethylsilylhydroxylamine (0.4 g, 3.6 mmol) is added slowly. After 5 minutes, the reaction is diluted with CH2Cl2 (20 mL) and washed with 2 N HCl (15 mL). The aqueous layer is back-extracted with CH2Cl2 (10 mL) and the combined organic layers are washed with water (50 mL), dried over MgSO4 and concentrated in vacuo. The crude residue is azeotroped with ether/petroleum ether and triturated with a large volume of petroleum ether to give (+)-(2R,3S)-3-(3,4-dimethoxyphenylsulfanyl)-2-methyl-7-phenylheptanoic acid hydroxyamide (0.45 g, 94%): [a]D23 +22° (c=1.0, CHCl3); 1H NMR (300 MHz, CD3OD) δ 7.25-7.21 (m, 2H), 7.15-7.10 (m, 3H), 7.05-6.98 (m, 2H), 6.87 (d, J=8.2 Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.17-3.14 (m,1H), 2.58-2.52 (m, 2H), 2.35-2.30 (m, 1H), 1.75-1.65 (m, 1H), 1.60-1.40 (m, 5H), 1.17 (d, J=7.0 Hz, 3H); MS (ion spray) m/e 404 (M+H)+ ; Anal. (C22H29NO4S) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.[CH2:16]([S:20][CH2:21][C:22](O)=[O:23])[CH2:17][CH2:18][CH3:19].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:22](=[O:23])[CH2:21][S:20][CH2:16][CH2:17][CH2:18][CH3:19])[CH:11]=1
Reactant: Fc1ccc(NCc2cccnc2)cc1
Reactant: CCCCSCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCSCC(=O)N(Cc1cccnc1)c1ccc(F)cc1

Procedure:
N-[(3-pyridyl)methyl]-N-(4-fluorophenyl)-α-(n-butylthio)acetamide was prepared by the method of Example 2 by reacting 10.1 g. of N-(4-fluorophenyl)-[(3-pyridyl)methyl]amine with 7.4 g. of α-(n-butylthio)acetic acid and 10.3 g. of N,N'-dicyclohexylcarbodiimide in 250 ml. of dichloromethane. Weight 6.5 g. as an oil.
Reaction SMILES: [F:1][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:4]=2[CH:3]=1.[C:13]([O:17][C:18](=[O:34])[C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][C:27]=2[CH3:33])=[CH:21][CH:20]=1)([CH3:16])([CH3:15])[CH3:14].C(OC(=O)C1C=CC=C(OC2C=CC(NC3C4C=C(F)N=CC=4N=CN=3)=CC=2C)C=1)(C)(C)C>>[C:13]([O:17][C:18](=[O:34])[C:19]1[CH:20]=[CH:21][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:9]3[C:4]4[CH:3]=[C:2]([F:1])[N:12]=[CH:11][C:5]=4[N:6]=[CH:7][N:8]=3)=[CH:28][C:27]=2[CH3:33])=[CH:23][CH:24]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: Cc1cc(N)ccc1Oc1ccc(C(=O)OC(C)(C)C)cc1
Reactant: O=c1[nH]cnc2cnc(F)cc12
Agent: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1Oc1cccc(C(=O)OC(C)(C)C)c1
Product: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1Oc1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared from 6-Fluoro-3H-pyrido[3,4-d]pyrimidin-4-one and 4-(4-Amino-2-methyl-phenoxy)-benzoic acid tert-butyl ester by a procedure analogous to the synthesis of 3-[4-(6-Fluoro-pyrido[3,4-d]pyrimidin-4-ylamino)-2-methyl-phenoxy]-benzoic acid tert-butyl ester above. LRMS: 447.3/391.2 (MH+); 1H NMR (DMSO-d6, 400 MHz): δ 10.03 (s, 1H), δ 8.90 (s, 1H), δ 8.65 (s, 1H), δ 8.24 (s, 1H), δ 7.75-7.87 (m, 4H), δ 7.07 (d, J=8.73, 1H), δ 6.90-6.93 (m, 2H), δ 2.12 (s, 3H), δ 1.49 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.[F:25][C:26]([F:31])([F:30])[CH2:27][NH:28][NH2:29]>>[F:25][C:26]([F:31])([F:30])[CH2:27][NH:28][NH:29][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4](/[CH:12]=[CH:13]/[C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=2)[CH:5]=1
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Reactant: NNCC(F)(F)F
Product: COc1ccc(C(=O)NNCC(F)(F)F)cc1/C=C/c1ccc(OC(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtained in step B of Example 2-2-1 and 2,2,2-trifluoroethylhydrazine in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [Li].[CH3:2][CH2:3][C:4](=[O:10])[CH2:5][C:6](=[O:9])[CH2:7][CH3:8].CN(C)C(=O)N(C)C.[CH2:19]([C:21](=[CH:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]2[O:34][CH2:35][O:36][C:30]=2[CH:29]=1)[CH2:22][CH2:23]I)[CH3:20]>>[CH2:19]([C:21](=[CH:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]2[O:34][CH2:35][O:36][C:30]=2[CH:29]=1)[CH2:22][CH2:23][CH:5]([C:4](=[O:10])[CH2:3][CH3:2])[C:6](=[O:9])[CH2:7][CH3:8])[CH3:20]
Reactant: CCC(=CCCc1ccc2c(c1)OCO2)CCI
Reactant: CCC(=O)CC(=O)CC
Agent: [Li]
Solvent: CN(C)C(=O)N(C)C
Product: CCC(=O)C(CCC(=CCCc1ccc2c(c1)OCO2)CC)C(=O)CC

Procedure:
A solution of 15 g. of the lithium salt of 3,5-heptanedione (prepared as described in Example 3 below) in 100 ml. of tetramethylurea was stirred under nitrogen at room temperature, and 10 g. of 3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl iodide (Preparation D1) was added. The reaction mixture was stirred for forty-eight hours, then concentrated to remove the solvent, and the residue slurried in ether and treated with excess glacial acetic acid. Water was added, the ether layer separated, washed with water and concentrated. The residue was distilled in a molecular still to remove volatile material at 110° C. (0.001 mm.), and the non-volatile residue was chromatographed on 10 g. of activated magnesium silicate in benzene solution and eluted with ethyl acetate to give 4-[3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]-3,5-heptanedione as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[N:28][OH:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)=[CH:8][CH:7]=1)=[N:4][OH:5].N1C(C)=CC=CC=1C.Cl[CH2:41][CH2:42][S:43](Cl)(=[O:45])=[O:44].Cl>C(Cl)Cl>[CH:42]([S:43]([OH:45])(=[O:5])=[O:44])=[CH2:41].[F:1][C:2]([F:30])([F:31])[C:3]([C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[N:28][O:29][S:43]([CH:42]=[CH2:41])(=[O:45])=[O:44])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)=[CH:10][CH:11]=1)=[N:4][OH:5]
Reactant: O=S(=O)(Cl)CCCl
Reactant: ON=C(c1ccc(OCCCOc2ccc(C(=NO)C(F)(F)F)cc2)cc1)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C=CS(=O)(=O)O
Product: C=CS(=O)(=O)ON=C(c1ccc(OCCCOc2ccc(C(=NO)C(F)(F)F)cc2)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
In 30 mL of CH2Cl2 are dissolved 3.0 g (6.66 mmol) of 2,2,2-Trifluoro-1-(4-{3-[4-(2,2,2-trifluoro-1-hydroxyimino-ethyl)-phenoxy]-propoxy}-phenyl)-ethanone oxime, which is prepared according to the method described in GB 2348644, and the solution is cooled in an ice-bath. To the solution are added successively 2,6-lutidine (3.5 mL, 30.0 mmol) and 2-chloroethanesulfonyl chloride (1.55 mL, 14.7 mmol), and the reaction solution is stirred at 0° C. for 1 h and at room temperature for 2.5 h. Then, it is poured into 1N HCl. The crude product is extracted with CH2Cl2, washed with 1N HCl, dried over MgSO4 and concentrated. The residue is purified by recrystallizaffon from methanol to afford the product as a beige solid. The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ [ppm]: 2.32 (m, 2H), 4.23 (t, 4H), 6.32 (d, 2H), 6.61 (d, 2H), 6.72 (dd, 2H), 7.00 (d, 4H), 7.50 (d, 4H). mp. 84-88° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]2[O:14][CH:3]12.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[S:24][C:23]([NH2:25])=[N:22][C:21]=2[CH:26]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[S:24][C:23]([NH:25][CH:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=4)[O:11][C:2]([CH3:15])([CH3:1])[CH:3]3[OH:14])=[N:22][C:21]=2[CH:26]=1
Reactant: Nc1nc2cc(Cl)ccc2s1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Product: CC1(C)Oc2ccc(C#N)cc2C(Nc2nc3cc(Cl)ccc3s2)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 5-chloro-benzothiazol-2-ylamine as starting material, the title compound was prepared as a white solid.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[N:8]=[N:7][C:6]([C:9]([O:11]CCCC)=O)=[CH:5][CH:4]=1>CO>[Cl:2][C:3]1[N:8]=[N:7][C:6]([C:9]([NH2:1])=[O:11])=[CH:5][CH:4]=1
Reactant: CCCCOC(=O)c1ccc(Cl)nn1
Reactant: N
Solvent: CO
Product: NC(=O)c1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.5 %

Procedure:
Excess gaseous ammonia was added to an ice bath cooled solution of n-butyl 6-chloropyridazine-3-carboxylate (40 g) in methanol (280 ml). The mixture was stirred at ambient temperature for 4 hours and the resulting residue filtered off, washed with methanol (20 ml) and dried to give 6-chloropyridazine-3-carboxamide (28.05 g, 95.5% yield), mpt. 243-5° C.
Reaction SMILES: CC(OC([NH:8][C@H:9]([C:16]([OH:18])=[O:17])[CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=O)(C)C.[CH2:19]([O:26][C:27](=[O:33])[C@@H:28]1[CH2:32][CH2:31][CH2:30][NH:29]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.O1CCOCC1.C(Cl)(Cl)[Cl:42].C(OCC)C>O1CCOCC1.CO>[CH3:15][S:12]([CH2:11][CH2:10][C@H:9]([NH2:8])[C:16]([OH:18])=[O:17])(=[O:13])=[O:14].[ClH:42].[CH2:19]([O:26][C:27](=[O:33])[C@@H:28]1[CH2:32][CH2:31][CH2:30][NH:29]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: ClC(Cl)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CCS(C)(=O)=O)C(=O)O
Agent: Cl
Agent: O=C(OCc1ccccc1)[C@@H]1CCCN1
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CO
Product: CS(=O)(=O)CC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-Boc-L-methionine sulfone-L-proline-O-benzyl ester (23.5 g, 50 mmole) in dry dioxane (300 mL) was added 100 mL of a 4M HCl/dioxane solution. The mixture was then stirred at room temperature for 1 hour until the starting material disappeared as shown by thin layer chromatography analysis (silica, 10% chloroform in methanol). Diethyl ether was added to the mixture to precipitate the title compound as a white hydrochloride salt. The mixture was filtered on a Buchner funnel and the solid was then dried under high vacuum to give 20.16 g (100%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].N1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[O:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[C:21]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:13])(=[O:20])[CH2:22][CH2:23][CH2:24][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:19]#[C:18][C:17]#[C:16][CH2:15][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: c1ccncc1
Reactant: C1CCOC1
Reactant: OCCOCCOCCOCCO
Product: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)OCCOCCOCCOCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
10,12-Tricosadiynoic acid (2.50 g, 0.007 mol) in tetrahydrofuran (30 ml) was reacted with oxalyl chloride (2.25 g, 0.017 mol) to obtain the corresponding acid chloride. This acid chloride (2.45 g, 0.007 mol) dissolved in anhydrous tetrahydrofuran (10 ml) was added dropwise to a mixture of tetraethylene glycol (1.32 g, 0.007 mol) and anhydrous pyridine (0.83 g, 0.01 mol) in anhydrous tetrahydrofuran (40 ml). The mixture was stirred overnight at room temperature. The precipitated pyridinium salt was filtered off and the solvent removed under vacuum. The resulting liquid was purified by flash chromatography (silica gel/ethyl acetate) to give 1.50 g (41%) of the title compound as a colourless oil. 1H NMR (60 MHz, CDCl3): δ0.88 (m, 3H, CH3CH2), 1.30 (m, 28H, CH2), 2.20 (m, 6H, CH2), 3.65 (s, 14H, 7×CH2O), 4.20 (m, 2H, CH2CO).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13]([CH3:15])=O.[C:16]([O:20][CH3:21])(=[O:19])[NH:17][NH2:18]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13](=[N:18][NH:17][C:16]([O:20][CH3:21])=[O:19])[CH3:15]
Reactant: CC(=O)c1nc(-c2ccccc2)[nH]c1C
Reactant: COC(=O)NN
Solvent: Cc1ccccc1
Product: COC(=O)NN=C(C)c1nc(-c2ccccc2)[nH]c1C

Procedure:
Methyl 5-methyl-2-phenyl-4-imidazolyl ketone (4.5 gm., 0.023 mole) is refluxed with methyl carbazate (2.4 gm., 0.023 mole) in toluene (112 ml.) for 5 hours. The toluene is removed, and the solid washed with water (3×50 ml.). The solid is recrystallized from methanol to yield the product (1.28 gm., 20.9%), m.p. 201°-201.5° C.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH:9]([CH2:17][CH3:18])[CH2:10][S:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].O>CS(C)=O>[O:8]=[C:9]([CH2:17][CH3:18])[CH2:10][S:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: CCC(O)CSCC(=O)OC
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: CCC(=O)CSCC(=O)OC
Reaction time: 1 h

Procedure:
Triethylamine (28.3 ml) is added to a solution of methyl 2-(2-hydroxybutylthio)acetate (6.00 g, Reference compound No. 35-1) in dimethyl sulfoxide (180 ml). A sulfur trioxide-pyridine complex (20.0 g) is added to the mixture, and the whole is stirred for one hour. Water is added to the reaction mixture, and the whole is stirred for 20 minutes and extracted with ethyl acetate. The extract is washed with water, 1 N hydrochloric acid and saturated brine successively and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled reference compound (5.93 g).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[C:7]([NH:10][CH2:11][C@@H:12]1[O:16][C:15](=[O:17])[N:14]([C:18]2[CH:23]=[CH:22][C:21]([S:24][CH2:25][CH2:26][OH:27])=[C:20]([F:28])[CH:19]=2)[CH2:13]1)(=[O:9])[CH3:8]>O.CO>[C:7]([NH:10][CH2:11][C@@H:12]1[O:16][C:15](=[O:17])[N:14]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH2:25][CH2:26][OH:27])=[O:2])=[C:20]([F:28])[CH:19]=2)[CH2:13]1)(=[O:9])[CH3:8]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(SCCO)c(F)c2)C(=O)O1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(S(=O)CCO)c(F)c2)C(=O)O1
Reaction time: 8 h

Procedure:
Sodium periodate (0.014 g, 0.065 mmol) in water (0.5 mL) was added to 5-(S)-acetamidomethyl-3-[4′-(2″-hydroxyethyl)thio-3′-fluorophenyl]-oxazo-lidine-2-one (0.020 g, 0.061 mmol) in methanol (1 mL), and the mixture was stirred at r.t overnight. Solvent was removed under vacuum, and the residue dissolved in ethyl acetate (ca. 5 mL). Resulting solution was washed with water, brine, and dried (MgSO4). Solvent was removed under vacuum, and the crude product purified by TLC (eluent: 10% methanol in dichloromethane). Yield 0.018 g (86%). MS (m/z): 345 [M+H]+. 1H NMR.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:9]=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[C:12]([OH:14])[CH:13]=1.COC(=O)[C:21](Cl)([F:23])[F:22].O>CN(C)C=O>[F:22][CH:21]([F:23])[O:14][C:12]1[CH:13]=[C:8]([F:7])[CH:9]=[CH:10][C:11]=1[N+:15]([O-:17])=[O:16]
Reactant: COC(=O)C(F)(F)Cl
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(F)cc1OC(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 71.9 %

Procedure:
Potassium carbonate (2.42 g, 17.5 mmol) was added to a solution of 5-fluoro-2-nitrophenol (785 mg, 5.00 mmol) in N,N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for 20 min. Chlorodifluoroacetic acid methyl ester (1.33 mL, 12.5 mmol) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 30 min and then stirred at an external temperature of 90° C. for 3 hr. After cooling, water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate and then the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→4:1) to afford 2-(difluoromethoxy)-4-fluoro-1-nitrobenzene as a pale yellow oil (745 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=O)[CH2:10]2)(=[O:3])[CH3:2].[ClH:16].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][CH2:23][NH2:24].C([BH3-])#N.[Na+].Cl>CO.O>[ClH:16].[C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([NH:24][CH2:23][CH2:22][C:18]1[S:17][CH:21]=[CH:20][CH:19]=1)[CH2:10]2)(=[O:3])[CH3:2]
Reactant: NCCc1cccs1
Reactant: CC(=O)Nc1cccc2c1CCC(=O)C2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)Nc1cccc2c1CCC(NCCc1cccs1)C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.03 g of (0.01 mol) of 5-acetylamino-2-tetralone, 3.2 g (0.02 mol) of 2-(2-thienyl)-ethyl-aminehydrochloride and 0.75 g (0.012 mol) of sodium cyanoborohydride are dissolved in 30 ml of methanol and stirred for 24 hours at ambient temperature. The mixture is then acidified by the dropwise addition of conc. hydrochloric acid with stirring and cooling with ice. After 10 minutes, 100 ml of water is added whilst stirring continues and then a total of 4.0 g of anhydrous soda is added in batches. Then extraction is carried out with 50 ml of methylene chloride and twice with 25 ml of methylene chloride. The combined extracts are washed with 20 ml of water, dried with sodium sulphate and after separation of the drying agent, concentrated by evaporation in a rotary evaporator, finally at 90° C. and under a complete water-jet vacuum. The residue is dissolved with 5 ml of methanol and 4.0 ml of 2.5 N ethanolic hydrochloric acid and the solution is mixed with diethylether until turbidity is just beginning. After standing for a period of about 12 hours at 5° C. the title compound is suction filtered, washed with ethanol/ether and dried at 80° C. until the weight remains constant. Yield: 3.1 g (88.3% of theory), melting point 276° C. (unchanged after recrystallisation from methanol/ether).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[N:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][C:42]=2[S:44](Cl)(=[O:46])=[O:45])[CH:37]=[CH:36][CH:35]=1.O>ClCCl>[CH3:25][C:21]([C:18]1[CH:17]=[CH:16][C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([S:44]([C:42]3[CH:41]=[CH:40][CH:39]=[C:38]4[C:43]=3[N:34]=[CH:35][CH:36]=[CH:37]4)(=[O:45])=[O:46])[C:13]2=[O:26])=[CH:20][CH:19]=1)([CH3:24])[C:22]#[N:23]
Reactant: Cc1ccc2ncc3[nH]c(=O)n(-c4ccc(C(C)(C)C#N)cc4)c3c2c1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc2ncc3c(c2c1)n(-c1ccc(C(C)(C)C#N)cc1)c(=O)n3S(=O)(=O)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 3, 100 mg, 0.29 mmol) and triethylamine (60 mg, 0.58 mmol) in dichloromethane (6 ml) was added quinoline-8-sulfonyl chloride (100 mg, 0.44 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 32 mg (20%); 1H NMR (DMSO-d6, 300 MHz): δ 9.468 (s, 1H), 8.700-8.729 (d, 1H, J=8.7 Hz), 8.539-8.558 (m, 2H), 8.449-8.479 (d, 1H, J=9 Hz), 7.974-8.004 (d, 1H, J=9 Hz), 7.864-7.916 (t, 1H), 7.716-7.744 (d, 2H, J=8.4 Hz), 7.519-7.600 (q, 1H), 7.470-7.491 (m, 3H), 6.435 (s, 1H), 2.118 (s, 3H), 1.743 (s, 6H); MS: m/z 534 (M+).