Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:8]([O:4][CH2:3][CH2:2][S:1][CH2:5][CH2:6][OH:7])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OCCSCCO
Solvent: c1ccncc1
Product: O=C(OCCSCCO)c1ccccc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 59 %

Procedure:
A solution of 8.5 ml of 2,2'-thiodiethanol (thiodiethyleneglycol) in 100 ml of pyridine is placed at -5° C. under argon gasification and treated dropwise within 10 minutes with 9.5 ml of benzoyl chloride. Thereby, the resulting mixture warms to about +8° C. and towards the end of the addition white crystals begin to precipitate. Subsequently, the mixture is stirred at room temperature for a further 36 hours and then the majority of the pyridine is distilled off on a rotary evaporator. The semicrystalline residue is added to 100 ml of ice-cold 2N hydrochloric acid and extracted three times with 100 ml of diethyl ether each time. The organic phases are washed twice with 100 ml of water each time and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated. Low-pressure chromatography (0.5 bar) of the residue (about 14 g) on silica gel with the use of toluene/ethyl acetate (3:1) as the elution agent gives in succession 1.5 g (5.5 percent) of crystalline dibenzoate and 11 g (59 percent) of 2-[(2-hydroxyethyl)thio]ethyl benzoate as a colorless, viscous oil. After bulb-tube distillation (160°-170° C./0.20-0.16 mm Hg) of the latter, there are obtained 9.7 g (52.4 percent) of 2-[(2-hydroxyethyl)thio]ethyl benzoate in 99.4 percent purity; nD23 =1.5566.
Reaction SMILES: C([O:4][CH2:5][C@@:6]1([CH2:20][O:19][C@H:18]([CH2:21][O:22]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@@H:8]1[O:9]C(=O)C)[OH:7])(=O)C.C[O-].[Na+]>C(Cl)(Cl)Cl>[CH2:20]1[O:19][C@H:18]([CH2:21][OH:22])[C@@H:13]([OH:14])[C@H:8]([OH:9])[C@:6]1([OH:7])[CH2:5][OH:4]
Reactant: CC(=O)OC[C@H]1OC[C@@](O)(COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: OC[C@H]1OC[C@@](O)(CO)[C@@H](O)[C@@H]1O
Temperature: 0 °C
Reaction time: 3 h
Yield: 66.6 %

Procedure:
1,3,4,6-Tetra-O-acetyl-2,5-O-methylene-D-mannitol 17 (2.8 kg, 7.73 mol) was added to chloroform (14 lit.) in 25 lit. round bottom flask with mechanical stirring. The reaction mixture was cooled to 0° C., and 0.5% NaOMe solution (6.5 lit.) was added slowly. The reaction mixture was stirred for 3 hours. The solid was filtered and dried to provide 1.0 kg (67%) of 2,5-O-methylene-D-mannitol 18, m.p. 172°-173° C., [α]D520° (c 1.18, CHCl3), TLC (silica gel), 1:4, methanol: chloroform, Rf=0.8. 1H NMR (D20): δ3.42 (m, 2H), 3.72 (m, 4H), 3.97 (m, 2H), 4.91 (s, 2H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]2[O:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]=2[C:18]([CH3:37])([CH3:36])[CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[Na].[O:39]=[O:40]>ClCCl>[C:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]23[O:40][O:39][C:12]2([C:18]([CH3:36])([CH3:37])[CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:13]([CH3:16])([CH3:17])[CH2:14][O:15]3)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=O
Reactant: CCOC(=O)CCCCCCCCCCOCC(C)(C)C1=C(c2cccc(OC(C)=O)c2)OCC1(C)C
Agent: [Na]
Solvent: ClCCl
Product: CCOC(=O)CCCCCCCCCCOCC(C)(C)C12OOC1(c1cccc(OC(C)=O)c1)OCC2(C)C

Procedure:
5-(3-acetoxyphenyl)-4-(13-ethoxycarbonyl-1,1-dimethyl-3-oxatridecan-1-yl)-3,3-dimethyl-2,3-dihydrofuran (compound (24)) (57.8 mg, 0.112 mmol) and TPP (0.6 mg) were added to dichloromethane (6 mL), and the mixture was irradiated with visible light by a 940 W sodium lamp in an oxygen atmosphere at 0° C. for 30 minutes. The reaction mixture was concentrated, and the concentrate was put into a silica gel column and developed with a mixed solvent of hexane and ethyl acetate (10:1 to 5:1), whereby 1-(3-acetoxyphenyl)-5-(13-ethoxycarbonyl-1,1-dimethyl-3-oxatridecan-1-yl)-4,4-dimethyl-2,6,7-trioxabicyclo[3.2.0]heptane (compound (25)) was obtained as a colorless oil in an amount of 46 mg in a yield of 75.0%.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:16]2[C:11](=[CH:12][CH:13]=[N:14][CH:15]=2)[N:10]2[C:17]3[C:7]([C:8]4[CH:21]=[C:20](B(O)O)[CH:19]=[CH:18][C:9]=42)=[CH:6][CH:5]=[CH:4][C:3]1=3.[C:26]1(C2C=CC=CC=2)[CH:31]=[CH:30][C:29]([N:32]([C:40]2[CH:45]=[CH:44][C:43](C3C=CC=CC=3)=[CH:42][CH:41]=2)[C:33]2[CH:38]=[CH:37][C:36](Br)=[CH:35][CH:34]=2)=[CH:28][CH:27]=1>>[CH3:1][C:2]1([CH3:25])[C:16]2[C:11](=[CH:12][CH:13]=[N:14][CH:15]=2)[N:10]2[C:17]3[C:7]([C:8]4[CH:21]=[C:20]([C:43]5[CH:42]=[CH:41][C:40]([N:32]([C:33]6[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=6)[C:29]6[CH:30]=[CH:31][CH:26]=[CH:27][CH:28]=6)=[CH:45][CH:44]=5)[CH:19]=[CH:18][C:9]=42)=[CH:6][CH:5]=[CH:4][C:3]1=3
Reactant: CC1(C)c2cnccc2-n2c3ccc(B(O)O)cc3c3cccc1c32
Reactant: Brc1ccc(N(c2ccc(-c3ccccc3)cc2)c2ccc(-c3ccccc3)cc2)cc1
Product: CC1(C)c2cnccc2-n2c3ccc(-c4ccc(N(c5ccccc5)c5ccccc5)cc4)cc3c3cccc1c32

Procedure:
The compound is synthesised by the same procedure as Example 7 by reaction of 36 g (110 mmol) of 8,8-dimethyl-8H-10,12b-diazabenzo[a]aceanthrylene-3-boronic acid with 52 g (110 mmol) of bis-biphenyl-4-yl(4-bromophenyl)amine. The residue is recrystallised from toluene and from CH2Cl2/isopropanol and finally sublimed in a high vacuum. Yield: 65 g (95 mmol), 88% of theory, purity according to HPLC 99.9%.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][C:13]([NH:15][CH2:16][C@@H:17]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:14])C1C=CC=CC=1>[Pd].C(O)C>[C:25]([O:24][C:22](=[O:23])[NH:21][CH2:20][CH2:19][CH2:18][C@H:17]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:16][NH:15][C:13](=[O:14])[CH2:12][CH2:11][NH2:10])([CH3:27])([CH3:28])[CH3:26]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CNC(=O)CCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCC[C@@H](CNC(=O)CCN)NC(=O)OC(C)(C)C
Reaction time: 12 h

Procedure:
40 mg of palladium on activated carbon (10%) are added to a mixture of 0.215 g (0.41 mmol) of the compound from Example 242A in 10 ml of ethanol, and the mixture is then hydrogenated under atmospheric pressure for 12 h. The reaction mixture is filtered through kieselguhr, and the filtrate is concentrated in vacuo and dried under high vacuum. The crude product is reacted without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25](O)=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1)[CH3:29]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)[CH2:24][C:25]([N:30]([CH2:28][CH3:29])[CH2:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]=2)=[O:26])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Reactant: CCNCc1ccc2ccccc2n1
Product: CCN(Cc1ccc2ccccc2n1)C(=O)CN(c1cccc(N(C)C)c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid with ethyl-quinolin-2-ylmethyl-amine
Reaction SMILES: [CH:1]([CH:4]1[C:9](=[S:10])[N:8]([CH2:11][C:12]([O:14]C)=[O:13])[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[O:5]1)([CH3:3])[CH3:2].Cl>[OH-].[Na+].O>[CH:1]([CH:4]1[C:9](=[S:10])[N:8]([CH2:11][C:12]([OH:14])=[O:13])[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[O:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)CN1C(=S)C(C(C)C)Oc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)C1Oc2ccccc2N(CC(=O)O)C1=S
Reaction time: 0.25 h

Procedure:
To a solution of methyl 3,4-dihydro-2-isopropyl-3-thioxo-2H-1,4-benzoxazine-4-acetate (16.7 g) in methanol-dioxane (2:3, 150 ml), 2N NaOH (60 ml) was added dropwise in 10 minutes with stirring. After completion of the addition, stirring was continued for further 15 minutes, and the mixture was diluted with water, acidified with 2N HCl, and subjected to extraction with ethyl acetate. The extract was washed with water, and dried (MgSO4), from which the solvent was evaporated off. To the residue, hexane was added, to give crystals of 3,4-dihydro-2-isopropyl-3-thioxo-2H-1,4-benzoxazine-4-acetic acid. Yield was 12.6 g (79.2%). Recrystallization from isopropyl ether-hexane gave yellow prisms (mp 99°-100° C.). Yield was 11.2 g (70.6%).
Reaction SMILES: [CH:1]1([N:4]2[C:9](=[O:10])[C:8]3[C:11](OS(C4C=CC(C)=CC=4)(=O)=O)=[CH:12][C:13](=[O:16])[N:14]([CH3:15])[C:7]=3[N:6]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:29]=3)[C:5]2=[O:39])[CH2:3][CH2:2]1.[F:40][C:41]1[CH:47]=[C:46]([Br:48])[CH:45]=[CH:44][C:42]=1[NH2:43]>>[Br:48][C:46]1[CH:45]=[CH:44][C:42]([NH:43][C:11]2[C:8]3[C:9](=[O:10])[N:4]([CH:1]4[CH2:3][CH2:2]4)[C:5](=[O:39])[N:6]([C:28]4[CH:29]=[C:30]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:31]=[CH:32][CH:33]=4)[C:7]=3[N:14]([CH3:15])[C:13](=[O:16])[CH:12]=2)=[C:41]([F:40])[CH:47]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(=O)n(C)c3c2c(=O)n(C2CC2)c(=O)n3-c2cccc(NS(C)(=O)=O)c2)cc1
Reactant: Nc1ccc(Br)cc1F
Product: Cn1c(=O)cc(Nc2ccc(Br)cc2F)c2c(=O)n(C3CC3)c(=O)n(-c3cccc(NS(C)(=O)=O)c3)c21
Temperature: 135 °C
Yield: 83.1 %

Procedure:
To toluene-4-sulfonic acid 3-cyclopropyl-1-(3-methanesulfonylaminophenyl)-8-methyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl ester 15 (3.5 g) obtained in Step 8 was added 2-fluoro-4-bromoaniline 16 (23 g), and the mixture was stirred under heating at 135° C. for 3 hrs. The reaction mixture was purified by column chromatography (chloroform:acetone=9:1) to give N-{3-[5-(4-bromo-2-fluoro-phenylamino)-3-cyclopropyl-8-methyl-2,4,7-trioxo-3,4,7,8-tetrahydro-2H-pyrido[2,3-d]pyrimidin-1-yl]phenyl}-methanesulfonamide 17 (3.0 g, 83%) as a white solid.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:11]1([C:17]2[CH:21]=[C:20]([NH2:22])[N:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(CC#N)(=O)C1C=CC=CC=1.N(C1C=CC=CN=1)N>>[C:11]1([C:17]2[C:21]3[C:4](=[O:6])[C:3]4[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=4)[NH:22][C:20]=3[N:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:18]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1cc(-c2ccccc2)nn1-c1ccccn1
Reactant: O=C(O)c1ccccc1I
Agent: N#CCC(=O)c1ccccc1
Agent: NNc1ccccn1
Product: O=c1c2ccccc2[nH]c2c1c(-c1ccccc1)nn2-c1ccccn1

Procedure:
Following the procedures described in Reference Example 2-5 and Example 2-12, the title compound was prepared from o-iodobenzoic acid and 3-phenyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine which was previously prepared from benzoylacetonitrile and 2-hydrazinopyridine following the method described in Reference Example 2-72 (58% yield).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([NH2:13])=[C:9]([CH:12]=1)[CH2:10][OH:11])(=[O:3])[CH3:2].O=[CH:15][C:16]([Cl:19])([Cl:18])[Cl:17]>C(OCC)C>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:13][CH:15]([C:16]([Cl:19])([Cl:18])[Cl:17])[O:11][CH2:10][C:9]=2[CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(N)c(CO)c1
Reactant: O=CC(Cl)(Cl)Cl
Solvent: CCOCC
Product: CC(=O)Oc1ccc2c(c1)COC(C(Cl)(Cl)Cl)N2
Reaction time: 0.08 h

Procedure:
5-Acetoxy-2-aminobenzyl alcohol (8.8 g.) was dissolved in dry diethyl ether (150 ml.), anhydrous chloral (9.6 ml.) was added with stirring over 5 minutes, and the mixture was stirred overnight at room temperature. The solvent was evaporated, and the residue crystallised on stirring with a mixture of methanol (50 ml.) and water (25 ml.) to give 6-acetoxy-1,2-dihydro-2-trichloromethyl-4H-benzo[d]-[1,3]-oxazine, m.p. 155°-157° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([S:15]([CH3:18])(=[O:17])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[C:4]([CH3:19])[C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][O:27][C:28]2[CH:41]=[CH:40][C:31]3[C@H:32]([CH2:35][C:36]([O:38]C)=[O:37])[CH2:33][O:34][C:30]=3[CH:29]=2)[CH:21]=1.[OH-].[Na+].Cl>C(O)C>[CH3:19][C:4]1[CH:5]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([S:15]([CH3:18])(=[O:17])=[O:16])[CH2:11][CH2:10]2)[CH:7]=[C:2]([CH3:1])[C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][O:27][C:28]2[CH:41]=[CH:40][C:31]3[C@H:32]([CH2:35][C:36]([OH:38])=[O:37])[CH2:33][O:34][C:30]=3[CH:29]=2)[CH:21]=1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CCN(S(C)(=O)=O)CC5)cc4C)c3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(OC2CCN(S(C)(=O)=O)CC2)cc(C)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Yield: 42.4 %

Procedure:
The crude (S)-methyl 2-(6-((2′,6′-dimethyl-4′-((1-(methylsulfonyl)piperidin-4-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 5a (28 mg, 0.05 mmol) was dissolved in 5 mL of ethanol, followed by addition of 1M aqueous sodium hydroxide solution (0.5 mL, 0.50 mmol). The reaction solution was reacted for 1 hour. 1M hydrochloric acid was added dropwise to the resulting solution to adjust the pH to 5, followed by extraction with ethyl acetate (20 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified using a method of preparative separation to obtain the title compound (S)-2-(6-((2′,6′-dimethyl-4′-((1-(methylsulfonyl)piperidin-4-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid 5 (12 mg, yield 44.0%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]Br>CC(O)=O>[NH2:1][C:2]1[C:10]([Br:12])=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: BrBr
Reactant: Nc1ccc(Cl)cc1C(=O)O
Solvent: CC(=O)O
Product: Nc1c(Br)cc(Cl)cc1C(=O)O
Temperature: 15 °C
Reaction time: 4 h
Yield: 79.8 %

Procedure:
To a solution of 200 g (1.05 mol) of 2-amino-5-chlorobenzoic acid in 3.4 L of HOAc at 15° C. was added dropwise 184 g (1.15 mol) of Br2. The mixture was stirred at 15° C. for 4 hrs, quenched slowly into 8 L of water, and extracted with 2×2 L of t-BuOMe. The combined extract was washed with water, dried over MgSO4 and concentrated. The crude product was treated with hot hexane, filtered and dried to give 210 g (80%) of 2-amino-3-bromo-5-chlorobenzoic acid as white solid. Mp. 225-2280° C. 1H NMR (DMSO-d6): δ7.70 (d, J=2.6 Hz, 1 H), 7.69 (d, J=2.6 Hz, 1 H), 6.8 (bs, 2 H). 13C NMR (DMSO-d6): δ168.16, 147.06, 136.25, 130.19, 118.22, 112.35,110.34. IR:3480 (m), 3350 (m), 2920 (s), 1670 (s) cm-1. Analysis calcd. for C7H5BrClNO2 : C, 33.53, H, 2.00, N, 5.59; Found: C, 33.63, H, 2.12, N, 5.70. ##STR22##
Reaction SMILES: [CH3:1][CH2:2][C:3]([NH:5][CH:6]1[C:25](=[O:26])[N:8]2[C:9]([C:22]([OH:24])=[O:23])=[C:10]([CH2:13][S:14][C:15]3[S:16][C:17]([CH2:20][NH2:21])=[N:18][N:19]=3)[CH2:11][S:12][C@H:7]12)=[S:4].C(N(CC)CC)C.[CH3:34][N:35]=[C:36]=[O:37]>O.O1CCCC1>[CH3:1][CH2:2][C:3]([NH:5][CH:6]1[C:25](=[O:26])[N:8]2[C:9]([C:22]([OH:24])=[O:23])=[C:10]([CH2:13][S:14][C:15]3[S:16][C:17]([CH2:20][NH:21][C:36]([NH:35][CH3:34])=[O:37])=[N:18][N:19]=3)[CH2:11][S:12][C@H:7]12)=[S:4]
Reactant: CCC(=S)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CN)s3)CS[C@H]12
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCC(=S)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CNC(=O)NC)s3)CS[C@H]12
Reaction time: 2 h
Yield: 96.2 %

Procedure:
7-Methylthioacetamido-3-(5-aminomethyl-1,3, 4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (1.8 g.) and triethylamine (0.8 g.) was dissolved in a mixture of water (40 ml.) and tetrahydrofuran (40 ml.). A solution of methyl isocyanate (0.46 g.) in tetrahydrofuran (10 ml.) was added dropwise to the solution at 0°-5° C, and the mixture was stirred at the same temperature for 2 hrs. The tetrahydrofuran was distilled off under reduced pressure from the reaction mixture. The residue was washed with ethyl acetate and then adjusted to pH1.0 with 10% hydrochloric acid. The precipitating crystals were collected by filtration and then washed with water to give 7-methylthioacetamido-3-[5-(3-methylureidomethyl)-1, 3,4-thiadiazol-2-yl]thiomethyl-3-cephem-4-carboxylic acid (1.96 g.). The product was suspended in water (50 ml.), and sodium bicarbonate (0.66 g.) was added to the suspension under ice-cooling to give a solution. The insoluble substance was filtered off from the solution, and the solution was adjusted to pH1.0 with 10% hydrochloric acid. The precipitating crystals were collected by filtration, washed with water to give the pure object compound. m.p. 177°-179° C (dec.).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.[C:12]1([CH:18](Br)[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:19][CH:18]([N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(Br)c1ccccc1
Reactant: O=Cc1cccc2[nH]ccc12
Product: CC(c1ccccc1)n1ccc2c(C=O)cccc21
Yield: 70 %

Procedure:
The same procedures used in Example 4 were repeated except for using 703 mg of indole-4-carbaldehyde and 987 mg of α-phenylethyl bromide instead of the 4-picolyl chloride hydrochloride to give 845 mg of 1-(α-methylbenzyl)indole-4-carbaldehyde as an orange-colored oily substance. The yield thereof was found to be 70%.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:12]1([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH2:25][CH2:26][C:27](=[O:30])[NH:28][N:29]=3)=[CH:20][C:19]=2[N+:31]([O-:33])=[O:32])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C(Cl)(Cl)Cl>[C:1]([NH:9][C:10]([N:15]1[CH2:16][CH2:17][N:12]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH2:25][CH2:26][C:27](=[O:30])[NH:28][N:29]=3)=[CH:20][C:19]=2[N+:31]([O-:33])=[O:32])[CH2:13][CH2:14]1)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: O=C1CCC(c2ccc(N3CCNCC3)c([N+](=O)[O-])c2)=NN1
Solvent: ClC(Cl)Cl
Product: O=C1CCC(c2ccc(N3CCN(C(=S)NC(=O)c4ccccc4)CC3)c([N+](=O)[O-])c2)=NN1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
A solution of 5.2 g (32 mmol) of benzoyl isothiocyanate in 20 ml of chloroform is added dropwise at room temperature to a suspension of 8.8 g (29 mmol) of 6-[4-(1-piperazinyl)-3-nitro-phenyl]-4,5-dihydro-3(2H)-pyridazinone in 300 ml of chloroform. The reaction mixture is stirred for 2 hours at 30° C. and cooled in an ice bath and the precipitated solid is separated by suction filtration. 12.5 g (93% of theoretical) of orange coloured crystals melting at 140°-141.5° C. remain after drying.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:15][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])=[C:13]([C:23]([OH:25])=O)[CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].N.C[N:28](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CC(N(C)C)=O>C(Cl)Cl.O>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:15][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])=[C:13]([C:23]([NH2:28])=[O:25])[CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(=O)Nc1cc(-c2cc(C(=O)O)c(-c3ccccc3Cl)o2)ccn1
Agent: F[B-](F)(F)F
Agent: N
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CC(=O)Nc1cc(-c2cc(C(N)=O)c(-c3ccccc3Cl)o2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
To a solution of 5-[2-(acetylamino)pyridin-4-yl]-2-(2-chlorophenyl)-3-furoic acid (0.10 g, 0.28 mmol) in DCM (15 mL) was added ammonia (0.5 M in 1,4-dioxane, 4.5 mL), TBTU (0.18 g, 0.56 mmol) and DMA (0.49 mL, 2.8 mmol). The mixture was allowed to stir at rt overnight. The reaction mixture was diluted with water and extracted with DCM. The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 5-[2-(acetylamino)pyridin-4-yl]-2-(2-chlorophenyl)-3-furamide (0.062 g, 62%) as a white solid. LCMS (FA): m/z=356.5 (M+H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH2:2][CH3:3].[I-:11].[Na+].C(#N)C.C(OCl)(C)(C)C>C(OCC)(=O)C.O>[I:11][C:8]1[CH:7]=[CH:6][C:5]([OH:10])=[C:4]([CH2:1][CH2:2][CH3:3])[CH:9]=1
Reactant: [I-]
Reactant: CCCc1ccccc1O
Agent: CC(C)(C)OCl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CCCc1cc(I)ccc1O
Reaction time: 0.17 h

Procedure:
A mixture of 6.8 g (50 mmol) of 2-propylphenol. 8.25 g (55 mmol) of sodium iodide. 175 ml of acetonitrile and 40 ml of water was cooled on ice. t-Butylhypochlorite, 6 g or 6.56 ml (55 mmol), was added slowly at 0° . After stirring for 10 minutes at 0° , 500 ml of ethyl acetate was added and the mixture was washed with 5% aqueous solution of sodium thiosulfate. The organic layer was dried and evaporated and the residue was chromatographed over 150 g of silica gel using methylene chloride/hexane 3:2. The more polar monoiodinated product was crystallized from petroleum ether to give colorless crystals with m.p. 54°-56°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([O:22]C)=[O:21])=[CH:13][C:12]=3[CH:24]=2)=[CH:4][CH:3]=1.[OH-].[Na+].CO>C(OCC)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([OH:22])=[O:21])=[CH:13][C:12]=3[CH:24]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C1=Cc2cc(-c3ccc(C)cc3)ccc2S(=O)(=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Reaction time: 8 h
Yield: 97.8 %

Procedure:
To methyl 7-(4-methylphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (1.6 g) was added 1N sodium hydroxide solution (50 ml), methanol (200 ml) and diethylether (100 ml), and the mixture was stirred overnight, concentrated and extracted with water. The aqueous layer was washed with ethyl acetate, made acidic with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-(4-methylphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (1.5 g; purity about 70%) as colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.O=[C:18]([CH3:37])[CH2:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([NH2:34])=[O:33])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:21].[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>C(O)C>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:18]([CH3:37])[C:19]([C:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]3[CH:29]=[CH:30][C:31]([C:32]([NH2:34])=[O:33])=[CH:35][CH:36]=3)[CH2:24][CH2:23]1)=[O:21])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CC(=O)CC(=O)N1CCC(c2ccc(C(N)=O)cc2)CC1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCO
Product: Cc1nc2ccc(Cl)cc2c(-c2ccccc2)c1C(=O)N1CCC(c2ccc(C(N)=O)cc2)CC1
Temperature: 82 °C
Yield: 75.8 %

Procedure:
To a solution of (2-amino-5-chlorophenyl)(phenyl)methanone (693 mg, 3.0 mmol) in ethanol (10 ml) was added 4-(1-(3-oxobutanoyl)piperidin-4-yl)benzamide (893 mg, 3.1 mmol) followed by ytterbium triflate (186 mg, 0.3 mmol). The mixture was heated at 82° C. for 12 hours. The reaction mixture was cooled to room temperature, and the white powder thus obtained was filtered off, washed with ethanol, ethyl acetate, and finally ether to provide 4-(1-(6-chloro-2-methyl-4-phenylquinoline-3-carbonyl)piperidin-4-yl)benzamide (1.1 g, 76%) as a free flowing white powder. 1H NMR (DMSO-d6, 400 MHz) 3:1 Rotameric forms complicates spectrum, the major rotamer is described; δ 8.09 (d, 1H, J=8.9 Hz); 7.9 (bs, NH, 1H); 7.8 (m, 3H); 7.7-7.5 (m, 6H); 7.25 (bs, NH, 1H); 6.8 (app d, 2H); 4.5 (d, 1H, J=12.9 Hz); 3.4-3.3 (m, 1H); 3.38 (s, 3H); 3.13 (app t, 1H, J=12.9 Hz); 2.8-2.4 (m, 2H); 2.5 (s, 3H); 0.72 (m, 1H); 0.54 (m, 1H). LC MS (CI) shows M+H 484.