Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH:5]([O:7][C:8](SCC)=[O:9])[CH3:6])(=[O:3])[CH3:2].S(Cl)([Cl:16])(=O)=O>>[C:1]([O:4][CH:5]([O:7][C:8]([Cl:16])=[O:9])[CH3:6])(=[O:3])[CH3:2]
Reactant: CCSC(=O)OC(C)OC(C)=O
Reactant: O=S(=O)(Cl)Cl
Product: CC(=O)OC(C)OC(=O)Cl
Reaction time: 0.5 h

Procedure:
The compound (394 mg) obtained in Step 1 of this Example was cooled to −30° C. Sulfuryl chloride (175 μL) was added thereto, and the mixture was then stirred for 30 minutes. The solvent in the reaction solution was distilled off under reduced pressure to obtain a crude product of the title compound.
Reaction SMILES: [CH:1]([C:4]1[C:5]2[CH:6]=[C:7]([CH3:28])[C:8]([NH:16][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=3)=[CH:9][C:10]=2[C:11]([CH3:15])([CH3:14])[CH2:12][CH:13]=1)([CH3:3])[CH3:2].[CH2:29]=O>>[CH3:29][N:16]([C:8]1[C:7]([CH3:28])=[CH:6][C:5]2[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:13][CH2:12][C:11]([CH3:14])([CH3:15])[C:10]=2[CH:9]=1)[C:17]1[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=1
Reactant: C=O
Reactant: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(C(C)C)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(N(C)c2cc3c(cc2C)C(C(C)C)=CCC3(C)C)cc1
Yield: 98.2 %

Procedure:
Following General Procedure D, ethyl 4-(5-isopropyl-3,8,8-trimethyl-7,8-dihydronaphthalen-2-ylamino)benzoate (Compound 48, 0.10 g, 0.26 mmol) was reacted with an aqueous solution of formaldehyde 37% (0.20 mL, 2.6 mmol) to give 0.10 g (100%) of the title compound as a clear oil.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[S:3]([CH:6]1[CH2:11][CH2:10][N:9](C(OCC2C=CC=CC=2)=O)[CH2:8][CH2:7]1)(=[O:5])=[O:4].[H][H]>CO.[Pd]>[CH3:1][N:2]([CH3:22])[S:3]([CH:6]1[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]1)(=[O:5])=[O:4]
Reactant: [H][H]
Reactant: CN(C)S(=O)(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CN(C)S(=O)(=O)C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
A solution of phenylmethyl 4-[(dimethylamino)sulfonyl]-1-piperidinecarboxylate (1.19 mmol) and 10% wt palladium/carbon (0.09 mmol) in methanol (10 ml) was vacuum pumped and back-filled with nitrogen three times. The nitrogen atmosphere was then replaced with hydrogen via a balloon and the reaction stirred for 1 hour at ambient temperature. The reaction was then filtered through a pad of celite and concentrated to give the title compound (200 mg, 87% yield), which was used directly in the next reaction without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.33 (bs, 1H) 3.30-3.22 (m, 1H) 2.96 (d, J=12.13, 2H) 2.84 (s, 6H) 2.46 (td, J=2.53, 12.38, 2H) 1.80 (d, J=12.13, 2H) 1.46 (qt, J=4.17, 12.34, 2H)
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:14])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([N:15]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[N:16]2)[CH:3]=1.COC1C(C)=C2C(C(O[CH:43]3[CH2:60][CH:59]4[CH:45]([C:46](=[O:66])[N:47]([CH3:65])[CH2:48][CH2:49][CH2:50][CH2:51][CH:52]=[CH:53][CH:54]5[C:56]([C:62]([OH:64])=[O:63])([NH:57][C:58]4=[O:61])[CH2:55]5)[CH2:44]3)=CC(C3SC=CN=3)=N2)=CC=1>>[C:20]([C:17]1[CH:18]=[CH:19][N:15]([C:4]2[CH:3]=[C:2]([O:1][CH:43]3[CH2:60][CH:59]4[CH:45]([C:46](=[O:66])[N:47]([CH3:65])[CH2:48][CH2:49][CH2:50][CH2:51][CH:52]=[CH:53][CH:54]5[C:56]([C:62]([OH:64])=[O:63])([NH:57][C:58]4=[O:61])[CH2:55]5)[CH2:44]3)[C:11]3[C:6](=[C:7]([CH3:14])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[N:5]=2)[N:16]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: COc1ccc2c(O)cc(-n3ccc(C(C)(C)C)n3)nc2c1C
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nccs3)nc2c1C
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-n3ccc(C(C)(C)C)n3)nc2c1C

Procedure:
The title compound was prepared from 4-hydroxy-2-(3-tert-butylpyrazol-1-yl)-7-methoxy-8-methylquinoline (126) and intermediate 26 following the procedure (Step D-F) reported for the preparation of 17-[7-methoxy-8-methyl-2-(thiazol-2-yl)quinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (29): m/z=644 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]2[N:27]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[N:26]=[N:25][N:24]=2)=[CH:11][C:10]=1[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39](O)=[O:40])[CH:34]=1)C1C=CC=CC=1.[CH3:42][N:43]([CH3:49])[CH2:44][CH2:45][CH2:46][NH:47][CH3:48]>>[CH3:42][N:43]([CH3:49])[CH2:44][CH2:45][CH2:46][N:47]([CH3:48])[C:39]([C:35]1[CH:34]=[C:33]([C:10]2[CH:11]=[C:12]([C:23]3[N:27]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[N:26]=[N:25][N:24]=3)[C:13]([OH:15])=[CH:14][C:9]=2[OH:8])[CH:38]=[CH:37][CH:36]=1)=[O:40]
Reactant: COCCCn1nnnc1-c1cc(-c2cccc(C(=O)O)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CNCCCN(C)C
Product: COCCCn1nnnc1-c1cc(-c2cccc(C(=O)N(C)CCCN(C)C)c2)c(O)cc1O

Procedure:
This product was synthesized using 2′,4′-bis-benzyloxy-5′-[1-(3-methoxy-propyl)-1H-tetrazol-5-yl]-biphenyl-3-carboxylic acid and N,N,N′-trimethyl-1,3-propanediamine as described in general procedure D. LCMS: 469 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][NH:7][C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[OH:16])=[C:4]([F:20])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>CC(C)=O>[CH2:32]([O:31][C:29](=[O:30])[CH2:28][O:16][C:10]1[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=1[C:8](=[O:17])[NH:7][CH2:6][C:5]1[CH:18]=[CH:19][C:2]([Br:1])=[CH:3][C:4]=1[F:20])[CH3:33]
Reactant: O=C(NCc1ccc(Br)cc1F)c1ccc(Cl)cc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(Cl)ccc1C(=O)NCc1ccc(Br)cc1F
Temperature: 50 °C
Yield: 93.8 %

Procedure:
A solution of N-(4-bromo-2-fluoro-benzyl)-4-chloro-2-hydroxy-benzamide (3.25 g, 9.06 mmol) in acetone (45 mL, 0.2 M) was treated with aq K2CO3 (2 M, 6.8 mL, 14 mmol) and ethyl bromoacetate (1.2 mL, 11 mmol). After being heated to 50° C. for 8 h, the solution was cooled to room temperature and concentrated under reduced pressure until most of the acetone was removed. The solution was acidified to pH 1-2 with 2 N HCl, diluted with ethyl acetate and washed with saturated aq NaCl. The organic layer was dried over Na2SO4, filtered and concentrated. Purification by MPLC (10-60% ethyl acetate in heptane, 23 mL/min, 70 min) gave [2-(4-bromo-2-fluoro-benzylcarbamoyl)-5-chloro-phenoxy]-acetic acid ethyl ester as a white crystalline solid (3.78 g, 94%): mp 126-127° C.; Rf 0.61 (50% ethyl acetate in heptane); 1H NMR (DMSO-d6, 300 MHz) δ 8.90 (t, J=6 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.52-7.47 (m, 1H), 7.39-7.31 (m, 2H),. 7.28 (d, J=1.8 Hz, 1H), 7.14 (dd, J=8.4 Hz, J2=1.8 Hz, 1H), 5.00, (s, 2H), 4.49 (d, J=6 Hz, 2H), 4.16 (q, J=7.2 Hz, 2H), 1.18 (t, J=6.6 Hz, 3H). ESI-LC/MS ml/z calcd for C18H16BrClFNO4: 444.7; found 446.0 (M+1)+. Anal. calcd for C18H16BrClFNO4: C, 48.62; H, 3.63; N, 3.15; Cl, 15.95. Found C, 48.57; H, 3.63; N, 3.11; Cl, 16.00.
Reaction SMILES: [CH:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].[C:11](#[N:14])[CH:12]=[CH2:13].Cl>CCOCC>[C:11]([CH2:12][CH2:13][C:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)#[N:14]
Reactant: O=CC1CCCCC1
Reactant: C=CC#N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: N#CCCC1(C=O)CCCCC1
Reaction time: 1 h
Yield: 37.7 %

Procedure:
To a stirred solution of cyclohexanecarboxaldehyde (100 g.; 0.89 mole) and 50% potassium hydroxide solution (10.2 g.) is added, dropwise, acrylonitrile (50.4 g.; 0.95 mole) over the course of one hour, maintaining the reaction temperature between 50°-60° C. by occasional cooling. After all has been added, the mixture is stirred for an additional one hour until the exotherm ceases and then heated to 50°-60° C. for 30 minutes. The product is acidified with dilute hydrochloric acid, taken up into ether, washed with water, dried (MgSO4) and distilled to afford 38% of colorless 1-(2-cyanoethyl)-1-formylcyclohexane (55.4 g.), b.p. 142°-146° C./5 mm.
Reaction SMILES: Br[C:2]1(Br)[CH:12]2[CH:3]1[CH2:4][O:5][C:6]1[C:11]2=[CH:10][CH:9]=[C:8]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:7]=1[C:20]([O:22][CH3:23])=[O:21].[Cl-].[NH4+]>C(O)C.[Zn]>[CH3:16][C:15]([CH3:18])([CH3:17])[C:14]([NH:13][C:8]1[C:7]([C:20]([O:22][CH3:23])=[O:21])=[C:6]2[C:11]([CH:12]3[CH2:2][CH:3]3[CH2:4][O:5]2)=[CH:10][CH:9]=1)=[O:19]
Reactant: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1OCC1C2C1(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Product: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1OCC1CC21
Yield: 41.7 %

Procedure:
Methyl (1aRS,7bSR)-1,1-dibromo-5-(2,2-dimethylpropionylamino)-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (Intermediate 44, 1.13 g) was suspended in ethanol (30 mL). Zinc dust (1.17 g), followed by ammonium chloride (1.31 g) were added and the reaction mixture was heated to reflux, under an atmosphere of nitrogen, for 6 hours. After cooling, the solid was filtered off and washed with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ether and cyclohexane, with a gradient of 5-12.5% to give methyl (1aRS,7bSR)-5-(2,2-dimethylpropionylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.310 g) as a colourless oil.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:10]=[CH:9][C:8]=1[O:27][CH2:28][CH:29]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[CH2:30][O:31]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>C(Cl)(Cl)Cl>[CH2:1]([C:7]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:10]=[CH:9][C:8]=1[O:27][CH2:28][CH:29]([O:51][CH2:52][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)[CH2:30][OH:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCCCCCCc1ccc(OCC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)OCc2ccccc2)c(CCCCCC)c1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCc1ccc(OCC(CO)OCc2ccccc2)c(CCCCCC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
A solution of 11.9 g of 2-hexyl-1-[2-(phenylmethoxy)-3-(triphenylmethoxy)propoxy]-4-tetradecylbenzene in 250 ml of chloroform was cooled to 0° C. A stream of dry hydrogen chloride gas was bubbled into the solution for 1/2 hour, then the mixture was stirred for 2 hours at 0° C. Solid sodium bicarbonate was added, the mixture stirred for 3 hours, then filtered and the chloroform evaporated. The residue was dissolved in ether, washed with aqueous sodium bicarbonate, dried and the residue chromatographed on silica gel. The column was eluted with hexane:ethyl acetate, giving 5.8 g of the desired compound, mp 32°-33° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[S:11]([O-])([O-:13])=[O:12].[Na+].[Na+]>ClS(O)(=O)=O.O.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([OH:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: O=S([O-])[O-]
Agent: O=S(=O)(O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)O)c1
Temperature: 120 °C
Yield: 31.8 %

Procedure:
A solution of 1-chloro-4-nitrobenzene (476 g, 3.02 mol) in chlorosulfonic acid (1 litre) was stirred and heated at 120° C. for 22 hours. The reaction was cooled to room temperature and was poured slowly with stirring onto ice (10 litres). The resulting dark brown precipitate was filtered, pressed dry, dried in a vacuum desiccators over night and was used without any further purification (770 g). The resulting 2-chloro-5-nitro-benzenesulfonyl chloride was suspended in water and cooled to 0° C. (ice bath). Sodium sulphite (1.9 Kg, 15 mol) was added to the stirred solution by portion (100 g portion and in a manner that the temperature remains under 25° C.). After the addition the mixture was allowed to warm back to room temperature and left stirring for one hour. During that time the pH of the solution was kept at pH 7-8 (Whattman pH paper) by addition of 8 M solution of sodium hydroxide (400 ml). The solution was then diluted with water (6 L) and sodium hydroxide was added to it (8 M, 0.5 L). The resulting mixture was filtered through a sintered funnel (number 3). The filtrate was cooled to 0° C. (ice bath) and acidify with concentrated HCl to pH<1. The brown solution then turn green and a silvery green plates precipitate. The solid was filtered, pressed dry and dried in a vacuum desiccator to give the title compound (213 g, 32%).
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10])[CH3:3].C(N)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:3]([NH:2][CH:4]=[C:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN(C)C=C1CCCC1=O
Reactant: NCc1ccccc1
Product: O=C1CCCC1=CNCc1ccccc1
Yield: 73.5 %

Procedure:
Using 2-dimethylaminomethylenecyclopentanone (50 mmol) and benzylamine (50 mmol) and proceeding according to the abovementioned method C, 2-benzylaminomethylenecyclopentanone (7.4 g, efficiency: 70%) is produced in the form of a pale yellow powder.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:30][O:31][CH2:32][CH2:33][O:34]C=O)[C:10]([NH:12][CH:13]2[C:28](=[O:29])[N:15]3[C:16]([C:25]([OH:27])=[O:26])=[C:17]([CH2:20][O:21][C:22](=[O:24])[NH2:23])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.[ClH:37].O1CCCC1>CO>[ClH:37].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:30][O:31][CH2:32][CH2:33][OH:34])[C:10]([NH:12][CH:13]2[C:28](=[O:29])[N:15]3[C:16]([C:25]([OH:27])=[O:26])=[C:17]([CH2:20][O:21][C:22](=[O:24])[NH2:23])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCOC=O)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCO)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.1 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-(2-formyloxyethoxyimino)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer, 1.5 g.), conc. hydrochloric acid (0.6 g.), tetrahydrofuran (7.5 ml.) and methanol (15.0 ml.) was stirred at room temperature for 6 hours. After concentrating the resultant solution in vacuo, the residue was pulverized with a mixture of methanol and diisopropyl ether. The precipitates were collected by filtration, washed with diisopropyl ether and dried to give 7-[2-(2-aminothiazol-4-yl)-2-(2-hydroxyethoxyimino)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer, 1.36 g.).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])[C:11]=1F.Cl>C1COCC1>[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])[C:11]=1[O:6][CH2:5][C:4]([F:8])([F:7])[F:3]
Reactant: OCC(F)(F)F
Reactant: CS(=O)(=O)c1c(C(=O)O)ccc(Cl)c1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1c(C(=O)O)ccc(Cl)c1OCC(F)(F)F
Yield: 99.9 %

Procedure:
Sodium hydride (1.05 g of 80% powder) was suspended in THF and to this was added a solution of 2,2,2-trifluoroethanol (1.9 g) in THF, followed by a solution of 4-chloro-3-fluoro-2-methylsulphonylbenzoic acid (4 g) in THF. The resultant mixture was stirred for 2 hours and then acidified with 2 M HCl. The mixture was extracted with ether, washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness yielding 4-chloro-2-methylsulphonyl-3-(2,2,2-trifluoroethoxy)benzoic acid (5.26 g) as a whim solid, NMR (DMSO d6) 2.5(s,3H), 4.8(q,2H), 7.5(d,1H), 8.0(d,1H).
Reaction SMILES: C(OC(N1C2C(=CC(C3C=CC=CC=3OC)=CC=2)C(C(O)C)=CC1(C)C)=O)(C)(C)C.[CH:31]1([CH2:37][O:38][CH:39]([C:41]2[C:50]3[C:45](=[CH:46][CH:47]=[C:48]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=4[O:57][CH3:58])[CH:49]=3)[NH:44][C:43]([CH3:60])([CH3:59])[CH:42]=2)[CH3:40])CCC[CH2:33][CH2:32]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1(CBr)CCCCC1>C1COCC1>[CH2:37]([O:38][CH:39]([C:41]1[C:50]2[C:45](=[CH:46][CH:47]=[C:48]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=3[O:57][CH3:58])[CH:49]=2)[NH:44][C:43]([CH3:60])([CH3:59])[CH:42]=1)[CH3:40])/[CH:31]=[CH:32]/[CH3:33]
Reactant: COc1ccccc1-c1ccc2c(c1)C(C(C)OCC1CCCCC1)=CC(C)(C)N2
Agent: BrCC1CCCCC1
Agent: COc1ccccc1-c1ccc2c(c1)C(C(C)O)=CC(C)(C)N2C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: C/C=C/COC(C)C1=CC(C)(C)Nc2ccc(-c3ccccc3OC)cc21
Yield: 25.6 %

Procedure:
4-(1-Cyclohexylmethoxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline 4-(1-Hydroxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylic acid tert-butyl ester (70 mg) was treated with 255 μL of 1 M solution of sodium bis(trimethylsilyl)amide in THF and 45 mg of cyclohexylmethyl bromide to give the alkylated product, which was deprotected to yield 8 mg of the title compound as an oil.
Reaction SMILES: [C:1](Cl)(=O)C.[CH:5]1([C:12]([OH:14])=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>CO>[CH3:1][O:13][C:12]([CH:5]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:14]
Reactant: CC(=O)Cl
Reactant: O=C(O)C1CCCCCC1
Solvent: CO
Product: COC(=O)C1CCCCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Methanol (20 ml) was cooled to 0° C. and acetyl chloride (2.0 ml) was added. The mixture was stirred for 10 minutes and cycloheptanecarboxylic acid (2.0 ml) was added. The cooling bath was removed and the mixture was heated to reflux and stirred for 8 hours. The mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was extracted with EtOAc. The organic layer washed with saturated aqueous sodium bicarbonate, dried (Na2SO4) and evaporated under reduced pressure, affording cycloheptanecarboxylic acid methylester (1.82 g) as a pale yellow liquid. This methylester intermediate (1.8 g) was dissolved in THF (25 ml) and cooled to −40° C. Lithium aluminium hydride (11.5 ml of a 1.0 M sol. in THF) was added drop-wise. The reaction mixture was allowed slowly to warm to 0° C. and stirring was continued at this temperature for 3 hours. Aqueous sodium hydroxide (5 ml of a 1 M sol.) was added and the mixture was filtrated. The filtrate was evaporated under reduced pressure and re-dissolved in EtOAc (20 ml), dried (Na2SO4) and evaporated under reduced pressure, and gave cycloheptyl-methanol (1.37 g) as a clear colourless oil. This alcohol intermediate was converted into the title compound, as described for preparation 66, using N-hydroxyphthalimide. 13C-NMR (DMSO-d6) δ 78.8, 37.1, 30.0, 27.9, 25.6.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][CH2:29][C:30](N(OC)C)=[O:31])[N:27]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH3:22])[CH3:12].[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][CH2:29][C:30]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[O:31])[N:27]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH3:22])[CH3:12]
Reactant: c1cscn1
Reactant: CCOc1ccc(-c2nc(CCC(=O)N(C)OC)cs2)cc1OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOc1ccc(-c2nc(CCC(=O)c3nccs3)cs2)cc1OCC
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
A solution (2 ml) of thiazole (129 mg, 1.5 mmol) in THF was cooled to −70° C., and n-butyllithium (a 2.44M hexane solution) (0.62 ml, 1.5 mmol) was added, and the resulting mixture was stirred at −70° C. for 30 minutes. A solution (4 ml) of 3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-N-methoxy-N-methylpropionamide (500 mg, 1.4 mmol) in THF was added to the reaction mixture, followed by stirring at −70° C. for 3 hours. After heating to room temperature, a saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated salt solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5). The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol, to thereby obtain 350 mg (yield: 66%) of 3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-1-thiazole-2-yl-1-propanone as colorless needles.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27]O)=[CH:21][N:20]=1)[P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C(Br)(Br)(Br)[Br:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>ClCCl>[CH2:1]([O:3][P:4]([CH:9]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][Br:30])=[CH:21][N:20]=1)[P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CCOP(=O)(OCC)C(Nc1ccc(CCCO)cn1)P(=O)(OCC)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(Nc1ccc(CCCBr)cn1)P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of [(5-(3-hydroxypropyl)-2-pyridinyl)aminomethylene]-bis(phosphonic acid] tetraethyl ester (10 mmol), carbon tetrabromide (11 mmol) and triphenyl phosphine (11 mmol) in dichloromethane (100 ml) is stirred at room temperature for 5 h. Water is added and the product is extracted with dichloromethane. The combined organic extracts are dried and concentrated. The residue is purified by flash column chromatography to give [(5-(3-bromopropyl)-2-pyridinyl)aminomethylene]bis[phosphonic acid] tetraethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]=[C:8]([NH:11][C:12](=[O:18])[C:13]([O:15]CC)=[O:14])[C:7](=[O:19])[C:6]=2[CH:20]=1.[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]=[C:8]([NH:11][C:12](=[O:18])[C:13]([OH:15])=[O:14])[C:7](=[O:19])[C:6]=2[CH:20]=1
Reactant: CCOC(=O)C(=O)Nc1coc2ccc(Cl)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(=O)Nc1coc2ccc(Cl)cc2c1=O

Procedure:
Ethyl (6-chloro-4-oxo-4H-1-benzopyran-3-yl)aminooxoacetate (2.7g, 0.92 mole) was suspended in ethanol (100 ml) and water (100 ml). 0.1N sodium hydroxide solution was added dropwise, with occasional warming on a steam bath, until the reaction mixture remained slightly basic. The color of the mixture changed to orange on addition of the base and then back to white. The sodium hydroxide solution was added until a faint orange color persisted. The product was filtered off, triturated with 1N hydrochloric acid, washed with water and sucked dry on filter. Recrystallization from methanol gave white crystals (2,3g, 94%), m.p. 213°-215° C.