Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C@@H:7]2[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])#[N:2].[H-].[Na+].Cl[CH2:23][C:24]([N:26]([CH3:28])[CH3:27])=[O:25]>CN(C=O)C>[C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C@@H:7]2[N:12]([CH2:23][C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])#[N:2]
Reactant: CN(C)C(=O)CCl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2c(C#N)cccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)CN(C(=O)OC(C)(C)C)[C@H]1CCc2c(C#N)cccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Prepared using General Procedure 9. To a solution of (S)-tert-butyl 4-cyano-2,3-dihydro-1H-inden-1-ylcarbamate INT-9 (3.0 g, 1.16 mmol) in DMF (20 mL) was added NaH (1.39 g of 60% dispersion in mineral oil, 34.8 mmol) at 0° C. with stirring for 3 h before the addition of 2-chloro-N,N-dimethylacetamide (2.82 g, 23.2 mmol). The reaction mixture was stirred at 0° C. for 0.5 h and then warmed to room temperature for 1 h. The reaction mixture was quenched with water (3 mL) slowly at 0° C. The mixture was partitioned between EA (3×20 mL) and water (50 mL). The combined organic layers were concentrated and purified by chromatography (DCM/MeOH) to provide product 3.82 g (96.0%) of (S)-tert-butyl 4-cyano-2,3-dihydro-1H-inden-1-yl(2-(dimethylamino)-2-oxoethyl)carbamate as a light brown solid. LCMS-ESI (m/z) calculated for C19H25ClN6O6; 343.4; found 366.1 [M+Na]+, tR=3.16 min.
Reaction SMILES: [N:1]1[C:10]2[C:9](=[O:11])[CH:8]=[CH:7][C:6](=[O:12])[C:5]=2[N:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[NH:13]([C:8]1[C:9](=[O:11])[C:10]2[N:1]=[CH:2][CH:3]=[N:4][C:5]=2[C:6](=[O:12])[CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1C=CC(=O)c2nccnc21
Reactant: Nc1ccccc1
Solvent: CCO
Product: O=C1C=C(Nc2ccccc2)C(=O)c2nccnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Approximately 2 g. of 5,8-quinoxalinedione were dissolved in 200 ml. of 2B ethanol. Aniline (1.2 g.) was added and the reaction was stirred overnight at room temperature. The reaction was evaporated, water was added, and the mixture was extracted several times with methylene chloride. The combined extracts were dried over sodium sulfate and evaporated to dryness. The residue was chromatographed over a silica gel column, eluting with ethyl acetate. The desired fractions were combined and evaporated. The material was crystallized from ethyl acetate to give 50 mg. of the title product as a red powder, m.p. about 203°-205° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15](OS(C(F)(F)F)(=O)=O)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[N:38]([CH3:39])[CH2:37][CH2:36][N:35]([CH3:40])[C:34]2=[O:41])=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15]([NH:26][C:27]4[CH:28]=[CH:29][C:30]([CH:33]5[N:38]([CH3:39])[CH2:37][CH2:36][N:35]([CH3:40])[C:34]5=[O:41])=[CH:31][CH:32]=4)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CN1CCN(C)C(c2ccc(N)cc2)C1=O
Reactant: COc1ccc(-c2ccc3cnc(OS(=O)(=O)C(F)(F)F)nn23)cn1
Product: COc1ccc(-c2ccc3cnc(Nc4ccc(C5C(=O)N(C)CCN5C)cc4)nn23)cn1

Procedure:
3-{4-[7-(6-Methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-1,4-dimethyl-piperazin-2-one was prepared from trifluoro-methanesulfonic acid 7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester and 3-(4-amino-phenyl)-1,4-dimethyl-piperazin-2-one in an analogous manner to Example 1061. Product isolated as an orange foam (79 mg, 61%). LCMS (m/e) 444 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.73-8.67 (m, 2H), 4.67 (dd, 1H, J=2.2 and 8.7 Hz), 7.58 (d, 2H, J=8.4 Hz), 7.33 (d, 2H, J=8.4 Hz), 6.95-6.81 (m, 4H), 4.03 (s, 3H), 3.79-3.67 (m, 2H), 3.26-3.18 (m, 1H), 3.07-2.98 (m, 1H), 2.99 (s, 3H), 2.73-2.64 (m, 1H), 2.20 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]2[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[OH:14][CH2:15][C@@H:16]1[O:20][C:19]([C:21]2[NH:25][C:24]([C:26]3[CH:27]=[C:28]([OH:38])[CH:29]=[C:30]([O:32][C@@H:33]([CH3:37])[CH2:34][O:35][CH3:36])[CH:31]=3)=[CH:23][CH:22]=2)=[N:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:11]1([S:8]([C:5]2[N:6]=[CH:7][C:2]([O:38][C:28]3[CH:27]=[C:26]([C:24]4[NH:25][C:21]([C:19]5[O:20][C@@H:16]([CH2:15][OH:14])[CH2:17][N:18]=5)=[CH:22][CH:23]=4)[CH:31]=[C:30]([O:32][C@@H:33]([CH3:37])[CH2:34][O:35][CH3:36])[CH:29]=3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:13][CH2:12]1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=NC[C@H](CO)O3)[nH]2)c1
Reactant: O=S(=O)(c1ccc(Cl)cn1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)C3CC3)nc2)cc(-c2ccc(C3=NC[C@H](CO)O3)[nH]2)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 34.2 %

Procedure:
5-Chloro-2-(cyclopropylsulfonyl)pyridine (168 mg, 0.77 mmol) synthesized in Example (125c) and 3-{5-[(5R)-5-(Hydroxylmethyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenol (401 mg, 1.16 mmol) synthesized in Example (125g) were dissolved in N,N-dimethylformamide (2 mL), and potassium carbonate (213 mg, 154 mmol) was added, followed by stirring at 100° C. for 3 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (30 mL) was added, and extraction was carried out twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0.5%-5%) to afford the desired compound (139 mg, yield 34%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8]2.[C-:17]1([CH2:22][C:23]([OH:25])=O)[CH:21]=[CH:20][CH:19]=[CH:18]1.[CH-:26]1[CH:30]=[CH:29][CH:28]=[CH:27]1.[Fe+2:31]>CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([N:13]([CH2:14][CH2:15][CH3:16])[C:23](=[O:25])[CH2:22][C-:17]1[CH:18]=[CH:19][CH:20]=[CH:21]1)[CH2:9][CH2:8]2.[CH-:26]1[CH:30]=[CH:29][CH:28]=[CH:27]1.[Fe+2:31]
Reactant: CCCNC1CCc2cccc(OC)c2C1
Reactant: O=C(O)C[c-]1cccc1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCN(C(=O)C[c-]1cccc1)C1CCc2cccc(OC)c2C1

Procedure:
Synthesis worked according to the preparation of A4-4 when using 360 mg (1.6 mmol) N-(8-methoxytetralin-2-yl)-N-propylamine (A2-1: R═OMe) and 240 mg (0.99 mmol) ferrocenylacetic acid (A3-7: W═OH, Cy=ferrocenyl). Flash chromatography of the residue on silica gel with a mixture of hexane/ethyl acetate 10/1 gave the crude product N-(8-methoxytetralin-2-yl)-N-propyl-2-ferrocenylacetamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:12][C:13]([CH3:15])=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH:13]([CH3:15])[CH3:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C1CCN(C(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To ethylpiperidine-4-carboxylate (1 eq) in methanol was added acetone (1 eq) and acetic acid (5%) and the resulting mixture was stirred for 2 h at ambient temperature. To it was then added sodium cyanoborohydride (1 eq) and continued stirring for 16 h. The mixture was then concentrated and to it was added sodium bicarbonate and was partitioned between ethyl acetate and water. The organic layer was dried with sodium sulfate and concentrated to yield ethyl-1-(methylethyl)piperidine 4-carboxylate. To this was then added concentrated hydrochloric acid and water (2:1) and the mixture was refluxed for 5 h. The resulting 1-(methylethyl)piperidine-4-carboxylic acid was then azeotroped with toluene. MS: MH+=172.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C:22]([C@H:24]([C@@H:26]([OH:42])[C@@H:27]([CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([OH:38])[C:32]=1[C:39]([OH:41])=[O:40])[CH3:28])[CH3:25])=[O:23])[C@H:4]1[O:8][C@@:7]([C@@H:11]2[O:16][C@@H:15]([CH3:17])[C@@:14]([OH:20])([CH2:18][CH3:19])[CH2:13][CH2:12]2)([CH2:9][CH3:10])[CH2:6][C@@H:5]1[CH3:21].[CH2:43](Cl)Cl.CI>[Ag]=O.CO>[CH3:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH2:29][CH:27]([CH3:28])[CH:26]([OH:42])[CH:24]([CH3:25])[C:22](=[O:23])[CH:3]([CH2:2][CH3:1])[CH:4]2[CH:5]([CH3:21])[CH2:6][C:7]([CH2:9][CH3:10])([CH:11]3[CH2:12][CH2:13][C:14]([CH2:18][CH3:19])([OH:20])[CH:15]([CH3:17])[O:16]3)[O:8]2)=[C:32]([C:39]([O:41][CH3:43])=[O:40])[C:33]=1[OH:38]
Reactant: CC[C@@H](C(=O)[C@@H](C)[C@@H](O)[C@H](C)CCc1ccc(C)c(O)c1C(=O)O)[C@H]1O[C@](CC)([C@H]2CC[C@](O)(CC)[C@H](C)O2)C[C@@H]1C
Reactant: ClCCl
Agent: O=[Ag]
Solvent: CO
Solvent: CI
Product: CCC(C(=O)C(C)C(O)C(C)CCc1ccc(C)c(O)c1C(=O)OC)C1OC(CC)(C2CCC(O)(CC)C(C)O2)CC1C
Reaction time: 18 h

Procedure:
To a solution of 6.2 g. of crystalline antibiotic X-537A in 125 ml. of methylene chloride was added 4.6 g. of silver oxide and 14 g. of methyl iodide. After stirring for 18 hours, the reaction mixture was filtered and the filtrate concentrated to 7.07 g. of a light yellow oil, which was decolorized with Darco, giving 6.09 g. of a colorless foam. A portion (4 g.) of the foam was chromatographed on a florisil column (150 g.) eluting with a gradient between methylene chloride (1 l.) to ether (1 l.) and then ether (500 ml.) to acetone (500 ml.). Rechromatography of the slightly yellow oil, recovered from the florisil column, on a 75 g. silica gel column and eluting with a gradient between methylene chloride (1 l.) and 15 percent ether/-methylene chloride gave 200 mg. of a clear viscous oil, Bp. 170°d/005 mm. [α] D25 -7.19° , (1.1 percent CH3OH).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8](=O)[CH2:9]Br)=[C:5]([CH3:7])[N:6]=1.[CH3:12][C:13]([CH3:18])([CH3:17])[C:14](=[S:16])[NH2:15].C(N(CC)CC)C>C(O)C>[C:13]([C:14]1[S:16][CH:9]=[C:8]([C:4]2[S:3][C:2]([NH2:1])=[N:6][C:5]=2[CH3:7])[N:15]=1)([CH3:18])([CH3:17])[CH3:12]
Reactant: CC(C)(C)C(N)=S
Reactant: Cc1nc(N)sc1C(=O)CBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nc(N)sc1-c1csc(C(C)(C)C)n1
Temperature: 25 °C

Procedure:
A mixture of 1-(2-amino-4-methyl-thiazol-5-yl)-2-bromo-ethanone (7.0 g, prepared as described in WO 2006/125805), 2,2-dimethylpropanethioamide (2.25 g, prepared as described by Boys and Downs in Synthetic Communications 2006, 36, 295-298.), triethylamine (7.2 ml) and ethanol (173 ml) are heated at reflux for 3.5 hours. On cooling to room temperature the reaction mixture is filtered, the filtrate evaporated and then partitioned between aqueous NaHCO3 and CH2Cl2, extracting 3×CH2Cl2. The organic layers are dried and evaporated then triturated 4× with diethyl ether (50 ml), the diethyl ether layers combined and extracted with 1M HCl (100 ml). The HCl layer is then washed 3× diethyl ether, basified with aqueous NaOH and extracted 4× diethyl ether and 2×CH2Cl2. The organic layers dried over Na2SO4 and evaporated to give the title compound as a red solid. Hplc/MS (Method B) RT 1.95 minutes, M+H 253.9.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[S:10]1[CH:11]=[CH:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=3)[N:7]=2)=[CH:9]1
Reactant: Clc1nccc(-c2ccsc2)n1
Reactant: COC(=O)c1ccc(CN)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CNc2nccc(-c3ccsc3)n2)cc1
Temperature: 130 °C
Yield: 48 %

Procedure:
To a solution of 14 (680 mg, 3.46 mmol) and methyl 4-(aminomethyl)benzoate (686 mg, 4.51 mmol) in dry 1,4-dioxane (10 mL) was added DIPEA (1.50 mL, 8.65 mmol) and the mixture was heated for 48 h at 130° C. in a sealed tube. Solvents were removed under vacuum and the residue was triturated with a mixture of EtOAc/Et2O, to form a solid, which was collected by filtration and dried. This material was purified by flash chromatography on silica gel (EtOAc/CH2Cl2: 30/70) to afford the title compound 15 (540 mg, 1.66 mmol, 48% yield). 1H NMR: (400 MHz, DMSO-d6) δ (ppm): 8.29-8.23 (m, 2H), 7.88 (d, J=8.4 Hz, 2H), 7.84-7.77 (m, 1H), 7.69-7.59 (m, 2H), 7.52-7.43 (m, 2H), 7.03 (d, J=5.2 Hz, 1H), 4.60 (d, J=6.4 Hz, 2H), 3.81 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([Cl:14])[CH:4]=1.[C-:15]#[N:16].[K+].C(O)C>O>[Cl:14][C:5]1[CH:4]=[C:3]([CH2:2][C:15]#[N:16])[CH:13]=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1ccc(CBr)cc1Cl
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc(CC#N)cc1Cl
Yield: 16 %

Procedure:
3.1 g (11.2 mmol) of ethyl 4-(bromomethyl)-2-chlorobenzoate are added dropwise to a solution composed of 0.94 g (14.3 mmol) of potassium cyanide, 3.75 ml of water and 8.8 ml of ethanol, heated under reflux. After refluxing for 3 hours, the medium is poured over 200 ml of water, and extracted with ethyl acetate. The organic phase is washed with a dilute HCl solution and then with water saturated with NaCl. The oil obtained after concentration of the organic phase is purified by flash chromatography on silica (hexane-ethyl acetate 1:0 to 1:1 gradient). 0.4 g of a brown solid is obtained (Yield=16%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:23]O>>[CH3:23][O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCOc1cnc(-c2cccc(O)c2)nc1
Reactant: CO
Product: CCCCCCCCOc1cnc(-c2cccc(OC)c2)nc1

Procedure:
5.52 g (21.05 mmol) of triphenylphosphine and 3.67 g (21.05 mmol) of diethyl azodicarboxylate are stirred at 0° C. for 30 minutes in 100 ml of tetrahydrofuran. 3.90 g (14.03 mmol) of 2-(3-benzyloxyphenyl)-5-hydroxypyrimidine and 2.74 g (21.05 mmol) of 1-octanol are subsequently added, and the resultant solution is stirred at room temperature for 18 hours. Evaporation to dryness and purification by chromatography (silica gel/dichloromethane) give 4.25 g of 2-(3-benzyloxyphenyl)-5-octyloxypyrimidine. ##STR29## Removal of the benzyl protecting group by hydrogenation analogously to Example 1 gives 2-(3-hydroxyphenyl)-5-octyloxypyrimidine. ##STR30## 2-(3-Hydroxyphenyl)-5-octyloxypyrimidine is reacted with methanol analogously to Example 1 to give 2-(3-methoxyphenyl)-5-octyloxypyrimidine. ##STR31## The compound has the phase sequence: X43 I
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.F[B-](F)(F)F.[CH2:15]([O:17][CH+:18][O:19][CH2:20][CH3:21])[CH3:16].C(N(CC)C(C)C)(C)C>>[CH2:15]([O:17][CH:18]([O:19][CH2:20][CH3:21])[CH:4]1[CH2:3][C:2]([CH3:9])([CH3:1])[CH2:7][CH2:6][C:5]1=[O:8])[CH3:16]
Reactant: CC1(C)CCC(=O)CC1
Reactant: CCO[CH+]OCC
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(OCC)C1CC(C)(C)CCC1=O

Procedure:
reacting 4,4-dimethylcyclohexanone, diethoxycarbenium fluoroborate and N,N-diisopropylethylamine to provide (2-(diethoxymethyl)-4,4-dimethylcyclohexanone and isolating or not isolating the 2-(diethoxymethyl)-4,4-dimethylcyclohexanone;
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])(=O)[NH2:2].P(Cl)(Cl)(Cl)=O.Cl.[H][H]>C(O)C.[Pd]>[NH2:2][CH2:1][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10]
Reactant: NC(=O)c1cncc(C(=O)O)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: NCc1cncc(C(=O)O)c1
Temperature: 100 °C

Procedure:
A mixture of 5-carbamoyl-nicotinic acid (compound F3) (5.00 g) and phosphorus oxychloride (50 mL, 0.55 mol) is heated to 100° C. for 5 h. After usual workup the crude product is dissolved in ethanol acidified with hydrochloric acid and hydrogenated with the use of Pd/C (1.00 g, 5% Pd) at 4 bar hydrogen pressure for 16 h. After filtration of the catalyst, the mixture is evaporated, and the residue is treated with ethanol and extracted several times with chloroform.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.C(N)=O.Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)=O.[CH:29]([NH2:31])=[S:30].[OH-].[Na+]>O1CCOCC1>[Br:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]2[N:31]=[CH:29][S:30][CH:19]=2)=[CH:23][CH:24]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: NC=S
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: NC=O
Product: Brc1ccc(-c2cscn2)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a stirred solution of phosphorus pentasulfide (24.5 g, 55 mmol) in dioxane (250 ml) was added formamide (28.4 g, 630 mmol), and the mixture was heated at reflux temperature for 2 hours. The reaction mixture was cooled down to room temperature, and the solution was decanted away from solids. To a stirred solution of 2,4′-dibromoacetophenone (15 g, 54 mmol) in dioxane (100 ml) was added the thioformamide solution, and the mixture was heated at reflux temperature for 6 hours. The reaction mixture was cooled down to room temperature, and made basic by addition of 2N NaOH aqueous solution. The whole was extracted with diethyl ether. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with CH2Cl2 to give title compound (12.3 g, 95% yield).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][C:9](=[O:11])[CH3:10].CN(C=O)C.[Cl:17][C:18]1[C:27]([OH:28])=[C:26]([S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21]>O>[Cl:17][C:18]1[C:27]([O:28][CH2:8][C:9]([CH3:10])=[O:11])=[C:26]([S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: CC(=O)CCl
Reactant: CCS(=O)(=O)c1ccc(C(=O)OC)c(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(C(=O)OC)c(Cl)c1OCC(C)=O
Temperature: 80 °C

Procedure:
0.922 g (7.2 mmol) of K2CO3, 0.179 g (1.10 mmol) of KI and 0.454 g (4.7 mmol) of chloroacetone were introduced into 30 ml of DMF. 1.000 g (3.6 mmol) of methyl 2-chloro-3-hydroxy-4-ethylsulfonylbenzoate were added at RT and the mixture was then heated for 4 hours at 80° C. The mixture was then poured into water and extracted with diisopropyl ether. The combined organic phases were washed with water, dried over Na2SO4 and evaporated to dryness. The resulting crude methyl 2-chloro-3-(methylcarbonylmethoxy)-4-ethylsulfonyl benzoate viscous oil was sufficiently pure for the subsequent reactions.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11]=1[OH:19]>CC#N.O>[Br:1][C:17]1[CH:18]=[C:10]([Cl:9])[C:11]([OH:19])=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)c1cccc(Cl)c1O
Solvent: CC#N
Solvent: O
Product: O=C(O)c1cc(Br)cc(Cl)c1O
Reaction time: 1 h
Yield: 93.9 %

Procedure:
N-Bromosuccinimide (2.38 g, 13.38 mmol) was added to a solution of 3-chlorosalicylic acid (2.1 g, 12.16 mmol) in CH3CN (10 mL) solution and stirred for 1 h. The reaction mixture was diluted with water (25 mL), solids were filtered and washed with water and dried to get 5-bromo-3-chloro-2-hydroxy-benzoic acid (2.87 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]([C:19]([O:21]CC)=[O:20])[N:16]([CH3:18])[CH:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].[OH-].[Na+].Cl>C(O)C.O1CCCC1>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]([C:19]([OH:21])=[O:20])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[CH:3][C:2]=1[F:1]
Reactant: CCOC(=O)c1nc(NC(=O)Nc2ccc(C)c(F)c2)cn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)Nc2cn(C)c(C(=O)O)n2)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
690 mg (2.15 mmol) of ethyl 4-({[(3-fluoro-4-methylphenyl)amino]carbonyl}amino)-1-methyl-1H-imidazole-2-carboxylate are suspended in 5 ml of ethanol and 12 ml of tetrahydrofuran. While cooling in ice, 2 ml (25 mmol) of 50% strength aqueous sodium hydroxide solution are added. The reaction mixture is stirred at room temperature overnight and then, while cooling in ice, acidified with 1N hydrochloric acid. The solution is extracted with dichloromethane. The organic phase is concentrated in vacuo.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].P(Cl)(Cl)(Cl)=O.CN(C=O)C.[CH3:21][O:22][C:23]([C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:33]=1[NH:32][CH:31]=[CH:30]2)=[O:24]>ClCCCl>[CH3:21][O:22][C:23]([C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:33]=1[NH:32][CH:31]=[C:30]2[CH:8]=[O:9])=[O:24]
Reactant: COC(=O)c1cccc2cc[nH]c12
Reactant: CN(C)C=O
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cccc2c(C=O)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a stirred mixture of phosphorus oxychloride-dimethylformamide in anhydrous 1,2-dichloroethane (prepared by the slow addition of phosphorus oxychloride (0.43 ml, 4.6 mmol) to anhydrous DMF (0.35 ml, 4.6 mmol) in anhydrous 1,2-dichloroethane (6 ml) cooled below 5° C.) a solution of 7-methoxycarbonylindole (0.69 g, 4 mmol) in anhydrous 1,2-dichloroethane (6 ml) was dropwise below 5° C. The mixture was stirred at room temperature for 2 h and then was heated at 50° C. for 30 minutes. After cooling, the precipitate was filtered off and washed with 1,2-dichloroethane. This precipitate was suspended in aq Na2CO3 10% (30 ml) and stirred at room temperature for 20 minutes; dichloromethane was added and stirring was continued 10 minutes more. The organic phase was separated and the aqueous phase was extracted with dichloromethane. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and evaporated to yield 0.75 g (93%) of the entitled product. Mp: 153–4° C.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]([O:15][CH:16]([CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:17])[CH:12]=[C:11]2[C:6]=1[CH:7]([CH2:31][CH2:32][CH:33]([OH:36])[CH2:34][CH3:35])[CH2:8][CH:9]1[CH2:30][CH2:29][CH2:28][CH2:27][N:10]12)(=O)C.OC(CC)CCC1N2C3C(CCC2CCC1)=CC=C(OC(CCCC1C=CC=CC=1)C)C=3.[OH-].[Na+]>O.N1C=CC=CC=1>[OH:4][C:5]1[CH:14]=[C:13]([O:15][CH:16]([CH2:18][CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH3:17])[CH:12]=[C:11]2[C:6]=1[CH:7]([CH2:31][CH2:32][C:33](=[O:36])[CH2:34][CH3:35])[CH2:8][CH:9]1[CH2:30][CH2:29][CH2:28][CH2:27][N:10]12
Reactant: CCC(O)CCC1CC2CCCCN2c2cc(OC(C)CCCc3ccccc3)cc(OC(C)=O)c21
Agent: CCC(O)CCC1CCCC2CCc3ccc(OC(C)CCCc4ccccc4)cc3N21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CCC(=O)CCC1CC2CCCCN2c2cc(OC(C)CCCc3ccccc3)cc(O)c21

Procedure:
A solution of 5.0 g. (0.02 mole) chromic anhydride in 5.0 ml. water is added with stirring and ice cooling to 50 ml. pyridine. To this is added at 10° C., 4.93 g. (0.01 mole) dl-7acetoxy-6-(3-hydroxypentyl)-9-(5-phenyl-2-pentyloxy)-2,3,4,4a,5,6-hexahydro-1H-pyrido[1,2-a]quinoline (prepared from dl-7-hydroxy-6-(3-hydroxypentyl-9-(5-phenyl-2-pentyloxy)-2,3,4,4a,5,6-hexahydro-1H-pyrido[1,2-a]quinoline by the procedure of Example 62, Part A) and the resulting mixture is stirred at ambient temperature for three hours. The mixture is then poured into water, made alkaline with sodium hydroxide and extracted with methylene chloride. The combined extracts are washed with water, brine, dried (MgSO4) and the solvent evaporated in vacuo. The residue is purified by silica gel chromatography.