Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:11]([O:13][CH3:14])=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1I)[CH3:2].Br[Zn][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1.CN1CCCC1>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:1]([C:3]1[C:4]([C:11]([O:13][CH3:14])=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[CH3:2]
Reactant: CCc1c(I)[nH]c(C=O)c1C(=O)OC
Reactant: Br[Zn]c1cccs1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CN1CCCC1
Solvent: C1CCOC1
Product: CCc1c(-c2cccs2)[nH]c(C=O)c1C(=O)OC
Temperature: 100 °C

Procedure:
Methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate was obtained following the procedures described in Example 3. To a solution of methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate (0.123 g, 0.40 mmol) and bromo(thien-2-yl)zinc (0.1374 g, 0.60 mmol) in THF (2.0 mL) was added Pd(Pt-Bu3)2 (0.0123 g, 0.02 mmol) and N-methylpyrrolidine (2.0 mL). The reaction was deoxygenated by bubbling argon through the solution prior to being heated to 100° C. and refluxed for 4 h under argon. After cooling to ambient temperature, the reaction was filtered through a pad of silica gel and concentrated. The resultant residue was dissolved in acetonitrile and purified by reverse phase HPLC. Proton NMR for the product was consistent with the title compound. 1H NMR (500 MHz, CDCl3) δ 10.14 (s, 1H); 7.42 (d, J=5.1 Hz, 1H); 7.24 (d, J=3.7 Hz, 1H); 7.14 (dd, J=3.7, 4.7 Hz, 1H); 3.94 (s, 3H); 2.94 (q, J=7.4 Hz, 2H); 1.24 (t, J=7.4 Hz, 3H). HRMS (ES) exact mass calculated C13H14NO3S (M+H): 264.0689. Found 264.0688
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]1[N:11]=[C:12]([NH2:15])[S:13][CH:14]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:16][CH2:17][C:18](Cl)=[O:19]>CC(N(C)C)=O>[CH3:1][O:2][N:3]=[C:4]([C:10]1[N:11]=[C:12]([NH:15][C:18](=[O:19])[CH2:17][Cl:16])[S:13][CH:14]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)C(=NOC)c1csc(N)n1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C(=NOC)c1csc(NC(=O)CCl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a solution of 10 g of ethyl α-methoxyimino-α-(2-aminothiazol-4-yl)acetate in 100 ml of dimethylacetamide is dropwise added 5.91 g of chloroacetyl chloride under ice-cooling. After the stirring for 1 hour at room temperature, the reaction mixture is poured into ice-water and the resultant solution is extracted with ethyl acetate. The organic layer is washed and dried, followed by the distillation of solvent to give 12.66 g of ethyl α-methoxyimino-α-[2-(chloroacetamido)thiazol-4-yl]acetate as a crystal. Melting point: 81°-82° C.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)CCC.[C@@H:19]1([N:27]2[CH:31]=[C:30](I)[CH:29]=[C:28]2[N+:33]([O-:35])=[O:34])[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[CH2:20]1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[C@@H:19]1([N:27]2[CH:31]=[C:30]([C:6]3[S:7][CH:8]=[CH:9][CH:10]=3)[CH:29]=[C:28]2[N+:33]([O-:35])=[O:34])[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[CH2:20]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: O=[N+]([O-])c1cc(I)cn1[C@H]1C[C@H](O)[C@@H](CO)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(-c2cccs2)cn1[C@H]1C[C@H](O)[C@@H](CO)O1
Yield: 64 %

Procedure:
2-(Tributylstannyl)thiophene (476 μL, 1.5 mmol) was added to a DMF (2.5 mL) solution containing 1-(2-deoxy-β-D-ribofuranosyl)-4-iodo-2-nitropyrrole (177 mg, 0.5 mmol) and bis(triphenylphosphine)palladium(II) dichloride (18 mg, 0.025 mmol). The mixture was reacted at 100° C. for 30 minutes in a microwave machine (standard mode). The reaction solution was separated between ethyl acetate (50 mL) and water (50 mL). The organic layer was concentrated and purified by HPLC to yield 1-(2-deoxy-β-D-ribofuranosyl)-4-(thien-2-yl)-2-nitropyrrole (97 mg, 0.32 mmol, 63%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[Cl:15])=[O:4].C(=O)([O-])[O-].[Na+].[Na+].Cl.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][SH:27].O>CN(C)C=O>[Cl:15][C:7]1[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[CH2:2][S:27][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23]
Reactant: CN(C)CCS
Reactant: O=C(CCl)Nc1ccc([N+](=O)[O-])cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCSCC(=O)Nc1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(chloroacetyl)-2-chloro-4-nitroaniline (3.01 g) in N,N-dimethylformamide (100 mL) is added powdered sodium carbonate (6.0 g) and 2-dimethylaminoethanethiol hydrochloride (6.0 g). The mixture is stirred for 1 hour at 25° C., poured into water and extracted into ethyl acetate. The ethyl acetate solution is dried over anhydrous potassium carbonate and concentrated under reduced pressure to give an oil. The oil is crystallized from toluene-hexanes (3:1) to yield a pale yellow crystalline solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[NH:11][N:10]=2)=[CH:6][CH:5]=1.C([O:26][C:27](=[O:47])[CH2:28][CH2:29][CH:30](OS(C)(=O)=O)[CH2:31][CH2:32][N:33]([CH3:41])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(C)(C)C.O>CC(N(C)C)=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[N:11]([CH:30]([CH2:31][CH2:32][N:33]([CH3:41])[CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:29][CH:28]([C:7]([CH3:20])([CH3:8])[CH3:6])[C:27]([OH:26])=[O:47])[N:10]=2)=[CH:20][CH:21]=1
Reactant: O=c1[nH]nc(Cc2ccc(Cl)cc2)c2ccccc12
Reactant: CN(CCC(CCC(=O)OC(C)(C)C)OS(C)(=O)=O)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(CCC(CC(C(=O)O)C(C)(C)C)n1nc(Cc2ccc(Cl)cc2)c2ccccc2c1=O)Cc1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
3 g sodium hydride (80%, in white oil) are added to 21.6 g 4(4-chlorobenzyl)-1(2H)-phthalazinone in 200 ml dimethylacetamide (DMA) with cooling in an ice bath. 37 g 6-(N-methyl -N-benzylamino )-4-methylsulfonyloxy-caproic acid-t-butyl ester in 80 ml DMA are then added dropwise with cooling and stirring continued for 0.5 hour. The mixture is allowed to warm slowly--overnight--to room temperature and is then heated for 2 hours to 40° C.-50° C. The mixture is hydrolyzed by addition of 200 ml water with ice cooling. The precipitated oil is separated and dissolved in dichloromethane. After extraction twice with water, the organic phase is dried and concentrated. The residue is chromatographed over silica gel (Eluent: dichloromethane/methanol/ammonia 25% 95:4:1). 3.5 g are obtained (yellow oil).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=O)=[O:9])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:35][C@H:36]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40].C(N(C(C)C)C(C)C)C>O1CCCC1>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:11]=1[CH2:12][CH2:13][C:14]([NH:35][C@H:36]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:16])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCCC(=O)c1ccc(Cl)cc1CCC(=O)O
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC[C@H](NC(=O)CCc1cc(Cl)ccc1C(=O)CCCNC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.10 g (0.01 mol) of 2-(4-acetamidobutyryl)-5-chlorohydrocinnamic acid and 1.70 g (0.015 mol) of 1,1'-carbonyldiimidazole are stirred at room temperature for 1 hour in 50 ml of tetrahydrofuran and 2.51 g (0.011 mol) of diethyl L-glutamate hydrochloride and 1.8 ml (0.011 mol) of N-ethyldiisopropylamine are then added thereto. After stirring at room temperature for 2 hours the solution is concentrated, extracted with methylene chloride/water, dried with sodium sulfate and the solvent is distilled in a vacuum. Chromatography on aluminum oxide with methylene chloride-methanol (97:3) and crystallization from ethyl acetate/hexane gives diethyl N-[2-(4-acetamidobutyryl)-5-chlorohydrocinnamoyl]-L-glutamate as white crystals with melting point 109°-111°.
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[C:7]([C:8]([OH:10])=O)=[C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:5]([CH3:22])[N:4]=1.Cl.[NH2:25][C@H:26]([C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34]C)=[O:33])=[CH:30][CH:29]=1)[CH3:27]>>[CH3:27][C@H:26]([NH:25][C:8]([C:7]1[C:3]([CH:2]([F:23])[F:1])=[N:4][N:5]([CH3:22])[C:6]=1[O:11][C:12]1[CH:13]=[C:14]([C:18]([F:19])([F:21])[F:20])[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:28]1[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:36][CH:37]=1
Reactant: Cn1nc(C(F)F)c(C(=O)O)c1Oc1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: C[C@H](NC(=O)c1c(C(F)F)nn(C)c1Oc1cccc(C(F)(F)F)c1)c1ccc(C(=O)O)cc1

Procedure:
Example 21 was prepared using 3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxylic acid and (S)-methyl 4-(1-aminoethyl)benzoate hydrochloride in a manner similar to the Example 4 above.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[S:8][C:9]=1[CH2:10][OH:11])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:28][O:29][C:30](=[O:40])[C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Br)=[CH:33][C:32]=1[F:39].[K]>CN(C=O)C>[CH3:28][O:29][C:30](=[O:40])[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][O:11][CH2:10][C:9]2[S:8][C:7]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:14][CH:13]=3)=[N:6][C:5]=2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:33][C:32]=1[F:39]
Reactant: COC(=O)c1ccc(CBr)cc1F
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K]
Solvent: CN(C)C=O
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COCc1ccc(C(=O)OC)c(F)c1
Reaction time: 8 h
Yield: 19.2 %

Procedure:
To a solution of [4-butyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-yl]-methanol (1.02 g, 3.24 mmol) in anhydrous DMF (150 mL) add cesium carbonate (2.7 g, 8.10 mmol) and 4-bromomethyl-2-fluoro-benzoic acid methyl ester (0.8 g, 3.24 mmol). Stir the resulting mixture overnight then pour into a 1M aqueous solution of potassium hydrogenophosphate and extracted three times with diisopropyl ether. Wash the combined extracts with water, dry over MgSO4, filter and concentrate under vacuum. Purify the residue by flash chromatography on silica gel (eluting with a gradient of heptane/ethyl acetate) to give the title compound (0.3 g) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH:15][CH:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.CC(C)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1>O>[F:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:12]=[C:11]([C:13]([NH:15][CH:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[O:10][N:9]=3)=[CH:4][CH:3]=2)=[CH:37][CH:38]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)C(NC(=O)c1cc(-c2ccc(O)cc2)no1)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)C(NC(=O)c1cc(-c2ccc(OCc3ccc(F)cc3)cc2)no1)C(C)C

Procedure:
To methyl 2-(3-(4-hydroxyphenyl)isoxazole-5-carboxamido)-3-methylbutanoate (150 mg) in, acetone (3 ml), potassium carbonate (78 mg) was added and stirred. To this 1-(bromomethyl)-4-fluorobenzene (0.07 ml) was added and the reaction mixture was refluxed for 2 hours and then cooled reaction. The mixture was filtered and filtrate was concentrated to obtain pale brown residue. To this residue, water was added and extracted with EtOAc. Organic layer was collected and dried over Na2SO4 and concentrated to obtain off white solid, which was crystallized using DCM-Petroleum ether to obtain the title compound as white solid. Yield: 170 (84%); MS (ES+): m/z 427 (M+1); 1HNMR (DMSO-d6; 300 MHz): δ 9.18 (d, 1H), 7.88 (d, 2H), 7.68 (s, 1H), 7.53 (m, 2H), 7.23 (m, 2H), 7.18 (d, 2H), 5.17 (s, 2H), 4.31 (m, 1H), 3.67 (s, 3H), 2.22 (m, 1H), 0.96 (d, 6H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[CH3:12][S:13][C:14](=[N:17][C:18]#[N:19])SC>>[C:18]([NH:17][C:14](=[N:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[S:13][CH3:12])#[N:19]
Reactant: CSC(=NC#N)SC
Reactant: NCCSCc1ccccn1
Product: CSC(=NCCSCc1ccccn1)NC#N

Procedure:
The reaction of 2-((2-aminoethyl)thiomethyl)pyridine with dimethylcyanodithioimidocarbonate by a method similar to that described in Example (3d) afforded N-cyano-N'-[2-(2-pyridylmethylthio)ethyl]-S-methylisothiourea, m.p. 85°-88°. (from isopropyl alcohol-ether) (Found: C, 49.6; H, 5.4; N, 21.0; S, 24.0% C11H14N4S2 requires: C, 49.6; H, 5.3; N, 21.0; S, 24.1%)
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].[Li]CCCC.Cl[Si:17]([CH3:28])([CH3:27])[CH:18]1[C:22]([CH3:23])=[C:21]([CH3:24])[C:20]([CH3:25])=[C:19]1[CH3:26]>C1COCC1>[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH:4][Si:17]([CH3:27])([CH3:28])[CH:18]1[C:22]([CH3:23])=[C:21]([CH3:24])[C:20]([CH3:25])=[C:19]1[CH3:26]
Reactant: CC1=C(C)C([Si](C)(C)Cl)C(C)=C1C
Reactant: Cc1cc(C)c(N)c(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=C(C)C([Si](C)(C)Nc2c(C)cc(C)cc2Br)C(C)=C1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under an argon atmosphere, to a solution of 13.9 g (69.5 mmol) of 2-bromo-4,6-dimethylaniline in 200 ml of THF, 27.9 ml of 2.5 M (69.5 mmol) nBuLi in hexanes were added at −50° C. This mixture was stirred for 2 hours at ambient temperature. The resulting solution was added dropwise over ca. 1 hour, while vigorously stirring, to a solution of 15.0 g (69.5 mmol) of chloro(dimethyl)(2,3,4,5-tetramethyl-2,4-cyclopentadien-1-yl)silane in 100 ml of THF at 0° C. The resulting mixture was stirred overnight at ambient temperature, then, evaporated to dryness. To the residue 100 ml of toluene were added. This mixture was filtered through a glass frit (G4). The filtrate was evaporated to dryness. Fractional distillation gave a yellow liquid, bp 180-184° C./0.5 mm Hg. Yield 20.1 g (77%).
Reaction SMILES: C([O:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]3[O:16][CH2:15][O:14][C:11]=3[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:17]([O:19]CC)=[O:18])C.[C:22]1(C)C=CC(S(O)(=O)=O)=C[CH:23]=1.[OH-].[Na+].Cl>>[CH2:22]([N:7]1[C:8]2[C:13](=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[C:4](=[O:3])[C:5]([C:17]([OH:19])=[O:18])=[CH:6]1)[CH3:23]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(=O)c1cnc2cc3c(cc2c1OCC)OCO3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCn1cc(C(=O)O)c(=O)c2cc3c(cc21)OCO3
Temperature: 180 °C
Yield: 4856.1 %

Procedure:
A mixture of 5 g of ethyl 4-ethoxy-6,7-methylenedioxyquinoline-3-carboxylate and 0.06 g of p-toluene-sulfonic acid was heated at 180°C for 3 hours and cooled. To the product was added 50 ml of a 5% aqueous sodium hydroxide solution. The resulting mixture was heated at 90°-100°C for 30 minutes, the acidified by the addition of dilute hydrochloric acid and cooled. The precipitate was collected by filtration, washed with water and dried. There was obtained 4.42 g of 1-ethyl-6,7-methylenedioxy-4-quinolone-3-carboxylic acid, m.p. 318°C (decomposition).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]2[CH:30]=[CH:29][C:28]([OH:31])=[C:27]3[C:22]=2[CH2:23][CH2:24][CH2:25][NH:26]3)[CH2:15][CH2:14]1.C(N(CC)CC)C>O1CCCC1>[C:1]([N:26]1[C:27]2[C:22](=[C:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][N:13]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[O:6][CH3:5])[CH2:14][CH2:15]3)[CH:30]=[CH:29][C:28]=2[OH:31])[CH2:23][CH2:24][CH2:25]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COc1ccccc1N1CCN(CCc2ccc(O)c3c2CCCN3)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(CCc2ccc(O)c3c2CCCN3C(C)=O)CC1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A solution of 1.45 ml of acetyl chloride is 20 ml of tetrahydrofuran is added at 5° C. to a solution of 7.34 g of 5-{2-[4-(2-methoxyphenyl)piperazinyl]ethyl}-8-hydroxy-1,2,3,4-tetrahydro quinoline in 140 ml of anhydrous tetrahydrofuran containing 2.8 ml of triethylamine. This is stirred for 2 hours at 5° C. and then for 1 hour at room temperature. Then, the insoluble substance is filtered off and concentrated to dryness under reduced pressure. The residue is purified by chromatoflash on 750 g of silica (70-230 mesh) by eluating with the mixture CH2Cl3 /CH3OH (95/5).
Reaction SMILES: ClC(O[C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:12])=O.[FH:13]>>[CH3:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=1[F:13]
Reactant: F
Reactant: Cc1cccc(C)c1OC(=O)Cl
Product: Cc1cccc(C)c1F
Yield: 51 %

Procedure:
1000 ml of anhydrous hydrogen fluoride were placed at 0° C. in a stainless steel laboratory autoclave and 500 g of 2,6-dimethylphenyl chloroformate were added dropwise. The reaction was carried out and the reaction mixture worked up as described in Example 9. 2,6-Dimethylfluorobenzene was obtained in a yield of 51%.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(OCC)(=O)C>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1
Solvent: CCOC(C)=O
Product: Nc1ccc(CN2CCOCC2)cc1

Procedure:
To a solution of 4-(4-Nitrobenzyl)morpholine from Preparation No. 21 (0.89 g) in ethyl acetate (10 mL) is added 5% platinuim on carbon (0.04 g). The reaction is shaken under 30 psi of hydrogen gas for 1 hour. The mixture is filtered with ethyl acetate washes. The filtrate is concentrated under reduced pressure to afford 0.71 g of the title compound as a yellow solid.
Reaction SMILES: [C:1](=[S:3])=S.[OH-].[Na+].[CH3:6][N:7]([CH2:9][C:10]1[O:14][C:13]([CH2:15][S:16][CH2:17][CH2:18][NH2:19])=[CH:12][CH:11]=1)[CH3:8].ClC(OCC)=O>O>[CH3:6][N:7]([CH3:8])[CH2:9][C:10]1[O:14][C:13]([CH2:15][S:16][CH2:17][CH2:18][N:19]=[C:1]=[S:3])=[CH:12][CH:11]=1
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: S=C=S
Agent: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)Cc1ccc(CSCCN=C=S)o1
Reaction time: 0.5 h

Procedure:
Carbon disulphide (1.52 g) was added with stirring to a cooled solution of sodium hydroxide (0.8 g) in water (1.7 ml). 2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (4.28 g) was added slowly and when addition was complete the mixture heated at 100° for 2 hr. After cooling to below 40° ethyl chloroformate (1.94 ml) was added and stirring continued for a further 30 mins. The lower thick yellow oil was extracted with chloroform, dried and evaporated to give N,N-dimethyl-5-[[[2-(isothiocyanato)ethyl]thio]methyl]furanmethanamine as an oil RF 0.43 (silica/methanol).
Reaction SMILES: C([O:5][C:6](=[O:44])[C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH:15]([C:26](=[O:43])[N:27]([C:34]2[O:42][C:38]3=[CH:39][CH:40]=[CH:41][C:37]3=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[CH3:14])=[CH:9][CH:8]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[O:42]1[C:38]2=[CH:39][CH:40]=[CH:41][C:37]2=[CH:36][CH:35]=[C:34]1[N:27]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:26]([CH:15]([N:13]([CH3:14])[C:10]1[CH:9]=[CH:8][C:7]([C:6]([OH:44])=[O:5])=[CH:12][CH:11]=1)[C:16]1[CH:17]=[CH:18][C:19]([C:22]([CH3:25])([CH3:23])[CH3:24])=[CH:20][CH:21]=1)=[O:43]
Reactant: CN(c1ccc(C(=O)OC(C)(C)C)cc1)C(C(=O)N(c1ccccc1)c1ccc2cccc-2o1)c1ccc(C(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(c1ccc(C(=O)O)cc1)C(C(=O)N(c1ccccc1)c1ccc2cccc-2o1)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 108.7 %

Procedure:
4-{[(4-Benzofuran-2-yl-phenylcarbamoyl)-(4-tert-butyl-phenyl)-methyl]-methyl-amino}-benzoic acid tert-butyl ester (˜140 mg, 0.19 mmol) was taken up in 5 mL of dichloromethane followed by addition of 0.5 mL of TFA and stirred for 16 h at RT. Removal of the organic layer and water was added to give a precipitate, which was filtered to give 110 mg (100%) of pinkish solids. LCMS (M−1=531.1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7](O)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[N:12]([O-])=[O:13].N([O-])=[O:16].[Na+].N([O-])=O.[K+]>>[N:12]([CH2:2][C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[OH:16])=[O:3])=[O:13]
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: O=N[O-]
Agent: [K+]
Agent: [Na+]
Product: O=NCC(=O)Nc1ccccc1O

Procedure:
According to this scheme 1a, the compounds of formula (Ia) are prepared by reaction of an appropriate 3-acetamidophenol compound (1) with a nitrite (2), such as a sodium nitrite (X═Na), a potassium nitrite (X═K), etc., at a temperature of −3° C. The nitroso acetamidophenol (3) thus obtained is subsequently reacted with 1,3-dihydroxynaphthalene (4) in a solvent such as butanol, by heating to a temperature of approximately 70° C., then adding concentrated sulfuric acid and continuing the heating to 90° C., and then cooling, so as to form the appropriate 9-acetamido-benzo[a]phenoxazin-5-one. The latter compound is subsequently hydrolyzed by heating with moderately concentrated sulfuric acid so as to give the 9-amino-benzo[a]phenoxazin-5-one (5). The last step is equivalent to that of scheme 1.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[OH:9].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[N:32]1[CH:37]=[C:36]([CH2:38][CH2:39][C:40]2[C:48]([C:49]3[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=3)=[CH:47][C:43]([C:44](O)=[O:45])=[CH:42][N:41]=2)[CH:35]=[N:34][CH:33]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[OH:9][C@@H:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C@H:3]1[NH:2][C:44](=[O:45])[C:43]1[CH:47]=[C:48]([C:49]2[CH:50]=[CH:51][C:52]([C:55]([F:56])([F:57])[F:58])=[CH:53][CH:54]=2)[C:40]([CH2:39][CH2:38][C:36]2[CH:35]=[N:34][CH:33]=[N:32][CH:37]=2)=[N:41][CH:42]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: O=C(O)c1cnc(CCc2cncnc2)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(CCc2cncnc2)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 44 %

Procedure:
A solution of (1R,2R)-2-amino-cyclohexanol hydrochloride (41 mg, 0.27 mmol) in N,N-dimethylformamide (1.2 ml) was added to a suspension of TBTU (234 mg, 0.73 mmol), 6-(2-pyrimidin-5-yl-ethyl)-5-(4-trifluoromethyl-phenyl)-nicotinic acid (0.24 mmol) and N-ethyldiisopropylamine (0.21 ml, 1.22 mmol) in N,N-dimethylformamide (1.7 ml). The reaction mixture was shaken at room temperature for 20 hours then concentrated in vacuo. The residue was then dissolved in dichloromethane (2 ml) and washed with water (2 ml). The aqueous layer was separated and extracted with dichloromethane (2 ml), the organics were combined and the whole was dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative HPLC to afford N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(2-pyrimidin-5-yl-ethyl)-5-(4-trifluoromethyl-phenyl)-nicotinamide, 49 mg (44% yield over 2 steps). LC at 215 nm; Rt 3.92: 92%, m/z (ES+): 471 (M+H).
Reaction SMILES: [OH-].[Na+].[C:3]([OH:6])(=[S:5])[CH3:4].[C:7]([NH:11][C:12](=[O:15])[CH2:13]Cl)(=[O:10])[CH2:8][CH3:9]>CO>[C:7]([NH:11][C:12](=[O:15])[CH2:13][S:5][C:3](=[O:6])[CH3:4])(=[O:10])[CH2:8][CH3:9]
Reactant: CCC(=O)NC(=O)CCl
Reactant: CC(O)=S
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(=O)NC(=O)CSC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Nitrogen was bubbled through 4.0 g. (0.1 mole) of sodium hydroxide in 200 ml. of methanol and to this there was added 7.1 ml. (0.1 mole) of thioacetic acid and then 16.0 g. (0.1 mole) of N-propionyl-2-chloroacetamide. The reaction mixture was stirred at ambient temperature for 2 hours and then stripped in vacuo and filtered. The product was dissolved in boiling water, treated with charcoal, filtered and dried in vacuo. A yield of 6.0 g. of white crystalline product was obtained.