Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]1[S:8][C:9]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:20]#[N:21])[CH:16]=3)[C:10]=2[N:11]=1)([CH3:5])[CH3:4].CCCCCC.[C:28](OCC)(=[O:30])C>>[CH3:4][C:3]1([CH3:5])[CH2:2][O:1][C:28](=[O:30])[N:6]1[C:7]1[S:8][C:9]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:20]#[N:21])[CH:16]=3)[C:10]=2[N:11]=1
Reactant: CCOC(C)=O
Reactant: CC(C)(CO)Nc1nc2c(s1)CCc1cc(C#N)ccc1-2
Solvent: CCCCCC
Product: CC1(C)COC(=O)N1c1nc2c(s1)CCc1cc(C#N)ccc1-2
Yield: 93 %

Procedure:
In the same manner as described in step 4 of Example 4, replacing 2-fluoro-4-{2-[(2-hydroxy-1,1-dimethyl-ethyl)amino]-1,3-thiazol-4-yl}benzonitrile with 2-[(2-hydroxy-1,1-dimethylethyl)amino]-4,5-dihydronaphtho[1,2-d][1,3]thiazole-7-carbonitrile, prepared in the previous step, and purification of the crude product on silica using a stepwise gradient of 6:1 to 1:1 hexane:ethyl acetate as the eluent gave the title compound (2.7 g, 93%), mp>230° C. (dec.).
Reaction SMILES: [CH3:1][C:2]([OH:16])([CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:3]#[CH:4].CN(C)[CH2:19][CH2:20]N(C)C>N1C=CC=CC=1>[CH3:13][CH:12]([CH2:11][CH2:10][CH2:9][CH:19]([CH3:20])[CH2:7][CH2:6][CH2:5][C:2]([CH3:1])([OH:16])[C:3]#[C:4][C:4]#[C:3][C:2]([CH3:1])([OH:16])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:13])[CH3:14])[CH3:14]
Reactant: CN(C)CCN(C)C
Reactant: C#CC(C)(O)CCCC(C)CCCC(C)C
Solvent: c1ccncc1
Product: CC(C)CCCC(C)CCCC(C)(O)C#CC#CC(C)(O)CCCC(C)CCCC(C)C
Yield: 81.8 %

Procedure:
In a 1-l three-necked and round-bottomed flask 10.5 g of 3,7,11-trimethyldodeca-1-yne-3-ol, 5.0 g of cuprous chloride, 12.0 g of tetramethylethylenediamine and 675 ml of pyridine were placed and the mixture was subjected to oxydative coupling reaction at 50° ~ 55° C for 6 hours under an oxygen atmosphere. After completion of the reaction, there remained no unreacted starting alcohol. The pyridine was distilled off the reaction system and 300 ml of benzene and 200 ml of water were added to the residue and decanted. The organic layer was washed with 3N--H2SO4 and water, and dried. The benzene was distilled off to afford 8.55 g of 2,6,10,15,19,23-hexamethyltetracosa-11,13-diyne-10,15-diol. A 5.0 g portion of this product was dissolved in 10 ml of n-hexane and 0.25 g of 3 % palladium on active carbon was added thereto. The mixture was subjected to hydrogenation at a temperature of 60° C of under a hydrogen pressure of 3 ~ 5 kg/cm2 to give 4.6 g of the product consisting of the compounds (V) and (VI) in the ratio of 95.0 : 5.0 % respectively.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[CH2:19][CH2:20][NH2:21].C(=O)(O)[O-].[Na+].O>CCO>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([NH:21][CH2:20][CH2:19][C:13]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=2[Cl:11])[CH:7]=1
Reactant: NCCc1ccc(Cl)cc1Cl
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CSc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Temperature: 85 °C
Yield: 72.3 %

Procedure:
A mixture of 4,6-dichloro-2-methylsulfanyl-pyrimidine (2.66 g, 13.6 mmol), 2-(2,4-dichloro-phenyl)-ethylamine (2.26 mL, 15 mmol) and sodium bicarbonate (2.29 g, 27.2 mmol) in EtOH (35 mL) is heated to 85° C. for 1 hour and poured into water (100 mL). The solid precipitate is collected by filtration and dissolved in hot EtOH (75 mL). After cooling overnight the crystals that formed are collected by filtration and dried to afford (6-chloro-2-methylsulfanyl-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine (3.43 g, 72%) as a solid.
Reaction SMILES: Br.[OH:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([OH:11])=[O:10])[CH:4]=1.[ClH:12].[CH2:13](O)[CH3:14]>>[ClH:12].[OH:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([O:11][CH2:13][CH3:14])=[O:10])[CH:4]=1
Reactant: CCO
Reactant: O=C(O)c1cc(O)ccn1
Agent: Br
Agent: Cl
Product: CCOC(=O)c1cc(O)ccn1
Temperature: 0 °C

Procedure:
To a 1 l. round bottom flask was added 45.5 g (0.21 mol) of 4-hydroxy-2-pyridinecarboxylic acid hydrobromide and 500 ml of ethanol saturated with hydrochloric acid. The mixture was heated to reflux overnight, cooled and concentrated under vacuum to 1/3 of its original volume. After cooling the mixture to about 0° C., the resultant crystals were collected by vacuum filtration, washed with ethanol and diethyl ether, and dried under vacuum to afford 29.5 g of ethyl 4-hydroxy-2-pyridinecarboxylate hydrochloride.
Reaction SMILES: [CH3:1][CH:2](OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]3[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]3)[N:12]=2)=[CH:7][CH:6]=1.[C-:39]#[N:40].[Na+]>CN(C=O)C>[CH3:1][CH:2]([CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]3[CH2:19][C:20]([CH3:27])([CH3:26])[NH:21][C:22]([CH3:24])([CH3:25])[CH2:23]3)[N:12]=2)=[CH:9][CH:10]=1)[C:39]#[N:40]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OC(C)CCc2ccc(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)cc2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C#N)CCc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)cc1

Procedure:
The title compound was prepared from toluene-4-sulfonic acid 1-methyl-3-{4-[2-(2,2,6,6-tetramethyl-piperidin-4-ylamino)-pyrimidin-4-yl]-phenyl}-propyl ester (Step A of Example 196) and NaCN in DMF. Yield 11 mg (72%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:23])=[C:4]([OH:22])[C:5]([CH:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH2:11]O)=[C:6]([CH3:9])[C:7]=1[CH3:8]>CCCCCC.C(OCC)(=O)C>[Br:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]2[CH:10]([C:13]3[CH:14]=[CH:15][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:17][CH:18]=3)[CH2:11][O:22][C:4]=2[C:3]=1[CH3:23]
Reactant: Cc1c(C)c(C(CO)c2ccc(C(C)C)cc2)c(O)c(C)c1Br
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1Br)OCC2c1ccc(C(C)C)cc1
Yield: 57 %

Procedure:
Using 3-bromo-6-(2-hydroxy-1-(4-isopropylphenyl)ethyl)-2,4,5-trimethylphenol synthesized in Reference Example 234, the title compound was synthesized in the same manner as in Reference Example 13. Yield 57%. Melting point: 56-57° C. (hexane-ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][NH:12][CH2:11][CH:10]2[N:14]([CH3:29])[C:15](=[O:28])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:30][C:31]1[N:35]=[C:34]([C:36]2[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][CH:37]=2)[O:33][N:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:40](=[O:41])[C:39]3[CH:38]=[CH:37][C:36]([C:34]4[O:33][N:32]=[C:31]([CH3:30])[N:35]=4)=[CH:44][CH:43]=3)[CH2:11][CH:10]2[N:14]([CH3:29])[C:15](=[O:28])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([C:24]([F:27])([F:25])[F:26])[CH:17]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1noc(-c2ccc(C(=O)O)cc2)n1
Reactant: COc1ccc(C(=O)N(C)C2CNCC2c2ccc(Cl)c(Cl)c2)cc1C(F)(F)F
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)c3ccc(-c4nc(C)no4)cc3)CC2c2ccc(Cl)c(Cl)c2)cc1C(F)(F)F

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzoyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide was prepared from N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using 4-(3-methyl-1,2,4-oxadiazol-5-yl)-benzoic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a light yellow oil. MS m/e: 633.1 [M]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[NH:7][C:8](=[N:23][C:24](=[O:41])[CH2:25][C:26]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH:39]=[CH2:40])=[CH:33][CH:32]=1)=[N:27][O:28][CH2:29][CH3:30])[CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([NH:17][C:18](=[O:21])[CH2:19]Br)=[C:12]([Cl:22])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:44]([NH2:49])[CH2:45][CH2:46][CH:47]=[CH2:48].C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([O:5][C:6](=[O:42])[NH:7][C:8](=[N:23][C:24](=[O:41])[CH2:25][C:26]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH:39]=[CH2:40])=[CH:33][CH:32]=1)=[N:27][O:28][CH2:29][CH3:30])[CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([NH:17][C:18](=[O:21])[CH2:19][NH:49][CH2:44][CH2:45][CH2:46][CH:47]=[CH2:48])=[C:12]([Cl:22])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCOc1ccc(C(CC(=O)N=C(Cc2cc(Cl)c(NC(=O)CBr)c(Cl)c2)NC(=O)OC(C)(C)C)=NOCC)cc1
Reactant: C=CCCCN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCCNCC(=O)Nc1c(Cl)cc(CC(=NC(=O)CC(=NOCC)c2ccc(OCC=C)cc2)NC(=O)OC(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl-1-(3-(4-(allyloxy)phenyl)-3-(ethoxyimino)-propanoylimino)-2-(4-(2-bromoacetamido)-3,5-dichlorophenyl)ethylcarbamate (100 mg) in dichloromethane (0.30 mL) at room temperature was added pent-4-en-1-amine hydrochloride (51 mg) and diisopropylethylamine (97 μL), and the resulting solution was stirred at room temperature for 2 h. The solvents were removed in vacuo to give the title compound as a white solid, which was used in Step B without purification. retention time: 2.14 min (method A). MS (ESI) (M+H)+ 703.24.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][NH:16][C:15]1=[O:19])[CH:6]=O.[NH2:20][OH:21]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][NH:16][C:15]1=[O:19])[CH:6]=[N:20][OH:21]
Reactant: COc1cc(C=O)ccc1OCCN1CCNC1=O
Reactant: NO
Solvent: CCO
Product: COc1cc(C=NO)ccc1OCCN1CCNC1=O
Reaction time: 4.5 h

Procedure:
To a solution of 3-methoxy-4-[2-(2-oxoimidazolidin-1-yl)ethoxy]benzaldehyde (25.6 g, 0.097 mol) in EtOH (250 mL) at 52° C. is added a solution of hydroxylamine (10.2 g, 0.155 mol, 50% in water, Aldrich) in EtOH (20 mL). The reaction medium is then stirred for 4.5 hours between 50 and 60° C. The reaction medium is then concentrated under reduced pressure (Tbath=42° C., 60 mbar) so as to obtain a residue of 70-80 mL. The precipitate obtained is filtered, washed with an EtOH/water mixture (twice 5 mL/15 mL) and dried under atmospheric pressure at room temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][C:22]2[N:23](CC3C=CC=CC=3)[CH:24]=[CH:25][N:26]=2)=[C:9]1[C:34]([O:36][CH2:37][CH3:38])=[O:35].Cl.CC(C)=O>C(O)C.[Pd]>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][C:22]2[NH:26][CH:25]=[CH:24][N:23]=2)=[C:9]1[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: CCOC(=O)C1=C(COCc2nccn2Cc2ccccc2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(COCc2ncc[nH]2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Yield: 47.8 %

Procedure:
4-(2-Chlorophenyl)-2-[(1-benzyl-2-imidazolyl)methoxymethyl]-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (Example 10) (2 g) was dissolved in ethanol (70 ml) and acidified with hydrogen chloride gas. Then 10% palladium on charcoal catalyst (0.25 g) was added and the suspension was stirred under hydrogen at 50 p.s.i. and room temperature overnight. Examination of the reaction mixture by t.l.c. showed that about one third of the starting material had been converted to a more polar product. The catalyst was removed by filtration, the ethanol was evaporated and the residue partitioned between chloroform (50 ml) and dilute aqueous ammonia (30 ml). The chloroform solution was dried (Na2CO3), filtered and evaporated. The residue was dissolved in a little toluene and chromatographed on silica (t.l.c. grade, 6 g). Elution with toluene removed unreacted starting material; elution with chloroform and then chloroform plus 2-4% v/v methanol gave the product, which was converted to the hydrochloride salt by addition of ethereal hydrogen chloride to an acetone solution of the free base. Recrystallisation of the hydrochloride salt from methanol-ethyl acetate (1:4) gave the title compound (430 mg), m.p. 190° C.
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.CCCCCC.[CH3:33][O:34][C:35]1[C:40]([CH:41]=O)=[CH:39][N:38]=[C:37]2[N:43]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[CH:44]=[CH:45][C:36]=12>C1COCC1>[CH3:33][O:34][C:35]1[C:40]([CH:41]=[CH2:2])=[CH:39][N:38]=[C:37]2[N:43]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[CH:44]=[CH:45][C:36]=12
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1c(C=O)cnc2c1ccn2COCC[Si](C)(C)C
Agent: [I-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=Cc1cnc2c(ccn2COCC[Si](C)(C)C)c1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.7 %

Procedure:
To a solution methyltriphenylphosphonium iodide (782 mg, 1.93 mmol) in dried THF (5 mL) was added 2.5 M n-BuLi in Hexane (0.74 mL, 1.85 mmol) at −78° C. After 10 minutes, 4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (493 mg, 1.61 mmol) was added to the reaction mixture. The reaction mixture was warmed to room temperature spontaneously. After 2 hours, the reaction mixture was quenched with water and was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, celite filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using (5% to 15% Ethyl acetate/Hexane) as a solvent to afford title compound (371 mg, 76% yield). 1H NMR (600 MHz, CDCl3) δ 8.40 (s, 1H), 7.27 (d, J=3.6 Hz, 1H), 7.07 (dd, J=11.4, 18 Hz, 1H), 6.78 (d, J=3.6 Hz, 1H), 5.78 (d, J=18 Hz, 1H), 5.70 (s, 2H), 5.30 (d, J=11.4 Hz, 1H), 4.38 (s, 3H), 3.60 (t, J=8.4 Hz, 2H), 0.97 (t, J=8.4 Hz, 2H), 0 (s, 9H). MS m/z: 305 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13]Cl)[CH:6]=[C:5]2[CH:15]=[O:16].[I-:17].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][I:17])[CH:6]=[C:5]2[CH:15]=[O:16]
Reactant: O=Cc1cn(CCCCl)c2ccc(Cl)cc12
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: O=Cc1cn(CCCI)c2ccc(Cl)cc12
Temperature: 25 °C
Yield: 95.9 %

Procedure:
A stirred solution of 5-chloro-1-(3-chloropropyl)indole-3-carboxaldehyde (3.8 g, 15 mmol) and sodium iodide (4.5 g, 30 mmol) in acetonitrile (50 mL) under argon was heated under reflux for 18 h, cooled to room temperature and partitioned between ether (3×30 mL) and water (50 mL). The combined organic extracts were washed (aqueous sodium metabisulfite solution, water, brine), dried (sodium sulfate) and concentrated in vacuo to give the product as a yellow oil (5.0 g, 96%) which was used immediately.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([OH:24])[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:45][S:46][C:47]1[CH:48]=[C:49]([CH2:53][CH2:54]O)[CH:50]=[CH:51][CH:52]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:54][CH2:53][C:49]3[CH:50]=[CH:51][CH:52]=[C:47]([S:46][CH3:45])[CH:48]=3)[CH:17]=2)[CH2:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13]1)=[O:4]
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(O)c2)Cc2ccccc2C1
Reactant: CSc1cccc(CCO)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(SC)c3)c2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.8 %

Procedure:
The compound of step 2 (0.380 g, 1.11 mmol) and triphenylphosphine (0.461 g, 1.67 mmol) were dissolved in THF. 2-(3-Methylsulfanyl-phenyl)-ethanol (0.281 g, 1.67 mmol) and DIAD (0.359 g, 1.67 mmol) were added and the reaction mixture was stirred at room temperature for 2 h. The volatiles were evaporated in vacuo and the residue was purified by preparative RP HPLC (water/ACN gradient) to give 0.217 g of the title compound.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].C(=O)([O-])[O-].[Na+].[Na+].[CH2:26]([N:28]([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][N:33]1[CH2:38][CH2:39][NH2:40])[CH2:29][CH3:30])[CH3:27]>C(#N)C>[CH2:26]([N:28]([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][N:33]1[CH2:38][CH2:39][NH:40][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3])[CH2:29][CH3:30])[CH3:27]
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: CCN(CC)CC1CCCCN1CCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCN(CC)CC1CCCCN1CCNC(=O)N1c2ccccc2C(=O)Nc2cccnc21

Procedure:
3.2 g (0.0117 mol) of 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 1.27 g (0.012 mol) of anhydrous sodium carbonate were heated to 60° C. for 4 hours in 100 ml of dry acetonitrile together with 3.0 g (0.014 mol) of 2-[2-[(diethylamino)-methyl]-piperidin-1-yl]ethanamine with stirring. The mixture was filtered while hot, the filtrate was cooled and the substance which crystallised out was suction filtered. 2.7 g (51% of theory) of colourless cyrstals were obtained, m.p. 175°-176° C.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9]O)[CH2:5][CH2:4]1.P(Br)(Br)[Br:12]>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:9][CH:6]1[CH2:7][CH2:8][CH:3]([O:2][CH3:1])[CH2:4][CH2:5]1
Reactant: COC1CCC(CO)CC1
Reactant: BrP(Br)Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC1CCC(CBr)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Methoxycyclohexylmethanol (10.5 g) was dissolved in carbon tetrachloride (45 g) and cooled with ice. Phosphorus tribromide (2.8 ml) was added dropwise to the above solution and stirred at ambient temperature overnight. The carbon tetrachloride layer was decanted and dried over magnesium sulfate. After filtering, the carbon tetrachloride from the filtrate was evaporated to yield pale yellow colored liquid of bromomethyl-4-methoxycyclohexane.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])=[O:7].[C:17]1(=[O:23])[CH2:22][CH2:21][CH2:20][CH:19]=[CH:18]1.Cl>C1(C)C=CC=CC=1>[C:9]([CH:8]([CH:19]1[CH2:20][CH2:21][CH2:22][C:17](=[O:23])[CH2:18]1)[C:6]([O:5][CH2:4][CH3:3])=[O:7])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C1C=CCCC1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)c1ccccc1)C1CCCC(=O)C1
Reaction time: 36 h
Yield: 66.6 %

Procedure:
To a suspension of 60 mg (0.0025 mole) of sodium hydride in 7 ml of toluene was added 4.32 ml (0.025 mole) of ethyl benzoyl acetate. After several minutes a solution was obtained to which was added 2.41 ml (0.025 mole) of cyclohexenone. The reaction was stirred 36 hrs. at room temperature and then added to 25 ml 1 N hydrochloric acid--25 ml saturated sodium chloride--150 ml ether. The ether extract was dried over magnesium sulfate and evaporated to an oil. This crude oil was purified via column chromatography on 300 g of silica gel eluted with 50% ether--pentane to yield 4.8 g (67%) of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][CH2:12][NH2:13])=[CH:4][N:3]=1.[N+:14]([NH:17][C:18](N)=N)([O-:16])=[O:15]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:10][CH2:11][CH2:12][NH:13][C:18]2=[N:17][N+:14]([O-:16])=[O:15])=[CH:4][N:3]=1
Reactant: N=C(N)N[N+](=O)[O-]
Reactant: NCCCNCc1ccc(Cl)nc1
Solvent: O
Product: O=[N+]([O-])N=C1NCCCN1Cc1ccc(Cl)nc1
Temperature: 80 °C
Yield: 45.2 %

Procedure:
A solution composed of N-(2-chloro-5-pyridylmethyl)trimethylenediamine (10 g), nitroguanidine (5.7 g) and water (80 ml) was heated at 80° C. for 3 hours. The reaction mixture was cooled to room temperature, and extracted twice with 50 ml of dichloromethane. Dichloromethane was distilled off from the extracts, and the tarry residue was purified by silica gel column chromatography to give almost colorless 1-(2-chloro-5-pyridylmethyl)-2-(nitroimino)tetrahydropyrimidine (6.1 g).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7]2([CH3:13])[CH2:11][C:10](=[O:12])[NH:9][NH:8]2)=[CH:3][CH:2]=1.[Cl:20]Cl>C(O)(=O)C>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:1]2[CH:6]=[CH:5][C:4]([C:7]3([CH3:13])[CH2:11][C:10](=[O:12])[NH:9][NH:8]3)=[CH:3][CH:2]=2)=[CH:19][CH:18]=1
Reactant: ClCl
Reactant: CC1(c2ccc(-c3ccccc3)cc2)CC(=O)NN1
Solvent: CC(=O)O
Product: CC1(c2ccc(-c3ccc(Cl)cc3)cc2)CC(=O)NN1

Procedure:
25.2 g of 3-(4-biphenylyl)-3-methyl-pyrazolidin-5-one are dissolved in 200 ml of acetic acid, a solution of 7.1 g of chlorine in 200 ml of acetic acid is added dropwise while stirring, and the mixture is stirred for a further hour and evaporated. Working up in the usual manner gives 3-(4'-chloro-4-biphenylyl)-3-methyl-pyrazolidin-5-one, m.p. 214°-215°.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:11])([CH3:3])[CH3:2].[Cl:12][S:13](O)(=[O:15])=[O:14]>C(Cl)Cl>[Cl:12][S:13]([C:8]1[CH:7]=[CH:6][C:5]([O:10][CH3:11])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:9]=1)(=[O:15])=[O:14]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccccc1C(C)C
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)Cl)cc1C(C)C
Temperature: 0 °C

Procedure:
To a solution of 2-isopropylanisole (0.40 g, 2.66 mmol) in CH2Cl2 (9 mL) cooled with an ice water bath was added slowly chlorosulfonic acid (4 mL). After 1.5 h of cooling, the mixture was poured into a flask containing ice (25 g). The product was extracted with CH2Cl2 (50 mL). The organic extract was washed with brine (25 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford 0.62 g of grayish oil as crude product. The crude product was purified by chromatography using the ISCO Combiflash SQ16x system (0 to 20% EtOAc in hexane, 20 min gradient, 35 g Redisep silica gel column) to give 0.56 g (84%) of compound 50a as a clear oil.
Reaction SMILES: CS(C)=O.[NH2:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]([C:21]([OH:23])=[O:22])=[CH:16][N:11]3[C@@H:12]([CH3:15])[CH2:13][O:14][C:9]([C:10]=23)=[C:8](F)[C:7]=1[F:25].C(OC([NH:33][C:34]12[CH2:39][CH:38]1[CH2:37][NH:36][CH2:35]2)=O)(C)(C)C>C(N(CC)CC)C>[NH2:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]([C:21]([OH:23])=[O:22])=[CH:16][N:11]3[C@@H:12]([CH3:15])[CH2:13][O:14][C:9]([C:10]=23)=[C:8]([N:36]2[CH2:37][CH:38]3[C:34]([NH2:33])([CH2:39]3)[CH2:35]2)[C:7]=1[F:25]
Reactant: CC(C)(C)OC(=O)NC12CNCC1C2
Reactant: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C[C@H]1COc2c(N3CC4CC4(N)C3)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 62.9 %

Procedure:
To a dimethyl sulfoxide (5 ml) solution of 8-amino-9,10-difluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid (200 mg, 0.68 mmol) were added 1-tert-butoxycarbonylamino-3-azabicyclo[3.1.0]hexane (Fr. 1; 270 mg, 1.36 mmol) and triethylamine (1 ml), and the mixture was heated at 100° C. for 24 hours. After evaporation of the solvent under a reduced pressure, the thus obtained residue was mixed with chloroform (50 ml), the resulting solution was washed with 10% citric acid (20 ml×2) and dried over sodium sulfate, and then the solvent was evaporated under a reduced pressure. The thus obtained residue was mixed with concentrated hydrochloric acid (5 ml) and stirred at room temperature for 5 minutes, and the mixture was washed with chloroform (30 ml×3), alkalified by adding 20% sodium hydroxide aqueous solution, then, adjusted to pH 7.2 with concentrated hydrochloric acid and extracted with chloroform (50 ml×3). The extract was dried over sodium sulfate, and the solvent was evaporated under a reduced pressure to yield 201 mg of the crude title compound. By recrystallizing this from 28% ammonia aqueous solution-ethanol, 160 mg (63%) of the title compound was obtained.