Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Cl[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)=[CH:7][CH:6]=1.[C:17]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].Cl>C(OCC)(=O)C.CO.CCOCC.C(O)C>[C:17]1([N:27]2[CH2:32][CH2:31][N:30]([CH2:3][CH2:4][C:5]3[CH:10]=[CH:9][C:8]([C:11]4[N:12]=[C:13]([NH2:16])[S:14][CH:15]=4)=[CH:7][CH:6]=3)[CH2:29][CH2:28]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Reactant: Nc1nc(-c2ccc(CCCl)cc2)cs1
Agent: Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CCOCC
Product: Nc1nc(-c2ccc(CCN3CCN(c4cccc5ccccc45)CC3)cc2)cs1

Procedure:
To a 35 ml round-bottomed flask equipped with condenser and N2 inlet were added 3.19 g (10 mmol) of 4-(4-(2-chloroethyl)phenyl)-2-aminothiazole hydrobromide, 2.12 g (10 mmol) of N-(1-naphthyl)piperazine, 2.79 ml (20 mmol) of triethylamine, 1.06 g (10 mmol) of sodium carbonate, 2 mg of sodium iodide, and 25 ml of ethanol. The reaction was heated at reflux for 5 days, cooled, and the precipitate filtered, and washed with ethanol and water. The orange solid was chromatographed on silica gel using ethyl acetate/methylene chloride as eluent to give a white solid. The solid was taken up in ethyl acetate/methanol, ether saturated with HCl added, the precipitate filtered, washed with ether, and dried to give a white solid, 1.61 g (31%), m.p. 274°-277° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
4-Oxo-piperidine-1-carboxylic acid tert-butyl ester (2.99 g, 15 mmole), morpholine (1.4 mL, 15.8 mmole), acetic acid (11.0 mL, 18 mmole) were dissolved in 30 mL dichloroethane and sodium triacetoxyborohydride (6.36 g, 30 mmole) was added and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane and then washed with 2N NaOH, water, and dried (MgSO4). Filtration and evaporation gave 3.84 g (95%) 4-morpholin-4-yl-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil that solidified on standing.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[Br:22][C:23]1[CH:24]=[CH:25][C:26](=O)[NH:27][CH:28]=1>>[Br:22][C:23]1[CH:24]=[CH:25][C:26]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)=[N:27][CH:28]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Product: N#Cc1ccc(N(CCOc2ccc(Br)cn2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 27B from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (Example 15B) and 5-bromo-2(1H)-pyridinone using dry DME as the reaction solvent: MS (ESI) m/z 468 (M+1, 79Br), 470 (M+1, 81Br).
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[N:5]=[CH:4]1.Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N+:19]([C:18]1[C:13]([N:8]2[CH2:9][CH2:10][C:11]3[NH:3][CH:4]=[N:5][C:6]=3[CH2:7]2)=[N:14][CH:15]=[CH:16][CH:17]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: c1nc2c([nH]1)CCNC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccnc1N1CCc2[nH]cnc2C1
Temperature: 25 °C

Procedure:
A mixture of 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine dihydrochloride (2.0 g, 12.5 mmol; prepared essentially as described by Habermehl, E., Heterocycles 5:127,133 (1976)), 2-chloro-3-nitropyridine (1.7 g, 11.25 mmol) and K2CO3 (5.2 g, 37.5 mmol) in 25 mL of DMF is heated at 50° C. for 4 hours and then allowed to cool to room temperature. The mixture is then partitioned between ethyl acetate and water and the layers are separated. The aqueous layer is then further extracted with ethyl acetate and the combined organic extracts are dried over Na2SO4, filtered and the solvents removed under reduced pressure. Column chromatography of the residue on silica gel (5% MeOH in CH2Cl2 as eluent) gives 5-(3-nitro-pyridin-2-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine as a yellow solid (1.5 g). 1H NMR δ (CDCl3): 8.34 (d, 1H), 8.16 (dd, 1H), 7.53(s, 1H), 6.74 (q, 1H), 4.31 (s, 2H), 3.94(t, 2H) and 2.91(t, 2H). MS: 246.3 (m+1).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)C=[C:9]1C(O)=O>C(Cl)Cl>[CH3:9][N:8]1[C:16]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:1]([C:2]([Cl:4])=[O:3])=[CH:7]1
Reactant: Cn1c(C(=O)O)cc2ccccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cn1cc(C(=O)Cl)c2ccccc21
Temperature: 25 °C

Procedure:
Oxalyl chloride (7.1 mL, 81.4 mmol) in 50 mL of methylene chloride was added under nitrogen dropwise to a solution of 1-methyl-1H-indole carboxylic acid (2.86 g, 16.3 mmol) in 100 mL of methylene chloride at room temperature. After the addition the reaction was stirred at room temperature until the reaction was determined by NMR analysis to be complete. The solvent and excess oxalyl chloride were removed under reduced pressure. The residue was taken up in benzene and then concentrated to dryness under reduced pressure to give 1-methyl-1H-indole-3-carbonyl chloride, which was used in the following reaction without purification.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH:26]([C:30]#[N:31])[CH2:25]1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:23][C@@H:24]4[CH2:29][CH2:28][CH2:27][C@H:26]([C:30]#[N:31])[CH2:25]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC1CCCC(N)C1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: N#C[C@H]1CCC[C@@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Yield: 23.5 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (1.01 g, 3.00 mmol), 3-amino-cyclohexanecarbonitrile (3.30 mmol assumed) and diisopropylethylamine (2.60 mL, 15.0 mmol) in propan-2-ol (30 mL) were heated to reflux for 2 hours. The cooled reaction mixture was filtered and the yellow solid further purified by column chromatography on silica gel (gradient: 0 to 10% ethyl acetate in toluene) to afford 300 mg (23%) of cis 3-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-4-ylamino)cyclohexanecarbonitrile. 1H NMR (400 MHz, DMSO) δ: 8.90 (s, 1H), 8.80 (d, 1H), 8.13 (m, 2H), 7.84 (d, 1H), 7.76 (m, 1H), 7.66 (m 2H), 7.09 (d, 1H), 4.11 (m, 1H), 3.10 (m, 1H), 2.28 (m, 1H), 1.98 (m, 2H), 1.79 (m, 2H), 1.50 (m, 3H). The filtrate was concentrated and purified by column chromatography on silica gel (gradient: 0 to 10% ethyl acetate in toluene) to afford 220 mg (17%) of trans 3-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-4-ylamino)cyclohexanecarbonitrile. LCMS (Method I, ESI): RT=3.76 min, m+H=426.1; 1H NMR (400 MHz, DMSO) δ: 8.92 (s, 1H), 8.13 (dd, 2H), 7.88 (d, 1H), 7.77 (t, 1H), 7.65 (t, 2H), 6.99 (d, 1H), 4.27 (m, 1H), 3.26 (m, 1H), 2.18 (m, 1H), 1.99 (m, 1H), 1.91 (m, 1H), 1.83-1.58 (m, 5H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=1[Cl:22])=O)(C)(C)C.[CH3:23][CH:24]([S:26]([C:29]1[CH:30]=[C:31]([C:35]2[N:43]3[C:38]([CH:39]=[N:40][C:41](O)=[N:42]3)=[CH:37][CH:36]=2)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27])[CH3:25]>>[Cl:22][C:16]1[CH:17]=[CH:18][C:19]([NH:21][C:41]2[N:40]=[CH:39][C:38]3=[CH:37][CH:36]=[C:35]([C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([S:26]([CH:24]([CH3:25])[CH3:23])(=[O:28])=[O:27])[CH:30]=4)[N:43]3[N:42]=2)=[CH:20][C:15]=1[O:14][CH2:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1
Reactant: CC(C)S(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cc(N)ccc1Cl
Product: CC(C)S(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(Cl)c(OC[C@@H]5CCCN5)c4)nn23)c1

Procedure:
This example was prepared by using (S)-2-(5-Amino-2-chloro-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (J. Med. Chem. 2007, 50, 4353) and 7-[3-(Propane-2-sulfonyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ol as described in Example 1255c followed by deprotection as described in Example 1223. 1H-NMR (DMSO) δ 9.7 (s, 1H), 9.35 (brs, 1H), 9.0 (s, 1H), 8.9 (brs, 1H), 8.5 (s, 1H), 8.45 (d, J=7.5 Hz, 1H), 7.8 (m, 2H), 7.5 (d, J=8.7 Hz, 1H), 7.4 (m, 2H), 7.3 (d, J=4.8 Hz, 1H), 7 (d, J=4.8 Hz, 1H), 4.1 (m, 1H), 4.0 (m, 1H), 3.5 (m, 1H), 3.2 (m, 1H), 2.0 (m, 2H), 1.9 (m, 1H), 1.7 (m, 1H), 1.1 (d, J=6.5 Hz, 6H). LC/MS (ESI+): 526 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][C@@H:23]([CH2:28][CH3:29])[CH2:24][C:25](O)=[O:26].C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[CH3:22][C@@H:23]([CH2:28][CH3:29])[CH2:24][C:25]([O:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][CH:11]=2)=[CH:20][CH:19]=1)=[O:26]
Reactant: Oc1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Reactant: CC[C@H](C)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC[C@H](C)CC(=O)Oc1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
{circle around (1)}: A mixture comprising 2.8 g of 4-(4′-benzyloxyphenyl)phenol, 1.2 g of (S)-2-methylbutylcarboxylic acid, 3.09 g of DCC and 15 g of dichloromethane was stirred at room temperature for 30 minutes. Then, a catalytic amount of 4-N,N-dimethylaminopyridine was added to the mixture, and the mixture was further stirred at room temperature for 12 hours. After finishing the reaction, insoluble substances were filtered off, followed by distilling off dichloromethane from the filtrate. The resultant residue was purified by means of silica gel column chromatography, whereby 3.5 g of (S)-4-[4′-(2″-methylbutylcarbonyloxy)phenyl]-1-benzyloxybenzene was obtained in the form of a colorless crystal.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C(Cl)Cl.C([O:15][C:16]([C:18]1[N:19]=[C:20]2[CH2:25][N:24]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:23][CH2:22][N:21]2[CH:33]=1)=O)C>C1(C)C=CC=CC=1>[CH2:26]([N:24]1[CH2:23][CH2:22][N:21]2[CH:33]=[C:18]([CH:16]=[O:15])[N:19]=[C:20]2[CH2:25]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1cn2c(n1)CN(Cc1ccccc1)CC2
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=Cc1cn2c(n1)CN(Cc1ccccc1)CC2
Reaction time: 1.5 h

Procedure:
1.01 M solution of DIBAL in toluene (1 mL+0.2 mL+0.3 mL) was added to the dry CH2Cl2 (5 mL) solution of 7-benzyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid ethyl ester (283 mg) under a nitrogen atmosphere at −78° C. and stirred for 1.5 h. The mixture was quenched with 1 M HCl (5 mL). The reaction mixture was filtered through a pad of Celite. The filtrate was washed with 50% K2CO3 aq. and the aqueous layer was extracted with CH2Cl2. The combined organic layer was dried (K2CO3) and filtered. The filtrate was concentrated under reduced pressure. The residue was applied to silica gel column chromatography, then the column was eluted with CHCl3-acetone (9/1˜4/1) and CHCl3-MeOH (19/1). The titled compound was obtained as colorless crystals (148 mg, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH2:7][C:8]2[N:9]([CH3:23])[C:10]3[C:15]([C:16]=2[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1>[Pd].CN(C)C=O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH2:7][C:8]2[N:9]([CH3:23])[C:10]3[C:15]([C:16]=2[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1
Reactant: COC(=O)C=Cc1c(COc2ccc(Cl)cc2)n(C)c2ccccc12
Agent: [Pd]
Solvent: CN(C)C=O
Product: COC(=O)CCc1c(COc2ccc(Cl)cc2)n(C)c2ccccc12
Reaction time: 2 h

Procedure:
A round bottom flask was charged with 10% palladium on activated carbon (0.150 g), 20 ml of N,N-dimethylformamide and 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-(methoxycarbonyl)ethenyl]-1H-indole (1.44 g, 4.22 mmol). The reaction vessel was then placed under a hydrogen atomsphere for two hours. The reaction mixture was then passed through a CELITE™ pad and then partitioned between water and methylene chloride. The aqueous fraction was extracted twice with methylene chloride. The organic fractions were combined, washed with water and then brine, and dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by chromatography.
Reaction SMILES: FC1C=CC=CC=1OC.C([Li])CCC.CN(C)CCN(C)CCN(C)C.CI.[Cl-].[Al+3].[Cl-].[Cl-].[Br:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1.[F:43][C:44]1[C:49]([CH3:50])=[CH:48][CH:47]=[CH:46][C:45]=1[O:51][CH3:52]>C1COCC1.CCCCCC.[N+](C1C=CC=CC=1)([O-])=O>[Br:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([C:48]2[CH:47]=[CH:46][C:45]([O:51][CH3:52])=[C:44]([F:43])[C:49]=2[CH3:50])=[O:39])=[CH:36][CH:35]=1
Reactant: COc1cccc(C)c1F
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: CN(C)CCN(C)CCN(C)C
Agent: COc1ccccc1F
Agent: [Al+3]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CI
Solvent: CCCCCC
Product: COc1ccc(C(=O)c2ccc(Br)cc2)c(C)c1F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Aa) A solution of 5.6 ml of 2-fluoroanisole in 60 ml of absolute THF is cooled to -78° C. and treated within 15 min. with 31.3 ml of 1.6M butyllithium in hexane. After 15 min. 8.7 g of 1,1,4,7,7-pentamethyldiethylenetriamine are added dropwise and, after a further 2 hrs. at -78° C., 9.4 ml of methyl iodide are added dropwise. The mixture is stirred at -78° C. overnight, then evaporated and taken up in ether/1N hydrochloric acid. The aqueous phase is extracted with ether and the organic phase is dried over sodium sulphate and evaporated in order to give crude 2-fluoro-3-methyl-anisole. 30 ml of nitrobenzene are cooled in an ice bath and then treated in succession with 8.1 g of aluminium chloride and 11.9 g of 4-bromobenzoyl chloride in 9 ml of nitrobenzene at a maximum 6° C. The mixture is stirred and then the 2-fluoro-3-methyl-anisole is added in such a manner that the temperature does not rise above 6° C. The solution is left to warm to room temperature overnight, poured into ice-water/ ethyl acetate and washed with 10% aqueous sodium chloride solution, dried and concentrated. After chromatography over silica gel with hexane/ether (95/5) as the eluent and crystallization from hexane there are obtained 4.0 g of (4-bromo-phenyl)-(3-fluoro-4-methoxy-2-methyl-phenyl)-methanone, m.p. 93-95° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13]([F:16])([F:15])[F:14].Cl.[NH:18]1[CH2:22][CH2:21][CH:20]([CH2:23][OH:24])[CH2:19]1.C(=O)([O-])[O-].[K+].[K+].O.C(OCC)(=O)C>CN(C)C=O>[F:14][C:13]([F:16])([F:15])[C:4]1[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:3]=1[CH2:2][N:18]1[CH2:22][CH2:21][CH:20]([CH2:23][OH:24])[CH2:19]1
Reactant: OCC1CCNC1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: OCC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.3 %

Procedure:
To a solution of 1-(bromomethyl)-2,4-bis(trifluoromethyl)benzene (7.29 g) in N,N-dimethylformamide (10 mL) were added pyrrolidin-3-ylmethanol hydrochloride (4.9 g) and potassium carbonate (9.84 g), and the mixture was stirred at room temperature for 3 hr. Water/ethyl acetate were added to the reaction mixture, and the organic layer was separated, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (5.00 g).
Reaction SMILES: [Cl:1]C(OCC)=O.[Cl:7][C:8]1[CH:35]=[CH:34][C:11]([CH2:12][NH:13][C:14]([C:16]2[C:17](=[O:33])[C:18]3[CH:25]=[C:24]([CH2:26]N4CCOCC4)[O:23][C:19]=3[N:20]([CH3:22])[CH:21]=2)=[O:15])=[CH:10][CH:9]=1.C(Cl)Cl.O>C(OCC)C>[Cl:7][C:8]1[CH:35]=[CH:34][C:11]([CH2:12][NH:13][C:14]([C:16]2[C:17](=[O:33])[C:18]3[CH:25]=[C:24]([CH2:26][Cl:1])[O:23][C:19]=3[N:20]([CH3:22])[CH:21]=2)=[O:15])=[CH:10][CH:9]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)oc21
Reactant: CCOC(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)oc21
Temperature: 39.5 °C
Reaction time: 2 h

Procedure:
Ethyl chloroformate (150.1 ml) was added to a suspension of N-(4-chlorobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 1, 262.0 g) and CH2Cl2 with very low water content (2.63 L). The slurry was warmed to 39-40° C. After 2 h, the reaction mixture was cooled to room temperature and ethyl ether (2.63 L) was added. The mixture was stirred overnight, filtered, was washed with ethyl ether (3×2 L), and dried in a vacuum oven (40° C.) to afford 221.8 g of the title compound as a colorless solid. Physical characteristics. 1H NMR (400 MHz, TFA-d) δ 11.50, 8.94, 7.23, 4.64, 4.27; 13C NMR (100 MHz, TFA-d) δ 167.3, 165.2, 155.8, 155.1, 140.4, 134.2, 132.7, 128.4, 128.3, 113.5, 110.6, 103.8, 43.4, 38.9, 33.8. Anal. Found: C, 55.89; H, 3.69; N, 7.60; Cl, 18.98.
Reaction SMILES: [C:1]([C@:4]1([OH:26])[CH2:21][C:20]2[C:19]([OH:22])=[C:18]3[C:9]([C:10](=[O:24])[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=4[C:17]3=[O:23])=[C:8]([OH:25])[C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C1CNC(=O)C1.[Br:33][Br-]Br>O1CCCC1>[Br:33][CH2:2][C:1]([C@:4]1([OH:26])[CH2:21][C:20]2[C:19]([OH:22])=[C:18]3[C:9]([C:10](=[O:24])[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=4[C:17]3=[O:23])=[C:8]([OH:25])[C:7]=2[CH2:6][CH2:5]1)=[O:3]
Reactant: CC(=O)[C@@]1(O)CCc2c(O)c3c(c(O)c2C1)C(=O)c1ccccc1C3=O
Agent: O=C1CCCN1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)c2c(O)c3c(c(O)c21)CC[C@](O)(C(=O)CBr)C3

Procedure:
Reaction of 9(R)-acetyl-6,9,11-trihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione ([α]D20 =-87° (c=0.1, CHCl3)) (11.5 g) with pyrrolidone hydrotribromide (18.19 g) was effected in tetrahydrofuran (1380 mg) at room temperature for 40 hours. After removing insoluble matters by filtration, the solvent was distilled off under reduced pressure to give 9(R)-bromoacetyl-6,9,11-trihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione, which was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12](=[O:15])[CH2:13]Cl)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([NH2:30])[CH:24]=2)=[CH:19][CH:18]=1.[I-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12](=[O:15])[CH2:13][NH:30][C:25]2[CH:24]=[C:23]([C:20]3[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=3)[CH:28]=[CH:27][C:26]=2[CH3:29])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(-c2ccc(F)cc2)cc1N
Reactant: O=C(CCl)Nc1ccc(Cl)cc1C(=O)O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccc(F)cc2)cc1NCC(=O)Nc1ccc(Cl)cc1C(=O)O
Yield: 20 %

Procedure:
1.0 g (4.0 mmol) of 5-chloro-2-[(chloroacetyl)amino]benzoic acid, 1.78 g (8.9 mmol) of 4′-fluoro-4-methylbiphenyl-3-amine, and 60 mg (0.4 mmol) of sodium iodide were stirred in 3 mL of DMF at 90° C. for 5.5 hours. Thereafter, the reaction mixture was diluted with ethyl acetate and washed with 1N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography. The separated fractions containing a target compound were combined and condensed. Ethyl acetate was added to the residue, and solids were collected by filtration. The resulting solids were recrystallized using ethyl acetate/n-hexane, thereby giving 334 mg of the target 5-chloro-2-{[N-(4′-fluoro-4-methylbiphenyl-3-yl)glycyl]amino}benzoic acid (yield: 20%).
Reaction SMILES: [CH:1]([C:4]1[S:8][C:7]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)=[O:11])=[N:6][CH:5]=1)([CH3:3])[CH3:2].C(O)(=O)C.O>C(O)C.[Fe]>[CH:1]([C:4]1[S:8][C:7]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=2)=[O:11])=[N:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cnc(NC(=O)Nc2cccc([N+](=O)[O-])c2)s1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC(C)c1cnc(NC(=O)Nc2cccc(N)c2)s1
Yield: 60.2 %

Procedure:
A mixture of 1.55 g (5.05 mmol) of (5-isopropyl-1,3-thiazol-2-yl)-N′-(3-nitrophenyl)urea prepared as described in example 5 and 0.98 g ((17.7 mmol) of iron dust with 2.02 ml (35.35 mmol) of glacial acetic acid in 50 ml of ethanol was stirred at reflux under argon atmosphere. After 5 hours 1.5 l of water was added and the product extracted with ethylacetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated. The residue was finally purified by chromatography on a silica gel column (chloroform/methanol 47/3) giving 0.84 g of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]([CH3:17])[C:5](O)([C:12]([F:15])([F:14])[F:13])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].CC1C=CC(S(O)(=O)=O)=CC=1>ClCCl>[NH2:1][C:2]1[S:3][C:4]([CH3:17])=[C:5]([C:12]([F:14])([F:13])[F:15])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C1=C(N)SC(C)C1(O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCOC(=O)c1c(N)sc(C)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed ethyl 2-amino-4-hydroxy-5-methyl-4-(trifluoromethyl)-4,5-dihydrothiophene-3-carboxylate (5.7 g, 21.01 mmol, 1.00 equiv), dichloromethane (20 mL), 4-methylbenzene-1-sulfonic acid (3.6 g, 20.91 mmol, 0.99 equiv). The resulting solution was stirred overnight at 25° C. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (40/60). The collected fractions were combined and concentrated under vacuum. This resulted in 3.95 g (71%) of ethyl 2-amino-5-methyl-4-(trifluoromethyl)thiophene-3-carboxylate as yellow oil.