Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:43]=[CH:42][C:7]([O:8][CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][NH:25][C:26]([C:28]3[CH:29]=[CH:30][C:31]([C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=4)=[N:32][CH:33]=3)=[O:27])=[CH:18][CH:17]=2)[C:10]([O:12]CC)=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][NH:25][C:26]([C:28]3[CH:29]=[CH:30][C:31]([C:34]4[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=4)=[N:32][CH:33]=3)=[O:27])=[CH:20][CH:21]=2)[C:10]([OH:12])=[O:11])=[CH:42][CH:43]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccc(OC)cc3)nc2)cc1)Oc1ccc(C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(-c2ccc(C(=O)NCCOc3ccc(CC(Oc4ccc(C(C)C)cc4)C(=O)O)cc3)cn2)cc1
Yield: 94.6 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-(4-isopropylphenoxy)-3-[4-[2-[2-(4-methoxyphenyl)pyridine-5-carbonylamino]ethoxy]phenyl]propionate (170 mg), which is the product of Example 98, was reacted with aqueous sodium hydroxide solution (1N, 0.58 ml) and the reaction mixture was treated to give the title compound (153 mg) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][C:6]([N+:13]([O-])=O)=[C:5]2[NH:16][C@H:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][C@@H:18]1[F:30].S(S([O-])=O)([O-])=O.[Na+].[Na+].CCOC(C)=O.CCCCCC>O1CCOCC1>[NH2:13][C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:16][C@H:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:19][C@@H:18]1[F:30])=[CH:3][C:2]([Br:1])=[C:11]([F:12])[CH:10]=2
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2c([N+](=O)[O-])cnc3cc(F)c(Br)cc23)[C@@H](F)C1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2c(N)cnc3cc(F)c(Br)cc23)[C@@H](F)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 107.3 %

Procedure:
(3S,4S)-tert-butyl 4-((6-bromo-7-fluoro-3-nitroquinolin-4-yl)amino)-3-fluoropiperidine-1-carboxylate (27 g, 0.055 mol) was taken in 1,4-dioxane (150 mL). Solution of sodium dithionite (29 g, 0.166 mol in 150 mL water) was added at RT and the resulting mixture was stirred for 5 h at RT. The reaction was monitored by TLC (50% EtOAc/hexane), after completion of reaction the reaction mixture was poured into ice water and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine and water, dried over sodium sulphate. The organic layer was evaporated under vacuum, to afford the (3S,4S)-tert-butyl 4-((3-amino-6-bromo-7-fluoroquinolin-4-yl)amino)-3-fluoropiperidine-1-carboxylate, 2 (27 g). This material used directly in next step without purification. LCMS: 99.5%, m/z=456.7 (M+).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:67]([CH3:70])[CH2:68][CH3:69])[C@H:26]([O:65][CH3:66])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:63][CH3:64])[C@@H:36]([CH3:62])[C:37]([NH:39][C@@H:40]([CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:41]([O:43][CH2:44][C:45]12[CH2:54][CH:49]3[CH2:50][CH:51]([CH2:53][CH:47]([CH2:48]3)[CH2:46]1)[CH2:52]2)=[O:42])=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12].[C:71]([OH:77])(=[O:76])[CH2:72][CH2:73][CH:74]=O.C([BH3-])#N.[Na+].Cl>C(OC(N[C@H](C(N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(OC(C)(C)C)=O)=O)C(C)C)=O)C1C=CC=CC=1>[C:71]([CH2:72][CH2:73][CH2:74][N:9]([CH3:8])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:67]([CH3:70])[CH2:68][CH3:69])[C@H:26]([O:65][CH3:66])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:63][CH3:64])[C@@H:36]([CH3:62])[C:37]([NH:39][C@@H:40]([CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)[C:41]([O:43][CH2:44][C:45]12[CH2:46][CH:47]3[CH2:53][CH:51]([CH2:50][CH:49]([CH2:48]3)[CH2:54]1)[CH2:52]2)=[O:42])=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH:11]([CH3:13])[CH3:12])([OH:77])=[O:76]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCC12CC3CC(CC(C3)C1)C2)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Reactant: O=CCCC(=O)O
Agent: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Agent: Cl
Agent: [BH3-]C#N
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCC12CC3CC(CC(C3)C1)C2)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Temperature: 100 °C

Procedure:
26 mg (26 μmol) of N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-(adamantan-1-ylmethoxy)-1-oxo-3-phenylpropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide trifluoroacetate and 33.9 μl of a 15% aqueous succinaldehydic acid solution (53 μmol) were dissolved in 957 μl of a 1:1-dioxane/water mixture and heated to 100° C. for 1 h. After brief cooling, 1.81 mg (29 μmol) of sodium cyanoborohydride were added. The reaction mixture was adjusted to pH 3 by adding 0.1 N hydrochloric acid and the mixture was heated to 100° C. for a further 2 h. After again adding the same amounts of succinaldehydic acid solution, sodium cyanoborohydride and hydrochloric acid, the mixture was heated once again to 100° C. for 2 h. The reaction mixture was then separated directly into its components by means of preparative HPLC. 18.5 mg (73% of theory) of the title compound were thus obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:13]1([C:19]2[C:32]3[C:23](=[C:24]4[C:29](=[CH:30][CH:31]=3)[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:27][CH:26]=[N:25]4)[N:22]=[CH:21][CH:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C1COCC1>[C:2]1([C:26]2[CH:27]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:29]3[C:24](=[C:23]4[C:32](=[CH:31][CH:30]=3)[C:19]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:20][CH:21]=[N:22]4)[N:25]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)ccnc23)cc1
Reactant: Brc1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(-c2cc(-c3ccccc3)c3ccc4c(-c5ccccc5)ccnc4c3n2)cc1
Temperature: -78 °C
Yield: 37.2 %

Procedure:
To a three-necked flask of 250 ml, 0.97 g (6.16 mmol) of bromobenzene and 70 ml of THF were charged, then 3.9 ml (22 mmol) n-butyllithium (1.6M in Hexane solution) was dropped under stirring at −78° C. in a nitrogen atmosphere. The mixture was stirred for one hour at −78° C., and a solution of 1.86 g (5.6 mmol) 4,7-diphenyl-1,10-phenanthroline in 30 ml THF was dropped. Then the mixture was stirred at room temperature for overnight and was added with water. The organic layer was extracted with Dichloromethane and dried with anhydrous magnesium sulfate, the solvent was removed by rotary evaporation. The product was purified by column chromatography on alumina using Dichloromethane/Hexane as eluent and dried in vacuo, obtaining white powder compound 0.85 g (yield of 37.21%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([NH2:13])=[O:12])=[O:8])=[O:4].[CH:14](=O)[CH:15]([CH3:17])[CH3:16]>>[CH:15]([CH:17]1[NH:1][CH2:2][C:3](=[O:4])[N:5]1[CH2:6][C:7]([NH:9][CH2:10][C:11]([NH2:13])=[O:12])=[O:8])([CH3:16])[CH3:14]
Reactant: CC(C)C=O
Reactant: NCC(=O)NCC(=O)NCC(N)=O
Product: CC(C)C1NCC(=O)N1CC(=O)NCC(N)=O

Procedure:
The same procedure of example 9, starting from glycylglycylglycinamide and isobutyraldehyde, afforded the title compound as a white hygroscopic solid, m.p. 65°-70° C. Mass spectrum (E.I., 70 eV, 1.5 mA), m/z=199 (M+ --C3H7).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]12[C:16]3[C:8](=[CH:9][C:10]([NH:17][C:18]4[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=4)=[CH:11][C:12]=3[CH2:13][CH2:14][CH2:15]1)[CH2:7][CH2:6][CH2:5]2.Br[CH2:30][CH3:31].[Cl-].[NH4+]>CN(C)C=O>[CH2:30]([N:17]([C:10]1[CH:9]=[C:8]2[C:16]3[C:4]([CH3:3])([CH2:5][CH2:6][CH2:7]2)[CH2:15][CH2:14][CH2:13][C:12]=3[CH:11]=1)[C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:27][CH:28]=1)[CH3:31]
Reactant: CCOC(=O)c1ccc(Nc2cc3c4c(c2)CCCC4(C)CCC3)cc1
Reactant: CCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N(CC)c2cc3c4c(c2)CCCC4(C)CCC3)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
A suspension of sodium hydride (60%, 0.013 g) in N,N-dimethylformamide (3 ml) was added with ethyl 4-[(6a-methyl-5,6,6a,7,8,9-hexahydro-4H-2-phenalenyl)amino]benzoate (0.055 g) dissolved in N,N-dimethylformamide (2 ml), and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was added with bromoethane (0.025 ml), the mixture was stirred overnight at room temperature, and then added with saturated aqueous ammonium chloride, and the mixture was extracted with diethyl ether. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:50) to obtain the title compound (0.058 g, yield: 98%).
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[C:5](=[C:7]([CH2:18][CH:19]=[CH2:20])[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:10]=1)[OH:6].[OH-].[Na+]>CO>[CH2:18]([C:7]1[C:5]([OH:6])=[C:4]([CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[CH:8]=1)[C:3]([OH:21])=[O:2])[CH:19]=[CH2:20]
Reactant: C=CCc1cc(-c2ccc(F)cc2)cc(C(=O)OC)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCc1cc(-c2ccc(F)cc2)cc(C(=O)O)c1O

Procedure:
A mixture of 3.9 g. methyl-3-allyl-5-(4'-fluorophenyl)-salicylate, 40 ml. of methanol, and 10 ml. of 2.5 N sodium hydroxide solution is heated at reflux for 15 minutes. The mixture is concentrated in vacuo to remove methanol, diluted to 60 ml. with water, and acidified with dilute hydrochloric acid. The product is collected by filtration, dried, and recrystallized from benzene. The yield of 3-allyl-5-(4'-fluorophenyl)-2-hydroxy-benzoic acid is 3.4 g., m.p. 170° - 172° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[N:9]=[C:10]([N:13]=[C:14]([NH2:16])[NH2:15])[S:11][CH:12]=2)=[CH:5][CH:4]=1.[CH3:17][O:18][C:19](=[O:25])[NH:20][C:21](=[NH:24])SC>C(N(CC)CC)C>[NH2:15][C:14](=[N:13][C:10]1[S:11][CH:12]=[C:8]([C:6]2[O:7][C:3]([CH2:2][NH:1][C:21]([NH2:24])=[N:20][C:19]([O:18][CH3:17])=[O:25])=[CH:4][CH:5]=2)[N:9]=1)[NH2:16]
Reactant: NCc1ccc(-c2csc(N=C(N)N)n2)o1
Reactant: COC(=O)NC(=N)SC
Solvent: CCN(CC)CC
Product: COC(=O)N=C(N)NCc1ccc(-c2csc(N=C(N)N)n2)o1
Temperature: 25 °C
Reaction time: 26 h
Yield: 23.3 %

Procedure:
A suspension of 4-(5-aminomethylfuran-2-yl)-2-(diaminomethyleneamino)thiazole (1.6 g), imino(methylthio)methylcarbamic acid methylester (1.2 g) and triethylamine (1.5 g) was stirred at room temperature for 26 hours and then refluxed for 2.5 hours. Imino(methylthio)methylcarbamic acid methylester (1.0 g) was added to the reaction mixture and the mixture was refluxed for 10 hours. The solvent was removed under reduced pressure. The residue was chromatographed on a silica gel column eluting with a mixture of chloroform and methanol (10:1, V/V). Recrystallization from a mixture of methanol and diisopropyl ether afforded 2-(diaminomethyleneamino)-4-[5-(2-methoxycarbonylguanidino)methylfuran-2-yl]thiazole (530 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([F:9])=[CH:7][C:6](Br)=[CH:5][C:4]=1[F:11].[C:12]([Cu])#[N:13]>CN(C=O)C.O>[F:11][C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([F:9])[C:3]=1[O:2][CH3:1])[C:12]#[N:13]
Reactant: COc1c(F)cc(Br)cc1F
Reactant: N#C[Cu]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(F)cc(C#N)cc1F
Temperature: 120 °C
Reaction time: 48 h
Yield: 30.9 %

Procedure:
A mixture of 4-bromo-2,6-difluorophenyl methyl ether (11.5 g, 0.0516 mol; see step (ii) above) and CuCN (6.92 g, 0.0774 mol) in dry DMF (15 mL) was stirred at 120° C. for two days under nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. Solvent evaporation under reduced pressure followed by column chromatography over silica gel, using 2% ethyl acetate in petroleum ether as eluent, yielded 2.7 g of the sub-title compound as a pale yellow solid.
Reaction SMILES: [NH2:1][N:2]1[C:6]([CH2:7][NH:8]C(=O)OC(C)(C)C)=[CH:5][C:4]([C:16]([F:19])([F:18])[F:17])=[N:3]1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]=O.C(O)(=O)C.C(OCC)(=O)C.CCCCCC>CO>[NH2:8][CH2:7][C:6]1[N:2]([NH:1][CH2:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=2)[N:3]=[C:4]([C:16]([F:17])([F:18])[F:19])[CH:5]=1
Reactant: CC(C)(C)OC(=O)NCc1cc(C(F)(F)F)nn1N
Reactant: O=Cc1ccccn1
Solvent: CO
Solvent: CCCCCC
Solvent: CC(=O)O
Product: NCc1cc(C(F)(F)F)nn1NCc1ccccn1
Yield: 103.9 %

Procedure:
To a solution of tert-butyl (1-amino-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylcarbamate (2 g, 0.0071 mol) in methanol (15 ml), picolinaldehyde (1.14 g (1 ml), 0.016 mol, 1.5 eq) taken in methanol (5 ml) was added. Then the reaction mixture was acidified with acetic acid (0.2 ml, catalytic) and heated to reflux for 24 hrs. Progress of the reaction was monitored by TLC (10% ethyl acetate/hexane, Rf˜0.4). On completion of the reaction, methanol was distilled off completely. Residue was taken in ice water (200 ml) and the product extracted with ethyl acetate (4×50 ml). Combined extract was washed with water (2×50 ml), dried over sodium sulfate and the ethyl acetate was distilled off completely. Crude obtained was recrystalised from hexane (10 ml) to yield the required product as liquid (2 g, 76% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6](O)=[O:7].C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([Cl:18])=[O:7]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
To a solution of 3-methoxy-4-nitrobenzoic acid (5.7 g, 30 mmol) in dichloromethane (100 mL) and N,N-dimethylformamide (5 mL) at 0° C. was added slowly oxalyl chloride (5.08 mL, 60 mmol). After stirring for 2 hours, the mixture was concentrated and the residue was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[S:13][C:14]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)C.C(O)(=O)C.[Zn]>[N:18]1[CH:19]=[CH:20][C:15]([C:14]2[S:13][C:12]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[N:11][C:10]=2[C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[NH2:1])=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1cccc(-c2nc(C3CCOCC3)sc2-c2ccncc2)c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccncc2)c1

Procedure:
To a solution of 4-[4-(3-nitrophenyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-5-yl]pyridine in absolute ethanol (5 mL) and acetic acid (1 mL), zinc (300 mg) was added. The mixture was stirred and heated to reflux for 3 h. The mixture was dried up and treated with a small amount of 1 N HCl. After stirring for 1 h, the solution was brought to pH 14 using sodium hydroxide and extracted with DCM. The organic layer was dried with sodium sulfate and evaporated to driness. The solid material so obtained was purified by silica gel column chromatography eluting with ethyl acetate/hex/ammonium hydroxyde 8/2/0.1 yielding the title compound (52 mg, 59%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([CH2:11][NH2:12])[OH:10])=[CH:4][C:3]=1[Cl:13].Br[CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][S:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[NH2:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([CH:9]([CH2:11][NH:12][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][S:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[OH:10])=[CH:6][C:7]=1[Cl:8]
Reactant: NCC(O)c1cc(Cl)c(N)c(Cl)c1
Reactant: BrCCCCOCCSCCc1ccccc1
Solvent: CN(C)C=O
Product: Nc1c(Cl)cc(C(O)CNCCCCOCCSCCc2ccccc2)cc1Cl
Yield: 64.1 %

Procedure:
A solution of 4-amino-α-(aminomethyl)-3,5-dichlorobenzenemethanol (1.53 g), [2-[[2-(4-bromobutoxy)ethyl]thio]ethyl]benzene (1.0 g) and DEA (0.71 g) in DMF (20 ml) was stirred under nitrogen at 100° for 2 h. The solvent was evaporated in vacuo and the residue purified by FCC eluting with System G (95:5:1) to give an oil. The oil was partitioned between dichloromethane (50 ml) and 8% sodium bicarbonate (75 ml) and the aqueous solution re-extracted with dichloromethane (50 ml). The organic extracts were dried and evaporated in vacuo to give the title compound (924 mg,) as a white solid m.p. 74°-77°.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[CH2:15][C@H:14]([OH:16])[C@@H:13]([CH2:17][OH:18])[CH2:12]1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].N1C=CN=C1>CN(C=O)C>[Si:19]([O:18][CH2:17][C@H:13]1[CH2:12][C@@H:11]([N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[Cl:1])[CH2:15][C@@H:14]1[OH:16])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: OC[C@H]1C[C@@H](n2cnc3c(Cl)ncnc32)C[C@@H]1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](n2cnc3c(Cl)ncnc32)C[C@@H]1O
Reaction time: 1 h
Yield: 67 %

Procedure:
To a solution of (1S,2R,4R)-4-(6-chloro-9H-purin-9-yl)-2-(hydroxymethyl)cyclopentanol (0.496 g, 0.0018 mol) in DMF (10 mL) was added tert-butyldimethylsilyl chloride (0.348 g, 0.0023 mol), N,N-dimethylaminopyridine (0.023 g, 0.00019 mol) and imidazole (0.276 g, 0.0041 mol). This solution was stirred for 1 h and then the reaction mixture was quenched with water and diluted with ethyl acetate. The organic layer was washed with water, concentrated and purified by flash chromatography (0 to 50% EtOAc/DCM) to afford the title compound (0.462 g, 65%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.Cl[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1>CCOCC.CC(C)=O>[NH:9]1[CH:13]=[CH:12][N:11]=[C:10]1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1
Reactant: c1c[nH]cn1
Reactant: N#Cc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: N#Cc1ccc(Cc2ncc[nH]2)cc1
Reaction time: 26 h

Procedure:
To 48.0 L of acetone under nitrogen is added 4.326 Kg of potassium carbonate, 0.26 Kg of potassium iodide, 3.2 Kg of imidazole and 4.745 Kg of alpha-chloro-4-tolunitrile. The mixture is stirred at 45° under nitrogen for 26 hours. The reaction is cooled, filtered and the solvent is evaporated at reduced pressure. The residue is redissolved in 40 L of methylene chloride, washed with 40 L of water and twice with 10 L of water. The organic phase is dried over magnesium sulfate and evaporated to yield the crude product which is stirred with 6.4 L of ether for 2 hours. The solid is filtered, washed with 9 L of ether and dried at 40° and 20 mm Hg for 17 hours to yield 4-(1-imidazolylmethyl)-benzonitrile, the compound of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:19][CH:20]3[CH2:38][CH:37]4[N:22]([C:23](=[O:43])[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]5[C:34]([C:40]([OH:42])=O)([NH:35][C:36]4=[O:39])[CH2:33]5)[CH2:21]3)=[CH:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10]2)=[CH:5][CH:4]=1.COC1C=C2C(C(OC3CC4N(C(=O)OCCCCC=CC5C(C([NH:84][S:85]([CH:88]6[CH2:90][CH2:89]6)(=[O:87])=[O:86])=O)(NC4=O)C5)C3)=CC(C3C=CC=CC=3)=N2)=CC=1>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:19][CH:20]3[CH2:38][CH:37]4[N:22]([C:23](=[O:43])[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]5[C:34]([C:40]([NH:84][S:85]([CH:88]6[CH2:90][CH2:89]6)(=[O:87])=[O:86])=[O:42])([NH:35][C:36]4=[O:39])[CH2:33]5)[CH2:21]3)=[CH:8][C:9]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCOC(=O)N4C3)cc(-c3ccccc3)nc2c1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCOC(=O)N4C3)cc(-c3ccccc3)nc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCOC(=O)N4C3)cc(-c3ccccc3)nc2c1

Procedure:
The title compound 25 was synthesized from compound 24 following the same procedure described for the synthesis of N-[17-(7-methoxy-2-phenylquinolin-4-yloxy)-2,14-dioxo-3,15-diaza-13-oxatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl]-(cyclopropyl)sulfonamide (23): m/z=689 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:15])[N:6]([CH3:14])[C:7](=O)[NH:8]2.C(N(CC)C(C)C)(C)C.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:7]1[N:6]([CH3:14])[C:5](=[O:15])[C:4]2[C:9](=[CH:10][CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[N:8]=1
Reactant: COc1cccc2[nH]c(=O)n(C)c(=O)c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2nc(Cl)n(C)c(=O)c12
Yield: 99.6 %

Procedure:
A mixture of 5-methoxy-3-methyl-1H-quinazoline-2,4-dione (165 mg, 0.800 mmol) and N,N-diisopropylethylamine (0.307 ml, 1.76 mmol) in phosphorus oxychloride (2.2 ml, 24.0 mmol) was refluxed for 18 h with stirring and concentrated to dryness under vacuum. The residue was diluted with water. The aqueous solution was extracted with dichloromethane. The extract was washed with water, dried over magnesium sulfate and concentrated under vacuum to afford 179 mg (99%) of the title compound. The residue was used for the next reaction without further purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[CH3:44][C:45]1[S:46][C:47]([CH3:54])=[C:48]([CH2:50][C:51](O)=[O:52])[N:49]=1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[CH3:44][C:45]1[S:46][C:47]([CH3:54])=[C:48]([CH2:50][C:51]([NH:2][CH2:3][C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[C:6](=[O:22])[N:7]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:8]3=[O:13])=[O:52])[N:49]=1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1nc(CC(=O)O)c(C)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1nc(CC(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)c(C)s1
Reaction time: 0.17 h
Yield: 72.2 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 2-(2,5-dimethyl-1,3-thiazol-4-yl)acetic acid (0.4 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (3×40 mL) and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: CH3OH: CH2Cl2 3:97) to afford 2-(2,5-dimethyl-1,3-thiazol-4-yl)-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-acetamide (0.7 g, 76%) as a white solid: mp 140-142° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=1.39 min. (99%); 1H NMR (DMSO-d6) δ 2.04-2.09 (m, 1H), 2.31 (s, 3H), 2.56 (s, 3H), 2.51-2.63 (m, 2H), 2.84-2.91 (m, 1H), 3.56 (s, 2H), 4.73 (d, J=5.9 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.7 Hz, 1H), 7.76-7.85 (m, 3H), 8.58 (t, J=6.0 Hz, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ 10.84, 18.56, 21.95, 30.91, 35.85, 37.94, 48.82, 121.81, 127.03, 127.91, 131.46, 133.21, 134.60, 139.26, 145.51, 160.87, 166.94, 167.48, 169.51, 169.79, 172.73; Anal. Calcd. for C21H20N4O5S: C, 57.27; H, 4.58; N, 12.72; S, 7.28. Found: C, 57.13; H, 4.71; N, 12.45; S, 7.18.