Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18]1([NH:21][C:22]([C:24]2[C:32]3[CH:31]=[C:30]([C:33]4[C:38]([F:39])=[CH:37][N:36]=[C:35](Cl)[N:34]=4)[S:29][C:28]=3[CH:27]=[CH:26][CH:25]=2)=[O:23])[CH2:20][CH2:19]1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:35]2[N:34]=[C:33]([C:30]3[S:29][C:28]4[CH:27]=[CH:26][CH:25]=[C:24]([C:22](=[O:23])[NH:21][CH:18]5[CH2:19][CH2:20]5)[C:32]=4[CH:31]=3)[C:38]([F:39])=[CH:37][N:36]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCN)CC1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3F)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(CCCNc2ncc(F)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Yield: 72.8 %

Procedure:
(4-(3-Aminopropyl)-piperazine-1-carboxylic acid tert-butyl ester (0.542 g, 2.23 mmol) is added to a stirred suspension of 2-(2-chloro-5-fluoropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (0.388 g, 1.12 mmol) and diisopropylethylamine (0.585 mL, 3.36 mmol) in anhydrous 1,4-dioxane (10 mL) at room temperature under nitrogen. The resultant mixture is heated in an oil bath at 95° C. for 24 hours. At room temperature, the mixture is concentrated and chromatographed on silica gel, eluting with 2 M NH3/CH3OH in dichloromethane: 0-7%, to give 4-{3-[4-(4-cyclopropylcarbamoyl-benzo[b]thiophen-2-yl)-5-fluoropyrimidin-2-ylamino]-propyl}-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (452 mg). The product is dissolved in CH3OH (80 mL) and dichloromethane (20 mL) and a small stream of anhydrous HCl gas is bubbled through the stirred solution for 3 minutes. The warm solution is capped with a glass stopper and stirred at room temperature overnight. After concentration, the title compound is obtained as a yellow solid (441 mg). ES+(m/z) 455 [M(free base)+H].
Reaction SMILES: [CH3:1][NH2:2].[I:3][C:4]1[N:5]=[C:6]([NH2:22])[C:7]2[N:8]=[CH:9][N:10]([C:20]=2[N:21]=1)[C@@H:11]1[O:19][C@H:16]([CH2:17][OH:18])[C@@H:14]([OH:15])[C@H:12]1[OH:13]>CO>[I:3][C:4]1[N:21]=[C:20]2[C:7](=[N:8][CH2:9][N:10]2[C@@H:11]2[O:19][C@H:16]([CH2:17][OH:18])[C@@H:14]([OH:15])[C@H:12]2[OH:13])[C:6]([NH:2][CH3:1])([NH2:22])[N:5]=1
Reactant: CN
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: CO
Product: CNC1(N)N=C(I)N=C2C1=NCN2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 40% aqueous methylamine (1 mL) and 2-iodoadenosine (100 mg) in methanol (2 mL) was stirred at room temperature for 12 hours. The precipitate was filtered off, washed with ether and dried under vacuum to afford 2-iodo-6-methylamino adenosine, a compound of formula (11).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:18][CH2:19]OS(C)(=O)=O)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]1=[O:25].[CH2:33]([O:35][CH2:36][CH2:37][N:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[N:47]1[CH2:53][CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)[CH3:34]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:18][CH2:19][N:50]2[CH2:51][CH2:52][CH2:53][N:47]([C:39]3[N:38]([CH2:37][CH2:36][O:35][CH2:33][CH3:34])[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=4[N:40]=3)[CH2:48][CH2:49]2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]1=[O:25]
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1cc(CN2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2=O)cc(OC)c1OC
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(Cc4cc(OC)c(OC)c(OC)c4)C3=O)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-(3,4,5-trimethoxybenzyl)-3-(2-methanesulfonyloxyethyl)-3-phenyl-2-oxopyrrolidine and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to give the title compound.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[F:21][C:22]([F:26])([F:25])[CH2:23][SH:24].Cl>CN(C)C=O>[CH3:14][S:11]([C:8]1[CH:9]=[CH:10][C:2]([S:24][CH2:23][C:22]([F:26])([F:25])[F:21])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Reactant: FC(F)(F)CS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(SCC(F)(F)F)c(C(=O)O)c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 4.58 mmol 2-fluoro-5-methanesulfonyl-benzoic acid (Example B4(b)) in 6 ml N,N-dimethylformamide were added 13.8 mol cesium carbonate and 9.16 mmol 2,2,2-trifluoro-ethanethiol and the mixture was stirred at 90° C. for 30 min. The reaction mixture was then cooled to room temperature and acidified to pH1 by addition of hydrochloric acid before being extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo to afford the title compound as a red-brown solid which was used in the next step without further purification (yield 99%). MS (m/e): 312.9 ([M−H]−, 100%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH3:10])=[CH:4][C:3]=1[S:11]([OH:14])(=[O:13])=[O:12].[NH:15]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[N:15]1([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH3:10])=[CH:4][C:3]=2[S:11]([OH:14])(=[O:13])=[O:12])[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: C1CNCCNC1
Reactant: CCCc1ccc(F)c(S(=O)(=O)O)c1
Product: CCCc1ccc(N2CCCNCC2)c(S(=O)(=O)O)c1
Yield: 37.2 %

Procedure:
According to the same method as in Example 2, from 0.61 g of 2-fluoro-5-n-propylbenzenesulfonic acid and 2.80 g of homopiperazine, 0.31 g (yield: 37.2%) of the above title product having the following physical property was obtained.
Reaction SMILES: [NH+]1C=CN[CH:2]=1.[N:6]1([C:11]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:14]=3[S:13](=[O:25])(=[O:24])[N:12]=2)[CH:10]=[CH:9]N=C1.C(N)CC>>[N+:21]([C:19]1[CH:18]=[CH:17][C:15]2[NH:16][C:11]([NH:6][CH2:10][CH2:9][CH3:2])=[N:12][S:13](=[O:25])(=[O:24])[C:14]=2[CH:20]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)N=C(n1ccnc1)N2
Reactant: c1c[nH+]c[nH]1
Solvent: CCCN
Product: CCCNC1=NS(=O)(=O)c2cc([N+](=O)[O-])ccc2N1

Procedure:
3-(Imidazol-1-yl)-7-nitro-4H-1,2,4-benzothiadiazine 1,1-dioxide imidazolium salt was treated with propylamine according to the general procedure Method A to give the title compound; m.p. 268-270° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][O:10][CH:9]([C:13]2([CH3:18])OCC[O:14]2)[CH2:8]1)=[O:6])[CH:2]=[CH2:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[C:13]([CH:9]1[O:10][CH2:11][CH2:12][N:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH2:8]1)(=[O:14])[CH3:18]
Reactant: C=CCOC(=O)N1CCOC(C2(C)OCCO2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: C=CCOC(=O)N1CCOC(C(C)=O)C1
Yield: 75.1 %

Procedure:
A solution of 4-allyloxycarbonyl-2-[2-methyl-1,3-dioxolan-2-yl)morpholine (2.20 g) in acetone (22 ml) was stirred at ambient temperature for 5 days in the presence of p-toluenesulfonic acid monohydrate (1.10 g). The mixture was concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (25 g) and eluted with a mixture of hexane and ethyl acetate (9:1, V/V) to give 2-acetyl-4-allyloxycarbonylmorpholine (1.37 g) as a syrup.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[C:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)(=[O:18])[CH3:17]>>[C:16]([C:19]1[CH:20]=[CH:21][C:22]([N:25]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])=[CH:23][CH:24]=1)(=[O:18])[CH3:17]
Reactant: COc1ccc(CNc2ccc(C(C)=O)cc2)cc1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Product: COc1ccc(CN(C(=O)C2CCCc3ccc(OC)cc32)c2ccc(C(C)=O)cc2)cc1
Yield: 24.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.63 g) and (4-acetylphenyl)[(4-methoxyphenyl)methyl]amine (0.78 g) as starting materials, N-(4-acetylphenyl)-7-methoxy-N-[(4-methoxyphenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.33 g) was obtained.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:35]=[CH:34][C:18]2[NH:19][C:20]([CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[N:21][C:17]=2[CH:16]=1)(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[F:33][C:30]([F:31])([F:32])[C:27]1[CH:28]=[CH:29][C:24]([O:23][CH2:22][C:20]2[NH:19][C:18]3[CH:34]=[CH:35][C:15]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[S:6]([NH2:5])(=[O:8])=[O:7])=[CH:16][C:17]=3[N:21]=2)=[CH:25][CH:26]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1

Procedure:
A solution of N-tert-butyl-2-[2-(4-trifluoromethyl-phenoxymethyl)-1H benzoimidazol-5-yl]-benzenesulfonamide (40.0 mg, 0.80 mmol) in trifluoroacetic acid (4 mL) was heated at 75° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The resulting TFA salt was diluted with methanol and passed though a sodium bicarbonate cartridge to afford the title compound as the free base (33.8 mg, 95% yield).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:19].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[O:1]1[CH2:5][CH2:4][C@H:3]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=2[O-:19])[CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc(CO[C@H]2CCOC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: [O-][n+]1ccccc1CO[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
(S)-2-(Tetrahydrofuran-3-yloxymethyl)pyridine (110.33 g, 0.616 mol, 1 eq) was dissolved in 900 mL DCM and cooled in an ice bath. 3-Chloroperoxybenzoic acid (151.77 g, 0.677 mol, 1.1 eq) was added and the solution was warmed to room temperature and stirred overnight. K2CO3 (85.09 g, 0.616 mol, 1 eq) was added as a solid and stirred for 2 hours. The white precipitate was filtered off and the filter cake washed with dichloromethane. Another portion of K2CO3 (85.09 g, 0.616 mol, 1 eq) was added to the filtrate and stirred for 3 days. The white solid was filtered off and the filtrate evaporated to give the title compound (119.62 g, 99%) as a yellow oil; LC-MS Retention time 1.27 min; (M+H)+ 196.
Reaction SMILES: [I:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20]CC)=[O:19]>CC(C)=O>[I:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:17][C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc(O)c(I)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(OCC(=O)O)c(I)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
The mixture of 6-iodo-2-picolin-5-ol (235 mg, 1.0 mmol), potassium carbonate (455 mg, 3.3 mmol), ethyl bromoacetate (250 mg, 1.49 mmol) and acetone (15 ml) was refluxed for 15 h. After cooling, the mixture was filtered to remove potassium carbonate. The filtrate was concentrated under reduced pressure. To this residue, 10 ml dioxane and 14 ml 5% sodium hydroxide solution were added. After the mixture was stirred at room temperature overnight, it was acidified with concentrated hydrochloric acid to pH 3, and then extracted three times with ethyl acetate (20 ml each). Organic phases were combined, washed with water and brine, dried over magnesium sulfate, filtered, and then evaporated in vacuo. The residue was recrystallized from ethanol and petroleum ether to give 165 mg 6-iodo-2-methylpyridine-5-oxyacetic acid as white crystals, mp 170-172° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[N:2]1.CCN(C(C)C)C(C)C.Cl.[C:19]12([CH2:29][NH2:30])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C.CCOC(C)=O.O>[C:19]12([CH2:29][NH:30][C:6]([C:3]3[CH:4]=[CH:5][NH:1][N:2]=3)=[O:8])[CH2:26][CH:25]3[CH2:24][CH:23]([CH2:22][CH:21]([CH2:27]3)[CH2:20]1)[CH2:28]2
Reactant: O=C(O)c1cc[nH]n1
Reactant: NCC12CC3CC(CC(C3)C1)C2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc[nH]n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1H-pyrazole-3-carboxylic acid (594 mg, 5.3 mmol) in 20 mL ACN is added 2.3 mL of DIEA (13.25 mmol), followed by 1.28 g of adamantylmethylamine hydrochloride salt (6.36 mmol). The resulting mixture is stirred for 5 min at RT. 2.81 g of BOP (6.36 mmol) is added. The reaction mixture is stirred for 30 min at RT. The mixture is diluted with EtOAc and water. The organic layer is separated, and the aqueous layer is back extracted with EtOAc. The combined organic layers are washed with brine, dried over sodium sulfate and concentrated. The residue is triturated with DCM and air-dried to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][C:11]([O:13]C)=O.O.Cl>C(Cl)Cl.C(O)(=O)C>[F:9][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][C:6]=1[Cl:8])[NH:1][C:11](=[O:13])[CH2:10]2
Reactant: COC(=O)Cc1cc(F)c(Cl)cc1N
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: O=C1Cc2cc(F)c(Cl)cc2N1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
Compound (III) is obtained by cyclizing (II) with an acid as shown in step [b] of Scheme 1. Compound (II) is dissolved in a mixture of an acid and a cosolvent, preferably the acid is glacial acetic acid in which instance the preferred cosolvent is water or the acid is hydrochloric acid in which instance the preferred cosolvent is methylene chloride. With acetic acid the ratio of the acid and cosolvent mixture ranges from 2:1 to pure acetic acid respectively, the preferred ratio being 6:1. With HCl, much less acid is required, preferably 1:4 3N HCl to CH2Cl2. Once compound (II) is dissolved, the reaction mixture is stirred at ambient temperature for from 6 to 7 hours to produce 5-fluoro-6-chlorooxindole (III). Compound (III) is readily purified by recrystallization from ethyl acetate to yield an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[F:22].C(N(CC)CC)C.[Cl:30][CH2:31][C:32](Cl)=[O:33]>ClCCl>[Cl:30][CH2:31][C:32]([NH:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH2:11][CH2:12]2)=[CH:4][C:3]=1[F:22])=[O:33]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)c(F)c2)CC1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)CCl)c(F)c2)CC1
Yield: 64 %

Procedure:
tert-Butyl 4-(4-amino-3-fluoro phenoxy)piperidine-1-carboxylate (7.54 g, 0.024 moles) was dissolved in dichloromethane (100 mL) and added triethylamine (3.6 g, 0.036 moles) at room temperature. To the resulting mass, a solution of chloro acetyl chloride (2.9 g, 0.026 moles) in dichloromethane (15 mL) was added drop wise at room temperature. After completion of the reaction, the organic mass was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude residue, which was further purified by flash chromatography using (ethyl acetate:hexane, 1:5) to afford the title compound 5.94 g (Yield: 64%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[Cl-].[Cl:12][C:13]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:14]=1[CH:15]=[N+:16]([CH3:18])[CH3:17].ClC1C=C(F)C=CC=1C=O.CNC>>[Cl:12][C:13]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:14]=1[CH:15]([N:16]([CH3:18])[CH3:17])[C:4]1[C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])[NH:6][CH:5]=1
Reactant: Cc1cccc2[nH]ccc12
Reactant: C[N+](C)=Cc1ccc(F)cc1Cl
Agent: CNC
Agent: O=Cc1ccc(F)cc1Cl
Agent: [Cl-]
Product: Cc1cccc2[nH]cc(C(c3ccc(F)cc3Cl)N(C)C)c12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 4-methylindole and (2-chloro-4-fluoro-benzylidene)-dimethyl-ammonium chloride, which had been prepared in accordance with example 24 from 2-chloro-4-fluoro-benzaldehyde and dimethylamine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12](=[C:15]2[NH:19][C:18]3[CH:20]=[CH:21][C:22]([N+:24]([O-])=O)=[CH:23][C:17]=3[NH:16]2)[C:13]#[N:14])[N:3]=1>CN(C=O)C.[Pd]>[NH2:24][C:22]1[CH:21]=[CH:20][C:18]2[NH:19][C:15](=[C:12]([C:4]3[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=3)[C:13]#[N:14])[NH:16][C:17]=2[CH:23]=1
Reactant: Cc1cc(C(F)(F)F)nc(C(C#N)=C2Nc3ccc([N+](=O)[O-])cc3N2)n1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Cc1cc(C(F)(F)F)nc(C(C#N)=C2Nc3ccc(N)cc3N2)n1

Procedure:
4-Nitro-1,2-phenylenediamine (50 mg; 0.32 mmol) and ethyl 2-cyano-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]acetate hydrochloride salt (101 mg; 0.32 mmol) were heated at 198° C. in a microwave for 3 min. Acetic acid (1.5 mL) was added to the crude material and the mixture heated at 100° C. for 6 hr. The solid was collected by filtration, washed with acetonitrile, and dried under high vacuum to give 2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]-2-(5-nitro-1H-benzimidazol-2(3H)-ylidene)acetonitrile (59 mg) as a yellow solid. 2-[4-Methyl-6-(trifluoromethyl)pyrimidin-2-yl]-2-(5-nitro-1H-benzimidazol-2(3H)-ylidene)acetonitrile (55 mg; 0.15 mmol) in DMF (3 mL) was hydrogenated over 10% palladium on carbon (11 mg). The mixture was filtered through diatomaceous earth, washing with methanol, and the filtrate was concentrated to give 2-(5-amino-1H-benzimidazol-2(3H)-ylidene)-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]acetonitrile, which was dissolved in DMF (1 mL) and added to a solution of N-methyl-L-proline (19.3 mg; 0.16 mmol), HBTU (56.8 mg; 0.15 mmol), and DIPEA (104.5 μL; 0.60 mmol) in DMF (1 mL). The mixture was stirred for 5 hr and then partitioned between EA and water. The EA phase was dried and concentrated to give 2-{5-[(S)-(1-methylpyrrolidin-2-yl)carbonylamino]-1H-benzimidazol-2 (3H)-ylidene}-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]acetonitrile (65 mg) as a brown oil. 2-{5-[(S)-(1-Methylpyrrolidin-2-yl)-carbonylamino]-1H-benzimidazol-2(3H)-ylidene}-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]-acetonitrile (65 mg) was dissolved in concentrated sulfuric acid and stirred at room temperature overnight. The mixture was diluted with ice-water and acetonitrile and, after coming to room temperature, was purified by reverse phase preparative HPLC using a Peeke Ultro 120, 7 μm, C18Q, 250×30 mm column at a flow rate of 42 mL/min and mobile phases of 95% water, 5% acetonitrile (with 0.01% hydrochloric acid) and 5% water, 95% acetonitrile (with 0.01% hydrochloric acid) to give 2-{5-[(S)-(1-methylpyrrolidin-2-yl)carbonylamino]-1H-benzimidazol-2 (3H)-ylidene}-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]acetamide hydrochloride salt (18 mg) as a yellow solid.
Reaction SMILES: C([O:5][C:6](=[O:31])[C@@H:7]([N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]1=[O:30])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:22]([NH:21][C:17]1[C:16](=[O:30])[N:15]([C@@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([OH:31])=[O:5])[CH:20]=[CH:19][CH:18]=1)(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)n1cccc(NC(=O)c2ccccc2)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cccn([C@@H](Cc2ccccc2)C(=O)O)c1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.8 %

Procedure:
A solution of (S)-2-(3-benzoylamino-2-oxo-2H-pyridin-1-yl)-3-phenyl-propionic acid tert-butyl ester (2.07 g, 4.95 mmol) in dichloromethane (25 mL) was cooled to 0° C. Trifluoroacetic acid (25 ml) was added and the resulting mixture allowed to warm to room temperature and stir for 5 hours. The mixture was then concentrated under reduced pressure and the residue re-dissolved in dichloromethane. This process was repeated several times in order to remove excess trifluoroacetic acid. The resulting solid was slurried in diethyl ether, filtered and washed with more diethyl ether. The solid was then dried to constant weight under vacuum. This gave the title product as a white solid (1.61 g, 90%); 1H NMR (400 MHz, CDCl3) δ 3.48 (1H, dd), 3.65 (1H, dd), 5.32 (1H, m), 6.35 (1H, t), 6.80 (1H, m), 7.08 (2H, d), 7.27-7.35 (3H, m), 7.56-7.65 (3H, m), 7.92 (2H, d), 8.65 (1H, d), 9.18 (1H, br s).
Reaction SMILES: CCO[C:4]([S-])=[S:5].[K+].[NH2:8][C:9]1[C:14]([NH2:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=1[O:17][CH2:18][CH:19]([OH:25])[CH2:20][NH:21][CH:22]([CH3:24])[CH3:23]>>[OH:25][CH:19]([CH2:20][NH:21][CH:22]([CH3:23])[CH3:24])[CH2:18][O:17][C:10]1[C:9]2[NH:8][C:4](=[S:5])[NH:15][C:14]=2[CH:13]=[C:12]([CH3:16])[CH:11]=1
Reactant: CCOC(=S)[S-]
Reactant: Cc1cc(N)c(N)c(OCC(O)CNC(C)C)c1
Agent: [K+]
Product: Cc1cc(OCC(O)CNC(C)C)c2[nH]c(=S)[nH]c2c1

Procedure:
From potassium xanthogenate and 2,3-diamino-1-[2-hydroxy-3-(2-propylamino)-propoxy]-5-methylbenzene, using the process described in Example 3, there is obtained the title compound which, after recrystallisation from ethanol, decomposes at 294°-295° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[NH2:11][NH2:12]>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:11][NH:12][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: NN
Solvent: CC(C)O
Product: COc1ccc(CNNCc2ccc(OC)cc2)cc1

Procedure:
Di-(4-methoxybenzyl) azine was first prepared by reacting 2 moles of p-methoxybenzaldehyde with 1 mole hydrazine in isopropyl alcohol at 10° C. Di-(4-methoxybenzyl) hydrazine was obtained by reacting the azine with diborane in tetrahydrofurane under nitrogen atmosphere at or below 10° C. and isolated as an oil. The dihydrochloride salt of bis-(4-methoxybenzyl) hydrazine was obtained as white solid by mixing with hydrogen chloride gas in isopropanol followed by addition of methylene chloride and toluene (81% yield based on azine). 1,2-Di-(4-methoxybenzyl)hydrazine (3.5 g., 0.01 mole) and 1,3-dimorpholine-1,2-nitropropane (2.6 g., 0.01 mole) were suspended in a mixture of 30 ml of methanol and 20 ml of toluene and heated to reflux for 3 hr. The reaction mixture was evaporated to dryness and the residue extracted with toluene and filtered. The toluene filtrate was evaporated to give 3.5 g. brown oil which was purified by column chromatography using 10% diethyl ether--90% methylene chloride on silica gel. Nuclear Magnetic Resonance and mass spectra confirmed the structure of title compound. The oil solidified after one day standing at room temperature.