Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23](=[O:27])[N:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+].[Br:34][CH2:35][CH2:36][CH2:37][CH2:38]Br.O>CN(C)C=O>[Br:34][CH2:35][CH2:36][CH2:37][CH2:38][O:21][C:15]1[CH:14]=[C:13]2[C:18]([C:9]([O:8][C:6]3[CH:5]=[CH:4][C:3]([NH:22][C:23](=[O:27])[N:24]([CH3:26])[CH3:25])=[C:2]([Cl:1])[CH:7]=3)=[N:10][CH:11]=[N:12]2)=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: COc1cc2c(Oc3ccc(NC(=O)N(C)C)c(Cl)c3)ncnc2cc1O
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(NC(=O)N(C)C)c(Cl)c3)ncnc2cc1OCCCCBr
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A starting compound (N′-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N,N-dimethylurea, 80 mg), potassium carbonate (138 mg), and 1,4-dibromobutane (0.12 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give an intermediate (N′-(4-{[7-(4-bromobutoxy)-6-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl)-N,N-dimethylurea). The intermediate, potassium carbonate (138 mg), and morpholine (0.043 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC by development with chloroform/methanol to give 47 mg (yield 44%) of the title compound.
Reaction SMILES: [ClH:1].Cl.[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]([C:15]2[CH:27]=[CH:26][C:25]3[C:24]4[C:19](=[CH:20][C:21]([C:28]([O:30][CH2:31][CH2:32][CH2:33][N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]5)=[O:29])=[CH:22][CH:23]=4)[C:18](=[O:40])[C:17]=3[CH:16]=2)=[O:14])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[BH4-].[Na+]>O>[OH2:12].[ClH:1].[ClH:1].[OH:40][CH:18]1[C:19]2[CH:20]=[C:21]([C:28]([O:30][CH2:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:29])[CH:22]=[CH:23][C:24]=2[C:25]2[C:17]1=[CH:16][C:15]([C:13]([O:12][CH2:11][CH2:10][CH2:9][N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)=[O:14])=[CH:27][CH:26]=2
Reactant: O=C(OCCCN1CCCCC1)c1ccc2c(c1)C(=O)c1cc(C(=O)OCCCN3CCCCC3)ccc1-2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: O=C(OCCCN1CCCCC1)c1ccc2c(c1)C(O)c1cc(C(=O)OCCCN3CCCCC3)ccc1-2

Procedure:
A solution of 10.3 (0.020 mole) of bis(3-piperidinopropyl)-9-oxofluorene-2,7-dicarboxylate dihydrochloride in 350 ml of warm water is cooled to room temperature and added to 3 g (0.079 mole) of NaBH4 in 15 ml of water with swirling. The resulting product is extracted 5 times with ether, and the combined ether extracts are washed with water, then with NaCl solution, and dried over anhydrous MgSO4. The mixture is filtered, the filtrate treated with ethereal HCl and most of the solvent distilled off. The residue is dissolved in 50 ml of hot ethanol, filtered through filter aid and the filtrate refrigerated. The crystallized solid is filtered off and is recrystallized twice from ethanol to give bis(3-piperidinopropyl) 9-hydroxyfluorene-2,7-dicarboxylate dihydrochloride hydrate.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7](Cl)=O)=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].[C:24]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1.[Cl-].[NH4+:39]>ClC1C=CC=CC=1Cl>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:31]=[C:30]([C:27]3[CH:28]=[CH:29][C:24]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:25][CH:26]=3)[N:39]=[C:30]([C:27]3[CH:26]=[CH:25][C:24]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:29][CH:28]=3)[N:31]=2)=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: N#Cc1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: O=S(Cl)Cl
Product: c1ccc(-c2ccc(-c3nc(-c4ccc(-c5ccccc5)cc4)nc(-c4ccc(-c5ccccc5)cc4)n3)cc2)cc1
Temperature: 150 °C
Yield: 72.6 %

Procedure:
In a 100 milliliter round bottom flask there was added 4-biphenylcarbonyl chloride (2.167 grams), 1,2-dichlorobenzene (27.0 milliliters), thionyl chloride (1.0 milliliter), and aluminum chloride (1.33 grams). With stirring, 4-biphenylcarbonitrile (3.58 grams) was added slowly, and the resulting reaction mixture was heated under argon to about 150° C. for 0.5 hour. The temperature of the reaction mixture was reduced to 120° C., then ammonium chloride (1.07 grams) was added in one portion. The reaction mixture was stirred at 150° C. for an additional 20 hours. The reaction flask was removed from the heater and cooled to room temperature, about 25° C. throughout. The resulting mixture was poured into 100 milliliters of methanol and stirred for 20 minutes. The precipitates were collected by filtration and dried in a vacuum oven to afford 3.9 grams of crude product which was further purified by sublimation. The above titled triazinyl product 2,4,6-tris-(4-biphenylyl)-1,3,5-triazine possessed a melting point of 283° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[CH:7]=[CH:8]/[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([CH:23]=[CH:24][CH:25]=2)[O:17][CH2:18][C:19]([O:21]C)=O)=[O:10])[CH:2]=1.[CH3:26][NH2:27].CO>CO>[CH3:26][NH:27][C:19]([CH2:18][O:17][C:16]1[CH:15]=[C:14]([CH:25]=[CH:24][CH:23]=1)[CH2:13][CH2:12][NH:11][C:9](=[O:10])/[CH:8]=[CH:7]/[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:21]
Reactant: COC(=O)COc1cccc(CCNC(=O)/C=C/c2cccnc2)c1
Reactant: CN
Solvent: CO
Product: CNC(=O)COc1cccc(CCNC(=O)/C=C/c2cccnc2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 88 %

Procedure:
Methyl [3-[2-[(E)-3-(3-pyridyl)acryloylamino]-ethyl]phenoxy]acetate (0.34 g, 1.0 mmol) obtained in Example 94 was dissolved in methanol (6 ml) and 40% methylamine-methanol solution (0.8 ml) was added and stirred at room temperature for 17 hours. After concentrating the reaction mixture under reduced pressure, the residue was recrystallized to yield the titled compound (0.30 g, 88%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:12][CH2:13][CH2:14][CH2:15][Cl:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:16][CH2:15][CH2:14][CH2:13][CH2:12][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: ClCCCCBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCCCCCl)cc1
Yield: 93.3 %

Procedure:
A mixture of para-nitrophenol (0.83 g, 6 mmoles), 1-bromo-4-chloro-butane (1.23 g, 7.2 mmoles), and K2CO3 (1.24 g, 9 mmoles) was stirred together in DMF at 80° C. for 1 hour. Reaction mixture was diluted with H2O, extracted with EtOAc, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by HPLC using as eluent 30% EtOAc/hexane to afford the title compound as an off-white solid (1.28 g, 5.6 mmoles).
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[CH:14])=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1.Br[C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[C:14][C:24]4[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=4)=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)c(Cl)c3)nc12
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)c(Cl)c4)nc23)cc1

Procedure:
The title compound was prepared from 7-cyclopropyl-5-(3,4-dichloro-phenyl)-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.8) (167 mg, 0.51 mmol) and 4-bromo-benzenesulfonamide (121 mg, 0.51 mmol) according to general procedure II. Obtained as a yellow solid (140 mg, 57%). MS (ISP) 483.4 [(M+H)+]; mp 259–261° C.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:12][N:13]1[CH:17]=[C:16]([C:18]2[CH:19]=[C:20]3[C:30](=[CH:31][CH:32]=2)[O:29][C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:22][C:21]3=[O:33])[CH:15]=[N:14]1.[CH:34]1([C:37]2[CH:38]=[CH:39][CH:40]=[C:41]3[C:46]=2[N:45]=[C:44]([C:47](O)=[O:48])[CH:43]=[C:42]3[OH:50])[CH2:36][CH2:35]1.O>CN(C=O)C>[CH:34]1([C:37]2[CH:38]=[CH:39][CH:40]=[C:41]3[C:46]=2[N:45]=[C:44]([C:47]([N:26]2[CH2:25][CH2:24][C:23]4([CH2:22][C:21](=[O:33])[C:20]5[C:30](=[CH:31][CH:32]=[C:18]([C:16]6[CH:15]=[N:14][N:13]([CH3:12])[CH:17]=6)[CH:19]=5)[O:29]4)[CH2:28][CH2:27]2)=[O:48])[CH:43]=[C:42]3[OH:50])[CH2:35][CH2:36]1
Reactant: O=C(O)c1cc(O)c2cccc(C3CC3)c2n1
Reactant: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)cn1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)c4cc(O)c5cccc(C6CC6)c5n4)CC2)O3)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
TEA (0.657 ml, 4.71 mmol) was added to a stirred mixture of HOBT (313 mg, 2.04 mmol), WSCDI (361 mg, 1.89 mmol), 6-(1-methyl-1H-pyrazol-4-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (629 mg, 1.89 mmol) and 8-cyclopropyl-4-hydroxyquinoline-2-carboxylic acid (360 mg, 1.57 mmol) in DMF (3.5 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water (20 ml) and stirred for 30 min. The resulted precipitate was filtered, washed with water and the solid was dried in vacuo at 70° C. The crude product was purified by silicagel column chromatography (CHCl3/AcOEt) to give intended compound as a pale brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:19])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[Cl:18])[C:5]([Cl:8])=[N:6][CH:7]=1.C(Cl)Cl.O1CCCC1.[Br:28]Br>C(O)(=O)C>[Br:28][CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[Cl:18])[C:9]([C:4]1[C:5]([Cl:8])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)=[O:19]
Reactant: O=C(Cc1cccc(Cl)c1Cl)c1cc(Br)cnc1Cl
Reactant: BrBr
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(c1cc(Br)cnc1Cl)C(Br)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
To a stirred solution of 1-(5-bromo-2-chloropyridin-3-yl)-2-(2,3-dichlorophenyl)ethanone (1.01 g, 2.66 mmol) in 1:1 methylene chloride/tetrahydrofuran (26 mL) was added bromine (136 μL, 2.66 mmol) and 3 mL acetic acid. The reaction mixture was stirred at room temperature overnight, at which point the orange color had dissipated. Concentration gave 2-bromo-1-(5-bromo-2-chloropyridin-3-yl)-2-(2,3-dichlorophenyl)ethanone as an orange oil (1.1 g, 95%), which was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([CH:11]=O)[C:5]=1[F:13].[NH2:15][OH:16]>C(O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([CH:11]=[N:15][OH:16])[C:5]=1[F:13]
Reactant: NO
Reactant: COC(=O)c1c(Cl)ccc(C=O)c1F
Solvent: CCO
Product: COC(=O)c1c(Cl)ccc(C=NO)c1F
Reaction time: 16 h

Procedure:
To a solution of methyl-6-chloro-2-fluoro-3-formylbenzoate (930 mg, 4294 μmol) in ethanol (14.5 ml) at RT was added hydroxylamine (50 wt. % aqueous solution) (1316 μl, 21469 μmol) and the solution was stirred for 16 hrs. The volatiles were removed by rotovap, the residue was diluted with water which caused a solid to precipitate. The solid was collected by filtration and washed with water and dried in vacuo to give the title compound as an off-white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH2:14])=[CH:8][CH:7]=2)=[CH:2]1.[CH3:16][N:17]([CH3:21])[C:18](Cl)=[O:19]>>[CH3:16][N:17]([CH3:21])[C:18]([NH:14][CH2:13][CH:12]([C:9]1[CH:10]=[CH:11][C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[CH:7][CH:8]=1)[CH3:15])=[O:19]
Reactant: CN(C)C(=O)Cl
Reactant: CC(CN)c1ccc(-c2ccsc2)cc1
Product: CC(CNC(=O)N(C)C)c1ccc(-c2ccsc2)cc1

Procedure:
The title compound was prepared 2-(4-(3-thienyl)phenyl)propylamine (see example 14) and N,N-dimethylcarbamoyl chloride in a manner analogous to the procedure described in example 14. The NMR spectrum was consistent with the proposed title structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.Cl[Si:16]([CH3:19])([CH3:18])[CH3:17]>C1(C)C=CC=CC=1>[CH3:17][Si:16]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)([CH3:19])[CH3:18]
Reactant: C[Si](C)(C)Cl
Reactant: Oc1cccc(Br)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)Oc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Bromophenol (17.3 g, 0.100 mol) and 9 ml of pyridine together with 100 ml of toluene were placed in a 3-necked 250 ml round-bottomed flask equipped with a reflux condensor, an addition funnel and thermometer/adaptor. Chlorotrimethylsilane (12.8 g, 15 ml, 0.12 mol) was added dropwise to the vigorously stirred solution. The resultant white reaction mixture was subsequently refluxed for 4 hrs and then stirred at room temperature overnight. The white precipitate was removed by filtration and the colorless filtrate was subjected to rotary evaporation to remove the solvent. The residual liquid was purified by simple distillation. The pure product was collected at 232°-233° C. Yield: 23.0 g (93%). Calc. for C9H13BrOSi: 44.08% C; 5.34% H; 32.59% Br. Found: 43.98% C; 5.36% H; 32.35% Br. Mass Spectroscopy: 244,246 (77%, 78%, M+) Proton NMR (δ in ppm, CHCl3); 0.27 (singlet, Me3Si--); 6.66-7.32 (complex, aromatic protons).
Reaction SMILES: F[C:2](F)(F)C(O)=O.[OH:8][C:9]1[C:10]([CH:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH2:29][C@H:30]3[CH2:34][CH2:33][CH2:32][O:31]3)[C:21]2=[O:35])=[CH:11][C:12]2[O:17][CH2:16][CH2:15][N:14]([CH3:18])[C:13]=2[CH:19]=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[CH3:18][N:14]1[C:13]2[CH:19]=[C:9]3[O:8][CH2:2][C:20]4([C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]([CH2:29][C@H:30]5[CH2:34][CH2:33][CH2:32][O:31]5)[C:21]4=[O:35])[C:10]3=[CH:11][C:12]=2[O:17][CH2:16][CH2:15]1
Reactant: CN1CCOc2cc(C3C(=O)N(C[C@H]4CCCO4)c4ccccc43)c(O)cc21
Reactant: O=C(O)C(F)(F)F
Agent: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: CN1CCOc2cc3c(cc21)OCC31C(=O)N(C[C@H]2CCCO2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 3-(6-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-one trifluoroacetate to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 4-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-3,4-dihydro-2H-spiro[furo[2,3-g][1,4]benzoxazine-8,3′-indol]-2′(1′H)-one was obtained (62%) as a pale yellow solid: mp 138-140° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) (diastereomers) δ 7.26 (dd, J=7.7, 7.7 Hz, 1H), 7.16-6.99 (m, 3H), 6.29 (s, 1H), 6.122, 6.117 (s, 1H), 4.86 (d, J=8.9 Hz, 1H), 4.61 (d, J=8.9 Hz, 1H), 4.31-4.21 (m, 1H), 4.13 (dd, J=4.5, 4.5 Hz, 2H), 3.99-3.66 (m, 4H), 3.23 (dd, J=4.5, 4.2 Hz, 2H), 2.87 (s, 3H), 2.07-1.83 (m, 3H), 1.81-1.67 (m, 1H); 13C NMR (75 MHz, CDCl3) (diastereomers) δ178.5, 178.3, 156.1, 143.1, 142.9, 139.0, 137.8, 132.7, 132.6, 128.7, 128.6, 123.84, 123.76, 123.2, 116.41, 116.35, 110.26, 110.22, 109.7, 109.4, 94.4, 80.2, 80.1, 77.3, 76.8, 68.38, 68.35, 64.5, 58.3, 49.2, 44.64, 44.58, 39.0, 29.4, 29.0, 25.9, 25.7; MS (ES+) m/z 393.0 (M+1).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:12]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:27][CH:26]=2)[N:11]=1>O>[ClH:9].[ClH:9].[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][N:16]3[CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)=[C:12]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([N:31]4[CH2:32][CH2:33][O:34][CH2:35][CH2:36]4)=[CH:29][CH:30]=3)[N:11]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Clc1nc(Nc2ccc(N3CCOCC3)cc2)c2ncn(C3CCCC3)c2n1
Solvent: O
Product: Cl
Product: N[C@H]1CC[C@H](Nc2nc(Nc3ccc(N4CCOCC4)cc3)c3ncn(C4CCCC4)c3n2)CC1
Temperature: 140 °C

Procedure:
800 mg of trans-1,4-diaminocyclohexane is taken to approximately 140° C. then 286 mg of the product obtained in Stage 1 above is added, the reaction medium is maintained under agitation at 140° C. for 5 hours then left to return to ambient temperature. Then 15 ml of water is added, followed by extracting with dichloromethane, drying and evaporating the solvent. The residue is chromatographed on silica (eluent: MeOH/NH4OH 98/2), followed by taking up in 4 ml of an ethanolic solution of hydrochloric acid, evaporating the solvents, drying under reduced pressure to 50° C. and 143 mg of expected product is recovered.
Reaction SMILES: [NH2:1][C:2](=[N:27][N+:28]([O-:30])=[O:29])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:24](O)=[O:25])[NH:8][C:9](=[O:23])[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH2:31][C:32]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][NH2:43])=[CH:38][CH:37]=1)=[O:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(#N)C>[NH2:31][C:32]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][NH:43][C:24](=[O:25])[C@@H:7]([CH2:6][CH2:5][CH2:4][NH:3][C:2]([NH2:1])=[N:27][N+:28]([O-:30])=[O:29])[NH:8][C:9](=[O:23])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:38][CH:37]=1)=[O:33]
Reactant: NCc1ccc(CCC(N)=O)cc1
Reactant: NC(=N[N+](=O)[O-])NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: NC(=O)CCc1ccc(CNC(=O)[C@@H](CCCNC(N)=N[N+](=O)[O-])NC(=O)C(c2ccccc2)c2ccccc2)cc1
Yield: 60 %

Procedure:
Prepared analogously to Example 4b) from (R)-N5 -[amino[nitroimino)methyl]-N2 -(diphenylacetyl)-ornithine, 4-[2-(aminocarbonyl)ethyl]benzenemethanamine and TBTU in a yield of 60% of theory. Colourless crystals, Mp. 139-140° C. (Acetonitrile).
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]1[CH2:11][C@H:7]2[O:8][CH2:9][CH2:10][C@@:6]2([C:12]([N:14]2[CH2:23][CH2:22][C:21]3[N:20]=[CH:19][C:18]([C:24]([F:27])([F:26])[F:25])=[CH:17][C:16]=3[CH2:15]2)=[O:13])[CH2:5]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:46][O:47][C@H:48]1[C:53](=O)[CH2:52][CH2:51][O:50][CH2:49]1>ClCCCl.C(Cl)Cl.ClCCCl>[CH3:46][O:47][C@H:48]1[C@@H:53]([NH:3][C@@H:4]2[CH2:11][C@H:7]3[O:8][CH2:9][CH2:10][C@@:6]3([C:12]([N:14]3[CH2:23][CH2:22][C:21]4[N:20]=[CH:19][C:18]([C:24]([F:27])([F:26])[F:25])=[CH:17][C:16]=4[CH2:15]3)=[O:13])[CH2:5]2)[CH2:52][CH2:51][O:50][CH2:49]1
Reactant: N[C@@H]1C[C@H]2OCC[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Reactant: CO[C@@H]1COCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1C[C@H]2OCC[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Temperature: 16 °C
Reaction time: 0.12 h

Procedure:
To a mixture of the product of Step K (the free base) (619.7 g, 1.74 mol) in 1,2-dichloroethane/CH2Cl2 (˜10 L) was added acetic acid (glacial, 180 mL) and the mixture was cooled to 16° C. Solid Na(OAc)3BH (463 g, 2.18 mol) was added and the suspension was stirred for 5-10 min. A solution of (R)-3-methoxydihydro-2H-pyran-4(3H)-one (prepared as described in Intermediate 1, 213 g, 1.63 mol) in 1,2-dichloroethane (1.75 L) was added over 20 min and the resulting mixture was stirred at rt overnight. Additional acetic acid, (R)-3-methoxytetrahydro-4H-pyran-4-one (28 g) and Na(AcO)3BH were added until TLC showed the reaction was complete. The reaction was quenched with saturated aqueous NaHCO3, the organic layer was separated and the aqueous layer was back-extracted with CH2Cl2. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated under reduced pressure. Purification was affected by chromatography with MeOH (7N NH3) in CH2Cl2. The collected enriched isomer was further purified using chiral chromatography on chiralpak AD column using a mixture of heptanes/EtOH/isopropyl alcohol to provide the product of Step L.
Reaction SMILES: N[C:2]1[CH:3]=[C:4](S(O)(=O)=O)[C:5]([CH:8]=[CH:9][C:10]2[C:11]([S:17]([OH:20])(=[O:19])=[O:18])=[CH:12][C:13]([NH2:16])=CC=2)=[CH:6][CH:7]=1.[N:25]1[C:32](Cl)=NC(Cl)=NC=1Cl.C(=O)([O-])[O-].[Na+].[Na+].[CH3:40][C:41]([CH3:43])=[O:42]>O>[CH:10]1[C:11]([S:17]([OH:20])(=[O:18])=[O:19])=[CH:12][C:13]([NH2:16])=[C:43]2[C:9]=1[CH:8]=[C:5]([S:17]([OH:20])(=[O:19])=[O:18])[CH:40]=[C:41]2[OH:42].[NH2:25][C:32]1[C:6]([CH3:5])=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: CC(C)=O
Reactant: Nc1ccc(C=Cc2ccc(N)cc2S(=O)(=O)O)c(S(=O)(=O)O)c1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccccc1N
Product: Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(O)c12

Procedure:
The above dyes can be prepared by a conventional method. For example, the dye (5) can be prepared as follows: One mole of 4,4'-diaminostilbene 2,2'-disulfonic acid is dissolved in water. To this solution, (1) 2 moles of cyanuric chloride dissolved in acetone and (2) an aqueous solution of sodium carbonate are simultaneously added at temperatures below 0° C., with the mixuture kept unalkaline, thereby allowing the added components to react for 2 hours. To the above reaction mixture is added a monoazo dye obtained by a conventional reaction of H-acid and o-toluidine. The monoazo dye is dissolved in the reaction mixture. To this reaction mixture, an aqueous solution of sodium carbonate is further added, with the reaction mixture kept unalkaline, so that the reaction mixture is allowed to react at room temperature for 10 hours. Thereafter, the temperature of the reaction mixture is gradually raised to 60° C. and the reaction is continued for 1 hour. Aniline and sodium carbonate are then added to the reaction mixture and the temperature of the reaction mixture is raised to 90° C., so that the reaction is further continued for 3 hours. After cooling the reaction mixture, the dye (5) is obtained by a salting-out technique using a 20% aqueous solution of sodium chloride.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]1[O:5][C:6]2[C:11]([C:12](=[O:21])[C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:3].C(N(CC)C(C)C)(C)C.Br[C:32]1[N:40]=[CH:39][N:38]=[C:37]2[C:33]=1[NH:34][CH:35]=[N:36]2>C(O)(C)(C)C>[N:40]1[C:32]([NH:1][C@@H:2]([C:4]2[O:5][C:6]3[C:11]([C:12](=[O:21])[C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH3:3])=[C:33]2[C:37]([NH:36][CH:35]=[N:34]2)=[N:38][CH:39]=1
Reactant: C[C@@H](N)c1oc2ccccc2c(=O)c1-c1cccc(F)c1
Reactant: Brc1ncnc2nc[nH]c12
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1ncnc2[nH]cnc12)c1oc2ccccc2c(=O)c1-c1cccc(F)c1

Procedure:
This example is also described in Example 56 of WO 2011/055215. To a solution of (R)-2-(1-Amino-ethyl)-3-(3-fluoro-phenyl)-chromen-4-one (0.41 g, 1.52 mmoles) in tert-butanol (7 ml), N,N-diisopropylethylamine (0.53 ml, 3.04 mmoles) and 6-bromopurine (0.242 g, 1.21 mmoles) are added and refluxed for 24 h. The reaction mixture is concentrated, diluted with water, and extracted with ethyl acetate. The organic layer is dried over sodium sulphate and concentrated under reduced pressure. The crude product is purified by column chromatography with methanol:ethyl acetate to afford the title compound as an off-white solid. MP: 274-276° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 12.96 (s, 1H), 8.14-8.01 (m, 4H), 8.11 (s, 1H), 7.81 (dt, J=8.5, 1.5 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.49 (m, 2H), 7.25-7.19 (m, 3H), 5.18 (br m, 1H), 1.56 (d, J=7.0 Hz, 3H). Mass: 402.04 (M++1).