Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])[C:10](=[O:24])[NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].F[B-](F)(F)F.[CH3:30][O+](C)C.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([N:13]2[C:14](=[O:23])[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]2=[O:22])[C:10]([O:24][CH3:30])=[N:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCNC(=O)C(N2C(=O)c3ccccc3C2=O)C1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)N1CCN=C(OC)C(N2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a solution of 45.00 g (135.82 mmol) of (+/−)-6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-5-oxo-[1,4]diazepane-1-carboxylic acid ethyl ester in 339 mL of anhydrous dichloromethane was added 22.09 g (149.40 mmol) of trimethyloxonium tetrafluoroborate. The resulting mixture was stirred at room temperature for 12 h. The mixture was hydrolyzed with a saturated aqueous solution of sodium hydrogen carbonate, extracted with dichloromethane, dried over sodium sulfate and the solvent was evaporated to afford 46.90 g (99%) of pure product as yellow oil. The compound was used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:28])[C:13]3[S:17][C:16]([NH:18][C:19](=[O:27])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH3:26])=[CH:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][C:7](=O)[C:6]=2[CH:30]=1.CO.[CH3:33][NH2:34].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:28])[C:13]3[S:17][C:16]([NH:18][C:19](=[O:27])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH3:26])=[CH:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([NH:34][CH3:33])[C:6]=2[CH:30]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3cc(Cl)ccc32)s1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)s2)c2ccc(Cl)cc21
Reaction time: 8 h

Procedure:
To a suspension of 7-chloro-5-oxo-1-[5-(2-methylbenzoylamino)thenoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1 g) in methanol (40 ml) are added molecular sieve 4A (2 g) and 40% methylamine methanol solution (10 ml), and the mixture is refluxed for 6 hours, and cooled. To the mixture is added with stirring sodium borohydride (0.13 g) at room temperature, and the mixture is stirred at the same temperature overnight. The reaction solution is filtered on Celite, and to the filtrate is added water, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography, and recrystallized from dichloromethane-diethyl ether to give 7-chloro-5-methylamino-1-[5-(2-methylbenzoylamino)thenoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.93 g) as white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][C:13]2([O:15][CH:14]2[CH3:16])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[FH:25]>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][C:13]([F:25])([CH:14]([OH:15])[CH3:16])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: F
Reactant: CC1OC12CCN(C(=O)OCc1ccccc1)C2
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(O)C1(F)CCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 0.247 g, (1 mmol) of 2-methyl-1-oxa-5-azaspiro[2,4]-heptane-5-carboxylic acid benzyl ester (Example A9) in dichloromethane (3 mL) is added to a polypropylene flask containing 0.5 mL of hydrogen fluoride-pyridine at −40° C. The reaction is allowed to come to room temperature and stirring is continued for 3 hours. The reaction mixture is poured into an aqueous ice-cold ammonium hydroxide solution (30 mL) and extracted with dichloromethane. The organic layer is dried, filtered and concentrated to afford the title compound (0.267 g). 1H NMR (200 MHz, CDCl3): δ 7.35 (s, 5H), 5.13 (s, 2H), 3.96–3.34 (m, 5H), 2.20–1.98 (m, 3H), 1.33–1.26 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH3:33])=[CH:4][CH:3]=1.[CH3:34][C:35]1([CH3:38])[CH2:37][O:36]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[OH:36][C:35]([CH3:38])([CH3:37])[CH2:34][O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH3:33])=[CH:6][CH:7]=1
Reactant: CC1(C)CO1
Reactant: CCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OCC(C)(C)O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
To a solution of 4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) and 2,2-dimethyloxirane (0.70 mL) in N,N-dimethylformamide (10 mL) was added cesium carbonate (1.5 g), and the mixture was stirred at 70° C. for 12 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.91 g, 78%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: N#Cc1ccccc1Cl
Reactant: Nc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1Sc1ccccc1N
Temperature: 100 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
In 10 ml of DMF was dissolved 1.25 g of orthoaminothiophenol followed by addition of 1.38 g of potassium carbonate. The mixture was preheated at 100° C. and after 1.45 g of o-chlorobenzonitrile was added, the mixture was stirred in an argon gas stream at 100° C. for 1 hour. To the reaction mixture was added ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water twice and dried over magnesium sulfate and the solvent was distilled off. The residue was crystallized from n-hexane-isopropyl ether to give 1.91 g of the title compound as white crystals, m.p. 88°-90° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[C:8]([CH2:10][C:11]([O:13][CH3:14])=[O:12])#[N:9].C([O-])(=O)C.[NH4+].C(O)(=O)C>O.C1C=CC=CC=1>[C:8]([C:10](=[C:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[C:11]([O:13][CH3:14])=[O:12])#[N:9]
Reactant: O=C1CCOCC1
Reactant: COC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C(C#N)=C1CCOCC1

Procedure:
A 50 ml round-bottom flask equipped with a Dean-Stark distillation setup and condenser was charged with tetrahydro-4H-pyran-4-one (4.61 ml, 50 mmol), methyl cyanoacetate (5.3 ml, 60 mmol), ammonium acetate (1 g, 13 mmol), acetic acid (0.57 ml, 10 mmol) and benzene (30 ml). The mixture was refluxed until no more water collected in the Dean-Stark (2 hours), cooled, benzene (30 ml) added and the organic layer washed with water (50 ml). The aqueous layer was extracted with CH2Cl2 (3×50 ml). The combined organic phase was washed with sat. NaHCO3 (100 ml), brine (100 ml) dried (MgSO4), filtered and concentrated. Purified by normal phase SiO2 chromatography (10 to 60% EtOAc/hexanes) to afford methyl 2-cyano-2-(oxan-4-ylidene)acetate as a colorless oil (6.30 g, 70%, m/z: 181.1 [M+H]+ observed).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14]1([CH2:20][CH2:21][NH2:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(C)C>CC(N(C)C)=O>[N+:11]([C:8]1[CH:9]=[CH:10][C:2]([NH:22][CH2:21][CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])([O-:13])=[O:12]
Reactant: NCCc1ccccc1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Solvent: CC(C)O
Solvent: CC(=O)N(C)C
Product: O=C(O)c1cc([N+](=O)[O-])ccc1NCCc1ccccc1

Procedure:
A solution of 5.6 g of 2-fluoro-5-nitrobenzoic acid and 14.5 g of 2-phenylethylamine in 20 ml of dimethylacetamide is reacted and worked up in analogy to Example 1. Yellow crystals from isopropanol, melting point 116°-118° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([NH2:16])[C:6]=2[CH:17]=1.[IH:18].CS[C:21]1[NH:22][CH2:23][CH2:24][N:25]=1.CCOCC>C(O)C>[IH:18].[NH:22]1[CH2:23][CH2:24][NH:25][C:21]1=[N:16][CH:7]1[C:6]2[CH:17]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[CH:11]=[CH:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]1=2
Reactant: CSC1=NCCN1
Reactant: NC1c2ccccc2C=Cc2ccc(Br)cc21
Agent: I
Solvent: CCOCC
Solvent: CCO
Product: Brc1ccc2c(c1)C(N=C1NCCN1)c1ccccc1C=C2

Procedure:
6.90 grams (0.024 mole) of 3-bromo-5H-dibenzo[a,d]cycloheptene-5-ylamine, 2.95 grams (0.012 mole) of 2-methylmercapto-4,5-dihydroimidazole hydroiodide, and 65 milliliters of absolute ethanol were stirred together and refluxed for 28 hours. At the end of this period, the solvent was evaporated under reduced pressure and the residue triturated with five 100 milliliter portions of diethyl ether to obtain a purified residue. The purified residue was dissolved in 20 milliliters of absolute ethanol and 300 milliliters of ether added thereto whereupon a solid precipitated. The mixture was stirred thoroughly, the solvent decanted to obtain a residue which was placed on a Still-silica column and eluted with 5 percent methanol in chloroform. The eluted fractions were examined by thin layer chromatography (TLC), the homogeneous TLC fractions combined, and the solvent then vaporized to obtain the desired N-(2-imidazolidinylidene)-3-bromo-5H-dibenzo[a,d]cyclohepten-5-amine hydroiodide product as residue. The product was crystallized from chloroform to obtain purified product, m.p. 240°-241° C. (dec.). Elemental analyses were as follows: Calc'd for C18H17BrIN3 : C, 44.84; H, 3.55; N, 8.72. Found: C, 44.75; H, 3.48; N, 8.46.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10]([C:12]2[C:13]([CH2:27][O:28]C)=[N:14][C:15]3[C:20]([C:21]=2[CH3:22])=[CH:19][CH:18]=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=3)=[O:11])[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br.CCOC(C)=O.CCCCCC.CCOC(C)=O.C(Cl)Cl>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10]([C:12]2[C:13]([CH2:27][OH:28])=[N:14][C:15]3[C:20]([C:21]=2[CH3:22])=[CH:19][CH:18]=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:16]=3)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: COCc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)NCc1cccc(F)c1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1c(C(=O)NCc2cccc(F)c2)c(CO)nc2cc(C(F)(F)F)ccc12
Temperature: 0 °C
Reaction time: 16 h
Yield: 51.9 %

Procedure:
A solution of 220 mg (0.54 mmol) N-[(3-fluorophenyl)-methyl]-2-(methoxymethyl)-4-methyl-7-(trifluoromethyl)-quinoline-3-carboxylic acid amide (Example 15) in DCM (5 ml) was cooled to −78° C. and 5.4 ml (5.4 mmol, 2M in DCM) boron tribromide was added. After heating to 0° C., the mixture was stirred for 16 h at this temperature. Quenching was then carried out with a 1M aq. NaHCO3 sol. (15 ml) and a 10%-strength aq. Na2S2O3 sol. It was then diluted with MeOH and DCM and the organic phase was separated, dried over MgSO4 and concentrated in a vacuum. After CC (EtOAc/hexane 1:1→EtOAc/DCM 1:1) of the residue, 110 mg (0.28 mmol, 52%) N-[(3-fluorophenyl)-methyl]-2-(hydroxy-methyl)-4-methyl-7-(trifluoromethyl)-quinoline-3-carboxylic acid amide (example 17) was obtained. MS: m/z 393.1 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C@H:10]([C@H:16]([OH:20])[CH2:17][CH2:18][CH3:19])[C:11]([O:13]CC)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].S(=O)(=O)(O)[O-].[Na+]>C1COCC1.C(O)C>[C:1]1([CH2:7][CH2:8][CH2:9][C@H:10]([C@H:16]([OH:20])[CH2:17][CH2:18][CH3:19])[C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC[C@@H](O)[C@@H](CCCc1ccccc1)C(=O)OCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCC[C@@H](O)[C@@H](CCCc1ccccc1)C(=O)O
Temperature: 23 °C
Reaction time: 20 h
Yield: 99.9 %

Procedure:
To a solution of ethyl (2R,3R)-2-(3-phenyl-1-propyl)-3-hydroxyhexanoate (1.70 g, 6.12 mmol) in THF-ethanol (2:1, 18 mL) is added 1 N aqueous sodium hydroxide solution (6.7 mL, 6.7 mmol). The solution is stirred at 23° C. for 20 h and is acidified to pH 3 with saturated aqueous sodium bisulfate and is extracted with two 50-mL portions of EtOAc. The combined organic layers are dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (2R,3R)-2-(3-phenyl-1-propyl)-3-hydroxyhexanoic acid as an oil (1.53 g, 100% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=O)=[CH:15]2)(=[O:8])=[O:7].[CH2:22]([S:29][C:30]([CH3:34])([CH3:33])[CH2:31][NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O>[CH2:22]([S:29][C:30]([CH3:34])([CH3:33])[CH2:31][NH:32][C:19]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8])=[O:21])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(CN)SCc1ccccc1
Reactant: O=C(O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(CNC(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1)SCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
To a mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.70 g), 2-(benzylthio)-2-methylpropylamine (0.47 g), 1H-1,2,3-benzotriazol-1-ol (0.35 g) and N,N-dimethylformamide (15 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.50 g) at 0° C., and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography and the title compound (0.86 g, yield 77%) was obtained as yellow crystals from a fraction eluted with ethyl acetate-hexane (1:9-42:3, volume ratio). melting point 170-171° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([NH:16][NH2:17])=O)=[N:4][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][N:7]=1.Cl.[C:19](N)(=[NH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])C.[Na+]>CN(C=O)C>[C:20]1([C:19]2[NH:26][C:14]([C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C:8]4[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=4)[N:4]=3)=[N:16][N:17]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NNC(=O)c1nc(-c2cccnc2)cnc1N
Reactant: N=C(N)c1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncc(-c2cccnc2)nc1-c1nnc(-c2ccccc2)[nH]1
Temperature: 200 °C
Yield: 22.9 %

Procedure:
A mixture of 3-amino-6-(3-pyridyl)pyrazine-2-carbohydrazide (40 mg, 0.173 mmol), benzamidine hydrochloride (27.2 mg, 0.173 mmol) and sodium ethanolate (11.82 mg, 0.173 mmol) were added to a 5 mL microwave vial in DMF (1 mL). The reaction mixture was heated in the microwave at 200° C. for 20 min. The mixture was concentrated in vacuo and the residue purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100 A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were freeze-dried to give the title compound as a solid (12.5 mg, 20% Yield). 1H NMR (500 MHz, DMSO) d 7.5 (m, 3H), 7.66 (m, 1H), 7.94 (br s, 2H), 8.16 (m, 2H), 8.66 (s, 1H), 8.79 (br s, 1H), 8.96 (s, 1H), 9.52 (s, 1H) and 14.94 (s, 1H) ppm; MS (ES+) 316
Reaction SMILES: C([NH:5][C:6]([NH:8][C@H:9]([CH2:12][C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)[CH2:10]O)=[S:7])(C)(C)C.C(O)C.C(OCC)C.[ClH:26]>CC(C)=O>[ClH:26].[S:15]1[CH:16]=[CH:17][C:13]([CH2:12][C@@H:9]2[CH2:10][S:7][C:6]([NH2:5])=[N:8]2)=[CH:14]1
Reactant: CC(C)(C)NC(=S)N[C@@H](CO)Cc1ccsc1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Solvent: CC(C)=O
Product: NC1=N[C@H](Cc2ccsc2)CS1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 0.94 g of N-(tert-butyl)-N′-[(1R)-2-hydroxy-1-(3-thienylmethyl)ethyl]thiourea in 9.2 cm3 of 6N hydrochloric acid is heated at a temperature in the region of 100° C. with stirring for 3 hours and is then concentrated under reduced pressure (2 kPa) at a temperature in the region of 40° C. A greenish oil is obtained, which is taken up in 10 cm3 of acetone to give a sticky gum. 1.5 cm3 of ethanol are then added, followed by dropwise addition, with stirring, of 6 cm3 of diethyl ether. The crystals obtained are filtered off on a sinter funnel, washed with diethyl ether and then dried in an oven under vacuum (10 Pa) at a temperature in the region of 50° C. 0.5 g of (−)-(4R)-4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine hydrochloride is obtained in the form of gray crystals melting at 152° C. 1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 2.99 (mt: 2H); 3.26 (dd, J=11 and 5.5 Hz: 1H); 3.59 (dd, J=11 and 8 Hz: 1H); 4.54 (mt: 1H); 7.10 (dd, J=5.5 and 1 Hz: 1H); 7.38 (mt: 1H); 7.54 (dd, J=5 and 3 Hz: 1H); from 9.15 to 10.55 (broad unres. mult.: 3H). (αD20=−4.3±0.5 at a concentration of 0.5% in methanol).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][CH:23]4[CH2:28][C@H:27]([CH3:29])[O:26][C@H:25]([CH3:30])[CH2:24]4)[N:16]=3)[C:12]([Cl:31])=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[CH3:32][O:33][CH2:34][CH2:35]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O>[Cl:31][C:12]1[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][CH:23]3[CH2:24][C@H:25]([CH3:30])[O:26][C@H:27]([CH3:29])[CH2:28]3)[N:16]=2)=[CH:14][C:9]([NH:8][C@H:5]2[CH2:6][CH2:7][C@H:2]([NH:1][CH2:35][CH2:34][O:33][CH3:32])[CH2:3][CH2:4]2)=[N:10][CH:11]=1
Reactant: C[C@@H]1CC(CNc2cccc(-c3cc(N[C@H]4CC[C@H](N)CC4)ncc3Cl)n2)C[C@H](C)O1
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COCCN[C@H]1CC[C@H](Nc2cc(-c3cccc(NCC4C[C@@H](C)O[C@@H](C)C4)n3)c(Cl)cn2)CC1
Temperature: 105 °C

Procedure:
The mixture of N2′-(trans-4-aminocyclohexyl)-5′-chloro-N6-(((2R,6S)-2,6-dimethyl tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine Compound 284 (20 mg, 0.045 mmol), p-toluenesulfonic acid 2-methoxyethyl ester (14 mg, 0.06 mmol) and sodium carbonate (9.6 mg, 0.09 mmol) in 1 ml DMSO was heated in a reaction vessel at 105° C. in an oil bath for 3 h. Formation of desired product was confirmed by LCMS, MH+502/504, 0.58 min, with ˜50% conversion. Mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate, and concentrated. Crude product was purified by HPLC to give desired product as TFA salt. LCMS (m/z): 502.2/504.2, retention time=0.56 min.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:19]Br>BrBr.O1CCOCC1>[Br:19][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][S:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])=[O:12])=[CH:8][CH:9]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccc(NS(=O)(=O)NC(C)(C)C)cc1
Solvent: C1COCCO1
Product: CC(C)(C)NS(=O)(=O)Nc1ccc(C(=O)CBr)cc1

Procedure:
A few drops of bromine (from a total of 10.3 g., 0.064 mole) is added to N-(4-acetylphenyl)-N'-tert.-butylsulfamide (17.3 g., 0.064 mole) in dioxane (200 ml.) solution at 15° C. and the solution is stirred until the color is discharged. The remainder of the bromine is added during 5 min. and the solution is stirred for an additional 10 min. thereafter. The solution is concentrated in vacuo and the residue triturated with isopropyl ether to give 20.7 g. (92%) of intermediate, recrystallized from isopropanol, m.p. 160.5°-161° C. (dec.)
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C[Al](C)C.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[C:15]3[C:24]([CH2:25][C:26](OC)=[O:27])=[N:23][N:22]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:21](=[O:36])[C:16]=3[N:17]([CH3:20])[C:18]=2[CH:19]=1.O>C1(C)C=CC=CC=1.ClCCl>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[C:15]3[C:24]([CH2:25][C:26]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:27])=[N:23][N:22]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:21](=[O:36])[C:16]=3[N:17]([CH3:20])[C:18]=2[CH:19]=1
Reactant: CCNCC
Reactant: COC(=O)Cc1nn(-c2ccccc2)c(=O)c2c1c1ccc(Cl)cc1n2C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: CCN(CC)C(=O)Cc1nn(-c2ccccc2)c(=O)c2c1c1ccc(Cl)cc1n2C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96 %

Procedure:
0.41 ml (4 mmol) of diethylamine is added at 0° C. under argon to a solution of 2 ml (4 mmol) of trimethylaluminium (2M in toluene) in 30 ml of toluene, the reaction mixture is stirred for 20 min at room temperature, 0.095 g (0.25 mmol) of methyl 7-chloro-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]-indole-1-acetate is added and the reaction mixture is stirred for 4 h at reflux. The mixture is cooled to 4° C., 3 ml of water and dichloromethane are added, the solution is filtered and the filtrate is concentrated under reduced pressure. Water, 1M hydrochloric acid and 150 ml of dichloromethane are added to the residue, the organic phase is separated, washed with water, dried over sodium sulphate, filtered and concentrated under reduced pressure and the residue is purified by chromatography on a column of silica gel. After recrystallization from diethyl ether, 0.10 g (0.24 mmol) of compound is isolated in the form of a white solid with a fluffy appearance.
Reaction SMILES: N[C@H](C=O)CCSC.[CH2:9]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl[CH2:33][C:34]([OH:36])=[O:35]>O>[CH2:9]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:33][C:34]([OH:36])=[O:35])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)CCl
Reactant: OCCOCCOCCOCCOCCOCc1ccccc1
Agent: CSCC[C@H](N)C=O
Solvent: O
Product: O=C(O)COCCOCCOCCOCCOCCOCc1ccccc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 201.8 %

Procedure:
Metal sodium (115 mg, 5.0 mmol) was added to pentaethylene glycol monobenzyl ether (328 mg, 1.0 mmol), and the mixture was stirred at 90° C. for three hours. Chloroacetic acid (47 mg, 0.5 mmol) was added to the mixture which was then stirred at 90° C. for 16 hours. Water was added to the mixture which was then washed with ethyl acetate. Next, the aqueous layer was made acidic by 1 N hydrochloric acid, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to obtain 390 mg of crude [2-(2-{2-[2-(2-benzyloxyethoxy)ethoxy]ethoxy}ethoxy)ethoxy]acetic acid in the form of a reddish brown substance.