Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][CH2:6][N:7]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:8]1([C:16](=[O:19])[NH:17][OH:18])[CH2:14][CH:13]2[O:15][CH:10]([CH2:11][CH2:12]2)[CH2:9]1)C.C1(C)C=CC=CC=1.O.[OH-].[Na+]>ClCCl>[F:36][C:33]1[CH:32]=[CH:31][C:30]([O:29][C:26]2[CH:27]=[CH:28][C:23]([S:20]([N:7]([C:8]3([C:16](=[O:19])[NH:17][OH:18])[CH2:9][CH:10]4[O:15][CH:13]([CH2:12][CH2:11]4)[CH2:14]3)[CH2:6][CH2:5][C:4]([OH:37])=[O:3])(=[O:21])=[O:22])=[CH:24][CH:25]=2)=[CH:35][CH:34]=1
Reactant: CCOC(=O)CCN(C1(C(=O)NO)CC2CCC(C1)O2)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(O)CCN(C1(C(=O)NO)CC2CCC(C1)O2)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 15.1 mmoles of the product from Step G in dichloromethane is concentrated by rotary evaporation with the addition of 75 mL of toluene. This solution is treated with 75 mL of water, cooled to 0° C., and treated with 6.05 g (151 mmol, 10 equivalents) of sodium hydroxide pellets over 10 minutes with vigorous stirring. This mixture is stirred for 15 minutes at 0° C. and warmed to ambient temperature over one hour. The aqueous phase is separated, diluted with 7.5 mL of tetrahydrofuran, cooled to 0° C., and treated with 33 mL of 6N aqueous hydrochloric acid over 20 minutes. This mixture is stirred with 75 mL of ethyl acetate at 0° C. to ambient temperature, and the ethyl acetate phase is separated and washed with water. The ethyl acetate solution was concentrated to yield the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:31][OH:32]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:32][CH2:31][C:30]2[CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=[C:28]([F:27])[CH:29]=2)[CH:7]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: OCc1cc(F)cc(C(F)(F)F)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCc3cc(F)cc(C(F)(F)F)c3)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.197 mmol), intermediate 42.1, and 3-fluoro-5-(trifluoromethyl)benzyl alcohol (158 mg; 0.789 mmol), example 78 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: Br[C:2]1[C:3]([CH3:16])=[C:4]([O:13][CH2:14][CH3:15])[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]=2[C:11]=1[CH3:12].[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1>>[CH2:14]([O:13][C:4]1[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]=2[C:11]([CH3:12])=[C:2]([N:27]2[CH2:26][CH2:25][N:24]([C:21]3[CH:20]=[CH:19][C:18]([F:17])=[CH:23][CH:22]=3)[CH2:29][CH2:28]2)[C:3]=1[CH3:16])[CH3:15]
Reactant: CCOc1c(C)c(Br)c(C)c2c1OC(C)C2
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: CCOc1c(C)c(N2CCN(c3ccc(F)cc3)CC2)c(C)c2c1OC(C)C2
Yield: 60.7 %

Procedure:
By using 5-bromo-7-ethoxy-2,4,6-trimethyl-2,3-dihydro-1-benzofuran (570 mg, 2.0 mmol) synthesized in Reference example 84 and 1-(4-fluorophenyl)piperazine (720 mg, 4.0 mmol), the reaction was carried out in the same manner as Example 21 to synthesize the title compound 467 mg (yield 61%). Melting point was 136 to 138° C. (ethanol-water).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][C@@H:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][C@@H:25]2[OH:33])[C:8]([F:11])=[CH:9][CH:10]=1.[C:35](Cl)(Cl)=[O:36]>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:14][C:13]=2[CH2:22][N:23]2[C@@H:24]3[C:32]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[CH2:26][C@@H:25]3[O:33][C:35]2=[O:36])[C:8]([F:11])=[CH:9][CH:10]=1
Reactant: O=C(Cl)Cl
Reactant: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2CN[C@@H]2c3ccccc3C[C@@H]2O)c1
Product: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H]3Cc4ccccc4[C@H]32)c1

Procedure:
Prepared according to the procedure described in Example 25, Step 5, using the following starting materials: {6-fluoro-2′-[((1R,2S)-2-hydroxy-indan-1-ylamino)-methyl]-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid methyl ester and phosgene (1.9M in toluene).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:19][N:6]2[CH2:7][CH2:8][N:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][N:12]=3)[CH2:10][C@@H:5]2[CH2:4]1.[C:20]([C:22]1[CH:23]=[C:24](O)[CH:25]=[CH:26][CH:27]=1)#[N:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:20]([C:22]1[CH:27]=[C:26]([CH:25]=[CH:24][CH:23]=1)[O:1][CH2:2][C@@H:3]1[CH2:19][N:6]2[CH2:7][CH2:8][N:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][N:12]=3)[CH2:10][C@@H:5]2[CH2:4]1)#[N:21]
Reactant: N#Cc1ccc(N2CCN3C[C@@H](CO)C[C@H]3C2)nc1
Reactant: N#Cc1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(N2CCN3C[C@@H](COc4cccc(C#N)c4)C[C@H]3C2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
The (7S,8aS)-7-hydroxymethyl-2-(5-cyanopyridin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine, 1.6 g (13.4 mmol) of 3-cyanophenol, and 2.8 g (11 mmol) of triphenylphosphine were dissolved in 20 mL of dry THF, the solution was treated with 1.7 mL (11 mmol) of diethyl azodicarboxylate (DEAD), and the reaction stirred at ambient temperature for 16 hours. The solvent was evaporated, the residue taken up in ethyl acetate, and washed with 1M NaOH (sodium hydroxide). The organic phase was extracted with 1M HCl (3×), and the aqueous acid was washed with ethyl acetate (1×). The aqueous phase was made basic with 1M NaOH, extracted with ethyl acetate (3×), and the combined organic phase dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 75:25 ethyl acetate:hexane gave 0.603 g (19%) of the title compound. Mp (.HCl) 197-200° C. HRMS calc'd for C21H22N5O (MH+): 360.1824, found: 360.1802.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[C:11](Cl)(=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]CC>O1CCCC1>[O:6]=[C:5]([CH2:7][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11])[CH2:4][C:3]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)CC(C)=O
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCC(=O)CC(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
Four liters of a suspension of 440 g (11 mol) of 60% sodium hydride in dried tetrahydrofuran was cooled to 0° C. Thereto was added dropwise 1.8 L of a tetrahydrofuran solution of 1.161 kg (10 mol) of methyl acetoacetate. After this mixture was stirred at room temperature for 1 hour, 3.023 kg (11 mol) of hexadecanoyl chloride was added dropwise at 0 to 5° C. and the resultant mixture was stirred at room temperature overnight. Thereafter, the tetrahydrofuran was distilled off, and the residue was poured into ice water and extracted with 8 L of ethyl acetate. The ethyl acetate was distilled off, and the residue was poured into a mixture of 400 g of a 28% methanol solution of sodium methoxide and 1.2 L of methanol. The resultant mixture was stirred with heating at 60 to 65° C. for 6 hours. The reaction mixture was cooled with ice, and the pH thereof was then adjusted to 5 with 10% sulfuric acid. This reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with 5% aqueous sodium carbonate solution and saturated aqueous common salt solution. Thereafter, the ethyl acetate was distilled off and the concentrate was recrystallized from methanol to obtain 1.72 kg (5.5 mol) of methyl 3-oxooctadecanoate. Yield, 55%.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[OH:14])[C:8]([OH:10])=[O:9])=[O:4].S(Cl)(Cl)=O.[CH3:19]O>>[Br:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[OH:14])[C:8]([O:10][CH3:19])=[O:9])=[O:4]
Reactant: O=C(O)c1ccc(O)c(C(=O)CBr)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(O)c(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound obtained in Step B (27.4 mmol) is dissolved in 150 ml of MeOH, and 54.8 mmol of thionyl chloride are added dropwise in the cold state. The mixture is then stirred for 1 hour at ambient temperature and then for 2 hours at reflux. After evaporating off the methanol and the thionyl chloride, the oily residue is taken up in AcOEt, washed with water and then dried over MgSO4. The solvent is evaporated off under reduced pressure and the solid obtained is recrystallised.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[N:14][CH:13]=[C:12]([C:18]([F:21])([F:20])[F:19])[C:11]=2[C:10](=O)[CH2:9]1.[C:23]([NH:26][NH2:27])([NH2:25])=[NH:24].Cl.[CH3:29][S:30]([OH:33])(=[O:32])=[O:31].C1C=CC=CC=1>C(O)C>[CH3:29][S:30]([OH:33])(=[O:32])=[O:31].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[N:14][CH:13]=[C:12]([C:18]([F:21])([F:20])[F:19])[C:11]=2[C:10](=[N:27][NH:26][C:23]([NH2:25])=[NH:24])[CH2:9]1
Reactant: O=C1CC(c2ccccc2Cl)Cc2nncc(C(F)(F)F)c21
Reactant: N=C(N)NN
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: c1ccccc1
Solvent: CCO
Product: N=C(N)NN=C1CC(c2ccccc2Cl)Cc2nncc(C(F)(F)F)c21

Procedure:
To a solution of 7-(2-chlorophenyl)-4-trifluoromethyl-5,6,7,8-tetrahydrocinnolin-5-one (0.335 g) and aminoguanidine hydrochloride (165 mg) in ethanol (10 ml) were added methanesulfonic acid (0.3 ml) and benzene (10 ml), and the mixture was refluxed for 80 minutes. Under reduced pressure, the solvent was evaporated, and to the residue was added sodium hydrogen carbonate solution to make the solution alkaline. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and concentrated under reduced pressure. The residue was dissolved in acetone, and to the solution was added methanesulfonic acid (0.15 ml). Precipitated crystals were filtered, washed with acetone and dried to give 7-(2-chlorophenyl)-5-guanidinoimino-4-trifluoromethyl-5,6,7,8-tetrahydrocinnoline methanesulfonate (Compound 136) (0.240 g) as yellow crystals.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([S:10]([N:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][C:15]([CH:24]=O)=[CH:14]2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].Cl.[CH3:27][NH2:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CO>[CH3:27][NH:28][CH2:24][C:15]1[CH:16]=[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:13]([S:10]([C:6]2[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:9]=[CH:8][CH:7]=2)(=[O:12])=[O:11])[CH:14]=1
Reactant: CN
Reactant: CC(=O)c1cccc(S(=O)(=O)n2cc(C=O)cc2-c2ccccc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(C(C)=O)c2)c1
Reaction time: 0.5 h
Yield: 3.2 %

Procedure:
1-[(3-Acetylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde (200 mg) was dissolved in methanol (30 mL), methylamine hydrochloride (192 mg) was added at room temperature and the mixture was stirred for 30 min. Sodium triacetoxyborohydride (360 mg) was added at room temperature and the mixture was stirred for 2 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate-methanol=1:0→7:3), and dissolved in ethyl acetate (10 mL). Oxalic acid (50 mg) was added and the mixture was stirred for 15 min. The crystallized crystals were collected by filtration to give the title compound as colorless crystals (yield 6.7 mg, 3%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:14]([N:18]1[CH:22]=[N:21][N:20]=[C:19]1[C:23]1[C:24]([O:33][CH3:34])=[CH:25][C:26]([O:31][CH3:32])=[C:27]([CH:30]=1)[CH:28]=O)[CH:15]([CH3:17])[CH3:16].C[O-].[Li+]>CN(C)C=O>[CH2:14]([N:18]1[CH:22]=[N:21][N:20]=[C:19]1[C:23]1[C:24]([O:33][CH3:34])=[CH:25][C:26]([O:31][CH3:32])=[C:27](/[CH:28]=[CH:2]/[C:1]([C:4]2[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=2)=[O:3])[CH:30]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Reactant: COc1cc(OC)c(-c2nncn2CC(C)C)cc1C=O
Agent: C[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c(-c2nncn2CC(C)C)cc1/C=C/C(=O)c1ccc(S(N)(=O)=O)cc1
Reaction time: 8 h

Procedure:
To a solution of 4-acetyl-benzenesulfonamide (Ex-26A, 0.12 g, 0.62 mmol) and 5-(4-isobutyl-4H-[1,2,4]triazol-3-yl)-2,4-dimethoxy-benzaldehyde (Ex-109E, 0.18 g, 0.62 mmol) in N,N-dimethylformamide (9 mL) was added lithium methoxide (1.0M in methanol, 2.4 mL, 2.4 mmol). The solution was allowed to stir overnight. The reaction was quenched with water. The aqueous solution was washed ethyl acetate, acidified to pH 5, extracted with dichloromethane, isopropyl alcohol (33%, v/v, in dichloromethane). The combined dichloromethane and isopropyl alcohol was washed with brine, dried over sodium sulfate and concentrated. The crude product was then stirred in ethanol (50%, v/v, in acetone) to give the title compound as a light yellow solid: m.p.>240° C. 1H NMR (DMSO-d6) δ 8.60 (s, 1H), 8.26 (d, J=8.1 Hz, 2H), 8.06 (d, J=15.3 Hz, 1H), 8.07 (s, 1H), 7.91 (d, J=8.1 Hz, 2H), 7.84 (d, J=15.3 Hz, 1H), 7.50 (s, 1H), 6.84 (s, 1H), 4.01 (s, 3H), 3.87 (s, 3H), 3.61 (d, J=7.3 Hz, 2H), 1.81–1.74 (m, 1H), 0.67 (d, J=16.7 Hz, 6H). MS m/z=471 ([M+H]+, 100%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3]OS(C(F)(F)F)(=O)=O.[CH2:14]([NH2:22])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C(C)=CC=CC=1>[CH2:14]([NH:22][CH2:3][C:2]([F:13])([F:12])[F:1])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCc1ccccc1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: Cc1ccccc1C
Product: FC(F)(F)CNCCc1ccccc1

Procedure:
1.9 g (8.3 mmol) 2,2,2-trifluoroethyltrifluoromethanesulphonate were added to 2.0 g (16.5 mmol) phenethylamine in 50 mL xylene and the reaction mixture was refluxed overnight. After cooling the precipitate formed was suction filtered, washed with DIPE and the filtrate washed evaporated down i.vac. The residue was purified by flash chromatography. The product fractions were combined and evaporated down i.vac.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.COC1C=CC=CC=1O.[CH:22]([Si:25]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])Cl)([CH3:24])[CH3:23]>C1(C)C(C)=CC=CC=1>[C:1]([O:5][Si:25]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:22]([CH3:24])[CH3:23])(=[O:4])[CH:2]=[CH2:3]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: C=CC(=O)O
Agent: COc1ccccc1O
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: C=CC(=O)O[Si](C(C)C)(C(C)C)C(C)C

Procedure:
72.1 g (1 mol) of glacial acrylic acid, 101.2 g (1 mol) of triethylamine 0.072 g of methoxyphenol and 300 ml of xylene is added to a four-neck, round bottom flask equipped with a stirrer, condenser, nitrogen inlet, thermometer and dropping funnel. Under a nitrogen blanket, a solution of 192.8 g (1 mol) of triisopropylchlorosilane in 100 ml of xylene is slowly added to the rapidly stirred reactants at room temperature. The temperature is permitted to rise to a maximum temperature of 55° C. and this temperature is maintained with cooling if necessary.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[N:6]1([CH2:11][CH2:12][CH2:13][C:14]2[C:22]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[NH:16][CH:15]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[K+].CN(C)[CH:27]=[O:28]>>[N:6]1([CH2:11][CH2:12][CH2:13][C:14]2[C:22]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[NH:16][C:15]=2[CH:27]=[O:28])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CN(C)C=O
Reactant: c1[nH]c2c(c1CCCN1CCCC1)CCCC2
Agent: [K+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1[nH]c2c(c1CCCN1CCCC1)CCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
Phosphorus oxychloride (2.0 mL, 21.2 mmol) was added dropwise to ice-cooled dimethylformamide (4.5 mL) and stirred at room temperature for 30 minutes. To the mixture at −5° C. was added a suspension of 3-(3-pyrrolidin-1-yl-propyl)-4,5,6,7-tetrahydro-1H-indole (4.5 g, 19.3 mmol) in 10 mL of dimethylformamide. The mixture was stirred at room temperature overnight. Ice cubes were added to the reaction followed by 10 N potassium hydroxide to pH 11–12. The mixture was stirred for 1 hour, extracted with ethyl acetate and the extract washed with brine and concentrated. The residue was dissolved in dichloromethane and filtered through silica gel eluting with 7% methanol in dichloromethane to give 3.8 g (76% yield) of the product. 1H-NMR (300 MHz, diemthylsulfoxide-d6) δ 11.28 (br, s, 1H, NH), 9.38 (s, 1H, CHO), 2.59 (t, 2H, CH2), 2.46 (m, 2H, CH2), 2.3–2.44 (m, 8H, 4×CH2), 1.55–1.65 (m, 10H, 5×CH2). MS m/z 260 [M+].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[C:45]1([CH:51]([CH3:54])[CH2:52][NH2:53])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:53][CH2:52][CH:51]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH3:54])=[O:21])=[CH:16][CH:15]=1
Reactant: CC(CN)c1ccccc1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCC(C)c4ccccc4)cc3)c2)o1
Reaction time: 18 h

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and 2-phenylpropylamine (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(2-phenylpropyl)-1,1′-biphenyl-4-carboxamide. LCMS; retention time 3.44 min, MH+ 412.
Reaction SMILES: [Na].[C:2]([C:4]1[C:5]([S-:15])=[N:6][S:7][C:8]=1[NH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:3].I[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O1CCCC1>[CH2:13]([O:12][C:10](=[O:11])[NH:9][C:8]1[S:7][N:6]=[C:5]([S:15][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:4]=1[C:2]#[N:3])[CH3:14]
Reactant: CCCCCI
Reactant: CCOC(=O)Nc1snc([S-])c1C#N
Agent: [Na]
Solvent: C1CCOC1
Product: CCCCCSc1nsc(NC(=O)OCC)c1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.7 %

Procedure:
A mixture of sodium, 4-cyano-5-ethoxycarbonylamino-isothiazole-3-thiolate (5.0 g, 20 mmol), 1-iodopentane (4.0 g, 20 mmol) and tetrahydrofuran (20 mL) was stirred at ambient temperature for 16 hours. After concentration in vacuo, the residue was partitioned between ethyl acetate and brine. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was filtered through a pad of silica gel using 1:1 ethyl acetate-hexane as eluent. The filtrated was concentrated and the residue was recrystallized from cold aqueous methanol, affording 2.5 g (42%) (4-cyano-3-pentylsulfanyl-isothiazol-5-yl)-carbamic acid ethyl ester as a colorless solid. An additional 0.5 g (8.4%) was obtained by concentration of the mother liquor and purification by radial chromatography (4 mm plate, 4:1 hexane-ethyl acetate). 1H NMR (400 MHz, acetone-d6) δ 11.1 (bs, 1 H), 4.32 (q, 2H, J=7.2 Hz), 3.21 (t, 2H, J=7.2 Hz), 1.73 (p, 2H, J=6.8 Hz), 1.44-1.28 (m, 7H), 0.90 (t, 3H, J=7.6 Hz) ppm; MS (APCl, m/z): 312 [M+Na]30 .
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14][N:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:11][N:10]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:9][CH2:8]1)=[O:5])[CH3:2].[CH2:31]([N:38]([CH2:43][CH:44]1[CH2:46][O:45]1)[S:39]([CH3:42])(=[O:41])=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(O)C>[CH2:31]([N:38]([S:39]([CH3:42])(=[O:41])=[O:40])[CH2:43][CH:44]([OH:45])[CH2:46][N:16]1[CH2:15][CH2:14][N:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:11][N:10]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:9][CH2:8][N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:18][CH2:17]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CS(=O)(=O)N(Cc1ccccc1)CC1CO1
Reactant: CCOC(=O)CN1CCNCCN(CC(=O)OCC)CCN(CC(=O)OCC)CC1
Solvent: CCO
Product: CCOC(=O)CN1CCN(CC(=O)OCC)CCN(CC(O)CN(Cc2ccccc2)S(C)(=O)=O)CCN(CC(=O)OCC)CC1

Procedure:
200 ml of absolute ethanol is poured over 8.61 g (20 mmol) of N,N',N"-tris-(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (produced according to DE 36 25 417 A1) in a bomb tube. After 4.83 g (20 mmol) of N-benzyl-N-[(2-oxiranyl)-methyl]-methanesulfonic acid amide is added (Example 2e), the bomb tube is closed, flushed with nitrogen, and the resulting reaction mixture is heated for 16 hours to 90° C. After the reaction (TLC control) is completed, the solvent is evaporated in a vacuum and the yellowish, oily residue is chromatographed on silica gel (eluent: chloroform/methanol; methanol: 0-80%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.ClCCl.[CH:10]1([N:16]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[C:17](=O)[N:18]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[NH3:38].CO>C1COCC1>[CH:10]1([N:16]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[C:17]([N:18]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[NH:38])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C(N(C1CCCCC1)C1CCCCC1)N(C1CCCCC1)C1CCCCC1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: N=C(N(C1CCCCC1)C1CCCCC1)N(C1CCCCC1)C1CCCCC1

Procedure:
A solution of dicyclohexylamine (3.9 mL, 19 mmol) and triethylamine (6 mL, 43 mmol) in THF (64 mL) was added dropwise to a stirred solution of triphosgene (1.99 g, 6.7 mmol) in THF (35 mL) at room temperature. The reaction mixture was stirred overnight. Then, a solution of dicyclohexylamine (3.9 mL, 18 mmol) and triethylamine (6 mL, 43 mmol) in THF (37 mL) was added. The reaction mixture was stirred overnight at reflux temperature. The reaction mixture was filtered and the filtrate was evaporated to dryness, yielding tetracyclohexylurea as a yellow solid. Yield: 4.5 g (65%). A solution of oxalyl chloride in dichloromethane (1.1 mL, 13 mmol) was added to a stirred solution of the urea (4.5 g, 11 mmol) in THF (50 mL). The reaction mixture was evaporated to dryness after overnight heating to reflux. A solution of ammonia in methanol (5 mL, 35 mmol, 7 M) was added to a solution of the formed solid in THF (40 mL). The reaction mixture was heated to reflux overnight and evaporated to dryness. The product was neutralized and treated with aqueous sodium hydroxide solution. The organic layer was extracted with diethyl ether and dried over magnesium sulfate. Crystallization from hexanes yielded the desired guanidine as a brown solid. Yield: 2.9 g (64%). 13C NMR (CDCl3, 75 MHz): δ 25.4, 26.2, 31.8, 58.0, 156.2 ppm.