Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([C:19]3[N:27]([S:28]([C:31]4[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=4)(=[O:30])=[O:29])[C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:21]4[CH:20]=3)=[CH:14][N:15]2[CH3:18])=[CH:11][C:10]=1[O:38][CH3:39])C1C=CC=CC=1.C[Si](I)(C)C>C(#N)C>[CH3:39][O:38][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:9]=1[OH:8])[N:15]([CH3:18])[CH:14]=[C:13]2[C:19]1[N:27]([S:28]([C:31]2[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=2)(=[O:30])=[O:29])[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH:20]=1
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCc1ccccc1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1O
Temperature: 50 °C
Yield: 69.7 %

Procedure:
A solution of 2-(6-benzyloxy-5-methoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.5 g; 2.79 mmol) in acetonitrile (120 ml) is placed in a 250 ml three-necked flask at 20° C., and then trimethylsilyl iodide (0.956 ml; 6.97 mmol) is added dropwise. The reaction mixture is heated at 50° C. for 4 hours and is then evaporated to dryness under reduced pressure. The evaporation residue is taken up in dichloromethane (200 ml) and then washed with distilled water (1×200 ml). The extracts are combined, washed with distilled water, dried over magnesium sulfate and evaporated under reduced pressure, to produce the crude compound which is purified by chromatography on a silica cartridge (AIT FlashSmart Pack, BP-0610300-093, 50 g silica), elution being carried out at 15 ml/min with a dichloromethane/ethyl acetate (95/5 v/v) mixture. The fractions containing the expected product are combined and evaporated to give 5-methoxy-1-methyl-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indol-6-ol (0.87 g; 70%) in the form of an ochre foam, which is used as it is for the following step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][CH:8]=1)[CH3:2].C(N(CC)CC)C.S([Cl:27])(C)(=O)=O>ClCCl>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][Cl:27])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CCc1ccc(CO)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-(4-hydroxymethylphenyl)propionic acid ethyl ester (P5, 2.9 g, 13.9 mmol) in triethylamine (4.0 mL, 27.8 mmol) and dichloromethane (30 mL) was slowly added at 0° C. mesyl chloride (1.6 mL, 20.9 mmol). The solution was stirred at room temperature for 18 hours, then the solution was washed with 1N aqueous hydrochloric acid. The organic phase was dried (anhydrous magnesium sulfate) and concentrated to afford the title compound as an oil.
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1>C1C=CC=CC=1>[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[N:1][C@@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[CH2:7][OH:8])=[CH:12][CH:11]=1
Reactant: CC(C)C[C@H](N)CO
Reactant: O=Cc1ccc(F)cc1
Solvent: c1ccccc1
Product: CC(C)C[C@@H](CO)N=Cc1ccc(F)cc1

Procedure:
A mixture of (L)-leucinol (1.13 g, 9.67 mmol) and 4-fluorobenzaldehyde (1.20 g, 9.67 mmol) was dissolved in benzene (30 mL) and heated at reflux for 1 hour, using a Dean-Stark apparatus to remove water. (S)-2-[(4-Fluorobenzylidene)-amino]-4-methylpentan-1-ol was isolated by concentration in vacuo, and was used immediately without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([N:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[N:24]=[CH:23]2)[CH:17]=1)=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@@H:8]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([N:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[N:24]=[CH:23]2)[CH:17]=1)=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ccnc(-n2cnc3ccccc32)c1)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](C(=O)N1CCC[C@H]1c1ccnc(-n2cnc3ccccc32)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of {(S)-2-[(S)-2-(2-benzoimidazol-1-yl-pyridin-4-yl)-pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethyl}-carbamic acid tert-butyl ester (70 mg, 0.14 mmol) in DCM (2 mL) is added TFA (2 mL). After stirring at room temperature for 1 h, the reaction mixture is concentrated down to give crude (S)-2-Amino-1-[(S)-2-(2-benzoimidazol-1-yl-pyridin-4-yl)-pyrrolidin-1-yl]-2-cyclohexyl-ethanone, which is used in next step without further purification.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([OH:32])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][C:14]1[N:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[O:17][C:18]=1[CH3:19])[CH2:2][CH2:3][CH3:4].Br[C:34]([CH3:41])([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:38]([O:37][C:35](=[O:36])[C:34]([O:32][C:7]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:21]=[CH:22][C:23]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:24][CH:25]=3)[O:17][C:18]=2[CH3:19])=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:6]=1)([CH3:41])[CH3:40])[CH3:39]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCCc1cc(O)ccc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCc1cc(OC(C)(C)C(=O)OCC)ccc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Temperature: 55 °C

Procedure:
A mixture of 3-butyl-4-[2-(5-methyl-2-biphenyl-4-yl-oxazole-4-yl)ethoxy]phenol (0.90 mmol), ethyl 2-bromo-2-methylpropanoate (2.25 mmol) and cesium carbonate (0.45 g, 1.38 mmol) in anhydrous DMF (4 mL) was heated for 24 h at 55° C. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate (50 mL) and water (40 mL), washed with brine, dried (Na2SO4), and removed in vacuo to give a crude oil which was purified using radial chromatography eluting with 2% ethyl acetate/dichloromethane to give 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-3-butylphenoxy}-2-methylpropionic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ8.04 (d, J=8.3 Hz, 2H), 7.66 (d, J=8.3 Hz, 2H), 7.63 (d, J=8.3 Hz, 2H), 7.46 (t, J=7.6 Hz, 2H), 7.37 (t, J=7.3 Hz, 1H), 6.71 (d, J=8.8 Hz, 1H), 6.69 (br s, 2H), 6.64 (dd, J=8.8, 2.9 Hz, 1H), 4.25-4.19 (m, 4H), 2.97 (t, J=6.4 Hz, 2H), 2.50 (t, J=7.5 Hz, 2H), 2.38 (s, 3H), 1.52 (s, 6H), 1.46 (quintet, J=7.6 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H), 0.88 (t, J=7 Hz, 3H); Rf=0.16 (25% ethyl acetate/hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29](=[O:36])[CH2:30][C:31]([O:33]CC)=O)([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:38]O.[OH-].[Na+].Cl>O.CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29]3[O:36][N:38]=[C:31]([OH:33])[CH:30]=3)([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)C[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(CC)CC)C1=O
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)N1C(=O)[C@@](C)(Cc2cc(O)no2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To an ice-cooled slurry of 65 mg (0.12 mmol) of ethyl 4-43R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)-3-oxobutanoate (Example 79, Step B) in water (2 mL) was added 53.5 mg (0.77 mmol) of hydroxylamine hydrochloride and 62 mg (1.55 mmol) of sodium hydroxide. After 5 min, THF (1 mL) and MeOH (1 mL) were added. The resulting cloudy light yellow solution was stirred at 0° C. for 20 min, then was warmed to room temperature and stirred for an additional 6 h. The reaction was acidified by dropwise addition of conc. HCl until strongly acidic, then was diluted with water and extracted with EtOAc (4×). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by reversed phase prep. HPLC (Sunfire™ Prep C18 OBD 10 μm column (Waters, Milford, Mass.), gradient elution of 55% MeCN in water to 85% MeCN in water over a 30 min period, where both solvents contain 0.1% TFA) provided the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[CH:35]1([N:39]2[CH2:45][CH2:44][CH2:43][N:42]([C:46]([N:48]3[CH2:51][CH:50]([O:52][C:53]4[CH:58]=[CH:57][C:56](I)=[CH:55][CH:54]=4)[CH2:49]3)=[O:47])[CH2:41][CH2:40]2)[CH2:38][CH2:37][CH2:36]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.ClCCl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:35]1([N:39]2[CH2:45][CH2:44][CH2:43][N:42]([C:46]([N:48]3[CH2:49][CH:50]([O:52][C:53]4[CH:58]=[CH:57][C:56]([C:5]5[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=5)=[CH:55][CH:54]=4)[CH2:51]3)=[O:47])[CH2:41][CH2:40]2)[CH2:38][CH2:37][CH2:36]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(N1CCCN(C2CCC2)CC1)N1CC(Oc2ccc(I)cc2)C1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc(OC3CN(C(=O)N4CCCN(C5CCC5)CC4)C3)cc2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.5 %

Procedure:
1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (21 mg, 101 μmol), tricyclohexylphosphine (3.1 mg, 11 μmol) and Pd2(dba)3 (4.2 mg, 5 μmol) were dissolved in dioxane (0.25 ml) under a nitrogen atmosphere. Solid 1-cyclobutyl-4-{[3-(4-iodophenoxy)azetidin-1-yl]carbonyl}-1,4-diazepane (42 mg, 92 μmol) was added followed by K3PO4 (122 μl of a 1.27 M aqueous solution, 156 μmol). The reaction was stirred at room temperature for 30 minutes and then at 110° C. for 16 hours. The reaction was diluted with dichloromethane (30 ml), filtered through celite, washed twice with saturated NaHCO3 (15 ml), dried (MgSO4), filtered and concentrated at reduced pressure. The residue was purified by FCC (DCM/MeOH/NH3 with gradient, 98:2:1 to 90:10:1) and then recrystallised (Heptane/EtOAc) to give the title product as white solid (16 mg, 42%).
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[CH2:24]([NH2:30])[C:25]1[O:29][CH:28]=[CH:27][CH:26]=1.CCN(CC)CC>CCO>[O:29]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:24][NH:30][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:9][C:10]([F:11])([F:12])[F:13])[CH2:14][C:15]([F:16])([F:17])[F:18])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22]
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Reactant: NCc1ccco1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(c1ccc(NCc2ccco2)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F

Procedure:
Following the general procedure for Intermediate 2 using 4-fluoro-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (100 mg, 0.287 mmol) and furfurylamine (0.028 mL, 0.315 mmol) in 3 mL of EtOH containing Et3N (0.080 mL, 0.574 mmol). The product was purified by flash chromatography on silica gel using 4:1/hexanes:EtOAc as eluent. Yield: 115 mg (94%); 1H NMR (CDCl3) 4.23 (q, J=8.40 Hz, 4H), 4.56 (d, J=5.66 Hz, 2H), 6.31 (d, J=3.12 Hz, 1H), 6.35 (m, 1H), 7.04 (d, J=8.98 Hz, 1H), 7.39 (s, 1H), 7.53 (d, J=8.89 Hz, 1H), 8.28 (s, 1H), 8.55 (s, 1H); MS (ESI) 426.21 (MH+).
Reaction SMILES: N#N.C[Si](C)(C)[S:5][Si](C)(C)C.C[O-].[Na+].[CH3:15][C:16]1([C:21]2[S:25][C:24]([CH2:26][C:27]#[N:28])=[CH:23][CH:22]=2)[O:20][CH2:19][CH2:18][O:17]1>CN(C=O)C.O>[CH3:15][C:16]1([C:21]2[S:25][C:24]([CH2:26][C:27]([NH2:28])=[S:5])=[CH:23][CH:22]=2)[O:17][CH2:18][CH2:19][O:20]1
Reactant: CC1(c2ccc(CC#N)s2)OCCO1
Reactant: C[Si](C)(C)S[Si](C)(C)C
Agent: C[O-]
Agent: N#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(c2ccc(CC(N)=S)s2)OCCO1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), hexamethyldisilthiane (8.9 mL, 42.31 mmol) was added dropwise to a solution of NaOMe (2.35 g, 42.31 mmol) in dry DMF (35 mL) and the reaction mixture was stirred at rt for 15 min. This dark blue solution was then added to a solution of [5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-yl]-acetonitrile (3.27 g, 16.93 mmol) in DMF (30 mL) and the reaction mixture was stirred for 2 days at rt. Water (100 mL) was then added and the mixture was extracted twice with EA (100 mL). The combined org. phases were dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (1:1 hept-EA) gave the title compound as a yellow oil. TLC: rf (1:1 hept-EA)=0.35. LC-MS-conditions 02: tR=0.81 min, [M+H]+=244.38.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[C:15](\[O:20][CH3:21])/[C:16]([O:18][CH3:19])=[O:17])=[CH:10][C:9]=2[O:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:5]=[CH:6][CH:7]=1.[CH2:27]([N:34]=[C:35]=[O:36])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>CCOCC>[CH2:23]([O:22][C:9]1[CH:10]=[C:11](/[CH:14]=[C:15](\[O:20][CH3:21])/[C:16]([O:18][CH3:19])=[O:17])[CH:12]=[CH:13][C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:35]([NH:34][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:36])[CH:3]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCOc1cc(/C=C(\OC)C(=O)OC)ccc1-c1cccc(N)c1
Reactant: CCCCCCCN=C=O
Solvent: CCOCC
Product: CCCCCCCNC(=O)Nc1cccc(-c2ccc(/C=C(\OC)C(=O)OC)cc2OCCCC)c1
Yield: 78.9 %

Procedure:
376 mg (1.1 mmol) of methyl (Z)-3-(3′-amino-2-butoxybiphenyl-4-yl)-2-methoxyacrylate and 0.3 mL (2.2 mmol) of heptyl isocyanate are heated at 100° C. by microwave in an Emrys Optimizer machine for 20 minutes. The residue obtained is taken up in ether and then filtered by suction. 431 mg (79%) of methyl (Z)-3-[2-butoxy-3′-(3-heptylureido)biphenyl-4-yl]-2-methoxyacrylate are obtained in the form of a white powder.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[C:7]([NH:9][C:10]([NH:22][CH3:23])=[N:11][CH2:12][CH2:13][S:14][CH2:15][C:16]1[NH:20][CH:19]=[N:18][C:17]=1[CH3:21])#[N:8]>O>[C:7]([NH:9][C:10]([NH:22][CH3:23])=[N:11][CH2:12][CH2:13][S:14]([CH2:15][C:16]1[NH:20][CH:19]=[N:18][C:17]=1[CH3:21])=[O:2])#[N:8]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CNC(=NCCSCc1[nH]cnc1C)NC#N
Agent: [Na+]
Solvent: O
Product: CNC(=NCCS(=O)Cc1[nH]cnc1C)NC#N
Reaction time: 1.5 h

Procedure:
Sodium metaperiodate (1.85 g, 8.68 m.mol.) was added to a stirred, cooled (5°) solution of N-cyano-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine (2.085 g, 8.27 m.mol.) in water (83 ml). After 90 minutes stirring at 5° thin layer chromatography indicated almost complete disappearance of starting material. The solution was allowed to stand overnight at room temperature to complete the reaction, then evaporated under reduced pressure to dryness, with azeotroping with n-propanol. The residue was boiled with isopropanol (60 ml), filtered hot, and the filtrate was evaporated to dryness to give the crude product as a glass. This was purified by charcoaling in methanol (40 ml), filtration and dilution with ether to 1500 ml. The liquid was decanted from the flocculent precipitated glass which was kept under a further 1500 ml ether to become semicrystalline, then filtered and allowed to stand overnight in air. The hardened glass was stirred with cold methanol (25 ml) filtered from insoluble crude product and and inorganics (0.28 g. m.p. 190°) and to the filtrate was carefully added ether (to 500 ml) so that two layers formed. On standing undisturbed for three days there separated off white crystals of N-cyano-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylsulphinyl)ethyl]guanidine (1.55 g), m.p. 185°-186.5° C. Found: C, 44.57; N, 6.08; N, 31.18; S, 11.91% C10H16N6OS requires C, 44.76; H, 6.01; N, 31.32; S, 11.95%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[C:19]([NH:22][C:23]1[CH:33]=[CH:32][CH:31]=[C:25]2[C:26]([O:28][C:29](=O)[C:24]=12)=[O:27])(=[O:21])[CH3:20]>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:29](=[O:28])[C:24]3[C:25](=[CH:31][CH:32]=[CH:33][C:23]=3[NH:22][C:19](=[O:21])[CH3:20])[C:26]2=[O:27])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Solvent: CC(=O)O
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Yield: 59.3 %

Procedure:
A stirred solution of 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (1.0 g, 3.7 mmol) and 3-acetamidophthalic anhydride (751 mg, 3.66 mmol) in acetic acid (20 mL) was heated at reflux for 15 h. The solvent was removed in vacuo to yield an oil. Chromatography of the resulting oil yielded the product as a yellow solid (1.0 g, 59% yield): mp, 144° C.; 1H NMR (CDCl3) δ1.47 (t, J=7.0 Hz, 3H, CH3), 2.26 (s, 3H, CH3), 2.88 (s, 3H, CH3), 3.75 (dd, J=4.4, 14.3 Hz, 1H, CHH), 3.85 (s, 3H, CH3), 4.11 (q, J=7 Hz, 2H, CH2), 5.87 (dd, J=4.3, 10.5 Hz, 1H, NCH), 6.82-6.86 (m, 1H, Ar), 7.09-7.11 (m, 2H, Ar), 7.47 (d, J=7 Hz, 1H, Ar), 7.64 (t, J=8 Hz, 1H, Ar), 8.74 (d, J=8 Hz, 1H, Ar), 9.49 (br s, 1H, NH); 13C NMR (CDCl3) δ14.61, 24.85, 41.54, 48.44, 54.34, 55.85, 64.43, 111.37, 112.34, 115.04, 118.11, 120.21, 124.85, 129.17, 130.96, 136.01, 137.52, 148.54, 149.65, 167.38, 169.09, 169.40; Anal Calc'd. for C22H24NO7S: C, 57.38; H, 5.25; N, 6.08. Found: C, 57.31; H, 5.34; N, 5.83.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=O)[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:25][OH:26].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9]/[C:10](/[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:25]\[OH:26])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CC(c1ccccc1)c1cccc(Br)c1)c1ccncc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O/N=C(\CC(c1ccccc1)c1cccc(Br)c1)c1ccncc1

Procedure:
In analogy to example 1, step 2, from 3-(3-bromo-phenyl)-3-phenyl-1-pyridin-4-yl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a colorless oil, MS (ESI+): m/z=381.0 ([M+H]+, 1Br).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH:22]=O)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:24]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25]1>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)C>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][N:24]4[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25]4)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: OC1CCNC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCO
Product: OC1CCN(CC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)C1
Yield: 91 %

Procedure:
4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde (350 mg, 1.103 mmol), 3-pyrrolidinol (200 mg, 2.02 mmol), absolute ethanol (40 ml), activated 3 Å molecular sieves (350 mg), titanium (IV) isopropoxide (1.62 ml, 5.48 mmol) and STAB (2.0 g, 9.74 mmol) were reacted in accordance with the general procedure D. The isolated crude product was purified by column chromatography on silica eluting with DCM:MeOH:NH3 (97:2:1) to give the title compound as a white solid (390 mg, 91%). 1H NMR (400 MHz, CDCl3) δ 7.20 (d, 2H), 6.87 (d, 2H), 4.10-4.01 (m, 3H), 3.81-3.68 (m, 3H), 3.55 (t, 2H), 2.67-2.48 (m, 9H), 2.28-1.61 (m, 15H).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH3:20])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:34][OH:35]>O1CCCC1>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH3:20])[N:16]=2)[CH2:11][C:12]([NH:34][OH:35])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: Cc1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.5 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)hexanoic acid (Preparation 45) (170 mg, 0.61 mmol) in anhydrous tetrahydrofuran (2 ml) was treated with 1,1′-carbonyldiimidazole (98 mg, 0.61 mmol) and the mixture stirred at room temperature under a nitrogen atmosphere for 20 minutes. Hydroxylamine hydrochloride (42 mg, 0.61 mmol) was then added and the mixture stirred for 18 hours. The solvent was removed under reduced pressure and the residue partitioned between hydrochloric acid (0.5M) and ethyl acetate. The layers were separated and the organic phase was washed with water, dried over anhydrous sodium sulphate, filtered and solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol (98:2) to afford the title compound as an oil (82 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[N:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH:25]=[N:24][NH:23][C:22]2=[O:26])=[CH:17][CH:16]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:23]1[C:22](=[O:26])[N:21]([C:18]2[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=2)[CH:25]=[N:24]1)[CH3:13]
Reactant: O=c1[nH]ncn1-c1ccncc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1ncn(-c2ccncc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 33.8 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.42 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 0.92 g of 4-(4-pyridyl)-3(2H,4H)-1,2,4-triazolone, 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-(4-pyridyl)-3(2H,4H)-1,2,4-triazolone (0.66 g) was obtained as colorless prisms.
Reaction SMILES: Cl.O[CH:3]([CH2:17][OH:18])[CH2:4][O:5][C:6]1[N:7]=[N:8][C:9]([NH:12][N:13]=[C:14]([CH3:16])[CH3:15])=[CH:10][CH:11]=1.Br>C(O)(=O)C.C(OC(C)C)(C)C>[O:18]1[CH2:17][CH:3]1[CH2:4][O:5][C:6]1[N:7]=[N:8][C:9]([NH:12][N:13]=[C:14]([CH3:15])[CH3:16])=[CH:10][CH:11]=1
Reactant: CC(C)=NNc1ccc(OCC(O)CO)nn1
Agent: Br
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: CC(=O)O
Product: CC(C)=NNc1ccc(OCC2CO2)nn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
A mixture of 3-(2,3-dihydroxypropoxy)-6-isopropylidenehydrazinopyridazine hydrochloride (34.7 g), acetic acid (50 ml) and 33% hydrogen bromide in acetic acid (143 ml) was stirred at room temperature for 2 hours, and diluted with diisopropyl ether (1.5 liter). After 30 minutes the precipitate was collected, protecting it from moisture with dry nitrogen, and dried under vacuum at room temperature. The solid was dissolved with methanol (600 ml) and heated at reflux for 2 hours. After stirring at room temperature for 15 hours, the solvent was removed under vacuum and the residue was diluted with acetone and evaporated again to dryness. To the residue were added dichloromethane (400 ml), cetyltrimethylammonium bromide (3.4 g) and, with vigorous stirring and keeping the internal temperature under 10° C., 2N sodium hydroxide (100 ml). Stirring was continued at room temperature for 90 minutes, then the phases were separated and the organic layer was washed with water (2×200 ml), then with a saturated solution of ammonium sulfate (135 ml). The organic solution was dried over MgSO4, evaporated under vacuum and the residue was triturated with diisopropyl ether (200 ml) to yield 20 g of the title compound as a pale yellow solid, m.p. 106°-109° C. (with decomposition).