Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40](=[O:49])[NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH2:39][CH2:38]1)=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12](C(OC2C=CC=CC=2)=O)[C:13](=O)[O:14]C2C=CC=CC=2)[CH:7]=1.[CH3:50][N:51]([CH3:60])[CH2:52][CH2:53][N:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1>CN(C)C=O>[CH3:50][N:51]([CH3:60])[CH2:52][CH2:53][N:54]1[CH2:59][CH2:58][N:57]([C:13]([NH:12][C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:31]=[CH:32][C:33]([NH:34][C:35]([C:37]4([C:40]([NH:41][C:42]5[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=5)=[O:49])[CH2:39][CH2:38]4)=[O:36])=[C:2]([F:1])[CH:3]=3)[CH:11]=[CH:10][N:9]=2)=[O:14])[CH2:56][CH2:55]1
Reactant: CN(C)CCN1CCNCC1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Solvent: CN(C)C=O
Product: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)c(F)c3)ccn2)CC1
Temperature: 25 °C
Reaction time: 25 h
Yield: 69.3 %

Procedure:
To a solution of phenyl N-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (50.0 mg) in N,N-dimethylformamide (1.0 ml) was added 1-(2-dimethylaminoethyl)piperazine (59.0 mg), followed by stirring at room temperature for 25 hr. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, the residue was purified by silica gel column chromatography (Fuji Silysia NH, heptane:ethyl acetate=1:2, ethyl acetate, then ethyl acetate:methanol=20:1). Fractions containing the target compound were concentrated. To the residue was added diethyl ether:hexane=1:3, and the precipitate was collected by filtration. This was washed with diethyl ether:hexane=1:3 and dried under aeration to provide the titled compound as white powder (31.7 mg, 69.6%).
Reaction SMILES: [N:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[CH2:2]2.[ClH:9].[NH2:10][OH:11]>CO>[ClH:9].[N:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[N:10][OH:11])[CH2:2]2
Reactant: O=C1CN2CCC1C2
Reactant: NO
Agent: Cl
Solvent: CO
Product: ON=C1CN2CCC1C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.7 %

Procedure:
1-Azabicyclo[2.2.1]heptan-3-one (2 g, 18 mmol) and hydroxylamine hydrochloride (1.25 g, 18 mmol) were dissolved in 10 mL MeOH and stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo. The crystalline residue was recrystallized from ethanol to afford 2.04 g (70%) of the title product, mp 211° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[N:16][C:17]#[N:18])OC2C=CC=CC=2)[CH:2]=1.[CH3:19][C@@H:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(C)C>CO>[C:17]([N:16]=[C:8]([NH:27][C@@H:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:19])[NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)#[N:18]
Reactant: N#CN=C(Nc1cccnc1)Oc1ccccc1
Reactant: C[C@@H](N)c1ccccc1
Solvent: CC(C)O
Solvent: CO
Product: C[C@@H](NC(=NC#N)Nc1cccnc1)c1ccccc1
Yield: 7403.7 %

Procedure:
A stirred mixture of N-(3-pyridyl)-N'-cyano-O-phenylisourea (see, Example 5 for procedure) (8.00 g, 0.336 mmol), (R)-α-methylbenzylamine (10.8 mL, 0.0835 mol) and isopropanol (53.3 mL) was refluxed, under nitrogen, for 4 hours. The reaction was complete by TLC with 10% MeOH-1% NH4OH-CHCl3. The mixture was concentrated in vacuo. The residue was mixed with EtOAc several times with concentration after each addition; the resulting solid was triturated with hot EtOAc, collected by filtration and recrystallized from MeOH-CH2Cl2 -EtOAc to give 6.6 g of product: mp 185°-187° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[C:8]([F:32])=[CH:7][C:5]=2[N:6]=1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>N1C=CC=CC=1.C(OCC)(=O)C>[C:29]([C:26]([C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][C:9]2[C:8]([F:32])=[CH:7][C:5]3[N:6]=[C:2]([NH:1][C:36]([CH:33]4[CH2:35][CH2:34]4)=[O:37])[S:3][C:4]=3[CH:10]=2)[CH:13]=1)=[O:31])([CH3:28])[CH3:27])#[N:30]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3cc4sc(N)nc4cc3F)c2)c1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3cc4sc(NC(=O)C5CC5)nc4cc3F)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.2 %

Procedure:
To a solution of N-{3-[(2-amino-5-fluoro-1,3-benzothiazol-6-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide (200 mg, 0.448 mmol) in pyridine (4.0 mL) was added cyclopropanecarbonyl chloride (61 μL, 0.672 mmol), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogencarbonate solution (100 mL) and saturated brine (100 mL), successively, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=60/40→0/100), and the obtained solution was concentrated under reduced pressure. The residue was triturated with ethyl acetate/diisopropyl ether/hexane to give the title compound (118 mg, 51%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[N+](C1C=CC=CC=1)([O-])=O>[C:13]1([C:12]2[NH:1][C:2]3[C:3]([C:4]([OH:6])=[O:5])=[CH:7][CH:8]=[CH:9][C:10]=3[N:11]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1cccc(C(=O)O)c1N
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(O)c1cccc2nc(-c3ccccc3)[nH]c12
Temperature: 25 °C
Yield: 67.8 %

Procedure:
A solution of methyl ester of 2,3-diaminobenzoic acid (4.00 g, 24.07 mmol) and benzaldehyde (2.56 g, 24.07 mmol) in nitrobenzene (60 ml) was stirred at 155-160° C. for 3 hrs. After being cooled to room temperature, the reaction mixture was purified by column chromatography on silica gel (n-hexane/ethyl acetate=20 and 4) to give methyl ester of 2-phenylbenzimidazole-4-carboxylic acid (3.89 g, 64%) as a pale yellow crystals.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:14]([O-:16])=[O:15])[C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=O)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:18]O.C([O-])=O.[Na+]>C(O)=O.O>[C:1]([C:5]1[CH:6]=[C:7]([N+:14]([O-:16])=[O:15])[C:8]([OH:13])=[C:9]([CH:12]=1)[C:10]#[N:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C=O)c(O)c([N+](=O)[O-])c1
Reactant: NO
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: CC(C)(C)c1cc(C#N)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
The above aldehyde (1.4 g, 6.3 mmol), hydroxylamine hydrochloride (0.438 g, 6.3 mmol), and sodium formate (0.771 g, 11.3 mmol) in formic acid (20 mL) were heated overnight, at reflux, then cooled to room temperature. The reaction was diluted with water, and the resulting precipitate was filtered. The solid was taken up in ether, dried over Na2SO4, filtered and concentrated in vacuo to yield 5-tert-butyl-2-hydroxyl-3-nitro-benzonitrile (1.21 g, 87%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([NH2:22])[C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH:23]1([C:29](O)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN(C=O)C>>[Cl:1][C:2]1[C:3]([CH:8]([NH:22][C:29]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:30])[C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C(O)C1CCCCC1
Reactant: NC(c1ccc(Oc2ccccc2)cc1)c1nccnc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC(c1ccc(Oc2ccccc2)cc1)c1nccnc1Cl)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 108.3 %

Procedure:
In a 10 mL flask were added C-(3-chloropyrazin-2-yl)-C-(4-phenoxyphenyl)-methylamine (110 mg, 0.35 mmol), cyclohexanecarboxylic acid (0.090 g, 0.00070 mol), DIEA (0.55 mL, 0.0032 mol), TBTU (0.17 g, 0.00053 mol) and DMF (5 mL, 0.07 mol) and the reaction mixture is stirred at rt for 10 min. Reaction mixture was stirred at rt over weekend. The reaction mixture was concentrated in vacuo dissolved in DCM and washed with sat. aq NaHCO3 followed by brine. The organics were collected and concentrated in vacuo to give 160 mg of the compound as a yellow solid. Purification by prep TLC in 60% EtOAc:hexanes afforded 110 mg of the title compound as a light yellow solid. Compound was carried on to the next step. MS(ES+): m/z 422.15 (100)[MH+]. HPLC: tR=3.97 min (Open Lynx, polar—5 min).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][NH:11][C:12](=[O:19])[CH2:13][CH2:14][NH:15][CH:16]([CH3:18])[CH3:17].CCN(CC)CC>CC#N>[Br:1][C:2]1[C:3]([N:15]([CH:16]([CH3:18])[CH3:17])[CH2:14][CH2:13][C:12]([NH:11][CH3:10])=[O:19])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CNC(=O)CCNC(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CNC(=O)CCN(c1nc(Cl)ncc1Br)C(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.5 %

Procedure:
5-Bromo-2,4-dichloropyrimidine (1.83 g, 8.00 mmol), N-methyl-3-(propan-2-ylamino)propanamide (Intermediate 14, 1.16 g, 8.00 mmol) and Et3N (1.2 mL, 8.16 mmol) were combined in MeCN (50 mL) and shaken at ambient temperature for 3 days before the solvent was removed under reduced pressure. Purification by column chromatography (SiO2, eluent gradient 2-10% MeOH to DCM) to afford the title compound (2.08 g, 78%) as a gum.
Reaction SMILES: C(OP([CH:9]([CH:12]([CH3:14])[CH3:13])[C:10]#[N:11])(OCC)=O)C.C[Si]([N-][Si](C)(C)C)(C)C.[K+].O[CH2:26][CH:27]=[C:28]([CH2:30][CH2:31][CH:32]=[C:33]([CH2:35][CH2:36][CH:37]=[C:38]([CH3:40])[CH3:39])[CH3:34])[CH3:29].O>C1(C)C=CC=CC=1>[CH3:14][CH:12]([C:9](=[CH:26][CH:27]=[C:28]([CH3:29])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:34])[CH2:35][CH2:36][CH:37]=[C:38]([CH3:40])[CH3:39])[C:10]#[N:11])[CH3:13]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCO
Reactant: CCOP(=O)(OCC)C(C#N)C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)=CCCC(C)=CCCC(C)=CC=C(C#N)C(C)C
Temperature: -70 °C
Yield: 94.9 %

Procedure:
To a solution of 2-(diethylphosphono)isovaleronitrile (8.72 g, 40 mmol) in toluene (75 ml) was gradually added a 0.5 M solution of potassium bis(trimethylsilyl)amide in toluene (75 ml) with stirring at -70° C. under argon atmosphere. The cooling bath was removed, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled to -70° C. again, and farnesol (5.88 g, 26.7 mmol) was added thereto with stirring, and the mixture was allowed to warm to room temperature. After addition of water, the organic layer was separated, washed with saturated aqueous sodium bicarbonate and then saturated aqueous sodium chloride, and dried over MgSO4. The organic layer was separated from MgSO4 by filtration and concentrated to give a residue, which was purified with silica gel column chromatography (solvent: n-hexane/ethyl acetate=100:1) to obtain the aimed 2 -(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraenenitrile (7.23 g, 96%; 2Z:2E=25.6:1).
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:21])O1.[S:23]([C:27]1[S:31][C:30]([NH:32][C:33](=[O:35])[CH3:34])=[N:29][N:28]=1)(=[O:26])(=[O:25])[NH2:24]>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]([O:11][CH3:12])[C:8](=[O:9])[CH:7]=[C:5]([OH:6])[C:4]([NH:24][S:23]([C:27]2[S:31][C:30]([NH:32][C:33](=[O:35])[CH3:34])=[N:29][N:28]=2)(=[O:26])=[O:25])=[O:21])=[CH:19][CH:18]=1
Reactant: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Reactant: CC(=O)Nc1nnc(S(N)(=O)=O)s1
Product: CON(Cc1ccc(F)cc1)C(=O)C=C(O)C(=O)NS(=O)(=O)c1nnc(NC(C)=O)s1

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide was treated with N-(5-sulfamoyl-[1,3,4]thiadiazol-2-yl)-acetamide as described in the preparation of compound 1 to yield the title compound. LCMS (M+H) calcd for C16H17FN5O7S2: 474.1; found: 474.1. 1H NMR (500 MHz, DMSO) δ: 2.21 (s, 3), 3.62 (s, 3), 4.72 (s, 2), 6.32 (s, 1), 6.95 (m, 2), 7.22 (m, 2).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=C(N)[N:5]=1.CI.[CH3:15][N:16]([CH:18]=O)[CH3:17]>>[Cl:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:18]([N:16]([CH3:15])[CH3:17])[N:5]=1
Reactant: CN(C)C=O
Reactant: COc1cc(Cl)nc(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COc1cc(Cl)nc(N(C)C)n1
Yield: 38 %

Procedure:
NaH (60% dispersion in oil, 0.201 g, 5.02 mmol, 2 eq) was added to a stirred solution of 4-chloro-6-methoxypyrimidin-2-amine (0.400 g, 2.51 mmol, 1 eq, Aldrich) and MeI (0.5 ml, 1.07 g, 7.52 mmol, 3 eq) in 2 ml anhydrous DMF at 0° C. After 1 h the reaction was quenched with water and diluted with EtOAc. The layers were separated. The organic layer was washed with water (×3), brine (×1), and dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo. Purification via flash chromatography yielded 0.180 g (0.96 mmol, 38% yield) of 4-chloro-6-methoxy-N,N-dimethylpyrimidin-2-amine.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[C:5]([O:10][CH3:11])=[C:4]([CH2:12][CH3:13])[CH:3]=1.C([Li])CCC.[C:19](=[O:21])=[O:20]>C1COCC1.CCOC(C)=O>[CH2:12]([C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([CH2:8][CH3:9])[C:5]=1[O:10][CH3:11])[C:19]([OH:21])=[O:20])[CH3:13]
Reactant: O=C=O
Reactant: CCc1cc(Br)cc(CC)c1OC
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1cc(C(=O)O)cc(CC)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
At -78° C., to a stirred solution of 4-bromo-2,6-diethylanisole (12.0 g, 49.4 mmol) in THF (329 mL) was added dropwise n-butyllithium (27.2 mL, 43.5 mmol). After 3 h, the reaction was poured into crushed dry ice and allowed to warm to ambient temperature. The reaction mixture was diluted with EtOAc, concentrated, suspended in H2O, acidified (pH 1), filtered and the collected solids washed with H2O. The crude product was slurried in hexane (15 mL), collected by filtration and dried to give 6.76 g (66%) of the title compound. 1H NMR: consistent. IR (KBr): consistent. mass spectrum (EI) m/z 208 (M+). Anal. Calcd. for C12H16O3 : C, 69.21; H, 7.74; N, 0.00. Found: C, 69.28; H, 7.49; N, 0.07.
Reaction SMILES: [C:1]([NH:20][CH2:21][CH:22]1[CH:27]([OH:28])[CH2:26][CH2:25][CH2:24][O:23]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>CS(C)=O>[C:1]([NH:20][CH2:21][CH:22]1[C:27](=[O:28])[CH2:26][CH2:25][CH2:24][O:23]1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCCOC1CNC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C1CCCOC1CNC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 10 h
Yield: 51.9 %

Procedure:
A solution of a sulfur trioxide-pyridine complex (23.7 g, 149 mmol) in dimethyl sulfoxide (150 mL) was added to a solution of 2-(tritylamino)methyl-3,4,5,6-tetrahydro-2H-pyran-3-ol (18.54 g, 49.6 mmol) and triethylamine (45 mL, 323 mmol) in dimethyl sulfoxide (150 mL) in a nitrogen atmosphere at room temperature. The mixture was stirred at the same temperature for 10 hours. The reaction solution was poured into ice water (1 L), followed by extraction with ethyl acetate (2×1 L). Then, the organic layers were combined and washed with water (2×1 L) and brine (1 L). The resulting organic layer was dried over anhydrous sodium sulfate and filtered. Then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95→10:90→20:80) to give 9.56 g (52%) of the title compound as a colorless transparent gummy solid.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[C:7]([CH3:16])=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[O:17]=[C:18]1[C:23]2=[CH:24][NH:25][C:26]([CH:27]=O)=[C:22]2[CH2:21][CH2:20][O:19]1>>[CH3:1][NH:2][S:3]([C:6]1[C:7]([CH3:16])=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:27][C:26]1[NH:25][CH:24]=[C:23]2[C:18](=[O:17])[O:19][CH2:20][CH2:21][C:22]=12)(=[O:5])=[O:4]
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Reactant: CNS(=O)(=O)c1ccc2c(c1C)CC(=O)N2
Product: CNS(=O)(=O)c1ccc2c(c1C)C(=Cc1[nH]cc3c1CCOC3=O)C(=O)N2
Yield: 96.4 %

Procedure:
4-Methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide (0.2 g, 0.83 mmol) was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde (1.2 eq, 0.17 g) to give 0.31 g (97%) of the title compound as a yellow solid.
Reaction SMILES: N[C:2]1[C:7]([Br:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].S(=O)(=O)(O)O.N([O-])=O.[Na+]>CCO>[Br:8][C:7]1[CH:2]=[C:3]([OH:12])[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: Nc1c(O)cc([N+](=O)[O-])cc1Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cc(O)cc(Br)c1
Yield: 85.2 %

Procedure:
Compound 98 (33.0 g, 0.14 mol) was treated with sulfuric acid (13.7 mL) and was refluxed in EtOH (550 mL) for 0.5 hours, followed by addition of NaNO2 (23.8 g, 0.35 mol). The resulting mixture was refluxed for additional 1 hour and the volatile was evaporated. The residue was taken up with ethyl acetate and water. The layers were separated and the organic layer was washed with water, saturated sodium bicarbonate, and brine. After removal of solvent, the residue was purified by column chromatography on silica gel to afford the title compound (26 g, 85%); 1H NMR (500 MHz, CD3OD): δ 5.00 (brs, 1H), 7.58 (dd, 1H, J=1.7, 2.3 Hz), 7.47 (t, 1H, J=2.1 Hz), 7.69 (t, 1H, J=1.9 Hz); 13C NMR (125 MHz, CD3OD): δ 110.5, 118.1, 123.7, 125.6, 151.0, 160.5; HRMS (FAB) calcd for C6H4BrNO3 (M+) 216.9375, found 216.9374.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]=[CH:11][C:10]([NH:13]C(=O)C)=[CH:9][CH:8]=2)[CH:2]=1.F[B-](F)(F)F.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([I+]C2C(C)=CC(C)=CC=2C)=[CH:26][CH:25]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(=O)C>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:4]2[CH:5]=[CH:6][C:1]([CH3:17])=[CH:2][C:3]=2[C:7]2[N:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)=[CH:26][CH:25]=1
Reactant: CC(=O)Nc1ccc(-c2cccc(C)c2)nc1
Reactant: Cc1cc(C)c([I+]c2ccc(Cl)cc2)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Solvent: CC(=O)O
Product: Cc1ccc(-c2ccc(Cl)cc2)c(-c2ccc(N)cn2)c1
Reaction time: 2 h
Yield: 72.5 %

Procedure:
To acetic acid (17 ml), N-(6-m-tolylpyridine-3-yl)acetamide (0.50 g, 2.2 mmol), (4-chlorophenyl)(2,4,6-trimethylphenyl)iodonium tetrafluoroborate (1.13 g, 2.5 mmol) synthesized in (ii) and palladium acetate (0.025 g, 0.11 mmol) were added, and reacted at 100° C. for 1 hour. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography. The solvent was distilled off under reduced pressure. Methanol and 35% hydrochloric acid were added, and the hydrolysis was carried out at 65° C. for 2 hours. Methanol was distilled off under reduced pressure. Purification by column chromatography gave the title compound (0.47 g, 72.5%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:22][C:23]1[O:24][C:25]([CH3:28])=[N:26][N:27]=1>CN(C)C=O>[CH3:28][C:25]1[O:24][C:23]([CH2:22][O:14][C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:12]=2)=[N:27][N:26]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: Cc1nnc(CCl)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nnc(COc2ccc(Oc3ccccc3)cc2)o1
Temperature: 20 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
9.3 g of 4-phenoxyphenol and 9 g of potassium carbonate are stirred in 75 ml of anhydrous dimethylformamide for 1 hour at 80° C. Subsequently, 6.6 g of 2-chloromethyl-5-methyl-1,3,4-oxadiazole in 20 ml of anhydrous dimethylformamide is dripped in. The mixture is stirred for 10 hours at 80° C. and at room temperature (approx. 20° C.) overnight. The mixture is then stirred into 500 ml of ice water and extracted three times with ethyl acetate. After drying over sodium sulfate and removal of the solvent, the residue is purified by chromatography over silica gel using n-hexane/ethyl acetate (4:1) as eluant. There is obtained 12 g of 5-methyl-2-[(4-phenoxyphenoxy)-methyl]-1,3,4-oxadiazole; colorless crystals; m.p.: 78°-79° C.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([C:35]3[N:39]([CH3:40])[C:38]4[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=4[N:36]=3)[CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([C:35]3[N:39]([CH3:40])[C:38]4[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=4[N:36]=3)[CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-butyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][OH:13])=[CH:8][CH:7]=1.[CH:17]([N:20]=[C:21]=[O:22])([CH3:19])[CH3:18]>>[CH:17]([NH:20][C:21](=[O:22])[O:13][CH2:12][CH2:11][O:10][C:9]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][CH:3]=[C:2]([CH3:16])[CH3:1])=[CH:7][CH:8]=1)([CH3:19])[CH3:18]
Reactant: CC(C)N=C=O
Reactant: CC(C)=CCOc1ccc(OCCO)cc1
Product: CC(C)=CCOc1ccc(OCCOC(=O)NC(C)C)cc1

Procedure:
Following the procedure of Example 9, 2[4-(3-methyl-2-butenoxy)phenoxy]ethanol and isopropyl isocyanate are reacted together to give O-2-[4-(3-methyl-2-butenoxy)phenoxy]ethyl N-isopropylcarbamate, MS, m/e 307 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[O:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[N:26][CH:27]=1>C(#N)C.O>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([C:8](=[O:10])[CH3:9])[CH:6]=[CH:7][C:2]=1[O:1][CH2:21][C:22]1[CH:27]=[N:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1
Reactant: COc1cc(C(C)=O)ccc1O
Reactant: COc1ccc(CCl)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(COc2ccc(C(C)=O)cc2OC)cn1
Reaction time: 2 h
Yield: 80.1 %

Procedure:
To a stirred suspension of 1-(4-hydroxy-3-methoxyphenyl)ethan-1-one (3.96 g, 23.82 mmol) and potassium carbonate (13.17 g, 95.29 mmol) in acetonitrile (75 mL) was added 5-(chloromethyl)-2-methoxypyridine hydrochloride (4.85 g, 25.01 mmol). After 2 h, the mixture was diluted with water (150 mL) and extracted with dichloromethane (3×100 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to provide a yellow oil. Trituration of the crude material with hexanes afforded 5.48 g (85%) of 1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethan-1-one as a white solid.