Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N(CC)CC)C.C(OC(Cl)=O)C.[N-:23]=[N+:24]=[N-:25].[Na+]>CC(C)=O.O>[N:23]([C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:9])=[N+:24]=[N-:25]
Reactant: O=C(O)c1ccccn1
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)c1ccccn1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 67.9 %

Procedure:
To a solution of picolinic acid (1.0 g, 8.12 mmol) in a mixture of acetone (10 mL) and water (3 mL) was added triethylamine (1.7 mL, 12.2 mmol). The mixture was cooled to 0° C. in a ice-bath. Ethylchloroformate (1.32 g, 12.2 mmol) was then added and the resulting mixture was stirred for 1.5 hours at 0° C. To the mixture was added sodium azide (0.844 g, 13.0 mmol), and the mixture was stirred for another 1.5 hours. The mixture was concentrated, the residue was diluted with dichloromethane and washed with water. The organic layer was dried over MgSO4 and concentrated to give desired product (817 mg, 68%). 1HNMR (CDCl3) (δ) 8.74 (d, 1H), 8.15 (d, 1H), 7.88 (m, 1H), 7.55 (m, 1H).
Reaction SMILES: C([O:4][C:5]1[C:6]([O:11][C:12]2[CH:17]=[C:16]([N:18]3[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]([CH3:29])[C:19]3=[O:30])[C:15]([F:31])=[CH:14][C:13]=2[Cl:32])=[N:7][CH:8]=[CH:9][CH:10]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>C(O)(=O)C>[Cl:32][C:13]1[CH:14]=[C:15]([F:31])[C:16]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]([CH3:29])[C:19]2=[O:30])=[CH:17][C:12]=1[O:11][C:6]1[C:5]([OH:4])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: CC(=O)Oc1cccnc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ncccc3O)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
A mixture of 100 mg of 3-acetoxy-2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}pyridine, 15 mg of potassium carbonate and 1 ml of methanol was stirred for 3 hours at room temperature. The reaction solution was poured into ice water, then, to this was poured acetic acid. The precipitated crystals were collected by filtration to obtain 65 mg of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-hydroxypyridine
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:29]=[CH:30][CH:31]=1)[C:12]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:16][CH2:15]1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O[CH2:42][CH2:43][O:44][CH:45]([CH3:47])[CH3:46])(=O)=O)=CC=1.[OH-].[K+]>CS(C)=O>[CH:45]([O:44][CH2:43][CH2:42][N:8]([C:9]1[CH:10]=[C:11]([CH:29]=[CH:30][CH:31]=1)[C:12]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[CH2:16][CH2:15]1)=[O:13])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])([CH3:47])[CH3:46]
Reactant: Cc1ccc(S(=O)(=O)OCCOC(C)C)cc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)OCCN(C(=O)OC(C)(C)C)c1cccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c1

Procedure:
6 g of 1-[3-(N-tert-butyloxycarbonylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]piperazine and 4.18 g of 2-isopropyloxyethyl p-toluenesulfonate are reacted in DMSO in the presence of 1.01 g of finely powdered KOH. The oily 1-{3-[N-(2-isopropyloxyethyl)-N-tert-butoxycarbonylamino]benzoyl}-4-[2-(4-chlorophenyl)ethyl]piperazine so obtained is reacted further directly.
Reaction SMILES: BrBr.[OH-:3].[Na+].[O:5]=[C:6](C)[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH3:20])=[C:12]1[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>O>[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH3:20])=[C:12]1[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)([OH:5])=[O:3]
Reactant: [OH-]
Reactant: CC(=O)CCCCn1c(-c2cccnc2)c(C)c2ccccc21
Agent: BrBr
Agent: [Na+]
Solvent: O
Product: Cc1c(-c2cccnc2)n(CCCCC(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Bromine (0.344 ml) is added to a solution of 692 mg of sodium hydroxide in 4 ml of water with ice bath cooling. The resulting solution is added to 400 mg of 1-(5-oxohexyl)-3-methyl-2-(3-pyridyl)indole and this mixture is stirred for 2 hours at room temperature. The mixture is washed with ether. The aqueous solution is filtered and acidified to pH 5-6 with 2 N HCl. A crude white solid is collected which melts in the range 108°-120°. TLC (silica gel; methylene chloride/methanol 9:1) separation gives 1-(4-carboxybutyl)-3-methyl-2-(3-pyridyl)indole of Example 5.
Reaction SMILES: C([O:4][CH2:5]/[CH:6]=[C:7](\[CH3:15])/[CH2:8][C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=1)(=O)C.[OH-].[Na+]>O>[C:9]1([CH2:8]/[C:7](/[CH3:15])=[CH:6]/[CH2:5][OH:4])[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=1
Reactant: CC(=O)OC/C=C(\C)CC1=CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C/C(=C\CO)CC1=CCCCC1
Temperature: 92.5 °C
Reaction time: 11 h
Yield: 93 %

Procedure:
(2E)-4-cyclohexenyl-3-methylbut-2-enyl acetate (2.08 kg, 10.0 mols, purity: 98%) sodium hydroxide (420 g, 10.5 mols) and water (8400 ml) were mixed together and heated at 90-95° C. under stirring for 10-12 h. The reaction mixture was cooled to 35° C. The aqueous phase was separated from the organic phase. The organic phase was washed once with 5% w/w aqueous NaCl and twice with water. The crude product was fractionated under reduced pressure to provide (2E)-4-cyclohexenyl-3-methylbut-2-en-1-ol (1.5 kg, yield: 93%; GC purity: 99% sum of the isomers). Reduced pressure (1 mmHg) to give 1.54 kg of (2E)-4-(cyclohex-1-en-1-yl)-3-methylbut-3-en-1-ol and (2E) isomer (yield: 93%; GC purity: 99% sum of the isomers).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:13](=[O:21])[CH2:14][N+:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11].[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[CH:23]=[CH2:24]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:13]([C:14]1[N:15]2[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]2)=[C:23]([C:22]([O:26][CH2:27][CH3:28])=[O:25])[CH:24]=1)=[O:21]
Reactant: COc1cc(C(=O)C[n+]2ccccc2)ccc1[N+](=O)[O-]
Reactant: C=CC(=O)OCC
Agent: [Br-]
Product: CCOC(=O)c1cc(C(=O)c2ccc([N+](=O)[O-])c(OC)c2)n2ccccc12

Procedure:
This compound is obtained according to the same method as the preceding example in Step B by 1,3-dipolar cycloaddition of 1-[2-(3-methoxy-4-nitrophenyl)-2-oxoethyl]pyridinium bromide (obtained in Step A of the preceding example) with ethyl acrylate. A yellow powder is obtained after purification by flash chromatography on a silica column, eluting with dichloromethane.
Reaction SMILES: Cl[C:2]1[N:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1)=O.[CH3:25][NH:26][NH2:27]>N1C=CC=CC=1>[C:17]([C:8]1[CH:7]=[C:6]([C:4]2[C:3]3[C:2](=[N:24][CH:23]=[CH:22][CH:21]=3)[N:26]([CH3:25])[N:27]=2)[CH:11]=[C:10]([C:12]([CH3:14])([CH3:13])[CH3:15])[C:9]=1[OH:16])([CH3:18])([CH3:20])[CH3:19]
Reactant: CC(C)(C)c1cc(C(=O)c2cccnc2Cl)cc(C(C)(C)C)c1O
Reactant: CNN
Solvent: c1ccncc1
Product: Cn1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c2cccnc21
Yield: 93.3 %

Procedure:
A mixture of 30 g of 4-(2-chloronicotinoyl)-2,6-di-tertiary butylphenol, 15 g of methylhydrazine and 150 ml of pyridine is reacted and treated in a similar manner as Example 1, and the obtained crude crystals are recrystallized from ethanol to give 27.3 g of 3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-1-methyl-1H-pyrazolo[3,4-b]pyridine as white crystals, melting at 152°-154° C.
Reaction SMILES: FC1C=C(CN)C=NC=1.[O:10]1[CH:14]=[C:13]([CH2:15][NH2:16])[N:12]=[CH:11]1.[F:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[CH2:27][CH2:26][N:25]([C:28]3[S:29][C:30]([C:34](O)=[O:35])=[C:31]([CH3:33])[N:32]=3)[C:24]2=[O:37])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[CH2:27][CH2:26][N:25]([C:28]3[S:29][C:30]([C:34]([NH:16][CH2:15][C:13]4[N:12]=[CH:11][O:10][CH:14]=4)=[O:35])=[C:31]([CH3:33])[N:32]=3)[C:24]2=[O:37])=[CH:20][CH:19]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1cocn1
Agent: NCc1cncc(F)c1
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cocn1
Yield: 32 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with oxazol-4-ylmethanamine to react with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid in place of 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 32% yield: mp 188-191° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.86 (s, 1H), 7.66 (s, 1H), 7.29-7.25 (m, 2H), 7.07-7.01 (m, 2H), 6.21-6.17 (m, 1H), 4.51 (d, J=5.8 Hz, 2H), 4.46 (s, 2H), 4.10-4.05 (m, 2H), 3.48-3.42 (m, 2H) 2.60 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 164.1, 162.4, 160.9, 157.5, 155.3, 152.9, 151.3, 136.8, 135.8, 131.4, 131.3, 130.1, 129.9, 117.5, 115.9, 115.7, 47.3, 41.9, 41.6, 35.6, 17.2; MS (ES+) m/z 416.1 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:9])=[N:5][O:6][C:7]=1[CH3:8].[C:10]1(=[O:20])[NH:14][C:13](=[O:15])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:9][C:4]1[C:3]([CH2:2][N:14]2[C:10](=[O:20])[C:11]3[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:13]2=[O:15])=[C:7]([CH3:8])[O:6][N:5]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1noc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1noc(C)c1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.8 %

Procedure:
4-Chloromethyl-3,5-dimethyl-isoxazole (500 μL, 3.40 mmol) was added to a mixture of phthalimide (500 mg, 3.40 mmol) and K2CO3 (500 mg, 3.62 mmol) in DMF (5 mL) and stirred at ambient temperature overnight. The reaction was then heated to 70° C. for 5 hours and subsequently cooled and partitioned between ethyl acetate and water. The organic layer was washed several times with water and concentrated to give 1.0 g of the sub-title compound as a white solid. MS: ESI (positive): 257 (M+H).
Reaction SMILES: [C:1]1(=[N:10]O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:12]1([N:18]2[C:22]3([CH2:27][CH2:26]N[CH2:24][CH2:23]3)[C:21](=O)[NH:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH:1]1([N:10]2[CH2:26][CH2:27][C:22]3([N:18]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:19][NH:20][CH2:21]3)[CH2:23][CH2:24]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: ON=C1CCc2ccccc21
Product: c1ccc(N2CNCC23CCN(C2CCc4ccccc42)CC3)cc1

Procedure:
The title compound, m.p.>250° C. and MS: m/e=348.4 (M+H+) was prepared in accordance with the general method of example 11 from 2,3-dihydro-1H-inden-1-one oxime and 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].C(N(CC)CC)C.Br[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1>C(#N)C.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].[Cu]I>[OH:4][CH2:1][C:2]#[C:3][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: C#CCO
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(C#CCO)cc1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
8.55 g (0.15 mol) of propargyl alcohol and 152 ml (110 g, 1.09 mol) of triethylamine are added to a solution of 20.2 g (0.1 mol) of 4-bromonitrobenzene in 285 ml of acetonitrile. The reaction solution is heated to 100° C. 11.9 g (10 mmol) of Pd(Pph3)4 and 3.94 g (20 mmol) of copper (I) iodide are added. After 10 minutes the solvent is eliminated in vacuo and the residue taken up in ethyl acetate. It is washed with water and ammonia water, filtered through Celite and the solvent is eliminated in vacuo. The product is obtained by chromatography on silica gel (dichloromethane/methanol=10:1).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[F:23][C:24]1[CH:32]=[C:31]([NH:33][CH:34]=[O:35])[C:30]2[C:26](=[CH:27][C:28](=[O:36])[N:29]=2)[CH:25]=1>>[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[C:31]([NH:33][CH:34]=[O:35])[CH:32]=1)[NH:29][C:28](=[O:36])/[C:27]/2=[CH:21]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:7](=[O:20])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CCC2
Reactant: O=CNc1cc(F)cc2c1=NC(=O)C=2
Product: Cc1c(/C=C2\C(=O)Nc3c(NC=O)cc(F)cc32)[nH]c2c1C(=O)N(CCN1CCOCC1)CCC2
Yield: 52 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 10 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 10c obtained from step 3 of Example 10 and (Z)—N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl)-formamide 20c as starting materials to obtain (Z)—N-{5-fluoro-3-[3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-7-yl}-formamide 20 (37 mg, yield 52%) as an orange solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].CC(C)([O-])C.[K+].Br[CH2:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19]>CN(C=O)C>[CH:21]([O:20][C:18](=[O:19])[CH2:17][O:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1)([CH3:23])[CH3:22]
Reactant: CC(C)OC(=O)CBr
Reactant: O=Cc1cccc(O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)COc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 42.4 %

Procedure:
A solution of 3-hydroxybenzaldehyde (6.75 g, 55.2 mmol) in DMF (55 mL) was stirred at room temperature under a nitrogen atmosphere as potassium tert-butoxide (6.2 g, 55.3 mmol) was added in portions. The resulting suspension was stirred an additional 15 minutes at room temperature before isopropyl bromoacetate (7.10 mL, 55.2 mmol) was added. The reaction was stirred at room temperature for 15 h and was then quenched with water (250 mL). The resulting aqueous solution was extracted with ethyl acetate, and the combined organic layers were washed several times with water, dried over MgSO4, filtered, and concentrated in vacuo. Purification via medium pressure liquid chromatography (0-10% hexane/ethyl acetate) afforded the title compound (5.2 g, 65%) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.30 (d, 6H) 5.04-5.32 (m, 1H) 7.21-7.28 (m, 1H) 7.38 (s, 1H) 7.44-7.60 (m, 2H) 9.98 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]([CH2:23][OH:24])[CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1)#[N:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH:11]([CH:23]=[O:24])[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1ccc(CC(CO)CCc2ccc(C#N)cc2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CC(C=O)CCc2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.4 %

Procedure:
A solution of 5.7 g (17.63 mmol) of methyl 4-[4-(4-cyanophenyl)-2-hydroxymethylbutyl]benzoate from Example 15A in 250 ml of dichloromethane is mixed with 4.56 g (21.15 mmol) of pyridinium chlorochromate (PCC) and stirred at room temperature for 5 hours. After conversion is complete, about 10 g of silica gel are added, and the solvent is removed to dryness in vacuo. The residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1→4:1). 4.16 g (12.94 mmol, 73% yield) of a colorless solid are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[NH:15][C:14]2[CH:16]=[CH:17][C:18]([C:20]([NH:22][OH:23])=[NH:21])=[CH:19][C:13]=2[N:12]=1.[CH3:24]CCCCCC>C(OCC)(OCC)OCC.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[NH:15][C:14]2[CH:16]=[CH:17][C:18]([C:20]3[N:21]=[CH:24][O:23][N:22]=3)=[CH:19][C:13]=2[N:12]=1
Reactant: CCCCCCC
Reactant: N=C(NO)c1ccc2[nH]c(-c3cc([N+](=O)[O-])ccc3Cl)nc2c1
Agent: Cl
Solvent: CCOC(OCC)OCC
Product: O=[N+]([O-])c1ccc(Cl)c(-c2nc3cc(-c4ncon4)ccc3[nH]2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
A stirred solution of 2-(2-chloro-5-nitro-phenyl)-N-hydroxy-1H-benzoimidazole-5-carboxamidine (5.29 g; 16.0 mmol) in triethyl orthoformate (50 ml) was heated to 80° C. Concentrated hydrochloric acid (3 drops) was added and heating continued for a further two hours. After cooling to room temperature, heptane (50 ml) was added which caused a precipitate to form. The solid was filtered off and washed with more heptane to afford 2-(2-chloro-5-nitro-phenyl)-5-[1,2,4]oxadiazol-3-yl-1H-benzoimidazole (3.30 g, 62%)
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:16]=[CH:15][C:10]([O:11]CC=C)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Cl[C:20]1[CH:25]=C(Cl)C=C(Cl)[CH:21]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([OH:11])=[C:15]([CH2:25][CH:20]=[CH2:21])[CH:16]=2)=[CH:17][CH:18]=1
Reactant: C=CCOc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: Clc1cc(Cl)cc(Cl)c1
Product: C=CCc1cc(Oc2ccc(Cl)cc2)ccc1O
Temperature: 25 °C

Procedure:
The crude allyl ether from step 3 (20.0 g) was dissolved in 2,4,6-trichlorobenzene (60 mL), and the solution was heated at reflux for 4 h. After being cooled to room temperature, the solution was directly loaded onto a column of silica gel and eluted sequentially with hexane and an 8:2 mixture of hexane and ethyl acetate to give 4-(4-chlorophenoxy)-2-(2-propenyl)phenol.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][N:18]4[N:21]=[CH:22][C:23]([CH:24]=O)=[C:17]4[N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:3][CH2:2]1.[NH:26]1[CH2:32][C:30](=[O:31])[NH:29][C:27]1=[O:28].N1CCCCC1.CO.C(Cl)Cl>CCO>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][N:18]4[N:21]=[CH:22][C:23]([CH:24]=[C:32]5[NH:26][C:27](=[O:28])[NH:29][C:30]5=[O:31])=[C:17]4[N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1cnn2ccc(Nc3cccc(CN4CCOCC4)c3)nc12
Reactant: O=C1CNC(=O)N1
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2cnn3ccc(Nc4cccc(CN5CCOCC5)c4)nc23)N1
Temperature: 70 °C

Procedure:
To 5-(3-(morpholinomethyl)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (56 mg, 0.166 mmol) in EtOH was added hydantoin (16.6 mg, 0.166 mmol) and piperidine (16.8 μL, 0.166 mmol). The mixture was heated at 70° C. overnight. The solid formed was filtered off and filtrated prepared by HPLC then TLC (1% MeOH/DCM) to yield 5-((5-(3-(morpholinomethyl)phenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=420)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]=[N+]=[N-])[C@H:10]([F:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][NH2:15])[C@H:10]([F:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN=[N+]=[N-])[C@H](F)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](CN)[C@H](F)C1
Reaction time: 2 h

Procedure:
To a stirred solution of (±)-cis-4-azidomethyl-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester (0.68 mmol, 160 mg) in methanol (1.5 mL) was added Pd—C (20% by wt., 35 mg). The reaction was hydrogenated under balloon pressure for 2 h at room temperature. The reaction was filtered through a bed of celite. The solvent was evaporated to provide (±)-cis-4-aminomethyl-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N:8]([CH3:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:3]=1.CCCCCC.[Li]CCCC.[CH:39]([N:42]=[C:43]=[O:44])([CH3:41])[CH3:40]>C(OCC)C>[CH:39]([NH:42][C:43]([C:2]1[CH:7]=[C:6]([N:8]([CH3:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:3]=1)=[O:44])([CH3:41])[CH3:40]
Reactant: CN(Cc1ccccc1)c1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Reactant: CC(C)N=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)NC(=O)c1cc(N(C)Cc2ccccc2)cc(Oc2cccc(C(F)(F)F)c2)n1
Reaction time: 0.17 h

Procedure:
2.22 g (0.0051 mol) of 2-bromo-4-{methyl(phenylmethyl)amino}-6-{3-(trifluoromethyl)phenoxy} pyridine was suspended in about 30 ml of diethyl ether. While cooling the obtained suspension in a dry ice-acetone bath in an argon atmosphere, 3.4 ml of a 1.65M-hexane solution of BuLi (0.0051×1.1 mol) was added thereto, followed by stirring the suspension for about 10 minutes. After 0.86 g (0.0051×2.0 mol) of isopropyl isocyanate dissolved in about 10 ml of diethyl ether was added to the reaction solution, the obtained solution was removed from the bath and stirred at room temperature for about one hour. The reaction solution was mixed with about 10 ml of a 1N-hydrochloric acid aqueous solution, and then distributed in ethyl acetate-saturated sodium bicarbonate water, followed by washing with saturated brine. The organic phase of the obtained solution was dried with anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH2:17]([NH2:19])[CH3:18]>C1COCC1>[Br:1][C:2]1[C:7]([NH:19][CH2:17][CH3:18])=[N:6][C:5]([NH2:11])=[N:4][C:3]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCN
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Solvent: C1CCOC1
Product: CCNc1nc(N)nc(-c2ccco2)c1Br

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine and ethylamine in THF. ES-MS m/e (%): 285 (M{81Br}+H+, 100), 283 (M{79Br}+H+, 95).
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:8]([NH:10][C@H:11]([C:16]([NH:18][C@@H:19]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)[CH3:20])=[O:17])[CH2:12][CH2:13][CH2:14][NH2:15])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:34].[N:35]1([C:40](N)=[NH:41])C=CC=N1.C(N(CC)CC)C.CCN(C(C)C)C(C)C>CN(C)C=O>[ClH:34].[C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:8]([NH:10][C@H:11]([C:16]([NH:18][C@@H:19]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)[CH3:20])=[O:17])[CH2:12][CH2:13][CH2:14][NH:15][C:40](=[NH:35])[NH2:41])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N=C(N)n1cccn1
Reactant: C[C@@H](NC(=O)[C@H](CCCN)NC(=O)C(c1ccccc1)c1ccccc1)c1ccc(Br)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)C(c1ccccc1)c1ccccc1)c1ccc(Br)cc1
Yield: 74.3 %

Procedure:
Prepared according to the method described in Example 2(f) above from (R)-N2 -(diphenylacetyl)-(S)-N-[1-(4-bromophenyl)ethyl]ornithine amide (free base; 0.20 g; 0.39 mmol; from step (d) above), 1H-pyrazole-1-carboxamidine mono hydrochloride (0.06 g; 0.39 mmol), triethylamine (0.08 g; 0.78 mmol; instead of DiPEA) and dimethyl formamide (1 mL), 5 hours reaction time. The solution was concentrated under vacuum and the crude product chromatographed on silica gel eluting with MeOH:CHCl3 :ammonium hydroxide (3:6:1). Conversion of the eluted compound to the hydrochloride salt gave the title compound as a white solid (0.17 g).