Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]([OH:12])[C:10]#[CH:11]>C(N(CC)CC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]#[C:10][CH2:9][OH:12])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: Fc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: OCC#Cc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 83.3 %

Procedure:
In a dry flask containing in suspension copper iodide (84 mg, 0.44 mmol) and triethylamine (24.70 mL), was added Pd(PPh3)2Cl2 (310 mg, 0.44 mmol) under N2. A yellow suspension is obtained. The reaction mixture was cooled to 0° C. in an ice-bath before the addition of 1-fluoro-4-iodobenzene (1.95 g, 8.80 mmol). After five minutes at 0° C., a solution of prop-2-yn-1-ol (493 mg, 8.80 mmol) in triethylamine (4 mL) was slowly added under N2 over a period of 15 min. Immediately the color of the reaction turns to black. The mixture was stirred 0° C. for 30 min and then warmed to room temperature for 20h under N2. Triethylamine was concentrated under reduce pressure and the residue was dissolved in DCM. The organic layer was washed with saturated NH4Cl, water, brine, dried (MgSO4) and concentrated. The crude product was purified by flash chromatography (prepacked 25 g silicagel column, DCM 100% as eluent) to afford 1.10 g of 3-(4-fluorophenyl)prop-2-yn-1-ol (Yield: 83%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]=O)=[CH:4][CH:3]=1.[NH2:12][N:13]1[C:17]([NH2:18])=[N:16][N:15]=[C:14]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[N:18][C:17]3[N:13]([C:14]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=4)=[N:15][N:16]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: Nc1nnc(Cc2ccc(O)cc2)n1N
Reactant: O=CC(=O)c1ccc(F)cc1
Solvent: CC(=O)O
Product: Oc1ccc(Cc2nnc3ncc(-c4ccc(F)cc4)nn23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
a mixture of (4-fluoro-phenyl)-oxo-acetaldehyde (72 mg, 0.4 mmol) and 4-(4,5-diamino-4H-[1,2,4]triazol-3-ylmethyl)-phenol (82 mg, 0.4 mmol) in acetic acid was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified on a silica gel column (CH2Cl2:EtOAc=2:8, 3:7) to afford two isomers 4-[7-(4-fluoro-phenyl)-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-ylmethyl]-pheno desired product 4-[6-(4-fluoro-phenyl)-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-ylmethyl ]phenol (Example 1).
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]1[S:24][C:25](Br)=[CH:26][CH:27]=1)[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][S:30]([NH:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:32])=[O:31].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH2:1]([N:8]([CH2:22][C:23]1[S:24][C:25]([C:38]2[CH:37]=[CH:36][CH:35]=[C:34]([NH:33][S:30]([CH3:29])(=[O:31])=[O:32])[CH:39]=2)=[CH:26][CH:27]=1)[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1C(F)(F)F)N(Cc1ccccc1)Cc1ccc(Br)s1
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1cccc(-c2ccc(CN(Cc3ccccc3)S(=O)(=O)c3ccccc3C(F)(F)F)s2)c1

Procedure:
In analogy to example 1, step 3, N-benzyl-N-(5-bromo-thiophen-2-ylmethyl)-2-trifluoromethyl-benzenesulfonamide was reacted with (3-methylsulfonylaminophenyl)-boronic acid, Na2CO3 and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct in dioxane/water to give N-benzyl-N-[5-(3-methanesulfonylamino-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide as a light yellow foam. MS: 598.3 ([M+NH4]+)
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:17]1(O)[C:26]2[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=2)[S:20][CH2:19][C:18]1([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[CH3:29])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([BH3-])#N.[Na+]>ClCCCl>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]1[C:26]2[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=2)[S:20][CH2:19][C:18]1([C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)[CH3:29])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2(O)C#CCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc(C2(C)CSc3cc(OC)ccc3C2CCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
4-[8-(t-Butyldimethylsilyloxy)-1-octynyl]-4-hydroxy-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman (14 g, 25.2 mmol) was dissolved in 1,2-dichloroethane (300 mL) and cooled to 0° C. Zinc iodide(II) (24.2 g, 75.69 mmol) and sodium cyanoborohydride (9.51 g, 151.38 mmol) was sequentially added and slowly warmed to room temperature and stirred for 2 hours. After the reaction was completed, the reaction solvent was removed under reduced pressure. The residue was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and removed by evaporation under vacuum. This product was purified by column chromatography on silica gel, eluting with 10% ethyl acetate in n-hexane. After removal of the solvent, crude 11 g of the title compound was obtained as pale yellow oil. (yield: 79.5%) Then, this compound thus obtained (11 g) was dissolved in tetrahydrofuran (300 mL). 0.2N NaHCO3(300 mL) and 10% palladium on carbon (3 g) was added and stirred for 2 day under hydrogen (atmospheric pressure). The reaction mixture was filtered through cellite and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, which was washed with water and brine. The organic solvent was dried over anhydrous magnesium sulfate and removed by evaporation under vacuum. This product was purified by column chromatography on silica gel, eluting with ethyl acetate:n-hexane=1:40. After removal of the solvent, 5.6 g of the title compound was obtained as colorless oil. (yield: 50.5%).
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:12]=[C:11]([Br:13])[CH:10]=[C:9]([Br:14])[CH:8]=1.[N+:15]([O-])([OH:17])=[O:16].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[Br:6][C:7]1[CH:12]=[C:11]([Br:13])[CH:10]=[C:9]([Br:14])[C:8]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: Brc1cc(Br)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1c(Br)cc(Br)cc1Br
Temperature: 50 °C

Procedure:
Sulfuric acid was poured into a solution of 1,3,5-tribromobenzene in chloroform, then, to this was added nitric acid and the mixture was heated for 5 hours at 50° C. After completion of the reaction, the organic layer was neutralized with a 5% aqueous potassium carbonate solution, then washed with water, and dried over magnesium sulfate. The solvent was removed to obtain a white solid which was re-crystallized from ethanol, to give 2,4,6-tribromonitrobenzene.
Reaction SMILES: [C:1]([C:4]#[C:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2].C[Si]([N:16]=[N+:17]=[N-:18])(C)C>CCOCC>[C:1]([C:4]1[N:16]=[N:17][NH:18][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(=O)C#Cc1ccccc1
Solvent: CCOCC
Product: CC(=O)c1nn[nH]c1-c1ccccc1
Temperature: 140 °C
Yield: 28 %

Procedure:
A mixture of 30 g (0.21 mole) of acetylphenyl-acetylene and 24 g (0.21 mole) of trimethylsilyl azide was heated at 140°C for 24 hours. It was then cooled, dissolved in ether, and extracted with dilute sodium hydroxide. This aqueous layer was separated and made acidic with dilute HCl. The precipitate was recrystallized from benzene-petroleum ether to give 11 g (28%) of 4-acetyl-5-phenyltriazole, m.p. 117°-118°C.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:13]C)[CH:11]=3)[C:6]([C:15]#[N:16])=[CH:5]2)[CH2:3][CH2:2]1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:1]1([N:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=3)[C:6]([C:15]#[N:16])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: COc1ccc2c(C#N)cn(C3CC3)c2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1cn(C2CC2)c2cc(O)ccc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.6 %

Procedure:
A solution of 1-cyclopropyl-6-methoxy-1H-indole-3-carbonitrile (3.60 g, 17.0 mmol) in CH2Cl2 (50.0 mL) was cooled to −78° C. and treated with BBr3 (21.27 g, 8.03 mL, 84.9 mmol), stirred for 10 min and then brought to room temperature and stirred for additional 30 minutes. The reaction mixture was poured into ice-water (150 mL), neutralized with NaHCO3 and the precipitate was collected by filtration, washed with water and purified on silica gel (CH2Cl2/EtOAc, 9:1) to provide 1-cyclopropyl-6-hydroxy-1H-indole-3-carbonitrile as a solid (3.02 g, 90%).
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]([CH2:12][CH2:13][CH3:14])=[C:9]([CH3:11])[CH:10]=1)([O:3][CH2:4][CH3:5])=[O:2].[CH3:15][CH:16]1OC(C)OC(C)O1>>[C:1]([C:6]1[NH:7][C:8]([CH2:12][CH2:13][CH3:14])=[C:9]([CH3:11])[C:10]=1[CH2:15][CH3:16])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CC1OC(C)OC(C)O1
Reactant: CCCc1[nH]c(C(=O)OCC)cc1C
Product: CCCc1[nH]c(C(=O)OCC)c(CC)c1C

Procedure:
The crude product, obtained in Example 68 but using 2-carbethoxy-4-methyl-5-n-propylpyrrole and paraldehyde, was crystallized from aqueous ethanol, sublimed, recrystallized and resublimed, m.p. 58°-59.5° C.
Reaction SMILES: [OH-].[Na+].[C@@H]1([N:12]2[CH:19]=[CH:18][C:16](=[O:17])[NH:15][C:13]2=[S:14])O[C@H](CO)[C@@H](O)[C@H]1O.CI.[C:22](O)(=O)C>O.C1COCC1>[CH3:22][S:14][C:13]1[NH:15][C:16](=[O:17])[CH:18]=[CH:19][N:12]=1
Reactant: CC(=O)O
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=S)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: CSc1nccc(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67 %

Procedure:
To a solution of sodium hydroxide (6.24 g, 156.07 mmol) in H2O (55 mL) at room temperature is added thiouridine (10 g, 78.03 mmol). The resulting mixture is stirred at room temperature for 20 min. Methyl iodide (5.45 mL, 87.40 mmol) in THF (10 mL) is added dropwise slowly and the mixture is stirred at room temperature for 18 hours. A white solid forms upon acidifying the mixture to pH 5 with glacial acetic acid. The mixture is allowed to stand at 0° C. (ice bath) for 2 hours and filtered to afford 7.4 g (67% yield) of the desired compound as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 2.45 (s, 3H), 6.07 (d, J=6.6 Hz, 1H), 7.85 (d, J=6.6 Hz, 1H).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[CH:7]=2)=[O:5])[CH2:3][CH2:2]1.[H][H]>[Pd].CO>[CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[CH:7]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: O=C(c1cccc([N+](=O)[O-])c1)C1CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(C(=O)C2CC2)c1

Procedure:
A Parr hydrogenation tube is charged with palladium on carbon (0.030 g). cyclopropyl-(3-nitrophenyl)methanone of Preparation 45 (0.250 g) and 10 mL of methanol. The tube is shaken at room temperature under 40 psi of hydrogen overnight. The reaction mixture is then filtered through Celite and concentrated to give 0.207 g of the title product which is used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:31])([F:30])[C:20]1[CH:21]=[C:22]([S:26](Cl)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH:15][S:26]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([C:19]([F:18])([F:30])[F:31])[CH:21]=3)(=[O:28])=[O:27])[CH:12]=[CH:11][CH:10]=2)=[CH:16][CH:17]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1cccc(COCc2ccc(F)cc2)n1
Product: O=S(=O)(Nc1cccc(COCc2ccc(F)cc2)n1)c1cccc(C(F)(F)F)c1

Procedure:
This material was prepared in analogy to example 1 from 6-(4-fluoro-benzyloxymethyl)-pyridin-2-ylamine (0.058 g) and 3-(trifluoromethyl)-benzenesulfonyl chloride (0.067 g) as a light yellow gum (0.08g). MS (ESI−): 439.1 ([M−H]−)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([OH:13])[CH3:12])[C:8]2[C:4](=[CH:5][N:6]([CH:14]3[CH2:16][CH2:15]3)[N:7]=2)[CH:3]=1.N12CCCN=C1CCCCC2.[Cl:28][C:29]([Cl:33])([Cl:32])[C:30]#[N:31].C(OCC)C>C(Cl)Cl>[Cl:28][C:29]([Cl:33])([Cl:32])[C:30](=[NH:31])[O:13][CH:11]([C:9]1[C:8]2[C:4](=[CH:5][N:6]([CH:14]3[CH2:16][CH2:15]3)[N:7]=2)[CH:3]=[C:2]([Cl:1])[CH:10]=1)[CH3:12]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CC(O)c1cc(Cl)cc2cn(C3CC3)nc12
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(Cl)cc2cn(C3CC3)nc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(±)-1-(5-Chloro-2-cyclopropyl-2H-indazol-7-yl)ethanol (240 mg, 1.01 mmol) was dissolved in methylene chloride (5 mL), cooled to 0° C. and treated with 1,8-diazabicyclo(5.4.0)undec-7-ene (31 μL, 0.2 mmol). The reaction was stirred for 10 min and treated with trichloroacetonitrile (1 mL, 10.1 mmol) dropwise over 10 min. The ice bath was removed and the reaction stirred at room temperature for 1 h and concentrated to give a dark brown solid. The crude product was treated with diethyl ether and stirred vigorously for 10 min. The resulting mixture was filtered through a pad of cotton and the ethereal concentrated to afford 365 mg (94%) as an oil. 1H-NMR (CDCl3, 300 MHz) δ 8.33 (s, 1H), 7.89 (s, 1H), 7.48 (m, 1H), 7.29 (m, 1H), 6.59 (q, J=6.6 Hz, 1H), 3.86-3.94 (m, 1H), 1.77 (d, J=6.6 Hz, 1H), 1.30-1.35 (m, 2H), 1.10-1.20 (m, 2H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][C:11]1[N:15]=[CH:14][NH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:10][C:11]1[N:15]=[CH:14][N:13]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[N:12]=1
Reactant: O=Cc1ccccc1F
Reactant: Cc1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ncn(-c2ccccc2C=O)n1
Temperature: 100 °C
Yield: 9.1 %

Procedure:
To a solution of 2-fluorobenzaldehyde (400 mg, 3.22 mmol) in DMSO (10 mL) are added 3-methyl-1H-1,2,4-triazole (321 mg, 3.87 mmol) and K2CO3 (890 mg, 6.45 mmol) at room temperature. The solution is heated to 100° C. for 2 hours. The solution is cooled down and extracted with H2O (10 mL) and EtOAc (3×10 mL). The combined organic layer is dried (MgSO4), filtered and concentrated. The residue is purified by silica gel chromatography eluting with 50% EtOAc in heptane as the eluent to afford 2-(3-methyl-1,2,4-triazol-1-yl)-benzaldehyde (55 mg, 8%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10](C=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([OH:25])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Oc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4-(4-fluorophenoxy)benzaldehyde (9.00 g, 41.63 mmol) in CHCl3 (75 mL) was treated with m-chloroperbenzoic acid (46-85%, 15.80 g, 52.00 mmol) and stirred for 3 h at room temperature. The reaction was washed with sat. aq. NaHSO3, sat. aq. NaHCO3, and water. The organic layer is concentrated and the residual oil taken up in MeOH (10 mL) containing a few drops of conc. HCL and stirred for 1 h at room temperature. The solvent is removed in vacuo and the resulting oil was chromatographed on silica gel (20% ethyl acetatelhexane) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:3]=1.[C:14]([N:17]1[CH2:21][C:20](=O)[N:19]=[CH:18]1)(=[O:16])[CH3:15]>>[C:14]([N:17]1[CH2:21][CH2:20][N:19]=[C:18]1[NH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:3]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)N1C=NC(=O)C1
Reactant: Cn1nc(-c2ccccc2)cc1N
Product: CC(=O)N1CCN=C1Nc1cc(-c2ccccc2)nn1C

Procedure:
5-Amino-1-methyl-3-phenylpyrazole (17.3 g.) and 1-acetyl-2-imidazolinone (15.4 g.) were reacted as described in Example I to give 14.0 g. product, mp 154°-155°.
Reaction SMILES: Cl[C:2]1[C:12]([N+:13]([O-])=O)=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CS(C)=O.O>[NH2:13][C:12]1[C:2]([NH:22][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[N:3][CH:4]=[C:5]([CH:11]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: NC1CCCCC1
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cnc(NC2CCCCC2)c(N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
Ethyl 6-chloro-5-nitronicotinate (1.00 g, 4.33 mmol) prepared according to A. H. Berrie et al. (J. Chem. Soc. 1951, 2590) was dissolved in DMSO (2 mL) and cyclohexylamine (0.54 g, 5.4 mmol) was added. The mixture was stirred for 1 h at room temperature, diluted with water and the yellow precipitate collected by filtration. The product was washed with water and dried (0.95 g, 74% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15]C(=O)[C@@H]3C(C)C)=[CH:8][C:6]=2[N:7]=1.[CH2:28]1[C@H:33]2[CH2:34]NCCN2[CH2:31][CH2:30][O:29]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]4[C@@H:33]([CH2:28][O:29][CH2:30][CH2:31]4)[CH2:34]3)=[CH:8][C:6]=2[N:7]=1
Reactant: C1CN2CCOC[C@H]2CN1
Reactant: CC(C)[C@H]1C(=O)NCCN1Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCN4CCOC[C@H]4C3)cc2n1

Procedure:
Prepared according to the method used in the preparation of (S)-4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-3-isopropyl-piperazin-2-one using (R)-octahydro-pyrazino[2,1-c][1,4]oxazine in place of (S)-3-isopropyl-piperazin-2-one. The title compound was obtained as a pale yellow solid (57 mg, 62%).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:5]1([CH2:11][O:12][CH3:13])[CH2:10][CH2:9][CH2:8][NH:7][CH2:6]1.[N:18]([O-])=O.[Na+]>O.C(O)(=O)C.[Zn]>[F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:5]1([CH2:11][O:12][CH3:13])[CH2:10][CH2:9][CH2:8][N:7]([NH2:18])[CH2:6]1
Reactant: COCC1(Cc2ccccc2F)CCCNC1
Reactant: O=N[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: COCC1(Cc2ccccc2F)CCCN(N)C1
Temperature: 25 °C

Procedure:
In an argon purged flask, 3-(2-fluorobenzyl)-3-(methoxymethyl)piperidine (337 mg, 1.23 mmol) was dissolved in water (0.8 mL) and acetic acid (2 mL). A solution of sodium nitrite (170 mg, 2.46 mmol) and water (1 mL) was drop wise added to the reaction flask. The reaction was stirred for an hour at room temperature. Water (5 mL) was added to the reaction mixture. The reaction mixture then was extracted 3 times with ethyl acetate (20 mL). The organic layers were combined, dried with sodium sulfate, and concentrated. The oil was dissolved in acetic acid (5 mL). The solution was drop-wise added to a suspension of Zn (321 mg, 4.92 mmol) in acetic acid (1 mL) and water (1 mL) solution. The reaction was stirred for 1.5 hour at room temperature. Upon completion, the reaction was filtered through celite. The Zn and salt was rinsed with 1N HCl in water. The filtrate was concentrated to yield crude hydrogen chloride salt of the amine. The crude product was progressed to the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[N+:13]([CH3:16])([O-:15])=[O:14]>O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([OH:12])[CH2:16][N+:13]([O-:15])=[O:14]
Reactant: C[N+](=O)[O-]
Reactant: O=C1Nc2ccc(F)cc2C1=O
Solvent: O
Product: O=C1Nc2ccc(F)cc2C1(O)C[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 8 h

Procedure:
5-fluoroisatin (0.082 g) and nitromethane (0.1 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 30° C. for 8 hours. The obtained product was extracted with ethyl acetate and purified by silica gel column chromatography using ethyl acetate/hexane as eluents to afford pure product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[C:20]3[C:19](=O)[CH2:18][CH2:17][C:16]=3[CH:15]=[N:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].FC1C=C(B(O)[OH:34])C=CC=1C(F)(F)F>>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[C:20]3[CH2:19][CH2:18][CH:17]([OH:34])[C:16]=3[CH:15]=[N:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:10])([F:9])[F:11]
Reactant: O=C1CCc2cncc(-c3ccc(C(F)(F)F)c(F)c3)c21
Reactant: OB(O)c1ccc(C(F)(F)F)c(F)c1
Product: OC1CCc2c(-c3ccc(C(F)(F)F)c(F)c3)cncc21
Yield: 55 %

Procedure:
In analogy to the procedure described for the preparation of example 1 (rac)-4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (intermediate A-4 [C2]) was reacted with 3-fluoro-4-(trifluoromethyl)phenylboronic acid to give the title compound as grey solid in 55% yield. MS: 298.1 (M+H+).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([S:55]([C:58]([CH3:61])([CH3:60])[CH3:59])(=[O:57])=[O:56])=[C:10]([CH2:12][N:13]([CH3:54])[C:14]([CH:16]([NH:28][C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[C:35]([N:39]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[N:34][CH:33]=[CH:32]3)[C:17]2[CH:22]=[CH:21][C:20]([C@@H:23]([CH3:26])[CH2:24][OH:25])=[C:19]([CH3:27])[CH:18]=2)=[O:15])[CH:11]=1>C(#N)C.C(Cl)Cl>[C:42]([O:41][C:40]([N:39]([C:35]1[C:36]2[C:31](=[CH:30][C:29]([NH:28][CH:16]3[C:14](=[O:15])[N:13]([CH3:54])[CH2:12][C:10]4[CH:11]=[C:6]([CH:7]=[CH:8][C:9]=4[S:55]([C:58]([CH3:61])([CH3:60])[CH3:59])(=[O:57])=[O:56])[NH:5][C:1](=[O:2])[O:25][CH2:24][C@H:23]([CH3:26])[C:20]4[CH:21]=[CH:22][C:17]3=[CH:18][C:19]=4[CH3:27])=[CH:38][CH:37]=2)[CH:32]=[CH:33][N:34]=1)[C:47](=[O:48])[O:49][C:50]([CH3:52])([CH3:53])[CH3:51])=[O:46])([CH3:43])([CH3:44])[CH3:45]
Reactant: O=C(Cl)Cl
Reactant: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)N(C)Cc2cc(N)ccc2S(=O)(=O)C(C)(C)C)ccc1[C@@H](C)CO
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cc2ccc1[C@@H](C)COC(=O)Nc1ccc(S(=O)(=O)C(C)(C)C)c(c1)CN(C)C(=O)C2Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.4 %

Procedure:
Phosgene (201 mg, 0.406 mmol) was added dropwise to a solution of 22D (297 mg, 0.369 mmol) in acetonitrile (4 mL)/CH2Cl2 (4 mL) at 0° C. The bath was removed and the mixture was stirred at rt for 30 min. Ar was bubbled though the solution (10 min) to remove excess phosgene. The resulting solution was added to a solution of TEA (0.257 mL, 1.847 mmol) in CH2Cl2 (40 mL) at 40° C. over 5 h via a syringe pump. The reaction was stirred at rt overnight, quenched with H2O (1 mL) and MeOH (5 mL) and then concentrated. The crude product was purified by flash chromatography to give a mixture of diastereoisomers. The diastereomers were separated by a prep chiral HPLC (R,R-Whelk-O column 21.1×250 mm) to give 22E (75 mg, 0.090 mmol, 24.46% yield). MS (ESI) m/z: 830.8 (M+H)+.