Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH2:11][NH:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][NH2:20])[C:14]=2[C:21]([F:24])([F:23])[F:22])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:31][C:32]([F:38])([F:37])[CH2:33][C:34](Cl)=[O:35]>CCOC(C)=O.C1COCC1>[F:31][C:32]([F:38])([F:37])[CH2:33][C:34]([NH:20][NH:19][C:15]1[C:14]([C:21]([F:24])([F:22])[F:23])=[C:13]([NH:12][CH2:11][C@H:9]2[CH2:10][C@@H:8]2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:18]=[CH:17][N:16]=1)=[O:35]
Reactant: O=C(Cl)CC(F)(F)F
Reactant: NNc1nccc(NC[C@H]2C[C@@H]2c2ccc(F)cc2)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(CC(F)(F)F)NNc1nccc(NC[C@H]2C[C@@H]2c2ccc(F)cc2)c1C(F)(F)F
Reaction time: 0.17 h
Yield: 79.5 %

Procedure:
A mixture of N-(((1S,2S)-2-(4-fluorophenyl)cyclopropyl)methyl)-2-hydrazinyl-3-(trifluoromethyl)pyridin-4-amine (0.38 g, 1.117 mmol) in EtOAc (3 mL) and THF (3 mL) and sat'd aqueous sodium carbonate (3 mL) was stirred as 3,3,3-trifluoropropanoyl chloride (0.213 g, 1.452 mmol) was added slowly. The mixture was stirred for 10 min. The reaction was diluted with EtOAc, washed with aqueous sodium bicarbonate, dried with brine, and concentrated. The crude product was purified by silica gel chromatography using 0-100% ethyl acetate/hexane as the eluent to give 3,3,3-trifluoro-N′-(4-((((1S,2S)-2-(4-fluorophenyl)cyclopropyl)methyl)amino)-3-(trifluoromethyl)pyridin-2-yl)propanehydrazide as an off-white solid (0.4 g, 71.6% yield). 1H NMR (400 MHz, CHLOROFORM-d) d 7.87 (d, J=6.3 Hz, 1H), 7.08-6.92 (m, 4H), 6.23 (d, J=6.3 Hz, 1H), 5.35 (d, J=3.8 Hz, 1H), 3.35-3.12 (m, 4H), 1.89 (dt, J=9.1, 4.9 Hz, 1H), 1.44-1.31 (m, 1H), 1.07 (dt, J=8.4, 5.5 Hz, 1H), 0.98 (dt, J=8.9, 5.5 Hz, 1H). LCMS M+1=451.1.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[C:11]([O-])([O-])=O.[Cs+].[Cs+].IC>CN(C=O)C>[CH3:11][O:1][C:2]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: OCc1ccc(I)cc1O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(I)ccc1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Hydroxy-4-iodo-benzylalcohol from Step 3 (1.0 g, 4.0 mmol), Cs2CO3 (1.3 g, 4.0 mmol) and iodomethane (0.25 mL, 4.0 mmol) were dissolved in DMF and heated to 80° for 1 hour and then stirred at room temperature for 2 hours. The DMF was removed in vacuo and the residue was partitioned between H2O and EtOAc. The aqueous layer was extracted with EtOAc (2×). The organic layers were combined, washed with H2O and brine, dried (MgSO4), filtered and concentrated to yield an oil. This oil was purified by flash chromatography eluting product with 30% EtOAC/Hexane to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][CH:20]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CO.C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][CH:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CCOC(=O)C(N)c1ccccc1F
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1ccccc1F

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl 2-amino-2-(2-fluorophenyl)acetate hydrochloride (prepared from 2-fluorophenylglycine (Fluka) and ethanol using General Procedure H), the title compound was prepared as a solid (mp=153-170° C.). The reaction was monitored by tlc (Rf=0.3 in 5% MeOH/CHCl3) and the product was purified by silica gel chromatography using 5% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane/acetonitrile.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14](B2OC(C)(C)C(C)(C)O2)=[CH:13][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:33]1[C:34]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[N:35][N:36]([CH3:38])[CH:37]=1>CN(C)C=O.O>[C:1]([NH:4][CH:5]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:33]2[C:34]([NH:39][C:40]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:46])=[N:35][N:36]([CH3:38])[CH:37]=2)=[CH:15][CH:16]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: COC(=O)C(Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)NC(C)=O
Reactant: Cn1cc(Br)c(NC(=O)OC(C)(C)C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(-c2cn(C)nc2NC(=O)OC(C)(C)C)cc1)NC(C)=O
Temperature: 85 °C
Reaction time: 8 h

Procedure:
1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (353 mg, 0.43 mmol) was added to a degassed, ambient temperature solution of methyl 2-(acetylamino)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (1.5 g, 4.3 mmol), potassium carbonate (2.39 g, 17.3 mmol) and tert-butyl (4-bromo-1-methyl-1H-pyrazol-3-yl)carbamate (1.19 g, 4.3 mmol) in wet N,N-dimethylformamide (40 mL). After stirring at 85° C. overnight, the reaction mixture was cooled, diluted with water and extracted with methylene chloride and ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% acetone/methylene chloride afforded methyl 2-(acetylamino)-3-(4-{3-[(tert-butoxycarbonyl)amino]-1-methyl-1H-pyrazo 1-4-yl}phenyl)propanoate.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:10]([C:11]2[NH:15][CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:12]=2[F:26])=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4].C1OCCOCCOCCOCCOC1.[F:42][C:43]1[CH:44]=[C:45]([S:49](Cl)(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1>O1CCCC1.O>[C:3]([C:5]1[C:10]([C:11]2[N:15]([S:49]([C:45]3[CH:46]=[CH:47][CH:48]=[C:43]([F:42])[CH:44]=3)(=[O:51])=[O:50])[CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[C:12]=2[F:26])=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CN(Cc1c[nH]c(-c2cccnc2C#N)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2cccc(F)c2)c(-c2cccnc2C#N)c1F)C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (5 mL) were added dropwise a solution (5 mL) of tert-butyl {[5-(2-cyanopyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (330 mg) in tetrahydrofuran, 15-crown-5 (330 mg) and 3-fluorobenzenesulfonyl chloride (292 mg) under ice-cooling and the mixture was stirred for 3 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→2:1) to give the title compound as a pale-yellow oil (yield 445 mg, 91%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([OH:11])=O)[CH:4]=1.[NH2:12][C:13]1[NH:17][N:16]=[N:15][N:14]=1>S(Cl)(Cl)=O>[NH:14]1[C:13]([NH:12][C:9]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=2)=[O:11])=[N:17][N:16]=[N:15]1
Reactant: COc1ccnc(C(=O)O)c1
Reactant: Nc1nnn[nH]1
Solvent: O=S(Cl)Cl
Product: COc1ccnc(C(=O)Nc2nnn[nH]2)c1
Yield: 11.7 %

Procedure:
1.67 g of 4-methoxy-2-pyridinecarboxylic acid, 20 ml of thionyl chloride and 1.2 g of 5-aminotetrazole are treated in the same manner as described in Example 1. The crude product thus obtained is recrystallized from ethanol, whereby 0.28 g of N-(5-tetrazolyl)-4-methoxy-2-pyridinecarboxamide is obtained.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([OH:17])[CH2:13][CH2:14][C:15]#[CH:16].C(N(CC)CC)C>ClCCl>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:17][CH2:12][CH2:13][CH2:14][C:15]#[CH:16])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: C#CCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 22 h
Yield: 87 %

Procedure:
p-Toluenesulfonyl chloride (21.4 g, 112 mmol) was added slowly to a stirred solution of 4-pentyn-1-ol (11.5 mL, 124 mL) and triethylamine (17.2 mL, 124 mmol) in dichloromethane (100 mL) at room temperature. After 22 hours, the solution was diluted with dichloromethane, washed with water, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, gradient elution from 95:5 to 85:15 hexanes/ethyl acetate) to afford the product pent-4-ynyl 4-methylbenzenesulfonate (23.4 g, 87%) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].O.[OH-].[K+].[C:13](#[N:16])[CH:14]=[CH2:15]>O1CCOCC1>[C:13]([CH2:14][CH2:15][O:1][CH2:2][C:3]([CH2:8][O:9][CH2:15][CH2:14][C:13]#[N:16])([CH2:6][O:7][CH2:15][CH2:14][C:13]#[N:16])[CH2:4][O:5][CH2:15][CH2:14][C:13]#[N:16])#[N:16]
Reactant: OCC(CO)(CO)CO
Reactant: C=CC#N
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: N#CCCOCC(COCCC#N)(COCCC#N)COCCC#N
Temperature: 0 °C
Reaction time: 48 h

Procedure:
Pentaerythritol (6.84 g, 50 mmol) was dissolved in 20 ml dioxane and 2 ml water and mixed up with 40% aqueous potassium hydroxide solution (w/v, 1 ml). After cooling to 0° C. in an ice bath, acrylonitrile (16.2 g, 300 mmol) was added and the mixture stirred for 48 h at room temperature. Solvents were evaporated, the remaining oil was diluted in 100 ml dichloromethane and washed with 10% aqueous sodium chloride solution (w/v, 50 ml). After re-extraction of the aqueous layer with dichloromethane (2×25 ml), the combined organic layers were dried over sodium sulfate and intensively evaporated. The nitrile was obtained as a colorless syrup: yield: 14.32 g (41 mmol, 82%). 1H-NMR (400 MHz, CDCl3) δ 2.60 (t, 8 H,—CH2CN), 3.50 (s, 8 H, —CqCH2O—), 3.65 (t, 8 H, —OCH2—). 13C-NMR (100 MHz, CDCl3) δ 18.86 (—CH2CN), 45.68 (Cq), 65.88 (—OCH2—), 68.82 (CqCH2O—), 118.22 (CN).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:28]1([C:34]2[S:35][C:36]([CH:39]=O)=[CH:37][N:38]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][CH2:39][C:36]4[S:35][C:34]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)=[N:38][CH:37]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: O=Cc1cnc(-c2ccccc2)s1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NCc4cnc(-c5ccccc5)s4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 12, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-phenyl-thiazole-5-carbaldehyde.
Reaction SMILES: [I-].[Na+].Br[CH:4](Br)[C:5]1[C:6]([CH:11](Br)Br)=[CH:7][CH:8]=[CH:9][CH:10]=1.[C:15](#[N:20])/[CH:16]=[CH:17]/[C:18]#[N:19].S([O-])(O)=O.[Na+]>CN(C)C=O>[C:18]([C:17]1[C:16]([C:15]#[N:20])=[CH:11][C:6]2[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:4]=1)#[N:19]
Reactant: BrC(Br)c1ccccc1C(Br)Br
Reactant: N#C/C=C/C#N
Agent: O=S([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc2ccccc2cc1C#N
Temperature: 75 °C
Reaction time: 7 h
Yield: 73 %

Procedure:
One hundred grams (0.67 mole) of sodium iodide was added to a well-stirred solution of 42.2 g (0.1 mole) of α,α,α',α'-tetrabromo-o-xylene and 13.5 g (0.173 mole) of fumaronitrile in 400 ml of anhydrous N,N-dimethylformamide, and the resulting mixture was stirred at 75° C. for about 7 hours in an atmosphere of nitrogen. After the reaction, the mixture was poured into about 2 kg of ice, and thereto was slowly added sodium hydrogen sulfite until the red-brown colored aqueous solution turned to light yellow. After adding a slightly excessive quantity of sodium hydrogen sulfite, the resulting mixture was stirred for a while and then allowed to stand overnight at room temperature. The deposited light yellow-colored solid product was collected by filtration with suction, thoroughly washed with water, and allowed to dry. The light yellow-colored solid product thus obtained was recrystallized from ethanol/chloroform mixture to obtain 13 g (73%) of 2,3-dicyanonaphthalene as a colorless crystalline material.
Reaction SMILES: C([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[CH2:21][CH2:20][C:14]3[N:15]=[C:16]([NH2:19])[N:17]=[CH:18][C:13]=3[CH2:12]2)[CH:6]=1)C.[OH-].[Na+]>O1CCOCC1>[NH2:19][C:16]1[N:17]=[CH:18][C:13]2[CH2:12][N:11]([C:7]3[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=3)[C:4]([OH:22])=[O:3])[CH2:21][CH2:20][C:14]=2[N:15]=1
Reactant: CCOC(=O)c1cccc(N2CCc3nc(N)ncc3C2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1ncc2c(n1)CCN(c1cccc(C(=O)O)c1)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of ethyl-3-(2-amino-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)-benzoate (958 mg, 3.21 mmol) in 1,4-dioxane (35 mL) was treated with 1.0N NaOH(aq.) (8.24 mL, 8.24 mmol) and the reaction mixture was refluxed for 21 hours. Upon cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated. The residue was diluted with water and the pH was adjusted to ˜4 with 1.0N HCl(aq.). The cloudy mixture was treated with ethyl acetate and the aqueous/organic mixture was stirred at room temperature for approx. 1 hour. The precipitate was filtered off, washed with water, ethyl acetate, and dried in vacuo at 50° C. to give the title compound as a yellow, amorphous solid (710.8 mg, 82%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][S:10][CH3:11])=[CH:4][C:3]=1[NH2:12].[CH3:13][O:14][C:15]([N:17]=[C:18]=[S:19])=[O:16]>CC(C)=O>[CH3:13][O:14][C:15]([NH:17][C:18](=[S:19])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][S:10][CH3:11])=[CH:4][C:3]=1[NH:12][C:18]([NH:17][C:15]([O:14][CH3:13])=[O:16])=[S:19])=[O:16]
Reactant: CSCOc1ccc(N)c(N)c1
Reactant: COC(=O)N=C=S
Solvent: CC(C)=O
Product: COC(=O)NC(=S)Nc1ccc(OCSC)cc1NC(=S)NC(=O)OC

Procedure:
The 1,2-diamino-4-methylthiomethoxybenzene prepared above is dissolved in 60 ml. acetone and treated overnight with 6 g. methoxycarbonyl isothiocyanate at room temperature. The mixture is concentrated and the residue stirred with 500 ml. water and the brown solid filtered off. The residue is extracted with 250 ml. dichloromethane, filtered, treated with charcoal, and recrystallized from dichloromethanebenzene to afford 1,2-bis(3-methoxycarbonyl-2-thioureido)-4-methylthiomethoxybenzene.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.C(OC(=O)[NH:33][CH2:34][CH2:35][NH:36][S:37]([C:40]1[S:41][C:42]([Cl:48])=[C:43]([N+:45]([O-])=O)[CH:44]=1)(=[O:39])=[O:38])(C)(C)C>>[NH2:33][CH2:34][CH2:35][NH:36][S:37]([C:40]1[S:41][C:42]([Cl:48])=[C:43]([NH:45][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:13])[CH:44]=1)(=[O:38])=[O:39]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1cc([N+](=O)[O-])c(Cl)s1
Product: NCCNS(=O)(=O)c1cc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(Cl)s1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and [2-(4-amino-5-chloro-thiophene-2-sulfonylamino)-ethyl]-carbamic acid tert-butyl ester (example B.17) according to general procedure II and subsequent removal of the protecting group with trifluoroacetic acid in dichloromethane at 0° C. for 3 h. Yellow solid. MS (ISP) 611.0 [(M−H)−]; mp 195° C.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=3Br)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(=O)([O-])[O-].[K+].[K+].[CH3:28][O:29][C:30]1[C:35](B(O)O)=[CH:34][CH:33]=[CH:32][N:31]=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]12([CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=3[C:35]3[C:30]([O:29][CH3:28])=[N:31][CH:32]=[CH:33][CH:34]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: N#Cc1ccc(OCC23CC4CC(CC(C4)C2)C3)c(Br)c1
Reactant: COc1ncccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ncccc1-c1cc(C#N)ccc1OCC12CC3CC(CC(C3)C1)C2
Temperature: 90 °C
Yield: 98.8 %

Procedure:
A reaction mixture of 4-(adamantan-1-ylmethoxy)-3-bromobenzonitrile (1.04 g, 3.00 mmol), potassium carbonate (1.00 g, 7.20 mmol) and (2-methoxypyridin-3-yl)boronic acid (0.92 g, 6.00 mmol) in dioxane (30 mL) was degassed three times with nitrogen, then tetrakis(triphenylphosphine)palladium(0) (0.18 g, 0.15 mmol) was added and the reaction mixture was degassed three further times with nitrogen. The resulting mixture was heated at 90° C. for 19 h, and then the reaction was cooled to ambient temperature, (2-methoxypyridin-3-yr)boronic acid (0.46 g, 3.00 mmol) and tetrakis(triphenylphosphfne)-pailadium(0) (0.09 g, 0.08 mmol) were added and the reaction was degassed three times with nitrogen and heated at 90° C. for further 7 h. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate (200 mL) and washed with water and brine; dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (15% ethyl acetate in hexanes) afforded the title compound as a colorless solid (1.11 g, 98%): 1H NMR (300 MHz, CDCl3) δ 8.20-8.16 (m, 1H), 7.62-7.48 (m, 3H), 6.96-6.91 (m, 2H), 3.87 (s, 3H), 3.48 (s, 2H), 1.89 (br s, 3H), 1.68-1.35 (m, 12H); MS (ES+) m/z: 375.2, (M+1).
Reaction SMILES: [CH3:1][N:2]([CH2:18][CH:19]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=1)[CH2:20][CH2:21]S(C)(=O)=O)[C:3](=[O:17])[C:4]1[CH:9]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][C:5]=1[O:15][CH3:16].I.[NH:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[C:44]([CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)=[O:45]>>[CH3:1][N:2]([CH2:18][CH:19]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=1)[CH2:20][CH2:21][N:49]1[CH2:50][CH2:51][CH:46]([C:44]([C:36]2[NH:35][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[N:37]=2)=[O:45])[CH2:47][CH2:48]1)[C:3](=[O:17])[C:4]1[CH:9]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][C:5]=1[O:15][CH3:16]
Reactant: COc1ccc(OC(F)(F)F)cc1C(=O)N(C)CC(CCS(C)(=O)=O)c1ccc(Cl)c(Cl)c1
Reactant: O=C(c1nc2ccccc2[nH]1)C1CCNCC1
Agent: I
Product: COc1ccc(OC(F)(F)F)cc1C(=O)N(C)CC(CCN1CCC(C(=O)c2nc3ccccc3[nH]2)CC1)c1ccc(Cl)c(Cl)c1

Procedure:
Prepare by the method of Example 1.7 using N-methyl-N-(2-(3,4-dichlorophenyl)-4-methanesulfonylbutyl)-2-methoxy-5-trifluoromethoxybenzamide and 4-(1H-benzimidazole-2-carbonyl)piperidine hydriodic acid salt to give the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[CH2:9]([SH:13])[CH2:10][CH2:11][SH:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>ClCCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[S:13][CH2:9][CH2:10][CH2:11][S:12]1
Reactant: O=Cc1ccccn1
Reactant: SCCCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCCl
Product: c1ccc(C2SCCCS2)nc1
Temperature: 5 °C
Yield: 85.2 %

Procedure:
A solution of pyridine-2-carboxaldehyde (26.7 g), propane-1,3-dithiol (94.4 g) and paratoluenesulphonic acid (3.7 g) in 1,2-dichloroethane (2500 cc) is kept at the boil for 20 hours so that the water formed is removed by azeotropic distillation. After cooling to 5° C., the reaction mixture is washed twice with an approximately 7 N aqueous solution of potassium hydroxide (540 cc in total) and then four times with distilled water (1400 cc in total). The organic solution is dried over anhydrous sodium sulphate and filtered and the filtrate is concentrated under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. 2-(Pyrid-2-yl)-1,3-dithiane (41.9 g) is thus obtained.
Reaction SMILES: C[O:2][C:3](=[O:25])[C@@H:4]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])[CH3:6].[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.O1CCOCC1.O>[C:21]([O:20][C:18]([NH:17][C@@H:4]([C@@H:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])[CH3:6])[C:3]([OH:25])=[O:2])=[O:19])([CH3:22])([CH3:23])[CH3:24]
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)Nc1ccccc1[N+](=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](Nc1ccccc1[N+](=O)[O-])[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2S,3S)-2-tert-butoxycarbonylamino-3-(2-nitro-phenylamino)-butyric acid methyl ester (5.71 g, 16.2 mmol) in dioxane water (1:1, 100 ml) was added an aqueous solution of 2.5 M lithium hydroxide (31 ml) and the reaction was stirred at ambient temperature for 2 h. The reaction was made acidic with 10% aqueous citric acid, diluted with water (60 ml) and extracted with ethyl acetate (2×100 mL). The organic layers were combined, washed with water (1×50 mL), brine, dried over sodium sulfate, filtered and concentrated in vacuo to give (2S,3S)-2-tert-butoxycarbonylamino-3-(2-nitro-phenylamino)-butyric acid which was carried to the subsequent step without purification (5.48 g, 99%).
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.Br[CH:23]([C:25]1[C:33]2[C:29](=[CH:30][N:31]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[N:32]=2)[CH:28]=[C:27]([C:42]([F:45])([F:44])[F:43])[CH:26]=1)[CH3:24].[H-].[Na+]>CN(C)C=O>[C:16]1([C:3]2([CH2:2][O:1][CH:23]([C:25]3[C:33]4[C:29](=[CH:30][N:31]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:39])([CH3:41])[CH3:40])[N:32]=4)[CH:28]=[C:27]([C:42]([F:45])([F:44])[F:43])[CH:26]=3)[CH3:24])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Reactant: CC(Br)c1cc(C(F)(F)F)cc2cn(COCC[Si](C)(C)C)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C(F)(F)F)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (±)-tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (193 mg, 0.66 mmol) and 7-(1-bromoethyl)-5-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole (280 mg, 0.66 mmol) in dimethylformamide (2.5 mL) at 0° C. was added sodium hydride (60% in mineral oil, 34.4 mg, 0.86 mmol). The resulting solution was stirred at 0° C. for 30 min. The reaction was quenched by the cautious addition of saturated ammonium chloride and diluted with diethyl ether. The ethereal was washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (12%→20% EtOAc/Hex) gave 62 mg (15%) as an oil. 1H-NMR (CDCl3, 500 MHz) δ 8.24 (s, 1H), 7.94 (s, 1H), 7.32-7.45 (m, 4H), 7.23-7.29 (m, 2H), 5.75 (m, 2H), 5.04 (q, J=6.4 Hz, 1H), 3.81 (m, 2H), 3.67 (m, 2H), 3.44 (qAB, JAB=9.2 Hz, 2H), 3.10 (m, 2H), 2.23 (m, 2H), 2.03 (m, 2H), 1.52 (d, J=6.4 Hz, 3H), 1.48 (s, 9H), 0.97 (m, 2H), 0.00 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 155.2, 147.4, 142.9, 135.5, 128.5, 127.3, 126.4, 124.8 (q, J=272 Hz), 124.7 (q, J=32 Hz), 124.6, 121.1, 117.9 (q, J=4.8 Hz), 117.3 (q, J=2.9 Hz), 82.0, 79.3, 78.2, 74.1, 67.8, 41.8, 40.3 (br), 31.8, 28.6, 22.8, 17.9, −1.4. Mass spec.: 634.17 (MH)+.