Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[F:25][C:26]([F:33])([C:29]([F:32])([F:31])[F:30])[CH2:27][NH2:28].C(N(CC)CC)C>CN(C=O)C>[Cl:15][C:12]([F:14])([F:13])[C:6]1[N:5]=[C:4]([C:16]([F:19])([F:17])[F:18])[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:2]([NH:28][CH2:27][C:26]([F:33])([F:25])[C:29]([F:32])([F:31])[F:30])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Reactant: NCC(F)(F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1NCC(F)(F)C(F)(F)F
Yield: 81.1 %

Procedure:
This compound was prepared as described in Example 37: 5.0 g (0.013 mol) of product of Example 28, 1.94 g (0.013 mol) of 2,2,3,3,3-pentafluoropropylamine, 1.81 ml (0.013 mol) of triethylamine in 30 ml of DMF were reacted at 50° C. for 64 hours, affording 5.36 g of oil. This oil was purified by HPLC using 1% ethyl acetate/cyclohexane as eluting solvent to give 1.82 g of oil which was kugelrohr distilled at 41 Pa, pot temperature 95° C., to give 1.55 g (23.4%) of product as a clear oil, n25D 1.4351.
Reaction SMILES: [OH2:1].[CH3:2][S:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[OH:11]O>C(O)(=O)C.C(Cl)(Cl)Cl>[CH3:2][S:3]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)(=[O:11])=[O:1]
Reactant: CSc1ccc(N)cc1
Reactant: OO
Reactant: O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(N)cc1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 75 %

Procedure:
67 mg of Na2WO4, 8 drops of acetic acid and 19 mL of H2O were introduced into a flask and heated to 65° C. Then, 19 mL (153 mmol) of 4-methylthioaniline was added followed by the dropwise addition of 34.5 mL (337 mmol) of H2O2. The mixture was stirred at 65° C. for 1.5 h and, after cooling, 800 mL of 1N HC and 500 mL of CHCl3 was added. The layers were separated and the aqueous phase was washed with more CHCl3. The aqueous phase was then basified with 25% NaOH and extracted with CHCl3. The organic phase was washed with brine and dried over MgSO4. The solvent was removed, yielding 19.80 g of the product as a white solid (75% yield).
Reaction SMILES: [Mg].C(Br)C.II.[CH:7]([N:10]([CH2:14][CH2:15][CH:16]([C:23]1[CH:28]=[C:27](Br)[CH:26]=[CH:25][C:24]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:11]([CH3:13])[CH3:12])([CH3:9])[CH3:8].[C:38](=[O:40])=[O:39].[Cl-:41].[NH4+]>C(OCC)C.O1CCCC1>[ClH:41].[CH:7]([N:10]([CH2:14][CH2:15][CH:16]([C:23]1[CH:28]=[C:27]([C:38]([OH:40])=[O:39])[CH:26]=[CH:25][C:24]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:11]([CH3:13])[CH3:12])([CH3:9])[CH3:8]
Reactant: [Cl-]
Reactant: O=C=O
Reactant: CC(C)N(CCC(c1ccccc1)c1cc(Br)ccc1OCc1ccccc1)C(C)C
Agent: II
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCBr
Product: CC(C)N(CCC(c1ccccc1)c1cc(C(=O)O)ccc1OCc1ccccc1)C(C)C
Product: Cl
Yield: 77 %

Procedure:
A mixture of magnesium (12.2 g, 0.5 mole), ethyl bromide (2 g), and iodine (a small crystal) in dry diethyl ether (200 mL) was warmed until the reaction started. (+)-N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropylamine (45.6 g, 0.095 mole) and ethyl bromide (32.7 g, 0.3 mole) dissolved in dry diethyl ether (250 mL) were then added dropwise under nitrogen atmosphere. The mixture was refluxed for 1.5 h and then cooled in an acetone/dry-ice bath, whereupon powdered dry ice (≈100 g) was added gently. Tetrahydrofuran was added when needed to prevent the mixture from solidification. The reaction mixture was stirred for 0.5 h when ammonium chloride (200 mL, 20% w/w) was added. The mixture was stirred vigorously until two transparent phases were formed, and then filtered through a pad of Celatom. The aqueous layer was washed with diethyl ether and then acidified with hydrochloric acid to pH 1. The precipitated semi-crystalline gum was washed with water, and then transferred to a round bottom flask. The product was dried by co-evaporation with acetone, benzene, toluene, diisopropyl ether and methanol, successively. The title compound (35.1 g, 77%) was isolated as friable shiny flakes and used without any further purification.
Reaction SMILES: [CH2:1]([C:3]([C:14]1[S:18][C:17]2[CH:19]=[C:20]([C:23]([OH:25])=[O:24])[CH:21]=[CH:22][C:16]=2[CH:15]=1)([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH3:13])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].OS(O)(=O)=O.[C:31]([O-])(O)=O.[Na+]>CO>[CH3:31][O:24][C:23]([C:20]1[CH:21]=[CH:22][C:16]2[CH:15]=[C:14]([C:3]([CH2:4][CH3:5])([C:6]3[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH3:13])[CH:7]=3)[CH2:1][CH3:2])[S:18][C:17]=2[CH:19]=1)=[O:25]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1cc2ccc(C(=O)O)cc2s1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: CCC(CC)(c1ccc(O)c(C)c1)c1cc2ccc(C(=O)OC)cc2s1
Yield: 98 %

Procedure:
A solution of 2-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-benzo[b]thiophene-6-carboxylic acid (3.98 g, 11.23 mmol) in MeOH (100 mL) is treated with H2SO4 (concentrated, 1.0 mL). The mixture is stirred at 80° C. for 8 h and neutralized with aqueous NaHCO3. The MeOH is removed under vacuum and the residue is extracted with EtOAc (2×100 mL). The combined organic layer is dried over Na2SO4, concentrated and purified by silica gel column chromatography (20% EtOAc/Hex) to give the product (4.05 g, 98%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:22])[C@@H:10]([OH:21])[CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].Cl[C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>CN(C)C=O.ClCCl>[OH:21][C@H:10]([C:9]([NH:8][C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[NH:1][C:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:22])[CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1ncc(NC(=O)[C@@H](O)CCNC(=O)OC(C)(C)C)c1N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1ncc(NC(=O)[C@@H](O)CCNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.7 %

Procedure:
To a solution of tert-butyl {(3S)-4-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-3-hydroxy-4-oxobutyl}carbamate (68.51 g) in N,N-dimethylformamide (350 ml) was added chlorotriphenylmethane (67 g). To the mixture was dropwise added triethylamine (67 ml). The mixture was stirred at room temperature for 12 hours. The reaction mixture was dissolved in dichloromethane (2 L). The solution was washed successively with water and brine. The extract was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated with acetonitrile and dried in vacuo to give tert-butyl ((3S)-3-hydroxy-4-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-4-oxobutyl)carbamate (64 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.CCCCCC.C([Li])CCC.[B:29](OC(C)C)([O:34]C(C)C)[O:30]C(C)C.Cl>C1(C)C=CC=CC=1.C1COCC1>[C:8]1([C:4]2[CH:3]=[C:2]([B:29]([OH:34])[OH:30])[CH:7]=[CH:6][CH:5]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1cccc(-c2cccc3ccccc23)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: OB(O)c1cccc(-c2cccc3ccccc23)c1
Temperature: -60 °C
Yield: 71.9 %

Procedure:
Under an argon gas atmosphere, a mixture of 200.0 g (706.3 mmol) of 1-(3-bromophenyl) naphthalene and 2.1 L of dehydrated THF was cooled down to −60 degrees C., and added with 543 mL (847 mmol) of hexane solution of 1.56M n-butyllithium in drops while being stirred. Then, the reaction mixture was stirred for two hours at −60 degrees C. The reaction solution was further cooled down to −60 degrees C. and added with 398.5 g (2.119 mol) of triisopropyl borate in drops. Subsequently, the reaction mixture was warmed up to room temperature, and stirred for 17 hours. The reaction mixture was further added with solution of hydrochloric acid to be stirred for one hour at room temperature. After the reaction, the reaction mixture was further added with toluene, so that aqueous phase thereof was eliminated. After organic phase thereof was dried with magnesium sulfate, the solvent was distilled away under reduced pressure. By recrystallizing the obtained solid by toluene, 126 g of 3-(1-naphthyl)phenylboronic acid was obtained at an yield of 67%.
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]1[C:13]([F:14])=[C:12]([F:15])[C:11]([F:16])=[C:10]([F:17])[C:7]=1[CH2:8]O.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[F:5][C:6]1[C:13]([F:14])=[C:12]([F:15])[C:11]([F:16])=[C:10]([F:17])[C:7]=1[CH2:8][Br:2]
Reactant: OCc1c(F)c(F)c(F)c(F)c1F
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Fc1c(F)c(F)c(CBr)c(F)c1F
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A mixture of phosphorus tribromide (2.1 g) and toluene (1 cm3) was added dropwise to a solution of 2,3,4,5,6-pentafluorobenzylalcohol (3.4 g) and pyridine (0.21 g) in toluene (10 cm3) at 0° C. The reaction mixture was stirred at 0° C. for 45 minutes, then at the ambient temperature (ca. 20° C.) for 75 minutes, and was then added to an excess of saturated sodium bicarbonate solution. The products were extracted into diethyl ether, and the combined ether layers dried and concentrated by evaporation under reduced pressure. The residual solution (still containing toluene) was passed through a plug of silica gel.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23](I)[CH2:24][CH3:25]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([CH2:23][CH2:24][CH3:25])=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1cc(-c2ccccc2)on1
Reactant: CCCI
Product: CCCc1c(OCCNC(=O)OC(C)(C)C)noc1-c1ccccc1
Yield: 65 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-phenylisoxazole (0.3 g) and propyl iodide (0.29 ml) were subjected to reaction and post-treatment in a similar manner to that described in Example 14(a) to obtain the title compound (0.22 g, 65%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[NH:17][C:16](=[O:18])[NH:15][C:11]3=[N:12][C:13]=2[CH3:14])=[CH:4][CH:3]=1.[CH:19](O)=O>>[CH3:19][NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[NH:17][C:16](=[O:18])[NH:15][C:11]3=[N:12][C:13]=2[CH3:14])=[CH:4][CH:3]=1
Reactant: Cc1nc2[nH]c(=O)[nH]c2cc1-c1ccc(N)cc1
Reactant: O=CO
Product: CNc1ccc(-c2cc3[nH]c(=O)[nH]c3nc2C)cc1

Procedure:
It is contemplated that 6-(4-aminophenyl)-1,3-dihydro-5-methyl-2H-imidazo[4,5-b]pyridin-2-one can be alkylated by reacting it with formic acid followed by reduction of the intermediate formylamino derivative to obtain 6-[4-(methylamino)phenyl]-1,3-dihydro-5-methyl-2H-imidazo[4,5-b]pyridin-2-one [I; Ar =4-CH3NHC6H4, R1 and R3H, R5 =CH3 ]; or by reacting it with formaldehyde under reducing conditions to obtain 6-[4-(dimethylamino)pheny]-1,3-dihydro-5-methyl-2H-imidazo[4,5-b]pyridin-2-one [I; Ar =4-(CH3)2NC6H4, R1 and R3 =H, R5 =CH3 ].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[Se](=O)=[O:14]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]=[O:14])[CH:6]=[CH:5]2
Reactant: O=[Se]=O
Reactant: Cc1ccc2cc(F)ccc2n1
Product: O=Cc1ccc2cc(F)ccc2n1
Yield: 70 %

Procedure:
The title compound was prepared from 6-fluoro-2-methylquinoline (6e) and selenium dioxide using methods as described in the literature for similar compounds (Barbier et al., 2000) in 70% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([Cl:18])[C:13]([CH3:17])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:26])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([Cl:18])[C:13]([CH2:17][Br:26])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(ccn2C(=O)OC(C)(C)C)c1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1ccc2c(Cl)c(CBr)ccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 32.7 %

Procedure:
To a stirred solution of 314 (38.1 g, 0.143 mol) in CCl4 (300 mL) at 80° C. was added NBS (30.6 g, 0.172 mol) followed by AIBN (1.2 g, 7.31 mmol), and the reaction mixture was stirred at 80° C. overnight. The cooled reaction mixture was diluted with EtOAc, and the organic layer was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (2 to 20% EtOAc) to afford 16.1 g (33%) of tert-butyl-5-(bromomethyl)-4-chloro-1H-indole-1-carboxylate (316) as a white solid: NMR (400 MHz, CDCl3) δ 8.03 (d, J=8.4 Hz, 1H), 7.63 (s, 1H), 7.36 (d, J=8.4 Hz, 1H), 6.71 (d, J=3.8 Hz, 1H), 4.75 (s, 2H), 1.67 (s, 9H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[C:16]1([P:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1C=CC=CC=1>[Br-:1].[C:9]1(=[O:10])[N:5]([CH2:4][CH2:3][CH2:2][P+:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:6](=[O:15])[C:7]2=[CH:14][CH:13]=[CH:12][CH:11]=[C:8]12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Solvent: c1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]

Procedure:
A mixture of 20 mmole of N-(3-bromopropyl)phthalimide and 22 mmole of triphenylphosphine in 50 ml of benzene is heated at reflux temperature for 2 days. The solid which separates on cooling is filtered, washed with benzene and dried under reduced pressure to give 3-phthalimidopropyl triphenylphosphonium bromide. To a solution of 100 ml of dry liquid ammonia is added finely divided sodium (0.46 g or 2 × 10-2M) and a catalytic amount of ferric nitrate. When the blue sodium solution turns gray 10 g or 2 × 10-2M of finely powdered 3-phthalimidopropyltriphenylphosphonium bromide is added. After stirring for 15 minutes the ammonia is evaporated under a stream of nitrogen. To the residue is added 100 ml of anhydrous benzene and the solution is boiled for about 10 minutes under nitrogen. The solid residue is filtered pff and to the filtrate, containing salt free 3-phthalimidopropylidene triphenylphosphorane is added 6.6 g of 5 × 10-2M of ethyl trifluoroacetate. The reaction mixture is heated at reflux temperature under nitrogen for 12 hours. Concentration of the solvent leaves a residue which is distilled under high vacuum to afford 2-ethoxy-1,1,1-trifluoro-5-phthalimidopent-2ene. A solution of 3 g of 2-ethoxy-1,1,1-trifluoro-5-phthalimidopent- 2-ene in 50 ml of ether is treated with a solution of 1 M of sulfuric acid in 50 ml of water. The reaction mixture is stirred for one half hour at 25° C. The ether phase is separated, washed with brine, and dried over magnesium sulfate and concenrated to give trifluoromethyl 3-phthalimidopropyl ketone.
Reaction SMILES: [Na].C(O)C.[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1.[C:15](OCC)(=[O:19])[CH2:16][CH2:17][CH3:18]>>[C:15]([CH:12]([C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=1)[C:13]#[N:14])(=[O:19])[CH2:16][CH2:17][CH3:18]
Reactant: CCCC(=O)OCC
Reactant: N#CCc1ccc(F)cc1
Agent: [Na]
Solvent: CCO
Product: CCCC(=O)C(C#N)c1ccc(F)cc1
Reaction time: 8 h

Procedure:
10.9 g of sodium are added to 150 ml of absolute ethanol. While maintaining reflux, a solution of 49.5 g of 4-fluorophenylacetonitrile in 65.2 g of ethyl butyrate is added. The reaction mixture is refluxed for 4 hours and then left to stand overnight at room temperature. The solvents are concentrated under vacuum and the residue is taken up in water and washed with ether. The aqueous phase is cooled in an ice bath and acidified to pH 5-6 by the addition of concentrated acetic acid to give crystals, which are filtered off, washed with water and dissolved in methylene chloride.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:19][C:18]=3[C:29]([F:32])([F:31])[F:30])(=[O:16])=[O:15])[CH2:11][NH:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].Cl[C:34]1[S:35][C:36]([C:39]([F:42])([F:41])[F:40])=[N:37][N:38]=1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:26])([F:27])[F:28])=[CH:19][C:18]=3[C:29]([F:31])([F:32])[F:30])(=[O:16])=[O:15])[CH2:11][N:10]2[C:34]2[S:35][C:36]([C:39]([F:42])([F:41])[F:40])=[N:37][N:38]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: FC(F)(F)c1nnc(Cl)s1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(OCC(F)(F)F)cc3C(F)(F)F)CN2)CC1
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(OCC(F)(F)F)cc3C(F)(F)F)CN2c2nnc(C(F)(F)F)s2)CC1

Procedure:
In analogy to the procedure described in example 335a, (2S,4R)-4-[4-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (example 211a) was reacted with 2-chloro-5-trifluoromethyl-[1,3,4]thiadiazole (CAS Reg. No. 53645-98-0) in a shaking reactor at 55° C. for 12 h to give the title compound as yellow solid. MS (ESI): m/z=638.1 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1>C(Cl)Cl>[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: C1=COCCC1
Reactant: CCOC(=O)CCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCOC(=O)CCCCCOC1CCCCO1

Procedure:
To a solution of 66 g. of ethyl 6-hydroxyhexanoate in 400 ml. of methylene chloride were added 1 g. of p-toluenesulphonic acid and 45 g. of 2,3-dihydropyran and the mixture was stirred at 25° C. for 20 minutes. The reaction mixture was then washed with an aqueous solution of sodium bicarbonate, dried and concentrated. The residue was distilled in vacuo to obtain 77 g. of the title compound having the following physical characteristics:-
Reaction SMILES: [NH2:1][OH:2].[F:3][C:4]([F:15])([F:14])[O:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9]>CCO>[OH:2][N:1]=[C:8]([C:7]1[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=1[O:5][C:4]([F:3])([F:14])[F:15])[NH2:9]
Reactant: NO
Reactant: N#Cc1ccccc1OC(F)(F)F
Solvent: CCO
Product: NC(=NO)c1ccccc1OC(F)(F)F
Temperature: 60 °C
Reaction time: 10 h
Yield: 93.5 %

Procedure:
Hydroxylamine (Fluka 55458; 50% in water; 4.81 mL; 80.16 mmol; 5 eq.) was added to a solution of 2-(trifluoromethoxy)benzonitrile (Apollo PC7438E; 3 g; 16.03 mmol; 1 eq.) in EtOH (20 mL) and the reaction mixture was stirred at 60° C. for 10 hours. Evaporation in vacuo gave a white solid, which was further dried under high vacuum to afford the title compound (3.30 g, 94%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH:8]([C:15]([OH:17])=[O:16])[CH2:7][CH2:6][C:5]2=1.Cl.[CH2:19](O)[CH3:20]>>[CH2:19]([O:16][C:15]([CH:8]1[CH2:7][CH2:6][C:5]2[C:4]3[C:12](=[CH:13][CH:14]=[C:2]([CH3:1])[CH:3]=3)[NH:11][C:10]=2[CH2:9]1)=[O:17])[CH3:20]
Reactant: CCO
Reactant: Cc1ccc2[nH]c3c(c2c1)CCC(C(=O)O)C3
Agent: Cl
Product: CCOC(=O)C1CCc2c([nH]c3ccc(C)cc23)C1
Reaction time: 48 h

Procedure:
6-Methyl-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid (10 g.) was dissolved in 300 ml. of warm ethanol and 5 ml. of 7N alcoholic hydrogen chloride was added. The solution was thoroughly mixed and allowed to remain at room temperature for 2 days. After cooling in an ice bath for 5 hours, the mixture was filtered and washed with several volumes of ethanol. Upon drying, a yield of 7.3 g. of 6-methyl-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid ethyl ester, m.p. 117°-118° , was obtained.
Reaction SMILES: [H-].[Na+].[CH:3]1([NH:6][C:7]2[C:12]3=[N:13][CH:14]=[C:15]([C:16]#[N:17])[N:11]3[N:10]=[C:9]([S:18][CH3:19])[N:8]=2)[CH2:5][CH2:4]1.Cl[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>CN(C=O)C>[CH:3]1([N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:7]2[C:12]3=[N:13][CH:14]=[C:15]([C:16]#[N:17])[N:11]3[N:10]=[C:9]([S:18][CH3:19])[N:8]=2)[CH2:4][CH2:5]1
Reactant: CSc1nc(NC2CC2)c2ncc(C#N)n2n1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2nc(SC)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
(I2C): Sodium hydride (60% in mineral oil, 0.890 g, 22.02 mmol) was added to a solution of 4-(cyclopropylamino)-2-(methylthio)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (3.39 g, 13.76 mmol) in DMF (110 mL) at room temperature and the resulting mixture was stirred for 30 min. 1-(chloromethyl)-4-methoxybenzene (3.05 mL, 22.02 mmol) was added and the reaction mixture was heated at 80° C. for 2 h. The reaction solution was quenched with ethyl acetate/sodium bicarbonate saturated solution. The organic phase was separated, washed with 10% lithium chloride solution, dried and concentrated. The crude product was purified by flash chromatography on silica gel using an automated ISCO system (220 g column, eluting with 5-20% ethyl acetate/hexanes). 4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylthio)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (4.59 g) was obtained as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:4]([N:9]2[CH2:15][CH2:14][C:13]3[C:16](O)=[N:17][CH:18]=[N:19][C:12]=3[CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.O=P(Cl)(Cl)[Cl:25]>CC#N.CCOC(C)=O>[Cl:25][C:16]1[C:13]2[CH2:14][CH2:15][N:9]([C:4]3[C:3]([C:2]([F:22])([F:21])[F:1])=[CH:8][CH:7]=[CH:6][N:5]=3)[CH2:10][CH2:11][C:12]=2[N:19]=[CH:18][N:17]=1
Reactant: Oc1ncnc2c1CCN(c1ncccc1C(F)(F)F)CC2
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cccnc1N1CCc2ncnc(Cl)c2CC1
Temperature: 90 °C
Yield: 33 %

Procedure:
To a solution of 7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ol (185 mg, 0.60 mmol) in CH3CN (2 mL) was added POCl3 (0.11 mL, 1.19 mmol). The reaction mixture was heated at 90° C. for 2 h. The mixture was cooled to rt, diluted with EtOAc, and quenched slowly with saturated (satd.) aq. NaHCO3. The combined organic layers were dried (Na2SO4) and concentrated. The crude residue was purified (FCC) to give the title compound (65 mg, 33%).