Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[N:4][C:3]=1Cl.O.[NH2:12][NH2:13]>O1CCOCC1.C(O)C>[Cl:1][C:2]1[C:3]([NH:12][NH2:13])=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=1
Reactant: NN
Reactant: Clc1nc(Cl)c(Cl)nc1Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CCO
Product: NNc1nc(Cl)c(Cl)nc1Cl
Temperature: 23 °C
Reaction time: 0.33 h

Procedure:
A solution was prepared by dissolving 21.8 grams of tetrachloropyrazine in 100 milliliters of dioxane. The solution was diluted with 250 milliliters of ethanol and 15 milliliters of hydrazine hydrate was slowly added thereto. The temperature rose from 23°C to 37°C. The solution was held, with stirring, at 23°C for 20 minutes and the 3,5,6-trichloro-2-hydrazinopyrazine product was isolated by pouring the reaction mixture in water and filtering off the solid product. The product melted at 167°-168°C and was recovered in a yield of 20.2 grams (94 percent of theoretical).
Reaction SMILES: [OH:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([OH:13])=[O:12].S(Cl)(Cl)=O.[CH3:18]O>>[OH:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([O:13][CH3:18])=[O:12]
Reactant: O=C(O)c1cc2ccccc2n1O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc2ccccc2n1O
Yield: 59.5 %

Procedure:
The reaction was carried out in a manner similar to Reference Example 6 except for using 3.99 g (22.5 mmol) of 1-hydroxy-2-indolecarboxylic acid, 5.36 g (45.0 mmol) of thionyl chloride and 100 ml of methanol. Thus 2.56 g (59.5%) of methyl 1-hydroxy-2-indolecarboxylate was obtained.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([CH:13]1[CH:18]2[CH2:19][N:15]([CH2:16][C:17]2([O:22][CH3:23])[O:20][CH3:21])[CH2:14]1)([O:11][CH3:12])=[O:10].I[C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1.O>C1COCC1.ClCCl>[N:26]1[CH:27]=[CH:28][N:29]=[CH:30][C:25]=1[C:13]1([C:9]([O:11][CH3:12])=[O:10])[CH:18]2[CH2:19][N:15]([CH2:16][C:17]2([O:20][CH3:21])[O:22][CH3:23])[CH2:14]1
Reactant: COC(=O)C1CN2CC1C(OC)(OC)C2
Reactant: Ic1cnccn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1(c2cnccn2)CN2CC1C(OC)(OC)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.3 %

Procedure:
Lithium diisopropylamide (3.7 ml of a 1.5M solution in THF, 5.58 mmol) was added dropwise to a solution of 3-carbomethoxy-5,5-dimethoxy-1-azabicyclo[2.2.1]heptane (1 g, 4.7 mmol) in THF (40 ml), at -78° C., and stirred for 2 h. A solution of 2-iodopyrazine (1.15 g, 5.58 mmol) in THF (5 ml) was added, at -78° C., stirred for 1 h, and then warmed to room temperature and stirred for 16 h. Water (25 ml) and dichloromethane (70 ml) were added and the aqueous extracted with dichloromethane (3×100 ml). The combined extracts were dried (Na2SO4), evaporated, and the crude product chromatographed through silica-gel using dichloromethane/methanol (92:8) as eluant to give the title compound as a yellow liquid (0.1 g); (Found: M+ =293.1378; C14H19N3O4 requires M+ =293.1376); m/e 293 (M+); δ (360 MHz, CDCl3) 2.34 (1H, d, J=16 Hz, CH of CH2N); 2.82 (1H, s, CH-bridgehead); 3.05 (1H, dd, J=4.3 and 14.6 Hz, CH of CH2 --N); 3.18 (3H, s, OMe); 3.20 (1H, dd, J=3.3 and 8.5 Hz, CH of CH2 --N); 3.28 (1H, d, J=12.7 Hz, CH of CH2 --N); 3.34 (3H, s, OMe); 3.59 (3H, s, CO2Me); 3.67 (1H, d, J=10.8 Hz, CH of CH2 --N); 3.91 (1H, dd, J=3 and 12.7 Hz, CH of CH2 --N); 8.45 (1H, d, J=3.7 Hz, pyrazine-H); 8.51 (1H, dd, J=2.5 and 3.7 Hz, pyrazine-H); 8.58 (1H, d, J=2.5 Hz, pyrazine-H).
Reaction SMILES: CC1C(=CC(=CC=1)N=C=O)N=[C:5]=[O:6].[CH:14]1[C:27]2NC3C(=CC=CC=3)SC=2C=C[CH:15]=1.[C:28]([O:32]CCO)(=O)[CH:29]=[CH2:30]>>[CH2:5]([OH:6])[CH2:30][CH2:29][CH2:28][OH:32].[CH2:15]([OH:6])[CH2:14][CH2:27][CH2:30][CH2:29][CH2:28][OH:32]
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Reactant: C=CC(=O)OCCO
Product: OCCCCCCO
Product: OCCCCO
Reaction time: 3 h

Procedure:
87 grams (0.5 mol) of toluene diisocyanate and 0.027 g of phenothiazine are placed in a 500 cm3 reactor under a nitrogen atmosphere. The temperature is kept at between 48° and 50° C. and 58 g, that is to say 0.5 mol, of freshly distilled hydroxyethyl acrylate are added in the course of two hours. When the introduction is complete, the mixture is stirred for a further 3 hours at the same temperature and 223 g, that is to say 0.25 mol, of an aliphatic polycarbonate-diol are then added, the latter having a molecular weight of 890 and being obtained by the phosgenation of a mixture of butane-1,4-diol and hexane-1,6-diol in proportions which are such that the resulting polycarbonate is equivalent to a mixture of 50% by weight of a polycarbonate obtained from hexane-1,6-diol by itself and 50% by weight of a polycarbonate obtained from butane-1,4-diol by itself. The reaction is allowed to proceed for 3 hours at 50° C. A few drops of methanol are added in order to neutralise any free isocyanate groups which could have remained.
Reaction SMILES: [CH2:1]([S:3]SCC)[CH3:2].[C:7]1([CH3:16])[CH:12]=[CH:11][C:10]([S:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.[Na+].II>>[C:7]1([CH3:16])[CH:12]=[CH:11][C:10]([S:13](=[O:15])([S:3][CH2:1][CH3:2])=[O:14])=[CH:9][CH:8]=1
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: CCSSCC
Agent: II
Agent: [Na+]
Product: CCSS(=O)(=O)c1ccc(C)cc1
Yield: 100 %

Procedure:
The reaction was carried out using 0.60 mL (4.87 mmoL) of diethyl disulfide, 2.78 g (15.6 mmoL) of sodium p-toluenesulfinate, 2.47 g (9.74 mmoL) of iodine in accordance with the method of Reference Example 3, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to obtain 2.11 g of the heading compound as a colorless oily substance (yield 100%).
Reaction SMILES: Cl[C:2]1[C:3]([C:12]([O:14]CC)=[O:13])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25][CH3:26])[CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl>CN1C(=O)CCC1.O>[F:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:2]2[C:3]([C:12]([OH:14])=[O:13])=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[C:20]([O:25][CH3:26])[CH:19]=1
Reactant: CCOC(=O)c1nc2ccccc2nc1Cl
Reactant: COc1cc(F)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc(F)ccc1Oc1nc2ccccc2nc1C(=O)O
Temperature: 100 °C
Reaction time: 3 h
Yield: 90.2 %

Procedure:
A mixture of ethyl 3-chloroquinoxaline-2-carboxylate (300 mg, 1.27 mmol), 4-fluoro-2-methoxy-phenol (289.0 μL, 2.54 mmol) and Cs2CO3 (826.3 mg, 2.54 mmol) in NMP (3.0 mL) was stirred at 100° C. for 3 hours. The reaction mixture was poured into water, the pH was adjusted to pH 6 with 1N HCl and the mixture was extracted with ethyl acetate (3×). The organics were combined, washed with brine, dried over Na2SO4 and evaporated to dryness. Purification by column chromatography using a gradient of MeOH in dichloromethane (0-10%) gave 3-(4-fluoro-2-methoxy-phenoxy)quinoxaline-2-carboxylic acid (360 mg, 90%) as a red oil. ESI-MS m/z calc. 314.07, found 315.1 (M+1)+; Retention time: 1.35 minutes (3 minutes run).
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])C.O.[OH-].[Li+]>CO.C1COCC1.O>[C:19]([O:18][C:16]([NH:15][CH2:14][C:8]1[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:23])=[O:3])=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CCOC(=O)COc1ccc(Cl)cc1CNC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cc(Cl)ccc1OCC(=O)O

Procedure:
The product from Step D was suspended in 1:1:1 methanol/THF/water (9 ml) and lithium hydroxide hydrate (126 mg, 3.0 mmol) was added. After 16 h the volatiles were removed in vacuo and the solution was diluted with water and was washed with ethyl acetate, adding sufficient brine to disperse the emulsion. The aqueous layer was acidified with 5% KHSO4 solution and was extracted with methylene chloride which was then dried (Na2 SO4) and evaporated in vacuo to give the title compound as a solid:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[N:7].[CH2:8]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)C(C)C)(C)C.[Cl-].[Na+]>CN(C)C=O.O>[CH2:16]([N:15]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[N:7])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: N#CCCCCBr
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCCCN(Cc1ccccc1)Cc1ccccc1
Temperature: 110 °C
Yield: 108.9 %

Procedure:
A solution of 5-bromopentanonitrile (16.20 g) in dry dimethylformamide (100 ml) was added dropwise over 15 minutes to a stirred solution of dibenzylamine (19.73 g) and N,N-diisopropylethylamine (35 ml, 26 g) in dry dimethylformamide (100 ml). The solution was heated (oil bath 110° C.) for 4 hours and was allowed to cool. The solution was poured onto a mixture of saturated aqueous sodium chloride (400 ml) and water (400 ml) and the mixture was extracted with ether (2×200 ml). The extracts were dried (Na2SO4) and concentrated in vacuo to give a mobile oil (30.32 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.[CH2:10](N)[CH2:11][NH2:12].[Cl-].[Na+]>C(Cl)(Cl)Cl.O>[NH:9]1[CH2:10][CH2:11][N:12]=[C:8]1[C:5]1[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: NCCN
Reactant: N#Cc1cnc(N)cn1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Nc1cnc(C2=NCCN2)cn1
Temperature: 120 °C
Yield: 48.1 %

Procedure:
A mixture of 2-amino-5-cyanopyrazine (500.0 mg, 4.163 mmol), ethylenediamine (3.0 mL, 44.88 mmol), and phosphorous pentasulfide (185.1 mg, 0.416 mmol) was placed in a sealed tube and heated at 120° C. for 3 h. At this time, the reaction was poured onto ice. The resulting reaction mixture was diluted with chloroform (50 mL), water (10 mL), and a saturated aqueous sodium chloride solution (20 mL). The layers were separated. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 5-(4,5-dihydro-1H-imidazol-2-yl)-pyrazin-2-ylamine (327.0 mg, 48.1%) as a white solid which was used without further purification.
Reaction SMILES: [CH3:1][CH2:2][C:3]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10](=[O:11])[NH:9][C:7](=[O:8])[NH:6][C:4]1=[O:5].C(N(CC)CC)C.Cl[CH2:26][CH:27]([OH:34])[CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH3:33].S(=O)(=O)(O)O>CN(C)C=O>[CH2:30]([O:29][CH2:28][CH:27]([OH:34])[CH2:26][N:6]1[C:4](=[O:5])[C:3]([CH2:2][CH3:1])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:11])[NH:9][C:7]1=[O:8])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCOCC(O)CCl
Reactant: CCC1(c2ccccc2)C(=O)NC(=O)NC1=O
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCOCC(O)CN1C(=O)NC(=O)C(CC)(c2ccccc2)C1=O
Reaction time: 8 h
Yield: 53.1 %

Procedure:
A solution of phenobarbital (69.6 g, 0.3 mole) in dimethylformamide (60 ml) containing triethylamine (20.2 g, 0.2 mole) was stirred with 1-chloro-3-n-butoxy-2-propanol (33.2 g, 0.2 mole) for 6 hours at 70° C. The reaction mixture was then poured into 3% sulphuric acid (500 ml) and the precipitated product was extracted with toluene (200 ml) at 70° C. The toluene layer was separated, washed with 3% aqueous sulphuric acid (200 ml) and left overnight at 4° C. The precipitated phenobarbital was filtered off and filtrate extracted with 5% aqueous sodium carbonate (5×100 ml). The organic layer was then extracted with 1M aqueous sodium hydroxide (2×200 ml), the aqueous layers collected, washed with toluene (100 ml) and the pH was adjusted to 3 with sulphuric acid. The precipitated product was extracted with toluene (150 ml), the organic layer was separated, dried and evaporated under reduced pressure to give the title compound (38.5 g, 53%); purity by HPLC 96.5% .
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[NH3:10].C(Cl)[Cl:12]>>[Cl:12][CH:3]([CH3:2])[CH2:4][CH2:5][S:6]([NH2:10])(=[O:8])=[O:7]
Reactant: ClCCl
Reactant: O=S(=O)(Cl)CCCCCl
Reactant: N
Product: CC(Cl)CCS(N)(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
To an ice-cooled solution of 4-chloro-1-butanesulfonyl chloride (D20) (43 g, 225 mmol, 1 equiv) in CH2Cl2 (350 ml) was slowly added aqueous ammonia solution (25%, 140 ml). The resulting mixture was stirred at room temperature for 16 h then concentrated in vacuo. The residue was diluted with AcOEt and washed with brine. The organic phase was dried over MgSO4 and concentrated in vacuo to give crude 3-chloro-1-butanesulfonamide (D21b) (31 g, 88%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([Cl:12])=[CH:10][C:9](=[O:13])[N:8]([CH3:14])[CH:7]=1)=[O:5])[CH3:2].C1C(=O)N([Cl:22])C(=O)C1>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:11]([Cl:12])=[C:10]([Cl:22])[C:9](=[O:13])[N:8]([CH3:14])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C)c(=O)cc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(C)c(=O)c(Cl)c1Cl
Reaction time: 1 h
Yield: 94.8 %

Procedure:
A mixture of 4-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester (1.00 g, 4.64 mmol) and NCS (0.68 g, 5.10 mmol) in DMF (30 mL) was stirred for 1 hour. The reaction mixture was diluted with EtOAc and washed with 0.1 N HCl solution. The organic layer was dried (MgSO4) and concentrated under reduced pressure to give 1.10 g (95%) of 4,5-dichloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:29][CH2:30][C:31]([OH:33])=O)[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[N:17]([CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[S:16]1(=[O:28])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.[CH:56]([NH:59][CH3:60])([CH3:58])[CH3:57]>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:29][CH2:30][C:31]([N:59]([CH:56]([CH3:58])[CH3:57])[CH3:60])=[O:33])[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[N:17]([CH2:21][CH2:22][Si:23]([CH3:24])([CH3:26])[CH3:25])[S:16]1(=[O:28])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC(C)C
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CCC(=O)O)cc2OCc2ccccc2)S1(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N(C)C(=O)CCc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid (0.10 g, 0.2 mmol), EDCl (0.38 g, 0.20 mmol) and HOAt (0.027 g, 0.20 mmol) in DMF (1 mL) is added N-isopropyl-N-methylamine (0.15 g, 0.2 mmol). The mixture is stirred at RT for 18 h, then poured into water. The mixture is extracted into EtOAc and the organic phase washed with water (3×) and sat. NaCl (1×). The organic solution is dried over Na2SO4 and the solvent removed under reduced pressure to afford the title compound. This is used directly in the next step.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][NH:6][C:7]1[C:12]([CH2:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:15][CH3:16])C.O.[NH2:19][NH2:20]>C(O)C>[CH2:15]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([CH2:13][CH3:14])[C:7]=1[NH:6][CH2:5][C:4]([NH:19][NH2:20])=[O:3])[CH3:16]
Reactant: NN
Reactant: CCOC(=O)CNc1c(CC)cccc1CC
Solvent: O
Solvent: CCO
Product: CCc1cccc(CC)c1NCC(=O)NN

Procedure:
58.7 g (0.25 mol) of 2,6-diethyl-anilino-acetic acid ethyl ester and 25 g of hydrazine hydrate were left to stand in 200 ml of ethanol for 24 hours. Thereafter, the mixture was concentrated by distilling off the solvent and the residue was extracted by stirring with water. After drying, 50.5 g (91% of theory) of colorless crystals of 2,6-diethyl-anilino-acetic acid hydrazide of melting point 71°-73° C. were obtained.
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:4][CH:3]1[C:5](O)=[O:6].O1CCCC1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:21][C:22]1[N:23]=[C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([CH3:47])=[C:35]([NH:37][C:38]([C:40]4[N:44]([CH3:45])[N:43]=[C:42]([CH3:46])[CH:41]=4)=[O:39])[CH:36]=3)=[N:26][N:25]2[CH:48]=1>CN(C)C=O.CN(C)C(=O)C>[F:1][C:2]1([F:8])[CH2:4][CH:3]1[C:5]([NH:21][C:22]1[N:23]=[C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([CH3:47])=[C:35]([NH:37][C:38]([C:40]4[N:44]([CH3:45])[N:43]=[C:42]([CH3:46])[CH:41]=4)=[O:39])[CH:36]=3)=[N:26][N:25]2[CH:48]=1)=[O:6]
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2C)n(C)n1
Reactant: O=C(O)C1CC1(F)F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5(F)F)cn4n3)ccc2C)n(C)n1
Yield: 72.7 %

Procedure:
In the same manner as in Example 259 and using 2,2-difluorocyclopropanecarboxylic acid (88 mg, 0.60 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (74 μL, 0.86 mmol), N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide hydrochloride (250 mg, 0.60 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (210 mg, 73%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2].Br[CH:19]([CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].C(OC1C=CC(/C=C2/C(=O)N(CCCNC(=O)OC(C)(C)C)C(=O)S/2)=CC=1)C>>[CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[N:11]([CH:19]([CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:25])[CH3:26])[C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC(Br)CNC(=O)OC(C)(C)C
Reactant: CCOc1ccc(/C=C2\SC(=O)NC2=O)cc1
Agent: CCOc1ccc(/C=C2\SC(=O)N(CCCNC(=O)OC(C)(C)C)C2=O)cc1
Product: CCOc1ccc(/C=C2\SC(=O)N(C(CNC(=O)OC(C)(C)C)CNC(=O)OC(C)(C)C)C2=O)cc1
Yield: 23.9 %

Procedure:
The title compound 21e was prepared from compound 2 (292 mg, 1.17 mmol) and di-tert-butyl (2-bromopropane-1,3-diyl)dicarbamate (413 mg, 1.17 mg) in a manner similar to that described for 21a. Yield=23.9%, 130 mg.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:9]2=[O:18])[CH2:4][CH2:3]1.F[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O.CO>[OH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][N:15]([C:20]4[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=4)[CH2:14][CH2:13]3)[C:9]2=[O:18])[CH2:6][CH2:7]1
Reactant: O=C1N([C@H]2CC[C@H](O)CC2)CCC12CCNCC2
Reactant: N#Cc1ccc(F)cc1
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N2CCC3(CC2)CCN([C@H]2CC[C@H](O)CC2)C3=O)cc1

Procedure:
A mixture of 2-(trans-4-hydroxycyclohexyl)-2,8-diazaspiro[4.5]decan-1-one (20 mg, 0.00008 mol), 4-fluorobenzonitrile (12.3 mg, 0.000102 mol) and N,N-diisopropylethylamine (44 μL, 0.00025 mol) in N-methylpyrrolidinone (0.5 mL) was irradiated under microwave at 200° C. for 15 min. The mixture was diluted with methanol (1.3 mL), and purified by Prep-HPLC to give 4-[2-(trans-4-hydroxycyclohexyl)-1-oxo-2,8-diazaspiro[4.5]dec-8-yl]benzonitrile. LCMS: (M+H)+=354.2.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[F:12][C:13]([F:18])([F:17])[CH2:14][CH2:15][OH:16]>>[F:12][C:13]([F:18])([F:17])[CH2:14][CH2:15][O:16][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: OCCC(F)(F)F
Reactant: COC(=O)c1ccc(Cl)nc1
Product: COC(=O)c1ccc(OCCC(F)(F)F)nc1
Yield: 47 %

Procedure:
The title compound is prepared in 47% yield (1.37 g, colorless oil) from methyl 6-chloronicotinate (2.0 g, 11.7 mmol) and 3,3,3-trifluoropropan-1-ol instead of 2,2,2-trifluoroethanol in a similar manner to Step-3 of Amine-9.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([Cl:10])=[N:8][CH:7]=[CH:6][N:5]=1.[OH:11][CH2:12][CH2:13][O:14][C:15]1[C:20]2[N:21]=[C:22]([NH2:24])[O:23][C:19]=2[CH:18]=[CH:17][CH:16]=1>>[Cl:10][C:9]1[C:4]([O:11][CH2:12][CH2:13][O:14][C:15]2[C:20]3[N:21]=[C:22]([NH2:24])[O:23][C:19]=3[CH:18]=[CH:17][CH:16]=2)=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: Nc1nc2c(OCCO)cccc2o1
Reactant: Clc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Product: Nc1nc2c(OCCOc3nccnc3Cl)cccc2o1

Procedure:
The title compound was prepared according to the procedure of Example 4, Step 1, except that 4 equiv of both NaH and 2,3-dichloropyrazine were used, starting from the product of Step 1. The reaction temperature was 90° C. The crude product was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]2[NH:7][C:8]([S:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]3[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][N:18]=3)=[N:9][C:5]=2[CH:4]=1.C(OCC)(=[O:29])C>>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]2[NH:7][C:8]([S:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]3[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][N:18]=3)=[O:29])=[N:9][C:5]=2[CH:4]=1
Reactant: CCOC(C)=O
Reactant: COc1ccnc(-c2ccccc2Sc2nc3cc(OC)ccc3[nH]2)c1
Product: COc1ccnc(-c2ccccc2S(=O)c2nc3cc(OC)ccc3[nH]2)c1

Procedure:
The product of step (c) above (103 mg) was dissolved in ethyl acetate (7.5 ml) and stirred at -10° . A solution of m-chloroperbenoic acid (58 mg of 85%) in ethyl acetate (0.5 ml) was added and the mixture stirred for 50 minutes. The solution was washed with sodium bicarbonate solution, sodium bisulphite solution, water and brine then dried and evaporated. After trituration with ether the solid was dried to afford the title compound. MS (FAB) M+1 at 380.
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.Br[C:9]1[CH:14]=CN=[C:11](C)[CH:10]=1.C([Si](C#CC1N=NN([CH:30]2[CH2:36][CH2:35]C3C=[CH:38][CH:39]=[CH:40][C:33]=3[N:32]([CH2:41][C:42](F)(F)[F:43])[C:31]2=O)C=1)(CC)CC)C>C1(P([Pd](Cl)(Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I.CN(C=O)C>[CH3:14][CH2:9][CH2:10][CH2:11][N+:32]([CH2:31][CH2:30][CH2:36][CH3:35])([CH2:33][CH2:40][CH2:39][CH3:38])[CH2:41][CH2:42][CH2:6][CH3:7].[F-:43]
Reactant: CCN(CC)CC
Reactant: CC[Si](C#Cc1cn(C2CCc3ccccc3N(CC(F)(F)F)C2=O)nn1)(CC)CC
Reactant: Cc1cc(Br)ccn1
Agent: Cl[Pd](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: CCCC[N+](CCCC)(CCCC)CCCC
Product: [F-]
Temperature: 90 °C

Procedure:
Triethyl amine (0.030 ml, 0.213 mmol), 4-bromo-2-methylpyridine (19 mg, 0.111 mmol), bis(triphenylphosphino)palladium dichloride (6 mg, 8.55 μmol), and DMF (2 ml) were added to the 25-mL flask containing the crude 3-(4-Ethynyl-1,2,3-triazol-1-yl)-1-(2,2,2-trifluoro-ethyl)-1,3,4,5-tetrahydro-1-benzazepin-2-one and the resulting brownish solution was degassed for 15 minutes by bubbling nitrogen through. Copper(I) iodide (1 mg, 5.25 μmol) was added and the mixture heated to 90° C. for 14 h. After cooling to room temperature the reaction mixture was passed through a silica gel pipette and the residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.1% TFA, to give the product as a colorless solid with some TBAF contamination. The residue was purified by column chromatography on silica gel (10 g prepacked) eluting with EtOAc/MeOH to give 3-[4-(2-Methyl-pyridin-4-ylethynyl)-1,2,3-triazol-1-yl]-1-(2,2,2-trifluoro-ethyl)-1,3,4,5-tetrahydro-1-benzazepin-2-one (11 mg) as a colorless solid.