Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([N:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH:15]=O)=[C:9]1[C:17](Cl)=[CH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH:5]=[CH:6][CH3:7]>C(O)C>[CH2:4]([N:8]1[C:9]2=[C:17]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:2]=[N:3][CH:15]=[C:10]2[C:11]([CH3:14])=[C:12]1[CH3:13])[CH:5]=[CH:6][CH3:7]
Reactant: NN
Reactant: CC=CCn1c(C)c(C)c(C=O)c1C(Cl)=CCc1ccc(F)cc1
Solvent: O
Solvent: CCO
Product: CC=CCn1c(C)c(C)c2cnnc(CCc3ccc(F)cc3)c21
Temperature: 75 °C
Yield: 62.9 %

Procedure:
0.10 g (0.0020 mole) of hydrazine hydrate was added to a solution of 0.39 g (0.00113 mole) of 1-(2-butenyl)-2-[1-chloro-3-(4-fluorophenyl)-1-propenyl]-3-formyl-4,5-dimethylpyrrole in 7 ml of ethanol and the resulting mixture was stirred at 75° C. for an hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the concentrate was diluted with ice-water. The aqueous mixture was extracted twice with 30 ml of ethyl acetate. The combined extracts were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography through silica gel using a 50:1 mixture of chloroform and methanol as an eluent to give 0.23 g of the title compound (cis/trans=22/78) as white powdery crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([CH2:17]Cl)=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[NH3:25]>O1CCCC1.C(O)C>[NH2:25][CH2:17][C:6]1[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:8](=[O:12])[C:9]2[C:4]([C:5]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2
Reactant: N
Reactant: CC(C)Cn1c(CCl)c(-c2ccccc2)c2cc(Br)ccc2c1=O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)Cn1c(CN)c(-c2ccccc2)c2cc(Br)ccc2c1=O
Temperature: 140 °C
Reaction time: 5 h
Yield: 53 %

Procedure:
A solution of 6-bromo-3-chloromethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone (10 g, 24.7 mmol) in tetrahydrofuran (20 mL) and a solution of 2M ammonia in ethanol (200 mL) were sealed in a stainless tube and stirred at 140° C. for 5 h. The reaction mixture was cooled and concentrated. The residue was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from diethyl ether and the precipitated crystals were collected by filtration to give 3-aminomethyl-6-bromo-2-isobutyl-4-phenyl-1(2H)-isoquinolinone (5.6 g, 53%) as crystals.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][C:19]([O:21]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:25][NH2:26]>C(O)C>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][C:19]([NH:25][NH2:26])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CSc1nc2ccccc2n1Cc1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)CSc1nc2ccccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of ethyl 2-(1-benzyl-1H-benzo[d]imidazol-2-ylthio)acetate 4b (200 mg, 0.61 mmol, 1.0 eq.) in ethanol (5 mL), was added hydrazine monohydrate (61 mg, 1.23 mmol, 2.0 eq.), and the reaction mixture was heated to reflux and stirred at that temperature for 16 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The mixture was dissolved in ethyl acetate (20 mL) and washed with water (20 mL) and brine (20 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo giving 4c as a pale yellow solid which was used without further purification (200 mg, 100%).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([NH2:7])[O:4][N:3]=1.[C:8]1([CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](Cl)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH3:1][C:2]1[N:6]=[C:5]([NH:7][C:15](=[O:16])[CH:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:4][N:3]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: Cc1noc(N)n1
Product: Cc1noc(NC(=O)C(c2ccccc2)c2ccccc2)n1

Procedure:
The title compound, white solid, m.p. 215° C. and MS: m/e=293 (M+) was prepared in accordance with the general method of example 44a from 3-methyl-[1,2,4]oxadiazol-5-ylamine (Helv. Chim. Acta, 49(1966), 1430-1432) and 2,2-diphenylacetic acid chloride.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=O)[CH3:2].[NH2:13][C:14]1[C:15]([C:22]([NH2:24])=[O:23])=[N:16][CH:17]=[CH:18][C:19]=1[C:20]#[N:21]>>[C:20]([C:19]1[CH:18]=[CH:17][N:16]=[C:15]([C:22]([NH2:24])=[O:23])[C:14]=1[NH:13][CH2:6][C:5]1[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=1[O:3][CH2:1][CH3:2])#[N:21]
Reactant: N#Cc1ccnc(C(N)=O)c1N
Reactant: CCOc1ccccc1C(=O)Cl
Product: CCOc1ccccc1CNc1c(C#N)ccnc1C(N)=O

Procedure:
The title compound was prepared from 2-ethoxybenzoyl chloride and 3-amino-4-cyanopyridine-2-carboxamide (Preparation 12), following the procedure of Preparation 7, and was obtained as a colourless solid. (6.2%), m.p. 150°-152° C. Found: C,61.99; H,4.62; N,17.84. C16H14N4O3 requires C,61.93; H,4.55; N,18.06%.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23](O)=[O:24])[CH:18]=2)[CH2:13][CH2:12]1.[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH2:31][CH:30]2[CH3:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([C:23]([C:19]1[N:20]=[CH:21][N:22]=[C:17]([N:14]3[CH2:13][CH2:12][CH:11]([N:3]4[C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[NH:10][C:2]4=[O:1])[CH2:16][CH2:15]3)[CH:18]=1)=[O:24])[CH2:31][CH:30]2[CH3:36]
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Reactant: CC1CNc2ccc(F)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC1CN(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)c2ccc(F)cc21

Procedure:
80 mg (0.24 mmol) 6-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 36 mg (0.24 mmol) 5-fluoro-3-methyl-2,3-dihydro-1H-indole, 70 μL (0.5 mmol) TEA and 90 mg (0.28 mmol) TBTU were stirred in 1.8 mL DMF overnight at RT. The reaction mixture was purified by HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:30]=[C:29]([CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:28]=[CH:27][C:26]=1B1OC(C)(C)C(C)(C)O1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:26]4[CH:27]=[CH:28][C:29]([CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][C:25]=4[F:24])[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Reactant: CC1(C)OB(c2ccc(CS(C)(=O)=O)cc2F)OC1(C)C
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(CS(C)(=O)=O)cc4F)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 2-(2-fluoro-4-methanesulfonylmethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane following a procedure analogous to that described for Intermediate 10. LC (method 1): tR=1.61 min; Mass spectrum (ESI+): m/z=491 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[C:5]([O:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH:4]=1)#[N:2].Cl.[NH2:24][OH:25].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[O:14][C:5]1[CH:4]=[C:3]([CH:13]=[CH:12][C:6]=1[NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:1](=[N:24][OH:25])[NH2:2]
Reactant: NO
Reactant: CS(=O)(=O)Nc1ccc(C#N)cc1Oc1ccc(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)Nc1ccc(C(N)=NO)cc1Oc1ccc(F)cc1F
Yield: 60.5 %

Procedure:
A mixture of 4'-cyano-2'-(2,4-difluorophenoxy)methanesulfonanilide (1.5 g), hydroxylamine hydrochloride (0.8 g), and sodium carbonate (1.2 g) in ethanol (21 ml) and water (32 ml) was refluxed for 13 hours. The mixture was concentrated and the residue was dissolved in water, acidified with diluted hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was purified by column chromatography on silica gel (40 g) eluting with a mixture of toluene and ethyl acetate (1:1) to give colorless crystals of 3-(2,4-difluorophenoxy)-4-(methanesulfonamido)benzamidoxime (1.0 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N+:9]=2[O-])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:18])=O>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][Cl:18])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc(-c2cccc(C)[n+]2[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2cccc(CCl)n2)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 2-(4-methylphenyl)-6-methylpyridine-N-oxide (2.8 g) in 1.0 ml of chloroform was added simultaneously phosphorus oxychloride (1.48 ml) in 10 ml of chloroform and triethylamine (2.22 ml) in 10 ml of chloroform, over a period of 15 minutes. An exothermic reaction took place initially, and then the mixture was refluxed for a further 30 minutes. The mixture was then cooled, washed with ice-water, the solvent evaporated under reduced pressure, and the residue flash-chromatographed on silica gel, eluting with 33% methylene chloride in heptane, to yield 1 g of 2-(4- methylphenyl)-6-chloromethylpyridine, m.p. 94° C.
Reaction SMILES: [S:1]1[C:5]([CH2:6]O)=[CH:4][C:3]2[CH:8]=[C:9]3[C:14](=[CH:15][C:2]1=2)[CH:13]=[CH:12][CH:11]=[CH:10]3.C(OCC)C.P(Br)(Br)[Br:22]>CO>[Br:22][CH2:6][C:5]1[S:1][C:2]2[CH:15]=[C:14]3[C:9](=[CH:8][C:3]=2[CH:4]=1)[CH:10]=[CH:11][CH:12]=[CH:13]3
Reactant: OCc1cc2cc3ccccc3cc2s1
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: CO
Product: BrCc1cc2cc3ccccc3cc2s1
Temperature: 0 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
Naptho[2,3-b]thiophene-2-methanol (12, 2.71 g, 12.6 mmol., 1.00 equiv.) and diethyl ether (76 mL) were added to a 280 mL Schlenk flask and the mixture was cooled to 0° C. Phosphorus tribromide was added (0.89 mL, 9.5 mmol., 0.75 equiv.) and the mixture was left to warm slowly to room temperature while stirring for 16 hours. The mixture was diluted with methanol (300 mL) and the solids were collected by filtration and washed with methanol (50 mL), giving a beige solid (2.98 g, 85% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.27 (s, 1H), 8.23 (s, 1H), 7.97-7.86 (m, 2H), 7.52-7.43 (m, 2H), 7.41 (s, 1H), 4.81 (s, 2H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH:30]([NH2:32])[CH3:31])=[CH:29][C:24]=2[O:23][CH2:22]1>C(#N)C.C(N(CC)C(C)C)(C)C>[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH:30]([NH:32][C:2]3[C:3]4[CH2:11][N:10]([C:12]5[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=5[C:14]#[N:15])[CH2:9][CH2:8][C:4]=4[N:5]=[CH:6][N:7]=3)[CH3:31])=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: CC(N)c1ccc2c(c1)OCO2
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCc3ncnc(NC(C)c4ccc5c(c4)OCO5)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (100 mg, 0.35 mmol) and 1-(benzo[d][1,3]dioxol-5-yl)ethanamine (150 mg, 0.91 mmol) in acetonitrile (1 mL) and N,N-diisopropylethylamine (400 μL) was subjected to microwave irradiation at 185° C. for 3 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC (100×20.2 mm, C18 column; 30-60% acetonitrile-water [10 mM Et2NH]) to afford a light yellow solid.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([P:19](=[O:32])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl.CCCCCC>C(Cl)Cl>[Br:8][C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:11]([O:10][CH3:9])=[CH:12][C:13]=1[P:19](=[O:32])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(OC)cc(P(=O)(c2ccccc2)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1cc(OC)c(Br)c(P(=O)(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
NBS (6.7 g, 37.6 mmol) was added to a solution of (3,5-dimethoxyphenyl)diphenylphosphine oxide (12.3 g, 36.4 mmol) in CH2Cl2 (140 ml) at 0° C. The resulting suspension was stirred at 0° C. for 1 h. Na2CO3 (saturated, 40 ml) was added to quench the reactions. It was stirred at RT for 30 min, the organic layer was separated and the aqueous layer was extracted with CH2Cl2 (40 ml×2). The combined organic layer washed with brine and dried over MgSO4. It was filtered and the solvent was removed to give the crude product as a pale yellow solid (14.3 g, 94% yield). It was sufficiently pure for the next step. The pure sample was obtained by crystallization from CH2Cl2/Hexane (1/15). 1H NMR (300 MHz, CD2Cl2) δ: 7.73-7.67 (m, 4H), 7.62-7.56 (m, 2H), 7.53-7.46 (m, 4H), 6.69 (d, J=3 Hz, 1H), 6.57 (dd, J1=3 Hz, J2=14.1 Hz, 1H), 3.89 (s, 3H), 3.68 (s, 3H). 31P NMR (121.5 MHz, CD2Cl2) δ: 30.72.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[C:13]([C:15](=[C:20]1[CH2:29][C:24]2([CH2:28][CH2:27][CH2:26][CH2:25]2)[O:23][CH2:22][CH2:21]1)[C:16]([O:18][CH3:19])=[O:17])#[N:14]>C1COCC1.[Cu](I)I>[C:13]([CH:15]([C:20]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:29][C:24]2([CH2:25][CH2:26][CH2:27][CH2:28]2)[O:23][CH2:22][CH2:21]1)[C:16]([O:18][CH3:19])=[O:17])#[N:14]
Reactant: Brc1ccccn1
Reactant: COC(=O)C(C#N)=C1CCOC2(CCCC2)C1
Agent: I[Cu]I
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COC(=O)C(C#N)C1(c2ccccn2)CCOC2(CCCC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
A solution of 2-bromopyridine (14.4 ml, 150 mmo) in THF (75 ml) was added dropwise to a solution of isopropylmagnesium chloride (75 ml, 2M in THF) at 0° C. under N2, the mixture was then stirred at rt for 3 h, copper Iodide (2.59 g, 13.6 mmol) was added and allowed to stir at rt for another 30 min before a solution of a mixture of E and Z isomers of methyl 2-cyano-2-[6-oxaspiro[4.5]decan-9-ylidene]acetate (16 g, 150 mmol) in THF (60 ml) was added in 30 min. The mixture was then stirred at rt for 18 h. The reaction mixture was poured into a 200 g ice/2 N HCl (100 ml) mixture. The product was extracted with Et2O (3×300 ml), washed with brine (200 ml), dried (Na2SO4) and concentrated. The residual was purified by flash chromatography (100 g silica gel column, eluted by EtOAc in hexane: 3% 2CV; 3-25%, 12 CV; 25-40% 6CV gave methyl 2-cyano-2-[9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetate (15.44 g, 72% yield, m/z 315.0 [M+H]+ observed) as an amber oil.
Reaction SMILES: CN.[CH2:3]([N:5](CC)CC)C.Cl.[F:11][C:12]([F:46])([F:45])[C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[N:16]=[C:15]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([C:35]3[CH:36]=[C:37]([S:41](Cl)(=[O:43])=[O:42])[CH:38]=[CH:39][CH:40]=3)[CH:30]=2)[N:14]=1>C1COCC1>[CH3:3][NH:5][S:41]([C:37]1[CH:38]=[CH:39][CH:40]=[C:35]([C:31]2[CH:30]=[C:29]([C:15]3[N:14]=[C:13]([C:12]([F:46])([F:45])[F:11])[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)[N:16]=3)[CH:34]=[CH:33][N:32]=2)[CH:36]=1)(=[O:43])=[O:42]
Reactant: CCN(CC)CC
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 0 °C
Yield: 85.4 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of methylamine solution (2M in THF) (1.5 ml, 3.0 mmol), triethylamine (0.29 ml, 2.1 mmol) and THF (4 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example 1.1) (0.58 g, 1.0 mmol) in THF (6 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH/hexane) yielded the title compound as a white solid (0.46 g, 92%). MS (ISP) 538.8 [(M+H)+]; mp 174° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH:7]([CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:6]2.[C-:25]#[N:26].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH:7]([CH2:13][C:25]#[N:26])[CH2:6]2
Reactant: COc1ccc2c(c1)CC(COS(=O)(=O)c1ccc(C)cc1)CO2
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CC(CC#N)CO2

Procedure:
1.6 g (4.56 mmol) of the tosylate obtained in Step B are dissolved in 25 ml of anhydrous N,N-dimethylformamide; 0.724 g (11.5 mmol) of potassium cyanide is then added to the solution. After 4 hours of reflux under argon, the solvent is evaporated in vacuo; the residue is then taken up in a saturated solution of sodium hydrogen carbonate. The aqueous phase is then extracted with dichloromethane. The organic phases, dried over magnesium sulphate and then filtered, are concentrated under reduced pressure. The title nitrile is obtained pure in the form of an oil which crystallises slowly after chromatography on silica gel (eluant: AcOEt/PE: 25/75).
Reaction SMILES: O=[C:2]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH2:3][C:4]#[N:5].[CH2:12]([O:14][CH:15]([O:19][CH2:20][CH3:21])[CH2:16][NH:17][NH2:18])[CH3:13].Cl>C(O)C.C(OCC)(=O)C>[CH2:12]([O:14][CH:15]([O:19][CH2:20][CH3:21])[CH2:16][N:17]1[C:4]([NH2:5])=[CH:3][C:2]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)=[N:18]1)[CH3:13]
Reactant: CCOC(CNN)OCC
Reactant: N#CCC(=O)c1cccnc1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(Cn1nc(-c2cccnc2)cc1N)OCC

Procedure:
With gentle heating, 125 g (812 mmol, purity 95%) of 3-oxo-3-(pyridin-3-yl)propionitrile [lit. for example: P. Seneci et al., Synth. Commun. 1999, 29 (2), 311-341; also available commercially] were dissolved in 1.25 liters of ethanol. 126 g (853 mmol) of (2,2-diethoxyethyl)hydrazine and 4.1 ml (4.06 mmol) of 1 M hydrochloric acid were then added. The reaction mixture was heated under reflux for 4 h, and all volatile components were then substantially removed on a rotary evaporator. The residue obtained was taken up in ethyl acetate, and the solution was washed with water and dried over anhydrous magnesium sulphate. After filtration, the mixture was evaporated to dryness. The residue that remained was triturated with diisopropyl ether at RT. The resulting solid was then filtered off with suction and dried under high vacuum. This gave 153 g (65% of theory, purity 96%) of the title compound.
Reaction SMILES: C1(C2N(S[CH2:13][N:14]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]=4[CH2:26][CH3:27])[S:15]3(=[O:17])=[O:16])N=NN=2)C=CC=CC=1.[Na].[C:29]1([N:35]2[C:39]([SH:40])=[N:38][N:37]=[N:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CN(C)C=O>[C:29]1([N:35]2[C:39](=[S:40])[N:38]([CH2:13][N:14]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]=4[CH2:26][CH3:27])[S:15]3(=[O:16])=[O:17])[N:37]=[N:36]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Sc1nnnn1-c1ccccc1
Reactant: CCc1cccc2c1C(=O)N(CSn1nnnc1-c1ccccc1)S2(=O)=O
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cccc2c1C(=O)N(Cn1nnn(-c3ccccc3)c1=S)S2(=O)=O
Yield: 60 %

Procedure:
A solution of 2-(5-phenyl-1-tetrazolyl)thiomethyl-4-ethylsaccharin (Example 30AE, 0.020 g) and 1-phenyltetrazol-5-thiol sodium salt (0.0026 g) in dimethylformamide (1 mL) was heated at 100° C. for three days, then poured into water. Recrystallization of the resulting solid from ethanol-water afforded 2-(4-phenyl-5-thioxo-1-tetrazolyl)methyl-4-ethylsaccharin, 0.012 g, 60% yield, mp 127°-129° C.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Br:6][C:7]1[C:12]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:11][CH:10]=[CH:9][N:8]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[Br:6][C:7]1[C:12]([O:13][CH2:14][C:15]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:17])=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: O=C(O)COc1cccnc1Br
Reactant: CCNCC
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)COc1cccnc1Br
Yield: 87.7 %

Procedure:
Diethylamine (0.874 g) was slowly added with cooling to [(2-bromo-3-pyridinyl)oxy]acetic acid (2.58 g) in toluene (10 ml). The solution was then dded to phosphorous pentoxide (1.87 g) and diethylamine (1.74 g) in toluene (10 ml). After the addition the mixture was heated under reflux overnight. The dark solution was diluted with water (20 ml), made alkaline with 8% sodium bicarbonate (20 ml) and extracted with ethyl acetate (3×30 ml). The combined organic extracts were dried and the solvent was evaporated in vacuo to give the title compound as a brown oil (2.8 g). t.l.c. (toluene-ethanol-0.88 ammonia 80:20:1) Rf 0.47.
Reaction SMILES: [CH3:1][CH:2]([C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH2:9])[CH2:3][CH2:4][CH2:5][CH2:6][OH:7].P(=O)(O)(O)O>>[CH3:1][C:2]1([CH:8]2[CH2:10][CH2:11][CH2:12][C:13]([CH3:14])([CH3:15])[CH2:9]2)[CH2:3][CH2:4][CH2:5][CH2:6][O:7]1
Reactant: C=C(CCC=C(C)C)C(C)CCCCO
Agent: O=P(O)(O)O
Product: CC1(C)CCCC(C2(C)CCCCO2)C1

Procedure:
The procedure of Example I was applied to a sample of 5-methyl-6-(4-methyl-3-pentenyl)-6-hepten-1-ol. This was stirred with 85 percent phosphoric acid for one hour at room temperature, and the ether-soluble, water-insoluble reaction product was chromatographed on alumina. A relatively non-polar material was eluted from the column immediately (polar materials such as alcohols remained on the column). The eluted product was identified by means of NMR and IR as 2-methyl-2-(3', 3'-dimethylcyclohexyl)-tetrahydropyran.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:12]=[C:13]2[C:18](Cl)=[C:17]([C:20]([NH2:22])=[O:21])[CH:16]=[N:15][N:14]2[CH:23]=1.Cl.[NH2:25][C@@H:26]([C@H:28]([C:31]1[O:32][CH:33]=[C:34]([C:36]([NH2:38])=[O:37])[N:35]=1)[CH2:29][CH3:30])[CH3:27]>CN(C=O)C>[Br:10][C:11]1[CH:12]=[C:13]2[C:18]([NH:25][C@@H:26]([C@H:28]([C:31]3[O:32][CH:33]=[C:34]([C:36]([NH2:38])=[O:37])[N:35]=3)[CH2:29][CH3:30])[CH3:27])=[C:17]([C:20](=[O:21])[NH2:22])[CH:16]=[N:15][N:14]2[CH:23]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: CC[C@@H](c1nc(C(N)=O)co1)[C@@H](C)N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@@H](c1nc(C(N)=O)co1)[C@@H](C)Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 90 °C
Yield: 93.7 %

Procedure:
DIPEA (1.08 ml, 6.21 mmol) was added in one portion to a solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (568 mg, 2.07 mmol) and 2-((2R,3R)-2-aminopentan-3-yl)oxazole-4-carboxamide hydrochloride (532 mg, 2.28 mmol) in DMF (6.9 ml). The reaction was heated to 90° C. overnight before evaporating in vacuo and treating the residue with water to precipitate 2-((2R,3R)-2-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)pentan-3-yl)oxazole-4-carboxamide (843 mg, 1.94 mmol, 94% yield) which was used immediately in the next reaction. 1H NMR (400 MHz, CCl3D) δ 8.00 (s, 1H), 7.81 (s, 1H), 7.34 (d, J=1.5 Hz, 1H), 6.76 (d, J=1.5 Hz, 1H), 4.51-4.37 (m, 1H), 2.90 (dt, J=9.6, 4.9 Hz, 1H), 1.78-1.53 (m, 2H), 1.08 (d, J=6.4 Hz, 3H), 0.65 (t, J=7.4 Hz, 3H). LC/MS: M+H+337.08, ret. time=0.84 min. Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 mL/min.