Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:14]=[CH:13][N:12]=2)=[CH:6][CH:5]=1)(=O)[CH3:2].[CH:23]([NH2:25])=[O:24].C(O)=O>O>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([CH:1]([NH:25][CH:23]=[O:24])[CH3:2])=[CH:5][CH:6]=3)[N:16]=2)[CH:18]=1
Reactant: CC(=O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Reactant: NC=O
Solvent: O
Solvent: O=CO
Product: CC(NC=O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Reaction time: 8 h

Procedure:
A mixture of 7.25 g of N-(4-acetylphenyl)-4-(3-pyridinyl)-2-pyrimidinamine, 100 ml of formamide and 31 ml, of 98% formic acid was refluxed with stirring overnight. The solvents were then boiled off for 1/2 hour, the reaction cooled and poured into one liter of water. This was extracted with 725 ml of chloroform. The chloroform extract was back washed with 150 ml of water, then dried, filtered and evaporated to a foam. The foam was partitioned between chloroform and water. An equal volume of saturated potassium bicarbonate was added. The organic phase was separated, dried, filtered and evaporated to a foam. This foam was chromatographed on silica gel topped with a thin layer of hydrous magnesium silicate and eluted with chloroform (first four fractions), then with 2% methanol in chloroform (last two fractions). The sixth (final) fraction was evaporated and then crystallized from chloroform-hexane, giving 1.05 g of the desired product as cream colored crystals, mp 118°-121° C.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(CC)CC)C.[CH3:13][C:14]1([CH3:31])[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]2[CH:19]=[C:18]([CH:26]=[CH:27][C:28](Cl)=[O:29])[CH:17]=[CH:16][C:15]1=2.O>C1COCC1>[CH3:5][O:4][N:3]([CH3:2])[C:28](=[O:29])/[CH:27]=[CH:26]/[C:18]1[CH:17]=[CH:16][C:15]2[C:14]([CH3:31])([CH3:13])[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]=2[CH:19]=1
Reactant: CC1(C)CCC(C)(C)c2cc(C=CC(=O)Cl)ccc21
Reactant: CNOC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CON(C)C(=O)/C=C/c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
727 mg (7.45 mmol) of N,O-dimethylhydroxyl-amine hydrochloride, 10 ml of THF and 2.3 ml (16.4 mmol) of triethylamine are introduced into a three-necked flask under a stream of nitrogen. A solution of 2.06 g (7.45 mmol) of 3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acryloyl chloride prepared in Example 1(c) in 20 ml of THF is added dropwise and the mixture is stirred at room temperature for six hours. The reaction medium is poured into water and extracted with ethyl acetate, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (80/20). After evaporating the solvents, 1 g (45%) of (E)-N-methoxy-N-methyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)acrylamide is collected in the form of an oil.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][C:6]=1[C:7]([O:9]CC(F)(F)F)=O.[NH2:27][CH:28]([CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][NH:31]1)[CH3:29]>>[F:26][C:2]([F:1])([F:25])[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:22])[F:23])=[CH:15][C:6]=1[C:7]([NH:27][CH:28]([CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][NH:31]1)[CH3:29])=[O:9]
Reactant: CC(N)C1CCCCN1
Reactant: O=C(OCC(F)(F)F)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Product: CC(NC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F)C1CCCCN1

Procedure:
Starting with 2,2,2-trifluoroethyl 2,5-bis(2,2,2-trifluoroethoxy)benzoate and 2-(1-aminoethyl)piperidine and using the procedure illustrated in Examples 21 and 22, the product 2,5-bis(2,2,2-trifluoroethoxy)-N-[1-(2-piperidyl)ethyl]-benzamide, m.p. 95°-97° C., is obtained as white needles.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[OH-].[Na+]>>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:2]2[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([NH:8][S:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)(=[O:11])=[O:10])[CH:7]=2)[CH2:24][CH2:23]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1NS(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CN1CCN(c2ccc([N+](=O)[O-])c(NS(=O)(=O)c3ccccc3)c2)CC1
Reaction time: 0.03 h
Yield: 78 %

Procedure:
N-(5-fluoro-2-nitrophenyl)benzenesulfonamide (2×0.50 g, 1.688 mmol) was treated with N-methyl-piperazine (2×4.65 g, 45.6 mmol) and put in two pyrex tubes and sealed. Each tube was put in a LabWell MW-10 microwave oven for 2 min at 50 W. The reaction mixtures were combined and poured into 0.5 M NaOH (aq) and extracted with CH2Cl2, dried (MgSO4) and concentrated to give 0.99 g, (2.63 mmol) in 78% yield as a yellow solid. Anal (C17H20N4O4S) C, H, N, S; MS (posES-FIA) m/z=found: 377.4; Calcd: 376.12.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:31])=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23](C(OCC)=O)[S:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:32][Mg]Br.[Cl-].[NH4+].[CH2:37]1[CH2:41][O:40]CC1>CCOCC.O.C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:31])=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([C:41]([OH:40])([CH3:37])[CH3:32])[S:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C[Mg]Br
Reactant: C1CCOC1
Reactant: CCOC(=O)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3C)n2)cs1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3csc(C(C)(C)O)n3)n2)ccc(C#N)c1Cl
Temperature: -78 °C
Reaction time: 8 h
Yield: 19.08 %

Procedure:
(S)-ethyl 4-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)thiazole-2-carboxylate (0.28 g, 0.611 mmol) was dissolved in dry THF under nitrogen atmosphere. The solution was cooled to −78° C. with acetone-dry ice-bath. Methylmagnesium bromide, 3 M solution in Et2O (0.408 ml, 1.223 mmol), was added dropwise. The reaction mixture was stirred in RT overnight. Next day the mixture was again cooled to −78° C. and 1.019 ml of methylmagnesium bromide, 3 M solution in Et2O, was added. The mixture was stirred in RT overnight. Saturated ammonium chloride was added and the mixture was diluted with water and DCM. The organic phase was washed with brine and water. The product was purified by Flash-chromatography. Yield 19.08%. 1H-NMR (400 MHz; CDCl3): δ 1.28 (d, 3H), 1.58 (s, 6H), 2.54 (s, 3H), 2.63 (s, 1H), 4.34 (dd, 1H), 4.44 (dd, 1H), 4.60 (m, 1H), 6.43 (d, 1H), 7.52 (m, 3H), 7.83 (d, 1H), 8.00 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15](B4OC(C)(C)C(C)(C)O4)=[C:16]([F:19])[CH:17]=3)[CH2:12][N:11]([CH3:29])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:31]1[N:32]=[N:33][C:34]([O:37][CH:38]([F:40])[F:39])=[CH:35][CH:36]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([C:31]4[N:32]=[N:33][C:34]([O:37][CH:38]([F:40])[F:39])=[CH:35][CH:36]=4)=[C:16]([F:19])[CH:17]=3)[CH2:12][N:11]([CH3:29])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1Cc2cc(B3OC(C)(C)C(C)(C)O3)c(F)cc2C(c2ccc(Cl)c(Cl)c2)C1
Reactant: FC(F)Oc1ccc(Cl)nn1
Product: CN1Cc2cc(-c3ccc(OC(F)F)nn3)c(F)cc2C(c2ccc(Cl)c(Cl)c2)C1
Yield: 66 %

Procedure:
A procedure similar to the one in Step A of Example 29 was used to couple (+)-4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline with 3-chloro-6-(difluoromethoxy)pyridazine. (+)-4-(3,4-Dichlorophenyl)-7-(6-(difluoromethoxy)pyridazin-3-yl)-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinoline was obtained in 66% yield as a brown oil: ESI MS m/z 454 [M+H]+.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:21][C:22](O)([CH3:24])[CH3:23].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:22]([O:19][C:18](=[O:20])[C@@H:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)([CH3:24])([CH3:23])[CH3:21]
Reactant: CC(C)(C)O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (S)—N-Boc-4-fluorophenylalanine (2.83 g, 10.0 mmol), DMAP (0.12 g, 1.0 mmol) in DCM (20 mL) and 2-methyl-2-propanol (1.05 mL, 11.0 mmol), was added DCC (2.27 g, 11.0 mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was filtered and washed several times with DCM. The filtrate was concentrated in vacuo and chromatographed on silica gel eluting with ethyl acetate:isohexane (1:4) to give the title compound. δH (CDCl3): 1.39 (9H, s), 1.41 (9H, s), 3.01 (2H, m), 4.41 (1H, m), 4.98 (1H, m), 6.95 (2H, m), 7.12 (2H, m).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[N:9]([C@@H:10]2[CH2:19][C:18]3[C:13](=[C:14]([F:21])[CH:15]=[C:16]([F:20])[CH:17]=3)[O:12][CH2:11]2)[C:8](=[S:22])[NH:7][CH:6]=1.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)C>[CH2:23]([NH:2][CH2:3][CH2:4][C:5]1[N:9]([C@@H:10]2[CH2:19][C:18]3[C:13](=[C:14]([F:21])[CH:15]=[C:16]([F:20])[CH:17]=3)[O:12][CH2:11]2)[C:8](=[S:22])[NH:7][CH:6]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1ccccc1
Reactant: NCCc1c[nH]c(=S)n1[C@H]1COc2c(F)cc(F)cc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Product: Fc1cc(F)c2c(c1)C[C@@H](n1c(CCNCc3ccccc3)c[nH]c1=S)CO2

Procedure:
A 250 L reactor was charged with 12.25 kg of (R)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione hydrochloride, 114.82 kg of 2-propanol was added and the mixture was stirred at maximum speed (140 rpm). Through a dropping funnel 1.856 kg of benzaldehyde was added followed by 3.945 kg of sodium triacetoxyborohydride in five portions at Ti=20-25° C. according to the following addition order:
Reaction SMILES: [CH3:1][N:2]1[C:14]2[CH2:13][CH2:12][CH:11](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[CH3:26][NH:27][CH3:28]>>[CH3:26][N:27]([CH3:28])[CH:11]1[CH2:10][C:9]2[C:8]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:2]([CH3:1])[C:14]=2[CH2:13][CH2:12]1
Reactant: Cc1ccc(S(=O)(=O)OC2CCc3c(c4ccccc4n3C)C2)cc1
Reactant: CNC
Product: CN(C)C1CCc2c(c3ccccc3n2C)C1

Procedure:
Following the procedure described in Example 18 and using 36.2 g. of 9-methyl-3-tosyloxy-1,2,3,4-tetrahydrocarbazole and 250 ml. of dimetylamine there was otained 9.5 g. of 3-(dimethylamino)-9-methyl-1,2,3,4-tetraydrocarbazole in the form of its hydrochloride salt and which melted at >300°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[N:12]3[N:29]=[CH:30][C:31]([CH:32]=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(O)C.[NH:37]1[CH2:43][C:41](=[O:42])[NH:40][C:38]1=[O:39].N1CCCCC1>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[CH2:20][CH2:21]3)[N:12]3[N:29]=[CH:30][C:31]([CH:32]=[C:43]4[C:41](=[O:42])[NH:40][C:38](=[O:39])[NH:37]4)=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Nc3cccc(Cl)c3)nc3c(C=O)cnn23)CC1
Reactant: O=C1CNC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Nc3cccc(Cl)c3)nc3c(C=C4NC(=O)NC4=O)cnn23)CC1
Temperature: 80 °C
Yield: 67 %

Procedure:
To the reaction flask, tert-butyl 4-(5-(3-chlorophenylamino)-3-formylpyrazolo[1,5-a]pyrimidin-7-ylamino)piperidine-1-carboxylate (811 mg, 1.7 mmol) was added to ethanol (6.3 mL) along with hydantoin (172 mg, 1.7 mmol) and piperidine (170 μL, 1.7 mmol). The reaction was heated at 80° C. for 12 hours then cooled to room temperature and diluted with water. The solid was collected by filtration, washed with water and cold ethanol. The material was dried under vacuum overnight. The product, tert-butyl 4-(5-(3-chlorophenylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)piperidine-1-carboxylate, was recovered as a red solid in 67% yield after further purification by recrystallization from ethyl acetate/hexanes. LCMS (M+1=553)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Mg].[CH2:10]([C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[C:22](=O)[CH2:23][CH2:24][CH2:25][CH:26]=2)[CH2:17][CH2:16]1)[CH2:11][CH2:12][CH2:13][CH3:14].Cl.C([O:31]CC)C>>[CH2:10]([C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[CH2:22][CH2:23][C:24]([C:2]3[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=3)([OH:31])[CH2:25][CH:26]=2)[CH2:17][CH2:16]1)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCOCC
Reactant: Brc1ccc(Br)cc1
Reactant: CCCCC[C@H]1CC[C@H](C2=CCCCC2=O)CC1
Agent: Cl
Agent: [Mg]
Product: CCCCC[C@H]1CC[C@H](C2=CCC(O)(c3ccc(Br)cc3)CC2)CC1

Procedure:
A solution of 7.2 g of p-dibromobenzene in 40 ml of anhydrous diethyl ether was added dropwise under stirring at 10°-15° C. to 0.66 g of magnesium metal powder, followed by reaction at room temperature for one hour so that a Grignard reagent was formed. After 5 g of trans-4-pentylcyclohexylcyclohexenone were added under stirring at -10 ° to 0° C. to the thus-formed Grignard reagent, they were reacted at room temperature for additional 1 hour. After the completion of the reaction, diluted hydrochloric acid was added dropwise to the reaction mixture, followed by the extraction of the reaction mixture with diethyl ether. After the extract was washed with saturated NaCl, anhydrous sodium sulfate was added to dry the extract. The diethyl ether was distilled off under reduced pressure, whereby 1-(trans-4-pentylcyclohexyl)-4-(4-bromophenyl)-4-hydroxycyclohexene was obtained as a crude reaction product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Cl[C:12]1[O:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1>CN(C=O)C>[OH:1][CH2:2][CH2:3][N:4]1[CH2:10][CH2:9][CH2:8][N:7]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:6][CH2:5]1
Reactant: Clc1nc2ccccc2o1
Reactant: OCCN1CCCNCC1
Solvent: CN(C)C=O
Product: OCCN1CCCN(c2nc3ccccc3o2)CC1
Reaction time: 17 h
Yield: 26.6 %

Procedure:
A 2.329 g portion of homopiperazine dissolved in 10 ml of THF was mixed with 830 mg of iodoethyl alcohol to carry out 24 hours of reaction at room temperature. The reaction mixture was concentrated under a reduced pressure, and the resulting residue was purified by Sephadex LH-20 (Pharmacia) (chloroform:methanol=1:1) and Diaion HP-20 (Mitsubishi Chemicals) to obtain 305 mg of 1-(2-hydroxyethyl)homo-piperazine. Next, Under cooling with ice, 150 mg of 1-(2-hydroxyethyl)homopiperazine and 159 mg of 2-chlorobenzoxazole were added to 3 ml of DMF, and the reaction was carried out for 17 hours at the same temperature and then for 24 hours at room temperature. The reaction mixture was concentrated under a reduced pressure, and the resulting residue was dissolved in 100 ml of ethyl acetate, washed with sodium hydrogencarbonate aqueous solution (pH 8) and water in that order, dehydrated with sodium sulfate and then concentrated under a reduced pressure. Thereafter, the resulting residue was purified by a silica gel column chromatography (chloroform:methanol=30:1) to obtain 72 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:9][CH2:10][CH3:11])[CH2:5][NH:6][C:7]#[N:8])[CH3:2].C(N(CC)CC)C.[CH3:19][Si:20](Cl)([CH3:22])[CH3:21]>C1COCC1>[CH2:1]([O:3][CH:4]([O:9][CH2:10][CH3:11])[CH2:5][N:6]=[C:7]=[N:8][Si:20]([CH3:22])([CH3:21])[CH3:19])[CH3:2]
Reactant: CCOC(CNC#N)OCC
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(CN=C=N[Si](C)(C)C)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2,2-diethoxyethylcyanamide (5.5 g.) in anhydrous THF (100 ml.) at 0° was added triethylamine (6.29 ml.) and trimethylsilyl chloride (5.73 ml.). The reaction mixture was stirred at room temperature for 3 hours, the precipitated triethylamine hydrochloride removed by filtration under nitrogen and the filtrate concentrated. The residue was taken up in CCl4, the solvent evaporated and the residue was distilled at 80°/0.2 mm to give 1-(2,2-diethoxyethyl)-3-trimethylsilylcarbodiimide (6.5 g.) having the following n.m.r. in CDCl3 : 0.219 (s, 9H); 1.244 (t, 6H); 3.256 (d, 2H); 3.486-3.798 (m, 4H); 4.55 (t, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Cl:14])[C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[CH:7][C:6]=2[CH:13]=1.CN(C(ON1N=[N:30][C:25]2[CH:26]=[CH:27][CH:28]=[N:29][C:24]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:39](N(CC)C(C)C)(C)[CH3:40]>CN(C=O)C>[ClH:1].[N:29]12[CH2:28][CH2:27][CH:26]([CH2:39][CH2:40]1)[C@@H:25]([NH:30][C:10]([C:8]1[O:9][C:5]3[C:4]([Cl:14])=[CH:3][C:2]([Cl:1])=[CH:13][C:6]=3[CH:7]=1)=[O:12])[CH2:24]2
Reactant: O=C(O)c1cc2cc(Cl)cc(Cl)c2o1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cl
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc(Cl)cc(Cl)c2o1

Procedure:
227 mg (0.98 mmol) of 5,7-dichlorobenzofuran-2-carboxylic acid, 200 mg (0.98 mmol) of R-3-aminoquinuclidine dihydrochloride, 449 mg (1.18 mmol) of HATU, 458 mg (3.54 mmol) of N,N-diisopropylethylamine and 2.0 ml of DMF are reacted according to the general procedure (variant B). The reaction mixture is purified by preparative HPLC. An excess of 1N hydrochloric acid is then added to the product. The solvent is removed under reduced pressure. 169 mg (46% of theory) of the title compound are isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH:15]([NH:18][C:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][N:22]=1)=[O:20])([CH3:17])[CH3:16]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:25]([C:24]2[CH:28]=[CH:29][C:21]([C:19]([NH:18][CH:15]([CH3:17])[CH3:16])=[O:20])=[N:22][CH:23]=2)=[O:26])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CC(C)NC(=O)c1ccc(C(=O)O)cn1
Product: CC(C)NC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cn1

Procedure:
250 mg of 5-(methoxycarbonyl)picolinic acid was coupled to isopropylamine via Procedure G. Crude methyl 6-(isopropylcarbamoyl)nicotinate was hydrolyzed via Procedure M to yield 227 mg of 6-(isopropylcarbamoyl)nicotinic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 6-(isopropylcarbamoyl)nicotinic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield N5-(4-chloro-3-(pyridin-2-yl)phenyl)-N2-isopropylpyridine-2,5-dicarboxamide. MS (Q1) 395.1 (M)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:29]=[CH:28][C:19]([CH:20]=[C:21]2[S:25][C:24](=[O:26])[NH:23][C:22]2=[O:27])=[CH:18][CH:17]=1.C(O)(=O)C.CO>[Pd].C(Cl)(Cl)Cl>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:29]=[CH:28][C:19]([CH2:20][CH:21]2[S:25][C:24](=[O:26])[NH:23][C:22]2=[O:27])=[CH:18][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=C2SC(=O)NC2=O)cc1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A stirred mixture of 5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzylidene}-2,4-thiazolidinedione (500 mg), 10% Pd-C (50% wet, 1.0 g) and acetic acid (50 ml) was hydrogenated at 70° C. and at atmospheric pressure for 3 hours. Methanol (20 ml) and chloroform (20 ml) were added to the mixture and the whole was heated at 60° C. for 5 minutes. The mixture was filtered hot and the filtrate was concentrated in vacuo. A solution of the residue in ethyl acetate was successively washed with saturated aqueous sodium bicarbonate solution and water, and dried over magnesium sulfate. The solvent was removed and the residue was recrystallized from ethanol to yield 5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl}-2,4-thiazolidinedione (the same compound as that obtained in Example 12) as crystals (415 mg, 82.7%). m.p. 113°-114° C.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[C:10]#[CH:11].C([Li])CCC.Br[C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:22]=[CH:21]2.Cl>O1CCCC1.CCCCCC.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>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1[C:10]#[C:11][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:22]=[CH:21]2
Reactant: C#CC1=C(C)CCCC1(C)C
Reactant: CCOC(=O)c1ccc2cc(Br)ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2cc(C#CC3=C(C)CCCC3(C)C)ccc2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 0.503 g (3.3916 mmol) 1,3,3-trimethyl-2-ethynylcyclohexene (G. Kobrich et al. Chem Ber., 1966, 99,689.) in 4 ml of dry tetrahydrofuran at 0 degrees C. under argon was added dropwise 2.1 ml of 1.6M (3.36 mmol) of n-butyllithium in hexane. This mixture was stirred at 0 degrees C. for 10 minutes, at room temperature for 10 minutes and cooled again to 0 degrees C. To this was added, via cannula, a solution of 0.480 g (3.52 mmol) fused zinc chloride in 4 ml of tetrahydrofuran with stirring at 0 degrees C. for 40 minutes and at room temperature for 5 minutes. A solution of 0.9186 g (3.29 mmol) of ethyl 6-bromo-2-naphthoate (Anderson, L. C. J. Am. Chem. Soc., 1943, 65,242.) in 5 ml of dry tetrahydrofuran was transferred by cannula into a suspension of 0.410 g (0.3584 mmol) tetrakis(triphenylphosphine)palladium in 5 ml of dry tetrahydrofuran and stirred for 5 minutes at room temperature. This mixture was then treated via cannula with the solution of alkynyl zinc and the resultant mixture stirred at room temperature for 18 hours. Ice and 30 ml of 3N HCl was added and the products extracted with 4×50 ml ether. The combined ether extracts were washed with saturated NaHCO3 and NaCl solution, dried (MgSO4) and concentrated to give a brown oil. This oil was purified by HPLC (Waters 6000; Partisil M-9 10/50; 2% ethyl acetate in hexanes) to give the title compound as a yellow oil.