Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][C:25](O)=[O:26])=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:28]([CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][C:25]([N:38]2[CH2:39][CH2:40][CH:35]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:36][CH2:37]2)=[O:26])=[CH:12][N:11]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1cc2c(CC(=O)O)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Reactant: c1ccc(CC2CCNCC2)cc1
Product: COc1cc2c(CC(=O)N3CCC(Cc4ccccc4)CC3)cnc(CNC(=O)OC(C)(C)C)c2cc1OC

Procedure:
As described in Example 1, 94 mg of [1-(tert-butoxycarbonylamino-methyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acid was coupled with 4-benzyl-piperidine to give 132 mg of {-4-[2-(4-benzyl-piperidin-1-yl)-2-oxo-ethyl]-6,7-dimethoxy-isoquinolin-1-ylmethyl}-carbamic acid tert-butyl ester. MS: APCI (M+H) calc'd for C31H39N3O5+H 534.7; found 534.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[CH:9]=[C:10]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[N+:12]([O-:14])[CH:13]=1>>[N:1]1([C:8]2[CH:9]=[C:10]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:11]=[N+:12]([O-:14])[CH:13]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: [O-][n+]1cc(Br)cc(Oc2ccccc2)c1
Reactant: C1CNCCN1
Product: [O-][n+]1cc(Oc2ccccc2)cc(N2CCNCC2)c1
Temperature: 150 °C

Procedure:
An intimate mixture of 43 g of piperazine with 26.6 g of 5-bromo-3-phenoxypyridine N-oxide [Agr. Biol. Chem., 34, 68 (1970)] is heated at 150° C. for five hours. The oil is concentrated at reduced pressure to remove excess piperazine. The mixture is dissolved in 1500 ml of dichloromethane, washed with excess 25% sodium hydroxide solution, dried over anhydrous MgSO4, filtered and concentrated to yield 5-piperazinyl-3-phenoxypyridine N-oxide as an oil. The oil is dissolved in 200 ml of toluene-methanol, (95-5) and chromatographed over 400 g, silica gel in toluene-methanol, (95-5). 5-Bromo-3-phenoxy-pyridine N-oxide is eluted first. Elution with toluene-methanol (50:50) yields 5-piperazinyl-3-phenoxypyridine N-oxide; mp 107°-115° C. after drying at 0.1 mm pressure for 16 hours.
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:28]=[N:27][CH:26]=[C:25]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=2[F:37])[C:21]=1[C:22]([OH:24])=O.C([O-])(=O)C.[NH4+]>CS(C)=O>[F:37][C:31]1[CH:32]=[C:33]([I:36])[CH:34]=[CH:35][C:30]=1[NH:29][C:25]1[CH:26]=[N:27][CH:28]=[C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[F:13])[C:21]=1[C:22]([NH2:3])=[O:24]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1c(Nc2ccc(I)cc2F)cncc1-c1ccccc1F
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: NC(=O)c1c(Nc2ccc(I)cc2F)cncc1-c1ccccc1F
Temperature: 60 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
1,1′-carbonyldiimidazole (70 mg, 0.43 mmol) was added to a solution of 3-(2-fluoro-phenyl)-5-(2-fluoro-4-iodo-phenylamino)-isonicotinic acid (130 mg, 0.29 mmol) in DMSO (1 mL), and stirred overnight at 60° C. Ammonium acetate (89 mg, 1.15 mmol) was added, and the reaction solution was stirred for an additional 4 h at 60° C. The reaction solution was quenched with H2O, diluted with EtOAc, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was purified via Biotage eluting with a gradient of 0 to 70% EtOAc in hexanes to afford the desired product (78 mg, 60%). LC-MS (M+H=452, obsd.=452).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][C:8](=[O:12])[CH2:7]1)=[O:5])[CH3:2].F[B-](F)(F)F.[CH3:18][O+](C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]=[C:8]([O:12][CH3:18])[CH2:7]1)=[O:5])[CH3:2]
Reactant: C[O+](C)C
Reactant: CCOC(=O)C1CCNC(=O)C1
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1CCN=C(OC)C1
Temperature: 0 °C

Procedure:
Add 2-oxopiperidine-4-carboxylic acid ethyl ester (6.0 g, 35 mmol) to a solution of trimethyloxonium tetrafluoroborate (9.0 g, 59.6 mmol) in dichloromethane (78 mL) cooled to 0° C. Stir the reaction for 3 hours and pour into an ice cold solution of saturated aqueous sodium bicarbonate. Separate layers and extract the aqueous layer with additional dichloromethane. Combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to afford the title compound which was used without further purification (5.87 g, 90%). Mass spectrum (m/z): 186 (M+1).
Reaction SMILES: [Na].[OH:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.Cl[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.Cl>C(O)C>[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[CH2:12][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: O=Cc1ccc(OCc2ccc3ccccc3n2)cc1
Yield: 91.4 %

Procedure:
To a solution of sodium metal (0.9 g, 39.13 g.a.) in absolute ethanol (50 mL) is added dropwise under nitrogen a solution of 4-hydroxybenzaldehyde (5 g, 40.94 mmole) in absolute ethanol (50 mL). The mixture is gently refluxed for 1 hour and then treated dropwise with a solution of 2-chloromethylquinoline (free base, 7.24 g, 40.76 mmole), freshly prepared from the HCl salt) in ethanol (50 mL). The mixture is refluxed for 24 hours, the solvent is evaporated and the residue is partitioned between water and ethyl acetate. The organic layer is washed with 5% NaOH (pH 8), water, brine to neutral and dried (MgSO4). Removal of the solvent yields the title compound as a yellow solid (9.81 g). The crude material is further purified by flash chromatography (on silica Merck-60, hexane-ethyl acetate 9:1 to remove less polar impurities and 8:2 to elute the product). Yield: 7.37 g (71.5%), m.p. 82°-83° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](B(O)O)[CH:7]=1.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]#[N:20])[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([C:19]#[N:20])[CH:14]=2)[CH:7]=1
Reactant: OB(O)c1cc(Cl)ccc1O
Reactant: N#Cc1cc(Cl)ccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cc(-c2cc(Cl)ccc2O)ccn1
Temperature: 100 °C
Yield: 8.6 %

Procedure:
(5-Chloro-2-hydroxyphenyl)boronic acid (2.0 g, 0.012 mol), 4-chloropyridine-2-carbonitrile (1.61 g, 0.012 mol), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (0.424 g, 0.00058 mol) and sodium carbonate (3.7 g, 0.035 mol) in 1,4-dioxane (20.0 mL) and deionised water (1.0 mL) were degassed with nitrogen (×3) before heating at 100° C. for 18 hours under nitrogen. The reaction was cooled and hydrochloric acid (2.0 M aqueous solution, 30.0 mL) added. Reaction was filtered, washing with ethyl acetate (50.0 mL). The organic layer was concentrated in vacuo and purified by flash column chromatography on the ISCO™ (40 g SiO2) eluting with ethyl acetate:heptane (gradient 0:1 to 7:3, by volume) to afford the title compound as a yellow solid, 0.23 g, 8.6% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:26][CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[NH2:26][CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][N:31]([C:4]([C:3]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH:14]([C:16]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=4[N:17]=3)[CH3:15])=[O:12])=[CH:10][C:2]=2[Cl:1])=[O:5])[CH2:30]1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: NCCC1CCCNC1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCCC(CCN)C2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-3-(2-aminoethyl)piperidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.88 minutes; C24H27Cl2N5O2 (488.42); mass spectrum: (M−H)−=487/489/491 (chlorine isotope).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2([CH3:12])[CH2:11][CH2:10]2)=[N:5][N:4]=[C:3]1[SH:13].[CH4:14].CI>[OH-].[Na+]>[NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2([CH3:12])[CH2:10][CH2:11]2)=[N:5][N:4]=[C:3]1[S:13][CH3:14]
Reactant: C
Reactant: CC1(c2nnc(S)n(N)c2=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Product: CSc1nnc(C2(C)CC2)c(=O)n1N
Reaction time: 6 h
Yield: 82.3 %

Procedure:
198 grams of the compound obtained according to (b) were dissolved in 500 ml of 2 normal NaOH and treated with 500 ml of methane and 150 grams of methyl iodide. The mixture was stirred for 6 hours at 20° to 30° C. The crystals formed were filtered off with suction, washed and dried. There are obtained 174.5 grams of final product (dried in a vacuum at 40° C.), white crystals, M.P. 115° to 116° C.
Reaction SMILES: [H-].[Na+].C(NC([N:10]1[CH2:13][CH:12]([OH:14])[CH2:11]1)=O)(C)(C)C.[CH2:15]([O:19][C:20]1[C:24](S(C)(=O)=O)=[N:23][S:22][N:21]=1)[CH2:16][CH2:17][CH3:18]>C1COCC1>[CH2:15]([O:19][C:20]1[C:24]([O:14][CH:12]2[CH2:11][NH:10][CH2:13]2)=[N:23][S:22][N:21]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCOc1nsnc1S(C)(=O)=O
Reactant: CC(C)(C)NC(=O)N1CC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOc1nsnc1OC1CNC1
Reaction time: 1 h

Procedure:
A suspension of NaH (0.24 g, 0.006 mol) in THF (30 mL) was treated with 1-t-butylcarbamoyl-3-hydroxyazetidine (1.1 g, 0.006 mol), the reaction stirred 1 h, followed by addition of 3-butyloxy-4-methanesulfonyl-1,2,5-thiadiazole (1.0 g, 0.0042 mol) in THF (5 mL). The reaction was heated to reflux for 4 h, the solvent evaporated, the residue treated with ice-water, and the mixture extracted with EtOAc. The extracts were dried and treated with a slow stream of HCl for 3 min. After 0.5 h, the solvent was evaporated, the residue treated with ice-water, and the solution extracted with ether. The aqueous phase was made basic, extracted with EtOAc, the extracts washed with brine, dried, and the solvent evaporated to give a clear oil. The HCl salt (0.77 g) crystallized from 2-propanol, m.p. 167-168.5° C. (Compound 50).
Reaction SMILES: [NH2:1][CH:2]([CH2:10][NH:11][C:12]1[C:17]([CH2:18][CH3:19])=[C:16]([N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[CH:35]=[CH:34][C:33]4[CH2:32][CH2:31][CH2:30][NH:29][C:28]=4[N:27]=3)[CH2:22][CH2:21]2)[N:15]=[CH:14][N:13]=1)[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[N+:36]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[N:45]=[C:46]=[O:47])([O-:38])=[O:37]>O1CCCC1>[CH2:18]([C:17]1[C:12]([NH:11][CH2:10][CH:2]([NH:1][C:46]([NH:45][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N+:36]([O-:38])=[O:37])=[O:47])[C:3]([O:5][C:6]([CH3:8])([CH3:7])[CH3:9])=[O:4])=[N:13][CH:14]=[N:15][C:16]=1[N:20]1[CH2:21][CH2:22][CH:23]([C:26]2[CH:35]=[CH:34][C:33]3[CH2:32][CH2:31][CH2:30][NH:29][C:28]=3[N:27]=2)[CH2:24][CH2:25]1)[CH3:19]
Reactant: CCc1c(NCC(N)C(=O)OC(C)(C)C)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: CCc1c(NCC(NC(=O)Nc2ccccc2[N+](=O)[O-])C(=O)OC(C)(C)C)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.5 %

Procedure:
A mixture of 240 mg (0.50 mmole) of tert-butyl 2-amino-3-{5-ethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-piperidin-1-yl]-pyrimidin-4-ylamino}-propionate and 82 mg (0.50 mmole) of 2-nitrophenylisocynate in 15 ml of tetrahydrofuran is stirred for 3 hours at ambient temperature. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue is taken up in ethyl acetate and water. The organic phase is separated, dried over magnesium sulphate and the solvent evaporated off under reduced pressure (2 kPa). The residue is chromatographed on alumina eluting with a gradient of ethyl acetate-methylene chloride-methanol from 50-50-0 to 50-50-10. 260 mg of expected product is obtained in the form of a yellow solid.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:12](=N)([O:17][CH2:18][CH3:19])[CH2:13][CH2:14][CH2:15][CH3:16]>CCO>[C:1]([NH:9][N:10]=[C:12]([O:17][CH2:18][CH3:19])[CH2:13][CH2:14][CH2:15][CH3:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccccc1
Reactant: CCCCC(=N)OCC
Agent: Cl
Solvent: CCO
Product: CCCCC(=NNC(=O)c1ccccc1)OCC
Reaction time: 3 h
Yield: 25.4 %

Procedure:
A solution of 2.2 g (15.9 mmol) of benzoic hydrazide in 50 ml of dry EtOH was stirred under N2 at -10° C. as a solution of 2.5 g (15.1 mmol) of ethyl valerimidate hydrochloride [prepared by method of A. H. Hill and I. Rabinowitz, J. Am. Chem. Soc. 48, 734 (1926)] in 50 ml of dry EtOH was added dropwise over about 15 minutes. Stirring was continued at -10° C. for 3 hours, during which time a white precipitate separated. The cold mixture was filtered through Celite, and the filtrate was co-evaporated with CHCl3 at 10° C. The residue was chromatographed twice on silica gel columns (gradient elution with 0.3-5% MeOH in CH2Cl2) to give 951 mg (25%) of the title compound as a cream-colored semi-solid, suitable for use without further purification (TLC in 97:3 CH2Cl2 -MeOH). 1H NMR (CDCl3, 400 MHz) was complex, suggesting that the product is a mixture of syn- and anti-isomers.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH3:26][N:27]([CH3:31])[C:28]([NH2:30])=[O:29]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:30][C:28](=[O:29])[N:27]([CH3:31])[CH3:26])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: CN(C)C(N)=O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)N(C)C)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 1,1-dimethylurea. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, CD3OD) δ ppm 7.83 (d, J=7.6 Hz, 1 H), 7.68 (t, J=3.6 Hz, 2 H), 7.42 (q, J=7.2 Hz, 2 H), 7.23-7.20 (m, 2 H), 7.15 (s, 1 H), 5.00 (s, 2 H), 4.45 (brs, 2 H), 3.42 (s, 2 H), 3.02 (s, 6 H), 2.30 (s, 3 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:4]([CH:5]=[C:6]([CH3:8])[CH3:7])[CH:3]1[C:9](Cl)=[O:10].[F:13][C:14]([F:31])([F:30])[CH:15]([OH:29])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:7][C:6]([CH3:8])=[CH:5][CH:4]1[CH:3]([C:9]([O:29][CH:15]([C:14]([F:13])([F:30])[F:31])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=2)=[O:10])[C:2]1([CH3:12])[CH3:1]
Reactant: CC(C)=CC1C(C(=O)Cl)C1(C)C
Reactant: OC(c1cccc(Oc2ccccc2)c1)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)=CC1C(C(=O)OC(c2cccc(Oc3ccccc3)c2)C(F)(F)F)C1(C)C
Yield: 93.9 %

Procedure:
This compound was prepared in the manner of Example II using 3.3 g of 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarbonyl chloride, whose preparation is described in J. Sci. Food and Agriculture, 18, 325 (1967), 4.3 g of α-trifluoromethyl-3-phenoxybenzyl alcohol, and 1.5 g of pyridine in 50 ml of toluene. Volatiles were distilled from the crude reaction product at 90°/0.08 mm for 1/2 hour, then at 100°/0.08 mm for 3/4 hour through a short path Kugelrohr distillation system to give as a residue 6.3 g of α-trifluoromethyl-3-phenoxybenzyl 3-(2,2-dimethylvinyl)-2,2-dimethylcyclopropanecarboxylate. The ir spectrum was consistent with the assigned structure.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[C:8]3[CH:9]=[CH:10][C:11]([CH2:15][C:16]([O:18]CC)=O)=[CH:12][C:13]=3[CH2:14][C:5]=2[N:4]2[CH:21]=[CH:22][N:23]=[C:3]12.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[CH2:24]([NH:31][C:16](=[O:18])[CH2:15][C:11]1[CH:10]=[CH:9][C:8]2[C:6]3[NH:7][C:2](=[O:1])[C:3]4[N:4]([CH:21]=[CH:22][N:23]=4)[C:5]=3[CH2:14][C:13]=2[CH:12]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)Cc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Solvent: ClCCl
Product: O=C(Cc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12)NCc1ccccc1
Temperature: 140 °C

Procedure:
A mixture of 0.618 g of ethyl [4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-8-yl]acetate and 10 ml of benzylamine is heated at 140° C. for 17 hours under a nitrogen atmosphere. After returning to room temperature, 50 ml of dichloromethane are added to the reaction mixture. The solid formed is filtered, washed with dichloromethane and then recrystallized from 25 ml of dimethylformamide. After drying under reduced pressure (1 mbar) at 60° C., 0.65 g of N-benzyl-2-(4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-8-yl)acetamide is thus obtained, which product has a melting point greater than 260° C. (Analysis; % Calculated C: 71.34, H: 4.90, N: 15.13, O: 8.64; % Calculated C: 71.1, H: 5.0, N: 15.2, O: 9.1).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[F:22][C:23]([F:30])([F:29])[C:24]1([OH:28])[CH2:27][NH:26][CH2:25]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:26]3[CH2:27][C:24]([OH:28])([C:23]([F:30])([F:29])[F:22])[CH2:25]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: OC1(C(F)(F)F)CNC1
Agent: Cl
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CC(O)(C(F)(F)F)C1
Yield: 55.7 %

Procedure:
In analogy to the procedure described in Example 127 e), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b, 40 mg, 141 μmol) was reacted with 3-(trifluoromethyl)azetidin-3-ol hydrochloride (CAN 848192-96-1, 30.0 mg, 169 μmol) to obtain the title compound (32 mg, 56%) as off-white solid, MS (EI): m/e=408.3 [MH+].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH3:9][NH:10][CH3:11]>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:10]([CH3:11])[CH3:9])[CH:5]=[CH:6][N:7]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CNC
Solvent: CO
Product: CN(C)c1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
2,4-dichloropyrimidine (104, 500 mg, 3.30 mmol) was dissolved in methanol (5 mL) having 2.0 M dimethylamine dissolved therein, stirred at room temperature for 3 hours. Then, the methanol solvent was removed under reduced pressure and water was added to the reaction mixture. Organic compounds were extracted with ethyl acetate, and the recovered organic solution was washed with a saturated aqueous solution of sodium chloride and evaporated after a treatment with sodium sulfate. Purification was performed by column chromatograph to give the target compound 2-chloro-4-(N,N-dimethylamino)pyrimidine (106c, 426 mg, 80%) as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:7](/[CH:10]=[C:11](\[CH2:16][C:17]2[O:18][C:19]([CH3:22])=[CH:20][CH:21]=2)/[C:12](OC)=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>O1CCCC1>[CH2:1]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:7](/[CH:10]=[C:11](\[CH2:16][C:17]2[O:18][C:19]([CH3:22])=[CH:20][CH:21]=2)/[CH2:12][OH:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C=C(\Cc2ccc(C)o2)C(=O)OC)n1Cc1ccccc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCCc1ncc(/C=C(/CO)Cc2ccc(C)o2)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of methyl (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(5-methyl-2-furyl)methyl-2-propenoate (Example 6, Method A) (1.5 mmol) in dry tetrahydrofuran (10 mL) held at -78° C. under argon is treated dropwise with a solution of diisobutyl aluminum hydride in toluene (3.30 mmol, 2.2 mL of 1.5M). The mixture is allowed to warm to ambient temperature and stirred an additional 17 hours. Excess reducing agent is quenched with methanol and water, dilute acetic acid and methylene chloride are added, and the organic layer is washed with sodium bicarbonate solution, dried and concentrated to give the title compound.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]([N:22]([CH:25]([CH3:27])[CH3:26])[CH2:23][CH3:24])(C)C>ClCCl>[C:1]1([S:7]([N:10]2[CH:14]=[CH:13][C:12]([C:15]3[C:16](=[O:18])[O:17][C:16](=[O:17])[C:15]=3[C:24]3[C:27]4[C:25](=[CH:26][CH:2]=[CH:1][CH:6]=4)[N:22]([CH3:19])[CH:23]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)Cc1ccn(S(=O)(=O)c2ccccc2)c1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1cc(C2=C(c3ccn(S(=O)(=O)c4ccccc4)c3)C(=O)OC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 22 h
Yield: 66.3 %

Procedure:
1 g of 1-(benzenesulphonyl)-3-pyrrolylacetic acid in 25 ml of dichloromethane was treated at 0° C. with a solution of 837 mg of 1-methylindole-3-glyoxylyl chloride in 25 ml of dichloromethane and then with 975 mg of diisopropylethylamine. The mixture was allowed to warm to room temperature and was then stirred for 22 hours. After concentration and chromatography of the residue on silica gel with ethyl acetate/hexane (1:1) there were obtained 540 mg of 3-[1-(benzenesulphonyl)-3-pyrrolyl]-4-(1-methyl-3-indolyl)furan-2,5-dione.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[S:8][CH:9]=[C:10]([CH3:11])[C:6]=2[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[N:4][C:3]1=[O:19].S(Cl)([Cl:23])(=O)=O.N>C(O)(=O)C>[CH3:1][N:2]1[C:7]2[S:8][C:9]([Cl:23])=[C:10]([CH3:11])[C:6]=2[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[N:4][C:3]1=[O:19]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1csc2c1c(-c1ccccc1F)nc(=O)n2C
Agent: N
Solvent: CC(=O)O
Product: Cc1c(Cl)sc2c1c(-c1ccccc1F)nc(=O)n2C
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of 500 mg of 1-methyl-4-(o-fluorophenyl)-5-methyl-1,2-dihydrothieno[2,3-d]pyrimidin-2-one in 15 ml of glacial acetic acid is added 295 mg of sulfuryl chloride in 3 ml of glacial acetic acid at 40°C. After stirring the reaction mixture for 19 hours at room temperature, the reaction mixture is neutralized with aqueous ammonia under cooling, then extracted with chloroform. The chloroform extracts are washed with water, dried, and evaporated under reduced pressure to a residue to give crystals of 1-methyl-4-(o-fluorophenyl)-5-methyl-6-chloro-1,2-dihydrothieno[2,3-d]pyrimidin-2-one, which are recrystallized from ethanol-ether to give crystals having a melting point of 175° - 176°C.