Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[SH:15][CH2:16][CH2:17][OH:18]>>[OH:18][CH2:17][CH2:16][S:15][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])c(Cl)c1
Reactant: OCCS
Product: CC(=O)Nc1ccc([N+](=O)[O-])c(SCCO)c1

Procedure:
Starting with 42.9 g (0.2 mol) of 2-chloro-4-acetylaminonitrobenzene and 23.4 g (0.3 mol) of 2-mercaptoethanol, pale yellow crystals (46.6 g) of the expected compound are obtained, the melting point of which is 174° C. (recrystallized from 96° ethanol) and the elemental analysis of which, calculated for C10H12N2O4S.1/2CH3CH2OH, is:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17][NH2:18])[CH2:6]2.[CH3:20][O:21][CH:22]([O:25][CH3:26])[CH:23]=O>C(O)C.O.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17][NH:18][CH2:23][CH:22]([O:25][CH3:26])[O:21][CH3:20])[CH2:6]2
Reactant: COC(C=O)OC
Reactant: COc1cc2c(cc1OC)[C@@H](CN(C)CCCN)C2
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: COc1cc2c(cc1OC)[C@@H](CN(C)CCCNCC(OC)OC)C2
Reaction time: 12 h
Yield: 90 %

Procedure:
1 g (3.7 mmoles) of N-{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}-N-methylpropane-1,3-diamine is dissolved in 20 mL of ethanol. 520 mg (0.45 mL) of a 60% solution of glyoxal 1,1-dimethyl acetal in water and then 100 mg of Pd/C 10% are added. The reaction mixture is hydrogenated at atmospheric pressure and ambient temperature for 12 hours. The catalyst is filtered off and the filtrate is evaporated to dryness. 1.2 g of expected product are obtained in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1Cl.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[N:16]1[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]1
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Reactant: CN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1ccc(N2CCN(C)CC2)c(Cl)c1

Procedure:
3',4'-Dichloroacetophenone (9.65 g., 0.05 mole) and N-methylpiperazine (10 g., 0.1 mole) are refluxed (165° C) for 24 hours. The solution is cooled and 100 ml. water containing 2 g. of sodium hydroxide is added. The oil is decanted and diluted with 200 ml. of toluene and washed first with dilute alkali then several times with water. The toluene layer is dried with magnesium sulfate and evaporated in vacuo to an oil. The residue is distilled 146°-150° at 0.1-0.3 mm., yield 3.0 g. This product is dissolved in ethyl ether and converted to the hydrochloride using isopropanolic hydrogen chloride and the salt crystallized from acetonitrile. The purified salt is reconverted to the base with dilute sodium hydroxide. The product is extracted using ethyl ether, separated, dried, evaporated to dryness to give 3'-chloro-4'-(4-methyl-1-piperazinyl)acetophenone as a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:12](=[O:13])[C:6]2[S:7][CH2:8][CH2:9][NH:10][CH2:11][C:5]=2[CH:4]=[N:3]1.N1C=CC=CC=1.[N+:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)([O-:22])=[O:21]>O>[CH3:1][N:2]1[C:12](=[O:13])[C:6]2[S:7][CH2:8][CH2:9][NH:10][CH:11]([C:27](=[O:28])[C:26]3[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:31][CH:30]=3)[C:5]=2[CH:4]=[N:3]1
Reactant: Cn1ncc2c(c1=O)SCCNC2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: c1ccncc1
Product: Cn1ncc2c(c1=O)SCCNC2C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 57.5 °C
Reaction time: 19 h
Yield: 77 %

Procedure:
To a suspension of 0.8 g (4.06 mmol) of 8-methyl-2,3,4,5-tetrahydro-9(8H)-pyridazino[4,5-b][1,5]thiazepinone in 8 ml of anhydrous pyridine 0.99 g (5.33 mmol) of 4-nitrobenzoyl chloride is added, whereafter the suspension is stirred for 18-20 hours at 55-60° C., while adding every 4 hours 0.5 g (2.54 mmol) of 4-nitrobenzoyl chloride. The reaction mixture is poured on 60 ml of icy water and extracted with 3×50 ml of dichloromethane. The organic phase is washed with 2×50 ml of 2 M hydrochloric acid solution, then with 30 ml of saturated sodium hydrogen carbonate solution and 2×60 ml of water. The organic phase is dried, filtered and evaporated. The residue is purified by column chromatography. In this way 1.08 g (77%) of the title compound is obtained with a melting point of 230-232° C.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8](=[O:13])O[C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[CH:4][C:3]=1[F:14].[CH2:15]1[C@@H:18](C(O)=O)[NH:17][CH2:16]1>CN(C)C=O.C(O)(=O)C>[F:1][C:2]1[C:7]2[C:8](=[O:13])[N:17]3[CH2:18][CH2:15][C@H:16]3[C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[CH:4][C:3]=1[F:14]
Reactant: O=C(O)[C@@H]1CCN1
Reactant: O=c1[nH]c2ccc(F)c(F)c2c(=O)o1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(F)c(F)c2C(=O)N2CC[C@@H]12
Yield: 68.3 %

Procedure:
A solution of 19.6 g (98.4 mmol) of 5,6-difluoro-2,4-dihydro-1H-3,1-benzoxazine-2,4-dione and 9.95 g (98.4 mmol) of L-azetidine-2-carboxylic acid in 125 ml of dimethylformamide and 25 ml of acetic acid was stirred at 120° for 16 hours. The brown solution was evaporated and the brown residue obtained was crystallized from ethanol. There were obtained 16 g (68%) of (S)-5,6-difluoro-1,2,4,9,10,10a-hexahydro-azeto[2,1-c][1,4]benzodiazepine-4,10-dione as colourless needles of m.p. >250°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][S:5][CH:6]=1.O.O.O.[C:14]([O-])(=[O:16])C.[Na+].C(O)=O>O>[CH:14]([NH:1][C:2]1[C:3]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][S:5][CH:6]=1)=[O:16]
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1cscc1N
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: COC(=O)c1cscc1NC=O

Procedure:
A stirred solution of methyl 4-amino-3-thenoate (4 g), sodium acetate trihydrate (2.8 g) and formic acid (27 ml) was heated at 95° C. for 1 hour. On cooling the solution was poured into water, and the solution filtered to give the title product as a solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:4])[CH3:3].[C:5]([O:9][OH:10])([CH3:8])([CH3:7])[CH3:6].CC(=C)C>C(O)(C)(C)C>[C:2]([O:10][O:9][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)C
Reactant: CC(C)(C)OO
Agent: C=C(C)C
Solvent: CC(C)(C)O
Product: CC(C)(C)OOC(C)(C)C

Procedure:
In practice of the invention as set forth in FIG. 2, effluent from a reactor wherein debutanized isobutane oxidate comprised of tertiary butyl hydroperoxide and tertiary butyl alcohol is reacted with isobutylene to form ditertiary butyl peroxide is combined with an azeotropic ditertiary butyl peroxide and tertiary butyl alcohol stream and fed to dehydration zone 102 via line 101. Dehydration zone 102 is a reactor distillation column provided with a central packed bed 103 of zeolite H--Y catalyst supported by conventional means. Fractional distillation zones 104 and 105 are located respectively above and below the catalyst bed.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=4)[CH:26]=3)[CH2:23][C:22](=[O:38])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3ccccn3)c2)=Nc2ccc(-c3ccccc3F)cc2N1

Procedure:
The title compound was prepared from {2′-fluoro-3-[3-oxo-3-(3-pyridin-2-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamic acid tert-butyl ester (Example M49) (350 mg, 0.66 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (153 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[H-].[Na+].[CH3:19]N(C=O)C.IC>O>[CH3:19][NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([F:11])([F:12])([F:13])([F:10])[F:9])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: Nc1ccc(S(F)(F)(F)(F)F)cc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CNc1ccc(S(F)(F)(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 4-amino-3-nitro-phenyl sulfur pentafluoride (2.0 g), 60% sodium hydride (oil) (310 mg) and DMF (15 ml) was added dropwise iodomethane (447 μL) while ice-cooling. After that, the mixture was stirred at room temperature for 3 hours. To the reaction mixture was poured water, and the precipitated solid was collected by filtration. The solid was washed with water and dried to give methyl-(2-nitro-4-pentafluorosulfanyl-phenyl)-amine (2.0 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH2:8][OH:9].C([Li])CCC.[C:15]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21])#[N:16]>C1COCC1>[OH:21][CH:20]([C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH2:8][OH:9])[C:19]1[CH:18]=[C:17]([CH:24]=[CH:23][CH:22]=1)[C:15]#[N:16]
Reactant: OCc1cnccc1Br
Reactant: N#Cc1cccc(C=O)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1cccc(C(O)c2ccncc2CO)c1
Reaction time: 0.25 h

Procedure:
To a solution of (4-bromo-pyridin-3-yl)-methanol (20 mg, 0.11 mmol) in THF (1 mL) at −78° C. was added dropwise 2.5M n-butyllithium (0.22 mL). After 15 min, a solution of 3-cyanobenzaldehyde (69 mg) in THF (0.5 mL) was added. The reaction mixture was stirred for 15 min, then quenched with ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography to yield 3-[hydroxy-(3-hydroxymethyl-pyridin-4yl)-methyl]-benzonitrile as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[O:15]([CH2:22][CH2:23][NH2:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[O:15]([CH2:22][CH2:23][NH:24][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Reactant: NCCOc1ccccc1
Product: O=[N+]([O-])c1cnc2cccnc2c1NCCOc1ccccc1
Yield: 88.6 %

Procedure:
Using the general method of Example 76, 4-chloro-3-nitro[1,5]naphthyridine (5.0 g, 24 mmol) was reacted with 2-phenoxyethylamine (3.5 mL, 27 mmol) to provide 6.6 g of N4-(2-phenoxyethyl)-3-nitro[1,5]naphthyridin-4-amine as a yellow solid, m.p. 107-108° C. Analysis: Calculated for C16H14N4O3: %C, 61.93; %H, 4.55; %N, 18.05; Found: %C, 61.99; %H, 4.58; %N, 18.42. 1H NMR (300 MHz, DMSO): δ 10.25 (broad s, 1H), 9.39 (broad s, 1H), 8.81 (dd, J=4.1, 1.7 Hz, 1H), 8.25 (dd, J=8.5, 1.7 Hz, 1H), 7.67 (dd, J=8.5, 4.1 Hz, 1H), 7.34-7.26 (m, 2H), 7.01-6.96 (m, 3H), 4.89 (broad s, 2H), 4.35 (t, J=5.1 Hz, 2H); MS (EI): m/e 310.1065 (310.1065 calc'd for C16H14N4O3).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[C:7]([F:20])=[CH:8][C:9]([CH3:19])=[C:10]([C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=1.CCN(CC)CC>C(Cl)Cl>[C:1]([NH:5][C:6]1[C:7]([F:20])=[CH:8][C:9]([CH3:19])=[C:10]([C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=O)c1cc(N)c(F)cc1C
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)c1cc(NC(C)=O)c(F)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
Acetyl chloride (3.12 g, 40 mmol) was added to a 0° C. solution of ethyl 2-(5-amino-4-fluoro-2-methylphenyl)-2-oxoacetate (9 g, 40 mmol) and Et3N (8.1 g, 80 mmol) in CH2Cl2 (80 mL). The resulting mixture was stirred at RT for 3 h. The solvent was removed under reduced pressure to give ethyl 2-(5-acetamido-4-fluoro-2-methylphenyl)-2-oxoacetate (10.7 g, 100% yield), which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3): δ 8.71 (d, J=6.0 Hz, 1 H), 7.37 (brs, 1 H), 6.95 (d, J=8.7 Hz, 1 H), 4.39 (q, J=7.2 Hz, 2 H), 2.50 (s, 3H), 2.10 (s, 3 H), 1.40 (t, J=7.2 Hz, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.OS(O)(=O)=O.[CH3:17]O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: CO
Reactant: Cc1cc(Cl)ccc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Cl)cc1C
Yield: 92 %

Procedure:
4-Chloro-2-methylbenzoic acid (3 g, 17.6 mmol) was suspended in 12 ml of MeOH with 1 ml of concentrated H2SO4. The mixture was refluxed overnight, MeOH was evaporated and the residue was extracted with EtOAc, dried over MgSO4 filtered and evaporated to give methyl 4-chloro-2-methylbenzoate as a colorless viscous liquid (2.96 g, 92%) that was used in the next step without further purification. The ester (2.96 g, 16 mmol) was, under inert atmosphere, dissolved in THF (100 mL) and NMP (9 mL) and Iron (III) acetylacetonate (318 mg, 0.9 mmol) was added giving a red solution. Then EtMgBr (7 ml of 1M solution in ether) was added dropwise under vigorous stirring. The mixture turned dark brown and then violet and then was stirred for 15 more min. The reaction was diluted with ether and quenched upon the addition of aq. HCl (1M, 10 ml). The crude product was extracted with ether. The combined organic layers were washed with water and brine, dried over MgSO4 and evaporated. The residue was purified on silica gel (30% EtOAc/hexanes) to give methyl 4-ethyl-2-methylbenzoate as an oil (2.37 g, 83%). (1H NMR (500 MHz, CDCl3): δ 1.26 (t, 3H), 2.63 (dd, 2H), 3.9 (s, 3H), 7.1 (b, 2H), 7.85 (d, 1H)).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:30][C:29]([C:31](=[O:34])[CH2:32][CH3:33])=[N:28][N:27]=2)=[CH:22][CH:21]=1>C1COCC1>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[S:30][C:29]([C:31]([C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)([OH:34])[CH2:32][CH3:33])=[N:28][N:27]=2)=[CH:24][CH:25]=1
Reactant: Ic1ccncc1
Reactant: CCC(=O)c1nnc(-c2ccc(F)cc2)s1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(O)(c1ccncc1)c1nnc(-c2ccc(F)cc2)s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 16.5 %

Procedure:
To a solution of 4-iodo pyridine (0.142 g, 0.635 mmol) in THF (12 mL) at −78° C. was added n-BuLi in hexane (1.6 M, 0.582 mL, 0.8474 mmol) and the mixture stirred for 30 min A solution of 1-(5-(4-fluorophenyl)-1,3,4-thiadiazole-2-yl)propan-1-one (0.1 g, 0.4237 mmol) in THF (8 mL) was added to above solution at −78° C. and the mixture stirred for 1 hour at −78° C. The reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and diluted with water (25 mL). The reaction mixture was extracted with ethyl acetate (200 mL), dried over sodium sulfate and concentrated under reduced pressure to obtain crude product. The crude compound was purified by preparative TLC (using 5% methanol and dichloromethane) to afford 1-(5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)-1-(pyridin-4-yl)propan-1-ol as white solid (22 mg, 17% yield). 1H NMR (400 MHz, DMSO-d6): δ8.55 (d, 2H), 8.0-7.96 (m, 2H), 7.56 (d, 2H), 7.35 (t, 2H), 7.06 (s, 1H), 2.40-2.30 (m, 2H), 0.80 (t, 3H); LC-MS m/z calculated for [M+H]+316.08. found 316.1.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:15][NH:14][CH2:13][CH2:12][NH:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.Cl[C:24]1[N:29]([CH3:30])[C:28](=[O:31])[CH:27]=[C:26]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[N:25]=1.ClC1C=CNC(=O)N=1>O1CCCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]2[CH2:15][N:14]([C:24]3[N:29]([CH3:30])[C:28](=[O:31])[CH:27]=[C:26]([C:32]4[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=4)[N:25]=3)[CH2:13][CH2:12][NH:11]2)=[CH:8][CH:9]=1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Reactant: Clc1ccc([C@@H]2CNCCN2)cc1
Agent: Cl
Agent: O=c1nc(Cl)cc[nH]1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCN[C@H](c3ccc(Cl)cc3)C2)nc(-c2ccncc2)cc1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.3 %

Procedure:
To a suspension of (R)-2-(4-chlorophenyl)piperazine dihydrochloride (1.09 g, 4.05 mmol) in tetrahydrofuran (24 ml) was added triethylamine (2.82 ml, 20.3 mmol). After stirring for 15 min at room temperature, 2-chloro-3-methyl-6-(4-pyridyl)-3H-pyrimidin-4-one (748 mg, 3.38 mmol) was added portionwise. Upon disappearance of the chloropyrimidone, the reaction mixture was condensed under reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate solution and dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give pale yellow solid, which was recrystallized from ethanol to afford (R)-2-(2-(4-chlorophenyl)piperazin-4-yl)-3-methyl-6-(4-pyridyl)-pyrimidin-4-one (998 mg, 77.4%) as white crystals. The enantiomer excess was determined by HPLC (>99% ee). The crystals were converted into its dihydrochloride salt.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[C:21]([C:24]1[CH:29]=[C:28]([Cl:30])[C:27]([NH:31][C:32](=[O:44])[CH2:33][N:34]2[CH2:39][CH2:38][NH:37][CH:36]([C:40]([NH:42][CH3:43])=[O:41])[CH2:35]2)=[C:26]([Cl:45])[CH:25]=1)(=[O:23])[CH3:22].C(N(CC)CC)C>COCCO>[C:21]([C:24]1[CH:29]=[C:28]([Cl:30])[C:27]([NH:31][C:32](=[O:44])[CH2:33][N:34]2[CH2:39][CH2:38][N:37]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:7]3[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=3)[CH:36]([C:40]([NH:42][CH3:43])=[O:41])[CH2:35]2)=[C:26]([Cl:45])[CH:25]=1)(=[O:23])[CH3:22]
Reactant: Fc1ccc(N(CCCCCl)c2ccc(F)cc2)cc1
Reactant: CNC(=O)C1CN(CC(=O)Nc2c(Cl)cc(C(C)=O)cc2Cl)CCN1
Solvent: CCN(CC)CC
Solvent: COCCO
Product: CNC(=O)C1CN(CC(=O)Nc2c(Cl)cc(C(C)=O)cc2Cl)CCN1CCCCN(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 72 h
Yield: 19 %

Procedure:
A mixture of 2.07 parts of N-(4-chlorobutyl)-4-fluoro-N-(4-fluorophenyl)benzenamine, 2.5 parts of N-(4-acetyl-2,6-dichlorophenyl)-3-[(methylamino)carbonyl]-1-piperazineacetamide, 1.3 parts of N,N-diethylethanamine and 97 parts of 2-methoxyethanol was stirred for 3 days at 70° C. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The desired fraction was collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding a first fraction of 0.74 parts (19.0%) of N-(4-acetyl-2,6-dichlorophenyl)-4-[4-[bis(4-fluorophenyl)amino]butyl]-3-[(methylamino)carbonyl]-1-piperazineacetamide; mp. 87.1° C. The second fraction was collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding a second fraction of 0.78 parts (20.1%) of N-(4-acetyl-2,6-dichlorophenyl)-4-[4-[bis(4-fluorophenyl)amino]butyl]-3[(methylamino)carbonyl]-1-piperazineacetamide; mp. 85.0° C. Total yield: 1.52 parts (39.1%) of N-(4-acetyl-2,6-dichlorophenyl)-4-[4-bis(4-fluorophenyl)amino]butyl]-3-[(methylamino)carbonyl]-1-piperazineacetamide (compound 97).
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:15][CH:16]1[NH:20][C:19](=O)[CH2:18][CH2:17]1>>[CH3:15][CH:16]1[N:20]=[C:19]([N:13]2[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[O:6][C:7]3[C:12]2=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:18][CH2:17]1
Reactant: CC1CCC(=O)N1
Reactant: c1ccc2c(c1)Nc1ccccc1O2
Product: CC1CCC(N2c3ccccc3Oc3ccccc32)=N1

Procedure:
Reaction of phenoxazine with 5-methyl-2-pyrrolidinone according to the procedure of Example 1 affords the free base 10-(5-METHYL-1-PYRROLIN-2-YL)PHENOXAZINE, m.p. 135°-137°C., from n-heptane. Conversion of the free base to the hydrochloride salt provides 10-(5-METHYL-1-PYRROLIN-2-YL)PHENOXAZINE HYDROCHLORIDE, m.p. 229.5°-236.0°C. (dec.) (corr.), in a 57% overall yield.
Reaction SMILES: [N:1]1[CH:5]=[CH:4][C:3]2=[CH:6][CH:7]=[CH:8][CH:9]=[CH:10][C:2]=12.C(Cl)(=O)[C:12](Cl)=[O:13].C([O-])(=O)C.[Na+].N>CN(C=O)C>[N:1]1[CH:5]=[CH:4][C:3]2=[CH:6][C:7]([CH:12]=[O:13])=[CH:8][CH:9]=[CH:10][C:2]=12
Reactant: c1ccc2ccnc-2cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: CC(=O)[O-]
Agent: N
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cccc2nccc-2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Cyclohepta[b]pyrrole-5-carboxylic acid nitrile: 800 mg of cyclohepta[b]pyrrole (manufactured according to Helv. Chim. Acta 67, 1647 (1984)) are added in portions, at 0°, to a solution of 1.1 ml of oxalyl chloride in 40 ml of DMF. The whole is subsequently stirred for 30 minutes at room temperature, then 60 ml of saturated sodium acetate solution are added and the pH is adjusted to 9 with concentrated ammonia. The cyclohepta[b]pyrrole-5-carbaldehyde formed is extracted with methylene chloride and purified by flash chromatography with solvent system N6. Rf (N6)=0.46.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=1.ClC1C=C(C2C(COC3C=CC(C(O)=O)=CN=3)=C(C)ON=2)C=CC=1.[NH2:48][CH:49]([OH:51])[CH3:50]>>[OH:20][CH2:19][CH2:18][C:17]1[N:16]=[C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])[CH:23]=[CH:22][C:50]=1[C:49]([NH2:48])=[O:51]
Reactant: CC(N)O
Reactant: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)cn1
Agent: Cc1onc(-c2cccc(Cl)c2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(N)=O)c(CCO)n1
Yield: 24 %

Procedure:
As described for example 98b, 6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (77.8 mg, 0.25 mmol) was converted, instead of 6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid, using aminoethanol instead of 2,2,2-trifluoroethylamine, to the title compound (21 mg, 24%) which was obtained as a white solid. MS: m/e=355.0 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH3:10])[C:8]#[N:9].C(O)(C)(C)C.[C:16]([O:20][CH3:21])(=[O:19])[CH:17]=[CH2:18]>O>[C:8]([C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([CH3:10])[CH2:18][CH2:17][C:16]([O:20][CH3:21])=[O:19])#[N:9]
Reactant: C=CC(=O)OC
Reactant: CC(C#N)c1ccccn1
Solvent: CC(C)(C)O
Solvent: O
Product: COC(=O)CCC(C)(C#N)c1ccccn1
Yield: 41.8 %

Procedure:
To a dried flask under nitrogen was added 2-(2-pyridinyl)-propanenitrile (Preparation 43, 6.26 g, 47.4 mmol), t-butanol (30 ml), Triton B (6.66 g, 39.8 mmol) and methyl acrylate (6.12 g, 71.1 mmol). The reaction mixture was heated at reflux for 2.5 h. The solid was removed, and the filtrate concentrated in vacuo to give a yellow oil. Water (30 ml) was added and the product was extracted with diethyl ether. The organic extracts were dried (Na2SO4) and concentrated in vacuo to give a light yellow oil (4.32 g, 42%).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH2:12][CH3:13])[N:3]=1.[C-:14]#[N:15].[K+]>CN(C)C=O>[CH2:12]([O:11][C:4]1[N:3]=[C:2]([C:14]#[N:15])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1)[CH3:13]
Reactant: [C-]#N
Reactant: CCOc1ccc([N+](=O)[O-])c(Br)n1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc([N+](=O)[O-])c(C#N)n1
Temperature: 80 °C
Yield: 38.7 %

Procedure:
To a solution of the compound prepared in Example 279 (0.317 g) in N,N-dimethylformamide (6 mL) was added potassium cyanide (0.100 g) at room temperature. The mixture was heated at 80° C. for 18 hours and then cooled to room temperature. The solids were filtered, and the filtrate diluted with ethyl acetate, washed with 1N hydrochloric acid and water. The organic layer was filtered, evaporated in vacuo and purified by column chromatography on silica gel (10-50% ethyl acetate in hexane) to obtain the title compound (0.096 g) having the following physical data.