Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10](=O)[CH3:11].[CH:13]1([NH2:16])[CH2:15][CH2:14]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH:10]([NH:16][CH:13]1[CH2:15][CH2:14]1)[CH3:11]
Reactant: NC1CC1
Reactant: CC(=O)C1Cc2ccccc2C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(NC1CC1)C1Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 27.3 %

Procedure:
To a cooled solution of 3.5 g (21.8 mmol) of 1-(indan-2-yl)ethanone in 100 ml of methanol, are added 10 g of 3 Å molecular sieves and 2.3 g (40.2 mmol) of cyclopropylamine followed by a slow addition of 2.87 ml (50.2 mmol) of acetic acid. The reaction mixture is stirred for 2.5 hrs at reflux. The reaction mixture is then cooled to 0° C. and 1.9 g (30 mmol) of sodium cyanoborohydride are slowly added and the reaction mixture is further stirred for 2 hrs at reflux. The cooled reaction mixture is then filtered over a cake of diatomaceous earth. The cake is washed twice by 80 ml of methanol and the combined methanolic extracts are concentrated under vacuum. 100 ml of water are then added to the residue and the pH is ajusted to 12 with a 0.5 N solution of sodium hydroxyde. The watery layer is extracted with 300 ml of ethyl acetate. The organic layer is washed twice by brine and filtered over a phase separator paper to yield after concentration 5 g of a yellow oil. Column chromatography on silica gel (gradient heptane/ethyl acetate) yields 1.2 g (28% yield) of N-[1-(indan-2-yl)ethyl]cyclopropanamine as a colourless oil (M+H =202).
Reaction SMILES: [NH:1]1[CH:7]([CH2:8][C:9]([OH:11])=O)[C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH:12]([C:15]1[N:19]([CH2:20][C:21]2[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=2)[C:18]2[CH:28]=[CH:29][CH:30]=[CH:31][C:17]=2[N:16]=1)([CH3:14])[CH3:13]>CS(C)=O>[O:3]=[C:2]1[NH:1][CH:7]([CH2:8][C:9]([NH:25][C:24]2[CH:23]=[CH:22][C:21]([CH2:20][N:19]3[C:18]4[CH:28]=[CH:29][CH:30]=[CH:31][C:17]=4[N:16]=[C:15]3[CH:12]([CH3:14])[CH3:13])=[CH:27][CH:26]=2)=[O:11])[C:5](=[O:6])[NH:4]1
Reactant: CC(C)c1nc2ccccc2n1Cc1ccc(N)cc1
Reactant: O=C(O)CC1NC(=O)NC1=O
Solvent: CS(C)=O
Product: CC(C)c1nc2ccccc2n1Cc1ccc(NC(=O)CC2NC(=O)NC2=O)cc1
Yield: 90.4 %

Procedure:
Commercially available (+/−) hydantoin-5-acetic acid (11 mg, 0.07 mmol) and 4-[(2-isopropyl-1H-benzimidazol-1-yl)methyl]aniline (30 mg, 0.06 mmol) were warmed in 1 mL dry DMSO until dissolved and coupled using GENERAL COUPLING METHOD A. Purified on silica gel using 5% MeOH in EtOAc to give 22 mg (89%) of a white solid. MS found: (M+H)+=406.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH:10]([S:13](Cl)(=[O:15])=[O:14])([CH3:12])[CH3:11]>N1C=CC=CC=1.Cl>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:13]([CH:10]([CH3:12])[CH3:11])(=[O:15])=[O:14])=[CH:5][CH:4]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CSc1ccc(N)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CSc1ccc(NS(=O)(=O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution of 4-methylsulfanyl-phenylamine (1.1 eq) in pyridine (1.3M) at 0° C. was added iso-propylsulfonyl chloride (1.5 eq). The mixture was stirred at room temperature for 12 h, poured in HCl (1N) and extracted with EtOAc. The combined organic extracts were washed with HCl (1N; 2×), water (2×), brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (Hex:EtOAc 0 to 50% in 15 min) and a suspension-filtration sequence in Hex/CH2Cl2 afforded the desired compound as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].O[Li].O>CCO.O>[CH:12]1([C:10]([C:5]2([C:3]([OH:4])=[O:2])[CH2:6][CH2:7][CH2:8][CH2:9]2)=[O:11])[CH2:14][CH2:13]1
Reactant: COC(=O)C1(C(=O)C2CC2)CCCC1
Agent: [Li]O
Solvent: O
Solvent: CCO
Product: O=C(O)C1(C(=O)C2CC2)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
To a solution of 1-cyclopropanecarbonyl-cyclopentane carboxylic acid methyl ester (0.62 g, 3.1 mmol) in EtOH (10 mL) were added LiOH.H2O (0.53 g, 12.6 mmol) and water (3 mL). The reaction mixture was stirred at room temperature overnight then diluted with water and washed with Et2O. The aqueous layer was acidified with conc. HCl to pH=2 then extracted with Et2O (2×). The combined second organic extracts were dried over Na2SO4 and concentrated to afford 0.36 g (64%) of 1-cyclopropanecarbonyl-cyclopentane carboxylic acid as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][NH:4][C:3]=1/[CH:15]=[C:16]1\[C:17](=[O:35])[NH:18][C:19]2[C:24]\1=[C:23]([C:25]1[CH:26]=[C:27]([CH2:31][C:32](O)=[O:33])[CH:28]=[CH:29][CH:30]=1)[CH:22]=[CH:21][CH:20]=2.[CH3:36][C@H:37]1[CH2:42][NH:41][CH2:40][C@@H:39]([CH3:43])[NH:38]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[CH3:36][C@H:37]1[NH:38][C@@H:39]([CH3:43])[CH2:40][N:41]([C:32](=[O:33])[CH2:31][C:27]2[CH:26]=[C:25]([C:23]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:24]=3/[C:16](=[CH:15]/[C:3]3[NH:4][CH:5]=[C:6]([C:7]([N:9]5[CH2:10][CH2:11][O:12][CH2:13][CH2:14]5)=[O:8])[C:2]=3[CH3:1])/[C:17](=[O:35])[NH:18]4)[CH:30]=[CH:29][CH:28]=2)[CH2:42]1
Reactant: Cc1c(C(=O)N2CCOCC2)c[nH]c1/C=C1\C(=O)Nc2cccc(-c3cccc(CC(=O)O)c3)c21
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCOC1
Product: Cc1c(C(=O)N2CCOCC2)c[nH]c1/C=C1\C(=O)Nc2cccc(-c3cccc(CC(=O)N4C[C@@H](C)N[C@@H](C)C4)c3)c21

Procedure:
(3-{3-[1-[3-Methyl-4-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-4-yl}-phenyl)-acetic acid was coupled with (2S,6R)-2,6-dimethyl-piperazine (3 eq.), EDC (1.5 eq.) and HOBt (1 eq.) in THF using the general amidation procedure to give the titled compound.
Reaction SMILES: [C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([F:19])[C:15](I)=[C:16]([F:17])[C:11]=3[N:10]=[C:9]2[O:20][CH:21]2[CH2:26][CH2:25][CH:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:22]2)=[CH:3][CH:2]=1.[C:38]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1.C([O-])([O-])=O.[K+].[K+]>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.CN(C=O)C>[C:38]1([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:43]=[CH:42][C:41]([C:15]2[C:14]([F:19])=[CH:13][C:12]3[N:8]([CH2:7][C:4]4[CH:5]=[CH:6][C:1]([C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)=[CH:2][CH:3]=4)[C:9]([O:20][CH:21]4[CH2:22][CH2:23][CH:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:25][CH2:26]4)=[N:10][C:11]=3[C:16]=2[F:17])=[CH:40][CH:39]=1
Reactant: CCOC(=O)C1CCC(Oc2nc3c(F)c(I)c(F)cc3n2Cc2ccc(-c3ccccc3)cc2)CC1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCC(Oc2nc3c(F)c(-c4ccc(-c5ccccc5)cc4)c(F)cc3n2Cc2ccc(-c3ccccc3)cc2)CC1
Temperature: 120 °C

Procedure:
A 250 mL flask was charged with ethyl 4-{[1-(biphenyl-4-ylmethyl)-4,6-difluoro-5-iodo-1H-benzimidazol-2-yl]oxy}cyclohexane carboxylate (2 g, 3.24 mmol), 4-Biphenylboronic acid (0.700 g, 3.53 mmol), Pd(PPh3)4 (0.185 g, 0.160 mmol), DMF (30 mL), and 1 M aqueous K2CO3 (6.5 ml, 6.50 mmol). The reaction was degassed with N2 and then heated at 120° C. for 1 hour. The volatiles were removed in vacuo and the resulting residue was partitioned between EtOAc and H2O. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated. Chromatography of the resulting residue over silica eluting with 15% [EtOAc:DCM (1:1)]/hexanes afforded the desired trans product as white solid. LC-MS: calculated for C41H36F2N2O3 642.27, observed m/e: 643.14 (M+H)+ (Rt 3.07/4 min).
Reaction SMILES: [NH2:1]/[C:2](=[CH:8]/[CH:9]([CH3:15])[CH2:10][P:11]([OH:14])([OH:13])=[O:12])/[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:16][C:17]1[CH:24]=[CH:23]C(CO)=[CH:19][CH:18]=1.Cl>ClCCl>[NH2:1]/[C:2](=[CH:8]/[CH:9]([CH3:15])[CH2:10][P:11]([OH:14])([OH:13])=[O:12])/[C:3]([O:5][CH2:6][C:7]1[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=1)=[O:4]
Reactant: OCc1ccc(Cl)cc1
Reactant: CCOC(=O)/C(N)=C\C(C)CP(=O)(O)O
Agent: Cl
Solvent: ClCCl
Product: CC(/C=C(/N)C(=O)OCc1ccc(Cl)cc1)CP(=O)(O)O

Procedure:
A mixture of 2.37 g (10 mmols) of ethyl E-2-amino-4-methyl-5-phosphono-pentenoate, 14.3 g (100 mmols) of p-chlorobenzyl alcohol, 10 ml of dichloromethane and 20 ml of 4N hydrochloric acid is allowed to stand at room temperature for 1 week. The reaction mixture is evaporated to dryness, the residue is dissolved in 25 ml of ethanol and a solution of 15 ml of propylene oxide in 15 ml of ethanol is added dropwise. The crystalline precipitate formed is collected, washed twice with water, filtrated and dried. p-chlorobenzyl E-2-amino-4-methyl-5-phosphono-pentenoate of m.p. 207°-208° is thus obtained.
Reaction SMILES: [C:1]([C:3]1[C:4](=O)[NH:5][CH:6]=[CH:7][C:8]=1[CH3:9])#[N:2].P(Cl)(Cl)(Cl)(Cl)[Cl:12].P(Cl)(Cl)(Cl)=O>>[Cl:12][C:4]1[C:3]([C:1]#[N:2])=[C:8]([CH3:9])[CH:7]=[CH:6][N:5]=1
Reactant: Cc1cc[nH]c(=O)c1C#N
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccnc(Cl)c1C#N
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 316.2 %

Procedure:
14 g (104 mmol) of 3-cyano-4-methylpyridone was slowly added to a mixture of 6.52 g (31.3 mmol) of phosphorus pentachloride and 30 ml (48 g, 313 mmol) of phosphorus oxychloride, followed by stirring at room temperature for 70 minutes and then under reflux with heating for 2 hours. After the reaction mixture was left to stand to cool, it was poured into ice water (400 ml) so that the surplus reagent was decomposed, followed by extraction with 100 ml of dichloromethane three times. The dichloromethane solution was washed with 100 ml of a saturated sodium chloride solution and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 15.1 g of crude crystals of 2-chloro-3-cyano-4-methylpyridine. 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 2.86 (s, 3H), 7.89 (d, J=5.6 Hz, 1H) 8.86 (d, J=5.6 Hz, 1H)
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([OH:19])[C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29]Cl.O>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([O:19][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)C(O)c1ccc(OCc2ccc(F)cc2)cc1
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCOCOC(C(=O)OC)c1ccc(OCc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
Methyl 2-{4-[(4-fluorobenzyl)oxy]phenyl}-2-hydroxyacetate (0.507 g, 1.75 mmol) was dissolved in tetrahydrofuran (9 ml), and sodium hydride (0.09 g, 2.27 mmol) was added thereto while being cooled with ice. The mixture was stirred for 30 minutes at room temperature, and 2-methoxyethoxymethylchloride (0.26 ml, 2.27 mmol) was added thereto while being cooled with ice. After being stirred for 62 hours at room temperature, the mixture, with water added thereto, was extracted with ethyl acetate. The organic layer was dried over MgSO4, and then the solvent was evaporated out. The obtained residue was purified by silica gel column chromatography (30% ethyl acetate/hexane), to give methyl 2-{4-[(4-fluorobenzyl)oxy]phenyl}-2-[(2-methoxyethoxy)methoxy]acetate (0.421 g, 64%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.[N+](C1C=CC([O:17][C:18]([O:20][CH:21]2[CH:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:25][C:24]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[N:23][CH2:22]2)=O)=CC=1)([O-])=O>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:18]([O:20][CH:21]2[CH:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:25][C:24]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[N:23][CH2:22]2)=[O:17])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(N)c1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CN=C(c2ccccc2)OC1c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COc1cccc(NC(=O)OC2CN=C(c3ccccc3)OC2c2ccccc2)c1
Temperature: 70 °C
Yield: 62.4 %

Procedure:
meta-Anisidine (1.72 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (5RS, 6SR)-5-(4-nitrophenoxycarbonyloxy)-2,6-diphenyl-5,6-dihydro-4H-1,3-oxazine (3 g) and 4-(dimethylamino)pyridine (0.3 g) in anhydrous N,N-dimethylformamide (50 cc). The solution obtained is heated to a temperature in the region of 70° C. for 6 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by chromatography on silica (0.063-0.2 mm; 50 g) contained in a column 2 cm in diameter [eluent: cyclohexane/ethyl acetate/triethylamine (65:30:5 by volume)], collecting 25-cc fractions. Fractions 2 to 5 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in diisopropyl ether, (5RS, 6SR)-5-(3-methoxyphenylcarbamoyloxy)-2,6-diphenyl-5,6-dihydro-4H-1,3-oxazine (1.8 g), m.p. 110° C. is obtained.
Reaction SMILES: [CH:1]([C:3]1[C:4]([OH:13])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)=O.C([O-])=O.[Na+].Cl.[NH2:19]O.C(O)=O>O>[C:1]([C:3]1[C:4]([OH:13])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)#[N:19]
Reactant: O=Cc1cc(C(F)(F)F)cnc1O
Reactant: NO
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: N#Cc1cc(C(F)(F)F)cnc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the compound from Step B above (18 g, 95 mmol), sodium formate (7.1 g, 110 mmol), hydroxylamine hydrochloride (7.3 g, 110 mmol), and formic acid (150 mL) was stirred at room temperature for 2 h and then heated to reflux overnight. The reaction mixture was cooled, allowed to stand at room temperature for 7 d, poured into water and extracted with three portions of ethyl acetate. The combined organic layers were washed sequentially with two portions of water, saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated in vacuo to yield the desired product as a brown powder. 1H NMR (400 MHz, CD3OD) δ 8.37 (d, J=2.7 Hz, 1H), 8.19 (q, J=0.7 Hz, 0.3 Hz, 1H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH2:8].S.[OH:10][CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH2:17][CH:18]([N:20]1[C:33]2[CH:32]=[C:31]([C:34](=S)N)[CH:30]=[CH:29][C:28]=2[S:27][C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH3:19].C(OC(C)C)(C)C>C(OCC)(=O)C>[NH:1]1[CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]2[N:8]=[C:34]1[C:31]1[CH:30]=[CH:29][C:28]2[S:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH:18]([CH3:19])[CH2:17][N:13]3[CH2:14][CH2:15][CH2:16][C@@H:12]3[CH2:11][OH:10])[C:33]=2[CH:32]=1
Reactant: CC(CN1CCC[C@@H]1CO)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Reactant: NC1CCCCC1N
Agent: S
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: CC(CN1CCC[C@@H]1CO)N1c2ccccc2Sc2ccc(C3=NC4CCCCC4N3)cc21
Temperature: 150 °C

Procedure:
1,2-Diaminocyclohexane (7.98 g) is added to an ethanolic solution (30 cc), saturated with hydrogen sulphide, of 10-{1-[(2R)-2-hydroxymethyl-1-pyrrolidinyl]-2-propyl}-2-phenothiazinecarbothioamide, L series (2.79 g). The mixture is heated in an autoclave at 150° C. for 17 hours, then diluted with ethyl acetate (250 cc) and washed with distilled water (4×200 cc). The organic phase is separated after settling has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is stirred with boiling acetonitrile (6×30 cc), and the oil obtained is solidified by stirring with isopropyl ether (100 cc). The residue is chromatographed on a column (height: 52 cm; diameter: 2.5 cm) of silica gel (0.2-0.06 mm), eluting with a 60:40 (by volume) mixture (2 liters) of 1,2-dichloroethane and methanol and collecting 120-cc fractions. The first liter is discarded, and fractions 4 to 7 containing the pure product are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give 2-(3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl)-10-{1-[(2R)-2-hydroxymethyl-1-pyrrolidinyl]-2-propyl}phenothiazine, L series (1.8 g) in the form of a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:25])=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10]C)=[O:9].[OH-].[Na+]>CO.O>[CH3:24][O:23][C:21]([C:5]1[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]([C:8]([OH:10])=[O:9])=[C:2]([CH3:1])[NH:3][C:4]=1[CH3:25])=[O:22]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Yield: 66.2 %

Procedure:
Dimethyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (17.3 g, 0.05 mole) is suspended in methanol (280 ml) and thereto a solution of NaOH (15.9 g, 0.4 mole) in water (52 ml) is added at room temperature under stirring. The reaction mixture is stirred at reflux temperature for 5 hours, cooled, water (1050 ml) is added under stirring and the resulting mixture is filtered. The precipitate is the unreacted starting compound, i.e. dimethyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate. To the clear filtrate activated carbon (1 g) is added and the mixture is stirred at 50°-60° C. for 30 minutes. After cooling the activated carbon is filtered off, the filtrate is acidified with 1 n HCl to pH 2.5 and the precipitate is filtered and washed with water (2×15 ml). Thus, there is obtained the pure title compound (11 g, 66%), m.p. 202°-206° C.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CC(C)=O>[CH3:10][O:9][C:7]([C:5]1[O:4][N:3]=[C:2]([O:1][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:6]=1)=[O:8]
Reactant: CCOC(=O)CBr
Reactant: COC(=O)c1cc(O)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(C(=O)OC)on1
Yield: 81 %

Procedure:
To a solution of methyl 3-hydroxy-isoxazole-5-carboxylate (7.14 mmol) in acetone (30 mL), was added potassium carbonate (1.2 g, 8.6 mmol) and ethyl bromoacetate (8.6 mmol). The reaction mixture was heated at reflux for 2 h, monitoring by TLC. At completion, acetone was removed in vacuo and the residue partitioned between water and ethyl acetate (50 mL). The organic layer was dried (MgSO4), filtered, and evaporated to afford the desired intermediate.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C@H:20]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:21]([N:23]([CH3:25])[CH3:24])=[O:22].CO>CCCCCCC>[CH3:24][N:23]([CH3:25])[C:21]([CH:20]([NH:19][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:22]
Reactant: CN(C)C(=O)[C@H](N)c1ccccc1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Solvent: CO
Solvent: CCCCCCC
Product: CN(C)C(=O)C(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)c1ccccc1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42 a) and (αR)-α-amino-N,N-dimethyl-benzeneacetamide hydrochloride (1:1) (CAN 129157-29-5) as starting materials. Racemization occurred during the synthesis and the product was isolated by chiral chromatography on Reprosil Chiral NR using heptane/20% ethanol as eluent. The (+)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 394.2120 (M+H)+, αD20 (MeOH)=+44.4°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[C:10]([N+:15]([O-:17])=[O:16])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:19]1CCN2C(=NCCC2)CC1.CI>CN(C=O)C>[C:1]([O:5][C:6](=[O:18])[N:7]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[C:10]([N+:15]([O-:17])=[O:16])[N:9]=1)[CH3:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)c([N+](=O)[O-])n1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1ccc(Br)c([N+](=O)[O-])n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 35.4 %

Procedure:
To a solution of (5-bromo-6-nitro-pyridin-2-yl)-carbamic acid tert-butyl ester (11) (4.2 g, 13.2 mmol) in dry DMF (21 mL), DBU (5.02 g, 33.0 mmol)! was added at 0° C. Methyl iodide (3.75 g, 26.4 mmol) was added slowly at 0° C. After stirring for 3 hours at 0° C. the reaction mixture was quenched and the product was precipitated upon addition of aqueous NaHSO4 (1M). The crude product was isolated by filtration and purified by recrystallisation from a mixture of MeCN and water to afford (5-bromo-6-nitro-pyridin-2-yl)-methyl-carbamic acid tert-butyl ester 12 (1.55 g).
Reaction SMILES: [CH3:1][O:2][NH:3][CH:4]([CH3:15])[CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[Cl:14].C(N(CC)CC)C.[F:23][CH:24]([F:34])[C:25]1[C:29]([C:30](Cl)=[O:31])=[CH:28][N:27]([CH3:33])[N:26]=1>ClCCl>[CH3:1][O:2][N:3]([CH:4]([CH3:15])[CH2:5][C:6]1[C:7]([Cl:14])=[CH:8][C:9]([Cl:13])=[CH:10][C:11]=1[Cl:12])[C:30]([C:29]1[C:25]([CH:24]([F:34])[F:23])=[N:26][N:27]([CH3:33])[CH:28]=1)=[O:31]
Reactant: CONC(C)Cc1c(Cl)cc(Cl)cc1Cl
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(C)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.3 %

Procedure:
To a solution of O-methyl-N-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-hydroxylamine (12.3 g, 0.046 mol) prepared as described in example P5a, in dichloromethane (120 ml) was added triethylamine (7.7 ml, 0.055 mol) followed by dropwise addition of a solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (9.1 g, 0.046 mol) in dichloromethane (10 ml) at 0° C. After complete addition of acid chloride the mixture was stirred 5 hours at ambient temperature. When the TLC confirmed completion of the reaction, the reaction mass was washed with 1N HCl (100 ml), followed by 1N NaOH (100 ml), then with water (2×100 ml) and finally with brine solution (50 ml) before drying over sodium sulfate and evaporation of the solvent. The resulting crude mass 20.5 g of a sticky dark brown oil was purified by column chromatography using 60-120μ mesh silica gel and product collected at 40% ethyl acetate in hexane as eluent to give 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid methoxy-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-amide (7.9 g, 41%) as off white solid. m.p: 110-112° C. 1H NMR (400 MHz, CDCl3): δ1.38-1.39 (d, 3H), 3.20-3.26 (dd, 1H), 3.32-3.37 (dd, 1H), 3.70 (s, 3H), 3.97 (s, 3H), 4.88-4.93 (m, 1H), 7.02-7.29 (t, 1H), 7.27 (s, 2H), 7.81 (s, 1H) MS [M+H]+ 426/428/430
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH3:15])[C:7](=[O:14])[N:8]2[CH2:11][CH2:12][OH:13])=[C:4](Cl)[N:3]=1.O.[NH2:18][NH2:19]>C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH3:15])[C:7](=[O:14])[N:8]2[CH2:11][CH2:12][OH:13])=[C:4]([NH:18][NH2:19])[N:3]=1
Reactant: Cn1c(=O)n(CCO)c2nc(N)nc(Cl)c21
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cn1c(=O)n(CCO)c2nc(N)nc(NN)c21
Temperature: 105 °C
Yield: 88.9 %

Procedure:
A mixture of 2-amino-6-chloro-9-(2-hydroxyethyl)-7-methyl-purin-8-one obtained in step 3 (8 g, 32.9 mmol), Hydrazine hydrate (16 ml, 32.9 mmol) and ethanol (300 ml) were heated at 100-110° C. for 16 hours. The reaction mixture was concentrated and solid obtained was filtered off and dried to obtain 2-amino-6-hydrazino-9-(2-hydroxyethyl)-7-methyl-purin-8-one (7 g, 89%) as an off white solid.