Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[OH-].[Na+].[CH3:5][CH:6]([CH2:10][C:11](=[O:16])[CH2:12][CH:13]([CH3:15])[CH3:14])[C:7]([OH:9])=O>CO>[CH2:12]([CH:11]1[O:16][C:7](=[O:9])[CH:6]([CH3:5])[CH2:10]1)[CH:13]([CH3:14])[CH3:15]
Reactant: CC(C)CC(=O)CC(C)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CC1CC(C)C(=O)O1
Temperature: -2.5 °C
Reaction time: 8 h

Procedure:
A cold solution (−5 to 8° C.) of sodium borohydride (0.6 g) in 2N-sodiumhydroxide (1.5 mL) was added dropwise very slowly to a stirred solution of 2,6-dimethyl-4-oxo-heptanoic acid (3) (1.0 g) in methanol (20 mL) and stirring was continued overnight. Methanol was evaporated and more water (3-4 mL) was added to the residue and the mixture was once again cooled to −5 to 0° C. and then acidified with cold dilute hydrochloric acid and then extracted with ether (3×50 mL). The combined extracts were washed with brine, dried (Na2SO4) and then concentrated to give a crude liquid which was loaded on silica gel column and the column was eluted with an increasing amount of hexane/ethyl acetate (100:0 to 95:5). The fractions were monitored on TLC plate and then the desired fractions were combined and solvent was removed under vacuum to afford 4-isobutyl-2-methyl-4-butanolide (trans:cis=68:32 on NMR basis) of formula (1) in 76% yield as a colourless oil with coconut flavour; Rf=0.80 (10% ethylacetate in hexane); IR (film) λmax 2962, 1772, 1558, 1457, 1362, 1173, 1135, 1004, 1024, 926 cm−1; 1H NMR δ 4.63-4.55 (dqd, 0.32H, cis-5-CH), 4.46-4.38 (dtd, 0.68H, trans-5-CH), 2.73-2.62 (m, 1H, 3-CH), 2.55-2.47 (m, 1H, 7-CH), 2.09-2.04 and 1.84-1.78 (2 m, 2H, 4-CH2), 1.67-1.61 and 1.50-1.41 (2 m, 2H, 6-CH2), 1.36-1.26 and 1.27-1.25 (2d, 3H, 10-CH3), 0.96-0.95 and 0.94-0.93 (2d, 6H, 8-CH3 & 9-CH3) (FIG. 3); 13C NMR δ 179.42 (d, C-2), 76.55 (d, C-5), 44.43 (d, C-3), 37.69 (s, C-4), 35.69 (d, C-7), 33.77 (s, C-6), 21.92 (d, C-10), 15.65, 14.89 (2s, C-8 and C-9) (FIG. 4); GC of compound 1 appeared at tr=30.24 and tr=30.44 also confirms the presence of isomers (FIG. 5); EIMS m/z 156 [M]+ (1.3), 99 (100%), 84 (5.4), 71 (28.5), 56 (14.7), 42 (12.8) (FIG. 6).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][C:3]=1[C:7]([NH2:9])=[O:8].[H-].[Na+].[C:12]([C:14]1[C:21]([Cl:22])=[CH:20][C:17]([CH2:18]Cl)=[CH:16][C:15]=1[Cl:23])#[N:13]>CN(C)C=O>[NH2:1][C:2]1[N:6]([CH2:18][C:17]2[CH:16]=[C:15]([Cl:23])[C:14]([C:12]#[N:13])=[C:21]([Cl:22])[CH:20]=2)[N:5]=[N:4][C:3]=1[C:7]([NH2:9])=[O:8]
Reactant: NC(=O)c1nn[nH]c1N
Reactant: N#Cc1c(Cl)cc(CCl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(Cl)cc(Cn2nnc(C(N)=O)c2N)cc1Cl
Reaction time: 0.17 h
Yield: 23.4 %

Procedure:
A stirred, ambient temperature solution of 5-amino-1,2,3-triazole-4-carboxamide (630 mg, 5.0 mmol) in dry N,N-dimethylformamide (20 ml) was treated with sodium hydride (250 mg of a 50% dispersion in mineral oil, 125 mg NaH, 5.2 mmol). The resulting suspension was stirred 10 min., 4-cyano-3,5-dichlorobenzyl chloride (1.1 g, 5.0 mmol) was added, and the mixture was stirred 2 hours. The reaction was quenched by pouring into ice and water (80 ml). The suspension was filtered and washed three times with water. The solid was suspended in 19:1 (v/v) dichloromethane-methanol and filtered to provide 364 mg (23%) 5-amino-1-(4-cyano-3,5-dichlorobenzyl)-1,2,3-triazole-4-carboxamide. Recrystallization from ethanol provided material of m.p. 238°-239.5° C.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:5]1[CH:9]=[C:8]([C:10]([O:12]CC)=[O:11])[NH:7][N:6]=1)[CH3:4]>CO>[CH2:3]([C:5]1[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[NH:7][N:6]=1)[CH3:4]
Reactant: CCOC(=O)c1cc(CC)n[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1cc(C(=O)O)[nH]n1
Yield: 62.4 %

Procedure:
Aqueous sodium hydroxide solution (10 M; 100 ml, 1.0 mol) was added dropwise to a stirred suspension of the title compound of example (4a) (66.0 g, 0.39 mol) in methanol and the resulting solution heated under reflux for 4 hours. The cool reaction mixture was concentrated under reduced pressure to ca. 200 ml, diluted with water (200 ml) and this mixture washed with toluene (3×100 ml). The resulting aqueous phase was acidified with concentrated hydrochloric acid to pH 4 and the white precipitate collected and dried by suction to provide the title compound (34.1 g). δ (DMSOd6): 1.13 (3H,t), 2.56 (2H,q), 6.42 (1H,s).
Reaction SMILES: C(OP([CH2:9][C:10]1[N:11]=[CH:12][N:13]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=1)(OCC)=O)C.[Li+].CC([N-]C(C)C)C.[CH:42]([CH:44]1[CH2:49][CH2:48][N:47]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:46][CH2:45]1)=O>C1COCC1>[C:28]1([C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:13]2[CH:14]=[C:10]([CH:9]=[CH:42][CH:44]3[CH2:49][CH2:48][N:47]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[CH2:46][CH2:45]3)[N:11]=[CH:12]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOP(=O)(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)OCC
Reactant: O=CC1CCN(c2ccccc2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C(=CC1CCN(c2ccccc2)CC1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
The product from Step D is dissolved in THF and cooled to −78° C. under nitrogen. A solution of LDA in THF is added dropwise. The reaction was stirred at −78° C. for 1 h, then a solution of 4-formyl-1-phenylpiperidine from Step A is added, and the reaction warmed to room temperature overnight. The reaction is quenched with ammonium chloride solution, and extracted with ethyl acetate. The title compound is obtained after chromatography on silica gel.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[S:37]([NH2:40])(=[O:39])=[O:38]>>[CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:40][S:37]([C:33]3[S:32][CH:36]=[CH:35][CH:34]=3)(=[O:39])=[O:38])=[O:31])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: NS(=O)(=O)c1cccs1
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2cccs2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of Example 18) and 2-thiophenesulfonamide (Huang, H. C.; Reinhard, E. J.; Reitz, D. B. Tetrahedron Lett., 1994, 35, 7201.; Graham, S. L.; Scholz, T. H. Synthesis, 1986, 1031).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C@@H:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C@@H:18]([C:33](=[O:43])[NH:34][O:35]CC3C=CC=CC=3)[CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C@@H:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)(=[O:23])=[O:24])[C@@H:18]([C:33](=[O:43])[NH:34][OH:35])[CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: COc1ccc(S(=O)(=O)N2CC[C@@H](C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)C[C@@H]2C(=O)NOCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(S(=O)(=O)N2CC[C@@H](C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)C[C@@H]2C(=O)NO)cc1

Procedure:
A mixture of (2R,4R)-4-[2-benzyloxycarbamoyl-1-(4-methoxy-benzene-sulfonyl)-piperidine-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (500 mg, 0.81 mmol) and 5% palladium on barium sulfate (250 mg) in 10 mL of methanol was shaken under a 40 psi atmosphere of hydrogen gas for 1.5 hours. Filtration through nylon and concentration of the filtrate provided (2R,4R)-4-[2-hydroxycarbamoyl-1-(4-methoxy-benzenesulfonyl)-piperidine-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester as a colorless solid, which was used in the subsequent step without purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[CH2:14][CH2:13][C@H:12]([NH:15][S:16]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[CH:24][CH:25]=4)[CH:20]=3)(=[O:18])=[O:17])[C:11]2=[O:31])[CH:6]=[CH:5][N:4]=1)#[N:2].Br[CH2:33][C:34]1[CH:38]=[CH:37][S:36][CH:35]=1>>[C:1]([C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[CH2:14][CH2:13][C@H:12]([N:15]([CH2:33][C:34]3[CH:38]=[CH:37][S:36][CH:35]=3)[S:16]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[CH:24][CH:25]=4)[CH:20]=3)(=[O:18])=[O:17])[C:11]2=[O:31])[CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: BrCc1ccsc1
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4ccnc(C#N)c4)C3=O)cc2c1
Product: COc1ccc2ccc(S(=O)(=O)N(Cc3ccsc3)[C@H]3CCN(Cc4ccnc(C#N)c4)C3=O)cc2c1

Procedure:
The title compound is prepared from 7-methoxynaphthalene-2-sulfonic acid [1-(2-cyanopyridin-4-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide as described in EXAMPLE 141, Part D using 3-bromomethylthiophene in place of benzyl bromide. The crude product is purified by column chromatography eluting with gradient of 10% EtOAc/CH2Cl2 to 25% EtOAc/CH2Cl2 to afford the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[N:15][O:16][CH3:17])[C:11]([NH:13][CH3:14])=[O:12].[Cl:18][C:19]1[CH:33]=[CH:32][CH:31]=[CH:30][C:20]=1[O:21][C:22]1[C:27]([F:28])=[C:26](F)[N:25]=[CH:24][N:23]=1>CN(C)C=O>[Cl:18][C:19]1[CH:33]=[CH:32][CH:31]=[CH:30][C:20]=1[O:21][C:22]1[N:23]=[CH:24][N:25]=[C:26]([O:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:10](=[N:15][O:16][CH3:17])[C:11]([NH:13][CH3:14])=[O:12])[C:27]=1[F:28]
Reactant: Fc1ncnc(Oc2ccccc2Cl)c1F
Reactant: CNC(=O)C(=NOC)c1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)C(=NOC)c1ccccc1Oc1ncnc(Oc2ccccc2Cl)c1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.3 %

Procedure:
With cooling, 0.4 g (0.01 mol) of sodium hydride (60%) are added to a mixture of 2 g (0.0096 mol) of 2-(2-hydroxy-phenyl)-2-methoxyimino-N-methyl-acetamide and 2.3 g (0.0095 mol) of 4-(2-chlorophenoxy)-5,6-difluoropyrimidine in 10 ml of dimethylformamide, and the mixture is stirred at 25° C. for 12 hours. The reaction mixture is poured onto water and extracted with dichloromethane, the organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. The residue is chromatographed over silica gel using a mixture of identical volumina of ethyl acetate and cyclohexane. 2.1 g (48.3% of theory) of 2-{2-[6-(2-chlorophenoxy)-5-fluoro-pyrimidine4-yloxy]-phenyl}-2-methoxyimino-N-methylacetamide are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][Si](C)(C)C)=[CH:15][CH:14]=1.C(#N)C>CN(C)P(=O)(N(C)C)N(C)C>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][S:19][C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: C[Si](C)(C)Sc1ccc(Cl)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(CSc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94.8 %

Procedure:
1.50 g (7.0 mmoles) of 4-nitrobenzyl bromide was added to a mixture of 1.36 g (6.3 mmoles) of 4-chlorophenylthio(trimethyl)silane, 20 ml of acetonitrile and 2.3 ml of hexamethylphosphoric triamide and the conversion was complete after stirring for 5 minutes at room temperature. The reaction mixture was evaporated to dryness and the residue was dissolved in 50 ml of ethyl acetate. The solution was washed sequentially with water (twice 10 ml), 10 ml of a 1N KOH solution and water (twice 10 ml), dried and evaporated to dryness. The solid residue was washed with heptane on a sintered glass filter and the crystals obtained were vacuum dried at room temperature to obtain 1.67 g (95% yield) of 4-chlorophenyl 4-nitrobenzyl sulfide melting at 66°-68° C.
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][N:3]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:2]2.[NH3:17]>>[NH2:17][CH:1]1[CH:5]([OH:6])[CH2:4][N:3]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2]1
Reactant: O=C(OCc1ccccc1)N1CC2OC2C1
Reactant: N
Product: NC1CN(C(=O)OCc2ccccc2)CC1O

Procedure:
6.5 g benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate in 80 mL 33% aqueous ammonia solution was stirred 20 h in a closed vessel. The reaction was cooled and extracted with dichlormethane. The organic layer was washed with sodium chloride solution and evaporated to give 6.1 g of the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH:28]1[CH2:31][CH2:30][CH2:29]1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[N:13]([CH:28]3[CH2:31][CH2:30][CH2:29]3)[N:14]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClC1CCC1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2nn(C3CCC3)c(-c3ccc(Cl)cc3)c2CC1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.40 mmol) in DMF (2 mL) was added NaH (60% dispersion in oil, 60 mg) at 25° C. After 10 min, the mixture was heated to 80° C., and chloro-cyclobutane (1.5 mmol) was added. The mixture was heated at this temperature for 16 h. The mixture was concentrated and purified by chromatography (SiO2, EtOAc/hexanes) to provide 3-(4-chloro-phenyl)-2-cyclobutyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester. The title compound (0.030 mg) was obtained from this ester according to the deprotection method in Example 103, Step C. The reaction sequence also yielded 3-(4-chloro-phenyl)-1-cyclobutyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C17H20ClN3, 301.13; found, m/z 302.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.52-7.51 (m, 2H), 7.30-7.29 (m, 2H), 4.70-4.60 (m, 1H), 3.40-3.89 (m, 2H), 3.27-3.21 (m, 4H), 2.79-2.76 (m, 2H), 2.60-2.50 (m, 2H), 2.30-2.20 (m, 2H), 1.81-1.65 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]([OH:19])[CH3:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][C@@H:17]([OH:19])[CH3:18])[CH2:14][CH2:15]2)=[CH:8][CH:9]=1
Reactant: C[C@H](O)CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@H](O)CN1CCN(c2ccc(N)cc2)CC1
Yield: 88.1 %

Procedure:
(S)-1-[4-(4-Nitro-phenyl)-piperazin-1-yl]-propan-2-ol (1.60 g, 0.00603 mol) was dissolved in Methanol (35.0 mL) and the solution was carefully added to a Parr vessel containing 10% Palladium on Carbon (90.10, carbon black. Palladium, 0.500 g, 0.0375 mol) under nitrogen. The reaction was then placed on a Parr hydrogenator and was allowed to shake until uptake of hydrogen had ceased (overnight). Catalyst was removed via filtration and filtrate was reduced en vacuo to afford 1.25 g of (5)-1-[4-(4-Amino-phenyl)-piperazin-1-yl]-propan-2-ol as a white powder. (M+H)=236.21. 1H NMR (400 MHz, DMSO, d6) δ 6.66 (d, 2H, J=8.72 Hz), 6.48 (d, 2H, J=8.72 Hz), 4.53 (s, 2H), 4.26 (d, 1H, J=4.00 Hz), 3.77 (m, 1H), 2.88 (m, 4H), 2.54 (m, 4H), 2.26 (m, 1H), 2.18 (m, 1H), 1.04 (d, 3H, J=6.17 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:26][CH3:27])=[C:20]([O:23][CH3:24])[CH:21]=3)[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][C@@H:14]([OH:28])[CH2:15]3)[N:10]=2)=[CH:7][CH:6]=[C:5]([O:29][CH3:30])[N:4]=1.[C:31]1([CH3:41])[CH:36]=[CH:35][C:34]([S:37](O)(=[O:39])=[O:38])=[CH:33][CH:32]=1>CC(O)C>[S:37]([O:28][C@@H:14]1[CH2:13][CH2:12][C@@H:11]2[C@@H:16]([C:17]3[C:22]([C:9]([C:8]4[C:3]([O:2][CH3:1])=[N:4][C:5]([O:29][CH3:30])=[CH:6][CH:7]=4)=[N:10]2)=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH3:27])[CH:18]=3)[CH2:15]1)([C:34]1[CH:35]=[CH:36][C:31]([CH3:41])=[CH:32][CH:33]=1)(=[O:39])=[O:38]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(OC)nc1OC)=N[C@@H]1CC[C@@H](O)C[C@H]21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: CCOc1cc2c(cc1OC)C(c1ccc(OC)nc1OC)=N[C@@H]1CC[C@@H](OS(=O)(=O)c3ccc(C)cc3)C[C@H]21
Temperature: 60 °C
Yield: 97.1 %

Procedure:
(2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol (1.5 g; 3.6 mmol) is dissolved in 9 ml of 2-propanol. The solution is heated up to 60° C. 723 mg (3.8 mmol) of p-toluenesulfonic acid are added. The solution is cooled down to room temperature and stirred over night. From a part of the solution seed crystals are produced and added to the remaining solution. The crystals are filtered off and dried to obtain 1.98 g (94%) of the title compound (m.p.: 218° C.).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([F:13])[C:3]=1[C:4]([NH:6][OH:7])=[NH:5].CO[C:16](OC)(N(C)C)[CH3:17]>CC(O)C>[Br:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([F:13])[C:3]=1[C:4]1[N:5]=[C:16]([CH3:17])[O:7][N:6]=1
Reactant: COC(C)(OC)N(C)C
Reactant: N=C(NO)c1c(F)cc(Cl)cc1Br
Solvent: CC(C)O
Product: Cc1nc(-c2c(F)cc(Cl)cc2Br)no1
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
To a solution of 2-bromo-4-chloro-6-fluoro-N-hydroxy-benzamidine (26.5 g, 99.25 mmol) in 2-propanol (200 ml) was added N,N-dimethylacetamide dimethyl acetal (35.2 ml, 238.20 mmol) slowly at 25° C. and the reaction mixture was stirred for 30 minutes. After completion of the reaction all volatiles were evaporated and the resulting crude product was purified by chromatography (silica gel; hexane/EtOAc 97:3) to obtain the title compound as white solid (27.5 g, 58%). MS: m/z=290 [M]+.
Reaction SMILES: [CH2:1]([C:12]1[NH:13][CH2:14][CH2:15][N:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19]>C(Cl)Cl>[C:17]([CH2:18][CH2:19][N:16]1[CH2:15][CH2:14][N:13]=[C:12]1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])([O:21][CH3:22])=[O:20]
Reactant: CCCCCCCCCCCC1=NCCN1
Reactant: C=CC(=O)OC
Solvent: ClCCl
Product: CCCCCCCCCCCC1=NCCN1CCC(=O)OC
Yield: 72.2 %

Procedure:
2.2 g (9.82 mmoles) of 2-undecyl-2-imidazoline and 1.4 g (16.3 mmoles) of methyl acrylate were dissolved in 50 ml of methylene chloride and the solution was heated to reflux. The reaction was followed by glc. The solution was concentrated and the residue was distilled at 160°-170° C./0.1 mm to give 2.2 g (72.4%) of product.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].Cl[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16]>N1C=CC=CC=1>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH:6][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: CN(C)CCCN
Solvent: c1ccncc1
Product: CN(C)CCCNc1ccccc1[N+](=O)[O-]
Temperature: 125 °C
Reaction time: 13 h
Yield: 99.9 %

Procedure:
N,N-Dimethyl-1,3-propanediamine (3.24 g) was added to a solution containing 2-chloronitrobenzene (2.00 g) in pyridine (2.56 ml). After being stirred for 13 hours at 120-130° C., the reaction mixture was concentrated. The residue, with toluene added thereto, was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated, thereby yielding the entitled compound (2.83 g) as orange oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1.[CH2:17]([NH2:20])[CH2:18][CH3:19].CCN(C(C)C)C(C)C>Cl.CCCCO>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:20][CH2:17][CH2:18][CH3:19])[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1
Reactant: CCCN
Reactant: COc1ccc(Nc2cc(Cl)ncn2)cc1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCCNc1cc(Nc2ccc(OC)cc2)ncn1
Temperature: 200 °C
Yield: 82 %

Procedure:
100 mg of 6-chloro-N-(4-methoxyphenyl)pyrimidine-4-amine in the form of a hydrochloride, 66 mg of propylamine and 120 mg of DIPEA were dissolved in 1 mL of n-BuOH and the mixture obtained was charged into a microwave vial and the vial obtained was heated to 200° C. for 60 minutes under microwave irradiation. Progress of the reaction was monitored by TLC. Upon termination of the reaction n-BuOH was evaporated off and the evaporation residue was subjected to crystallization from n-BuOH-EtOH solvent mixture. N4-(4-Methoxyphenyl)-N6-propylpyrimidine-4,6-diamine was obtained in the form of a colorless solid.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][CH:11]2[CH2:13][CH2:12]2)[N:5]=[C:4]([S:14][CH3:15])[N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O>>[CH:11]1([NH:10][C:6]2[C:7]([CH:8]=[O:9])=[C:2]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[F:16])[N:3]=[C:4]([S:14][CH3:15])[N:5]=2)[CH2:13][CH2:12]1
Reactant: CSc1nc(Cl)c(C=O)c(NC2CC2)n1
Reactant: OB(O)c1ccccc1F
Product: CSc1nc(NC2CC2)c(C=O)c(-c2ccccc2F)n1

Procedure:
Prepared as described above in Example 11 starting from 4-chloro-6-cyclopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 2-fluorophenylboronic acid to give the title compound 4-cyclopropylamino-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 0.66 (m, 2H), 0.92 (m, 2H) 2.60 (s, 3H), 3.11 (m, 1H), 7.10-7.30 (m, 2H), 7.41-7.57 (m, 2H), 9.10 (br s, 1H), 9.66 (s, 1H). LC MS (m/e)=304 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:22])[CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[OH:10].[CH:23]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29])=[O:24].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:21][C:6]1[CH:5]=[N+:4]([O-:22])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@H:9]([O:10][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][CH:33]=[C:25]([CH:23]=[O:24])[CH:26]=1)[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: COc1ccc([C@@H](O)Cc2c(Cl)c[n+]([O-])cc2Cl)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2cccc(C=O)c2)cc1OC
Yield: 90.6 %

Procedure:
A solution of (S)-3,5-dichloro-4-(2-(3,4-dimethoxyphenyl)-2-hydroxyethyl)pyridine 1-oxide (0.688 g, 2 mmol), 3-formylbenzoic acid (0.300 g, 2 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.767 g, 4 mmol), and 4-(dimethylamino)pyridine (0.122 g, 1 mmol) in anhydrous DCM (30 mL) was stirred at RT for 21 hours. The reaction mixture was partitioned between saturated aqueous NaHCO3 (20 mL) and DCM (10 mL) and filtered through a phase separator. The solvent was removed in vacuo and the crude material was purified by silica gel column chromatography eluting with 1:1 DCM:EtOAc to afford the title compound as an off-white solid (0.863 g, 91%).