Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg]I.Cl[C:5]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[C:12]2[C:7](=[CH:8][C:9]([O:26][CH3:27])=[C:10]([O:24][CH3:25])[CH:11]=2)[N:6]=1>C1COCC1>[CH:21]([C:18]1[CH:19]=[CH:20][C:15]([C:13]2[C:12]3[C:7](=[CH:8][C:9]([O:26][CH3:27])=[C:10]([O:24][CH3:25])[CH:11]=3)[N:6]=[C:5]([CH3:1])[N:14]=2)=[CH:16][CH:17]=1)([CH3:23])[CH3:22]
Reactant: COc1cc2nc(Cl)nc(-c3ccc(C(C)C)cc3)c2cc1OC
Reactant: C[Mg]I
Solvent: C1CCOC1
Product: COc1cc2nc(C)nc(-c3ccc(C(C)C)cc3)c2cc1OC
Reaction time: 1 h

Procedure:
To 166 mg (1.16 mmol) CuBr in 4 ml THF are added dropwise at −78° C. 773 μl (2.32 mmol) of a 3M solution of methylmagnesium iodide. After stirring for 20 minutes 50 mg (0.145 mmol) 2-chloro-4-(4-isopropyl-phenyl)-6,7-dimethoxy-quinazoline are added at the same temperature. After stirring for 1 h the reaction mixture is allowed to reach rt and stirring is continued overnight. After dilution with 50 ml ethyl acetate and filtration the reaction mixture is extracted with brine. Evaporation of the organic phase yields the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([I:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[CH:21]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22]1.CC(C)([O-])C.[Na+]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:26][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5]2[C:10]([I:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: NC1CCCC1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)nc(Cl)nc21
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1cc(I)c2c(NC3CCCC3)nc(Cl)nc21
Temperature: 70 °C
Yield: 94 %

Procedure:
2,4-Dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), cyclopentanamine (1 equiv), sodium tert-butoxide (7.5 equiv), and 1,4-dioxane (0.28 M) were combined in a sealable vessel with a stir bar. The resulting mixture was put under nitrogen atmosphere, sealed, stirred vigorously, and heated at 70° C. After cooling to room temperature, the reaction mixture was loaded directly onto a silica gel column and purified using flash chromatography (Biotage) (0-20% ethyl acetate in hexane) to give the title compound (94% yield) as a yellow solid. MS (ESI) m/z 493.2 [M+1]+.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=2)[NH:6][CH:5]=1.[NH:17]1C=CN=[CH:18]1>C1(C)C(C)=CC=CC=1>[N:2]1([CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=3)[NH:6][CH:5]=2)[CH:16]=[CH:18][N:17]=[CH:1]1
Reactant: c1c[nH]cn1
Reactant: CN(C)Cc1c[nH]c2ccc([N+](=O)[O-])cc12
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1ccc2[nH]cc(Cn3ccnc3)c2c1
Yield: 93.5 %

Procedure:
A mixture of N,N-dimethyl-5-nitro-1H-indole-3-methanamine (J.Med, Chem, 9, 140,(1966)) (9.10 g) and imidazole (2.96 g) in xylene (120 ml) was heated under reflux for 2.5 hours and then cooled. The solid was filtered off, washed with ether and dried to give the title compound (9.40 g), m.p. 230°-232° C. (from ethyl acetate/methanol). Found: C,59.85; H,4.39; N,22.80. C12H10N4O2 requires: C,59.50; H,4.16; N,23.13%.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:6][N:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22]CC)=[O:21])=[CH:16][C:15]=2[N+:25]([O-:27])=[O:26])[C:4]1=[O:28].O1CCOCC1.Cl>O>[Cl:1][CH2:2][CH:3]1[CH:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:6][N:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][C:15]=2[N+:25]([O-:27])=[O:26])[C:4]1=[O:28]
Reactant: CCOC(=O)c1ccc(N2OC(c3ccccc3)C(CCl)C2=O)c([N+](=O)[O-])c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(N2OC(c3ccccc3)C(CCl)C2=O)c([N+](=O)[O-])c1

Procedure:
270 g (0.67 mols.) of 4-chloromethyl-5-phenyl-2-(4-ethoxycarbonyl-2-nitrophenyl)isoxazolin-3-one was added to 2.5 liters of 1,4-dioxane, and 300 ml of concentrated hydrochloric acid was added thereto, followed by refluxing the mixture for 8 hours under heating. After cooling, water was added to the reaction solution, and the crystals which precipitated were collected by filtration, washed with water, and dried.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[C:5]([CH3:21])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1.C([Sn](CCCC)(CCCC)[C:37]1[CH:42]=[N:41][CH:40]=[CH:39][N:38]=1)CCC>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:21][C:5]1[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[N:7][C:2]([C:37]2[CH:42]=[N:41][CH:40]=[CH:39][N:38]=2)=[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:4]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(-c2cnccn2)nc1C(=O)N1CCC(N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 50.5 %

Procedure:
To a degassed solution of 0.20 g (0.44 mmol) of [6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 3) in 8.0 ml of DMF was added 0.051 g (0.044 mmol) of tetrakis-(triphenylphosphine)-palladium and the reaction mixture was stirred for 20 min at RT. Then, 0.49 g (1.32 mmol) of 2-tributylstannanyl-pyrazine were added and the reaction was heated up to 100° C. After 6 hours, it was cooled down to RT, poured into crashed ice and extracted three times with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 9:1) to give 0.11 g (50%) of the title compound as yellow oil. MS: 496.2 (MH−).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH2:15])=[CH:12][C:11]([C:16]([F:19])([F:18])[F:17])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[OH:20][CH2:21][CH:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)=[CH:27][C:26]=1[F:41])[CH2:23][OH:24]>CN(C=O)C.O>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH:15][C:32]([NH:31][C:28]3[CH:29]=[CH:30][C:25]([CH:22]([CH2:21][OH:20])[CH2:23][OH:24])=[C:26]([F:41])[CH:27]=3)=[O:33])=[CH:12][C:11]([C:16]([F:17])([F:18])[F:19])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1ccc(C(CO)CO)c(F)c1)Oc1ccccc1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)Nc1ccc(C(CO)CO)c(F)c1
Reaction time: 16 h
Yield: 35.7 %

Procedure:
To a stirred solution of (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (153 mg, 0.4918 mmol, 1.0 eq) in DMF (5 mL) was added TEA (0.205 mL, 1.4754 mmol, 3.0 eq) followed by phenyl 4-(1,3-dihydroxypropan-2-yl)-3-fluorophenylcarbamate (150 mg, 0.4918 mmol, 1.0 eq) at RT and the mixture stirred for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL). The organic layer was washed with water (10 mL) and brine (5 mL), dried over anhydrous Na2SO4, and evaporated under vacuum. The crude product was purified by neutral alumina column chromatography using MeOH/CHCl3 (1:19) as eluent to get 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(4-(1,3-dihydroxypropan-2-yl)-3-fluorophenyl)urea (85.5 mg; 36%) as off white solid; TLC system: MeOH/CHCl3 (1:9); Rf: 0.5).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[C:9]1([O:17][CH3:18])[C:10](=[CH:13][CH:14]=[CH:15][CH:16]=1)[O:11][CH3:12]>>[OH:8][CH:7]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[C:16]1[CH:15]=[CH:14][CH:13]=[C:10]([O:11][CH3:12])[C:9]=1[O:17][CH3:18]
Reactant: O=Cc1ccncc1
Reactant: COc1ccccc1OC
Product: COc1cccc(C(O)c2ccncc2)c1OC

Procedure:
In Scheme F, step d, 4-pyridinecarboxaldehyde (9) is reacted with lithiated veratrole to give 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]pyridine (10).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=2[N:7]=1.[C:26]([O:30][C:31](=[O:38])[NH:32][C@H:33]1[CH2:36][C@H:35]([OH:37])[CH2:34]1)([CH3:29])([CH3:28])[CH3:27]>O1CCCC1.CCOC(C)=O>[C:26]([O:30][C:31](=[O:38])[NH:32][C@H:33]1[CH2:36][C@H:35]([O:37][C:4]2[C:5]3[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=4)=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=3[N:7]=[C:2]([Cl:1])[N:3]=2)[CH2:34]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](O)C1
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccccn2)c2c(Cl)nc(Cl)nc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](Oc2nc(Cl)nc3c2c(-c2ccccn2)cn3COCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,4-dichloro-5-(pyridin-2-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (318 mg, 0.804 mmol) in tetrahydrofuran (8 mL) was added tert-butyl(trans-3-hydroxycyclobutyl)carbamate and potassium hexamethyldisilizane (642 mg, 3.2 mmol) and the mixture stirred at ambient temperature for 1 hr. The reaction mixture was diluted with EtOAc (10 mL) and washed with water (20 mL). The aqueous layer was extracted with EtOAc (three×10 mL) and the combined organics were dried over MgSO4, filtered and stripped to give the title compound (485 mg, 110 yield). The crude material was used for the next step. m/z (APCI+) for C17H33N5O4ClSi 546.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]#[N:15])=[C:12]([CH3:16])[O:11][N:10]=1.C(O[CH:22](N(C)C)[N:23]([CH3:25])[CH3:24])(C)(C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]#[N:15])=[C:12](/[CH:16]=[CH:22]/[N:23]([CH3:25])[CH3:24])[O:11][N:10]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C#N
Solvent: Cc1ccccc1
Product: CN(C)/C=C/c1onc(-c2c(F)cccc2Cl)c1C#N

Procedure:
To a solution of 1.5 g (6.3389 mmol) 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonitrile in 100 mL dry toluene, were added 2.10 g (12.6779 mmol) tert-Butoxy-bis(dimethylamino)methane. The reaction mixture was heated under reflux for 12 h. The mixture was concentrated in vacuo and was dried in the high vacuum. Petroleum ether was added to the crystallized residue. The product was collected by filtration and 1.791 g (yield of theory: 95.9%) of clean product were obtained. Result of LC/MS MH+: 292.0; 1H NMR (DMSO-d6; CCl4): 2.93 (3H, s, N—CH3), 3.17 (3H, s, N—CH3), 5.15-5.20 (1H, d, C2H2), 7.74-7.78 (1H, d C2H2), 7.45-7.52 (1H, dd, CH-arom.), 7.57-7.59 (1H, d, CH-arom.), 7.65-7.71 (1H, d, CH-arom.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[C:9]1[C:14]1[S:30][C:17]2[C:18]3[CH:26]=[CH:25][C:24]([C:27]([O-:29])=O)=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1.O=S(Cl)[Cl:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[C:9]1[C:14]1[S:30][C:17]2[C:18]3[CH:26]=[CH:25][C:24]([C:27]([Cl:33])=[O:29])=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1
Reactant: O=S(Cl)Cl
Reactant: O=C([O-])c1ccc2c(c1)OCCc1cc(-c3n[nH]c(=O)n3-c3ccccc3Cl)sc1-2
Product: O=C(Cl)c1ccc2c(c1)OCCc1cc(-c3n[nH]c(=O)n3-c3ccccc3Cl)sc1-2

Procedure:
A solution of 2-(4-(2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylate acid (400 mg, 0.91 mmol) in 20 mL of SOCl2 was heated at 80° C. for 3 h. Concentration gave 2-(4-(2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carbonyl chloride.
Reaction SMILES: CCN=C=NCCCN(C)C.[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([NH2:23])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[F:24][C:25]([F:44])([F:43])[C:26]1[CH:27]=[C:28]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[C:29]([NH:31][CH2:32][C:33](O)=[O:34])=[O:30]>>[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([NH:23][C:33](=[O:34])[CH2:32][NH:31][C:29](=[O:30])[C:28]2[CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=[C:26]([C:25]([F:24])([F:43])[F:44])[CH:27]=2)[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(O)CNC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Agent: CCN=C=NCCCN(C)C
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CNC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1

Procedure:
The title compounds were prepared as white solids from EDCI coupling between 3-amino-azetidine-1-carboxylic acid tert-butyl ester and (3,5-bistrifluoromethyl-benzoylamino)-acetic acid (prepared by the method similar to Ingersoll, A. W. et. al., Organic Syntheses 1932, XII, 40-2) using the procedure described in Step C of Example 1.
Reaction SMILES: CO[C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH2:12][CH3:13].C([O-])(=O)C.[Na+].[CH2:23]([O:25][CH:26]([O:29][CH2:30][CH3:31])[CH2:27][NH2:28])[CH3:24]>C(#N)C>[CH2:23]([O:25][CH:26]([O:29][CH2:30][CH3:31])[CH2:27][N:28]1[CH:10]([CH:11]([N+:14]([O-:16])=[O:15])[CH2:12][CH3:13])[C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:3]1=[O:17])[CH3:24]
Reactant: CCOC(CN)OCC
Reactant: CCC(=Cc1ccccc1C(=O)OC)[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(CN1C(=O)c2ccccc2C1C(CC)[N+](=O)[O-])OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of 2-(2-nitro-1-butenyl)-benzoic acid methyl ester (49 g, described in Example 29) sodium acetate (27.5 g) and 2,2-diethoxyethanamine (44 g) in acetonitrile (1000 ml) is stirred at 25° C. for 24 hr and filtered. The filtrate is evaporated and the residue is dissolved in chloroform. The organic solution is washed with water, 10% hydrochloric acid and brine, dried and evaporated to obtain the title compound as a mixture of isomers (67 g).
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]2[N:10]=[C:11](Cl)[N:12]=[C:13]([N:14]3[CH2:19][CH2:18][S:17](=[O:20])[CH2:16][CH2:15]3)[C:8]=2[N:7]=[CH:6][N:5]=1)[CH3:2].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CS(C)=O.O>[CH2:1]([S:3][C:4]1[C:9]2[N:10]=[C:11]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:12]=[C:13]([N:14]3[CH2:19][CH2:18][S:17](=[O:20])[CH2:16][CH2:15]3)[C:8]=2[N:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: C1CNCCN1
Reactant: CCSc1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12
Solvent: CS(C)=O
Solvent: O
Product: CCSc1ncnc2c(N3CCS(=O)CC3)nc(N3CCNCC3)nc12
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A solution of 3,4 gm (0.01 mol) of 8-ethylthio-2-chloro-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p. 197°-199° C.) in 100 ml of dimethylsulfoxide was slowly poured, while stirring, into a solution of 4.3 gm (0.05 mol) of piperazine in 75 ml of dimethylsulfoxide at 40° C., and the mixture was stirred for 1 hour at 40° C. The reaction mixture was then taken up in about 1 liter of water, whereby the reaction product slowly precipitated in crystalline form. After standing for a short period of time, the precipitate was suction-filtered off, washed with water and dried at about 70° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]1[C:14]([CH2:19]O)=[N:15][CH:16]=[CH:17][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+]>ClCCl.O>[CH2:5]([O:12][C:13]1[C:14]([CH2:19][Cl:3])=[N:15][CH:16]=[CH:17][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ncccc1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: ClCc1ncccc1OCc1ccccc1
Temperature: 25 °C
Yield: 95 %

Procedure:
25.2 ml of thionyl chloride are added to the solution of 40 g (0.19 mol) of 3-(benzyloxy)-2-(hydroxymethyl)pyridine (CAS 6059-29-6; Desideri, N; Sestili, I; Manarini, S; Cerletti, C; Stein; Eur. J. Med. Chem. Chim. Ther.; 26 (4) 1991; 455-460) in 265 ml of dichloromethane. The solution is stirred at ambient temperature under nitrogen, and then concentrated to dryness. The residue obtained is dissolved in water. Sodium bicarbonate is added until a solution at neutral pH is obtained. The aqueous solution is extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulphate, and then concentrated to dryness. 41 g (95%) of a brown oil are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:24][C:10]1[N:9]=[C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([C:29]3[CH:28]=[N:27][C:26]([NH2:25])=[CH:31][CH:30]=3)[CH:3]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cncc(Br)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cncc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 5′-bromo-6-methyl-4-(4-trifluoromethyl-phenyl)-[2,3′]bipyridinyl (example E.24) (0.15 g, 0.38 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.092 g, 0.42 mmol) according to the general procedure VI. Obtained as a white solid (0.085 g, 54%). MS (ISP) 407.2 [(M+H)+]; mp 161-177° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[C:3]=1[CH2:10][CH3:11].[P:12]([O:19]CC)([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([CH2:10][CH3:11])=[C:4]([CH2:8][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOP(OCC)OCC
Reactant: CCc1c(Br)cccc1CBr
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1cccc(Br)c1CC)OCC
Temperature: 130 °C
Yield: 99.9 %

Procedure:
To a solution of 1-bromo-3-(bromomethyl)-2-ethylbenzene (D134) (1.3 g, 4.68 mmol) in Toluene (10 mL) was added triethyl phosphite (0.818 mL, 4.68 mmol). The reaction solution was heated in a sealed tube at 130° C. for 2 days. The solvent was removed in vacuo to afford diethyl [(3-bromo-2-ethylphenyl)methyl]phosphonate (D135) (1.567 g), which was used directly without further purification. MS (ES): C13H20BrO3P requires 334.0. found 335.0 (M+H+).
Reaction SMILES: [CH2:1]([C:17]1([CH3:75])[CH2:26][CH2:25][C:24]2[C:19](=[C:20]([CH3:74])[C:21]([CH3:73])=[C:22]([O:28][CH2:29][CH2:30][O:31][C:32](=[O:72])[NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([N:41]3[CH2:45][CH:44]([OH:46])[CH2:43][CH:42]3[CH:47]([C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=3)[O:48][CH:49]([C:58]3[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][CH:59]=3)[C:50]3[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=3)=[O:40])[C:23]=2[CH3:27])[O:18]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:76]1(=[O:82])[O:81][C:79](=[O:80])[CH2:78][CH2:77]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:57][O:56][C:53]1[CH:54]=[CH:55][C:50]([CH:49]([C:58]2[CH:59]=[CH:60][C:61]([O:64][CH3:65])=[CH:62][CH:63]=2)[O:48][CH:47]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[CH:42]2[N:41]([C:39](=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][NH:33][C:32]([O:31][CH2:30][CH2:29][O:28][C:22]3[C:23]([CH3:27])=[C:24]4[C:19](=[C:20]([CH3:74])[C:21]=3[CH3:73])[O:18][C:17]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])([CH3:75])[CH2:26][CH2:25]4)=[O:72])[CH2:45][CH:44]([O:46][C:76](=[O:82])[CH2:77][CH2:78][C:79]([OH:81])=[O:80])[CH2:43]2)=[CH:51][CH:52]=1
Reactant: O=C1CCC(=O)O1
Reactant: CCCCCCCCCCCCCCCCC1(C)CCc2c(C)c(OCCOC(=O)NCCCCCC(=O)N3CC(O)CC3C(OC(c3ccc(OC)cc3)c3ccc(OC)cc3)c3ccccc3)c(C)c(C)c2O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCC1(C)CCc2c(C)c(OCCOC(=O)NCCCCCC(=O)N3CC(OC(=O)CCC(=O)O)CC3C(OC(c3ccc(OC)cc3)c3ccc(OC)cc3)c3ccccc3)c(C)c(C)c2O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.3 %

Procedure:
Referring to scheme 7, Compound 19 (5.1 g, 5 mmol) was mixed with succinic anhydride (0.75 g, 7.5 mmol) and DMAP (0.062 g, 0.5 mmol) and dried in a vacuum at 40° C. overnight. The mixture was dissolved in anhydrous dichloromethane (25 mL), triethylamine (1.52 g, 2 mL, 15 mmol) was added and the solution was stirred at room temperature under argon atmosphere for 16 h. It was then diluted with dichloromethane (50 mL) and washed with ice cold aqueous citric acid (5% wt., 50 mL) and water (2×50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness. The crude product was purified by column chromatography to afford compound 21 as white foamy solid (2.85 g, 51% yield; Rf=0.65 in 10% MeOH/CHCl3).
Reaction SMILES: C(#N)C.C(=O)([O-])[O-].[K+].[K+].[C:10]([N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])(OCC)=O.Cl.N[C@@H:28]1[C:33](C)([CH3:34])[CH2:32][CH2:31][C@H:30]([OH:36])[CH2:29]1>O>[OH:36][C@@H:30]1[CH2:31][C@H:10]([N:15]2[C:16](=[O:25])[C:17]3[C:18](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:20])[C:33]([CH3:34])([CH3:32])[CH2:28][CH2:29]1
Reactant: CC1(C)CC[C@H](O)C[C@@H]1N
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC1(C)CC[C@H](O)C[C@@H]1N1C(=O)c2ccccc2C1=O
Reaction time: 2 h
Yield: 52.3 %

Procedure:
Acetonitrile (5 ml), potassium carbonate (3.1 mmol, 423 mg) and N-carboethoxyphthalimide (3.1 mmol, 670 mg) were added to a solution of cis-3-amino-4,4-dimethylcyclohexanol hydrochloride (500 mg, 2.8 mmol) in water (10 ml), and the resulting mixture was stirred as it was for 2 hours. The crystals precipitated were collected by filtration and then recrystallized from chloroform-diethyl ether to obtain cis-2-(5-hydroxy-2,2-dimethylcyclohexyl)-1H-isoindole-1,3(2H)-dione (400 mg, 53%, containing about 10% of trans isomer) as white powder.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:14]([O-:16])=[O:15])[C:8]([O:12][CH3:13])=[C:9](N)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(ON=O)CC(C)C.[CH3:25][S:26]SC>C(#N)C>[C:1]([C:5]1[CH:6]=[C:7]([N+:14]([O-:16])=[O:15])[C:8]([O:12][CH3:13])=[C:9]([S:26][CH3:25])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(N)cc(C(C)(C)C)cc1[N+](=O)[O-]
Reactant: CSSC
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COc1c(SC)cc(C(C)(C)C)cc1[N+](=O)[O-]

Procedure:
2 g 5-tert-butyl-2-methoxy-3-nitro-phenylamine are dissolved in 20 ml acetonitrile, combined successively with 3.6 ml isopentylnitrite as well as 2.4 ml dimethyldisulphide and refluxed for 2 h. The solvents are eliminated in vacuo and the residue is chromatographed on silica gel (petroleum ether/ethyl acetate 90:10).
Reaction SMILES: C(OC([NH:8][C@H:9]1[C@H:14]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:13][CH2:12][N:11]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:10]1)=O)(C)(C)C.[OH-].[Na+]>Cl.C(#N)C>[NH2:8][C@H:9]1[C@H:14]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:13][CH2:12][N:11]([C:21]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
(3S,4S)-benzyl 3-(tert-butoxycarbonylamino)-4-cyclohexylpiperidine-1-carboxylate (35 mg, 0.084 mmol) was dissolved in 1:1 2N aq HCl/acetonitrile (8 mL) and stirred overnight at rt. LC-MS showed the reaction was complete. The reaction mixture was basified with 5% aq NaOH solution to about pH=9. The acetonitrile was removed under vacuum. The aqueous residue was extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with brine (10 mL) and dried over Na2SO4. Concentration afforded (3S,4S)-benzyl 3-amino-4-cyclohexylpiperidine-1-carboxylate (23 mg, 86% yield). The crude product was used in the next step without further purification. LC-MS (3 min) tR=1.31 min., m/z 317 (M+1).