Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:35])[CH2:21][C:22]2[C:30]([CH:31]3[CH2:33][CH2:32]3)=[CH:29][C:25]([C:26]([OH:28])=O)=[C:24]([F:34])[CH:23]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH:1]([N:14]1[CH2:15][CH2:16][N:17]([C:20](=[O:35])[CH2:21][C:22]2[C:30]([CH:31]3[CH2:33][CH2:32]3)=[CH:29][C:25]([C:26]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:28])=[C:24]([F:34])[CH:23]=2)[CH2:18][CH2:19]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cc(C2CC2)c(CC(=O)N2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(CC(=O)N2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.3 %

Procedure:
A mixture of 4-(2-(4-benzhydrylpiperazin-1-yl)-2-oxoethyl)-5-cyclopropyl-2-fluorobenzoic acid (35 mg, 0.074 mmol), methanesulfonamide (11 mg, 0.11 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (28 mg, 0.15 mmol) and 4-dimethylaminopyridine (18 mg, 0.15 mmol) in dichloromethane (2 mL) was stirred at room temperature for 16 h. The mixture was diluted with DCM (10 mL), washed with HCl (2M, 8 mL) and brine (8 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Combiflash (30%-40% CH3CN in 0.1% NH4HCO3) to afford target compound (5 mg, 12.3%) as a white solid. LCMS (ESI) Method A: RT=5.17 min, m/z: 550.2 [M+H]+. 1H NMR (500 MHz, DMSO-d6): δ 7.44-7.43 (m, 4H), 7.31-7.26 (m, 5H), 7.21-7.18 (m, 2H), 6.82 (d, J=11.0 Hz, 1H), 4.34 (s, 1H), 3.81 (s, 2H), 3.53 (brs, 4H), 2.88 (s, 3H), 2.28 (brs, 4H), 1.76-1.75 (m, 1H), 0.83-0.81 (m, 2H), 0.51-0.49 (m, 2H).
Reaction SMILES: C([Sn](CCCC)CCCC)CCC.[Cl:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[CH:21]=[C:22]([C:24]3S[CH:26]=[CH:27][N:28]=3)[S:23][C:16]=12.Br[C:30]1[N:31](C)C=CN=1>>[Cl:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[CH:21]=[C:22]([C:24]3[N:31]([CH3:30])[CH:26]=[CH:27][N:28]=3)[S:23][C:16]=12
Reactant: Clc1ccnc2cc(-c3nccs3)sc12
Reactant: Cn1ccnc1Br
Agent: CCCC[Sn](CCCC)CCCC
Product: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Yield: 95 %

Procedure:
Starting from tributyltin compound 98 (scheme 19) and following the procedure described above for the synthesis of compound 10 (scheme 2, step 2, example 12) but replacing 2-bromothiazole with 2-bromo-1-methyl-1H-imidazole, title compound 214 was obtained in 95% yield. MS (m/z) 250.1 (100%), 252.1 (37%), (M+H).
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH2:6]([O:8][C:9](=[O:23])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=1[C:20](=O)[CH3:21])=O)[CH3:7]>C(O)(=O)C>[Br:19][C:16]1[CH:15]=[C:14]2[C:13](=[CH:18][CH:17]=1)[N:12]=[C:10]([C:9]([O:8][CH2:6][CH3:7])=[O:23])[N:5]=[C:20]2[CH3:21]
Reactant: [NH4+]
Reactant: CCOC(=O)C(=O)Nc1ccc(Br)cc1C(C)=O
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(C)c2cc(Br)ccc2n1
Yield: 49.3 %

Procedure:
Ammonium acetate (400.0 mg, 5.19 mmol) was added to ethyl[(2-acetyl-4-bromophenyl)amino](oxo)acetate (163.0 mg, 518.9 μmol) in acetic acid (5.2 mL) at room temperature and the reaction was heated at reflux for 19 hours. The reaction mixture was concentrated, then water was added, and the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 2:3 ethyl acetate:hexanes to give 75.5 mg (49%) of ethyl 6-bromo-4-methyl-2-quinazolinecarboxylate as a solid. 1H NMR (400 MHz, d6-DMSO): δ 8.63 (d, J=2 Hz, 1H), 8.21 (dd, J=9, 2 Hz, 1H), 8.07 (d, J=9 Hz, 1H), 4.41 (q, J=7 Hz, 2H), 2.97 (s, 3H), 1.35 (t, J=7 Hz, 3H). ESI-LCMS m/z 295 (M+H)+.
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[OH-].[Li+].Cl.[NH2:13]O.Cl>C(O)C.O>[NH2:9][C:8]1[CH:7]=[C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])[O:6][N:13]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NO
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(N)no1
Reaction time: 0.5 h
Yield: 62.5 %

Procedure:
In a 100 ml. round bottom 3-neck flask there was placed 2 g. of pivalyl acetonitrile, 25 ml. of ethanol, and 10 ml. of water. While this mixture was refluxed, a solution of 0.89 g. of lithium hydroxide and 1.5 g. of hydroxylamine hydrochloride in 25 ml. of water was added. At the end of the addition, the pH of the reaction mixture was about 7.2. The pH was adjusted to about 6.8 using concentrated aqueous hydrochloric acid. After 30 minutes the pH was about 6.0 and was readjusted to about 6.5 using an aqueous solution of lithium hydroxide. After 1 hour the pH was about 6.2 and was adjusted to about 6.8 using an aqueous solution of lithium hydroxide. At 1.5 hours the pH was about 6.6. At 2 hours the pH was about 6.7. At 21/2 hours the pH was about 6.8. At 3 hours the pH was about 7.0 and was adjusted to about 6.5 using concentrated aqueous hydrochloric acid. After 20 hours the pH was about 7.0. The reaction mixture was cooled and the ethanol stripped on the rotovapor. The solid which precipitated was filtered off and dried. It weighed 1.4 g., had a melting point of about 105°-106° C., and was determined by vpc to contain 98.5% of 3-amino-5-(t-butyl)isoxazole and 1% of 5-amino-3-(t-butyl)isoxazole. Yield: 62.5% of desired isomer.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1.[N+:15]([O-])([OH:17])=[O:16]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[NH:10][C:11]([N+:15]([O-:17])=[O:16])=[C:12]([CH3:14])[N:13]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc(C)c[nH]2)cc1
Reactant: O=[N+]([O-])O
Product: COc1ccc(-c2nc(C)c([N+](=O)[O-])[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 25 %

Procedure:
A mixture of 2-(p-methoxyphenyl)-4-methylimidazole (5.2 g, 0.0277 mole) and 3N HNO3 (125 ml) was stirred at room temperature. After 15 minutes, the mixture was placed in a preheated 90° C. bath. Heating was continued for 20 minutes and the hot solution was quenched in ice-water (250 ml). The yellow solid was collected, washed with water, and suspended in cold saturated NaHCO3 solution (25 ml). After a 15 minute period of stirring, the product was collected and recrystallized from 50% EtOH to yield 1.6 g (25%) of 41; m.p. 198°-204° C. A sample recrystallized from 50% EtOH melted at 199°-204° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:28][O:29][C:30]1[C:31](=[O:58])[C:32]([CH3:57])=[C:33]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([O:49][CH2:50][C:51]3[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=3)=[C:44]([CH:48]=2)[C:45](O)=[O:46])[C:34](=[O:38])[C:35]=1[O:36][CH3:37]>C(Cl)Cl>[CH3:28][O:29][C:30]1[C:31](=[O:58])[C:32]([CH3:57])=[C:33]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([O:49][CH2:50][C:51]3[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=3)=[C:44]([CH:48]=2)[C:45]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=2)=[O:46])[C:34](=[O:38])[C:35]=1[O:36][CH3:37]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)O)c2)=C(C)C1=O
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)Nc3ccc(C(F)(F)F)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 12.4 %

Procedure:
4-Trifluoromethylaniline (0.242 g, 1.500 mmol), triethylamine (0.152 g, 1.500 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.254 g, 1.500 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-pyridylmethyloxy)benzoic acid (0.215 g, 0.500 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.035 g, 0.0618 mmol, 12%).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[OH:9][CH2:10][CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.CCCCCC>C(O)C>[C:1]([C:3](=[CH:17][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH2:10][OH:9])=[CH:20][CH:19]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: O=Cc1ccc(OCCO)cc1
Reactant: CCOC(=O)CC#N
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)C(C#N)=Cc1ccc(OCCO)cc1
Temperature: 25 °C

Procedure:
Ethyl cyanoacetate (1.1 eq.) and 4-(2-hydroxyethoxy)benzaldehyde (1 eq.) were combined in ethanol (1.2 M). The reaction mixture was stirred at RT for 48. To this was then added an equal volume of hexane and the title compound was isolated by filtration as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][C:12]3=[O:25])[CH:9]=2)[C:4]2[CH2:26][CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][C:3]1=2.[ClH:37]>CO.CCOCC>[ClH:37].[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][C:12]3=[O:25])[CH:9]=2)[C:4]2[CH2:26][CH2:27][NH:28][CH2:29][C:3]1=2
Reactant: Cn1c2c(c3ccc(N4CCN(CCc5ccccc5)CC4=O)cc31)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Cn1c2c(c3ccc(N4CCN(CCc5ccccc5)CC4=O)cc31)CCNC2
Reaction time: 18 h
Yield: 33 %

Procedure:
tert-Butyl 9-methyl-7-(2-oxo-4-phenethylpiperazin-1-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (35 mg, 0.071 mmol) was dissolved in MeOH (2 mL), and 2 N HCl in Et2O (10 mL) was added. The reaction was allowed to proceed for 18 h. The mixture was concentrated, and the residue was partitioned between CH2Cl2 and sat. Na2CO3 solution. The organic phase was removed, and the aqueous phase was back extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered and concentrated to dryness. The residue was dissolved in MeOH (1 mL), treated with 2 N HCl in Et2O (12 μL, 0.024 mmol), and concentrated to provide the title compound (10 mg, 33%) as a white solid: 1H NMR (500 MHz, CD3OD) δ 7.60 (d, J=8.3 Hz, 1H), 7.45 (s, 1H), 7.41-7.34 (m, 4H), 7.33-7.27 (m, 1H), 7.67 (d, J=8.2 Hz, 1H), 4.54 (s, 2H), 4.24-4.15 (m, 2H), 4.15-4.03 (m, 2H), 3.91-3.76 (m, 2H), 3.72 (s, 3H), 3.61-3.54 (m, 4H), 3.22-3.16 (m, 2H), 3.14-3.08 (m, 2H); ESI MS m/z 389 [M+H]+; HPLC (Method B) 94.4% (AUC), tR=10.2 min.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][CH:10]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[Se].C(N=C=[Se:41])C1C=CC=CC=1>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][N:9]=[C:10]=[Se:41])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CNCCc1ccccc1
Reactant: [Se]=C=NCc1ccccc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Se]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [Se]=C=NCCc1ccccc1
Yield: 95 %

Procedure:
(AS3.091) A mixture of phenylethylformamide (g, 1.5 mmol), triethylamine (6.4 mmol), 4 Å molecular sieves (g), triphosgene (0.8 mmol), and selenium powder (3.0 mmol) in CH2Cl2 was refluxed and worked up as mentioned for 2a. The crude residue thus obtained was purified by silica gel column chromatography (EtOAc/hexanes 2:98) to give 0.96 g (95%) of 2b as an oil. 1H NMR (CDCl3) δ 3.03 (t, 2H, J=6.9 Hz), 3.81 (t, 2H, J=6.9 Hz) 7.20-7.38 (m, 5H); HRMS (EI) calcd for C9H9NSe, 210.9895; found, 210.9892.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1Cl)[CH3:2].[C:13]1([C:19]2[O:20][CH:21]=[C:22](B3OC(C)(C)C(C)(C)O3)[N:23]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[C:13]1([C:19]2[O:20][CH:21]=[C:22]([C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:4]([O:3][CH2:1][CH3:2])=[O:12])[N:23]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: CC1(C)OB(c2coc(-c3ccccc3)n2)OC1(C)C
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cccnc1-c1coc(-c2ccccc2)n1
Temperature: 65 °C
Yield: 42 %

Procedure:
[1,3-Bis(2,6-Diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride (22 mg, 0.032 mmol) was added to a mixture of ethyl-2-chloronicotinate (120 mg, 0.647 mmol) and 2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (220 mg, 0.811 mmol) in dioxane (5 mL). After the addition of K2CO3 (402 mg, 2.910 mmol) the reaction mixture was heated at 65° C. for 4 h and then allowed to cool to room temperature. Water was added and the mixture was extracted with EtOAc. The combined organic layers were washed with water and dried (MgSO4). Purification of the thus obtained raw product by flash column chromatography (dichloromethane/EtOAc, gradient 5-10% EtOAc) provided the title compound (80 mg, 42%); ESI-MS [M+H+]=295.1.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([CH2:11][CH2:12][CH2:13][N:14]3[C:18]4=[N:19][CH:20]=[C:21]([CH2:23][C:24]5[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=5)[CH:22]=[C:17]4N=N3)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-:30].[NH4+]>O>[N:1]1[C:10]2[CH:9]([CH2:11][CH2:12][CH2:13][NH:14][C:18]3[C:17]([OH:30])=[CH:22][C:21]([CH2:23][C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][N:19]=3)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1cncc(Cc2cnc3c(c2)nnn3CCCC2CCCc3cccnc32)c1
Reactant: [OH-]
Agent: [NH4+]
Solvent: O
Product: Oc1cc(Cc2cccnc2)cnc1NCCCC1CCCc2cccnc21
Reaction time: 0.83 h

Procedure:
A mixture of 3-[3-(5,6,7,8-tetrahydroquinol-8-yl)propyl]-6-(pyrid-3-ylmethyl)-3H-1,2,3-triazolo[5,4-b]pyridine (3.56 g) and polyphosphoric acid (17.5 g) were heated with stirring at 188°-197° C. for 50 minutes. Water (30 ml) was added to the hot residue and, after slight cooling, the solution was basified with aqueous ammonium hydroxide to pH 10 and then extracted with chloroform. The combined chloroform extracts were dried over magnesium sulphate, concentrated in vacuo and the residue was chromatographed on silica eluted with 5% v/v methanol in chloroform to give the title compound as a brown gum (0.68 g). The aqueous portion after extraction, was concentrated to dryness, to give a paste, water (100 ml) was then added, the mixture was refluxed for 1 hour and a brown oil which formed was extracted with chloroform (3×100 ml). The extracts were dried, combined and concentrated to give a further quantity of the title compound as an oil (0.31 g). The two portions of the product were combined, converted to the trihydrochloride with ethanolic HCl and then recrystallised, first from isopropanol and then from isopropanol/methanol to give the title compound as a buff solid (0.5 g).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[OH-].[Na+].O.Cl[C:10]1[N:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[N:11]=1>CC(C)=O>[Cl:17][C:12]1[CH:13]=[C:14]([Cl:16])[N:15]=[C:10]([NH:4][C:3]([NH2:5])=[NH:2])[N:11]=1
Reactant: N=C(N)N
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: N=C(N)Nc1nc(Cl)cc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.7 %

Procedure:
A solution of 141.8 g (1.48 mole) of guanidine hydrochloride, 59.3 g (1.48 m) of sodium hydroxide and 709 ml of water was added to a solution of 183.4 g (0.74 m) of 2,4,6-trichloropyrimidine in 2127 ml of acetone causing a mild exothermic reaction. After stirring for 1 hour at room temperature, a mixture of solid and oil had formed. Refrigeration caused complete crystallization. The crystals were filtered, then suspended in 1200 ml of water and stirred for 1 hour, filtered, washed with water, then acetone and air dried to give 53.0 g (35%) of 4,6-dichloro-2-guanidinopyrimidine, mp>360°.
Reaction SMILES: [NH2:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.O.[C:12](=[O:15])([O-])[O-:13].[K+].[K+]>O1CCCC1.CN(C1C=CN=CC=1)C>[C:2]([O:13][C:12]([NH:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:15])([CH3:8])([CH3:7])[CH3:3]
Reactant: NC1(C(=O)O)CCCCC1
Reactant: O=C([O-])[O-]
Agent: CN(C)c1ccncc1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(C(=O)O)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
To a slurry of 1-amino-1-cyclohexane-carboxylic acid, 5.0 g (35.0 mmol) in 50 mL of tetrahydrofuran and 50 mL of water was added 14.5 g (105.0 mmol) of potassium carbonate, 7.7 g (35.0 mmol) of BOC-anhydride and 5 mg of DMAP. The mixture was stirred overnight at rt. and the organics were evaporated off in vacuo. The aqueous layer was acidified to pH=1 with 5 N HCl and extracted with 20% isopropanol/chloroform. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to dryness to yield 1.83 g (21%) of the desired product as a white oil that solidifies upon standing. MS (IS) 244.2 (M+).
Reaction SMILES: I[CH:2]1[C@H:19]([CH3:20])[C@@:18]2([CH3:21])[C:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:22])=[CH:4][C:3]1=[O:23].C(=O)([O-])[O-].[Li+].[Li+].O>CN1CCCC1=O>[CH3:20][C:19]1[C@@:18]2([CH3:21])[C:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:22])=[CH:4][C:3](=[O:23])[CH:2]=1
Reactant: C[C@H]1C(I)C(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC1=CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]12C

Procedure:
14.9 g of 2-iodo-1α-methyl-androst-4-ene-3,17-dione crude product of example 7 and 4.73 g (64 mmol) of anhydrous lithium carbonate are stirred in 95 ml of N-methyl-pyrrolidone for 1 hour at 130° C. under nitrogen atmosphere. After cooling of the reaction solution it is added to 0.6 1 of water and the product is extracted 3 times with 450 ml of ethyl acetate. The combined ethyl acetate phases are dried on sodium sulfate and then concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate/hexane as mobile solvent. After concentration by evaporation of the fractions and recrystallization of the substance from ethyl acetate, 6.9 g of 1-methyl-androsta-1,4-diene-3,17-dione (69% of theory over 2 stages relative to 1α-methyl-androst-4-ene-3,17-dione in example 7) of melting point 168°-169° C. is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][N:11](C(OC(C)(C)C)=O)[CH2:12][CH:13]=2)=[CH:4][CH:3]=1.Cl>ClCCl.C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Fc1ccc(C2=CCNCC2)cc1
Reaction time: 8 h
Yield: 141.1 %

Procedure:
A solution of Example 6B (0.5 g, 1.8 mmol) in dichloromethane (5 mL) at room temperature was treated with 2M HCl in diethyl ether (5 mL), stirred overnight, and concentrated to provide the desired product (0.45 g, 95%). MS (ESI) m/e 178 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:10][CH2:11][C:12]#N.C>O>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:12]([CH2:11][Cl:10])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: N#CCCl
Reactant: Nc1cc(Br)cnc1N
Solvent: O
Product: ClCc1nc2cc(Br)cnc2[nH]1
Temperature: 100 °C

Procedure:
3.0 g of 5-bromo-2,3-diaminopyridine (S.-X. Cai et al., J. Med. Chem. 1997, 40(22), 3679-3686) in 120 g of polyphosphoric acid are heated at 160° C. for 0.5 h. The solution is cooled to 100° C. and 1.26 ml of chloroacetonitrile are added. Thereafter, the reaction mixture is heated to 170° C. for 22 h. After cooling, the polyphosphoric acid is hydrolysed with 81 ml of water. After reheating to 90° C., charcoal is added under vigorous stirring. Subsequently, the suspension is filtered through a celite pad while still hot (70° C.). The filter cake is rinsed with 85 ml of water and the pH 4 using 9 M aqueous sodium hydroxide solution. The precipitate is collected, suspended in 100 ml of hot methanol and filtered over celite. The filtrate is concentrated to dryness to afford 2.78 g of the title compound as a beige, amorphous solid. M.p. >325° C. MS: 246.2/248.2/250.3 (MH+, 77%/100%/25%). TLC: Rf=0.42 (dichloromethane/methanol 10:1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[C:9]([S:11][CH2:12][C:13](=O)[CH3:14])[CH:8]=[C:7]([C:16]([F:19])([F:18])[F:17])[CH:6]=1)[CH3:2].Cl.[Cl:22][C:23]1[CH:24]=[C:25]([NH:29]N)[CH:26]=[CH:27][CH:28]=1>>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:6]=[C:7]([C:16]([F:19])([F:18])[F:17])[CH:8]=[C:9]([S:11][C:12]2[C:26]3[C:25](=[CH:24][C:23]([Cl:22])=[CH:28][CH:27]=3)[NH:29][C:13]=2[CH3:14])[CH:10]=1)[CH3:2]
Reactant: NNc1cccc(Cl)c1
Reactant: CCOC(=O)c1cc(SCC(C)=O)cc(C(F)(F)F)c1
Agent: Cl
Product: CCOC(=O)c1cc(Sc2c(C)[nH]c3cc(Cl)ccc23)cc(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: 3-trifluoromethyl-5-(2-oxo-propylsulfanyl)-benzoic acid ethyl ester and 3-chlorophenylhydrazine hydrochloride.
Reaction SMILES: [C:1]([C:6]1[C:18]([CH3:19])=[CH:17][C:9]2[N:10]([CH3:16])[C:11]([C:13]([OH:15])=[O:14])=[N:12][C:8]=2[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[C:20](#N)[CH3:21].C(N(CC)CC)C.C(OC(OCC)=O)(=O)OCC>C(OCC)(=O)C>[C:1]([C:6]1[C:18]([CH3:19])=[CH:17][C:9]2[N:10]([CH3:16])[C:11]([C:13]([O:15][CH2:20][CH3:21])=[O:14])=[N:12][C:8]=2[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cc2nc(C(=O)O)n(C)c2cc1C
Reactant: CC#N
Agent: CCOC(=O)OC(=O)OCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCC(=O)c1cc2nc(C(=O)OCC)n(C)c2cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.0 g of 5-butyryl-1,6-dimethyl-benzimidazole-2-carboxylic acid are introduced, in the course of 15 minutes, into a mixture of 150 ml of acetonitrile, 15 ml of triethylamine and 18.5 g of diethyl pyrocarbonate, while stirring at room temperature. The mixture is left to stand overnight, the acetonitrile is stripped off under reduced pressure, the residue is taken up in ethyl acetate and the resulting solution is washed with water, dried over sodium sulphate and evaporated to dryness. Ethyl 5-butyryl-1,6-dimethyl-benzimidazole-2-carboxylate, which is initially obtained as an oil but soon crystallises, is filtered off. When recrystallised from ethyl acetate/cyclohexane, it melts at 106°-108°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.N#N.[CH3:12][O:13][C:14]([C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[NH2:19])=[O:15].Cl>O.CO>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][C:18]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:16]([C:14]([O:13][CH3:12])=[O:15])[CH:17]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: COC(=O)c1cc(N)ccc1OC
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Cl
Agent: N#N
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(Nc2nc(Cl)ncc2F)ccc1OC
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
The reaction flask equipped with a magnetic stirring bar and a rubber septum (to prevent loss of 2,4-dichloro-5-fluoropyrimidine and N2 inlet was charged with 3-methyloxycarbonyl-4-methoxyaniline (0.88 g, 4.86 mmol), MeOH (3 mL), H2O (7 mL) and 2,4-dichloro-5-fluoropyrimidine (0.81 g, 4.86 mmol). The reaction mixture was stirred at 60° C. for 30 min., diluted with H2O (50 mL), acidified with 2N HCl (6 mL) and sonicated. The solid obtained was filtered, washed with H2O and dried to produce 2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamine R940302. 1H NMR (DMSO-d6): δ 10.10 (1H, s), 8.39 (1H, d, J=3.6 Hz), 8.04 (1H, d, J=2.7 Hz), 7.98-7.93 (1H, m), 7.30 (1H, d, J=9 Hz), 3.92 (3H, s), 3.89 (3H, m); purity 96%; MS (m/e): 312 (MH+).