Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[C:9]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)([O-:3])=[O:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][C:24]=1[C:32]([F:35])([F:34])[F:33]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[C:9]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:30]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([Cl:22])=[C:24]([C:32]([F:34])([F:33])[F:35])[CH:25]=2)=[O:31])=[CH:17][CH:16]=1)([O-:3])=[O:2]
Reactant: Nc1ccc(Oc2ccnc3c([N+](=O)[O-])cccc23)cc1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccnc3c([N+](=O)[O-])cccc23)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.4 %

Procedure:
4-(8-Nitroquinolin-4-yloxy)phenylamine (7.5 mg, 0.027 mmol) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate (11.8 mg, 0.054 mmol) were dissolved in tetrahydrofuran, and stirred at room temperature for 12 hours. When the reaction was completed, the solvent was removed by vacuum distillation, and a white solid product was filtered to obtain 12.0 mg of the desired compound (yield 88.9%).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:14]([N:21]=[C:22]=[S:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C.CN(C)C1C=CN=CC=1>[CH:8]1([N:7]([C:22]([NH:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[S:23])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: c1ccc(NC2CCCCC2)cc1
Reactant: S=C=NCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: S=C(NCc1ccccc1)N(c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N-cyclohexylaniline (0.1 ml, 0.57 mmol) in acetonitrile (4 ml) was added a catalytic amount of 4-(dimethylamino)pyridine (5 mg, 0.04 mmol). To this mixture was added benzyl isothiocyanate (0.11 ml, 0.83 mmol) dropwise, and the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, and the residue purified on preparative silica gel plates, developing with 20% ethyl acetate/hexanes, to furnish (N-cyclohexyl-N-phenylamino)-N-benzylthiocarboxamide as a white solid, (M+1)=324.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[C:14]=2[OH:23])=[O:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.IC.[C:26]([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[C:14]=2[O:23][CH3:26])=[O:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(OC)cc(C(=O)c2ccc(OC)c(OC)c2O)c1
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(C(=O)c2ccc(OC)c(OC)c2OC)c1
Temperature: 35 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
To a mixture of (3,5-dimethoxyphenyl)-(2-hydroxy-3,4-dimethoxyphenyl) methanone (1.59 g, 5.00 mmol) in DMF (25 ml) was added iodomethane (0.62 ml, 10.00 mmol), and powdered Na2CO3 (1.06 g, 10.00 mmol) at rt. The suspension was stirred at ˜35° C. overnight. DMF was evaporated in vacuo and to the residue was added CH2Cl2 (100 ml) and washed with H2O (3×80 ml). The white salt was filtered and the solution was washed with 5 N KOH (4×80 ml), H2O (1×80 ml), dried over MgSO4 and concentrated to a brown oil, which was purified via flash column chromatography (20% EtOAc in hexane) to give (3,5-dimethoxy-phenyl)-(2,3,4-trimethoxy-phenyl)methanone as a clear oil (1.49 g, 90%): 1HNMR (CDCl3) δ 7.12 (d, J=8 Hz, 1H, Ar), 6.94 (d, J=2 Hz, 2H, Ar), 6.71 (d, J=8 Hz, 1H, Ar), 6.65 (t, J=2 Hz, 1H, Ar), 3.93 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 3.81 (s, 6H, 2OCH3), 3.79 (s, 3H, OCH3); 13C NMR (CDCl3) δ 195.2, 160.7, 156.3, 152.9, 142.2, 140.5, 126.6, 125.1, 107.7, 106.8, 105.4, 62.0, 61.1, 56.3, 55.7; Anal. Calcd. For C18H20O6: C, 65.05; H, 6.07. Found: C, 64.93; H, 6.09. The product was carried over to the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=O)[CH:3]=1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=[CH:11][C:12]([OH:14])=[O:13])[CH:3]=1
Reactant: O=Cc1cc(Br)ccn1
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cc(Br)ccn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
4-Bromo-pyridin-2-carbaldehyde (10.0 g, 53.5 mmol), malonic acid (12.5 g, 120.5 mmol), and piperidine (4.4 mL, 44.4 mmol) were added to pyridine (32.5 mL). The reaction mixture was stirred at 100° C. for 1 hour, concentrated under reduced pressure, and then distilled water was added thereto. The mixture was filtered and then the resulting solid was dried under reduced pressure to give 6.3 g of the titled compound as a white solid.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[CH:5][N:6]=1.[NH2:15][C:16]1[CH:17]=[C:18]([NH:22][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=1>CC(O)C>[C:11]([C:10]1[CH:13]=[CH:14][C:7]([C:4]2[O:3][C:2]([NH:15][C:16]3[CH:17]=[C:18]([NH:22][S:23]([C:26]([F:29])([F:27])[F:28])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=3)=[N:6][CH:5]=2)=[CH:8][CH:9]=1)#[N:12]
Reactant: N#Cc1ccc(-c2cnc(Cl)o2)cc1
Reactant: Nc1cccc(NS(=O)(=O)C(F)(F)F)c1
Solvent: CC(C)O
Product: N#Cc1ccc(-c2cnc(Nc3cccc(NS(=O)(=O)C(F)(F)F)c3)o2)cc1
Temperature: 80 °C
Yield: 76 %

Procedure:
A mixture of 4-(2-chlorooxazol-5-yl)benzonitrile 2 (0.30 g, 1.47 mmol) and N-(3-aminophenyl)-1,1,1-trifluoromethanesulfonamide 43 (0.35 g, 1.45 mmol) in 2-propanol (25 mL) was heated to 80° C. for 14 h with stirring. Upon cooling, solvent was evaporated and silica column purified (Biotage) (Acetone/hexane as an eluent) to provide N-(3-((5-(4-cyanophenyl)oxazol-2-yl)amino)phenyl)-1,1,1-trifluoromethane sulfonamide 44 (0.45 g, 75% yield) as a solid. MS (ES) m/z 409 (M+H+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)=[CH:4][C:3]=1[N+:14]([O-:16])=O.[N:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH2:24])=[CH:19][CH:18]=1.[OH-].[Na+]>C(O)C>[N:9]1([CH2:8][C:5]2[CH:6]=[CH:7][C:2]3[N:24]=[C:23]([C:20]4[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=4)[N:14]([OH:16])[C:3]=3[CH:4]=2)[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: O=[N+]([O-])c1cc(Cn2ccnc2)ccc1F
Reactant: NCc1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: On1c(-c2ccncc2)nc2ccc(Cn3ccnc3)cc21
Temperature: 60 °C
Reaction time: 6 h
Yield: 61 %

Procedure:
A mixture of 13.2 parts of 1-[(4-fluoro-3-nitrophenyl)methyl]-1H-imidazole, 13 parts of 4-pyridinemethanamine and 80 parts of ethanol was stirred for 6 hours at 60° C. 14.5 Parts of sodium hydroxide were added and the whole was stirred for 30 minutes at 60° C. The reaction mixture was evaporated. The residue was dissolved in 100 parts of water. Hydrochloric acid was added dropwise till a pH between 6 and 7 was reached. The product was filtered off, washed with water and 2-propanol and crystallized from 80 parts of 2-propanol. The product was filtered off and dried, yielding 10.7 parts (61%) of 6-(1H-imidazol-1-ylmethyl)-2-(4-pyridinyl)-1H-benzimidazol-1-ol; mp. 198.1° C. (compound 209).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:31]/[O:32][C:33]2([C:36]([O:38][CH:39]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[CH2:35][CH2:34]2)/[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23][N:24]2[N:28]=[C:27]([CH2:29][OH:30])[CH:26]=[N:25]2)=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.O=[Mn]=O>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:31]/[O:32][C:33]2([C:36]([O:38][CH:39]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[O:37])[CH2:34][CH2:35]2)/[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23][N:24]2[N:28]=[C:27]([CH:29]=[O:30])[CH:26]=[N:25]2)=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2ncc(CO)n2)cs1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2ncc(C=O)n2)cs1
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.4 %

Procedure:
To a solution of benzhydryl 1-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((2R,3S)-2-((4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylate (440 mg, 0.614 mmol) in THF (4 mL) was added MnO2 (1.2 g, 13.51 mmol). After stirring at rt for 20 h, the reaction mixture was filtered through a pad of celite with THF wash (20 mL). The filtrate was concentrated, and the residue was purified via silica gel chromatography (MeOH-DCM, 0-5%) to afford the title compound (300 mg, 68%). LCMS: Rt=1.04 min, m/z=715.3 (M+H). Method 2m_acidic.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([N:11]([CH3:30])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:10].[C:31]1([CH3:41])[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1.[OH-].[Na+]>O1CCOCC1>[S:37]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([N:11]([CH3:30])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:10])([C:34]1[CH:35]=[CH:36][C:31]([CH3:41])=[CH:32][CH:33]=1)(=[O:39])=[O:38]
Reactant: CCCCCCCCCCCCCCCCCCN(C)C(=O)c1ccccc1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCCCCCN(C)C(=O)c1ccccc1COS(=O)(=O)c1ccc(C)cc1

Procedure:
A solution of [2-(hydroxymethyl)phenyl]-N-methyl-N-octadecylformamide and p-toluenesulfonyl chloride in 1,4-dioxane is added to sodium hydroxide solution and the reaction is effected at room temperature to obtain [2-(tosyloxymethyl)phenyl]-N-methyl-N-octadecylformamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18](F)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][C:13]=1[C:25]#[N:26].[CH3:27][N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH2:35][CH2:36][NH2:37])[CH2:30][CH2:29]1>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([NH:37][CH2:36][CH2:35][CH2:34][CH:31]3[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]3)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][C:13]=1[C:25]#[N:26]
Reactant: CN1CCC(CCCN)CC1
Reactant: COc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1F
Solvent: CN1CCCC1=O
Product: COc1cc(Nc2c(C#N)cnc3cc(NCCCC4CCN(C)CC4)c(OC)cc23)c(Cl)cc1Cl
Yield: 38.4 %

Procedure:
Following the procedure used to prepare Example 27, 250 mg (0.64 mmol) of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-fluoro-6-methoxyquinoline-3-carbonitrile is reacted with 600 mg (3.80 mmol) of 3-(1-methylpiperidin-4-yl)propylamine in 2 mL of 1-methyl-2-pyrrolidinone at 105° C. for 18 hours to yield 130 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-{[3-(1-methylpiperidin-4-yl)propyl]amino}quinoline-3-carbonitrile as a white solid, mp 122-124° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[NH:28]1[CH2:33][CH2:32][S:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:28]4[CH2:33][CH2:32][S:31][CH2:30][CH2:29]4)[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: C1CSCCN1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N4CCSCC4)c3)nc12
Temperature: 140 °C
Yield: 55.4 %

Procedure:
A stirred suspension of 500 mg (1.11 mmol) 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide. 1.5 g (11.1 mmol) thiomorpholine and 725 mg (2.23 mmol) cesium carbonate in a thick-walled glass pressure tube fitted with a teflon cap was heated at 140° C. for 48 h. The reaction mixture was then cooled to room temperature and poured onto water. The mixture was extracted three times with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over sodium sulfate, and concentrated in vacuo. Flash chromatography (1/99 methanol/dichloromethane) followed by trituration in ether/ethyl acetate/hexane afforded 290 mg (55%) N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-thiomorpholin-4-yl-isonicotinamide as an off-white crystalline solid. ES-MS m/e (%)): 472 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH2:22]>>[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Reactant: COc1ccc(OC)c(N)c1
Product: COc1ccc(OC)c(Nc2cc(C(F)(F)F)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2,5-dimethoxyaniline (59 mg, 0.386 mmol) similar to Example 58 and isolated as a light brown solid (36 mg, 50%). 1H NMR (DMSO-d6): 9.65 (s, 1H), 8.76-8.73 (m, 1H), 8.32 (d, J=7.8 Hz, 2H), 8.03-7.97 (m, 1H), 7.58-7.54 (m, 2H), 7.05 (d, J=9.0 Hz, 1H), 6.70 (dd, J=3.0, 8.7 Hz, 1H), 3.84 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1(/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:36]1([CH2:42][CH2:43][CH2:44]Br)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1(/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:44][CH2:43][CH2:42][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[C:20]([C:25]([F:28])([F:26])[F:27])[CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: BrCCCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1(/C=C/c2ccc(O)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(/C=C/c2ccc(OCCCc3ccccc3)c(C(F)(F)F)c2)COC(C)(C)OC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Compound 93-8 (400 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (397 mg) and 3-phenylpropylbromide (0.175 ml) were added, and the mixture was stirred at 50° C. for 2 hr, and at 70° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (560 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[C:5]#[CH:6])[CH3:2].[CH3:8][CH:9]([CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[CH2:10][CH2:11][OH:12].CN1CCOCC1>C(OCC)C>[CH2:1]([O:3][C:4](=[O:7])/[CH:5]=[CH:6]/[O:12][CH2:11][CH2:10][CH:9]([CH3:8])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[CH3:2]
Reactant: C#CC(=O)OCC
Reactant: CC(C)=CCCC(C)CCO
Solvent: CN1CCOCC1
Solvent: CCOCC
Product: CCOC(=O)/C=C/OCCC(C)CCC=C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 9.3 %

Procedure:
The reaction was performed in standard glassware under an atmosphere of N2. To 100 ml of diethylether were added 8.0 g (0.82 mol) propiolic acid ethyl ester, 12.8 g (0.82 mol) 3,7-dimethyl-oct-6-en1-ol and 8.3 g (0.82 mol) N-methylmorpholine. This solution was kept without stirring at room temperature for 24 hours. The mixture was evaporated under vacuum and the residue purified by bulb to bulb distillation (bp: 70-75° C.; 0.006 mbar) to yield 19.4 g (76%) of an oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[N:30]=[C:31]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[C:32]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:39]1([C:31]2[C:32]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[C:20]3[N:19]=[C:18]([C:15]4[CH:16]=[CH:17][C:12]([C:8]5([NH2:7])[CH2:9][CH2:10][CH2:11]5)=[CH:13][CH:14]=4)[C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][N:21]3[N:30]=2)[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(-c5ccccc5)c(-c5ccccc5)nn4cc3-c3ccccc3)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1(c2ccc(-c3nc4c(-c5ccccc5)c(-c5ccccc5)nn4cc3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the solution of 9-5 (60 mg, 0.1 mmol) in 1 mL of DCM was added TFA (1 mL) and the mixture was stirred at room temperature for 3 h. The mixture was concentrated by evaporation and the residue was purified by prep.HPLC to give the product 9-6.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]([Br:24])(Br)Br.C(N(CC)CC)C.[C:32]([O:36][C:37](=[O:48])[N:38]([C@H:40]1[CH2:45][CH2:44][C@H:43]([CH:46]=O)[CH2:42][CH2:41]1)[CH3:39])([CH3:35])([CH3:34])[CH3:33]>C(Cl)Cl>[C:32]([O:36][C:37](=[O:48])[N:38]([C@H:40]1[CH2:45][CH2:44][C@H:43]([CH:46]=[C:21]([Br:24])[Br:20])[CH2:42][CH2:41]1)[CH3:39])([CH3:35])([CH3:33])[CH3:34]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C=O)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C=C(Br)Br)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 52.45 g (200 mmol) triphenylphosphine in 200 ml CH2Cl2 was treated with 33.16 g (100 mmol) tetrabromomethane (the reaction heated up to reflux) and after 50 min with 32.06 ml (230 mmol) triethylamine (the reaction heated up to reflux and became dark violet). After cooling (0° C.), 12.83 g (50 mmol) of trans-(4-Formyl-cyclohexyl)-methyl-carbamic acid tert-butyl ester in 125 ml CH2Cl2 were added during 10 min. The solution was stirred for 16 h at RT, evaporated and filtered through silica gel (deactivated with hexane/Et3N) with hexane and then hexane/ether 4:1 to 1:1 as eluent to yield 13.28 g (67%) of trans-[4-(2,2-Dibromo-vinyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester, mp: 93-99° C., dec.; MS: 396 (MH+, 2Br).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[NH:18][C:19]([CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])=[N:20][N:21]=4)[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[NH:18][C:19]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[N:20][N:21]=4)[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1nnc(-c2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCc1nnc(-c2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)[nH]1
Reaction time: 8 h
Yield: 31.3 %

Procedure:
To a flask containing ethyl 3-{5-{3-(4-fluorophenyl)-1H-indazole-5-yl]-4H-1,2,4-triazol-3-yl}propanoate (37mg, 0.1 mmol) was added lithium hydroxide monohydrate (8.2 mg, 0.2 mmol). This was taken up in tetrahydrofuran and allowed to stir under a nitrogen atmosphere overnight. The reaction was acidified slightly. The product was found to be soluble in both the aqueous and organic layers. The layers were concentrated and the product was purified by semipreparative HPLC (20-80% acetonitrile with 0.1% formic acid over 30 minutes). The fractions containing the compound were concentrated to yield the title compound (11 mg, 32% yield). 1H NMR (DMSO-d6) δ 13.5 (s, 1H), 8.6 (s, 1H), 8.0 (m, 3H), 7.6 (d, 1H), 7.4 (t, 2H), 2.95 (m, 2H), 2.7 (m, 2H); ES-MS m/z 352 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH3:18])[C:4](=[O:19])[CH:3]=1.[N:20]([O-])=[O:21].[Na+].C(O)(=O)C>O>[CH2:8]([N:7]1[C:2]([NH2:1])=[C:3]([N:20]=[O:21])[C:4](=[O:19])[N:5]([CH2:16][CH2:17][CH3:18])[C:6]1=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCCn1c(=O)cc(N)n(Cc2ccccc2)c1=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCn1c(=O)c(N=O)c(N)n(Cc2ccccc2)c1=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
2.0 g (7.7 mmol) of 6-amino-1-benzyl-3-propyluracil are heated to 80° C. in 15 ml of water and mixed with a solution of 0.55 g of sodium nitrite in 3 ml of water. After the addition of 1 ml of glacial acetic acid, a red solid is precipitated. The pH is adjusted to 4 and the suspension is stirred for a further 30 minutes at 80° C. After cooling, the crystals are filtered under suction and washed with water. 1.9 g of the title compound are obtained in the form of reddish-violet crystals (86% of theory), m.p. 208°-212° C./decomposition.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([NH:12][C:13]([C:15]2[S:16][C:17]([CH:23]([CH3:25])[CH3:24])=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=2)=[O:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5]>[OH-].[Na+]>[F:1][C:2]1[CH:11]=[C:10]([NH:12][C:13]([C:15]2[S:16][C:17]([CH:23]([CH3:25])[CH3:24])=[C:18]([CH:20]([CH3:21])[CH3:22])[CH:19]=2)=[O:14])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(C(C)C)c(C(C)C)s2)cc1F
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1cc(C(=O)Nc2ccc(C(=O)O)c(F)c2)sc1C(C)C
Yield: 83.9 %

Procedure:
The aforementioned ester (42 mg, 0.116 mmol) was hydrolyzed with sodium hydroxide in a conventional manner, and extraction and recrystallization were performed to obtain the title compound (39, 34 mg, 83%) as colorless prisms.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH2:9])=[O:8])[S:5][CH:6]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>>[CH3:12][N:13]([CH:15]=[N:9][C:7]([C:4]1[S:5][CH:6]=[C:2]([Br:1])[CH:3]=1)=[O:8])[CH3:14]
Reactant: NC(=O)c1cc(Br)cs1
Reactant: COC(OC)N(C)C
Product: CN(C)C=NC(=O)c1cc(Br)cs1
Temperature: 85 °C

Procedure:
A mixture of 4-bromo-thiophene-2-carboxylic acid amide (206 mg, 1.0 mmol) and N,N-dimethylformamide dimethyl acetal (0.5 mL, 3.8 mmol) was heated at 85° C. for 1.5 h. The resulting mixture was cooled, and then concentrated under high vacuum to yield 4-bromo-thiophene-2-carboxylic acid dimethylaminomethyleneamide as a light tan solid, which was directly used in the next step without purification.