Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[CH2:12]([OH:14])[CH3:13]>CCOCC>[ClH:2].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[NH:11])[O:14][CH2:12][CH3:13])=[CH:5][CH:4]=1
Reactant: CCO
Reactant: N#CCc1ccc(Cl)cc1
Agent: Cl
Solvent: CCOCC
Product: CCOC(=N)Cc1ccc(Cl)cc1
Reaction time: 72 h

Procedure:
Dry hydrogen chloride was passed into a mixture of 4-chlorophenylacetonitrile (50.5 g.) and dry ethanol (16.1 g., 20.1 ml.) until a weight increase of 14.6 g. was obtained. The mixture was allowed to stand at room temperature for 3 days; the resulting crystalline mass was broken up, digested thoroughly with dry ether, filtered, and dried in vacuo to give ethyl 4-chlorophenylacetimidate hydrochloride.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[NH:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13]=[O:14].[CH3:15][Si:16]([CH3:23])([CH3:22])[CH2:17][CH2:18][O:19][CH2:20]Cl>CCCCCC>[CH3:15][Si:16]([CH3:23])([CH3:22])[CH2:17][CH2:18][O:19][CH2:20][N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13]=[O:14]
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=Cc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C[Si](C)(C)CCOCn1ccnc1C=O
Reaction time: 1.5 h
Yield: 98 %

Procedure:
Sodium hydride (463 mg, 60% dispersion in mineral oil, 11.4 mmol) was washed with hexane under an atmosphere of dry nitrogen. N,N-Dimethylformamide (15 ml) was added, the resultant mixture was stirred at room temperature and imidazole-2-carboxaldehyde (1 g, 10.4 mmol) was added portionwise. The reaction was then stirred for 1.5 hours, 2-(trimethylsilyl)ethoxy methyl chloride (2.03 ml, 11.4 mmol) was added, and the resultant mixture was then stirred at room temperature for 18 hours. The reaction was quenched by the addition of aqueous ammonium chloride solution and the resultant mixture then extracted with ethyl acetate (2×). The combined organic extracts were dried (Na2SO4), filtered, concentrated under reduced pressure and then azeotroped with xylene to give the title compound, 2.3 g, 98% yield.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:21])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH2:3]1.C1COCC1.[H][H]>C(O)C.[Pd]>[OH:1][C@@H:2]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:21])[CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)[CH2:3]1
Reactant: [H][H]
Reactant: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)C=Cc3ccncc3)CC[C@@H]12
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)CCc3ccncc3)CC[C@@H]12
Reaction time: 5 h
Yield: 37.9 %

Procedure:
A solution of 3α-hydroxy-21-(4-pyridylmethylene)-5β-pregnan-20-one (100 mg, 0.245 mmol) in 4 mL each of ethanol and THF containing 20 mg of 5% Pd/C was subjected to hydrogen atmosphere via a balloon, and stirred for 5hours. The catalyst was then filtered off and the solution concentrated in vacuo. The residue was subjected to flash column chromatography eluting with hexane:acetone to give the title compound (38 mg) as a solid; TLC Rf (hexane:acetone 2:1)=0.28.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][CH:27]([CH2:30][OH:31])[CH2:28][OH:29]>CN1CCCC1=O.O>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:26][CH:27]([CH2:30][OH:31])[CH2:28][OH:29])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: NC(CO)CO
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(CO)CO)c2c1
Temperature: 160 °C
Reaction time: 16 h
Yield: 15 %

Procedure:
A solution of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (200.0 mg, 0.54 mmol, prepared in analogy to the one in Example 2-1) and 2-aminopropane-1,3-diol (420.0 mg, 4.6 mmol) in 1-methyl-2-pyrrolidinone (1.0 mL) was stirred at 160° C. for 16 hours. After being cooled to room temperature and diluted with water (50 mL), the resulting mixture was extracted with ethyl acetate (100 mL), washed with brine (50 mL×2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford 34.6 mg of the product as a white solid (yield was 15%). MS obsd. (ESI+) [(M+H)+] 428, 1H NMR (400 MHz, CD3OD) δ ppm 7.99 (dd, J=7.83, 1.01 Hz, 1 H), 7.86 (d, J=7.07 Hz, 1 H), 7.71-7.58 (m, 2 H), 7.51-7.40 (m, 2 H), 7.36-7.24 (m, 1 H), 6.16 (s, 1 H), 5.16 (s, 2 H), 4.79-4.59 (m, 1 H), 4.54 (brs, 1 H), 3.81 (s, 5 H), 3.69-3.50 (m, 2 H), 2.42 (s, 3 H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.O.[CH3:16][N:17]1CCCC1=O>>[C:16]([C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3)#[N:17]
Reactant: CN1CCCC1=O
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Solvent: O
Product: N#Cc1ccc2[nH]c3ccccc3c2c1
Yield: 40 %

Procedure:
A solution of 3-bromo-9H-carbazole (23.08 g, 0.094 mol) and cuprous cyanide (9.33 g, 0.103 mol) in N-methyl-pyrrolidone (300 ml) was heated at 200° C. for 5 h. The cooled reaction mixture was poured on to water (600 ml) and the precipitate was filtered off and washed with ethyl acetate (3×50 ml). The filtrate was extracted with ethyl acetate (3×250 ml) and the combined ethyl acetate extracts were washed with water (150 ml), brine (150 ml), dried (MgSO4) and concentrated in vacuo. The residue was crystallised from heptanes and recrystallised from acetonitrile (70 ml) affording 7.16 g (40%) of 3-cyano-9H-carbazole as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([I:13])[CH:3]=1.Br[CH:15]([CH3:17])[CH3:16]>>[Cl:1][C:2]1[C:11]([O:12][CH:15]([CH3:17])[CH3:16])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([I:13])[CH:3]=1
Reactant: CC(C)Br
Reactant: Oc1c(Cl)cc(I)c2cccnc12
Product: CC(C)Oc1c(Cl)cc(I)c2cccnc12
Yield: 80 %

Procedure:
Following the procedure described in Example 8, 7-chloro-5-iodo-8-hydroxy-quinoline 20 and 2-bromopropane gave 7-chloro-5-iodo-8-isopropoxy-quinoline 21 (80%). 1H NMR (CDCl3/DMSO-d6 (19:1), 400 MHz): δ 9.09 (m, 1 H), 8.55 (m, 1 H), 8.10 (s, 1 H), 7.63 (m, 1 H), 5.15 (m, 1 H), 1.49 (s, 3 H), 1.47 (s, 3 H).
Reaction SMILES: [CH2:1]([N:9]1[C:18]2[C:13](=[C:14]([CH3:26])[C:15]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:16]([CH3:19])[CH:17]=2)[CH2:12][CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[N+:27]([O-])([OH:29])=[O:28].C(=O)([O-])O.[Na+]>C(OC(=O)C)(=O)C>[CH2:1]([N:9]1[C:18]2[C:13](=[C:14]([CH3:26])[C:15]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:16]([CH3:19])[C:17]=2[N+:27]([O-:29])=[O:28])[CH2:12][CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN1CCCc2c1cc(C)c(CC(=O)OCC)c2C
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCN1CCCc2c(C)c(CC(=O)OCC)c(C)c([N+](=O)[O-])c21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
1 -Octyl-6-ethoxycarbonylmethyl-5,7-dimethyl-1,2,3,4-tetrahydro-quinoline (1.0 g) was dissolved in acetic anhydride (5 ml), and a solution of 70% nitric acid (517 mg) in acetic anhydride (3 ml) was dropwise added, which was followed by stirring at the same temperature for 0.5 hr. The reaction mixture was poured into ice water (50 ml), neutralized with saturated aqueous solution of sodium hydrogencarbonate, and extracted with chloroform (50 ml). After washing with water, the chloroform layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane-ethyl acetate/n-hexane=1/5) to give 700 mg of oily 1-octyl-6-ethoxycarbonylmethyl-5,7-dimethyl-8-nitro-1,2,3,4-tetrahydroquinoline.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][NH2:13])[CH:10]=2)[C:5]([NH2:14])=[N:4][CH:3]=1.[C:15]([CH:18]1[C:23](=[O:24])[CH2:22][C:21]([CH3:26])([CH3:25])[CH2:20][C:19]1=O)(=O)[CH3:16]>CCO.C(O)(=O)C>[NH2:14][C:5]1[C:6]2[C:11](=[CH:10][C:9]([N:12]3[C:19]4[CH2:20][C:21]([CH3:25])([CH3:26])[CH2:22][C:23](=[O:24])[C:18]=4[C:15]([CH3:16])=[N:13]3)=[CH:8][CH:7]=2)[C:2]([Br:1])=[CH:3][N:4]=1
Reactant: CC(=O)C1C(=O)CC(C)(C)CC1=O
Reactant: NNc1ccc2c(N)ncc(Br)c2c1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1nn(-c2ccc3c(N)ncc(Br)c3c2)c2c1C(=O)CC(C)(C)C2
Yield: 80.6 %

Procedure:
A suspension of 4-Bromo-6-hydrazino-isoquinolin-1-ylamine (0.097 g, 0.38 mmol) and 2-acetyl-5,5-dimethyl-1,3-cyclohexanedione (0.074 g, 0.41 mmol) in EtOH/Acetic acid (3:1, 7 mL) is microwaved at 150° C. for 20 min. The solvent is evaporated and the residue is dried under vacuum. Purification of the crude material using a Biotage column (0-10% MeOH/CH2Cl2) afforded 0.1223 g (80%) of 1-(1-Amino-4-bromo-isoquinolin-6-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indazol-4-one. LC/MS m/z=400 [M+H]+.
Reaction SMILES: C(O[C:4]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)=[O:5])C.[CH2:11]([Mg]Br)[CH3:12].S(=O)(=O)(O)O>C(OCC)C>[S:8]1[CH:9]=[CH:10][C:6]([C:4]2([OH:5])[CH2:12][CH2:11]2)=[CH:7]1
Reactant: CC[Mg]Br
Reactant: CCOC(=O)c1ccsc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: OC1(c2ccsc2)CC1
Reaction time: 1.5 h

Procedure:
1.37 ml (10.00 mmol) ethylthiophene-3-carboxylate and 0.29 ml (1.00 mmol)titanium tetra-isopropyloxide are placed in 5 ml diethyl ether, 21.20 ml (21.20 mmol) ethylmagnesium bromide (Grignard reagent in tetrahydrofuran) in 15 ml diethyl ether are added dropwise within 1 hour, while the temperature should not rise above 20° C. The reaction mixture is stirred for 1.5 hours, then hydrolysed with 10% sulphuric acid. The aqueous phase is extracted with diethyl ether, the combined organic phases are dried and evaporated to dryness. The residue is purified by chromatography. Yield: 0.330 g (24% of theoretical)
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[C:11]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22])#[N:12]>>[CH3:8][C:6]1([CH3:9])[CH2:7][C:2]2[N:1]=[C:2]3[CH:3]([C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7]3)[CH:17]([C:16]3[CH:19]=[CH:20][C:13]([C:11]#[N:12])=[C:14]([N+:21]([O-:23])=[O:22])[CH:15]=3)[C:3]=2[C:4](=[O:10])[CH2:5]1
Reactant: N#Cc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: CC1(C)CC(=O)C=C(N)C1
Product: CC1(C)CC(=O)C2C(=NC3=C(C(=O)CC(C)(C)C3)C2c2ccc(C#N)c([N+](=O)[O-])c2)C1

Procedure:
Reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 4-cyano-3-nitrobenzaldehyde in an analogous manner to that described in Example 1 gave 4-(2,3,4,5,6,7,8,9-octahydro-3,3,6,6-tetramethyl-1,8-dioxo-1H-acridin-9-yl)-2-nitrobenzonitrile. Crystallization from methanol gave a yellow crystalline solid of melting point 274-275° C.
Reaction SMILES: O[CH:2]([N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])[CH3:3].[C:10]([O:16]CC)(=[O:15])[CH2:11][C:12]([CH3:14])=[O:13].[Na]>>[C:10]([O:16][CH2:3][CH2:2][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])(=[O:15])[CH2:11][C:12]([CH3:14])=[O:13]
Reactant: CC(O)N1CCCC1=O
Reactant: CCOC(=O)CC(C)=O
Agent: [Na]
Product: CC(=O)CC(=O)OCCN1CCCC1=O
Yield: 4 %

Procedure:
A mixture of 20 g (0.16 mol) of 1-hydroxyethyl-2-oxo-pyrrolidine, 40 g (0.31 mole) of ethyl acetoacetate and 100 mg of sodium was heated at 140°-150° C. for six hours. Residual ethanol was removed in vacuo and the resultant oil was kugelrohr distilled (200° C./1 mm) to give 1.38 g (40%) of the product. NMR: (CDCl3) δ 2.1 (7H, m), 3.4 (6H, m) 4.1 (2H, t)
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)[CH:17]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:34]2)=CC=1.C(=O)(O)[O-].[Na+]>ClC(Cl)C>[CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)[CH:17]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[S:34]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CNC(=O)c1cc(C(=O)OC(C)(C)C)cc(-c2ccc(C)cn2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CNC(=S)c1cc(C(=O)OC(C)(C)C)cc(-c2ccc(C)cn2)c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 3-[(methylamino)carbonyl]-5-(5-methylpyridin-2-yl)benzoate (1.0 g, 3.06 mmol) in dichloroethane (8 mL) was added 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (0.68 g, 1.69 mmol). The reaction mixture was heated to 50° C. After 3 h, saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→90% dichloromethane/methanol) gave the title compound. MS 343.0 (M+1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O.[NH:33]1[CH:37]=[CH:36][N:35]=[CH:34]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([N:33]1[CH:37]=[CH:36][N:35]=[CH:34]1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1c[nH]cn1
Reactant: CCCCCCCCC(O)CCCCCCCCCOCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCCCCCCCC(CCCCCCCCCOCc1ccccc1)n1ccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.7 %

Procedure:
18-(benzyloxy)octadecan-9-ol (6 g, 15.93 mmol), DMAP (0.195 g, 1.59 mmol) and TEA (2.9 ml, 20.71 mmol) in dry DCM (90 ml) were cooled to 0° C., then methanesulfonyl chloride (1.64 ml) was added under N2. The reaction was warmed to room temperature and stirring continued for another 3 h. The reaction mixture was diluted with DCM (100 ml), washed with 1N HCl, water, and brine solution and dried over MgSO4. The crude compound and imidazole (2.17 g, 31.86 mmol) were then heated at 70° C. for 16 h. The crude product was purified by silica gel column (1.5% MeOH in DCM) to give 1-(18-(benzyloxy)octadecan-9-yl)-1H-imidazole as a gummy liquid (2.22 g, 33%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[NH:13])SC)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH4+:14].[OH-]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH2:13])=[NH:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: [NH4+]
Reactant: CSC(=N)Nc1ccc(Cl)c(Cl)c1
Agent: [OH-]
Solvent: CCO
Product: N=C(N)Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
To the solution of 13 (2.29 g, 6.31 mmol) in 23 ml of ethanol was added 6.87 ml of NH4OH. The reaction mixture was stirred at room temperature for 10 minutes, and the clear solution was refluxed for 12 hours. The solvent was removed under reduced pressure and the residue was suspended in saturated Na2CO3 solution. The solid was collected, washed sequentially with H2O and Et2O and dried to give the title compound as a white solid (1.16 g, 90%), mp 208° C. 1H NMR (600 MHz, DMSO-d6): δ 7.39 (d, J=8.6 Hz, 1H), 7.02 (d, J=2.4 Hz, 1H), 6.79 (dd, J=8.6 and 2.4 Hz, 1H), 5.79 (br s, 3H); 13C NMR: δ 155.38, 130.69, 130.28, 124.30, 123.50. IR: 1684, 1624, 1559, 1472, 1380, 1328, 869, 818, 671 cm−1. MS (m/z): 204 (M+), 187, 162, 127, and 90.
Reaction SMILES: Cl[C:2](Cl)=[CH:3][CH:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[N:10]=1)=[O:8])[CH3:5].[OH-:27].[Na+]>CN1CCCC1=O>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([C:7]2[O:8][C:3]([CH2:2][OH:27])=[C:4]([CH3:5])[N:6]=2)=[N:10]1
Reactant: [OH-]
Reactant: CC(C=C(Cl)Cl)NC(=O)c1nn(Cc2ccccc2F)c2ccccc12
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1nc(-c2nn(Cc3ccccc3F)c3ccccc23)oc1CO
Yield: 60 %

Procedure:
730 mg of 1,1-dichloro-3-[1-(2-fluorobenzyl)indazole-3-carboxamido]-but-1-ene (1.86 mmol) and 3.75 ml of NaOH, 1N (3.75 mmol) were stirred in 7.4 ml of N-methylpyrrolidone at 50° C. under argon overnight. After cooling, the mixture was poured onto ice-water and the product which had precipitated out was filtered off and dried. Finally, it was purified by column chromatography (SiO2, cyclohexane:ethyl acetate 2:1). 375 mg (60%) of 2-[1-(2-fluorobenzyl)indazol-3-yl]-5-hydroxymethyl-4-methyl-oxazole were obtained as white crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:26][CH2:25][C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[C:5]([Cl:27])=[CH:4][N:3]=1.Cl.[CH3:29][N:30]1[CH:34]=[C:33]([NH2:35])[CH:32]=[N:31]1.CCN(C(C)C)C(C)C>CCCCO>[Cl:27][C:5]1[C:6]([NH:8][CH:9]2[CH2:26][CH2:25][C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)=[N:7][C:2]([NH:35][C:33]2[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3nc(Cl)ncc3Cl)CC2)CC1
Reactant: Cn1cc(N)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cn1cc(Nc2ncc(Cl)c(NC3CCC4(CC3)CCN(C(=O)OC(C)(C)C)CC4)n2)cn1
Temperature: 150 °C
Reaction time: 8 h
Yield: 33.2 %

Procedure:
To a solution of tert-butyl 9-((2,5-dichloropyrimidin-4-yl)amino)-3-azaspiro[5.5]undecane-3-carboxylate (230.0 mg, 0.55 mmol) and 1-methyl-1H-pyrazol-4-amine hydrochloride (185.4 mg, 1.39 mmol) in n-BuOH (3 mL) was added DIPEA (215.7 mg, 1.67 mmol). The mixture was stirred at 150° C. overnight and then concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/100 to 1/70) to give the product as a light yellow solid (87.0 mg, 33.0%).
Reaction SMILES: C(O[K])(C)(C)C.[OH:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=[O:11].Cl[CH2:17][O:18][CH3:19]>CN(C=O)C>[CH3:17][O:18][CH2:19][O:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=[O:11]
Reactant: O=Cc1ccccc1O
Reactant: COCCl
Agent: CC(C)(C)O[K]
Solvent: CN(C)C=O
Product: COCOc1ccccc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
Into a solution of tert-butoxy potassium (30.0 g, 0.27 mol) in DMF (200 mL) was dropped a solution of 2-hydroxybenzaldehyde (30.0 g, 0.25 mol) in DMF (100 mL) at 0° C. followed by stirring at room temperature for 1 hour. After addition of DMF (200 mL) thereto, a solution of chloromethylmethyl ether (21 mL, 0.27 mol) in DMF (200 mL) was dropped thereinto at 0° C. following by stirring at room temperature for 20 hours. The reaction mixture was poured over ice water followed by extracting with diethyl ether. The organic layer was washed with a 10% aqueous sodium hydroxide and a saturated saline solution successively and then dried over anhydrous sodium sulfate. The solvent was evaporated therefrom in vacuo to give the title compound (32.6 g, 80%) as an oily substance.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:25]3[C:24](=[O:26])[NH:23][CH:22]=[N:21][C:20]=3[O:19][CH:18]=2)=[CH:13][CH:12]=1)[CH3:10]>C(#N)C.ClC(Cl)(Cl)Cl>[CH2:9]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[C:25]3[C:24](=[O:26])[NH:23][CH:22]=[N:21][C:20]=3[O:19][C:18]=2[I:1])=[CH:15][CH:16]=1)[CH3:10]
Reactant: CCc1ccc(-c2coc3nc[nH]c(=O)c23)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: CCc1ccc(-c2c(I)oc3nc[nH]c(=O)c23)cc1
Temperature: 25 °C

Procedure:
Add 7.0 g (31.3 mmol) of N-iodosuccinimide to a solution of 5.0 g (20.9 mmol) of 5-(4-ethylphenyl)furo[2,3-d]pyrimidin-4(3H)-one in 250 ml of acetonitrile/tetrachloromethane (1:1). Stir the resulting suspension under reflux for two hours. After cooling to room temperature, concentrate the reaction mixture under reduced pressure. Stir the residue in ethyl acetate and filter. Add water to the filtrate. After removal of the organic phase, extract the aqueous phase repeatedly with ethyl acetate. Concentrate the combined organic phases under reduced pressure. Take up the residue in ethyl acetate and chromatograph it on silica gel (eluent: cyclohexane/ethyl acetate 1:1→1:2). Stir the resulting solid in diethyl ether/n-pentane and filter. 1.4 g (85% purity, 16% of theory) of the target compound are obtained.
Reaction SMILES: S(Cl)([Cl:3])=O.O[C:6]1[C:7]2[C:14]([C:15]3[S:16][CH:17]=[CH:18][N:19]=3)=[CH:13][S:12][C:8]=2[N:9]=[CH:10][N:11]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:3][C:6]1[C:7]2[C:14]([C:15]3[S:16][CH:17]=[CH:18][N:19]=3)=[CH:13][S:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: Oc1ncnc2scc(-c3nccs3)c12
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ncnc2scc(-c3nccs3)c12
Temperature: 73 °C
Yield: 27.1 %

Procedure:
A mixture of thionyl chloride (15 ml, 200 mmol), 4-hydroxy-5-(thiazol-2-yl)thieno[2,3-d]pyrimidine (1.44 g, 12 mmol) and N,N-dimethylformamide (3 mL) was heated at 73° C. for 3 hours and then carefully poured into 200 mL of ice/water. The pH was adjusted to between 7 and 8 with sodium bicarbonate and then the product was extracted with ethyl acetate (2×450 mL). The organic fractions were combined, dried (MgSO4) and concentrated. The resulting residue was purified by column chromatography over silica gel using a gradient elution from 10 to 20% ethyl acetate in hexanes to give 0.825 g (53%) of 4-chloro-5-(thiazol-2-yl)thieno[2,3-d]pyrimidine as a brown solid. MS [M+H] 254.0, 1H NMR (400 MHz, 10% CD3OD/CDCl3) δ (ppm) 8.92 (s, 1H), 8.00 (d, J=3.2 Hz, 1H), 7.85 (s, 1H), 7.55 (d, J=3.2 Hz, 1H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[OH:38])[CH:33]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:33][C:32]3[CH:31]=[C:30]([OH:29])[C:37]([OH:38])=[CH:36][CH:35]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1ccc(O)c(O)c1
Product: Oc1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1O

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 3,4-dihydroxy-benzaldehyde according to the procedure of Example 66. MS (ES) m/z 499.0.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[C:12]([F:22])[C:8]2[NH:9][CH:10]=[N:11][C:7]=2[CH:6]=1)=[O:4].[Cl:23]N1C(=O)CCC1=O>>[CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:23])=[CH:17][C:16]=2[CH3:21])=[C:12]([F:22])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2nc[nH]c2c(F)c1Nc1ccccc1C
Reactant: O=C1CCC(=O)N1Cl
Product: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Cl)cc1C

Procedure:
7-Fluoro-6-o-tolylamino-3H-benzoimidazole-5-carboxylic acid methyl ester 7a is converted by the procedure already described for bromination, except N-chlorosuccinimide is used instead of N-bromosuccinimide, to yield the desired product. MS ESI (+) m/z 334, 336 (M+, Cl pattern) detected.