Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([CH:13]1[CH2:18][CH2:17][C:16]([CH3:19])=[CH:15][CH2:14]1)=[O:12])=[O:4].[CH3:33][N:34]([CH2:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39](F)[CH:38]=1)[CH3:35].[H-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.O>[CH3:33][N:34]([CH2:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39]([O:26][C@H:23]2[CH2:24][CH2:25][C@H:20]([N:10]([C:11]([CH:13]3[CH2:18][CH2:17][C:16]([CH3:19])=[CH:15][CH2:14]3)=[O:12])[C:9]3[CH:8]=[C:7]([C:27]#[C:28][C:29]([CH3:30])([CH3:31])[CH3:32])[S:6][C:5]=3[C:3]([OH:2])=[O:4])[CH2:21][CH2:22]2)[CH:38]=1)[CH3:35]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CC=C(C)CC1)[C@H]1CC[C@H](O)CC1
Reactant: CN(C)Cc1ccnc(F)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1=CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)[C@H]2CC[C@H](Oc3cc(CN(C)C)ccn3)CC2)CC1
Temperature: 90 °C

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-[(4-hydroxy-trans-cyclohexyl)-(4-methyl-cyclohex-3-enecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (40 mg, 0.088 mmol) and (N,N-dimethyl)-(2-fluoro-pyridin-4-ylmethyl)amine (84 mg, 0.55 mmol) in DMF (1 mL) were treated with sodium hydride (22 mg, 60% oil dispersion, 0.55 mmol). After the bubbling slowed, the reaction mixture was sealed and heated by microwave (90° C.) for 70 min. The reaction mixture was treated with 10% citric acid (2-3 mL) followed by water (2-3 mL). The organics were extracted twice with ethyl acetate, dried over sodium sulfate, filtered and concentrated. The residue was purified by reverse phase HPLC to give the Compound 337, 18 mg (35% yield): MS (m/z): 578.0 [M+H]+; HPLC retention time 3.53 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:18]3[CH:25]=[CH:24][N:23]([CH3:26])[C:19]=3[N:20]=[CH:21][N:22]=2)[CH:9]=1)(O)=[O:6]>>[ClH:3].[Cl:3][C:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:18]3[CH:25]=[CH:24][N:23]([CH3:26])[C:19]=3[N:20]=[CH:21][N:22]=2)[CH:9]=1)=[O:6]
Reactant: O=S(Cl)Cl
Reactant: Cn1ccc2c(-n3cc(C(=O)O)c4ccccc43)ncnc21
Product: Cl
Product: Cn1ccc2c(-n3cc(C(=O)Cl)c4ccccc43)ncnc21

Procedure:
6 cm3 of thionyl chloride are added to 0.9 g (3.08 mmol) of 3-carboxy-1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-indole at a temperature in the region of 20° C. under an argon atmosphere. After stirring under reflux for 2 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), triturated twice successively with 30 cm3 of dichloromethane and then concentrated to dryness under reduced pressure (2.7 kPa), giving 0.92 g of 3-chlorocarbonyl-1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-indole hydrochloride in the form of a yellow powder, which is used directly in the following step.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[CH3:15][C:16](=O)[CH2:17][C:18](=[O:20])[CH3:19].[NH2:22]/[C:23](/[CH3:32])=[CH:24]\[C:25]([O:27][CH:28]1[CH2:31][CH2:30][CH2:29]1)=[O:26].C(O)(=O)C>CC(O)C>[C:18]([C:17]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:24]([C:25]([O:27][CH:28]2[CH2:31][CH2:30][CH2:29]2)=[O:26])=[C:23]([CH3:32])[NH:22][C:16]=1[CH3:15])(=[O:20])[CH3:19]
Reactant: C/C(N)=C/C(=O)OC1CCC1
Reactant: CC(=O)CC(C)=O
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC(=O)C1=C(C)NC(C)=C(C(=O)OC2CCC2)C1c1cccc2c(=O)cc(C)oc12

Procedure:
100 mg (0.53 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 93.1 mg (0.93 mmol) of 2,4-pentanedione, 82.5 mg (0.53 mmol) of cyclobutyl 3-aminocrotonate and 31.9 mg (0.53 mmol) of acetic acid in 5 ml of 2-propanol and heated to reflux under argon for 10 h. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 82 mg (37% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[F:8][CH2:9][CH:10]1[CH2:13][NH:12][CH2:11]1.BrCCO.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:8][CH2:9][CH:10]1[CH2:13][N:12]([CH2:2][CH2:3][OH:5])[CH2:11]1
Reactant: O=C(O)C(F)(F)F
Reactant: FCC1CNC1
Agent: O=C([O-])[O-]
Agent: OCCBr
Agent: [K+]
Solvent: CC#N
Product: OCCN1CC(CF)C1
Temperature: 80 °C
Yield: 78.1 %

Procedure:
A mixture of 3-(fluoromethyl)azetidine 2,2,2-trifluoroacetate (Intermediate 6, 100 mg, 0.5 mmol), 2-bromoethanol (60 mg, 0.5 mmol), and potassium carbonate (0.2 g, 1.5 mmol) in acetonitrile (5 mL) was heated to 80° C. overnight. After cooling, solids were filtered off and washed with acetonitrile. The filtrate was concentrated on a rotary evaporator to give a residue that was purified by silica gel chromatography eluting with 10:7 ethyl acetate/hexanes to 10:7:2:1 ethyl acetate/hexane/methanol/triethylamine to afford 52 mg of 2-(3-(fluoromethyl)azetidin-1-yl)ethanol as a pale yellow oil. 1H NMR (DMSO-d6): δ 5.13 (t, 1H), 4.62 (d, 1H), 4.50 (d, 1H), 4.06 (t, 2H), 3.84 (dd, 2H), 3.54 (q, 2H), 3.11 (t, 2H), 3.06-3.03 (m, 1H).
Reaction SMILES: [Mg].[CH2:2](Br)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].O=[C:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[C:20]=2[O:26][CH3:27])[CH2:14][CH2:13]1.Cl.C1C[O:32]CC1>>[OH:32][C:5]([N:18]([CH:15]1[CH2:16][CH2:17][CH2:12][CH2:13][CH2:14]1)[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[C:20]=1[O:26][CH3:27])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][CH2:3][CH3:2]
Reactant: CCCCCCCCBr
Reactant: C1CCOC1
Reactant: COc1c(NC2CCC(=O)CC2)ccnc1C
Agent: Cl
Agent: [Mg]
Product: CCCCC(O)(CCC)N(c1ccnc(C)c1OC)C1CCCCC1

Procedure:
The Grignard solution is prepared from 0.73 g of magnesium and 6.0 g of octyl bromide in 50 ml of absolute THF. 2.8 g of 4-(4-oxocyclohexylamino)-3-methoxy-2-methylpyridine in 20 ml of THF are added dropwise to the solution. After 2 hours the mixture is acidified with 2N HCl. The THF is then distilled off in vacuo at room temperature and the product is extracted from the solution which is rendered alkaline with methylene chloride. Further working up takes place as in the previous working procedure.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)[C:7]=1[O:23][CH3:24].[CH2:25]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[ClH:38]>>[ClH:1].[ClH:38].[ClH:1].[CH2:25]([N:32]1[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][CH2:4][S:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]3[NH:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[N:15]=3)[C:7]=2[O:23][CH3:24])[CH2:34][CH2:33]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COc1c(SCCCCl)ccnc1CSc1nc2ccccc2[nH]1
Agent: Cl
Product: COc1c(SCCCN2CCN(Cc3ccccc3)CC2)ccnc1CSc1nc2ccccc2[nH]1
Yield: 59 %

Procedure:
According to the procedure indicated in Examples 1), 3) and 6), reaction of 2-{[[4-(3-chloropropylthio)-3-methoxy-2-pyridinyl]methyl]thio}-1H-benzimidazole with N-benzylpiperazine and subsequent conversion into the hydrochloride gives the title compound; m.p. 180° C., dec.; colorless crystals; yield 59% of theory.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[CH:22]1([CH2:25]Br)[CH2:24][CH2:23]1>>[CH:22]1([CH2:25][O:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]3[C:19](=[O:20])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]3=[O:21])[CH:5]=[CH:6][CH:7]=2)[CH2:24][CH2:23]1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Reactant: BrCC1CC1
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(OCC2CC2)c1

Procedure:
Alkylation reaction of phenol 58 with cyclopropylmethylbromide gave 2-(3-(3-(cyclopropylmethoxy)phenyl)propyl)isoindoline-1,3-dione as yellow oil. Yield (0.410 g, 36%): 1H NMR (400 MHz, CDCl3) δ 7.81-7.84 (m, 2H), 7.69-7.72 (m, 2H), 7.11-7.16 (m, 1H), 6.73-6.78 (m, 2H), 6.67 (dd, J=8.0, 2.4 Hz, 1H), 6.73 (s, 1H), 6.65 (dd, J=7.6, 2.4 Hz, 1H), 4.52 (s, 2H), 3.94 (t, J=6.0 Hz, 2H), 3.72-3.78 (m, 4H), 2.65 (t, J=7.6 Hz, 2H), 1.98-2.07 (m, 2H), 1.24-1.28 (m, 1H), 0.62-0.66 (m, 2H), 0.32-0.36 (m, 2H).
Reaction SMILES: B.C1COCC1.[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24]>C1COCC1>[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24]
Reactant: O=C(O)CCCCCCCCCCCCCCCBr
Agent: B
Solvent: C1CCOC1
Product: OCCCCCCCCCCCCCCCCBr
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
Under inert atmosphere 10 ml of BH3.THF complex (1.0 M THF solution) were added to 30 ml THF solution of 2.15 gr (6.41 mmole) of 16-bromohexadecanoic acid at −20° C. Reaction mixture was stirred at this temperature for 2 hrs and then additional 1 hr at RT. After that time the resulted mixture was poured, with stirring, into a vessel containing 200 ml of ice/saturated sodium bicarbonate aqueous solution. Organic compounds were extracted with 3×200 ml of ether. The ether fractions were combined and dried over sodium sulfate. After removal of ether material was dissolved in minimum amount of dicloromethane and purified by silica gel chromatography (100% dicloromethane as eluent). 1.92 gr (93% yield) of the desired product were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](OC)[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.[C:13]([O-])([O-])=O.[K+].[K+].C(N(CC)CC)C.[F:26][C:27]([F:36])([F:35])/[CH:28]=[CH:29]/[C:30]([O:32][CH2:33][CH3:34])=[O:31].Cl>CS(C)=O>[Br:1][C:2]1[CH:9]=[C:6]2[C:5](=[C:4]([CH3:13])[CH:3]=1)[O:10][CH:28]([C:27]([F:35])([F:36])[F:26])[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:7]2
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: COc1cc(Br)cc(C=O)c1O
Agent: Cl
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)C1=Cc2cc(Br)cc(C)c2OC1C(F)(F)F
Temperature: 90 °C
Yield: 67.3 %

Procedure:
A mixture of 5-bromo-2-hydroxy-3-methoxybenzaldehyde (1.40 g, 6.51 mmole), K2CO3 (1.80 g, 13.02 mmole), triethylamine (2.63 g, 26.05 mmole), and ethyl 4,4,4-trifluorocrotonate (4.38 g, 26.05 mmole) in anhydrous DMSO (5.0 mL) was heated to 90 ° C. under a dry N2 atmosphere for 18 hrs. The contents were poured into 2.4 N HCl (50 ml) and extracted with EtOAc (2×100 mL). The combined extracts were washed with brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo to give a dark yellow oil which was subject to flash chromatography (silica gel) and eluted with 10% EtOAc in hexanes to give a yellow solid (1.6 g, 68%). GCMS m/z 364.0 (M+). 1H NMR (CDCl3/400 MHz) 7.59 (s, 1H), 7.27 (s, 1H), 7.16 (s, 1H), 5.70 (q, 1H, J=7.0 Hz), 4.29 (m, 2H), 2.19 (s, 3H), 1.32 (m, 3H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:17](=[O:18])[N:4]2[C:5]([C:14]([OH:16])=[O:15])=[C:6]([CH2:9]OC(=O)C)[CH2:7][S:8][C@H:3]12.C(=O)(O)[O-].[Na+].[OH-].[Na+].[N-:26]=[N+:27]=[N-:28].[Na+]>CC(C)=O.O>[NH2:1][C@@H:2]1[C:17](=[O:18])[N:4]2[C:5]([C:14]([OH:16])=[O:15])=[C:6]([CH2:9][N:26]=[N+:27]=[N-:28])[CH2:7][S:8][C@H:3]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To 7β-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid (27.2 g, 99.9 mmol) was added water (500 ml) and sodium bicarbonate (9.3 g, 111 mmol); the pH of the mixture was adjusted to 6.5 with 10% sodium hydroxide solution. Sodium azide (13.1 g, 201 mmol) was added to the mixture followed by acetone (350 ml). The mixture was heated at 60° C. for 6 h and left stirring at room temperature overnight. Acetone was removed under reduced pressure and the mixture was cooled in an ice-bath, acidified with concentrated hydrochloric acid to pH 3.5; the precipitated solid was filtered off, dried overnight over P2 05 to give 14.3 g (56%) of 7β-amino-3-azidomethyl-3-cephem-4-carboxylic acid. IR (Nujol) ν max 2095, 1796, 1732 cm-1.
Reaction SMILES: C(=O)(O)O.[NH:5]([C:7](=[NH:9])[NH2:8])[NH2:6].[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1>N1C=CC=CC=1.C(Cl)Cl>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:6][NH:5][C:7](=[NH:8])[NH2:9])=[O:16])=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: N=C(N)NN
Agent: O=C(O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: N=C(N)NNC(=O)c1ccc(Cl)cc1
Temperature: 15 °C
Reaction time: 8 h

Procedure:
To a solution of hydrazinecarboximidamide bicarbonate salt (2.3 g, 31.05 mmol) in pyridine (70 ml) was added dropwise 4-chlorobenzoyl chloride (4.5 g, crude) in DCM (20 ml). After stirring overnight at 15° C., the resulting mixture was concentrated under vacuum, quenched by the addition of water (20 ml) and adjusted to pH 13 with sodium hydroxide solution (10N). The product was collected by filtration and dried to give 2-(4-chlorobenzoyl)hydrazinecarboximidamide as a white solid (2.1 g, crude).
Reaction SMILES: [C:1]1([CH3:38])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][C:10]1[C:23]2[C:22](=[O:24])[C:21]3[C:16](=[C:17]([NH:26][C:27]4[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=4[CH3:35])[CH:18]=[C:19](Br)[CH:20]=3)[C:15](=[O:36])[C:14]=2[CH:13]=[C:12](Br)[CH:11]=1.[C:39]1([S-:45])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[Na+].CO>CN(C=O)C>[C:1]1([CH3:38])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][C:10]1[C:23]2[C:22](=[O:24])[C:21]3[C:16](=[C:17]([NH:26][C:27]4[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=4[CH3:35])[CH:18]=[C:19]([S:45][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH:20]=3)[C:15](=[O:36])[C:14]=2[CH:13]=[C:12]([S:45][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:11]=1
Reactant: [S-]c1ccccc1
Reactant: Cc1cc(C)c(Nc2cc(Br)cc3c2C(=O)c2cc(Br)cc(Nc4c(C)cc(C)cc4C)c2C3=O)c(C)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc(C)c(Nc2cc(Sc3ccccc3)cc3c2C(=O)c2cc(Sc4ccccc4)cc(Nc4c(C)cc(C)cc4C)c2C3=O)c(C)c1
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
16.5 g of 1,5-bis(mesitylamino)-3,7-dibromoanthraquinone are suspended at RT in 50 ml of DMF and heated to 120° C. After cooling to 50° C., a suspension of 8.5 g of sodium thiophenolate in 25 ml of DMF is added thereto. The mixture is then heated to 120° C. again and stirred at that temperature for 1.5 hours. After cooling the mixture to 60° C., 100 ml of methanol are added and the mixture is stirred overnight at RT. The precipitate is filtered off, washed with a methanol/water mixture (1:1) and dried in vacuo.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][N:23]=1)[C:19]#[N:20].C([O-])(O)=O.[Na+]>CN(C=O)C.O>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][N:23]=2)[C:19]#[N:20])[CH2:4][CH2:3]1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: CN1CCC(CCCCO)CC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCC(CCCCOc2cc(C#N)ccn2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.5 %

Procedure:
To a stirred solution of 4-(1-methyl-piperidin-4-yl)-butan-1-ol (1.0 g, 5.85 mmol) in DMF (12 mL) at 0° C. was added NaH (60%; 280 mg, 7.02 mmol). The mixture was warmed to rt for 1 h, then cooled to 0° C. A solution of 2-chloro-isonicotinonitrile (810 mg, 5.85 mmol) in DMF (4 mL) was added dropwise. The mixture was stirred at rt for 18 h, and then was diluted with water (5 mL) and satd. aq. NaHCO3 (25 mL). The mixture was extracted with CHCl3 (3×25 mL), dried (Na2SO4), filtered, and. Purification by Method 1 afforded 440 mg (28%) of a yellow oil.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:8][C:9]1[NH:10][C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:13]=1.C(OCC)(=O)C>O1CCCC1.[Cl-].[Na+].O>[NH2:8][C:9]1[N:13]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:10]=1
Reactant: CCOC(=O)CBr
Reactant: Nc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1c(N)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 35.8 %

Procedure:
Ethyl bromoacetate (3.50 mL, 31.87 mmol) was added to a solution of 2-amino-4,5-diphenylimidazole (7.50 g, 31.87 mmol) and 1,8-diazobicyclo[5.4.0]undec-7-ene (4.80 mL, 31.87 mmol) in anhydrous tetrahydrofuran (150 mL). The mixture was heated to about 75° C. for about 2 hours and at about 65° C. for about 16 hours before it was cooled to room temperature and treated with brine. After about 15 minutes, ethyl acetate was added and the organic phase was separated, washed with saturated sodium bicarbonate solution and brine prior to drying and solvent concentration to one quarter volume. The precipitate which formed on concentration of the solvent was collected by suction-filtration. There was isolated 3.67 g (36%) of the title compound as an off-white solid. An additional 2.56 g (25%) of the title compound was isolated from the filtrate on concentration, m.p. 173°-175° C.; 1H NMR (CD3SOCD3) δ 7.46-7.36 (m, 3H), 7.32-7.29 (m, 2H), 7.25-7.21 (m, 2H), 7.17-7.04 (m, 2H), 7.03-6.99 (m, 1H), 5.78 (s, 2H), 4.36 (s, 2H), 4.03 (q, J=7.1 Hz, 2H), 1.08 (t, J=7.1 Hz, 3H); 13C NMR (CD3SOCD3) ppm 170.07, 151.51, 137.08, 133.74, 133.02, 132.50, 130.74, 130.01, 129.59, 128.55, 127.26, 127.06, 124.83, 62.62, 45.71, 15.69; IR (KBr, cm-1) 3410, 3390, 3062, 2980, 1744, 1660, 1562, 1476, 1340, 1240, 1222, 1212, 1026, 772, 700; MS m/z (MH+) calcd 322.1556, obsd 322.1555.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1.N.[CH3:23]O>>[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([O:17][CH3:23])=[O:16])=[CH:11][CH:12]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: CO
Agent: N
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccccc1-c1ccc(C)cc1
Temperature: 0 °C

Procedure:
6 g of sulfuric acid in 12 ml of methanol was added to 3.2 g of 2-(4-methylphenyl)benzoic acid [see A. I. Meyers et al., J. Org. Chem., 43, 1372 (1978)], and the mixture was heated under reflux for 8 hr. The refluxed solution was cooled, poured into ice water, weakly alkalified with aqueous ammonia and extracted with ether. The extract was dried over anhydrous magnesium sulfate. The dried extract was concentrated, and the residue was recrystallized from n-hexane to prepare 2.4 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[C:10](=[O:22])[O:11][C:12]2([CH2:19][CH2:18][N:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[C:13]=1[OH:14].C(N(CC)CC)C.CN(C)C1C=CN=CC=1.CN(C1C=CN=CC=1)C.Cl[C:49]([O:51][CH2:52][CH3:53])=[O:50]>C1COCC1>[CH2:52]([O:51][C:49](=[O:50])[O:14][C:13]1[C:12]2([CH2:19][CH2:18][N:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[O:11][C:10](=[O:22])[C:9]=1[C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1])[CH3:53]
Reactant: CCOC(=O)Cl
Reactant: CON1CCC2(CC1)OC(=O)C(c1cc(C)ccc1C)=C2O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)OC1=C(c2cc(C)ccc2C)C(=O)OC12CCN(OC)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(2,5-dimethyl-phenyl)-4-hydroxy-8-methoxy-1-oxa-8-aza-spiro[4.5]dec-3-en-2-one (120 mg, 0.40 mmol), triethylamine (0.08 ml, 60 mg, 0.60 mmol) and 4-dimethylaminopyridine DMAP (2 mg, 0.02 mmol) in 4 ml THF at 0° C. was added a solution of ethyl chloroformate (0.05 ml, 52 mg, 0.50 mmol) dissolved in 1 ml THF dropwise. The suspension was kept at 0° C. for 30 minutes under argon and left stirring at room temperature overnight. Then the solvent was removed under vacuum. Ethyl acetate was added to the residue and the precipitation was filtered off. The filtrate was concentrated under vacuum to give the crude product, which was purified by column chromatography on silica gel (ethyl acetate/cyclohexane 1:9). Yield: 111 mg of carbonic acid 3-(2,5-dimethylphenyl)-8-methoxy-2-oxo-1-oxa-8-aza-spiro[4.5]dec-3-en-4-yl ester ethyl ester (title compound P1.1) as a light yellow gum.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([C:17]([OH:19])=[O:18])[CH2:12]1>>[B:8]([C:5]1[CH:4]=[N:3][C:2]([N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([C:17]([OH:19])=[O:18])[CH2:12]2)=[N:7][CH:6]=1)([OH:10])[OH:9]
Reactant: OB(O)c1cnc(Cl)nc1
Reactant: O=C(O)[C@H]1CCCNC1
Product: O=C(O)[C@H]1CCCN(c2ncc(B(O)O)cn2)C1

Procedure:
The title compound was synthesised from (2-chloropyrimidin-5-yl)boronic acid and (3S)-piperidine-3-carboxylic acid in accordance with General Method C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[NH2:24][C:25]1[CH:35]=[CH:34][C:28]2[N:29]([CH3:33])[C:30](=[O:32])[NH:31][C:27]=2[CH:26]=1.[OH-].[Na+]>CN(C=O)C.CO>[CH3:33][N:29]1[C:28]2[CH:34]=[CH:35][C:25]([NH:24]/[C:13](=[C:6]3\[C:5](=[O:23])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[CH:10][CH:11]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:26][C:27]=2[NH:31][C:30]1=[O:32]
Reactant: Cn1c(=O)[nH]c2cc(N)ccc21
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1c(=O)[nH]c2cc(N/C(=C3\C(=O)Nc4ccccc43)c3ccccc3)ccc21

Procedure:
Prepared from 1-acetyl-3-{1-ethoxy-1-phenylmethylidene}-2-indolinone and 3 equivalents of crude 5-amino-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole in DMF followed by treatment with 1N sodium hydroxide solution in MeOH.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[Br:12][C:13]1[CH:14]=[C:15]2[C:20](=[C:21]([N+:24]([O-:26])=[O:25])[C:22]=1[CH3:23])[N:19]=[CH:18][N:17]=[C:16]2Cl>CC(O)C>[Br:12][C:13]1[CH:14]=[C:15]2[C:20](=[C:21]([N+:24]([O-:26])=[O:25])[C:22]=1[CH3:23])[N:19]=[CH:18][N:17]=[C:16]2[NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Cc1c(Br)cc2c(Cl)ncnc2c1[N+](=O)[O-]
Solvent: CC(C)O
Product: Cc1c(Br)cc2c(Nc3cccc(C(F)(F)F)c3)ncnc2c1[N+](=O)[O-]
Temperature: 140 °C
Yield: 48 %

Procedure:
To a microwave vial were added 3-(trifluoromethyl)aniline (343 μl, 2777 μmol), 6-bromo-4-chloro-7-methyl-8-nitroquinazoline (840 mg, 2777 μmol) and IPA (5 mL). The reaction mixture was heated to 140° C. for 20 min. On cooling a ppt was observed to form which was then washed with hexane, filtered and air-dried to afford 6-bromo-7-methyl-8-nitro-N-(3-(trifluoromethyl)phenyl)quinazolin-4-amine (569 mg, 48.0% yield) as an amorphous yellow solid. MS (M+H)+ 427, 429.