Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:16])([CH3:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:5]=[CH:4][C:3]=1[CH:17]1[CH2:22][CH2:21][CH2:20][C:19](=[O:23])[CH2:18]1.[C:24](OC(=O)C)(=[O:26])[CH3:25].Cl>N1C=CC=CC=1>[C:24]([O:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:16])([CH3:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:5]=[CH:4][C:3]=1[CH:17]1[CH2:22][CH2:21][CH2:20][C:19](=[O:23])[CH2:18]1)(=[O:26])[CH3:25]
Reactant: CCCCCCC(C)(C)c1ccc(C2CCCC(=O)C2)c(O)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCC(C)(C)c1ccc(C2CCCC(=O)C2)c(OC(C)=O)c1
Reaction time: 18 h

Procedure:
A solution of 2.0 g of 3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]cyclohexanone in 15 ml of pyridine is treated at 10° C. with 10 ml acetic anhydride and the mixture stirred for 18 hours under nitrogen. It is then poured onto ice/water and acidified with dilute hydrochloric acid. The acidified mixture is extracted with ethyl acetate (2×100 ml), the extracts combined, washed with brine and dried (MgSO4). Evaporation under reduced pressure give the title product as an oil.
Reaction SMILES: [F:1][CH:2]([F:15])[C:3]1N(C)[C:7]([CH:10]([OH:12])[CH3:11])=[C:6]([OH:13])[C:5](=[O:14])[CH:4]=1.[OH-:16].[Na+].[CH:18]1[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][CH:19]=1>CO>[CH2:24]([O:13][C:6]1[C:5](=[O:14])[CH:4]=[C:3]([CH:2]([F:15])[F:1])[O:16][C:7]=1[CH:10]([OH:12])[CH3:11])[C:21]1[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1
Reactant: CC(O)c1c(O)c(=O)cc(C(F)F)n1C
Reactant: BrCc1ccccc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1oc(C(F)F)cc(=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The 6-difluoromethyl-3-hydroxy-2-(1-hydroxy-ethyl)-1-methyl-1H-pyridin-4-one product obtained in the 2 experiments in step 1 above were combined together and dissolved in MeOH (50 mL). A 6.0 M NaOH solution (4 mL, 24 mmol) and BnBr (2.85 mL, 24 mL) were successively added at room temperature. The progress of the reaction was monitored by HPLC Method 1 as described above. After 1.5 hrs, HPLC analysis of the reaction mixture indicated presence of about 15% of unreacted starting material. Thus, another 1 mL of a 6.0 M NaOH solution and 1 mL of BnBr were added, and the mixture was refluxed for 1 hr. The mixture was cooled to room temperature, and evaporated to dryness. The residue was taken up in CH2Cl2, and the organic layer was washed with brine (40 mL). The aqueous brine layer was back washed with CH2Cl2 (40 mL). The organic fractions were combined, dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by column chromatography on silica gel using a mixture of CH2Cl2 and MeOH (100/3, v/v) as eluant. Fractions rich in product were combined together, and concentrated to give 3-benzyloxy-6-difluoromethyl-2-(1-hydroxy-ethyl)-pyran-4-one (4.00 g) as a bright yellow oil. HPLC purity (peak area percent) of this material is 88.8% at λ=280 nm using HPLC Method 1 as described above.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21])(=[O:12])=[O:11])[CH3:2].[N:24]1([CH2:33][C:34](O)=[O:35])[CH:32]=[C:30]([CH3:31])[C:28](=[O:29])[NH:27][C:25]1=[O:26]>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21])(=[O:12])=[O:11])[C:34](=[O:35])[CH2:33][N:24]1[CH:32]=[C:30]([CH3:31])[C:28](=[O:29])[NH:27][C:25]1=[O:26])[CH3:2]
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Product: CCOC(=O)CN(CCNS(=O)(=O)c1ccc(Cl)cc1[N+](=O)[O-])C(=O)Cn1cc(C)c(=O)[nH]c1=O
Yield: 92.5 %

Procedure:
The title compound (2.46 g, 92%) was synthesized by the reaction of N-[2-(4-chloro-2-nitro-benzenesulfonylamino)-ethyl]-glycine ethyl ester (1.84 g, 5 mmol) and (thymin-1-yl)-acetic acid (0.92 g, 5 mmol) as per the procedure of example 46. 1H-NMR (500 MHz; DMSO-d6) δ 11.31 (s, 0.6H), 11.28 (s, 0.4H), 8.31˜7.95 (m, 4H), 7.31 (s, 0.6H), 7.23 (s, 0.4H), 4.64 (s, 1.2H), 4.46 (s, 0.8H), 4.28 (s, 0.8H), 4.16 (q. 0.8H), 4.07 (q. 1.2H), 4.00 (s, 1.2H), 3.49 (t, 1.2H), 3.22 (q, 1.2H), 3.12˜3.01 (m, 1.6H), 1.74 (s, 3H), 1.22 (t, 1.2H), 1.17 (t, 1.8H).
Reaction SMILES: S(Cl)(Cl)=O.C1(CCCC(O)=O)C=CC=CC=1.C1(CCCC(Cl)=O)C=CC=CC=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][C:40]=1[O:41][CH3:42])[N:37]=[CH:36][N:35]=[C:34]2[O:43][C:44]1[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][CH:45]=1.[C:51]1([CH2:57][CH2:58][CH2:59][C:60]([N:62]=[C:63]=[S:64])=[O:61])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C1(C)C=CC=CC=1.C(O)C>[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][C:40]=1[O:41][CH3:42])[N:37]=[CH:36][N:35]=[C:34]2[O:43][C:44]1[CH:50]=[CH:49][C:47]([NH:48][C:63]([NH:62][C:60](=[O:61])[CH2:59][CH2:58][CH2:57][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)=[S:64])=[CH:46][CH:45]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(CCCc1ccccc1)N=C=S
Agent: O=C(Cl)CCCc1ccccc1
Agent: O=C(O)CCCc1ccccc1
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)CCCc4ccccc4)cc3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 4-phenylbutanoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 4-phenylbutanoyl isothiocyanate was prepared using the resultant 4-phenylbutanoyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-phenylbutanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (37 mg, yield 45%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:52])[C:19]([C:27]3[N:28]=[C:29]([NH:32][C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[S:30][CH:31]=3)=[N:20][O:21]C(C)(OC)C)[C:15](=[O:53])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].[CH2:54]([NH:56][CH2:57][CH3:58])[CH3:55].O>CC(C)=O.Cl>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:52])[C:19]([C:27]3[N:28]=[C:29]([NH:32][C:33]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[S:30][CH:31]=3)=[N:20][OH:21])[C:15](=[O:53])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].[CH2:54]([NH:56][CH2:57][CH3:58])[CH3:55]
Reactant: COC(C)(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Solvent: CCNCC
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NO)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1

Procedure:
A solution of 7.6 g of the syn isomer of diethylamine 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(1-methyl-1-methoxy-ethoxyimino)-acetamido]-ceph-3-eme-4-carboxylate in 30 ml of acetone and 10 ml of 2 N hydrochloric acid was stirred for 40 minutes at room temperature and then 20 ml of water were added thereto. The acetone was evaporated at 30° C. under reduced pressure and 25 ml of ethyl acetate were added thereto. The mixture was decanted and re-extracted and the organic phase was washed with water, dried and vacuum filtered. 1 ml of diethylamine was added to the filtrate and the mixture was triturated and iced. The mixture was vacuum filtered and the recovered product was washed with ether to obtain 6 g of pure syn isomer of diethylamine 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:10][CH:9]1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)(C)(C)C.Cl>O1CCOCC1>[F:17][C:14]1[CH:13]=[CH:12][C:11]([CH:9]2[CH2:10][CH:8]2[NH2:7])=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)NC1CC1c1ccc(F)cc1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CC1c1ccc(F)cc1

Procedure:
In a round flask was added [2-(4-fluoro-phenyl)-cyclopropyl]-carbamic acid tert-butyl ester (350 mg) and 4N HCl in 1,4-dioxane (3 mL) for 2 hours. The reaction mixture was concentrated by rotavaping to obtain the crude product of 270 mg as white solid. LC-MS m/e 152 (MH+). The crude product was directly used for next step.
Reaction SMILES: NC1(OC2C=CC=C(C(F)(F)F)C=2)C2N=CC=C(C)C=2C=C(OC)C1.ICCCC([N:32]1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42])C.IC(N1C(=O)C2=CC=CC=C2C1=O)CCCC.C(N(CC)CC)C>C(OCCO)C.C(Cl)Cl>[C:36]1(=[O:37])[NH:32][C:33](=[O:42])[C:34]2=[CH:41][CH:40]=[CH:39][CH:38]=[C:35]12
Reactant: CC(CCCI)N1C(=O)c2ccccc2C1=O
Agent: CCCCC(I)N1C(=O)c2ccccc2C1=O
Agent: COC1=Cc2c(C)ccnc2C(N)(Oc2cccc(C(F)(F)F)c2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCCO
Product: O=C1NC(=O)c2ccccc21
Reaction time: 4.5 h
Yield: 0.3 %

Procedure:
A solution of 8-amino-6-methoxy-4-methyl-8-(3-trifluoromethylphenoxy)quinoline (5.26 g, 15 mmol), 1-iodo-4-phthalimidopentane (5.26 g, 15 mol) in 2-ethoxyethanol (25 mL) was heated at 110° for 1.5 hour after which time an additional 7.5 mmol of iodophthalimidopentane and triethylamine were added. After stirring 1.5 hour an additional 7.5 mmol of each reagent was added. After stirring an additional 4.5 hours the reaction mixture was diluted with CH2Cl2 and the organic layer was washed with water (×3). After drying (K2CO3) the organic layer was concentrated to dryness and the residue was chromatographed over a silica gel column (33 mm×500 mm). Elution with chloroform afforded the intermediate phthalimide (6.65 g, 79%) which could be crystallized from EtOH to give mp 122°-124°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11](=O)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:9]#[N:10])=[CH:4][CH:3]=1.O.[NH2:20][NH2:21].C(O)(=O)C>C1C=CC=CC=1>[NH2:10][C:9]1[NH:21][N:20]=[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: N#CC(C(=O)c1ccncc1)c1ccc(F)cc1
Reactant: NN
Solvent: c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: Nc1[nH]nc(-c2ccncc2)c1-c1ccc(F)cc1

Procedure:
A mixture of 2-(4-fluorophenyl)-3-oxo-3-(pyridin-4-yl)propanenitrile (10 g), hydrazine monohydrate (2.4 ml) and acetic acid (5.2 ml) in dry benzene (100 ml) was refluxed for 4 hours. The reaction mixture was cooled and extracted with 3N-hydrochloric acid (80 ml×3). The extracts were concentrated in vacuo to 100 ml of the volume and the solution was neutralized with aqueous ammonia solution. The separated solid was collected, washed with water and dried to give 5-amino-4-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazole (2.02 g).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[O:20]1[CH2:24][CH2:23][CH:22]([CH2:25][C:26](O)=[O:27])[CH2:21]1>>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:26](=[O:27])[CH2:25][CH:22]3[CH2:23][CH2:24][O:20][CH2:21]3)[N:11]=2)[CH:17]=[CH:16][N:15]=1
Reactant: O=C(O)CC1CCOC1
Reactant: Nn1nc(-c2ccnc(Cl)c2)c2ccccc2c1=O
Product: O=C(CC1CCOC1)Nn1nc(-c2ccnc(Cl)c2)c2ccccc2c1=O

Procedure:
The product from Example 29B and 2-(tetrahydrofuran-3-yl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 8.60-8.60 (bs, 1H), 8.55-8.59 (m, 1H), 8.54-8.57 (m, 1H), 7.84-7.93 (m, 2H), 7.69-7.73 (m, 1H), 7.62 (s, 1H), 7.50-7.53 (m, 1H), 3.92-4.04 (m, 2H), 3.78-3.85 (m, 1H), 3.64-3.68 (m, 1H), 2.77-2.87 (m, 1H), 2.50-2.67 (m, 2H), 2.21-2.30 (m, 1H), 1.69-1.81 (m, 1H); MS (APCI+) M/Z 385 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:12]2[CH2:14][O:13]2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C[O-].[Na+].[OH2:18].[CH3:19]O>>[F:1][C:2]1[CH:3]=[C:4]([C@@H:12]([OH:18])[CH2:14][O:13][CH3:19])[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: Fc1cc([C@@H]2CO2)ccc1C(F)(F)F
Reactant: O
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Product: COC[C@H](O)c1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.9 %

Procedure:
To a solution of 312 (0.600 g, 2.91 mmol) and MeOH (1 mL) was added NaOMe (11.6 mL, 5.82 mmol) in MeOH and the reaction was stirred at RT for 3 d, then poured into water and extracted with DCM. The combined organic extractions were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (500:10) to afford 0.630 g (90.9%) of (R)-1-(3-fluoro-4-(trifluoromethyl)phenyl)-2-methoxyethanol (314) which was contaminated with a small amount of the regioisomeric epoxide ring-opening product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C1(C)C=CC=CC=1>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[O:1][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: ClCCCN1CCOCC1
Reactant: COc1ccc(C#N)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(C#N)cc1OCCCN1CCOCC1
Temperature: 85 °C
Yield: 98.3 %

Procedure:
A mixture of 3-hydroxy-4-methoxybenzonitrile (34.3 kg), potassium carbonate (54.5 kg) and N,N-dimethylformamide (226 kg) was stirred and heated to approximately 85° C. A toluene solution (91.4 kg) containing N-(3-chloropropyl)morpholine (41.1 kg) was added to the heated mixture and the resultant mixture was heated to about 85° C. for an additional 10 hours. The bulk of the N,N-dimethylformamide was removed by vacuum distillation and the residue was diluted with water (286 liters). The aqueous mixture was extracted with three portions of a 1:1 mixture of heptane and ethyl acetate (239 liters, 139 liters and 139 liters respectively). The combined organic layers were washed with water, concentrated to approximately 150 liters by vacuum distillation and diluted with glacial acetic acid (133 kg). Additional solvent was removed by vacuum distillation. Addition of glacial acetic acid (84 kg) provided a solution of 4-methoxy-3-(3-morpholinopropoxy)benzonitrile (62.5 kg) in acetic acid (122 kg) which was used without further purification.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Cs+].[Cs+].[C:7]1([CH3:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:13]([O:4][CH2:1][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
A solution of compound 7, the properly substituted benzyl alcohol (1.1 eq), palladium(II) acetate (0.02 eq), 2-dit-butylphosphino-3,4,5,6-tertamethyl-2′,4′,6′-triisopropyl-1,1′biphenyl (0.02 eq), cesium carbonate (1.5 eq) in degassed toluene (4 ml/mmol) was heated at 75° C. for 16 hrs. Conversion was checked by TLC analysis. The solution was cooled to room temperature, diluted with DCM, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give compound 9 in yields varying from 30-80%.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][CH:4]=1)=O.[CH2:20]([NH2:26])[C:21]1[O:25][CH:24]=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C.C(OCC)(=O)C>[O:25]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:20][NH:26][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Cc1ccc(C=O)cc1
Reactant: NCc1ccco1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)C(C)(C)Cc1ccc(CNCc2ccco2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 55 %

Procedure:
At room temperature, a solution of 1.00 g (3.81 mmol) of tert-butyl 3-(4-formylphenyl)-2,2-dimethylpropionate (Example I-3) and 0.37 g (3.81 mmol) of furfurylamine in 10 ml of dichloroethane is stirred for 30 min, 1.21 g (5.72 mmol) of sodium triacetoxyborohydride are added and the mixture is then stirred at room temperature for 22 h. 6 ml of sat. NaHCO3 solution and 10 ml of ethyl acetate are then added, the phases are separated, the aqueous phase is extracted 2× with ethyl acetate and the combined organic phases are dried over sodium sulphate. The solvent is removed under reduced pressure, and chromatographic purification on silica gel (cyclohexane→cyclohexane/ethyl acetate 10:1→2:1) then gives 720 mg (55%) of tert-butyl 3-(4-{[(2-furylmethyl)amino]methyl}phenyl)-2,2-dimethylpropionate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[S:11].C(=O)([O-])[O-].[K+].[K+].[CH2:22](I)[CH3:23]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[N:12][C:13](=[O:15])[CH3:14])[S:11][CH2:22][CH3:23]
Reactant: CC(=O)NC(=S)Nc1c(Cl)cccc1Cl
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCSC(=NC(C)=O)Nc1c(Cl)cccc1Cl
Reaction time: 5 h
Yield: 56 %

Procedure:
7.9 g (0.03 M) of N-(2,6-dichlorophenyl)-N'-acetylthiourea, 3.0 g (0.022 M) of ground potassium carbonate, 3.0 ml (0.04 M) of ethyliodide and 100 ml of acetone are mixed and then boiled for 5 hours. The acetone then is distilled off. The residue is washed with water and filtered. 6.8 g (80.5 % of the theoretical yield) of N-(2,6-dichlorophenyl)-N'-acetyl-S-ethylisothiourea with a melting point of 97°-100° are obtained. After recrystallization from ethyl alcohol the product has a melting point of 99°-102° C. The yield is 56 % of the theoretical one.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]2[C:18](=[O:19])[CH:17]=[CH:16][C:15]([C:20](=[S:22])[NH2:21])=[N:14]2)[CH:7]=1)[CH3:2].[CH2:24]1[CH2:28][N:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:37]Br)=O)=[CH:31][CH:30]=2)[CH2:26][CH2:25]1>CCO>[CH2:1]([O:3][C:4](=[O:23])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]2[C:18](=[O:19])[CH:17]=[CH:16][C:15]([C:20]3[S:22][CH:37]=[C:35]([C:32]4[CH:33]=[CH:34][C:29]([N:27]5[CH2:28][CH2:24][CH2:25][CH2:26]5)=[CH:30][CH:31]=4)[N:21]=3)=[N:14]2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Nc1cccc(Cn2nc(C(N)=S)ccc2=O)c1
Reactant: O=C(CBr)c1ccc(N2CCCC2)cc1
Solvent: CCO
Product: CCOC(=O)Nc1cccc(Cn2nc(-c3nc(-c4ccc(N5CCCC5)cc4)cs3)ccc2=O)c1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
104 mg (0.31 mmol) of ethyl[3-(6-oxo-3-thiocarbamoyl-6H-pyridazin-1-yl-methyl)phenyl]carbamate are suspended in 2 ml of EtOH, and 100 mg (0.37 mmol) of α-bromo-4-(1-pyrrolidino)acetophenone are added. The reaction mixture is stirred at 80° C. for 15 h. The precipitate formed is filtered off with suction and washed with ethanol and dried in vacuo.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH:22]([CH2:24][OH:25])[CH2:21][CH2:20][CH:19]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[CH:24]([CH:22]1[CH2:23][N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:12])[CH3:13])=[O:17])[CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20][CH2:21]1)=[O:25]
Reactant: CC(C)(C)OC(=O)N1CC(CO)CCC1c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC(C=O)CCC1c1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of oxalyl chloride (15.44 ml, 2 M in DCM, 30.9 mmol) in DCM (100 ml) was added DMSO (4.38 ml, 61.8 mmol) at −78° C. The mixture was stirred at −78° C. for 5 min. Followed by the addition of tert-butyl-5-(hydroxymethyl)-2-phenylpiperidine-1-carboxylate (3.6 g, 12.35 mmol) in DCM (10 mL). The resulting mixture was stirred at −78° C. for 15 min, then triethyl amine (13.78 ml, 99 mmol) was added. The mixture was warmed up to 0° C., quenched with NH4Cl aqueous, and diluted with ether. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting crude product was directly used in the next step.
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[NH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[N+:21]([O-:23])=[O:22].C(OCC)C>C(#N)C>[N+:21]([C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[O-:11])([O-:23])=[O:22].[NH2:10][N+:6]1[CH:7]=[CH:8][C:9]2[O:1][CH:2]=[CH:3][C:4]=2[CH:5]=1
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: c1cc2occc2cn1
Solvent: CCOCC
Solvent: CC#N
Product: N[n+]1ccc2occc2c1
Product: O=[N+]([O-])c1ccc([O-])c([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 15 h
Yield: 80.3 %

Procedure:
To a solution of furo[3,2-c]pyridine (960 mg, 8.06 mmol) in acetonitrile (5.0 mL) was added 1-(aminooxy)-2,4-dinitrobenzene (1.77 g, 8.89 mmol) at room temperature, and the mixture was stirred at 40° C. for 15 hr. Diethyl ether was added, and the resulting precipitate was collected by filtration and washed with diethyl ether to give the title compound (2.06 g, yield 80%).
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:24])=[CH:9][C:10]([O:22][CH3:23])=[CH:11][C:12]=3[C@@:13]32[CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)=[CH:4][CH:3]=1.[F:25][C:26]1[C:31](B(O)O)=[CH:30][CH:29]=[CH:28][N:27]=1.FC(F)(F)S(O[CH2:41][C:42]([F:45])(C)[CH3:43])(=O)=O>>[F:24][C:8]1[C:7]2[O:6][C:5]3[C:14](=[CH:15][C:2]([C:31]4[C:26]([F:25])=[N:27][CH:28]=[CH:29][CH:30]=4)=[CH:3][CH:4]=3)[C@@:13]3([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)[C:12]=2[CH:11]=[C:10]([O:22][CH2:23][C:42]([F:45])([CH3:43])[CH3:41])[CH:9]=1
Reactant: CC(C)(F)COS(=O)(=O)C(F)(F)F
Reactant: COc1cc(F)c2c(c1)[C@]1(CCOC(N)=N1)c1cc(Br)ccc1O2
Reactant: OB(O)c1cccnc1F
Product: CC(C)(F)COc1cc(F)c2c(c1)[C@]1(CCOC(N)=N1)c1cc(-c3cccnc3F)ccc1O2

Procedure:
The title compound was synthesized by steps analogous to those described in method A8 above, but using intermediate 20B, 2-fluoropyridin-3-ylboronic acid and 2-fluoro-2-methylpropyl trifluoromethanesulfonate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([S:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)(=[O:12])=[O:11])[C:8](=[O:21])[N:7]([CH:22]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:23]([NH:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]3)=[O:24])[C:6]=2[CH:47]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([S:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)(=[O:11])=[O:12])[C:8](=[O:21])[N:7]([CH:22]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:23]([NH:25][CH2:26][CH2:27][N:28]3[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]3)=[O:24])[C:6]=2[CH:47]=1
Reactant: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)NCCN3CCN(C(=O)OC(C)(C)C)CC3)c3ccccc3)c3cc(Cl)ccc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)NCCN3CCNCC3)c3ccccc3)c3cc(Cl)ccc32)cc1
Temperature: 25 °C

Procedure:
520 (0.76 mmol) of tert-butyl 4-(2-{2-[6-chloro-3-(4-methoxybenzenesulfonyl)-2-oxo-2,3-dihydrobenzimidazol-1-yl]-2-phenyl-acetylamino}-ethyl)piperazine-1-carboxylate (Example 130) were dissolved in dichlormethane (6 ml) and, while stirring at room temperature, trifluoroacetic acid (4 ml) was added. The reaction solution was stirred for 2 h and then the solvent and excess trifluoroacetic acid were removed in vacuo. The residue was taken up once again in toluene, concentrated in vacuo and then dried in vacuo. The residue was dissolved in 6 ml of dichloromethane, mixed with 3 eq. of MP carbonate (Argonaut, 1.69 mmol/g) and stirred at room temperature for 2 h. The solid phase reagent was filtered off and washed with dichloromethane. The filtrate was concentrated under reduced pressure and dried in vacuo. Yield: 430 mg (97%) of colorless oil.