Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([NH:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[O:15])=[CH:13][C:8]=2[N:7]=[C:6]1[C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=1.[H][H]>CO.Cl.[Pd]>[NH2:30][CH2:29][C:26]1[CH:25]=[CH:24][C:23]([C:6]2[N:5]([CH2:4][CH2:3][CH2:2][NH2:1])[C:9]3[CH:10]=[CH:11][C:12]([C:14]([NH:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[O:15])=[CH:13][C:8]=3[N:7]=2)=[CH:28][CH:27]=1
Reactant: COC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc(C#N)cc1)n2CCCN
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc(CN)cc1)n2CCCN

Procedure:
3 g of 1-(3-amino-propyl)-2-(4-cyano-phenyl)-5-[(2-methoxycarbonyl-ethyl)-aminocarbonyl]-benzimidazole are treated in a mixture of 50 ml of methanol and 10 ml of methanolic hydrochloric acid with 5 bars of hydrogen in the presence of 1 g of 10% palladium/charcoal for 20 hours at ambient temperature. After the catalyst has been filtered off the mixture is evaporated to dryness in vacuo and the residue is purified by chromatography on silica gel (eluant:methanol/2N ammonia=5:1.5 to 5:2). Yield: 1.5 g (55% of theory), Rf value: 0.24 (silica gel; methanol/2N ammonia=5:1.5 after developing twice)
Reaction SMILES: [CH:1]1([CH3:13])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([C:10](Cl)=[O:11])[CH2:2]1.Cl.[CH2:15]([O:18][C:19](=[O:22])[CH2:20][NH2:21])[CH2:16][CH3:17].C(=O)(O)[O-].[Na+]>>[CH2:15]([O:18][C:19](=[O:22])[CH2:20][NH:21][C:10]([CH:3]1[CH:4]([CH:7]([CH3:9])[CH3:8])[CH2:5][CH2:6][CH:1]([CH3:13])[CH2:2]1)=[O:11])[CH2:16][CH3:17]
Reactant: CCCOC(=O)CN
Reactant: CC1CCC(C(C)C)C(C(=O)Cl)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCOC(=O)CNC(=O)C1CC(C)CCC1C(C)C

Procedure:
Following the procedure of Example 2 p-menth-3-oyl chloride (2.0 g., 0.01 moles), was reacted with glycine propyl ester hydrochloride (1.5 g., 0.01 moles) and sodium bicarbonate (1.6 g., 0.02 moles). The crude product was distilled b.p. 170°/0.1 mm. (After distillation the product rapidly solidifies). (Found, C: 68.2; H: 1016; N: 5.0. C16H29NO3 requires, C: 67.8; H: 10.6; N: 4.9.)
Reaction SMILES: [CH3:1][C:2]1([C:8]([OH:10])=O)[CH2:5][CH:4]([CH2:6][CH3:7])[CH2:3]1.[CH3:11]COCC>>[CH3:11][C:8]([C:2]1([CH3:1])[CH2:3][CH:4]([CH2:6][CH3:7])[CH2:5]1)=[O:10]
Reactant: CCOCC
Reactant: CCC1CC(C)(C(=O)O)C1
Product: CCC1CC(C)(C(C)=O)C1

Procedure:
A solution of 5.0 g (35 mmol) of 1-methyl-(3-ethyl)-cyclobutanecarboxylic acid (prepared in Example 2A) in 35 ml of dry ether was stirred with ice-bath cooling under an argon atmosphere and 40 ml of a 2 M solution of methyllithuim in ether was added thereto. The resultant mixture was stirred without cooling for 3 hr. This mixture was then quenched by pouring the mixture into a vigorously stirred solution of 30 ml of methanol and 70 ml of water. The aqueous phase was separated and extracted twice with ether. The combined ether extract was dried over anhydrous magnesium sulfate and evaporated. The residue was distilled at reduced pressure to yield 2.5 g of the title compound having the following physical characteristics:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:12])[CH2:10][CH3:11])=[CH:5][CH:4]=1.Br[CH2:14][C:15]([O:17][CH3:18])=[O:16].Cl>C1(C)C=CC=CC=1.C1COCC1>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:12])[CH:10]([CH3:11])[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:5][CH:4]=1
Reactant: CCC(=O)c1ccc(SC)cc1
Reactant: COC(=O)CBr
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)CC(C)C(=O)c1ccc(SC)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of potassium hexamethylsilazane (0.158 mole) in toluene (254 ml) and THF (160 ml) at -78° C. was added dropwise the ketone from Step A of this Example (25.8 g) in THF (90 ml). The reaction mixture was stirred 30 minutes at -78° C. Methyl bromoacetate (16.2 ml) in THF (25 ml) was added dropwise. After stirring 1.5 hours at -78° C. the reaction mixture was poured into 1N HCl (400 ml). The organic layer was separated and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were washed with water, dried over Na2SO4 and evaporated to give a yellow oil which was purified on a flash silica gel column (1 kg) using hexane/EtOAc (10:2) as eluant to give the title compound as an oil.
Reaction SMILES: Cl.[CH:2]([N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[CH:20]=[C:19]([C:21](O)=[O:22])[NH:18][C:15]3=[N:16][CH:17]=2)[CH2:7][CH2:6]1)([CH3:4])[CH3:3].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51][NH2:52])=[CH:49][CH:48]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51][NH:52][C:21]([C:19]2[NH:18][C:15]3=[N:16][CH:17]=[C:12]([O:11][CH:8]4[CH2:9][CH2:10][N:5]([CH:2]([CH3:4])[CH3:3])[CH2:6][CH2:7]4)[CH:13]=[C:14]3[CH:20]=2)=[O:22])=[CH:49][CH:48]=1
Reactant: NCc1ccc(F)cc1
Reactant: CC(C)N1CCC(Oc2cnc3[nH]c(C(=O)O)cc3c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N1CCC(Oc2cnc3[nH]c(C(=O)NCc4ccc(F)cc4)cc3c2)CC1
Yield: 37 %

Procedure:
The title compound was synthesized in analogy to example 9, intermediate a), from 5-(1-isopropyl-piperidin-4-yloxy)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, 4-fluorobenzylamine and N,N-diisopropylethylamine (7 eq.) in DMF to give the desired product as a light yellow solid (37%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:11][C:12]2[C:17]([N:18]=1)=[C:16]([N:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[CH2:21][CH2:20]1)[N:15]=[C:14]([CH3:27])[N:13]=2.[CH3:28][O:29][CH2:30]Br>O1CCCC1>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]([CH2:28][O:29][CH3:30])[C:12]2[C:17]([N:18]=1)=[C:16]([N:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[CH2:21][CH2:20]1)[N:15]=[C:14]([CH3:27])[N:13]=2
Reactant: CCN1CCN(c2nc(C)nc3[nH]c(-c4ccccc4Cl)nc23)CC1
Reactant: COCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CCN(c2nc(C)nc3c2nc(-c2ccccc2Cl)n3COC)CC1
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 11.1 %

Procedure:
Add sodium hydride (0.031 g, 0.0013 mol) to a solution of 8-(2-chlorophenyl)-6-(4-ethylpiperazin-1-yl)-2-methyl-9H-purine (0.233 g, 0.00065 mol) in dry tetrahydrofuran (20 mL) at 0° C. Stir the reaction mixture for 15 min, then cool to −30° C. and add bromomethyl methyl ether (0.081 g, 0.00065 mol). Warm the reaction mixture to room temperature and stir for one hour. Quench the reaction mixture with water, remove the tetrahydrofuran by evaporation and then extract the reaction mixture with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to give the residue. Purify the residue through preparative reverse phase HPLC (X-Bridge column, 5 mM NH4OAc/acetonitrile) to give the title compound (0.029 g). ES/MS m/z 401 (M+1).
Reaction SMILES: O=[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][NH:3]1.P(Cl)(Cl)([Cl:25])=O.[OH-].[Na+]>>[Cl:25][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1
Reactant: O=c1cc(-c2c(-c3ccccc3)nn3ccccc23)cc[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Clc1cc(-c2c(-c3ccccc3)nn3ccccc23)ccn1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
A mixture of 3-(2-oxo-1,2-dihydropyridin-4-yl)-2-phenylpyrazolo[1,5-a]pyridine (0.6 g) and phosphorus oxychloride (1.8 ml) was stirred for 6 hours at 70° C. After cooling, the reaction mixture was poured onto ice (30 g) and made alkaline with 24% aqueous solution of sodium hydroxide (pH=10) and extracted with chloroform (18 ml). The combined extract was washed with water and sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was chromatographed on silica gel (12 g) with chloroform as an eluent. The fractions containing the object compound were combined and evaporated in vacuo and recrystallized from a mixture of ethyl acetate and diisopropyl ether to give 3-(2-chloropyridin-4-yl)-2-phenylpyrazolo[1,5-a]pyridine (0.21 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[S:15][C:5]=2[NH:6][C:7]2[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:8]=2[N:9]=1.[C:22]1([CH3:28])C=CC=CC=1>>[F:14][C:12]1[CH:11]=[CH:10][C:8]2[N:9]=[C:3]([N:2]3[CH2:28][CH2:22][N:6]([CH3:7])[CH2:5][CH2:4]3)[C:4]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[S:15][C:5]=3[NH:6][C:7]=2[CH:13]=1
Reactant: NC1=Nc2ccc(F)cc2Nc2sc3ccccc3c21
Reactant: Cc1ccccc1
Agent: Cl
Product: CN1CCN(C2=Nc3ccc(F)cc3Nc3sc4ccccc4c32)CC1
Temperature: 70 °C

Procedure:
12-Amino-8-fluoro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine hydrochloride (102 g) was suspended in toluene (600 ml), and the mixture was stirred under reflux with heating for 3 hours to remove water. The mixture was cooled to 70° C. under a nitrogen atmosphere, and N-methylpiperazine (300 ml) was added. The mixture was stirred with heating under a nitrogen atmosphere until the inside temperature reached 120° C. while removing toluene for 1.5 hours. The mixture was heated under a nitrogen atmosphere at 120° C. for 2.5 hours and cooled to 25° C. under a nitrogen atmosphere. Ethyl acetate (600 ml) and water (450 ml) were added to the reaction mixture for extraction and the obtained ethyl acetate layer was washed three times with water (300 ml). After confirming pH 7-8 of washing water, the solvent was concentrated under reduced pressure. Acetonitrile (100 ml) was added and the mixture was azeotropically concentrated to dryness under reduced pressure. To the residue was added acetonitrile (300 ml) and the mixture was heated for dissolution. The solution was cooled and stirred at −10° C.-−5° C. for 2.5 hours to allow precipitation of crystals. The precipitated crystals were filtered by suction and washed with acetonitrile (100 ml), followed by drying to give 8-fluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine (65.5 g).
Reaction SMILES: Br[C:2]1[N:3]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:4]=[C:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[N:6]=1.C([C:27]([O:29][CH2:30][CH3:31])=[O:28])#N>>[CH3:22][Si:21]([CH3:24])([CH3:23])[CH2:20][CH2:19][O:18][CH2:17][N:3]1[CH:4]=[C:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[N:6]=[C:2]1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)C#N
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)OCc2ccccc2)nc1Br
Product: CCOC(=O)c1nc(C(=O)OCc2ccccc2)cn1COCC[Si](C)(C)C

Procedure:
The title compound was prepared using the procedure described in Example 52(d) starting from benzyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (0.609 mmol, 250 mg) and ethyl cyanoformate (0.91 mmol, 90 mg). Yield 97 mg. 1H-NMR (400 MHz; CDCl3): δ −0.08 (s, 9H), 0.91 (t, 2H), 1.42 (t, 3H), 3.57 (t, 2H), 4.43 (q, 2H), 5.38 (s, 2H), 5.78 (s, 2H), 7.30-7.39 (m, 3H), 7.43-7.46 (m, 2H), 7.90 (s, 1H). LC-MS: [M+1]=405.13.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24]([OH:26])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:31][C:32]1[CH:33]=[N:34][C:35]([C:38]2([NH2:41])[CH2:40][CH2:39]2)=[N:36][CH:37]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:26])[NH:41][C:38]5([C:35]6[N:34]=[CH:33][C:32]([CH3:31])=[CH:37][N:36]=6)[CH2:39][CH2:40]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Reactant: Cc1cnc(C2(N)CC2)nc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(C)cn5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.04 g, 0.099 mmol, 1 eq), 1-(5-methylpyrimidin-2-yl)cyclopropanamine (125 mg, crude), Py-Bop (0.067 g, 0.13 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.026 g, 0.3 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative TLC (Eluent Chloroform:Methanol 9.5:0.5, 200 ml). Yield: 29 mg (54%). 1H NMR (400 MHz, CD3OD): δ 8.50 (d, J=0.5 Hz, 2H), 8.03-7.94 (m, 2H), 7.89-7.82 (m, 2H), 7.69-7.64 (m, 2H), 7.47-7.37 (m, 2H), 7.33-7.24 (m, 2H), 2.96 (s, 3H), 2.36 (s, 3H), 2.29 (s, 3H), 1.77-1.70 (m, 2H), 1.47-1.40 (m, 2H) LCMS: (ES+) m/z=535.2 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[C:11]1[N:12]=[N:13][CH:14]=[CH:15][CH:16]=1.Br[C:18]1[N:22]2[N:23]=[CH:24][C:25]([C:27]([OH:30])([CH3:29])[CH3:28])=[N:26][C:21]2=[N:20][CH:19]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]2[N:22]3[N:23]=[CH:24][C:25]([C:27]([OH:30])([CH3:28])[CH3:29])=[N:26][C:21]3=[N:20][CH:19]=2)=[CH:4][C:3]=1[C:11]1[N:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(O)c1cnn2c(Br)cnc2n1
Reactant: OB(O)c1ccc(F)c(-c2cccnn2)c1
Product: CC(C)(O)c1cnn2c(-c3ccc(F)c(-c4cccnn4)c3)cnc2n1

Procedure:
4-Fluoro-3-(pyridazin-3-yl)phenylboronic acid (50 mg, 0.23 mmol) was coupled to 2-(7-bromoimidazo[1,2-b][1,2,4]triazin-3-yl)propan-2-ol (56 mg, 0.22 mmol) using the method of Example 20. Purification by chromatography (silica gel, 3% MeOH/CH2Cl2) gave the title compound as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 1.72 (6H, s), 7.37 (1H, dd, J 11, 9 Hz), 7.60 (1H, dd, J 9, 5 Hz), 8.04 (1H, dt, J 9, 2 Hz), 8.14-8.19 (1H, m), 8.31 (1H, s), 8.82 (1H, s), 8.90 (1H, dd, J 7, 2 Hz), 9.22 (1H, dd, J 5, 2 Hz); MS (ES+) m/z 351 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:10][OH:11])=[C:4](F)[CH:3]=1.N12CCCN=C1CCCCC2>O1CCCC1>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[C:9]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[N:10][O:11][C:4]=2[CH:3]=1
Reactant: ON=C(c1ccncc1)c1cc(F)c(Br)cc1F
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Fc1cc2c(-c3ccncc3)noc2cc1Br
Yield: 27.6 %

Procedure:
A solution of Z/E (4-bromo-2,5-difluorophenyl)(4-pyridinyl)methanone oxime (Intermediate 5, 124 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (40 mg) in tetrahydrofuran (1.5 ml) was heated at 150° C. in a microwave oven for 30 min. The solvent was removed under vacuum and the residue was triturated with a small quantity of methanol to give the title compound as a cream coloured solid (32 mg).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([OH:10])=[CH:5][C:4]=1[NH:11][NH:12][CH:13]=[O:14].[OH-].[Na+].CO.[CH3:19][C:20]([CH3:22])=O>O>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH2:22][C:20]#[CH:19])=[CH:5][C:4]=1[NH:11][NH:12][CH:13]=[O:14]
Reactant: O=CNNc1cc(O)c(Cl)cc1Cl
Reactant: CC(C)=O
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C#CCOc1cc(NNC=O)c(Cl)cc1Cl
Temperature: 40 °C

Procedure:
A stirred suspension of formic acid N'-(2,4-dichloro-5-hydroxyphenyl)-hydrazide sodium salt (1.1 g, 5 mmol) in a mixture of 25 ml acetone and 25 ml water is reacted at room temperature with benzene sulfonic acid-(2-propargyl)ester (1.01 g, 5 mmol). Sodium hydroxide solution (0,2 g, 5 mmol in 5 ml water) is added dropwise within 30 minutes so that the pH value lies between 9.5 and 10. The result is reacted with 10 ml methanol to produce a clear solution. This is heated to 40° C. for 30 minutes during which a precipitate forms. The result is stirred over night, the product is filtered off and washed with water. Yield: 0.8 g (61%) pale brown crystals Melting point: 184° C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][C@H:6]1[CH3:20])=[O:4].[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([OH:32])=[C:26]([CH:31]=1)[C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC.C(OCC)(=O)C>[CH3:30][O:29][C:27](=[O:28])[C:26]1[CH:31]=[C:22]([Cl:21])[CH:23]=[CH:24][C:25]=1[O:32][CH2:2][C:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][C@H:6]1[CH3:20])=[O:4]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CCl
Reactant: COC(=O)c1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: COC(=O)c1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Yield: 99.3 %

Procedure:
To a solution of (2R, 5S)-2-chloro-1-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-ethanone (2.75 g, 9.2 mmol) in butanone (50 ml) was added methyl 5-chloro-2-hydroxybenzoate (1.55 g, 9.2 mmol), potassium carbonate (2.54 g, 18.4 mmol) and potassium iodide (1.52 g, 9.2 mmol). The resulting mixture was stirred at reflux for 6 hours. The reaction was then cooled, diluted with ethyl acetate, and washed with brine. The organics were dried over magnesium sulfate, filtered and concentrated in vacuo to give an orange oil. Chromatography on silica gel gave the title compound (4.1 g, 100% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:8]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[NH:6][C:5]=1[C:14]1[S:15][CH:16]=[CH:17][CH:18]=1.[F:19][C:20]([F:27])([F:26])[C:21](OCC)=[O:22]>C(Cl)(Cl)Cl>[F:19][C:20]([F:27])([F:26])[C:21]([NH:1][CH2:2][CH2:3][C:4]1[CH:8]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[NH:6][C:5]=1[C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)=[O:22]
Reactant: NCCc1cc(-c2cccs2)[nH]c1-c1cccs1
Reactant: CCOC(=O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C(NCCc1cc(-c2cccs2)[nH]c1-c1cccs1)C(F)(F)F
Reaction time: 8 h
Yield: 45 %

Procedure:
A solution containing 100 mg (0.36 mmol) of 3-(2-aminoethyl)-2,5-dithienylpyrrole (XXII), 2 mL of ethyl trifluoroacetate, and 5 mL of CHCl3 was allowed to stand at ambient temperature overnight. The CHCl3 solvent was removed in vacuo, and the product XXIII isolated by preparative SiO2 -TLV plates (20 ×20 ×1000u) eluted with a 9:1 toluene-dioxane solvent mixture. Sixty mg of compound XXIII was obtained (45% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:65][C:66]1[CH:74]=[CH:73][CH:72]=[CH:71][C:67]=1[C:68]([NH2:70])=[O:69]>C(Cl)Cl>[C:68]([C:67]1[CH:71]=[CH:72][CH:73]=[CH:74][C:66]=1[NH:65][C:28]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:31])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10]1)=[O:29])(=[O:69])[NH2:70]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: NC(=O)c1ccccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccccc2C(N)=O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.26 mmol) was added followed by the addition of DIPEA (90 uL, 0.52 mmol) and 2-amino benzamide (Aldrich, 35 mg, 0.26 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, eluent, 20% EtOAc/hexanes) to give a white solid. 30 mg.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:15]=[CH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)[CH2:3]1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:22][C:23]1[C:24](F)=[N:25][CH:26]=[CH:27][CH:28]=1>CN(C=O)C.O>[Br:22][C:23]1[C:24]([N:2]2[CH2:3][CH:4]([C:6]3[CH:15]=[CH:14][C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[N:7]=3)[CH2:5]2)=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: Fc1ncccc1Br
Reactant: c1ccc2nc(C3CNC3)ccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cccnc1N1CC(c2ccc3ccccc3n2)C1
Temperature: 90 °C
Yield: 56.8 %

Procedure:
To a solution of 2-azetidin-3-yl-quinoline hydrochloride (1.70 g, 7.75 mmol) in DMF (30 mL) at room temperature was added Cs2CO3 (5.2 g, 16 mmol) and 3-bromo-2-fluoro-pyridine (1.5 g, 9.0 mmol). The reaction mixture was heated to 90° C. overnight and then diluted with water (60 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with water (60 mL) and brine (60 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (5% to 30% EtOAc in hexanes) to give the title product (1.50 g, 4.4 mmol, 58% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:15]B(O)O)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH3:14].O[C:20]1[CH:21]=[CH:22][C:23]2[S:29](=[O:31])(=[O:30])[CH2:28][CH2:27][C:26]([C:32]([O:34][CH3:35])=[O:33])=[CH:25][C:24]=2[CH:36]=1.C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH3:14])[O:15][C:20]1[CH:21]=[CH:22][C:23]2[S:29](=[O:31])(=[O:30])[CH2:28][CH2:27][C:26]([C:32]([O:34][CH3:35])=[O:33])=[CH:25][C:24]=2[CH:36]=1
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Reactant: CCCOCCOc1ccc(OB(O)O)cc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOCCOc1ccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1C
Reaction time: 24 h
Yield: 69.2 %

Procedure:
To 3-methyl-4-propoxyethoxyphenylboric acid (710 mg), methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (400 mg) and cupric acetate (270 mg) suspended in dichloromethane (15 ml) was added triethylamine (1.04 ml). The resulting mixture was stirred for one day with a calcium chloride tube attached to the reaction vessel, was then mixed with celite and was filtered to remove an insoluble material. The filtrate was concentrated and the residue was subjected to purification using silica gel column chromatography to obtain methyl 7-[3-methyl-4-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (475 mg) as a brown oily substance.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][NH:8][C:9](=[N:12][N+:13]([O-:15])=[O:14])[S:10][CH3:11])=[CH:5][N:6]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].Cl>N1C=CC=CC=1>[C:16]([N:8]([CH2:7][C:4]1[S:3][C:2]([Cl:1])=[N:6][CH:5]=1)[C:9](=[N:12][N+:13]([O-:15])=[O:14])[S:10][CH3:11])(=[O:18])[CH3:17]
Reactant: CSC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CSC(=N[N+](=O)[O-])N(Cc1cnc(Cl)s1)C(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
A mixture consisting of 1 g N-(2-chloro-5-thiazolylmethyl)-S-methyl-N'-nitroisothiourea, 1.15 g acetic anhydride and 25 ml pyridine was stirred at room temperature for 3 hours. The reaction mixture was added into an aqueous hydrochloric acid solution (concentrated hydrochloric acid 20 ml, water 50 ml, ice 10 g) for separation into layers. The resultant aqueous layer was extracted with 120 ml of chloroform, while the resultant organic layers were combined together, dried over magnesium sulfate and concentrated to afford 1.15 g of N-acetyl-N-(2-chloro-5-thiazolylmethyl)-S-methyl-N'-nitroisothiourea as a brown crystal, mp 77°-78° C.