Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]([C:16]([OH:18])=O)=[C:13]([CH3:15])[N:14]=3)[C:6]2=[O:19])[CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[F:51][C:52]1[CH:53]=[C:54]([CH2:58][NH2:59])[CH:55]=[N:56][CH:57]=1>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([CH2:4][N:5]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]([C:16]([NH:59][CH2:58][C:54]4[CH:55]=[N:56][CH:57]=[C:52]([F:51])[CH:53]=4)=[O:18])=[C:13]([CH3:15])[N:14]=3)[C:6]2=[O:19])[CH2:2][CH2:3]1
Reactant: NCc1cncc(F)c1
Reactant: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)NCc1cncc(F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 47 %

Procedure:
To a solution of 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid (1.00 g, 3.55 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 1.70 g, 4.47 mmol) and triethylamine (1.00 mL, 7.17 mmol) in N,N-dimethylformamide (15 mL) was added (5-fluoropyridin-3-yl)methanamine (0.55 g, 4.36 mmol). The reaction mixture was stirred at ambient temperature for 20 h, diluted with ethyl acetate (200 mL) and washed with water and brine. The organic solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was recrystallized from ethyl acetate to afford the title compound as a white powder in 47% yield (0.65 g): mp 144-145° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.53 (J=6.0 Hz, 1H), 8.43-8.38 (m, 2H), 7.59-7.56 (m, 1H), 4.39 (d, J=6.0 Hz, 2H), 4.00-3.95 (m, 2H), 3.64-3.59 (m, 2H), 3.06 (d, J=6.0 Hz, 2H), 2.44 (s, 3H), 0.95-0.87 (m, 1H), 0.48-0.42 (m, 2H), 0.20-0.16 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 162.4, 161.1, 157.9, 155.2, 145.5, 137.9, 136.6, 122.5, 122.3, 117.6, 48.2, 42.5, 42.3, 40.8, 17.6, 9.3, 3.6; MS (ES+) m/z 389.9 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=O)C.[NH2:28][C:29]1[N:34]=[CH:33][C:32]([CH2:35][N:36]([CH3:42])[CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])=[CH:31][CH:30]=1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[CH3:40][N:39]([CH3:41])[CH2:38][CH2:37][N:36]([CH2:35][C:32]1[CH:31]=[CH:30][C:29]([NH:28][C:4]([C:6]2[C:7]3[N:8]=[CH:9][CH:10]=[N:11][C:12]=3[C:13]([C:16]3[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=3[F:22])=[CH:14][CH:15]=2)=[O:3])=[N:34][CH:33]=1)[CH3:42]
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Reactant: CN(C)CCN(C)Cc1ccc(N)nc1
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN(C)CCN(C)C)cn3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 5 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1), N-(6-amino-pyridin-3-ylmethyl)-N,N′,N′-trimethyl-ethane-1,2-diamine (prepared as described in Example 26 but using N,N,N′-trimethyl-ethane-1,2-diamine in Step 26.2 and purified by column chromatography), 1.5 equiv of trimethyl aluminum, stirring the reaction mixture for 5 h at 80° C. and pouring it onto a saturated aqueous solution of NaHCO3 and DCM. The title compound: ESI-MS: 537.1 [M+H]+; tR=3.31 min (System 1); TLC: Rf=0.13 (DCM/MeOH, 95:5).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[F:21][C:22]([F:29])([F:28])[C:23]1[CH:24]=[N:25][NH:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:21][C:22]([F:29])([F:28])[C:23]1[CH:24]=[N:25][N:26]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=3[N:12]=2)[CH:27]=1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: FC(F)(F)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3-n3cc(C(F)(F)F)cn3)nc2c1
Temperature: 50 °C
Yield: 91.1 %

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.18 g of 4-(trifluoromethyl)pyrazole, 0.55 g of potassium carbonate and 2 ml of DMF was stirred while heating at 50° C. for 1.5 hours. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.36 g of 2-{3-[4-(trifluoromethyl)pyrazole-1-yl]pyridin-4-yl}-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 62”).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH:10]2[N:22]([C:25](=[O:42])[CH:26]([NH:31][C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:23][CH2:24][CH:9]12)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.CO>C(Cl)Cl>[CH2:35]([O:34][C:32](=[O:33])[NH:31][CH:26]([C:25]([N:22]1[CH2:23][CH2:24][CH:9]2[NH:8][CH2:12][CH:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=3)[CH:10]12)=[O:42])[C:27]([CH3:30])([CH3:29])[CH3:28])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(F)c(F)c2)C2C1CCN2C(=O)C(NC(=O)OCc1ccccc1)C(C)(C)C
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(NC(=O)OCc1ccccc1)C(=O)N1CCC2NCC(Oc3ccc(F)c(F)c3)C21
Temperature: 0 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
The Boc-containing compound 23 (1.0 g, 1.70 mmol) was dissolved in DCM (4 mL) and cooled to 0° C. before TFA (2 mL) was added and the reaction stirred at 0° C. for 1 h. TLC analysis (10:1 DCM/MeOH) indicated the starting material had all been consumed and the product had formed. The reaction mixture was concentrated at low pressure on the rotary evaporator. The crude residue was dissolved in DCM and washed successively with saturated aqueous NaHCO3 (3×), and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to afford 845 mg of 24 as a white foam. Mass spectrum, m/z [488.3] (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.C1CCN2C(=NCCC2)CC1.C1N=[CH:26][N:25]([C:28](N2C=NC=C2)=[O:29])[CH:24]=1.CNC>C(#N)C>[CH3:24][N:25]([CH3:26])[C:28]([NH:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1)=[O:29]
Reactant: Nc1nc2c(s1)C(=O)CCC2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CN(C)C(=O)Nc1nc2c(s1)C(=O)CCC2
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 2-amino-5,6-dihydro-4H-benzothiazol-7-one (10 g, 59 mmol), DBU (18 mL, 0.12 mol) and CDI (24 g, 0.15 mol) in 400 mL acetonitrile is stirred for 5 h at 100° C. Then dimethylamine (150 mL, 2M in THF) is added and the reaction mixture is stirred overnight at 100° C. The reaction mixture is concentrated under reduced pressure and the residue is poured in water. The mixture is acidified to pH 5 with 6 M HCl in water and extracted with ethyl acetate. The combined organic phases are dried over MgSO4 and concentrated under reduced pressure. The residue is triturated with diethyl ether. Yield: 9.1 g.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:10]([N:2]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)CCN
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCN(Cc1ccccc1)Cc1ccccc1
Yield: 97 %

Procedure:
Heat a solution of ethyl 3-aminopropanoate hydrochloride (80.0 g, 0.52 mol), benzylbromide (186.7 g, 1.1 mol) and K2CO3 (179.4 g, 1.3 mol) in acetonitrile (1 L) at 40° C. overnight. Concentrate the mixture to dryness, treat with water, extract with EtOAc (3×), wash the combined organics with brine, dry over Na2SO4, concentrate to dryness and purify via silica gel chromatography (Pet Ether/EtOAc, 50:1) to afford the title compound (150 g, 97% yield). 1H NMR (400 MHz, CDCl3): δ 7.35-7.21 (m, 10H), 4.09 (q, J=7.2 Hz, 2H), 3.58 (s, 4H), 2.82 (t, J=7.2 Hz, 2H), 2.50 (t, J=7.2 Hz, 2H), 1.21 (t, J=7.2 Hz, 3H).
Reaction SMILES: C(O)(=O)C.[NH:5]1[CH2:8][CH:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6]1.[CH:16]([C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1)=O.C([BH3-])#N.[Na+]>CO>[C:22]([C:21]1[CH:24]=[CH:25][C:18]([CH2:16][N:5]2[CH2:6][CH:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8]2)=[CH:19][CH:20]=1)#[N:23]
Reactant: CC(C)(C)OC(=O)C1CNC1
Reactant: N#Cc1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(C#N)cc2)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of tert-butyl azetidine-3-carboxylate acetic acid salt (92.0 g, 0.423 mol) in methanol (1.0 L) at room temperature was added 4-formylbenzonitrile (50.8 g, 0.381 mol). The reaction mixture was cooled to 0° C., and sodium cyanoborohydride (28.8 g, 0.458 mol) was added portion-wise. The reaction mixture was allowed to warm to room temperature and stirring continued overnight. After the reaction mixture was concentrated under reduced pressure the residue was diluted with 10% aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was collected, washed with brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by silica gel chromatography using 20% ethyl acetate in petroleum ether afforded tert-butyl 1-(4-cyanobenzyl)azetidine-3-carboxylate (89%) (After chromatography, Int.1-D contained a small amount of 4-hydroxymethylbenzonitrile. This material was taken forward to the next step without further purification). LC/MS M+1=273.18. 1H NMR (400 MHz, CDCl3) δ ppm 1.46 (s, 9H), 3.22-3.31 (m, 3H), 3.48-3.56 (m, 2H), 3.66 (s, 2H), 7.39 (d, J=8.28 Hz, 2H), and 7.60 (d, J=8.28 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:23])[CH:6]=1)[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=3)[C:14]=2[CH3:23])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(C)cc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: CCn1cc(Br)cn1
Product: CCOC(=O)c1cc(C)cc(Sc2c(C)n(-c3cnn(CC)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: 3-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-5-methyl-benzoic acid ethyl ester and 4-bromo-1-ethylpyrazole.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])([CH3:4])([CH3:3])[CH3:2].[C:14]([C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1)(=O)[CH3:15].[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:14]([C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1)[CH3:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: CC(=O)c1cnccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(NCCCCNC(=O)OC(C)(C)C)c1cnccn1
Yield: 91 %

Procedure:
Using General Procedure B: Reaction of (4-amino-butyl)-carbamic acid tert-butyl ester and 2-acetyl pyrazine in MeOH with NaBH4 gave [4-(1-pyrazin-2-yl-ethylamino)-butyl]-carbamic acid tert-butyl ester (294 mg, 91%) as a colorless oil. 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.50-1.57 (m, 4H), 1.59 (d, 3H, J=6.6 Hz), 2.38-2.43 (m, 1H), 2.51-2.59 (m, 1H), 3.08-3.14 (m, 2H), 3.08 (m, 2H), 3.91 (d, 1H, J=6.7 Hz), 4.72 (bs, 1H), 8.45 (d, 1H, J=2.5 Hz), 8.53 (d, 1H, J=2.6 Hz), 8.60 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2Cl.[NH2:16][C:17]1[C:18]([CH3:23])=[N:19][N:20]([CH3:22])[CH:21]=1.Cl.CN1C(C)(C)CCCC1(C)C>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2[NH:16][C:17]1[C:18]([CH3:23])=[N:19][N:20]([CH3:22])[CH:21]=1
Reactant: Cc1nn(C)cc1N
Reactant: O=[N+]([O-])c1cnc2ccc(Br)cc2c1Cl
Agent: CN1C(C)(C)CCCC1(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Cc1nn(C)cc1Nc1c([N+](=O)[O-])cnc2ccc(Br)cc12
Temperature: 50 °C
Reaction time: 4.5 h

Procedure:
To a mixture of 6-bromo-4-chloro-3-nitro-quinoline (Stage A.4, 3.0 g, 20.43 mmol) and 4-amino-1,3-dimethylpyrazole.HCl (ChemCollect, Remscheid, Germany, 1.85 g, 12.53 mmol) in DMA (45 ml) was added 1,2,2,6,6-pentamethylpiperidine (6.67 ml, 36.5 mmol). The RM was stirred at 50° C. for 4.5 h. Then the RM was cooled down to rt and quenched with H2O. The suspension was filtered, the solid cake was washed with H2O and dried under vacuum, before being dissolved in EtOAc. The solution was washed with brine (2×), dried over Na2SO4, filtered and evaporated to dryness to give the title compound as an orange solid (HPLC tR 2.55 min (Method A); M+H=362; M−H=360 MS-ES)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:20])=[C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:17]#N)[C:11]=2[CH3:19])[CH:9]=1)[CH3:2].[OH-:21].[Na+].S(=O)(=O)(O)O.[CH2:28]([OH:30])[CH3:29]>>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:20])=[C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:17]([O:30][CH2:28][CH3:29])=[O:21])[C:11]=2[CH3:19])[CH:9]=1)[CH3:2]
Reactant: CCO
Reactant: [OH-]
Reactant: CCOc1ccc(F)c(-c2cc(C)nc(C#N)c2C)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1nc(C)cc(-c2cc(OCC)ccc2F)c1C
Temperature: 100 °C
Reaction time: 5 h
Yield: 98.6 %

Procedure:
To a stirred solution of 4-(5-ethoxy-2-fluoro-phenyl)-3,6-dimethyl-pyridine-2-carbonitrile (which may be prepared as described in Description 138) (4.76 g, 17.61 mmol) in ethanol (25 mL) was added 8M sodium hydroxide (13.21 mL, 105.66 mmol). The resulting mixture was left to stir at 100° C. for 5 h. The reaction mixture was cooled and concentrated. The pH was adjusted to 1 with the careful addition of 5M aq. HCl. The reaction mixture was extracted with DCM and the organic layers were collected by passing down a PhaseSep cartridge. Evaporation of solvent under reduced pressure gave a colourless oily solid. This was dissolved in ethanol (60 mL) and sulfuric acid (5.18 mL, 96.73 mmol) was added. The resulting mixture was left to stir under reflux for 24 h. The solution was allowed to cool and concentrated. It was quenched with crushed ice and treated with 2M aq. NaOH to give pH=7. The mixture was extracted with DCM twice and the combined organic layers dried over sodium sulfate, filtered and evaporated. The crude residue was purified by silica gel chromatography (50 g SiO2) eluting with ethyl acetate in iso-hexane (10-70%). Evaporation of desired fractions gave ethyl 4-(5-ethoxy-2-fluoro-phenyl)-3,6-dimethyl-pyridine-2-carboxylate (D139) (5.51 g, 17.363 mmol, 98.6% yield) as colourless solid;
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]1[CH2:51][O:50][C:13]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])([CH2:14][CH2:15][C@H:16]2[C@H:20]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[CH2:19][C@H:18]([OH:28])[C@@H:17]2[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38])[O:12]1.C(N(CC)CC)C>ClCCl>[CH2:51]1[CH2:11][O:12][C:13]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])([CH2:14][CH2:15][C@H:16]2[C@H:20]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[CH2:19][C:18](=[O:28])[C@@H:17]2[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38])[O:50]1
Reactant: CCCCCCCC1(CC[C@@H]2[C@@H](C/C=C\CCCCCC(=O)OC(C)C)[C@@H](O)C[C@H]2OC2CCCCO2)OCCO1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCCCCCCC1(CC[C@H]2[C@H](OC3CCCCO3)CC(=O)[C@@H]2C/C=C\CCCCCC(=O)OC(C)C)OCCO1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 89.2 %

Procedure:
Oxalyl chloride (2M;0.45 ml) and DMSO (0.13 ml) were added to dichloromethane (5ml) which was previously cooled to −70° C. and the mixture was agitated for 15 minutes. The solution of isopropyl (Z)-9-[(1R,2R,3R,5S)-2-(3,3-ethylene dioxydecyl)-5-hydroxy-3-(tetrahydropyranyloxy)cyclopentyl]-7-nonenoate (3-a)(0.350 g) in dichloromethane (7 ml) was dropped into the mixture. The resultant mixture was warmed to −55° C. and agitated for 15 minutes, and then triethylamine (0.25 ml) was added to the mixture. The resultant mixture was warmed to 10° C. over 6 hours. The crude product obtained by the conventional treatment of the reaction mixture was purified on silica gel column to give the titled compound (5-a)[yield:0.311 g (89%)].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:22]2[CH2:26][CH:25]([CH2:27][OH:28])[O:24][C:23]2=[O:29])[CH:5]=[C:6]([F:21])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.C(Cl)Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[F:21][C:6]1[CH:5]=[C:4]([N:22]2[CH2:26][CH:25]([CH2:27][O:28][S:36]([C:33]3[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=3)(=[O:38])=[O:37])[O:24][C:23]2=[O:29])[CH:3]=[C:2]([F:1])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(F)cc(N3CC(CO)OC3=O)cc2F)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CN(c3cc(F)c(N4CCN(C(=O)OC(C)(C)C)CC4)c(F)c3)C(=O)O2)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 89.3 %

Procedure:
The [3-[3,5-difluoro-4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methanol (24.2 g, 59 mmol) was dissolved in pyridine (110 mL) and then cooled to 0° C. (ice bath). Freshly recrystalized p-toluenesulfonyl chloride (13.4 g, 70 mmol) of was added and the reaction was allowed to stir at 0° C. for 2.5 hours under N2. The flask was then stoppered and stored in the refrigeratior (5° C.) overnight. The reaction mixture became a pale pink slurry. TLC revealed that some alcohol still remained. The reaction mixture was treated with additional p-toluenesulfonyl chloride (1.12 g, 5.85 mmol), catalytic 4-(dimethylamino)pyridine, and 20 mL of dry CH2Cl2 to facilitate stirring. After 4 hours at 0° C., the reaction was found to be complete by TLC (5% MeOH/CH2Cl3, UV short wave). The mixture was added to 750 mL ice water and the precipitated product isolated via suction filtration, washing it with both water (1 L) and ether (500 mL). After drying in vacuo, 29.921 g (90%) of the title compound was obtained as white solid with mp 150.5°-151.5° C.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=[CH:9]1)(N1C=CN=C1)=O.[NH2:13][C:14]1[CH2:20][N:19]=[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]2[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:16]=2[N:15]=1.[O:32]1C[CH2:35][CH2:34][CH2:33]1.CN(C)C=O>>[Cl:31][C:28]1[CH:29]=[CH:30][C:16]2[N:15]3[C:35]([CH2:11][CH2:12][N:8]([CH3:1])[CH3:9])=[CH:34][C:33](=[O:32])[N:13]=[C:14]3[CH2:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:17]=2[CH:27]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C1CCOC1
Reactant: NC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Solvent: CN(C)C=O
Product: CN(C)CCc1cc(=O)nc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 16, carbonyldiimidazole, 4-dimethylamino-butyn-2-oic acid and 2-amino-7-chloro-5-phenyl-3H-1,4-benzodiazepine was stirred in tetrahydrofuran-dimethylformamide to give 9-chloro-1(dimethylaminoethyl)-7-phenylpyrimido[1,2-a][1,4]-benzodiazepin-3(5H)-one.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][CH:3]=1.O.[NH2:13][NH2:14].O>C(O)C>[I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:13][NH2:14])=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc(I)cc1
Temperature: 25 °C

Procedure:
To Methyl 4-iodobenzoate (30.0 g, 114 mmol) in ethanol (180.0 ml) was added hydrazine hydrate (30.0 g, 599 mmol). The reaction mixture was reflux for 22.5 hours. Heating was stopped and then water (300.0 ml) was added. After cooling down to room temperature, white solid was appeared. The white product solid was collected by filtration. The product was washed with water and dried under vacuum. Final white pure product was obtained in 26.0 g (86.7%). 1H NMR (400 MHz, DMSO-d6, δ): 9.84 (s, 1H, NH), 7.82 (d, J=8.4 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H), 4.50 (s, 2H, NH2).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[C:16]([F:23])[C:15]=2[O:24][CH3:25])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[F:26][CH:27]([F:39])[O:28][C:29]1[CH:30]=[C:31]([S:35]([Cl:38])(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>>[ClH:38].[F:39][CH:27]([F:26])[O:28][C:29]1[CH:30]=[C:31]([S:35]([NH:20][C:18]2[CH:19]=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:15]([O:24][CH3:25])=[C:16]([F:23])[CH:17]=2)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1
Reactant: COc1c(F)cc([N+](=O)[O-])cc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=S(=O)(Cl)c1cccc(OC(F)F)c1
Product: COc1c(F)cc(NS(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCNCC1
Product: Cl

Procedure:
The compound was prepared by analogy to Example 7, starting from commercially available 1-bromo-3-fluoro-2-methoxy-5-nitrobenzene, which was reacted with tert.butyloxycarbonyl-piperazine by analogy to preparation example 3.1 top yield 1-(N-boc-piperazin-4-yl)-3-fluoro-2-methoxy-5-nitrobenzene. Reduction of the nitro group to the corresponding aniline by analogy to preparation example 3.2, subsequent coupling with commercially available 3-difluoromethoxybenzenesulfonylchloride by analogy to preparation example 1.4, and final deprotection of the tert.-butoxycarbonyl group under acidic conditions by analogy to example 1 yielded the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([F:32])[C:29]=1[O:30][CH3:31])[C:24](Cl)=[O:25]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([F:32])[C:29]=1[O:30][CH3:31])[C:24]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:25]
Reactant: c1ccc2c(c1)NCS2
Reactant: COc1c(F)cc(C(=O)Cl)cc1Cl
Agent: C=O
Agent: Nc1ccccc1S
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1c(F)cc(C(=O)N2CSc3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (346 mg) and 37% formalin (0.23 mL) in the same manner as in Example 1 was dissolved in chloroform (3 mL), and triethylamine (0.38 mL) and 3-chloro-5-fluoro-4-methoxybenzoyl chloride were added to the solution, and then the mixture was stirred at room temperature for 90 minutes. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=8:1) to obtain the title compound (356 mg) as a pale yellow oily substance.