Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[N:20]1([CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:31][CH2:30]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: C1CCN(CCCC2CCNCC2)CC1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Product: O=C1Nc2cccnc2N(C(=O)N2CCC(CCCN3CCCCC3)CC2)c2ccccc21
Yield: 81 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 4-[3-(1-piperidinyl)propyl]piperidine in a yield of 81% of theory. Colourless crystals, m.p. 200° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:12]([CH3:22])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:7][CH:6]=1.[Br:24]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:24][CH:4]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH:12]([CH3:22])[CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[CH:9][CH:10]=1)[C:3]([O:2][CH3:1])=[O:23]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc(OC(C)COc2ccc(Cl)cc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc(OC(C)COc2ccc(Cl)cc2)cc1
Yield: 97.1 %

Procedure:
A mixture of 10.0 g of methyl{p-[2-(p-chlorophenoxy)-1-methylethoxy]phenyl}acetate, 5.87 g of N-bromosuccinimide and 120 ml of carbon tetrachloride is stirred and refluxed for 5 days. The mixture is cooled, filtered and the filtrate is passed through a short column of silica gel (125 ml cuts). The first two cuts are combined and the solvent removed to give 12.0 g of colorless gum.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]2[S:29][CH:30]([CH2:33][C:34](O)=[O:35])[CH2:31][N:32]=2)=[CH:15]3)=[N:9][CH:10]=1)(=[O:4])=[O:3].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[NH:60]1[CH2:63][CH:62]([OH:64])[CH2:61]1>O.CN(C)C=O.C(N(CC)CC)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:20]=2)[NH:17][C:16]([C:28]2[S:29][CH:30]([CH2:33][C:34]([N:60]4[CH2:63][CH:62]([OH:64])[CH2:61]4)=[O:35])[CH2:31][N:32]=2)=[CH:15]3)=[N:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: OC1CNC1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)N5CC(O)C5)S4)cc3c2)nc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 62 %

Procedure:
A mixture of {2-[5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (190 mg), 1H-1,2,3-benzotriazol-1-ol (70 mg), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (100 mg), azetidin-3-ol hydrochloride (80 mg), triethylamine (80 mg) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 15 hr. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and eluted with ethyl acetate-methanol (100/0 to 90/10, volume ratio) to give colorless crystals. The crystals were recrystallized from acetone-hexane to give the title compound (130 mg, yield 62%) as colorless prism crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH2:12])=[S:11])[CH:5]=[C:6]([F:8])[CH:7]=1.BrBr>ClCCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]2[S:11][C:10]([NH2:12])=[N:9][C:4]=2[CH:3]=1
Reactant: NC(=S)Nc1cc(F)cc(F)c1
Agent: BrBr
Solvent: ClCCCl
Product: Nc1nc2cc(F)cc(F)c2s1
Temperature: 10 °C
Yield: 90.7 %

Procedure:
To a suspension of N-(3,5-difluorophenyl)thiourea (3.40 g, 18.07 mmol) in DCE (95 mL) was added a solution of bromine in DCE (5 mL) below 30° C. The mixture was heated at reflux for 2.5 h, then cooled to 10° C., and the precipitate formed was collected by filtration and washed with DCE. The solid was stirred with water (200 mL), basified by treatment with conc. ammonium hydroxide, filtered, and dried in a vacuum oven to afford 5,7-difluoro-1,3-benzothiazol-2-amine (3.05 g, 90%). ret. time 2.18; m/z 187.1 (MH+); 1H NMR (400 MHz, DMSO-d6) δ 6.92 (m, 1H), 7.00 (m, 2H), 7.92 (s, 2H).
Reaction SMILES: [Na].CO.Cl.[NH2:5][C:6]([NH2:8])=[NH:7].Cl.[Cl:10][C:11]([C:13]1[CH:17]=[CH:16][N:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[C:14]=1[CH3:28])=[O:12]>COCCOC>[ClH:10].[NH:7]([C:11]([C:13]1[CH:17]=[CH:16][N:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[C:14]=1[CH3:28])=[O:12])[C:6]([NH2:8])=[NH:5]
Reactant: N=C(N)N
Reactant: Cc1c(C(=O)Cl)ccn1-c1ccc2ccccc2n1
Agent: Cl
Agent: [Na]
Solvent: COCCOC
Solvent: CO
Product: Cc1c(C(=O)NC(=N)N)ccn1-c1ccc2ccccc2n1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 38.2 %

Procedure:
0.795 g (33.1 mmol) of sodium is added at 20° C. under an argon atmosphere to 30 mL of methanol. After complete dissolution, 2.97 g (31.2 mmol) of guanidine hydrochloride are added. After stirring at 20° C. for 0.5 hour, the reaction mixture is filtered under an argon atmosphere. The filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue that is dissolved in 15 mL of 1,2-dimethoxyethane. 2 g of 3-chlorocarbonyl-2-methyl-1-(quinol-2-yl)-1H-pyrrole hydrochloride, suspended in 15 mL of 1,2-dimethoxyethane, are then added at 20° C. under an argon atmosphere. After stirring at 20° C. for 8 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue that is triturated in 100 mL of water for 16 hours. After filtering off and drying the solid residue under reduced pressure (2.7 kPa), a residue is obtained, which residue is purified by flash chromatography [eluent: dichloromethane/methanol/acetonitrile (86/7/7 by volume) and then dichloromethane/methanol/20% aqueous ammonia (96/24/2 by volume)]. After concentrating the fractions under reduced pressure, a beige-coloured solid is obtained, which solid is triturated in 100 mL of N hydrochloric acid for 15 hours. After filtration, the solid residue is recrystallised under hot conditions from 30 mL of methanol to give 0.82 g of 3-guanidinocarbonyl-2-methyl-1-(quinol-2-yl)-1H-pyrrole hydrochloride in the form of a pinkish solid melting at 250° C. Mass spectrum (EI): m/e 293 (M+.), m/e 206 (base peak).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[NH:18]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH2:22][CH2:21][CH2:20][CH2:19]1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([N:18]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:6]
Reactant: c1ccc2c(c1)CCCCN2
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1CCCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
A solution of 42.6 g (0.211 mol) of 2-chloro-4-nitrobenzoic acid is reacted with 420 ml of thionyl chloride (refluxed for 3 hours and the excess thionyl chloride removed). Toluene is added several times and the solvent removed. The residue is dissolved in 400 ml of CH2Cl2 and added dropwise to a cold (ice bath) solution of 28.2 g (0.192 mol) of 1,2,3,4-tetra-hydro-5H-1-benzazepine and 29.4 ml of triethylamine in 320 ml of dichloromethane. The mixture is stirred at room temperature overnight and is washed with H2O, 10% HCl and 10% NaHCO3. Activated carbon is added to the organic layer and the mixture is filtered through a layer of MgSO4. The solvent is removed under vacuum and the residue chromatographed on silica gel (in two batches) with ethyl acetate-CH2Cl2 (5:95) as eluent. The fractions containing product are combined and the solvent removed. The residue is dissolved in ethyl acetate and the solvent removed (foams). The residue is heated with hexane to give a solid (lumps broken up) and the mixture is filtered. The solid is washed with hexane and dried to give 59.9 g of 1,2,3,4-tetrahydro-1-(2-chloro-4-nitrobenzoyl)-5H-l-benzazepine as off-white crystals, m.p. 112°-114° C., mass spectrum (CI) 321 (MH+)
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([N:13]([C:15]2[S:16][C:17](=[CH:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=3[C:39]([F:42])([F:41])[F:40])[N:26]=[CH:25]4)[C:18](=[O:20])[N:19]=2)[CH3:14])[CH2:10][CH:9]1[C:43](O)=[O:44])=O)(C)(C)C.Cl.[CH3:47][O:48][NH2:49].CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:47][O:48][NH:49][C:43]([CH:9]1[CH2:10][CH:11]([N:13]([C:15]2[S:16][C:17](=[CH:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=3[C:39]([F:41])([F:40])[F:42])[N:26]=[CH:25]4)[C:18](=[O:20])[N:19]=2)[CH3:14])[CH2:12][NH:8]1)=[O:44]
Reactant: CN(C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1)C1CC(C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CONC(=O)C1CC(N(C)C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CN1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-({5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-methyl-amino)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (0.066 g, 0.1 mmol) and methoxyamine hydrochloride (0.014 g, 0.15 mmol) in DMF (2 mL) was added EDC hydrochloride (0.03 g, 0.15 mmol) followed by DIPEA (0.3 mL, 1.72 mml). The reaction mixture was stirred at room temperature for 16 hours and partitioned between water and dichloromethane. The dichloromethane layer was washed with brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude solid. The crude solid was purified via flash chromatography (100% ethyl acetate) to yield the title compound.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[CH2:9][C:10](=[O:12])[CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[N:17](OCCCC)=O.[ClH:24]>CCOCC>[ClH:24].[NH2:17][CH:9]1[C:8]2[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=2[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:11][CH:10]1[OH:12]
Reactant: O=C1Cc2ccccc2-c2ccccc2C1
Reactant: CCCCON=O
Agent: Cl
Solvent: CCOCC
Product: NC1c2ccccc2-c2ccccc2CC1O
Temperature: 0 °C

Procedure:
A round bottom flask was charged with 5,7-dihydro-6H-dibenzo[a,c]cyclohepten-6-one (1.0 g, 4.81 mmol)(CAS#1139-82-8, prepared as described in Tetrahedron Letters, Vol. 28, No. 23, (1987), pp 2633-2636) and butyl nitrite (0.673 ml, 5.77 mmol) (Aldrich) in Et2O. The solution was cooled to 0° C. and treated drop-wise with a saturated solution of HCl(g)/Et2O. After 5 h at 0° C. the resulting precipitate was filtered, rinsed with cold Et2O and vacuum dried to give the title compound as a colorless solid.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:20]=[C:19]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([C:29](=[O:31])[CH3:30])=[CH:15][C:16]=3[C:17]([C:21]3[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][CH:22]=3)=[CH:18]2)=[C:9]([CH3:32])[CH:8]=1>C(Cl)Cl>[OH:6][C:7]1[CH:20]=[C:19]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([C:29](=[O:31])[CH3:30])=[CH:15][C:16]=3[C:17]([C:21]3[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=3)=[CH:18]2)=[C:9]([CH3:32])[CH:8]=1
Reactant: COc1ccc(-c2cc3cc(OC)cc(C)c3c3ccc(C(C)=O)cc23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)c(-c1ccc(O)cc1)cc1cc(O)cc(C)c12
Temperature: -28.5 °C
Reaction time: 8 h

Procedure:
BBr3 (100 ml, 1M in CH2Cl2) was added to the compound from Step A (6.76 g, 18.3 mmol) dissolved in CH2Cl2 (200 ml) at −60 to −70° C. The reaction was stirred overnight at −60 to 3° C. and then poured into water/ice (500 ml) and extracted with CHCl3/Acetone (2.5 L, 5/1). After evaporating the solvent, the residue was chromatographed on silica gel using a gradient of ethyl acetate:methanol (95:5) to ethyl acetate: methanol (80:20) to give the title compound. 1H-NMR (400 MHz, DMSO-d6) δH2.16 (3H, s, CH3), 2.67 (3H, s, COCH3), 6.52-8.48 (10H, ArH), 8.81 (1H, br, OH), 9.91 (1H, br, OH).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=[C:5]([Br:13])[C:3]=1N.OS(O)(=O)=O.N([O-])=O.[Na+].CCOC(C)=O>CCO.O>[Br:1][C:2]1[CH:8]=[C:7]([C:9]([CH3:11])([CH3:10])[CH3:12])[CH:6]=[C:5]([Br:13])[CH:3]=1
Reactant: CC(C)(C)c1cc(Br)c(N)c(Br)c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(Br)cc(Br)c1
Reaction time: 37 h

Procedure:
To a stirring solution of 2,6-dibromo-4-tert-butylaniline in 115 mL of EtOH was added 11.5 mL of concentrated H2SO4. To the stirring solution at 90° C. was added 8.8 g of NaNO2 in several portions. After 37 h, EtOAc and 120 mL of H2O were added, and the layers separated. The organic layer was washed with 40 mL of brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (hexanes) provided 8.15 g of 1,3-dibromo-5-tert-butylbenzene as a yellow-brown oil with some impurity.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[CH3:25][C:26](=[CH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:27](O)=[O:28].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:25][C:26](=[CH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:27]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:28]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: CC(=Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C(C)=Cc1ccccc1
Yield: 93.7 %

Procedure:
The same procedures as in Example 146 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), α-methylcinnamic acid (2.3 g), WSC.HCl (2.7 g), and methylene chloride (80 mL), to give the captioned compound (4.0 g, 94%) as an oily product.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[C:13]([C:15]1[C:23]2[C:18](=[CH:19][C:20]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:21][CH:22]=2)[NH:17][C:16]=1[CH3:29])=[O:14])[CH:2]=[CH2:3].[H-].[Na+].[S:32](Cl)([C:35]1[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=1)(=[O:34])=[O:33]>CN(C=O)C>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[C:13]([C:15]1[C:23]2[C:18](=[CH:19][C:20]([O:24][C:25]([F:28])([F:26])[F:27])=[CH:21][CH:22]=2)[N:17]([S:32]([C:35]2[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[C:16]=1[CH3:29])=[O:14])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(OC)ccc1C(=O)c1c(C)[nH]c2cc(OC(F)(F)F)ccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(OC)ccc1C(=O)c1c(C)n(S(=O)(=O)c2ccc(C)cc2)c2cc(OC(F)(F)F)ccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6 (8.0 g, 20 mmol) in DMF (200 mL) was added NaH (1.5 eq). Mixture stirred for 15 min before addition of TsCl (1.5 eq, 5.6 g). After 1 hour, the reaction mixture was poured into ice water and extracted with CH2Cl2. The organic layer was washed with NH4Cl (2×), NaHCO3 and brine, then dried with Na2SO4 and concentrated. Purification via flash chromatography eluding with 20% EtOAc/hexanes afforded the product as a viscous yellow oil.
Reaction SMILES: [C:1]([CH2:6][CH2:7]C1C=C2C(=CC=1)NC=C2CCN)([O:3]CC)=[O:2].[CH:20](/[O:27]S(O)(=O)=O)=N/N/C(/N)=N/O.C([OH:35])(C)C.CCOCC>O>[OH2:2].[C:20]([OH:27])(=[O:35])/[CH:7]=[CH:6]\[C:1]([OH:3])=[O:2]
Reactant: N/C(=N\O)N/N=C\OS(=O)(=O)O
Reactant: CCOC(=O)CCc1ccc2[nH]cc(CCN)c2c1
Reactant: CC(C)O
Solvent: O
Solvent: CCOCC
Product: O=C(O)/C=C\C(=O)O

Procedure:
The title compound was prepared from 2-[5-(2-(carboethoxy)ethyl)-1H-indol-3-yl]ethylamine and hydroxy guanidine sulphate using the procedure described for Example 6. The hydrogen maleate salt was prepared, mp 147°-148° C. (isopropylalcohol/ether); (Found: C, 53.89; H, 5.47; N, 17.67. C14H17N5O. C4H4O4. 0.75 H2O requires C, 53.93; H, 5.65; N, 17.47%); δ(360 MHz, D2O) 3.12 (2H, t, J=6.9 Hz, CH2); 3.17 (4H, t, J=4.1 Hz, 2 of CH2); 3.29 (2H, t, J=6.9 Hz, CH2); 7.11 (1H, dd, J=1.5 and 8.4 Hz, aromatic-H); 7.27 (1H, s, aromatic-H); 7.40 (1H, s, aromatic-H); 7.44 (1H, d, J=8.4 Hz, aromatic-H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[C:11]([CH:14]1[N:19]([CH3:20])[CH2:18][CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]1)(=[S:13])[NH2:12]>CCO>[CH3:20][N:19]1[CH2:18][CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH2:15][CH:14]1[C:11]1[S:13][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:12]=1
Reactant: CN1CCN(C(=O)OC(C)(C)C)CC1C(N)=S
Reactant: O=C(CBr)c1ccccc1
Solvent: CCO
Product: CN1CCN(C(=O)OC(C)(C)C)CC1c1nc(-c2ccccc2)cs1
Temperature: 70 °C
Yield: 64.2 %

Procedure:
A mixture of 2-bromoacetophenone (130 mg, 0.65 mmol) and tert-butyl 3-carbamothioyl-4-methylpiperazine-1-carboxylate (170 mg, 0.65 mmol) in EtOH (15 mL) was heated to 70° C. for 4 h. The reaction mixture was cooled to room temperature and solvent was evaporated under reduced pressure. The residue was diluted with water and the organic product was extracted with EtOAc. The combined extracts were washed with H2O and brine, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 20-25% EtOAc in petroleum ether) to afford tert-butyl 4-methyl-3-(4-phenylthiazol-2-yl)piperazine-1-carboxylate (150 mg, yield 64%). 1H NMR (300 MHz, CDCl3) δ 7.92-7.90 (m, 2H), 7.49 (m, 1H), 7.46-7.41 (m, 2H), 7.37-7.34 (m, 1H), 4.03-3.98 (m, 1H), 3.67-3.64 (m, 2H), 3.23-3.15 (m, 2H), 2.97-2.93 (m, 2H), 2.26 (s, 3H), 1.46 (s, 9H). MS (ESI) m/z: Calculated for C19H25N3O2S: 359.17. found: 360.2 (M+H)+
Reaction SMILES: CS(O[CH:6]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][CH2:8][C@@H:9]1[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:12](=[O:25])[CH2:11][CH2:10]1)(=O)=O.[N-:31]=[N+:32]=[N-:33].[Na+]>CN(C)C=O>[N:31]([CH:6]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][CH2:8][C@@H:9]1[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:12](=[O:25])[CH2:11][CH2:10]1)=[N+:32]=[N-:33]
Reactant: CCCCCC(CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC)OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCC(CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC)N=[N+]=[N-]

Procedure:
A solution of 1.35 g. of ethyl 15-methanesulfonyloxy 9-oxo-prostanoate (Example 90) in 60 ml. of N,N-dimethylformamide containing 1.25 g. of sodium azide is heated on the steam-bath for 18 hours. The cooled solution is poured into 300 ml. of water and the resulting mixture is extracted several times with ether. The combined ether extracts are washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness. The residual oil is chromatographed on silica gel to give 737 mg. (62%) of oil; λmax. 4.77 (azido) and 5.78 μ (carbonyl groups).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:6]2[C:7](=[O:9])[CH:8]=1.[Br:15]N1C(=O)CCC1=O.C(O)(=O)C>O>[Br:15][C:8]1[C:7](=[O:9])[N:6]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:5]2=[N:4][C:3]=1[CH2:2][Cl:1]
Reactant: O=c1cc(CCl)nc2ccc(F)cn12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: O
Product: O=c1c(Br)c(CCl)nc2ccc(F)cn12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 2-(chloromethyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one (8.310 g, 39.09 mmol), N-bromosuccinimide (8.055 g, 42.99 mmol), and acetic acid (110.3 mL) was stirred at rt. After 6 h, the mixture was poured into water (300 mL) and the resulting precipitate was collected by filtration, washed with water (400 mL), and dried to give 3-bromo-2-(chloromethyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one as a brown solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.97 (1 H, td), 8.19 (1 H, ddd, J=9.9, 7.1, 2.9 Hz), 7.86-7.94 (1 H, m), 4.81 (2 H, s); Mass Spectrum (ESI) m/e=292.9 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:40]=[CH:39][C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]([N:16]([C:18]2[C:19]([Cl:38])=[C:20]([C:34]([Cl:37])=[CH:35][CH:36]=2)[CH2:21][O:22][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]3[C:32]=2[N:31]=[C:30]([CH3:33])[CH:29]=[CH:28]3)[CH3:17])=[O:15])=[O:11])=[CH:6][CH:5]=1)([OH:3])=O.Cl.[CH2:42]([NH2:44])[CH3:43].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O>[Cl:38][C:19]1[C:18]([N:16]([C:14](=[O:15])[CH2:13][NH:12][C:10](=[O:11])[CH:9]=[CH:8][C:7]2[CH:6]=[CH:5][C:4]([C:1](=[O:3])[NH:44][CH2:42][CH3:43])=[CH:40][CH:39]=2)[CH3:17])=[CH:36][CH:35]=[C:34]([Cl:37])[C:20]=1[CH2:21][O:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:32]=1[N:31]=[C:30]([CH3:33])[CH:29]=[CH:28]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(C(=O)O)cc4)c3Cl)c2n1
Reactant: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4ccc(C)nc34)c2Cl)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.9 %

Procedure:
To a mixture of 8-[3-[N-(4-carboxycinnamoylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (100 mg), ethylamine hydrochloride (16.9 mg) and N,N-dimethylformamide (2 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (32.2 mg) and 1-hydroxybenzotriazole (30.4 mg), and the mixture was stirred for 6 hours at ambient temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (methylene chloride--methanol) to give 8-[2,6-dichloro-3-[N-[4-(ethylcarbamoyl)cinnamoylglycyl]-N-methylamino]benzyloxy]-2-methylquinoline (91 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:14][C:15](=[O:24])OCC2C=CC=CC=2)[C@H:11]2[CH2:13][O:12]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[C@@H:25]1([NH2:35])[C:34]2[C:29](=CC=CC=2)[CH2:28][CH2:27][CH2:26]1.[CH2:36]([N:39]([CH2:53][CH2:54][CH3:55])[C:40]([C:42]1[CH:43]=[C:44]([CH:48]=[C:49]([CH2:51]C)[CH:50]=1)C(O)=O)=[O:41])[CH2:37][CH3:38]>>[NH:35]([CH2:13][C@@H:11]([OH:12])[C@@H:10]([NH:14][C:15](=[O:24])[C:44]1[CH:48]=[C:49]([CH3:51])[CH:50]=[C:42]([C:40]([N:39]([CH2:36][CH2:37][CH3:38])[CH2:53][CH2:54][CH3:55])=[O:41])[CH:43]=1)[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)[C:25]1[CH:34]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCCN(CCC)C(=O)c1cc(CC)cc(C(=O)O)c1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=C(N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1)OCc1ccccc1
Product: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNc2ccccc2)c1

Procedure:
Following the general procedure of EXAMPLEs 4, 5 and 6 and making non-critical variations but using tert-butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V), aniline (VI) and and “5-Me-PHTH” (IX), the title compound is obtained, MH+=538.