Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.C1C(=O)N([Br:18])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CCOCC.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:18][CH2:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2sccc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: BrCc1ccc2sccc2c1
Yield: 99.8 %

Procedure:
A mixture of 5-methylbenzo[b]thiophene (3.8 g, 25.6 mmol), NBS (4.7 g, 27 mmol), and benzoyl peroxide (310 mg, 1.3 mmol) were refluxed one hour in CCl4 (100 mL) while being irradiated with a sunlamp. Upon completion, the reaction was cooled, diluted with Et2O, filtered and concentrated to yield 5.8 g of 5-bromomethylbenzo[b]thiophene. The crude 5-bromomethylbenzo[b]thiophene was refluxed for 36 hours in 1:1 dioxane/2N aq. NaOH (128 mL). After cooling, extraction with EtOAc and concentration of the extracts, the residue was chromatographed on silica gel eluting 2.6 g of 5-hydroxymethylbenzo[b]thiophene with 35% EtOAc/hexane. The title compound (1.96 g) was obtained after filtration and concentration of the reaction product produced by refluxing 5-hydroxymethylbenzo[b]thiophene (2.08 g, 12.7 mmol) and 50% MnO2 /C (17.6 g, 101 mmol) for five hours in toluene while H2O was continually removed using a Dean-Stark trap.
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1.O.[C:20]([O:24][C:25](=[O:34])[N:26]([CH3:33])[CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:20]([O:24][C:25](=[O:34])[N:26]([CH:27]1[CH2:28][CH2:29][N:30]([CH2:2][C:3]2[S:11][C:10]3[C:9]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)=[N:8][C:7]([Cl:18])=[N:6][C:5]=3[CH:4]=2)[CH2:31][CH2:32]1)[CH3:33])([CH3:23])([CH3:21])[CH3:22]
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.1 %

Procedure:
To a solution of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (85 mg, 0.244 mmol) in DMF (2 mL) were added water (13 μL), methyl-piperidin-4-yl-carbamic acid tert-butyl ester (105 mg, 0.489 mmol) and cesium carbonate (159 mg, 0.489 mmol). The resulting mixture was stirred at RT for 18 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH. The resultant residue was purified by column chromatography to give the title compound as a pale brown solid (73 mg, 62%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.ClC(Cl)(O[C:17](=[O:23])[O:18][C:19](Cl)(Cl)Cl)Cl.[N-:25]=[C:26]=[O:27]>CCOC(C)=O.CN(C=O)C>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:26]([NH:25][C:3]2[C:19]3[O:18][C:17](=[O:23])[NH:8][C:7]=3[CH:6]=[CH:5][CH:4]=2)=[O:27])=[CH:5][CH:4]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: [N-]=C=O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cccc2[nH]c(=O)oc12
Temperature: 80 °C
Yield: 19.5 %

Procedure:
Commercially available 4-trifluoromethylbenzylamine (1 ml, 7 mmol) was dissolved in 20 ml of AcOEt and at 0° C. triphosgene (2 g, 7 mmol) was added to the solution. The mixture was warmed at 80° C. for 4 hours then evaporated and the residue was dissolved in 5 ml of DMF. The solution of the isocyanate was added dropwise to a solution in DMF (10 ml) of compound 1c (700 mg, 4.66 mmol) and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt 4/petroleum ether 6). The solvent was evaporated and the crude was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by chromatographic column gave 320 mg of a white solid. Yield=19.5% 1HNMR (DMSO, 400 MHz) δ 4.41 (2H, d, J=6 Hz), 6.67 (1H, dd, J=7.6 Hz, J′=1.2 Hz), 7.00 (1H, t, J=8 Hz), 7.09 (1H, t), 7.51 (2H, d, J=8 Hz), 7.70 (3H, m), 8.73 (1H, s), 10.60 (1H, bs); [M+1] 352.1 (C16H12F3N3O3 requires 351.3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[CH2:20]([O:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([O:35][CH2:36][CH3:37])[C:31]=1[O:32][CH2:33][CH3:34])[C:26](Cl)=[O:27])[CH3:21].[Al+3].[Cl-].[Cl-].[Cl-].O>C(Cl)Cl.CCOC(C)=O>[CH2:36]([O:35][C:30]1[CH:29]=[C:25]([CH:24]=[C:23]([O:22][CH2:20][CH3:21])[C:31]=1[O:32][CH2:33][CH3:34])[C:26]([C:10]1[C:11]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:12]=2[S:13][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:27])[CH3:37]
Reactant: CCOc1cc(C(=O)Cl)cc(OCC)c1OCC
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOc1cc(C(=O)c2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc(OCC)c1OCC
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
To a well stirred solution of 2-(4'-methoxyphenyl)-6-methoxybenzo[b]thiophene (0.501g, 1.85 mmol) and 3,4,5-triethoxybenzoyl chloride (1.00 g, 3.66 mmol) in CH2Cl2 (45 ml) was added AlCl3 (0.870 g, 6.52 mmol) portion-wise over a 15 minute period. After 30 minutes, water was added, and the product was isolated initially by extraction with CH2Cl2 and subsequently by extraction with EtOAc. The organic layers were separately washed with brine and then combined and dried over MgSO4. Purification by flash chromatography (silica gel, 70:30 EtOAc/hexanes) afforded the title compound (0.827 g, 1.63 mmol, 88%) as a pale yellow solid. Recrystallization (EtOAc/hexanes) afforded a highly pure, crystalline sample with mp 108°-110° C. 1H-NMR (CDCl3, 360 Mhz): δ=7.64 (d,J=8.9 Hz, 1H, ArH), 7.32 (d,J=2.3 Hz, 1H, ArH), 7.29 (d,J=8.7 Hz, 2H, ArH), 7.02(s,2H, ArH), 6.99 (dd,J=9.0,2.4 Hz, 1H, ArH), 6.73 (d,J=8.7 Hz, 1H, ArH), 4.06 (q,J=7.1 Hz, 2H, CH2), 3.91 (q,J=7.0, 4H, CH2), 3.89 (s,3H, --OCH3), 3.74 (s,3H, --OCH3), 1.34 (t,J=7.0 Hz, 6H, CH3), 1.28 (t,J=7.1 Hz, 3H, CH3 ; 13C-NMR (CDCl3, 90 MHz): δ=193.2 , 159.8, 157.7, 152.5, 143.6, 142.6, 140.0, 133.9, 132.3, 130.3, 130.1, 126.0, 124.2, 114.8, 114.0, 108.9, 104.4, 68.8, 64.6, 55.6, 55.2, 15.4, 14.7. HRMS (EI) M+ calcd for C29H30O6S 506.1763, found 506.1777. Anal. Calcd for C29H30O6S: C, 68.75; H, 5.97; S, 6.33. Found: C, 68.67; H, 5.97; S, 6.27.
Reaction SMILES: [C:1]1([CH3:33])[CH:6]=[CH:5][C:4]([N:7]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]3([CH2:29][C:30](O)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:17][CH2:16]2)[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[NH2:47][C:48]1[CH:53]=[N:52][CH:51]=[CH:50][N:49]=1>ClCCl.CN(C)C=O>[N:49]1[CH:50]=[CH:51][N:52]=[CH:53][C:48]=1[NH:47][C:30]([CH2:29][C:23]1([CH2:22][CH2:21][N:18]2[CH2:19][CH2:20][CH:15]([N:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:33])=[CH:2][CH:3]=3)[C:8]([C:10]3[O:11][CH:12]=[CH:13][CH:14]=3)=[O:9])[CH2:16][CH2:17]2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1)=[O:31]
Reactant: Nc1cnccn1
Reactant: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CC(=O)O)CCCCC3)CC2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CC(=O)Nc4cnccn4)CCCCC3)CC2)cc1
Reaction time: 1.5 h
Yield: 49.3 %

Procedure:
To a solution of [1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]acetic acid (synthesized in Example 3B-1) (201 mg) dissolved in dichloromethane (6 mL) was added N,N-dimethylformamide (2 drops). Oxalyl chloride (0.060 mL) was then added to the solution dropwise under ice cooling. The solution was stirred for 1.5 hours. After addition of triethylamine (0.12 mL) at that temperature, the solution was stirred for 20 minutes. 2-Aminopyrazine (128 mg) was then added to the solution and it was stirred at that temperature. The temperature was allowed to rise to room temperature and the solution was stirred for 16 hours. NH Silica gel was added to the reaction solution, and it was concentrated under reduced pressure. The resulting residue was purified by chromatography [at the first stage; NH silica gel, hexane-ethyl acetate (2:1) and at the second stage; silica gel, chloroform-methanol (10:1)] to give the title compound (116 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C@@H:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][CH2:8]Cl.[NH4+:19].[OH-].CCO.C(O)(=O)/C=C\C(O)=O>CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C@@H:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][CH2:8][NH2:19]
Reactant: Fc1cccc(O[C@H](CCCl)c2ccccc2)c1
Reactant: [NH4+]
Agent: O=C(O)/C=C\C(=O)O
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: NCC[C@@H](Oc1cccc(F)c1)c1ccccc1

Procedure:
A solution of (R)-3-(3-fluorophenoxy)-3-phenylpropyl chloride (0.971 g, 3.96 mmol), conc. NH4OH (30 mL) and EtOH (20 mL) were shaken at 90° C. on a Parr apparatus (50-90 psig) for 18 h. The mixture was then evaporated under vacuum and the residue was dissolved in Et2O (100 mL) and washed with H2O (2×25 mL). The organic layer was dried (anh. Na2SO4), filtered, and evaporated under vacuum to provide a yellow oil. This material was then dissolved in EtOAc (50 mL) and filtered. A solution of maleic acid (0.272 g, 2.6 mmol, 0.93 equiv) dissolved in hot EtOAc (5 mL) was added to precipitate the maleate salt (519 mg, 53.5%) as a white solid: TLC Rf 0.25 (1% MeOH—CHCl3); GC, tr 7.37 min; MS, m/z 245 (M+). The synthesis of Compound 187 was accomplished as follows.
Reaction SMILES: O.[Cl:2]C1C=C(O)C=CC=1C(O)=O.C(OC([N:20]1[CH2:35][CH2:34][N:23]2[C:24](=[O:33])[C:25]3[C:30]([CH:22]2[CH2:21]1)=[CH:29][CH:28]=[CH:27][C:26]=3[S:31][CH3:32])=O)(C)(C)C.C(OC(N1CCN2C(=O)C3C(C2C1)=CC(OC)=CC=3Cl)=O)(C)(C)C>>[ClH:2].[CH3:32][S:31][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:25]=1[C:24](=[O:33])[N:23]1[CH2:34][CH2:35][NH:20][CH2:21][C@H:22]12
Reactant: O=C(O)c1ccc(O)cc1Cl
Reactant: CSc1cccc2c1C(=O)N1CCN(C(=O)OC(C)(C)C)CC21
Agent: COc1cc(Cl)c2c(c1)C1CN(C(=O)OC(C)(C)C)CCN1C2=O
Solvent: O
Product: CSc1cccc2c1C(=O)N1CCNC[C@@H]21
Product: Cl

Procedure:
Prepared according to procedures described in Examples 59 and 60 with substitution of 2-(methylthio)benzoic acid for 2-chloro-4-hydroxybenzoic acid hydrate in Example 59, Step A, and (±)-N-(t-butoxycarbonyl)-1,3,4,10b-tetrahydro-7-methylthio-pyrazino[2,1-a]isoindol-6(2H)-one (Example 45) for (±)-N-(t-butoxycarbonyl)-1,3,4,10b-tetrahydro-7-chloro-9-methoxy-pyrazino[2,1-a]isoindol-6(2H)-one in Example 60, Step A. MS (ESI) 235.2 (M−Cl).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][OH:24])=[CH:17][CH:16]=1.C([N:27]([CH2:30][CH3:31])CC)C.[C:32]([O:35]CC)(=[O:34])C>CS(Cl)(=O)=O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][O:24]/[N:27]=[C:30](/[C:31]2[CH:11]=[CH:12][CH:7]=[CH:8][CH:9]=2)\[C:32]([OH:35])=[O:34])=[CH:19][CH:20]=1
Reactant: CCN(CC)CC
Reactant: CCOC(C)=O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCCO)cc1
Agent: CS(=O)(=O)Cl
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CCCO/N=C(\C(=O)O)c2ccccc2)cc1
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of 3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propanol (1.00 g) and triethylamine (0.866 ml) in ethyl acetate (30 ml), methanesulfonyl chloride (0.478 ml) was added dropwise at 0° C., and the mixture was stirred for 1 hour. The reaction mixture was washed with saturated aqueous sodium chloride, dried (MgSO4), and then concentrated. The residue was dissolved in N,N-dimethylformamide (10 ml), and methyl Z-2-hydroxyimino-2-phenylacetate (830 mg) and sodium hydride (60%, in oil, 185 mg) were added, and the mixture was stirred for 2 hours at room temperature. After adding 1N HCl (7 ml) and then aqueous sodium bicarbonate, the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain a colorless oil from a fraction eluted with ethyl acetate-hexane-toluene (1:5:5, v/v). This oil was dissolved in tetrahydrofuran (10 ml)-methanol (5 ml), and 1N aqueous solution of sodium hydroxide (5 ml) was added, and then the mixture was stirred for 2 hour at 40° C. After adding 1N HCl (5.5 ml) to the reaction mixture, the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residual crystal was recrystallized from ethyl acetate-hexane to obtain Z-2-[3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propoxyimino]-2-phenylacetic acid (1.13 g, yield 78%) as colorless crystals. m.p. 165-166° C. (decomposition)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C@@H:17]([NH:20]C(OC(C)(C)C)=O)[CH2:18][CH3:19])[CH2:13][CH:12]1[C:28](=[O:30])[NH2:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C@@H:17]([NH2:20])[CH2:18][CH3:19])[CH2:13][CH:12]1[C:28](=[O:30])[NH2:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C1CCN(C(=O)OCc2ccccc2)C(C(N)=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](N)C1CCN(C(=O)OCc2ccccc2)C(C(N)=O)C1
Reaction time: 1 h

Procedure:
To a solution of 84% 4-((S)-1-tert-butoxycarbonylamino-propyl)-2-carbamoyl-piperidine-1-carboxylic acid benzyl ester (0.7 g, 1.4 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid (2 mL). After 1 hour, the reaction was monitored by HPLC-MS. Additional TFA (1 mL) was added. After 30 minutes, the reaction was concentrated to afford 4-((S)-1-amino-propyl)-2-carbamoyl-piperidine-1-carboxylic acid benzyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:13](OC(OCC)OCC)C.C(O)(=O)C.[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([NH2:37])[CH:31]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:12][O:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:13][N:37]([C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][C:33]=1[CH3:36])[C:29]([O:28][CH3:27])=[O:38])[C:4]2=[O:6]
Reactant: COC(=O)c1ccc(C)c(N)c1
Reactant: COc1ccc(N)c(C(=O)O)c1
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C)c(-n2cnc3ccc(OC)cc3c2=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 2-amino-5-methoxybenzoic acid (18.7 g) in toluene (250 ml) was added triethylorthoformate (19.6 ml) and acetic acid (0.64 ml) and heated at 110° C. for 3 hours when methyl-3-amino-4-methylbenzoate (16.7 g) was added and heating continued for a further 16 hours at 110° C. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed with 1N NaOH and 1N HCl. The organic phase was left to stand for 54 hours which resulted in crystallisation of a solid which was collected by filtration and air dried to give methyl 3-(6-methoxy-4-oxoquinazolin-3(4H)-yl)-4-methylbenzoate (9.3 g); NMR Spectrum: (DMSOd6) 2.18 (s, 3H), 3.84 (s, 3H), 3.92 (s, 3H), 7.28 (m, 1H), 7.59 (m, 2H), 7.73 (d, 1H), 7.93 (s, 1H), 7.98 (m, 1H), 8.19 (s, 1H); Mass Spectrum: M+H+ 325.
Reaction SMILES: CS[C:3]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[C:4]([C:7]#[N:8])[C:5]#[N:6].O.[NH2:17][NH2:18]>CCO>[NH2:6][C:5]1[NH:18][N:17]=[C:3]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4]=1[C:7]#[N:8]
Reactant: CSC(Nc1ccccc1)=C(C#N)C#N
Reactant: NN
Solvent: CCO
Solvent: O
Product: N#Cc1c(Nc2ccccc2)n[nH]c1N
Temperature: 0 °C

Procedure:
Dissolved 2-((methylthio)(phenylamino)methylene)malononitrile (3.2 g) in EtOH (100 mL) and added hydrazine hydrate (1 eq), then heated to reflux until complete by TLC (absence of starting material, 18 hrs). Poured into ice water and filtered to obtain 5-amino-3-(phenylamino)-1H-pyrazole-4-carbonitrile as a yellow powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@@H:4]([CH:5]=[C:6]([Br:8])[Br:7])[C@H:3]1[C:9]([OH:11])=[O:10].Cl[CH2:14][C:15]1[N:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCCOCCOCCOCCOCC1.C(C(C)=O)C>[CH3:1][C:2]1([CH3:12])[C@@H:4]([CH:5]=[C:6]([Br:8])[Br:7])[C@H:3]1[C:9]([O:11][CH2:14][C:15]1[N:19]=[C:18]([O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[S:17][N:16]=1)=[O:10]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C=C(Br)Br
Reactant: ClCc1nsc(Oc2ccccc2)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC1(C)[C@H](C(=O)OCc2nsc(Oc3ccccc3)n2)[C@@H]1C=C(Br)Br
Reaction time: 24 h
Yield: 59.9 %

Procedure:
A mixture of 3.3 g of (1R,3R) 2,2-dimethyl-3-(2,2-dibromoethenyl)-cyclopropane-1-carboxylic acid, 2.2 g of the product of Step A, 1.5 g of potassium carbonate, 100 mg of 1,4,7,10,13,16-hexaoxacyclooctadecane and 50 ml of methyl ethyl ketone wasrefluxed for 24 hours and was evaporated to dryness under reduced pressure.The residue was added to water and the aqueous mixture was extracted with ethyl acetate. The organic phase was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution withbenzene yielded 2.84 g of [5-phenoxy-(1,2,4)-thiadiazol-3-yl]-methyl (1R,3R) 2,2-dimethyl-3-(2,2-dibromoethenyl)-cyclopropane-1-carboxylate.
Reaction SMILES: OC(C(F)(F)F)=O.[CH:8]([N:11]1[C:15]([C:16]2[S:17][C:18]3[CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=4[C:24]=3[N:25]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].[CH3:36][O:37][CH2:38][CH2:39]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)Cl>[CH:8]([N:11]1[C:15]([C:16]2[S:17][C:18]3[CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][N:33]([CH2:39][CH2:38][O:37][CH3:36])[CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=4[C:24]=3[N:25]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9]
Reactant: COCCBr
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCNCC3)ccc1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCN1CCC(c2ccc3c(c2)OCCc2sc(-c4ncnn4C(C)C)nc2-3)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
To a solution of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 375 (300 mg, 0.59 mmol) in DMF (3.5 mL) was added 2-bromoethyl methyl ether (60 μL, 0.65 mmol) and potassium carbonate (285 mg, 2.07 mmol) and the reaction mixture stirred at 60° C. for 2 h. The reaction mixture was diluted with DCM and washed with saturated aqueous sodium bicarbonate, then water followed by brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-10% MeOH in DCM) followed by trituration in cyclohexane to give 511 (187 mg, 70%). LCMS: RT=3.42 min, [M+H]+=454. 1H NMR 400 MHz (DMSO-d6) δ: 8.23 (1 H, d, J=8.19 Hz), 8.05 (1 H, s), 7.04 (1 H, dd, J=8.22, 1.79 Hz), 6.88 (1 H, d, J=1.74 Hz), 5.77-5.76 (1 H, m), 4.31 (2 H, t, J=5.00 Hz), 3.44-3.34 (5 H, m), 3.20 (3 H, s), 2.93 (3 H, d, J=10.98 Hz), 2.02 (2H, t, J=11.43 Hz), 1.71 (3 H, m), 1.64-1.53 (2 H, m), 1.50 (6 H, d, J=6.58 Hz)
Reaction SMILES: [Br-:1].[C:2]([CH:5]([CH2:18][CH3:19])[CH2:6][CH2:7][N+:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][C:9]=1[CH3:17])([OH:4])=[O:3].C(O[C:24](=O)[CH3:25])(=O)C>C(O)(=O)C>[Br-:1].[NH:8]([CH:7]=[CH:24][CH:25]=[CH:17][C:9]1[S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:8]=1[CH2:7][CH2:6][CH:5]([C:2]([OH:4])=[O:3])[CH2:18][CH3:19])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCC(CC[n+]1c(C)sc2ccccc21)C(=O)O
Agent: [Br-]
Solvent: CC(=O)O
Product: CCC(CC[n+]1c(C=CC=CNc2ccccc2)sc2ccccc21)C(=O)O

Procedure:
The desired compound is prepared by heating 3.44 g of 3-carboxypentyl-2-methylbenzothiazolium bromide, 5.14 g of malonaldehyde dianil hydrochloride and 2 mL of acetic anhydride in 30 mL of acetic acid for 6 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C@H:7]1[CH2:12][CH2:11][CH2:10][NH:9][C@H:8]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+].O(OC(C(C)(C)C)=O)[O:26][C:27](C(C)(C)C)=O.[C:40]([OH:44])([CH3:43])([CH3:42])[CH3:41]>>[C:40]([O:44][C:27]([N:9]1[CH2:10][CH2:11][CH2:12][C@H:7]([NH:6][CH2:5][C:4]2[CH:19]=[CH:20][CH:21]=[CH:22][C:3]=2[O:2][CH3:1])[C@@H:8]1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:26])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)C(=O)OOOC(=O)C(C)(C)C
Reactant: CC(C)(C)O
Reactant: COc1ccccc1CN[C@H]1CCCN[C@H]1c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccccc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1

Procedure:
To a stirred and ice-cooled mixture of Compound 15 (10 g, 27 mmol), 3M NaOH aq. (36 ml, 110 mmol) and tert-BuOH (15 ml) was added (tert-BuOCO)2O (7.4 g, 34 mmol) in one portion. After stirring at room temperature overnight, the mixture was extracted with AcOEt. The combined AcOEt extracts were washed with H2O, and sat. NaCl aq, dried (Na2 SO4), and concentrated in vacuo to give Compound 16 (11 g, quant.) as a pale yellow oil.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:11]=[C:12]([C:17]([N+:20]([O-:22])=[O:21])=[CH:18][N:19]=1)[C:13]([O:15]C)=[O:14])[CH2:3][CH2:2]2.[OH-].[Li+].CO.O>O1CCCC1>[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:11]=[C:12]([C:17]([N+:20]([O-:22])=[O:21])=[CH:18][N:19]=1)[C:13]([OH:15])=[O:14])[CH2:3][CH2:2]2
Reactant: COC(=O)c1cc(N2CCN3CCC2CC3)ncc1[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(N2CCN3CCC2CC3)ncc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 55.6 %

Procedure:
To a solution of methyl 2-(1,4-diazabicyclo[3.2.2]nonan-4-yl)5-nitroisonicotinate (Intermediate 27A) (6.0 g, 19.6 mmol) in tetrahydrofuran (15 mL) under nitrogen was added lithium hydroxide (2.47 g, 58.8 mmol), methanol (10 mL) and water (15 mL), reaction then stirred overnight. The reaction mixture was concentrated and purified by a 50 g silica column eluting with 10-40% methanol in DCM to afford 2-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-5-nitroisonicotinic acid (3.2 g, 10.9 mmol).