Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Br:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][CH2:8][N:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[C:35]([N:37]=[C:38]([N:40]1CCNCC1)[S-])#[N:36].O.[NH2:47]N>>[NH2:47][C:38]1[N:37]=[C:35]([N:13]2[CH2:14][CH2:15][CH:10]([N:9]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:19][CH:18]=3)[CH2:8][CH2:7][C:6]3[CH:27]=[CH:28][C:3]([Br:2])=[CH:4][CH:5]=3)[CH2:11][CH2:12]2)[NH:36][N:40]=1
Reactant: N#CN=C([S-])N1CCNCC1
Reactant: NN
Reactant: NS(=O)(=O)c1ccc(CN(CCc2ccc(Br)cc2)C2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Nc1n[nH]c(N2CCC(N(CCc3ccc(Br)cc3)Cc3ccc(S(N)(=O)=O)cc3)CC2)n1

Procedure:
4-(((4-Bromophenethyl)(piperidin-4-yl)amino)methyl)benzenesulfonamide hydrochloride obtained in Step 2 was reacted with K2CO3 and S,S′-dimethyl-N-cyano-dithioiminocarbonate, followed by the cyclization of the intermediate (N-cyanopiperazine-1-carbimidothioate) with hydrazine monohydrate in a manner described in Procedure 3.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])/[CH:10]=[N:11]/[S@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:27]([Li])([CH3:30])([CH3:29])[CH3:28].C1C[O:35][CH2:34]C1>>[Si:1]([O:8][C@H:9]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:22])[C@@H:10]([NH:11][S@:12]([C:14]([CH3:15])([CH3:16])[CH3:17])=[O:13])[CH2:28][CH:27]1[CH2:30][CH2:34][O:35][CH2:29]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(C)(C)[S@](=O)/N=C/[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: [Li]C(C)(C)C
Product: CC(C)(C)[S@](=O)N[C@@H](CC1CCOC1)[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
A solution of azeotropically dried (S,E)-N-((S)-2,3-bis(tert-butyldimethylsilyloxy)propylidene)-2-methylpropane-2-sulfinamide (2.3 g, 5 mmol) and 3-(iodomethyl)-THF (1 g, 7 mmol) in dry THF (10 mL) was brought to −78° C. followed by the dropwise addition of tert-butyllithium (6 mL, 11 mmol). A white precipitate was formed. The resulting solution was stirred at −78° C. for 40 min, quenched with sat NH4Cl and extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, concentrated, and chromatographed on silica gel using 0-5% EtOAc/hexanes to afford a colorless oil as (S)-N-((2S,3S)-3,4-bis(tert-butyldimethylsilyloxy)-1-(tetrahydrofuran-3-yl)butan-2-yl)-2-methylpropane-2-sulfinamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](Cl)=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[C:14]([NH2:16])=[O:15].CS(C)=O.[Cl:21][C:22]1[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:23]=1[NH:29][C:30]([NH:32][CH:33]1[CH2:35][CH2:34]1)=[O:31].CC(C)([O-])C.[K+]>O.O.CC(C)=O>[Cl:21][C:22]1[CH:27]=[C:26]([CH:25]=[CH:24][C:23]=1[NH:29][C:30]([NH:32][CH:33]1[CH2:34][CH2:35]1)=[O:31])[O:28][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([C:14]([NH2:16])=[O:15])[CH:5]=2)[N:10]=[CH:9][CH:8]=1
Reactant: O=C(Nc1ccc(O)cc1Cl)NC1CC1
Reactant: COc1cc2nccc(Cl)c2cc1C(N)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)c2cc1C(N)=O
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
In a reaction vessel were placed 7-methoxy-4-chloro-quinoline-6-carboxamide (5.00 kg, 21.13 mol), dimethylsulfoxide (55.05 kg), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (5.75 kg, 25.35 mol) and potassium t-butoxide (2.85 kg, 25.35 mol) in that order, under a nitrogen atmosphere. After stirring at 20° C. for 30 minutes, the temperature was raised to 65° C. over a period of 2.5 hours. After stirring at the same temperature for 19 hours, 33% (v/v) acetone water (5.0 L) and water (10.0 L) were added dropwise over a period of 3.5 hours. Upon completion of the dropwise addition, the mixture was stirred at 60° C. for 2 hours, and 33% (v/v) acetone water (20.0 L) and water (40.0 L) were added dropwise at 55° C. or higher over a period of 1 hour. After then stirring at 40° C. for 16 hours, the precipitated crystals were collected by filtration using a nitrogen pressure filter, and the crystals were washed with 33% (v/v) acetone water (33.3 L), water (66.7 L) and acetone (50.0 L) in that order. The obtained crystals were dried at 60° C. for 22 hours using a conical vacuum drier to give 7.78 kg of the title compound (96.3% yield).
Reaction SMILES: [C:1]([C:3]1([N:9]([CH3:11])[CH3:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].S(=O)(=O)(O)[OH:13]>O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>[CH3:10][N:9]([CH3:11])[C:3]1([C:1]([NH2:2])=[O:13])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=S(=O)(O)O
Reactant: CN(C)C1(C#N)CCCCC1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Product: CN(C)C1(C(N)=O)CCCCC1
Reaction time: 0.25 h

Procedure:
1-Cyano-N,N-dimethyl cyclohexylamine (10 g.) was added portionwise to conc. sulphuric acid (20 ml.) and the solution left for 15 minutes. The cooled solution was diluted with ice-cold water and neutralised with barium hydroxide octahydrate. The mixture was filtered on hyflo and the filtrate evaporated to dryness when the residual oil (9.1 g., 81%) crystallised on standing. Recrystallisation from petrol (80/100) afforded 1-dimethylamino cyclohexane carboxamide m.p. 65°-69°.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14](Br)[C:15]([O:17][CH3:18])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-:20].[K+].C(N)(=O)C>>[C:1]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([F:20])[C:15]([O:17][CH3:18])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:1]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [F-]
Reactant: COC(=O)C(Br)CCCCOC(=O)c1ccccc1
Agent: CC(N)=O
Agent: [K+]
Product: COC(=O)C(F)CCCCOC(=O)c1ccccc1
Product: COC(=O)CCCCCOC(=O)c1ccccc1
Temperature: 105 °C
Reaction time: 6 h
Yield: 58.3 %

Procedure:
A mixture of methyl 6-benzoyloxy-2(RS)-bromohexanoate (e) (14.02 g), potassium fluoride (12.59 g) and acetamide (12.3 g) was stirred at 105° C. for 6 hours. The crude product obtained by treating in the conventional manner was subjected to silica gel chromatography to give the title compound (f) and methyl 6-benzoyloxyhexanoate (g) (3.11 g, yield: 29%).
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:15]([OH:17])=O.[NH2:18][C@H:19]([C:24]([NH:26][C@H:27]([C:32]([NH:34][C@H:35]([C:40]([NH:42][C@H:43]1[CH2:47][CH2:46][O:45][CH:44]1[O:48][CH3:49])=[O:41])[CH2:36][CH:37]([CH3:39])[CH3:38])=[O:33])[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22]>>[CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:15]([NH:18][C@H:19]([C:24]([NH:26][C@H:27]([C:32]([NH:34][C@H:35]([C:40]([NH:42][C@H:43]1[CH2:47][CH2:46][O:45][CH:44]1[O:48][CH3:49])=[O:41])[CH2:36][CH:37]([CH3:38])[CH3:39])=[O:33])[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17]
Reactant: O=C(O)c1ccc2c(c1)Nc1ccccc1S2
Reactant: COC1OCC[C@@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(C)C
Product: COC1OCC[C@@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)c1ccc2c(c1)Nc1ccccc1S2
Yield: 21 %

Procedure:
The experimental protocol of this peptide condensation is the same as that described for the synthesis of intermediate 1.1, this time using 10H-phenothiazine-2-carboxylic acid (intermediate 1.10) and L-leucyl-L-leucyl-N1-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide (intermediate 1.8). The reaction product is purified by chromatography on silica (eluent: ethyl acetate/heptane in proportions of 7/3 to 1/1). 228 mg of a yellow solid is obtained with a yield of 21%. Melting point: 164-165° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:12]([CH3:14])[N:13]=2)[CH:5]=[C:6]([C:8]([NH2:10])=[O:9])[CH:7]=1.[CH2:20]([C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:23]=1[CH2:24]Cl)[CH3:21].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(Cl)Cl.CC(C)=O>[NH2:10][C:8]([C:6]1[CH:7]=[C:2]([NH:1][CH2:24][C:23]2[C:26]([CH3:30])=[CH:27][CH:28]=[CH:29][C:22]=2[CH2:20][CH3:21])[C:3]2[N:4]([C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:12]([CH3:14])[N:13]=2)[CH:5]=1)=[O:9]
Reactant: CCOC(=O)c1c(C)nc2c(N)cc(C(N)=O)cn12
Reactant: CCc1cccc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCOC(=O)c1c(C)nc2c(NCc3c(C)cccc3CC)cc(C(N)=O)cn12
Yield: 56 %

Procedure:
Ethyl 8-amino-6-(aminocarbonyl)-2-methylimidazo[1,2-a]pyridine-3-carboxylate (0.41 g, 1.6 mmol), 2-ethyl-6-methylbenzylchloride, sodium carbonate (0.7 g, 6.6 mmol), sodium iodide (0.15 g, 1.0 mmol) and acetone (20 ml) were refluxed for 44 h. Methylene chloride was added and the solids were removed by filtration. The filtrate was evaporated under reduced pressure and purification of the residue by column chromatography on silica gel eluting with methylene chloride:methanol (100:4) gave 0.35 g (56%) of the title compound. 1H-NMR (300 MHz, CDCl3): δ1.25 (t, 3H), 1.45 (t, 3H), 2.35 (s, 3H), 3.65 (s, 3H), 2.7 (q, 2H), 4.4-4.45 (m, 4H), 5.0 (t, 1H), 6.95 (s, 1H), 7.0-7.2 (m, 3H), 9.2 (s, 1H)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][O:6][NH2:7])[CH3:2].[C:9](O)(=[O:14])[CH2:10][CH2:11][C:12]#[CH:13].C1(N=C=NC2CCCCC2)CCCCC1>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:8])[CH2:5][O:6][NH:7][C:9](=[O:14])[CH2:10][CH2:11][C:12]#[CH:13])[CH3:2]
Reactant: C#CCCC(=O)O
Reactant: CCOC(=O)CON
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: C#CCCC(=O)NOCC(=O)OCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-Aminoxy-acetic acid ethyl ester (573 mg, 4.8 mmol) and 4-Pentynoic acid (441 mg, 4.5 mmol) in 15 mL EtOAc were added dicyclohexylcarbodiimide (928 mg, 4.5 mmol) and the resulting mixture was stirred at room temperature for 16 h.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH:8]([CH2:9][CH2:10]1)CC(C(O)=O)C2)(O)=O.C([N:17]([CH2:20][CH3:21])CC)C.C1(P([N:36]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[ClH:39]>C1(C)C=CC=CC=1>[ClH:39].[ClH:39].[NH2:36][C:4]12[CH2:11][CH:8]([CH2:9][CH2:10]1)[CH2:21][CH:20]([NH2:17])[CH2:1]2
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)C1CC2CCC(C(=O)O)(C2)C1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: Cc1ccccc1
Product: NC1CC2CCC(N)(C1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.5 %

Procedure:
A suspension of 1,3-dicarboxybicyclo[3.2.1]octane (6.15 g, 31 mmol) in toluene (150 mL) was azeotroped under a Dean-Stark trap to dryness, then cooled to room temperature under nitrogen and treated with triethylamine (12.2 mL, 87.5 mmol) and diphenylphosphoryl azide (20.4 g, 74 mmol). The solution was slowly and cautiously warmed to 80° C. (some exotherm and much evolution of gas observed) and stirred at 80°-90° C. for 3 h, then concentrated in vacuo to remove toluene and the residue cooled on an ice bath and treated with 6N hydrochloric acid (60 mL, 360 mmol). The bath was removed and the mixture stirred at room temperature for 3 h, then partially concentrated to remove most water. Acetonitrile (150 mL) was added, and the suspension was cooled for an hour in a refrigerator, filtered, and the solid rinsed with acetonitrile and dried in vacuo to afford 5.25 g (79%) of subject material as a white solid. [M+H]+=141.3. 1H NMR (d6-DMSO) δ 8.55 (br s, 6H), 2.23 (m, 1H), 1.91 (m, 2H), 1.55-1.75 (m, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([OH:29])=[O:28].COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)N(CC3C=CC(C(O)=O)=CC=3)N=2)C=CC=1OC>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:23][C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=3)[C:27]([OH:29])=[O:28])[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: O=C(O)c1cccc(CBr)c1
Agent: COc1ccc(C2=NN(Cc3ccc(C(=O)O)cc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(Cc3cccc(C(=O)O)c3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound 1 and 3-bromomethylbenzoic acid as described for compound 83. Purified by chromatography (ethyl acetate). Crystallized from diethyl ether. M.p. 133°-136° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=1.IN1C(=O)CCC1=O.[C:25]1([SH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[CH3:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:6]=1[S:31][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Sc1ccccc1
Reactant: COC(=O)c1cn(-c2ccccc2)cc1C
Agent: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cn(-c2ccccc2)c(Sc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
To a solution of methyl 4-methyl-1-phenyl-1H-pyrrole-3-carboxylate (540 mg) in tetrahydrofuran (10 mL) were added N-iodosuccinimide (677 mg) and thiophenol (0.257 mL), and the mixture was stirred at room temperature for 2 days. Saturated aqueous sodium thiosulfate solution (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a pale-yellow oil (yield 812 mg, about 100%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.C(N(C(C)C)C(C)C)C.Cl.[F:20][C:21]1[CH:31]=[CH:30][C:24]([O:25][CH:26]2[CH2:29][NH:28][CH2:27]2)=[CH:23][CH:22]=1>CC(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:28]2[CH2:29][CH:26]([O:25][C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:31][CH:30]=3)[CH2:27]2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1ccc(OC2CNC2)cc1
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(OC2CN(c3nc(Cl)ncc3F)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution 2,4-dichloro-5-fluoropyrimidine (150.0 mg, 0.898 mmol) in 2-propanol (4.00 mL) at RT was added N-ethyl-N-isopropylpropan-2-amine (0.469 mL, 2.70 mmol) followed by 3-(4-fluorophenoxy)azetidine hydrochloride (183 mg, 0.898 mmol). The resulting reaction mixture was stirred at RT for 1 h and concentrated. Purification of the crude using MPLC (25 g cartridge, 40 g column, 0 to 60% EtOAc-hexanes) gave 2-chloro-5-fluoro-4-(3-(4-fluorophenoxy)azetidin-1-yl)pyrimidine (240.6 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:28][CH3:29])=[CH:11][C:12]([N+:25]([O-:27])=[O:26])=[C:13]([CH:24]=1)[C:14]([O:16]CC1C=CC=CC=1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CCO.O>[CH2:1]([O:8][C:9]1[C:10]([O:28][CH3:29])=[CH:11][C:12]([N+:25]([O-:27])=[O:26])=[C:13]([CH:24]=1)[C:14]([OH:16])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc([N+](=O)[O-])c(C(=O)OCc2ccccc2)cc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc([N+](=O)[O-])c(C(=O)O)cc1OCc1ccccc1
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a solution of benzyl 5-(benzyloxy)-4-methoxy-2-nitrobenzoate (1.4 g, 3.56 mmol) in EtOH (10 mL) was added 1N NaOH (4.27 mL, 4.27 mmol). The mixture was stirred at RT for 1 h, upon which an additional aliquot of NaOH (4.27 mL, 4.27 mmol) was added. Stirring was continued at RT overnight. The mixture was diluted with water (20 mL) and washed with CH2Cl2 (2×25 mL). The aqueous layer was acidified to pH=2 with 0.5 N HCl and extracted with EtOAc (3×50 mL). The combined organics were dried (Na2SO4), filtered and concentrated in vacuo to give 5-(benzyloxy)-4-methoxy-2-nitrobenzoic acid (1.02 g, 3.37 mmol, 94%).
Reaction SMILES: O.C([O:9][C:10](=[O:23])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])C1C=CC=CC=1>[Pd].CO>[C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:10]([OH:23])=[O:9])(=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CCCCCC(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.8 %

Procedure:
10% Pd-C (3.00 g) was added to a 1% water-containing methanol solution (200 ml) of N-hexanoyl-L-proline benzyl ester (25.61 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 1.5 hours. After the catalyst was filtered off, the filtrate was concentrated to obtain 17.61 g of N-hexanoyl-L-proline.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].Cl.Cl.[CH2:7]([N:9]([CH2:31][CH3:32])[CH2:10][CH:11]([N:13]1[C:26]2[CH:25]=[C:24]([C:27](=[NH:30])OC)[CH:23]=[CH:22][C:21]=2[S:20][C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:12])[CH3:8].O>CO>[CH2:7]([N:9]([CH2:31][CH3:32])[CH2:10][CH:11]([N:13]1[C:26]2[CH:25]=[C:24]([C:27]([NH:4][CH2:1][CH2:2][CH3:3])=[NH:30])[CH:23]=[CH:22][C:21]=2[S:20][C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:12])[CH3:8]
Reactant: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C(=N)OC)cc21
Reactant: CCCN
Agent: Cl
Solvent: CO
Solvent: O
Product: CCCNC(=N)c1ccc2c(c1)N(C(C)CN(CC)CC)c1ccccc1S2
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A solution of propylamine (1.95 cc) in methanol (5 cc) is added dropwise in the course of 5 minutes to a solution, cooled to 0°-5° C., of methyl 10-[(2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarboximidate dihydrochloride (3.49 g) in methanol (21 cc). The mixture is stirred for 2 hours at 5° C. and then concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. to give a residue which is taken up with distilled water (50 cc). The solution is washed with distilled water (50 cc) alkalinized to pH 9 with N sodium hydroxide. The two phases are allowed to settle and the organic phase is separated and washed with half-saturated (sodium chloride) solution (50 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. The residue is purified by chromatography on neutral alumina (height: 20 cm; diameter: 2.1 cm), eluting with pure ethyl acetate (375 cc) and finally with mixtures of ethyl acetate and methanol in proportions (by volume) of 99:1 (375 cc), 98:2 (500 cc), 95:5 (500 cc), 90:10 (500 cc) and 80:20 (500 cc) and collecting 25-cc fractions. Fractions 40 to 70 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. to give 10-[(2RS)-1-diethylamino-2-propyl]-N-propyl-2-phenothiazinecarboxamidine (1.49 g) in the form of a yellow product of meringue-like consistency.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1.O.O.Cl[Sn]Cl.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3](=[O:15])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1
Reactant: COC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC(=O)C=Cc1ccc(N)cc1
Temperature: 75 °C

Procedure:
A mixture of 3-(4-nitro-phenyl)-acrylic acid methyl ester (72) (39.54 g, 0.191 mol) and SnCl2.2H2O (220 g, 0.98 mol) in anhydrous ethanol (300 ml) was heated at 50° C. for 1 hour and at 75° C. for 1 hour. The reaction mixture was allowed to cool to 10° C., treated with 20% NaOH solution to pH 8-9, and extracted with ethyl acetate (3×200 ml). The organic extract was washed with saturated NaCl (3×150 ml), dried (MgSO4), and evaporated under reduced pressure. Recrystallization from isopropanol (180 ml) afforded pure title compound in a form of yellowish crystals (17.938 g, 53%). 1H NMR (DMSO-d6, HMDSO), δ: 3.64 (3H, s); 5.73 (2H, s); 6.22 (1H, d, J=16.0 Hz); 6.57 (2H, d, J=8.0 Hz); 7.38 (2H, d, J=8.0 Hz); 7.50 (1H, d, J=16.0 Hz).
Reaction SMILES: [Br:1][CH:2]([CH3:9])[C:3](=[O:8])[C:4]([O:6][CH3:7])=[O:5].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=1>COCCOC>[BrH:1].[Cl:17][C:14]1[CH:15]=[CH:16][C:11](=[NH:10])[N:12]([CH:2]([CH3:9])[C:3](=[O:8])[C:4]([O:6][CH3:7])=[O:5])[CH:13]=1
Reactant: COC(=O)C(=O)C(C)Br
Reactant: Nc1ccc(Cl)cn1
Solvent: COCCOC
Product: Br
Product: COC(=O)C(=O)C(C)n1cc(Cl)ccc1=N
Temperature: 25 °C
Reaction time: 20 h
Yield: 62 %

Procedure:
To a solution of methyl 3-bromo-2-oxobutanoate (8.26 g, 42.4 mmol) in DME (33 mL) at room temperature was added 2-amino-5-chloropyridine (5.45 g, 42.4 mmol). The reaction mixture was stirred at room temperature for 20 h. The solid was collected by filtration, washed with EtOAc (2×), and dried under high vacuum to give methyl 3-(5-chloro-2-iminopyridin-1(2H)-yl)-2-oxobutanoate hydrobromide (8.51 g, 26.3 mmol, 62% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:12].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].CCCCCC.C(OCC)(=O)C>CC(C)=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: Oc1ccc2ccccc2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NCCOc1ccc2ccccc2c1Cl
Yield: 77 %

Procedure:
To a solution of 1-chloronaphthalen-2-ol (1.68 mmol) and K2CO3 (3.36 mmol) in acetone was added tert-butyl (2-bromoethyl)carbamate (1.85 mmol). The resulting mixture was heated at reflux overnight. After TLC control (n-hexane/ethyl acetate 7:3) showed the disappearance of 1-chloronaphthalen-2-ol, solvent was evaporated in vacuo and the residue was dissolved in 15 mL of ethyl acetate and washed with water (3×5 mL), brine (10 mL) and dried over Na2SO4. The evaporation of solvent afforded tert-butyl {2-[(1-chloronaphthalen-2-yl)oxy]ethyl}carbamate as a grey solid (77% yield) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([NH2:14])=O)[CH:6]=[CH:5]2.N1C=CC=CC=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]#[N:14])[CH:6]=[CH:5]2
Reactant: NC(=O)c1ccc2cc(Br)ccc2c1
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.3 %

Procedure:
To 6-bromo-2-naphthamide (1 g, 4.00 mmol) in dioxane (8.00 ml) at 0° C. was added pyridine (0.647 ml, 8.00 mmol) and then TFAA (0.621 ml, 4.40 mmol) dropwise. The reaction was stirred at room temperature for 3 h. The mixture was quenched with H2O and extracted with EtOAc two times, dried over magnesium sulfate, filtered, concentrated. The title compound (653 mg, 70%) was isolated as a beige solid, and used as is for the next step.