Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:12]1[CH:21]=[C:20]2[C:15]([C:16](=[O:24])[CH2:17][C:18]([CH2:22][CH3:23])=[N:19]2)=[CH:14][CH:13]=1)(OCC)=[O:8].O.C(OCC)(=O)C>C1COCC1>[CH2:22]([C:18]1[CH2:17][C:16](=[O:24])[C:15]2[C:20](=[CH:21][C:12]([CH2:7][OH:8])=[CH:13][CH:14]=2)[N:19]=1)[CH3:23]
Reactant: CCOC(=O)c1ccc2c(c1)N=C(CC)CC2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCC1=Nc2cc(CO)ccc2C(=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Lithium aluminium hydride (0.6 g) was added to a solution of 7-carboethoxy-2-ethyl-4-quinolone (2.65 g) in THF (200 ml) and the resulting suspension stirred for 2 hours at ambient temperature. Water (100 ml) was slowly added, followed by ethyl acetate (100 ml). The suspension was filtered and washed with ethyl acetate (100 ml). The phases of the filtrate were separated and the aqueous layer re-extracted with ethyl acetate (100 ml). The combined organic phases were dried (MgSO4) and evaporated to give a solid which on recrystallisation from ethyl acetate gave 2-ethyl-7-hydroxymethyl-4-quinolone as a white powder, m.p. 254°-257° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:33])([CH3:32])[CH2:30][OH:31])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[CH3:37][O:38][N:39]([CH3:49])[C:40](=[O:48])[CH2:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:45]3[CH2:44][CH2:43][N:42]([CH2:41][C:40]([N:39]([O:38][CH3:37])[CH3:49])=[O:48])[CH2:47][CH2:46]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:33])([CH3:32])[CH2:30][OH:31])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(C)(C)CO)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CON(C)C(=O)CN1CCNCC1
Product: CCOc1cc(C(C)(C)CO)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)OC)CC1
Product: Cl

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-N-methoxy-N-methyl-acetamide hydrochloride was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12g) and N-methoxy-N-methyl-2-piperazin-1-yl-acetamide (example 16b) in an analogous manner as described in example 25. LR-MS: 696.5 [(M+H)+]
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].C([O-])([O-])=O.[Na+].[Na+].Cl[C:20]([O:22][CH3:23])=[O:21]>[OH-].[Na+]>[CH3:23][O:22][C:20]([NH:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])=[O:21]
Reactant: NC(Cc1ccccc1)C(=O)O
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)NC(Cc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
2-Amino-3-phenyl-propionic acid (1.65 g) was dissolved in 1 N NaOH (10 mL), and Na2CO3 (530 mg) was added. The mixture was cooled to 0° C. and methyl chloroformate was added slowly, and then stirred for overnight at room temperature. The mixture was washed with DCM and acidified with 3 mL of 2N HCl, and then was taken up in ether (200 mL). The organic phase was dried over sodium sulfate. Removing the solvent to give 2-Methoxycarbonylamino-3-phenyl-propionic acid (1.95 g, 87%) as an off-white solid.
Reaction SMILES: BrC1C=CC(Br)=CN=1.NN.[Br:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18]N)=[N:16][CH:17]=1.N(C1C=CC=CN=1)N.[CH3:28][CH:29]([CH3:33])[C:30](=O)[CH3:31]>COCCO.C1C=CC=CC=1>[Br:11][C:12]1[CH:13]=[C:14]2[C:29]([CH3:33])([CH3:28])[C:30]([CH3:31])=[N:18][C:15]2=[N:16][CH:17]=1
Reactant: NNc1ccc(Br)cn1
Reactant: CC(=O)C(C)C
Agent: Brc1ccc(Br)nc1
Agent: NN
Agent: NNc1ccccn1
Solvent: c1ccccc1
Solvent: COCCO
Product: CC1=Nc2ncc(Br)cc2C1(C)C
Temperature: 110 °C

Procedure:
To 40 g of 2,5-dibromopyridine in 200 mL of 2-methoxyethanol is added 53 mL of anhydrous hydrazine and the mixture is heated at 110° C. for 3 hours to generate the 5-bromo-2-hydrazinopyridine. A mixture of 10 g of this hydrazinopyridine is heated at reflux overnight with 11 mL of 3-methyl-2-butanone in 40 mL of benzene equipped, using a condenser equipped with a Dean-Stark trap. All of the volatile components are removed under reduced pressure and the resulting residue is heated in 62 g of polyphosphoric acid at 140° C. for 45 minutes. The reaction mixture is poured into water, neutralized with sodium hydroxide and extracted with ethyl acetate. The resulting crude residue is purified by chromatography on silica gel, eluting with 1:1 ethyl acetate/hexanes, to yield 1.44 g of the product.
Reaction SMILES: [CH:1](=[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[OH:14]O>O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+].C(O)C>[CH3:2][CH:1]1[O:14][C:3]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CC=C(C(=O)OCC)C(=O)OCC
Reactant: OO
Agent: O=[W](=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)OC1C
Temperature: 80 °C
Yield: 74.1 %

Procedure:
A mixture of 50 grams (0.27 mole) of diethyl ethylidenemalonate, 455 grams (4.02 moles) of 30% hydrogen peroxide, 17.6 gram (0.053 mole) of sodium tungstate dihydrate and 400 milliliters of ethanol was stirred and heated at 80° C. for one hour, cooled to room temperature and stirred for an additional hour. Ethanol was removed under reduced pressure and the produce extracted into dichloromethane (3×200 milliliters), the extract then water-washed, dried (MgSO4), filtered and solvent removed to give the crude product. Vacuum distillation gave 40.45 grams (0.20 mole) of diethyl 3-methyloxirane-2,2-dicarboxylate having a boiling point of 120° C. at 4millimeters of Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[S:10]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)(=[O:12])=[O:11])[C:8]#[N:9]
Reactant: C1CCNC1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)c(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Product: N#Cc1ccc(S(=O)(=O)N2CCCC2)c(Cl)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
900 mg (4 mmol) of 2-chloro-4-cyanobenzenesulfonic acid chloride is dissolved in 3 mL of pyridine and, after the addition of 0.5 mL (5.8 mmol) of pyrrolidine, stirred for one hour at 80° C. Then the mixture is cooled, mixed with ice, and adjusted to pH 5-6 with 1 molar hydrochloric acid. The precipitate formed is suction filtered, washed with water and dried. Yield: 1.1 g (100% of theory); Rf value: 0.20 (silica gel; petroleum ether/ethyl acetate=4:1).
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([CH2:12][CH3:13])[C:4]=1[CH:5]=[O:6])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].IC.[CH3:22][CH2:23]OCC>CN(C)C=O>[CH2:22]([O:11][C:9]1[CH:8]=[C:7]([CH2:12][CH3:13])[C:4]([CH:5]=[O:6])=[C:3]([CH2:1][CH3:2])[CH:10]=1)[CH3:23]
Reactant: CCc1cc(O)cc(CC)c1C=O
Reactant: CCOCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOc1cc(CC)c(C=O)c(CC)c1
Temperature: 60 °C
Yield: 82 %

Procedure:
To a solution of 1.10 g (5.92 mmol)) 2,6-diethyl-4-hydroxy-benzaldehyde in 15 ml N,N-dimethylformamide in a pressure tube were added 4.83 g (14.8 mmol) cesium carbonate and 1.05 ml (13.0 mmol) iodomethane. The tube was sealed and the reaction mixture was heated at 60° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with ether, and washed with saturated brine. The phases were separated and the organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, ethyl acetate/heptane gradient) to afford 1.00 g (82%) of the title compound as a yellow oil. 1H-NMR (CDCl3): 1.25 (6H, t, 2×CH3), 1.44 (3H, t, CH3), 2.98 (4H, q, 2×CH2), 4.10 (2H, q, OCH2), 6.62 (2H, s, 2×ArH), 10.45 (1H, s, CH═O).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10]C)=[O:9])[N:6]=1.[CH3:12][O-:13].[Na+:14]>CO>[CH3:12][O:13][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O-:10])=[O:9])[N:6]=1.[Na+:14]
Reactant: COC(=O)Cc1csc(Br)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(CC(=O)[O-])cs1

Procedure:
A solution of methyl 2-(2-bromothiazol-4-yl)acetate (80 mg, 0.34 mmol), and sodium methanolate (300 mg) in MeOH was stirred at 85° C. overnight. Then the reaction mixture was concentrated to give the desired product. 1H NMR (METHANOL-d4) δ: 4.04 (s, 3H), 3.47 (d, J=1.1 Hz, 2H), 3.37 (s, 1H). LC-MS: m/z (M+H)=174.2
Reaction SMILES: [H-].[Na+].[CH2:3]([CH2:5][NH2:6])[OH:4].Cl[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1>O1CCCC1>[NH3:6].[C:9]1([CH2:8][O:4][CH2:3][CH2:5][NH2:6])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: ClCc1cccc2ccccc12
Reactant: NCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N
Product: NCCOCc1cccc2ccccc12
Temperature: 25 °C
Yield: 71547.7 %

Procedure:
Sodium hydride (1.00 g, 0.025 mmol) was added portionwise to a cooled (0° C.) solution of ethanolamine (1.51 ml, 0.025 mmol) in tetrahydrofuran (25 ml). The reaction mixture was then heated to reflux for 30 minutes. Chloromethylnaphthalene (3.4 ml, 0.0225 mmol) was added and the reaction mixture heated at reflux for a further 3 hours. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. The residue was partitioned between dichloromethane (50 ml) and 1 N aqueous sodium hydroxide (50 ml). The organic phase was separated and the aqueous phase extracted with dichloromethane (2×50 ml). The combined organic extracts were reduced in vacuo and the residue purified by flash column chromatography eluting with dichloromethane:methanol: 880 ammonia (98:2:0.2 changing to 90:10:1 by volume) to give the title compound as a colourless oil (1.80 g, 40%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.N1C=CC=CC=1.[C:17](Cl)(=[O:19])[CH3:18]>C(Cl)Cl.CCOC(C)=O>[C:17]([O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[O:9][CH3:10])(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: COc1cc(F)ccc1O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(F)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
To a solution of 4-fluoro-2-methoxyphenol (569 mg, 4.0 mmol) and pyridine (0.56 mL, 7.0 mmol) in CH2Cl2 (8.0 mL) at 0° C. was added acetyl chloride (0.33 mL, 4.6 mmol). The mixture was stirred at rt for 2.0 h and then diluted with EtOAc and washed with 4.0 N HCl. The organic layer was washed with brine and dried over Na2SO4. After evaporation of the solvent, 64A (680 mg, 92% yield) was obtained as a solid used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 2.29 (s, 3H) 3.79 (s, 3H) 6.62 (m, 1H) 6.68 (dd, J=10.33, 2.86 Hz, 1H) 6.95 (dd, J=8.79, 5.71 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][NH:10][C:11]1[N:21]=[CH:20][CH:19]=[CH:18][C:12]=1[C:13]([O:15][CH2:16]C)=[O:14].C(C(CC)CNC1N=CC=CC=1C(OCC)=[O:31])C>>[CH3:22][C:2]1([CH3:1])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][N:10]1[C:11]2[N:21]=[CH:20][CH:19]=[CH:18][C:12]=2[C:13](=[O:14])[O:15][C:16]1=[O:31]
Reactant: CCOC(=O)c1cccnc1NC[C@@H]1CC[C@H]2C[C@@H]1C2(C)C
Reactant: CCOC(=O)c1cccnc1NCC(CC)CC
Product: CC1(C)[C@H]2CC[C@@H](Cn3c(=O)oc(=O)c4cccnc43)[C@@H]1C2

Procedure:
The title compound was prepared according to the procedure of Example 3B substituting the product of Example 31A for the product of Example 3A (0.570 g, 95%). 1H NMR (300 MHz, DMSO-d6) δ 0.79 (d, J=9.56 Hz, 1H), 1.14 (s, 3H), 1.22 (s, 3H), 1.62 (m, 1H), 1.87 (m, 5H), 2.26 (m, 1H), 2.53 (m, 1H), 4.04 (dd, J=13.05, 6.07 Hz, 1H), 4.28 (dd, J=13.24, 9.19 Hz, 1H), 7.37 (dd, J=7.72, 4.78 Hz, 1H), 8.38 (dd, J=7.72, 1.84 Hz, 1H), 8.76 (dd, J=4.78, 1.84 Hz, 1H).
Reaction SMILES: [P:1]([Cl:12])(Cl)([O:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:2].Cl.[CH2:14]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH2:19])[CH3:15].[CH3:22][CH2:23]N(CC)CC>C(Cl)Cl>[Cl:12][P:1]([NH:19][C@H:18]([C:17]([O:16][CH2:14][CH2:15][CH2:22][CH3:23])=[O:21])[CH3:20])([O:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:10])=[CH:8][CH:9]=1)=[O:2]
Reactant: CCOC(=O)[C@H](C)N
Reactant: O=P(Cl)(Cl)Oc1ccc(Cl)cc1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClCCl
Product: CCCCOC(=O)[C@H](C)NP(=O)(Cl)Oc1ccc(Cl)cc1

Procedure:
Following the procedure described for Example 1, step 2, treatment of a solution in DCM (0.090 M) of the commercially available 4-chlorophenyl dichlorophosphate with L-alanine ethyl ester hydrochloride (1.0 eq.) and Et3N (2.0 eq.) provided the title compound as a colorless oil as a 1.1:1* mixture of diastereoisomers. 31P NMR (400 MHz, CDCl3): δ: 9.52 and 9.28*
Reaction SMILES: I[CH2:2][CH3:3].[OH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[Na].[CH2:27](O)[CH3:28]>[O-]CC.[Na+]>[CH2:27]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O:15][CH2:2][CH3:3])=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:28]
Reactant: CCO
Reactant: CCI
Reactant: CCOC(=O)c1c(C(=O)OCC)c(O)c2ccccc2c1O
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Product: CCOC(=O)c1c(C(=O)OCC)c(OCC)c2ccccc2c1OCC
Reaction time: 8 h

Procedure:
Iodoethane (70 g) was added to a solution of diethyl 1,4-dihydroxy-2,3-naphthalenedicarboxylate (35 g) in ethanolic sodium ethoxide, prepared from sodium (7.6 g) and ethanol (250 ml), and the mixture was heated under reflux for 3 hours. After keeping overnight at room temperature, the mixture was poured onto ice-hydrochloric acid (500 ml). The oil was separated, washed with aqueous sodium bicarbonate and crystallised from ethanol to give diethyl 1,4-diethoxy-2,3-naphthalenedicarboxylate, (IV) m.p. 68°.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:4](=[O:31])[C:3]=1[Cl:32].[C:33](OC(=O)C)(=[O:35])[CH3:34].[O:40]1CCO[CH2:42][CH2:41]1>CN(C1C=CN=CC=1)C>[C:33]([N:1]([C:2]1[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=3)[CH:10]=2)[N:5]([CH2:27][CH:28]([CH3:29])[CH3:30])[C:4](=[O:31])[C:3]=1[Cl:32])[C:41](=[O:40])[CH3:42])(=[O:35])[CH3:34]
Reactant: CC(C)Cn1c(=O)c(Cl)c(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc21
Reactant: CC(=O)OC(C)=O
Reactant: C1COCCO1
Agent: CN(C)c1ccncc1
Product: CC(=O)N(C(C)=O)c1c(Cl)c(=O)n(CC(C)C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 60 °C

Procedure:
To the product of EXAMPLE 61 (70 mg) in 1,4-dioxane (1 mL) was added acetic anhydride (2 mL) and DMAP (25 mg). The reaction was heated to 60° C. After about 1 hour the reaction was cooled to room temperature and quenched with methanol (1 mL) the reaction was diluted with EtOAc and washed with saturated aqueous NaHCO3/1 M aqueous NaOH solution (1:1). The organic layer was dried (Na2SO4). The concentrated residue was purified by flash chromatography on silica gel gradient eluted with 0-100% EtOAc in hexane affording the title compound. HPLC/MS: 590.0 (M+1), 592.0 (M+3); Rt=4.59 min.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].C([O-])([O-])=O.[Cs+].[Cs+].[Cs].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CO.O.CN(C=O)C>[NH2:1][C@H:2]([C:10]([O:12][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Cs]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: N=C(N)NCCC[C@H](N)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Water (2 ml) was added to a solution of Boc-Arg-OH (2.5 mmol) in methanol (20 ml). The solution was neutralised with a 20% solution of Cs2CO3 in water and then evaporated in vacuo to dryness. Residual water was removed by repeated addition and evaporation of toluene. The solid cesium salt of Boc-arginine was treated with DMF (25 ml) and benzyl bromide (3 mmol) and stirred at room temperature for 6 h. The DMF was removed in vacuo and the product was dissolved in acetone and filtered. The filtrate was evaporated in vacuo and the product was treated with 95% trifluoroactetic acid (TFA) (4 ml). The resulting product H-Arg-OBzl was isolated by tituration by diethyl ether. The salt of H-Arg-OBzl was isolated by treating the product with para-toluenesulfonic acid (5 mmol) in ether.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][C:10](=[CH2:12])[CH3:11].C(Cl)Cl.FC(F)(F)S(O)(=O)=O>C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]([CH3:12])([CH3:11])[CH3:9])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: C=C(C)C
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)Oc1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
4-Bromophenol(57.8 moles, 10.0 g) was added to a -30° C. solution of isobutylene (40 ml) and methylene chloride (50 ml) and then cooled to -78° C. Trifluoromethanesulfonic acid (4 moles, 0.35 ml) was added. The mixture was held at -78° C. for 4 hours and then allowed to warm to room temperature. Triethylamine (0.5 ml) was added; the solvent was removed. The residue was chromatographed over silica gel eluted with 1% ethyl acetate in hexane to yield 12.4 g. (MS)
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([NH:10][C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[C:5]([C:7]([OH:9])=O)[N:6]=1.[CH2:17]([O:24][C:25](=[O:41])[NH:26][C@@H:27]1[CH2:33][CH2:32][CH2:31][N:30]([C:34]2[N:35]([CH3:40])[N:36]=[CH:37][C:38]=2[NH2:39])[CH2:29][CH2:28]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH3:42]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH2:17]([O:24][C:25](=[O:41])[NH:26][C@@H:27]1[CH2:33][CH2:32][CH2:31][N:30]([C:34]2[N:35]([CH3:40])[N:36]=[CH:37][C:38]=2[NH:39][C:7]([C:5]2[N:6]=[C:2]([Br:1])[S:3][C:4]=2[NH:10][C:11]([O:13][C:14]([CH3:16])([CH3:42])[CH3:15])=[O:12])=[O:9])[CH2:29][CH2:28]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)OC(=O)Nc1sc(Br)nc1C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cn1ncc(N)c1N1CCC[C@@H](NC(=O)OCc2ccccc2)CC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@@H](NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 168 h
Yield: 99.7 %

Procedure:
To a stirred solution of 2-bromo-5-(isopropoxycarbonylamino)-thiazole-4-carboxylic acid (650.0 mg, 2.01 mmol) and [(R)-1-(4-amino-2-methyl-2H-pyrazol-3-yl)-azepan-4-yl]-carbamic acid benzyl ester (828.9 mg, 2.41 mmol, 1.2 eq.) in anhydrous N,N-dimethylformamide (22 mL) was added HATU (1.07 g, 2.81 mmol, 1.4 eq.) followed by N,N-diisopropylethylamine (0.88 mL, 5.03 mmol, 2.5 eq.), and the reaction mixture was stirred at RT under N2 for 7 days. The reaction mixture was diluted with ethyl acetate (150 mL). The organic layer was washed with 50% brine/water, water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified via flash column chromatography eluted with 45 to 100% ethyl acetate/heptane to give 1.30 g (79.7%) of ((R)-1-{4-[(2-Bromo-5-tert-butoxycarbonylamino-thiazole-4-carbonyl)-amino]-2-methyl-2H-pyrazol-3-yl}-perhydro-azepin-4-yl)-carbamic acid benzyl ester as a tacky gel. 1H NMR (400 MHz, CDCl3) δ 10.28 (s, 1H), 8.39 (s, 1H), 7.74 (s, 1H), 7.33 (s, 5H), 5.09 (s, 2H), 4.98 (s, 1H), 3.89 (s, 1H), 3.72 (s, 3H), 3.36-3.21 (m, 2H), 3.16-3.03 (m, 2H), 2.19-2.01 (m, 2H), 2.00-1.61 (m, 4H), 1.51 (s, 9H)
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].C(Cl)(=O)C1C=CC=CC=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1>CC(C)=O>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:2]([NH2:3])=[S:1])=[N:16][CH:17]=1
Reactant: Nc1ccc(Br)cn1
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: O=C(Cl)c1ccccc1
Product: NC(=S)Nc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63 %

Procedure:
1.1 Ammoniumthiocyanat (76 mmol, 1.2 eq.) is dissolved in acetone (75 ml) and benzoylchloride (1 eq.) is added dropwise. 20 min after stirring at RT, the reaction is heated to reflux. 2-Amino-5-bromopyridine (71 mmol) in acetone (50 ml) is added and 30 min heated to reflux. Afterwards, the reaction solution is poured onto ice. The precipitate is filtered and washed with water/methanol (1:1). The precipitate is dissolved in 2M NaOH (120 ml) at 80° C. and stirred 10 min at 80° C. The solution is poured into an HCl solution (5%) at 0° C. The pH of the solution is adjusted to 8 with a saturated Na2CO3 solution. The resulting precipitate is filtered and washed with water. (5-Bromo-pyridine-2-yl)-thiourea (“1”) is obtained after drying in vacuo at 40° C. as a pale yellow solid in a yield of 63%. HPLC (method C): 1.43 min; LC-MS (method A): 1.062 min, 231.95 (MH+).
Reaction SMILES: O.[NH2:2][NH2:3].C([O:8][CH2:9][CH3:10])(=O)CO.[CH2:11]([N:15]=[C:16]=[S:17])[CH2:12][CH2:13][CH3:14].[OH-].[Na+].Cl>C(O)C>[CH2:11]([N:15]1[C:16]([SH:17])=[N:3][N:2]=[C:10]1[CH2:9][OH:8])[CH2:12][CH2:13][CH3:14]
Reactant: NN
Reactant: CCCCN=C=S
Reactant: CCOC(=O)CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCn1c(S)nnc1CO
Temperature: 25 °C
Reaction time: 6 h
Yield: 80.8 %

Procedure:
To a solution of hydrazine monohydrate (7.5 g) in ethanol (75 ml), ethyl glycolate (15.6 g) was slowly added dropwise with keeping the reaction temperature under 10° C. at room temperature. The mixture was stirred for 6 hours at room temperature, and n-butyl isothiocyanate (17.3 g) was slowly added dropwise thereto with keeping the reaction temperature under 10° C. The mixture was stirred at room temperature for 5 hours and at 40° C. for 8 hours, cooled to room temperature, and ice-water (50 ml) was added to the mixture. The mixture was stirred for 15 miuntes, 5N aqueous solution of sodium hydroxide (40 ml) was added to the mixture, and the mixture was stirred for 6 hours at 60° C. Concentrated hydrochloric acid was added dropwise to the solution at 0° C. to adjust pH to 6, and the precipitated crystals were removed by filtration. The mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration. The crystals were washed with water, to give 4-n-butyl-3-hydroxymethyl-5-mercapto-4H-1,2,4-triazole (22.67 g) as colorless crystals.
Reaction SMILES: C([N:4]1[C:17]2[CH:16]=[CH:15][C:14]([N:18]([CH3:20])[CH3:19])=[CH:13][C:12]=2[S:11][C:10]2[C:5]1=[CH:6][CH:7]=[C:8]([N:21]([CH3:23])[CH3:22])[CH:9]=2)(=O)C.[CH2:24]([S:30]([OH:33])(=[O:32])=[O:31])[CH2:25][S:26]([OH:29])(=[O:28])=[O:27]>C(O)C>[CH2:24]([S:30]([O-:33])(=[O:32])=[O:31])[CH2:25][S:26]([O-:29])(=[O:28])=[O:27].[CH3:19][NH+:18]([CH3:20])[C:14]1[CH:15]=[CH:16][C:17]2[NH:4][C:5]3[C:10]([S:11][C:12]=2[CH:13]=1)=[CH:9][C:8]([NH+:21]([CH3:23])[CH3:22])=[CH:7][CH:6]=3
Reactant: O=S(=O)(O)CCS(=O)(=O)O
Reactant: CC(=O)N1c2ccc(N(C)C)cc2Sc2cc(N(C)C)ccc21
Solvent: CCO
Product: C[NH+](C)c1ccc2c(c1)Sc1cc([NH+](C)C)ccc1N2
Product: O=S(=O)([O-])CCS(=O)(=O)[O-]

Procedure:
The synthesis of LMT.EDSA was carried out by acid hydrolysis of 10-acetyl-N,N,N′,N′-tetramethyl-10H-phenothiazine-3,7-diamine. The acid used was 1,2-ethanedisulfonic acid and the solvent combination was aqueous ethanol.