Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[O:35])[C@H:3]([NH:17][C:18]1[C:26]([F:27])=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[C:20]([NH:28][C:29]2[S:33][N:32]=[C:31]([CH3:34])[CH:30]=2)[CH:19]=1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8](C2C=CN=CC=2)=[CH:7][CH:6]=1.[N:36]1[CH:41]=[CH:40][CH:39]=[C:38](B(O)O)[CH:37]=1>>[NH2:1][C:2](=[O:35])[C@H:3]([NH:17][C:18]1[C:26]([F:27])=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[C:20]([NH:28][C:29]2[S:33][N:32]=[C:31]([CH3:34])[CH:30]=2)[CH:19]=1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:38]2[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=2)=[CH:7][CH:6]=1
Reactant: Cc1cc(Nc2cc(N[C@H](Cc3ccc(-c4ccncc4)cc3)C(N)=O)c(F)cc2C(N)=O)sn1
Reactant: OB(O)c1cccnc1
Product: Cc1cc(Nc2cc(N[C@H](Cc3ccc(-c4cccnc4)cc3)C(N)=O)c(F)cc2C(N)=O)sn1

Procedure:
The titled compound (13 mg) was synthesized analogously by procedures described in the Example for (R)-4-(1-amino-1-oxo-3-(4-(pyridin-4-yl)phenyl)propan-2-ylamino)-5-fluoro-2-(3-methylisothiazol-5-ylamino)benzamide, using pyridine-3-boronic acid in place of pyridine-4-boronic acid. MS 491.5 (M+H); UV 205.2, 244.2, 299.4 nm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[N:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:26]2[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=2)[CH:16]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(-c2ccncc2)c1
Yield: 71.1 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(pyridin-4-yl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), pyridin-4-ylboronic acid (0.025 g; 0.177 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 18 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.047 g (71%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(pyridin-4-yl)benzamide as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+].[Cl:9][C:10]1[N:15]=[C:14](Cl)[N:13]=[C:12]([N:17]2[C:22]([CH3:24])([CH3:23])[CH2:21][C:20]3([O:28][CH2:27][CH2:26][O:25]3)[CH2:19][C:18]2([CH3:30])[CH3:29])[N:11]=1>O.C1(C)C=CC=CC=1>[Cl:9][C:10]1[N:15]=[C:14]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:13]=[C:12]([N:17]2[C:22]([CH3:24])([CH3:23])[CH2:21][C:20]3([O:28][CH2:27][CH2:26][O:25]3)[CH2:19][C:18]2([CH3:30])[CH3:29])[N:11]=1
Reactant: CC1(C)CC2(CC(C)(C)N1c1nc(Cl)nc(Cl)n1)OCCO2
Reactant: C1COCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)CC2(CC(C)(C)N1c1nc(Cl)nc(N3CCOCC3)n1)OCCO2
Reaction time: 1.5 h

Procedure:
3.8 g of morpholine and, 15 minutes later, a solution of 1.7 g of NaOH in 5 ml of water are added to a solution of 30 g of 2,4-dichloro-6-(4,4-ethylenedioxy-2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine (product from Example 17) in 100 ml of toluene. The mixture is then warmed to 6020 and after 45 minutes a further 3.8 g of morpholine and 1.7 g of NaOH in 5 ml of water are added. After a further 1.5 hours, the reaction has ended. After cooling and adding 200 ml of toluene, the phases are separated. The organic phase is dried over Na2SO4 and evaporated. Recrystallizing from acetonitrile leads to the compound of the above structure which melts at 154°-156° (white powder).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[S:10][CH2:11][CH2:12][C:13]([F:22])([F:21])[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[O:4].[OH-].[K+].CCO>CCO.O>[F:22][C:13]([F:21])([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:12][CH2:11][S:10][C:6]1[N:7]=[CH:8][S:9][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1scnc1SCCC(F)(F)c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1scnc1SCCC(F)(F)c1ccc(F)cc1
Temperature: 120 °C
Yield: 82.3 %

Procedure:
4-[[3,3-Difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-thiazole-5-carboxylic acid methyl ester (0.88 g, 2.54 mmol) is taken in EtOH/water (1:1) (4 ml) powdered KOH (0.36 g, 6.34 mmol) is added. The mixture is refluxed vigorously at 120° C. for 16 h. After completion of the reaction, EtOH is evaporated. The residue is diluted with water (20 ml), acidified with 2M hydrochloric acid to pH 3, and extracted with EtOAc (3×30 ml). The combined organic layers are dried over sodium sulfate, evaporated to dryness yielding 4-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-thiazole-5-carboxylic acid (0.7 g, 2.09 mmol, 83%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][NH:11][C:5]=2[CH:4]=[N:3]1.[H-].[Na+].[F:14][C:15]([F:33])([F:32])[C:16]1[CH:31]=[CH:30][C:19]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=2)=[O:21])=[CH:18][CH:17]=1.O>CN(C=O)C>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][N:11]([CH2:26][C:25]3[CH:28]=[CH:29][C:22]([C:20](=[O:21])[C:19]4[CH:30]=[CH:31][C:16]([C:15]([F:14])([F:32])[F:33])=[CH:17][CH:18]=4)=[CH:23][CH:24]=3)[C:5]=2[CH:4]=[N:3]1
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(C(F)(F)F)cc1
Reactant: Cn1ncc2[nH]ccc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc2c(ccn2Cc2ccc(C(=O)c3ccc(C(F)(F)F)cc3)cc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
A solution of 5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (298 mg) in DMF (10 ml) was dripped into a suspension of 60% sodium hydride-oil (96 mg) in DMF (8 ml) on an ice-water bath. The mixture was stirred at room temperature for 1 hour, after which a solution of 4-(4-trifluoromethylbenzoyl)benzyl bromide (755 mg) in DMF (15 ml) was added and the mixture was further stirred at room temperature for 3 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=1:2) to provide the title compound as light-brown powder (436 mg, yield 53%).
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+].[NH:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1.[Cl:59][C:60]1[CH:65]=[C:64]([Cl:66])[CH:63]=[CH:62][C:61]=1Br>C1COCC1>[Cl:59][C:60]1[CH:65]=[C:64]([Cl:66])[CH:63]=[CH:62][C:61]=1[N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1
Reactant: Clc1ccc(Br)c(Cl)c1
Reactant: C1CNCCN1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1CCOC1
Product: Clc1ccc(N2CCNCC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
BINAP (219 mg), Pd(II) acetate (397 mg, 0.176 mmol), tBuONa (1.19 g, 12.3 mmol), piperazine (837 mg, 9.73 mmol) and THF (40 mL) were mixed together and stirred at room temperature for 30 min under nitrogen atmosphere. 2,4-dichlorobromobenzene (2 g, 8.84 mmol) in THF (10 mL) was added to the mixture drop wise and heated at 70° C. for 14 h. Excess THF was then evaporated and extracted with ethyl acetate. The crude product was obtained on concentration of the ethyl acetate layer after washing with brine and drying. Flash chromatography on silica gel eluting with 2% MeOH in CHCl3 gave 1-(2,4-Dichloro-phenyl)-piperazine.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C(N(CC)C(C)C)(C)C.Cl[S:15]([C:18]1[CH:19]=[C:20]([C:24]2[C:33]([CH3:35])([CH3:34])[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:36]([O:38][CH3:39])=[O:37])[CH:30]=3)[N:25]=2)[CH:21]=[CH:22][CH:23]=1)(=[O:17])=[O:16]>ClCCl>[CH3:2][N:3]([CH3:4])[S:15]([C:18]1[CH:19]=[C:20]([C:24]2[C:33]([CH3:34])([CH3:35])[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:36]([O:38][CH3:39])=[O:37])[CH:30]=3)[N:25]=2)[CH:21]=[CH:22][CH:23]=1)(=[O:16])=[O:17]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)Cl)c1)=N2
Reactant: CNC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)N(C)C)c1)=N2
Yield: 25 %

Procedure:
To a stirred solution of dimethylamine hydrochloride (82 mg, 1.0 mmol) and N,N-diisopropylethyl amine (388 mg, 3.0 mmol) in dichloromethane (4 mL) was added a solution of methyl 2-(3-(chlorosulfonyl)phenyl)-3,3-dimethyl-3,4-dihydroquinoline-6-carboxylate (394 mg, crude product) in dichloromethane (4 mL). The mixture was purified on preparative Thin layer chromatography to afford 100 mg of methyl 2-(3-(N,N-dimethylsulfamoyl)phenyl)-3,3-dimethyl-3,4-dihydroquinoline-6-carboxylate, which was used directly.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:31])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:22][CH2:21][C:20]3[C:16](=[CH:17][N:18](S(C(F)(F)F)(=O)=O)[N:19]=3)[CH2:15]2)[C:10]1=[O:30].[C:40]1([CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.[Li+].[OH-]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:49]2[CH2:50][CH2:51][CH:46]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:47][CH2:48]2)[CH:5]=[C:6]([Cl:31])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:22][CH2:21][C:20]3[C:16](=[CH:17][NH:18][N:19]=3)[CH2:15]2)[C:10]1=[O:30]
Reactant: O=C1[C@H](Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1[C@H]1CCc2nn(S(=O)(=O)C(F)(F)F)cc2C1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C1[C@H](Cc2c(Cl)cc(N3CCC(c4ccccc4)CC3)cc2Cl)CCN1[C@H]1CCc2n[nH]cc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.1 %

Procedure:
Heat a solution of (3R,5S)-Trifluoro-methanesulfonic acid 3,5-dichloro-4-[2-oxo-1-(2-trifluoromethanesulfonyl-4,5,6,7-tetrahydro-2H-indazol-5-yl)-pyrrolidin-3-ylmethyl]-phenyl ester (Preparation 43) (0.10 g, 0.155 mmol) and 4-phenylpiperidine (0.063 g, 0.39 mmol) in 1-methyl-2-pyrrolidine (2.5 mL) to 201° C. for 1.5 hours in a microwave reactor. Cool the reaction to room temperature and treat with 2M LiOH (1 mL) and stir for 16 hours at room temperature. Dilute the reaction with ethyl acetate and wash with water. Dry the organic layer (Na2SO4) and remove the solvent in vacuo to afford crude product. Purify with a 0 to 5% methanol in CH2Cl2 gradient to afford 0.039 g (48%) of the title compound. MS (m/z): 523 (M+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([CH2:23][OH:24])=[C:21]([Cl:25])[N:20]=[C:19]2[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:13][CH:12]=1)([O:3]C)=[O:2].C(O)(=[O:32])C>O.[O-2].[O-2].[O-2].[Cr+6]>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][N:18]2[C:22]([C:23]([OH:24])=[O:32])=[C:21]([Cl:25])[N:20]=[C:19]2[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:15][CH:16]=1)([OH:3])=[O:2]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Reactant: CC(=O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Product: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 1.03 g of 1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole in 10 mL of anhydrous acetic acid at 25° was added a solution of 0.62 g of chromium trioxide in 10 mL of water. The mixture was stirred at 25° for 15 minutes and then poured into water. The precipitated solids were recovered by filtration and then dissolved in 50 mL of 1.0N aqueous sodium hydroxide solution. The alkaline solution was allowed to stand at 25° overnight and then was acidified to pH 3 with 10% aqueous hydrochloric acid. The precipitated solid was recovered by filtration and recrystallized from ethyl acetate to afford 0.10 g of 1-[(2'-carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloroimidazole-5-carboxylic acid (m.p. 186°-187° (decomp.)). NMR (DMSO-d6) δ 12.97 (br s, 2H); 7.68 (d, 1H); 7.53 (t, 1H); 7.41 (t, 1H); 7.34 (d, 1H); 7.28 (d, 2H); 7.02 (d, 2H); 5.61 (s, 2H); 2.60 (t, 2H); 1.53 (quint., 2H); 1.27 (sext., 2H); 0.81 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]1([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]2[CH:22]=[CH:21][C:20](B3OC(C)(C)C(C)(C)O3)=[CH:19][CH:18]=2)[CH3:16])[CH2:10][CH2:9]1.Br[C:38]1[CH:39]=[CH:40][C:41](=[O:45])[N:42]([CH3:44])[CH:43]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]1([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]2[CH:18]=[CH:19][C:20]([C:38]3[CH:39]=[CH:40][C:41](=[O:45])[N:42]([CH3:44])[CH:43]=3)=[CH:21][CH:22]=2)[CH3:16])[CH2:10][CH2:9]1
Reactant: Cn1cc(Br)ccc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2F)OC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2F)OC1=O
Yield: 12.2 %

Procedure:
To a solution of (S)-6-(2-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (120 mg, 0.24 mmol), 5-bromo-1-methylpyridin-2-(1H)-one (54 mg, 0.28 mmo), 2N aq Cs2CO3 (2 mL) in dioxane (8 mL) was added Pd(PPh3)2Cl2 (17 mg, 0.024 mmol) under N2. The reaction mixture was refluxed for 2 h and quenched by addition of water. The mixture was extracted with EtOAc (30 mL), and the organic layer was washed with H2O and brine, dried over Na2SO4, and filtered. The filtrate was concentrated to give the crude product, which was purified by preparative TLC and preparative HPLC to afford (S)-6-(2-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (14 mg, yield: 10%). LC-MS Method 2 tR=1.2 min, m/z=473.9; 1H NMR (CDCl3): δ1.21 (s, 3H), 1.30 (s, 3H), 1.48 (d, J=7.2 Hz, 3H), 2.15-2.26 (m, 3H), 2.33 (dd, J=11.2, 26.4 Hz, 1H), 2.43-2.46 (m, 1H), 2.79-2.85 (m, 1H), 3.63 (s, 3H), 5.62 (q, J=6.8 Hz, 1H), 6.58-6.60 (m, 1H), 6.89-6.94 (m, 1H), 7.00-7.02 (m, 2 H), 7.10-7.24 (m, 3H), 7.34-7.39 (m, 1H), 7.40-7.45 (m, 1H), 7.48-7.70 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]([C:5]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][NH:7][N:6]=1)=[O:4].Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.[Cu-]=O>[CH3:1][N:2]([CH3:13])[C:3]([C:5]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:6]=1)=[O:4]
Reactant: Brc1ccccn1
Reactant: CN(C)C(=O)c1n[nH]cc1[N+](=O)[O-]
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1nn(-c2ccccn2)cc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A solution of 4-nitro-1H-pyrazole-3-carboxylic acid dimethylamide (250 mg, 1.36 mmol) in DMF (5 ml) was flushed with argon. 2-Bromopyridine (0.17 ml, 1.76 mmol), ferric acetylacetone (144 mg, 0.4 mmol), copper(I)oxide (20 mg, 0.14 mmol) and cesium carbonate (885 mg, 2.7 mmol) were added consecutively and the reaction mixture was stirred at 110° C. overnight. After cooling down, the reaction mixture was partitioned between ethyl acetate (30 ml) and water (15 ml) and extracted. The organic layer was washed with brine, dried and the solvent was evaporated. The product was obtained after purification by silica gel chromatography using a heptane/ethyl acetate gradient as light yellow solid (102 mg, 29%).
Reaction SMILES: BrC1C(O)=C(C(CSC2C=CC=CC=2OC)=CC=1)C(OC)=O.[Br:23][C:24]1[C:25]([O:36][CH3:37])=[C:26]([C:31]([CH2:34]Br)=[CH:32][CH:33]=1)[C:27]([O:29][CH3:30])=[O:28].[SH:38][C:39]1[CH:40]=[C:41]([OH:45])[CH:42]=[CH:43][CH:44]=1>>[Br:23][C:24]1[C:25]([O:36][CH3:37])=[C:26]([C:31]([CH2:34][S:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([OH:45])[CH:40]=2)=[CH:32][CH:33]=1)[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)c1c(CBr)ccc(Br)c1OC
Reactant: Oc1cccc(S)c1
Agent: COC(=O)c1c(CSc2ccccc2OC)ccc(Br)c1O
Product: COC(=O)c1c(CSc2cccc(O)c2)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 82, starting from methyl 3-bromo-6-bromomethyl-2-methoxybenzoate (Intermediate 89) and 3-mercaptophenol and used without further characterization.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[CH:10]([NH2:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O-])([O-])=O.[K+].[K+].ClC(OCC)=O.B>C1COCC1.O>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[CH:10]([NH:20][CH3:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: NC1CN(Cc2ccccc2)CC1c1cccc(Cl)c1
Agent: B
Agent: CCOC(=O)Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CNC1CN(Cc2ccccc2)CC1c1cccc(Cl)c1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 55.7 %

Procedure:
To a solution of (3RS,4SR)-1-benzyl-4-(3-chloro-phenyl)-pyrrolidin-3-ylamine (4.47 g, 16.0 mmol) in THF (50 ml) was added a solution of K2CO3 (4.31 g, 31 mmol) in H2O (35 ml). After 10 minutes, ethyl chloroformate (2.97 ml, 31 mmol) was added and stirring was continued at RT for an additional 4 h. The intermediate carbamate was then extracted with Et2O, dried over Na2SO4 and concentrated under vacuo to give viscous oil. The oil was taken up in THF (10 ml) and a solution of borane in THF (1M) was added (62 ml). The reaction mixture was then heated at 65° C. over night, cooled to RT and carefully quenched with conc. HCl (5 ml). The mixture was then heated at 80° C. for 2 h, cooled to RT, concentrated under vacuo, diluted with Et2O (50 ml) and neutralized with an aqueous solution of NaHCO3. The organic phases were dried over Na2SO4 and the product purified by flash chromatography (SiO2, CH2Cl2/MeOH 9:1) to afford 2.68 g (57%) of the title compound as a colorless oil. ES-MS m/e: 301.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:7]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=1)[CH2:5]O.S(Cl)([Cl:19])=O>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([C:7]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=1)[CH2:5][Cl:19]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(Sc2ccccc2)c(CO)c1
Solvent: c1ccccc1
Product: Cc1ccc(Sc2ccccc2)c(CCl)c1
Reaction time: 1.5 h

Procedure:
570.7 g of 3-methyl-6-(phenylthio)-benzyl alcohol are dissolved in 1.5 litres of benzene and heated under reflux. There are added dropwise thereto within 45 minutes 352 ml of thionyl chloride and the mixture is boiled for a further 90 minutes. Then the mixture is concentrated under reduced pressure and there is obtained 3-methyl-6-(phenylthio)-benzyl chloride as a red-brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([OH:20])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.F[B-](F)(F)F.C[N+](C)=C(N(C)C)O.C(N(C(C)C)C(C)C)C.[NH2:43][CH:44]([C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([OH:53])[CH:48]=1)[C:45]#[N:46]>CC#N>[C:45]([CH:44]([NH:43][C:18]([C@@H:13]1[CH2:14][CH2:15][CH2:16][CH2:17][C@H:12]1[NH:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])=[O:20])[C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([OH:53])[CH:48]=1)#[N:46]
Reactant: O=C(O)[C@@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: N#CC(N)c1cccc(O)c1
Agent: CN(C)C(O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#CC(NC(=O)[C@@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(Cl)cc1)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Trans-2-(4-Chloro-benzenesulfonylamino)-cyclohexanecarboxylic acid (0.095 g, 0.3 mmol) is dissolved in CH3CN. O-1,2-Dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TPTU, 90.2 mg, 0.3 mmol), N-Ethyldiisopropylamine (DIPEA, 0.208 ml, 1.21 mmol) are added. The amino-(3-hydroxy-phenyl)-acetonitrile in CH3CN (1.5 ml) is added. The mixture is stirred at RT for 16 hours. The solution is filtered and concentrated. The residue is dissolved in CH2Cl2 (15 mL) and extracted with NH4Cl (2×10 ml). The H2O layers are extracted with CH2Cl2 (2×15 ml). The collected CH2Cl2 layers are dried over MgSO4 and evaporated. The solid is purified by preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[N:9]=[C:10]([CH2:13][C:14]#[N:15])[S:11][CH:12]=2)=[C:5]([CH3:7])[N:6]=1.C(N(CC)C(C)C)(C)C.[N:25]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:26]=[O:27]>C(Cl)Cl>[C:14]([CH2:13][C:10]1[S:11][CH:12]=[C:8]([C:4]2[S:3][C:2]([NH:1][C:26]([NH:25][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:27])=[N:6][C:5]=2[CH3:7])[N:9]=1)#[N:15]
Reactant: Cc1nc(N)sc1-c1csc(CC#N)n1
Reactant: CCOC(=O)CCN=C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNC(=O)Nc1nc(C)c(-c2csc(CC#N)n2)s1
Temperature: 50 °C
Reaction time: 36 h

Procedure:
(2′-Amino-4′-methyl-4,5′-bi-1,3-thiazol-2-yl)acetonitrile, prepared in Step I, described above (236.3 mg; 1 mmol; 1 eq.), is suspended in DCM (5 ml). N,N-Diisopropylethylamine (377 μl; 2.20 mmol; 2.20 eq.) is added, followed by a solution of ethyl 3-isocyanatopropionate (143.1 mg; 1 mmol; 1 eq.) in DCM (3 ml). The reaction mixture is heated at 50° C. overnight. As the reaction is not complete, a second batch of ethyl 3-isocyanatopropionate (Aldrich) (143.1 mg; 1 mmol; 1 eq.) is added. After 36 hours the reaction is complete. The solvents are evaporated. EtOAc is added and the mixture is washed with brine, dried over MgSO4 and evaporated. The resulting crude product is purified by preparative HPLC, affording Compound (50) as white-off solid (76.6 mg; 20%). 1H NMR (DMSO-d6, 300 MHz) δ 1.21 (t, J=7.5 Hz, 3H), 2.44 (s, 3H), 2.58 (m, 2H), 3.39 (q, J=6 Hz, 2H), 4.10 (q, J=7.5 Hz, 2H), 4.62 (s, 2H), 6.72 (t, J=6 Hz, 1H), 7.64 (s, 1H), 10.49 (br s, 1H). M− (ESI): 378.17; M+ (ESI): 380.10. HPLC (method A), Rt: 2.60 min (purity: 100%).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[C:13](Cl)(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[OH-].[Na+].Cl>O.C(O)(C)C>[C:13]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCCCCC(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Temperature: 11.5 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To 1,106 g of L-arginine were added 6,919 g of isopropyl alcohol and 2,964 g of water. Thereto were concurrently added dropwise 1,522 g of lauroyl chloride (manufactured by Nippon Oil and Fats Co., Ltd.) and 27 wt % NaOH aqueous solution over a period of 2 hours with the pH being maintained at 10.5 to 11.5 and the reaction temperature being maintained at 10 to 13° C. After 1 hour of aging, the reaction mixture was warmed to 50° C. and adjusted to pH 3.8 by adding concentrated hydrochloric acid to dissolve the reaction product completely. Thereafter, the pH was adjusted to 6.0 by adding 27 wt % NaOH aqueous solution to precipitate crystals and the resulting slurry was gradually cooled to 10° C. with stirring. When the slurry was cooled to 10° C., the crystals were collected by filtration and washed with 10 kg of water and 4.4 kg of isopropyl alcohol, successively. The resulting washed crystals were dried under reduced pressure to obtain 2,081 g of mono-Nα-lauroyl-L-arginine as flake-shaped crystals (yield 92.3%).