Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27](O)=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH3:51][O:52][C:53](=[O:62])[CH:54]([NH2:61])[CH:55]1[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1>CN(C=O)C.C(Cl)CCl>[CH3:51][O:52][C:53](=[O:62])[C@@H:54]([NH:61][C:27]([C:18]1[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@H:8]2[C:6](=[O:7])[NH:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[O:30])[N:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:19]=1)=[O:28])[CH:55]1[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60]1
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reactant: COC(=O)C(N)C1CCCCC1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C1CCCCC1
Reaction time: 12 h

Procedure:
To a solution of 250 mg 5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 4 ml DMF were added 124 mg HOAt, 174 mg EDC, 0.37 ml DIPEA and 126 mg amino cyclohexylacetic acid methyl ester hydrochloride. After stirring for 12 h it was concentrated and the residue dissolved in dichloromethane. It was extracted with aqueous LiCl (4% w/w), aqueous NaHCO3 and 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated to furnish the crude coupling product as colorless oil. Yield: 428 mg.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH3:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>CN(C=O)C>[CH3:13][N:14](/[CH:16]=[C:3](\[C:2](=[O:1])[CH2:9][CH3:10])/[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:15]
Reactant: CCOC(=O)CC(=O)CC
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=C/N(C)C)C(=O)CC
Yield: 100 %

Procedure:
According to Scheme 9 Step 1: A solution of ethyl 3-oxopentanoate (13.9 mmol, 2.00 g) and of 1,1-dimethoxy-N,N-dimethylmethanamine (13.9 mmole, 1.84 mL) in DMF (10 mL) was microwaved for 30 min at 120° C. After evaporation of the solvent, 2.76 g (13.9 mmol) of (E)-ethyl 2-((dimethylamino)methylene)-3-oxopentanoate were obtained and used without further purification.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@@H:2]([C:10]([NH:12][C@@H:13]([C:26]([O:28][CH3:29])=[O:27])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][CH:16]=1)=[O:11])[C@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[H][H]>[Pd]>[NH2:1][C@@H:2]([C:10]([NH:12][C@@H:13]([C:26]([O:28][CH3:29])=[O:27])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][CH:16]=1)=[O:11])[C@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: [H][H]
Reactant: COC(=O)[C@@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@H](NC(=O)OCc1ccccc1)[C@H](C)OC(C)(C)C
Agent: [Pd]
Product: COC(=O)[C@@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@H](N)[C@H](C)OC(C)(C)C
Reaction time: 4 h
Yield: 95 %

Procedure:
4.03 g of Z-D-Thr(tBu)-D-Tyr(tBu)-OMe (7.45 mmoles) were dissolved in 250 ml of CH30H. After addition of 850 mg of 10% Pd on activated charcoal (Fluka, cat. No 75990) a hydrogen stream was blown on the solution at room temperature under shaking for 4 h. The hydrogenation reaction was monitored by TLC. After removal of the catalyst by filtration and evaporation of the filtrate, 2.88 g (7.08 mmoles, yield 95%) of H-D-Thr(tBu)-D-Tyr(tBu)-OMe were obtained in the form of pure oil (TLC).
Reaction SMILES: CSC.B.[F:5][C:6]1([F:25])[C:11](=O)[NH:10][CH2:9][C:8]2([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[O:7]1>C1COCC1>[F:25][C:6]1([F:5])[CH2:11][NH:10][CH2:9][C:8]2([CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:16][CH2:17]2)[O:7]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(=O)C(F)(F)O2
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CNCC(F)(F)O2
Temperature: 55 °C

Procedure:
Borane methyl sulfide complex (2M in THF, 2.69 mL) was added dropwise to a solution of tert-butyl 2,2-difluoro-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 37, step b) (0.55 g) in THF (15 mL). The reaction mixture was heated at 55° C. under nitrogen for 25 minutes and then cooled to room temperature. The mixture was quenched by careful dropwise addition of methanol (5 mL). N1,N2-dimethylethane-1,2-diamine (0.633 g) was then added and the mixture heated at 70° C. for 40 minutes. The solvents were removed under reduced pressure and the residue was purified by flash silica chromatography using 4% methanol in dichloromethane with 1% triethylamine as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.32 g. Used directly.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH2:10])=[CH:8][NH:7][N:6]=1)=[O:4].[OH-].[Na+].[O:13](C(OC(C)(C)C)=O)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=O>O1CCOCC1>[C:17]([O:16][C:14]([NH:10][C:9]1[C:5]([C:3]([OH:2])=[O:4])=[N:6][NH:7][CH:8]=1)=[O:13])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COC(=O)c1n[nH]cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1c[nH]nc1C(=O)O
Temperature: 50 °C
Reaction time: 5 h
Yield: 86.8 %

Procedure:
To a mixture of 4-amino-1H-pyrazole-3-carboxylic acid methyl ester (50.0 g, 355 mmol) in dioxane (500 mL) was added 2M aqueous NaOH solution (213 mL, 426 mmol), the mixture heated to 50° C. and stirred for 5 h. To this mixture was then added (BOC)2O (81.4 g, 373 mmol), using a dioxane rinse (100 mL) and the mixture heated at 50° C. for a further 5 h, then stirred at ambient for 14 h. The dioxane was removed in vacuo and water (1 L) added. The mixture was taken to pH˜2 using conc. aqueous HCl solution and the solid formed collected by filtration and dried on the filter. The solid was dried further through azeotrope with toluene (×3) and in the vacuum oven to give 4-tert-butoxycarbonylamino-1H-pyrazole-3-carboxylic acid (70.0 g, 87%) as a violet solid.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.[CH3:16][C:17]1([CH3:23])[NH:21][C:20](=O)[CH2:19][CH2:18]1.P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:20]3[CH2:19][CH2:18][C:17]([CH3:23])([CH3:16])[N:21]=3)[C:4]=2[CH:3]=1
Reactant: CC1(C)CCC(=O)N1
Reactant: Clc1ccc2c(c1)Nc1ccccc1O2
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)CCC(N2c3ccccc3Oc3ccc(Cl)cc32)=N1

Procedure:
Reaction of 2-chlorophenoxazine, 5,5-dimethyl-2-pyrrolidinone and phosphorus oxychloride according to the procedure of Example 1 provides 2-CHLORO-10-(5,5-DIMETHYL-1-PYRROLIN-2-YL)PHENOXAZINE, m.p. 118°-120° C., from ethanol.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.Br[CH:15]([CH2:18][CH3:19])[CH:16]=O>>[CH2:18]([C:15]1[S:7][C:6]([C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=2[N+:11]([O-:13])=[O:12])=[N:8][CH:16]=1)[CH3:19]
Reactant: CCC(Br)C=O
Reactant: Cc1ccc(C(N)=S)c([N+](=O)[O-])c1
Product: CCc1cnc(-c2ccc(C)cc2[N+](=O)[O-])s1
Yield: 61 %

Procedure:
The procedure described in Example 15-1 was followed, except that 4-methyl-2-nitro-thiobenzamide (56) was used instead of 4-trifluoromethyl-2-nitro-thiobenzamide, and 2-bromo-butyraldehyde (54) was used instead of 1-bromo-3-methyl-butan-2-one, which gave the title compound (60 mg, 61%). LC/MS: (Method I): tR=1.52 min, >95%, m/z (ESI+)=249 (MH+).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]2[C:9]([C:25]3[CH:26]=[N:27][C:28]4[C:33]([CH:34]=3)=[CH:32][CH:31]=[CH:30][CH:29]=4)=[C:10]3[CH2:16][CH2:15][C@H:14]([NH:17]C(=O)OC(C)(C)C)[CH2:13][CH2:12][N:11]3[C:7]=2[N:6]=[CH:5][N:4]=1.[OH-].[Na+]>C(O)C>[N:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[C:25]([C:9]2[C:8]3[C:3]([NH2:2])=[N:4][CH:5]=[N:6][C:7]=3[N:11]3[CH2:12][CH2:13][C@@H:14]([NH2:17])[CH2:15][CH2:16][C:10]=23)[CH:26]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ncnc2c1c(-c1cnc3ccccc3c1)c1n2CC[C@@H](N)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
5 N Hydrochloric acid (1 ml) was added to a solution of (S)-tert-butyl (4-amino-5-(quinolin-3-yl)-7,8,9,10-tetrahydro-6H-pyrimido[5′,4′:4,5]pyrrolo[1,2-a]azepin-8-yl)carbamate (436 mg) obtained in Step 8 in ethanol (4 ml) at room temperature. The mixture was stirred at 60° C. for 3 hours. After cooling, the reaction mixture was basified with a 5 N aqueous sodium hydroxide solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: chloroform/methanol) to obtain the title compound as a light-yellow solid (320 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([C:8](=[S:10])[NH2:9])[CH:7]=1.Br[CH2:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18].C(OCC)(=O)C.CCCCCC>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([C:8]2[S:10][CH2:15][C:16]([C:17]([F:20])([F:19])[F:18])([OH:21])[N:9]=2)[CH:7]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: Cc1ccc([N+](=O)[O-])c(C(N)=S)c1
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc([N+](=O)[O-])c(C2=NC(O)(C(F)(F)F)CS2)c1
Temperature: 25 °C

Procedure:
The product from Step B (5.5 g, 0.028 mol) was dissolved in ethyl alcohol (100 mL). 3-bromo-1,1,1-trifluoroacetone (5.3 g, 0.028 mol) was added and the resulting solution refluxed for 3 h. After cooling to room temperature, the reaction mixture was evaporated to dryness. The residue was partitioned between ethyl acetate and 10% aqueous sodium carbonate (200 mL each). The organic layer was separated, dried (MgSO4) and then concentrated to give an oil. Flash chromatography of this oil on silica gel eluting with 20% ethyl acetate/hexane afforded a solid which was further purified by recrystallization from chlorobutane/hexane. Yield: 4.4 g (51%) of the title compound as a white solid melting at 148°-151° C. 1H NMR (300 MHz, CDCl3) δ 7.96-7.98 (m,1H), 7.42-7.44 (m,2H), 3.86-3.89 (m,1H), 3.34 (s,1H), 2.49 (s,3H).
Reaction SMILES: [CH3:1][CH:2]([CH2:35][CH3:36])[CH2:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([CH3:34])[C:31]([CH3:33])=[CH:32][C:6]=2[N:5]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][CH:2]([CH2:35][CH3:36])[CH2:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([CH3:34])[C:31]([CH3:33])=[CH:32][C:6]=2[N:5]=1
Reactant: CCC(C)Cc1nc2cc(C)c(C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)Cc1nc2cc(C)c(C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-(2-methylbutyl)-5,6-dimethyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH2:1]([O:5][C@@H:6]([CH3:12])[C@@H:7]([CH3:11])[C:8](O)=[O:9])[CH2:2][CH2:3][CH3:4].C(Cl)(=O)C([Cl:16])=O>>[CH2:1]([O:5][C@@H:6]([CH3:12])[C@@H:7]([CH3:11])[C:8]([Cl:16])=[O:9])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCO[C@@H](C)[C@@H](C)C(=O)O
Product: CCCCO[C@@H](C)[C@@H](C)C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 1.1 g of the (2R,3S)-3-butoxy-2-methylbutyric acid produced in the above i) was added in small portions 5 ml of oxalyl chloride at room temperature. The mixture was stirred for 2 hours at room temperature and then for 30 minutes at 50° C. Excess oxalyl chloride was removed by distillation under reduced pressure. The residue was subjected to Kugel-rohr distillation under reduced pressure to obtain 0.88 g of (2R,3S)-3-butoxy-2-methylbutyric acid chloride.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([S:8][CH3:9])[CH:7]=1.C([Li])CCC.CCCCCC.[CH:21]([C:23]1[N:24]=[CH:25][N:26]2[CH:30]=[CH:29][S:28][C:27]=12)=[O:22]>>[CH3:9][S:8][C:6]1[CH:7]=[C:2]([CH:21]([OH:22])[C:23]2[N:24]=[CH:25][N:26]3[CH:30]=[CH:29][S:28][C:27]=23)[CH:3]=[N:4][CH:5]=1
Reactant: CSc1cncc(Br)c1
Reactant: O=Cc1ncn2ccsc12
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CSc1cncc(C(O)c2ncn3ccsc23)c1
Yield: 64 %

Procedure:
7-[(5-Methylthiopyridin-3-yl)hydroxymethyl]imidazo-[5,1-b]thiazole (119 mg) was prepared in substantially the same manner as in step a) of Synthesis Example 5, except that 204 mg of 3-bromo-5-methylthiopyridine, 0.656 ml of a 1.6 N n-butyllithium/n-hexane solution, and 102 mg of 7-formylimidazo[5,1-b]thiazole were used as the starting materials.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[C:12]1=[O:29].[OH-].[Na+]>CO>[CH3:28][C:25]1[CH:24]=[CH:23][C:22]([N:13]2[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:15][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:30])=[O:2])[C:12]2=[O:29])=[CH:27][CH:26]=1
Reactant: COC(=O)CCCCCCCn1cc(-c2ccccc2)n(-c2ccc(C)cc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-n2c(-c3ccccc3)cn(CCCCCCCC(=O)O)c2=O)cc1

Procedure:
The product is produced as described in example 18 from 18.1 g of 8-[3-(4-methylphenyl)-2-oxo-4-phenyl-4-imidazolin-1-yl] caprylic acid methyl ester and 1.8 g of NaOH in 90 cc. of methanol. Further purification by chromatography on silicic acid gel using chloroform as eluant.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[CH:3]=1.C([Li])CCC.[CH2:15]([Sn:19](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18]>C(OCC)C>[CH3:8][C:6]1[CH:7]=[C:2]([Sn:19]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:15][CH2:16][CH2:17][CH3:18])[CH:3]=[C:4]([CH3:9])[N:5]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1cc(Br)cc(C)n1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1cc(C)nc(C)c1
Temperature: -60 °C
Reaction time: 0.25 h
Yield: 101.1 %

Procedure:
A 22 L flask was charged with 740 g of 4-bromo-2,6-lutidine and 10.0 L of diethyl ether and cooled to -60° C. in a Dry Ice/acetone bath under nitrogen. A solution of 4.0 moles of n-butyllithium was added dropwise over 1 hour maintaining a temperature below -58° C. to form an orange-yellow precipitate. After continued stirring in the cold for 15 minutes, 1280 g of tributyltin chloride was added over 2 hours at a temperature of -60° to -57° C. to form a solution. The reaction was stirred cold for 45 minutes before it was slowly (2 hours) warmed to 20° C. A portion of Super-Cel (100 g) was added and the reaction mixture was filtered to remove the precipitated lithium chloride. The cake was washed with diethyl ether (2×500 ml). After concentration to dryness a total of 1575 g (99.7% yield) of product was obtained which was used without further purification.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl[CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1.Cl>CS(C)=O.C(=O)(O)[O-].[Na+]>[O:7]([CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc(CCl)cc1
Reactant: Oc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)c1ccc(COc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.4 %

Procedure:
Phenol 2 (4.706 g, 50.0 mmol) and KOH (6.172 g, 110 mmol) were combined in dimethyl sulfoxide (DMSO) (250 ml). 4-Chloromethylbenzoic acid 1 (8.530 g, 50.0 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was then poured into H20 and acidified with concentrated HCl. The solution was then extracted and concentrated to give a solid. The solid was dissolved in an aqueous sodium bicarbonate solution, then washed with ethyl acetate. The aqueous mixture was then acidified with dilute HCl forming a precipitate which was filtered and dried to give about 3.7 g of 4-phenoxymethylbenzoic acid 3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=O.[C:14]1([C:20]2[N:21]=[C:22]([CH:31]([NH2:33])[CH3:32])[O:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:14]1([C:20]2[N:21]=[C:22]([CH:31]([NH:33][CH:8]3[C:9]4[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=4)[CH2:5][CH2:6][CH2:7]3)[CH3:32])[O:23][C:24]=2[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1cccc2c1CCCC2=O
Reactant: CC(N)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cccc2c1CCCC2NC(C)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.4 %

Procedure:
A solution of 5-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene (0.67 g), 1-(4,5-diphenyloxazol-2-yl)ethylamine (0.98 g) and p-toluenesulfonic acid (catalytic amount) in toluene (30 ml) was refluxed for 7 hours with Dean-stark equipment. The solution was evaporated in vacuo and methanol (MeOH) (10 ml) was added to the residue. To the MeOH solution, NaBH4 (0.21 g) was added at 0° C. After being stirred for 2 hours at room temperature, the solution was evaporated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine. The dried solvent was evaporated in vacuo, and the residue was purified by chromatography on silica gel to give 1-[1-(4,5-diphenyloxazol-2-yl)ethylamino]-1,2,3,4-tetrahydro-5-methoxynaphthalene (0.73 g). MS (m/z): 425 (M+ +1) NMR (CDCl3, δ): 1.60 (3H, d, J=6.8 Hz), 1.60-2.08 (6H, m), 2.42-2.86 (2H, m), 3.80 (1.5H, s), 3.81 (0.5H, q, J=6.8 Hz), 3.82 (1.5H, s), 3.90 (0.5H, m), 4.29 (0.5H, q, J=6.8 Hz), 4.77 (0.5H, m), 6.73 (1H, m), 7.00-7.20 (2H, m), 7.33-7.39 (6H, m), 7.57-7.68 (4H, m)
Reaction SMILES: C([CH:3]1[C:8]2[S:9][C:10]([C:12]([OH:14])=O)=[N:11][C:7]=2[CH2:6][CH2:5][N:4]1/[C:15](/[S:23][CH3:24])=[N:16]/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)C.CCN=C=NCCCN(C)C.[CH:36]1[CH:37]=[CH:38][C:39]2[N:44](O)N=[N:42][C:40]=2[CH:41]=1.C(N(CC)CC)C>CN(C=O)C>[NH2:42][C:40]1[CH:41]=[CH:36][CH:37]=[CH:38][C:39]=1[NH:44][C:12]([C:10]1[S:9][C:8]2[CH2:3][N:4]([C:15]([S:23][CH3:24])=[N:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:5][CH2:6][C:7]=2[N:11]=1)=[O:14]
Reactant: On1nnc2ccccc21
Reactant: CCC1c2sc(C(=O)O)nc2CCN1/C(=N/c1ccccc1)SC
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSC(=Nc1ccccc1)N1CCc2nc(C(=O)Nc3ccccc3N)sc2C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A suspension of ethyl 5-[(Z)-(methylthio)(phenylimino)methyl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid obtained in step III (1 eq), mono Boc-protected o-phenylene diamine (1.2 eq), EDCI (1.2 eq), HOBt (1.2 eq) and triethylamine in DMF were stirred at room temperature for 15 h. Solvent was evaporated and the residue was treated with etheral HCl at room temperature for 5-15 h. Solvent was evaporated and the residue was purified by either column chromatography or preparative HPLC to afford methyl 2-[(2-aminophenyl)carbamoyl]-N-phenyl-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)carbimidothioate.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:8]=[C:9]([N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)[C:10]1[CH:32]=[CH:31][C:13]([C:14]([O:16][C@@H:17]([CH2:19]OS(C2C=CC(C)=CC=2)(=O)=O)[CH3:18])=[O:15])=[CH:12][CH:11]=1.[Br-:38].[Li+]>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:8]=[C:9]([N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)[C:10]1[CH:32]=[CH:31][C:13]([C:14]([O:16][C@@H:17]([CH2:19][Br:38])[CH3:18])=[O:15])=[CH:12][CH:11]=1
Reactant: [Br-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](C)OC(=O)c2ccc(C(=N)N3CCCC3)cc2)cc1
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](CBr)OC(=O)c1ccc(C(=N)N2CCCC2)cc1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
(2R)-3-{[(4-methylphenyl)sulfonyl]oxy}-2-propyl 4-[imino(pyrrolidin-1-yl)methyl]benzoate trifluoroacetate (45.1 mg, 0.083 mmol) obtained in Step 1 was dissolved in DMF (2 ml), lithium bromide (72 mg, 0.83 mmol) was added thereto, and the mixture was stirred at 50° C. for 2 days. The solvent was evaporated under reduced pressure, and the obtained residue was purified by reversed-phase HPLC in the same manner as in Step 4 of Example 1 to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][O:11][C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=3)[C:15]([O:17][CH3:18])=[O:16])[N:7]([CH3:22])[C:6]=2[CH:23]=1.[Br:24][C:25]1[CH:26]=[C:27]([CH3:32])[C:28](F)=[N:29][CH:30]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu](I)I.CN(C=O)C>[Br:24][C:25]1[CH:26]=[C:27]([CH3:32])[C:28]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[N:9]=[C:8]([CH2:10][O:11][C:12]4[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=4)[C:15]([O:17][CH3:18])=[O:16])[N:7]([CH3:22])[C:6]=3[CH:23]=2)=[N:29][CH:30]=1
Reactant: COC(=O)c1cccc(OCc2nc3ccc(O)cc3n2C)c1
Reactant: Cc1cc(Br)cnc1F
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OCc2nc3ccc(Oc4ncc(Br)cc4C)cc3n2C)c1
Yield: 13.5 %

Procedure:
The reaction and post-treatment were carried out according to Example (1f) using methyl 3-[(6-hydroxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzoate produced in Example (1e) (3.12 g, 10.0 mmol), 5-bromo-2-fluoro-3-methylpyridine (2.09 g, 11.0 mmol), copper iodide (0.19 g, 1.00 mmol), 1,10-phenanthroline (0.18 g, 1.00 mmol), cesium carbonate (9.77 g, 30.0 mmol) and DMF (50 mL) to obtain the title compound (0.65 g, 14%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([O:11][CH3:12])[C:7]=1[C:8]([OH:10])=O.S(Cl)(Cl)=O.C1(C)C=CC=CC=1.[NH2:24][C:25]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]>N1C=CC=CC=1.CN(C=O)C>[C:27]([C:26]1[CH:29]=[CH:30][C:31]([CH3:33])=[CH:32][C:25]=1[NH:24][C:8](=[O:10])[C:7]1[C:6]([O:11][CH3:12])=[CH:5][CH:4]=[CH:3][C:2]=1[F:1])#[N:28]
Reactant: COc1cccc(F)c1C(=O)O
Reactant: Cc1ccc(C#N)c(N)c1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1cccc(F)c1C(=O)Nc1cc(C)ccc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
6-Fluoro-2-anisoic acid (110 g, 0.70 mol) was added in portions over 15 minutes to a mixture of thionyl chloride (230 ml, 3.2 mol), toluene (200 mL), and DMF (1 mL). The resulting mixture was stirred overnight at room temperature. The solution was evaporated to dryness and added dropwise to an ice-bath cooled solution of 2-amino-4-methylbenzonitrile (92.5 g, 0.70 mol) in pyridine (200 mL). The dropping funnel was rinsed with a minimal amount of acetonitrile. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere and was subsequently poured into 2 L ice water. The resulting slurry was stirred vigorously for 1 hour. The formed solid was collected by filtration and was washed twice with water. The filter cake was dissolved in 2 L dichloromethane, and this solution was washed with 1 N aq. HCl (400 mL) and with saturated aq. NaCl (400 mL), dried over sodium sulfate, filtered, and evaporated to dryness to give N-(2-cyano-5-methylphenyl)-2-fluoro-6-methoxybenzamide (186 g, 93%) as a brownish solid. 1H-NMR (CDCl3, 200 MHz): δ 9.09 (s, 1H), 8.58 (s, 1H), 7.59-7.42 (m, 2H), 7.09-7.02 (m, 1H), 6.94-6.83 (m, 2H), 4.11 (s, 3H), 2.57 (s, 3H) ppm.