Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:18]([CH3:22])[C:19](F)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH3:29].O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:18]([CH3:22])[C:19]([NH2:29])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C(=O)F)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: N
Solvent: O
Solvent: C1CCOC1
Product: CC(C(N)=O)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-3-phenylpropanoyl fluoride (0.32 mmol) in anhydrous THF (5 mL) at −78° C. was bubbled NH3 (g) for 10 minutes. The reaction mixture was sealed and stirred at −78° C. for 15 min and at rt for 1 hr. Water (100 mL) was added, the reaction mixture was extracted with ethyl acetate (100 mL), dried (Na2SO4), and concentrated to give 115 mg (100% yield) of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-3-phenylpropanamide, the NMR spectrum of which was consistent with the desired structure.
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[C:33]#[N:34]>>[C:33]([C:32]1[CH:31]=[C:30]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([CH2:16][NH:15][CH:12]3[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]3)[CH:18]=2)[CH:37]=[CH:36][CH:35]=1)#[N:34]
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: N#Cc1cccc(Br)c1
Product: COc1ccc(-c2cccc(C#N)c2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 4 (359 mg, 0.92 mmol) is coupled to 3-bromobenzonitrile (200 mg, 1.10 mmol) using Method B to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].C([Li])CCC.Cl[Si:15]([CH3:18])([CH3:17])[CH3:16]>C1COCC1.CCCCCC>[CH3:16][Si:15]([CH3:18])([CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8]
Reactant: Cc1ccccc1Br
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccccc1[Si](C)(C)C
Temperature: -78 °C

Procedure:
In a 10 ml volume double neck flask substituted with argon gas, was laid 2 ml of a THF solution containing 0.32 mmol/L of o-bromotoluene obtained in the step 2 of Example 1, followed by cooling at −78° C. in an atmosphere of argon gas. To the solution, while stirring using a magnetic stirrer, 0.34 ml of a n-hexane containing 1.58 mol/L of n-butyl lithium was slowly drop wise added and stirred at −78° C. for 30 min. Subsequently, 0.59 ml of a THF solution containing 0.96 mmol/L of chlorotrimethylsilane was slowly drop wise added and stirred at −78° C. for 60 min. After reaction, the resulting solution was analyzed using GC (CBP column 1; 0.25 mm×25 m; starting temperature 50° C.; rate of temperature increase 10° C./min). As a result, o-trimethylsilyltoluene was obtained with a quantitative yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]([CH3:24])[C:7]([Cl:23])([CH:22]=1)/[CH:8]=[C:9](/[C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]=1)\[C:10](O)=[O:11].C(Cl)(=O)C([Cl:28])=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]([CH3:24])[C:7]([Cl:23])([CH:22]=1)/[CH:8]=[C:9](/[C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]=1)\[C:10]([Cl:28])=[O:11]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC1=CC(Cl)(/C=C(\C(=O)O)C2=CCc3ccccc32)C(C)C=C1
Solvent: C1CCOC1
Product: COC1=CC(Cl)(/C=C(\C(=O)Cl)C2=CCc3ccccc32)C(C)C=C1

Procedure:
(Z)-5-Methoxy-2-methyl-1-chlorobenzylidene-3-indenylacetic acid (70 mmol) in THF (500 ml) is allowed to react with oxalylchloride (2 M in CH2Cl2 ; 70 mmol) under reflux conditions (24 hours). The solvent is evaporated to yield the title compound, which is used as such in the next step.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([NH:14][C@@:15]([C:30]1[CH:35]=[C:34]([O:36][C:37]([F:42])([F:41])[CH:38]([F:40])[F:39])[CH:33]=[C:32]([F:43])[CH:31]=1)([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13].[C:44]([O-])([O-])=O.[K+].[K+].CI>CC#N>[F:43][C:32]1[CH:31]=[C:30]([C@:15]([NH:14][C:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]2[N:4]=[N:3][N:2]([CH3:44])[N:1]=2)=[O:13])([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:35]=[C:34]([O:36][C:37]([F:42])([F:41])[CH:38]([F:40])[F:39])[CH:33]=1
Reactant: O=C(NCCCCCc1nn[nH]n1)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: Cn1nnc(CCCCCNC(=O)N[C@](Cc2ccccc2)(c2ccc(F)cc2)c2cc(F)cc(OC(F)(F)C(F)F)c2)n1
Temperature: 80 °C
Yield: 17 %

Procedure:
To a solution of (R)-1-(5-(2H-tetrazol-5-yl)pentyl)-3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)urea (12 mg, 0.019 mmol) in MeCN (115 μl) at rt was added K2CO3 (3.2 mg, 0.023 mmol) followed by MeI (1.5 μL, 0.023 mmol). The reaction mixture was heated to 80° C. overnight. The reaction mixture was quenched by addition of H2O and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were concentrated and the residue was dissolved in MeOH and purified by preparative HPLC (Phenoma Luna AXIA 10A, C18, eluting with MeCN/H2O containing 0.1% TFA, monitoring at 220 nm) to provide (R)-1-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(5-(2-methyl-2H-tetrazol-5-yl)pentyl)urea (Example 260, 2 mg, 18% yield) as white solid. 1H NMR (500 MHz, CDCl3) ppm 7.17-7.08 (m, 5H), 6.99-6.85 (m, 5H), 6.67 (d, J=5 Hz, 2 H), 5.98-5.75 (m, 1H), 4.23 (s, 3H), 3.82 (d, J=15 Hz, 1H), 3.68 (d, J=15 Hz, 1H), 3.10-3.07 (m, 2H), 2.85-2.82 (m, 2H), 1.77-1.71 (m, 2H), 1.46-1.40 (m, 2H), 1.32-1.26 (m, 2H); LC/MS: RT=3.218 min [M+H] 621.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeCN/H2O over 4 minutes containing 0.1% NH4OAc; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]([C:15](Cl)=[O:16])=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[CH:20][CH:19]=3)[N:10]2[CH3:30])=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.[NH:38]1[CH2:43][CH2:42][CH:41]([O:44][CH2:45][C:46]([O:48]CC)=[O:47])[CH2:40][CH2:39]1>O1CCCC1>[C:46]([CH2:45][O:44][CH:41]1[CH2:40][CH2:39][N:38]([C:15]([C:12]2[C:13](=[O:14])[N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[N:10]([CH3:30])[C:11]=2[C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:20][CH:19]=2)=[O:16])[CH2:43][CH2:42]1)([OH:48])=[O:47]
Reactant: CCOC(=O)COC1CCNCC1
Reactant: Cn1c(-c2ccc(-c3ccccn3)cc2)c(C(=O)Cl)c(=O)n1-c1ccc(C#N)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(-c2ccc(-c3ccccn3)cc2)c(C(=O)N2CCC(OCC(=O)O)CC2)c(=O)n1-c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.9 %

Procedure:
A mixture of 1.62 g of 1-(4-cyanophenyl)-4-chlorocarbonyl-2-methyl-3-[4-(2-pyridyl)phenyl]-2H-pyrazol-5-one, 2.04 g of triethylamine, 20 ml of tetrahydrofuran and 1.35 g of ethyl 4-piperidinoxyacetate was stirred at room temperature for 16 hours. The reaction solution was evaporated under reduced pressure, and the resulting residue was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride and dried over sodium sulfate. The insolubles were filtered off, and the solvent was removed by evaporation. The resulting residue was crystallized in chloroform-methanol-ethyl acetate to give 250 mg of the title compound as pale yellow crystals. The mother liquor was evaporated under reduced pressure, and the resulting residue was purified by silica gel chromatography (eluent;ethyl acetate:methanol 9:1). The resulting crude crystals were recrystallized in chloroform-methanol-ethyl acetate to give 601 mg of the title compound as pale pink crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5].[N+:13]([CH3:16])([O-:15])=[O:14].C1CCN2C(=NCCC2)CC1.Cl>CCOCC>[CH3:1][C:2]([CH3:12])([CH2:16][N+:13]([O-:15])=[O:14])[CH2:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5]
Reactant: CC(C)=CC(=O)c1cccnc1
Reactant: C[N+](=O)[O-]
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Product: CC(C)(CC(=O)c1cccnc1)C[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a mixture of 3-methyl-1-pyridin-3-yl-but-2-en-1-one (440 mg, 2.73 mmol) and nitromethane (0.74 mL, 13.65 mmol) that is cooled with a water bath, add DBU (0.41 mL, 2.73 mmol) dropwise. After 30 min, add ether (15 mL) and 1N hydrochloric acid (15 mL). Neutralize with 1M NaOH and extract with ether. Dry over magnesium sulfate and evaporate to obtain 340 mg (61%) of the title compound as a yellow solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:4]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.ClC1C=CC=C(C(OO)=[O:29])C=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[CH3:2][C:3]1[C:4]([S:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[O:29])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nc2ccccc2nc1SCc1ccccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1nc2ccccc2nc1S(=O)Cc1ccccn1
Yield: 67.2 %

Procedure:
In a mixture of 36 ml of chloroform and 18 ml of methanol was dissolved 2.6 g of 3-methyl-2-(2-pyridylmethylthio)quinoxaline hydrochloride. To the chilled solution kept at a temperature of lower than 0° C. (temperature of solution) was added 1.77 g of m-chloroperbenzoic acid (purity 70%). After the reaction was complete, chloroform and saturated aqueous NaHCO3 solution were added to the reaction mixture under chilling. The organic layer was separated and dried over sodium sulfate. The sodium sulfate was then removed by filtration, and the solvent was evaporated under reduced pressure from the filtrate. The residue was purified by silica gel column chromatography (chloroform/methanol), and recrystallized from ethyl/hexane to give 1.63 g of 3-methyl-2-(2-pyridylmethylsulfinyl)quinoxaline as an orange crystalline powder, m.p. 85°-88° C. (decompn.).
Reaction SMILES: O=[C:2]1[C:7]2[CH:8]=[C:9]([CH3:12])[CH:10]=[CH:11][C:6]=2[S:5][CH2:4][CH:3]1[CH2:13][C:14]([OH:16])=O.O.[NH2:18][NH2:19]>C(O)C>[CH3:12][C:9]1[CH:10]=[CH:11][C:6]2[S:5][CH2:4][CH:3]3[C:2](=[N:18][NH:19][C:14](=[O:16])[CH2:13]3)[C:7]=2[CH:8]=1
Reactant: NN
Reactant: Cc1ccc2c(c1)C(=O)C(CC(=O)O)CS2
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(c1)C1=NNC(=O)CC1CS2
Yield: 50.9 %

Procedure:
A mixture of 2 g of α-(2,3-dihydro-4-oxo-6-methyl-4H-1-benzothiopyran-3-yl)acetic acid and 0.8 g of 100% hydrazine hydrate in 50 ml of ethanol is refluxed under heating for 8 hours. After about half the volume of ethanol is distilled off under reduced pressure and the residue is allowed to cool, the precipitated crystals are collected by filtration and recrystallized from acetic acid to give 1 g of 9-methyl- 2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin 3-one, melting at 217°-219° C., as colorless prisms.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C@H:7]([C:11]([OH:13])=O)[CH:8]([CH3:10])[CH3:9])=[O:5])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][N:40]([NH2:64])[CH2:41][C@H:42]([OH:63])[C@@H:43]([NH:51][C:52](=[O:62])[C@H:53]([CH:59]([CH3:61])[CH3:60])[NH:54][C:55]([O:57][CH3:58])=[O:56])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:35][CH:34]=2)=[CH:31][N:30]=[CH:29]1>CN(C=O)C>[S:28]1[C:32]([C:33]2[CH:34]=[CH:35][C:36]([CH2:39][N:40]([NH:64][C:11](=[O:13])[C@H:7]([CH:8]([CH3:9])[CH3:10])[NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:41][C@H:42]([OH:63])[C@@H:43]([NH:51][C:52](=[O:62])[C@H:53]([CH:59]([CH3:61])[CH3:60])[NH:54][C:55]([O:57][CH3:58])=[O:56])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:37][CH:38]=2)=[CH:31][N:30]=[CH:29]1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2cncs2)cc1)C(C)C
Reactant: CCOC(=O)N[C@H](C(=O)O)C(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOC(=O)N[C@H](C(=O)NN(Cc1ccc(-c2cncs2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)C)C(C)C

Procedure:
Analogously to Example 7, 213 mg (1.13 mmol) of N-ethoxycarbonyl-(L)-valine, 431 mg (2.25 mmol) of EDC and 304 mg (2.25 mmol) of HOBT in 18 ml of DMF and 627 μl (4.5 mmol) of TEA are reacted with 0.75 mmol of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-valyl)amino-6-phenyl-2-azahexane (Example 7b) to form the title compound: m.p: 243-244° C.; HPLC20-100 : tRet =14.0; FAB MS (M+H)+ =697.
Reaction SMILES: [Cl-:1].[OH:2][CH:3]([CH2:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][N+:11]([CH3:14])([CH3:13])[CH3:12].C(O)C.[CH2:38]=[C:39]1[O:43][C:41](=[O:42])[CH2:40]1>N1C=CC=CC=1>[Cl-:1].[C:41]([O:2][CH:3]([CH2:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][N+:11]([CH3:12])([CH3:13])[CH3:14])(=[O:42])[CH2:40][C:39]([CH3:38])=[O:43]
Reactant: CCCCCCCCCCCCCCCCCCOCC(O)COCCOCC[N+](C)(C)C
Reactant: C=C1CC(=O)O1
Agent: [Cl-]
Solvent: CCO
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCOCC(COCCOCC[N+](C)(C)C)OC(=O)CC(C)=O
Temperature: 45 °C
Reaction time: 0.08 h
Yield: 86 %

Procedure:
1.5 g (2.94 millimole) of 2-[2-[2-hydroxy-3-(octadecyloxy)propyloxy]ethoxy]ethyltrimethylammonium chloride was dissolved in 80 ml of pyridine, to which 2 ml of diketene was added, and the mixture was stirred at 45° C. for 5 minutes. 10 ml of ethanol was added thereto, and the mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (Merck Co., Art.7734, 38 g, Eluant; chloroform-methanol=4:1-2:1), to give 1.5 g (86%) of the above-captioned compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[CH3:12].[CH3:13][C:14]1[C:18]([CH3:19])=[C:17]([CH3:20])[NH:16][N:15]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:15]2[C:14]([CH3:13])=[C:18]([CH3:19])[C:17]([CH3:20])=[N:16]2)=[CH:5][C:4]=1[CH3:12]
Reactant: Cc1n[nH]c(C)c1C
Reactant: COc1ccc(B(O)O)cc1C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: c1ccncc1
Product: COc1ccc(-n2nc(C)c(C)c2C)cc1C
Yield: 52.6 %

Procedure:
A mixture of 4-methoxy-3-methyl-phenylboronic acid 10 g, 3,4,5-trimethyl-1H-pyrazole (described in Reference Preparation example 49) 7.3 g, copper(II) acetate 18.4 g, pyridine 10.0 g, molecular sieves 4 A 20.0 g and acetonitrile 300 ml was stirred with heating under reflux for thirty hours. The reaction mixture was filtered through Celite and was concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 1-(4-methoxy-3-methyl-phenyl)-3,4,5-trimethyl-1H-pyrazole 7.3 g.
Reaction SMILES: [Br:1]Br.[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH2:17][CH2:18][O:19][CH3:20])[C:15]3[C:21]([O:35][CH3:36])=[CH:22][C:23]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[S:32]([CH3:34])=[O:33])=[CH:24][C:14]=3[N:13]=2)=[CH:8][CH:7]=1)([CH3:5])[CH3:4].CCOC(C)=O>C(O)(=O)C>[Br:1][C:24]1[C:14]2[N:13]=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([CH:3]([CH3:5])[CH3:4])=[CH:7][CH:8]=3)[N:16]([CH2:17][CH2:18][O:19][CH3:20])[C:15]=2[C:21]([O:35][CH3:36])=[CH:22][C:23]=1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32]([CH3:34])=[O:33]
Reactant: BrBr
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(Cc3ccccc3S(C)=O)cc(OC)c21
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(Cc3ccccc3S(C)=O)cc(OC)c21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 501.7 %

Procedure:
53 μl (0.122 mmol) bromine are added to a solution of 496 mg (1.03 mmol) 2-(4-isopropyl-phenyl)-5-(2-methanesulfinyl-benzyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole in 22 ml glacial acetic acid. The reaction mixture is stirred at room temperature for 10 min. Then 25 ml EtOAc are added and this solution is washed with 4N NaOH (2×), water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=1:4) to afford 340 mg of the title compound as colorless crystals.
Reaction SMILES: CCC([O-])(C)C.[Na+].Cl[C:9]1[C:10]([Cl:16])=[N:11][C:12]([Cl:15])=[N:13][CH:14]=1.[CH3:17][CH:18]([CH3:22])[CH2:19][CH2:20][OH:21]>>[Cl:15][C:12]1[N:11]=[C:10]([Cl:16])[CH:9]=[C:14]([O:21][CH2:20][CH2:19][CH:18]([CH3:22])[CH3:17])[N:13]=1
Reactant: CC(C)CCO
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: CCC(C)(C)[O-]
Agent: [Na+]
Product: CC(C)CCOc1cc(Cl)nc(Cl)n1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
A solution of 28.6 g (0.26 mol) of sodium tert-amylate in 150 ml of 3-methylbutanol is stirred at 45°-50° C. for 30 minutes, cooled to 20° C. and added dropwise at -30° C. to a solution of 30 ml (0.26 mol) of trichloropyrimidine in 150 ml of 3-methylbutanol. When the solution has been added, the temperature is 0° C. The reaction mixture is left to stand overnight. The solvent is removed and the residue is taken up in 150 ml of water. Extraction three times with toluene, drying of the combined organic phases using MgSO4 and evaporation give 60.36 g (98.7% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:11])[CH3:10].Cl[Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[CH:4][C:3]=1[CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)c1cc(O)ccc1Br
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cc(O[Si](C)(C)C(C)(C)C)ccc1Br
Yield: 86.8 %

Procedure:
A solution of 4-bromo-3-isopropyl-phenol (Intermediate 144, 1.13 g, 5.25 mmols), chloro-tert-butyl-dimethylsilane (0.95 g, 6.30 mmols), and imidazole (428.0 mg, 6.3 mmols) in 10 mL DMF was stirred at 25° C. for 3 hours. The solution was diluted with H2O and extracted with Et2O and the combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (MgSO4) before being concentrated under reduced pressure. Column chromatography (1-2% EtOAc-hexanes) afforded 1.50 g (87%) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:8]([OH:10])=[O:9])[N:6]=1.[C:19](OC(=O)C)(=[O:21])C.C(=O)(O)[O-].[Na+].Cl>C(O)=O>[CH:19]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:8]([OH:10])=[O:9])[N:6]=1)=[O:21]
Reactant: Nc1nc(C(=NOC2CCCCC2)C(=O)O)cs1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: O=CNc1nc(C(=NOC2CCCCC2)C(=O)O)cs1
Yield: 60.4 %

Procedure:
2-(2-Aminothiazol-4-yl)-2-cyclohexyloxyiminoacetic acid (syn isomer, 1.5 g.), acetic anhydride (2.27 g.) and formic acid (1.03 g.) were treated in a similar manner to that of Example F-(5), and the oil obtained was suspended in an aqueous solution of sodium bicarbonate. The suspension was adjusted to pH 3.5 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water and dried to give 2-(2-formamidothiazol-4-yl)-2-cyclohexyloxyiminoacetic acid (syn isomer, 1.0 g.), mp. above 230° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11][CH2:10][CH2:9]1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1>C1(C)C=CC=CC=1.O1CCOCC1>[CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:43]
Reactant: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)C1(CCNC(=O)OC(C)(C)C)CCCC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=S)C1(CCNC(=O)OC(C)(C)C)CCCC1
Reaction time: 24 h
Yield: 74.4 %

Procedure:
To a solution of N-[[1-[2-[[(1,1-dimethylethoxy)carbonyl]amino]ethyl]cyclopentyl]carbonyl]-4-nitro-L-phenylalanine methyl ester (1.00 g, 2.16 mmol) in toluene/dioxane (1:1, 10 mL) was added Lawesson's reagent (0.524 g, 1.29 mmol). The resultant mixture was warmed to 50° C. and was stirred for 24 h. The reaction mixture was filtered through a sintered glass funnel and the filtrate was concentrated in vacuo. Purification of the crude product by silica gel flash column chromatography (hexane-ethyl acetate, 6:1 then 4:1), afforded N-[[1-[2-[[(1,1-dimethylethoxy)carbonyl]amino]ethyl]cyclopentyl]thioxomethyl]-4-nitro-L-phenylalanine methyl ester (460 mg, 44%; 65% based on recovered starting material) as a light yellow oil. HR MS: Obs. mass, 478.2014. Calcd. mass, 478.2012 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[O:10](C(OC(C)(C)C)=O)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=O>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:10])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:10])[N:3]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Cc1cc(Cl)nc(N)n1
Agent: CN(C)c1ccncc1
Product: Cc1cc(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1

Procedure:
Method 24 was followed using 4-chloro-6-methylpyrimidin-2-amine (1.0 equiv.), BOC2O (2.0 equiv.), and DMAP (cat.) to afford 4-chloro-N,N-di-BOC-6-methylpyrimidin-2-amine in 71%. LCMS (m/z): 344.2 (MH+); LC Rt=4.3 min.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20]>C(OCC)C>[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:20]
Reactant: Oc1ccccc1
Reactant: O=C(Cl)c1cccc(Br)c1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(Oc1ccccc1)c1cccc(Br)c1

Procedure:
To a solution of phenol (2.3 g, 24.4 mmol) and triethylamine (3.2 g, 32 mmol) in diethyl ether (150 mL) was slowly added 3-bromobenzoyl chloride (5 g, 22.8 mmol) and the mixture was heated to reflux for about 1 hour. The mixture was cooled, filtered, and the filtrate was successively washed with water, 0.2N hydrochloric acid, and saturated aqueous sodium carbonate. The organic layer was dried (MgSO4), filtered, and concentrated under vacuum. The residue was triturated with hexane and dried under vacuum to provide the desired product. 1H NMR (500 MHz, CDCl3) δ 7.22 (m, 3H), 7.42 (m, 3H), 7.79 (d, J=8 Hz, 1H), 8.15 (d, J=8 Hz, 1H), 8.37 (br s, 1H).
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][NH:9][N:8]=1.[C:17](O)([CH2:20][CH3:21])([CH3:19])[CH3:18]>C(OCC)(=O)C>[Br:6][C:7]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][N:9]([C:17]([CH2:20][CH3:21])([CH3:19])[CH3:18])[N:8]=1
Reactant: CCC(C)(C)O
Reactant: CCOC(=O)c1c[nH]nc1Br
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(C(C)(C)CC)nc1Br
Temperature: 100 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
Concentrated sulfuric acid (0.45 mL, 4.8 mmol) was added to a mixture of ethyl 3-bromo-1H-pyrazole-4-carboxylate (1.0 g, 4.6 mmol) and tert-amyl alcohol (3.0 mL, 27 mmol). The reaction was heated to 100° C. for 2.5 hours. The reaction was then cooled to room temperature and left stirring overnight. The reaction was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated to yield ethyl 3-bromo-1-tert-pentyl-1H-pyrazole-4-carboxylate (1.3 g) as a crude brown oil.