Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:14]=[C:13]2[C:7]([N:8]([CH3:16])[C:9](=[O:15])[CH2:10][CH2:11][NH:12]2)=[CH:6][N:5]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[NH4+]>CC(N(C)C)=O.CO>[CH2:17]([N:12]1[CH2:11][CH2:10][C:9](=[O:15])[N:8]([CH3:16])[C:7]2[C:13]1=[N:14][C:4]([Cl:3])=[N:5][CH:6]=2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CN1C(=O)CCNc2nc(Cl)ncc21
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CC(=O)N(C)C
Solvent: CO
Product: CN1C(=O)CCN(Cc2ccccc2)c2nc(Cl)ncc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a cooled (ice/water bath) suspension of sodium hydride (60% dispersion in mineral oil; 6.5 mg, 0.16 mmol) in DMA (0.5 mL) was added a solution of 10-chloro-6-methyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 100; 32 mg, 0.15 mmol) in DMA (1.0 mL). The reaction mixture was allowed to stir, under nitrogen, in an ice bath for 15 minutes prior to addition of Benzyl bromide (Aldrich; 20 μl, 0.17 mmol). The reaction mixture was stirred on an ice bath for 15 minutes and then at ambient temperature for 3 hrs A further addition of Sodium hydride (2 mg) was made and stirring continued for 6 hrs. Saturated ammonium chloride (0.5 ml) was added and the reaction mixture poured directly onto an SCX-3 cartridge (2 g). The cartridge was washed with methanol (˜30 mL) before eluting products with 2M ammonia in methanol (˜30 mL). Product containing fractions were evaporated to dryness to give a colourless gum, which was combined with the cartridge methanol pre-wash and this solution evaporated to dryness. The resultant material was partitioned between DCM (10 mL) and water (10 mL). The organic phase was collected by gravity elution through a PTFE filter cup and evaporated to give the title compound as a pale yellow opaque gum (46 mg, 89%)
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:21]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3C(C)=NO[N:16]=3)[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CC[C@H](OC(=O)C(F)(F)F)C2)C2N=NNC=2N=1)(C)(C)C.Cl[CH2:53][C:54]1[O:55]C(C)=N[N:58]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:21]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[O:55][C:54]([CH3:53])=[N:58][N:16]=3)[N:13]=2)[N:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1nonc1Cn1nc2nc(C(C)(C)C)nc(N3CC[C@H](O)C3)c2n1
Reactant: Cc1nnc(CCl)o1
Agent: CC(C)(C)c1nc(N2CC[C@H](OC(=O)C(F)(F)F)C2)c2nn[nH]c2n1
Product: Cc1nnc(Cn2nc3nc(C(C)(C)C)nc(N4CC[C@H](O)C4)c3n2)o1

Procedure:
In analogy to the procedure described for the synthesis of (S)-1-[5-tert-Butyl-2-(4-methyl-furazan-3-ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol (example 73), the title compound was prepared from Trifluoro-acetic acid (S)-1-(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-yl-ester and 2-(chloromethyl)-5-methyl-1,3,4-oxadiazole and isolated as light yellow gum. MS (m/e): 359.5 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].[N+:10]([O-])([O-])=O.[NH4+].N>C(O)C>[NH2:10]/[C:3](/[C:2]([CH3:9])([CH3:8])[CH3:1])=[CH:4]\[C:5]#[N:6]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(C)(C)C(=O)CC#N
Agent: N
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)/C(N)=C/C#N
Temperature: 25 °C

Procedure:
To a solution of 4,4-dimethyl-3-oxo-pentanenitrile (22 g, 175.76 mmol) in 250 mL of ethanol is added ammonium nitrate (21 g; 263.64 mmol). The mixture is stirred under reflux overnight while ammonia gas is bubbled through the solution. The mixture is cooled to room temperature and diluted with 100 mL of water. The mixture is concentrated under reduced pressure to remove most of the ethanol. Aqueous sodium hydroxide (140 mL, 0.3N) is added and the mixture is extracted with ether (2×200 mL). The combined organic layers are washed with 50 mL of water, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford title compound. Assumed quantitative yield and used crude in subsequent reaction. ESI m/z 125=MH+
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH:10]([NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C:11]([O:13][CH3:14])=[O:12].C(N(CC)CC)C.Cl[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C)C=O>[CH2:19]([O:18][C:16]([NH:15][CH:10]([CH2:9][NH:8][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:11]([O:13][CH3:14])=[O:12])=[O:17])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)C(CN)NC(=O)OCc1ccccc1
Reactant: CCOC(=O)CCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CNCC(NC(=O)OCc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of methyl 3-amino-2-([(benzyloxy)carbonyl]amino]propanoate trifluoroacetate (8.9 g) and triethylamine (30.6 ml) in dimethylformamide (89 ml) was treated by a slow dropwise addition of a solution of ethyl chloroacetate (7.8 ml) in dimethylformamide (20 ml). After stirring at room temperature for 12 hours, triethylamine (20.4 ml) was added again, and the mixture was treated by a slow dropwise addition of a solution of ethyl chloroacetate (5.2 ml) in dimethylformamide (15 ml) and stirred at room temperature for further 6 hours. The system was partitioned between water and ethyl acetate and the organic phase was washed with saturated brine, dried (MgSO2) and concentrated under reduced pressure. The residue was purified by a column chromatography on a silica gel (hexane:ethyl acetate=1:4) to obtain methyl 2-[[(benzyloxy)carbonyl]amino]-3-((2-ethoxy-2-oxoethyl)amino]propanoate (6.6 g) as a colorless oil.
Reaction SMILES: N[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH3:14].N([O-])=O.[Na+].[F:19][B-](F)(F)F.[H+]>O>[F:19][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH3:14]
Reactant: F[B-](F)(F)F
Reactant: Cc1c(N)ccc(C#N)c1C(F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: Cc1c(F)ccc(C#N)c1C(F)(F)F
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
4-amino-3-methyl-2-(trifluoromethyl)benzonitrile (CAS 573764-86-0, 2.0 g, 9.99 mmol) was dissolved in fluoroboric acid, HBF4 solution (15 mL) at −10° C. (ice/MeOH). To the pre-cooled solution was added NaNO2 (689 mg, 9.992 mmol) in 2 mL H2O drop by drop under constant stirring. The reaction mixture was allowed to stir for 15 min at −10° C. and filtered off. The white residue was washed with cold EtOH and cold ether to get the diazosalt as a white crystalline solid. The salt is dried over high vacuum for 4-5 h. to provide 1.9 g. The salt was heated up (>250° C.) and sublimed under reduced pressure to get the crude fluoro compound as an oil. The oil is chromatographed to get the pure 4-fluoro-3-methyl-2-(trifluoromethyl)benzonitrile as a clear oil (700 mg): 1H NMR (400 MHz, CDCl3, δ in ppm) 7.68 (dd, J=5.0, 9.0 Hz, 1H), 7.33 (t, J=9 Hz, 1H), 2.43 (quin, J=2 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH2:16][CH2:15][O:14][CH:13]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:12]1>>[CH3:7][N:6]1[C:2]([N:11]2[CH2:16][CH2:15][O:14][CH:13]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:12]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: CC(C)(C)OC(=O)NCC1CNCCO1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Product: Cn1ncc([N+](=O)[O-])c1N1CCOC(CNC(=O)OC(C)(C)C)C1
Yield: 93 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and tert-butyl morpholin-2-ylmethylcarbamate gave tert-butyl (4-(1-methyl-4-nitro-1H-pyrazol-5-yl)morpholin-2-yl)methylcarbamate as a yellow oil (196 mg, 93%). 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 4.92 (s br, 1H), 4.00 (dd, J=11.3, 2.9 Hz, 1H), 3.90-3.68 (m, 5H), 3.57 (td, J=11.6, 3.2 Hz, 1H), 3.38-3.24 (m, 2H), 3.15 (ddd, J=14.1, 7.1, 5.1 Hz, 1H), 2.86 (d, J=11.8 Hz, 1H), 2.77 (d, J=11.8 Hz, 1H), 1.45 (s, 9H)
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[O:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:14][N:13]=2)=[CH:7][N:6]=1.[N:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>CCOC(C)=O.O.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[C:22]1([C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]([NH:11][C:8]3[CH:7]=[N:6][C:5]([O:4][C:3]4[CH:28]=[CH:29][CH:30]=[CH:31][C:2]=4[C:35]4[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=4)=[N:10][CH:9]=3)=[N:13][N:14]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1ccncc1
Reactant: Brc1ccccc1Oc1ncc(Nc2nnc(-c3ccccc3)c3ccccc23)cn1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc(-c2nnc(Nc3cnc(Oc4ccccc4-c4ccncc4)nc3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In an argon-purged sealed tube, N-(2-(2-bromophenoxy)pyrimidin-5-yl)-4-phenylphthalazin-1-amine (150 mg, 319 μmol), pyridin-4-ylboronic acid (157 mg, 1.27 μmol), Pd(DPPF)Cl2 (47 mg, 64 μmol), sodium carbonate (239 μl, 478 μmol), and 1,4-dioxane (1.60 ml, 319 μmol) were added. The reaction was stirred at RT for 5 min. The tube was sealed and heated to 100° C. for 18 h. After 16 h, the reaction was cooled to RT, diluted with EtOAc and 10 mL of water. The product was extracted into EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The product was purified by column chromatography on silica gel using 60:40 DCM:(90:10:1 DCM:MeOH:NH4OH). The resulting light brown solid was dissolved in 15 mL of DCM, the solvent were removed under vacuum, affording the title compound as a light brown solid. MS Calcd for C29H20N6O: [M]+=468. Found: [M+H]+=469.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][C:13]4([CH2:18][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1)[O:17][CH2:16][CH2:15][O:14]4.[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][C:21]=1[Cl:27].Cl>C(O)C>[Cl:27][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[C:3]3[C:10]4[CH2:11][CH2:12][C:13]5([CH2:18][C:9]=4[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[O:17][CH2:16][CH2:15][O:14]5)[CH:25]=[CH:26][C:20]=1[F:19]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Clc1ncnc2sc3c(c12)CCC1(C3)OCCO1
Agent: Cl
Solvent: CCO
Product: Fc1ccc(Nc2ncnc3sc4c(c23)CCC2(C4)OCCO2)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.6 %

Procedure:
To a stirring solution of 4-chloro-5,8-dihydro-6H-spiro[1-benzothieno[2,3-d]pyrimidine-7,2′-[1,3]dioxolane] (7.0 g, 24.8 mmol) in ethanol (100 mL) was added 4-fluoro-3-chloroaniline (3.6 g, 24.8 mmol) and HCl (4N in dioxane, 0.05 mL). The contents were heated to reflux for 5 h, after which time the contents were removed from heating and allowed to cool to rt. The solvent was removed under reduced pressure, the crude residue suspended in aq NaHCO3 (100 mL), and stirred for 15 min. The contents were again filtered, and the solid filter cake washed with water. The collected yellow solid was triturated with diethyl ether (50 mL) to afford the final product (5.5 g, 57%) as a light yellow solid. 1H-NMR (DMSO-d6) δ 8.41 (s, 1H), 8.28 (s, 1H), 7.78 (dd, 1H), 7.58 (m, 1H), 7.35 (t, 1H), 3.97 (s, 4H), 3.22 (t, 2H), 3.00 (s, 2H), 1.93 (t, 2H); LCMS RT=3.26 min; [M+H]+=392.3.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:11]N1C(=O)CCC1=O>CN(C=O)C>[Br:11][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([N+:8]([O-:10])=[O:9])[N:4]=1
Reactant: O=[N+]([O-])c1ncccc1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1nc(Br)ccc1O
Temperature: 0 °C
Reaction time: 15 h
Yield: 115.1 %

Procedure:
3-Hydroxy-2-nitropyridine (100 g, 0.714 mole) was dissolved in DMF (1 L), the solution was cooled to 0° C., and N-bromosuccinimide (165 g, 0.927 mole) was added portionwise over 5 hr. The mixture was then stirred at RT for 15 hr and concentrated in vacuo. The residue was taken up in Et2O (500 mL) and the mixture was stirred for 30 min. The precipitate was removed by suction filtration, and the filtrate was concentrated in vacuo to afford the title compound (180 g): MS (ES) m/e 219.0 (M+H)+. This material was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.OC1C2N=N[NH:17][C:16]=2C=CC=1.C(N(C(C)C)CC)(C)C.CN>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:17][CH3:16])=[O:7])=[CH:4][CH:3]=1
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(O)c1ccc(Br)cc1
Agent: CN
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-bromobenzoic acid (300 mg, 1.49 mmol), hydroxybenzotriazole (1.1 eq), 1(3-dimethylaminoprpyl)-3-ethylcarbodiimide HCl (1.1 eq) and diisopropylethylamine (2 eq) in DMF (2 mL) was stirred at rt for 20 min. Methylamine (1 eq) was added and the reaction stirred at rt for 16 h then quenched with saturated aqueous sodium hydrogencarbonate solution and extracted into ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo to give 4-bromo-N-methylbenzamide. 1H NMR (d6-DMSO) δ 10.07 (s, 1H), 9.03 (s, 1H), 8.56 (s, 1H), 8.38 (s, 1H), 8.32-8.36 (m, 2H), 8.05-8.09 (m, 2H), 7.94 (s, 1H), 7.67 (s, 1H), 3.87 (s, 3H), 2.83 (d, 3H); LC-MS method B, (ES+) 349.0, RT=6.68 min.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:12]([C:16]([F:19])([F:18])[F:17])[O:13]2)=[CH:8][CH:7]=1)([CH3:5])[CH:3]=O.[CH2:25]([NH2:28])[CH2:26][CH3:27].C([BH3-])#N.[Na+]>CO.CC(O)=O.C1COCC1>[CH3:5][C:2]([C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:12]([C:16]([F:18])([F:17])[F:19])[O:13]2)=[CH:8][CH:7]=1)([CH3:1])[CH2:3][NH:28][CH2:25][CH2:26][CH3:27]
Reactant: CCOC(=O)C1=Cc2ccc(C(C)(C)C=O)cc2OC1C(F)(F)F
Reactant: CCCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CCCNCC(C)(C)c1ccc2c(c1)OC(C(F)(F)F)C(C(=O)OCC)=C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the title product of Example 113 Step 3 (198 mg, 0.579 mmole) in 8 mL of MeOH and 1 mL of HOAc was added n-propylamine (68 mg, 1.2 mmoles), 0.9 mL of 1 M sodium cyanoborohydride in THF, and 1 g of activated 4 Å molecular sieves. The resulting mixture was stirred overnight at room temperature. The mixture was diluted with MeOH, filtered through Celite, concentrated, azeotropically distilled with toluene. Chromatography of the residue over silica gel using 10% MeOH—DCM gave the title compound, 220 mg, as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[NH:25][C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=[C:5]2[C:4]=1[CH2:26][CH3:27])[CH3:2].[H-].[Na+].Br[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].Cl>CN(C=O)C.O>[CH2:1]([C:3]1[N:25]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)[N:10]=[C:5]2[C:4]=1[CH2:26][CH3:27])[CH3:2]
Reactant: CCOC(=O)CCCCCCBr
Reactant: CCc1[nH]c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2c1CC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCCn1c(CC)c(CC)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 6,7-diethyl-2,3-dip-tolyl-5H-pyrrolo[2,3-b]pyrazine (step 1) (14 mg, 0.039 mmol) in dry DMF (1 ml) under nitrogen was treated with NaH (1.733 mg, 0.043 mmol). The resulting mixture was stirred at RT for 20 minutes and treated with ethyl 7-bromoheptanoate (8.44 μl, 0.043 mmol). After stirring at RT for 3 hours, the mixture was added to water and the pH was adjusted to pH1 using 2M HCl. The aqueous was extracted with EtOAc (×3) and the combined organic extracts were sequentially washed with water (×1) and brine (×1), dried (MgSO4), filtered and concentrated under reduced pressure to afford the title compound (with trace hydrolysis acid product present);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH2:17])[CH:13]=2)[N:8]=1.[CH:22]([N:25]=[C:26]=[O:27])([CH3:24])[CH3:23]>C1(C)C=CC=CC=1>[CH:22]([NH:25][C:26]([NH:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:6][CH2:5][C:4]1[CH:18]=[CH:19][CH:20]=[CH:21][C:3]=1[O:2][CH3:1])[CH:16]=[CH:15]2)=[O:27])([CH3:24])[CH3:23]
Reactant: COc1ccccc1CNc1ccc2cc(N)ccc2n1
Reactant: CC(C)N=C=O
Solvent: Cc1ccccc1
Product: COc1ccccc1CNc1ccc2cc(NC(=O)NC(C)C)ccc2n1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
N2-(2-Methoxy-benzyl)-quinoline-2,6-diamine (example 10, step B, 50 mg, 0.179 mmol) was dissolved in 1 mL toluene. Isopropyl isocyanate (15 mg, 0.179 mmol) was added and the reaction mixture was stirred at 60° C. overnight. The reaction mixture was cooled to room temperature and the crystals were filtered off and washed with dichloromethane. The title compound was obtained as an off-white solid (24 mg, 37%), MS: m/e=365.3 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[CH:14]=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[N+:25]([CH3:28])([O-:27])=[O:26]>>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[CH:14]=[CH:13][C:10]=1[CH:11]=[CH:28][N+:25]([O-:27])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(C=O)c(OCc2ccccc2)c1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC(C)c1ccc(C=C[N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To 100 mL of nitromethane were added 10.44 g of 2-benzyloxy-4-isopropylbenzaldehyde and 4.71 g of ammonium acetate. After being stirred at external 100° C. for 3 hours, the reaction mixture was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate, and the organic layer was washed successively with 1 mol/L hydrochloric acid, and saturated aqueous sodium bicarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 9.45 g of 2-benzyloxy-4-isopropyl-1-(2-nitrovinyl)benzene.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:37])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:30]=[N:31][C:32]([CH2:35][CH3:36])=[CH:33][CH:34]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:35]([C:32]1[N:31]=[CH:30][C:29]([C:25]2[CH:24]=[C:23]([C:21]3[CH2:20][C:19](=[O:37])[NH:18][C:9]4[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:28]=[CH:27][CH:26]=2)=[CH:34][CH:33]=1)[CH3:36]
Reactant: CCc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1ccc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from (2-{3-[3-(6-ethyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M173) (257 mg, 0.49 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (134 mg, 67%).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[CH2:17]OS(C)(=O)=O)=[O:6])[CH:2]=[CH2:3].[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1.O.Cl>C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH2:9][C@H:8]1[CH2:17][N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1COS(C)(=O)=O
Reactant: c1c[nH]cn1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1Cn1ccnc1
Reaction time: 7 h
Yield: 65.9 %

Procedure:
A mixture of {2S,4R)-1-allyloxycarbonyl-4-methanesulfonyloxy-2-(methanesulfonyloxy)methylpyrrolidine (8.73 g) and imidazole (4.16 g) was stirred at 70°-75° C. for 7 hours. After cooling, the reaction mixture was dissolved in ethyl acetate (30 ml), water (30 ml) and conc. hydrochloric acid (8.0 ml) with stirring. The aqueous layer was separated, adjusted to pH 9.0 with 10% aqueous sodium hydroxide and extracted twice with ethyl acetate (50 ml). The extract was dried over anhydrous magnesium sulfate and evaporated in vacuo to give (2S,4R)-1-allyloxycarbonyl-2-(imidazol-1-yl)methyl-4-methanesulfonyloxypyrrolidine (5.30 g).
Reaction SMILES: [Br-:1].[C:2]([CH:5](CC)[CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][C:9]1=[CH:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N+:21]([CH3:28])=[CH:20][CH:19]=1)([OH:4])=[O:3].[Br-].C(C(C)CCC[N+]1C2C=CC=CC=2SC=1C)(O)=O.[Br-].CC1SC2C=CC=CC=2[NH+]=1.[Br-].C[N+]1C2C(=CC=CC=2)C(C=C2N(CCCCC(O)=O)C3C=CC=CC=3S2)=CC=1>>[Br-:1].[C:2]([CH2:5][CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][C:9]1=[CH:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N+:21]([CH3:28])=[CH:20][CH:19]=1)([OH:4])=[O:3]
Reactant: CCC(CCN1C(=Cc2cc[n+](C)c3ccccc23)Sc2ccccc21)C(=O)O
Agent: C[n+]1ccc(C=C2Sc3ccccc3N2CCCCC(=O)O)c2ccccc21
Agent: Cc1[nH+]c2ccccc2s1
Agent: Cc1sc2ccccc2[n+]1CCCC(C)C(=O)O
Product: C[n+]1ccc(C=C2Sc3ccccc3N2CCCC(=O)O)c2ccccc21
Yield: 26 %

Procedure:
Furthermore, 4-((3-(3-carboxypentyl)benzo[d]thiazole-2(3H)-ylidene) methyl)-1-methylquinoliniumbromide with a linker (a polymethylene chain linked to a carboxyl group) having a carbon number n of 5 was synthesized from the mixture of 3-(4-carboxypentyl)-2-methylbenzothiazolium bromide and 2-methylbenzothiazolium bromide by the same method as that used for Compound 107, which was obtained with a yield of 26%. The instrumental analytical values are indicated below.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:6]2[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:5]=2[N:4]=1.S(Cl)(Cl)=O.[NH2:25][C:26]1[CH:31]=[C:30]([O:32][C:33]([F:36])([F:35])[F:34])[CH:29]=[CH:28][C:27]=1O.C(N(CC)CC)C.CS(O)(=O)=O.C(=O)([O-])O.[Na+]>O.O1CCCC1>[F:34][C:33]([F:35])([F:36])[O:32][C:30]1[CH:29]=[CH:28][C:27]2[O:20][C:18]([C:16]3[CH:15]=[CH:14][C:6]4[N:7]([CH:8]5[CH2:9][CH2:10][O:11][CH2:12][CH2:13]5)[C:3]([CH3:2])=[N:4][C:5]=4[CH:17]=3)=[N:25][C:26]=2[CH:31]=1
Reactant: Nc1cc(OC(F)(F)F)ccc1O
Reactant: Cc1nc2cc(C(=O)O)ccc2n1C1CCOCC1
Agent: CS(=O)(=O)O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: O
Solvent: O=S(Cl)Cl
Product: Cc1nc2cc(-c3nc4cc(OC(F)(F)F)ccc4o3)ccc2n1C1CCOCC1
Yield: 25.1 %

Procedure:
To 2-methyl-1-(tetrahydropyran-4-yl)benzimidazole-5-carboxylic acid HCl salt (see Working Example 4-3) (182 mg, 0.612 mmol) was added thionyl chloride (2 mL), and this was stirred at reflux for 3 hours. After the reaction was complete, concentration at reduced pressure gave a residue that was added to 2-amino-4-trifluoromethoxyphenol (117 mg, 0.612 mmol), triethylamine (309 mg, 3.06 mmol) and tetrahydrofuran (5 mL), and this was stirred at room temperature for 14 hours. After the reaction was complete, this was concentrated, and to a dioxane (5 mL) solution of the residue obtained was added methanesulfonic acid (353 mg, 1.46 mmol), and this was heated to reflux for 18 hours. After the reaction solution was cooled, water and saturated aqueous sodium hydrogen carbonate solution were added, and this was extracted with chloroform. After the organic layer obtained was dried over anhydrous sodium sulfate, it was filtered and concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (64 mg, 25% yield) as pink crystals.