Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+:25]([O-:27])=[O:26])=[C:11]([CH:22]=[CH:23][CH:24]=1)[C:12]([O:14]CC1C=CC=CC=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[C:10]([N+:25]([O-:27])=[O:26])=[C:11]([CH:22]=[CH:23][CH:24]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)c1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 5 h
Yield: 101.5 %

Procedure:
To 20.7 g of benzyl 3-benzyloxy-2-nitrobenzoate were added 100 ml of ethanol and 120 ml of 1N aqueous solution of sodium hydroxide and the mixture was stirred at room temperature for one night, at 60° C. for 3 hours and at 80° C. for 5 hours. After ethanol was evaporated in vacuo, the resulting aqueous solution was washed with ether and hydrochloric acid was added. The resulting precipitate was filtered and dried in vacuo to give 15.8 g of 3-benzyloxy-2-nitrobenzoic acid.
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5](Br)[N:4]([CH3:11])[N:3]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13].O>C(O)C>[Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([NH:16][C:12]([CH3:15])([CH3:14])[CH3:13])[N:4]([CH3:11])[N:3]=1
Reactant: CC(C)(C)N
Reactant: Cn1nc(Br)c([N+](=O)[O-])c1Br
Solvent: CCO
Solvent: O
Product: Cn1nc(Br)c([N+](=O)[O-])c1NC(C)(C)C
Yield: 78 %

Procedure:
1.5 g (5.26 mmoles) of 3,5-dibromo-1-methyl-4-nitropyrazole are heated in a solution of 20 ml tert-butylamine in 30 ml ethanol for 20 hours at boiling temperature. After cooling, the reaction mixture is poured on 150 ml water, the separated product is filtered and washed with 100 ml water. After vacuum drying, 1.14 g (78 percent of theory) of 3-bromo-5-tert-butylamino-1-methyl-4-nitropyrazole are obtained in the form of pale yellow flakes with a melting point of 75° to 77° C.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:12][C:13]1[N:14]=[CH:15][N:16]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=2)[CH:17]=1
Reactant: Cc1c[nH]cn1
Reactant: COC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2cnc(C)c2)cc1
Temperature: 110 °C
Reaction time: 24 h
Yield: 9.8 %

Procedure:
A mixture of methyl 4-fluorobenzoate (1.00 g, 6.49 mmol), 4-methylimidazole (559 mg, 6.81 mmol), potassium carbonate (941 mg, 6.81 mmol) and DMF (30 ml) was stirred at 110° C. for 24 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was subjected to column chromatography using basic silica gel and eluted with ethyl acetate-methanol (1:0-1:1, v/v) to give the title compound (137 mg, 10%) as a colorless oil.
Reaction SMILES: O[C:2]1([CH3:10])[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH2:3]1.[C:11]([O-:14])([O-])=O.[K+].[K+].FC1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>CN(C=O)C>[CH:5]([C:4]1[CH:7]=[CH:8][C:9]([O:14][C:11]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)=[C:2]([CH3:10])[CH:3]=1)=[O:6]
Reactant: CC1(O)C=CC=C(C=O)C1
Reactant: N#Cc1ccc(F)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C=O)ccc1Oc1ccc(C#N)cc1
Temperature: 130 °C
Yield: 51.8 %

Procedure:
Dissolve 3-hydroxy-3-methyl-benzaldehyde (1.02 g, 7.49 mmol) in DMF (10 mL), add K2CO3 (1.45 g, 10.49 mmol) and 4-fluorobenzonitrile (906 mg, 7.49 mmol), heat the mixture at 130° C. overnight. Add water and extract the aqueous layer with EtOAc. Combine organic layers and dry over Na2SO4. Eliminate the solvent and purify by flash chromatography on silica gel (eluent: EtOAc/hexane 15/85) to give the title compound (920 mg, 52%). TLC: Rf in EtOAc/hexane 20/80: 0.32. 1H-NMR (CDCl3, 200 MHz): 9.96 (s, 1H), 7.84-7.61 (m, 4H), 7.05-6.98 (m, 3H), 2.31 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:51])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C@@H:16]([CH2:47][C:48](O)=[O:49])[CH2:15]2)=[CH:10][CH:9]=1.ClC(N(C)C)=C(C)C.[C:60]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])(=[O:63])[NH:61][NH2:62].CCN(CC)CC>C(Cl)Cl>[C:65]([O:64][C:60]([NH:61][NH:62][C:48](=[O:49])[CH2:47][C@H:16]1[CH2:15][C@H:14]([C:11]2[CH:12]=[CH:13][C:8]([CH2:7][O:6][CH2:5][C@@H:4]([CH3:51])[CH2:3][O:2][CH3:1])=[CH:9][CH:10]=2)[C@@H:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=3[CH:36]=2)[CH2:18][N:17]1[S:37]([C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=1)(=[O:39])=[O:38])=[O:63])([CH3:68])([CH3:67])[CH3:66]
Reactant: CC(C)(C)OC(=O)NN
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)O)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)NNC(=O)OC(C)(C)C)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 1 mmol of [(2R,4R,5R)-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-acetic acid (example 1g) in 5 ml of CH2Cl2 is treated at RT with 1.5 mmol of 1-chloro-N,N,2-trimethylpropenylamine, and stirred at RT for 2.5 h. This solution is added slowly, at 0° C., to a solution of 5 mmol of tert-butyl carbazate [870-46-2] and 5 mmol of Et3N in 1 ml of CH2Cl2. The reaction mixture is stirred at 4° C. for 16.5 h, then quenched with H2O. The aqueous layer is extracted with CH2Cl2 (2×). The combined organic extracts are washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a yellow oil. Rf=0.34 (EtOAc/Heptane 2:1); Rt=5.28 (gradient I).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13]1[CH:14]=[C:15]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1)[CH3:11]>C(O)CO>[Cl:1][C:2]1[N:7]=[C:6]([NH:23][CH:20]2[CH2:21][CH2:22][N:17]([CH2:16][C:15]3[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:13]([O:12][CH2:10][CH3:11])[CH:14]=3)[CH2:18][CH2:19]2)[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Reactant: Cc1cnc(Cl)nc1Cl
Solvent: OCCO
Product: CCOc1cc(CN2CCC(Nc3nc(Cl)ncc3C)CC2)ccc1OC
Yield: 7 %

Procedure:
A solution of 2,4-dichloro-5-methyl-pyrimidine (16.3 mg, 0.10 mmol, 1.0 equiv; commercially available) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (39.7 mg, 0.15 mmol, 1.5 equiv; intermediate A1) in ethylene glycol (2 mL) was heated by microwave irradiation to 200° C. for 15 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 4.0 mg (7%) of the title compound. MS (ESI): 391.4 [M+H]+.
Reaction SMILES: CN1CCOCC1.[CH:8]1([CH2:13][C@H:14]([CH2:35][N:36]([CH:45]=[O:46])[O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:15]([N:17]2[C@H:21]([C:22]([OH:24])=O)[CH2:20][CH2:19][N:18]2[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9]1.COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[CH3:64][N:65]([CH3:78])[C@H:66]1[CH2:70][CH2:69][N:68]([C:71]2[N:76]=[C:75]([NH2:77])[CH:74]=[CH:73][N:72]=2)[CH2:67]1>C(#N)C.C(Cl)Cl>[CH:8]1([CH2:13][C@H:14]([CH2:35][N:36]([CH:45]=[O:46])[O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:15]([N:17]2[C@H:21]([C:22]([NH:77][C:75]3[CH:74]=[CH:73][N:72]=[C:71]([N:68]4[CH2:69][CH2:70][C@H:66]([N:65]([CH3:78])[CH3:64])[CH2:67]4)[N:76]=3)=[O:24])[CH2:20][CH2:19][N:18]2[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CN(C)[C@H]1CCN(c2nccc(N)n2)C1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Solvent: CC#N
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CN(C)[C@H]1CCN(c2nccc(NC(=O)[C@@H]3CCN(C(=O)OCc4ccccc4)N3C(=O)[C@H](CC3CCCC3)CN(C=O)OCc3ccccc3)n2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 44.8 %

Procedure:
4-Methylmorpholine (36.8 μl, 0.335 mmol) was added into the solution of (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (150 mg, 0.279 mmol) and 4-[4,6-bis(methyloxy)-1,3,5-triazin-2-yl]-4-methylmorpholin-4-ium (110 mg, 0.335 mmol) in acetonitrile (4.7 ml). The resulting solution was cooled to 0° C., and it was stirred at 0° C. for 15 min. To the reaction mixture was added 2-[(3S)-3-(dimethylamino)-1-pyrrolidinyl]-4-pyrimidinamine (69.4 mg, 0.335 mmol). After stirring for 2 days at ambient temperature, the reaction mixture was concentrated to yield a residue. The residue was dissolved in DCM. The resulting solution was washed with aqueous saturated Na2SO4 and brine, respectively. The solvent was removed to yield a residue again. The residue was purified by RP-HPLC to yield phenylmethyl (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-3-[({2-[(3S)-3-(dimethylamino)-1-pyrrolidinyl]-4-pyrimidinyl}amino)carbonyl]-1-pyrazolidinecarboxylate (91 mg, 0.125 mmol, 45% yield). MS (ES+) m/z 727.2 (MH+).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[NH:22][CH:23]=[CH:24][N:25]=3)[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C[Si](C)(C)[O:40][NH2:41].CO>O1CCCC1>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[NH:22][CH:23]=[CH:24][N:25]=3)[N:16]=2)[CH2:11][C:12]([NH:41][OH:40])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)ON
Reactant: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(Cc2ncc[nH]2)no1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CO
Solvent: C1CCOC1
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(Cc2ncc[nH]2)no1)NO
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-[3-(1H-imidazol-2-ylmethyl)-1,2,4-oxadiazol-5-yl]hexanoic acid (Preparation 103) (200 mg, 0.43 mmol) in anhydrous tetrahydrofuran (5 ml) was treated with 1,1′-carbonyidiimidazole (77 mg, 0.48 mmol) and stirred under a nitrogen atmosphere for 30 minutes. O-(Trimethylsilyl)hydroxylamine (160 μl, 1.30 mmol) was added and the mixture was stirred for 18 hours. The mixture was then treated with methanol (4 ml) and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 90:10:1 (dichloromethane:methanol:ammonia) to afford a colourless oil which began to crystallise once a little methanol and dichloromethane were added. The solid was triturated with dichloromethane and dried under reduced pressure to afford the title compound as a solid (49 mg).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=2[C:16]2[C:17]3[CH:26]=[CH:25][NH:24][C:18]=3[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=2)=[CH:4][CH:3]=1.CN1C=C(C2C=C([N+]([O-])=O)C=CC=2OC2C=CC=CC=2)C2C=CNC=2C1=O>>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:27]=[CH:28][C:2]([F:1])=[CH:3][CH:4]=2)=[C:8]([C:16]2[C:17]3[CH:26]=[CH:25][NH:24][C:18]=3[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=2)[CH:9]=1
Reactant: Cn1cc(-c2cc([N+](=O)[O-])ccc2Oc2ccc(F)cc2)c2cc[nH]c2c1=O
Agent: Cn1cc(-c2cc([N+](=O)[O-])ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Product: Cn1cc(-c2cc(N)ccc2Oc2ccc(F)cc2)c2cc[nH]c2c1=O

Procedure:
Example 26b was prepared according to the procedure used for the preparation of Example 3, substituting the product of Example 26a for the product of Example 2b, to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[C:21]([F:28])[C:3]=1[O:4][C:5]1[N:9]([CH3:10])[N:8]=[C:7]([CH3:11])[C:6]=1[C:12]1[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=1[F:20].[Cl-].[NH4+].O>C(O)C.C(OCC)(=O)C.[Fe]>[CH3:10][N:9]1[C:5]([O:4][C:3]2[C:2]([F:1])=[CH:24][C:23]([NH2:25])=[CH:22][C:21]=2[F:28])=[C:6]([C:12]2[C:13]([F:20])=[CH:14][C:15]([F:19])=[CH:16][C:17]=2[F:18])[C:7]([CH3:11])=[N:8]1
Reactant: Cc1nn(C)c(Oc2c(F)cc([N+](=O)[O-])cc2F)c1-c1c(F)cc(F)cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nn(C)c(Oc2c(F)cc(N)cc2F)c1-c1c(F)cc(F)cc1F
Reaction time: 0.5 h

Procedure:
5-(2,6-Difluoro-4-nitrophenoxy)-1,3-dimethyl-4-(2,4,6-trifluorophenyl)-1H-pyrazole (i.e. the product of Synthesis Example 8) (0.780 g, 1.95 mmol) was combined with iron powder (325 mesh, 0.58 g, 10 mmol) and ammonium chloride (64 mg, 1.2 mmol) in ethanol (27 mL) to which water (3 mL) had been added. The mixture was heated at reflux for 1.25 h and then allowed to cool. The reaction mixture was diluted with an equal volume of ethyl acetate and filtered through Celite filter aid. The filtrate was dried with MgSO4 and concentrated. Analysis by LC/MS showed the major component (93%) to have mass 370 amu (AP+). The residue was dissolved in anhydrous dimethyl sulfoxide (8 mL), and a commercial solution of sodium methoxide in methanol (0.45 mL of 25% solution) was added. This solution was stirred under nitrogen and heated at reflux for 1 h. Additional sodium methoxide/methanol solution (0.20 mL) was added, and heating was continued for an additional 30 minutes. The reaction mixture was allowed to cool, and it was then treated with aqueous citric acid solution (1 M, 5 mL), diluted with water (50 mL) and extracted with ethyl acetate (2×25 mL). The organic phase was washed with water (3×) and with brine, dried over MgSO4, and concentrated to leave the title product, a compound of the present invention, as a viscous oil (0.52 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C>ClCCl.C1COCC1>[CH2:17]([O:16][C:14]1[C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=[C:6]([CH2:4][OH:3])[CH:15]=1)[CH3:18]
Reactant: CCOC(=O)c1cc(OCC)c2[nH]c(=O)oc2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOc1cc(CO)cc2oc(=O)[nH]c12
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of 4-ethoxy-2-oxo-2,3-dihydro-benzooxazole-6-carboxylic acid ethyl ester (1.1 g, 4.38 mmol, 1.0 equiv; prepared as described in I. Kompis, A. Wick Helv. Chim. Acta 1977, 60, 3025-3034) in a mixture of dichloromethane (20 mL) and THF (10 mL) at −78° C. under Ar was slowly added diisobutylaluminium hydride (14.0 mL, 14.02 mmol, 3.2 equiv, 1 M solution in dichloromethane) over a time period of 15 min, the cooling bath removed on completion of addition and the reaction allowed to reach 0° C. After 1 h, the excess hydride was quenched by cautious addition of a sat. solution of potassium sodium tartrate (10 mL). The solidified mixture was extracted with hot THF, the combined organic phases concentrated by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with hexane/ethyl acetate (1:2) providing 0.69 g (75%) of the title compound. 1H NMR (300 MHz, DMSO): δ 1.37 (t, J=7.0 Hz, 3H), 4.15 (q, J=7.0 Hz, 2H), 4.49 (d, J=5.6 Hz, 2H), 5.21 (t, J=5.6 Hz, 1H), 6.82 (s, 1H), 6.85 (s, 1H), 11.64 (br s, 1H). 13C NMR (75 MHz, DMSO): δ 14.61, 62.89, 64.26, 100.74, 106.46, 117.80, 137.50, 142.74, 144.05, 154.54. MS (ISP): 209.8 [M+H]+.
Reaction SMILES: N1C=CC=CC=1.[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][NH2:15].[Cl:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[CH:23]=[C:24]([C:26]([O-])=[O:27])[S:25][C:18]=12.[Li+]>>[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][NH:15][C:26]([C:24]1[S:25][C:18]2[C:19](=[N:20][CH:21]=[CH:22][C:17]=2[Cl:16])[CH:23]=1)=[O:27]
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: NCCc1ccccn1
Agent: [Li+]
Solvent: c1ccncc1
Product: O=C(NCCc1ccccn1)c1cc2nccc(Cl)c2s1

Procedure:
The title compound was prepared from 2-pyridine-2-yl-ethylamine pyridine and lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate by a procedure analogous to Example 1B. MS: 318/320 (MH+); HPLC Rf: 4.33 min.; HPLC purity: 97%.
Reaction SMILES: CN(C)[CH:3]=[O:4].C(Cl)(=O)C(Cl)=O.[CH3:12][O:13][C:14]1[CH:18]=[CH:17][O:16][CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:3][O:4][C:18]=1[CH:17]=[O:16]
Reactant: COc1ccoc1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccoc1C=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 54.9 %

Procedure:
A 3-L, one-necked, round-bottomed flask was equipped with a Teflon-coated magnetic stirbar. The system was flame-dried and flushed with argon. The flask was charged with a solution of N,N-dimethylformamide (31.9 mL, 413 mmol, 1.35 equiv) in dichloromethane (1.2 L). The solution was cooled to 0° C. in a dry ice-acetone bath, and then oxalyl chloride (32.5 mL, 367 mmol, 1.2 equiv) was added over 16 min. Vigorous bubbling occurred and a white solid precipitated. After stiffing for 20 min, the reaction mixture was cooled to −40° C. by addition of dry ice to the cooling bath and a solution of 3-methoxyfuran (Meister, C.; Scharf, H.-D. Synthesis 1981, 737-739) (30 g, 306 mmol, 1 equiv) in dichloromethane (100 mL) was added via cannula. A dark-brown color formed during the addition. After stiffing for 20 min, the cooling bath was removed and saturated aqueous sodium bicarbonate solution (1.5 L) was added. The biphasic mixture was stirred vigorously for 6 hours, and then was partitioned. The aqueous layer was further extracted with dichloromethane (2×800 mL). The organic layers were combined and the combined layers were dried over sodium sulfate. The solids were filtered and the filtrate was concentrated. The residue obtained was purified by flash-column chromatography on silica gel (100% diethyl ether) to furnish 3-methoxyfurfural 6 (21.2 g, 55%) as a light-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])/[CH:5]=[CH:6]/[C:7]([OH:9])=O.Cl.[CH3:15][CH:16]1[CH2:22][NH:21][CH2:20][CH2:19][NH:18][C:17]1=[O:23]>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:6]/[C:7]([N:21]2[CH2:22][CH:16]([CH3:15])[C:17](=[O:23])[NH:18][CH2:19][CH2:20]2)=[O:9])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: O=C(O)/C=C/c1ccc(Cl)c(Cl)c1
Reactant: CC1CNCCNC1=O
Agent: Cl
Product: CC1CN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCNC1=O

Procedure:
In analogy to the procedure described in intermediate 78C, (E)-3,4-dichlorocinnamic acid and 6-methyl-[1,4]diazepan-5-one hydrochloride gave the title compound as a colorless gum, MS: 327.1 (MH+).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[C:37]([O:43][CH2:44][CH2:45][O:46][CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][O:48]2)[C:36]=1[F:53])=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C>[F:53][C:36]1[C:37]([O:43][CH2:44][CH2:45][O:46][CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][O:48]2)=[CH:38][C:39]([O:41][CH3:42])=[CH:40][C:35]=1[C:21](=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1)[C:20]1[NH:19][C:18](=[O:17])[N:1]([C:3]2[N:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(OCCOC2CCCCO2)c1F
Reactant: NNc1ncccn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(OCCOC2CCCCO2)c(F)c(C(=Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
After adding 13 mg of 2-hydrazinopyrimidine and 0.016 ml of triethylamine to a solution of 69 mg of (2-{2-fluoro-5-methoxy-3-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene)carbamic acid methyl ester in 1 ml of DMF, the mixture was stirred at 85° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated to give a crude product of 5-({2-fluoro-5-methoxy-3-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]methyl)-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one.
Reaction SMILES: [ClH:1].Cl.[C:3]([C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([CH2:16][CH:17]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[CH:25][CH:24]=3)[C:18]([O:20]CC)=[O:19])=[CH:13]2)=[CH:8][CH:7]=1)(=[NH:5])[NH2:4]>Cl>[OH2:19].[ClH:1].[C:3]([C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([CH2:16][CH:17]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[CH:25][CH:24]=3)[C:18]([OH:20])=[O:19])=[CH:13]2)=[CH:8][CH:7]=1)(=[NH:4])[NH2:5]
Reactant: CCOC(=O)C(Cc1ccc2ccc(C(=N)N)cc2c1)c1ccc(OCC2CCNCC2)cc1
Agent: Cl
Product: N=C(N)c1ccc2ccc(CC(C(=O)O)c3ccc(OCC4CCNCC4)cc3)cc2c1
Product: O
Reaction time: 62 h
Yield: 114.6 %

Procedure:
1.51 g of ethyl 3-(7-amidino-2-naphthyl)-2-[4-[(4-piperidinyl)methoxy]phenyl]propionate dihydrochloride was dissolved in 50 ml of concentrated hydrochloric acid, and the solution was allowed to stand still in a sealed container at room temperature for 62 hours. After drying the resulting reaction solution under a reduced pressure, the thus obtained residue was purified by applying it to a column packed with a highly porous polymer type synthetic adsorbent (styrene-divinylbenzene polymer: HP-20). Thereafter, the thus eluted fractions of interest were pooled, and mixed with a small amount of ethanol, and then the crystals thus precipitated were collected by filtration. In this way, 0.79 g of the title compound was obtained in the form of crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.[OH-].[K+].Cl[C:13]([F:23])([F:22])C(C1C=CC=CC=1)=O>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:13]([F:23])[F:22])=[C:4]([Cl:9])[CH:3]=1
Reactant: O=C(c1ccccc1)C(F)(F)Cl
Reactant: Oc1ccc(Br)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: FC(F)Oc1ccc(Br)cc1Cl
Temperature: 80 °C
Reaction time: 40 h
Yield: 52 %

Procedure:
A solution of 4-bromo-2-chlorophenol (830 mg) and a 30% potassium hydroxide solution (16 mL) in acetonitrile (16 mL) was cooled to −78° C. 2-Chloro-2,2-difluoroacetophenone (2.95 mL) was added and the mixture was stirred at 80° C. for 40 hours. The reaction solution was cooled to room temperature and extracted with diethyl ether. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1→10:1) to give 4-bromo-2-chloro-1-(difluoromethoxy)benzene as a colorless oil (533 mg, 52%).