Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:50][CH:51]1[C@H:55]2[C@H:56](OC3CCCCO3)[N:57](C(OC(C)(C)C)=O)[C:58]3[CH:65]=[CH:64][C:63]([O:66][CH3:67])=[CH:62][C:59]=3[C:60](=[O:61])[N:54]2[CH2:53][C:52]1=[CH2:82])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH:18]1[C@H:22]2[C@H:23](OC3CCCCO3)[N:24](C(OC(C)(C)C)=O)[C:25]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:26]=3[C:27](=[O:28])[N:21]2[CH2:20][C:19]1=[CH2:49].C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:16]([O:17][CH:18]1[C@@H:22]2[CH:23]=[N:24][C:25]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:26]=3[C:27](=[O:28])[N:21]2[CH2:20][C:19]1=[CH2:49])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:50][CH:51]1[C@@H:55]2[CH:56]=[N:57][C:58]3[CH:65]=[CH:64][C:63]([O:66][CH3:67])=[CH:62][C:59]=3[C:60](=[O:61])[N:54]2[CH2:53][C:52]1=[CH2:82]
Reactant: C=C1CN2C(=O)c3cc(OC)ccc3N(C(=O)OC(C)(C)C)[C@@H](OC3CCCCO3)[C@@H]2C1OCCCCCCCCCOC1C(=C)CN2C(=O)c3cc(OC)ccc3N(C(=O)OC(C)(C)C)[C@@H](OC3CCCCO3)[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C=C1CN2C(=O)c3cc(OC)ccc3N=C[C@H]2C1OCCCCCCCCCOC1C(=C)CN2C(=O)c3cc(OC)ccc3N=C[C@@H]12
Reaction time: 1 h
Yield: 54.1 %

Procedure:
95% TFA (2 mL) was added dropwise to dimer compound 28b (89 mg, 0.085 mmol) at 0° C. which was stirred for 1 h and then poured into saturated aqueous NaHCO3 (30 mL). The mixture was extracted with chloroform (3×20 mL) and the organic layer washed with water (20 mL), brine (20 mL), dried (MgSO4) and filtered. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 29b (30 mg, 0.046 mmol, 55%) as a solid: [α]27D=+308° (c=0.24, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.30-1.39 (m, 6H, 15-H, 16-H), 1.40-1.50 (m, 4H, 14-H), 1.82-1.91 (m, 4H, 13-H), 2.89-2.97 (m, 2H, 1-H), 3.06-3.16 (m, 2H, 1-H), 3.81-3.90 (m, 2H, 11a-H), 3.93 (s, 6H, 7-OMe), 3.98-4.10 (m, 4H, 12-H), 4.28 (s, 4H, 3-H), 5.16-5.19 (m, 4H, 2a-H), 6.79 (s, 2H, 9-H), 7.48 (s, 2H, 6-H), 7.66 (d, 2H, J=4.44 Hz, 11-H); 13C NMR (CDCl3, 100 MHz): δ 25.8, 28.8, 29.2, 29.4, 35.2, 51.3, 53.8, 56.2, 69.0, 109.3, 110.3, 111.3, 119.5, 140.6, 141.7, 151.0, 162.4, 164.8; IR (neat): 2928, 2854, 1624, 1599, 1506, 1464, 1429, 1381, 1261, 1216, 1096, 729 cm−1; MS (ES+) m/z (relative intensity) 641 ([M+H]+., 100), 642 ([M+2H]+., 52), 339 (97).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)[S:24][CH:25]=1.O>CN(C=O)C>[F:38][C:35]([F:36])([F:37])[O:34][C:31]1[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:23]2[S:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][O:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)[N:22]=2)=[CH:29][CH:30]=1
Reactant: FC(F)(F)Oc1ccc(C=Cc2nc(CCl)cs2)cc1
Reactant: Oc1ccc(COCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)Oc1ccc(/C=C/c2nc(COc3ccc(COCCn4ccnn4)cc3)cs2)cc1
Reaction time: 0.25 h

Procedure:
182 mg (7.00 mmol) 95% Sodium hydride were given to a solution of 1.50 g (7.00 mmol) 4-(2-[1,2,3]triazol-1-yl-ethoxymethyl)-phenol in 7.0 ml DMF and stirred for 15 min. 2.06 g (7.00 mmol) 4-Chloromethyl-2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-thiazole were added and stirring continued at r.t. overnight. After addition of 20 ml water the resulting precipitate was washed twice with 10 ml water, then with n-heptane and finally a little amount of diethyl ether and dried at 45° C. in vacuum. Yield 2.4 g.
Reaction SMILES: [CH3:1][N:2]1[C:15]2[C:6]([CH:7]=[CH:8][C:9]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:18][CH:17]=[C:11]4[NH:12][C:13](=[O:16])[C:14]=2[C:10]=34)=[C:5]([N+:26]([O-])=O)[CH:4]=[CH:3]1.[Cl-].[NH4+].O>O1CCCC1.C(O)C.[Zn]>[NH2:26][C:5]1[CH:4]=[CH:3][N:2]([CH3:1])[C:15]2[C:6]=1[CH:7]=[CH:8][C:9]1[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:18][CH:17]=[C:11]3[NH:12][C:13](=[O:16])[C:14]=2[C:10]=13
Reactant: CN1C=CC([N+](=O)[O-])=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccccn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CN1C=CC(N)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccccn1
Yield: 88.5 %

Procedure:
A mixture of Example 82c (0.09 g, 0.241 mmol), zinc dust (0.236 g, 3.62 mmol) and ammonium chloride (0.129 g, 2.411 mmol) in tetrahydrofuran (2.6 mL), ethanol (1.3 mL), and water (0.65 mL) was stirred at ambient temperature for 1 hour and then filtered to remove the solid. The filtrate was concentrated and then slurried in water. The solid was collected by filtration and dried in a vacuum oven at 70° C. to give 0.0732 g (88%) of the title compound as an impure mixture.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]([NH2:17])[CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[S:5][CH:6]=1.[CH3:18][CH:19]([CH3:23])[CH2:20][CH:21]=O.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]([NH:17][CH2:21][CH2:20][CH:19]([CH3:23])[CH3:18])[CH2:8][O:9][Si:10]([C:13]([CH3:14])([CH3:16])[CH3:15])([CH3:12])[CH3:11])[S:5][CH:6]=1
Reactant: CC(C)CC=O
Reactant: CC(C)(C)[Si](C)(C)OCC(N)c1cc(Br)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCNC(CO[Si](C)(C)C(C)(C)C)c1cc(Br)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(4-bromothiophen-2-yl)-2-{[tert-butyl(dimethyl)silyl]oxy}ethanamine (216 mg, 0.642 mmol) was dissolved in 1.5 mL MeOH. Molecular sieves (3 Å) and 3-methylbutanal (79 μL, 0.739 mmol) were then added. The resulting mixture was stirred at room temperature overnight. Sodium borohydride (36.4 mg, 0.963 mmol) was added and the mixture was stirred for 1 hour, and then quenched with aqueous sodium hydrogen carbonate. DCM was added and the phases separated. The solvent was removed under reduced pressure. The resulting solid was used without further purification.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:23]=[CH:22][C:14]2[C:15]([CH3:21])([CH3:20])[O:16][C:17](=[O:19])[NH:18][C:13]=2[CH:12]=1)(=O)=O.[Cl:24][C:25]1[CH:26]=[C:27]([SH:32])[CH:28]=[CH:29][C:30]=1[Cl:31]>>[Cl:24][C:25]1[CH:26]=[C:27]([S:32][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:23]=[CH:22][C:14]3[C:15]([CH3:20])([CH3:21])[O:16][C:17](=[O:19])[NH:18][C:13]=3[CH:12]=2)[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: CC1(C)OC(=O)Nc2cc(OCCCCOS(C)(=O)=O)ccc21
Reactant: Sc1ccc(Cl)c(Cl)c1
Product: CC1(C)OC(=O)Nc2cc(OCCCCSc3ccc(Cl)c(Cl)c3)ccc21

Procedure:
Prepared analogously to Example 210 from 7-(4-methanesulfonyloxy-butoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 3,4-dichloro-thiophenol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12]3)[CH:5]=[C:4]([F:19])[C:3]=1[C:20]([F:23])([F:22])[F:21].[H-].[Na+].[CH3:26]OS(OC)(=O)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C.O.CCCCCC>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:26])[C:13](=[O:18])[CH2:12]3)[CH:5]=[C:4]([F:19])[C:3]=1[C:20]([F:23])([F:22])[F:21]
Reactant: O=C1Cc2cc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)ccc2N1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCCC
Product: CN1C(=O)Cc2cc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-[(2-chloro-α,α,α,6-tetrafluro-p-tolyl)oxy]-2-indolinone (16.8 g, 0.0485 mol) in toluene is treated in a single portion with a 60% sodium hydride dispersion in mineral oil (2.13 g, 0.0534 mol NaH) at 60° C., stirred for 30 minutes, treated dropwise with a solution of dimethylsulfate (5.1 mL, 0.0534 mol) in toluene over a 20 minute period at 60° C., stirred for 2 hours, cooled to room temperature and diluted with a mixture of ethyl acetate and water. The phases are separated, the organic phase is washed with brine and the aqueous phases are combined and further extracted with ethyl acetate. All organic phases are combined, dried over MgSO4, and concentrated in vacuo to give a light brown semi-solid residue. Trituration under a mixture of 3-5% ethyl acetate in hexane and filtration yields the title product as a light pink solid, 13.45 g (77%), mp 111°-112° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.O[CH:32]([CH2:35][CH2:36][CH:37]([N:40]1[C:44](=[O:45])[C:43]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:42]2[C:41]1=[O:50])[CH2:38][F:39])[CH:33]=[CH2:34].CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O>[F:39][CH2:38][CH:37]([N:40]1[C:41](=[O:50])[C:42]2=[CH:49][CH:48]=[CH:47][CH:46]=[C:43]2[C:44]1=[O:45])[CH2:36][CH2:35][CH:32]([N:24]1[C:20](=[O:30])[C:21]2=[CH:29][CH:28]=[CH:27][CH:26]=[C:22]2[C:23]1=[O:25])[CH:33]=[CH2:34]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=CC(O)CCC(CF)N1C(=O)c2ccccc2C1=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C=CC(CCC(CF)N1C(=O)c2ccccc2C1=O)N1C(=O)c2ccccc2C1=O
Reaction time: 72 h

Procedure:
To a solution of triphenylphosphine (103 g, 0.39 mol), phthalimide (57.8 g, 0.43 mol) and 3-hydroxy-7-fluoro-6-phthalimidoheptene (109 g, 0.39 mol) in dry THF (2 L) under nitrogen, was added dropwise a solution of diethylazodicarboxylate (75.4 g, 0.43 mol) in dry THF (1 L). The solution was kept <20° C. The reaction mixture was stirred for 72 hours. The THF layer was separated and evaporated to give an oil which was boiled in water (5×250 mL), the water was decanted and the residue was dissolved in dichloromethane. After washing with water, the organic phase was separated, dried over Na2SO4 and evaporated to eliminate triphenylphosphine oxide. Evaporation of the ether phase and chromatography of the residue (200 g) on silica gel (1.5 kg), elution with petroleum ether/ethyl acetate (2:3) afforded the title compound (8, R=--CH2F) as a white solid: 36.4 g (22.8%). TLC PE/EtOAc 1:1, Rf=0.78. NMR (1H, CDCl3, 90 MHz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[C:20]([C:21]2[CH:30]=[C:29]3[C:24]([CH2:25][CH2:26][NH:27][CH:28]3[CH3:31])=[CH:23][CH:22]=2)=[CH:19][CH:18]=[CH:17][N:16]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][C:21]([C:20]5[C:15]([F:14])=[N:16][CH:17]=[CH:18][CH:19]=5)=[CH:22][CH:23]=4)[CH:28]3[CH3:31])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2ccc(-c3cccnc3F)cc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2cc(-c3cccnc3F)ccc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-(2-Fluoro-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[C:12]([O:14][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]([N+:25]([O-])=O)=[CH:17][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[O:6])[CH2:3][CH2:2]1.[H][H]>CO.CC(O)=O.[Pt]>[NH2:25][C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]([O:14][C:12]2[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)=[O:6])[CH:13]=2)=[CH:16][CH:17]=1
Reactant: [H][H]
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ccn1)NC1CC1
Agent: [Pt]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ccc(Oc2ccnc(NC(=O)NC3CC3)c2)c2ccccc12

Procedure:
A solution of 1-cyclopropyl-3-(4-((4-nitronaphthalen-1-yl)oxy)pyridin-2-yl)urea (118 mg, 0.324 mmol) in a mixture of MeOH (20 mL) and AcOH (0.5 mL) was subjected to hydrogenation by passage through a Thales H-cube (1.0 mL min−1, 25° C., 70 mm, 10% Pt—C Cat-Cart, full hydrogen mode). The reaction mixture was evaporated in vacuo and the residue was partitioned between DCM (20 mL) and saturated aq. NaHCO3 (10 mL). The organic phase was separated and was washed with brine (10 mL), and then dried and evaporated in vacuo to afford the title compound, Intermediate D3, as a brown solid (90 mg, 83%); Rt 1.52 min (Method 2); m/z 335 (M+H)+ (ES+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](O)=O)[C:9]=2[CH3:24])=[CH:4][CH:3]=1.[CH2:25]([NH:27][C:28]([CH3:33])([CH3:32])[C:29]([NH2:31])=[O:30])[CH3:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[N:27]([CH2:25][CH3:26])[C:28]([CH3:33])([CH3:32])[C:29](=[O:30])[N:31]=3)[C:9]=2[CH3:24])=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CCNC(C)(C)C(N)=O
Product: CCN1C(c2nn(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)c2C)=NC(=O)C1(C)C

Procedure:
Compound 7 was synthesized from 4a (251 mg, 0.66 mmol) and 5b (140 mg, 1.08 mmol) as a white solid (110 mg, 35%) in a manner similar to that described in Example 36. 1H NMR (400 MHz, CDCl3) δ 7.43 (d, 1H), 7.28 (d, 2H), 7.25 (dd, H), 7.14 (d, 1H), 7.04 (d, 2H), 3.90 (q, 2H), 2.37 (s, 3H), 1.41 (s, 6H), 1.27 (t, 3H); ESMS m/z: 475.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:13])=[C:6](/[CH:8]=[C:9](\[CH3:12])/[CH:10]=O)[CH:7]=1.CC1C=CC(S([NH:24][NH2:25])(=O)=O)=CC=1.[OH-].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:13])=[C:6]([C:8]2[NH:25][N:24]=[CH:10][C:9]=2[CH3:12])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: C/C(C=O)=C\c1cc(Cl)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1cn[nH]c1-c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (E)-3-(5-chloro-2-hydroxyphenyl)-2-methylacrylaldehyde (40 mg, 0.203 mmol) and 4-methylbenzenesulfonohydrazide (41.7 mg, 0.224 mmol) in Acetonitrile (3 mL) were stirred at room temperature for 3 h and then acetonitrile (2 mL), Sodiumhydroxide (8.95 mg, 0.224 mmol) were added and the mixture was heated at reflux for 16 h. Product was used for further reaction without purification.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([NH:26][CH3:27])=[O:25])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([NH:26][CH3:27])=[O:25])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CNC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 95.9 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-{3-[(methylamino)carbonyl]-1,2,4-oxadiazol-5-yl}hexanoate (Preparation 7, 380 mg, 1.00 mmol) in dichloromethane (10 ml) was treated with trifluoroacetic acid (5 ml) and the mixture was stirred at room temperature for 3.5 hours. The solvent was removed under reduced pressure and the residue azeotroped with toluene (×2). The residue was dissolved in ethyl acetate and washed sequentially with a saturated aqueous solution of sodium citrate then brine. The organic layer was dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was crystallised from hexane to afford the title compound as a white solid (310 mg).
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])[N:5]=[C:4]([C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:24])[N:3]=1.[F-:25].[K+].C1OCCOCCOCCOCCOCCOC1>S1(CCCC1)(=O)=O>[Cl:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=1[C:4]1[N:3]=[C:2]([F:25])[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])[N:5]=1
Reactant: Fc1cccc(Cl)c1-c1nc(Cl)n(-c2ccccc2C(F)(F)F)n1
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: Fc1cccc(Cl)c1-c1nc(F)n(-c2ccccc2C(F)(F)F)n1
Temperature: 140 °C

Procedure:
A mixture of 2.61 g (6.9 mmol) of 5-chloro-3-(2-chloro-6-fluorophenyl)-1-(α,α,α-trifluoro-o-tolyl)-1H-1,2,4-triazole, 0.84 g (14.5 mmol) of dry potassium fluoride and 0.23 g (0.9 mmol) of 18-crown-6 in 15 ml of dry sulfolane is heated at 140° C. for 65 hours. The reaction mixture is subsequently cooled and eluted on silica gel (φ 40-63 μm, column: 0 7 cm, height 20 cm) with ethyl acetate/n-hexane (7:13). There is obtained 3-(2-chloro-6-fluorophenyl)-5-fluoro-1-(α,α,α-trifluoro-o-tolyl)-1H-1,2,4-triazole as white crystals, m.p. 68°-70° C.; mass spectrum: 359(100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[C:7]#[N:8].Cl.[NH2:12][OH:13].C(=O)(O)[O-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[C:7](=[N:12][OH:13])[NH2:8]
Reactant: NO
Reactant: Cc1ccc(Cl)cc1C#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(Cl)cc1C(N)=NO
Temperature: 25 °C
Yield: 98.6 %

Procedure:
A solution of 5-chloro-2-methylbenzonitrile (1.5 g, 9.89 mmol), hydroxylamine hydrochloride (1.38 g, 19.79 mmol) and sodium bicarbonate (3.33 g, 39.6 mmol) in methanol (100 mL) was heated to 70° C. for 6 h. The mixture was cooled to room temperature and diluted with methanol (100 mL). The mixture was filtered, and the filtrate was concentrated, diluted with water and extracted with EtOAc (100 mL, 3×). The EtOAc extract was dried over MgSO4, filtered and concentrated under reduced pressure to obtain crude 5-chloro-N′-hydroxy-2-methylbenzimidamide (1.8 g, 99% crude yield). LC/MS: m/e 185.0 (M+H)+. 1H NMR (400 MHz, CD3OD) δ ppm 7.30-7.29 (2 H, m), 7.23 (1 H, d), 2.36 (3H, s).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][CH2:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15].C(N(CC)CC)C>C1COCC1>[CH3:15][C:14]([OH:16])([CH2:13][CH2:12][NH:11][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[CH3:17]
Reactant: CC(C)(O)CCN
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(O)CCNc1ccccc1[N+](=O)[O-]
Yield: 83.2 %

Procedure:
A solution of 1-fluoro-2-nitrobenzene (1.9 mL, 18 mmol), 4-amino-2-methyl-2-butanol (1.6 g, 15 mmol) and triethylamine (6.4 mL, 46 mmol) in THF (30 mL) was refluxed for 8 h. Then the reaction was quenched by addition of water (50 mL) and extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine (50 mL) and dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (5/1-2/1) to afford 2.8 g (82%) of the title compound.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH:25][CH:26]=[C:27]([C:33]([O:35]CC)=O)[C:28]([O:30]CC)=[O:29])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24].O.C(OCC)(=O)C>[N+](C1C=CC=CC=1)([O-])=O>[OH:35][C:33]1[C:20]2[C:19](=[CH:18][C:17]([O:16][CH3:15])=[C:22]([O:23][CH3:24])[CH:21]=2)[N:25]=[CH:26][C:27]=1[C:28]([OH:30])=[O:29]
Reactant: CCOC(=O)C(=CNc1ccc(OC)c(OC)c1)C(=O)OCC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc2ncc(C(=O)O)c(O)c2cc1OC
Temperature: 150 °C
Reaction time: 18 h
Yield: 56.9 %

Procedure:
10.2 g of phosphorus pentoxide were added cautiously, with mechanical stirring, to a mixture of 21.1 g of diethyl 2-[(3,4-dimethoxyphenylamino)methylene]malonate in 42 cm3 of nitrobenzene. The reaction mixture was maintained at a temperature in the region of 150° C. for 4 hours. After cooling to about 20° C. and stirring for 18 hours at this same temperature, 14 cm3 of water were added dropwise and the reaction mixture was then heated to about 110° C. for 7 hours. After cooling to a temperature in the region of 20° C., 42 cm3 of ethyl acetate were added. The suspension was stirred under these conditions for 18 hours, the phases were then separated by settling, the organic phase was filtered and the filter cake was washed with 3 times 40 cm3 of ethyl acetate, 40 cm3 of ethanol and 40 cm3 of water. 9.25 g of 4-hydroxy-6,7-dimethoxyquinoline-3-carboxylic acid were obtained in the form of a cream-colored solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([P:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:25](OC)[N:26]([CH3:28])[CH3:27]>>[CH3:25][N:26]([CH3:28])[CH:27]=[CH:2][C:1]([C:4]1[CH:5]=[C:6]([P:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1cccc(P(c2ccccc2)c2ccccc2)c1
Reactant: COC(OC)N(C)C
Product: CN(C)C=CC(=O)c1cccc(P(c2ccccc2)c2ccccc2)c1

Procedure:
A mixture of 9.9 g (32.6 mmol) of (3-acetylphenyl)diphenyl phosphane and 7.7 g (64.7 mmol) of N,N-dimethylformamide dimethylacetal is refluxed under cover gas for 2 h. After removal of the volatiles in high vacuum, the product crystallizes at room temperature. The orange solid is washed with diethyl ether. (Purity: >95%)
Reaction SMILES: C1(S(CC2C(C(O)=O)=C(OCCNC(OC(C)(C)C)=O)C(C3C=COC=3)=CC=2)(=O)=O)C=CC=CC=1.[C:36]([O:40][C:41]([NH:43][CH2:44][CH2:45][O:46][C:47]1[C:56]([C:57]2[CH:61]=[CH:60][O:59][CH:58]=2)=[CH:55][CH:54]=[C:53]([CH2:62][S:63]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=2[O:72][CH3:73])(=[O:65])=[O:64])[C:48]=1[C:49]([O:51]C)=[O:50])=[O:42])([CH3:39])([CH3:38])[CH3:37]>>[C:36]([O:40][C:41]([NH:43][CH2:44][CH2:45][O:46][C:47]1[C:56]([C:57]2[CH:61]=[CH:60][O:59][CH:58]=2)=[CH:55][CH:54]=[C:53]([CH2:62][S:63]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=2[O:72][CH3:73])(=[O:65])=[O:64])[C:48]=1[C:49]([OH:51])=[O:50])=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2OC)ccc(-c2ccoc2)c1OCCNC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)NCCOc1c(-c2ccoc2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O
Product: COc1ccccc1S(=O)(=O)Cc1ccc(-c2ccoc2)c(OCCNC(=O)OC(C)(C)C)c1C(=O)O

Procedure:
Prepared by proceeding in a similar manner to Intermediate 6, starting from methyl 2-[2-(t-butoxycarbonyl)aminoethoxy]-3-(furan-3-yl)-6-(2-methoxybenzenesulphonylmethyl)benzoate (Intermediate 14).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([NH:14][CH2:15][CH3:16])=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:15]([NH:14][C:7]1[C:6]([CH2:4][OH:3])=[CH:11][N:10]=[C:9]([S:12][CH3:13])[N:8]=1)[CH3:16]
Reactant: CCNc1nc(SC)ncc1C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCNc1nc(SC)ncc1CO
Reaction time: 0.17 h
Yield: 91.6 %

Procedure:
A solution of 4-ethylamino-2-methylthio-5-pyrimidinecarboxylate ethyl ester (8.93 g, 37.1 mmol) in 100 mL of tetrahydrofuran was added dropwise to a room temperature suspension of lithium aluminum hydride (2.30 g, 60.5 mmol) in 100 mL of tetrahydrofuran. After 10 minutes, the reaction was carefully quenched with 4.5 mL of water, 4.5 mL of 15% NaOH, and 16 mL of water, and the mixture was stirred for 1.5 hours. The white precipitate was removed by filtration washing with ethyl acetate. The filtrate was concentrated in vacuo and 1:1 hexane:ethyl acetate was added. The solids were collected to give 6.77 g (92%) of 4-ethylamino-2-methylthio-5-pyrimidinemethanol; mp 152°-156° C.