Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][C:9]1([C:22]2[S:23][C:24]([C:27]3[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([NH:34][C:35]4[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][N:36]=4)[N:28]=3)=[CH:25][N:26]=2)[CH2:18][CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:19]([OH:21])=O)[CH:12]=[CH:11][C:10]1=2.[Cl-].[NH4+].F[P-](F)(F)(F)(F)F.[N:54]1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C.CS(C)=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][C:9]1([C:22]2[S:23][C:24]([C:27]3[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([NH:34][C:35]4[CH:40]=[C:39]([C:41]([F:43])([F:44])[F:42])[CH:38]=[CH:37][N:36]=4)[N:28]=3)=[CH:25][N:26]=2)[CH2:18][CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:19]([NH2:54])=[O:21])[CH:12]=[CH:11][C:10]1=2
Reactant: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnc(C3(O)CCCc4cc(C(=O)O)ccc43)s2)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnc(C3(O)CCCc4cc(C(N)=O)ccc43)s2)c1
Temperature: 50 °C
Yield: 55.1 %

Procedure:
To a solution of (rac)-5-hydroxy-5-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid, trifluoroacetate salt (50 mg, 0.078 mmol), ammonium chloride (62.6 mg, 1.171 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (44.5 mg, 0.117 mmol) in DMF (781 μL) was added diisopropylethylamine (40.9 μl, 0.234 mmol), and the reaction was heated at 50° C. for 16 h. The reaction mixture was then diluted with DMSO (1 mL), barrier filtered, and purified by reverse-phase HPLC (C18 column, water-acetonitrile, TFA modifier) to give (rac)-5-hydroxy-5-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]-5,6,7,8-tetrahydronaphthalene-2-carboxamide, trifluoroacetate salt (27.4 mg, 0.043 mmol, 43% yield) as a yellow solid. MS ESI calcd for C26H22F3N5O2S [M+H]+ 526, found 526. 1H NMR (500 MHz, DMSO) δ 10.21 (s, 1H), 8.64 (s, 1H), 8.48 (s, 1H), 8.22 (s, 1H), 7.88 (s, 1H), 7.64 (s, 1H), 7.57 (s, 1H), 7.35 (s, 1H), 7.28 (s, 1H), 7.25 (d, J=8.2 Hz, 1H), 7.21 (d, J=4.5 Hz, 1H), 7.11 (s, 1H), 2.89-2.80 (m, 2H), 2.39-2.32 (m, 1H), 2.30 (s, 3H), 2.15-2.07 (m, 1H), 2.04-1.89 (m, 2H) ppm.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[CH3:5].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH3:24])[CH:18]=[C:19]([O:22][CH3:23])[C:20]=1[OH:21]>>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:4]([CH3:5])[CH2:3][CH2:2][O:21][C:20]2[C:19]([O:22][CH3:23])=[CH:18][C:17]([CH3:24])=[CH:16][C:15]=2[O:14][CH3:13])=[CH:7][CH:8]=1
Reactant: CC(CCBr)c1ccc(F)cc1
Reactant: COc1cc(C)cc(OC)c1O
Product: COc1cc(C)cc(OC)c1OCCC(C)c1ccc(F)cc1
Yield: 81.7 %

Procedure:
Example 4a (2.54 g, 11 mmol) and 3,5-dimethoxy-4-hydroxy-toluene (1.68 g, 10 mmol) were reacted as described under General Procedure A and the crude product was purified by flash chromatography (silica-gel, hexane/EtOAc 19:1) to provide the product as a clear oil (2.6 g, 82%). 1H NMR (300 MHz, CDCl3) δ 7.20-7.15 (m, 2H), 6.97-6.91 (m, 2H), 6.35 (s, 2H), 3.85-3.37 (m, 8H), 3.10-3.02 (m, 1H), 3.28 (s, 3H), 2.04-1.89 (m, 2H), 1.26 (d, J=6.9 Hz, 3H).
Reaction SMILES: B([O-])([O-])[O-:2].C1C(=O)N(OC(CCCCCN[C:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH:27]2[S:31][CH2:30][CH:29]3[NH:32][C:33]([NH:35][CH:28]23)=[O:34])=[O:22])=O)C(=O)C1>[Na+].[Cl-]>[OH:2][C:21]([CH2:23][CH2:24][CH2:25][CH2:26][C@H:27]1[C@@H:28]2[C@@H:29]([NH:32][C:33]([NH:35]2)=[O:34])[CH2:30][S:31]1)=[O:22]
Reactant: O=C(CCCCC1SCC2NC(=O)NC21)NCCCCCC(=O)ON1C(=O)CCC1=O
Reactant: [O-]B([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21

Procedure:
50 mg bovine serum albumin (BSA) (Fraction V, Fluka) were dissolved in pH 8.5 50 mM NaCl, 20 mM borate buffer. A solution of biotin X NHS (20 mg/200 μl anhydrous dimethylformamide) was then added, and the following steps were identical to those described for the preparation of biotinylated XO.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH:14]([N:19]=[N+]=[N-])[CH2:13][CH2:12][C:11]=2[C:10]=1[C:22]([NH2:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C)C.[BH4-].[Na+].Cl>O>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH:14]([NH2:19])[CH2:13][CH2:12][C:11]=2[C:10]=1[C:22]([NH2:24])=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=NC1CCc2c(ccc(OCc3ccccc3)c2C(N)=O)C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: NC(=O)c1c(OCc2ccccc2)ccc2c1CCC(N)C2

Procedure:
A solution was prepared from 3.4 g. of dl-2-benzyloxy-6-azido-5,6,7,8-tetrahydro-1-naphthalenecarboxamide (from Example 4) and 100 ml. of isopropanol. The solution was cooled and 0.5 g. sodium borohydride added thereto in small portions. After the addition had been completed, the reaction mixture was heated to reflux temperature under a nitrogen blanket for about 18 hours. The reaction mixture was then cooled and the cooled mixture diluted with water. The aqueous mixture was made acidic by the addition of 1 N aqueous hydrochloric acid. The aqueous acidic layer was extracted with ether and the ether extract discarded. The aqueous acidic layer was made basic by the addition of 10% aqueous sodium hydroxide. The alkaline layer was extracted several times with equal volumes of a 3:1 chloroform/methanol solvent mixture. The organic extracts were combined and the combined extracts washed with saturated aqueous sodium chloride and then dried. Evaporation of the solvent therefrom yielded a residue comprising dl-2-benzyloxy-6-amino-5,6,7,8-tetrahydro-1-naphthalenecarboxamide. TLC indicated a single spot at the origin. An infrared spectrum of the solid indicated no absorption attributable to an azide group. The residue was dissolved in chloroform and the chloroform solution saturated with gaseous hydrogen chloride. The solvent was removed in vacuo and the residue dissolved in methanol. Ether was added to the point of incipient precipitation and the solution was cooled overnight. Forty-eight hundredths grams of tan crystals melting above 235° C. consisting of dl-2-benzyloxy-6-amino-5,6,7,8-tetrahydro-1-naphthalenecarboxamide hydrochloride were recovered.
Reaction SMILES: [Li]CCCC.[CH:6]1([N:9]2[C:13]([CH3:14])=[N:12][N:11]=[C:10]2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH2:8][CH2:7]1.Br[CH:22]([C:24]1[N:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)[O:26][N:25]=1)[CH3:23]>C1COCC1>[Cl:35][C:31]1[CH:30]=[C:29]([C:27]2[O:26][N:25]=[C:24]([CH:22]([CH3:23])[CH2:14][C:13]3[N:9]([CH:6]4[CH2:8][CH2:7]4)[C:10]([C:15]4[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=4)=[N:11][N:12]=3)[N:28]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: Cc1nnc(-c2ccncc2)n1C1CC1
Reactant: CC(Br)c1noc(-c2cccc(Cl)c2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(Cc1nnc(-c2ccncc2)n1C1CC1)c1noc(-c2cccc(Cl)c2)n1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
n-BuLi (210 ml, 2.5 M in hex., 0.52 mmol) was added dropwise to a solution of 4-(4-cyclopropyl-5-methyl-4H-1,2,4-triazol-3-yl)pyridine (80 mg, 0.4 mmol) in THF (10 ml) at −78° C. under an atm. of nitrogen. After stirring for 15 min 3-(1-Bromo-ethyl)-5-(3-chloro-phenyl)-[1,2,4]oxadiazole (115 mg, 0.4 mmol) in THF (2 ml) was added. The mixture was stirred for 2 h at −78° C. and then at r.t. for 1 h. The solvent was removed under reduced pressure and the desired product was obtained by prep. HPLC in 20 mg yield. 1H NMR: 0.7 (m, 2 H) 1.2 (ddd, 2 H) 1.6 (d, 3 H) 3.2 (dd, 1 H) 3.3 (ddd, 1 H) 3.6 (dd, 1 H) 3.9 (m, 1 H) 7.5 (t, 1 H) 7.6 (m, 1 H) 7.7 (m, 2 H) 8.0 (m, 1 H) 8.1 (t, 1 H) 8.7 (m, 2 H)
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:34])([F:33])[F:32])[C:19]4[CH:35]=[CH:36][CH:37]=[CH:38][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:39][O:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>C(N(CC)CC)C>[CH3:39][O:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][N:46]([CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:24]=[CH:23][C:22]4[CH2:21][CH:20]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[C:31]([F:33])([F:32])[F:34])[C:19]5[CH:35]=[CH:36][CH:37]=[CH:38][C:18]=5[C:17]=4[N:16]=3)=[CH:10][CH:9]=2)[CH2:45][CH2:44]1
Reactant: COCCN1CCNCC1
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccccc2C(F)(F)F)C3)cc1
Solvent: CCN(CC)CC
Product: COCCN1CCN(CCc2ccc(Nc3ncc4c(n3)-c3ccccc3C(c3ccccc3C(F)(F)F)C4)cc2)CC1

Procedure:
This was synthesized by using 4-(6-(2-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate, 1-(2-methoxyethyl)piperazine and triethylamine as described in general procedure 2 to afford the desired product. M.p.=139-140° C. 1H NMR 400 MHz (DMSO-d6) δ 9.55 (s, 1 H); 8.38-8.34 (m, 2 H), 7.82-7.75 (m, 3 H), 7.56 (t, 1 H), 7.49-7.40 (m, 3 H), 7.27 (d, J=8.0 Hz, 1 H), 7.18-7.15 (m, 2 H), 6.76 (d, J=7.2 Hz, 1 H), 4.64 (t, J=7.6 Hz, 1 H), 3.43-3.37 (m, 2 H), 3.34 (s, 3 H), 3.21-3.11 (m, 2 H), 2.69-2.65 (m, 2 H), 2.50-2.43 (m, 12). LCMS 588 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:70]=[CH:69][C:53]2[NH:54][C:55]([CH:57]([NH2:68])[CH2:58][C:59]3[CH:64]=[C:63]([CH3:65])[C:62]([OH:66])=[C:61]([CH3:67])[CH:60]=3)=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:49][C:50]1[CH:70]=[CH:69][C:53]2[NH:54][C:55]([CH:57]([NH:68][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH2:58][C:59]3[CH:60]=[C:61]([CH3:67])[C:62]([OH:66])=[C:63]([CH3:65])[CH:64]=3)=[N:56][C:52]=2[CH:51]=1
Reactant: Cc1cc(CC(N)c2nc3cc(Cl)ccc3[nH]2)cc(C)c1O
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(C(=O)NC(Cc2cc(C)c(O)c(C)c2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and rac.-1-(5-chloro-1H-benzimidazol-2-yl)-2-(4-hydroxy-3,5-dimethylphenyl)ethylamine in tetrahydrofuran. Yield: %; Rf value: 0.45 (silica gel: dichloromethane/ethanol=9:1); C30H31ClN4O3 (531.06); mass spectrum: (M+H)+=531/533 (chlorine isotope).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C@@H:14]([CH2:15][CH2:16][OH:17])[O:13][CH2:12][CH2:11][N:10]2[C:18](=[O:31])[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:39][S:40]([O:17][CH2:16][CH2:15][C@H:14]1[O:13][CH2:12][CH2:11][N:10]([C:18](=[O:31])[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH:9]1[C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(=O)N2CCO[C@H](CCO)C2c2ccc(Cl)c(Cl)c2)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCO[C@H](CCOS(C)(=O)=O)C2c2ccc(Cl)c(Cl)c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
30.0 g (63.8 mmole) of 2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethanol [prepared as described in step (d) above] were dissolved in 500 ml of methylene chloride. 11.5 ml (83.0 mmole) of triethylamine and 5.93 ml (76.6 mmole) of methanesulfonyl chloride were then added, in that order, to the mixture, whilst ice-cooling, and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction mixture was then diluted with methylene chloride and washed with 1 N aqueous hydrochloric acid, and then with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 1:4 to 1:9 by volume as the eluent, to give 34.8 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[CH2:21])=[CH:18][CH:17]=1.[Li]CCCC>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:21][CH2:20][C:19]3[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: C=Cc1ccc(OC)cc1
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: [Li]CCCC
Product: COc1ccc(CCN2CCN(c3ccc(F)cc3)CC2)cc1

Procedure:
According to GP, 2.22 mmol (=0.40 g) of 1-(4-fluorophenyl)piperazine and 2.22 mmol (=0.30 g=0.30 ml) of para-methoxystyrene are reacted with 5 mol % (=0.111 mmol=70 μl) of n-BuLi solution. Column-chromatographic separation with ethyl acetate gives the product 1-(4-fluorophenyl)-4-[2-(4-methoxyphenyl)-1-ethyl]piperazine as a light-yellow solid.
Reaction SMILES: [N+:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:13])([O-:3])=[O:2].IC.[C:16]([O-])([O-])=O.[K+].[K+]>>[N+:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[O:13][CH3:16])([O-:3])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cccc(O)c1[N+](=O)[O-]
Agent: [K+]
Solvent: CI
Product: COc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
A mixture of 2,3-dinitrophenol (5.43 mmol, 1 g), iodomethane (21.7 mmol, 1.35 mL) and K2CO3 (21.7 mmol, 2.99 g) was stirred at room temperature for 14 h. The reaction was then filtered through celite and the filter bed was washed with additional acetone. The filtrate was concentrated to provide 2,3-dinitroanisole (100%), which was dissolved in a mixture of EtOH/H2O (1:1, 20 mL) and Fe (19.4 mmol, 1.06 g) and concentrated HCl (8 drops) was added. The mixture was refluxed for 90 min., after which it was filtered through celite and the filter bed was washed with additional EtOH. The filtrate was concentrated and basified (pH>12) with 4 M NaOH and the aqueous layer was extracted with CH2Cl2. The organic phase was then separated and washed with brine, dried MgSO4 and concentrated to provide 2,3-diaminoanisole 36b (0.65 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][C:14]3=[O:19])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:30]=[CH:29][C:24]([CH2:25][N:26]=[C:27]=[O:28])=[CH:23][CH:22]=1>CN(C=O)C>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][NH:26][C:27]([N:16]2[CH2:17][CH2:18][N:13]([CH2:12][C:8]3[CH:7]=[C:6]4[C:11]([C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)=[CH:10][CH:9]=3)[C:14](=[O:19])[CH2:15]2)=[O:28])=[CH:29][CH:30]=1
Reactant: Nc1ncnc2cc(CN3CCNCC3=O)ccc12
Reactant: O=C=NCc1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: Nc1ncnc2cc(CN3CCN(C(=O)NCc4ccc(Cl)cc4)CC3=O)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
To a solution of 1-(4-aminoquinazoline-7-ylmethyl)piperazine-2-one (25 mg, 0.097 mmol), EXAMPLE 72, in 1 mL of DMF is added 4-chloro-benzyl isocyanate (22 mg, 0.13 mmol, prepared as described in EXAMPLE 37). After stirring 1 h at room temperature, the solution is concentrated. The crude product is purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 80% CH3CN/H2O (0.1% TFA) and the appropriate product fractions are combined and lyopholized to provide the title compound (36 mg, 0.067 mmol) as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ9.76 (bs, 2H), 8.83 (s, 1H), 8.38 (d, 1H), 7.64 (d, 1H), 7.60 (s, 1H), 7.34 (d, 2H), 7.31 (m, 1H), 7.26 (d, 2H), 4.75 (s, 2H), 4.22 (d, 2H), 4.08 (s, 2H), 3.60 (m, 2H), 3.35 (m, 2H). ESI MS, [M+H]+=425,427 (Cl pattern).
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH2:27]([O:37][C:38]([NH:40][C:41]1[CH:46]=[CH:45][N:44]([CH2:47][C:48](O)=[O:49])[C:43](=[O:51])[N:42]=1)=[O:39])[C:28]1[CH:36]=[CH:35][C:34]2[O:33][CH2:32][O:31][C:30]=2[CH:29]=1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:48](=[O:49])[CH2:47][N:44]2[CH:45]=[CH:46][C:41]([NH:40][C:38]([O:37][CH2:27][C:28]3[CH:36]=[CH:35][C:34]4[O:33][CH2:32][O:31][C:30]=4[CH:29]=3)=[O:39])=[N:42][C:43]2=[O:51])[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: O=C(O)Cn1ccc(NC(=O)OCc2ccc3c(c2)OCO3)nc1=O
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccn(CC(=O)N2CCN(S(=O)(=O)c3nc4ccccc4s3)C(=O)C2)c(=O)n1)OCc1ccc2c(c1)OCO2

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [4-N-(piperonyloxycarbonyl)-cytosin-1-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 10.76 (hrs, 1H), 8.36 (m, 1H), 8.28 (m, 1H), 7.92 (d, 0.6H), 7.86 (d, 0.4H), 7.73 (m, 2H), 7.03 (t, 1H), 7.00 (s, 1H), 6.92 (s, 2H), 6.03 (s, 2H), 5.08 (s, 2H), 4.84 (s, 1.2H), 4.74 (s, 0.8H), 4.47 (s, 0.8H), 4.30 (s, 1.2H), 4.24 (t, 1.2H), 4.08 (t, 0.8H), 4.01 (t, 1.2H), 3.89 (t, 0.8H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH3:30])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1>C1COCC1>[CH2:29]([O:28][C:22]1[CH:21]=[C:20]2[C:25]([C:16]([O:14][C:10]3[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=3)[NH2:7])=[N:17][CH:18]=[N:19]2)=[CH:24][C:23]=1[O:26][CH3:27])[CH3:30]
Reactant: CCOc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
To a stirred slurry of cesium carbonate (2.99 g, 9.20 mmol) in anhydrous THF (50 mL) at rt, was added 3-aminophenol (1.00 g, 9.17 mmol). After stirring for 30 mins, 4-chloro-7-ethoxy-6-methoxyquinazoline (prepared as described in Example 6A Steps 1 through 5) (2.19 g, 9.20 mmol) was added and the reaction mixture was heated at 50° C. for 18 h. The mixture was cooled to rt and concentrated under reduced pressure and the resulting solid was washed with water (three times) then ethyl acetate (three times) to afford 3-(7-ethoxy-6-methoxyquinazolin-4-yloxy)aniline (1.75 g, 61%) as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.51 (s, 1H), 7.35 (s, 1H), 7.09 (m, 1H), 6.37-6.50 (m, 3H), 5.31 (brs, 2H), 4.25 (q, J=7 Hz, 2H), 3.97 (s, 3H), 1.44 (t, J=7 Hz, 3H); LC-MS (ESI) m/z 312 (M+H)+.
Reaction SMILES: [OH-].[Li+].[NH2:3][C:4]1[C:9]([F:10])=[C:8]([CH2:11][CH3:12])[N:7]=[C:6]([C:13]([O:15]C)=[O:14])[C:5]=1[Cl:17]>O.O1CCCC1>[NH2:3][C:4]1[C:9]([F:10])=[C:8]([CH2:11][CH3:12])[N:7]=[C:6]([C:13]([OH:15])=[O:14])[C:5]=1[Cl:17]
Reactant: CCc1nc(C(=O)OC)c(Cl)c(N)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc(C(=O)O)c(Cl)c(N)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
A solution of lithium hydroxide (0.49 g, 11.73 mmol) in water (25 mL) was added to a solution of methyl 4-amino-3-chloro-6-ethyl-5-fluoropyridine-2-carboxylate (1.36 g, 5.86 mmol) in tetrahydrofuran (25 mL). The mixture was vigorously stirred at room temperature overnight and was then concentrated to half volume. After adding water the reaction mixture was washed once with ethyl acetate to remove unreacted starting material. The aqueous layer was then acidified to pH<3 with 1N HCl, concentrated and the residue partitioned between tetrahydrofuran and brine. The aqueous layer was discarded and the organic layer concentrated and dried under vacuum to provide 4-amino-3-chloro-6-ethyl-5-fluoropyridine-2-carboxylic acid (1.01 g, 4.60 mmol) as a white solid, mp 144-145° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:30])[C@H:11]([OH:29])[C@H:12]2[O:17][CH2:16][CH2:15][N:14]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([N+:25]([O-])=O)[CH:19]=3)[C:13]2=[O:28])=[CH:5][CH:4]=1)#[N:2]>C(O)(C)=O.O.[Fe]>[NH2:25][C:20]1[CH:19]=[C:18]([N:14]2[CH2:15][CH2:16][O:17][C@H:12]([C@@H:11]([OH:29])[C:10]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[O:30])[C:13]2=[O:28])[CH:23]=[CH:22][C:21]=1[CH3:24]
Reactant: Cc1ccc(N2CCO[C@H]([C@@H](O)C(=O)Nc3ccc(C#N)cc3)C2=O)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(N2CCO[C@H]([C@@H](O)C(=O)Nc3ccc(C#N)cc3)C2=O)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
To a solution of compound 9-4 (70 mg) in AcOH—H2O (2 mL-0.1 mL), was added electrolytic iron powder (95.3 mg). The reaction mixture was stirred at room temperature for 1 hour then at 40° C. for 2 hours to complete the reaction. The reaction mixture was filtered with Celite® pad to remove iron powder. The filtrate was concentrated in vacuo. The resulting residue was purified by amino-silica gel flash column chromatography (eluent: CH2Cl2/MeOH=98/2-95/5) to obtain compound 9-5 (30 mg) as a colorless amorphous solid.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)=[CH:6][CH:7]=1.[F:14][C:15]([F:30])([C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2)[C:16]([NH:18][NH2:19])=O.CS(O)(=O)=O>COCC(O)C>[F:30][C:15]([F:14])([C:16]1[N:3]2[N:4]=[C:5]([C:8]3[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=3)[CH:6]=[CH:7][C:2]2=[N:19][N:18]=1)[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2
Reactant: Cn1cc(-c2ccc(Cl)nn2)cn1
Reactant: NNC(=O)C(F)(F)c1ccc2ncccc2c1
Agent: CS(=O)(=O)O
Solvent: COCC(C)O
Product: Cn1cc(-c2ccc3nnc(C(F)(F)c4ccc5ncccc5c4)n3n2)cn1
Temperature: 80 °C

Procedure:
To a reactor under inert atmosphere was added 73.84 g (0.38 mol) 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine, 90 g (0.38 mol) 2,2-difluoro-2-quinolin-6-ylacetohydrazide and 1200 mL 1-methoxy-2-propanol. Then 29.85 mL (0.455 mol) methane sulphonic acid was added and the reaction mixture was heated at 80° C. for 8 hours. After cooling to ambient temperature the mesylate salt of the title compound was filtered off from the reaction mixture. This salt was dissolved in a mixture of 400 mL ethanol and 300 mL water, after alkalisation at 80° C. with 50 mL ammonia (0.65 mol) in 200 mL water the free base of the title compound precipitates and was filtered off. This precipitate was dried at 50° C. and was subsequently re-crystallized from 2-propanol (1.8 L/mol) to yield the title compound in 75% yield.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])C.O>ClC1C=CC=CC=1>[CH3:13][C:8]1[C:7]2[S:6][CH:5]=[CH:4][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(CSc1ccccc1C)OCC
Solvent: O
Solvent: Clc1ccccc1
Product: Cc1cccc2ccsc12
Yield: 93.8 %

Procedure:
To a solution of intermediate 136, (2,2-diethoxyethyl)(o-tolyl)sulfane (0.58 g, 2.41 mmol) in chlorobenzene (20 mL) was added polyphosphoric acid. The reaction mixture was stirred at reflux for 18 h. Water (100 mL) was then added and the organic material was extracted with CH2Cl2 (2×50 mL). The organic solution was dried (MgSO4) and concentrated in vacuo to afford 335 mg (94% yield) of the title compound: 1H NMR (400 MHz, CDCl3) δ: 7.68 (1H, d, J=7.8 Hz), 7.43 (1H, d, J=5.4 Hz), 7.36 (1H, d, J=5.4 Hz), 7.30 (1H, dd, J=7.8, 7.1 Hz), 7.14 (1H, d, J=7.1 Hz), 2.58 (3H, s); LCMS (M+H)+ m/z 148.