Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].C(=O)(O)[O-].[Na+].[Br:19][CH2:20][C:21](Br)=[O:22]>C(Cl)(Cl)Cl>[Br:19][CH2:20][C:21]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:10])([F:11])[F:12])[CH:5]=[CH:4][C:3]=1[OH:13])=[O:22]
Reactant: O=C(Br)CBr
Reactant: Nc1cc(OC(F)(F)F)ccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C(CBr)Nc1cc(OC(F)(F)F)ccc1O
Temperature: 0 °C
Yield: 87.1 %

Procedure:
2-amino-4-[(trifluoromethyl)oxy]phenol (3.0 g, 15.5 mmol) was dissolved in 100 mL of chloroform. 54 mL of saturated sodium bicarbonate solution was added and the new bi-phase mixture was stirred vigorously and cooled to 0° C. using an ice bath. Bromoacetylbromide (2.1 mL, 23.3 mmol) was added drop-wise. Fifteen minutes later the solution was removed from the ice bath and maintained at room temperature for 2 hours before it was determined to be complete by LCMS (two Aquasil C18, 20×1 mm columns were run in sequence, 4 minutes at 0.1 mL/min, 1-99% CH3CN/H2O with 0.018% trifluoroacetic acid, ES) Rt=1.77 min and m/e 314 [M+1+. The organic layer was separated and the aqueous phase was extracted with 100 mL of chloroform. The combined organic phases were dried over Na2SO4, filtered and concentrated to give 2-bromo-N-{2-hydroxy-5-[(trifluoromethyl)oxy]phenyl}acetamide (4.23 g, 13.5 mmol, 87%) as a brown amorphous solid. MS (ES) m/e 314 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[N:11]1([CH2:16][C:17]2[CH:18]=[CH:19][C:20](Br)=[N:21][CH:22]=2)[CH:15]=[CH:14][N:13]=[CH:12]1>>[N:11]1([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:4]3[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=3)=[N:21][CH:22]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Nc1cccc(B(O)O)c1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Product: Nc1cccc(-c2ccc(Cn3ccnc3)cn2)c1

Procedure:
Synthesized using 3-aminophenylboronic acid 230 mg, 1.68 mmol) and 1a (200 mg, 0.84 mmol) according to Method C. Orange solid. Yield: 144 mg, 0.56 mmol, 67%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=5.11 (s, 2H), 6.72 (ddd, J=7.6, 2.4, 0.9 Hz, 1H), 6.89 (brs, 1H), 7.08 (bs, 1H), 7.21 (t, J=7.7 Hz, 1H), 7.28 (dt, J=7.8, 1.3 Hz, 1H), 7.33 (t, J=2.2 Hz, 1H), 7.41 (dd, J=8.2, 2.2 Hz, 1H), 7.55 (brs, 1H), 7.62 (d, J=8.2 Hz, 1H), 8.50 (d, J=2.2 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.0, 113.3, 116.0, 117.0, 119.0, 120.5, 129.6, 129.9, 130.1, 135.6, 137.2, 139.5, 146.9, 148.3, 157.6; MS (ESI): m/z=251.13 [M+H]+.
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.NC1C=C2C(=CC=1)CN(C(N[C:42]1[CH:47]=[CH:46][C:45]([C:48](=[O:53])NCCC)=[CH:44][CH:43]=1)=O)C2>>[C:48]([N:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1)(=[O:53])[C:45]1[CH:46]=[CH:47][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(Nc1ccc(C2CCNCC2)cc1)N1Cc2ccccc2C1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Solvent: CC(=O)Cl
Product: O=C(Nc1ccc(C2CCN(C(=O)c3ccccc3)CC2)cc1)N1Cc2ccccc2C1

Procedure:
The title compound was prepared as described in Example 278, substituting benzoyl chloride for acetyl chloride and N-[4-(piperidin-4-yl)phenyl]-1,3-dihydro-2H-isoindole-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.29 (s, 1H), 7.47-7.50 (m, 2H), 7.41-7.47 (m, 5H), 7.34-7.38 (m, 2H), 7.29-7.33 (m, 2H), 7.16-7.18 (m, 2H), 4.75-4.76 (bs, 4H), 4.54-4.64 (m, 1H), 3.57-3.74 (m, 1H), 3.02-3.21 (m, 1H), 2.79-2.93 (m, 1H), 2.75 (tt, J=11.9, 3.4 Hz, 1H), 1.68-1.88 (m, 2H), 1.54-1.63 (m, 2H); MS (ESI(−)) m/e 424 (M−H)−.
Reaction SMILES: Cl.[CH2:2]([O:18][CH2:19][CH:20]([CH2:26][O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[O:21][CH2:22][CH2:23][CH2:24][NH2:25])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+].C1C=CC=CC=1.[C:56](Cl)(=[O:58])[CH3:57]>O>[CH2:2]([O:18][CH2:19][CH:20]([CH2:26][O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[O:21][CH2:22][CH2:23][CH2:24][NH:25][C:56](=[O:58])[CH3:57])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CC(=O)Cl
Reactant: CCCCCCCCCCCCCCCCOCC(COCCCCCCCCCCCCCCCC)OCCCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCOCC(COCCCCCCCCCCCCCCCC)OCCCNC(C)=O
Reaction time: 1 h
Yield: 79 %

Procedure:
1,3-Di-O-(n-hexadecyl)-2-O-(3-aminopropyl)-glycerol hydrochloride (1.0 g., 1.6 mmoles) was added to a mixture of potassium carbonate (830 mg., 6.0 mmoles) and benzene (75 ml.). Acetyl chloride (150 mg., 1.9 mmoles) was then added and the resulting mixture stirred for one hour at reflux. Additional acetyl chloride (150 mg., 1.9 moles) was added and the reaction mixture stirred for another hour at reflux. TLC analysis showed that the reaction was essentially complete. The reaction mixture was cooled, water (75 ml.) added, and the resulting mixture extracted with ether (3×100 ml.). The combined ether extract was dried (MgSO4), filtered and evaporated in vacuo to yield the named compound [800 mg., 79% yield, m.p. 53°-54° C., ir (CHCl3) 3400 and 1670 cm-1, n.m.r. (CDCl3) δ1.97 (s, 3, --NHCOCH3)].
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH2:12][OH:13])[CH:9]=[CH:10][CH:11]=1.N1C=CC=CC=1.[Cl:20][C:21]([Cl:31])=[CH:22][C@@H:23]1[C@H:25]([C:26](Cl)=[O:27])[C:24]1([CH3:30])[CH3:29]>C1(C)C=CC=CC=1>[Cl:20][C:21]([Cl:31])=[CH:22][C@@H:23]1[C@H:25]([C:26]([O:13][CH2:12][C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[CH:7]=2)=[O:27])[C:24]1([CH3:29])[CH3:30]
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Reactant: OCc1cccc(-c2ccco2)c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)OCc1cccc(-c2ccco2)c1
Yield: 94.3 %

Procedure:
This reaction was conducted in the manner of Example 3, Step 2 using 1.5 g (0.009 mol) of 3-(2-furanyl)phenylmethanol, 0.7 g (0.009 mol) of pyridine, 50 mL of toluene, and 2.0 g (0.009 mol) of cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride. The crude oily product was subjected to distillation under reduced pressure to give 3.1 g of [3-(2-furanyl)phenyl]methyl cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate, b.p. 160° C./0.1 mm.
Reaction SMILES: C(OC([N:6]1[CH2:15][CH:14]([CH3:16])[C:13]2[C:12]3[CH2:17][CH2:18][CH:19]([C:20]([F:23])([F:22])[F:21])[C:11]=3[S:10][C:9]=2[CH2:8][CH2:7]1)=O)C.[Si](I)(C)(C)C>C(Cl)(Cl)Cl>[CH3:16][CH:14]1[C:13]2[C:12]3[CH2:17][CH2:18][CH:19]([C:20]([F:23])([F:21])[F:22])[C:11]=3[S:10][C:9]=2[CH2:8][CH2:7][NH:6][CH2:15]1
Reactant: CCOC(=O)N1CCc2sc3c(c2C(C)C1)CCC3C(F)(F)F
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: CC1CNCCc2sc3c(c21)CCC3C(F)(F)F
Temperature: 70 °C

Procedure:
The product of step (e) (diastereomer 1 and diastereomer 2, separately, 20 mg, 0.06 mmol) was dissolved in 3 mL CHCl3 and treated with TMSI (40 uL, 0.29 mmol). After heating to 70° C. overnight, the reaction was quenched with MeOH (5 mL) and 1 M NaOH (2 mL). The title compound was extracted into CHCl3 (2×10 mL) and subsequently purified by preparative HPLC-MS.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[CH:22]=[CH:21][N:20]=[C:19]2[CH2:23]O)=[C:6]([CH:17]=1)[C:7]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[F:16])=[O:8].[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[CH:22]=[CH:21][N:20]=[C:19]2[CH2:23][N:29]2[C:25](=[O:35])[C:26]3=[CH:34][CH:33]=[CH:32][CH:31]=[C:27]3[C:28]2=[O:30])=[C:6]([CH:17]=1)[C:7]([C:9]1[C:10]([F:16])=[CH:11][CH:12]=[CH:13][C:14]=1[F:15])=[O:8]
Reactant: O=C(c1cc(Cl)ccc1-n1ccnc1CO)c1c(F)cccc1F
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(c1cc(Cl)ccc1-n1ccnc1CN1C(=O)c2ccccc2C1=O)c1c(F)cccc1F

Procedure:
In the manner given in Example 17, 5-chloro-2',6'-difluoro-2-[2-(hydroxymethyl)imidazol-1-yl]benzophenone is treated with phthalimide and triphenylphosphine and finally with diethyl azodicarboxylate to give 5-chloro-2',6'-difluoro-2-[2-(phthalimidomethyl)imidazol-1-yl]benzophenone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=O)[CH:11]=[C:10]([CH3:15])[CH:9]=2)=[CH:4][CH:3]=1.P(Br)(Br)([Br:18])=O>C1(C)C=CC=CC=1>[Br:18][C:12]1[CH:11]=[C:10]([CH3:15])[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: O=P(Br)(Br)Br
Reactant: Cc1cc(-c2ccc(Cl)cc2)[nH]c(=O)c1
Solvent: Cc1ccccc1
Product: Cc1cc(Br)nc(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was prepared from 6-(4-chloro-phenyl)-4-methyl-1H-pyridin-2-one (1.1 g, 5 mmol) and phosphoryl bromide (4.63 g, 16 mmol) in toluene (9.5 mL) according to the general procedure Ia to d preparation of bromides. Obtained as a light brown solid (1.0 g, quant., 74% purity). MS (ISP) 282.0 [(M+H)+], 284.0 [(M+2+H)+] and 286.0 [(M+4+H)+].
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=1)[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].O1CCC[CH2:30]1.[H-].[Na+].IC>C(=O)([O-])O.[Na+]>[CH3:30][O:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][O:18][Si:19]([CH:23]([CH3:25])[CH3:24])([CH:26]([CH3:28])[CH3:27])[CH:20]([CH3:21])[CH3:22])=[CH:13][CH:12]=1)[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7]
Reactant: CC(C)[Si](OCc1ccc(C(O)c2cccc(C#N)c2)cc1)(C(C)C)C(C)C
Reactant: C1CCOC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COC(c1ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cc1)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
A solution of 3-[hydroxy-(4-triisopropylsilanyloxymethyl-phenyl)-methyl]-benzonitrile (0.64 g, 1.62 mmol) and tetrahydrofuran (10 mL) is stirred at 0° C. Sodium hydride, 60% in mineral oil, (80 mg, 1.95 mmol) is added and the mixture is stirred at room temperature 10 min. The mixture is cooled to 0° C. and iodomethane (0.12 mL, 1.8 mmol) is added. The resulting mixture is stirred at room temperature 18 hr. The mixture is diluted with aqueous saturated sodium hydrogen carbonate, extracted with ethyl acetate, and the organic layer concentrated. The residue is purified via silica chromatography eluting with hexanes to 9:1 hexanes:ethyl acetate to provide 400 mg, 60% the title compound, as a colorless oil. 1H NMR (CDCl3) δ 7.70 (s, 1H), 7.55-7.69 (m, 2H), 7.27-7.46 (m, 5H), 5.27 (s, 1H), 4.88 (s, 2H), 3.41 (s, 3H), 1.05-1.29 (m, 21H).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][CH2:10][NH:9][S:8]2(=[O:14])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CS(C)=O>[O:13]=[S:8]1(=[O:14])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12][CH2:11][CH2:10][N:9]1[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: O=S1(=O)NCCCN1c1ccccc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)CN1CCCN(c2ccccc2)S1(=O)=O
Reaction time: 4 h
Yield: 82.5 %

Procedure:
To 2-phenyl-1,2,6-thiadiazinan 1,1-dioxide (400 mg, 1.89 mmol) in DMSO (15 mL), were added K2CO3 (522.4 mg, 3.78 mmol) and ethyl bromoacetate (379.1 mg, 2.27 mmol). The reaction mixture was agitated for 4 hr and extracted with ethyl acetate and brine. The organic layer was dried over MgSO4 and the residue was purified by silica gel column chromatography to yield ethyl 2-(1,1-dioxido-6-phenyl-1,2,6-thiadiazinan-2-yl)acetate (468 mg, 1.56 mmol, 83%, white solid). 1H NMR (300 MHz, CDCl3): δ 7.45-7.34 (m, 3H), 7.30-7.25 (m, 1H), 4.28-4.20 (q, J=7.1 Hz, 2H), 4.03 (s, 2H), 3.82-3.73 (m, 4H), 1.99-1.91 (m, 2H), 1.30 (t, J=7.1 Hz, 3H).
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([CH3:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[NH2:34][CH:35]1[CH2:38][NH:37][CH2:36]1.CN1CCCC1>C(O)C>[NH2:34][CH:35]1[CH2:38][N:37]([C:20]2[C:21]([Cl:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([CH3:30])=[CH:9][C:8]([F:31])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:36]1
Reactant: NC1CNC1
Reactant: Cc1cc(F)c(N)nc1-n1cc(C(=O)O)c(=O)c2cc(F)c(F)c(Cl)c21
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1cc(F)c(N)nc1-n1cc(C(=O)O)c(=O)c2cc(F)c(N3CC(N)C3)c(Cl)c21
Temperature: 85 °C
Reaction time: 0.75 h
Yield: 79.2 %

Procedure:
To 250 mg of N,N-dimethylformamide were added 80 mg of 1-(6-amino-5-fluoro-3-methylpyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 60 mg of 3-aminoazetidine dihydrochloride, and 120 mg of N-methylpyrrolidine, and the mixture was stirred at 85° C. for 45 minutes. After adding 0.5 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 72 mg of the title compound as a colorless powder.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.[C:34](O)(=[O:37])[CH2:35][OH:36]>>[OH:37][CH2:34][C:35]([N:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1)=[O:36]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Reactant: O=C(O)CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)CO)C3)ccc1-2
Yield: 27 %

Procedure:
Following the procedure for 318, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 31 and glycolic acid were reacted. Purification by reverse phase preparative HPLC (Gemini C18 column, gradient 5-98% MeOH in H2O+0.1% HCO2H) gave 397 as a white solid (46 mg, 27%). LCMS: RT=10.33 min, [M+H]+=426. 1H NMR δ (ppm) (DMSO-d6): 8.30 (1H, d, J=8.20 Hz), 8.05 (1H, s), 7.20-7.15 (1H, m), 7.01 (1H, d, J=1.82 Hz), 5.82-5.72 (1H, m), 4.88-4.81 (1H, m), 4.55-4.46 (1H, m), 4.34-4.29 (2H, m), 4.30-4.17 (1H, m), 4.16 (1H, dd, J=9.24, 5.41 Hz), 3.90 (2H, d, J=5.77 Hz), 3.89-3.77 (2H, m), 3.41-3.35 (2H, m), 1.49 (6H, d, J=6.59 Hz)
Reaction SMILES: [I:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[N:5][NH:6][C:7]2=O.P(Cl)(Cl)([Cl:16])=O>CCOC(C)=O>[Cl:16][C:7]1[C:8]2[C:3](=[C:2]([I:1])[C:11]([CH3:12])=[CH:10][CH:9]=2)[CH:4]=[N:5][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2c(=O)[nH]ncc2c1I
Solvent: CCOC(C)=O
Product: Cc1ccc2c(Cl)nncc2c1I
Temperature: 108 °C
Yield: 62 %

Procedure:
A suspension of 5-iodo-6-methylphthalazin-1(2H)-one (8.51 g, 29.7 mmol) in phosphorous oxychloride (200 ml, 2146 mmol), charged to a 500 mL was stirred at 108° C. (reflux) for 90 min. The POCl3 was then removed under vacuum, and the resulting residue was azeotroped 2× with toluene. The resulting residue was dissolved in a mixture of DCM and MeOH and water. The layers were separated the aqueous layer was washed with DCM 3×. The combined organics were washed with saturated aqueous sodium carbonate and brine. The organic layer was then dried over magnesium sulfate, and loaded on to silica. 1-Chloro-5-iodo-6-methylphthalazine (5.604 g, 61.9% yield) was obtained by column chromatography (ISCO 330 g 15%-60% EtOAc in Hex 60 min) as a yellow solid. MS (M+H)+ 305.
Reaction SMILES: C(O)(=O)C.[C:5]([N:8]1[C:12]2=[CH:13][C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[N:15][N:11]2[C:10]([C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[C:22]([N+:28]([O-])=O)[C:21]=2[CH3:31])=[N:9]1)(=[O:7])[CH3:6].[H][H]>[Ni].C1COCC1>[C:5]([N:8]1[C:12]2=[CH:13][C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[N:15][N:11]2[C:10]([C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[C:22]([NH2:28])[C:21]=2[CH3:31])=[N:9]1)(=[O:7])[CH3:6]
Reactant: [H][H]
Reactant: CC(=O)n1nc(-c2c(C)cc(C)c([N+](=O)[O-])c2C)n2nc(C(C)(C)C)cc12
Agent: [Ni]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)n1nc(-c2c(C)cc(C)c(N)c2C)n2nc(C(C)(C)C)cc12
Yield: 92.5 %

Procedure:
Acetic acid (0.5 ml) was added to Raney nickel (8 spoon-spatulas full) and after washing with THF the catalyst was added to the product of part (a) (16.6 g, 44.9 mmole) in THF (160 ml). The resulting mixture was shaken in an atmosphere of hydrogen at atmospheric pressure for 4 hours and then filtered, the catalyst washed with THF and the filtrate evaporated to give a solid (14.1 g). This material was chromatographed on a dry deactivated silica gel column eluting with 1% ethyl acetate in methylene chloride to give the partially hydrated product, m.p. 206°-207° C., 12.7 g (83%).
Reaction SMILES: [OH-:1].[Na+].Br.[C:4]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[N:13]=[C:14]([N:17]=[C:18]([NH2:20])[NH2:19])[S:15][CH:16]=2)[CH:7]=1)#[N:5]>CO.O1CCCC1>[C:4]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[N:13]=[C:14]([N:17]=[C:18]([NH2:20])[NH2:19])[S:15][CH:16]=2)[CH:7]=1)(=[O:1])[NH2:5]
Reactant: N#Cc1ccnc(-c2csc(N=C(N)N)n2)c1
Reactant: [OH-]
Agent: Br
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)c1ccnc(-c2csc(N=C(N)N)n2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1N-Aqueous sodium hydroxide (10 ml) was added to a suspension of 4-(4-cyanopyridin-2-yl)-2-(diaminomethyleneamino)thiazole hydrobromide (1.00 g) in a mixture of methanol (10 ml) and tetrahydrofuran (10 ml). After the mixture was stirred for one day at ambient temperature, the solvent was evaporated in vacuo and the residue was mixed with water (10 ml). The resulting precipitate was collected by filtration, washed with water and recrystallized from a mixture of N,N-dimethylformamide and water to give 4-(4-carbamoylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (0.45 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][NH:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:37](Cl)(=[O:39])[CH3:38]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][N:30]([CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[C:37](=[O:39])[CH3:38])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CC(=O)Cl
Reactant: Clc1cc(Nc2ncnc3cccc(OCCNC4CCOCC4)c23)ccc1OCc1ccccn1
Product: CC(=O)N(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C1CCOCC1
Yield: 68 %

Procedure:
The procedure described in Example 5 was repeated using N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(tetrahydro-2H-pyran-4-ylamino)ethoxy]quinazolin-4-amine and acetyl chloride to give the title compound in 68% yield; NMR spectrum (DMSO-d6) 1.49-1.71 (m, 2H), 1.75-1.98 (m, 2H), 2.11 (s, 3H), 3.36-3.45 (m, 2H), 3.78-3.96 (m, 5H), 4.26-4.46 (m, 2H), 5.31 (s, 2H), 7.22 (d, 1H), 7.26 (d, 1H), 7.33 (d, 1H), 7.35-7.40 (m, 1H), 7.56-7.63 (m, 2H), 7.69-7.75 (m, 1H), 7.86-7.91 (m, 1H), 7.99-8.03 (m, 1H), 8.46 (s, 1H), 8.61 (d, 1H), 9.98 (s, 1H); Mass spectrum MH+ 548.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:12])[N:4]([CH3:11])[CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1>C(Cl)Cl.CO>[NH2:8][C:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:12])[N:4]([CH3:11])[CH:5]=1
Reactant: Cn1cc([N+](=O)[O-])cc(F)c1=O
Solvent: CO
Solvent: ClCCl
Product: Cn1cc(N)cc(F)c1=O

Procedure:
The title compound was prepared in analogy to the procedure described in Step 5.2 using 3-fluoro-1-methyl-5-nitropyridin-2(1H)-one (Step 14.1). tR: 0.22 min (LC-MS 2); ESI-MS: 143 [M+H]+ (LC-MS 2); Rf=0.25 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[C:8]3[C:13]([C:14]([CH2:15][CH2:16][NH2:17])=[C:6]2[CH2:5][CH2:4][CH2:3]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.C(N(C(C)C)CC)(C)C.[CH3:27][N:28]([CH3:38])[C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>>[CH3:27][N:28]([CH3:38])[C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:17][CH2:16][CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]3[C:2](=[O:1])[CH2:3][CH2:4][CH2:5][C:6]=23)=[O:34])=[CH:31][CH:30]=1
Reactant: NCCc1c2n(c3ccccc13)C(=O)CCC2
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1ccc(C(=O)NCCc2c3n(c4ccccc24)C(=O)CCC3)cc1

Procedure:
E10 was prepared analogously to E9 from 7 g D4 of EP-0167901, 11.2 ml diisopropylethylamine and 4.5 g 4-dimethylaminobenzoic acid chloride.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:7][C:6]2[CH:8]=[CH:9][N:10]=[CH:11][C:5]=2[NH:4][C:3]1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1>>[CH3:1][C:2]1([CH3:13])[O:7][C:6]2[CH:8]=[CH:9][N:10]=[CH:11][C:5]=2[NH:4][CH2:3]1
Reactant: CC1(C)Oc2ccncc2NC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CNc2cnccc2O1
Yield: 100 %

Procedure:
By the same method as in the step c) of Example 2, 2,2-dimethyl-4H-pyrido[4,3-b][1,4]oxazin-3-one (120 mg, 0.67 mmol) was reacted with 1.0M Lithium aluminum hydride dissolved in tetrahydrofuran (1.4 ml, 1.4 mmol) to obtain 2,2-dimethyl-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (110 mg, quantitative yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:22]=[CH:21][C:7]([O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[CH3:32][S:33]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:15]([C:16]#[N:17])[CH:14]=2)=[CH:21][CH:22]=1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1cccc(COCCOc2ccc(CCO)cc2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ccc(OCCOCc2cccc(C#N)c2)cc1
Reaction time: 2 h

Procedure:
To a solution of 3-({2-[4-(2-hydroxyethyl)phenoxy]ethoxy}methyl)benzonitrile (5.04 g) and diisopropylethylamine (5.94 ml) in dichloromethane (50 ml) at 0° C. was added methanesulphonyl chloride (1.58 ml) dropwise and the mixture allowed to stir for 2 h. The resultant mixture was partitioned between dichloromethane and saturated sodium hydrogen carbonate. The organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound (6.02 g). LCMS RT=3.22 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=1.O.[NH2:11][NH2:12]>>[NH:11]([C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=1)[NH2:12]
Reactant: NN
Reactant: COc1ccc(Cl)nc1
Solvent: O
Product: COc1ccc(NN)nc1

Procedure:
The above-obtained 2-chloro-5-methoxypyridine (4.0 g) in hydrazine monohydrate (30 mL) was stirred at 100° C. for 24 hours, and then cooled in air. The reaction solvent was removed under reduced pressure, and the residue was partitioned by use of chloroform and aqueous 1N sodium hydroxide. The organic layer was dried over magnesium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, to thereby give 2-hydrazino-5-methoxypyridine as an oily product (705 mg, 18%).