Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[NH:7][N:6]=1.Cl[C:19]1[N:24]=[C:23]([NH2:25])[N:22]=[C:21]([NH2:26])[N:20]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.CO>[F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[N:7]([C:19]2[N:24]=[C:23]([NH2:25])[N:22]=[C:21]([NH2:26])[N:20]=2)[N:6]=1
Reactant: Nc1nc(N)nc(Cl)n1
Reactant: Fc1ccccc1Cc1n[nH]c2cccnc12
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1nc(N)nc(-n2nc(Cc3ccccc3F)c3ncccc32)n1

Procedure:
A solution of 100 mg (0.44 mmol) of 3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridine from example 4A, 64 mg (0.44 mmol) of 6-chloro-1,3,5-triazine-2,4-diamine, 8.1 mg (0.009 mmol) of tris(di-benzylideneacetone)dipalladium, 13 mg (0.026 mmol) of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (XPHOS) and 201 mg (0.62 mmol) of cesium carbonate in 3 ml of degassed toluene is heated at 90° C. for 20 h. It is then diluted with ethyl acetate and methanol, filtered and concentrated in vacuo. The residue is crystallized from methanol to result in 42 mg (28% of theory) of the title compound as pale yellow crystals.
Reaction SMILES: F[C:2]1[N:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[C:15]1([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][CH2:34][OH:35])[CH2:27][CH2:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.CC(C)([O-])C.[Na+]>CN1C(=O)CCC1>[CH3:13][C:6]1([CH3:14])[C:5]2[C:10](=[N:11][C:2]([O:35][CH2:34][CH2:33][CH2:32][CH2:31][N:28]3[CH2:29][CH2:30][N:25]([C:15]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH:18]=[CH:17][CH:16]=4)[CH2:26][CH2:27]3)=[CH:3][CH:4]=2)[NH:9][C:8](=[O:12])[CH2:7]1
Reactant: CC1(C)CC(=O)Nc2nc(F)ccc21
Reactant: OCCCCN1CCN(c2cccc3ccccc23)CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC1(C)CC(=O)Nc2nc(OCCCCN3CCN(c4cccc5ccccc45)CC3)ccc21
Temperature: 70 °C
Yield: 48 %

Procedure:
7-Fluoro-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one (247 mg, 1.272 mmol), 4-(4-naphthalen-1-yl-piperazin-1-yl)-butan-1-ol (365 mg, 1.285 mmol) and sodium t-butoxide (367 mg, 3.82 mmol) were combined in a dried flask 3 necked flask under N2. NMP was added and the solution was heated in an oil bath to 70° C. for 4 hours. The reaction was cooled to room temperature and poured into ice water. The solid that was collected was slurried in CH2Cl2 and ethyl acetate and purified by liquid chromatography (MPLC, gradient of 100% CH2Cl2 to 100% ethyl acetate) to give the title compound as a foam (280 mg, 0.610 mmol, 48%). MS: APCI: M+1: 459.2 (Exact Mass: 458.27).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:30]I.O>CN(C)C=O>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:21]=[CH:22][C:23]([C:24]#[N:25])=[CH:26][CH:27]=3)[N:19]=2)[CH3:30])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: N#Cc1ccc(-c2csc(NC3CCN(Cc4ccccc4)CC3)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1nc(-c2ccc(C#N)cc2)cs1)C1CCN(Cc2ccccc2)CC1
Reaction time: 0.25 h
Yield: 67 %

Procedure:
1.3 g of 4-{2-[N-(1-benzylpiperid-4-yl)amino]-1,3-thiazol-4-yl}benzonitrile dissolved in 5 ml of N,N-dimethylformamide are added, at room temperature, to 146 mg of sodium hydride (at 60% in dispersion in oil) in suspension in 13 ml of N,N-dimethylformamide and the reaction mixture is stirred for 15 minutes at this temperature. 0.23 ml of methyl iodide is then added, the reaction mixture is stirred for 4 hours at room temperature, and it is poured over water and extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulphate and evaporated. The residue is purified by silica gel chromatography, eluting with dichloromethane. Yellow crystals are obtained which melt at 136° C.; yield: 67%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([NH:13][C:14]3[C:23]4[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=4)[N:17]=[C:16]([C:25]4[CH:30]=[C:29]([N+]([O-])=O)[CH:28]=[CH:27][C:26]=4[S:34]([CH3:37])(=[O:36])=[O:35])[C:15]=3[CH3:38])=[CH:11][C:10]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:9][N:8]=2)[CH2:3][CH2:2]1.C(=N/[OH:53])/C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([NH:13][C:14]3[C:23]4[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=4)[N:17]=[C:16]([C:25]4[CH:30]=[C:29]([OH:53])[CH:28]=[CH:27][C:26]=4[S:34]([CH3:37])(=[O:35])=[O:36])[C:15]=3[CH3:38])=[CH:11][C:10]([N:39]3[CH2:40][CH2:41][O:42][CH2:43][CH2:44]3)=[CH:9][N:8]=2)[CH2:3][CH2:2]1
Reactant: O/N=C\c1ccccc1
Reactant: Cc1c(-c2cc([N+](=O)[O-])ccc2S(C)(=O)=O)nc2cc(F)ccc2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(-c2cc(O)ccc2S(C)(=O)=O)nc2cc(F)ccc2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
The N-(2,5-dimorpholinopyridin-3-yl)-7-fluoro-3-methyl-2-(2-(methylsulfonyl)-5-nitrophenyl)quinolin-4-amine (3.0 mg, 4.8 μmol), (Z)-benzaldehyde oxime (1.0 μL, 9.6 μmol), 325 mesh potassium carbonate (2.7 mg, 0.019 mmol) and DMSO (9.6 μL) was heated in a microwave reactor for 45 min at 100° C. The reaction was cooled and diluted with water. The mixture was extracted with EtOAc (2×35 mL). The combined organic layers were washed with brine (1×20 mL) and dried over magnesium sulfate. The crude material was purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 90% over 20 min to provide 3-(4-(2,5-dimorpholinopyridin-3-ylamino)-7-fluoro-3-methylquinolin-2-yl)-4-(methylsulfonyl)phenol after extracting with satd sodium bicarbonate solution. 1H NMR (CDCl3) δ ppm 8.00 (1H, br. s.), 7.94 (1H, d, J=8.8 Hz), 7.84 (1H, d, J=7.8 Hz), 7.65 (1H, br. s.), 7.43 (1H, t, J=8.2 Hz), 6.91 (1H, d, J=8.4 Hz), 6.85 (1H, br. s.), 6.52 (1H, br. s.), 3.83-4.05 (4H, m), 3.76 (4H, t, J=4.7 Hz), 3.42 (2H, br. s.), 2.93-3.20 (9H, m), 1.99 (3H, br. s.). Mass Spectrum (ESI) m/e=594.2 (M+1).
Reaction SMILES: P([O-])([O-])([O-])=O.[CH3:6][CH2:7][C@H:8]1[O:23][C:21](=[O:22])[C@H:20]([CH3:24])[C@@H:19]([O:25][C@@H:26]2[O:31][C@@H:30]([CH3:32])[C@H:29]([OH:33])[C@@:28]([O:35][CH3:36])([CH3:34])[CH2:27]2)[C@H:18]([CH3:37])[C@@H:17]([O:38][C@@H:39]2[O:44][C@H:43]([CH3:45])[CH2:42][C@H:41]([N:46]([CH3:48])[CH3:47])[C@H:40]2[OH:49])[C@@:16]([OH:51])([CH3:50])[CH2:15][C@@H:14]([CH3:52])[C:12](=[O:13])[C@H:11]([CH3:53])[C@@H:10]([OH:54])[C@@:9]1([OH:56])[CH3:55].[CH3:57]O>>[CH3:6][CH2:7][C@H:8]1[O:23][C:21](=[O:22])[C@H:20]([CH3:24])[C@@H:19]([O:25][C@@H:26]2[O:31][C@@H:30]([CH3:32])[C@H:29]([OH:33])[C@@:28]([O:35][CH3:36])([CH3:34])[CH2:27]2)[C@H:18]([CH3:37])[C@@H:17]([O:38][C@@H:39]2[O:44][C@H:43]([CH3:45])[CH2:42][C@H:41]([N:46]([CH3:47])[CH3:48])[C@H:40]2[OH:49])[C@@:16]([O:51][CH3:57])([CH3:50])[CH2:15][C@@H:14]([CH3:52])[C:12](=[O:13])[C@H:11]([CH3:53])[C@@H:10]([OH:54])[C@@:9]1([OH:56])[CH3:55]
Reactant: CO
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: O=P([O-])([O-])[O-]
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(OC)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O

Procedure:
Each fraction was analyzed by thin layer chromatography (E. Merck Darmstadt. thin layer chromatography plate silica gel 60 silanized precoated, thickness 0.25 mm), developing in a mixture of methanol and a 0.1 M phosphate buffer solution (pH 7.0) (3:2). The fractions having Rf value 0.42 (c.f., erythromycin A, Rf value 0.46) were combined and most of the methanol was evaporated in vacuo. The residue was made alkaline with sodium carbonate and extracted with chloroform. The chloroform layer was washed with water, dried and concentrated in vacuo. The crystals obtained were recrystallized from a mixture of chloroform and diisopropyl ether (1:2), giving 700 mg of pure 6-O-methylerythromycin A (formula(I), R1 is hydrogen) in the form of colorless needles.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:31])[C:15](=[O:30])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)=[C:4]([OH:32])[CH:3]=1.Cl[CH2:34][CH2:35][OH:36]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:31])[C:15](=[O:30])[C:16]2[CH:17]=[C:18]([C:26]([F:27])([F:28])[F:29])[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=2)=[C:4]([O:32][CH2:34][CH2:35][OH:36])[CH:3]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccc(F)cc1O
Reactant: OCCCl
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccc(F)cc1OCCO

Procedure:
The title compound was prepared in analogy to example 49, from N-[4-(4-fluoro-2-hydroxy-phenyl)-pyridin-3-yl]-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 48) and 2-chloroethanol (CAS RN 107-07-3). Off-white solid (62%). MS (ESI): m/z=502.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8].C(N(CC)CC)C.[C:32](Cl)(=[O:36])[CH:33]([CH3:35])[CH3:34]>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH2:12][CH2:11]1)=[O:8]
Reactant: CC(C)C(=O)Cl
Reactant: O=C(NC1CCNCC1)c1ccccc1Oc1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)N1CCC(NC(=O)c2ccccc2Oc2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
To an ice cooled solution of 4-[2-(2,4-dichlorophenoxy)-N-piperidin-4-ylbenzamide (AMR01077, 100 mg, 0.274 mmol) in dry DCM (5 mL) were added triethylamine (0.2 mL, 1.37 mmol) and isobutyryl chloride (0.035 mL, 0.33 mmol). The reaction mixture was stirred at room temperature until completion by TLC (1.5 h), and quenched with saturated NaHCO3. The organic solution was evaporated to dryness and the oil obtained was purified by column chromatography using DCM/MeOH 95:5 as eluent. Further purification was carried out by treating a DCM solution of the obtained compound with trisamine scavenger (100 mg) for 2 h. The scavenger was filtered off, and the solvent evaporated to give 2-(2,4-dichlorophenoxy)-N-(1-isobutyrylpiperidin-4-yl)benzamide (93 mg, 77%) as a white solid. Rf: 0.15 (hexane/AcOEt 4:6), mp 51-54° C. LC/MS (APCI) tr=4.66 min, m/z 437.33 (66), 435.31 (M++H, 100). HPLC tr=2.39 min (97.97%) 1H NMR (270 MHz, CDCl3) δ 1.10 (6H, d, J=6.7 Hz, 2CH3), 1.36 (2H, m, CH2), 2.00 (2H, m, CH2), 2.78 (1H, hept, J=6.7 Hz, CHMe2), 2.80 (1H, m, ½CH2), 3.18 (1H, br t, ½CH2), 3.83 (1H, m, ½CH2), 4.19 (1H, m, CH), 4.44 (1H, m, ½CH2), 6.79 (1H, d, J=8.6 Hz, ArH), 6.87 (1H, d, J=8.7 Hz, ArH), 7.19-7.28 (2H, m, ArH), 7.35 (1H, br s, NH), 7.40 (1H, m, ArH), 7.50 (1H, d, J=2.5 Hz, ArH) and 8.17 (1H, dd, J=7.7, 1.7 Hz, ArH).
Reaction SMILES: C(OC([N:6]([CH2:8][CH:9]([OH:15])[CH2:10][P:11](=[O:14])([OH:13])[OH:12])[OH:7])=O)C.O.N>Cl.CO>[OH:15][CH:9]([CH2:8][NH:6][OH:7])[CH2:10][P:11](=[O:12])([OH:14])[OH:13]
Reactant: CCOC(=O)N(O)CC(O)CP(=O)(O)O
Agent: Cl
Agent: N
Solvent: O
Solvent: CO
Product: O=P(O)(O)CC(O)CNO
Yield: 36.7 %

Procedure:
A solution of 3-(N-ethoxycarbonyl-N-hydroxyamino)-2-hydroxypropylphosphonic acid (2.4 g.) in 1 N hydrochloric acid (100 ml.) was heated to reflux for 14 hours. The reaction mixture was evaporated to dryness under reduced pressure to give a residue, to which was added water (20 ml.), washed twice with chloroform (each 10 ml. portion) and decolorized with activated charcoal (200 mg.). The activated charcoal was filtered off and the filtrate was evaporated to dryness under reduced pressure to give a dark reddish oil, to which was added water (3 ml) and adjusted to pH 4.0 with 28% aqueous ammonia. This aqueous solution was diluted with methanol and allowed to stand at ambient temperature, and then the precipitating crystals were collected by filtration to give 2-hydroxy-3-(N-hydroxyamino)propylphosphonic acid (0.62 g.).
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[Cl:5][C:6]1[CH:7]=[C:8]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([OH:26])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH:9]=[CH:10][C:11]=1[Cl:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:5][C:6]1[CH:7]=[C:8]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH2:2][C:3]#[N:4])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH:9]=[CH:10][C:11]=1[Cl:12]
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1O
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
Bromoacetonitrile (2.1 ml, 30.1 mmol) was added to a mixture of 4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-ol (10.12 g; 30.1 mmol) and potassium carbonate (16.6 g; 120.1 mmol) in DMF (200 ml). The mixture was stirred at room temperature overnight. The solvent was removed under high vacuum and the residue was triturated with water, filtered, washed with a mixture of hexane and ether (1/1) and dried under vacuum to give {[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}acetonitrile (9.6 g; 91% yield). 1H NMR (400 MHz; DMSO-d6): 3.99 (s, 3H), 5.40 (s, 2H), 7.41 (s, 1H), 7.64 (d, 1H), 7.87 (dd, 1H), 7.90 (s, 1H), 8.23 (d, 1H), 8.57 (s, 1H), 9.69 (s, 1H); MS (EI) for C17H12Cl2N4O2: 375.06 (MH+).
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10]C(C)(C)C)=O)#[N:2].FC(F)(F)C(O)=O.[CH2:22]([C:34]1[CH:42]=[CH:41][C:37](C(O)=O)=[CH:36][CH:35]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl.CCOC(C)=O>[CH2:22]([C:34]1[CH:35]=[CH:36][C:37]([C:8]([N:4]2[CH2:5][CH2:6][CH2:7][C@H:3]2[C:1]#[N:2])=[O:10])=[CH:41][CH:42]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C#N
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCc1ccc(C(=O)N2CCC[C@H]2C#N)cc1
Temperature: 50 °C
Yield: 22 %

Procedure:
General procedure D was used to deprotect 0.4 grams (2.05 mmols) of 28 using 21 mL of dichloromethane and trifluoroacetic acid. After standard work-up procedures, the TFA salt of 28 was coupled to 0.6 grams (2.05 mmols) of 4-dodecylbenzoic acid using 1.1 grams (2.05 mmols) of PyBOP and 1.1 grams (8.2 mmols) of N,N-diisopropylethylamine in 21 mL of dichloromethane according general procedure E and heating to 50° C. After previously described work-up and purification procedures (column chromatography, 25% EtOAc in hexanes), 0.17 grams (0.45 mmols, 22%) of the title product was recovered as an off-white solid. 1H NMR (500 MHz, CDCl3) δ 7.50 (d, J=8.0 Hz, 2H), 7.22 (d, J=7.6 Hz, 2H), 4.96-4.84 (m, 1H), 3.73-3.63 (m, 1H), 5.62-3.52 (m, 1H), 2.68-2.58 (m, 2H), 2.39-2.26 (m, 1H), 2.24-2.10 (m, 1H), 2.06-1.96 (m, 1H), 1.67-1.55 (m, 1H), 1.39-1.18 (m, 18H), 0.87 (t, J=6.9 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 170.18, 146.28, 128.40, 127.61, 127.17, 118.73, 49.51, 46.87, 35.84, 31.91, 31.20, 30.30, 29.65, 29.56, 29.46, 29.34, 29.23, 25.58, 22.68, 14.12.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[C:17]2[C:8]([S:9][C:10]3[CH:11]=[C:12]([C:20]#[N:21])[CH:13]=[CH:14][C:15]=3[C:16]2=[O:19])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N-:22]=[N+:23]=[N-:24].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O>[C:1]([C:5]1[CH:18]=[C:17]2[C:8]([S:9][C:10]3[CH:11]=[C:12]([C:20]4[NH:24][N:23]=[N:22][N:21]=4)[CH:13]=[CH:14][C:15]=3[C:16]2=[O:19])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2sc3cc(C#N)ccc3c(=O)c2c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc2sc3cc(-c4nnn[nH]4)ccc3c(=O)c2c1

Procedure:
A mixture of 7-tert.butyl-3-cyanothioxanthone (1.25g), sodium azide (0.31g), ammonium chloride (0.25g) and dimethylformamide (15ml) was heated at 125°- 130° C for 4 hr., cooled, and poured into dilute hydrochloric acid. The yellow precipitated product was filtered off and recrystallised from dimethylformamide to yield 7-tert.butyl-3-(5-tetrazolyl)thioxanthone, m.p. 277° C. with decomposition. Found: C 64.33%; H 5.11%; N 16.68%. C18H16O4OS requires C 64.27%; H 4.80%; N 16.66%.
Reaction SMILES: [F:1][C@H:2]1[CH2:4][C@H:3]1[C:5]([NH:7][C:8]1[N:9]=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18]1[CH:19]=[N:20][C:21]([CH:25]([OH:30])[C:26]([F:29])([F:28])[F:27])=[CH:22][C:23]=1[CH3:24])[CH:12]=2)=[O:6].ClCCl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:36]>S([O-])([O-])(=O)=S.[Na+].[Na+]>[F:1][C@H:2]1[CH2:4][C@H:3]1[C:5]([NH:7][C:8]1[N:9]=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18]1[CH:19]=[N:20][C:21]([C:25]([OH:36])([OH:30])[C:26]([F:29])([F:28])[F:27])=[CH:22][C:23]=1[CH3:24])[CH:12]=2)=[O:6]
Reactant: Cc1cc(C(O)C(F)(F)F)ncc1-c1ccc2cc(NC(=O)[C@@H]3C[C@@H]3F)ncc2c1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(C(O)(O)C(F)(F)F)ncc1-c1ccc2cc(NC(=O)[C@@H]3C[C@@H]3F)ncc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.8 %

Procedure:
A solution of (1S,2S)-2-fluoro-N-(7-(4-methyl-6-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide (139.1 mg; 0.3317 mmol) in dichloromethane (5 mL; 78.00 mmol) was treated with Dess-Martin periodinane (172.7 mg; 0.3950 mmol) and stirred at room temperature. After 3 hours, additional Dess-Martin periodinane was added (142 mg). After an additional 5 hours, 30 mL of 10% aqueous sodium thiosulfate was added and the reaction mixture stirred for 10 minutes. The reaction mixture was washed with 2 M aqueous sodium carbonate, dried over MgSO4, filtered, and concentrated to yield 113.8 mg (79%) of the title compound. LCMS (ESI): M+H=436.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[CH:17][CH:18]=1)[C:5]([OH:15])([C:10]#[C:11][CH:12]1[CH2:14][CH2:13]1)[C:6]([F:9])([F:8])[F:7].C(N(C(C)C)CC)(C)C.Br[CH:39]([CH2:43][CH2:44][Br:45])[C:40](Cl)=[O:41]>C(Cl)Cl>[Br:45][CH2:44][CH2:43][CH:39]1[O:15][C:5]([C:10]#[C:11][CH:12]2[CH2:13][CH2:14]2)([C:6]([F:7])([F:8])[F:9])[C:4]2[CH:3]=[C:2]([Cl:1])[CH:18]=[CH:17][C:16]=2[N:19]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[C:40]1=[O:41]
Reactant: O=C(Cl)C(Br)CCBr
Reactant: COc1ccc(CNc2ccc(Cl)cc2C(O)(C#CC2CC2)C(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)C(CCBr)OC(C#CC3CC3)(C(F)(F)F)c3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
To a solution of 1.64 g of 3-chloro-6-(4-methoxyphenyl)methylamino-α-cyclopropylethynyl-α-(trifluoromethyl)benzyl alcohol and 2.0 mL of diisopropylethylamine in 30 mL of dry methylene chloride was added 1.6 g of 2,4-dibromobutyryl chloride. After stirring at room temperature overnight, the mixture was poured onto water and extracted with ether. The ether layer was washed with aqueous sodium bicarbonate, dried, and evaporated to an oil. This material was subjected to column chromatography over silica gel (elution with 5-10% ethyl acetate in hexanes) affording 1.13 g of the title compound as a mixture of diastereomers.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[C:7]([Br:21])[CH:6]=1.[I-:23]>S([O-])([O-])(=O)=O.[Ag+].[Ag+].CO>[Br:11][C:9]1[CH:10]=[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:22])[CH:6]=[C:7]([Br:21])[C:8]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([I:23])[CH:14]=1
Reactant: COC(=O)Cc1cc(Br)c(Oc2ccc(OC)cc2)c(Br)c1
Reactant: [I-]
Agent: [Ag+]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COC(=O)Cc1cc(Br)c(Oc2ccc(OC)c(I)c2)c(Br)c1
Reaction time: 0.17 h
Yield: 64.1 %

Procedure:
Methyl[3,5-dibromo-4-(4-methoxyphenoxy)phenyl]acetate (1.0 g, 2.3 mmol), silver (I) sulfate (1.6 g, 4.6 mmol) and methanol (10 mL) was stirred in the dark at −78° C. Iodide (1.2 g, 4.6 mmol) was added and the reaction mixture was allowed to reach room temperature after 10 minutes. The yellow precipitate was filtered off, the eluate dissolved in ethyl actetate and washed with water. After concentration of the organic phase, 0.82 g (64%) of methyl [3,5-dibromo-4-(4-methoxy-3-iodophenoxy)phenyl]acetate was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)=[O:13])[CH2:11][C:4]=2[CH:3]=1.C(O)(=O)/C=C\C(O)=O.ClC1[N:38]=[N:37]C2CCNCC=2C=1.C1C2C(=CC=CC=2)C=CC=1C(Cl)=O>C(O)C>[NH:37]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)=[O:13])[CH2:11][C:4]=2[CH:3]=1)[NH2:38]
Reactant: O=C(c1ccc2ccccc2c1)N1CCc2nnc(Cl)cc2C1
Reactant: Clc1cc2c(nn1)CCNC2
Agent: O=C(Cl)c1ccc2ccccc2c1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Product: NNc1cc2c(nn1)CCN(C(=O)c1ccc3ccccc3c1)C2

Procedure:
The 3-chloro-6-(2-naphthoyl)-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine, required as starting material, is produced in a manner analogous to that described in Example 8 (g), from 3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine maleate and 2-naphthoyl chloride. Reaction time 22 hours at room temperature. M.P. 167°-170° (decomp., from 95% ethanol).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:3][CH2:2]1.Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:29])[NH:22][CH2:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:17][CH:16]=1)=[O:13]>ClCCl>[CH3:26][C:25]([CH3:28])([CH3:27])[CH2:24][CH2:23][NH:22][C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][C:12]([N:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[CH2:6][CH2:7]2)=[O:13])=[CH:20][CH:19]=1)=[O:29]
Reactant: CC(C)(C)CCNC(=O)c1ccc(OC(=O)Cl)cc1
Reactant: C1CN(CC2CC2)CCN1
Solvent: ClCCl
Product: CC(C)(C)CCNC(=O)c1ccc(OC(=O)N2CCN(CC3CC3)CC2)cc1
Reaction time: 16 h

Procedure:
The title product was prepared from 1-cyclopropylmethylpiperazine (0.35 mmol) dissolved in dichloromethane (5 ml). 4-(3,3-dimethyl-butylcarbamoyl)-phenyl chloroformate (0.35 mmol) was added at room temperature. The reaction mixture was stirred for 16 h and evaporated to dryness and subjected to preparative HPLC (method C) (5%, white crystals). HPLC-MS m/z=388.2 (M+1), Rt: 2.43 min.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])=[CH:4][C:3]=1[S:21][C:22]1N(C)N=NN=1.Cl[C:29]1C(=O)C2C(=CC=CC=2)C(=O)C=1NC1C=CC(S(NC2C=CC(OC)=CC=2)(=O)=O)=C(OC)C=1>>[CH2:22]([S:21][C:3]1[CH:4]=[C:5]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:29]
Reactant: Cn1nnnc1Sc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Reactant: COc1ccc(NS(=O)(=O)c2ccc(NC3=C(Cl)C(=O)c4ccccc4C3=O)cc2OC)cc1
Product: CCSc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O

Procedure:
5.2.52 N-(3-(ethylthio)-4-hydroxynaphthalen-1-yl)thiophene-2-sulfonamide (14j) was prepared according to the procedure for 14d except using (E)-N-(3-ethylthio-4-oxonaphthalen-1(4H)-ylidene)thiophene-2-sulfonamide (13j), which afforded the title compound 14 mg (100%) as a grey solid, m.p.: ° C.