Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[OH-].[K+].[CH2:11](Br)[CH2:12][OH:13].N1C=CC=NC=1>C(O)C>[OH:13][CH2:12][CH2:11][N:4]1[CH:3]=[C:2]([F:1])[CH:7]=[N:6][C:5]1=[O:8]
Reactant: OCCBr
Reactant: O=c1ncc(F)c[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: c1cncnc1
Product: O=c1ncc(F)cn1CCO
Yield: 50 %

Procedure:
5-Fluoropyrimid-2-one (0.008 mol) was dissolved in a solution of potassium hydroxide (0.008 mol) in absolute ethanol (100 ml) at 80° C. and ethylene bromohydrin (0.008 mol) added gradually with stirring. The alkylation was incomplete when the pH had become neutral. The reaction was further monitored by chromatography and equivalent amounts of potassium hydroxide and ethylene bromohydrin added until all the pyrimidine had been alkylated. The reaction mixture was then filtered and the filtrate evaporated to dryness before the residue was triturated with ether and extracted with warm acetone. Evaporation of the acetone solution left the title compound in 50% yield, m.p. 134°-136° C. after recrystallisation from ethanol; Found: C, 45.83; H, 4.42; Calc. for C6H7FN2O2 : C, 45.58; H, 4.46.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([CH3:32])[CH:11]=1>>[CH3:30][C:29]1[C:24]([N:21]2[CH2:20][CH2:19][N:18]([C:16]([C:13]3[CH:14]=[CH:15][C:10]([N:7]4[C@H:3]([CH2:2][OH:1])[CH2:4][CH2:5][C:6]4=[O:8])=[CH:11][C:12]=3[CH3:32])=[O:17])[CH2:23][CH2:22]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Reactant: O=C1CC[C@@H](CO)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CC[C@H]4CO)cc3C)CC2)c(C)c1
Yield: 17.6 %

Procedure:
Using (S)-5-hydroxymethylpyrrolidin-2-one (168 mg) and (4-bromo-2-methylphenyl) [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (516 mg) described in Preparation Example 118 and by the reaction and treatment in the same manner as in Example 1, the title compound (99 mg) was obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19]2)=[N:2]1.[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][NH:29][CH3:30].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[CH:22]=[CH:21][C:20]([CH2:23][N:29]([CH3:30])[CH2:28][CH2:27][N:26]([CH3:31])[CH3:25])=[CH:19]2)=[N:2]1
Reactant: CNCCN(C)C
Reactant: O=Cc1ccn(-c2ccccc2/C=C/c2n[nH]c3ccccc23)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CN(C)CCN(C)Cc1ccn(-c2ccccc2/C=C/c2n[nH]c3ccccc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
Compound 167 (0.06 g, 0.19 mmol) was dissolved in dichloroethane (2.0 mL) and the solution was added with N,N,N′-trimethylethylenediamine (62 μL, 0.57 mmol), acetic acid (63 μL, 0.57 mmol) and sodium triacetoxyborohydride (0.12 g, 0.57 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture was added with water, extracted with ethyl acetate and the organic layer was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=9/1) to obtain Compound 188 (41 mg, 54%).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(=O)(O)(O)[OH:20]>>[C:1]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15](=[O:20])[CH2:14]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(O)(O)O
Reactant: O=C(c1ccccc1)c1cccc2c(Cl)c[nH]c12
Product: O=C1Cc2cccc(C(=O)c3ccccc3)c2N1

Procedure:
The process as defined in claim 7 wherein 7-benzoyl-3-chloro-indole is hydrolyzed with phosphoric acid in a solvent at reflux temperature to produce 7-benzoylindolin-2-one.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]([C:10]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[O:11])=[C:8]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])[C:6]1=[O:38].[C:39]1([N:45]=[C:46]=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl>[O:38]=[C:6]1[N:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])[C:8]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:9]([C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])[N:5]1[CH2:4][CH2:3][CH2:2][NH:1][C:46]([NH:45][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:47]
Reactant: O=C=Nc1ccccc1
Reactant: Cc1ccccc1-n1c(-c2ccccc2)c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)n(CCCN)c1=O
Solvent: ClCCl
Product: Cc1ccccc1-n1c(-c2ccccc2)c(C(=O)N2CCNCC2)n(CCCNC(=O)Nc2ccccc2)c1=O
Temperature: 30 °C
Reaction time: 1.5 h

Procedure:
To a solution of 201 (27 mg, 0.05 mmol) in CH2Cl2 (1 mL), which was stirred at room temperature and was added phenyl isocyanate (6.5 mg, 0.055 mmol). The reaction mixture was stirred for 1.5 hours at 30° C., and was evaporated under reduced pressure. The residue was purified by flash chromatography, afforded 201H (21 mg) as a white solid. LCMS: purity=96%. MS (EZ, m/e): 639.2 (M+H)+.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:95]=[CH:96][CH:97]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:70]=[CH:69][C:68]([NH:71][CH:72]5[CH2:77][CH2:76][N:75]([C:78]([O:80][C:81]([CH3:84])([CH3:83])[CH3:82])=[O:79])[CH2:74][CH2:73]5)=[CH:67][CH:66]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:95]=[CH:96][CH:97]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([NH:71][CH:72]5[CH2:77][CH2:76][N:75]([C:78]([O:80][C:81]([CH3:83])([CH3:84])[CH3:82])=[O:79])[CH2:74][CH2:73]5)=[CH:69][CH:70]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(NC5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cc2)CC1
Yield: 58.8 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl 4-((4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amino)piperidine-1-carboxylate (130 mg, 0.18 mmol) was hydrolyzed with lithium hydroxide (37 mg, 0.9 mmol) in THF/methanol/water (2/2/1 mL) to yield 60 mg (58.8% yield) after purification by preparative TLC (Silicagel-1000 micron) using 3% methanol in chloroform as eluent. MS: m/z=566.8 (M+1).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([NH:26][CH2:27][C@@H:28]([C:37]1[CH:48]=[CH:47][C:40]2[O:41][C:42]([CH3:46])([CH3:45])[O:43][CH2:44][C:39]=2[CH:38]=1)[O:29][Si](CC)(CC)CC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C1COCC1.C(OCC)C>[CH2:19]([NH:26][CH2:27][C@@H:28]([C:37]1[CH:48]=[CH:47][C:40]2[O:41][C:42]([CH3:45])([CH3:46])[O:43][CH2:44][C:39]=2[CH:38]=1)[OH:29])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC[Si](CC)(CC)O[C@@H](CNCc1ccccc1)c1ccc2c(c1)COC(C)(C)O2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OCc2cc([C@@H](O)CNCc3ccccc3)ccc2O1
Yield: 73.5 %

Procedure:
Tetrabutylammonium fluoride (395 ml, 1M in THF) was added dropwise to a stirred solution of N-benzyl-N-{(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-[(triethylsilyl)oxy]ethyl}amine (129.9 g) in THF (900 ml) at 5° C. Upon complete addition the reaction mixture was maintained at this temperature for 15 min before water (600 ml) was added. The resulting slurry was diluted with diethyl ether (500 ml) and filtered. The filtrate was washed with water (2×500 ml) and brine (500 ml) before being dried over anhydrous Na2SO4. The resulting mixture was filtered and concentrated under reduced pressure to give a solid which was triturated with diisopropyl ether to give the title compound (70 g) as a solid, LC RT=3.34 min, δ (CDCl3) 7.31 (5H, m), 7.09 (1H, d, J 8 Hz), 6.98 (1H, s), 6.77 (1H, d J 8 Hz), 4.82 (2H, s), 4.63 (1H, m), 3.83 (2H, d, J 4 Hz), 2.80 (2H, m), 1.52 (6H, s).
Reaction SMILES: [CH3:1][C@@:2]1([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:22][CH:23]4[CH2:28][CH2:27][C:26]5([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]5)[CH2:25][CH2:24]4)[C:14]=3[C:18]([F:21])([F:20])[F:19])[CH:9]=2)[CH2:6][O:5]C(=O)[NH:3]1.[OH-].[Li+].C(O)C.O>>[NH2:3][C@@:2]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:22][CH:23]3[CH2:28][CH2:27][C:26]4([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)[CH2:25][CH2:24]3)[C:14]=2[C:18]([F:20])([F:21])[F:19])[CH:9]=1)([CH3:1])[CH2:6][OH:5]
Reactant: C[C@@]1(c2ccc3c(C(F)(F)F)c(OC4CCC5(CCCCC5)CC4)ccc3c2)COC(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@](N)(CO)c1ccc2c(C(F)(F)F)c(OC3CCC4(CCCCC4)CC3)ccc2c1
Yield: 66.3 %

Procedure:
The mixture of (4R)-4-methyl-4-(6-(spiro[5.5]undecan-3-yloxy)-5-(trifluoromethyl)naphthalen-2-yl)oxazolidin-2-one (62.5 mg, 0.000135 mol) and lithium hydroxide (36 mg, 0.0015 mol) in ethanol (2 mL, 0.04 mol) and water (0.7 mL, 0.04 mol) was heated to reflux for overnight. The solvent was removed under vacuum and the residue was partitioned between water/CH2Cl2. The aqueous was extensively extracted with CH2Cl2. And the combined organic phase was dried over Na2SO4. The concentrated residue was taken up into methylene chloride and subjected to chromatography purification with MeOH/CH2Cl2 (10:90 to 80:20) to give (2R)-2-amino-2-(6-(spiro[5.5]undecan-3-yloxy)-5-(trifluoromethyl)naphthalen-2-yl)propan-1-ol as a white gel (39.0 mg, 66%). LCMS: Rf=1.86 min 419.30 ([M-16], 100%). 1H NMR (400 MHz, MeOD) δ=8.15 (dd, J=1.9, 9.2 Hz, 1 H), 8.07 (d, J=9.2 Hz, 1 H), 7.96 (d, J=2.1 Hz, 1 H), 7.71 (dd, J=2.2, 9.3 Hz, 1 H), 7.47 (d, J=9.3 Hz, 1 H), 4.68-4.59 (m, 1 H), 3.76 (d, J=10.8 Hz, 1 H), 3.70 (d, J=10.8 Hz, 1 H), 1.95-1.83 (m, 2 H), 1.82-1.67 (m, 4 H), 1.54 (s, 3 H), 1.53-1.42 (m, 8 H), 1.42-1.28 (m, 4 H).
Reaction SMILES: [F-].[K+].I[C:4]1[C:20]([O:21][CH2:22][C@@H:23]([N:28]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]2=[O:38])[CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:19][C:7]2[N:8]([CH3:18])[C:9](=[O:17])[C:10]3[C:15]([C:6]=2[CH:5]=1)=[CH:14][CH:13]=[N:12][C:11]=3[CH3:16].C[Si](C)(C)[C:41]([F:44])([F:43])[F:42].N>[Cu]I.CN1CCCC1=O>[CH3:16][C:11]1[N:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[C:9](=[O:17])[N:8]([CH3:18])[C:7]1[CH:19]=[C:20]([O:21][CH2:22][C@@H:23]([N:28]3[C:29](=[O:38])[C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:36]3=[O:37])[CH2:24][CH:25]([CH3:27])[CH3:26])[C:4]([C:41]([F:44])([F:43])[F:42])=[CH:5][C:6]2=1
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)N3C(=O)c4ccccc4C3=O)c(I)cc21
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cu]I
Agent: N
Agent: [F-]
Solvent: CN1CCCC1=O
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)N3C(=O)c4ccccc4C3=O)c(C(F)(F)F)cc21
Temperature: 200 °C
Yield: 19.6 %

Procedure:
Dried potassium fluoride (19.51 mg, 0.336 mmol) and copper(I) iodide (64.0 mg, 0.336 mmol) were mixed and heated to 200° C. under gentle shaking at reduced pressure (1 Torr) until a light yellow-greenish color appeared. After cooling, anhydrous N-methyl-2-pyrrolidinone (1 mL) was added, followed by (S)-2-(1-((9-iodo-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)isoindoline-1,3-dione (100 mg, 0.168 mmol) and trimethyl(trifluoromethyl)silane (0.075 mL, 0.504 mmol). The brown solution thus obtained was heated at 90° C. for 16 h. After cooling, aqueous ammonia (10 mL) was added to the reaction mixture. The reaction mixture was and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (1×10 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate: petroleum ether as eluent system) to afford (S)-2-(1-(4,6-dimethyl-5-oxo-9-(trifluoromethyl)-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yloxy)-4-methylpentan-2-yl)isoindoline-1,3-dione (80 mg, 0.033 mmol, 20% yield, 22% purity) as a pale yellow solid. LC/MS (ESI) m/e 538.6 [(M+H)+, calcd for C29H27F3N3O4 538.2] LC/MS retention time (method E): tR=1.27 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12](=[O:44])[O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[CH:28]=[C:27]([Cl:29])[C:26]([C:30]([F:33])([F:32])[F:31])=[CH:25][C:24]=3[NH:34][C:35]([C:37]3[CH:41]=[C:40]([CH3:42])[N:39]([CH3:43])[N:38]=3)=O)=[CH:18][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl>[OH-].[Na+].C(O)C.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12](=[O:44])[O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[C:23]4[CH:28]=[C:27]([Cl:29])[C:26]([C:30]([F:32])([F:31])[F:33])=[CH:25][C:24]=4[N:34]=[C:35]3[C:37]3[CH:41]=[C:40]([CH3:42])[N:39]([CH3:43])[N:38]=3)=[CH:18][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(Nc3cc(Cl)c(C(F)(F)F)cc3NC(=O)c3cc(C)n(C)n3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(-n3c(-c4cc(C)n(C)n4)nc4cc(C(F)(F)F)c(Cl)cc43)cc2)cc1
Temperature: 50 °C
Reaction time: 85 h
Yield: 21.3 %

Procedure:
A mixture of 2-(4-{[5-chloro-2-{[(1,5-dimethyl-1H-pyrazol-3-yl)carbonyl]amino}-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl (4-methylphenyl)sulfonylcarbamate (step 3, 145 mg, 0.223 mmol) in 2N NaOH (1 ml) and ethanol (2 ml) was stirred at 50° C. for 85 h. After cooling, the pH value was adjusted to 4.0 by addition of 2N HCl. The mixture was diluted with water (80 ml), and extracted with dichloromethane (80 ml×3). The combined organic layer was washed with brine (50 ml), dried (MgSO4), and concentrated. Purification by PTLC eluting with hexane/ethyl acetate (1:3) to afford 30 mg (21%) of the title compound as a red solid.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[F:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:20])[C:13]([OH:19])=[CH:14][N:15]2[CH3:18])=[CH:10][CH:9]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([S:3]([O:19][C:13]1[C:12](=[O:20])[C:11]2[C:16](=[CH:17][C:8]([F:7])=[CH:9][CH:10]=2)[N:15]([CH3:18])[CH:14]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)Cl
Reactant: Cn1cc(O)c(=O)c2ccc(F)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)Oc1cn(C)c2cc(F)ccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethanesulphonyl chloride (1.5 ml) was added to a stirred mixture of 7-fluoro-3-hydroxy-1-methyl-4quinolone (3.0 g), obtained as described in Example 3a-f, triethylamine (4.35 ml) and dry dichloromethane (100 ml) at ambient temperature and the resultant solution stirred for 5 minutes then kept at ambient temperature overnight. Further ethanesulphonyl chloride (0.2 ml) was added and the solution stirred at ambient temperature for 4 hours and then kept at this temperature for 3 days. The mixture was filtered and the filtrate was washed with water (2×150 ml). The dichloromethane solution was dried over magnesium sulphate and the solvent evaporated to give a residue which was crystallised from industrial methylated spirit (100 ml). The solid was triturated with diethyl ether (100 ml) and then water (500 ml) to give the novel compound 7-fluoro-1-methyl-4-oxo-1,4-dihydro-quinol-3-yl ethanesulphonate, m.p. 154°-156.5°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12](OC)=[O:13])[CH:6]=[CH:5]2.Cl.O>CCOCC.C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][OH:13])[CH:6]=[CH:5]2
Reactant: COC(=O)c1ccc2cc(Cl)ccc2c1
Agent: Cl
Solvent: O
Solvent: c1ccccc1
Solvent: CCOCC
Product: OCc1ccc2cc(Cl)ccc2c1
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A solution of the methyl 6-chloro-2-naphthoate (111 g.) in ether (2.5 l.) is added, dropwise below 25° C. under nitrogen, to a stirred mixture of ether (250 ml.) and a 70% solution (250 ml.) of sodium dihydro-bis-(2-methoxyethoxy)aluminate in benzene during 1 hour. The mixture is stirred for a further 30 minutes and 2N-hydrochloric acid (250 ml.) is added cautiously. The solution is decanted from undissolved solid, and concentrated hydrochloric acid is added to the solid until it dissolves. The two solutions thus obtained are combined, and ether (1 l.) and a mixture of ice and water (1 l.) are added. The ethereal layer is separated, and the aqueous phase extracted with ether. The ethereal solutions are combined, washed with water, dried and evaporated to give 6-chloro-2-hydroxymethylnaphthalene (95 g.) which may be further purified by crystallisation from toluene to give material of m.p. 134°-137° C.
Reaction SMILES: [C:1]([C:4]1[N:5]=[N:6][C:7]([NH:20][C@H:21]2[CH2:26][CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]2)=[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[S:10][C:9]=12)(=[O:3])[NH2:2].Cl>>[F:19][C:15]1[CH:14]=[C:13]([C:11]2[S:10][C:9]3=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=[N:6][C:7]([NH:20][C@H:21]4[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]4)=[C:8]3[CH:12]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Nc2nnc(C(N)=O)c3sc(-c4cccc(F)c4)cc23)C1
Agent: Cl
Product: NC(=O)c1nnc(N[C@H]2CCCNC2)c2cc(-c3cccc(F)c3)sc12

Procedure:
The crude product from step 5 (5)-tert-butyl 3-(7-carbamoyl-2-(3-fluorophenyl)thieno[2,3-d]pyridazin-4-ylamino)piperidine-1-carboxylate was treated with HCl (4N in dioxane, 3 mL) at room temperature for 30 min. Then the solvent was removed under reduced pressure and the residue was purified with HPLC to obtain the final compound (S)-2-(3-fluorophenyl)-4-(piperidin-3-ylamino)thieno[2,3-d]pyridazine-7-carboxamide. HPLC-MS tR=1.27 min (UV254 nm); mass calculated for formula C18H18FN5OS 371.1, observed LCMS m/z 372.1 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH2:37][CH2:38][OH:39])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[OH:39][CH2:38][CH2:37][NH:36][S:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:28]=1)(=[O:35])=[O:34]
Reactant: O=S(=O)(NCCO)c1cccc(Br)c1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=S(=O)(NCCO)c1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 3-bromo-N-(2-hydroxy-ethyl)-benzenesulfonamide (example B.34) (252 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (340 mg, 61%). MS (ISP) 555.1 [(M+H)+]; mp 213° C.
Reaction SMILES: N[C:2]1[C:7]2[N:8]([CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9](=[O:11])[NH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.N([O-])=O.[Na+].C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[K+].[K+].[BrH:35]>C(O)(=O)C.S(=O)(=O)(O)O.[Cu]Br>[Br:35][C:2]1[C:7]2[N:8]([CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9](=[O:11])[NH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Br
Reactant: CCOC(=O)CCCn1c(=O)[nH]c2cccc(N)c21
Agent: [Cu]Br
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Product: CCOC(=O)CCCn1c(=O)[nH]c2cccc(Br)c21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 20 %

Procedure:
To a solution of ethyl 4-(7-amino-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)butanoate (23.0 g, 87.3 mmol) in acetic acid (250 mL) was added dropwise sodium nitrite (6.32 g, 91.7 mmol) in conc. sulfuric acid (80 mL) at 0° C., and the mixture was stirred at 0° C. for 20 min. The mixture was added dropwise to a solution of copper(I) bromide (50.1 g, 350 mmol) in conc. hydrobromic acid (150 mL) at 0° C., and the mixture was stirred at room temperature for 2 hr. The mixture was poured into aqueous sodium hydrogen carbonate, neutralized with potassium carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with diisopropyl ether, recrystallized from ethyl acetate to give the title compound as a pale yellow crystal (5.79 g, 17.7 mmol, 20%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[CH:13]([O:15]CCCC)=[CH2:14].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>CS(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:13]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6])(=[O:15])[CH3:14]
Reactant: C=COCCCC
Reactant: COC(=O)c1ccc(C)c(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CS(C)=O
Product: COC(=O)c1ccc(C)c(C(C)=O)c1
Temperature: 120 °C
Reaction time: 12 h
Yield: 46.3 %

Procedure:
Into a 250-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a mixture of methyl 3-iodo-4-methylbenzoate (compound 5.3, 4.50 g, 16.3 mmol), 1-(vinyloxy)butane (4.21 mL, 32.6 mmol), TEA (4.53 mL, 32.5 mmol), 1,3-bis(diphenylphosphino)propane (672 mg, 1.63 mmol) and Pd(OAc)2 (349 mg, 1.55 mmol) in DMSO (50 mL). The mixture was stirred for 12 hours at 120° C., then cooled to room temperature. The pH was adjusted to 1-2 with aqueous hydrogen chloride (2 M) and stirred for 1 hour. The aqueous phase was extracted with ethyl acetate (3×200 mL) and the combined organic layers were washed with water (100 mL), then brine (3×100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:50) as the eluent to yield 1.45 g (46%) of the title compound as a yellow solid.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5](OC)=[C:6]([CH:8](O)[C:9]#CC2C=CC=CC=2)[CH:7]=1.[CH3:20][O:21][C:22]1[CH:29]=[C:28]([Br:30])[C:27]([O:31][CH3:32])=[CH:26][C:23]=1[CH:24]=[O:25]>>[Br:30][C:28]1[C:27]([O:31][CH3:32])=[CH:26][C:23]([CH:24]([OH:25])[C:9]#[C:8][C:6]2[CH:7]=[CH:2][CH:3]=[CH:4][CH:5]=2)=[C:22]([O:21][CH3:20])[CH:29]=1
Reactant: COc1ccc(F)cc1C(O)C#Cc1ccccc1
Reactant: COc1cc(C=O)c(OC)cc1Br
Product: COc1cc(C(O)C#Cc2ccccc2)c(OC)cc1Br
Yield: 100 %

Procedure:
Following the procedure used to prepare 1-(5-fluoro-2-methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol, 2,5-dimethoxy-4-bromobenzaldehyde was reacted to give the title compound as a colourless oil (1.45 g, 100%). LCMS (Method B): RT=4.49 min, [M+Na]+=369/371.