Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:12][C:13]([C:15]2[CH:16]=[C:17]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=3)[CH:18]=[CH:19][C:20]=2[OH:21])=[O:14])[C:9]([OH:11])=O)=[CH:3][CH:2]=1.COC(=O)[C@@H:39]([NH:53]C(C1C=C(C2C=CC(F)=C(Cl)C=2)C=CC=1O)=O)CC1C=CC(C2C=CC=CC=2)=CC=1.CN.C1COCC1.C[Si](Br)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[C:1]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]([NH:12][C:13]([C:15]2[CH:16]=[C:17]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=3)[CH:18]=[CH:19][C:20]=2[OH:21])=[O:14])[C:9](=[O:11])[NH:53][CH3:39])=[CH:5][CH:6]=1
Reactant: O=C(N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O)c1cc(-c2ccc(F)c(Cl)c2)ccc1O
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(-c2ccc(F)c(Cl)c2)ccc1O
Agent: CN
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CNC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(-c2ccc(F)c(Cl)c2)ccc1O

Procedure:
Resin bound 3-(Biphenyl-4-yl)-(2S)-[(3′-chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionic acid (30 mg, 0.09 mmol) prepared from resin bound 3-(Biphenyl-4-yl)-(2S)-[(3′-chloro-4′-fluoro-4-hydroxy-biphenyl3-carbonyl)-amino]-propionic acid methyl ester following general procedure C, was reacted with methyl amine in THF(0.45 mmol) as described in general procedure A, then cleaved with TMSBr/TFA/DCM (1:1:5) at rt for 4 h. The residue obtained after removing the solvent was purified by chromatography to give the title compound. (36 mg). LC/MS (m/z): 503 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH:8]([CH2:11][C:12]1[CH:20]=[C:19]([CH3:21])[C:18]2[C:14](=[CH:15][N:16]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[N:17]=2)[CH:13]=1)[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CS(C)=O.CO>[C:1]([O:5][C:6](=[O:30])[NH:7][CH:8]([CH2:11][C:12]1[CH:20]=[C:19]([CH3:21])[C:18]2[C:14](=[CH:15][N:16]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[N:17]=2)[CH:13]=1)[CH:9]=[O:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(CC(CO)NC(=O)OC(C)(C)C)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CO
Product: Cc1cc(CC(C=O)NC(=O)OC(C)(C)C)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 5 °C
Reaction time: 0.02 h

Procedure:
tert-Buty-1-hydroxy-3-(7-methyl-2-[{2-[trimethylsilyl]ethoxy}methyl]-2H-indazol-5-yl)propan-2-ylcarbamate (0.3 g, 0.69 mmol) was dissolved in anhydrous dimethyl sulfoxide (2.5 mL). Triethylamine (0.29 mL, 2.07 mmol) was then added and the reaction mixture cooled to ca. 5° C. using an ice bath. A solution of sulfur trioxide pyridine complex (0.33 g, 2.07 mmol) in dimethyl sulfoxide (2 mL) was added in one portion. After 1 min, the ice bath was removed and the reaction mixture stirred at room temperature for 20 min. The reaction mixture was poured into an ice slurry and extracted with ethyl acetate (3×). The combined organic extracts were washed with 10% citric acid (2×), water (2×), 5% sodium bicarbonate (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography afforded 0.2 g (74%). Mass spec. (in methanol): 466.25 (M+MeOH+H)+.
Reaction SMILES: CN1CCN2CCN(C)P1N(C)CC2.C(#N)C.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:26][C:27]([CH3:33])=[C:28]([CH2:30][CH2:31]I)[N:29]=2)=[CH:21][CH:20]=1>C1COCC1>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[O:26][C:27]([CH3:33])=[C:28]([CH:30]=[CH2:31])[N:29]=2)=[CH:23][CH:24]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCI
Agent: CN1CCN2CCN(C)P1N(C)CC2
Solvent: CC#N
Solvent: C1CCOC1
Product: C=Cc1nc(-c2ccc(Br)cc2)oc1C
Reaction time: 4 h
Yield: 78.8 %

Procedure:
Add 2,8,9-trimethyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (3.17 g, 14.7 mmol) as a solution using acetonitrile (10 mL) to a solution of 2-(4-bromo-phenyl)-4-(2-iodo-ethyl)-5-methyl-oxazole (See Intermediate 30) (4.38 g, 11.1 mmol) in 2.8:1 acetonitrile:THF (190 mL). After 4 hrs, concentrate under reduced pressure and add EtOAc and water to the residue. Separate the layers and extract the aqueous material with EtOAc. Wash the crude organic extract with water, dry over MgSO4, filter and concentrate. Purify on silica gel eluting with 7% EtOAc to give 2-(4-bromo-phenyl)-5-methyl-4-vinyl-oxazole (2.31 g, 83%): 1H NMR (400 Hz): (CDCl3) δ 7.89 (d, 2H, J=8 Hz), 7.57 (d, 2H, J=8 Hz), 6.54 (dd, 1H, J=17, 11 Hz), 5.93 (dd, 1H, J=17, 2 Hz), 5.29 (dd, 1H, J=11, 2 Hz), 2.40 (s, 3H).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][C@H:12]([O:14][C:15]2[CH:20]=[C:19]([NH:21][C@@H:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][C@@H:23]3[O:31][CH3:32])[N:18]=[CH:17][N:16]=2)[CH2:11][C@H:10]1[CH2:33]O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:35]([NH:42][SH:43](=[O:45])=[O:44])([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:65](C(OCC)=O)=NC(OCC)=O>CCOC(C)=O>[NH2:65][S:43]([N:42]([CH2:33][C@@H:10]1[CH2:11][C@@H:12]([O:14][C:15]2[CH:20]=[C:19]([NH:21][C@@H:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][C@@H:23]3[O:31][CH3:32])[N:18]=[CH:17][N:16]=2)[CH2:13][C@@H:9]1[O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:35](=[O:36])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])(=[O:44])=[O:45]
Reactant: CO[C@H]1Cc2ccccc2[C@H]1Nc1cc(O[C@@H]2C[C@@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)C2)ncn1
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: CC(C)(C)OC(=O)N[SH](=O)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CO[C@H]1Cc2ccccc2[C@H]1Nc1cc(O[C@@H]2C[C@@H](CN(C(=O)OC(C)(C)C)S(N)(=O)=O)[C@@H](O[Si](C)(C)C(C)(C)C)C2)ncn1
Reaction time: 4 h
Yield: 93.9 %

Procedure:
To a solution of {(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]cyclopentyl}methanol (105.3 mg, 0.0002168 mol), N-Boc-sulfonamide (58.9 mg, 0.000300 mol) and triphenylphosphine (85.3 mg, 0.000325 mol) in EtOAc (4.15 mL) under an atmosphere of nitrogen was added diethyl azodicarboxylate (51.9 μL, 0.000330 mol). The mixture was stirred for four hours. The solvent was removed and the orange residue was purified by flash chromatography (10 to 50% EtOAc/hexanes) to obtain 135.2 mg (94%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([OH:13])=[O:12].Br[CH2:15][C:16]#[CH:17].C1COCC1>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([CH2:17][C:16]#[CH:15])(=[O:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)O)c1
Reactant: C#CCBr
Solvent: C1CCOC1
Solvent: O
Product: C#CCS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Yield: 73.2 %

Procedure:
110.7 g (0.5 mol) of 2-chloro-5-nitrobenzenesulfinic acid were dissolved in 500 ml of water at pH 6.5 and the solution was added to a solution of 65.5 g (0.55 mol) of 3-bromoprop-1-yne and 100 ml of THF. The reaction mixture was then heated to 40°-50° C. After the reaction had ended (check by TLC), the reaction product was extracted with 1.5 l of ethyl acetate, and the organic phase was neutralized and dried over sodium sulfate. The solvent was evaporated off to leave 95 g of 2-chloro-5-nitro-1-(prop-1-yn-3-ylsulfonyl)benzene (melting point 238°-241° C.). ##STR28##
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[O:12]=[C:13]1[CH2:18][CH2:17][CH2:16][CH2:15][N:14]1[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([CH:28]([O:32][C:33]2[CH:42]=[C:41]3[C:36]([CH:37]=[CH:38][N:39]=[C:40]3[N+:43]3C=CC=CC=3)=[CH:35][CH:34]=2)[CH2:29][CH2:30][CH3:31])=[O:27])=[CH:21][CH:20]=1.O>C(CN)O>[O:12]=[C:13]1[CH2:18][CH2:17][CH2:16][CH2:15][N:14]1[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:27])[CH:28]([O:32][C:33]2[CH:42]=[C:41]3[C:36]([CH:37]=[CH:38][N:39]=[C:40]3[NH2:43])=[CH:35][CH:34]=2)[CH2:29][CH2:30][CH3:31])=[CH:21][CH:20]=1
Reactant: CCCC(Oc1ccc2ccnc(-[n+]3ccccc3)c2c1)C(=O)Nc1ccc(N2CCCCC2=O)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: NCCO
Solvent: O
Product: CCCC(Oc1ccc2ccnc(N)c2c1)C(=O)Nc1ccc(N2CCCCC2=O)cc1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
The crude 1-(7-{1-[4-(2-oxopiperidin-1-yl)phenylcarbamoyl]butoxy}-isoquinolin-1-yl)pyridinium toluene4-sulfonate obtained in this way is dissolved in 4 ml of ethanolamine, and the mixture is stirred at room temperature for 42 hours. The reaction mixture is introduced into water and extracted with ethyl acetate. The organic phase is evaporated, and the residue is chromatographed on a silica-gel column, giving N-[4-(2-oxopiperidin-1-yl)phenyl]-2-(1-aminoisoquinolin-7-yloxy)pentanamide (“AA”) as a colourless solid; ESI 433.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([OH:12])=[C:7]([CH3:13])[C:6]=1[CH3:14])(=[O:3])[CH3:2].C=O.[CH2:17]([OH:21])[CH2:18][CH2:19][CH3:20].[CH2:22](NCCCC)CCC.C(O)(=O)C>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH2:22][O:21][CH2:17][CH2:18][CH2:19][CH3:20])[C:8]([OH:12])=[C:7]([CH3:13])[C:6]=1[CH3:14])(=[O:3])[CH3:2]
Reactant: CCCCNCCCC
Reactant: CC(=O)Oc1c(C)cc(O)c(C)c1C
Reactant: CCCCO
Agent: C=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCCCOCc1c(C)c(OC(C)=O)c(C)c(C)c1O
Reaction time: 7 h

Procedure:
4-Acetoxy-2, 3, 5-trimethylphenol (1.8 g; 9.3 mmol), 87.3 % paraformaldehyde (0.38 g; 11.2 mmol), 1-butanol (4.48 g; 60.5 mmol), dibutylamine (0.12 g; 0.93 mmol) and acetic acid (0.28 g; 4.7 mmol) were mixed together, then the mixture was reacted under reflux with stirring for 7 hours. After completion of the reaction, toluene was added into the resulting mixture for extraction of the resulting product in toluene, and then the toluene phase was separated. After the separated toluene phase was sequentially washed with water, an aqueous 1% dilute sulfuric acid solution, an aqueous 5% sodium hydrogen carbonate solution and water, the toluene phase was distilled under reduced pressure to distill off compounds with low boiling points, to give 4-acetoxy-2,3,5-trimethyl-6-butoxymethyl-1-hydroxybenzene.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:8]=[C:7]([N:9]2[CH2:13][C@@H:12]3[C@@H:14]([NH2:17])[CH2:15][CH2:16][C@@H:11]3[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>ClCCl>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:17][C@@H:14]2[C@@H:12]3[C@@H:11]([CH2:10][N:9]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:18])[F:19])[N:8]=4)[CH2:13]3)[CH2:16][CH2:15]2)(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine from Example 264 Step A (0.050 g, 0.184 mmol) in dichloromethane (0.3 mL) was added triethylamine (0.051 mL, 0.369 mmol) followed by 4-chlorobenzene-1-sulfonyl chloride (0.047 g, 0.221 mmol). The reaction was stirred at ambient temperature overnight. The crude material was purified using a 12 g silica gel cartridge eluting with 5-50% ethyl acetate/hexanes over 25 minutes to give the title compound: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.58 (s, 1H), 8.01-7.95 (m, 2H), 7.47-7.41 (m, 3H), 6.93 (d, J=7.3, 1H), 6.45 (d, J=8.5, 1H), 3.79-3.68 (m, 1H), 3.52-3.43 (m, 3H), 3.25 (dd, J=11.0, 4.1, 1H), 2.83-2.66 (m, 2H), 2.07-1.90 (m, 2H), 1.69 (dq, J=12.7, 7.9, 1H), 1.39-1.27 (m, 1H); MS (ESI+) m/z 446 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:30])[CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:30])[CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCc1cccnc1)NCCCCC1CCNCC1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCc1cccnc1)NCCCCC1CCN(C(=O)c2ccccc2)CC1

Procedure:
3.48 ml (30 mmol) benzoyl chloride, 8.7 g (30 mmol) N-(4-piperidin-4-yl-butyl)-3-(pyridin-3-yl)-propionamide and 16.6 g (120 mmol) potassium carbonate are stirred in 160 ml DMF at RT overnight. Subsequently, this is filtered and the filtrate is concentrated under vacuum to a large extent. The residue is taken up in 400 ml CHCl3 and washed twice, each with 100 ml water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH (95/5) and precipitates as an amorphous solid after drawing off the solvent.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]([C@@H:5]1[C@@H:10]2[CH2:11][CH2:12][N:7]([CH:8]([CH:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]2=O)[CH2:6]1)=[O:4].[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:31]=1[CH2:32][NH2:33].O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1.C(O)(=O)C>[CH3:1][N:2]([CH3:27])[C:3]([C@@H:5]1[C@@H:10]2[CH2:11][CH2:12][N:7]([C@@H:8]([CH:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C@H:9]2[NH:33][CH2:32][C:31]2[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=[CH:37][C:30]=2[O:29][CH3:28])[CH2:6]1)=[O:4]
Reactant: CN(C)C(=O)[C@H]1CN2CC[C@@H]1C(=O)C2C(c1ccccc1)c1ccccc1
Reactant: COc1ccc(OC)c(CN)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc(OC)c(CN[C@H]2[C@H]3CCN(C[C@@H]3C(=O)N(C)C)[C@H]2C(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
A mixture of 47 (3.9 g, 10 mmol), 2,5-dimethoxybenzyl amine (1.9 g, 11 mmol) camphor sulfonic acid (120 mg) in toluene (40 ml) was heated at reflux with removal of water for 8 hours and then the solvent was removed. The residue was dissolved in small amount of THF (5 ml) and this solution was added to a solution of sodium triacetoxyborohydride (5.3 g, 25 mmol) in acetic acid (100 ml) at room temperature. The mixture was stirred at room temperature for 4 hours and the solvent was removed. Water (25 ml) was added and the mixture was neutralized with sodium bicarbonate (NaHCO3) and extracted with ethyl acetate (EtOAc) three times. The combined extracts were dried over sodium sulfate (Na2SO4) and concentrated. The crude was purified by recrystallization from EtOAc to give 49 (2.4 g, 4.4 mmol, 44%)
Reaction SMILES: [C:1]1([C@H:7]([CH3:20])[CH2:8]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-:21].[K+]>[Cl-].[Na+]>[F:21][CH2:8][C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:20]
Reactant: [F-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](C)c2ccccc2)cc1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Product: C[C@H](CF)c1ccccc1
Temperature: 62.5 °C
Reaction time: 48 h
Yield: 62.3 %

Procedure:
9.62 g of toluene-4-sulfonic acid (S)-2-phenyl-propyl ester (33.13 mmol) were dissolved in 80 ml of polyethylenglycol 400. 9.62 g of potassium fluoride (165.6 mmol) were added and the reaction mixture was stirred at 50° C. for 3 days and another 2 days at 55-70° C. The reaction was treated with 150 ml of saturated aqueous sodium chloride solution, extracted three times with diethyl ether, and the combined organic layers were dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified via silica gel chromatography using cyclohexyane/ethyl acetate 15% as eluent. 2.85 g of the desired product were isolated, containing ˜25% of the elimination side product.
Reaction SMILES: [Na].[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[C:13]([OH:25])[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15]2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:26]1([CH2:32][CH2:33][Cl:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C(O)C.C1C=CC=CC=1>[ClH:34].[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[C:13]([O:25][CH2:33][CH2:32][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15]2)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: ClCCN1CCCCC1
Reactant: CCOC(=O)c1cc2cccc(OCc3ccccc3)c2cc1O
Agent: [Na]
Solvent: CCO
Solvent: c1ccccc1
Product: CCOC(=O)c1cc2cccc(OCc3ccccc3)c2cc1OCCN1CCCCC1
Product: Cl
Reaction time: 48 h
Yield: 38 %

Procedure:
To a stirred solution of 1.4 g (0.062 g atom) of sodium, in 500 cc ethanol, was added 20 g (0.063 mole) of ethyl 5-benzyloxy-3-hydroxy-2-naphthoate. The reaction mixture was warmed to reflux for one hour. 2-Piperidinoethyl chloride (16.2 g 0.11 mole) dissolved in 100 cc of benzene was added dropwise to the reaction mixture. The benzene was removed by azeotropic distillation during which time the reaction volume was maintained at 500 cc by the periodic addition of ethanol. Refluxing was continued for 48 hours. The reaction mixture was filtered and the solvent removed from the filtrate. The residue was treated with water and extracted with ether. The ether solution was washed with water and then dried over anhydrous MgSO4. Hydrogen chloride precipitated the hydrochloride salt which was then crystallized from acetonitrile to yield ethyl 5-benzyloxy-3-(2- piperidinoethoxy)-2-naphthoate hydrochloride, m.p. 163°-6° C. in 38 percent yield (10.8 g).
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.C([Li])CCC.CCCCCC.[CH:35]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.O>O1CCCC1>[CH:35]1([C:41]([C:2]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:3]=2[O:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=3)[N:8]=[CH:7][CH:6]=2)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: COc1cc2nccc(Oc3ccc(C)cc3Br)c2cc1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)cc3C(=O)C3CCCCC3)c2cc1OC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 16 %

Procedure:
4-(2-Bromo-4-methylphenoxy)-6,7-dimethoxyquinoline (101 mg) was dissolved in tetrahydrofuran (5 ml) to prepare a solution which was then cooled to −78° C. A 1.59 M n-butyllithium/hexane solution (0.4 ml) was added to the cooled solution, and the mixture was stirred at −78° C. for 20 min. Cyclohexanecarbonyl chloride (0.2 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 3 hr. Further, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (17 mg, yield 16%).
Reaction SMILES: [OH-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([C:16]([NH:18][C:19]3[C:20]([CH3:30])=[C:21]([CH:26]=[CH:27][C:28]=3[CH3:29])[C:22]([O:24]C)=[O:23])=[O:17])[C:13]([CH3:31])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.CO>C1COCC1>[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([C:16]([NH:18][C:19]3[C:20]([CH3:30])=[C:21]([CH:26]=[CH:27][C:28]=3[CH3:29])[C:22]([OH:24])=[O:23])=[O:17])[C:13]([CH3:31])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2nc(N3CCC(O)CC3)ccc2C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(N2CCC(O)CC2)nc1C(=O)Nc1c(C)ccc(C(=O)O)c1C
Reaction time: 16 h
Yield: 41.1 %

Procedure:
A solution of aqueous 2N NaOH (2.00 ml) is added to a stirred solution of methyl 3-[[6-(4-hydroxy-1-piperidyl)-3-methyl-pyridine-2-carbonyl]amino]-2,4-dimethyl-benzoate (0.21 g, 0.52 mmol) in THF:MeOH (3 ml:1 ml). After 16 h at ambient temperature, the organic solvent is removed under reduced pressure and the residue is diluted with water, acidified to pH 6 with aqueous 1N HCl, and extracted with ethyl acetate (2×20 ml). The organic layers are combined and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the resulting precipitate is triturated with pentane and filtered to afford the title compound as a white solid (0.082 g, 39%). Mass spectrum (m/z): 384.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([CH:14]=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)=[CH:4][C:3]=1[NH:21][S:22]([CH3:25])(=[O:24])=[O:23].C(Cl)(Cl)Cl.[I:30]N1C(=O)CCC1=O.C(Cl)Cl>O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([I:30])=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)=[CH:4][C:3]=1[NH:21][S:22]([CH3:25])(=[O:23])=[O:24]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(=O)Nc1cn2nc(-c3cnc(Cl)c(NS(C)(=O)=O)c3)ccc2n1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(C)(=O)=O)c3)nn2c1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.1 %

Procedure:
To a 50 mL round-bottomed flask was added N-(6-(6-chloro-5-(methylsulfonamido)pyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide (Example 19) (0.404 g, 1.06 mmol), chloroform (20 mL) and N-iodosuccinimide (0.48 g, 2.1 mmol). The mixture was stirred at 25° C. for 1 h then poured into CH2Cl2 (200 mL) and water (200 mL). The solution contained a precipitate. This was filtered and the filtercake was washed with water and then dried under vacuum. The solid was taken up in MeOH/CH2Cl2 and concentrated onto Celite® (diatomaceous earth). Purification by silica gel chromatography (2.0 to 10% MeOH/CH2Cl2) afforded the title compound as a yellow solid (0.199 g, 37%). MS (ESI, positive ion) m/z: 506.4 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.07 (s, 3H), 3.20 (s, 3H), 7.96 (d, J=9.6 Hz, 1H), 8.20 (d, J=9.4 Hz, 1H), 8.55 (d, J=2.2 Hz, 1H), 8.98 (d, J=2.2 Hz, 1H), 9.98 (s, 1H), 10.13 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5]Br)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C(=O)C.[F:22][C:23]1[N:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1>O>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][O:29][C:26]1[CH:25]=[CH:24][C:23]([F:22])=[N:28][CH:27]=1)[CH3:2]
Reactant: CCOC(CBr)OCC
Reactant: Oc1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(COc1ccc(F)nc1)OCC
Temperature: 100 °C
Reaction time: 15 h
Yield: 99.3 %

Procedure:
Bromoacetaldehyde diethyl acetal (6.75 ml, 44.9 mmol) and cesium carbonate (30.9 g, 95.0 mmol) were added to an N,N-dimethylacetamide solution (60 ml) of 6-fluoropyridin-3-ol (3.0 g, 24.9 mmol, purity: at most 94%), and stirred under a nitrogen atmosphere at 100° C. for 15 hours. The reaction solution was cooled with ice, water was added, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage, hexane:ethyl acetate=17:1 to 6:1) to obtain 5-(2,2-diethoxyethoxy)-2-fluoropyridine (5.67 g, yield: 99%) as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.NC(N)=[S:17]>>[CH3:13][N:12]([CH3:14])[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2](=[S:17])[N:11]=1
Reactant: CN(C)c1nc(Cl)nc2ccccc12
Reactant: NC(N)=S
Product: CN(C)c1nc(=S)[nH]c2ccccc12

Procedure:
Prepared as in Example 46 from 2-chloro-N,N-dimethylquinazolin-4-amine (Example 40) and thiourea. 1H NMR (400 MHz, DMSO-d6) δ3.31 (s, 6H), 7.24-7.19 (m, 1H), 7.40-7.38 (m, 1H), 7.65-7.61 (m, 1H), 8.00 (d, J=8.0 Hz, 1H), 12.35 (s, 1H). MS 206 (MH+).