Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22]O)[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.S(Cl)([Cl:26])=O>>[ClH:26].[Cl:26][CH2:22][C:13]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=1
Reactant: Nc1nc2ccccc2c2c1nc(CO)n2Cc1ccccc1
Reactant: O=S(Cl)Cl
Product: Cl
Product: Nc1nc2ccccc2c2c1nc(CCl)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Amino-1-phenylmethyl-1H-imidazo[4,5-c]-quinoline-2-methanol (2.0 g; 0.0066 mol, Example 27) was added in small portions to thionyl chloride (10 mL). After stirring at room temperature for 30 min the product had crystallized from solution. The mixture was diluted with dry ether (75 mL). The solid was filtered from the mixture, washed with ether, and thoroughly dried. The product was used as such without further characterization or purification.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([C:22]2[CH:27]=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:25]=[CH:24][C:23]=2[F:37])[CH:21]=1>>[F:37][C:23]1[CH:24]=[CH:25][C:26]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:27][C:22]=1[C:20]1[CH:19]=[N:18][CH:17]=[C:16]([F:15])[CH:21]=1
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2ccc(F)c(-c3cncc(F)c3)c2)OC1(C)C
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cncc(F)c4)c3)cnc2n1
Yield: 21 %

Procedure:
2-(3-Bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol was coupled with 3-fluoro-5-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pyridine as described in Example 65 to give 2-{3-[4-fluoro-3-(5-fluoropyridin-3-yl)phenyl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol as an off-white solid (30 mg, 21%). Bis-hydrochloride salt (from ethyl acetate: ethanol (1:1)): δH (360 MHz, d6-DMSO) 1.56 (6H, s), 7.67-7.73 (1H, m), 7.83-7.89 (2H, m), 8.05-8.07 (1H, m), 8.11-8.15 (1H, m), 8.51 (1H, s), 8.71 (1H, s), 8.80 (1H, s), 9.36 (1H, d, J 7).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(C)(C)C.[K+]>CS(C)=O>[CH2:11]([C:18]1[CH:19]=[CH:20][C:21]([NH:22][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:23][CH:24]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Nc1ccc(Cc2ccccc2)cc1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccccc1Nc1ccc(Cc2ccccc2)cc1

Procedure:
The product (621 mg) is obtained according to the method of stage 1 of Example 4, by using 958 μL of 2-fluoro-nitrobenzene and 2 g of 4-benzylaniline in the presence of 1.63 of potassium tert-butanolate in 30 mL of DMSO.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]([O:8][C:9]1[CH:14]=[C:13]([C:15](=[O:23])NC2CCNCC2)[CH:12]=[C:11]([O:24][CH3:25])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].C([O:29]C(=O)C(OC1C=C(OC)C=C(C=O)C=1)(C)C)C.Cl([O-])=O.[Na+]>>[CH2:1]([O:3][C:4]([C:5]([CH3:6])([O:8][C:9]1[CH:14]=[C:13]([CH:12]=[C:11]([O:24][CH3:25])[CH:10]=1)[C:15]([OH:23])=[O:29])[CH3:7])=[O:26])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cc(OC)cc(C(=O)NC2CCNCC2)c1
Reactant: CCOC(=O)C(C)(C)Oc1cc(C=O)cc(OC)c1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Product: CCOC(=O)C(C)(C)Oc1cc(OC)cc(C(=O)O)c1

Procedure:
In analogy to the procedure described in example 50k), 2-[3-methoxy-5-(piperidin-4-ylcarbamoyl)-phenoxy]-2-methyl-propionic acid ethyl ester [prepared by i) oxidation of 2-(3-formyl-5-methoxy-phenoxy)-2-methyl-propionic acid ethyl ester with sodium chlorite in analogy to example 60c) to give 3-(1-ethoxycarbonyl-1-methyl-ethoxy)-5-methoxy-benzoic acid; ii) subsequent condensation with 4-amino-piperidine-carboxylic acid tert-butyl ester, using acid activation with 2-chloro-4,6-dimethoxy-1,3,5-triazine in analogy to the procedure described in example 50 h) followed by Boc cleavage with TFA in analogy to the procedure described in example 50i)] was reacted with 3,5-diethoxy-4-fluoro-benzaldehyde (example 50 g), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless foam. MS: 561.6 (MH+).
Reaction SMILES: CN1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.ClC(OCC(C)C)=O.[CH:16]1[CH:21]=[CH:20][C:19](CCN)=[CH:18][CH:17]=1>O1CCCC1>[CH2:4]([O:5][CH2:6][CH3:7])[CH3:3].[CH3:20][CH2:21][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: NCCc1ccccc1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: CCCCCC
Product: CCOCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 229.6 %

Procedure:
To a stirred suspension of N-[(2-adamantyloxy)-carbonyl)-α-methyl-β-(2-pyridyl-1-oxide)-D,L-alanine (2.43 g, 6.5 mmol) in 150 mL dry tetrahydrofuran at -20° C. was added N-methylmorpholine (0.76 g, 7.5 mmol) and isobutyl chloroformate (1.02 g, 7.5 mmol). The mixture was stirred for 20 minutes at this temperature followed by addition of 2-phenethylamine (1.21 g, 10 mmol), stirred for 3 hours at -25° C., and then warmed to room temperature. The solvent was removed in vacuo at room temperature, and theresidue was diluted with ethyl acetate and water. The solution was washed with 5% citric acid (3×) and water (2×) followed by 5% potassium hydrogen carbonate (3×), water (2×), and brine. The organic phase was dried over magnesium sulfate. The solvent was removed invacuo to yield an oily residue which crystallized by addition of diethyl ether/n-hexane (2.76 g, 89% yield), m.p. 76°-80° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16](=O)[CH3:17])=[CH:15][C:10]=2[N:9]=[CH:8]1.[BH4-].[Na+].[CH3:21][NH2:22]>CO>[CH3:21][NH:22][CH:16]([C:14]1[CH:13]=[CH:12][C:11]2[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[CH:8]=[N:9][C:10]=2[CH:15]=1)[CH3:17]
Reactant: CN
Reactant: CC(=O)c1ccc2c(c1)ncn2C1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNC(C)c1ccc2c(c1)ncn2C1CCCCO1
Reaction time: 8 h
Yield: 15 %

Procedure:
A solution of 82 (1.2 g, 4.9 mmol) in 30% methanamine in MeOH (50 mL) was stirred at RT for 15 h. To the reaction mixture was added NaBH4 (186 mg, 4.9 mmol) at RT in several portions and stirred overnight. The reaction mixture was concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (100:1) followed by reverse phase chromatography on CombiFlash® eluting with 0.01% NH4OH ammonia in water (solvent A) and MeCN (solvent B) to afford 200 mg (15%) of (±)-N-methyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)ethanamine (84) as yellow oil: MS (ESI) m/z=260.3 (M+1).
Reaction SMILES: [O:1]=[C:2]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=O.[NH:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=[O:20]>>[NH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([C:2]([CH2:3][CH2:4][C:5]([N:17]2[CH2:24][CH2:23][CH2:22][C@H:18]2[C:19]([OH:21])=[O:20])=[O:7])=[O:1])=[CH:9]1
Reactant: O=C(O)CCC(=O)c1c[nH]c2ccccc12
Reactant: O=C(O)[C@@H]1CCCN1
Product: O=C(CCC(=O)N1CCC[C@H]1C(=O)O)c1c[nH]c2ccccc12

Procedure:
As for Example 1, 4-oxo-4-(3-indolyl)butyric acid (0.1 mole) is coupled to L-proline to give 1-[3-(3-indolylcarbonyl)propionyl]-L-proline. The preceding compound is reacted with bromine in acetic acid and the brominated derivative is reacted with sodium thioacetate in acetonitrile to give the product of the Example as a glass.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=[C:20]([CH3:28])[C:4]=1[C:5]([C:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][N+:10]([O-])=[CH:9][C:8]=1[O:18][CH3:19])=[O:6].C1(C)C=CC=CC=1.P(Br)(Br)([Br:38])=O>CN(C)C=O>[CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=[C:20]([CH3:28])[C:4]=1[C:5]([C:7]1[C:8]([O:18][CH3:19])=[CH:9][N:10]=[C:11]([Br:38])[C:12]=1[C:13]([F:16])([F:15])[F:14])=[O:6]
Reactant: COc1cc(C)c(C(=O)c2c(OC)c[n+]([O-])cc2C(F)(F)F)c(OC)c1OC
Reactant: O=P(Br)(Br)Br
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(C)c(C(=O)c2c(OC)cnc(Br)c2C(F)(F)F)c(OC)c1OC
Yield: 49.1 %

Procedure:
Using 7.2 g (18 mmol) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-3-methoxy-5-trifluoromethylpyridine-N-oxide, 7 ml of toluene, 17 ml of dimethylformamide and 10 g (35 mmol) of phosphorus oxybromide, 4.1 g (yield 49%) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-2-bromo-3-trifluoromethyl-5-methoxypyridine (compound No. 124; m.p. 145-147° C.) was obtained in the same process as in Synthesis Example 9 step (f).
Reaction SMILES: [CH3:1][C:2](C)([O-:4])[CH3:3].[K+].[C:7]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:8]C(C)=O.[CH3:16][O:17][C:18]1[CH:27]=[CH:26][C:21]([C:22](=[O:25])[CH2:23]Br)=[CH:20][CH:19]=1>C1C=CC=CC=1>[CH3:16][O:17][C:18]1[CH:27]=[CH:26][C:21]([C:22](=[O:25])[CH2:23][CH:8]([CH2:1][C:2](=[O:4])[CH3:3])[C:7]([O:13][CH2:14][CH3:15])=[O:12])=[CH:20][CH:19]=1
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(=O)C(CC(C)=O)CC(=O)c1ccc(OC)cc1
Yield: 87 %

Procedure:
After adding potassium tert-butoxide to a solution of ethyl acetoacetate (25.7 g) in benzene (420 ml) while cooling on ice, 4-methoxyphenacyl bromide (24.8 g) was gradually added and the mixture was refluxed for an hour. After allowing the reaction solution to cool, it was washed with 5% sodium hydroxide and purified water, and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 26.2 g of ethyl 2-[2-(4-methoxyphenyl)-2-oxoethyl]-4-oxopentanoate (87.0% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([CH2:7][NH:8][C:9]([C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([C@@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23](=[O:44])[CH2:24][C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:17])=[O:10])[CH2:2]1.[CH:45](=O)[CH2:46][CH3:47]>>[CH2:45]([N:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([CH2:7][NH:8][C:9]([C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([C@@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23](=[O:44])[CH2:24][C:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:17])=[O:10])[CH2:2]1)[CH2:46][CH3:47]
Reactant: O=C(NC[C@H]1CCCNC1)[C@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCC=O
Product: CCCN1CCC[C@H](CNC(=O)[C@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1

Procedure:
The title compound was prepared by a method similar to Step 3 of Example 17, using (2R)-N-((3S)-3-piperidylmethyl)-1-{(2S)-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonylpyrrolidine-2-carboxamide and propionaldehyde. The product was obtained as a white solid.
Reaction SMILES: [C:1]1(O)[C:10]2[CH2:9][CH:8]=[CH:7][CH2:6][C:5]=2[C:4]([OH:11])=[CH:3][CH:2]=1.[OH-].[Na+].S([O:20][CH3:21])(OC)(=O)=O.[CH2:22](O)C>O>[CH3:22][O:11][C:4]1[C:5]2[CH2:6][CH:7]=[CH:8][CH2:9][C:10]=2[C:1]([O:20][CH3:21])=[CH:2][CH:3]=1
Reactant: CCO
Reactant: Oc1ccc(O)c2c1CC=CC2
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(OC)c2c1CC=CC2
Temperature: 75 °C

Procedure:
A suspension of 63.18 g (0.39 mole) of 5,8-dihydro-1,4-naphthalenediol in 300 ml of absolute ethanol is heated briefly until solution is achieved. To this hot stirred solution is added alternately in five portions a solution of 40 g of sodium hydroxide in 100 ml of water, and 120 g of dimethyl sulfate. The heat evolved during the addition causes the solution to reflux. After the addition is complete a solution of 10 g of sodium hydroxide in 20 ml of water is added and the mixture is heated overnight at 75° C.
Reaction SMILES: [Br:1][C:2]([Cl:13])([C:9]([F:12])([F:11])[F:10])[CH:3](O)[CH:4]=[C:5]([CH3:7])[CH3:6].[C:14](OC)([O:18][CH3:19])([O:16]C)[CH3:15]>O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>[Br:1][C:2]([Cl:13])([C:9]([F:10])([F:11])[F:12])[CH:3]=[CH:4][C:5]([CH3:7])([CH3:6])[CH2:15][C:14]([O:18][CH3:19])=[O:16]
Reactant: COC(C)(OC)OC
Reactant: CC(C)=CC(O)C(Cl)(Br)C(F)(F)F
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: O
Product: COC(=O)CC(C)(C)C=CC(Cl)(Br)C(F)(F)F
Temperature: 111 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
5-Bromo-5-chloro-4-hydroxy-2-methyl-6,6,6-trifluorohex-2-ene (10.0 g), trimethyl orthoacetate (16.0 g) and Montmorillonite KSF (0.5 g) were charged to a round-bottomed flask fitted with: nitrogen inlet/bubbler, thermometer and still-head. The mixture was heated with agitation, and the methanol-trimethyl orthoacetate distillates were collected until the reactor temperature increased to 111° C. (ca. 1 hr). The reaction was then heated to 135° C. and held for a further 1 hour. The methanol/trimethyl orthoacetate distillates were recharged and the distillation procedure repeated twice. Once the reaction was complete, the Montmorillonite was removed by filtration. The residual trimethyl orthoacetate was then removed by distillation under vacuum (ca. 50° C. @100 mmHg) to give the product, methyl 6-bromo-6-chloro-3,3-dimethyl-7,7,7-trifluorohept-4-enoate as a brown oil (7.8 g, 59% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[CH:5].N1C=CN=C1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>CN(C=O)C.O>[Si:11]([O:1][CH2:2][CH2:3][C:4]#[CH:5])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#CCCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C#CCCO[Si](C)(C)C(C)(C)C
Reaction time: 24 h
Yield: 89.1 %

Procedure:
A solution of 1-hydroxybut-3-yne (2.0 g, 0.028 mol) and imidazole (2.9 g, 0.043 mol) in DMF (5 ml) was treated with t-butyldimethylsilyl chloride (6.4 g, 0.043 mol). After 24 hr. at RT, the reaction was diluted with water and extracted with diethyl ether. The organic extracts were washed with water, dried, evaporated, and the volatile organics were removed by vacuum to afford the title compound as an oil (4.6 g, 89%). 1H NMR (400 MHz, CDCl3): δ 3.67 (t, J=7.1 Hz, 2H), 2.32 (m, 2H), 1.88 (s, 1H), 0.82 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[S:5][CH:6]=[C:7]([CH3:12])[C:8]=1[C:9]([OH:11])=[O:10].O>C(O)(=O)C>[Br:1][C:6]1[S:5][C:4]([CH3:3])=[C:8]([C:9]([OH:11])=[O:10])[C:7]=1[CH3:12]
Reactant: Cc1csc(C)c1C(=O)O
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: Cc1sc(Br)c(C)c1C(=O)O
Temperature: 10 °C
Yield: 88.3 %

Procedure:
A solution of bromine (0.73 mL, 2.25 g, 14 mmol) in glacial acetic acid (8 mL) was added to a solution of 2,4-dimethylthiophene-3-carboxylic acid (2.1 g, 13 mmol) in glacial acetic acid (24 mL) at 6° C. Upon completion, the reaction was stirred at 10° C. for an hour, diluted with glacial acetic acid (30 mL), stirred for 14 hours at room temperature, poured into water (400 mL) and extracted with ether (3×40 mL). The combined ethereal extracts were extracted with dilute sodium hydroxide (0.2 N, 3×30 mL). The combined basic extracts were cooled in an ice bath and then acidified to pH 3 using concentrated hydrochloric acid. Precipitated solids were extracted with ether (3×40 mL). Pooled organic extracts were washed with water (50 mL) and brine (50 mL), dried over magnesium sulphate and concentrated under reduced pressure. The residue was recrystallised from ethyl acetate/hexane to give product as an amorphous white solid (2.7 g, 85%): mp 183-184° C.; 1H NMR (CDCl3) δ 2.67 (s, 3H), 2.38 (s, 3H); EI/MS 235 m/e (M+); IR (liq film) 1674 cm−1; Calcd. for C7H7BrO2S: C, 35.8; H, 3.00; S, 13.6; Found: C, 35.8; H, 2.99; N, 13.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:25][C@H:26]2[CH2:46][CH2:45][C:28]3([O:32][C@H:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C@@H:30]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:29]3)[CH2:27]2)[C:13](=O)[CH2:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C([O-])(=O)C.[NH4+:51].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([C:13]2[NH:51][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:15][CH:14]=2)[CH2:25][C@H:26]2[CH2:46][CH2:45][C:28]3([O:29][C@H:30]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C@@H:31]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[O:32]3)[CH2:27]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)C(=O)CCC(=O)c2ccccn2)cc1Cl
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)c2ccc(-c3ccccn3)[nH]2)cc1Cl
Temperature: 110 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To a solution of 5-[3-chloro-4-(methylsulfonyl)phenyl]-6-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]-1-(pyridin-2-yl)hexane-1,4-dione (698 mg) in acetic acid (5 mL) was added ammonium acetate (1.31 g), and the mixture was stirred at 110° C. for 1 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (580 mg, yield 85%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]1([C:11]2[N:12]=[CH:13][S:14][C:15]=2C(O)=O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N-:19]=[N+]=[N-].[Na+].C([O:25][CH2:26]C)C>C1C=CC=CC=1.O>[N:12]1[C:11]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[C:26](=[O:25])[NH:19][C:15]=2[S:14][CH:13]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)c1scnc1-c1ccccc1
Reactant: CCOCC
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: O=c1[nH]c2scnc2c2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
Thionyl chloride (1 ml) was added to a suspension of 4-phenyl-1,3-thiazole-5-carboxylic acid (300 mg, 1.46 mmol) in 10 ml of dry benzene and the mixture was refluxed for 2 hours. The solvent and the excess of thionyl chloride were removed under reduced pressure; the residue was taken up using 10 ml of dry THF and cooled to 0° C. Sodium azide (1.5 mmol) dissolved in the minimal amount of water was quickly added and the resulting solution was stirred for 1 hour at room temperature. After pouring into 100 ml of cracked ice/H2O and extraction with diethyl ether (4×100 ml), the collected organic layers were dried over Na2SO4. The filtrate was gently evaporated under reduced pressure, the residue was dissolved in 10 ml of o-dichlorobenzene, and the resulting mixture was refluxed for 5-10 hours. The mixture was then cooled, and directly submitted to flash chromatography, elution with dichloromethane/methanol (99/1) afforded to the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([CH2:33][CH2:34][CH2:35][N:36]=[N+]=[N-])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].CC#N.O>C1COCC1>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([CH2:33][CH2:34][CH2:35][NH2:36])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCN=[N+]=[N-])CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(CCCN)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triphenylphosphine (0.657 g, 2.50 mmol) is added to a stirred solution of 4-(3-azido-propyl)-piperidine-1-carboxylic acid tert-butyl ester (0.560 g, 2.09 mmol) in THF (2 mL)/CH3CN (5 mL)/H2O (1 mL) and the mixture is stirred at ambient temperature for 18 hours. After concentration and subsequent chromatography purification on silica gel, eluting with 2 M NH3/MeOH in dichloromethane 0-15%, the title compound is obtained as a clear oil (0.420 g, 83% yield).
Reaction SMILES: [Na].[CH3:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[CH:12](OCC)=O.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[N:19]=1.[OH-].[Na+]>>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]2[C:20](=[N:24][C:3]([C:5]3[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=3)=[CH:2][CH:12]=2)[N:19]=1
Reactant: Nc1cccc(N)n1
Reactant: CCOC=O
Reactant: CC(=O)c1ccc(F)cc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Product: Nc1ccc2ccc(-c3ccc(F)cc3)nc2n1
Yield: 74.5 %

Procedure:
The procedure is analogous to that described in Example 11 below, but starting with sodium (2.3 g), 4-fluoroacetophenone (13.8 g) and ethyl formate (11 g). The solid obtained (17.8 g) is then added to 2,6-diaminopyridine (11 g). The product obtained after hydrolysis and neutralization with sodium hydroxide is separated by filtration, washed with distilled water (6×100 cc) and air-dried. 2-Amino-7-(4-fluorophenyl)-1,8-naphthyridine (17.8 g), m.p. 175° C., is thus obtained.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([OH:10])[N:7]([CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:22]([O:10][C:8]1[N:7]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=2)[N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:9]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(Cn2nc(C(C)(C)C)cc2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2nc(C(C)(C)C)cc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
A mixture of methyl 4-[(3-tert-butyl-5-hydroxy-1H-pyrazol-1-yl)methyl]benzoate (2.00 g, 6.94 mmol), benzyl bromide (0.91 mL, 7.7 mmol), potassium carbonate (0.96 g, 6.9 mmol) and N,N-dimethylformamide (25 mL) was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate/hexane) to give the title compound (2.14 g, yield 81%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.[CH:16]([S:19](Cl)(=[O:21])=[O:20])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:19]([CH:16]([CH3:18])[CH3:17])(=[O:21])=[O:20])=[CH:6][CH:7]=1
Reactant: Clc1ccc(NCc2cccnc2)cc1
Reactant: CC(C)S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(C)S(=O)(=O)N(Cc1cccnc1)c1ccc(Cl)cc1

Procedure:
A 3.3 g. portion of 3-(4-chlorophenylaminomethyl)pyridine was dissolved in chloroform and reacted with 2.4 g. of isopropanesulfonyl chloride in the presence of 2.3 g. of potassium carbonate for several days at ambient temperature. The reaction mixture was worked up as described in Example 4, and the oily product was dissolved in chloroform and purified over silica gel, eluting with chloroform, to obtain 0.6 g. of the desired product, the elemental analysis which was as follows.
Reaction SMILES: [C:1]1(Cl)[C:7](=[O:8])[C:6]([Cl:9])=[C:5]([Cl:10])[C:3](=[O:4])[C:2]=1[Cl:11].C(=O)([O-])O.[Na+].[CH:18]1([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(C(C)=O)C>[Cl:9][C:6]1[C:7](=[O:8])[C:1]([O:24][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:2]([Cl:11])[C:3](=[O:4])[C:5]=1[Cl:10]
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Reactant: OC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)=O
Product: O=C1C(Cl)=C(Cl)C(=O)C(OC2CCCCC2)=C1Cl
Temperature: 55 °C
Yield: 66.7 %

Procedure:
Chloranil (0.06 mole) and sodium hydrogen carbonate (0.075 mole) were added to 300 ml of methyl ethyl ketone (MEK). The mixture was heated to 55° C. before adding cyclohexanol (0.5 mole) dropwise with stirring. When the reaction was complete (as judged by HPLC) the MEK solvent was removed from the product mixture under vacuum. The resultant orange gum was recrystallised from petroleum ether to provide the bright orange crystalline title product (0.04 moles).