Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[NH:3][C:4](=[O:21])[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[N:7]=1>[OH-].[Pd+2].[OH-]>[O:21]=[C:4]1[NH:3][CH:2]=[N:7][C:6]([N:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)=[N:5]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)[nH]c(=O)n2)CC1
Agent: [Pd+2]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCN(c2nc[nH]c(=O)n2)CC1

Procedure:
tert-Butyl 4-(6-chloro-4-oxo-4,5-dihydro-1,3,5-triazin-2-yl)piperazine-1-carboxylate (14.2 g, 45.0 mmol) synthesized in Reference Synthesis Example 6 and palladium hydroxide-activated carbon catalyst (142 mg) were used to obtain a crude product of the title compound by synthesis in a similar manner to Reference Synthesis Example 3. The crude product was used in the next reaction as it was.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[N:5][N:6]=1.ClC1C=C(Cl)C=C(Cl)C=1[O:24][C:25](=O)[CH:26]([CH3:39])[C:27](OC1C(Cl)=CC(Cl)=CC=1Cl)=[O:28].ClC1C=CC=CC=1>CCCCCC>[CH2:8]([S:7][C:4]1[S:3][C:2]2=[N:1][C:27]([OH:28])=[C:26]([CH3:39])[C:25](=[O:24])[N:6]2[N:5]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCSc1nnc(N)s1
Reactant: CC(C(=O)Oc1c(Cl)cc(Cl)cc1Cl)C(=O)Oc1c(Cl)cc(Cl)cc1Cl
Solvent: CCCCCC
Solvent: Clc1ccccc1
Product: CCCCCCCSc1nn2c(=O)c(C)c(O)nc2s1
Reaction time: 0.75 h
Yield: 78 %

Procedure:
A mixture of 19.7 g of the thus obtained 2-amino-5-heptylthio-1,3,4-thiadiazole, 40.9 g of bis(2,4,6-trichlorophenyl)-2-methyl-malonate and 55 ml of chlorobenzene was stirred at 140°~144° C. for 45 minutes. After cooling, n-hexane was added thereto, the precipitate was collected by filtration. Further n-hexane was added to the filtrate, and the precipitate was collected The collected precipitates were combined. The combined precipitate was washed with n-hexane and thus 21.2 g of 2-heptylthio-7-hydroxy-6-methyl-5H-1,3,4-thiadiazolo-[3,2-a] pyrimidin-5-one was obtained. m.p. 141°~143° C. Yield 78%.
Reaction SMILES: C([O:8][C:9]([C@H:11]([CH3:40])[CH2:12][C@H:13]([NH:27][C:28]([C:30]1[O:35][C:34]([C:36]([OH:38])=[O:37])=[CH:33][C:32](=[O:39])[CH:31]=1)=[O:29])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)=[O:10])C1C=CC=CC=1.B(Cl)(Cl)Cl.Cl>C(Cl)Cl>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:19]=[CH:20][C:15]([CH2:14][C@@H:13]([NH:27][C:28]([C:30]2[O:35][C:34]([C:36]([OH:38])=[O:37])=[CH:33][C:32](=[O:39])[CH:31]=2)=[O:29])[CH2:12][C@H:11]([C:9]([OH:10])=[O:8])[CH3:40])=[CH:16][CH:17]=1
Reactant: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(=O)cc(C(=O)O)o1)C(=O)OCc1ccccc1
Agent: Cl
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(=O)cc(C(=O)O)o1)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Next, to a solution of 6-((1S,3R)-3-benzyloxycarbonyl-1-biphenyl-4-ylmethyl-butylcarbamoyl)-4-oxo-4H-pyran-2-carboxylic acid (100 mg, 0.185 mmol) in methylene chloride (5 mL) is added BCl3 (65.1 mg, 0.556 mmol) and the mixture is stirred at room temperature for 10 minutes. The mixture is acidified to pH 2-3 with aqueous 1M HCl and is extracted with ethyl acetate. The organic phase is washed with water and brine and is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by preparative HPLC using a gradient of 10-100% MeCN/water (0.1% TFA) to elute the product. The proper fractions are lyophilized to furnish 6-((1S,3R)-1-biphenyl-4-ylmethyl-3-carboxy-butylcarbamoyl)-4-oxo-4H-pyran-2-carboxylic acid. MS 450.1 (M+1); 1H-NMR (400 Hz, DMSO-d6); δ ppm 1.07 (d, J=7.07 Hz, 3H), 1.59 (m, 1H), 1.88 (m, 1H), 2.45 (m, 1H), 2.84 (d, J=6.69 Hz, 2H), 4.19 (m, 1H), 6.84 (s, 1H), 6.93 (s, 1H), 7.32 (dd, J=8.08 Hz, 6.57 Hz, 3H), 7.45 (t, J=7.83 Hz, 2H), 7.58 (d, J=8.21 Hz, 2H), 7.64 (d, J=7.33 Hz, 2H), 8.61 (d, J=8.72 Hz, 1H).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:24]=[N:25][CH:26]=[N:27][CH:28]=1)=[CH:8]2)=[O:4].[NH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:29])[C:5]([C:3]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:24]=[N:25][CH:26]=[N:27][CH:28]=2)[C:10]1=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ncc2c(cc(-c3cncnc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3cncnc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 65.9 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-pyrimidin-5-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (58 mg, 0.15 mmol), β-alanine (706 mg, 7.9 mmol) and NaOMe solution (12 mL, 6.0 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 4. The organic layer was dried over MgSO4 and concentrated. The crude solid was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 4 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 44 mg of the title compound. MS: (+) m/z 446.27 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[O:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2I)=[O:16])[CH2:4][O:3]1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1([CH3:25])[O:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:27]2[S:26][CH:30]=[CH:29][CH:28]=2)=[O:16])[CH2:4][O:3]1
Reactant: CC1(C)OC[C@H](NC(=O)Nc2ccccc2I)[C@H](c2ccccc2)O1
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CC1(C)OC[C@H](NC(=O)Nc2ccccc2-c2cccs2)[C@H](c2ccccc2)O1
Temperature: 80 °C
Yield: 37.3 %

Procedure:
To a reaction flask charged with 10.6 mg (0.0092 mmol) of tetrakis(triphenylphosphine)palladium(0) in ethylene glycol dimethyl ether (1.8 mL) under nitrogen was added 104 mg (0.23 mmol) of the product from Example 6. The resulting yellow solution was stirred for 10-15 min before the addition of 34.5 mg (0.27 mmol) of 2-thiopheneboronic acid dissolved in ethanol (0.2 mL) and ethylene glycol dimethyl ether (0.2 mL) and the subsequent addition of 0.23 mL (0.46 mmol) of a 2 M sodium carbonate aqueous solution. The reaction mixture was heated at 80° C. for 24 h and then cooled to room temperature. The liquid was separated from the solid residue, and the residue was rinsed with dichloromethane, which was subsequently combined with the isolated liquid. The solvent was evaporated, and the crude product was partitioned between brine (˜4 mL) and dichloromethane (˜4 mL). The organic layer was washed with additional brine, dried over magnesium sulfate, and filtered. The solvent was evaporated, and the dark residue was purified by column chromatography (hexanes/ethyl acetate) to yield 35 mg (37%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14](=O)[CH3:15])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C([O:19]/[C:20](/[CH3:27])=[CH:21]/C(OCC)=O)C.Cl.C(=O)=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4](/[C:14](/[CH3:15])=[CH:21]/[C:20](=[O:19])[CH3:27])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)/C=C(\C)OCC
Reactant: CC(=O)c1ccc(C2CCCCC2)c(Cl)c1
Agent: Cl
Agent: O=C=O
Solvent: CN(C)C=O
Product: CC(=O)/C=C(\C)c1ccc(C2CCCCC2)c(Cl)c1
Temperature: 0 °C

Procedure:
87.6 Gm (0.781 mol) of potassium-tert.butylate were added all at once to a solution of 185.0 gm (0.781 mol) of 3'-chloro-4'-cyclohexyl-acetophenone and 123.0 gm (0.777 mol) of ethyl (E)-3-ethoxy-crotonate in 1.1 liters of anhydrous dimethyl formamide, whereby the temperature rose spontaneously from +20° to +38°C and the mixture turned deep red. The mixture was stirred for another hour with the temperature being maintained at 32°-35°C, and then 200 ml of concentrated hydrochloric acid added dropwise to the still warm mixture, and the resulting mixture was heated for 60 minutes at a temperature of 90°-100°C. After carbon dioxide evolution had ceased, the cooled mixture was stirred into 1 liter of ice water, and the aqueous mixture was exhaustively extracted with ether. The combined ether extracts were washed with water, dried over sodium sulfate and concentrated by evaporation. The residue was distilled in a vacuum (b.p. 175°-183°C at 0.1 mm Hg) and subsequently recrystallized twice from methanol, in the presence of activated charcoal. The colorless crystals, m.p. 56.5°-57.5°C were obtained with a yield of 132 gm (61% of theory).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([C:14](=[CH:20][N:21](C)C)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:25])=[C:7]([F:24])[CH:8]=2)[N:3]=1.[CH:26]([N:28]([CH3:30])N)=[O:27].C1CCN2C(=NCCC2)CC1>C(O)C>[Cl:25][C:6]1[C:7]([F:24])=[CH:8][C:9]2[C:4]([CH:5]=1)=[N:3][C:2]1[N:21]([N:28]([CH:26]=[O:27])[CH3:30])[CH:20]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:12](=[O:13])[C:11]=1[CH:10]=2
Reactant: CN(N)C=O
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(Cl)cc2nc1Cl
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cn(N(C)C=O)c2nc3cc(Cl)c(F)cc3cc2c1=O
Yield: 86.9 %

Procedure:
The 8-chloro-3-ethoxycarbonyl-7-fluoro-1-(N-formyl-N-methylamino)-4-oxo-1,4-dihydrobenzo [b][1,8]naphthyridine is prepared under the conditions described in Example 1 but starting from 19.25 g of ethyl 2-(2,7-dichloro-6-fluoroquinoline-3-carbonyl)-3-dimethylaminoacrylate, 4.05 g of N-formyl-N-methylhydrazine and 1.6 g of DBU in 200 cm3 of ethanol. 16.4 g of 8-chloro-3-ethoxycarbonyl-7-fluoro-1-(N-formyl-N-methylamino)-4-oxo-1,4-dihy drobenzo [b][1,8]naphthyridine are obtained in the form of a colourless solid melting at 296°-298° C.
Reaction SMILES: [OH:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]3[NH:18][C:17]4[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH3:22])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][CH3:26])[C:12]=4[N:11]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.CCN(CC)CC.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[O:23]=[C:14]1[N:13]([CH2:24][CH2:25][CH3:26])[C:12]2[N:11]=[C:10]([C:5]34[CH2:8][CH2:9][C:2]([O:1][S:35]([CH3:34])(=[O:37])=[O:36])([CH2:7][CH2:6]3)[CH2:3][CH2:4]4)[NH:18][C:17]=2[C:16](=[O:19])[N:15]1[CH2:20][CH2:21][CH3:22]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(O)(CC3)CC4)nc2n(CCC)c1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCn1c(=O)c2[nH]c(C34CCC(OS(C)(=O)=O)(CC3)CC4)nc2n(CCC)c1=O
Reaction time: 8 h
Yield: 58.6 %

Procedure:
To a solution of 50 mg of 8-(4-Hydroxy bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (Example 13a) (0.14 mmol) in CH2Cl2 (5 ml) was added 20 μL of Et3N and the reaction mixture cooled in an ice bath. To this was added 20 μL of methanesulfonyl chloride (0.26 mmol) and the reaction mixture kept at 10° C. overnight. The reaction mixture was concentrated in vacuo and the residue taken up in EtOAc and washed 2× with dilute HCl (5 ml). The organic layer was dried over NaSO4 and conc'd. The residue was triturated in acetonitrile to afford 36 mg (59%) of pure white solid (MH+=439.4).
Reaction SMILES: C(O)(=O)C.[CH2:5]([N:12]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:13](=[O:33])[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[C:23]1[NH:28][C:29](=[O:32])[C:30](=C)[N:22]1[CH2:21]2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[S:41](=[O:45])(=[O:44])([OH:43])[OH:42]>O>[S:41]([OH:45])([OH:44])(=[O:43])=[O:42].[CH2:34]([N:12]([CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:13](=[O:33])[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[C:23]1[NH:28][C:29](=[O:32])[CH2:30][N:22]1[CH2:21]2)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: C=c1c(=O)[nH]c2n1Cc1cc(OCCCC(=O)N(Cc3ccccc3)Cc3ccccc3)ccc1N=2
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C1CN2Cc3cc(OCCCC(=O)N(Cc4ccccc4)Cc4ccccc4)ccc3N=C2N1

Procedure:
N,N-dibenzyl-4-(2-oxo-3-methylene-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutanamide acetate (1.0 g) is dissolved in 50 ml water containing a stoichiometric equivalent of sulfuric acid, and the solution evaporated to dryness. The product is suspended in ethanol and filtered, air dried and recrystallized from methanol/acetone to yield N,N-dibenzyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutanamide sulfate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([CH:13]=1)[O:7][CH2:8][CH2:9][N:10]=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([CH:13]=1)[O:7][CH2:8][CH2:9][NH2:10]
Reactant: COc1ccc(F)cc1OCCN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(F)cc1OCCN
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.2 %

Procedure:
A solution of 2-(5-fluoro-2-methoxy-phenoxy)ethylazide (3.97 g, 0.019 mol) and triphenylphosphine (5.95 g, 0.023 mol) in tetrahydrofuran (80 ml) and water (1.5 ml) was allowed to stir for 18 hours at room temperature. The solvent was removed under vacuum. Chromatography (ethyl acetate) removed triphenylphosphine and triphenylphosphine oxide and (25-50% methanol-ethyl acetate plus ammonium hydroxide) afforded 3.14 g (90%) of product as a clear oil. MS EI m/e 185 (M+)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](=[O:10])[CH3:9])[CH:3]=1.[CH3:11][Mg]Br>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])([CH3:11])[CH3:9])[CH:3]=1
Reactant: CC(=O)c1cc(Cl)ncn1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(Cl)ncn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 39.6 %

Procedure:
To a stirred solution of 1-(6-chloro-4-pyrimidinyl)ethanone (Intermediate 18, 500 mg, 3.19 mmol)) in THF (5 mL) was added methylmagnesium bromide (1.171 mL, 3.51 mmol), and the resulting mixture stirred under argon at 0° C. for 2 hrs. The reaction was quenched with water (25 mL) with stirring and extracted with ethyl acetate (50 mL). The combined organic layers were dried (MgSO4), filtered and evaporated to dryness to afford the crude residues. Crude residues were then purified on Biotage Isolera on a pre-packed silica cartaridge (25 g) eluting with 0-20% ethyl acetate-isohexane. The appropriate fractions were combined and evaporated in vacuo to give the required product as a yellow oil (218 mg).
Reaction SMILES: [Br:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:12])[CH:3]=1.[BH4-].[Na+]>CO.C(OCC)C>[Br:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([F:12])[CH:3]=1
Reactant: COc1cc(C=O)c(F)cc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: COc1cc(CO)c(F)cc1Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Bromine (15 mL, 0.3 mol) was added slowly to a solution of 2-fluoro-5-methoxy-benzaldehyde (23.1 g, 0.15 mol) in chloroform (500 mL) and the mixture was stirred at room temperature for 5 days. The mixture was poured into water (200 ml) and extracted with chloroform (2×200 mL). The organics were washed with water, brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography (2–16% EtOAc in hexanes to give 4-bromo-2-fluoro-methoxy-benzaldehyde (20.7 g, 60%). To a solution of 4-bromo-2-fluoro-5-methoxy-benzaldeyde (4.0 g, 17.3 mmol) in MeOH at 0° C. was added NaBH4 (0.65 g, 17.3 mmol). After the reaction mixture was stirred at 0° C. for 2 hours, it was allowed to warm to room temperature. The organic layer was taked up in ethyl ether washed with water and dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (25–45% EtOAc in hexanes) to give the product. (3.9 g, 99%). 1H NMR (300 MHz, CDCl3): δ 3.90 (s, 3 H), 4.74 (d, J=6.02 Hz, 2 H), 6.82 (q, J=6.1 Hz, 1 H), 7.29 (d, J=10.58 Hz, 1 H).
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:8]([C:12]([NH:14][C@H:15]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:16][OH:17])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:29][CH:30]1[CH2:33][CH2:32][CH2:31]1.CN(C=O)C>O>[CH:30]1([CH2:29][O:1][C:2]2[C:3]3[N:4]([C:8]([C:12]([NH:14][C@H:15]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:16][OH:17])=[O:13])=[C:9]([CH3:11])[N:10]=3)[CH:5]=[CH:6][CH:7]=2)[CH2:33][CH2:32][CH2:31]1
Reactant: BrCC1CCC1
Reactant: CCCC[C@H](CO)NC(=O)c1c(C)nc2c(O)cccn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC[C@H](CO)NC(=O)c1c(C)nc2c(OCC3CCC3)cccn12
Reaction time: 1 h

Procedure:
100 mg (0.34 mmol) of 8-hydroxy-N-[(2R)-1-hydroxyhexan-2-yl]-2-methylimidazo[1,2-a]-pyridine-3-carboxamide, 246 mg (0.76 mmol) of caesium carbonate and 56 mg (0.38 mmol) of (bromomethyl)cyclobutane were added to 4.9 ml of dry DMF and the mixture was stirred for 60 min in an oil bath preheated to 60° C. After cooling, about 40 ml of water were added to the reaction mixture and the solution formed was extracted 3× with ethyl acetate. The combined organic phases were concentrated and the residue was purified by preparative HPLC (RP18 column, mobile phase: water/methanol gradient with addition of 0.1% TFA). All product-containing fractions were combined and concentrated. Saturated aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered, concentrated and dried under high vacuum. This gave 78 mg of the target compound (63% of theory, purity 100%).
Reaction SMILES: [O:1]=[S:2]1(=[O:35])[C:8]2[CH:9]=[C:10]([O:14][CH2:15][C:16]([O:18]CC)=[O:17])[C:11]([Br:13])=[CH:12][C:7]=2[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:5][C:4]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:3]1.[OH-].[Na+].CC(O)=O>C(O)C>[O:35]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([O:14][CH2:15][C:16]([OH:18])=[O:17])[C:11]([Br:13])=[CH:12][C:7]=2[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:5][C:4]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:3]1
Reactant: CCCCC1(CCCC)CN(c2ccccc2)c2cc(Br)c(OCC(=O)OCC)cc2S(=O)(=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCC1(CCCC)CN(c2ccccc2)c2cc(Br)c(OCC(=O)O)cc2S(=O)(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 41; 2.2 g, 3.88 mmol) was dissolved in ethanol (15 ml). NaOH (0.8 g in 1.5 ml water) was added to the solution and the mixture was stirred for 30 min at room temperature. AcOH (2 ml) was added. The solvent was evaporated under reduced pressure and the residue was extracted with EtOAc/water. The EtOAc layer was separated, dried and evaporated under reduced pressure to give the title compound 2.0 g (95%). NMR (500 MHz) 0.7-0.8 (m, 6H), 1.0-1.5 (m, 12H), 3.2 (brs, 2H), 3.7 (brs, 2H), 4.7 (s, 2H), 7.0-7.3 (m, 6H), 7.4 (s, 1H).
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]4[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:4]=1.Cl.[NH2:30][C:31]1[C:36]([C:37](=[O:40])[CH2:38][CH3:39])=[CH:35][CH:34]=[C:33]([NH:41][CH:42]2[CH2:47][CH2:46][CH2:45][NH:44][CH2:43]2)[N:32]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:30][C:31]1[C:36]([C:37](=[O:40])[CH2:38][CH3:39])=[CH:35][CH:34]=[C:33]([NH:41][CH:42]2[CH2:47][CH2:46][CH2:45][N:44]([C:3]3[N:8]4[N:9]=[C:10]([CH:12]5[CH2:17][CH2:16][N:15]([CH:18]6[CH2:19][CH2:20]6)[CH2:14][CH2:13]5)[N:11]=[C:7]4[CH:6]=[C:5]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])[N:4]=3)[CH2:43]2)[N:32]=1
Reactant: CCC(=O)c1ccc(NC2CCCNC2)nc1N
Reactant: Clc1ccc(-c2cc3nc(C4CCN(C5CC5)CC4)nn3c(Cl)n2)c(Cl)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCC(=O)c1ccc(NC2CCCN(c3nc(-c4ccc(Cl)cc4Cl)cc4nc(C5CCN(C6CC6)CC5)nn34)C2)nc1N
Temperature: 120 °C

Procedure:
25 mg (0.06 mmol) of 5-chloro-7-(2,4-dichlorophenyl)-2-(1-cyclopropylpiperidin-4-yl)-[1,2,4]-triazolo[1,5-c]pyrimidine hydrochloride, 20 mg (0.07 mmol) of 1-[2-amino-6-(piperidin-3-ylamino)pyridin-3-yl]propan-1-one hydrochloride (Example 27A) and 65 μl (0.4 mmol) of N,N-diisopropylethylamine were initially charged in 1.25 ml of DMSO. The mixture was heated in the microwave at 120° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 21 mg (56% of theory) of the product as a solid.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[CH2:3]1.[Br:17][CH2:18][CH2:19][OH:20].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Br:17][CH2:18][CH2:19][O:20][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[CH2:3]1
Reactant: ClC1Cc2ccccc2Sc2ccccc21
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: BrCCOC1Cc2ccccc2Sc2ccccc21
Temperature: 50 °C
Reaction time: 6 h
Yield: 100.4 %

Procedure:
10-Chloro-10,11-dihydrodibenzo[b,f]thiepine (10 g, 0.041 mol, prepared as described in Monatshefte 96, 182, 1965) was slowly added to a mixture of 2-bromoethanol (44 g, 0.35 mol) and powdered potassium carbonate (10 g, 0.072 mol) at room temperature. After stirring for 6 h, dichloromethane (15 ml) was added, and the reaction mixture was heated at 50° C. for 3 h. After cooling, dichloromethane (35 ml) was added and the mixture was filtered. The dichloromethane was evaporated and excess of 2-bromoethanol was distilled off in vacuo. The oily residue was dissolved in benzene (100 ml), washed with water (3×70 ml), dried (K2CO3) and the solvent was evaporated to give 13.8 g of crude 10-(2-bromoethoxy)-10,11-dihydrodibenzo[b,f]thiepine as an oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([NH2:15])=[C:4]([NH:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH:3]=1.C(N(CC)CC)C.[CH2:36]([O:38][CH2:39][C:40](Cl)=[O:41])[CH3:37]>ClCCl>[CH2:36]([O:38][CH2:39][C:40]([NH:15][C:5]1[C:6]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:7][C:2]([CH3:1])=[CH:3][C:4]=1[NH:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)=[O:41])[CH3:37]
Reactant: Cc1cc(NCCOCCCc2cccnc2)c(N)c(Oc2ccccc2)n1
Reactant: CCOCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCC(=O)Nc1c(NCCOCCCc2cccnc2)cc(C)nc1Oc1ccccc1
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
Under a nitrogen atmosphere, a solution of 6-methyl-2-phenoxy-N4-{2-[3-(pyridin-3-yl)propoxy]ethyl}pyridine-3,4-diamine (5.2 g, 14 mmol), anhydrous dichloromethane (40 mL), and anhydrous triethylamine (2.3 mL, 16.5 mmol) was cooled to 5° C. A solution of ethoxyacetyl chloride (1.77 g, 14.4 mmol) in dichloromethane (10 mL) was then added over a period of ten minutes, and the reaction was stirred for 30 minutes. The reaction mixture was diluted with dichloromethane (25 mL), washed with aqueous saturated sodium bicarbonate (3×) and brine (3×), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 5.8 g of 2-ethoxy-N-(6-methyl-2-phenoxy-4-{2-[3-(pyridin-3-yl)propoxy]ethylamino}pyridin-3-yl)acetamide as an oil.