Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13](Cl)[N:12]=[C:11]([N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[C:7]=3[NH:8][C:9]=2[CH:10]=1.[CH3:22][CH2:23][O-:24].[Na+]>CCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([O:24][CH2:23][CH3:22])[N:12]=[C:11]([N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: Clc1nc(N2CCNCC2)c2[nH]c3cc(Br)ccc3c2n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(N2CCNCC2)c2[nH]c3cc(Br)ccc3c2n1

Procedure:
200 mg (0.55 mmol) 7-bromo-2-chloro-4-(piperazin-1-yl)-5H-pyrimido[5,4-b]indole and 1.64 ml (1.64 mmol) 1 M NaOEt solution (EtOH) in 6 ml EtOH were heated in a microwave oven to 130° C. for 3 h. Then, the solvent was removed and the residue was suspended in water and sucked off. 200 mg (97%) of the title substance was obtained. ESI-MS [m/z]: 376, 378 [M+H]+
Reaction SMILES: [CH2:1]([CH:3]1[C:15]2[NH:14][C:13]3[CH:12]=[CH:11][C:10](OCC4C=CC=CC=4)([O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:9][C:8]=3[C:7]=2[CH2:6][CH:5]([C:32]([OH:34])=[O:33])[CH2:4]1)[CH3:2].CO>[OH-].[Na+]>[CH2:1]([CH:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][C:10]([O:16][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:11][CH:12]=3)[C:7]=2[CH2:6][CH:5]([C:32]([OH:34])=[O:33])[CH2:4]1)[CH3:2]
Reactant: CCC1CC(C(=O)O)Cc2c1[nH]c1c2CC(OCc2ccccc2)(OCc2ccccc2)C=C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC1CC(C(=O)O)Cc2c1[nH]c1ccc(OCc3ccccc3)cc21
Yield: 87.1 %

Procedure:
To a suspension of 3.107 gm (8.9 mMol) ethyl 6-benzyloxy-3-carboxy-6-benzyloxy-1,2,3,4-tetrahydro-9H-carbazole in 100 mL 2N sodium hydroxide were added 100 mL methanol and the reaction mixture stirred at reflux for 3.5 hours. The reaction mixture was concentrated to about half volume and the pH adjusted to between 5 and 7 by the addition of concentrated hydrochloric acid. The mixture was extracted well with 4:1 dichloromethane:isopropanol. The organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure to give 2.71 gm (95%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[N:12][CH:13]=[C:7]2[C:6]=1Cl)=[O:4].[F:15][C:16]1[CH:21]=[C:20]([S:22][CH3:23])[CH:19]=[CH:18][C:17]=1[NH2:24].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.ClCCl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[N:12][CH:13]=[C:7]2[C:6]=1[NH:24][C:17]1[CH:18]=[CH:19][C:20]([S:22][CH3:23])=[CH:21][C:16]=1[F:15])=[O:4]
Reactant: COC(=O)c1ccn2cncc2c1Cl
Reactant: CSc1ccc(N)c(F)c1
Agent: [Pd]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1ccn2cncc2c1Nc1ccc(SC)cc1F
Temperature: 100 °C
Yield: 38.7 %

Procedure:
A suspension of 8-chloro-imidazo[1,5-a]pyridine-7-carboxylic acid methyl ester (223 mg, 1.06 mmol), 2-fluoro-4-methylsulfanyl-phenylamine (200 mg, 1.27 mmol), Pd2dba3 (39 mg, 0.04 mmol), 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (79 mg, 0.17 mmol) and K3PO4 (315 mg, 1.48 mmol) in toluene (4 mL) was degassed and then heated at 100° C. for 18 hours. The reaction mixture was then cooled to room temperature and diluted with ethyl acetate. The resultant mixture was washed with water followed by brine, before being loaded onto a 10 g Isolute® SCX-2 cartridge which was eluted with methanol, and then a 2M solution of ammonia in methanol. The appropriate fractions were combined and concentrated in vacuo to give a residue. The residue was subjected to flash chromatography (Si-PPC, gradient 0% to 10%, ethyl actetate in dichloromethane) to afford the title compound as a yellow oil (136 mg, 39%). LCMS (method B): RT=3.26 min, [M+H]+=332.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].[CH3:12][CH2:13][CH2:14][CH:15]([NH2:19])[CH2:16][CH2:17][CH3:18]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:19][CH:15]([CH2:16][CH2:17][CH3:18])[CH2:14][CH2:13][CH3:12])=[O:8])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1Cl
Reactant: CCCC(N)CCC
Product: CCCC(CCC)NC(=O)c1ccc(Cl)c(C)c1

Procedure:
Prepared in a similar manner to example 4 using 4-chloro-3-methyl benzoic acid and heptan-4-amine. MS (M+H, 268).
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].S(=O)(=O)(O)O.[Cl:12][C@H:13]([CH3:17])[C:14]([OH:16])=[O:15].[C:18](O)([CH3:21])([CH3:20])[CH3:19].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:12][C@H:13]([CH3:17])[C:14]([O:16][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:15]
Reactant: C[C@@H](Cl)C(=O)O
Reactant: CC(C)(C)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: C[C@@H](Cl)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 94.4 %

Procedure:
Prepared according to Wright et al. Tetrahedron Lett. 1997, 38, 7345. A 500 mL glass bomb was charged with magnesium sulfate (4.21 g, 35.0 mmol) and DCM (43.8 mL). To this suspension was added sulfuric acid (486 μL, 8.75 mmol), drop-wise with vigorous stirring. After 15 min of stirring, (R)-2-chloropropanoic acid (950 mg, 8.75 mmol) was added followed by tert-butanol (4.20 ml, 43.8 mmol). The bomb was sealed and stirred at rt for 19 h, whereupon sodium bicarbonate (aq satd, 100 mL) was carefully added, at which point all solids had dissolved. The layers were separated and the aqueous layer was extracted with DCM (2×). The combined organics layers were washed with brine, dried over Na2SO4 and concentrated in vacuo (20° C. bath, 50 mBar) to afford the title compound (1.36 g, 94%) as a light pink oil. 1H NMR (500 MHz, CDCl3) δ 4.29 (q, J=6.9 Hz, 1H) 1.65 (d, J=6.9 Hz, 3H) 1.49 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:28][CH:29]1[CH2:31][O:30]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][CH:29]2[CH2:31][O:30]2)=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Reactant: BrCC1CO1
Product: O=C(c1cn(CC2CO2)c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Yield: 47 %

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (prepared according to example 69) with commercially available 2-bromomethyl-oxirane gave the title compound in 47% yield. ES-MS m/e (%): 423.4 (M+H+).
Reaction SMILES: [C:1]([N:4]([N:14]1[CH:18]=[N:17][N:16]=[CH:15]1)[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H][H]>[C].[Pd].CO>[C:1]([N:4]([N:14]1[CH:15]=[N:16][N:17]=[CH:18]1)[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N(c1ccc([N+](=O)[O-])cc1)n1cnnc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(=O)N(c1ccc(N)cc1)n1cnnc1
Yield: 98.8 %

Procedure:
A proper amount of 10% palladium-carbon was added to 15 ml of a methanol solution containing 0.38 g of 4-[N-acetyl-N-(4-nitrophenyl)amino]-4H-1,2,4-triazole and the mixture was subjected to catalytic reduction in the presence of hydrogen gas at room temperature for about 40 minutes. After completion of reaction, the catalyst was removed by filtration, and the resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 0.33 g of 4-[N-acetyl-N-(4-aminophenyl)amino]-4H-1,2,4-triazole from the chloroform/methanol (50/1) eluate.
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[O:5][C:4](=[O:17])[CH:3]=1.C1CCN2C(=NCCC2)CC1.[C:29](Cl)(=[O:31])[CH3:30].O>C1(C)C=CC=CC=1>[C:29]([O:1][C:2]1[CH2:7][CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[O:5][C:4](=[O:17])[CH:3]=1)(=[O:31])[CH3:30]
Reactant: CCCCCCCCCC1CC(O)=CC(=O)O1
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CCCCCCCCCC1CC(OC(C)=O)=CC(=O)O1
Reaction time: 2 h
Yield: 87.6 %

Procedure:
To a solution of 4.5 g (0.019 mole) of 4-hydroxy-5,6-dihydro-6-nonyl-2-pyrone and 3.15 g (0.021 mole) of DBU in 60 ml of toluene was added dropwise. Then, 1.65 g (0.021 mole) of acetyl chloride with cooling in an ice-water bath. The mixture was stirred for 2 hours and water was added to the reaction mixture. The reaction mixture was extracted with toluene and the toluene layer was washed with an aqueous 5% Na2CO3 solution, with 2N-HCl and finally with an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed under a reduced pressure to obtain 4.7 g (yield: 89%) of 4-acetoxy-5,6-dihydro-6-nonyl-2-pyrone. The acyloxypyrone was dissolved in 30 ml of toluene and 0.13 g of 4-pyrrolidinopyridine was added to the solution. The mixture was refluxed for 3 hours. The residue obtained by evaporation of the solvent was purified by silica gel column chromatography and recrystallized to obtain 2.4 g (yield: 51%) of 3-acetyl-6-nonyltetrahydropyran-2,4-dione.
Reaction SMILES: [CH2:1]([N:4]([CH:11]([CH3:22])[CH2:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1I)[C:5](=[O:10])[C:6]([F:9])([F:8])[F:7])[CH:2]=[CH2:3].CC([O-])=O.[K+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C)C=O.[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].CC([O-])=O.CC([O-])=O.[Pd+2]>[F:7][C:6]([F:9])([F:8])[C:5]([N:4]1[CH2:1][C:2](=[CH2:3])[C:14]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:13]=2[CH2:12][CH:11]1[CH3:22])=[O:10]
Reactant: C=CCN(C(=O)C(F)(F)F)C(C)Cc1cc(OC)ccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: C=C1CN(C(=O)C(F)(F)F)C(C)Cc2cc(OC)ccc21
Reaction time: 8 h
Yield: 43 %

Procedure:
A solution of N-allyl,N-trifluoroacetyl-1-(2-iodo-5-methoxyphenyl)-2-propylamine (4.45 g, 10.8 mmol) in dimethylformamide (120 mL) was treated with KOAc (3.17 g, 32.3 mmol), n-Bu4NBr (3.47 g, 10.8 mmol), PPh3 (0.283 g, 1.08 mmol), Pd(OAc)2 (0.242 g, 1.08 mmol) and stirred overnight at 80 C. The product mixture was cooled to 20 C, filtered, diluted with water (200 mL), extracted with ether (3×200 mL), the combined organic phases washed with water (100 mL), brine (100 mL), dried with Na2SO4 and concentrated. Flash chromatography (10% EtOAc in hexane, silica) resulted in 1.39 g of a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=O.[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14].N1CCCCC1>>[CH2:19]([O:18][C:16](=[O:17])[C:15]([C:13]#[N:14])=[CH:6][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=1)[CH3:20]
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: CCOC(=O)CC#N
Solvent: C1CCNCC1
Product: CCOC(=O)C(C#N)=Cc1cc(OC)cc(OC)c1

Procedure:
Alternatively, compounds of Formula III can be prepared as shown in Schemes 3 and 4. Condensation of 3,5-dimethoxybenzaldehyde with ethyl cyanoacetate in the presence of a base such as piperidine produces the 3-(3,5-dimethoxyphenyl)-2-cyano-acrylic acid ethyl ester. Treatment of the ester with 3-methoxyphenol in the presence of NaH produces the 3-cyano-7-methoxy-4-(3,5-dimethoxyphenyl)-2-oxo-2H-chromene. Similarly, reaction of 3-(3-methoxy-phenyl)-2-cyano-acrylic acid ethyl ester with 4-hydroxyindole produces 3-cyano-4-(3-methoxyphenyl)-2-oxo-2H-pyrrolo[2,3-h]chromene.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](O)=[CH:10][C:9](=[O:13])[N:8]([CH2:14][CH2:15][CH3:16])[C:7]=1[CH3:17])=[O:5])[CH3:2].P(Cl)(Cl)([Cl:20])=O.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:11]([Cl:20])=[CH:10][C:9](=[O:13])[N:8]([CH2:14][CH2:15][CH3:16])[C:7]=1[CH3:17])=[O:5])[CH3:2]
Reactant: CCCn1c(C)c(C(=O)OCC)c(O)cc1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCn1c(C)c(C(=O)OCC)c(Cl)cc1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-hydroxy-2-methyl-6-oxo-1-propyl-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester (2.00 g, 8.36 mmol) and phosphoryl chloride (4.67 mL, 50.2 mmol), triethylamine (1.16 mL, 8.36 mmol) and methylene chloride (2 mL) were added and the mixture was stirred at r.t. overnight. It was concentrated in vacuo, poured into ice and carefully neutralised with sat.aq. K2CO3 solution. It was extracted with ethyl acetate (3×300 mL), the combined organic solution was washed with brine (20 mL), dried (MgSO4) and evaporated. The title compound was purified by flash chromatography, yield 0.6 g, 30%. LC-MS (m/z) 258.5 (MH+); tR=1.21 (method C).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].N12CCCN=C1CC[CH2:17][CH2:16][CH2:15]2.IC(C)C>CN(C)C=O.O>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[N:8]([CH:16]([CH3:17])[CH3:15])[C:9](=[O:11])[S:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2s1
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)I
Product: CC(C)n1c(=O)sc2cc([N+](=O)[O-])ccc21
Temperature: 50 °C
Reaction time: 0.67 h

Procedure:
A stirred solution of 6-nitro-2-benzothiazolinone (5.0 g, 25.5 mmol) in anhydrous N,N-dimethylformamide (51 mL) under N2 is treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (4.96 mL, 33.1 mmol) dropwise. Following a slight exotherm, the reaction mixture is heated up to 50° C. and treated with 2-iodopropane (12.7 mL, 127 mmol). The resulting mixture is quickly heated up to 75° C., stirred at this temperature for 40 mins, cooled to ambient temperature and diluted with ice (100 mL) and water (100 mL). The precipitate is isolated by filtration and recrystallized from ethyl acetate/hexanes to give the title compound, mp 138-142° C.
Reaction SMILES: [CH:1]1([CH2:5][N:6]2[CH2:11][CH2:10][N:9]([C:12](=[O:24])[CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][C:15]=3[CH3:23])[CH2:8][CH2:7]2)[CH2:4][CH2:3][CH2:2]1.[CH3:25][N:26]1[C:35]2[NH:34][C:33]3[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=3[NH:31][CH2:30][C:29]=2[CH:28]=[N:27]1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH:1]1([CH2:5][N:6]2[CH2:7][CH2:8][N:9]([C:12](=[O:24])[CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([N:31]4[CH2:30][C:29]5[CH:28]=[N:27][N:26]([CH3:25])[C:35]=5[NH:34][C:33]5[CH:36]=[CH:37][CH:38]=[CH:39][C:32]4=5)=[O:19])=[CH:16][C:15]=3[CH3:23])[CH2:10][CH2:11]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C(=O)O)ccc1CC(=O)N1CCN(CC2CCC2)CC1
Reactant: Cn1ncc2c1Nc1ccccc1NC2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CC(=O)N1CCN(CC2CCC2)CC1
Yield: 32 %

Procedure:
WSCD (76 mg, 0.39 mmol) and DMAP (7 mg, 0.06 mmol) were added to a solution of 4-[2-(4-cyclobutylmethyl-piperazin-1-yl)-2-oxo-ethyl]-3-methyl-benzoic acid from Example E85.2 (100 mg, 0.30 mmol) and 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (61 mg, 0.30 mmol) in dichloromethane (20 ml) and DIEA (0.16 ml, 0.91 mmol). The mixture was heated at reflux for 20 h and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 4% methanol:96% dichloromethane to 6% methanol:94% dichloromethane to 1% 35% ammonia:7% methanol:92% dichloromethane) to give an off-white solid identified as the title compound (50 mg, 32%).
Reaction SMILES: [Na].[N:2]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N+:3]=[N-:4].[CH3:11][Si:12]([CH3:22])([CH3:21])[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[Cl-].[NH4+]>C(O)C>[N:2]([C:5](=[CH:17][C:16]1[CH:19]=[CH:20][C:13]([Si:12]([CH3:11])([CH3:22])[CH3:21])=[CH:14][CH:15]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N+:3]=[N-:4]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: C[Si](C)(C)c1ccc(C=O)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=Cc1ccc([Si](C)(C)C)cc1)N=[N+]=[N-]
Temperature: 25 °C
Yield: 62.4 %

Procedure:
1.26 g (54.96 mmol) of sodium and 30 mL of anhydrous ethanol are introduced into a 100 mL round-bottomed flask, equipped with a magnetic stirrer and maintained under a nitrogen atmosphere. The reaction mixture is stirred at room temperature until a homogeneous solution is obtained. To this solution, cooled to −10° C., is added dropwise a solution containing 16.83 mL (54.96 mmol) of ethyl azidoacetate (34% in CH2Cl2) and 5 g (27.48 mmol) of 4-trimethylsilylbenzaldehyde in 5 mL of ethanol. The reaction mixture is then stirred at 0° C. for 4 hours. The reaction medium is hydrolysed by adding, with vigorous stirring, 100 mL of ammonium chloride solution (30% aqueous). The product is extracted with three times 50 mL of ethyl acetate. The combined organic phases are washed with twice 20 mL of water, dried over sodium sulfate and concentrated under reduced pressure. The resulting oil is purified by chromatography on a column of silica gel, eluting with a mixture of heptane and dichloromethane. 4.96 g of the expected product are isolated in the form of a yellow oil.
Reaction SMILES: C(OC[N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]([OH:21])[CH3:20])[C:10](=[O:22])[N:9]([CH3:23])[C:8]=2[N:7]=[C:6]1[S:24][CH2:25][CH2:26][Cl:27])C.Cl>C(O)C>[Cl:27][CH2:26][CH2:25][S:24][C:6]1[NH:5][C:13]2[C:12](=[O:14])[N:11]([CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]([OH:21])[CH3:20])[C:10](=[O:22])[N:9]([CH3:23])[C:8]=2[N:7]=1
Reactant: CCOCn1c(SCCCl)nc2c1c(=O)n(CCCC[C@@H](C)O)c(=O)n2C
Agent: Cl
Solvent: CCO
Product: C[C@@H](O)CCCCn1c(=O)c2[nH]c(SCCCl)nc2n(C)c1=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
To a stirring slurry of (R)-7-ethoxymethyl-8-(2-chloroethylsulfanyl)-1-(5-hydroxyhexyl)-3-methylxanthine (150 mg, 0.322 mmol) in ethanol (9.0 ml) was added concentrated hydrochloric acid (1.0 ml). After stirring at 80° C. for 3 hours and concentrating under reduced pressure, (R)-8-(2-chloroethylsulfanyl)-1-(5-hydroxyhexyl)-3-methylxanthine (100 mg, 86% yield) was obtained as a beige powder.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:35])([CH2:32][CH2:33][CH3:34])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:31])=[N:15][N:16]2[C:21]([O:22][CH2:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:20][C:19]([CH3:30])=[CH:18][C:17]=12)=[O:12])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]([CH3:35])([CH2:32][CH2:33][CH3:34])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:31])=[N:15][N:16]2[C:21]([O:22][CH2:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:20][C:19]([CH3:30])=[CH:18][C:17]=12)=[O:12]
Reactant: CCCC(C)(CNC(=O)c1c(C)nn2c(OCC3CCCCC3)cc(C)cc12)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC(C)(N)CNC(=O)c1c(C)nn2c(OCC3CCCCC3)cc(C)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 40 mg (0.047 mmol, 59% pure) of rac-[1-({[7-(cyclohexylmethoxy)-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl]carbonyl}amino)-2-methylpentan-2-yl]carbamic acid tert-butyl ester (Example 121A) in 2 ml of dichloromethane was admixed with 0.072 ml (0.94 mmol) of trifluoroacetic acid. The resulting solution was stirred at room temperature overnight. After the reaction had ended, the solvent was drawn off under reduced pressure and the residue was purified by preparative HPLC chromatography (Method 21), which gave 8 mg (43% of theory) of the target compound.
Reaction SMILES: B(F)(F)F.O(CC)CC.[CH:10]1([CH:16]([OH:18])[CH3:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[CH3:19][C:20]1([O:23][CH2:22]1)[CH3:21]>C1CCCCC1>[CH:10]1([CH:16]([O:18][C:20]([CH3:21])([CH3:19])[CH2:22][OH:23])[CH3:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC1(C)CO1
Reactant: CC(O)C1CCCCC1
Agent: FB(F)F
Solvent: C1CCCCC1
Solvent: CCOCC
Product: CC(OC(C)(C)CO)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
BF3—OEt2 (2.0 ml) is added dropwise to a solution of 1-cyclohexylethanol (16.6 g, 127.0 mmol) and isobutylene oxide (2.9 g, 40.0 mmol) in cyclohexane (20 ml) that has been cooled to 0° C. The reaction mixture is now stirred at 0° C. for a further 30 minutes, and further, BF3—OEt2 (2.0 ml) is then added. After a further 3 hours at 0° C., the cooling is removed and the reaction solution is washed once with 1 M NaOH (15 ml). The organic phase is dried over Na2SO4, filtered off and freed from solvent in a rotary evaporator. The 1-cyclohexylethanol that has not completely reacted is removed from the crude product; thus, obtained by means of bulb tube distillation (BTD) and 5.3 g crude 2-(1-cyclohexylethoxy)-2-methyl-1-propanol is obtained which has a GC content of 75% and can be used in the next reaction without further purification.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:19])[CH:9]([NH2:18])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[S:28](Cl)(=[O:30])=[O:29].CCN(CC)CC.C(=O)([O-])[O-].C(O)C(N)(CO)CO>ClCCCl>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[S:28]([NH:18][CH:9]([C:8]([N:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]1)=[O:19])[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:29])=[O:30]
Reactant: CC1CCN(C(=O)C(N)CCc2ccccc2)CC1
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Agent: NC(CO)(CO)CO
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1cccc(Cl)c1S(=O)(=O)NC(CCc1ccccc1)C(=O)N1CCC(C)CC1
Reaction time: 16 h

Procedure:
A mixture of 20 mg (0.077 mmol) of 1-(4-methylpiperidin-1-yl)-1-oxo-4-phenylbutan-2-amine, 0.11 mmol of 2-chloro-6-methylbenzene-sulfonyl chloride, and 0.2 mmol of Et3N in 1 mL of DCE is stirred for 16 h, and 240 mg of MP-carbonate and 170 mg of PS-trisamine are added. The mixture is shaken for 2 days, filtered, and concentrated to provide Example 54.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[N:11][C:10]([O:13][CH:14]([C:16]([O:18]CC)=[O:17])[CH3:15])=[N:9]1.[OH-].[K+]>C(O)C>[C:16]([CH:14]([O:13][C:10]1[N:11]=[CH:12][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:9]=1)[CH3:15])([OH:18])=[O:17]
Reactant: CCOC(=O)C(C)Oc1ncn(-c2ccccc2Cl)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(Oc1ncn(-c2ccccc2Cl)n1)C(=O)O

Procedure:
Ten g of the compound of Example 4 was refluxed for 4 hours with 3.8 g of potassium hydroxide in 100 ml of ethanol, and the product was collected as shown in Example 22 and recrystallized from toluene and then from ethanol to obtain 3.1 g of the desired product, m.p. 104°-106°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([O:23][CH3:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:3]=1[NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].O.C>CS(C)=O.C(OCC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([C:17]3([O:23][CH3:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:3]=1[NH:25][C:26](=[O:31])[C:27]([CH3:29])([CH3:28])[CH3:30]
Reactant: COC1(c2ccc(C=Cc3cc(F)cc(F)c3NC(=O)C(C)(C)C)cc2)CCOCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCOCC
Product: COC1(c2ccc(/C=C/c3cc(F)cc(F)c3NC(=O)C(C)(C)C)cc2)CCOCC1

Procedure:
The product from Example 6 (3.0 g) was dissolved in dimethylsulphoxide and Pd(dba)2 (200 mg) was added. The mixture was treated with H2 at atmospheric pressure until gas uptake ceased. On completion, the reaction was added to water (500 ml) and extracted with ethyl acetate (2×400 ml). The combined organic extracts were washed with water (2×300 ml) and then dried on MgSO4, and filtered. Removal of the solvent in vacuo gave a yellow oil which was dissolved in diethyl ether, treated with charcoal, then filtered through, Hyflo. Removal of the solvent from the filtrate gave the crude title product. Precipitation from ethyl acetate/40°-60° petroleum ether afforded the title product as a white solid; mp 150°-151° C.