Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:2]1.CN1CCOCC1.[ClH:28].C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[CH:51]([NH:54][C:55](=[O:63])[CH2:56][N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1)([CH3:53])[CH3:52].C(OCC)(=O)C.Cl>C(Cl)(Cl)Cl.CO>[ClH:28].[ClH:28].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:60]3[CH2:59][CH2:58][N:57]([CH2:56][C:55](=[O:63])[NH:54][CH:51]([CH3:52])[CH3:53])[CH2:62][CH2:61]3)=[O:18])=[CH:19][CH:20]=2)=[N:2]1
Reactant: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Reactant: CC(C)NC(=O)CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)NC(=O)CN1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1
Yield: 37.3 %

Procedure:
The crude product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (200 mg, 0.757 mmol) obtained in Step 6 of Example 1, N-methylmorpholine (0.166 mL, 1.51 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (203 mg, 1.06 mmol), 1-hydroxybenzotriazole monohydrate (133 mg, 0.984 mmol) and-N-isopropyl-2-(piperazin-1-yl)acetamide (210 mg, 1.14 mmol) in a similar manner to Step 7 of Example 1, was purified by silica gel column chromatography (chloroform/methanol=80/20), followed by treating with 4 mol/L hydrogen chloride-ethyl acetate solution (0.665 mL) to obtain Compound 135 (99.7 mg, 26%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][C:11]1=[O:19].[OH-:20].[Na+].[OH-].[K+]>C(O)CCC>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:18]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:12][C:11]([OH:19])=[O:20]
Reactant: [OH-]
Reactant: O=C1Cc2ccccc2N1c1c(Cl)cc(O)cc1Cl
Agent: [K+]
Agent: [Na+]
Solvent: CCCCO
Product: O=C(O)Cc1ccccc1Nc1c(Cl)cc(O)cc1Cl
Temperature: 0 °C

Procedure:
The 2-[(2,6-dichloro-4-methoxyphenyl)amino]phenylacetic acid (0.1 mol) from example 23 was added in portions to a melt of 200 g of pyridine hydrochloride (1.75 mol) at 170° C. The mixture was heated at 180° C. for 3 h and poured onto 2000 ml of ice water while hot. The precipitated product was filtered off, washed with water, and dissolved in 1000 ml of ethyl acetate. The organic phase was washed with 200 ml of 1N HCl in water (2×100 ml) and evaporated to give N-(2,6-dichloro-4-hydroxyphenyl)oxindole. To a solution of 8 g of N-(2,6-dichloro-4-hydroxyphenyl)-oxindole in 200 ml of n-butanol were added 7 g of NaOH and 1 g of KOH, and the reaction mixture was refluxed for 24 h and evaporated in vacuo. The residue was dissolved in 700 ml of water and the aqueous solution was extracted with ether (2×200 ml), cooled to 0° C., and acidified with concentrated HCl. The precipitate was taken up in 300 ml of ether. The organic phase was washed with 30 ml of water, 0.5N NaHCO3 (5×80 ml), and 80 ml of 2N KHCO3 solution. The combined NaHCO3 extracts were cooled to 0° C. and acidified with 2N HCl, and the precipitate was dissolved in 200 ml of ether. The organic layer was washed with 30 ml of water and evaporated to yield 2-[(2,6-dichloro-4-hydroxyphenyl)amino]phenylacetic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:11]=[N:10][NH:9][C:8]=2[C:12]2[CH:29]=[CH:28][C:15]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:14][CH:13]=2)=[CH:3][CH:2]=1.[F:30]C1C=C(C(=O)CC2C=CN=CC=2)C=CC=1OCC1C=CC2C(=CC=CC=2)N=1>>[F:30][C:14]1[CH:13]=[C:12]([C:8]2[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[CH:11][NH:10][N:9]=2)[CH:29]=[CH:28][C:15]=1[O:16][CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)c(F)c1
Reactant: c1ccc2nc(COc3ccc(-c4[nH]ncc4-c4ccncc4)cc3)ccc2c1
Product: Fc1cc(-c2n[nH]cc2-c2ccncc2)ccc1OCc1ccc2ccccc2n1

Procedure:
Following the procedure for the preparation of 2-[-4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl}-quinoline but substituting 1-[3-Fluoro-4-(quinolin-2-ylmethoxy)-phenyl]-2-pyridin-4-yl-ethanone provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.47 (bs, 2H), 8.19 (d, J=8.7 Hz, 1H), 8.05 (d, J=8.3 Hz, 1 H), 7.71 (m, 4H), 7.54 (t, J=7.1 Hz, 1H), 7.18 (m, 3H), 7.07 (m, 2 H), 5.42 (s, 2 H); MS: (M+H m/z=397.0).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([CH2:13][N:14]([C:27]2[CH:32]=[CH:31][C:30](Br)=[CH:29][CH:28]=2)[C:15]([C@@H:17]2[CH2:19][C@H:18]2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[N:21]=2)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].C[CH2:42][O:43][C:44]([CH3:46])=O>CC#N.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([CH2:13][N:14]([C:15]([C@@H:17]2[CH2:19][C@H:18]2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[N:21]=2)=[O:16])[C:27]2[CH:32]=[CH:31][C:30]([C:8]3[CH:12]=[CH:11][C:46]([CH2:44][O:43][CH3:42])=[CH:10][CH:9]=3)=[CH:29][CH:28]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(CN(C(=O)[C@@H]2C[C@H]2c2cccc(F)n2)c2ccc(Br)cc2)CCCC1
Reactant: CCOC(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COCc1ccc(-c2ccc(N(CC3(NC(=O)OC(C)(C)C)CCCC3)C(=O)[C@@H]3C[C@H]3c3cccc(F)n3)cc2)cc1
Reaction time: 0.33 h

Procedure:
A mixture of [1-({(4-bromo-phenyl)-[trans-2-(6-fluoro-pyridin-2-yl)-cyclopropanecarbonyl]-amino}-methyl)-cyclopentyl]-carbamic acid t-butyl ester (95 mg, 0.18 mmol), arylboronic acid (0.22 mmol), Pd(PPh3)2Cl2 (14 mg, 0.02 mmol) and K2CO3 (47 mg, 0.34 mmol) in CH3CN/H2O (3.5/0.5 mL) was macrowaved at 140° C. for 20 min. The reaction mixture was passed through a short silica pad (EtOAc) and concentrated. The residue was subjected to ISCO (12 g column, 0-50% EtOAc in hexane over 25 min) to give the desired products. MS (MH+ 574).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([S:14][CH3:15])[S:9][C:10]=1[C:11](Cl)=[O:12])=[O:5])[CH3:2].[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17].Cl>ClCCl>[C:16]([NH:20][C:11]([C:10]1[S:9][C:8]([S:14][CH3:15])=[N:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:12])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCOC(=O)c1nc(SC)sc1C(=O)Cl
Reactant: CC(C)(C)N
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)c1nc(SC)sc1C(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 100.2 %

Procedure:
3.50 g (13.2 mmol) of 4-ethoxycarbonyl-2-methylthiothiazole-5-carboxylic acid chloride was dissolved in 20 ml of dichloromethane and dripped, at 0° C., into a solution of 3.20 g (44 mmol) of tert-butylamine in 50 ml of dichloromethane. The mixture was allowed to warm up to room temperature and was then stirred for 14 hours. 100 ml of 10% strength hydrochloric acid was added and the organic phase was separated, washed with 50 ml of water and dried over sodium sulfate. The solvent was removed under reduced pressure, leaving 4.00 g (100%) of product as a yellow crystalline slurry.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]=[C:28]=[O:29]>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:28](=[O:29])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccccc1F
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Product: NC(=O)c1[nH]c2ncccc2c1-c1ccc(NC(=O)Nc2ccccc2F)cc1

Procedure:
66.6 mg of solid beige-coloured 3-{4-[3-(2-fluorophenyl)ureido]phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and 2-fluorophenyl isocyanate.
Reaction SMILES: Cl.C(O[C:5](=[O:9])[CH2:6][NH:7][CH3:8])C.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[S:22])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:10]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:5](=[O:9])[CH2:6][N:7]([CH3:8])[C:21]2=[S:22])=[CH:16][CH:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1ccc(N=C=S)cc1
Reactant: CCOC(=O)CNC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN1CC(=O)N(c2ccc(C(C)(C)C)cc2)C1=S
Temperature: 25 °C
Yield: 75.5 %

Procedure:
A mixture of sarcosine ethyl ester hydrochloride (7.68 g), 4-t-butylphenylisothiocyanate (9.6 g), triethyl amine (10.1 g) and chloroform (250 mL) was heated at reflux for 3 hours. The mixture was cooled to ambient temperature, washed with 2N HCl (2×200 mL), then with water (200 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was crystallized from ethanol to give the title compound (9.9 g), m.p. 156°-158° C. Anal. Calcd. for C14H18N2O S: C, 64.09; H, 6.91; N,10.68. Found: C, 63.83; H, 7.15; N, 10.53. Mass spectrum (EI, M.+) m/z 262.
Reaction SMILES: NC1N(CC2CCC2)C(=O)N(CC2CCC2)C(=O)C=1.[NH2:20][C:21]1[N:26]([CH2:27][CH:28]2C[CH2:31][CH2:30][CH2:29]2)[C:25](=[O:33])[N:24]([CH2:34][CH:35]2[CH2:39][CH2:38][CH2:37]C2)[C:23](=[O:40])[C:22]=1[N:41]=[O:42]>>[NH2:20][C:21]1[N:26]([CH2:27][CH:28]2[CH2:31][CH2:30][CH2:29]2)[C:25](=[O:33])[N:24]([CH2:34][CH:35]2[CH2:39][CH2:38][CH2:37]2)[C:23](=[O:40])[C:22]=1[N:41]=[O:42]
Reactant: Nc1c(N=O)c(=O)n(CC2CCCC2)c(=O)n1CC1CCCC1
Agent: Nc1cc(=O)n(CC2CCC2)c(=O)n1CC1CCC1
Product: Nc1c(N=O)c(=O)n(CC2CCC2)c(=O)n1CC1CCC1

Procedure:
In the manner of step (c) of Example 1, 6-amino-1,3-bis(cyclobutylmethyl)uracil (from step (b), 5.75 g, 21.8 mmol) was converted to 6-amino-1,3-bis(cyclopentylmethyl)-5-nitrosouracil, isolated as purple flakes (5.60 g, 88%), m.p. 251°-252° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:13]([CH:14]=2)=[N:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[CH:17][CH:16]=2)[CH:10]=3)[CH2:3][CH2:2]1.[Br:32]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.O>C(OCC)(=O)C>[Br:32][C:14]1[C:13]2[C:9](=[CH:10][N:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][Si:22]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:29]([CH3:31])[CH3:30])=[CH:17][CH:16]=3)[N:12]=2)[CH:8]=[CH:7][C:6]=1[O:5][CH2:4][CH:1]1[CH2:2][CH2:3]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)[Si](Oc1ccc(-n2cc3ccc(OCC4CC4)cc3n2)cc1)(C(C)C)C(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)[Si](Oc1ccc(-n2cc3ccc(OCC4CC4)c(Br)c3n2)cc1)(C(C)C)C(C)C
Temperature: 80 °C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
To a solution of 6-(cyclopropylmethoxy)-2-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-2H-indazole (1.31 g) in ethyl acetate (15 mL) were added N-bromosuccinimide (0.56 g) and azobisisobutyronitrile (99 mg), and the mixture was stirred at 80° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as an orange oil (1.41 g).
Reaction SMILES: [F:1][CH2:2][CH:3]([NH2:18])[CH2:4][CH2:5][CH2:6][N:7]1C(=O)C2=CC=CC=C2C1=O.C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)(Cl)Cl>[F:1][CH2:2][CH:3]([NH:18][C:26](=[O:28])[CH3:27])[CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: CC(=O)Cl
Reactant: NC(CF)CCCN1C(=O)c2ccccc2C1=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)NC(CF)CCCN

Procedure:
A solution of 1 mmole of N-(4-fluoromethyl-4-aminobutyl)phthalimide in 10 ml of chloroform is treated with 1 ml of triethylamine followed by 78 mg (1 mM) of acetyl chloride in 5 ml of chloroform. After 1 hour at 25° C the solution is washed with water, dried and concentrated. The resulting residue is dissolved in 10 ml of ethanol and treated with 60 mg (1.1 mM) of hydrazine hydrate at reflux for 2 hours after which the solvent is evaporated. The residue is treated with 1 N sodium hydroxide solution until the solid dissolves then is extracted with dichloromethane. The organic phase is dried and concentrated to give N-(1-fluoromethyl-4-aminobutyl)-acetamide.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]([CH2:11][O:12][Si](C(C)C)(C(C)C)C(C)C)[CH:10]=1)([CH3:4])[CH3:3]>C1COCC1>[F:1][C:2]([C:5]1[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[N:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)[Si](OCc1cncc(C(C)(C)F)c1)(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(F)c1cncc(CO)c1

Procedure:
To 2-(5-((triisopropylsilyloxy)methyl)pyridin-3-yl)propan-2-ol (1.1 g, 3.4 mmol) in DCM (30 mL) at −78° C. was added diethylaminosulfur trifluoride (DAST) (0.67 mL, 5.1 mmol) and stirred at the same temperature for 1 hr, then warmed to 0° C. for 3 hrs. The resulting mixture was quenched with MeOH and saturated aqueous NaHCO3. The mixture was extracted with EtOAc three times and dried with anhydrous NaSO4, filtered and concentrated to dryness. Careful purification by flash chromatography (silica gel, hexanes/EtOAc) gave the desired fluoride (3-(2-fluoropropan-2-yl)-5-((triisopropylsilyloxy)methyl)pyridine) as a light yellow solid (0.43 g). 1H NMR (CDCl3): d: 1.127 (d, J=6.3 Hz, 18H), 1.204 (m, 3H), 1.712 (s, 3H), 1.786 (s, 3H), 4.922 (s, 2H), 7.781 (s, 1H), 8.566 (s, 2H). 3-(2-fluoropropan-2-yl)-5-((triisopropylsilyloxy)methyl)pyridine was deprotected with excess aqueous HF in THF to provide (5-(2-fluoropropan-2-yl)pyridin-3-yl)methanol as a white solid. (5-(2-fluoropropan-2-yl)pyridin-3-yl)methanol was then oxidized to 5-(2-fluoropropan-2-yl)nicotinaldehyde using standard Swern Oxidation conditions.
Reaction SMILES: [F:1][CH2:2][O:3][N:4]=[C:5]([C:10]1[N:14]=[C:13]([NH:15]C=O)[S:12][N:11]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+].Cl>O>[F:1][CH2:2][O:3][N:4]=[C:5]([C:10]1[N:14]=[C:13]([NH2:15])[S:12][N:11]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)C(=NOCF)c1nsc(NC=O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(C(=NOCF)C(=O)O)ns1
Temperature: 5 °C
Reaction time: 30 h
Yield: 817.5 %

Procedure:
To a suspension of methyl 2-fluoromethoxyimino-2-(5-formamido-1,2,4-thiadiazole-3-yl)-acetate (syn-isomer) (5.24 g, 20 mmol) in water (26 ml), sodium hydroxide (3.2 g, 80 mmol) in water (16 ml) was added at 0° C., and the mixture was stirred at 5° C. for 30 hrs. and then adjusted to pH 1 or lower with concentrated hydrochloric acid (7.0 ml, 84 mmol), and extracted four times with ethyl acetate (30 ml). The resulting ethyl acetate layer was dried over sodium sulfate and decolorized with activated carbon (0.5 g). The ethyl acetate was distilled off, to the residue, isopropyl ether was added. The resultant solution was cooled to precipitate. The precipitates were filtered off and dried to give 2-fluoromethoxyimino-2-(5-amino-1,2,4-thiadiazole-3-yl) acetic acid (syn-isomer) (36 g, yield: 81.8%).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][NH:12][C:13]([C:15]2[C:16]3[N:17]([CH:24]=[CH:25][N:26]=3)[C:18]([NH:22][CH3:23])=[C:19]([Cl:21])[CH:20]=2)=[O:14])[CH2:7][CH2:6]1)[CH2:2][CH2:3]C.[CH3:27][O:28]CCCN1CCC(CN)CC1>>[Cl:21][C:19]1[CH:20]=[C:15]([C:13]([NH:12][CH2:11][CH:8]2[CH2:9][CH2:10][N:5]([CH2:1][CH2:2][CH2:3][O:28][CH3:27])[CH2:6][CH2:7]2)=[O:14])[C:16]2[N:17]([CH:24]=[CH:25][N:26]=2)[C:18]=1[NH:22][CH3:23]
Reactant: CCCCN1CCC(CNC(=O)c2cc(Cl)c(NC)n3ccnc23)CC1
Reactant: COCCCN1CCC(CN)CC1
Product: CNc1c(Cl)cc(C(=O)NCC2CCN(CCCOC)CC2)c2nccn12

Procedure:
The title compound was prepared, according to the procedure described in the step 3 of EXAMPLE 5, from 6-chloro-5-(methylamino)imidazo[1,2-a]pyridine-8-carboxylic acid hydrochloride (EXAMPLE 8, Step 4) and {1-[3-(methyloxy)propyl]-4-piperidinyl}methylamine (EXAMPLE 7, Step 2).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](C(OCC)=O)([CH3:11])[CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[CH3:2].[Cl-].[Li+].O>CS(C)=O>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([CH3:11])[CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[CH3:2]
Reactant: CCOC(=O)C(C)(CC=C(C)C)C(=O)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C(C)CC=C(C)C
Temperature: 0 °C

Procedure:
85.3 g of 2-ethoxycarbonyl-2,5-dimethyl-4-hexenoic acid ethyl ester was dissolved in 645 ml of dimethyl sulfoxide and combined in succession with 29.7 g of lithium chloride and 6.3 ml of distilled water. The reaction mixture was thereafter heated a total of 13 hours to 200° C. and subsequently--after cooling--poured on 1 liter of ice water. The aqueous phase was extracted three times with respectively 500 ml of methylene chloride. The combined organic extracts then were washed twice with water, dried over magnesium sulfate, concentrated on a forced circulation evaporator, and distilled under vacuum, thus isolating 53.1 g, bp13 75°-78° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:14]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=O)[NH:10][C:11]([NH2:13])=[O:12])=[CH:5][CH:4]=1.C(O)C>[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14]([C:16]3[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)=[N:13][C:11]([OH:12])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N(NC(N)=O)C(=O)c2ccc(OC)nc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-n2nc(O)nc2-c2ccc(OC)nc2)cc1
Temperature: 60 °C
Yield: 53.9 %

Procedure:
A mixture of 2-(4-methoxyphenyl)-2-((6-methoxypyridin-3-yl)carbonyl)hydrazine carboxamide (550 mg, 1.74 mmol) in 10% sodium hydroxide solution (4 mL)-ethanol (2 mL) was heated at 60° C. for 1 hour. After cooling, the solvent was removed under reduced pressure. 2N-HCl was added to the residue and the mixture was adjusted pH to ca. 4. A generated precipitate was isolated by filtration, washed with water, dried in vacuo to give 1-(4-methoxyphenyl)-5-(6-methoxypridin-3-yl)-1H-1,2,4-triazol-3-ol (280 mg, 54% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([NH:10][C:11](=[O:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:9]=1)=O.NO.Cl.C[O-].[Na+].C(N(C(C)C)CC)(C)C.CN(C([O:42][N:43]1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.NO>O.CO>[OH:42][NH:43][C:3]([C:5]1[S:6][C:7]([NH:10][C:11](=[O:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:9]=1)=[O:2]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: COC(=O)c1ccc(NC(=O)Cc2ccccc2)s1
Agent: C[O-]
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccccc1)Nc1ccc(C(=O)NO)s1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 5-phenylacetylamino-thiophene-2-carboxylic acid methyl ester (92.7 mg, 0.34 mmol) were added NH2OH.HCl (110.0 mg, 1.58 mmol) and 5 mL of anhydrous MeOH. A solution of NaOMe (4.37 M in MeOH, 0.75 mL, 3.28 mmol) was added. The resulting mixture was allowed to stir at 50° C. for 6 h, at ii for 14 h, again at 50° C. for 3 days and then at rt for additional 2 days. Five mL of water was added and the mixture was stirred at rt for 3 days. A solution of NaOMe (4.37 M in MeOH, 0.75 mL, 3.28 mmol) was then added and the resulting mixture was allowed to stir at rt for additional 3 days. After the reaction was complete, MeOH was removed and the aqueous layer was acidified with 2N aqueous HCl to pH≈2. After extracted with 2×15 mL of EtOAc, the combined organic layer was concentrated and dried under high vacuum. The residue was subsequently dissolved in 6 mL of anhydrous DMF and the mixture was cooled to 0° C. Diisopropylethylamine (0.20 mL, 1.15 mmol) and HBTU (210.7 mg, 0.56 mmol) were added. After stirring at 0° C. for 1 h and at it for additional 1 h, 1.3 mL of 50% aqueous NH2OH solution was added and the mixture was allowed to stir at rt overnight. After concentration under high vacuum, the resulting residue was purified by flash column chromatography (70% EtOAc/hexanes to EtOAc and then to 10% MeOH/EtOAc) to give 5-phenylacetylamino-thiophene-2-carboxylic acid hydroxyamide as a pale solid. 1H NMR (DMSO-d6, 200 MHz) δ 7.55-7.15 (m, 6H), 6.64 (d, J=4.0 Hz, 1H), 3.68 (s, 2H). MS (EI): cal'd 277.31 (MH+), exp 277.25 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[CH2:10][N:11]1[CH2:16][CH2:15][S:14][CH2:13][CH2:12]1.[CH3:17][C@@H:18]1[CH2:23][NH:22][CH2:21][C@H:20]([CH3:24])[NH:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:22]2[CH2:21][C@@H:20]([CH3:24])[NH:19][C@@H:18]([CH3:17])[CH2:23]2)=[CH:4][C:3]=1[CH2:10][N:11]1[CH2:16][CH2:15][S:14][CH2:13][CH2:12]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: O=Cc1ccc(Br)c(CN2CCSCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(Br)c(CN3CCSCC3)c2)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-bromo-3-(thiomorpholinomethyl)benzaldehyde (0.73 g, 2.43 mmol) in dichloromethane (24.32 ml) was added (2R,6S)-2,6-dimethylpiperazine (0.416 g, 3.65 mmol). The mixture was allowed to stir at RT for 40 minutes before sodium triacetoxyborohydride (0.773 g, 3.65 mmol) was added. The reaction was stirred at RT for 2 hours. The mixture was diluted with dichloromethane and washed with saturated NaHCO3(aq), dried (MgSO4) and evaporated to give the sub-title compound as a pale yellow oil. Yield: 0.92 g
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.C(N(CC)CC)C.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>ClCCl>[CH3:26][S:23]([O:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CO)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCO[C@H](COS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
To a solution of (S)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (3.0 g, 13.8 mmol) and triethylamine (4.2 g, 41.4 mmol) in dichloromethane (80 mL) at 0° C. was dropwise added mesyl chloride (1.9 g, 16.5 mmol). The reaction mixture was stirred at 0° C. for 2 hour, and then diluted with dichloromethane (100 mL). The organic layers were washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, filtered and concentrated to afford (S)-tert-butyl 2-((methylsulfonyloxy)methyl)morpholine-4-carboxylate as a purple oil (4.0 g, 98%), which was directly used in the next step without further purification. MS (ES+) C11H21NO6S requires: 295, found: 240 [M+H-56]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6]1(=[O:12])[NH:10][C:9](=[O:11])[CH:8]=[CH:7]1>>[CH:2]12[O:1][CH:5]([CH2:4][CH2:3]1)[CH:8]1[CH:7]2[C:6](=[O:12])[NH:10][C:9]1=[O:11]
Reactant: c1ccoc1
Reactant: O=C1C=CC(=O)N1
Product: O=C1NC(=O)C2C3CCC(O3)C12

Procedure:
This compound can be obtained by Diels-Alder reaction of furan with maleimide, for example in analogy to Fisera, L., Melnikov, J., Pronayova, N., Ertl, P., Chem. Pap. 1995, 49 (4), 186–191.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@H:21]3[O:27][C:25](=[O:26])[CH2:24][C@H:23]([OH:28])[CH2:22]3)[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:29])[CH2:9]1)=[O:6])[CH3:4].C1([NH2:36])CCCCC1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@H:21]3[O:27][C:25](=[O:26])[CH2:24][C@H:23]([OH:28])[CH2:22]3)[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:29])[CH2:9]1)=[O:6])[CH3:4].[CH:13]1([C:8]([NH2:36])=[O:7])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:12]1
Reactant: NC1CCCCC1
Agent: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: NC(=O)C1CCCCC1
Temperature: 25 °C

Procedure:
A mixture of 5 g (0.012 mol) of lovastatin, 6 ml (0.052 mol) of cyclohexylamine and 50 ml of toluene was refluxed for 6 hours. The reaction mixture was cooled to RT and 20 ml of ethyl acetate was added. The mixture was washed with 2N HCl (2×30 ml) and water (2×20 ml). The organic layer was dried with sodium sulfate, filtered and evaporated to a volume of 15 ml. 50 ml of hexane was added and the precipitate was filtered to give 5.5 g of lovastatin cyclohexanamide as a white powder.