Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])=[O:11])=[C:5](C)[CH:4]=1.[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH:30]=O.C(OC)(OC)OC.[BH4-].[Na+]>CO>[CH2:21]([N:17]([CH2:18][CH2:19][CH3:20])[CH2:16][CH2:15][CH2:14][CH2:13][NH:12][C:10]([NH:9][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][CH2:30][C:26]2[NH:25][CH:29]=[CH:28][N:27]=2)=[CH:8][CH:7]=1)=[O:11])[CH2:22][CH3:23]
Reactant: O=Cc1ncc[nH]1
Reactant: CCCN(CCC)CCCCNC(=O)Nc1ccc(CN)cc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: CCCN(CCC)CCCCNC(=O)Nc1ccc(CNCc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 43.1 %

Procedure:
The compound (195.6 mg) obtained in Example 12-2 was dissolved in anhydrous methanol (7.8 ml) and added with 2-imidazole carboxaldehyde (88.4 mg) and trimethyl orthoformate (0.200 ml) and the whole was stirred at room temperature for 14 hours. Then, the solution was added with sodium borohydride (69.2 mg) and stirred at room temperature for 1.5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The resultant was added with water and subjected to extraction with chloroform. The extract was washed with a saturated saline solution and dried with magnesium sulfate. The solvent was distilled off and the residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (101 mg) as a colorless oily substance.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[CH:29]=[CH:28][C:18]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])=[O:20])=[C:17]([Cl:30])[CH:16]=1.C(N(CC)CC)C>CCOC(C)=O>[Cl:30][C:17]1[CH:16]=[C:15]([NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:2](=[O:3])[O:4][CH2:5][Cl:6])[CH:29]=[CH:28][C:18]=1[C:19](=[O:20])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27]
Reactant: O=C(Cl)OCCl
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2N)cc1Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2NC(=O)OCCl)cc1Cl
Reaction time: 4 h

Procedure:
To a cooled (0° C.) solution of chloromethyl chloroformate (4.27 mmol) in EtOAc (20 ml) was slowly added a solution of 4-(2-aminophenylamino)-2-chloro-2′-methylbenzophenone (4.0 mmol) and triethylamine (4.45 mmol) in EtOAc (20 ml) under stirring. Stirring was continued at room temperature for 4 h. The reaction mixture was washed with water and 0.5 M tartaric acid, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by chromatography using Et2O/hexane 4:1 as eluent to give the title compound as white crystals.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][CH:13]1[CH2:16][CH:15]([C:17]#[N:18])[CH2:14]1.CCN(C(C)C)C(C)C>C(#N)C>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:12][CH:13]2[CH2:16][CH:15]([C:17]#[N:18])[CH2:14]2)[CH:7]=1
Reactant: N#CC1CC(N)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#CC1CC(Nc2cc(F)ccc2[N+](=O)[O-])C1
Yield: 67.3 %

Procedure:
2,4-Difluoro-1-nitrobenzene (0.38 g, 2.4 mmol), 3-aminocyclobutanecarbonitrile (0.23 g, 2.4 mmol) and then DIPEA (0.425 mL, 2.4 mmol) were added to acetonitrile (10 mL) and the resultant mixture stirred at 20° C. for 16 hours under a nitrogen atmosphere. The mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (Si—PPC; eluting with ethyl acetate in cyclohexane 0-50%) to give the title compound as a yellow solid (0.38 g, 68%). 1H NMR (CDCl3) δ: 8.23 (1H, dd, J=9.2, 5.8 Hz), 8.20 (1H, br s), 6.41-6.49 (1H, m), 6.29 (1H, dd, J=11.0, 2.7 Hz), 4.30-4.43 (1H, m), 3.20-3.31 (1H, m), 2.87-2.98 (2H, m), 2.42-2.55 (2H, m)
Reaction SMILES: FC(F)(F)C1C=C(C(Cl)=O)C=CC=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][CH:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1.[F:36][C:37]([F:50])([F:49])[C:38]1[CH:39]=[C:40]([C:44]([N:46]=[C:47]=[S:48])=[O:45])[CH:41]=[CH:42][CH:43]=1>C1(C)C=CC=CC=1.C(O)C>[F:49][C:37]([F:36])([F:50])[C:38]1[CH:39]=[C:40]([C:44]([N:46]=[C:47]=[S:48])=[O:45])[CH:41]=[CH:42][CH:43]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][CH:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:47]([NH:46][C:44](=[O:45])[C:40]2[CH:41]=[CH:42][CH:43]=[C:38]([C:37]([F:36])([F:50])[F:49])[CH:39]=2)=[S:48])=[CH:31][CH:30]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: O=C(N=C=S)c1cccc(C(F)(F)F)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(C(F)(F)F)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
3-(Trifluoromethyl)-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-(trifluoromethyl)-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-(trifluoromethyl)-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (67 mg, yield 75%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:23]=[C:22]4[CH2:24][CH2:25][CH2:26][C:27](=[CH:30]N(C)C)[C:28](=O)[C:21]4=[CH:20][C:19]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.O.[NH2:42][NH2:43]>C(O)C>[C:34]1([C:19]2[CH:20]=[C:21]3[C:28]4=[N:42][NH:43][CH:30]=[C:27]4[CH2:26][CH2:25][CH2:24][C:22]3=[N:23][C:18]=2[C:15]2[CH:14]=[CH:13][C:12]([C:8]3([NH2:7])[CH2:11][CH2:10][CH2:9]3)=[CH:17][CH:16]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CN(C)C=C1CCCc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2C1=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-c3n[nH]cc3CCC4)cc2)CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.3 %

Procedure:
To a solution of tert-butyl(1-(4-(6-((dimethylamino)methylene)-5-oxo-3-phenyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-2-yl)phenyl)cyclobutyl)carbamate (90 mg, 0.17 mmol) in anhydrous ethanol (2 mL) was added hydrazine hydrate (25 μL, 0.5 mmol). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. The reaction mixture was concentrated to dryness under reduced pressure, purified by Biotage chromatography (silica, hexane:ethyl acetate, gradient elution from 99:1 to 60:40) and preparative HPLC (Method G, gradient 5 to 95% 0.1% FA/ACN in 0.1% FA/H2O, 20 minutes run) to give the desired product as a white solid (50 mg, 58% yield). 1H NMR (500 MHz, CDCl3) 7.49 (s, 1H), 7.38 (d, 2H), 7.29 (d, 2H), 7.21-7.25 (br m, 5H+1H), 3.25 (m, 2H), 2.94 (t, 2H), 2.53-2.61 (br m, 1H), 2.42-2.52 (m, 2H), 2.31-2.41 (br m, 1H), 2.14-2.21 (m, 2H), 1.98-2.10 (m, 1H), 1.74-1.85 (m, 1H), 1.30-1.43 (br s, 9H). LCMS (Method A): RT=6.09 min, M+H+=507.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([NH:25][C:17]([C:15]2[CH:16]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:12]=[N:13][CH:14]=2)=[O:19])[CH:26]=[CH:27][CH:28]=1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: COc1cccc(N)c1
Product: CCc1cc(-c2cncc(C(=O)Nc3cccc(OC)c3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 3-methoxy-aniline to afford the title compound. MS: m/e=364 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:8][CH3:9].CN(C=O)C.[CH:15]1([C:19]2[C:28]([CH:29]3[CH2:31][CH2:30]3)=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([OH:32])[CH:20]=2)[CH2:18][CH2:17][CH2:16]1>O>[CH:15]1([C:19]2[C:28]([CH:29]3[CH2:30][CH2:31]3)=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([O:32][CH2:8][CH3:9])[CH:20]=2)[CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)c1cc(C2CC2)c(C2CCC2)cc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C2CCC2)c(C2CC2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cesium carbonate (3.44 g) and iodoethane (0.55 mL) were added to a DMF (25 mL) solution of methyl 4-cyclobutyl-5-cyclopropyl-2-hydroxybenzoate (1.3 g) under ice cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, followed by extraction with ethyl acetate twice. Combined organic layers were washed with water and saturated saline in this order and dried over anhydrous sodium sulfate, and then, the solvent was distilled off under reduced pressure to obtain the title compound (1.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21][CH2:20]3)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:26].[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].N1C=CN=C1.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:18][C@H:19]3[CH2:20][CH2:21][C@H:22]([O:25][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:23][CH2:24]3)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1Nc2nc(N[C@H]3CC[C@H](O)CC3)ncc2CN1c1ccccc1Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](Nc2ncc3c(n2)NC(=O)N(c2ccccc2Cl)C3)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A suspension of 3-(2-chlorophenyl)-7-(trans-4-hydroxycyclohexylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (1.86 g, 5 mmol) (prepared as described in Example 73) was combined with tert-butyldimethylsilyl chloride (1.05 g, 7 mmol) and imidazole (0.75 g, 11 mmol) in dimethylformamide (35 mL). The reaction mixture was heated at 50° C. for 24 hours, cooled to room temperature and added to water, stirred for 30 minutes, filtered and dried to give 1.88 g of 3-(2-chlorophenyl)-7-(trans-4-tert-butyl-dimethylsilyloxycyclohexylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one, m.p.289-294° C.
Reaction SMILES: [CH2:1]([SH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.FC(F)(F)S([O-])(=O)=O.[F:37][C:38]([I+]C1C=CC=CC=1)([F:43])[C:39]([F:42])([F:41])[F:40]>C(Cl)Cl>[F:37][C:38]([F:43])([S:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:39]([F:42])([F:41])[F:40]
Reactant: CCCCCCCCCCCCS
Reactant: FC(F)(F)C(F)(F)[I+]c1ccccc1
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCCCSC(F)(F)C(F)(F)F
Temperature: 25 °C

Procedure:
2.0 ml of methylene chloride, 0.10 ml (0.42 mmol) of 1-dodecanethiol and 87 mg (0.42 mmol) of 2,6-di-tert-butyl-4-methylpyridine were added to a flask, and 198 mg (0.42 mmol) of pentafluoroethylphenyliodonium trifluoromethanesulfonate was added thereto in small portions while stirring at room temperature, followed by stirring at room temperature for 20 minutes. The resulting white precipitate was filtered and subjected to column chromatography of silica gel. Iodobenzene and the product was eluted with pentane and purified by gas chromatography to obtain 1-pentafluoroethylthiododecane as an oily substance. Yield, 87%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[CH:22]=[C:21]([C@:26]2([CH3:32])[CH2:30][O:29]C(=O)[NH:27]2)[CH:20]=[CH:19]3)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.O.[OH-].[Li+]>>[NH2:27][C@@:26]([C:21]1[CH:20]=[CH:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]([S:15][C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)[CH:17]=2)[CH:22]=1)([CH3:32])[CH2:30][OH:29]
Reactant: C[C@@]1(c2ccc3cc(Sc4cccc(OCc5ccccc5)c4)ccc3c2)COC(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@](N)(CO)c1ccc2cc(Sc3cccc(OCc4ccccc4)c3)ccc2c1
Yield: 92.1 %

Procedure:
(R)-4-(6-(3-(benzyloxy)phenylthio)naphthalen-2-yl)-4-methyloxazolidin-2-one (30.0 mg, 0.0000679 mol) was dissolved in ethanol (2 mL, 0.03 mol) and water (0.8 mL, 0.05 mol) then lithium hydroxide (17 mg, 0.00072 mol) was added and was heated to reflux overnight. LCMS shows no SM and a new peak at 1.51 399.17 ([M−NH2]+, 100). After concentration, the residue was taken up into methylene chloride and water. The aqueous layer was extracted with methylene chloride and concentrated. Column chromatography with MeOH/methylene chloride gave (R)-2-amino-2-(6-(3-(benzyloxy)phenylthio)naphthalen-2-yl)propan-1-ol as a white solid (26.0 mg, 92%). LCMS 1.51 399.17 ([M−NH2]+, 100%). 1H NMR (400 MHz, MeOD) δ=7.95 (br. s., 1H), 7.89-7.76 (m, 3H), 7.64 (d, J=8.6 Hz, 1H), 7.43-7.20 (m, 7H), 6.98-6.87 (m, 3H), 5.00 (br. s., 2H), 3.84-3.77 (m, 1H), 3.77-3.69 (m, 1H), 1.60 (s., 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([NH2:11])[C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[F:20]>CN1CCCC1=O>[F:20][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:14]=1[NH:11][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[C:2]1[CH3:1]
Reactant: Cc1cc2ccccc2n1N
Reactant: Fc1cnccc1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Product: Cc1cc2ccccc2n1Nc1ccncc1F

Procedure:
The title compound was prepared from 2-methyl-1H-indol-1-amine and 4-chloro-3-fluoropyridine hydrochloride in 1-methyl-2-pyrrolidone for 1 hour in substantially the same manner as in Example 1, m.p. 157°-158° C.
Reaction SMILES: Cl[CH:2]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:6]=2[C:7]=1[CH3:8].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:29])=[CH:24][CH:23]=1>>[CH:15]1([CH:2]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[CH:26][CH:27]=2)[C:3]2[O:4][C:5]3[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:6]=3[C:7]=2[CH3:8])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1ccc2oc(C(Cl)C3CCCCC3)c(C)c2c1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: COc1ccc2oc(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)c(C)c2c1

Procedure:
Using 2-[chloro(cyclohexyl)methyl]-5-methoxy-3-methyl-1-benzofuran (395 mg) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (338 mg) synthesized in Example 2(2) and in the same manner as in Example A22(4), the title object compound (305 mg, 47%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([N:13]([CH2:31][CH:32]([CH3:34])[CH3:33])[C@@H:14]3[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][C@H:16]([C:27]([O:29]C)=[O:28])[CH2:15]3)=[O:12])[N:7]([CH2:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1CO>[C:23]([O:22][C:20]([N:18]1[CH2:19][C@@H:14]([N:13]([C:11]([C:8]2[N:7]([CH2:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:10]=3[N:9]=2)=[O:12])[CH2:31][CH:32]([CH3:33])[CH3:34])[CH2:15][C@@H:16]([C:27]([OH:29])=[O:28])[CH2:17]1)=[O:21])([CH3:25])([CH3:26])[CH3:24]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)OC)CN(C(=O)OC(C)(C)C)C2)nc2c(F)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: OCC1CCCO1
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2c(F)cccc21
Temperature: 45 °C
Reaction time: 4 h
Yield: 94.7 %

Procedure:
1-tert-Butyl 3-methyl (3R,5S)-5-{{{4-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}piperidine-1,3-dicarboxylate (195 mg) was dissolved in tetrahydrofuran-methanol (1:2, 15 ml), 2M aqueous sodium hydroxide solution (1 ml) was added, and the mixture was stirred at 45° C. for 4 hr. The reaction mixture was concentrated under reduced pressure, neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, concentration under reduced pressure to give the object product (180 mg).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[OH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C>CN(C=O)C>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([N:16]2[CH2:17][CH2:18][CH:13]([OH:12])[CH2:14][CH2:15]2)=[N:3][CH:4]=1)=[O:7]
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: OC1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(N2CCC(O)CC2)nc1
Temperature: 80 °C
Yield: 86.1 %

Procedure:
To a solution of methyl 6-chloronicotinate (890 mg, 1.00 equiv; 5.03 mmol) in dry DMF (30 mL) is added 4-hydroxypiperidine (1.5 equiv; 7.55 mmol; 778.95 mg) and triethylamine (1.05 mL; 1.5 equiv; 7.55 mmol). The system is flushed with N2 and heated at 80° C. for 4.5 h. The reaction is allowed to reach room temperature and is diluted with water/EtOAc. The aqueous layer is extracted with ethyl acetate (3×). The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue is purified via chromatography eluting with hexane/EtOAc 2:1 to 1:2 to yield an orange solid. The solid is triturated with hexane/EtOAc 4:1 and filtered to provide the title compound (1.023 g, 86%) as a white solid. ES/MS m/z 237.0 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])C=CN=3)[S:10][C:3]=12.Br[C:18]1[N:19]=[CH:20]N(C)C=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:16][N:19]([CH3:20])[CH:18]=3)[S:10][C:3]=12
Reactant: Cn1cnc(Br)c1
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Product: Cn1cnc(-c2cc3nccc(Cl)c3s2)c1

Procedure:
Following the procedure described for compound 7 (example 2, step 3) but substituting 2-bromo-1-methyl-1H-imidazole for 4-bromo-1-methyl-1H-imidazole [a) Begtrup, M.; Larsen, P.; Acta Chem. Scand. 44, 10:1990:1050-1057, b) Begtrup, M.; Bull. Soc. Chim. Belg.; 97; 8-9; 1988; 573-598, c) Begtrup, M.; Larsen, P.; Chem. Pharm. Bull. 42, 9; 1994; 1784-1790.], title compound 10 was obtained as an off-white solid (29% yield). MS (m/z): 250.1 (M+H).
Reaction SMILES: [OH:1][CH:2]([CH2:44][N:45]1[C:49](=[O:50])[C:48]2([CH2:55][C:54]([CH3:57])([CH3:56])[N:53]([CH2:58][CH2:59][OH:60])[C:52]([CH3:62])([CH3:61])[CH2:51]2)[NH:47][C:46]1=[O:63])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]([OH:43])[CH2:23][N:24]3[C:28](=[O:29])[C:27]4([CH2:34][C:33]([CH3:36])([CH3:35])[N:32]([CH2:37][CH2:38][OH:39])[C:31]([CH3:41])([CH3:40])[CH2:30]4)[NH:26][C:25]3=[O:42])=[CH:16][CH:15]=2)([CH3:13])[CH3:12])=[CH:7][CH:6]=1.C(O[C:68](=[O:70])[CH3:69])(=O)C>>[C:17]([O:1][CH:2]([CH2:44][N:45]1[C:49](=[O:50])[C:48]2([CH2:51][C:52]([CH3:62])([CH3:61])[N:53]([CH2:58][CH2:59][O:60][C:2](=[O:1])[CH3:3])[C:54]([CH3:57])([CH3:56])[CH2:55]2)[N:47]([C:68](=[O:70])[CH3:69])[C:46]1=[O:63])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]([O:43][C:5](=[O:4])[CH3:6])[CH2:23][N:24]3[C:28](=[O:29])[C:27]4([CH2:30][C:31]([CH3:40])([CH3:41])[N:32]([CH2:37][CH2:38][O:39][C:38](=[O:39])[CH3:37])[C:33]([CH3:35])([CH3:36])[CH2:34]4)[N:26]([C:28](=[O:29])[CH3:27])[C:25]3=[O:42])=[CH:16][CH:15]=2)([CH3:13])[CH3:12])=[CH:9][CH:10]=1)(=[O:20])[CH3:16]
Reactant: CC(C)(c1ccc(OCC(O)CN2C(=O)NC3(CC(C)(C)N(CCO)C(C)(C)C3)C2=O)cc1)c1ccc(OCC(O)CN2C(=O)NC3(CC(C)(C)N(CCO)C(C)(C)C3)C2=O)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCCN1C(C)(C)CC2(CC1(C)C)C(=O)N(CC(COc1ccc(C(C)(C)c3ccc(OCC(CN4C(=O)N(C(C)=O)C5(CC(C)(C)N(CCOC(C)=O)C(C)(C)C5)C4=O)OC(C)=O)cc3)cc1)OC(C)=O)C(=O)N2C(C)=O
Temperature: 0 °C

Procedure:
A mixture of 1 g of 2,2-bis{4-[2-hydroxy-3-(8-β-hydroxyethyl-7,7,9,9-tetramethyl-2,4-dioxo-1,3,8-triazaspiro[4.5]dec-3-yl)propoxy]phenyl}propane (obtained as described in Example 18) and 20 g of acetic anhydride was refluxed for 60 hours. After completion of the reaction, the reaction mixture was poured into ammoniacal ice-water, extracted with benzene and then purified by column chromatography through silica gel eluted with a 2:1 by volume mixture of benzene and ethyl acetate, to give the desired Compound No. 188 in the form of white crystals. The compound had an Rf value of 0.86 on thin-layer chromatography on silica gel using a 1:1:1 by volume mixture of n-hexane, benzene and ethyl acetate as developing solvent.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[CH:17]=[C:18]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:19]=[C:20](S(C)(=O)=O)[C:15]4=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[NH2:32][CH2:33][CH2:34][C:35]#[C:36][CH2:37][NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42].C1(C)C=CC=CC=1>CN(C)C=O>[CH:1]1([NH:4][C:5]([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[CH:17]=[C:18]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:19]=[C:20]([NH:32][CH2:33][CH2:34][C:35]#[C:36][CH2:37][NH:38][C:39](=[O:45])[O:40][C:41]([CH3:43])([CH3:42])[CH3:44])[C:15]4=[N:14][CH:13]=3)=[CH:8][CH:7]=2)=[O:31])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NCC#CCCN
Reactant: CS(=O)(=O)c1nc(-c2ccccc2)cn2c(-c3ccc(C(=O)NC4CC4)cc3)cnc12
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCC#CCCNc1nc(-c2ccccc2)cn2c(-c3ccc(C(=O)NC4CC4)cc3)cnc12
Temperature: 50 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
To a solution of 75 mg (173 μmol) N-cyclopropyl-4-[8-(methylsulfonyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamide which was prepared according to intermediate example 9-1 in 0.3 mL N,N-dimethylformamide were added 60 μL tert-butyl (5-aminopent-2-yn-1-yl)carbamate and the mixture was stirred at 50° C. overnight. Toluene was added and the mixture was evaporated. The residue was purified by chromatography to give 23.6 mg (25%) of the title compound
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH:11]([C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1.Br[CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C=O)C>[NH2:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH:11]([C:17]2[N:18]=[CH:19][N:20]([CH:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:21]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(Cc1ccc(N)nc1)c1c[nH]cn1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(Cc1ccc(N)nc1)c1cn(C(c2ccccc2)c2ccccc2)cn1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
11 mg (0.23 mmol, 50%) of sodium hydride were added to a solution of 50 mg (0.19 mmol) of ethyl 3-(6-aminopyridin-3-yl)-2-(1H-imidazol-4-yl)propionate (example 1g) in 0.5 ml of DMF at RT and stirred for 1 h. Then 48 mg (0.19 mmol) of bromodiphenyl-methane were added, and the mixture was stirred at RT for 3.5 h. It was then heated at 60° C. for 2 h and, after cooling, 1 ml of water was added, the mixture was extracted with EA, and the organic phase was dried over Na2SO4, filtered and concentrated. Chromatography on silica gel afforded ethyl 3-(6-aminopyridin-3-yl)-2-(1-benzhydryl-1H-imidazol-4-yl)propionate. The product obtained in this way was taken up in 0.4 ml of 50% concentrated hydrochloric acid and treated in a microwave at 180° C. for 3 min. Freeze-drying after cooling of the reaction mixture afforded 5 mg of the title compound as bishydrochloride.