Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[N+:14]([O-])=O.O.O.[Sn](Cl)Cl>C(O)C>[NH2:14][C:3]1[CH:4]=[C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: COC(=O)/C=C/c1ccc(N)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COC(=O)/C=C/c1ccc(N)c(N)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 57 %

Procedure:
To a solution of methyl (2E)-3-(4-amino-3-nitrophenyl)acrylate (from Step 2, 1 eq) in ethanol (0.2 M) was added tin(II) chloride dihydrate (5.75 eq). The reaction mixture was heated to reflux for 8 h. At this time the reaction was allowed to cool to RT, concentrated and diluted with EtOAc. A saturated aqueous solution of NaHCO3 was added slowly. The mixture was stirred for 20 min; the organic layer was washed with brine, dried over Na2SO4 filtered and evaporated in vacuo. The residue was purified by flash chromatography (SiO2; 70% EtOAc in PE) to afford the title compound (57%). 1H-NMR (400 MHz; DMSO-<d6, 300 K) δ 3.67 (s, 3H), 4.59 (s, 2H), 5.17 (s, 2H), 6.08 (d, J 15.6, 1H), 6.5 (d, J 8.0, 1H), 6.74 (d, J 7.6, 1H), 6.82 (s, 1H), 7.39 (d, J 15.6, 1H); MS (ES+) m/z 193 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:12])[C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH3:13]O>Cl[Ti](Cl)(Cl)Cl>[CH3:13][O:6][C:5](=[O:7])[C:4]1[CH:3]=[C:2]([I:1])[C:10]([OH:11])=[C:9]([I:12])[CH:8]=1
Reactant: O=C(O)c1cc(I)c(O)c(I)c1
Reactant: CO
Agent: Cl[Ti](Cl)(Cl)Cl
Product: COC(=O)c1cc(I)c(O)c(I)c1
Yield: 76 %

Procedure:
To a stirring solution of 3,5-diiodo-4-hydroxybenzoic acid (10.00 g, 25.65 mmol) in dry methanol (250 mL) was added TiCl4 (1.41 mL, 12.82 mmol) in one lot. The reaction was stirred at reflux for 6 h and was then stirred at room temperature for 24 h. The mixture was concentrated down and the residue was taken up in diethyl ether and filtered through a plug of silica gel. The filtrate was concentrated down and the residue was recrystallized from hot methanol to give 7.84 g (76%) of the ester as white crystalline needles. 1H NMR (DMSO-d6) δ 10.41 (br s, 1H), 8.22 (s, 2H), 3.79 (s, 3H).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[C:13]([O:17][C:18](=[O:36])[NH:19][C:20]([N:29]1[CH2:34][CH2:33][CH:32](O)[CH2:31][CH2:30]1)=[N:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:16])([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:24]([O:23][C:22](=[O:28])[NH:21][C:20]([N:29]1[CH2:34][CH2:33][CH:32]([O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH2:31][CH2:30]1)=[N:19][C:18](=[O:36])[O:17][C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:25])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCC(O)CC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCC(ON2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
To a mixture of N-hydroxyphthalimide (1.89 g, 11.62 mmol), di-tert-butyl[(4-hydroxypiperidin-1-yl)methylylidene]biscarbamate 63 (2.00 g, 5.81 mmol, US 2004/209921 A1) and triphenylphosphine (3.05 g, 11.62 mmol) in THF (100 mL) was added diisopropyl azodicarboxylate (2.47 mL, 12.78 mmol) slowly at room temperature. The resulting mixture was stirred at room temperature overnight and concentrated to provide a residue which was subjected to chromatography to give 64 (0.9 g) as a white solid.
Reaction SMILES: C(Cl)(Cl)Cl.[SH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1.Br[CH2:17][CH2:18][CH2:19][OH:20]>C(N(CC)CC)C>[OH:20][CH2:19][CH2:18][CH2:17][S:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=1
Reactant: OCCCBr
Reactant: COC(=O)c1ccc(S)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(SCCCO)cc1
Yield: 67 %

Procedure:
To 40 ml of chloroform were added 4.0 g of methyl 4-mercaptobenzoate, 3.3 g of 3-bromo-1-propanol and 2.38 g of triethylamine, and the mixture was stirred for an hour and then evaporated under a reduced pressure. After adding 50 ml of ethyl acetate, the mixture was washed with 30 ml each of water, 1N hydrochloric acid and a saturated sodium bicarbonate aqueous solution, dried over magnesium sulfate and evaporated under a reduced pressure. The residue was applied to a silica gel column and eluted with chloroform/methanol (100:3) to obtain 3.6 g of methyl p-(3-hydroxypropylthio)benzoate as a colorless crystal. To 3.0 g of this crystal was added 1.44 g of phosphorus tribromide, and the mixture was heated at 80° C. for 2 hours, poured into 50 ml of ice-water, and extracted three times with 20 ml of ethyl acetate. The extract was dried over magnesium sulfate, and evaporated under a reduced pressure. The residue was applied to a silica gel column and eluted with chloroform/hexane (1:1) to obtain 3.0 g of the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH2:13]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>COC(C)(C)C>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([OH:26])([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: O
Solvent: COC(C)(C)C
Product: OC1(c2cccnc2)CCN(Cc2ccccc2)CC1
Temperature: -75 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
(α) A solution of 16.7 g (106 mmol) of 3-bromo-pyridine in 200 ml of tert-butyl methyl ether was cooled to -75° C. Thereto there was added dropwise within 45 minutes a solution of 66 ml (106 mmol) of n-butyllithium (1.6M in hexane) and the mixture was stirred at -75° C. for one hour. Subsequently, a solution of 10.0 g (52.8 mmol) of 1-benzyl-4-piperidone in 50 ml of tert-butyl methyl ether was added dropwise at -70° C. to -75° C. and thereafter the mixture was stirred for 2 hours. Subsequently, the mixture was left to warm to room temperature. Thereafter, it was hydrolyzed with 50 ml of water and extracted with 100 ml of ethyl acetate. The organic phase was dried over magnesium sulphate and finally the solvent was evaporated under reduced pressure, with the product beginning to separate. From the evaporated mother liquor there were isolated by crystallization from a mixture of ethyl acetate and hexane a further 1.9 g, so that a total of 8.4 g (60% of theory) of 1'-benzyl-2',3',5',6'-tetrahydro-1'H-[3,4']bipyridinyl-4'-ol were obtained as a colourless solid; MS: 268 (M+H)+.
Reaction SMILES: C=O.[CH2:3]([OH:5])[CH3:4].OC[CH2:8][NH:9][CH2:10][C:11]([NH:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])[NH:20][C:21]2=[O:24])=[CH:16][CH:15]=1)=[O:12]>O>[OH:5][CH2:3][CH2:4][N:9]1[CH2:10][C:11](=[O:12])[N:13]([C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:34])([F:33])[F:32])[NH:20][C:21]3=[O:24])=[CH:16][CH:15]=2)[CH2:8]1
Reactant: O=C(CNCCO)Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Reactant: CCO
Agent: C=O
Solvent: O
Product: O=C1CN(CCO)CN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Yield: 27 %

Procedure:
A 37% formalin aqueous solution (3.8 μl, 0.0469 mmol) was added to an ethanol solution (2 ml) that contained the 2-(2-hydroxyethylamino)-N-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]acetamide (19 mg, 0.0469 mmol) obtained in step B. The obtained mixture was stirred under heating to reflux for 3 hours. Thereafter, water was added to the reaction solution, and the mixture was then extracted with ethyl acetate. The extract was washed with water and a saturated saline solution, and was then dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=25:1), so as to obtain 7-[3-(2-hydroxyethyl)-5-oxoimidazolidin-1-yl]-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (5.2 mg, 27%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.Cl[CH2:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)=[O:14]>C(OCC)C>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH:18]2[CH2:19][CH2:20][N:15]([C:13](=[O:14])[CH2:12][NH:1][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[NH:7][N:6]=[CH:5]4)[CH2:16][CH2:17]2)=[CH:23][CH:24]=1
Reactant: O=C(CCl)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: Nc1ccc2[nH]ncc2c1
Solvent: CCOCC
Product: O=C(CNc1ccc2[nH]ncc2c1)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from 5-aminoindazol (Aldrich) and 2-chloro-1-[4-(4-fluoro-benzyl)-piperidin-1-yl]-ethanone (Example 197a) according to the method described in Example 142b. Melting Point: 113-114° C. (diethylether)
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.C(O)(=O)CC.[C:18]1([NH:24][C:25](=O)[CH2:26][CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.B.[N:35]1[C:43]2[C:38]3[C:39](=[CH:44][CH:45]=[CH:46][C:37]=3[C:36]=1S)[CH:40]=[CH:41][CH:42]=2>O1CCCC1>[N:28]1([CH2:27][CH2:26][CH2:25][N:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:36]2[C:37]3[CH:46]=[CH:45][CH:44]=[C:39]4[C:38]=3[C:43](=[CH:42][CH:41]=[CH:40]4)[N:35]=2)[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: O=C(CCn1ccnc1)Nc1ccccc1
Reactant: SC1=Nc2cccc3cccc1c23
Agent: B
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCC(=O)O
Product: c1ccc(N(CCCn2ccnc2)C2=Nc3cccc4cccc2c34)cc1

Procedure:
The reaction of 1,1'-carbonyldiimidazole and 3-(1e,uns/H/ -imidazol-1yl)propanoic acid in tetrahydrofuran solution, followed by treatment with aniline leads to the formation of N-phenyl-3-(1H-imidazol-1-yl)propanamide. Reduction with borane in tetrahydrofuran solution then gives N-phenyl-3-(1H-imidazol-1-yl)propanamide. Reduction with borane in tetrahydrofuran solution then gives N-phenyl-3-(1H-imidazol-1-yl)propanamide. The latter compound with molar equivalents of benz(cd)indol-2-thiol and mercuric acetate in refluxing ethanol leads tot eh formation of the title compound, under the conditions of Example 55.
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([N:15]2[CH2:20][CH2:19][C:18]3([C:32]4[CH:31]=[N:30][N:29]([CH3:33])[C:28]=4[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:21]3)[CH2:17][CH2:16]2)=[O:14])=[C:9](OC)[CH:8]=1)(=[O:6])=[O:5])(C)C.F[C:37]1C=CC(C(N2CCC3(C4C=NN(C)C=4C4C=CC=CC=4O3)CC2)=O)=CC=1C>>[CH3:33][N:29]1[C:28]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:21][C:18]3([CH2:19][CH2:20][N:15]([C:13]([C:10]4[CH:11]=[CH:12][C:7]([S:4]([CH3:1])(=[O:5])=[O:6])=[C:8]([CH3:37])[CH:9]=4)=[O:14])[CH2:16][CH2:17]3)[C:32]=2[CH:31]=[N:30]1
Reactant: Cc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)ccc1F
Reactant: COc1cc(S(=O)(=O)C(C)C)ccc1C(=O)N1CCC2(CC1)Oc1ccccc1-c1c2cnn1C
Product: Cc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)ccc1S(C)(=O)=O

Procedure:
(4-(Isopropylsulfonyl)-2-methoxyphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone was also synthesized using the procedures described above. (1-Methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)(3-methyl-4-(methylsulfonyl)phenyl)methanone was synthesized from (4-fluoro-3-methylphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone using the procedures described above.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[S-:11][C:12]#[N:13].[K+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:13]=[C:12]=[S:11])=[O:7])=[CH:4][CH:3]=1
Reactant: N#C[S-]
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(N=C=S)c1ccc(F)cc1
Yield: 96.3 %

Procedure:
A mixture o 4-fluorobenzoyl chloride (50 g), potassium thiocyanate (36.7 g) and anhydrous toluene (100 ml) is refluxed for six hours. After cooling, the reaction mixture is filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by distillation under reduced pressure to give 4-fluorobenzoyl isothiocyanate (55 g), b.p. 92° C/3 mmHg.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:22])[C:5]2[CH:6]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[N:8]=[N:9][C:10]=2[CH:11]=1.CI.[C:25](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:25][O:22][C:4]1[CH:3]=[C:2]([CH3:1])[CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[N:8]=[N:9]2
Reactant: Cc1cc(O)c2cc(-c3cccc(C(F)(F)F)c3)nnc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(C)cc2nnc(-c3cccc(C(F)(F)F)c3)cc12
Yield: 15.7 %

Procedure:
To an acetone solution (5 mL) of 7-methyl-3-(3-trifluoromethylphenyl)cinnolin-5-ol (30.4 mg, 0.1 mmol) obtained in Example 70 were added methyl iodide (0.006 mL, 0.11 mmol) and potassium carbonate (13.8 mg, 0.11 mmol), followed by reaction at room temperature over night. To residue obtained by concentration of the reaction liquid under reduced pressure was added distilled water (1 mL) and extracted with ethyl acetate. Residue obtained after concentration of an organic layer under reduced pressure was purified with silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain an objective compound (5 mg, 15%) as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:16](=[O:18])[CH3:17])[CH:5]=[CH:6][C:7]=1[C:8]1[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][CH:9]=1.[K+].[C:20]([C:22]1[N:23]=[C:24]([C:35]([O-])=[O:36])[N:25]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:26]=1)#[N:21]>CCOC(C)=O.CCCCCC>[C:16]([C:4]1[CH:5]=[CH:6][C:7]([C:8]2[CH2:13][CH2:12][C:11]([CH3:14])([CH3:15])[CH2:10][CH:9]=2)=[C:2]([NH:1][C:35]([C:24]2[N:25]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:26]=[C:22]([C:20]#[N:21])[N:23]=2)=[O:36])[CH:3]=1)(=[O:18])[CH3:17]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC(=O)c1ccc(C2=CCC(C)(C)CC2)c(N)c1
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(C2=CCC(C)(C)CC2)c(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c1
Yield: 84 %

Procedure:
The title compound was prepared by the procedure of Example 11, step (f) using 1-[3-amino-4-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-ethanone (as prepared in the previous step, 243 mg, 1.00 mmol) and potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 11, step (d), 321 mg, 1.05 mmol). Silica gel chromatography (5-15% EtOAc/hexane) afforded the title compound (415 mg, 84%) as a white solid. Mass spectrum (ESI, m/z): Calcd. for C27H36N4O3Si, 493.3 (M+H), found 493.0.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[O:15][CH:16]([CH3:25])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:4].[OH-].[Na+]>C1COCC1.CO>[CH3:25][CH:16]([O:15][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][C:5]=1[C:3]([OH:4])=[O:2])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc2ccccc2c1OC(C)COc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(COc1ccccc1)Oc1c(C(=O)O)ccc2ccccc12
Reaction time: 16 h
Yield: 79.9 %

Procedure:
To 0.47 g of 1-(1-methyl-2-phenoxy-ethoxy)-naphthalene-2-carboxylic acid methyl ester in 5 ml of THF and 2 ml methanol were added 10 ml of 2 M aqueous sodium hydroxide. After 16 h at room temperature and 2 h at reflux the organic solvents were removed in vacuo. The residue was treated with 2 M hydrochloric acid, and three times extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulphate, concentrated and dried in vacuo to yield 0.36 g of 1-(1-methyl-2-phenoxy-ethoxy)-naphthalene-2-carboxylic acid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([N:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:25][CH2:26][OH:27])[C:17]4[CH2:23][NH:22][CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[N:3]1.C(O)(=O)C.[CH:38](=O)[CH2:39][CH3:40].C([BH3-])#N.[Na+]>CO>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]3[N:15]=[C:16]([N:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:25][CH2:26][OH:27])[C:17]4[CH2:23][N:22]([CH2:38][CH2:39][CH3:40])[CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:11][CH:12]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2ccc(Nc3nc4c(c(N(CCO)c5ccccc5)n3)CNCC4)cc2)cn1
Reactant: CCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN1CCc2nc(Nc3ccc(-c4cnn(C)c4)cc3)nc(N(CCO)c3ccccc3)c2C1
Yield: 17.5 %

Procedure:
2-((2-(4-(1-Methyl-1H-pyrazol-4-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (40 mg, 0.09 mmol, Example 38a) was dissolved in methanol (2 mL). Acetic acid (1.037 μL, 0.02 mmol) was added followed by propionaldehyde (0.013 mL, 0.18 mmol). The reaction mixture was stirred for 30 minutes at room temperature before sodium cyanoborohydride (11.39 mg, 0.18 mmol) was added. The solvent was evaporated under reduced pressure, the crude dissolved in few drops of dimethylformamide and acetonitrile, filtered and purified by preparative HPLC yielding 2-((2-(4-(1-methyl-1H-pyrazol-4-yl)phenylamino)-6-propyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (7.6 mg, 15.4%) as acetic acid salt.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[CH:13]=1)[C:8]([OH:10])=O)([CH3:3])[CH3:2].[CH2:25]([O:27][P:28]([CH2:33][NH:34][C:35]([C:37]1[N:38]=[C:39]([NH2:42])[S:40][CH:41]=1)=[O:36])(=[O:32])[O:29][CH2:30][CH3:31])[CH3:26]>>[CH2:25]([O:27][P:28]([CH2:33][NH:34][C:35]([C:37]1[N:38]=[C:39]([NH:42][C:8](=[O:10])[C:7]2[CH:11]=[C:12]([O:14][C:15]3[CH:16]=[CH:17][C:18]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:19][CH:20]=3)[CH:13]=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[CH:6]=2)[S:40][CH:41]=1)=[O:36])(=[O:32])[O:29][CH2:30][CH3:31])[CH3:26]
Reactant: CCOP(=O)(CNC(=O)c1csc(N)n1)OCC
Reactant: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)O)c1
Product: CCOP(=O)(CNC(=O)c1csc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OC(C)C)c2)n1)OCC

Procedure:
The above prepared 3-isopropoxy-5-(4-methanesulfonyl-phenoxy)-benzoic acid is coupled with {[(2-amino-thiazole-4-carbonyl)-amino]-methyl}-phosphonic acid diethyl ester following the procedure described in Example 1, Step D to give [({2-[3-isopropoxy-5-(4-methanesulfonyl-phenoxy)-benzoylamino]-thiazole-4-carbonyl}-amino)-methyl]-phosphonic acid diethyl ester.
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:10][N:9]2[C@H:4]([CH2:5][C:6](=O)[CH2:7][C:8]2([CH3:12])[CH3:11])[CH2:3]1.[C:15]1([C@@H:21]([NH2:23])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[F:1][C:2]1([F:14])[CH2:10][N:9]2[C@H:4]([CH2:5][C:6](=[N:23][C@H:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH3:22])[CH2:7][C:8]2([CH3:12])[CH3:11])[CH2:3]1
Reactant: C[C@H](N)c1ccccc1
Reactant: CC1(C)CC(=O)C[C@@H]2CC(F)(F)CN21
Solvent: Cc1ccccc1
Product: C[C@H](N=C1C[C@@H]2CC(F)(F)CN2C(C)(C)C1)c1ccccc1
Reaction time: 22 h

Procedure:
A toluene (12 ml) solution of (R)-2,2-difluoro-hexahydro-5,5-dimethylindolizin-7(1H)-one (487.8 mg, 2.4 mmol) and (S)-1-phenylethylamine (306 μL, 2.4 mmol) was heated under reflux in a flask equipped with a Dean-Stark distillation receiver. After 22 hours, most solvent was distilled off through Dean-Stark distillation receiver, and remaining solvent was removed in vacuo. Compound (1S)—N—((R)-2,2-difluoro-hexahydro-5,5-dimethylindolizin-7(1H)-ylidene)-1-phenylethanamine was obtained as a brown oil and was used directly in next reaction.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([NH:25][CH:26]([CH3:28])[CH3:27])[CH:19]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Li+].[N:32]#[C:33]Br.C(O)C>ClCCl>[CH:26]([N:25]1[C:20]2[CH:19]=[C:18]([C:9]3[NH:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:11][C:10]=3[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:23]=[CH:22][C:21]=2[N:24]=[C:33]1[NH2:32])([CH3:28])[CH3:27]
Reactant: N#CBr
Reactant: CC(C)Nc1cc(-c2[nH]c(-c3ccccc3)nc2-c2ccccc2)ccc1N
Agent: C[O-]
Agent: [Li+]
Solvent: CCO
Solvent: ClCCl
Product: CC(C)n1c(N)nc2ccc(-c3[nH]c(-c4ccccc4)nc3-c3ccccc3)cc21
Yield: 38.1 %

Procedure:
Stir a mixture of 2,4-diphenyl-5-(3-(isopropyl)amino-4-aminophenyl)imidazole (0.075 g, 0.20 mmol), lithium methoxide (0.41 mmol, 15 mg) and cyanogen bromide (0.6 mmol, 0.2 ml of 3N in dichloromethane) in dichloromethane (5 ml) under nitrogen for 1 hour. Add ethanol (5 ml), and continue stirring for 5 hours. Pour reaction mixture over an SCX column, and elute sequentially with methanol followed by 2N ammonia in methanol. Combine the basic fractions and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 9:1 dichloromethane:methanol to provide the title compound as a white solid (30 mg, 38%).
Reaction SMILES: [C:1]([C:3]1([N:9]([CH3:11])[CH3:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].S(=O)(=O)(O)[OH:13]>O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>[CH3:10][N:9]([CH3:11])[C:3]1([C:1]([NH2:2])=[O:13])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CN(C)C1(C#N)CCCCC1
Reactant: O=S(=O)(O)O
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Product: CN(C)C1(C(N)=O)CCCCC1
Reaction time: 0.25 h

Procedure:
1-Cyano-N,N-dimethyl cyclohexylamine (10 g.) was added portionwise to conc. sulphuric acid (20 ml.) and the solution left for 15 minutes. The cooled solution was diluted with ice-cold water and neutralised with barium hydroxide octahydrate. The mixture was filtered on hyflo and the filtrate evaporated to dryness when the residual oil (9.1 g., 81%) crystallised on standing. Recrystallisation from petrol (80/100) afforded 1-dimethylamino cyclohexane carboxamide m.p. 65°69°.
Reaction SMILES: [C:1]([O-:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:15]C(C)=O>>[C:1]([O:14][CH3:15])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CC(C)=O
Reactant: CCCCCCCCCCCC(=O)[O-]
Product: CCCCCCCCCCCC(=O)OC

Procedure:
As internal standard, 0.06 g of methayl laurate and 2 g of a sample were prepared and dissolved in 4 g of acetone, and the obtained solution (2 μL) was introduced to a device. An analytical curve was formed from the peak area of the internal standard, and the peak area obtained when the concentration of methyl laurate was changed, and an amount of an unreacted component contained the sample was determined.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH3:17])[C:13]2([CH2:15][CH2:14]2)[C:12](=[O:16])[NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:20]([N:11]1[CH2:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])([CH3:17])[C:13]2([CH2:14][CH2:15]2)[C:12]1=[O:16])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)NC1(C)CNC(=O)C12CC2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(C)CN(Cc2ccccc2)C(=O)C12CC2
Reaction time: 0.67 h
Yield: 98 %

Procedure:
To a solution (65 mL) of 7-(tert-butoxycarbonylamino)-7-methyl-5-azaspiro[2.4]heptan-4-one (3.12 g, 12.97 mmol) in dimethylformamide in an ice bath was gradually added sodium hydride (55%, dispersion in a mineral oil, 538 mg, 12.33 mmol) in 5 minutes, and the mixture was stirred at the same temperature for 40 minutes. Benzyl bromide (1.851 mL, 15.56 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted by adding ethyl acetate (300 mL), and the solution was washed with water (100 mL×2) and saturated aqueous solution of sodium chloride (100 mL). After drying the solution with anhydrous sodium sulfate and removing the dessicating agent by filtration, the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane : ethyl acetate, 9:1→4:1→2:1) to obtain 4.20 g (12.71 mmol, 98%) of the target compound as a colorless transparent gummy solid.