Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(S(F)(F)[F:7])CC.O[CH:11]([C:13]1[CH:31]=[C:16]2[C:17]([C:23]3[CH:24]([CH3:30])[CH2:25][C:26](=[O:29])[NH:27][N:28]=3)=[CH:18][CH:19]=[C:20]([O:21][CH3:22])[N:15]2[N:14]=1)[CH3:12]>C(Cl)(Cl)Cl>[F:7][CH:11]([C:13]1[CH:31]=[C:16]2[C:17]([C:23]3[CH:24]([CH3:30])[CH2:25][C:26](=[O:29])[NH:27][N:28]=3)=[CH:18][CH:19]=[C:20]([O:21][CH3:22])[N:15]2[N:14]=1)[CH3:12]
Reactant: CCN(CC)S(F)(F)F
Reactant: COc1ccc(C2=NNC(=O)CC2C)c2cc(C(C)O)nn12
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2=NNC(=O)CC2C)c2cc(C(C)F)nn12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
DAST (51.2 mg) was added dropwise to a solution of the compound of Example 238 (80.0 mg) in chloroform (10 mL) at 0° C. and the mixture was stirred at 0° C. for 30 min. The reaction was quenched by adding a saturated aqueous sodium bicarbonate solution and the reaction mixture was extracted with chloroform (30 mL). The extract was washed with water and saturated brine and dried over anhydrous sodium sulfate. The dried extract was concentrated and purified by silica gel column chromatography (hexane:ethyl acetate=1:4) to afford the title compound as a pale yellow powder (30.6 mg).
Reaction SMILES: Br.[CH2:2]([N:19]([CH2:21][CH:22]([OH:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])C)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH:11]([OH:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])C>>[CH2:2]([NH:19][CH2:21][CH:22]([OH:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][CH2:10][CH:11]([OH:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCC(O)CN(C)CCCCCCN(C)CC(O)CCCCCC
Agent: Br
Product: CCCCCCC(O)CNCCCCCCNCC(O)CCCCCC

Procedure:
In a manner similar to that of Example 22, methylation of N,N'-(1,6-hexylene)-bis[2-hydroxyoctylamine] (35 g.) and treatment of the resulting product (b.p. 177°-182° C./1 mm.) with hydrogen bromide gave N,N'-(1,6-hexylene)-bis[N-methyl-2-hydroxyoctylamine] (I: R = CH3 (CH2)5, R' = CH3, X = (CH2)6, Z = H) dihydrobromide (19.1 g., m.p. 167.0°-168.8° C.).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([CH3:7])=[O:6].[H-].[Na+].[Li]CCCC.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:33])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][C:32]2([CH:34]3[CH2:35][CH2:36][CH2:37][CH2:38]3)[O:33][C:3](=[O:2])[CH2:4][C:5](=[O:6])[CH2:7]2)=[CH:28][CH:29]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=C(CCc1ccc(OCc2ccccc2)cc1)C1CCCC1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CC(=O)OC(CCc2ccc(OCc3ccccc3)cc2)(C2CCCC2)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 52 %

Procedure:
Methylacetoacetate (1.63 mL, 15.1 mmol) was dissolved in dry THF (42 mL) and cooled to 0° C. NaH (60% in mineral oil, 0.604 g, 15.1 mmol) were carefully added and the reaction mixture was stirred for 20 min. A solution of BuLi in hexanes (1.6 M, 9.44 mL, 15.1 mmol) was added dropwise and the resulting mixture was stirred an additional 20 min. A solution of 3-(4-benzyloxyphenyl)-1-cyclopentylpropan-1-one (2.33 g, 7.55 mmol) from Step 5 above in THF (37 mL) was added dropwise. After stirring 1 h, the reaction mixture was quenched with saturated aq NH4Cl (100 mL) and extracted with Et2O (600 mL). The organic phase was dried over MgSO4 and evaporated. The residue was then stirred overnight in a mixture of 0.1 M NaOH (370 mL) and THF (37 mL). After the addition of an aq solution of 10% aq KHSO4 (50 mL) the resulting mixture was stirred 30 min and then extracted with Et2O (600 mL). The organic phase was washed with brine, dried over MgSO4 and evaporated. The residue was purified by flash column chromatography (50% EtOAc in hexanes) to give the product (1.54 g, 52%) as a white foam.
Reaction SMILES: [N:1]([CH:4]([CH3:20])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][CH:4]([CH3:20])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1
Reactant: CC(CCC1CCN(C(=O)OC(C)(C)C)CC1)N=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: CC(N)CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 103.8 %

Procedure:
A suspension of tert-butyl 4-(3-azidobutyl)piperidine-1-carboxylate (3.81 g) and 5% palladium/carbon (containing water (50%), 800 mg) in methanol (100 mL) was stirred at room temperature for 15 hr under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (3.59 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[C:12](=O)([O-])[O-].[K+].[K+].CI.C(OCC)(=O)C>CN(C)C=O.CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: [Pd]
Agent: [K+]
Solvent: CI
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(N)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Fluoro-4-nitrophenol (10.17 g, 64.7 mmol) (Aldrich) was dissolved in dimethylformamide (210 mL). Potassium carbonate (45 g, 323 mmol) and methyl iodide (5 mL, 77.64 mmol) (Aldrich) were added and the reaction mixture was stirred at room temperature overnight. (TLC: 20% ethyl acetate in hexanes showed complete conversion). The reaction mixture was filtered through a bed of Celite®, and concentrated under reduced pressure. The crude material was triturated with ether and insoluble materials were removed by filtration. The filtrate was concentrated under reduce pressure to afford an orange solid. This material (11.43 g) was dissolved in methanol (150 mL) and hydrogenated for 1.5 hours in a Parr apparatus at 50 psi, in the presence of 10% palladium on carbon (1.5 g) (Aldrich). (TLC: 20% ethyl acetate in hexanes showed complete conversion). The reaction mixture was filtered through Celite® washed with ethyl acetate, then concentrated under reduced pressure to afford 2-fluoro-4-methoxyaniline as a solid. (Yield 3.81 g, 26.99 mmol).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)([F:13])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO>[F:21][C:16]1[CH:15]=[C:14]([C:10]2([F:13])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:19]=[C:18]([F:20])[CH:17]=1
Reactant: Fc1cc(F)cc(C2(F)CCN(Cc3ccccc3)C2)c1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Fc1cc(F)cc(C2(F)CCNC2)c1
Temperature: 25 °C
Yield: 31.6 %

Procedure:
A mixture of 1-benzyl-3-(3,5-difluorophenyl)-3-fluoropyrrolidine (0.65 g, 2.2 mmol) and ammonium formiate (1.4 g, 22 mmol) in methanol (50 mL) was purged with nitrogen and palladium on carbon (65 mg) was added. The mixture was refluxed for 8 h and palladium on carbon (30 mg) was added at 4 h, 6 h and 7 h respectively. The mixture was cooled to ambient temperature and filtered through a pad of celite. The filtrate was evaporated, aqueous sodium carbonate (10%, 50 mL) was added and the aqueous phase was extracted with dichloromethane (2×50 mL). Purification by flash column chromatography on silica gel (ethyl acetate/methanol, 1:1 to 0:1) gave the title compound (0.14 g). The amine was converted to the oxalic acid salt and recrystallized from methanol/diethyl ether: M.p. 176-177° C.; MS m/z (relative intensity, 70 eV) 201 (M+, bp), 181 (20), 180 (29), 158 (21), 151 (53).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][N:4]=1.[Se](=O)=O>O1CCOCC1.ClCCl>[C:3]1([CH:2]=[O:1])[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][N:4]=1
Reactant: OCc1nccc2c1CCCC2
Agent: O=[Se]=O
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=Cc1nccc2c1CCCC2
Temperature: 82.5 °C
Yield: 90.1 %

Procedure:
1-Hydroxymethyl-5,6,7,8-tetrahydroisoquinoline (4.14 g, 25.4 mmole) is dissolved in 75 ml dioxane in a 200 ml one neck round bottom flask under nitrogen. The solution is treated with selenium dioxide (1.56 g, 14.0 mmole) and the reaction mixture is warmed to 80-85° C. for 2.5 h. The mixture is cooled to room temperature, is diluted with 125 ml dichloromethane and is filtered through celite. The filter cake is washed well with fresh dichloromethane and the filtrate is concentrated in vacuo to an amber oil. The crude material is chromatographed over 200 g silica gel (230-400 mesh), eluting with 1:5:4 acetone/chloroform/hexane while collecting 50 ml fractions. Fractions 11-18 are combined and concentrated to give 3.69 g (90%) of 5,6,7,8,-tetrahydroisoquinoline-1-carbaldehyde.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Br[CH:27]([CH2:29][CH3:30])[CH3:28]>>[CH:27]([O:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])([CH2:29][CH3:30])[CH3:28]
Reactant: COc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1O
Reactant: CCC(C)Br
Product: CCC(C)Oc1cc(-c2nc(CCC(=O)c3ncccc3C)co2)ccc1OC

Procedure:
Using the compound obtained in Example 136 and 2-bromobutane, yellow oily 3-[2-(3-sec-butoxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][CH2:11][N:12]=2)=[CH:4][C:3]=1[F:13].[BH3-]C#N.[Na+].C(O)(=O)C>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][CH2:11][NH:12]2)=[CH:4][C:3]=1[F:13]
Reactant: Fc1cc(C2=NCCC2)ccc1Br
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Fc1cc(C2CCCN2)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of 5-(4-bromo-3-fluorophenyl)-3,4-dihydro-2H-pyrrole ((12.7 g, 52.7 mmol) in 360 mL methanol was added NaBH3CN (6.6 g, 105 mmol) at 0° C. The resulting solution was adjusted to pH=6 with acetic acid. The reaction mixture was stirred at room temperature overnight. The reaction was quenched with 2 N HCl and the methanol was removed by evaporation. The residue was diluted with water, the aqueous phase adjusted to pH=10 with NaOH, extracted with ethyl acetate, dried by Na2SO4, concentrated and the residue was purified by chromatography on silica gel to give 2-(4-bromo-3-fluorophenyl)pyrrolidine as a yellow solid (12.5 g, yield 98%). LC-MS (ESI) m/z: 244 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[CH3:44][O:45][C:46]1[CH:52]=[CH:51][CH:50]=[CH:49][C:47]=1[NH2:48]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36]([NH:48][C:47]4[CH:49]=[CH:50][CH:51]=[CH:52][C:46]=4[O:45][CH3:44])[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: COc1ccccc1N
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(Nc4ccccc4OC)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 68 %

Procedure:
In a manner analogous to that described in Example 3 a), the amination of [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(R)-4-(5-bromo-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-amine (intermediate C4.1) with 2-methoxyaniline yielded the title compound (68% yield) as a yellow foam. MS (ISP): m/z=696.5 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.C1(S(O[CH2:21][CH2:22][Cl:23])(=O)=O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:23][CH2:22][CH2:21][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(=O)(OCCCl)c1ccccc1
Reactant: NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: NC(=O)c1ccc(OCCCl)cc1

Procedure:
A mixture of 4-hydroxybenzamide (194 g, 1.25 M), 2-(benzenesulphonyloxy)ethyl chloride (359 g, 1.8 M), and potassium carbonate (172.8 g, 1.25 M) in butan-2-one (2.16 l) was stirred at reflux for 24 hours. After cooling, distilled water (2.0 l) was added and the resultant precipitate filtered off, washed with water, and dried. Crystallisation from ethanol gave the title compound, yield (232.0 g), m.p. 66°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[NH:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([Cl:12])=[CH:7][C:6]=1I.[C:15]([Si:17]([CH3:20])([CH3:19])[CH3:18])#[CH:16].Cl>C(N(CC)CC)C.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.[Cu]I>[CH3:1][O:2][C:3](=[O:14])[NH:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([Cl:12])=[CH:7][C:6]=1[C:16]#[C:15][Si:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)Nc1cc(F)c(Cl)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)Nc1cc(F)c(Cl)cc1C#C[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Pd(PPh3)2Cl2 (153 mg, 0.22 mmol) and copper(I)iodide (42 mg, 0.22 mmol) were dissolved in triethylamine (40 ml) and refluxed under argon for 20 min. The reaction mixture was then cooled down to 0° C. and (4-chloro-5-fluoro-2-iodo-phenyl)-carbamic acid methyl ester (7.2 g, 21 mmol) was added. After 10 min stirring at rt, ethinyltrimethylsilane (3.45 ml, 24.9 mmol) was added dropwise (exothermic, temperature raises from 18 to 33° C.) and the reaction mixture was stirred for one hour at rt. The reaction mixture was then poured on 1N aq. HCl solution (180 ml) and ice and extracted twice with ethyl acetate (180 ml). The combined organic phases were washed with water and sat. aq. NaCl solution, dried over magnesium sulfate, filtered and concentrated in vacuo to yield crude (4-chloro-5-fluoro-2-trimethylsilanylethynyl-phenyl)-carbamic acid methyl ester.
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=2)[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([O:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=3)[CH:13]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2]>[C].[Pd]>[NH2:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][C:14]2[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:29]=[CH:30][CH:31]=[C:6]([C:3]4([C:1]#[N:2])[CH2:5][CH2:4]4)[CH:7]=3)[CH:17]=[CH:16][C:15]=2[CH3:18])=[CH:25][CH:24]=1
Reactant: Cc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Product: Cc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc(N)cc1

Procedure:
Using 3-(1-cyanocyclopropyl)-N-[4-methyl-3-(4-nitrophenoxy)phenyl]benzamide (2.07 g, 5.0 mmol) and 10%-palladium carbon (0.5 g), and in the same manner as in Example A25(iv), the title compound (1.92 g, quantitatively) was obtained as a pink amorphous substance.
Reaction SMILES: [OH:1][CH:2]([C:29]([NH:31][O:32][CH3:33])=[O:30])[CH:3]([NH:11][C:12](=[O:28])[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][C:14]=1[N:19]1[CH:27]=[C:26]2[C:21]([CH:22]=[CH:23][CH:24]=[CH:25]2)=[N:20]1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CS(C)=O.IC1C=CC=CC=1C(O)=O.C([O-])(O)=O.[Na+]>ClCCl.O>[N:20]1[N:19]([C:14]2[N:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]([NH:11][CH:3]([C:2](=[O:1])[C:29]([NH:31][O:32][CH3:33])=[O:30])[CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:28])[CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][CH:24]=[CH:25]2
Reactant: CONC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc2ccccc2n1
Agent: O=C(O)c1ccccc1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: CONC(=O)C(=O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc2ccccc2n1
Reaction time: 3 h
Yield: 92.6 %

Procedure:
To a solution of N-[3-hydroxy-4-(methoxyamino)-4-oxo-1-phenylbutan-2-yl]-2-(2H-indazol-2-yl)nicotinamide (1050 mg; 2.357 mmol) in DMSO (30 ml) 2-iodobenzoic acid (470 mg, 0.755 mmol) was added. After stirring for 4 hours at 30° C. additional 2-iodobenzoic acid (470 mg, 0.755 mmol) was added and stirring was continued for 3 hour at 30° C. and then overnight at room temperature. After cooling the reaction mixture to 15° C. a saturated aqueous solution of NaHCO3 (40 ml), water (40 ml) and dichloromethane (80 ml) were added. The organic layer was collected and the aqueous layer re-extracted twice with dichlormethane (CH2Cl2). The combined organic layers were then dried over MgSO4, filtered and concentrated to give 968 mg of a yellow-brown solid. Purification by chromatography over silica gel (eluent: CH2Cl2+0 to 10% (v/v) methanol) gave 800 mg of a raw product which was recrystallized from isopropanole yielding 456 mg of the title compound as a white solid.
Reaction SMILES: C([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([Cl:30])[C:20]([O:26][CH:27]([CH3:29])[CH3:28])=[N:21][CH:22]=3)[C:17]2=[O:31])=[C:13]([CH3:32])[CH:12]=[C:11]([CH3:33])[N:10]=1)C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[Cl:30][C:19]1[C:20]([O:26][CH:27]([CH3:29])[CH3:28])=[N:21][CH:22]=[C:23]2[C:18]=1[C:17](=[O:31])[N:16]([CH2:15][C:14]1[C:9](=[O:8])[NH:10][C:11]([CH3:33])=[CH:12][C:13]=1[CH3:32])[CH2:25][CH2:24]2
Reactant: Cc1cc(C)c(CN2CCc3cnc(OC(C)C)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(CN2CCc3cnc(OC(C)C)c(Cl)c3C2=O)c(=O)[nH]1
Yield: 42.6 %

Procedure:
A solution of 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-7-(propan-2-yloxy)-3,4-dihydro-2,6-naphthyridin-1(2H)-one (112f, 22 mg, 0.05 mmol) in TFA (2 mL) was stirred at room temperature for 24 hours. Volatiles were removed under vacuum and the residue was diluted in MeOH (1 mL). The solution was neutralized by 7N NH3 in MeOH (1.5 mL) and the product was purified by prep TLC (100% EtOAc) to afford the title compound as a white solid (Example 112, 8 mg, 50%). 1H NMR (400 MHz, DMSO-d6) δ 1.30 (s, 3H) 1.32 (s, 3H) 2.12 (s, 3H) 2.15 (s, 3H) 2.75 (t, J=6.17 Hz, 2H) 3.43 (t, J=6.17 Hz, 2H) 4.56 (s, 2H) 5.21-5.30 (m, 1H) 5.88 (s, 1H) 8.02 (s, 1H) 11.56 (br. s., 1H); MS 376.2 [M+1].
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:39]([C:42]3[S:43][CH:44]=[CH:45][N:46]=3)=[CH:40][N:41]=2)[CH:5]=[C:6]([C:8]2[C:9]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)=[N:10][N:11]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:12]=2)[CH:7]=1.[CH3:47][N:48](C)C(=O)C>O.C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.[Zn].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].C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2]>[F:38][C:35]1[CH:34]=[CH:33][C:32]([C:9]2[C:8]([C:6]3[CH:7]=[C:2]([C:47]#[N:48])[C:3]4[N:4]([C:39]([C:42]5[S:43][CH:44]=[CH:45][N:46]=5)=[CH:40][N:41]=4)[CH:5]=3)=[CH:12][N:11]([C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:10]=2)=[CH:37][CH:36]=1
Reactant: Fc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2cc(Cl)c3ncc(-c4nccs4)n3c2)cc1
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1cc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)nc2-c2ccc(F)cc2)cn2c(-c3nccs3)cnc12
Temperature: 150 °C

Procedure:
A solution of 213 mg 2-{8-chloro-6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]imidazo[1,2-a]pyridin-3-yl}-1,3-thiazole obtained in Example 404 in 2 mL N,N-dimethylacetamide, together with 24 mg zinc cyanide, 6 mg zinc powder, 12 mg tris(dibenzylidene acetone)dipalladium (0) and 15 mg diphenylphosphinoferrocene, was heated at 150° C. for 5 hours, and the reagents were added in the same amounts as described above, and the mixture was heated at 150° C. for 10 hours. The reaction solution was diluted with water and ethyl acetate and filtered through Celite, and the organic layer was washed with brine. The solution was dried over anhydrous sodium sulfate, the solvent was removed, and the resulting crude product was purified by silica gel column chromatography (ethyl acetate/hexane) and then recrystallized to give 68 mg of the title compound (yellow solid).
Reaction SMILES: C(OC([N:8]1[CH2:28][CH2:27][CH2:26][C:10]2([N:13]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:12][C:11]2([F:25])[F:24])[CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>>[CH2:17]([O:16][C:14]([N:13]1[C:10]2([CH2:26][CH2:27][CH2:28][NH:8][CH2:9]2)[C:11]([F:25])([F:24])[CH2:12]1)=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCCC2(C1)N(C(=O)OCc1ccccc1)CC2(F)F
Agent: Cl
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1CC(F)(F)C12CCCNC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 118.9 %

Procedure:
To an optically-active compound of 3,3-difluoro-1,6-diaza-spiro[3.5]nonane-1,6-dicarboxylic acid 1-benzyl ester 6-tert-butyl ester (12.6 g) was added 4M hydrochloric acid-1,4-dioxane (126 ml), and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, and thereto was added toluene. The mixture was concentrated under reduced pressure again to give the titled compound (11.2 g).
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=[O:5].C1C(=O)N([Br:22])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[CH3:1][C:2]([CH3:14])([CH3:13])[CH2:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][Br:22])=[CH:10][CH:11]=1)=[O:5]
Reactant: Cc1ccc(C(=O)CC(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)CC(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
Heat a mixture of 3,3,4′-trimethylbutyrophenone (2 g, 10.52 mmol), NBS (2.061 g, 11.57 mmol), and AIBN (43 mg, 0.263 mmol) in carbon tetrachloride (60 mL) for 14 h at reflux. Cool the reaction mixture to ambient temperature and wash sequentially with water, 1M aqueous HCl, 5% aqueous NaHCO3 and brine. Concentrate the organic layer in vacuo to provide the desired intermediate as oil (2.54 g, 90%) that was used without any further purification.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[O:5][C@H:4]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[N:18][CH:19]=[N:20][CH:21]=3)=[CH:12][CH:11]=2)[C@@H:3]1[CH2:22][CH2:23][N:24]1[C:29](=[O:30])[C:28]2[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=2[N:26]=[N:25]1.[O:35]1CCCC1.I([O-])(=O)(=O)=O.[Na+].[Mn]([O-])(=O)(=O)=O.[K+]>C(O)(C)(C)C>[CH:6]([O:5][C@H:4]([CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[N:20][CH:19]=[N:18][CH:17]=2)=[CH:14][CH:15]=1)[C@H:3]([CH2:22][CH2:23][N:24]1[C:29](=[O:30])[C:28]2[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=2[N:26]=[N:25]1)[C:2]([OH:1])=[O:35])=[O:7]
Reactant: C1CCOC1
Reactant: O=c1c2ccccc2nnn1CC[C@@H]1[C@H](O)[C@H](O)O[C@@H]1CCc1ccc(-c2cncnc2)cc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: O=CO[C@H](CCc1ccc(-c2cncnc2)cc1)[C@H](CCn1nnc2ccccc2c1=O)C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of the compound obtained from step m above (0.25 g) in tert-butanol:tetrahydrofuran (5 mL:5 mL) at 0° C., a solution of sodium metaperiodate (0.465 g in 5 mL of water) was added. The reaction mixture was stirred for 2 hours at the same temperature and potassium permanganate (0.017 g) was added at 0° C. After stirring the reaction mixture for an additional 6 hours at room temperature, the reaction mixture was evaporated on a rotary evaporator. The residue was taken into water and extracted with ethyl acetate. The organic layer was washed with water and brine solution and dried over anhydrous sodium sulphate. The solvent was evaporated under the reduced pressure to afford the title compound (0.25 g).