Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].S(C1C=CC(C)=CC=1)(O[CH2:13][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)(=O)=O>>[CH:14]1([CH2:13][S:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[OH:8])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCC2)cc1
Reactant: Oc1ccccc1S
Product: Oc1ccccc1SCC1CCCC1
Yield: 83 %

Procedure:
This compound was prepared in 83% yield from 2-mercaptophenol and cyclopentylmethyl tosylate according to the procedure for 1p in Example VIII. Colorless oil; 1H NMR (CDCl3): δ 1.20-1.26 (m, 2H), 1.50-1.65 (m, 4H), 1.78-1.84 (m, 2H), 1.99 (s-7, J=7.45 Hz, 1H), 2.68 (J=7.40 Hz, 2H), 6.78 (s, 1H), 6.86 (dt, J=1.35 Hz, J=7.55 Hz, 1H), 7.24 (dt, J=1.65 Hz, J=7.85 Hz, 1H), 7.46 (dd, J=1.65, J=7.70 Hz, 1H); 13C NMR (CDCl3): δ 25.38, 32.32, 39.71, 43.33, 114.74, 119.64, 120.79, 130.94, 135.89, 156.90; HRMS (FAB): 208.09219 calcd for C12H16OS [M]+. found 208.09134 (−4.3 ppm, −0.9 mmu).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:19][N:6]2[CH2:7][CH2:8][N:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[CH2:10][C@@H:5]2[CH2:4]1.[F:20][C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:1][CH2:2][C@@H:3]2[CH2:19][N:6]3[CH2:7][CH2:8][N:9]([C:11]4[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=4)[CH2:10][C@@H:5]3[CH2:4]2)=[CH:23][CH:22]=1
Reactant: N#Cc1ccc(N2CCN3C[C@@H](CO)C[C@H]3C2)cc1
Reactant: Oc1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(N2CCN3C[C@@H](COc4ccc(F)cc4)C[C@H]3C2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
A solution of 0.25 g (0.97 mmol) of (7S,8aS)-7-hydroxymethyl-2-(4-cyanophenyl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 16), 0.164 g (1.46 mmol) of 4-fluorophenol, 0.31 g (1.15 mmol) of triphenylphosphine in 10 mL of THF was treated with 0.18 mL (1.15 mmol) of diethyl azodicarboxylate and the solution stirred at ambient temperature for 16 hours. The solvent was removed by rotary evaporation, and the residue partitioned between chloroform and 1M sodium hydroxide. The layers were separated, and the organic phase was dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 1:1 ethyl acetate:hexane gave 0.225 g (66%) of the title compound. Mp (.HCl) 81-85° C. HRMS calc'd for C21H23FN3O (MH+): 352.1825, found: 352.1817.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[CH2:12][N:13]([CH3:18])[C:14](=[O:17])[CH:15]=[CH2:16].Br[C:20]1[CH:21]=[C:22]2[C:27](=[N:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24][CH2:23]2.CCN(C(C)C)C(C)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[CH2:12][N:13]([CH3:18])[C:14](=[O:17])/[CH:15]=[CH:16]/[C:20]1[CH:29]=[N:28][C:27]2[NH:26][C:25](=[O:30])[CH2:24][CH2:23][C:22]=2[CH:21]=1
Reactant: O=C1CCc2cc(Br)cnc2N1
Reactant: C=CC(=O)N(C)Cc1c(C)c2ccccc2n1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)n(C)c2ccccc12
Temperature: 25 °C
Yield: 59.1 %

Procedure:
To a stirred solution of N-(1,3-dimethyl-1H-indol-2-ylmethyl)N-methylacrylamide (1.7 g, 7 mmole) in propionitrile (50 mL) was added 6-bromo3,4-dihydro-1H-1,8-naphthyridin-2-one (1.16 g, 5.1 mmole), DIEA (1.8 mL, 10.3 mmole), palladium(II) acetate (112 mg, 0.5 mmole), and tri-o-tolylphosphine (304 mg, 1.0 mmole). The reaction was purged with argon and heated at reflux for 16 hr, then was cooled to RT and concentrated under vacuum. Purification by flash chromatography on silica gel (5% methanol/CHCl3), trituration with ethyl acetate, filtration, and drying under vacuum gave the title compound (1.17 g, 59%) as an off-white solid: LCMS (ES) m/e 389.2 (M+H)+.
Reaction SMILES: [Si:1]([CH:8]1[C:12](=[CH:13][O:14][Si](C(C)(C)C)(C)C)[C:11]2[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:10]=2[O:9]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl>CO>[Si:1]([C:8]1[O:9][C:10]2[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:11]=2[C:12]=1[CH:13]=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1ccc2c(c1)OC([Si](C)(C)C(C)(C)C)C2=CO[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CO
Product: COc1ccc2c(C=O)c([Si](C)(C)C(C)(C)C)oc2c1
Reaction time: 0.5 h

Procedure:
To a solution of 2-t-butyldimethylsilyl-3-(t-butyldimethylsilyloxymethylene)-6-methoxy-benzofuran (1.09 g, 2.69 mmol) in methanol (100 mL) was added concentrated hydrochloric acid (200 μL) and the reaction was stirred for 30 minutes (monitored by tlc), quenched with triethylamine (2 mL) and the solvent removed by distillation under vacuum. The residue was dissolved in dichloromethane (20 mL), washed with water (10 mL), dried over magnesium sulfate, concentrated under vacuum and co-distilled with toluene (20 mL); 1H NMR (300 MHz, CDCl3) δ 7.57 (d, 1H, J=8.57 Hz), 7.00 (d, 1H, J=2.17 Hz), 6.86 (dd, 1H, J=8.55, 2.22 Hz), 4.81 (s, 2H, CH2), 3.84 (s, 3H, OMe), 0.94 (s, 9H), 0.37 (s, 6H). The crude yellow paste (˜985 mg) was dissolved in dry dichloromethane (4 mL) and added to a stirred solution of Collin's reagent (chromium trioxide (1.01 g), pyridine (1.65 mL) in dry dichloromethane (30 mL)). The suspension was stirred for 10 minutes, filtered and the residue washed with diethyl ether (20 mL). The filtrate was concentrated onto silica (10 g) and purified by flash chromatography (silica gel, eluent=hexane/diethyl-ether/triethylamine (90:9:1) to afford the title compound as a light yellow oil which crystallized on standing (485 mg, 68%); 1H NMR (300 MHz, CDCl3) δ 10.25 (s, 1H, CHO), 8.06 (d, 1H, J=8.61 Hz), 7.03 (d, 1H, J=2.16 Hz), 6.95 (dd, 1H, J=8.60, 2.19 Hz), 3.84 (s, 3H, OMe), 0.97 (s, 9H), 0.46 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 186.91 (CHO), 174.18, 159.19, 159.17, 132.82, 122.77, 117.34, 113.56, 95.36, 55.60, 27.04, 17.09, −5.24.
Reaction SMILES: [C:1]([CH2:4][CH:5]1[C:9]2[C:10]([C:16]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=3[Cl:26])=[O:17])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH2:6]1)([OH:3])=O.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][NH2:34])[CH:28]=1>>[Cl:25][C:24]1[CH:23]=[N:22][CH:21]=[C:20]([Cl:26])[C:19]=1[NH:18][C:16]([C:10]1[C:9]2[CH:5]([CH2:4][C:1]([NH:34][CH2:33][C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)=[O:3])[CH2:6][O:7][C:8]=2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)=[O:17]
Reactant: NCc1cccnc1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)NCc1cccnc1
Yield: 19 %

Procedure:
Substantially the same procedure as in Example 13 was repeated using Compound 9 (0.30 g) obtained in Example 9 and 3-pyridylmethylamine to give Compound 18 (0.07 g, 19%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[C:30]([O:34][C:35]([NH:37][C:38]1[CH:43]=[C:42]([I:44])[CH:41]=[C:40]([I:45])[CH:39]=1)=[O:36])([CH3:33])([CH3:32])[CH3:31].[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:37]([C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:36])[C:38]2[CH:39]=[C:40]([I:45])[CH:41]=[C:42]([I:44])[CH:43]=2)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Reactant: CC(C)(C)OC(=O)Nc1cc(I)cc(I)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCN(C(=O)OC(C)(C)C)c2cc(I)cc(I)c2)c1CCC(=O)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.7 %

Procedure:
To a mixture of the 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (3.6 g, 7.6 mmol), N-tert-butoxycarbonyl-3,5-diiodoaniline (2.8 g, 6.3 mmol) in DMF (60 mL) was added NaH (60% dispersion in mineral oil), (504 mg, 12.6 mmol). The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with EtOAc (120 mL), then washed with brine. The organic phase was dried over Na2SO4 and evaporated under reduced pressure. Purification by Isco chromatography (Gradient of 20 minutes from hexanes to Hexanes/EtOAc 80%) afforded the title compound (3.3 g, 60%) as a light yellow oil. HR-ES(+): calculated for C34H47N1O7I2 (M+Na)+ 858.1334, found 858.1325.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C@:9]1([CH2:28][F:29])[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[O:12][C:11]([NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:10]1.F[C:31]1[CH:36]=[N:35][CH:34]=[CH:33][N:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:31]2[CH:36]=[N:35][CH:34]=[CH:33][N:32]=2)=[CH:4][C:3]=1[C@:9]1([CH2:28][F:29])[CH2:14][C@@H:13]([C:15]([F:18])([F:16])[F:17])[O:12][C:11]([NH:19][C:20](=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:10]1
Reactant: Fc1cnccn1
Reactant: O=C(NC1=N[C@](CF)(c2cc(O)ccc2F)C[C@@H](C(F)(F)F)O1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(NC1=N[C@](CF)(c2cc(Oc3cnccn3)ccc2F)C[C@@H](C(F)(F)F)O1)c1ccccc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 75.5 %

Procedure:
To a microwave vial were added N-((4S,6S)-4-(2-fluoro-5-hydroxyphenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (95 mg, 0.229 mmol), 2-fluoro-pyrazine (24.74 mg, 0.252 mmol), cesium carbonate (90 mg, 0.275 mmol) in DMSO (459 μL). The vial was heated in microwave instrument at 100° C. for 30 min. After cooling to room temperature, water was added to the reaction mixture and precipitate was observed. After stirring for 10 min, the precipitate was collected by filtration, washed with water and hexane, dried in vacuum oven at 60° C. for 1 h to provide N-((4S,6S)-4-(2-fluoro-5-(pyrazin-2-yloxy)phenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (85 mg, 0.173 mmol, 75% yield) as off-white solid. MS m/z=493 [M]+. Calculated for C23H17F5N4O3: 492.4.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:33])([CH2:30][CH2:31][CH3:32])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:29])=[N:15][N:16]2[C:21]([O:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:20][C:19]([CH3:28])=[CH:18][C:17]=12)=[O:12])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]([CH3:33])([CH2:30][CH2:31][CH3:32])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:29])=[N:15][N:16]2[C:21]([O:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:20][C:19]([CH3:28])=[CH:18][C:17]=12)=[O:12]
Reactant: CCCC(C)(CNC(=O)c1c(C)nn2c(OCCC(C)C)cc(C)cc12)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC(C)(N)CNC(=O)c1c(C)nn2c(OCCC(C)C)cc(C)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 80 mg (0.091 mmol, 54% pure) of rac-[1-({[2,5-dimethyl-7-(3-methylbutoxy)pyrazolo[1,5-a]pyridin-3-yl]carbonyl}amino)-2-methylpentan-2-yl]carbamic acid tert-butyl ester (Example 124A) in 4 ml of dichloromethane was admixed with 0.140 ml (1.82 mmol) of trifluoroacetic acid. The resulting solution was stirred at room temperature overnight. After the reaction had ended, the solvent was drawn off under reduced pressure and the residue was purified by preparative HPLC chromatography (Method 21), which gave 17 mg (50% of theory) of the target compound.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][C:30]([CH3:32])=O>>[CH:30]([N:26]1[CH2:25][CH2:24][N:23]([CH2:22][C:16]2([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][CH:12]=3)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[CH2:28][CH2:27]1)([CH3:32])[CH3:29]
Reactant: CC(C)=O
Reactant: c1cc(C2(CN3CCNCC3)CCOCC2)ccc1OCCCN1CCCC1
Product: CC(C)N1CCN(CC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)CC1
Yield: 44 %

Procedure:
The title compound (78 mg, 44%) was prepared from 1-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}piperazine and acetone similarly to the procedure used for example 54. 1H NMR (400 MHz, CDCl3) δ 0.98 (d, 6H), 1.77-1.80 (m, 4H), 1.86-1.93 (m, 2H), 1.98-2.02 (m, 2H), 2.06-2.09 (m, 2H), 2.20-2.22 (m, 4H), 2.34-2.36 (m, 6H), 2.50-2.54 (m, 5H), 2.62 (t, 2H), 3.52 (t, 2H), 3.71-3.75 (m, 2H), 4.02 (t, 2H), 6.85 (d, 2H), 7.21 (d, 2H). HRMS ESI+ m/z 430.3417 [MH]+.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH:23]12[NH:31][CH:27]([CH2:28][O:29][CH2:30]1)[CH2:26][O:25][CH2:24]2.[F-].[K+]>CN(C=O)C.CCOC(C)=O>[CH:27]12[N:31]([C:3]3[C:2]([Br:1])=[CH:21][C:6]([C:7]([NH:9][C:10]4[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=4)=[O:8])=[CH:5][N:4]=3)[CH:23]([CH2:30][O:29][CH2:28]1)[CH2:24][O:25][CH2:26]2
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: C1OCC2COCC1N2
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2C3COCC2COC3)c(Br)c1
Temperature: 140 °C
Reaction time: 18 h

Procedure:
5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2, 55.4 mg, 0.14 mmol) and 3,7-Dioxa-9-aza-bicyclo[3.3.1]nonane (Organic Chemistry (2006), 71(1), 413-415) (24.53 mg, 0.14 mmol) were dissolved in DMF (150 μL). KF (24.4 mg, 0.42 mmol) was added and the RM mixture was stirred at 140° C. for 18 h in a pressure safe vial. After cooling at RT, the RM was dissolved in EtOAc and washed with brine. The organic phase was dried over Na2SO4 and evaporated to dryness under reduced pressure to give a residue that was purified by flash chromatography (RediSep® Silica gel column, n-hexane/EtOAc from 20% to 60% EtOAc) to afford the title compound as a white solid. HPLC (Condition 4) tR=5.84 min, UPLC-MS (Condition 3) tR=1.19 min, m/z=490.1 [M+H]+.
Reaction SMILES: O1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:19]3[C:18]4=[N:28][N:29]=[C:30]([C:31]5[N:32]=[CH:33][NH:34][CH:35]=5)[N:17]4[CH:16]=[CH:15][C:14]=3[N:13]=2)=[CH:8][CH:7]=1.Cl.Cl.[NH2:38][OH:39]>O1CCOCC1.O>[NH:34]1[CH:35]=[C:31]([C:30]2[N:17]3[C:18]([C:19]4[CH:20]=[C:21]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:12]([C:9]5[CH:8]=[CH:7][C:6]([CH:2]=[N:38][OH:39])=[CH:11][CH:10]=5)=[N:13][C:14]=4[CH:15]=[CH:16]3)=[N:28][N:29]=2)[N:32]=[CH:33]1
Reactant: NO
Reactant: c1ccc(-c2cc3c(ccn4c(-c5c[nH]cn5)nnc34)nc2-c2ccc(C3OCCO3)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: ON=Cc1ccc(-c2nc3ccn4c(-c5c[nH]cn5)nnc4c3cc2-c2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 22-1 (0.8 g, 1.7 mmol) in 1,4-dioxane (3 ml) was added 3N HCl (1.1 ml, 3.4 mmol) dropwise. After stirring for 10 min the solution was treated with hydroxylamine hydrochloride (0.5 g, 6.9 mmol) in water (0.5 ml). The mixture was stirred for 1 h and was then quenched with NaHCO3(s) until pH=8. Upon solvent removal the residue was taken up in water, filtered, and dried azeotropically with toluene to afford 22-2 as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].F[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])=[N:12][CH:13]=1
Reactant: N#Cc1cccc(O)c1
Reactant: Cc1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Oc2cccc(C#N)c2)nc1
Temperature: 150 °C
Yield: 35.9 %

Procedure:
A mixture of 3-hydroxy-benzonitrile (500 mg, 4.17 mmol), 2-fluoro-5-methyl pyridine (467 mg, 4.17 mmol) and K2CO3 (150 mg) in N,N-dimethylformamide (5 mL) was heated at 150° C. overnight. The reaction mixture was poured into water, and extracted with ethyl acetate (2×). The solvent was removed, and the resulting residue was chromatographered using hexane/ethyl acetate (2:1) to give the title compound (315 mg, 36%). MS (DCI/NH3) m/z 211 (M+1)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (s, 3H) 7.02 (d, J=8.59 Hz, 1H) 7.45 (ddd, J=8.29, 1.53, 0.92 Hz, 1H) 7.61 (m, 3H) 7.71 (ddd, J=8.29, 2.46, 0.61 Hz, 1H) 7.99 (dt, J=2.45, 0.61 Hz, 1H).
Reaction SMILES: C(OC(Cl)=O)C.[C:7]([NH:17][CH2:18][C:19]([OH:21])=O)([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].CN1CCOCC1.[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]([N:39]([CH3:41])[CH3:40])[CH3:38])=[CH:32][CH:31]=1>O1CCCC1>[C:7]([NH:17][CH2:18][C:19]([NH:29][C:30]1[CH:31]=[CH:32][C:33]([N:36]=[C:37]([N:39]([CH3:40])[CH3:41])[CH3:38])=[CH:34][CH:35]=1)=[O:21])([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CC(=Nc1ccc(N)cc1)N(C)C
Agent: CCOC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(=Nc1ccc(NC(=O)CNC(=O)OCc2ccccc2)cc1)N(C)C
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
22.8 g (0.21 mol) of chloroformic acid ethyl ester were added dropwise at -15° C to a solution of 41.8 g (0.2 mol) of N-(carbobenzoxy)-glycine and 21.3 g (0.21 mol) of N-methylmorpholine in 250 ml of absolute tetrahydrofuran. The mixture was stirred for 10 minutes at -10° C and was then filtered. A solution of 33.7 g (0.19 mol) of N'-(4-aminophenyl)-N,N-dimethylacetamidine in 100 ml of absolute tetrahydrofuran was added dropwise to the filtrate at -10° C. The mixture was then stirred for 30 minutes at -10° C, 1 hour at 0° C and 2 hours at room temperature. Thereafter, the mixture was concentrated on a rotary evaporator, suspended in sodium hydroxide solution and repeatedly extracted with chloroform. The chloroform phase was dried with Na2SO4 and concentrated. The residue was recrystallized from benzene-ligroin. 39.2 g of N'-[4-(carbobenzoxyglycylamino)-phenyl]-N,N-dimethylacetamidine of melting point 133° C were thus obtained and were slowly introduced into 800 ml of HBr/glacial acetic acid, with cooling. The mixture was stirred for 2 hours at room temperature and was then stirred into 2 liters of dry ether. A crystalline precipitate formed and this was filtered off, washed with ether and then dissolved in water. The aqueous solution was rendered alkaline, with cooling, and was repeatedly extracted with chloroform. The organic extracts were dried over Na2SO4 and concentrated in vacuo. The residue was recrystallized from toluene to afford 22.9 g (51% of theory) of N,N-dimethyl-N'-(4-glycylaminophenyl)acetamidine, melting point 142°-145° C.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)[C:9]=2[N:10]=1.[Cl:27][C:28]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O>>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:9]=[C:11]([NH:15][C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:32]4[CH:31]=[CH:30][CH:29]=[C:28]([Cl:27])[C:33]=4[Cl:34])=[CH:19][CH:18]=3)=[O:24])[CH:12]=[CH:13][C:14]=2[N:10]=1
Reactant: OB(O)c1cccc(Cl)c1Cl
Reactant: CN(C)CCN(C)c1nc2c(NC(=O)c3ccc(I)cc3)cccc2s1
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(-c4cccc(Cl)c4Cl)cc3)cc2s1

Procedure:
The title compound is prepared by following a procedure analogous to Example 113, Step 1, using N-{2-[(2-dimethylamino-ethyl)-methyl-amino]-benzothiazol-yl}-4-iodo-benzamide (0.15 g, 0.31 mmol) and 2,3-dichloro-phenyl boronic acid (0.072 g, 0.38 mmol) to afford 0.13 g (83%). LC/MS, Retention time=5.08 min; (m/z): calcd for C25H24Cl2N4OS: 499.5; found: 499.0.
Reaction SMILES: Cl[C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[O:17]1CCOCC1.CO>[OH-].[K+].Cl.O>[N+:11]([C:5]1[CH:4]=[C:3]([N+:14]([O-:16])=[O:15])[C:2]([OH:17])=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8])([O-:13])=[O:12]
Reactant: NC(=O)c1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: C1COCCO1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC(=O)c1cc(O)c([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 98 %

Procedure:
A solution of 5-chloro-2,4-dinitrobenzamide (5.50 g, 0.022 mmol) in p-dioxane/methanol (1:1, 120 mL) and 6N aqueous KOH (20 mL) is stirred at room temperature for 2 h. After acidification with concentrated HCl, the mixture is diluted with water and extracted into EtOAc. Workup gives 2,4-dinitro-5-hydroxybenzamide (4.91 g, 98%) as yellow cubes. 1H NMR (DMSO) δ8.64 (1H, s), 8.16 (1H, brs), 7.81 (1H, brs), 7.13 (1H, s), 5.80 (1H, brs).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:22]2[CH2:24][CH2:23]2)[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9](Cl)[N:8]=1.[NH4+:25].[OH-]>O1CCOCC1.O>[Br:1][C:2]1[N:3]=[C:4]([CH:22]2[CH2:24][CH2:23]2)[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH2:25])[N:8]=1
Reactant: C[Si](C)(C)CCOCn1c(C2CC2)nc(Br)c1-c1ccnc(Cl)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1c(C2CC2)nc(Br)c1-c1ccnc(N)n1
Yield: 91 %

Procedure:
4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine (1 g, 2.4 mmol) was combined with aqueous 28% NH4OH solution (8 mL) in 1,4-dioxane (8 mL) and the resulting mixture was split evenly between two reaction vials. Each was irradiated in a microwave reactor for 40 minutes at 130° C. TLC analysis indicated complete reaction. The combined reactions were then diluted with water (100 mL) followed by extraction with EtOAc (100 mL). The EtOAc layer was washed with brine then dried (Na2SO4), and concentrated. Purification of the resulting residue by flash chromatography on silica gel using an EtOAc-hexanes gradient (0 to 60%) provided 0.87 g of (2.1 mmol, 91%) of 4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-amine as a white solid: LCMS(m/z): 410.0 (MH+), tR=0.81 minute.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH2:21]1[C:24]2([CH2:28][CH2:27][CH2:26][NH:25]2)[CH2:23][CH2:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:23]1[C:24]2([CH2:28][CH2:27][CH2:26][N:25]2[C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[CH2:21][CH2:22]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: C1CNC2(C1)CCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CCCC12CCC2

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 5-azaspiro[3.4]octane (52876-78-5) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=378.5 [MH+].
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[N:8]=[C:7]2[NH:9][N:10]=[C:11]([OH:12])[C:6]2=[CH:5][CH:4]=1.[CH3:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22](Cl)=[O:23])[CH2:18][CH2:17]1>>[CH3:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:12][C:11]2[C:6]3[C:7](=[N:8][C:3]([C:2]([F:13])([F:1])[F:14])=[CH:4][CH:5]=3)[N:9]([C:22]([N:19]3[CH2:20][CH2:21][CH:16]([CH3:15])[CH2:17][CH2:18]3)=[O:23])[N:10]=2)=[O:23])[CH2:18][CH2:17]1
Reactant: Oc1n[nH]c2nc(C(F)(F)F)ccc12
Reactant: CC1CCN(C(=O)Cl)CC1
Product: CC1CCN(C(=O)Oc2nn(C(=O)N3CCC(C)CC3)c3nc(C(F)(F)F)ccc23)CC1

Procedure:
In analogy to example, 1, 120 mg (0.59 mmol) of 6-trifluoromethyl-1H-pyrazolo-[3,4-b]pyridin-3-ol were reacted with 143.3 mg (0.89 mmol) of 4-methylpiperidine-1-carbonyl chloride. Yield: 71 mg (26%), M+H+: 454.27.