Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][S:9]([O-:12])(=[O:11])=[O:10].[C:13](=[O:29])([O:19][C:20]1[CH:25]=[CH:24][C:23]([S+:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=1)[O:14][C:15]([CH3:18])(C)C.[CH3:30][S+:31]([CH3:39])[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1.[CH3:40][O:41][S:42]([O-:45])(=[O:44])=[O:43]>>[CH3:7][O:8][S:9]([O-:12])(=[O:11])=[O:10].[C:13](=[O:29])([O:19][C:20]1[CH:21]=[CH:22][C:23]([S+:26]([CH3:27])[CH3:28])=[CH:24][CH:25]=1)[O:14][CH2:15][CH2:18][CH2:32][CH3:33].[CH3:30][S+:31]([CH3:39])[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1.[CH3:40][O:41][S:42]([O-:45])(=[O:44])=[O:43]
Reactant: C[S+](C)c1ccc(OC(=O)OC(C)(C)C)cc1
Agent: COS(=O)(=O)[O-]
Agent: C[S+](C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Product: CCCCOC(=O)Oc1ccc([S+](C)C)cc1

Procedure:
The procedure of Example 7 was repeated with the exception that potassium carbonate was not used. The amount of the sulfonuim compound obtained was 2.99 g. An NMR analysis showed that the sulfonuim compound was a 33: 67 (mol/mol) mixture of tert-butyl p-dimethylsulfoniophenyl carbonate methylsulfate and p-dimethylsulfoniophenol methylsulfate. The yields of butyl p-dimethylsulfoniophenyl carbonate methylsulfate and p-dimethylsulfoniophenol methylsulfate were 33% and 67%, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]([C:15](=[O:23])[C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:33][C:34]1[C:42]([CH3:43])=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37]>ClCCl>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]([C:15]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:36](=[O:37])[C:35]4[CH:39]=[CH:40][CH:41]=[C:42]([CH3:43])[C:34]=4[CH3:33])=[CH:18][CH:17]=3)=[O:23])[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3cc(Cl)ccc32)cc1
Reactant: Cc1cccc(C(=O)Cl)c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C(=O)Nc2ccc(C(=O)N3Cc4ccccc4Cc4cc(Cl)ccc43)cc2)c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
As described for Example 136, a mixture of 0.349 g of 2-chloro-5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.131 g of triethylamine and 0.219 g of 2,3-dimethylbenzoyl chloride in 13 ml of dichloromethane is stirred at room temperature for 18 hours. Work-up gives a solid which is recrystallized from dichloromethane-hexane to give 0.38 g of crystals 191°-193° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C@H:19]1[C@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:23]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@@:22]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([CH2:50][C:51]3[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH:59]([F:61])[F:60])=[CH:53][CH:52]=3)[CH:44]=2)([O:41][CH3:42])[O:21][C@@H:20]1[CH2:62][OH:63])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([O:18][C@H:19]1[C@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:23]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@@:22]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([CH2:50][C:51]3[CH:52]=[CH:53][C:54]([O:57][CH2:58][CH:59]([F:60])[F:61])=[CH:55][CH:56]=3)[CH:44]=2)([O:41][CH3:42])[O:21][C@@H:20]1[CH:62]=[O:63])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)F)cc3)c2)O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)F)cc3)c2)O[C@H](C=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 89.2 %

Procedure:
Oxalyl chloride (0.18 mL, 2.16 mmol) was dissolved in 5 mL methylene chloride and cooled to −78° C., followed by dropwise addition of a solution (3 mL) of dimethyl sulfoxide (0.23 mL, 3.31 mmol) in methylene chloride, and the reaction mixture was stirred for 15 minutes. 10 mL solution of [(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2-difluoroethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 12h (1.23 g, 1.66 mmol) in methylene chloride were dropwise added before the mixture was stirred for 40 minutes. The reaction mixture was warmed to room temperature and stirred for 3 hours after triethylamine (1.2 mL, 8.31 mmol) was dropwise added. Thereafter, the reaction mixture was partitioned after 5 mL 1 M hydrochloric acid were added. The aqueous phase was extracted with ethyl acetate (20 mL×2) and the organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2-difluoro-ethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 12i (1.10 g, yellow grease), which was used directly in the next step without purification.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]5[CH:23]=[N:24][N:25]([C:27]([CH3:32])([CH3:31])[C:28](O)=[O:29])[CH:26]=5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:33]=2)=[N:7][C:6]([CH3:34])=[N:5]1)([CH3:3])[CH3:2].[NH4+].[Cl-].CC[N:39](C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]5[CH:23]=[N:24][N:25]([C:27]([CH3:32])([CH3:31])[C:28]([NH2:39])=[O:29])[CH:26]=5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:33]=2)=[N:7][C:6]([CH3:34])=[N:5]1)([CH3:2])[CH3:3]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C(C)(C)C(=O)O)c4)cc2OCC3)n(C(C)C)n1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C(C)(C)C(N)=O)c4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoic acid 251 (90 mg, 0.2 mmol) was dissolved in DMF (2 mL) and treated with NH4Cl (40 mg, 0.8 mmol), DIPEA (0.3 mL, 2 mmol) followed by N,N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU, 100 mg, 0.4 mmol). The mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate was added, and the mixture was extracted with EtOAc. The combined organics were dried over sodium sulfate and concentrated. The crude was purified by 10% MeOH/EtOAc following by trituration with minimal EtOAc to provide 74 mg (82% yield) of 196. LC/MS (ESI+): m/z 463 (M+H). 1H NMR (500 MHz, DMSO) δ 8.44-8.26 (m, 2H), 8.01 (s, 1H), 7.86 (s, 1H), 7.44 (dd, J=8.4, 1.8, 1H), 7.35 (d, J=1.7, 1H), 7.15 (s, 1H), 6.79 (s, 1H), 5.82 (dt, J=13.3, 6.6, 1H), 4.52 (s, 4H), 2.25 (s, 3H), 1.75 (s, 6H), 1.47 (d, J=6.6, 6H)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8](Cl)=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)=[O:5])[CH3:2].[SH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([S:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)=[O:5])[CH3:2]
Reactant: Oc1ccc(S)cc1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc([N+](=O)[O-])c(Sc2ccc(O)cc2)s1
Temperature: 25 °C

Procedure:
The product from Example 351A (1 equiv) and 4-mercaptophenol (1 equiv) were dissolved in dimethylformamide and cesium carbonate (5 equiv) added. The resultant mixture was stirred at 80° C. for 2.5 hours, cooled to room temperature and water added. The solution was extracted with ethyl acetate, the organic extracts dried and concentrated under vacuum to provide the title product.
Reaction SMILES: C([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[S:11][CH:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([OH:15])=O)(O)=O.[C:20]([O-])(=[O:22])[CH3:21].[Na+].C(OC(=O)C)(=O)C>O>[C:20]([O:15][C:13]1[C:6]2[CH:7]=[C:8]([Cl:10])[CH:9]=[CH:4][C:5]=2[S:11][C:12]=1[CH2:16][CH2:17][CH2:18][CH3:19])(=[O:22])[CH3:21]
Reactant: CC(=O)[O-]
Reactant: CCCCC(Sc1ccc(Cl)cc1C(=O)O)C(=O)O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCCCc1sc2ccc(Cl)cc2c1OC(C)=O
Temperature: 80 °C

Procedure:
A mixture of 2-(2'-carboxy-4'-chlorophenylthio)hexanoic acid (2.3 g, 7.6 mmol), anhydrous sodium acetate (1.0 g), and acetic anhydride (5 ml) was heated at 80° C. for 30 minutes. After gas evolution had ceased, the temperature was gradually raised to 120° C. which was maintained for 30 minutes. The cooled reaction mixture was then poured into water and extracted with diethyl ether. The combined ethereal extracts were washed with 1% aqueous sodium hydroxide solution, water, and saturated aqueous sodium chloride solution, dried (sodium sulfate) and evaporated. The residue was vacuum filtered through a pad of silica gel (Merck No. 7734) eluting with 25:1 hexane-ether to give 3-acetoxy-2-butyl-5-chlorobenzo[b]thiophene as a colorless oil; yield 1.1 g (40% overall from the 2-step sequence), m/z 282 (M+.).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH3:13])=[C:7](B(O)O)[CH:8]=1)=[O:2].Br[C:15]1[CH:25]=[CH:24][C:18]2[O:19][C:20]([F:23])([F:22])[O:21][C:17]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>O.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:23][C:20]1([F:22])[O:19][C:18]2[CH:24]=[CH:25][C:15]([C:7]3[CH:8]=[C:3]([CH:4]=[CH:5][C:6]=3[O:12][CH3:13])[CH:1]=[O:2])=[CH:16][C:17]=2[O:21]1
Reactant: COc1ccc(C=O)cc1B(O)O
Reactant: FC1(F)Oc2ccc(Br)cc2O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: O
Product: COc1ccc(C=O)cc1-c1ccc2c(c1)OC(F)(F)O2
Temperature: 25 °C
Reaction time: 16 h
Yield: 39 %

Procedure:
To a solution of 5-formyl-2-methoxy phenyl boronic acid (1.0 g, 5.5 mmol) in water (6 mL) and methanol (30 mL), was added 5-bromo-2,2-difluoro-1,3-benzodioxole (0.97 mL, 7.2 mmol), solid potassium carbonate (1.5 g, 11 mmol), and palladium(II) acetate (25 mg, 0.11 mmol). The reaction was stirred at room temperature for 16 h. The black mixture was diluted with water (30 mL) and extracted with ethyl acetate (2×30 mL). The combined extracts were decolorized with activated charcoal, dried over sodium sulfate, filtered, and concentrated to 20 mL under vacuum. The solution was purified by silica gel column chromatography eluting with hexanes/ethyl acetate (11:1) to give I-172 (620 mg, 39% yield) as a white solid.
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[CH:11]=[C:10]([C:12]([OH:14])=O)[N:9]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[N:8]=1.C(N(CC)CC)C.[NH2:29][C:30]1[C:38]([CH3:39])=[CH:37][C:36]([Cl:40])=[CH:35][C:31]=1[C:32](O)=[O:33]>C(#N)C>[Cl:40][C:36]1[CH:37]=[C:38]([CH3:39])[C:30]2[N:29]=[C:12]([C:10]3[N:9]([C:15]4[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=4)[N:8]=[C:7]([Cl:6])[CH:11]=3)[O:14][C:32](=[O:33])[C:31]=2[CH:35]=1
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Reactant: O=C(O)c1cc(Cl)nn1-c1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Cl)nn3-c3ncccc3Cl)nc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of methanesulfonyl chloride (6.96 g, 61.06 mmol) in acetonitrile (150 mL) was added dropwise a mixture of 3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (i.e. the carboxylic acid product of Step D) (15.0 g, 58.16 mmol) and triethylamine (5.88 g, 58.16 mmol) in acetonitrile (150 mL) at −5° C. The reaction mixture was then stirred for 30 minutes at 0° C. Then, 2-amino-3-methyl-5-chlorobenzoic acid (i.e. the product from Example 1, Step A) (10.79 g, 58.16 mmol) was added, and stirring was continued for an additional 10 minutes. A solution of triethylamine (11.77 g, 116.5 mmol) in acetonitrile was then added dropwise while keeping the temperature below 10° C. The reaction mixture was stirred 60 minutes at 0° C., and then methanesulfonyl chloride (6.96 g, 61.06 mmol) was added. The reaction mixture was then warmed to room temperature and stirred for an additional 2 hours. The reaction mixture was then concentrated, and the crude product was chromatographed on silica gel using methylene chloride as eluent to afford the title product as a yellow solid (9.1 g). 1H NMR (CDCl3) δ 1.81 (s, 3H), 7.16 (s, 1H), 7.51 (m, 2H), 7.98 (d, 2H), 8.56 (d, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:35][CH2:36]SC)[C:13]([NH:15][C@H:16]1[CH2:21][CH2:20][C@@H:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][C@H:17]1[CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+]>IC.CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:35][CH2:36][N:15]([C@H:16]2[CH2:21][CH2:20][C@@H:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH2:18][C@H:17]2[CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:13]1=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)C[C@H]1CS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](CS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 38 %

Procedure:
Tert-butyl (1R,3R,4S)-4-((S)-2-benzyloxycarbonylamino-4-(methylthio)butanamido)-3-(methylsulfonylmethyl)cyclohexylcarbamate (6.9 g) was dissolved in iodomethane (100 mL), and the resulting solution was stirred at rt for 72 h before being concentrated in vacuo. The residue was dissolved in methylene chloride, and the resulting solution was concentrated; this was repeated to afford the salt. MS found: (M+H)+=586.5. This material was dissolved in DMF (20 mL) and the solution was charged with Cs2CO3 (12.0 g). After 12 h, the reaction was partitioned between EtOAc and brine. The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford tert-butyl (1R,3R,4S)-4-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-3-(methylsulfonylmethyl)cyclohexylcarbamate (2.4 g). MS found: (M+H)+=524.3.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH:17]([CH3:19])[CH3:18].[Cl:20][C:21]1[N:22]=[C:23]([C:28](O)=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.CC(N(C)C)=O>[Cl:20][C:21]1[N:22]=[C:23]([C:28]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27]
Reactant: CC(C)CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OCC(C)C)nc1Cl
Yield: 86.7 %

Procedure:
The same operation as in Example (106d) was performed using tert-butyl cis(±)-4-amino-3-isobutoxypiperidine-1-carboxylate obtained in Example (117d) (1.26 g, 4.6 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (85% content, 1.02 g, 5 mmol), WSC hydrochloride (2.88 g, 15 mmol), HOBt (1.01 g, 7.5 mmol), DMA (15 mL) and dichloromethane (15 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 2/3, 3/2, 4/1) to obtain 1.71 g of the title compound as a colorless solid (87%).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[CH:8]1([NH:12][C:13]2[N:18]=[C:17]3[CH2:19][NH:20][CH2:21][CH2:22][C:16]3=[N:15][C:14]=2[N:23]2[CH2:28][CH2:27][CH:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=3[F:38])[CH2:25][CH2:24]2)[CH2:11][CH2:10][CH2:9]1.C(OC(=O)C)(=O)C.N1C=CC=CC=1>C(Cl)Cl>[CH:8]1([NH:12][C:13]2[N:18]=[C:17]3[CH2:19][N:20]([C:2](=[O:1])[CH3:4])[CH2:21][CH2:22][C:16]3=[N:15][C:14]=2[N:23]2[CH2:28][CH2:27][CH:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=3[F:38])[CH2:25][CH2:24]2)[CH2:9][CH2:10][CH2:11]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: COc1ccc(OC2CCN(c3nc4c(nc3NC3CCC3)CNCC4)CC2)c(F)c1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(OC2CCN(c3nc4c(nc3NC3CCC3)CN(C(C)=O)CC4)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of N-cyclobutyl-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (10.1 mg, 0.019 mmol), acetic anhydride (3.8 mg, 0.037 mmol) and pyridine (4 mg, 0.056 mmol) in DCM (190 μL) was stirred at room temperature for 30 min. The mixture was purified by HPLC Method A to give the title compound as a TFA salt (9.7 mg, 89%) as a yellow film. 1H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm 1.78-1.87 (m, 2H), 1.91-2.01 (m, 2H), 2.03-2.16 (m, 4H), 2.19 (s, 1.2H), 2.21 (s, 1.8H), 2.38-2.50 (m, 2H), 2.70-2.76 (m, 0.8H), 2.80-2.87 (m, 1.2H), 3.00-3.11 (m, 2H), 3.40-3.50 (m, 2H), 3.76 (s, 3H), 3.79-3.83 (m, 1.2H), 3.84-3.88 (m, 0.8H), 4.34-4.48 (m, 2H), 4.57 (s, 0.8H), 4.61 (s, 1.2H), 6.64-6.69 (m, 1H), 6.74 (dd, J=12.8, 2.9 Hz, 1H), 7.08 (t, J=9.2 Hz, 1H); ESI-MS m/z [M+H]+ 470.4.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:10]=[C:9]2[S:18][C:19]2[CH:24]=[CH:23][C:22](N)=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].[PH2](O)=O>Cl.O>[C:5]1([N:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:10]=[C:9]2[S:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1cn(-c2ccc(N)cc2)c(Sc2ccc(N)cc2)n1
Agent: Cl
Agent: O=N[O-]
Agent: O=[PH2]O
Solvent: O
Product: CCOC(=O)c1cn(-c2ccccc2)c(Sc2ccccc2)n1
Reaction time: 1 h
Yield: 67.3 %

Procedure:
Ethyl 1-(4-aminophenyl)-2-[(4-aminophenyl)thio]-1H-imidazole-4-carboxylate (1.90 g) was dissolved in concentrated hydrochloric acid (30 mL), and a solution of sodium nitrite (1.00 g) in water (5 mL) was added dropwise at 5-10° C. The mixture was stirred at the same temperature for 1 hr, and the obtained reaction mixture was added dropwise to 50% aqueous hypophosphorous acid solution (30 mL) by small portions. The mixture was stirred at room temperature for 3 hr, and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a yellow oil (yield 1.17 g, 67%).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[F:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH2:14]Br>>[F:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH2:14][N:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[C:2]([I:1])=[N:3]1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: Ic1n[nH]c2ncccc12
Product: Fc1ccc(Cn2nc(I)c3cccnc32)c(F)c1
Temperature: 0 °C

Procedure:
Analogously to the synthesis of Example 7A, 54.00 g (215.98 mmol) of 3-iodo-1H-pyrazolo[3,4-b]pyridine (synthesis described in WO 2006/130673, Example 4) were reacted with 50.18 g (237.578) of 2,4-difluorobenzyl bromide. Ice-water was added to the crude product, the mixture was filtered off with suction and the precipitate was washed with isopropanol and pentane and then dried under high vacuum. This gave 76.7 g of the title compound (89% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[N:4][CH:3]=1.CC#N.N1C=CC=CC=1.[C:17]1([O:23][C:24](Cl)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:24](=[O:25])[O:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:3][N:4]=1
Reactant: Nc1ccnnc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CC#N
Product: O=C(Nc1ccnnc1)Oc1ccccc1
Reaction time: 18 h
Yield: 35.3 %

Procedure:
A solution of 4-aminopyridazine (2.5 g, 26.3 mmol) in a mix of 1:1 THF:MeCN (20 mL), and pyridine (2.18, 27.6 mmol) was treated dropwise with phenylchloroformate (1.3 g, 27.6 mmol) in THF (10 mL). After stirring for 18 h, the resulting solid was collected and dried to provide the title compound (2 g, 37%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[O:16][C:15]=3[CH2:23][CH2:24][CH2:25][CH3:26])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:27].Br[CH2:29][C:30]([O:32]C)=[O:31]>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[O:16][C:15]=3[CH2:23][CH2:24][CH2:25][CH3:26])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:27][CH2:29][C:30]([OH:32])=[O:31]
Reactant: COC(=O)CBr
Reactant: CCCCc1oc2ccccc2c1C(=O)c1ccc2c(Br)c(O)ccc2c1
Product: CCCCc1oc2ccccc2c1C(=O)c1ccc2c(Br)c(OCC(=O)O)ccc2c1

Procedure:
The title compound was prepared from 1-bromo-6-(2-butyl-benzofuran-3-carbonyl)-naphthalen-2-ol, and methyl bromoacetate, in substantially the same manner, as described in Example 4, and was obtained as a white solid, mp 163-165° C.; MS m/e 680 (M+);
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([CH:29]([CH3:33])[C:30](O)=[O:31])=[CH:25][CH:24]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[NH2:36][CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[N:39]1([CH2:38][CH2:37][NH:36][C:30](=[O:31])[CH:29]([C:26]2[CH:27]=[CH:28][C:23]([C:21]3[CH:20]=[N:19][N:18]4[C:14]([C:10]5[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:35])([F:34])[F:1])=[O:6])[CH:9]=5)=[CH:15][N:16]=[C:17]4[CH:22]=3)=[CH:24][CH:25]=2)[CH3:33])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1
Reactant: NCCN1CCOCC1
Reactant: CC(C(=O)O)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1
Product: CC(C(=O)NCCN1CCOCC1)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1

Procedure:
This compound was prepared by using procedure analogous to those described for the synthesis of Example 98, Step 9 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}phenyl)propanoic acid and N-(2-aminoethyl)morpholine. LCMS (M+H)+: m/z=596.3.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH3:13])=[O:11])(OCC)=O)C.[H-].[Na+].[C:16]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:29][CH3:30])[CH:25]=2)[CH:20]=1)(=O)[CH3:17].[NH4+].[Cl-]>C1COCC1.O>[CH3:30][O:29][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([C:16]([CH3:17])=[CH:9][C:10]([O:12][CH3:13])=[O:11])[CH:28]=[CH:27]2
Reactant: COc1ccc2cc(C(C)=O)ccc2c1
Reactant: CCOP(=O)(CC(=O)OC)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C=C(C)c1ccc2cc(OC)ccc2c1
Yield: 58.5 %

Procedure:
Methyl diethylphosphonoacetate (1.6 g, 7 5 mmol) and NaH (0.19 g, 7.5 mmol) in THF (25 mL) was added to 2-acetyl-6-methoxynaphthalene (1.5 g, 7.5 mmol) in THF (50 mL) at 23° C. under nitrogen. After refluxing for 20 hours, the reaction mixture was cooled, saturated NH4Cl added, and the mixture poured into water. The solution was extracted with ether and the organic extracts were dried (MgSO4) and the solvent evaporated. Chromatography (silica gel, ether/pentane) afforded methyl 3-(6-methoxy-2-naphthyl)-2-butenoate (0.75 g). This intermediate (0.51 g, 2 mmol) in methanol (50 mL) was hydrogenated with 20% Pd/C (50 mg) at 3 atm at 23° C. until the theoretical amount of hydrogen was taken up. Removal of solvent and catalyst gave the crude ester which was dissolved in isopropanol/water : 2/1 (40 mL). Lithium hydroxide (82 mg, 2 mmol) was added and the reaction mixture stirred at 23° C. for 1 hour. Saturated ammonium chloride was added and the mixture extracted with ethyl acetate. Removal of solvent followed by recrystallization from methanol/water gave 3-(6-methoxy-2-naphthyl) butyric acid (0.45 g). Bromine (3 mL of a 1M solution in CCl4, 3 mmol) was added slowly to the acid (0.37 g, 1.5 mmol) and PBr3 (0.4 g, 1.5 mmol) in CCl4 (20 mL) at 23° C. under nitrogen. The mixture was heated at 80° C. for 20 hours. The mixture was then cooled and poured into ice water. Extraction with benzene followed by drying (Na2SO4) and evaporation gave a crude residue which was distilled under reduced pressure (0.5 mm) to afford 2-bromo-3-(6-methoxy-2-naphthyl)butyrylbromide (0.55 g). 1H NMR(60 MHz, DMSO-d6): 1.30 (3H, d J=7 Hz), 3.80 (3H, s), 4.01 (1H, g, J=7 Hz), 4.20 (1H, d, J=7 Hz), 7.0-8.0 (6H, m); Mass Spectrum: 386(M+).