Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][O:40][C:41]1[CH:42]=[C:43]([NH:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH:44]=[CH:45][C:46]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:39][O:40][C:41]1[CH:42]=[C:43]([NH:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH:44]=[CH:45][C:46]=1[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: COc1cc(NS(C)(=O)=O)ccc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cc(NS(C)(=O)=O)ccc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Yield: 76.7 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (170 mg, 0.29 mmol) was treated with N-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (190 mg, 0.58 mmol, described at WO 2012015723 A1 20120202), sodium carbonate (100 mg, 0.94 mmols) and bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (50 mg, 0.06 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 80%, hexane-ethyl acetate) to give 159 mg (71% yield) of the title compound. Purity 91%.
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH3:7][CH2:6][O:5][C:3]([C:2]([O:17][C:14]1[CH:13]=[CH:12][C:11]([Cl:10])=[CH:16][CH:15]=1)([CH3:9])[CH3:8])=[O:4]
Reactant: Oc1ccc(Cl)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 2-bromo-2-methyl-propanoate and p-chlorophenol was dissolved in dry acetone and treated with potassium carbonate. After stirring at rt for 30 min., the mixture was refluxed for 16 h. The reaction mixture was poured into water and extracted with DCM. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (silica, hexanes:EtOAc, 9:1, 6:1 to 3:1) to give the desired product, which was used in the following step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[C:6]([NH:12][C:13]3[N:18]=[C:17]([NH:19][CH:20]4[CH2:37][CH2:36][C:23]5([CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)[CH2:22][CH2:21]4)[C:16]([CH3:38])=[CH:15][N:14]=3)[CH:7]=[CH:8]2)=[N:3]1.Cl>C(OCC)(=O)C>[CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[C:6]([NH:12][C:13]3[N:18]=[C:17]([NH:19][CH:20]4[CH2:37][CH2:36][C:23]5([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[CH2:22][CH2:21]4)[C:16]([CH3:38])=[CH:15][N:14]=3)[CH:7]=[CH:8]2)=[N:3]1
Reactant: Cc1cnc(Nc2ccc3c(C)n(C)nc3c2)nc1NC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1cnc(Nc2ccc3c(C)n(C)nc3c2)nc1NC1CCC2(CCNCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To tert-butyl 9-((2-((2,3-dimethyl-2H-indazol-6-yl)amino)-5-methylpyrimidin-4-yl)amino)-3-azaspiro[5.5]undecane-3-carboxylate (1.04 g, 2.00 mmol) was added a solution of hydrogen chloride in ethyl acetate (8 mL, 3 mol/L). The reaction was stirred at rt overnight and then concentrated in vacuo. The residue was diluted with Na2CO3 solution (sat, 100 mL), the mixture was extracted with DCM/MeOH (10/1, 150 mL×3). The organic layers were dried with Na2SO4, filtered and concentrated in vacuo to give the title compound as a yellow solid (804 mg, 95.8%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]#[N:17])([CH2:14][CH3:15])[CH2:9][CH2:10][C:11](O)=[O:12])=[CH:4][CH:3]=1.[OH:18]S(O)(=O)=O.[OH-].[Na+]>C(O)(=O)C>[CH3:15][CH2:14][C@@:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[C:16](=[O:18])[NH:17][C:11](=[O:12])[CH2:10][CH2:9]1
Reactant: O=S(=O)(O)O
Reactant: CCC(C#N)(CCC(=O)O)c1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC[C@]1(c2ccc(N)cc2)CCC(=O)NC1=O
Temperature: 60 °C
Yield: 97 %

Procedure:
4-(4-Aminophenyl)-4-cyanohexanoic acid (Example 9; 1.8 g, 7.7 mmol), enriched in the (R)-enantiomer, was dissolved in glacial acetic acid (6.0 ml) contained in a 25 ml round-bottomed flask. The resulting mixture was heated to 60° C. with the aid of an oil bath followed by dropwise addition of conc. H2SO4 (3.0 ml). The solution was then heated to 100° C. and maintained there for 30 minutes before pouring onto ice (100 g). The pH is adjusted to 6 using 5M NaOH followed by extraction with dichloromethane (3×200 ml). The extracts were pooled, dried (over MgSO4) and concentrated under reduced pressure, giving (R)-aminoglutethimide (1.75 g, 97%) as a brown oil. Chiral HPLC analysis (Chiralcel OJ column; mobile phase 1:1 n-heptane-isopropanol) indicated an ee of 78%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.O.[Se](=O)=[O:22]>O1CCOCC1>[OH2:2].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([C:17](=[O:19])[CH:18]=[O:22])=[CH:15][CH:16]=2)=[CH:7][CH:8]=1
Reactant: O=[Se]=O
Reactant: COc1ccc(COc2ccc(C(C)=O)cc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(COc2ccc(C(=O)C=O)cc2)cc1

Procedure:
A 10.0 g portion of 1-[4-[(4-methoxyphenyl)-methoxy]phenyl]ethanone was dissolved in 50 ml of hot p-dioxane. A 2.0 ml portion of water and 4.4 g of selenium dioxide were added and the mixture was stirred at reflux for 67 hours, then cooled and filtered through diatomaceous earth. The filtrate was poured into 300 ml of water and the solid collected. This solid was extracted with eight 100 ml portions of ethyl acetate. The extracts were combined, washed with water, dried and evaporated. The residue was dissolved in 100 ml of boiling toluene, treated with charcoal and filtered through diatomaceous earth. The filtrate was treated with 200 ml. of hexane, giving the desired product as a pale yellow solid, m.p. 127°-138° C.
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([C:22]#[N:23])[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.ClCCCN1CC[S:31]CC1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]#[N:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][S:31][CH2:3][CH2:2]1
Reactant: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: ClCCCN1CCSCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC1(c2ccc(OCCCN3CCSCC3)cc2)CCOCC1
Yield: 28.5 %

Procedure:
4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile (750 mg, 3.69 mmol), 4-(3-chloro-propyl)-thiomorpholine (1.06 g, 5.91 mmol), DMF (15 ml) and K2CO3 (2.05 g, 14.83 mmol) were reacted together according to general procedure E. Purification by chromatography on silica, eluant DCM:MeOH:NH3 (96:3:1) provided the title compound (365 mg, 29%) as an off white solid. 1H NMR (400 MHz, CDCl3), δ 7.37 (d, 2H), 6.93 (d, 2H), 4.12-4.04 (m, 2H), 4.01 (t, 2H), 3.89 (td, 2H), 2.77-2.64 (m, 8H), 2.54 (t, 2H), 2.16-1.99 (m, 4H), 1.95 (p, 2H).
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[CH2:9]1COC[CH2:10]1.C([Mg]Br)C.B(F)(F)F>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].O>[N:4]1[CH:5]=[CH:6][CH:7]=[N:8][C:3]=1[C:1]1([NH2:2])[CH2:10][CH2:9]1
Reactant: N#Cc1ncccn1
Reactant: C1CCOC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: CC[Mg+]
Solvent: O
Product: NC1(c2ncccn2)CC1
Reaction time: 0.25 h

Procedure:
2-Cyano pyrimidine (5 g, 47.6 mmol, 1 eq) was taken in a Dry THF under Argon atmosphere, then Titanium isopropoxide (17 ml, 57.1 mmol, 1.2 eq) was added slowly at ambient temperature and the reaction mixture was stirred for 15 mins. Ethyl magnesium bromide (1M solution) in THF (107 ml, 809 mmol, 2.5 eq) was added via syringe slowly at ambient temperature, (During the addition of EtMgBr reaction mass becomes black). Then the reaction mass was stirred for an hour. BF3.EtO (16.7 ml, 119.0 mmol, 2.5 eq) was added slowly through syringe at 0° C. The mixture was allowed to attain ambient temperature and stirred for another one hour. 50 ml of Water was added to the reaction mixture and filtered through the Celite and washed the bed with water and Ethyl acetate. The reaction mass was basified with 10% NaOH solution (pH=9) then extracted with DCM and washed with brine solution. The required product was purified by silica gel (230-400) column chromatography using DCM/methanol as the eluent. Yield: 2.1 g (30%). 1H NMR (400 MHz, DMSO-d6): δ 1.49-1.52 (m, 2H), 1.59-1.62 (m, 2H), 7.47-7.49 (t, 1H, J=4.80), 8.83-8.84 (d, 2H, J=4.80).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([C:11]([OH:13])=O)=[CH:7][C:6]=2[CH:5]=[C:4]([F:14])[CH:3]=1.Cl.Cl.[NH2:17][C@@H:18]1[CH:23]2[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]2)[CH2:19]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:20]12[CH2:25][CH2:24][CH:23]([CH2:22][CH2:21]1)[C@@H:18]([NH:17][C:11]([C:8]1[O:9][C:10]3[C:2]([Br:1])=[CH:3][C:4]([F:14])=[CH:5][C:6]=3[CH:7]=1)=[O:13])[CH2:19]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)c1cc2cc(F)cc(Br)c2o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc(F)cc(Br)c2o1
Reaction time: 0.33 h

Procedure:
143 mg (0.55 mmol) of 5-fluoro-7-bromo-1-benzofuran-2-carboxylic acid (Example 4A), 100 mg (0.50 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 229.14 mg (0.6 mmol) of HATU, 234 mg (1.81 mmol) of N,N-diisopropylethylamine and 2.0 ml of DMF are reacted by general method C. DMF is removed under reduced pressure, and the crude product is dissolved in 1N sodium hydroxide solution. The aqueous phase is extracted with ethyl acetate, and the organic phase is washed with saturated aqueous sodium chloride solution. The combined organic phases are dried over magnesium sulphate, and the solvent is removed in a rotary evaporator under reduced pressure. The crude product is taken up in methanol and shaken together with acidic ion exchanger (Dowex® WX2-200) for about 20 min. The loaded ion exchanger is washed three times with 30 ml of methanol each time, then with water, again with methanol, with dichloromethane and finally again with methanol. The product is eluted with methanol/triethylamine 95:5. The solvent is removed in a rotary evaporator under reduced pressure. 181 mg (98% of theory) of the title compound are isolated.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[O:13][C:12]=2[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][CH2:32]Cl)[CH3:28]>>[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][CH2:32][O:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[O:13][C:12]=2[C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1)[CH3:28]
Reactant: CCN(CC)CCCCl
Reactant: Cc1ccc(-c2oc3ccccc3c2S(=O)(=O)c2ccc(O)cc2)cc1
Product: CCN(CC)CCCOc1ccc(S(=O)(=O)c2c(-c3ccc(C)cc3)oc3ccccc23)cc1

Procedure:
Reaction of 3-(4-hydroxyphenylsulfonyl)-2-(4-tolyl)benzofuran with 3-diethylaminopropyl chloride according to the procedure described in Example 1 gives the title compound.
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:10][C:9]([C:19](OCC)=[O:20])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[C:1]1([N:7]2[C:11]([NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:10][C:9]([CH2:19][OH:20])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cc(Nc2ccccc2)n(-c2ccccc2)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCc1cc(Nc2ccccc2)n(-c2ccccc2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 106.8 %

Procedure:
A solution of ethyl 1-phenyl-5-(phenylamino)-1H-pyrazole-3-carboxylate (345 mg) in tetrahydrofuran (10 mL) was cooled to −78° C., and a 1.5 mol/L solution (3.7 mL) of diisobutylaluminum hydride in toluene was added dropwise. After stirring at 0° C. for 1 hr, the mixture was treated with 1 mol/L hydrochloric acid, and extracted with ethyl acetate. The extract was washed with 1 mol/L hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=2:1→1:2) to give the title compound as a pale-yellow oil (yield 318 mg, yield quantitative).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[F:5][C:6]([C:41]([F:44])([F:43])[F:42])([O:10][C:11]([F:40])([F:39])[C:12]([F:38])([C:34]([F:37])([F:36])[F:35])[O:13][C:14]([F:33])([F:32])[C:15]([F:31])([C:27]([F:30])([F:29])[F:28])[O:16][C:17]([F:26])([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[C:7](F)=[O:8].Cl>>[CH2:1]([NH:4][C:7](=[O:8])[C:6]([F:5])([C:41]([F:42])([F:43])[F:44])[O:10][C:11]([F:39])([F:40])[C:12]([F:38])([C:34]([F:35])([F:36])[F:37])[O:13][C:14]([F:32])([F:33])[C:15]([F:31])([C:27]([F:30])([F:29])[F:28])[O:16][C:17]([F:26])([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[CH:2]=[CH2:3]
Reactant: O=C(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F
Reactant: C=CCN
Agent: Cl
Product: C=CCNC(=O)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F
Yield: 51.7 %

Procedure:
A 100 mL round bottom flask equipped with a magnetic stirring bar and an addition funnel was charged with 9.0 g of allyl amine (160 mmoles). The liquid was stirred and 40 g of 97% perfluoro-2,5,8-trimethyl-3,6,9-trioxadodecanoyl fluoride (60 mmoles) was added dropwise. Dilute hydrochloric acid was added to the flask and the two phase mixture was transferred into a separatory funnel and the aqueous layer separated from the amide layer. The amide layer was washed again with dilute hydrochloric acid and twice with water. The amide layer was transferred into a round bottom flask and distilled at 101° C. and 3 mmHg to yield a fraction of 21.6 (52% yield) of >99% N-allylperfluoro-2,5,8-trimethyl-3,6,9-trioxadodecanamide (31 mmoles).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[NH:9][C:8]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=4)=[N:19][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.C[N:38](C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[Cl-].[NH4+]>C(OCC)(=O)C.O.CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[NH:9][C:8]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:22]=[CH:23][C:24]([C:25]([NH2:38])=[O:26])=[CH:28][CH:29]=4)=[N:19][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3)cc1
Reactant: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: NC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.7 %

Procedure:
To a mixture of 0.05 g (0.12 mmole) of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid (I-131) and 0.06 g (0.15 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 2 mL of dimethylformamide was added 0.03 mL (0.186 mmole) of diisopropylethylamine. After stirring at room temperature for 30 minutes, 0.01 g (0.186 mmole) of ammonium chloride was then added. The mixture was stirred at room temperature for 18 hours and then diluted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate, and the combined organic layers washed with water, then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with hot methanol to give 0.01 g of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzamide (I-132).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:16]([C:18]2[C:19]([O:25][C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=3[Cl:33])=[N:20][CH:21]=[C:22]([F:24])[CH:23]=2)=[O:17])[CH2:8][CH2:7]1)C.[OH-].[Na+]>C1COCC1>[Cl:33][C:27]1[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=1[O:25][C:19]1[C:18]([C:16]([N:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:6]([CH2:5][C:4]([OH:34])=[O:3])[CH2:7][CH2:8]2)=[O:17])=[CH:23][C:22]([F:24])=[CH:21][N:20]=1
Reactant: CCOC(=O)CN1CCN(C(=O)c2cc(F)cnc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CN1CCN(C(=O)c2cc(F)cnc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Temperature: 120 °C
Yield: 9.7 %

Procedure:
To a solution of {4-[2-(2,5-dichloro-phenoxy)-5-fluoro-pyridine-3-carbonyl]-3,4-dihydro-2H-quinoxalin-1-yl}-acetic acid ethyl ester (82 mg, 0.163 mmol, 1.0 equiv; Example 154) in THF (1 mL) was added a 5 M solution of sodium hydroxide (0.5 mL, 2.5 mmol, 15 equiv; [CAS RN 1310-73-2]) and the reaction mixture heated by microwave irradiation to 120° C. for 30 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 7.5 mg (10%) of the title compound as a light yellow powder. MS (ISP): 476.0 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][C:12]=2[C:13]([O:15]C)=[O:14])[N:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>CO.C1COCC1.O>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][C:12]=2[C:13]([OH:15])=[O:14])[N:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCc1ccc(Nc2cc(C(C)(C)C)nn2-c2ccccc2C)c(C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(Nc2cc(C(C)(C)C)nn2-c2ccccc2C)c(C(=O)O)c1
Temperature: 40 °C
Yield: 100.1 %

Procedure:
To a solution of methyl 2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-5-ethylbenzoate (Example 235, 115 mg, 0.29 mmol) in a mixture of methanol (1 mL) and THF (1 mL) was added lithium hydroxide monohydrate (123 mg, 2.94 mmol) in water (2 mL), and the mixture was heated to 40° C. for 1 h. The reaction mixture was then cooled to rt, and the pH of the solution was adjusted to 5 using 0.5 N aq HCl. The solvent was removed under reduced pressure, and the residue was subjected to HPLC purification using gradient elution from 10% to 90% acetonitrile in water to afford 109.6 mg (99%) of the title compound. 1H NMR (300 MHz, CD2Cl2) δ 9.28 (s, 1H), 7.76 (s, 1H), 7.26-7.37 (m, 6H), 6.15 (s, 1H), 2.60 (q, 2H), 2.08 (s, 3H), 1.37 (s, 9H), 1.23 (t, 3H). ES-MS m/z 378.3 (MH+); HPLC RT (min) 3.64.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH2:22][C:21](NCCN(C)C)=[CH:20][C:19]2=[O:29])=[CH:4][CH:3]=1.ClC1C=CC(C2N=C3C=CC=CN3C=2CN2CC(OC)=CC2=O)=CC=1.[NH:55]1[CH2:60][CH2:59][CH:58]([OH:61])[CH2:57][CH2:56]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH2:22][C:21]([N:55]3[CH2:60][CH2:59][CH:58]([OH:61])[CH2:57][CH2:56]3)=[CH:20][C:19]2=[O:29])=[CH:6][CH:7]=1
Reactant: OC1CCNCC1
Reactant: CN(C)CCNC1=CC(=O)N(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)C1
Agent: COC1=CC(=O)N(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)C1
Product: O=C1C=C(N2CCC(O)CC2)CN1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12

Procedure:
The title compound was prepared according to the experimental for compound 237 from 1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-4-methoxy-1H-pyrrol-2(5H)-one and piperidin-4-ol. (49 mg, 41%) m/e+=423 (M+H+). 1H-NMR (400 MHz, CDCl3, δ): 8.47 (d, 1H, D, J=7.0 Hz), 7.73 (d, 2H, D, J=8.4 Hz), 7.62 (d, 1H, D, J=9.2 Hz), 7.47 (d, 2H, D, J=8.8 Hz), 7.25 (t, 1H, D, J=7.3 Hz), 6.85 (t, 1H, D, J=7.3 Hz), 5.09 (s, 2H), 4.73 (s, 1H), 3.87 (m, 1H), 3.57 (s, 2H), 3.25 (m, 2H), 2.87 (m, 2H), 1.7 (m, 4H).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]([CH3:17])[CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1.[Cl:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>O1CCOCC1.CO>[Cl:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21]([NH:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N:9]([CH3:17])[CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[C:2]=1[F:1])=[O:22]
Reactant: CN1CCC(N(C)c2cccc(N)c2F)CC1
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN1CCC(N(C)c2cccc(NC(=O)c3ccc(F)cc3Cl)c2F)CC1
Yield: 100 %

Procedure:
Heat 2-fluoro-N-methyl-N-(1-methyl-piperidin-4-yl)-benzene-1,3-diamine (Preparation 22, 44 mg) with 2-chloro-4-fluorobenzoyl chloride (40 mg) in 1,4-dioxane (5 mL) at reflux for 2 hr. Dilute the reaction mixture with methanol (5 mL) and load on a SCX column (10 g). After wash with methanol, elute the product with 2 M NH3 in methanol, evaporate to give 73 mg of the title compound: mass spectrum (electric spray) m/z=394 (M+1); 1H NMR (CDCl3): 8.29 (br d, 1H), 7.94 (t, 1H), 7.81 (dd, 1H), 7.18 (dd, 1H), 7.05 (m, 2H), 6.77 (ddd, 1H), 3.15 (m, 1H), 2.72 (s, 3H), 2.26 (s, 3H), 1.96 (m, 2H), 1.83 (m, 2H), 1.70 (m, 2H).
Reaction SMILES: [CH3:1][O:2][P:3]([O:22][CH3:23])([C:5](=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([OH:21])[CH:14]=1)[C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7])=[O:4].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][P:3]([O:22][CH3:23])([C:5](=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:14]=1)[C:6]([O:8][CH:9]([CH3:10])[CH3:11])=[O:7])=[O:4]
Reactant: COc1ccc(C=C(C(=O)OC(C)C)P(=O)(OC)OC)cc1O
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCOc1cc(C=C(C(=O)OC(C)C)P(=O)(OC)OC)ccc1OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Isopropyl 2-(dimethoxyphosphinyl)-3-(3-hydroxy-4-methoxy-phenyl)propenoate (2 g; 0.0058 mol; Table 1, No. 26), 1-bromohexane (0.85 ml; 0.006 mol), 30 ml of dimethylformamide (DMF) and potassium carbonate (ground, 0.89 g; 0.0065 mol) were mixed and stirred at room temperature for 6 hours. The filtrate after removal of the inorganic salts was evaporated under reduced pressure. Residues of DMF were removed from the resulting oily residue in a kugelrohr apparatus at 70° C./0.02 mm Hg, and it was then chromatographed on silica gel eluting with a dichioromethane:ethane acetate (8:2) mixture. This resulted in a pale oil. Yield: 3.6 g (72.5% of theory)