Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[C:14]2[S:18][N:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[N:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[C:38]([C:43]3[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([F:52])([F:51])[F:50])[CH:44]=3)[CH:39]=[CH:40][C:41]=2[OH:42])=[CH:32][N:31]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([S:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[C:14]2[S:18][N:17]=[CH:16][N:15]=2)(=[O:11])=[O:12])[CH:6]=[CH:7][C:8]=1[O:42][C:41]1[CH:40]=[CH:39][C:38]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([F:50])([F:51])[F:52])[CH:44]=2)=[CH:37][C:36]=1[C:33]1[CH:34]=[CH:35][N:30]=[N:31][CH:32]=1)#[N:2]
Reactant: Oc1ccc(-c2cccc(C(F)(F)F)c2)cc1-c1ccnnc1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(-c4cccc(C(F)(F)F)c4)cc3-c3ccnnc3)c(C#N)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 109.7 %

Procedure:
To a solution of 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 19, 206 mg, 0.474 mmol) and 3-pyridazin-4-yl-3′-(trifluoromethyl)biphenyl-4-ol (Preparation 3, 150 mg, 0.474 mmol) in dimethylsulfoxide (5 mL) was added potassium carbonate (196 mg, 1.42 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with a 1M aqueous solution of sodium hydroxide whereupon a fine precipitate formed. The mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford the title compound as an oil (380 mg, 111%, contains residual dimethylsulfoxide). The material was used without purification in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][CH3:10])[CH:5]=[C:4]([CH3:11])[C:3]=1[C:12]1[C:13](=[O:19])[CH2:14][CH2:15][C:16]=1[O:17]C.Cl.O.C(OCC)(=O)C>CC(C)=O>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][CH3:10])[CH:5]=[C:4]([CH3:11])[C:3]=1[CH:12]1[C:13](=[O:19])[CH2:14][CH2:15][C:16]1=[O:17]
Reactant: CC#Cc1cc(C)c(C2=C(OC)CCC2=O)c(C)c1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC#Cc1cc(C)c(C2C(=O)CCC2=O)c(C)c1
Temperature: 60 °C

Procedure:
To a solution of 2-(2,6-dimethyl-4-prop-1-ynylphenyl)-3-methoxycyclopent-2-enone (0.193 g, 0.76 mmol) in acetone (2.0 ml) is added 2M hydrochloric acid (2.0 ml). The mixture is heated at 60°C. under microwave irradiation for 20 minutes, then distilled water and ethyl acetate are added and the phases separated. The aqueous phase is extracted with ethyl acetate (×3), and combined organic fractions are washed with brine, dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo. The crude product is purified by flash column chromatography (ethyl acetate and isohexane as eluant) to afford 2-(2,6-dimethyl-4-prop-1-ynylphenyl)cyclopentane-1,3-dione.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18](=[O:31])[C:19]([C:28](O)=[O:29])=[CH:20][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[CH:22]=2)=[CH:13][CH:12]=1.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.[NH2:59][C:60]1[CH:65]=[CH:64][C:63]([C:66]2[C:67]([NH2:73])=[N:68][CH:69]=[C:70]([Br:72])[CH:71]=2)=[CH:62][CH:61]=1>CN(C=O)C.O>[NH2:73][C:67]1[C:66]([C:63]2[CH:62]=[CH:61][C:60]([NH:59][C:28]([C:19]3[C:18](=[O:31])[C:17]([C:14]4[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=4)=[CH:22][N:21]([CH2:23][C:24]([F:26])([F:25])[F:27])[CH:20]=3)=[O:29])=[CH:65][CH:64]=2)=[CH:71][C:70]([Br:72])=[CH:69][N:68]=1
Reactant: Nc1ccc(-c2cc(Br)cnc2N)cc1
Reactant: O=C(O)c1cn(CC(F)(F)F)cc(-c2ccc(F)cc2)c1=O
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)cc1-c1ccc(NC(=O)c2cn(CC(F)(F)F)cc(-c3ccc(F)cc3)c2=O)cc1
Reaction time: 0.42 h
Yield: 89.9 %

Procedure:
DIPEA (414 μl) was added to a solution of the compound obtained in Step 2 of Example 9 (500 mg) and COMU (883 mg) in DMF (8.0 ml) at room temperature, and the mixture was stirred for 25 minutes. The compound obtained in Step 1 of Example 1 (440 mg) was added at room temperature. The mixture was stirred for 19 hours, followed by the addition of water. The precipitated solid was collected by filtration, suspended in chloroform/diisopropyl ether and then collected by filtration to give 800 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:21])=[O:20])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Nc1ccc(F)c2cccnc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc(F)c2cccnc12)c1ccccc1
Yield: 60.5 %

Procedure:
In a similar fashion using route 14 general procedure 27, 5-fluoroquinolin-8-amine (Intermediate 50) (150 mg, 0.93 mmol), benzenesulfonyl chloride (196 mg, 1.11 mmol) and DMAP (cat) gave the title compound (170 mg, 61%) after column chromatography with DCM eluent.
Reaction SMILES: [CH:1](=[CH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:17]([CH3:20])([O-:19])=[O:18].C(NCC)C>CO>[N+:17]([CH2:20][CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])([O-:19])=[O:18]
Reactant: C[N+](=O)[O-]
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Solvent: CCNCC
Solvent: CO
Product: O=C(CC(C[N+](=O)[O-])c1ccccc1)c1ccccc1
Yield: 96.3 %

Procedure:
In a 1 L flask, 94.7 g (0.455 mol) of benzylideneacetophenone were dissolved in 600 g of methanol, admixed with 138.9 g (2.275 mol) of nitromethane and 166.4 g (2.275 mol) of diethylamine and refluxed for 16 h. The solvent was half distilled off in vacuo and the precipitated solid was separated off and dried to constant weight in vacuo to obtain 118 g (438 mmol) of 4-nitro-1,3-diphenylbutan-1-one.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH3:9][C:10](C)([O-])C.[K+].C(I)C>C(O)C>[CH2:9]([S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH2:1])[CH3:10]
Reactant: CC(C)(C)[O-]
Reactant: Nc1ccccc1S
Agent: [K+]
Solvent: CCO
Solvent: CCI
Product: CCSc1ccccc1N
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 84.8 %

Procedure:
2-Aminothiophenol (5.0 g, 40 mmol, Lancaster Synthesis Inc., Windham, N.H.) was stirred in dry ethanol (100 mL) and cooled in an ice bath. Potassium t-butoxide (4.5 g, 40 mmol) was added portionwise over 15 minutes and the mixture was stirred for an additional 45 minutes. Ethyl iodide (3.3 mL, 41 mmol) was added dropwise over 15 minutes and the mixture was allowed to warm to room temperature and stirred for 45 minutes. The mixture was filtered and the filtrate evaporated to dryness in vacuo. The resulting residue was treated with dichloromethane (100 mL) and filtered and the resulting filtrate was evaporated to dryness in vacuo to give 2-(ethylthio)aniline (5.2 g).
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=2)[CH:8]=1)=[O:6])([CH3:3])[CH3:2].[C:25]1([C:31]([OH:35])([C:33]#[CH:34])[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>CN(C=O)C.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl.[Cu]I>[CH:1]([NH:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:34]#[C:33][C:31]([OH:35])([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:32])[CH:19]=2)[CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Reactant: C#CC(C)(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)c1cn(-c2cccc(C#CC(C)(O)c3ccccc3)c2)c2ncccc2c1=O
Temperature: 85 °C
Reaction time: 3 h

Procedure:
A mixture of N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from Step 4 of PREPARATIVE EXAMPLE 1, 2-phenyl-3-butyn-2-ol (2 eq), triethylamine (1.66 eq), bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 eq), and copper (I) iodide (5 mg/mmol) in DMF (20 mL/mmol) was heated at 85° C. for 18 hours. After cooling to room temperature, the resulting mixture was quenched with saturated aqueous ammonium chloride solution and partitioned between ethyl acetate and water. The crude product from the organic phase was chromatographed on silica gel eluting with 20% ether in methylene chloride. The purified product was stirred in ether at room temperature for 3 hours and filtered to afford the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22](CN)[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:8]=1)=[O:5].CC(O)=O.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:46][N:47]([CH:49]=O)[CH3:48]>>[Cl:1][C:2]1[CH:23]=[C:22]([CH2:49][N:47]([CH3:46])[CH3:48])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:8]=1)=[O:5]
Reactant: NCc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: CN(C)C=O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(C)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reaction time: 16 h

Procedure:
2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(aminomethyl)benzamide (80 mg, 0.20 mmol) was dissolved in DMF (5 mL) and treated with AcOH (10 uL), paraformaldehyde (43 mg, 0.47 mmol), and sodium triacetoxyborohydride (125 mg, 0.59 mmol). After stirring for 16 h, the solvent was evaporated and the residue was dissolved in ethyl acetate. The organic layer was washed with 1 N Sodium hydroxide, dried (MgSO4) and concentrated. The crude product was purified by reverse phase HPLC to produce 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((dimethylamino)methyl) benzamide. MS (Q1) 400.0 (M)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][CH:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[CH3:54][S:55](Cl)(=[O:57])=[O:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][CH:47]1[CH2:51][CH2:50][N:49]([S:55]([CH3:54])(=[O:57])=[O:56])[CH2:48]1
Reactant: O=C(CC1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: CS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)C1
Yield: 48 %

Procedure:
The desired compound was prepared according to the procedure of Example A42, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-pyrrolidin-3-ylacetamide tris(trifluoroacetate) and methanesulfonyl chloride as starting materials in 48% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.10 (s, 1H), 9.48 (s, 1H), 9.41 (s, 1H), 9.08 (s, 1H), 8.33 (s, 2H), 8.21 (s, 1H), 7.69 (s, 1H), 7.32 (d, 1H), 7.09 (d, 1H), 3.95 (s, 2H), 3.44 (m, 1H), 3.37 (m, 1H), 3.25 (m, 1H), 3.00 (m, 4H), 2.90 (s, 3H), 2.62 (m, 1H), 2.05 (m, 1H), 1.62 (m, 2H). LCMS for C24H27ClN7O3S (M+H)+: m/z=528.2.
Reaction SMILES: [OH-].[Na+].[C:3]([CH:11]([CH2:17][C:18]#[CH:19])[C:12](OCC)=[O:13])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:20][NH:21]O.Cl>O.CO.CCOCC>[CH3:20][N:21]1[C:12](=[O:13])[CH:11]([CH2:17][C:18]#[CH:19])[CH:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[O:10]1
Reactant: C#CCC(C(=O)OCC)C(=O)c1ccccc1
Reactant: CNO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: C#CCC1C(=O)N(C)OC1c1ccccc1
Temperature: -30 °C
Reaction time: 0.17 h
Yield: 34.5 %

Procedure:
A stirred solution of 0.28 g (7.0 mmol) of NaOH in 3 mL of water and 7 mL of methanol was cooled to -30° C. and and a solution of 1.42 g (6.2 mmol) of ethyl α-benzoyl-α-propargylacetate in 2 mL of methanol was added dropwise over 2 min. The mixture was stirred at -30° C. for 10 min and a precooled slurry of 0.54 g (13.5 mmol) of NaOH and 1.02 g (12.2 mmol) of N-methylhydroxylamine in 1.5 mL of water was added in one portion. After the mixture had been stirred at -30° C. for 2 h, a 2 mL portion of conc HCl was added and the mixture was heated at reflux for 1 h. The mixture was allowed to cool to room temperature, diluted-with 150 mL of ether, washed with 50 mL of water and 50 mL of saturated aqueous NaHCO3 and dried. Removal of the solvent on the rotovap left 1.09 g of an oil which was purified by flash chromatography on a column of 30 g of silica gel eluted successively with 100 mL portions of 20, 30, 40, 50, 60, 70 and 80% ether in hexanes to afford 0.46 g of 2-methyl-5-phenyl-4-propargylisoxazolin-3-one (Compound 1) as a white solid, m.p. 85°-87° C.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=5)[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:28][C:29]([OH:46])([CH3:45])[CH2:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1>>[CH3:28][C:29]([OH:46])([CH3:45])[CH2:30][N:31]1[CH:35]=[C:34]([C:2]2[CH:27]=[CH:26][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH2:19][C:20]6[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=6)[N:16]=[CH:17][N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:33]=[N:32]1
Reactant: Brc1ccc2c(c1)OCCc1sc(-c3ncnn3Cc3ccccn3)nc1-2
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4Cc4ccccn4)nc2-3)cn1

Procedure:
Following the procedure for 114, 8-Bromo-2-(2-pyridin-2-ylmethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 2-Methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol to give 417. MS (ESI+) 500.1. 1H NMR (400 MHz, CDCl3) δ 8.56-8.52 (d, J=4.2, 1H), 8.19 (s, 1H), 8.14 (s, 1H), 8.03 (d, J=8.3, 1H), 7.92 (s, 1H), 7.78 (td, J=7.7, 1.8, 1H), 7.32-7.26 (m, 2H), 7.24 (d, J=1.7, 1H), 7.16 (d, J=7.9, 1H), 6.17 (s, 2H), 4.71 (s, 1H), 4.34 (t, J=5.0, 2H), 4.03 (s, 2H), 3.41 (t, J=5.0, 2H), 1.09 (s, 6H)
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]([OH:27])=O)=[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.[CH3:37][N:38](C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.CN>O1CCCC1.C(OCC)(=O)C.O.CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[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]([NH:38][CH3:37])=[O:27])=[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: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3)cc1
Reaction time: 0.5 h
Yield: 19 %

Procedure:
To a mixture of 0.075 g (0.19 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 0.09 g (0.24 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 0.06 mL (0.37 mmole) of diisopropylethylamine. The mixture was stirred for 30 minutes and then 0.14 mL (0.28 mmole) of 2M methylamine in tetrahydrofuran was added. The mixture was stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate and water and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with water, then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate to give 0.015 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)-N-methyl-benzamide (I-133).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[CH2:20]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11]([N:33]3[CH2:34][CH2:35][N:30]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:31][CH2:32]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: CCCCCCCCCCN1CCNCC1
Product: CCCCCCCCCCN1CCN(C(=O)N2Cc3ccccc3Oc3ccc(Cl)cc32)CC1
Yield: 65.6 %

Procedure:
The title compound of Example 2 (1.0 g, 3.4 mmol) was combined with 1-decylpiperazine (0.77 g, 3.4 mmol) and the reaction was carried out by the method of Example 4. Following chromatographic purification, 1.08 g of the title product was obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:19]([N:26]([CH2:28][CH3:29])[CH3:27])=[N:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO>O>[CH2:28]([N:26]([CH3:27])[C:19]1[C:18]([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7]2)=[O:17])=[C:23]([CH3:24])[CH:22]=[C:21]([CH3:25])[N:20]=1)[CH3:29]
Reactant: CCOC(=O)C1(NC(=O)c2c(C)cc(C)nc2N(C)CC)Cc2ccccc2C1
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: CCN(C)c1nc(C)cc(C)c1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Reaction time: 18 h
Yield: 74.2 %

Procedure:
A 100 mL round bottom flask which contains 2-{[2-(ethyl-methyl-amino)-4,6-dimethyl-pyridine-3-carbonyl]-amino}-indan-2-carboxylic acid ethyl ester (348, 260 mg, 0.66 mmol) is charged with 1,4-dioxane (3 mL) and MeOH (3 mL). A stirring bar is added and stirring is initiated. After dissolution, water (1.5 mL) is added followed by the LiOH monohydrate (70 mg, 1.66 mmol). After 18 h, tlc analysis (silica, 50% EtOAc/heptanes) indicates that the starting material is completely consumed. Amberlyst highly acidic exchange resin (0.5 g) is added to the reaction vial. The reaction is capped and allowed to stir at ambient temperature. After 38 h, the contents of the flask are filtered through a pad of Celite. The solvent is removed from the filtrate. The residue is reconstituted with iPrOH/toluene (20+20 mL) and the solvent is removed. This process is repeated 1 time. Pumping to constant weight provides white solid (0.18 g, 75%).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[CH:7]1([CH:12]([C:18](=O)[CH3:19])[C:13](OCC)=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8]1.C(N(CCCC)CCCC)CCC>[OH-].[Na+]>[CH3:19][C:18]1[C:12]([CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[C:13]([OH:14])[N:3]2[N:4]=[CH:5][N:6]=[C:2]2[N:1]=1
Reactant: Nc1nc[nH]n1
Reactant: CCOC(=O)C(C(C)=O)C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCN(CCCC)CCCC
Product: Cc1nc2ncnn2c(O)c1C1CCCC1
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
A mixture of 3-amino-1,2,4-triazole (14 g), ethyl 2-cyclopentyl-3-oxobutanoate (0.17 mol, Ex. 1) and tributylamine (50 ml) was heated at 180° C. for 6 hours. The reaction mixture was cooled to about 70° C., and aqueous NaOH solution (21 g in 200 ml of H2O) was then added and the solution was stirred for another 30 min. Following phase separation and extraction with diethyl ether, the aqueous phase was acidified with conc. HCl solution. The precipitate gave 19 g of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[N:3]=[CH:2]1.F[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:11]=1[F:20].C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:20][C:11]1[CH:12]=[C:13]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=[CH:15][C:10]=1[N:1]1[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[N:3]=[CH:2]1
Reactant: O=C(O)c1c[nH]cn1
Reactant: CS(=O)(=O)c1ccc(F)c(F)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(-n2cnc(C(=O)O)c2)c(F)c1
Temperature: 120 °C

Procedure:
A mixture of 1H-imidazole-4-carboxylic acid (500 mg), 1,2-difluoro-4-methanesulfonylbenzene (1.2 g), and N,N-diisopropyl-ethyl-amine (4 mL) in N,N-dimethylformamide (6 mL) is heated to 120° C. overnight. The crude product is purified by HPLC. LC (method 20): tR=1.69 min; Mass spectrum (APCI): m/z=285 [M+H]+.
Reaction SMILES: [CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[CH:29]([OH:32])([CH3:31])C>C(O)(=O)C>[CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:29]([O-:32])(=[O:14])[CH3:31]
Reactant: CC(C)O
Agent: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Solvent: CC(=O)O
Product: CC(=O)[O-]
Temperature: 80 °C
Reaction time: 8.5 h

Procedure:
Sitagliptin (5 g) and isopropanol (75 mL) are charged into a round-bottom flask and the mixture is heated to about 80° C. for about 20 minutes to obtain a clear dissolution. Acetic acid (0.73 g) is added and the reaction mixture is refluxed for about 1.5 hours. The reaction mixture is cooled to about 30° C. and stirred for about 8.5 hours. The separated solid is filtered, washed with isopropanol (5 mL), and dried under reduced pressure at about 30° C. for about 3.5 hours to afford the title compound. (Yield: 5.6 g; MC: 0.79% w/w; HPLC purity: 99.81%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([C:8](=O)[CH2:9][F:10])[CH:7]=1.[CH3:13][C:14]([S@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15].O.CCOC(C)=O>O1CCCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6](/[C:8](=[N:19]/[S@@:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18])/[CH2:9][F:10])[CH:7]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=C(CF)c1cc(Br)ccc1F
Agent: [Ti+4]
Agent: CC[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)/N=C(\CF)c1cc(Br)ccc1F
Reaction time: 18 h
Yield: 84.9 %

Procedure:
Titanium (IV) ethoxide (4.05 mL, 19.6 mmol) was added via syringe to a solution of 1-(5-bromo-2-fluorophenyl)-2-fluoroethanone (2.3 g, 9.79 mmol) and (R)-(+)-2-methyl-2-propanesulfinamide (2.37 g, 19.57 mmol) in tetrahydrofuran (20 ml) at RT. The reaction was stirred for 18 hours and then the reaction was slowly poured into a vigorously stirred water/EtOAc mixture. After stirring 15 minutes, the mixture was filtered through a Celite pad, which was rinsed with ethyl acetate, and the phases were separated. The aqueous layer was extracted with ethyl acetate; the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica-gel chromatography, eluting with 10% EtOAc in hexanes, to provide the title compound (2.81 g, 8.31 mmol, 85% yield) as a yellow oil. LC/MS (ESI+) m/z=338, 340 (M+H; 2 bromine isotopes).