Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:24]=[C:5]2[NH:6][C:7]([CH3:23])=[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)[N:4]2[N:3]=1.[C:25]1(=O)[O:30][C:28](=[O:29])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.C(N(CC)CC)C>C1(C)C=CC=CC=1.N1C=CC=CC=1>[C:16]([C:13]1[CH:12]=[CH:11][C:10]([CH:9]2[N:4]3[N:3]=[C:2]([N:1]4[C:28](=[O:29])[C:27]5[C:26](=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:25]4=[O:30])[N:24]=[C:5]3[NH:6][C:7]([CH3:23])=[C:8]2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:15][CH:14]=1)#[N:17]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCOC(=O)C1=C(C)Nc2nc(N)nn2C1c1ccc(C#N)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(C)Nc2nc(N3C(=O)c4ccccc4C3=O)nn2C1c1ccc(C#N)cc1
Reaction time: 12 h

Procedure:
Under argon, ethyl 2-amino-7-(4-cyanophenyl)-5-methyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate (5.0 g, 15.4 mmol) and phthalic anhydride (3.4 g, 23.1 mmol, 1.5 eq.) were dissolved in a mixture of toluene (400 ml) and pyridine (200 ml), triethylamine (42 μl, 0.3 mmol, 0.2 eq.) was added and the mixture was heated under reflux for 12 h. The reaction mixture was then concentrated under reduced pressure. The residue was taken up in ethyl acetate (600 ml) and extracted twice with saturated sodium bicarbonate solution (150 ml each). The organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was suspended in ethanol (100 ml) and stirred for 12 h, and the solid was then filtered off and dried under high vacuum. This gave 6.67 g (95% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].N1C=CC=CC=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:9])=[C:4]([NH:5][S:24]([C:18]2[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=2[F:16])(=[O:26])=[O:25])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1F
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc(Br)c1F)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
3-Bromo-2-fluoroaniline (10 g, 52.63 mmol) was dissolved in DCM (100 mL) under nitrogen atmosphere. Dry pyridine was added (6 mL, 73.68 mmol, 1.4 eq), followed by 2,5-difluorobenzenesulfonyl chloride (7.08 mL, 52.63 mmol, 1 eq) and the mixture was stirred at r.t. for 2 h. It was then diluted with DCM and washed with aqueous 0.5 N HCl (3×80 mL) and brine. The organic layer was dried over Na2SO4 and evaporated to dryness. The solid was taken up with ethyl ether and stirred for 30 minutes. It was then filtered and dried at 40° C. under reduced pressure to give 17.8 g of N-(3-bromo-2-fluoro-phenyl)-2,5-difluoro-benzenesulfonamide as a pale yellow solid (92%). HPLC (254 nm): Rt: 6.28 min; 1H NMR (DMSO-d6) Shift: 10.86 (s, 1H), 7.50-7.73 (m, 4H), 7.23-7.31 (m, 1H), 7.12 (dt, J=1.3, 8.1 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:23])[CH:3]=1.[O:24]1[CH2:28][CH:27]=[N:26][C:25]1=[O:29]>>[F:23][C:4]1[CH:3]=[C:2]([N:26]2[CH2:27][CH2:28][O:24][C:25]2=[O:29])[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)nc1
Reactant: O=C1N=CCO1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3F)CC2)nc1
Yield: 68.7 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using (4-bromo-2-fluorophenyl)[4-(5-methylpyridin-2-yl)piperazin-1-yl]methanone (378 mg) described in Preparation Example 184 and oxazolin-2-one (104 mg), the title compound (264 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])=[CH:22][CH:21]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccc(Cl)cc1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3ncoc3-c3ccc(Cl)cc3)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(4-chloro-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]3[CH:16]=[CH:15][C:14](=[O:18])[N:13]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:12]=3[S:11][C:10]=2[C:25]([N:27]2[CH2:31][CH2:30][C@@H:29]([O:32]C3CCCCO3)[CH2:28]2)=[O:26])=[CH:4][C:3]=1[CH3:39].Cl.[OH-].[Na+]>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]3[CH:16]=[CH:15][C:14](=[O:18])[N:13]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:12]=3[S:11][C:10]=2[C:25]([N:27]2[CH2:31][CH2:30][C@@H:29]([OH:32])[CH2:28]2)=[O:26])=[CH:4][C:3]=1[CH3:39]
Reactant: Cc1cc(Nc2c(C(=O)N3CC[C@@H](OC4CCCCO4)C3)sc3c2ccc(=O)n3-c2ccccc2)ccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Nc2c(C(=O)N3CC[C@@H](O)C3)sc3c2ccc(=O)n3-c2ccccc2)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
A suspension of Example 26 (5.8 g) in EtOH (180 ml) was treated with 1.3M HCl (32 ml). The mixture was stirred at ambient temperature overnight. The pH was adjusted to 8 using 2M sodium hydroxide. The resulting mixture was concentrated to remove the EtOH, and the solid was filtered off, washed with water, then reslurried in 25 ml water for 1 h. The suspension was filtered, washed with water, and the product was dried in a vacuum oven at 45° C. overnight. The beige solid was recrystallised from 19 volumes of EtOH, to give the title compound as a crystalline solid (3.52 g). δH (CDCl3) 9.65 (s, 1H), 7.65-7.50 (3H, m), 7.35-7.50 (2H, m), 7.25 (1H, d, J 9 Hz), 6.85-7.00 (3H, m), 6.40 (1H, d, J 9 Hz), 4.50 (1H, br s), 3.55-3.80 (4H, m), 2.25 (3H, br s), 1.95-2.05 (2H, m), 1.80 (1H, d, J 4 Hz). LCMS (ES+) RT 2.90 min, 464 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:18]([F:34])=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:18]([F:34])=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCc1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)c(F)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(C)Oc1ccc(-c2nc(-c3c(F)ccc4c(CCC(=O)O)cn(C)c34)no2)cc1Cl
Temperature: 90 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
To a solution of ethyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1-methyl-1H-indol-3-yl]propanoate (D147) (330 mg) in isopropanol (7 mL) and water (7 mL) was added NaOH (6.79 mL, 0.5 M aqueous solution) at room temperature. The reaction suspension was stirred at 90° C. for 2 hours, and the solution turned clear. Isopropanol was removed in vacuo and water (8 mL) was added to the residue. The aqueous solution was acidified to pH=1 and extracted with ethyl acetate (3×10 mL). The combined organic phase was dried over sodium sulphate. The organic solution was concentrated and the residue was purified by MDAP to afford 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1-methyl-1H-indol-3-yl]propanoic acid (E104) (136 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.29 (6H, s), 2.53 (2H, t), 2.87 (2H, t), 3.29 (3H, s), 4.83 (1H, m), 7.02 (1H, m), 7.10 (1H, s), 7.39 (1H, d), 7.75 (1H, m), 8.07 (1H, dd), 8.14 (1H, d), 12.07 (1H, s). MS (ES): C23H21ClFN3O4 requires 457; found 458.2 (M+H+).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([N:18]3[CH2:26][C:25]4[CH:24]=[CH:23][N:22]=[CH:21][C:20]=4[CH2:19]3)=[O:17])=[CH:11][CH:10]=2)O1.FC(F)(F)S(O[C:34]1[CH2:39][CH2:38][CH:37]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36][CH:35]=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].CO>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.O>[CH2:26]1[C:25]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[CH2:19][N:18]1[C:16]([NH:15][C:12]1[CH:11]=[CH:10][C:9]([C:34]2[CH2:39][CH2:38][CH:37]([NH:40][C:41](=[O:42])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[CH2:36][CH:35]=2)=[CH:14][CH:13]=1)=[O:17]
Reactant: CC1(C)OB(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CC=C(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)CC1
Temperature: 80 °C

Procedure:
N-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxamide (1.692 g, 4.63 mmol), 4-(tert-butoxycarbonylamino)cyclohex-1-enyl trifluoromethanesulfonate (1.6 g, 4.63 mmol) and cesium carbonate (3.77 g, 11.58 mmol) were suspended in terahydrofuran (30 ml), methanol (5.00 ml) and water (15.00 ml). Nitrogen was bubbled throught the solution for 10 min when PdCl2(dppf)-dichloromethane adduct (0.189 g, 0.232 mmol) was added and the mixture was heated to 80° C. for 7 h. After dilution with ethyl acetate and brine, the separated aqueous layer was extracted several times with ethyl acetate and the combined organic layers were dried over magnesium sulfate, filtered and concentrated. Flash chromatography provided the title compound.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:2]([NH2:4])=[S:3].C([O-])(=O)C.[Na+].Br[CH:22]([CH:25]=O)[CH:23]=[O:24]>C1COCC1.C(O)(=O)C>[CH:23]([C:22]1[S:3][C:2]([NH:1][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[N:4][CH:25]=1)=[O:24]
Reactant: O=CC(Br)C=O
Reactant: CC(C)(C)OC(=O)NCCCNC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCCNc1ncc(C=O)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 33 %

Procedure:
To a solution of material from Example 59 (3.4 g, 10.20 mmol) in a mixture of THF (30 mL) and acetic acid (5.00 mL) is added sodium acetate (1.004 g, 12.24 mmol) followed by 2-bromomalonaldehyde (1.540 g, 10.20 mmol). The resulting mixture is stirred at room temp for 18 h, then filtered thru a ground glass frit and the filtrate is concentrated in vacuo. The resulting residue treated with EtOAc, filtered thru a ground glass frit and the filtrate is extracted with sodium bicarbonate, water, brine, dried over Na2SO4, filtered and evaporated to dryness. The residue is purified by BIOTAGE® Silica gel chromatography on an 80 g Thompson Single Step silica cartridge using a linear gradient from 30% EtOAc/hexanes to 100% EtOAc over 11.25 column volumes to give 960 mg (29.7%) of the title compound as a yellow solid. LC/MS (Condition A): ret. T=2.92 min, (M+Na)+ 308.13. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.64 (1 H, s), 8.83-8.98 (1 H, m), 8.06 (1 H, s), 6.89 (1 H, t, J=5.40 Hz), 3.31 (2 H, d, J=5.27 Hz), 2.99 (2 H, q, J=6.69 Hz), 1.69 (2 H, t, J=7.03 Hz), 1.39 (9 H, s).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:39])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][CH2:23][O:24][CH3:25])[CH:17]=[C:16]([C:26]([OH:28])=[O:27])[C:15]3=[O:29])=[C:8]([C:30]2[S:31][CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[N:34]=2)[CH:7]=1)[CH3:2].C1COCC1.[OH-].[Na+:46]>CO>[CH2:1]([NH:3][C:4](=[O:39])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][CH2:23][O:24][CH3:25])[CH:17]=[C:16]([C:26]([O-:28])=[O:27])[C:15]3=[O:29])=[C:8]([C:30]2[S:31][CH:32]=[C:33]([C:35]([F:37])([F:38])[F:36])[N:34]=2)[CH:7]=1)[CH3:2].[Na+:46]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)O)cn3CCOC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)[O-])cn3CCOC)cn1
Yield: 85.7 %

Procedure:
6-(6-(3-Ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(2-methoxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.032 g, 0.06 mmol, Example 1) was suspended in MeOH (1.0 mL)/THF (1.0 mL). 1N NaOH (0.057 mL, 0.06 mmol) was added. Once in solution, the reaction mixture was concentrated under reduced pressure and dried for several hours to yield a white solid (0.030 g).
Reaction SMILES: [CH3:1][C:2]([C:12]1[C:20]2[O:19][CH2:18][O:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[Br:21]N1C(=O)CCC1=O>C1COCC1.C(#N)C>[Br:21][C:14]1[CH:13]=[C:12]([C:2]([CH3:1])([CH3:11])[CH2:3][C:4]2([C:7]([F:8])([F:10])[F:9])[CH2:6][O:5]2)[C:20]2[O:19][CH2:18][O:17][C:16]=2[CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cccc2c1OCO2
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(CC1(C(F)(F)F)CO1)c1cc(Br)cc2c1OCO2
Reaction time: 8 h
Yield: 54.5 %

Procedure:
To a solution of 0.1 g (0.35 mmol) of 4-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]benzo[1,3]dioxole in 5 mL of THF was added 0.06 g (0.35 mmol) of N-bromosuccinimide. The reaction was monitored by TLC. After stirring overnight, TLC showed starting material and a new slightly more polar spot. The reaction was concentrated in vacuo and the residue was diluted with hexanes. The resulting suspension was filtered to remove insoluble material and the filtrate was purified by chromatography over silica gel eluting with ethyl acetate-hexanes (0-10%) to afford an oil as a mixture of starting material and product (3.5:1) by proton NMR. The residue was dissolved in 3 mL of acetonitrile and 0.06 g (0.35 mmol) of N-bromosuccinimide was added. After 3 hours, a TLC indicated the reaction was complete and it was worked up as above to afford 0.07 g (54%) of 6-bromo-4-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]benzo[1,3]dioxole as a yellow oil.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:20]=[C:19]([CH:21]([NH2:23])[CH3:22])[O:18][N:17]=3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[C:26](Cl)(=[O:28])[CH3:27]>O1CCCC1.C(N(CC)CC)C.ClC(Cl)C>[CH:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:20]=[C:19]([CH:21]([NH:23][C:26](=[O:28])[CH3:27])[CH3:22])[O:18][N:17]=3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(Oc2ccc(-c3cc(C(C)N)on3)cc2)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC(Cl)Cl
Product: CC(=O)NC(C)c1cc(-c2ccc(Oc3ccc(OC(C)C)cc3)cc2)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
A solution of Example 17F (600 mg, 1.79 mmol) in tetrahydrofuran (5 mL) and triethyl amine (1.0 mL) was cooled to 0° C. To this was added acetyl chloride (300 μL, 4.22 mmol) at 0° C. The mixture was stirred at room temperature for 30 minutes. The reaction was diluted with dichloroethane, which was washed with water and concentrated. The residue was purified on silica gel eluting with hexane and ethyl acetate gradient to give the desired product as a white solid (500 mg, 77%). MS (DCI): m/z 381 (M+H); 1H NMR (300 MHz, CDCl3) δ ppm 7.66-7.76 (m, 2H), 6.95-7.04 (m, 4H), 6.86-6.93 (m, 2H), 6.40 (s, 1H), 5.82 (d, J=8.46 Hz, 1H), 5.32-5.47 (m, 1H), 4.43-4.59 (m, 1H), 2.04 (s, 3H), 1.58 (d, J=6.99 Hz, 3H), 1.35 (d, J=6.25 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5](OC)=[O:6].O.[NH2:14][NH2:15]>C(O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([NH:14][NH2:15])=[O:6]
Reactant: COC(=O)c1ccc(C)c(N)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1ccc(C(=O)NN)cc1N
Temperature: 100 °C
Reaction time: 2 h
Yield: 69.6 %

Procedure:
Into a round-bottom flask, was placed a solution of methyl 3-amino-4-methylbenzoate (6.60 g, 40.0 mmol, 1.00 equiv) in ethanol (100 mL). Hydrazine hydrate (10.0 g, 200 mmol, 5.00 equiv) was added to the reaction. The resulting solution was stirred for 2 h at 100° C. in an oil bath. After cooling to ambient temperature, the mixture was concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate (20 mL). The aqueous layer was extracted with 4×20 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried under high-vacuum to yield 4.60 g (70%) of the title compound as a brown solid.
Reaction SMILES: [OH:1][C@@H:2]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][CH2:4][C@@H:5]([O:14][CH2:15][CH:16]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1)[C:6]1[S:10][C:9]([C:11](O)=[O:12])=[CH:8][CH:7]=1.Cl.CN(C)CCCN=C=NCC.[CH3:39][S:40]([NH2:43])(=[O:42])=[O:41]>CN(C)C1C=CN=CC=1.CN(C=O)C.CCOC(C)=O>[OH:1][C@@H:2]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][CH2:4][C@@H:5]([O:14][CH2:15][CH:16]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1)[C:6]1[S:10][C:9]([C:11]([NH:43][S:40]([CH3:39])(=[O:42])=[O:41])=[O:12])=[CH:8][CH:7]=1
Reactant: CCCCC[C@H](O)CC[C@@H](OCC1CCC(=O)N1)c1ccc(C(=O)O)s1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCC[C@H](O)CC[C@@H](OCC1CCC(=O)N1)c1ccc(C(=O)NS(C)(=O)=O)s1
Temperature: 25 °C
Yield: 24.5 %

Procedure:
Acid 6 (12 mg, 0.031 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 8.4 mg, 0.044 mmol), 4-dimethylaminopyridine (DMAP, 4.6 mg, 0.038 mmol) and methanesulfonamide (9 mg, 0.095 mmol) were dissolved in DMF (0.2 mL) and the resulting solution was stirred at room temperature under an atmosphere of nitrogen. After 15 h the solution was diluted with EtOAc (20 mL) and washed with 1N aqueous HCl (3×5 mL) and brine (5 mL), then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the crude residue by flash column chromatography on 4 g of silica gel (CH2Cl2→10% MeOH/CH2Cl2, gradient) afforded 3.5 mg (25%) of the title compound (7).
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:8][N:7]([CH:9]([CH3:11])[CH3:10])[C:6]2[N:12]=[C:13]([NH:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][C:18]=3[O:26][CH3:27])[N:14]=[CH:15][C:5]=2[N:4]([CH3:28])[C:3]1=[O:29].C([N:33](C(C)C)C(C)C)C.[Cl-].[NH4+]>CN(C)C=O>[F:30][C:2]1([F:1])[CH2:8][N:7]([CH:9]([CH3:11])[CH3:10])[C:6]2[N:12]=[C:13]([NH:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH2:33])=[O:23])=[CH:19][C:18]=3[O:26][CH3:27])[N:14]=[CH:15][C:5]=2[N:4]([CH3:28])[C:3]1=[O:29]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C(C)C)CC(F)(F)C(=O)N2C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1cc(C(N)=O)ccc1Nc1ncc2c(n1)N(C(C)C)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a mixture of 0.08 g (0.19 mmole) of 4-(7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-292), 0.13 mL (0.76 mmole) of ethyldiisopropyl amine and 0.020 g (0.38 mmole) of ammonium chloride in 2.0 mL of dimethylformamide was added 0.082 g (0.21 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted three times with dichloromethane. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-90:10) gave 0.074 g of 4-(7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzamide (I-294) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[NH:15][C:14]([O:25][CH3:26])=[N:13][C:12]=1[CH2:27]C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(O)(O)(=O)=O.COC(=N)N.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[NH:15][C:14]([O:25][CH3:26])=[N:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)NC(OC)=N1
Agent: COC(=N)N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Product: COC1=NC(C)=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)N1
Temperature: 70 °C
Reaction time: 20 h
Yield: 58 %

Procedure:
5-(Benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(3,4-difluorophenyl)pyrimidine. A suspension of benzyl 3-[(3,4-difluorophenyl)methylene]-4-oxopentancate (16.0 g, 48.0 mmol), O-methylisourea hydrogen sulfate (16.65 g, 97.02 mmol), NaHCO3 (16.3 g, 130.2 mmol) in DMF (190 mL) was stirred at 70° C. for 20 h. After cooling to room temperature, the mixture was filtered and the filtrate was diluted with EtOAc (300 mL) and then washed with water (4×100 mL), brine (200 mL) and dried over Na2SO4. After removal of solvent, the residue was purified by column chromatography (SiO2, EtOAc/Hexane, 10%-30%) to get 5-(benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-methyl-6-(3,4-difluorophenyl)pyrimidine as a colorless oil (10.6 g, 58%). The NMR analysis showed it to be a mixture of amine/imine tautomers and was used as is in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12]O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.P(Br)(Br)[Br:15]>C(Cl)(Cl)Cl>[Br:15][CH2:12][C:11]1[C:2]([Cl:1])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: BrP(Br)Br
Reactant: OCc1cc2ccccc2nc1Cl
Solvent: ClC(Cl)Cl
Product: Clc1nc2ccccc2cc1CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of (2-chloroquinolin-3-yl)methanol (0.96 g, 4.95 mmol) in anhydrous chloroform at 0° C. was added phosphorous tribromide (1.34 g, 4.95 mmol). After stirring at room temperature for 2 hours, the solvent was evaporated to provide 3-(bromomethyl)-2-chloroquinoline (1.27 g), which was used in the next step without purification.
Reaction SMILES: [Br-].[CH2:2]([Al+2])[C:3]#[CH:4].[Br-].C(Br)C#C.[Al].CO[CH:14]([O:20][CH3:21])[C:15]1[O:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.O1CCCC1>[O:19]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH:14]([O:20][CH3:21])[CH2:4][C:3]#[CH:2]
Reactant: COC(OC)c1ccco1
Reactant: C#CC[Al+2]
Agent: C#CCBr
Agent: [Al]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C#CCC(OC)c1ccco1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of propargyl aluminum bromide, prepared from 52.9 g of 80% propargyl bromide in toluene, 6.41 g of aluminum splutters activated with 70 mg of mercuric choride and 80 ml of tetrahydrofuran, was added dropwise a solution of 42.2 g of furfural dimethyl acetal [J. Org. Chem., 40, 1478 (1975)] in 30 ml of tetrahydrofuran during a 15 minute period while maintaining a temperature of. 25° to 30° C. The mixture was stirred for 20 minutes at 25° C., then partitioned with ether and ice-water. The organic layer was separated, washed with water, then aqueous sodium bicarbonate, finally with brine and dried. After evaporation the residue was distilled, giving 39.8 g of the desired compound, bp 68°-69° C. (11 mm).