Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[C:12]([C:14]([O:16]CC)=[O:15])[C:11]([CH3:19])=[N:10]2)=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C>[F:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[C:11]([CH3:19])=[N:10]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nn(-c2ccc(F)cc2)cc1C(=O)O
Reaction time: 2 h

Procedure:
To a mixed solvent of ethanol (40 ml) and water (40 ml) were added ethyl 1-(4-fluorophenyl)-3-methylpyrazole-4-carboxylate (8.5 g) and sodium hydroxide (1.66 g), and the mixture was stirred at a refluxing temperature for 2 h. After the reaction, ethanol was evaporated and to the residue was added dilute hydrochloric acid. The obtained solid was recrystallized from aqueous methanol solution to give the title compound, melting point: 194–195° C.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]([F:23])([F:22])[C:7]1[CH:8]=[C:9]([C:13]2([CH2:16][C:17](=[O:21])[C:18]([OH:20])=O)[CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1.[NH2:24][C:25]1[CH:26]=[CH:27][C:28]2[C:33](=[O:34])[O:32][N:31]=[C:30]([CH3:35])[C:29]=2[CH:36]=1>CC(N(C)C)=O>[F:22][C:6]([F:5])([F:23])[C:7]1[CH:8]=[C:9]([C:13]2([CH2:16][C:17](=[O:21])[C:18]([NH:24][C:25]3[CH:26]=[CH:27][C:28]4[C:33](=[O:34])[O:32][N:31]=[C:30]([CH3:35])[C:29]=4[CH:36]=3)=[O:20])[CH2:14][CH2:15]2)[CH:10]=[CH:11][CH:12]=1
Reactant: Cc1noc(=O)c2ccc(N)cc12
Reactant: O=C(O)C(=O)CC1(c2cccc(C(F)(F)F)c2)CC1
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: Cc1noc(=O)c2ccc(NC(=O)C(=O)CC3(c4cccc(C(F)(F)F)c4)CC3)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.8 ml Thionylchloride are added at −10° C. to 6.0 g of 3-[1-(3-trifluoromethylphenyl)-cyclopropyl]-2-oxo-propionic acid (prepared as described in WO 98/54159) in 60 ml of dimethyl acetamide. The mixture is stirred for 30 min. at −10° C. and for 1 hour at 0° C. and then admixed to 5 g of 6-amino-4-methyl-2,3-benzoxazin-1-one. After 16 hours at ambient temperature, the phases are separated between water and ethyl acetate. The organic phase is washed with brine, dried over sodium sulfate and concentrated. After chromatography on silica gel using hexane and ethyl acetate (10-20%) as a liquid phase, 6.78 g of 6-{3-[1-(3-trifluoromethylphenyl)-cyclopropyl]-2-oxo-propionylamino}-4-methyl-2,3-benzoxazin-1-one are obtained (m.p. 136-139° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[CH3:13][C:14]1([CH3:36])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:26]=[CH:25][C:24](B3OC(C)(C)C(C)(C)O3)=[CH:23][CH:22]=2)[O:15]1>C1COCC1.C(=O)([O-])[O-].[Ag+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][C:18]1([CH3:20])[C:14]([CH3:13])([CH3:36])[O:15][B:16]([C:21]2[CH:26]=[CH:25][C:24]([C:2]3[CH:7]=[CH:6][C:5]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][CH:3]=3)=[CH:23][CH:22]=2)[O:17]1
Reactant: CC1(C)OB(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)OC1(C)C
Reactant: CS(=O)(=O)Cc1ccc(Br)cc1
Agent: [Ag+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(-c3ccc(CS(C)(=O)=O)cc3)cc2)OC1(C)C
Temperature: 80 °C

Procedure:
1-bromo-4-((methylsulfonyl)methyl)benzene (1.5 g, 6.02 mmol), 1,4-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene (4.97 g, 15.05 mmol), and silver carbonate (1.826 g, 6.62 mmol) were dissolved in THF (60.2 ml) and sparged with N2 for 15 min. Then Pd(PPh3)4 (0.348 g, 0.301 mmol) was added and the reaction was heated to 80° C. overnight. The reaction was then cooled to rt, filtered through Celite™ and concentrated in vacuo. The resulting residue was purified by column chromatography on a Biotage™ 50 g column by eluting with 5% to 50% EtOAc:Hex to yield the desired product. 1H NMR δ (ppm) 7.83 (d, 2H), 7.69 (d, 2H), 7.64 (d, 2H), 7.54 (d, 2H), 4.46 (s, 2H), 2.89 (s, 3H), 1.4 (12H).
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[NH2:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([NH2:12])=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14].O>COCCOC>[NH2:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([NH:12][CH2:2][CH2:1][OH:3])=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14]
Reactant: C1CO1
Reactant: Nc1cc([N+](=O)[O-])c(N)cc1F
Solvent: O
Solvent: COCCOC
Product: Nc1cc(F)c(NCCO)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Ethylene oxide is passed in portions into a mixture of 34 g (0.2 mol) of 1,4-diamino-5-fluoro-2-nitrobenzene, 200 ml of water and 17 g of monoethylene glycol dimethyl ether at 60° C. in the course of 90 minutes and the reaction is monitored by thin layer chromatography. When the monohydroxyethylation is complete, the mixture is cooled slowly to room temperature and the solid precipitate is filtered off and washed twice with 25 ml of a water/ethanol mixture (1/1) each time.
Reaction SMILES: [NH2:1][CH2:2][C@:3]1([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH2:5][C@@H:4]1[CH2:6]O.NO.S(Cl)(Cl)=O.[OH-].[Na+]>C(OC(C)C)(=O)C>[Cl:15][C:10]1[CH:9]=[C:8]([C@@:3]23[CH2:5][C@@H:4]2[CH2:6][NH:1][CH2:2]3)[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: NC[C@]1(c2ccc(Cl)c(Cl)c2)C[C@@H]1CO
Agent: NO
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CC(=O)OC(C)C
Product: Clc1ccc([C@]23CNC[C@H]2C3)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.9 %

Procedure:
Title compound 487 (4.63 g, 18.81 mmol) was dissolved in isopropyl acetate (24.5 mL). The above crude amino alcohol solution in isopropyl acetate was slowly subsurface-added to a solution of thionyl chloride (1.61 ml, 22.06 mmol) in isopropyl acetate (17.5 mL) at ambient temperature over 2 hours. After aging additional 1-5 h, 5.0 N sodium hydroxide (16.4 mL) was added over 1 hour while the batch temperature was maintained at <30° C. with external cooling. The two-phase reaction mixture was stirred for 1 hour at ambient temperature to allow pH to stabilize (usually to 8.5-9.0) with sodium hydroxide pH titration. The organic phase was washed with 40% aqueous isopropanol (21 mL) followed by water (10.5 mL). Concentrated HCl (1.69 mL) was added. The aqueous isopropyl acetate was azeotropically concentrated in vacuum to ca. 24.5 mL. Methylcyclohexane (17.5 mL) was added dropwise over 2 hours. Compound did not crystallize out. The pH was adjusted to neutral and organic layer was separated. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by ISCO (EtOAc to 60% MeOH in EtOAc, 40 g silica column) to afford title compound 488 (1.8 g, 42%) as a thick yellow oil. 1H NMR (CD3OD) δ (ppm): 7.44 (d, J=8.4 Hz, 1H), 7.41 (d, J=2.2 Hz, 1H), 7.18 (dd, J=8.4, 2.2 Hz, 1H), 3.31-3.30 (m, 2H), 3.23-3.17 (m, 2H), 1.97-1.93 (m, 1H), 1.20-1.04 (m, 2H). MS (m/z)=228.15 (M+H)
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([NH:12][C:13]2[CH:14]=[C:15]([C:19]3[C:20]([CH:25]=O)=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:16]=[CH:17][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][NH:28]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClC(Cl)C>[CH2:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][N:28]1[CH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([NH:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([CH3:1])[CH:11]=2)[CH:14]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Cc1cc(Nc2cccc(-c3ccccc3C=O)c2)c2ccccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1cc(Nc2cccc(-c3ccccc3CN3CCc4ccccc4C3)c2)c2ccccc2n1
Reaction time: 48 h
Yield: 23.7 %

Procedure:
To a solution of 100 (166 mg, 0.49 mmol) and 40 (0.06 mL, 0.473 mmol) in dichloroethane (4.9 mL) were sequentially added NaBH(OAc)3 (155 mg, 0.73 mmol) and HOAc (0.03 mL, 0.52 mmol). The reaction was stirred for 48 hours and then extracted with dichloromethane (2×30 mL). The dichloromethane extracts were washed with 2 N NaOH (aq. 15 mL), brine (15 mL), dried (MgSO4), and concentrated. The residue was chromatographed on silica gel (ethyl acetate) to give desired product as a yellow solid (51 mg, 23.7%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1O>C[Si](OP(=O)=O)(C)C>[O:8]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:6]1[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[C:3]([O:11][CH3:12])[CH:4]=1
Reactant: COc1cc(C(=O)O)ccc1O
Reactant: Nc1ccccc1O
Agent: C[Si](C)(C)OP(=O)=O
Product: COc1cc(-c2nc3ccccc3o2)ccc1O
Temperature: 180 °C
Reaction time: 8 h

Procedure:
4-hydroxy-3-methoxybenzoic acid (25 g, 150 mmol) and 2-amino phenol (16 g, 150 mmol) were combined in a round bottom flask. Trimethylsilyl polyphosphate (80 mL) was added. The mixture was heated at 180° C. for 30 min. The mixture was poured over ice and allowed to stir overnight. The suspension was filtered to afford 4-(1,3-benzoxazol-2-yl)-2-methoxyphenol as a pale green solid. MS (ESI) 242 (M+H).
Reaction SMILES: [N:1]1([C:6](=[O:34])[CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21](B5OC(C)(C)C(C)(C)O5)[CH:20]=4)=[N:17][CH:18]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:36]1[N:40]([CH3:41])[CH:39]=[N:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+].C1CCCCC1>O.C(Cl)Cl>[CH3:41][N:40]1[C:36]([C:21]2[CH:20]=[C:19]([C:16]3[N:15]=[CH:14][C:13]([C:11]4[CH:10]=[N:9][N:8]([CH2:7][C:6]([N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[O:34])[CH:12]=4)=[CH:18][N:17]=3)[CH:24]=[CH:23][CH:22]=2)=[CH:37][N:38]=[CH:39]1
Reactant: Cn1cncc1Br
Reactant: CC1(C)OB(c2cccc(-c3ncc(-c4cnn(CC(=O)N5CCCC5)c4)cn3)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCCCC1
Product: Cn1cncc1-c1cccc(-c2ncc(-c3cnn(CC(=O)N4CCCC4)c3)cn2)c1
Temperature: 120 °C
Yield: 44 %

Procedure:
A mixture of 1-Pyrrolidin-1-yl-2-(4-{2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-ethanone (4 mL of the solution obtained in step 1), 5-bromo-1-methyl-1H-imidazole (35 mg; 0.22 mmol; 1.0 eq.), Pd(Ph3)4 (13 mg; 0.01 mmol; 0.05 eq.) and potassium carbonate (90 mg; 0.65 mmol; 3.0 eq.) in water (0.73 mL) was heated at 120° C. in MW for 30 min. Addition of 5-bromo-1-methyl-1H-imidazole (35 mg; 0.22 mmol; 1.0 eq.) and heating at 120° C. for 30 min had to be repeated twice to complete the reaction. The reaction mixture was then diluted with water and extracted twice with EtOAc. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica (DCM:MeOH, gradient from 100:0 to 80:20) gave a black gum which was redissolved in DCM. Addition of cyclohexane afforded a brown precipitate which was filtered and dried under vacuum to give the title compound as a beige solid (40 mg, 44%). 1H NMR (300 MHz, DMSO-d6) δ 9.20 (s, 2H), 8.47-8.46 (m, 1H), 8.41-8.37 (m, 2H), 8.14 (d, J=0.6 Hz, 1H), 7.76 (s, 1H), 7.68-7.60 (m, 2H), 7.15 (s, 1H), 5.12 (s, 2H), 3.74 (s, 3H), 3.52 (t, J=6.8 Hz, 2H), 3.32 (t, J=6.8 Hz, 2H), 1.93 (quint., J=6.8 Hz, 2H), 1.80 (quint., J=6.8 Hz, 2H). HPLC (Condition A): Rt 2.21 min (purity 96.2%). MS (ESI+): 414.4.
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][C:7](=O)[CH2:8][CH2:9][C:10](=O)[CH3:11])[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.C([O-])(=O)C.[NH4+:24].[Cl-].[NH4+]>C(O)(=O)C>[C:1]1(=[O:19])[N:5]([CH2:6][C:7]2[NH:24][C:10]([CH3:11])=[CH:9][CH:8]=2)[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12
Reactant: [NH4+]
Reactant: CC(=O)CCC(=O)CN1C(=O)c2ccccc2C1=O
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CC(=O)O
Product: Cc1ccc(CN2C(=O)c3ccccc3C2=O)[nH]1

Procedure:
36.3 g (0.14 mol) of 6-phthalimido-2,5-hexanedione, 54 g (0.7 mol) of ammonium acetate and 1 g of ammonium chloride are stirred in 700 ml of acetic acid at 80° C. for 1 hour and the mixture is worked up as in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]([C:21]([O:23]CC)=[O:22])[N:15]([CH2:17][CH:18]3[CH2:20][CH2:19]3)[CH:16]=2)=[O:10])=[C:4]([CH3:26])[CH:3]=1.O.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]([C:21]([OH:23])=[O:22])[N:15]([CH2:17][CH:18]3[CH2:20][CH2:19]3)[CH:16]=2)=[O:10])=[C:4]([CH3:26])[CH:3]=1
Reactant: CCOC(=O)c1nc(NC(=O)Nc2ccc(Cl)cc2C)cn1CC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(Cl)ccc1NC(=O)Nc1cn(CC2CC2)c(C(=O)O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10.6 g (28.1 mmol) of ethyl 4-({[(4-chloro-2-methylphenyl)amino]carbonyl}amino)-1-(cyclopropylmethyl)-1H-imidazole-2-carboxylate are suspended in 158 ml of ethanol. With ice cooling, 16.4 ml of water and 6 ml (112 mmol) of a 50% aqueous sodium hydroxide solution are added. The reaction mixture is stirred at room temperature for 1 h and then concentrated in vacuo. The residue is taken up in 100 ml of isopropanol, and 100 ml of 1N hydrochloric acid are added with ice cooling. The crystals are collected by suction filtration and dried at 40° C. in vacuo.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C@@H:14]([NH2:17])[C@H:13]([OH:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1([N:24]2[CH2:30][C:29]([F:32])([F:31])[C:28](=[O:33])[N:27]([CH3:34])[C:26]3[CH:35]=[N:36][C:37]([NH:39][C:40]4[CH:48]=[CH:47][C:43]([C:44](O)=[O:45])=[CH:42][C:41]=4[O:49][CH3:50])=[N:38][C:25]2=3)[CH2:23][CH2:22][CH2:21][CH2:20]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C>O.CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:44](=[O:45])[C:43]2[CH:47]=[CH:48][C:40]([NH:39][C:37]3[N:36]=[CH:35][C:26]4[N:27]([CH3:34])[C:28](=[O:33])[C:29]([F:31])([F:32])[CH2:30][N:24]([CH:19]5[CH2:23][CH2:22][CH2:21][CH2:20]5)[C:25]=4[N:38]=3)=[C:41]([O:49][CH3:50])[CH:42]=2)[CH:13]([OH:18])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: N[C@@H]1CCN(C(=O)OCc2ccccc2)C[C@H]1O
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(C(=O)OCc3ccccc3)CC2O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
A mixture of 0.067 g (0.15 mmole) of (rac)-(3R,4R)-4-amino-3-hydroxy-piperidine-1-carboxylic acid benzyl ester, 0.042 g (0.17 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.057 g (0.15 mmole) 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate, 0.039 g (0.30 mmole) of diisopropylethylamine and 2 mL of dimethylformamide was stirred at room temperature for 1 hour. The mixture was poured into 50 mL of water and extracted three times with 25 mL of ethyl acetate. The combined organic extracts were washed three times with 25 mL of water, once with 25 mL of saturated aqueous ammonium chloride solution, once with 25 mL of saturated aqueous sodium bicarbonate solution, once with 25 mL of brine and dried over anhydrous magnesium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (96:4) to give 0.061 g of rac-(3R,4R)-4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-3-hydroxy-piperidine-1-carboxylic acid benzyl ester (I-54) as a foam. Tritruration of the foam with diethyl ether gave a white solid.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C.[OH-].[Li+:26]>O1CCCC1.O.C(#N)C>[Li+:26].[F:23][C:20]([F:21])([F:22])[C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH2:5][C:4]([O-:24])=[O:3])[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: CCOC(=O)CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O
Product: O=C([O-])CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1

Procedure:
4-[4-(4-Trifluoromethyl-phenyl)-piperazin-1-yl]-butyric acid ethyl ester (660 mg; 1.92 mmol, prepared in accordance with Example 2) and lithium hydroxide are dissolved in a mixture of tetrahydrofuran (2.8 mL) and water (1.2 mL). The resulting mixture is irradiated in a mono-mode microwave oven for 30 minutes at 70° C. The mixture is then diluted with acetonitrile (20 mL) and the precipitate formed is filtered and rinsed with acetonitrile (10 mL). The solid obtained is then dried under high vacuum to deliver the desired product (584 mg; 1.81 mmol).
Reaction SMILES: [CH3:1][N:2]([C:10]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH:19]([C:23]2[O:24][C:25]3[CH:32]=[CH:31][C:30]([O:33][CH:34]4[CH2:39][CH2:38][S:37][CH2:36][CH2:35]4)=[CH:29][C:26]=3[C:27]=2[CH3:28])[CH:20]([CH3:22])[CH3:21])=[CH:14][CH:13]=1)=[O:11])[CH2:3][CH2:4][C:5]([O:7]CC)=[O:6].[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:1][N:2]([C:10]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][CH:19]([C:23]2[O:24][C:25]3[CH:32]=[CH:31][C:30]([O:33][CH:34]4[CH2:35][CH2:36][S:37][CH2:38][CH2:39]4)=[CH:29][C:26]=3[C:27]=2[CH3:28])[CH:20]([CH3:22])[CH3:21])=[CH:16][CH:17]=1)=[O:11])[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OC4CCSCC4)cc3c2C)C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C(C)C)oc2ccc(OC3CCSCC3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
Ethyl 3-(methyl{[4-({2-methyl-1-[3-methyl-5-(tetrahydro-2H-thiopyran-4-yloxy)-1-benzofuran-2-yl]propyl}amino)phenyl]carbonyl}amino)propanoate (485 mg) synthesized in Example A203 was dissolved in ethanol (2.0 mL) and tetrahydrofuran (2.0 mL), and 1N aqueous sodium hydroxide solution (1.96 mL) was added to the solution, and the mixture was stirred at room temperature for 0.5 hr. The solvent was evaporated under reduced pressure, water (4 mL) was added to the residue, and the mixture was neutralized with 1N hydrochloric acid (1.96 mL) under ice-cooling, and stirred for 30 min. The resulting precipitate was collected by filtration, and dried to give the title compound (421 mg, 91%) as a colorless amorphous form.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[C:26](Cl)(=[O:30])[CH:27]([CH3:29])[CH3:28]>>[CH3:28][CH:27]([CH3:29])[C:26]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)=[O:30]
Reactant: CC(C)C(=O)Cl
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Product: CC(C)C(=O)NCCc1ccc(-c2ccc(C(C)CNS(=O)(=O)C(C)C)cc2)cc1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.6 g (1.8 mmol) of material from Example 50 and0.11 μL (0.11 mmol) isobutyryl chloride. NMR was consistent with the proposed compound.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:22][CH:21]=2)=[CH:5][N:6]2[C:11]=1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:9][CH:8]=[CH:7]2)[CH3:2].[CH3:34][C:35](=[O:38])[C:36]#[CH:37]>>[C:35]([C:36]1[CH:37]=[C:5]2[N:6]3[C:11](=[C:10]([O:12][CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:9]=[CH:8][C:7]=13)[C:3]([CH2:1][CH3:2])=[C:4]2[C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][CH:25]=1)(=[O:38])[CH3:34]
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)cn2cccc(OCc3ccccc3)c12
Reactant: C#CC(C)=O
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2cc(C(C)=O)c3ccc(OCc4ccccc4)c1n32
Yield: 14 %

Procedure:
1-Ethyl-8-benzyloxy-2-(4-benzyloxyphenyl)indolizine was reacted with 3-butyn-2-one by the general synthetic principles outlined in example 73, step 1, to afford the title compound as yellow crystals in 14% yield. M.p. 147-149° C. MS(SP): m/z 499 (M+). 1H--NMR (DMSO-d6, 200 MHz) δ: 1.37 (t, 3 H); 2.65 (s, 3 H); 3.16 (q, 2 H); 5.22 (s, 2 H); 5.53 (s, 2 H); 7.23 (d, 2 H); 7.33-7.83 (m, 13 H); 8.13 (s, 1 H); 8.28 (d, 1 H).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[NH:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][OH:24]>ClCCl>[CH3:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[NH:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=[O:24]
Reactant: Cc1cccc(Nc2ccccc2CO)c1C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1cccc(Nc2ccccc2C=O)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
A suspension of pyridinium chlorochromate (47.5 g, 0.22 mol) and neutral alumina (170 g) in dichloromethane (600 ml) is stirred for 30 minutes at room temperature. 2-[(2,3-dimethylphenyl)amino]benzyl alcohol (25 g, 0.11 mol) is added and the reaction mixture is stirred at room temperature overnight. The suspension is filtered through a pad of silica gel (1000 g) and the product is eluted with dichloromethane (2500 ml). The combined filtrate and eluant are evaporated and the residue is recrystallized from cold methanol/water to give 2-[(2,3-dimethylphenyl)amino]benzaldehyde (11.95 g, 48%). Recrystallization from hexane at 0° C. gives analytical material; mp 45°-47° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:24])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21]CC)=[O:20])=[CH:14][CH:13]=1.[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:24])[NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:16][CH:17]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)Nc2ccccc2OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1NC(=O)Nc1ccc(CC(=O)O)cc1
Yield: 91.8 %

Procedure:
To a stirred solution of ethyl 4-[N′-(2-methoxyphenyl)ureido]phenylacetate (2.22 g, 6.78 mmol) in MeOH (30 ml) was added 1.0 M-NaOH aq. (10.2 ml, 10.2 mmol), and the resulting mixture was stirred overnight 1N-HCl (aq.) was added and the mixture was concentrated in vacuo. Water was added to the residue to give precipitate, which was collected by filtration. The crude solid was recrystallized from EtOH/hexane to give 4-[N′-(2-methoxyphenyl)ureido]phenylacetic acid as a white powder (1.87 g, 92%). mp 165-168° C.; 1H-NMR (CD3OD) δ2.30 (s, 3 H), 3.55 (s, 2 H), 4.87 (s, 3 H), 6.87-6.92 (m, 2 H), 6.97-6.99 (m, 2 H), 7.10-7.24 (m, 2 H), 7.53-7.58 (m, 1 H), 8.04 (d, J=7.2 Hz, 1 H); MS (ESI) m/z 300 (M+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][NH:5][CH2:6][C:7](=[O:18])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[C:9]=1[OH:17].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:19])[CH2:4][NH:5][CH2:6][C:7](=[O:18])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[C:9]=1[OH:17]
Reactant: [H][H]
Reactant: COC(=O)CNCC(=O)c1cccc([N+](=O)[O-])c1O
Agent: [Pd]
Solvent: CO
Product: COC(=O)CNCC(=O)c1cccc(N)c1O
Yield: 76.5 %

Procedure:
A solution of 5.78 g (21.5 mmol, 1 eq) of methyl[(2-hydroxy-3-nitrobenzoyl)methylamino]acetate in 75 ml of methanol in the presence of 0.52 g (10% by weight) of Pd/C 10% was stirred at hydrogen atmospheric pressure for two and a half hours. The reaction medium was filtered through celite and the filtrate was evaporated. The residue (4.78 g) was chromatographed on silica gel (300 g prepacked column, eluent heptane/ethyl acetate from 40% to 90% of ethyl acetate, 120 ml/min). 3.92 g of methyl[(3-amino-2-hydroxybenzoyl)methylamino]acetate were obtained in the form of a yellow oil. Yield=76%.