Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]([CH2:12][CH3:13])[C:4]=1[CH:5]=[O:6])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([O:11][C:10]1[C:3]([CH2:1][CH3:2])=[C:4]([C:7]([CH2:12][CH3:13])=[CH:8][CH:9]=1)[CH:5]=[O:6])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCc1ccc(O)c(CC)c1C=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCc1ccc(OCc2ccccc2)c(CC)c1C=O

Procedure:
3-Benzyloxy-2,6-diethyl-benzaldehyde was prepared from 2,6-diethyl-3-hydroxy-benzaldehyde, cesium carbonate and benzyl bromide in analogy to Example 213b): yellow oil; 1H-NMR (CDCl3): 1.20 (3H, t, CH3), 1.21 (3H, t, CH3), 2.87 (2H, q, CH2), 3.03 (2H, q, CH2), 5.09 (2H, s, OCH2), 7.04 (2H, ABq, 2×ArH), 7.33-7.45 (5H, m, Ph), 10.58 (1H, s, CH═O).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[C:18]1([CH2:24][CH:25]=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)(Cl)Cl.O>[CH3:16][C:13]1([CH3:17])[N:12](/[CH:25]=[CH:24]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:11]([CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)[C:14]1=[O:15]
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: O=CCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1/C=C/c1ccccc1
Reaction time: 2 h
Yield: 5.2 %

Procedure:
A solution of 2-(adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one (50.0 mg, 0.213 mmol) prepared in Process 3 of Example 12 in chloroform (3 mL) was added sequentially with phenylacetaldehyde (25.6 mg, 0.213 mmol), sodium triacetoxyborohydride (67.8 mg, 0.320 mmol) and acetic acid (15.4 mg, 0.256 mmol) at room temperature, and the resultant was stirred at the same temperature for 2 hours. The reaction solution was added with water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, the obtained residue was purified using Preparatory Thin-Layer chromatography (hexane:ethyl acetate=4:1), and the title compound (3.70 mg, 5.20%) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10]2[C:21]3[C:20]4[C@@H:19]([CH2:22][C:23]([NH2:25])=[O:24])[CH2:18][CH2:17][C:16]=4[S:15][C:14]=3[N:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1.Cl[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][N:2]([CH2:27][C:28](=[O:29])[N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10]2[C:21]3[C:20]4[C@@H:19]([CH2:22][C:23]([NH2:25])=[O:24])[CH2:18][CH2:17][C:16]=4[S:15][C:14]=3[N:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1
Reactant: O=C(CCl)N1CCCC1
Reactant: CNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CC(=O)N1CCCC1)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
A solution of 2-[(3R)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetamide (90 mg, 0.25 mmol, 1.00 equiv) in 8 mL of DMF was added 2-chloro-1-(pyrrolidin-1-yl)ethan-1-one (55 mg, 0.37 mmol, 1.50 equiv) and potassium carbonate (69 mg, 0.50 mmol, 2.00 equiv) and the resulting solution was stirred overnight at room temperature. The reaction was quenched with water and extracted with DCM. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (80 mg) was purified by preparative HPLC under the following conditions (SHIMADZU): column: SunFire Prep C18, 19*150 mm 5 um; mobile phase: water with 0.05% NH4HCO3 and CH3CN (6.0% CH3CN up to 50.0% in 16 min); flow rate: 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired 2-[(3R)-12-[(4-[methyl[2-oxo-2-(pyrrolidin-1-yl)ethyl]amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetamide (50 mg) as a white solid. LCMS (ES): m/z 472 [M+H]+. 1H NMR (300 MHz, CD3OD): δ 8.43 (1H, s), 5.25-5.20 (1H, m), 3.85-3.69 (1H, m), 3.52 (2H, t), 3.42 (2H, t), 3.37 (2H, s), 3.15-2.85 (2H, m), 2.73-2.58 (2H, m), 2.29-2.18 (7H, m), 1.96-1.79 (6H, m), 1.67-1.47 (4H, m).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[CH:6]=[CH:7][CH:8]=1.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:34]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[CH:6]=[CH:7][CH:8]=1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(CO)c2)C(OCc2ccc3ccccc3c2)C1
Reactant: O=C(Cl)c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(COC(=O)c3ccccc3)c2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22(k), by acylating tert-butyl (3RS,4RS)-4-(3-hydroxymethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with benzoyl chloride there was obtained tert-butyl (3RS,4RS)-4-(3-benzoyloxymethyl-phenyl)-3-naphthalen-2-ylmethoxy-piperidine-1-carboxylate as a colourless oil; MS: 569 (M+NH4)+.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[CH2:15][NH:16][CH3:17].[CH2:18]([O:25][C:26]([NH:28][C@@H:29]([C:33](O)=[O:34])[CH2:30][CH2:31][CH3:32])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1C=CC2N(O)N=NC=2C=1.O.CCN(CC)CC.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:11])([CH3:12])[CH3:10])=[O:7])=[CH:4][C:3]=1[CH2:15][NH:16][CH2:17][C:33](=[O:34])[C@@H:29]([CH2:30][CH2:31][CH3:32])[NH:28][C:26]([O:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:27]
Reactant: CNCc1cc(C(=O)OC(C)(C)C)ccc1F
Reactant: CCC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCC[C@@H](NC(=O)OCc1ccccc1)C(=O)CNCc1cc(C(=O)OC(C)(C)C)ccc1F
Yield: 97.3 %

Procedure:
According to the procedure of Preparation 4 (c), except using tert-butyl 4-fluoro-3-(methylaminomethyl)benzoate (4.00 g, 16.7 mmole), N-(benzyloxycarbonyl)-D-norvaline (4.20 g, 16.7 mmole), HOBt.H2O (2.3 g, 17 mmole), Et3N (2.4 mL, 17.1 mmole), EDC.HCl (3.3 g, 17.2 mmole), and 1:1 DMF/CH2Cl2 (100 mL), the title compound (7.68 g, 97%) was prepared as a thick yellow oil following flash chromatography on silica gel (30% EtOAc/hexanes): 1H NMR (300 MHz, DMSO-d6) mixture of amide rotamers δ 7.81-7.92 (m, 1H), 7.70-7.80 (m, 1H), 7.52-7.65 (m, 1H), 7.25-7.38 (m, 5H), 4.62-5.08 (m, 3 H), 4.38-4.53 (m, 2H), 2.83 & 3.07(2s, 3H), 1.52-1.58 (m, 2H), 1.52 (s, 9H), 1.15-1.37 (m, 2H), 0.74 & 0.87 (2 t, 3H).
Reaction SMILES: B.N1C=CC=CC=1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[N:17][N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:28])=[CH:12][C:11]=1[CH3:29]>C(O)(=O)C>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:28])=[CH:12][C:11]=1[CH3:29]
Reactant: COc1ccc(C=NN2C(=O)c3ccccc3C2=O)cc1C
Agent: B
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: COc1ccc(CNN2C(=O)c3ccccc3C2=O)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.9 %

Procedure:
Acetic acid (40 ml) and pyridine-borane (4.3 ml) were added to 2-{[1-(4-methoxy-3-methylphenyl)-methylidene]amino}isoindole-1,3-dione (2.50 g) prepared in the Step 15-1-1, and the mixture was stirred under a room temperature for 0.5 hours. The mixture was concentrated under a reduced pressure, and under an ice cooling 10% hydrochloric acid (10 ml) was added to the resulting residue. Sodium hydroxide (1.1 g) was added thereto, and the resulting mixture was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated saline solution, and then dried over sodium sulfate and concentrated under a reduced pressure. To the resulting residue, ethanol (10 ml) was added, and the mixture was stirred at a room temperature. The precipitate was separated by filtration, washed with ethanol, and concentrated under a reduced pressure to give the title compound (1.71 g, 68%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[O:12][CH3:13].[B-](F)(F)(F)[CH:15]=[CH2:16].[K+].ClCCl.C(N(CC)CC)C>C(O)C>[CH3:13][O:12][C:3]1[C:4]2[CH2:8][O:7][C:6](=[O:9])[C:5]=2[CH:10]=[CH:11][C:2]=1[CH:15]=[CH2:16]
Reactant: C=C[B-](F)(F)F
Reactant: COc1c(Br)ccc2c1COC2=O
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: C=Cc1ccc2c(c1OC)COC2=O

Procedure:
To a 100 mL round bottom flask was added 5-Bromo-4-methoxy-2-benzofuran-1(3H)-one (430 mg, 1.8 mmol, 1.0 eq), potassium trifluoro(vinyl)borate (474 g, 3.5 mmol, 2.0 eq), [1,1′-bis(diphenylposphino)-ferrocene]dichloropalladium (II) complex with dichloromethane(1:1) (144 mg, 0.2 mmol, 0.1 eq) and triethylamine (493 μL, 3.5 mmol, 2.0 eq). To above mixture was added ethanol (12 mL). The flask was degassed and filled with nitrogen. The reaction was heated to reflux for 12 hr. The mixture was then diluted with EtOAc, filtered through a pad of celite and washed with brine. The organic phase was dried over Na2SO4, filtered and purified by flash column chromatography using biotage and the solvent systems (0-50% EtOAc/Hexane). The fractions containing desired product were collected and concentrated to 4-methoxy-5-vinyl-2-benzofuran-1(3H)-one.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10]([CH3:12])([CH3:11])[S:9][CH2:8][CH2:7][N:6]1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:4].[C:23]1([C:29]#[C:30][CH2:31]O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:11][C:10]1([CH3:12])[S:9][CH2:8][CH2:7][N:6]([S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:31][C:30]#[C:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:20][CH:21]=2)(=[O:15])=[O:14])[C@H:5]1[C:3]([O:2][CH3:1])=[O:4]
Reactant: OCC#Cc1ccccc1
Reactant: COC(=O)C1N(S(=O)(=O)c2ccc(O)cc2)CCSC1(C)C
Product: COC(=O)[C@@H]1N(S(=O)(=O)c2ccc(OCC#Cc3ccccc3)cc2)CCSC1(C)C
Yield: 55.3 %

Procedure:
According to the procedure of Step 2 of Example 248, Mitsunobu coupling of 0.345 g (1.0 mmol) of 4-(4-hydroxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid methyl ester and 0.159 g (1.2 mmol) of 3-phenyl-2-propyn-1-ol provided 0.254 g (55%) of methyl(3S)-2,2-dimethyl-4-({4-[(3-phenyl-2-propynyl)oxy]phenyl}sulfonyl)-3-thiomorpholine carboxylate as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][NH:5][CH:6]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.N1C=CC=CC=1>CN(C)C(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:5]1[CH:6]=[C:2]([CH3:1])[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4]1
Reactant: COc1ccccc1B(O)O
Reactant: CCOC(=O)c1n[nH]cc1C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: CCOC(=O)c1nn(-c2ccccc2OC)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.7 %

Procedure:
Ethyl 4-methyl-1H-pyrazole-3-carboxylate (4.0 g) was dissolved in N,N-dimethylacetamide (30 mL), 2-methoxyphenylboronic acid (7.9 g), copper acetate (9.5 g) and pyridine (8.4 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1N hydrochloric acid (50 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (1.6 g, 25%) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[CH3:23][N:24]([CH3:45])[C:25]([CH:27]1[CH2:31][C:30]2[CH:32]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:34]=[CH:35][C:29]=2[O:28]1)=[O:26]>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:33]3[CH:34]=[CH:35][C:29]4[O:28][CH:27]([C:25]([N:24]([CH3:23])[CH3:45])=[O:26])[CH2:31][C:30]=4[CH:32]=3)[C:16]2=[CH:15][N:14]=1
Reactant: CN(C)C(=O)C1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2O1
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5c(c4)CC(C(=O)N(C)C)O5)n[nH]c3n2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-benzofuran-2-carboxamide (Peak II from chiral separation, Example 4, Step 1). LCMS (M+H)+=482.1. 1H NMR (300 MHz, DMSO-d6) δ: 14.25 (s, 1H), 9.77 (s, 1H), 8.01 (s, 1H), 7.91 (d, J=8.5 Hz, 1H), 7.18 (t, J=8.4 Hz, 1H), 6.97 (d, J=8.5 Hz, 1H), 5.83-5.70 (m, 1H), 3.94 (s, 6H), 3.55-3.49 (m, 2H), 3.13 (s, 3H), 2.90 (s, 3H).
Reaction SMILES: [H-].[Na+].C1C=CC=CC=1.[F:9][C:10]([F:30])([F:29])[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[CH:17]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1[C:25]([F:28])([F:27])[F:26])[OH:18].[C:31](Cl)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33]>CN(C)C=O>[F:28][C:25]([F:27])([F:26])[C:24]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[CH:17]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:11]=1[C:10]([F:9])([F:29])[F:30])[O:18][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)C(=O)Cl
Reactant: OC(c1cnccc1C(F)(F)F)c1cnccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(C)(C)C(=O)OC(c1cnccc1C(F)(F)F)c1cnccc1C(F)(F)F
Temperature: 50 °C
Yield: 63.4 %

Procedure:
To a mixture of 0.029 g of sodium hydride in 20 ml of a 1:1 solution of benzene and dimethylformamide were added 0.25 grams of 1,1-bis-(4-trifluoromethylpyrid-3-yl)methanol. After the gas evolution had subsided, 0.14 grams of pivaloyl chloride were added. After stirring for an hour at 50° C., the reaction mixture was partitioned between 25 ml of water and 50 ml of ethyl ether. The ethyl ether layer was washed with water, washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 0.24 g of the crude product as a light brown semisolid. This crude material was then purified via chromatography on a silica gel column using ethyl acetate-hexane (1:3) as the eluant to afford 0.2 g of 1,1-bis-(4-trifluoromethylpyrid-3-yl)-1-trimethylacetoxymethane as a light brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]=[CH:10][C:11]([C:13]1[N:14]=[C:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:36])[CH2:25][N:26]3[C:30]([CH3:31])=[CH:29][C:28]([C:32]([F:35])([F:34])[F:33])=[N:27]3)[CH2:20][CH2:19]2)[S:16][CH:17]=1)=O.Cl.[NH2:38][OH:39]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]=[CH:10][C:11]([C:13]1[N:14]=[C:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:36])[CH2:25][N:26]3[C:30]([CH3:31])=[CH:29][C:28]([C:32]([F:35])([F:34])[F:33])=[N:27]3)[CH2:20][CH2:19]2)[S:16][CH:17]=1)=[N:38][OH:39]
Reactant: NO
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)C=Cc3c(F)cccc3F)cs2)CC1
Agent: Cl
Solvent: CO
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(C=Cc3c(F)cccc3F)=NO)cs2)CC1

Procedure:
A solution of 3-(2,6-difluorophenyl)-1-[2-[1-[2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolyl]-2-propen-1-one (i.e. the product of Example 2, Step A) (0.5 g, 0.93 mmol) and hydroxylamine hydrochloride (0.078 g, 1.14 mmol) in methanol (10 mL) was heated at reflux for 2 h. The reaction mixture was concentrated under reduced pressure and partitioned between dichloromethane and saturated sodium bicarbonate. The mixture was poured onto a Celite® extraction tube (ChemElute® diatomaceous earth-based liquid-liquid exchange cartridge), eluted with dichloromethane and concentrated to provide 0.5 g of the title compound.
Reaction SMILES: ClCC([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:34][O:35][CH3:36])[C:12]([NH:14][C@H:15]2[C@@H:18]([O:19][C:20](=[O:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:17]([S:29]([O-:32])(=[O:31])=[O:30])[C:16]2=[O:33])=[O:13])[N:10]=1)=O.[Na+:37].CSC(=S)N.[Na]>O>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:34][O:35][CH3:36])[C:12]([NH:14][C@H:15]2[C@@H:18]([O:19][C:20](=[O:28])[CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:17]([S:29]([O-:32])(=[O:30])=[O:31])[C:16]2=[O:33])=[O:13])[N:10]=1.[Na+:37]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1OC(=O)Cc1ccccc1)c1csc(NC(=O)CCl)n1
Agent: CSC(N)=S
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1OC(=O)Cc1ccccc1)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 50.7 %

Procedure:
To a solution of 0.10 g of sodium (3S,4R)-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-4-phenylacetoxy-2-oxoazetidine-1-sulfonate in 7 ml of water is added under ice-cooling 0.027 g of sodium monomethyldithiocarbamate, and the mixture is stirred at room temperature for 1.5 hours. Insolubles are filtered off, and the filtrate is purified on an XAD-II column to yield 0.044 g of sodium (3S,4R)-3-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-4-phenylacetoxy-2-oxoazetidine-1-sulfonate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:25]=[C:24]2[C:20](/[C:21](=[CH:27]/[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=3)/[C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1.C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1>ClCCl.C(O)(C)(C)C>[C:1]([O:5][C:6]([CH:7]1[NH:8][CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:21]2([C:20]3[C:24](=[CH:25][C:17]([Cl:16])=[CH:18][CH:19]=3)[NH:23][C:22]2=[O:26])[CH:27]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C/c1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester (4.8 g, 22.5 mmol) prepared in Example 1 and E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one (4.9 g, 17 mmol) prepared in Example 61 in dichloromethane (200 mL) were added triethylamine (14 mL, 99 mmol) and AgF (3.3 g, 26 mmol). The mixture was stirred at room temperature for 18 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and brine. The organic layer was separated, washed with water, dried over MgSO4, and concentrated. The residue was dissolved into t-butanol (30 mL), and DBU (21 g, 138 mmol) was added. The reaction mixture was heated at 80° C. for 2 h. The mixture was then cooled to room temperature and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:CH2Cl2=1:20, 1:10) to give as rac-(2′S,3′R,4′R)-6-chloro-4′-(3-chloro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester a white solid (3.8 g, 45%)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:4]=1[C:5]([NH:7][C:8]1[C:17]2[N:16]=[CH:15][C:14]3[C:18](=[O:22])[NH:19][N:20]([CH3:21])[C:13]=3[C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:6].Cl.Cl[CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:3]([Cl:2])[C:4]=1[C:5]([NH:7][C:8]1[C:17]2[N:16]=[CH:15][C:14]3[C:18](=[O:22])[N:19]([CH2:30][C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)[N:20]([CH3:21])[C:13]=3[C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: ClCc1ccncc1
Reactant: Cn1[nH]c(=O)c2cnc3c(NC(=O)c4c(Cl)cccc4Cl)cccc3c21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c2c(cnc3c(NC(=O)c4c(Cl)cccc4Cl)cccc32)c(=O)n1Cc1ccncc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6-(2,6-dichlorobenzoylamino)-2,3-dihydro-1-methyl-1H-pyrazolo[4,3-c]quinolin-3-one hydrochloride (85 mg), 4-chloromethylpyridine hydrochloride (40 mg) and potassium carbonate (111 mg) in dimethylformamide (1 ml) was stirred for 3 hours at ambient temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give 6-(2,6-dichlorobenzoylamino)-2,3-dihydro-1-methyl-2-(pyridin-4-ylmethyl)-1H-pyrazolo[4,3-c]quinolin-3-one.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[CH:5][CH:4]=1.Cl.Cl.[NH:16]1[CH2:19][CH:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH2:17]1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[O:13]=[C:11]([N:16]1[CH2:19][CH:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH2:17]1)/[CH:10]=[CH:9]/[C:6]1[CH:5]=[CH:4][C:3]([NH2:2])=[N:8][CH:7]=1
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Reactant: c1cc(COC2CNC2)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ccc(/C=C/C(=O)N2CC(OCc3ccncc3)C2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
To a solution of (2E)-3-(6-aminopyridin-3-yl)acrylic acid hydrochloride (42 mg, 0.21 mmol; which may be prepared as described in Step 2) in DMF (5 mL) were added 4-[(azetidin-3-yloxy)methyl]pyridine dihydrochloride (50 mg, 0.25 mmol; which may be prepared as described in Step 4), DIPEA (171 μL, 1.04 mmol), DMAP (2.5 mg, 0.02 mmol) and EDAC (48 mg, 0.25 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was partitioned between a NaHCO3 5% solution and DCM. The aqueous phase was extracted twice with DCM, dried over sodium sulfate, filtered and concentrated under vacuum to give an orange solid. The crude was purified on preparative TLC (eluent: 90/10 DCM/MeOH+1% NH4OH) to give the title compound (21 mg, 33%) as a pale yellow solid.
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[C:9](=[O:10])[O:8][C:6](=[O:7])[CH2:5]1)=[O:2].[NH2:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[CH:1]([NH:3][C@H:4]([C:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[CH2:5][C:6](=[O:7])[OH:8])=[O:2]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=CN[C@H]1CC(=O)OC1=O
Solvent: O
Product: O=CN[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
reacting the formyl-L-aspartic anhydride of formula (II) with the L-phenylalanine in the presence of water at a pH 9-13 and at a temperature of from about -5° C. to 5° C., to produce a formyl-L-aspartyl-L-phenylalanine;