Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[CH2:9]([O:11][C:12](=[O:23])[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1)=O)[CH3:10].N1C=CC=CC=1>O>[CH2:9]([O:11][C:12](=[O:23])[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1)=[N:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8])[CH3:10]
Reactant: CCOC(=O)CC(=O)c1cccc(C)n1
Reactant: NN1CCCC1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)CC(=NN1CCCC1=O)c1cccc(C)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Add 1-aminopyrrolidin-2-one hydrochloride (Zubek, A. Z. Chem. 1969, 9(2), 58; 99.4 g, 0.73 mol) to a 3 L flask equipped with mechanical stirrer and nitrogen inlet. Add 3-(6-methyl-pyridin-2-yl)-3-oxo-propionic acid ethyl ester (Preparation 1, Part A; 154 g, 0.66 mol), then pyridine (280 mL). Stir the reaction mixture at room temperature for 20 h. Dilute the mixture with water (200 mL) and extract with toluene (2×250 mL). Combine the organic layers, filter, and concentrate in vacuo to yield the subtitled product (201 g) as a dark oil. MS ES+ m/e 290 (M+1).
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12](=[O:18])[N:13]([CH3:17])[C:14]=1[CH2:15]Br)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[OH:31]>CO>[OH:31][C:23]1[CH:24]=[CH:25][C:26]([N+:28]([O-:30])=[O:29])=[CH:27][C:22]=1[N:21]1[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:9]2[C:14]([N:13]([CH3:17])[C:12](=[O:18])[N:11]([CH3:19])[C:10]2=[O:20])=[CH:15]1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Solvent: CO
Product: Cn1c(=O)c2c(-c3ccccc3)n(-c3cc([N+](=O)[O-])ccc3O)cc2n(C)c1=O
Yield: 113.3 %

Procedure:
In a 25 mL round bottom flask was placed 4a (1.00 g, 2.97 mmol) (see Example 2 for synthesis of 4a), 2-amino-4-nitrophenol (921 mg, 5.98 mmol), and methanol (12 mL). The reaction was stirred at reflux for 5 h, then cooled in an ice bath. The precipitate was filtered and rinsed with cold methanol to give 5g (1.32 g, 94%). 1H NMR (600 MHz, DMSO-d6) δ 11.72 (s, 1H), 8.19 (d, J=2.8, 1H), 8.15 (dd, J=2.9, 9.1, 1H), 7.31-7.21 (m, 5H), 7.08 (s, 1H), 7.01 (d, J=9.1, 1H), 3.34 (s, 3H), 3.21 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 159.26, 159.03, 150.85, 138.89, 134.18, 130.34, 129.34, 128.85, 128.14, 127.36, 126.15, 126.09, 125.45, 116.60, 105.95, 102.41, 31.52, 27.48. MS (ES+) (m/z): [M+1]+ calculated for C20H17N4O5, 393.12. found 393.02.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:20][C:21]2[CH:25]=[C:24]([O:26][CH:27]([CH3:29])[CH3:28])[NH:23][N:22]=2)=[N:4][C:5]([NH:10][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH3:12])=[C:6]([CH:9]=1)[C:7]#[N:8].[OH-:30].[K+].OO>CO>[F:1][C:2]1[C:3]([NH:20][C:21]2[CH:25]=[C:24]([O:26][CH:27]([CH3:29])[CH3:28])[NH:23][N:22]=2)=[N:4][C:5]([NH:10][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH3:12])=[C:6]([CH:9]=1)[C:7]([NH2:8])=[O:30]
Reactant: [OH-]
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cc3)c(C#N)cc2F)n[nH]1
Agent: OO
Agent: [K+]
Solvent: CO
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cc3)c(C(N)=O)cc2F)n[nH]1
Temperature: 65 °C
Yield: 27.8 %

Procedure:
(S)-5-Fluoro-2-(1-(4-fluorophenyl)ethylamino)-6-(5-isopropoxy-1H-pyrazol-3-ylamino)nicotinonitrile (Example 16; 0.15 g, 0.38 mmol), was placed in MeOH (7 ml) at 25° C. A 25% aqueous solution (0.4 ml) of KOH (0.11 g, 1.9 mmol) was then added, followed by the addition of 0.1 ml of 30% H2O2. The resulting dark red solution was heated to 65° C. for 1 h, cooled to 25° C., and concentrated. The resulting residue was dissolved in EtOAc (50 ml), washed with water (30 ml), dried, filtered, and concentrated. The resulting solid was purified by column chromatography (DCM-MeOH=25:1) to give the title compound (0.044 g, 28%). 1H NMR (400 MHz, CD3OD) δ 7.75 (d, J=11.7 Hz, 1H), 7.39-7.36 (m, 2H), 7.04-7.00 (m, 2H), 5.37 (s, 1H), 5.11-5.00 (m, 1H), 4.61-4.52 (m, 1H), 1.53 (d, J=7.0 Hz, 3H), 1.31 (m, 6H). MS: Calcd.: 416. Found: [M+H]+417.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-])=O)=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+].[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1Nc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1Nc1ccc(Br)cc1)c1ccccc1
Temperature: 25 °C
Yield: 44 %

Procedure:
3.8 g (13 mmol) of (4-bromophenyl)-(2-nitrophenyl)amine was dissolved in 30 mL of tetrahydrofuran. The resulting solution was stirred at room temperature in the argon atmosphere. During the stirring, a solution of 11 g (64 mmol) of sodium hydrosulfite/30 mL of water was added dropwise. After stirring for 5 hours, 20 mL of ethyl acetate was added, and then a solution of 2.2 g (26 mmol) of sodium hydrogen carbonate/20 mL of water was added. Further, a solution of 2.5 g (18 mmol) of benzoyl chloride/10 mL of ethyl acetate was added dropwise, and the resultant was stirred at room temperature for 1 hour. The resultant was extracted with ethyl acetate, and sequentially washed with an aqueous 10% potassium carbonate solution, water and saturated saline. Thereafter, the solution was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, whereby 2.1 g (yield 45%) of N-[2-(4-bromophenylamino)phenyl]benzamide was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][N:34]1[CH:38]=[CH:37][C:36]([C:39]2([NH2:42])[CH2:41][CH2:40]2)=[N:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:27])[NH:42][C:39]5([C:36]6[CH:37]=[CH:38][N:34]([CH3:33])[N:35]=6)[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: Cn1ccc(C2(N)CC2)n1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccn(C)n5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.15 g, 0.35 mmol, 1 eq), 1-(1-methyl-1H-pyrazol-3-yl)cyclopropanamine (0.058 g, 0.42 mmol, 1.2 eq), HOBT (0.08 g, 0.069 mmol, 1.7 eq), EDC.HCl (0.073 g, 0.014 mmol, 1.8 eq), in DCM at ambient temperature under nitrogen was added Diisopropylehtylamine (0.297 g, 2.2 mmol, 5.0 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer is further washed with water, dried over sodium sulphate and concentrated. The product obtained was further purified by column chromatography (neutral alumina) using 0.5% Methanol/DCM and the final purification was done by preparative HPLC. Yield: 0.06 g (45%)1H NMR (400 MHz, DMSO-d6): δ 1.18-1.20 (m, 4H), 2.29 (s, 3H), 2.81-2.82 (d, 3H, J=4.64 Hz), 3.73 (s, 3H), 3.96 (s, 3H), 6.06-6.07 (d, 1 H, J=2.4 Hz), 7.12 (s, 1H), 7.32-7.34 (dd, 1H, J=8.4, 1.6 Hz), 7.38-7.42 (t, 2H, J=8.8 Hz), 7.48-7.49 (d, 2H, J=2.34 Hz), 7.59 (s, 1H), 7.71-7.73 (d, 1H, J=8.4 Hz), 7.97-7.97-8.01 (m, 2H), 8.47-8.48 (d, 1H, J=4.8 Hz), 8.69 (s, 1H). LCMS: (ES+) m/z=553.2 (M+H).: Column-Ascentis Express C18 (5×2.1 mm-2.7 μm) Mphase A: 2% MeCN-98% H2O-10 mM NH4COOH Mphase B: 98% MeCN-2% H2O-10 mM NH4COOH Flow: 1 mL/Min
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7]Cl)=[CH:5][N:6]=1.CN(C)C=O.[CH3:14][N:15]1[C:20](=[N:21][N+:22]([O-:24])=[O:23])[NH:19][CH2:18][O:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[Cl:1][C:2]1[S:3][C:4]([CH2:7][N:19]2[CH2:18][O:17][CH2:16][N:15]([CH3:14])[C:20]2=[N:21][N+:22]([O-:24])=[O:23])=[CH:5][N:6]=1
Reactant: ClCc1cnc(Cl)s1
Reactant: CN1COCNC1=N[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CN1COCN(Cc2cnc(Cl)s2)C1=N[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 5 h

Procedure:
2.5 g of 2-chloro-5-chloromethyl-thiazole, 12 ml of dimethylformamide, 2 g of 3-methyl-4-nitroimino-perhydro-1,3,5-oxadiazine and 3.8 g of potassium carbonate are combined and the mixture is stirred for 5 hours at 50° C. The mixture is cooled to room temperature and 50 ml of water and 50 ml of dichloromethane are added. The organic phase is separated off and dried over magnesium sulfate; the solvent is evaporated off in vacuo. Purification is carried out by column chromatography on silica gel using hexane/ethyl acetate (1:1), yielding the title compound (compound 2-2).
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]2[CH:11]=[N:12][N:13]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=3)[C:14]=2[OH:15])=[C:5]([CH3:25])[CH:4]=1)#[N:2].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:9][C:8]1[CH:7]=[C:6]([C:10]2[CH:11]=[N:12][N:13]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:22])=[CH:18][N:17]=3)[C:14]=2[OH:15])[C:5]([CH3:25])=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: C1COCCN1
Reactant: Cc1cc(C#N)c(F)cc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: Cc1cc(C#N)c(F)cc1-c1cnn(-c2ccc(C(=O)N3CCOCC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-5-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and morpholine. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.42 (s, 3H) 3.40-3.87 (m, 8H) 7.79 (d, J=7.07 Hz, 1H) 7.88 (d, J=10.86 Hz, 1H) 8.10 (dd, J=8.59, 2.02 Hz, 1H) 8.27 (br. s., 1H) 8.44 (br. s., 1H) 8.57 (dd, J=2.27, 0.76 Hz, 1H) 13.47 (br. s., 1H); ESI-MS m/z [M+H]+408.3.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:12][N:13]([CH3:27])[CH:14]1[CH2:19][CH2:18][C:17]([C:20]2[N:25]=[C:24]([NH2:26])[CH:23]=[CH:22][CH:21]=2)=[CH:16][CH2:15]1>>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:26][C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([C:17]2[CH2:18][CH2:19][CH:14]([N:13]([CH3:27])[CH3:12])[CH2:15][CH:16]=2)[N:25]=1)=[O:5]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CN(C)C1CC=C(c2cccc(N)n2)CC1
Product: CN(C)C1CC=C(c2cccc(NC(=O)c3ccc(Cl)cc3Cl)n2)CC1
Product: Cl
Yield: 67 %

Procedure:
Using a method similar to example 1, using 2,4-dichloro-benzoyl chloride (126 mg, 0.60 mmol) and 6-(4-dimethylamino-cyclohex-1-enyl)-pyridin-2-ylamine, isomer 1 (preparation 10, 100 mg, 0.46 mmol) provides the free base of the title compound as a colorless oil (120 mg, 67%): MS (ES): m/z=390.1 (M+H)+; 1H NMR (CDCl3): δ 8.90 (s, br, 1H), 8.20 (d, 1H), 7.73 (t, 1H), 7.57 (d, 1H), 7.45 (d, 1H), 7.28 (dd, 1H), 7.14 (d, 1H), 6.63 (m, 1H), 2.67 (m, 1H), 2.44 (m, 3H), 2.36 (s, 6H), 2.15 (m, 2H), 1.54 (m, 1H). Di-hydrochloride salt: Anal. cal'd for C20H21Cl2N3O.2HCl: C, 51.86; H, 5.00; N, 9.07. Found: C, 51.78; H, 5.04; N, 8.99.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21](Cl)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][N:29]=[C:28]2[Cl:34].C(O)(C)C.ClC1C2C(=CC=C(NC3C4C=C(C5CCNCC=5)NC=4N=CN=3)C=2)NN=1.C(N(CC)C(C)C)(C)C.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:24][C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[NH:30][N:29]=[C:28]5[Cl:34])[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Reactant: Nc1ccc2[nH]nc(Cl)c2c1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Clc1n[nH]c2ccc(Nc3ncnc4[nH]c(C5=CCNCC5)cc34)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4ccc5[nH]nc(Cl)c5c4)ncnc3[nH]2)CC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (49.6 mg, 0.148 mmol) and 5-amino-3-chloroindazole (26.5 mg, 0.155 mmol) in isopropyl alcohol (2.5 mL, 0.033 mol) in a sealed tube was heated to 90° C. (bath temp.) for 3.5 h. The bath temperature was increased to 105° C., and heating was continued overnight. The bath temperature was increased to 120° C., and heating was continued for 5 d. LC/MS at that time indicated loss of Boc group, i.e., (3-chloro-1H-indazol-5-yl)-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine, C18H16ClN7, MW=365.83. Solvents were evaporated. The reddish residue was suspended in N,N-dimethylformamide (3 mL). N,N-diisopropylethylamine (52 μL, 0.30 mmol) and di-tert-butyldicarbonate (33 mg, 0.15 mmol) were added, and the mixture was stirred at rt for 2 h. DMF was evaporated, water and CH2Cl2 were added, and the insoluble brown material was filtered off and washed with CH2Cl2 and water. The layers of the filtrate were separated; the organic layer was washed with water (2×) and brine and dried over MgSO4. The drying agent was filtered off, and the filtrate was concentrated, redissolved in MeOH, passed a through 0.45 μm filter, and purified by MDP. One obtained the title compound as light tan solid. MS (ES+): m/z 465.9/467.9 (100/38) [MH+]. HPLC: tR=2.7 min (ZQ2000, polar—5 min). 1H NMR (DMSO-d6, 400 MHz): δ=1.43 (s, 9H), 2.37-2.44 (brs, 2H), 3.51-3.58 (mc, 2H), 3.99-4.07 (m, 2H), 6.36 (s, 1H), 6.54 (s, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.55 (d, J=8.8 Hz, 1H), 8.05 (s, 1H), 8.12 (s, 1H), 9.21 (s, 1H), 11.88 (brs, 1H), 13.43 (brs, 1H).
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12]CC)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1.Cl.O1CCOCC1.C(O)[C@H](O)[C@H]1OC(=O)C(O)=C1O>C1(C)C=CC=CC=1>[OH:12][C:10]1[C:20]2[C:19](=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=2)[N:23]=[C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: COc1cccc(N)c1
Agent: Cl
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COc1ccc2c(O)cc(-c3ccccc3)nc2c1
Temperature: 280 °C

Procedure:
A solution of ethyl benzoylacetate (b) (100.0 g, 0.52 mol), m-anisidine (a) (128.1 g, 1.04 mol) and 4 N HCl/dioxane (5.2 mL) in toluene (1.0 L) was refluxed for 6.25 h in a Dean-Stark apparatus. The cooled toluene solution was successively washed with aqueous 10% HCl (2×300 mL), 1 N NaOH (2×300 mL), H2O (300 mL) and brine (150 mL). The toluene phase was dried (MgSO4), filtered and concentrated under reduced pressure to give a 1.2:1.0 mixture of ester c and amide d (144.6 g, 45%/38% crude yield) as a dark brown oil. The crude oil was heated to 280° C. for 80 min while distilling generated EtOH. The cooled dark solid obtained was triturated with CH2Cl2 (200 mL). The suspension was filtered and the resulting solid washed with CH2Cl2 to give e (22.6 g, 17% from a) as a beige solid: 1H NMR (DMSO-d6) δ 8.00 (d, J=9.0 Hz, 1H), 7.81-7.82 (m, 2H), 7.57-7.59 (m, 3H), 7.20 (d, J=2.2 Hz, 1H), 6.94 (dd, J=9.0, 2.2 Hz, 1H), 6.26 (s, 1H), 3.87 (s, 3H).
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[F:17][C:18]1[CH:19]=[CH:20][C:21]([N+:25]([O-:27])=[O:26])=[C:22]([OH:24])[CH:23]=1.O[CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[F:17][C:18]1[CH:19]=[CH:20][C:21]([N+:25]([O-:27])=[O:26])=[C:22]([CH:23]=1)[O:24][CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)ccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Yield: 36.4 %

Procedure:
Di-tert-butyl azodicarboxylate (5.27 g, 23.0 mmol) in DCM (10 mL) was added into a solution of 5-fluoro-2-nitrophenol (10 g, 63.7 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (4.22 g, 21.0 mmol) and triphenyl phosphine (6.0 g, 23.0 mmol) in anhydrous DCM (40 mL) at 0° C. The solution was allowed to warm to ambient temperature overnight, concentrated in vacuo and the crude product triturated with n-pentane/diethyl ether (×2) to remove the triphenyl phosphine oxide by-product. The sample was purified by dry flash chromatography (1:10→1:1 EtOAc/iso-hexane) to yield yellow oil (2.6 g, 40%).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[CH3:13])[CH2:4]1.[CH3:30][O:31][CH2:32][CH:33]=O>>[Cl:14][C:11]1[C:12]([CH3:13])=[C:7]([CH:5]2[CH2:4][N:3]([CH2:33][CH2:32][O:31][CH3:30])[CH2:6]2)[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]2[C:21]3=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]3[C:19]([CH3:27])=[N:18]2)[CH3:16])[CH:10]=1
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Reactant: COCC=O
Agent: Cl
Product: COCCN1CC(c2c(C)c(Cl)cc(C(C)n3nc(C)c4c(N)ncnc43)c2OC)C1

Procedure:
This compound was prepared using procedures analogous to those for Example 1, with racemic 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride from Example 2, Step 1 and methoxyacetaldehyde instead of acetone. The crude was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. The product was isolated as a racemic mixture. LCMS calculated for C22H30ClN6O2 (M+H)+: m/z=445.2; Found: 445.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[N:16]=[C:15]([CH2:17][C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[C:14]([CH2:26][NH:27][S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=3)(=[O:30])=[O:29])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CO.[C:41]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CCCCCC.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[N:16]=[C:15]([CH2:17][C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[C:14]([CH2:26][N:27]([CH3:41])[S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=3)(=[O:30])=[O:29])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(S(=O)(=O)NCc2ccc(S(=O)(=O)c3ccc(Cl)cc3)nc2Cc2cc(F)ccc2F)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: CO
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(Cc1ccc(S(=O)(=O)c2ccc(Cl)cc2)nc1Cc1cc(F)ccc1F)S(=O)(=O)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.8 %

Procedure:
To a tetrahydrofuran (0.5 ml) solution of N-[[6-(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methylpyridin-3-yl]methyl]-3-cyanobenzenesulfonamide (21 mg, 0.037 mmol) were added methanol (0.003 ml, 0.073 mmol), triphenylphosphine (19 mg, 0.073 mmol) and diisopropyl azodicarboxylate (0.014 ml, 0.073 mmol) sequentially at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel chromatography. The fraction obtained from the hexane:ethyl acetate=2:1 eluate was concentrated under reduced pressure to give the title compound (13 mg, 0.021 mmol, 58%) as a white solid.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[Si]([O:33][CH2:34][CH2:35][O:36][C:37]1[CH:42]=[C:41]([F:43])[C:40]([C:44]2[N:49]=[C:48]([C:50](O)=[O:51])[CH:47]=[CH:46][C:45]=2[F:53])=[C:39]([F:54])[CH:38]=1)(C(C)(C)C)(C)C>>[NH2:9][C@H:8]1[C@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:50](=[O:51])[C:48]2[CH:47]=[CH:46][C:45]([F:53])=[C:44]([C:40]3[C:41]([F:43])=[CH:42][C:37]([O:36][CH2:35][CH2:34][OH:33])=[CH:38][C:39]=3[F:54])[N:49]=2)[CH2:6][CH2:7]1
Reactant: CC(C)(C)[Si](C)(C)OCCOc1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2ccc(F)c(-c3c(F)cc(OCCO)cc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2,6-difluorophenyl)-5-fluoropicolinic acid (see US2012/225062) gave 209. 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.26 (dd, J=8.6, 4.0 Hz, 1H), 8.11 (t, J=8.9 Hz, 1H), 7.92 (s, 1H), 6.93 (d, J=10.2 Hz, 2H), 4.98 (br, 1H), 4.82 (dd, J=10.3, 3.7 Hz, 1H), 4.24 (ddt, J=49.2, 6.1, 2.6 Hz, 1H), 4.11 (t, J=4.8 Hz, 2H), 4.07-3.84 (m, 2H), 3.80-3.69 (m, 5H), 3.15-3.01 (m, 1H), 2.12-2.01 (m, 1H), 1.83-1.58 (m, 3H). LCMS (ES+) m/z 524 (M+1).
Reaction SMILES: Br[CH2:2][C:3](=[CH2:8])[C:4]([O:6][CH3:7])=[O:5].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18]C=O)=[CH:13][CH:12]=1.C(O)(=O)C>O>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH:7]2[O:6][C:4](=[O:5])[C:3](=[CH2:8])[CH2:2]2)=[CH:13][CH:12]=1
Reactant: C=C(CBr)C(=O)OC
Reactant: COc1ccc(CCC=O)cc1
Solvent: O
Solvent: CC(=O)O
Product: C=C1CC(CCc2ccc(OC)cc2)OC1=O
Temperature: 50 °C
Reaction time: 9 h
Yield: 54.6 %

Procedure:
To a suspension formed from metallic tin (730 mg, 6.15 mmoles), diethyl ether (12.5 ml) and water (3.1 ml) were added 1.10 g (6.15 mmoles) of methyl 2-bromomethyl-2-propenoate and 1.11 g (6.77 mmoles) of 3-(4-methoxyphenyl) propanal, with catalytic quantities of acetic acid. The mixture was kept warm at 50° C. with stirring for 9 hours. At the end of this time it was poured into water (200 ml) and an extraction was performed with diethyl ether (3×100 ml). The result was dried over anhydrous sodium sulphate and vacuum concentrated, giving an oil 780 mg (70% yield) of 5-[2-(4-methoxyphenyl)-ethyl]-3-metylene-dihydrofuran-2-one [(I), R═CH3; R1═H].
Reaction SMILES: C(N(CC)CC)C.[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].C(Cl)Cl.[OH:19][CH:20]([C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:29]([C@@H:31]1[CH2:35][CH2:34][CH2:33][N:32]1[C:36]([NH:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])=[O:30])[CH2:21][CH2:22][OH:23]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[Si:8]([O:23][CH2:22][CH2:21][CH:20]([C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:29]([C@@H:31]1[CH2:35][CH2:34][CH2:33][N:32]1[C:36]([NH:38][CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:37])=[O:30])[OH:19])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(NCc1ccccc1)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)CCO
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCC(O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
Triethylamine (0.5 ml), 4-dimethylaminopyridine (20 mg) and tert-butyldimethylsilyl chloride (497 mg) were added to a methylene chloride solution (6 ml) of (S)-2-[[(S)-2-(1,3-dihydroxypropyl)-1-pyrrolidinyl]carbonyl]-N-(phenylmethyl)-1-pyrrolidinecarboxamide (1.13 g), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate and saturated brine in order, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent: chloroform-methanol) to give the title compound (1.02 g).