Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([Si](C)(C)[O:6][C@H:7]([C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1)[CH2:8][N:9]([CH2:17][C@H:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]3[CH:43]=[CH:42][C:31]([C:32]([O:34]CC4C=CC=CC=4)=[O:33])=[C:30]([O:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH:29]=3)[CH:24]=2)[O:19]1)C(OC(C)(C)C)=O)(C)C.Cl>C(O)C.O1CCOCC1.[Pd]>[OH:6][C@H:7]([C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1)[CH2:8][NH:9][CH2:17][C@H:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]3[CH:43]=[CH:42][C:31]([C:32]([OH:34])=[O:33])=[C:30]([O:44][C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH:29]=3)[CH:24]=2)[O:19]1
Reactant: CC(C)(C)OC(=O)N(C[C@H]1CCc2cc(-c3ccc(C(=O)OCc4ccccc4)c(Oc4ccccc4)c3)ccc2O1)C[C@H](O[Si](C)(C)C(C)(C)C)c1cccnc1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: O=C(O)c1ccc(-c2ccc3c(c2)CC[C@H](CNC[C@H](O)c2cccnc2)O3)cc1Oc1ccccc1

Procedure:
Phenylmethyl 4-{(2R)-2-[([(2R)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-(3-pyridinyl)ethyl]{[(1,1-dimethylethyl)oxy]carbonyl}amino)methyl]-3,4-dihydro-2H-chromen-6-yl}-2-(phenyloxy)benzoate (Example 191, 69 mg, 0.086 mmol) was stirred over a suspension of 10% Pd/C (7 mg) in ethanol (5 mL) under a hydrogen atmosphere for 15 hours. Solids were removed by filtration through Celite®, and the filtrate was concentrated in vacuo. The carboxylic acid intermediate was collected as a colorless oil (25 mg, 41%): 1H NMR (300 MHz, CD3OD) δ 8.66-8.58 (m, 2 H), 7.99 (d, 1 H), 7.92 (d, 1 H), 7.58-7.54 (m, 2 H), 7.51-7.41 (m, 2 H), 7.37-7.34 (m, 2 H), 7.21-7.16 (m, 2 H), 7.10 (d, 2 H), 6.86 (d, 1 H), 5.27-5.15 (m, 1 H), 4.38-4.31 (m, 1 H), 3.86-3.54 (m, 4 H), 2.96-2.90 (m, 2 H), 2.13-2.00 (m, 1 H), 1.87-1.75 (m, 1 H), 1.56 (d, 9 H), 1.00 (s, 9 H), 0.18 (d, 3 H), 0.00 (s, 3 H). The carboxylic acid intermediate (25 mg, 0.04 mmol) was stirred in an excess of 4M HCl in dioxane at room temperature for 18 hours. The volatile components were removed by rotary evaporation, and the residue was washed with dichloromethane. After drying under vacuum, the title compound was collected as the di-hydrochloride salt (16 mg, 80%): 1H NMR (300 MHz, CD3OD) δ 9.04 (broad s, 1 H), 8.89 (broad s, 1 H), 8.77 (d, 1 H), 8.15 (t, 1 H), 8.00 (d, 1 H), 7.46 (d, 1 H), 7.38-7.33 (m, 4 H), 7.14-7.08 (m, 2 H), 6.98 (d, 3 H), 5.45 (d, 1 H), 4.50 (t, 1 H), 3.76-3.55 (m, 5 H), 3.52-3.35 (m, 2 H), 2.99-2.85 (m, 2 H), 2.18-2.11 (m, 1 H), 1.85-1.75 (m, 1 H); MS m/z 497.2 (MH+ of the free base).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[C:9](OS(C(F)(F)F)(=O)=O)=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=2.[NH:30]1[C:38]2[C:33](=[CH:34][C:35](B(O)O)=[CH:36][CH:37]=2)[CH:32]=[CH:31]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[NH:30]1[C:38]2[C:33](=[CH:34][C:35]([C:9]3[C:8]([N:3]4[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]4[CH3:1])=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=4)[N:10]=3)=[CH:36][CH:37]=2)[CH:32]=[CH:31]1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCC[C@@H]3C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc4[nH]ccc4c3)c(N3CCCC[C@@H]3C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 34.2 %

Procedure:
To a solution of (S)-methyl 3-(2-methylpiperidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (250 mg, crude) in dioxane (5 mL) was added Pd(PPh3)4 (33 mg, 0.03 mmol), 1H-indol-5-ylboronic acid (234 mg, 1.45 mmol), K3PO4 (367 mg, 1.74 mmol) and water (5 drops). The resulting solution was stirred for 1 h at 90° C. with an inert atmosphere of nitrogen and then concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting with 1%-10% ethyl acetate in petroleum ether to afford (S)-methyl 2-(1H-indol-5-yl)-3-(2-methylpiperidin-1-yl)quinoxaline-6-carboxylate as a yellow solid (79 mg).
Reaction SMILES: N1C=CC=CC=1.[C:7](Cl)(=[O:10])[CH2:8][CH3:9].[NH2:12][C:13]1[N:17]([C:18]2[C:23]([Cl:24])=[CH:22][C:21]([Cl:25])=[CH:20][N:19]=2)[N:16]=[CH:15][CH:14]=1>C(Cl)Cl>[C:7]([NH:12][C:13]1[N:17]([C:18]2[C:23]([Cl:24])=[CH:22][C:21]([Cl:25])=[CH:20][N:19]=2)[N:16]=[CH:15][CH:14]=1)(=[O:10])[CH2:8][CH3:9]
Reactant: Nc1ccnn1-c1ncc(Cl)cc1Cl
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)Nc1ccnn1-c1ncc(Cl)cc1Cl
Reaction time: 5 h
Yield: 91.3 %

Procedure:
4.3 ml (0.053 mole) of pyridine and 3.6 ml (0.051 mole) of propionyl chloride are successively added dropwise to 11 g (0.048 mole) of 5-amino-1-(3,5-dichloropyrid-2-yl)-pyrazole in 80 ml of methylene chloride at room temperature, with stirring. When the addition has ended, stirring is continued for a further 5 hours, the mixture is diluted with 70 ml of methylene chloride, washed successively with dilute hydrochloric acid, saturated sodium bicarbonate solution and sodium chloride solution and dried over magnesium sulphate and the solvent is removed in vacuo. 12.5 g (91.4% of theory) of 5-propionamido-1-(3,5-dichloropyrid-2-yl)-pyrazole of melting point 116°-124° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][C@:7]([OH:18])([C:15]([OH:17])=O)[CH2:8]2.[CH3:19][Li].Cl>CCOCC.C(Cl)(Cl)Cl>[C:15]([C@@:7]1([OH:18])[CH2:6][CH2:5][C:4]2[C:9](=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[CH2:8]1)(=[O:17])[CH3:19]
Reactant: [Li]C
Reactant: COc1ccc(OC)c2c1CC[C@](O)(C(=O)O)C2
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COc1ccc(OC)c2c1CC[C@](O)(C(C)=O)C2

Procedure:
To an ether solution (15 ml) of 12b having an optical purity of 100% (M.P. 117°-120° C.; [α]D20 -37.9° (c=1.01, chloroform)) (670 mg, 2.66 mmole), an ether solution of methyl lithium (0.84 mmole/ml, 33 ml, 28.3 mmole) is gradually added in 1 hour and 20 minutes in an argon stream. The resultant mixture is stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture is slowly poured into dilute hydrochloric acid (conc. hydrochloric acid: water=4:30) (270 ml) under stirring, and after saturation with sodium chloride, extracted with ether (150 ml×2). The ether extracts are combined, washed with a saturated aqueous solution of sodium hydrogen carbonate (20 ml), a 10% aqueous solution of sodium thiosulfate (10 ml) and a saturated aqueous solution of sodium chloride (20 ml) in order and dried over anhydrous magnesium sulfate. After filtration and evaporation, pale yellow needles (615 mg) are obtained. Purification by column chromatography (silica gel, 60 g; ether-hexane (4:1)) affords the objective 13b having an optical purity of 100% as pale yellow needles (420 mg, 63%). M.P. 119°-126° C. [α]D20 -47.4° (c=1.06, chloroform). The product is recrystallized from chloroform-ether to obtain an analytical sample as colorless needles. M.P. 128°-129° C. [α]D20 -48.2° (c=0.982, chloroform). IRνmaxNujol cm-1 : 3480 (OH), 1700 (COCH3). NMR (in CDCl3): 1.87 (2H, broad t, J=6.5 Hz, CH2CH2CCH2), 2.29 (3H, s, COCH3), 2.52-3.02 (4H, m, CH2CH2CCH2), 3.52 (1H, s, OH), 3.76 (3H, s, OCH3), 3.78 (3H, s, OCH3), 6.62 (2H, s, aromatic proton).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](O)=[O:7])#[N:2].Cl.[CH3:17][NH:18][O:19][CH3:20].C(N(CC)C(C)C)(C)C.CCOC(OC(OCC)=O)=O>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([N:18]([O:19][CH3:20])[CH3:17])=[O:7])#[N:2]
Reactant: N#Cc1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: CNOC
Agent: CCOC(=O)OC(=O)OCC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cc(C#N)cc(C(F)(F)F)c1
Yield: 81.6 %

Procedure:
A solution of 3-cyano-5-(trifluoromethyl)benzoic acid (200 mg, 0.93 mmol) in tetrahydrofuran (2 mL) was added with N,O-dimethylhydroxyamine hydrochloride (145 mg, 1.49 mmol), N,N-diisopropylethylamine (470 mg, 3.64 mmol) and DEPC (227 mg, 1.39 mmol) with stirring on an ice bath, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the resulting residue was added with 1 M hydrochloric acid (0.5 mL), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain 3-cyano-N-methoxy-N-methyl-5-(trifluoromethyl)benzamide (196 mg, 82%) as pale yellow solid.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[NH2:12][CH2:13][C:14]1[CH:15]=[C:16]([C:20]2[C:21]([F:41])=[C:22]([C:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:30][CH:29]=3)=[CH:26][N:27]=2)[C:23]#[N:24])[CH:17]=[CH:18][CH:19]=1.[C:42](OC(=O)C)(=[O:44])[CH3:43]>ClCCl.[Cl-].[Na+].O.O>[C:23]([C:22]1[C:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:30][CH:29]=2)=[CH:26][N:27]=[C:20]([C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[CH2:13][NH:12][C:42](=[O:44])[CH3:43])[C:21]=1[F:41])#[N:24]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)cnc(-c2cccc(CN)c2)c1F
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(=O)NCc1cccc(-c2ncc(-c3ccc(Oc4ccccc4)cc3)c(C#N)c2F)c1
Reaction time: 1 h
Yield: 89.7 %

Procedure:
Hunig's base (0.045 mL, 0.256 mmol) was added to a mixture of 2-(3-(aminomethyl)phenyl)-3-fluoro-5-(4-phenoxyphenyl)isonicotinonitrile bis-HCl salt (12 mg, 0.026 mmol) and acetic anhydride (0.012 mL, 0.128 mmol) in dichloromethane (3 mL). After 1 h at room temperature, the mixture was diluted with brine (10 mL), water (10 mL) and extracted with dichloromethane (3×10 mL). The combined extracts were dried (MgSO4) and concentrated. Silica gel chromatography, loading with dichloromethane and eluting with 50-100% ethyl acetate in hexanes, gave N-(3-(4-cyano-3-fluoro-5-(4-phenoxyphenyl)pyridin-2-yl)benzyl)acetamide as off-white solid (10.2 mg, 91% yield), 1H NMR (500 MHz, CDCl3) δ ppm 8.73 (1H, s), 7.89-7.98 (2H, m), 7.57-7.66 (2H, m), 7.47-7.55 (1H, m), 7.37-7.47 (3H, m), 7.18-7.25 (1H, m), 7.14-7.18 (2H, m), 7.12 (2H, δ, J=7.70 Hz), 5.87 (1H, br. s), 4.55 (2H, δ, J=5.77 Hz), 2.07 (3H, s); MS (ES+) m/z: 438 (M+H); LC retention time: 4.388 min (analytical HPLC Method A).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][S:12][CH:13]1[NH:16][C:15](=[O:17])[CH:14]1[CH:18]([O:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:22])[CH3:19].Br[CH2:35][C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)=[O:37]>O1CCCC1.CN(C=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:11][S:12][CH:13]1[N:16]([CH2:35][C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=2)=[O:37])[C:15](=[O:17])[CH:14]1[CH:18]([O:20][C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=1)=[O:22])[CH3:19]
Reactant: O=C(CBr)OCc1ccc([N+](=O)[O-])cc1
Reactant: CSC1NC(=O)C1C(C)OC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CSC1C(C(C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1CC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
2.2 ml of a 1 M solution of lithium bis-(trimethylsilyl)amide are added with stirring at -70° C. in the course of 5 minutes to a mixture of 680 g (2mmol) of 4-methylthio-3-[1-(p-nitrobenzyloxycarbonyloxy)-ethyl]-azetidin-2-one and 602 mg (2.2 mmol) of p-nitrobenzyl bromoacetate in 2 ml of dry tetrahydrofuran and 2 ml of dry DMF. The reaction mixture is stirred at -70° C. during the course of 30 minutes, diluted with 30 ml of ethyl acetate and 70 ml of toluene and washed twice with dilute NaCl solution. The organic phase is dried over MgSO4 and filtered, and the solvent is evaporated in vacuo. The residue is chromatographed on 65 g of silica gel using toluene/ethyl acetate 4:1, 520 mg of a yellow oil being obtained. IR spectrum in CH2Cl2 : 2920, 2850, 1765, 1750, 1605, 1520, 1355, 1345 cm-1.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH2:25]([NH:27][CH2:28][CH2:29][CH3:30])[CH3:26]>>[CH2:25]([N:27]([CH2:28][CH2:29][CH3:30])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)[CH3:26]
Reactant: CCCNCC
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Product: CCCN(CC)CCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1

Procedure:
The product from Example 1C and ethyl(propyl)amine were processed as described in Example 1D to provide the titled compound. MS (DCI) m/z 333 (M+H)+;
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:34]([C:37]1[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[CH:39][CH:38]=1)([O-:36])=[O:35].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[O:14][C:41](=[O:42])[C:40]1[CH:39]=[CH:38][C:37]([N+:34]([O-:36])=[O:35])=[CH:45][CH:44]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H]1O
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1OC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 4 h
Yield: 70.8 %

Procedure:
To a solution of trans-2-(tert-butoxycarbonyl)aminocyclopentan-1-ol (Prepn. 47, 3.00 g) triphenyl phosphine (5.90 g) and 4-nitrobenzoic acid (2.50 g) in THF (90 mL) was added, at 0° C., diisopropyl azodicarboxylate (4.50 mL). After stirring for 4 h, the solvent was evaporated and the crude product was purified by flash chromatography (SiO2, CH2Cl2:acetone 99:1) to give cis-2-(tert-butoxycarbonyl)amino-1-(4-nitrobenzoyloxy)cyclopentane (3.70 g, 70%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 8.33 (2H, d), 8.23 (2H, d), 7.08 (1H, d), 5.25 (1H, m), 3.92 (1H, m), 1.40-2.10 (6H, m), 1.28 (9H, s).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[C:6]([Cl:16])[C:7]([CH3:15])=[C:8]([O:11][CH2:12][C:13]#[N:14])[CH:9]=2)[C:4](=[O:17])[C:3]21[CH2:21][CH2:20][CH2:19][CH2:18]2.[N-:22]=[N+:23]=[N-:24].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O>[O:1]=[C:2]1[C:10]2[C:5](=[C:6]([Cl:16])[C:7]([CH3:15])=[C:8]([O:11][CH2:12][C:13]3[NH:24][N:23]=[N:22][N:14]=3)[CH:9]=2)[C:4](=[O:17])[C:3]21[CH2:21][CH2:20][CH2:19][CH2:18]2
Reactant: Cc1c(OCC#N)cc2c(c1Cl)C(=O)C1(CCCC1)C2=O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1c(OCc2nnn[nH]2)cc2c(c1Cl)C(=O)C1(CCCC1)C2=O
Temperature: 95 °C

Procedure:
A stirred mixture of [1',3'-dioxo-4'-chloro-5'-methylspiro(cyclopentane-1,2'-indan)-6'-yloxy]acetonitrile (9.0 g., 0.03 mole), sodium azide (3.9 g., 0.06 mole) and ammonium chloride (3.2 g., 0.06 mole) in dimethylformamide (150 ml.) is heated at 95°C. for 2 hours then cooled and poured into dilute aqueous hydrochloric acid affording 9.9 g. of 5-[1',3'-dioxo-4'-chloro-5'-methylspiro(cyclopentane-1,2'-indan)-6'-yloxymethyl]tetrazole which melts at 211°-212°C. after recrystallization from acetic acid-water.
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[NH:18]2)=[CH:9]1)(C)(C)C.[C:29]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:29][N:18]1[CH:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][C:6]([OH:5])=[O:28])[CH:9]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:19]1(=[O:26])=[O:27]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)Cn1cc(C2NS(=O)(=O)c3ccccc32)c2ccccc21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(c2cn(CC(=O)O)c3ccccc23)c2ccccc2S1(=O)=O

Procedure:
The intermediate from example 1, step d (33 mg, 0.08 mmol) was dissolved in DMF (1 mL) and treated with K2CO3 (28 mg, 0.2=mmol) followed by methyl iodide. The reaction was heated to 70°-80° C. for 1 h. The reaction mixture was cooled and partitioned between EtOAc and water. The organic layer was washed several times with water then concentrated to dryness. The crude residue was then treated with TFA (2 mL) for 2 h. The reaction was concentrated and purified by preparative LCMS to give the title compound. 1H NMR (DMSO-d6) δ 8.22-8.20 (m, 1H), 7.88-7.85 (m, 2H), 7.81 (s, 1H), 7.54 (d, J=8.1 Hz, 1H), 7.40-7.35 (m, 1H), 7.28 (t, J=7.5 Hz, 1H), 7.17 (d, J=7.8 Hz, 1H), 7.05 (t, J=7.2 Hz, 1H), 5.94 (s, 1H), 4.80 (s, 2H), 2.88 (s, 3H); MS: ESI (negative): 355 (M−H).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH3:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1>>[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH2:10][CH2:9]1
Reactant: CN1CCNCC1
Reactant: C=CC(=O)OC
Product: COC(=O)CCN1CCN(C)CC1
Temperature: 0 °C

Procedure:
In a 500-mL 3-neck round bottom flask, 150.0 g (1.7 moles) of methyl acrylate is charged. The reactor is cooled to 0° C. using an ice bath. Then, 77.0 g (0.77 moles) of 1-methyl piperazine are added slowly to prevent overheating of the reaction mass. The temperature should be maintained below 50° C. by controlling the addition rate of 1-methyl piperazine. Overheating may cause polymerization of the excess methyl acrylate present in the reactor. Once the addition is completed, the mixture is agitated using a magnetic stirring bar and the temperature adjusted to 50° C. for at least 16 hours. Then, the reaction is allowed to cool to ambient temperature and the excess methyl acrylate is removed under vacuum. The final product is a light brown liquid at ambient temperature. The transformation is monitored with thin layer chromatography (TLC) using 9:1 CHCl3/MeOH. Complete conversion is apparent from the lack of olefinic protons in the 1H-NMR spectra. 1H-NMR (300 MHz, CDCl3): δ 3.20 (s, 3H), 2.12 (t, 7.3 Hz, 2H), 1.94 (m, 10H), 1.71 (s, 3H). 13C-NMR (75 MHz, CDCl3): δ 171.31, 54.00, 52.41, 51.78, 50.22, 44.92, 30.96.
Reaction SMILES: CC1(C)[O:7][CH2:6][CH:5]([CH2:8][CH2:9][N:10]2[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]2=[O:17])[CH2:4][O:3]1.C(=O)([O-])[O-].[K+].[K+]>Cl>[OH:3][CH2:4][CH:5]([CH2:6][OH:7])[CH2:8][CH2:9][N:10]1[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]1=[O:17]
Reactant: CC1(C)OCC(CCn2ccc(=O)[nH]c2=O)CO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=c1ccn(CCC(CO)CO)c(=O)[nH]1
Temperature: 110 °C
Yield: 87.9 %

Procedure:
A mixture of compound 34 (60 g, 0.239 mol) in 1N HCl (450 mL) was heated to 110° C. for 30 min. The reaction mixture was cooled, carefully neutralized with potassium carbonate to pH=7 and concentrated under vacuum. The residue was passed through small column using 20% methanol in chloroform to give the title compound (45 g, 88%) as a thick liquid. TLC: Chloroform/Methanol, 6:4, Rf=0.2
Reaction SMILES: [Si]([N:8]1[CH:11]([CH2:12][C:13](=[O:28])[CH2:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[CH2:10][C:9]1=[O:29])(C(C)(C)C)(C)C.Cl.P([O-])([O-])(O)=O.[K+].[K+]>CO>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:15]([CH2:14][C:13](=[O:28])[CH2:12][CH:11]2[NH:8][C:9](=[O:29])[CH2:10]2)=[O:16])=[CH:20][CH:21]=1)([O-:27])=[O:26]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CO
Product: O=C(CC(=O)OCc1ccc([N+](=O)[O-])cc1)CC1CC(=O)N1
Reaction time: 3.33 h
Yield: 90.8 %

Procedure:
A solution of N-(t-butyldimethylsilyl)-4-[3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]-azetidin-2-one (5.17 g, 12.3 mMol) in methanol (55 ml) is treated with 1 N hydrochloric acid (6.2 ml) and then kept at room temperature for 200 mins. The solution is treated with 1 M dipotassium hydrogenphosphate (6.2 ml) and concentrated under vacuum. The residue is taken up in ethyl acetate (100 ml), washed with brine, dried over magnesium sulfate, filtered, and evaporated under vacuum. Triturating the resulting oil with diethyl ether yields 4-[3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]-azetidin-2-one (3.42 g, 91%) as an off-white powder: mp 50°-52°; IR (CH2Cl2) 3416, 1767, 1723, 1528, and 1352 cm-1 ; NMR (CDCl3) α2.60 (ddd,1,J=1,2.7, and 15.1,H3β), 2.77 (dd,1,J=8.4 and 18.2, CHCH2CO), 3.13 (dd,1,J=5.1 and 18.2, CHCH2CO), 3.20 (ddd,1,J=2.4, 5.0, and 15.1, H3α), 3.57 (s,2,COCH2CO2), 3.98 (m,1,H4); 5.27 (s,2,CH2Ar), 6.28 (br s,1,NH), 7.53 and 8.23 (two d's,4,J=8.5, ArH); mass spectrum m/e 306(M+), 264(M+-42), 237, 153, 125, 111, and 136.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:40][CH3:41])=[C:33]2[C:37]=1[C:36](=[O:38])[N:35]([CH3:39])[CH2:34]2>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([O:40][CH3:41])=[C:33]4[C:37]=3[C:36](=[O:38])[N:35]([CH3:39])[CH2:34]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)(=[O:25])[O:22][CH2:23][CH3:24])[CH3:21]
Reactant: COc1ccc(N)c2c1CN(C)C2=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(OC)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate and 7-Amino-4-methoxy-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 205A). MS (ES+): m/z 581.20 (100) [MH+] HPLC: tR=1.08 min (UPLC, purity).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.C1C(=O)N([Br:19])C(=O)C1.C([O-])(O)=O.[Na+]>CC#N>[Br:19][C:4]1[S:3][C:2]([CH3:1])=[N:6][C:5]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1csc(C)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1nc(C)sc1Br
Reaction time: 0.08 h
Yield: 40.1 %

Procedure:
To a solution of ethyl 2-methyl-1,3-thiazole-4-carboxylate (14.53 g) in MeCN (150 mL) was added NBS (22.66 g), followed by heating under reflux for 3 hours. To the reaction mixture was added NBS (7.55 g), followed by heating under reflux for 2 hours. Under ice-cooling, to the reaction mixture was added a saturated aqueous NaHCO3 solution, followed by stirring for 5 minutes, and then extraction with EtOAc. The organic layer was dried over MgSO4 and then concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:EtOAc=from 100:0 to 60:40) to obtain ethyl 5-bromo-2-methyl-1,3-thiazole-4-carboxylate (8.52 g) as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([CH3:24])[CH:20]([NH:25][CH3:26])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>>[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([CH3:24])[CH:20]([N:25]([CH3:26])[C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CNC1CN(Cc2ccccc2)CCC1C
Reactant: Clc1nc[nH]c2nccc1-2
Solvent: CCN(CC)CC
Product: CC1CCN(Cc2ccccc2)CC1N(C)c1ncnc2[nH]ccc12
Temperature: 100 °C
Yield: 48.7 %

Procedure:
A solution of 4-chloropyrrolo[2,3-d]pyrimidine (2.4 grams, 15.9 mmol), prepared by the method of Davoll, J. Am. Chem. Soc., 82, 131 (1960), which is incorporated by reference in its entirety, and the product from Method A (1.7 grams, 7.95 mmol) dissolved in 2 equivalents of triethylamine was heated in a sealed tube at 100° C. for 3 days. Following cooling to room temperature and concentration under reduced pressure, the residue was purified by flash chromatography (silica; 3% methanol in dichloromethane) affording 1.3 grams (50%) of the title compound as a colorless oil. LRMS: 336.1 (M+1).