Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:38][CH2:39][CH2:40][C:41]#[N:42].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O.O>[C:39]([CH2:40][CH2:41][NH:42][C:8]([C:7]1[CH:6]=[C:5]([CH:13]=[CH:12][CH:11]=1)[C:3]([O:2][CH3:1])=[O:4])=[O:10])#[N:38]
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: N#CCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(C(=O)NCCC#N)c1
Yield: 88.1 %

Procedure:
Preparation H7, Step 1: To a soultion of 3-(methoxycarbonyl)benzoic acid (800 mg, 4.4 mmol) in DMF (15 mL) at rt was added HATU (2g, 5.3 mmol), 3-aminopropanenitrile (0.33 mL, 4.4 mmol), and iPr2NEt (0.92 mL, 5.3 mmol). The mixture was stirred at rt for 16 h before water and EtOAc were added. The organic layer was separated and re-washed twice before it was collected, dried over Na2SO4, and concentrated to provide methyl 3-((2-cyanoethyl)carbamoyl)benzoate as a glassy solid (900 mg). MS found: (M+H)+=233.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]4[C:25]5[CH2:24][CH2:23][NH:22][CH2:21][C:20]=5[S:19][C:18]=4[CH3:26])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>C(N(CC)CC)C.C(Cl)(Cl)Cl>[C:29]([N:22]1[CH2:23][CH2:24][C:25]2[C:17]([CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][CH:9]([C:6]4[C:5]5[CH:27]=[CH:28][C:2]([F:1])=[CH:3][C:4]=5[O:8][N:7]=4)[CH2:10][CH2:11]3)=[C:18]([CH3:26])[S:19][C:20]=2[CH2:21]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1sc2c(c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCNC2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1sc2c(c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCN(C(=O)c1ccccc1)C2
Yield: 63.5 %

Procedure:
To a mixture of 0.5 g of 3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine in 0.5 ml of triethylamine and 10 ml of chloroform was added 0.18 g of benzoyl chloride under cooling and the mixture was stirred for an hour, and then poured into water. The organic layer was washed with water, dried and concentrated. The residue was purified by column chlomatogaphy to give 0.4 g of 6-benzoyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil, m.p. 192°-195° C. as oxalate 1/4hydrate thereof.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(N(C(C)C)C(C)C)C.[F:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1>C1C=CC=CC=1>[F:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([N:7]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:37])=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)CCCNc1ccccc1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccccc1
Product: CCOC(=O)CCCN(C(=O)c1ccc(F)cc1)c1ccccc1-c1ccccc1
Yield: 84.6 %

Procedure:
Analogously to Example 47b), 10.0 g of ethyl 4-(biphenyl-2-yl)aminobutyrate and 4.6 g of ethyldiisopropylamine in 50 ml of benzene are reacted with 5.6 g of p-fluorobenzoyl chloride. The reaction product is recrystallized from cyclohexane to obtain 12.1 g (84.6% of theory) of ethyl 4-[p-fluoro-N-(biphenyl-2-yl)-benzamido]butyrate, MP 83° to 84°.
Reaction SMILES: [CH3:1][N:2]1[C:6]2([CH2:15][CH2:14][C:9]3(OCC[O:10]3)[CH2:8][CH2:7]2)[CH2:5][N:4]([CH3:16])[C:3]1=[O:17].Cl>C1COCC1>[CH3:1][N:2]1[C:6]2([CH2:15][CH2:14][C:9](=[O:10])[CH2:8][CH2:7]2)[CH2:5][N:4]([CH3:16])[C:3]1=[O:17]
Reactant: CN1CC2(CCC3(CC2)OCCO3)N(C)C1=O
Agent: Cl
Solvent: C1CCOC1
Product: CN1CC2(CCC(=O)CC2)N(C)C1=O
Temperature: 50 °C
Reaction time: 48 h
Yield: 65.6 %

Procedure:
1,3-Dimethyl-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one (3.16 g, 13.2 mmol) was dissolved in 66 mL of THF and a portion of 130 mL of 3N HCl aqueous solution was added. The resulting mixture was stirred at 50° C. for two days. THF was removed under vacuum then the remaining mixture was extracted with two portions of dichloromethane. The organic portions were combined, dried over anhydrous Na2SO4 and concentrated. The crude was purified by silica gel column chromatography using a gradient from 2% CH2Cl2:MeOH to 10% CH2Cl2:MeOH as eluent to afford 1,3-dimethyl-1,3-diaza-spiro[4.5]decane-2,8-dione (1.7 g, 66%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:19])[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1.[C:20]([CH:22]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)#[CH:21]>>[CH:22]1([C:20]#[C:21][C:2]2[CH:3]=[C:4]([CH:8]([OH:19])[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C#CC1CCCCCCC1
Reactant: CC(C)(C)OC(=O)NCCC(O)c1cccc(Br)c1
Product: CC(C)(C)OC(=O)NCCC(O)c1cccc(C#CC2CCCCCCC2)c1

Procedure:
Sonogashira reaction of 39 with ethynyl cyclooctane yielded tert-butyl 3-(3-(2-cyclooctylethynyl)phenyl)-3-hydroxypropylcarbamate as light yellow oil. Yield (470 mg, 91%): 1H NMR (400 MHz, CDCl3) δ 7.39 (s, 1H), 7.22-7.29 (m, 3H), 4.86 (bs, 1H), 4.72 (m, 1H), 3.23 (bs, 1H), 3.11-3.19 (m, 1H), 2.76-2.79 (m, 2H), 1.92-1.96 (m, 2H), 1.74-1.81 (m, 6H), 1.53-1.60 (m, 6H), 1.45 (s, 9H), 1.27 (m, 2H).
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])=[CH:8][CH:7]1[NH:21][C:22]([O:24]C(C)(C)C)=[O:23])(=O)=O>N1C=CC=CC=1>[N+:18]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:12]=1[C:9]1[CH2:10][CH2:11][CH:6]2[O:24][C:22](=[O:23])[NH:21][CH:7]2[CH:8]=1)([O-:20])=[O:19]
Reactant: CC(C)(C)OC(=O)NC1C=C(c2ccncc2[N+](=O)[O-])CCC1OS(C)(=O)=O
Solvent: c1ccncc1
Product: O=C1NC2C=C(c3ccncc3[N+](=O)[O-])CCC2O1
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
The mixture of 2-(tert-butoxycarbonylamino)-4-(3-nitropyridin-4-yl)cyclohex-3-enyl methanesulfonate (1.0 equiv.) in pyridine (0.21 M) was stirred at 110° C. for 10 min in microwave. Pyridine was removed under reduced pressure. The residue was dissolved in ethyl acetate, and washed with sat NaCl. The organic was dried with MgSO4, filtered and concentrated to give 5-(3-nitropyridin-4-yl)-3,3a,7,7a-tetrahydrobenzo[d]oxazol-2(6H)-one (85%), which was used in the next step without further purification. LC/MS (m/z): MH+=262.1, Rt=0.49
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH:7]=[O:8])[CH2:3][CH2:2]1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([Mg]Cl)[CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1.Cl>O1CCCC1>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[OH:8])[CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1
Reactant: O=CC1CCOCC1
Reactant: COc1cc(OC)cc([Mg]Cl)c1
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(O)C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tetrahydropyran-4-carboxaldehyde (16.0 g, 0.14 mol) in tetrahydrofuran (60 ml) is added dropwise over 1 hour to a 1 M solution of 3,5-dimethoxyphenylmagnesium chloride in tetrahydrofuran (140 ml), maintaining the reaction at or below reflux by external cooling. Once the addition is complete, and the exotherm has subsided, the reaction mixture is allowed to stir at room temperature overnight. A solution of dilute aqueous hydrochloric acid (300 ml) is added carefully and the reaction mixture is extracted with ethyl acetate. The organic extract is dried over anhydrous magnesium sulfate, filtered, and the filtrate evaporated in vacuo. Purification by column chromatography on silica gel gives (3,5-dimethoxyphenyl) (tetrahydropyran-4-yl)methanol as a cream solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([F:13])[C@H:9]1[C:14]([O:16]CC1C=CC=CC=1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([F:13])[C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](F)[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](F)[C@H]1C(=O)O
Yield: 70 %

Procedure:
A solution of (2R,3S)-3-fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (252 mg, 0.778 mmol; 72% purity by HPLC/215 nm) in MeOH (20 mL) was hydrogenated at RT (1 atm) over Pd/C 10% (35 mg, 10% w/w) for 24 h. The reaction mixture was filtered through a 0.45 microns filter and concentrated under reduced pressure to give the crude title compound (70% purity by HPLC/215 nm) as a white solid. This material was used in the next reaction step without further purification. MS (LC/MS): 232 [M−H]+; tR (HPLC conditions b): 2.78 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:27]4[CH:26]=[CH:25][CH:24]=[C:23]([F:22])[CH:28]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Reactant: OB(O)c1cccc(F)c1
Product: COc1ccc(-c2nc3cc(-c4cccc(F)c4)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 3-fluorophenylboronic acid (120 mg, 0.86 mmol) the subtitle compound was obtained, (103 mg, 49%). 1H NMR (DMSO) δ 8.59(d, 1H), 8.40(dd, 1H), 8.08(d, 1H), 7.82(d, 1H), 7.72(dd, 1H), 7.52(m, 4H), 7.17(dt, 1H), 4.02(s, 3H).
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[C:32](Cl)(=[O:41])[O:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1>O1CCCC1>[F:40][C:37]1[CH:38]=[CH:39][C:34]([O:33][C:32]([N:13]2[CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8][C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:11]3[CH2:12]2)=[O:41])=[CH:35][CH:36]=1
Reactant: O=C(Cl)Oc1ccc(F)cc1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Oc1ccc(F)cc1)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
To a solution of hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (50 mg, 0.17 mmol) in tetrahydrofuran (2 mL) were sequentially added diisopropylethylamine (0.30 mL, 1.7 mmol) and 4-fluorophenyl chlorocarbonate (45 mg, 0.26 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1) and crystallized from diisopropyl ether to obtain the title compound (58 mg, yield 79%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[C:4]=1[CH:5]=[O:6].[Mn]([O-])(=O)(=O)=[O:17].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[C:4]=1[C:5]([OH:17])=[O:6]
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1OC
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc([N+](=O)[O-])c(C(=O)O)c1OC

Procedure:
2,3-Dimethoxy-6-nitrobenzaldehyde from Example 6 (331 g) was added to acetone (2.5 1) in a 12 1 flask. A saturated solution (approximately 60-65 g/ 1) of potassium permanganate was added until TLC showed no starting material. Approximately 7 1 was required. The reaction mixture was filtered to remove the MnO2 and was washed with 2.5N KOH and acetone (2 1 each). The combined filtrates were evaporated to dryness and acidified with concentrated HCl. The precipitated solid was collected on a filter, washed with water (250 ml) and dried overnight. The solid was dissolved in 2 1 acetone, treated with MgSO4 and charcoal, evaporated to 500 ml and cooled to 5°. The crystals were filtered, washed with acetone and hexane and dried to afford dimethoxy acid (234 g, 65.7%) mp 187°-189° C.
Reaction SMILES: C(OC([N:6]([CH2:13]/[CH:14]=[CH:15]/[P:16](=[O:19])([OH:18])[OH:17])[O:7]C(OCC)=O)=O)C.Cl.C>O.C(O)C.N1C=CC=CC=1>[OH:7][NH:6][CH2:13]/[CH:14]=[CH:15]/[P:16](=[O:17])([OH:19])[OH:18]
Reactant: CCOC(=O)ON(C/C=C/P(=O)(O)O)C(=O)OCC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: O
Product: O=P(O)(O)/C=C/CNO
Yield: 54.2 %

Procedure:
A mixture of 3-(N-ethoxycarbonyl-N-ethoxycarbonyloxyamino)-trans-1-propenylphosphonic acid (8.53 g.) and 1 N hydrochloric acid (250 ml.) was refluxed for 16 hours. The resultant mixture was concentrated under reduced pressure to give a residue, which was dissolved in water (30 ml.). The aqueous solution was treated with activated charcoal (0.5 g.) and concentrated under reduced pressure to give an oily residue (5.85 g.), which was dissolved in water (10 ml.). The aqueous solution was passed through a column of anion exchange resin, Amberlite IRA 400 (100 ml.). The column was washed with water (600 ml.) and the object compound was eluted with 1 N hydrochloric acid (300 ml.). The eluate was concentrated under reduced pressure to give an oily residue (3.9 g.), to which were added ethanol (10 ml.) and water (2 ml.). The mixture was adjusted to pH 4-4.5 with pyridine and then to the mixture was added ethanol (30 ml.). The supernatant was removed by decantation to give residue, which was pulverized with ethanol (30 ml.) to give powdery 3-(N-hydroxyamino)-trans-1-propenylphosphonic acid (2.38 g.).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.CN(C)/[CH:20]=[CH:21]\[N+:22]([O-:24])=[O:23]>ClCCl>[N+:22]([CH:21]=[CH:20][C:6]1[C:5]2[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[NH:8][CH:7]=1)([O-:24])=[O:23]
Reactant: CN(C)/C=C\[N+](=O)[O-]
Reactant: Fc1ccc2cc[nH]c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])C=Cc1c[nH]c2cc(F)ccc12
Temperature: 2.5 °C
Reaction time: 0.75 h

Procedure:
Combine 6-fluoroindole (108 g, 0.8 mol) and dichloromethane (324 ml). Cool in an ice bath. Add trifluoroacetic acid (308 ml) over a few minutes (exothermic). Add a solution of Z-1-dimethylamino-2-nitroethylene (94.7 g, 0.816 mol) in dichloromethane (600 ml) during 40 minutes while maintaining the temperature at about 0-5° C. After 45 minutes, warm to about 20° C. After 2 hours, pour over 1.2 L ice water and stirring overnight with seeding to give a solid. Collect the solid by filtration, wash first with 100 ml of a mixture dichloromethane-cyclohexane 1/1, then with 750 ml of water and dry at 4° C. to give 3-(2-nitrovinyl)-6-fluoroindole.
Reaction SMILES: C([O:4][CH:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][CH2:6]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:4][CH:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:13])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:7][CH2:6]1
Reactant: CC(=O)OC1CCC(NC(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCC(O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.8 %

Procedure:
A mixture of 4-[[(tert-butoxy)carbonyl]amino]cyclohexyl acetate (2.43 g, 9.44 mmol, 1.00 equiv), methanol (30 mL) and potassium carbonate (2 g, 14.37 mmol, 1.50 equiv) was stirred overnight at 25° C. The resulting mixture was concentrated under vacuum. Water (50 mL) was added and the resulting solution was extracted with 3×70 mL of dichloromethane. The organic layers were combined and washed with 2×200 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give 2.19 g of crude tert-butyl N-(4-hydroxycyclohexyl)carbamate as yellow oil.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)#[N:2].CO.[ClH:17].CO[CH:20](OC)[CH2:21][NH2:22]>CCOCC>[ClH:17].[NH:2]1[CH:20]=[CH:21][N:22]=[C:1]1[CH2:3][CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1
Reactant: COC(CN)OC
Reactant: COC(=O)c1ccc(CCC#N)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1ccc(CCc2ncc[nH]2)cc1

Procedure:
Nitrile 23-3 (400 mg, 2.11 mmol) was dissolved in 10 mL Et2O at 0° MeOH (289 μL, 4.2 mmol) was added, the mixture was saturated with anhydrous HCl. Once the white ppt. formed, the solvent was evaporated and replaced with MeOH (5 mL), cooled to 0°, and aminoacetaldehyde dimethylacetal (250 μL, 2.3 mmol) was added. The reaction was heated to reflux for 3 days then concentrated, diluted in 10 mL 6 N HCl and concentrated again providing 23-4 as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](Cl)=[O:6].[Si:13]([O:20][CH2:21][CH2:22][NH:23][CH3:24])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[OH-].[Na+]>C(Cl)Cl>[Si:13]([O:20][CH2:21][CH2:22][N:23]([CH3:24])[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([F:11])=[C:2]([Cl:1])[C:3]=1[F:12])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15]
Reactant: O=C(Cl)c1ccc(F)c(Cl)c1F
Reactant: CNCCO[Si](C)(C)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1ccc(F)c(Cl)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 68.2 %

Procedure:
3-Chloro-2,4-difluorobenzoyl chloride (1.92 g, 9.1 mmol) was added slowly to a stirred solution of (2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)methylamine (1.89 g, 10.0 mmol) in a 1:1 mixture of 10% sodium hydroxide solution and DCM at 0° C. The reaction mixture was then allowed to warm up to RT and left to stir for 5 hours. The phases were separated and the aqueous phase was extracted with DCM (3×50 mL). The combined extracts were dried (MgSO4), filtered and evaporated to give a pale yellow oil. Purification by column chromatography on silica, eluting with 0-50% ethyl acetate in hexanes, gave the title compound as a colourless oil (2.26 g) 1H NMR δ (CDCl3): 0.00 (s, 6H), 0.82 (s, 9H), 2.93 (s, 3H), 3.58 (t, 2H), 3.81 (t, 2H), 6.95 (dtd, 1H), 7.16-7.22 (m, 1H)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([C:20]([NH:22][CH2:23][C:24]3[C:25]([NH:37][CH:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[C:26]4[CH:34]=[N:33][N:32]([CH2:35][CH3:36])[C:27]4=[N:28][C:29]=3[CH2:30][CH3:31])=[O:21])[CH:14]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH:44]([C:46]1[CH:47]=[C:48](B(O)O)[CH:49]=[CH:50][CH:51]=1)=[O:45].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.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>[CH2:35]([N:32]1[C:27]2=[N:28][C:29]([CH2:30][CH3:31])=[C:24]([CH2:23][NH:22][C:20]([C:15]3[CH:16]=[C:17]([CH3:19])[CH:18]=[C:13]([C:11]([NH:10][CH2:9][C:4]4[CH:3]=[C:2]([C:50]5[CH:49]=[CH:48][CH:47]=[C:46]([CH:44]=[O:45])[CH:51]=5)[C:7]([CH3:8])=[CH:6][CH:5]=4)=[O:12])[CH:14]=3)=[O:21])[C:25]([NH:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[C:26]2[CH:34]=[N:33]1)[CH3:36]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(C)c(Br)c2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(C)c(-c3cccc(C=O)c3)c2)c1
Yield: 60.8 %

Procedure:
N-[(3-Bromo-4-methylphenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-5-methyl-1,3-benzenedicarboxamide (840 mg, 1.297 mmol), (3-formylphenyl)boronic acid (194 mg, 1.297 mmol), potassium carbonate (538 mg, 3.89 mmol), and Pd(Ph3P)4 (74.9 mg, 0.065 mmol) were divided into 3 portions and added to three 2-5 mL Biotage microwave vials in 1,4-dioxane (3 mL) and water (1 mL). The vials were capped and the mixture was microwaved at normal power in the Emrys Optimizer at 100° C. for 15 min. The combined crude product was partitioned between EtOAc (75 mL) and water (20 mL). The phases were separated, and the organic washed with water (2×20 mL), brine (20 mL), dried over anhydrous Na2SO4 filtered and evaporated to give the crude residue. The residue was taken up in DCM and absorbed on Isolute® Sorbent and purified by Combiflash using an 80 g silica column eluted with 0-10% DCM/MeOH. The product fractions were combined and concentrated to give (N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-6-methyl-3-biphenylyl)methyl]-5-methyl-1,3-benzenedicarboxamide (537 mg, 0.789 mmol, 60.8% yield)) as a white solid. LC-MS m/z 673.4 (M+H)+, 0.99 min (ret time); mp 117-120° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[NH:13][CH:12]([C:14]([OH:16])=[O:15])[CH2:11][S:10]2)=[CH:5][CH:4]=1.O.Cl.N[C@H](C(O)=O)CS.C([O-])(=O)C.[Na+].N[C@H](C(O)=O)CS.[CH3:38][O:39][C:40]1[CH:47]=[CH:46][C:43]([CH:44]=[O:45])=[CH:42][CH:41]=1>C(O)C.O>[CH3:38][O:39][C:40]1[CH:47]=[CH:46][C:43]([CH:44]=[O:45])=[CH:42][CH:41]=1.[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[NH:13][CH:12]([C:14]([OH:16])=[O:15])[CH2:11][S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2NC(C(=O)O)CS2)cc1
Agent: CC(=O)[O-]
Agent: COc1ccc(C=O)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(C2NC(C(=O)O)CS2)cc1
Reaction time: 0.5 h

Procedure:
Preparation of (R)-2-(4-methoxy-phenyl)-thiazolidine-4-carboxylic acid (A compound of Formula IIIa): A 22 L three-necked round bottom flask fitted with an internal temperature probe and a mechanical stirrer was charged with L-cysteine hydrochloride monohydrate (500.0 g, 2.85 mol), sodium acetate (260.0 g, 3.17 mol) and 4.00 L of water. The mixture was stirred until all of the L-cysteine dissolved. A solution of p-methoxybenzaldehyde (426.0 g, 3.13 mol) in 3.50 L of ethanol was prepared and added to the reaction such that the internal reaction temperature was kept below 30° C. The reaction becomes a thick white slurry during the addition of the p-methoxybenzaldehyde solution. After 30 minutes, 3.50 L of ethanol was added to the reaction. Stirring was continued for 1 hour and then the solid was isolated by filtration. A 1.50 L portion of ethanol was used to wash the solid. The solid was dried in a vacuum oven at 50° C. for 48 hours. Approximately 610 g of 2-(4-methoxy-phenyl)-thiazolidine-4-carboxylic acid was obtained (90% yield). 1H NMR (300 MHz, DMSO) δ 7.41-7.31 (m, 4H), 6.93-6.83 (m, 4H), 5.56 (s, 1H), 5.42 (s, 1H), 4.23 (dd, J=6.7, 4.4 Hz, 1H), 3.84 (dd, J=7.6, 7.1 Hz, 1H), 3.73 (s, 3H), 3.71 (s, 3H), 3.37-3.23 (m, 2H), 3.16-3.00 (m, 2H).