Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5](=[O:37])[CH:6](Cl)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:32]=[CH:33][C:34]=1[Cl:35])[C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:14])=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH:38][C:39]1[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][C:40]=1[NH:49][S:50]([CH3:53])(=[O:52])=[O:51].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:35][C:34]1[CH:33]=[CH:32][C:12]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:14])=[CH:11][C:10]=1[NH:9][C:7]([CH:6]([O:38][C:39]1[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][C:40]=1[NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[C:5](=[O:37])[C:1]([CH3:4])([CH3:3])[CH3:2])=[O:8]
Reactant: CCCCCCCCCCCCCCCCOC(=O)c1ccc(Cl)c(NC(=O)C(Cl)C(=O)C(C)(C)C)c1
Reactant: COC(=O)c1ccc(O)c(NS(C)(=O)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCOC(=O)c1ccc(Cl)c(NC(=O)C(Oc2ccc(C(=O)OC)cc2NS(C)(=O)=O)C(=O)C(C)(C)C)c1
Yield: 61 %

Procedure:
A suspension of 8.35 g (15 mmol) of 2, 3.68 g (15 mmol) of methyl 4-hydroxy-3-(methanesulfonamido)-benzoate 3 and 6.22 g (45 mmol) of potassium carbonate in 180 mL of acetone was heated at reflux overnight. Thin layer chromatographic analysis indicated reaction was complete. The solvent was removed under vacuum to near dryness, and the residue was treated with a mixture of ethyl acetate and water. The organic liquid phase was washed with dilute hydrochloric acid and then with brine, and then concentrated under vacuum to an oil. The crude product was purified by column chromatography on silica gel using an elution solvent of 30 volume percent ethyl acetate in ligroin. There was thus obtained 7 g (61% yield ) of coupler Y-1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>>[CH3:21][N:22]([CH3:24])/[CH:23]=[CH:9]/[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH:11]([OH:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:4]=1)=[O:10]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc(F)c(C(O)c2ccccc2)c1
Product: CN(C)/C=C/C(=O)c1ccc(F)c(C(O)c2ccccc2)c1

Procedure:
A round-bottomed flask was charged with 1-{4-fluoro-3-[hydroxy(phenyl)methyl]phenyl}ethanone (140 mg) and dimethylformamide dimethylacetal (4 mL). The mixture was heated to reflux for 18 h then concentrated to dryness. The residue was taken up in minimal methylene chloride then added to rapidly stirring diethyl ether to induce a solid. The solids were collected on filter and washed with diethyl ether to provide (2E)-3-(dimethylamino)-1-{4-fluoro-3-[hydroxy(phenyl)methyl]phenyl}-2-propen-1-one as a white powder (60 mg). 8.09 (dd, 1H), 7.82 (m, 1H), 7.69 (d, 1H), 7.31 (m, 4H), 7.21 (m, 1H), 7.14 (dd, 1H), 6.06 (d, 1H), 5.94 (d, 1H), 5.75 (d, 1H), 3.14 (s, 3H), 2.88 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:38]=[CH:39][CH:40]=1)[CH2:7][C:8]1[C:9](=[O:37])[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][C:34](=[O:36])[O:33][N:32]=3)=[CH:21][CH:20]=2)[C:11]([CH2:15][CH2:16][CH3:17])=[N:12][C:13]=1[CH3:14])(=[O:3])[CH3:2].[BH4-].[Na+]>O1CCCC1CO.C(OCC)(=O)C>[OH:3][CH:1]([C:4]1[CH:5]=[C:6]([CH:38]=[CH:39][CH:40]=1)[CH2:7][C:8]1[C:9](=[O:37])[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][C:34](=[O:36])[O:33][N:32]=3)=[CH:21][CH:20]=2)[C:11]([CH2:15][CH2:16][CH3:17])=[N:12][C:13]=1[CH3:14])[CH3:2]
Reactant: CCCc1nc(C)c(Cc2cccc(C(C)=O)c2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: OCC1CCCO1
Solvent: CCOC(C)=O
Product: CCCc1nc(C)c(Cc2cccc(C(C)O)c2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
To a solution of 5-(3-acetylbenzyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one (0.20 g) in tetrahydrofuran-methanol (1:1, 4 mL) was added sodium borohydride (0.014 g), and the mixture was stirred for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (0.14 g, 69%) as a colorless solid.
Reaction SMILES: CC(S([NH:7][C:8]1([C:18]2[S:19][C:20]([C:23]3[CH:28]=[C:27]([NH:29][C:30]4[N:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][N:31]=4)[CH:26]=[C:25]([CH3:40])[CH:24]=3)=[CH:21][N:22]=2)[CH2:17][CH2:16][C:11]2(OCC[O:12]2)[CH2:10][CH2:9]1)=O)(C)C.C(Cl)(Cl)Cl.[N-:45]=[N+]=[N-].[Na+].CS(O)(=O)=O>O>[NH2:7][C:8]1([C:18]2[S:19][C:20]([C:23]3[CH:28]=[C:27]([NH:29][C:30]4[N:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][N:31]=4)[CH:26]=[C:25]([CH3:40])[CH:24]=3)=[CH:21][N:22]=2)[CH2:17][CH2:16][NH:45][C:11](=[O:12])[CH2:10][CH2:9]1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(NS(=O)C(C)(C)C)CCC4(CC3)OCCO4)s2)c1
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(N)CCNC(=O)CC3)s2)c1
Temperature: 65 °C
Yield: 63.8 %

Procedure:
To the product of Step 2 (100 mg, 0.13 mmol) was added chloroform (630 pt), sodium azide (24.5 mg, 0.38 mmol), and methanesulfonic acid (98 μL, 1.51 mmol). The mixture was heated to 65° C. for 1.5 h., cooled to room temperature, diluted with water, and extracted with ethyl acetate (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase HPLC (35:65 to 70:30 acetonitrile:water with a 0.1% trifluoroacetic acid modifier). The fractions containing the desired product were diluted with ethyl acetate and free based with saturated aqueous sodium bicarbonate. The separated organic layer was dried over magnesium sulfate, filtered and concentrated to afford the title compound (38 mg, 0.083 mmol, 66% yield) as an orange oil. MS ESI: [M+H]+ m/z 463. 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.83 (s, 1H), 8.75 (s, 1H), 8.02 (s, 1H), 7.93 (s, 1H), 7.49 (s, 1H), 7.28 (d, J=4.7, 1H), 7.16 (s, 1H), 2.39-2.08 (m, 9H), 1.30-0.99 (m, 4H). rhSYK activity=+++
Reaction SMILES: [N:1]1[N:8]2[C:4]([O:5][C:6]3[CH2:12][O:11][CH2:10][CH2:9][C:7]=32)=[CH:3][C:2]=1[C:13]([O-])=[O:14].[BH4-].[Li+].CO>C1COCC1>[N:1]1[N:8]2[C:4]([O:5][C:6]3[CH2:12][O:11][CH2:10][CH2:9][C:7]=32)=[CH:3][C:2]=1[CH2:13][OH:14]
Reactant: O=C([O-])c1cc2oc3c(n2n1)CCOC3
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cc2oc3c(n2n1)CCOC3
Temperature: 4 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
To the stirred solution of 7,8-dihydro-5H-pyrano[4,3-d]pyrazolo[5,1-b][1,3]oxazole-2-carboxylate (1.5 g, 6.3 mmol) of in 100 ml of THF was added 1.05 g of lithium borohydride and 1.54 g of methanol. The solution was heated at 4° C. for 2.5 hour. The reaction was quenched by 1N HCl, and adjusted to pH 1.3 and stirred at room temperature for 1 hour. The reaction mixture was adjusted pH to 8 with k2CO3. The reaction mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4, and concentrated to an oil and column chromatographyed to give 0.74 g of the desired product (60%). (M+H) 196.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][CH:6]1[OH:7])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:22](Cl)(=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CN(C)C=O>[C:1]([NH:4][C@@H:5]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][O:15][C:22](=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[O:8][C@@H:6]1[OH:7])(=[O:3])[CH3:2]
Reactant: CCCCCCCC(=O)Cl
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCCCCCCC(=O)OC[C@H]1O[C@H](O)[C@H](NC(C)=O)[C@@H](O)[C@@H]1O
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To 0.5 g of N-acetylglucosamine, 5 mL of pyridine and 5 mL of N,N-dimethylformamide were added, and the mixture was heated to 70° C. under stirring, and 0.46 mL of n-octanoyl chloride was dropwise added, and the reaction was carried out for 4 hours. On completion of the reaction, the reaction was extracted with ethyl acetate and washed with 2 mol/L hydrochloric acid, and the obtained ethyl acetate layer was dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent; chloroform:methanol=15:1) to obtain 170 mg of 2-acetamido-2-deoxy-6-O-octanoyl-α-D-glucopyranose as a white crystal.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=1.[C:9](=O)([O-])[O-].[K+].[K+].F[C:16]1[CH:21]=[C:20](C)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:17]=1[CH3:26].O.Cl>CS(C)=O>[Br:1][C:2]1[C:3](=[O:8])[N:4]([C:16]2[C:17]([CH3:26])=[CH:18][C:19]([N+:23]([O-:25])=[O:24])=[CH:20][C:21]=2[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1F
Reactant: O=c1[nH]cccc1Br
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(C)c1-n1cccc(Br)c1=O
Temperature: 120 °C
Reaction time: 3.5 h

Procedure:
150 g (750 mmol) of 3-bromopyridin-2(1H)-one (O. S. Tee, M. Pavent, J. Am. Chem. Soc. 1982, 104, 4142-4146.) and 207 g (1.50 mol) of potassium carbonate are dissolved in 2.9 l of dimethyl sulphoxide and heated to 120° C. At this temperature, a solution of 317 g (750 mmol) of 1-fluoro-2,5-dimethyl-4-nitrobenzene in 700 ml of dimethyl sulphoxide is added dropwise over a period of 60 min, and the mixture is stirred at 120° C. for 3.5 h. After cooling, the reaction solution is stirred into a water/hydrochloric acid mixture. The mixture is extracted with ethyl acetate, the phases are separated and the aqueous phase is once more extracted with ethyl acetate. The combined organic phases are then washed with water. The phases are separated, and the organic phase is dried over sodium sulphate. After concentration under reduced pressure, the residue is purified by chromatography on silica gel (dichloromethane, then ethyl acetate/dichloromethane 1:20). The product-containing fractions are combined, the solvents are removed and the residue is triturated with diethyl ether. This gives 112 g (46% of theory) of the desired compound.
Reaction SMILES: [CH3:1][N:2]([CH3:62])[C:3](=[O:61])[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH:31][CH2:32][C@H:33]([OH:60])[CH2:34][O:35][C:36]4[CH:41]=[CH:40][C:39]([O:42][Si](C(C)(C)C)(C5C=CC=CC=5)C5C=CC=CC=5)=[CH:38][CH:37]=4)=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:7][CH:6]=1>C(Cl)(Cl)Cl.CO>[OH:60][C@H:33]([CH2:34][O:35][C:36]1[CH:37]=[CH:38][C:39]([OH:42])=[CH:40][CH:41]=1)[CH2:32][NH:31][CH2:30][CH2:29][C:26]1[CH:25]=[CH:24][C:23]([NH:22][CH:19]2[CH2:20][CH2:21][N:16]([C:14]([NH:13][CH2:12][CH2:11][C:8]3[CH:9]=[CH:10][C:5]([O:4][C:3](=[O:61])[N:2]([CH3:1])[CH3:62])=[CH:6][CH:7]=3)=[O:15])[CH2:17][CH2:18]2)=[CH:28][CH:27]=1
Reactant: CN(C)C(=O)Oc1ccc(CCNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)cc4)cc3)CC2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)Oc1ccc(CCNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1
Yield: 56.6 %

Procedure:
4-{2-[({4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-1-piperidinyl)carbonyl)amino]ethyl}phenyl dimethylcarbamate (0.22 g, 0.256 mmol) was reacted according to Procedure H (eluant: 10:1 chloroform-methanol) to give the title compound (0.09 g, 0.145 mmol).
Reaction SMILES: [C:1]1([C:14]2[C:22]3[C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[S:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[B:32](OC)([O:35]C)[O:33]C.Cl>CCCCCC.O1CCCC1>[C:1]1([C:14]2[C:22]3[C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[S:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[C:13]([B:32]([OH:35])[OH:33])[C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)sc1cccc(-c3cccc4sc5ccccc5c34)c12
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1cccc2c1sc1cccc(-c3cccc4sc5ccccc5c34)c12
Temperature: -80 °C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
Into a 500-mL three-neck flask was put 5.0 g (13 mmol) of 4,4′-bidibenzothiophene, and the air in the flask was replaced with nitrogen. Into this flask was put 100 mL of tetrahydrofuran (THF), and this solution was cooled down to −80° C. To this solution, 8.7 mL (14 mmol) of n-butyllithium (a 1.6 mol/L hexane solution) was dripped with a syringe. After the dripping, this solution was stirred for 2 hours while its temperature was returned to room temperature. After the stirring, this solution was cooled down to −80° C. To this solution, 1.9 mL (17 mmol) of trimethyl borate was added, and the mixture was stirred for 18 hours while its temperature was returned to room temperature. After the stirring, approximately 50 mL of dilute hydrochloric acid (1.0 mol/L) was added to this solution, followed by stirring for 1 hour. After the stirring, the aqueous layer of this mixture was extracted with ethyl acetate, and the extracted solution and the organic layer were combined and washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated brine. The organic layer was dried with magnesium sulfate, and then this mixture was gravity-filtered. The resulting filtrate was concentrated to give a white solid. This solid was washed with 100 mL of hot toluene to give 2.6 g of white powder, which was an objective substance, in 50% yield. Synthesis Scheme (a-2) of Step 2 is shown below.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])[C:13]=2[CH3:25])[CH:7]=[CH:6][C:5]=1[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[F:34].O.O.[OH-].[Li+]>CO.C1COCC1>[CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:13]=2[CH3:25])[CH:7]=[CH:6][C:5]=1[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[F:34]
Reactant: CCOC(=O)CCc1ncnc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(COc3ncnc(CCC(=O)O)c3C)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
To a solution of ethyl 3-(6-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-5-methylpyrimidin-4-yl)propanoate (180 mg) in methanol (2.0 mL) and THF (2.0 mL) were added water (2.0 mL) and lithium hydroxide monohydrate (75 mg), and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative HPLC to give the title compound (88 mg) as a white solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].I[CH2:6][CH2:7][O:8][C:9]([C@:11]1([F:31])[C@@H:16]2[C@H:12]1[CH2:13][C@@H:14]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C@@:15]2([NH2:20])[C:17]([OH:19])=[O:18])=[O:10]>CN(C)C=O.O>[N:1]([CH2:6][CH2:7][O:8][C:9]([C@:11]1([F:31])[C@@H:16]2[C@H:12]1[CH2:13][C@@H:14]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C@@:15]2([NH2:20])[C:17]([OH:19])=[O:18])=[O:10])=[N+:2]=[N-:3]
Reactant: N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@H]1OCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)OCCI
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](OCc3ccc(Cl)c(Cl)c3)[C@@](N)(C(=O)O)[C@@H]21
Temperature: 60 °C
Reaction time: 12 h
Yield: 46.3 %

Procedure:
6 mg of sodium azide was added to 18 mg of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6-(2-iodoethyl) ester dissolved in a mixture of 0.2 mL of N,N-dimethylformamide and 0.02 mL of water at room temperature, and the mixture was stirred for 12 hours at 60° C. After standing to cool, the solvent was distilled under reduced pressure, and the residue was purified by reverse phase column chromatography (Wako gel 50C18, eluent: water to a 70% aqueous solution of acetonitrile), thereby yielding 7 mg of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6-(2-azidoethyl) ester
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[C:7]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=2)(=[O:21])=[O:20])[N:6]=[C:5]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([C:35]([OH:37])=O)[CH:30]=2)[N:4]=1.[CH3:38][N:39]1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.Cl.CN>CN(C=O)C>[CH3:38][NH:39][C:35]([C:31]1[CH:30]=[C:29]([C:5]2[N:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][CH3:17])=[C:7]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=3)(=[O:21])=[O:20])[N:6]=2)[CH:34]=[CH:33][N:32]=1)=[O:37]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(C(=O)O)c2)nc1OC
Reactant: CN1CCOCC1
Agent: CN
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(-c2nc(NS(=O)(=O)c3ccc(C)cn3)c(Oc3ccccc3OC)c(OC)n2)ccn1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
70 mg of 4-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-pyridine-2-carboxylic acid, product of example 21, dissolved in DMF (5 ml) was treated at RT with 30 mg of 4-methylmorpholine, then cooled to 0° C. and further treated with 26 mg of 2-chloro-4,6-dimethoxy-1,3,5-triazine followed. The solution was stirred at RT for 90 minutes, then treated with 10 mg of metylamine hydrochloride and stirred for 12 h at RT. The mixture was partitioned between cold diluted HCl and EtOAc. The layers were separated, the organic layer washed with water, dried over Na2SO4 and the solvent was removed in vacuo. The solid residue was triturated with ether, filtered off and dried in a high vacuum to give 4-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-pyridine-2-carboxylic acid methyl amide as a white crystalline solid. ISN mass spectrum, m/e 535.2 (M−1 calculated for C25H24N6O6S: 535).
Reaction SMILES: O[CH2:2][C:3]1([C:19]2[C:28]([OH:29])=[CH:27][C:26]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[CH:20]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:4]1=[O:18].OC1C=C2C(CCC2)=CC=1C1(CO)C2C(=CC=CC=2)N(CC(OCC)=O)C1=O>>[O:18]=[C:4]1[C:3]2([CH2:2][O:29][C:28]3[CH:27]=[C:26]4[C:21](=[CH:20][C:19]2=3)[CH2:22][CH2:23][CH2:24][CH2:25]4)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]1[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CN1C(=O)C(CO)(c2cc3c(cc2O)CCCC3)c2ccccc21
Agent: CCOC(=O)CN1C(=O)C(CO)(c2cc3c(cc2O)CCC3)c2ccccc21
Product: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)CCCC4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 1.45, and making non-critical variations using ethyl [3-(hydroxymethyl)-3-(3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate to replace ethyl [3-(6-hydroxy-2,3-dihydro-1H-inden-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate, the title compound was obtained (24% in three steps): 1H NMR (300 MHz, CDCl3) δ 7.29 (td, 1H), 7.19 (d, 1H), 7.07 (t, 1H), 6.79 (d, 1H), 6.66 (s, 1H), 6.51 (s, 1H),), 4.91 (d, 1H), 4.67 (d, 1H), 4.52 (ABq, 2H), 4.24 (q, 2H), 2.77-2.51 (m, 4H), 1.77-1.64 (m, 4H), 1.29 (t, 3H); MS (ES+) m/z 378 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=[C:4]([CH2:11]Cl)[CH:3]=1.[C-:13]#[N:14].[Na+].O>CS(C)=O>[Cl:1][C:2]1[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=[C:4]([CH2:11][C:13]#[N:14])[CH:3]=1
Reactant: ClCc1cc(Cl)c2c(c1)OCO2
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1cc(Cl)c2c(c1)OCO2
Temperature: 40 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
A mixture of 4-chloro-6-(chloromethyl)benzo[d][1,3]dioxole (6.0 g, 29 mmol) and NaCN (1.6 g, 32 mmol) in DMSO (20 mL) was stirred at 40° C. for 1 h and was then poured into water. The mixture was extracted with EtOAc (30 mL×3). The combined organic layers were washed with water and brine, dried over Na2SO4 and evaporated under reduced pressure to afford 2-(7-chlorobenzo[d][1,3]dioxol-5-yl)acetonitrile (3.4 g, 58%). 1H NMR 8 6.81 (s, 1 H), 6.71 (s, 1 H), 6.07 (s, 2 H), 3.64 (s, 2 H). 13C-NMR δ149.2, 144.3, 124.4, 122.0, 117.4, 114.3, 107.0, 102.3, 23.1.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][C:11]=1[F:17]>CC(O)=O.C1(C)C=CC=CC=1>[Br:9][C:10]1[C:11]([F:17])=[CH:12][C:13]([NH2:14])=[C:15]([I:1])[CH:16]=1
Reactant: Nc1ccc(Br)c(F)c1
Reactant: O=C1CCC(=O)N1I
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Nc1cc(F)c(Br)cc1I
Temperature: 25 °C
Yield: 87 %

Procedure:
N-iodosuccinimide (2.90 ml, 28.9 mmol) was added to a solution of 4-bromo-3-fluoroaniline (5.00 g, 26.3 mmol) in AcOH (52.6 ml). The reaction was maintained at ambient temperature for 1.5 h, then diluted with 20 mL toluene and concentrated. The residue was dissolved in EtOAc and washed with 2 N aqueous NaOH. The organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40-g Ultra SNAP column, 25-g silica gel loading column, 2-10% EtOAc/Heptane) to give 4-bromo-5-fluoro-2-iodoaniline (7.23 g, 22.89 mmol, 87% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.74-7.78 (m, 1H), 6.53-6.57 (m, 1H). m/z (ESI) 315.9 (M+H)+.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(OC([NH:32][C:33]1([C:48]([OH:50])=O)[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=O)(C)(C)C.[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([CH:58]([CH:60]2[CH2:62][CH2:61]2)[NH2:59])=[CH:54][CH:53]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[NH2:32][C:33]1([C:48]([NH:59][CH:58]([C:55]2[CH:54]=[CH:53][C:52]([Cl:51])=[CH:57][CH:56]=2)[CH:60]2[CH2:62][CH2:61]2)=[O:50])[CH2:34][CH2:35][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:37][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: NC(c1ccc(Cl)cc1)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: NC1(C(=O)NC(c2ccc(Cl)cc2)C2CC2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.228 g) was added to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (0.181 g), (4-chlorophenyl)(cyclopropyl)methanamine (Intermediate 3) (0.091 g) and DIPEA (0.261 mL) in DMA (5 mL) at 25° C. The resulting solution was stirred at 50° C. for 1 hour. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7N ammonia/MeOH and pure fractions were evaporated to dryness. This crude material was suspended in dichloromethane (25 mL), and TFA (5 mL) was added. The reaction mixture was stirred for 1 hour, then the crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7N ammonia/MeOH and pure fractions were evaporated to dryness to afford the crude material as a white solid. This material was triturated under cold methanol to give the pure product, 4-amino-N-((4-chlorophenyl)(cyclopropyl)methyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide as a white solid (0.167 g, 79%).