Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][C:4]=1[C:18]([O:20]C)=O.Cl.[CH3:23][O:24][C:25](=[O:31])[C@H:26]([CH:28]([CH3:30])[CH3:29])[NH2:27].C(N(CC)CC)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:29][CH:28]([CH3:30])[C@H:26]([N:27]1[CH2:2][C:3]2[C:4](=[CH:5][C:6]([C:9]3[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=3)=[CH:7][CH:8]=2)[C:18]1=[O:20])[C:25]([O:24][CH3:23])=[O:31]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: COC(=O)c1cc(-c2ccc([N+](=O)[O-])cc2)ccc1CBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc([N+](=O)[O-])cc3)cc2C1=O

Procedure:
A mixture of the compound of example 4 (1.54 g, 0.0044 mol) and L-valine methyl ester hydrochloride (0.813 g, 0.0048 mol) was taken in toluene (30 mL) in a round bottom flask. To this reaction mixture, triethyl amine (0.98 g, 0.0097 mol) was added and refluxed for 3-4 h. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over anhydrous sodium sulfate and concentrated to obtain an oily material, which was purified by column chromatography (silicagel, 30% ethyl acetate in petroleum ether).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][CH:9]1[C:15]([O:17]C)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:13])([F:14])[CH2:10][CH:9]1[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1CC(F)(F)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(F)(F)CC1C(=O)O
Reaction time: 1 h
Yield: 92.4 %

Procedure:
To a stirred solution of methyl 1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidine-2-carboxylate (885 mg, 3.34 mmol) in THF (25 ml) was added 0.25 N NaOH (26.7 ml, 6.67 mmol) and the stirring was continued for 1 h. The mixture was poured into 1 N HCl (100 ml) and extracted with CHCl3 (2×200 ml). The combined extracts were washed with brine (100 ml), dried over MgSO4, and evaporated to give 1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidine-2-carboxylic acid (775 mg, 92%) as a yellow crystalline solid. mp 113–117° C.; 1H-NMR (CDCl3) δ 1.44 and 1.49 (s, each, total 9 H), 2.53–2.80 (m, 2 H), 3.71–3.90 (m, 2 H), 4.20–4.61 (m, 1 H); MS (FAB) m/z, 252 (M++1); Anal. Calcd for C10H15F2O4: C, 47.81; H, 6.02; N, 5.58. Found: C, 48.06; H, 6.05; N, 5.45.
Reaction SMILES: N1(C2C=CC(C3N4CCC5NC(=O)C=CC(C=54)=CN=3)=C(C)C=2)CCOCC1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[O:34]=[C:35]1[NH:44][C:43]2[CH2:42][CH2:41][N:40]3[C:45]([C:48]4[CH:55]=[CH:54][C:51]([CH:52]=O)=[CH:50][CH:49]=4)=[N:46][CH:47]=[C:38]([C:39]=23)[CH:37]=[CH:36]1.[K+].[Br-]>CO.C(Cl)(Cl)Cl>[N:28]1([CH2:52][C:51]2[CH:54]=[CH:55][C:48]([C:45]3[N:40]4[CH2:41][CH2:42][C:43]5[NH:44][C:35](=[O:34])[CH:36]=[CH:37][C:38]([C:39]=54)=[CH:47][N:46]=3)=[CH:49][CH:50]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: O=Cc1ccc(C2=NC=C3C=CC(=O)NC4=C3N2CC4)cc1
Reactant: C1COCCN1
Agent: Cc1cc(N2CCOCC2)ccc1C1=NC=C2C=CC(=O)NC3=C2N1CC3
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C1C=CC2=CN=C(c3ccc(CN4CCOCC4)cc3)N3CCC(=C23)N1

Procedure:
Using the reductive amination procedure described in Example 32, 0.097 g (38%) of 1-(4-morpholin-4-yl methyl-phenyl)-8,9-dihydro-7H-2,7,9a-triaza-benzo[cd]azulen-6-one was prepared from morpholine and 4-(6-oxo-6,7,8,9-tetrahydro-2,7,9a-triaza-benzo[cd]azulen-1-yl)-benzaldehyde as a white solid: mp=285-286° C. (dec); Rf=0.11 (5% MeOH/CHCl3); IR (KBr) 1661, 1653, 1483, 1113 cm−1; 1H NMR (DMSO-d6) δ 2.40-2.41 (m, 4H), 3.15-3.17 (m, 2H), 3.26-3.61 (m, 6H), 4.45-4.46 (m, 2H), 7.35 (t, 1H, J=7.8 Hz), 7.51 (d, 2H, J=8.1 Hz), 7.82 (d, 2H, J=8.1 Hz), 7.84-7.90 (m, 2H), 8.43-8.47 (m, 1H). HRMS calcd for C21H22N4O2 362.1743 (M+), found 362.1737. Anal. (C21H22N4O2) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:25][N:24]=[CH:23][C:22]=2[CH2:26][CH2:27][C:28](O)=[O:29])=[CH:17][CH:16]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:12]([O:11][C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[CH2:27][CH2:26][C:22]2[CH:23]=[N:24][O:25][C:21]=2[C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)=[CH:7][CH:6]=1)=[O:10])[CH3:13]
Reactant: O=C(O)CCc1cnoc1-c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(NC(=O)CCc2cnoc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
A mixture of ethyl 4-aminophenylacetate (0.32 g), 3-[5-(4-chlorophenyl)-4-isoxazolyl]propionic acid (0.37 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.28 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.35 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(4-ethoxycarbonylmethylphenyl)-3-[5-(4-chlorophenyl)-4-isoxazolyl]propionamide (0.56 g, yield 93%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 117–118° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([I:9])[CH:8]=1)[NH2:5].O.[N:11]([O-])=O.[Na+]>Cl>[I:1][C:2]1[CH:3]=[C:4]([NH:5][NH2:11])[CH:6]=[C:7]([I:9])[CH:8]=1
Reactant: O=N[O-]
Reactant: Nc1cc(I)cc(I)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc(I)cc(I)c1
Temperature: -10 °C
Reaction time: 0.67 h

Procedure:
3,5-Diiodoaniline was obtained by the procedure of M. Bérubé (M. Bérubé, et al. Synthesis of Simplified Hybrid Inhibitors of Type 1 17β-Hydroxysteroid Dehydrogenase via the Cross-Metathesis and the Sonogashira Coupling Reactions, Organic Lett. 6 (2004) 3127-3130). 5 g (14.5 mmol) of 3,5-diiodoaniline were stirred with the solution of 5 mL of concentrated hydrochloric acid and 5 mL of water. The mixture was cooled to about −10° C. and 5.5 mL of 20% aqueous solution of NaNO2 was added dropwise with continuous stirring. The suspension was allowed to stir for another 40 minutes. Next, the cooled solution of 10.8 g (47.9 mmol) of SnCl2-2H2O in 11 mL of concentrated HCl was added dropwise at −10° C. to the suspension of diazocompound. The reaction mixture was kept −10° C. for one hour and at 5° C. overnight. The obtained precipitate of a double salt with tin chloride was filtered off and washed with water. The residue was resuspended in water and added concentrated aqueous solution of NaOH to alkaline medium. The 3,5-diiodophenylhydrazine was extracted with ether, the organic layer was washed in turn with aqueous NaOH, Na2S2O3 and water, and dried with CaCl2. Ether was evaporated to give 4.2 g of 3,5-diiodophenylhydrazine. 1H-NMR (200 MHz, DMSO-d6), δ, ppm: 7.10 (2H, d, 1.2 Hz, arom.), 6.92 (1H, d, 1.2 Hz, arom.), 5.51 (1H, s, NH), 4.12 (2H, broad s, NH2).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[C:7](=[O:21])[O:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[O:19][CH3:20])[CH:10]=1)=[O:4]>O=O>[CH3:1][O:2][C:3]([NH:5][CH:6]([CH2:10][CH2:9][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=1[O:19][CH3:20])[C:7]([OH:21])=[O:8])=[O:4]
Reactant: COC(=O)NC1=CC(c2cccc(OC)c2OC)OC1=O
Agent: O=O
Product: COC(=O)NC(CCc1cccc(OC)c1OC)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 3-methoxycarbonylamino-5-(2,3-dimethoxyphenyl)-2,5-dihydrofuran-2-one (500 mg, 1.7 mmoles) in oxygen free methanol (0.25M) is placed into a Parr hydrogenator, the catalyst (SS)-EtDiPhos(COD)OTs (1.5 μmoles) is added and the mixture is stirred for 1.5 hr at room temperature under hydrogen pressure (30 psi).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[N-:12]=[N+:13]=[N-:14].[Na+].CC(O)C.[OH-].[Na+]>[Br-].[Zn+2].[Br-].O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[NH:14][N:13]=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc2c(c1)CCO2
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: c1cc2c(cc1-c1nnn[nH]1)CCO2
Temperature: 80 °C
Reaction time: 48 h
Yield: 65.8 %

Procedure:
A mixture of 2,3-dihydro-1-benzofuran-5-carbonitrile (1.29 g, 8.89 mmol), sodium azide (1.16 g, 17.78 mmol), zinc bromide (1.00 g, 4.45 mmol), 2-propanol (15 mL) and water (30 mL) was stirred at 80° C. for 48 hr. The reaction mixture was basified with an aqueous sodium hydroxide solution, and washed with ethyl acetate. The aqueous layer was acidified with hydrochloric acid, and extracted with ethyl acetate/tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (1.10 g, yield 66%) as colorless crystals.
Reaction SMILES: C([O:5][C:6](=[O:26])[CH2:7][N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C:9]1=[O:25])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:18]([O:17][C:15]([NH:14][C:10]1[C:9](=[O:25])[N:8]([CH2:7][C:6]([OH:26])=[O:5])[CH:13]=[CH:12][CH:11]=1)=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)Cn1cccc(NC(=O)OCc2ccccc2)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cn1cccc(NC(=O)OCc2ccccc2)c1=O
Yield: 77.2 %

Procedure:
(3-Benzyloxycarbonylamino-2-oxo-2H-pyridin-1-yl)acetic acid tert-butyl ester (0.485 g, 1.35 mmol) was stirred in a 1:1 mixture of trifluoroacetic acid and CH2Cl2 at 23° C. for 1 h. The volatiles were then removed under reduced pressure and the residue was triturated with Et2O (40 mL). The resulting solid was filtered through a medium frit, washed with Et2O (20 mL) and air-dried to give the title intermediate (0.315 g, 77%): mp=171-173° C.; 1H NMR (DMSO-d6) δ 4.67 (s, 2H), 5.15 (s, 2H), 6.28 (t, 1H, J=7.1), 7.29-7.43 (m, 7H), 7.85 (dd, 1H, J=7.4, 1.7), 8.47 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16](=S)[CH2:17][C:18](=O)[CH3:19])[C@H:13]([C:22]([O:24][CH3:25])=[O:23])[CH2:12]1)(=[O:10])=[O:9].[C:26]1([CH2:32][CH2:33][CH2:34][NH:35][NH2:36])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:25][O:24][C:22]([C@@H:13]1[CH2:12][C@@H:11]([S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:9])=[O:10])[CH2:15][N:14]1[C:16]1[N:35]([CH2:34][CH2:33][CH2:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:36]=[C:18]([CH3:19])[CH:17]=1)=[O:23]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=S)CC(C)=O
Reactant: NNCCCc1ccccc1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1cc(C)nn1CCCc1ccccc1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-methyl 4-(2-chlorophenylsulfonyl)-1-(3-oxobutanethioyl)pyrrolidine-2-carboxylate (example 253c) was reacted with 1-(3-phenylpropyl)hydrazine (CAS Reg. No. 3381-02-0) to give the title compound as yellow oil. MS (ESI): m/z=502.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[I-:14].[Na+].CNC1CCCCC1NC>[Cu]I.O1CCOCC1>[I:14][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [I-]
Reactant: Brc1cccc(-c2ccccc2)c1
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Agent: [Na+]
Solvent: C1COCCO1
Product: Ic1cccc(-c2ccccc2)c1
Temperature: 25 °C
Yield: 91.3 %

Procedure:
3-bromo-1,1′-biphenyl (5.00 g, 21.5 mmol), sodium iodide (6.43 g, 42.9 mmol), copper(I) iodide (1.226 g, 6.43 mmol), and dioxane (214 ml) were added into a 500 mL 3-necked flask. N1,N2-dimethylcyclohexane-1,2-diamine (1.691 ml, 10.72 mmol) was then added. The solution was heated and refluxed overnight. Upon completion of the reaction, the reaction mixture was cooled to room temperature, filtered through a pad of celite and washed several times with dichloromethane. The solvents are evaporated under vacuum and the crude material was purified via column chromatography using hexane/DCM (90/10). The target 3-iodo-1,1′-biphenyl (5.5 g, 19.64 mmol, 92% yield) was afforded as a colorless oil.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:10]2[CH2:11][O:12][CH2:13][C:14](=O)[N:9]2[CH2:8][CH2:7]1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1.C(Cl)Cl>[CH2:11]1[CH:10]2[CH:6]([CH2:4][OH:3])[CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][O:12]1
Reactant: CCOC(=O)C1CCN2C(=O)COCC12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: OCC1CCN2CCOCC12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 69 (1.1 g, 5.0 mmol) in 50 ml of anhydrous THF are added LAH (400 mg, 10 mmol) and the mixture refluxed for 18 hours. The mixture is cooled to 0° C. and treated successively with 0.4 ml of water, 0.4 ml of 3N aq. sodium hydroxide, and 1.2 ml of water. The mixture is stirred for 15 min. and then extracred three times with DCM. The combined organic phases are dried over anhydrous sodium sulphate and evaporated. The residual yellow oil (880 mg) is purified by chromatography (Silica gel 60, 0.063-0.2 mesh, DCM/MeOH/conc. ammonia 90:9:1).
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[N:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[CH2:52][N:53]1[CH:57]=[C:56]([C:58]2[C:66]3[C:61](=[N:62][CH:63]=[C:64]([C:67]4[CH:72]=[CH:71][C:70]([CH:73]5[CH2:78][CH2:77][N:76]([C:79]([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=[O:80])[CH2:75][CH2:74]5)=[CH:69][CH:68]=4)[CH:65]=3)[N:60](S(C3C=CC(C)=CC=3)(=O)=O)[CH:59]=2)[CH:55]=[N:54]1.[OH-].[Li+]>C1COCC1.CO.O>[N:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[CH2:52][N:53]1[CH:57]=[C:56]([C:58]2[C:66]3[C:61](=[N:62][CH:63]=[C:64]([C:67]4[CH:68]=[CH:69][C:70]([CH:73]5[CH2:74][CH2:75][N:76]([C:79]([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=[O:80])[CH2:77][CH2:78]5)=[CH:71][CH:72]=4)[CH:65]=3)[NH:60][CH:59]=2)[CH:55]=[N:54]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4ccccn4)c3)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6ccccn6)c5)c4c3)cc2)CC1
Yield: 101.4 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl 4-(4-(3-(1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (140 mg, 0.203 mmol) was hydrolyzed by lithium hydroxide (44 mg, 1.04 mmol) in THF/methanol/water (4/4/2 ml) to yield 110 mg (98.5% yield) of the titled compound. MS: m/z=535.3 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([CH2:12][CH2:13][CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(Cl)Cl.[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23]>N1C=CC=CC=1>[CH2:12]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][CH:2]1[O:1][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][CH:27]=[C:19]([CH3:18])[CH:20]=1)[CH2:13][CH3:14]
Reactant: CCCC1(C(=O)OCC)CCCC1O
Reactant: Cc1cccc(C(=O)Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC1(C(=O)OCC)CCCC1OC(=O)c1cccc(C)c1
Reaction time: 12 h

Procedure:
Ethyl 2-hydroxy-1-n-propyl-cyclopentane carboxylate (6.00 g) was diluted using 60 ml of methylene chloride. At room temperature and with magnetic stirring, pyridine (3.66 ml) was slowly added, then 3-methyl-benzoyl chloride (6.00 ml) was dropwise added, Upon the completion of the addition, the reaction was continued for 12 hours. Then solvent was removed, and the residue was extracted using ethyl acetate and water. Organic layer was washed, in turn, using 10% hydrochloric acid aqueous solution to pH of about 2, using saline solution to neutrality, using 10% aqueous solution of sodium carbonate for three times, and then using saline solution to neutrality. The organic layer was dried, and removing solvent gave 10.05 g of yellow liquid. MS: m/e 319(M++1), 318(M+″), 273, 259, 244, 226, 199, 182, 119(base), 91, 77.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1.O.CCOC(C)=O>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH:23]2[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CCN(C(=O)OC(C)(C)C)CC4)nc(Cl)nc32)cc1
Temperature: 70 °C
Reaction time: 20 h
Yield: 79.8 %

Procedure:
A mixture of 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (171 mg, 0.500 mmol), 4-amino-1-N-Boc-piperidine (100 mg, 0.500 mmol) and TEA (0.150 mL, 1.08 mmol) in dioxane (4 mL) was stirred at 70° C. for 20 h. Water and EtOAc were added. The organic phase was separated, washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give tert-butyl 4-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidine-1-carboxylate (202 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:54]1[CH:59]=[C:58]([O:60][CH3:61])[N:57]=[C:56]([S:62][CH2:63][C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([F:70])[C:65]=2[F:71])[N:55]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:71][C:65]1[C:66]([F:70])=[CH:67][CH:68]=[CH:69][C:64]=1[CH2:63][S:62][C:56]1[N:55]=[C:54]([NH:12][S:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][NH2:1])=[CH:8][CH:7]=2)(=[O:10])=[O:11])[CH:59]=[C:58]([O:60][CH3:61])[N:57]=1
Reactant: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1cc(NS(=O)(=O)c2ccc(CN)cc2)nc(SCc2cccc(F)c2F)n1
Temperature: 100 °C

Procedure:
A mixture of 4-(aminomethyl)benzenesulfonamide (0.37 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (1.0 g) and, 4-Chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidine (the product from example 35 step i), (0.25 g) in dioxane (20 ml) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 3 h. The reaction mixture was then reduced in vacuo and the residue partitioned between DCM (150 ml) and H2O (150 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give a yellow solid. This solid was then purified by prep HPLC to give the title compound as a white solid. Yield: 19 mg
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)=[CH:18][CH:17]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)[CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][CH2:39][CH3:40]>CC(N(C)C)=O>[CH2:37]([N:2]1[CH:3]=[C:4]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][N:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)=[CH:20][CH:21]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)[CH:5]=[N:1]1)[CH2:38][CH2:39][CH3:40]
Reactant: c1cc(-c2cn[nH]c2)n2nc(Nc3ccc(OCCN4CCCC4)cc3)nc2c1
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCCCn1cc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of [5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (0.05 g, 0.128 mmol) in dimethylacetamide (1 ml) was added potassium carbonate (265 mg, 0.192 mmol) followed by 1-bromobutane (13 μl, 0.115 mmol). The mixture was stirred for 18 hours at room temperature, then filtered and concentrated in vacuo. The product was purified by preparatory HPLC to yield the desired product. LCMS: RT: 2.56 min, MI: 446, Method: 2; 1H NMR (DMSO, 300 MHz): 9.42 (s, 1H), 8.84 (s, 1H), 8.47 (s, 1H), 8.25 (s, 1H), 7.64 (d, 2H), 7.57 (d, 1H), 7.40 (dd, 2H), 6.95 (d, 2H), 4.26 (t, 2H), 4.09 (t, 2H), 2.96 (t, 2H), 2.72 (s, 4H), 1.88 (t, 2H), 1.83 (s, 4H), 1.30 (dd, 2H), 0.92 (t, 3H).
Reaction SMILES: [NH2:1][C:2]([NH:4][C@@:5]([CH3:18])([C:14](OC)=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([I:13])[CH:8]=1)=[O:3].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.CCOC(C)=O>[I:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[CH2:6][C@@:5]1([CH3:18])[NH:4][C:2](=[O:3])[NH:1][C:14]1=[O:15]
Reactant: COC(=O)[C@@](C)(Cc1cccc(I)c1)NC(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C[C@]1(Cc2cccc(I)c2)NC(=O)NC1=O
Temperature: 110 °C
Yield: 69.7 %

Procedure:
A mixture of methyl N-(aminocarbonyl)-3-iodo-α-methyl-D-phenylalaninate (0.82 g) and potassium carbonate (624 mg) in dimethyl sulfoxide (5 ml) was heated to 110° C. for 3 h and then allowed to cool to 20° C. overnight. The mixture was diluted with EtOAc and washed with 2M HCl, brine, dried (MgSO4) and evaporated to dryness to give the title compound (521 mg) LCMS RT=2.61 min
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]([C@H:13]1[N:16]([CH:17]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:15](=[O:36])[C@@H:14]1[C@H:37]([O:39][C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41])[CH3:38])=[CH2:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.C(OCC)(=O)C.[Ni](Cl)Cl>[CH2:1]([O:8][C:9]([CH:11]([C@H:13]1[N:16]([CH:17]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:15](=[O:36])[C@@H:14]1[C@H:37]([O:39][C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41])[CH3:38])[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C(=O)OCc1ccccc1)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)[C@H]([C@@H](C)OC(=O)OCc3ccccc3)[C@H]2C(C)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (3S,4S)-4-(1-benzyloxycarbonylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (63 mg) in methanol (1.5 ml) was treated with sodium borohydride (7.7 mg) in the presence of nickel chloride (1.3 mg) at 0°-5° C. for 15 minutes. After stirring at room temperature for an additional 1 hour, the reaction mixture was diluted with ethyl acetate (30 ml), washed with brine and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave an oily residue, which was purified by thin-layer chromatography (SiO2) to yield (3S,4S)-4-(1-benzyloxycarbonylethyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone.