Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][S:5]([NH:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]2[C:15]([CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[C:16]3[C:23]4[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:22]=4[CH2:21][N:20]([CH3:30])[CH2:19][CH2:18][N:17]3[C:31]=2[CH:32]=1)=[O:10])(=[O:7])=[O:6].O.[OH-].[Na+].Cl>O1CCOCC1>[CH:33]1([C:15]2[C:14]3[CH:13]=[CH:12][C:11]([C:9]([NH:8][S:5]([CH2:4][C:3]([OH:39])=[O:2])(=[O:7])=[O:6])=[O:10])=[CH:32][C:31]=3[N:17]3[CH2:18][CH2:19][N:20]([CH3:30])[CH2:21][C:22]4[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=4[C:16]=23)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: COC(=O)CS(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(C)Cc1cc(OC)ccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2c(c1)CN(C)CCn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)CC(=O)O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of methyl({[(14-cyclohexyl-3-methoxy-6-methyl-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocin-11-yl)carbonyl]amino}sulfonyl)acetate (from example 5) in dioxane (0.04 M) was added an equal volume of water and 4 eq of NaOH (1 N aqueous solution). The reaction was stirred vigorously at RT for 1 h. The reaction was acidified with aqueous HCl (1 N) and reduced in vacuo to remove dioxane. The resultant aqueous slurry was diluted with MeCN and water and freeze dried to leave a white powder. The crude was then purified by automated RP-MS-HPLC (stationary phase: column Waters XTERRA prep. C18, 5 um, 19×100 mm. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound as a white powder (72%).
Reaction SMILES: C([O:3][C:4](=O)[NH:5][C:6](=[O:14])[C:7]([C:12]#[N:13])=[CH:8]OCC)C.[CH2:16]([O:18][CH:19]([O:23][CH2:24][CH3:25])[CH2:20][CH2:21][NH2:22])[CH3:17]>O>[CH2:16]([O:18][CH:19]([O:23][CH2:24][CH3:25])[CH2:20][CH2:21][N:22]1[CH:8]=[C:7]([C:12]#[N:13])[C:6](=[O:14])[NH:5][C:4]1=[O:3])[CH3:17]
Reactant: CCOC(CCN)OCC
Reactant: CCOC=C(C#N)C(=O)NC(=O)OCC
Solvent: O
Product: CCOC(CCn1cc(C#N)c(=O)[nH]c1=O)OCC
Temperature: 80 °C
Yield: 92.2 %

Procedure:
(2-Cyano-3-ethoxy-acryloyl)-carbamic acid ethyl ester (Prep 33, 300 mg, 1.42 mmol) was suspended in water (20 mL); 3,3-diethoxypropylamine (460 μl, 2.84 mmol) was added and the mixture warmed at 80° C. for 10 minutes. The reaction mixture was lyophilized and the residue was purified by flash chromatography with petroleum ether-ethyl acetate (1-1) to give 350 mg of the title compound (91% yield)
Reaction SMILES: C(O[NH:9][CH2:10][CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:12]([OH:14])=[O:13])C1C=CC=CC=1.[C:20]([O:23][C:24](=O)[CH3:25])(=[O:22])C>C(O)=O.ClCCl>[CH2:24]([O:23][C:20]([NH:9][CH2:10][CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:12]([OH:14])=[O:13])=[O:22])[C:25]1[CH:17]=[CH:16][CH:15]=[CH:11][CH:10]=1
Reactant: CCCCCC(CNOCc1ccccc1)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O=CO
Product: CCCCCC(CNC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 199.2 %

Procedure:
To a cold solution of 2-(benzyloxyaminomethyl)heptanoic acid (1.57 g, 5.92 mmol) in HCO2H (29 mL) and dichloromethane (29 mL) was added acetic anhydride (5.9 mL, 62.75 mmol) at 0° C. The mixture was stirred at 0° C. for 3 hours. The volatiles were removed by evaporation under vacuum. Dichloromethane (50 mL) was added to the residue, and the solution was washed with brine, and dried over MgSO4. Filtration and evaporation under vacuum provided the title compound (1.73 g, 100%). 1H NMR (400 MHz, CHCl3) δ 8.07 (br s, 1H), 7.29 (m, 5H), 4.91–4.71 (m, 2H), 3.76 (m, 2H), 2.67 (m, 1H), 1.54 (m, 1H), 1.41(m, 1H), 1.20 (m, 6H), 0.80 (t, J=7.0 Hz, 3H). MH+ 294.
Reaction SMILES: O1CCOCC1.[CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=1.[C:13]1([NH:19]O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[C:7]1([NH:19][CH:13]2[CH2:18][CH2:17][CH:16]=[CH:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C1=CCCCC1
Reactant: ONc1ccccc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: C1=CCC(Nc2ccccc2)CC1
Yield: 95 %

Procedure:
A stirred mixture containing dioxane (12 mL), 3 mL of cyclohexene, 1 g of 4A Molecular Sieves, and 0.11 mmol of (2,6-dipicolinato)(HMPA)Mo(O)(ONPh) is heated at reflux (ca. 100° C.) under a nitrogen atmosphere while a toluene solution (50 mL) of N-phenyl hydroxylamine (1.26 g, 11.6 mmol) is added dropwise over a 24 hr period. After heating an additional 12-24 hr, the mixture was allowed to cool and the volatiles were removed by evaporation at reduced pressure. Chromatography of the residue over silica gel and elution with pentane afforded phenyl 3-cyclohexenyl amine (>95% one isomer by NMR, GC/MS) in 15-25% yield based on the hydroxylamine. Later fractions contained aniline, azobenzene and azoxybenzene.
Reaction SMILES: [Br:1]Br.[OH:3][C:4]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)([C:6]1[S:7][CH:8]=[CH:9][N:10]=1)[CH3:5].C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:8]1[S:7][C:6]([C:4]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)([OH:3])[CH3:5])=[N:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(C)(O)c2nccs2)CC1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(C(C)(O)c2ncc(Br)s2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.5 %

Procedure:
Bromine (0.071 mL, 1.383 mmol) was added dropwise to a stirred mixture of the product of Step 1 (180 mg, 0.576 mmol) and sodium acetate (236 mg, 2.88 mmol) in acetic acid (2.31 mL), and the mixture was stirred at room temperature for 2 h. Acetic acid was removed by evaporation under vacuum and the residue was treated with saturated NaHCO3 solution, and extracted with ethyl acetate (×3). The combined organic fractions were washed with brine, dried (Na2SO4), concentrated, and purified by flash chromatography to give tert-butyl 4-[1-(5-bromo-1,3-thiazol-2-yl)-1-hydroxyethyl]piperidine-1-carboxylate (87 mg, 0.222 mmol, 38.6%). APCI: [M+H]+ m/z 379.1.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C@H:6]([O:13][C:14]3[CH:15]=[CH:16][C:17]4[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=4)[CH:19]=3)[CH2:7][CH2:8][C@@H:9]2[NH2:12])=[CH:4][CH:3]=1.ClC(Cl)(Cl)C[O:29][C:30](=O)[NH:31][C:32]1[N:33]([CH3:41])[N:34]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:36]=1.CCN(C(C)C)C(C)C>O1CCOCC1.CCN(C(C)C)C(C)C>[C:37]([C:35]1[CH:36]=[C:32]([NH:31][C:30]([NH:12][C@@H:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[C@H:6]([O:13][C:14]3[CH:15]=[CH:16][C:17]4[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=4)[CH:19]=3)[CH2:7][CH2:8]2)=[O:29])[N:33]([CH3:41])[N:34]=1)([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)c1nnc2ccc(O[C@@H]3CC[C@H](N)c4cc(F)ccc43)cn12
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4C)c4cc(F)ccc43)cn12
Yield: 63.1 %

Procedure:
Intermediate 19b (85.0 mg, 0.250 mmol) and (5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (US2004/192653, 99 mg, 0.300 mmol) were dissolved in 1,4-dioxane (3 mL) and DIPEA (70 μL, 0.400 mmol). The reaction was heated at reflux for 1.75 h, then more (5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (35 mg, 0.100 mmol) and DIPEA (3 drops) were added. After a further 4 h the mixture was concentrated in vacuo. The residue was purified by FCC, using 0-15% MeOH in DCM, to give impure product (82 mg). Further purification twice by HPLC (C18 X-select column, 40-98% MeCN in H2O, 0.1% HCO2H) gave the title compound as a white powder after freeze-drying (44 mg, 34%). LCMS (Method 5): Rt 3.83 min, m/z 520.1 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.21 (9H, s), 1.35-1.43 (6H, m), 1.85-2.25 (4H, m), 3.51-3.62 (4H, m), 4.80-4.91 (1H, m), 5.50-5.57 (1H, m), 6.02 (1H, s), 7.09 (1H, d, J 8.8), 7.11-7.17 (2H, m), 7.20 (1H, dd, J 9.6, 2.2), 7.44-7.50 (1H, m), 7.69 (1H, d, J 9.6), 8.22 (1H, br d), 8.40 (1H, s).
Reaction SMILES: Cl[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:22]([NH:23][C:24](=[O:71])[CH:25]([C:46]3[N:47]=[C:48]([NH:51][C:52]([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)([C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)[C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[S:49][CH:50]=3)[O:26][CH:27]([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[CH2:28][F:29])[C:21](=[O:72])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:10].[I-:73].[Na+]>CC(C)=O>[I:73][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:22]([NH:23][C:24](=[O:71])[CH:25]([C:46]3[N:47]=[C:48]([NH:51][C:52]([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)([C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)[C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[S:49][CH:50]=3)[O:26][CH:27]([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[CH2:28][F:29])[C:21](=[O:72])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:10]
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(NC(=O)C(OC(CF)C(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(COC(=O)C2=C(CI)CS[C@@H]3C(NC(=O)C(OC(CF)C(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1

Procedure:
130 mg (0.125 mmol) of p-methoxybenzyl 3-chloromethyl-7-{2-(2-tritylamino-4-thiazolyl)-2-(1-diphenylmethoxycarbonyl-2-fluoroethoxy) acetamido}-ceph-3-em-4-carboxylate-syn isomer was dissolved in 1 l ml of acetone, and 0.5 ml of acetone solution containing 28 mg (0.19 mmol) of sodium iodide was added to the resulting solution at room temperature and reacted for 40 minutes. After the reaction, the solvent was distilled out, methylene chloride was added to the resulting residue, the insoluble materials were filtrated out, and the remaining filtrate was concentrated under reduced pressure to obtain p-methoxybenzyl 3-iodomethyl-7-{2-(2-tritylamino-4-thiazolyl)-2-(1-diphenylmethoxycarbonyl-2-fluoroethoxy)acetamido}-ceph-3-em-4-carboxylate-syn isomer. To this was added 23 mg (0.15 mmol) of 1-(2-fluoroethyl)-4-pyridothione, and the resulting mixture was dissolved in 1 ml of chloroform and reacted for 1 hour at room temperature. After the reaction, the chloroform was distilled out under reduced pressure, and the residue was purified by silicagel-chromatography (chloroform/methanol=10/1) and dissolved in 0.15 ml of anisole, and then, 1.5 ml of trifluoroacetic acid was added thereto, while cooled with ice, and reacted for 1 hour. After the reaction, isopropylether was added to the reaction solution to form a precipitate therein. After dried, 70 mg of a powder was obtained. To this was added 1 ml of water and the pH value of the resulting solution was adjusted to 7.8 with sodium hydrogencarbonate, and the solution was purified with HP-b 20 resin (methanol/H2O=1/4) to obtain 32 mg of the above entitled compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][C:19](=[N:21][OH:22])[NH2:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.C(N(CC)CC)C.[C:30](Cl)(=O)[O:31]C1C=CC=CC=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][C:19]3[NH:20][C:30](=[O:31])[O:22][N:21]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[N:10]=2)[CH:7]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NC(Cc1c(-c2ccc(F)cc2)nc2ccc(F)cn12)=NO
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=c1[nH]c(Cc2c(-c3ccc(F)cc3)nc3ccc(F)cn23)no1
Reaction time: 1 h

Procedure:
A solution of 2-(6-fluoro-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-3-yl)-N′-hydroxyacetimidamide (0.040 g, 0.13 mmol) and triethylamine (0.025 mL, 0.198 mmol) in CHCl3 (1 mL) was treated with phenyl carbonochloridate (0.018 mL, 0.19 mmol) and stirred for 1 h. The reaction mixture was washed with water (30 mL) and dichloromethane (30 mL). The organic solution was dried with Na2SO4, evaporated under vacuum. The crude product was purified by HPLC to provide the title product. M/e+ 329 for C16H11F2N4O2 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.69 (dd, J=4.0, 2.2 Hz, 1H), 7.77 (dd, J=9.9, 4.7 Hz, 1H), 7.69 (m, 2H), 7.62 (m, 2H), 7.29 (m, 2H), 4.45 (s, 2H) ppm.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:13][C:10]2[CH:11]=[CH:12][C:3]([C:2]([F:1])([F:14])[F:15])=[C:4]3[C:9]=2[N:8]=[CH:7][CH:6]=[CH:5]3)(=[O:25])=[O:24])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=1
Reactant: Nc1ccc(C(F)(F)F)c2cccnc12
Reactant: O=[N+]([O-])c1cc(Cl)ccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(Cl)ccc1S(=O)(=O)Nc1ccc(C(F)(F)F)c2cccnc12
Yield: 46.8 %

Procedure:
In a similar fashion using route 14 general procedure 27, 5-trifluoromethyl-quinolin-8-ylamine (Intermediate 45) (390 mg, 1.83 mmol), 4-chloro-2-nitrobenzene-1-sulfonyl chloride (Intermediate 454) (565 mg, 2.22 mmol), DMAP(cat) and pyridine (0.3 ml, 5.55 mmol) in DCM (7 ml) gave the title compound (370 mg, 46%) after purification by column chromatography with n-hexane/EtOAc (90:10) as the eluent.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[NH2:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[OH:26]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[OH:26])=[O:14]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: N[C@@H]1CCCC[C@H]1O
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-(2-Fluoro-4-iodo-phenylamino)-N-(trans-2-hydroxy-cyclohexyl)-isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.27 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.40 mmol of trans-2-aminocyclohexanol. LC/MS [6.40 (10 min) min; 640 (M+1)]
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].Br[CH:6]1[CH2:11][CH2:10][CH2:9][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]1=O>>[CH3:2][C:1]1[S:3][C:6]2[CH2:11][CH2:10][CH2:9][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]=2[N:4]=1
Reactant: CCOC(=O)C1CCCC(Br)C1=O
Reactant: CC(N)=S
Product: CCOC(=O)C1CCCc2sc(C)nc21

Procedure:
This compound is prepared by action of thioacetamide on 2-bromo-6-carbethoxy-cyclohexanone (II), according to the process described in Example 1. B.p.0.1 =102°-105° C.
Reaction SMILES: S([O-])(O)=O.[Na+].[C:6]([NH:16][C@H:17]([CH:22]=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[C-:24]#[N:25].[K+]>O.C(OCC)(=O)C>[C:6]([NH:16][CH:17]([CH2:18][CH:19]([CH3:20])[CH3:21])[CH:22]([OH:23])[C:24]#[N:25])([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: CC(C)C[C@@H](C=O)NC(=O)OCc1ccccc1
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)CC(NC(=O)OCc1ccccc1)C(O)C#N
Reaction time: 14 h
Yield: 81.6 %

Procedure:
A solution containing 3.43 g of sodium hydrogen sulfite in 20 ml of water was added to 2.81 g of N-carbobenzoxy-L-leucinal, and the mixture was stirred for 14 hours under ice-cooling. A solution of 1.41 g of potassium cyanide in 50 ml of water and 200 ml of ethyl acetate were added to the reaction mixture, and the mixture was stirred for 4 hours at room temperature. The ethyl acetate layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give 2.54 g of 3-carbobenzoxyamino-2-hydroxy-5-methylhexanenitrile as a colorless oil. A mixture of 20 ml of dioxane and 20 ml of concentrated hydrochloric acid was added to 500 mg of the nitrile, and the mixture was heated under reflux for 12 hours. The reaction mixture was evaporated under reduced pressure, and the residual crystals were purified by cation exchange column chromatography (eluent: a 2N aqueous NH4OH solution) to obtain 254 mg of (2RS, 3S)-3-amino-2-hydroxy-5-methylhexanoic acid as colorless crystals (a mixture in ratio of 2R and 2S being about 7:3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([I:10])[C:7]([CH3:11])=[C:6]([NH2:12])[CH:5]=1.[N+:14]([O-])(OCCC(C)C)=O>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7]([CH:11]=[N:14][NH:12]2)=[C:8]([I:10])[CH:9]=1)=[O:13]
Reactant: COC(=O)c1cc(N)c(C)c(I)c1
Reactant: CC(C)CCO[N+](=O)[O-]
Solvent: CC(=O)O
Product: COC(=O)c1cc(I)c2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
To a solution of 3-amino-5-iodo-4-methyl-benzoic acid methyl ester (1.22 g, 4.21 mmol) in acetic acid (20 mL) was added isoamyl nitrate (0.675 mL, 4.63 mmol). The mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. The residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give 1.15 g (91%) of 4-iodo-1H-indazole-6-carboxylic acid methyl ester, MS (M+H)=303.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:10]([C:15]([NH:17][CH3:18])=[O:16])=[N:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27]2.CCCCO.Cl>CCOC(C)=O>[CH3:18][NH:17][C:15](=[O:16])[C:10]1[C:9]([NH:8][C:6]2[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=[C:2]([NH:23][C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[NH:29][C:28](=[O:33])[CH2:27]4)[CH:7]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CNC(=O)c1ncccc1Nc1cc(Cl)ncc1C(F)(F)F
Reactant: Nc1ccc2c(c1)CC(=O)N2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: CNC(=O)c1ncccc1Nc1cc(Nc2ccc3c(c2)CC(=O)N3)ncc1C(F)(F)F
Temperature: 160 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a high pressure vial was added 3-(2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)-N-methylpicolinamide (0.205 g, 0.62 mmol) and 5-aminoindolin-2-one (0.138 g, 1.2 eq) and n-BuOH (5 mL). HCl (˜1.25M HCl in ethanol, 0.5 mL, 1.0 eq) was added to the above mixture. The vial was sealed and heated at 160° C. with stirring overnight in an oil bath. The mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude. The crude was dissolved in EtOAc and washed with saturated NaHCO3 solution. The organic layers were concentrated and the crude was purified by silica gel chromatography (20%˜100% EtOAc/Hex). The product was precipitated from EtOAc and filtered to obtain the desired product as the free base (isolated yield 56%). The product was converted to the HCl salt.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][CH2:43][S:44](Cl)(=[O:46])=[O:45]>ClCCl>[Cl:42][CH2:43][S:44]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:46])=[O:45]
Reactant: O=S(=O)(Cl)CCl
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)CCl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 35.4 %

Procedure:
In a similar manner to Step 1 of Example 227, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0853 g, 0.185 mmol) was dissolved in dichloromethane (3.0 mL), and the solution was treated with triethylamine (0.129 mL, 0.924 mmol) and chloromethanesulfonyl chloride (0.0490 mL, 0.554 mmol) to obtain 4-chloromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0376 g, yield 35%).
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[N+:14]([O-])=O)[C:8]([NH2:10])=[O:9].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:14][C:13]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][C:5]=1[O:4][C:3]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:2]=1[F:1]
Reactant: NC(=O)c1ccc([N+](=O)[O-])c(Oc2ccc(F)cc2F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: NC(=O)c1ccc(N)c(Oc2ccc(F)cc2F)c1
Yield: 91.3 %

Procedure:
A mixture of 3-(2,4-difluorophenoxy)-4-nitrobenzamide (1 g), iron powder (1 g), and ammonium chloride (0.1 g) in ethanol (20 ml) and water (10 ml) was refluxed with stirring for an hour. The insoluble materials were filtered off and the filtrate was concentrated under reduced pressure to give pale yellow crystals of 4-amino-3-(2,4-difluorophenoxy)benzamide (0.82 g).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[C:14][C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[CH:17]=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].C(OCC)(=O)C>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[CH:17]=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccccc1C#CCCCCCCC1CCCCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=Cc1ccccc1CCCCCCCCC1CCCCC1

Procedure:
To an ice cold solution of 1-hexyne (49.6 mmoles) in freshly distilled tetrahydrofuran (50 ml) containing a trace of triphenylmethane was added dropwise n-butyl lithium in hexane (49.5 mmoles). About 10 minutes after the addition was stopped, sieve dried hexamethylphosphoramide (57.5 mmoles) was added and the solution stirred for 10 minutes. A solution of 2-cyclohexylethyl bromide (51.3 mmoles) in tetrahydrofuran (10 ml) was added and the reaction mixture was stirred for about 3 hours as the temperature rose to room temperature. The mixture was en up in ether (100 ml) and washed with water (3×100 ml) and sodium chloride solution (100 ml). The organic phase was dried over magnesium sulfate and evaporated to leave an oil which was purified by flash chromatography to give 1-cyclohexyloct-3-yne. This compound (20.8 mmoles) was treated with potassium hydride (36.8 mmoles) in propylene diamine to obtain the isomeric 8-cyclohexyloct-1-yne as an oil. A mixture of 2-bromobenzaldehyde (12.59 mmoles), 8-cyclohexyloct-1-yne (14.87 mmoles), cuprous iodide (0.17 mmoles) and bis(triphenylphosphine) palladium (II) chloride (0.26 mmoles) in triethylamine (35 ml) was refluxed under argon for 1.5 hours. The reaction mixture was cooled, filtered and the filtrate evaporated. The resulting residue was dissolved in ether (100 ml), washed with 3N hydrochloric acid (50 ml) and saturated sodium chloride solution (50 ml) and then dried over anhydrous magnesium sulfate and charcoal. The solution was evaporated to afford an oil which was purified by flash chromatography (2% ether/hexane) to yield 2-(8-cyclohexyl-1-octynyl)benzaldehyde as an oil. This benzaldehyde (10.22 mmoles) was hydrogenated with 10% palladium on charcoal in ethyl acetate to give the desired product as an oil, after chromatography (3% ether/hexane).