Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]([N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23])[CH:9]([OH:12])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(OCC)(=O)C>[O:23]=[C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21](=[O:22])[N:13]1[C@@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@H:9]([OH:12])[CH2:10][O:11][S:31]([CH3:30])(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1c2ccccc2C(=O)N1C(Cc1ccccc1)C(O)CO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OC[C@@H](O)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 43 %

Procedure:
A solution of 0.51 g of an 83:17 mixture of the (1S,2S) and (1S,2R) isomers of 2-(1-benzyl-2,3-dihydroxypropyl)-2,3-dihydro-1H-isoindole-1,3-dione, 0.4 ml of pyridine and 1 ml of ethyl acetate is treated with 0.15 ml of methanesulfonyl chloride and the mixture is stirred at room temperature for 4 hours. The mixture is diluted with ethyl acetate and washed with 2% hydrochloric acid, and the extracts are dried and filtered. The filtrate is evaporated and the residue is purified on silica gel with methylene chloride/isopropanol (100:1). After evaporation and drying there is obtained 0.28 g (43%) of pure methanesulfonic acid (2S,3S)-3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-2-hydroxy-4-phenylbutyl ester, NMR (CDCl3): 7.7 (m,4H); 7.1 (m,5H); 4.6 (m,2H); 4.3 (m,2H); 3.55 (d,J=7,1H); 3.3 (m,2H); 3.1 (s,3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@@:6]3([C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=4[F:23])[C@H:14]([C:24](O)=[O:25])[NH:13][C:12]43[CH2:29][C:28]([CH2:32][F:33])([CH2:30][F:31])[CH2:27]4)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[NH2:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37][CH2:36]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@@:6]3([C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=4[F:23])[C@H:14]([C:24]([NH:34][C@H:35]4[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37][CH2:36]4)=[O:25])[NH:13][C:12]43[CH2:27][C:28]([CH2:30][F:31])([CH2:32][F:33])[CH2:29]4)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1NC2(CC(CF)(CF)C2)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Reactant: N[C@H]1CC[C@H](O)CC1
Product: O=C(N[C@H]1CC[C@H](O)CC1)[C@@H]1NC2(CC(CF)(CF)C2)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F

Procedure:
The compound (70 mg, 0.14 mmol) obtained in Step 1 above and trans-4-aminocyclohexanol (19.4 mg, 0.17 mmol) were used as starting materials and treated in the same way as in Step 2 of Example 12 to give 56 mg (67%) of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:5])([CH3:4])Cl.[CH2:6]([N:8](CC)[CH2:9][CH3:10])[CH3:7].C(NCC)C>CCCCCC>[CH2:6]([N:8]([Si:2]([CH3:5])([CH3:4])[CH3:1])[CH2:9][CH3:10])[CH3:7]
Reactant: CCN(CC)CC
Reactant: C[Si](C)(C)Cl
Solvent: CCCCCC
Solvent: CCNCC
Product: CCN(CC)[Si](C)(C)C
Temperature: 55 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
In a 1 liter four-neck flask equipped with a stirrer, a reflux condenser, a dropping funnel and a thermometer were placed 108.5 g (1.0 mol) of trimethylchlorosilane, 111.1 g (1.1 mol) of triethylamine and 300 ml of hexane. Thereto, 73.0 g (1.0 mol) of diethylamine was added dropwise from the dropping funnel over a 1-hour period. During the addition, the temperature of the reaction system was kept within the range of 20° C. to 60° C. to make the reaction be proceeding. At the conclusion of the addition, the temperature was raised to 50-60° C. and kept there for 2 hours, whereby the reaction was matured. Then, the reaction mixture was filtered through a glass filter to remove the salt yielded as a by-product. The filtrate was allowed to stand for one day at room temperature to precipitate the salt. The salt precipitated was filtered off, and the filtrate was subjected to distillation under ordinary pressure to obtain 136.3 g of diethylaminotrimethylsilane as a fraction having a boiling point of 125-126° C. The yield was 94%, and the chlorine concentration was 146 ppm.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:20]=[C:19]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[C:13]2[CH2:14][CH:15]([CH2:17][OH:18])[O:16][C:12]=2[CH:11]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:32]I>C1COCC1>[C:3]([O:7][C:8]([C:10]1[CH:20]=[C:19]([O:21][C:22]2[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[C:13]2[CH2:14][CH:15]([CH2:17][O:18][CH3:32])[O:16][C:12]=2[CH:11]=1)=[O:9])([CH3:5])([CH3:6])[CH3:4]
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2c(c1)OC(CO)C2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC1Cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)OC(C)(C)C)cc2O1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
NaH (50 mg, 60% in mineral oil, 1.3 mmol) was added to a solution of 2-hydroxymethyl-4-(4-methanesulfonyl-phenoxy)-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (200g) (409 mg, 0.97 mmol) in THF (5 mL). The resulting mixture was stirred at 0° C. for 10 min and then methyl iodide (80 uL, 1.3 mmol) was added. The mixture was stirred at room temperature for 2 hr and then quenched with H2O (20 mL), extracted with EtOAc (2×20 mL). The organic layers were dried over MgSO4 and concentrated. The residue was purified by flash column chromatograph eluting with 20-30% EtOAc in hexanes to give a colorless oil (295 mg, 70% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 1.56 (s, 9 H) 2.89 (dd, J=16.55, 7.20 Hz, 1 H) 3.07 (s, 3 H) 3.08-3.17 (m, 1 H) 3.39-3.44 (m, 3 H) 3.58 (d, J=5.05 Hz, 2 H) 4.99-5.08 (m, 1 H) 7.04-7.10 (m, 2 H) 7.21 (d, J=1.01 Hz, 1 H) 7.30 (d, J=1.26 Hz, 1 H) 7.86-7.93 (m, 2 H); LCMS for C22H26O7S m/z 457.00 (M+Na)+.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:26]COC)([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=2[CH2:30][CH2:31][CH3:32])[CH2:7][C@H:6]1[CH3:33])=[O:4].[O:34]1[CH2:39][CH2:38][O:37][C:36]2[CH:40]=[C:41]([C:44]3([CH3:51])[NH:48][C:47](=[O:49])[NH:46][C:45]3=[O:50])[CH:42]=[CH:43][C:35]1=2>>[O:34]1[CH2:39][CH2:38][O:37][C:36]2[CH:40]=[C:41]([C:44]3([CH3:51])[NH:48][C:47](=[O:49])[N:46]([CH2:2][C:3]([N:5]4[CH2:10][CH2:9][N:8]([C:11]5[CH:16]=[CH:15][C:14]([C:17]([OH:26])([C:22]([F:25])([F:23])[F:24])[C:18]([F:21])([F:19])[F:20])=[CH:13][C:12]=5[CH2:30][CH2:31][CH3:32])[CH2:7][C@H:6]4[CH3:33])=[O:4])[C:45]3=[O:50])[CH:42]=[CH:43][C:35]1=2
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CBr)[C@H](C)C1
Reactant: CC1(c2ccc3c(c2)OCCO3)NC(=O)NC1=O
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CN2C(=O)NC(C)(c3ccc4c(c3)OCCO4)C2=O)[C@H](C)C1

Procedure:
(R)-2-bromo-1-(4-{4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl]-2-propylphenyl}-2-methylpiperazin-1-yl)ethanone and 5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methylimidazolidine-2,4-dione were used for a similar reaction and treatment as Examples 14-1 and 15-1, and the title compound was obtained as a yellow oil.
Reaction SMILES: O.O.O.O.O.O.[Fe:7](Cl)(Cl)Cl.OO.[Fe-3:13]([C:24]#[N:25])([C:22]#[N:23])([C:20]#[N:21])([C:18]#[N:19])([C:16]#[N:17])[C:14]#[N:15].[K+].[K+].[K+].[Fe:29](Cl)(Cl)Cl.O=O>O>[Fe-4:13]([C:22]#[N:23])([C:18]#[N:19])([C:14]#[N:15])([C:16]#[N:17])([C:20]#[N:21])[C:24]#[N:25].[Fe+3:7].[Fe-4:13]([C:22]#[N:23])([C:18]#[N:19])([C:14]#[N:15])([C:16]#[N:17])([C:20]#[N:21])[C:24]#[N:25].[Fe-4:13]([C:22]#[N:23])([C:18]#[N:19])([C:14]#[N:15])([C:16]#[N:17])([C:20]#[N:21])[C:24]#[N:25].[Fe+3:29].[Fe+3:7].[Fe+3:7]
Reactant: Cl[Fe](Cl)Cl
Reactant: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: O=O
Agent: OO
Agent: [K+]
Solvent: O
Product: N#C[Fe-4](C#N)(C#N)(C#N)(C#N)C#N
Product: [Fe+3]
Reaction time: 0.5 h

Procedure:
The electrochromic layer was prepared in the following manner: Into a tall 180 mL beaker equipped with a stirring bar was measured 85 g of distilled water, 0.230 g of iron (III) chloride hexahydrate and about 0.6 mL of the 1% hydrogen peroxide solution. Into a 100 mL beaker was measured 60 g of distilled water, 0.2 g of potassium ferricyanide (III) and about 0.6 mL of the 1% hydrogen peroxide solution. With vigorous stirring, the potassium ferricyanide (III) solution was slowly added dropwise to the iron (III) chloride solution. The solution turned blue and generated oxygen bubbles. The solution was allowed to stir for 30 minutes to complete the reaction. This resulted in an aqueous dispersion with iron (III) ferrocyanide particles about 2 nm in average size. The dispersion was covered and allowed to settle.
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([NH:9][NH2:10])[CH3:8].O=[C:12]([CH2:18][C:19](=O)[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14].O.C([O-])([O-])=O.[K+].[K+]>C(O)(=O)C.C(OCC)(=O)C>[CH2:7]([N:9]1[C:19]([CH3:20])=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:10]1)[CH3:8]
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: CCNN
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(C)n(CC)n1
Temperature: 25 °C

Procedure:
N-Ethylhydrazine oxalate (12 g) in glacial acetic acid (100 ml) was cooled in an ice-bath and treated with ethyl 2,4-dioxovalerate (11.24 ml). After addition was complete the mixture was stirred at room temperature; after ca. 45 min the mixture was warmed to dissolve insoluble ethylhydrazine oxalate. The mixture was stirred for a further 2 h and then poured into water(ca. 300 ml)/ethyl acetate (ca. 700 ml) and solid K2CO3 was carefully added, with stirring, until the pH was neutral. After separation the aqueous layer was re-extracted with ethyl acetate. The combined ethyl acetate extracts were dried (MgSO4), and the solvents removed to leave an oil. Chromatography on silica gel, loading in CH2Cl2 /hexane and eluting with a gradient elution of ethyl acetate/hexane mixtures (from 2:8 to 1:1) gave ethyl 1-ethyl-5-methylpyrazole-3-carboxylate as an oil (13.2 g); νmax (CH2Cl2) 1717, 1446, 1389, and 1219 cm-1 ; δ (CDCl3) 1.38 (3H, t, J 7.2 Hz), 1.42 (3H, t, J 7.3 Hz), 2.30 (3H, s), 4.17 (2H, q, J7.3 Hz), 4.38 (2H, q, J7.1 Hz), 6.55 (1H, s); (Found m/z 182.1055. C9H14N2O2 requires m/z 182.1055).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([CH2:19][CH3:20])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:17][CH3:18])=[C:12]([CH:16]=1)[C:13](O)=[O:14])=[O:5])[CH3:2].ClC(OCC)=O.C(N(CC)CC)C>O1CCCC1>[OH:14][CH2:13][C:12]1[CH:16]=[C:8]([CH:9]=[CH:10][C:11]=1[O:17][CH3:18])[CH2:7][CH:6]([CH2:19][CH3:20])[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)C(CC)Cc1ccc(OC)c(C(=O)O)c1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(CC)Cc1ccc(OC)c(CO)c1
Reaction time: 0.17 h
Yield: 98.9 %

Procedure:
0.50 g of 5-[2-(ethoxycarbonyl)butyl]-2-methoxybenzoic acid was dissolved in 8 ml tetrahydrofuran, and 0.20 ml ethyl chloroformate and 0.29 ml triethylamine were added under ice-cooling. After the reaction solution was stirred for 10 minutes under ice-cooling, insoluble matters were filtered off. The mother liquor was ice-cooled again, and 10 L water and 136 mg sodium borohydride were added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction product, followed by extracting with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evapoarated. The residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (3:1), 0.47 g of ethyl 2-[3-(hydroxymethyl)-4-methoxybenzyl]butanoate was obtained.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][O:5][C:6]1[CH:14]=[C:13]2[CH2:15][CH2:16][CH2:17][C:12]2=[C:11]2[C:7]=1[C:8]([C:32](=[O:36])[C:33]([NH2:35])=[O:34])=[C:9]([CH3:31])[N:10]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[S:26][C:27]([Br:30])=[CH:28][CH:29]=1.[OH-].[Li+].Cl>O1CCOCC1.O>[NH2:35][C:33](=[O:34])[C:32]([C:8]1[C:7]2[C:11](=[C:12]3[CH2:17][CH2:16][CH2:15][C:13]3=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:37])=[O:2])[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[S:26][C:27]([Br:30])=[CH:28][CH:29]=2)[C:9]=1[CH3:31])=[O:36]
Reactant: COC(=O)COc1cc2c(c3c1c(C(=O)C(N)=O)c(C)n3Cc1ccccc1-c1ccc(Br)s1)CCC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cc3c(c2n1Cc1ccccc1-c1ccc(Br)s1)CCC3
Reaction time: 0.25 h
Yield: 51.2 %

Procedure:
A mixture of 2-[[3-(2-amino-1,2-dioxoethyl)-2-methyl-1-[2-(5-bromothiophen-2-yl)benzyl]-1,6,7,8-tetrahydrocyclopent[g]indol-4-yl]oxy]acetic acid methyl ester (50 mg, 0.086 mmol) in dioxane (5 mL) was warmed until a clear solution was obtained. This solution was treated with 1M lithium hydroxide solution (1 mL) at room temperature for 90 min. The pH was adjusted to ˜3 with hydrochloric acid. The mixture was diluted with water and stirred for 15 min. The resulting precipitate was collected via vacuum filtration to provide 25 mg (51%) of the title compound as a green solid. TOS MS ES+ exact mass calculated for C27H24BrN2O5S (p+1): m/z=567.0589. Found: 567.0603.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][C:8]([NH:10][NH:11][C:12]([N:14]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[O:17][C:16]2[CH:25]=[CH:26][C:27]([N+:29]([O-])=O)=[CH:28][C:15]1=2)=[O:13])=[O:9])(=[O:5])=[O:4])[CH3:2].[H][H]>O1CCCC1.[Pd]>[CH2:1]([S:3]([CH2:6][CH2:7][C:8]([NH:10][NH:11][C:12]([N:14]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[O:17][C:16]2[CH:25]=[CH:26][C:27]([NH2:29])=[CH:28][C:15]1=2)=[O:13])=[O:9])(=[O:5])=[O:4])[CH3:2]
Reactant: [H][H]
Reactant: CCS(=O)(=O)CCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: C1CCOC1
Product: CCS(=O)(=O)CCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(N)cc21

Procedure:
A solution of the title compound of Example 10 (4.0 g) in tetrahydrofuran (250 mL) was shaken in a Parr Hydrogenator at 38 psi hydrogen over 5% palladium on carbon for 18 hours. The catalyst was filtered from the reaction, and the solution was evaporated under vacuum. Crystallization of the residue from ethanol (3A) yielded the title compound as a yellow solid. Recrystallization of this from ethanol (3A) yielded the pure title compound as yellow crystals. Mp: 172°-179° C.
Reaction SMILES: [C:1]1([CH:7]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]([O:10][C@@H:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[F:37])=[O:29]>C(#N)C>[Br-:26].[F:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[C:28](=[O:29])[CH2:27][N+:13]12[CH2:14][CH2:15][CH:16]([CH2:17][CH2:18]1)[C@@H:11]([O:10][C:8](=[O:9])[CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:12]2
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1)c1ccccc1
Reactant: O=C(CBr)c1ccc(F)cc1F
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(Nc1ccccc1)c1ccccc1)C2)c1ccc(F)cc1F
Product: [Br-]
Yield: 43.5 %

Procedure:
To a solution of (R)-phenyl-phenylamino-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Diastereoisomer 1 of C2) (50 mg, 0.15 mmol) in acetonitrile (1 mL), is added 2-bromo-1-(2,4-difluoro-phenyl)-ethanone (35 mg, 0.15 mmol) and the mixture reacted in a closed vessel under MW irradiation for 1 hour at 100° C. (UPLC-MS monitoring: complete conversion). The solvent is evaporated and the resulting crude is purified by flash chromatography (DCM/MeOH=95/5) to obtain the title compound as a white solid (37.3 mg, 44% yield, bromide salt, single diastereoisomer).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([CH3:52])([CH3:51])[CH2:35][CH:36]([Sn:38]([CH2:47][CH2:48][CH2:49][CH3:50])([CH2:43][CH2:44][CH2:45][CH3:46])[CH2:39][CH2:40][CH2:41][CH3:42])O)=[CH:30][CH:29]=1>C(Cl)Cl.C(#N)C>[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([CH3:52])([CH3:51])[CH2:35][CH:36]([I:25])[Sn:38]([CH2:47][CH2:48][CH2:49][CH3:50])([CH2:43][CH2:44][CH2:45][CH3:46])[CH2:39][CH2:40][CH2:41][CH3:42])=[CH:30][CH:29]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C(O)CC(C)(C)c1ccc(F)cc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CC#N
Product: CCCC[Sn](CCCC)(CCCC)C(I)CC(C)(C)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 39.8 %

Procedure:
A solution of 30.4 grams (0.116 mole) of triphenylphosphine in about 116 mL of methylene chloride is stirred, and 7.9 grams (0.116 mole) of imidazole is added. Upon completion of addition, the reaction mixture is stirred about one hour until the imidazole dissolves, then 29.4 grams (0.116 mole) iodine is added portionwise. After the iodine dissolves, the reaction mixture is cooled to 0° C., and a solution of 36.3 grams (0.077 mole) of 3-(4-fluorophenyl)-3-methyl-1-tributylstannylbutanol in about 77 mL of methylene chloride is added dropwise, while maintaining the reaction mixture temperature below 0° C. Upon completion of addition, the reaction mixture is allowed to warm to ambient temperature where it is stirred for about 18 hours. The reaction mixture is then taken up in about 500 mL of acetonitrile and extracted with three 300 mL portions of hexane. The combined extracts are concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel, using petroleum ether as the eluant. The product containing fractions are combined and concentrated under reduced pressure, yielding 17.8 grams of 3-(4-fluorophenyl)-3-methyl-1-iodo-1-tributylstannylbutane. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([Br:12])[C:9](=[O:13])[NH:8][C:7]=1[C:14]([F:17])([F:16])[F:15])=[O:5])[CH3:2].[CH2:18](O)[C:19]([F:22])([F:21])[F:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.CCCCCCC>[CH2:1]([O:3][C:4](=[O:5])[C:6]1[CH:11]=[C:10]([Br:12])[C:9]([O:13][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:8][C:7]=1[C:14]([F:17])([F:15])[F:16])[CH3:2]
Reactant: CCOC(=O)c1cc(Br)c(=O)[nH]c1C(F)(F)F
Reactant: OCC(F)(F)F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CCOC(=O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Temperature: 50 °C
Reaction time: 18 h
Yield: 87.6 %

Procedure:
5-Bromo-1,6-dihydro-6-oxo-2-(trifluoromethyl)-3-pyridinecarboxylic acid ethyl ester (111 g, 0.35 mol) was dissolved in tetrahydrofuran (1600 mL). To the solution were added trifluoroethanol (38 mL, 0.53 mol), triphenylphosphine (117 g, 0.42 mol) and diisopropyl azodicarboxylate (89.4 mL, 0.42 mol) at 0° C. The mixture was stirred for 30 min at 0° C., for 1 h at room temperature and for 18 h at 50° C. The mixture was cooled, poured into n-heptane (3.8 L) and extracted with 80% methanol (2×3.8 L). The methanol phase was extracted with another 3.8 L of n-heptane, the n-heptane phases were combined and dried with MgSO4. The solvent was removed in vacuo to give the title compound (121.5 g) as yellowish oil.
Reaction SMILES: [N:1]([C@H:4]([CH2:28][O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@H:5]1[O:11][CH:8]([O:9]C)[C@H:7]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:6]1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[N+:2]=[N-:3].FC(F)(F)C(O)=O.O>O1CCCC1>[N:1]([C@H:4]([CH2:28][O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C@H:5]1[O:11][CH:8]([OH:9])[C@H:7]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@H:6]1[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[N+:2]=[N-:3]
Reactant: COC1O[C@H]([C@@H](COCc2ccccc2)N=[N+]=[N-])[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: [N-]=[N+]=N[C@H](COCc1ccccc1)[C@H]1OC(O)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -10 °C
Reaction time: 24 h
Yield: 91.2 %

Procedure:
Methyl 5-azido-2,3,6-tri-O-benzyl-5-deoxy-D-glucofuranoside (10.8 g, 22.2 mmol) was dissolved at room temperature in tetrahydrofuran (20 ml). The solution was cooled at -10° C. and trifluoroacetic acid (120 ml) was added dropwise followed by addition of water (20 ml). The mixture was stirred at 0° C. during 24 h. The mixture was evaporated under reduced pressure without heating. The residue was taken with ether and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Flash chromatography on silica gel and elution with a 20:80 mixture of ethyl acetate and hexane afforded 5-azido-2,3,6-tri-O-benzyl-5-deoxy-D-glucofuranose as a colorless oil (9.63 g, 90%).
Reaction SMILES: [OH-].[Na+].[S:3]1[CH:7]=[CH:6][C:5]2[CH:8]=[C:9]([CH:12]=O)[CH:10]=[CH:11][C:4]1=2.[CH3:14][C:15]([CH3:17])=[O:16]>O>[S:3]1[CH:7]=[CH:6][C:5]2[CH:8]=[C:9]([CH:12]=[CH:14][C:15](=[O:16])[CH3:17])[CH:10]=[CH:11][C:4]1=2
Reactant: O=Cc1ccc2sccc2c1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1ccc2sccc2c1

Procedure:
An aqueous solution of 10% sodium hydroxide (1 ml) was added dropwise to a solution of benzo[b]thiophene-5-carboxaldehyde (7.0 g) in acetone (15 ml) and water (5 ml), the temperature of the reaction mixture being maintained below 30° C. during the addition. On completion of the reaction (ca 3 hrs) the mixture was poured into water. The dried (MgSO4) dichloromethane extract was evaporated to give 1-(benzo[b]thien-5-yl)but-1-en-3-one as a yellow solid, mp 75° C.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([NH:10][CH:11]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[C:12]2[C:13]([CH3:30])=[N:14][N:15]([C:20]3[C:21]([O:28][CH3:29])=[N:22][C:23]([O:26][CH3:27])=[N:24][CH:25]=3)[C:16]=2[C:17](O)=[O:18])[CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([N:10]2[CH:11]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[C:12]3[C:13]([CH3:30])=[N:14][N:15]([C:20]4[C:21]([O:28][CH3:29])=[N:22][C:23]([O:26][CH3:27])=[N:24][CH:25]=4)[C:16]=3[C:17]2=[O:18])[CH:3]=1
Reactant: COc1ncc(-n2nc(C)c(C(Nc3cc(Cl)c(=O)n(C)c3)c3ccc(Cl)cc3)c2C(=O)O)c(OC)n1
Solvent: CO
Solvent: ClCCl
Product: COc1ncc(-n2nc(C)c3c2C(=O)N(c2cc(Cl)c(=O)n(C)c2)C3c2ccc(Cl)cc2)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-(((5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)amino)(4-chlorophenyl)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-3-methyl-1H-pyrazole-5-carboxylic acid (Step 52.4). tR: 4.45 min (HPLC 1); tR: 1.02 min (LC-MS 2); ESI-MS: 527/529 [M+H]+ (LC-MS 2); Rf=0.41 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.99 (s, 3H) 3.41 (s, 3H) 3.93 (s, 3H) 3.96 (s, 3H) 6.21 (s, 1H) 7.30-7.36 (m, 2H) 7.38-7.44 (m, 2H) 7.87 (d, J=2.7 Hz, 1H) 7.92 (d, J=2.7 Hz, 1H) 8.56 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:38])[C:6]=1[C:7]1[CH:8]=[C:9]2[CH2:15][N:14]([C@@H:16]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)[CH2:17][N:18]3C(=O)C4C(=CC=CC=4)C3=O)[C:13](=[O:37])[C:10]2=[N:11][CH:12]=1.O1C=CC=C1.NN>CO>[NH2:18][CH2:17][C@@H:16]([N:14]1[CH2:15][C:9]2[C:10](=[N:11][CH:12]=[C:7]([C:6]3[N:5]([CH3:38])[N:4]=[CH:3][C:2]=3[Cl:1])[CH:8]=2)[C:13]1=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1
Reactant: Cn1ncc(Cl)c1-c1cnc2c(c1)CN([C@@H](Cc1cccc(F)c1)CN1C(=O)c3ccccc3C1=O)C2=O
Agent: NN
Solvent: c1ccoc1
Solvent: CO
Product: Cn1ncc(Cl)c1-c1cnc2c(c1)CN([C@H](CN)Cc1cccc(F)c1)C2=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 33.1 %

Procedure:
2-[(2S)-2-[3-(4-Chloro-1-methyl-1H-pyrazol-5-yl)-7-oxo-5,7-dihydro-6H-pyrrolo [3,4-b]pyridin-6-yl]-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (48 mg, 0.91) was dissolved in methanol (2 mL), tetrahydron furan (2 mL) and hydrazine (0.2 mL). The resulting reaction mixture was stirred at 50° C. for 2 h. Direct purification on prep.—HPLC (pH=10) afforded 12 mg (30.1% yield) of the desired intermediate as white solid. LC-MS found: 400.1 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm: 8.78 (d, J=1.8 Hz, 1H), 8.32 (d, J=1.8 Hz, 1H), 7.74 (s, 1H), 7.26 (ddd, J1=7.8 Hz, J2=6.3 Hz, J3=8.1 Hz, 1H), 7.06 (m, 2H), 6.96 (dd, J1=8.7 Hz, J2=8.4 Hz, 1H), 4.51 (s, 2H), 4.34 (m, 1H), 3.80 (s, 3H), 3.01 (m, 2H), 2.91 (m, 2H).