Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:9](=[O:10])[N:8]2[CH:3]1[S:4][CH2:5][C:6]([CH2:14][S:15][C:16]1[N:20]([CH3:21])[N:19]=[N:18][N:17]=1)=[C:7]2[C:11]([OH:13])=[O:12].[S:22]([C:26]1[N:27]([CH2:31][C:32](Cl)=[O:33])[CH:28]=[CH:29][N:30]=1)([CH3:25])(=[O:24])=[O:23].C(=O)(O)[O-].[Na+]>O.[Na].CC(C)=O>[C:11]([C:7]1[N:8]2[CH:3]([S:4][CH2:5][C:6]=1[CH2:14][S:15][C:16]1[N:20]([CH3:21])[N:19]=[N:18][N:17]=1)[CH:2]([NH:1][C:32](=[O:33])[CH2:31][N:27]1[CH:28]=[CH:29][N:30]=[C:26]1[S:22]([CH3:25])(=[O:24])=[O:23])[C:9]2=[O:10])([OH:13])=[O:12]
Reactant: CS(=O)(=O)c1nccn1CC(=O)Cl
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CC(C)=O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cn3ccnc3S(C)(=O)=O)C2SC1
Temperature: 4 °C
Yield: 3.8 %

Procedure:
Acetone (200 cc.) is added to a solution of 7-amino-2-carboxy-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl]-8-oxo-5-thia-1-aza-bicyclo[4,2,0]oct-2-ene (18.4 g.) in water (110 cc.) and sodium bacarbonate (9.41 g). The mixture is cooled to about 4° C., and (2-mesyl-imidazol-1-yl)-acetyl chloride (12.4 g.) in acetone (50 cc.) is added dropwise while keeping the pH at 7 by adding a saturated aqueous solution of sodium bicarbonate. After having allowed reaction to take place for 1 hour, the acetone is removed under reduced pressure (20 mm.Hg). The pH is brought to 2.5 by adding 6 N hydrochloric acid; a solid precipitates. Ethyl acetate (100 cc.) is added, the mixture is stirred, and then the solid is filtered off and washed with ethyl acetate (500 cc.). The combined organic filtrates are dried over sodium sulphate and concentrated to dryness under reduced pressure (20 mm.Hg). A residue (8.7 g.) is obtained and is taken up in a saturated aqueous solution of sodium bicarbonate (100 cc.). The aqueous phase is washed with ethyl acetate (100 cc.) and then acidified to pH 5 by adding 6 N hydrochloric acid; a slight amount of insoluble matter is filtered off and then the filtrate is acidified to pH 2.5: a product precipitates. Extraction is effected using ethyl acetate (800 cc.), and the organic extracts are dried over sodium sulphate and concentrated to dryness under reduced pressure (20 mm.Hg). The residue is stirred with acetonitrile (40 cc.) and the solid formed is collected to yield 2-carboxy-7-[(2-mesyl-imidazol-1-yl)-acetamido] -3-[(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene (1.08 g.), m.p. approx. 230° C., [α]D20 = -42°± 1 (c= 0.87, dimethylformamide).
Reaction SMILES: [CH:1]1([C:4](=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1.[CH:11](OCC)(OCC)OCC.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][N:23]=1>>[Cl:21][C:22]1[N:23]=[CH:24][C:25]([NH:28][CH:11]=[C:5]([C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:10])[C:6]([O:8][CH3:9])=[O:7])=[CH:26][CH:27]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: COC(=O)CC(=O)C1CC1
Reactant: CCOC(OCC)OCC
Product: COC(=O)C(=CNc1ccc(Cl)nc1)C(=O)C1CC1
Temperature: 145 °C
Yield: 29.9 %

Procedure:
A mixture of methyl 3-cyclopropyl-3-oxopropanoate (7.2 g, 50 mmol), triethyl orthoformate (13 mL, 75 mmol) and 2-chloro-5-aminopyridine (6.4 g, 50 mmol) was heated at 145° C. for 3 h in a round bottomed flask that was equipped with a short path distillation apparatus to collect the ethanol generated during the reaction. The reaction was cooled, concentrated and the residue was purified by chromatography (silica, hexanes/ethyl acetate) to afford the desired product (4.2 g, 28%) as a pale yellow oil: 1H NMR (300 MHz, CDCl3) δ 12.78 (d, 12.5 Hz, 1H), 8.40-8.34 (m, 1H), 8.28 (d, J=2.9 Hz, 1H), 7.51-7.44 (m, 1H), 7.35 (d, J=8.6 Hz, 1H), 4.30 (q, J=7.1 Hz, 2H), 3.28-3.18 (m, 1H), 1.36 (t, J=7.1 Hz, 3H), 1.17-1.09 (m, 2H), 1.02-0.86 (m, 2H). ESI MS m/z 281 [M+H]+.
Reaction SMILES: O.O.[Sn](Cl)Cl.[F:6][C:7]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:8]=1[O:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=1[N+:18]([O-])=O.CCOC(C)=O.O>CCO.Cl>[NH2:18][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:10]=1[O:9][C:8]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:7]=1[F:6])[C:14]#[N:15]
Reactant: N#Cc1ccc(Oc2cc(F)ccc2F)c([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(Oc2cc(F)ccc2F)c(N)c1
Temperature: 70 °C
Yield: 72.1 %

Procedure:
A mixture of Tin (II) chloride dihydrate (18.238 g, 81.00 mmol) in EtOH (65.00 mL) and HCl (12 M, 10.00 mL) was stirred at 70° C. until the solution became clear. Compound 21 (5.60 g, 20.28 mmol) was then added over 10 min. The solution was kept slightly refluxing during addition. The reaction was monitored with TCL (25% EtOAc in hexanes, Rf=0.65). The reaction was complete after refluxing for 1.5 hrs, as indicated by the absence of the starting material (TLC). Water (80 mL) was added and the resulting solution was allowed to cool to room temperature. The desired product was precipitated out as a white solid during cooling. The mixture was further cooled and stirred for 30 min at 15° C. The resulting precipitation was collected via filtration under vacuum, washed with water, and dried under vacuum to yield compound 22 as a white solid (3.60 g, 99.0% HPLC purity, 63% yield). 1H NMR (500 MHz, DMSO-d6): δ 7.44 (m, 1H), 7.09 (m, 2H), 7.04 (m, 1H), 6.92 (dd, J1=2 Hz, J2=8 Hz, 1H), 6.78 (d, J=8 Hz, 1H), 5.65 (s, 2H).
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.[CH3:14][C:15]([Si:18]([CH3:68])([CH3:67])[O:19][C:20]([C:23]#[C:24][CH:25](OC(=S)NC1C=CC=CC=1)[C@H:26]([C:28]1[C@:45]2([CH3:46])[C@H:31]([C:32]3[C@H:42]([CH2:43][CH2:44]2)[C@:40]2([CH3:41])[C:35]([CH2:36][C@@H:37]([O:47][Si:48]([CH3:56])([CH3:55])[C:49]([CH3:54])([CH3:53])[CH:50]([CH3:52])[CH3:51])[CH2:38][CH2:39]2)=[CH:34][CH:33]=3)[CH2:30][CH:29]=1)[CH3:27])([CH3:22])[CH3:21])([CH3:17])[CH3:16]>CCCCCC.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:14][C:15]([Si:18]([CH3:67])([CH3:68])[O:19][C:20]([C:23]#[C:24][CH2:25][C@H:26]([C:28]1[C@:45]2([CH3:46])[C@H:31]([C:32]3[C@H:42]([CH2:43][CH2:44]2)[C@:40]2([CH3:41])[C:35]([CH2:36][C@@H:37]([O:47][Si:48]([CH3:55])([CH3:56])[C:49]([CH3:54])([CH3:53])[CH:50]([CH3:51])[CH3:52])[CH2:38][CH2:39]2)=[CH:34][CH:33]=3)[CH2:30][CH:29]=1)[CH3:27])([CH3:21])[CH3:22])([CH3:17])[CH3:16]
Reactant: CC(C)C(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)C(=CC=C3[C@@H]2CC[C@]2(C)C([C@H](C)C(C#CC(C)(C)O[Si](C)(C)C(C)(C)C)OC(=S)Nc4ccccc4)=CC[C@@H]32)C1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CCCCCC
Product: CC(C)C(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)C(=CC=C3[C@@H]2CC[C@]2(C)C([C@H](C)CC#CC(C)(C)O[Si](C)(C)C(C)(C)C)=CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 133.6 %

Procedure:
To a mixture of 70.5 mL (262 mmol) tributyltin hydride and 1.08 g (6.55 mmol) 2,2'-azobis(2-methylpropionitrile) (AIBN) in 50 mL of hexane at 80° C. was added a solution of 117 g (131 mmol) crude phenyl-carbamothioic acid O-[(3β)-25-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3-[[dimethyl(1,1,2-trimethylpropyl)silyl]oxy]cholesta-5,7,16-trien-23-yn-22-yl] ester in 1.5 L of hexane over 45 min. After refluxing for 1 hr, additional tributyltin hydride (35 mL, 131 mmol) and AIBN (1.07 g, 6.52 mmol) were added. After 30 min. of refluxing, the mixture was cooled to room temperature and stirred for 1 hr. The precipitate was filtered, and the filtrate was concentrated. The residue was dissolved in 200 mL of hexane and purified by filtration through 425 g of silica gel. The column was eluted with hexane and then with 20% toluene in hexane. The fractions containing the product were combined and concentrated to give 114 g (overweight) of crude [[(3β)-25-[[(1,1-dimethylethyl)dimethylsilyl]oxy]cholesta-5,7,16-trien-23-yn-3-yl]oxy]dimethyl (1,1,2-trimethylpropyl)silane as a light yellow oil. This crude material was used in the next step. An analytical sample was obtained by chromatographic purification followed by crystallization from ethyl acetate/methanol (1:1): mp 62°-66° C.;Anal. Calcd. for C41H70O2Si2 : C, 75.62, H, 10.84; Si, 8.63. Found C, 75.12; H, 10.77; Si, 8.55
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[N:9][C:8]2[C:3]1=[N:4][C:5]([Cl:12])=[N:6][C:7]=2Cl.[CH2:13]([NH2:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Cl:12][C:5]1[N:4]=[C:3]2[C:8]([N:9]=[CH:10][N:2]2[CH3:1])=[C:7]([NH:21][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:6]=1
Reactant: NCCc1ccccc1
Reactant: Cn1cnc2c(Cl)nc(Cl)nc21
Product: Cn1cnc2c(NCCc3ccccc3)nc(Cl)nc21

Procedure:
Was prepared according to Example 4 from 9-methyl-2,6-dichloro-9H-purine and phenethylamine.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC([NH:30][C:31]([NH:42]C(OC(C)(C)C)=O)=[N:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1)=O)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:17]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:9][O:10][C:38]2[CH:37]=[CH:36][C:35]([CH2:34][CH2:33][NH:32][C:31]([NH2:42])=[NH:30])=[CH:40][CH:39]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: OCCC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC(=NCCc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N=C(N)NCCc1ccc(OCCC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
A solution of 3,3,3-triphenylpropanol (11.54 g, 40 mmol), N,N'-Bis(t-butoxycarbonyl)-N"-2-(4-hydroxyphenyl)ethylguanidine (15.18 g, 40 mmol), and triphenyphosphine (1.54 g, 44 mmol) in THF (400 mL) was cooled to -15° C., and a solution of diethyl azodicarboxylate (7.66 g, 44 mmol) in 50 mL THF was added dropwise with stirring. The mixture was allowed to warm to room temperature, and then refluxed for 4 hr. The mixture was concentrated, and the residue taken up in toluene (300 mL). Triphenylphosphine oxide was removed by filtration, and the filtrate concentrated and chromatographed on silica gel with dichloromethane. N',N'-bis(t-butoxycarbonyl)-N-(2-(4-(3,3,3-triphenylpropoxy)phenyl)ethylguanidine was obtained as a colorless gum (8.0 g, 31%). This material was dissolved in isopropanol (50 mL) containing anisole (8 g) and anhydrous hydrogen chloride (10 g), and the solution heated until gas evolution was observed, at ca. 50° C. The solution was maintained at this temperature for 15 minutes, then concentrated in vacuo. The residue was stirred vigorously for two days with a mixture of ethyl acetate (200 mL) and 1.0N aqueous sodium bicarbonate, and the resulting white solid collected by filtration, and washed with water, acetone, ethyl acetate, and THF, to provide the bicarbonate salt, containing about 0.75 equivalents of water, as a white powder, mp 172°-176° C. (dec). This material was suspended in 250 mL water, and stirred vigorously while heating to 90° C. Gas evolution was observed, and the solid became gummy for a time, then once again became powdery. When gas evolution had ceased, the mixture was cooled, and the solid collected by filtration and dried in vacuo overnight. The title compound was obtained as the carbonate salt, a white powder, mp 150°-180° C. (dec) with slow heating, 180°-183° C. (dec) with rapid heating. Anal. calcd. for C30H31N3O·0.5CH2O3 : C, 76.22; H, 6.71; N, 8.74. Found: C, 75.79; H, 6.68; N, 8.87.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][CH2:3][C:2]2=O.[C:8]([O:15]CC)(=[O:14])[C:9](OCC)=O.CC(C)([O-])C.[K+].[NH:24]([C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1)[NH2:25].Cl>C(O)C.C1COCC1.CO>[N:27]1[CH:28]=[CH:29][N:30]=[CH:31][C:26]=1[N:24]1[C:2]2[C@H:1]3[CH2:6][C@H:5]3[CH2:4][C:3]=2[C:9]([C:8]([OH:15])=[O:14])=[N:25]1
Reactant: O=C1CC[C@@H]2C[C@H]12
Reactant: NNc1cnccn1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1nn(-c2cnccn2)c2c1C[C@@H]1C[C@H]21
Temperature: 40 °C
Reaction time: 3.5 h
Yield: 81.2 %

Procedure:
To a solution of (1S,5R)-bicyclo[3.1.0]hexan-2-one (52.9 g, 539 mmol) and diethyl oxalate (0.073 L, 539 mmol) in absolute ethanol (0.9 L) (not denatured with methanol) was added a THF solution of potassium tert-butoxide (1.0 M, 0.539 L, 539 mmol) over 15 min (maintaining the temperature below 43° C.). The resulting yellow solution was stirred at 40° C. for 3.5 h. 2-Hydrazinylpyrazine (59.4 g, 539 mmol) was added followed by a 6.0 M aqueous solution of hydrogen chloride (0.270 L, 1618 mmol). The reaction was stirred at 50° C. for 1.5 h. The mixture was poured into ice-water (5 L). A precipitate appeared immediately. After sitting for 30 minutes in an ice bath, the solid was collected by filtration, rinsed with water (5×1 L); and dried to give the title compound (106 g) as an off-white solid 1H NMR. LCMS m/z=271.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.47 (td, J=4.7, 3.3 Hz, 1H), 1.27 (td, J=8.0, 4.9 Hz, 1H), 1.41 (t, J=7.1 Hz, 3H), 2.26-2.32 (m, 1H), 2.77-2.82 (m, 1H), 2.88 (dd, J=16.7, 1.4 Hz, 1H), 2.99 (dd, J=16.6, 6.4 Hz, 1H), 4.40 (q, J=7.1 Hz, 2H), 8.41 (dd, J=2.5, 1.5 Hz, 1H), 8.52 (d, J=2.5 Hz, 1H), 9.40 (d, J=1.5 Hz, 1H).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][C:10]1([CH3:27])[CH2:19][C:18](=O)[C:17]2[C:12](=[CH:13][C:14]([O:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:15][CH:16]=2)[O:11]1.Cl>C1COCC1>[CH3:9][C:10]1([CH3:27])[CH:19]=[C:18]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:17]2[C:12](=[CH:13][C:14]([O:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:15][CH:16]=2)[O:11]1
Reactant: Br[Mg]c1ccccc1
Reactant: CN(C)CCOc1ccc2c(c1)OC(C)(C)CC2=O
Agent: Cl
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc2c(c1)OC(C)(C)C=C2c1ccccc1

Procedure:
To a stirred solution of phenylmagnesium bromide [from bromobenzene and magnesium in dry tetrahydrofuran] was added 2,2-dimethyl-7-(2-dimethylaminoethoxy)-chroman-4-one in dry THF and the resulting solution was boiled under reflux for 2 weeks. The cooled reaction mixture was decomposed with 2.5 N hydrochloric acid and the organic layer separated and dried (magnesium sulphate). Removal of the solvent gave a yellow oil which was chromatographed on silica in 3% ether-97% light petroleum (b.p. 60°-80°) gave the title compound as a colourless oil. Dissolution in dry ether and passage of dry hydrogen chloride through the solution gave the hydrochloride salt, m.p. 186.5°-187.5°. An analogous procedure yielded 7-(2-N-benzyl-N-methyl-aminoethoxy)-4-(4-fluorophenyl)-2,2-dimethyl-2H-chromene as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[N:23]=[C:22]3[N:16]([CH2:17][CH2:18][O:19][C:20]4[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][C:21]=43)[CH:15]=2)=[N:12][C:11]([CH3:30])=[N:10]1.[AlH4-].[Li+]>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[N:23]=[C:22]3[C:21]4[CH:24]=[CH:25][C:26]([CH2:28][NH2:29])=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][N:16]3[CH:15]=2)=[N:12][C:11]([CH3:30])=[N:10]1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C#N)cc2OCC3)n(-c2ccc(F)cc2F)n1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(CN)cc2OCC3)n(-c2ccc(F)cc2F)n1
Reaction time: 2 h

Procedure:
To 2-[2-(2,4-Difluoro-phenyl)-5-methyl-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-8-carbonitrile in tetrahydrofuran was added Lithium tetrahydroaluminate (1M in THF), dropwise at 0° C. The reaction was stirred for 2 hours and quenched with saturated Na2SO4 until H2 evolution ceased. MgSO4 was added and the whole was diluted with copious amounts of methylene chloride, filtered over celite, and concentrated in vacuo. The crude was purified by flash chromatography (1-15% MeOH in DCM spiked with Et3N) to afford to give 355. MS (ESI+) 409.1. 1H NMR (400 MHz, DMSO) δ 7.89 (s, 1H), 7.68 (td, J=8.7, 6.2 Hz, 1H), 7.64-7.52 (m, 2H), 7.32-7.25 (m, 1H), 6.95 (s, 1H), 6.91 (dd, J=8.2, 1.2 Hz, 1H), 4.48-4.38 (m, 4H), 3.66 (s, 2H), 2.35 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][C:10]([N:15]([CH2:20][CH2:21][CH2:22][C:23]#[N:24])[S:16]([CH3:19])(=[O:18])=[O:17])=[C:11]([I:14])[CH:12]=2)[O:7][C:6]=1[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)=[O:4].B>C1COCC1>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][C:10]([N:15]([CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[S:16]([CH3:19])(=[O:18])=[O:17])=[C:11]([I:14])[CH:12]=2)[O:7][C:6]=1[C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1)=[O:4]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(CCCC#N)S(C)(=O)=O)c(I)cc12
Agent: B
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(CCCCN)S(C)(=O)=O)c(I)cc12
Temperature: 0 °C
Yield: 44.6 %

Procedure:
To the 6-[(3-Cyano-propyl)-methanesulfonyl-amino]-2-(4-fluoro-phenyl)-5-iodo-furo[2,3-b]pyridine-3-carboxylic acid methylamide (11 mg, 0.020 mmol) at 0° C. is added 0.5 mL 1N Borane in THF and stirred at 0° C. 5 min then stirred at room temperature overnight. The mixture is quenched with 1N HCl and THF is removed with a stream of N2. Purification is achieved by reverse phase HPLC with a C8 column with 10-50% ACN/H2O (0.1% NH4OH) to give 5 mg title compound. MS (ESI) m/z 561.0 (M+1). Retention time=1.00 min, Method A. 1H NMR (400 MHz, CD3CN) δ ppm 8.71 (s, 1H), 8.02-8.07 (m, 2H), 7.95 (t, 2H) 3.74 (t, 3H), 3.15 (s, 3H), 2.91 (d, 3H), 2.13-2.54 (m, 6H)
Reaction SMILES: CS(O[CH:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[CH3:7])(=O)=O.[F:21][C:22]([F:31])([F:30])[C:23]1[CH:24]=[C:25]([SH:29])[CH:26]=[CH:27][CH:28]=1.C([O-])([O-])=O.[K+].[K+].CN(C)C=O>CCOCC>[F:31][C:22]([F:21])([F:30])[C:23]1[CH:24]=[C:25]([S:29][CH:6]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:12][CH2:13]2)[CH3:7])[CH:26]=[CH:27][CH:28]=1
Reactant: FC(F)(F)c1cccc(S)c1
Reactant: CC(OS(C)(=O)=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(Sc1cccc(C(F)(F)F)c1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Yield: 98.3 %

Procedure:
To a 250 ml round bottom flask was added tert-butyl 4-{1-[(methylsulfonyl)oxy]ethyl}piperidine-1-carboxylate (11 g, 35.8 mmol), 3-(trifluoromethyl)benzenethiol (7.6 g, 43 mmol), K2CO3 (9.9 g, 72 mmol) and 80 ml dimethylformamide. The reaction mixture was heated at 50° C. for 36 hr under N2, then cooled down to room temperature, 150 ml ether was added. The resulting mixture was sequentially washed with 250 ml water, 100 ml 5% KOH solution and 75 ml brine. The organic layers were dried over sodium sulfate, filtered and concentrated to give 13.7 g crude product. It was used for next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19](Br)[CH:20]=[CH2:21].[I-].[Li+].C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>O1CCCC1>[CH3:11][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH2:21][CH:20]=[CH2:19])[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:18]
Reactant: C=CCBr
Reactant: CC(C(=O)OCc1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(C)(C(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
A solution of 2-phenyl-propionic acid benzyl ester (2.0 g, 8.32 mmol), allyl bromide (0.865 mL, 9.99 mmol), and lithium iodide (1 g) in tetrahydrofuran (15 mL) at 0° C. was treated dropwise with the lithium hexamethyldisilazide (9.99 mL, 1M in tetrahydrofuran, 9.99 mmol). The reaction was allowed to warm to 25° C. and stirred for 18 hours. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the ethyl acetate layers were combined, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, then 10% ethyl acetate in hexane, and 20% ethyl acetate in hexane to give the title compound (2.31 g, 99%). 1H NMR (300 MHz, CDCl3): δ ppm 1.56 (m, 3 H) 2.68 (m, 1 H) 2.85 (m, 1 H) 5.05 (m, 4 H) 5.59 (m, 1 H) 7.26 (m, 10 H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.F[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])=[N:9][CH:10]=1
Reactant: Cc1ncc[nH]1
Reactant: Cc1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-n2ccnc2C)nc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2-Methylimidazole (2.0 g, 24 mmol) and 2-Fluoro-5-methylpyridine (5.41 g, 49 mmol) were dissolved in 40 ml dimethyl formamide. Cesium carbonate (23.8 g, 73 mmol) was added, and the reaction mixture was stirred at 100° C. overnight. The reaction mixture was poured into 100 mL water and extracted three times with ethyl acetate (150 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The desired compound was obtained as a brown oil (4.0 g, 95%), MS: m/e=174.1 (M+H+).
Reaction SMILES: [F-:1].[K+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[C:11](I)[CH:12]=1)[C:9](=[O:14])[N:8]([CH:15]1[CH2:17][CH2:16]1)[CH:7]2[CH3:18].COC(=O)[C:22](Cl)([F:24])[F:23]>CN(C=O)C.[Cu]I>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[C:11]([C:22]([F:24])([F:1])[F:23])[CH:12]=1)[C:9](=[O:14])[N:8]([CH:15]1[CH2:17][CH2:16]1)[CH:7]2[CH3:18]
Reactant: CC1c2cc(Cl)cc(I)c2C(=O)N1C1CC1
Reactant: [F-]
Reactant: COC(=O)C(F)(F)Cl
Agent: [Cu]I
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1c2cc(Cl)cc(C(F)(F)F)c2C(=O)N1C1CC1
Temperature: 140 °C
Reaction time: 18 h
Yield: 19.7 %

Procedure:
CuI (0.080 g, 0.42 mmol) and potassium fluoride (0.024 g, 0.42 mmol) were added under an N2 atmosphere to a solution 5-chloro-2-cyclopropyl methyl-7-iodo-2,3-dihydro-isoindol-1-one (0.123 g, 0.35 mmol) and chloro-difluoro-acetic acid methyl ester (0.046 mL, 0.42 mmol) in DMF (4 mL). The mixture was stirred at 140° C. for 18 h. The reaction was cooled and the solvent evaporated. Silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-chloro-2-cyclopropyl methyl-7-trifluoromethyl-2,3-dihydro-isoindol-1-one (0.020 g, 20%). 1H NMR (300 MHz, CDCl3): δ (ppm) 0.33 (s, 2H), 0.59 (m, 2H), 1.05 (m, 1H), 3.48 (d, 2H) 4.53 (s, 2H), 7.64 (s, 1H), 7.73 (s, 1H). GC-MS: m/z 289 (M)+, 274 (M-15)+.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[OH:5][CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH3:12].C(N(CC)CC)C.[ClH:20]>C(Cl)Cl>[Cl:20][CH2:9][CH2:10][CH2:11][CH:7]1[CH2:6][O:5][C:1](=[O:2])[N:8]1[CH3:12]
Reactant: Cl
Reactant: O=C(Cl)Cl
Reactant: CN1CCCC1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C(=O)OCC1CCCCl
Reaction time: 1 h

Procedure:
A cold (ice bath) solution of 4.0 g (0.041 mole) of phosgene dissolved in 50 ml of methylene chloride was treated dropwise with a solution of 4.7 g (0.041 mole) of 2-hydroxymethyl-1-methylpyrrolidine in 15 ml of methylene chloride at such a rate that the temperature did not exceed 10° C. After addition was complete, the solution was stirred in the cold for 1 hr and then treated dropwise with 4.0 g (0.041 mole) of triethylamine at such a rate that the temperature did not exceed 25° C. The mixture was stirred at ambient temperature for 3 hr and then treated with 50 ml of 1N hydrochloric acid. The layers were separated and the organic layer was washed successively with 50 ml of 1N hydrochloric acid, 50 ml of 4% sodium hydroxide, and 50 ml of brine. The organic layer was dried over sodium sulfate and concentrated to give 2.5 g of oil as residue. This oil was purified by column chromatography on 50 g of silica gel eluted with benzene. Fractions containing the desired product were combined and concentrated to give 1.8 g (25%) of product as an oil.