Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C@@H:7]([O:8][N+:9]([O-:11])=[O:10])[CH2:6][C@H:5]([C:12]([OH:14])=[O:13])[CH2:4]1.[C:15](Cl)(=O)[C:16]([Cl:18])=O.C(=O)C>CN(C)C=O.[Cl-].[Zn+2].[Cl-]>[CH3:1][O:2][C@@H:3]1[C@@H:7]([O:8][N+:9]([O-:11])=[O:10])[CH2:6][C@H:5]([C:12]([O:14][CH:16]([Cl:18])[CH3:15])=[O:13])[CH2:4]1
Reactant: CO[C@H]1C[C@@H](C(=O)O)C[C@@H]1O[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Agent: CC=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: CO[C@H]1C[C@@H](C(=O)OC(C)Cl)C[C@@H]1O[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a d-chloroform (60 mL) solution of (1R,3S,4S)-3-methoxy-4-(nitrooxy)cyclopentane carboxylic acid (4.59 g, 22.4 mmol) was added oxalyl chloride (2.40 mL, 27.4 mmol), followed by a few drops of N,N-dimethylformamide. After 60 minutes, 1H-NMR showed that the reaction was complete. To this reaction mixture was added zinc chloride (0.31 g, 2.27 mmol). The suspension was cooled to 0° C., and a d-chloroform solution (10 mL) of acetaldehyde (2.6 mL, 46.0 mmol) was slowly added to the reaction mixture over 5 minutes. The reaction was warmed up to room temperature and stirred for 17 hours. 1H-NMR confirmed that the starting acid chloride has been consumed and most of the material was converted to the desired product. The reaction mixture was concentrated in vacuo, and chromatography of the residue over silica gel, eluting with 2/98→20/80 ethyl acetate/hexanes, afforded the title compound as a colorless liquid. 1H NMR (500 MHz, CDCl3) δ 1.80 (d, J=5.9 Hz, 3H), 2.04-2.14 (m, 2H), 2.28-2.36 (m, 1H), 2.50-2.60 (m, 1H), 3.01 (quintet, J=8.3 Hz, 1H), 3.37 (s, 3H), 3.81-3.85 (m, 1H), 5.26-5.31 (m, 1H), 6.54 (q, J=5.8 Hz, 1H, D1), 6.54 (q, J=5.9 Hz, 1H, D2).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH:13]([CH3:14])[NH:12][C:11](=[O:15])[C:10]1([CH3:17])[CH3:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([Cl:27])[CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:27][C:21]1[CH:20]=[C:19]([N:12]2[C@@H:13]([CH3:14])[C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:10]([CH3:16])([CH3:17])[C:11]2=[O:15])[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]
Reactant: CC1NC(=O)C(C)(C)C1O[Si](C)(C)C(C)(C)C
Reactant: N#Cc1ccc(Br)cc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: C[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)C(=O)N1c1ccc(C#N)c(Cl)c1

Procedure:
Using (4RS,5SR)-4-(tert-butyldimethylsilyloxy)-3,3,5-trimethylpyrrolidin-2-one (105.9 mg), 4-bromo-2-chlorobenzonitrile (89 mg), cesium carbonate (200 mg), tris(dibenzylideneacetone)dipalladium(0) (20 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (25 mg), and in the same manner as in Reference Example 3, the title compound was obtained as a colorless solid (yield: 121 mg, 75%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].[Si:53]([O:70][CH2:71][C:72]1[N:77]=[CH:76][N:75]=[C:74]([C:78]([CH:85]2[CH2:87][CH2:86]2)=[CH:79][C:80]([O:82][CH2:83][CH3:84])=[O:81])[CH:73]=1)([C:66]([CH3:69])([CH3:68])[CH3:67])([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.C(O)(C)(C)C>C1(C)C=CC=CC=1.[Cu]Cl.CO>[Si:53]([O:70][CH2:71][C:72]1[N:77]=[CH:76][N:75]=[C:74]([CH:78]([CH:85]2[CH2:87][CH2:86]2)[CH2:79][C:80]([O:82][CH2:83][CH3:84])=[O:81])[CH:73]=1)([C:66]([CH3:67])([CH3:68])[CH3:69])([C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1
Reactant: CCOC(=O)C=C(c1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ncn1)C1CC1
Agent: Cl[Cu]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOC(=O)CC(c1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ncn1)C1CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 101.1 %

Procedure:
Under an argon atmosphere, to a solution of 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (844 mg) in toluene (50 mL) were added copper (I) chloride (134 mg) and sodium tert-butoxide (130 mg), and the mixture was stirred at room temperature for 5 min. To the obtained yellow suspension were successively added ethyl 3-(6-(((tert-butyldiphenylsilyl)oxy)methyl)pyrimidin-4-yl)-3-cyclopropylacrylate (6.60 g), polymethylhydrosiloxane (8.10 mL) and tert-butyl alcohol (2.56 mL) at room temperature, and the mixture was directly stirred for 7 hr. To the reaction mixture was added methanol, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.70 g) as a pale-yellow oil.
Reaction SMILES: [NH3:1].[F:2][C:3]1([F:34])[C:7](=S)[NH:6][C:5]2([C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[CH:20]=3)[O:15][C:14]3[C:9]2=[CH:10][C:11]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[CH:12][CH:13]=3)[CH2:4]1>C1COCC1>[F:2][C:3]1([F:34])[C:7]([NH2:1])=[N:6][C:5]2([C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[CH:20]=3)[O:15][C:14]3[C:9]2=[CH:10][C:11]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[CH:12][CH:13]=3)[CH2:4]1
Reactant: N
Reactant: FC1(F)CC2(NC1=S)c1cc(-c3cccnc3)ccc1Oc1ncc(-c3cccnc3)cc12
Solvent: C1CCOC1
Product: NC1=NC2(CC1(F)F)c1cc(-c3cccnc3)ccc1Oc1ncc(-c3cccnc3)cc12
Temperature: 55 °C
Reaction time: 12 h

Procedure:
Ammonia gas was bubbled through a solution of 4′,4′-difluoro-3,7-di(pyridin-3-yl)spiro[chromeno[2,3-b]pyridine-5,2′-pyrrolidine]-5′-thione (0.019 g, 0.041 mmol) in THF (0.691 mL) at 55° C. for 2 minutes. Mercuric chloride (0.019 g, 0.070 mmol) was added in one portion and ammonia gas was bubbled through for 5 more minutes while heating at 55° C. (THF solution replenished as necessary to maintain a volume of ˜0.6 mL). The resulting reaction was stirred at 55° C. under nitrogen atmosphere for 12 hours to completion. After cooling, the reaction was filtered with CH2Cl2, MeOH, and 2:1 mixture of CHCl3/i-PrOH. The filtrate was diluted with a 10:1 mixture of saturated aqueous ammonium chloride/ammonium hydroxide (10 mL), the layers were separated and the aqueous layer was extracted with a 2:1 mixture of CHCl3/i-PrOH (3×20 mL). The combined organic extracts were washed with a 10:1 mixture of saturated aqueous ammonium chloride/ammonium hydroxide, water, saturated aqueous sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to afford a residue that was purified by silica gel chromatography (1:20 MeOH in CH2Cl2, followed by 1:10 2 M ammonia MeOH solution in CH2Cl2) to provide 4′,4′-difluoro-3,7-di(pyridin-3-yl)-3′,4′-dihydrospiro[chromeno[2,3-b]pyridine-5,2′-pyrrol]-5′-amine as an off-white solid after triturating with diethyl ether and pentane. MS m/z=442.0 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]([C:18]3[NH:23][C:22]4[CH:24]=[CH:25][C:26]([C:28]#[N:29])=[CH:27][C:21]=4[S:20](=[O:31])(=[O:30])[N:19]=3)=[C:14]([OH:32])[C@H:13]3[C@@H:8]2[C@H:9]2[CH2:33][C@@H:12]3[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[ClH:36]>CO.[Pd]>[ClH:36].[NH2:29][CH2:28][C:26]1[CH:25]=[CH:24][C:22]2[NH:23][C:18]([C:15]3[C:16](=[O:17])[N:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:35][CH:34]=4)[C@@H:8]4[C@H:13]([C:14]=3[OH:32])[C@@H:12]3[CH2:33][C@H:9]4[CH2:10][CH2:11]3)=[N:19][S:20](=[O:31])(=[O:30])[C:21]=2[CH:27]=1
Reactant: N#Cc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(1R,2S,7R,8S)-3-[3-(4-Fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazine-7-carbonitrile (0.38 g, 0.77 mmol) was dissolved in methanol (required gentle heating via heat gun). Concentrated aqueous hydrochloric acid solution (5 mL) was added followed by 10% palladium on carbon (˜150 mg). The mixture was degassed and backfilled with hydrogen gas via balloon. The mixture stirred at 25° C. for 3 h. The mixture was passed through a plug of Celite, eluting with additional methanol (200 mL). The filtrate was concentrated in vacuo to afford the desired product, (1R,2S,7R,8S)-5-(7-aminomethyl-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one hydrochloride (˜0.77 mmol), as a pale yellow solid. The solid was used directly in the next step without further purification or characterization. LC-MS (ESI) calculated for C25H25FN4O4S 496.16. found 497.3 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5]2.Br[C:20]1[C:21](=[O:28])[N:22]([CH3:27])[CH:23]=[C:24]([Br:26])[CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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].O1CCOCC1>[Br:26][C:24]1[CH:25]=[C:20]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5]3)[C:21](=[O:28])[N:22]([CH3:27])[CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc2C1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)C3)c1=O
Temperature: 25 °C
Yield: 74.9 %

Procedure:
A 100 mL round bottomed flask was charged with tert-butyl 6-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (2 g, 8 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (1.8 g, 6.7 mmol), cesium carbonate (4.4 g, 13.4 mmol), XantPhos (0.41 g, 0.7 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.64 g, 0.7 mmol) and 1,4-dioxane (50 mL).The reaction mixture was refluxed under argon atmosphere for 2 h. After this time, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with 25:1 dichloromethane/methanol to give 258a (2.18 g, 63%). LC/MS: m/z 435 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]2[CH:10]3[O:20][CH:13]([CH2:14][C:15]=2[C:16]=1[C:17]([OH:19])=O)[CH2:12][CH2:11]3)=[O:5].[F:29][C:30]([F:35])([F:34])[CH2:31][CH2:32][NH2:33].N>>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]2[CH:10]3[O:20][CH:13]([CH2:14][C:15]=2[C:16]=1[C:17]([NH:33][CH2:32][CH2:31][C:30]([F:35])([F:34])[F:29])=[O:19])[CH2:12][CH2:11]3)=[O:5]
Reactant: O=C(Nc1sc2c(c1C(=O)O)CC1CCC2O1)c1c(F)cccc1C(F)(F)F
Reactant: NCCC(F)(F)F
Agent: N
Product: O=C(Nc1sc2c(c1C(=O)NCCC(F)(F)F)CC1CCC2O1)c1c(F)cccc1C(F)(F)F

Procedure:
The title compound was prepared from the product of Example 4A and commercially available 3,3,3-trifluoropropylamine according to the procedure described for Example 4B. MS (DCI/NH3) m/z 511 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:22][CH:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1)[C:11]1[CH:12]=[C:13]([C:17]#[C:18][CH2:19][CH2:20][NH2:21])[CH:14]=[CH:15][CH:16]=1>CO.[Pt]=O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:22][CH:23]1[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]1)[C:11]1[CH:12]=[C:13]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH:14]=[CH:15][CH:16]=1
Reactant: CN1CCC(OC(c2cccc(C#CCCN)c2)c2nc3ccccc3[nH]2)CC1
Agent: O=[Pt]
Solvent: CO
Product: CN1CCC(OC(c2cccc(CCCCN)c2)c2nc3ccccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)-methyl]phenyl}but-3-ynylamine (50 mg) in methanol (2.5 mL) is added platinum oxide (8 mg). The flask is purged with argon then put under one atmosphere of hydrogen. The reaction mixture is stirred overnight at room temperature then filtered on celite, cake washed with methanol. The solvent is removed under reduced pressure to give 4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}butylamine.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[S:9])[NH:8][C:4]=2[CH:3]=1.[ClH:12].[N:13]1([CH2:19][CH2:20][Cl:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])O.[Na+]>CO>[ClH:21].[ClH:12].[N:13]1([CH2:19][CH2:20][S:9][C:7]2[NH:8][C:4]3[CH:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:5]=3[N:6]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Cc1ccc2[nH]c(=S)[nH]c2c1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1ccc2nc(SCCN3CCCCC3)[nH]c2c1

Procedure:
4.87 g (30 mmoles) of 5-methyl-benzimidazoline-2-thione, 6.54 g (35.5 mmoles) of 2-(1-piperidyl)-ethylchloride hydrochloride, 2.78 g (33 mmoles) of sodium hydrogencarbonate are dissolvent in 60 ml of methanol and the mixture is refluxed for 6 hours. The inorganic salt is filtered off, the filtrate is evaporated, and the title compound is precipitated by adding ethyl acetate and hydrochloric ethyl acetate. Weight: 9.32 g (90%). Melting point: 229°-230° C., which does not change after recrystallization from ethanol.
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1>[OH-].[Na+].CS(C)=O>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[S:1][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Sc1ncccn1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cccnc1Sc1ncccn1
Temperature: 82 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A mixture of 2.8 g of 2-mercaptopyrimidine in 35 ml 5.5% aqueous sodium hydroxide solution was added to 3.95 g 2-chloro-3-nitropyridine in 15 ml DMSO that was preheated to 92° C. The mixture, already containing precipitated product, cooled, and then was reheated to reflux at 82° C. After one hour, the reaction was allowed to cool and then poured into 150 ml ice-water. The precipitate was collected by filtration, washed with water and 95% ethanol, and then recrystallized from 95% ethanol to give 4.34 g (74% yield), mp 122.5°-124° C.
Reaction SMILES: CN(C)C(=O)[S:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:8]=[CH:7][C:6]=1[CH2:17][CH2:18][CH3:19].[OH-].[K+].CNC.Cl>O.C(O)COCCO>[CH3:15][CH:14]([CH3:16])[CH2:13][CH2:12][O:11][C:9]1[CH:8]=[CH:7][C:6]([CH2:17][CH2:18][CH3:19])=[C:5]([SH:4])[CH:10]=1
Reactant: CCCc1ccc(OCCC(C)C)cc1SC(=O)N(C)C
Agent: CNC
Agent: Cl
Agent: [K+]
Solvent: OCCOCCO
Solvent: O
Product: CCCc1ccc(OCCC(C)C)cc1S

Procedure:
A solution of 136.1 parts of S-5-(3-methylbutoxy)-2-propylphenyl N,N-dimethylthiocarbamate and 280 parts of potassium hydroxide in 1000 parts of digol was stirred under nitrogen at 120° - 130° for 9 hours, after which no dimethylamine could be detected in the effluent nitrogen. The mixture was cooled, poured into 8000 parts of water and the resulting solution was acidified to pH 1 with hydrochloric acid. The mixture was extracted with ether and the latter was washed with water, dried over magnesium sulphate, filtered and evaporated to dryness to give 95.7 g of the desired product 5-(3-methylbutoxy)-2-propylthiophenol.
Reaction SMILES: [N:1]([CH2:4][CH:5]([NH:12][C:13]([C:15]1[S:16][CH:17]=[CH:18][C:19]=1[NH:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]2[NH:27][CH:28]=[CH:29][C:22]=12)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][CH2:4][CH:5]([NH:12][C:13]([C:15]1[S:16][CH:17]=[CH:18][C:19]=1[NH:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]2[NH:27][CH:28]=[CH:29][C:22]=12)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [H][H]
Reactant: [N-]=[N+]=NCC(NC(=O)c1sccc1Nc1ccnc2[nH]ccc12)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: NCC(NC(=O)c1sccc1Nc1ccnc2[nH]ccc12)c1ccccc1
Yield: 78.5 %

Procedure:
A solution of 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-azido-1-phenyl-ethyl)-amide (120 mg, 0.27 mmol), 5% Pd/C (cat) in methanol (5 mL) was subjected to an atmosphere of hydrogen (balloon). After completion the solution was filtered and concentrated in vacuo. The residue was purified by ISCO Companion (silica, 10% methanol, methylene chloride, 1% ammonium hydroxide) to afford 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-amino-1-phenyl-ethyl)-amide (80 mg, 75%) (ESI) 378 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.51 (1H, br. s.) 8.00 (1H, d, J=5.47 Hz) 7.82 (1H, d, J=5.42 Hz) 7.45 (1H, d, J=5.42 Hz) 7.25-7.35 (5H, m) 7.16-7.24 (1H, m) 6.75 (1H, d, J=5.47 Hz) 6.39 (1H, d, J=3.12 Hz) 4.97 (1H, dd, J=8.03, 5.34 Hz) 2.85-2.94 (1H, m) 2.77-2.85 (1H, m)
Reaction SMILES: [F:1][C:2]([F:26])([CH3:25])[CH2:3][N:4]1[CH2:21][CH:20]([CH2:22][O:23][CH3:24])[O:19][C:6]2([CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[CH2:5]1.[ClH:27].O1CCOCC1>>[ClH:27].[F:26][C:2]([F:1])([CH3:25])[CH2:3][N:4]1[CH2:5][C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[O:19][CH:20]([CH2:22][O:23][CH3:24])[CH2:21]1
Reactant: COCC1CN(CC(C)(F)F)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Agent: Cl
Solvent: C1COCCO1
Product: COCC1CN(CC(C)(F)F)CC2(CCNCC2)O1
Reaction time: 2 h
Yield: 99 %

Procedure:
Tert-butyl 8-(2,2-difluoropropyl)-10-(methoxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (77.0 mg, 0.204 mmol) was treated with HCl in dioxane (509 μL of 4 M, 2.04 mmol) and stirred for 2 h. The solvent was evaporated to provide 4-(2,2-difluoropropyl)-2-(methoxymethyl)-1-oxa-4,9-diazaspiro[5.5]undecane hydrochloride as yellow solid (64 mg, 0.20 mmol, 99%). ESI-MS m/z calc. 278.2. found 279.3 (M+1)+; Retention time: 0.79 minutes (3 min run).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].Cl[C:11]1[N:16]=[C:15]([NH:17][CH2:18][CH3:19])[C:14]([N+:20]([O-:22])=[O:21])=[CH:13][N:12]=1>C(N(CC)C(C)C)(C)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[O:9][C:11]1[N:16]=[C:15]([NH:17][CH2:18][CH3:19])[C:14]([N+:20]([O-:22])=[O:21])=[CH:13][N:12]=1
Reactant: CCNc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: Oc1c(F)cccc1F
Solvent: CCN(C(C)C)C(C)C
Product: CCNc1nc(Oc2c(F)cccc2F)ncc1[N+](=O)[O-]
Temperature: 130 °C
Yield: 73 %

Procedure:
2,6-Difluorophenol (2.1 g, 16.1 mmol) is added to a solution of (2-chloro-5-nitro-pyrimidin-4-yl)-ethyl-amine, 6, (3.0 g, 14.9 mmol) in N,N-diisopropyl ethylamine (50 mL). The reaction is heated to reflux (˜130° C.) under N2 for 3 hours at which point monitoring of the reaction via LC/MS indicates the starting material is consumed. The mixture is diluted with 1 N HCl (500 mL) and the resulting mixture extracted three times with EtOAc (500 mL). The organic layers are combined, dried over MgSO4 and concentrated in vacuo to an oil which is purified over silica (15% EtOAc/hexane) to afford 3.2 g (73% yield) of the desired product as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 9.07 (s, 1H), 8.43 (br s, 1H), 7.13-7.23 (m, 1H), 6.98 (t, J=7.8 Hz, 2H), 3.44-3.53 (m, 2H), 1.22 (t, J=7.2 Hz, 3H); ESI/MS: 297 (M+H).
Reaction SMILES: C(SC1C=C2C(C(Cl)=CC=N2)=CC=1)C1C=CC=CC=1.ClN1C(C)(C)C(=O)N(Cl)C1=O.[Cl:31][C:32]1[C:41]2[C:36](=[CH:37][C:38]([S:42](Cl)(=[O:44])=[O:43])=[CH:39][CH:40]=2)[N:35]=[CH:34][CH:33]=1.[F:46][C:47]1[C:52]([F:53])=[C:51]([F:54])[C:50]([F:55])=[C:49]([F:56])[C:48]=1[OH:57].C(N(CC)CC)C>CCOC(C)=O.O.C(O)(=O)C.C(#N)C>[Cl:31][C:32]1[C:41]2[C:36](=[CH:37][C:38]([S:42]([O:57][C:48]3[C:47]([F:46])=[C:52]([F:53])[C:51]([F:54])=[C:50]([F:55])[C:49]=3[F:56])(=[O:43])=[O:44])=[CH:39][CH:40]=2)[N:35]=[CH:34][CH:33]=1
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)ccnc2c1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Agent: Clc1ccnc2cc(SCc3ccccc3)ccc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Cl)ccnc2c1
Reaction time: 0.33 h
Yield: 100 %

Procedure:
A round-bottom flask was charged with 7-(benzylthio)-4-chloroquinoline (7.35 g, 25.7 mmol), acetonitrile (242 ml), acetic acid (9.08 ml), and water (6.05 ml), and after cooling the suspension in an ice bath for 10 minutes, 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (10.13 g, 51.4 mmol) was added in one portion to form a heterogeneous solution. After 20 minutes, conversion to 4-chloroquinoline-7-sulfonyl chloride was observed, and 2,3,4,5,6-pentafluorophenol (9.47 g, 51.4 mmol) was added, followed by drop wise addition of triethylamine (8.96 ml, 64.3 mmol). After 40 minutes, the mixture was diluted with EtOAc (200 mL) and washed with water (2×200 mL) and brine, and then dried over sodium sulfate. After filtration and concentration under a vacuum, the material was purified via silica gel chromatography (120-g column) eluting with 0 to 35% ethyl acetate in heptane to yield perfluorophenyl 4-chloroquinoline-7-sulfonate (10.54 g, 25.7 mmol, 100% yield) as a light yellow oily solid. m/z (ESI) 410.1 (M+H)+.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9](O)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.B(F)(F)F>CC([O-])=O.[Na+]>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16]
Reactant: Oc1cccc(O)c1
Reactant: O=C(O)c1ccccc1
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Product: O=C(c1ccccc1)c1ccc(O)cc1O
Yield: 46.4 %

Procedure:
Resorcinol (1.10 g, 10.0 mmol) and benzoic acid (1.22 g, 1.01 eq.) were treated with BF3-etherate (7.55 mL, 6 eq.) and heated for 2 h to 95° C. After cooling the reaction mixture was carefully poured onto 500 mL of 10% aq. NaOAc solution, twofold extracted with AcOEt, washed with water, dried over sodium sulfate, and evaporated to dryness. Flash chromatography (SiO2, heptane/AcOEt=8/2), followed by direct crystallization after reducing the volume, afforded 0.994 g of the title compound as off-white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]([O:17]CC)=[O:16].CO.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)C=CC=Cc1ccc(OC)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C=CC=CC(=O)O)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
To 9.44 g (36.0 mmol) of said ethyl 5-(2,4-dimethoxyphenyl)-2,4-pentadienoate was added 80 ml of methanol to give a solution. To thesolution was then added a solution of 14.40 g (360 mmol) of sodium hydroxide dissolved in 20 ml of water, and the mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure followed by addition of water and a hydrochloric acid solution to adjust the pH to 1 and extraction with chloroform. The organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave 7.70 g (32.9 mmol) of 5-(2,4-dimethoxyphenyl)-2,4-pentadienoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]#[C:5][CH:6]=[CH:7][CH:8]=1.[CH3:9][N:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:12]2[CH2:13][CH2:14][N:10]([CH3:9])[C:11]2=[O:15])[CH:6]=[CH:5][CH:4]=1
Reactant: COc1c#cccc1
Reactant: CN1CCCC1=O
Product: COc1cccc(C2CCN(C)C2=O)c1

Procedure:
Following the procedure of Example 3, reaction of the lithium anion of 1-methyl-2-pyrrolidone with m-methoxybenzyne (from lithium 2,2,6,6-tetramethylpiperidide and o-chloroanisole) followed by aqueous workup gives 3-(3-methoxyphenyl)-1-methyl-2-pyrrolidone. Removal of the protecting group using iodotrimethylsilane gives the title compound m.p. 113°-4° C. (ethylacetate-hexane).