Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([C:7]#[N:8])[N:6]=1.C[O-].[Na+].[Cl-].[NH4+:13]>CO>[ClH:1].[Cl:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH2:13])=[NH:8])[N:6]=1
Reactant: N#Cc1csc(Cl)n1
Reactant: [NH4+]
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: Cl
Product: N=C(N)c1csc(Cl)n1

Procedure:
10 mmol 2-chloro-4-cyanothiazole was dissolved in 10 ml anhydrous methanol, and 10 mmol sodium methoxide was added. Upon complete reaction of the starting materials, 20 mmol ammonium chloride was added, to carry out reaction in closed state for 12 hr. The reaction product was filtered to remove inorganic salt, and then the resultant filtrate was concentrated to obtain 2-chloro-4-thiazolformamidine hydrochloride.
Reaction SMILES: [OH:1][C@H:2]1[C@H:18]([CH2:19][CH2:20][C@@H:21]([OH:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C@H:5]2[CH2:6][C:7]3[C:12]([CH2:13][C@H:4]2[CH2:3]1)=[C:11]([O:14][CH2:15][C:16]#N)[CH:10]=[CH:9][CH:8]=3.[OH-:28].[K+].Cl.C[OH:32]>>[CH3:26][CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]([OH:27])[CH2:20][CH2:19][C@H:18]1[C@H:2]([OH:1])[CH2:3][C@H:4]2[C@@H:5]1[CH2:6][C:7]1[C:12]([CH2:13]2)=[C:11]([O:14][CH2:15][C:16]([OH:32])=[O:28])[CH:10]=[CH:9][CH:8]=1
Reactant: [OH-]
Reactant: CO
Reactant: CCCCC[C@H](O)CC[C@@H]1[C@H]2Cc3cccc(OCC#N)c3C[C@H]2C[C@H]1O
Agent: Cl
Agent: [K+]
Product: CCCCC[C@H](O)CC[C@@H]1[C@H]2Cc3cccc(OCC(=O)O)c3C[C@H]2C[C@H]1O
Temperature: 10 °C
Yield: 81 %

Procedure:
2-((1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-2-hydroxy-1-((S)-3-hydroxyoctyl)-1H-cyclopenta[b]naphthalen-5-yloxy)acetonitrile (2 g, 0.05 mol) in methanol (18 ml) was treated with 20% KOH (6 ml) and refluxed for 3 hr. The reaction was then cooled to 10° C. and 3N HCl was added slowly until pH=˜8. The solvent was removed in vacuo. Ethyl acetate and brine were added and then 3N HCl was added slowly until pH=2. The reaction mixture was extracted with ethyl acetate. The combined ethyl acetate extracts were dried over anhydrous magnesium sulfate. The solid was filtered off. The solvent was evaporated off under vacuum. The crude product was purified by crystallization from ethanol/H2O. The titled compound was obtained in a crystalline form. Yield: 81%.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([NH2:7])=[N:4][CH:3]=1.[CH:8]1[C:21]2[CH:20]([C:22](Cl)=[O:23])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[O:13][C:12]=2[CH:11]=[CH:10][CH:9]=1>>[CH3:1][C:2]1[O:6][C:5]([NH:7][C:22]([CH:20]2[C:21]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[O:13][C:14]3[C:19]2=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:23])=[N:4][CH:3]=1
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Reactant: Cc1cnc(N)o1
Product: Cc1cnc(NC(=O)C2c3ccccc3Oc3ccccc32)o1

Procedure:
The title compound, white solid, m.p. 217-220° C. and MS: m/e=306.1 (M+) was prepared in accordance with the general method of example 44a from 5-methyl-oxazol-2-ylamine [Ber. 95, 2419(1962)] and 9-xanthene-carboxylic acid chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[N+:11]([O-:13])=[O:12])=[CH:5][CH:4]=1.[CH:14](=[O:18])[CH:15]([CH3:17])[CH3:16].CC(O)C.CCCCCC>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]([CH2:10][N+:11]([O-:13])=[O:12])[C:15]([CH3:17])([CH3:16])[CH:14]=[O:18])=[CH:7][CH:8]=1
Reactant: CC(C)C=O
Reactant: COc1ccc(/C=C/[N+](=O)[O-])cc1
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Solvent: CC(C)O
Product: COc1ccc([C@H](C[N+](=O)[O-])C(C)(C)C=O)cc1

Procedure:
The title compound was prepared from trans-1-methoxy-4-(2-nitrovinyl) benzene and isobutyraldehyde according to general method. The enantiomeric excess was determined by HPLC with Chiralpak AS-H column at 210 nm (2-propanol:hexane=20:80), 1 ml/min; tmajor=12.7 min, tminor=15.8 min, [α]D20=+9.1 (c=1.2, CHCl3);
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[NH2:15][CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:27]3=[C:28]4[S:34][CH:33]=[CH:32][C:29]4=[N:30][CH:31]=[C:26]3[N:25]=[C:24]2[C@H:35]([OH:37])[CH3:36])[CH2:19][CH2:18]1.C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>C(Cl)Cl>[OH:37][C@@H:35]([C:24]1[N:23]([C@H:20]2[CH2:21][CH2:22][C@H:17]([CH2:16][NH:15][S:46]([CH3:45])(=[O:48])=[O:47])[CH2:18][CH2:19]2)[C:27]2=[C:28]3[S:34][CH:33]=[CH:32][C:29]3=[N:30][CH:31]=[C:26]2[N:25]=1)[CH3:36].[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4]
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CN)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CNS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (1R)-1-{1-[trans-4-(aminomethyl)cyclohexyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol bis(trifluoroacetate) (16 mg, 0.029 mmol) and triethylamine (20. μL, 0.14 mmol in methylene chloride (1 mL) was added methanesulfonyl chloride (2.7 μL, 0.034 mmol). The mixture was stirred at room temperature for 1 h, then stripped to dryness and purified on prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 60 mL/min) to give the desired compound as TFA salt (1.9 mg, 16%) as TFA salt. LCMS calculated for C18H25N4O3S2 (M+H)+: m/z=409.1. Found: 409.1.
Reaction SMILES: [Li]C(C)(C)C.[N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]=1[CH2:15][C:16]([O:18]CC)=O.[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26]([N:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH3:37])[CH2:32][CH2:31]2)[CH:25]=[CH:24][CH:23]=1>C1COCC1>[NH2:29][C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[N:30]2[CH2:31][CH2:32][N:33]([CH2:36][CH3:37])[CH2:34][CH2:35]2)[NH:21][C:16](=[O:18])[C:15]=1[C:7]1[NH:6][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=1
Reactant: CCOC(=O)Cc1nc2ccccc2[nH]1
Reactant: CCN1CCN(c2cccc(N)c2C#N)CC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCN1CCN(c2cccc3[nH]c(=O)c(-c4nc5ccccc5[nH]4)c(N)c23)CC1
Reaction time: 8 h

Procedure:
t-BuLi (3.1 eq) was added to ethyl 2-benzimidazol-2-ylacetate (1.0 eq) and 6-amino-2-(4-ethylpiperazinyl)benzenecarbonitrile (1.0 eq) in THF at 0° C. The reaction was stirred overnight. The resulting mixture was quenched with NH4Cl (aq, saturated) and extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield a brown solid. The crude material was triturated with CH2Cl2 and MeOH to provide a tan solid. LC/MS m/z 389.1 (MH+), Rf 1.80 minutes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]3[S:19][C:20](S(C)(=O)=O)=[N:21][N:22]=3)[CH:16]=2)[N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH:10]=1.[OH-:37].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]3[S:19][C:20]([OH:37])=[N:21][N:22]=3)[CH:16]=2)[NH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(F)cc3F)c3cc(-c4nnc(S(C)(=O)=O)s4)ccc32)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Oc1nnc(-c2ccc3[nH]cc(-c4ccc(F)cc4F)c3c2)s1
Reaction time: 0.17 h
Yield: 11.28 %

Procedure:
A solution of 2-(3-(2,4-difluorophenyl)-1-tosyl-1H-indol-5-yl)-5-(methylsulfonyl)-1,3,4-thiadiazole (0.010 g, 0.018 mmol), dioxane (0.5 mL), and NaOH (1 M, 0.1 mL) was heated in a Biotage microwave for 10 min at 100° C., then at 120° C. for an additional 10 min. The mixture was purified by preparative HPLC (20-90% AcCN/H2O/0.1% TFA) to give 5-(3-(2,4-difluorophenyl)-1H-indol-5-yl)-1,3,4-thiadiazol-2-ol (1 mg, 2.068 μmol, 11.28%). MS (ESI, pos. ion) m/z: 330 (M+1). 1H NMR (400 MHz, CD3OD) δ ppm 7.99 (1H, s), 7.67-7.75 (1H, m), 7.53-7.64 (3H, m), 7.07-7.15 (2H, m).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:31])=[C:16]([O:21][CH2:22][CH:23]=[CH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:33])[CH3:32])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H][H]>C(O)C.[C].[Pd]>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[C:14]3[C:15]([CH3:31])=[C:16]([O:21][CH2:22][CH2:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:33])[CH3:32])=[CH:8][CH:9]=1)([CH3:2])[CH3:3]
Reactant: Cc1c(C)c2c(c(C)c1OCC=Cc1ccccc1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1OCCCc1ccccc1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 75.7 %

Procedure:
3-(4-Isopropylphenyl)-2,2,4,6,7-pentamethyl-5-(3-phenyl-2-propen-1-yl)oxy-2,3-dihydrobenzofuran (800 mg, 1.82 mmol) and 10% palladium-carbon (hydrate) (80 mg) were suspended in ethanol (20 mL), and the mixture was stirred for 3 hours in a hydrogen atmosphere at room temperature. The catalyst was removed through filtration, and the filtrate was concentrated under reduced pressure. The residue was crystallized from methanol to obtain the title compound (610 mg, yield 76%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:8][C:9]([CH:12]=O)=[CH:10][N:11]=1.[NH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][OH:21])[CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:8][C:9]([CH2:12][N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][OH:21])[CH2:16][CH2:15]2)=[CH:10][N:11]=1
Reactant: OCC1CCNCC1
Reactant: O=Cc1cnc(-c2ccccn2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: OCC1CCN(Cc2cnc(-c3ccccn3)s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
The compound prepared in Example 139 (0.569 g), piperidin-4-ylmethanol (0.689 g) and sodium triacetoxyborohydride (1.902 g) were suspended in 1,2-dichloroethane (15 mL) and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed sequentially with saturated aqueous sodium bicarbonate solution, ammonium chloride solution and brine. The organics were then dried over magnesium sulfate, filtered and concentrated under reduced pressure and to afford the crude material, which was purified by flash column chromatography (eluant: 10% (9:1 methanol/concentrated ammonium hydroxide)/ethyl acetate) to furnish the title compound (0.571 g) having the following physical properties.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:10][C:6]=2[CH:5]=1.C([O-])(=O)C.[Na+].CN(C=O)C>O>[CH:3]([C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:10][C:6]=2[CH:5]=1)=[CH2:2]
Reactant: NS(=O)(=O)c1cc2cc(CCBr)ccc2s1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1ccc2sc(S(N)(=O)=O)cc2c1
Yield: 101 %

Procedure:
A solution of 4.0 g (0.012 mol) of 5-(2-bromoethyl)-2-sulfamoylbenzo[b]thiophene, 2.0 g (0.024 mol) of sodium acetate and 40 ml of DMF was heated at 100° C. under nitrogen. After 15 hours the mixture was poured into water and the aqueous phase was extracted 3× with ethyl acetate. The extracts were dried, filtered and concentrated to dryness. The residue was chromatographed on silica gel by elution with 20% (V/V) ethyl acetate-hexane to yield 2.9 g (30%) of 5-ethenyl-2-sulfamoylbenzo[b]thiophene, m.p. 168°-170° C. (1,2-dichloroethane). Further elution with 40% (V/V) ethyl acetate-hexane yielded 3.74 g (59%) of 5-(2-acetoxyethyl)-2-sulfamoylbenzo[b]thiophene, m.p. 120°-122° C. (1,2-dichloroethane).
Reaction SMILES: C1C2C3C=CC(C2C=C1)C3.C(C1CCC=CC1)=C.C(C1CCCCC=1)=C.C1CC=CC=1.[CH2:32]1[CH:36]2[CH:37]3[CH:41]4[CH:42]5[CH:46]=[CH:45][CH:44]([CH:40]4[CH:39]([CH:35]2C=[CH:33]1)[CH2:38]3)C5>C1CCCCC1>[CH:41]1([CH:37]2[CH2:38][CH:39]3[CH2:35][CH:36]2[CH:32]=[CH:33]3)[CH2:40][CH2:44][CH:45]=[CH:46][CH2:42]1
Reactant: C1=CC2C(C1)C1CC2C2C3C=CC(C3)C12
Agent: C1=CCC=C1
Agent: C=CC1=CCCCC1
Agent: C=CC1CC=CCC1
Solvent: C1=CC2C3C=CC(C3)C2C1
Solvent: C1CCCCC1
Product: C1=CCC(C2CC3C=CC2C3)CC1

Procedure:
Dicyclopentadiene and 4-vinylcyclohexene in equimolar mixture were heated in an autoclave at 240° C. for 4-4.5 hours. The reaction product was diluted with cyclohexane and passed through a packed bed of alumina to remove the t-butylcatechol inhibitor introduced with the reactants. The resulting product mixture was distilled in a wiped film evaporator at 3 mm Hg pressure at 90° C. to produce a light fraction containing unreacted vinylcyclohexene and dicyclopentadiene and the mono-adducts of 4-vinylcyclohexene and cyclopentadiene. A 150 g sample of this distillate was vacuum distilled using a 10-tray Oldershaw column to give four fractions. The fourth fraction, 65 g, was shown by gas chromatographic analysis to consist of 0.15% dicyclopentadiene, 88.3% endo-5-(3-cyclohexen-1-yl)-2-norbornene, 6.1% exo-5-(3-cyclohexen-1-yl)-2-norbornene and two additional components present in the amount of 1.9% and 2.4% which are believed to be isomeric adducts of the formula ##STR4## several additional components totalling about 0.4%, 0.4% tricyclopentadiene and about 0.4% unidentified components. Analysis of the fraction by nuclear magnetic resonance indicated about 87 mole percent of the endo adduct, about 9 mole percent of the exo adduct and about 5% of the isomeric adducts.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH3:13])=[N:7]2.[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([S:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:19]([NH2:21])[CH:20]=1>>[CH2:12]([C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:21][C:19]3[CH:20]=[C:15]([CH3:14])[CH:16]=[CH:17][C:18]=3[S:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1)[CH3:13]
Reactant: Cc1ccc(Sc2ccccc2)c(N)c1
Reactant: CCc1ccc2c(Cl)ccnc2n1
Product: CCc1ccc2c(Nc3cc(C)ccc3Sc3ccccc3)ccnc2n1

Procedure:
The product from Example 3f (88 mg, 0.46 mmol) was reacted with the product from Example 1f (100 mg, 0.46 mmol) for 24 h following the procedure from Example 1f giving the title compound as a hydrochloride salt which was triturated with ether giving (134 mg, 70%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.34 (t, J=7.35 Hz, 3H) 3.02 (q, J=7.35 Hz, 2H) 6.69 (d, J=6.99 Hz, 1H) 6.97 (d, J=8.82 Hz, 2H) 7.10 (dd, J=7.35 Hz, 1H) 7.15 (d, J=8.82 Hz, 2H) 7.30 (dd, J=8.09 Hz, J=7.72 Hz, 2H) 7.56 (dd, J=2.94 Hz, J=9.19 Hz, 1H) 7.71 (d, J=2.57 Hz, 1H) 7.88 (d, J=8.82 Hz, 1H) 8.52 (d, J=6.99 Hz, 1H) 9.02 (d, J=8.45 Hz, 1H) 11.16 (br s, 1H) 14.56 (br s, 1H); MS (ESI+) m/z 376 (M−Cl)+; (ESI−) m/z 374 (M−HCl)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][C@H:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[NH2:31][C@H:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][C@H:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:31][C@H:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1)=[O:29]
Reactant: COc1ccc(C[C@@H]2NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: O=C(Br)CBr
Reactant: N[C@@H]1CCc2ccccc21
Product: COc1ccc(C[C@H]2c3cc(OC)c(OC)cc3CCN2CC(=O)N[C@@H]2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of (1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with (1R)-1-amino-indane
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]([O:20][CH2:21][CH2:22]Cl)([C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CCOCC>[N:24]1([CH2:2][CH2:3][O:4][C:5]([O:20][CH2:21][CH2:22][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(c1ccccc1)C(OCCCl)(OCCCl)c1ccccc1
Reactant: C1CCNCC1
Solvent: CCOCC
Product: O=C(c1ccccc1)C(OCCN1CCCCC1)(OCCN1CCCCC1)c1ccccc1

Procedure:
With stirring, 35 g (0.1 mole) of benzil-di-(2-chloroethyl)ketal and 77 g (0.9 mole) of piperidine are kept for 7 hours at 105° C. After cooling, the reaction mixture is diluted with ether and the piperidine hydrochloride is collected by filtration. The ether is distilled off and the residual oil is dried in a high vacuum.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])[CH:2]=[CH2:3].[F:17][C:18]1[C:23](O)=[C:22]([F:25])[C:21]([F:26])=[C:20]([F:27])[C:19]=1[F:28].C1CCC(N=C=NC2CCCCC2)CC1.II>C(OCC)(=O)C.CCCCCC>[CH2:1]([O:4][CH2:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([O:10][C:23]1[C:22]([F:25])=[C:21]([F:26])[C:20]([F:27])=[C:19]([F:28])[C:18]=1[F:17])=[O:9])[CH:2]=[CH2:3]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: C=CCOCc1c(OC)cccc1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: II
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=CCOCc1c(OC)cccc1C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Yield: 110 %

Procedure:
Into a 200 mL round bottom flask was added 6.6 g (0.0297 mol) of 2-allyloxymethyl-3-methoxy benzoic acid and 40 mL of ethyl acetate. 24.05 g of a 25% pentafluorophenol (6.01 g, 0.0327 mol) solution in ethyl acetate was added while stirring. The reaction flask was placed into a water bath and while stirring small portions of DCC (6.2 g, 0.030 mol) were added. The stirring continued overnight at room temperature. The reaction was filtered through two Whatman #541 filters to remove the DCU precipitate. The ethyl acetate solution was concentrated to yield 12.8 g (110% yield), indicating presence of DCC and DCU. This was confirmed by TLC (1:1 ethyl acetate:hexane), which indicated a Rf of 0.72 plus other less polar compounds (I2 stain indicates about 85% purity). 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.7 (d, 1H), 7.45 (t, 1H), 7.15 (d, 1H), 6.0-5.9 (m, 1H), 5.3-5.1 (2d, 2H), 4.88-4.83 (d, 2H), 4.06 (d, 2H), 3.90 (s, 3H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[O-:10].[Na+]>O.O1CCOCC1>[CH3:1][S:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:10]
Reactant: CSc1ccccc1
Reactant: [O-]Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)c1ccccc1

Procedure:
To a solution of methyl-phenyl-sulphide (6.2 g) in water (2 ml) and dioxane (98 ml), stirred at 20° C. (external bath), sodium hypochlorite (88.69 g, titre 4.19%, pH 12.5) is added in 30 minutes.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][C:10]=1[O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:21]1[CH:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[N:28]=2)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:25]2[CH:26]=[CH:21][CH:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[N:28]=3)[CH:24]=2)=[CH:11][C:10]=1[O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cccc(-c2cccc(Br)c2)n1
Reactant: COc1cc(B(O)O)ccc1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc(-c2cccc(-c3cccc(C(F)(F)F)n3)c2)ccc1OCc1ccccc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-benzyloxy-3-methoxyphenylboronic acid (1.0 g, 3.87 mmol) and 2-(3-bromophenyl)-6-(trifluoromethyl)pyridine (1.063 g, 3.52 mmol) in toluene (10 mL) and ethanol (1 mL) at room temperature under argon was added 2 N aqueous sodium carbonate solution (5.41 mL, 10.82 mmol) followed by tetrakis(triphenylphosphine)palladium (0.22 g, 0.19 mmol). The resulting mixture was stirred at 90° C. for two hours and then allowed to cool to room temperature. The phases were separated and the aqueous phase was extracted with toluene (5 mL). The combined organic phases were washed with water and brine, then dried over anhydrous sodium sulphate and filtered. Evaporation of the solvent left a brown oil that was chromatographed over silica gel (petroleum ether/ethyl acetate, 9:1) to give 2-(4′-(benzyloxy)-3′-methoxybiphenyl-3-yl)-6-(trifluoromethyl)pyridine as a clear oil, 1.072 g (70%).
Reaction SMILES: [CH2:1]=O.Cl.[CH3:4][NH:5][CH3:6].[NH:7]1[C:11]2=[N:12][CH:13]=[C:14](/[CH:16]=[CH:17]/[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:15]=[C:10]2[CH:9]=[CH:8]1>C(O)(C)C>[CH3:4][N:5]([CH2:1][C:9]1[C:10]2[C:11](=[N:12][CH:13]=[C:14](/[CH:16]=[CH:17]/[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:15]=2)[NH:7][CH:8]=1)[CH3:6]
Reactant: CNC
Reactant: C=O
Reactant: CC(C)(C)OC(=O)/C=C/c1cnc2[nH]ccc2c1
Agent: Cl
Solvent: CC(C)O
Product: CN(C)Cc1c[nH]c2ncc(/C=C/C(=O)OC(C)(C)C)cc12
Yield: 46.7 %

Procedure:
Formaldehyde (37% in water, 219 μL, 2.92 mmol) and dimethylamine hydrochloride (237 mg, 2.92 mmol) were added to a solution of (E)-tert-butyl 3-(1H-pyrrolo[2,3-b]pyridin-5-yl)acrylate (420 mg, 1.72 mmol) in isopropanol (42 mL) at room temperature. The reaction mixture was stirred at reflux overnight. Since the LCMS monitoring still indicated the presence of remaining starting material, formaldehyde (25 μL) and dimethyl amine hydrochloride (28 mg) were added. The reaction mixture was stirred at reflux for an additional 4 hours and concentrated to dryness. The residue was solubilized in an aqueous solution of potassium carbonate (3N, 100 mL) and the solution was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with a saturated solution of sodium chloride (50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The crude was tritured in pentane to give the title compound as a white solid (242 mg, 46%).
Reaction SMILES: [N:1]1([CH:6]2[CH2:11][CH2:10][N:9]([C:12]([C@@H:14]3[CH2:18][C@H:17]([S:19]CC4C=CC(OC)=CC=4)[CH2:16][N:15]3C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=[O:13])[CH2:8][CH2:7]2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])O.[Na+]>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.C(OCC)(=O)C>[N:1]1([CH:6]2[CH2:11][CH2:10][N:9]([C:12]([C@@H:14]3[CH2:18][C@H:17]([SH:19])[CH2:16][NH:15]3)=[O:13])[CH2:8][CH2:7]2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCC(n4ccnc4)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C([C@@H]1C[C@H](S)CN1)N1CCC(n2ccnc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 165.1 %

Procedure:
1.44 g of (2S,4S)-2-[4-(imidazol-1-yl)piperidin-1-ylcarbonyl]-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (1) above] were dissolved in a mixture of 1.5 ml of anisole and 7.5 ml of trifluoroacetic acid, and 350 μl of trifluoromethanesulfonic acid were added to the resulting solution, whilst ice-cooling. The resulting mixture was then stirred at room temperature for 1 hour and then at 35° C. for 30 minutes, after which it was concentrated by evaporation under reduced pressure. The resulting residue was washed with diethyl ether four times to give a colorless powder. The whole of this powder was suspended in ethyl acetate, and the suspension was made alkaline by the addition of an aqueous solution of sodium hydrogencarbonate. The ethyl acetate phase was separated and washed with an aqueous solution of sodium chloride, after which this phase was dehydrated over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, to give 1150 mg of the title compound, as a colorless powder.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](O)=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:21])=O.CN(C)C=O>ClCCl>[C:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([Cl:21])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(C(=O)c2ccccc2)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Benzoylbenzoic acid (226 mg, 1.0 mmol) in dichloromethane (1.5 mL) was treated with a solution of oxalyl chloride (1.5 mL of 2 M in dichloromethane, 3 mmol) and a catalytic amount of N,N-dimethylformamide. The reaction was stirred overnight at ambient temperature. The excess oxalyl chloride was removed in vacuo to afford 3-benzoylbenzoyl chloride.