Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)(C)(C)C.[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18]>ClCCl>[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[NH2:7][C@@H:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CC[C@H](O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a round-bottomed flask, (cis-3-hydroxy-cyclopentyl)-carbamic acid tert-butyl ester (320 mg, 1.59 mmol) was dissolved in dichloromethane (10 ml) and trifluoroacetic acid (3.6 ml, 46.7 mmol) was slowly added. The reaction mixture was stirred at room temperature for 2 h then concentrated to afford cis-3-amino-cyclopentanol trifluoroacetate as a light yellow oil which was used without further purification.
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)(=[O:5])[CH3:4].[CH2:15](Br)[CH:16]=[CH2:17].O>CN(C=O)C>[C:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH2:17][CH:16]=[CH2:15])=[O:11])=[CH:8][CH:7]=1)(=[O:5])[CH3:4]
Reactant: C=CCBr
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)c1ccc(C(C)=O)cc1
Temperature: 25 °C

Procedure:
1.65 g (55 mmol) of sodium hydride (80% in oil) and 50 ml of DMF are introduced under a stream of nitrogen into a round-bottomed flask. 8.2 g (50 mmol) of 4-acetylbenzoic acid, dissolved in 100 ml of DMF, are added dropwise and the mixture is stirred at room temperature until gaseous evolution has ceased. 4.6 ml (55 mmol) of allyl bromide are then introduced and the mixture is stirred at room temperature for 24 hours. The reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, then dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column, eluting with a mixture of dichloromethane and hexane (80:20). After evaporation of the solvents, 7.2 g (71%) of allyl ester are collected in the form of a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[NH:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.C(=O)([O-])[O-].[K+].[K+].[CH3:25][O:26][CH:27]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:28]([CH:30]1[C:35](=O)[CH2:34][CH2:33][O:32][CH2:31]1)=O>C(O)C>[CH3:25][O:26][CH:27]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:28]1[C:30]2[CH2:31][O:32][CH2:33][CH2:34][C:35]=2[N:17]=[C:16]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:18]=1
Reactant: COC(C(=O)C1COCCC1=O)c1ccccc1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1cc(Nc2nc3c(c(C(OC)c4ccccc4)n2)COCC3)ccc1-n1cnc(C)c1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 2.7 %

Procedure:
A reaction mixture of 1-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)guanidine (0.300 g, 0.81 mmol) and potassium carbonate (0.337 g, 2.44 mmol) in ethanol (5 mL) was stirred at 50° C. for 5 minutes. 3-(2-methoxy-2-phenylacetyl)dihydro-2H-pyran-4(3H)-one (0.161 g, 0.65 mmol) in ethanol (0.5 mL) was added dropwise to the reaction mixture and the resulting mixture was stirred at 50° C. overnight. The solvent was evaporated and the residue was partitioned between water and dichloromethane. The water phase was extracted twice with dichloromethane. The combined organic layer was dried over MgSO4, filtered, concentrated and purified by preparative HPLC yielding 4-(methoxy(phenyl)methyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine (8.00 mg, 2%).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[S:3]([O:6][C:7]1[CH:8]=[C:9]([C:13]23[CH2:20][CH2:19][C:16]([CH2:21][CH2:22][O:23][CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])([CH2:17][CH2:18]2)[CH2:15][O:14]3)[CH:10]=[CH:11][CH:12]=1)(=[O:5])=[O:4].C(O)=O>C(Cl)Cl>[F:33][C:2]([F:1])([F:32])[S:3]([O:6][C:7]1[CH:8]=[C:9]([C:13]23[CH2:18][CH2:17][C:16]([CH2:21][CH2:22][O:23][CH2:24][C:25]([OH:27])=[O:26])([CH2:19][CH2:20]2)[CH2:15][O:14]3)[CH:10]=[CH:11][CH:12]=1)(=[O:4])=[O:5]
Reactant: CC(C)(C)OC(=O)COCCC12CCC(c3cccc(OS(=O)(=O)C(F)(F)F)c3)(CC1)OC2
Solvent: O=CO
Solvent: ClCCl
Product: O=C(O)COCCC12CCC(c3cccc(OS(=O)(=O)C(F)(F)F)c3)(CC1)OC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.4 %

Procedure:
A mixture of tert-butyl 2-(2-(1-(3-(((trifluoromethyl)sulfonyl)oxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethoxy)acetate (28 mg, 0.057 mmol) and formic acid (0.022 mL, 0.57 mmol) in CH2Cl2 (0.5 mL) was stirred at rt for 18 h, then was concentrated in vacuo. The crude material was purified by preparative LC/MS (Column: Waters XBridge C18, 19×100 mm, 5-nm particles; Mobile Phase A: 5:95 MeCN:water with 0.1% TFA; Mobile Phase B: 95:5 MeCN:water with 0.1% TFA; Gradient: 40-80% B over 10 min, then a 5-min hold at 100% B; Flow rate: 20 mL/min) to give the title compound (19 mg, 0.043 mmol, 76% yield) as a clear oil. LCMS [M−H]+=437.0; 1H NMR (DMSO-d6) δ: 7.53-7.48 (m, 2H), 7.42 (d, J=2.7 Hz, 1H), 7.34 (dt, J=7.3, 2.3 Hz, 1H), 3.96 (s, 2H), 3.80 (s, 2H), 3.50 (t, J=6.7 Hz, 2H), 2.16-2.05 (m, 2H), 1.89-1.74 (m, 2H), 1.73-1.59 (m, 4H), 1.42 (t, J=6.8 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[CH:10]([CH3:24])[C:11]([C:17]1[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:10]([CH3:24])[C:11]([C:17]1[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=1)([OH:16])[C:12]([F:15])([F:14])[F:13]
Reactant: COc1ccc(Cl)c(C(C)C(O)(c2ccnc(Cl)c2)C(F)(F)F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(c1cc(O)ccc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
3-(2-Chloro-5-methoxy-phenyl)-2-(2-chloro-pyridin-4-yl)-1,1,1-trifluoro-butan-2-ol (Example 115, 293 mg) was dissolved in CH2Cl2 (30 mL) and cooled to 0° C. A solution of boron tribromide (1M in CH2Cl2, 3.08 mL) was added drop wise and stirring was continued at 0° C. for 1 hour. The reaction mixture was diluted with CH2Cl2, extracted with sat. NaHCO3 solution and brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, ethyl acetate in heptane 3:7) to give the title compound as a colorless solid (230 mg). MS (m/e)=366.0 (MH+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([C:42](O)=[O:43])[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[C:42]([CH:39]2[CH2:40][CH2:41][N:36]([C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH2:37][CH2:38]2)=[O:43])=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCCN1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCCCC2C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Piperidine-2-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (74) (1.00 g; 2.64 mmol) is dissolved in methylene chloride (25 mL) at ambient temperature. 1 -tert-Butoxycarbonyl-piperidine4-carboxylic acid (0.73 g; 3.17 mmol), N,N-diisopropylethylamine (0.75 g; 5.81 mmol) and PyBOP (1.65 g; 3.17 mmol) are added sequentially. The reaction is stirred for 16 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography (30%→50% ethyl acetate in hexanes) affording the desired product (75) as a solid. ESMS:MH+ 590.6
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[Br:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1
Reactant: OCc1ccc(CBr)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1ccc(CBr)cc1
Temperature: 25 °C
Yield: 57.3 %

Procedure:
The 4-bromomethylbenzyl alcohol (9.0 g, 43 mmol) was reduced to the corresponding aldehyde by dissolving the above-synthesized intermediate in methylene chloride and then adding pyridinium chlorochromate (14.1 g, 6.5 mmol). The reaction mixture was then allowed to stir at room temperature under a nitrogen atmosphere for about oone hour. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was then filtered through a CELITE® pad, concentrated in vacuo, and then partitioned between equal volumes of diethyl ether and water. The organic fraction was washed with water, then with brine, and dried over magnesium sulfate. The solvents were removed in vacuo to yield a white crystalline solid. Recrystallization from hot diethyl ether yielded 4.9 grams of 4-(bromomethyl)benzaldehyde as needle-like crystals.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([SH:7])[NH:4][N:3]=1.[OH-].[Na+].Cl[CH2:11][CH2:12][CH2:13][OH:14]>>[NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:11][CH2:12][CH2:13][OH:14])[NH:4][N:3]=1
Reactant: Nc1n[nH]c(S)n1
Reactant: OCCCCl
Agent: [Na+]
Agent: [OH-]
Product: Nc1n[nH]c(SCCCO)n1
Yield: 66.1 %

Procedure:
A mixture of 3-amino-5-mercapto-1,2,4-triazole (1.16 g.), 2 N aqueous sodium hydroxide (6 ml.) and 3-chloropropanol (1.1 g.) was heated at 90° for 1 hour and then cooled. The white solid which crystallised was collected to give 3-amino-5-(3-hydroxypropylthio)-1,2,4-triazole (1.15 g.), m.p. 136°-137°.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[CH2:11][NH:10][CH:9]=[N:8][CH2:7]1)=[O:5].N12CCCN=C1CCCCC2.[C:23](Cl)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[C:24]1([C:23]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:8]2[CH2:7][CH:6]([C:4]([O:3][CH3:2])=[O:5])[CH2:11][N:10]=[CH:9]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C1CN=CNC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C1CN=CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C

Procedure:
1,4,5,6-Tetrahydro-5-methoxycarbonylpyrimidine hydrochloride (I.49 g, 8.3 mmol), 1,8 diazabicyclo [5.4.0] undec-7ene, (hereinafter diazabicycloundecene and/or DBU), (2.5 mL, 16.6 mmol), and tritylchloride (2.32 g, 8.3 mmol) were suspended in anhydrous DMF (20 ml) with stirring under nitrogen at room temperature. After 18 hours stirring the suspension was evaporated in vacuo and the residue chromatographed (silica, chloroform/methanol, 9:1) to yield 2.28 g (rf=0.15, 71%) white crystalline solid identified by 300 MHz nmr and ms m/z=384.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH2:7]([NH:9][CH2:10][CH2:11][NH2:12])[CH3:8].O>C(O)(C)C.[Cu].[Cu]Cl>[CH2:7]([N:9]([C:2]1[S:3][CH:4]=[CH:5][N:6]=1)[CH2:10][CH2:11][NH2:12])[CH3:8]
Reactant: CCNCCN
Reactant: Brc1nccs1
Agent: Cl[Cu]
Agent: [Cu]
Solvent: CC(C)O
Solvent: O
Product: CCN(CCN)c1nccs1
Temperature: 70 °C
Yield: 8 %

Procedure:
47 mg (0.74 mmol) of copper and 225 mg (2.27 mmol) of copper(I) chloride were added to a solution of 1.35 g (15.0 mmol) of 2-bromothiazole and 9.48 ml (90.0 mmol) of N-ethylethylenediamine in isopropanol (7.5 ml). The mixture was then heated to 70° C. for 1 h. After cooling to RT, the reaction solution was poured into water and extracted with EA. The organic phase was dried over MgSO4, filtered and evaporated under a vacuum. 200 mg (1.2 mmol, 8%) of N1-ethyl-N1-(thiazol-2-yl)ethane-1,2-diamine were obtained by carrying out CC twice (i. DCE/EtOH 5:1; ii. DCE/EtOH/conc. aq. NH4OH soln. 5:1:0.06) with the residue.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:15]1(O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.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>C(Cl)Cl.C1(C)C=CC=CC=1>[C:4]([O:3][C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccccc1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
A solution of (S)-(−)-1-Boc-2-pyrrolidine methanol (0.267 g, 1.33 mmol), phenol (0.38 g, 4.02 mmol) and triphenylphosphine (0.71 g, 2.71 mmol) in DCM (5 mL) was cooled in an ice-bath and a solution of diisopropyl azodicarboxylate (0.55 g, 2.71 mmol) in toluene (3 mL) was added. The ice-bath was removed and the reaction mixture was stirred at room temperature over the weekend. The mixture was diluted with ether and washed with sodium hydroxide (3 M), then brine, dried over sodium sulfate and evaporated. The resultant solid was suspended in ethyl acetate and cyclohexane and the resultant white crystalline solid was removed by filtration. The filtrate was evaporated and the crude material was purified by column chromatography using a 10 g Si II cartridge eluting with 10% ethyl acetate in cyclohexane to afford (S)-2-phenoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester as a clear oil (0.22 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.C1C=CC2N(O)N=NC=2C=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH2:28][C:29](O)=[O:30])[CH:25]=[CH:26][CH:27]=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[Cl:21][C:22]1[CH:23]=[C:24]([CH2:28][C:29]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[CH:5]3)=[O:30])[CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: Nc1ccc2[nH]ncc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(Cc1cccc(Cl)c1)Nc1ccc2[nH]ncc2c1
Reaction time: 0.17 h

Procedure:
To a solution of 5-aminoindazole (1 mmol), HOBt (1 mmol) and 3-chlorophenylacetic acid (1.1 mmol) in DMF (4 mL) was added N-methylmorpholine (1.1 mmol). After stirring for 10 minutes, EDC-HCl (1.1 mmol) was added and the reaction mixture stirred overnight at ambient temperature. The reaction mixture was concentrated and the residue purified by reverse phase preparative HPLC [Waters Delta-Pak C18, 15 uM, 100A column, gradient 10%–100% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 10 minutes at 25 mL/min] to afford compound I-6 (79 mg, 42%). 1H NMR (400 MHz, DMSO-d6) δ 3.68 (2H, s), 7.12–7.73 (6H, m), 8.00 (1H, s), 8.11 (1H, s), 10.10 (1H, s), 12.97 (1H, bs); MS (ES+): m/e=(M+H) 286.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=O)[CH:3]=1.CCN=C=NCCCN(C)C.Cl.C[NH:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:42][C:41]([CH3:44])([CH3:43])[O:40][C:38](=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][NH:26][C:5]([C:4]1[CH:3]=[C:2]([CH:10]=[CH:9][CH:8]=1)[C:1]([OH:12])=[O:11])=[O:7]
Reactant: CNCCOCCOCCOCCC(=O)OC(C)(C)C
Reactant: O=C(O)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCOCCOCCOCCNC(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.2 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of isophthalic acid (1.7 g, 10.24 mmol, 2.98 equiv) in dichloromethane (10 mL), EDC.HCl (660 mg, 3.44 mmol, 1.00 equiv), 4-dimethylaminopyridine (420 mg, 3.44 mmol, 1.00 equiv), and tert-butyl 3-(2-(2-(2-(methylamino)ethoxy)ethoxy)ethoxy)propanoate 8b (1 g, 3.44 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was washed with 2×20 mL of water and 1×20 mL of NH4Cl (aq). The mixture was dried over sodium sulfate and concentrated under vacuum. The crude product (1 g) was purified by reverse phase chromatography with a water/methanol gradient to yield 500 mg (33%) of 3-((14,14-dimethyl-12-oxo-3,6,9,13-tetraoxapentadecyl)carbamoyl)benzoic acid. as yellow oil. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.087 (s, 2H), 7.664-7.560 (m, 2H), 3.785-3.499 (m, 14H), 3.144-3.705 (m, 3H), 2.489-2.448 (m, 2H), 1.469-1.456 (s, 9H). MS (ES, m/z): 440 [M+H]+.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[O-2].[Mg+2].[Cl:7][C:8]1[S:12][C:11]([S:13](Cl)(=[O:15])=[O:14])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18]>O.C1COCC1>[OH:2][CH2:1][CH2:3][NH:4][S:13]([C:11]1[S:12][C:8]([Cl:7])=[C:9]([N+:17]([O-:19])=[O:18])[CH:10]=1)(=[O:15])=[O:14]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)sc1Cl
Reactant: NCCO
Agent: [Mg+2]
Agent: [O-2]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cc(S(=O)(=O)NCCO)sc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
To a stirred solution of ethanolamine (0.67 g, 11 mmol) in water (4 ml) was added at room temperature magnesium oxide (2.22 g, 55 mmol) and THF (12 ml). The suspension was stirred at room temperature for 30 min and a solution of 5-chloro-4-nitrothiophene-2-sulfonyl chloride (3.46 g, 13.2 mmol) in THF (4 ml) was added. The light yellow suspension was stirred at room temperature for 1 h and, after filtration on Dicalit, evaporated. Water (60 ml) was added and the mixture was extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (70 ml), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on silica gel (heptane/ethyl acetate) and subsequent crystallization from ethyl acetate/hexane to yield 5-chloro-4-nitro-thiophene-2-sulfonic acid (2-hydroxy-ethyl)-amide (1.39 g, 44%) as a yellow solid. MS (ISP) 284.8 [(M−H)−], mp 99° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH2:8][N:9]2[CH2:14][CH2:13][C:12]3([C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15]3)[CH2:11][CH2:10]2)=[C:5]([CH3:7])[N:6]=1.[Li]CCCC.CN([CH:31]=[O:32])C.[NH4+].[Cl-]>C1COCC1.O>[CH3:7][C:5]1[N:6]=[C:2]([CH:31]=[O:32])[S:3][C:4]=1[CH2:8][N:9]1[CH2:14][CH2:13][C:12]2([C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)[CH2:11][CH2:10]1
Reactant: Cc1nc(Br)sc1CN1CCC2(C=Cc3ccccc32)CC1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(C=O)sc1CN1CCC2(C=Cc3ccccc32)CC1
Temperature: -45 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a solution of 2-bromo-4-methyl-5-(spiro[indene-1,4′-piperidine]-1′-ylmethyl) thiazole (3.8 g, 10.12 mmol) in THF is added n-BuLi (0.713 g, 11.13 mmol) at −78° C. The mixture is warmed to −45° C. and stirred for 30 minutes. DMF (1.5 mL) is added dropwise to the mixture at −78° C. and the mixture is slowly warmed to room temperature and stirred for an hour. The mixture is cooled to −78° C., diluted with water, followed by NH4Cl solution. The mixture is extracted with ethyl acetate, dried over Na2SO4, and evaporated to dryness to give the title compound (2.8 g, 85%). ESI/MS m/z 325 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([CH2:18][CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[C:20]([C:23]1[CH:27]=[C:26]([C:28](O)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21]>>[C:20]([C:23]1[CH:27]=[C:26]([C:28]([NH:1][C@H:2]([CH2:18][CH3:19])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=3)=[N:5]2)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Reactant: CC[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: CC[C@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(C(C)=O)n[nH]1
Yield: 49.8 %

Procedure:
(R)-4-(1-(2-aminobutyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (300 mg, 1.1 mmol) was coupled with 3-acetyl-1H-pyrazole-5-carboxylic acid (202 mg, 1.3 mmol) using the method of Example 34(d). Crude product was purified by CombiFlash (column: C-18 silica, eluent: 0-100% MeCN in water) to obtain 225 mg (50%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 0.90 (t, 3H), 1.43-1.65 (m, 2H), 2.49 (s, 3H), 4.22-4.41 (m, 3H), 6.91 (d, 1H), 7.32 (s, 1H), 7.79 (d, 1H), 7.86-8.05 (m, 3H), 8.38 (d, 1H), 14.1 (bs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)=[O:4].[CH3:15][C@H:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][C@H:16]([CH3:15])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:11])=[CH:8][CH:7]=1)=[O:4]
Reactant: CCCCCC[C@H](C)O
Reactant: COC(=O)Oc1ccc(C(=O)O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCC[C@@H](C)OC(=O)c1ccc(OC(=O)OC)cc1

Procedure:
Compound 2 (15.0 g, 77 mmol), (S)-(+)-octan-2-ol (10.0 g, 77 mmol) and diethyl azodicarboxylate (3.4 g, 77 mmol) were dissolved in THF (250 ml) and triphenylphosphine (22.3 g, 85 mmol) in THF (50 ml) was added dropwise with stirring. The reaction mixture was left stirring under nitrogen until no further reaction was visible by TLC. The solvent was then removed in vacuo and the resulting slurry was purified by column chromatography [petroleum ether (bp 40-60° C.): dichloromethane (12:1)] on silica to yield a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1)[C:5]([C:7]1C=CC=CC=1)=[O:6].[CH3:19][S:20](Cl)(=[O:22])=[O:21].O>N1C=CC=CC=1>[C:5]([C:4]1[CH:3]=[C:2]([NH:1][S:20]([CH3:19])(=[O:22])=[O:21])[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=1)(=[O:6])[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(C(=O)c2ccccc2)cc([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)c1cc(NS(C)(=O)=O)cc([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
3-Amino-5-nitrobenzophenone (4 g; synthesized by the process reported by Berend et al., J. Prakt. Chem., vol. 69, p. 471 (1904)) was dissolved in pyridine (40 mL), and the temperature was maintained at 50° C. Methanesulfonyl chloride (1.9 mL) was added, followed by stirring for 2 hours. Additional methanesulfonyl chloride (1.7 mL) was added, followed by stirring at 50° C. for 2 hours. The reaction mixture was cooled down to room temperature and then poured into water (200 mL). The deposited precipitate was collected by filtration and dried under reduced pressure to yield N-(3-acetyl-5-nitrophenyl)methanesulfonamide (5.4 g) as a crude product. The whole quantity of the crude product was dissolved in ethanol (40 mL), and zinc dust (20 g) was added. After further adding concentrated hydrochloric acid (2 mL), the mixture was heated to reflux for 4 hours. The reaction mixture was filtered. To the filtrate, ethyl acetate (100 mL) was added. The resulting mixture was washed with water (100 mL) three times and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (95:5 chloroform/methanol) to yield N-(3-acetyl-5-aminophenyl)methanesulfonamide (3.9 g).