Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:5]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:6][O:7][C:8]1[C:17]2[CH:16]=[C:15]3[S:18][CH:19]=[CH:20][C:14]3=[C:13]([O:21][CH2:22][CH:23]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:12]=2[CH:11]=[C:10]2[S:34][CH:35]=[CH:36][C:9]=12)[CH2:2][CH2:3][CH3:4].C([Li])CCC.[Sn:48](Cl)([CH3:51])([CH3:50])[CH3:49].O>C1COCC1.CCCCCC>[CH2:1]([CH:5]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:6][O:7][C:8]1[C:9]2[CH:36]=[C:35]([Sn:48]([CH3:51])([CH3:50])[CH3:49])[S:34][C:10]=2[CH:11]=[C:12]2[C:17]=1[CH:16]=[C:15]1[C:14](=[C:13]2[O:21][CH2:22][CH:23]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:20]=[C:19]([Sn:48]([CH3:51])([CH3:50])[CH3:49])[S:18]1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Sn](C)(C)Cl
Reactant: CCCCCCC(CCCC)COc1c2ccsc2cc2c(OCC(CCCC)CCCCCC)c3ccsc3cc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCCCCCC(CCCC)COc1c2cc([Sn](C)(C)C)sc2cc2c(OCC(CCCC)CCCCCC)c3cc([Sn](C)(C)C)sc3cc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
A solution in which 0.48 g of 4,9-bis(2-butyloctyloxy)-1,6-dithia-dicyclopenta[b,g]-naphthalene (0.78 mmol) prepared in Example 2 was dissolved in 20 mL of dry THF was cooled to −78° C., 1.9 mL of n-butyllithium (2.5M solution in hexane, 4.72 mmol) was added thereto. The reaction solution was stirred for 30 minutes and then stirred again at room temperature for 30 minutes. The reaction solution was cooled to −78° C. again, and 4.72 mL of Me3SnCl (1M solution in hexane, 4.72 mmol) was slowly dropped therein. After the reaction solution was stirred again for 30 minutes, a temperature of the reaction solution was raised to room temperature, and the reaction solution was stirred for 12 hours. Water was added to the reaction solution, and a solvent layer was separated. The separated solvent layer was condensed, diluted with hexane, washed with distilled water, dried over Na2SO4, followed by filtering. Then, the obtained filtrate was condensed. The condensed filtrate was recrystallized using isopropanol, thereby obtaining 0.5 g of the title compound (68%) as a yellow solid.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].Br[CH:6]([CH3:12])[C:7]([O:9]CC)=[O:8].O(CC)[CH2:14][CH3:15]>>[CH2:14]([N:4]([CH2:1][CH2:2][CH3:3])[C@H:6]([C:7]([OH:9])=[O:8])[CH3:12])[CH3:15]
Reactant: CCOCC
Reactant: CCOC(=O)C(C)Br
Reactant: CCCN
Product: CCCN(CC)[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
To a stirred solution of 11.8 parts of 1-propanamine in 24.9 parts of 1,1'-oxybis ethane there was added dropwise a solution of 18.1 parts of ethyl 2-bromopropanoate in 24.9 parts of 1,1'-oxybisethane. After stirring for 72 hours at room temperature, the reaction mixture was filtered and the filtrate was rinsed with 1,1'-oxybisethane. The combined 1,1'-oxybisethane layers were evaporated, yielding 15.9 parts (100%) of ethyl N-propylalanine as a residue (interm. 38).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH2:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=3)[N:12]=[C:11]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.O[N:33]1[C:37]2[N:38]=CC=C[C:36]=2[N:35]=[N:34]1.C([N:45](CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH2:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:38][CH2:37][C:36]4[NH:45][N:33]=[N:34][N:35]=4)=[O:21])=[CH:17][CH:16]=3)[N:12]=[C:11]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: On1nnc2cccnc21
Reactant: COc1ccc(-c2cc(-c3cc(Cl)cc(Cl)c3)n(Cc3ccc(C(=O)O)cc3)n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(-c2cc(-c3cc(Cl)cc(Cl)c3)n(Cc3ccc(C(=O)NCc4nnn[nH]4)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the intermediate from example 76 step A (100 mg, 0.22 mmol) in 1:1 DMF/DCM (0.54 mL) was added 1-hydroxy-7-azabenzo-triazole (35 mg, 0.264 mmol), N,N-diisopropylethyl amine (92 μL, 0.53 mmol) amino methyl tetrazole (26 mg, 0.26 mmol) and 1-(3-(Dimethylamino)propyl-3-ethyl carbodiimide hydrochloride (51 mg, 0.26 mmol). The reaction was left stirring at room temperature for 18 hours. The reaction was diluted with ethyl acetate, washed with 1N HCl, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC (Gilson) to give the title compound. 1H NMR (DMSO, 500 MHz): δ 9.22(t, J=5.5 Hz, 1H), 7.84(d, J=8.5 Hz, 2H), 7.79(d, J=8.9 Hz, 2H), 7.69(t, J=1.9 Hz, 1H), 7.54(d, J=1.8 Hz, 2H), 7.17(d, J=8.2 Hz, 2H), 7.06(s, 1H), 7.0(d, J=8.7 Hz, 2H), 5.53(s, 2H), 4.74(d, J=5.5 Hz, 2H), 3.79(s, 3H). LC-MS: 2.32 min; (M+H)=534.3.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](OC)=[O:22])[NH:12][C:11]=3[CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:26][OH:27].[OH-].[K+]>C1COCC1>[OH:27][NH:26][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:13]1[NH:12][C:11]2[CH:25]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=[CH:9][C:10]=2[N:14]=1
Reactant: NO
Reactant: COC(=O)CCCCCCc1nc2ccc(-c3ccccc3)cc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(CCCCCCc1nc2ccc(-c3ccccc3)cc2[nH]1)NO
Temperature: 0 °C
Reaction time: 2 h
Yield: 53.3 %

Procedure:
To a solution of methyl 7-(6-phenyl-1H-benzo[d]imidazol-2-yl)heptanoate (50 mg, 0.15 mmol) in THF at 0° C. was added 50% hydroxylamine solution (0.10 mL, 1.5 mmol). To this was added KOH (0.45 mL, 1M in MeOH, 0.45 mmol) dropwise. The reaction was stirred at 0° C. for 2 hr, briefly concentrated and neutralized by adding 1 N HCl solution until pH was 7. The white precipitate was collected by filtration and purified by biotage column chromatography to give N-hydroxy-7-(6-phenyl-1H-benzo[d]imidazol-2-yl)heptanamide 18 (27 mg). MS (M+1=338)
Reaction SMILES: ClC(OC=C)=O.[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([CH:16]2[CH2:22][CH:21]3[N:23](C)[CH:18]([CH2:19][CH2:20]3)[CH2:17]2)=[N:8]1.C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([CH:16]2[CH2:22][CH:21]3[NH:23][CH:18]([CH2:19][CH2:20]3)[CH2:17]2)=[N:8]1
Reactant: CN1C2CCC1CC(c1nsc3ccccc13)C2
Agent: C=COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Product: c1ccc2c(C3CC4CCC(C3)N4)nsc2c1
Yield: 101 %

Procedure:
Vinyl chloroformate (4.4 g) was added dropwise to a solution of 3-(1,2-benzisothiazol-3-yl)-8-methyl-8-azabicyclo[3.2.1]octane (8.9 g) and potassium carbonate (4.76 g) in 250 ml of 1,2-dichloroethane. The resulting suspension was heated at reflux for 3 hours, and then the solution was cooled, and the solvent was removed in vacuo. The residue was suspended in isopropyl alcohol and acidified with HCl in isopropanol (to about a pH of 1 ), and the mixture was heated at reflux for 1 hour. The mixture was cooled, made basic, and then the product was extracted into dichloromethane. The combined organic layers were dried over MgSO4, filtered and concentrated to provide 8.5 g of 3-(1,2-benzisothiazol-3-yl)-8-azabicyclo[3.2.1]octane which was used subsequently without purification.
Reaction SMILES: [Na].[CH2:2]([OH:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH3:20]>>[CH2:16]([O:15][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCBr
Reactant: OCCCCCCCCCCCCO
Agent: [Na]
Product: CCCCCOCCCCCCCCCCCCO
Yield: 52 %

Procedure:
The monosodium salt of 1,12-dodecanediol is reacted with pentyl bromide to give 12-pentoxydodecanol which, after elution on a silica gel column with ligroin-methyl ethyl ketone (4:1 v/v), gives a thin layer chromatographically uniform oil. The yield is 52% of theory. This is then brominated with phosphorus tribromide in the presence of pyridine and, after fractionation on a silica gel column (diethyl ether-ligroin 1:99 v/v as elution agent) gives 47% of theory of thin layer chromatographically uniform oily 12-pentoxydodecyl bromide. This bromide is reacted with the monosodium salt of 1,3-propanediol and then gives, in a yield of 56% of theory, after column purification (elution agent diethyl ether-ligroin 1:1 v/v), 3-(12-pentoxydodecyloxy)propanol; m.p. 25° C. Phosphorylation, hydrolysis and reaction with trimethylamine take place in the manner described in Example 1 to give a yield of 41% of theory of the desired product; m.p. 63° C. (sinters), 240°-243° C. (decomp.). It crystallizes with 1 mole of water of crystallization.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][NH:4]1.[OH-].[K+].[C:18](=[S:20])=[S:19].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>CO.C(O)C>[OH:1][CH2:2][C@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][N:4]1[C:18]([S:20][CH2:26][C:25]1[CH:28]=[CH:29][C:22]([Cl:21])=[CH:23][CH:24]=1)=[S:19]
Reactant: ClCc1ccc(Cl)cc1
Reactant: S=C=S
Reactant: OC[C@H]1Cc2c([nH]c3ccccc23)CN1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: OC[C@H]1Cc2c([nH]c3ccccc23)CN1C(=S)SCc1ccc(Cl)cc1
Yield: 67 %

Procedure:
In the same manner as described in Example 8 by using (3R)-3-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline (1.01 g), 2N KOH (2.5 ml), CS2 (0.3 ml), 4-chlorobenzyl chloride (0.81 g) and 70% ethanol (20 ml), there is prepared the title compound (1.34 g, 67%) as white powder, [α]D20 -111.8° (c=1.0, methanol). NMR (CDCl3 -DMSO-d6, δ): 4.56 (s, 2H, CSSCH2C6H4 -p-Cl), Mass m/e: 402 (M+), 244 (M+ -p-Cl-C6H4CH2SH).
Reaction SMILES: O1CCCC1.[CH:6]1([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19](Cl)=[N:20][OH:21])=[CH:14][CH:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1.[C:23]([C:25]1[C:26]([NH2:31])=[N:27][CH:28]=[CH:29][CH:30]=1)#[CH:24].C(N(CC)CC)C>O>[CH:6]1([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]3[CH:24]=[C:23]([C:25]4[C:26]([NH2:31])=[N:27][CH:28]=[CH:29][CH:30]=4)[O:21][N:20]=3)=[CH:14][CH:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: ON=C(Cl)Cc1ccc(OC2CCCC2)cc1
Reactant: C#Cc1cccnc1N
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2ccc(OC3CCCC3)cc2)no1
Temperature: 50 °C
Reaction time: 3 h
Yield: 22 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-cyclopentyloxy-phenyl)-acetohydroximoyl chloride (150 mg, 0.592 mmol) described in Manufacturing Example 78-1-4 and 3-ethynyl-pyridin-2-ylamine described in Manufacturing Example 1-2-3 (45 mg, 0.378 mmol) was added triethylamine (206 μL, 1.48 mmol), which was stirred for 3 hours at 50° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=4:1-2:1) to obtain the title compound (44 mg, 22%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([Cl:11])[CH:3]=1.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.Cl.[CH3:31][NH:32][O:33][CH3:34].C(N(CC)CC)C>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:32]([O:33][CH3:34])[CH3:31])=[O:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: CNOC
Reactant: O=C(O)c1ccc(Br)cc1Cl
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1ccc(Br)cc1Cl
Reaction time: 72 h
Yield: 90.3 %

Procedure:
A solution of 4-bromo-2-chloro-benzoic acid (3.30 g, 14 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (2.44 g, 14 mmol) and N-methylmorpholine in tetrahydrofuran were stirred for 2 hours at room temperature. N,O-Dimethylhydroxyamine hydrochloride (1.37 g, 14 mmol) and triethylamine (2 mL, 14 mmol) were added and the resulting mixture was stirred for 3 days. The reaction mixture was evaporated and ethyl acetate was added. The mixture was washed with 1N aqueous hydrochloric acid, water, brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 4-bromo-2-chloro-N-methoxy-N-methyl-benzamide (3.52 g, 91%).
Reaction SMILES: C(OC([NH:8][C:9]([CH3:30])([CH3:29])[CH2:10][O:11][C:12](=[O:28])[C@H:13]([CH:25]([CH3:27])[CH3:26])[NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:9]([CH3:30])([CH3:29])[CH2:10][O:11][C:12](=[O:28])[C@H:13]([CH:25]([CH3:26])[CH3:27])[NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(N-(tert.-butyloxycarbonyl)-amino)-2-methyl-1-(N-benzyloxycarbonyl-L-valyloxy)-propane (10 g, 23 mmole) in dichloromethane (150 ml) was added trifluoroacetic acid (30 ml) and the mixture was stirred for 1 hour at room temperature. The solution was evaporated under reduced pressure and 10% sodium carbonate solution was added. The product was extracted four times with dichloromethane, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with dichloromethane/methanol. Yield: 3.0 g=40% (crude)
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[F:24][C:25]1[CH:26]=[C:27]([C:35](O)=[O:36])[C:28]2[O:33][CH2:32][O:31][CH2:30][C:29]=2[CH:34]=1>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:35]([C:27]3[C:28]4[O:33][CH2:32][O:31][CH2:30][C:29]=4[CH:34]=[C:25]([F:24])[CH:26]=3)=[O:36])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Reactant: O=C(O)c1cc(F)cc2c1OCOC2
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3cc(F)cc4c3OCOC4)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 6-fluoro-4H-benzo[1,3]dioxine-8-carboxylic acid. LC-MS (basic): tR=0.89 min; [M+H]+=512.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1.[NH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25].C(NC(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1NC(=O)c1cc(Cl)ncn1
Reactant: COC(=O)CN
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)CNS(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-(6-chloropyrimidine-4-carboxamido)-3-methylbenzene-1-sulfonyl chloride (Intermediate 30, 1.2 g; 3.47 mmol) in THF (100 ml) was treated with methyl 2-aminoacetate (540 mg; 4.34 mmol) and diisopropylamine (2 ml; 14.3 mmol). After stirring at RT for 18 hours the solvent was removed in vacuo and the residue redissolved in DCM and washed with water. The organic extracts were passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc. The title product was obtained as a white solid (1.05 g, 76%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:14][S:15]([O:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)(=[O:17])=[O:16]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Reaction time: 0.5 h
Yield: 106.2 %

Procedure:
To (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (87 mg, 0.465 mmol) in DCM (2 mL) at 0° C. was added methanesulfonyl chloride (58.5 mg, 0.511 mmol) and triethylamine (56.4 mg, 0.558 mmol). The cold bath was removed and the reaction was stirred for 30 minutes. The reaction was diluted with 5 mL DCM, washed with water and brine, dried (Na2SO4) and concentrated to give final product (131 mg).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([O:10]C)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Li+].[OH-].CCOC(C)=O.Cl>CO.O>[O:1]=[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1cccn(-c2ccccc2)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)c1cccn(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
A mixture of methyl 2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate (70 mg, 0.31 mmol) and LiOH (40 mg) in methanol (6 mL) and water (1 mL) was stirred at rt overnight. To the reaction mixture were added EtOAc (50 mL) and 1 N aq HCl (15 mL). The EtOAc layer was separated, dried over MgSO4, and concentrated in vacuo to afford the product (55 mg, 83%) as a light yellow solid. 1H NMR (DMF-d7) δ 11.77 (br s, 1H), 8.57 (dd, 1H, J=7.4, 2.0 Hz), 8.26 (dd, 1H, J=6.6, 1.6 Hz), 7.64-7.55 (m, 5H), 6.88 (t, 1H, J=7.0 Hz); MS(ESI+) m/z 216.2 (M+H)+.
Reaction SMILES: [C:1]([C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])#[CH:2].O1[CH2:20][CH2:19]OCC1.[NH:21]1[CH2:25]C[CH2:23][CH2:22]1.C=O>C(O)(=O)C>[N:21]1([CH2:25][C:2]#[C:1][C@H:3]2[CH2:7][CH2:6][CH2:5][N:4]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:20][CH2:19][CH2:23][CH2:22]1
Reactant: C1CCNC1
Reactant: C1COCCO1
Reactant: C#C[C@H]1CCCN1C(=O)OC(C)(C)C
Agent: C=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C#CCN1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3.5 g of (R)-2-ethynyl-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester, 75 ml dry dioxane, 3.0 ml pyrrolidine, 1.43 g of paraformaldehyde, 7.0 ml of glacial acetic acid and 50 mg of cuprous chloride is stirred at room temperature for 15 minutes then refluxed for 2 hours. The reaction is cooled and concentrated in vacuo. The residue is partitioned between water and methylene chloride and the pH of the mixture is adjusted to pH 11 with ammonium hydroxide. The basified reaction is extracted with methylene chloride and dried over sodium sulfate. The methylene chloride solution is passed over hydrous magnesium silicate and concentrated in vacuo to give 5.65 g of a dark yellow oil. The product is purified by chromatography using deactivated alumina as the absorbant, to give 0.55 g of the product as a pale yellow oil, [α]D26° =+100.6°±0.8 (C=1.22%, methylene chloride).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]3[CH:15]=[CH:14][CH:13]=[CH:12][C:6]3=[CH:7][CH:8]=2)[N:3]=1.C([Li])CCC.CCCCCC.CN(C)[C:29](=[O:31])[CH3:30].Cl>C1COCC1>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]3[CH:12]=[CH:13][CH:14]=[CH:15][C:5]3=2)[CH:10]=[CH:11][C:2]=1[C:29](=[O:31])[CH3:30]
Reactant: Brc1ccc2ccc3ccccc3c2n1
Reactant: CC(=O)N(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)c1ccc2ccc3ccccc3c2n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
A solution of 2-bromobenzo[h]quinoline (1.52 g, 5.89 mmol) in THF (36 ml) was cooled to −78° C. After 10 minutes a solution of 2.5 M n-butyllithium in n-hexane (2.47 ml, 6.18 mmol) was added. The resulting dark red solution was again stirred at −78° C. for 1 hour after which N,N-dimethylacetamide (0.60 ml, 6.45 mmol) was added drop-wise. The solution was stirred for 1 h at −78° C. and allowed to warm slowly to ambient temperature. A solution of 1 M HCl (7.4 ml, 7.4 mmol) was then added, the organic phase was separated and the aqueous phase was extracted with Et2O (2×15 ml). The organic phases were combined, dried over anhydrous Na2SO4 and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography (petroleum ether/acetate=95/5) to give 1.00 g (77% yield) of 1-(benzo[h]quinolin-2-yl)ethanone in the form of a yellow solid: mp 113-115° C.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C.[CH2:56]([C:63]1[S:67][C:66]([NH2:68])=[N:65][N:64]=1)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>ClCCl>[CH2:56]([C:63]1[S:67][C:66]([NH:68][C:20]([C:19]2[CH:23]=[CH:24][C:16]([C@H:13]3[CH2:12][CH2:11][C@H:10]([O:9][CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:15][CH2:14]3)=[CH:17][CH:18]=2)=[O:21])=[N:65][N:64]=1)[C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1
Reactant: CC(C)(C)OC(=O)CO[C@H]1CC[C@H](c2ccc(C(=O)O)cc2)CC1
Reactant: Nc1nnc(Cc2ccccc2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CO[C@H]1CC[C@H](c2ccc(C(=O)Nc3nnc(Cc4ccccc4)s3)cc2)CC1
Reaction time: 16 h

Procedure:
0.6 g of trans-4-(4-tert-butoxycarbonylmethoxycyclohexyl)benzoic acid (1.79 mmol, 1 eq.) is placed in 8 mL of dichloromethane with stirring. 0.7 mL of diisopropylethylamine (4.49 mmol, 2.5 eq.), 0.275 g of hydroxybenzotriazole (1.79 mmol, 1 eq.) and 0.413 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.15 mmol, 1.2 eq.) are successively added, followed, after 10 minutes, by addition of 0.377 g of 5-benzyl-1,3,4-thiadiazol-2-amine (1.97 mmol, 1.1 eq.). After 16 hours, 0.137 g of hydroxybenzotriazole (0.895 mmol, 0.5 eq.) and 0.172 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.17 mmol, 0.5 eq.) are added. After 18 hours, the medium is evaporated, diluted with ethyl acetate and washed three times with brine. The organic phase is dried over sodium sulfate, filtered and evaporated. The residue is chromatographed on silica gel with a gradient of methanol in dichloromethane ranging from 0% to 2%. 0.09 g of tert-butyl trans-{4-[4-(5-benzyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenyl]cyclohexyloxy}acetate is obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[CH:3][C:2]=1[OH:12].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CN(C=O)C>O>[CH2:19]([O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[C:2]([OH:12])[CH:3]=[CH:4]2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Oc1ccc2cccc(O)c2n1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccc2cccc(OCc3ccccc3)c2n1
Temperature: 65 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
To a flask was added quinoline-2,8-diol (20.0 g, 124.1 mmol), K2CO3 (17.15 g, 124.1 mmol), benzyl bromide (14.76 ml, 124.1 mmol) and DMF (124.1 ml, 124.1 mmol). The resulting mixture was heated to 65° C. overnight. The reaction mixture was poured into 1000 ml water and stirred for 5 hours, filtered solids and then washed with 1000 ml diethyl ether to yield 26.5 g (85% yield) of desired product.