Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24]C(C)(C)C)=O)[CH2:18][CH2:17]2)=[O:15])[NH:12][CH:13]=1.Cl.CO.[C:32](O)(=O)[CH:33]=C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([C:14]([N:16]2[CH2:17][CH2:18][N:19]([C:22](=[O:24])[CH:32]=[CH2:33])[CH2:20][CH2:21]2)=[O:15])[NH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(-c3ccc(Cl)cc3Cl)c[nH]2)CC1
Reactant: C=CC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N1CCN(C(=O)c2cc(-c3ccc(Cl)cc3Cl)c[nH]2)CC1
Reaction time: 1 h
Yield: 16.5 %

Procedure:
The mixture of tert-butyl 4-(4-(2,4-dichlorophenyl)-1H-pyrrole-2-carbonyl)piperazine-1-carboxylate (270 mg, 0.64 mmol) in HCl/MeOH (20 mL, 57.2 mmol) was stirred for 1 h. The mixture was concentrated in vacuo and the residue was dissolved in DMF (5 mL). To this mixture, acrylic acid (50 mg, 0.7 mmol), BOP (437 mg, 0.72 mmol) and DIEA (248 mg, 1.92 mmol) were added. The reaction mixture was stirred at room temperature for 1 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=60:1) to afford the desired product (40 mg, 27% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 11.88 (s, 1H), 7.66-7.63 (m, 2H), 7.43 (m, 1H), 7.38 (s, 1H), 6.91 (s, 1H), 6.85-6.78 (m, 1H), 6.18-6.13 (dd, J=2.4, 12.4 Hz, 1H), 5.74-5.71 (dd, J=2.4, 10.4 Hz, 1H), 3.76 (s, 4H), 3.68-3.63 (m, 4H). ESI-MS m/z: 377.3 [M−H]−.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[NH:8][C:7](=[O:9])[NH:6][C:5](=[O:10])[CH:4]=1.[Br:13]Br>O>[Br:13][C:4]1[C:5](=[O:10])[NH:6][C:7](=[O:9])[NH:8][C:3]=1[C:2]([F:1])([F:11])[F:12]
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)[nH]1
Reactant: BrBr
Solvent: O
Product: O=c1[nH]c(C(F)(F)F)c(Br)c(=O)[nH]1
Temperature: 25 °C

Procedure:
6-(Trifluoromethyl)uracil (4.0 g., 0.22 mole) was dissolved in 75 ml. water at 70°C. Bromine (3.55 g., 0.022 mole) was added in portions with vigorous stirring. A white precipitate formed almost immediately. The suspension was allowed to cool to room temperature and then chilled before being filtered. The product after air drying weighed 4.75 g. (82.5%) and had a melting point of 231°-234°C. The analytical sample melting point was 236°-240°C. After recrystallization from water.
Reaction SMILES: [CH:1]1([CH2:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][N:29]2[C:37]3[C:32](=[CH:33][C:34]([C:38](O)=[O:39])=[CH:35][CH:36]=3)[C:31]([CH3:41])=[C:30]2[CH3:42])=[CH:24][CH:23]=1)=[O:15])(C)(C)C>>[CH:1]1([CH2:7][NH:8][C:38]([C:34]2[CH:33]=[C:32]3[C:37](=[CH:36][CH:35]=2)[N:29]([CH2:28][C:25]2[CH:24]=[CH:23][C:22]([C:17]4[C:16]([C:14]([OH:15])=[O:13])=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:27][CH:26]=2)[C:30]([CH3:42])=[C:31]3[CH3:41])=[O:39])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCC1CCCCC1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCC3CCCCC3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using cyclohexylmethylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][NH2:12])[CH2:6][CH2:5]1.[CH2:13]1[NH:15][CH2:14]1.[Cl-].[NH4+]>>[NH2:15][CH2:14][CH2:13][NH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][NH2:12])[CH2:6][CH2:5]1
Reactant: NCCC1CCC(CCN)CC1
Reactant: C1CN1
Agent: [Cl-]
Agent: [NH4+]
Product: NCCNCCC1CCC(CCN)CC1

Procedure:
1,4-Bis-(2-aminoethyl)cyclohexane (68 gm., 0.4 mole) and ethyleneimine (4.3 gm., 0.1 mole) with 0.4 g. ammonium chloride are mixed in a glasslined pressure reactor and filled with nitrogen to 100 psi. The mixture is shaken and heated at 85°-95° C. for 48 hours. After cooling, it is distilled rapidly free of the salt and then fractionated under high vacuum. The starting diamine is readily distinguished from the triamine product by thin layer chromatography on silica gel using a mixture of 1 volume concentrated aqueous ammonium hydroxide with 4 volume methyl alcohol, the diamine having a much higher Rf.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH:15]([O:16]C(=O)C3C=CC=CC=3)[CH2:14][CH:13]([CH:25]=[CH:26][P:27]([O:32]CC)([O:29]CC)=[O:28])[O:12]2)=[C:4](Cl)[N:3]=1.C[Si](Br)(C)C.[N:41]1C(C)=CC=CC=1C>CC#N>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[O:12][CH:13]([CH:25]=[CH:26][P:27](=[O:28])([OH:29])[OH:32])[CH2:14][CH:15]2[OH:16])=[C:4]([NH2:41])[N:3]=1
Reactant: CCOP(=O)(C=CC1CC(OC(=O)c2ccccc2)C(n2cnc3c(Cl)nc(N)nc32)O1)OCC
Reactant: Cc1cccc(C)n1
Agent: C[Si](C)(C)Br
Solvent: CC#N
Product: Nc1nc(N)c2ncn(C3OC(C=CP(=O)(O)O)CC3O)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.3 %

Procedure:
Compound 13.1 (147.5 mg, 0.283 mmol) was dissolved in 3 mL CH3CN, treated with TMSBr (0.3 mL) and 2,6-lutidine (0.075 mL). The mixture was stirred at room temperature for 1.5 h, concentrated and coevaporated with CH3CN under reduced pressure. The residue was dissolved in 30% NH3 in water, and the mixture was stirred at 100° C. for 1.5 h. The mixture was then treated with NaHCO3 (500 mg) and concentrated under reduced pressure. The residue was subjected to reverse phase HPLC eluting with 0-25% CH3CN in water to yield compound 13.2 (81 mg, 74.3% yield). 1H NMR (D2O) δ 2.05-2.25 (m, 2H), 4.58 (m, 1H), 5.8 (d, 1H, J=1.5), 5.95 (m, 1H), 6.15 (m, 1H), 7.8 (s, 1H). 31P NMR (D2O) d 9.15. LRMS (ESI) MH+ C11H15N6O5P requires 343.3. Found 343.1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][S:12][C:13]1[S:17][C:16]([CH:18]=O)=[CH:15][CH:14]=1>N1CCCCC1.C(O)C>[CH3:11][S:12][C:13]1[S:17][C:16]([CH:18]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])=[CH:15][CH:14]=1
Reactant: CSc1ccc(C=O)s1
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CSc1ccc(C=C2C(=O)Nc3ccccc32)s1
Temperature: 90 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
A reaction mixture of 134.0 mg of oxindole, 189.9 mg of the 5-methylmercaptothiophene-2-carboxaldehyde, and 3 drops of piperidine in 2 mL of ethanol was stirred at 90° C. for 3 h. After cooling, the precipitate was filtered, washed with cold ethanol, and dried to yield 246.6 mg (90%) of the title compound as a orange solid.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12]([CH3:14])=[C:11]([CH3:15])[N:10]=[C:9]([NH2:16])[C:8]=2[N:7]=[C:6]1[CH2:17][NH:18][O:19][CH3:20])[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1>ClCCl.C1(C(Cl)=O)CC1>[NH2:16][C:9]1[C:8]2[N:7]=[C:6]([CH2:17][N:18]([O:19][CH3:20])[C:31]([CH:28]3[CH2:30][CH2:29]3)=[O:32])[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:13]=2[C:12]([CH3:14])=[C:11]([CH3:15])[N:10]=1
Reactant: CONCc1nc2c(N)nc(C)c(C)c2n1CC(C)C
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(Cc1nc2c(N)nc(C)c(C)c2n1CC(C)C)C(=O)C1CC1
Temperature: -5 °C
Reaction time: 2 h
Yield: 44.3 %

Procedure:
Under a nitrogen atmosphere, 1-isobutyl-2-[(methoxyamino)methyl]-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine (0.53 g, 1.91 mmol) was dissolved in dichloromethane (19 mL) and cooled to −5° C. Triethylamine (293 uL, 2.10 mmol) was added followed by dropwise addition of cyclopropane carbonyl chloride (173 uL, 1.91 mmol). The solution was allowed to stir at RT for 2 hours, then cooled back to −5° C. More triethylamine (38 uL, 0.27 mmol) and cyclopropane carbonyl chloride (23 uL, 0.25 mmol) were added and the reaction was allowed to stir at 0° C. for 45 minutes. More cyclopropane carbonyl chloride (5 uL, 0.06 mmol) was added and stirring continued for another 30 minutes. Dichloromethane (100 mL) was added and the solution was washed successively with saturated aqueous sodium bicarbonate (30 mL), water (3×25 mL), and brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by HPFC eluting with a gradient of 0-35% CMA in chloroform and then recrystallized from ethyl acetate/hexanes to provide 292 mg of pure product as an off-white powder, mp 135.0-137.0° C. Anal. Calcd for C18H27N5O2 C, 62.59; H, 7.88; N, 20.27. Found: C, 62.68; H, 7.82; N, 19.93.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[C-:13]#[N:14].[K+]>C(#N)C.C1OCCOCCOCCOCCOCCOC1>[C:13]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:14]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cccc(CC#N)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.8 %

Procedure:
To a solution of methyl 3-(bromomethyl)benzoate (10.0 g, 44 mmol) in acetonitrile (100 mL) were added potassium cyanide (5.7 g, 87 mmol) and 18-crown-6 (1.0 g), and the mixture was stirred at room temperature for 3 days. The reaction mixture was filtrated, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→30/70). The combined solution was concentrated under reduced pressure to give the title compound (7.0 g, 91%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][OH:13])[CH:6]=[CH:5]2.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]=[O:13])[CH:6]=[CH:5]2
Reactant: OCc1ccc2cc(Br)ccc2c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1ccc2cc(Br)ccc2c1
Reaction time: 1 h
Yield: 77.6 %

Procedure:
To a three-necked flask (250 ml) was added (6-bromonaphthalen-2-yl)methanol (40.0 g, 0.170 mol) and dichloromethane (1.6 L) with magnetic stirring under nitrogen to form a clear solution. To this solution, Pyridinium chlorochromate (40.0 g, 0.186 mol) was added, and the resulting mixture turned black at once. Stirring was continued for 1 hour. The mixture was filtered through a short silica gel column, eluted with dichloromethane; the filtrate was dried over anhydrous magnesium sulphate, and then filtered under reduced pressure. The solvent was removed to afford a light brown solid, which was recrystallized from ethanol-water solution (50%) to afford a white solid 6-bromo-2-naphthaldehyde (31 g).
Reaction SMILES: [CH3:1][N+:2]([CH2:5][C@H:6]([NH2:11])[CH2:7][C:8]([O-:10])=[O:9])([CH3:4])[CH3:3].[C:12]([C:18]1[O:22][C:21]([C:23](ON2C(=O)CCC2=O)=[O:24])=[CH:20][CH:19]=1)#[C:13][CH2:14][CH2:15][CH2:16][CH3:17].CN(C=O)C.C(N(CC)CC)C>C(OCC)C>[C:12]([C:18]1[O:22][C:21]([C:23]([NH:11][C@@H:6]([CH2:5][N+:2]([CH3:3])([CH3:4])[CH3:1])[CH2:7][C:8]([O-:10])=[O:9])=[O:24])=[CH:20][CH:19]=1)#[C:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCC#Cc1ccc(C(=O)ON2C(=O)CCC2=O)o1
Reactant: C[N+](C)(C)C[C@H](N)CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCC#Cc1ccc(C(=O)N[C@H](CC(=O)[O-])C[N+](C)(C)C)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.9 %

Procedure:
(R)-aminocarnitine (20 mg, 0.12 mmol) and 2,5-dioxopyrrolidin-1-yl 5-(hex-1-ynyl)furan-2-carboxylate (68 mg, 0.23 mmol) were dissolved into DMF (1 mL). Triethylamine (50 μL, 0.36 mmol) was added and the solution was stirred at room temperature for 18 h. Diethyl ether (20 mL) was added and a white precipitate was collected. The powder was purified by silica gel chromatography (elution 10% MeOH/CH2Cl2 to 80% MeOH/CH2Cl2) to give the title compound as a white powder (16 mg, 40%). 1H NMR (400 MHz, D2O) δ 7.02 (d, 1H, J=3.7 Hz), 6.53 (d, 1H, J=3.6 Hz), 4.90-4.80 (m, 1H), 3.63-3.58 (m, 1H), 3.47-3.42 (m, 1H), 3.06 (s, 9H), 2.45-2.42 (m, 2H), 2.35 (t, 2H, J=6.9 Hz), 1.47-1.41 (m, 2H), 1.35-1.29 (m, 2H), 0.78 (t, 3H, J=7.3 Hz); MS ESI 335.2 [M+H]+, calcd for [C18H26N2O4+H]+ 335.19.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=1)[C:8]([NH:10][C:11]1[S:12][C:13](Br)=[CH:14][N:15]=1)=[O:9])([CH3:3])[CH3:2].[SH:27][CH2:28][C:29]([O:31][CH3:32])=[O:30]>>[CH3:32][O:31][C:29](=[O:30])[CH2:28][S:27][C:13]1[S:12][C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:17]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:19]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:6]=2)=[N:15][CH:14]=1
Reactant: COC(=O)CS
Reactant: CC(C)Oc1cc(Oc2ccccc2)cc(C(=O)Nc2ncc(Br)s2)c1
Product: COC(=O)CSc1cnc(NC(=O)c2cc(Oc3ccccc3)cc(OC(C)C)c2)s1
Yield: 25.7 %

Procedure:
[2-(3-Isopropoxy-5-phenoxy-benzoylamino)-thiazol-5-yl-sulfanyl]-acetic acid methyl ester (100 mg) was prepared from 3-isopropyloxy-5-phenoxy-N-(5-bromothiazol-2-yl)-benzamide (370 mg, 0.85 mmol) and methyl mercaptoacetate (0.4 mL, 4.0 mmol) in 26% yield following the general procedure F.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[Cl:22])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>CO>[ClH:21].[ClH:23].[Cl:22][C:16]1[C:17]([Cl:21])=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(Cl)c2Cl)CC1
Agent: Cl
Solvent: CO
Product: Clc1cccc(CN2CCNCC2)c1Cl
Reaction time: 8 h

Procedure:
To a solution of N-[(tert-butyloxycarbonyl]-N′-(2,3-dichlorobenzyl)piperazine [Intermediate 3, (8.25 g, 24 mmol)] in MeOH (200 mL) was added concentrated aqueous HCl solution (15 mL) slowly in portions. The reaction was stirred overnight and the first crop of product crystallized out. The reaction mixture was filtered and the filter cake was rinsed with Et2O to afford a white crystalline solid (4.1 g). The filtrate was concentrated to about ⅓ of the original volume and a second crop of crystalline product was collected by filtration (2.9 g). The combined yield of the title product was 92%. 1H NMR (DMSO-d6) δ 9.81 (br, 2H), 7.87 (d, J=7.5 Hz, 1H), 7.75 (d, J=8.0 Hz), 7.47 (t, J=7.9 Hz), 4.45 (s, 2H), 3.40 (s, 4H), 3.16 (s, 1H); 13C NMR (DMSO-d6) δ 133.0, 132.6, 132.5, 131.9, 128.7, 56.9, 48.2, 40.6; MS Calcd for [C11H14Cl2N2+H]+: 245. found: 245.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[N:6][CH:7]=1.[Li]CCCC.CO[C:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23].Cl.C([O-])(O)=O.[Na+]>C1COCC1.C(OCC)(=O)C.O.CO>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]1[NH:1][C:2]2[CH:7]=[N:6][CH:5]=[N:4][C:3]=2[CH:8]=1
Reactant: Cc1ncncc1N
Reactant: COC(=O)c1ccccc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: Fc1ccccc1-c1cc2ncncc2[nH]1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 51.4 %

Procedure:
5-amino-4-methylpyrimidine (5 g, 45 mmol) was dissolved in 200 mL THF and cooled to −20° C. A solution of n-BuLi (112.5 mmol) was added over 10 minutes and the solution was kept at −20° C. for 30 min, then warmed to room temp and stirred for 3 h. It was then cooled to −40° C. and to it was added methyl-2-fluorobenzoate (1.75 mL, 13.7 mmol) and the solution stirred at −40° C. for 30 min and then warmed to room temp for 1 h. 50 mL of methanol was then added over 5 min, followed by 6N aq HCl. The solution was stirred for 18 h at room temp. It was then neutralized with NaHCO3 to pH 8 and then diluted with ethyl acetate and water. The organics were washed with water three times and then brine and dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography using 10% methanol/DCM. 1.5 g of product was isolated as a yellow solid (16%). 1H-NMR: (d6-DMSO, 400 MHz) δ 12.22 (s, 1H), 8.86 (s, 1H), 8.83 (s, 1H), 7.98(dt, 1H), 7.46 (m, 1H), 7.38 (m, 2H), 7.02(s, 1H) LC/MS: calculated for C12H8FN3: 213.2; found 214.10 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40][CH:41]([C:45](O)=[O:46])[C:42](O)=[O:43])([CH3:33])[CH3:32]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[O:11][C:42](=[O:43])[C:41]([S:40][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[CH:31]([CH3:32])[CH3:33])=[C:45]([OH:46])[CH:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CC(=O)c1cc(C)cc(C)c1
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)cc(-c2cc(O)c(Sc3ccccc3C(C)C)c(=O)o2)c1

Procedure:
The title compound was prepared by Method A using 3', 5'-dimethylacetophenone (0.714 g, 4.83 mmol), trimethylsilyl triflate (1.12 mL, 5.79 mmol), triethylamine (1.34 mL, 9.66 mmol), methylene chloride (17 mL), and diethyl ester of [(2-isopropylphenyl)thio]propanedioic acid (1.00 g, 3.22 mmol) m.p. 154-155° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.24 (d, 6H), 2.35 (s, 6H), 3.40 (m, 1H), 6.90 (d, 1H), 7.05 (t, 1H), 7.11 (dt, 2H), 7.20 (s, 1H), 7.27 (d, 1H), 7.45 (s, 2H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:14][C@H:13]([NH2:15])[CH2:12]1.[Cl:16][C:17]1[C:22](Cl)=[N:21][CH:20]=[CH:19][N:18]=1>C(O)(C)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:12][C@H:13]([NH:15][C:22]2[C:17]([Cl:16])=[N:18][CH:19]=[CH:20][N:21]=2)[CH2:14]1
Reactant: N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Reactant: Clc1nccnc1Cl
Solvent: CC(C)O
Product: Clc1nccnc1N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Temperature: 150 °C

Procedure:
Trans-N1-(benzo[d]thiazol-2-yl)cyclobutane-1,3-diamine (intermediate 11, 0.058 g, 0.264 mmol) and 2,3-dichloropyrazine (0.035 ml, 0.336 mmol) were suspended in isopropanol (1 mL) in a microwave vial. The mixture was heated at 150° C. for 90 minutes. The mixture was evaporated to dryness under reduced pressure and purified using silica chromatography (hexane to ethyl acetate gradient) to give trans-N1-(benzo[d]thiazol-2-yl)-N3-(3-chloropyrazin-2-yl)cyclobutane-1,3-diamine (0.0594 g, 0.179 mmol, 67.7% yield) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:12]=1.[CH2:13](O)[CH2:14][OH:15]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7]3([O:15][CH2:14][CH2:13][O:11]3)[C:6]=2[CH:12]=1
Reactant: O=C1CCSc2ccc(Br)cc21
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1ccc2c(c1)C1(CCS2)OCCO1
Yield: 78.8 %

Procedure:
14.7 g (0.060 mol) of the title compound of Step B, 11 mL (0.19 mol) of ethylene glycol (purchased from Aldrich Chemical Company), and 0.4 g (2.10 mmol) of p-toluenesulfonic acid monohydrate (purchased from Aldrich Chemical Company) were added to 125 mL of toluene. The solution was stirred at reflux under nitrogen overnight, and was then washed with 1M sodium carbonate (2×250 mL), followed by water (2×250 mL). The organic layer was dried (Na2SO4), filtered, and evaporated to dryness to yield 13.58 g of the title compound of Step C as an oil. 1H NMR (CDCl3): δ2.2 (m,2H), 3.16 (m,2H), 4.1 (m,2H), 4.2 (m,2H), 7.0-7.6 (3H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH:13]3[CH2:18][CH2:17][N:16](C(OCC4C=CC=CC=4)=O)[CH2:15][CH2:14]3)[CH2:9][CH2:8]2)[C@@H:5]2[CH2:29][CH2:30][CH2:31][CH2:32][C@H:4]2[NH:3]1>CO.[Pd]>[N:10]1([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:9][CH2:8][CH:7]([N:6]2[C@@H:5]3[CH2:29][CH2:30][CH2:31][CH2:32][C@H:4]3[NH:3][C:2]2=[O:1])[CH2:12][CH2:11]1
Reactant: O=C(OCc1ccccc1)N1CCC(N2CCC(N3C(=O)N[C@@H]4CCCC[C@H]43)CC2)CC1
Agent: [Pd]
Solvent: CO
Product: O=C1N[C@@H]2CCCC[C@H]2N1C1CCN(C2CCNCC2)CC1
Reaction time: 12 h
Yield: 97.9 %

Procedure:
To a solution of benzyl 4-[(3aR,7aR)-2-oxooctahydro-1H-benzimidazol-1-yl]-1,4′-bipiperidine-1′-carboxylate-(880 mg, 2.0 mmol) in methanol (25 mL) was added 10% Pd/C (0.1 g), the mixture was hydrogenated at 40 psi for 12 h. Filtration of catalyst and concentration of solvents afforded crude product (600 mg, 98%), which was used for the next step without further purification. MS (M+1): 307.31
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[NH2:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]=[CH:10]2
Reactant: O=[N+]([O-])c1ccc2c(ccn2Cc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc2c(ccn2Cc2ccccc2)c1
Temperature: 25 °C
Yield: 9 %

Procedure:
A solution of 1-benzyl-5-nitroindole (0.51 g, 0.02 mol) in a mixture of ethyl acetate (25 ml) and methanol (25 ml) was carefully added to 10% palladium on charcoal (45 mg). The resulting suspension was stirred at room temperature under an atmosphere of hydrogen. When the reaction was complete (indicated by tlc or calculated uptake of hydrogen) the suspension was filtered through a pad of Hyflo™, and the filtrate evaporated to dryness to give 5-amino-1-benzylindole (0.40 g, 91%) as an off-white solid; m.p. 66-68° C.; δH [2H6]-DMSO 7.30-7.12 (6H, m, 2-H, 2″-H, 3″-H, 4″-H, 5″-H, 6″-H), 7.08 (1H, d, J 8, 7-H), 6.70 (1H, s, 4-H), 6.49 (1H, d, J 8, 6-H), 6.18 (1H, s, 3-H), 5.28 (2H, s, CH2), 4.38 (2H, br s, NH2).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:11]([OH:13])=O.O[N:24]=[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[NH2:26].CCN(C(C)C)C(C)C>>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:25]1[N:24]=[C:11]([C:10]2[CH:14]=[CH:15][C:16]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[C:8]([CH3:7])[CH:9]=2)[O:13][N:26]=1
Reactant: Cc1cc(C(=O)O)ccc1N1CCCCC1
Reactant: COc1ccccc1C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1noc(-c2ccc(N3CCCCC3)c(C)c2)n1

Procedure:
Oxalyl chloride (139 μL; 1.64 mmol; 3 eq.), Intermediate 33 (120 mg; 0.55 mmol; 1 eq.), Intermediate 1 (91 mg; 0.55 mmol, 1 eq.) and DIEA (283 μL; 1.64 mmol; 3 eq.) were reacted according to general procedure 2. Purification by preparative HPLC (increasing amount of 0.1% TFA in CH3CN, in 0.1% TFA in water) afforded the title compound as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=3)[N:13]=2)=[CH:5][CH:4]=1.[CH:26]([C:29]1[S:33][C:32]([NH2:34])=[N:31][N:30]=1)([CH3:28])[CH3:27]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH:26]([C:29]1[S:33][C:32]([NH:34][S:22]([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:12]3[N:13]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[O:10][CH:11]=3)=[CH:17][CH:18]=2)(=[O:24])=[O:23])=[N:31][N:30]=1)([CH3:28])[CH3:27]
Reactant: COc1ccc(-c2nc(COc3ccc(S(=O)(=O)Cl)cc3)co2)cc1
Reactant: CC(C)c1nnc(N)s1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1ccc(-c2nc(COc3ccc(S(=O)(=O)Nc4nnc(C(C)C)s4)cc3)co2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.6 %

Procedure:
580 mg 4-[2-(4-Methoxy-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonyl chloride were added to a stirred solution of 275 mg 5-isopropyl-[1,3,4]thiadiazol-2-ylamine in 35 ml pyridine. 18 mg 4-Dimethylaminopyridine were added. The reaction mixture was stirred at room temperature overnight. The pyridine was removed in vacuo and the residue coevaporated with 15 ml toluene. The residue was purified by RP-HPLC to obtain 19 mg N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-[2-(4-methoxy-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonamide.