Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]12([C:17]3[CH:26]=[C:25]4[C:20]([CH:21]=[CH:22][C:23]([C:27]5[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=5)=[CH:24]4)=[CH:19][C:18]=3[O:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH3:42])[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2.O>C1COCC1>[C:7]12([C:17]3[CH:26]=[C:25]4[C:20]([CH:21]=[CH:22][C:23]([C:27]5[CH:35]=[CH:34][C:30]([C:31]([N:1]6[CH2:6][CH2:5][O:4][CH2:3][CH2:2]6)=[O:32])=[CH:29][CH:28]=5)=[CH:24]4)=[CH:19][C:18]=3[O:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH3:42])[CH2:16][CH:11]3[CH2:10][CH:9]([CH2:15][CH:13]([CH2:12]3)[CH2:14]1)[CH2:8]2
Reactant: C1COCCN1
Reactant: COCCOCOc1cc2ccc(-c3ccc(C(=O)Cl)cc3)cc2cc1C12CC3CC(CC(C3)C1)C2
Solvent: C1CCOC1
Solvent: O
Product: COCCOCOc1cc2ccc(-c3ccc(C(=O)N4CCOCC4)cc3)cc2cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.8 ml (20.6 mmol) of morpholine and 40 ml of THF were introduced into a round-bottomed flask. A solution of 3.5 g (6.9 mmol) of 4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzoic acid chloride in THF was added dropwise and the reaction mixture was stirred at room temperature for two hours. The reaction mixture was poured into water and extracted with ethyl acetate and the organic phase was separated by settling, dried over magnesium sulfate and evaporated. The solid obtained was triturated in hexane, filtered and dried. 2.8 g (74%) of the expected amide were collected, which amide had a melting point of 86°-7° C.
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:8][C:7]([O:17][CH3:18])=[CH:6][CH:5]=2.O1CCN(CCO[C:29]2[CH:37]=[C:36]3[C:32]([C:33](C4C=CC=CC=4)=C(Br)C3=O)=[CH:31][CH:30]=2)CC1.B(O)(O)C1C=CC(C)=CC=1>>[CH3:18][O:17][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3](=[O:19])[C:2]([C:29]1[CH:37]=[CH:36][C:32]([CH3:33])=[CH:31][CH:30]=1)=[C:10]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Reactant: COc1ccc2c(c1)C(c1ccccc1)=C(Br)C2=O
Agent: Cc1ccc(B(O)O)cc1
Product: COc1ccc2c(c1)C(c1ccccc1)=C(c1ccc(C)cc1)C2=O
Reaction time: 0.17 h
Yield: 70 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-5-methoxy-3-phenyl-1H-inden-1-one obtained in Step 4 of Example 129 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, p-tolylboronic acid instead of 3-pyridinylboronic acid, and being stirred for 10 min to obtain the title compound (70%).
Reaction SMILES: [C:1]([C:3]([S:6][N:7]([CH3:11])[C:8](F)=[O:9])([CH3:5])[CH3:4])#[N:2].[OH:12][C:13]1[CH:14]=[N:15][N:16]([CH:18]([CH3:20])[CH3:19])[CH:17]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([C:3]([S:6][N:7]([CH3:11])[C:8](=[O:9])[O:12][C:13]1[CH:14]=[N:15][N:16]([CH:18]([CH3:20])[CH3:19])[CH:17]=1)([CH3:5])[CH3:4])#[N:2]
Reactant: CN(SC(C)(C)C#N)C(=O)F
Reactant: CC(C)n1cc(O)cn1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)n1cc(OC(=O)N(C)SC(C)(C)C#N)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
12 g (0.075 mole) of N-(2-cyanoprop-2-ylsulphenyl)-N-methyl-carbamoyl fluoride are added dropwise to a mixture of 9.45 g (0.075 mole) of 4-hydroxy-1-isopropylpyrazole, 8.5 g (0.085 mole) of triethylamine and 100 ml of toluene at 25° C. When the addition has ended, the mixture is stirred at room temperature for 18 hours. For working up, the reaction mixture is washed twice with water, dried over sodium sulphate and freed from the solvent in vacuo. 18 g (85% of theory) of O-(1-isopropylpyrazol-4-yl) N-(2-cyanoprop-2-ylsulphenyl)-N-methyl-carbamate are obtained in the form of a yellow oil of refractive index nD21 1.5070.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:20][C:21]([F:31])([F:30])[C:22]1[N:27]=[CH:26][C:25]([CH:28]=O)=[CH:24][CH:23]=1>>[F:19][C:16]([F:18])([F:17])[C:13]1[N:11]2[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:28][C:25]4[CH:26]=[N:27][C:22]([C:21]([F:31])([F:20])[F:30])=[CH:23][CH:24]=4)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)cn12
Product: FC(F)(F)c1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4c3)CC2)cn1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine with 6-(trifluoromethyl)pyridine-3-carbaldehyde was carried out according to General Synthetic Method 9. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 3-(trifluoromethyl)-6-[4-[[6-(trifluoromethyl)pyridin-3-yl]methyl]piperazin-1-yl]-[1,2,4]triazolo[4,3-a]pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.C(=O)(O)[O-].[Na+].[Br:17]Br.O>CO>[Br:17][C:7]1[C:2]([Cl:1])=[N:3][C:4]([O:10][CH3:11])=[N:5][C:6]=1[O:8][CH3:9]
Reactant: BrBr
Reactant: COc1cc(Cl)nc(OC)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nc(Cl)c(Br)c(OC)n1
Reaction time: 1 h
Yield: 31.3 %

Procedure:
4-Chloro-2,6-dimethoxy-pyrimidine (2.2 g, 12.6 mmol) and sodium bicarbonate (2.39 g, 28.4 mmol) were stirred in aqueous methanol (50%, 40 mL) at room temperature. Bromine (3.52 g, 22.0 mmol) was added dropwise over a period of 60 minutes. After the addition was complete, stirring was continued or additional 60 minutes. The solid was collected and was washed with water to yield 6.2 g of crude material. 3.1 g of the crude material were dissolved in hot methanol (40 mL) and water (10 mL) was added. The resultant precipitate was collected and dried in vacuo to yield the product (1.0 g, 3.95 mmol). 1H (CDCl3): δ=4.05 (s, 3H), 3.99 (s, 3H) ppm.
Reaction SMILES: ClC1C=CC=C2C=1NC([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=C2.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][N:26]2[CH3:31]>>[CH3:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[C:25]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)[N:26]2[CH3:31]
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Reactant: COc1cccc2c1ccn2C
Product: COc1cccc2c1cc(B1OC(C)(C)C(C)(C)O1)n2C

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using 4-methoxy-1-methyl-1H-indole.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]1[CH2:18][CH:17]1[CH2:19][CH2:20][NH2:21]>>[CH2:16]1[CH2:18][CH:17]1[CH2:19][CH2:20][NH:21][C:11](=[O:13])[C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: NCCC1CC1
Product: O=C(NCCC1CC1)c1ccc(-c2ccccc2)cc1

Procedure:
Using Preparation Method 1, 4-phenylbenzoic acid was reacted with (2-cyclopropyl)ethylamine. The resulting reaction mixture was purified using SiO2 with CH2Cl2 100%. A white crystalline solid was obtained (29%). NMR 1H (ppm, CDCl3): 7.82 (d, J3=8.2 Hz, 2H), 7.64 (d, J3=8.4 Hz, 2H), 7.60 (d, J3=7.5 Hz, 2H), 7.47-7.34 (m, 3H), 6.26 (br. s., 1H), 3.60-3.53 (m, 2H), 1.54 (quart., J3=6.8 Hz, 2H), 0.76-0.71 (m, 1H), 0.51-0.48 (m, 2H), 0.13-0.11 (m, 2H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)=[C:2]=[S:3].[C:11]([NH2:19])([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:12]>>[C:11]([NH:19][C:2]([NH:1][CH2:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)=[S:3])([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:12]
Reactant: CC(C)(C)CC(C)(C)N
Reactant: S=C=NCCc1cccs1
Product: CC(C)(C)CC(C)(C)NC(=S)NCCc1cccs1
Yield: 82.1 %

Procedure:
The procedure of step (1-1) of Example 1 was repeated except for using the compound obtained in step (2-1) (2.5 g, 15.0 mmol) and t-octyl amine (1.6 mL, 10.2 mmol), to obtain the title compound (2.5 g, 83%).
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][C@:14]2([OH:21])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([O:39]C(C)=O)[C:5]([C@@:7]1([CH3:38])[C@H:12]([C@@H:13]2[O:22][C:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[C@:11]2([O:33][C:34]([CH3:36])=[O:35])[CH2:31][O:32][C@@H:10]2[CH2:9][C@@H:8]1[OH:37])=[O:6]>O>[CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][C@:14]2([OH:21])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([OH:39])[C:5]([C@@:7]1([CH3:38])[C@H:12]([C@@H:13]2[O:22][C:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[C@:11]2([O:33][C:34]([CH3:36])=[O:35])[CH2:31][O:32][C@@H:10]2[CH2:9][C@H:8]1[OH:37])=[O:6]
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](O)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Solvent: O
Product: CC(=O)O[C@@]12CO[C@@H]1C[C@@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](O)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C

Procedure:
When Baccatin III was used as the starting material the reaction using water as the solvent also proceeds to the 10-DAB product; however, with a prolonged reaction time the yield is low and the 7-epi-10-DAB was formed in considerable amounts.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C(#N)C>[CH2:13]([N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCBr
Reactant: CC1(C)CC(O)CC(C)(C)N1
Solvent: CC#N
Product: CCCCCCN1C(C)(C)CC(O)CC1(C)C

Procedure:
258.9 Parts of 2,2,6,6-tetramethylpiperidin-4-ol, 540 parts of bromohexane and 1000 parts of acetonitrile were heated at reflux for 72 hours. After cooling the solid was filtered off and the filtrate evaporated in vacuo to yield a semi-solid material. Addition of petroleum ether of boiling range 40° to 60°C gave further precipitation and the solution was filtered once more. Evaporation in vacuo of the filtrate gave a liquid which was distilled at 116°C/0.1 mm to give 106.1 parts of 1-n-hexyl-2,2,6,6-tetramethylpiperidin-4-ol. This material gave the following elemental analysis by weight:
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[C:17]([Cl:18])[N:11]2[N:10]=[C:9]1[CH:19]=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]1([Mg]Br)[CH2:23][CH2:22]1>C(Cl)Cl.C1COCC1>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[C:17]([Cl:18])[N:11]2[N:10]=[C:9]1[CH:19]([CH:21]1[CH2:23][CH2:22]1)[OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1nn2c(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=c1c2ccc(Cl)n2nc(C(O)C2CC2)n1Cc1ccccc1
Reaction time: 1 h
Yield: 69.8 %

Procedure:
To a solution of 3-benzyl-7-chloro-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-2-carbaldehyde (1.50 g, 5.21 mmol) in anhydrous CH2Cl2 (20 mL) at −76° C. under nitrogen was added dropwise cyclopropylmagnesium bromide (Boulder Scientific, 0.76 M, 20 mL, 15.2 mmol) in THF over 15 min. The reaction mixture was stirred at −70–50° C. for 1 h, quenched with aq. NH4Cl and 1 N HCl, and extracted with EtOAc (3×70 mL). The EtOAc layers were dried and concentrated. Purification of the crude product by flash column chromatography (SiO2, EtOAc/hexane 1.5:8.5 to 1:4) gave the title compound as a pale oil (1.2 g, 70%): 1H NMR (CDCl3) δ 7.24 (m, 2H), 7.19 (m, 1H), 7.09 (m, 2H), 7.00 (d, 1H, J=4.4 Hz), 6.44 (d, 1H, J=4.4 Hz), 5.33 (q, 2H, AB), 4.10 (t, 1H, J=7.15 Hz), 2.62 (d, 1H, J=7.7 Hz), 1.40 (m, 1H), 0.51 (m, 2H), 0.32 (m, 1H), 0.14 (m, 1H); 13C NMR (CDCl3) δ 154.3, 150.5, 136.1, 129.0, 127.8, 126.2, 117.8, 117.3, 110.2, 108.6, 72.76, 44.6, 15.5, 3.0; MS (ESI+) 330.10 (M++H), 352.13, 354.13 (M++Na).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH2:9]([C:13]1[NH:14][CH:15]=[C:16]([CH2:18][OH:19])[N:17]=1)[CH2:10][CH2:11][CH3:12]>C(OCC)(=O)C>[CH2:9]([C:13]1[NH:14][C:15]([Cl:1])=[C:16]([CH2:18][OH:19])[N:17]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCc1nc(CO)c[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Product: CCCCc1nc(CO)c(Cl)[nH]1
Reaction time: 8 h

Procedure:
9.52 g (0.071 mol) of N-chlorosuccinimide are introduced, at a temperature of between 0° and 5° C., into 10 g (0.065 mol) of 2-butylimidazole-4-methanol in suspension in 200 ml of ethyl acetate. The mixture is stirred overnight while maintaining this temperature. The solution is filtered and the solid is washed with 20 ml of ice-cold ethyl acetate, drained and washed with water in order to remove traces of succinimide and starting product, and then dried.
Reaction SMILES: [F:1][C:2]([F:16])([O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].[NH2:17][C:18]([CH3:34])([CH2:21][N:22]1[CH:30]=[C:29]2[C:24]([C:25]([Cl:33])=[C:26]([Cl:32])[CH:27]=[C:28]2[Cl:31])=[N:23]1)[C:19]#[N:20]>C1COCC1>[C:19]([C:18]([NH:17][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][C:7]([O:6][C:2]([F:16])([F:1])[CH:3]([F:5])[F:4])=[CH:8][CH:9]=1)([CH3:34])[CH2:21][N:22]1[CH:30]=[C:29]2[C:24]([C:25]([Cl:33])=[C:26]([Cl:32])[CH:27]=[C:28]2[Cl:31])=[N:23]1)#[N:20]
Reactant: CC(N)(C#N)Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1
Reactant: O=C(Cl)c1ccc(OC(F)(F)C(F)F)cc1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1ccc(OC(F)(F)C(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 4-(1,1,2,2-tetrafluoroethoxy)benzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,6,7-trichloro-2H-indazol-2-yl)propionitrile (0.075 mmole, described in Example 147) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (6 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=523, RT=0.73 min.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[C:12]([C:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=3)=[N:13][O:14][C:8]=2[C:7]=1[OH:21])=[O:5])C.[NH2:22][CH2:23][C:24]([OH:26])=[O:25].[O-]CC.[Na+].Cl>CN(C=O)C.O.CCOC(C)=O>[C:15]1([C:12]2[C:9]3[CH:10]=[N:11][C:6]([C:4]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:5])=[C:7]([OH:21])[C:8]=3[O:14][N:13]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2c(C3=CCCCC3)noc2c1O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)CNC(=O)c1ncc2c(C3=CCCCC3)noc2c1O
Temperature: 25 °C
Yield: 75.9 %

Procedure:
3-Cyclohex-1-enyl-7-hydroxy-isoxazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (77 mg, 0.27 mmol) was dissolved in 10 mL of DMF. Glycine (0.40 g, 5.35 mmol) and sodium ethoxide (0.27 g, 4.01 mmol) were added and the mixture was refluxed for 2 h. The mixture was cooled to room temperature and diluted with 60 mL of water. EtOAc (50 mL) was added and the resulting biphasic mixture was stirred vigorously as 4M hydrochloric acid was added dropwise until pH was 3. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. The solvent was evaporated and the solid residue was taken up in 50 mL of saturated sodium bicarbonate solution. The aqueous phase was washed with hexanes and EtOAc. The aqueous layer was then acidified to pH 2 by addition of concentrated hydrochloric acid and the resulting precipitate was isolated by filtration to give 65 mg of the title compound. MS: (+) m/z 318.26 (M+1).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[O:20][C:19]([C:21]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([N:30]3[CH2:35][CH2:34][CH:33]([C:36]([O:38]C(C)(C)C)=[O:37])[CH2:32][CH2:31]3)=[N:28][CH:29]=2)=[O:22])=[N:18][N:17]=1.[ClH:43]>C(Cl)Cl.O1CCOCC1>[ClH:43].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[O:20][C:19]([C:21]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([N:30]3[CH2:31][CH2:32][CH:33]([C:36]([OH:38])=[O:37])[CH2:34][CH2:35]3)=[N:28][CH:29]=2)=[O:22])=[N:18][N:17]=1
Reactant: CC(C)(C)OC(=O)C1CCN(c2ccc(NC(=O)c3nnc(Nc4ccccc4F)o3)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(N2CCC(C(=O)O)CC2)nc1)c1nnc(Nc2ccccc2F)o1
Yield: 42 %

Procedure:
TFA (0.307 mL; 4.0 mmol) was added to a suspension of tert-Butyl 1-{5-[({5-[(2-fluorophenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]pyridin-2-yl}piperidine-4-carboxylate (483 mg; 1.0 mmol) in DCM (5 mL). After 3 days more TFA was added in aliquots (0.31 mL) over 2 days then HCl (1 mL of a 4M solution in 1,4-dioxan) was added. After 24 h the mixture was filtered and the solid was washed with ether and dried under vacuum at 60° C. to give the title compound (193 mg, 42%) as a solid; 1H NMR δ1.55-1.74 (m, 2H), 1.88-2.06 (m, 2H), 2.56-2.69 (m, 1H), 2.69-2.81 (m, 1H), 3.18-3.35 (m, 2H), 4.17 (d, 2H), 7.13-7.22 (m, 1H), 7.24-7.31 (m, 1H), 7.31-7.37 (m, 1H), 7.44 (d, 1H), 7.98-8.09 (m, 1H), 8.19-8.28 (m, 1H), 8.51-8.59 (m, 1H), 10.87 (s, 1H), 11.37 (s, 1H); MS m/e MH+ 427.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH2:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.O=[C:10]1[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][C:17](OC)=[O:18])[CH2:11]1.O.C(O)(=O)C>C1(C)C=CC=CC=1>[CH:4]1[CH:3]=[CH:2][N:1]2[CH2:6][CH2:7][N:8]3[C:17](=[O:18])[CH2:16][CH:12]4[CH2:13][C:14]3([CH2:15][CH2:10][CH2:11]4)[C:5]=12
Reactant: NCCn1cccc1
Reactant: COC(=O)CC1CCCC(=O)C1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: O=C1CC2CCCC3(C2)c2cccn2CCN13

Procedure:
A solution of 1.3 g of 2-(1-pyrrolyl)-ethylamine, 2.0 g of methyl 3-oxocyclohexylacetate in 150 ml toluene is stirred and refluxed overnight using a Dean Stark water separator. The reaction is cooled and 7 ml glacial acetic acid is added. The solution is stirred and refluxed as before for 6 hours, cooled and the organic solvents are evaporated under reduced pressure. The residue is dissolved in ether and washed with ice cold 1N aqueous sodium hydroxide. The organic layer is separated, dried over magnesium sulfate, and filtered. The ether solution is evaporated under reduced pressure and the residue is crystallized from ether to give 5,6,10,11,12,13-hexahydro-10,13a-methano-13aH-pyrrolo[2',1':3,4]pyrazino[1,2-a]azocin-8(9H)-one, m.p. 130°-132°, the compound of formula II wherein R, R1R2 and R3 represent hydrogen.
Reaction SMILES: C(C(C1C=[CH:26][C:25]([NH2:28])=[CH:24]C=1)C(O)=O)(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.C1C=[CH:31][C:32]2[N:37](O)N=N[C:33]=2C=1.O.[CH3:40]N(C=O)C.C(Cl)Cl>>[CH3:26][CH:25]([CH3:24])[N:28]=[C:40]=[N:37][CH:32]([CH3:33])[CH3:31]
Reactant: On1nnc2ccccc21
Reactant: Nc1ccc(C(C(=O)O)C(=O)OCC2c3ccccc3-c3ccccc32)cc1
Reactant: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC(C)N=C=NC(C)C
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A solution of Fmoc-4-aminophenylacetic acid (0.098M), HOBt.H2O (0.12M) and DIC (0.2M) in 20% DMF/DCM was prepared. To this solution was added the Fmoc-deprotected Lanterns. The mixture was then gently agitated at room temperature for 21 h. At the completion of the reaction, the coupling solution was removed and the Lanterns washed with DMF (3×10 min), 50% DMF/DCM (3×10 min) and DCM (3×10 min). The Lanterns were air-dried overnight.
Reaction SMILES: [ClH:1].[CH3:2][CH:3]1[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5][N:4]1[C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17]>CO>[ClH:1].[CH3:2][CH:3]1[CH2:8][NH:7][CH2:6][CH2:5][N:4]1[C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17]
Reactant: CC(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)CC1C
Agent: Cl
Solvent: CO
Product: CC(C)OC(=O)N1CCNCC1C

Procedure:
Concentrated hydrochloric acid (6.0 mL) was added to a solution of 4-tert-butyl 1-isopropyl 2-methylpiperazine-1,4-dicarboxylate (4.2 g, 14.6 mmol) in methanol (250 mL) and allowed to stir at ambient temperature under N2 blanket for 3d. The solution was then evaporated to dryness and the resultant viscous yellow oil triturated in acetone to precipitate a fine white powder which was isolated by filtration, under N2 blanket, to afford 2.0 g. LRMS (ESI) m/z 187.0 [(M+H)]+, calc'd for C9H18N2O2: 186.26.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:9]=O.[S:11]1[CH2:15][C:14](=[O:16])[NH:13][C:12]1=[O:17]>C(O)C>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:9][N:13]1[C:14](=[O:16])[CH2:15][S:11][C:12]1=[O:17]
Reactant: O=C1CSC(=O)N1
Reactant: C=O
Reactant: Cc1ccccc1N
Solvent: CCO
Product: Cc1ccccc1NCN1C(=O)CSC1=O

Procedure:
A mixture of 10.7 g of o-toluidine, 3.3 g. of paraformaldehyde, and 11.7 g of 2,4-thiazolidinedione in 100 ml of absolute ethanol was refluxed 5 hrs under nitrogen atmosphere. On cooling, the resulting precipitate was filtered off to give 22.1 g of N-(2-methylphenylaminomethyl)-2,4-thiazolidinedione, mp 109°-111° C; identified by IR and NMR.
Reaction SMILES: [C:1]1([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[CH:17]=[CH2:18].[OH-].[Na+].O>C(O)C>[C:10]1([CH:9]([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:8])[CH2:18][CH2:17][C:16]([O:20][CH2:21][CH3:22])=[O:19])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C=CC(=O)OCC
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCC(C(=O)c1ccccc1)c1ccccc1
Reaction time: 2.5 h
Yield: 68.9 %

Procedure:
To a solution of 140 g (0.71 mol) of deoxybenzoin and 170 g (1.7 mol) of ethyl acrylate in 2 L of absolute ethanol at ambient temperature was added in portions 20 mL of 50% aqueous sodium hydroxide. An additional 170 g (1.7 mol) of ethyl acrylate was then added over a 15 min. period. The mixture was stirred vigorously for 2.5 h, poured into 1 L of water and extracted with 3×1 L of ether. The organic layers were combined, washed with water and brine, and dried over sodium sulfate. The filtrate was concentrated to near dryness, triturated with 1.5 L of pentane, filtered and the filtrate allowed to stand at -20° C. giving 145 g (69%) of ethyl 4,5-diphenyl-5-oxopentanoate as a white solid (top 45°-57° C.).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1>O1CCOCC1>[N:13]1([CH2:2][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: c1nc[nH]n1
Solvent: C1COCCO1
Product: c1ccc2c(CCn3cncn3)c[nH]c2c1

Procedure:
A solution of 3-(2-bromo-ethyl)-1H-indole (4.92 g, 22 mmol) and 1,2,4-triazole (3.03 g, 44 mmol) in abs. dioxane (50 ml) was stirred at 80° C. for 24 h. The solvent was then removed i. vac., CHCl3 (100 ml) was added to the residue and the mixture was washed twice with water. The organic phase was dried over Na2SO4 and concentrated i. vac. and the residue which remained was purified by flash chromatography with CHCl3/MeOH (50:1). Yield: 0.792 g (Ind-72, 17%), colourless oil