Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:11][C:10]3[CH:22]=[CH:23][CH:24]=[N:25][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C:38](Cl)=[O:39].C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[CH2:15]([C:12]1[C:13](=[O:14])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:38]([C:34]3[O:33][CH:37]=[CH:36][CH:35]=3)=[O:39])[CH:3]=2)[C:9]2[N:25]=[CH:24][CH:23]=[CH:22][C:10]=2[N:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Reactant: O=C(Cl)c1ccco1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1)c1ccco1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 4-(3-aminophenyl)-2-benzyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (150 mg) and triethylamine (0.1 ml) in dichloromethane (4 ml) was added 2-furoyl chloride (0.05 ml). The mixture was stirred at room temperature for 20 minutes, then poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was crystallized from ethanol to give 2-benzyl-4-[3-(2-furoylamino)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (145 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[C:6]([CH2:8]Br)[CH:7]=1.[OH:17][CH2:18][C:19]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.[H-].[Na+]>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][O:17][CH2:18][C:19]2([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Reactant: Fc1ccc(-c2cc(Br)cc(CBr)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc(-c3ccc(F)cc3)c2)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Bromo-5-(bromomethyl)-4′-fluorobiphenyl (398 mg, 1.16 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (280 mg, 0.96 mmol) were combined in dimethylformamide (5 mL) and cooled to 0° C. The reaction was treated with sodium hydride (46 mg, 1.92 mmol), stirred at 0° C. for 1 h, and at room temperature for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (20% ethyl acetate/hexanes) gave 470 mg (73%). 1H-NMR (CDCl3, 500 MHz) δ 7.51 (s, 1H), 7.28-7.42 (m, 6H), 7.19-7.23 (m, 2H), 7.06-7.14 (m, 3H), 4.34 (s, 2H), 3.69-3.74 (m, 2H), 3.40 (s, 2H), 2.98-3.06 (m, 2H), 2.14-2.19 (m, 2H), 1.81-1.90 (m, 2H), 1.41 (s, 9H). Mass spec.: 556.37 (MH)+.
Reaction SMILES: [BH4-].[Na+].II.[C:5]([C:8]1[CH:9]=[CH:10][C:11]2[C:17](=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:16]3[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=3[CH2:14][O:13][C:12]=2[CH:28]=1)(O)=[O:6]>C1COCC1.C(OCC)(=O)C>[OH:6][CH2:5][C:8]1[CH:9]=[CH:10][C:11]2[C:17](=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:16]3[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=3[CH2:14][O:13][C:12]=2[CH:28]=1
Reactant: CCOC(=O)C=C1c2ccccc2COc2cc(C(=O)O)ccc21
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C=C1c2ccccc2COc2cc(CO)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
Sodium borohydride (2.22 g) was dissolved in 300 ml of THF, and 7.45 g of iodine was added to the solution under ice cooling. Then, 300 ml of a solution of 7.63 g of Compound 1-a in THF was added under the same conditions and the mixture was stirred at room temperature overnight, followed by addition of ice chips. The mixture was then diluted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: chloroform] to give 6.58 g (90.2%) of the product as a colorless oily substance.
Reaction SMILES: C(O)(=O)C.C(=O)([O-])[O-].[K+:9].[K+].[C:11]([O:22]C1C=CC=CC=1)(=[O:21])[C:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:13]>CC(C)=O.O>[C:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:13])[C:11]([O-:22])=[O:21].[K+:9]
Reactant: O=C(Oc1ccccc1)C(=O)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: O=C([O-])C(=O)Oc1ccccc1
Reaction time: 4 h
Yield: 173.3 %

Procedure:
In a 1,000 mL-volume three-necked flask, 27.3 g of diphenyl oxalate was dissolved in 600 mL of acetone. In the solution, an aqueous solution of 6.76 g of acetic acid and 7.77 g of potassium carbonate in 25 mL of water was dropwise added under stirring for 4 hours. The mixture was then stirred for 2 hours, and the produced precipitate was collected on a filter by suction. The collected precipitate was washed with acetone and dried under reduced pressure to give 19.9 g of potassium phenyl oxalate. These procedures were performed at room temperature.
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[C:9]([I:10])[N:4]2[N:3]=1.[C:11]([NH:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)(=[O:13])[CH3:12].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[I:10][C:9]1[N:4]2[C:5]([S:6][C:2]([C:19]3[CH:20]=[C:15]([NH:14][C:11](=[O:13])[CH3:12])[CH:16]=[CH:17][CH:18]=3)=[N:3]2)=[N:7][CH:8]=1
Reactant: Brc1nn2c(I)cnc2s1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(-c2nn3c(I)cnc3s2)c1
Temperature: 110 °C

Procedure:
A mixture of 2-bromo-5-iodoimidazo[2,1-b][1,3,4]thiadiazole (0.127 g, 0.4 mmol, 1 eq), 3-acetamidobenzeneboronic acid (0.091 g, 1.3 equiv, 1.3 eq), dichlorobis(triphenylphosphine)palladium(II) (0.055 g, 02 eq) and 2M aq Na2CO3 (1.1 ml) in dioxane (5 mL) was heated at 110° C. for 3 h. The solvent was removed under reduced pressure, redissolved in ethylacetate and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated. The residue (0.167 g) was used in the next step of the synthesis without further purification. HPLC-MS (10-95% B in 4 min at 0.5 mL+2 min 100% B, flow 0.8 mL/min, 50° C.): tR=4.03 min, [M+H]+ m/z 385.1.
Reaction SMILES: I[C:2]1[C:3]([CH3:13])=[N:4][N:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=1.[N:14]1[C:23]2[CH:22]([C:24](=O)C)CCCC=2C=CC=1.C1(N)CC1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O.[Cu]Br>[CH:23]1([NH:14][C:2]2[C:3]([CH3:13])=[N:4][N:5]([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=2)[CH2:22][CH2:24]1
Reactant: CC(=O)C1CCCc2cccnc21
Reactant: Cc1nn(-c2cccnc2)cc1I
Agent: [Cu]Br
Agent: NC1CC1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nn(-c2cccnc2)cc1NC1CC1
Temperature: 35 °C
Reaction time: 48 h
Yield: 89.5 %

Procedure:
To a solution of 3-(4-iodo-3-methyl-1H-pyrazol-1-yl)pyridine (2.0 g, 7.02 mmol) in dimethylsulfoxide (7.02 ml) was added 1-(5,6,7,8-tetrahydroquinolin-8-yl)ethanone (0.246 g, 1.403 mmol), cyclopropanamine (0.486 ml, 7.02 mmol), cesium carbonate (6.86 g, 21.05 mmol) and copper(I) bromide (0.101 g, 0.702 mmol). The reaction mixture was stirred at 35° C. for 2 days. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organics were washed with brine, concentrated and chromatographed (0-100% ethyl acetate/hexanes) to give N-cyclopropyl-3-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine (269 mg, 1.255 mmol, 17.90%) as a yellow solid: mp 104.0-107.0° C.; 1H NMR (400 MHz, CDCl3) δ 8.89 (dd, J=2.7, 0.5 Hz, 1H), 8.41 (dd, J=4.7, 1.4 Hz, 1H), 7.96 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.51 (s, 1H), 7.33 (ddd, J=8.3, 4.7, 0.7 Hz, 1H), 3.42 (s, 1H), 2.53-2.42 (m, 1H), 2.22 (s, 3H), 0.72-0.65 (m, 2H), 0.60-0.53 (m, 2H); ESIMS m/z 215 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:5]=[CH:6][CH:7]=1.O[CH2:17][CH2:18][CH2:19][CH:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22].N(C(OCC)=O)=NC(OCC)=O.C1(O)C=CC=CC=1>O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH2:17][CH2:18][CH2:19][CH:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCOC(=O)C(CCCO)C(=O)OCC
Reactant: CCCCCCC#Cc1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Oc1ccccc1
Solvent: C1CCOC1
Product: CCCCCCC#Cc1cccc(OCCCC(C(=O)OCC)C(=O)OCC)c1
Temperature: 10 °C
Yield: 19 %

Procedure:
1-(3-Hydroxyphenyl)-oct-1-yne, (2.20 g, 0.01M) and diethyl 2-(3-hydroxypropyl)propane-1,3-dioate [2.40 g, 0.01M, (prepared by the method of A.G. Just et al, Tet. Letts., 3645-3647, (1979)] were dissolved in dry tetrahydrofuran, (50 ml) and triphenylphosphine, (4.20 g, 0.016M), added. The solution was stirred at 10° C. and diethyl azodicarboxylate, (2.80 g, 0.016M), added dropwise. The reaction was stirred for 0.5 h after which time TLC showed some unreacted phenol remaining. Further aliquots of the alcohol, (2.40 g, 0.01M), triphenylphosphine, (4.20 g, 0.016M) and dietyl azodicarboxylate (2.80 g, 0.016M) were added and the reaction stirred for 0.5 h. Evaporation of the solvent in vacuo gave a red oil which was purified by chromatography on silica gel eluting with dichloromethane→chloroform, to yield 0.770 g (19%) of the title compound as a colourless oil. νmax (film 1580, 1600, 1610, 1740, 1758, 2225 (weak) cm-1 ; δ(CDCl3) 0.87 (3H, distorted t, terminal CH3), 1.26 (6H, t, J 7 Hz, 2×ester CH3), 1.33 (8H, m, alkylene chain), 1.93 (4H, m, OCH2CH2CH2), 2.34 (2H, t, J 6 Hz, acetylenic CH2), 3.37 (1H, t, J 7 Hz, CH), 3.91 (2H, t, J 6 Hz, OCH2), 4.16 (4H, q, J 7 Hz, 2×ester CH2), 7.00 (4H, m, aromatics).
Reaction SMILES: CN(C1C=CC=CN=1)C.[C:10]1([N:16]=[C:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH2:19][C@@H:20]1[C:56]([CH3:58])([CH3:57])[C@H:55]2[C@@:23]3([O:51][C:27]4[C:28]5[CH2:29][N:30]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:31](=[O:43])[C:32]=5[CH:33]=[C:34]([O:35][CH2:36][C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[C:26]=4[CH2:25][C@:24]3([CH3:60])[C@@H:52]([CH3:59])[CH2:53][CH2:54]2)[CH2:22][CH2:21]1>C1COCC1>[CH2:36]([O:35][C:34]1[C:26]2[CH2:25][C@:24]3([CH3:60])[C@@H:52]([CH3:59])[CH2:53][CH2:54][C@H:55]4[C:56]([CH3:58])([CH3:57])[C@@H:20]([NH:19][C:17]([NH:16][C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=5)=[O:18])[CH2:21][CH2:22][C@@:23]34[O:51][C:27]=2[C:28]2[CH2:29][N:30]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:31](=[O:43])[C:32]=2[CH:33]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@@H](N)CC[C@]23Oc2c(c(OCc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Reactant: O=C=Nc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: C[C@H]1CC[C@H]2C(C)(C)[C@@H](NC(=O)Nc3ccccc3)CC[C@]23Oc2c(c(OCc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
Under nitrogen, 2 mg (0.017 mmol) of dimethylaminopyridine and 12 μl (0.11 mmol) of phenyl isocyanate were added to a solution of Compound (45a) (50 mg, 0.087 mmol) in 2.0 ml of dry THF, and the mixture stirred at room temperature for 30 min. The reaction mixture was then concentrated under reduced pressure. The residue was purified by a preparative thin layer chromatography (Merck, Kieselgel 60 F254, 0.5 mm; chloroform:methanol=40:1) to give 49 mg (81%) of Compound (45e).
Reaction SMILES: [CH2:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[S:6]([C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)=[CH:13][CH:14]=1)(=[O:8])=[O:7])[CH3:28]
Reactant: CCCCNS(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: CCOC(=O)CBr
Product: CCCCN(CC(=O)OCC)S(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared with N-butyl-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide and ethyl bromoacetate according to the procedure of Intermediate 2 as a yellow oil; 1H NMR (CDCl3) δ 0.88 (t, J=7.29 Hz, 3H), 1.23 (t, J=7.11 Hz, 3H), 1.19-1.35 (m, 2H),-1.48-1.56 (m, 2H), 2.58 (t, J=6.18 Hz, 4H), 3.20 (t, J=7.47 Hz, 2H), 3.74 (t, J=6.09 Hz, 4H), 4.03 (s, 2H), 4.13 (q, J=7.14 Hz, 2H), 6.89-6.95 (m, 2H), 7.72-7.78 (m, 2H); MS (ES) m/z 397.2 (MH+); HRMS for C19H28N2O5S: 397.1791
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>O1CCOCC1>[N:14]1([C:2]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: C1COCCN1
Solvent: C1COCCO1
Product: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of 2-fluoro-5-nitrobenzoic acid (4.86 g, 26.2 mmol) in dioxane (50 ml) was added morpholine (11.5 mL). The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo. The residue was dissolved in water, and the mixture was acidified with HCl 2N. The solid was filtered, washed with water and dried to provide the title compound (6.2 g, 93%) as a yellow solid, MS (m/e): 251.2 (MH−, 100%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]([CH3:25])=[C:16]([CH2:18][CH2:19]OS(C)(=O)=O)[N:17]=2)=[CH:9][CH:8]=1>C1COCC1>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]([CH3:25])=[C:16]([CH2:18][CH2:19][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[N:17]=2)=[CH:9][CH:8]=1
Reactant: CCNCC
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCOS(C)(=O)=O
Solvent: C1CCOC1
Product: CCN(CC)CCc1nc(-c2ccc(Br)cc2)oc1C
Temperature: 60 °C
Yield: 66.6 %

Procedure:
Add diethyl amine (0.488 g, 6.68 mmol) to a solution of methanesulfonic acid 2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl ester (See Intermediate 13) (0.240 g, 0.668 mmol) in anhydrous THF (5 mL) in a sealed tube, and heat at 60° C. overnight. Add dichloromethane and wash the crude organic layer with saturated sodium chloride solution. Dry the organic extracts over Na2SO4, filter, and concentrate. Purify on silica gel eluting with 5% anmioniated methanol in dichloromethane to give {2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl}-diethyl-amine (0.150 g, 67%): MS (nme): 337 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[N:11][C:12]([CH:15]2[CH2:17][CH2:16]2)=[N:13][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[CH:15]1([C:12]2[N:13]=[CH:14][C:9]([OH:8])=[CH:10][N:11]=2)[CH2:17][CH2:16]1
Reactant: c1ccc(COc2cnc(C3CC3)nc2)cc1
Agent: [Pd]
Solvent: CO
Product: Oc1cnc(C2CC2)nc1
Yield: 53 %

Procedure:
5-(Benzyloxy)-2-cyclopropylpyrimidine (4.0 g, 18 mmol) was dissolved in MeOH (100 mL) and 10% palladium on carbon (0.170 g) was added. The mixture was hydrogenated at ambient temperature and 1.013 bar pressure overnight. Filtration and concentration gave a crude product that was filtered through a short silica gel column using 5% MeOH-EtOAc as eluent. Evaporation of the solvent gave 1.3 g (54% yield) of the subtitle compound as a colourless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.CN(C=O)C.[H-].[Na+].Cl.[N:19]1[CH:24]=[CH:23][C:22]([CH2:25]Cl)=[CH:21][CH:20]=1>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C:22]3[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=3)[CH:9]=[CH:10][C:3]=12
Reactant: ClCc1ccncc1
Reactant: Brc1ccnc2[nH]ccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1ccnc2c1ccn2Cc1ccncc1
Temperature: -15 °C
Reaction time: 0.42 h

Procedure:
A 250-mL argon-purged round-bottomed flask equipped with a magnetic stirrer is charged with 4-Bromo-1H-pyrrolo[2,3-b]pyridine (0.70 g, 3.55 mmol) and DMF (25 mL) and the solution is cooled to −15° C. A 60% dispersion of sodium hydride in mineral oil (183 mg, 4.58 mmol) is then added and the reaction stirred at −15° C. for 25 min. The reaction is then charged with 4-picolylchloride hydrochloride (376 mg, 2.29 mmol) and stirred at −15° C. for a further 5 min. After such time the cooling bath is removed and the reaction is stirred for 30 min at ambient temperature. Additional 4-picolylchloride hydrochloride (117 mg, 0.71 mmol) and a 60% dispersion of sodium hydride in mineral oil (28 mg, 0.71 mmol) are then added and the reaction is stirred at ambient temperature for a further 30 min. The reaction is then poured into ethyl acetate (100 mL) and the mixture is washed with 3% aqueous sodium bicarbonate (1×100 mL), water (2×100 mL) and brine (1×100 mL). The organic layer is separated, dried over sodium sulfate and concentrated in vacuo to provide a residue, which is then purified by flash chromatography to afford 1b as a yellow solid.
Reaction SMILES: C(O)(=O)C[C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].P(=O)(O)(O)O>>[C:5]([OH:7])(=[O:6])[CH:3]([CH2:8][C:9]([OH:11])=[O:10])[OH:4]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=P(O)(O)O
Product: O=C(O)CC(O)C(=O)O

Procedure:
5 pounds of citric acid; 4 pounds of Red Punch 586323 CE, available from Premium Ingredients, Franklin Park, Ill.; 8 pounds of Tropical Fruit 597540 C, available from Premium Ingredients, Franklin Park, Ill.; 8 pounds of Raspberry Flavor 01-EF956, available from Western Flavors and Fragrances, Livermore, Calif., may be added. The combined admixture may be mixed for 2 minutes, and the pH may be checked and adjusted if necessary with phosphoric acid to the desired target pH of about 2.8-3.4, usually about pH 3.1.
Reaction SMILES: C[N:2](C)/[C:3](=[N:5]/[C:6]([C:8]1[N:17]=[C:16]2[N:10]([CH2:11][CH2:12][O:13][C:14]3[CH:21]=[C:20]([Br:22])[CH:19]=[CH:18][C:15]=32)[CH:9]=1)=O)/[CH3:4].Cl.[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[NH:33]N>C(O)(=O)C>[Br:22][C:20]1[CH:19]=[CH:18][C:15]2[C:16]3[N:10]([CH2:11][CH2:12][O:13][C:14]=2[CH:21]=1)[CH:9]=[C:8]([C:6]1[N:33]([C:27]2[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=2[F:25])[N:2]=[C:3]([CH3:4])[N:5]=1)[N:17]=3
Reactant: C/C(=N\C(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2)N(C)C
Reactant: NNc1ccc(F)cc1F
Agent: Cl
Solvent: CC(=O)O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(-c2ccc(F)cc2F)n1
Temperature: 95 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid [1-dimethylamino-eth-(E)-ylidene]-amide (0.0162 mol) was dissolved in Acetic acid (50 mL). 2,4-Difluorophenylhydrazine hydrochloride (3.52 g, 0.0195 mol) was added and the reaction was stirred at 95° C. overnight. The acetic acid was removed in vacuo. The crude was loaded as a solid onto silica gel and purified by flash chromatography (4-10% methanol in methylene chloride) to afford 3.662 g 8-Bromo-2-[2-(2,4-difluoro-phenyl)-5-methyl-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene as an orange solid. MS (ESI+) 458.0/460.0
Reaction SMILES: Cl.[C:2](Cl)(=O)[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.I.[CH:12]1([NH:15][C:16](=[N:19][NH2:20])[NH:17][CH3:18])[CH2:14][CH2:13]1.O>N1C=CC=CC=1>[CH:12]1([NH:15][C:16]2[N:17]([CH3:18])[C:2]([C:3]3[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=3)=[N:20][N:19]=2)[CH2:14][CH2:13]1
Reactant: O=C(Cl)c1ccncc1
Reactant: CNC(=NN)NC1CC1
Agent: Cl
Agent: I
Solvent: O
Solvent: c1ccncc1
Product: Cn1c(NC2CC2)nnc1-c1ccncc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Isonicotinoyl chloride hydrochloride (630 mg, 3.5 mmol) was added to N-cyclopropyl-N′-methylcarbonohydrazonic diamide hydroiodide (900 mg 3.5 mmol) in pyridine (10 ml) and the mixture was stirred at r.t. for 2 h. The mixture was the heated to 160° C. under microwave irradiation for 10 min. Water (50 ml) was added and the mixture was extracted with DCM. The pooled organic phases were dried and concentrated and the desired product was obtained by prep. HPLC. LCMS (M++1) 216
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:5]2[C:14]([CH3:21])=[C:15]([NH2:20])[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]=2[O:3]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[C:28](Cl)=[O:29]>C(OCC)(=O)C.CCCCCC>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[C:28]([NH:20][C:15]1[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]2[O:3][C:2]([CH3:22])([CH3:1])[CH:6]([C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=3)[C:5]=2[C:14]=1[CH3:21])=[O:29]
Reactant: Cc1ccc(C2c3c(C)c(N)c(C)c(C)c3OC2(C)C)cc1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(C)cc2)C(C)(C)O3)cc1OC
Yield: 90 %

Procedure:
By using 2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine and 3,4-dimethoxybenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 90%. Melting point: 169-171° C. (Ethyl acetate-hexane)
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:47]=[CH:48][CH:49]=[CH:50][C:4]=2[NH:3]1.[CH3:51][O:52][CH2:53][CH2:54]O>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=3)[C:19]([N:21]3[CH2:22][CH2:23][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([O:36][CH2:54][CH2:53][O:52][CH3:51])=[O:35])[CH2:29][CH2:28]4)[CH2:25][CH2:26]3)=[O:20])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:47]=[CH:48][CH:49]=[CH:50][C:4]=2[NH:3]1
Reactant: COCCO
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)O)CC3)CC2)cc(C)c1O
Product: COCCOC(=O)CN1CCC(C2CCN(C(=O)[C@@H](Cc3cc(C)c(O)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1

Procedure:
Prepared analogously to Example 3c from 80 mg (0.12 mmol) (R)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 18 μL (0.23 mmol) 2-methoxy-ethanol.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11](/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:12][NH:13]2)C1C=CC=CC=1>C(O)C.[C].[Pd]>[OH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:12][NH:13]2
Reactant: C(=C/c1c[nH]c2cccc(OCc3ccccc3)c12)\c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Oc1cccc2[nH]cc(CCc3ccccc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 4-benzyloxy-3-[(E)-2-phenylvinyl]indole (0.1 g) in ethanol (5 mL) was added 10% palladium-carbon powder (25 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on aminopropylated silica gel (eluent: n-hexane/ethyl acetate=3/1) to give the title compound (70 mg).