Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23]>CN(C=O)C>[C:14]1(=[O:23])[N:13]([CH2:12][CH2:11][CH2:10][CH2:9][O:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]12
Reactant: Oc1ccncc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCOc1ccncc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 17.8 %

Procedure:
To a solution of 4.76 g (50 mmol) of 4-hydroxypyridine and 15.52 g (55 mmol) of N-(4-bromobutyl)phthalimide in 80 ml of DMF was added 8.23 ml (5 mmol) of 1,8-diazabicyclo(5.4.0]-7-undecene. The mixture was stirred at room temperature for 7 hours. After the solvent was distilled off, the mixture was poured into water and extracted with ethyl acetate. The mixture was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 2.63 g of the desired compound (yield: 17.2%, colorless crystals). mp: 126°-127° C.
Reaction SMILES: Cl[C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([CH3:15])[C:5]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH2:19][CH:20]([CH2:22][CH2:23][CH3:24])[CH3:21]>C1C=CC=CC=1>[CH3:21][CH:20]([NH:19][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([S:11]([CH3:14])(=[O:13])=[O:12])=[C:4]([CH3:15])[C:3]=1[N+:16]([O-:18])=[O:17])[CH2:22][CH2:23][CH3:24]
Reactant: Cc1c(S(C)(=O)=O)cc([N+](=O)[O-])c(Cl)c1[N+](=O)[O-]
Reactant: CCCC(C)N
Solvent: c1ccccc1
Product: CCCC(C)Nc1c([N+](=O)[O-])cc(S(C)(=O)=O)c(C)c1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
A mixture of 3-chloro-6-(methylsulfonyl)-2,4-dinitrotoluene (10.0 g., 0.034 mole) and 2-aminopentane (6.1 g. 0.07 mole) is refluxed in benzene (75 ml.) for 4 hours. After standing overnight, the mixture is successively washed with dilute hydrochloric acid, water, a 5% aqueous potassium carbonate solution and finally water. The mixture is then dried over magnesium sulfate. Removal of the magnesium sulfate and solvent leaves the desired product as a yellow oil which readily crystallized on cooling. The crude product is recrystallized from ethanol to give 9.5 grams with m.p. 85°-88° C.
Reaction SMILES: [CH2:1]([N:3](CC)[CH2:4]C)C.[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19].C(Cl)(=O)C(C)(C)C.Cl.CNC>CN(C)C=O>[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([N:3]([CH3:4])[CH3:1])=[O:14])=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCN(CC)CC
Agent: CC(C)(C)C(=O)Cl
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reaction time: 0.25 h

Procedure:
Triethylamine (3.48 ml) was added to a solution containing 4-chloro-3-nitrobenzoic acid (5.04 g) in N,N-dimethylformamide (25 ml) while being cooled with ice, and then pivaloyl chloride (3.08 ml) was added thereto. The mixture was stirred for 15 minutes, and then dimethylamine hydrochloride (2.24 g) and triethylamine (3.83 ml) were added thereto. The reaction mixture was stirred for 15 minutes while being cooled with ice and futher stirred for 14 hours at room temperature, and then concentrated. The residue, with ethyl acetate added thereto, was washed with water, 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated, thereby yielding the entitled compound (4.85 g) as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:14][CH:13]3[N:15](C(O)=O)[CH:10]([CH2:11][CH2:12]3)[CH:9]=2)=[CH:4][CH:3]=1>C(O)(=O)C.O.[Zn]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:9][CH:10]3[NH:15][CH:13]([CH2:12][CH2:11]3)[CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)N1C2C=C(c3ccc(Cl)cc3)CC1CC2
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: Clc1ccc(C2=CC3CCC(C2)N3)cc1
Yield: 81.5 %

Procedure:
Racemic 3-(4-Chloro-phenyl)-8-aza-bicyclo[3.2.1]oct-2-ene-8-carboxylic acid #2,2,2-trichloro-ethyl ester (7.5 g, 18.98 mmol) in acetic acid (75 mL) and water (10 mL) was heated at 45° C. Zinc (16.63 g, 257.39 mmol) was added portionwise to the reaction over 1 hour. Mix was filtered through Celite and the filtrate was concentrated to a clear oil. The oil was dissolved in water (100 mL) adjusted to PH=12 with 1N sodium hydroxide and extracted with ethyl acetate (2×200 mL). The combined organic layer was washed with brine (100 mL), dried with magnesium sulfate and concentrated to yield racemic 3-(4-Chloro-phenyl)-8-aza-bicyclo[3.2.1]oct-2-ene (3.4 g, 81.5%) as a white solid with had the following properties: Mp 91-93° C.; 1H NMR CDCl3 δ: 7.30-7.21 (m, 4H), 6.41 (d, J=5.6 Hz, 1H), 3.85 (t, J=5.6 Hz, 1H), 3.80 (t, J=5.6 Hzm 1H), 2.80 (d, J=17.2 Hz, 1H), 2.17 (d, J=17.2 Hz, 1H), 2.11-1.69 (m, 3H), 1.66-1.57 (m, 1H). IR (KBr): 3965, 3887, 3721, 3664, 3477, 3304, 3237, 3081, 3048, 3020, 2966, 2928, 2882, 2835, 2710, 2675, 2595, 2495, 2425, 2396, 2362, 2314, 2104, 1967, 1935, 1913, 1894, 1847, 1791, 1707, 1630, 1589, 1563, 1494, 1466, 1446, 1428, 1403, 1380, 1360, 1341, 1307, 1279, 1249, 1239, 1221, 1190, 1151, 1092, 1068, 1030, 1008, 973, 948, 935, 916, 876, 850, 811, 755, 738, 726, 706, 672, 665, 631, 610, 554, 544, 524, 519, 469, 445, 433, 421, (cm−1). Analysis calculated for C13H14ClN.⅓ H2O: C, 69.18; H, 6.55; N, 6.21; Found: C, 69.42; H, 6.36; N, 6.15.
Reaction SMILES: [CH2:1]1[C:10]2[C:5]3=[C:6]([CH2:11][CH2:12][CH2:13][N:4]3[C:3](=[O:14])[CH2:2]1)[CH:7]=[CH:8][CH:9]=2.[Br:15]N1C(=O)CCC1=O.O.CC(C)=O.CCOCC>CN(C=O)C>[Br:15][C:8]1[CH:9]=[C:10]2[C:5]3=[C:6]([CH2:11][CH2:12][CH2:13][N:4]3[C:3](=[O:14])[CH2:2][CH2:1]2)[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CCc2cccc3c2N1CCC3
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CC(C)=O
Product: O=C1CCc2cc(Br)cc3c2N1CCC3
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 1,2,6,7-tetrahydro-5H-pyrido[3,2,1-ij]quinolin-3-one (9.1 g, 48.6 mmol) in 100 ml dry DMF was added dropwise a solution of N-bromosuccinimide (9.08 g, 51.0 mmol) in 150 ml dry DMF at 0° C. The mixture was stirred at 0° C. for 2 h, then 400 ml water was added and the solution was extracted with ethyl acetate (3×150 ml). The organic phase was washed with water (2×200 ml), then dried over MgSO4 and evaporated, affording a yellow solid, which was purified by crystallization from acetone/ether providing pure 9-bromo-1,2,6,7-tetrahydro-5H-pyrido[3,2,1-ij]quinolin-3-one (6.53, 24.5 mmol, 50%) as pale yellow needles.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][C:5]([OH:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9](NC)=[O:10]>ClC1C=CC=CC=1Cl>[CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][C:5]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:6][C:7]2[C:8](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:9](=[O:10])[O:23]1
Reactant: CNC(=O)c1ccccc1CC(O)(CCN(C)C)c1ccccc1
Solvent: Clc1ccccc1Cl
Product: CN(C)CCC1(c2ccccc2)Cc2ccccc2C(=O)O1

Procedure:
To a flask equipped with a stirrer, condenser and gas inlet tube maintained under a nitrogen atmosphere there is added at room temperature 16.3 g (0.05 mole) of 2-(β-[2-dimethylaminoethyl]-β-hydroxyphenethyl)-N-methylbenzamide and 170 ml of o-dichloro benzene. Stirring is initiated and the mixture is heated at reflux for 18 hours. The excess o-dichlorobenzene is then removed by distillation in vacuo and the resulting oil is crystallized from ether to give 3-[2-dimethylaminoethyl]-3,4-dihydro-3-phenylisocoumarin; m.p. 95.0°-95.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([N:13]1[CH2:20][CH:19]2[CH:15]([CH2:16][NH:17][CH2:18]2)[CH2:14]1)=[O:12].Cl[C:22]1[N:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([N:13]1[CH2:20][CH:19]2[CH:15]([CH2:16][N:17]([C:22]3[N:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]=3)[CH2:18]2)[CH2:14]1)=[O:12]
Reactant: COc1ccc(C(=O)N2CC3CNCC3C2)c(OC)c1
Reactant: Cc1ccnc(Cl)n1
Product: COc1ccc(C(=O)N2CC3CN(c4nccc(C)n4)CC3C2)c(OC)c1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 38 and 2-chloro-4-methylpyrimidine. MS (ESI): mass calculated for C20H24FN4O3, 368.43; m/z found 369.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:28][C:29]([NH:31][C:32](=[O:40])[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[S:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21](S(C)(=O)=O)=[CH:20][CH:19]=3)[S:17][C:10]=12.FC1C=C(N)C=CC=1OC1C=CN=C2C=C(C3C=CC(S(C)(=O)=O)=CC=3)SC=12.NC1C=CC(OC2C=CN=C3C=C(C4C=CC([N:90]5[CH2:95][CH2:94][N:93]([C:96]([O:98][C:99]([CH3:102])([CH3:101])[CH3:100])=[O:97])[CH2:92][CH2:91]5)=CC=4)SC=23)=C(F)C=1>>[F:1][C:2]1[CH:3]=[C:4]([NH:28][C:29]([NH:31][C:32](=[O:40])[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[S:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([N:90]4[CH2:91][CH2:92][N:93]([C:96]([O:98][C:99]([CH3:102])([CH3:101])[CH3:100])=[O:97])[CH2:94][CH2:95]4)=[CH:22][CH:23]=3)[S:17][C:10]=12
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cc4nccc(Oc5ccc(N)cc5F)c4s3)cc2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)cc1
Agent: CS(=O)(=O)c1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)cc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cc4nccc(Oc5ccc(NC(=S)NC(=O)Cc6ccccc6)cc5F)c4s3)cc2)CC1
Yield: 41 %

Procedure:
Following the procedure described above for the synthesis of compound 50 (scheme 10, example 55) but substituting amine 49 for the amine 157, title compound 158 was obtained in 41% yield. LRMS (M+1) 697.2 (100%).
Reaction SMILES: C(O)[C@H]1[O:7][C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8CO)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO.[OH:78][C:79]1[CH:84]=[C:83](O)[C:82]([C:86]([OH:88])=[O:87])=[CH:81][C:80]=1[CH:89]=[CH:90][C:91]([C:93]1[CH:98]=[CH:97][CH:96]=[CH:95][CH:94]=1)=[O:92]>C(O)[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO>[OH:78][C:79]1[CH:84]=[CH:83][C:82]([C:86]([OH:88])=[O:87])=[CH:81][C:80]=1[CH:89]=[CH:90][C:91]([C:93]1[CH:98]=[CH:97][C:96]([OH:7])=[CH:95][CH:94]=1)=[O:92]
Reactant: OC[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8CO)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO
Reactant: O=C(C=Cc1cc(C(=O)O)c(O)cc1O)c1ccccc1
Agent: OC[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO
Product: O=C(O)c1ccc(O)c(C=CC(=O)c2ccc(O)cc2)c1

Procedure:
2,4'-Dihydroxy-5-carboxychalcone is prepared in substantially the same manner as in Example 8, except that 4.5 g of the fixed α-cyclodextrin prepared in Example 10 is used as a catalyst instead of the fixed β-cyclodextrin. The recovery of the catalyst, the yield of and the selectivity for 2,4-dihydroxy-5-carboxychalcone are 100%, 53% on molar basis and 93%, respectively.
Reaction SMILES: [OH-].[Na+].[N+](C1C=CC(C([O:12][C@H:13]2[CH2:16][C@H:15]([CH2:17][CH2:18][O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:14]2)=O)=CC=1)([O-])=O.CC(O)=O>O1CCOCC1>[CH2:20]([O:19][CH2:18][CH2:17][C@H:15]1[CH2:14][C@H:13]([OH:12])[CH2:16]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O[C@H]1C[C@H](CCOCc2ccccc2)C1)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: O[C@H]1C[C@H](CCOCc2ccccc2)C1
Reaction time: 0.67 h
Yield: 97.4 %

Procedure:
Aqueous NaOH (0.4 mol/L, 52 mL, 20.8 mmol) was added to a stirred solution of trans-3-(benzyloxyethyl)cyclobutyl 4-nitrobenzoate (3.7 g, 10.4 mmol) in 80 mL 1,4-dioxane at ambient temperature. After 40 min, AcOH (0.9 mL, 15.4 mmol) was added drop by drop. After 5 min, the reaction mixture was concentrated by rotovap. The residue was partitioned between EtOAc (50 mL) and saturated NaHCO3 (2×50 mL). The organic phase was dried over MgSO4 and solvent evaporation gave light yellow oil (2.09 g, 97.5%). 1H NMR (CDCl3, 300 MHz): δ 1.71-1.78 (m, 2H), 1.94 (bs, 1H), 2.03-2.07 (m, 3H), 2.60-2.74 (m, 1H), 3.40-3.45 (t, J=6.9, 2H), 4.49 (s, 2H), 7.27-7.37 (m, 5H). 13C NMR (CDCl3, 75 MHz): δ 24.58, 36.11, 37.90, 39.95, 66.63, 69.17, 73.10, 127.65, 127.69, 128.45, 138.60.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:15][N:16](C)C=O>O.ClCCl>[CH3:1][N:2]([CH3:14])[C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[C:15]#[N:16]
Reactant: CN(C)C=O
Reactant: CN(C)c1cc(Br)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O
Product: CN(C)c1cc(C#N)cc(C(F)(F)F)c1

Procedure:
To a solution of 3-dimethylamino-5-trifluoromethylbromobenzene (7.3 g) in N,N-dimethylformamide (20 mL) is added cuprous cyanide (2.7 g) and the reaction heated at reflux for 12 hours. The reaction is diluted with water (40 mL) and dichloromethane is added. The dichloromethane fraction is washed with concentrated ammonium hydroxide, then water. The solution is dried over anhydrous magnesium sulfate, filtered and concentrated to give a yellow solid which is recrystallized from hexanes to give a yellow solid, (4.7 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]2[C:7]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][CH:18]=[C:17]4[C:13]=3[CH:14]=[C:15]([C:21]([OH:23])=O)[NH:16]4)=[CH:8][O:9][C:5]=2[CH:4]=1.Cl.Cl.Cl.[NH2:29][CH:30]1[CH2:35][CH2:34][N:33]([CH2:36][C@@H:37]([N:39]2[CH2:44][CH2:43][C@H:42]([OH:45])[C@@H:41]([CH3:46])[CH2:40]2)[CH3:38])[CH2:32][CH2:31]1>>[OH:45][C@H:42]1[CH2:43][CH2:44][N:39]([C@@H:37]([CH3:38])[CH2:36][N:33]2[CH2:32][CH2:31][CH:30]([NH:29][C:21]([C:15]3[NH:16][C:17]4[C:13]([CH:14]=3)=[C:12]([O:11][CH2:10][C:7]3[C:6]5[CH:24]=[CH:25][C:3]([O:2][CH3:1])=[CH:4][C:5]=5[O:9][CH:8]=3)[CH:20]=[CH:19][CH:18]=4)=[O:23])[CH2:35][CH2:34]2)[CH2:40][C@@H:41]1[CH3:46]
Reactant: C[C@H]1CN([C@@H](C)CN2CCC(N)CC2)CC[C@@H]1O
Reactant: COc1ccc2c(COc3cccc4[nH]c(C(=O)O)cc34)coc2c1
Agent: Cl
Product: COc1ccc2c(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@H](C)N6CC[C@H](O)[C@@H](C)C6)CC5)cc34)coc2c1

Procedure:
This compound is synthesized analogously to example 1 from 4-(6-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid, 120 (see example 86) and amine 56.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[Br:13][C:14]1[CH:15]=[C:16]([NH2:28])[C:17]([NH:20][CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:18][CH:19]=1>C1COCC1.C([O-])(O)=O.[Na+]>[Br:13][C:14]1[CH:19]=[CH:18][C:17]2[N:20]([CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[C:6](=[O:7])[NH:28][C:16]=2[CH:15]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(Br)ccc1NCCN1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(Br)ccc2n1CCN1CCCC1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
600 mg (3.70 mmol) CDI are added to a solution of 853 mg (3.00 mmol) 4-bromo-N1-(2-pyrrolidin-1-yl-ethyl)-benzene-1,2-diamine in 20 mL THF at RT. The reaction solution is heated to 40° C. and stirred for 30 min at this temperature. A further 600 mg (3.70 mmol) CDI are added and the reaction is stirred for a further 30 min at 40° C. The solution is diluted with semisaturated NaHCO3 solution and the aqueous phase is extracted twice with EtOAc. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. The residue is triturated with acetonitrile, the precipitate is filtered and dried in the air.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([C:26]3([C:29]([F:32])([F:31])[F:30])[CH2:28][CH2:27]3)=[CH:24][N:25]=[C:20]2[C@H:19]([NH:33]C(=O)OC(C)(C)C)[CH2:18][CH2:17]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([C:26]3([C:29]([F:32])([F:30])[F:31])[CH2:28][CH2:27]3)=[CH:24][N:25]=[C:20]2[C@H:19]([NH2:33])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C3(C(F)(F)F)CC3)cnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C3(C(F)(F)F)CC3)cnc21
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (2 mL) was added to a solution of tert-butyl {(6S,9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl)cyclopropyl]-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-yl}carbamate (170 mg, 0.361 mmol, described in Intermediate 8) in CH2Cl2 (2 mL). After 1 h, saturated NaHCO3 was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with saturated brine, dried over MgSO4, filtered and concentrated in vacuo to give the title compound. MS: m/z=372 (M+1).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:30])([CH3:29])[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]2[C:13]3[C@H:14]([CH2:27][OH:28])[CH2:15][C:16]4[CH:17]=[C:18]([O:25][CH3:26])[CH:19]=[CH:20][C:21]=4[C:22]=3[CH2:23][CH2:24][C@:8]12[CH3:9])([CH3:4])[CH3:3].N.[Li].[Cl-].[NH4+]>O1CCCC1.C(O)C>[CH3:4][C:2]([Si:5]([CH3:30])([CH3:29])[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:22]([CH2:23][CH2:24][C@:8]12[CH3:9])[C:21]1[CH2:20][CH:19]=[C:18]([O:25][CH3:26])[CH2:17][C:16]=1[CH2:15][C@H:14]3[CH2:27][OH:28])([CH3:1])[CH3:3]
Reactant: COc1ccc2c(c1)C[C@@H](CO)C1=C2CC[C@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]12
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: CCO
Solvent: C1CCOC1
Product: COC1=CCC2=C(C1)C[C@@H](CO)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]12
Temperature: -40 °C
Yield: 98 %

Procedure:
i)—A solution of (7α,17β)-17-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3-methoxyestra-1,3,5(10),8-tetraene-7-methanol [Kuenzer, H. et al, Tetrahedron Lett. 32, 743 (1991); 7.3 g] in dry tetrahydrofuran (100 ml) was added to liquid ammonia (400 ml), cooled at −40° C. Lithium granulate (3.58 g) was added and the reaction mixture was stirred at reflux temperature for 1 h. Ethanol (22.1 ml) was added carefully and the mixture was stirred for 30 min. Solid ammonium chloride was added and the ammonia was allowed to evaporate. Water was added and the product was extracted into ethyl acetate. The combined organic phases were washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure, to give (7α,17β)-17-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3-methoxyestra-2,5(10)-diene-7-methanol (7.22 g). The product was used in the following step without further purification.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[N:12]=[CH:13][C:14]2[CH2:20][N:19]([C:21]([O:23][CH2:24][CH2:25][CH2:26][C:27]#[N:28])=[O:22])[CH2:18][CH2:17][C:15]=2[N:16]=1.[N:29]([Si](C)(C)C)=[N+:30]=[N-:31].C([Sn](CCCC)=O)CCC>C1(C)C=CC=CC=1.ClCCl>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[N:12]=[CH:13][C:14]2[CH2:20][N:19]([C:21]([O:23][CH2:24][CH2:25][CH2:26][C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[O:22])[CH2:18][CH2:17][C:15]=2[N:16]=1
Reactant: N#CCCCOC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(OCCCc1nnn[nH]1)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Temperature: 25 °C
Yield: 40.9 %

Procedure:
Heat a solution of 3-cyanopropyl 2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (0.24 g; 1.0 equiv; 0.64 mmoles), azidotrimethylsilane (0.85 mL; 10 equiv; 6.38 mmoles) and dibutyloxostannane (0.040 g; 0.25 equiv; 0.16 mmoles) in toluene (5 mL) to 100° C. for 24 hours, then cool to ambient temperature and concentrate. Purify the crude material by reverse phase chromatography to afford impure product. Dissolve the impure product in 50 mL dichloromethane and wash with saturated sodium bicarbonate, and further extract the aqueous layer 2× dichloromethane. Dry the combined organic extracts over sodium sulfate, filter, and concentrate to afford 3-(1H-tetrazol-5-yl)propyl 2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (0.110 g; 41%) as a yellow solid: MS (m/z): 421 (M+1).
Reaction SMILES: [S:1]([C:5]([C:8]([C:11]([C:14]([F:17])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([O-:4])(=[O:3])=[O:2].[OH:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([S+:26]([CH3:28])[CH3:27])=[CH:21][C:20]=1[CH3:29].C(=O)([O-])[O-].[K+].[K+].[C:36](OC(=O)C)(=[O:38])[CH3:37]>CC(C)=O>[S:1]([C:5]([C:8]([C:11]([C:14]([F:15])([F:16])[F:17])([F:12])[F:13])([F:10])[F:9])([F:7])[F:6])([O-:4])(=[O:3])=[O:2].[C:36]([O:18][C:19]1[C:20]([CH3:29])=[CH:21][C:22]([S+:26]([CH3:27])[CH3:28])=[CH:23][C:24]=1[CH3:25])(=[O:38])[CH3:37]
Reactant: Cc1cc([S+](C)C)cc(C)c1O
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Oc1c(C)cc([S+](C)C)cc1C
Reaction time: 4 h

Procedure:
20.0 g of 4-Hydroxy-3,5-dimethyl phenyl dimethyl sulphonium nonaflate was taken in a round bottom flask, 50 ml acetone and 5.73 g of potassium carbonate were added and then 4.23 g of acetic anhydride was added dropwise at room temperature. The resulting mixture was stirred for 4 hours. The solution was then extracted with chloroform, washed with water, dried over sodium sulphate and filtered. The solution was concentrated and drowned into ether; a precipitate was formed, filtered and dried in the vacuum dryer at less than 40° C., yielding 4-acetoxy-3,5-dimethyl phenyl dimethyl sulphonium nonaflate, 15.0 g (70%). The solid product gave the following analytical results: 1H NMR (DMSO-d6), 2.35 (s, 6H, 2CH3); 2.45 (s, 3h, CH3); 3.5 (s, 6H, 2CH3); 7.80 (s, 2H, aromatic), mp 168° C.
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:17])[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([C:12]1[NH:13][CH:14]=[CH:15][N:16]=1)=[O:11].S([O-])([O-])(=O)=S.[Na+].[Na+].C[N:26](C=O)C>>[NH2:26][N:16]1[CH:15]=[CH:14][N:13]=[C:12]1[C:10]([NH:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH3:17])=[O:11]
Reactant: CN(C)C=O
Reactant: Cc1ccccc1NC(=O)c1ncc[nH]1
Agent: O=S([O-])([O-])=S
Agent: [H-]
Agent: [Na+]
Product: Cc1ccccc1NC(=O)c1nccn1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
240 mg (6.02 mmol) of sodium hydride (60% dispersion in mineral oil) were added to a 0° C. cooled solution of N-o-tolyl-1H-imidazole-2-carboxamide (0.93 g, 4.63 mmol) in DMF (120 mL). The mixture was stirred at 0° C. for 30 minutes and DPPONH2 (1.51 g, 6.49 mmol, available from Sigma Aldrich®, cat. no. 5994-87-6) was added portionwise. The mixture was stirred at room temperature for 2 hours and then it was poured into 200 mL of a saturated aqueous solution of sodium thiosulphate and extracted with ethyl acetate. The combined organic layer was dried over sodium sulphate, filtered and concentrated. The crude product was purified by flash chromatography (20% to 50% AcOEt/Hexanes) to yield 0.55 g (55%) of the title compound as a beige solid.