Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][C:14]([OH:21])([C:17]([F:20])([F:19])[F:18])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CCO.[Pd]>[F:20][C:17]([F:18])([F:19])[C:14]1([OH:21])[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1
Reactant: O=C(OCc1ccccc1)N1CCC(O)(C(F)(F)F)CC1
Agent: [Pd]
Solvent: CCO
Product: OC1(C(F)(F)F)CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
In a round-bottomed flask, 4-hydroxy-4-trifluoromethyl-piperidine-1-carboxylic acid benzyl ester (0.82 g, 2.7 mmol) was dissolved in EtOH (5 mL). 10% Palladium on carbon (Degussa type, 82 mg) was added and the flask was evacuated, flushed with argon, evacuated and flushed with hydrogen. The reaction mixture was stirred under hydrogen atmosphere (balloon) at room temperature overnight then filtered over Celite and rinsed with MeOH. The filtrate was concentrated to afford 0.44 g (97%) of 4-trifluoromethyl-piperidin-4-ol as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[CH2:9][C:8]12[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:4].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:16]=1)[CH2:9][C:8]12[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)C1(CCCC1)CC(c1cccc(Br)c1)N2
Reactant: C1COCCN1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: COC(=O)c1ccc2c(c1)C1(CCCC1)CC(c1cccc(N3CCOCC3)c1)N2
Temperature: 25 °C
Yield: 79.9 %

Procedure:
A mixture solution of 2′-(3-bromo-phenyl)-2′,3′-dihydro-1′H-spiro[cyclopentane-1,4′-quinoline]-6′-carboxylic acid methyl ester (600 mg, 1.5 mmol), morpholine (2.6 mL, 29.4 mmol), copper(I) iodide (340 mg, 1.8 mmol), N,N-dimethylglycine hydrochloride (340 mg, 2.4 mmol), and potassium carbonate (1.2 g, 9.0 mmol) in dimethyl sulfoxide (6.5 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature. The reaction mixture was extracted with ethyl acetate (200 mL×2), washed with saturated aqueous ammonium chloride solution (50 mL×3) and brine (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 30-50% ethyl acetate in petroleum ether) to afford 2′-(3-morpholinophenyl)-2′,3′-dihydro-1′H-spiro[cyclopentane-1,4′-quinoline]-6′-carboxylic acid methyl ester (487.2 mg, 80%) as a white solid: MS (ESI) M+1=407.0.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:9]([OH:11])=O)=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[NH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(Cl)Cl>[OH:19][CH:16]1[CH2:17][CH2:18][CH:13]([NH:12][C:9]([C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][NH:7][N:6]=2)=[O:11])[CH2:14][CH2:15]1
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NC1CCC(O)CC1)c1n[nH]cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.2 %

Procedure:
A mixture of 4-nitro-3-pyrazolecarboxylic acid (4.98 g, 31.7 mmol), trans 4-aminocyclohexanol (3.65 g, 31.7 mmol), EDAC (6.68 g, 34.8 mmol) and HOBt (4.7 g, 34.8 mmol) in DMF (120 ml) was stirred at ambient temperature for 16 hours. The mixture was reduced in vacuo, the residue taken up in CH2Cl2 and washed successively with 5% citric acid, saturated aqueous sodium bicarbonate, water and brine. The product was found to be mainly in the citric acid wash, which was basified and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and evaporated to give a white solid, which was triturated with CHCl3 to give 1.95 g of 4-nitro-1H-pyrazole-3-carboxylic acid 4-hydroxy-cyclohexylamide. (LC/MS: Rt 1.62, [M+H]+ 255).
Reaction SMILES: C(O)=O.[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][CH:14]([NH:29]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:15][NH:16][C:17](=[O:28])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])=[CH:5]1>C(Cl)Cl>[NH2:29][CH:14]([CH2:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][CH:5]=1)[CH2:15][NH:16][C:17](=[O:28])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27]
Reactant: COc1ccccc1CCC(=O)NCC(Cc1c[nH]c2ccccc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=CO
Product: COc1ccccc1CCC(=O)NCC(N)Cc1c[nH]c2ccccc12
Reaction time: 4 h
Yield: 90 %

Procedure:
Formic acid (9.0 ml, 238.540 mmoles) was added to a stirring solution of 3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]-2-(N-triphenylmethylamino)propane (14.11 g, 23.763 mmoles) in anhydrous methylene chloride under a nitrogen atmosphere at 0° C. After 4 hours, the reaction mixture was concentrated to an oil on a rotary evaporator and redissolved in diethyl ether and 1.0 N hydrochloric acid. The aqueous layer was washed twice with diethyl ether and basified with sodium hydroxide to a pH greater than 12. The product was extracted out with methylene chloride (4×). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated on a rotary evaporator to a white foam. The compound 2-amino-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]propane (7.52 g, 21.397 mmols) was isolated giving a 90% yield. No further purification was necessary.
Reaction SMILES: ClC1C=CC2C3N=C(NC4C=C(C=CC=4)C(O)=O)N=CC=3CC(=O)NC=2C=1.NCCCCNC(=O)OC(C)(C)C.C(OC(=O)[NH:47][CH2:48][CH2:49][CH2:50][CH2:51][NH:52][C:53](=[O:78])[C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([NH:60][C:61]2[N:62]=[CH:63][C:64]3[CH2:70][C:69](=[O:71])[NH:68][C:67]4[CH:72]=[C:73]([Cl:76])[CH:74]=[CH:75][C:66]=4[C:65]=3[N:77]=2)[CH:55]=1)(C)(C)C>>[NH2:47][CH2:48][CH2:49][CH2:50][CH2:51][NH:52][C:53](=[O:78])[C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([NH:60][C:61]2[N:62]=[CH:63][C:64]3[CH2:70][C:69](=[O:71])[NH:68][C:67]4[CH:72]=[C:73]([Cl:76])[CH:74]=[CH:75][C:66]=4[C:65]=3[N:77]=2)[CH:55]=1
Reactant: CC(C)(C)OC(=O)NCCCCNC(=O)c1cccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)c1
Agent: CC(C)(C)OC(=O)NCCCCN
Agent: O=C1Cc2cnc(Nc3cccc(C(=O)O)c3)nc2-c2ccc(Cl)cc2N1
Product: NCCCCNC(=O)c1cccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)c1

Procedure:
In a manner similar to Method N, 3-(9-chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzoic acid (I-62-a) and tert-butyl 4-aminobutylcarbamate were converted to {4-[3-(9-chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzoylamino]-butyl}-carbamic acid tert-butyl ester. Subsequent deprotection (Method K) and purification by C-18 RP LC-MS chromatography afforded I-64 (10%): HRMS Calcd. for C11H23ClN6O2: 451.1649, Found 451.1668.
Reaction SMILES: [CH:1]([CH:4]1[N:9]([C:10]2[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20](O)=[O:21])=[CH:12][N:11]=2)[CH2:8][CH2:7][N:6]2[C:23]3[CH:29]=[C:28]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:27]=[CH:26][C:24]=3[N:25]=[C:5]12)([CH3:3])[CH3:2].C[N:35](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C.O>[CH:1]([CH:4]1[N:9]([C:10]2[N:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[C:13]([C:20]([NH2:35])=[O:21])=[CH:12][N:11]=2)[CH2:8][CH2:7][N:6]2[C:23]3[CH:29]=[C:28]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:27]=[CH:26][C:24]=3[N:25]=[C:5]12)([CH3:2])[CH3:3]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)C1c2nc3ccc(S(C)(=O)=O)cc3n2CCN1c1ncc(C(=O)O)c(C(F)(F)F)n1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C1c2nc3ccc(S(C)(=O)=O)cc3n2CCN1c1ncc(C(N)=O)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
To a solution of 2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylic acid (50 mg, 0.10 mmol) in DMF (10 mL) was added HATU (59 mg, 0.16 mmol), NH4CI (100 mg, 1.97 mmol), Et3N (30 mg, 0.31 mmol) under N2. The mixture was stirred at rt for 2 h. The mixture was diluted with water (15 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by basic preparative HPLC to afford a racemic mixture of 2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxamide (13.4 mg, 27% yield) as a white solid. LC-MS m/z 483.1 [M+H]+. 1H NMR (CDCl3 400 MHz): δ 8.77 (s, 1H), 8.02 (s, 1H), 7.92-7.83 (m, 2H), 6.12 (d, J=8.4 Hz, 1H), 8.78 (brs, 2H), 5.48-5.38 (m, 1H), 4.41-4.34 (m, 1H), 4.25-4.12 (m, 1H), 3.87-3.77 (m, 1H), 3.10 (s, 3H), 2.52 (brs, 1H), 1.34 (d, J=6.8 Hz, 3H), 1.10 (d, J=6.8 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[O:5].C(=O)([O-])[O-].[Ca+2].[CH3:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(O)C>[CH3:26][CH:27]1[CH2:32][CH2:31][N:30]([C:2]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:3]=2[C:4]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)=[O:5])[CH2:29][CH2:28]1
Reactant: COc1ccc(C(=O)c2cc([N+](=O)[O-])ccc2Cl)cc1
Reactant: CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Product: COc1ccc(C(=O)c2cc([N+](=O)[O-])ccc2N2CCC(C)CC2)cc1
Yield: 54.2 %

Procedure:
Proceeding as indicated in example 2, with 0.0635 mole (18.5 g) of 2-chloro-4'-methoxy-5-nitro-benzophenone, 0.076 mole (10.5 g) of calcium carbonate and 0.127 mole (12.57 g) of 4-methyl piperidine in 50 cm3 of ethanol, 12.2 g (Yield: 53%) of the expected product are obtained. M.P. 119° C.
Reaction SMILES: [C:1]([C:3]1[CH:32]=[CH:31][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:19]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[CH:21]=2)[C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1)#[N:2].[C:33]([O:37][C:38](=[O:43])[NH:39][CH2:40][CH2:41]Br)([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38](=[O:43])[NH:39][CH2:40][CH2:41][N:16]1[CH2:17][CH2:18][N:13]([C:11](=[O:12])[C:10]2[CH:9]=[C:8]([O:7][C:6]3[CH:31]=[CH:32][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:21]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[CH:19]=2)[CH2:14][CH2:15]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)N3CCNCC3)c2)cc1
Product: CC(C)(C)OC(=O)NCCN1CCN(C(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 85.9 %

Procedure:
Following the procedure of Example 11(e) 4-[3,5-bis-(4-cyano-phenoxy)-benzoyl]-piperazine 0.35 g (0.82 mmol) and (2-bromo-ethyl)-carbamic acid tert-butyl ester (0.183 g, 0.82 mmol) were used to afford 0.4 g of the required product. 1H NMR (DMSO-d6): 1.39 (9H, s), 2.28 (6H, m), 3.04 (2H, m), 3.54 (2H, m), 6.65 (1H, brs), 6.98 (2H, d), 7.05 (1H, t), 7.25 (4H, d), 7.88 (4H, d).
Reaction SMILES: Cl[C:2]1[C:3]2[S:20][C:19]([NH2:21])=[N:18][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:7]=1.[NH2:22][CH:23]([CH2:26][OH:27])[CH2:24][OH:25]>>[NH2:21][C:19]1[S:20][C:3]2[C:2]([NH:22][CH:23]([CH2:26][OH:27])[CH2:24][OH:25])=[N:7][C:6]([S:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=3[F:17])=[N:5][C:4]=2[N:18]=1
Reactant: NC(CO)CO
Reactant: Nc1nc2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Product: Nc1nc2nc(SCc3cccc(F)c3F)nc(NC(CO)CO)c2s1

Procedure:
Prepared by the method of example 2 step a), using the product of example 4, step b) and 2-amino-1,3-propandiol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[C:16]([OH:23])[CH:15]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[C:25]1([CH3:34])[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][CH2:32]O)[CH:26]=1>>[CH3:1][O:2][C:3]([C:5]1([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[C:16]([O:23][CH2:32][CH2:31][C:27]3[CH:26]=[C:25]([CH3:34])[CH:30]=[CH:29][CH:28]=3)[CH:15]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1)=[O:4]
Reactant: COC(=O)C1(NC(=O)c2ccc(C(C)=O)c(O)c2)CCCCCC1
Reactant: Cc1cccc(CCO)c1
Product: COC(=O)C1(NC(=O)c2ccc(C(C)=O)c(OCCc3cccc(C)c3)c2)CCCCCC1

Procedure:
The compound of step 1 and 2-m-tolylethanol were reacted in analogy to step 1 of example 1 to yield the title compound.
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:2]12.CCN(CC)CC.[CH:18]([N:21]1[C:25]([C:26]2[N:35]=[C:34]3[N:28]([CH2:29][CH2:30][O:31][C:32]4[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][C:33]=43)[CH:27]=2)=[N:24][CH:23]=[N:22]1)([CH3:20])[CH3:19]>C(Cl)Cl>[CH2:1]1[N:6]([S:40]([C:37]2[CH:38]=[CH:39][C:32]3[O:31][CH2:30][CH2:29][N:28]4[CH:27]=[C:26]([C:25]5[N:21]([CH:18]([CH3:19])[CH3:20])[N:22]=[CH:23][N:24]=5)[N:35]=[C:34]4[C:33]=3[CH:36]=2)(=[O:42])=[O:41])[CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:2]12
Reactant: C1CCN2CCNCC2C1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)Cl)ccc1OCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)N3CCN4CCCCC4C3)ccc1OCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of octahydropyrido[1,2-a]pyrazine (50 mg, 0.38 mmol) and NEt3 (83 μL, 0.59 mmol) in DCM (15 mL) at 0° C. was added a suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfonyl chloride from Example 121 (93 mg, 0.12 mmol) in DCM (5 mL) and the resulting mixture warmed to RT after 10 min then stirred for 1 h. The reaction mixture was diluted with DCM, washed with a saturated aqueous NaHCO3 solution then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-8% MeOH in EtOAc) then freeze-dried from MeCN/H2O affording 132 (36 mg, 62%) as a white solid. LCMS: RT 2.90 min [M+H]+ 498.3. 1H NMR (DMSO, 400 MHz): δ 8.78 (1H, d, J=2.41 Hz), 8.01 (1H, s), 7.94 (1H, s), 7.63 (1H, dd, J=8.63, 2.42 Hz), 7.28 (1H, d, J=8.62 Hz), 5.73-5.72 (1H, m), 4.63-4.59 (4H, m), 3.53 (1H, d, J=11.02 Hz), 3.43 (1H, d, J=9.07 Hz), 2.70-2.68 (2H, m), 2.33-2.32 (1H, m), 2.19-2.11 (1H, m), 1.93-1.92 (3H, m), 1.62 (1H, d, J=12.59 Hz), 1.57-1.52 (2H, m), 1.49 (6H, t, J=6.30 Hz), 1.38-1.16 (2H, m), 1.01-0.87 (1H, m)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)C(C)C)(C)C.[C:34]([O:41][CH3:42])(=[O:40])[CH2:35][CH2:36][C:37]([O-])=[O:38].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][N:21]([C:37](=[O:38])[CH2:36][CH2:35][C:34]([O:41][CH3:42])=[O:40])[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)CCC(=O)[O-]
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@@H]2CCCNC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CCC(=O)N1CCC[C@@H](CN2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
To a solution of N-(3,4-dichlorophenyl)-4-[(3R)-piperidin-3-ylmethyl]piperazine-1-carboxamide (200 mg), N,N-di-isopropylethylamine (0.19 mL) and monomethyl succinate (79 mg) in dimethylformamide (5 mL) was added O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-Tetramethyluronium Hexafluoro-Phosphate. The solution was stirred at room temperature overnight and then loaded directly onto an SCX-2 column and eluted with methanol then 7M NH3 in methanol. The basic fraction was concentrated at reduced pressure and the residue was purified by silica column chromatography, eluting with a gradient of 0 to 10% methanol in dichloromethane to give the title compound as a white foam (252 mg, 96%).
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7](=[CH:12][CH:13]=1)[C:8]([O:10][CH3:11])=[O:9])([O-])=O.[Na].[OH:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>CN(C=O)C>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([O:19][C:4]2[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7](=[CH:12][CH:13]=2)[C:8]([O:10][CH3:11])=[O:9])[CH:21]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C(=O)OC
Reactant: Oc1cccnc1
Agent: [Na]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2cccnc2)cc1C(=O)OC

Procedure:
Dimethyl 4-nitrophthalate was reacted in DMF with 3-hydroxypyridine sodium salt in analogy to a process known from the literature (J. Org. Chem. Vol. 42, No. 21, 1977, 3419-3425) to give dimethyl 4-(3-pyridyloxy)phthalate. After standard working up and chromatography using hexane/EA, the diester was isolated as a yellowish oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](OS(C2C=CC(C)=CC=2)(=O)=O)=[C:6]([O:21][CH3:22])[CH:5]=1)(=[O:3])[CH3:2].[C:23]([C:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1)#[CH:24]>C(Cl)Cl>[C:25]1([C:23]#[C:24][C:7]2[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][C:6]=2[O:21][CH3:22])[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1
Reactant: C#CC1=CCCCC1
Reactant: COc1cc(C(C)=O)ccc1OS(=O)(=O)c1ccc(C)cc1
Solvent: ClCCl
Product: COc1cc(C(C)=O)ccc1C#CC1=CCCCC1

Procedure:
This product was prepared from toluene-4-sulfonic acid 4-acetyl-2-methoxy-phenyl ester and 1-ethynyl-cyclohexene following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: DCM; yield (114 mg, 90%); 1H NMR δ (CDCl3): 7.53-7.41 (m, 3H), 6.29 (m, 1H), 3.92 (s, 3H), 2.51 (s, 3H), 2.31-2.12 (dm, 4H), 1.73-1.57 (m, 4H); LCMS m/z: 254.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([NH:12][C:13]1[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)[N:17]=[CH:16]3)=[N:5][CH:6]=[N:7]2.[C:30]([O:35][CH3:36])(=[O:34])[C@@H:31]([CH3:33])[OH:32]>>[F:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[CH2:22][N:18]1[C:19]2[C:15](=[CH:14][C:13]([NH:12][C:4]3[C:3]4[C:8](=[CH:9][CH:10]=[CH:11][C:2]=4[O:32][C@@H:31]([CH3:33])[C:30]([O:35][CH3:36])=[O:34])[N:7]=[CH:6][N:5]=3)=[CH:21][CH:20]=2)[CH:16]=[N:17]1
Reactant: COC(=O)[C@@H](C)O
Reactant: Fc1cccc(Cn2ncc3cc(Nc4ncnc5cccc(F)c45)ccc32)c1
Product: COC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12

Procedure:
The 5-fluoro-N-[1-(3-fluorobenzyl)-1H-indazol-5-yl]quinazolin-4-amine (2.4 g, 6.48 mmol) was reacted as in Example 5 starting material, except that (R)-methyl lactate was used instead of (s)-methyl lactate, to give methyl (2S)-2-[(4-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([NH:13][CH2:14][C:15]1[O:16][C:17]([CH3:20])=[CH:18][CH:19]=1)=[N:8]2.C(N(CC)CC)C.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>C1COCC1>[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:1][CH2:2][C:3]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:4]=2[CH:5]=[CH:6][C:7]([NH:13][CH2:14][C:15]2[O:16][C:17]([CH3:20])=[CH:18][CH:19]=2)=[N:8]3)=[O:34])=[CH:31][CH:30]=1
Reactant: Cc1ccc(CNc2ccc3c(CN)cccc3n2)o1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(CNc2ccc3c(CNC(=O)c4ccc(F)cc4)cccc3n2)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.5 %

Procedure:
To a cooled (ice bath) and stirred solution of (5-aminomethyl-quinolin-2-yl)-(5-methyl-furan-2-ylmethyl)-amine (95 mg, 0.355 mmol) and triethyl amine (39.6 mg, 0.39 mmol) in THF (2 ml) was added 4-fluorobenzoyl chloride (62 mg, 0.39 mmol) and the mixture was allowed to stir at room temperature for 16 h. Evaporation and purification by flash chromatography (ethyl acetate/heptane) on silica gel yielded the title compound as off-white solid (67 mg, 48%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C@@H:17]([C:18]([O:20]CC)=[O:19])[C@H:16]3[CH2:23][C@@H:13]2[CH2:14][CH2:15]3)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CO.[OH-].[Na+].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C@@H:17]([C:18]([OH:20])=[O:19])[C@H:16]3[CH2:23][C@@H:13]2[CH2:14][CH2:15]3)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)[C@H]1[C@@H]2CC[C@@H](C2)N1S(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N2[C@H]3CC[C@H](C3)[C@@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl (1S, 3R, 4R)-2-[(4-methoxyphenyl)sulfonyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate (965 mg, 2.84 mmol) in tetrahydrofuran (40 ml)-methanol (10 ml) was added 1N sodium hydroxide (16 ml), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, to give (1S, 3R, 4R)-2-[(4-methoxyphenyl)sulfonyl]-2-azabicyclo[2.2.1]heptane-3-carboxylic acid.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[CH3:6][C:7](=O)[CH2:8][CH2:9][C:10](=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>CO>[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:1]2[C:2]=1[CH:3]=[CH:4][CH2:5]2
Reactant: CCCCCCCCC(=O)CCC(C)=O
Reactant: C1=CCC=C1
Solvent: CO
Product: CCCCCCCCc1ccc(C)c2c1CC=C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
9 ml (110 mmol) of cyclopentadiene were added to a solution of 28.0 g (250 mmol) of potassium t-butylate in 50 ml of methanol at 0° C. 21.2 g (100 mmol) of 2,5-tridecanedione were then added dropwise at 0° C. After the mixture had been stirred at 0° C. for 1 hour, it was stirred at room temperature for a further 3 hours. Working up was carried out analogously to Example 6. Column chromatography gave 16.9 g (70 %) of the indene 5.
Reaction SMILES: N[C@@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].N([O-])=[O:11].[Na+].C([O-])(O)=O.[Na+].[Na+].[Cl-]>OS(O)(=O)=O.O>[OH:11][C@H:2]([C@@H:3]([CH3:4])[CH2:5][CH3:6])[C:7]([OH:9])=[O:8]
Reactant: O=N[O-]
Reactant: CC[C@H](C)[C@@H](N)C(=O)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: O
Product: CC[C@H](C)[C@@H](O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (-)-D-allo-isoleucine [1.00 g, 7.634 mmol, [α]D20 =-37°(5% in 6M HCl)] in 26 ml of 1N aq. H2SO4 at 2° was slowly added (ca. 12 h) a solution of NaNO2 (1.67 g, 24.13 mmol) in 26 ml of demineralised water. After stirring overnight at room temperature, 0.62 g of powdered NaHCO3 were added to bring the pH above 2. The solution was saturated with NaCl and extracted 6 times with ethyl acetate, maintaining the pH between 2 and 3 (1N aq. H2SO4, pH meter). After drying (Na2SO4), the organic layer was concentrated and the crude product (0.91 g, 91%) was directly used in the next step without further purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[CH2:6](Cl)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:6]([S:5][CH2:4][CH2:3][NH2:2])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ClCc1ccccc1
Reactant: NCCS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NCCSCc1ccccc1
Reaction time: 8 h

Procedure:
A suspension of 2-aminoethanethiol hydrochloride (2.27 g, 20.0 mmol), benzyl chloride (2.42 mL, 21.0 mmol) and cesium carbonate (19.5 g, 60 mmol) in DMF (100 mL) was stirred overnight. The reaction mixture was then diluted with ethyl acetate (200 mL) and filtered into a separation funnel. The solid residue was washed with ether (50 mL×3). The combined filtrates were then washed with water (80 mL×5) and brine (50 mL), dried over potassium carbonate and filtered. The filtrate was concentrated first with rotary evaporator (water bath at 80° C.), then by high vacuum (1 mm Hg) to give 2-benzylthioethylamine in good purity. The crude product was used for next step without further purification.