Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].N1C2C(=CC=CC=2)C(CC[CH2:18][C:19]([N:21](CC(N)=O)[CH2:22][CH2:23][C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:26][CH:25]=2)=O)=C1.O>O1CCCC1>[CH2:19]([NH:21][CH2:22][CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)[CH3:18]
Reactant: NC(=O)CN(CCc1c[nH]c2ccccc12)C(=O)CCCc1c[nH]c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCNCCc1c[nH]c2ccccc12
Temperature: 0 °C
Yield: 185.2 %

Procedure:
Lithium aluminum hydride in tetrahydrofuran (1M, 30 mL) was added dropwise to a stirring solution of N-[2-(1H-indol-3-yl)ethylacetyltryptamineacetamide (2.02 g) in tetrahydrofuran (10 mL) at 0° C. The solution was then heated at reflux overnight. The solution was cooled to 0° C. and water was very carefully added dropwise. The white solid was filtered and rinsed with ether/methanol (9:1, 2×25 mL). The solvent was removed from the filtrate, giving N-ethyl-2-(1H-indol-3-yl)ethanamine as a viscous pale yellow oil (1.75 g, 93%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[NH2:12][C:13]1[N:14]=[C:15]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:16]([C:22]2[CH:23]=[CH:24][C:25](=[O:31])[N:26]([CH:28]([CH3:30])[CH3:29])[N:27]=2)=[N:17][C:18]=1[S:19]([CH3:21])=[O:20]>C(Cl)Cl>[NH2:12][C:13]1[N:14]=[C:15]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:16]([C:22]2[CH:23]=[CH:24][C:25](=[O:31])[N:26]([CH:28]([CH3:30])[CH3:29])[N:27]=2)=[N:17][C:18]=1[S:19]([CH3:21])(=[O:9])=[O:20]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)n1nc(-c2nc(S(C)=O)c(N)nc2-c2ccccc2)ccc1=O
Solvent: ClCCl
Product: CC(C)n1nc(-c2nc(S(C)(=O)=O)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 27.5 °C
Reaction time: 5 h
Yield: 67 %

Procedure:
Under ice-cooling, m-chloroperbenzoic acid (70-75% purity) (530 mg) was added to a mixture of 6-[5-amino-6-(methylsulfinyl)-3-phenyl-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (750 mg) in CH2Cl2 (7.5 ml). The mixture was stirred at 25-30° C. for 5 hours, washed with saturated aq. sodium thiosulfate, saturated aq. NaHCO3 and brine, dried over MgSO4 and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (30:70 v/v) to give 6-[5-amino-6-(methylsulfonyl)-3-phenyl-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone as a solid (524 mg).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])[CH3:2].Br[CH2:18][CH2:19][OH:20].C(N(CC)CC)C>C(O)C>[CH2:1]([N:3]([CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])[CH2:18][CH2:19][OH:20])[CH3:2]
Reactant: OCCBr
Reactant: CCNCCN1C(=O)c2ccccc2C1=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCN(CCO)CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 72.2 %

Procedure:
To a solution of compound 2 (15.00 g, 68.7 mmol) in anhydrous ethanol (300 mL) were successively added, under argon, 2-bromoethanol (14.8 mL, 0.21 mol) and triethylamine (29.0 mL, 0.21 mol). The mixture was stirred under reflux for 60 h. After cooling to room temperature, the solvent was evaporated under vacuum and the residue was chromatographed (SiO2, AcOEt/EtOH, 99/1, v/v) to give compound 3 (13.00 g, 49.6 mmol) as a white solid. Yield 72%; Rf (SiO2, AcOEt/EtOH, 99/1, v/v) 0.49; mp 56-58° C.; IR (KBr) ν 1018, 1387, 1405, 1702, 2825, 2959, 3400-3600 cm−1; 1H NMR (200 MHz, CDCl3) δ 0.93 (t, 3H, J=7.1 Hz), 2.58 (q, 2H, J=7.1 Hz), 2.68 (t, 2H, J=5.3 Hz), 2.76 (t, 2H, J=6.2 Hz), 3.11 (se, 1H), 3.53 (t, 2H, J=5.3 Hz), 3.77 (t, 2H, J=6.2 Hz), 7.71 (m, 2H), 7.82 (m, 2H); MS m/z 262 (M+, 1), 231 (11), 174 (21), 130 (8), 102 (100), 76 (10), 58 (29).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[CH:11]=1.[CH3:12][O-:13].[Na+]>CO>[CH3:12][O:13][CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[CH:11]=1
Reactant: ClCc1cn2ccccc2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1cn2ccccc2n1

Procedure:
To a solution of 3.0 g of 2-chloromethylimidazo [1,2-a]pyridine in 50 ml of methanol is added 1.1 g of sodium methoxide, followed by heating under reflux for 3 hours. Methanol is distilled off under reduced pressure and chloroform is added to the residue. The resulting insoluble substance is filtered off, and the filtrate is washed with water and dried over anhydrous sodium sulfate. After distilling chloroform off, 2.9 g of the title compound is obtained as crystals.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](Cl)=[O:29])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([S:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:19])=[O:29])=[CH:23][CH:22]=1
Reactant: Nn1nc(Sc2ccccc2)c2ccccc2c1=O
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(Sc2ccccc2)c2ccccc2c1=O

Procedure:
The product from Example 57B and 2-(4-chlorophenyl)acetyl chloride were processed using a method similar to that described in Example 4C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 8.34 (dd, J=7.9, 1.1, 1H), 8.08 (d, J=7.4, 1H), 8.00 (td, J=7.7, 1.5, 1H), 7.94 (td, J=7.6, 1.3, 1H), 7.40 (d, J=8.8, 9H), 3.66 (s, 2H); MS (APCI+) M/Z 422 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH2:14][CH2:15][CH:11]2[NH:10][C:9]1=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:18][CH2:19][CH2:20][O:21][CH3:22]>>[C:1]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH2:14][CH2:15][CH:11]2[N:10]([CH2:18][CH2:19][CH2:20][O:21][CH3:22])[C:9]1=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCCBr
Reactant: CC(C)(C)OC(=O)N1C(=O)NC2CCCC21
Product: COCCCN1C(=O)N(C(=O)OC(C)(C)C)C2CCCC21

Procedure:
The title compound was prepared in accordance with the general method of example 1, step 2 starting from (rac)-(3aSR,6aRS)-2-oxo-hexahydro-cyclopentaimidazole-1-carboxylic acid tert-butyl ester (Example 1, step 1) and using 1-bromo-3-methoxypropane instead of iodoethane to yield the desired product as a light yellow oil which was directly used in the next step without further characterisation.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[OH:13][C:14]1[C:23]2[C@@H:22]3[CH2:24][C:25]([C:28]([OH:30])=[O:29])=[CH:26][CH2:27][C@H:21]3[C:20]([CH3:32])([CH3:31])[O:19][C:18]=2[CH:17]=[C:16]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:15]=1.O[N:39]1[C:43](=[O:44])[CH2:42][CH2:41][C:40]1=[O:45].CCOC(C)=O>C(Cl)Cl>[OH:13][C:14]1[C:23]2[C@@H:22]3[CH2:24][C:25]([C:28]([O:30][N:39]4[C:43](=[O:44])[CH2:42][CH2:41][C:40]4=[O:45])=[O:29])=[CH:26][CH2:27][C@H:21]3[C:20]([CH3:31])([CH3:32])[O:19][C:18]=2[CH:17]=[C:16]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:15]=1
Reactant: CCCCCc1cc(O)c2c(c1)OC(C)(C)[C@@H]1CC=C(C(=O)O)C[C@@H]21
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCCc1cc(O)c2c(c1)OC(C)(C)[C@@H]1CC=C(C(=O)ON3C(=O)CCC3=O)C[C@@H]21

Procedure:
In an alternate approach, 2 equivalents of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC-HCl) as the coupling reagent in the reaction of (XI) were mixed with 1.5 equivalents of N-hydroxysuccinimide in CH2Cl2 at reflux for 24 h. Dilution of the resulting reaction mixture with EtOAc, washing with water, saturated NaHCO3, saturated NaCl, drying over Na2SO4 and evaporation in vacuo then gave a gum. This was subjected to chromatography on silica, eluting with EtOAc-hexanes (1:1) to give (XII) as an off-white foam, [α]D -208° (CHCl3), (M+H)+ (FAB) 442.2260 (Calc 442.2230).
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:26][S:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28]>>[CH3:26][S:27]([C:30]1[CH:35]=[C:34]([C:2]2[CH:25]=[CH:24][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH2:19][C:20]([F:22])([F:23])[F:21])[N:16]=[CH:17][N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CS(=O)(=O)c1cccc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)c1

Procedure:
Following the procedure for 114, 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 3-methylsulfonylphenylboronic acid to give 148. MS(ESI+) 507.0. 1H NMR (400 MHz, DMSO) δ 8.44 (d, J=8.3, 1H), 8.31 (s, 1H), 8.25 (s, 1H), 8.14 (d, J=8.0, 1H), 7.93 (d, J=7.8, 1H), 7.75 (t, J=7.8, 1H), 7.67 (dd, J=8.3, 1.7, 1H), 7.55 (d, J=1.7, 1H), 5.88 (q, J=8.6, 2H), 4.45 (t, J=4.9, 2H), 3.52 (t, J=4.9, 2H), 3.32 (s, 3H)
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39])(=O)=O.[CH2:42]([OH:45])[C:43]#[CH:44]>C(NCC)C.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.[Cu](I)I>[OH:45][CH2:42][C:43]#[C:44][C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39]
Reactant: C#CCO
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(C#CCO)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 37.3 %

Procedure:
In a similar manner to Step 2 of Example 161, 4-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (60.0 mg, 0.101 mmol) was dissolved in diethylamine (3.0 mL), and the solution was treated with bis(triphenylphosphine)dichloropalladium (8.6 mg, 0.012 mmol), copper iodide (6.9 mg, 0.036 mmol), propargyl alcohol (0.029 mL, 0.51 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=5/1) to obtain 4-(3-hydroxy-1-propinyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (18.8 mg, yield 37%).
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.[CH3:24][C:25]1[N:26]=[C:27]([N:33]2[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][C:41]([F:44])([F:43])[F:42])[C:34]2=[O:45])[S:28][C:29]=1[C:30](O)=[O:31]>>[CH3:24][C:25]1[N:26]=[C:27]([N:33]2[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][C:41]([F:44])([F:43])[F:42])[C:34]2=[O:45])[S:28][C:29]=1[C:30]([NH2:7])=[O:31]
Reactant: Cc1nc(N2CCN(CCCC(F)(F)F)C2=O)sc1C(=O)O
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(CCCC(F)(F)F)C2=O)sc1C(N)=O
Yield: 52 %

Procedure:
Following the procedure as described in Example 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-(4,4,4-trifluorobutyl)-imidazolidin-1-yl)thiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 52% yield: 1H NMR (300 MHz, CDCl3) δ 5.58 (s, 2H), 4.17-4.11 (m, 2H), 3.64-3.59 (m, 2H), 3.44-3.39 (m, 2H), 2.61 (s, 3H), 2.22-2.08 (m, 2H), 1.92-1.82 (m, 2H); 13C NMR (75 MHz, CDCl3) δ164.3, 157.7, 155.6, 155.5, 153.8, 128.6, 124.9, 116.9, 42.9, 42.3, 42.0, 31.8, 31.4, 30.9, 30.6, 20.2, 20.1, 17.3; MS (ES+) m/z 336.8 (M+1).
Reaction SMILES: [C:1]([NH:9][CH2:10][CH2:11][C:12]1[CH:19]=[CH:18][C:16]([OH:17])=[C:14]([OH:15])[CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH3:20][C:21]([CH3:26])([CH3:25])[C:22](Cl)=[O:23]>C(Cl)(Cl)Cl>[C:22]([O:15][C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][NH:9][C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[O:8])[CH:19]=[CH:18][C:16]=1[O:17][C:22](=[O:23])[C:21]([CH3:26])([CH3:25])[CH3:20])(=[O:23])[C:21]([CH3:26])([CH3:25])[CH3:20]
Reactant: O=C(NCCc1ccc(O)c(O)c1)c1cccnc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)Oc1ccc(CCNC(=O)c2cccnc2)cc1OC(=O)C(C)(C)C

Procedure:
To a suspension of 5.16 g (0.02 mol) finely powdered nicotinoyldopamine in 100 ml chloroform, 7.23 g (0.06 mol) trimethylacetyl chloride were added under stirring. The mixture was refluxed for 6 hours and then filtered. The filtrate was washed with water free of chloride ions, then washed once with a 5% solution of NaHCO3, then with water. The chloroform was evaporated and the residue was chromatographed by using a silica gel G column and 2% methanol in chloroform as the eluent. The first fraction was collected and evaporated and the residue was crystallized from ether/petroleum ether. Yield, 6.2 g (73%) of a white crystalline solid, m.p. 112°-114° C., NMR (CDCl3) δ9.06 (bs, 1H, C2 pyridine proton), 8.73 (bd, 1H, C6 pyridine proton) 8.30-8.13 (m, 1H, C4 pyridine proton), 7.46-7.10 (m, 5H, C6H3 +C5 pyridine proton+CONH), 3.66 (q, 2H, J=6.25 Hz, --N--CH2), 3.0 (t, 2H, J=6 Hz, --CH2), 1.41 [s, 18H, 2--C(CH3)3 ]. Anal. Calcd for C24H30N2O5 : C, 67,58; H, 7.09; N, 6.56. Found: C, 67.61; H, 7.10; N, 6.54.
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][S:17]2(=[O:22])=[O:21])[CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10].[CH:24]1([C:27]2[C:28]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[N:29][CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=2)[CH2:26][CH2:25]1>>[O:23]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][S:17]2(=[O:21])=[O:22])[CH:13]=[CH:12][C:8]=1[C:9]([N:40]1[CH2:41][CH2:42][N:37]([C:28]2[C:27]([CH:24]3[CH2:25][CH2:26]3)=[CH:32][C:31]([C:33]([F:36])([F:34])[F:35])=[CH:30][N:29]=2)[CH2:38][CH2:39]1)=[O:10]
Reactant: FC(F)(F)c1cnc(N2CCNCC2)c(C2CC2)c1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1N1CCCS1(=O)=O
Product: O=C(c1ccc(N2CCCS2(=O)=O)cc1N1CCCS1(=O)=O)N1CCN(c2ncc(C(F)(F)F)cc2C2CC2)CC1
Yield: 47.2 %

Procedure:
Using 2,4-bis(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (200 mg) described in Preparation Example 34 and 1-(3-cyclopropyl-5-trifluoromethylpyridin-2-yl)piperazine (150 mg) described in Preparation Example 90 and by the reaction and treatment in the same manner as in Example 87, the title compound (160 mg) was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=1.[NH:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=[C:2]([N:19]3[CH:23]=[CH:22][CH:21]=[CH:20]3)[N:7]=2)=[CH:9][CH:10]=1
Reactant: c1cc[nH]c1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(Cl)n1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-n2cccc2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidine (example A.1) (0.15 g, 0.5 mmol) and commercially available pyrrole (0.067 g, 1.0 mmol) according to the general procedure IVa. Obtained as a light brown solid (0.12 g, 74%). MS (EI) 323.1 [(M)+]; mp 128.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([NH2:16])=[C:4]([NH2:17])[N:3]=1.[C:18](N1C=CN=C1)(N1C=CN=C1)=[O:19].O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]2[C:4]([N:3]=1)=[N:17][C:18](=[O:19])[N:16]=2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc(N)c(N)c(OCC2CCCCC2)n1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(OCC2CCCCC2)c2c(n1)=NC(=O)N=2
Reaction time: 2 h
Yield: 58.7 %

Procedure:
A solution of 2,5,6-triamino-4-cyclohexylmethyloxypyrimidine (1.0 g, 4.24 mmol) and 1,1′-carbonyldiimidazole (0.69 g, 4.24 mmol) in anhydrous DMF (5 ml) was stirred under nitrogen at ambient temperature for 48 h. Addition of water (100 ml) afforded a white solid which was collected by filtration, redissolved in 2 M sodium hydroxide solution (200 ml), and filtered. The filtrate was neutralised with glacial acetic acid and allowed to stand at 4° C. for 2 h, when the precipitate which deposited was collected and washed thoroughly with water. Recrystallisation from aqueous ethanol yielded the required product (0.65 g, 58%), m.p. 297° C.; (Found: C. 54.66; H, 6.47;. N, 26.63% C12 H17 N5O2 requires C, 54.75; H, 6.46; N, 26.62%); δH (200 MHz, d6-DMSO) 1.04-1.39 (δH, m, C6H11), 1.76-1.90 (6H, m, C6H11), 4.17 (2H, OCH2, J=6.53 Hz), 6.15 (2H. br s, NH2), 10.49 (1H, br s, NH), 1 1.09 (1H, br s, NH); m/z (+EI) 263 (M+, 75%), 167 (MH+—C7H13, 100), 81 (6), 69 (7).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.C(O[C:38]([N:40]([CH2:42][C:43](O)=[O:44])C)=O)(C)(C)C>>[ClH:28].[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19](=[O:20])[NH:18][C:15]2[CH:14]=[CH:13][C:12]([N:7]3[CH:6]=[N:5][C:4]4[C:8]3=[N:9][CH:10]=[N:11][C:3]=4[NH:2][C:43](=[O:44])[CH2:42][NH:40][CH3:38])=[CH:17][CH:16]=2)=[CH:23][C:24]=1[C:29]([F:31])([F:32])[F:30]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: Cl
Product: CNCC(=O)Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The titled compound can be synthesized from 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride and tert-butoxycarbonyl-sarcosine by using the same method as in Example 96.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.[CH2:12]([OH:15])[C:13]#[CH:14].C(N(CC)CC)C>ClCCl.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>[CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[C:14]#[C:13][CH2:12][OH:15])[CH:7]=[CH:8][N:9]=1
Reactant: Brc1cccc2ccncc12
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OCC#Cc1cccc2ccncc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In an inert atmosphere, 0.068 g of bis(triphenylphosphine)palladium dichloride and 0.013 g of cuprous iodide was added with stirring to a deoxygenated solution of 1 g of 8-bromoisoquinoline, 0.56 mL of propargyl alcohol and 2 mL of triethylamine in 25 mL of dichloromethane. The mixture was stirred at room temperature for 2 hours and then at reflux for 20 hours. The cooled reaction was filtered and the filtrate was concentrated in vacuo. The residual oil was purified by HPLC (ethyl acetate-toluene; 2:3) to yield 0.4 g of 3-(8-isoquinolinyl)-2-propyn-1-ol, mp 138°-139° C.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15](=[O:23])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[OH:22])=[CH:11][CH:12]=2)[C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([CH3:24])[CH2:6][C:5]1([CH3:32])[CH3:31])(=[O:3])[CH3:2].[CH3:33][C:34]1[C:38]([S:39](Cl)(=[O:41])=[O:40])=[C:37]([CH3:43])[O:36][N:35]=1>N1C=CC=CC=1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15](=[O:23])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][S:39]([C:38]3[C:34]([CH3:33])=[N:35][O:36][C:37]=3[CH3:43])(=[O:41])=[O:40])=[CH:11][CH:12]=2)[C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([CH3:24])[CH2:6][C:5]1([CH3:32])[CH3:31])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(NC(=O)c3ccccc3O)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)N1c2ccc(NC(=O)c3ccccc3OS(=O)(=O)c3c(C)noc3C)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Sulfonylation of 1-acetyl-6-(2-hydroxybenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (20 mg) with 3,5-dimethylisoxazole-4-sulfonyl chloride (27 mg) in pyridine (2 ml) was performed according to the method described in example 58.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.C([Li])CCC.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>C1COCC1>[S:1]1[C:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:28])([CH3:30])[CH3:29])([CH3:25])[CH3:26])=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1
Reactant: c1csc(-c2cccs2)c1
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCCCc1ccc(-c2cccs2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
To a stirred solution of 2,2′-bithiophene (10.0 g, 60.24 mmol) in dry THF (150 ml) was added n-butyllithium (2.5 M in hexanes, 20.0 ml, 50.0 mmol) dropwise at −78° C. under nitrogen. After complete addition, the mixture was allowed to warm to room temperature, with stirring, over 2 h, followed by the addition of 6-bromohexyloxy-tert-butyldimethylsilane (14.75 g, 50.0 mmol). The resultant mixture was stirred overnight at room temperature. The reaction was quenched with sat. aq. ammonium chloride, and the reaction mixture was extracted with ethyl acetate (3×70 ml). The combined organic extracts were washed with water, brine, and dried over magnesium sulphate. The solvent was removed under reduced pressure and the residue was chromatographyed (silica gel, petroleum/ethyl acetate from 100:0 to 20:1), to afford the product as a pale green oil (15.07 g, 79%). 1H NMR (300 MHz, CDCl3): δ (ppm) 7.08 (m, 1H, Ar—H), 7.03 (m, 1H, Ar—H), 6.92 (m, 2H, Ar—H), 6.61 (d, J=3.6 Hz, 1H, Ar—H), 3.55 (t, J=6.2 Hz, 2H, OCH2), 3.34 (t, J=6.8 Hz, 2H, ArCH2), 1.25-1.85 (m, 8H, CH2), 0.86 (s, 9H, CH3), 0.01 (s, 6H, CH3); 13C NMR (75 MHz, CDCl3): δ (ppm) 145.1 (quat.), 138.0 (quat.), 134.8 (quat.), 127.6 (CH), 124.7 (CH), 123.7 (CH), 123.4 (CH), 122.9 (CH), 63.0 (OCH2), 33.8 (CH2), 32.9 (CH2), 32.7 (CH2), 28.0 (CH2), 26.0 (CH3) 25.1 (CH2), 18.4 (quat.), −5.2 (CH3); MS (m/e): 380 (M+, 27%), 323 (63), 179 (100), 75 (37).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH:9][CH:10](O)[C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[O:5][CH:6]=1.[N:16]([CH:19]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=C=O>C1C=CC=CC=1.C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH:9][CH:10]([NH:16][CH:19]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[O:5][CH:6]=1
Reactant: O=C(NC(O)C(Cl)(Cl)Cl)c1cc(Br)co1
Reactant: O=C=NC1CCCCCCC1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NC(NC1CCCCCCC1)C(Cl)(Cl)Cl)c1cc(Br)co1
Yield: 67.7 %

Procedure:
4-Bromo-N-(2,2,2-trichloro-1-hydroxyethyl)furan-2-carboxamide 125 (0.16 g, 0.47 mmol) and isocyanatocyclooctane (0.08 mL, 0.51 mmol) in benzene (2 mL) with triethyl amine (2 drops) was heated to 95° C. for 1.5 hours. The mixture was concentrated onto silica gel and purified by chromatography (7:3 to 6:4 hexane:CH2Cl2) to give 4-bromo-N-(2,2,2-trichloro-1-(cyclooctylamino)ethyl)furan-2-carboxamide (Compound-51) (142 mg, 67%). 1H NMR (300 MHz, CDCl3): δ=7.50 (d, J=0.9 Hz, 1H), 7.21 (d, J=0.9 Hz, 1H), 6.59 (d, J=9.6 Hz, 1H), 5.55 (t, J=9.3 Hz, 1H), 2.96-2.85 (m, 1H), 1.79-1.42 (m, 15H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=2)=O)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=2)=[S:35])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCNC(=S)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Reaction time: 1 h

Procedure:
To a suspension of 35 in toluene is added Lawesson's Reagent. The suspension is heated at reflux while stirring for 1 h. The reaction mixture is cooled over ice to precipitate the product. The product is then filtered, washed with hexane, and dried to give 156.