Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[C:11]([CH3:50])[C:12]([C:14]3[N:19]4[N:20]=[C:21]([C:23]5[CH:24]=[C:25]([C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=6[CH2:35][CH2:36][CH:37]=[CH2:38])[CH:26]=[CH:27][CH:28]=5)[CH:22]=[C:18]4[N:17]=[C:16]([CH3:39])[C:15]=3[C@H:40]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[C:41]([O:43][CH3:44])=[O:42])=[CH:13][C:5]1=2)C=C>ClCCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C(OC(C)C)=CC=CC=3)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[C:46]([O:45][C@@H:40]([C:15]1[C:16]([CH3:39])=[N:17][C:18]2=[CH:22][C:21]3=[N:20][N:19]2[C:14]=1[C:12]1[CH:13]=[C:5]2[C:6]([O:7][CH2:8][CH2:9][N:4]2[CH2:1][CH:38]=[CH:37][CH2:36][CH2:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[C:25]2[CH:24]=[C:23]3[CH:28]=[CH:27][CH:26]=2)=[CH:10][C:11]=1[CH3:50])[C:41]([O:43][CH3:44])=[O:42])([CH3:49])([CH3:48])[CH3:47]
Reactant: C=CCCc1ccccc1-c1cccc(-c2cc3nc(C)c([C@H](OC(C)(C)C)C(=O)OC)c(-c4cc5c(cc4C)OCCN5CC=C)n3n2)c1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: ClCCCl
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1-c1cc2c(cc1C)OCCN2CC=CCCc1ccccc1-c1cccc-3c1
Reaction time: 1.5 h

Procedure:
A solution of (2S)-methyl 2-(7-(4-allyl-7-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(2′-(but-3-en-1-yl)-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.030 g, 0.045 mmol) in dry DCE (5 mL) was heated (70° C. oil bath) and then treated with Hoveyda-Grubbs Cat. 2nd Gen. (3 mg, 5 μmol). The reaction was stirred for 90 min. The solvent was removed and the intermediate was used immediately in the following step. LCMS (M+H)=643.4.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][NH:39][C:40]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])=[CH:33][C:32]=2[CH3:50])=[C:28]([CH:51]([CH3:53])[CH3:52])[NH:27][N:26]=1)(=O)C.C[O-].[Na+]>CO>[CH2:43]([O:42][C:40]([NH:39][CH2:38][CH2:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[N:26][NH:27][C:28]=2[CH:51]([CH3:53])[CH3:52])=[C:32]([CH3:50])[CH:33]=1)=[O:41])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCNC(=O)OCc3ccccc3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(CCNC(=O)OCc2ccccc2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[2-(benzyloxycarbonylamino)ethyl]-2-methylphenyl)methyl}-5-isopropyl-1H-pyrazole (20 mg) was dissolved in methanol (1 mL). To the solution was added sodium methoxide (28% methanol solution, 0.005 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give 4-({4-[2-(benzyloxycarbonylamino)ethyl]-2-methylphenyl}methyl)-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole. This material was dissolved in methanol (1 mL). To the solution was added 10% palladium-carbon powder (5 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 6 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (11 mg).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.[OH-].[Na+].[CH3:21][NH:22][CH3:23]>>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([N:22]([CH3:23])[CH3:21])[N:3]=1
Reactant: CNC
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Agent: [Na+]
Agent: [OH-]
Product: CN(C)c1nc(N)nc2c1ncn2[C@H]1C=C[C@@H](CO)C1

Procedure:
(±)-cis-4-(2-Amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol (0.400 g, 1.5 mmol) from Example 4 and dimethylamine (25% aqueous solution, 20 mL) was stirred at 80° C. for 0.5 hours. The reaction mixture was allowed to cool to room temperature before the addition of 1.5 mL of 1 N NaOH. Concentration of the solution afforded the crude product which was purified by elution from a silica gel column with 5% methanol-chloroform (0.310 g, 75%). Crystallization of such a sample from ethanol-water gave an off-white powder m.p. 173-174° C.:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:13][C:14](=O)[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]([NH2:12])=O)=[CH:5][CH:4]=1.CSC.B.Cl.[OH-].[Na+]>C1COCC1.O.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[CH2:10][NH2:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(=O)N[C@@H](C(N)=O)c2ccc(OC)cc2)cc1
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CSC
Product: COc1ccc(CCN[C@@H](CN)c2ccc(OC)cc2)cc1
Yield: 104.7 %

Procedure:
A solution of 2-(R)-(4-methoxyphenyl)-2-[2-(4-methoxyphenyl)-acetylamino]-acetamide (316 g, 0.96 mol) in THF (2 L) is heated to 35° C. and borane dimethyl sulfide (428 mL, 4.28 mol) is added over approximately 1 hour after which the reaction is heated to reflux for 18 hours. After cooling the reaction solution to 8° C. sufficient 3N HCl (approx. 400 mL) is added until the pH of the solution is approximately 1. The reaction solution is then heated to reflux for 1 hour. The reaction is then cooled and the pH adjusted to 8 by the slow addition of 25% aqueous NaOH (300 mL). The entire reaction solution is poured into a vessel containing a mixture of CH2Cl2 (3 L) and water (1.5 L). The organic layer is decanted and the water layer treated with CH2Cl2 (1.5 L). The organic layers are combined, washed with brine (2.5 L) then dried over Na2SO4. The solvent in removed in vacuo to afford 302 g (quantitative yield) of the desired product as an amber colored oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]([CH2:9][NH2:10])([CH2:7][CH3:8])[CH2:5][CH3:6].[CH3:12][C:13]([CH3:15])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:1][O:2][C:3](=[O:11])[C:4]([CH2:5][CH3:6])([CH2:9][NH:10][CH:13]([CH3:15])[CH3:12])[CH2:7][CH3:8]
Reactant: CC(C)=O
Reactant: CCC(CC)(CN)C(=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CCC(CC)(CNC(C)C)C(=O)OC
Reaction time: 8 h
Yield: 52.7 %

Procedure:
Methyl2-(aminomethyl)-2-ethyl-butanoate (Intermediate 201; 8 g, 50 mmol) and acetone (4.35 g, 75 mmol) were added to methanol (230 mL) and stirred for 10 minutes before the rapid addition of sodium triacetoxyborohydride (15.9 g, 75 mmol). The reaction was stirred overnight before being evaporated to dryness. The residue was quenched with saturated K2CO3(aq) (100 mL), extracted with DCM (3×150 mL), dried and solvent evaporated to yield a dark liquids. Purification was achieved via distillation (65 oC @ 0.18 mbar) to yield the title compound as clear oil (5.3 g, 53%)
Reaction SMILES: OCCS(CCN[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)(=O)=O.[NH2:48][CH2:49][CH2:50][NH:51][C@:52]12[CH2:87][CH2:86][C@@H:85]([C:88]([CH3:90])=[CH2:89])[C@@H:53]1[C@@H:54]1[C@@:67]([CH3:70])([CH2:68][CH2:69]2)[C@@:66]2([CH3:71])[C@@H:57]([C@:58]3([CH3:84])[C@@H:63]([CH2:64][CH2:65]2)[C:62]([CH3:73])([CH3:72])[C:61]([C:74]2[CH:83]=[CH:82][C:77]([C:78]([O:80]C)=[O:79])=[CH:76][CH:75]=2)=[CH:60][CH2:59]3)[CH2:56][CH2:55]1>>[NH2:48][CH2:49][CH2:50][NH:51][C@:52]12[CH2:87][CH2:86][C@@H:85]([C:88]([CH3:90])=[CH2:89])[C@@H:53]1[C@@H:54]1[C@@:67]([CH3:70])([CH2:68][CH2:69]2)[C@@:66]2([CH3:71])[C@@H:57]([C@:58]3([CH3:84])[C@@H:63]([CH2:64][CH2:65]2)[C:62]([CH3:73])([CH3:72])[C:61]([C:74]2[CH:75]=[CH:76][C:77]([C:78]([OH:80])=[O:79])=[CH:82][CH:83]=2)=[CH:60][CH2:59]3)[CH2:56][CH2:55]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(NCCS(=O)(=O)CCO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCN)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the hydrolysis method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(2-hydroxyethylsulfonyl)ethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-aminoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (4 mg, 0.006 mmol) as starting material. The title compound was isolated as a white solid (2.4 mg, 67%). LCMS: m/e 573.2 (M+H)+, 2.39 min (method 10). 1H NMR (500 MHz, Acetic acid d4) δ ppm 8.03 (d, J=8.24 Hz, 2H), 7.30 (d, J=8.24 Hz, 2H), 5.37 (d, J=4.27 Hz, 1H), 4.87 (s, 1H), 4.76 (s, 1H), 3.80-3.68 (m, 3H), 3.68-3.59 (m, 1H), 2.97-2.80 (m, 1H), 2.38-1.21 (m, 22H), 1.78 (s, 3H), 1.20 (s, 3H), 1.14 (s, 3H), 1.09 (s, 3H), 1.01 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: [F:1][C:2]1([F:46])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([OH:33])=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[C:9]=2[CH:34]([F:45])[C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC(S(O[CH2:63][C@@H:64]2[CH2:68][O:67][C:66]([CH3:70])([CH3:69])[O:65]2)(=O)=O)=CC=1.O>CN1CCCC1=O.C(OCC)(=O)C>[F:46][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:19])([CH3:20])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:22][CH2:23][N:24]([C:27]4[N:32]=[CH:31][C:30]([O:33][CH2:63][C@@H:64]5[CH2:68][O:67][C:66]([CH3:70])([CH3:69])[O:65]5)=[CH:29][N:28]=4)[CH2:25][CH2:26]3)[C:9]=2[CH:34]([F:45])[C:35]2[CH:36]=[CH:37][C:38]([C:41]([F:43])([F:42])[F:44])=[CH:39][CH:40]=2)[CH2:6][CH2:7]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(O)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: CC1(C)Cc2nc(C3CCN(c4ncc(OC[C@@H]5COC(C)(C)O5)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1
Temperature: 70 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a solution of 389 mg (0.600 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Example 4, in 3 ml of 1-methyl-2-pyrrolidone, 489 mg (1.50 mmol) of cesium carbonate and 344 mg (1.20 mmol) of (S)-(+)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl p-toluene sulfonate were added, and the reaction solution was stirred at 70° C. for 2 hours. After completion of the reaction, water and ethyl acetate were poured into the reaction solution and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=95/5-50/50 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 400 mg (0.524 mmol) of 4-(4,4-difluorocyclohexyl)-2-[1-(5-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}pyrimidin-2-yl)piperidin-4-yl]-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol as a white solid.
Reaction SMILES: S1C=CC=C1.C(O)C.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:45]2[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=2)[CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]([NH:29][C:30]3[C:35]([CH3:36])=[CH:34][C:33]([N+:37]([O-])=O)=[CH:32][C:31]=3[CH3:40])=[O:28])[CH:22]([C:41]([NH:43][CH3:44])=[O:42])[CH2:21]2)=[CH:12][CH:11]=1.[H][H]>[Pd].CO>[NH2:37][C:33]1[CH:34]=[C:35]([CH3:36])[C:30]([NH:29][C:27](=[O:28])[CH2:26][N:23]2[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][CH2:17][CH:16]([C:13]3[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=3)[C:45]3[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=3)[CH2:21][CH:22]2[C:41]([NH:43][CH3:44])=[O:42])=[C:31]([CH3:40])[CH:32]=1
Reactant: CNC(=O)C1CN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CCN1CC(=O)Nc1c(C)cc([N+](=O)[O-])cc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccsc1
Solvent: CCO
Solvent: CO
Product: CNC(=O)C1CN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CCN1CC(=O)Nc1c(C)cc(N)cc1C

Procedure:
To 1 part of a solution of 2 parts of thiophene in 40 parts of ethanol were added 3 parts of 4-[4,4-bis(4-fluorophenyl)butyl]-N-(2,6-dimethyl-4-nitrophenyl)-2-[(methylamino)carbonyl]-1-piperazineacetamide and 120 parts of methanol. The whole was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was suspended in 2,2'-oxybispropane, yielding 2.14 parts of N-(4-amino-2,6-dimethylphenyl)-4-[4,4-bis(4-fluorophenyl)butyl]-2-[(methylamino)carbonyl]-1-piperazineacetamide; mp. 111.7° C. (compound 162).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[Br:12]Br.S(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[Br:12][C:7]1[CH:6]=[C:5]([O:8][CH3:9])[C:4]([O:10][CH3:11])=[CH:3][C:2]=1[I:1]
Reactant: COc1ccc(I)cc1OC
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(Br)c(I)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
4-iodoveratrole (26.0 g. 0.0985M) in acetic acid (25 ml) was treated with bromine (6.5 ml. 0.127M) in acetic acid (30 ml) and stirred at room temperature for one hour. The mixture was diluted with water (300 ml) and treated with sodium bisulfite to discharge the excess bromine. The white solid was filtered, washed with water and dried in vacuo over P2O5 to give 4-bromo-5-iodoveratrole (33.0 g, 95% yield) as a white solid, mp 98°-100° C. (literature: Baker et al., J. Chem. Soc. 3986 (1961), mp 102°-104° C.). NMR (CDCl3) δ 3.83 ppm (s, 6H, (2×) OCH3), 7.06 (s, 1H, ArH), 7.21 (s, 1H, ArH).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3I)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:19]([OH:22])[C:20]#[CH:21]>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>[Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:21]#[C:20][CH2:19][OH:22])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(I)ncn2-c2cccc(Cl)c2C1=O
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CN1Cc2c(C#CCO)ncn2-c2cccc(Cl)c2C1=O

Procedure:
5.20 g (14 mmol) of 7-chloro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one were heated to boiling under reflux for 4 hours with 1.04 g (18.5 mmol) of propargyl alcohol, 70 mg of bis-(triphenyl -phosphine)-palladium(II) dichloride and 10 mg of copper(I) iodide in 35 ml of diethylamine. The reaction mixture was evaporated and the residue was suspended in methylene chloride. The suspension was suction filtered and the suction filter cake was washed with ethyl acetate. After two successive recrystallizations from ethanol and, respectively, N,N-dimethylformamide there was obtained 7-chloro-4,5-dihydro-3-(3-hydroxy-1-propynyl)-5-methyl-6H -imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 250-252°.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[O:9][CH3:10].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[CH3:10][O:9][C:3]1[C:4]([NH2:8])=[N:5][CH:6]=[N:7][C:2]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COc1c(N)ncnc1Cl
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Product: COc1c(N)ncnc1N1CCCC1
Temperature: 25 °C
Yield: 84.5 %

Procedure:
In a flask was added 6-chloro-5-methoxypyrimidin-4-amine (500 mg, 3.13 mmol) and pyrrolidine (0.523 ml, 6.27 mmol) in toluene (5 ml). The reaction was heated to 80 C for 16 hours and then cooled to room temperature. The reaction was then concentrated to a white solid to give 5-methoxy-6-(pyrrolidin-1-yl)pyrimidin-4-amine (514 mg, 84% yield). LC/MS R.T.=1.25 mins (M+H=195.2).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[NH:20][N:19]=2)=[CH:13][C:12]=1[NH:29][C:30]([CH2:32][N:33]([CH3:38])[CH2:34][C:35]([OH:37])=O)=[O:31].[Cl-].[Na+]>CC(N(C)C)=O.O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[NH:20][N:19]=2)=[CH:13][C:12]=1[N:29]1[C:30](=[O:31])[CH2:32][N:33]([CH3:38])[CH2:34][C:35]1=[O:37]
Reactant: CN(CC(=O)O)CC(=O)Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CN1CC(=O)N(c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)C(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
O-Benzotriazol-1-yl-N,N,N′N′-tetramethyluronium tetrafluoroborate (0.108 g, 0.34 mmol) and diisopropylethylamine (0.074 g, 0.57 mmol) were added sequentially at ambient temperature to a stirred solution of N-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenylcarbamoylmethyl]-N-methylglycine (0.103 g, 0.26 mmol) in dimethylacetamide (1 ml), the mixture was stirred at ambient temperature for 1 hour, then it was diluted with water (10 ml). Sodium chloride (1 g) was added, the mixture was stirred at ambient temperature for 30 minutes, then the resulting solid was collected by filtration, washed with water (1 ml) and dried in vacuo to give 1-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]-4-methylpiperazine-2,6-dione (0.071 g) as a beige solid, m.pt. 205–208° C.; 250 MHz 1H-nmr (CDCl3) δ (ppm): 2.4 (s, 3H) (CH3), 3.5 (q, 4H) (2×CH2), 4.25 (s, 2H) (ArCH2—), 7.1 (m, 2H) (2×ArH), 7.25 (m, 1H) (ArH), 7.7–7.85 (m, 3H) (3×ArH), 8.4 (m, 1H) (ArH), 10.35 (s, 1H) (CONH); m/z (M+H)+. 381, 100% purity.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)[N:3]=1.[Br:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[Br:19][C:20]1[CH:25]=[C:24]([C:2]2[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]3[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=3)[N:3]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(Cl)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-methyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example A.4) (0.41 g, 1.5 mmol) and commercially available 3-bromo-benzene-boronic acid (0.33 g, 1.64 mmol) according to the general procedure IIb. Obtained as a light yellow solid (0.30 g, 51%). MS (ISP) 394.0 [(M+H)+]; mp 130° C.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:15][CH:14]=3)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:27][O:28]C1C=CC(CC=O)=CC=1>C(Cl)Cl.CO>[CH3:27][O:28][C:4]1[CH:3]=[CH:2][C:1]([C:7]2[S:11][C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:15][CH:14]=3)=[N:9][CH:8]=2)=[CH:6][CH:5]=1
Reactant: COc1ccc(CC=O)cc1
Reactant: c1ccc(-c2cnc(Nc3ccc(OCCN4CCCC4)cc3)s2)cc1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(-c2cnc(Nc3ccc(OCCN4CCCC4)cc3)s2)cc1

Procedure:
The title compound is prepared as described in Example 1 for (5-phenyl-thiazol-2-yl)-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine but using (4-methoxy-phenyl)-acetaldehyde. Title compound: ES-MS: 396.0 [M+H]+; single peak at tR=6.36 min (System 1); R4=0.28 (CH2Cl2/MeOH, 80/20).
Reaction SMILES: Cl.[C:2]1([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][CH2:18]O)[CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C1([CH:37](C2C=CC=CC=2)[N:38]2CCC(CCCCOS(C)(=O)=O)CC2)C=CC=CC=1.[C-]#N.[Na+]>ClCCl.CN(C=O)C.C1OCCOCCOCCOCCOC1>[C:2]1([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:37]#[N:38])[CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: CS(=O)(=O)OCCCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: C1COCCOCCOCCOCCO1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#CCCCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
24.9 (69.2 mmol) 4-(1-diphenylmethyl-piperidin-4-yl)-butan-1-ol hydrochloride are suspended in 160 ml absolute dichloromethane and cooled to ca. 0° C. under moisture exclusion. At this temperature, 16.0 g (159 mmol) TEA are first added and thereafter a solution of 0.3 g (90.0 mmol) methanesulfonoic acid chloride in a little absolute dichloromethane is added dropwise. The mixture is then subsequently stirred for three hours at RT and then placed in ice water. The organic phase is washed once with 50 ml water, dried over sodium sulfate and the solvent is removed under vacuum. The resulting methanesulfonoic acid-4-(1-diphenylmethyl-piperidin-4-yl)-butyl ester is dissolved in 120 ml DMF without further purification and with 7.7 g (158 mmol) sodium cyanide and two drops 15-crown-5 and stirred for six hours at 65° C. After cooling, the mixture is poured in ice water. The precipitated solid is drawn off and dried at 40° C. in high-vacuum. The solid is processed further without additional purification. Yield: 19.9 g (86%).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15].[I:21][C:22]1[CH:23]=[C:24]2[C:40]([C:41]([NH:43][CH3:44])=[O:42])=[C:39]([C:45]3[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=3)[O:38][C:25]2=[N:26][C:27]=1[N:28]([CH2:33][CH2:34][CH2:35][CH:36]=[O:37])[S:29]([CH3:32])(=[O:31])=[O:30]>C1COCC1>[OH:37][CH:36]([CH2:35][CH2:34][CH2:33][N:28]([C:27]1[N:26]=[C:25]2[O:38][C:39]([C:45]3[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=3)=[C:40]([C:41](=[O:42])[NH:43][CH3:44])[C:24]2=[CH:23][C:22]=1[I:21])[S:29]([CH3:32])(=[O:31])=[O:30])[C:14]([CH3:16])([CH3:15])[C:13]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(C)C
Reactant: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCCC=O)S(C)(=O)=O)c(I)cc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C)(C)C(O)CCCN(c1nc2oc(-c3ccc(C)cc3)c(C(=O)NC)c2cc1I)S(C)(=O)=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of diisopropylamine (1.4 eq., 18 μl) in THF (0.5 ml) cooled at 0° C. was added n-BuLi (1.6 M in hexane, 1.2 eq., 68 μl). The resultant solution was stirred at 0° C. for 10 min and cooled to −78° C., and then a solution of ethyl isobutyrate (1 eq., 10.5 mg) in THF (0.5 ml) was added. After the reaction mixture was stirred at −78° C. for 1 h, a solution of 5-iodo-N-methyl-6-(N-(4-oxobutyl)methylsulfonamido)-2-p-tolylfuro[2,3-b]pyridine-3-carboxamide (1 eq., 50.0 mg) in THF (1 ml) was introduced. The reaction mixture was stirred at −78° C. for 1 h, quenched with saturated aqueous NH4Cl, and extracted with diethyl ether. The combined ethereal layers were washed with brine, dried over MgSO4, filtered, and concentrated to yield the crude title compound which was used in next step without purification.