Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[BH4-].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:11][C@@H:12]3[N:18]([CH:19]=2)[C:17](=[O:20])[C:16]2[CH:21]=[C:22]([O:66][CH3:67])[C:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]4[C:63]([O:64][CH3:65])=[CH:62][C:35]5[C:36](=[O:61])[N:37]6[CH:52]=[C:51]([C:53]7[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=7)[CH2:50][C@H:38]6[C:39](=O)[N:40](COCC[Si](C)(C)C)[C:34]=5[CH:33]=4)=[CH:24][C:15]=2[N:14](COCC[Si](C)(C)C)[C:13]3=O)=[CH:6][CH:5]=1.CCO>C1COCC1>[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:11][C@@H:12]3[N:18]([CH:19]=2)[C:17](=[O:20])[C:16]2[CH:21]=[C:22]([O:66][CH3:67])[C:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]4[C:63]([O:64][CH3:65])=[CH:62][C:35]5[C:36](=[O:61])[N:37]6[CH:52]=[C:51]([C:53]7[CH:54]=[CH:55][C:56]([O:59][CH3:60])=[CH:57][CH:58]=7)[CH2:50][C@H:38]6[CH:39]=[N:40][C:34]=5[CH:33]=4)=[CH:24][C:15]=2[N:14]=[CH:13]3)=[CH:6][CH:5]=1
Reactant: COc1ccc(C2=CN3C(=O)c4cc(OC)c(OCCCCCOc5cc6c(cc5OC)C(=O)N5C=C(c7ccc(N)cc7)C[C@H]5C(=O)N6COCC[Si](C)(C)C)cc4N(COCC[Si](C)(C)C)C(=O)[C@@H]3C2)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(C2=CN3C(=O)c4cc(OC)c(OCCCCCOc5cc6c(cc5OC)C(=O)N5C=C(c7ccc(N)cc7)C[C@H]5C=N6)cc4N=C[C@@H]3C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.6 %

Procedure:
Fresh LiBH4 (66 mg, 3.04 mmol) was added to a stirred solution of the SEM-dilactam 12 (428 mg, 0.42 mmol) in THF (3 mL) and EtOH (3 mL) at 0° C. (ice bath). The ice bath was removed and the reaction mixture was allowed to reach room temperature (vigorous effervescence). After 2 hours LC/MS analysis indicated the complete consumption of starting material. The reaction mixture was poured onto ice (50 mL) and allowed to warm to room temperature with stirring. The aqueous mixture was extracted with DCM (3×50 mL) and the combined organic layers washed with H2O (50 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo. The resulting residue was treated with DCM (2 mL), EtOH (5 mL), H2O (2.5 mL) and silica gel (3.7 g). The viscous mixture was allowed to stir at room temperature for 3 days. The mixture was filtered through a sinter funnel and the silica residue washed with 90% CHCl3: 10% MeOH (˜250 mL) until UV activity faded completely from the eluent. The organic phase was dried (MgSO4) filtered and evaporated in vacuo to provide the crude material. The crude product was purified by flash chromatography (99.5% CHCl3: 0.5% MeOH to 97.5% CHCl3: 2.5% MeOH in 0.5% increments)) to provide the pure C2/C2′ aryl PBD dimer 13 (59 mg, 52%).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]([CH3:24])=[C:22]3[C:17]([C:18](=O)[NH:19][N:20]=[C:21]3[CH3:25])=[C:16]2[CH3:27])=[CH:11][CH:10]=1)[CH3:7]>>[Cl:3][C:18]1[C:17]2=[C:16]([CH3:27])[N:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:6][CH3:7])=[CH:10][CH:11]=3)[C:23]([CH3:24])=[C:22]2[C:21]([CH3:25])=[N:20][N:19]=1
Reactant: CCOc1ccc(-n2c(C)c3c(C)n[nH]c(=O)c3c2C)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: CCOc1ccc(-n2c(C)c3c(C)nnc(Cl)c3c2C)cc1
Temperature: 25 °C

Procedure:
A solution of POCl3 (15 mL) and 6-(4-ethoxyphenyl)4,5,7-trimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (1.5 g) were combined and heated at reflux for 48 h. The reaction mixture was allowed to cool to rt, and was quenched by the careful addition of water (50 mL) followed by a saturated aqueous solution NaHCO3 (50 mL). The reaction mixture was extracted with CH2Cl2 (5×50 mL), and the combined organic extracts were dried (MgSO4) and concentrated under reduced pressure to yield 1-chloro-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine as a yellow/green solid. MS (ESI) 316 (M+H)+.
Reaction SMILES: C[Si]([CH:5]=[CH:6][CH2:7][NH2:8])(C)C.C([Li])CCC.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>C(OCC)C>[CH2:23]([Sn:18]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:19][CH2:20][CH2:21][CH3:22])/[CH:5]=[CH:6]\[CH2:7][NH2:8])[CH2:24][CH2:25][CH3:26]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: C[Si](C)(C)C=CCN
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](/C=C\CN)(CCCC)CCCC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
To a solution of N-trimethylsilylallylamine (21.0 mL, 125. mmol) in diethyl ether (323 mL) at 0° C. under an atmosphere of nitrogen was added 2.5M n-butyllithium in hexanes (100. mL, 250. mmol). The solution was stirred at 0° C. for 15 minutes then the reaction was allowed to warm to room temperature and stirred for 16 hours. To the reaction mixture was added a solution of tributyltin chloride (33.6 mL, 124. mmol) in diethyl ether (158 mL) slowly at 0° C., then the reaction was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was quenched with saturated ammonium chloride solution then extracted twice with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and then concentrated. The residue was purified using column chromatography on silica gel (400 gr Analogix column, gradient DCM to 10% MeOH in DCM over 30 minutes) to give the product (30.6 g, 71%). 1H NMR (400 MHz, CDCl3) δ: 6.81-6.37 (m, 1H), 6.03-5.76 (m, 1H), 3.31-3.17 (m, 2H), 1.60-1.22 (m, 12H), 1.00-0.79 (m, 15H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4]([CH2:6][C:7]([OH:9])=[O:8])[OH:5].C(OC(=NC(C)C)NC(C)C)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:28](Cl)Cl>CN(C=O)C>[CH3:28][O:8][C:7](=[O:9])[CH2:6][CH:4]([OH:5])[C:3]([O:2][CH2:1][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]
Reactant: COC(=O)C(O)CC(=O)O
Reactant: CC(C)N=C(NC(C)C)OCc1ccccc1
Reactant: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)CC(O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Malic acid monomethyl ester (Example 2A) was dissolved in DMF and one equivalent of O-benzyl-N,N'-diisopropylisourea was added. The reaction mixture was stirred at room temperature for about 17 hours. Methylene chloride was added to the mixture and the suspension was filtered to remove the diisopropylurea. The filtrate was further diluted with methylene chloride and washed with water, 10% aqueous sodium carbonate, water, and with brine and was dried over magnesium sulfate. After filtration and evaporation the monobenzyl monomethyl ester was obtained as an oil.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][CH3:19])[CH:10]=1)[CH2:4][CH:5]([OH:8])[CH2:6][CH3:7].[C:20]([NH:23][C:24]1[CH:34]=[CH:33][CH:32]=[C:26]2[C:27]([O:29][C:30](=O)[C:25]=12)=[O:28])(=[O:22])[CH3:21].C(N(CC)CC)C>CN(C=O)C>[CH2:18]([O:17][C:11]1[CH:10]=[C:9]([CH:3]([N:2]2[C:30](=[O:29])[C:25]3[C:26](=[CH:32][CH:33]=[CH:34][C:24]=3[NH:23][C:20](=[O:22])[CH3:21])[C:27]2=[O:28])[CH2:4][CH:5]([OH:8])[CH2:6][CH3:7])[CH:14]=[CH:13][C:12]=1[O:15][CH3:16])[CH3:19]
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Reactant: CCOc1cc(C(N)CC(O)CC)ccc1OC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc(C(CC(O)CC)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Temperature: 85 °C
Yield: 77.2 %

Procedure:
A stirred mixture of 5-amino-5-(3-ethoxy-4-methoxyphenyl)pentan-3-ol hydrochloride(1.15 g, 3.97 mmol), 3-acetamidophthalic anhydride (0.82 g, 3.97 mmol) and triethylamine (0.4 g, 3.97 mmol) in DMF (20 mL) was heated at 80-90° C. for 6 hours. The mixture was then concentrated in vacuo. The residue was dissolved in ethyl acetate (80 mL), washed with water (30 mL), brine (30 mL) and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by chromatography (Silica gel, methylene chloride:ethyl acetate 8:2) to give N-{2-[1-(3-ethoxy-4-methoxyphenyl)-3-hydroxypentyl]-1,3-dioxoisoindolin-4-yl}acetamide (1.35 g, 77%) ; 1H NMR (CDCl3) δ 9.52 (s, 1H), 8.71 (d, J=8.4 Hz, 1H), 7.63 (t, J=7.6 Hz, 1H), 7.48 (d, J=7.3 Hz, 1H), 7.09-7.07 (m, 2H), 6.83-6.80 (m, 1H), 5.61-5.55 (J=3.9, 11.9 Hz, 1H), 4.11 (q, J=6.9 Hz, 2H), 3.84 (s, 3H), 3.47 (m, 1H), 2.97-2.86 (m, 1H), 2.25 (s, 3H), 2.06-1.95 (m, 1H), 1.78 (b, 1H), 1.62-1.52 (m, 2H), 1.45 (t, J=7.0 Hz, 3H), 0.95 (t, J=7.3 Hz, 3H); 13C NMR (CDCl3) δ 170.39, 169.23, 168.11, 148.94, 148.14, 137.32, 135.83, 131.81, 131.19, 124.72, 120.30, 117.94, 115.31, 112.87, 111.09, 70.01, 64.36, 55.86, 51.29, 37.92, 30.46, 24.92, 14.73, 9.90.
Reaction SMILES: C([O-])(=[O:3])C.[Pb+2].C([O-])(=O)C.[CH3:10][C:11]1[CH2:17][C:15](=[O:16])[CH2:14][C:13]([CH3:19])([CH3:18])[CH:12]=1.O=O>N1C=CC=CC=1>[O:3]=[C:12]1[C:13]([CH3:19])([CH3:18])[CH2:14][C:15](=[O:16])[CH:17]=[C:11]1[CH3:10]
Reactant: CC1=CC(C)(C)CC(=O)C1
Reactant: CC(=O)[O-]
Agent: O=O
Agent: [Pb+2]
Solvent: c1ccncc1
Product: CC1=CC(=O)CC(C)(C)C1=O

Procedure:
3,8 g. of lead acetate in 100 ml. of pyridine are treated with 69 g. of β-isophorone. The mixture is gassed with oxygen at 70° C. for 2 hours with intensive stirring and subsequently worked up by distillation. [b.p. 62°-64° C., 0,2 Torr]. The conversion of β-isophorone used amounts to 31 g. corresponding 45%. Ketoisophorone is obtained in a yield of 26 g. corresponding to 76%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]2[N:11]=[C:12]([CH3:23])[C:13]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=3[CH3:22])=[C:9]2[N:8]=[C:7]([CH3:24])[CH:6]=1.[O:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[O:25]1[CH2:30][CH2:29][CH:28]([NH:1][CH2:2][CH2:3][NH:4][C:5]2[N:10]3[N:11]=[C:12]([CH3:23])[C:13]([C:14]4[C:15]([CH3:22])=[CH:16][C:17]([Cl:21])=[CH:18][C:19]=4[CH3:20])=[C:9]3[N:8]=[C:7]([CH3:24])[CH:6]=2)[CH2:27][CH2:26]1
Reactant: Cc1cc(NCCN)n2nc(C)c(-c3c(C)cc(Cl)cc3C)c2n1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1cc(NCCNC2CCOCC2)n2nc(C)c(-c3c(C)cc(Cl)cc3C)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
Dissolve 7-(2-aminoethylamino)-2,5-dimethyl-3-(4-chloro-2,6-dimethylphenyl)-pyrazolo [1,5-a] pyrimidine (0.183 g, 5.4×10−4 mol, 339.2 g/mol) in dichloroethane (5 mL) and add tetrahydro-4H-pyran-4-one (0.068 g, 0.060 mL, 100.12 g/mol) and sodium triacetoxyborohydride (0.172 g, 211.94 g/mol). To the resultant slurry, add glacial acetic acid (0.032 mL, 5.4×10−4 mol) and stir at ambient temperature under N2 for 3 hours. Partition between CH2Cl2 (3 mL) and 1.0 N NaOH (10 mL), then separate the layers and chromatograph the CH2Cl2 layer using [10% (2.0M NH3 in MeOH)/90% CH2Cl2] as eluent. Obtained 0.16 g white solid-foam upon evaporation. TLC: Rf=0.65. LCMS=422.5 (MH+); 420.5 (M−). 1H-NMR (CDCl3): 6.67 (s, 2H); 5.79 (d, 1H, J=8.8 Hz); 3.98 (br. d, 2H, J=12 Hz); 3.78 (s, 3H); 3.52 (t, 2H, J=6 Hz); 3.39 (br. t, 2H, J=12 Hz); 3.37 (s, 1H); 3.04 (t, 2H, J=6 Hz); 2.75-2.81 (m, 2H); 2.40 (s, 3H); 2.18 (s, 3H); 2.00 (s, 6H); 1.89 (br. d, 2H, J=12 Hz); 1.47-1.53 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[C:12]([CH3:25])=[N:13][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)[C:15]=3[CH3:16])=[CH:9][N:8]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:44]2[CH:49]=[CH:48][C:47]([C:50]3[CH:55]=[CH:54][N:53]=[CH:52][CH:51]=3)=[CH:46][CH:45]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[F:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:14]1[C:15]([CH3:16])=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:44]4[CH:45]=[CH:46][C:47]([C:50]5[CH:51]=[CH:52][N:53]=[CH:54][CH:55]=5)=[CH:48][CH:49]=4)[CH:3]=3)[N:8]([S:26]([C:29]3[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=3)(=[O:28])=[O:27])[CH:9]=2)[C:12]([CH3:25])=[N:13]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(Br)cnc32)cc1
Reactant: CC1(C)OB(c2ccc(-c3ccncc3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(-c5ccncc5)cc4)cnc32)cc1
Yield: 70.8 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (step-i of example-14) (150 mg, 0.27 mmol) was coupled with 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridine (intermediate 45) (91.44 mh, 0.32 mmol) in sodium carbonate (85.86, 0.81 mmol), toluene/ethanol/water (5/5/2 ml). This afforded 120 mg (70.5% yield) of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([CH:24]=[O:25])=[C:5]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH2:32]([Mg]Cl)[CH2:33][CH2:34][CH3:35].C(OCC)(=O)C.C(OC(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=1)[C:6]([CH:24]([OH:25])[CH2:32][CH2:33][CH2:34][CH3:35])=[C:5]2[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CS(=O)(=O)c1ccc(Cn2c(C=O)c(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1
Reactant: CCCC[Mg]Cl
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCC(O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
In the same manner as in Example 313, the title compound was synthesized using 6-chloro-2-(4-methanesulfonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbaldehyde and a solution (2M) of n-butylmagnesium chloride in THF. Crystals (ethyl acetate-diisopropyl ether).
Reaction SMILES: B(F)(F)F.[CH3:5][CH2:6][O:7][CH2:8][CH3:9].[Cl:10][C:11]1[N:16]=[CH:15]C(N)=[CH:13][C:12]=1C.N(OC(C)(C)C)=[O:20]>COCCOC.ClCCl.CCCCC>[C:6]([O:7][C:8]1[CH:15]=[N:16][C:11]([Cl:10])=[C:12]([CH3:13])[CH:9]=1)(=[O:20])[CH3:5]
Reactant: CCOCC
Reactant: Cc1cc(N)cnc1Cl
Reactant: CC(C)(C)ON=O
Agent: FB(F)F
Solvent: COCCOC
Solvent: ClCCl
Solvent: CCCCC
Product: CC(=O)Oc1cnc(Cl)c(C)c1
Temperature: -10 °C
Reaction time: 0.42 h
Yield: 60 %

Procedure:
In a 100 mL R.B. flask, Boron trifluoride diethyl etherate (1.8 mL, 0.0143 mol, Sigma Aldrich) was added drop wise to a cooled mixture (−15° C.) of 6-chloro-5-methylpyridine-3-amine (1.0 g, 0.0070 mol) in DME (7.5 mL) and dichloromethane (2.5 mL). Then tert-butyl nitrite (0.85 g, 0.0082 mol, Sigma-Aldrich) was added drop wise and the reaction mixture was stirred at −10° C. for 25 min. The reaction mixture was allowed to warm to 0° C. and stirred for additional 20 min. The reaction mixture was diluted with pentane (50 mL) and the tetrafluoroborate diazonium salt was collected by filtration. The salt was dissolved in acetic anhydride (10 mL) and heated at 95° C. for 2 h. The reaction mixture was cooled to ambient temperature and then partitioned between ethyl acetate (50 mL) and sat.aq.sodium bicarbonate solution (100 mL). The aqueous solution was separated and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford a brown oil. This oil was purified by column chromatography on silica gel, eluting with 5% ethyl acetate in petroleum ether to give 6-chloro-5-methylpyridine-3-yl acetate as pale yellow oil (780 mg, 62%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[S:18][C:17]([N:19]([CH3:30])[CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)=[N:16][N:15]=1.CC(O)=[O:33].CC(OC(C)=O)=O>CO.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[C:3]([C:14]2[S:18][C:17]([N:19]([CH3:30])[CH:20]3[CH2:21][C:22]([CH3:29])([CH3:28])[NH:23][C:24]([CH3:26])([CH3:27])[CH2:25]3)=[N:16][N:15]=2)=[C:4]([OH:33])[CH:5]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:7]=1
Reactant: CN(c1nnc(-c2ccc(-c3cnn(C)c3)cc2Cl)s1)C1CC(C)(C)NC(C)(C)C1
Reactant: CC(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: CN(c1nnc(-c2c(O)cc(-c3cnn(C)c3)cc2Cl)s1)C1CC(C)(C)NC(C)(C)C1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 5-(2-chloro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (Example 25) (125 mg, 0.281 mmol) in 1:1 AcOH:Ac2O (2.8 mL) was added Phl(OAc)2 (127 mg, 0.393 mmol) followed by Pd(OAc)2 (6 mg, 0.028 mmol). The reaction mixture was warmed to 80° C. and stirred for 48 hours. The reaction mixture was cooled to room temperature, then diluted with MeOH (10 mL) and loaded onto a 2 g SCX cartridge (pre-wet with MeOH). The cartridge was washed with MeOH (10 mL) then flushed with 7M NH3 in MeOH (10 mL). The MeOH/NH3 was removed in vacuo to afford the crude product as a brown glass-like solid. The crude material was taken up in MeOH (3 mL), passed through a syringe filter, and purified by mass-directed preparative HPLC under basic conditions (5 mM NH4OH) to give the crude product as a brown glass-like solid. The crude solid was re-dissolved in MeOH (3 mL) and re-purified by UV-directed preparative HPLC under acidic conditions (0.1% TFA), collecting at 348 nm. The combined fractions were loaded onto a 1 g SCX cartridge (pre-wet with MeOH) and the cartridge washed with MeOH (10 mL) then flushed with 7M NH3 in MeOH (10 mL). The MeOH/NH3 was removed in vacuo to afford the title compound as an off-white glass-like solid (6 mg, 5% yield). LC-MS: Rt 0.52 mins; MS m/z 461.3/463.2 [M+H]+ [Method D]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.26 (s, 1H), 7.95 (s, 1H), 7.32 (s, 1H), 7.15 (d, J=1.52 Hz, 1H), 4.35 (br. s., 1H), 3.87 (s, 3H), 3.01 (s, 3H), 1.65 (d, J=9.60 Hz, 2H), 1.48 (br. s., 2H), 1.22 (br. s., 6H), 1.11 (br. s., 6H).
Reaction SMILES: C(OC(=O)C[C@@H](N1C=CC(C2C=CC=CC=2)=C1)C(N[C@H](C(=O)NC)C(C)(C)C)=O)C1C=CC=CC=1.[CH2:36]([O:43][C:44](=[O:77])[CH2:45][C@@H:46]([NH:69][C:70](OC(C)(C)C)=O)[C:47]([NH:49][C@@H:50]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[CH2:51][O:52][C:53]([O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:54])=[O:48])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CC(C)(C)[C@H](NC(=O)[C@H](N1C=[CH:93][C:92]([C:95]2[CH:100]=[CH:99][C:98]([C:101]3[CH:106]=[CH:105][N:104]=[CH:103][CH:102]=3)=[CH:97][CH:96]=2)=[CH:91]1)CC(O)=O)CO.CO.C(Cl)Cl>ClCCCl>[CH2:36]([O:43][C:44](=[O:77])[CH2:45][C@@H:46]([N:69]1[CH:70]=[CH:91][C:92]([C:95]2[CH:100]=[CH:99][C:98]([C:101]3[CH:106]=[CH:105][N:104]=[CH:103][CH:102]=3)=[CH:97][CH:96]=2)=[CH:93]1)[C:47]([NH:49][C@@H:50]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[CH2:51][O:52][C:53]([O:55][CH2:56][C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1)=[O:54])=[O:48])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(C)[C@@H](CO)NC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccc(-c3ccncc3)cc2)c1
Reactant: CC(C)(C)OC(=O)N[C@H](CC(=O)OCc1ccccc1)C(=O)N[C@H](COC(=O)OCc1ccccc1)c1ccccc1
Agent: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccccc2)c1)C(C)(C)C
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CO
Product: O=C(C[C@H](C(=O)N[C@H](COC(=O)OCc1ccccc1)c1ccccc1)n1ccc(-c2ccc(-c3ccncc3)cc2)c1)OCc1ccccc1
Yield: 56 %

Procedure:
According to the procedure described in Example 1(b) for the preparation of N-(2,2-dimethyl-1(S)-methylcarbamoylpropyl)-3(R)-(3-phenyl-1H-pyrrol-1-yl)succinamic acid benzyl ester, N-(2-benzyloxycarbonyloxy-1(S)-phenyl-ethyl)-3(R)-(t-butoxycarbonylarnino)succinamic acid benzyl ester and 2,5-dimethoxy-3-(4-pyridin-4-yl-phenyl)-tetrahydrofuran (prepared as described in Example 5(a)) were condensed in wet 1,2-dichloroethane at 80-90° C. after 18 hours. Flash column chromatagraphy with 4% MeOH/CH2Cl2 as eluant gave 140 mg (56%) of N-(2-benzyloxycarbonyloxy-1(S)-phenylethyl)-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid benzyl ester as a yellow solid, mp 138-40° C. 1H NMR (CDCl3): δ 8.66 (bs, 2H), 7.60 (s, 5H), 7.50 (d, 3H, J=5.3 Hz), 7.34-7.22 (m, 10H), 7.19 (d, 1H, J=2.2 Hz), 7.17 (d, 1H, J=1.9 Hz), 7.09 (t, 1H, J=1.9 Hz), 6.77 (dd, 1H, J=2.5, 2.8 Hz), 6.57 (bt, 1H, J=1.9, 2.5 Hz), 6.24 (d, 1H, J=7.8 Hz), 5.26 (m, 1H), 4.25 (dd, 1H, J=7.2, 11.5 Hz), 3.44 (dd, 1H, J=7.2, 16.8 Hz), 3.00 (dd, 1H, 8.7, 16.8 Hz). IR (KBr): 2985, 1738, 1657, 1598, 1560, 1495, 1202, 815, 697 cm−1. HRFABMS: Calculated for C42H37N3O6Cs (M+Cs+): 812.1737. Found: 812.1712. Anal. Calculated for C42H37N3O6•0.25 CHCl3: C, 71.51; H, 5.29. Found: C, 71.72; H, 5.60.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11]O)=[C:9]([S:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)[N:8]([CH:22]([CH3:24])[CH3:23])[N:7]=1)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:45]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11][Br:45])=[C:9]([S:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)[N:8]([CH:22]([CH3:24])[CH3:23])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nn(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)c1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)c1nn(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)c1CBr
Reaction time: 8 h
Yield: 62.7 %

Procedure:
To a solution of 504 mg 5-(3,5-dichlorophenylthio)-4-hydroxymethyl-1-isopropyl-1H-pyrazole-3-carboxylic acid ethyl ester in 5 ml of dichloromethane was added 375 mg of triphenylphosphine and 474 mg of carbon tetrabromide. The reaction mixture was stirred overnight. The solvent was removed and the residue was purified by flash chromatography on silica gel using diethyl ether/iso-hexane for the elution to give 367 mg of 4-bromomethyl-5-(3,5-dichlorophenylthio)-1-isopropyl-1H-pyrazole-3-carboxylic acid ethyl ester as a colourless gum. Mass spectrum (ES) m/z 451 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C:9]2[C:10]3[CH2:31][NH:30][CH2:29][CH2:28][C:11]=3[N:12]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][N:24]=[C:23]4[CH3:27])=[CH:18][CH:17]=3)[N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:32](=O)[CH2:33][OH:34]>>[CH:1]1([CH2:7][CH2:8][C:9]2[C:10]3[CH2:31][N:30]([CH2:32][CH2:33][OH:34])[CH2:29][CH2:28][C:11]=3[N:12]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][N:24]=[C:23]4[CH3:27])=[CH:18][CH:17]=3)[N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(CCC4CCCCC4)n2)CNCC3)cc1
Reactant: O=CCO
Product: Cc1nccn1-c1ccc(Nc2nc(CCC3CCCCC3)c3c(n2)CCN(CCO)C3)cc1

Procedure:
2-(4-(2-Cyclohexylethyl)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanol was synthesised from 4-(2-cyclohexylethyl)-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (example 47a) and glycol aldehyde according to the general procedure for reductive amination.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1)=[O:6].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(N(CC)CC)C>ClCCCl>[N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][CH:7]=1.[O:6]1[CH2:2][CH2:3][N:4]=[CH:5]1
Reactant: O=C(NCCO)c1ccc2ccccc2n1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: C1=NCCO1
Product: c1ccc2ncccc2c1
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
N-(2-hydroxyethyl)quinoline-2-carboxamide was dissolved in DCE (40 mL) in an oven dried 100 mL pear bottomed flask. To a 250 mL 3 necked round bottomed flask was fitted a water condenser, and a magnetic stir bar was added. p-Toluene sulfonyl chloride (2.2288 g, 11.65 mmol) and N,N-dimethylaminopyridine (95.4 mg, 0.78 mmol) were added to the reaction flask. The flask was placed under N2 atmosphere. DCE (30 mL) was added to the reaction flask and cooled to −5° C. The reaction flask was charged with triethylamine (5.50 mL, 39 mmol). The reaction mixture was stirred for 10 min and allowed react according to the formula