Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([C:21]3[CH2:26][CH2:25][N:24]([S:27]([CH2:30][C:31](OCC)=O)(=[O:29])=[O:28])[CH2:23][CH:22]=3)=[CH:17][C:15]=2[N:16]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C1C[O:45][CH2:44]C1>>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([C:21]3[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:44][OH:45])(=[O:28])=[O:29])[CH2:23][CH:22]=3)=[CH:17][C:15]=2[N:16]=1
Reactant: CCOC(=O)CS(=O)(=O)N1CC=C(c2ccc3oc(-c4ccc(S(C)(=O)=O)cc4F)nc3c2)CC1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CS(=O)(=O)c1ccc(-c2nc3cc(C4=CCN(S(=O)(=O)CCCO)CC4)ccc3o2)c(F)c1
Reaction time: 1.5 h

Procedure:
Example 59 (200 mg, 0.42 mmol) was dissolved in DCM (30 ml) and added TFA (1.5 ml, 9.2 mmol). This mixture was stirred at rt for 3 h and DCM was removed on rotavapour to obtain a residue. Residue was co-distilled with diethyl ether to obtain 2-(2-fluoro-4-(methyl sulfonyl)phenyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d]oxazole 2,2,2-trifluoroacetate (210 mg). 2-(2-fluoro-4-(methylsulfonyl)phenyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d]oxazole 2,2,2-trifluoroacetate (200 mg, 0.4 mmol) was dissolved in DCM (10 ml) and added TEA (0.46 ml, 3.3 mmol). This mixture was stirred at rt for 30 mins. After 30 mins reaction mixture cooled to 0° C. and added ethyl 3-(chlorosulfonyl)propanoate (164 mg, 0.4 mmol). This reaction continued for 30 mins at rt. Work up (H2O/DCM) followed by column purification on combiflash using a gradient mixture of EtOAc and Petether (45:55) as eluent afforded ethyl 2-{4-[2-(2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}-5,6-dihydropyridin-1(2H)-ylsulfonyl)acetate (120 mg). Ethyl 2-{4-[2-(2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}-5,6-dihydropyridin-1(2H)-ylsulfonyl)acetate (100 mg, 0.19 mmol) was dissolved in THF (5 ml) and added Lithiumaluminium hydride (14 mg, 0.38 mmol) at 0° C. This mixture was stirred at same temperature for 90 mins. After completion of the reaction, reaction mass quenched with 1N HCl (7 ml). Work up (DCM/H2O) followed by purification on combiflash using a gradient mixture of EtOAc and Petether (80:20) as eluent afforded the titled compound (40 mg) as a white solid. M.P.: 184-186° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.48 (t, J 8.1, 1H), 8.06 (dd, J 1.6, 10.1, 1H), 8.00-7.94 (m, 2H), 7.84 (d, J 8.6, 1H), 7.63 (dd, J 1.8, 8.5, 1H), 6.29 (s, 1H), 4.64 (t, J 5.3, 1H), 3.94 (d, J 2.9, 2H), 3.50-3.42 (m, 4H), 3.36 (s, 3H), 3.18-3.10 (m, 2H), 2.70-2.62 (m, 2H), 1.88-1.80 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][O:5][C:4]2[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28]C(=O)OC(C)(C)C)[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]([C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)=[CH:12][C:3]1=2.CO>ClCCl>[NH2:28][C:24]1([C:21]2[CH:22]=[CH:23][C:18]([C:10]3[C:11]([C:13]4[CH:17]=[CH:16][S:15][CH:14]=4)=[CH:12][C:3]4[N:2]([CH3:1])[C:7](=[O:8])[CH2:6][O:5][C:4]=4[N:9]=3)=[CH:19][CH:20]=2)[CH2:27][CH2:26][CH2:25]1
Reactant: CN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccsc3)cc21
Solvent: CO
Solvent: ClCCl
Product: CN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccsc3)cc21
Reaction time: 12 h
Yield: 29 %

Procedure:
Tert-butyl (1-(4-(1-methyl-2-oxo-7-(thiophen-3-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (25 mg, 0.051 mmol) was dissolved in dichloromethane (0.5 ml); this solution was added to a scx-2 catch and release cartridge (5 g), precalibrated using methanol (15 ml) and dichloromethane (15 ml). After allowing binding for 12 hours, the column was washed with methanol (6 ml), then the product eluted with 7M ammonia in methanol (4×2 ml). The combined product fractions were concentrated to dryness under reduced pressure to give the desired product as a white solid (5.8 mg, 30% yield). LCMS (Method D): RT=0.777 min, M+1=393. 1H-NMR (500 MHz, CD3OD) δ 7.35-7.29 (3H, m), 7.28-7.25 (1H, dd), 7.21-7.18 (1H, s), 7.17-7.14 (1H, dd), 7.07-7.03 (1H, dd), 6.71-6.67 (1H, dd), 4.80 (2H, s), 3.32 (3H, s), 2.51-2.37 (4H, m), 2.25-2.13 (1H, m).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH3:13])[C:9]2[CH:8]=[CH:7][CH2:6][C:5]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([OH:14])[C:4]=2[N:3]=1.[Cl:21][C:22]1[N:23]=[CH:24][N:25]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][C:28]=2[O:34][CH3:35])[CH:26]=1>O1CCOCC1.C(O)(=O)C>[Cl:21][C:22]1[N:23]=[CH:24][N:25]([C:27]2[CH:33]=[CH:32][C:30]([NH:31][C:2]3[N:11]=[C:10]([NH:12][CH3:13])[C:9]4[CH:8]=[CH:7][CH2:6][C:5]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)([OH:14])[C:4]=4[N:3]=3)=[CH:29][C:28]=2[O:34][CH3:35])[CH:26]=1
Reactant: CNc1nc(Cl)nc2c1C=CCC2(O)c1ccccc1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1C=CCC2(O)c1ccccc1
Yield: 43.6 %

Procedure:
A solution of 2-chloro-4-(methylamino)-8-phenyl-7,8-dihydroquinazolin-8-ol (25 mg) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (29 mg) in dioxane (0.2 mL) and acetic acid (0.2 mL) was heated at 85° C. for 4 h. THF was removed in vacuo, and the residue was purified by reverse phase preparative to give the title compound (as its TFA salt) as an oil (18 mg). LC-MS (M+H)+=475.26. 1H NMR (TFA salt, 500 MHz, CD3OD) δ ppm 7.2-7.9 (m), 6.56 (1H, m), 6.18 (1H, m), 3.94 (3H, s), 3.20 (3H, s), 3.10 (2H, m).
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[F:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[O:43][C:44]3[CH:54]=[C:53]([N:55]([CH3:60])[S:56]([CH3:59])(=[O:58])=[O:57])[C:52](B4OC(C)(C)C(C)(C)O4)=[CH:51][C:45]=3[C:46]=2[C:47]([NH:49][CH3:50])=[O:48])=[CH:38][CH:37]=1.[CH2:70]([O:77][C:78]1[C:79]([C:85]([O:87][CH3:88])=[O:86])=[N:80][C:81](Br)=[CH:82][CH:83]=1)[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:70]([O:77][C:78]1[C:79]([C:85]([O:87][CH3:88])=[O:86])=[N:80][C:81]([C:52]2[C:53]([N:55]([CH3:60])[S:56]([CH3:59])(=[O:58])=[O:57])=[CH:54][C:44]3[O:43][C:42]([C:39]4[CH:38]=[CH:37][C:36]([F:35])=[CH:41][CH:40]=4)=[C:46]([C:47](=[O:48])[NH:49][CH3:50])[C:45]=3[CH:51]=2)=[CH:82][CH:83]=1)[C:71]1[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: COC(=O)c1nc(Br)ccc1OCc1ccccc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OCc4ccccc4)c(C(=O)OC)n3)cc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
Pd2(dba)3 (45 mg, 0.05 mmol) and X-phos (48 mg, 0.1 mmol) were added to a mixture of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (500 mg, 1 mmol), methyl 3-(benzyloxy)-6-bromopicolinate (350 mg, 1.1 mmol) and K3PO4.3H2O (798 mg, 3 mmol) in 1,4-dioxane/H2O (5 mL/0.5 mL) under N2. The mixture was stirred at 80° C. for 8 h, and after being filtered through celite, the filtrate was concentrated in vacuo, diluted with water and extracted with EtOAc. The residue was purified by column chromatography (DCM:EtOAc=40:1 to 10:1) to obtain methyl 3-(benzyloxy)-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)picolinate (540 mg, yield: 88%). 1H-NMR (CDCl3, 400 MHz) δ 7.88˜8.04 (m, 3H), 7.70 (d, J=8.8 Hz, 1H), 7.62 (s, 1H), 7.45˜7.56 (m, 3H), 7.41 (t, J=7.2 Hz, 2H), 7.32˜7.38 (m, 1H), 7.20 (t, J=8.4 Hz, 2H), 5.90 (d, J=4.0 Hz, 1H), 5.27 (s, 2H), 3.97 (s, 3H), 3.22 (s, 3H), 2.98 (d, J=4.8 Hz, 3H), 2.72 (s, 3H). MS (M+H)+: 618.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[F:7][C:8]([F:19])([F:18])[C:9]1C(C(O)=O)=[CH:13][N:12]=[CH:11][CH:10]=1.CN(C)C=O>ClCCl>[F:7][C:8]([F:19])([F:18])[C:9]1[C:1]([C:2]([Cl:4])=[O:3])=[CH:13][N:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cnccc1C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cnccc1C(F)(F)F

Procedure:
Oxalyl chloride (6.4 ml, 2M) was added to a suspension of 4-trifluoromethylnicotinic acid (2 g) and a catalytic amount of N,N-dimethylformamide in dichloromethane, and stirred at 20° C. for 1 hour to give a solution of 4-trifluoromethylnicotinic acid chloride. N,N-Ethylenethiourea (2.23 g) was added to sodium hydride (0.82 g, 60% dispersion in mineral oil) in tetrahydrofuran, and the mixture was stirred at 20° C. for 1 hour, and then added to the above solution of 4-trifluoromethylnicotinic acid chloride with ice bath cooling, then stirred at 20° C. for 1 hour. Ethyl acetate was added and the mixture washed with water, dried (magnesium sulfate), evaporated and the residue crystallized (ethanol) to give N-(4-trifluoromethyl-3-pyridylcarbonyl)-imidazolin-2-thione (1.35 g, Compound S-356).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O.P(Cl)(Cl)(Cl)(Cl)Cl.Cl[Sn](Cl)(Cl)Cl.[CH2:34]([O:36][C:37](=[O:40])[C:38]#[N:39])[CH3:35]>O=P(Cl)(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]1[N:39]=[C:38]([C:37]([O:36][CH2:34][CH3:35])=[O:40])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1
Reactant: CCOC(=O)C#N
Reactant: O=C(CCN1C(=O)c2ccccc2C1=O)Nc1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(CCN2C(=O)c3ccccc3C2=O)nc2ccccc12
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Into a 2000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-N-phenylpropanamide (40 g, 135.91 mmol, 1.00 equiv) in POCl3 (300 mL). This was followed by the addition of PCl5 (30 g, 144.06 mmol, 1.06 equiv). The mixture was stirred for 2 h at 65° C. The resulting mixture was concentrated under vacuum. The residue was poured into chlorobenzene (500 mL). To this was added SnCl4 (53 g) and 2-ethoxy-2-oxoacetonitrile (26 g, 262.39 mmol, 1.93 equiv) dropwise with stirring. The resulting solution was stirred for 2 h at 120° C. in an oil bath. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 7.0 g (14%) of ethyl 2-[2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)ethyl]quinazoline-4-carboxylate as a white solid. MS (ESI) m/z 376 ([M+H]+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][N:30]([CH3:34])[C:31](=[O:33])[CH3:32])[N:20]=[CH:19][N:18]=2)=[CH:12][C:11]=1[CH3:35]>>[CH3:34][N:30]([CH2:29][CH2:28][O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:2][C:3]3[CH:7]=[C:6]([CH3:8])[O:5][N:4]=3)=[C:11]([CH3:35])[CH:12]=1)=[N:18][CH:19]=[N:20]2)[C:31](=[O:33])[CH3:32]
Reactant: CC(=O)N(C)CCOc1cccc2ncnc(Nc3ccc(O)c(C)c3)c12
Reactant: Cc1cc(CCl)no1
Product: CC(=O)N(C)CCOc1cccc2ncnc(Nc3ccc(OCc4cc(C)on4)c(C)c3)c12
Yield: 14 %

Procedure:
The procedure described in Example 3 was repeated using 3-(chloromethyl)-5-methylisoxazole and N-[2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)ethyl]-N-methylacetamide (obtained as described in Example 75, preparation of starting materials) to give the title compound as a white solid in 14% yield; NMR spectrum (DMSO-d6 373K) 1.95 (s, 3H), 2.23 (s, 3H), 2.43 (s, 3H), 3.57 (s, 3H), 3.88 (t, 2H), 4.47 (m, 2H), 5.15 (s, 2H), 6.29 (s, 1H), 7.05 (d, 1H), 7.15 (d, 1H), 7.34 (d, 1H), 7.48 (d, 1H), 7.54 (dd, 1H), 7.69 (t, 1H), 8.42 (s, 1H), 9.64 (s, 1H); Mass spectrum MH+ 462.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]([OH:30])=O)[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:17](=[O:33])[N:18]([CH3:32])[C:19]2=[O:31])=[N:14]1.[CH:38]1([NH2:41])[CH2:40][CH2:39]1.C(P(=O)(OCC)OCC)#N>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]([NH:41][CH:38]3[CH2:40][CH2:39]3)=[O:30])[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:34][CH:35]([CH3:36])[CH3:37])[C:17](=[O:33])[N:18]([CH3:32])[C:19]2=[O:31])=[N:14]1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3ccnc4ccc(Cl)cc34)nc21
Reactant: NC1CC1
Agent: CCOP(=O)(C#N)OCC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)NC4CC4)cn3C)n(Cc3ccnc4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 5-{2-[(6-chloroquinolin-4-yl)methyl]-7-isobutyl-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and cyclopropylamine using diethyl cyanophosphonate as a coupling reagent. Mass: 560.22 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2[CH3:18])=[O:9])[CH:3]=1.[CH:19]1([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([O:25][C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=3[CH3:18])=[O:9])[CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Cc1cc(O)ccc1NC(=O)c1cc(Cl)ncn1
Reactant: OC1CCCCC1
Product: Cc1cc(O)ccc1NC(=O)c1cc(OC2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 26, starting from 6-chloro-N-(4-hydroxy-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 8) and cyclohexanol (Fluka), the title compound was obtained as a yellow solid after purification by preparative HPLC.
Reaction SMILES: Br[C:2]1[C:3](C2C=CC=CC=2)=[N:4][NH:5][CH:6]=1.C1C=C[C:16](/[CH:19]=[CH:20]/[C:21](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=O)=[CH:17][CH:18]=1.C1C=C[C:34](/[CH:37]=[CH:38]/[C:39](/[CH:41]=[CH:42]/[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd:67].[Pd].Cl.[Pd]>CC(C)=O.C1COCC1>[CH2:2]([C:3]1[N:4]([C:48]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:42]2[CH:34]=[CH:37][CH:38]=[C:39]([OH:40])[CH:41]=2)[N:5]=[C:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:23]=1[C:21]1[CH:18]=[CH:17][CH:16]=[CH:19][CH:20]=1)[CH3:6].[Pd:67]
Reactant: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Reactant: Brc1c[nH]nc1-c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCc1c(-c2ccccc2)c(-c2ccccc2)nn1-c1ccccc1-c1cccc(O)c1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
The reaction of Example 1 (reaction scale: 10 mmol of bromophenyl pyrazole) was conducted with 0.1 mole % of Pd2(dba)3. After the reaction was judged to be essentially complete, the reaction mixture was neutralized with 1N aqueous HCl to a pH of 7.0 to 7.5. The crude product, whose palladium level was 270 ppm, was dissolved in acetone (16 mL/g of bromophenyl pyrazole starting material) and THF (2.65 mL/g) at 50° C. TMT (0.23 equiv.) was added, and the mixture was stirred at 50° C. for 15 min, cooled to room temperature, and filtered three times through a Darco zeta pad. A sample of filtrate was evaporated to dryness, affording a solid containing 92 ppm of palladium. The remaining filtrate was concentrated and recrystallized by adding water, affording 2′-(5-ethyl-3,4-diphenyl-1H-pyrazol-1-yl)-[1,1′]-biphenyl-3-ol containing 51 ppm of palladium.
Reaction SMILES: [OH:1][P:2]([CH2:5][CH:6]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([OH:9])=O)([CH3:4])=[O:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:30]1([NH:36][C:37](=[O:44])[C@H:38]([CH2:40][CH:41]([CH3:43])[CH3:42])[NH2:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1.C(OCC)(=O)C>[C:30]1([NH:36][C:37](=[O:44])[C@H:38]([CH2:40][CH:41]([CH3:42])[CH3:43])[NH:39][C:7](=[O:9])[CH:6]([CH2:5][P:2]([OH:1])([CH3:4])=[O:3])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CP(=O)(O)CC(CCc1ccccc1)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)Nc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)C(CCc1ccccc1)CP(C)(=O)O)C(=O)Nc1ccccc1
Temperature: 25 °C
Yield: 94.1 %

Procedure:
A portion (313 mg) of the crude 2-((hydroxy(methyl)phosphinyl)methyl)-4-phenylbutanoic acid from Step B was dissolved in tetrahydrofuran (3.0 mL) and 4 Å molecular sieves (0.40 g) were added. The mixture was stirred at room temperature and 1,1'-carbonyldiimidazole (215 mg, 1.33 mmol) was added, followed 15 min later by L-leucine N-phenylamide (297 mg, 1.44 mmol).7After 22 h, the mixture was diluted with ethyl acetate (30 mL) and washed with 2N aqueous hydrochloric acid (2×15 mL) and saturated aqueous sodium chloride (15 mL). The organic layer was dried (sodium sulfate) decanted, and evaporated to give 511 mg of colorless foam. The two diastereomers of a portion (145 mg) of the crude product were separated by high pressure liquid chromatography on a 22 mm×25 cm reverse phase column (Whatman ODS-3, Partisil 10) eluting with 60% methanol/40% water/0.05% trifluoroacetic acid (flow rate of 25 mL/min, detection at 250 nm). This yielded the more mobile isomer (43 mg, 31% yield for Steps B-C) and the less mobile isomer (51 mg, 36% yield for Steps B-C), both obtained as brittle films.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[Cl:7][CH2:8][CH2:9][N:10]=[C:11]=[O:12]>CCOCC>[CH2:1]([NH:6][C:11]([NH:10][CH2:9][CH2:8][Cl:7])=[O:12])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CCN
Reactant: O=C=NCCCl
Solvent: CCOCC
Product: CC(C)CCNC(=O)NCCCl
Reaction time: 1 h

Procedure:
Isopentylamine (8.7 g, 0.1 mol) was dissolved in 100 ml of anhydrous ether and cooled to less than 10° C. 2-Chloroethyl isocyanate (10.5 g, 0.1 mol) was dissolved in 20 ml of ether and added to the rapidly stirring reaction mixture at less than 10° C. Stirring continued 1 hr. longer and the preciptiate was filtered and washed with four 20 ml portions of chilled ether. After drying in vacuo overnight, 16.5 g (85%) of product obtained as a white powder, MP 58°-9° C. IR analysis showed peaks at 1620/cm (C=O) and 1575/cm (N--C=O). NMR showed a doublet (6H, J=7 Hz) at 0.9 ppm, a triplet (2H, J=7 Hz) at 1.4 ppm, a multiplet (1H) at 1.8 ppm, a multiplet (1H) at 3.2 ppm, a multiplet (4H) at 3.6 ppm, a singlet ( 1H) at 5.7 ppm, and a singlet (1H) at 6.0 ppm.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][CH2:28][O:29][C:22]=3[CH:21]=2)[C:11]2[C:16]([CH3:17])=[CH:15][S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][CH2:28][O:29][C:22]=4[CH:21]=3)[C:11]3[C:16]([CH3:17])=[CH:15][S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: Cc1csc2nc(Cl)nc(NCc3ccc4c(c3)OCCO4)c12
Product: Cc1csc2nc(-n3ccnc3C)nc(NCc3ccc4c(c3)OCCO4)c12

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5-methyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5-methyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [O:1]=[C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][N:5]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:4]([CH2:23][N:24]2[CH2:29][CH2:28][N:27](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:26](=[O:49])[C:25]2=[O:50])=[CH:3]1.C(O)=O>ClCCl>[O:1]=[C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][N:5]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:4]([CH2:23][N:24]2[CH2:29][CH2:28][NH:27][C:26](=[O:49])[C:25]2=[O:50])=[CH:3]1
Reactant: O=C1C(=O)N(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCN1Cc1cc(=O)c(OCc2ccccc2)cn1Cc1ccccc1
Solvent: O=CO
Solvent: ClCCl
Product: O=C1NCCN(Cc2cc(=O)c(OCc3ccccc3)cn2Cc2ccccc2)C1=O
Reaction time: 72 h
Yield: 94.9 %

Procedure:
To a solution of 1-[[1,4-dihydro-4-oxo-5-(phenylmethoxy)-1-(phenylmethyl)-2-pyridinyl]-methyl]-4-(triphenylmethyl)-2,3-piperazinedione (8.77 g, 13.23 mmol) in 65 ml of dichloromethane was added dropwise at room temperature 65 ml of formic acid. After stirring for three days, the volatiles were distilled off in vacuo and the residue triturated twice with ether to give 5.24 g of 1-[[1,4-dihydro-4-oxo-5-(phenylmethoxy)-1-(phenylmethyl)-2-pyridinyl]methyl]-2,3-piperazinedione, melting point 260°-265° C.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[N:12]=[C:11]2[N:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH2:26][CH3:27])[NH:15][C:16](=[O:17])[C:10]2=[CH:9][N:8]=1.ClC1C=C(C=CC=1)C(OO)=[O:33]>ClCCl>[CH3:1][S:2]([CH2:3][CH2:4][CH2:5][NH:6][C:7]1[N:12]=[C:11]2[N:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH2:26][CH3:27])[NH:15][C:16](=[O:17])[C:10]2=[CH:9][N:8]=1)=[O:33]
Reactant: CCCOc1ccccc1-c1nc2nc(NCCCSC)ncc2c(=O)[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCOc1ccccc1-c1nc2nc(NCCCS(C)=O)ncc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 240 h

Procedure:
A cool (0° C.) solution of 7-(3-methylthiopropylamino)-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (1.84 g) and m-chloroperoxybenzoic acid (0.97 g) in dichloromethane (180 ml) was allowed to warm to ambient temperature with stirring. The solution was then stirred for 18 hours at ambient temperature and allowed to stand for 10 days . The reaction mixture was evaporated under reduced pressure and the residue eluted from a silica column with chloroform:methanol (gradient elution). The combined fractions containing product were evaporated under reduced pressure and the residue was recrystallized from isopropanol to yield the title compound, 1.73 g, m. p. 188-9° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[N:11](COCC[Si](C)(C)C)[N:10]=2)=[N:6][C:7]=1F.Cl.[NH:33]1[CH2:37][CH2:36][C@@H:35]([OH:38])[CH2:34]1>>[Br:1][C:2]1[C:7]([N:33]2[CH2:37][CH2:36][C@@H:35]([OH:38])[CH2:34]2)=[N:6][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[NH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: O[C@@H]1CCNC1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)c(F)n2)c2cc(-c3cccnc3)ncc21
Agent: Cl
Product: O[C@@H]1CCN(c2nc(-c3n[nH]c4cnc(-c5cccnc5)cc34)ccc2Br)C1
Yield: 9.6 %

Procedure:
Following the procedures as described in Example 241 and starting with 3-(5-bromo-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and (R)-pyrrolidin-3-ol hydrochloride, 293 was obtained as an off-white solid (3.50 mg, 9.60%) over two steps. ESI MS m/z=437.1 (M+1)
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:17][C:16]2[CH:19]=[CH:20][C:13]([N:10]3[CH2:11][CH2:12][CH:7]([CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)=[CH:14][CH:15]=2)[CH2:24][CH2:23]1
Reactant: CN1CCNCC1
Reactant: O=Cc1ccc(N2CCC(CN3CCCC3)CC2)cc1
Product: CN1CCN(Cc2ccc(N3CCC(CN4CCCC4)CC3)cc2)CC1

Procedure:
Prepared from the product of Example 9 and N-methylpiperazine.