Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[C:8]([CH2:19][NH2:20])=[CH:7]2.[NH2:21][C:22]1[N:30]=[C:29]2[C:25]([NH:26][CH:27]=[N:28]2)=[C:24](Cl)[N:23]=1.C(N(CC)CC)C>CC(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[C:8]([CH2:19][NH:20][C:24]1[N:23]=[C:22]([NH2:21])[N:30]=[C:29]3[C:25]=1[N:26]=[CH:27][NH:28]3)=[CH:7]2
Reactant: Cc1ccccc1-c1nc2c(C)cccc2cc1CN
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1ccccc1-c1nc2c(C)cccc2cc1CNc1nc(N)nc2[nH]cnc12
Temperature: 150 °C

Procedure:
A mixture of (8-methyl-2-o-tolylquinolin-3-yl)methanamine (40 mg, 0.15 mmol), 2-amino-6-chloropurine (52 mg, 0.30 mmol), and triethylamine (42 μL, 0.30 mmol) in i-PrOH (0.8 mL) was heated in a microwave reactor at 150° C. four times for 20 min. The mixture was partitioned between saturated aqueous NaHCO3 (15 mL) and EtOAc (15 mL), the layers were separated, and the aqueous layer was extracted with EtOAc (2×15 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting yellow oil was dissolved in CH2Cl2, evaporated onto silica gel, and purified by flash chromatography (Biotage® Si 25+M) eluting with MeOH/CH2Cl2 (5% to 10%) to provide a white solid. The compound was further purified by reversed-phase HPLC (Gilson) eluting with H2O/MeCN/TFA to provide a white solid [PI3Kδ IC50=82 nM]. MS (ESI+) m/z=396.2 (M+1).
Reaction SMILES: [CH3:1][O:2]C1C=CC2N=CC=C([C@H](O)[C@@H]3N4C[C@H](C=C)C(CC4)C3)C=2C=1.CN1[C@H]2CC3C=CC([O:43]C)=CC=3[C@]3([C@@H]2CCCC3)CC1.CCC1C=CC=C2C=C(C(O)CNC(C)(C)C)OC=12.[CH:64]1[N:65]=[C:66]([NH2:111])[C:67]2[N:72]=[CH:71][N:70]([C@@H:73]3[O:77][C@H:76]([CH2:78][O:79][P:80]([O:83][P:84]([O:87][CH2:88][C@H:89]4[O:93][C@@H:92]([N:94]5[CH:99]=[C:98]([C:100]([NH2:102])=[O:101])[CH2:97][CH:96]=[CH:95]5)[C@H:91]([OH:103])[C@@H:90]4[OH:104])([OH:86])=[O:85])([OH:82])=[O:81])[C@@H:75]([OH:105])[C@H:74]3[O:106][P:107]([OH:110])([OH:109])=[O:108])[C:68]=2[N:69]=1>>[CH:96]1[CH:95]=[N+:94]([C@@H:92]2[O:93][C@H:89]([CH2:88][O:87][P:84]([O:83][P:80]([O:79][CH2:78][C@H:76]3[O:77][C@@H:73]([N:70]4[C:68]5[N:69]=[CH:64][N:65]=[C:66]([NH2:111])[C:67]=5[N:72]=[CH:71]4)[C@H:74]([O:106][P:107]([OH:109])([OH:110])=[O:108])[C@@H:75]3[OH:105])([OH:82])=[O:81])([OH:86])=[O:85])[C@@H:90]([OH:104])[C@H:91]2[OH:103])[CH:99]=[C:98]([C:100]([NH2:102])=[O:101])[CH:97]=1.[CH2:88]([O:87][P:84]([OH:86])([OH:83])=[O:85])[C@H:89]1[O:93][C@@H:92]([OH:43])[C@H:91]([OH:103])[C@@H:90]([OH:104])[C@@H:1]1[OH:2]
Reactant: C=C[C@H]1CN2CCC1C[C@@H]2[C@@H](O)c1ccnc2ccc(OC)cc12
Reactant: COc1ccc2c(c1)[C@]13CCCC[C@@H]1[C@H](C2)N(C)CC3
Reactant: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: CCc1cccc2cc(C(O)CNC(C)(C)C)oc12
Product: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Product: O=P(O)(O)OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The control inhibitor (quinidine) and marker substrate (dextromethorphan or bufuralol) were transferred to the incubation vessels (60 μL aliquots each). After a pre-incubation period at 37° C., the reactions were initiated by the addition of a 40 μL aliquot of NADPH regenerating system (BD Gentest). A 40 μL aliquot (diluted 6:19 with incubation buffer) provided final concentrations of 1.3 mM NADP+, 3.3 mM glucose-6-phosphate and 0.4 U/mL glucose-6-phosphate dehydrogenase. Incubation times were 12 minutes for both dextromethorphan and bufuralol. Reactions were terminated by the direct addition of acetonitrile (160 μL) to the incubation mix followed by transfer to a pooling plate containing additional acetonitrile (400 μL).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:17][CH2:16][CH2:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:7]=1.[NH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH2:24])=[O:23].C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:7]=[C:2]([NH:18][CH2:19][CH2:20][CH2:21][C:22]([NH2:24])=[O:23])[C:3]3[CH2:17][CH2:16][CH2:15][C:4]=3[N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cccc(-c2nc(Cl)c3c(n2)CCC3)c1
Reactant: NCCCC(N)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: NC(=O)CCCNc1nc(-c2cccc(Cl)c2)nc2c1CCC2
Yield: 47.9 %

Procedure:
A solution of 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.032 g, 0.12 mmol), 4-aminobutanamide (0.061 g, 0.60 mmol), and N,N-diisopropylethylamine (0.031 g, 0.24 mmol) in NMP (3 mL) was heated at 90° C. overnight. After this time, the reaction mixture was cooled, diluted water, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to afford the title compound (0.019 g, 61%) as a white solid. MW=330.81. 1H NMR (DMSO-d6, 500 MHz) δ 8.31-8.26 (m, 2H), 7.51-7.46 (m, 2H), 7.27 (s, 1H), 7.03 (t, J=5.5 Hz, 1H), 6.73 (s, 1H), 3.48 (q, J=6.7 Hz, 2H), 2.81 (t, J=7.6 Hz, 2H), 2.68 (t, J=7.3 Hz, 2H), 2.16 (t, J=7.6 Hz, 2H), 2.03 (quin, J=7.6 Hz, 2H), 1.84 (quin, J=7.3 Hz, 2H); APCI MS m/z 331 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19]([O:21]CC)=[O:20])=[CH:15][N:14]=2)[CH2:8]1)[CH3:2].O[Li].O>C1COCC1.O>[CH2:1]([O:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][N:14]=2)[CH2:8]1)[CH3:2]
Reactant: CCOC(=O)c1cnc(N2CCC[C@@H](Oc3ccccc3OCC)C2)nc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)O)cn2)C1
Temperature: 22.5 °C
Reaction time: 24 h
Yield: 78.5 %

Procedure:
To a solution of ethyl (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylate (71.5 g, 193 mmol) in THF/H2O (1:1, 2 L) was added LiOH.H2O (24.2 g, 578 mmol) at 20-25° C. The reaction mixture was stirred at 20-25° C. for 24 hours. The mixture was concentrated, and the aqueous phase was washed with diethyl ether (2 times with 500 mL). The aqueous phase was acidified to pH 2 with 1N HCl (˜400 mL). The precipitated solid was filtered and dried to afford (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid (52 g, 78%). MS (ES+) 344.18 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.[F:37][C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1B(O)O.[F-].[Cs+]>C(#N)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>[F:37][C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]=1[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:18][CH:19]=1
Reactant: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: OB(O)c1ccc(F)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(F)cc3F)ccc2c1

Procedure:
Dissolve trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-yl ester (1.00 g, 1.91 mmol) in 20 mL of degassed acetonitrile and add 2,4-difluorophenyl boronic acid (0.60 g, 3.82 mmol), trans[dichlorobis(triphenylphosphine)]palladium II (0.27 g, 0.38 mmol) and sonicate briefly. Next add cesium fluoride (2.61 g, 17.19 mmol) and heat to 75° C. for one hour. Add Celite and filter. Concentrate the solvent under vacuum, dissolve in methanol and purify on an SCX cartridge, eluting with 2N ammonia/methanol to isolate the title compound.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][N:10]([CH2:12][C:13]1[CH:31]=[CH:30][C:16](/[CH:17]=[N:18]/[C:19]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]3[C:20]=2[CH2:21][O:22][C:23]3=[O:29])=[CH:15][CH:14]=1)[CH3:11].[O-:32][CH2:33][CH3:34].[Na+].C(O)C>C(OCC)(=O)CC>[CH3:9][N:10]([CH2:12][C:13]1[CH:31]=[CH:30][C:16]([CH:17]2[CH:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:33](=[O:32])[C:34]3[C:24]([C:23]([O:22][CH2:21][CH3:20])=[O:29])=[CH:25][C:26]([F:28])=[CH:27][C:19]=3[NH:18]2)=[CH:15][CH:14]=1)[CH3:11]
Reactant: O=Cc1ccccc1
Reactant: CN(C)Cc1ccc(/C=N/c2cc(F)cc3c2COC3=O)cc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCOC(=O)CC
Solvent: CCO
Product: CCOC(=O)c1cc(F)cc2c1C(=O)C(c1ccccc1)C(c1ccc(CN(C)C)cc1)N2
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 25 %

Procedure:
A mixture of compound benzaldehyde (75 mg, 0.705 mmol) and (E)-4-(4-((dimethylamino)methyl)benzylideneamino)-6-fluoroisobenzofuran-1(3H)-one (220 mg, 0.705 mmol) in ethyl propionate (5 mL) was cooled to 0° C. Then a solution of sodium ethoxide in ethanol (sodium (65 mg, 2.82 mmol) in ethanol (3 mL)) was added dropwise. After the addition, the mixture was stirred at room temperature for 2.5 hr. The mixture was quenched with water (20 mL) and solvent was removed in vacuum. The residue was dissolved in water and extracted with ethyl acetate for three times. The extract was washed with water and brine and then the solvent was evaporated. The crude product was purified by chromatography to obtain the title compound as a yellow solid (80 mg, yield 25%). LC-MS (ESI) m/z: 447 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[CH:7][C:8]3[CH:22]=[N:21][CH:20]=[N:19][C:9]=3[C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([OH:18])=O)[C:11]=3[N:5]2[CH2:4][N:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:36][C:37]([CH:39]1[CH2:41][CH2:40]1)=[NH:38].C(O)(=O)C>CN(C=O)C>[CH:39]1([C:37]2[N:38]=[C:16]([C:12]3[C:11]4[N:5]5[CH2:4][N:3]=[C:2]([CH3:1])[C:6]5=[CH:7][C:8]5[CH:22]=[N:21][CH:20]=[N:19][C:9]=5[C:10]=4[CH:15]=[CH:14][CH:13]=3)[O:18][N:36]=2)[CH2:41][CH2:40]1
Reactant: N=C(NO)C1CC1
Reactant: CC1=NCN2C1=Cc1cncnc1-c1cccc(C(=O)O)c12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC1=NCN2C1=Cc1cncnc1-c1cccc(-c3nc(C4CC4)no3)c12
Temperature: 85 °C
Yield: 59 %

Procedure:
To a suspension of 6-methyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid (1.0 g, 3.4 mmol) in DMF (15 mL) was added 1,1′-carbonyldiimidazole (0.61 g, 3.76 mmol) followed by N-hydroxy-cyclopropanecarboxamidine and the resulting solution was heated at 85° C. for 1.5 h. Then acetic acid (3.4 mL) was added and the resulting mixture heated at 130° C. for 40 min. After cooling, the mixture was evaporated and dissolved n DCM (15 mL). This DCM extract was washed with sodium hydrogen carbonate (saturated solution, 40 mL) and then the aqueous phase was washed with DCM (20 mL). The combined DCM layers were then dried over MgSO4 and evaporated. The residue was recrystallized from ethyl acetate: hexane to afford the product (720 mg, 59%) as white crystals, mp 216-218° C., m/z 356 (M).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[CH3:16]>O>[C:5]([NH:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[CH3:16])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(F)cc1N
Solvent: O
Product: CC(=O)Nc1cc(F)ccc1C
Temperature: 25 °C

Procedure:
139 ml (150.4 g; 1.473 molecules) of acetic anhydride were added in one portion to a hot (35° ) stirred mixture of 90.0 g (0.719 molecule) of 2-amino-4-fluorotoluene (1) in 513 ml of water. The temperature rose to 73° and a solid separated out (by precipitation). The mixture was cooled to ambient temperature and the solid was recovered on a filter, washed with water (525 ml), then dried in vacuo at 80°, yield: 115.7 g (96.2%); m.p.: 127°-128°. The material was still transformable.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[C:3](=[O:8])[NH:2]2.[CH3:9][S:10]([OH:13])(=[O:12])=[O:11].[OH2:14]>O1CCCC1>[CH3:9][S:10]([OH:13])(=[O:12])=[O:11].[NH2:2][C@@H:1]1[CH2:7][C@H:4]([C:3]([OH:8])=[O:14])[CH:5]=[CH:6]1
Reactant: O=C1NC2C=CC1C2
Reactant: O
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Product: N[C@H]1C=C[C@@H](C(=O)O)C1
Temperature: 35 °C
Yield: 0.6 %

Procedure:
A solution of (-)-2-azabicyclo[2.2.1]hept-5-en-3-one (97.45 g, 0.8929 mol, Enzymatix Ltd.) in tetrahydrofuran (500 mL) was filtered and warmed to 35° C. A solution of methanesulfonic acid (63.7 mL, 0.9817 mol) in water (24.1 mL, 1.34 mol) was added over the course of 1.5 hours such that the ensuing exotherm did not exceed 45° C. The resulting slurry was heated at 60° C. for three hours, then allowed to cool to room temperature over the course of 15 hours. The slurry was filtered and the cake washed twice with anhydrous tetrahydrofuran (200 mL). An analytical sample of the wet cake was removed and dried to give the title compound as a white solid (1.264 g); m.p. 167°-169.2° C.; 1H-NMR (DMSO-d6)δ: 12.6 (br s, 1H, CO2H), 8.04 (br s, 3H, NH3+), 6.10 (dr, J=5.6, 2.0, 2.0 Hz, 1H, vinyl), 5.85 (dt, J=5.3, 2.3, 2.3Hz, 1H, vinyl), 4.19 (br s, w1/2=20Hz, 1H, allylic H), 3.61 (m, w1/2=22Hz, 1H, allylic H), 2.53 (quintet, J=5.3 Hz (overlapping with DMSO peak), 1/2CH2), 2.39 (s, 3H, CH3SO3H), 1.93 (dt, J=6.7, 6.7, 13.7 Hz, 1H, 1/2CH2); [α]20589 -83.8°, [α]20578 -87.4°, [α]20546 -101.2°, [α]20436 -186.7°, [α]20365 -316.2° (c=1.42, methanol); CI-MS (CH4): 128(M+1); EI-MS: 127(M).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=1.C([O:16][C:17]([C:19]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][N:24]=[C:25]([CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:26]=2)[N:21]([CH3:37])[CH:20]=1)=O)C>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH:11][C:17]([C:19]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][N:24]=[C:25]([CH2:30][N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH:26]=3)[N:21]([CH3:37])[CH:20]=2)=[O:16])=[CH:8][CH:7]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cn(C)c2cnc(CN3CCOCC3)cc2c1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)ncc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
At 0° C., a solution of 2.0M AlCl3 in toluene (0.14 mL) is added to a solution of 4-chlorobenzylamine (0.044 mL) in CH2Cl2 (5 mL). The compound from ethyl-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro[1,7]naphthyridine-3-carboxylate (Preparation 46, 0.058 g) is added and the mixture allowed to stir at room temperature for 3 hours at which time the mixture is partitioned between CH2Cl2 (30 mL) and water (30 mL). The organics are dried with Na2SO4, filtered and the solvent evaporated. The remaining solid is chromatographed with MeOH/CH2Cl2 (1-4%) to obtain 0.049 g (67%) of the title compound as an off-white solid. Physical characteristics: MS (ESI+) m/z 427 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[O:10][C:11]([F:14])([F:13])[F:12].Cl.C=O.CO[CH2:20][Cl:21]>O.C(O)(=O)C>[F:14][C:11]([F:12])([F:13])[O:10][C:3]1[CH:4]=[C:5]([CH3:9])[C:6]([CH2:20][Cl:21])=[C:7]([CH3:8])[C:2]=1[CH3:1]
Reactant: Cc1cc(C)c(C)c(OC(F)(F)F)c1
Reactant: COCCl
Agent: C=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(OC(F)(F)F)c(C)c(C)c1CCl

Procedure:
A solution of 31.5 (0.15 mol) of 2,3,5-trimethyl-1-trifluoromethoxybenzene, 315 ml of acetic acid, 31.5 ml of concentrated hydrochloric acid, 31.5 ml of aqueous formaldehyde and 13 g (0.185 mol) of chloromethyl methyl ether was heated to 85° C. for 72 hours. (Small samples were worked up periodically after 48 hours to optimize the ratio of monochloromethyl product:dichloromethyl product:starting material). The solution was then cooled, poured into 1.5 liters of water and extracted with 3×500 ml of hexane. The hexane extracts were washed with 1 liter of water and 500 ml of saturated NaHCO3 solution, dried (MgSO4), filtered, and concentrated to give 30 g of crude (4-trifluoromethoxy 2,3,6-trimethylphenyl)methyl chloride containing some starting material, 2,3,5-trimethyl-1-trifluoromethoxybenzene, which was removed by distillation at 24°-30° C./0.05 mm. The residue (22 g), crude (4-trifluoromethoxy-2,3,6-trimethylphenyl)methyl chloride, was used directly in the next step.
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:45][CH2:46][CH2:47][N:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1>C1COCC1.C(OCC)(=O)C.C(N(CC)CC)C>[C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:45][CH2:46][CH2:47][N:48]3[CH2:52][CH2:51][CH2:50][CH2:49]3)=[O:14])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Reactant: NCCN1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCCN1CCCC1)c1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of 4-([1,1′-biphenyl]-4-ylmethoxy)benzoic acid (3 g) in THF (200 ml) were added WSC (2 g) and HOBt (1.5 g) followed by the addition of 1-(2-aminoethyl)pyrrolidine (1.1 g). After stirring at room temperature for 30 min, triethylamine (2 ml) added to the reaction mixture, which was stirred at room temperature for additional 72 hr. The reaction mixture was diluted with ethyl acetate, washed with 10% aqueous potassium carbonate and water sequentially, dried, and concentrated. The residue was recrystallized from ethanol/ethyl ether to obtain the titled compound (2.7 g).
Reaction SMILES: [C:1]([C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[N:6][NH:7][C:8]2=[O:15])#[CH:2].Cl.Br[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>C(NCC)C.O.[Cu]I>[CH3:14][O:13][C:12]1[C:3]([C:1]#[C:2][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:15])[NH:7][N:6]=[CH:5]2
Reactant: C#Cc1c(OC)ccc2c(=O)[nH]ncc12
Reactant: Brc1ccncc1
Agent: [Cu]I
Agent: Cl
Solvent: O
Solvent: CCNCC
Product: COc1ccc2c(=O)[nH]ncc2c1C#Cc1ccncc1
Temperature: 75 °C
Yield: 86 %

Procedure:
A suspension of 5-ethynyl-6-methoxy-2H-phthalazin-1-one (1.9 g, 9.49 mmoles), prepared as described in example 140, 4-bromopyridine hydrochloride (2.214 g, 11.39 mmoles), bis(triphenylphosphine)PdCl2 (133 mg, 0.1998 mmole) and CuI (36 mg, 0.1898 mmole) in diethylamine (40 ml) was heated at 75° C. for 1 hour, cooled, diluted with water (40 ml) and the solid was filtered after 30 minutes under stirring. The solid was suspended in acetone, stirred for 15 minutes, filtered again and dried in oven at 45° C. under vacuum giving 2.263 g of the title compound (yield: 86%).
Reaction SMILES: [I-].[K+].[F:3][C:4]([F:29])([F:28])[C:5]1[CH:6]=[CH:7][C:8]2[N:14]3[C:15]([CH2:18]Cl)=[N:16][N:17]=[C:13]3[CH2:12][N:11]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:9]=2[CH:27]=1.C[NH:31]C1CC1.O1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[F:3][C:4]([F:29])([F:28])[C:5]1[CH:6]=[CH:7][C:8]2[N:14]3[C:15]([CH2:18][NH:31][CH2:36][CH:37]4[CH2:39][CH2:38]4)=[N:16][N:17]=[C:13]3[CH2:12][N:11]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:9]=2[CH:27]=1
Reactant: C1CCOC1
Reactant: CNC1CC1
Reactant: FC(F)(F)c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Agent: [I-]
Agent: [K+]
Product: FC(F)(F)c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CNCC3CC3)n1-2

Procedure:
In the manner given in Example 2, potassium iodide and 8-(trifluoromethyl)-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in tetrahydrofuran is treated with methylcyclopropylamine to give 8-(trifluoromethyl)-1-[(cyclopropylmethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: C(O[C:4]([CH2:6][N:7]1[C:12](=[O:13])[C:11]([C:14](=[O:17])[NH:15][CH3:16])=[CH:10][C:9]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[N:8]1)=[O:5])C.[NH2:26][CH2:27][CH2:28][OH:29]>CO>[OH:29][CH2:28][CH2:27][NH:26][C:4]([CH2:6][N:7]1[C:12](=[O:13])[C:11]([C:14](=[O:17])[NH:15][CH3:16])=[CH:10][C:9]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)=[N:8]1)=[O:5]
Reactant: NCCO
Reactant: CCOC(=O)Cn1nc(-c2ccc(OC)cc2)cc(C(=O)NC)c1=O
Solvent: CO
Product: CNC(=O)c1cc(-c2ccc(OC)cc2)nn(CC(=O)NCCO)c1=O
Yield: 91 %

Procedure:
In methanol, 2-ethoxycarbonylmethyl-6-(4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one and 2-aminoethanol were heated under reflux for 4 hours. Post-treatments were conducted as in Example 43, whereby the title compound was obtained in a yield of 91.0%.
Reaction SMILES: [F:1][C:2]1[CH:56]=[CH:55][C:5]([CH2:6][NH:7][C:8]([O:10][CH2:11][C@H:12]2[N:17](C(OC(C)(C)C)=O)[CH2:16][C@@H:15]([CH2:25][CH2:26][C:27]3[C:28]([NH:33][C:34](=[O:54])[C@H:35]([CH:41]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[NH:36][C:37]([O:39][CH3:40])=[O:38])=[N:29][CH:30]=[CH:31][CH:32]=3)[O:14][CH2:13]2)=[O:9])=[CH:4][CH:3]=1.C(Cl)Cl.[C:60]([OH:66])([C:62]([F:65])([F:64])[F:63])=[O:61]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([O:10][CH2:11][C@H:12]2[NH:17][CH2:16][C@@H:15]([CH2:25][CH2:26][C:27]3[C:28]([NH:33][C:34](=[O:54])[C@H:35]([CH:41]([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[NH:36][C:37]([O:39][CH3:40])=[O:38])=[N:29][CH:30]=[CH:31][CH:32]=3)[O:14][CH2:13]2)=[O:9])=[CH:55][CH:56]=1.[C:60]([OH:66])([C:62]([F:65])([F:64])[F:63])=[O:61]
Reactant: COC(=O)N[C@H](C(=O)Nc1ncccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](COC(=O)NCc2ccc(F)cc2)CO1)C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N[C@H](C(=O)Nc1ncccc1CC[C@@H]1CN[C@H](COC(=O)NCc2ccc(F)cc2)CO1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl (2R,5S)-5-({[(4-fluorobenzyl)carbamoyl]oxy}methyl)-2-[2-(2-{[N-(methoxycarbonyl)-β-phenyl-L-phenylalanyl]amino}pyridin-3-yl)ethyl]morpholine-4-carboxylate in a 1:1 mixture of CH2Cl2/TFA (0.1 M) was stirred at rt for 1 hr. The reaction mixture was concentrated under reduced pressure and the residue was co-evaporated twice with heptane and triturated in Et2O to afford the desired product as a TFA salt. Alternatively, the TFA salt, after concentration, could be neutralized with aqueous saturated NaHCO3, extracted with EtOAc, dried over Na2SO4, filtered and concentrated and then purified by automated SiO2 flash chromatography system using solvent gradient of 0% to 10% MeOH/CH2Cl2 to afford the desired compound. Alternatively, the free base could be purified by filtration on SCX SPE cartridge made of pTSA-SiO2 eluted first with MeOH to remove non basic impurities and eluted then with 10% NH4OH/MeOH to elute the free base and afford the desired compound after concentration under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([C:11]2[C:19]3[O:18][CH:17]=[CH:16][C:15]=3[CH:14]=[C:13]([F:20])[CH:12]=2)=[O:10])=[CH:4][N:3]=1.[NH3:21]>C1(C)C=CC=CC=1>[NH2:21][C:6]1[C:5]([C:9]([C:11]2[C:19]3[O:18][CH:17]=[CH:16][C:15]=3[CH:14]=[C:13]([F:20])[CH:12]=2)=[O:10])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1
Reactant: O=C(c1cnc(Cl)nc1Cl)c1cc(F)cc2ccoc12
Reactant: N
Solvent: Cc1ccccc1
Product: Nc1nc(Cl)ncc1C(=O)c1cc(F)cc2ccoc12
Yield: 52 %

Procedure:
At 20° C., a stirred suspension of (2,4-dichloro-pyrimidin-5-yl)-(5-fluoro-benzofuran-7-yl)-methanone (0.80 g, 2.6 mmol, Step E) in toluene (70 mL) was treated with a slow stream of ammonia gas (Matheson) for 1 hour. The suspension was cooled, filtered and the filter cake washed with water. The filter cake was dissolved in acetonitrile, filtered through celite and the solvent removed to give a solid. This was crystallized from acetonitrile to give 0.4 g of (4-amino-2-chloro-pyrimidin-5-yl)-(5-fluoro-benzofuran-7-yl)-methanone (52%) as a white solid. HRMS, observed: 291.0208; Calcd for (M+H)+: 291.0211