Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[CH:12][C:11]=2[F:23])=[C:6]([F:24])[C:5]([CH3:25])=[CH:4][C:3]=1[OH:26].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36].O>CN(C=O)C>[F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[CH:12][C:11]=2[F:23])=[C:6]([F:24])[C:5]([CH3:25])=[CH:4][C:3]=1[O:26][CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36]
Reactant: Cc1cc(O)c(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCC(=O)OC(C)C)c(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
2,4-difluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]-5-methyl-phenol (206 mg, 0.57 mmol, 1.0 eq) was dissolved in DMF (15 mL). Cs2CO3 (279 mg, 0.86 mmol, 1.5 eq) was added and the reaction mixture stirred for 30 min at room temperature. Isopropyl bromoacetate (124 mg, 0.68 mmol, 1.2 eq) was added and the reaction stirred a further 1 h at room temperature. The resulting mixture was poured into water and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether: EtOAc, 50:1 to 30:1) to give the title compound as a colorless oil (200 mg, 76%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br>CC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([O:14][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([F:22])[CH:24]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: Fc1cccc(CBr)c1
Reactant: COC(=O)c1cccc(O)c1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OCc2cccc(F)c2)c1C(=O)OC
Yield: 112.5 %

Procedure:
To a stirred suspension of 3-hydroxyphthalic acid dimethyl ester (1.4 g, 6.7 mmol) in acetone (30 mL) and potassium carbonate (2.8 g, 20 mmol) was added 3-fluorobenzyl bromide (0.89 mL, 7.0 mmol) and refluxed overnight. The solvent was evaporated and the residue was partitioned between water (100 mL) and ethyl acetate (150 mL) and washed with water (2×100 mL). The combined organic phases was dried, concentrated and purified by flash column chromatography (EtOAc/Hexane) to give 3-(3-fluoro-benzyloxy)-phthalic acid dimethyl ester (2.4 g, 113% crude yield). The product was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O)(=O)C>C(O)C.[Pt]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:19]2[CH2:20][CH2:21][CH:16]([OH:15])[CH2:17][CH2:18]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: OC1CCNCC1
Agent: [Pt]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(O)CC2)CC1
Reaction time: 6 h
Yield: 13.7 %

Procedure:
1-tert-Butoxycarbonyl-4-piperidone (3 g, 0.0151 mol, 1 eq) and 4-hydroxypiperidine (1.56 g, 0.0154 mol, 1 eq) were stirred at room temperature in ethanol (10 ml) and acetic acid (1 ml) for 30 minutes. To the solution was added 0.4 g of 5% platinum on carbon type 117 Johnson Matthey catalyst. The reaction was then hydrogenated under a pressure of 3 bar at room temperature for 6 hours. The reaction was filtered through CELITE™ and washed with ethanol (40 ml). The 4-(hydroxy)-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester (13.7% purity by HPLC area %) was not isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([C:17]4[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=4)[C:11]=3[C:10](=[O:23])[NH:9]2)=[CH:4][CH:3]=1.Cl[C:25]1[CH:26]=[C:27]([CH3:35])[C:28]2[N:29]([C:31]([CH3:34])=[N:32][N:33]=2)[N:30]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([C:17]4[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=4)[C:11]=3[C:10](=[O:23])[N:9]2[C:25]2[CH:26]=[C:27]([CH3:35])[C:28]3[N:29]([C:31]([CH3:34])=[N:32][N:33]=3)[N:30]=2)=[CH:6][CH:7]=1
Reactant: Cc1nn(-c2ccnn2C)c2c1C(c1ccc(Cl)cc1)NC2=O
Reactant: Cc1cc(Cl)nn2c(C)nnc12
Product: Cc1nn(-c2ccnn2C)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3n1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 110 using 4-(4-chlorophenyl)-3-methyl-1-(1-methyl-1H-pyrazol-5-yl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Step 114.2) and 6-chloro-3,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine (Step 111.2). The crude material was first purified by silica gel column chromatography (CH2Cl2/MeOH 1-5%), followed by preparative achiral SFC (column NH2, gradient 9-14% in 6 min_total 11 min) and trituration in Et2O. tR: 4.37 min (HPLC 1); tR: 1.01 min (LC-MS 2); ESI-MS: 474 [M+H]+ (LC-MS 2); ESI-MS: 472 [M−H]− (LC-MS 2); Rf=0.45 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.05 (s, 3H) 2.53 (s, 3H) 2.56 (s, 3H) 3.85 (s, 3H) 6.60 (s, 1H) 6.65 (d, J=2.0 Hz, 1H) 7.39 (d, J=8.2 Hz, 2H) 7.54-7.60 (m, 3H) 8.02-8.05 (m, 1H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][NH2:7].[C:8]1([C:14](Cl)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>ClCCl>[NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][NH:7][C:14]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: NCC1CCCN1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: c1ccc(C(NCC2CCCN2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 3 h

Procedure:
Pyrrolidin-2-ylmethylamine (527 mg) in dichloromethane (10 mL) was treated with triphenylmethyl chloride (1.47 g) and triethylamine (1.5 mL), stirred for 3 hours, treated with dichloromethane, washed with water, saturated NaHCO3, and water, and concentrated. The concentrate was flash chromatographed on silica gel with a gradient of 3%-10% methanol in 99:1 dichloromethane/triethylamine. 1H NMR (DMSO-d6) δ 7.4 (m, 6H), 7.3 (m, 6H), 7.2 (m, 3H), 3.2 (m, 1H), 2.8-2.5 (m, 2H), 2.0 (m, 1H), 1.9 (m, 1H), 1.7 (m, 1H), 1.5 (m, 2H), 1.2 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16].CCOC(C)=O>C1CCCCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[Cl:9])[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: Oc1ccccc1Cl
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: Clc1cncc(Oc2ccccc2Cl)n1
Yield: 89 %

Procedure:
Using Method DD with 2,6-dichloropyrazine (250 mg, 1.69 mmol) and 2-chlorophenol (193 μL, 1.86 mmol, d=1.24 g/mL), and purification by column chromatography (AcOEt:cyclohexane, 1:1), the title compound was obtained (363 mg). Yield: 89%. 1H NMR (250 MHz, DMSO-d6) δ 7.37-7.39 (m, 1H, Harom 4), 7.46-7.47 (m, 2H, Harom 5+6), 7.64 (d, 1H, Harom 3, J=8.2 Hz), 8.55 (s, 1H, HPz 5), 8.65 (s, 1H, HPz 3). m/z: 240.0 [(M)+, calcd for C10H6Cl2N2O 240.0].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][CH2:20][CH2:21][CH2:22][Cl:23])=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[C:30]([Cl:31])=[CH:29][N:28]=[C:27]2[O:32][CH2:33][O:34][C:26]=12>>[Cl:31][C:30]1[C:25]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:19][CH2:20][CH2:21][CH2:22][Cl:23])=[CH:9][C:10]=3[O:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:5]=[CH:4][N:3]=2)=[C:26]2[O:34][CH2:33][O:32][C:27]2=[N:28][CH:29]=1
Reactant: Nc1c(Cl)cnc2c1OCO2
Reactant: ClCCCOc1cc(OC2CCOCC2)c2c(Cl)ncnc2c1
Product: ClCCCOc1cc(OC2CCOCC2)c2c(Nc3c(Cl)cnc4c3OCO4)ncnc2c1
Yield: 78 %

Procedure:
Using an analogous procedure to that described in Example 1, 4-chloro-7-(3-chloropropoxy)-5-tetrahydropyran-4-yloxyquinazoline was reacted with 4-amino-5-chloro-2,3-methylenedioxypyridine to give the title compound in 78% yield; Mass Spectrum: M+H+ 493 and 495.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][O:8][C:9](=[O:28])[N:10]([C:21]2[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=2)[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[O:19][CH3:20])[CH:2]=1.[CH3:29][N:30]([CH3:41])[CH2:31][CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=1.C(O)(C)C.FC(F)(F)C(O)=O>C(OCC)(=O)C>[CH3:20][O:19][C:12]1[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=1[N:10]([C:21]1[CH:26]=[CH:25][N:24]=[C:23]([NH:40][C:37]2[CH:36]=[CH:35][C:34]([O:33][CH2:32][CH2:31][N:30]([CH3:41])[CH3:29])=[CH:39][CH:38]=2)[N:22]=1)[C:9](=[O:28])[O:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C)CCOc1ccc(N)cc1
Reactant: COc1ccc(N(C(=O)OCc2cccnc2)c2ccnc(Cl)n2)c(OC)c1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(N(C(=O)OCc2cccnc2)c2ccnc(Nc3ccc(OCCN(C)C)cc3)n2)c(OC)c1
Temperature: 60 °C

Procedure:
A resealable tube was charged with (2-chloro-pyrimidin-4-yl)-(2,4-dimethoxy-phenyl)-carbamic acid pyridin-3-ylmethyl ester (0.100 g, 0.249 mol), 4-(2-dimethylamino-ethoxy)-phenylamine (0.100 g, 0.51 mmol), and isopropanol (2 mL). Trifluoroacetic acid (0.074 g, 0.050 mL, 0.65 mmol) was added. The tube was sealed and the mixture was heated at 60° C. for 20 h. The reaction mixture was cooled to room temperature and concentrated to afford a pale purple oil. The resulting solution was diluted with ethyl acetate and the mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to afford an oil. This oil was purified via column chromatography on silica gel (gradient elution with 0-100% dichloromethane-(90:10:1, dichloromethane/methanol/ammonium hydroxide)) to afford 3-pyridinylmethyl 2,4-bis(methyloxy)-phenyl(2-((4-((2-(dimethylamino)ethyl)oxy)phenyl)amino)-4-pyrimidinyl)-carbamate as a tan solid. MS (MH+) 545; Calculated 544.61 for C29H32N6O5.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C)[CH:20]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15]O)[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.C(Cl)Cl.B(Br)(Br)[Br:31].O>CCOC(C)=O>[Br:31][CH2:15][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[N:4]=[C:3]([NH:17][CH2:18][C:19]3[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: BrB(Br)Br
Reactant: COc1cccc(CNc2nc(Nc3cccc(CO)c3)ncc2Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: Oc1cccc(CNc2nc(Nc3cccc(CBr)c3)ncc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
Into a 1-neck round-bottom flask were added [3-({5-chloro-4-[(3-methoxybenzyl)amino]pyrimidin-2-yl}amino)phenyl]methanol (0.66 g, 1.8 mmol) and 5 mL of methylene chloride. To the above mixture was slowly added a solution of boron tribromide in methylene chloride (2.7 mL, 2.7 mmol, 1.0 M) at 0° C. The mixture was allowed to warm up to room temperature (“rt”) and stirred overnight. The resultant mixture was cooled in a dry ice bath when water (10 mL) was added. The mixture was allowed to warm up to rt, followed by an addition of EtOAc. The aqueous layer was extracted with EtOAc twice. The organic layers were combined and solvent removed under vacuum. The crude was purified by prep-HPLC to give the desired product (730 mg, 99%). LCMS for C18H17BrClN4O (M+H)+: m/z=418.9, 420.9. 1H NMR (400 MHz, DMSO-d6): δ 9.55 (s, 1H), 9.34 (br s, 1H), 8.18 (s, 1H), 8.04 (s, 1H), 7.68 (t, J=1.7 Hz, 1H), 7.41 (m, 1H), 7.16 (t, J=7.9 Hz, 1H), 7.09 (t, J=7.9 Hz, 1H), 6.98 (d, J=7.7 Hz, 1H), 6.70 (m, 1H), 6.59 (m, 1H), 4.58 (d, J=6.6 Hz, 2H), 4.49 (s, 2H).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:9]2[C:10](=[O:25])[N:11]([CH3:24])[CH2:12][C:13]3[N:14]([CH:15]=[N:16][C:17]=3[C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:8]=2[CH:7]=[CH:6][CH:5]=1.[CH3:26]I.O>CS(C)=O>[Cl:3][C:4]1[C:9]2[C:10](=[O:25])[N:11]([CH3:24])[CH2:12][C:13]3[N:14]([CH:15]=[N:16][C:17]=3[C:18]#[C:19][C:20]([O:23][CH3:26])([CH3:22])[CH3:21])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CN1Cc2c(C#CC(C)(C)O)ncn2-c2cccc(Cl)c2C1=O
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COC(C)(C)C#Cc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Reaction time: 0.75 h

Procedure:
1.20 g (18.6 mmol) of freshly powdered potassium hydroxide was stirred at room temperature for 5 minutes in 15 ml of dimethyl sulfoxide. 1.65 g (5 mmol) of 7-chloro-4,5-dihydro-3-(3-hydroxy-3-methyl-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one and 1.42 g (10 mmol) of methyl iodide were then added thereto in succession, whereby the temperature rises to 35°. The reaction mixture was stirred for 45 minutes and then poured into 50 ml of water. The mixture was extracted five times with methylene chloride, the combined organic phases were dried over magnesium sulphate and evaporated. After crystallization from diisopropyl ether there was obtained 7-chloro-4,5-dihydro-3-(3-methoxy-3-methyl-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 172°-174°.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[S:7]1[C:15]2[CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:10]=2[CH:9]=[C:8]1[C:23](OCC)=[O:24].C(OCC)(=O)C.CCCCCC>O1CCCC1>[OH:24][CH2:23][C:8]1[S:7][C:15]2[CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:10]=2[CH:9]=1
Reactant: CCOC(=O)c1cc2c(s1)CCN(C(=O)OC(C)(C)C)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2sc(CO)cc2C1
Temperature: 0 °C
Reaction time: 0.21 h

Procedure:
Tetrahydrofuran (10 ml) was added dropwise to lithium aluminium hydride (0.46 g, 2 eq.) at 0° C. and the mixture was stirred for 10-15 min at the same temperature. Then a solution of 5-tert-butyl 2-ethyl 6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxylate (2 g, 0.006 mol) in tetrahydrofuran (10 ml) was added dropwise to the mixture at 0° C. and the resulting reaction mixture was stirred for 1-2 h at the same temperature. Progress of the reaction was monitored by TLC (30% ethyl acetate/hexane). Upon completion of the reaction the reaction mixture was poured into ice water and quenched with saturated sodium sulfate solution at 0° C. The mixture was filtered over a bed of Celite and the filtrate was extracted with ethyl acetate (2×150 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to yield the crude product as a pale yellow colored liquid. The crude product obtained was directly employed in the next step. Yield: 1.6 g (92%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3=[N:14][CH:15]=[CH:16][C:17]([C:18]4[CH:19]=[N:20][C:21]5[C:26]([CH:27]=4)=[CH:25][CH:24]=[CH:23][CH:22]=5)=[C:12]3[C:11]([CH:28]([CH3:30])[CH3:29])=[N:10]2)=[CH:5][C:4]=1[NH:31][CH:32]1[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]1)#[N:2].C(Cl)(Cl)Cl.O.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[CH:28]([C:11]1[C:12]2[C:13](=[N:14][CH:15]=[CH:16][C:17]=2[C:18]2[CH:19]=[N:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([NH:31][CH:32]3[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]3)[CH:5]=2)[N:10]=1)([CH3:30])[CH3:29]
Reactant: CC(C)c1nn(-c2ccc(C#N)c(NC3CCN(C(=O)OC(C)(C)C)CC3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC(C)c1nn(-c2ccc(C#N)c(NC3CCNCC3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
Tert-butyl 4-{2-cyano-5-(3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)phenylamino}piperidine-1-carboxylate obtained in Example 76 was dissolved in trifluoroacetic acid, followed by stirring at room temperature for 1 hr. The reaction solution was distributed between chloroform and saturated sodium bicarbonate water, and the organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. After distillation of the solvent, the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain (77a) (the second stage yield: 56%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH:19]([CH3:21])[CH3:20])=[C:13]([N+:15]([O-])=O)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)(=O)C.[Cl-].[Cl-].[Cl-].[Ti+3]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH:19]([CH3:21])[CH3:20])=[C:13]([NH2:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Oc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: [Ti+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)Oc1ccc(OCc2ccccc2)cc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.7 %

Procedure:
Titanium trichloride (10% solution in 20-30% hydrochloric acid, 50 mL) was added to a solution of 5-benzyloxy-2-isopropoxynitrobenzene (Description 108, 2.78 g, 9.7 mmol) in acetic acid (50 mL) and the mixture was stirred at room temperature for 18 h. The mixture was poured into ice-cooled aqueous sodium hydroxide (4M, 400 mL) and the mixture was extracted with dichloromethane (8×100 mL). The combined organic fractions were washed with saturated aqueous sodium hydrogen carbonate (2×200 mL), dried MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a dark oil (1.74 g, 71%). 1H NMR (360 MHz, CDCl3) δ 7.42-7.25 (5H, m), 6.71 (1H, d, J 8.7 Hz), 6.41 (1H, d, J 2.9 Hz), 6.30 (1H, dd, J 8.7, 2.9 Hz), 4.97 (2H, s), 4.38 (1H, hept, J 6.0 Hz), 3.6 (2H, br s), and 1.32 (6H, d, d 6.0 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.[N:10]1([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>C(O)(=O)C>[CH3:9][C:5]1[C:6]([NH2:8])=[N:7][C:2]([NH:23][C:20]2[CH:19]=[CH:18][C:17]([CH2:16][N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)=[CH:22][CH:21]=2)=[N:3][CH:4]=1
Reactant: Nc1ccc(CN2CCOCC2)cc1
Reactant: Cc1cnc(Cl)nc1N
Solvent: CC(=O)O
Product: Cc1cnc(Nc2ccc(CN3CCOCC3)cc2)nc1N
Temperature: 70 °C
Yield: 83.5 %

Procedure:
A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.40 g, 2.8 mmol) and 4-morpholin-4-ylmethyl-phenylamine (0.60 g, 3.1 mmol) in acetic acid (15 mL) was heated at 70° C. for 17 h. After cooling to room temperature, the mixture was concentrated. The residue was taken in water (30 mL) and neutralized with 10% NaOH solution until pH˜10. The resulting aqueous layer was extracted with EtOAc (2×30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to afford the title compound as a brown syrup (0.70 g, 83%). It was used in the next step without purification. MS (ES+): m/z 300 (M+H)+
Reaction SMILES: [OH:1][C@@H:2]([C:6]([O:19][CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O-:5])=[O:4].Cl[C@H](C1C=CC(Cl)=CC=1)C[NH3+].CC(C)([O-])C.[Na+].[CH3:38][C:39]1[CH:44]=[C:43]([CH3:45])[N:42]=[C:41](S(C)(=O)=O)[N:40]=1.O>CN(C=O)C>[CH3:45][C:43]1[CH:44]=[C:39]([CH3:38])[N:40]=[C:41]([O:1][C@@H:2]([C:6]([O:19][CH3:20])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]([OH:5])=[O:4])[N:42]=1
Reactant: COC(c1ccccc1)(c1ccccc1)[C@H](O)C(=O)[O-]
Reactant: Cc1cc(C)nc(S(C)(=O)=O)n1
Agent: CC(C)(C)[O-]
Agent: [NH3+]C[C@H](Cl)c1ccc(Cl)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(c1ccccc1)(c1ccccc1)[C@H](Oc1nc(C)cc(C)n1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a 25 mL three neck flask with stirring arrangement, (1 gm) (R)-2,4-dichlorophenylethyl ammonium (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionate and (0.622 gm) sodium tertiary butoxide (6.488 mmol) in 10 ml DMF at 25° C. were taken and stirred for 5 min. (0.604 gm) 4,6-dimethyl-2-(methylsulfonyl)pyrimidine (3.244 mmol) was added to the reaction mixture in one lot. The reaction mixture was stirred at room temperature for 4 hours and subsequently dumped into cold water and aqueous layer was washed with toluene. Aqueous layer was collected and acidified with HCl to adjust pH to 2. Solid white material was precipitated. Solid white material was precipitated. The solid so obtained was filtered, washed with water and dried.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[OH:14].[OH-].[Na+]>O>[C:2](=[O:3])([O:4][CH3:5])[O:14][C:8]1[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:7]=1[Cl:6]
Reactant: COC(=O)Cl
Reactant: Oc1ccc(F)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)Oc1ccc(F)cc1Cl
Yield: 79.1 %

Procedure:
Methyl chloroformate (77.3 g, 0.82 mol) was added dropwise to a −10° C. solution of 2-chloro-4-fluorophenol (100 g, 0.68 mol) and sodium hydroxide (32.8 g, 0.82 mol) in water (550 mL). After complete addition, the precipitated solid was collected by filtration and washed with water to give 2-chloro-4-fluorophenyl methyl carbonate (110 g, 79% yield). 1H NMR (300 MHz, DMSO-d6): δ 7.62 (dd, J=8.1, 2.7 Hz, 1H), 7.50 (dd, J=9.0, 5.4 Hz, 1H), 7.30 (td, J=8.1, 3.0 Hz, 1H), 3.86 (s, 3H); MS (ESI) m/z: 205.2 (M+H+).
Reaction SMILES: [C:1]1([N:10]2[CH2:14][CH2:13][C@H:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11]2)[C:2]2[N:3]([CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:5][N:6]=1.Cl>O1CCOCC1>[C:1]1([N:10]2[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11]2)[C:2]2[N:3]([CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2nccn3cccc23)C1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CCN(c2nccn3cccc23)C1
Temperature: 60 °C
Yield: 100 %

Procedure:
To a solution of (S)-tert-butyl N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)carbamate (0.88 g, 2.9 mmol, 1 eq) in 3.6 mL of dioxane was added a solution of 4.0 M HCl in dioxane (3.6 mL, 14.5 mmol, 5 eq). After heating for 1 h at 60° C., the mixture was concentrated to afford (S)-1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-amine (0.79 g, 2.9 mmol, 100%).
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([OH:29])=O)[CH2:10]2)=CC=1.[CH3:32][C@@H:33]1[CH2:38][NH:37][CH2:36][CH2:35][N:34]1[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][CH:44]=1)=[O:40]>>[SH:8][C@@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:15])[C@H:11]([C:27]([N:37]2[CH2:36][CH2:35][N:34]([C:39]([O:41][CH2:42][C:43]3[CH:44]=[CH:45][C:46]([N+:49]([O-:51])=[O:50])=[CH:47][CH:48]=3)=[O:40])[C@H:33]([CH3:32])[CH2:38]2)=[O:29])[CH2:10]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: C[C@@H]1CNCCN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Product: C[C@@H]1CN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CCN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 69.4 %

Procedure:
Following a procedure similar to that described in Preparation 8, but using 0.23 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid, 0.10 g of N,N'-carbonyldiimidazole and 0.17 g of (2R)-2-methyl-1-(4-nitrobenzyloxycarbonyl)piperazine, 0.21 g of the title compound was obtained as an amorphous solid.