Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:20][CH:19]=4)[N:15]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:4][C:3]=1[NH2:41].[CH:42]1([NH:45][C:46](=O)[O:47]C2C=CC=CC=2)[CH2:44][CH2:43]1.O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]3[CH:17]=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][CH2:27][N:28]([CH2:29][CH3:30])[CH2:31][CH3:32])=[CH:22][CH:23]=4)[N:15]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:38])([CH3:39])[CH3:40])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:4][C:3]=1[NH:41][C:46]([NH:45][CH:42]1[CH2:44][CH2:43]1)=[O:47]
Reactant: CCN(CC)CCCOc1ccc(-c2cc3c(Oc4ccc(N)c(Cl)c4)ncnc3n2COCC[Si](C)(C)C)cc1
Reactant: O=C(NC1CC1)Oc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: CCN(CC)CCCOc1ccc(-c2cc3c(Oc4ccc(NC(=O)NC5CC5)c(Cl)c4)ncnc3n2COCC[Si](C)(C)C)cc1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
After dissolving the 2-chloro-4-[6-[4-(3-diethylaminopropoxy)phenyl]-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]phenylamine synthesized in Production Example 160-2 in 0.6 ml of dimethylsulfoxide, 23 mg of phenyl cyclopropylcarbamate was added and the mixture was stirred at 80° C. for 1.5 hours. After further adding 75 mg of phenyl cyclopropylcarbamate and stirring at 100° C. for 5 hours, 70 mg of the same reagent was added prior to stirring overnight. The mixture was then returned to room temperature, water was added, and liquid separation and extraction were performed with an ethyl acetate:tetrahydrofuran (5:1) mixed solvent. The organic layer was dried over sodium sulfate, concentrated and subjected to NH silica gel column chromatography (hexane-ethyl acetate) to obtain 18 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]=[C:14]2[O:16][C:17]([CH3:28])([CH3:27])[CH2:18][CH:19]([NH:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:13]2=[CH:12][C:11]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1.Cl.[NH2:37][OH:38].C([O-])(O)=O.[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:37][OH:38])=[NH:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]=[C:14]2[O:16][C:17]([CH3:27])([CH3:28])[CH2:18][CH:19]([NH:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:23])[CH3:24])[C:13]2=[CH:12][C:11]=1[C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1
Reactant: NO
Reactant: CC1(C)CC(NC(=O)C(C)(C)C)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(C#N)cc3Cl)nc2O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC1(C)CC(NC(=O)C(C)(C)C)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(C(=N)NO)cc3Cl)nc2O1

Procedure:
A solution of Example 317 (120 mg, 0.24 mmol), hydroxylamine hydrochloride (65.6 mg, 0.94 mmol), and NaHCO3 (119 mg, 1.42 mmol) in 10 mL of EtOH was refluxed for 16 h. The reaction mixture was partitioned between brine (50 mL) and CH2Cl2 (50 mL). The aq layer was separated and extracted with CH2Cl2 (2×50 mL). The organic layers were combined, dried over MgSO4, and concentrated to give the product, which was taken into the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1.O[CH2:74][CH2:75][CH2:76][N:77]1[CH2:82][CH2:81][N:80]([CH3:83])[CH2:79][CH2:78]1>C1COCC1>[CH3:83][N:80]1[CH2:81][CH2:82][N:77]([CH2:76][CH2:75][CH2:74][O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])[CH2:78][CH2:79]1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: CN1CCN(CCCO)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CN1CCN(CCCOc2ccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c2CNC3=O)CC1
Yield: 57.9 %

Procedure:
In a similar manner to Step 1 of Example 149, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0817 g, 0.177 mmol) was dissolved in THF (4.0 mL), and the solution was treated with triphenylphosphine (0.0930 g, 0.354 mmol), 40% DEAD-toluene solution (0.161 mL, 0.354 mmol) and 1-(3-hydroxypropyl)-4-methylpiperazine (0.140 g, 0.855 mmol), followed by purification by flash column chromatography (chloroform/methanol=7/3) to obtain 4-[3-(4-methylpiperazin-1-yl)propoxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0617 g, yield 58%).
Reaction SMILES: Cl[P:2]1[O:9][C:8]2[C:10]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:13][C:7]=2[CH2:6][C:5]2[CH:22]=[C:23]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[C:25]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:4]=2[O:3]1.[OH2:34].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:34]=[PH:2]1[O:9][C:8]2[C:10]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:13][C:7]=2[CH2:6][C:5]2[CH:22]=[C:23]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[C:25]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:4]=2[O:3]1
Reactant: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OP(Cl)Oc1c(cc(C(C)(C)C)cc1C(C)(C)C)C2
Reactant: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)O[PH](=O)Oc1c(cc(C(C)(C)C)cc1C(C)(C)C)C2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.8 %

Procedure:
To a solution of 8.9 g (0.019 mol) of the compound of Example 4 in 150 mL of toluene at ambient temperature is added dropwise a solution of 0.34 mL (0.019 mol) of distilled water in 4.0 mL (0.029 mol) of triethylamine. After the addition is complete, the reaction mixture is stirred at ambient temperature for 15 minutes. The reaction solvent is removed under vacuum and the residue is recrystallized twice with 50 mL of acetonitrile. The acetonitrile is then removed in vacuo and the residue is dried under vacuum to give 2.4 g (79.5% yield) of the title compound as an off-white solid melting at 164° C.
Reaction SMILES: CC([N:5]([CH2:9][CH2:10][NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH:29]3[CH2:34][CH2:33][N:32]([C:35]4[O:39][N:38]=[C:37]([CH:40]([CH3:42])[CH3:41])[N:36]=4)[CH2:31][CH2:30]3)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])C(=O)[O-])(C)C.[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44]>C(Cl)Cl>[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44].[F:46][C:45]([F:48])([F:47])[C:43]([OH:49])=[O:44].[NH2:5][CH2:9][CH2:10][NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH:29]3[CH2:30][CH2:31][N:32]([C:35]4[O:39][N:38]=[C:37]([CH:40]([CH3:42])[CH3:41])[N:36]=4)[CH2:33][CH2:34]3)=[CH:25][CH:26]=2)=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc(S(=O)(=O)NCCN(C(=O)[O-])C(C)(C)C)cc4)cc3)CC2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc(S(=O)(=O)NCCN)cc4)cc3)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A mixture of 1,1-dimethylethyl{2-[({4′-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]-4-biphenylyl}sulfonyl)amino]ethyl}carbamate (Example 108, 160 mg, 0.27 mmol) and TFA (0.3 mL) in CH2Cl2 (3 mL) was stirred at ambient temperature for 1 h. The crude product was concentrated and purified by reverse-phase preparative HPLC using a CH3CN:H2O gradient (0.5:99.5 to 90:10) with 0.05% TFA as a modifier to give 123 mg (91%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.09 (bs, 2H), 7.86 (d, 2H, J=8.2 Hz), 7.60 (d, 2H, J=8.2 Hz), 7.46 (d, 2H, J=8.8 Hz), 7.33 (bs, 1H), 6.92 (d, 2H, J=8.8 Hz), 4.24-4.14 (m, 2H), 3.84 (d, 2H, J=6.2 Hz), 3.27 (bs, 4H), 3.14-3.04 (m, 2H), 2.94-2.81 (m, 1H), 2.10-2.00 (m, 1H), 1.98-1.88 (m, 2H), 1.51-1.37 (m, 2H), 1.27 (d, 6H, J=7.0 Hz); LRMS (ESI), m/z 500 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([N:32]1[CH2:37][CH2:36][CH:35]([CH2:38]O)[CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:25]([N:32]1[CH2:37][CH2:36][CH:35]([CH2:38][N:15]2[C:14](=[O:17])[N:11]3[N:12]=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[C:9]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[C:10]3=[N:16]2)[CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: OCC1CCN(Cc2ccccc2)CC1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1n(CC2CCN(Cc3ccccc3)CC2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Reaction time: 1 h
Yield: 10.2 %

Procedure:
To a THF solution (2 ml) of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (40 mg, 0.11 mmol), prepared as described in Example 1, (1-benzyl-4-piperidyl)methanol (27 mg 0.13 mmol), and triphenylphospine (86 mg, 0.32 mmol) was added diethyl azodicarboxylate (0.15 ml, 0.38 mmol). After 1 hour, the reaction mixture was concentrated. The crude material was purified by preparative HPLC to give the title compound, 2-((1-benzylpiperidin-4-yl)methyl)-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (6.1 mg, 10%) as a yellow solid. MS M+H=544; 1HNMR (CDCl3) δ 8.19 (1H), 7.42 (2H), 7.32-7.20 (9H), 7.11 (2H), 4.19 (1H), 4.02 (2H), 3.66 (2H), 2.63 (2H), 2.12 (2H), 1.91 (4H).
Reaction SMILES: [CH:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH:17]([CH3:22])[C:18]([O:20]C)=[O:19])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].Cl>C(O)C.O>[CH:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH:17]([CH3:22])[C:18]([OH:20])=[O:19])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)C(C)c1ccc(C2CCCCC2)c2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C(=O)O)c1ccc(C2CCCCC2)c2ccccc12
Yield: 82.6 %

Procedure:
4.44 g (0.015 mole) of methyl 2(4-cyclohexyl-1-naphthyl)-propionate were solubilized in 50 ml of ethyl alcohol and 50 ml of water under heating. 2.8 g of KOH in 50 ml of water were then added and the mixture was heated with reflux for 10 hours. The conventional treatment followed by an acidification with diluted HCl and a recrystallization from a mixture of ethyl alcohol/water gave 3.5 g of 2-(4-cyclohexyl-1-naphthyl)propionic acid.
Reaction SMILES: [CH:1]1([CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH:9]2[CH2:13][O:12]C(C)(C)[O:10]2)[CH2:3][CH2:2]1>CC(O)=O>[CH:1]1([CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH:9]([OH:10])[CH2:13][OH:12])[CH2:2][CH2:3]1
Reactant: CC1(C)OCC(CCC=CCC2CC2)O1
Solvent: CC(=O)O
Product: OCC(O)CCC=CCC1CC1

Procedure:
Stirred 4-(5-Cyclopropyl-pent-3-enyl)-2,2-dimethyl-[1,3]dioxolane (0.30 g, 1.4 mmol) in 80% AcOH (5 mL) overnight at room temperature. Concentrated and purified by silica gel chromatography (70˜90% EtOAc in hexanes) to collect 7-Cyclopropyl-hept-5-ene-1,2-diol as a clear oil. 1H NMR (400 MHz, CDCl3): δ 5.52-5.47 (m, 1H), 5.41-5.35 (m, 1H), 3.77-3.71 (m, 1H), 3.66 (d, 1H, J=11.2 Hz), 3.46 (dd, 1H, J1=11.2 Hz, J2=7.7 Hz), 2.19-2.10 (m, 2H), 1.97 (t, 2H, J=7.1 Hz), 1.53-1.46 (m, 2H), 0.74-0.68 (m, 1H), 0.44-0.39 (m, 2H), 0.08-0.04(m, 2H).
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20]>CCO>[CH2:11]([O:10][C:2](=[O:9])[CH:3]([CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:12]
Reactant: COCCOCCBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CCOCCOC)C(=O)OCC
Yield: 48.3 %

Procedure:
Sodium (0.72 g, 31.31 mmol) was added in portions to EtOH (99.5%, 35 mL) under stirring. When all sodium had dissolved, diethyl malonate (4.80 g, 29.97 mmol) was added slowly during 5 minutes and the reaction mixture was stirred for another 15 minutes. 1-Bromo-2-(2-methoxyethoxy)-ethane (5.50 g, 30.05 mmol) was added and the reaction mixture was refluxed for 2 hrs. Any solids were filtered off and the clear solution was concentrated in vacuo. The residue was taken up in water and diethyl ether and the two phases were separated. The organic phase was dried over MgSO4 and concentrated in vacuo. The residue was purified with column chromatography (silica gel, eluting with EtOAc/MeOH:20/1) to give the title compound as a colourless oil (3.80 g), 1H NMR (300 MHz, CDCl3) δ 4.19 (q, 4H), 3.54 (m, 7H), 3.38 (s, 3H), 2.19 (m, 2H), 1.27 (t, 6H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][N:19]3[C:23]4=[N:24][CH:25]=[C:26]([C:28]([OH:30])=O)[CH:27]=[C:22]4[N:21]=[CH:20]3)[CH:15]=[CH:14][C:12]=2[N:13]=1.C1COCC1.[CH3:36][NH:37][CH3:38].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][N:19]3[C:23]4=[N:24][CH:25]=[C:26]([C:28]([N:37]([CH3:38])[CH3:36])=[O:30])[CH:27]=[C:22]4[N:21]=[CH:20]3)[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: O=C(O)c1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Reactant: CNC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
To a stirred mixture of 3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (65 mg, 0.153 mmol) from Example 81 and TEA (77 mg, 0.767 mmol) in a mixture of anhydrous THF (1.5 mL) and anhydrous DMF (0.5 mL) at rt was added dimethylamine (2 M solution in MeOH, 383 μL, 0.767 mmol) followed by benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (102 mg, 0.230 mmol). The resulting mixture was stirred at rt for 2 h. The mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford 3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-6-carboxamide (33 mg, 48%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.45 (s, 1H), 8.16 (s, 1H), 7.96 (d, J=7.54 Hz, 1H), 7.68 (s, 1H), 7.20-7.33 (m, 2H), 5.50 (s, 2H), 4.73 (d, J=4.90 Hz, 1H), 3.51 (m, 1H), 3.30 (m, 1H), 2.99 (br. s., 6H), 2.02 (m, 1H), 1.87 (m, 1H), 1.55-1.65 (m, 2H), 1.10-1.30 (m, 4H). LCMS (ESI) m/z 451 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])=[N:14][C:15]=2[NH:17][CH2:18][CH:19]([OH:21])[CH3:20])[N:10]([CH2:31][OH:32])[N:9]=1.C(NC(C)C)(C)C.CN(C1C=CC=CN=1)C.[C:49]1(=[O:55])[O:54][C:52](=[O:53])[CH2:51][CH2:50]1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])=[N:14][C:15]=2[NH:17][CH2:18][CH:19]([OH:21])[CH3:20])[N:10]([CH2:31][O:32][C:49](=[O:55])[CH2:50][CH2:51][C:52]([OH:54])=[O:53])[N:9]=1
Reactant: O=C1CCC(=O)O1
Reactant: CC(O)CNc1nc(Oc2ccc(F)cc2F)nc2c1c(-c1ccccc1Cl)nn2CO
Agent: CN(C)c1ccccn1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(O)CNc1nc(Oc2ccc(F)cc2F)nc2c1c(-c1ccccc1Cl)nn2COC(=O)CCC(=O)O
Temperature: 25 °C
Yield: 25.7 %

Procedure:
1-[3-(2-Chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1-hydroxymethyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-propan-2-ol (2.0 g, 4.3 mmol) was dissolved in 80 mL THF, and diisopropylamine (0.78 g, 5.6 mmol), dimethyamino pyridine (52 mg, 0.4 mmol) and succinic anhydride (703 mg, 7.0 mmol) were added while stirring at room temperature. The reaction mixture was stirred for 16 hours at room temperature, then partitioned between water and ethyl acetate, and the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was dissolved in EtOAc and purified by flash chromatography (silica gel, hexanes/EtOAc 1:1 to EtOAc/AcOH 100:1) to give 0.62 g of succinic acid mono-[3-(2-chloro-phenyl)-6-(2,4-difluoro-phenoxy)-4-(2-hydroxy-propylamino)-pyrazolo[3,4-d]pyrimidin-1-ylmethyl]ester, MS (M+H)=562
Reaction SMILES: [CH3:1][C:2]([O:41][CH2:42][C@@H:43]1[CH2:45][O:44]1)([CH3:40])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:13]2)=[O:11])=[N:5]1.[CH3:46][NH2:47]>C(O)(C)C>[OH:44][C@@H:43]([CH2:45][NH:47][CH3:46])[CH2:42][O:41][C:2]([CH3:40])([CH3:1])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:37])([CH3:39])[CH3:38])[NH:13]2)=[O:11])=[N:5]1
Reactant: CN
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@@H]3CO3)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: CC(C)O
Product: CNC[C@H](O)COC(C)(C)Cn1ccc(NC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)n1
Yield: 16.2 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {1-[2-methyl-2-((S)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3-yl}-amide (87.5 mg, 0.133 mmol), isopropyl alcohol (2 mL), and methylamine (1.0 mL, 2 mmol, 2 M in methanol; old bottle) was microwaved at 130° C. for 15 min. The solvent evaporated under reduced pressure. The resulting oil was purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)pyrrolidine-2-carboxylic acid {1-[2-((S)-2-hydroxy-3-methylamino-propoxy)-2-methyl-propyl]-1H-pyrazol-3-yl}-amide (14.9 mg, 16.2%) as an off-white powder. HRMS (ES+) m/z Calcd for C34H42Cl2F2N6O3S+H [(M+H)+]: 691.2737. found: 691.2731.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[O-:6][N+:7]1[C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][C:11]=2[N:10]=[C:9]([CH2:20][CH2:21][CH:22]=O)[N:8]=1)[CH2:17][CH2:16][CH2:15]3.[BH3-]C#N.[Na+].CC(O)=O>CO>[N:1]1([CH2:22][CH2:21][CH2:20][C:9]2[N:8]=[N+:7]([O-:6])[C:12]3[CH:13]=[C:14]4[C:18]([CH2:17][CH2:16][CH2:15]4)=[CH:19][C:11]=3[N:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: O=CCCc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: [O-][n+]1nc(CCCN2CCCC2)nc2cc3c(cc21)CCC3
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
Pyrrolidine (3.0 g, 42 mmol) was added to a stirred solution of propanal 75 (1.5 g, 6.2 mmol) in MeOH (100 mL) at 0° C. and the solution stirred for 30 min. NaCNBH3 (1.5 g, 24 mmol) was added and the solution stirred at 0° C. for 30 min and then HOAc (2 mL) was added and the mixture was stirred at 20° C. for 16 h. The solvent was evaporated and the residue was partitioned between DCM (200 mL) and water (200 mL). The aqueous phase was extracted with DCM (2×200 mL), the combined organic phase was dried and the solvent evaporated. The residue was purified by chromatography, eluting with 10% MeOH/EtOAc, to give 1-oxide 84 (1.5 g, 84%) as a yellow oil: 1H NMR [(CD3)2SO] δ 8.25 (s, 1H, H-9), 7.74 (s, 1H, H-5), 3.10-3.16 (m, 4H, H-6, H-8), 3.02-3.09 (m, 2H, CH2N), 2.80-2.88 (m, 6H, 3×CH2), 2.17-2.28 (m, 4H, H-7, CH2), 1.82-1.90 (m, 4H, 2×CH2); 13C NMR δ 165.0, 154.8, 149.2, 147.2, 132.3, 122.7, 114.3, 55.0, 53.4 (2), 34.8, 33.2, 32.8, 25.7, 25.5, 23.4 (2); HRMS calcd for C17H22N4O (M+) m/z 298.1794, found 298.1794.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([OH:20])=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:27]=[C:26]([CH2:28]O)[CH:25]=[CH:24][N:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:19]([O:20][CH2:28][C:26]3[CH:25]=[CH:24][N:23]=[C:22]([F:21])[CH:27]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2O)CC1
Reactant: OCc1ccnc(F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCc2ccnc(F)c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 3′-hydroxy-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (304 mg, 1.08 mmol), 2-Fluoro-4-pyridinemethanol (138 mg, 1.08 mmol), and triphenylphosphine (286 mg, 1.09 mmol) in THF (5 mL) was added diethyl azidocarboxylate (210 mg, 1.21 mmol) dropwise. The resulting clear brown solution was stirred at room temperature for 16 h, then concentrated in vacuo. The crude solids were purified by flash chromatography (silica gel, 1:2 EtOAc:Hexanes). Product 3′-(2-fluoro-pyridin-4-ylmethoxy)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester was obtained as white solid (113 mg, 26.9% yield).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][CH2:4][CH:5]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)[OH:6].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>COC(C)(C)C>[F:1][C:2]([F:18])([F:19])[CH2:3][CH2:4][CH:5]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)[O:6][S:28]([CH3:27])(=[O:30])=[O:29]
Reactant: CCOC(=O)c1ccc(C(O)CCC(F)(F)F)cc1
Reactant: CS(=O)(=O)Cl
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C(CCC(F)(F)F)OS(C)(=O)=O)cc1
Reaction time: 1 h

Procedure:
To a solution of ethyl (+/−)-4-(4,4,4-trifluoro-1-hydroxybutyl)benzoate (264 mg, 0.956 mmol) in tert-butyl methyl ether (4.8 mL) was added triethylamine (0.201 mL, 1.43 mmol), followed by methanesulfonyl chloride (0.091 mL, 1.15 mmol). The resulting mixture was stirred for 1 hour. Then, the reaction mixture was diluted with tert-butyl methyl ether (25 mL) and washed with water (15 mL), sat. aq sodium bicarbonate (15 mL), then sat. aq sodium chloride (15 mL). The organic layer was dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure to give ethyl (+/−)-4-(4,4,4-trifluoro-1-((methylsulfonyl)oxy)butyl)benzoate. This material was used without further purification. 1HNMR (400 MHz, CDCl3) δ 8.12 (d, J=8.4 Hz, 2 H), 7.48 (d, J=8.2 Hz, 2 H), 5.63 (dd, J=7.9, 4.8 Hz, 1 H), 4.41 (q, J=7.0 Hz, 2 H), 2.77 (s, 3 H), 2.39-2.08 (m, 4 H), 1.41 (t, J=7.1 Hz, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([CH2:15][CH2:16][C:17](OCC)=[O:18])=[N:13][CH:14]=[C:7]1[C:6](=[O:22])[NH:5]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([CH2:15][CH2:16][CH2:17][OH:18])=[N:13][CH:14]=[C:7]1[C:6](=[O:22])[NH:5]2
Reactant: CCOC(=O)CCc1ncc2c(=O)[nH]c3cc(Cl)ccc3n12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(Cl)ccc2n2c(CCCO)ncc12
Reaction time: 0.5 h

Procedure:
Fifty (50) mg of ethyl 3-(7-chloro-4-oxo-4,5-dihydroimidazo-[1,5-a]quinoxalin-1-yl)propanoate as synthesized in Example 176 was dissolved in 5 mL of tetrahydrofuran, and to the solution 8.9 mg of lithium aluminum hydride was added under cooling with ice. After 30 minutes' stirring, the residual lithium aluminum hydride was quenched with ice pieces, and the reaction liquid was extracted with ethyl acetate. The extract was washed with saturated aqueous ammonium chloride solution, saturated aqueous sodium hydrogencarbonate solution, and with saturated brine by the order stated, and dried over anhydrous sodium sulfate. Distilling the solvent off from the product, 38 mg of the title compound was obtained.