Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH:19]1([NH:22][C:23]([C:25]23[CH2:49][CH2:48][C:47]([O:54][Si](CC)(CC)CC)([C:50]([F:53])([F:52])[F:51])[CH2:46][CH:26]2[CH2:27][CH2:28][CH2:29][C:30]2[C:31]3=[CH:32][C:33]3[CH:34]=[N:35][N:36]([C:39]4[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=4)[C:37]=3[CH:38]=2)=[O:24])[CH2:21][CH2:20]1>C(Cl)Cl>[CH:19]1([NH:22][C:23]([C:25]23[CH2:49][CH2:48][C:47]([OH:54])([C:50]([F:51])([F:53])[F:52])[CH2:46][CH:26]2[CH2:27][CH2:28][CH2:29][C:30]2[C:31]3=[CH:32][C:33]3[CH:34]=[N:35][N:36]([C:39]4[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=4)[C:37]=3[CH:38]=2)=[O:24])[CH2:21][CH2:20]1
Reactant: CC[Si](CC)(CC)OC1(C(F)(F)F)CCC2(C(=O)NC3CC3)c3cc4cnn(-c5ccc(F)cc5)c4cc3CCCC2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: O=C(NC1CC1)C12CCC(O)(C(F)(F)F)CC1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Reaction time: 1 h
Yield: 78 %

Procedure:
TBAF (1 M solution in THF, 0.560 mL, 0.560 mmol) was added to a solution of rac-(3R,4aR,12bS)—N-cyclopropyl-9-(4-fluorophenyl)-3-((triethylsilyl)oxy)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazole-12b-carboxamide (44, R1=4-Fluorophenyl, R2′=Cyclopropyl, R3=Trifluoromethyl) (0.230 g, 0.374 mmol) and DCM (6 mL). After about 1 h, TBAF (1 M solution in THF, 0.30 mL, 0.30 mmol) was added. After about 30 min, DCM (50 mL) was added. The solution was washed with water (4×20 mL) and sat. aq. NaCl (20 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was loaded onto silica gel (6 g) and purified on silica gel (40 g) using a gradient of 0-30% EtOAc in DCM. The product fractions were combined and concentrated to give rac-(3R,4aR,12bS)—N-cyclopropyl-9-(4-fluorophenyl)-3-hydroxy-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazole-12b-carboxamide (45, R1=4-Fluorophenyl, R2′=Cyclopropyl, R3=Trifluoromethyl) (0.150 g, 78% yield); LC/MS, method 3, Rt=2.46 min.; MS m/z: 502 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.31 (d, J=0.8 Hz, 1H), 7.88 (s, 1H), 7.84-7.74 (m, 2H), 7.57 (s, 1H), 7.45-7.36 (m, 2H), 6.37 (d, J=3.8 Hz, 1H), 5.89 (s, 1H), 2.90-2.64 (m, 2H), 2.63-2.50 (m, 2H), 2.50-2.36 (m, 2H), 2.17-2.06 (m, 1H), 2.03-1.88 (m, 2H), 1.81-1.66 (m, 2H), 1.58-1.35 (m, 2H), 1.32-1.13 (m, 1H), 0.56-0.40 (m, 2H), 0.37-0.15 (m, 2H).
Reaction SMILES: C1CO[C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5OCC[O:28][C:21]=5[CH:20]=4)[C:15]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1.OC1C=C(NC2N=C(NC3C=CC=C(O)C=3)C(Br)=CN=2)C=CC=1.[CH2:58]1[O:66]C2C=CC(B(O)O)=CC=2[O:59]1>>[OH:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([OH:28])[CH:20]=3)[C:15]([C:29]3[CH:34]=[CH:33][C:32]4[O:59][CH2:58][O:66][C:31]=4[CH:30]=3)=[CH:14][N:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: c1ccc(-c2cnc(Nc3ccc4c(c3)OCCO4)nc2Nc2ccc3c(c2)OCCO3)cc1
Agent: Oc1cccc(Nc2ncc(Br)c(Nc3cccc(O)c3)n2)c1
Product: Oc1cccc(Nc2ncc(-c3ccc4c(c3)OCO4)c(Nc3cccc(O)c3)n2)c1

Procedure:
In a manner similar to the preparation of N2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine, N2,N4-bis(3-hydroxyphenyl)-5-bromo-2,4-pyrimidinediamine and 3,4-methylenedioxyphenylboronic acid were reacted to yield N2,N4-bis(3-hydroxyphenyl)-5-(3,4-methylenedioxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.82 (s, 1H), 7.13-7.06 (m, 3H), 7.04-7.01 (m, 2H), 6.97 (dt, 1H, J=1.2 and 8.7 Hz), 6.94-6.88 (m, 3H), 6.52 (ddd, 1H, J=1.2, 2.4, and 6.9 Hz), 6.42 (dt, 1H, J=2.1 and 7.5 Hz), 6.01 (s, 2H); LCMS: ret. time: 21.11 min.; purity: 99%; MS (m/e): 415 (MH+).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[N:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:13]2C(=O)C3C(=CC=CC=3)C2=O)[NH:3]1.O.NN>C(O)C>[NH2:13][CH2:12][C:4]1[NH:3][C:2](=[O:1])[C:11]2[C:6]([N:5]=1)=[N:7][CH:8]=[N:9][CH:10]=2
Reactant: O=C1c2ccccc2C(=O)N1Cc1nc2ncncc2c(=O)[nH]1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1nc2ncncc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.1 %

Procedure:
A suspension of 2-(4-oxo-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2-ylmethyl)-isoindole-1,3-dione (50 mg, 0.163 mmol) and hydrazine monohydrate (0.25 mL, 5.09 mmol) in ethanol (3 mL) was stirred at ambient temperature for 4 hours. A light yellow solid of 2-amino-isoindole-1.3-dione was filtered off, the filtrate was evaporated and purified by column chromatography (silica gel, EtOAc/MeOH, 1/1) to yield 2-aminomethyl-3H-pyrimido[4,5-d]pyrimidin-4-one (24 mg, 83%) as a off-white solid. MS (m/e): 176.2 [M−H−].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38][CH2:37][NH:36]1.N1C=CC=CC=1.C(Cl)Cl>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23]([N:36]4[CH2:37][CH2:38][C:39]5[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=5)[CH2:35]4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: c1ccc2c(c1)CCNC2
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(N4CCc5ccccc5C4)c3)cn2)CC1
Temperature: 25 °C

Procedure:
A mixture of 4-{4-[6-Amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB4) (93.9 mg, 0.200 mmol), 1,2,3,4-tetrahydroisoquinoline (53.3 mg, 0.400 mmol), cupric acetate (36.3 mg, 0.200 mmol), pyridine (32 μL, 0.40 mmol) and DCM (5 mL, 80 mmol) was stirred at rt under an atmosphere of air (Reaction A). Another reaction was set up with the same amount of above reagents, and 4 Å molecular sieves (53 mg, 264 mg/mmol SM) was added (Reaction B). After stirring overnight at rt, the same amount of molecular sieve as in reaction B was added to reaction A. After stirring at rt for 7 h, both reaction mixtures were combined, washed with EDTA solution (2%, 3×30 ml), water (30 ml) and brine (30 ml), dried over MgSO4, filtered, and concentrated in vacuo to give a dark-blue solid. Purification by prep. TLC eluting with 5% MeOH/DCM gave 4-{4-[6-amino-5-(3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester as brown oil; MS(ES+): m/z=475.12 [MH+]. This brown oil was dissolved in MeOH (10 mL), 1.0 M of HCl in Et2O (10 mL) was added, and the solution was stirred at rt for 3 d. The solvent was removed; the residue was dissolved in DMSO and purified by Gilson HPLC to give the title compound as light-brown oil. 1H NMR (400 MHz, DMSO-d6): δ=1.99-2.11 (m, 2H), 2.12-2.19 (m, 2H), 2.89-2.99 (m, 2H), 3.00-3.05 (m, 2H), 3.12-3.18 (m, 2H), 3.26-3.33 (m, 2H), 4.10 (s, 2H), 4.33-4.43 (m, 1H), 5.51 (brs, 2H), 7.13-7.19 (m, 4H), 7.47 (d, J=2.0 Hz, 1H), 7.82 (s, 1H), 7.99 (d, J=2.0 Hz, 1H), 8.13 (s, 1H), 8.30 (brs, 2H). MS(ES+): m/z=375.17 (42) [MH+]. HPLC: tR=1.73 min (ZQ2, polar—5 min).
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[C:5]([C@@H:7]2[CH2:12][CH2:11][N:10](C(OC)=O)[C@H:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[CH2:8]2)[O:4][NH:3]1.Br>>[F:25][C:23]([F:24])([F:26])[C:19]1[CH:18]=[C:17]([C@@H:9]2[CH2:8][C@H:7]([C:5]3[O:4][NH:3][C:2](=[O:1])[CH:6]=3)[CH2:12][CH2:11][NH:10]2)[CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@H]1c1cccc(C(F)(F)F)c1
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@H](c3cccc(C(F)(F)F)c3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.3 %

Procedure:
(2S,4R)-Methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(3-(trifluoromethyl)phenyl)piperidine-1-carboxylate (0.152 g, 0.42 mmol) (from example 30, step 3) was dissolved in hydrogen bromide (33% in acetic acid, 3.30 mL, 18.83 mmol) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2S,4R)-2-(3-(trifluoromethyl)phenyl)piperidin-4-yl)isoxazol-3(2H)-one (28 mg, 22%). 1H NMR (600 MHz, dmso) δ 1.35 (q, 1H), 1.47 (qd, 1H), 1.87 (d, 1H), 2.00 (d, 1H), 2.73 (dt, 1H), 2.84-2.91 (m, 1H), 3.09-3.14 (m, 1H), 3.75 (d, 1H), 5.74 (s, 1H), 7.50-7.54 (m, 1H), 7.55-7.58 (m, 1H), 7.66 (d, 1H), 7.71 (s, 1H). HRMS Calculated for [C15H15F3N2O2+H]+: 313.1164. Found: 313.1158
Reaction SMILES: S(C)C.[C:4]([NH:7][C:8]1[C:18]2[NH:17][C:16](=O)[CH2:15][N:14]3[C:20]4[CH:21]=[C:22]([C:33]([O:35]C)=[O:34])[CH:23]=[CH:24][C:25]=4[C:26]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[C:13]3[C:12]=2[CH:11]=[CH:10][CH:9]=1)(=O)[CH3:5]>C1COCC1>[CH:27]1([C:26]2[C:25]3[CH:24]=[CH:23][C:22]([C:33]([OH:35])=[O:34])=[CH:21][C:20]=3[N:14]3[C:13]=2[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]4[N:7]=[C:4]([CH3:5])[N:17]([C:18]=24)[CH2:16][CH2:15]3)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)Nc1c(NC(C)=O)cccc1-3
Solvent: C1CCOC1
Solvent: CSC
Product: Cc1nc2cccc3c2n1CCn1c-3c(C2CCCCC2)c2ccc(C(=O)O)cc21
Reaction time: 0.75 h
Yield: 36 %

Procedure:
Me2S complex (2M in THF) (20 eq) was added to a stirred solution of methyl 4-(acetylamino)-13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepine-10-carboxylate in anhydrous THF (0.02 M) at RT under N2. After 45 min further BH3.Me2S complex (2M in THF) (5 eq) were introduced and the reaction left to stir for 1 h. The reaction was quenched by cautious addition of 1N HCl (aq) and MeOH before partitioning between saturated NaHCO3 (aq) and EtOAc. The organics were washed with water, brine before being dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the crude product. Purification by flash chromatography (3% MeOH/CH2Cl2) afforded the title compound (36%). MS (ES+) m/z 414 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].Cl[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([O:8][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:6][N:7]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1cc(O)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2cnc(Cl)c(C)c2)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 6-chloro-5-methylpyridin-3-ol (250 mg, 0.0017 mol), 1-(chloromethyl)-4-methoxybenzene (0.328 g, 0.0020 mol, Sigma Aldrich), and potassium carbonate (0.482 g, 0.0034 mol) in DMF (5 mL) was allowed to stir for 3 h at 60° C. After completion of the reaction, reaction mixture was cooled to ambient temperature and poured into ice cold water (25 mL). The obtained solid was filtered, washed with water (2×10 mL) and dried to obtain 2-chloro-5-((4-methoxybenzyl)oxy)-3-methylpyridine as an off white solid (400 mg, 87%).
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[CH:4]=1.[CH3:17][O:18][CH2:19][CH2:20][NH2:21].CCN(C(C)C)C(C)C>CCCCO>[Cl:16][C:12]1[CH:11]=[C:10]([NH:9][C:5]2[CH:4]=[C:3]([NH:21][CH2:20][CH2:19][O:18][CH3:17])[N:8]=[CH:7][N:6]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Clc1cccc(Nc2cc(Cl)ncn2)c1
Reactant: COCCN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COCCNc1cc(Nc2cccc(Cl)c2)ncn1
Temperature: 200 °C
Yield: 70 %

Procedure:
75 mg of 6-chloro-N-(3-chlorophenyl)pyrimidin-4-amine hydrochloride, 30 mg of 2-methoxyethanamine and 88 mg of DIPEA were dissolved in 1 mL of n-BuOH and charged into a microwave vial and the vial obtained was heated to 200° C. for 60 minutes under microwave irradiation. The reaction was monitored by TLC. The crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using EtOAc. N4-(3-Chlorophenyl)-N6-(2-methoxyethyl)pyrimidine-4,6-diamine in the form of a colorless solid was obtained.
Reaction SMILES: Br[C:2]1[O:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1>>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:2]2[O:6][C:5]([N:7]3[CH2:11][C@:10]4([CH:16]5[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]5)[CH2:12]4)[O:9][C:8]3=[O:19])=[CH:4][CH:3]=2)[CH:21]=1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(Br)o1
Reactant: OB(O)c1cccnc1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(-c2cccnc2)o1

Procedure:
The title compound was prepared by a method analogous to that described in Example 12 from (R)-3′-(5-bromofuran-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and pyridine-3-boronic acid. The title compound (206 mg) was obtained as a pale solid, m/z 326 (MH+).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:40])[O:5][C@:6]1([C@:30]2([CH3:31])[C@H:16]([C@H:17]3[C@:27]([F:37])([C@@H:28]([O:32][Si](C)(C)C)[CH2:29]2)[C@:25]2([CH3:26])[C:20](=[CH:21][C:22](=[O:38])[CH:23]=[CH:24]2)[CH2:19][CH2:18]3)[CH2:15][C@@H:14]1[CH3:39])[C:7](=[O:13])[CH2:8][O:9]C(=O)C)[CH3:2].Cl>CO.C(Cl)(Cl)Cl>[CH2:1]([NH:3][C:4](=[O:40])[O:5][C@:6]1([C@:30]2([CH3:31])[C@H:16]([C@H:17]3[C@:27]([F:37])([C@@H:28]([OH:32])[CH2:29]2)[C@:25]2([CH3:26])[C:20](=[CH:21][C:22](=[O:38])[CH:23]=[CH:24]2)[CH2:19][CH2:18]3)[CH2:15][C@@H:14]1[CH3:39])[C:7](=[O:13])[CH2:8][OH:9])[CH3:2]
Reactant: CCNC(=O)O[C@]1(C(=O)COC(C)=O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O[Si](C)(C)C)C[C@@]21C
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCNC(=O)O[C@]1(C(=O)CO)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
Solid (11β,16β)-21-(acetyloxy)-9-fluoro-16-methyl-3,20-dioxo-11-[(trimethylsilyl)oxy]-pregna-1,4-dien-17-yl ethylcarbamate (2.22 g, 3.84 mmol) was dissolved in 128 mL of a pre-mixed solution of methanol/chloroform/6N HCl (10:2:1) and stirred at room temperature. After 16 hours, an additional 2 mL of 6N HCl was added. After 5 hours more, the solution was partitioned between ethyl acetate and water. The organic phase was washed successively with sat. NaHCO3, water, and brine. The organic layer was dried over Na2SO4, filtered and evaporated in vacuo to give a pale yellow oil. Purification by flash chromatography through a column of 500 g of silica gel, eluting with hexane/ethyl acetate/dichloromethane/methanol (3:3:3:1) yielded 0.890 g of (11β,16β)-9-fluoro-11,21-dihydroxy-16-methyl-3,20-dioxopregna-1,4-dien-17-yl ethylcarbamate as a white powder.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([C:13]3[N:17]=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([CH:25]=4)[C:23]#[N:24])[O:15][N:14]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2.Br[CH2:31][C:32]([O:34][CH3:35])=[O:33].C([O-])([O-])=O.[K+].[K+]>CC#N.[Cl-].[Na+].O>[C:23]([C:22]1[CH:25]=[C:18]([C:16]2[O:15][N:14]=[C:13]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[C:9]=3[CH2:10][CH2:11][CH2:12][C@H:3]4[NH:2][CH2:31][C:32]([O:34][CH3:35])=[O:33])[N:17]=2)[CH:19]=[CH:20][C:21]=1[O:26][CH:27]([CH3:29])[CH3:28])#[N:24]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4N)no2)cc1C#N
Reactant: COC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CC#N
Product: COC(=O)CN[C@@H]1CCCc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Reaction time: 18 h
Yield: 79.2 %

Procedure:
To a stirring solution of (R)-5-(3-(5-amino-5,6,7,8-tetrahydronaphthalen-1-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 3 (119 mg, 0.32 mmol) in CH3CN (5.0 mL) was added methyl bromoacetate (53.5 μL, 0.35 mmol) and K2CO3 (138 mg, 1.27 mmol). After stirring for 18 h, the mixture was diluted with brine and washed with NaHCO3. The organic layer was dried with Na2SO4 and concentrated. The resulting crude solid was purified by chromatography (MeOH/DCM) to provide 113.1 mg (79%) of (R)-methyl 2-((5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)amino)acetate INT-18. LCMS-ESI (m/z) calculated for C25H26N4O4: 446.5; found 447.2 [M+H]+, tR=2.52 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[C:4]([Cl:28])[CH:3]=1.[CH3:29][C:30]1[CH:31]=[C:32](B(O)O)[S:33][CH:34]=1.CC(C)([O-])C.[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:28][C:4]1[CH:3]=[C:2]([C:32]2[S:33][CH:34]=[C:30]([CH3:29])[CH:31]=2)[CH:7]=[CH:6][C:5]=1[S:8]([NH:11][C:12]1[CH:17]=[C:16]([N:18]2[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]2)[CH:15]=[CH:14][C:13]=1[O:26][CH3:27])(=[O:10])=[O:9]
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1Cl
Reactant: Cc1csc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2cc(C)cs2)cc1Cl
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-2-chloro-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]benzenesulfonamide (E104) (70 mg, 0.14 mmol) and (4-methyl-2-thienyl)boronic acid (40 mg, 0.28 mmol) in DME (3 ml) was added potassium tert-butoxide (142 mg, 1.26 mmol) and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.01 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. Additional (4-methyl-2-thienyl)boronic acid (20 mg, 0.14 mmol) and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.01 mmol) were then added and the mixture stirred in a microwave (set at high absorbance) at 100° C. for a further 30 minutes. The solvent was evaporated after transfer to a new flask with methanol and a few drops of toluene and the residue passed through an SCX column eluting with methanol followed by 2M ammonia in methanol. The appropriate fractions were collected and evaporated in vacuo and the residue purified further by mass directed autoprep HPLC to afford the title compound (E113). MS (ES+) m/e 506/508 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([N:19]1[CH2:24][CH2:23][C@@H:22]([CH3:25])[C@@H:21]([NH:26][CH3:27])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C>CC(O)C>[CH2:12]([N:19]1[CH2:24][CH2:23][C@@H:22]([CH3:25])[C@@H:21]([N:26]([CH3:27])[C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=2[N+:9]([O-:11])=[O:10])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1nccc(Cl)c1[N+](=O)[O-]
Reactant: CN[C@H]1CN(Cc2ccccc2)CC[C@H]1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@@H]1CCN(Cc2ccccc2)C[C@@H]1N(C)c1ccnc(N)c1[N+](=O)[O-]
Yield: 89.8 %

Procedure:
In a microwave reaction vessel 4-chloro-3-nitro-2-pyridinamine (125 mg) and (3R,4R)-1-benzyl-N,4-dimethyl-3-piperidinamine (314 mg) were suspended in 2-propanol (6.25 mL). To the mixture was added N,N-diisopropylethylamine (0.63 mL). The vessel was sealed and reacted in the microwave reactor at 135° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with chloroform and methanol (100:0 to 90:10) to give N4-[(3R,4R)-1-benzyl-4-methyl-3-piperidinyl]-N4-methyl-3-nitro-2,4-pyridinediamine (230 mg) as a yellow amorphous.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]([NH:14][C@H:15]([C:20](O)=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>>[C:7]([NH:14][C@H:15]([C:20]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:21])[CH2:16][CH:17]([CH3:18])[CH3:19])([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8]
Reactant: C1CCNCC1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCCC1
Yield: 80 %

Procedure:
In substantially the same manner as Working Example 2, piperidine (0.86 g, manufactured by Wako Pure Chemical Industries, Ltd.).was condensed with Boc-L-leucine (2.74 g, manufactured by Peptide Institute, Inc.) to give N-(Boc-L-leucyl)piperidine (3.34 g) as white needles (yield 80%). The Boc group of the product was deprotected by using TFA, and 1.20 g of thus-deprotected compound was condensed, in substantially the same manner as Working Example 2, with (2S,3S)-ethyl hydrogen N-Z-aziridine-2,3-dicarboxylate (Compound 1, 1.93 g) to give the above-titled compound (Compound 23; 1.10 g) as a pale yellow oily product (yield 39%).
Reaction SMILES: C(O[CH:4](OCC)[C:5](=[NH:8])OC)C.[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][NH2:20])=[CH:17][CH:18]=1>CO>[CH3:12][C:13]1[CH:14]=[C:15]2[C:4](=[CH:17][CH:18]=1)[CH:5]=[N:8][C:19]([NH2:20])=[CH:16]2
Reactant: CCOC(OCC)C(=N)OC
Reactant: Cc1ccc(CN)cc1
Solvent: CO
Product: Cc1ccc2cnc(N)cc2c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 63.2 %

Procedure:
To a solution of methyl 2,2-diethoxyacetimidate (1.1 g, 6.82 mmol) in methanol (8 mL) was added p-tolylmethanamine (0.788 g, 6.50 mmol) dropwise at ambient temperature. The reaction flask was then placed into a preheated oil-bath and stirred at 70° C. for 16 h, then removed and allowed cooled. The volatiles were removed under reduced pressure and the crude material was added dropwise to sulfuric acid (5 mL) at ambient temperature. The reaction mixture was stirred for 72 h, then the flask was placed into an ice-water bath, diluted with water (50 mL), and slowly neutralized to pH=10 with sodium hydroxide (10 N). As the reaction mixture became basic, a grey precipitate formed. This precipitate was filtered, washed with water, and dried to afford 6-methylisoquinolin-3-amine (0.65 g, 63%), as a grey powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.73 (s, 1H), 7.69 (d, J=8.28 Hz, 1H), 7.29 (s, 1H), 7.00 (d, J=8.28 Hz, 1H), 5.81 (s, 1H), 2.40 (s, 3H). MS (LC/MS) R.T.=1.37; [M+H]+=159.10.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH:16]2[CH2:18][CH2:17]2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:5]2[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:4]2[N:3]=1.[OH:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.CCO>[CH:16]1([N:8]([C:6]2[N:5]3[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:4]3[N:3]=[C:2]([C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([OH:24])[CH:30]=3)[CH:7]=2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N(c1cc(Cl)nc2c(C=O)cnn12)C1CC1
Reactant: OB(O)c1cccc(O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N(c1cc(-c2cccc(O)c2)nc2c(C=O)cnn12)C1CC1
Temperature: 85 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
To tert-butyl 5-chloro-3-formylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (650 mg, 1.93 mmol) in 14 mL of a 2:1 mixture of 1,2-dimethoxyethane/EtOH was added 3-hydroxyphenyl boronic acid (399 mg, 2.89 mmol), tetrakis(triphenylphosphine)palladium(0) (112 mg, 0.096 mmol), and 2M aqueous solution of Na2CO3 (2.9 mL, 5.79 mmol). The mixture was stirred at 85° C. for 1 h. The volatiles were removed by rotary evaporation and the residue was purified by silica gel chromatography (0%-30% EtOAc/Hexanes) to provide 400 mg of tert-butyl cyclopropyl(3-formyl-5-(3-hydroxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl)carbamate. (52%). LCMS (M+1=395)