Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:18]=[O:19])=[CH:14][NH:15]2)=[CH:11][CH:10]=1.I[CH:21]([CH3:23])[CH3:22]>CN(C=O)C>[CH3:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:18]=[O:19])=[CH:14][N:15]2[CH:21]([CH3:23])[CH3:22])=[CH:11][CH:10]=1
Reactant: CC(C)I
Reactant: COc1ccc2c(C=O)c[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc2c(C=O)cn(C(C)C)c2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
Cesium carbonate (577 mg, 1.77 mmol) was added to a stirred room temperature solution of 6-methoxy-1H-indole-3-carbaldehyde (104 mg, 0.590 mmol) in DMF (1.0 mL) and the mixture was stirred at room temperature for 15 minutes when 2-iodopropane (0.118 mg, 1.181 mmol) was added. The solution was stirred at 80° C. for 2 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate (2×20 mL) and saturated sodium bicarbonate (5 mL), washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to give the title intermediate (120 mg).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([N:10]=C=O)([CH3:9])[CH3:8])[CH:4]=[N:3][CH:2]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C(OCC)(=O)C.C1COCC1>[N:1]1[CH:6]=[C:5]([C:7]([NH2:10])([CH3:9])[CH3:8])[CH:4]=[N:3][CH:2]=1
Reactant: CC(C)(N=C=O)c1cncnc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(N)c1cncnc1

Procedure:
The crude 2-(5-pyrimidinyl)-2-propylisocyanate was treated with a mixture of 1.0N sodium hydroxide (26 mL), water (20 mL) and THF (100 mL) at 0° C. for 30 min, then the mixture was poured into ethyl acetate (200 mL) and water (100 mL). The aqueous layer was acidified to pH 5 with 10% citric acid, extracted twice with ethyl acetate, and then adjusted to pH 11, saturated with sodium chloride, and extracted with methylene chloride (3×250 mL). The combined methylene chloride extracts were dried (Na2SO4) and concentrated in vacuo to give 2-(5-pyrimidinyl)-2-propylamine (950 mg) as a colorless oil.
Reaction SMILES: [C:1]([S:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16]([OH:18])=O)[NH:8][C:7]1=[O:19])(=[O:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH2:34]([C@@H:41]1[CH2:45][O:44][C:43](=[O:46])[NH:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C([Li])CCC.O1CCNC1=O>O1CCCC1.CCCCCC>[C:1]([S:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16]([N:42]2[C@H:41]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:45][O:44][C:43]2=[O:46])=[O:18])[NH:8][C:7]1=[O:19])(=[O:3])[CH3:2]
Reactant: CC(=O)SC[C@H]1CCCCCC[C@H](C(=O)O)NC1=O
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C1NCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC(=O)SC[C@H]1CCCCCC[C@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)NC1=O
Temperature: -78 °C
Reaction time: 3 h

Procedure:
Trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecane-10-carboxylic acid (2.90 g, 10.1 mmol) is dissolved in tetrahydrofuran (45.0 mL), triethylamine (1.48 mL, 10.2 mmol) is added, and the reaction is cooled to -78° C. Pivaloyl chloride (1.31 mL, 10.2 mmol) is added, the reaction is warmed to 0° C., stirred for 3 hours, and then cooled down again to -78° C. Meanwhile, in a separate flask, (R)-4-benzyl-2-oxazolidinone (1.88 g, 10.2 mmol) is dissolved in tetrahydrofuran (35 mL) and cooled to -78° C.; butyl lithium (6.63 mL of a 1.6M solution in hexane, 10.2 mmol) is added and the reaction is stirred at -78° C. for 30 minutes. This oxazolidinone anion is then cannulated into the first reaction flask, which is stirred at -78° C. for an additional 1 hour, and then allowed to warm up to room temperature and stir overnight. The reaction is quenched with saturated ammonium chloride, and all of the solvent is evaporated. The product is purified by an initial silica gel chromatography (50% ethyl acetate/hexane) to give N-[[trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecan-10-yl]-carbonyl]-(R)-4-benzyl-2-oxazolidinone as a mixture of two chiral diastereomers. These diastereomers are then separated by another silica gel chromatography (15% ether/40% hexane/45% methylene chloride) to yield the less polar (minor) chiral isomer, and the more polar (major) chiral isomer, m.p. 65°-66° C., [α]D +10.97° (c=7.52 mg/ml, CH2Cl2) leading to the more active NEP inhibiting enantiomer.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12.[H-].[Na+].CI.[C:15](O)(=O)C>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][N:8]([CH3:15])[C:7]=12
Reactant: Clc1nccc2cc[nH]c12
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ccc2ccnc(Cl)c21
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution of 259 (250 mg, 1.64 mmol) in DMF (16 mL) at 0° C. was added NaH (197 mg, 4.92 mmol, 60% in mineral oil), and the mixture was stirred for 30 min, followed by addition of MeI (112 □L, 1.80 mmol). The reaction mixture was stirred at room temperature for 2 h before acetic acid (1 mL) was added. Solvents were removed under reduced pressure, the residue was partitioned between water and EtOAc. Organic phase was collected, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography, eluent EtOAc/hexane (1:1), to afford the title compound 263 (200 mg, 92% yield) as an off-white solid. MS (m/z): 167.1(M+H) (found).
Reaction SMILES: [CH3:1][C:2]([CH3:56])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:53])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:52])[CH2:21][CH2:22][C@@:23]3(/[CH:40]=[CH:41]/[C:42]([NH:44][CH2:45][CH:46]4[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]4)=[O:43])[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:55])[CH3:54])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:46]1([CH2:45][NH:44][C:42](=[O:43])/[CH:41]=[CH:40]/[C@:23]23[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:38])[CH3:39])=[C:24]2[C@@H:25]2[C@@:20]([CH3:52])([CH2:21][CH2:22]3)[C@@:19]3([CH3:53])[C@@H:28]([C@:29]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:54])([CH3:55])[C@@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:56])[C:3]([OH:5])=[O:4])[CH2:31][CH2:30]4)[CH2:27][CH2:26]2)[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)NCC2CCCCC2)CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)NCC2CCCCC2)CC1=O
Temperature: 30 °C
Reaction time: 2 h
Yield: 29.6 %

Procedure:
To a solution of 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-((cyclohexylmethyl)amino)-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (200 mg, 0.258 mmol) in DCM (10 mL) stirred at room temp was added TFA (5 mL, 64.9 mmol). The reaction mixture was stirred at 30° C. for 2 h. The product was evaporated to dryness and then diluted with 200 mL DCM. The organic phase was washed with saturated NaHCO3, water and brine. The organics were dried and concentrated under reduced pressure to afford crude product, which was purified by preparative-HPLC to afford the title compound (55 mg, 29%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=12.18 (br. s., 1H), 7.93 (t, J=5.8 Hz, 1H), 6.60 (d, J=15.8 Hz, 1H), 5.89 (d, J=15.8 Hz, 1H), 4.39 (dd, J=4.6, 11.2 Hz, 1H), 3.27-3.12 (m, 1H), 3.03-2.87 (m, 2H), 2.73 (dd, J=3.5, 11.8 Hz, 1H), 2.24-1.99 (m, 3H), 1.96-0.70 (m, 57H); LC/MS: m/z calculated 719.5. Found 720.5 (M+1)+.
Reaction SMILES: N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:25]I.[CH:27]1([C:30]2[O:31][C:32]3[C:33](=[C:35]([C:52]#[N:53])[C:36]([CH3:51])=[C:37]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:38]=3[CH:39]([CH2:43]O)[CH2:40][CH:41]=[CH2:42])[N:34]=2)[CH2:29][CH2:28]1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C1C=CC=CC=1>[CH:27]1([C:30]2[O:31][C:32]3[C:33](=[C:35]([C:52]#[N:53])[C:36]([CH3:51])=[C:37]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:38]=3[CH:39]([CH2:43][I:25])[CH2:40][CH:41]=[CH2:42])[N:34]=2)[CH2:29][CH2:28]1
Reactant: II
Reactant: C=CCC(CO)c1c(-c2ccccc2)c(C)c(C#N)c2nc(C3CC3)oc12
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: c1ccccc1
Product: C=CCC(CI)c1c(-c2ccccc2)c(C)c(C#N)c2nc(C3CC3)oc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 80.3 %

Procedure:
Imidazole (321 mg, 4.71 mmol), triphenyl phosphine (1.235 g, 4.71 mmol) and then iodine (956 mg, 3.77 mmol) were added to a solution of 2-cyclopropyl-7-(1-hydroxymethylbut-3-enyl)-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-297) (675 mg, 1.88 mmol) dissolved in benzene (20 ml). The solution was stirred under nitrogen atmosphere at room temperature for 20 hours, then aqueous saturated sodium thiosulfate solution was added, followed by stirring at the same temperature for 10 minutes. The aqueous layer was separated, this was extracted three times with ethyl acetate. The organic layers were combined, washed with saturated brine, then dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, n-hexane:ethyl acetate=19:1, v/v) to obtain the entitled compound (707 mg, 80%).
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.C(N(CC)C(C)C)(C)C.[CH2:34]([S:36](Cl)(=[O:38])=[O:37])[CH3:35]>>[CH2:34]([S:36]([NH:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:38])=[O:37])[CH3:35]
Reactant: CCS(=O)(=O)Cl
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)O
Temperature: -78 °C
Reaction time: 12 h
Yield: 79 %

Procedure:
To a stirring suspension of D-phenylalanine (50 g, 300 mmol) in THE (400 mL) was added N,O-bis(trimethylsilyl) acetamide (92 g, 450 mmol). After stirring for 12 h, the solution was cooled to −78° C. and N,N-diisopropylethylamine (58 mL, 330 mmol) was added. To this solution was slowly added ethanesulfonyl chloride (31 mL, 330 mmol) and the cold bath was removed. After stirring for 20 h, the solvents were removed in vacuo and the residue was partitioned between saturated aqueous NaHCO3 and ethyl acetate. The aqueous phase was washed with diethyl ether, acidified with solid citric acid and extracted twice with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried with MgSO4, filtered and concentrated in vacuo to give 61 g (79%) of a thick colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[O:16][C:7]1([CH2:11][CH2:10][CH:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:8]1)[CH2:6][C:5]2=O.C[Si]([N:25]=[C:26]=[N:27][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[O:16][C:7]1([CH2:11][CH2:10][CH:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:8]1)[CH2:6]/[C:5]/2=[N:27]\[C:26]#[N:25]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: CC(C)(C)C1CCC2(CC(=O)c3cc(Br)ccc3O2)C1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)C1CCC2(C/C(=N\C#N)c3cc(Br)ccc3O2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To a solution of 6-bromo-3′-tert-butylspiro[chroman-2,1′-cyclopentan]-4-one (200 mg, 0.60 mmol) in dried CH2Cl2 (10 mL) was added TiCl4 (1 M solution in DCM, 1.20 mmol) dropwise within 15 minutes. The mixture was stirred for 1 h after addition. To this mixture was added bis-trimethylsilylcarbodiimide (244 mg, 1.31 mmol) dropwise. The resulting mixture was stirred for 18 h after addition. The reaction mixture was poured into ice-water (30 g) and extracted with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give (E)-N-(6-bromo-3′-tert-butylspiro[chroman-2,1′-cyclopentane]-4-ylidene)cyanamide (200 mg, crude), which was used for the next step without further purification.
Reaction SMILES: [CH:1]([C@H:14]1[CH2:19][C@@H:18]([NH2:20])[CH2:17][CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.C(O)(=O)C.[BH3-]C#N.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.CO.O>[CH:1]([C@H:14]1[CH2:19][C@@H:18]([NH:20][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=2)[CH2:17][CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: N[C@H]1CCO[C@@H](C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Solvent: CC(=O)O
Product: Fc1ccc(CN[C@H]2CCO[C@@H](C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 79.5 %

Procedure:
To a solution of cis-4-amino-2-diphenylmethylpyran 6a (0.2 g, 0.75 mmol), 4-fluorobenzaldehyde (0.83 g, 0.67 mmol) and glacial acetic acid (0.45 g, 0.75 mmol) in 1,2-dichloroethane (20 ml), was added portion wise NaCNBH3 (0.57 g, 0.9 mmol) dissolved in methanol (5 ml). After 4 hr, water was added to quench the reaction and the mixture was stirred for 30 minutes at 0° C. Then the mixture was made basic with saturated aqueous NaHCO3 and extracted thrice with methylene chloride (3×30 ml). The combined organic phases were washed with brine, water and dried over anhydrous Na2SO4. Solvent was removed in vacuo to collect the crude residue, which was purified by flash chromatography (Hexane/Ethyl Acetate/Triethylamine 3:2:0.2) to give cis-2-diphenylmethyl-4-(4-fluorobenzylamino)-tetrahydropyran 7a (0.20 g, 72.6%) as a liquid.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.CC([O-])(C)C.[K+].CC(O)(C)C.[N+:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38]Cl)([O-:31])=[O:30].Cl>O>[F:1][C:2]1[C:3]([NH:17][S:38][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N+:29]([O-:31])=[O:30])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: Nc1nc(OCc2ccc(F)cc2)ncc1F
Reactant: O=[N+]([O-])c1ccccc1SCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=[N+]([O-])c1ccccc1SNc1nc(OCc2ccc(F)cc2)ncc1F
Reaction time: 1 h
Yield: 25.6 %

Procedure:
To a solution of 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (0.05 g, 0.2 mmol) and a 1.0 M solution of KOtBu in tBuOH (1.0 mL, 1.0 mmol) was added nitrobenzene-sulfenyl chloride (0.044 g, 0.23 mmol) in one portion, and the resulting brown solution was stirred for 60 min. The reaction was diluted with water (2 mL) and neutralized to pH 7 with 1N HCl. The aq. phase was extracted with EtOAc (5 mL), and the organics were combined, dried over Na2SO4, filtered, and concentrated. The crude material was purified by reverse phase chromatography to yield the title compound (0.020 g, 26%) as a yellow solid: mp 184° C.; 1H NMR (300 MHz, CDCl3) δ 8.36 (d, J=7.25 Hz, 1H), 8.09 (d, J=2.3 Hz, 1H), 7.59 (m, 1H), 7.36 (m, 2H), 7.29 (m, 2H), 6.88 (m, 2H), 6.23 (bs, 1H), 5.19 (s, 2H); HPLC-MS (ESI) m/z 391 (M+H)+, 389 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.CC1(C)C(C)(C)OB([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39]3[O:40][C:41]4[C:47]([CH3:48])=[CH:46][C:45]([CH3:49])=[CH:44][C:42]=4[N:43]=3)=[CH:34][CH:33]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]3)[N:9]=[C:10]([C:32]3[CH:33]=[CH:34][C:35]([NH:38][C:39]4[O:40][C:41]5[C:47]([CH3:48])=[CH:46][C:45]([CH3:49])=[CH:44][C:42]=5[N:43]=4)=[CH:36][CH:37]=3)[C:3]=12
Reactant: Cc1cc(C)c2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(I)c3c(N)ncnc32)C1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(C)c2oc(Nc3ccc(-c4nn(C5CCN(C(=O)OC(C)(C)C)C5)c5ncnc(N)c45)cc3)nc2c1
Temperature: 80 °C
Yield: 198.7 %

Procedure:
To a solution of rac-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-pyrrolidinecarboxylate (0.412 g, 0.958 mmol) in ethylene glycol dimethyl ether (6 mL) and water (3 mL) was added N2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5,7-dimethyl-1,3-benzoxazol-2-amine (0.436 g, 1.20 mmol), tetrakis(triphenylphosphine) palladium (0) (0.055 g, 0.048 mmol), and sodium carbonate (0.254 g, 2.39 mmol). The solution was heated at 80° C. for 18 h, and then cooled to room temperature. The reaction mixture was partitioned between ethyl acetate (10 mL) and water (10 mL). The organic layer was separated and washed with brine (10 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to afford rac-tert-butyl 3-(4-amino-3-{4-[(5,7-dimethyl-1,3-benzoxazol-2-yl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-pyrrolidinecarboxylate as an orange solid (1.029 g), which was used in the next step without further purification.
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH:11]=[CH:12][CH:13]=[CH:14][C:15]([OH:17])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[NH2:24][OH:25]>ClCCl.O1CCCC1>[OH:25][NH:24][C:15](=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH2:10][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8]
Reactant: NO
Reactant: O=C(O)C=CC=CCS(=O)(=O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(C=CC=CCS(=O)(=O)c1ccccc1)NO
Reaction time: 1 h
Yield: 29.6 %

Procedure:
To a solution of 6-benzenesulfonyl-hexa-2,4-dienoic acid (0.292 g, 1.15 mmol) in dry dichloromethane (5 mL) was added dropwise oxalyl chloride, at 0° C. under an atmosphere of argon. One drop on dimethylformamide was then added. After stirring at 2020 C. for one hour, a solution of aqueous hydroxylamine (50%, 0.17 mL, 2.5 mmol) in tetrahydrofuran (5 mL) was added. The mixture was stirred for an additional hour and concentrated under reduced pressure to give a yellow foam that was purified by column chromatography (8:2 ethyl acetate:40-60° C. petroleum to 100% ethyl acetate). The title compound (91 mg, 31%) was obtained as a white foam.
Reaction SMILES: [O:1]=[C:2]([C:6]1[N:14]2[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:8][C:7]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3](Cl)=[O:4].[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([N:29]2[CH2:34][CH2:33][N:32]([C:35]3[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=3)[CH2:31][CH2:30]2)[CH:23]=1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([N:29]2[CH2:34][CH2:33][N:32]([C:35]3[CH:40]=[CH:39][C:38]([NH:41][C:3](=[O:4])[C:2](=[O:1])[C:6]4[N:14]5[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]5)=[CH:8][C:7]=4[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:37][CH:36]=3)[CH2:31][CH2:30]2)[CH:23]=1
Reactant: Cc1cc(C)nc(N2CCN(c3ccc(N)cc3)CC2)c1
Reactant: O=C(Cl)C(=O)c1c(-c2ccccc2)cc2n1CCCC2
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1cc(C)nc(N2CCN(c3ccc(NC(=O)C(=O)c4c(-c5ccccc5)cc5n4CCCC5)cc3)CC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 30.5 %

Procedure:
Oxo-(2-phenyl-5,6,7,8-tetrahydro-indolizin-3-yl)-acetyl chloride (prepared as described in Reference Example 21, 40 g, 0.14 mol) was added portion-wise to a solution of 4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylamine (prepared as described in Reference Example 94, 18 g, 63.8 mmol) in pyridine (150 mL). The reaction mass was stirred for 1 hour then quenched slowly into cold water (3 L). The precipitated solid was filtered and washed with water (3×50 mL). The solid was dissolved in chloroform (200 mL) and washed successively with bicarbonate solution (3×200 mL) and brine (200 mL). The chloroform layer was separated, diluted with chloroform (800 mL), and to this was added neutral alumina (150 g) and charcoal (5 g). The mixture was stirred for 2 hours at room temperature then filtered through celite. The treatment was repeated with another 75 g of neutral alumina with over night stirring. Filtration and concentration gave a solid which was dissolved in toluene (500 mL) and extracted with 25% aqueous acetic acid solution (3×500 mL). The combined aqueous layers were basified with 25% ammonium hydroxide solution (2 L) to pH ˜7 and extracted with diethyl ether (2×300 mL). The combined ether extracts were washed with bicarbonate solution (2×200 mL), brine (200 mL), dried over sodium sulfate and concentrated in vacuo to give a solid. This was further purified by passing through a short silica pad (60-120 silica gel) eluting with 30% ethyl acetate in chloroform. After concentration, the solid was dissolved at reflux in ethanol (300 mL). The solution was cooled to 0° C., and stirred for 15 minutes, whereupon the precipitated solid was filtered and dried on the sinter. Further drying at 60° C. under high vacuum afforded the title compound N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(2-phenyl-5,6,7,8-tetrahydro-indolizin-3-yl)-acetamide (10.4 g, 30.5%) as a yellow powder.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.Cl.Cl[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[N:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[N:18]=2)[N:3]=1
Reactant: CC(C)c1cccc(CCl)n1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(Br)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1cccc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)n1
Reaction time: 18 h
Yield: 67 %

Procedure:
To 3-bromo-4-nitro-1H-indazole (4.91 g, 20.3 mmol) in DMF (50 mL) was added 2-(chloromethyl)-6-isopropylpyridine hydrochloride (4.18 g, 20.3 mmol) and K2CO3 (8.41 g, 60.8 mmol). The reaction mixture was stirred for 18 hours. Solvent was removed under reduced pressure. The residue was diluted with EtOAc (100 mL). The resulting suspension was washed with water and brine. The combined organic extracts were dried (Na2SO4), filtered and purified by silica gel flash chromatography (1:2 EtOAc/hexanes) to give the desired product (67%).
Reaction SMILES: [CH2:1]([N:4]([CH2:33][CH2:34][CH3:35])[C:5]([C:7]1=[CH:8][C:9]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)=[CH:22][C:10]=2[N:11]=[C:12]([NH:14]C(=O)OC(C)(C)C)[CH2:13]1)=[O:6])[CH2:2][CH3:3].C(O)(C(F)(F)F)=O>ClCCl>[NH2:14][C:12]1[CH2:13][C:7]([C:5]([N:4]([CH2:33][CH2:34][CH3:35])[CH2:1][CH2:2][CH3:3])=[O:6])=[CH:8][C:9]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)=[CH:22][C:10]=2[N:11]=1
Reactant: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc(O)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc(O)cc3)cc2N=C(N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.9 %

Procedure:
tert-Butyl (1E,4E)-4-(dipropylcarbamoyl)-8-(4-hydroxyphenyl)-3H-benzo[b]azepin-2-ylcarbamate (0.040 g, 0.084 mmol) was dissolved in 1 ml of dichloromethane. 0.5 ml of TFA was then added and the mixture was stirred at room temperature for one hour. The reaction was then quenched by the addition of saturated sodium bicarbonate solution and stirred for 15 minutes, then extracted twice with dichloromethane, extracts dried over sodium sulfate and concentrated. Preparative thin layer chromatography (0.5 mm plate, 7% MeOH/DCM) afforded 6 mgs (19%) of (1E,4E)-2-amino-8-(4-hydroxyphenyl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.47-7.53 (m, 2H), 7.41-7.44 (m, 1H), 7.30-7.33 (m, 1H), 6.88-6.93 (m, 2H), 6.83 (s, 2H), 3.42-3.54 (m, 4H), 2.81 (s, 2H), 1.61-1.72 (m, 4H), 0.89-0.97 (m, 6H); m/z (APCI-pos) M+1=378.2.