Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH2:15][CH:16]=[O:17])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])[CH3:3].[BH4-].[Na+]>C(O)C.O>[CH3:14][C:11]([C:9]1[CH:8]=[C:7]([CH2:15][CH2:16][OH:17])[CH:6]=[C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[CH:10]=1)([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1cc(CC=O)cc(C(C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(CCO)cc(C(C)(C)C)c1

Procedure:
To a solution of the title product of Example 18 (500 mg, 2.14 mmoles) in ethanol (10 ml) is added a solution of sodium borohydride (80.8 mg, 2.14 mmoles) in water (1 ml). After disappearance of starting material as judged by TLC, excess reagent is destroyed by addition of acetic acid, and the mixture concentrated. The residue is partitioned between diethyl ether and water, the organic layer dried over sodium sulfate, filtered, and evaporated. Chromatography of the residue over silica gel using mixtures of ethyl acetate and hexane as eluents affords the title compound.
Reaction SMILES: [C:1]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C@@H:8]([CH2:37][C:38]2[CH:43]=[C:42]([O:44][CH3:45])[C:41]([O:46][CH3:47])=[C:40]([O:48][CH3:49])[CH:39]=2)[C:9]([NH:11][C@@H:12]([CH:34]([CH3:36])[CH3:35])[C:13]([NH:15][C@H:16]([B:21]2[O:29][C@H]3[C@](C)([C@H]4C[C@@H](C3)C4(C)C)[O:22]2)[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])=[O:10])[CH:2]=1.Cl>CO.CCCCCC>[C:1]1([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C@@H:8]([CH2:37][C:38]2[CH:39]=[C:40]([O:48][CH3:49])[C:41]([O:46][CH3:47])=[C:42]([O:44][CH3:45])[CH:43]=2)[C:9]([NH:11][C@@H:12]([CH:34]([CH3:36])[CH3:35])[C:13]([NH:15][C@H:16]([B:21]([OH:29])[OH:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])=[O:10])[CH:2]=1
Reactant: COc1cc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)B2O[C@@H]3C[C@@H]4C[C@@H](C4(C)C)[C@]3(C)O2)C(C)C)cc(OC)c1OC
Agent: Cl
Solvent: CO
Solvent: CCCCCC
Product: COc1cc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)B(O)O)C(C)C)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
I-BuB(OH)2 is added to a mixture of (S)-2-[(S)-2-(Biphenyl-3-ylamino)-3-(3,4,5-trimethoxy-phenyl)-propionylamino]-3-methyl-N-[(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-butyl]-butyramide, methanol (4.3 mL), hexane (4.3 mL) and 1N HCl (1.45 mL). The reaction mixture is stirred for 2 h at rt and then diluted with methanol (8 mL) and hexane (8 mL). The two layers are separated. The methanol layer is washed twice with hexane, diluted with CH2Cl2, washed with H2O, dried (Na2SO4), filtered and concentrated. The residue is dissolved in CH2Cl2 and purified by silica gel (20 g) column chromatography (CH2Cl2/MeOH, 80/20) to afford the title compound as a pale yellow foam.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[IH:14]>>[I:14][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][N:3]=1
Reactant: Clc1ccc(-c2ccccc2)cn1
Reactant: I
Product: Ic1ccc(-c2ccccc2)cn1

Procedure:
15.98 g of 2-chloro-5-phenylpyridine were dissolved in 150 ml of 55% aqueous hydroiodic acid and the solution was heated at reflux for 2 hours. Upon cooling a solid precipitated and this was filtered off and washed with water The solid was partitioned between diethyl ether and 2M sodium hydroxide solution, and the organic phase was dried over sodium sulphate and evaporated to give 15.87 g of 2-iodo-5-phenylpyridine which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:15]3[C:10]([CH:11]=[C:12]([F:25])[C:13]([F:24])=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28](=[O:39])[C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[C:31]([Cl:38])[CH:30]=1.CCN(CC)CC>ClCCCl>[CH3:26][O:27][C:28](=[O:39])[C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([N:17]([C:16]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=[C:10]3[C:15]=2[CH:14]=[C:13]([F:24])[C:12]([F:25])=[CH:11]3)[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:37])=[C:31]([Cl:38])[CH:30]=1
Reactant: COC(=O)c1ccc(N=C=O)c(Cl)c1
Reactant: Fc1cc2nn(-c3ccc(Cl)cc3)c(NC3CCCCC3)c2cc1F
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)N(c2c3cc(F)c(F)cc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(Cl)c1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-5,6-difluoro-2H-indazol-3-yl]-cyclohexyl-amine was reacted with 3-chloro-4-isocyanato-benzoic acid methyl ester (example 9.1) in 1,2-dichloroethane in the presence of Et3N (1.4 eq.) for 4 d under reflux conditions to give the title compound as light brown gum. MS: m/e=573.0 [M+H+].
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=C[CH:2]=1.[C:12]([C:15]12[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2)([OH:14])=[O:13]>C(O)C>[CH2:1]([O:13][C:12]([C:15]12[CH2:24][CH:19]3[CH2:18][CH:17]([CH2:23][CH:21]([CH2:20]3)[CH2:22]1)[CH2:16]2)=[O:14])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Solvent: CCO
Product: CCOC(=O)C12CC3CC(CC(C3)C1)C2

Procedure:
In the presence of an acid catalyst (p-toluenesulfonic acid), 1-carboxyadamantane obtained in Example 2 was allowed to react with an excess amount of ethanol to give 1-ethoxycarbonyladamantane.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@@H:4]([C@H:6]([CH3:8])[OH:7])[NH2:5].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CO>[CH3:1][O:2][C:3](=[O:9])[C@@H:4]([C@H:6]([CH3:8])[OH:7])[NH:5][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)[C@H](N)[C@H](C)O
Reactant: O=C(Cl)c1ccccc1
Solvent: CO
Solvent: O
Product: COC(=O)[C@H](NC(=O)c1ccccc1)[C@H](C)O
Temperature: 12 °C
Reaction time: 1 h
Yield: 104.4 %

Procedure:
A crude D-threonine methyl ester (39.49 g) was dissolved in 300 mL of methanol and than transferred to the 1 L 3-neck round bottom flask equipped with a thermocouple, magnetic stirrer and cooling ice bath. A solution was chilled to 12° C., and a total of 64.1 g (0.63 mol, 3 eq.) was added to the flask and then cooled to −10° C. A total of 30.9 g (0.21 mol) of benzoyl chloride was added to the solution and resulting mixture stirred at 0° C. for 1 hour. After this period of time the solvent was removed on rotovap to yield a viscous semi-solid. A total of 300 mL of cold water was added to the residue and organic material was extracted with ethyl acetate (2×300 mL). The organic phase was separated, washed with brine (200 mL) and dried over sodium sulfate. The solvent was removed on rotovap to yield 52.02 g (104%) of a clear yellow oil with Rf=0.39 in EtOAc/hexane=6:4). Obtained oil was crystallized from 200 mL of ether to give a white solid, which was filtered off, washed with hexane (2×100 mL) and dried under suction. An additional drying in a vacuum desiccator yielded 42.35 g (84.7% yield in 2 steps).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:5]([CH2:9][C:10]2[C:18]([Cl:19])=[CH:17][C:13]3[O:14][CH2:15][O:16][C:12]=3[CH:11]=2)[C:6]=1[CH:7]=[O:8].[H-].[Na+].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([SH:36])=[CH:32][CH:31]=1>>[Cl:19][C:18]1[C:10]([CH2:9][N:5]2[C:6]([CH:7]=[O:8])=[C:2]([S:36][C:33]3[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)[N:3]=[C:4]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:11][C:12]2[O:16][CH2:15][O:14][C:13]=2[CH:17]=1
Reactant: O=Cc1c(Br)nc(-c2ccccc2)n1Cc1cc2c(cc1Cl)OCO2
Reactant: COc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(Sc2nc(-c3ccccc3)n(Cc3cc4c(cc3Cl)OCO4)c2C=O)cc1

Procedure:
The operation is carried out as in Example 2 starting with 4 g of the product of Example 6 using 640 mg of sodium hydride at 50% in oil and 1.64 ml of 4-methoxy thiophenol and in this way 4.05 g of expected product is obtained. (M.p.=116° C.).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[NH2:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C@H:16]([C:18]2[N:19]=[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26](O)=[O:27])[N:21]3[C:29]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:17])[C:10]=1[C:36]#[N:37].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:8][C:9]1[C:10]([C:36]#[N:37])=[C:11]([NH:15][C@H:16]([C:18]2[N:19]=[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[O:27])[N:21]3[C:29]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:17])[N:12]=[CH:13][N:14]=1
Reactant: CN1CCNCC1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2cccc(C(=O)O)n2c1-c1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2cccc(C(=O)N3CCN(C)CC3)n2c1-c1ccccc1

Procedure:
A solution of N-methylpiperazine (0.040 mL, 0.356 mmol), (S)-2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-3-phenylimidazo[1,2-a]pyridine-5-carboxylic acid (0.071 g, 0.178 mmol), PyBOP (0.185 g, 0.356 mmol) and DIEA (0.062 mL, 0.356 mmol) in DMF (1.78 mL) was stirred at rt for 1 h. The solution was loaded onto silica gel and purified by MPLC (eluted with a gradient of 0-10% MeOH in DCM) to afford an off-white solid that was repurified by MPLC (eluted with a gradient of 0-80% (1:10:90 NH4OH:MeOH:DCM) solution in DCM) to afford 4-amino-6-(((1S)-1-(5-((4-methyl-1-piperazinyl)carbonyl)-3-phenylimidazo[1,2-a]pyridin-2-yl)ethyl)amino)-5-pyrimidinecarbonitrile as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (dd, J=14.18, 6.75 Hz, 3H) 1.88-2.01 (m, 1H) 2.03-2.10 (m, 1H) 2.12-2.44 (m, 6H) 3.00-3.14 (m, 1H) 3.22 (m, J=9.19 Hz, 1H) 3.40 (d, J=4.30 Hz, 1H) 5.13-5.34 (m, 1H) 6.75-6.98 (m, 2H) 7.16-7.53 (m, 8H) 7.75 (m, J=9.00, 5.09 Hz, 1H) 7.94 (d, J=6.85 Hz, 1H). LC-MS (ESI) m/z 482.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[C:3]=1[C:23](O)=[O:24].Cl.Cl.[NH:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH2:38][CH2:37][CH2:36][C@H:35]2[CH2:39][OH:40])[CH2:30][CH2:29]1>>[OH:40][CH2:39][C@@H:35]1[CH2:36][CH2:37][CH2:38][N:34]1[CH:31]1[CH2:32][CH2:33][N:28]([C:23]([C:3]2[C:4]([C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)=[N:5][N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=3)[C:2]=2[CH3:1])=[O:24])[CH2:29][CH2:30]1
Reactant: OC[C@@H]1CCCN1C1CCNCC1
Reactant: Cc1c(C(=O)O)c(-c2ccncc2)nn1-c1cccc(C(F)(F)F)c1
Agent: Cl
Product: Cc1c(C(=O)N2CCC(N3CCC[C@H]3CO)CC2)c(-c2ccncc2)nn1-c1cccc(C(F)(F)F)c1
Yield: 14 %

Procedure:
In analogy to the procedure described in Example 160E], 5-methyl-3-pyridin-4-yl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid (Example 160D]) and ((S)-1-piperidin-4-yl-pyrrolidin-2-yl)-methanoldihydrochloride (Example 161A]) gave the title compound as a light yellow oil (14%). MS: 514.0 (MH+).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[C:8]([NH2:17])[NH:7][N:6]=1)[CH3:2].[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=O)[CH2:26][C:27](OCC)=[O:28])=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH2:1]([O:3][CH2:4][C:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[C:8]2[NH:17][C:27](=[O:28])[CH:26]=[C:25]([C:22]3[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=3)[N:7]2[N:6]=1)[CH3:2]
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: CCOCc1n[nH]c(N)c1-c1ccc(C)cc1
Solvent: c1ccncc1
Product: CCOCc1nn2c(-c3ccc(F)cc3)cc(=O)[nH]c2c1-c1ccc(C)cc1
Temperature: 25 °C

Procedure:
3-(Ethoxymethyl)-4-(4-methylphenyl)-1H-pyrazol-5-amine (133 mg) and ethyl 3-(4-fluorophenyl)-3-oxopropanoate (0.2 mL) are stirred at 84° C. for 14 hours in a pyridine (10 mL) solvent. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and purified by column chromatography to yield 132 mg of the target compound. 1H NMR (CDCl3, 300 MHz): δ 10.08 (s, 1H), 7.98 (m, 2H), 7.28 (m, 4H), 7.13 (m, 2H), 4.43 (s, 2H), 4.04 (br, 1H), 3.50 (m, 2H), 2.35 (s, 3H), 1.06 (t, 3H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH:34]1[O:38][CH2:37][CH2:36][O:35]1.O>CN(C)C=O>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:33][CH:34]4[O:38][CH2:37][CH2:36][O:35]4)=[CH:23][CH:24]=3)[N:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2nc(-c3ccc(O)cc3)cc3ccccc23)CC1
Reactant: BrCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCN(c2nc(-c3ccc(OCC4OCCO4)cc3)cc3ccccc23)CC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
The resulting 1-(4-ethylpiperazin-1-yl)-3-(4-hydroxyphenyl)isoquinoline (0.53 g) was dissolved in N,N-dimethylformamide (5 ml), to which were added potassium carbonate (0.24 g) and 2-bromomethyl-1,3-dioxolane (250 ml), and the mixture was stirred at 90° C. overnight. Water was added to the reaction solution, and then the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 0.47 g of the title compound as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6].[C:14](OCC)(OCC)(OCC)[CH3:15].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH3:14][C:15]1[O:13][C:3]2[C:4]([C:5]#[N:6])=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:2]=2[N:1]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: N#Cc1ccc([N+](=O)[O-])c(N)c1O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Product: Cc1nc2c([N+](=O)[O-])ccc(C#N)c2o1
Temperature: 25 °C
Yield: 70.3 %

Procedure:
To a solution of 11A (0.2 g, 1.12 mmol) in xylene (6 mL) was added triethyl orthoacetate (0.62 mL, 3.35 mmol) and pyridinium p-toluenesulfonate (0.04 g, 1.12 mmol). The mixture was refluxed for 3 h, then allowed to cool to rt and partitioned between H2O and EtOAc. The separated EtOAc layer was concentrated under reduced pressure and the residue was chromatographed eluting with 20% EtOAc in hexane to afford compound 11B (0.16 g) as a solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:27]=[O:28])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[BH4-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[NH:3][C:4]([CH2:27][OH:28])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Yield: 88.6 %

Procedure:
To a solution of diethyl 2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (2.0881 g) in ethanol (20 ml) was gradually added sodium borohydride (0.1892 g) under stirring and the resultant mixture was further stirred at room temperature for an hour. The solution was acidified with dilute hydrochloric acid and stirred at room temperature for 30 minutes. After the resultant solution was filtered, the filtrate was concentrated under reduced pressure and extracted with ethyl acetate. The extract was washed with water and dried and then the solvent was removed to give orange oil (1.8596 g) of diethyl 2-methyl-4-(2-nitrophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate. After the crude product was dissolved in ethanol, the solution was filtered. The filtrate was concentrated under reduced pressure and the oily residue was allowed to stand for 3 days. Thus obtained crystals were recrystallized from ether to give pure product, m.p. 112° to 113° C.
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[C:9]2[N:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11]([C@@H:13]([NH2:15])[CH3:14])=[N:12][C:8]=2[CH:7]=[CH:6][CH:5]=1.Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1.CCN(C(C)C)C(C)C>CC(O)C>[Br:3][C:4]1[C:9]2[N:10]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:11]([C@@H:13]([NH:15][C:23]3[N:31]=[CH:30][N:29]=[C:28]4[C:24]=3[N:25]=[CH:26][N:27]4[CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[CH3:14])=[N:12][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2cccc(Br)c2n1-c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2cccc(Br)c2n1-c1ccccc1
Yield: 67.1 %

Procedure:
(S)-1-(7-Bromo-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (1 g, 2.5 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.736 g, 3.1 mmol) and DIPEA (2.26 mL, 13 mmol) in IPA (4 mL) were heated in a sealed tube for 4 h. The cooled reaction mixture was concentrated in vacuo; the residue dissolved in EtOAc and the resulting solution washed with water, brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified on silica (Si—PCC, 0-10% MeOH in DCM) to give the product as a white solid (870 mg, 67%). LCMS (Method B): RT 3.48 min; m/z [M+H]+ 518/520
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Br:12])C=C.C(N(CC)[C:16]1[CH:21]=CC=C[CH:17]=1)C>>[CH2:21]([C:10]1[CH:9]=[C:8]([Cl:11])[CH:7]=[C:6]([Br:12])[C:5]=1[OH:4])[CH:16]=[CH2:17]
Reactant: CCN(CC)c1ccccc1
Reactant: C=CCOc1ccc(Cl)cc1Br
Product: C=CCc1cc(Cl)cc(Br)c1O
Temperature: 25 °C
Yield: 77.1 %

Procedure:
A solution of 1-(allyloxy)-2-bromo-4-chlorobenzene (4.122 g, 16.65 mmol) in N,N-diethylaniline (20 mL, 100 mmol) was heated at 200° C. for 15 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and 1M aqueous HCl, and the organic layer washed with an additional portion of 1M aqueous HCl and then brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (0 to 20% ethyl acetate in heptanes) to yield 3.1761 g (77%) of 2-allyl-6-bromo-4-chlorophenol as a clear, colorless oil. 1H NMR (400 MHz, CDCl3) δ: 7.33 (d, J=2.4, 1H), 7.07 (d, J=2.3, 1H), 5.94 (ddt, J=16.8, 10.3, 6.6, 1H), 5.53 (s, 1H), 5.18-5.06 (m, 2H) 3.40 (d J=6.6, 2H).
Reaction SMILES: [ClH:1].O1CCOCC1.[Br:8][C:9]1[O:13][C:12]([C:14]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH:17]2[CH2:29][O:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[O:15])=[CH:11][CH:10]=1>CO>[ClH:1].[ClH:1].[Br:8][C:9]1[O:13][C:12]([C:14]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH:17]2[CH2:29][O:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[O:15])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Br)o2)C(COc2cccnc2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(c1ccc(Br)o1)N1CCNCC1COc1cccnc1
Reaction time: 8 h
Yield: 94 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(5-bromofuran-2-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (75 mg, 0.16 mmol) in MeOH (1 mL). After stirring overnight, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The desired chromatography fractions were concentrated under reduced pressure, dissolved in MeOH (1 mL), and treated with 4 M HCl in 1,4-dioxane (6 mL). This was concentrated under reduced pressure, yielding 66 mg (94%) of the desired product as a white solid. LC-MS: RT=3.54 min, [M+H]+=366.0.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:18]([OH:20])=O)[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH:10]=1)[CH3:3].Cl.Cl.[CH3:23][C:24]1[N:29]=[CH:28][C:27]([C@H:30]([NH2:32])[CH3:31])=[CH:26][CH:25]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:18]([NH:32][C@@H:30]([C:27]2[CH:28]=[N:29][C:24]([CH3:23])=[CH:25][CH:26]=2)[CH3:31])=[O:20])[CH:8]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[CH:10]=1)[CH3:1]
Reactant: Cc1ccc([C@@H](C)N)cn1
Reactant: Cc1ccc(-c2cc(CN(C)C)cc(C(=O)O)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(CN(C)C)cc(C(=O)N[C@H](C)c3ccc(C)nc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-((dimethylamino)methyl)-4′-methylbiphenyl-3-carboxylic acid (20 mg, 0.074 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (40 mg, 0.19 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (60 mg, 0.16 mmol), and N,N-diisopropylethylamine (200 μL, 1.15 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford the final product.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:20])[CH:11]=2)[NH:6][C:5]1=O.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:5]1[N:4]([CH2:3][CH2:2][Cl:1])[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:20])[CH:11]=2)[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)N1CCCl
Product: ClCCN1C(Cl)=Nc2ccc(Cl)cc2C1c1ccccc1
Temperature: 105 °C
Reaction time: 20 h

Procedure:
A mixture of 3.21 g of 3-(2-chloroethyl)-4-phenyl-6-chloro-3,4-dihydro-2(1H)-quinazolinone and 10 g of phosphorus oxychloride was heated with stirring at 105° C. for 20 hours. The resulting solution was evaporated in vacuo to dryness and the resulting residue was dissolved in chloroform. The chloroform solution was washed with an aqueous sodium bicarbonate solution and then with water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 2,6-dichloro-3-(2-chloroethyl)-4-phenyl-3,4-dihydroquinazoline. The crude solid was chromatographed on silica gel using chloroform as an eluting solvent. Removal of the solvent and recrystallization of the residue from a mixture of benzene and petroleum benzin gave 0.60 g of pure product, m.p. 169°-170° C. To a solution of 0.34 g of 2,6-dichloro-3-(2-chloroethyl)-4-phenyl-3,4-dihydroquinazoline in 2 ml of dimethylformamide was added 0.59 g of n-propylamine and the mixture was heated at 105° C. for 5 hours. After cooling, 10 ml of water was added to the reaction mixture and the resulting mixture was extracted with chloroform. The organic phase was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel using chloroform as an eluting solvent to give 0.24 g of 1-(n-propyl)-5-phenyl-7-chloro-1,2,3,5-tetrahydroimidazo-[2,1-b]quinazoline hydrochloride. Recrystallization from a mixture of ethanol and diisopropyl ether gave slightly brown fine crystals, m.p. 258° C.