Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[S:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[O:33]([CH2:40][C:41](Cl)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][N:21]([C:41](=[O:42])[CH2:40][O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:20][CH2:19]2)[C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[S:8][C:6]=2[N:7]=1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3ccc(F)cc3)sc2n1
Reactant: O=C(Cl)COc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(N2CCN(C(=O)COc3ccccc3)CC2)c2nc(-c3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.1 %

Procedure:
To a solution of 5-amino-2-(4-fluorophenyl)-7-piperazin-1-yl-thiazolo[5,4-d]pyrimidine (50 mg, 0.15 mmol) in DMF (2 ml) was added diisopropylethylamine (0.33 mmol, 55 μL) followed by phenoxyacetyl chloride (0.17 mmol). The reaction was stirred at room temperature for 4 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 0.5% CH3OH in CH2Cl2), yielding the pure title compound (30 mg) which was characterized by its mass spectrum: MS m/z (%): 465 ([M+H]+, 100).
Reaction SMILES: [C:1]1([N:7]2[CH:15]=[C:14]3[C:9]([N:10]=[CH:11][C:12]([NH2:16])=[CH:13]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC#N>[C:1]1([N:7]2[CH:15]=[C:14]3[C:9]([N:10]=[CH:11][C:12]([NH:16][S:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)(=[O:31])=[O:30])=[CH:13]3)=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cnc2nn(-c3ccccc3)cc2c1
Solvent: c1ccncc1
Solvent: CC#N
Product: O=S(=O)(Nc1cnc2nn(-c3ccccc3)cc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
To a solution of 3C (305 mg, 1.458 mmol) and pyridine (0.7 mL) in CH3CN (30 mL) cooled to 0° C. was added bezenesulfonyl chloride (274 mg, 1.550 mmol). After addition, the reaction mixture was stirred at RT for 1 hour, then concentrated under reduced pressure. The resultant residue was dissolved in CH2Cl2 (100 mL), washed with water (2×50 mL), saturated NaCl (50 mL). The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by silica gel column chromatography eluting with 2% of 2 M NH3 in MeOH/CH2Cl2 to give the title compound as a light brown solid (200 mg, 40% yield). LC/MS (method A): retention time=2.78 min, (M+H)+=351.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[I-:28].[Na+]>[Cu]I>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([I:28])=[CH:3][C:4]=3[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: [I-]
Agent: [Cu]I
Agent: [Na+]
Product: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 53.6 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (980 mg) described in Preparation Example 112, sodium iodide (650 mg) and copper(I) iodide (205 mg) and by the reaction and treatment in the same manner as in Preparation Example 154, the title compound (580 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[NH:11][C:12]=2C2C=CN=CC=2)=[CH:4][CH:3]=1.FC1C=CC(C2N=C(C3C=CC(C#N)=CC=3)NC=2[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:26][CH:27]=3)[NH:11][C:12]=2[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Reactant: N#Cc1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccccn3)[nH]2)cc1
Product: O=C(O)c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccccn3)[nH]2)cc1

Procedure:
The title compound was prepared using the procedure in U.S. Pat. No. 5,656,644 (Example 9) to prepare 4- [4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2yl]benzoic acid except using 4-[4-(4-fluorophenyl)-5-(2-pyridyl)-1H-imidazol-2yl]benzonitrile. ESMS (M+H)+=360.1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li]C(C)(C)C.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[CH2:15]([C:5]1[S:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc2sccc2c1
Reactant: BrCc1ccccc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: c1ccc(Cc2cc3ccccc3s2)cc1

Procedure:
2-Benzylbenzo[b]thiophene was prepared by the method of Example 40A with benzo[b]thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7 M, 11.2 mmoles, 6.6 ml), benzyl bromide (10.2 mmoles, 1.3 ml) and THF (20 ml). Flash chromatography (hexanes) provided 0.66 g (39%) of a yellow solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:28][N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17](=[O:19])(=[O:18])[NH:35][CH:32]2[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]2)=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: CN1CCC(N)CC1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)NC3CCN(C)CC3)sc2Br)s1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 74 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (200 mg; 0.48 mmol; 1 eq), is dissolved in anhydrous DCM (10 ml). The reaction mixture is cooled down to 0° C. and put under nitrogen. Triethylamine (0.27 ml; 1.92 mmol; 4 eq) and 1-methyl-piperidin-4-ylamine (0.11 ml; 0.96 mmol; 2 eq) are added successively and the reaction mixture is stirred at 0° C. for 40 minutes. It is then washed with water, NaHCO3 and dried over MgSO4, affording the title compound (185 mg; 74%).
Reaction SMILES: C1(C2CCNCC2)C=CC=CC=1.C(Br)CO.[C:17]1([CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][OH:31])[CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH2:32]=[C:33]1[O:37][C:35](=[O:36])[CH2:34]1>>[C:35]([O:31][CH2:30][CH2:29][N:26]1[CH2:25][CH2:24][CH:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:28][CH2:27]1)(=[O:36])[CH2:34][C:33]([CH3:32])=[O:37]
Reactant: C=C1CC(=O)O1
Reactant: OCCN1CCC(c2ccccc2)CC1
Agent: OCCBr
Agent: c1ccc(C2CCNCC2)cc1
Product: CC(=O)CC(=O)OCCN1CCC(c2ccccc2)CC1

Procedure:
4-Phenylpiperidine was reacted with ethylene bromohydrin in the same manner as Reference Example 5, and the resulting oily 4-phenyl-1-piperidineethanol was further reacted with diketene to give 2-(4-phenylpiperidino)ethyl acetoacetate as an oil.
Reaction SMILES: [C:1]1([C:6]([C:8]2[CH:20]=[CH:19][C:11]([CH:12]([CH3:18])[C:13](OCC)=[O:14])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH:22][NH2:23].[OH-].[K+]>CO>[C:1]1([C:6]([C:8]2[CH:20]=[CH:19][C:11]([CH:12]([CH3:18])[C:13]([NH:23][OH:22])=[O:14])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: CCOC(=O)C(C)c1ccc(C(=O)c2cccs2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C(=O)NO)c1ccc(C(=O)c2cccs2)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 12.6 parts of ethyl p-(2-thenoyl)-hydratropate in 35 parts of methanol is added successively and while cooling, first a solution of 6.05 parts of hydroxyl amine hydrochloride in 35 parts of methanol and then a solution of 7.3 parts of potassium hydroxide in 35 parts of methanol. Upon completion, the whole is stirred for 30 minutes. The mixture is filtered and the filtrate is stirred for 3 days at room temperature. The reaction mixture is evaporated and the residue is taken up in water. The aqueous solution is acidified with hydrochloric acid solution and the product is extracted with ether. The extract is washed with water, dried, filtered and evaporated. The residue is taken up in water, alkalized with sodium hydroxide solution, washed with ether and the aqueous phase is acidified with concentrated hydrochloric acid solution. The product is extracted with ether. The latter is washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silicagel, using a mixture of chloroform and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is triturated in a mixture of petroleumether and diisopropylether. The solid product is filtered off and crystallized from 2-propanol, yielding p-(2-thenoyl)hydratropohydroxamic acid; m.p. 143.5° C.
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[C:24]([C:27]#[N:28])[CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[CH:12][C:11]=2[Cl:37])C=CC=CC=1.[CH3:39][N:40](C)C=O.CN.O1CCCC1>O>[CH2:30]([O:29][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([O:16][C:13]3[CH:14]=[CH:15][C:10]([NH:9][C:8]([NH:40][CH3:39])=[O:7])=[C:11]([Cl:37])[CH:12]=3)=[CH:18][CH:19]=[N:20]2)=[CH:25][C:24]=1[C:27]#[N:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Oc4ccccc4)c(Cl)c3)ccnc2cc1OCc1ccccc1
Reactant: CN(C)C=O
Agent: CN
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc(Oc2ccnc3cc(OCc4ccccc4)c(C#N)cc23)cc1Cl
Reaction time: 0.17 h

Procedure:
[4-(7-Benzyloxy-6-cyanoquinolin-4-yloxy)-2-chlorophenyl]carbamic acid phenyl ester (1.17 g) was added to dimethylformamide (6 ml), and then a methylamine-containing 2N tetrahydrofuran solution (0.4 ml) was added and the mixture was stirred for 10 minutes. Water (15 ml) was added, and the precipitated crystals were filtered out and washed with diethyl ether to obtain the title compound (968 mg).
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH3:6][O:7][N+:8]12[CH2:15][CH2:14][N:11]([CH2:12][CH2:13]1)[CH2:10][CH2:9]2.B(F)(F)[F:17].FF>C(#N)C>[F:1][B-:2]([F:5])([F:4])[F:3].[F:1][B-:2]([F:5])([F:4])[F:3].[F:17][N+:11]12[CH2:14][CH2:15][N+:8]([O:7][CH3:6])([CH2:13][CH2:12]1)[CH2:9][CH2:10]2
Reactant: FB(F)F
Reactant: CO[N+]12CCN(CC1)CC2
Agent: FF
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: CO[N+]12CC[N+](F)(CC1)CC2

Procedure:
A solution of 1-methoxy-4-aza-1-azoniabicyclo[2.2.2]octane tetrafluoroborate (23 g, 10 mmole) and boron trifluoride gas (6.7 g, 10 mmole) in acetonitrile (125 mL) was cooled to 8° C. and treated with a mixture of fluorine in nitrogen (10 % V/V, 12 mmole). The reaction was evaporated, the remaining solid washed with DME and dried to afford 1 -fluoro-4-methoxy- 1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate).
Reaction SMILES: NC1C(C)=CC=CC=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])=[O:10].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[Cl:26])[NH2:22].FC1C=CC=CC=1C#N>>[NH2:22][C:21]1[CH:20]=[C:19]([Cl:18])[C:25]([Cl:26])=[CH:24][C:23]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])=[O:10]
Reactant: Cc1cccc(C(=O)c2ccccc2F)c1N
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: N#Cc1ccccc1F
Product: Nc1cc(Cl)c(Cl)cc1C(=O)c1ccccc1F
Yield: 17 %

Procedure:
In a manner similar to that described above for compound 1b, 3,4-dichloroaniline and 2-fluorobenzonitrile were converted to 1ad (17% yield) MS m/z=284 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][N:31]([CH3:33])[CH3:32])[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[CH2:39][C:40](Cl)=[O:41]>>[CH3:32][N:31]([CH2:30][C:26]1[CH:25]=[C:24]([NH:23][C:19]2[N:18]=[C:17]([C:16]3[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:40](=[O:41])[CH2:39][C:35]5[S:34][CH:38]=[CH:37][CH:36]=5)[CH:7]=[CH:6][CH:5]=4)=[N:9][N:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=34)[CH:22]=[CH:21][N:20]=2)[CH:29]=[CH:28][CH:27]=1)[CH3:33]
Reactant: CN(C)Cc1cccc(Nc2nccc(-c3c(-c4cccc(N)c4)nn4ccccc34)n2)c1
Reactant: O=C(Cl)Cc1cccs1
Product: CN(C)Cc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)Cc5cccs5)c4)nn4ccccc34)n2)c1
Yield: 88 %

Procedure:
The title compound was prepared from 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-{3-[(dimethylamino)methyl]phenyl}-2-pyrimidinamine and 2-thiopheneacetyl chloride using acylation conditions described in Example 1, Step F to generate the product in 88% yield. 1H NMR (400 MHz, DMSO-d6): δ 2.11 (s, 6H), 3.26 (s, 2H), 3.86 (s, 2H), 6.46 (d, 1H, J=5.3 Hz), 6.85 (d, 1H, J=7.5 Hz), 6.96 (m, 2H), 7.10-7.19 (m, 2H), 7.26 (d, 1H, J=7.9 Hz), 7.36-7.48 (m, 3H), 7.62 (d, 1H, J=8.2 Hz), 7.69 (s, 1H), 7.73 (d, 1H, J=9.1 Hz), 7.89 (s, 1H), 8.23 (d, 1H, J=5.3 Hz), 8.51 (d, 1H, J=8.8 Hz), 8.82 (d, 1H, J=6.9 Hz), 9.52 (s, 1H), 10.35 (s, 1H); ES-LC/MS m/z=560 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:13])[C:5]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:6][CH:7]=1.[CH:14]([C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19])=O.OOS([O-])=O.[K+].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([C:9]([CH3:10])([CH3:12])[CH3:11])[C:14]([C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[C:18]#[N:19])=[N:13][C:4]=2[CH:3]=1
Reactant: CC(C)(C)Nc1ccc(Br)cc1N
Reactant: N#Cc1ccccc1C=O
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)n1c(-c2ccccc2C#N)nc2cc(Br)ccc21
Reaction time: 2 h
Yield: 104.8 %

Procedure:
To a solution of 4-bromo-N1-tert-butyl-benzene-1,2-diamine (500 mg, 2.06 mmol) in DMF (20 mL) is added 2-formyl-benzonitrile (270 mg, 2.06 mmol) at room temperature. Oxone (758 mg, 1.23 mmol) is added and the solution is stirred at the same temperature for 2 hours. The reaction mixture is poured into 0.5 M K2CO3 solution (30 mL). The product is extracted into EtOAc (3×) and the combined organics are then dried (Na2SO4), filtered, and concentrated. Purification via flash chromatography (25 g silica gel, 0-4% MeOH/CH2Cl2) affords 2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-benzonitrile (765 mg, 100%).
Reaction SMILES: SC([OH:4])C.ICC(N([C:17](=[O:31])[CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]1[C@@H:30]2[C@@H:25]([NH:26][C:27]([NH:29]2)=[O:28])[CH2:24][S:23]1)CCCCCCN)=O>>[OH:4][C:17]([CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]1[C@@H:30]2[C@@H:25]([NH:26][C:27]([NH:29]2)=[O:28])[CH2:24][S:23]1)=[O:31]
Reactant: NCCCCCCN(C(=O)CI)C(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: CC(O)S
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21

Procedure:
The mellitin peptide (10 mg) was reduced with mercaptoethanol as described for the 3.2 peptide in Example 1. After rotary evaporation, the sample was resuspended in 2 ml 0.1 M Tris-HCl, 5 mm EDTA, pH 8.0 and reacted with ml dimethylsulfoxide (DMSO), containing 4.3 mg N-iodoacetyl-N-biotinylhexylendiamine (Pierce). This was allowed to react for 15 minutes at room temperature and the biotinylated derivative separated from byproducts on a Sephadex G10 column.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:19][CH:20]1[CH2:24][CH2:23][CH2:22][NH:21]1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:22][CH2:23][CH2:24][CH:20]2[CH3:19])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: CC1CCCN1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Solvent: CO
Product: CC1CCCN1c1nc(Cl)nc2c1CCC2c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 33.9 %

Procedure:
To a solution of 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) (200 mg, 0.706 mmol) in MeOH (7064 μL) was added 2-Methylpyrrolidine (82 μL, 0.848 mmol). The resulting mixture was stirred at RT for 2 days. The reaction mixture was then concentrated in vacuo. The resulting oil was purified by flash chromatography (Silica, EtOAc/Hexanes) to give two racemic pairs of diasteriomers 2-chloro-7-(4-fluorophenyl)-4-(2-methylpyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine. (Hc1, Diastereomer 1, racemic, first to elute) (79.5 mg, 0.240 mmol, 33.9% yield). LC-MS (M+H)+=332.1; 1H NMR (500 MHz, MeOD) δ ppm 7.16 (2H, d, J=5.49 Hz), 7.04 (2H, s), 4.42-4.54 (1H, m), 4.09-4.22 (1H, m), 3.86-4.00 (1H, m), 3.71-3.82 (1H, m), 3.24-3.31 (1H, m), 3.10-3.22 (1H, m), 2.54-2.65 (1H, m), 2.05-2.16 (2H, m), 1.94-2.05 (2H, m), 1.69-1.80 (1H, m), 1.27 (3H, d, J=6.10 Hz). (Hc2, Diastereomer 2, racemic, second to elute) (89.5 mg, 0.270 mmol, 38% yield). LC-MS (M+H)+=332.1; 1H NMR (500 MHz, MeOD) δ ppm 7.14 (2H, d, J=5.49 Hz), 6.99-7.08 (2H, m), 4.42-4.54 (1H, m), 4.13-4.22 (1H, m), 3.86-4.00 (1H, m), 3.71-3.83 (1H, m), 3.25-3.32 (1H, m), 3.14-3.25 (1H, m), 2.52-2.67 (1H, m), 2.05-2.19 (2H, m), 1.94-2.05 (2H, m), 1.68-1.78 (1H, m), 1.19-1.32 (3H, m). The relative stereochemistry for Hc1 and Hc2 was not determined
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([CH2:15][OH:16])=[CH:13][O:12][N:11]=2)=[CH:6][CH:5]=1.Cl[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=1.[Cl-].[Na+]>C1COCC1>[CH3:25][O:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][C:18]([O:16][CH2:15][C:14]2[C:10]([C:7]3[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=3)=[N:11][O:12][CH:13]=2)=[N:19][CH:20]=1
Reactant: OCc1conc1-c1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a suspension of sodium hydride (55% dispersion in mineral oil, 1.16 g, 26.5 mmol) in THF (30 mL) was added a solution of [3-(4-chloro-phenyl)-isoxazol-4-yl]-methanol (24.1 mmol) in THF (60 mL) at 0° C. and the reaction mixture warmed to room temperature over 30 min. Then a solution of methyl 6-chloronicotinate (4.65 g, 26.5 mmol) in THF (60 mL) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=4:1 to 2:1) afforded 6-[3-(4-Chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (72%) which was obtained as a light yellow solid. To a suspension of 6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (1.0 mmol) in THF (3 mL) and methanol (3 mL) was added a solution of lithium hydroxide monohydrate (85.1 mg, 2.0 mmol) in water (3 mL) and the resulting mixture stirred at room temperature overnight. The mixture was acidified to pH 4 with HCl (1 N, 30 mL) and the resulting mixture was filtered. The solid was dried to afford the title compound (100%) which was obtained as a light yellow solid. MS: m/e=331.1 [M−H]−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:25][C:24]4=[N:26][CH:27]=[C:28](I)[N:23]4[N:22]=3)=[CH:17][C:16]=2[O:30][CH3:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:32][C:33]1[N:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][N:34]=1.O1CCOCC1.C([O-])([O-])=O.[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:25][C:24]4=[N:26][CH:27]=[C:28]([C:36]5[CH:35]=[N:34][C:33]([NH2:32])=[N:38][CH:37]=5)[N:23]4[N:22]=3)=[CH:17][C:16]=2[O:30][CH3:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: COc1cc(-c2nn3c(I)cnc3s2)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-c2nn3c(-c4cnc(N)nc4)cnc3s2)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 120 °C
Yield: 14.3 %

Procedure:
A mixture of 4-[4-(5-iodo-imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-methoxy-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (82 mg, 0.147 mmol, 1 eq), 2-aminopyrimidine-5-boronic acid pinacol ester (48 mg, 0.22 mmol, 1.5 eq), 1,4-dioxane (4 mL), K2CO3 (61 mg, 0.441 mmol, 3 eq), H2O (1.6 ml) and Pd(PPh3)2Cl2 (10 mg, 0.0147 mmol, 0.1 eq) was heated under microwave irradiation (120° C., 30 min). Solvents were removed and the residue was purified in an Isolute Flash Si II column (0-3% MeOH in DCM). The product obtained was triturated with EtOAc and filtered. The filtrate was evaporated and the residue was triturated with acetone. The filtrate was evaporated. The residue was purified by column chromatography (EtOAc) to give the desired product (11 mg, 14%). HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=5.90 min, [M+H]+ m/z 524.2; 1H NMR (300 MHz, CDCl3) δ 8.86 (s, 2H), 7.43 (m, 2H), 7.36 (dd, J=8.3, 2.1 Hz, 1H), 6.96 (d, J=8.4 Hz, 1H), 5.26 (s, 2H), 4.53 (m, 1H), 3.93 (s, 3H), 3.75 (m, 2H), 3.29 (m, 2H), 1.93 (m, 2H), 1.81 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:21])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[NH:13][C:14]1[CH:15]=[N:16][C:17]([F:20])=[CH:18][CH:19]=1)=[O:4].Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][NH:27]3)[CH3:21])=[C:7]([NH:13][C:14]2[CH:15]=[N:16][C:17]([F:20])=[CH:18][CH:19]=2)[CH:8]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)C(=O)Nc1ccc(F)cc1Nc1ccc(F)nc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)C(=O)Nc1ccc(F)cc1Nc1ccc(F)nc1
Temperature: 100 °C
Yield: 94.1 %

Procedure:
A mixture of (S)-2-amino-N-[4-fluoro-2-(6-fluoropyridin-3-ylamino)phenyl]propionamide (193 mg, 0.66 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (165 mg, 0.69 mmol) and DIPEA (0.34 mL, 1.98 mmol) in n-butanol (1 mL) was heated at 100° C. in a sealed vial for 16 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge then washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to afford the title compound as a red solid (255 mg, 94%). LCMS (Method C): RT 2.40 min [M+H]+ 411.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([F:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[NH:20]([CH3:22])[CH3:21]>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:20]([CH3:22])[CH3:21])[C:11]([F:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(F)cc1[N+](=O)[O-]
Reactant: CNC
Solvent: CS(C)=O
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1F

Procedure:
The title compound was prepared from (5-chloro-4-fluoro-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example B6) (4.94 g, 17 mmol) and Me2NH (40% in H2O, 7.9M, 10.9 mL, 86 mmol) in DMSO (35 mL) at 23° C. according to the general procedure C. Obtained as a yellow solid (4.93 g).