Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-:1].[Ce+3].[Cl-].[Cl-].[I-].[Na+].[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16](=[O:19])[CH2:17]Br)=[CH:15][C:10]=2[O:9][CH2:8]1.[CH2:20]([N:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[ClH:1].[CH2:20]([N:27]1[CH2:32][CH2:31][C:30]([CH2:17][C:16]([C:14]2[CH:13]=[CH:12][C:11]3[O:7][CH2:8][O:9][C:10]=3[CH:15]=2)=[O:19])([OH:33])[CH2:29][CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: O=C(CBr)c1ccc2c(c1)OCO2
Reactant: [Cl-]
Agent: [Ce+3]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cl
Product: O=C(CC1(O)CCN(Cc2ccccc2)CC1)c1ccc2c(c1)OCO2
Reaction time: 2 h
Yield: 44.9 %

Procedure:
Anhydrous cerium chloride (0.99 g, 4.0 mmol) and sodium iodide (1.8 g of, 12.0 mmol) are added to 10 ml of anhydrous tetrahydrofuran as a solvent to form a suspension. Dissolving 0.97 g (4.0 mmol) of 1-(benzo[d][1,3]dioxol-5-yl)-2-bromoethanone and 0.76 g (4.0 mmol) of N-benzyl-4-piperidone into 10 ml of anhydrous tetrahydrofuran, and the solution is added dropwise to the above suspension and reacting at room temperature for 2 hours. Operating according to the post-treatment procedure in General Method three to obtain 0.70 g of a white crystal, with yield of 42.9%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11](O)=O.[N:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]([NH:25][NH2:26])=O)=[CH:22][C:17]=2[NH:16][CH:15]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1.O=P(Cl)(Cl)Cl>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[S:36][C:23]([C:21]2[CH:20]=[CH:19][C:18]3[NH:14][CH:15]=[N:16][C:17]=3[CH:22]=2)=[N:25][N:26]=1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Reactant: O=C(O)CCc1ccc(F)cc1F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: Fc1ccc(CCc2nnc(-c3ccc4[nH]cnc4c3)s2)c(F)c1

Procedure:
The compound was synthesized starting from 3-(2,4-difluorophenyl)propionic acid (187 mg; 1 mmol), benzimidazol-5-carbohydrazide (176 mg; 1 mmol), Lawesson's reagent (606 mg; 1.5 mmol) and POCl3 (0.137 ml; 1.5 mmol) as described in method 3; yield: 0.009 g (2.6%); MS m/z: 342.2 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 3.12 (t, 2H, 3J=7.5 Hz); 3.44 (t, 2H, 3J=7.5 Hz); 7.02-7.05 (m, 1H); 7.17-7.22 (m, 1H); 7.40-7.46 (m, 1H); 7.79 (d, 1H, 3J=8.7 Hz); 7.87 (dd, 1H, 4J=1.7 Hz, 3J=8.7 Hz); 8.19 (d, 1H, 4J=1.7 Hz); 8.72 (s, 1H); HPLC (METHOD [A]): rt 12.69 min (85.5%)
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH2:22][C:23]([O:25]C)=[O:24])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.O[Li].O.O>C1COCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:12][C:13]=2[F:14])=[N:6][CH:7]=1
Reactant: COC(=O)COc1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Nc1cnc(-c2ccc(-c3ccccc3OCC(=O)O)cc2F)cn1
Temperature: 25 °C
Reaction time: 14 h
Yield: 84.2 %

Procedure:
To a solution of methyl 2-(4′-(5-aminopyrazin-2-yl)-5′-fluorobiphenyl-2-yloxy)acetate (50 mg, 0.14 mmol) in THF (2 mL) were added LiOH.H2O (63 mg, 1.5 mmol) and H2O (2 mL). The mixture was stirred at rt for 14 hours. The THF was removed under reduced pressure, and the residue diluted with 15 mL of water, washed with DCM (5 mL×2), and then acidified with 1 N HCl to pH=7. The precipitate was collected and washed with water and dried under high vacuum to give the title compound (40 mg, 95% yield). MS (ESI): mass calcd. for C18H14FN3O3, 339.10; m/z found, 340.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 8.36 (s, 1H), 8.01 (s, 1H), 7.88 (m, 1H), 7.55 (d, J=13.0, 1H), 7.48 (d, J=9.2, 1H), 7.40 (d, J=7.4, 1H), 7.33 (m, 1H), 7.08-7.00 (m, 2H), 6.69 (s, 2H), 4.76 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][Cl:17])[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+].CO>O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][Cl:17])[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)C(=NOCCCl)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(C(=NOCCCl)C(=O)O)cs1
Yield: 85.3 %

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)-2-(2-chloroethoxyimino)acetate (syn isomer, 30.5 g.), 1N aqueous solution of sodium hydroxide (220 ml.), methanol (110 ml.) and tetrahydrofuran (140 ml.) were treated in a similar manner to that of Example F-(4) to give 2-(2-aminothiazol-4-yl)-2-(2-chloroethoxyimino)acetic acid (syn isomer, 23.4 g.), mp 201° C. (dec.).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCC1C=C([F:39])C=CC=1OC>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:21]=[C:20]([F:39])[CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1CC(O)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Reactant: COc1ccc(F)cc1CCl
Product: COc1ccc(F)cc1CC(O)(c1ccccc1)C1CN(Cc2ccccc2)CCO1

Procedure:
The procedure for the synthesis of example 1a, 1-(4-Benzyl-morpholin-2-yl)-2-(2-methoxy-phenyl)-1-phenyl-ethanol, was followed using 2-chloromethyl-4-fluoro-1-methoxy-benzene (synthesized as described above) as starting material making non-critical variations, to yield the title compound which was taken without further purification in the next step. LCMS (6 minutes method) [M+H]+=422 @ Rt 2.85 min. major peak.
Reaction SMILES: O.[NH2:2][NH2:3].[CH:4]([C:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][C@H:14]2[CH2:16][C@@H:15]2[CH3:17])[C:7]=1[C:18]([O:20]C)=O)=O>C(O)(=O)C>[CH3:12][C:9]1[N:8]([CH2:13][C@H:14]2[CH2:16][C@@H:15]2[CH3:17])[C:7]2[C:18](=[O:20])[NH:2][N:3]=[CH:4][C:6]=2[C:10]=1[CH3:11]
Reactant: NN
Reactant: COC(=O)c1c(C=O)c(C)c(C)n1C[C@H]1C[C@@H]1C
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(C)n(C[C@H]2C[C@@H]2C)c2c(=O)[nH]ncc12
Temperature: 90 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
Hydrazine hydrate (1.92 g, 38.4 mmol) was added to a solution of methyl 3-formyl-4,5-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrole-2-carboxylate (7.96 g 31.9 mmol) in acetic acid (38 ml) at room temperature and the mixture was stirred at 90° C. for 1 hour. After the reaction was completed, the reaction mixture was cooled to room temperature and poured into ice-water. The crude crystals were collected by filtration, washed with water and dissolved in a mixture of chloroform and methanol (9:1). The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and to the residue was added a mixture of toluene and hexane. The precipitate was collected by filtration to afford the desired compound (7.02 g, 95.0%) as a pale yellowish white powder.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([S:8]([OH:11])(=[O:10])=[O:9])[CH:2]=1.[OH2:12]>>[C:6]1([OH:7])[CH:1]=[CH:2][CH:3]=[CH:4][CH:5]=1.[S:8](=[O:9])(=[O:12])([OH:10])[OH:11]
Reactant: O
Reactant: O=S(=O)(O)c1ccc(O)cc1
Product: O=S(=O)(O)O
Product: Oc1ccccc1

Procedure:
Polish patent No. 99,682 (CA 91, 107,806) has disclosed that anhydrous phenolsulfonic acid can be obtained from phenol and sulfuric acid if the water of reaction, formed during the reaction, is removed from the reaction medium. This is effected by sulfonating phenol with H2SO4 and dripping the sulfonation mixture through a column with a heating jacket, in which a counter-current gas stream of an inert organic solvent, for example C7H16, azeotropically removes the water of reaction. The disadvantages of this process are the expense for equipment and the expensive separation of the organic solvent from the reaction product. According to Ind. eng. Chem. 32, 408 (1940), the water of reaction can also be removed by addition of BF3 to the reaction mixture, by distillation in the form of BF3. 2 H2O, but the BF3 must then be recovered via Ca(BF4)2 in a downstream stage.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11](=[O:27])[N:12]([CH3:26])[C:13](=[O:25])[N:14]([C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:17])[CH:15]=1)(C(C)(C)C)(C)C.CC(O)=O.C1COCC1.O>O>[CH2:19]([NH:18][C:16]([N:14]1[CH:15]=[C:10]([CH2:9][OH:8])[C:11](=[O:27])[N:12]([CH3:26])[C:13]1=[O:25])=[O:17])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCNC(=O)n1cc(CO[Si](C)(C)C(C)(C)C)c(=O)n(C)c1=O
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCCCNC(=O)n1cc(CO)c(=O)n(C)c1=O
Reaction time: 22 h
Yield: 89.6 %

Procedure:
5-[[tert-Butyl(dimethyl)silyl]oxymethyl]-N-hexyl-3-methyl-2,4-dioxo-pyrimidine-1-carboxamide (0.05 g, 0.13 mmol) was treated with AcOH/THF/H2O (3 mL, 4:1:1) at room temperature. The reaction was stirred for 22 hrs. Water (3 mL) was added, and the solution extracted with EtOAc/cyclohexane 1:1 (3×6 mL). The combined organic phases were concentrated to approx. 1 mL, which was then diluted with dichloromethane (1.5 mL) and injected onto a 4 g SiO2 column followed by purification by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 70:30) to afford the title compound (0.033 g, 88%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 0.90 (t, J=6.8 Hz, 3H), 1.28-1.38 (m, 6H), 1.55-1.65 (m, 2H), 2.53 (bs, 1H), 3.38 (s, 3H), 3.39 (td, J=6.9, 5.8 Hz, 2H), 4.48 (s, 2H), 8.44 (bs, 1H), 9.26 (t, J=4.5 Hz, 1H). 13C NMR (101 MHz, CDCl3): δ 14.15, 22.66, 26.67, 28.06, 29.30, 31.53, 41.47, 59.62, 114.39, 133.97, 150.22, 152.31, 162.77. MS (ESI) m/z: 284 [M-H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:18][CH3:19])[CH:5]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH:7]=1.[CH:20](=O)[CH3:21].[BH3-]C#N.[Na+].C(O)(=O)C>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([N:18]([CH2:20][CH3:21])[CH3:19])[CH:5]=[C:6]([S:8][C:9]2[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: CC=O
Reactant: CNc1cc(Br)cc(Sc2ccc([N+](=O)[O-])cc2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCN(C)c1cc(Br)cc(Sc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
0.34 g (0.001 mol) of [3-bromo-5-(4-nitrophenylsulphanyl)-phenyl]-methylamine was dissolved in 10 ml of acetonitrile, treated with 1.4 ml (0.025 mol) of acetaldehyde, 0.74 g (0.010 mol) of NaBH3CN and 1.76 ml of acetic acid and stirred at room temperature for 1 hr. Thereafter, the solvent was removed, the residue was partitioned in ethyl acetate/water and the organic phase was washed with sat. sodium chloride solution, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel with ethyl acetate/hexane 1:19. There was obtained 0.33 g (93%) of [3-bromo-5-(4-nitro-phenylsulphanyl)-phenyl]-ethylmethylamine as an orange-red oil. MS (EI): me/e=368, 366 (C15H15BrN2O2S+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][S:15]([O:18][CH2:19][CH:20]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=1[Cl:38])[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[Cl:28])(=[O:17])=[O:16]>CN(C)C=O>[CH3:14][S:15]([O-:18])(=[O:17])=[O:16].[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[CH:20]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=1[Cl:38])[CH2:19][N+:11]1[CH:12]=[CH:13][N:9]([CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:10]=1
Reactant: CS(=O)(=O)OCC(OCc1ccc(Cl)cc1Cl)c1ccc(Cl)cc1Cl
Reactant: c1ccc(CCn2ccnc2)cc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)[O-]
Product: Clc1ccc(COC(C[n+]2ccn(CCc3ccccc3)c2)c2ccc(Cl)cc2Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
A mixture of 8.6 parts of 1-(2-phenylethyl)-1H-imidazole, 24.5 parts of 2,4-dichloro-β-(2,4-dichlorophenylmethoxy)benzeneethanol methanesulfonate and 150 parts of N,N-dimethylformamide is stirred and refluxed overnight. The mixture is allowed to cool to room temperature, poured onto water and extracted twice with trichloromethane. The combined organic phases are washed three times with water, dried, filtered and evaporated, yielding 1-[2,4-dichloro-β-(2,4-dichlorobenzyloxy)phenethyl]-3-phenethylimidazolium methanesulfonate as an oily residue. The oily residue is taken up in ethanol and brought on an ion exchange column (Amberlite IRA 400) previously converted into the hydroxyl form by treatment with a sodium hydroxide solution. The product in the form of a quaternary imidazolium hydroxide is eluted with ethanol and to the eluate there are added 30 parts of a concentrated hydrochloric acid solution. After evaporating off the solvent there is obtained 1-[2,4-dichloro-62 -(2,4-dichlorobenzyloxy)phenethyl]-3-phenethylimidazolium chloride, m.p. 158.9° C.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[Li+].CC([N-]C(C)C)C.[C:21]([O:25][C:26]([N:28]1[CH2:32][CH:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:30][C@@H:29]1[C:41]([OH:43])=[O:42])=[O:27])([CH3:24])([CH3:23])[CH3:22].CI>C1COCC1>[C:21]([O:25][C:26]([N:28]1[CH2:32][CH:31]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:30][C:29]1([CH3:1])[C:41]([OH:43])=[O:42])=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CC(OCc2ccccc2)C[C@@H]1C(=O)O
Reactant: CC(C)NC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(OCc2ccccc2)CC1(C)C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 21.7 %

Procedure:
To a cooled (−78° C.) solution of diisopropylamine (0.032 mol) in dry THF (15 mL), n-BuLi (0.030 mol) was added dropwise under argon atmosphere, and the reaction was stirred for 30 min at −78° C., then for one hour at −20° C. The resulting LDA solution was transferred to the solution of the known compound (R)-4-benzyloxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (CAS: 54631-81-1, e.g. Tetrahedron, 42(21), 6039-45; 1986) (3.5 g, 0.011 mol) in THF (15 mL) at −78° C., and the mixture was stirred for 30 minutes at −78° C., then at 0° C. for one hour. The reaction mixture was once again cooled to −78° C. and methyl iodide (0.82 mL, 0.013 mol) was added to it over 10 min and stirred the reaction mixture was stirred at 0° C. then at rt for one hour. After completion of the reaction by TLC, the reaction mixture was quenched with 1N HCl (20 mL) and extracted with DCM. The organic layer was concentrated under reduced pressure to give a crude material, which was purified through column chromatography (10-20% ethyl acetate:hexane, basic alumina, diameter of column—2.5 cm, height of alumina—approx. 7 inch) to afford the desired (rac)-4-benzyloxy-2-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 800 mg (22%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:39]2[CH:40]=[N:41][C:42]([NH2:45])=[N:43][CH:44]=2)O1>>[NH2:45][C:42]1[N:43]=[CH:44][C:39]([C:2]2[N:3]=[C:4]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:40][N:41]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde 10 from Example 3 (4.17 g) was converted via General Procedure B-3 to yield 5.67 g of tert-butyl 4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carboxylate. Tert-butyl 4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carboxylate (1 g) was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure A to give 1.02 g of tert-butyl 4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carboxylate. This intermediate was then converted to the HCl salt of 5-(4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine via General Procedure D.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=3)[CH:14]=[CH:13][C:5]=1[C:6](Cl)=[N:7]2.Cl.[NH2:24][CH2:25][C:26]1[S:27][CH:28]=[CH:29][N:30]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CC(N(C)C)=O>[Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=3)[CH:14]=[CH:13][C:5]=1[C:6]([NH:24][CH2:25][C:26]1[S:27][CH:28]=[CH:29][N:30]=1)=[N:7]2
Reactant: NCc1nccs1
Reactant: Cn1cc(-c2ccc3c(Cl)nc4ccnc(Cl)c4c3c2)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: Cn1cc(-c2ccc3c(NCc4nccs4)nc4ccnc(Cl)c4c3c2)cn1
Temperature: 130 °C

Procedure:
To a solution of 1,6-dichloro-9-(1-methyl-1H-pyrazol-4-yl)benzo[c]-1,6-naphthyridine (50 mg, 0.152 mmol) and 2-aminomethylthiazole hydrochloride (92 mg, 0.608 mmol) in DMA (1.5 mL), triethylamine (85 μl, 0.608 mmol) was added. The reaction mixture was heated to 130° C. for 1 h via microwave irradiation. After cooling to room temperature, aqueous sodium hydrogen carbonate (saturated) was added. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to afford 1-chloro-9-(1-methyl-1H-pyrazol-4-yl)-N-(1,3-thiazol-2-ylmethyl)benzo[c]-1,6-naphthyridin-6-amine as a yellow solid. LRMS (APCI) calc'd for (C20H16ClN6S) [M+H]+, 407.1; found 407.0.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:27][C:15]3[N:16]=[C:17](Cl)[N:18]=[C:19]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)=[O:4].CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=2)O1>>[NH2:43][C:40]1[N:41]=[CH:42][C:37]([C:17]2[N:18]=[C:19]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[C:14]3[CH:13]=[C:12]([CH2:11][N:8]4[CH2:9][CH2:10][N:5]([C:3]([N:2]([CH3:28])[CH3:1])=[O:4])[CH2:6][CH2:7]4)[S:27][C:15]=3[N:16]=2)=[CH:38][N:39]=1
Reactant: CN(C)C(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: CN(C)C(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3s2)CC1

Procedure:
4-(2-Chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidin-6-ylmethyl)-piperazine-1-carboxylic acid dimethylamide was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine in General Procedure A. Purification on silica yielded 128. NMR (CDCl3): 2.55 (m, 4H, 2×CH2), 2.84 (s, 6H, 2×CH3), 3.32 (m, 4H, 2×CH2), 3.79 (s, 2H, CH2), 3.89-3.91 (m, 4H, 2×CH2), 3.95-3.97 (m, 4H, 2×CH2), 5.24 (sbr, 2H, NH2), 7.14 (s, H, ArH), 9.30 (s, 2H, 2×ArH). MS: (ESI+): MH+=484.31
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19](Br)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.[CH3:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19]([C:29]4[CH:28]=[N:27][N:26]([CH3:25])[CH:30]=4)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(Br)c2n1C
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(-c3cnn(C)c3)c2n1C
Temperature: 140 °C
Yield: 79.6 %

Procedure:
A mixture of 4-Amino-6-[(S)-1-(7-bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethylamino]-pyrimidine-5-carbonitrile, (0.10 g, 0.26 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.069 g, 0.33 mmol), tetrakis(triphenylphosphine)palladium(0) (0.015 g, 0.01 mmol) and caesium carbonate (0.17 g, 0.51 mmol) in dioxane (3 mL) and water (1.5 mL) was placed in a sealed tube and degassed with nitrogen for 5 minutes, then heated for 30 minutes at 140° C. by microwave irradiation. The resulting mixture was loaded onto an Isolute® SCX-2 cartridge then washed with MeOH and the product eluted with 2M NH3/MeOH and concentrated in vacuo. The resulting residue was purified by chromatography (SiO2, 0-10% (2M ammonia in methanol) in DCM) then by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 78 min gradient 20-98% 0.1% HCO2H in acetonitrile/water) to give 427 as a white solid (0.081 g, 81%). LCMS (Method K): RT 2.50 min [M+H]+ 392.1. 1H NMR (DMSO-d6, 400 MHz): δ 8.24 (1H, s), 7.92 (1H, s), 7.67-7.59 (2H, m), 7.31 (2H, s), 7.12-7.08 (1H, m), 5.64 (1H, m), 3.93 (3H, s), 3.17 (3H, s), 1.58 (3H, d, J=6.74 Hz)
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]1=[O:13].[CH2:14](Br)[CH2:15][CH2:16][CH2:17][CH3:18].O>CN(C)C=O>[CH2:14]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]1=[O:13])[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCBr
Reactant: O=C1Nc2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCN1C(=O)C(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.7 %

Procedure:
A stirred solution of 270 mg of sodium hydride was added to 1.00 g of 2,3-dihydro-1H-indol-2,3-dione in dimethylformamide at room temperature. After the reaction mixture was stirred at room temperature for 10 minutes, 5 ml of a dimethylformamide solution of 2.10 g of pentyl bromide was added dropwise thereto. After the reaction mixture was stirred at room temperature for 20 minutes, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After the extract was washed with water and dried, the solvent was removed by evaporation. The residue was purified by silica gel column chromatography [ethyl acetate-hexane (1:5)] to afford 1.31 g of 2,3-dihydro-1-pentyl-1H-indol-2,3-dione as orange crystals. Melting point: 50° to 51° C.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1([CH3:32])[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([C:16]([NH:18][C:19]3[C:20]([CH3:30])=[C:21]([CH:26]=[CH:27][C:28]=3[CH3:29])[C:22]([O:24]C)=[O:23])=[O:17])[C:13]([CH3:31])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.CO>C1COCC1>[OH:3][C:4]1([CH3:32])[CH2:5][CH2:6][N:7]([C:10]2[N:15]=[C:14]([C:16]([NH:18][C:19]3[C:20]([CH3:30])=[C:21]([CH:26]=[CH:27][C:28]=3[CH3:29])[C:22]([OH:24])=[O:23])=[O:17])[C:13]([CH3:31])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2nc(N3CCC(C)(O)CC3)ccc2C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(N2CCC(C)(O)CC2)nc1C(=O)Nc1c(C)ccc(C(=O)O)c1C
Reaction time: 1 h
Yield: 0 %

Procedure:
A solution of aqueous 2N NaOH (5.00 ml) is added to a stirred solution of methyl 3-[[6-(4-hydroxy-4-methyl-1-piperidyl)-3-methyl-pyridine-2-carbonyl]amino]-2,4-dimethyl-benzoate (0.27 g, 656.13 mmol) in THF:MeOH (10 ml:5 ml). After 1 hour 50° C., the organic solvent is removed under reduced pressure and the residue is diluted with water, acidified to pH 6 with 5N HCl, and extracted with ethyl acetate. The organic layers are combined and concentrated under reduced pressure. The solids are triturated with acetone/acetonitrile and filtered. The filtrate is dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as an off-white solid (75 mg, 29%). Mass spectrum (m/z): 398.2 (M+1).