Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([NH:20][C:21](=[O:32])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)[CH:17]=[CH:16][C:15]=3[CH3:33])=[O:12])[S:8][C:5]2=[N:6][CH:7]=1.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36](B(O)O)[CH:35]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>CC(O)CC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:33][C:15]1[CH:16]=[CH:17][C:18]([NH:20][C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)=[CH:19][C:14]=1[NH:13][C:11]([C:9]1[S:8][C:5]2=[N:6][CH:7]=[C:2]([C:36]3[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=3)[N:3]=[C:4]2[CH:10]=1)=[O:12]
Reactant: OB(O)c1cccnc1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1NC(=O)c1cc2nc(Cl)cnc2s1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCC(C)O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1NC(=O)c1cc2nc(-c3cccnc3)cnc2s1
Yield: 9.2 %

Procedure:
A mixture of 2-chloro-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)thieno[2,3-b]pyrazine-6-carboxamide 68 (100 mg, 0.204 mmol), pyridine-3-boronic acid (37.6 mg, 0.306 mmol), potassium phosphate, tribasic (86 mg, 0.407 mmol), tris(dibenzylideneacetone)dipalladium(0) (9.33 mg, 10.19 μmol) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (9.71 mg, 0.020 mmol) in butane-2-ol was stirred was stirred at 100° C. for 30 min in microwave. Water was added and extracted with EtOAc. Organic layer was washed with water, brine, dried and evaporated. Crystallization with acetonitrile gave the title compound N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-2-(pyridin-3-yl)thieno[2,3-b]pyrazine-6-carboxamide 69 (10 mg, 9%). NMR (400 MHz, DMSO-d6) 2.29 (s, 3H), 7.33 (d, J=8.6 Hz, 1H), 7.65 (m, 2H), 7.80 (t, J=7.8 Hz, 1H), 7.92 (d, J=2.0 Hz, 1H), 7.98 (d, J=8.2 Hz, 1H), 8.28 (d, J=7.8 Hz, 1H), 8.32 (s, 1H), 8.61 (s, 1H), 8.63 (t, J=1.6 Hz, 1H), 8.76 (dd, J=4.7 Hz and 1.6 Hz, 1H), 9.43 (d, J=2.0 Hz, 1H), 9.46 (s, 1H), 10.54 (s, 1H), 10.55 (s, 1H). (m/z)=535 (M+H)+.
Reaction SMILES: C[O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30]C1C=CC=CC=1>CO.[Pd]>[CH3:30][O:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][OH:2]
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCOCCOCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COCCOCCOCCOCCOCCOCCOCCOCCOCCO
Yield: 74 %

Procedure:
A solution of nonaethylene glycol benzyl methyl ether from above (38 g) in methanol (200 ml) was shaken with 10% palladium on activated charcal (Aldrich, 1.0 g) under hydrogen 344.7 kPa (50 psi) on a Parr apparatus overnight. The catalyst was filtered off (Celite™), and the filtrate was concentrated in vacuo to provide nonaethylene glycol monomethyl ether as an oil (23 g, 74%), 1H-NMR (CDCl3) δ: 3.67-3.47 (m, 36, 18 OCH2), 3.32 (s, 3, CH3).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([N:12]3C(=O)C4C(=CC=CC=4)C3=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.NN>C(O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH2:12])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1c1cnc2cc(Br)ccc2c1
Agent: NN
Solvent: CCO
Product: Nc1cnc2cc(Br)ccc2c1
Yield: 55.4 %

Procedure:
A suspension of 2-(7-bromoquinolin-3-yl)isoindoline-1,3-dione (10 g, 28.3 mmol) in ethanol (200 mL) was treated with hydrazine (1.777 mL, 56.6 mmol) then heated under reflux for 1 h. The mixture was allowed to cool, the precipitate was collected and washed with a little ethanol, and the filtrate was evaporated to a grey solid. The isolated solid was dissolved in warm ethanol and adsorbed onto silica gel. Purification of the solid by silica gel chromatography (50-100% ethyl acetate/hexanes) afforded the title compound (3.5 g, 56%). 1H NMR (400 MHz, DMSO-d6) δ ppm 5.83 (s, 2 H) 7.14 (d, J=2.53 Hz, 1 H) 7.49 (dd, J=8.84, 2.02 Hz, 1 H) 7.54-7.65 (m, 1 H) 7.94 (d, J=1.77 Hz, 1 H) 8.46 (d, J=2.78 Hz, 1 H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[C:6]([C:14]#[C:15][Si](C)(C)C)=[CH:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:14]([C:6]1[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[N:8][C:3]([NH:2][CH3:1])=[N:4][CH:5]=1)#[CH:15]
Reactant: CNc1ncc(C#C[Si](C)(C)C)c(-c2cccs2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cnc(NC)nc1-c1cccs1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 25 mL round bottom flask was charged with N-methyl-4-(thiophen-2-yl)-5-(2-(trimethylsilyl)ethynyl)pyrimidin-2-amine (0.518 g, 1.80 mmol), methanol (20 mL), and potassium carbonate (0.747 g, 5.41 mmol), and the reaction mixture stirred at room temperature for 24 hours. The reaction mixture was concentrated and the residue was purified via column chromatography on silica gel (gradient elution with 0-100% ethyl acetate-hexane) to 5-ethynyl-N-methyl-4-(thiophen-2-yl)pyrimidin-2-amine. MS m/z=216 [M+H]+. Calc'd for C11H9N3S: 215.
Reaction SMILES: CN(C=O)C.[H-].[Na+].[CH3:8][CH:9]([CH2:12][CH3:13])[CH2:10][SH:11].[NH2:14][C:15]1[N:23]=[C:22](Cl)[N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>[Cl-].[Na+].O>[NH2:14][C:15]1[N:23]=[C:22]([S:11][CH2:10][CH:9]([CH3:8])[CH2:12][CH3:13])[N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCC(C)CS
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)CSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 100 °C
Yield: 31.7 %

Procedure:
To DMF suspension (10 ml) containing sodium hydride (300 mg, 7.5 mmol, 60% in mineral oil) were added 2-methylbutane-1-thiol (1 ml, 8.0 mmol) and 6-amino-9-benzyl-2-chloropurine (200 mg, 0.77 mmol) in order. The mixture was stirred under heating at 100° C. for 4.5 hours. Brine was added thereto and the mixture was extracted with chloroform. The organic layer was dried on magnesium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (80 mg, yield 32%).
Reaction SMILES: [C:1]([NH:4][C:5](=[O:15])[CH2:6][S:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH3:18]I>CN(C)C=O>[CH3:18][N:4]([C:1](=[O:3])[CH3:2])[C:5](=[O:15])[CH2:6][S:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CI
Reactant: CC(=O)NC(=O)CSCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(C)C(=O)CSCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 11.15 g. (0.05 mole) of the product of Step A above in 75 ml. of dimethylformamide was cooled to -5° C. and there was then added 2.4 g. (0.05 mole) of 50% sodium hydride. The reaction mixture was aged for 30 minutes at -5° C., after which there was added 3.2 ml. (0.05 mole) of methyl iodide, and the reaction mixture was aged for 1 hour, 15 minutes at 0° C. and 45 minutes at room temperature. The reaction mixture was poured into ice water, seeded and placed in a refrigerator overnight. It was then filtered, washed with water and air dried. A yield of 9.0 g. of product was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][CH2:38][OH:39]>C(#N)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([CH2:36][CH2:37][CH2:38][OH:39])[S:25]([CH3:28])(=[O:27])=[O:26])[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: OCCCBr
Reactant: CNC(=O)c1c2cc(C3CC3)c(NS(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCCO)S(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 48.8 %

Procedure:
To a solution of Compound (1) (50 mg, 0.11 mmol) in ACN (4 mL) was added potassium carbonate (30 mg, 0.22 mmol) followed by 3-bromo-1-propanol (38 μL, 0.32 mmol). The mixture was heated to 80° C. and stirred for 16 h at which time no starting material was observed. The mixture was cooled to RT, diluted with EtOAc (10 mL), washed with water (3 mL), brine (3 mL) and dried (MgSO4). The solvent was removed in vacuo to give the crude mixture which was purified by flash column chromatography eluting with EtOAc/hexane (5-100%) to give 2-(4-bromophenyl)-5-cyclopropyl-6-[(3-hydroxypropyl)(methylsulfonyl)amino]-N-methyl-2H-indazole-3-carboxamide (4) (28 mg, 50%). ESI-MS m/z calculated for [M+H]+: 521.09/523.08; found: 521.03/523.03.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[C:36]3[C:31](=[C:32]([Cl:38])[CH:33]=[C:34]([Cl:37])[CH:35]=3)[NH:30][CH:29]=2)[CH:9]([C:13]2[CH:27]=[CH:26][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.[CH3:39]C(N(C)C)=O>CC([O-])(C)C.[K+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[C:36]3[C:31](=[C:32]([Cl:38])[CH:33]=[C:34]([Cl:37])[CH:35]=3)[N:30]([CH3:39])[CH:29]=2)[CH:9]([C:13]2[CH:27]=[CH:26][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CC(=O)N(C)C
Reactant: CCCC(c1ccc(C(=O)NCCC(=O)OC)cc1)C(c1ccc(Cl)cc1)c1c[nH]c2c(Cl)cc(Cl)cc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCC(c1ccc(C(=O)NCCC(=O)OC)cc1)C(c1ccc(Cl)cc1)c1cn(C)c2c(Cl)cc(Cl)cc12

Procedure:
A solution of KOtBu (1.0M THF, ca. 3 drops, 0.045 ml) was added to a dimethylacetamide solution (2 ml) of the intermediate from EXAMPLE 1, Step C (faster eluting enantiomer on ChiralPak AD 10% EtOH/Heptane, 4 mg, 0.007 mmol). Methyl iodide (three drops, excess) was then added dropwise. The progress of the reaction during the addition was monitored by MS-HPLC in order to minimize over alkylation. The reaction was quenched with aqueous 1N HCl. The mixture was extracted with EtOAc and the combined organics washed with water and brine. The solution was then dried over Na2SO4, filtered and concentrated to give the title compound which was used without further purification. LCMS1 4.40 min. (M+H)=585. The procedure was also carried out as described on the intermediate from Example 1, Step C (slower eluting enantiomer). LCMS1 4.39 min. (M+H)=585
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26](O)=[O:27])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[C:37](=[N:39]O)[NH2:38]>>[F:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[C:37]1[N:39]=[C:26]([CH:12]2[CH2:13][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:20][CH:21]=3)[CH2:15][N:10]([C:8]([N:5]3[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]3)=[O:9])[CH2:11]2)[O:27][N:38]=1
Reactant: NC(=NO)c1cc(F)ccc1F
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Product: O=C(N1CCC(O)CC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3cc(F)ccc3F)no2)C1

Procedure:
100 mg (0.250 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 99A) and 47.3 (0.275 mmol) of 2,5-difluoro-N′-hydroxybenzenecarboximidamide (Example 74A) were reacted according to the General Method 1. Yield: 68.1 mg (51% of theory).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[NH:9][CH2:10][CH2:11][N:12]=2)=[CH:3][CH:2]=1>C(O)C.[Ni]>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[NH:12][CH:11]=[CH:10][N:9]=2)=[CH:3][CH:2]=1
Reactant: c1cc(CC2=NCCN2)ccn1
Agent: [Ni]
Solvent: CCO
Product: c1cc(Cc2ncc[nH]2)ccn1
Temperature: 210 °C
Yield: 62.9 %

Procedure:
The mixture of 2-(4-pyridylmethyl)-imidazoline (6.6 g, 0.04M) and Raney-Nickle (3 g) was heated initially at 210° C. and gradually raised to 250° C. in 15 min. After the reaction, the reaction was dissolved in ethanol (50 ml) and filtered to remove the catalyst. The filtrate was stripped to dryness and distilled (0.25 mmHg, 180° C.) to give 2-(4-pyridylmethyl)-imidazole (4.1 g, 62% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[C@@H:15]([CH3:16])[CH2:14][O:13][CH2:12][C@H:11]2[CH3:17])=[O:9])=[CH:4][CH:3]=1.[C:18]([O:21][CH2:22][C:23]1[C:24]([N:38]2[CH2:50][CH2:49][N:41]3[C:42]4[CH2:43][CH2:44][CH2:45][CH2:46][C:47]=4[CH:48]=[C:40]3[C:39]2=[O:51])=[N:25][CH:26]=[CH:27][C:28]=1[C:29]1[CH:34]=[C:33](Br)[C:32](=[O:36])[N:31]([CH3:37])[CH:30]=1)(=[O:20])[CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:18]([O:21][CH2:22][C:23]1[C:24]([N:38]2[CH2:50][CH2:49][N:41]3[C:42]4[CH2:43][CH2:44][CH2:45][CH2:46][C:47]=4[CH:48]=[C:40]3[C:39]2=[O:51])=[N:25][CH:26]=[CH:27][C:28]=1[C:29]1[CH:34]=[C:33]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]3[C@@H:15]([CH3:16])[CH2:14][O:13][CH2:12][C@H:11]3[CH3:17])=[O:9])=[CH:6][N:7]=2)[C:32](=[O:36])[N:31]([CH3:37])[CH:30]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)OCc1c(-c2cc(Br)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: C[C@@H]1COC[C@H](C)N1C(=O)c1ccc(N)nc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4[C@H](C)COC[C@@H]4C)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 25 °C
Yield: 58.8 %

Procedure:
A 25-mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with (6-aminopyridin-3-yl)((3R,5S)-3,5-dimethylmorpholino)methanone 320a (120 mg, 0.50 mmol), (4-(5-bromo-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-3-yl)methyl acetate 217a (262 mg, 0.50 mmol), cesium carbonate (326 mg, 1.0 mmol), and 1,4-dioxane (6 mL). After bubbling nitrogen through the suspension for 10 minutes, Xantphos (58 mg, 0.10 mmol) and tris(dibenzylideneacetone)dipalladium(0) (45 mg, 0.050 mmol) were added. The system was subjected to three cycles of vacuum/nitrogen flush and heated at reflux for 2.5 h. It was then cooled to room temperature and filtered. The solid was washed with dichloromethane (3×10 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80/1 to 50/1) to afford 322a (200 mg, 59%) as a yellow solid. MS-ESI: [M+H]+ 680.3
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH3:15])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[CH2:16]O.P(Br)(Br)[Br:19]>ClCCl>[Br:19][CH2:16][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH3:15])[CH2:10][CH2:9]2)=[CH:7][C:2]=1[Cl:1]
Reactant: CCN1CCN(c2ccc(CO)c(Cl)c2)CC1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CCN1CCN(c2ccc(CBr)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
[2-chloro-4-(4-ethylpiperazin-1-yl)phenyl]methanol was dissolved in dichloromethane (30 mL) at 0° C. under nitrogen. Phosphorus tribromide (4.2 mL, 42 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched by addition of 10% NaHCO3 solution (5 mL). After 10 minutes, Na2SO4 (30 g) was added. The solvent was filtered and evaporated to provide 1-[4-(bromomethyl)-3-chlorophenyl]-4-ethylpiperazine, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.Cl.[H][H]>CO.[Pt](=O)=O>[CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: [H][H]
Reactant: Cc1nccc2ccccc12
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: Cc1nccc2c1CCCC2
Yield: 100.2 %

Procedure:
A solution of 1-methylisoquinoline (1.0 g) in methanol (30 ml) was saturated with gaseous hydrogen chloride at room temperature. The mixture was treated with platinum(IV) oxide (0.2 g). The mixture was vigorous stirred under hydrogen atmosphere at room temperature until hydrogen absorption was stopped. The reaction mixture was filtered off to remove the catalyst. The filtrate was concentrated in vacuo and the residue was taken up with water. The mixture was alkalized with sodium carbonate and the resultant precipitate was extracted with isopropyl ether. The extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give 1-methyl-5,6,7,8-tetrahydroisoquinoline (1.03 g) as a brown oil. 1H NMR (CDCl3, δ): 1.6-2.0 (4H, m), 2.42 (3H, s), 2.5-2.9 (4H, m), 6.82 (1H, m), 8.16 (1H, m)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[CH2:22]([S:24](Cl)(=[O:26])=[O:25])[CH3:23]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]([S:24]([CH2:22][CH3:23])(=[O:26])=[O:25])[S:10]([CH2:13][CH3:14])(=[O:11])=[O:12])[CH:5]=[N:6][CH:7]=1
Reactant: CCS(=O)(=O)NCc1cncc(Br)c1
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N(Cc1cncc(Br)c1)S(=O)(=O)CC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of N-((5-bromopyridin-3-yl)methyl)ethanesulfonamide (1.8 g, 5.55 mmol) and triethylamine (1.683 g, 16.64 mmol) in DCM (20 mL) at 0° C. is added ethanesulfonyl chloride (1.426 g, 11.09 mmol), and the mixture is stirred at 0° C. for 1 h. Silica gel (10 g) is added and the mixture is concentrated in vacuo. The residue is purified by silica chromatography eluting with 0 to 2% MeOH-DCM to give N-((5-bromopyridin-3-yl)methyl)-N-(ethylsulfonyl)ethanesulfonamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (t, J=7.3 Hz, 6H), 3.48 (q, J=7.3 Hz, 4H), 4.92 (s, 2H), 8.0 (t, J=2.1 Hz, 1H), 8.59 (d, J=2.0 Hz, 1H), 8.72 (d, J=2.3 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.CO.[CH2:13](Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:13][O:9][C:8](=[O:10])[C:7]1[C:2]([Br:1])=[CH:3][CH:4]=[N:5][CH:6]=1
Reactant: O=C(O)c1cnccc1Br
Reactant: ClCCCl
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cnccc1Br
Temperature: 0 °C
Yield: 45.6 %

Procedure:
To a solution of 4-bromonicotinic acid (16.8 g, 83.2 mmol, 1.0 eq.) in DCM (250 mL) at 0° C. was added DMAP (1.0 g, 8.2 mmol, 0.1 eq.). MeOH (2.7 g, 83.7 mmol, 1.0 eq.) was added dropwise with stirring at 0° C. EDC (16.8 g, 87.6 mmol, 1.1 eq.) was then added. The resulting solution was stirred for 3 hours at 0° C. The reaction was then quenched with water (100 mL). The resulting solution was extracted with DCM. The organic layer was washed with saturated aqueous NaCl (3×100 mL), dried over anhydrous Na2SO4 and concentrated under vacuum to yield 4-bromonicotinic acid methyl ester (8.2 g) as a yellow oil.
Reaction SMILES: C([C@@H]1CC[C@@H](C)C[C@H]1[N:11]([C@H:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1)[CH3:16])C(=O)[O-])(C)C.[Si](I)(C)(C)C>C(Cl)(Cl)Cl>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C@@H:15]([NH2:11])[CH3:16])=[N:18][CH:19]=1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1N(C(=O)[O-])[C@@H](C)c1ccc(F)cn1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: C[C@H](N)c1ccc(F)cn1
Temperature: 0 °C
Yield: 79 %

Procedure:
(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl [(1S)-1-(5-fluoropyridin-2-ypethyl]carbamate (Method 5; 3.0 g, 9.3 mmol) and TMSI (2.7 ml, 18.6 mmol) in chloroform (10 ml) was heated at 68° C. for 24 hours. Ice water (15 ml) was added carefully and extracted with ether (2×100 ml). The aqueous layer was separated, neutralized with solid sodium bicarbonate to PH=9 and extracted with ether (5×200 ml). The combined organic was dried over sodium sulfate and concentrated to give the title compound (1.03 g, 79%) as pale yellow oil. 1H NMR (400 MHz) 8.44 (d, J=2.8 Hz, 1H), 7.66 (ddd, J=2.8, 2.8 and 2.8 Hz, 1H), 7.53 (m, 1H), 4.01 (q, J=6.8 Hz, 1H), 1.94 (b, 2H), 1.26 (d, J=6.8 Hz, 3H). MS: Calcd.: 140. Found: [M+H]+141.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[CH:21][C:22]([C:25](O)=[O:26])=[N:23][CH:24]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][NH:39][CH3:40]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([N:39]([CH2:38][CH2:37][N:36]([CH3:41])[CH3:35])[CH3:40])=[O:26])=[N:23][CH:24]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1
Reactant: CC1Cc2ccc(-c3ccc(C(=O)O)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CNCCN(C)C
Product: CC1Cc2ccc(-c3ccc(C(=O)N(C)CCN(C)C)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 50B starting from 5-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (Example 50B, Step 1) and N,N,N′-trimethylethylenediamine (Aldrich, Cat. No. 127124). LCMS (M+H)+: m/z=544.3.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1.CCN(CC)CC.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C=O)C.CC(OC)(C)C>[Cl:1][C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][CH:5]=[C:6]([CH2:8][O:9][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1ncc(CO)cc1Cl
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ncc(CO[Si](C)(C)C(C)(C)C)cc1Cl
Yield: 93.6 %

Procedure:
A solution of methyl 3-chloro-5-(hydroxymethyl)-2-pyridinecarboxylate (332.6 mg, 1.650 mmol), Et3N (0.345 ml, 2.475 mmol), and tert-butyldimethylsilyl chloride (261 mg, 1.732 mmol) in DMF (4 ml) was stirred at room temperature for 3 h. The crude was diluted with TBME (40 ml) and organic phase was washed with water and brine. Combined organic phases were washed with sat NH4Cl, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (488 mg, 84% yield) as yellow oil pure enough to be used in the next step.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:17]=[CH:16][CH:15]=[C:9]2[C:10]([NH:12][C:13](=[O:14])[C:8]=12)=[O:11].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C(OCC)C>[N:18]1([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]2[CH:17]=[CH:16][CH:15]=[C:9]3[C:10]([NH:12][C:13](=[O:14])[C:8]=23)=[O:11])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: O=C1NC(=O)c2c(CCCCCBr)cccc21
Reactant: C1COCCN1
Solvent: CCOCC
Product: O=C1NC(=O)c2c(CCCCCN3CCOCC3)cccc21

Procedure:
5-Bromopentylphthalimide (432 mg; 2.0 mmoles) and morpholine (0.35 ml; 4.0 mmoles) were dissolved in anhydrous ethyl ether (5 ml). Reaction times and process as per Example 1.