Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11](=[O:13])[CH3:12])[CH:4]=[CH:3][N:2]=1.[BH4-].[Na+]>CCO>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH:11]([OH:13])[CH3:12])[CH:4]=[CH:3][N:2]=1
Reactant: CC(=O)c1cccc2ccncc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1cccc2ccncc12
Reaction time: 8 h

Procedure:
1-(isoquinolin-8-yl)ethanone (0.64 g, 3.74 mmol) in EtOH (37 mL) was added with sodium borohydride (2.26 g, 59.8 mmol). The reaction mixture was stirred overnight. The reaction mixture was quenched with 1M NaOH and extracted with DCM. Purified by normal phase chromatography (10-60% EtOAc in hexane) to yield 1-(isoquinolin-8-yl)ethanol as an oil. Chiral separation (ChiralPak AD-H) provided (S)-1-(isoquinolin-8-yl)ethanol and (R)-1-(isoquinolin-8-yl)ethanol.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9]([C:11]([NH2:14])([CH3:13])[CH3:12])=[CH:8][C:6]=2[N:7]=1.CCN(CC)CC.[C:28](Cl)(=[O:30])[CH3:29].CC1(C)C(C)(C)OB([C:40]2[CH:48]=[CH:47][CH:46]=[C:45]3[C:41]=2[CH:42]=[N:43][NH:44]3)O1>C(Cl)Cl>[NH:44]1[C:45]2[C:41](=[C:40]([C:2]3[N:3]=[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:5]4[S:10][C:9]([C:11]([NH:14][C:28](=[O:30])[CH3:29])([CH3:13])[CH3:12])=[CH:8][C:6]=4[N:7]=3)[CH:48]=[CH:47][CH:46]=2)[CH:42]=[N:43]1
Reactant: CC(C)(N)c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC(C)(C)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-amine (400 mg, 1.3 mmol) in CH2Cl2 (20 mL) was added Et3N (630 μL, 4.5 mmol) and acetyl chloride (180 μL, 2.6 mmol). The resulting mixture stirred at room temperature overnight. The reaction was quenched by the addition of saturated aqueous NaHCO3. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-100% EtOAc in hexane). A portion (0.2 mmol) of the resulting pure product was utilized in a Suzuki coupling using General Procedure A with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide 399 after reverse phase HPLC purification (36 mg). MS (Q1) 437 (M)+
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].[CH2:5]([O:7][C:8]([C:10]1[C:11](Cl)=[N:12][C:13]2[C:18]([C:19]=1[CH3:20])=[CH:17][CH:16]=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=2)=[O:9])[CH3:6]>CCO.O.CCOC(C)=O>[CH2:5]([O:7][C:8]([C:10]1[C:11]([O:3][CH2:2][CH3:1])=[N:12][C:13]2[C:18]([C:19]=1[CH3:20])=[CH:17][CH:16]=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=2)=[O:9])[CH3:6]
Reactant: CC[O-]
Reactant: CCOC(=O)c1c(Cl)nc2cc(C(F)(F)F)ccc2c1C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(OCC)nc2cc(C(F)(F)F)ccc2c1C
Temperature: 60 °C
Reaction time: 16 h
Yield: 96.9 %

Procedure:
1.2 g (17.8 mmol) sodium ethylate was added to a solution of 5.1 g (16.1 mmol) 2-chloro-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester in EtOH (20 ml) at RT. The RS was subsequently heated to 60° C. for 4 h and then stirred for 16 h at RT. The solution was then diluted with water and EtOAc. The organic phase was separated and washed with a 4N aq. NH4Cl sol., dried over MgSO4 and concentrated in a vacuum. 5.1 g (15.6 mmol, 97%) 2-ethoxy-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester was obtained as a residue. The raw product was further converted without additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=[O:14].S(Cl)(Cl)(=O)=O.[CH2:21](O)[CH3:22]>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13]([O:15][CH2:21][CH3:22])=[O:14]
Reactant: CCO
Reactant: O=C(O)Cc1cc([N+](=O)[O-])c(F)cc1Cl
Solvent: O=S(=O)(Cl)Cl
Product: CCOC(=O)Cc1cc([N+](=O)[O-])c(F)cc1Cl
Yield: 97.8 %

Procedure:
A solution of 2-(2-chloro-4-fluoro-5-nitrophenyl)acetic acid (20.5 g, 88 mmol) in ethanol (150 mL) was treated with sulfuryl dichloride (21 g, 0.17 mol) at 0° C., then the mixture was heated to reflux for 1 h. The reaction mixture was concentrated under reduced pressure and the pH was adjusted to between pH 7-8 by addition of saturated Na2CO3 solution. Then resultant mixture was extracted with EtOAc (3×100 mL) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated to give ethyl 2-(2-chloro-4-fluoro-5-nitrophenyl)acetate (22.5 g, 97.8%). 1HNMR (400 Hz, DMSO-d6): δ 8.32 (d, J=8.0 Hz, 1 H), 7.91 (d, J=11.2 Hz, 1 H), 4.09 (q, J=7.2 Hz, 2 H), 3.92 (s, 2 H), 1.17 (t, J=7.2 Hz, 3 H).
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][CH:7]([CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:8]([OH:10])=[O:9].O.[CH2:23](O)[CH3:24]>>[Br:6][CH:7]([CH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[C:8]([O:10][CH2:23][CH3:24])=[O:9]
Reactant: CCO
Reactant: COc1ccc(CCCC(Br)C(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)C(Br)CCCc1ccc(OC)cc1
Temperature: 25 °C

Procedure:
Concentrated sulfuric acid (1 ml) was added to a solution of the 2-bromo-5-(4-methoxyphenyl)pentanoic acid crude product (Reference Example 37) (1000 mg) in ethanol (15 ml) at room temperature and the resulting mixture was heated under reflux for 2 hours. After being allowed to cool to room temperature, the reaction solution was poured into water (50 ml) and extracted with ethyl acetate (50 ml). The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution (30 ml) and a saturated aqueous sodium chloride solution (30 ml) and then dried over sodium sulfate. The dried organic layer was concentrated under reduced pressure and the crude product thus obtained was purified by HPLC to obtain ethyl 2-bromo-5-(4-methoxyphenyl)pentanoate (740 mg).
Reaction SMILES: [CH:1]([C:4]1[NH:12][C:11]2[C:10](=O)[NH:9][C:8](=[O:14])[N:7]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:6]=2[N:5]=1)([CH3:3])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:23].[OH-].[Na+]>N1C=CC=CC=1>[CH:1]([C:4]1[NH:12][C:11]2[C:10](=[S:23])[NH:9][C:8](=[O:14])[N:7]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:6]=2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c([nH]1)c(=O)[nH]c(=O)n2Cc1ccncc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CC(C)c1nc2c([nH]1)c(=S)[nH]c(=O)n2Cc1ccncc1
Temperature: 5 °C
Yield: 136.5 %

Procedure:
1.19 g of 8-isopropyl-3-(4-picolyl)-xanthine and 1.07 g of phosphorus pentasulfide were heated under reflux in 25 ml of pyridine for 4 hours. After cooling to 5° C., 5.28 ml (10.6 mM) of 2N NaOH were added. The solid was filtered off and washed with pyridine. The filtrate was evaporated to dryness, the residue suspended in water and the solid collected, redissolved in 40 ml of 1N NaOH, treated with 0.2 g of charcoal, filtered and neutralized to pH 7.5. The solid was collected, washed and dried to give the title compound (0.99 g) as a white solid mp 310-14° C. (decomposition);
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([CH2:17][CH:18]([CH3:20])[CH3:19])[N:5]([P:13]([CH3:16])([CH3:15])=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:22][O:23][K].Cl>>[OH:23][NH:22][C:3](=[O:2])[C@H:4]([N:5]([P:13]([CH3:16])([CH3:15])=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:17][CH:18]([CH3:20])[CH3:19]
Reactant: COC(=O)[C@@H](CC(C)C)N(Cc1ccccc1)P(C)(C)=O
Reactant: NO[K]
Agent: Cl
Product: CC(C)C[C@H](C(=O)NO)N(Cc1ccccc1)P(C)(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-(Dimethylphosphinyl)-N-benzyl-D-leucine methyl ester (158 mg, 0.51 mmol) is treated with a solution of NH2OK (2.8 mL, 1.76M in methanol) prepared as described in Fieser and Fieser, Vol. 1, p. 478). The reaction is allowed to stir 3 hours at room temperature at which time is determined complete by TLC. The reaction mixture is neutralized with 1M aqueous HCl; the volatiles are removed until the product oils out. Methanol is then added followed by water dropwise until the solution appears cloudy. The crystals are collected by filtration to give N-hydroxy-2(R)-[[dimethylphosphinyl]benzylamino]-4-methyl-pentanamide as a colorless solid: MS-IS m/z 313 [M+H]+, 335 [M+Na]+, 357 [M+K]+. (R2 =isobutyl, R1 =benzyl, R3 =methyl, R4 =phenyl).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH3:15])[CH:7]=1.[CH3:17][S:18]([C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:24]([OH:26])=O)(=[O:20])=[O:19]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:15])[C:24](=[O:26])[C:23]2[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=[C:21]([S:18]([CH3:17])(=[O:19])=[O:20])[CH:22]=2)[CH:7]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1cc(F)ccc1C
Product: Cc1ccc(F)cc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(5-fluoro-2-methyl-phenyl)-pyridin-3-yl]-methyl-amine and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (example 114, intermediate a) after a reaction time of 20.5 hours. The compound was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Colorless foam (20%). MS (ESI): m/z=467.10 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7](Cl)=C(C2C=CC(OC)=CC=2)N=C(C(Cl)=O)[CH:3]=1.[F-].[K+].[F:22][C:23]1[C:28]([F:29])=[C:27]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[N:26]=[C:25]([C:38](F)=[O:39])[CH:24]=1.C(N(CC)CC)C.C([OH:51])(C)C>S1(CCCC1)(=O)=O.O>[F:22][C:23]1[C:28]([F:29])=[C:27]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[N:26]=[C:25]([C:38]([O:39][CH:2]([CH3:7])[CH3:3])=[O:51])[CH:24]=1
Reactant: COc1ccc(-c2nc(C(=O)F)cc(F)c2F)cc1
Reactant: COc1ccc(-c2nc(C(=O)Cl)cc(Cl)c2Cl)cc1
Reactant: CC(C)O
Agent: [F-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: COc1ccc(-c2nc(C(=O)OC(C)C)cc(F)c2F)cc1
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 25 %

Procedure:
To a solution of 4,5-dichloro-6-(4-methoxyphenyl)-picolinoyl chloride (2.5 g, 7.9 mmol) in sulfolane (40 mL, dried over 4 Å molecular sieves, 100 ppm of water) was added potassium fluoride (2.75 g, 47.4 mmol). The reaction mixture was heated at 150° C. for 24 h. Additional potassium fluoride (1.4 g, 24 mmol) was added and reaction mixture was heated at 150° C. for an additional 24 h. Reaction mixture was analyzed by GC-MS and 19F NMR. (Data for 4,5-difluoro-6-(4-methoxyphenyl)-picolinoyl fluoride, GC-MS: m/z=267, 224, 176; 19F NMR (376 MHz, toluene) δ 16.94 (s), −124.65 (d, J=19.1 Hz), −141.23 (d, J=19.1 Hz). Reaction was allowed to cool to room temperature and triethylamine (1.4 mL, 9.9 mmol) and isopropanol (0.9 mL, 11.9 mmol) were added. After stirring for 1.5 h, the reaction mixture was diluted with water (125 mL) and transferred to a reparatory funnel. The reaction mixture was extracted with methyl tert-butyl ether (MTBE, 2×75 mL). The combined organic extracts were washed with water (3×75 mL) and saturated NaCl (75 mL) and concentrated under reduced pressure to provide a brown oil. The crude product oil was purified by silica gel flash chromatography (hexane/ethyl acetate gradient, 100% hexane→20% hexane/ethyl acetate) to provide 0.60 g (25% yield) of isopropyl 4,5-difluoro-6-(4-methoxyphenyl)-picolinate as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.08-8.01 (m, 2H), 7.82 (dd, J=9.5, 5.2 Hz, 1H), 7.04-6.97 (m, 2H), 5.30 (hept, J=6.3 Hz, 1H), 3.86 (s, 3H), 1.42 (d, J=6.3 Hz, 6H), 13C NMR (101 MHz, CDCl3) δ 162.93 (s), 161.22 (s), 156.68 (dd, J=263.5, 12.7 Hz), 147.70 (dd, J=267.9, 10.9 Hz), 146.61 (dd, J=286.4, 10.5 Hz), 145.18 (s), 130.53 (d, J=6.6 Hz), 126.43, 114.02 (s), 112.77 (d, J=16.1 Hz), 69.99 (s), 55.32 (s), 21.82 (s), 19F NMR (376 MHz, CDCl3) δ −125.81 (d, J=17.7 Hz), −145.30 (d, J=19.1 Hz), LRMS. Calcd. for C16H15F2NO3: 307.10. Found: m/z=307 (M+), 221, 206.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([CH2:12][NH2:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[OH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][CH:22]=1>CN(C=O)C>[NH2:13][CH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][CH:22]=1
Reactant: NCc1cccc2c(Cl)ccnc12
Reactant: NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NCc1cccc2c(Oc3ccc(C(N)=O)cc3)ccnc12
Temperature: 100 °C

Procedure:
A mixture of C-(4-chloroquinolin-8-yl)methylamine (Preparation 89) (129 mg, 0.67 mmol), K2CO3 (186 mg, 1.34 mmol) and 4-hydroxybenzamide (110 mg, 0.81 mmol) in DMF (4 mL) were heated in a microwave at 100° C. for 40 min (150 W). Solvent removed in vacuo. The mixture was partitioned between EtOAc (50 mL) and water (20 mL), and the aqueous phase was further extracted with EtOAc (2×20 mL). The combined organic phase was washed with brine (20 mL) and dried (MgSO4). Solvent was removed in vacuo and the residue purified by column chromatography (0.25% to 0.75% NH4OH(aq), 2% to 8% MeOH in DCM) to give the title compound: RT=2.15 min; m/z (ES+)=294.1 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]([CH3:15])[CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][C:20]=1[C:28]([F:31])([F:30])[F:29].C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:2][C:3]2[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH3:15])[CH:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:16][CH:17]=2)=[O:24])=[CH:21][C:20]=1[C:28]([F:29])([F:30])[F:31]
Reactant: O=C(O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(Cc1ccc(NC(=O)c2ccc(Cl)c(C(F)(F)F)c2)cc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
EDIC hydrochloride (0.33 mmol, 0.07 g) was added in one portion to a suspension of (4-amino-benzyl)-methyl-(tetrahydro-pyran-4-yl)-amine Compound 1d (0.25 mmol, 0.06 g), 4-chloro-3-trifluoromethyl-benzoic acid Compound 7a (0.22 mmol, 0.05 g) and HOBt (0.22 mmol 0.03 g) in DMF (5.0 mL) at 0° C. The resulting suspension was warmed to r.t. and a crystal of DMAP and Et3N (0.65 mmol, 0.1 mL) were added. The mixture was stirred overnight and produced an orange-yellow suspension. The suspension was poured into water and the aqueous layer was extracted with EtOAc (25 mL). The organic layer was washed with water (2×20 mL), then a solution of 5% NaOH (10 mL) and brine. The organic layer was separated, dried over Na2SO4 and filtered. The solvent was removed in vacuo to yield a residue, which was purified via preparative TLC (15:1 CH2Cl2:MeOH) to provide 4-chloro-N-(4-{[methyl-(tetrahydro-pyran-4-yl)-amino]-methyl}-phenyl)-3-trifluoromethyl-benzamide Compound 7b (0.06 g, 63%) as a pale yellow solid. MS m/e 427 (M+H, 100%).
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].CCN(C(C)C)C(C)C.C1N=CN([C:19](N2C=NC=C2)=[O:20])C=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([NH:39][CH2:40][C:41]2[CH:45]=[CH:44][S:43][CH:42]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C([O-])(O)=O.[Na+]>CC#N>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([N:39]([CH2:40][C:41]2[CH:45]=[CH:44][S:43][CH:42]=2)[C:19]([NH:4][O:2][CH3:3])=[O:20])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CON
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ccsc2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CONC(=O)N(Cc1ccsc1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a suspension of methoxylamine hydrochloride (0.520 g, 6.25 mmol) in CH3CN (15 ml) was added DIPEA (1.09 ml, 6.25 mmol) followed by CDI (1.02 g, 6.25 mmol) and the reaction stirred at rt for 1.5 h after which a solution of the amine from above (0.880 g, 3.12 mmol) in CH3CN (10 ml) was added and the reaction stirred at 60° C. overnight. The solution was cooled, treated with saturated aqueous NaHCO3 (20 ml) and extracted with CH2Cl2 (3×15 ml). The combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification by column chromatography on silica gel (CH2Cl2:MeOH:NH4OH, 96:3:1, v/v/v) gave 4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidine-1-carboxylic acid tert-butyl ester as a white foam (0.95 g, 86%). 1H-NMR (CDCl3) δ 1.43 (s, 9H), 1.54 (m, 1H), 1.75 (d, 2H, J=9.0 Hz), 2.79 (br t, 1H), 3.65 (s, 3H), 4.17 (m, 2H), 4.27 (s, 2H), 6.96 (d, 1H, J=3.0 Hz), 7.08 (s, 1H), 7.11 (s, 1H), 7.36 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][NH2:17])[N:8]=1.[CH:21](OCC)=[O:22]>CCO>[F:20][C:2]([F:1])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][NH:17][CH:21]=[O:22])[N:8]=1
Reactant: CCOC=O
Reactant: NCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Solvent: CCO
Product: NC(=NCC(F)(F)F)Nc1ccnc(SCCCNC=O)n1

Procedure:
A mixture of 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(3-aminopropylthio)pyrimidine (0.3 g.), ethyl formate (5 ml.) and EtOH (2 ml.) was heated under reflux for 48 hours, then evaporated to dryness. The residue was dissolved in N aqueous HCl and the solution washed with EtOAc. The aqueous phase was basified with 10N aqueous NaOH, extracted with EtOAc and the extract dried and evaporated to dryness. The residue was recrystallised from EtOAc to give N-[3-(4-[2-(2,2,2-trifluoroethyl)guanidino]pyrimid-2-ylthio)propyl]formamide (0.2 g.), m.p. 165°-166°.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Cl:23][C:24]1[CH:25]=[C:26]([O:30][CH2:31][CH2:32][CH2:33][Br:34])[CH:27]=[CH:28][CH:29]=1>CC#N>[Br-:34].[Cl:23][C:24]1[CH:25]=[C:26]([O:30][CH2:31][CH2:32][CH2:33][N+:1]23[CH2:6][CH2:5][C:4]([C:9]([OH:10])([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)([CH2:3][CH2:2]2)[CH2:7][CH2:8]3)[CH:27]=[CH:28][CH:29]=1
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Reactant: Clc1cccc(OCCCBr)c1
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCCOc3cccc(Cl)c3)(CC1)CC2
Product: [Br-]
Yield: 74 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0479 g, 0.163 mmol) and 3-bromopropyl 3-chlorophenyl ether (0.0552 g, 0.221 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0655 g, 74.4%). EI-MS m/z 462 (M+) Rt (2.17 min).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]3[N:36]([CH3:37])[N:35]=[CH:34][CH:33]=3)[N:26]=2)=[CH:21][CH2:20]1)[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=1)(C(C)(C)C)(C)C.C(OCC)(=[O:40])C>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C@H:10]([N:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]4[N:36]([CH3:37])[N:35]=[CH:34][CH:33]=4)[N:26]=3)=[CH:21][C:20]2=[O:40])[CH2:9][OH:8])=[CH:12][C:13]=1[F:18]
Reactant: CCOC(C)=O
Reactant: Cn1nccc1Nc1nccc(C2=CCN([C@H](CO[Si](C)(C)C(C)(C)C)c3ccc(Cl)c(F)c3)C=C2)n1
Product: Cn1nccc1Nc1nccc(-c2ccn([C@H](CO)c3ccc(Cl)c(F)c3)c(=O)c2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.6 %

Procedure:
Crude (S)-1-(2-((tert-butyldimethylsilyl)oxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H-one (48 mg) was dissolved in ethyl acetate (4 mL) and treated dropwise slowly (over 2 minutes) with an ethyl acetate solution (1.0 mL, which had been saturated with HCl gas). The reaction stirred at room temperature for 15 minutes, after which time LCMS indicated complete consumption of the starting material. The reaction mixture was concentrated to an oily residue and purified by prep RP HPLC to yield (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (20.8 mg, 54.6% yield) as a lyophilized powder. 1H NMR (400 MHz, (CD3)2SO) δ 9.58 (s, 1H), 8.60 (d, J=5.1 Hz, 1H), 7.91 (t, J=9.0 Hz, 1H), 7.58 (t, J=8.1 Hz, 1H), 7.52-7.41 (m, 2H), 7.37 (d, J=1.8 Hz, 1H), 7.14 (dd, J=10.7, 5.1 Hz 2H), 6.86 (dd, J=7.3, 1.8 Hz, 1H), 6.27 (d, J=1.7 Hz, 1H), 5.97 (dd, J=7.7, 5.7 Hz, 1H), 5.31 (t, J=5.2 Hz, 1H), 4.15 (m, 1H), 4.10-3.95 (m, 1H), 3.69 (s, 3H); LCMS m/z 441 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[N:9]=[C:8]([CH3:10])[NH:7][C:6]=2[CH:11]=1.[H-].[Na+].[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[N:9]=[C:8]([CH3:10])[N:7]([S:29]([C:26]3[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][CH:25]=3)(=[O:31])=[O:30])[C:6]=2[CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1nc2c(OCc3ccccc3)cc(Br)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2c(C)nc3c(OCc4ccccc4)cc(Br)cc32)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.4 %

Procedure:
To a suspension of 6-bromo-2-methyl-4-[(phenylmethyl)oxy]-1H-benzimidazole (79.2 g, 250 mmol, STEP 1) in N,N-dimethylformamide (500 mL) was added sodium hydride (60% in mineral oil, 12.0 g, 300 mmol) at 0° C. After stirring at room temperature for 20 minutes, the reaction mixture was cooled to 0° C. To the mixture was added 4-methylbenzenesulfonyl chloride (47.6 g, 250 mmol) at 0° C., and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was quenched with water (800 mL), and the white precipitates were collected by filtration, washed with diisopropyl ether (500 mL), and dried in vacuum at 70° C. for 7 hours to afford the title compound as a white solid (116 g, 98%).
Reaction SMILES: [CH:1]1([N:7]([C@H:19]2[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.SC[C@@H]([C@@H](CS)O)O.[N:34](=[CH:42][CH2:43]Cl)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]Cl>>[N:34]1([CH2:42][CH2:43][S:16][C:13]2[S:12][C:11]([NH:10][C:8](=[O:9])[N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C@H:19]3[CH2:20][CH2:21][C@H:22]([CH3:25])[CH2:23][CH2:24]3)=[N:15][CH:14]=2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: ClCC=NCCCCCCCl
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(SC#N)s2)C2CCCCC2)CC1
Agent: O[C@H](CS)[C@@H](O)CS
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCCN3CCCCCC3)s2)C2CCCCC2)CC1

Procedure:
Prepared as described in general procedure (H) using 1-cyclohexyl-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and 2-(hexamethyleneimino)ethyl chloride.