Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:29])[C:10]=1[C:11](=[O:28])[NH:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([N:19]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:21]=2)[CH:18]=1)=[O:5])C.O.[OH-].[Li+]>CO.O>[CH3:29][N:9]1[C:10]([C:11](=[O:28])[NH:12][C:13]2[CH:14]=[CH:15][C:16]3[N:17]([N:19]=[C:20]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[N:21]=3)[CH:18]=2)=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccc2nc(N3CCOCC3)nn2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(N3CCOCC3)nn2c1
Temperature: 55 °C
Reaction time: 18 h
Yield: 70.9 %

Procedure:
A mixture of 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid ethyl ester (282 mg, 0.71 mmol) and lithium hydroxide hydrate (88.9 mg, 2.12 mmol) in methanol (10 ml) and water (3 ml) was stirred for 18 hours at 55° C. The solvents were evaporated under reduced pressure and the residue treated with water (5 ml) and hydrogen chloride (1 molar in water, 2.12 ml). The precipitated solid was filtered off, washed with water and dried under reduced pressure, affording 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (187 mg, 71%) as light brown solid. Mp.: 294° C. MS: m/z=372.0 (M+H+).
Reaction SMILES: C(N(CC)CC)C.C(O)=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1OS(C(F)(F)F)(=O)=O)[CH:16]=[O:17]>CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].CN(C=O)C>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17]
Reactant: COc1cc(C=O)ccc1OS(=O)(=O)C(F)(F)F
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cccc(C=O)c1
Temperature: 80 °C

Procedure:
To a round-bottomed flask equipped with magnetic stirring bar was charged DMF (5 mL) and triethylamine (2.81 g, 27.8 mmol). Next, 98% formic acid (1.28 g, 27.8 mmol) was added dropwise over 1 min. Then, 2a (1 g, 3.5 mmol) was added followed by Pd(OAc)2 (30 mg, 0.13 mmol) and DPPF (150 mg, 0.27 mmol). All the solids dissolved to give a clear orange solution. The mixture was then heated to 80° C. and after about 15 min a yellow solid precipitated. The mixture was cooled to room temperature and filtered. The filtrate was partitioned between Et2O (25 mL) and H2O (25 mL). The organic layer was further washed with H2O (25 mL) followed by brine. The organic phase was dried over anhydrous MgSO4 and evaporated under reduced pressure to yield a brown oil. Distillation under reduced pressure (0.1 torr) gave 3a as a colorless, mobile liquid (400 mg, 85%), lit. bp. 121° C./14 torr. 1H NMR (CDCl3): δ 9.97 (s, 1H), 7.47-7.42 (m, 2H), 7.39-7.37 (m, 1H), 7.20-7.14 (m, 1H), 3.86 (s, 3H); 13C NMR (CDCl3): δ 192.29, 160.38, 138.03, 130.22, 123.71, 121.70, 112.28, 55.67. Anal. Calcd for C8H8O2: C, 70.57; H, 5.92. Found: C, 70.27; H, 5.95.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17]([O:19][CH3:20])=[N:16][CH:15]=[N:14][C:13]=2[C:12]([CH2:21][NH:22][C@H:23]([C@H:29]([OH:35])[C:30](OCC)=[O:31])[C:24](OCC)=[O:25])=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+]>C(OCC)C.CO>[CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17]([O:19][CH3:20])=[N:16][CH:15]=[N:14][C:13]=2[C:12]([CH2:21][NH:22][C@@H:23]([CH2:24][OH:25])[C@H:29]([OH:35])[CH2:30][OH:31])=[CH:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@H](O)[C@@H](NCc1cn(COCc2ccccc2)c2c(OC)ncnc12)C(=O)OCC
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CO
Product: COc1ncnc2c(CN[C@@H](CO)[C@H](O)CO)cn(COCc3ccccc3)c12

Procedure:
To a stirred solution of the product from Example 15.1 (0.166 g, 0.34 mmol) in diethyl ether (10 ml) was added methanol (0.14 ml, 3.41 mmol) and then lithium borohydride (0.85 ml, 1.71 mmol, 2.0M in THF). After 30 mins the reaction mixture was diluted with methanol and then concentrated. The residue was dissolved in methanol, diluted with concentrated aqueous ammonia (1 ml) and evaporated on to silica gel. The material was chromatographed on silica gel (DCM-methanol-conc. ammonia, 85:15:2, then 70:30:2, then 50:50:4). This gave three distinct compounds; firstly the title compound and then two different salt forms of the title compound. The three compounds were combined to give a colourless oil (0.103 g, 75%). 1H NMR (CD3OD) δ 8.42 (s, 1H), 7.64 (s, 1H), 7.28-7.16 (m, 5H), 5.75 (s, 2H), 4.50 (s, 2H), 4.10 (s, 3H), 3.83-3.68 (m, 3H), 3.63 (d, J=5.5 Hz, 2H), 3.31 (pentet, J=1.6 Hz, 1H).
Reaction SMILES: C([S:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@H:6]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:7]([O:9][CH3:10])=[O:8])(=O)C.[OH-].[Na+].Cl>CO>[C:15]([O:14][C:12]([NH:11][C@@H:6]([C@@H:5]([SH:4])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:7]([O:9][CH3:10])=[O:8])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](SC(C)=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](S)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.8 %

Procedure:
The acetylated thiol 7 (290 mg, 0.82 mmol) was dissolved in methanol (4 mL) and NaOH was added (4.1 mL, 0.2N aqueous). The reaction was stirred at room temperature for 20 min (monitored by TLC). The solution was then carefully neutralized with dilute HCl. The volatiles were removed in vacuo and the residue was extracted with Cl2CH2 (3×). The organic layer was washed with brine and dried over Na2SO4. The crude product was purified by flash column chromatography (silica, 10% ethyl acetate/hexane) to give the desired thiol 9 (242 mg, 95%) as a white solid. mp 76°-77° C. (ether-hexane); [α]20D =+92.3 (c=0.96, CHCl3); 1H NMR (CDCl3).δ1.392 (s, 9H), 2.207 (d, J=7.3 Hz, SH), 3.698 (s, 3H), 4.471 (dd, J=6.7, 6.3 Hz, 1H, CH--S), 4.800 (dd, J=8.7, 6.3 Hz, 1H, CH--N), 5.059 (bd, J=8.7 Hz, 1H, NH), 7.370-7.282 (m, 5H); 13C NMR (CDCl3).δ28.0, 52.1, 59.5, 80.1, 127.5, 127.6, 128.8, 138.8, 155.9, 171.5; IR (KBr) 3335, 2990, 1740, 1685, 1530, 1165 cm-1 ; MS m/z 312 [M+H]+ ;. Anal. Calcd. for C15H21O4NS: C, 57.88; H, 6.75. Found: C, 58.08; H, 6.88.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][F:6].[F:7][C:8]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].C(O)C.[OH-].[K+]>O>[F:7][C:8]1[CH:16]=[C:15]([O:17][CH2:2][CH2:3][CH2:4][CH2:5][F:6])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: FCCCCBr
Reactant: O=C(O)c1ccc(O)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(OCCCCF)cc1F
Temperature: 80 °C
Reaction time: 17 h
Yield: 39.1 %

Procedure:
1-Bromo-4-fluorobutane (3.57 g, 23.1 mmol) was added dropwise to a mixture of 2-fluoro-4-hydroxybenzoic acid (3.00 g, 19.2 mmol), ethanol (11.5 ml) and water (2.3 ml), potassium hydroxide (2.37 g, 42.3 mmol) at 80° C., and the mixture was stirred at 80° C. for 17 hrs. The solvent was evaporated under reduced pressure. The residue was dissolved in water and the solution was acidified by adding 1N hydrochloric acid. The insoluble materials were filtered off and dried to give the title compound (1.73 g) as a pale-brown powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[N:8][N:9]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:10]=2[CH:11]=[C:12](Br)[CH:13]=1)=[O:4].[CH3:22][N:23](C=O)C>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].[C-]#N.[Zn+2].[C-]#N.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].[Zn]>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[N:8][N:9]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:10]=2[CH:11]=[C:12]([C:22]#[N:23])[CH:13]=1)=[O:4]
Reactant: COC(=O)c1cc(Br)cc2c1cnn2-c1ccc(F)cc1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COC(=O)c1cc(C#N)cc2c1cnn2-c1ccc(F)cc1
Temperature: 120 °C

Procedure:
A sealed tube was charged with 6-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid methyl ester (1.5 g, 4.3 mmol), Pd2(dba)3 (0.4 g, 0.4 mmol), zinc cyanide (0.6 g, 5 mmol), dppf (0.3 g, 0.4 mmol) and zinc powder (0.2 g, 3 mmol) and DMF (20 mL). The reaction solution was degassed with argon for 15 minutes and warmed at 120° C. for 3 hours. The reaction was cooled to room temperature, diluted with saturated aqueous ammonium chloride (10 mL) and ethyl acetate (50 mL). The organic layer was separated and washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-20% ethyl acetate in hexanes to afford 6-cyano-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid methyl ester.
Reaction SMILES: C([O:8][C:9]([CH2:11][C:12]1[CH:13]=[C:14]([NH:18][C:19](=[O:57])[NH:20][CH2:21][C:22]([N:24]2[CH:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[F:35])[CH:27]([S:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)(=[O:38])=[O:37])[CH2:26][CH:25]2[C:45]([N:47]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH2:50][CH2:49][CH2:48]2)=[O:46])=[O:23])[CH:15]=[CH:16][CH:17]=1)=[O:10])C1C=CC=CC=1>C(O)C.[Pd]>[F:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH:28]1[N:24]([C:22](=[O:23])[CH2:21][NH:20][C:19](=[O:57])[NH:18][C:14]2[CH:13]=[C:12]([CH2:11][C:9]([OH:10])=[O:8])[CH:17]=[CH:16][CH:15]=2)[CH:25]([C:45]([N:47]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH2:50][CH2:49][CH2:48]2)=[O:46])[CH2:26][CH:27]1[S:36]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)(=[O:37])=[O:38]
Reactant: O=C(NCC(=O)N1C(C(=O)N2CCCc3ccccc32)CC(S(=O)(=O)c2ccccc2)C1c1ccccc1F)Nc1cccc(CC(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)Cc1cccc(NC(=O)NCC(=O)N2C(C(=O)N3CCCc4ccccc43)CC(S(=O)(=O)c3ccccc3)C2c2ccccc2F)c1
Yield: 66.6 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 2A, but from 2.83 g of (2RS,4SR,5RS)-1-{2-[3-(3-(benzyloxycarbonylmethyl)phenyl)ureido]acetyl}-5-(2-fluorophenyl)-2-(1,2,3,4-tetrahydro-1-quinolylcarbonyl)-4-(phenylsulphonyl)pyrrolidine and 0.36 g of 10% palladium-on-charcoal in 150 cm3 of ethanol. After treatment, there are obtained 1.67 g of (2RS,4RS,5SR)-3-{3-[2-(5-(2-fluorophenyl)-2-(1,2,3,4-tetrahydro-1-quinolylcarbonyl)-4-(phenylsulphonyl)-1-pyrrolidinyl)-2-oxoethyl]ureido}phenylacetic acid [Rf =0.49; eluent: methylene chloride/methanol (90/10)].
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH:17]([N:20]([CH:24]([CH3:26])[CH3:25])[C:21](Cl)=[O:22])([CH3:19])[CH3:18].O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:21]([N:20]([CH:24]([CH3:26])[CH3:25])[CH:17]([CH3:19])[CH3:18])=[O:22])=[N:6][CH:7]=1
Reactant: CC(C)N(C(=O)Cl)C(C)C
Reactant: NNc1ccc(F)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)N(C(=O)NNc1ccc(F)cn1)C(C)C
Temperature: 45 °C
Yield: 50.1 %

Procedure:
To a solution of (5-fluoro-pyridin-2-yl)-hydrazine (for reference procedure see WO2010022076; 200 mg, 1.57 mmol) in DCM (15 mL) was added triethylamine (328 μL, 2.35 mmol) followed by N,N-diisopropylcarbamoyl chloride (282 mg, 1.73 mmol). The reaction mixture was heated at 45° C. for 4 h then poured into water and extracted with DCM (×3). The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-100% EtOAc in cyclohexane, to afford the title compound (200 mg, 50%). 1H NMR (400 MHz, CDCl3): 1.30 (12H, d, J=6.8 Hz), 3.80-4.03 (2H, m), 6.17 (1H, s), 6.53 (1H, s), 6.67-6.81 (1H, m), 7.24-7.36 (1H, m), 8.02 (1H, d, J=3.0 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:10](=[O:17])[C@@H:9]([CH2:18][C:19]([O:21]CC)=[O:20])[O:8][C@H:7]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[C:6]=2[CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:10](=[O:17])[C@@H:9]([CH2:18][C:19]([OH:21])=[O:20])[O:8][C@H:7]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[C:6]=2[CH:30]=1
Reactant: CCOC(=O)C[C@H]1O[C@H](c2ccccn2)c2cc(Br)ccc2N(CC(C)(C)C)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)CN1C(=O)[C@@H](CC(=O)O)O[C@H](c2ccccn2)c2cc(Br)ccc21
Yield: 69.9 %

Procedure:
In 20 ml of methanol was dissolved 1.9 g of ethyl trans-7-bromo-1-neopentyl-5-(2-pyridyl)-2-oxo-1,2,3,5- tetrahydro-4,1-benzoxazepine-3-acetate obtained in Example 131. To the solution was added 10 ml of an aqueous solution containing 1.1 g of potassium carbonate. The mixture was heated and refluxed for 30 minutes, and then concentrated under reduced pressure. The concentrate was crystallized by the addition of 30 ml of a hydrochloric acid aqueous solution. The product was collected by filteration and recrystallized from hexane and ethanol to give 1.25 g of trans-7-bromo-1-neopentyl-5-(2-pyridyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid as prisms, m.p. >263° C. (decomp.)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][S:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1.S(=O)(=O)(O)O.[CH3:20]O>>[CH3:20][O:11][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:6]([S:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][CH:8]=1
Reactant: CO
Reactant: COCCSc1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Product: COCCSc1ccc(C(=O)OC)cc1
Yield: 78 %

Procedure:
4-(2-Methoxy-ethylsulfanyl)-benzoic acid was esterified in methanol by adding catalytic amount of sulfuric acid. Subsequent work up afforded 4 g of desired product in 78% yield.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:2].[NH2:18][OH:19]>CCO>[NH2:2][C:1](=[N:18][OH:19])[C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CCCOc1cccc(C#N)c1
Reactant: NO
Solvent: CCO
Product: CCOC(=O)CCCOc1cccc(C(N)=NO)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.1 %

Procedure:
Ethyl 4-(3-cyanophenoxy)butanoate (3.79 g; 16.25 mmol; 1 eq.) was suspended in EtOH (75.80 mL). Hydroxylamine (2.40 mL; 81.24 mmol; 5 eq.) was added in one portion and the reaction mixture was stirred at RT for 24 hours. The reaction mixture was concentrated affording the title compound as a white solid (4.29 g, 99%). 1H NMR (DMSO-d6, 300 MHz) δ 9.61 (br s, 1H), 7.27-7.20 (m, 3H), 6.94-6.90 (m, 1H), 5.79 (br s, 2H), 4.11-3.98 (m, 4H), 2.48-2.44 (t, J=7.15 Hz, 2H), 2.01-1.93 (m, 2H), 1.20-1.15 (t, J=7.03 Hz, 3H). LC/MS (Method A): 266.8 (M+H)+. HPLC (Method A) Rt 2.62 min (Purity: 98.8%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH2:22]([C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][CH:30]2[CH2:32][O:31]2)=[CH:26][CH:25]=1)[CH3:23]>>[CH2:22]([C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][CH:30]([OH:31])[CH2:32][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[CH:26][CH:25]=1)[CH3:23]
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: CCc1ccc(OCC2CO2)cc1
Product: CCc1ccc(OCC(O)CN2CCC3(CC2)CSC2=C(O3)c3ccccc3C(=O)C2=O)cc1

Procedure:
Compound 170 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-[(4-ethylphenoxy)methyl]oxirane and conditions outlined in procedure X. LCMS: 480 [M+H]; Rt=1.09 min.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:14][CH3:15])[C:11](=[O:13])[CH3:12])=[C:6]([CH3:16])[CH:5]=1.Cl.[N:18]1([C:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[S:26][N:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[S:26]1[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:24]([N:18]2[CH2:19][CH2:20][N:21]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][C:7]([N:10]([CH2:14][CH3:15])[C:11](=[O:13])[CH3:12])=[C:6]([CH3:16])[CH:5]=3)[CH2:22][CH2:23]2)=[N:25]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: CCN(C(C)=O)c1ccc(CCCl)cc1C
Agent: Cl
Product: CCN(C(C)=O)c1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1C
Yield: 70 %

Procedure:
Starting with N-[4-(2-chloro-ethyl)-2-methyl-phenyl]-N-ethyl-acetamide (0.169 g, 0.706 mmol) and 3-piperazin-1-yl-benzo[d]isothiazole hydrochloride (0.271 g, 1.059 mmol) and following the procedure as outlined in Example 501, N-{4-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-2-methyl-phenyl}-N-ethyl-acetamide (0.227 g, 0.494 mmol) was isolated in 100% purity @ 254 nm; LCMS (APCI): 423 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 11.37 (bs, 1H), 8.13 (d, J=7.84 Hz, 1H), 8.09 (d, J=7.84 Hz, 1H), 7.57 (t, J=7.12 Hz, 1H), 7.45 (t, J=7.12 Hz, 1H), 7.28 (s, 1H), 7.23–7.11 (m, 2H), 4.07 (bd, J=13.09 Hz, 2H), 3.88 (sextet, J=6.23 Hz, 1H), 3.66 (bd, J=11.22 Hz, 2H), 3.51 (bt, J=11.22 Hz, 2H), 3.45–3.37 (m, 2H), 3.35 (bs, DMSO-H2O), 3.33–3.22 (m, 3H), 2.14 (s, 3H), 1.58 (s, 3H), 0.97 (t, J=7.11 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C@H:4]([CH2:28][CH2:29][S:30][CH3:31])[NH:5][C:6](=[O:27])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[CH:9][C:8]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:32])[C@H:4]([CH2:28][CH2:29][S:30][CH3:31])[NH:5][C:6](=[O:27])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[CH:9][C:8]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26]
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C=Cn2ccnc2)cc1-c1ccccc1C
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CCn2ccnc2)cc1-c1ccccc1C
Reaction time: 5 h
Yield: 56.5 %

Procedure:
A mixture of the product of Example 278A (171 mg, 0.38 mmol) and palladium (10%) on carbon (489 mg, 0.46 mmol of palladium) in methanol was flushed with hydrogen, and stirred under a hydrogen balloon for 5 hours. The mixture was then filtered through Celite, rinsed, with ethyl acetate, and concentrated in vacuo. The residue was purified by column chromatography (5% methanol-ethyl acetate) to give the title compound (97 mg, 56%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[B:14](OC)([O:17]C)[O:15]C>>[F:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:5]=[CH:6][C:7]=1[B:14]([OH:17])[OH:15]
Reactant: Fc1ccccc1-c1ccccn1
Reactant: COB(OC)OC
Product: OB(O)c1cccc(-c2ccccn2)c1F

Procedure:
2-(2-Fluorophenyl)pyridine was lithiated and reacted with trimethyl borate as described in Example 31 to give 2-fluoro-3-(pyridin-2-yl)benzeneboronic acid as a white solid: m/z (ES+) 218 (M++H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH2:17]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]2)=[CH:30][CH:29]=1)(=[O:27])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][CH:37]([NH:1][CH2:2][CH:3]([OH:4])[C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[CH2:36][CH2:35]2)=[CH:30][CH:29]=1)(=[O:26])=[O:27])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1CCN(c2ccc(S(=O)(=O)NCc3ccccc3)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc(C(O)CNC2CCN(c3ccc(S(=O)(=O)NCc4ccccc4)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from N-[5-(2-Amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide and Reference Example 70, N-benzyl-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, according to the procedure of Example 1 as an off-white solid. 1H NMR (DMSO) δ 1.33 (m, 2H), 1.86 (m, 2H), 2.67(m, 3H), 2.89(s, 3H), 2.99(m, 2H), 3.69(m, 2H), 3.85(s, 2H), 4.49(m, 1H), 6.83 (d, 1H, J=6.0 Hz), 7.00(m, 2H), 7.19 (s, 1H), 7.24 (m, 6H), 7.56 (d, 2H, J=6.6 Hz); MS (ES) m/z: 575.1 (MH+); HRMS for C27H34N4O6S2: 575.2015 (MH+)
Reaction SMILES: CN1CCOCC1.OC(C(F)(F)F)=O.[N:15]1([C:21]2[N:26]=[CH:25][C:24]([C:27]3[CH:28]=[N:29][C:30]4[N:31]([C:33]([C:36]5([C:39]6[CH:40]=[C:41]7[C:46](=[CH:47][CH:48]=6)[N:45]=[CH:44][CH:43]=[CH:42]7)[CH2:38][CH2:37]5)=[CH:34][N:35]=4)[CH:32]=3)=[CH:23][CH:22]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.Cl[C:50]([O:52][CH3:53])=[O:51]>C(#N)C.CO>[N:45]1[C:46]2[C:41](=[CH:40][C:39]([C:36]3([C:33]4[N:31]5[CH:32]=[C:27]([C:24]6[CH:23]=[CH:22][C:21]([N:15]7[CH2:16][CH2:17][N:18]([C:50]([O:52][CH3:53])=[O:51])[CH2:19][CH2:20]7)=[N:26][CH:25]=6)[CH:28]=[N:29][C:30]5=[N:35][CH:34]=4)[CH2:38][CH2:37]3)=[CH:48][CH:47]=2)[CH:42]=[CH:43][CH:44]=1
Reactant: c1cnc2ccc(C3(c4cnc5ncc(-c6ccc(N7CCNCC7)nc6)cn45)CC3)cc2c1
Reactant: COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COC(=O)N1CCN(c2ccc(-c3cnc4ncc(C5(c6ccc7ncccc7c6)CC5)n4c3)cn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Methylmorpholine (19.3 μL, 0.175 mmol) was added to a solution of 6-{1-[6-(6-piperazin-1-ylpyridin-3-yl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinoline TFA salt (25.0 mg, 0.0292 mmol) in acetonitrile (0.8 mL), followed by addition of methyl chloroformate (3.39 μL, 0.0438 mmol). The mixture was stirred at RT for 30 min, and was diluted with methanol (1.0 mL). The resulting solution was purified by RP-HPLC (pH=10) to give the desired product. LCMS: (M+H)=506.1.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:16])([F:15])[C:7]1[N:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][CH:8]=1>C(Cl)Cl>[Cl:3][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]([F:16])([F:15])[F:5])=[N:12][CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(C(F)(F)F)nc1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(CCl)cn1

Procedure:
Thionyl chloride (40.3 mL, 554 mmol) was slowly added to a solution of (6-trifluoromethylpyridin-3-yl)-methanol (19.6 g, 111 mmol) in DCM (195 mL) at room temperature under nitrogen. The reaction mixture was stirred at reflux for 16 hours then concentrated under reduced pressure. The residue was dissolved in AcOEt (200 mL), washed with saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give crude 5-chloromethyl-2-trifluoromethylpyridine as a brown oil which was used in the following step without further purification (19.5 g, 90%). 1H NMR (400 MHz, CDCl3) δ ppm 8.74 (s, 1 H), 7.94 (d, J=8.4 Hz, 1 H), 7.72 (d, J=8.4 Hz 1H), 4.66 (s, 2 H). 19F NMR (400 MHz, CDCl3) δ 168 cm−1. MS m/z 196.15; 198.09
Reaction SMILES: [CH:1]1([CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2/[C:17](=[N:19]/[OH:20])/[NH2:18])(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CC[O:25][CH2:24]C1.O.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>C(O)=O>[CH:1]1([CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2/[C:17](=[N:19]/[O:20][CH:24]=[O:25])/[NH2:18])(=[O:9])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN1CCOCC1
Reactant: N/C(=N\O)[C@@H]1CCCCN1S(=O)(=O)CC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O=CO
Solvent: O
Product: N/C(=N\OC=O)[C@@H]1CCCCN1S(=O)(=O)CC1CCCCC1

Procedure:
The title compound was prepared by a similar method to Preparation 5 from (Z)-(2S)-1-[cyclohexylmethylsulfonyl]-N′2-hydroxy-2-piperidinecarboximidamide [see Preparation 28], formic acid, N-methyl morpholine, hydroxybenzotriazole hydrate and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, to afford (Z)-(2S)-1-[(cyclohexylmethyl)sulfonyl]-N′2-(formyloxy)-2-piperidinecarboximidamide as a colourless oil.