Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([CH2:13][O:14][CH:15]([F:17])[F:16])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(OCC)(=O)C>[CH2:6]([NH:5][C:3](=[O:4])[C@H:2]([NH:1][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:13][O:14][CH:15]([F:16])[F:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: N[C@H](COC(F)F)C(=O)NCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N[C@H](COC(F)F)C(=O)NCc1ccccc1
Reaction time: 0.25 h
Yield: 22.3 %

Procedure:
A solution of (2R)-2-amino-N-benzyl-3-(difluoromethoxy)propanamide (113 mg, 0.46 mmol) in ethyl acetate was cooled in an ice bath. To the cooled solution was added triethylamine (139 mg, 1.38 mmol) followed by methanesulfonylchloride (63 mg, 0.55 mmol). The reaction mixture was stirred for 15 minutes and then quenched with water, extracted with ethyl acetate and washed with brine. The organic layer was dried, concentrated and triturated with diethyl ether to give the product (33 mg, 22%) as a white solid. 1H NMR (300 MHz, CDCl3): δ(ppm) 7.31 (m, 5H), 6.73 (br, 1H), 6.24 (t, 1H), 5.21 (d, 1H), 4.48 (d, 2H), 4.21 (m, 3H), 3.01 (s, 3H)
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][O:12][C:13](=[O:20])[CH2:14][C:15](=[O:19])[CH2:16][O:17][CH3:18]>N1C=CC=CC=1.C(O)(=O)CCCCC.C1C=CC=CC=1>[CH3:11][O:12][C:13](=[O:20])[C:14](=[CH:4][C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:10])[C:2]=1[Cl:1])[C:15](=[O:19])[CH2:16][O:17][CH3:18]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: COCC(=O)CC(=O)OC
Solvent: CCCCCC(=O)O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COCC(=O)C(=Cc1cccc(Cl)c1Cl)C(=O)OC
Yield: 95.8 %

Procedure:
A solution containing 160 ml of anhydrous benzene, 5 g of 2,3-dichlorobenzaldehyde, 4.2 g of 4-methoxy-3-oxo-butanoic acid methyl ester, 16 drops of pyridine and 22 drops of hexanoic acid is heated under reflux for one hour, removing the water formed. The mixture is then washed with a saturated sodium bicarbonate solution and then with a 0.1N hydrochloric acid solution. The organic phase is taken and evaporated to dryness so as to obtain 8.3 g of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5]O.P(Br)(Br)[Br:13].O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][Br:13]
Reactant: BrP(Br)Br
Reactant: COc1ccc(CO)cc1Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CBr)cc1Cl
Temperature: 25 °C

Procedure:
To a solution of 3-chloro-4-methoxybenzyl alcohol (164 g) in dichloromethane (800 ml) was added phosphorus tribromide (45.1 ml) under ice-cooing and the mixture was stirred at ambient temperature for an hour followed by adding water to the mixture. The separated aqueous layer was extracted with dichloromethane. The combined organic layers were washed with an aqueous saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The oily residue was triturated with n-hexane to obtain 3-chloro-4-methoxybenzyl bromide (200 g) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH3:23][N:24]=[C:25]=[O:26]>C(Cl)Cl>[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:10]2[CH2:15][CH2:14][N:13]([C:25]([NH:24][CH3:23])=[O:26])[CH2:12][CH2:11]2)=[CH:21][CH:20]=1
Reactant: Fc1ccc(NC(c2ccc(F)cc2)C2CCNCC2)cc1
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)N1CCC(C(Nc2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
A mixture of 1.91 g (6.25 mmol) of the N,α-bis(4-fluorophenyl)-4-piperidinemethanamine and 0.45 g (7.9 mmol) of methyl isocyanate in 300 mL of CH2Cl2 was stirred at room temperature overnight. The solvent was removed in vacuo, and the residue was subjected to flash column chromatography (silica gel, gradiently eluted with 1 to 4% CH3OH in CH2Cl2) to give 1.54 g (68.6%) of white solid, mp 86°-90° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[C:5]3[N:14]=[C:13](Cl)[C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:11][N:6]3[N:7]=2)[CH:3]=1.[C:22]([O:26][C:27](=[O:48])[NH:28][C:29]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31][CH2:30]1)([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[Na+].[Na+]>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>[C:22]([O:26][C:27](=[O:48])[NH:28][C:29]1([C:33]2[CH:34]=[CH:35][C:36]([C:13]3[C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:11][N:6]4[N:7]=[C:8]5[C:4]([CH:3]=[C:2]([Br:1])[CH:10]=[CH:9]5)=[C:5]4[N:14]=3)=[CH:37][CH:38]=2)[CH2:30][CH2:31][CH2:32]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: Clc1nc2c3cc(Br)ccc3nn2cc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c5cc(Br)ccc5nn4cc3-c3ccccc3)cc2)CCC1
Yield: 21 %

Procedure:
1 g (2.9 mmol) 9-Bromo-2-chloro-3-phenylpyrimido[1,2-b]indazole (intermediate example Int-1-2), 1.09 g (2.9 mmol) {1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclobutyl}carbamic acid tert-butyl ester, 322 mg (0.28 mmol) tetrakis(triphenylphosphine)palladium and 886 mg (8.4 mmol) sodium carbonate in 30 mL dioxane and 4.2 mL water were heated over night at 105° C. The reaction mixture was poured on water/dichloromethane and vigorously stirred for 30′. The organic phase was separated, washed with brine, dried, filtered, and the solvent was evaporated. The residue was purified by HPLC yielding 346.4 mg (20.6%) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=O.[I-].[Na+].[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][NH:29][C:30]([NH2:32])=[S:31])[CH2:22][CH2:21]1>CC(C)=O.C(=O)([O-])O.[Na+].O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:5]2([C:3]3[N:32]=[C:30]([NH:29][CH2:28][CH2:27][CH2:26][N:23]4[CH2:22][CH2:21][O:20][CH2:25][CH2:24]4)[S:31][CH:2]=3)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[CH:12][CH:13]=1
Reactant: NC(=S)NCCCN1CCOCC1
Reactant: O=C(CCl)C1(c2ccc(Cl)cc2)CCCCC1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Clc1ccc(C2(c3csc(NCCCN4CCOCC4)n3)CCCCC2)cc1
Temperature: 50 °C

Procedure:
A solution of 2-chloro-1-[1-(4-chloro-phenyl)-cyclohexyl]-ethanone (191.5 mg, 0.71 mmol) and sodium iodide (105.8 mg, 0.71 mmol) in acetone (5 mL) was stirred at room temperature for 10 min. Next, 1-(3-morpholinopropyl)-2-thiourea (143.6 mg, 0.71 mmol) was added. The resulting mixture was heated at 50° C. overnight. After the mixture was allowed to cool to room temperature, it was diluted with 5% sodium hydrogen carbonate in water and then extracted with ethyl acetate (3×20 mL). The extracts were combined, and dried over anhydrous sodium sulfate, filtered and concentrated to give an oil. The crude was purified by column chromatography on silica gel using dichloromethane/2 N ammonia in ethanol (95:5) to give {4-[1-(4-chloro-phenyl)-cyclohexyl]-thiazol-2-yl}-(3-morpholin-4-yl-propyl)-amine, 94, as an oil (187.1 mg, 63%). 1H (CDCl3, 300 MHz) δ 7.31-7.21 (m, 4H), 6.01 (s, 1H), 5.93 (s, 1H), 3.70-1.52 (m, 24H) ppm;13C (C6D6, 75 MHz) δ 23.5, 25.5, 26.9, 36.7, 45.7, 46.4, 54.2, 57.7, 67.4, 101.3, 128.8, 129.4, 132.0, 146.8, 160.1, 169.5 ppm.
Reaction SMILES: [CH2:1]([P:3](Cl)([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])[CH:8]=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24])=[O:4])[CH3:2].[OH:27][N:28]=[C:29]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:30]([O:32][CH3:33])=[O:31]>C(Cl)Cl>[CH2:1]([P:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])[CH:8]=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24])([O:27][N:28]=[C:29]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:30]([O:32][CH3:33])=[O:31])=[O:4])[CH3:2]
Reactant: COC(=O)C(=NO)c1ccccc1
Reactant: CCP(=O)(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Solvent: ClCCl
Product: CCP(=O)(ON=C(C(=O)OC)c1ccccc1)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Following the procedure of Example 2, P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinic chloride is reacted with methyl 2-hydroxyimino-2-phenylacetate (357 mg, 1.5 eq.) in methylene chloride, with stirring at RT for 24 hours. The reaction is worked up and purified as in Example 2 to give methyl 2-[P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinyloxyimino]-2-phenylacetate.
Reaction SMILES: N.[H][H].[CH3:4][C:5]1[C:15]([CH3:16])=[C:14]([CH2:17][CH2:18][O:19][CH2:20][CH3:21])[CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]=[N:10]O>[Ni].CO>[CH3:4][C:5]1[C:15]([CH3:16])=[C:14]([CH2:17][CH2:18][O:19][CH2:20][CH3:21])[CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH2:9][NH2:10]
Reactant: CCOCCc1ccc(OCC=NO)c(C)c1C
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CCOCCc1ccc(OCCN)c(C)c1C
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
Into a 20-liter autoclave charged were Raney nickel prepared (50 g as 50% alloy), 10 liters of methanol and 1.5 kg of liquid ammonia. After the hydrogen pressure was adjusted to 20 atm., the mixture was heated to 100° C. with stirring and stirred for one hour. Into the mixture of activated Raney nickel thus obtained was charged 820 g of 2-[2,3-dimethyl-4-(2-ethoxyethyl)-phenoxy]-acetaldehyde oxime. Hydrogen was introduced until 20 atm., and the mixture was heated and stirred at 100° C. Absorption of hydrogen began at around 80° C. When the pressure was lowered, hydrogen was introduced to maintain the pressure at 20 atm. After about 0.5 to 2.5 hours, theoretical amount of hydrogen was absorbed, and then after cooling and releasing pressure, the catalyst was removed by filtration through a Nutze having Celite. The filtrate was concentrated under reduced pressure to obtain a crude product. Yield 85-93%. The crude product was purified by distillation to obtain 2-[2,3-dimethyl-4-(2-ethoxyethyl)phenoxy]ethylamine (boiling point 170°-175° C./1 mmHg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:13]2[NH:25][CH:26]2[CH2:28][CH2:27]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.O1CCOCC1.Br[C:37]1[S:38][C:39]2[C:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:44][CH:43]=[CH:42][C:40]=2[N:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:37]3[S:38][C:39]4[C:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:44][CH:43]=[CH:42][C:40]=4[N:41]=3)[CH2:14][C@H:13]2[NH:25][CH:26]2[CH2:27][CH2:28]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cccc2nc(Br)sc12
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NC2CC2)nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](NC4CC4)C3)sc12
Yield: 25.6 %

Procedure:
The same operation as in Example (196c) was performed using tert-butyl cis(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-(cyclopropylamino)piperidine-1-carboxylate obtained in Example (213a) (34.0 mg, 0.083 mmol), 4 N hydrochloric acid/1,4-dioxane (2 mL), ethyl 2-bromo-1,3-benzothiazole-7-carboxylate obtained in Example (1f) (26 mg, 0.091 mmol) and sodium carbonate (87 mg, 0.825 mmol), to obtain 11 mg of the title compound (26%) as a pale yellow oily substance.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.[Li+].[Cl-].[CH:14]([C:16]1[C:24]([O:25][CH3:26])=[CH:23][C:22]([CH3:27])=[C:21]2[C:17]=1[CH:18]=[CH:19][N:20]2[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:15]>C1COCC1.[NH4+].[Cl-].[Cl-].[Na+].O>[C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][C:2]([CH:14]([OH:15])[C:16]3[C:24]([O:25][CH3:26])=[CH:23][C:22]([CH3:27])=[C:21]4[C:17]=3[CH:18]=[CH:19][N:20]4[C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])=[N:3][C:4]=2[CH:9]=1)#[N:11]
Reactant: N#Cc1ccc2ocnc2c1
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C=O
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(O)c1nc2cc(C#N)ccc2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of benzo[d]oxazole-5-carbonitrile (CAS #:132227-01-1) (0.996 g, 6.91 mmol) in THF (20 mL), TMPMgCl.LiCl (1 M in THF) (6.91 mL, 6.91 mmol) was added at −78° C. After stirring for 30 min, tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 19-D) (1.00 g, 3.46 mmol) was added at −78° C. Then, the reaction mixture was warmed to rt. After stirring for 10 min, the reaction was heated at 50° C. After stirring for 1.5 h, the reaction mixture was cooled to rt, and diluted with aq. NH4Cl and brine. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with a 1:1 solution of 1M aq. NaHSO4 and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (heptane/EtOAc=100:0 to 40:60) to give the title compound. MS (ESI) m/z 432.3 (MH).
Reaction SMILES: C(NC(=O)[O-])C.[OH:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:12]([CH3:20])[CH:13]3[CH2:17][NH:16][CH2:15][CH:14]3[C:18]=2[CH:19]=1.[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24]Br>>[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:12]([CH3:20])[CH:13]3[CH2:17][NH:16][CH2:15][CH:14]3[C:18]=2[CH:19]=1
Reactant: CC1c2ccc(O)cc2C2CNCC12
Reactant: Fc1ccccc1CBr
Agent: CCNC(=O)[O-]
Product: CC1c2ccc(OCc3ccccc3F)cc2C2CNCC12

Procedure:
The subtitle compound was prepared by the method of Example 43, Step B utilizing N-ethylcarbamate-5-hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 43, Step A) (0.1 mmol) and 2-fluorobenzyl bromide. The crude product was obtained without further purification. MS calculated for C22H24FNO3+H: 370, observed: 370.
Reaction SMILES: O[C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[C:4](=[O:13])[O:3]1.[C:20]([O:24][C:25](=[O:33])[NH:26][CH2:27][CH2:28][NH:29][CH2:30][C:31]#[N:32])([CH3:23])([CH3:22])[CH3:21].Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[C:20]([O:24][C:25](=[O:33])[NH:26][CH2:27][CH2:28][N:29]([CH2:30][C:31]#[N:32])[C:4]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[CH:9][C:10]=1[C:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:3])=[O:13])([CH3:23])([CH3:21])[CH3:22]
Reactant: COc1ccc2c(c1)C(O)(c1ccccc1)OC2=O
Reactant: CC(C)(C)OC(=O)NCCNCC#N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N(CC#N)CCNC(=O)OC(C)(C)C)c(C(=O)c2ccccc2)c1
Yield: 72.6 %

Procedure:
A solution of 110 (2.55 g, 9.96 mmol), 111 (2.38 g, 12.0 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.30 g, 12.0 mmol), 1-hydroxy-7-azabenzotriazole (1.63 g, 12.0 mmol) in N,N-dimethylformamide was stirred at room temperature for 4 days. The contents of the reaction flask were poured into water and sat. sodium bicarbonate. Extracted with methylene chloride (3×). The combined organic extracts were dried with sodium sulfate (anh.) and filtered. Concentration of the filtrate in vacuo followed flash column chromatography (hexane:ethyl acetate 60:40) gave 112 as a white foam (3.16 g, 7.23 mmol, 72.6%).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[NH2:30][C:31]1[CH:32]=[C:33]([N:37]2[CH2:42][CH2:41][N:40]([CH2:43][C:44]([CH3:47])([OH:46])[CH3:45])[CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1>COCC(O)C>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:30][C:31]3[CH:32]=[C:33]([N:37]4[CH2:38][CH2:39][N:40]([CH2:43][C:44]([CH3:47])([OH:46])[CH3:45])[CH2:41][CH2:42]4)[CH:34]=[CH:35][CH:36]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: CC(C)(O)CN1CCN(c2cccc(N)c2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1ccccc1-c1ccc2cnc(Nc3cccc(N4CCN(CC(C)(C)O)CC4)c3)nn12
Yield: 14.5 %

Procedure:
2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004350 mol), N,N-Diisopropylethylamine (0.114 mL, 0.000652 mol) and 1-[4-(3-Amino-phenyl)-piperazin-1-yl]-2-methyl-propan-2-ol (0.217 g, 0.000870 mol) were dissolved in 1-Methoxy-2-propanol (1.2 mL) and the reaction was microwaved on 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to provide 29.84 mg of 1-(4-{3-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperazin-1-yl)-2-methyl-propan-2-ol as a lyophilized powder. (M+H)=473.8. 1H NMR (400 MHz, DMSO, d6) δ 9.29 (s, 1H), 8.96 (s, 1H), 7.72 (dd, 1H, J=1.64, 5.93 Hz), 7.46 (m, 1H), 7.33 (m, 1H), 7.18 (m, 2H), 7.08 (m, 2H), 6.91 (m, 2H), 6.53 (dd, 1H, J=1.84, 6.29 Hz), 3.77 (s, 3H), 3.55 (m, 2H), 3.34 (m, 2H), 3.19 (m, 4H), 3.05 (m, 2H), 1.29 (s, 6H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][N:2]1[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([S:13]([NH2:16])(=[O:15])=[O:14])=[C:8](Cl)[C:7]=1[N+:18]([O-:20])=[O:19].[H-].[Na+].[OH2:23]>>[O:1]1[CH2:5][CH2:4][CH2:3][N:2]1[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([S:13]([NH2:16])(=[O:15])=[O:14])=[C:8]([OH:23])[C:7]=1[N+:18]([O-:20])=[O:19]
Reactant: NS(=O)(=O)c1c(Cl)cc(N2CCCO2)c([N+](=O)[O-])c1Cl
Reactant: O
Agent: [H-]
Agent: [Na+]
Product: NS(=O)(=O)c1c(Cl)cc(N2CCCO2)c([N+](=O)[O-])c1O
Yield: 74 %

Procedure:
Following the general hydrolysis procedure outlined in example 15, (N-isoxazolidinyl)-2,6-dichloro-3-nitrobenzenesulfonamide (1.08 g, 3.3 mmol), 80% NaH (0.3 g, m10.0 mol) and water (72 μL, 4 mmol) were reacted to form the desired product (0.79 g, 77%). LC-MS m/z 309(M+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:21](O)=[O:22])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[N:48]([C@:51]1([C:68]([O:70][CH2:71][C:72](=[O:79])[C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)=[O:69])[C@@H:55]([CH2:56][CH2:57][CH2:58][B:59]2[O:63][C:62]([CH3:65])([CH3:64])[C:61]([CH3:67])([CH3:66])[O:60]2)[CH2:54][NH:53][CH2:52]1)=[N+:49]=[N-:50].CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[N:48]([C@:51]1([C:68]([O:70][CH2:71][C:72](=[O:79])[C:73]2[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=2)=[O:69])[C@@H:55]([CH2:56][CH2:57][CH2:58][B:59]2[O:60][C:61]([CH3:67])([CH3:66])[C:62]([CH3:65])([CH3:64])[O:63]2)[CH2:54][N:53]([C:21](=[O:22])[C@H:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][CH:12]=2)[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:52]1)=[N+:49]=[N-:50]
Reactant: CC1(C)OB(CCC[C@H]2CNC[C@@]2(N=[N+]=[N-])C(=O)OCC(=O)c2ccccc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)C(=O)N1C[C@H](CCCB2OC(C)(C)C(C)(C)O2)[C@](N=[N+]=[N-])(C(=O)OCC(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.1 %

Procedure:
A mixture of N-(tert-butoxycarbonyl)-4-(trifluoromethyl)phenylalanine (268 mg, 0.804 mmol), 1-hydroxybenzotriazole hydrate (123 mg, 0.804 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (154 mg, 0.804 mmol) in dry methylene chloride (10 mL) and DMF (3 mL) was stirred at room temperature. After 1 h, a second solution of racemic 2-oxo-2-phenylethyl (3R,4S)-3-azido-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]pyrrolidine-3-carboxylate hydrochloride (350 mg, 0.73 mmol) in methylene chloride (3.5 mL) was added, followed immediately by Et3N (204 uL, 1.46 mmol), and the resulting homogeneous mixture was stirred at room temperature for 3.5 h. Once complete, the mixture was diluted with dichloromethane (8 mL), washed successively with water (2×20 mL), saturated aqueous NaHCO3 (2×20 mL) and saturated aqueous sodium chloride, dried over Na2SO4 and concentrated. Purification by silica gel chromatography (90 g column, 15-35% ethyl acetate in hexanes) gave 2-oxo-2-phenylethyl (3R,4S)-3-azido-1-[N-(tert-butoxycarbonyl)-4-(trifluoromethyl)phenylalanyl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]pyrrolidine-3-carboxylate (233 mg, ˜60% purity) as a white foam which was used without further purification. LC-MS ESI+MS found for C37H47BF3N5O8 m/z 758.3 (M+H), 780.3 (M+Na); ESI−MS m/z 756.5 (M−H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:36])([CH2:33][CH2:34][CH3:35])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:32])=[N:15][N:16]2[C:21]([O:22][CH2:23][C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:20][C:19]([CH3:31])=[CH:18][C:17]=12)=[O:12])(C)(C)C.O.[OH-].[Na+]>FC(F)(F)C(O)=O>[NH2:7][C:8]([CH3:36])([CH2:33][CH2:34][CH3:35])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:32])=[N:15][N:16]2[C:21]([O:22][CH2:23][C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:20][C:19]([CH3:31])=[CH:18][C:17]=12)=[O:12]
Reactant: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3ncccc3F)cc(C)cc12)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCCC(C)(N)CNC(=O)c1c(C)nn2c(OCc3ncccc3F)cc(C)cc12
Temperature: 50 °C
Yield: 9.9 %

Procedure:
20 mg (0.039 mmol) of rac-{1-[({7-[(3-fluoropyridin-2-yl)methoxy]-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl}carbonyl)amino]-2-methylpentan-2-yl}carbamic acid tert-butyl ester (Example 144A) were dissolved in 1 ml of trifluoroacetic acid. The reaction mixture was heated to 50° C. for 1 hour. Water was added, and the pH was adjusted to −9 with 2 N sodium hydroxide solution. The aqueous phase was extracted with dichloromethane, separated off and concentrated under reduced pressure. The residue was purified by preparative HPLC chromatography (Method 21), which gave 1.59 mg (10% yield) of the target compound.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[S:5].[Cl:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:18][CH:10]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:9][C:2]([CH3:1])([CH3:17])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[S:5]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=S)CC(C)(C)CCc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=S)CC(C)(C)CC(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.06 g (3.09 mmol) of ethyl 3,3-dimethyl-5-phenylthiopentanoate in 10 mL of carbon tetrachloride was added 590 mg (4.4 mmol) of 1-chloro-2,5-pyrrolidinedione, and the mixture was stirred at room temperature for 2 hours. The mixture was filtered, and the filtrate concentrated to give ethyl 5-chloro-3,3-dimethyl-5-phenylthiopentanoate as an oil. The product was used without further purification in the reaction described in Example 3 below. NMR Data (CDCl3):
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.CON(C)C(=O)[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1>>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:2]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: CON(C)C(=O)c1cccnc1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: [Li]CCCC
Product: COc1ccc(-c2cccnc2)c(C(=O)O)c1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with N-methoxy-N-methylnicotinamide. After precipitation in aqueous phase at pH 4, followed by filtration and drying, a beige-coloured powder is obtained.