Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=3)[C:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:4]=2[CH:3]=1.[C:28]([Cu])#[N:29].[CH3:31][N:32]1C(=O)CCC1>>[C:31]([C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([C:28]#[N:29])=[CH:9][CH:10]=3)[C:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:4]=2[CH:3]=1)#[N:32]
Reactant: N#C[Cu]
Reactant: CCCCCCC1(CCCCCC)c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: CN1CCCC1=O
Product: CCCCCCC1(CCCCCC)c2cc(C#N)ccc2-c2ccc(C#N)cc21
Temperature: 90 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2,7-dibromo-9,9-dihexylfluorene (10 mmol) and CuCN (35 mmol) in NMP (30 mL) was purged with argon and refluxed for 4 h. The hot reaction mixture (˜120° C.) was then slowly poured into a stirred acidified aqueous FeCl3 solution. The mixture was stirred for additional 20 min at 90° C. and then extracted with toluene. The combined organic layer was washed with HCl until the dark heavy organic layer disappeared, and then with water, 10% NaOH solution, and water again until pH reaches about 7. It was dried over anhydrous MgSO4. After removal of the solvent, the residue was purified by column chromatography on silica gel using AcOEtand hexane (20/80) as the eluent, followed by recrystallization from hexane to afford colourless crystals in yield of 3.21 g (83.35%). M.P.=116-118° C.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][C:4]([CH3:8])([CH3:7])[CH2:5][NH2:6].P(=O)(O)(O)O.[C:15](O)(=[O:18])[CH:16]=[CH2:17]>C1(NC2C=CC3C(=CC=CC=3)C=2)C=CC=CC=1>[CH3:1][N:2]([CH3:9])[CH2:3][C:4]([CH3:8])([CH3:7])[CH2:5][NH:6][C:15](=[O:18])[CH:16]=[CH2:17]
Reactant: CN(C)CC(C)(C)CN
Reactant: C=CC(=O)O
Agent: O=P(O)(O)O
Agent: c1ccc(Nc2ccc3ccccc3c2)cc1
Product: C=CC(=O)NCC(C)(C)CN(C)C
Temperature: 200 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
A 500-ml three-neck flask fitted with a magnetic agitator, a thermometer, and a short column with a distillation set was charged with 260 g (2 mol) 3-dimethylamino-2,2-dimethylpropylamine; 4 g N-phenyl-β-naphthylamine; and 4 ml 85% phosphoric acid. 144 g (2 mol) acrylic acid was added drop by drop for 0.5 hours, whereupon the temperature of the mixture rose to 150° C. Finally, the mixture was heated to 200° C. in a nitrogen atmosphere for 2 hours, and then stirred at this temperature for 1 hour. During this time, 35.5 g of the distillate was obtained. Distillation was carried out in a vacuum after cooling and 247 g (67%) N-(3-dimethylamino-2,2-dimethylpropyl)acrylamide, boiling point 110°-115° C. at 66.5 Pa, was obtained.
Reaction SMILES: [CH:1]([CH2:3][C:4](O)=[O:5])=[CH2:2].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[F:22][C:23]1[CH:24]=[C:25]([C@H:31]2[NH:36][C@@H:35]([CH:37]=[CH:38][C:39]([O:41][CH3:42])=[O:40])[CH2:34][O:33][CH2:32]2)[CH:26]=[C:27]([F:30])[C:28]=1[F:29].Cl>C1COCC1.C(OCC)(=O)C.C(N(CC)CC)C>[C:4]([N:36]1[C@H:31]([C:25]2[CH:26]=[C:27]([F:30])[C:28]([F:29])=[C:23]([F:22])[CH:24]=2)[CH2:32][O:33][CH2:34][C@@H:35]1/[CH:37]=[CH:38]/[C:39]([O:41][CH3:42])=[O:40])(=[O:5])[CH2:3][CH:1]=[CH2:2].[C:4]([N:36]1[C@H:31]([C:25]2[CH:26]=[C:27]([F:30])[C:28]([F:29])=[C:23]([F:22])[CH:24]=2)[CH2:32][O:33][CH2:34][C@@H:35]1/[CH:37]=[CH:38]\[C:39]([O:41][CH3:42])=[O:40])(=[O:5])[CH2:3][CH:1]=[CH2:2]
Reactant: C=CCC(=O)O
Reactant: COC(=O)C=C[C@H]1COC[C@@H](c2cc(F)c(F)c(F)c2)N1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CCC(=O)N1[C@@H](/C=C/C(=O)OC)COC[C@H]1c1cc(F)c(F)c(F)c1
Product: C=CCC(=O)N1[C@@H](/C=C\C(=O)OC)COC[C@H]1c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (0.2 mL), vinylacetic acid (0.09 mL), and BOPCl (275 mg) were sequentially added to a solution of methyl 3-[(3S,5R)-5-(3,4,5-trifluorophenyl)morpholin-3-yl]acrylate (217 mg) in THF (5 mL) at 0° C., and the reaction solution was stirred at room temperature for two hours. Ethyl acetate and 0.5 N hydrochloric acid were added to the reaction solution, and the organic layer was separated. The resulting organic layer was sequentially washed with a 0.5 N sodium hydroxide solution and brine, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: heptane->heptane:ethyl acetate=1:1) to obtain 110 mg of methyl (E)-3-[(3S,5R)-4-(3-butenoyl)-5-(3,4,5-trifluorophenyl)morpholin-3-yl]acrylate and 132 mg of methyl (Z)-3-[(3S,5R)-4-(3-butenoyl)-5-(3,4,5-trifluorophenyl)morpholin-3-yl]acrylate. The property values of the isomers are as follows.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[O:16][C:17]([CH3:20])=[N:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.Cl.[CH3:35][O:36][C:37]1[CH:45]=[N:44][C:43]([N:46]2[CH:50]=[C:49]([CH3:51])[N:48]=[N:47]2)=[C:42]2[C:38]=1[C:39]([C:52](=[O:56])C(O)=O)=[CH:40][NH:41]2.C(N(CC)CC)(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl>[C:21]1([C:14](=[C:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:52]([C:39]3[C:38]4[C:42](=[C:43]([N:46]5[CH:50]=[C:49]([CH3:51])[N:48]=[N:47]5)[N:44]=[CH:45][C:37]=4[O:36][CH3:35])[NH:41][CH:40]=3)=[O:56])[CH2:9][CH2:10]2)[C:15]2[O:16][C:17]([CH3:20])=[N:18][N:19]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cnc(-n2cc(C)nn2)c2[nH]cc(C(=O)C(=O)O)c12
Reactant: Cc1nnc(C(=C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2)o1
Agent: CCN(CC)C(C)C
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cnc(-n2cc(C)nn2)c2[nH]cc(C(=O)C(=O)N3CCC(=C(c4ccccc4)c4nnc(C)o4)CC3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.5 %

Procedure:
To a solution of 4-[1-phenyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)methylene]piperidine-1-carboxylic acid tert-butyl ester (0.0300 g, 0.084 mmol) in CH2Cl2 (1 mL) was added TFA (0.4 mL) and the reaction mixture was stirred at rt for 30 min. The solvent was subsequently removed in vacuo and the material was dissolved in CHCl3 (3 mL). To this solution was then added 4-methoxy-7-(4-methyl-1,2,3-triazol-1-yl)-6-azaindol-3-yl-oxoacetic acid hydrochloride salt (0.0250 g, 0.084 mmol) and iPrNEt2 (0.059 mL, 0.338 mmol), followed by BOP-Cl (0.0210 g, 0.084 mmol). The mixture was allowed to stir at rt for 2 h and then the solvent was removed in vacuo. The residue was diluted with H2O and extracted with EtOAc (×3). The combined organic layers were washed (H2O, brine), dried (Na2SO4) and concentrated, and the residue was purified by preparative HPLC (NH4OAc) affording the title compound (0.0174 g, 39%) as a colorless solid:
Reaction SMILES: [C:1]([C:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][C:10]=1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]2[O:28][CH2:27]2)=[CH:20][CH:19]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]([NH2:32])([CH3:31])[CH3:30]>>[C:1]([C:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][C:10]=1[C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH:26]([OH:28])[CH2:27][NH:32][CH:29]([CH3:31])[CH3:30])=[CH:22][CH:23]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1c(-c2ccc(OCC3CO3)cc2)oc2ccccc12
Reactant: CC(C)N
Product: CC(C)NCC(O)COc1ccc(-c2oc3ccccc3c2C(=O)c2ccccc2)cc1

Procedure:
3-Benzoyl-2-[4'-(2,3-epoxypropoxy)phenyl]benzofuran (1.9 g., 5.2 mmol.) was dissolved in 30 ml. of freshly distilled isopropylamine and the mixture was heated in a stainless steel pressure bomb at 100° for 4.5 hours. The contents of the bomb were concentrated under reduced pressure to give the title compound. The title compound was dissolved in ether and an ethereal solution of hydrochloric acid was added to precipitate the corresponding hydrochloride salt, m.p. 53°-59°.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.[Li]CCCC.CN([CH:20]=[O:21])C>C1COCC1>[Cl:11][C:9]1[C:10]2[C:2]([CH:20]=[O:21])=[CH:3][NH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CN(C)C=O
Reactant: Clc1ncnc2[nH]cc(Br)c12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1c[nH]c2ncnc(Cl)c12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (E-2) (2.33 g, 10.0 mmol, 1.0 eq) in anhydrous THF (100 mL) at −78° C. under argon, n-BuLi solution (2.5 M in THF, 8.8 mL, 22.0 mmol, 2.2 eq) is added dropwise (over 10 min). The resulting mixture is stirred at −78° C. for 1 h and then DMF (2.0 g, 11.0 mmol, 1.1 eq) is added dropwise (over 10 min). The mixture is stirred at −78° C. for an additional 30 min and then stirred at RT overnight. The reaction mixture is quenched with H2O (50 mL) and then concentrated in vacuo. The residue is triturated with saturated aqueous NH4Cl solution. The solid is collected by filtration, rinsed with ethyl acetate, and dried in vacuo to afford the product, 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde (E-3).
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[C:24]4[C:23]([CH3:25])=[C:22]([CH3:26])[S:21][C:20]=4[CH:19]=[C:18]4[C:13]=3[CH:14]=[CH:15][CH:16]=[CH:17]4)[CH:9]=[CH:8][C:7]=2[O:27][C:28](=[O:30])[CH3:29])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:31]Br>C(Cl)Cl>[CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[C:24]4[C:23]([CH3:25])=[C:22]([CH3:26])[S:21][C:20]=4[C:19]([Br:31])=[C:18]4[C:13]=3[CH:14]=[CH:15][CH:16]=[CH:17]4)[CH:9]=[CH:8][C:7]=2[O:27][C:28](=[O:30])[CH3:29])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(=O)Oc1ccc(-c2c3ccccc3cc3sc(C)c(C)c23)cc1C1CCCC1
Reactant: BrBr
Solvent: ClCCl
Product: CC(=O)Oc1ccc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1C1CCCC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 71.1 %

Procedure:
To acetic acid 2-cyclopentyl-4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester (2.9 g, 7.7 mmol) in anhydrous methylene chloride (68 mL) was added ferric chloride (66 mg, 0.41 mmol). The reaction mixture was placed under nitrogen and cooled to −78° C. The reaction mixture was protected from light and a solution of bromine (0.44 mL, 8.5 mmol) in anhydrous methylene chloride (11 mL) was added dropwise over a period of 15 min. After stirring at −78° C. for 45 min the reaction was quenched with dilute sodium bisulfite, and then poured into water (200 mL). The resulting mixture was extracted with diethyl ether (300 mL), and the diethyl ether layer was washed with water and then brine. Concentration under reduced pressure and chromatography with petroleum ether:ethyl acetate (95:5) gave the title compound as a white solid (2.7 g, 79%): (CDCl3): δ 8.28 (d, 1H), 7.58-7.52 (m, 2H), 7.39-7.34 (m, 1H), 7.29 (d, 1H), 7.18 (dd, 1H), 7.14 and 7.13 (d, 1H), 3.18 (quintet, 1H), 2.44 (s, 3H), 2.40 (s, 3H), 2.06-2.02 (m, 2H), 1.75-1.45 (in containing a singlet at δ 1.60, 9H); MS(EI): [M+], 1 bromine isotope pattern, 492/494; Anal. Calc. for C27H25BrO2S: C, 65.72, H, 5.11, N, 0.00. Found: C, 63.18, H, 4.96, N, 0.00.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[F:42][C:43]([F:49])([F:48])[S:44](Cl)(=[O:46])=[O:45]>ClCCl>[F:42][C:43]([F:49])([F:48])[S:44]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:46])=[O:45]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reaction time: 0.8 h
Yield: 92.9 %

Procedure:
4-Hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (80.0 mg, 0.173 mmol) was suspended in dichloromethane (4.8 mL), and the suspension was added with triethylamine (0.072 mL, 0.52 mmol) and trifluoromethanesulfonyl chloride (0.022 mL, 0.21 mmol) under ice-cooling, followed by stirring for 0.8 hour. The reaction mixture was filtered and the filtrate was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (95.4 mg, yield 93%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([NH:27][CH3:28])[CH:24]([CH3:26])[CH3:25].C(N(CC)CC)C>CS(C)=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:27]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH3:28])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCC(C)C
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F

Procedure:
The title compound was prepared from (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example B5) (4.00 g, 11.7 mmol), N-isobutyl-methyl-amine (1.54 g, 17.6 mmol) and triethylamine (5.73 ml, 41.1 mmol) in DMSO (30 mL) at RT according to the general procedure C. Obtained as a yellow solid (4.18 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH:10]([CH3:14])[C:11]([OH:13])=O)=[O:8])=[CH:4][CH:3]=1.[CH3:15]CN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:48]([N:50]1[CH2:55][CH2:54][N:53]([C:56]([C:58]2[CH:64]=[CH:63][C:61]([NH2:62])=[CH:60][CH:59]=2)=[O:57])[CH2:52][CH2:51]1)[CH3:49]>CN(C=O)C>[CH3:15][C:64]1[CH:63]=[C:61]([NH:62][C:11]([CH:10]([NH:9][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:8])[CH3:14])=[O:13])[CH:60]=[CH:59][C:58]=1[C:56]([N:53]1[CH2:52][CH2:51][N:50]([CH2:48][CH3:49])[CH2:55][CH2:54]1)=[O:57]
Reactant: CC(NC(=O)c1ccc(Cl)s1)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Reactant: CCN1CCN(C(=O)c2ccc(N)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCN1CCN(C(=O)c2ccc(NC(=O)C(C)NC(=O)c3ccc(Cl)s3)cc2C)CC1

Procedure:
200 μl of a 0.05-molar solution of 2-[(5-chloro-thiophene-2-carbonyl)-amino]-propionic acid, which additionally contains 0.05 mol/l DIPEA, in DMF are combined with 100 μl of a 0.1-molar solution of HATU in DMF on a microtitre plate and mixed for 10 min on a shaker. Then 200 μl of a 0.05-molar solution of 4-(4-ethyl-piperazin-1-yl-carbonyl)-aniline which additionally contains 0.05 mol/l DIPEA are pipetted in and the mixture is again combined by jogging. After 16 h at 80° C. the mixture is filtered through basic aluminium oxide and washed again with DMF/methanol=9:1. Then it is evaporated down i. vac.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[NH2:14][CH:15]1[CH2:19][CH2:18][C:17]2([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:16]1.N1C=CC=CC=1>O>[CH2:16]1[C:17]2([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:18][CH2:19][CH:15]1[NH:14][C:11]([C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:12]
Reactant: O=C(Cl)c1cnc2ccccc2n1
Reactant: NC1CCC2(CCCCC2)C1
Solvent: O
Solvent: c1ccncc1
Product: O=C(NC1CCC2(CCCCC2)C1)c1cnc2ccccc2n1
Yield: 84.3 %

Procedure:
Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), 2-aminospiro(4.5)decane (150 mg, 0.79 mmol), pyridine (5 mL), and water (100 mL) yielding 206 mg (74%) of (236):
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[N:4][N:5]([C:7]([CH3:12])([CH3:11])[C:8]([NH2:10])=[O:9])[CH:6]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][CH3:22])[C:18]([C:23]([F:26])([F:25])[F:24])=[CH:17][N:16]=1.FC(F)(F)C(O)=O.C([O-])([O-])=O.[Na+].[Na+]>COCCO.O>[CH3:12][C:7]([N:5]1[CH:6]=[C:2]([NH:1][C:15]2[N:20]=[C:19]([NH:21][CH3:22])[C:18]([C:23]([F:26])([F:24])[F:25])=[CH:17][N:16]=2)[C:3]([CH3:13])=[N:4]1)([CH3:11])[C:8]([NH2:10])=[O:9]
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Reactant: Cc1nn(C(C)(C)C(N)=O)cc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: COCCO
Product: CNc1nc(Nc2cn(C(C)(C)C(N)=O)nc2C)ncc1C(F)(F)F
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 51.1 %

Procedure:
To a solution of 2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanamide (250 mg, 1.37 mmol) in 2-methoxyethanol (5 mL) was added 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (290 mg, 1.37 mmol) and trifluoroaceticacid (156 mg, 1.37 mmol), the reaction was stirred at 70° C. for about 0.5 h. The reaction mixture was cooled to ambient temperature followed with the addition of water (10 mL) and the pH of solution was adjusted to 8 with sat. Na2CO3 The aqueous phase was extracted with ethyl acetate (10 mL×3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to dry to give a residue which was purified by column chromatography on silica gel (CH2Cl2:MeOH=20:1) to give 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanamide (250 mg, 51%) as white solid. LCMS (m/z) ES+358 (m+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11]([O:14][C:15]1[CH:16]=[C:17]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[O:18][CH2:19][CH2:20][CH2:21][OH:22])(=[O:13])=[O:12].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11]([O:14][C:15]1[CH:16]=[C:17]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[O:18][CH2:19][CH2:20][CH:21]=[O:22])(=[O:13])=[O:12]
Reactant: COc1ccc(OC)c(S(=O)(=O)Oc2cc(C)cc(OCCCO)c2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1ccc(OC)c(S(=O)(=O)Oc2cc(C)cc(OCCC=O)c2)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 74.9 %

Procedure:
To a cooled (0° C.), stirred solution of 360 mg (0.941 mmol) of 3-[3-(2,5-dimethoxyphenylsulfonyloxy)-5-methylphenoxy]propanol, as prepared in the preceding step, 344 μL (1.98 mmol) of N,N-diisopropylethylamine and 200 μL (2.82 mmol) of anhydrous dimethyl sulfoxide in 6.0 mL of anhydrous dichloromethane was added 300 mg (1.88 mmol) of sulfur trioxide pyridine complex. The mixture was warmed to ambient temperature over 30 min and stirred for 16 h. The mixture was then poured into 15 mL of dichloromethane and washed with 5% (w/v) aqueous citric acid (2×25 mL). Each wash was extracted with 5 mL of dichloromethane and the combined extracts were washed with brine (25 mL), dried over Na2SO4 and concentrated. The resulting material was chromatographed on 35 g of silica gel with dichloromethane followed by 2.5% ethyl acetate-dichloromethane to afford 268 mg (75%) of the.title compound as a colorless resin: 1H-NMR (300 MHz; CDCl3) δ 9.83 (t, 1 H, J=1.4 Hz), 7.34 (d, 1 H, J=3.1 Hz), 7.15 (dd, 1 H, J=9.1, 3.1 Hz), 7.03 (d, 1 H, J=9.1 Hz), 6.59 (m, 1 H), 6.56 (m, 1 H), 6.47 (t, 1 H, J=2.1 Hz), 4.20 (t, 2 H, J=6.1 Hz), 3.97 (s, 3 H), 3.76 (s, 3 H), 2.86 (td, 2 H, J=6.1, 1.4 Hz), and 2.25 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[C@@H:4]([NH:32][S:33]([C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)(=[O:35])=[O:34])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)[CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:65]1([C@H:71](O)[CH2:72][CH3:73])[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:45])[C@@H:4]([N:32]([S:33]([C:36]1[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=1)(=[O:35])=[O:34])[C@H:71]([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[CH2:72][CH3:73])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)[CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@H](c1cccc(OCc3ccc(Cl)c(Cl)c3)c1)O2)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CC[C@@H](O)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[C@@H](c1ccccc1)N([C@@H](Cc1ccc2c(c1)OC[C@H](c1cccc(OCc3ccc(Cl)c(Cl)c3)c1)O2)C(=O)OC)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.6 %

Procedure:
(S)-3-{(S)-2-[3-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-(4-nitro-benzenesulfonylamino)-propionic acid methyl ester (0.37 g) was dissolved in 2 mL dry THF and triphenylphosphine (0.29 g) and (R)-(+)-1-phenyl-1-propanol (0.15 g) were added. The mixture was stirred at 0° C. for 10 min, then DIAD 933 μL (0.22 g, 1.1 mmol) was added over 2 minutes. The reaction stirred at room temperature for 5 hours, then was evaporated. The residue was purified by silica gel flash chromatography (9:1 to 7:3 hexanes/EtOAc) to give (S)-3-{(S)-2-[3-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-[(4-nitro-benzenesulfonyl)-((S)-1-phenyl-propyl)-amino]-propionic acid methyl ester (0.42 g). This material was dissolved in DMF (0.7 mL), and then mercapto acetic acid (0.15 g) and DBU (0.48 g) were added and stirred at room temperature for 2 hours. The reaction was quenched by addition of NaHCO3 solution (4 mL) and product was extracted with ether. The ether layer was washed with water and brine, and then dried (Na2SO4), filtered, and evaporated. The residue was purified by silica gel column (5% EtOAc in hexanes to 15% EtOAc in hexanes) to get pure (S)-3-{(S)-2-[3-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-((S)-1-phenyl-propylamino)-propionic acid methyl ester (0.2 g). LCMS (m/z): 607.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:18][C:19]([OH:21])=[O:20])[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:24]1C=CN=C1)=O>O1CCCC1>[OH2:20].[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:18][C:19]([NH2:24])=[O:21])[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2ccc(Cl)nc21
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: NC(=O)Cn1c(-c2ccc(Cl)cc2)nc2ccc(Cl)nc21
Product: O
Temperature: 25 °C
Reaction time: 48 h
Yield: 54.5 %

Procedure:
A suspension of 5-chloro-2-(4-chlorophenyl)-3H-imidazo [4,5-b]pyridine-3-acetic acid (3.1 g, 0.00963 mole) and 1,1'-carbonyldiimidazole (1.56 g, 0.00963 mole) in tetrahydrofuran (100 ml) was refluxed under nitrogen for 1.5 hours, cooled to room temperature, and a stream of nitrogen, was bubbled through the solution for one hour. The solution was cooled in a dry ice/acetone bath and liquid ammonia (50 ml) was added. The reaction mixture was allowed to warm to room temperature and was stirred at room temperature for two days. The solvents were removed under reduced pressure and the solid was triturated in water (100 ml), collected by filtration, and rinsed twice with water, twice with a 5% potassium hydroxide solution, and twice again with water. The solid was recrystallized twice from isopropyl alcohol/water and dried under high vacuum at 70° C. to give 1.78 g (54%) of title compound, mp>250° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([OH:14])=O.[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=1[N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([NH:21][C:20]1[CH:22]=[CH:23][C:17]([O:16][CH3:15])=[C:18]([N:24]2[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]2)[CH:19]=1)=[O:14]
Reactant: O=C(O)c1cccc2c(Br)cccc12
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Product: COc1ccc(NC(=O)c2cccc3c(Br)cccc23)cc1N1CCN(C)CC1

Procedure:
The title compound was prepared from 5-bromo-1-naphthoic acid (J. Chem. Soc., 1950, 991) and 4-methoxy-3-(4-methylpiperazin-1-yl)aniline (EP0533268A1) using a similar procedure to Example 1.