Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C[O:3][C:4](=[O:15])[C@H:5]([NH2:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[N:16]1[S:20][N:19]=[C:18]2[C:21]([S:25]([NH:28][C:29]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:30]=3[C:31](O)=[O:32])(=[O:27])=[O:26])=[CH:22][CH:23]=[CH:24][C:17]=12>>[N:16]1[S:20][N:19]=[C:18]2[C:21]([S:25]([NH:28][C:29]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:30]=3[C:31]([NH:14][C@H:5]([CH2:6][C:7]3[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=3)[C:4]([OH:3])=[O:15])=[O:32])(=[O:27])=[O:26])=[CH:22][CH:23]=[CH:24][C:17]=12
Reactant: COC(=O)[C@H](N)Cc1ccc(Cl)cc1
Reactant: O=C(O)c1cc(Cl)ccc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Product: O=C(N[C@H](Cc1ccc(Cl)cc1)C(=O)O)c1cc(Cl)ccc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
(R)-2-(tert-Butoxycarbonylamino)-3-(4-chloro-phenyl)-propionic acid was treated as in EXAMPLE 2, Part A, to produce (R)-2-amino-3-(4-chloro-phenyl)-propionic acid methyl ester hydrochloride as a white solid. This ester was coupled with 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-5-chloro-benzoic acid as in EXAMPLE 1, Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, Part E, to afford the title compound. HPLC: RT=10.28 min. MS (ESI−): mass calcd. for C22H16Cl2N4O5S2, 549.99; m/z found, 549/551 [M−H]−. 1H NMR (500 MHz, CDCl3): 10.92 (s, 1H), 8.30 (d, J=7.0, 1H), 8.19 (d, J=8.8, 1H), 7.70-7.66 (m, 1H), 7.64 (d, J=9.0, 1H), 7.31-7.26 (m, 3H), 7.14 (d, J=2.3, 1H), 7.08 (d, J=8.3, 2H), 6.38 (d, J=7.3, 1H), 5.00-4.96 (m, 1H), 3.29 (dd, J=14.3, 5.7, 1H), 3.20 (dd, J=14.2, 5.8, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.C[Al](C)C.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[N:19]1[C:24]2[N:25]=[C:26]([NH:37][CH2:38][C:39](OC)=[O:40])[N:27]=[C:28]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[CH3:36])[C:23]=2[CH:22]=[CH:21][C:20]1=[O:43]>>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[N:19]1[C:24]2[N:25]=[C:26]([NH:37][CH2:38][C:39](=[O:40])[N:1]3[CH2:6][CH2:5][S:4][CH2:3][CH2:2]3)[N:27]=[C:28]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[CH3:36])[C:23]=2[CH:22]=[CH:21][C:20]1=[O:43]
Reactant: C1CSCCN1
Reactant: COC(=O)CNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: C[Al](C)C
Product: Cc1cc(F)ccc1-c1nc(NCC(=O)N2CCSCC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 86.5 %

Procedure:
Following the general procedure outlined in Example 193, thiomorpholine (0.22 mL, 2.2 mmol), trimethylaluminum (1.1 mL, 2.2 mmol) and the product of Example 190 (200 mg, 0.44 mmol) were reacted to give the desired product 200 mg (86%). LC-MS: 526.0 (MH+, m/z), 2.07 (Rt, min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[C:32]1[NH:36][C:35](=[O:37])[O:34][N:33]=1)[O:6][CH2:7][C:8]1[S:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:23]OS(C)(=O)=O.C(N(C(C)C)CC)(C)C.[CH3:47][S:48]([N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)(=[O:50])=[O:49]>CN(C)C=O>[CH3:47][S:48]([N:51]1[CH2:56][CH2:55][N:54]([CH2:23][C:9]2[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][CH:14]=3)[S:12][C:8]=2[CH2:7][O:6][C:5]2[CH:29]=[CH:30][C:31]([C:32]3[NH:36][C:35](=[O:37])[O:34][N:33]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:53][CH2:52]1)(=[O:50])=[O:49]
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2COS(C)(=O)=O)ccc1-c1noc(=O)[nH]1
Reactant: CS(=O)(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CN2CCN(S(C)(=O)=O)CC2)ccc1-c1noc(=O)[nH]1
Temperature: 90 °C
Yield: 11.9 %

Procedure:
To a solution of 50 mg of methanesulfonic acid 5-[3-methoxy-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxymethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethyl ester in 2 mL of dimethylformamide was added 80 μL of diisopropylethyl amine and 19.2 mg of 1-methylsulfonylpiperazine. The resulting mixture was heated in a sealed tube to 90° C. under microwave irradiation for 5 minutes and then concentrated under reduced pressure. The residue was purified by chromatography on a SCX Waters column with gradient CH2Cl2/MeOH 30/70 to 7N NH3 in MeOH followed by recrystallization in dichloromethane 9/methanol 1 to give 6.7 mg of 3-{4-[4-(4-methanesulfonyl-piperazin-1-ylmethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl}-4H-[1,2,4]oxadiazol-5-one.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH2:15][F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:17][C:18]1([CH2:24][C:25]([NH2:27])=[O:26])[CH2:21][S:20](=[O:23])(=[O:22])[CH2:19]1>>[NH2:27][C:25](=[O:26])[CH2:24][C:18]1([NH:17][C:10]([C:7]2[CH:6]=[C:5]([O:13][CH2:14][CH2:15][F:16])[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:9][N:8]=2)=[O:12])[CH2:19][S:20](=[O:22])(=[O:23])[CH2:21]1
Reactant: O=C(O)c1cc(OCCF)c(C2CC2)cn1
Reactant: NC(=O)CC1(N)CS(=O)(=O)C1
Product: NC(=O)CC1(NC(=O)c2cc(OCCF)c(C3CC3)cn2)CS(=O)(=O)C1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-cyclopropyl-4-(2-fluoroethoxy)-pyridine-2-carboxylic acid (example 146b) and 2-(3-amino-1,1-dioxo-thietan-3-yl)acetamide (example 160d) as starting materials and isolated (30 mg, 34%); MS (ESI, m/z): 386.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:15]3[CH:16]=[CH:17][S:18][C:14]=3[CH2:13][CH2:12][NH:11]2)=[CH:6][CH:5]=1.CN(C)C=O.[CH3:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1.Cl.CN(C)CCCN=C=NCC.[Na+].[Cl-]>ClCCl>[F:20][C:2]([F:1])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:15]3[CH:16]=[CH:17][S:18][C:14]=3[CH2:13][CH2:12][N:11]2[C:32]([C:31]2[CH:35]=[CH:36][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)=[O:33])=[CH:6][CH:5]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: FC(F)(F)Oc1ccc(C2NCCc3sccc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(=O)N2CCc3sccc3C2c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(4-Trifluoromethoxyphenyl)4,5,6,7-tetrahydro-thieno[3,2-c]pyridine in N,N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) was added to a solution of 4-methoxybenzoic acid in N,N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol). To this solution 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) was added. The mixture was shaken overnight at room temperature at 1000 rpm, added saturated NaCl (2 ml), and extracted with ethyl acetate (2×1 ml). The combined organic extracts were evaporated to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:29]3[CH:33]=[CH:32][N:31]=[C:30]3[CH3:34])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][CH2:24][C:25]([O:27]C)=[O:26])=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:29]3[CH:33]=[CH:32][N:31]=[C:30]3[CH3:34])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:4][CH:3]=1
Reactant: COC(=O)CCc1ccccc1OCCCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCOc2ccccc2CCC(=O)O)o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of methyl 3-[2-[3-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]propoxy]phenyl]propionate (400 mg), tetrahydrofuran (5 ml) and ethanol (5 ml) was added 5 ml of a 1 N aqueous solution of sodium hydroxide, and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water (100 ml), and the mixture was neutralized with 1 N hydrochloric acid. The resulting solid precipitate was filtered, washed with water and air-dried to give crude crystals of 3-[2-[3-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]propoxy]phenyl]propionic acid. Recrystallization from tetrahydrofuran-hexane gave colorless prisms (260 mg, 54%). Melting point 184-185° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.[NH2:12][C:13]1[S:14][C:15]([CH3:19])=[C:16]([CH3:18])[N:17]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([NH:8][C:9]([NH:12][C:13]2[S:14][C:15]([CH3:19])=[C:16]([CH3:18])[N:17]=2)=[S:10])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1N=C=S
Reactant: Cc1nc(N)sc1C
Product: Cc1ccc(Cl)cc1NC(=S)Nc1nc(C)c(C)s1
Yield: 31.4 %

Procedure:
Prepared using Method B from 4.5 g (24.5 mmol) of 5-chloro-2-methyl-phenyl isothiocyanate and 2.79 g (24.5 mmol) of 2-amino-4,5-dimethylthiazole to give 2.4 g of title compound as a white solid (31% yield, m.p. 188-189° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:18]=[C:19]([N:20]3[CH2:24][CH2:23][N:22]([CH3:25])[C:21]3=[O:26])[C:12]2=[N:11][C:10]=1[C:33](=[S:35])[NH2:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:36](N(C(C)C)CC)(C)C.CI>C1COCC1>[CH3:36][S:35][C:33]([C:10]1[N:11]=[C:12]2[C:19]([N:20]3[CH2:24][CH2:23][N:22]([CH3:25])[C:21]3=[O:26])=[CH:18][C:17]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:16][N:13]2[C:14](=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[NH:34]
Reactant: CCN(C(C)C)C(C)C
Reactant: CN1CCN(c2cc(N3CCOCC3)cn3c(=O)c(OCc4ccccc4)c(C(N)=S)nc23)C1=O
Solvent: CI
Solvent: C1CCOC1
Product: CSC(=N)c1nc2c(N3CCN(C)C3=O)cc(N3CCOCC3)cn2c(=O)c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 74.7 %

Procedure:
To a solution of the product of example 74 (250 mg, 0.5 mmol) in THF (20 ml) was added diisopropyl ethylamine (65 mg, 0.5 mmol) and methyl iodide (140 mg, 1 mmol), and the mixture was stirred at 60° C. for 1.5 h. The reaction mixture was added ice water, and extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate solution and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give title product (190 mg, 74%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[Cl:15]C1C=CC(S(CCC)(=O)=O)=CC=1>>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[Cl:15]
Reactant: CCCS(=O)(=O)c1ccc(Cl)cc1
Reactant: CCCS(=O)(=O)c1ccc(F)c(Br)c1
Product: CCCS(=O)(=O)c1ccc(Cl)c(Br)c1
Yield: 86 %

Procedure:
Following the general method as outlined in Intermediate 106, starting from 1-chloro-4-(propylsulfonyl)benzene (Intermediate 125), the title compound was obtained as an oil which solidified upon standing in 86% yield.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[N:25]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])[C:24]3[C:23](=[O:34])[N:22]([CH3:35])[C:21](=[O:36])[N:20]([CH3:37])[C:19]=3[C:18]=2[C:38]([O:40]C)=[O:39])[CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[Cl-].[NH4+]>O1CCOCC1>[C:3]([O:7][C:8]([NH:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[N:25]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])[C:24]3[C:23](=[O:34])[N:22]([CH3:35])[C:21](=[O:36])[N:20]([CH3:37])[C:19]=3[C:18]=2[C:38]([OH:40])=[O:39])[CH2:12]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)c1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2ccccc2Cl)c2c(=O)n(C)c(=O)n(C)c12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1c(=O)c2c(c(C(=O)O)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Temperature: 80 °C
Reaction time: 5 h
Yield: 96.2 %

Procedure:
A 1M aqueous sodium hydroxide solution (10 ml) was added to a solution of methyl 6-{(3R)-3-[(tertbutoxycarbonyl)amino]piperidin-1-yl}-5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (2.08 g) in 1,4-dioxane (10 ml), and the resulting mixture was stirred at 80° C. for 5 hours. After the reaction solution was cooled to 25° C., a saturated aqueous ammonium chloride solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure to obtain the title compound (1.95 g) as a light-yellow amorphous substance.
Reaction SMILES: FC1C=C(NC2N=C3NN=CC3=C([C:24]3[CH:25]=[C:26]([NH:30][C:31](=[O:34])[CH:32]=[CH2:33])[CH:27]=[CH:28][CH:29]=3)N=2)C=CC=1N1CCOCC1.ClC1N=C(Cl)N=C2NN=CC=12.O1C=CCCC1.CC1C=CC(S(O)(=O)=O)=CC=1.Cl[C:64]1[N:69]=[C:68]([Cl:70])[N:67]=[C:66]2[N:71]([CH:74]3[CH2:79][CH2:78][CH2:77][CH2:76][O:75]3)[N:72]=[CH:73][C:65]=12.C(NC1C=C(B(O)O)C=CC=1)(=O)C=C>C(Cl)Cl.C1COCC1>[Cl:70][C:68]1[N:67]=[C:66]2[N:71]([CH:74]3[CH2:79][CH2:78][CH2:77][CH2:76][O:75]3)[N:72]=[CH:73][C:65]2=[C:64]([C:28]2[CH:27]=[C:26]([NH:30][C:31](=[O:34])[CH:32]=[CH2:33])[CH:25]=[CH:24][CH:29]=2)[N:69]=1
Reactant: Clc1nc(Cl)c2cnn(C3CCCCO3)c2n1
Reactant: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CCOCC4)c(F)c3)nc3[nH]ncc23)c1
Agent: C1=COCCC1
Agent: C=CC(=O)Nc1cccc(B(O)O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CC(=O)Nc1cccc(-c2nc(Cl)nc3c2cnn3C2CCCCO2)c1
Reaction time: 13 h

Procedure:
As an example, N-(3-(6-((3-fluoro-4-morpholinophenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)phenyl)acrylamide can be prepared according to Route II. Beginning with 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine, protection can be accomplished by reaction with 3,4-dihydro-2H-pyran in the presence of p-TsOH in a suitable solvent such as a solution of THF and methylene chloride. The reaction is carried out for a suitable period of time, e.g. about 8-18 hr, at a suitable temperature, e.g. about 15-30° C., until the reaction is complete. The completeness of the reaction can be ascertained by several convenient methods, including monitoring the reaction by TLC. The resulting 4,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine can then be coupled with (3-acrylamidophenyl)boronic acid under palladium catalyzed conditions to provide N-(3-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)phenyl)acrylamide.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[C:24]([O:28][C:29]([N:31]1[CH2:32][CH:33]=[C:34]([C:2]2[C:6]3[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]4[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=4[Cl:22])[CH3:13])[C:5]=3[O:4][CH:3]=2)[CH2:35][CH2:36]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCN(C(=O)OC(C)(C)C)CC3)coc12)c1c(Cl)ccc(F)c1Cl

Procedure:
A mixture of 3-bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-furo[3,2-c]pyridin-6-ylamine (100.0 mg, 0.2381 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (88.3 mg, 0.286 mmol), Pd(PPh3)4 (10 mg, 0.01 mmol), potassium carbonate (98.7 mg, 0.714 mmol) and 4:1 dioxane:water (4 mL) was microwaved at 100° C. for 2 h. The solution was concentrated in vacuo, and dry-loaded onto silica gel for column chromatography, eluted with 2-5% MeOH in DCM. Fractions containing the product were concentrated in vacuo to afford the title compound as an off-white solid. 1H NMR (CD3OD, 400 MHz): δ=1.49 (s, 9H), 1.88 (d, J=6.8 Hz, 3H), 2.48 (d, J=1.5 Hz, 2H), 3.59-3.69 (m, 2H), 4.11 (br, s, 2H), 6.26 (br, s, 1H), 6.50 (q, J=6.9 Hz, 1H), 7.19-7.25 (m, 1H), 7.40 (dd, J=9.0, 4.9 Hz, 1H), 7.64 (s, 1H), 8.20 (s, 1H). MS (ES+): m/z 522.14 [MH+]. HPLC: tR=3.51 min (ZQ3, polar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:3]=1[NH2:4].C(=O)([O-])O.[Na+].O.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29]>O1CCCC1.C(OCC)(=O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:4][C:3]2[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:2]=2[F:1])(=[O:26])=[O:25])=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: COc1cccc(F)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc(F)c1NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
To a mixture of 2-fluoro-6-methoxyaniline (0.56 g), sodium hydrogen carbonate (0.67 g) and water (2 mL) in tetrahydrofuran (20 mL) was added a solution of 4-chloro-3-nitrobenzenesulfonyl chloride (1.0 g) in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=2/3) to give 4-chloro-N-(2-fluoro-6-methoxyphenyl)-3-nitrobenzenesulfonamide (0.56 g). This material was dissolved in N,N-dimethylformamide (15 mL). To the solution were added methyl iodide (0.15 mL) and sodium hydride (55%, 75 mg) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=1/1) to give 4-chloro-N-(2-fluoro-6-methoxyphenyl)-N-methyl-3-nitrobenzenesulfonamide (0.4 g). This material was dissolved in tetrahydrofuran (3 mL). To the solution were added methanol (3 mL) and nickel(II) bromide (12 mg). To the mixture was added sodium borohydride (0.12 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 1 hour. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=1/4) to give the title compound (0.3 g).
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([OH:11])=O)[C:4]=1[CH3:12])=[O:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[CH3:49][N:50]([CH3:54])[CH2:51][CH2:52][NH2:53].[OH-].[Na+]>CN(C)C=O.[Cl-].[Na+].O.O>[CH3:49][N:50]([CH3:54])[CH2:51][CH2:52][NH:53][C:9]([C:5]1[C:4]([CH3:12])=[C:3]([CH:1]=[O:2])[NH:7][C:6]=1[CH3:8])=[O:11]
Reactant: CN(C)CCN
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN(C)C
Reaction time: 0.08 h
Yield: 42 %

Procedure:
To a mixture of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1.67 g, 10 mmol) in dimethylformamide (10 mL) was added benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent, 6 g, 13.5 mmol) followed by 3 mL diisopropylethylamine. After stirring for 5 minutes, 1 mL of N,N-dimethylethylendiamine was added and the mixture was stirred at room temperature for 24 hours. To the reaction mixture was added 25 mL of 1N sodium hydroxide and 25 mL of brine. After stirring for 30 minutes, the reaction mixture was poured into water (100 mL) and extracted (3×200 mL) with 10% of methanol in dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and evaporated using a rotary evaporator. The residue which remained was purified by chromatography (silica gel column, 5%-10% methanol in dichloromethane) to give 1 g (42%) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-dimethylamino-ethyl)-amide.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[CH2:17][CH2:16][N:15]([C:18]([O-:20])=[O:19])[CH2:14]1)=[O:6]>CO>[C:7]([O:20][C:18]([N:15]1[CH2:16][CH2:17][CH:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:5]([OH:4])=[O:6])[CH2:14]1)=[O:19])([CH3:12])([CH3:8])[CH3:5]
Reactant: COC(=O)c1ccccc1C1CCN(C(=O)[O-])C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2C(=O)O)C1
Temperature: 65 °C
Reaction time: 8 h
Yield: 195.6 %

Procedure:
NaOH 5M (7.7 ml, 38.6 mmol, 2 eq) is added to a stirred solution of 3-[2-(methoxycarbonyl)phenyl]pyrrolidine-1-carboxylate a1-2 (5.9 g, 19.3 mmol, 1 eq) in MeOH (50 ml) at 65° C. The reaction mixture is stirred overnight at 65° C., then evaporated under vacuum and water (40 ml) is added. The resulting mixture is extracted with ethyl acetate/ethanol (100 ml/10 ml) and again with ethyl acetate (100 ml). The combined organic layers are dried over MgSO4, filtered off and evaporated under vacuum to afford 5.5 g of pure 2-[1-(tert-butoxycarbonyl)pyrrolidin-3-yl]benzoic acid a1-3.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[C:10]=2[CH3:18])[O:3]1>CO>[CH3:18][C:10]1[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:19])([CH3:1])[O:3]2)=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:15]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1[N+](=O)[O-]
Solvent: CO
Product: Cc1c(N)cccc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 13 h
Yield: 109 %

Procedure:
A 500-mL round-bottomed flask equipped with a magnetic stirrer was charged with 4,4,5,5-Tetramethyl-2-(2-methyl-3-nitro-phenyl)-[1,3,2]dioxaborolane (6) (8.44 g; 32.1 mmol) and methanol (150 mL). The reaction flask was twice evacuated and back-filled with argon. 10% Palladium on charcoal (50% wet, 425 mg dry weight) was then added to the solution, and the reaction flask evacuated and back-filled with hydrogen three times. The reaction was then stirred under balloon pressure of hydrogen at room temperature for 13 h. After this time, the flask was twice evacuated and back-filled with argon, then filtered through a pad of Celite 521 and the filtrate concentrated in vacuo. The resulting residue was dried under high vacuum for 1 d to afford a quantitative yield (8.16 g) of 2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (7) as a white solid: mp 110-112° C.; MS (ESI+) m/z 234 (M+H).