Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[CH:23])[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:25]1[CH:26]=[C:27]([C:31]2[S:32][C:33]([CH3:36])=[N:34][N:35]=2)[CH:28]=[CH:29][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.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>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:29]4[CH:30]=[CH:25][CH:26]=[C:27]([C:31]5[S:32][C:33]([CH3:36])=[N:34][N:35]=5)[CH:28]=4)[CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH2:20]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1nnc(-c2cccc(I)c2)s1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCC(=O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C#Cc3cccc(-c4nnc(C)s4)c3)CCC(=O)CC2)cc1OC1CCCC1
Reaction time: 15 h
Yield: 82.2 %

Procedure:
A stirred mixture of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-one (0.100 g, 0.32 mmol) and 2-(3-iodophenyl)-5-methyl-[1,3,4]thiadiazole (0.097 g, 0.32 mmol) in dry triethylamine (2.5 mL) was treated under argon with a mixture of tetrakis(triphenylphosphine)palladium (0.016 g, 0.013 mmol), cuprous iodide (0.0033 g, 0.017 mmol), and triphenylphosphine (a small crystal) at 70° C. for 1 h and at 25° C. for 15 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between methylene chloride and cold dilute hydrochloric acid. The organic phase was chromatographed (silica, 10 to 20% ethyl acetate in methylene chloride) and the pure fractions were combined, concentrated in vacuo and dried at 50° C. in vacuo and the brittle resin ground to afford the titled compound as a yellow powder (0.128 g, 79%). Anal. (C29H3ON2)3S.H2O) calcd: C 69.02, H 6.39, N 5.55, found: C 68.91, H 6.21, N 5.35. 1H-NMR (400 MHz, CDCl3) δ 8.06 (t, J=1.6 Hz, 1H), 7.88 (d-t, J=1.4 Hz, J=8.1 Hz, 1H), 7.58 (d-d, J=1.2 Hz, J=9.0 Hz, 1H), 7.45 (t, J=7.8 Hz), 7.21 (d, J=2.2, 1H), 7.14 (dd, J=8.4 Hz, J=2.1 Hz, 1H), 6.88 (d, J=8.5, 1H), 4.82 (p, J=4.1 Hz, 1H), 3.86 (s, 3H), 3.04 (d-t, J=6.1 Hz, J=14.2, 2H), 2.84 (s, 3H), 2.50 (d,br, J=14.9, 2H), 2.42-2.32 (m, 2H), 2.27 (d-t, J=2.8 Hz, J=14.2 Hz, 2H), 2.00-1.5 (m, 12H with H2O).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]([C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[NH2:31])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[CH3:40][O:41][C:42](=[O:47])[CH2:43][C:44](Cl)=[O:45]>CCOC(C)=O>[CH3:40][O:41][C:42](=[O:47])[CH2:43][C:44]([NH:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=1[C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([S:15]([C:13]2[CH:14]=[C:10]([C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:34])=[NH:9])[S:11][C:12]=2[S:32][CH3:33])(=[O:17])=[O:16])[CH:19]=1)=[O:45]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2N)c1
Reactant: COC(=O)CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CC(=O)Nc1cccc(C)c1-c1cccc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
{[4-(2′-Amino-6′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (22 mg, 0.04 mmol, Example 25: step c ) was dissolved into THF (1 mL) and to this was added chlorocarbonyl-acetic acid methyl ester (9 μL, 0.085 mmol). The reaction was heated to 50° C. for 5 hours and then allowed to stir at RT for 48 hours. The reaction mixture was dissolved into EtOAc and washed with brine. The organic layers were dried (MgSO4) and removal of the solvents in vacuo was followed by purification by preparative TLC (SiO2) (30% EtOAc in hexanes) that yielded the title compound. ESI-MS (m/z): Calcd. for C28H31N3O7S3: 618.1 (M+1) found: 617.9.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C@@H:30]1[CH2:32][C@@H:31]1[C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)=[O:29])[CH3:26]>CCO>[CH2:25]([O:27][C:28]([C@@H:30]1[CH2:32][C@@H:31]1[C:33]1[CH:38]=[CH:37][C:36]([C:20]2[CH:21]=[CH:22][C:17]([C:16]3[O:15][N:14]=[C:13]([CH3:24])[C:12]=3[C@@H:10]([OH:11])[CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:18][CH:19]=2)=[CH:35][CH:34]=1)=[O:29])[CH3:26]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)COCc1ccccc1
Reactant: CCOC(=O)[C@@H]1C[C@@H]1c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Solvent: CCO
Product: CCOC(=O)[C@@H]1C[C@@H]1c1ccc(-c2ccc(-c3onc(C)c3[C@@H](O)COCc3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 2-benzyloxy-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]ethanol and (cis)-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester. After the reaction the crude material was dissolved in EtOH (3 mL) and purified via preparatory chiral HPLC (Chiralcel-AD column, 8% EtOH in hexanes, 70 minutes) to afford three separate compounds. The first compound off of the column, containing a mixture of cis-cyclopropyl diastereomers, was the title compound.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][N:4]=1)#[CH:2].[N:12]([C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[N:19][CH:20]=1)=[N+:13]=[N-:14]>O1CCOCC1.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[Cl:21][C:18]1[N:19]=[CH:20][C:15]([N:12]2[CH:2]=[C:1]([C:3]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[NH:5][N:4]=3)[N:14]=[N:13]2)=[CH:16][CH:17]=1
Reactant: [N-]=[N+]=Nc1ccc(Cl)nc1
Reactant: C#Cc1n[nH]c2ccccc12
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Clc1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cn1
Temperature: 80 °C

Procedure:
3-Ethynyl-1H-indazole (249 mg; 1.75 mmol; 1.0 eq.) and 5-azido-2-chloropyridine (270 mg; 1.75 mmol; 1.0 eq.) were dissolved in 1,4-dioxane (11 mL). D-(−)-isoascorbic acid sodium salt (69 mg; 0.35 mmol; 0.2 eq.) was added followed by copper sulfate pentahydrate (17.5 mg; 0.07 mmol; 0.04 eq.) in water (3.7 mL) and the reaction mixture was heated at 80° C. for 2 days. The precipitate obtained was filtered, washed with water and EtOAc and dried under vacuum to afford the title compound as a beige powder. m.p.=272-280° C. 1H NMR (300 Mz, DMSO-d6) δ 13.40 (s, 1H), 9.44 (s, 1H), 9.16 (d, J=2.8 Hz, 1H), 8.56 (dd, J=2.9, 8.8 Hz, 1H), 8.33 (d, J=8.1 Hz, 1H), 7.83 (d, J=8.9 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.44 (m, 1H), 7.26 (m, 1H). HPLC (Condition A): Rt 3.30 min (purity 100%).
Reaction SMILES: C([O-])(=O)C.[Na+].[CH3:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][C:14]#[N:15])=[CH:10][CH:9]=1.Cl.[NH2:19][OH:20]>CO>[OH:20][NH:19][C:14](=[NH:15])[CH2:13][O:12][C:11]1[CH:16]=[CH:17][C:8]([O:7][CH3:6])=[CH:9][CH:10]=1
Reactant: NO
Reactant: COc1ccc(OCC#N)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(OCC(=N)NO)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Add sodium acetate (5.1 g, 62 mmol) to 4-methoxyphenoxyacetonitrile (5.0 g, 31 mmol) and hydroxylamine hydrochloride (4.3 g, 62 mmol) in methanol (100 mL). Stir the resulting mixture at room temperature for 20 hours. Filter the resulting mixture through Celite, concentrate, stir in chloroform for 18 hours and filter. Concentrate the resulting solution to the title compound (5.1 g). LC-MS (m/e): 197 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[C:17]([CH3:23])=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:24]([C:28]1[CH:32]=[C:31]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[N:30]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[N:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([C:28]1[CH:32]=[C:31]([NH:33][C:34]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[C:17]=2[CH3:23])=[O:35])[N:30]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[N:29]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3C)c2cc1OC
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C)cc4)c3C)c2cc1OC
Yield: 80 %

Procedure:
The title compound was prepared from 3-(6,7-dimethoxyquinazolin-4-yloxy)-2-methylaniline (93 mg, 0.3 mmol) and phenyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate (105 mg, 0.3 mmol) using the procedure in Example 115C to give 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)-2-methylphenyl)urea (134 mg, 0.24 mmol, 79%). 1H NMR (300 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.52 (s, 1H), 8.41 (s, 1H), 7.72 (d, 1H), 7.60 (s, 1H), 7.47-7.32 (m, 5H), 7.25 (t, 1H), 6.96 (d, 1H), 6.37 (s, 1H), 3.99 (s, 6H), 2.36 (s, 3H), 1.95 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 567 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1>C(Cl)(Cl)Cl>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][O:1][C:2]2[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=2)=[CH:25][CH:24]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccc(Cl)cc2)cn1
Reaction time: 0.17 h

Procedure:
A mixture of 5-hydroxy-2-nitropyridine (7 g), K2CO3 (6.9 g) and DMF (100 ml) is stirred for about 10 minutes. To the mixture is added 4-chlorobenzyl chloride (8.1 g) in portions over about 15 minutes. The reaction mixture is stirred about 16 hours and then heated to 45° for about 30 minutes. After cooling, the reaction is diluted with CHCl3, washed with water and saturated NaCl, dried (Na2SO4) and stripped. The crystalline solid is washed with 20% ethyl acetate/hexane, giving 5-(4-chlorobenzyloxy)-2-nitropyridine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[C:10]=1[CH2:19][CH2:20][CH3:21])[CH3:2].[S:23]([O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35]OS(=O)(=O)C)(=[O:26])(=[O:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([O:18][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][S:23]([CH3:24])(=[O:25])=[O:26])[C:10]=1[CH2:19][CH2:20][CH3:21])[CH3:2]
Reactant: CS(=O)(=O)OCCOCCOCCOS(C)(=O)=O
Reactant: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1OCCOCCOCCOS(C)(=O)=O
Yield: 44.6 %

Procedure:
A mixture of 4.0 g of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butanoic acid ethyl ester, 19.9 g of triethylene glycol dimesylate and 3.6 g of anhydrous potassium carbonate in 80 ml of anhydrous acetone and 40 ml of anhydrous dimethylformamide was stirred at reflux for 23 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to an oil which was purified by high pressure liquid chromatography using 30% ethyl acetate-toluene to give 3.0 g (45% yield) of 4-[4-acetyl-3-[2-[2-[2-[(methylsulfonyl)oxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoic acid ethyl ester as an oil.
Reaction SMILES: [C:1]1([C:9]([CH:11]([C:13]2[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=2)O)=[O:10])[CH:8]=[CH:7][C:4]([O:5][CH3:6])=[CH:3][CH:2]=1.C(Cl)[Cl:22].S(Cl)(Cl)=O>N1C=CC=CC=1>[Cl:22][CH:11]([C:13]1[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=1)[C:9](=[O:10])[C:1]1[CH:8]=[CH:7][C:4]([O:5][CH3:6])=[CH:3][CH:2]=1
Reactant: COc1ccc(C(=O)C(O)c2ccc(OC)cc2)cc1
Reactant: ClCCl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: COc1ccc(C(=O)C(Cl)c2ccc(OC)cc2)cc1
Reaction time: 0.83 h

Procedure:
Anisoin (2.87 g), 100 mL of methylene chloride, and pyridine (2.02 g) are placed in a flask under nitrogen. Thionyl chloride (1.60 ml) is added dropwise over 5 minutes using a water bath to maintain the reaction temperature between 25° C. and 30° C. After allowing the mixture stir for 50 minutes the reaction is quenched by washing with water (2×100 mL) and 100 mL of brine. The organics are dried over sodium sulfate, filtered, then concentrated. The resulting oil is taken up in 25 mL of diethyl ether and filtered. The filter cake is rinsed with 25 ml of diethyl ether. To the filtrate is added 25 ml of ethanol and the solution is concentrated. Crystals are allowed to form over 24 hours. The precipitate which forms is filtered, washed with 25 mL of ethanol, and dried in vacuo at 45° C. to give 4.00 g of product. (69%). Analysis calculated for C16H14ClO3 : C, 66.10; H, 5.20; Cl, 12.19. Found: C, 66.29; H, 5.32; Cl, 12.56. MS(FD) 290.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[N:8]=[CH:7]1)([CH3:5])[CH:3]=O.[CH3:14][C@H:15]1[O:20][C@@H:19]([CH3:21])[CH2:18][NH:17][CH2:16]1>>[CH3:21][CH:19]1[O:20][CH:15]([CH3:14])[CH2:16][N:17]([CH2:3][C:2]([CH3:1])([N:6]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[N:8]=[CH:7]2)[CH3:5])[CH2:18]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: CC(C)(C=O)n1cnc([N+](=O)[O-])c1
Product: CC1CN(CC(C)(C)n2cnc([N+](=O)[O-])c2)CC(C)O1

Procedure:
2-Methyl-2-(4-nitro-imidazol-1-yl)-propionaldehyde was reacted with cis-2,6-dimethyl morpholine to provide the title compound: C13 NMR (100 MHz, CDCl3) 19.0, 25.7, 60.8, 61.5, 68.5, 72.0, 118.0, 134.5; MS m/z 283.2 (M+1).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[NH:6][C:5]2[N:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[N:10]=[C:11]([CH:12]3[CH2:15][CH2:14][CH2:13]3)[C:4]=2[CH:3]=1.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[C:25]([Cl:27])[CH:26]=1.[F-].[Cs+]>C(COC)OC.C(Cl)Cl.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:16]([N:9]1[C:5]2[NH:6][C:7](=[O:8])[C:2]([C:23]3[CH:22]=[C:21]([Cl:20])[CH:26]=[C:25]([Cl:27])[CH:24]=3)=[CH:3][C:4]=2[C:11]([CH:12]2[CH2:15][CH2:14][CH2:13]2)=[N:10]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)n1nc(C2CCC2)c2cc(Br)c(=O)[nH]c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: ClCCl
Product: CC(C)(C)n1nc(C2CCC2)c2cc(-c3cc(Cl)cc(Cl)c3)c(=O)[nH]c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 12 %

Procedure:
To a stirring solution of 5-bromo-1-tert-butyl-3-cyclobutyl-1,7-dihydro -pyrazolo[3,4-b]pyridin-6-one (50.0 mg, 0.15 mmol) in dimethoxyethane (1.5 mL) was added 3,5-dichlorophenyl-boronic acid (32.6 mg, 0.17 mmol), followed by cesium fluoride (51.9 mg, 0.34 mmol), and Pd(PPh3)4 (catalytic amount, 0.005 mmol). The reaction mixture was heated to reflux. After 3 hr, additional amounts of 3,5-dichlorophenyl-boronic acid (32.6 mg, 0.17 mmol), cesium fluoride (51.9 mg, 0.34 mmol), and Pd(PPh3)4 (catalytic amount, 0.005 mmol) were added. After a total of 18 hr, the reaction was cooled to room temperature, diluted with CH2Cl2 and washed with water. The organic layer was dried over MgSO4, filtered through a fritted funnel, and concentrated under reduced pressure. Purification of the resulting material was accomplished by flash chromatography with a Biotage® column, eluting with 5% EtOAc/toluene. The product-containing fractions were collected and concentrated to give the title compound (7.0 mg, 12% yield). LRMS m/z (APCl) 390. 392(M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].[CH2:11]([O:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27](O)=[O:28])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:11]([O:18][C:19](=[O:20])[NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27](=[O:28])[NH:1][C:2]1[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=1[NH2:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: O=C(O)CCCCCNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: N#Cc1ccc(N)c(NC(=O)CCCCCNC(=O)OCc2ccccc2)c1
Reaction time: 20 h
Yield: 65.9 %

Procedure:
The compound (510 mg) obtained in Example 46-1 was dissolved in DMF (20 ml). To this solution, a solution which was previously prepared by dissolving 6-benzyloxycarbonylamino-hexanoic acid (1.10 g) in DMF (10 ml), adding thereto WSCI hydrochloride (1.08 g) and HOBt (762 mg), and stirring the mixture for 30 minutes was dropped. The whole was stirred for 20 hours. The residue obtained by distilling the solvent off was subjected to extraction with chloroform. The organic layer was washed with water and a saturated saline solution, and dried with anhydrous sodium sulfate. The residue obtained by distilling the solvent off was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (961 mg) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[NH:5][C:4]=1[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1.C(N(C(C)C)CC)(C)C.[C:27]([CH2:31][CH2:32][C:33](Cl)=[O:34])([O:29][CH3:30])=[O:28]>C(Cl)Cl>[C:27]([CH2:31][CH2:32][C:33]([NH:1][CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[NH:5][C:4]=1[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[O:34])([O:29][CH3:30])=[O:28]
Reactant: COC(=O)CCC(=O)Cl
Reactant: NCc1cc(-c2cccs2)[nH]c1-c1cccs1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CCC(=O)NCc1cc(-c2cccs2)[nH]c1-c1cccs1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79.1 %

Procedure:
To a solution of 400 mg (1.54 mmol) of 3-aminomethyl-2,5-dithienylpyrrole (XVIII) and 378 ul (3.07 mmol) of diisopropylethylamine in 15 ml of anhydrous methylene chloride was added 3-carbomethoxypropionyl chloride (1.6 ml, 9.23 mmol). After stirring for 5 minutes at room temperature, the reaction mixture was quenched by the addition of 1 ml of water. The aqueous layer was extracted three times with 5 ml portions of chloroform and the combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude reaction product was chromatographed on 100 g of silica gel. Elution with chloroform:methanol, 95:5, gave 456 mg (39%) of the amide (XXVI) as a greenish solid having a mp of 48°-49° C., and Rf :0.55 (chloroform:methanol, 98:2).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[CH2:6][N:7]1[CH2:11][C@H:10]2[C@@H:12]([NH:15][C:16](=[O:23])[C@H:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH2:18])[CH2:13][CH2:14][C@H:9]2[CH2:8]1.C(N(CC)CC)C.[CH:36]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37]1>ClCCl>[CH:36]1([S:39]([NH:18][C@H:17]([C:16]([NH:15][C@@H:12]2[C@H:10]3[C@H:9]([CH2:8][N:7]([CH2:6][C:5]4[CH:24]=[CH:25][CH:26]=[C:3]([C:2]([F:27])([F:1])[F:28])[CH:4]=4)[CH2:11]3)[CH2:14][CH2:13]2)=[O:23])[CH2:19][CH:20]([CH3:21])[CH3:22])(=[O:41])=[O:40])[CH2:38][CH2:37]1
Reactant: CC(C)C[C@H](N)C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Reactant: O=S(=O)(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@H](NS(=O)(=O)C1CC1)C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N1-{(3aS,4S,6aR)-2-[3-(trifluoromethyl)benzyl]octahydrocyclopenta[c]pyrrol-4-yl}-L-leucinamide from Step A (80 mg, 0.184 mmol) in dichloromethane (0.5 mL) was added triethylamine (0.064 mL, 0.461 mmol) followed by cyclopropanesulfonyl chloride (38.9 mg, 0.277 mmol) in a solution of 300 μL dichloromethane and the reaction mixture was stirred at room temperature overnight. The reaction was reduced in volume and loaded onto a silica gel cartridge (Analogix®, Burlington, Wis., RS-12). The title compound was eluted with a gradient of 20% to 100% ethyl acetate/hexanes over 20 minutes to give N2-(cyclopropylsulfonyl)-N1-{(3aS,4S,6aR)-2-[3-(trifluoromethyl)benzyl]octahydrocyclopenta[c]pyrrol-4-yl}-L-leucinamide: 1H NMR (500 MHz, pyridine-d5) δ ppm 9.34 (d, J=9.0, 1H), 8.84 (d, J=6.8, 1H), 7.73 (s, 1H), 7.64 (d, J=7.5, 1H), 7.59 (d, J=12.3, 1H), 7.43 (dd, J=6.6, 14.3, 1H), 4.53-4.42 (m, 2H), 3.76 (d, J=13.2, 1H), 3.41 (d, J=13.2, 1H), 2.99 (qd, J=4.2, 8.0, 1H), 2.90 (dd, J=3.6, 9.5, 1H), 2.82-2.74 (m, 1H), 2.57-2.48 (m, 1H), 2.40 (dd, J=8.5, 19.8, 2H), 2.30 (dd, J=3.4, 9.2, 1H), 2.02 (td, J=6.5, 13.7, 1H), 1.94-1.85 (m, 2H), 1.85-1.78 (m, 1H), 1.71 (td, J=6.2, 11.6, 1H), 1.67-1.58 (m, 1H), 1.40-1.28 (m, 2H), 1.22 (dt, J=4.7, 10.8, 1H), 0.93 (ddd, J=6.6, 12.3, 14.0, 2H), 0.87 (d, J=6.5, 3H), 0.84 (d, J=6.7, 3H); MS (ESI+) m/z 502 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][C:17]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)=[O:18].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([C:17]([O:16][CH3:15])=[O:18])[CH:24]=2)=[CH:4][N:3]=1
Reactant: Clc1ncc(Br)cn1
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cccc(-c2cnc(Cl)nc2)c1
Temperature: 110 °C
Reaction time: 10.5 h
Yield: 14.9 %

Procedure:
To a solution of 1.93 g (10.0 mmol) of 2-chloro-5-bromopyrimidine in 30 ml of toluene, 4.12 g (30.0 mmol) of potassium carbonate, 1.89 g (10.5 mmol) of 3-(methoxycarbonyl)phenylboronic acid and 1.0 g (0.87 mmol) of tetrakis(triphenyl phosphine)palladium (0) were added, and the reaction solution was stirred at 110° C. for 10.5 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride aqueous solution in order and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=95/5-0/100 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 0.37 g of the title compound as a yellow solid (yield: 14%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([OH:22])=O)=[CH:14][CH:13]=3)=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[S:8][C:7]=2[CH:31]=1.[F:32][C:33]([F:38])([F:37])[CH2:34][CH2:35][NH2:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([NH:36][CH2:35][CH2:34][C:33]([F:38])([F:37])[F:32])=[O:22])=[CH:14][CH:13]=3)=[C:9]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[S:8][C:7]=2[CH:31]=1
Reactant: NCCC(F)(F)F
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/C(=O)O)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/C(=O)NCCC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a 30 mL vial containing (E)-3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (41 mg, 0.10 mmol) was added DMF (3 mL), followed by 3,3,3-trifluoropropan-1-amine (13.94 mg, 0.12 mmol), HATU (54.1 mg, 0.14 mmol), and DIEA (0.050 mL, 0.28 mmol). The mixture was stirred at room temperature for 30 min after which the reaction was quenched with sat. aq. NH4Cl and diluted with DCM. The organic phase was collected (phase separator) and concentrated in vacuo onto silica gel. The crude material was purified by column chromatography (SiO2, 0-30% EtOAc/heptane) to afford (E)-3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)-N-(3,3,3-trifluoropropyl)acrylamide (38 mg, 0.07 mmol, 72% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm=7.64 (d, J=9.09 Hz, 2H), 7.45-7.56 (m, 3H), 7.42 (d, J=2.02 Hz, 1H), 7.25 (d, J=8.59 Hz, 1H), 6.90-7.02 (m, 5H), 6.47 (d, J=15.66 Hz, 1H), 3.88 (s, 3H), 3.74-3.85 (m, 3H), 3.54 (t, J=7.07 Hz, 2H), 2.34-2.56 (m, 2H). LC/MS (m/z, MH+): 528.3.