Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:18][C:19](=[O:28])[C:20]1[CH:25]=[C:24]([Br:26])[CH:23]=[CH:22][C:21]=1[OH:27])[CH2:5]C1C=CC(C2C=CC=CC=2)=CC=1.[CH2:30]([O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44]Cl)=[CH:40][C:39]=1[O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH3:1][O:2][C:3](=[O:29])[CH:4]([NH:18][C:19](=[O:28])[C:20]1[CH:25]=[C:24]([Br:26])[CH:23]=[CH:22][C:21]=1[O:27][CH2:44][C:41]1[CH:42]=[CH:43][C:38]([O:37][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:39]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:40]=1)[CH3:5]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(Br)ccc1O
Reactant: ClCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Product: COC(=O)C(C)NC(=O)c1cc(Br)ccc1OCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Yield: 61.1 %

Procedure:
3-Biphenyl-4-yl-2-S)-[2-(3,4-bis-benzyloxy-benzyloxy)-5-bromo-benzoylamino]-propionic acid methyl ester (340 mg) was prepared from 3-biphenyl-4-yl-2-(S)-(5-bromo-2-hydroxy-benzoylamino)-propionic acid methyl ester (400 mg, 0.92 mmol) (See example 136) and 1,2-bis-benzyloxy-4-chloromethyl-benzene (374 mg, 1.1 mmol) as described in general procedure G and purified over silica gel (8:2, DCM-hexanes).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([CH2:10]OC)OC.Br[C:14]1[CH:15]=[N:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2>C(Cl)(Cl)Cl>[C:23]1([C:14]2[CH:15]=[N:16][C:19]3[C:7]([CH:10]=2)=[CH:21][CH:22]=[CH:17][CH:18]=3)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:15]=[CH:14][CH:23]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: COCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: c1ccc2ncc(-c3cccc4ccccc34)cc2c1
Temperature: 90 °C

Procedure:
Next, 1.0 mL of 2.0 M potassium carbonate aqueous solution and tris(triphenylphosphine)palladium [Pd(PPh3)4] (30 mg, 0.026 mmol) were added to 4 mL of dimethoxyethane (DME) solution of the 1-naphthylboronic acid ester (2-1) (1.00 g, 5.00 mmol) and 3-bromoquinoline (0.62 g, 3.00 mmol), which then was refluxed at 90° C. for 12 hours. After completion of the reaction, it was cooled to room temperature, and 100 mL of chloroform was added thereto. This was washed with 100 mL of water twice and subsequently was washed with 50 mL of saturated saline. The solvent was removed therefrom and this then was purified by column chromatography using chloroform as a developing solvent. Thus 3-(1-naphthyl)quinoline (2-2) was obtained (84 mg, 11%). The instrumental analysis data of this 3-(1-naphthyl)quinoline (2-2) is indicated below.
Reaction SMILES: C[Al](C)C.[NH:5]1[CH2:10][CH2:9][S:8][CH2:7][CH2:6]1.C[O:12][C:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:23]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)=[N:24][O:25][C:26]=2[CH3:27])=[N:16][CH:15]=1.O>O1CCOCC1>[F:34][C:30]1[CH:29]=[C:28]([C:23]2[C:22]([CH2:21][O:20][C:17]3[N:16]=[CH:15][C:14]([C:13]([N:5]4[CH2:10][CH2:9][S:8][CH2:7][CH2:6]4)=[O:12])=[CH:19][CH:18]=3)=[C:26]([CH3:27])[O:25][N:24]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: C1CSCCN1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: O
Product: Cc1onc(-c2cccc(F)c2)c1COc1ccc(C(=O)N2CCSCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 600 μL, 1.2 mmol) was added dropwise (exothermic) to a solution of thiomorpholine (124 mg, 120 μL, 1.2 mmol) in dioxane (7.5 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (103 mg, 0.3 mmol) in dioxane (4 mL) was added. The resulting mixture was then heated at 85-95° C. for 4 h and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:3) afforded the title compound (124 mg, 100%) which was obtained as a light yellow gum. MS: m/e=414.4 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11].[CH3:13][Si](C=[N+]=[N-])(C)C>C1COCC1>[CH3:13][O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][Br:1]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)Cc1ccccc1CBr
Solvent: C1CCOC1
Product: COC(=O)Cc1ccccc1CBr
Temperature: 0 °C
Reaction time: 14 h
Yield: 32 %

Procedure:
To an ice-cold solution of (2-bromomethylphenyl)acetic acid (1 g, 4.4 mmol) in THF (2.4 mL) was added trimethylsilyldiazomethane (3 mL of a 2 M solution in hexanes, 6 mmol), and the reaction mixture was stirred for 14 h. The reaction was quenched with AcOH, and the solvent was removed under reduced pressure. Purification by flash column chromatography (silica, eluent 98:2 to 94:6 methylene chloride/hexanes) afforded methyl(2-bromomethylphenyl)acetate as a light yellow solid (0.34 g, 32%): 1H NMR (300 MHz, CDCl3) δ 7.40-7.20 (m, 4H), 4.59 (s, 2H), 3.81 (s 2H), 3.71 (s, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([C:11]#[N:12])=[CH:9][NH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].Cl>CO>[C:11]([C:10]1[C:6]([C:4]([OH:5])=[O:3])=[CH:7][NH:8][CH:9]=1)#[N:12]
Reactant: CCOC(=O)c1c[nH]cc1C#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1c[nH]cc1C(=O)O
Temperature: 50 °C
Reaction time: 5 h
Yield: 78.9 %

Procedure:
To a solution of 4-cyano-1H-pyrrole-3-carboxylic acid ethyl ester (1.1 g) in methanol (65 mL) was added 1 mol/L aqueous sodium hydroxide solution (65 mL), and this mixture was stirred at 50° C. for 5 hours. To this reaction mixture was added 1 mol/L hydrochloric acid, this mixture was extracted with ethyl acetate. This organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. This obtained residue was washed with diethyl ether to give the title compound (0.72 g).
Reaction SMILES: C(/[CH:4]=[CH:5]/[C:6]1[C:7]([O:14][CH3:15])=[N:8][C:9]([O:12][CH3:13])=[N:10][CH:11]=1)(O)=O.C([O-])([O-])=O.[K+].[K+].[Br:22]N1C(=O)CCC1=O>CN(C=O)C>[Br:22]/[CH:4]=[CH:5]/[C:6]1[C:7]([O:14][CH3:15])=[N:8][C:9]([O:12][CH3:13])=[N:10][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ncc(/C=C/C(=O)O)c(OC)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ncc(/C=C/Br)c(OC)n1

Procedure:
To a solution of E-5-(2-carboxyvinyl)-2,4-dimethoxypyrimidine (0.300 g; 1.43 retool) in dry DMF (5 ml) was added K2CO3 (0.45 g: 5.25 mmol). After stirring at ambient temperature for 15 min. a solution of N-bromosuccinimide (0.258 g; 1.45 mmol) in dry DMF (4 ml) was added dropwise over 10 min. The suspension was immediately filtered, the solid washed with DMF and the filtrate evaporated in high vacuum. The solid residue was purified by column chromatography by preloading on SiO2 and eluting with EtOAc-hexane (7:3, v/v). Product fractions were pooled and evaporated to give fine white crystals, yield 0.561 g (45%). FAB mass spectrum: m/z245 and 247 (M+H)+. Analysis, found: C,39.9; H, 3.6; N, 11.5% C8H9BrN2O2 requires C, 40.20; H, 3.70; N. 11.43%.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C@@:7]23[CH2:14][C@@H:13]([OH:15])[CH2:12][N:11]2[C:10](=[O:16])[N:9]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=2)[C:8]3=[O:25])=[CH:4][CH:3]=1.[CH3:28][CH2:29][O:30]C(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)(=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@:7]23[CH2:14][C@H:13]([O:15][C:29](=[O:30])[CH3:28])[CH2:12][N:11]2[C:10](=[O:16])[N:9]([C:17]2[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([Cl:23])[CH:22]=2)[C:8]3=[O:25])=[CH:26][CH:27]=1
Reactant: CCOC(=O)/N=N/C(=O)OCC
Reactant: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]2(Cc3ccc(Br)cc3)C[C@@H](O)CN12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)O[C@@H]1CN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)[C@]2(Cc2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (5S,7R)-5-(4-bromobenzyl)-3-(3,5-dichlorophenyl)-7-hydroxy-1,3-diazabicyclo[3.3.0]octane-2,4-dione (0.21 g) in THF (5 mL) was added DEAD (0.09 mL), triphenylphosphine (0.15 g), and acetic acid (0.035 mL). After stirring overnight at room temperature, the mixture was concentrated. Purification by chromatography (Silica gel: 25% EtOAc/hexane, Chromatotron) afforded the titled compound (0.151 g). MS (m/z) 511 (MH+), mp 149.8° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:12]2[NH:13][C:14](=[O:21])[C:15]([CH:18]([CH3:20])[CH3:19])([CH3:17])[N:16]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[OH:22][C:23]([CH3:27])([CH3:26])[C:24]#[CH:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C>[OH:22][C:23]([CH3:27])([CH3:26])[C:24]#[C:25][C:2]1[CH:3]=[N:4][C:5]([C:12]2[NH:13][C:14](=[O:21])[C:15]([CH:18]([CH3:20])[CH3:19])([CH3:17])[N:16]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cnc1C1=NC(C)(C(C)C)C(=O)N1
Reactant: C#CC(C)(C)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C#CC(C)(C)O)cnc1C1=NC(C)(C(C)C)C(=O)N1

Procedure:
A stirred mixture of 12.6 g of 5-bromo-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinic acid, methyl ester, 3.4 g of 3-hydroxy-3-methyl-1-butyne, 0.02 g of bis(triphenylphosphine)palladium(II)-chloride, 0.04 g of triphenylphosphine, and 0.02 g of cuprous iodide in 300 mL of dry triethylamine is heated at reflux for 72 hours. The reaction is then filtered hot through celite, and the filtering agent is washed with methylene chloride. The combined filtrates were concentrated in vacuo, and the residue is partitioned between dilute aqueous hydrochloric acid and methylene chloride. The organic phase is washed with brine, dried, concentrated in vacuo, and the residue is chromatographed on silica gel using ether-methylene chloride mixtures to afford the desired product, mp 142°-145°.
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[C:13]([N:14]=[C:15]=[S:16])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)[NH:27][NH2:28])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[C:13]([NH:14][C:15](=[S:16])[NH:27][NH2:28])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1N=C=S
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccccc1Oc1ncccc1NC(=S)NN
Reaction time: 2 h
Yield: 118.9 %

Procedure:
A mixture of Example 1a (1 g, 3.51 mmol) and tert-butylcarbazate (465 mg, 3.51 mmol) in DCM (10 mL) was stirred at rt for 2 h. Trifluoroacetic acid (2 mL) was added and mixture was stirred for 2 h. The solvent was removed and the residue was dissolved in EtOAc (15 mL), washed with saturated sodium bicarbonate solution, dried (anh. MgSO4), filtered and evaporated to give the title compound (1.32 g) as a brown solid. (M+H)+=317.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7](/[CH:9]=[CH:10]/[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl.N1C=CC=CC=1>[CH3:25][S:26]([NH:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7](/[CH:9]=[CH:10]/[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1)(=[O:28])=[O:27]
Reactant: Nc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.5 %

Procedure:
To a stirred solution of (E)-5-amino-1-(2-pyridyl)-2-styryl-1H-benzimidazole (162 mg, 0.52 mmol) in dichloromethane (3 ml) and pyridine (1 ml) was added a solution of methanesulfonyl chloride (63 mg, 0.55 mmol) in dichloromethane (2 ml) dropwise. The reaction mixture was stirred for 2 h at room temperature and then partitioned between ethyl acetate (50 ml) and saturated aqueous sodium bicarbonate solution (50 ml). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (50 ml). The combined extracts were washed with brine (50 ml), dried (sodium sulfate) and concentrated in vacuo to give brown oil. It was purified by column chromatography (silica gel, 20 g; n-hexane/ethyl acetate (5/1)). Recrystallization of the residue from ethyl acetate afforded 70 mg (34%) of the titled compound as off white solids.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:6][CH2:7][CH3:8])[C:3]([NH2:5])=[O:4].[Cl:10]O>C(OCC)(=O)C>[Cl:10][NH:5][C:3](=[O:4])[C:2]([CH3:9])([CH3:1])[CH2:6][CH2:7][CH3:8]
Reactant: OCl
Reactant: CCCC(C)(C)C(N)=O
Solvent: CCOC(C)=O
Product: CCCC(C)(C)C(=O)NCl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
A stirred suspension of 2,2-dimethyl valeramide (35 g, 271 mmol) in ethyl acetate (200 ml) was cooled to 0° C. and hypochlorous acid (40.0 g of 36.2% solution, 276 mmol) was added dropwise over 12 minutes. The resulting clear yellow solution was then stirred for 30 minutes at room temperature, the organic phase separated and dried (MgSO4) and the ethyl acetate removed in vacuo to give 39.35 g of low-melting solid product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([F:20])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([C:15]([CH2:8][C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)([CH2:14][N:11]1[CH2:10][CH2:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)([F:20])[CH2:13][CH2:12]1)[C:16]([O:18][CH3:19])=[O:17])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC(=O)CCN1CCC(F)(c2ccc(Cl)cc2)CC1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COC(=O)C(Cc1ccccc1)(Cc1ccccc1)CN1CCC(F)(c2ccc(Cl)cc2)CC1
Yield: 38 %

Procedure:
This compound was prepared from methyl 3-[4-(4-chlorophenyl)-4-fluoropiperidin-1-yl]propionate and 2.5 equivalents of both lithium hexamethyldisilazide and benzyl bromide as described in Step 2 of Example 4 in 38% yield.
Reaction SMILES: C([O:5][C:6](=[O:43])[C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:21]=2[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:10]=[C:9]([Br:42])[CH:8]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Br:42][C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:21]=2[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:10]=1)[C:6]([OH:43])=[O:5]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)OC(C)(C)C)c2)c1CCC(=O)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)O)c2)c1CCC(=O)OCC
Reaction time: 4 h
Yield: 99.9 %

Procedure:
To a solution of 3-bromo-5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-benzoic acid tert-butyl ester (2.3 g, 3.46 mmol) in dichloromethane (25 mL) was added trifluoroacetic acid (10 mL) at room temperature. The resulting light brown solution was stirred for 4 h. Then, the dichloromethane and excess TFA was removed under reduced pressure and the residue was dissolved in toluene and again removed under reduced pressure to remove all TFA to obtain 3-bromo-5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-benzoic acid (2.1 g, 100%) as a light brown oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH2:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)[CH3:18]>>[CH2:17]([C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[N:6][CH:5]=[C:4]([CH:3]=2)[C:14]([OH:16])=[O:15])=[CH:21][CH:20]=1)[CH3:18]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(Br)c1
Product: CCc1ccc(-c2cc(C(=O)O)cnc2OCC(F)(F)F)cc1

Procedure:
The title compound was synthesized in analogy to Example BQ using 5-bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1211586-75-2) and B-(4-ethylphenyl)-boronic acid, (CAN 63139-21-9) as starting materials; LC-MS (UV peak area/ESI) 95.8%, 324.0859 (M−H)−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[NH:16][CH:15]=[CH:14][N:10]3[C:11](=[O:13])[CH:12]=2)=[N:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31]OS(C)(=O)=O)=[C:26]([O:37][CH3:38])[CH:25]=1>CN(C)C=O>[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][N:16]2[C:9]3=[N:8][C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][N:3]=4)=[CH:12][C:11](=[O:13])[N:10]3[CH:14]=[CH:15]2)=[C:26]([O:37][CH3:38])[CH:25]=1
Reactant: COc1cc(F)ccc1CCOS(C)(=O)=O
Reactant: O=c1cc(-c2ccncn2)nc2[nH]ccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(F)ccc1CCn1ccn2c(=O)cc(-c3ccncn3)nc12
Temperature: 70 °C

Procedure:
A suspension of 0.4 g (1.88 mmol) of 7-(pyrimidin-4-yl)-1H-imidazo[1,2-a]pyrimidin-5-one in 10 ml of anhydrous N,N-dimethylformamide was treated with 337 mg (2.44 mmol) of potassium carbonate and the resulting mixture was heated at 70° C. for 30 min. 605 mg (2.44 mmol) of methanesulfonic acid 2-(4-fluoro-2-methoxy-phenyl)-ethyl ester was added and the reaction mixture was heated at 80° C. during 16 h.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]([CH:24]2[CH2:27][C:26]([F:29])([F:28])[CH2:25]2)=[CH2:23])[N:16]=3)=[C:9]([F:30])[CH:8]=1.[I-].[CH3:32][S+](C)(C)=O.CC([O-])(C)C.[K+]>C1COCC1.CS(C)=O>[O:3]1[CH2:4][CH2:5][CH2:6][O:1][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]2([CH:24]4[CH2:27][C:26]([F:29])([F:28])[CH2:25]4)[CH2:32][CH2:23]2)[N:16]=3)=[C:9]([F:30])[CH:8]=1
Reactant: C=C(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1)C1CC(F)(F)C1
Reactant: C[S+](C)(C)=O
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(C3(C4CC(F)(F)C4)CC3)nc2s1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
A solution of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-(3,3-difluoro-cyclobutyl)vinyl)thiazolo[5,4-b]pyridine (299.1 mg, 0.692 mmol) in THF (13.33 mL) was added a solution of trimethylsulfoxonium iodide (913 mg, 4.15 mmol) and potassium 2-methylpropan-2-olate (466 mg, 4.15 mmol) in DMSO (8.0 mL) under argon, and the resulting solution was stirred at 60° C. for 2.5 h. The reaction mixture was then cooled to 25° C., THF was removed in vacuo, and the residual mixture was diluted with DCM (200 mL). The resulting solution was sequentially washed with sat. aq. NH4Cl and brine). The combined aqueous layers were extracted with DCM, and the combined organic layers were then dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-70% EtOAc/hexanes) furnished 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-(3,3-difluoro-cyclobutyl)cyclopropyl)thiazolo[5,4-b]pyridine as a light yellow solid. MS (ESI) m/z: Calculated: 446.1; Observed: 447.1 (M++1).
Reaction SMILES: C([Li])CCC.[C:6]([C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])#[CH:7].[CH2:20]([Sn:24](Cl)([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23].C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:29]([Sn:24]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:25][CH2:26][CH2:27][CH3:28])[C:7]#[C:6][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:30][CH2:31][CH3:32]
Reactant: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](C#C[C@@H]1CCCN1C(=O)OC(C)(C)C)(CCCC)CCCC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
n-Butyl lithium (2.5M solution in hexanes. 11 mL) was added dropwise to a cooled solution of tert-butyl (S)-2-ethynylpyrrolidine-1-carboxylate (prepared according A Paul et al, Tetrahedron, 2006, 62, 8919, 4.49 g) in dry THF (230 ml) under an atmosphere of nitrogen while maintaining the temperature below −65° C. When the addition was completed, the mixture was stirred at −78° C. for 15 minutes then allowed to warm to 0° C. and stirred for 2.5 hours. Tributyl tin chloride (7.7 mL) was added dropwise over five minutes and the mixture was stirred at room temperature for 1.5 hours. The mixture was cooled to 0° C. and saturated sodium bicarbonate was added while maintaining the temperature below 15° C. The layers were separated and the aqueous layer was extracted with ethyl acetate, washed with saturated sodium bicarbonate, water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of pentane and ethyl acetate with a gradient of 0-7.5% to give tert-butyl (S)-2-tributylstannanylethynylpyrrolidine-1-carboxylate (0.39 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:5](O)=[O:6].S(Cl)(Cl)=O.C[N:18](C=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:5]([NH2:18])=[O:6]
Reactant: CN(C)C=O
Reactant: COc1cc(Br)cc(C(=O)O)c1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1cc(Br)cc(C(N)=O)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
To a suspension of 3-bromo-5-(methyloxy)benzoic acid (9.6 g, 41.6 mmol) in toluene (60 mL) were added thionyl chloride (9.89 g, 83.1 mmol) and DMF (0.10 mL) and the mixture stirred at 50° C. for 4 h. The mixture was allowed to cool to room temperature, and then the excess thionyl chloride was removed in vacuo. The residue was dissolved in toluene (50 mL), and the mixture was added to a solution of ammonia (25%, 50 mL). A precipitate formed and was filtered off using Celite, and dried to afford 3-bromo-5-(methyloxy)benzamide (8.70 g, 90%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[Br:20]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Br:20][C:3]1[C:4]2=[N:5][CH:6]=[C:7]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH:8]=[C:9]2[NH:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(OCc1ccccc1)c1cnc2cc[nH]c2c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cnc2c(Br)c[nH]c2c1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
To a 0° C. solution of benzyl 1H-pyrrolo[3,2-b]pyridine-6-carboxylate (830 mg, 3.29 mmol) in N,N-dimethylformamide (19 mL) was added N-bromosuccinimide (609 mg, 3.42 mmol). The reaction was allowed to gradually warm to room temperature and stir over the weekend. The reaction was diluted with ethyl acetate and washed successively with saturated aqueous sodium thiosulfate, saturated aqueous sodium bicarbonate, water, and brine. The organics were dried over sodium sulfate, filtered, and concentrated to give the title compound (1.08 g, quantitative). +ESI (M+1+H) 333.0; 1H NMR (400 MHz, DMSO-d6, δ): 12.06 (br. s., 1 H), 8.99 (d, J=1.8 Hz, 1 H), 8.37 (d, J=2.0 Hz, 1 H), 8.14 (d, J=2.9 Hz, 1 H), 7.52 (m, 2 H), 7.41 (m, 3 H), 5.41 (s, 2 H).
Reaction SMILES: C([NH:4][C:5]1[C:10]2[CH2:11][C:12]([CH3:15])([CH3:14])[O:13][C:9]=2[C:8]([C:16]([O:18]C)=[O:17])=[CH:7][CH:6]=1)(=O)C.[OH-].[K+].Cl>O>[NH2:4][C:5]1[C:10]2[CH2:11][C:12]([CH3:15])([CH3:14])[O:13][C:9]=2[C:8]([C:16]([OH:18])=[O:17])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(NC(C)=O)c2c1OC(C)(C)C2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC1(C)Cc2c(N)ccc(C(=O)O)c2O1
Reaction time: 3 h
Yield: 79 %

Procedure:
A mixture of 58 parts of methyl 4-(acetylamino)-2,3-dihydro-2,2-dimethyl-7-benzofurancarboxylate, 123 parts of potassium hydroxide and 1100 parts of water was stirred for 3 hours at reflux temperature. After cooling, the reaction mixture was acidified to pH 1 with HCl. The precipitate was filtered off and dried in vacuo at 80° C., yielding 36 parts (79.0%) of 4-amino-2,3-dihydro-2,2-dimethyl-7-benzofurancarboxylic acid (interm. 6).