Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.S(=O)(=O)(O)O.[CH3:19]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:19])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Br)cc1[N+](=O)[O-]

Procedure:
To a methanol solution (50 ml) of 4-bromo-2-nitrobenzoic acid (2.54 g) was added concentrated sulfuric acid (1.0 ml), followed by heating at reflux for 4 hours. The reaction solution was concentrated under reduced pressure, and water (20 ml) was added to the residue. Under ice cooling, 5 N aqueous sodium hydroxide solution (2.0 ml) and a saturated aqueous sodium hydrogen carbonate solution were added, and extracted with dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford methyl 4-bromo-2-nitrobenzoate (619 mg).
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1OC)[C@H:13]1[NH:23][C@H:12]1[CH2:11]3.[CH2:26]([NH2:29])[CH:27]=[CH2:28]>CO>[C:18](=[O:17])([OH:19])[NH2:20].[OH:17][CH2:16][CH:15]1[C:6]2[C:4](=[O:5])[C:3]([NH:29][CH2:26][CH:27]=[CH2:28])=[C:2]([CH3:1])[C:8](=[O:9])[C:7]=2[N:10]2[CH2:11][CH:12]3[NH:23][CH:13]3[C:14]12[O:21][CH3:22]
Reactant: C=CCN
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Solvent: CO
Product: C=CCNC1=C(C)C(=O)C2=C(C1=O)C(CO)C1(OC)C3NC3CN21
Product: NC(=O)O
Reaction time: 8 h
Yield: 52.8 %

Procedure:
To a solution of 100 mg (0.28 mmol) of mitomycin A in 8 ml of anhydrous methanol, 150 mg (2.6 mmol) of allylamine was added with constant stirring. The reaction mixture was stirred overnight whereupon TLC indicated the absence of starting material. The solvent was then evaporated under reduced pressure and the residue was chromatographed using silica-gel as adsorbent. The fraction obtained by eluting the column from ethyl acetate was evaporated under reduced pressure. Recrystallization from a mixture of methylene chloride and hexane gave 29 mg (27.0% yield) of the desired product as purple-colored crystals having a melting point of 81°-82° (decomposing) and providing the following analysis:
Reaction SMILES: IC.[C:3]([O-])([O-])=O.[K+].[K+].[Cl:9][C:10]1[C:11]([C:29]2[N:33]=[CH:32][NH:31][N:30]=2)=[C:12]([NH:15][C:16](=[O:28])[CH2:17][N:18]2[C:23](=[O:24])[CH:22]=[CH:21][N:20]3[N:25]=[CH:26][CH:27]=[C:19]23)[S:13][CH:14]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:9][C:10]1[C:11]([C:29]2[N:33]=[CH:32][N:31]([CH3:3])[N:30]=2)=[C:12]([NH:15][C:16](=[O:28])[CH2:17][N:18]2[C:23](=[O:24])[CH:22]=[CH:21][N:20]3[N:25]=[CH:26][CH:27]=[C:19]23)[S:13][CH:14]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(Cn1c(=O)ccn2nccc12)Nc1scc(Cl)c1-c1nc[nH]n1
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1cnc(-c2c(Cl)csc2NC(=O)Cn2c(=O)ccn3nccc23)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Iodomethane (36 mg, 0.255 mmol) and K2CO3 (44 mg, 0.319 mmol) were added to a solution of N-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl)acetamide (80 mg, 0.212 mmol) in DMF (1 mL). The reaction mixture was stirred at room temperature for 30 minutes and was subsequently diluted with ethyl acetate and washed with brine. The organic phase was dried (Na2SO4), filtered, concentrated under vacuum and purified by preparative HPLC to give N-(4-chloro-3-(1-methyl-1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl)acetamide. Retention time (min)=3.00, method [7], MS(ESI) 390.1 (M+H); 1H NMR (300 MHz, CD3Cl) δ 8.25 (d, J=8.2 Hz, 1H), 7.90 (s, 1H), 7.76 (d, J=2.1 Hz, 1H), 6.79 (s, 1H), 6.22 (d, J=8.2 Hz, 1H), 5.97 (d, J=2.1 Hz, 1H), 5.36 (s, 2H), 3.99 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([S:12]([NH:15][C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])(=[O:14])=[O:13])[N:11]=[C:4]2[N:3]=1.[CH3:24]C(C)([O-])C.[K+].CI>C(#N)C.C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([S:12]([N:15]([CH3:24])[C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])(=[O:13])=[O:14])[N:11]=[C:4]2[N:3]=1
Reactant: Cc1cc(C)n2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2n1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Solvent: CI
Product: Cc1cc(C)n2nc(S(=O)(=O)N(C)c3c(Cl)cccc3Cl)nc2n1
Temperature: 25 °C
Yield: 51.4 %

Procedure:
A mixture of 3.00 g (8.06 mmol) of 5,7-dimethyl-N-(2,6-dichlorophenyl)-1,2,4-triazolo[1,5-a]-pyrimidine-2-sulfonamide and 0.90 g (8.1 mmol) of potassium t-butoxide in 30 ml of acetonitrile was heated at reflux for 40 minutes. After cooling to room temperature 1.14 g (8.06 mmol) of methyl iodide was added, and the reaction was heated at reflux for 1 hour. After cooling to room temperature, the reaction mixture was diluted with methylene chloride and washed with 1% aqueous NaOH. The organic phase was separated, dried (MgSO4) and evaporated at reduced pressure. The brown solid residue was recrystallized from acetone to give 1.60 g (51%) of the desire product as a tan solid, mp 220°-222° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@@H:10]([OH:13])[CH2:11]O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[OH-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@H:10]1[O:13][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CO1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To the mixture of (2R,3S)-3-(t-butoxycarbonyl)amino-4-phenyl-butane-1,2-diol (44 g) and 400 ml of pyridine, 60 g (2 equivalents) of p-TsCl was added and the solution was stirred at 0° C. for 4 hours. After pH of the solution was adjusted 10 with 25% NaOH and it was stirred at 0° C. for 3 hours. 400 ml of methylene chloride was added to the solution and it was washed by 400 ml of 1N HCl, 400 ml of 5% aq.NaHCO3 and 400 ml of water and was distillated under reduced pressure. A white crystal compound of (2R,3S)-3-(t-butoxycarbonyl)amino-1,2-epoxy-4-phenylbutane was obtained using a column chromatography.
Reaction SMILES: Br[CH2:2][CH:3]([CH3:31])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11]([CH2:12][C@@H:13]([O:27][CH2:28][O:29][CH3:30])[CH2:14][C@@H:15]2[O:23][CH2:24][O:25][CH3:26])=[CH:10][CH:9]=3)[CH2:6][CH2:5]1.[C:32]1([CH3:41])[CH:37]=[CH:36][C:35]([S:38]([O-:40])=[O:39])=[CH:34][CH:33]=1.[Na+].BrCC(C)[C@@H]1[C@]2(C)[C@H](C3[C@H](CC2)[C@]2(C)C(C[C@@H](OC(OC)=O)C[C@@H]2OC(OC)=O)=CC=3)CC1.C1(S([O-])=O)C=CC=CC=1.[Na+]>>[CH3:31][CH:3]([C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11]([CH2:12][C@@H:13]([O:27][CH2:28][O:29][CH3:30])[CH2:14][C@@H:15]2[O:23][CH2:24][O:25][CH3:26])=[CH:10][CH:9]=3)[CH2:6][CH2:5]1)[CH2:2][S:38]([C:35]1[CH:36]=[CH:37][C:32]([CH3:41])=[CH:33][CH:34]=1)(=[O:40])=[O:39]
Reactant: COCO[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CBr)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OCOC)C1
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CBr)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Agent: O=S([O-])c1ccccc1
Agent: [Na+]
Product: COCO[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CS(=O)(=O)c5ccc(C)cc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OCOC)C1
Yield: 63.3 %

Procedure:
The procedure of Example 5 was repeated except that 59 mg of 21-bromo-20-methyl-1α,3β-bis(methoxymethoxy)pregna-5,7-diene and 95 mg of sodium p-toluenesulfinate were used in lieu of 65 mg of 21-bromo-20-methyl-1α,3β-bis(methoxycarbonyloxy) pregna-5,7-diene and 80 mg of sodium benzenesulfinate, respectively, to give 43 mg of 20-methyl-1α,3β-bis(methoxymethoxy)-21-p-tolylsulfonylpregna-5,7-diene.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.[Cl:19][C:20]1[C:25]2[CH:26]=[N:27][NH:28][C:24]=2[CH:23]=[CH:22][N:21]=1>ClCCl>[Cl:19][C:20]1[C:25]2[CH:26]=[N:27][N:28]([CH:18]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:24]=2[CH:23]=[CH:22][N:21]=1
Reactant: Clc1nccc2[nH]ncc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: Clc1nccc2c1cnn2C1CCCCO1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
p-Toluenesulfonic acid monohydrate (2.4 g, 13 mmol) and 3,4-dihydro-2H-pyran (99%, 45 mL, 520 mmol) were sequentially added to a suspension of 4-chloro-1H-pyrazolo[4,3-c]pyridine (20.0 g, 130 mmol) in dichloromethane (400 mL). The reaction mixture was allowed to stir at room temperature for 24 hours, at which time it was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Eluents: 10%, then 30%, then 50% ethyl acetate in heptane) afforded the product as a white solid. Yield: 27.51 g, 115.7 mmol, 89%. LCMS m/z 238.1 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J=6.0 Hz, 1H), 8.16 (d, J=0.9 Hz, 1H), 7.47 (dd, J=6.0, 0.9 Hz, 1H), 5.73 (br dd, J=9.0, 2.7 Hz, 1H), 3.97-4.04 (m, 1H), 3.72-3.80 (m, 1H), 2.43-2.53 (m, 1H), 2.07-2.20 (m, 2H), 1.65-1.85 (m, 3H).
Reaction SMILES: [CH2:1]1[CH2:6]CC(N=C=NC2CCCCC2)C[CH2:2]1.[I:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1>CN(C)C1C=CN=CC=1.C(O)CC>[I:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([O:23][CH2:2][CH2:1][CH3:6])=[O:22])=[CH:19][CH:18]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)c1ccc(I)cc1
Agent: CN(C)c1ccncc1
Solvent: CCCO
Product: CCCOC(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
DCC (13.4 g) was added in one portion to 4-iodobenzoic acid (15.0 g), n-propanol (7.2 g) and 4-(dimethylamino)pyridine (0.6 g) in MC (50 ml) at 0° under nitrogen. The mixture was stirred at 0° for 10 min and at room temperature for 3 h, diluted with ER (50 ml), filtered and evaporated. The residue was treated with CX (50 ml), filtered and the filtrate evaporated to give the title compound as a pale yellow oil (16.2 g). T.l.c. (CX-ER 3:1) Rf 0.8.
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[H-].[Na+].[C:13]([O:22]C)(=O)[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:16].[CH3:24][OH:25]>C1(C)C(C)=CC=CC=1>[CH:20]1[C:14]2[C:13](=[O:22])[C:2]3[C:3](=[O:4])[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=4[O:25][C:24]=3[O:16][C:15]=2[CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccccc1O
Reactant: O=C(CO)c1ccccc1
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: O=c1c2ccccc2oc2oc3ccccc3c(=O)c12
Reaction time: 7 h

Procedure:
The starting material was prepared as follows: 13.6 g. 2-hydroxyacetophenone and 19.2 g NaH in 200 ml. of dry xylene containing 2 drops of methanol were heated under reflux to boiling. Then 15.2 g of methyl salicylate were added and heating continued for 7 hours. The needlemass was washed with ether and ice-water/acetic acid (2:1) and then recrystallized from C Cl4. Yield 5.0 g (20%); colorless crystals; m. 118°C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[S-:13][C:14]#[N:15].[K+].BrBr>C(O)(=O)C>[NH2:15][C:14]1[S:13][C:11]2[C:2](=[C:3]([C:4]([O:6][CH3:7])=[O:5])[CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:1]=1
Reactant: N#C[S-]
Reactant: COC(=O)c1cc(C)ccc1N
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: COC(=O)c1cc(C)cc2sc(N)nc12
Temperature: 0 °C

Procedure:
50 g (0.303 mol) of methyl 2-amino-5-methylbenzoate are dissolved in 300 ml of glacial acetic acid, and 120.6 g (1.24 mol) of potassium thiocyanate--dissolved in 200 ml of glacial acetic acid--are added. At 10° C., 17.42 ml (0.335 mol) of bromine are added dropwise, and the mixture is then stirred without cooling for 2 hours. The suspension is tipped into 3 l of ice-water, while stirring, and the precipitated product is filtered off with suction and washed with dilute sodium carbonate solution and water. The filter cake is suspended in H2O and the suspension is stirred at 100° C. overnight. After cooling, the product is filtered off with suction, washed with H2O and dried at 40° C. in vacuo.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)=[O:5])[CH3:2].Br[C:16]1[CH:17]=[N:18][N:19]2[CH:24]=[CH:23][CH:22]=[N:21][C:20]=12.C(Cl)Cl.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[N:18]1[N:19]2[CH:24]=[CH:23][CH:22]=[N:21][C:20]2=[C:16]([C:9]2[CH:10]=[CH:11][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)[CH:17]=1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: Brc1cnn2cccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1ccc(-c2cnn3cccnc23)cc1
Temperature: 85 °C

Procedure:
Water (160 mL) was added dropwise at room temperature to a mixture of 4-ethoxycarbonylphenylboronic acid (50 g, 0.26 mol), 3-bromopyrazolo[1,5-a]pyrimidine (56.25 g, 0.28 mol), Pd(ddpf)Cl2.CH2Cl2 (4.25 g, 5.21 mmol), and Cs2CO3 (169.42 g, 0.52 mol) in 1,4-dioxane (1 L). The reaction mixture was then heated 85° C. for 4 h. The reaction mixture was cooled, poured into water and extracted with EtOAc (2×300 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with a gradient of petroleum ether: EtOAc (100:10 to 3:1) to deliver the title compound (64 g, 93%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>C(N(C(C)C)C(C)C)C>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C#N)cn2)CC1
Yield: 63 %

Procedure:
A mixture of 6-chloro-nicotinonitrile (2.1 g, 15.16 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (4.86 g, 24.25 mmol, 1.6 equiv; commercially available) in N-ethyl diisopropylamine (5 mL) and anhydrous DMF (10 mL) was stirred at 60° C. for 3 d. To the reaction mixture was added a sat. solution of Na2CO3 (100 mL) and the crude extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified with silica column chromatography eluting with toluene/ethyl acetate (4:1) to provide 2.90 g (63%) of the title compound. 1H NMR (300 MHz, DMSO): δ1.24-1.42 (m, 2H), 1.41 (s, 9H), 1.84-1.89 (m, 2H), 2.85-2.94 (m, 2H), 3.87-3.91 (m, 2H), 3.98 (br s, 1H), 6.54 (d, J=8.9 Hz, 1H), 7.53 (d, J=7.5 Hz, 1H), 7.66 (dd, J=8.9 Hz, J=2.1 Hz, 1H), 8.38 (d, J=2.1 Hz, 1H). 13C NMR (75 MHz, DMSO): δ28.04, 31.19, 42.25, 47.12, 78.58, 94.49, 108.62, 118.91, 138.53, 153.00, 153.89, 159.17. MS (ISP): 303.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([SH:9])[N:3]=1.[Br:10][C:11]1[S:15][C:14]([CH:16]=O)=[CH:13][CH:12]=1.C(O)(=O)C.CN(C=O)C>O>[Br:10][C:11]1[S:15][C:14]([CH:16]=[C:7]2[C:6](=[O:8])[NH:5][C:4](=[S:9])[NH:3][C:2]2=[O:1])=[CH:13][CH:12]=1
Reactant: Oc1cc(O)nc(S)n1
Reactant: O=Cc1ccc(Br)s1
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1NC(=S)NC(=O)C1=Cc1ccc(Br)s1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 29 %

Procedure:
In a procedure identical to Example 1, 0.144 g (1 mmol) of 4,6-dihydroxy-2-mercaptopyrimidine, and 0.207 g (1 mmol) of 5-bromothiophenecarboxaldehyde in a solution of 2 ml of glacial acetic acid and 4 ml of DMF was heated at 80° C. for 12 hours. Upon cooling to room temperature, the reaction was poured into water and the precipitate collected by filtration. The crude product was washed with water, and the solid boiled in methanol for 1 minute. Filtration provided 92 mg of product as an orange solid.
Reaction SMILES: CNC(=O)C1C=CC=C(C2C=CC([O:16][C@@H]3[C@@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O3)=C(C)C=2)C=1.C([O:33][C@@H:34]1[C@@H:39]([O:40]C(=O)C)[C@@H:38]([CH2:44][O:45]C(=O)C)[O:37][C@H:36]([O:49][C:50]2[CH:55]=[CH:54][C:53](Br)=[CH:52][C:51]=2[C:57]([F:60])([F:59])[F:58])[C@H:35]1CC([O-])=O)(=O)C.[CH3:65][NH:66][C:67]([C:69]1[CH:70]=[C:71](B2OC(C)(C)C(C)(C)O2)[CH:72]=[C:73]([C:75]([NH:77][CH3:78])=[O:76])[CH:74]=1)=[O:68]>>[CH3:78][NH:77][C:75]([C:73]1[CH:72]=[C:71]([C:53]2[CH:54]=[CH:55][C:50]([O:49][C@@H:36]3[C@@H:35]([OH:16])[C@@H:34]([OH:33])[C@H:39]([OH:40])[C@@H:38]([CH2:44][OH:45])[O:37]3)=[C:51]([C:57]([F:58])([F:59])[F:60])[CH:52]=2)[CH:70]=[C:69]([C:67]([NH:66][CH3:65])=[O:68])[CH:74]=1)=[O:76]
Reactant: CNC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)NC)c1
Reactant: CC(=O)OC[C@H]1O[C@H](Oc2ccc(Br)cc2C(F)(F)F)[C@@H](CC(=O)[O-])[C@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CNC(=O)c1cccc(-c2ccc(O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)c(C)c2)c1
Product: CNC(=O)c1cc(C(=O)NC)cc(-c2ccc(O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)c(C(F)(F)F)c2)c1
Yield: 69 %

Procedure:
Using the procedure outlined in the synthesis of 5b with [(2R,3S,4S,5R,6R)-4,5-diacetoxy-6-(acetoxymethyl)-2-(4-bromo-2-trifluoromethyl-phenoxy)tetrahydropyran-3-yl]acetate (0.57 g) and N1,N3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,3-dicarboxamide (9) (0.48 g), the title compound was obtained (0.340 g) in 69% yield for the two steps. 1H NMR (300 MHz, METHANOL-d4) δ ppm 8.17-8.24 (m, 1H), 8.14 (d, J=1.65 Hz, 2H), 7.92 (d, J=1.92 Hz, 1H), 7.87 (dd, J=2.20, 8.79 Hz, 1H), 7.57 (d, J=8.79 Hz, 1H), 5.64 (d, J=1.65 Hz, 1H), 4.04 (dd, J=1.65, 3.30 Hz, 1H), 3.87-3.96 (dd, 1H), 3.64-3.83 (m, 3H), 3.48-3.63 (m, 1H), 2.93 (s, 6H). MS (ESI): found: [M+H]+, 515.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:11][CH:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)=[CH:3][CH:2]=1.[N:15]1([C:22](=O)[CH3:23])[CH2:21][CH2:20][CH2:19]NCC1.[CH3:25]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(Cl)Cl>CC#N>[N:15]1([C:12]([C:9]2[CH:8]=[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[S:11][CH:10]=2)=[O:14])[CH2:21][CH2:20][CH2:19][CH2:25][CH2:23][CH2:22]1
Reactant: CC(=O)N1CCCNCC1
Reactant: O=C(O)c1csc(-c2ccncc2)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: ClCCl
Product: O=C(c1csc(-c2ccncc2)c1)N1CCCCCC1
Reaction time: 72 h
Yield: 28.8 %

Procedure:
5-Pyridin-4-yl-thiophene-3-carboxylic acid (0.4 mmol) was dissolved in MeCN (2 mL). 1-[1,4]Diazepan-1-yl-ethanone (1.8 mmol), and HATU (0.4 mmol) were added and the reaction mixture stirred for 72 hours. DCM (20 mL) was added and the organic solution was separated and the solvent removed by evaporation. The residue was purified by HPLC, eluting with 10%-90% acetonitrile in water (0.1% formic acid) over 30 minutes. The fractions containing the desired product were concentrated under vacuum and freeze-dried to give the title compound as a white solid (33 mg). LCMS m/z 287.09 [M+H]+ RT=5.20 min. (Analytical Method 2). 1H NMR (400 MHz, MeCN-d): δ 8.6 (d, 2H), 7.95 (d, 2H), 7.9 (s, 1H), 7.8 (s, 1H), 3.6 (t, 2H), 3.5 (t, 2H), 1.8-1.6 (m, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[CH2:23]Br)[CH:7]=1)[CH3:2].[CH3:26][CH:27]([SH:29])[CH3:28]>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[CH2:23][S:29][CH:27]([CH3:28])[CH3:26])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(Cl)c(Oc2ccc([N+](=O)[O-])cc2CBr)c1
Reactant: CC(C)S
Product: CCOC(=O)Cc1ccc(Cl)c(Oc2ccc([N+](=O)[O-])cc2CSC(C)C)c1

Procedure:
[3-(2-Bromomethyl-4-nitro-phenoxy)-4-chloro-phenyl]-acetic acid ethyl ester was treated with 2-propanethiol as described in Example 21, Step 8 to provide [4-chloro-3-(2-isopropylsulfanylmethyl-4-nitro-phenoxy)-phenyl]-acetic acid ethyl ester, which was reduced to [3-(4-amino-2-isopropylsulfanylmethyl-phenoxy)-4-chloro-phenyl]-acetic acid ethyl ester as described in Example 21, Step 9. Treatment of the amine with pivaloyl chloride as described in Example 21, Step 10 provided {4-chloro-3-[4-(2,2-dimethyl-propionylamino)-2-isopropylsulfanylmethyl-phenoxy]-phenyl}-acetic acid ethyl ester. Hydrolysis of the ester to the acid was carried out as described in Example 21, Step 11.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[CH:8]=[N:7][C:6]([CH3:12])=[CH:5][C:4]=2[C:3]=1[NH2:13].[F:14][C:15]([F:28])([F:27])[O:16][C:17]1[CH:26]=[CH:25][C:20]([CH2:21][N:22]=[C:23]=[O:24])=[CH:19][CH:18]=1>>[F:1][C:2]1[C:3]([NH:13][C:23]([NH:22][CH2:21][C:20]2[CH:19]=[CH:18][C:17]([O:16][C:15]([F:14])([F:28])[F:27])=[CH:26][CH:25]=2)=[O:24])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([CH3:12])=[CH:5]2
Reactant: O=C=NCc1ccc(OC(F)(F)F)cc1
Reactant: Cc1cc2c(N)c(F)ccc2cn1
Product: Cc1cc2c(NC(=O)NCc3ccc(OC(F)(F)F)cc3)c(F)ccc2cn1

Procedure:
Prepared from 6-fluoro-3-methylisoquinohn-5-amine (Description 79) and [4-(trifluoromethoxy)benzyl]isocyanate (Description 59) according to Description 61. m/z (ES+) 394 (M+H)+.
Reaction SMILES: [O:1]1CCC[CH2:2]1.Br[C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[O:17][CH2:16][CH2:15][O:14]2)=[CH:9][N:8]=1.C([Li])CCC.CN(C)C=O>O>[O:14]1[CH2:15][CH2:16][O:17][CH:13]1[C:10]1[CH:11]=[CH:12][C:7]([CH:2]=[O:1])=[N:8][CH:9]=1
Reactant: C1CCOC1
Reactant: Brc1ccc(C2OCCO2)cn1
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(C2OCCO2)cn1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 47 %

Procedure:
To a tetrahydrofuran (100 mL) solution of 2-bromo-5-[1,3]dioxolan-2-yl-pyridine (4.77 g, 20.7 mmol) described in Manufacturing Example 154-1-2 was added n-butyl lithium (14.3 mL, 1.6 M hexane solution, 22.8 mmol) under nitrogen atmosphere at −78° C., which was stirred for 20 minutes at −78° C. Then, N,N-dimethylformamide (1.92 mL, 24.8 mmol) was added to the reaction mixture, which was stirred for 15 minutes while the temperature was raised to room temperature. Water was added to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (1.73 g, 47%).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([I:8])[C:5]([OH:9])=[CH:4][CH:3]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][CH:12]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[F:1][C:2]1[N:7]=[C:6]([I:8])[C:5]([O:9][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)nc1I
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc(F)nc3I)c2cc1OC
Temperature: 140 °C
Reaction time: 5 h
Yield: 5.6 %

Procedure:
6-Fluoro-2-iodo-pyridin-3-ol (20 mg), 4-chloro-6,7-dimethoxyquinoline (56 mg), and 4-dimethylaminopyridine (31 mg) were suspended in o-dichlorobenzene (2 ml), and the suspension was stirred at 140° C. for 5 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (2 mg, yield 6%).