Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][O:4][N:3]=1.COC(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1>>[O:16]([C:2]1[CH2:6][CH2:5][O:4][N:3]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:10][CH:11]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: BrC1=NOCC1
Product: c1ccc(OC2=NOCC2)cc1

Procedure:
3-phenoxy-4,5-dihydroisoxazole I-176a and I-176b were prepared in 2 steps from racemic compound I-14. Bromo-4,5-dihydroisoxazole I-14 was reacted with 3-hydroxybenzoic acid methyl ester using Method 5 followed by hydroysis using the analogous conditions as in example 94. [M+H]+=368.0 m/z. Activity: C
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]3[S:19][C:20]([CH2:23][NH2:24])=[CH:21][N:22]=3)[CH:13]=2)[O:8]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[O:55]1[C:59]([C:60](O)=[O:61])=[CH:58][CH:57]=[N:56]1>CN(C=O)C.O>[C:1]1([CH3:25])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]3[S:19][C:20]([CH2:23][NH:24][C:60]([C:59]4[O:55][N:56]=[CH:57][CH:58]=4)=[O:61])=[CH:21][N:22]=3)[CH:13]=2)[O:8]1
Reactant: Cc1ccccc1C1CCc2cc(Oc3ncc(CN)s3)ccc2O1
Reactant: O=C(O)c1ccno1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: Cc1ccccc1C1CCc2cc(Oc3ncc(CNC(=O)c4ccno4)s3)ccc2O1
Reaction time: 16 h
Yield: 58.2 %

Procedure:
To a solution of [2-(2-o-tolyl-chroman-6-yloxy)-thiazol-5-ylmethyl]amine (150 mg, 0.43 mmol) in DMF (2 ml), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (114 mg, 0.60 mmol, 1.4 eq), 1-hydroxy-benzotriazole (81 mg, 0.60 mmol, 1.4 eq) and N-methylmorpholine (107 mg, 1.07 mmol, 2.5 eq) and isoxazole-5-carboxylic acid (72 mg, 0.64 mmol, 1.5 eq) were added. The mixture was stirred for 16 h, then diluted with water, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with a diluted aqueous solution of sodium carbonate and brine, dried over sodium sulfate and filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel, ethyl acetate/methanol gradient). Isoxazole-5-carboxylic acid [2-(2-o-tolyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-amide (112 mg, 59%) was obtained as a white solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.Cl.[NH:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:18][N:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH2:23][S:22][C:21]2[CH:30]=[CH:31][CH:32]=[CH:33][C:20]1=2>C(Cl)(Cl)Cl>[NH:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:18][N:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH2:23][S:22](=[O:9])[C:21]2[CH:30]=[CH:31][CH:32]=[CH:33][C:20]1=2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc2c(c1)CSc1ccccc1N2C[C@@H]1CCCN1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: O=S1Cc2ccccc2N(C[C@@H]2CCCN2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.9 %

Procedure:
A solution of meta-chloroperbenzoic acid (105 mg) in chloroform (5 ml) was added to a solution of (S)-5,11-dihydro-5-(2-pyrrolidinylmethyl)dibenzo[b,e][1,4]thiazepine hydrochloride (see Preparation 21) (200 mg) in chloroform (10 ml) and the mixture stirred at room temperature for 4 hours, washed with 10% aqueous sodium carbonate solution, dried over sodium sulphate and evaporated under reduced pressure to give the title compound as a colourless gum, (180 mg, 96%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[N:24]=[C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[S:26][CH:27]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[N:24]=[C:25]([N:28]2[CH2:29][CH2:30][N:31]([C:8]([NH:7][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)=[O:15])[CH2:32][CH2:33]2)[S:26][CH:27]=1
Reactant: Fc1ccccc1-c1csc(N2CCNCC2)n1
Reactant: O=C(Nc1cnccn1)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cnccn1)N1CCN(c2nc(-c3ccccc3F)cs2)CC1
Temperature: 70 °C
Reaction time: 84 h
Yield: 5.5 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyrazin-2-ylcarbamate (226 mg, 0.835 mmol), 4-[4-(2-fluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.760 mmol) and diisopropylethylamine (0.265 ml, 1.52 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 3.5 days. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and ethyl acetate to give the desired product (16.0 mg, 5.5%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([CH3:11])[C:8](O)=O)=[CH:4][CH:3]=1.[NH2:14][NH:15][C:16]([NH2:18])=[S:17].P(Cl)(Cl)(Cl)=O>O1CCOCC1>[CH3:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([C:8]2[S:17][C:16]([NH2:18])=[N:15][N:14]=2)[CH3:11])=[CH:4][CH:3]=1
Reactant: Cc1ccc(OC(C)C(=O)O)cc1
Reactant: NNC(N)=S
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(OC(C)c2nnc(N)s2)cc1
Temperature: 90 °C

Procedure:
A 100 milliliter flask adapted with a paddle stirrer, thermometer, addition funnel, condenser and drying tube was charged with 7.2 grams (0.040 mole) of 2-(4-methylphenoxy)propanoic acid, 3.6 grams (0.040 mole) of thiosemicarbazide and 30 milliliters of dioxane, and heated to 90° C., the addition funnel was charged with phosphorous oxychloride (POCl3), (6.7 grams, 0.4 mole) which was slowly added for 15 minutes while maintaining the temperature within 90°-95° C. When the addition was completed, the mixture was refluxed for 60 minutes. The flask was evacuated by using a water aspirator to remove volatiles (HCl, POCl3 and some dioxane), and then 50 milliliters of water was added and mixture was made basic by the addition of 50 percent solution of NaOH until the pH of the solution was 10. The white precipitate was filtered off, washed with water and dried in a vacuum oven at 80° C. to 7.7 grams of tan crystals (melting point 142°-162° C.) which were crystallized from the minimum amount of a water ethanol mixture, filtered off and dried in a vacuum oven at 80° C. to 4.8 grams of yellow crystals of 5-[1-(4-methylphenoxy)ethyl]-2-amino-1,3,4-thiadiazole (melting point 178°-180° C.).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[I:12][C:13]1[CH:18]=[CH:17][C:16](O)=[C:15]([CH3:20])[CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC([O-])=O>C1COCC1>[Cl:1][CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[O:5][C:16]1[CH:17]=[CH:18][C:13]([I:12])=[CH:14][C:15]=1[CH3:20]
Reactant: O[C@@H](CCCl)c1ccccc1
Reactant: Cc1cc(I)ccc1O
Agent: CCOC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(I)ccc1O[C@H](CCCl)c1ccccc1
Yield: 70.4 %

Procedure:
The compound [R]-(+)-1-chloro-3-phenyl-3-(4-iodo-2-methylphenoxy)propane (Compound 5) was prepared in the same manner as for the preparation of Compound 2 in Example 1, but using [S]-3-chloro-1-phenylpropanol (1.0 g, 5.88 mmol), 4-iodo-2-methylphenol (1.38 g, 5.88 mmol), triphenylphosphine (1.54 g, 5.88 mmol), and ethyl azodicarboxylate (0.93 mL, 1.04 g, 5.88 mmol) in THF (15 mL) at room temperature for 15 hours. Workup and purification gave 1.60 g (70%) of Compound 5 as a thick pale yellow liquid: [απ25D +14.02 (c 7.7, CHCL3); 1H NMR (CDCl3, 250 MHz) δ 7.41-7.20 (m, 7H), 6.39 (d, J=8.8 Hz, 1H), 5.34 (dd, J=4.4, 8.8 Hz, 1H), 3.81-3 72 (m, 1H), 3.63-3.55 (m, 1H), 2.55-2.41 (m, 1H), 2.31-2.16 (m, 1H), 2.7 (s, 3H); FTIR (neat) 3080, 3020, 2970, 2915, 1585, 1485(s), 1450, 1390, 1360, 1290, 1245(s), 1180, 1130 cm-1. Anal. C17H20INO: C,H.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:35]3[CH2:34][CH2:33][N:32]([C:25]4[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:24]=4[O:23][CH3:22])[CH2:37][CH2:36]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: COc1ccc(N2CCNCC2)c(OC)c1
Product: COc1ccc(N2CCN(C(=O)Oc3ccc(Oc4ccc(C(F)(F)F)cn4)cc3)CC2)c(OC)c1
Yield: 69 %

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(2,4-dimethoxyphenyl)-piperazine. Purified by flash chromatography (ethyl acetate—heptane 1:4), yield 69%. White crystals, m.p. 98-99° C.; HPLC-MS: m/z=504 (M+1) at Rt=4.0 min.; IR (KBr): ν 1733, 1712 (C═O) cm−1.
Reaction SMILES: [CH2:1]([N:8]([CH3:19])[C:9](=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:22]=1[NH2:23].C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1.[Cu]>[CH2:1]([N:8]([CH3:19])[C:9](=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:23][C:22]1[C:21]([Cl:20])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)C(=O)Cc1ccccc1Br
Reactant: Nc1c(Cl)cccc1Cl
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: CN(Cc1ccccc1)C(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Yield: 60.6 %

Procedure:
A mixture of 10.0 g (0.031 mole) of N-benzyl-N-methyl-o-bromophenylacetamide having a boiling point of 202° to 203° C. under 0.5 mmHg, 6.1 g (0.037 mole) of 2,6-dichloroaniline, 5.2 g (0.037 mole) of anhydrous potassium carbonate, 2.6 g of cuprous bromide and 2.6 g of copper powder was reacted in 150 ml of xylene for 72 hours to obtain 7.5 g of a colorless needle having a melting point of 85° to 86° C. The yield was 56.0%.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.[CH3:19][C:20]1([CH3:26])[CH2:24][NH:23][C:22](=[O:25])[CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:19][C:20]1([CH3:26])[CH2:24][N:23]([C:5]2[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][N:6]=2)[C:22](=[O:25])[CH2:21]1
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Reactant: CC1(C)CNC(=O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC1(C)CC(=O)N(c2ncc(C#Cc3ccccc3)cn2)C1
Temperature: 100 °C
Reaction time: 4 h
Yield: 28.2 %

Procedure:
(100 mg, 0.39 mmol) 2-Methanesulfonyl-5-phenylethynyl-pyrimidine (Example 115, step 1) was dissolved in 1 ml dioxane. 4,4-Dimethylpyrrolidin-2-one (53 mg, 465 μmol, 1.2 equiv.) and cesium carbonate (190 mg, 580 μmol, 1.5 equiv.) were added at room temperature. The mixture was stirred for 4 hours at 100° C. The reaction mixture was cooled, evaporated and extracted with saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column and eluting with an ethyl acetate:heptane gradient 0:100 to 100:0. The desired 4,4-dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-pyrrolidin-2-one (32 mg, 28% yield) was obtained as a light yellow solid, MS: m/e=292.1 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][CH:20]([C:25]3[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][N:26]=3)[C:21]([F:24])([F:23])[F:22])=[CH:15][CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl>C1COCC1.O1CCOCC1.C(OCC)(=O)C.C1COCC1>[Br:31][C:28]1[CH:29]=[CH:30][C:25]([CH:20]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([CH:10]3[CH2:11][CH2:12][NH:8][CH2:9]3)=[CH:14][CH:15]=2)[C:21]([F:22])([F:24])[F:23])=[N:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(c3ccc(Br)cn3)C(F)(F)F)cc2)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: FC(F)(F)C(Nc1ccc(C2CCNC2)cc1)c1ccc(Br)cn1
Temperature: 60 °C
Yield: 55.6 %

Procedure:
To a stirred solution of (RS)-3-{4-[(RS)-1-(5-bromo-pyridin-2-yl)-2,2,2-trifluoro-ethylamino]-phenyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (27 mg) in THF (1 ml) was added dropwise a solution of hydrogen chloride in dioxane (0.20 ml, 4 M solution) and the mixture was heated at 60° C. for 4 hours. The mixture was then cooled to room temperature, diluted with ethyl acetate/THF (1:1), and washed sequentially with 2 N aq. sodium hydroxide solution and with saturated brine. The organic phase was separated, dried over sodium sulphate, and concentrated in vacuo. The reside was purified by flash column chromatography (silical gel; gradient: heptane/dichloromethane/methanol) to give [(RS)-1-(5-bromo-pyridin-2-yl)-2,2,2-trifluoro-ethyl]-((RS)-4-pyrrolidin-3-yl-phenyl)-amine (12 mg, 56%) as a yellow amorphous solid. MS (ISP): 402.1 ([{81Br}M+H]+), 400.1 ([{79Br}M+H]+).
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.[C:25](OC(=O)C)(=[O:27])C>C(O)=O>[CH:25]([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:27]
Reactant: Nc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CNc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Temperature: 50 °C
Yield: 15 %

Procedure:
To a solution of (E)-5-amino-1-(2-pyridyl)-2-styryl-1H-benzimidazole (300 mg, 0.96 mmol) in formic acid (5 ml) was added acetic anhydride (1 ml) via syringe and the reaction mixture was warmed to 50° C. for 1 h. Volatiles were removed under reduced pressure and the residual viscous oil was poured into saturated aqueous sodium bicarbonate solution (50 ml) and the aqueous mixture was extracted with ethyl acetate (100 ml). The organic extract was washed consecutively with water (50 ml) and brine (50 ml), dried (sodium sulfate) and concentrated in vacuo. Recrystallization of the residue from ethyl acetate afforded 50 mg (15%) of the titled compound as light brown solids.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][CH:16]=[CH:15][C:14]=3[C:18]=2[OH:19])=[O:9])=[CH:4][CH:3]=1.[Cl-].[CH2:23]=[N+:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(=O)(O)[O-].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:15][C:14]=3[C:18]=2[OH:19])=[O:9])=[CH:20][CH:21]=1
Reactant: C=[N+]1CCOCC1
Reactant: O=C(NCc1ccc(Cl)cc1)c1ccc2sccc2c1O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Product: O=C(NCc1ccc(Cl)cc1)c1ccc2sc(CN3CCOCC3)cc2c1O
Yield: 71.1 %

Procedure:
A mixture of N-(4-chlorobenzyl)-4-hydroxy-1-benzothiophene-5-carboxamide (Preparation 14, 0.15 g), 4-methylenemorpholin4-ium chloride (0.13 g), and anhydrous acetonitrile (5 mL) is heated at reflux for 2 hours. Upon cooling, a saturated solution of sodium bicarbonate is added until the pH=9 and this solution is partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated to give a pink oil. Chromatography on a Biotage column eluting with 20% ethyl acetate in heptane (250 mL) and 50% ethyl acetate in heptane (500 mL) affords 140 mg (76%) of the title compound as a white solid. Physical characteristics: Mp 200° C.; MS (ESI+) for C21H21ClN2O3S m/z 417 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[OH-].[K+].[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]Cl)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(OCC)(=O)C.CCCCCC>CN(C=O)C>[CH2:8]([O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:20][CH:21]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: c1cn[nH]c1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: c1ccc(COc2ccc(Cn3cccn3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After a mixture of pyrazole (7.73 mmol) and potassium hydroxide (7.73 mmol) in DMF (35 mL) was stirred at room temperature for 30 min., a solution of 1-(benzyloxy)-4-(chloromethyl)benzene (6.44 mmol) in DMF (7 mL) was added dropwise. The reaction mixture was stirred at room temperature overnight and the product obtained from a standard aqueous work up. Column chromatography (1:2 ethyl acetate/hexane) of the residue yielded compound 58.1 as a white solid. LC-MS ESI (pos.) m/e: 265 (M+H); 1H NMR (500 MHz) (DMSO-d6) δ 7.79 (1H, m); 7.46 (3H, m); 7.40 (2H, m); 7.36 (1H, m); 7.21 (2H, d, J=9 Hz)); 5.27 (2H, s); 5.11 (2H, m).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:13]4[S:18][CH:17]=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C1C=C[NH+]=CC=1.Br[Br-]Br.C(O)(=[O:36])C>O>[O:22]1[CH2:21][CH2:20][N:19]([C:12]2[C:13]3[S:18][CH:17]=[CH:16][C:14]=3[N:15]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH2:3][C:2](=[O:36])[NH:1]4)[N:11]=2)[CH2:24][CH2:23]1
Reactant: CC(=O)O
Reactant: c1cc(-c2nc(N3CCOCC3)c3sccc3n2)c2cc[nH]c2c1
Agent: c1cc[nH+]cc1
Solvent: O
Product: O=C1Cc2c(cccc2-c2nc(N3CCOCC3)c3sccc3n2)N1
Temperature: 80 °C

Procedure:
To a solution of 2-(1H-Indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine 199 (90 mg) in acetic acid (2 ml) and water (1 ml) was added pyridinium bromide perbromide (103 mg) as a solution in acetic acid (4 ml) and the reaction mixture was heated to 80° C. for 4 hours. The mixture was then basified and extracted into dichloromethane, organic layer was dried (Mg2SO4), filtered and volatiles removed in vacuo. Purification on silica yielded 198 (23 mg). NMR: (CDCl3): 3.39-3.43 (4H, m), 4.03-4.08 (4H, m), 4.10 (2H, s), 6.95 (1H, d, J=7.4), 7.36 (1H, t, J=7.9), 7.49 (2H, m), 7.79 (1H, d, J=5.6), 8.10 (1H, d, J=7.9) MS: (ESI+): MH+ 353 (100%)
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([O:12][C:13](=[O:29])[NH:14][C:15](=[N:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])N1C=CC=N1)([CH3:11])([CH3:10])[CH3:9]>C1COCC1>[C:25]([O:24][C:22](=[O:23])[NH:21][C:15](=[N:14][C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:29])[N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Reactant: OC1CCNCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCC(O)CC1
Reaction time: 1 h
Yield: 62.2 %

Procedure:
4-Hydroxypiperidine (0.25 g, 2.5 mmol) and (tert-butoxycarbonylimino-pyrazol-1-yl-methyl)-carbamic acid tert-butyl ester (0.78 g, 2.2 mmol) (Drake, B. et al. Synthesis 1994, 6, 579-582) were dissolved in THF (1 mL) and stirred for 1 hour. The solvent was removed under reduced pressure and EtOAc (20 mL) was added. The organic was washed with an aqueous solution of 15% NaOH (5×15 mL), dried (Na2SO4) and concentrated under reduced pressure to afford [tert-butoxycarbonylimino-(4-hydroxy-piperidin-1-yl)-methyl]-carbamic acid tert-butyl ester as a white solid (0.47 g, 55%).
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:18]=[C:17]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])[N:16]=[CH:15][C:14]=3[N:27]=2)[CH:7]=[CH:8][C:9]=1[OH:10].Br[CH2:30][CH:31]1[CH2:33][C:32]1([F:35])[F:34]>>[F:34][C:32]1([F:35])[CH2:33][CH:31]1[CH2:30][O:10][C:9]1[CH:8]=[CH:7][C:6]([C:11]2[O:12][C:13]3[CH:18]=[C:17]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])[N:16]=[CH:15][C:14]=3[N:27]=2)=[CH:5][C:4]=1[O:3][CH:2]([F:1])[F:28]
Reactant: FC1(F)CC1CBr
Reactant: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(O)c(OC(F)F)c3)nc2cn1
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCC4CC4(F)F)c(OC(F)F)c3)nc2cn1

Procedure:
Using N-((2S)-1-((2-(3-(difluoromethoxy)-4-hydroxyphenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide and 2-(bromomethyl)-1,1-difluorocyclopropane, and in the same manner as in Example 5, the title compound was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]1[CH:23]=[C:22]([N:24]([CH3:26])[CH3:25])[CH:21]=[CH:20][C:4]=1[C:5]([C:7]1[C:15]([Cl:16])=[C:14]([Cl:17])[C:13]([Cl:18])=[C:12]([Cl:19])[C:8]=1[C:9](O)=[O:10])=[O:6].CN(C)C1C=CC=C(N(C)C)C=1.C(OC(=O)C)(=O)C>CCCCCC>[CH3:27][N:2]([CH3:1])[C:3]1[CH:23]=[C:22]([N:24]([CH3:26])[CH3:25])[CH:21]=[CH:20][C:4]=1[CH:5]1[C:7]2[C:8](=[C:12]([Cl:19])[C:13]([Cl:18])=[C:14]([Cl:17])[C:15]=2[Cl:16])[C:9](=[O:10])[O:6]1
Reactant: CN(C)c1ccc(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c(N(C)C)c1
Agent: CN(C)c1cccc(N(C)C)c1
Solvent: CC(=O)OC(C)=O
Solvent: CCCCCC
Product: CN(C)c1ccc(C2OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c(N(C)C)c1

Procedure:
A mixture of most of the 2-(2,4-bis(dimethylamino)benzoyl)-3,4,5,6-tetrachlorobenzoic acid from part A of this example, N,N,N',N'-tetramethyl-m-phenylenediamine (0.82 g. plus 0.4 g.) and acetic anhydride was heated under reflux. Concentration of a toluene extract of the resulting product gave a tar, which was slurried in hexane, affording 3,3-bis(2,4-bis(dimethylamino)phenyl-4,5,6,7-tetrachlorophthalide (I: X = Y2 = Y4 = (CH3)2N, Z4 = Z5 = Z6 = Z7 = Cl) (m.p. 195°-197° C.).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].N[C@@H](C(O)=O)CCC(=O)N.N[C@H](C(O)=O)CS.N[C@H](C(O)=O)CCS(C)=O.N[C@H](C(O)=O)CCC(=O)O.N[C@H](C(O)=O)CC(C(N)=S)C(=O)O.N[C@@H](C(O)=O)CCC(=O)O.N[C@H](C(O)=O)CC(=O)N.N[C@H](C(O)=O)CCC>>[NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6]
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCC[C@H](N)C(=O)O
Agent: CS(=O)CC[C@H](N)C(=O)O
Agent: NC(=O)CC[C@@H](N)C(=O)O
Product: NC(=O)CC[C@H](N)C(=O)O

Procedure:
Z-Gln, D-Gln, Pro, Cys (S—CONH2), Met(O), Glu, Glu(γ-cyano), Glu(γCS—NH2), D-Glu, Asn, NorVal
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:21])=[N:4][C:5]([F:20])=[C:6]([Cl:19])[C:7]=1[CH2:8][C:9]([O:11]CC1C=CC=CC=1)=[O:10]>[Pd].C(O)C>[Cl:19][C:6]1[C:5]([F:20])=[N:4][C:3]([F:21])=[C:2]([Cl:1])[C:7]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(Cc1c(Cl)c(F)nc(F)c1Cl)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)Cc1c(Cl)c(F)nc(F)c1Cl
Yield: 93.3 %

Procedure:
Benzyl 2-(3,5-dichloro-2,6-difluoropyridin-4-yl)acetate (30.9 g, 93 mmol), anhydrous ethanol, and 10% palladium on carbon were placed into a 500 mL bottle. The mixture was then hydrogenated using Parr Hydrogenator under hydrogen atmosphere (20 psi) for 30 min. The reaction mixture was then filtered through celite pad and the pad was washed with ethanol. The filtrate was evaporated in vacuo and the residue was recrystallized from MC to afford 21 g (89%) of 2-(3,5-dichloro-2,6-difluoropyridin-4-yl)acetic acid as a white solid. m.p. 157-159° C. 1H NMR (200 MHz, CDCl3) δ 4.13 (2H, s).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8](/[CH:10]=[CH:11]/[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH:22]([CH3:24])[CH3:23])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.Cl.[NH2:26][C:27]([NH2:29])=[O:28]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[O:20][CH2:21][CH:22]([CH3:24])[CH3:23])[NH:29][C:27](=[O:28])[N:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NC(N)=O
Reactant: CC(C)COc1ccccc1C(=O)/C=C/c1ccc2c(c1)OCO2
Agent: Cl
Product: CC(C)COc1ccccc1-c1cc(-c2ccc3c(c2)OCO3)nc(=O)[nH]1
Temperature: 120 °C
Yield: 3.4 %

Procedure:
To a sealed pressure vessel were added (E)-3-(benzo[d][1,3]dioxol-5-yl)-1-(2-isobutoxyphenyl)prop-2-en-1-one (256 mg, 0.8 mmol), 4N HCl in dioxanes (5 mL), and urea (242 mg, 4 mmol). The pressure vessel was sealed and heated to 120° C. for 20 h. Another 200 mg of urea were added and heated for another 5 h. The reaction was then cooled to room temperature, concentrated under reduced pressure and the product was purified by preparative HPLC to result in 10 mg (34%) of the title compound. 1H-NMR (400 MHz, d6-DMSO): δ 7.74 (d, 1H), 7.67 (d, 1H), 7.63 (d, 1H), 7.50 (m, 1H), 7.18 (d, 2H), 7.05-7.10 (m, 2H), 3.85 (dd, 2H), 2.02 (m, 1H), 0.95 (d, 6H). MS (EI) for C21H20N2O4: 364 (MH+).