Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:32])[C@@H:13]([NH:24]C(OC(C)(C)C)=O)[CH2:14][CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:32])[C@@H:13]([NH2:24])[CH2:14][CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCOCc2ccccc2)NC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCOCc2ccccc2)CC1
Reaction time: 12 h

Procedure:
To a solution of 1.23 g 4-((S)-4-benzyloxy-2-tert-butoxycarbonylamino-butyryl)-piperazine-1-carboxylic acid ethyl ester in 7 ml dichloromethane were added 2 ml TFA. After stirring for 12 h and evaporation of the solvents the crude trifluoroacetate salt was obtained as colorless oil. Yield: 1.30 g.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:19])([F:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[F:9][C:10]([F:18])([F:19])[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:2]2[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: O=Cc1ccc(Br)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccc(C(F)(F)F)cc2)s1
Temperature: 100 °C
Reaction time: 68 h
Yield: 29 %

Procedure:
To a solution of 5-bromothiophene-2-carbaldehyde (0.12 mL, 1.0 mmol) and 4-trifluoromethylphenol (195 mg, 1.20 mmol) in 3 mL dimethylformamide was added potassium carbonate (276 mg, 2.00 mmol). The resulting suspension was stirred at 100° C. for 68 h before being cooled to room temperature and poured into 20 mL 0.2 N hydrochloric acid. Organics were extracted with ether (3×25 mL), washed with 2 N NaOH (2×30 mL), 0.2 N hydrochloric acid and brine (30 mL each), dried over magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel with gradient elution (5-10% ethyl acetate in hexanes+2% triethylamine) to give 5-(4-(trifluoromethyl)phenoxy)thiophene-2-carbaldehyde (79 mg, 29%) as an off-white solid. Used without further characterization.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([Cl:19])=[C:15]([CH3:18])[CH:16]=3)[O:11][C:10](=[O:20])[C:9]=2[CH2:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[C:32]([F:35])([F:34])[F:33])=[O:23])[CH:5]=[CH:6][CH:7]=1.[C:36]([O:40][CH3:41])(=[O:39])[CH:37]=[CH2:38].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.CC(O)=O.CC(O)=O.[Pd].O>[Cl:19][C:14]1[CH:13]=[C:12]2[C:17]([C:8]([C:4]3[CH:3]=[C:2](/[CH:38]=[CH:37]/[C:36]([O:40][CH3:41])=[O:39])[CH:7]=[CH:6][CH:5]=3)=[C:9]([CH2:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[C:32]([F:34])([F:35])[F:33])=[O:23])[C:10](=[O:20])[O:11]2)=[CH:16][C:15]=1[CH3:18]
Reactant: C=CC(=O)OC
Reactant: Cc1cc2c(-c3cccc(Br)c3)c(CC(=O)Nc3ccc(Cl)cc3C(F)(F)F)c(=O)oc2cc1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)/C=C/c1cccc(-c2c(CC(=O)Nc3ccc(Cl)cc3C(F)(F)F)c(=O)oc3cc(Cl)c(C)cc23)c1
Temperature: 120 °C
Yield: 67 %

Procedure:
A solution of 2-[4-(3-bromophenyl)-7-chloro-6-methyl-2-oxo-2H-chromene-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide (500 mg) in DMF (5 ml) was combined with methyl acrylate (0.14 ml), triethylamine (0.21 ml), pd(OAc)2 (5 ml) and triphenylphosphine (10 mg) under argon atmosphere, and heated at 120° C. for 3 hours. After the reaction was completed, the mixture was combined with water, and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and then concentrated. The resultant residue was purified by a silica gel chromatography (eluent: hexane-ethyl acetate=2:1), and then recrystallized from THF-ethyl acetate to obtain the title compound as a colorless crystal (333 mg, yield: 67%). Melting point: 202-204° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C@H:5]([O:7][C:8]1[C:9](Cl)=[N:10][C:11]([Cl:15])=[N:12][C:13]=1[Cl:14])[CH3:6])[CH3:2].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(N(CC)CC)C>C(O)C>[CH2:1]([O:3][C:4](=[O:17])[C@H:5]([O:7][C:8]1[C:13]([Cl:14])=[N:12][C:11]([Cl:15])=[N:10][C:9]=1[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH3:6])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)[C@@H](C)Oc1c(Cl)nc(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)[C@@H](C)Oc1c(Cl)nc(Cl)nc1N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.4 %

Procedure:
A mixture of (R)-2-(2,4,6-trichloro-pyrimidin-5-yloxy)-propionic acid ethyl ester (522 mg, 1.74 mmol), morpholine (152 μL, 1.74 mmol) and triethylamine (484 μL, 3.48 mmol) in ethanol (15 mL) was stirred at RT for 18 hours then partitioned between ethyl acetate and water. The aqueous phase was extracted with further ethyl acetate and the combined organic extracts dried (Na2SO4) and concentrated in vacuo affording (R)-2-(2,4-Dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-propionic acid ethyl ester (490 mg, 80%). LCMS: RT=3.57 min, [M+H]+=350/352.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=1[NH2:1])[CH3:18]
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(F)cc1N
Temperature: 25 °C

Procedure:
A total of 10 g of 2-amino-4-fluoro-benzoic acid was dissolved in 129 ml of ethanol, 6.45 ml of sulfuric acid was added and the mixture was heated under reflux for 11 hours. After cooling to room temperature, the solvent was evaporated to about half. Water was added and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried over magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:5), to give 7.57 g of the title compound as a pale yellow oil.
Reaction SMILES: CS(O[CH2:6][C@@H:7]([O:32][CH2:33][CH3:34])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)(=O)=O.[N-:35]=[N+]=[N-].[Na+].[H-].[H-].[H-].[H-].[Li+].[Al+3]>CN(C=O)C.C(OCC)C>[NH2:35][CH2:6][C@@H:7]([O:32][CH2:33][CH3:34])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:26])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCO[C@H](COS(C)(=O)=O)Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCO[C@H](CN)Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 174.7 %

Procedure:
(2S)-3-[4-(2-{4-[(tert-Butoxycarbonyl)amino]phenyl}ethoxy)phenyl]-2-ethoxypropyl methanesulfonate (described in Example 4a) (0.43 g, 0.87 mmole) was dissoved in dry DMF (5 ml). Sodium azide (0.23 g, 3.50 mmole) was added and the reaction mixture was heated to 80° C. and stirred overnight. The reaction was quenched with water and extracted with diethyl ether. The organic phase was washed with water, dried with magnesium sulfate and evaporated. The crude product was dissolved in dry diethyl ether and added to a solution of LAH (0.10 g, 2.62 mmole) in dry diethyl ether (50 ml). After one hour the reaction was quenched with water (0.5 ml), 5 M NaOH (1 ml) and water (0.5 ml) again. The mixture was refluxed for half an hour and the white precipitate was filtered off and the filtrate dried with magnesium sulfate and evaporated giving 0.63 g (72% yield) of the product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:12][C:13](=O)C(F)(F)F)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C=O.[C:21](O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[CH3:21][N:12]([CH3:13])[C:4]1[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=[C:2]([NH2:1])[CH:3]=1
Reactant: CC(=O)O
Reactant: Nc1cc(NC(=O)C(F)(F)F)cc(C(F)(F)F)c1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN(C)c1cc(N)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 89 %

Procedure:
In 3 mL of methanol, 150 mg (0.55 mmol) of N-(3-amino-5-(trifluoromethyl)phenyl)-2,2,2-trifluoroacetamide, 0.076 mL (0.9 mmol) of a 37% formaldehyde aqueous solution and 0.05 mL of acetic acid were dissolved, and 47 mg (0.74 mmol) of sodium cyanoborohydride was added thereto, and the mixture solution was stirred at room temperature for 15 hours. The reaction solution was poured into water and extracted with ethyl acetate, and the extract was washed with a saturated sodium chloride solution and concentrated, and the residue was dissolved in 6 mL of tetrahydrofuran. To this solution, 10 mL of a saturated sodium bicarbonate solution was added and the mixture solution was heated at 50° C. for 20 hours. The reaction solution was poured into water and extracted with ethyl acetate, and the extract was dried on anhydrous magnesium sulfate and concentrated, and the residue was purified by silica gel column chromatography to obtain 100 mg (89%) of a brownish oily target product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[C:23]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[N:25]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].N(C(C)(C)C#N)=NC(C)(C)C#N.C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[C:23]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH:31]4[CH2:32][CH2:33][CH2:34][CH2:35]4)[N:25]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([NH:17][CH:18]4[CH2:19][CH2:20][CH2:21][CH2:22]4)[N:11]3[N:10]=2)=[CH:3][CH:2]=1
Reactant: Clc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 25 °C

Procedure:
To a solution of 2-(3-bromo-4-chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-α]pyridin-7-amine (200 mg, 0.36 mmol) in toluene (15 mL) was added 2,2′-azobisisobutyronitril (30 mg, 0.18 mmol) and tributyltin hydride (282 mg, 97 mmol). After heated at reflux for 24 hours, the reaction mixture was cooled to room temperature. Concentration followed by purification with flash chromatograph (30:70 ethyl acetate/hexanes) gave 2-(4-chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-α]pyridin-7-amine as a white foam. 1H NMR (CDCl3): δ 8.02 (d, 1H), 7.72 (m, 1H), 7.60 (d, 2H), 7.41 (d, 2H), 7.35 (m, 1H), 6.31 (d, 1H), 6.03 (m, 2H), 5.17 (br, 1H), 4.32 (m, 1H), 4.00 (m, 1H), 2.18–2.05 (m, 4H), 1.82–1.50 (m, 12H). MS m/z 474 (M+1).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH:6]1[C:13](=[O:14])[CH2:12][C:10](=[O:11])[NH:9][C:7]1=[O:8].CN([CH:18]=[O:19])C>>[O:8]=[C:7]1[NH:9][C:10](=[O:11])[CH:12]([CH:18]=[O:19])[C:13](=[O:14])[NH:6]1
Reactant: CN(C)C=O
Reactant: O=C1CC(=O)NC(=O)N1
Solvent: O=P(Cl)(Cl)Cl
Product: O=CC1C(=O)NC(=O)NC1=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
9.03 ml of phosphoryl chloride are added dropwise to 2 ml of dry DMF with ice-cooling. 1.5 g of barbituric acid are subsequently added, and the mixture is stirred at 100° for 4 h. The mixture is cooled, poured into ice-water, the precipitate is separated off, rinsed with water and dried at 45°, giving 2.5 g of “1”.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:14]3[CH:19]=[CH:18][C:17](Br)=[CH:16][N:15]=3)[CH:10]=2)[S:5][CH2:4][CH2:3]1.C([Li])(C)(C)C.CN(C)[CH:29]=[O:30].[NH4+].[Cl-]>CCOCC.CCCCC>[CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:14]3[CH:19]=[CH:18][C:17]([CH:29]=[O:30])=[CH:16][N:15]=3)[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CN(C)C=O
Reactant: CC1(C)CCSc2ccc(C#Cc3ccc(Br)cn3)cc21
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCCCC
Solvent: CCOCC
Product: CC1(C)CCSc2ccc(C#Cc3ccc(C=O)cn3)cc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled (-78° C.) solution of 358 mg (1.0 mmol) of 2-(4,4-dimethylthiochroman-6-yl)ethynyl-5-bromopyridine in 5 ml of anhydrous ether was added slowly under nitrogen 1.3 ml of 1.7M (2.21 mmol) tert-butyl lithium in pentane. The mixture was stirred at -78° C. for 1 h and then treated with 95 mg (1.3 mmol) of anhydrous dimethylformamide. The mixture was stirred at -78° C. for a further 0.5 hours, then warmed to 0° C. and treated with 5 ml of saturated NH4Cl solution followed by 5 ml of ether. The organic layer was separated and the aqueous layer was extracted with ether. The organic layers were combined, washed successively with water and saturated NaCl solution and then dried (MgSO4). The solvent was then removed in vacuo and the residue purified by flash chromatography (silica; 15% ethyl acetate in hexanes) followed by high pressure liquid chromatography (Whatman M-9 Partisil 10/50 column, 15% ethyl acetate in hexanes) to give the title compound as a pale yellow solid.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][C:14](I)=[CH:13][C:12]=3[N:11]=[C:10]([C:20]3C(C)=CC(C)=CC=3C)[C:9]=2[CH:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2].[C:29]1([CH3:41])[CH:34]=[C:33]([CH3:35])[CH:32]=[C:31]([CH3:36])[C:30]=1OB(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>COC(OC)C.O.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>[CH2:1]([CH:3]([N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][C:14]([C:30]4[C:31]([CH3:36])=[CH:32][C:33]([CH3:35])=[CH:34][C:29]=4[CH3:41])=[CH:13][C:12]=3[N:11]=[C:10]([CH3:20])[C:9]=2[CH:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: Cc1cc(C)c(OB(O)O)c(C)c1
Reactant: CCC(CC)n1ccc2c(-c3c(C)cc(C)cc3C)nc3cc(I)ccc3c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COC(C)OC
Agent: [Ba+2]
Solvent: O
Product: CCC(CC)n1ccc2c(C)nc3cc(-c4c(C)cc(C)cc4C)ccc3c21
Yield: 51 %

Procedure:
A solution of 1-(1-ethylpropyl)-7-iodo-4-mesityl-1H-pyrrolo[3,2-c]quinoline (32 mg, 0.09 mmol), mesitylboric acid (17 mg, 0.10 mmol), Pd(PPh3)4 (5 mg, 4.23×10−3 mmol) and barium hydroxide octahydrate (40 mg, 0.13 mmol) in 2,2-dimethoxyethane (6.0 mL) and water (1.0 mL) was stirred at 80° C. for one day. After filtering through Celite, the filtrate was diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (10% ethyl acetate/hexane), to give the title compound (17 mg) as white crystals.
Reaction SMILES: [C:1]1([N:7]2[C:15]([NH2:16])=[C:14]3[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]1([N:7]2[C:15]([N:16]=[CH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:14]3[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]3)=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1c2ccccc2nn1-c1ccccc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: C(=Nc1c2ccccc2nn1-c1ccccc1)c1ccccc1
Yield: 107.1 %

Procedure:
To a solution of 2-phenyl-2H-indazol-3-amine (300 mg, 1.4 mmol; Shirtcliff, Laura D.; Rivers, Jazmin; Haley, Michael M, Journal of Organic Chemistry (2006), 71(17), 6619-6622) in CH2Cl2 (16 ml) was added benzaldehyde (730 μl, 7.2 mmol; [100-52-7]), acetic acid (220 ul, 4.3 mmol) and sodium triacetoxyborohydride (912 mg, 4.3 mmol) at ambient temperature under an argon atmosphere. The reaction mixture was heated under reflux conditions for 64 h, poured onto ice water/aqueous NaHCO3 solution 1/1 and extracted two times with CH2Cl2. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure, the resulting yellow oil was purified by column chromatography (silica gel, iPrOAc/heptane) to give the title compound (470 mg, 1.5 mmol; quant.) as yellow solid. MS: m/e=298.1 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1ccc(-c2ccccc2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(-c2ccccc2)ccc1C(=O)O

Procedure:
Ethyl 2-methyl-6-phenylnicotinate (D18) (284 mg, 1.2 mmol) was treated with aq. 2M NaOH in ethanol at reflux giving the title compound as an off white solid (108 mg). MS (AP): MH+ 214, M-H+ 212.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.FC(F)(F)S(O[CH2:23][C:24]([F:27])([F:26])[F:25])(=O)=O.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([CH2:23][C:24]([F:27])([F:26])[F:25])[CH2:3][CH2:2]1)=[O:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCN(CC(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 112.9 %

Procedure:
Benzyl 1-piperazinecarboxylate (2.0 g, 9.08 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.5 g, 10.8 mmol) and triethylamine (1.9 mL, 13.8 mmol) were dissolved in 50 mL of tetrahydrofuran, and the reaction mixture was stirred at 60° C. for two hours. After cooling to room temperature, the reaction mixture was mixed with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate twice. The combined organic layers were sequentially washed with water and brine in this order. The mixture was dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (Fuji Silysia, NH Silica gel; ethyl acetate:hexane=50:50) to give 4-(2,2,2-trifluoroethyl)piperazin-1-carboxylic acid benzyl ester (3.1 g) as a colorless oil.
Reaction SMILES: [CH2:1]([NH:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH3:3].Cl[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22]>CN1CCCC1=O>[N+:21]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:15]=1[N:4]([CH2:1][CH2:2][CH3:3])[N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CCCNn1ccc2ccccc21
Solvent: CN1CCCC1=O
Product: CCCN(c1ccncc1[N+](=O)[O-])n1ccc2ccccc21

Procedure:
The title compound was prepared from N-propyl-1H-indol-1-amine and 4-chloro-3-nitropyridine in 1-methyl-2-pyrrolidinone at 100° C. for 4 hours in substantially the same manner as in Example 1, m.p. 84°-86° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:11]([OH:15])(=[O:14])[CH:12]=[CH2:13].C(OC(=O)C)(=O)C>C(O)(=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH2:13][CH2:12][C:11]([OH:15])=[O:14])[NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2cc[nH]c2c1
Reactant: C=CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(O)CCc1cc2ccc(F)cc2[nH]1
Temperature: 20 °C
Yield: 52.2 %

Procedure:
The solution of 6-fluoroindol (300 mg, 2.22 mmol), acrylic acid (352 mg, 4.88 mmol) and acetic anhydride (453 mg, 4.44 mmol) in acetic acid (1.1 mL) was heated at 90° C. for 15 h. The reaction mixture was cooled to 20° C. then concentrated in vacuo. The residue was dissolved in 3N NaOH. The solution was filtered to remove insoluble material and the filtrate was acidified with conc. HCl and extracted with CHCl3. The organic solution was dried over MgSO4, filtered and concentrated in vacuo to give 3-(6-fluoroindolyl)propionic acid (240 mg, 52%) as a yellow solid.
Reaction SMILES: [CH2:1]([C:4]1([S:7]([N:10]2[C:14]3=[CH:15][C:16]4[S:20][N:19]=[N:18][C:17]=4[C:21]([F:22])=[C:13]3[N:12]([C:23]3[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=3[F:30])C2=O)(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].C[Si](C)(C)[O-].[K+]>C1COCC1>[CH2:1]([C:4]1([S:7]([NH:10][C:14]2[C:13]([NH:12][C:23]3[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=3[F:30])=[C:21]([F:22])[C:17]3[N:18]=[N:19][S:20][C:16]=3[CH:15]=2)(=[O:8])=[O:9])[CH2:5][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(S(=O)(=O)n2c(=O)n(-c3ccc(I)cc3F)c3c(F)c4nnsc4cc32)CC1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCC1(S(=O)(=O)Nc2cc3snnc3c(F)c2Nc2ccc(I)cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
To a solution of 7-((1-allylcyclopropyl)sulfonyl)-4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one (60 mg, 0.11 mmol) in THF (5 mL) was added potassium trimethylsilanolate (14 mg, 0.11 mmol). The reaction was stirred at room temperature for 1 h and quenched with saturated NH4Cl (aq.). The aqueous layer was extracted with EA (10 mL×2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1-3:1, v/v) to give the desired product (50 mg, 87.3% yield). 1H NMR (400 MHz, CDCl3): δ 8.24 (s, 1H), 7.65-7.63 (m, 2H), 7.31 (m, 1H), 7.01 (s, 1H), 6.83 (s, 1H), 5.74-5.56 (m, 1H), 5.02 (m, 2H), 2.77-2.71 (m, 1H), 2.12-2.0 (m, 1H), 1.75-1.71 (m, 2H), 1.21-0.97 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([Br:20])[C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C(=N)O[C:25]([CH3:28])([CH3:27])[CH3:26].B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([Br:20])[C:17]([O:19][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Reactant: O=C(NCCCC[C@H](Br)C(=O)O)OCc1ccccc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)C(Br)CCCCNC(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
(S)-6-{[(Benzyl-oxy)carbonyl]amino}-2-bromohexanoic acid, 10.0 g (0.029 mole), was dissolved in chloroform, 20 mL. To this was added a solution of t-butyl trichloroacetimidate, 12.7 g (0.058 mole), dissolved in chloroform, 50 mL, drop-wise over 30 minutes. The mixture was allowed to stir an additional 5 minutes and boron trifluoride etherate, 100 μL, was added. The reaction mixture was allowed to stir overnight. Sodium bicarbonate, 5 g, was added. After stirring 10 minutes, hexanes, 50 mL, was added and the mixture filtered to remove the solids present. The filtrate was evaporated and the residue purified by flash chromatography, ethyl acetate-hexanes, to give a clear-colorless oil. The yield was 8.5 g, 73% based on starting (S)-6-{[(benzyloxy)carbonyl]amino}-2-bromohexanoic acid. NMR is consistent with structure.
Reaction SMILES: [NH2:1][CH:2]=[C:3]([C:8]1[N:9]([CH3:18])[C:10]([CH3:17])=[CH:11][C:12]=1[C:13](OC)=[O:14])[C:4]([O:6][CH3:7])=[O:5].CC(C)([O-])C.[K+]>CN(C)C=O>[CH3:18][N:9]1[C:8]2[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:2][NH:1][C:13](=[O:14])[C:12]=2[CH:11]=[C:10]1[CH3:17]
Reactant: COC(=O)C(=CN)c1c(C(=O)OC)cc(C)n1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1c[nH]c(=O)c2cc(C)n(C)c12
Temperature: 160 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
A mixture of methyl 2-{2-amino-1-[(methyloxy)carbonyl]ethenyl}-1,5-dimethyl-1H-pyrrole-3-carboxylate (1.42 g), potassium tert-butoxide (0.13 g) and dimethylformamide (10 ml) was heated under microwave conditions at 160° C. for twenty minutes. The solvent was evaporated and then the residue was suspended in water (20 ml). 2N hydrochloric acid (0.5 ml), then saturated aqueous sodium bicarbonate (1 ml) were added and the mixture stirred for one hour. The solid was collected by filtration, washed with water, then diethyl ether, and dried to afford the title compound 0.789 g.