Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[CH3:14][CH:13]([S:10]([NH:9][CH2:8][CH:7]([O:6][C:5]1[CH:17]=[CH:18][C:2]([C:24]2[CH:25]=[CH:26][C:21]([C:20]([F:31])([F:30])[F:19])=[CH:22][CH:23]=2)=[CH:3][CH:4]=1)[CH3:16])(=[O:12])=[O:11])[CH3:15]
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(Br)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 21.3 %

Procedure:
The title compound (68 mg, 21.5%, white foam) was prepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (267 mg, 0.794 mmol, prepared in example 1), 4-trifluoromethylbenzeneboronic acid (180 mg, 0.948 mmol), dichlorobis(triphenylphosphine)palladium(II) (22 mg, 0.031 mmol), 2 M sodium carbonate (285 mg in 1.35 mL water), and 1,2-dimethoxyethane (5.25 mL) in a manner analogous to the procedure described in Example 8. The crude material was purified utilizing a Chromatotron® with a 2000 μm rotor in a 1:1 hexane:ethyl acetate solvent system, yielding 190 mg of a co-eluting mixture of unreacted starting material and title compound. This mixture was further purified by reverse phase chromatography on a Vydac C-18 column on a gradient of 5 to 70% of 0.1% trifluoroacetic acid/acetonitrile in water over 45 minutes at 200 mL/min elution rate.
Reaction SMILES: Cl.Cl.Cl.Cl.[N:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[O:15])[NH2:13])=[CH:7][CH:6]=1.[Cl:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:39](O)=[O:40])=[CH:33]2>>[Cl:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:39]([NH:13][C@@H:12]([C:14]([N:16]1[CH2:21][CH2:20][N:19]([CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[CH2:18][CH2:17]1)=[O:15])[CH2:11][C:8]1[CH:7]=[CH:6][N:5]=[CH:10][CH:9]=1)=[O:40])=[CH:33]2
Reactant: CN1CCC(N2CCN(C(=O)[C@H](N)Cc3ccncc3)CC2)CC1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Product: CN1CCC(N2CCN(C(=O)[C@@H](Cc3ccncc3)NC(=O)c3cc4cc(Cl)ccc4[nH]3)CC2)CC1

Procedure:
Using methods substantially equivalent to those described in Method D-1, the titled compound was prepared from 1-[β-(4-pyridinyl)-D-alanyl]-4-(1-methylpiperidin-4-yl)piperazine tetrahydrochloride and 5-chloroindole-2-carboxylic acid (47%).
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([C@@H:8]2[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]2)[C:6]2[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:5]=2[N:4]=1.[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][C@H:24]([CH:29]=O)[CH2:23]2>>[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][C@H:24]([CH2:29][NH:13][C@H:10]1[CH2:11][CH2:12][C@@H:8]([N:7]3[C:6]4[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:5]=4[N:4]=[C:3]3[CH3:2])[CH2:9]1)[CH2:23]2
Reactant: O=C[C@H]1Cc2ccc(Br)cc2C1
Reactant: Cc1ccc2c(c1)nc(C)n2[C@@H]1CC[C@H](N)C1
Agent: Cl
Product: Cc1ccc2c(c1)nc(C)n2[C@@H]1CC[C@H](NC[C@H]2Cc3ccc(Br)cc3C2)C1

Procedure:
This compound was prepared from cis-3-(2,5-dimethyl-benzoimidazol-1-yl)-cyclopentylamine hydrochloride and (S)-5-bromo-indan-2-carbaldehyde using the same reductive amination method described in previous example. 1H-NMR is consistent with the assigned structure. LC-MS showed a single peak, C24H28BrN3 (m/e) calcd 437.1467, obsd 438.1 (M+H).
Reaction SMILES: FO[C:3]([F:6])(F)F.[CH3:7][O:8][C:9]1[CH:14]=[CH:13]C=[C:11]([O:15][CH3:16])[C:10]=1[C:17](=[O:20])[CH2:18][CH3:19]>>[F:6][C:3]1[C:11]([O:15][CH3:16])=[C:10]([C:17](=[O:20])[CH2:18][CH3:19])[C:9]([O:8][CH3:7])=[CH:14][CH:13]=1
Reactant: FOC(F)(F)F
Reactant: CCC(=O)c1c(OC)cccc1OC
Product: CCC(=O)c1c(OC)ccc(F)c1OC

Procedure:
Trifluoromethyl hypofluorite was bubbled through a stirred mixture of 1-(2,6-dimethoxyphenyl)- Propan-1-one (9.02 g, 46.5 mmol) and Freon (40 mL) under nitrogen at -78° C. The reaction was monitored frequently by thin layer chromatography, and passage of the gas was stopped when most of the starting material had been converted to the desired product but only a trace of the less polar difluorinated derivative had been formed. The reaction was quenched by pouring the mixture into a stirred mixture of ice and methylene chloride, and the crude product from the organic layer was submitted to column chromatography (160 g of Merck AG silica gel eluted with 1:10 ethyl acetate/hexane). The title product was the second material eluted. NMR δ (250 MHz, CDCl3, TMS) 7.03 (lH, q, ArH) 6.55 (lH, q, ArH) 3.90 (3H, d, OMe) 3.77 (3H, s, OMe) 2.76 (2H, q, CH2) 1.16 (3H, t, CH3)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]2=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:24][C:21]3[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: COc1ccc(N)cc1
Product: COc1ccc(NC2CCCc3c2[nH]c2ccc(Br)cc32)cc1

Procedure:
6-Bromo-N-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-one (100 mg, 0.38 mmol) and p-anisidine (94 mg, 0.76 mmol) in a similar manner as described in Example 13 to give 41 mg (29%) of a light brown solid. 1H-NMR (DMSO-d6): δ 811.05 (s, 1H), 7.54 (s, 1H), 7.22 (d, 1H), 7.11 (d, 1H), 6.73-6.66 (m, 4H), 5.48 (d, 1H), 4.70-4.65 (m, 1H), 3.63 (s, 3H), 2.66-2.53 (m, 2H), 1.98-1.89 (m, 2H), 1.79-1.71 (m, 2H); MS m/z (M−1) 369, 371.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[N:14][CH:13]=3)[CH2:9][C:8](=[O:18])[NH:7][C:6]=2[CH:19]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[N:14][CH:13]=3)[CH2:9][C:8](=[O:18])[NH:7][C:6]=2[CH:19]=1
Reactant: OB(O)c1ccccc1F
Reactant: O=C1CC(c2ccnnc2)=Nc2ccc(Br)cc2N1
Product: O=C1CC(c2ccnnc2)=Nc2ccc(-c3ccccc3F)cc2N1

Procedure:
The title compound was prepared from 8-bromo-4-(pyridazin-4-yl)-1H-benzo[b][1,4]diazepin-2(3H)-one (Example 1; 1 mmol) and commercial available 2-fluorophenylboronic acid (CAS-No: 1993-03-9; 1.5 mmol) according to the general procedure G. Obtained as a yellow solid (67%), MS (EI) 333 [(M+1)+].
Reaction SMILES: OO.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:12][C@@H:11]([CH2:19][CH:20]=[O:21])[O:10][C@H:9]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]4[O:28][CH2:29][CH2:30][O:31][C:23]=34)[C:8]=2[CH:32]=1.[OH:33]P([O-])(O)=O.[Na+].Cl([O-])=O.[Na+]>C(#N)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH2:14][C:15]([CH3:17])([CH3:18])[CH3:16])[CH2:12][C@@H:11]([CH2:19][C:20]([OH:33])=[O:21])[O:10][C@H:9]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]4[O:28][CH2:29][CH2:30][O:31][C:23]=34)[C:8]=2[CH:32]=1
Reactant: O=P([O-])(O)O
Reactant: CC(C)(C)CN1C[C@@H](CC=O)O[C@H](c2cccc3c2OCCO3)c2cc(Cl)ccc21
Agent: OO
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Product: CC(C)(C)CN1C[C@@H](CC(=O)O)O[C@H](c2cccc3c2OCCO3)c2cc(Cl)ccc21
Reaction time: 0.75 h
Yield: 72.6 %

Procedure:
Aqueous hydrogen peroxide (30% by weight; 69 mL, 605 mmol) was added to a solution of [trans-7-chloro-5-(2,3-ethylenedioxyphenyl)-1-neopentyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]-acetaldehyde (250 mg, 582 mmol), aqueous sodium phosphate monobasic (63 mg in 1 mL water) and acetonitrile (1.25 mL). Sodium chlorite (1M in water; 640 mL, 640 mmol) was then added dropwise. After 45 minutes, the reaction mixture was quenched with saturated aqueous sodium sulfite, concentrated, taken up in water and extracted with ethyl acetate (3×). The combined organics were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash column chromatography (2% methanol/chloroform) to give 170 mg (66%) of the title compound as a white foam.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.S(Cl)(Cl)=O.[CH2:19](O)[CH3:20]>>[CH2:19]([O:13][C:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH2:1])[CH:3]=2)[CH:8]=1)=[O:14])[CH3:20]
Reactant: CCO
Reactant: Nc1ccc2cc(C(=O)O)ccc2c1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc2cc(N)ccc2c1

Procedure:
To a solution of 6-amino-2-naphthoic acid (1 g, 5.34 mmol) in ethanol (20 mL), is added dropwise thionyl chloride (0.622 mL, 10.7 mmol). The resulting reaction solution is heated to reflux temperature under a N2 atmosphere for 3 hours. Concentration and trituration with methanol gives 6-amino-2-naphthoic acid ethyl ester as a brown oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([NH2:14])=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][CH:11]=[CH:10]2)=[O:4].[OH-].[Na+]>O1CCOCC1.CO>[NH2:14][C:6]1[C:5]([C:3]([OH:4])=[O:2])=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1
Reactant: COC(=O)c1c(N)ccc2cc[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: Nc1ccc2cc[nH]c2c1C(=O)O
Temperature: 60 °C

Procedure:
To a solution of 85.2 mg (0.45 mmol) of 6-amino-1H-indole-7-carboxylic acid methyl ester in 4 mL of dioxane and 1 mL of methanol, is added 0.45 mL (0.9 mmol) of an aqueous solution of NaOH 2N. The mixture is stirred over the night at 60° C. A new addition of 0.22 mL (0.45 mmol) of an aqueous solution of NaOH 2N is made and the mixture is stirred again 6 h at 60° C. and then cooled to ambient temperature. After evaporation of all the solvents, a crude yellowish residue is obtained and used directly in the next step; 1H-NMR (MeOD4, 400 MHz): 7.51 (m, 1H), 7.05 (d, 1H), 6.55 (d, 1H), 6.33 (m, 1H) ppm.
Reaction SMILES: [CH:1]([C:3]1[C:8]([C:9]([O:11]CC)=O)=[C:7]([S:14][CH3:15])[N:6]=[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:4]=1)=O.Cl.Cl.[NH2:24][NH2:25]>C(O)C>[CH3:15][S:14][C:7]1[C:8]2[C:9](=[O:11])[NH:25][N:24]=[CH:1][C:3]=2[N:4]=[C:5]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:6]=1
Reactant: NN
Reactant: CCOC(=O)c1c(C=O)nc(-c2ccccc2)nc1SC
Agent: Cl
Solvent: CCO
Product: CSc1nc(-c2ccccc2)nc2cn[nH]c(=O)c12
Yield: 97.2 %

Procedure:
To a solution of ethyl 4-formyl-6-(methylthio)-2-phenylpyrimidine-5-carboxylate (600 mg, 1.98 mmol) in ethanol (15 mL) was added hydrazine dihydrochloride (0.2 g, 1.98 mmol) and the mixture refluxed for 1 hour. The precipitated solid was filtered and dried in vacuum. The desired product (520 mg) was obtained by column chromatography over silica gel using methanol/dichloromethane as eluent. 1H-NMR (400 Hz, DMSO-d6): δ 13.19 (s, 1H), 8.54 (d, J=8.0 Hz, 2H), 8.36 (s, 1H), 7.64-7.58 (m, 3H), 2.67 (s, 3H); MS m/z 271.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:11]([C:15]1[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])[CH2:23][CH2:22]2)[CH:18]=[C:17]([CH:32]2[CH2:35][CH2:34][CH2:33]2)[N:16]=1)([CH3:14])([CH3:13])[CH3:12].C(N(C(C)C)CC)(C)C.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[C:11]([C:15]1[N:20]=[C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])[CH2:25][CH2:26]2)[CH:18]=[C:17]([CH:32]2[CH2:35][CH2:34][CH2:33]2)[N:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: O=C(O)c1ccccc1F
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCN)CC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCNC(=O)c3ccccc3F)CC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.5 %

Procedure:
0.29 g of 2-fluoro-benzoic acid (2.03 mmol) and 0.7 g of 4-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-butylamine (2.03 mmol) were dissolved in 25 ml of dichloromethane. 1.04 g of diisopropylethylamine (8.04 mmol), 0.19 g of hydroxybenzotriazole (HOBt, 1.4 mmol), and 0.46 g of N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDCl, 2.4 mmol) were added at 0° C. and the reaction mixture was stirred for 16 h at room temperature. 25 ml of dichloromethane were added, the organic layer washed with aqueous saturated sodium chloride, the aqueous phase re-extracted once with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using ethyl acetate and ethyl acetate-methanol (5%). Fractions containing the product were combined. The solvent was evaporated to yield 0.84 g of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([O:5][C:6](=O)C(F)(F)F)=[O:4].O[CH2:15][N:16]([N+:18]([O-:20])=[O:19])C>ClCCl>[F:1][C:2]([F:13])([F:12])[C:3]([O:5][CH2:6][N:16]([N+:18]([O-:20])=[O:19])[CH3:15])=[O:4]
Reactant: CN(CO)[N+](=O)[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CN(COC(=O)C(F)(F)F)[N+](=O)[O-]

Procedure:
Trifluoroacetic anhydride (20 ml, 103.6 g, 0.49 moles) was added to a stirred solution of 1-hydroxy-2-nitro-2-azapropane (40.0 g, 0.38 moles) in dichloromethane (60 ml) at -5° to 0° C. during 11/2 hours. The resulting solution was then distilled without warming at 20 mm, then to 3 mm. The product was distilled at 1.5 mm, 65° C. to give 2-nitro-2-azapropyl trifluoroacetate; yield: 48 g (63%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[CH:5][C:6]([NH:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])=[C:7]([CH:12]=1)[C:8]([O:10]C)=[O:9].[OH-].[Li+].Cl>C1COCC1.O>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:4]=[CH:5][C:6]([NH:13][S:14]([C:17]([F:18])([F:19])[F:20])(=[O:16])=[O:15])=[C:7]([CH:12]=1)[C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1cc(C(F)(F)F)ccc1NS(=O)(=O)C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(C(F)(F)F)ccc1NS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Yield: 77 %

Procedure:
Preparation B6, Step 4: To a solution of methyl 5-(trifluoromethyl)-2-(trifluoromethylsulfonamido)benzoate (2.7 g, 7.7 mmol) in 55 ml of THF was added lithium hydroxide (0.97 g, 23.1 mmol) in 55 ml of water and stirred at RT over night. The reaction mixture was acidified with 1.5N HCl and extracted with ethyl acetate. The organic layer was washed with water, brine and concentrated to give 5-(trifluoromethyl)-2-(trifluoromethylsulfonamido)benzoic acid (2 g) as white solid. 1H NMR (DMSO-d6, 400 MHz) δ 7.77 (m, 2H), 8.18 (s, 1H). MS found: (M−H)−=336.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][O:5][C:4](=[O:7])[CH2:3]1.ClC(Cl)(Cl)C(=N)O[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.FC(F)(F)S(O)(=O)=O>C(Cl)Cl.C1CCCCC1>[CH2:12]([O:1][CH:2]1[CH2:6][O:5][C:4](=[O:7])[CH2:3]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CC(O)CO1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCCCC1
Product: O=C1CC(OCc2ccccc2)CO1
Temperature: 0 °C
Reaction time: 48 h
Yield: 75.5 %

Procedure:
To a stirred solution of 4-hydroxydihydrofuran-2(3H)-one (25 g, 245 mmol) and benzyl 2,2,2-trichloroacetimidate (68.6 mL, 367 mmol) in CH2Cl2 (500 mL) and cyclohexane (500 mL) at 0° C. was added, dropwise, trifluoromethanesulfonic acid (2.175 mL, 24.49 mmol) over 10 min. The reaction mixture was stirred for 2 h at 0° C. and 48 h at room temperature. After this, it was diluted with hexanes (0.75 L), filtered and the filtrate washed with sat. aq. NaHCO3 (150 mL), dried (Na2SO4), filtered and concentrated. The resulting yellow oil was purified by flash column chromatography on silica gel column using 5-40% ethyl acetate/hexane (5% increment for every liter) to afford 4-(benzyloxy)dihydrofuran-2(3H)-one (35.52 g, 185 mmol, 75% yield) as a clear yellow oil. 1H NMR (500 MHz, CDCl3) δ: 7.34-7.39 (2 H, m), 7.29-7.34 (3 H, m), 4.53 (1 H, d, JAB=11.9 Hz), 4.52 (1 H, d, JAB=11.90 Hz), 4.34-4.41 (3 H, m), 2.64-2.68 (2 H, m).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([F:12])[CH:4]=1.[P:13]([O:20]CC)([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>O>[F:12][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[N+:9]([O-:11])=[O:10])[CH2:2][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1F
Reactant: CCOP(OCC)OCC
Solvent: O
Product: CCOP(=O)(Cc1ccc([N+](=O)[O-])c(F)c1)OCC

Procedure:
4-(Bromomethyl)-2-fluoro-1-nitrobenzene (34.72 g, 148 mmol) and triethyl phosphite (25.8 mL) were heated at 140° C. for 4 hours. Water was added and the mixture was extracted with diethyl ether. The organics were dried with magnesium sulphate, filtered and evaporated under reduced pressure to afford the title compound (40.94 g). 1H NMR (CDCl3, 400 MHz): δ 8.03 (t, 1H), 7.24 (s, 1H) 7.21 (s, 1H) 4.08 (m, 4H), 3.20 (d, 2H), 1.27 (m, 6H)
Reaction SMILES: [CH3:1][O-:2].[Na+].F[C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15])[C:8]([OH:10])=[O:9].Cl>CO.CS(C)=O>[CH3:1][O:2][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15])[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1ccc(C(F)(F)F)c(F)c1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: COc1cc(C(=O)O)ccc1C(F)(F)F
Temperature: 90 °C
Reaction time: 3.5 h

Procedure:
28% Sodium methoxide in methanol (50 ml) was added to a solution of 3-fluoro-4-(trifluoromethyl)benzoic acid (20.8 g) in dimethylsulfoxide (200 ml). The mixture was stirred at 90° C. for 3.5 hours. After cooling at room temperature, the resulting mixture was poured into ice-water (1.5 l) and made acidic with diluted hydrochloric acid. After being stirred for 30 minutes, the resulting precipitates were collected by filtration and air-dried to give a colorless powder of 3-methoxy-4-(trifluoromethyl)benzoic acid (22.95 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[CH:24]=[N:23]2)[CH:5]=[C:6]([Cl:21])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([S:17](Cl)(=[O:19])=[O:18])[CH:10]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>CN(C)C=O.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[CH:24]=[N:23]2)[CH:5]=[C:6]([Cl:21])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([S:17]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)(=[O:19])=[O:18])[CH:10]=1
Reactant: COc1ccc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1S(=O)(=O)Cl
Reactant: C1CCNCC1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1S(=O)(=O)N1CCCCC1
Reaction time: 1 h

Procedure:
To a stirred solution of 2-[3,5-dichloro-4-(3-chlorosulfonyl-4-methoxy-phenoxy)-phenyl]-2H-[1,2,4]triazine-3,5-dione (0.7 g) in dimethylformamide (8 mL) was added piperidine (0.4 mL). After 1 h, the reaction was diluted in diethyl ether, washed with 1N hydrochloric acid, brine, dried (Na2SO4) and concentrated in vacuo to a solid. Recrystallization from diethyl ether/petroleum ether afforded the title compound of Step B, 0.5 g. MS Calc.:527.4 Found:527.0.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[S:15][CH2:14][CH2:13][O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([O:9][CH2:10][CH:11]1[S:15][CH2:14][CH2:13][O:12]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC[C@H]1OCCS1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(OCC1OCCS1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.3 %

Procedure:
2(S)-(Benzoyloxymethyl)-1,3-oxathiolane (0.045 mmol, 10 mg, 1.0 equiv.), para-toluenesulfonic acid monohydrate (0.015 mmol, 3 mg, 0.3 equiv.) and toluene (1 mL) were heated to reflux and stirred while monitoring the racemization reaction by chiral HPLC. After 24 h, the reaction was allowed to cool to ambient temperature and washed with saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate and concentrated by rotary evaporation to give 8 mg (80% yield) of (+/−)-2-(benzoyloxymethyl)-1,3-oxathiolane.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5](=O)[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:18][NH:19][NH2:20]>C(O)C>[OH:1][C:2]1[CH:3]=[C:4]([C:5]2[CH2:6][CH:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:19]([CH3:18])[N:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CNN
Reactant: O=C(C=Cc1ccccc1)c1cccc(O)c1
Solvent: CCO
Product: CN1N=C(c2cccc(O)c2)CC1c1ccccc1
Yield: 96.9 %

Procedure:
To a 100 ml round bottom flask equipped with a magnetic stirrer and reflux condenser was charged 1.0 g (0.0045 moles) of 3'-hydroxychalcone, and 25 mls of absolute ethanol. To this solution was then added 0.21 g (0.0045 moles) of methyl hydrazine in one portion. The reaction was then heated to reflux for two hours, then cooled. The solvent was removed under reduced pressure to afford 1.1 g of 3-(3-hydroxylphenyl)-1-methyl-5-phenyl-2-pyrazoline as a thick brown oil in 97% yield
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[N+:23]([O-])=O)[NH:7][C:8]([CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)=[O:9])([O-])=O.[CH:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:27]1([C:26]2[NH:23][C:22]3[CH:21]=[CH:20][C:6]([NH:7][C:8]([CH:10]4[CH2:19][CH2:18][C:17]5[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=5)[CH2:11]4)=[O:9])=[CH:5][C:4]=3[N:1]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)C1CCc2ccccc2C1
Product: O=C(Nc1ccc2[nH]c(-c3ccccc3)nc2c1)C1CCc2ccccc2C1

Procedure:
Compound 204 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(1,2,3,4-tetrahydronaphthalen-2-oyl)aniline and benzaldehyde. [M+H]+ calcd for C24H21N3O: 368.17; found: 368.00.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](O)=[O:5].O.[CH:13]([NH2:15])=O>>[Br:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:13][N:15]=[C:4]2[OH:5]
Reactant: NC=O
Reactant: Nc1ccc(Br)cc1C(=O)O
Solvent: O
Product: Oc1ncnc2ccc(Br)cc12
Temperature: 165 °C
Yield: 95 %

Procedure:
A suspension of 2-amino-5-bromobenzoic acid (5.4 g, 25 mmol) in formamide (40 ml) was heated at 165° C. for 6 hours. After cooling to room temperature, water (100 ml) was added to the reaction mixture. The precipitate was collected by filtration, washed with water and dried over P2O5, yielding the title compound as a white solid (5.3 g, yield: 95%) which was characterized by its mass spectrum as follows: MS (m/z): 225 ([M+H]+, 100).
Reaction SMILES: [CH:1]([C:3]1[C:4]([C:9]#[N:10])=[N:5][CH:6]=[CH:7][CH:8]=1)=O.Br.Br.Br.[CH2:14]([C:16]1[C:17]([C:24]2[CH:32]=[C:31]3[C:27]([C:28]([C:33]4[NH:34][C:35]5[CH2:40][CH2:39][NH:38][CH2:37][C:36]=5[N:41]=4)=[N:29][NH:30]3)=[CH:26][CH:25]=2)=[CH:18][C:19]([F:23])=[C:20]([OH:22])[CH:21]=1)[CH3:15]>>[CH2:14]([C:16]1[CH:21]=[C:20]([OH:22])[C:19]([F:23])=[CH:18][C:17]=1[C:24]1[CH:32]=[C:31]2[C:27]([C:28]([C:33]3[NH:34][C:35]4[CH2:40][CH2:39][N:38]([CH2:1][C:3]5[C:4]([C:9]#[N:10])=[N:5][CH:6]=[CH:7][CH:8]=5)[CH2:37][C:36]=4[N:41]=3)=[N:29][NH:30]2)=[CH:26][CH:25]=1)[CH3:15]
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Reactant: N#Cc1ncccc1C=O
Agent: Br
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(Cc3cccnc3C#N)C4)n[nH]c2c1
Yield: 22.9 %

Procedure:
The title compound was prepared from 3-formyl-pyridine-2-carbonitrile (26 mg, 198 μmol) and 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50 mg, 132 μmol) using the method of Example 22. The crude material was purified by HPLC Method A to afford 14.9 mg of the title compound.