Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([C:17]3[CH:22]=[CH:21][C:20](OC)=[CH:19][CH:18]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].[F:26]C1C=CC(N)=CC=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([C:17]3[CH:22]=[CH:21][C:20]([F:26])=[CH:19][CH:18]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2-c1ccc(OC)cc1
Reactant: Nc1ccc(F)cc1
Product: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2-c1ccc(F)cc1

Procedure:
Prepared similarly according to a reaction sequence in Example 138 steps (a) and (b) for the synthesis of 2,3-dibromo-4-hydroxy-1-(4-methoxy-phenyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester starting from 4-fluoroaniline. The title compound, ESI MS (m/z): 457 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[CH:6]=1.[ClH:15]>CO.[Pd]>[ClH:15].[F:14][C:2]([F:1])([F:13])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][NH2:12])[CH:6]=1
Reactant: N#Cc1cc(OCC(F)(F)F)ccn1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1cc(OCC(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.5 %

Procedure:
A mixture of 4-(2,2,2-trifluoroethoxy)picolinonitrile (0.71 g, 3.51 mmol, Step-1), hydrochloric acid (0.21 mL, 7.03 mmol) and palladium 10% on carbon (0.15 g) in methanol (35 mL) is vigorously stirred at room temperature under hydrogen atmosphere (0.3 MPa) for 4 hours. After filtration through a pad of celite, the filtrate is concentrated in vacuo. The residue is crystallized from ethyl acetate to give 0.43 g (44% yield) of the title compound as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[N:21]1([C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][CH:28]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[C:33]([C:30]1[CH:29]=[CH:28][C:27]([N:21]2[CH2:22][CH2:23][N:24]([C:15](=[O:17])[CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=3)[CH2:25][CH2:26]2)=[CH:32][CH:31]=1)(=[O:35])[CH3:34]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)N2CCN(c3ccc(C(C)=O)cc3)CC2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 1-(4-piperazin-1-yl-phenyl)-ethanone via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C24H28N2O6 [M+H]+: 441.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:13][C:14]3[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=3)[N:8]=[C:9]2Cl)=[CH:4][CH:3]=1.[CH:20]([OH:23])([CH3:22])[CH3:21]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:13][C:14]3[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=3)[N:8]=[C:9]2[O:23][CH:20]([CH3:22])[CH3:21])=[CH:4][CH:3]=1
Reactant: CC(C)O
Reactant: Cc1cc(Nc2cc3ccc(Br)cc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccc(Br)cc3c(OC(C)C)n2)n[nH]1

Procedure:
Similar procedure as described in example 376 was used, starting from (7-Bromo-1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and isopropanol to give (7-Bromo-1-isopropoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 361 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:49])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([N:35]3[CH2:39][CH2:38][CH:37]([C:40]([OH:42])=O)[CH2:36]3)=[O:34])[N:28]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].CC[N:52]([CH:56]([CH3:58])[CH3:57])C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CC1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:49])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([N:35]3[CH2:39][CH2:38][CH:37]([C:40](=[O:42])[NH:52][CH:56]4[CH2:58][CH2:57]4)[CH2:36]3)=[O:34])[N:28]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC(C(=O)O)C3)n(-c3ccccc3)n2)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC(C(=O)NC4CC4)C3)n(-c3ccccc3)n2)CC1

Procedure:
To a solution of 200 mg 4-[(S)-4-tert-butoxycarbonyl-2-({5-[2-(3-carboxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester in 5 ml DMF were added 48 μl DIPEA, 11 mg HATU and 20 μl cyclopropylamine. After stirring for 12 h saturated aqueous NaHCO3 solution was added and the mixture loaded on a Chem Elut® cartridge, the crude product being eluted with dichloromethane. The solution was concentrated to a volume of 5 ml and stirred in the presence of 324 μl TFA. After stirring for 14 h the solvents were removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 30 mg MS (ES+): m/e=668.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[C:10]([NH2:14])([CH3:13])([CH3:12])[CH3:11]>CN1C(=O)CCC1>[C:10]([NH:14][C:6]1[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([NH2:1])[N:7]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CC(C)(C)N
Solvent: CN1CCCC1=O
Product: CC(C)(C)Nc1cc(Cl)nc(N)n1
Yield: 100.9 %

Procedure:
A solution of 2-amino-4,6-dichloropyrimidine (400 mg, 2.44 mmol) and t-butylamine (2.6 ml, 25.0 mmol) in NMP (1 ml) was heated in a microwave at 150° C. for 60 minutes. The reaction mixture was partitioned between water (10 ml) and ethyl acetate (10 ml), the organic phase separated, dried and reduced in vacuo. Purification by flash column chromatography on silica gel eluting with ethyl acetate:pentane (30:70 changing to 80:20 by volume) to yield the title compound as a colourless solid (494 mg, 100%).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][NH2:14])[CH2:8][CH2:7]1)=[O:5])C>Cl>[NH2:14][CH2:13][CH2:12][N:9]1[CH2:10][CH2:11][C:6]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C1(Cc2ccccc2)CCN(CCN)CC1
Agent: Cl
Product: NCCN1CCC(Cc2ccccc2)(C(=O)O)CC1
Temperature: 90 °C

Procedure:
1-(2-Amino-ethyl)-4-benzyl-piperidine-4-carboxylic acid ethyl ester (2.5 g, 10 mmol) is dissolved in 6N aqueous HCl (40 mL) and the mixture heated at 90° C. for 96 h. The reaction mixture is evaporated to provide the title compound as hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10](/[N:12]=[C:13]2/[NH:14][C:15]3([CH2:22][CH2:21][N:20]([C:23](=[O:37])[CH2:24][CH2:25][C:26]4[CH:36]=[CH:35][C:29]([O:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:28][CH:27]=4)[CH2:19][CH2:18]3)[CH2:16][NH:17]/2)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.Cl[CH2:39][C:40]([N:42]([CH2:46][CH2:47][CH3:48])[CH2:43][CH2:44][CH3:45])=[O:41].C(=O)([O-])O.[Na+]>CN(C=O)C.O.C(Cl)Cl>[CH2:43]([N:42]([CH2:46][CH2:47][CH3:48])[C:40]([CH2:39][O:33][C:32](=[O:34])[CH2:31][O:30][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH2:24][C:23]([N:20]2[CH2:21][CH2:22][C:15]3([NH:14]/[C:13](=[N:12]/[C:10]([C:3]4[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=4)=[O:11])/[NH:17][CH2:16]3)[CH2:18][CH2:19]2)=[O:37])=[CH:36][CH:35]=1)=[O:41])[CH2:44][CH3:45]
Reactant: CCCN(CCC)C(=O)CCl
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCN(C(=O)CCc4ccc(OCC(=O)O)cc4)CC3)N2)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CCCN(CCC)C(=O)COC(=O)COc1ccc(CCC(=O)N2CCC3(CC2)CN/C(=N\C(=O)c2nc(Cl)c(N)nc2N)N3)cc1
Temperature: 70 °C

Procedure:
A solution of [4-(3-{2-[(E)-3,5-Diamino-6-chloro-pyrazine-2-carbonylimino]-1,3,8-triaza-spiro[4.5]dec-8-yl}-3-oxo-propyl)-phenoxy]-acetic acid (Step 1) (811 mg, 1.53 mmol) in DMF (30 ml) was treated with 2-chloro-N,N-dipropyl-acetamide (813 mg, 4.59 mmol) and sodium hydrogen carbonate (808 mg, 8.92 mmol). The reaction mixture was heated at 70° C. for 7 days. The reaction was allowed to cool to RT and diluted with water (100 ml). A white precipitate formed which was extracted into EtOAc (2×75 ml) and DCM (2×75 ml). The organic extracts were combined, dried over MgSO4 and concentrated in vacuo to afford a brown oil. Purification by chromatography on silica eluting with a gradient of 0-20% EtOH/DCM afforded a yellow oily solid which was dissolved in DCM (˜5 ml) and filtered through a 2 μM syringe filter. The solution was concentrated in vacuo to 1 ml, and diethyl ether (10 ml) was added. The resulting white precipitate was collected by filtration and dried in vacuo at 50° C. overnight to afford the title compound; 1H NMR (400 MHz, DMSO-d6) δ 9.10-7.94 (1H br), 8.43 (1H br s), 8.36 (1H, br s), 7.15 (2H, d), 6.96-6.45 (1H, br s), 6.86 (2H, d), 6.72 (2H, br s), 4.88 (2H, s), 4.81 (2H, s), 3.62-3.37 (4H, m), 3.38 (2H, s), 3.19-3.14 (4H, m), 2.74 (2H, t), 2.59 (2H, t), 1.67-1.54 (4H, m), 1.54-1.45 (4H, m), 0.85 (3H, t), 0.80 (3H, t). LC-MS Rt 4.45 mins; 672.5 [M+H]+, Method 10minLC_v003.
Reaction SMILES: [CH:1]1([N:4]2[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[N:5]2)[CH2:3][CH2:2]1>C(O)C>[CH:1]1([N:4]2[CH:8]=[C:7]([NH2:9])[CH:6]=[N:5]2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cnn(C2CC2)c1
Solvent: CCO
Product: Nc1cnn(C2CC2)c1
Reaction time: 2 h
Yield: 45.6 %

Procedure:
A 250-mL Parr reactor bottle was purged with nitrogen and charged with 10% palladium on carbon (50% wet, 117 mg dry weight) and a solution of 109a (500 mg, 6.73 mmol) in ethanol (36 mL). The bottle was attached to a Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 2 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. Celite 521 (1.00 g) was added, and the mixture was filtered through a pad of Celite 521. The filter cake was washed with ethanol (2×25 mL), and the combined filtrates were concentrated to dryness under reduced pressure to afford a 94% yield of 109b (378 mg) as a purple oil: 1H NMR (300 MHz, CDCl3) δ 7.13 (s, 1H), 7.07 (s, 1H), 3.47 (m, 1H), 2.87 (br s, 2H), 0.96 (m, 4H); MS (ESI+) m/z 124.1 (M+H).
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1[N:11]=[CH:12][S:13][C:14]=1[CH3:15].[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1[N:11]=[CH:12][S:13][C:14]=1[CH2:15][Br:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1scnc1-c1ccc(Cl)cc1Cl
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(-c2ncsc2CBr)c(Cl)c1

Procedure:
The product was neutralised and the free thiazole was treated with N-bromosuccinimide in refluxing carbon tetrachloride for 16 hours with irradiation by a lamp to give 4-(2',4'-dichlorophenyl)-5-bromomethyl thiazole The crude product was dissolved in dry acetonitrile, sodium triazole (0.91 g; 0.01 mole) was added and the mixture stirred for 16 hours at 20° C. to give, after chromatography using silica gel/chloroform: 2% ethanol, the title compound (0.71 g; 23%). m.p. 120°-123° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][NH:13][C:14]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)=[O:15].[OH-].[Na+]>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][NH:13][C:14]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)=[O:15]
Reactant: COC(=O)c1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 74 %

Procedure:
Into a suspension of methyl 4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}benzoate (80 mg, 0.18 mmol) in THF (5 mL) was added NaOH (0.2 M, 2.5 mL). The resulting solution was stirred at rt for 5 hrs and quenched with HCl (1N, 2 mL) and water (5 mL). A yellow solid precipitated out. Filtration, washing with water (2×1 mL) and drying under vacuo at rt for 72 hrs to give the tilte compound as a yellow powder (58 mg, 75%) in 98.6% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [C:1]([C:5]1[CH:29]=[CH:28][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=2)=[O:19])=[O:10])=[C:7]([O:30][CH:31]2[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1(OC)C=CC=CC=1.[C:52]([OH:58])([C:54]([F:57])([F:56])[F:55])=[O:53]>ClCCl>[F:55][C:54]([F:57])([F:56])[C:52]([OH:58])=[O:53].[C:1]([C:5]1[CH:29]=[CH:28][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=2)=[O:19])=[O:10])=[C:7]([O:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2C(=O)Nc2ccncc2C(=O)Nc2ccc(Cl)cn2)CC1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc(C(=O)Nc2ccncc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCNCC2)c1
Reaction time: 2 h
Yield: 88 %

Procedure:
To a stirring solution of 4-[4-tert-butyl-2-(1-Boc-piperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-3-carboxamide (0.099 g, 0.163 mmol) and anisole (0.1 mL) in dichloromethane (5 mL) was added TFA (0.5 mL). After 2 h, the solvent was removed in vacuo and the residue was suspended in toluene and concentrated in vacuo. The residue was then diluted with diethyl ether and concentrated in vacuo. Finally, the residue was again diluted with diethyl ether with vigorous stirring to yield a solid precipitate, which was filtered and washed with diethyl ether and dried in vacuum to give the title compound (0.089 g, 88%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[F:33].[N:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[C:35]=[O:36]>>[F:33][C:3]1[CH:4]=[C:5]([C:8]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:24]([F:25])([F:26])[F:27])[C:28]([F:30])([F:31])[F:29])=[CH:19][CH:18]=3)[CH2:14][CH2:15]2)=[O:9])[CH:6]=[CH:7][C:2]=1[NH:1][C:35]([NH:34][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:36]
Reactant: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Reactant: O=C=Nc1ccccc1
Product: O=C(Nc1ccccc1)Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Temperature: 100 °C
Yield: 56.8 %

Procedure:
(4-Amino-3-fluorophenyl)(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-1-yl)methanone (0.209 mmol, 0.1 g) and isocyanatobenzene (0.229 mmol, 0.025 mL, 0.027 g) were combined and heated in the microwave at 100° C. for 10 minutes. Further isocyanatobenzene (0.229 mmol, 0.025 mL, 0.027 g) was added and the reaction heated in the microwave for a further 10 minutes at 100° C. The reaction mixture was concentrated under reduced pressure and purified by acidic preparative HPLC to afford the title compound (71 mg). MS (ESI) m/z 599.0 [M+H]+
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:9]=[C:10]([C:16](=[O:18])[CH3:17])[CH:11]=[C:12]([F:15])[C:13]=1[F:14].[C:19](OCC)(=[O:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(OCC)C>[O:25]=[C:19]([CH2:17][C:16](=[O:18])[C:10]1[CH:9]=[C:8]([F:7])[C:13]([F:14])=[C:12]([F:15])[CH:11]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1cc(F)c(F)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCOC(=O)C(=O)CC(=O)c1cc(F)c(F)c(F)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Potassium tert.-butoxide (1.12 g, 10.0 mmol) was added to a solution of 1-(3,4,5-trifluoro-phenyl)-ethanone (1.74 g, 10.0 mmol) and diethyl oxalate (1.49 mL, 11.0 mmol) in diethyl ether (20 mL) cooled to 0° C. The heterogenous mixture was stirred for 15 min at 0° C. followed by 15 h at 20° C. The mixture was partitioned between 3 N hydrochloric acid (20 mL) and diethyl ether (50 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate and evaporated under reduced pressure and the residual oil was crystallized from diethyl ether/heptane to give the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11](=O)[CH3:12])[CH:6]=[CH:7][CH:8]=1.Cl.[NH2:17][OH:18].[OH-].[Na+]>CO>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11](=[N:17][OH:18])[CH3:12])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)C=Cc1cccc(C(F)(F)F)c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C=Cc1cccc(C(F)(F)F)c1)=NO
Yield: 64.2 %

Procedure:
In a 250 ml single neck flask was charged 6.4 g (29.9 mmoles, 1.0 eq.) of 4-(3-trifluoromethylphenyl)-3-buten-2-one and 5.2 g (75.4 mmoles, 2.5 eq) of hydroxylamine hydrochloride and 6 g of 50% sodium hydroxide (75 mmoles, 2.5 eq) and 100 ml of methanol. The reaction mixture was stirred at reflux for 2 hours. The reaction mixture was concentrated, diluted with water (50ml), and then extracted with ethyl acetate (2×50 ml). The organic phase was dried and concentrated, to obtain 4.4 g of 4-(3-trifluoromethylphenyl)-3-buten-2-one 2-oxime (E/Z mixture of isomers) as an oil in 64.2% yield.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C(=O)([O-])O.[Na+].Cl[CH2:15][C:16](=[O:18])[CH3:17].[OH-].[Na+]>O.C(O)(C)C>[CH2:15]([O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])[C:16]([CH3:17])=[O:18]
Reactant: CC(=O)CCl
Reactant: Oc1ccccc1O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(=O)COc1ccccc1O
Reaction time: 4 h
Yield: 46.6 %

Procedure:
11 g of catechol, 16.8 g of sodium hydrogencarbonate and 9.5 g of monochloroacetone were dissolved in a mixed solvent of 300 ml of water and 100 ml of isopropyl alcohol, and the solution was heated up to 50° to 60° C. and then stirred for 4 hours. Afterward, 50 ml of a 8% aqueous sodium hydroxide solution and 9.3 g of monochloroacetone were further added, followed by stirring at 50° C. for 5 hours. After standing for cooling, insolubles were removed from the solution by filtration, and the resultant filtrate was concentrated until the volume of the solution became about 300 ml, and then extracted with chloroform. The chloroform layer was washed with a dilute aqueous sodium hydroxide solution and then with water. The solvent was distilled off, and the residue was purified through a silica gel column chromatograph (chloroform/hexane=7/3 to chloroform alone in volume ratio), and then recrystallized from ether/hexane, thereby obtaining 7.73 g of crystals of 2-acetonyloxyphenol.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:18]=[CH:17][C:7]2[CH2:8][CH:9]3[CH:13]([C:14](=[O:15])[C:6]=2[CH:5]=1)[CH2:12][N:11]([CH3:16])[CH2:10]3.O>C(O)C>[Cl:3][C:4]1[CH:18]=[CH:17][C:7]2[CH2:8][CH:9]3[CH:13]([CH:14]([OH:15])[C:6]=2[CH:5]=1)[CH2:12][N:11]([CH3:16])[CH2:10]3
Reactant: CN1CC2Cc3ccc(Cl)cc3C(=O)C2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN1CC2Cc3ccc(Cl)cc3C(O)C2C1
Temperature: 25 °C

Procedure:
1.6 g of sodium borohydride in 20 ml of ethanol are added at 0°-5° to a solution of 10 g of 6-chloro-3a,4,9,9a-tetrahydro-2-methylbenz[f]isoindolin-4-one in 100 ml of ethanol, stirred at room temperature for a further hour, water is added and the mixture evaporated. The residue is taken up in 10% tartaric acid, the aqueous phase extracted with ether, mixed with 2 N caustic soda solution and extracted with ethyl acetate. The ethyl acetate phase is dried over sodium sulphate and evaporated. The residue is crystallised from methylene chloride/pentane to yield 6-chloro-3a,4,9,9a-tetrahydro-2-methylbenz[f]isoindolin-4-ol. M.P. 178°-182°.
Reaction SMILES: CS[C:3]1[N:8]2[N:9]=[CH:10][CH:11]=[C:7]2[N:6]=[CH:5][CH:4]=1.F[B-](F)(F)F.C[O+](C)C>C(Cl)Cl>[N:9]1[N:8]2[CH:3]=[CH:4][CH:5]=[N:6][C:7]2=[CH:11][CH:10]=1
Reactant: CSc1ccnc2ccnn12
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: c1cnc2ccnn2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
The quaternised pyrazolo [1,5-a]pyrimidine starting material was prepared as follows: To a solution of 7-methylthiopyrazolo[1,5-a]pyrimidine (1 g, 6 mmoles) in methylene chloride (25 ml) was added trimethyloxonium tetrafluoroborate (1 g, 6.7 mmoles). After stirring at room temperature for 1 hour, the solid was filtered and used without further purification, nmr 2.93 (s, 3 H): 4.27 (s, 3 H): 7.2 (d, 1 H) 7.55 (d, 1 H): 8.6 (d, 1 H): 9.0 (d, 1 H). Yield 27%.
Reaction SMILES: [C:1]([OH:15])(=[O:14])[C:2]1[C:3](=[CH:7][C:8](=[CH:12][CH:13]=1)[C:9]([OH:11])=[O:10])[C:4]([OH:6])=[O:5].P(Cl)(Cl)(Cl)(Cl)Cl.Cl[C:23]1[C:24](Cl)=[C:25](Cl)[CH:26]=[CH:27][CH:28]=1>>[C:1]([O:15][C:2]1[CH:3]=[CH:7][CH:8]=[CH:12][CH:13]=1)(=[O:14])[C:2]1[C:3](=[CH:7][C:8](=[CH:12][CH:13]=1)[C:9]([O:11][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:10])[C:4]([O:6][C:28]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:5]
Reactant: O=C(O)c1ccc(C(=O)O)c(C(=O)O)c1
Reactant: Clc1cccc(Cl)c1Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=C(Oc1ccccc1)c1ccc(C(=O)Oc2ccccc2)c(C(=O)Oc2ccccc2)c1
Temperature: 60 °C

Procedure:
42 grams of commercially available trimellitic acid was mixed with 138 g. of PCl5 in 100 ml. trichlorobenzene. An exothermic reaction was observed. After completion of the reaction, most of the trichlorobenzene was removed by vacuum distillation. The remaining crude acid chloride was added dropwise with stirring to 65 grams of phenol in about 145 ml. of pyridine. The solution was stirred and cooled with an ice bath during the 10 minute addition period, and then stirred one hour without cooling. The mixture was then heated to 60°C. After being allowed to cool to room temperature, the mixture was poured onto ice having 170 ml. of concentrated HCl therein. An offwhite crystalline solid formed. This was collected by filtration, washed with 5-6 portions of water, and air dried. This product (triphenyl trimellitate) weighed 81 grams. Trichlorobenzene was still detectable in the product; it was therefore recrystallized from 275 ml. methyl ethyl ketone. The white, very fine, fibrous crystals were filtered and washed with two portions of cold methyl ethyl ketone. After air-drying overnight, the final yield of triphenyl trimellitate was 49.5 grams (M.p. 156.5°-157.5°C.)